Clinical trial NCT00267865
Conditions: AIDS-Related-Primary Central Nervous System Lymphoma
Keywords: Human immunodeficiency virus Acquired immunodeficiency syndrome High Dose Methotrexate Methotrexate Rituximab CNS Lymphoma Central Nervous System Lymphoma AR-PCNSL Epstein-Barr virus
Sponsor: National Cancer Institute (NCI)
Start date: 2006-09-14; Completion date: 2019-09-19
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will investigate the use of chemotherapy plus highly active antiretroviral therapy (HAART) in patients with Acquired Immunodeficiency Syndrome (AIDS)-related primary brain lymphoma. None of the drugs used in this study are experimental, but chemotherapy plus HAART has not been established as a standard treatment in patients with AIDS. The chemotherapy regimen used in this study (see below) was chosen because it may be less toxic to immune cells called T-lymphocytes than most drug treatments for lymphoma.

People with AIDS 18 and older and have primary brain lymphoma may be eligible for this study. Candidates are screened with a medical history and physical examination, magnetic resonance imaging (MRI), computed tomography (CT) and positron emission tomography (PET) scans, cerebrospinal fluid studies, brain biopsy at tumor sites, if possible, electrocardiogram and blood tests.

Participants undergo six 2-week "induction treatment" cycles of HAART plus chemotherapy with methotrexate, rituximab and leucovorin, followed by two 4-week "consolidation" treatment cycles using HAART, methotrexate and leucovorin, and then HAART alone. Rituximab is given by intravenous (intravenous (IV), through a vein) day 1 of each cycle. Also on day 1 IV fluids are given to lower acidity in the urine to protect the kidneys from the methotrexate. On day 2, methotrexate is infused through a vein over 4 hours. Starting 24 hours after initiation of the methotrexate infusion, leucovorin is given every 3 to 6 hours (first IV and then possibly by mouth) until the drug decreases to a target level in the blood. HAART is begun as soon as possible. The specific HAART regimen for each patient is determined individually. All patients are hospitalized the first week of every 2-week treatment cycle for safety monitoring. In addition to HAART and chemotherapy, patients undergo the following tests and procedures:

* Intellectual functioning: Before starting treatment, patients are tested for their ability to understand basic concepts and coordination in order to be able to evaluate how the brain lymphoma affects thinking and concentration. After the lymphoma appears to have resolved, more formal and intensive tests are done. The intensive tests are repeated each year, and shorter, interim tests are done about every 6 months. Also, a specialist periodically monitors patients' understanding of HAART and the importance of this therapy.
* Blood tests: Blood is drawn every day during hospitalizations to measure methotrexate levels and to evaluate kidney and liver function and blood counts. Blood is also drawn before starting therapy, when the lymphoma disappears, 6 months after completing treatment, and any time it appears that the lymphoma may have recurred to test for Epstein-Barr virus (EBV), a virus that is almost always present in AIDS-related primary brain lymphoma.
* Imaging tests: Patients undergo magnetic resonance imaging (MRI) and positron emission tomography (PET) scans periodically to monitor the effects of treatment on the lymphoma. MRI scans are done after the 2nd, 4th, 6th, and 8th treatments, then every 2 months for three times, every 3 months for six times, every 6 months for four times, and then every year for 5 years, or sooner if there is a concern about the brain. PET scans are done after the first cycle, after the MRI suggests the lymphoma is gone, and then yearly.
* Lumbar puncture (spinal tap): This test is done to look for EBV in the cerebrospinal fluid (CSF). Under local anesthetic, a needle is inserted in the space between the bones in the lower back where the CSF circulates below the spinal cord and a small amount of fluid is collected through the needle. This test is done at the same times as the blood tests for EBV.
* Eye examinations: Patients' eyes are examined periodically because brain lymphoma can sometimes spread to the eye and because some people with AIDS-related primary brain lymphoma are at risk of certain eye infections.

Detailed description:
Background: Acquired Immunodeficiency Syndrome (AIDS)-related primary central nervous system lymphoma (AR-PCNSL) is an Epstein-Barr virus (EBV)-driven lymphoproliferative process that typically results in death within a few months. Essentially all of the cases are immunoblastic cluster of differentiation 20 (CD20+) tumors, and occur once the cluster of differentiation 4 (CD4+) cells have fallen to below 50 cells/mm\^3. Highly active antiretroviral therapy (HAART) can result in immune reconstitution that decreases the risk of AR-PCNSL. However, a subset of human immunodeficiency virus (HIV)-infected patients still develops ARPCNSL, often because they are unaware that they are HIV infected, or they do not take HAART. Treatment options for such patients are limited. In the non-AIDS setting, chemotherapy has become the standard of care for primary central nervous system lymphoma (PCNSL) and late neurocognitive decline consequent to radiotherapy can be avoided by such approaches. In the pre-HAART era, AR-PCNSL was generally treated with whole brain radiotherapy, however death due to recurrent lymphoma or to other AIDS complications occurred prior to the potential manifestations of late occurring radiation-related neurotoxicity. Radiation-sparing approaches have not been studied in AR-PCNSL in the HAART era, where advances in antiretroviral therapy have made curative intent chemotherapy feasible for most patients with HIV infection.

Objectives: The primary objective of this study is to estimate the fraction of patients with AR-PCNSL receiving experimental treatment consisting of HAART, combined with rituximab, high-dose methotrexate and leucovorin (R-HD-MTX) who are alive and without recurrent lymphoma or severe cognitive problems at two years. .

Eligibility: HIV-infected, age 18 years or older, AR-PCSNL that has not previously been treated, and be able to give informed consent or have a durable power of attorney who can provide informed consent, HIV profile that makes them likely to respond to HAART. There are a number of other specific inclusion and exclusion criteria, in part to exclude patients who would be unlikely to tolerate the therapy.

Design: Phase II pilot study investigating R-HD-MTX given with leucovorin rescue and HAART as a treatment for AR-PCNSL. Evaluation will include quantitative measurement of lymphocyte subsets, quantitative polymerase chain reaction (PCR) of HIV and EBV viral loads (including both blood and cerebrospinal fluid in the case of EBV) to assess immune response and anti-viral effects. Tumor evaluation with brain magnetic resonance imaging (MRI) and brain fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET scans) will be used for staging and response assessment. Longitudinal neuropsychologic testing after complete responses are documented will serve to evaluate neurocognitive parameters post therapy.

a separate cohort for additional secondary endpoints.

Arms: arm 1: Induction treatment cycles with rituximab, high-dose methotrexate and leucovorin will be administered every 2 weeks for 6 cycles. Two additional consolidation cycles of high-dose methotrexate without rituximab will be administered at 4 weeks and 8 weeks following completion of the combined therapy.
Interventions: intervention 1: Methotrexate intervention 2: Rituximab intervention 3: Leucovorin
Intervention descriptions: intervention 1: 6000 mg/m\^2 will be administered by intravenous infusion over 4 hours after confirming that the recipient patients urine pH is within the range greater than or equal to 7 to less than or equal to 8, and urine output is greater than or equal to 100 mL/hour. intervention 2: 375 mg/m\^2 intravenous (IV) day 1 of each cycle prior to administration of high-dose methotrexate intervention 3: Leucovorin calcium doses will be administered orally or by short intravenous (IV) infusion over 15 minutes

Protocol documents:
Prot_SAP_000.pdf: 
1
Abbreviated Title: AIDS Brain Lymphoma
CC Protocol #: 06C0051 L
Version Date: 02/28/2018
NCT Number: NCT00267865
Title: AIDS-related Primary Central Nervous System Lymphoma: A Phase II Pilot Study
of High-Dose Intravenous Methotrexate with Rituximab, Leucovorin Rescue and Highly 
Active Antiretroviral Therapy 
NCI Principal Investigator: Robert Yarchoan, MD
HIV and AIDS Malignancy Branch
Center for Cancer Research
National Cancer Institute
10 Center Drive, Room 6N106
Bethesda, MD 20892-1868
Tel: 240-760-6075
Email: robert.yarchoan@nih.gov
Commercial Agents: Methotrexate, Rituximab, Leucovorin


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PRÉCIS
Background:  AIDS-related primary central nervous system lymphoma (AR-PCNSL) is 
an Epstein-Barr virus (EBV)-driven lymphoproliferative process that typically results in 
death within a few months.  Essentially all of the cases are immunoblastic CD20+ 
tumors, and occur once the CD4+ cells have fallen to below 50 cells/mm3.  Highly active 
antiretroviral therapy (HAART) can result in immune reconstitution that decreases the 
risk of AR-PCNSL.  However, a subset of HIV-infected patients still develops AR-
PCNSL, often because they are unaware that they are HIV infected, or they do not take 
HAART.   Treatment options for such patients are limited.  In the non-AIDS setting, 
chemotherapy has become the standard of care for primary central nervous system 
lymphoma (PCNSL) and late neurocognitive decline consequent to radiotherapy can be 
avoided by such approaches.  In the pre-HAART era, AR-PCNSL was generally treated 
with whole brain radiotherapy, however death due to recurrent lymphoma or to other 
AIDS complications occurred prior to the potential manifestations of late occurring 
radiation-related neurotoxicity. Radiation-sparing approaches have not been studied in 
AR-PCNSL in the HAART era, where advances in antiretroviral therapy have made
curative intent chemotherapy feasible for most patients with HIV infection.  
Objectives:  The primary objective of this study is to estimate the fraction of patients 
with AR-PCNSL receiving experimental treatment consisting of HAART, combined with 
rituximab, high-dose methotrexate and leucovorin who are alive and without recurrent 
lymphoma or severe cognitive problems at two years. 
Eligibility: HIV-infected, age 18 years or older, AR-PCSNL that has not previously 
been treated, and be able to give informed consent or have a durable power of attorney 
who can provide informed consent, HIV profile that makes them likely to respond to 
HAART.  There are a number of other specific inclusion and exclusion criteria, in part to 
exclude patients who would be unlikely to tolerate the therapy.
Design: Phase II pilot study investigating high-dose methotrexate-rituximab given with 
leucovorin rescue and HAART as a treatment for AR-PCNSL.  Evaluation will include 
quantitative measurement of lymphocyte subsets, quantitative polymerase chain reaction 
(PCR) of HIV and EBV viral loads (including both blood and cerebrospinal fluid in the 
case of EBV) to assess immune response and anti-viral effects.  Tumor evaluation with 
brain magnetic resonance imaging (MRI) and brain fluoro-2-deoxy-d-glucose positron 
emission tomography (FDG-PET scans) will be used for staging and response 
assessment.  Longitudinal neuropsychologic testing after complete responses are 
documented will serve to evaluate neurocognitive parameters post therapy.  Chronic 
administration of HAART and longer-term evaluation of immune system parameters will 
be studied as part of an overall assessment of the therapy. Patients with AR-PCNSL who 
cannot receive high-dose methotrexate due to poor renal or cardiac function will receive 
HAART and “Radiation-Sparing Best Available Care”, generally consisting of dose-
dense rituximab, and will be evaluated as a separate cohort for additional secondary 
endpoints. 


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TABLE OF CONTENTS
PRÉCIS............................................................................................................................... 2 
TABLE OF CONTENTS.................................................................................................... 3 
1 
INTRODUCTION.............................................................................................. 5 
1.1 
Study Objectives................................................................................................. 5 
1.2 
Background and Rationale.................................................................................. 5 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT .................................. 17 
2.1 
Eligibility Criteria............................................................................................. 17 
2.2 
Research Eligibility Evaluation ........................................................................ 18 
2.3 
Registration Procedures .................................................................................... 20 
2.4 
Treatment Assignment...................................................................................... 20 
3 
STUDY IMPLEMENTATION........................................................................ 20 
3.1 
Study Design..................................................................................................... 20 
3.2 
Phase II Study Design for High-Dose Methotrexate with Leucovorin Rescue 
and Rituximab .................................................................................................. 22 
3.3 
Drug Administration: HIGH-DOSE METHOTREXATE with Leucovorin 
Rescue and Rituximab, and HAART ............................................................... 23 
3.4 
Treatment Modifications: High-Dose Methotrexate with Leucovorin Rescue 
and Rituximab .................................................................................................. 25 
3.5 
Criteria for Discontinuing Rituximab and High-Dose Methotrexate with 
Leucovorin Rescue........................................................................................... 29 
3.6 
“Radiation-sparing Best Available Therapy” for patients not eligible for High-
Dose Methotrexate in the Phase II cohort ........................................................ 29 
3.7 
Second-line therapy .......................................................................................... 32 
3.8 
On Study Evaluation......................................................................................... 32 
3.9 
Concurrent Therapies........................................................................................ 36 
3.10 
Radiation Therapy Guidelines .......................................................................... 38 
3.11 
Criteria for Removal from Protocol Therapy and Off Study Criteria............... 39 
3.12 
Post-Study Evaluation....................................................................................... 40 
4 
SUPPORTIVE CARE ...................................................................................... 40 
4.1 
Pneumocystis Jiroveci Pneumonia.................................................................... 40 
4.2 
Cytomegalovirus (CMV) .................................................................................. 40 
4.3 
Fungal Infections .............................................................................................. 40 
4.4 
Mycobacterial diseases ..................................................................................... 41 
4.5 
Toxoplasmosis .................................................................................................. 41 
4.6 
Prophylaxis for Febrile Neutropenia................................................................. 41 
4.7 
Febrile neutropenia ........................................................................................... 41 
4.8 
Anemia.............................................................................................................. 41 
4.9 
Thrombocytopenia............................................................................................ 41 
4.10 
Central venous access ....................................................................................... 42 
4.11 
Immune Reconstitution Inflammatory syndrome (IRIS).................................. 42 
4.12 
Nutritional Assessment and Psychological Support ......................................... 43 


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5 
DATA COLLECTION AND EVALUATION ................................................ 43 
5.1 
Data Collection ................................................................................................. 43 
5.2 
Exceptions to Reporting.................................................................................... 44 
5.3 
Response Criteria.............................................................................................. 44 
5.4 
Toxicity Criteria................................................................................................ 45 
6 
STATISTICAL CONSIDERATIONS............................................................. 45 
7 
HUMAN SUBJECTS PROTECTIONS........................................................... 47 
7.1 
Rationale for Subject Selection......................................................................... 47 
7.2 
Participation of Children................................................................................... 48 
7.3 
Participation of Subjects Unable to Give Consent............................................ 48 
7.4 
Evaluation of benefits and risks/discomforts.................................................... 48 
7.5 
Specimen Handling Guidelines......................................................................... 49 
7.6 
Consent Procedures and Documents................................................................. 50 
8 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY 
MONITORING PLAN ..................................................................................................... 51 
8.1 
Definitions......................................................................................................... 52 
8.2 
NCI-IRB and Clinical Director Reporting........................................................ 53 
9 
PHARMACEUTICAL INFORMATION ........................................................ 54 
9.1 
Rituximab.......................................................................................................... 54 
9.2 
Methotrexate ..................................................................................................... 57 
9.3 
Leucovorin calcium .......................................................................................... 61 
9.4 
Levoleucovorin calcium pentahydrate.............................................................. 62 
9.5 
Glucarpidase ..................................................................................................... 63 
9.6 
Filgrastim.......................................................................................................... 64 
10 
REFERENCES................................................................................................. 67 
11 
APPENDICES.................................................................................................. 75 
11.1 
Appendix 1: Folstein Mini Mental Status Examination ................................... 75 
11.2 
Appendix 2: Neurological Function Class........................................................ 76 
11.3 
Appendix 3: On-Study Evaluations .................................................................. 77 
11.4 
Appendix 4: Calculation of Creatinine Clearance ............................................ 79 
11.5 
Appendix 5: Neuropsychological Test Battery................................................. 80 
11.6 
Appendix 6:  Adherence Assessment ............................................................... 81 
11.7 
Appendix 7: Knowledge Questionnaire............................................................ 82 
11.8 
Appendix 8:  Recruitment Announcement ....................................................... 83 
11.9 
APPENDIX 9: Rituximab combined with High-Dose Methotrexate with 
Leucovorin Rescue HAART and Chemotherapy Administration, Methotrexate 
Monitoring and Supportive Care Guidelines.................................................... 85 


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1
INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Primary
1.1.1.1 The primary objective of this study is to preliminarily estimate the fraction of 
patients with primary brain lymphoma receiving experimental treatment 
consisting of HAART with R-HD-MTX who are alive and without recurrent 
lymphoma or severe cognitive problems (as defined by Neurological Function 
Class 3 in Appendix 2) at two years. It will also be important to determine if this 
fraction may be sufficiently high for further investigation.
1.1.2
Secondary
1.1.2.1 To describe the acute toxicities associated with administering a regimen of high-
dose methotrexate with leucovorin and rituximab with HAART in patients with 
AR-PCNSL
1.1.2.2 To estimate the complete response rate, progression-free, disease-free, and overall 
survivals to high-dose methotrexate with leucovorin and rituximab given with 
HAART in patients with AR-PCNSL
1.1.2.3 To describe HIV disease, EBV infection, and lymphoma tumor biology
1.1.2.4 To assess the neurotoxicity associated with this regimen by monitoring 
neuropsychologic function over time through longitudinal psychometric testing 
1.1.2.5 To assess overall survival, progression-free survival, and long-term 
neurocognitive outcomes in patients with AR-PCNSL in who high-dose 
methotrexate is contraindicated and are therefore treated with radiation-sparing 
therapy consisting of dose-modified, dose-dense rituximab combined with 
HAART but no high-dose methotrexate.
1.1.2.6 To assess overall survival and long-term neurocognitive outcomes in patients with 
AR-PCNSL who receive “Radiation Sparing Best Available Care”, consisting of 
HAART and any additional first or second line radiation-sparing approaches 
1.2
BACKGROUND AND RATIONALE 
1.2.1
Biology, Epidemiology and Scope of Problem
AIDS-related primary central nervous system lymphoma (AR-PCNSL) is a rare but 
lethal complication of advanced HIV disease1-4.  Essentially 100% of AR-PCNSL is 
Epstein-Barr virus (EBV)-associated B-cell tumors.  They occur almost exclusively in 
persons with CD4+ cells that are depleted below 50 cells/mm3.  Histologically, these 
tumors are overwhelmingly represented by diffuse large B-cell lymphomas (DLBCL), 
typically the immunoblastic variant with pathobiological markers suggesting 
histogenic derivation from post germinal center B-cells at late stages of maturation5-7.
Thus, most cases show absence of bcl-6 protein while MUM1and CD138/syndecan-1,


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and bcl-2 are expressed8, 9.  While essentially all cases are EBV-associated, the EBV 
expression pattern in AR-PCNSL can differ.  Moreover, the histological and 
pathobiological characteristics of AR-PCNSL appear to segregate according to EBV 
expression patterns.  In cases that are negative for LMP-1 expression, bcl-6 protein is 
expressed, whereas bcl-2 is not9. This pattern is invariably associated with a large
non-cleaved morphology similar to HIV-negative cases, and suggests germinal center 
B-cell histogenic derivation.  In contrast to AR-PCNLS in which a proportion of 
tumors appear to derive from non-germinal center B-cells, in HIV-unrelated PCNSL 
in which EBV is almost never found, the pattern of biologic markers is essentially 
always most consistent with germinal center histogenic derivation9, 10.  Treatment 
outcome and prognosis in AR-PCNSL may be heterogeneous and in part related to 
these biologic characteristics 11 as has been shown in systemic HIV-unrelated NHL12-
14.  In general, a more favorable prognosis in peripheral NHL is seen in tumors that 
derive from germinal center-like B-cells.  While this appears also to be the case in 
PCNSL11, there is uncertainty because of other factors involved in AIDS that affect 
prognosis.  Determination of tumor biology in AR-PCNSL is important toward 
understanding treatment outcomes, and forms part of the rationale for tumor 
acquisition on this study.     
Prior to the availability of highly active antiretroviral therapy (HAART), nearly 20% 
of all lymphomas in AIDS patients were AR-PCNSLs15, 16.  The relative risk of 
developing PCNSL in AIDS was 1000-fold that of the non-AIDS population17.  As a 
consequence of better preserved immune function with HAART18, the incidence of
AR-PCNSL has fallen substantially.  In the pre-HAART era the incidence was more 
than 300% higher than currently seen 3, 19.  Similarly, a much smaller proportion of 
AIDS-related lymphomas (ARL) are PCNSL, because the decrease in incidence of 
this tumor is greater than for the other ARLs 19.  HAART has also favorably affected 
survival in patients with ARL, including AR-PCNSL.  Before HAART availability, 
the median survival after diagnosis of AR-PCNSL was 2 to 3 months. However, six-
fold or greater increases in survival are reported when HAART is given compared to 
cases not treated with HAART 16, 20, though this is not a consistent finding21.    While 
AR-PCNSL currently affects relatively few individuals, this may not be a lasting 
phenomenon as the AIDS epidemic evolves.  The number of HIV-infected individuals 
in the United States continues to increase.  At present, estimates suggest at least 
950,000 Americans are infected, a quarter of whom do not know their seropositive 
status22.  These people often do not receive antiretroviral therapy until after they are 
confronted with opportunistic disease, including AR-PCNSL22-26.  As a consequence, 
AR-PCNSL may continue to be a serious medical problem, especially in medically 
underserved demographic groups most affected by the HIV epidemic.  In such 
resource poor settings where treatment access is often delayed and HAART is not 
readily available, AR-PCNSL continues to be a rapidly lethal complication of AIDS4.
In addition to the changing demographics of persons with AIDS, there has been more 
than a 50% increase in the prevalence of persons living with AIDS because of the 
increased longevity consequent to HAART27.  Since 1996, when HAART was 
introduced, the number of persons with AIDS in the Unites states increased from 
approximately 200,000 to nearly 400,00022.  There is thus an expanding at-risk 


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population for malignant complications of AIDS, now the major form of HIV-related 
morbidity and mortality in resource-rich societies where HAART is commonly 
used27-29.  Additionally, in Western Europe, the proportion of primary brain 
lymphomas as an AIDS-defining condition in HIV-infected patients has remained 
relatively steady in the period 1988-200030.   Therefore, even though this tumor is 
currently rare, it is quite conceivable that the absolute numbers of cases of AR-
PCNSL will increase consequent to a number of issues.  With increased longevity 
there may be an overall increase in lifetime risk of malignant complications of HIV 
disease31.  As the AIDS epidemic continues to shift to medically underserved 
populations, individuals may be more likely to first present with complications related 
to advanced immune depletion, such as AR-PCNSL.
1.2.2
Radiation Related Neurotoxicity and Beyond
In the non-AIDS setting, whole brain radiotherapy (WBRT) has been supplanted by 
chemotherapy using high-dose methotrexate usually combined with other agents 
because this approach appears associated with superior survival and avoids the high 
risk of late occurring neurotoxicity associated with WBRT, especially in high-risk 
patients32, 33.   The risk of neurotoxicity increases with age.  In those older than 60 
years, virtually all long-term survivors after a combined treatment of radiation and 
methotrexate will develop severe delayed neurotoxicity with devastating 
consequences in terms of reduced quality of life34. In those younger than 60 years, 
little is known about the exact incidence of this complication.  Generally, cognitive 
dysfunction is less severe in younger patients, and may not be recognized unless 
formally assessed.  Harder et al. investigated a series of 19 consecutive young 
patients treated in a prospective trail for PCNSL with combined modality treatment 
with systemic and intrathecal high-dose methotrexate-based chemotherapy followed 
by WBRT and found cognitive impairments in 63%, including 21% with severe 
impairment35.  This contrasts sharply with studies reporting absence of 
neurocognitive decline in patients treated with high dose methotrexate and not 
radiotherapy36, 37.
AIDS patients often have greater than anticipated radiation related toxicity, at least in 
mucocutaneous sites38.  Excessive neurotoxicity in ARL has also been reported39.  In 
a phase II study of dose-adjusted EPOCH chemotherapy for peripheral AIDS-related 
lymphomas, death due to the neurotoxic effects of combined chemotherapy and 
cranial radiotherapy for CNS involvement was not uncommon39, underscoring the 
generally accepted principle that AIDS patients are at increased vulnerability to the 
toxic effects of radiotherapy38, 40, 41.
The response to WBRT or to large-volume radiotherapy has been divided into three 
categories based on the timing of onset for neurological symptoms42.  In general, the 
early effects are reversible, whereas late onset effects are not.  The acutely occurring 
effects within the first weeks of fractionated radiotherapy are generally characterized 
by drowsiness, headache, nausea, emesis, and worsening of pre-existing focal 
symptoms.  It is thought that increased cerebral edema causes the symptoms, and so 


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dexamethasone is commonly used and generally results in symptomatic improvement.  
It is important to note, however, than in advanced HIV disease, high-dose steroid 
administration can be associated with increased risk of opportunistic illnesses, and is 
therefore avoided whenever possible.   At 1 to 6 months after completion of 
radiotherapy, early delayed or subacute encephalopathy typically presents, and is also 
reversible.  Symptoms include headache, somnolence, fatigability, and deterioration 
in pre-existing deficits43.  Subacute encephalopathy is believed to be secondary to 
diffuse demyelination44.  Although corticosteroids are useful in diminishing the 
symptoms, spontaneous resolution generally occurs within several months after 
presentation and so the role of steroids is uncertain.  The generally irreversible and 
progressive late delayed neurologic effects of radiotherapy typically appear more than 
6 months after completion of radiotherapy 45.  Injury is often localized to the white 
matter, and is thought to be a consequence of vascular injury, demyelination, and 
ultimately brain tissue necrosis.  Late effects can be further characterized as focal 
radiation-related necrosis, diffuse white matter injury, and combined chemotherapy-
radiotherapy leukoencephalopathy.  Symptoms vary depending on type and location 
of injury.  In focal radiation necrosis, symptoms include seizures, signs of increased 
intracranial pressure, and neuroanatomic-specific effects, such as functional cord 
transection46.  MRI reveals an area of irregular enhancement often with surrounding 
edema. Focal radiation necrosis is often difficult to distinguish from recurrent or 
progressive tumor and can thus represent a treatment and diagnostic dilemma46.
Although positron emission tomography (PET) and magnetic resonance spectroscopy 
(MRS) may help differentiate the two, tissue biopsy is currently required to make a
definitive diagnosis.  Symptoms of diffuse white matter injury range from mild 
lassitude to significant memory loss and severe dementia 47. Combined therapy 
leukoencephalopathy can be similar to diffuse white matter injury, but it can also 
include ataxia, confusion, dysarthria, seizures, and ultimately incapacitating dementia 
or death48.  Imaging findings are similar to that of diffuse white matter injury, but 
they also may include dystrophic calcification of the basal ganglia and gray–white 
matter interface47.  Since HIV-infected patients may be more vulnerable to the toxic 
effects of radiation-induce injury, and to the corticosteroids used to manage the 
complications, this is a critical consideration for AR-PCNSL15, 46.
The standard of care in AR-PCNSL remains whole brain radiotherapy (WBRT) to 40-
50 Gy.  This therapy can successfully induce complete responses in the majority of 
AR-PCNSL cases15.  Recurrent lymphoma or other fatal AIDS-related complications 
severely limits survival, and in practice, the therapeutic intent has generally been 
palliative.  Yet, the treatment advances now standard in non-AIDS PCNSL have not 
been widely applied in AIDS.  Reasons for this vary, but in part it is because of the 
general perception that such patients cannot tolerate aggressive chemotherapy, and 
the notion that disease-related death will occur prior to the occurrence of radiation-
related neurotoxicity.  However, improved tolerance to antineoplastic therapy with 
HAART has rendered reflexive palliative approaches inappropriate for potentially 
curable AIDS-related tumors, and improved survival prospects raise concerns 
regarding neurotoxicity risks 28, 49-51.  Treatment of peripheral ARL has in particular 
guided this paradigm shift in cancer therapy for patients with AIDS.  With HAART, 


