A Randomized Phase II Trial of Myeloablative Versus Non-Myeloablative Consolidation Chemotherapy for Newly Diagnosed Primary CNS B-cell Lymphoma
Phase: PHASE2
Conditions: Lymphoma
Sponsor: Alliance for Clinical Trials in Oncology

1 
Update #11 
 
 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
_________________________________________ 
 
PROTOCOL UPDATE TO CALGB 51101 
_________________________________________ 
 
A RANDOMIZED PHASE II TRIAL OF MYELOABLATIVE VERSUS NON-MYELOABLATIVE 
CONSOLIDATION CHEMOTHERAPY FOR NEWLY DIAGNOSED PRIMARY CNS B-CELL LYMPHOMA  
 
This study is open to FACT-accredited institutions only. 
 
 
 
 
 
 
X Update: 
 
 
Status Change: 
 
 
 
 
 
 
Eligibility changes 
 
 
Activation 
 
 
 
 
 
 
Therapy / Dose Modifications / Study Calendar changes 
 
 
Closure 
 
 
 
 
 
 
Informed Consent changes 
 
 
Suspension / temporary closure 
 
 
 
 
 
X Scientific / Statistical Considerations changes 
 
 
Reactivation 
 
 
 
 
 
 
Data Submission / Forms changes 
 
 
 
 
 
 
 
 
X Editorial / Administrative changes 
 
 
 
 
 
 
 
 
 
Other: 
 
 
 
 
 
 
IRB approval (or disapproval) is required within 90 days. Expedited review is allowed. 
Please follow your IRB of record guidelines. 
 
 
 
 
UPDATES TO THE PROTOCOL: 
 
Cover Page 
• 
 
  
 
Section 2.2 (Secondary Objective) 
Section 2.2.10 has been revised to read: “To analyze tumor tissue for gene mutational analysis via whole 
exome sequencing, copy number aberrations, and expression profiles, and to correlate these profiles with 
treatment outcomes (CALGB 151113).” 

2 
 
Section 10.2 (Biomarker Correlative Science Companion Study [CALGB 151113]) 
In Section 10.2.2, the first sentence has been revised to read: “Tumor tissue will also be analyzed for whole 
exome sequencing, copy number aberrations, and gene expression profiles in order to validate genetic 
prognostic markers and gene expression profiles in order to validate gene signatures associated with…” 
 
Section 14.4 (Sample Size Modification) 
A new final paragraph has been added to describe the revised final analysis timing due to low event rate as 
of protocol Update #11. 
 
_____________________________________________________________________________________ 
 
UPDATES TO THE MODEL CONSENT: 
 
No changes have been made to the model consent.  
 
 
 
Replacement protocol and model consent documents have been issued. 
This study remains closed to new patient accrual. 
____________________________________________________________ 
ATTACH TO THE FRONT OF EVERY COPY OF THIS PROTOCOL 
____________________________________________________________ 
 

CALGB 51101 
Version Date: 07/31/2020 
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Update #11 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
 
CALGB 51101 
A RANDOMIZED PHASE II TRIAL OF MYELOABLATIVE VERSUS NON-MYELOABLATIVE 
CONSOLIDATION CHEMOTHERAPY FOR NEWLY DIAGNOSED PRIMARY CNS B-CELL LYMPHOMA  
This study is open to FACT-accredited institutions only. 
Clinicaltrials.gov Identifier: NCT01511562 
 
Study Chair 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SWOG Co-chair 
 
 
 
  
 
 
Lymphoma Committee Chair 
 
 
Transplant Committee Chair 
 
 
Imaging Committee Chair 
 
 
 
Health Outcomes Committee Chairs 
 
 
 
Neuro-Oncology Committee Chair 
 
 
 
Pathology Committee Chair and Correlative Study Co-
Chair 
 
 
 
Neurocognitive/Quality of Life Study Co-Chair 
 
 
 
Primary Statistician 
 
 
 
Data Coordinator 
 
 
 
Imaging Study Co-Chair 
 
 
 
 
Secondary Statistician 
 
 
 
Protocol Coordinator 
 
 
 
Participating NCTN Groups: ALLIANCE/Alliance for Clinical Trials in Oncology, ECOG-ACRIN/ECOG-
ACRIN Cancer Research Group, SWOG/SWOG, and NRG/NRG Oncology. 
 

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Update #11 
Protocol Resources: 
Alliance Central Protocol Operations Program Office 
 
 
 
Alliance Statistics and Data Center 
 
 
 
Alliance Biorepository at Ohio State University (OSU) 
 
 
 
 
 
Alliance Imaging Core Lab 
 
 
 
 
OPEN 
(Oncology Patient Enrollment Network) 
 
 
AE Reporting  
 
 
Pharmacy Liaisons 
Nursing Liaison 
 
 
 
 
 
 
 
 
 
 
 

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Update #11 
CANCER TRIALS SUPPORT UNIT (CTSU) CONTACT INFORMATION 
 
For regulatory requirements: 
For patient enrollments: 
For study data submission: 
Regulatory documentation must 
be submitted to the CTSU via the 
Regulatory Submission Portal. 
 
Regulatory Submission Portal: 
(Sign in at 
            
and select the Regulatory 
Submission sub-tab under the 
Regulatory tab.)  
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately at 
to receive further 
instructions and support. 
 
Contact the CTSU Regulatory 
Help Desk at 
for 
regulatory assistance. 
Please refer to the patient 
enrollment section for 
instructions on using the 
Oncology Patient Enrollment 
Network (OPEN) which can 
be accessed at 
 
 
Contact the CTSU Help Desk 
with any OPEN-related 
questions at 
 
 
Data collection for this study will 
be done exclusively through 
Medidata Rave. Please see the 
data submission section of the 
protocol for further instructions. 
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific page of the CTSU Member website located at 
Access 
to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program - 
Identity and Access Management (CTEP-IAM) registration system and requires user log on with 
CTEP-IAM username and password. Permission to view and download this protocol and its supporting 
documents is restricted and is based on person and site roster assignment housed in the CTSU RSS. 
 
For clinical questions (i.e. patient eligibility or treatment-related) contact the Study PI of the Lead 
Protocol Organization. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail: 
CTSU General Information Line – 
 All calls and 
correspondence will be triaged to the appropriate CTSU representative. 
The CTSU website is located at 
 
 

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Update #11 
A RANDOMIZED PHASE II TRIAL 
OF MYELOABLATIVE 
VERSUS NON-MYELOABLATIVE 
CONSOLIDATION CHEMOTHERAPY FOR NEWLY DIAGNOSED PRIMARY CNS B-CELL LYMPHOMA  
Schema page 1 of 1 
 
Eligibility Criteria 
Required Laboratory Values 
Diffuse large B-cell lymphoma confined to the CNS; diagnosis by brain 
biopsy or resection, CSF, or vitreous fluid 
ANC:                ≥ 1500/mcL 
AST & ALT:   ≤ 2 x ULN 
No evidence of NHL outside of CNS; no history of NHL 
Total bilirubin: ≤ 3 mg/dL 
No prior chemotherapy or radiation therapy for lymphoma 
Age 18 – 75 years 
Platelets:          ≥100,000/mcL 
CrCl:                ≥ 50 mL/min 
Karnofsky Performance Scale ≥ 30 (≥ 50 for patients ages 60-70) 
Non-pregnant and non-nursing 
Negative HIV serology 
Negative HCV serology 
No history of organ transplantation or ongoing immunosuppressant therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*One cycle will be 28 days in length 
**Please note for institutions that cannot 
administer Rituximab on day 3, +/- 3 day 
windows are allowed.  
Induction (5 cycles*) 
 
Cycle 1: 
Methotrexate 8 g/m2 IV, Days 1 and 15 
Temozolomide 150 mg/m2 PO, Days 7-11 
Rituximab 375 mg/m2 IV, Days 3, 10, 17, 24** 
Cycle 2: 
Methotrexate, 8 g/m2 IV, Days 1 and 15 
Temozolomide, 200 mg/m2 PO, Days 7-11 
Rituximab 375 mg/m2 IV, Days 3 and 10** 
 
Cycles 3 and 4: 
Methotrexate 8 g/m2 IV, Days 1 and 15 
Temozolomide 200 mg/m2 PO, Days 7-11 
Cycle 5: 
Cytarabine, 2 g/m2 IV, Q12 hours, Days 1 and 2 
 
CONSOLIDATION WITH STEM CELL RESCUE 
Carmustine, 400 mg/m2 IV, Day -6 
Thiotepa, 5mg/kg IV Q12 hours, Days -5 and -4 
Stem Cell Infusion, Day 0 
G-CSF 5 mcg/kg/day SC, Day +4 until ANC> 1500 mcL 
 
CONSOLIDATION (1 cycle*) 
 
Cytarabine 2 g/m2 IV Q12 hours, Days 1-4 
 
Etoposide 5 mg/kg IV over 12 hours Q12 hours 
x 8 doses (total dose 40 mg/kg CIVI over 96 
hours), Days 1-4 
 
G-CSF 5 mcg/kg/day SC, Day +4 until ANC> 
1500 mcL 
ARM 1 
ARM 2 
STEM CELL MOBILIZATION AND 
COLLECTION, Per Institutional Guidelines 
Option: G-CSF, 10 mcg/kg SC for 4 consecutive days, 
Collection on 5th day 
RESTAGING 
RANDOMIZATION TO ARM 1 OR ARM 2 
REGISTRATION 

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Update #11 
TABLE OF CONTENTS 
1.0     INTRODUCTION ............................................................................................................................. 7 
1.1 
BACKGROUND ................................................................................................................................ 7 
1.2 
INDUCTION CHEMOTHERAPY FOR PCNSL ..................................................................................... 7 
1.3 
CONSOLIDATION CHEMOTHERAPY FOR PCNSL ............................................................................ 9 
1.4 
HDT/ASCT FOR NEWLY DIAGNOSED PCNSL ............................................................................... 9 
1.5 
INCLUSION OF WOMEN AND MINORITIES ..................................................................................... 11 
2.0 
OBJECTIVES ................................................................................................................................ 11 
2.1 
PRIMARY OBJECTIVE .................................................................................................................... 11 
2.2 
SECONDARY OBJECTIVES ............................................................................................................. 11 
3.0 
ON-STUDY GUIDELINES ........................................................................................................... 12 
4.0 
ELIGIBILITY CRITERIA ........................................................................................................... 13 
4.1 
DOCUMENTATION OF DISEASE ..................................................................................................... 13 
4.2 
OTHER LYMPHOMAS .................................................................................................................... 13 
4.3 
PREVIOUS TREATMENT ................................................................................................................. 13 
4.4 
AGE ............................................................................................................................................... 13 
4.5 
KARNOFSKY PERFORMANCE SCALE ............................................................................................. 13 
4.6 
PREGNANCY AND NURSING STATUS ............................................................................................ 13 
4.7 
HIV ............................................................................................................................................... 13 
4.8 
HEPATITIS ..................................................................................................................................... 13 
4.9 
ORGAN TRANSPLANT OR IMMUNOSUPPRESSANT THERAPY ........................................................ 13 
4.10 
REQUIRED INITIAL LABORATORY VALUES: ............................................................................. 13 
5.0 
REGISTRATION/RANDOMIZATION, DATA SUBMISSION, HISTOLOGY REVIEW, 
AND CORRELATIVE SCIENCE SAMPLE SUBMISSION ............................................................... 14 
5.1 
REGISTRATION REQUIREMENTS ................................................................................................... 14 
5.2 
CTEP REGISTRATION PROCEDURES ............................................................................................. 14 
5.3 
CTSU SITE REGISTRATION PROCEDURES .................................................................................... 15 
5.4 
REGISTRATION TO COMPANION STUDIES CALGB 151113, 581101, AND 71105 ........................ 17 
5.5 
STRATIFICATION FACTORS ........................................................................................................... 17 
5.6 
DATA SUBMISSION ....................................................................................................................... 18 
5.7 
SPECIMEN REGISTRATION AND TRACKING .................................................................................. 19 
5.8 
HISTOLOGIC REVIEW .................................................................................................................... 19 
5.9 
SAMPLE SUBMISSION FOR CORRELATIVE STUDY 151113 ............................................................ 20 
5.10 
IMAGE SUBMISSION FOR CORRELATIVE STUDY CALGB 581101 ............................................ 21 
5.11 
DATA SUBMISSION FOR NEUROCOGNITIVE AND QUALITY OF LIFE CORRELATIVE STUDY 
CALGB 71105......................................................................................................................................... 22 
6.0 
REQUIRED DATA ........................................................................................................................ 24 
7.0 
TREATMENT PLAN .................................................................................................................... 26 
7.1 
INDUCTION CHEMOTHERAPY (CYCLES 1 AND 2).......................................................................... 26 
7.2 
INDUCTION CHEMOTHERAPY (CYCLES 3 AND 4).......................................................................... 27 
7.3 
INDUCTION CHEMOTHERAPY (CYCLE 5) ...................................................................................... 28 
7.4 
RESTAGING ................................................................................................................................... 29 
7.5 
ARM 1 CONSOLIDATION THERAPY ............................................................................................... 29 
7.6 
ARM 2 CONSOLIDATION THERAPY ............................................................................................... 30 
8.0 
DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITY ........................................ 31 
8.1 
HEMATOLOGIC TOXICITY ............................................................................................................. 31 
8.2 
HEPATIC DYSFUNCTION ............................................................................................................... 32 
8.3 
NEUROPSYCHIATRIC TOXICITY .................................................................................................... 32 

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8.4 
GASTROINTESTINAL TOXICITY ..................................................................................................... 33 
8.5 
RENAL DYSFUNCTION .................................................................................................................. 33 
8.6 
PULMONARY TOXICITIES .............................................................................................................. 33 
8.7 
OTHER NON-HEMATOLOGIC TOXICITY DOSE MODIFICATIONS ................................................... 34 
8.8 
DOSE MODIFICATION FOR NON-OBESE AND OBESE PATIENTS .................................................... 34 
9.0 
ANCILLARY THERAPY ............................................................................................................. 34 
9.1 
SUPPORTIVE CARE ........................................................................................................................ 34 
9.2 
STEROIDS ...................................................................................................................................... 34 
9.3 
ANTICONVULSANTS ...................................................................................................................... 34 
9.4 
PALLIATIVE RADIATION ............................................................................................................... 35 
9.5 
ALLIANCE POLICY CONCERNING THE USE OF GROWTH FACTORS .............................................. 35 
10.0 
CORRELATIVE SCIENCE COMPANION STUDIES ......................................................... 35 
10.1 
IMAGING CORRELATIVE SCIENCE COMPANION STUDY (CALGB 581101) .............................. 35 
10.2 
BIOMARKER CORRELATIVE SCIENCE COMPANION STUDY (CALGB 151113) ......................... 40 
10.3 
NEUROCOGNITIVE AND QUALITY OF LIFE CORRELATIVE SCIENCE STUDY (CALGB 71105) . 41 
11.0 
DRUG FORMULATION, AVAILABILITY AND PREPARATION ................................... 45 
11.1 
METHOTREXATE ....................................................................................................................... 45 
11.2 
LEUCOVORIN ............................................................................................................................. 46 
11.3 
TEMOZOLOMIDE ........................................................................................................................ 46 
11.4 
RITUXIMAB ............................................................................................................................... 47 
11.5 
CYTARABINE ............................................................................................................................. 48 
11.6 
G-CSF ....................................................................................................................................... 49 
11.7 
CARMUSTINE ............................................................................................................................. 49 
11.8 
THIOTEPA .................................................................................................................................. 50 
11. 9 
ETOPOSIDE ................................................................................................................................ 50 
12.0 
CRITERIA FOR RESPONSE, PROGRESSION AND RELAPSE ....................................... 51 
12.1 
DEFINITIONS OF RESPONSE ....................................................................................................... 51 
13.0 
REMOVAL OF PATIENTS FROM PROTOCOL THERAPY ............................................ 52 
13.1 
DURATION OF TREATMENT ....................................................................................................... 52 
13.2 
EXTRAORDINARY MEDICAL CIRCUMSTANCES ......................................................................... 52 
14.0 
STATISTICAL CONSIDERATIONS ...................................................................................... 53 
14.1 
RANDOMIZATION ...................................................................................................................... 53 
14.2 
SAMPLE SIZE / POWER CALCULATION ...................................................................................... 53 
14.3 
ANALYSIS PLAN FOR PRIMARY ENDPOINT ............................................................................... 53 
14.4 
SAMPLE SIZE MODIFICATION .................................................................................................... 54 
14.5 
MONITORING FOR ADVERSE EVENTS AND STUDY FEASIBILITY .............................................. 54 
14.6 
SECONDARY ENDPOINTS ........................................................................................................... 55 
14.7 
CORRELATIVE SCIENCE COMPANION STUDY ANALYSES ......................................................... 55 
14.8 
ACCRUAL AND FOLLOW-UP ...................................................................................................... 57 
14.9 
CDUS REPORTING .................................................................................................................... 57 
15.0 
EXPEDITED ADVERSE EVENT REPORTING ................................................................... 58 
15.1 
CALGB 51101 REPORTING REQUIREMENTS ............................................................................ 58 
16.0 
REFERENCES ........................................................................................................................... 61 
APPENDIX I 
IDEAL BODY WEIGHT TABLE FOR CORRECTED BODY WEIGHT 
FORMULA 
67 
APPENDIX II 
PERFORMANCE STATUS CRITERIA................................................................... 68 
 
 

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1.0 
INTRODUCTION 
1.1 
Background 
Primary central nervous system lymphoma (PCNSL), an uncommon form of extranodal non-
Hodgkin lymphoma (NHL), is a potentially curable cancer. However, the 5-year survival rates 
for PCNSL are inferior to those achieved for other forms of extranodal NHL. An estimated 1,927 
cases of PCNSL were diagnosed each year in the U.S. from 2004 to 2006 and the number of 
cases is expected to increase further with the aging of the U.S. population [1]. The optimal 
treatment approach for newly diagnosed PCNSL patients has yet to be defined, partially due to 
the lack of data from prospective randomized trials. Age and performance status are important 
prognostic factors in patients with PCNSL [2]. The International PCNSL Collaborative Group 
(IPCG) has established consensus guidelines for extent of disease evaluation, neurocognitive 
assessment, and tumor response in the newly diagnosed PCNSL patient population [2, 3]. 
Historically, whole brain irradiation was an integral component of therapy for newly diagnosed 
PCNSL. However, the limitations of treating PCNSL initially with whole brain irradiation alone 
are clear. Despite maximization of radiation dose, median survival has remained in the range of 
10-18 months. A plateau in survival has been achieved with current therapy using methotrexate-
based regimens plus whole brain irradiation. This approach results in a median survival of 
approximately 40 months with a 22% five-year survival [4]. These results are in contrast to the 
treatment outcome of patients who have localized non-CNS NHL who have at least a 75% rate 
of long-term disease-free survival with combined modality therapy [5]. Moreover, regimens that 
include whole brain irradiation are associated with a significant risk of long-term neurotoxicity. 
The median age of persons diagnosed with PCNSL is 60 [1]. The majority of patients aged 60 
or over who are treated with whole brain irradiation will exhibit clinically measurable 
neurotoxicity [4]. It is also recognized that a significant proportion of patients under the age of 
60 who are treated with whole brain irradiation will also manifest symptoms and signs of 
neurotoxicity.  Preliminary reports suggest that when lower doses of whole brain irradiation are 
administered with chemotherapy the risk of neurotoxicity may be lower, although these reports 
have yet to be confirmed [6]. In one study reduction of whole brain irradiation compromised 
survival in the PCNSL patient population [7]. Moreover, preclinical studies indicate that even 
single fractions of whole brain irradiation may lead to irreversible injury to neural progenitor 
cell populations [7]. Therefore, there has been significant interest in developing alternatives to 
whole brain irradiation in the induction and consolidation treatment phases for PCNSL patients. 
1.2 
Induction Chemotherapy for PCNSL 
Deferral of whole brain irradiation and use of chemotherapy alone in the newly diagnosed 
PCNSL patient population is a strategy used by an increasing number of clinicians [8]. Primary 
central nervous system lymphomas exhibit a unique responsiveness to methotrexate compared 
to systemic lymphomas [9, 10]. High-dose methotrexate-based therapies currently represent the 
most effective regimen in this disease. A univariate analysis of a retrospective series of 226 
patients diagnosed with PCNSL suggests that use of high-dose methotrexate is the only 
treatment-related factor with independent positive prognostic value after adjustment for age, 
performance status and CSF protein level. Treatment with regimens that included high-dose 
methotrexate were associated with significantly better overall survival compared with other 
treatments (p<0.0007) [9]. High-dose methotrexate treatment results in prolonged cytotoxic CSF 
concentrations that are comparable to those achieved with intrathecal administration of the drug 
[11]. Although the optimal dose and administration schedule of methotrexate remain a topic of 
debate it appears that doses > 3 g/m2 every 14-21 days are preferable in this patient population. 
Toxicity is acceptable with moderate nausea and reversible nephrotoxicity being the most 
common early side effects. Delayed toxicities such as brain necrosis and dementia, which are 
observed in patients receiving whole brain irradiation, are rare in patients treated with single-