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patients with ARL have improved overall survival52, equivalent to their HIV-not 
infected counterparts for certain NHL subtypes 39, 53.  Longer survival and PCNSL 
remission in the HAART era is dependent in general on reduced AIDS complications 
consequent to immune reconstitution and also appears related in part to improved 
immunosurveillance against EBV-related proteins that may help to reduce the risk of 
PCNSL recurrence54.  The latter concept is reinforced by case reports that have 
documented radiographic improvements in AR-PCNSL with HAART alone55,
consistent with the known effects of immunomodulation on EBV-driven 
lymphoproliferations in the transplant literature56. Thus, improved survival prospects 
for these patients raises the specter that late occurring toxic effects associated with 
WBRT will diminish the therapeutic benefits.  These effects can seriously affect both 
quality of life and limit survival37, potentially annulling any life-prolonging benefit 
from HAART and tumor eradication that patients may otherwise enjoy.  Therefore, 
development of effective non-neurotoxic therapy for AR-PCNSL would advance the 
field of AIDS oncology.  The purpose of this study is to investigate relatively non-
immunosuppressive systemic therapy in AR-PCNSL and to simultaneously promote 
CD4+ cell recovery in order to preserve brain function through tumor control and 
avoidance of late radiotherapy-related neurotoxic complications. 
1.2.3
Methotrexate-based Systemic Therapy in PCNSL
Because up to 80% or more of high-risk patients treated with WBRT develop severe 
radiation induced neurological injury37, clinical research for non-HIV-related PCNSL 
has focused on the development of strategies to reduce this risk.  Reduction of WBRT 
doses to 30 Gy or exposure focus by stereotactic administration of radiotherapy 
following high-dose methotrexate has been one approach that has appeared to be 
useful in some patients 57. However, in AR-PCNSL, treatment to doses higher than 
30Gy have been associated with higher response rates 16.  Often, AR-PCNSL is not 
amendable to stereotactic administration of radiotherapy because of the numerous 
mass lesions throughout the brain.  Also there has been interest in treating PCNSL 
with systemic therapy, deferring radiation whenever possible.  This has led to the use 
of high-dose methotrexate as a major focus of systemic chemotherapy regimens 58, 59.
Studies have shown that when brain radiotherapy is avoided, that neurocognitive 
function is much better preserved37, though as reviewed below, findings are mixed in 
terms of overall survival between the two general approaches.  In non-HIV-related 
cases, median survival with WBRT typically ranges from 12-18 months60.  The 
addition of chemotherapy to the treatment (combined modality therapy) has been 
associated with increases in survival to more than 40 months in some studies59.
However, the risk of neurotoxicity is increased with the combined modality therapy, 
so that as a result of severely impaired cognition there is no overall improvement in 
the desired outcome (alive without brain dysfunction)37.  Equivalent data for patients 
with AR-PCNSL is not available.
Although a substantial body of literature has evolved supporting the use of 
chemotherapy and combined modality therapy with limited radiotherapy in PCNSL, 
no large prospective trials have been conducted to inform comparisons of 


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chemotherapy alone or combined chemo-radiotherapy with radiotherapy alone.  
Consistent with basic established principles in lymphoma therapy, most (but not all) 
studies have avoided monotherapy approaches in favor of combination chemotherapy 
approaches.   Although there is not yet a regimen that can be proclaimed as the 
standard of care in PCNSL, one element from the research to date is quite clear: 
regimens used for treatment of systemic non-Hodgkin’s lymphomas (NHL), such as 
CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) combined with 
WBRT are toxic and do not confer advantage over WBRT alone61.  Thus, it has been 
emphasized that CHOP or similar regimens have no role in the treatment of PCNSL62.
However, this finding does not undermine the basic principle that combined 
chemotherapy approaches are superior to monotherapy in NHL.  
As mentioned above, high-dose methotrexate has been the major focus of clinical 
investigation in PCNSL.  Methotrexate was originally chosen for PCNSL because of
its ability to penetrate the blood-brain barrier, and its known activity against 
lymphoma.  Doses of methotrexate for PCNSL have ranged from 1 gram/m2 to over 8 
grams/m2, with doses of 3 grams/m2 penetrating into the CNS more reliably than 
lower doses 63.  Some evidence suggests a positive dose-response relationship to 
antitumor potential in favor of the higher methotrexate doses64.  High-dose 
methotrexate is considered to be the single most important agent for the treatment of 
PCNSL in immunocompetent patients, but as monotherapy there are mixed results as 
it compares to WBRT alone or when given along with additional agents.  Indeed, as 
mentioned above, monotherapy for aggressive non-Hodgkin’s lymphoma is contrary 
to the treatment principles established over the past three decades.  Thus while high-
dose methotrexate monotherapy is not of current interest in clinical investigation, 
information from previous investigations in the HIV unrelated setting are informative.  
For example, overall survival correlates favorably with high-dose methotrexate as 
part of a combined high-dose methotrexate and WBRT regimen, providing 
encouraging phase II data that high-dose methotrexate has an important role in this 
disease 65, 66.    A multicenter phase II trial conducted by the New Approaches to 
Brain Tumor Therapy CNS Consortium reported a 52% complete response rate, and 
an overall response of 74% with high-dose methotrexate at 8 grams/m2 every 2 
weeks, an outcome comparable to multiagent, generally more toxic regimens65.
However, phase II trials combining high-dose methotrexate with vincristine and 
procarbazine before WBRT have resulted in median survivals of 33 to 60 months, an 
apparent improvement over WBRT alone33.  The use of high-dose methotrexate with 
procarbazine and vincristine without WBRT has resulted in similar outcomes, again 
pointing out the feasibility of avoiding radiotherapy in this disease 33.  Similarly, 
multiagent regimens designed on a backbone of high-dose methotrexate and also 
using agents such as carmustine, teniposide, cytarabine, ifosfamide, 
cyclophosphamide, vinca alkaloids and other agents have been explored58, 59.  In a 
report of 15 patients treated with high-dose methotrexate of 8.4 g/m2 and leucovorin 
rescue, thiotepa, vincristine, dexamethasone, intrathecal cytarabine and methotrexate, 
the complete response rate was 79%, and the median progression-free survival 16.5 
months67.  Seven patients in this study had formal neuropsychometric testing, and five 
had no evidence of neurocognitive decline.  Two patients had severe neurocognitive 


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and neuromotor deterioration after therapy, though one of these had evidence of prior 
multi-infract brain pathology.  In general, preservation of neurocognitive function 
appears feasible with systemic chemotherapy.  However, the acute myelosuppression 
and lymphocytotoxicity associated with these regimens is substantial.  This feature of 
the therapy may be counterproductive to overall outcome in AR-PCNSL owing to the 
clear relationship between immune status and tumor development.  Given that more 
than 12 months is required for lymphocyte recovery to baseline levels following the 
completion of lymphocytotoxic chemotherapy for ARL39, regimen components 
associated with these toxicities may best be avoided in this setting.  A successful 
treatment strategy in this disease may require an emphasis on early CD4+ lymphocyte 
restoration.    
1.2.4
CD4+ Lymphocyte Sparing Therapy for AR-PCNSL
1.2.4.1 High-dose Methotrexate and Leucovorin
Attempts to promote more rapid CD4+ lymphocyte reconstitution requires use of 
relatively T-lymphocyte sparing regimens, and this may be a more suitable 
approach in the AIDS population.  Given with leucovorin rescue, high-dose 
methotrexate itself is relatively non-myelotoxic and relatively non-injurious to the 
immune system68, 69.  There is no specific data to unequivocally determine the best 
dose for high-dose methotrexate in this setting.  However, considering higher 
doses appear to be associated with better outcome and that doses less than 3 
gram/m2 may be insufficient for optimal tumor penetration, combined with the 
mono-cytotoxic approach in this clinical trial, a relatively high dose within the 
spectrum of that typically used appears logical. The strategy in this study therefore 
will be to use high-dose methotrexate at 6 grams/m2 with leucovorin rescue in 
combination with agents not associated with particular T-lymphocyte depletion. 
Although use of high-dose methotrexate in AR-PCNSL has not been extensively 
studied, there is some prior experience with its use in this setting.  Pre-HAART, a 
small study suggested that the toxicity was substantial but that some patients did 
benefit from the approach70. High-dose methotrexate in combination with 
HAART has been feasible in certain systemic AIDS-related lymphomas associated 
with advanced immune depletion69.  There is substantial precedent for high-dose 
chemotherapy in the HAART era for patients with AIDS and cancer.  High-dose 
chemotherapy and both autologous and allogeneic bone-marrow transplant has 
been successfully undertaken in AIDS patients51, 71-74.  Thus a treatment strategy 
for primary brain lymphoma that utilizes high-dose methotrexate with leucovorin 
rescue, similar to the non-AIDS setting, is worth investigating in AIDS.  By 
combining HAART with the therapy, it may be possible to promote earlier control 
of HIV infection and initiate immune recovery.  
1.2.4.2 Highly Active Antiretroviral Therapy


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Immunologic recovery is essential toward preventing the substantial risk of death 
due to other AIDS complications, and may also help to prevent lymphoma 
recurrence, as mentioned above.   There are several features of AR-PCNSL that 
highlight the importance of immune recovery as a component of therapy in this 
disease:  100% of AR-PCNSL are EBV-associated lymphoproliferations; AR-
PCNSL rarely occurs until the CD4+ lymphocyte subsets are depleted to less than 
50 cells/mm3; and a number of case reports have stressed that complete tumor 
regressions occasionally occur in parallel with immune recovery on HAART alone 
55.   In immunologically normal individuals, activated T-cells traffic through 
normal brain tissue75.  These cells may perform an important function in tumor 
immunosurveillance against viral and/or tumor-associated antigens and this 
concept is consistent with the constant finding that profound immune depletion is 
directly related to AR-PCNSL risk.  Restoration of this immunosurveillance may 
hence be important to the outcome in therapy for this disease.  Therefore, HAART 
should be considered as part of the oncologic therapy for purposes of this clinical 
trial.
1.2.4.3 Rituximab
In devising an overall T-cell sparing therapeutic regimen for AR-PCNSL to 
augment the high-dose methotrexate (and HAART), it is worth noting that AR-
PCNSL are virtually all B-cell immunoblastic tumors associated with latent EBV 
infection showing only latent expression patterns6.  The brain lymphoma cells 
typically express the CD20+ antigen in both AIDS-related and non-AIDS PCNSL, 
whereas normal neurons or glia do not.  This observation has informed 
development of small studies that have investigated the use of the monoclonal anti-
CD20 antibody, rituximab, in non-AIDS PCNSL76-79.   There are a number of 
issues that on the surface may cast doubt on the capacity of this therapy to work as 
effectively in PCNSL as it does in peripheral lymphomas.  However, closer 
examination of the data appears to in fact support the use of rituximab in PCNSL.  
For example, following infusion of the standard dose of rituximab (375 mg/m2), 
serum rituximab levels typically range from 107 to 962 mcg/mL80.
Pharmacokinetic studies have shown that the cerebrospinal fluid (CSF) levels of 
rituximab are approximately 0.1 to 1% of serum levels associated with therapeutic 
activity in patients with systemic NHL, a finding not surprising given its high 
molecular weight81, 82.  Although this may at first seem to represent insufficient 
CSF penetration, it ranges from 1 to nearly 10 times the amount of rituximab 
shown to saturate 90% of cell surface CD20 antigen83 and thus in fact provides 
more than sufficient rituximab exposure to have the desired biologic effect.  It is 
important to recognize that CSF drug levels do not adequately reflect parenchymal 
brain tumor exposure to agents, as log-fold greater drug concentrations can be 
found within brain tumors compared to the CSF84.   On the other hand, there has 
been no data to suggest that radiolabeled rituximab concentrates in PCNSL 
preferentially.   Again, close examination of this finding reveals it to be not fully 
relevant to the use of unlabeled rituximab for CNS lymphoma.  A case report of 
single photon emission computed tomography (SPECT) imaging of non-AIDS 
PCNSL using idodine-123 labeled rituximab failed to demonstrate rituximab 


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uptake in PCNSL in three of four patients, suggesting that systemic rituximab-
based radiotherapy approaches would not be feasible for this tumor85.  The strength 
of these observations is weak.  For example, a similar technique in peripheral 
lymphoma (for which rituximab is approved by the US Food and Drug 
Administration), delineated tumor in only 14 of 37 patients studied, because sites 
in proximity to blood vessels could not be adequately defined86.  Thus, this 
technique, though informative, has limitations that must be taken into account, 
particularly as relates to the case studies that failed to show increased uptake in the 
few cases of PCNSL studied.  An additional consideration may be that the standard 
pre-infusion with unlabeled rituximab that is first administered in such studies 
could potentially have the effect of competing with the radiolabeled product for 
antigen and thus underestimating rituximab penetration into the tumor.  Also, the 
extent to which these results inform the use of biotherapy should be placed into the 
context of toxicity related to radiolabeled rituximab.  There is organ specific 
toxicity that limits repeated dosing of radiolabeled rituximab.  Therefore, if the 
tumor-specific exposure is not sufficient for adequate therapeutic effect over one 
or two dosing administrations, radiolabeled rituximab is not a feasible treatment 
because repetitive dosing becomes too toxic.  Thus, while the results of the case-
control report cast real doubt on the use of radiolabeled rituximab for PCNSL, it 
does not necessarily address the use of unlabeled rituximab.  In contrast to 
radiolabeled rituximab, unlabeled rituximab can be safely administered over 
multiple doses, so that even if there is only a moderate tumor-drug interaction per 
dose, repeated doses can be safely used to treat the tumor.  
Encouraging data on the utility of unlabeled rituximab in AIDS-unrelated PCNSL 
has been reported in small studies.  Since CNS lymphoma has a predisposition for 
perivascular infiltration that disrupts the blood brain barrier87, greater anticancer 
agent penetration into areas of the brain affected by tumor are seen when compared 
to surrounding normal brain, as shown in biopsy and autopsy specimen in studies 
addressing this88.  Indeed, there is mounting clinical experience that rituximab can 
be useful in primary brain lymphoma when administered intravenously 76, 77, 89, 90.
In small studies of refractory PCNSL, responses have been seen in the majority of 
treated patients who received rituximab monotherapy or rituximab in combination 
with cytotoxic agents.  Although reports that rituximab monotherapy in previously 
treated refractory-relapsed PCNSL results in clinical and radiographic responses 
suggests that rituximab can penetrate into areas of bulky disease in the brain91,
there is insufficient data to know with certainty what the overall contribution of 
rituximab is in the combination chemotherapy setting.   However, PCNSL experts 
have supported its clinical trials development90, 92-94.  The Cancer and Acute 
Leukemia Group B trial 50202 entitled “Intensive Chemotherapy and 
Immunotherapy in Patients with Newly Diagnosed Primary CNS Lymphoma" is a
multi-institutional study further investigating rituximab combining it with high-
dose methotrexate and temozolomide.  Thus, there is well-established precedent 
for investigating the use of rituximab in PCNSL in the HIV unrelated setting.  
Likewise, rituximab may be a promising agent in AIDS-related PCNSL as 


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articulated above. The core regimen in this protocol will thus investigate the use of 
leucovorin protected high-dose methotrexate with rituximab and HAART.  
Rituximab will be omitted from cycles 7 and 8.  The rationale for this is that only 
patients who have achieved a complete response will receive the additional two 
cycles.  Therefore, it is assumed that rituximab penetration into the area previously 
affected by obvious tumor will become insufficient due to improved blood-brain 
barrier integrity.   However, it may be beneficial to administer additional high-dose 
methotrexate cycles with increased dose-intervals in order to help prevent early 
tumor recurrence while allowing for additional time for greater immunologic 
recovery.
It should be noted that rituximab is not considered at present to be a standard of 
care in HIV-associated lymphomas, and it appears to be associated with excess 
morbidity and mortality when used with CHOP chemotherapy for peripheral ARL, 
especially for patients with advanced CD4+ depletion95.  The NCI sponsored AIDS 
Malignancy consortium has reported published results of a large multicenter trial 
of ARL in which all patients received HAART and CHOP and were randomized to 
receive rituximab or not95.  Treatment related deaths occurred in 14% on the 
rituximab arm compared to 2% of those not receiving rituximab.  Moreover, the 
complete response rate was not different between the two arms, and survival was 
not improved.  Thus, there was excess treatment-related mortality without 
sufficient evidence of benefit in this trial.  Subset analysis suggested that there may 
have been a subset of patients for whom a benefit could be realized, but the study 
was not designed to assess this with scientific validity.   In contrast, positive 
benefit of rituximab in ARL has been reported in pooled results of three phase 2 
trials of R-iCDE (rituximab with infusional cyclophosphamide, doxorubicin, and 
etoposide).   The complete response rate of 70% was quite high (substantially 
higher than that previously seen with CDE alone), but again there was evidence of 
excess treatment-related deaths with approximately 20% of patients having non-
fatal infectious complications96.  For these reasons, some experts have now 
recommended that rituximab not be used in ARL as standard practice, but that 
additional investigational studies are needed to better understand the role of 
rituximab in AIDS 97 (Yarchoan et al, Nat. Onc. in press) 95, 96.   Experience from 
the transplant setting is also in evaluating rituximab in immunocompromised 
patients.  High-dose rituximab of up to 1000 mg/m2 has been reported to be 
potentially more effective than standard dose in high-risk lymphoma patients being 
treated with bone marrow transplant, a finding that also emphasizes the relative 
safety of rituximab in immunosuppressed patients.   Transplant-related EBV 
lymphoproliferative disease has been successfully forestalled and treated with 
rituximab98, 99. Additionally, there is increasing evidence supporting the use of 
rituximab for primary CNS post- transplant lymphoproliferative disorder. In a 
retrospective multicenter review of 71 cases, 48% received rituximab as part of 
their treatment, including 8 patients who received rituximab alone.  Patients 
receiving rituximab had improved 3-year progression free survival (40% vs. 22%,
p= 0.02) and a trend towards a significant improvement in 3 year overall survival 


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15
(43% vs. 22%, p=0.06).100 In a review of 9 cases of AR-PCNSL treated by HAMB 
investigators with HAART, rituximab, and various chemotherapies, the estimated 
overall survival at one year and beyond is 77.8%.  This series included one patient 
treated with HAART and rituximab alone due to significant cardiac comorbidity 
and poor performance status, who has achieved a complete response to therapy 
with 21 months follow up, has evidence of immune reconstitution on HAART, 
improvement in performance status, and no evidence of AR-PCNSL recurrence.101
Thus, although there is clinical data that emphasizes the need for cautionary use of 
rituximab in immunosuppressed patients, there is also data supporting its use, 
particularly in poor prognosis aggressive lymphoma.  The present protocol has 
been designed to avoid multiple lymphocytotoxic agents in an attempt to reduce 
the infectious risks associated with rituximab when combined with CHOP in ARL.  
Additionally, other approaches that can be considered for AR-PCNSL (e.g. 
published combination chemotherapy regimens used in AIDS-unrelated PCNSL) 
are likely to be substantially more toxic than rituximab, even as reported in 
advanced AIDS when combined with CHOP.  Safety may also be improved this 
with filgrastim, shown to rapidly reverse the late-onset leucopenic effects of 
rituximab102, 103.  It is predicted that since rituximab as a single agent is very well 
tolerated80, it is unlikely to show excessive toxicity when given with high-dose 
methotrexate and leucovorin with HAART.  Careful assessment of this is one of 
the study objectives, and the data generated on the study will inform as to the 
outcome in this regard.  Vigilant surveillance and monitoring will be required in 
this regard.
1.2.5
Novel Tumor Assessment and Psychometric Testing
In addition to the antitumor therapy, this protocol will in a preliminary manner assess 
novel measures of response and predictors of disease recurrence based on important 
recent advances in the diagnosis of AR-PCNSL.  Based on the finding that essentially 
all AR-PCNSL are EBV associated104-106, RT-PCR detection of EBV in the CSF has 
been found to be a sensitive and specific marker for lymphoma in HIV-infected 
patients with focal brain lesions106, 107.  In combination with SPECT thallium or 
fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) scanning of the 
brain, a minimally invasive diagnostic procedure for AR-PCNSL appears feasible106, 
108.  The combination of positive EBV PCR in the CSF and positive SPECT thallium 
has been shown to have 100% positive predictive value for lymphoma in AIDS 
patients with cerebral mass lesions106, 108 Likewise, if both tests are negative, the 
negative predictive value for lymphoma is 100%.  Discordant findings require biopsy 
or persistent growth in the presence of anti-toxoplasmosis therapy in order for an 
empiric lymphoma diagnosis to be made.  While minimally invasive approaches to 
defining focal brain lesions has gained acceptance and is considered an acceptable 
standard of care for initiation of specific therapy in AR-PCNSL in certain settings51,
the use of these studies have not been studied in terms of tumor response to therapy or 
in the relapsed setting.  Also, the peripheral blood EBV loads have not been well 
correlated with AR-PCNSL, though there is evidence that the peripheral EBV load is 


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16
elevated in the setting of AR-PCNSL109.  Thus, study of EBV in the spinal fluid and 
plasma before, during and after treatment may provide preliminary information that 
can be useful for developing additional measures to assess tumor response (e.g. 
relatively non-invasive measures of minimal residual disease) and could provide a 
means toward predicting durability of response.  Along with the more standard 
response assessments utilizing MRI and FDG-PET used in brain lymphoma, serial 
EBV DNA quantitation by PCR of the CSF and plasma will be used to provisionally 
assess response in correlation with the other standard outcome measures.  
Neurocognitive preservation is central to the goals of this clinical investigation, and 
serial neuropsychometric testing will be performed on patients.  Since at the time of 
presentation patients are expected to have tumor related cognitive impairment, 
baseline neuropsychometric testing will be performed within the first two months of 
the time of complete tumor response.  Repeat testing will be performed every 3 to 6 
months up to 2 years following end of treatment, and then again at 3 years.  Such 
measures have been found to be useful in PCNSL patients for assessing 
neurocognitive functioning over time110.
The protocol will also assess patients from the standpoint of the underlying HIV 
infection.  Since justification for pursuing non-radiation-based therapy is that 
HAART may improve survival such that patients live long enough to experience 
radiation-induced brain injury, patients with multidrug resistant HIV not amenable to 
suppression will not be eligible for the study, because a meaningful lasting immune 
recovery will not be feasible. Thus, immune parameters such as the CD4+ and CD8+ 
cell counts, HIV viral loads, HIV resistance mutations, and HAART adherence will 
be recorded.  Patients who fail to maintain low HIV viral loads and as a consequence 
experience other HIV-related complications that can affect neurocognitive function 
will be censored as soon as this becomes evident, and such patients can be replaced, 
as discussed in the statistical section of the protocol.
1.2.6
Summary of Study Direction
The intent of this protocol is to provide data regarding the feasibility and 
effectiveness of high-dose methotrexate with leucovorin and rituximab given with 
HAART from a small number of patients with AR-PCNSL who have a favorable 
prognosis from the standpoint of their HIV disease.  A major focus is to determine if 
a majority are alive without substantial brain dysfunction at two years after diagnosis.  
If the trial is favorable, then the approach may be of interest for further development 
in the extramural multicenter setting.  The NCI-sponsored AIDS Malignancy 
Consortium will be apprised of the results as the trial progresses, as this is the group 
in the United States most likely to be interested in pursuing further research in the 
area.  
This protocol was originally conducted in conjunction with a protocol being 
conducted by NIAID investigators in collaboration with our group focused on 
diagnosis of CNS brain masses (Protocol Number 05-CC-0246, Principal Investigator 


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Leatha Healey, MD) Patients diagnosed with AR-PCNSL were followed up to 24 
months on the NIAID study.  The NIAID investigators on that study are also 
associate investigators on this study. Although 05-CC-0246 has since closed, we 
continue to collaborate with NIAID investigators, and patients may be concurrently 
enrolled in 06-C-0051 and appropriate NIAID protocols. Continued collaboration 
comprises a comprehensive diagnostic and treatment research effort that is intended 
to help foster further collaborative research and improved ability to study this disease 
in the extramural NIAID and NCI communities.  
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT
2.1
ELIGIBILITY CRITERIA
2.1.1
Inclusion Criteria
2.1.1.1 Positive HIV serology (previous records acceptable) 
2.1.1.2 Diagnosis of Primary Central Nervous System Lymphoma
2.1.1.3 Confirmed histopathologic diagnosis by NCI Laboratory of Pathology
2.1.1.4 If tissue diagnosis is not feasible for any reason, such as undue risk to the patient 
to acquire tissue diagnosis, the following will be accepted as confirmed AR-
PCNSL diagnosis:
x
Positive brain FDG-PET and 
x
EBV detected in the CSF using PCR
2.1.1.5 Age 18 years or greater
2.1.1.6 ECOG performance 0-4
2.1.1.7 Ability to understand and willing to provide informed consent
2.1.1.7.1 If patient unable to understand informed consent, a previously designated 
durable power of attorney for healthcare or an individual with legal authority 
may substitute in this capacity
2.1.1.7.2 Assignment of a durable power of attorney for healthcare if not already done
2.1.2
Exclusion Criteria
2.1.2.1 Prior therapy for CNS lymphoma
2.1.2.1.1 Steroids not an exclusion
2.1.2.2 Evidence of lymphoma outside of the central nervous system
2.1.2.2.1 Ocular involvement will not exclude
2.1.2.3 Multidrug resistant HIV not amenable to long-term suppression based on either or 
both:
2.1.2.3.1 Clinical history of poor adherence to multiple antiretroviral drugs deemed 
sufficient to render effective HIV control unattainable;
2.1.2.3.2 HIV mutational analysis (genotyping and/or phenotyping) that reveals high-
level resistance such that a combination regimen comprised of agents from at 
least two drug classes cannot be devised to suppress HIV long-term. 
2.1.2.3.3 Refusal to adhere to HAART
2.1.2.4 Concurrent malignancy other than Kaposi sarcoma, resectable squamous cell or 


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basal cell skin cancer, or T1 anal cancer amenable to surgical resection.
2.1.2.5 Heart failure, Class IV by New York Heart Association criteria
2.1.2.6 Chronic Liver Disease, Child-Pugh class B or C
2.1.2.7 Pregnancy
2.1.2.8 Refusal to practice contraception during chemotherapy.
2.1.2.9 Any condition or set of circumstances that the Principal Investigator (PI) or Lead 
Associate Investigator (LAI) interprets as creating undue risk to the patient by 
participating on this study or would make the patient unlikely to comply with 
the study.
2.2
RESEARCH ELIGIBILITY EVALUATION
2.2.1
Screening Studies
All radiographic studies and EKG must be completed within 3 weeks prior to study 
entry; all standard laboratory tests must be done within 72 hours prior to entry; tumor 
diagnostic studies and viral studies may be done at any time prior to entry)
2.2.1.1 History and physical examination with documentation of abnormal findings
2.2.1.1.1 Evaluation of ECOG status
2.2.1.1.2 Detailed history of antiretroviral therapy and assessment for potential 
multidrug resistant HIV
2.2.1.1.3 HIV genotyping and/or phenotyping if needed to assess for HIV resistance 
(previous outside reports adequate if done within prior 6 months)
2.2.1.2 Brain Imaging Studies
2.2.1.2.1 MRI scan
2.2.1.2.2 FDG-PET scan
2.2.1.3 Computed tomography scans of the chest abdomen and pelvis to assess for 
peripheral lymphoma
2.2.1.4 Cerebrospinal fluid studies (if previously performed on sister NIAID protocol, not 
necessary to repeat)
2.2.1.4.1 Cytopathological examination
2.2.1.4.2 Flow cytometric examination
2.2.1.4.3 Measurement of cell count with differential, glucose and protein
2.2.1.4.4 Quantitative EBV PCR (CC Microbiology)
2.2.1.4.5 Ig PCR and EBV PCR (Molecular Pathology, Dr. Mark Raffeld, 2N116-A)
2.2.1.5 Brain Biopsy at site of tumor
2.2.1.5.1 May be omitted if unsafe and if FDG-PET and EBV studies are positive
2.2.1.6 Serum creatinine
2.2.1.6.1 Calculated and/or measured creatinine clearance 
2.2.1.7 Complete blood count and differential
2.2.1.8 PT and PTT
2.2.1.9 Biochemical assessment
2.2.1.9.1 Serum electrolytes


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2.2.1.9.2 Hepatic panel
2.2.1.9.3 Mineral panel
2.2.1.10 EKG
2.2.1.11 HIV serology if previous records not available
2.2.1.12 Obtaining consent from a patient without capacity
When a subject does not have the capacity to give informed consent to enroll in 
this protocol, consent may be obtained from the subject’s legal guardian or the 
subject’s durable power of attorney for health care. In these cases, assent will be 
obtained if the subject is capable of providing it, and the subject’s dissent will be 
respected. 
Typically, the surrogate must be present to give informed consent. In exceptional 
cases, when it is not feasible for the surrogate to come to the Clinical Center, 
surrogate consent may be obtained by telephone. When this approach is used, a
copy of the consent form will be provided to the surrogate ahead of time. In 
addition, a copy of legal guardianship papers, patient’s durable power of attorney 
for health care, or documentation that the individual has legal authority will be 
placed in the patient’s chart. 
At the beginning of the call, the surrogate will be asked to identify themselves and 
confirm that they are the subject’s legal guardian or hold the subject’s durable 
power of attorney, and that they have the written consent form with them. The 
study, including the purpose, risks, potential benefits, and alternatives will be 
explained by a member of the Clinical Investigator from the research team who is 
authorized to obtain informed consent for the study. The surrogate will be offered 
the opportunity to ask any questions, and to deliberate and discuss with other 
parties before making a decision. If the surrogate wants more time, a second call 
will be arranged. 
The conversation will be monitored by a third party at the Clinical Center who is 
not a member of the research team (e.g. nurse, social worker, bioethics). The 
surrogate will be asked to sign the consent form, retain a copy, and mail the 
original to the research team. An explanation of the circumstances and manner of 
obtaining the surrogate’s consent, the names of the person providing consent, the 
person obtaining consent, and the monitor, will be documented in a progress note 
in the subject’s medical record, and signed and dated.
When surrogate consent is obtained by telephone, the research team will establish 
a reliable means of communicating with the surrogate regarding future decisions, 
and will consider the possibility of having someone present at the Clinical Center 
to make day-to-day decisions on the patient’s behalf. At the time of continuing 
review, the research team will provide the IRB with a summary of the instances in 
which telephone consent was used, and the justifications for using it.


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2.3
REGISTRATION PROCEDURES
Each patient will be discussed with the Principal Investigator or Lead Associate 
Investigator, or other designated Associate Investigator.  Once it has been determined that 
a patient qualifies, informed consent will be obtained from the patient, as documented by 
a signed statement of informed consent approved by the NCI-IRB.  
Authorized staff must register an eligible candidate with NCI Central Registration Office 
(CRO) within 24 hours of signing consent.  A registration Eligibility Checklist from the 
web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed 
and sent via encrypted email to:  NCI Central Registration Office ncicentralregistration-
l@mail.nih.gov.  After confirmation of eligibility at Central Registration Office, CRO 
staff will call pharmacy to advise them of the acceptance of the patient on the protocol 
prior to the release of any investigational agents.  Verification of Registration will be 
forwarded electronically via e-mail to the research team. A recorder is available during 
non-working hours. 
2.4
TREATMENT ASSIGNMENT
Cohorts
Number
Name
Description
1
Single Cohort
HIV-infected, adult patients with AIDS-related primary central 
nervous system lymphoma
Arms
Number
Name
Description
1
Single arm
Induction treatment cycles with rituximab, high-dose 
methotrexate and leucovorin will be administered every 2 
weeks for 6 cycles. Two additional consolidation cycles of 
high-dose methotrexate without rituximab will be administered 
at 4 weeks and 8 weeks following completion of the combined 
therapy.
3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN
The primary objective of this study is to estimate the fraction of patients with AR-PCNSL 
receiving experimental treatment consisting of HAART and rituximab combined with 
high-dose methotrexate and leucovorin who are alive and without recurrent lymphoma or 
severe cognitive problems at two years. 
3.1.1
Additional exclusion criteria that would prohibit use of high dose methotrexate
In order to receive the primary protocol therapy, patients must not have any of 
these additional exclusion criteria that would prohibit the use of high dose 
methotrexate:
3.1.1.1 ECOG Performance Status = 4
3.1.1.2 Laboratory abnormalities that make the protocol therapy unsafe to administer:
3.1.1.2.1 Platelet count <50,000/mm3


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21
3.1.1.2.2 Inability to obtain an absolute neutrophil count >1000 cells/mm3 despite use of 
filgrastim for at least 5 days (see section 3.3.5.6)
3.1.1.2.3 ALT and/or AST >2 X upper limit of normal unless due antiretroviral therapy 
or other necessary medications, in which case ALT and AST exclusion cut-off 
is >5X upper limit of normal
3.1.1.2.4 Bilirubin >2 X upper limit of normal unless due to protease inhibitor therapy
3.1.1.2.5 Creatinine >1.5 mg/dL, unless estimated or measured creatinine clearance is 
60 mL/min.
x
If creatinine clearance estimated with the method of Cockcroft 
and Gault is <100 mL/min, a measured creatinine clearance 
should be obtained.
3.1.1.3 Patients with Class III or higher New York Heart Association Classification of 
Congestive Heart Failure unresponsive to treatment that would make hydration 
infeasible.
3.1.1.4 Evidence of other opportunistic diseases or complications of HIV infection that 
would make the protocol therapy infeasible to administer. Examples include, but 
are not limited to:
3.1.1.4.1 Aggressive symptomatic Kaposi’s sarcoma requiring systemic therapy
3.1.1.4.2 Uncontrolled systemic and/or CNS-invasive fungal infection 
3.1.1.5 Hypersensitivity to murine proteins or any component of rituximab
Patients who are ineligible to receive rituximab, high-dose methotrexate and 
leucovorin will be treated with “Radiation-sparing Best Available Care”, as 
outlined in Section 3.6.


Version Date:  02/28/2018
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22
Figure 1: Study Schema: Eligibility Evaluation and Initial Therapy
Meet Protocol Eligibility 
Criteria 
(Section 2.1.)
Enroll 06-C-0051
 
Evaluation for eligibility to 
receive
Rituximab, High-Dose 
Methotrexate and Leucovorin
(Section 3.1)
Has 3.1.1 Exclusion 
Criteria

Treat with HAART and 
“Radiation Sparing Best 
Available Therapy” 
(Section 3.6)
No Exclusion Criteria
 
Treat with HAART and  
Rituximab, High-Dose 
Methotrexate and Leucovorin
(Section 3.3)
3.2
PHASE II STUDY DESIGN FOR HIGH-DOSE METHOTREXATE WITH LEUCOVORIN 
RESCUE AND RITUXIMAB
Induction treatment cycles with rituximab, high-dose methotrexate and leucovorin will be 
administered every 2 weeks for 6 cycles.  Two additional consolidation cycles of high-
dose methotrexate without rituximab will be administered at 4 weeks and 8 weeks 
following completion of the combined therapy. 
MRI will be repeated at the end of cycles 2, 4, 6, and 8, and additionally as clinically 
indicated.  At the time of first evidence for complete tumor response by MRI criteria, 
FDG-PET scan and EBV DNA assessments of the blood and CSF will be repeated.  If 
there is not a complete response by end of cycle 6, patients will be categorized as 
treatment failures and will not receive the two additional high-dose methotrexate doses.  
At end of treatment, restaging by MRI will be performed once every 2 months x 3; then 
once every 3 months x 6; then once every 6 months x 2; then as clinically indicated or
annually up to year 5.  After this period, clinical evaluations may continue and restaging 


Version Date:  02/28/2018
Abbreviated Title: AIDS Brain lymphoma
23
performed if clinical suspicion of CNS pathology.  Additionally, FDG-PET scan will be 
repeated as outlined in section 3.8.4.2. (See also Appendix 3).
3.3
DRUG ADMINISTRATION: HIGH-DOSE METHOTREXATE WITH 
LEUCOVORIN RESCUE AND RITUXIMAB, AND HAART
3.3.1
Review all concomitant medications prior to day 1 of each cycle. Discontinue any 
drug that may potentially interact with methotrexate elimination.
3.3.2
Rituximab
3.3.2.1 Rituximab 375 mg/m2 IV day 1 of each cycle prior to administration of high-dose 
methotrexate.
3.3.2.2 Administer the first dose at an initial rate of 50 mg/hr; if hypersensitivity 
reactions and/or infusion-related events do not occur, the infusion rate may be 
increased in increments of 50 mg/hour every 30 minutes to a maximum infusion 
rate of 400 mg/hour.  Subsequent rituximab infusions may be administered at an 
initial infusion rate of 100 mg/hour; the rate of infusion may be increased every 
30 minutes in increments of 100 mg/hour as tolerated to a maximum infusion 
rate of 400 mg/hour.  Rituximab must be diluted prior to injection (See Section 
9.1).  No other drugs should be added or administered in the same IV line as 
rituximab.
3.3.2.3 Administer acetaminophen 650 mg PO 30-60 minutes prior to starting rituximab 
administration (May hold if a patient is unable to swallow oral medications).  
3.3.2.4 Administer diphenhydramine 25 – 50 mg IV 10- 30 minutes prior to starting 
rituximab administration. 
3.3.2.5 Consider holding antihypertensive medication during the 12-hour period prior to 
dosing rituximab, and on the day of rituximab administration.
3.3.3
Intravenous fluid and urine alkalization
3.3.3.1 On Day 1, 12 – 18 hours before the anticipated start of methotrexate, start IV 
hydration containing sodium bicarbonate (NaHCO3) to alkalinize a patient’s 
urine to pH 7.0, but d 8.0 at a rate that achieves a urine output 100 mL/hr
(recommended start by 6PM local time on day 1). See Table below for options
recommended to initially produce an alkaline urine.
3.3.3.1.1 Order q 6-hour urine pH measurements (e.g., 0000, 0600, 1200, 1800) and 
strict urine output monitoring to start with initiation of IV hydration. Record 
urine output hourly until urine output is > 100 cc/hour, then at least every four 
hours.
3.3.3.1.2 Nursing staff should notify a medically responsible individual (investigator or 
staff on-call) for urine output <100 mL/hour or urine pH <7 or >8.
3.3.3.2 UrLQHDONDOLQL]DWLRQWRS+WRDQGXULQHRXWSXW mL/hour often 
initially requires more NaHCO3 and more rapid hydration rates than will be 
required to maintain either or both parameters after they are achieved.
3.3.3.2.1 The amount of sodium bicarbonate added to intravenously administered fluids 
should produce a solution with sodium content not greater than the 
FRQFHQWUDWLRQRIVRGLXPLQ6RGLXP&KORULGH,QMHFWLRQ mEq/L).


Version Date:  02/28/2018
Abbreviated Title: AIDS Brain lymphoma
24
3.3.3.2.2 Recommendations for initially achieving XULQHDONDOLQL]DWLRQWRS+WR
DQGXULQHRXWSXW mL/hour:
Fluid
Administration 
Rate
Sodium Bicarbonate Content          
(per 1,000 mL)
0.45%NS
150 –
250 mL/h
50 – 75 mEq
0.2%NS
100 – 125 mEq
D5W/0.45%NS
50 – 75 mEq
D5W/0.2%NS
100 – 125 mEq
D5W
150 mEq
D5W: 5% Dextrose Injection, USP
NS: Sodium Chloride Injection, USP
3.3.3.3 In cases where the investigators feel that a patient can reliably maintain adequate 
hydration orally, intravenous hydration may be discontinued after the serum 
methotrexate level is <0.5 mcmol/L.
3.3.3.3.1 Continue to monitor urine output and pH
3.3.3.3.2 Hydration should be resumed if needed to maintain urine pH 7.0 WR and 
urine output >100 mL/hour
3.3.4
High-Dose Methotrexate with sodium bicarbonate followed by leucovorin rescue
3.3.4.1 Prior to HIGH-DOSE METHOTREXATE infusion, administer anti-emetic 
medication.  Recommended: ondansetron 24 mg orally 1 hour prior to 
methotrexate, followed by ondansetron 8 mg orally every 8 – 12 hours for 3 
days.  
3.3.4.2 On day 2, after urine pH 7.0 and urine output >100 mL/hour are confirmed,
administer methotrexate 6000 mg/m2 IV over 4 hours (goal start time for 
methotrexate administration is 9AM – 10AM):
3.3.4.2.1 Administer methotrexate 6000 mg/m2 x 1 bottle with NaHCO3 25-75 mEq 
diluted in 5% Dextrose/0.45% Sodium Chloride Injection (qs.) 1000 mL at 250 
mL/hour (i.e., over 4 hours).
3.3.4.2.2 Order daily serum methotrexate levels timed to start 24 hours after 
methotrexate administration begins and continue daily measurements until the 
serum methotrexate OHYHOLV mcmol/L.
3.3.4.2.3 Continue IV or oral hydration ZLWKXULQHDONDOLQL]DWLRQS+WRuntil 
serum PHWKRWUH[DWHOHYHOLV mcmol/L (see sections 3.3.3.3 and 3.3.4.2)
3.3.4.3 Leucovorin rescue, starting 24 hours after methotrexate administration began
(generally on day 3):
3.3.4.3.1 Administer leucovorin calcium 100 mg/m2 per dose IV (preferred) or 
levoleucovorin calcium 50 mg/m2 per dose IV every 6 hours until the serum 
methotrexate level is <0.5 mcmol/L.  
3.3.4.3.2 When the methotrexate level is <0.5 mcmol/L, parenterally administered 
leucovorin or levoleucovorin may be replaced with leucovorin administered 


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25
orally (10 mg/m2, or a fixed 25-mg dose for patients with BSA <2.5 m2), until 
the methotrexate level is 0.05 mcmol/L.  
3.3.4.3.3 For patients with delayed methotrexate clearance, see sections 3.4.3 and 3.4.4.
3.3.5
Filgrastim
3.3.5.1 Routine use of filgrastim is not required for this therapy
3.3.5.2 Do not administer filgrastim within 24 hours before administering methotrexate
3.3.5.2.1 If filgrastim has already been administered, delay methotrexate until >24 hours
have passed since filgrastim administration
3.3.5.2.2 Do not administer filgrastim after methotrexate administration until 
methotrexate levels have decreased to <0.05 mcmol/L.
3.3.5.3 Pegfilgrastim may not be used.
3.3.5.4 Indications for filgrastim use for patients on this study:
3.3.5.4.1 HIV-related neutropenia
x Includes neutropenia related to antiretroviral therapy, or other 
HIV-disease-related therapy
3.3.5.4.2 Methotrexate-related neutropenia
3.3.5.4.3 Rituximab-related neutropenia
x Includes delayed-onset neutropenia
3.3.5.5 Filgrastim doses will be individually titrated according to the clinical scenario.
3.3.5.6 Filgrastim 300-480 mcg/day subcutaneously may be used as needed to maintain 
an absolute neutrophil count 1000 cells/mm3. Filgrastim will not be 
administered more frequently than once daily.  Intravenous administration may 
be utilized.  
3.3.6
Highly Active Antiretroviral Therapy (HAART)
3.3.6.1 Whenever possible, patients should be taking HAART as soon as is feasible 
3.3.6.2 HAART interruptions for toxicity and tolerance are allowed
3.3.6.3 Refusal to adhere to HAART is not permitted, as it is considered part of the 
oncology therapy for this protocol
3.3.6.4 A regimen of highly active anti-retroviral therapy will be initiated as soon as 
feasible in all patients.  Treatment will in general be based on Department of 
Health and Human Services Antiretroviral Guidelines for Adults and 
Adolescents found at http://www.aidsinfo.nih.gov/guidelines/ . Particular events 
may require treatment suspension, modification and will be considered 
individually for best medical care.  Therapy may be managed by NCI and or 
NIAID co-investigators on this protocol or on the NIAID sister protocol. 
3.3.6.5 Order HLA B*5701 Pharmacogenetic test at baseline to evaluate for possible use 
of abacavir. Recommend a tenofovir-free regimen to avoid potential 
nephrotoxicity and potential deleterious effect on methotrexate renal excretion.
3.4
TREATMENT MODIFICATIONS: HIGH-DOSE METHOTREXATE WITH 
LEUCOVORIN RESCUE AND RITUXIMAB
3.4.1
Rituximab


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Abbreviated Title: AIDS Brain lymphoma
26
3.4.1.1 For infusion related events or hypersensitivity reactions, the infusion rate should 
be slowed (e.g. for moderate flu-like symptoms of fever, chills, rigors; other 
infusion related reactions such as nausea, urticaria, pruritus, rash, fatigue, 
headache) or infusion of the drug should be interrupted or discontinued as 
clinically indicated (e.g. for reactions such as angioedema, hypotension, 
bronchospasm); following appropriate treatment and/or resolution of the 
reaction(s), administration of rituximab may be reinitiated at a slower infusion 
rate (one-half the previous infusion rate), and the rate of infusion may be 
incrementally increased as tolerated.
3.4.2
High-dose methotrexate 
3.4.2.1 The creatinine clearance (CrCl) will be calculated by method of Cockcroft-Gault 
prior to each cycle (see Appendix 4).  If CrCl is 100 mL/min, then no dose 
adjustment is necessary.  If CrCl is <100 mL/min, then the methotrexate dose is 
adjusted by the fraction of CrCl less than 100 mL/min (e.g., methotrexate dose = 
6000 mg/m2 x CrCl/100).
3.4.2.1.1 For estimated creatinine clearance <100 mL/min, a 24-hour urine collection 
should be obtained plus a serum creatinine at the end of the collection period to 
determine a measured creatinine clearance.
3.4.2.2 Delayed methotrexate serum clearance (>3 days after methotrexate infusion) may 
occur and mandates accelerated rescue and continued hydration and 
alkalinization.  The minimum interval between achieving a serum methotrexate 
level  mcmol/L and the start of a subsequent treatment cycle is 7 days.
3.4.2.3 For creatinine clearance <60 mL/min, no methotrexate will be administered. 
Administer rituximab without methotrexate after discussion with a medically 
responsible investigator if renal function cannot be expected to be optimized 
(CrCl 60 mL/min) within 3 days.
3.4.2.4 For transient ALT and/or AST elevations 10X the upper limit of normal, 
withhold methotrexate until both ALT and AST are 5 X the upper limit of 
normal, then permanently reduce methotrexate dosage by 25% for all 
subsequent cycles beginning with the next cycle.
3.4.2.5 For ANC <1000 cells/mm3, delay methotrexate until ANC recovers to 
PP3.
3.4.2.6 For platelet counts <50,000/mm3, delay methotrexate until platelet count recovers
WRPP3.
3.4.2.7 For any other Grade 3 or greater toxicities related to methotrexate, with the 
exception of hematologic toxicity, hold methotrexate until toxicity abates to 
Grade 2.
3.4.2.8 For pulmonary toxicity related to methotrexate, permanently discontinue 
methotrexate.
3.4.2.9 Note, if toxicity attributed to methotrexate prevents subsequent methotrexate
treatment prior to the time of complete response, patient will be considered a 
treatment failure.  Failure of toxicity to resolve and thus creating dose delays in 
excess of 15 days will result in methotrexate discontinuation.


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Abbreviated Title: AIDS Brain lymphoma
27
3.4.3
Leucovorin
3.4.3.1 In the case of delayed early methotrexate elimination (see Table 1 below) and/or 
evidence of acute renal injury, administer leucovorin calcium according to Table 
1 until the serum methotrexate level is 0.05 mcmol/L.
3.4.3.2 If leucovorin is not available (e.g., due to a drug shortage), replace leucovorin 
with levoleucovorin calcium every 6 hours until serum methotrexate level is 
0.5 mcmol/L, see Table 1 for dosing.
3.4.3.3 Alternatively, glucarpidase (formerly “carboxypeptidase G2”) may be used (see 
section 3.4.4 below) 
3.4.3.3.1 Evidence of acute renal injury includes a 100% or greater increase in serum 
creatinine level at 24 hours after methotrexate administration (e.g., an increase 
from 0.5 mg/dL to a level 1 mg/dL).


Version Date:  02/28/2018
Abbreviated Title: AIDS Brain lymphoma
28
Table 1: Leucovorin and Levoleucovorin dosing for delayed methotrexate clearance
Methotrexate Level
Leucovorin Dose
Levoleucovorin Dose
24 hours:
>10 mcmol/L
100 mg/m2 IV q 6 hours
50 mg/m2 IV q 6 hours
48 hours:
>1 mcmol/L
100 mg/m2 IV q 3 hours
50 mg/m2 IV q 3 hours
60 hours:
>2 mcmol/L
200 mg/m2 IV q 3 hours
100 mg/m2 IV q 3 hours
72 hours:
>0.1 mcmol/L
100 mg/m2 IV q 6 hours
50 mg/m2 IV q 6 hours
:KHQWKHPHWKRWUH[DWHOHYHOLV mcmol/L, leucovorin/levoleucovorin may 
be administered as oral leucovorin calcium until serum methotrexate level is 
0.05 mcmol/L (see Section 3.3.4.3.2).
3.4.3.4 In addition to appropriate leucovorin/levoleucovorin therapy, these patients 
require continuing hydration and urinary alkalinization, and close monitoring of 
fluid and electrolyte status, until the serum methotrexate level has fallen to 
<0.05 mcmol/L and renal failure has resolved.
3.4.3.5 Serum methotrexate monitoring levels are now performed at Children’s Hospital 
7 days per week at 2PM.  Specimens collected for methotrexate monitoring must 
be delivered to the NIH CC Department of Laboratory Medicine’s Chemistry 
Service during morning hours so they can be delivered to Washington’s 
Children’s Hospital and processed in a timely manner. This process is designed 
to obtain same day results for patients on 06-C-0051 so the clinical team can 
make protocol-defined treatment decisions, such as stopping leucovorin or IV 
fluids, or implementing treatment for delayed methotrexate clearance with 
glucarpidase (Voraxaze®)
3.4.3.5.1 Methotrexate Levels need to be drawn at scheduled times
3.4.4
Glucarpidase Rescue of Methotrexate toxicity and Acute Renal Failure
3.4.4.1 Glucarpidase may be utilized in addition to leucovorin or levoleucovorin for 
methotrexate toxicity in the setting of renal toxicity and delayed methotrexate 
clearance.
3.4.4.2 Glucarpidase may ONLY be administered with the approval of a medically 
responsible study investigator.
3.4.4.3 Clinical prerequisites:
3.4.4.3.1 Serum methotrexate concentration of >10 mcmol/L at 24-48 hours after 
methotrexate infusion,
3.4.4.3.2 Urine output decreases (less than 50% excretion of the input hydration) or a 
serum creatinine >1.5-times the upper limit of normal, and
3.4.4.4 Documented increase of serum creatinine during the infusion period.
3.4.4.5 Glucarpidase administration:
3.4.4.5.1 Glucarpidase 50 Units/kg of body weight is administered as a single IV 
injection over 5 minutes.


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Abbreviated Title: AIDS Brain lymphoma
29
3.4.4.5.2 Do not administer leucovorin or levoleucovorin within 2 hours either 
before or after a dose of glucarpidase because reduced folates such as 
leucovorin and levoleucovorin are substrates for degradation by glucarpidase.
3.4.4.5.3 For the first 48 hours after glucarpidase, administer leucovorin or 
levoleucovorin at the same dose and schedule as were given prior to 
administering glucarpidase.  At times >48 hours after glucarpidase, administer 
leucovorin or levoleucovorin based on measured methotrexate concentrations.
3.4.4.5.4 Do not discontinue leucovorin or levoleucovorin based on the determination of 
a single methotrexate concentration <0.05 mcmol/L. Leucovorin or 
levoleucovorin should be continued until the methotrexate concentration has 
been maintained <0.05 mcmol/L for a minimum of 3 days.
3.4.4.5.5 Continue hydration and alkalinization of urine as indicated per protocol, or as 
directed by a medically responsible study investigator.
3.5
CRITERIA FOR DISCONTINUING RITUXIMAB AND HIGH-DOSE METHOTREXATE
WITH LEUCOVORIN RESCUE 
3.5.1
Completion of therapy
3.5.2
Delayed methotrexate clearance due to impaired renal function, requiring 
glucarpidase
3.5.3
Creatinine clearance <60 mL/min based on a 24-hour urine collection that cannot 
be corrected within 2 weeks
3.5.4
Any creatinine clearance <30 mL/min based on 24-hour urine collection.
3.5.5
Inability to tolerate required intravenous hydration (minimum 60 hours of 
intravenous fluid at a rate t100 mL/hour)
3.5.6
Dose delays in excess of 15 days 
3.5.7
Withdrawal of consent.
3.5.8
Inability to administer to HAART or other oncologic therapies.
3.5.9
Progressive neurologic symptoms attributed to progressive AR-PCNSL
3.5.10 Untreatable concurrent illness
3.5.11 Methotrexate with leucovorin rescue may be discontinued, if in the opinion of the 
PI or LAI, the risk of continued therapy outweighs the potential benefit of 
continued therapy, or if patient non-adherence interferes with study objectives.
3.5.12 Patients who discontinue Rituximab and methotrexate with leucovorin rescue may 
continue with “Radiation-sparing Best Available Therapy”, including dose-dense 
Rituximab, if clinically indicated.
3.6
“RADIATION-SPARING BEST AVAILABLE THERAPY” FOR PATIENTS NOT 
ELIGIBLE FOR HIGH-DOSE METHOTREXATE IN THE PHASE II COHORT
Patients with EBV+ AR-PCNSL that have co-morbidities prohibiting administration of 
high dose methotrexate will receive HAART combined with dose-dense rituximab111
unless there is a clinical reason that this should not be used or would not be considered 
best therapy, such as hypersensitivity to murine proteins.  