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Update #11 
agent high-dose methotrexate. In a multicenter phase II study of high-dose methotrexate (8 g/m2) 
alone in patients with newly diagnosed PCNSL, the complete response (CR) proportion was 
52%, the progression-free survival was 12.8 months, the overall survival was 55.4 months and 
the disease-specific survival was 72.3+ months. The median number of cycles to achieve CR 
was 6 in this study. Five of 25 of these patients had not relapsed after a median follow-up of 
approximately 7 years. Less than half of these patients experienced CTC grades 3 or 4 toxicities 
[8, 12]. A subsequent randomized study (IELSG 20) of methotrexate monotherapy versus 
methotrexate + cytarabine in 79 newly diagnosed PCNSL patients demonstrated a higher overall 
and complete radiographic response proportion in the combination arm versus methotrexate 
alone, 69% and 46% versus 41% and 18%, respectively. Hematologic and infectious 
complications were more common in the methotrexate and cytarabine arm compared to the 
methotrexate monotherapy arm [3]. Based on these and other studies methotrexate has emerged 
as the foundation of the chemotherapy regimens for patients with newly diagnosed PCNSL. 
Rituximab, a chimeric anti-CD20 monoclonal antibody, is a potentially attractive therapeutic 
agent for PCNSL since at least 90% of CNS lymphomas express CD20. Rituximab enhances 
the efficacy of cytotoxic therapy in the treatment of diffuse large cell lymphoma (the most 
common histologic subtype in PCNSL) [13]. While penetration of this macromolecule into the 
CNS is limited, there are several facts that support the notion that rituximab may be a beneficial 
agent for PCNSL therapy. During the first weeks of treatment of PCNSL, the tumor is associated 
with an abnormal vasculature devoid of a normal blood-brain-barrier. After 5 weeks of 
treatment, blood-brain permeability values approach the level of normal brain [14]. Compromise 
of the blood-brain barrier through tumor cell angiotropism and by the elaboration of cytokines 
may contribute to this increased permeability [15]. Rituximab can be reproducibly detected in 
the CSF of patients with PCNSL who are treated systemically with this drug [16-18]. In 
individual case reports complete and partial responses have been described in patients with 
either PCNSL or post-transplant lymphoproliferative disorder (PTLD) involving the CNS who 
have been treated with intravenous rituximab [16, 17]. In a pilot study of 12 patients with 
relapsed or refractory PCNSL treated with rituximab alone (375 mg/m2 weekly x 8 doses), 
radiographic responses were observed in 5 patients (4 CR, 1 PR) and the median progression-
free and overall survival in the responding patients was 7.6 months and 47 months, respectively 
[19]. Finally, there is minimal toxicity associated with rituximab treatment of PCNSL, nor is 
there overlapping toxicity with the co-administration of rituximab and high-dose methotrexate 
(8 g/m2) or cytarabine [16]. 
Temozolomide is an oral alkylating agent that is highly lipophilic and thus exhibits good CNS 
penetrance. Based on these properties it is an attractive candidate drug for use in PCNSL. In a 
phase II study of 23 patients with relapsed PCNSL who were treated with temozolomide alone, 
radiographic responses were observed in 6 patients (5 CR, 1 PR) and the median progression-
free survival was 2 months (range 0.4 to 36 months) [20]. In a study of 17 elderly PCNSL 
patients (ages 62-90) treated with single-agent temozolomide, 8/17 (47%) achieved a complete 
radiographic response with a median progression-free survival of 5 months and a median overall 
survival of 21 months [21]. In another study of elderly PCNSL patients, temozolomide and 
methotrexate (3 g/m2) were administered to 23 patients and 55% of patients achieved a complete 
radiographic response with a median progression-free survival of 8 months and a median overall 
survival of 35 months [22]. In a study of temozolomide and rituximab for relapsed and refractory 
PCNSL patients, 8/15 patients achieved radiographic responses; the median progression-free 
survival was 7.7 months and the overall survival was 14 months [23]. In another study of 8 
patients with newly diagnosed or relapsed CNS lymphoma, temozolomide and rituximab were 
administered together for 4 weeks followed by 8 monthly cycles of temozolomide alone. Seven 
(5 CR, 2 PR) patients achieved a radiographic response with a median progression-free survival 
of 6 months and median overall survival of 8 months [24]. These phase II studies demonstrate 
that temozolomide alone or in combination with rituximab or methotrexate has objective activity 

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Update #11 
against PCNSL and provides a strong rationale for assessment of a combination regimen 
containing all of these agents in this patient population. 
The combination of methotrexate, temozolomide, and rituximab (MTR) as induction 
chemotherapy has been utilized successfully in both the single center and the multicenter setting 
as induction therapy in PCNSL. In a single-center study MTR was administered as induction 
therapy to newly diagnosed (10) or relapsed (6) PCNSL patients with 10/10 (9 CR, 1 PR) and 
6/6 (4 CR, 2 PR) radiographic responses, respectively [25]. In a multicenter phase II study 
(CALGB 50202) MTR was administered to 46 newly diagnosed PCNSL patients. In this latter 
study, 63% of patients achieved a complete radiographic response [26]. As noted above, each 
of the drugs in the MTR regimen has been studied in single-agent trials with objective efficacy 
observed in the PCNSL patient population. 
1.3 
Consolidation Chemotherapy for PCNSL 
The optimal consolidation regimen for PCNSL has yet to be established. Whole brain irradiation 
is associated with a high frequency of neurotoxicity, especially in patients over the age of 60 
[27]. Study results from the largest prospective, randomized trial conducted in the newly 
diagnosed PCNSL population regarding the role of whole brain irradiation (G-PCNSL-SG-1) 
have yielded conflicting interpretations [28]. In the intent to treat analysis of this study, whole 
brain irradiation as consolidation improved progression-free survival but not overall survival. 
Lower doses of whole brain irradiation have been advocated but there is no proof that such a 
strategy is associated with a lower incidence of neurotoxicity [28]. Deferral of whole brain 
irradiation and use of chemotherapy is associated with a lower incidence of neurotoxicity and 
may be as effective as regimens that contain whole brain irradiation. Chemotherapy alone is 
associated with promising 2-year progression-free survival proportions of 30-57% [3, 26, 29]. 
However, the optimal consolidation chemotherapy for the PCNSL patient population has yet to 
be defined. 
In the phase II CALGB 50202 study consolidation consisted of etoposide and cytarabine. This 
regimen has been used effectively as a salvage regimen for PCNSL patients [30]. Good diffusion 
of cytarabine and etoposide in the CNS has been demonstrated. High-dose cytarabine achieves 
effective levels in brain parenchyma and CSF. Regimens that include cytarabine are also 
associated with improved survival in PCNSL on univariate analysis (p<0.04) [31]. 
Neurotoxicity with high-dose cytarabine is preventable when doses are reduced in accordance 
with serum creatinine levels [32]. There is no cross-resistance between cytarabine, etoposide 
and methotrexate. This regimen is efficacious in patients with Burkitt lymphoma and initial CNS 
disease [33]. Moreover, the combination of high-dose cytarabine plus etoposide appears to be 
feasible and safe in the multicenter setting. In a study of 128 patients with AML treated with 
autologous stem cell transplantation in first remission, only two patients experienced transient 
neurotoxicity related to high-dose cytarabine but both recovered completely [34]. In CALGB 
50202 the treatment was associated with reversible grade IV myelotoxicity but was feasible and 
reasonably well tolerated in the multicenter setting [26]. Moreover, this consolidation strategy 
was associated with excellent 2-year progression-free survival (55%) and 2-year overall survival 
(71%). 
1.4 
HDT/ASCT for Newly Diagnosed PCNSL 
Although the studies are relatively small and non-randomized, high-dose therapy and autologous 
stem cell transplant (HDT/ASCT) is associated with promising long-term OS results for PCNSL 
patients. The avoidance of whole brain irradiation appears to preserve cognitive function in 
long-term survivors. HDT/ASCT studies for PCNSL are summarized in Table 1. Demonstration 
that HDT/ASCT is superior to consolidation non-myeloablative chemotherapy could rapidly 
change the standard of care for the newly diagnosed PCNSL patient population under the age of 
70 (> 50% of all PCNSL patients in the United States). 

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Update #11 
HDT/ASCT was initially studied in the PCNSL patient population in the setting of relapsed or 
refractory disease [30]. Investigators administered a salvage regimen consisting of cytarabine 
or etoposide followed by conditioning therapy with thiotepa, busulfan, and cyclophosphamide 
[30]. Based on promising median PFS and OS results of 41 and 58 months, respectively, this 
strategy was next employed in the newly diagnosed PCNSL population, initially in combination 
with whole brain irradiation. Although initial results in this setting were disappointing using the 
BEAM conditioning regimen [35], subsequent studies employed regimens with potentially 
better CNS penetration including busulfan, thiotepa, and carmustine [36-38]. Recent studies 
with the latter agents have eliminated whole brain irradiation and the median PFS and OS 
achieved in these studies are promising. In a multicenter phase II study of newly diagnosed 
PCNSL patients, induction therapy with high dose methotrexate (HD-MTX), high dose 
cytarabine, and thiotepa was followed by a conditioning chemotherapy regimen consisting of 
carmustine (400 mg/m²) and thiotepa (2 x 5 mg/kg) followed by ASCT. Whole brain irradiation 
was then given as consolidation. With a median follow-up of 63 months, the 5-year OS was 
69% for all patients and 87% for those completing HDT/ASCT [39].  In a follow-up trial this 
protocol was modified with intensification of the chemotherapy and restriction of whole brain 
irradiation only for patients who did not achieve CR after induction therapy. Seven of 11 patients 
were in CR following ASCT and 3 in PR upon ASCT received whole brain irradiation as 
consolidative treatment. After a median follow-up of 25 months, 3-year OS was 77%. None of 
the patients suffered from severe neurotoxicity during the follow-up period [40]. In summary, 
HDT followed by ASCT is likely to assume an increasingly important role in patients with 
PCNSL in the newly diagnosed and relapsed setting. ASCT may be effective in patients with 
poor prognostic features as well [41]. 
Reference 
N 
Median 
Age 
Induction 
regimen 
Conditioning 
regimen 
WBI 
 
CRR
[%] 
FU 
[mos] 
Survival 
TRM 
Columbat et 
al 2006 [42] 
25 
51 
MBVP 
+i.t. AraC 
BEAM 
yes 
44% 
34 
4-y EFS: 
46% 
4% 
Abrey et al 
2003 [35] 
28 
53 
MTX 
AraC 
BEAM 
no 
18% 
27 
mEFS: 9 
mo 
0% 
Stewart et 
al 2004 [36] 
11 
56 
MTX 
Thiotepa 
Busulfan 
Cy 
yes 
82% 
22 
3-yr OS: 
61% 
18% 
Illerhaus et 
al 2006 [39] 
30 
54 
MTX (8g) 
AraC/TT 
Thiotepa 
(10mg/kg) 
BCNU 
yes* 
76% 
63 
5-yr OS: 
69% 
3% 
Monte-
murro et al 
2007 [37] 
23 
55 
MTX (8g) 
Bu / TT 
(10mg/kg) 
yes* 
69% 
15 
2-yr OS: 
48% 
13% 
Illerhaus et 
al 2008 [40] 
13 
54 
MTX (8g) 
AraC/TT 
TT (20mg/kg) 
/BCNU  
no 
54% 
25 
3-yr OS: 
77% 
0% 
AraC, cytarabine; ASCT, autologous stem cell transplantation; BCNU, carmustine; BEAM (regimen), carmustine, 
etoposide, cytarabine, and melphalan; Bu, busulfan; Cy, cyclophosphamide; IFO, ifosfamide; i.t., intrathecal; MBVP 
(regimen), methotrexate, carmustine, etoposide, and methylprednisolone; OS, overall survival; TRM, treatment-
related mortality; TT, thiotepa; WBI, whole-brain irradiation.  
*Only for patients not achieving a complete remission 

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1.5 
Inclusion of Women and Minorities 
It is the intent of Alliance to enroll patients regardless of gender or race. Both men and women 
of all races and ethnic groups are eligible for this study. In the development of this protocol, the 
possibility of inherent gender or racial/ethnic differences in treatment response has been 
considered. 
PLANNED ENROLLMENT REPORT 
Racial 
Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ 
Alaska Native 
0 
0 
0 
0 
0 
Asian 
3 
3 
0 
0 
6 
Native Hawaiian 
or Other Pacific 
Islander 
1 
1 
0 
0 
2 
Black or African 
American 
3 
3 
0 
0 
6 
White 
38 
47 
2 
1 
88 
More Than One 
Race 
5 
1 
1 
1 
8 
Total 
50 
55 
3 
2 
110 
 
2.0 
OBJECTIVES  
2.1 
Primary Objective 
To compare the two-year progression-free survival (PFS) of patients treated with the 
myeloablative consolidation treatment strategy of HDT/ASCT versus those treated with non-
myeloablative consolidation chemotherapy with cytarabine and etoposide 
2.2 
Secondary Objectives 
2.2.1 To compare the two-year event-free survival (EFS) of patients treated with consolidation 
HDT/ASCT versus those treated with consolidation chemotherapy consisting of etoposide 
and cytarabine 
2.2.2 To compare the overall survival (OS) of patients treated with the consolidation HDT/ASCT 
versus those treated with consolidation chemotherapy consisting of etoposide and 
cytarabine 
2.2.3 To assess the toxicities associated with consolidation HDT/ASCT versus consolidation 
consisting of etoposide and cytarabine 
2.2.4 To determine diffusion MRI metrics (ADCmini, ADC25%, and ADCmean) prior to induction 
chemotherapy, after one full induction chemotherapy cycle, and at the end of induction 
chemotherapy as a predictor of response and outcome (CALGB 581101) 
2.2.5 To determine brain FDG-PET metrics (tumor SUV and tumor versus background SUV) 
prior to induction chemotherapy, after one full induction chemotherapy cycle, and at the 
end of induction chemotherapy as a predictor of response and outcome (CALGB 581101) 
2.2.6 To determine whether low baseline ADC measurements are associated with shorter PFS 
and OS (CALGB 581101) 

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2.2.7 To determine whether reduction in tumor SUV by > 25% on brain FDG-PET/CT after one 
cycle of induction therapy is associated with improved PFS and OS (CALGB 581101) 
2.2.8 To determine which IHC-based biomarkers are predictive of an adverse prognosis 
(CALGB 151113) 
2.2.9 To determine which IHC-based biomarkers are predictive of a favorable prognosis 
(CALGB 151113) for BCL6 (B-cell CLL/lymphoma 6), and STAT 6 (signal transducer 
and activator of transcription 6, interleukin-4 induced) 
2.2.10 To analyze tumor tissue for gene mutational analysis via whole exome sequencing, copy 
number aberrations, and expression profiles, and to correlate these profiles with treatment 
outcomes (CALGB 151113) 
2.2.11 To determine whether CSF proteome is a predictor of outcomes (prognostic marker) 
irrespective of treatment arm [43] (CALGB 151113) for (IL-10 (interleukin 10) and C3 
(complement component 3) 
2.2.12 To assess the neurocognitive function of patients treated with consolidation HDT/ASCT 
versus those treated with consolidation chemotherapy (etoposide and cytarabine) as 
measured by serial administration of the International PCNSL Collaborative Group (IPCG) 
neurocognitive battery and evaluate the long-term survivorship differences between the 
two arms (CALGB 71105) 
2.2.13 To assess the quality of life of patients treated with consolidation HDT/ASCT versus those 
treated with consolidation etoposide and cytarabine as measured by the EORTC Quality of 
Life Questionnaire-Core 30/Brain Cancer Module-20 (EORTC-QLQ30/BCM20), and to 
evaluate the long-term survivorship differences between the two arms (CALGB 71105) 
3.0 
ON-STUDY GUIDELINES 
This clinical trial can fulfill its objectives only if patients appropriate for this trial are enrolled. All 
relevant medical and other considerations should be taken into account when deciding whether this 
protocol is appropriate for a particular patient. Physicians should consider the risks and benefits of 
any therapy, and therefore only enroll patients for whom this treatment is appropriate. Although 
they will not be considered formal eligibility (exclusion) criteria, physicians should recognize that 
the following may seriously increase the risk to a patient entering this protocol: 
• 
Psychiatric illness that would prevent the patient from giving informed consent. 
• 
Medical condition such as uncontrolled infection, uncontrolled diabetes mellitus or cardiac 
disease, which, in the opinion of the treating physician, would make this protocol unreasonably 
hazardous for the patient. 
• 
Patients with prior or concurrent malignancies other than surgically cured CIS of the uterus or 
cervix and carcinoma of the skin without evidence of disease for ≥ 5 years. 
• 
Women and men of reproductive potential should agree to use an appropriate method of birth 
control throughout their participation in this study due to the teratogenic potential of the therapy 
utilized in this trial. Appropriate methods of birth control include abstinence, oral 
contraceptives, implantable hormonal contraceptives, or double barrier method (diaphragm 
plus condom). 
• 
Patients must be considered to be a suitable candidate for high dose chemotherapy and 
autologous stem cell transplant at the time of initial evaluation based on medical history, 
physical examination, and available basic laboratory tests. Specific testing for organ function 
is not required, but if available, these tests may be used to judge suitability. 

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Update #11 
4.0 
ELIGIBILITY CRITERIA 
All questions regarding eligibility criteria should be directed to the Alliance Study Chair. Please 
note that the Study Chair cannot grant waivers to eligibility requirements. 
4.1 
Documentation of Disease 
Diagnosis of primary CNS diffuse large B-cell lymphoma confirmed by one of the following: 
Brain biopsy or resection 
Cerebrospinal fluid 
Vitreous fluid 
4.2 
Other Lymphomas 
Patients must have no evidence or history of non-Hodgkin lymphoma (NHL) outside of CNS. 
4.3 
Previous Treatment 
Patients must have no prior chemotherapy or radiation therapy for lymphoma. 
4.4 
Age 
Patients must be between the ages of 18 and 75 years. 
4.5 
Karnofsky Performance Scale 
Patients must measure Karnofsky Performance Scale ≥ 30 (≥ 50 for patients ages 60-70). 
4.6 
Pregnancy and Nursing Status 
Patients must be non-pregnant and non-nursing. Due to the unknown teratogenic potential of 
this regimen, pregnant or nursing patients may not be enrolled. Women of childbearing potential 
must have a negative serum or urine pregnancy test 10-14 days prior to registration. In addition, 
women and men of childbearing potential must commit to use an effective form of contraception 
throughout their participation in this study due to the teratogenic potential of the therapy utilized 
in this trial. Appropriate methods of birth control include abstinence, oral contraceptives, 
implantable hormonal contraceptives, or double barrier method (diaphragm plus condom). 
4.7 
HIV 
Patients must have negative HIV serology. 
4.8 
Hepatitis 
Patients must have negative HCV serology. All patients must be screened for hepatitis B 
infection before starting treatment. Those patients who test positive for hepatitis B should be 
closely monitored for evidence of active HBV infection and hepatitis during and for several 
months after rituximab treatment. PCNSL patients with a history of hepatitis B infection should 
be treated with entecavir or lamivudine (physician discretion for choice of drug) as antiviral 
prophylaxis to prevent hepatitis B reactivation. 
4.9 
Organ Transplant or Immunosuppressant Therapy 
Patient must have no history of organ transplantation or ongoing immunosuppressant therapy. 
4.10 
Required Initial Laboratory Values: 
ANC 
≥ 1500/mcL 
AST and ALT 
< 2 x upper limit of normal (ULN) 
Total bilirubin 
≤ 3 mg/dL 

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Creatinine clearance 
≥ 50 mL/min 
Platelet count 
≥ 100,000/mcL 
5.0 
REGISTRATION/RANDOMIZATION, 
DATA 
SUBMISSION, 
HISTOLOGY 
REVIEW, 
AND 
CORRELATIVE SCIENCE SAMPLE SUBMISSION 
5.1 
Registration Requirements 
The patient must be aware of the neoplastic nature of his/her disease and willingly consent after 
being informed of the procedure to be followed, the experimental nature of the therapy, 
alternatives, potential benefits, side effects, risks, and discomforts. Human protection committee 
approval of this protocol and a consent form is required. 
Registration must occur prior to the initiation of therapy.  
Registration to the optional correlative science companion studies will be performed at the time 
registration occurs to the treatment study. Registration to both the treatment study and the 
correlative studies will not be completed if eligibility requirements are not met for both trials. 
5.1.1 Quarterly Teleconference  
Institutional PIs will be invited and strongly encouraged to participate in quarterly 
teleconference calls with the study team to discuss patient enrollment and protocol 
treatment questions. 
5.2 
CTEP Registration Procedures  
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually. To register, all individuals must obtain a Cancer Therapy Evaluation 
Program 
(CTEP) 
Identity 
and 
Access 
Management 
(IAM) 
account 
. In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff 
requiring write access to OPEN, RAVE, or TRIAD or acting as a primary site contact) must 
complete their annual registration using CTEP’s web-based Registration and Credential 
Repository (RCR) 
 Documentation requirements per 
registration type are outlined in the table below. 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 

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Update #11 
Documentation Required 
IVR 
NPIVR 
AP 
A 
CV (optional) 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and CTSU (Cancer Trials Support Unit) websites and applications. In addition, IVRs and 
NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the FDA 
Form 1572 in RCR to allow the following: 
• Added to a site roster 
• Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• Act as the site-protocol PI on the IRB approval 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
< 
 