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Abbreviated Title: AIDS Brain lymphoma
30
Dose dense administration of rituximab increases serum concentration112, which would 
be expected to allow for better distribution to the CNS.  Patients will receive one 4-week 
cycle, consisting of a total of 6 doses of rituximab administered on Days 1, 3, 5, 8, 15, 
and 21.  
Patients who are hypersensitive to murine proteins or any component of rituximab, or 
other clinical contraindications to using the dose-dense rituximab regimen, will receive 
HAART (See Section 3.6.2).  If clinically indicated, additional chemotherapy or 
radiotherapy may be employed in such patients (See Section 3.6.3).
3.6.1
Rituximab
3.6.1.1 Rituximab 375 mg/m2 IV days 1, 3, 5, 8, 15, and 21
3.6.1.2 Administer the first dose at an initial rate of 50 mg/hr; if hypersensitivity 
reactions and/or infusion-related events do not occur, the infusion rate may be 
increased in increments of 50 mg/hour every 30 minutes to a maximum infusion 
rate of 400 mg/hour.  Subsequently, rituximab infusions may be administered at 
an initial infusion rate of 100 mg/hour; the rate of infusion may be increased 
every 30 minutes in increments of 100 mg/hour as tolerated to a maximum 
infusion rate of 400 mg/hour.  Rituximab must be diluted prior to injection (See 
Section 9.1).  No other drugs should be added or administered in the same IV 
line as rituximab.
3.6.1.3 Administer acetaminophen 650 mg PO 30-60 minutes prior to starting rituximab 
administration (May be held if a patient is unable to swallow oral medications).  
3.6.1.4 Administer diphenhydramine 25 – 50 mg IV 10-30 minutes prior to starting 
rituximab administration. 
3.6.1.5 Consider holding antihypertensive medication during the 12-hour period prior to 
dosing rituximab, and on the day of administration, especially if systolic blood 
pressure is <105 mm Hg. If antihypertensive medications are held, patients 
should continue to have blood pressure monitored at least every 8 hours.  
Antihypertensive medication should generally be continued or resumed if 
systolic blood pressure is >160 mm Hg or diastolic blood pressure is >100 mm
Hg
3.6.2
Highly Active Antiretroviral Therapy (HAART)
3.6.2.1 Whenever possible, patients should be taking HAART as soon as is feasible 
3.6.2.2 HAART interruptions for toxicity and tolerance are allowed
3.6.2.3 Refusal to adhere to HAART is not permitted, as it is considered part of the 
oncology therapy for this protocol
3.6.2.4 A regimen of highly active anti-retroviral therapy will be initiated as soon as
feasible in all patients.  Treatment will in general be based on Department of 
Health and Human Services Antiretroviral Guidelines for Adults and 
Adolescents found at http://www.aidsinfo.nih.gov/guidelines/. Particular events 
may require treatment suspension, modification and will be considered 
individually for best medical care.  Therapy may be managed by NCI and or 


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Abbreviated Title: AIDS Brain lymphoma
31
NIAID co-investigators on this protocol or on NIAID protocols. Recommend 
tenofovir-free regimen to avoid potential nephrotoxicity and potential effect on 
methotrexate renal excretion.
3.6.3
Treatment modification: “Radiation-sparing Best Available Therapy”
3.6.3.1 Chemotherapy
Alternative or additional chemotherapy may be employed in patients who: 
x
Cannot receive the methotrexate or the dose-intense rituximab 
regimens
x
Have stable disease or partial response as a best response to 
therapy
x
Have disease recurrence after either regimen 
Choice of additional chemotherapeutic agents will be individualized, and 
agents and regimens used in treating PCNSL in immunocompetent hosts. 
Patients treated with second-line chemotherapy can be followed on study 
as long as they remain on HAART and are evaluable for long-term 
neurocognitive outcomes.
3.6.3.2 Whole Brain Radiation Therapy
Following the Guidelines in Section 3.10 patients may also, or as 
an alternative, receive whole brain radiation therapy if indicated. 
As noted in Section 3.12.2, patients treated with radiotherapy can 
be followed on study as long as they remain on HAART and are 
evaluable for long-term neurocognitive outcomes.
3.6.4
Supportive Care
The following supportive care measures may be individualized to patients’
symptoms and laboratory abnormalities:
3.6.4.1 Filgrastim
3.6.4.1.1 Routine use of filgrastim are not routinely required for this therapy
3.6.4.1.2 Indications for use on this study:
x
HIV-related neutropenia
o
Includes neutropenia related to antiretroviral therapy, or 
other HIV-disease-related therapy
x
Rituximab related neutropenia
o
Includes delayed onset neutropenia
3.6.4.1.3 Filgrastim dose will be individually titrated according to the clinical scenario.
3.6.4.1.4 Filgrastim 300-480 mcg/day subcutaneously may be used as needed to 
maintain the absolute neutrophil count 1000 cells/mm3. Filgrastim will not 
be administered more than once daily.  Intravenous administration may be 
utilized.  
3.6.4.2 Steroids, systemically administered
3.6.4.2.1 Doses of steroids up to dexamethasone 4 mg every 6 hours or equivalent may 
be used for patients with neurologic symptoms attributed to lymphoma


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3.6.4.2.2 Duration of steroids will be generally not be greater than 5 days, in same cases 
tapering of steroids will be required
3.6.4.2.3 Courses of steroid treatment may be repeated if needed
3.7
SECOND-LINE THERAPY
Second-line chemotherapy AND/OR radiotherapy assessment and treatment may be 
included as part of the protocol when necessary for best patient care; in such a case, 
patient can remain on-study if they are evaluable for disease specific and overall survival 
endpoints. Importantly, such patients will be assessed for long-term neurocognitive 
outcomes using protocol defined neuropsychometric testing. This will be to assess in an 
observational manner late term neurotoxicity should the patient survive long enough to 
manifest this complication. Patients receiving radiation therapy will be evaluated 
separately in regards to neuropsychometric testing. As noted in section 3.6 and 5.3.6,
patients requiring radiotherapy will be considered treatment failures for statistical 
purposes of the protocol.  If patient is unable or unwilling to participate in 
neuropsychometric testing, patient will remain on study until completion of second-line 
therapy at NCI or until referral to another facility, whichever is first.
3.8
ON STUDY EVALUATION
3.8.1
Research Specimens
3.8.1.1 Baseline 
3.8.1.1.1 Cerebrospinal fluid (not necessary to repeat if previously acquired within 21 
days before starting therapy)
x Ig PCR and EBV PCR (Molecular Pathology, Dr. Mark Raffeld, 
2N116-A)
x Cytopathology
x Flow Cytometry (Room B1B58) 
x Quantitative EBV PCR (CC Microbiology)
3.8.1.1.2 Blood (not necessary to repeat if previously acquired within 14 days before
starting therapy)
x Quantitative EBV PCR (CC Microbiology)
x HIV viral load
x T-cell subsets (Randy Stevens, Leidos Biomedical Research, Inc.,
Frederick)
x Storage:  1 red top for serum; 1 yellow top for plasma; 1 green top 
for cells 
3.8.1.2 Sequence based HLA B for HLA B*5701 Pharmacogenetic testing. This may be 
excluded if HLA type has been previously documented.
3.8.1.3 Every odd-numbered cycle
3.8.1.3.1 Blood
x Quantitative EBV PCR (CC Microbiology)
x HIV viral load


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x T-cell subsets (Randy Stevens, Leidos Biomedical Research, Inc.,
Frederick)
x Storage:  1 red top for serum; 1 yellow top for plasma; 1 green top 
for cells 
3.8.1.4 End of therapy (see Appendix 3)
3.8.1.4.1 Blood: days 29 (+/- 7 days) then monthly for 2 months, then every 2 months 
x3, then every 3 months x 6, then every 6 months x 2, then every 12 months x 
2 (for patients co-enrolled in 01-C-0038 and followed clinically beyond year 
3). Also obtain at time of lymphoma recurrence in concert with CSF studies 
outlined in section 3.8.5.4.2
x Quantitative EBV PCR (CC Microbiology) 
x HIV viral load
x T-cell subsets (Randy Stevens, Leidos Biomedical Research, Inc.,
Frederick)
x Storage:  1 red top for serum; 1 yellow top for plasma; 1 green top 
for cells
3.8.2
Clinical and laboratory assessments
3.8.2.1 Baseline assessment prior to treatment (within 72 hours before therapy)
3.8.2.1.1 Physical examination with particular emphasis on neurological examination)
3.8.2.1.2 Folstein Mini Mental Status Exam (MMSE).  See Appendix 1.
3.8.2.1.3 Assignment of Neurologic Function Class (see Appendix 2)
3.8.2.1.4 CBC with differential (CBC with differential drawn up to 24 hours prior to 
starting therapy acceptable for patients receiving filgrastim to manage 
neutropenia) 
3.8.2.1.5 Electrolytes
3.8.2.1.5.1 Serum creatinine
x
calculated and/or measured creatinine clearance
x
Whenever the calculated creatinine clearance is <100 mL/min, a measured 
creatinine clearance should be obtained.
3.8.2.1.5.2 Hepatic panel
3.8.2.1.5.3 Mineral panel
3.8.2.1.6 Ophthalmologic examination to assess for ocular involvement by lymphoma
3.8.2.1.7 Viral hepatitis studies (not necessary to repeat previously documented positive 
studies; results not required prior to treatment):
x
Hepatitis A
x
anti-HAV IgG
x
Hepatitis B
x
anti-HBsAg
x
HBsAg
x
Anti-HB core
x
Hepatitis C
x
anti-HCV


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3.8.2.1.8 Serum anti-toxoplasmosis antibody titers (not necessary to repeat if already 
obtained on NIAID protocol)
3.8.2.1.9 Syphilis serology (not necessary to repeat if already available within 6 months 
prior to study entry)
3.8.2.1.10 HIV viral load if not available within 14 days prior to enrollment
3.8.2.1.11 T-cell subsets if not available within 14 days prior to enrollment
3.8.2.1.12 HIV genotype or Virtual Phenotype® to assess for resistant HIV if not 
previously done 
3.8.3
Day 1 each cycle; then monthly for 2 months, then every 2 months  x3, then every 
3 months x6, then every 6 months x 2, then every 12 months x 2 (for patients co-
enrolled in 01-C-0038 and followed clinically beyond year 3).
For “Radiation-Sparing Best Available Care” Cohort, scheduled evaluations on Days 
1, 8, 15, 21, 28 then monthly for 2 months, then every 2 months for 3 times, then every 
3 months of total of 36 months, then yearly for 2 years (for patients followed clinically 
beyond year 3).
3.8.3.1 Physical examination with documentation of abnormalities
3.8.3.2 Particular emphasis on neurological examination
3.8.3.3 Assign neurologic function class (see Appendix 2)
3.8.3.4 CBC with differential (CBC with differential drawn up to 24 hours prior to 
starting therapy acceptable for patients receiving filgrastim to manage 
neutropenia) 
3.8.3.5 Electrolytes
3.8.3.5.1 Serum creatinine
x calculated and/or measured creatinine clearance
x Whenever the calculated creatinine clearance is <100 mL/min, a 
measured creatinine clearance should be obtained.
3.8.3.5.2 Hepatic panel
3.8.3.5.3 Mineral panel
3.8.3.6 During treatment cycles until serum methotrexate level 0.05 mcmol/L:
3.8.3.6.1 Blood specimens for methotrexate levels must be drawn at scheduled times
3.8.3.6.2 Hepatic panel every other day
3.8.3.6.3 CBC with differential daily
3.8.3.6.4 Electrolytes, creatinine, BUN daily
3.8.4
Baseline Staging
3.8.4.1 MRI: if done within 2 weeks before study entry, repeat only if interval clinical 
deterioration has occurred
3.8.4.2 FDG-PET:  not necessary to repeat if previously done within 3 weeks of study 
entry
3.8.5
Restaging
3.8.5.1 MRI
3.8.5.1.1 End of cycles 2, 4, 6 and 8, then every 2 months x3, then every 3 months x 6, 
then every 6 months x 2, then as clinically indicated, or annually up to year 5


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(for patients followed clinically beyond year 3). For “Radiation-Sparing Best 
Available Care” Cohort, Scheduled evaluations on Week 4, Week 8, Week 12, 
then every 2 months x3, then every 3 months x 5, then every 6 months x 2, 
then as clinically indicated, or annually up to year 5 (for patients followed 
clinically beyond year 3).
3.8.5.2 Ophthalmologic
3.8.5.2.1 If ocular involvement, restage same schedule as with MRI
3.8.5.2.2 If no ocular involvement, examine for lymphoma if clinically indicated
3.8.5.3 FDG-PET
3.8.5.3.1 End of cycle 1
3.8.5.3.2 At the time of complete response (or CRu) by MRI criteria
x Due to scheduling, may be done at following cycle
3.8.5.3.3 End of cycle 6 if best response less than CRu, otherwise, end of cycle 8
3.8.5.3.4 At month 12 at time of MRI
3.8.5.3.5 At the time of suspected disease recurrence/progression by MRI criteria 
following complete response and previous negative FDG-PET
3.8.5.4 Cerebrospinal Fluid
3.8.5.4.1 At the time of complete response (or CRu) by MRI criteria
x Due to scheduling, may be done at following cycle
3.8.5.4.2 At the time of suspected disease recurrence/progression by MRI criteria
x Ig PCR and EBV PCR  (Molecular Pathology, Dr. Mark Raffeld, 
2N116-A)
x Flow cytometry (Maryalice Stetler-Stevenson,  Room B1 B58)
x Cytopathology
x Quantitative EBV PCR (CC Microbiology)
x Cell count with differential, glucose, protein
3.8.5.4.3 At end of treatment and at 6 months post treatment:
x Ig PCR and EBV PCR (Mark Raffeld)
x Quantitative EBV PCR (CC Microbiology)
x Cytopathology
x Flow cytometry (Maryalice Stetler-Stevenson, Room B1 B58)
x Cell count with differential, glucose, protein
3.8.6
Neuropsychometric testing
3.8.6.1 Folstein Mini-Mental Status Examination will be done for comparative purposes 
prior to therapy, after cycle 1, and again at completion of treatment course.  
3.8.6.2 Baseline formal neuropsychologic assessment will be administered 1-2 months 
after completion of chemotherapy treatment course.
3.8.6.3 Follow-up assessments will be administered at 6, 12, 18, 24, and 36 months (± 3 
months) after completion of therapy.  Comprehensive assessment will be 
performed at the post-therapy baseline and annually thereafter whereas 
monitoring assessments will be administered at the half-year evaluations (see 
Appendix 5 for the comprehensive and monitoring neuropsychologic test 


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36
batteries).
3.8.7
Adherence Assessment
3.8.7.1 At 1-2 months after completion of therapy, patients will complete measures 
assessing barriers to adherence, knowledge of HIV, and perceived social support 
(see Appendix 6 and Appendix 7).  
3.8.7.2 A follow-up knowledge and social support assessment will be administered at 6 
months. Follow-up adherence assessments (via self-report) will be conducted 
every 3 months, beginning 3 months post-treatment through month 24.  Results
from these data will guide interventions aimed at identifying patterns of non-
adherence and specific barriers identified by the patient as being problematic.
3.8.8
Optional Blood Draws
Up to 50 cc of blood may optionally be drawn for immunological testing, establishment 
of cell lines, evaluation of hematologic parameters, or other studies that become clinically 
important during conduct of the trial.  However, this should not be drawn if it brings the 
total amount of blood drawn to more than 450 mL during a 6-week period.  Blood and 
tissue specimens collected in the course of this research project may be banked and used 
in the future to investigate new scientific questions related to this study. However, this 
research may only be done if the risks of the new questions were covered in the consent 
document or are of minimal risk.  If new and significant risks are associated with the 
research (e.g. analysis of germ line genetic mutations) the principal investigator must 
obtain IRB approval. Handling of optional biospecimens is outlined in Section 7.5.
3.9
CONCURRENT THERAPIES
3.9.1
Anti-retroviral therapy
See section 3.6.2
3.9.2
Contraception
All females of childbearing potential will be given contraception or provided with 
barrier contraceptive devices.
3.9.3
Pneumocystis jiroveci prophylaxis (PJP/PCP)
All patients will receive PCP prophylaxis throughout the treatment period and until the 
CD4+ cells are sustained over 200 cells/mm3 for a 3-month or longer period of time.  
If cotrimoxazole (trimethoprim+sulfamethoxazole; Bactrim®) is used, it should be 
withheld during methotrexate treatment until completion of leucovorin rescue.
Alternatives include:
x
Dapsone 50 – 100 mg PO daily or 100 mg PO 2x/week
x
Aerosolized pentamidine 300 mg by inhalation, monthly
x
Atovaquone 750 mg PO BID 
3.9.4
MAC prophylaxis
Essentially all patients on study will require prophylaxis since AR-PCNSL occurs in 
those with CD4+ cells <50/mm3.
Azithromycin 1200 mg orally once weekly is recommended, but other agents are 


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acceptable.  
3.9.5
Antibacterial Prophylaxis
For patients with anticipated severe neutropenia (ANC <500 cells/mm3) related to 
cyclic chemotherapy, consider levofloxacin 500 mg PO daily for up to seven 
consecutive days, timed to coincide with periods of severe neutropenia that cannot be 
managed with filgrastim.
3.9.6
Hepatitis B antigenemia
For patients with serologic evidence of chronic persistent/active HBV infection, 
lamivudine 150 mg PO daily, tenofovir 300 mg PO daily, or other agents with 
demonstrated anti-HBV activity should be given continually throughout treatment 
cycles until a medically-responsible investigator advises discontinuation.  Since 
chemotherapy in general and rituximab in particular are associated with HBV 
reactivation, this should also be considered in patients with anti-HB core-alone 
positivity. 
3.9.7
Contraindicated therapies
Trimethoprim/sulfamethoxazole should not be given within 48 hours prior to 
methotrexate administration and until methotrexate concentration is <0.05 mcmol/L.


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Methotrexate should not be given concurrently with any of the following medications
without the approval of a medically responsible study investigator:
1.
Asparaginase
2.
Aspirin
3.
Acidic drugs
4.
Amoxicillin
5.
Cephalosporins
6.
Chloramphenicol
7.
Cholestyramine
8.
Cotrimoxazole
9.
Cyclosporine
10.
Diclofenac
11.
Ibuprofen
12.
Indomethacin
13.
Ketoprofen
14.
Mercaptopurine
15.
Mezlocillin
16.
Naproxen
17.
Non-steroidal anti-inflammatory drugs
18.
Omeprazole
19.
Penicillins
20.
Piperacillin (±tazobactam)
21.
Probenecid
22.
Proton pump inhibitors (e.g., dexlansoprazole, esomeprazole, 
lansoprazole, omeprazole, pantoprazole, rabeprazole)
23.
Pyrimethamine
24.
Salicylates
25.
Sulfonamides
26.
Sulindac
27.
Tetracyclines
28.
Tolmetin
29.
Trimethoprim
30.
Trimethoprim/sulfamethoxazole
31.
Vaccines, Live (viral and bacterial)
Generally, these agents should be withheld 48 hours prior to the initiation of methotrexate 
and until methotrexate concentration is <0.05 mcmol/L.
3.10 RADIATION THERAPY GUIDELINES
3.10.1 Radiation therapy to the brain will be deferred in all patients unless there is 
progression of disease with high-dose methotrexate- rituximab, or radiation-
sparing best therapy, stable disease or partial response as best response to high-
dose methotrexate- rituximab or radiation-sparing best therapy, or recurrence 
following apparent complete response with high-dose methotrexate- rituximab or 


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39
radiation-sparing best therapy, and further chemotherapy approaches by 
themselves are not assessed by the treatment team to be clinically appropriate.  
Patients requiring radiotherapy (or any other additional therapy for AR-PCNSL) 
will be considered treatment failures for this study.  Patients requiring such 
therapy will be returned to the care of the referring physicians when possible.   If 
possible, continuation of neuropsychometric testing outlined in the study will 
continue, to describe the cognitive outcome.   
3.10.2 Radiation following high-dose methotrexate may confer additional risk of 
neurotoxicity.  For this reason, when feasible, salvage chemotherapy strategies 
will be considered as appropriate.  
3.10.3 Progressive disease
3.10.3.1 Alternative chemotherapy or WBRT to achieve best tumor control.
3.10.4 Partial Response
3.10.4.1 Limited volume RT (if possible) to achieve best tumor control and limit CNS 
exposure and late term radiation-related neurotoxicity.
3.10.5 Early Recurrence
3.10.5.1 Minimal disease will be treated with limited volume RT if possible, to achieve 
best tumor control and limit CNS exposure and late term radiation-related 
neurotoxicity.  WBRT will be utilized if indicated.
3.10.6 Diffuse recurrence may be treated with WBRT if indicated to achieve best tumor 
control
3.11 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
Prior to removal from study, effort must be made to have all subjects complete a safety 
visit approximately 30 days following the last dose of study therapy.
3.11.1 Criteria for removal from protocol therapy
x
Completion of therapy
x
Dose delays in excess of 15 days
x
Withdrawal of consent 
x
Inability to tolerate HAART or other oncologic therapies
See Section 3.5 for additional criteria for discontinuing rituximab and high-dose 
methotrexate with leucovorin rescue.
3.11.2 Off Study Criteria
x Refusal to adhere with HAART
x Refusal of oncologic therapy
x Patient or patient advocate (if patient not competent) voluntary withdrawal
x Progression of disease and either refusing or not eligible to receive second-line 
chemotherapy AND/OR radiotherapy
x Progressive, irreversible neurocognitive deficits, not attributed to AIDS-PCNSL 
or treatable infection, occurring greater than 90 days after the completion of 


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40
radiation therapy that would be scored as grade 3 or higher by the 
RTOG/EORTC Late Radiation Morbidity Scoring Scheme
x Completion of 5 years follow-up with no recurrent AR-PCNSL 
3.11.3 Off Protocol Therapy and Off-Study Procedure
Authorized staff must notify Central Registration Office (CRO) when a subject is taken 
off protocol therapy and when a subject is taken off-study. A Participant Status Update
Form from the web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm ) main 
page must be completed and sent via encrypted email to:  NCI Central Registration 
Office ncicentralregistration-l@mail.nih.gov.
3.12 POST-STUDY EVALUATION
3.12.1 Patients will be followed on study for 3 years on protocol (see Appendix 3).  After 
the end of the three-year period, patients may be followed for clinical assessment 
on an annual basis for up to a total of 5 years.  Specific additional assessments 
will be determined according to clinical findings at that time, and in concert with 
referring physicians.
3.12.2 Patients followed in the “Radiation-sparing Best Available Care” cohort will be 
followed using the same schedule as those receiving protocol defined therapy.
4
SUPPORTIVE CARE
4.1
PNEUMOCYSTIS JIROVECI PNEUMONIA
Patients who develop PCP will receive standard of care including trimethoprim-
sulfamethoxazole, steroids when appropriate and alternative standard agents such as IV 
pentamidine, atovaquone, or trimetrexate in combination with leucovorin when 
trimethoprim-sulfamethoxazole cannot be used. Trimethoprim-sulfamethozole must be 
held during administration of high dose –methotrexate and leucovorin rescue, as outlined 
in Section _Contraindicated_therapies3.9.7.
4.2
CYTOMEGALOVIRUS (CMV)
Periodic ophthalmologic evaluations will be conducted on all patients, as this subset of 
AIDS patients are at particular risk of CMV retinitis.  Baseline examination will be 
conducted as soon as possible at entry, and then approximately every 1-3 months until the 
CD4+ cells are over 75 cells/mm3.   Ganciclovir ocular implants will in general be the 
initial treatment choice.  Intravenous ganciclovir or oral valganciclovir can be considered, 
but due to its hematological toxicity, it should not be used without consulting the PI or 
LAI.  Both cidofovir and foscarnet are effective in CMV, but are nephrotoxic, and will 
not be used during high-dose methotrexate.  Urinalysis for proteinuria and creatinine 
clearance estimates or measurements made if these agents are to be used.  All cases of 
CMV infection must be discussed with the PI or LAI.
4.3
FUNGAL INFECTIONS
4.3.1
Oral Candidiasis – if asymptomatic, recommend clotrimazole troches.  If 
symptomatic, recommend oral fluconazole.  
4.3.2
Esophageal Candidiasis – recommend oral fluconazole, but if no response, 


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41
consider itraconazole, amphotericin B.
4.3.3
Aspergillosis, scedosporiosis and other invasive fungal infections infection may 
present as meningitis, pneumonia, or fungemia.  Treatment decisions will be made 
in concert with infectious disease consultants, and may include the use of agents 
such as voriconazole, liposomal amphotericin B, or other novel agents as the 
clinical presentation requires. 
4.4
MYCOBACTERIAL DISEASES
4.4.1
Mycobacterium tuberculosis – Inactive versus active infection must be 
distinguished.  In patients with low CD4+ counts, 2/3’s present with 
extrapulmonary disease.  Diagnosis may require biopsies in addition to culture.  
There is a high incidence of drug resistant strains.  Consultation with the 
infectious disease service is mandatory for these patients.  Combination therapy 
with isoniazid, rifampin, pyrazinamide, ethambutol and pyridoxine (vitamin B6) 
is usually initiated.  These drugs may cause hepatitis, bone marrow suppression, 
optic neuritis and peripheral neuropathy. Careful monitoring of toxicities is 
required if these drugs are given concomitantly with HAART and/or with high-
dose methotrexate.
4.4.2
Mycobacterium avium complex usually occurs in patients with CD4+ count 
<100/mm3.  Disseminated infection presents with fever, weight loss, night sweats, 
diarrhea, anemia, neutropenia, and thus may be difficult to differentiate from “B” 
symptoms.  Sputum and blood cultures should be obtained. Clarithromycin or 
azithromycin in combination with clofazimine or rifampin are recommended.  
4.5
TOXOPLASMOSIS
Patients with concurrent toxoplasmosis will be treated in concert with infectious disease 
consultation.  In patients receiving high-dose methotrexate, sulfadiazine should not be 
given 48 hours prior to administration of methotrexate administration through completion 
of leucovorin rescue due its effect on renal excretion of methotrexate, (see Section 3.7)
therefore sulfadiazine-sparing regimens are preferred.
4.6
PROPHYLAXIS FOR FEBRILE NEUTROPENIA
See Sections 3.6.4.1 and 3.9.5 for guidelines on use of filgrastim and antibiotics.
4.7
FEBRILE NEUTROPENIA
A life-threatening complication requiring hospitalization and urgent broad-spectrum 
antibiotics.
4.8
ANEMIA
If symptomatic or if the hemoglobin falls below 8 mg/dL, erythropoietin may be 
considered. Red blood cell transfusions are sometimes associated with increased HIV 
replication and opportunistic infections, but if necessary, red blood cell transfusion 
support should be utilized.      
4.9
THROMBOCYTOPENIA 
Should be treated conservatively.  In the absence of bleeding or a planned invasive 


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42
procedure, platelet transfusions should be given for a platelet count below 10,000/mm3.
If invasive procedures (including lumbar puncture) are planned or the patient develops 
bleeding, platelet transfusions should be administered in accordance with standard of 
practice, usually maintaining a platelet count >50,000/mm3.
4.10 CENTRAL VENOUS ACCESS
If peripheral access not feasible for a patient, temporary lines are preferred (removed 
after completion of each infusion) and include: internal jugular line; PICC lines via the 
brachial vein.  Other lines include semi-permanent HICKMAN, GROSHONG catheters 
or medi-port implanted devices.  All devices will have nursing supervision to include 
patient self-care and cleaning/flushing of the devices.
4.11 IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME (IRIS)
IRIS will be defined using AIDS Clinical Trial Group (ACTG) 2009 Criteria, using the 
following criteria: 
4.11.1 Initiation, reintroduction or change in antiretroviral therapy/regimen or therapy 
for opportunistic infections (OI).  
AND
4.11.2 Evidence of:  
4.11.2.1 $QLQFUHDVHLQ&'FHOOFRXQWDVGHILQHGE\FHOOVPPRUD- fold rise 
in CD4+ cell count, and/or   
4.11.2.2 Decrease in the HIV-1 viral load of >0.5 log10 and/or   
4.11.2.3 Weight gain or other investigator-defined signs of clinical improvement in 
response to initiation, reintroduction or change of either antiretroviral 
therapy/regimen or OI therapy.
AND
4.11.2.4 Symptoms and/or signs that are consistent with an infectious or inflammatory 
condition.    
AND
4.11.2.5 These symptoms and/or signs cannot be explained by a newly acquired 
infection, the expected clinical course of a previously recognized infectious 
agent, or the side effects of medications.
AND
4.11.2.6 The infectious/inflammatory condition must be attributable to a specific 
pathogen or condition.
Although ACTG IRIS criteria does not explicitly include CNS IRIS due to EBV-
associated PCNSL, it is biologically likely that a reconstituted immune system 
would react to EBV associated antigens in AIDS-PCNSL.  As such, patients with 
neurologic deterioration on therapy who do not meet criteria for progressive 
lymphoma and have evidence of CNS edema on brain MRI or CT imaging and T-
cells in the central nervous system will be managed for CNS IRIS.


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All patients with IRIS will be managed with appropriate antibiotics, and steroids.  
For CNS IRIS, patients can receive up to 1gram of solumedrol (or equivalent) 
daily for a minimum of 4 days, followed by tapering of steroids.  Protocol therapy 
for AR-PCNSL will not be discontinued due to CNS IRIS, although treatment may 
be delayed to perform diagnostic studies or in cases with Grade 4 Neurotoxicity at 
least possibly attributable to CNS IRIS if the PI or LAI determines that treatment 
delay is clinically indicated to diagnose and treat CNS IRIS.
4.12 NUTRITIONAL ASSESSMENT AND PSYCHOLOGICAL SUPPORT
AR-PCNSL is commonly complicated by malnutrition.  Patients with weight loss or 
evidence of wasting syndrome should have a nutritional consult and nutritional intake 
should be optimized by either enteral or parental means.  All patients on the study will be 
informed of and encouraged to see a NIH Social Worker for evaluation and support.  
5
DATA COLLECTION AND EVALUATION
5.1
DATA COLLECTION
The members of the Retroviral Diseases Section Research Team will collect data.  
The PI will be responsible for overseeing entry of data into C3D, an in-house password 
protected electronic system and ensuring data accuracy, consistency and timeliness. The 
principal investigator, associate investigators/research nurses and/or a contracted data 
manager will assist with the data management efforts.  All data obtained during the 
conduct of the protocol will be kept in secure network drives or in approved alternative 
sites that comply with NIH security standards. Primary and final analyzed data will have 
identifiers so that research data can be attributed to an individual human subject 
participant.
All adverse events, including clinically significant abnormal findings on laboratory 
evaluations, regardless of severity, will be followed until return to baseline or 
stabilization of event. Patients will be followed for adverse events for 30 days after 
removal from study treatment or until off-study, whichever comes first.
An abnormal laboratory value will be recorded in the database as an AE only if the 
laboratory abnormality is characterized by any of the following:
x
Results in discontinuation from the study
x
Is associated with clinical signs or symptoms 
x
Requires treatment or any other therapeutic intervention
x
Is associated with death or another serious adverse event, including 
hospitalization. 
x
Is judged by the Investigator to be of significant clinical impact
x
If any abnormal laboratory result is considered clinically significant, the 
investigator will provide details about the action taken with respect to the test 
drug and about the patient’s outcome.