 
5.3 
CTSU Site Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval:   
Each investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory 
Office before they can be approved to enroll patients. Assignment of site registration status in 
the CTSU Regulatory Support System (RSS) uses extensive data to make a determination of 
whether a site has fulfilled all regulatory criteria including but not limited to the following:  
• 
An active Federal Wide Assurance (FWA) number 
• 
An active roster affiliation with the Lead Network or a participating organization 
• 
A valid IRB approval 
• 
Compliance with all protocol specific requirements 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• 
Active registration status 
• 
The IRB number of the site IRB of record listed on their Form FDA 1572 
• 
An active status on a participation roster at the registering site 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are 
not required to submit IRB approval documentation to the CTSU Regulatory Office. For sites 
using the CIRB, IRB approval information is received from the CIRB and applied to the RSS in 
an automated process. Signatory Institutions must submit a Study Specific Worksheet for Local 
Context (SSW) to the CIRB via IRBManager to indicate their intent to open the study locally. 
The CIRB’s approval of the SSW is then communicated to the CTSU Regulatory Office. In 
order for the SSW approval to be processed, the Signatory Institution must inform the CTSU 
which CIRB-approved institutions aligned with the Signatory Institution are participating in the 
study. 
5.3.1 
Downloading Site Registration Documents  
Site registration forms may be downloaded from the CALGB-51101 protocol page located 
on the CTSU members’ website.  
• 
Go to 
and log in to the members’ area using your CTEP-
IAM username and password 
• 
Click on the Protocols tab in the upper left of your screen 

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Update #11 
• 
Either enter the protocol # in the search field at the top of the protocol tree, or 
• 
Click on the By Lead Organization folder to expand 
• 
Click on the Alliance link to expand, then select trial protocol #CALGB-51101 
• 
Click on LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided.   
5.3.2 
Requirements for CALGB 51101 Site Registration  
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol of Human 
Subjects Assurance Identification/IRB Certification/Declaration of Exemption 
Form, or combination is accepted) 
5.3.3 
Checking Your Site’s Registration Status  
You can verify your site registration status on the members’ section of the CTSU website.   
• 
Go to 
and log in to the members’ area using your CTEP-
IAM username and password 
• 
Click on the Regulatory tab 
• 
Click on the Site Registration tab 
• 
Enter your 5-character CTEP Institution Code and click on Go 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements outlined by the Lead Network. It does not 
reflect compliance with protocol requirements for individuals participating on the protocol 
or the enrolling investigator’s status with the NCI or their affiliated networks. 
5.3.4 
Submitting Regulatory Requirements  
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal, where they will be entered and tracked in the CTSU RSS.  
Regulatory Submission Portal: 
(members’ area)  Regulatory Tab  Regulatory Submission 
When applicable, original documents should be mailed to: 
 
 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instructions 
and support.  
5.3.5 OPEN Access Requirements and Procedures 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN). OPEN is a web-based registration system available on a 24/7 basis. To access 
OPEN, the site user must have an active CTEP-IAM account (check at < 
>) and a 'Registrar' role on either the LPO or participating 
organization roster.  Registrars must hold a minimum of an AP registration type. 
All site staff will use OPEN to enroll patients to this study. It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the 
patient in the Rave database. OPEN can be accessed at 
 or from the 
OPEN tab on the CTSU members’ side of the website at 
 To assign 
an IVR or NPIVR as the treating, crediting, consenting, drug shipment (IVR only), or 

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Update #11 
investigator receiving a transfer in OPEN, the IVR or NPIVR must list on their Form FDA 
1572 in RCR the IRB number used on the site’s IRB approval. 
Prior to accessing OPEN, site staff should verify the following: 
• All eligibility criteria have been met within the protocol stated timeframes.  
• All patients have signed an appropriate consent form and HIPAA authorization form 
(if applicable). 
Note: The OPEN system will provide the site with a printable confirmation of registration 
and treatment information. Please print this confirmation for your records. 
Further instructional information is provided on the OPEN tab of the CTSU members’ side 
of the CTSU website at 
or at 
For any additional 
questions contact the CTSU Help Desk at 
 
5.4 
Registration to Companion Studies CALGB 151113, 581101, and 71105 
There are three correlative science companion studies within CALGB 51101: 
CALGB 151113, Exploratory Analyses of Biomarkers as Potential Predictors of 
Outcome for Primary CNS B-cell Lymphoma 
CALGB 581101, Imaging Markers of Outcome After Chemotherapy in Patients with 
Newly Diagnosed Primary CNS B-cell Lymphoma 
CALGB 71105, Neurocognitive Function and Quality of Life in Patients with Primary 
CNS B-cell Lymphoma 
The companion studies 151113 and 71105 must be offered to all patients enrolled on CALGB 
51101, although patients may opt not to participate. The companion study 581101 is only 
available at limited access institutions. Please see the study website for a list of limited access 
institutions that may register patients to 581101. The full descriptions of the companion studies 
are found in Section 10.0. 
If a patient answers “yes” to Model Consent Question #1, then the patient should be registered 
to CALGB 71105 at the same time that s/he is registered to the treatment trial (51101) with 
assessment data submitted per Section 5.11.  
If a patient answers “yes” to Model Consent Question #2, then the patient should be registered 
to CALGB 151113 at the same time that s/he is registered to the treatment trial (51101) with 
samples submitted per Section 5.9.  
If a patient is being treated at a CALGB 581101 limited access institution, and the patient 
answers “yes” to Model Consent Question #6, then the patient should be registered to CALGB 
581101 at the same time that s/he is registered to the treatment trial (51101) with images 
submitted per Section 5.10. 
5.5 
Stratification Factors 
After registration, randomization will occur according to the following three stratification 
factors (see Section 14.1): 
Age < 51 years 
Age ≥ 51 years and Karnofsky Performance Status (KPS) score ≥ 70 
Age ≥ 51 years and KPS < 70 

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5.6 
Data Submission 
Data collection for this study will be done exclusively through the Medidata Rave clinical data 
management system. Access to the trial in Rave is granted through the iMedidata application to 
all persons with the appropriate roles assigned in Regulatory Support System (RSS). To access 
Rave via iMedidata, the site user must have an active CTEP-IAM account (check at < 
>) and the appropriate Rave role (Rave CRA, Read-Only, Site 
Investigator) on either the LPO or participating organization roster at the enrolling site. To the 
hold Rave CRA role or CRA Lab Admin role, the user must hold a minimum of an AP 
registration type. To hold the Rave Site Investigator role, the individual must be registered as 
an NPIVR or IVR. Associates can hold read-only roles in Rave. 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent a study invitation e-mail from iMedidata.  To accept the 
invitation, site users must log into the Select Login 
) 
using their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page.  Please note, site users will not be able to access the study 
in Rave until all required Medidata and study specific trainings are completed.  Trainings will 
be in the form of electronic learnings (eLearnings), and can be accessed by clicking on the link 
in the upper right pane of the iMedidata screen. 
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata 
to activate their account. Account activation instructions are located on the CTSU website, Rave 
tab under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance). Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab at 
or by contacting the CTSU Help Desk at 
   
5.6.1 Routine Adverse Event Data Submission 
Common Terminology Criteria for Adverse Events: This study will utilize the 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 for routine 
toxicity and adverse event (AE) reporting. However, CTCAE v5.0 must be used for 
serious AE reporting through CTEP-AERS as of April 1, 2018. Please note that AE 
reporting stops at disease progression. 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those 
who will enroll in future studies using similar agents. Adverse events are reported in a 
routine manner at scheduled times during the trial using Medidata Rave. Additionally, 
certain adverse events must be reported in an expedited manner for more timely 
monitoring of patient safety and care. The following sections provide information about 
expedited reporting. For this trial the following forms are used for routine AE reporting 
in Rave: 
Adverse Event Form: Solicited  
Required at each assessment according to the 
Required Data Table (Section 6.0) 
Adverse Event Form: Other 
Required if any event occurs that is not pre-
populated on Adverse Event Form: Solicited 
Adverse Event Form: Late 
Required if any event occurs after the 24 month 
requirements 
 
For reporting of secondary cancers or other report forms available in Rave: 

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Update #11 
 
Malignancy Screening Form 
Submission (regardless of whether screening took 
place) required every 6 months from the start of 
treatment while on study 
Institutional Contact Information 
One time optional form available at baseline 
Family Cancer History Form 
One time optional form available at baseline 
Patient Cancer History Form 
One time optional form available at baseline 
New Malignancy Form 
Required if a new malignancy is diagnosed 
5.7 
Specimen Registration and Tracking  
USE OF THE ALLIANCE BIOSPECIMEN MANAGEMENT SYSTEM (BioMS) IS 
MANDATORY AND ALL SPECIMENS MUST BE LOGGED AND SHIPPED VIA THIS 
SYSTEM.  
BioMS is a web-based system for logging and tracking all biospecimens collected on Alliance 
trials. Authorized 
individuals 
may 
access 
BioMS 
at 
the 
following 
URL: 
 using most standard web browsers (Safari, Firefox, Internet 
Explorer).  For information on using the BioMS system, please refer to the ‘Help’ links on the 
BioMS web page to access the on-line user manual, FAQs, and training videos.  To report 
technical problems, such as login issues or application errors, please contact: 
For assistance in using the application or questions or problems related to specific 
specimen logging, please contact: 
 
After logging collected specimens in BioMS, the system will create a shipping manifest. This 
shipping manifest must be printed and placed in the shipment container with the specimens. 
5.8 
Histologic Review 
Submission of a tissue block is critical for confirmation of lymphoma diagnosis. High 
quality hematoxylin and eosin staining and any required confirmatory studies (such as 
immunohistochemistry and in situ hybridization) may be done most efficiently from the tissue 
block in laboratories of the Alliance Central Protocol Operations Program Office.  
Within 60 days of registration, send a formalin-fixed, paraffin-embedded block of well-fixed 
lymphoma tissue containing adequate material for histologic confirmation of diagnosis. A block 
at least 1 cm x 1 cm x 2 mm is preferable, although smaller is acceptable if no other block is 
suitable. If only one block exists, and the tissue is sufficiently large, it is acceptable to split the 
block into two and submit one. Contact 
 with questions. 
For patients in whom diagnosis was based on a fluid sample (CSF, vitreous), submission of 
the diagnostic slide for digital microscopy scanning and copy of pathology report (include 
consultative pathology reports) is preferred. 
Samples should be logged and shipped via the BioMS system, see Section 5.7 for 
instructions. The requested tissue block should be labeled with the protocol number (51101), 
institutional surgical pathology number, patient study ID number, institution, date of acquisition, 
and tissue source. A copy of the shipping manifest produced by BioMS must be printed and 
placed in the shipment with the specimens. In addition to the pathology specimen and the 
shipping manifest, send a copy of the pathology report (include consultative pathology reports, 
if available) to the Alliance Central Protocol Operations Program Office. 

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Failure to submit pathology materials within 60 days of patient registration will be considered 
a major protocol violation.  
If a patient has consented to participate in the biomarker correlative science research proposed 
(Model Consent Question #2), only one tissue block need be submitted to accommodate both 
histologic confirmation of diagnosis and correlative science studies (see Section 5.9.1). 
The Alliance has instituted special considerations for the small percentage of institutions whose 
policies prohibit release of any blocks. If, due to institutional policy, a block cannot be sent, 
please call 
 obtain a protocol for submission of representative tissue from your 
institution. 
Please note if a patient is positive in flow cytometry, slides do not need to be submitted.  
5.9 
Sample Submission for Correlative Study 151113 
All participating institutions must ask patients for their consent to participate in the biomarker 
correlative science companion study CALGB 151113 (Model Consent Question #2) planned for 
CALGB 51101, although patient participation is optional. Rationale and methods for the 
scientific components of this study are described in Section 10.2. 
For patients who consent to participate in CALGB 151113, the following specimens will be 
collected prior to initiation of therapy. 
 
Time Point 
 
Sample Type 
Pre-Treatment 
Ship to: 
FFPE Tissue* 
1 block 
Biorepository 
CSF Sample** (black top) 
2 to 3 mL 
Biorepository 
* 
Only for patients whose diagnosis is based on biopsy or resection. 
** Only in patients who have undergone a lumbar puncture for diagnostic or treatment-related 
purposes. A separate lumbar puncture for CSF sample collection for CALGB 151113 
should NOT be performed. 
5.9.1 Paraffin-Embedded Tissue Block Submission 
Send a formalin-fixed, paraffin-embedded block of well-fixed lymphoma tissue. A 
block at least 1 cm x 1 cm x 2 mm is preferable, although smaller is acceptable if no 
other block is suitable. If only one block exists, and the tissue is sufficiently large, it is 
acceptable to split the block into two and submit one. Contact 
 with questions. 
Samples should be logged and shipped via the BioMS system, see Section 5.7 for 
instructions. The requested tissue block should be labeled with the protocol number 
(51101), institutional surgical pathology number, patient study ID number, institution, 
date of acquisition, and tissue source. A copy of the shipping manifest produced by 
BioMS must be printed and placed in the shipment with the specimens. In addition to 
the pathology specimen and the shipping manifest, send a copy of the pathology report 
(include consultative pathology reports, if available) to the Alliance Biorepository at 
Ohio State University (OSU). 
The Alliance has instituted special considerations for the small percentage of 
institutions whose policies prohibit release of any blocks. If, due to institutional policy, 
a block cannot be sent, please call 
to obtain a protocol for submission of 
representative tissue from your institution. 

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Update #11 
5.9.2 CSF Sample Submission 
For patients who have undergone a lumbar puncture for diagnostic or treatment-related 
purposes, and who consent to participate (Model Consent Question #2), a 2 to 3 mL 
sample of cerebrospinal fluid (CSF) will be collected prior to initiation of therapy. These 
will be collected in black top culture tubes (Corning Falcon® catalogue number 
352045) and stored at negative -20° C, for no longer than 3 days, until shipped on dry 
ice. 
5.9.3 Shipping FFPE Tissue and CSF Samples 
Ship samples by overnight courier Monday through Thursday. Do not ship specimens 
on Fridays or Saturdays. Ship specimens to the Alliance Biorepository at Ohio State 
University (OSU). 
 
 
 
 
 
 
5.10 
Image Submission for Correlative Study CALGB 581101 
All limited access institutions must ask patients for their consent to participate in the imaging 
correlative science companion study CALGB 581101 (Model Consent Question #6) planned for 
CALGB 51101, although patient participation is optional. A list of limited access institutions 
for 581101 is available on the CALGB 51101 study page on the Alliance website. Rationale and 
methods for the scientific components of this study are described in Section 10.1.  
For patients who consent to participate in CALGB 581101 (Model Consent Question #6), 
imaging studies will be conducted and submitted at the following time points: 
 
Time Point 
 
Imaging Study 
Prior to study Within 7 days prior 
to day 1 of cycle 2 
Post induction cycle 5 
Submit to: 
Diffusion MRI 
A 
X 
C 
ICL 
FDG-PET Brain1 
B 
X 
D 
ICL 
1 
Institutions that are able to perform the brain FDG-PET/CT are strongly encouraged to do 
so, as this is an important component of this study. Institutions that are not able to perform 
the brain FDG-PET/CT due to institutional or financial constraints may be excused from 
the brain FDG-PET/CT imaging requirement. 
A 
Within 14 days prior to day 1 of cycle 1 
B 
Within 21 days prior to day 1 of cycle 1 
C 
Within 7 days after the last day of induction cycle 5 
D 
Within 28 days after the last day of induction cycle 5 
5.10.1 Diffusion MRI and FDG-PET/CT Submission 
Data must be electronically submitted to the Imaging Core Lab (ICL) by either web 
transfer or FTP transfer. 

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The complete MR imaging data and PET/CT scans will be submitted to the ICL in 
digital DICOM format. BMP files, JPG files, or hard copies (films) are not acceptable. 
The raw data of the entire study should be saved until the scan is accepted by the ICL. 
De-identify the patient data using institutional procedures to remove patient name and 
medical record number while preserving the patient study ID number and protocol 
number. The de-identified digital images may be burned to a CD and then transferred 
to a PC-based system.  
For PET/CT the following complete data sets must be sent: 
1) CT data, and 
2) Emission data with CT attenuation correction. 
The above entire PET/CT imaging data in DICOM format together with the CALGB 
581101 Form must be submitted to the ICL within no more than 3 business days once 
the image acquisition is completed at the site. The CALGB 581101 Form is found on 
the CALGB 51101 study website under Supplemental Materials. The ICL will notify 
the site and the Alliance imaging committee within 24 hours of the data receipt as well 
as within 72 hours of the quality check report. 
Diffusion MRI analysis will be performed at University of California San Francisco by 
 
 laboratory. The de-identified and complete MR imaging data including 
diffusion MRI will be transferred from the ICL to 
laboratory using either a 
CD or via a secure FTP site. 
Send an e-mail notification to 
 to inform the ICL 
of the data submission once the data transfer is completed. 
5.10.1.2 
Web Transfer 
Any PC with Internet access and a web browser (e.g., Internet Explorer, Mozilla 
Firefox) can be used to web transfer DICOM images and other required files to the 
ICL via 
 The standard Web Transfer 
information will be provided separately through the specific trial e-mail 
per the request by participating sites before 
their first data submission. 
5.10.1.3 
FTP Transfer 
Any FTP software can be used to initiate access to the secure FTP Server of the 
ICL. The standard FTP access information will be provided separately through the 
specific trial e-mail 
per the request by 
participating sites before their first data submission. 
For any questions or problems regarding the data transfer to the ICL, call the ICL 
IT group at 
for help. 
5.11 
Data Submission for Neurocognitive and Quality of Life Correlative Study CALGB 
71105 
All participating institutions must ask patients for their consent to participate in the 
neurocognitive and quality of life correlative science companion study CALGB 71105 (Model 
Consent Question #1) planned for CALGB 51101, although patient participation is optional. 
Rationale and methods for the scientific components of this study are described in Section 10.3.  
Both the quality of life and neurocognitive assessments are to be completed at the following 
time points: 
- 
Within 2 weeks prior to the start of treatment (baseline) 

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Update #11 
- 
Within 7 days prior to the start of induction cycle 5 
- 
Every 6 months for up to 5 years (starting 6 months post-treatment completion); then every 
12 months for the subsequent 5 years (for up to 10 years of follow-up) 
Send a copy of each assessment to the following fax for quality assurance review: 
 
 
For patients with evidence of disease progression during the study period, a neurocognitive 
evaluation will be performed at the time of radiographic progression and prior to initiation of 
additional therapy. 
Please see Section 10.3.3 for instructions on accessing, training, and administering the 
neurocognitive and quality of life assessments. 
 
 

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6.0 
REQUIRED DATA 
Guidelines for Pre-Study Testing 
To be completed within 14 DAYS before registration: 
- 
All blood work 
- 
History and physical, including height weight, KPS, vital signs 
Tests & Observations 
Prior 
to 
Study 
Day 1 
Induction 
Cycles 1-5 
Time of 
Restaging 
Post Cycle 5 
Consolidation 
Day 1* 
Follow-
Up** 
Medical history 
X 
X 
K 
X 
X 
Physical examination 
X 
C 
K 
X 
X 
Neurological examination9 
X 
C 
K 
X 
X 
Pulse, blood pressure 
X 
C 
K 
X 
X 
Height 
X 
 
 
 
 
Weight/body surface area 
X 
C 
K 
X 
X 
ECOG performance status 
X 
C 
K 
 
X 
Drug toxicity assessment 
 
X 
K 
X 
X 
Echocardiogram (transthoracic) 
 
 
R 
 
 
Pulmonary function test (with DLCO) 
 
 
R  
 
 
Laboratory Studies 
 
 
 
 
 
Creatinine clearance1 
X 
C, D 
 
N 
 
CBC, differential, platelets 
X 
E 
K 
O,P 
X 
Serum creatinine, BUN 
X 
E 
K 
O 
X 
Serum electrolytes, Ca++ 
X 
E 
K 
O 
X 
Serum methotrexate 
 
F 
 
 
 
AST, ALT, ALK Phos, total bilirubin 
X 
G 
K 
O 
X 
LDH 
X 
 
 
 
X 
Serum or urine βHCG*** 
X 
 
 
 
 
HBsAg, HBsAb, HB core antibody 
X 
 
 
 
 
HCV 
X 
 
 
 
 
HIV  
X 
 
 
 
 
CMV antibody**** 
X 
 
 
 
 
Staging 
 
 
 
 
 
Contrast-enhanced brain MRI with tumor 
measurements8 
X 
H 
 
L 
 
X 
Lumbar puncture2 
X 
I 
M 
 
I 
Ophthalmological examination3 
X 
J 
M 
 
J 
Testicular ultrasound4 
Q 
 
 
 
 
KPS 
X 
C 
K 
 
 
Bone marrow aspirate and biopsy 
A 
 
 
 
 
PET/CT, CT, or MRI of chest/abdomen/pelvis5 
A 
 
 
 
 
Histological review6 
B 
 
 
 
 
MMSE7 
X 
 
K 
 
X 
* 
For Arm 1, day -6 (start of carmustine); for Arm 2, day 1 of consolidation chemotherapy. 
** Every 3 months for the first 2 years after completion of therapy, then every 6 months for the 
next 3 years, then annually for the next 5 years. Total follow up is a maximum of 10 years 
from date of registration. 
*** βHCG is only required for women of childbearing potential 
**** All institutions may follow institutional guidelines for the CMV antibody assessment 
1 
Estimated creatinine clearance using Cockcroft-Gault formula for all cycles.  
2 
Lumbar puncture should be performed in all patients deemed safe for procedure 
3 
Ophthalmological examination should be performed by an ophthalmologist and must include 
slit lamp examination 
4 
Male patients 

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Update #11 
5 
FDG-PET/CT is recommended; body and brain FDG-PET/CT should be done the same day 
with single contrast injection (only for limited access sites that are able to complete the brain 
FDG-PET/CT, as well as patients enrolled on the correlative study CALGB 581101, see 
Sections 5.10 and 10.1). If the patient is receiving inpatient care, CT alone with IV contrast 
or whole body MRI is sufficient. 
6 
See Section 5.8. 
7 
Mini-Mental Status Examination (0-30) 
8 
Collect 2 perpendicular measurements per lesion, with a maximum of 6 lesions 
9 
The Neurological Examination may be performed by any physician. 
A 
Within 28 days prior to registration 
B 
To be submitted within 60 days of registration 
C 
Prior to each dose of methotrexate. Use initial weight unless > 10% difference from baseline.  
D 
Within 48 hours prior to day 1 of cytarabine in cycle 5 
E 
Within 48 hours prior to day of each induction cycle and daily while inpatient for 
methotrexate cycles 
F 
Daily methotrexate levels should be obtained beginning 24 hours after the start of the 
methotrexate infusion and until methotrexate concentration is < 0.10 mcM. 
G 
Every other day while inpatient for methotrexate cycles and prior to each Temozolomide 
course in cycles 1-4 
H 
Within 7 days after completion of induction cycle 1 only 
I 
In patients with positive/suspicious/atypical cytology, flow cytometry, or IgH PCR 
demonstrating a monoclonal cell population, the lumbar puncture should be repeated (if 
deemed safe) after completion of all induction therapy and after completion of all 
consolidation therapy. In patients with negative CSF at baseline, lumbar puncture does not 
need to be repeated. 
J 
In patients with positive slit lamp examination or positive/suspicious/atypical cytology or 
flow cytometry or IgH PCR demonstrating a monoclonal cell population, the slit lamp 
examination should be repeated after completion of all induction and after completion of all 
consolidation therapy. In patients with negative slit lamp examination or vitreous fluid, the 
slit lamp examination should only be repeated after completion of all consolidation therapy. 
K 
Within 7 days prior to day 1 of consolidation, both Arm 1 and Arm 2 
L 
Within 7 days after the last day of induction cycle 5 
M 
Within 21 days prior to day 1 of consolidation, and only if positive at baseline (contrast-
enhancing lymphoma on spine MRI; positive ocular examination for lymphoma; positive, 
suspicious, or atypical cytology; positive flow cytometry; positive IgH PCR) 
N 
In Arm 2, prior to starting cytarabine and etoposide 
O 
Every day while inpatient and receiving etoposide/cytarabine or carmustine/thiotepa 
P 
Consolidative therapy is to begin as soon as blood counts are permissible (ANC ≥ 1500 and 
platelets ≥ 100,000), but no earlier than 4 weeks and no later than 12 weeks after day 1 of 
cycle 5 of induction therapy. In patients who do not have sufficient blood counts at week 4, 
weekly CBC with differentials are required. Treatment is to start as soon as counts are 
permissible, however, if 12 weeks or more has passed, then the patient will go off study.   
Q 
If the patient has a negative PET/CT that includes the testicles, testicular ultrasound is not 
required. 
R 
For Arm 1 only, PFT and echocardiogram are to be performed at time of restaging post 
induction cycle.  
 

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Update #11 
7.0 
TREATMENT PLAN 
Protocol treatment is to begin within 7 days of registration (unless otherwise specified by Study 
Chair) and within 28 days of pathological diagnosis. Questions regarding treatment should be 
directed to the Alliance Study Chair. It is acceptable for individual chemotherapy doses to be 
delivered ≤ a 24-hour (business day) window before and after the protocol-defined date for Day 1 
of a new cycle. For example, if the treatment due date is a Friday, the window for treatment includes 
the preceding Thursday through the following Monday.  
Each cycle will be 28 days in length. 
Arm 1 and Arm 2 receive the same induction therapy (cycles 1-5). 
7.1 
Induction Chemotherapy (Cycles 1 and 2) 
Pneumocystis prophylaxis with cotrimoxazole double strength by mouth twice a day, two times 
per week beginning prior to initiation of therapy. Cotrimoxazole will continue unless ANC ≤ 
500/mcL. Cotrimoxazole is not to be given within 48 hours prior to initiation of 
methotrexate and until methotrexate concentration is < 0.10 mcM. If patients are allergic to 
sulfa drugs or if the treating physician has a preference for non-sulfa prophylaxis, dapsone, 
atovaquone or aerosolized pentamidine may be substituted. 
Dosing for all drugs on induction chemotherapy cycles 1 and 2 is based on actual body weight. 
7.1.1 Methotrexate 8 g/m2 IV (dose adjusted for creatinine clearance, see below) over 4 
hours on days 1 and 15 of cycle 1 and cycle 2.  
Each methotrexate dose will be followed by leucovorin rescue (see Section 7.1.2). 
Salicylates, non-steroidal anti-inflammatory drugs, sulfonamides, and penicillins are 
not to be used within 48 hours prior to the initiation of methotrexate and until 
methotrexate concentration is < 0.10 mcM. Patients will be hospitalized for high-dose 
methotrexate administration. 
Recommended hydration before and after methotrexate includes IV fluids at rate of 500 
mL/hour over 2 hours, then 150 mL/hour to assure a urine output > 100 mL/hour for at 
least 4 hours prior to methotrexate. Continue hydration during methotrexate 
administration and leucovorin rescue. Add 50-150 mEq NaHCO3 per liter of fluid to 
achieve and maintain a urine pH ≥ 7 or per institutional guidelines. Check urine pH with 
every void or per institutional standard of care. 
Methotrexate doses will be based on CrCl calculated by the Cockcroft-Gault formula as 
follows: 
(140-age) x weight in kg. 
x 
0.85 for females 
72 x serum creatinine 
1.0 for males 
 
 
 
• 
Note: In markedly obese patients, the Cockcroft-Gault formula will tend to 
overestimate the CrCl. (Adipose tissue tends to contribute little creatinine requiring 
renal clearance.) 
If CrCl is greater than 100 mL/min, then no dose adjustment is necessary. If CrCl is less 
than 100 mL/min, then the methotrexate dose is reduced by the fraction of CrCl below 
100 mL/min (i.e., methotrexate dose = 8 g/m2 x CrCl/100). 
7.1.2 Leucovorin Rescue and Serum Methotrexate Levels 
Leucovorin 100 mg/m2 IV every 6 hours beginning 24 hours after the start of each 
methotrexate dose (for all patients, regardless of methotrexate level). Continue 
leucovorin until serum methotrexate level ≤ 0.10 mcM. Daily methotrexate levels are 

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Update #11 
to be obtained beginning 24 hours after the initiation of methotrexate and until 
methotrexate concentration is < 0.10 mcM. The leucovorin dose is adjusted based on 
serum methotrexate levels as follows: 
Methotrexate Level 
Leucovorin Dose* 
24 Hours: 
100 mg/m2 IV q 6 hours until level is ≤ 0.10 mcM 
> 10 mcM 
48 Hours: 
100 mg/m2 IV q 3 hours until level is ≤ 0.10 mcM 
>1 mcM 
60 Hours: 
200 mg/m2 IV q 3 hours until level is ≤ 0.10 mcM 
>2 mcM 
72 Hours: 
> 0.1 mcM 
100 mg/m2 IV q 6 hours until level is ≤ 0.10 mcM 
* When methotrexate level is ≤ 0.5 mcM, the leucovorin dose may be administered orally 
(instead of IV) and continued until methotrexate level is ≤ 0.10 mcM. The oral dose is 
10 mg/m2 every 6 hours (may be rounded up to within 5% of the calculated dose). 
If the patient’s creatinine is stable and there is evidence of appropriate clearance of 
methotrexate, and if the methotrexate level is decreasing for two consecutive time points 
below 1 mcM, then pharmacokinetic calculation may be performed to predict the time 
point when methotrexate level will be < 0.10 mcM. The patient may then be discharged 
to home with oral leucovorin rescue until the serum methotrexate level is predicted to 
be < 0.10 mcM. 
Please note that the above are guidelines, and treating physicians may follow their own 
institutional guidelines set for administration of leucovorin including the dose and 
schedule.  
7.1.3 Rituximab 375 mg/m2 IV (maximum infusion rate 400 mg/hour) on days 3, 10, 17, 24 
of cycle 1, and days 3 and 10 of cycle 2 (i.e., a total of 6 doses). 
Suggested premedications include acetaminophen 650 mg by mouth and 
diphenhydramine 25-50 mg IV or by mouth. 
Please note for institutions that cannot administer Rituximab on day 3, +/- 3 day 
windows are allowed.  
7.1.4 Temozolomide 150 mg/m2/day (rounded to the nearest 5 mg) by mouth on days 7-11 
of cycle 1.  
In cycle 2 days 7-11, temozolomide will be increased to 200 mg/m2/day.  
7.2 
Induction Chemotherapy (Cycles 3 and 4) 
Pneumocystis prophylaxis with cotrimoxazole double strength by mouth twice a day, two times 
per week beginning prior to initiation of therapy. Cotrimoxazole will continue unless ANC 
≤ 500/mcL. Cotrimoxazole is not be given within 48 hours prior to initiation of 
methotrexate and until methotrexate concentration is < 0.10 mcM. If patients are allergic to 
sulfa drugs or if the treating physician has a preference for non-sulfa prophylaxis, dapsone, 
atovaquone or aerosolized pentamidine may be substituted. 
Dosing for all drugs on induction chemotherapy cycles 3 and 4 is based on actual body weight. 

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Update #11 
7.2.1 Methotrexate 8 g/m2 IV (dose adjusted for CrCl, see Cockcroft-Gault formula in 
Section 7.1.1) over 4 hours on days 1 and 15 of cycles 3 and 4.  
Salicylates, non-steroidal anti-inflammatory drugs, sulfonamides, and penicillins are 
not be used within 48 hours prior to the initiation of methotrexate and until methotrexate 
concentration is < 0.10 mcM. Patients will be hospitalized for high-dose methotrexate 
administration. 
Recommended hydration before and after methotrexate includes IV fluids at rate of 500 
mL/hour over 2 hours, then 150 mL/hour to assure a urine output > 100 mL/hour for at 
least 4 hours prior to methotrexate. Continue hydration during methotrexate 
administration and leucovorin rescue. Add 50-150 mEq NaHCO3 per liter of fluid to 
achieve and maintain a urine pH ≥ 7 or per institutional guidelines. Check urine pH with 
every void or per institutional guidelines. 
7.2.2 Leucovorin Rescue and Serum Methotrexate Levels 
Leucovorin 100 mg/m2 IV every 6 hours beginning 24 hours after the start of 
methotrexate (for all patients, regardless of methotrexate level). Leucovorin should 
continue until serum methotrexate level ≤ 0.10 mcM. Daily methotrexate levels should 
be obtained beginning 24 hours after the initiation of methotrexate and until 
methotrexate level is < 0.10 mcM. The leucovorin dose is adjusted based on serum 
methotrexate levels as noted in Section 7.1.2. 
When methotrexate level is ≤ 0.5 mcM, the leucovorin dose may be administered orally 
(10 mg/m2) until methotrexate level is ≤ 0.10 mcM. 
Please note that the above are guidelines and treating physicians may follow their own 
institutional guidelines set for administration of leucovorin. 
7.2.3 Temozolomide 200 mg/m2/day (rounded to the nearest 5 mg) by mouth on days 7-11 
of cycles 3-4.  
7.3 
Induction Chemotherapy (Cycle 5) 
Induction cycle 5 is to begin no earlier than 4 weeks and no later than 8 weeks after day 1 of 
cycle 4. 
G-CSF is allowed. 
In order to receive induction cycle 5, patients must have the following: 
serum creatinine < 2.0 mg/dL or a 24 hour creatinine clearance must be > 50 mL/min,  
total bilirubin < 2 x ULN,  
AST < 3 x ULN, 
ANC > 1000/mcL without G-CSF, 
no less than 1 week since receiving G-CSF, 
platelets > 100,000/mcL, and  
neither active infection nor a need for ongoing antibiotics. 
Cytarabine 2 g/m2 (corrected body weight) IV every 12 hours (or twice a day) as a 2-hour 
infusion on days 1 and 2. 
Corticosteroid ophthalmic preparation to begin 6-12 hours before the first dose of cytarabine 
and continuing at least 48 hours after the last high-dose to prevent conjunctivitis. 

C A L G B 5 1 1 0 1 
Versi o n Date: 0 7 /3 1/ 2 0 2 0  
2 9  
U p date # 1 1  
D ose  s h o ul d  be  base d  o n  c orrecte d  wei g ht,  calc ulate d  as  i deal  b o d y  wei g ht  +  2 5 %  of  t he 
differe nce bet wee n act ual a n d i deal b o d y wei g ht. If act ual wei g ht is less  t ha n i deal wei g ht, use 
act ual b o d y wei g ht. If t he patie nt’s act ual wei g ht is > 1 5 0 % of i deal, t he n t he c orrecte d wei g ht 
is i deal b o d y wei g ht x 1. 1 2 5. ( See A p pe n di x II f or i deal b o d y wei g ht ta ble.) 
I n  patie nts  e x hi biti n g  si g ns  or  s y m pt o ms  of  cere bellar  d ysfu ncti o n,  i n d ucti o n  c ycle  5  wit h 
c ytara bi ne will be o mitte d , b ut patie nts ma y recei ve all ot her t hera p y. If t he treati n g p h ysicia n 
belie ves t he patie nt has si g ns of cere bellar d ysf u ncti o n, t he y s h o ul d c o ntact t he st u d y c hair.   
7. 4 
Rest a gi n g  
Resta gi n g will o cc ur after c o m pleti o n of i n d ucti o n c ycle 5. Patie nts w h o ac hie ve a c o m plete 
res p o nse,  c o m plete  res p o nse  u nc o nfir me d,  partial res p o nse,  or  sta ble  disease  will pr ocee d  t o 
c o ns oli dati o n t hera p y. Patie nts wit h pr o gressi ve disease will be re m o ve d fr o m pr ot oc ol t hera p y. 
( See Secti o n 1 2. 0  f or defi niti o ns of res p o nse.) 
7. 5 
Ar m 1  C o ns oli d ati o n T her a p y  
C o ns oli dati ve  t hera p y  is  t o  be gi n  as  s o o n  as  bl o o d  c o u nts  are  per missi ble  ( A N C  ≥1 5 0 0  a n d 
platelets ≥1 0 0, 0 0 0) , b ut n o earlier t ha n 4 wee ks a n d n o later t ha n 1 2 wee ks after da y 1 of c ycle 
5 of i n d ucti o n t hera p y. I n patie nts w h o d o n ot ha ve s ufficie nt bl o o d c o u nts at wee k 4, wee kl y 
C B C  wit h  differe ntials  are  re q uire d.  Treat me nt  is  t o  start  as  s o o n  as  c o u nts  are  per missi ble, 
h o we ver, if 1 2 wee ks or m o re has passe d, t he n t he patie nt will g o off st u d y. 
C o n diti o ni n g r e gi me n ma y be a d mi nistere d per i nstit uti o nal sta n dar ds; e x perie nce d sites ma y 
a d mi nister c o n diti o ni n g c he m ot hera p y as ‘ o ut patie nt’ a n d a d mit t o h os pital o nl y at t he p oi nt of  
ste m cell i nf usi o n. 
7. 5. 1 Ste m Cell M o biliz ati o n  
Bet wee n 3 a n d 5 wee ks after da y 1 of c ytara bi ne i n d ucti o n c ycle 5 , patie nts ra n d o mize d 
t o Ar m 1  will pr ocee d t o ste m cell m o bilizati o n per partici pati n g i nstit uti o n g ui deli nes.  
T he tar get g oal is a C D 3 4 + cell d ose > 5 x 1 0 6/ k g (act ual b o d y wei g ht) a n d t he mi ni m u m 
C D 3 4 +  cell  d ose  is  2  x  1 0 6/ k g.  T he  f oll o wi n g  are  s u g gesti o ns,  n ot  pr ot oc ol 
re q uire me nts.  Ste m  cell  m o bilizati o n  ma y  be gi n wit h  dail y G- C S F  i njecti o ns  at  1 0 
mc g / k g S C pe r d a y f or f o ur c o nsec uti ve d a ys wit h pl a n ne d ste m cell c ollecti o n o n 
d a y 5.  If ste m cell yiel d of da y 1 c ollecti o n is less t ha n 1 x 1 06 C D 3 4 + cells/ k g t he n t he 
G- C S F d ose ca n be i ncrease d t o 1 5 mc g/ da y.  I n ge neral, pr ocess 1 2-1 8 L of bl o o d o ver 
3- 4 h o urs e ac h le u ka p heresis at fl o w rates of 7 0- 9 0 m L/ mi n ute. If C D 3 4 cell yiel ds are 
l o w  at  first,  it  is  rec o m me n de d  t hat  1-2  da ys  be  s ki p pe d  u ntil  W B C  is  2 0, 0 0 0 -
4 0, 0 0 0/ L. Cells s h o ul d be fr oze n acc or di n g t o i nstit uti o nal sta n dar ds a n d practices. If 
ste m cell m obi lizati o n is u ns uccessf ul ( < 2 x 1 06/ k g C D 3 4 + cells), t he n c o ntact t he St u d y 
C hair or  C o -C hair.  A re m o bilizati o n  of  peri p heral  bl o o d  ste m  cells  or  a  pel vic b o ne 
marr o w har vest ma y be per mitte d.   
7. 5. 2 Hi g h -D ose T her a p y wit h Ste m Cell Resc ue  
All dr u g c he m ot hera p y d oses are base d o n c orrecte d b o d y wei g ht.  Bet wee n 2 t o 4 wee ks 
after t he last da y of s uccessf ul ste m cell c ollecti o n, patie nts will be a d mitte d f or hi g h-
d ose t hera p y wit h ste m cell resc ue. Ste m cell resc ue re q uires a de q uate peri p heral bl o o d 
ste m cell c ollecti o n wit h C D 3 4 cell d ose > 2 x 1 0 6/ k g (act ual b o d y wei g ht or st u d y c hair-
a p pr o ve d alter nati ve). 
Pri or  t o  hi g h  d ose  t hera p y,  patie nts  m ust  ha ve  ser u m  creati ni ne  <  2. 0  m g/ d L,  t otal 
bilir u bi n  <  2  x  U L N  a n d  A S T  <  3  x  U L N  a n d  neit her  acti ve  i nfecti o n  n or  nee d  f or 
o n g oi n g a nti bi otics.  

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Update #11 
7.5.2.1 
Carmustine 400 mg/m2 IV infused over 2 hours on day -6.  
7.5.2.2 
Thiotepa 5 mg/kg IV infused over 2 hours, every 12 hours, on days   -5 and -4.  
7.5.2.3 
Infusion of autologous peripheral blood stem cells on day 0. Peripheral blood 
stem cells should be thawed in a 37° C water bath and immediately infused 
intravenously. If autologous pelvic marrow is infused, premedicate with 25 g 
mannitol IV 6 hours after infusion. 
7.5.2.4 
G-CSF 5 mcg/kg subcutaneous daily starting on day +4 until ANC >1500/mcL 
on two separate occasions or >5000/mcL once. If actual weight is < 60 kg, use 300 
mcg/dose; if actual weight is 60-99 kg, use 480 mcg/dose; if actual weight is 100-
130 kg use 600 mcg/dose; if actual weight is >130 kg, use 780 mcg/dose.  
7.5.3 Infection Prophylaxis 
Levofloxacin 500 mg by mouth daily or other IV or oral antibiotic as per institutional 
preference beginning when ANC drops to ≤ 500/mcL and continuing until ANC 
>500/mcL. 
Fluconazole 200 mg by mouth daily or other IV or oral antifungal as per institutional 
preference beginning on day 6 and continuing until ANC ≥ 500/mcL. 
Acyclovir 200 mg by mouth three times a day or 2 mg/kg IV twice a day (actual body 
weight) rounded to the next highest 25 mg or other IV or oral antiviral as per 
institutional preference beginning on day 6 and continuing for 6 months. 
7.5.4 Carmustine Pneumonitis Surveillance 
Surveillance for carmustine pneumonitis should occur in the post-autologous stem cell 
treatment period, especially the first 4 months.  
7.6 
Arm 2 Consolidation Therapy  
Consolidative therapy is to begin as soon as blood counts are permissible (ANC ≥1500 and 
platelets ≥100,000), but no earlier than 4 weeks and no later than 12 weeks after day 1 of cycle 
5 of induction therapy. In patients who do not have sufficient blood counts at week 4, weekly 
CBC with differentials are required. Treatment is to start as soon as counts are permissible, 
however, if 12 weeks or more has passed, then the patient will go off study.     
In order to receive consolidation therapy in Arm 2, patients must have: serum creatinine < 2.0 
mg/dL or a 24 hour CrCl must be >50 mL/min; total bilirubin < 2 x ULN; AST < 3 x ULN; 
ANC > 1000/mcL without G-CSF; platelets > 100,000/mcL; have neither active infection nor a 
need for ongoing antibiotics (other than those used for pneumocystis prophylaxis). 
One cycle of therapy will be considered 28 days. It is strongly advised that consolidation therapy 
for Arm 2 be administered on an inpatient hospital service. 
Pneumocystis prophylaxis with cotrimoxazole double strength by mouth twice a day, two 
times a week (or equivalent) should begin prior to initiation of therapy. Cotrimoxazole will 
continue through consolidation, unless ANC ≤ 500/mcL. If patients are allergic to sulfa drugs, 
or if the treating physician has a preference for non-sulfa prophylaxis, dapsone, atovaquone or 
aerosolized pentamidine may be substituted.  
In patients exhibiting signs or symptoms of cerebellar dysfunction, cytarabine will be omitted 
from consolidation therapy. 