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End of study procedures: Data will be stored according to HHS, FDA regulations, and 
NIH Intramural Records Retention Schedule as applicable. 
Loss or destruction of data: Should we become aware that a major breach in our plan to 
protect subject confidentiality and trial data has occurred, the IRB will be notified. 
5.2
EXCEPTIONS TO REPORTING
5.2.1
Grade 4 events related to AR-PCNSL or HIV and not to therapy will not require 
reporting.  Examples include:
5.2.1.1 Grade 4 lymphocytopenia
5.2.1.2 Grade 4 CPK
5.2.1.3 Grade 4 hyperuricemia 
5.2.1.4 Grade 4 hyperamylasemia without physiologic correlates of non-pancreatic 
origin. 
5.2.1.5 Since lymphocytopenia is a hallmark of HIV infection and this is highly likely in 
this population of patients, Adverse Event Reporting will not be required for any 
grade lymphocytopenia.
5.2.2
Grade 4 treatment-related events not requiring reporting:
5.2.2.1 Leucopenia
5.2.2.2 Neutropenia
5.2.2.3 Uncomplicated (no microbiologic confirmation of infection) treatment-related 
febrile neutropenia requiring hospitalization. 
5.2.3
Unexpected drug toxicities will be reported to the FDA via MedWatch. 
5.3
RESPONSE CRITERIA
Response criteria are based on published standards for phase II studies of supratentorial 
malignant glioma113 and a modification of the response assessment of aggressive non-
Hodgkin’s lymphoma by integrated international workshop criteria and fluorine-18 –
fluorodeoxyglucose positron emission tomography114, and an international workshop to 
standardize baseline evaluation and response criteria for primary CNS lymphoma 115.
Cross-sectional measurements of tumors will be used to assess baseline and responses.
5.3.1
Complete Response - disappearance of all enhancing lesions on MRI of the brain, 
negative FDG-PET scan persisting for at least 4 weeks in patients who were off 
corticosteroids, negative CSF cytology and neurologically improved from 
baseline.
5.3.2
Complete Response Unconfirmed (CRu) – either a CRu, PR or SD by MRI 
criteria with a completely negative FDG-PET off steroids, and negative CSF 
cytology.  If there is no evidence of progression while off steroids for 4 months, 
response will be reclassified as CR.
5.3.3
Partial Response 
5.3.3.1 A reduction of enhancing tumor volume by more than 50% maintained for at least 
4 weeks, steroids stable or reduced, and neurologically stable or improved with 
positive FDG-PET, or


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5.3.3.2 Normalization of MRI, negative FDG-PET, but with persistent disease by CSF 
cytology.  
5.3.4
Progressive disease - an increase of tumor volume of more than 25% or 
occurrence of new lesions, or neurologically worse, steroids stable or increased.
5.3.5
Stable disease – not meeting the criteria for complete response, partial response,
or progressive disease and with a positive FDG-PET
5.3.6
Treatment failure - progressive or stable disease, relapse after initial response, 
death, or discontinuation of chemotherapy because of complications or because of 
patient’s or Investigator’s decision.  Patients who require radiotherapy will be 
considered treatment failures for purposes of the protocol, regardless of long-term 
outcome.
5.3.7
Substantial brain dysfunction and cognitive problems (as referred to in sections 
1.2.3 and 7.4.4) that will define treatment failure refer to post-treatment recurrent 
brain lymphoma, treatment related functional brain pathology, and/or neurologic 
function class 3 or 4 as defined in Appendix 2: Neurological Function Class.
5.4
TOXICITY CRITERIA
This study will utilize the Common Terminology Criteria for Adverse Events (CTCAE) 
version 3.0.  CTCAE version 3.0 can be downloaded from the CTEP homepage at 
http://ctep.info.nih.gov/ .  All appropriate treatment areas should have access to a copy of 
CTCAE version 3.0.  
6
STATISTICAL CONSIDERATIONS 
6.1.1
Racial/gender make-up
Subjects from both genders and all racial/ethnic groups are eligible for this study if 
they meet the eligibility criteria outlined in section 2.1.  To date, there is no 
information that suggests that differences in drug metabolism or disease response 
would be expected in one group compared to another.  Efforts will be made to extend 
accrual to a representative population, but in this preliminary study, a balance must be 
struck between patient safety considerations and limitations on the number of 
individuals exposed to potentially toxic and/ or ineffective treatments on the one hand, 
and the need to explore gender and ethnic aspects of clinical research on the other 
hand.  If differences in outcome that correlate to gender or to ethnic identity are noted, 
accrual may be expanded or a follow-up study may be written to investigate those 
differences more fully.  As a practical matter, it should be noted as outlined in the 
background section, that the demographics of the AIDS epidemic are shifting in the 
United States.  Currently, the largest growing population is African-American women.  
It is difficult to predict how these changing demographics will affect accrual for this 
particular protocol, but patients from minority populations are disproportionately 
affected by HIV disease and thus efforts to inform minority communities about this 
study will be a priority in the recruitment effort.
6.1.2
Age Exclusion
Children under 18 years of age are excluded from the study.  AR-PCNSL in children is 
extremely rare, and comprises less than 1% of all cases of AR-PCNSL.  For example,


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only 1 child was reported with AR-PCNSL in 1996116. The incidence of vertical 
transmission of HIV in the United States has become extraordinarily low and in 2003, 
147 cases of perinatal HIV infection were documented and only 161 cases of 
HIV/AIDS were diagnosed in those 13 years of age or under117.  The estimated 
number of AIDS cases in this age group was only 59 for 2003.  The study requires 
multiple invasive procedures and is not designed to assess the tolerability of the 
treatments in young children.  However, if the preliminary study results are favorable, 
and pediatric cases with AR-PCNSL otherwise eligible for the study except for age 
criteria come to our attention, if appropriate, the study may be amended after 
discussion with the NCI IRB if the risks and benefits appear to be in favor of including 
children on the study.
6.1.3
Sample Size and Accrual Limits
The primary objective of this study is to preliminarily estimate the magnitude of, and 
determine if there is potentially an acceptable fraction of, patients with primary brain 
lymphoma, who will receive the experimental treatment consisting of HAART with 
high-dose methotrexate-rituximab who are able to survive without recurrent 
lymphoma or severe cognitive problems (as defined by Neurological Function Class 3 
in Appendix 2) for at least two years. 
The goal of this limited size pilot trial is to enroll 15 evaluable patients who receive all 
treatment, including high-dose methotrexate. With conventional treatments, including 
whole brain irradiation, it would be expected that only 25-30% of all such patients 
with this disease would be alive without recurrent brain lymphoma and free of 
cognitive problems at the end of two years (a satisfactory result, but in too small a 
fraction of patients). We believe it quite possible that by using this particular 
chemotherapy, as many as 65% would be alive without recurrent lymphoma and 
without cognitive problems after two years. Sixty five percent is a figure chosen that is 
within range of the outcome expected in high-risk patients with non-AIDS primary 
brain lymphoma treated with high-dose methotrexate based strategies. With 15 
patients, using a one-sided 0.1 alpha level exact test of binomial proportions, there is 
88% power to rule out 30% with a satisfactory result after two years in favor of 65% 
with a satisfactory result. Should the results appear at all promising, even if not to this 
degree, the strategy may be taken to the AIDS Malignancy Consortium to see if they 
are interested in pursuing the idea in a larger, more definitive fashion.  The results of 
this study will be weighed against the best available data from other studies to make a 
reasonable determination as to how to proceed with or modify this approach for further 
development. 
Additionally, up to 10 additional patients who are not eligible to receive high-dose 
methotrexate may be accrued in the “Radiation-sparing Best Available Care” Cohort. 
The patients enrolled in this limited size cohort will be evaluated for the same 
endpoints as in the main cohort receiving high-dose methotrexate, but given the 
limited number of patients who will enroll into this cohort, all analyses in this cohort 
will be considered hypothesis generating and exploratory. Accrual to this cohort will 
close when 15 evaluable patients have been enrolled in the main cohort.


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All secondary endpoints will be evaluated using explorative techniques, and will be 
reported as exploratory, since the study is not designed to address any of these points 
with more than minimal power.
Since part of the treatment strategy is aimed at HIV suppression and immune 
reconstitution, up to 3 patients who are non-adherent with HAART within the first 9 
months of therapy may be replaced.  It can often take up to 9 months to adjust 
medications for purposes of optimizing medication tolerance and adherence to 
antiretroviral therapy.  Patients who are clearly non-adherent and thus are unable to 
maintain an HIV viral load of <5000 copies HIV mRNA/mL plasma and do not have 
an increment in the CD4+ cells to above 75/mm3 by the end of 9 months may be 
replaced.  Patients who maintain lower HIV viral loads but do not have adequate 
immune recovery will not be replaced, and will be considered treatment failures in the 
event of tumor recurrence.  Informal comparison will be made between those who are 
HAART naive at entry and those who are antiretroviral experienced.  
This is a rare condition, and it is expected to take between 6 and 10 years to enroll 15 
patients onto this trial in the main cohort and up to 10 in the cohort not receiving high-
dose methotrexate. Up to three patients may be replaced if during the first 9 months 
they are clearly non-adherent with HAART as described above. Thus an accrual 
ceiling of 28 patients will be used.
7
HUMAN SUBJECTS PROTECTIONS
7.1
RATIONALE FOR SUBJECT SELECTION
7.1.1
AR-PCNSL is a rare disease.  HIV-infected individuals are at increased risk of 
this lymphoma.  The purpose of the study is to investigate therapy that avoids 
late-occurring neurocognitive toxicities associated with WBRT.  Selection of 
individuals with favorable survival prospects from the standpoint of the 
underlying HIV disease is essential in order to study late occurring treatment 
toxicities for this disease.  Therefore, patients who have resistant HIV that cannot 
be suppressed and would therefore not be able to have immunologic recovery 
(thought essential to maintaining the lymphoma in remission), will not be 
appropriate subjects for this trial.  Additionally, up to 3 patients who do not 
adhere to HAART and have high HIV viral loads (see section 6.1.3) without 
immune recovery and have a lymphoma relapse within the first 9 months may be 
replaced as subjects.
7.1.2
Strategies for recruitment will include announcements on the World Wide Web 
(see Appendix 8) as well as letters to referring physicians and AIDS treatment 
bulletins.
7.1.3
Pregnancy is excluded on the basis of the overall toxicity expected from the 
treatment, which would likely threaten fetal viability and potentially increase the 
risk to the mother and the potential teratogenicity of high-dose methotrexate.
7.1.4
Exclusion of patients less than 18 years of age is based on the extreme rarity of 
this disease in children.  Inclusion of children on the study would result in such an 


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insufficient number that it would not be possible to evaluate the therapy relative 
to the purpose of the study.
7.2
PARTICIPATION OF CHILDREN
See section 7.1.4 above.  The standard of care for AR-PCNSL is currently WBRT.  The 
treatments in this protocol have uncertain efficacy, and the risk to very young children 
may be more than minimal while the estimates of benefit are not fully known.  If the 
therapy appears beneficial, a risk/benefit assessment will be made for the potential 
enrollment of children, and if it appears reasonable to do so, consideration for amending 
the protocol for enrollment of children will be made.
7.3
PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT
Adults who are unable to provide initial informed consent are eligible for enrolling in this 
protocol as noted in Section 2.2.1.12. There is also a possibility, though unlikely, that 
subjects who provide initial consent could become decisionally impaired. For this reason 
and because there is a prospect of direct benefit from research participation (section 7.4), 
all subjects will be offered the opportunity to fill in their wishes for research and care, 
and assign a substitute decision maker on the “NIH Advance Directive for Health Care 
and Medical Research Participation” form so that another person can make decisions 
about their medical care in the event that they become incapacitated or cognitively 
impaired during the course of the study. Note: The PI or AI will contact the NIH Ability 
to Consent Assessment Team for evaluation.  For those subjects that become 
incapacitated and do not have pre-determined substitute decision maker, the procedures 
described in MAS Policy 87-4 for appointing a surrogate decision maker for adult 
subjects who are (a) decisionally impaired, and (b) who do not have a legal guardian or 
durable power of attorney, will be followed.
7.4
EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS
7.4.1
The investigational nature and objectives of this trial, the procedures and 
treatments involved and their attendant risks and discomforts, potential benefits, 
and potential alternative therapies will be carefully explained to the patient or the 
patient’s surrogate, and a signed informed consent document will be obtained.
7.4.2
The potential benefit is that the protocol therapy may result in specific control of 
AR-PCNSL in those patients to whom it is administered and potentially avoid the 
late occurring neurotoxic effects associated with WBRT.    
7.4.3
The potential risk is that the protocol therapy may be toxic, and/or be ineffective.  
It is not known whether in AIDS, high-dose methotrexate will cause CNS 
damage, though the limited available data suggests that it does not cause excess 
neurological damage.  The treatment requires up to 6 or more in-patient 
admissions that are likely to last 7 days or longer on each admission.
Additionally, the staging and restaging requirements of the study requires 
frequent, sometimes invasive, evaluations.  Thus, the time commitment and 
potential morbidity associated with tumor biopsy represents a potential risk and 
discomfort to study participants.
7.4.4
Discussion of risks to subjects in relation to anticipated benefits and the 


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importance of the knowledge that may reasonably be expected from the results:  
as outlined in the introduction, the standard of care for AR-PCNSL is predicted to 
cause serious brain dysfunction in patients who survive long enough for late-
occurring radiation neurotoxic effects to manifest.  The median time to cognitive 
decline following WBRT in high risk populations is 12-18 months.  This study is 
aimed at developing a strategy toward long-term remission of AR-PCNSL in part 
through novel relatively non-lymphocytotoxic chemotherapeutic approaches and 
in part through efforts at immune reconstitution. 
7.5
SPECIMEN HANDLING GUIDELINES 
7.5.1
It is understood that per the NCI policy regarding the Requirements for the 
Research Use of Stored Human Specimens and Data, prospective NIH IRB 
approval and continuing IRB oversight must be obtained for research involving 
identified or coded samples or data where investigators can identify the source. 
This policy applies to research protocols where the remaining research activities 
are limited to data analysis and to the subsequent research use of specimens or 
data previously collected under a now terminated protocol.   The following 
guidelines describe how these principles apply to this specific protocol.  
7.5.2
Many samples on this study will be processed and stored in the AIDS Monitoring 
Laboratory (AML) run by Leidos Biomedical Research, Inc. in the NCI-Frederick 
facility located with Fort Detrick.  The samples are stored under code, and the 
information linking these unique codes to the patients is kept on the AML 
database.  The laboratory informatics system conforms to NIH Information 
Technology Security Requirements and NIH Protection of Human Research
Subjects Guidelines.  All laboratory staff is trained to adhere to NIH Information 
Technology Security Requirements and NIH Protection of Human Research 
Subjects Guidelines.  Computers used to access inventory systems require 
username and password for login. The laboratory database is housed in a secure, 
protected environment and backups are performed routinely.  Access to specimen 
information, clinical data, and stored specimens is limited to approved laboratory 
staff and the investigator in charge of the study (or individuals authorized by the 
investigator).
AIDS Monitoring Laboratory
Leidos Biomedical Research, Inc.
Frederick National Laboratory for Cancer Research
Frederick, MD 21702-1201
Phone: 301-846-5217
7.5.3
The protocol team will inform the AML staff when tests are to be run with the 
specimens, and the samples used for testing will be tracked by the AML.  This 
information will in turn be shared with the protocol team.  The research nurse on 
the study will be in charge of tracking this information for the protocol team.
7.5.4
Some of the specimens are sent to the laboratory of Dr. Denise Whitby, also in the 
Leidos Biomedical Research, Inc. NCI-Frederick facility located with Fort 


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Detrick.  The samples sent are coded by the protocol research team and have no 
patient identifiers.  They are logged in by Dr. Whitby’s laboratory and kept in a 
locked facility.  They are run in batch when enough specimens are collected. 
Records are kept when the specimens are used for analysis. 
7.5.5
Denise Whitby, PhD
Leidos Biomedical Research, Inc.
50 Boyles St, Building 535, Room 428A
Frederick, MD
301-846-5828
7.5.6
A limited number of samples are sent to Dr. Yarchoan’s laboratory.  This is a 
locked laboratory, and a log is kept of the specimens and when they are utilized.  
7.5.7
Robert Yarchoan, MD
Center Drive, Room 5A-25
Bethesda, MD 20892
301-402-3630
7.5.8
Clinical testing of all samples will be one in accordance to the protocol.  The 
protocol team will inform the AML staff when tests are to be run with the 
specimens, and the samples used for testing will be tracked by the AML.  This 
information will in turn be shared with the protocol team.  The research nurse on 
the study will be in charge of tracking this information for the protocol team.
7.5.9
Many routine samples and a sample of the biopsy specimens are sent to the 
Clinical Pathology or Pathology Departments of the NIH Clinical Center.  These 
samples will be handled according to the procedures of these departments.  
7.5.10 If patients have co-enrolled on study 01-C-0038 (Collection of Blood, Bone 
Marrow, Tumor, or Tissue Samples from Patients with HIV Infection, KSHV 
Infection, Viral-related Pre-Malignant Lesions, and/or Cancer), then the samples 
may also be tested under the specifications of that study.  Similarly, if patients 
have co-enrolled on other studies approved by the NCI IRB that call for 
maintaining and testing the samples, then they may be transferred to those studies.
7.5.11 At the termination of the study, if patients have co-enrolled on study 01-C-0038
(Collection of Blood, Bone Marrow, Tumor, or Tissue Samples from Patients 
with HIV Infection, KSHV Infection, Viral-related Pre-Malignant Lesions, and/or 
Cancer), then the samples will be transferred to that study unless the patients 
request that this not occur.  Also, if patients have co-enrolled on other studies 
approved by the NCI IRB that call for maintaining the samples, then they will be 
maintained on those protocols.  Otherwise, the unused samples will be destroyed.
7.5.12 The PI will report any loss or destruction of the samples to the IRB, and any new 
use of the samples, specimens, or data will require prospective IRB approval.
7.6
CONSENT PROCEDURES AND DOCUMENTS
All patients or the appropriate power of attorney for health care will read and sign the 
informed consent document prior to enrollment.  Members of the protocol team will 


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describe the protocol, alternative therapies, and the risks and benefits of each to the 
individual signing the consent. 
7.6.1
Telephone Consent 
Telephone consent may obtained via the following procedure: The informed consent 
document will be sent to the subject.  An explanation of the study will be provided over 
the telephone after the subject has had the opportunity to read the consent form.  The 
subject will sign and date the informed consent. A witness to the subject’s signature will 
sign and date the consent.
The original informed consent document will be sent back to the consenting investigator 
who will sign and date the consent form with the date the consent was obtained 
via 
telephone.  
A fully executed copy will be returned via mail for the subject’s records.
The informed consent process will be documented on a progress note by the consenting 
investigator.
7.6.2
Informed consent of non-English speaking subjects
If there is an unexpected enrollment of a research participant for whom there is no 
translated extant IRB approved consent document, the principal investigator and/or those 
authorized to obtain informed consent will use the Short Form Oral Consent Process as 
described in MAS Policy M77-2, OHSRP SOP 12 and 45 CFR 46.117 (b) (2).  The 
summary that will be used is the English version of the extant IRB approved consent 
document.  Signed copies of both the English version of the consent and the translated 
short form will be given to the subject or their legally authorized representative and the 
signed original will be filed in the medical record.
Unless the PI is fluent in the prospective subject’s language, an interpreter will be present 
to facilitate the conversation (using either the long-translated form or the short form). 
Preferably someone who is independent of the subject (i.e., not a family member) will 
assist in presenting information and obtaining consent. Whenever possible, interpreters 
will be provided copies of the relevant consent documents well before the consent 
conversation with the subject (24 to 48 hours if possible). 
We request prospective IRB approval of the use of the short form process for non-English 
speaking subjects and will notify the IRB at the time of continuing review of the 
frequency of the use of the Short Form.
8
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY 
MONITORING PLAN
Adverse events while on-treatment and for 30-days after the last dose of therapy will be 
reported to the NCI IRB according to the guidelines below.  All serious adverse events 
occurring while on study will be reported as outlined in section 8.2.1. Since all therapy 
will be standard, commercially available therapy, data will not be reported to other 
organizations.  The Principal Investigator will be responsible for data safety monitoring.


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8.1
DEFINITIONS
8.1.1
Adverse Event
Any untoward medical occurrence in a human subject, including any abnormal sign (for 
example, abnormal physical exam or laboratory finding), symptom, or disease, 
temporally associated with the subject’s participation in research, whether or not 
considered related to the subject’s participation in the research. 
8.1.2
Suspected adverse reaction
Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety 
reporting, ‘reasonable possibility’ means there is evidence to suggest a causal relationship 
between the drug and the adverse event. A suspected adverse reaction implies a lesser 
degree of certainty about causality than adverse reaction, which means any adverse event 
caused by a drug.
8.1.3
Unexpected adverse reaction
An adverse event or suspected adverse reaction is considered “unexpected” if it is not 
listed in the investigator brochure or is not listed at the specificity or severity that has 
been observed; or, if an investigator brochure is not required or available, is not 
consistent with the risk information described in the general investigational plan or 
elsewhere in the current application. "Unexpected” also refers to adverse events or 
suspected adverse reactions that are mentioned in the investigator brochure as occurring 
with a class of drugs or as anticipated from the pharmacological properties of the drug, 
but are not specifically mentioned as occurring with the particular drug under 
investigation.
8.1.4
Serious
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a 
Serious Adverse Event or if it compromises the safety, welfare or rights of subjects or 
others.
8.1.5
Serious Adverse Event
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following:
x Death,
x A life-threatening adverse drug experience
x Inpatient hospitalization or prolongation of existing hospitalization
x Persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions
x A congenital anomaly/birth defect.
x Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse drug experience 
when, based upon appropriate medical judgment, they may jeopardize the patient 


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or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.
8.1.6
Disability
A substantial disruption of a person’s ability to conduct normal life functions.
8.1.7
Life-threatening adverse drug experience
Any adverse event or suspected adverse reaction that places the patient or subject, in the 
view of the investigator or sponsor, at immediate risk of death from the reaction as it 
occurred, i.e., it does not include a reaction that had it occurred in a more severe form, 
might have caused death.
8.1.8
Protocol Deviation (NIH Definition)
Any change, divergence, or departure from the IRB-approved research protocol.
8.1.9
Non-compliance (NIH Definition)
The failure to comply with applicable NIH Human Research Protections Program 
(HRPP) policies, IRB requirements, or regulatory requirements for the protection of 
human research subjects.
8.1.10 Unanticipated Problem
Any incident, experience, or outcome that:
x Is unexpected in terms of nature, severity, or frequency in relation to 
(a) the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure or other study documents, 
and
(b) the characteristics of the subject population being studied; AND
x Is related or possibly related to participation in the research; AND
x Suggests that research places subjects or others at a greater risk of harm
(including physical, psychological, economic, or social harm) than was previously 
known or recognized.
8.2
NCI-IRB AND CLINICAL DIRECTOR REPORTING
8.2.1
NCI-IRB and NCI CD Expedited Reporting of Unanticipated Problems and 
Deaths
The Protocol PI will report in the NIH Problem Form to the NCI-IRB and NCI Clinical 
Director:
x All deaths, except deaths due to progressive disease 
x All Protocol Deviations
x All Unanticipated Problems
x All non-compliance


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As noted in section 8, this reporting applies to events while on-treatment and for 30-days 
after the last dose of therapy.  Reports must be received within 7 days of PI awareness via 
iRIS.
8.2.2
NCI-IRB Requirements for PI Reporting at Continuing Review
The protocol PI will report to the NCI-IRB: 
1. A summary of all protocol deviations in a tabular format to include the date the 
deviation occurred, a brief description of the deviation and any corrective action.
2. A summary of any instances of non-compliance
3. A tabular summary of the following adverse events:
x
All Grade 2 unexpected events that are possibly, probably or definitely 
related to the research; 
x
All Grade 3 and 4 events that are possibly, probably or definitely related to the 
research; 
x
All Grade 5 events regardless of attribution; 
x
All Serious Events regardless of attribution. 
NOTE: Grade 1 events are not required to be reported. Also, as noted in section 8,
reporting is required only for events while on-treatment and for 30-days after the last 
dose of therapy.  
9
PHARMACEUTICAL INFORMATION
9.1
RITUXIMAB
9.1.1
Source:  rituximab will be purchased by the NIH Clinical Center Pharmacy 
Department from commercial sources.  
9.1.2
Toxicity:
9.1.2.1 Hypersensitivity Reaction
9.1.2.2 Angioedema
9.1.2.3 Bronchospasm
9.1.2.4 Hypotension
9.1.2.5 Cardiac arrhythmia
9.1.2.6 Rash
9.1.2.7 Headache
9.1.2.8 Pruritus
9.1.2.9 Fatigue
9.1.2.10 Severe infusion reaction
9.1.2.11 Fatal reactions within 24 hours after administration
9.1.2.12 80% of fatal infusion reactions occurred in association with the first infusion
9.1.2.13 After an infusion reaction complex including 1 or more:
9.1.2.14 Hypoxia


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9.1.2.15 Pulmonary infiltrates
9.1.2.16 Acute respiratory distress syndrome
9.1.2.17 Myocardial infarction
9.1.2.18 Ventricular fibrillation
9.1.2.19 Cardiogenic shock 
9.1.2.20 Severe Mucocutaneous Reactions, some with fatal outcome
9.1.2.21 Constitutional symptoms  
9.1.2.22 Fever
9.1.2.23 Chills
9.1.2.24 Infection
9.1.2.25 Asthenia
9.1.2.26 Headache
9.1.2.27 Abdominal Pain
9.1.2.28 Pain
9.1.2.29 Back Pain
9.1.2.30 Throat Irritation
9.1.2.31 Flushing
9.1.2.32 Cardiovascular System
9.1.2.33 Hypotension
9.1.2.34 Hypertension
9.1.2.35 Digestive System
9.1.2.36 Nausea
9.1.2.37 Diarrhea
9.1.2.38 Vomiting
9.1.2.39 Hematologic and Lymphatic System
9.1.2.40 Lymphopenia
9.1.2.41 Leukopenia
9.1.2.42 Neutropenia
9.1.2.43 Thrombocytopenia
9.1.2.44 Anemia
9.1.2.45 Metabolic and Nutritional Disorders
9.1.2.46 Angioedema
9.1.2.47 Hyperglycemia
9.1.2.48 Peripheral Edema
9.1.2.49 LDH Increase
9.1.2.50 Musculoskeletal System
9.1.2.51 Myalgia
9.1.2.52 Arthralgia


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9.1.2.53 Nervous System
9.1.2.54 Dizziness
9.1.2.55 Anxiety
9.1.2.56 Respiratory System
9.1.2.57 Increased Cough
9.1.2.58 Rhinitis
9.1.2.59 Bronchospasm
9.1.2.60 Dyspnea
9.1.2.61 Sinusitis
9.1.2.62 Skin and Appendages
9.1.2.63 Night Sweats
9.1.2.64 Rash
9.1.2.65 Pruritus
9.1.2.66 Urticaria
9.1.3
Formulation and Preparation
9.1.3.1 How Supplied
9.1.3.1.1 RITUXAN® (Rituximab) is supplied as 100 mg and 500 mg of sterile, 
preservative-free, single-use vials.
9.1.3.1.2 Single unit 100 mg carton: Contains one 10 mL vial of RITUXAN (10 
mg/mL). (NDC 50242-051-21)
9.1.3.1.3 Single unit 500 mg carton: Contains one 50 mL vial of RITUXAN (10 
mg/mL). (NDC 50242-053-06)
9.1.3.2 Mixing and Dilution:
9.1.3.2.1 Use appropriate aseptic technique. Withdraw an amount of rituximab 
appropriate for a patient’s dose and dilute it to a final concentration of 
2 mg/mL in an infusion bag containing either 0.9% Sodium Chloride Injection, 
USP, or 5% Dextrose Injection, USP. Gently invert the bag to mix the solution. 
Discard any unused portion left in the vial. Parenteral drug products should be 
inspected visually for particulate matter and discoloration prior to 
administration.
9.1.4
Stability and Storage
9.1.4.1 Rituximab solutions for infusion may be stored at 2°—8°C (35.6°—46.4°F) for 
24 hours. Rituximab solutions for infusion have been shown to be stable for an 
additional 24 hours at room temperature after storage for up to 24 hours under 
refrigeration. However, since rituximab solutions do not contain a preservative, 
diluted solutions should be stored refrigerated (2°—8°C). No incompatibilities 
between rituximab and polyvinylchloride or polyethylene bags have been 
observed. 
9.1.4.2 Intact vials should be stored at 2°—8°C (36°—46°F). Do not use beyond the 
labeled expiration date. Rituximab vials should be stored in the original 