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7.6.1 Cytarabine 2 g/m2 (corrected body weight) IV over 2 hours every 12 hours x 8 doses, 
on days 1-4 
Corticosteroid ophthalmic preparation to begin 6 – 12 hours before the first dose of 
cytarabine and continuing at least 48 hours after the last high-dose to prevent 
conjunctivitis. 
Dose should be based on corrected weight, calculated as ideal body weight + 25% of 
the difference between actual and ideal body weight. If actual weight is less than ideal 
weight, use actual body weight. If the patient’s actual weight is >150% of ideal, then 
the corrected weight is ideal body weight x 1.125. (See Appendix II for ideal body 
weight table.) 
7.6.2 Etoposide 5 mg/kg IV (corrected body weight) over 12 hours every 12 hours x 8 doses 
(total dose 40 mg/kg CIVI over 96 hours) on Days 1-4 
Dose should be based on corrected weight, calculated as ideal body weight + 25% of 
the difference between actual and ideal body weight. If actual weight is less than ideal 
weight, use actual body weight. If the patient’s actual weight is >150% of ideal, then 
the corrected weight is ideal body weight x 1.125. See Appendix II for ideal body weight 
table. 
7.6.3 G-CSF 5 mcg/kg/day subcutaneous beginning on day +4 and continuing either until 
ANC ≥ 500 mcL for two consecutive days or ≥ 1500/mcL for one day. For G-CSF, if 
actual weight is < 60 kg, use 300 mcg/dose; if actual weight is 60-99 kg, use 480 
mcg/dose; if actual weight is 100-130 kg use 600 mcg/dose; if actual weight is > 130 
kg, use 780 mcg/dose.  
7.6.4 Infection Prophylaxis 
Levofloxacin 500 mg by mouth daily or other IV or oral antibiotic as per institutional 
preference beginning when ANC drops to ≤ 500/mcL and continuing until ANC 
>500/mcL. 
Fluconazole 200 mg by mouth daily or other IV or oral antifungal as per institutional 
preference beginning on Day 6 and continuing until ANC ≥ 500/mcL. 
Acyclovir 200 mg by mouth three times a day or 2 mg/kg IV twice a day [actual 
body weight] rounded to the next highest 25 mg or other IV or oral antiviral as per 
institutional preference beginning on day 6 and continuing for 6 months. 
8.0 
DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITY 
Drug 
Starting Dose 
Dose Level -1 
Dose Level -2 
Methotrexate (actual weight) 
8 g/m2 
6 g/m2 
4 g/m2 
Temozolomide cycle 1 (actual weight) 
150 mg/m2 
100 mg/m2 
N/A 
Temozolomide cycles 2-4 (actual weight) 
200 mg/m2 
150 mg/m2 
100 mg/m2 
Cytarabine (induction cycle 5, corrected weight) 
2 g/m2 
1 g/m2 
N/A 
8.1 
Hematologic Toxicity 
8.1.1 Hematologic Toxicity/Methotrexate Dose Modifications 
Decrease methotrexate by one dose level if ANC is ≤ 500/mcL for three or more days, 
platelets ≤ 25,000/mcL, and/or febrile neutropenia (defined as temperature ≥ 38.5°C 

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[101°F] sustained for more than one hour concomitant with an ANC <500/mcL). The 
reduced methotrexate dose should be used for all subsequent doses. 
8.1.2 Hematologic Toxicity/Temozolomide Dose Modifications 
Growth factors cannot be used to induce elevations in neutrophil count for the purposes 
of administration of temozolomide on time. 
Based on blood counts obtained within two days prior to day of treatment, the following 
dose modifications should be made: 
For grade 3 or 4 ANC, delay temozolomide until ANC improves to ≤ grade 2, then 
decrease temozolomide by 1 dose level for all subsequent cycles. 
For grade 3 or 4 thrombocytopenia, delay temozolomide until platelets improve to ≤ 
grade 2, then decrease temozolomide by 1 dose level for all subsequent cycles. 
Patients who require dose reductions to a dose level <100 mg/m2/day will discontinue 
temozolomide. 
8.1.3 Febrile Neutropenia During Consolidation Chemotherapy 
Febrile neutropenia is expected during consolidation with the combination of cytarabine 
+ etoposide or carmustine + thiotepa. Prophylactic antibiotics and G-CSF are utilized 
during this cycle of therapy. No dose modifications will be made for febrile neutropenia 
during consolidation therapy. 
8.2 
Hepatic Dysfunction 
8.2.1 Hepatic Dysfunction/ALT/AST Toxicity 
ALT/AST should return to within 3 x upper limit of normal prior to next dose of MTX 
treatment. No dose adjustment is needed based on transient transaminitis regardless of 
grade.  
8.2.2 Hepatic Dysfunction/Total Bilirubin 
Give the following dose reduction of methotrexate based on total bilirubin obtained 
within 2 days prior to treatment: 
 
Total Bilirubin 
(mg/dL) 
Methotrexate Dose 
Reduction 
< 1.5 
Starting Dose 
≥ 1.5 but <3.0 
Level -1 
≥ 3.0 but <5.0 
Level -2 
≥ 5.0 
Stop 
8.2.3 Hepatic Toxicity  
For grade 3 or 4 ALT, AST, or Total Bilirubin on day 7 and considered at least possibly 
related to Temozolomide, skip Temozolomide for that cycle. 
8.3 
Neuropsychiatric Toxicity 
If cytarabine neurotoxicity develops or is suspected during its administration (dysmetria, 
dysdiadokinesis, truncal/gait ataxia, dysarthria, and/or cerebral psychiatric abnormalities not 
explainable by other medications or tumor location), stop cytarabine immediately. 

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8.4 
Gastrointestinal Toxicity 
Mucositis, dysphagia, and diarrhea: For grade 3 or 4 oral ulceration or diarrhea, hold all therapy 
and delay the next treatment until mucositis or diarrhea improves to ≤ grade 2. Resume 
methotrexate with one dose level reduction for the next dose.  
8.5 
Renal Dysfunction 
8.5.1 Renal Dysfunction/Methotrexate Dose Modifications 
The CrCl will be estimated by method of Cockcroft Gault formula prior to every cycle. 
If CrCl is greater than 100 mL/min, then no dose adjustment is necessary. If CrCl is less 
than 100 mL/min, then the methotrexate dose is adjusted by the fraction of CrCl below 
100 mL/min (i.e., methotrexate dose = 8 g/m2 x CrCl/100). Treatment will proceed with 
rituximab, temozolomide and methotrexate as scheduled. 
Delayed serum clearance (>3 days after infusion) may occur and mandates accelerated 
rescue and continued hydration and alkalinization. A minimum of 7 days should have 
elapsed from serum clearance (methotrexate level ≤ 0.10 mcM) prior to start of next 
methotrexate dose. 
8.5.2 Renal Dysfunction/Cytarabine Dose Modifications 
Give the following cytarabine dose reductions for renal dysfunction based on serum 
creatinine on any day of induction or arm 2 consolidation high-dose cytarabine 
administration.  
For creatinine 1.5-2 mg/dL or an increase of 0.5-1.2 mg/dL over baseline, decrease 
cytarabine by 1 dose level. For creatinine > 2.0 mg/dL or an increase of ≥ 1.3 mg/dL 
over baseline, omit the cytarabine dose. 
8.6 
Pulmonary Toxicities 
8.6.1 Diffuse Alveolar Hemorrhage 
Diffuse alveolar hemorrhage (DAH) presents as hypoxemia, dyspnea, fever and/or 
pulmonary infiltrates at the time of granulocyte engraftment.  Bronchoalveolar lavage 
(BAL) reveals alveolar blood, which increases with serial lavages and is negative for 
infection. This is an uncommon complication of any high-dose conditioning regimen 
and is potentially fatal.  Sensitivity to the diagnosis must be high and initiation of 
corticosteroids must be prompt in order to prevent death. Once DAH is suspected or 
confirmed, methylprednisolone 1000 mg IV twice a day is started for a minimum of 3 
days. If the patient responds, then the methylprednisolone dose is halved every 3 days 
until a 3 to 4 week course is completed. 
8.6.2 Carmustine Pneumonitis 
Carmustine pneumonitis complicates 10-60% of stem cell transplants in which 450-600 
mg/m2 of carmustine is administered. The incidence is related to carmustine dose and 
is expected to be about 10% in this study where the carmustine dose is capped at 400 
mg/m2. Although it can occur up to one year from administration, it is most frequent 
one-and-a-half to four months after carmustine is received. Presenting features are dry 
cough, dyspnea, fatigue, a “tight” feeling in the chest, hypoxemia, pulmonary infiltrates, 
and/or an absolute >10% drop in the percentage predicted diffusing capacity of the lung 
for carbon monoxide (DLCO). Anyone suspected of having carmustine pneumonitis 
should have 0.5 mg/kg (actual body weight) prednisone started by mouth twice a day 
followed by evaluations such as chest X-ray, pulmonary function tests with DLCO, 
sputum analysis, bronchoalveolar lavage, etc. If carmustine pneumonitis is suspected or 

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confirmed, then high-dose prednisone is continued for 10-14 days followed by a 
corticosteroid taper over 8 weeks. Carmustine pneumonitis is potentially fatal but 
uniformly reversible if prednisone is started early in the inflammatory phase. Therefore 
a high degree of sensitivity to and surveillance for this complication is warranted. 
8.7 
Other Non-Hematologic Toxicity Dose Modifications 
8.7.1 Temozolomide Dose Modifications for Other Non-Hematologic Toxicities 
If at any time a patient experiences grade 3 or 4 non-hematologic toxicity considered at 
least possibly related to temozolomide, decrease temozolomide by one dose level for all 
subsequent cycles. Patients who require a dose reduction to a dose level < 100 
mg/m2/day will have temozolomide discontinued. 
8.7.2 All non-hematologic grade 2, 3 and 4 toxicities must have resolved to at least grade 1 
prior to repeat dosing or grade 2 if, in the treating physician’s opinion, the non-
hematologic toxicity does not warrant further delay. Please contact the Study Chair 
to discuss delays in therapy caused by the need to delay temozolomide. If a 
temozolomide dose were to be delayed, a 4-week interval must occur between 
successive courses of temozolomide. 
8.8 
Dose Modification for Non-Obese and Obese Patients 
High-dose chemotherapy can adversely impact the outcomes of obese patients when dosing is 
performed according to actual body weight. Therefore, drug dosing for induction cycle 5 
cytarabine (both arms) and for consolidation etoposide and cytarabine (arm 2) will be 
determined using a corrected weight. Patient ideal body weight is derived from Appendix II 
using frame size and height. The corrected weight is calculated using the following formula with 
all weights in kg: 
Corrected weight = (0.25)(actual weight-ideal weight) + (ideal weight) 
Doses are then based on corrected weight or BSA calculated using corrected weight. 
For patients whose actual weight is >150% of their ideal, their "actual" weight will be capped 
at 150% of ideal (i.e., their corrected weight will be 112.5% of ideal). For patients whose actual 
weight is less than ideal, use their actual weight as the corrected weight. 
9.0 
ANCILLARY THERAPY 
9.1 
Supportive Care 
Patients should receive full supportive care, including transfusions of blood and blood products, 
antibiotics, antiemetics, etc. when appropriate per institutional guidelines. For CMV negative 
patients, use CMV negative blood products. In addition, all blood products should be 
leukofiltered and irradiated to reduce/prevent alloimmunization and transfusion graft-versus-
host disease.  
9.2 
Steroids 
Steroids may be used in the management of symptoms related to mass effect from lymphoma or 
to manage pulmonary toxicity. Steroids should be tapered as soon as possible. 
9.3 
Anticonvulsants 
Administration of anticonvulsants is at the discretion of the treating physician. In accordance 
with the practice parameters described by the American Academy of Neurology, the use of 
prophylactic anticonvulsants should be avoided [44]. In patients with no history of a seizure, it 

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is recommended that anti-convulsants started before/after biopsy or craniotomy should be 
tapered after the first postoperative week [44]. 
9.4 
Palliative Radiation 
Palliative radiation therapy may not be administered. 
9.5 
Alliance Policy Concerning the Use of Growth Factors 
9.5.1 Epoetin (EPO) 
 
The use of an erythropoiesis-stimulating agent (ESA) is allowed. If an ESA is used, it 
should be within the context of the most current ASCO guidelines [45]. 
9.5.2 G-CSF 
1. The use of G-CSF is allowed. G-CSF is required during HDT/ASCT (Arm 1) and 
etoposide and cytarabine (Arm 2) consolidation due to the intense nature of the 
treatment. 
2. Elsewhere in the protocol, G-CSF may NOT be used 
a. 
to avoid dose reductions, delays or to allow for dose escalations specified in the 
protocol, 
b. 
prophylactically because of concern about myelosuppression from prior 
chemotherapies, and 
c. 
for the treatment of febrile neutropenia the use of colony-stimulating factors 
should not be routinely instituted as an adjunct to appropriate antibiotic therapy. 
However, the use of colony-stimulating factors may be indicated in patients 
who have prognostic factors that are predictive of clinical deterioration such as 
pneumonia, hypotension, multi-organ dysfunction (sepsis syndrome) or fungal 
infection, as per the ASCO guidelines [46]. Investigators should therefore use 
their own discretion in using the colony-stimulating factors in this setting. The 
use of colony-stimulating factors (G-CSF) must be documented and reported on 
the Ancillary Therapy form.  
d. 
If G-CSF is used, it must be obtained from a commercial sources. 
10.0 CORRELATIVE SCIENCE COMPANION STUDIES 
The images obtained for the embedded correlative science companion imaging study CALGB 
581101 will be analyzed once funding is obtained for this study. In addition, the samples obtained 
for the embedded correlative science companion biomarker study CALGB 151113 will be analyzed 
once funding is obtained for this study. 
10.1 
Imaging Correlative Science Companion Study (CALGB 581101)  
Imaging Markers of Outcome After Chemotherapy in Patients with Newly Diagnosed PCNSL 
CALGB 581101 has two components, an MRI study and a FDG-PET/CT study. CALGB 
581101 is open to limited access institutions only. Please see the study website for the list of 
limited access institutions that may register patients to CALGB 581101. Patients enrolled 
through the limited access institutions who answer ‘Yes’ to Model Consent Question #6 may be 
registered to CALGB 581101. Limited access institutions are required to offer patients 
participation in CALGB 581101. However, patients at the limited access institutions who are 
participating in the treatment study CALGB 51101 may opt not to participate in the imaging 
correlative study CALGB 581101. Patients who consent to participate in CALGB 581101 are 
consenting to participate in both the MRI and the FDG-PET/CT portions of the study. Limited 
access institutions that are able to perform the brain FDG-PET/CT are strongly encouraged to 
do so, as this is an important component of this study. Limited access institutions that are not 

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able to perform the brain FDG-PET/CT due to institutional or financial constraints may be 
excused from the brain FDG-PET/CT imaging requirement. Limited access institutions unable 
to participate in the brain FDG-PET/CT component of the imaging study are still required to 
participate in the MRI component. A maximum number of 25 patients per treatment arm will be 
enrolled on the MRI study. There is no maximum number of patients per treatment arm in the 
PET study. 
10.1.1 Background 
10.1.1.1 
Diffusion MRI Background 
Diffusion-weighted imaging (DWI) is a noninvasive MR imaging technique that 
produces in vivo images of the brain based on differential rate of water diffusion 
or Brownian motion within the extracellular space. DWI is an essential tool to 
diagnose acute infarction in the brain due to its ability to detect early changes in 
altered water diffusion due to cellular cytotoxic damage. DWI has also been used 
in neuro-oncology to assess tumor biology. Specifically, the apparent diffusion 
coefficient (ADC) values derived from DWI have been shown to correlate with 
glioma grade [47, 48], tumor cellularity [49], and treatment response [50-56]. One 
study also suggests that ADC values may be helpful in predicting clinical outcome 
in immunocompetent patients with primary CNS lymphoma [29]. 
10.1.1.2 
Brain FDG-PET/CT Background 
FDG-PET/CT is a standard test for the staging and response assessment of patients 
with systemic lymphoma [57]. It is also a useful test in the systemic staging of 
patients with primary CNS lymphoma (PCNSL). In one study, 8 of 42 patients 
showed sites of abnormal FDG uptake outside the brain [58]. Six of these 8 patients 
underwent biopsy (three lymphoma, one second primary, one benign adenoma, 
one inconclusive). Eleven patients in the study also underwent FDG-PET/CT of 
the torso at the time of CNS relapse; systemic lymphoma was noted on PET in 
three cases (27%). Of note, CT scans of the torso were entirely negative in these 
three individuals. 
The utility of FDG-PET/CT for assessing the primary disease site in PCNSL has 
been investigated in a number of studies. Early data showed tumor to normal (T:N) 
tissue uptake ratios in the range of 1.2 – 3.5; the normal tissue region was placed 
in the contralateral hemisphere in the identical location as the PCNSL [59]. A 
subsequent study reported standardized update value (SUV) in PCNSL in the range 
of 4.3 – 10.7 and T:N ratios of 1.4 – 3.0, indicating that these lesions are usually 
well recognized on PET (one small 4 mm was not identified in this study) [60]. A 
study in 13 patients reported SUVs in the range of 6.6 – 23.2 (mean 13.9 +/- -5.6) 
and T:N ratios of 0.8 – 5.2 (mean 2.7 +/- 1.2) [61]. All primary lesions were clearly 
identified on PET. A retrospective analysis in 28 patients with PCNSL showed 
clearly increased FDG update in 75% of lesions at baseline [62]. 
The intensity of FDG update (measured by SUV) in PCNSL at baseline may have 
prognostic value. In a study of 17 patients, the SUVmax at baseline ranged from 
6.3 to 23.3 [63]. Eight of the 17 patients showed moderate FDG update (SUVmax 
< 12) and 9/17 showed high uptake (SUVmax > 12). The median survival time 
was > 26 months in the group with moderate update, and 12 months in the group 
with high uptake. Both OS and PFS were significantly shorter for patients for high 
baseline SUV. The treatment regimen was uniform in all patients. 
Few data are available regarding the potential utility of FDG-PET/CT for response 
assessment in PCNSL [62-64]. One study evaluated 8 patients undergoing 

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chemotherapy; FDG-PET/CT was true negative in 5 out of 8 and true positive in 3 
out of 5 [60]. Another study found persistent elevated FDG uptake in 50% of 
patients during response assessment or scans obtained for clarification of 
nonspecific MRI findings; these data were helpful in guiding patient management 
[62]. 
In summary, there are sufficiently promising data to warrant further exploration of 
FDG-PET/CT in PCNSL for identifying patients with better or worse prognosis, 
and for response assessment. However, because the available data are still limited, 
FDG-PET/CT at this time cannot be used to guide patient management. 
Accordingly, the use of FDG-PET/CT in the current trial is exploratory. If 
successful, the data may potentially be useful for future risk and response adapted 
therapy trials. 
10.1.2 Methods 
10.1.2.1 
Diffusion MRI Methods 
Diffusion MRI sequences (ADCmini, ADC25%, and ADCmean) will be obtained prior 
to induction therapy, and post cycles 1 and 5 of induction therapy in a subset of 
patients in each arm (25 per arm) [29]. These sequences will be obtained as part of 
the baseline and routine cranial MRI studies for each patient. The diffusion MRI 
parameters needed for ADC calculation are 
b=0 and 1000 s/mm2, 
2-5 mm slice thickness without gap (whole brain coverage), 
Spin-echo, and 
Echo planar imaging. 
10.1.2.2 
Brain FDG-PET Methods 
Brain FDG-PET/CT will be obtained prior to induction therapy in a subset of 
patients in each arm. The same brain FDG-PET/CT will also be obtained after 
cycles 1 and 5 of induction chemotherapy. In addition to serial SUV measurements 
(baseline and scan after 4 weeks), we will also investigate changes in ratios of 
tumor FDG uptake versus uptake in contralateral white matter and normal cortex. 
No clear threshold is established for reliable response prediction and assessment 
in this setting. A decline in tumor SUV by at least 25% from baseline will be 
considered consistent with metabolic response in the week 4 scan. We hypothesize 
that individuals with greater decline in tumor SUV (or greater decline in tumor 
versus background ratios) in the 4 week scan will have a better outcome. 
Parameters to be recorded include SUV in PCNSL and a contralateral identical 
region, as well as physiologic FDG uptake in various other brain regions (e.g. 
contralateral thalamus, contralateral frontal and parietal cortex), and presence or 
absence of crossed cerebellar diaschisis. SUVmax and its variations (mean, peak) 
will be measured within a volumetric region of interest completely encompassing 
the lesion or normal brain region. The use of SUV thresholds (e.g. 42% and 75% 
will be explored [60, 65]. 
FDG-PET/CT findings will not be used to guide patient management. 
Nevertheless, we tentatively define CR as no residual abnormal uptake (non-
detectable or equal to contralateral white matter), PR as decline in SUV by at least 
25% and similar decline in T:N ratio, PD as increase in SUV and T:N ratio by at 