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packaging carton, protected from direct sunlight. 
9.1.5
Administration Procedures
9.1.5.1 DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS.
9.1.5.2 Since transient hypotension may occur during rituximab infusion, consideration 
should be given to withholding antihypertensive medications 12 hours prior to 
rituximab infusion, and on the day of rituximab administration.
9.1.5.3 First Infusion
9.1.5.3.1 The rituximab solution for infusion should be administered intravenously at an 
initial rate of 50 mg/h (25 mL/h). Rituximab should not be mixed or diluted 
with other drugs. If hypersensitivity or infusion reactions do not occur, escalate 
the infusion rate in 50 mg/h (25 mL/h) increments every 30 minutes, to a 
maximum of 400 mg/h (200 mL/h). If hypersensitivity (non-IgE-mediated) or 
an infusion reaction develops, the infusion should be temporarily slowed or 
interrupted. The infusion can continue at one-half the previous rate upon 
improvement of patient symptoms.”
9.1.5.4 Subsequent Infusions
9.1.5.4.1 If the patient tolerated the first infusion well, subsequent rituximab infusions 
can be administered at an initial rate of 100 mg/h (50 mL/h), and increased by 
100 mg/h (50 mL/h) increments at 30-minute intervals, to a maximum of 400 
mg/h (200 mL/h) as tolerated. If the patient did not tolerate the first infusion 
well, follow the guidelines under First Infusion.
9.2
METHOTREXATE 
9.2.1
Source: Preservative-free methotrexate will be purchased by the NIH Clinical 
Center Pharmacy Department from commercial sources.  
9.2.2
Formulation: Methotrexate Injection, USP, is available in single-dose vials 
containing 50, 100, 200, 250, or 1000 mg of sterile, isotonic, preservative-free 
methotrexate sodium for parenteral administration.
9.2.3
Preparation: Dilute an amount of preservative-free methotrexate appropriate for a 
patient’s dose in (qs.) 1000 mL 5% Dextrose/0.45% Sodium Chloride Injection,
USP, with an amount of sodium bicarbonate equivalent to what is given over 
4 hours in hydration to maintain a patient’s urine pH within the range of 7-8.
9.2.4
Stability: When prepared as described above and stored at room temperature or 
under refrigeration, methotrexate is physically and chemically stable for at least 
24 hours.  
9.2.5
Storage: Store intact vials containing preservative-free methotrexate at controlled 
room temperature 15°–30°C (59°–86°F), and protect methotrexate-containing 
solutions from light. The extent of photodegradation correlates inversely with 
methotrexate concentration and is exacerbated by admixture with sodium 
bicarbonate.  
9.2.6
Administration: 


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9.2.6.1 Pre-hydration: Patients will receive IV hydration with a suitable parenteral fluid 
containing sodium bicarbonate (e.g., 5% Dextrose with 0.45% Sodium Chloride 
Injection + 50-150 P(TVRGLXPELFDUERQDWHWRDONDOLQL]HWKHXULQHWRDS+
EXW,QWUDYHQRXVK\GUDWLRQVKRXOGFRPPHQFHRQ'D\DQGFRQWLQXH at least
until serum methotrexate levels are less than 0.5 mcmol/L.  (See Sections
3.3.3.2.2, 3.3.3.3 and 3.4.3.4.)
9.2.6.2 Methotrexate 6000 mg/m2 will be administered by intravenous infusion over 
4 hours after confirming that the recipient patient’s urine pH is within the range 
 to DQGXULQHRXWSXWLV mL/hour.
9.2.7
Adverse Events: 
9.2.7.1 Hematologic: Leukopenia, thrombocytopenia, agranulocytosis, eosinophilia, and 
megaloblastic anemia. Other rarely reported hematologic adverse events, 
include: aplastic anemia, lymphadenopathy, lymphoproliferative disorders, and 
hypogammaglobulinemia.  
9.2.7.2 Cardiovascular: Pericarditis, pericardial effusion, hypotension, and 
thromboembolic events (arterial thrombosis, DVT, retinal vein thrombosis, 
thrombophlebitis, and pulmonary embolism) have occurred with the use of 
methotrexate. 
9.2.7.3 Central Nervous System: Headache, drowsiness, aphasia, paresis, blurred vision, 
transient blindness, dysarthria, hemiparesis and convulsions. A transient, acute 
neurologic syndrome was observed 6 days after a second or third weekly 
treatment with methotrexate 8000–9000 mg/m2 IV over 4 hours, followed by 
leucovorin rescue. The most common findings were behavioral abnormalities, 
focal sensorimotor signs, and abnormal reflexes, and may be accompanied by 
seizure activity.  Leukoencephalopathy has been associated with intravenous 
administration of methotrexate in patients who received craniospinal irradiation. 
Demyelinating  leukoencephalopathy may occur many months to years after 
onset of therapy, and is characterized by dementia, ataxia, spasticity, seizures, 
and coma. Its incidence is further increased in patients who received cranial 
irradiation therapy plus intrathecal methotrexate therapy and varies directly with 
the amount of methotrexate administered. 
9.2.7.4 Gastrointestinal: Gingivitis, pharyngitis, anorexia, ulcerative stomatitis, diarrhea, 
hematemesis, melena, and GI bleeding or ulceration. Nausea and vomiting are 
observed in approximately 25% of patients treated with high-dose therapy.  
Mucositis, characterized by mouth soreness, stomatitis, or diarrhea has been 
reported with methotrexate therapy. Mucositis usually occurs 7–14 days after 
therapy and lasts 4–7 days.  
9.2.7.5 Genitourinary:  Defective oogenesis or spermatogenesis, transient oligospermia, 
menstrual dysfunction, vaginal discharge, gynecomastia, abortion, fetal defects, 
fetal death and infertility. Nephrotoxicity occurs when the concentration of 
excreted methotrexate and its metabolites exceed their solubility in the renal 
tubules. Methotrexate precipitation in the renal tubules produces obstructive 
renal failure. The concentration threshold at which methotrexate precipitates is 
approximately 1 mg/mL at a urine pH of 5.7 and 10 mg/mL at a urine pH of 6.9.  
Therefore, patients will receive IV hydration containing sodium bicarbonate to 


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alkalinize the urine to a pH 7.0.  Methotrexate therapy has been associated with 
azotemia, cystitis, severe nephropathy, and hematuria. Increased BUN and 
serum creatinine have also been reported with methotrexate and may indicate 
nephrotoxicity 
9.2.7.6 Hepatic: Increased serum transaminases, LDH, alkaline phosphatase, and 
bilirubin may indicate drug induced liver dysfunction.  Hepatitis from high dose 
therapy is uncommon and is associated with prolonged and high serum 
methotrexate concentrations.  
9.2.7.7 Dermatologic: Erythematous rashes, pruritus, urticaria, photosensitivity, 
pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis, 
erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, 
skin necrosis, and exfoliative dermatitis, acral erythema, nail hyperpigmentation 
and acute paronychia, methotrexate-induced solar and thermal burn reactivation, 
radiation recall dermatitis, toxic epidermal necrolysis have been reported. 
9.2.7.8 Hypersensitivity: Anaphylactic reactions with rash, periorbital edema and pruritus 
have been reported with both initial and repeated exposure to methotrexate 
9.2.8
Methotrexate is categorized as a HAZARDOUS DRUG at the NIH Clinical 
Center.  
9.2.9
Drug Interactions:  Methotrexate should not be given concurrently with non-
steroidal anti-inflammatory drugs, or with penicillins, cephalosporins, salicylates, 
sulfonamides, and other acidic drugs that compete with methotrexate for renal 
excretion. Other folate inhibitors (e.g., trimethoprim, pyrimethamine) may 
interfere with assays for methotrexate in body fluids and should be avoided when 
possible.  Methotrexate toxicity has been reported in several patients taking a 
variety of penicillins (amoxicillin, mezlocillin, piperacillin, penicillin). See 
Section 3.9.7 for a list of potentially interacting drugs that should be avoided 
during administration of high-dose methotrexate and leucovorin rescue. 
Methotrexate is eliminated by the kidney through both tubular secretion and 
glomerular filtration. Consequently, penicillins decrease methotrexate renal 
clearance due to competition for tubular secretion and potentially may enhance 
methotrexate toxicity.  Tissue culture and animal studies have demonstrated that 
the administration of asparaginase immediately prior to or concurrently with 
methotrexate can diminish or abolish methotrexate antineoplastic activity. The 
effect persists as long as plasma asparagine levels are suppressed.  Concomitant 
aspirin and methotrexate therapy has been reported to result in increased 
methotrexate toxicity (leukopenia, thrombocytopenia, anemia, nephrotoxicity, 
mucosal ulcerations). Methotrexate, its 7-hydroxy metabolite, and salicylates 
compete for renal tubular secretion. The effect of aspirin is to decrease the rate of 
methotrexate clearance, prolonging systemic exposure to toxic concentrations of 
the drug and its metabolites. Patients receiving methotrexate should not receive 
salicylates.  Cholestyramine may enhance the nonrenal elimination of 
methotrexate by binding methotrexate in the gut, thus decreasing the amount 
available for reabsorption; i.e., interrupting its enterohepatic circulation.  Oral 
antibiotics such as chloramphenicol may decrease intestinal absorption of 
methotrexate or interfere with enterohepatic circulation by inhibiting bowel flora 


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and suppressing metabolism of the drug by enteric bacteria Coadministered 
cotrimoxazole (trimethoprim/sulfamethoxazole) may increase methotrexate 
toxicity, often manifesting as myelotoxicity and pancytopenia. The mechanism of 
this interaction is thought to be additive inhibition of dihydrofolate reductase by 
methotrexate and trimethoprim.  In addition, sulfamethoxazole may increase free 
serum levels of methotrexate by displacement of methotrexate from plasma 
protein binding sites or decreased renal tubular elimination. Concomitant 
administration of methotrexate and cyclosporine may interfere with the 
elimination of both drugs, resulting in increased blood concentrations of both 
drugs and increased toxicity.  Use of NSAIDs (including diclofenac, ibuprofen, 
indomethacin, ketoprofen, naproxen, sulindac, tolmetin), with methotrexate has 
been shown to delay methotrexate elimination and increase the potential for 
methotrexate toxicities (leukopenia, thrombocytopenia, anemia, nephrotoxicity, 
mucosal ulcerations). In case reports, deaths have resulted from severe 
hematologic and gastrointestinal toxicity. Preexisting renal dysfunction and 
NSAID-induced renal dysfunction also increases the risk of adverse reactions. 
Live virus vaccines (e.g., vaccinia, rotavirus) and bacterial vaccines should not be 
administered to patients whose immunity is suppressed by chemotherapeutic 
agents. Administration to immune compromised patients has resulted in severe 
and fatal infections. In patients whose immunity is suppressed only by 
chemotherapy treatment, at least three months should elapse between the 
discontinuation of chemotherapy and vaccination with a live vaccine.  
Concomitant administration of oral mercaptopurine 75 mg/m2 and oral 
methotrexate 20 mg/m2 resulted in significantly increased mercaptopurine AUC 
and peak serum levels (31% and 26%, respectively).  One case report describes a 
patient who experienced elevated methotrexate levels for several days. 
Methotrexate levels rapidly declined after omeprazole was discontinued, which 
suggests that omeprazole may inhibit H+-, K+-ATPase in the kidney, thereby 
blocking active methotrexate secretion in the kidney. Omeprazole may have to be 
temporarily discontinued after methotrexate administration to avoid the potential 
for methotrexate toxicity.  Increased phenytoin elimination has been reported with 
high-dose methotrexate. In addition, methotrexate is partially bound to serum 
albumin, and methotrexate toxicity (myelotoxicity, pancytopenia, megaloblastic 
anemia) may be increased because of displacement by phenytoin.  Concomitant 
use of methotrexate and probenecid reduces methotrexate renal clearance by 
interfering with tubular secretion in the proximal tubule and greatly increases 
serum methotrexate levels, thus increasing the risk of toxicities from methotrexate 
(leukopenia, thrombocytopenia, anemia, nephrotoxicity, mucosal ulcerations).  
Coadministration of pyrimethamine with methotrexate may increase the risk of 
bone marrow suppression. In addition, pyrimethamine has been shown to cross-
react with methotrexate in the TDX (FPIA) assay used by the Clinical Pathology 
Dept.  Sulfonamides may increase free serum levels of methotrexate by displacing 
of methotrexate from plasma protein binding sites or decreasing methotrexate 
excretion by the renal tubules.  Oral antibiotics such as tetracycline may decrease 
intestinal absorption of methotrexate or interfere with enterohepatic circulation by 
inhibiting bowel flora and suppressing metabolism of the drug by enteric bacteria.  


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Methotrexate may decrease the clearance of theophylline. A pharmacokinetic 
study in steroid dependent asthma patients demonstrated that concurrent use of 
methotrexate intramuscularly and oral theophylline resulted in a 19% decrease in 
theophylline clearance presumably by decreasing theophylline metabolism in the 
liver.  Trimethoprim: see the statements for “cotrimoxazole” and 
“pyrimethamine”, above.  
9.3
LEUCOVORIN CALCIUM 
9.3.1
Source: Leucovorin calcium will be purchased by the NIH Clinical Center 
Pharmacy Department from commercial sources.  
9.3.2
Formulations 
9.3.2.1 Parenteral Leucovorin Calcium for Injection is a sterile product indicated for 
intramuscular or intravenous administration, and is supplied in vials containing 
50 mg, 100 mg, 200 mg, or 350 mg leucovorin calcium. Each milligram of 
leucovorin calcium contains leucovorin 0.002 mmol and calcium 0.002 mmol 
(0.004 mEq). 
9.3.2.2 Leucovorin calcium oral tablets: Leucovorin Calcium Tablets, USP, contain either 
5 mg or 25 mg leucovorin as the calcium salt, equivalent to either 5.40 mg or 
27.01 mg of anhydrous leucovorin calcium, respectively. Each tablet also 
contains the following excipients: microcrystalline cellulose, corn starch, 
croscarmellose sodium, povidone, colloidal silicon dioxide, and magnesium 
stearate. The 25-mg tablets also contain D&C yellow #10 (product label dated 
08/1999; Roxane Laboratories, Inc., Columbus, OH).  
9.3.3
Preparation 
9.3.3.1 Parenteral leucovorin calcium: Reconstitute leucovorin calcium with SWFI, as 
follows:
Amount of 
Leucovorin Calcium 
per Vial
Volume of Diluent per Vial
Concentration After 
Reconstitution
50 mg
5 mL
10 mg/mL
100 mg
10 mL
200 mg
20 mL
350 mg
17.5 mL
20 mg/mL
9.3.3.2 An amount of leucovorin appropriate for a patient’s dose will be further diluted in 
25 mL 0.9%NS or D5W for clinical use.  
9.3.4
Stability 
9.3.4.1 Parenteral leucovorin calcium: Leucovorin calcium 10 mg/mL in SWFI stored at 
4°C and 25°C is stable for 7 days.  
9.3.4.2 Leucovorin calcium oral tablets: Bottles containing leucovorin tablets are stable 
until the manufacturer’s expiration date if they are maintained under the 


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recommended storage conditions. 
9.3.5
Storage 
9.3.5.1 Parenteral leucovorin calcium: Store at 25°C (77° F), protected from light.  
9.3.5.2 Leucovorin calcium oral tablets: Store at 15°–30°C (59°–86°F) and protect the 
product from light and moisture.  
9.3.6
Administration
9.3.6.1 Oral absorption of leucovorin is saturable at doses >25 mg. The apparent oral 
bioavailability of leucovorin was 97% for 25 mg, 75% for 50 mg and 37% for 
100 mg administered orally.  
9.3.6.2 Leucovorin calcium doses will be administered orally or by short IV infusion over 
15 minutes.  Because of its calcium content, leucovorin calcium should not be 
administered intravenously at a rate >160 mg/minute.  
9.3.7
Adverse Events: Allergic sensitization, including anaphylactoid reactions and 
urticaria, has been reported following administration of both oral and parenteral 
leucovorin. Anaphylactic reactions, including shock, have been reported.  
Seizures and syncope have been reported rarely in patients with cancer who 
received leucovorin, usually during concomitant treatment with a 
fluoropyrimidine. 
9.3.8
Drug Interactions: Capecitabine: see the statement for “fluorouracil”, below. 
Leucovorin increases the concentration of fluorouracil and enhances its toxicity. 
The pharmacodynamics effects of fluorouracil are enhanced by leucovorin
coadministration, including a predisposition to increased toxicity 
(granulocytopenia, anemia, thrombocytopenia, stomatitis, vomiting) 
Fosphenytoin: see the statement for “phenytoin”, below.  Leucovorin can 
counteract the therapeutic effect of folic acid antagonists, including methotrexate.  
Folic acid (dihydrofolate) may counteract the anticonvulsant effect of 
phenobarbital resulting in increased seizure frequency.  Folic acid (dihydrofolate) 
may counteract the anticonvulsant effect of phenytoin resulting in decreased 
phenytoin levels and increased seizure frequency in some patients.  Folic acid 
(dihydrofolate) may counteract the anticonvulsant effect of primidone.  
9.4
LEVOLEUCOVORIN CALCIUM PENTAHYDRATE
9.4.1
Source: Levoleucovorin calcium pentahydrate will be purchased by the NIH 
Clinical Center Pharmacy Department from commercial sources.  
9.4.2
Formulation: Parenteral levoleucovorin calcium pentahydrate for Injection (Brand 
name Fusilev®, Spectrum Pharmaceuticals) is a sterile product indicated for 
intravenous administration, and is supplied in vials containing 64 mg 
levoleucovorin calcium pentahydrate (equivalent to 50 mg levoleucovorin ) and 
50 mg mannitol.  
9.4.3
Preparation: Parenteral levoleucovorin calcium pentahydrate : Prior to intravenous 
injection, the 50 mg vial of Fusilev for Injection is reconstituted with 5.3 mL of 
0.9% Sodium Chloride Injection, USP to yield a levoleucovorin concentration of 
10 mg per mL. Reconstitution with Sodium Chloride solutions with preservatives 


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(e.g. benzyl alcohol) has not been studied. The use of solutions other than 0.9% 
Sodium Chloride Injection, USP is not recommended.
9.4.4
Stability: After reconstitution, levoleucovorin solutions may be further diluted, 
immediately, to concentrations of 0.5 mg/mL to 5 mg/mL in 0.9% Sodium 
Chloride Injection, USP or 5% Dextrose Injection, USP. Initial reconstitution or 
further dilution using 0.9% Sodium Chloride Injection, USP may be held at room 
temperature for not more than a total of 12 hours. 
9.4.5
Storage: Store at 25° C (77 °F) in carton until contents are used. Excursions 
permitted from 15-30° C (59-86 °F). [See USP Controlled Room Temperature]. 
Protect from light.
9.4.6
Administration: Levoleucovorin calcium doses will be administered by short IV 
infusion over 15 minutes.  Because of its calcium content, leucovorin calcium 
should be administered intravenously at a rate NOT GREATER THAN 160 mg of 
levoleucovorin per minute.  
9.4.7
Adverse Events: Allergic sensitization, including anaphylactoid reactions and 
urticaria, has been reported following administration of parenteral leucovorin. 
Gastrointestinal adverse reactions, including stomatitis, nausea, and vomiting 
have also been reported.
9.4.8
Drug Interactions:
9.4.8.1 Capecitabine: see the statement for “fluorouracil”, below. 
9.4.8.2 Leucovorin increases the concentration of fluorouracil and enhances its toxicity. 
The pharmacodynamics effects of fluorouracil are enhanced by leucovorin 
coadministration, including a predisposition to increased toxicity 
(granulocytopenia, anemia, thrombocytopenia, stomatitis, vomiting)
9.4.8.3 Fosphenytoin: see the statement for “phenytoin”, below.
9.4.8.4 Leucovorin can counteract the therapeutic effect of folic acid antagonists, 
including methotrexate.
9.4.8.5 Folic acid (dihydrofolate) may counteract the anticonvulsant effect of 
phenobarbital resulting in increased seizure frequency.
9.4.8.6 Folic acid (dihydrofolate) may counteract the anticonvulsant effect of phenytoin 
resulting in decreased phenytoin levels and increased seizure frequency in some 
patients.
9.4.8.7 Folic acid (dihydrofolate) may counteract the anticonvulsant effect of primidone.  
9.5
GLUCARPIDASE
9.5.1
Source: On January 17, 2012, glucarpidase (brand name Voraxaze®) was 
approved by FDA for the treatment of toxic plasma methotrexate concentrations 
(>1 mcmole per liter) in patients with delayed methotrexate clearance due to 
impaired renal function.  Glucarpidase is commercially available for intravenous 
use under the brand name, Voraxaze®. Glucarpidase will be purchased by the 
NIH Clinical Center Pharmacy Department from commercial sources.  
9.5.2
Formulation: Parenteral glucarpidase for Injection (Brand name Voraxaze®, BTG 


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International Inc.) is a sterile, preservative-free white lyophilized powder. Each  
individually packaged vial contains 1,000 Units of glucarpidase, lactose 
monohydrate (10 mg), Tris-HCl (0.6 mg) and zinc acetate dihydrate (0.002 mg). 
The individually packaged glass vial is closed with bromo butyl elastomerase 
stopper and blue flip-off seal. NDC 50633-210-11
9.5.3
Preparation: Prior to intravenous injection, reconstitute the contents of 1 vial 
glucarpidase 1,000 Units with 1 mL of 0.9% sterile Sodium Chloride Injection, 
USP. Roll and tilt the vial gently to mix, do not shake. Inspect the vial and discard 
if the solution is not clear, colorless, and free of particulate matter.
9.5.4
Stability: After reconstitution, use reconstituted glucarpidase immediately or store 
under refrigeration at 36° to 46°F (2° to 8°C) for up to 4 hours if not used 
immediately. Glucarpidase contains no preservative and is supplied as a single-
use vial. Discard any unused product. 
9.5.5
Storage: Store glucarpidase (Voraxaze®) at 36°F to 46°F (2°C to 8°C). Do not 
freeze. Do not use glucarpidase after the expiration date on the vial.
9.5.6
Administration: Glucarpidase will be administered by a short IV infusion over 5 
minutes.  Flush intravenous line before and after glucarpidase administration with 
0.9% Sodium Chloride Injection. Continue to administer leucovorin or 
levoleucovorin after glucarpidase. Do not administer leucovorin or levoleucovorin 
within 2 hours before or after a dose of glucarpidase because leucovorin is a 
substrate for glucarpidase.
9.5.7
Adverse Events: Allergic sensitization, including anaphylactoid reactions may 
occur. The most common adverse reactions (incidence >1%) with glucarpidase 
include paraesthesias, flushing, nausea and/or vomiting, hypotension, and 
headache. 
9.5.8
Drug Interactions: Leucovorin is a substrate for glucarpidase. Do not administer 
leucovorin within 2 hours before or after a dose of glucarpidase. Beyond 2 hours, 
no dose adjustment is recommended for continuing a leucovorin regimen, because 
the leucovorin dose is based on the patient’s pre-glucarpidase serum methotrexate 
concentration. Other potential exogenous substrates of glucarpidase may include 
reduced folates and folate antimetabolites.
9.6
FILGRASTIM 
9.6.1
Source: Filgrastim will be purchased by the NIH Clinical Center Pharmacy 
Department from commercial sources.  
9.6.2
Formulation: Filgrastim is a single chain, nonglycosylated, 175-amino acid 
polypeptide recombinant (human) Granulocyte-Colony Stimulating Factor, 
expressed by Escherichia coli, marketed as Neupogen® (Amgen, Inc., Thousand 
Oaks, CA). Specific activity = 1 x 108 U/mg of protein. Fifty Units is defined as 
the amount required for 50% of maximal stimulation of colony formation by 
normal marrow cells.  The drug product is a clear, colorless, preservative-free 
solution for parenteral injection in 2 mL capacity single-use vials. Each vial 
contains 300 mcg/mL or 480 mcg/1.6 mL. Each milliliter also contains acetate 


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0.59 mg/mL, mannitol 50 mg/mL, TWEEN 80 0.004%, sodium 0.035 mg/mL, 
and water for injection, USP, qs. 1 mL. Product pH = 4.0. 
9.6.3
Stability: When refrigerated (2°–8°C or 35.6°–46.4°C), intact vials are stable for 
at least two years after manufacture. Avoid shaking the vials.  Filgrastim 
aggregates when frozen (–4°C; 20°F) and when held at temperatures >30°C 
(>86°F); therefore, it should not be exposed to temperatures exceeding those 
extremes. When maintained between 9°–30°C (47°–86°F), the drug product is 
stable and safe to use for up to 24 hours provided that the solution remains clear 
(not cloudy) and contains no particulate matter.  
9.6.4
Storage: Intact vials should be stored under refrigeration. Do not allow the 
product to freeze. 
9.6.5
Administration: Filgrastim is suitable for subcutaneous or direct IV injection. 
Filgrastim may be administered at doses of 300 – 480 mcg/day subcutaneously 
starting after completion of leucovorin rescue and continuing until the AGC 
PP'RVHDGMXVWPHQWVZLOOEHDOORZHGDVFOLQLFDOO\LQGLFDWHG3DWLHQWV
and/or their caregivers will be instructed how to administer filgrastim 
subcutaneously. 
9.6.6
Adverse Events: The most frequent complication associated with filgrastim use is 
mild-to-moderate bone pain and musculoskeletal pain that occurs during or after 
intravenous or subcutaneous administration. In general, patients characterize bone 
pain as non-specific or specific with distribution to the shoulders, legs, chest, 
lower back, ribs, lumbar spine, and sternum. Symptoms are often described 
during a first course of filgrastim, but there is considerable variation in onset; e.g.,
after the first dose, during growth factor administration, a few hours after 
completing administration (for infusional delivery), or after patients’ granulocyte 
counts normalize. Once and twice-daily administration schedules produce similar 
adverse event profiles, including mild to moderate bone pain, headache, and mild 
fatigue. Bone pain often can be prevented by prophylactic acetaminophen ± 
diphenhydramine administered prior to filgrastim; however, pain can sometimes 
be severe requiring opioid analgesics. Acute fever and neutrophilic dermatosis 
(Sweet syndrome), which is characterized by rapid onset of erythematous and 
tender plaques, fever, and leukocytosis, neutrophilia, sudden onset of asymmetric, 
painful skin lesions and oral mucosa with dense dermal infiltrates of mature 
neutrophils without signs of vasculitis and biopsy-proven cutaneous 
leukocytoclastic vasculitis that usually follows an increase in ANC, subsides after 
ANC decreases, does not recur if ANC was kept <800/mm3, and can be managed 
by reducing filgrastim doses, discontinuing therapy, and use of topical steroids. 
Skin rash and edema are infrequently observed during filgrastim therapy.  
Filgrastim may exacerbate and precipitate psoriasis. Other neutrophilic 
dermatoses associated with filgrastim use include pyoderma gangrenosum, 
neutrophilic eccrine hidradenitis, and single cases of temporally-related lichenoid 
cutaneous reaction at injection sites, and a disseminated eruption characterized by 
the presence of numerous large, atypical histiocytes in the dermis with several 
mitotic figures, mimicking dermal involvement by a malignant process also have 
been reported.  Conjunctival erythema, iridocyclitis scleritis, and migrainous 


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episodes have occurred in patients treated with filgrastim. Iridocyclitis was 
controlled easily with homatropine eye drops. Severe photophobia has been the 
treatment-limiting toxicity with filgrastim doses of 30,000 and 100,000 mcg/m2
per day. All symptoms resolve within 24–48 hours after discontinuing filgrastim.  
Filgrastim has been implicated in exacerbating chemotherapy-induced pulmonary 
toxicity when used in conjunction with bleomycin and cyclophosphamide ± other 
antineoplastics. However, randomized controlled studies have failed to show 
increased pulmonary toxicity when filgrastim accompanied bleomycin therapy 
and it has been suggested that an increase in pulmonary toxicity may be 
attributable to the concomitant use of other antineoplastics.  Increased serum uric 
acid has been observed in patients treated with filgrastim, particularly with high 
doses (30–60 mcg/kg per day). The effect is transient and probably is related to  
increased leukocyte turnover.  Reactivation of various inflammatory disorders 
have been reported following of granulocyte colony-stimulating factors 
administration, including rheumatoid arthritis and pseudogout.  Allergic-type 
reactions have been reported in <1 of 4000 patients treated with filgrastim.  
Reactions tend to occur within the first 30 minutes after administration and appear 
to be more frequent in patients who receive filgrastim by the intravenous route. 
Some reactions occurred on initial exposure. Symptoms recurred in more than 
half the patients who were rechallenged. In most cases, symptoms have rapidly 
resolved after administering antihistamines, steroids, bronchodilators and/or 
epinephrine.  Fever >38°C occurred in eight of 39 patients (21%) who received 
intravenous filgrastim to shorten the duration of chemotherapy-induced 
neutropenia. These patients had no evidence of acute infection. Fever occurred 4–
8 days after initiating daily intravenous filgrastim infusions, which commenced 
three days after intensive chemotherapy. In several patients, fever developed only 
with filgrastim therapy, and not after chemotherapy alone.  Splenic enlargement 
was observed on magnetic resonance imaging in six patients with cyclic 
neutropenia during treatment with filgrastim; however, no clinical symptoms were 
observed, and there were no abnormalities in splenic architecture or blood-cell 
morphology. Splenic enlargement was also reported in two of five patients who 
received filgrastim for congenital agranulocytosis. Spontaneous splenic rupture 
four days after a six-day course of filgrastim was reported in a donor of peripheral 
blood stem cells. Other side-effects that have been associated with filgrastim use 
include pain and paresthesias secondary to submental nerve compression; 
increased leukocyte and serum alkaline phosphatases and LDH; and decreased 
platelet counts which usually are not clinically significant, anemia, epistaxis, 
headache, diarrhea, and cutaneous vasculitis.  