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least 25%, and SD as minor changes in FDG uptake not meeting aforementioned 
criteria. 
10.1.3 Diffusion MRI Procedures, Interpretation, and Analysis  
10.1.3.1 
Diffusion MRI Procedures 
Diffusion MRI data will be processed on an offline workstation to generate 
apparent diffusion coefficient (ADC) maps. Regions of interest (ROIs) outlining 
the contrast enhancing tumor region on post-contrast T1-weighted images will be 
performed. ADC maps will be co-registered with the post-contrast T1-weighted 
images containing the ROIs. The ADC values (mean, minimum, maximum, and 
25th percentile) of the entire contrast-enhancing tumor will be measured. Tumor 
ADC 25% greater than the median value of 692 will be considered high ADC 
patient cohort.  Based on our preliminary data, approximately 60% of patients are 
expected to be in the high ADC cohort. 
10.1.3.2 
Diffusion MRI Interpretation and Analysis 
Pre-therapy baseline tumor ADC25% < 692 and ≥ 692 will be designated into low 
and high-ADC groups, respectively. The difference in ADC values will be 
measured between 1) baseline and after one cycle of induction therapy, 2) baseline 
and after five cycles of induction therapy, and 3) after one and five cycles of 
induction therapy. 
Clinical outcomes (time-to-progression and overall survival) difference between 
low and high-ADC groups will be determined. In addition, we will determine 
whether changes in ADC during and after therapy predict clinical outcomes.  
10.1.4 Brain FDG-PET Imaging Procedures, Interpretation, and Analysis 
18F-FDG PET/CT imaging MUST be performed according to the protocol criteria at 
both baseline and follow-up. 
10.1.4.1 
FDG-PET/CT Institutional Requirements for Participation and Credentialing 
Procedures for FDG-PET/CT Imaging 
All limited access institutions that may participate in CALGB 581101 have been 
previously credentialed by the Alliance Imaging Core Lab (ICL). In order for a 
limited access institution to participate in CALGB 581101, the ICL must be 
contacted at 
to arrange for a credentialing 
update. 
The ICL regularly performs team telephone calls as well as virtual site visits, and 
serves as a consultant to help the local sites resolve questions with regard to 
adherence to the acquisition and reconstruction protocol.  
10.1.4.2 
FDG-PET/CT Imaging Timelines 
For 581101 PET/CT imaging, the following brain PET/CT images will be 
collected digitally for evaluation and archival:  
Baseline (within 21 days prior to day 1 of induction therapy) 
Prior to cycle 2 of induction chemotherapy (within 7 days prior to day 1 of cycle 
2) 
After cycle 5 of induction chemotherapy (within 28 days after the last day of 
induction cycle 5) 

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10.1.4.3 
Patient Preparation 
Patients should avoid any strenuous exercise for 24 hours prior to the PET scan 
and fast for no less than 4 hours prior to the injection of FDG. Patients must have 
a fasting blood glucose level ≤ 200 mg/dL prior to FDG injection. In patients 
presenting with fasting glucose > 200 mg/dL, an initial attempt may be made to 
lower blood glucose level according to local institutional guidelines. If the first 
attempt to control the blood glucose level fails (i.e., glucose remains > 200 mg/dL), 
then the patient will not be included in the FDG imaging study.   
Patients should be adequately hydrated with plain water. Weight (kg), height (cm), 
and blood glucose (mg/dL) will be measured and recorded prior to the injection of 
FDG.  
Patients should wait in a warm room to avoid false positive brown fat FDG uptake. 
Following FDG injections, patients should rest in a warm, quiet, and dimly lit (or 
dark) room during the FDG uptake period. FDG will be synthesized and prepared 
in accordance with the institution’s standard procedures or obtained from a 
commercial supplier. 
10.1.4.4 
FDG Dosing and Administration 
The administered activity of FDG should be based on the PET/CT system 
manufacturer’s recommendation. The recommended FDG activity is 6-10mCi, 
bolus injection followed by a saline flush (per institutional procedure). Pre-
injection FDG syringe dose, FDG dose injected and post-injection FDG dose 
residual and corresponding time should be documented on form CALGB 581101. 
10.1.4.5 
FDG-PET/CT Imaging Acquisition 
Brain PET/CT at all time points (baseline, prior to induction cycle 2, and at the end 
of induction therapy) MUST start 60-80 minutes after FDG injection. The timing 
should stay the same for follow-up PET/CT scans from the baseline (no more than 
a ± 10 minute difference). It is critical that follow-up PET/CT scans will be 
performed in an identical way to the baseline scan, with the same scanner and same 
patient preparation. Preferably, patients should be scheduled for baseline and 
follow-up scans at the same time of day (AM or PM) to improve reproducibility. 
The field of view is to encompass the brain (top of skull to skull base/upper neck). 
The head should be placed in a head holder and in the same position for all scans. 
The low dose CT will be done according to the institutional practice patterns, but 
using no less than 120kV, 120mA. The CT data will be used for attenuation 
correction of PET emission data. 
For the emission scanning, the acquisition should be performed in 3D mode in 
accordance with the manufacturer’s recommendations. The emission scan must be 
corrected for scatter, random events, and dead-time losses using the 
manufacturer’s recommended procedure. The image reconstruction will be 
performed using the manufacturer’s recommended parameters.  
Images should be attenuation-corrected using CT data. 
10.1.5 MRI and FDG-PET/CT Data Submission 
Both the MR and FDG-PET/CT images will be submitted to the ICL. Please see Section 
5.10.1 for MRI and FDG-PET/CT image storage and submission procedures. 

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10.1.6 Virtual Conferences and Training 
The Alliance ICL enables Internet-based visual and virtual conferences 
 that allow the simultaneous display of images 
(desktop presentations/desktop applications such as PowerPoint) and mutual 
communication between participating sites and the ICL in a secure manner (SSL-
encoded). The ICL will set up virtual meetings for problem solving and site training 
when necessary. 
10.2 
Biomarker Correlative Science Companion Study (CALGB 151113) 
Exploratory Analyses of Biomarkers as Potential Predictors of Outcome for Primary CNS B-
Cell Lymphoma 
10.2.1 Immunohistochemistry 
Based on prior studies, it is hypothesized that a number of IHC-based biomarkers will 
be predictive of an adverse prognosis: P-STAT-6, STAT-6 (signal transducer and 
activator of transcription 6, interleukin-4 induced) [66-69]. These markers arose from 
gene expression profiling studies carried out by 
 that identified IL-4 
pathway as important in CNS lymphoma. Activation of this pathway as measured by 
phospho-STAT6 expression was found as a predictor of adverse outcome in primary 
CNS B-cell lymphoma [66]. Thus, we intend to validate this finding prospectively in a 
uniformly treated patient population. In an exploratory manner, we also will study total 
STAT6 to determine whether total levels can yield similar information given the lability 
of phosphoproteins [70]. 
Conversely, it is hypothesized that BCL-6 (B-cell CLL/lymphoma 6) will be predictive 
of a favorable prognosis. Data generated from a prior study by 
has 
identified the germinal center B-cell marker BCL6 as a marker of favorable outcome in 
primary CNS lymphoma. Approximately 20% of cases lacked BCL6 expression by 
immunohistochemistry and median survivals were significantly decreased (101 months 
versus 12.7 months, P=0.002) compared to cases that expressed BCL6 [69]. Recent 
studies have not replicated this data; however, methodological and scoring issues 
confound the results [71]. Thus, prospective assessment using methods originally 
described [69] are required to validate this potential biomarker. 
A tissue microarray (TMA) will be constructed from cases with sufficient representative 
material. TMAs are constructed by removing two 1 mm diameter tissue cores from the 
lymphoma tissue block using a specially designed instrument (Beecher Instruments, 
Sun Prairie, WI). The resulting tissue array can contain 100 cases in a single tissue 
block, and allows rapid, high throughput analysis of markers by immunohistochemistry 
or in situ hybridization. The original tissue block remains intact with only a small 
amount of tissue removed with no significant distortion. Given the generally small 
nature of CNS lymphoma biopsies, whole tissue section staining will be performed in 
cases judged insufficient for TMA construction. 
For BCL6, automated staining using Pg-B6p (DAKO) will be performed with nuclear 
immunoreactivity in 10% as the cutoff [69]. pSTAT6 and STAT6 staining using 
pSTAT6 antibodies from Upstate Biotechnology as previously described with positive 
staining will be defined as high cellularity areas expressing pSTAT6 [66]. Total STAT6 
will be assessed using monoclonal anti-STAT6 (Clone 253906, R&D Systems) and 
scored similarly. Immunostains will be performed in the laboratories of 
 
 
Other candidate protein biomarkers of prognosis may be considered and tested. 

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10.2.2 Genomic and Expression Profiling 
Tumor tissue will also be analyzed for whole exome sequencing, copy number 
aberrations, and gene expression profiles in order to validate genetic prognostic markers 
and gene expression profiles in order to validate gene signatures associated with 
germinal center B, activated B-cell, or type 3 large B-cell lymphoma and signatures [66] 
of primary CNS lymphoma [72]. Aneuploidy versus diploid dichotomy was found in 
one study [73] and del 6(q) was found at very high frequency (75%) [74] suggesting the 
potential presence of a tumor suppressor gene.  Verification of these findings, and their 
potential clinical correlates is needed.  Furthermore, use of higher resolution techniques 
and/or sequence analysis may provide more detail on important genetic changes in 
primary CNS lymphoma. DNA will be purified from diagnostic tumor specimens 
(formalin-fixed paraffin-embedded) and genomic aberrations will be analyzed using 
either sequencing methods or hybridization methods such as Illumina genotyping/copy 
number chip. 
10.2.3 Circulating Protein Marker Analyses 
We will validate candidate diagnostic and prognostic protein biomarkers in the CSF 
using ELISA methods.  We will evaluate CSF protein and metabolites as biomarkers of 
prognosis. Candidate molecules include IL-10 (interleukin 10) and C3 (complement 
component 3) which have been identified using proteomic techniques and for which 
ELISA methods have been established in CSF [43]. We have used metabolic profiling 
to identify lactate and TCA cycle intermediates as selectively upregulated in the CSF of 
patients with CNS lymphoma, and it is hypothesized that these may be prognostic [75, 
76]. 
10.3 
Neurocognitive and Quality of Life Correlative Science Study (CALGB 71105) 
Neurocognitive Function and Quality of Life in Patients with Primary CNS B-Cell Lymphoma 
10.3.1 Background 
Cognitive dysfunction in PCNSL patients is related to multiple factors including the 
effects of the tumor itself, age, and the delayed adverse effects of whole brain radiation 
therapy (WBRT) and HD-MTX either combined or alone [77]. Delayed treatment-
related cognitive dysfunction has been recognized as a significant problem as effective 
treatment for PCNSL has increased survival rates [4, 77, 78]. Neurotoxicity is 
considered the most frequent complication among long-term survivors [79], and often 
interferes with the patient’s ability to function at premorbid levels, despite adequate 
disease control [80, 81]. 
A review of the literature [27] indicated that in the three published cross-sectional 
studies that assessed cognitive outcome after treatment with WBRT + HD-MTX [80-
82], there was evidence of cognitive impairment in the majority of patients. Quality of 
life assessment showed lower scores in cognitive emotional and social functioning in 
patients compared to controls [81], and reduced rates of employment [82]; however, the 
retrospective designs limited the ability to determine the specific contribution of disease 
and treatment. In prospective studies, including patients treated with WBRT and blood 
brain barrier disruption (BBBD) chemotherapy, the results were more equivocal with 
subsets of patients showing cognitive decline [83, 84]. Preliminary findings from a 
recent prospective study involving PCNSL patients treated with rituximab, MTX, 
vincristine and procarbazine (R-MPV), reduced-dose WBRT and high-dose cytarabine 
showed pre-treatment (baseline) impairments in executive function, verbal memory and 
motor speed. There was a significant improvement in cognitive function after induction 
chemotherapy and cognitive function remained relatively stable up to two years 

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following treatment completion; assessment of quality of life showed significant 
improvement after induction therapy and between the 6- and 12-month follow-up 
periods [6, 85]. 
To avoid the neurotoxic effects of WBRT, studies have explored the use of HD-MTX 
alone particularly in patients who are 60 years of age and older [3, 86]. Recent studies 
suggest that HD-MTX alone can be efficacious and reduce delayed neurotoxicity [8, 28, 
87, 88]. However, disease relapse is relatively common and many patients require 
salvage therapy with WBRT or high-dose chemotherapy [8, 89]. Studies that assessed 
cognitive outcome after treatment with HD-MTX alone were mostly prospective, and 
reported either stable or improved cognitive performance in the majority of patients [87, 
90-93]. Correa et al (2003) studied fourteen patients (mean age=54 years, SD=6.8) prior 
and at 6-month intervals subsequent to treatment with induction HD-MTX followed by 
myeloablative BEAM chemotherapy and autologous stem cell rescue [94]. Patients 
performed in the impaired range (i.e., test scores ≤ 1.5 SD below normative means) at 
baseline in attention and executive function, psychomotor speed, memory, and 
language. Improvement was observed in the seven patients available for post-induction 
follow-up, particularly in attention and executive functions. Cognitive performance 
remained stable (but within 1 SD below normative means) in three patients 18 months 
post-transplant (all patients had a CR). Patients did not complete all follow-up 
assessments due to disease progression or acute non-neurologic toxicity. Overall, in 
some studies, methodological problems limited the ability to discern the specific 
contributions of the disease and treatment to cognitive outcome [27]. As chemotherapy 
alone regimens have been used more frequently in the treatment of PCNSL, it is relevant 
to assess whether this therapy is associated with cognitive adverse effects.  
In light of the recognized relevance of studying cognitive outcome and quality of life in 
PCNSL patients and the paucity of multicenter systematic studies in the literature, this 
study offers a unique opportunity to incorporate a comprehensive evaluation of these 
domains. We plan to use the core neuropsychological test battery proposed by the 
International PCNSL Collaborative Group (IPCG) to evaluate patients longitudinally 
for up to 10 years [27].  
We hypothesize that in both treatment arms, there will be an improvement in cognitive 
function after induction chemotherapy followed by relatively stable cognitive 
performance in patients without evidence of disease progression – i.e. no cognitive 
decline after consolidation chemotherapy or HDT/ASCT in the absence of disease 
progression. Furthermore, we hypothesize that in both treatment arms, patients with 
relapsed disease requiring salvage therapy will have less preserved long-term cognitive 
function than patients without history of relapse. 
10.3.2 IPCG Assessment 
NOTE: English-speaking participants will be eligible to participate in the 
neurocognitive assessment component of this study. All eligible patients enrolled onto 
CALGB 51101 should be offered to participate in this correlative study.  
The tests in the IPCG neurocognitive test battery are standardized psychometric 
instruments shown to be sensitive to the impact of cancer and the adverse effects of 
cancer treatment in studies of PCNSL patients [80, 85]. The tests have published 
normative data that takes into account age, and where available, education. The tests are 
given by trained and certified site administrators, and the total time for the assessment 
is approximately 45 minutes. 
The IPCG test battery consists of the following: 

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Neuropsychological Evaluation:  
Attention/Executive Function: 
- Brief Test of Attention  
- Trail Making Test, Part A & B 
Verbal Memory: 
- Hopkins Verbal Learning Test-Revised (HVLT-R) 
Motor Speed:  
- Grooved Pegboard Test 
The quality of life evaluation consists of the following: 
EORTC Quality of Life Questionnaire-Core 30/Brain Cancer Module-20 
(EORTCQLQ30/BCM20) 
The EORTC QLQ30/BCM20 were developed and validated for use in patients with 
brain tumors [95]. These questionnaires have been used in many large cooperative trials 
within the RTOG and other clinical studies [96]. This quality of life component follows 
the methodology used in past clinical trials to assess change, and the purpose of this 
component is in part to investigate how possible changes in quality of life may impact 
patient outcomes.  
Timetable for cognitive functions: 
Tests 
Time points 
Cognitive 
and 
QOL tests 
≤ 2 weeks prior 
to 
treatment 
start 
Induction 
therapy cycle 4, 
day 28 
Every 6 months up to year 5 
(starting 6 months after treatment 
completion) then every 12 months 
for 5 years (for up to 10 years of 
follow-up) 
IMPORTANT: For patients with evidence of disease progression during the study 
period, a neurocognitive evaluation will be performed at the time of radiographic 
progression and prior to initiation of additional therapy. Subsequent follow-up will 
occur as described above. The treatment regimen at relapse will be considered in the 
long-term neurocognitive analyses. 
Two of the cognitive tests to be administered have alternate forms or versions in order 
to reduce the effects of practice. See the table below for the versions to be administered 
at each session. The forms should continue to be alternated in this order for the duration 
of the study. 
The following is a timetable for cognitive evaluations and alternate forms to be used at 
each data collection time point. 
Alternate forms to be used at each visit: 
Test 
≤ 2 weeks prior to 
treatment start 
Induction therapy cycle 4, day 28 
Every 6 months up to year 5 
(starting 
6 
months 
after 
treatment 
completion) 
then 
every 12 months for 5 years (for 
up to 10 years of follow-up) 
HVLT-R 
Form 1 
Form 2 
Form 3* 
TRAILS B 
Form 1 
Form 2 
Form 2** 
* 
HVLT-R: Continue to alternate order at subsequent 6-month intervals: Form 4, 
Form 5, Form 6, Form 1, Form 3, Form 4, Form 5, Form 6 

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** TRAILS B: Continue to alternate order at subsequent 6-month intervals: Form 1, 
Form 2, Form 1, Form 2, etc. 
10.3.3 CALGB 71105 Training and Certification Procedures 
If the patient consents to participate in the neurocognitive function component of the 
study (Model Consent Question #1), sites are required to administer the baseline 
cognitive and quality of life assessments prior to the start of protocol treatment, and at 
the subsequent intervals specified. The healthcare professional (e.g., nurse, research 
assistant, psychologist) who is responsible for test administration in this study must be 
pre-certified by 
   
Institutions with patients participating in the quality of life/neurocognitive function 
(NCF) components of this study must meet certification requirements for administering 
neurocognitive assessments. The healthcare professional responsible for test 
administration in this study at each site must be pre-certified by 
  
Prior to registering and/or testing a patient, potential examiners must: 
(1) Contact 
in order to obtain the training and 
certification materials, and test forms and test materials including: 
Neurocognitive Administration Instructions Manual 
Web address for the training video 
Cognitive and QOL Test Forms  
Grooved Pegboard and stopwatch 
Test Summary Form 
Certification Worksheet 
All of these materials will be mailed to the participating sites. 
(2) Read the entire Neurocognitive Administration Instruction Manual 
(3) Log on to the video website and enter the specified logon and password. Watch the 
training video. 
(4) Administer a practice assessment on a “non-patient volunteer” 
(5) Complete the Test Summary Form and the Certification Worksheet  
(6) Fax all materials pertaining to the practice assessment (i.e., practice test forms, 
summary form, and certification worksheet) to 
The 
materials will be reviewed and corrections to any procedural errors will be made and 
re-reviewed with the tester. 
(7) The tester will be notified of the certification approval to administer the tests to study 
subjects as part of CALGB 51101. A certification approval notice will be sent to the 
Alliance and to the Cancer Trials Support Unit (CTSU) for the registration process and 
to ensure that only approved examiners are testing subjects on protocol 51101. 
(8) All neurocognitive test and summary test forms for the first study patient at each site 
should be sent via fax to 
for review. In addition, send a 
copy of each assessment performed of each patient registered on study via fax to 
 
 for review. 
(9) During the study period, enter the data from the summary test form for each 
assessment performed on each patient into Medidata Rave. Keep all original test forms 
at a secure location at your site. 
If you have any questions please contact 
  

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11.0 DRUG FORMULATION, AVAILABILITY AND PREPARATION 
Qualified personnel who are familiar with procedures that minimize undue exposure to themselves 
and to the environment should undertake the preparation, handling, and safe disposal of 
chemotherapeutic agents in a self-contained, protective environment. 
Discard unused portions of injectable chemotherapeutic agents that do not contain a bacteriostatic 
agent or are prepared with unpreserved diluents (i.e., Sterile Water for Injection USP or 0.9% 
Sodium Chloride for Injection USP) within eight hours of vial entry to minimize the risk of bacterial 
contamination. 
The total administered dose of chemotherapy may be rounded up or down within a range of 5% of 
the actual calculated dose. 
11.1 
Methotrexate 
Please refer to the FDA-approved package insert for more information. 
Availability 
Methotrexate is commercially available for the preparation of high dose (i.e., > 1g/m2, as in this 
study) as a powder for reconstitution in vials containing 1000 mg. Solutions for injection that 
contain preservatives should not be used for the preparation of high doses 
Storage & Stability 
Intact vials should be stored at room temperature and protected from light. Reconstituted 
solutions (50 mg/mL) are stable for 7 days at room temperature. Solutions further diluted for IV 
infusion are stable for 24 hours at room temperature. 
Preparation 
Methotrexate powder for injection should be reconstituted with 19.4 mL of D5W or NS for a 
final concentration of 50 mg/mL, or according to institutional procedures. The desired volume 
should then be withdrawn and further diluted in 500 mL D5W or NS for IV infusion. The 
infusion solution should be protected from light. NaHCO3 50-150 mEq per liter of fluid may be 
added to the infusion solution to maintain urinary alkalinization (pH ≥ 7). Please note the 
information provided above are guidelines, institutions may follow their own institutional 
guidelines in place of this preparation. 
Administration 
Methotrexate will be administered as an IV infusion over 4 hours. Urine output and urinary 
alkalinization should be adequate before beginning methotrexate, as described in Sections 7.1.1 
and 7.2.1. Additional NaHCO3 may be added to the infusion solution to maintain urinary 
alkalinization (pH ≥ 7).  
Toxicity 
Toxicities 
associated 
with 
methotrexate 
include 
myelosuppression 
(neutropenia, 
thrombocytopenia, anemia) GI toxicities (nausea, vomiting, diarrhea, mucositis, anorexia), 
dermatologic (rash [including erythema multiforme and exfoliative dermatitis], photosensitivity, 
alopecia), and ocular irritation. In addition, transient elevations in hepatic enzymes are 
frequently seen with high doses of methotrexate, such as the dose used in this protocol. 
Precipitation of methotrexate and its 7- hydroxy-metabolite in an acidic urine can lead to renal 
tubular obstruction with resultant delayed administration of the drug and enhanced toxicity 
(myelosuppression, mucositis). This is seen with high doses (≥ 1 g/m2) and is prevented with 
hydration and urinary alkalinization. 