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Abrey LE, Batchelor TT, Ferreri AJ, et al. Report of an international workshop to 
standardize baseline evaluation and response criteria for primary CNS lymphoma. 
J Clin Oncol 2005;23:5034-43.
116.
CDC. HIV/AIDS Surveillance Report. Atlanta: Centers for Disease Control and 
Prevention; 1996 December. Report No.: Volume 8 No. 2.
117.
CDC. HIV/AIDS Surveillance Report. Atlanta: Centers for Disease Control and 
Prevention; 2003. Report No.: Volume 15.


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11 APPENDICES
11.1 APPENDIX 1: FOLSTEIN MINI MENTAL STATUS EXAMINATION


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11.2 APPENDIX 2: NEUROLOGICAL FUNCTION CLASS
1. Able to work and perform normal activities. Neurological findings minor or absent. 
2. Able to carry out normal activities with minimal difficulty. Neurological impairment 
does not require nursing care or hospitalization.
3. Seriously limited in performing normal activities; requires nursing care or 
hospitalization. Patient confined to bed or wheelchair or with significant intellectual 
impairment. 
4. Unable to perform even minimal normal activities. Requires hospitalization and/or 
constant nursing care. Patient unable to communicate or in a coma. 


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11.3 APPENDIX 3: ON-STUDY EVALUATIONS
Cycle/ 
Visit
H&P
Ophtho 
Exam
Toxicity 
Assess
MMSE
Clin. 
Labs
Cr.
Cl.
Screen
MRI
PET
CSF 
HIV/
CD4
EBV 
Research 
Blood
Neuro-
psych
Adherence
Cycle 1
X
X
X
X
X
X2
X2
X2
X2
X
X
Cycle 2
X
X
X
X
X
X
Cycle 3
X
X
X
X
X
X
X
X
Cycle 4
X
X
X
X
Cycle 5
X
X
X
X
X
X
X
X
Cycle 6
X
X
X
X
Cycle 7
X
X
X
X
X
X
X
X
Cycle 8
X
X
X
X
CR by MRI
X1
X
X
End Rx 
X
X1
X
X
X
X
X
X
X
X
X
X
X
Follow-up
Q2 mo x3
Month 2
X
X
X
X
X
X
Month 4
X
X
X
X
X
X
Month 6
X
X
X
X
X
X
X
X
Q3 mo x6
Month 9
X
X
X
X
X
X
Month 12
X
X
X
X
X
X
X
X
X
Month 15
X
X
X
X
X
X
Month 18
X
X
X
X
X
X
X
X
Month 21
X
X
X
X
X
X
Month 24
X
X
X
X
X
X
X
Q6 mo x 2
Month 30
X
X
X
X
X
X
Month 36
X
X
X
X
X
X
X
Q12 mo x2
(Optional Clinical Follow up)
Month 48
X
X
X
Month 60
X
X
X
1. Repeat if abnormal at baseline.
H&P= History and Physical, including ECOG; Ophtho Exam = Ophthalmology exam for orbital involvement; Clin. Labs = CBC with differential and Retic, Chem. 20, PT/PTT, Urine: UA, E-hCG 
(women); Cr. Cl. = estimated creatinine clearance by Cockcroft-Gault formula (Appendix 4), Serology = Hepatitis and Toxoplasmosis serologies, RPR; CSF = CSF cell count, glucose, protein, EBV, 
molecular pathology, flow cytometry ; HIV/CD4 = Baseline HIV Serology, genotype if indicated, HIV viral load, and lymphocyte subset TBNK; EBV = EBV quantitative PCR, blood; Neuropsych, See 
Appendix 5; Adherence, see Appendix 6. BL = Baseline Studies; End Rx = End of therapy, Cycle 8, Day 28 (Month 1 follow-up).
For patients that relapse, re-staging will include: MRI-brain with contrast, CNS FDG-PET, CSF studies, quantitative EBV-PCR, and ophthalmologic examination. See Section 3.8.5.


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On-Study Evaluations for Best Available Radiation Sparing Therapy (no Methotrexate)
Cycle/ 
Visit
H&P
Ophtho 
Exam
Toxicity 
Assess
MMSE
Clin. 
Labs
Cr.
Cl.
Serology
MRI
PET
CSF 
HIV/
CD4
EBV 
Research 
Blood
Neuro-
psych
Adherence
Screen/BL
X
X
X
X
X
X
X
X
X
Day 1
X
X
X
X
X
X
X
X
Day 3
X
X
X
X
Day 5
X
X
X
X
X
X
Day 8
X
X
X
X
Day 15
X
X
X
X
X
X
X
Day 21
X
X
X
X
CR by MRI
X1
X
X
End Rx 
X
X1
X
X
X
X
X
X
X
X
X
X
X
Follow-up
Week 2
X
X
X
Week 4
X
X
X
X
X
X
X
Q2 mo x3
Month 2
X
X
X
X
X
X
Month 4
X
X
X
X
X
X
Month 6
X
X
X
X
X
X
X
X
Q3 mo x6
Month 9
X
X
X
X
X
X
Month 12
X
X
X
X
X
X
X
X
X
Month 15
X
X
X
X
X
X
Month 18
X
X
X
X
X
X
X
X
Month 21
X
X
X
X
X
X
Month 24
X
X
X
X
X
X
X
Q6 mo x 2
Month 30
X
X
X
X
X
X
Month 36
X
X
X
X
X
X
X
Q12 mo x2
(Optional Clinical Follow up)
Month 48
X
X
X
Month 60
X
X
X
1. Repeat if abnormal at baseline.
H&P= History and Physical, including ECOG; Ophtho Exam = Ophthalmology exam for orbital involvement; Clin. Labs = CBC with differential and Retic, Chem. 20, PT/PTT, Urine: UA, E-hCG (women); Cr. Cl. = estimated 
creatinine clearance by Cockcroft-Gault formula (Appendix 4), Serology = Hepatitis and Toxoplasmosis serologies, RPR; CSF = CSF cell count, glucose, protein, EBV, molecular pathology, flow cytometry ; HIV/CD4 = 
Baseline HIV Serology, genotype if indicated, HIV viral load, and lymphocyte subset TBNK; EBV = EBV quantitative PCR, blood; Neuropsych, See Appendix 5; Adherence, see Appendix 6. BL = Baseline Studies; End Rx = 
End of therapy, Day 28 (Week 1 follow-up.) 
For patients that relapse, re-staging will include: MRI-brain with contrast, CNS FDG-PET, CSF studies, quantitative EBV-PCR, and ophthalmologic examination.


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11.4 APPENDIX 4: CALCULATION OF CREATININE CLEARANCE 
I.
Calculation: Cockcroft-Gault formula for Creatinine Clearance (CrCl) 
estimate
A.
Male CrCl = (140 - age) x (weight) / (sCr x 72) 
B.
Female CrCl = (140 - age) x (weight) x 0.85 / (sCr x 72) 
C.
Annotation 
1.
Where creatinine clearance is expressed in mL/min 
2.
Where age is in years 
3.
Where weight is Actual Body Weight in kilograms 
4.
Where sCr is Serum Creatinine in mg/dL 
D.
Efficacy 
1.
As accurate as CrCl measured from a 24-hour urine collection in 
many cases 
2.
Exceptions: See 24-hour CrCl indications below
3.
For estimated creatinine clearance of <100 mL/min, a 24-hour 
urine collection should be obtained plus a serum creatinine at the 
end of the collection period to determine a measured creatinine 
clearance (per section 3.4.2.1.1).
E.
Resources: http://www.kidney.org/professionals/
II.
Calculation:  Measured Creatinine Clearance from 24-hour urine collection
A.
CrCl = (uCr x uV) / (sCr x 1440) 
B.
Annotation 
1.
Where CrCl is Creatinine clearance in mL/min 
2.
Where uCr is Urine Creatinine in mg/dL 
3.
Where sCr is Serum Creatinine in mg/dL 
4.
Where uV is 24-hour urine volume in mL 
5.
Where 1440 represents number of minutes in 24 hours
C.
Indications (where calculation above is inaccurate) 
1.
Altered protein intake 
a.
Vegetarian diet 
b.
Creatine Supplementation 
2.
Altered muscle mass and muscle injury
a.
Malnutrition, muscle wasting, muscle trauma
b.
Amputation
3.
Females
4.
Unstable renal function (changing serum creatinine)
5.
Obesity


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11.5 APPENDIX 5: NEUROPSYCHOLOGICAL TEST BATTERY
At entry into the study, patients will be administered a comprehensive 
neuropsychological battery of tests.  The major domains of functioning to be evaluated 
for the comprehensive and monitoring assessment batteries are indicated below.  The 
specific tests to be used for the protocol will be selected by the NCI/MICC 
neuropsychology group.  Such tests have been shown to provide an effective 
assessment of functioning in similar chronically ill populations.  The tests do not 
require complicated instrumentation and can be done with high reliability and validity 
by trained personnel.  Repeated neuropsychological assessments will be administered to 
the patient according to the schedule specified in the protocol.  The monitoring battery, 
which may be administered at shorter intervals, includes tests less subject to practice 
effects.  The same domains should be assessed using the same test instruments 
throughout the study.  
Comprehensive Assessment
General Cognitive
Language/Verbal
Visual-Perceptual
Processing Speed
Memory (working, immediate and delayed, visual and auditory)
Executive Function
Attention
Fine Motor
Mood/QOL
Monitoring assessment
General Cognitive
Language/Verbal
Visual-Perceptual
Processing Speed
Working memory
Executive Function
Attention
Fine motor
Mood/QOL
--Additional neuropsychological tests may be administered to more comprehensively 
assess the patients if needed to further explore specific areas of functioning
--The comprehensive assessment is administered at baseline and then annually, whereas 
the monitoring assessment is administered at the half-year assessments.  


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11.6 APPENDIX 6: ADHERENCE ASSESSMENT 
Baseline, 6, and 12 months
Estimated Time
Knowledge Questionnaire
Pills Identification Test
Interview
5 minutes
5 minutes
10 minutes
20 minutes total
Baseline, 3 and 9 months
Interview
10 minutes
10 minutes total


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11.7 APPENDIX 7: KNOWLEDGE QUESTIONNAIRE 
Please circle the best response for the questions below.  Circle one and only one
response for each question.  
1. HIV is a virus that: 
a) can be cured with a vaccine.
b) cannot be controlled with medication.
c) can often be controlled with antiretroviral 
medicine taken the way it is prescribed.
d) can be controlled with antiretroviral medication
in people who have received the vaccine. 
2. It is important for people to take HIV medicine  
the way it is prescribed because this will help the  
body:
a) get a higher viral load.
b) build up resistance to the medicine.
c) keep a strong immune system. 
d) all of the above.
3. Resistance means:
a) HIV resists the process of changing into AIDS.
b) immune cells fight with HIV cells.
c) HIV learns to grow even with medicine in the body.
d) HIV is killed by the medicine.
4. A measure of “viral load” tells us:
a) How many different viruses are in someone’s  
blood.
b) How many T-cells a person has.
c) How much HIV is in someone’s blood.
d) What kinds of HIV cells are in someone’s saliva.
5. If you run out of HIV medicine, you should:
a) schedule an appointment at NIH to get more.
b) call the nurse or doctor right away to get more.
c) borrow some pills from a friend until you can get 
more from the pharmacy. 
d) both B and C are correct.
6. The best thing to have is: 
a)  high viral load and low T-cells.
b)  low viral load and low T-cells.
c)  high viral load and high T-cells.
d)  low viral load and high T-cells.
7. The best way to fight HIV is:
a)  take HIV medicines the way they are prescribed.
    b)  eat healthy foods.
c)  get the HIV vaccine.
d)  exercise every day.
8. Which of these statements is NOT true? 
a)  A person can only be resistant to one medicine 
at a time.
b)  Doctors can do a test to see which HIV 
medicines work best for a person.
c)  If you become resistant to a medicine, the 
medicine probably won’t work for you.
d) There are many different types or “strains” of 
HIV.
9. If a person doesn’t take his medicine every day, 
a)  the medicine will work better. 
b)  his red blood cells will be destroyed.
c)  his T-cells will become resistant to the
medicine.
d)  the HIV will become resistant to the medicine.
10. If a person skips doses of her HIV medicine,  
a) her viral load will probably go to zero.
b) she will probably gain weight.
c) her CD4 cells will probably double.
d) her body could become resistant to the medicine.
Hosp #:
Protocol:
Name:
Date:


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11.8 APPENDIX 8: RECRUITMENT ANNOUNCEMENT 
Clinical Trial for AIDS-related Primary Central Nervous System Lymphoma
HIV and AIDS Malignancy Branch
National Cancer Institute
National Institutes of Health
Bethesda, Maryland
Individuals with AIDS-related primary central nervous system (brain) lymphoma are 
invited to participate in a clinical trial designed to study the feasibility of treating this 
cancer without using the radiation therapy approaches traditionally used in this setting.  
Patients are invited to contact the NCI if they are HIV-infected and have a brain mass, 
even if the diagnosis for the cause of the brain mass has not been made.  In certain 
circumstances, the diagnostic procedures may also be done at the National Institutes of 
Health.
AIDS-related primary brain lymphoma is a serious and life threatening complication of 
HIV infection.  Few individuals with this cancer survive for one year.  Radiation therapy 
to the brain is the treatment commonly administered.  Radiation therapy can make the 
lymphoma go away.  However, many patients have recurrence of the lymphoma after 
radiation therapy, or develop other AIDS complications that limit survival.  With the 
availability of highly active antiretroviral therapy, many individuals with AIDS-related 
primary brain lymphoma may be able to control the HIV infection long-term and go on to 
good health if the lymphoma can be cured.  Many not HIV-infected people treated with 
radiation therapy for brain lymphoma survive several years, but have severe brain 
problems related to the radiation treatment.  Therefore, in not HIV-infected people, 
chemotherapy has become the standard of care for treating this cancer.  Survival with a 
healthy brain in such people is improved with this strategy.  This clinical trial will assess 
whether chemotherapy will lead to several years or longer survival without brain 
problems in people with AIDS-related primary brain lymphoma.  
The treatment being studied in this experimental trial is to give a combination of high-
dose methotrexate, leucovorin, rituximab, and highly active antiretroviral therapy.  This 
treatment is designed to treat the lymphoma without causing additional toxicity to the 
CD4+ lymphocytes.  CD4+ lymphocyte recovery is essential for the long-term survival 
prospects of people with advanced AIDS.  High-dose methotrexate is the core of most 
treatments for this tumor in HIV-unrelated primary brain lymphoma and it is used in that 
setting in conjunction with other medications.  When given with leucovorin, high-dose 
methotrexate can usually be given without causing the expected toxicity to the bone 
marrow and to the immune system.  Rituximab is being given because it is a monoclonal 
antibody that targets the lymphoma cells and helps the methotrexate kill the cancer cells.   
Since rituximab does not attach to the CD4+ lymphocytes, it may be possible to give 
methotrexate, leucovorin, and rituximab along with highly active antiretroviral therapy 
and simultaneously treat the cancer and the HIV. Some patients may not be able to 
receive high-dose methotrexate due to problems with their kidneys or heart.  In such 
cases, treatment may still be possible, and will generally include rituximab and 
antiretroviral therapy. It may be possible to commence immune system recovery during 


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the lymphoma therapy.  Immune system recovery may be essential not only to prevention 
of other AIDS complications, but also to prevention of recurrent brain lymphoma.
The study is designed to test the ability of this treatment to make the cancer go away, to 
see the extent of immune recovery that is feasible with the treatment, and to see whether 
the cancer comes back or not.  Also, a series of tests will be done to measure the effects 
of this therapy on brain function, to see whether this therapy is less toxic to the brain than 
would be potentially expected with radiation therapy.
Frequent visits and prolonged stays at the NIH may be necessary since this disease is a 
very serious condition causing many complications.  Each treatment will require a week 
or longer in the hospital.  The treatments will be repeated up to 8 times depending on how 
well it is tolerated, and the effects on the tumor.  All of the diagnostic tests and medical 
treatments administered at the National Institutes of Health are free of charge.  If the 
cancer goes away, treatment for HIV may continue for up to three years while additional 
tests on your immune system and brain function are made.
Transportation costs to the NIH will be paid for those who do not live close to the NIH 
campus.  
For further information about coming to the NIH for consultation and possible enrollment 
into this clinical trial, contact Dr. Robert Yarchoan at 240-760-6075, or 1.800.243.2732, 
and then hit 4. 


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11.9 APPENDIX 9: RITUXIMAB COMBINED WITH HIGH-DOSE METHOTREXATE WITH 
LEUCOVORIN RESCUE HAART AND CHEMOTHERAPY ADMINISTRATION,
METHOTREXATE MONITORING AND SUPPORTIVE CARE GUIDELINES
Baseline/Admission: 
1. Determine HAART regimen. Tenofovir sparing regimens preferred due to 
potential overlapping renal toxicity.  Pharmacogenetic testing for abacavir; check 
HLA B*5701 
2. PCP prophylaxis; monthly pentamidine or atovaquone preferred
3. MAC prophylaxis: azithromycin 1200 mg /m2 weekly for CD4 < 100 cells/microL
4. HSV prophylaxis: Valacyclovir 1000 mg/daily
5. Evaluate for thrush daily
6. Check Cockcroft-Gault estimate of creatinine clearance. If < 100mL/min, order 
24 hour urine collection for creatinine clearance
7. Daily weights
Day -1 Each Cycle:
1. Check Cockcroft-Gault estimate of Creatinine clearance. If < 100mL/min, order 
24-hour creatinine clearance.
2. Confirm at least 7 days serum methotrexate mcmol/L from previous cycle 
to next dose of methotrexate.
3. Evaluate for possible methotrexate dose adjustments based on toxicities from 
previous cycle.
Day 1 of each cycle:
1. Review all concomitantmedications prior to day 1 of each cycle. Discontinue any 
drug that would have interaction with methotrexate excretion. See list below. No 
filgrastim within 24 hours before methotrexate administration.
2. Rituximab 375 mg/m2
3. Start IV fluid hydration by 18:00, using one of the protocol specified alkalinized 
IVF order sets in CRIS for 06-C-0051
4. Order q6 hour urine pH > 7.0 (00:00, 6:00, 12:00, 18:00) and STRICT URINE 
OUTPUT monitoring record urine output every hour
5. Draw the following blood work until methotrexate level is < or equal to 0.05 
mcmol/L:
a.
Hepatic panel every other day
b. CBC/Diff, Chem 7 daily


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Day 2:
1. 7 am: notify MD of urine pH and hourly UOP. If UOP < 100mL/hour or urine pH 
<7 or >8, adjust IVF.
2. Methotrexate 6000 mg/m2. Order within the 06-C-0051 CRIS order set.  Include 
Sodium Bicarbonate 45mEq as an additive. (May be adjusted between 25-75mEq 
depending on individual patient needs).
a.
For creatinine clearance 60-100 mL, adjust methotrexate dose using 
formula: (Creatinine Clearance)/100 x 6000 mg/m2
b. For creatinine clearance < 60ml/min, methotrexate will NOT be 
administered.
c.
If episodic AST/ALT elevation > 10X upper limit normal on previous 
cycle, decrease methotrexate by 25%
3. Goal Start time: administer methotrexate starting between 9:00-10:00 am
Day 3-End Leucovorin Rescue:
1. Start leucovorin 100 mg/m2 IV q6 hours starting 24 hours AFTER INITIATION
of methotrexate administration.
2. Serum methotrexate monitoring levels is now performed at Children’s Hospital 7 
days a week at 2 p.m.  Specimens collected for methotrexate monitoring must be 
delivered to the NIH CC Department of Laboratory Medicine’s Chemistry Service 
in the morning so they can be delivered to Washington’s Children’s Hospital and 
processed in a timely manner. This process is designed to obtain same day results 
for patients on 06-C-0051 so the clinical team can make protocol defined 
treatment decisions, such as stopping leucovorin or IV fluids, or implementing 
treatment of delayed methotrexate clearance with glucarpidase (Voraxaze®).  
3. 24 hours AFTER INITIATION of methotrexate, draw red top tube for serum 
methotrexate level. Methotrexate Levels need to be drawn at scheduled time. 
4. Repeat every 24 hours: 48 hr, 72 hr, 96 hr, until methotrexate monitoring no 
longer required.
5. Check methotrexate levels same day, evaluate for delayed methotrexate clearance. 
Notify Research team for:
a.
Methotrexate > 10 mcmol/L at 24 hours
b. Methotrexate > 1 mcmol/L at 48 hours
c.
Methotrexate > 0.1 mcmol /L at 72/hours
d. For delayed methotrexate elimination see pages 26 and 27 3.4.3), Table 1 
(Leucovorin dose at 24, 48, 60 and 72 hours), and 3.4.4 for use of 
glucarpidase guidelines.
6. Stop intravenous leucovorin and switch to oral leucovorin 25 mg PO (Alternative 
10 mg/m2 PO) q6 hours
a.
If methotrexate level is <0.5 mcmol/L, see section 3.3.4.3.2
b. Patient does NOT have delayed methotrexate clearance (Defined, Point 5 
above.)
c.
Discuss discontinuing IVF research team


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87
7. Stop oral leucovorin and urine monitoring once serum methotrexate OHYHOLV
0.05 mcmol/L
Medications to avoid during Methotrexate administration:
1. Asparaginase
2. Aspirin
3. Acidic drugs
4. Amoxicillin
5. Cephalosporins
6. Chloramphenicol
7. Cholestyramine
8. Cotrimoxazole
9. Cyclosporine
10. Diclofenac
11. Ibuprofen
12. Indomethacin
13. Ketoprofen
14. Mercaptopurine
15. Mezlocillin
16. Naproxen
17. Non-steroidal anti-inflammatory drugs
18. Omeprazole
19. Penicillins
20. Piperacillin (±tazobactam)
21. Probenecid
22. Proton pump inhibitors (e.g., dexlansoprazole, esomeprazole, lansoprazole, 
omeprazole, pantoprazole, rabeprazole)
23. Pyrimethamine
24. Salicylates
25. Sulfonamides
26. Sulindac
27. Tetracyclines
28. Tolmetin
29. Trimethoprim
30. Trimethoprim/sulfamethoxazole
31. Vaccines, Live (viral and bacterial)

ICF_001.pdf: 
 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
INSTITUTE: 
National Cancer Institute 
STUDY NUMBER: 
06-C-0051 
PRINCIPAL INVESTIGATOR: 
Robert Yarchoan, MD 
STUDY TITLE:  
AIDS-related Primary Central Nervous System Lymphoma:  A Phase II Pilot Study of 
High-Dose Intravenous Methotrexate with Rituximab, Leucovorin Rescue and Highly 
Active Antiretroviral Therapy 
Continuing Review Approved by the IRB on 06/26/17 
Amendment Approved by the IRB on 03/17/18 (L) 
Date posted to web: 03/22/18  
Standard 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
 
 
INTRODUCTION 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
First, we want you to know that: 
Taking part in NIH research is entirely voluntary.  
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  However, 
to receive care at the NIH, you must be taking part in a study or be under evaluation for 
study participation. 
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future. 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your NIH doctors or research team before you agree 
to the study. 
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional.   
Why is this study being done?  
The purpose of this research study is to see if brain lymphoma treatment that is based on the type 
of treatment given to people without AIDS can be given safely to people with AIDS who are 
taking HAART.  One of the goals of the study is to see if this therapy results in at least a 2-year 
remission of the brain lymphoma without the kind of late-occurring brain problems expected 
with radiation therapy. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 06-C-0051 
CONTINUATION: page 2 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
Why are you being asked to take part in this study? 
You have a disease called AIDS-related primary central nervous system lymphoma.  
Sometimes this can be referred to as primary brain lymphoma.  Lymphoma is a kind of cancer 
that involves lymphocytes.  Lymphocytes are cells that make up part of the immune system.  
Brain lymphoma is usually a subset of lymphocytes called “B”- lymphocytes.  B-lymphocytes 
in AIDS-related primary brain lymphoma are almost always infected with a virus called 
Epstein-Barr virus, or EBV.  Almost all cases of AIDS-related primary brain lymphoma 
develop once HIV has caused another kind of lymphocyte called CD4 cells, to become very 
low. Usually the CD4 cells are less than 50 when the brain lymphoma develops.  Before highly 
active antiretroviral therapy (HAART) was available, the CD4 cells progressively decreased 
due to uncontrolled HIV infection, and most people eventually had their CD4 cells fall below 
50.  Before HAART, once the CD4 cells were so low and if brain lymphoma developed, most 
people survived less than a few months.  This is because when the CD4 cells were so low and 
there was not effective treatment for HIV, other AIDS complications often prevented effective 
treatment for lymphoma, and people died either of the lymphoma or the other complications of 
AIDS.   
People who do not have AIDS can also develop brain lymphoma.  In the past, treatment for 
brain lymphoma was almost always radiation therapy given to the whole brain.  Radiation can 
make the lymphoma go away.  However, many people without AIDS who get radiation to the 
brain will later develop brain problems due to the radiation they received for the lymphoma.  
Sometimes these brain problems are so severe that people can no longer take care of 
themselves, and sometimes these problems can be fatal.  As a result, the standard treatments 
for non-AIDS brain lymphoma have been changing so that radiation therapy is not used as 
often as it was in the past.  Instead, non-AIDS brain lymphoma is generally treated with 
chemotherapy that is given through a vein, or sometimes taken by mouth.  In general, people 
with brain lymphoma who are treated with chemotherapy live longer with better brain function 
than was attained with radiation therapy.  Chemotherapy in AIDS-related brain lymphoma has 
not been studied very extensively because people with AIDS-related brain lymphoma tolerate 
radiation therapy pretty well in the short term, and before HAART was available, they usually 
died before the late occurring radiation-related brain problems develop.  Now that HAART is 
available, brain lymphoma occurs more rarely, and so it has not been studied well.  
Now that HIV can be better managed with HAART, AIDS complications, including non-brain 
lymphoma, can be treated more effectively.  There is some evidence that people with AIDS 
who develop non-brain lymphoma can be cured of their lymphoma and live for a number of 
years.  There is also some evidence that they can tolerate treatments that are similar to those 
now used in patients without AIDS.  This appears to be due in part to the ability of patients 
with AIDS to tolerate lymphoma therapy better since HAART was developed, and also 
because HAART can reduce the other AIDS complications.  Therefore, after the lymphoma 


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CONTINUATION SHEET for either: 
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PATIENT IDENTIFICATION 
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therapy has been completed, other AIDS complications can be less of a problem.  However, 
there has not been very much information on the optimal treatment for AIDS-related brain 
lymphoma since HAART was developed.   
How many people will take part in this study?  
Up to 28 patients will take part in this research study. 
Description of Research Study 
This is a research study designed to investigate the use of chemotherapy and HAART in 
patients with AIDS-related primary brain lymphoma.  The study is designed to estimate the 
percentage of patients treated with the experimental therapy who are alive, free of lymphoma, 
and who do not have severe brain problems after 2 years from the lymphoma diagnosis.   
None of the drugs used in this research study are experimental drugs.  Rather, this is research 
because the drugs are being used in people with AIDS, and for people with AIDS this has not 
been established as the standard treatment.  The treatment consists of highly active 
antiretroviral therapy selected to be most effective against your HIV infection and easiest for 
you to take.  In addition, there will be six cycles of induction chemotherapy.  A cycle lasts for 
2 weeks.  The chemotherapy consists of high-dose methotrexate and a monoclonal antibody 
called rituximab (Rituxan®).  The combination of high-dose methotrexate and rituximab has 
not been given in AIDS-related brain lymphoma.  It has been given to some patients with non-
AIDS-related brain lymphoma in other research studies, but the results of these studies have 
not been published yet.  While the drugs by themselves are tolerated if used appropriately, 
there is a possibility that in using them together, there would be unpredicted toxicity. High-
dose methotrexate is the most commonly used drug in brain lymphoma in people who do not 
have AIDS.  Rituximab is used in certain lymphomas because of its ability to kill B-
lymphocytes and lymphoma cells, and it helps other drugs like methotrexate, to kill lymphoma 
cells.  In patients without AIDS who have certain types of lymphomas, rituximab added to 
chemotherapy results in longer survival and better lymphoma remission compared to 
chemotherapy given without rituximab.  This has not been shown with certainty in brain 
lymphoma or in any kind of AIDS-related lymphoma.  In addition to these drugs, a kind of 
vitamin called leucovorin will be given.  Leucovorin helps to prevent many of the toxic effects 
of methotrexate.  The combination of methotrexate, leucovorin, and rituximab has been chosen 
based on the possibility that it may be relatively less toxic to your T-lymphocytes compared to 
most chemotherapy regimens for lymphoma.  Most combination chemotherapy regimens for 
lymphoma can severely deplete T-lymphocytes, including CD4 cells.  Part of the research 
question is to determine the effects of the combination of HAART, methotrexate, leucovorin, 
and rituximab on your CD4 cells.   We want to see if your CD4 cells will increase to a level 
higher than they were when your AIDS-related brain lymphoma was diagnosed.  If the CD4 


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cells increase, it is possible that better control of AIDS-related complications, and possibly 
better control of the lymphoma, may occur. It will take 12 weeks to complete the 6 induction 
cycles of induction treatment.  After the completion of induction therapy, if it appears that the 
lymphoma is completely gone; two additional consolidation cycles of treatment will be given, 
at 4 week intervals.  This treatment will consist only of HAART, high-dose methotrexate, and 
leucovorin.  At the end of these two treatments, only the HAART will be continued. 
Some patients may not be able to receive methotrexate, mainly due to problems with their 
kidneys or heart.  In some cases, such patients can also be treated, but their treatment will be 
modified to include six doses of rituximab over 1 month, combined with HAART, but no 
methotrexate and no leucovorin.  
What will happen if you take part in this research study?   
Before you begin the study 
One of the other research questions is to determine the level of intellectual function you have 
after the brain lymphoma has resolved, and to monitor this function over a period of 2 years to 
see whether there are any long-term effects of the treatment.  A series of tests to assess this will 
be done.  Before you start treatment, a short test will be done to determine your ability to 
understand basic concepts and coordination so that we can know whether the brain lymphoma 
is causing you severe problems with thinking and concentrating.  After the lymphoma appears 
to have resolved, more formal and intensive tests will be done.  The intensive tests will be done 
each year.  Also, shorter interim tests to monitor for any potential problems will be done about 
every 6 months.  In addition, you will have sessions with a specialist who will monitor your 
understanding of HAART and to help you understand and insure that you are able to take your 
anti-HIV medications.  Some of these tests and sessions may be mentally challenging and for 
that reason cause you to feel frustrated or embarrassed.  If you feel negative feelings about 
these sessions, please tell your doctors or nurses, or anyone on the health care team.  The 
purpose of these tests and sessions is to help you, and to help us to understand how the 
treatment affects you, not to embarrass or frustrate you. 
To receive the chemotherapy, you will have to be in the hospital at the NIH Clinical Research 
Center.  High-dose methotrexate must be given with intravenous fluid that is mixed with 
bicarbonate to make the acid in your urine reach a low level.  This is to protect your kidneys 
from the methotrexate.  The methotrexate levels in your blood have to be measured every day.  
The leucovorin has to be given by intravenous injection every 3-6 hours. In rare cases, a drug 
called glucarpidase (Voraxaze®) may also be used to prevent methotrexate toxicity should you 
develop problems with your kidneys during treatment. Glucarpidase (Voraxaze®) is given as a 
onetime dose by intravenous injection.  


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During the study 
Your kidney function, liver function, and blood counts have to be measured by doing blood 
tests very frequently.  It may take 5-10 days to safely stop all of the leucovorin and blood 
monitoring before you can safely leave the hospital.  Therefore, for the first 12 weeks, you will 
be in the hospital for about a week, every other week.  If you have complications or are very 
sick, you may be in the hospital longer.  During the final two consolidation cycles of 
chemotherapy, you will also spend about 1 week in the hospital getting methotrexate, fluid, and 
leucovorin. Glucarpidase may be utilized rather than leucovorin or levoleucovorin for 
methotrexate toxicity in the setting of renal toxicity and delayed methotrexate clearance. The 
Glucarpidase has to be given by intravenous injection.  
You will also be treated with highly active antiretroviral therapy.  We refer to this as HAART.  
There are twenty or more drugs to choose from to treat HIV, but the medications must be taken 
in appropriate combinations to give the best effect.  Your doctors will discuss the specific 
regimen and alternative regimens with you that would have the best probability of working 
well for you.  HIV grows in the blood, and HAART can inhibit this growth to very low levels.  
When the HIV is kept at low levels with HAART, the CD4 cells may increase.  If the HIV is 
allowed to grow, the CD4 cells will not increase.  They will probably decrease, because HIV 
kills CD4 cells.  The lower the CD4 cells, the more likely you are to get sick with problems 
related to AIDS.  It may be possible to help prevent your brain lymphoma from coming back if 
the CD4 cells can increase to high levels.   
Most anti-HIV medications are taken by mouth.  Some are taken by injection.  We will discuss 
the specific drugs with you and provide you with information on the drugs.  We will evaluate 
your understanding of the HAART medications and the need for them periodically in order to 
help you understand how important they are, and to help us understand any issues involved that 
make it difficult for you to take all of your medications every day.  If you decide you do not 
want to take HAART, you cannot participate on this research study.  If HAART is not able to 
keep your HIV at low levels, you may not be able to continue participation in the study. 
None of the chemotherapy medications or HAART medications in this research study are 
experimental drugs, because they are all approved by the Food and Drug administration for the 
treatment of lymphoma or HIV.  The experimental part of this study is the combination of 
HAART and high-dose methotrexate with rituximab and leucovorin in AIDS-related brain 
lymphoma, because this combination of treatment has not been studied before.  Therefore, it is 
not known whether the treatment will improve your chances to be cured of the lymphoma, or if 
you will be able to tolerate the treatment.  If you are unable to tolerate the treatment, it will 
have to be stopped. 
In order to see the effect of the treatment on your lymphoma, MRI and FDG-PET scans of your 
brain will have to be periodically repeated.  These tests will be done before you start treatment, 


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and the follow-up tests will be for comparison.  The FDG-PET scan will be repeated after the 
first cycle, again at the time that the MRI suggests all of the lymphoma is gone, and then 
yearly.  The MRI scan will be repeated after the 2nd, 4th, 6th, and 8th treatments, and then every 
2 months for 3 times, then every 3 months for 6 times, then every 6 months for 4 times, and 
then every year for 5 years, or sooner if there is a concern about your brain.  If there is 
evidence that your lymphoma has not completely responded to therapy, you may be offered 
second-line chemotherapy or whole brain radiation therapy on this protocol. 
Because of the relationship of EBV to the brain lymphoma, we want to study what happens to 
the EBV in your blood and spinal fluid as you get the treatment.  Before you start therapy, the 
EBV will be measured in your blood and spinal fluid.  The EBV measurements will be 
repeated at the time that you appear to have complete resolution of your lymphoma, again at 6 
months after completion of treatment, and at any time if it appears the lymphoma may have 
come back.  The spinal fluid will also be examined for any evidence of abnormal cells each 
time it is examined for the EBV.  The repeated analysis of the blood and spinal fluid for EBV 
is part of the research.  Later in this informed consent document, you will find a description of 
the procedure we use to obtain the spinal fluid.  If you agree to allow optional studies (see page 
9 of this consent form), additional blood samples (up to 3.5 tablespoons) may be drawn on 
occasion to store for future studies designed to learn more about cancer, HIV or other diseases. 
You do not need to agree to optional studies in order to participate in this study. 
Periodic eye examinations will be done while you are participating on this study.  The reasons 
for this are that brain lymphoma can sometimes get into the eye.  The other reason is that 
people with low CD4 cells are at risk of certain eye infections. 
Birth Control 
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
of the adverse effects of methotrexate to your baby or unborn child. If you are a woman who can 
become pregnant, or are the partner of a woman who can become pregnant, you will need to 
practice an effective form of birth control before starting study treatment, during study treatment, 
and for 3 months after you finish study treatment.  If you think that you or your partner is 
pregnant, you should tell your study doctor or nurse at once.   
Effective forms of birth control include:  
• abstinence  
• intrauterine device (IUD) 
• hormonal [birth control pills, injections, or implants] 
• tubal ligation 
• vasectomy 


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CONTINUATION SHEET for either: 
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PATIENT IDENTIFICATION 
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File in Section 4:  Protocol Consent 
 
 
Risks or Discomforts of Participation 
This section will discuss a number of issues that you should know about before agreeing to 
participate in this clinical research trial.  In general, the number of tests that are done will be 
more than if you were treated with standard therapy.  You may spend more time at the NIH in 
the hospital and coming to clinic visits than you would if you were treated with radiation 
therapy.  High-dose methotrexate and rituximab have certain risks associated with their use.  
The details of these issues follow. 
In this research study there are 3-4 repeated evaluations of the spinal fluid for EBV.  This 
requires that spinal fluid be removed from your body.  This is done by inserting a small needle 
between the bones of your vertebral column, which some people refer to as the back bone.  The 
procedure for removing spinal fluid is called a lumbar puncture, and some people call it a 
spinal tap.  Less than 2 tablespoons of fluid are removed.  A medicine to numb the skin is first 
injected in the area where the lumbar puncture is to be performed.  After that, a needle is 
inserted between the vertebral bones into the space where the spinal fluid is.  The fluid drains 
out on its own.  After the needle is removed, sometimes the fluid can continue to leak a little 
bit, and cause headaches.  If this happens, we may have to patch the needle hole, but usually it 
stops on its own.  Sometimes if there is a brain lymphoma causing too much pressure in the 
brain, it is not safe to do a lumbar puncture.  One of the reasons to perform the MRI scan is to 
make sure it is safe to do the lumbar puncture.  If it appears that it is not safe, then the lumbar 
puncture will not be done.   
In addition to the lumbar puncture, blood will be drawn from a vein.  The amount of blood 
varies depending on what other tests are being done.  For the purpose of looking for EBV in 
the blood, about 1 teaspoon of blood will be drawn.  Additional blood tests, including to check 
your HIV viral load and CD4 cell counts and routine blood work to check for any toxicity 
related to the treatment can required up to 14 tablespoons (but usually much less) of blood to 
be drawn.  This amount of blood is not dangerous to draw from you. 
MRI scans can make some people feel claustrophobic.  The MRI machine is noisy, and you 
have to lie very still while the machine scans your brain to take a picture of your lymphoma. If 
you have feelings of claustrophobia, it is important to tell us so that we can help you with this. 
The FDG-PET scans require that you not eat for 12 hours before the scan.  You have to lie very 
still in the FDG-PET scan machine while the scan is being done.  Before you get the scan, a 
radioactive medication with sugar (the FDG) will be given you by vein.  The FDG accumulates 
in the lymphoma more than it does in the normal brain, and it is a sensitive way to visualize the 
brain lymphoma.  The test requires you lie very still for up to an hour while the scan is being 
done. 
We will now discuss the treatment medications and toxicities: 


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HAART 
It is a requirement that you take HAART on this research study.  HAART probably should be 
taken every day for your entire life, unless at some future point an improved kind of therapy 
for HIV is developed or you decide you no longer want to be treated for your AIDS.  HAART 
can have side effects.  Some of the side effects can come very quickly.  The specific side 
effects depend on the specific medications that make up your HAART regimen.  These side 
effects can include headaches, nausea, diarrhea, fatigue, trouble sleeping, bad dreams, anemia, 
liver function problems, and pancreas problems.  Usually we can change the medications to 
minimize these kinds of side effects, and most people are able to take HAART without having 
many side effects.  HAART can also have longer-term side effects.  These longer-term side 
effects can include changes in fat metabolism and the distribution of fat on your body.  Certain 
drugs seem to be more likely to cause these kinds of side effects, and we will avoid them 
whenever possible.  In general, we will try to devise a regimen that has the least likelihood of 
causing you either short-term or long-term side effects, and use the fewest number of pills 
possible.  However, sometimes this is not possible, and the only way to keep the HIV from 
growing is with drugs that have some side effects, and sometimes requires more medications.  
The specific toxicities of each medication you take will be discussed with you. 
If you currently have an infection that is very mild or without symptoms, HAART could 
temporarily worsen your clinical condition by making your body react more to it—this is 
called Immune Reconstitution Inflammatory Syndrome or IRIS.  It is also possible that IRIS 
can occur in your brain as your immune system recovers and reacts to your primary central 
nervous system lymphoma. This may lead to a temporary worsening of neurologic symptoms. 
If you have IRIS to another infection or your lymphoma, you will get treatment for the 
infection or continued lymphoma therapy, and will also receive steroids to treat the IRIS 
reaction.   
Rituximab 
Rituximab is a monoclonal antibody, meaning it reacts with a specific protein.  The protein it 
reacts to is called CD20, which is found on some B-lymphocytes, including most B-cell 
lymphomas.  The drug is given by intravenous injection.  During infusion, it can sometimes 
cause a reaction of blood pressure changes, chest tightness with difficulty breathing, back pain, 
shaking chills, and a severe allergic reaction, which can rarely be fatal.  Rituximab can cause 
low blood counts, muscle aches, joint pains, nausea, vomiting, diarrhea, and itching.  You may 
be given acetaminophen and diphenhydramine to help prevent reactions related to rituximab. 
Rituximab appears to be more toxic to some people with AIDS compared to people without 
AIDS.  In a randomized study of non-brain lymphoma in people with AIDS, some people were 
given rituximab and combination anti-lymphoma chemotherapy with HAART, and others were 
given only the combination chemotherapy and HAART, but no rituximab.  More people in the 


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group that received rituximab had infections, and more people in the group that received 
rituximab died from complications related to the treatment.  Most of the people who died of 
treatment-related complications had low CD4 cells.  In order to minimize infectious 
complications while taking part in this study, you will receive medications to prevent infection.  
You will be monitored closely for infections both while you are receiving therapy, and during 
the time period after therapy in which your immune system is recovering. 
In this study, most people who will be treated with rituximab also will have low CD4 cells.  It 
is not known whether the treatment with methotrexate and rituximab will have the same 
potential for causing problems as the combination anti-lymphoma chemotherapy and rituximab 
did in the randomized trial. 
High-dose methotrexate with leucovorin rescue  
The doses of methotrexate given in this research are very high.  Many of the toxicities of high-
dose methotrexate can be prevented or reversed with leucovorin, a vitamin.  We call it 
leucovorin rescue because the doses of methotrexate given are too high to be given safely 
without the leucovorin.   
High-dose methotrexate can cause nausea, vomiting, and sores in the mouth, throat, stomach, 
intestines, and anus.  It can cause the bone marrow to stop making blood cells, and this can 
lead to infections, anemia (low red blood cells), and bleeding.  Methotrexate can cause you to 
lose all of your hair, but when leucovorin is administered, hair loss may be decreased.   
The methotrexate can cause your kidneys to stop functioning.  Your kidney function will be 
assessed prior to each dose of methotrexate, and it will not be given if there is evidence of poor 
kidney function that would make it too dangerous for you to get methotrexate.  To help prevent 
kidney problems, you will receive large amounts of fluid by vein before the methotrexate is 
given.  The fluid will contain bicarbonate so that we can adjust the acid content of the urine.  
Reducing the acid content in the urine protects the kidneys.  The fluid will have to be 
continued for several days.  Sometimes the kidneys can be damaged even when the precautions 
are taken.  If this occurs, higher more frequent doses of the leucovorin are given to try to 
reverse this and to prevent additional toxicity.  If the kidney failure is severe enough, dialysis 
may be necessary to help support you.  Kidney failure due to methotrexate can become life 
threatening, although this is not common when hydration and leucovorin are used to prevent it.  
In addition, a new drug called glucarpidase (Voraxaze®) has been used to decrease the 
methotrexate levels.  Glucarpidase (Voraxaze®) is not yet approved by the FDA, but the 
Cancer Treatment Evaluation Program at the National Cancer Institute can supply the drug if 
your condition appears such that you would benefit from it. If you need the glucarpidase 
(Voraxaze®), the drug will be explained to you in detail, and a separate informed consent will 
be provided to you for review before you consent to be treated with it. 


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You should not be pregnant or plan on becoming pregnant while being treated with 
methotrexate. Your sperm should not be used to impregnate while you are receiving a 
treatment regimen that includes methotrexate. 
Many medications can decrease the ability of the kidneys to excrete methotrexate, and so you 
should not be on Bactrim, penicillin, aspirin, or nonsteroidal anti-inflammatory drugs such as 
ibuprofen while getting methotrexate.   
Leucovorin (or levoleucovorin) is usually well tolerated, but can sometimes cause an allergic 
reaction.  Most often it will be given by intravenous infusion, but if when your methotrexate 
levels are low enough and if you are able to drink lots of fluids and take oral medication, the 
leucovorin (or levoleucovorin) may be given by pill form. 
Filgrastim 
Filgrastim in a medication that is injected which can help to keep your white blood cells from 
being too low for long periods of time.  If your white blood count goes too low, you will be 
treated with filgrastim injections.  These can cause local irritation at the injection site, bone and 
muscle pain, and sometimes fevers. 
Glucarpidase 
Glucarpidase usually well tolerated, but can sometimes cause an allergic reaction. The most 
common adverse reactions (incidence >1%) with glucarpidase include paraesthesias, flushing, 
nausea and/or vomit, hypotension, and headache   
Potential Benefits of Participation 
Methotrexate is a standard treatment for primary brain lymphoma, and there is a reasonably 
good chance that the treatment will have beneficial treatment effect on your lymphoma.  It is 
important to realize that if the treatment is not effective, you may not receive any benefit from 
participation.  If the treatment does not work, and if it appears that you would need to have 
radiation therapy to your brain, it is theoretically possible that the toxicity effects of radiation 
might be worse because you have already received methotrexate.  If other medical or 
chemotherapy-based treatment options are reasonable, we will recommend that as an option to 
radiation.  However, if the rituximab and methotrexate work and the lymphoma does not come 
back, and you do not have to receive radiation therapy, you are not at risk for developing 
radiation-related brain problems.  Additionally, HAART and its effects on your HIV will be 
monitored carefully while you are on the research study. 


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Increasingly, rituximab has become a standard treatment for primary brain lymphoma in 
patients without AIDS, including those who have other forms of immune system suppression, 
for example, due to medications used in organ transplant. For patients who cannot receive high 
dose methotrexate due to other health problems, it is possible that HAART and rituximab alone 
may effectively treat your brain lymphoma and spare the need for radiation. During your 
treatment, you will be monitored closely, and if this treatment does not work, additional 
chemotherapy or radiation therapy will be offered to you. 
Alternative Approaches or Treatments 
The most common treatment that is given for AIDS-related brain lymphoma is radiation 
therapy to the whole brain.  The lymphoma goes completely away in almost everyone with 
AIDS-related brain lymphoma who receives whole brain radiation.  Before the HAART was 
available, many people with AIDS-related brain lymphoma would have a recurrence of the 
lymphoma after the radiation was given.  After the whole brain is radiated, additional radiation 
may not be possible because it can cause too much damage to the normal brain.  Now that 
HAART is available, it is possible that the lymphoma may be less likely to come back after 
whole brain radiation, particularly if the CD4 cells increase with HAART.   However, many 
people with brain lymphoma not related to AIDS develop problems with their brain after being 
treated with radiation and it may be that the risk of these problems occurring after radiation in 
AIDS-related brain lymphoma could be a problem.  How often this occurs in AIDS patients is 
not known.  It is known that patients with HIV infection have greater radiation-related toxicity 
to certain tissues, such as the gastrointestinal tract and mucous membranes.  This does not 
mean that people with HIV will absolutely be at greater risk than HIV-negative people for 
brain problems after radiation for brain lymphoma.  Because there is not sufficient information 
to know what the risk of brain injury is from radiation, and because it is considered the 
standard treatment for AIDS-related brain lymphoma, it is a reasonable option to consider 
instead of being treated on this experimental study. 
There are other chemotherapy approaches that may be reasonable to consider for AIDS-related 
brain lymphoma.  The chemotherapy given in this research study does not contain as many 
anti-lymphoma drugs as the chemotherapy regimens for non-AIDS brain lymphoma.  That 
raises the question of whether the chemotherapy in this study will work as well as the regimens 
for non-AIDS brain lymphoma.  The answer to that question is not known, and this research 
study may help to answer that question.  It may be reasonable to consider having the same 
treatment as is given to people without HIV.  The treatments given to people without HIV tend 
to destroy the CD4 cells however, and this could potentially be a problem with AIDS-related 
brain lymphoma. 
A few people have taken only HAART for their AIDS-related brain lymphoma.  Very rarely 
this may work, and the lymphoma can go away just by taking HAART.  This has only been 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 06-C-0051 
CONTINUATION: page 12 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
rarely reported in the medical literature.  This is a reasonable option if you do not want to 
receive aggressive therapy for your lymphoma and would rather die of your lymphoma than to 
fight it very hard, but want to do something that may have a small chance of making things 
better.  This is reasonable for people who feel that the prognosis for AIDS-brain lymphoma is 
so bad that they do not want to spend time in the hospital getting treatment that cannot 
guarantee them a high probability of cure.  There is not treatment available for AIDS-brain 
lymphoma that can guarantee a high probability of cure with years of good life after the 
treatment is finished, but this research study is an attempt to begin working toward that goal. 
Because of this however, some people may feel that they would rather not even take HAART, 
and that they would just like to be made comfortable and not suffer.  For some people this is a 
reasonable option. 
Research Subject’s Rights 
What are the costs of taking part in this study?  
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 
• 
You will receive study treatment at no charge to you. This may include 
surgery, medicines, laboratory testing, x-rays or scans done at the 
Clinical Center, National Institutes of Health (NIH), or arranged for you 
by the research team to be done outside the Clinical Center, NIH if the 
study related treatment is not available at the NIH.  
• 
There are limited funds available to cover the cost of some tests and 
procedures performed outside the Clinical Center, NIH.  You may have 
to pay for these costs if they are not covered by your insurance company. 
• 
Medicines that are not part of the study treatment will not be provided or 
paid for by the Clinical Center, NIH. 
• 
Once you have completed taking part in the study, medical care will no 
longer be provided by the Clinical Center, NIH. 
Will your medical information be kept private?  
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Organizations that may look at 
and/or copy your medical records for research, quality assurance, and data analysis include: 
• The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), which are involved in keeping research safe for people. 
• National Cancer Institute Institutional Review Board 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 06-C-0051 
CONTINUATION: page 13 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. At 
most, the Web site will include a summary of the results. You can search this Web site at any 
time. 
Stopping Therapy 
Your doctor may decide to stop your therapy for the following reasons: 
• if he/she believes that it is in your best interest 
• if your disease comes back during treatment 
• if you have side effects from the treatment that your doctor thinks are too severe 
• if new information shows that another treatment would be better for you 
In this case, you will be informed of the reason therapy is being stopped. 
You can stop taking part in the study at any time. However, if you decide to stop taking part in 
the study, we would like you to talk to the study doctor and your regular doctor first. 
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to designated representatives. 
If you withdraw your consent and leave the trial, any samples of yours that have been obtained 
for the study and stored at the NCI can be destroyed upon request. However, any samples and 
data generated from the samples that have already been distributed to other researchers or placed 
in the research databases cannot be recalled and destroyed. 
 
Certificate of Confidentiality  
To help us protect your privacy, we have obtained a Certificate of Confidentiality. The 
researchers can use this Certificate to legally refuse to disclose information that may identify you 
in any federal, state, or local civil, criminal, administrative, legislative, or other proceedings, for 
example, if there is a court subpoena. The researchers will use the Certificate to resist any 
demands for information that would identify you, except as explained below. 
You should also know that there are several circumstances in which the Certificate does not 
provide coverage. These include when information:  
• will be used for auditing or program evaluation internally by the NIH; or  


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 06-C-0051 
CONTINUATION: page 14 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
• must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA).  
• is necessary for your medical treatment and you have consented to this disclosure;  
• is for other research.  
In addition, identifiable, sensitive information protected by this Certificate cannot be admissible 
as evidence or used for any purpose in any action, suit, or proceeding without your consent.  
You should understand that a Certificate of Confidentiality does not prevent you or a member of 
your family from voluntarily releasing information about yourself or your involvement in this 
research. If an insurer, employer, or other person obtains your written consent to receive research 
information, then the researchers will not use the Certificate to withhold that information. 
The Certificate of Confidentiality will not protect against the required reporting by hospital staff 
of information on suspected child abuse, reportable communicable diseases, and/or possible 
threat of harm to self or others. 
Conflict of Interest 
 
The National Institutes of Health reviews NIH staff researchers at least yearly for conflicts of 
interest. This process is detailed in a Protocol Review Guide. You may ask your research team 
for additional information or a copy of the Protocol Review Guide or for more information.  
Members of the research team who do not work for NIH are expected to follow these guidelines 
but they do not need to report their personal finances to the NIH.  
One or more investigators participating in this study may have less than $15,000 of stock in the 
manufacturer of the product(s) used in this study. Under federal regulations, however, this is 
permissible and does not create a conflict of interest.  
Use of Specimens and Data for Future Research 
 
To advance science, it is helpful for researchers to share information they get from studying 
human samples.  They do this by putting it into one or more scientific databases, where it is 
stored along with information from other studies. A researcher who wants to study the 
information must apply to the database and be approved.  Researchers use specimens and data 
stored in scientific databases to advance science and learn about health and disease.   
 
We plan to keep some of your specimens and data that we collect and use them for future 
research and share them with other researchers. We will not contact you to ask about each of 
these future uses.  If you have given permission for your samples to be used for research on 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 06-C-0051 
CONTINUATION: page 15 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
another protocol, they may be used as described in that protocol. Otherwise, these specimens and 
data will be stripped of identifiers such as name, address or account number, so that they may be 
used for future research on any topic and shared broadly for research purposes. Your specimens 
and data will be used for research purposes only and will not benefit you.  It is also possible that 
the stored specimens and data may never be used.   
Results of research done on your specimens and data will not be available to you or your doctor.  
It might help people who have cancer and other diseases in the future.   
 
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers. 
 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER: 06-C-0051 
CONTINUATION: page 16 of 17 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
OTHER PERTINENT INFORMATION 
1. 
Confidentiality.  When results of an NIH research study are reported in medical journals 
or at scientific meetings, the people who take part are not named and identified.  In most cases, 
the NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance. 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations. 
2. 
Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-
term medical care for any injury resulting from your participation in research here.  In general, 
no long-term medical care or financial compensation for research-related injuries will be 
provided by the National Institutes of Health, the Clinical Center, or the Federal Government.  
However, you have the right to pursue legal remedy if you believe that your injury justifies such 
action. 
3. 
Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research studies at 
the National Institutes of Health.  Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines. 
4. 
Problems or Questions.  If you have any problems or questions about this study, or 
about your rights as a research participant, or about any research-related injury, contact the 
Principal Investigator, Dr. Robert Yarchoan, M.D., Building 10, Room 6N106, Bethesda, MD 
20892, Telephone:  240-760-6075. You may also call the Clinical Center Patient Representative 
at 301-496-2626. If you have any questions about the use of your specimens or data for future 
research studies, you may also contact the Office of the Clinical Director at 240-760-6070.  
5. 
Consent Document.  Please keep a copy of this document in case you want to read it 
again. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER: 06-C-0051 
CONTINUATION: page 17 of 17 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby consent to 
take part in this study. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby give 
permission for my child to take part in this 
study.   
(Attach NIH 2514-2, Minor’s Assent, if 
applicable.) 
 
  
  
 
 
 
Signature of Adult Patient/ 
Legal Representative 
Date 
Signature of Parent(s)/ Guardian Date 
 
 
Print Name 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to 
participate in the study. 
 
  
  
 
Signature of Parent(s)/Guardian 
Date 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM JUNE 26, 2017 THROUGH JUNE 25, 2018.  
 
 
 
 
 
 
 
 
 
Signature of Investigator 
Date 
Signature of Witness 
Date 
 
 
Print Name 
 
 
Print Name