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11.2 
Leucovorin 
Please refer to the FDA-approved package insert for more information. 
Availability 
Leucovorin is commercially available in 50 mL vials containing 10 mg/mL; and in 50 mg, 100 
mg, and 350 mg vials of lyophilized powder for reconstitution. Follow the manufacturer’s 
labeling for reconstitution of vials containing powders. Leucovorin is also available in 5 mg, 10 
mg, 15 mg, and 25 mg tablets. In the case of leucovorin shortage, please refer to the Leucovorin 
Shortage memorandum posted on the Alliance website. 
Storage & Stability 
Store intact vials and tablets at room temperature between 15° and 25°C (59° and 77°F). Protect 
from light and moisture. Solutions reconstituted with bacteriostatic water are stable for at least 
7 days at room temperature. 
Preparation 
Reconstitute with bacteriostatic or sterile water for injection according to package insert 
instructions. If reconstituted with sterile water for injection, use immediately. If bacteriostatic 
water for injection is used, the solution is stable for 7 days.  
Administration 
Leucovorin is administered IV by bolus injection or short infusion. If leucovorin is required 
every 3 hours, a continuous infusion may be used if institutional preference. Oral administration 
is allowed at doses of 10 mg/m2, provided that methotrexate level is ≤ 0.1 mcM as described in 
Section 7.2.3. Leucovorin is to begin 24 hours after the start of each methotrexate dose. 
Toxicity 
The only adverse events usually associated with leucovorin are allergic reactions. These are 
extremely uncommon. 
11.3 
Temozolomide 
Please refer to the FDA-approved package insert for more information. 
Availability 
Temozolomide is available in 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, and 250 mg capsules.  
Storage and Stability 
Temozolomide capsules should be stored at controlled room temperature. 
Administration 
The capsules are administered orally and should not be chewed. They should be swallowed 
whole with a glass of water. Procedures for handling and disposal of anticancer drugs should be 
considered. 
Toxicities 
Myelosuppression 
(including 
neutropenia, 
lymphopenia, 
leukopenia, 
anemia, 
an 
thrombocytopenia), has been reported in patients receiving temozolomide and is a dose-limiting 
side effect. Thrombocytopenia and leukopenia reach grade 2 or higher in up to 40% of patients 
on temozolomide therapy. Leukocyte/platelet nadirs usually occur in 3 weeks (about day 22) 
with a 5-day schedule, although leukocyte nadirs may be seen slightly later (day 29). Dose-
limiting thrombocytopenia has persisted for 7 to 42 days, whereas recovery from leukopenia 
may be quicker. Bleeding has been infrequent with temozolomide therapy. In one large trial 

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involving adult patients with malignant glioma, the predominant effect was lymphopenia, which 
reached grade 3 and grade 4 in 41% and 15%, respectively, receiving a 5-day schedule of 
temozolomide. Corresponding incidences of neutropenia were 2% and 4%. The incidence of 
grade 3 or 4 thrombocytopenia was 11%. The incidence of myelosuppression may be higher 
with the use of a dose intense regimen. Opportunistic infections (e.g., pneumocystis jiroveci 
pneumonia (PCP)) have been reported with the use of temozolomide. Rarely, aplastic anemia 
and secondary leukemia have been described with temozolomide. 
Hepatic toxicity: Mild transaminase elevations (up to 40% of patients) and hyperbilirubinemia 
(up to 19%) have been reported; increases in alkaline phosphatase have also occurred in some 
patients. Grade 4 increases in bilirubin have been seen rarely. Cases of hepatic injury, including 
fatal hepatic failure, have been reported in patients receiving Temozolomide. Hepatic toxicities 
has been reported several weeks or more after initiation of treatment with Temozolomide or 
after discontinuation. 
Fatigue is among the most commonly reported adverse effect with the use of temozolomide in 
clinical trials, and is clearly drug-related. Fatigue with temozolomide therapy may be moderate 
to severe. The estimated incidence is 34%. 
Nausea and vomiting occur in up to 75% of patients with temozolomide therapy, but is not 
usually severe (mostly grade 1 or 2). These symptoms have often been limited to day 1 of the 
first cycle of temozolomide. Standard antiemetics have been effective in most patients. The 
estimated incidence is 42% to 53%. Bedtime administration of temozolomide may help to 
minimize nausea and vomiting.  
11.4 
Rituximab 
Please refer to the FDA-approved package insert for more information. 
Availability 
Rituximab is commercially available in 10 mL and 50 mL single-use vials containing 100 mg 
or 500 mg rituximab solution, respectively, at a concentration of 10 mg/mL. 
Storage and Stability 
Intact vials should be stored under refrigeration. Dilute solutions for infusion (1-4 mg/mL) are 
stable for 24 hours under refrigeration, and for an additional 24 hours at room temperature. 
Preparation 
The desired dose of rituximab should be diluted in 0.9% NaCl or D5W to a final concentration 
of 1-4 mg/mL. The solution should be mixed by gently inverting the bag. 
Administration 
Initial infusion rate is 50 mg/hr. If tolerated, the rate may be increased by 50 mg/hr every 30 
minutes, to a maximum of 400 mg/hr. If this rate of escalation is tolerated, the second and 
subsequent infusions can begin at a rate of 100 mg/hr and increase in 100 mg/hr increments 
every 30 minutes to a maximum of 400 mg/hour. 
Toxicity 
The most severe serious adverse events associated with rituximab include severe infusion 
reactions, tumor lysis syndrome, and severe mucocutaneous reactions. Severe infusion reactions 
consisting of hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial 
infarction, ventricular fibrillation or cardiogenic shock may be fatal. Most reported fatal 
reactions occurred within 24 hours of the first dose of rituximab.  

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Tumor lysis syndrome resulting in renal failure has been described, and occasional fatalities 
noted. Tumor lysis syndrome is more likely in patients with high numbers of circulating 
malignant cells (≥ 25,000/μL). 
Severe mucocutaneous reactions associated with rituximab include Stevens-Johnson syndrome 
and toxic epidermal necrolysis. The onset of these reactions has been from 1-3 weeks. 
Less severe infusion reactions are common with rituximab. These include fever, chills, and 
dyspnea. The mechanism of rituximab infusion reactions is thought to be secondary to release 
of cytokines. If a reaction occurs, then the infusion should be stopped until the symptoms 
resolve, and then restarted at a 50% slower rate. 
Recent reports describe hepatitis B reactivation with fulminant hepatitis, hepatic failure and 
death in some patients with hematologic malignancies treated with rituximab. The majority of 
these patients received rituximab in combination with chemotherapy. The median time to 
diagnosis of hepatitis was approximately 4 months after starting rituximab and approximately 1 
month after the last dose. 
Exacerbation or reactivation of other viral infections has also been reported with rituximab. 
Recent reports describe JC virus reactivation leading to progressive multifocal 
leukoencephalopathy (PML) in patients who were receiving rituximab. Patients presenting with 
new neurologic findings (e.g., major changes in vision, unusual eye movements, loss of balance 
or coordination, confusion) should be evaluated for PML. 
11.5 
Cytarabine 
Please refer to the FDA-approved package insert for more information. 
Availability 
Cytarabine is commercially available as a powder for reconstitution in 100 mg, 500 mg, 1 g and 
2 g vials, or a preservative free solution of 20 mg/mL (5 mL and 50 mL vials) and 100 mg/mL 
(20 mL vials). 
Storage and Stability 
Intact vials of cytarabine should be stored at room temperature. Vials of solution should be 
protected from light. Reconstituted solutions and solutions further diluted for infusion are stable 
at room temperature for up to 8 days. 
Preparation 
Cytarabine powder should be reconstituted with water for injection or 0.9% NaCl, to a 
concentration of 100 mg/mL. Diluents with bacteriostat should not be used to reconstitute high 
doses such as those used in this study (e.g., ≥ 1 g/m2). Solutions are further diluted in 0.9% NaCl 
or D5W for IV infusion. 
Administration 
Each dose of cytarabine will be administered IV over 2 hours. 
Toxicity 
The most common adverse events reported with cytarabine (“usual dosage” i.e., ≤ 200 mg/m2) 
include hematologic, gastrointestinal, dermatologic, and hepatic toxicities. Myelosuppression 
includes neutropenia, thrombocytopenia, and anemia. Cytarabine is considered highly 
emetogenic. In addition to nausea and vomiting, diarrhea and mucositis are reported in > 10% 
of patients. Alopecia is common. Rash, including palmar-plantar erythrodysesthesia (hand-foot 
syndrome) is also reported. Mild jaundice and elevations in transaminases are also reported in 

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> 10% of patients. Fever (non-infectious) is also reported among the most common adverse 
events associated with cytarabine. 
Less commonly, a “cytarabine syndrome” or “ara-C syndrome” has been reported. The 
syndrome may be characterized by fever, myalgia, bone pain, rash, malaise, chest pain, and, 
rarely, pericarditis. 
In addition to the above, the following adverse events have been described with high-dose (≥ 1 
g/m2/day) cytarabine. Neurologic toxicity is primarily cerebellar (nystagmus, dysarthria, 
disdiadochokinesia, ataxia, abnormal gait) but cerebral toxicity (somnolence, confusion, 
psychosis, seizures) may also be seen. Ocular toxicity, including photophobia and conjunctivitis 
are described with high-dose cytarabine. A steroid ophthalmic preparation should be 
administered, beginning 6-12 hours before the first dose of cytarabine and continuing for 48 
hours after the last “high dose,” to prevent conjunctivitis. Pulmonary edema has been rarely 
reported in association with high-dose cytarabine. 
11.6 
G-CSF 
Please refer to the FDA-approved package insert for more information. 
Availability 
G-CSF is commercially available in 1 mL and 1.6 mL vials containing 300 mcg and 480 mcg 
G-CSF, and in prefilled syringes containing 300 mcg/0.5 mL or 480 mcg/0.8 mL. 
Storage and Stability 
Intact vials and prefilled syringes should be stored in the refrigerator at 2°-8° C (36°-46° F). Do 
not freeze. 
Administration 
In Arm 1, is given for mobilization at a dose of 10 mcg/kg/day SC. In both Arm 1 and Arm 2, 
G-CSF may be used for neutropenia. 
Toxicity 
The most common adverse event associated with G-CSF is bone pain. Bone pain is usually 
reported as mild or moderate and, if necessary, may be treated with nonopioid or opioid 
analgesics. 
11.7 
Carmustine 
Please refer to the FDA-approved package insert for more information. 
Availability 
Commercially available as a powder for reconstitution in vials containing 100 mg carmustine. 
Each vial is packaged with a vial of diluent (3 mL absolute ethanol). 
Storage and Stability 
Intact vials should be stored in the refrigerator (2°-8°C). Un-reconstituted vials are stable for 7 
days at room temperature. Reconstituted solutions with ethanol diluent are stable for 24 hours 
under refrigeration and protected from light. Further diluted solutions for administration are 
stable for 48 hours under refrigeration and protected from light, but are stable only for 4-6 hours 
at room temperature and protected from light. 
Preparation 

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Reconstitute each vial with 3 mL absolute ethanol diluent. Further dilute in 500 – 1000 mL D5W 
or NS. Solutions for infusion should be prepared in glass or non-PVC plastic containers and 
protected from light. 
Administration 
In Arm 1, carmustine is infused IV over 2 hours. 
Toxicity 
Hypotension and facial flushing occur frequently during administration. These effects are 
related to the alcohol diluent. Arrhythmias and encephalopathy may also be seen. High dose 
carmustine is considered highly emetogenic. Onset of nausea and vomiting is within 2-4 hours 
of drug administration. Myelosuppression is expected with high dose therapy, as is alopecia. 
Late effects include nephrotoxicity and interstitial pneumonitis. Interstitial pneumonitis should 
be treated with steroids as described in (Section 8.6.2). Veno-occlusive disease of the liver is a 
complication associated with multiple drugs given in SCT regimens. 
11.8 
Thiotepa 
Please refer to the FDA-approved package insert for more information. 
Availability 
Thiotepa is commercially available as a powder for reconstitution in vials containing 15 mg or 
30 mg. 
Storage and Stability 
Intact vials should be stored under refrigeration and protected from light at all times. 
Reconstituted solutions are stable for 28 days under refrigeration and 7 days at room 
temperature. Solutions further diluted for infusion in D5W are stable for 14 days under 
refrigeration and 3 days at room temperature; infusion solutions in 0.9% NaCl are stable for 48 
hours under refrigeration and 24 hours at room temperature.  
Preparation 
Reconstitute each vial with sterile water for injection concentration of 10 mg/mL.   
Drug should be further diluted in D5W to a concentration of 5 mg/mL for IV infusion, using a 
0.22 micron filter. 
Administration 
Thiotepa will be infused over 2 hours in Arm 1. 
Toxicity 
Adverse 
events 
associated 
with 
thiotepa 
are 
myelosuppression 
(neutropenia, 
thrombocytopenia), oral mucositis, hyperpigmentation, and CNS toxicity. CNS toxicity is more 
prominent at high doses in stem cell transplants, and may include confusion, inappropriate 
behavior, and somnolence. CNS toxicities reported at lower doses include dizziness, fatigue, 
and headache. 
11. 9 Etoposide 
Please refer to the FDA-approved package insert for more information. 
Availability 
Etoposide is commercially available in 5 mL, 25 mL, and 50 mL vials containing 20 mg/mL. 
Storage and Stability 

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Unopened vials should be stored at room temperature and protected from light. Solutions diluted 
to a concentration of 0.2 or 0.4 mg/mL (in D5W or NS) are stable for 96 and 24 hours, 
respectively, at room temperature under normal light. 
Preparation 
The dose of etoposide should be diluted in D5W or 0.9% NaCl to a final concentration of ≤ 0.4 
mg/mL. 
Administration 
Etoposide will be administered IV, over 96 hours, in Arm 2. 
Toxicity 
Myelosuppression is expected with high dose etoposide. GI toxicities associated with high dose 
etoposide include severe nausea and vomiting, and mucositis. Hypotension is associated with 
shorter infusion times (e.g. 30 minutes). 
12.0 CRITERIA FOR RESPONSE, PROGRESSION AND RELAPSE  
12.1 
Definitions of Response 
Response will be defined using the modified IPCG criteria as noted below [97].  
 
Response 
CNS imaging 
Corticosteroid 
dose 
Eye exam 
CSF cytology 
CR 
No enhancing disease 
 
None 
Normal 
Negative 
uCR 
 
No enhancing disease 
 
Any 
Normal 
Negative 
Minimal enhancing 
disease 
 
Any 
Minor RPE 
abnormality 
Negative 
PR 
50% decrease in 
enhancement 
N/A 
Minor RPE 
abnormality or 
normal 
 
Negative 
No enhancing disease 
N/A 
Decrease in 
vitreous cells or 
retinal infiltrate 
 
Persistent or 
suspicious 
PD 
25% increase in 
enhancement 
 
N/A 
Recurrent or new 
disease 
Recurrent or 
positive 
Any new site of disease 
 
 
 
 
SD 
All scenarios not covered by responses above 
 
Abbreviations:  CR, complete response; uCR, unconfirmed complete response; PR, partial 
response; PD, progressive disease; RPE, retinal pigment epithelium. 

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12.1.1 Complete Response (CR): 
A complete response is defined as disappearance of all contrast-enhancing CNS (brain 
and spine if latter abnormal at baseline) disease, absence of any systemic corticosteroids 
prescribed to treat lymphoma (prophylactic steroid eye drops, topical steroids, 
corticosteroid antiemetics and steroids prescribed for non-disease reasons [e.g. asthma 
exacerbation, dermatologic or rheumatologic conditions] are allowed and not 
considered in the definition of CR), resolution of abnormal ocular findings on 
ophthalmological examination, negative CSF cytology.  
12.1.2 Complete Response Unconfirmed (CRu) 
An unconfirmed complete response is defined as CR but with either residual 
requirement for any corticosteroid dose or minimally enhancing abnormality on CNS 
imaging or minor abnormalities on ophthalmological examination. 
12.1.3 Partial Response (PR): 
A partial response is defined as >50% reduction in contrast-enhancing CNS (brain and 
spine if latter abnormal at baseline) disease either with minor abnormalities on 
ophthalmological examination or normal ophthalmological examination OR 
disappearance of all contrast-enhancing CNS (brain and spine if latter abnormal at 
baseline) but only reduction of vitreous cells or retinal infiltrates or residual suspicious 
or positive CSF cytology. 
12.1.4 Stable Disease (SD)  
All scenarios not covered by definitions of CR, CRu, PR or PD. 
12.1.5 Progressive Disease (PD)/Recurrence: 
Progressive disease is defined as > 25% increase in contrast-enhancing CNS (brain and 
spine if latter abnormal at baseline) disease, appearance of any new, measurable (>/= 
10mm) contrast-enhancing disease or recurrent or new ocular or CSF disease. 
13.0 REMOVAL OF PATIENTS FROM PROTOCOL THERAPY 
13.1 
Duration of Treatment 
13.1.1 (CR, CRu, PR, SD) 
Patients 
will 
be 
assessed 
for 
response 
after 
4 
cycles 
of 
methotrexate/temozolomide/rituximab and 1 cycle of cytarabine (5 cycles of remission 
induction therapy) per modified IPCG criteria [97]. Patients who achieve a complete 
response (CR), complete response/unconfirmed (CRu), partial response (PR) or stable 
disease (SD) will proceed to consolidation therapy with either etoposide and cytarabine 
or HDT/ASCT, depending on the initial randomization.   
13.1.2 (PD) 
At any point during protocol therapy, remove any patient with progressive disease (PD). 
Document details, including tumor measurements, on flow sheets. 
13.2 
Extraordinary Medical Circumstances  
If, at any time the constraints of this protocol are detrimental to the patient's health and/or the 
patient no longer wishes to continue protocol therapy, protocol therapy shall be discontinued. In 
this event: 
• 
Notify the Study Chair. 

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• 
Document the reason(s) for discontinuation of therapy on the Off Treatment form. 
• 
Follow the patient for relapse, progression, survival, and secondary malignancy or new 
primaries. 
14.0 STATISTICAL CONSIDERATIONS 
14.1 
Randomization 
Randomization will be stratified by 
age < 51 years, 
age ≥ 51 years and KPS ≥ 70, and 
age ≥ 51 years and KPS < 70. 
The use of this simple prognostic model consisting of age and performance status has been 
validated in the multicenter setting [2]. 
14.2 
Sample Size / Power Calculation 
A total of 160 patients (80 per arm) will be randomized between the control and experimental 
arms with 50:50 allocation proportions. The randomization will be conducted at registration, i.e. 
before induction therapy. Assuming that 80% of randomized subjects will achieve a 
radiographic response (CR, CRU, or PR) or stability (SD) and 5% will withdraw or will be 
ineligible, approximately 120 patients will be eligible for proceeding to either HCT/ASCT or 
chemotherapy. Further assumptions of this sample size calculation are as follows. 
1) 
For the patients who have CR, CRU, iPR, or SD from the induction therapy, we 
hypothesize a two-year PFS of 50% for the control arm, based on CALGB 50202 [26]. We 
will be highly interested in the experimental arm if its two-year PFS is 70% or higher. 
2) 
For the patients who develop tumor progression during induction therapy, we assume three 
months of median PFS. 
3) 
We assume exponential distributions for PFS. 
4) 
We expect an accrual rate of 6 patients per month. The patients will be followed for an 
additional three years after the completion of patient accrual. 
Under these assumptions, the intent to treat (ITT) analysis using the log-rank test with a one-
sided alpha=10% will have 90% power to compare two-year PFS of 50% and 70% between the 
two arms. The final analysis will be conducted when 95 events (progressions or deaths) are 
observed, which is expected to occur approximately 63 months after study activation. 
14.3 
Analysis Plan for Primary Endpoint 
14.3.1 Interim Analysis 
An interim analysis for futility testing will be conducted when 20 events are observed, 
which is expected to occur approximately 1.5 years after study activation. The study 
will be closed early because of futility if the one-sided p-value is larger than or equal to 
c1=0.691 (or equivalent if the standardized log-rank statistic is smaller than -0.5). 
14.3.2 Final Analysis 
The final analysis will be conducted when 60 events (progressions or deaths) are 
observed from the patients who proceed to either HDT/ASCT or chemotherapy (or 
about 95 events from all the eligible patients). All randomized patients will be included 
in the final data analysis based on intent-to-treat analysis. The experimental therapy will 

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be accepted for further investigation if the one-sided p-value is smaller than 0.1. The 
critical value c at the final analysis will be obtained by solving 1-alpha=P(Z1 > c1, Z > 
c) with respect to c, where  (Z1, Z) is a bivariate normal random vector with means 0, 
variances 1 and correlation coefficient r=(v1/v)1/2, and v1 and v are variance estimates 
of the log-rank test at the interim and final analyses, respectively. Through simulations, 
the two-stage design is found to have about 9.7% of type I error and 87% power.  
A secondary analysis will be conducted using the stratified log-rank test adjusting for 
the stratification factor. We will also conduct a secondary analysis including only the 
patients who proceeded to either HDT/ASCT or chemotherapy. The latter analysis will 
be more powerful than the primary analysis based on ITT by excluding the patients who 
will receive the induction therapy only. The secondary analyses will be conducted only 
at the final analysis time. 
14.4 
Sample Size Modification 
Due to the lower than expected accrual rate, the accrual goal was lowered from 160 to 110 with 
update #09, when approximately 95 patients were registered. We recalculate the power of the 
new sample size assuming a median PFS of 2 years for the control arm and 4.5 years for the 
experimental arm, and an expected accrual rate of 4 patients per month, with other design 
parameters the same as before: (i) 50:50 randomization, (ii) 5% of withdrawal, (iii) 80% of 
randomized subjects achieve a radiographic response (CR, CRU, or PR) or stability (SD) and 
proceed to the allocated treatments, (iv) a median PFS of 3 months for the patients who develop 
tumor progression during induction therapy, (v) 2 years of additional follow-up, and (vi) 
modified intent to treat (ITT) analysis to exclude ineligible patients. 
Under these assumptions, a sample size of N=110 guarantees 84% of power by the log-rank test 
with a one-sided alpha=10%. The final analysis will be conducted when 64 events (progressions 
or deaths) are observed, which is expected to occur approximately 52 months (=28 months for 
patient accrual + 24 months for additional follow-up) after study activation. Since this sample 
size modification occurred after the interim analysis that was planned by the original design was 
conducted and concluded to proceed to the second stage, there will be no more interim analysis. 
As of protocol Update #11, the following change has been made: 
Revised final analysis timing due to low event rate: 
This study closed to accrual May 2 2017, having registered 113 patients. A total of 108 patients 
are considered evaluable for the primary analysis, excluding 4 patients who never started 
treatment and 1 ineligible patient. As of March 2020, the pooled event rate was lower than that 
specified by the study design. According to the study design, we would have expected 64 events 
needed to trigger the final analysis in May 2019. However, with a median follow-up of 42 
months (IQR 34 to 56), the observed number of events is 50. Considering data maturity and 
ability to provide a timely final analysis, the final analysis will be performed when all patients 
have been followed for at least 36 months, which is expected in May 2020. 
14.5 
Monitoring for Adverse Events and Study Feasibility 
14.5.1 Adverse Event Monitoring 
About 10% of patients are expected to experience grade 3 or higher unexpected 
toxicities from the consolidation therapies. We consider 30% of 3 or higher unexpected 
toxicities from the consolidation therapies too high. Each time both the experimental 
and control groups enroll 10 additional patients, adverse events (AEs) will be 
monitored. We will consider suspension of the study for a protocol amendment if, in 
either of the study arms, 5 or more of the first 10 patients experience any unexpected 
grade 3 or higher toxicities (≥5/10), ≥7/20, ≥8/30, or ≥10/40. This monitoring rule has 

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a 1.1%, 32.5%, and 83.4% probability of rejecting each arm due to toxicity if the grade 
3 or higher unexpected toxicity rate is 10%, 20%, and 30%, respectively. 
14.5.2 Study Feasibility 
We expect (1) about 75% of patients will achieve SD or better response from the 
induction therapy and continue to the randomized arms, and (2) about 5% of patients 
with SD or better response from the induction therapy will withdraw from the 
randomized arms. We will perform interim analyses to check these assumptions as 
follows:  
The study will be stopped for feasibility if (1) among the first 80 randomized patients 
the overall observed proportion of patients receiving the randomized therapy is less than 
65%, or (2) among the first 80 patients eligible to receive randomized treatment (i.e., 
patients achieving SD or better) the observed non-adherence (due to withdrawal) rates 
differ between the arms by more than 10%. These rules have stopping probabilities of 
(1) 85%, 20% and 3% if the true probability to continue to the randomized therapy is 
60%, 70% and 75%, respectively, or (2) 2.2% and 88% if the true probabilities of non-
adherence in two arms are (5%, 5%) and (5%, 25%), respectively. 
14.6 
Secondary Endpoints 
14.6.1 The event-free survival (EFS) and the overall survival (OS) will be estimated for each 
arm by the Kaplan-Meier method, and compared between the two arms using the log-
rank test. We will also conduct a multivariate analysis of these outcomes adjusting 
for the predictors, such as age and KPS. 
14.6.2 Toxicity data will be summarized by grade and attribution for induction therapy and 
for each of HCT/ASCT and chemotherapy consolidation arms. The toxicity rate will 
be compared between the arms using Fisher’s exact method. 
14.7 
Correlative Science Companion Study Analyses 
14.7.1 Exploratory Analyses on Genomic and Proteomic Studies of FFPE Tissue, CSF 
Specimens, and Whole Blood Specimens (151113) 
We assume that specimens will be available from about 80% of patients. IHC-based 
markers will be associated with PFS and OS. In a previous study (CALGB 50202), 
 
observed amplification of STAT6 in about 50% of PCNSL patients. With 
66 (=82 eligible patients x 0.8), we will have about 90% power to detect a median PFS 
of 1.5 years vs. 4.5 years between STAT6 amplification and non-amplification groups 
by the log-rank test with two-sided 5% alpha. 
We will also investigate the impact of del 6q on PFS and OS. Cady et al observed a del 
6q frequency of 45% in a prior study [98]. At first this analysis will be conducted within 
each treatment arm. Assuming a del 6q prevalence of 40%, this analysis will have about 
88% power to detect a median PFS of 1.5 years vs. 4.5 years between del 6q+ and del 
6q- groups by the log-rank test with two-sided 5% alpha. 
These analyses will be conducted by stratifying the treatment allocation. A multivariate 
analysis will be conducted adjusting for the stratification factors together with the 
treatment arm and the interaction between treatment and marker value. 
14.7.2 Diffusion MRI Metrics (581101) 
In order to determine diffusion MRI metrics (ADCmini, ADC25%, and ADCmean) prior to 
induction chemotherapy, after the first cycle of induction chemotherapy, and after the 
last cycle of induction chemotherapy as a predictor of response and outcome, ADC 

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values (ADCmini, ADC25%, and ADCmean) will be collected at baseline (pretreatment) and 
post induction cycles 1 and 4 during treatment from the 25 patients per arm. An inverse 
correlation between ADC values and cellular density will be investigated using scatter 
plots and correlation coefficients. Others have observed a correlation coefficient of 
about 0.5 [29]. We will have 75% and 96% power to detect a true correlation coefficient 
of 0.5 with n=25 and 50 (by combining the two arms), respectively, with a two-sided 
alpha=5%. 
ADC values will be correlated with PFS, EFS, and OS using Jung et al, 1995 [99]. This 
approach is to investigate the global association between a continuous marker and a 
survival endpoint by calculating the log-rank test statistics between low and high marker 
value groups using all possible cutoff values for the marker. The testing distribution will 
be approximated using a permutation method [100]. Multivariate analyses adjusting for 
other predictors will be conducted using Cox regression method.  
These analyses will be conducted for each arm. If the treatment effect is not significant, 
the data from the two arms will be combined for pooled analyses. We will consider 
transforming (e.g. log transformation) the positive measurements, like ADC values and 
cellular density, for variance stabilization and symmetry of the distributions. 
14.7.3 FDG-PET Metrics (581101) 
There is no clear threshold established for reliable response prediction and assessment 
for FDG-PET in the setting of PCNSL. Tentatively, a decline in tumor SUV by at least 
25% from baseline will be considered consistent with metabolic response on the 4-week 
scan. We hypothesize that patients with > 25% decline in tumor SUV (or greater decline 
in tumor versus background ratios) on the 4-week brain FDG-PET scan will have a 
better prognosis. The association between decline in tumor SUV and metabolic response 
on the 4-week scan will be tested using Fisher's exact test. 
14.7.4 Cognitive and Quality of Life Evaluation (71105) 
In both arms, the cumulative incidence approach will be used to estimate the median 
time to neurocognitive failure to account for the competing risks of death.  
Neurocognitive decline will be defined as the first cognitive failure on 2 or more of the 
following tests: Digits Forward and Backward (WAIS-III); Brief Test of Attention; the 
HVLT-R for Free Recall, Delayed Recall and Recognition; the Trail Making Test Part 
A or B; and the Grooved Pegboard Test (average of left and right hand scores). 
Cognitive failure for each test is defined as a change in a score that meets or exceeds 
the Reliable Change Index (RCI) value for each test indicating a performance that is 
worse than the patient’s baseline score. 
The standardized test score will also be calculated for each test and to determine which 
tests are most sensitive to detect cognitive impairment/change. The cut-offs for 
standardized scores will be determined through receiver operating characteristic (ROC) 
methods.  
To capture possible cognitive dysfunction associated with disease burden from relapses 
and salvage treatments, we will perform neurocognitive follow-up in both arms for at 
least the initial 5 years, regardless of disease status (including in patients with disease 
progression). Additionally, yearly cognitive follow-ups will be performed from years 
5-10. Longitudinal data analysis will be performed to assess if there is a difference over 
time (i.e. change rate) across the two treatment arms using a generalized estimating 
equation (GEE), based on working independent correlation structure [101]. In this 
analysis, the 6-month observation will be used as the baseline. The treatment regimen 

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received subsequent to disease progression will also be considered in the longitudinal 
data analyses. The data may be transformed to improve the linearity of the longitudinal 
trend and normality of the marginal distribution. If no linear trend seems to fit the trend, 
we will compare the areas under the fitted trend. 
The pattern of missing data (i.e. missing probabilities at measurement times) will be 
investigated for each arm. If the missing probabilities are similar between arms, we will 
apply the GEE method without imputing missing data [101]. However, if the missing 
trend is different, we will consider using Rubin-type (1978) multiple imputation 
method. Most missing data in this study is expected be monotone missing. We will test 
the similarity of missing pattern by comparing the time to missing data between two 
arms using the log-rank test.   
Similar approaches will be used for the EORTC QLQ30/BCM20. Differences of at least 
10 points will be classified as the minimum clinically meaningful change in a health-
related quality of life (HRQOL) measure.  For example, an increase of 10 points or more 
on a functional scale would mean a moderate improvement, whereas a decrease of 10 
points or more would be interpreted as moderate worsening.  Furthermore, a rise in a 
symptom score means deterioration. Changes of less than 10 points will be regarded as 
no change or as clinically irrelevant, and changes of more than 20 points will be 
considered large effects. This approach has been used in several multi-center trials. 
From CALGB 50202, which has a similar patient population to this study, we observed 
a 5-year survival rate of 62%. Assuming that about 80% of the living patients will be 
participating in this HRQOL study at any time and OS has an exponential distribution, 
the expected missing probability is 27%, 34%, 40%, 45%, and 50% at year 1, 2, 3, 4, 
and 5, respectively. We assume monotone missing pattern in this power calculation. For 
dependency structure of longitudinal data, we assume a continuous autoregressive 
correlation model with correlation coefficient rho=0.65 between two repeated 
measurements of 1 year apart. With a maximum of 10 measurement times (0.5 year, 1 
year, 1.5 years, 2 years, 2.5 years, 3 years, 3.5 years, 4 years, 4.5 years, and 5 years), 
we assume a linear trend in an HRQOL measure (possibly after a transformation such 
as logarithm) whose difference in mean level becomes 0.3 times the standard deviation 
(SD) of the error terms after 1 year.  
With n=82 patients in two arms, we have 88% power to detect this amount of difference 
in change rate between two arms by the GEE test with two-sided alpha=5% using the 
working independent correlation structure. For example, for EORTC QLQ30/BCM20, 
the SD was observed to be about 30 from brain cancer patients [102]. Thus, if the time 
trend in mean functional scale splits by 9 (=0.3 x SD) points between two arms after 
about 1 year post-induction, then we will have 88% power. The first study results will 
be reported at 5 years.  
14.8 
Accrual and Follow-up 
A total of 110 patients (55 per arm) will be randomized between the control and experimental 
arms with 50:50 allocation proportions. We expect an accrual rate of 4 patients per month. The 
patients will be followed for a maximum of 10 years after registration. 
Based on the power calculation, the study is expected to last for approximately 52 months (28 
months for patient accrual plus 24 months for additional follow-up). 
14.9 
CDUS Reporting 
The Alliance Statistics and Data Center will submit quarterly reports to CTEP by electronic 
means using the Clinical Data Update System (CDUS). 

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15.0 EXPEDITED ADVERSE EVENT REPORTING 
Investigators are required by Federal Regulations to report serious adverse events as defined below. 
Investigators are required to notify the Alliance Central Protocol Operations Program Office, the 
Study Chair, and their Institutional Review Board (IRB) if a patient has a reportable serious adverse 
event. The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting beginning April 1, 2018.  
All appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A copy of 
the 
CTCAE 
version 
5.0 
can 
be 
downloaded 
from 
the 
CTEP 
web 
site 
 
All 
reactions 
determined to be “reportable" in an expedited manner must be reported using the CTEP Adverse 
Event Expedited Reporting System (CTEP-AERS). 
15.1 
CALGB 51101 Reporting Requirements 
CALGB 51101:  Expedited Reporting Requirements for Adverse Events that Occur in a Non-
IND trial within 30 Days of the Last Administration of a Commercial Agent 1 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether 
or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI 
via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
• Grade 
1 
Timeframe
s 
• Grade 2 Timeframes • Grade 
3 
Timeframes 
• Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 

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NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in 
the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
• 
“24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 
24 hours of learning of the AE, followed by a complete expedited report within 5 
calendar days of the initial 24-hour report. 
• 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 
10 calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs that are at least possibly related to treatment 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization, 
that are at least possibly related to treatment 
• 
Grade 3 adverse events that are at least possibly related to treatment 
Effective Date: July 25, 2011 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements for 
Commercial Agents in a Non-IND trial: 
• 
All adverse events reported via CTEP-AERS (i.e., serious adverse events) should also be 
forwarded to your local IRB. 
• 
Grade 3/4 myelosuppression and hospitalization resulting from such do not require CTEP-
AERS, but should be submitted as part of study results. 
• 
Febrile neutropenia and hospitalization from such do not require CTEP-AERS. 
• 
Grade 3/4 nausea or vomiting and hospitalization resulting from such do not require CTEP-
AERS, but must be reported as part of study results. 
• 
Grade 3/4 neurotoxicity and hospitalization resulting from such do not require CTEP-AERS, 
but must be reported as part of study results. 
• 
Secondary malignancy: A secondary malignancy is a cancer caused by treatment for a 
previous malignancy (e.g., treatment with investigational agent/intervention, radiation or 
chemotherapy). A secondary malignancy is not considered a metastasis of the initial 
neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an agent under 
an NCI IND/IDE be reported via CTEP-AERS. In CTCAE version 5.0, three options are 
available to describe the event:  
-Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML])  
-Myelodysplastic syndrome (MDS)  
-Treatment-related secondary malignancy  
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol. 
Second malignancy: A second malignancy is one unrelated to the treatment of a prior 
malignancy (and is NOT a metastasis from the initial malignancy). Second malignancies 
require ONLY routine reporting unless otherwise specified. 

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• 
Treatment expected adverse events include those listed in Section 11.0, in the package inserts 
for all agents, and in the CAEPR for rituximab (see Section 15.2). In the ASAEL column of 
the rituximab CAEPR, grade 3-5 events are NOT exceptions to CTEP-AERS reporting. 
• 
The reporting of adverse events described in the table above is in addition to and does not 
supplant the reporting of adverse events as part of the report of the results of the clinical trial, 
e.g., cooperative group data reporting (see Section 5.6)  
• 
In CTCAE v5.0, pregnancy loss is defined as “Death in utero,” and any pregnancy loss should 
be reported expeditiously as Grade 4 “Pregnancy loss” under the Pregnancy, puerperium and 
perinatal conditions SOC. A pregnancy loss should NOT be reported as a Grade 5 event under 
the Pregnancy, puerperium and perinatal conditions SOC as currently CTEP-AERS 
recognizes this event as a patient death.  
A neonatal death should be reported expeditiously as Grade 4, “Death neonatal” under the 
General disorders and administration SOC. 
• 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in the 
system organ class (SOC) “General disorders and administration site conditions.” Evidence 
that the death was a manifestation of underlying disease (e.g., radiological changes suggesting 
tumor growth or progression: clinical deterioration associated with a disease process) should 
be submitted. 

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16.0 REFERENCES 
1. 
CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed 
in the United States in 2004-2006. 2010, Central Brain Tumor Registry of the United States: 
Hinsdale, IL. 
2. 
Abrey, L.E., et al., Primary central nervous system lymphoma: the Memorial Sloan-Kettering 
Cancer Center prognostic model. J Clin Oncol, 2006. 24(36): p. 5711-5. 
3. 
Ferreri, A.J., et al., High-dose cytarabine plus high-dose methotrexate versus high-dose 
methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial. 
Lancet, 2009. 374(9700): p. 1512-20. 
4. 
Abrey, L.E., L.M. DeAngelis, and J. Yahalom, Long-term survival in primary CNS 
lymphoma. J Clin Oncol, 1998. 16(3): p. 859-63. 
5. 
Miller, T.P., et al., Chemotherapy alone compared with chemotherapy plus radiotherapy for 
localized intermediate- and high-grade non-Hodgkin's lymphoma. N Engl J Med, 1998. 
339(1): p. 21-6. 
6. 
Shah, G.D., et al., Combined immunochemotherapy with reduced whole-brain radiotherapy 
for newly diagnosed primary CNS lymphoma. J Clin Oncol, 2007. 25(30): p. 4730-5. 
7. 
Bessell, E.M., et al., Importance of radiotherapy in the outcome of patients with primary CNS 
lymphoma: an analysis of the CHOD/BVAM regimen followed by two different radiotherapy 
treatments. J Clin Oncol, 2002. 20(1): p. 231-6. 
8. 
Gerstner, E.R., et al., Long-term outcome in PCNSL patients treated with high-dose 
methotrexate and deferred radiation. Neurology, 2008. 70(5): p. 401-2. 
9. 
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APPENDIX I 
IDEAL BODY WEIGHT TABLE FOR CORRECTED BODY WEIGHT FORMULA 
 
 
 
 
 
 
 
Height (Feet/Inch) 
Small Frame (kg) 
Medium Frame (kg) 
Large Frame (kg) 
 
 
 
 
 
MEN 
 
 
 
 
 
5’2” 
54 
59 
64 
 
5’3” 
56 
60 
65 
 
5’4” 
57 
62 
67 
 
5’5” 
59 
63 
69 
 
5’6” 
60 
65 
71 
 
5’7” 
62 
67 
73 
 
5’8” 
64 
69 
75 
 
5’9” 
66 
71 
77 
 
5’10” 
68 
73 
79 
 
5’11” 
70 
75 
81 
 
6’0” 
72 
77 
84 
 
6’1” 
74 
79 
86 
 
6’2” 
76 
82 
88 
 
6’3” 
78 
84 
90 
 
6’4” 
79 
86 
93 
 
 
 
 
 
WOMEN 
 
 
 
 
 
4’10” 
45 
49 
54 
 
4’11” 
46 
50 
55 
 
5’0” 
47 
51 
57 
 
5’1” 
49 
53 
58 
 
5’2” 
50 
54 
59 
 
5’3” 
51 
55 
61 
 
5’4” 
53 
57 
63 
 
5’5” 
54 
59 
64 
 
5’6” 
56 
61 
66 
 
5’7” 
58 
63 
68 
 
5’8” 
59 
65 
70 
 
5’9” 
61 
67 
72 
 
5’10” 
64 
69 
74 
 
5’11” 
65 
70 
76 
 
6’0” 
67 
72 
79 
 
 
 

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APPENDIX II 
PERFORMANCE STATUS CRITERIA 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able to 
carry on all pre-disease performance 
without restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or sedentary 
nature (e.g., light housework, office 
work). 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time. 
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities. Up and about more 
than 50% of waking hours. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time. Capable of 
only limited self-care, confined to 
bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or 
chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead.