Clinical trial NCT02059239
Conditions: Hodgkin's Lymphoma Non-Hodgkin's Lymphoma
Keywords: Non-Hodgkin's Lymphoma Hodgkin's Lymphoma Lymphoma Transplant
Sponsor: Weill Medical College of Cornell University
Start date: 2014-06-04; Completion date: 2020-06-15
Enrollment: 34 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This clinical trial is for men and women with whose lymphoma (non-Hodgkin or Hodgkin) did not respond to treatment or has returned after responding to previous therapy, and who are in need of a stem cell transplant.

The purpose of this study is to test the safety and effectiveness of giving the drug Bendamustine, followed by high dose chemotherapy, within two weeks prior to a stem cell transplant for lymphoma that has not achieved a complete response to salvage (treatment used for relapsed disease) chemotherapy.

Detailed description:
Subjects with Hodgkin's or Non-Hodgkin's lymphoma that did not respond to treatment or have disease that has returned after responding to previous treatment, and are in need of a stem cell transplant will be eligible for this pilot study. Thirty subjects will be enrolled, with 15 subjects assigned to the autologous transplant cohort (according to disease status and eligibility) and 15 subjects to the allogeneic transplant cohort (according to diseases status and eligibility).

Subjects will undergo the following a number of screening procedures to determine eligibility. All eligible subjects will receive bendamustine at a dose of 200 mg/ m2/ day for two days on Days - 24 and Day - 23 followed by a short break of 10 - 14 days. Subjects will then receive the conditioning regimen, BEAM (carmustine, etoposide, cytarabine arabinoside, and Melphalan) and alemtuzumab for 6 days (Day -6 to Day -1) followed by an autologous or allogeneic transplant.

Subjects with pathological confirmed B-cell malignancies will also receive rituximab 375 mg/m2 on Days + 1 and +8 post-transplant. Subjects with T-cell lymphoma will be enrolled in the study but will not receive rituximab.

After the transplantation all subjects will receive medication to prevent graft vs host disease and supportive care to prevent infections. To speed up the recovery of stem cells, subjects will receive post-transplant filgrastim (G-CSF).

After discharge from the hospital, subjects will be seen regularly in the clinic for an exam and assessments. All these tests are considered standard of care.

Arms: arm 1: Bendamustine 200 mg/ m2/ day on Days - 24 and Day - 23 followed by a short break of 10 - 14 days, followed by Melphalan, Carmustine, Etoposide, Cytarabine (BEAM) and alemtuzumab, plus rituximab for all b-cell malignancies, followed by autologous transplant arm 2: Bendamustine 200 mg/ m2/ day on Days - 24 and Day - 23 followed by a short break of 10 - 14 days, followed by Melphalan, Carmustine, Etoposide, Cytarabine (BEAM) and alemtuzumab, plus rituximab for all b-cell malignancies, followed by allogeneic transplant
Interventions: intervention 1: Bendamustine intervention 2: Carmustine intervention 3: Etoposide intervention 4: Melphalan intervention 5: Cytarabine intervention 6: Alemtuzumab intervention 7: Autologous Stem Cell Transplantation intervention 8: Allogeneic Stem Cell Transplantation intervention 9: Rituximab
Intervention descriptions: intervention 1: Days - 24 and Day - 23 followed by a short break of 10 - 14 days. intervention 2: 300 mg/m2 on Day -6 intervention 3: 100 mg/m2 on days -5 to -2 intervention 4: 140mg/m2 on Day -1 intervention 5: 200 mg/m2 on days -5 to -2 intervention 6: 20 mg/m2 days -6 to -2 for UNRELATED donors, and 20 mg/m2 days -4 to -2 for RELATED donors intervention 7: None intervention 8: None intervention 9: Only to be administered in subjects with B-cell malignancies. Dose is 375 mg/m2 on Days 1 and 8 post-transplant

Protocol documents:
Prot_SAP_000.pdf: 
Title: A Pilot Study of a Sequential Regimen of Intensive Chemotherapy Followed by Autologous or 
Allogeneic Transplantation for Refractory Lymphoma (Non-Hodgkin’s and Hodgkin’s) and an Expansion 
Phase 2 Cohort 
NCT02059239 
 
Initial IRB Approval Date: 1/23/2013 
 
Amendment History 
• 
Original Protocol Date: 13 August 2012 
• 
Amendment #1: 03 June 2014 
• 
Amendment #2: 12 June 2015 
• 
Amendment #3: 17 February 2016 
• 
Amendment #4: 01 September 2016 
• 
Amendment #5: 14 June 2017 
• 
Amendment #6: 05 October 2017 
 
 






3 
 
 
 
 
 
 
 
 
  
 
 
 


4 
 
TABLE OF CONTENTS 
 
 
Page 
SCHEMA CHART ....................................................................................................................... 3 
 
1. OBJECTIVES ....................................................................................................................... 6 
1.1 
Primary Objectives .................................................................................................... 6 
1.2 
Secondary Objectives ............................................................................................... 6 
 
2. BACKGROUND .................................................................................................................... 6 
2.1 
Refractory and Relapsed Non-Hodgkin’s and Hodgkin’s Lymphoma ......................... 6 
2.2 
Study Rationale…………………………………………………………………………..….7 
2.2.1 Dose Density Combined with Dose Intensity …………………………………..…..……7 
2.2.2  High Dose Bendamustine .......................................................................................... 8 
 
2.2.3 The Use of Allogeneic Transplantation in Selected Subjects 8-9 
2.2.4   Treatment Justification ............................................................................................. 10 
 
3. STUDY DESIGN ................................................................................................................. 10 
 
4. SUBJECT SELECTION ................................................................................................. 10-11 
4.1 
Inclusion Criteria  ..................................................................................................... 11 
4.2 
Exclusion Criteria .................................................................................................... 12 
4.3 
Donor Selection ....................................................................................................... 12 
4.4 
Hematopoietic Progenitor Cell Source ..................................................................... 12 
 
5. REGISTRATION PROCEDURES ....................................................................................... 12 
5.1  
Central Patient Registration ..................................................................................... 12 
 
6. ASSESSMENTS... ......................................................................................................... 12-13 
6.1  
Pre-Transplant Evaluation ....................................................................................... 13 
6.1.1    Evaluation at Enrollment-before bendamustine bridge………………………13 
6.1.2 Evaluation after bendamustine but before Transplant conditioning………..14 
6.2  
Post-Transplant Evaluation ................................................................................. 14-15 
 
7. TREATMENT PLAN ........................................................................................................... 16 
7.1 
Agents Administration ............................................................................................. 16 
7.1.1  Bendamustine Bridge .............................................................................................. 16 
7.1.2  Conditioning Regimen and Transplantation ............................................................. 16 
7.1.2.1 Regimen for Related Marrow or Peripheral Blood SCT ............................................ 16 
7.1.2.2 Regimen for UnrelatedMarrow or Peripheral Blood SCT ......................................... 17 
7.1.2.3 Regimen for Autologous Transplantation………………………………………………19 
7.1.3  Rituximab ................................................................................................................ 20 
7.1.4  GVHD Prophylaxis for Related and Unrelated Transplants ...................................... 20 
7.1.5  GVHD Prophylaxis for Alternative Donor Haplo/Cord and Double Cord 
Transplants................................................................................................................20 
7.2 
Mobilization and Stem Cell Collection of Donors 17 
7.3        General Concomitant Medication and Supportive Care Guidelines .......................... 20 
7.4       Duration of Therapy and Criteria for Removal from Study........................................ 20 
7.5       Duration of Follow Up .............................................................................................. 20 
 
8. DOSING DELAYS/DOSE MODIFICATIONS ...................................................................... 21 
 
9. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ..................................... 21 


5 
 
9.1  
Study Agent Risks ................................................................................................... 19 
9.2  
Adverse Event Characteristics ................................................................................. 19 
9.3  
Recording of Adverse Events .................................................................................. 19 
9.4  
Serious Adverse Event Reporting ............................................................................ 20 
 
9.4.1 Definition of SAE ..................................................................................................... 20 
9.4.2 Reporting of SAE to IRB .......................................................................................... 20 
9.4.3 Reporting of SAE to FDA  ........................................................................................ 21 
 
10. DATA REPORTING / REGULATORY CONSIDERATIONS ............................................... 21 
 
10.1 
Data Collection ........................................................................................................ 21 
 
10.2 
Accuracy of Data Collection ..................................................................................... 21 
 
10.3 
RedCap 
 ............................................................................................................... 21 
 
10.4 
Protocol Compliance ................................................................................................ 22 
 
11. STATISTICAL CONSIDERATIONS .................................................................................... 22 
11.1     
Study Endpoints ................................................................................................. 22 
11.2      
Sample Size, Analysis Plan and Accrual Rate ................................................... 23 
11.3   
Toxicity Stopping Guidelines .............................................................................. 23 
11.3.1  
Transplant-Related Mortality (TRM) ................................................................... 23 
11.3.2  
Graft Failure ....................................................................................................... 24 
11. 4     
Reporting ........................................................................................................... 24 
11.4.1   
Evaluation of toxicity .......................................................................................... 24 
11.4.2  
Evaluation of response ...................................................................................... 24 
 
12. DATA SAFETY MONITORING BOARD ............................................................................. 24 
     12.1     
Interim Analysis ................................................................................................. 25 
 
13. REGULATORY CONSIDERATIONS .................................................................................. 23 
13.1 
Institutional Review Board/Ethics Committee Approval ...................................... 25 
13.2 
Informed Consent Procedures ........................................................................... 25 
13.3 
Protocol Amendments and Deviations ............................................................... 26 
13.4  
Protecting Privacy and Confidentiality ................................................................ 26 
13.5 
Study records requirements ............................................................................... 26 
13.6 
Protection of Human Rights ............................................................................... 27 
13.7 
Premature Discontinuation of Study ................................................................... 27 
13.8 
Benefits of the Protocol ...................................................................................... 27 
13.9 
Risks in Relation to Anticipated Benefit .............................................................. 27 
13.10 
Alternative Treatments ....................................................................................... 27 
13.11 
Incentives .......................................................................................................... 28 
13.12 
Costs ................................................................................................................. 28 
 
APPENDICES 
 
APPENDIX A 
Performance Status Criteria ...................................................................................................... 29 
 
APPENDIX B 
WCMC SAE Reporting Forms ............................................................................................. 30 
 
APPENDIX C 
Cheson criteria .................................................................................................................... 31 
 
 


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APPENDIX D  
Package Insert for Bendamustine........................................................................................ 32 
 
APPENDIX E 
Background Drug Information ......................................................................................... 33-42 
 
APPENDIX E 
Acute Graft versus Host Disease ........................................................................................ 43 
 
APPENDIX F 
Chronic Graft versus Host Disease ...................................................................................... 44-46 
 
REFERENCES .................................................................................................................... 48-51 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1. OBJECTIVES 
 
1.1. 
Primary Objectives 
 
 
 To determine the safety and efficacy of high dose bendamustine induction 
followed by high dose chemotherapy in the treatment of relapsed and 
refractory lymphoma  
 
 
 
 To determine ability to recover after high dose chemotherapy and proceed 
to transplant within 14 days +/- 5 days from start of bendamustine.  
 
1.2. 
Secondary Objectives 
 
 Overall Survival (OS) at Days 100 and 360 post transplant 
 Disease Free Survival (DFS) 
 Response (complete or partial remission, stable disease, progressive 
disease) 
 To determine PET response after treatment with high dose bendamustine  
 Transplant Related Mortality (TRM) 
. 
2. BACKGROUND 
 
2.1 
Refractory and Relapsed Non-Hodgkin’s and Hodgkin’s Lymphoma 
 
Refractory is a term that refers to patients that do not respond to treatment, while 
relapsed patients’ malignancies have recurred after treatment. Patients with aggressive 
Non-Hodgkin’s Lymphoma (NHL) and Hodgkin’s Lymphoma (HL) that have relapsed 
after or are refractory to standard induction chemotherapy normally undergo autologous 
stem cell transplantation if their disease is chemosensitive (i.e. responding) to salvage 
therapy (therapy used for relapsed disease) . 1 
 
Traditionally, patients with such chemotherapy sensitive relapses are thought to have 
cure rates of approximately 50 to 60% with autologous stem cell transplantation    
(PARMA study). More recent data suggest that patients failing initial treatment with 
rituximab containing regimens (which constitute the large majority of lymphoma 
patients) or those with early relapses represent a more unfavorable group.  
 
The CORAL study showed that subjects had only approximately a 20% cure rate with 
salvage autologous transplant, as did those with early relapses (< 1year)2. Subjects’ 
whose disease did not demonstrate chemosensitivity did not benefit from standard 
autologous transplantation, even with intensified regimens.1 
 
Over the past decade PET scanning has emerged as an effective method for assessing 
chemotherapy responsiveness in patients with refractory or relapsed lymphoma.  Also, 
persistent PET positivity prior to stem cell transplantation is an unfavorable feature and 
a harbinger of early disease progression. 3, 4,5, 6 
 
 


8 
 
 
2.2 
StudyRationale 
 
Alternative approaches are warranted to improve outcome of patients failing current 
regimens of front line chemotherapy.  A large number of novel drug treatments are 
under active investigation, but the concept of dose intensification continues to have 
appeal due to its proven track record in inducing durable remissions, be it in a relatively 
small percentage of patients.  
 
In our attempt to improve subject outcomes, we will study several modifications to the 
current standard practice: 
1) Dose density combined with dose intensity 
2) High dose bendamustine 
3) The use of allogeneic transplantation in selected subjects (based on entry 
criteria).  
 
2.2.1 Dose Density Combined with Dose Intensity 
 
Dose density is an approach used to overcome lymphoma resistance to therapy. This 
method involves giving chemotherapy frequently within a short time frame so as not to 
allow the malignant clone to recover. One example is the dose dense approach of the 
German lymphoma group, Pfreundschuh, who used the CHOP regimen every 14 days 
rather than every 21 days in the front line lymphoma setting. 7 Gianni’s group used a 
high dose sequential chemotherapy approach (dose dense) followed by autologous 
transplantation for NHL (dose intense). This study showed a marginal benefit over 
standard chemotherapy and autologous transplant but this could not be reproduced in a 
multicenter trial due to excessive toxicity.8 
 
Dose intensity is the hallmark of high dose chemotherapy regimens, but attempts at 
both dose intensity and dose density (e.g. double autologous transplant) have often 
faltered because of inordinate delays between successive cycles of chemotherapy. 
Examples of this approach include a recent study of tandem autologous transplant for 
relapsed and refractory lymphoma with the first transplant using myeloablative BEAM as 
the conditioning regimen and the second transplant using radioimmunotherapy.9 The 
estimated 4-year OS and PFS were 67% and 64%, respectively.  
 
A second study of tandem transplants had an overall survival of 59% at 114 months 
post-transplant, which was better than the standard results noted in the CORAL study 
for single transplants in this situation.10 Furthermore, 86% of patients who achieved a 
complete response (CR) remained alive and disease free for 114 months.  Nonetheless, 
there is a significant time required to recover from one transplant to go on to the next 
and not all patients are able tomove forward to the 2nd transplant.  
 
Many patients with recurrent NHL and HL have disease that tends to grow quickly, 
repopulating malignant cells between salvage cycles. Such disease is often 
characterized by intense uptake on PET scans and, more readily measured, a high 
serum lactate dehydrogenase (LDH). Such disease may be more effectively addressed 


9 
 
by combinations of dose density and dose intensity. Such approaches have already 
demonstrated certain success in the front line treatment of lymphoma.   
A combination of dose intensity and dose density is used in the French rituximab, 
doxorubicine, cyclophosphamide, vindesine, bleomycine, prednisolone (R-ACVBP) 
(ACBVP R) regimen11. This study included subjects with diffuse large B-cell lymphoma 
with 2 or 3 International Prognostic Index factors. Subjects received four cycles of 
intensive biweekly chemotherapy with R-ACVBP followed by auto-transplantation in 
responding subjects. This resulted in a in a 78% 4-year overall survival. These results 
warrant being compared to other approaches. 
 
The approach of giving a high dose salvage regimen followed quickly and sequentially 
by an allogeneic transplant, timed such that the disease does not have the opportunity 
to regrow between cycles, has been pioneered in patients with acute leukemia.  
Patients with refractory leukemia have been treated with an intensive cycle of salvage 
chemotherapy and then proceeded to allogeneic transplant within 14 days of treatment, 
with a significant benefit to this approach.12, 13, 14 This protocol will emulate these 
protocols in refractory and relapsed lymphoma, using drugs that are standard of care in 
the treatment of lymphoma, but using the timing/ sequential strategy that has been 
developed in the refractory leukemia population. Currently, no timing-to-transplant 
regimen has been approved by the U.S. Food and Drug Administration (FDA). Also, the 
FDA has not approved any transplant conditioning regimens; only the use of individual 
drugs.  
 
2.2.2 High Dose Bendamustine 
 
Bendamustine is an FDA approved drug that has efficacy in treating lymphoma and has 
a unique mechanism of action.15We propose to use high dose bendamustine at a dose 
of 200 mg/m2/day for two consecutive daysas a dose intense approach to relapsed and 
refractory lymphomas prior to proceeding to transplant with BEAM conditioning, a 
commonly used conditioning regimen. This will be done in a sequential manner so that 
dose density will also be maximized.  
 
The current standard dose of bendamustine in treating malignancies, such as 
lymphoma, is 240 mg/m2 per cycle.16 In one study. Bendamustine had been used in a 
conditioning regimen for autologous lymphoma transplants up to 200 mg/m2/day over 2 
days, for a total of 400 mg/m2 and this still was not the maximally tolerated dose.17In 
this modified Fibonacci dose-escalation study, subjects received 160-200 mg/m2 daily 
x2 on days -7 and -6 prior to autologous SCT.  Dose escalation proceeded up to the 
maximum planned dose (400 mg/m2 cumulative) without any non-hematologic dose-
limiting toxicity.  As prior phase I studies of bendamustine in advanced solid tumors 
demonstrated cardiac toxicity at 280 mg/m2 as a single dose (not seen when 
fractionated over 2 days as in the proposed schedule), additional subjects were enrolled 
and 0 of 6 demonstrated dose-limiting toxicity. Bendamustine has been used in at 
WCMC as part of a conditioning regimen for auto-transplantation in multiple myeloma. 
In that study, a dose of 225 mg/m2 of bendamustine was been combined with 
melphalan with no major toxicities. 18 
 
 


10 
 
 
 
2.2.3 The Use of Allogeneic Transplantation in Selected Subjects  
 
Patients with chemotherapy resistant disease or those who have disease progression 
despite autologous transplantation are often considered for allogeneic transplantation.19 
Allogeneic transplantation offers the benefit of an immunological strategy (graft versus 
lymphoma effect) in addition to the intensive chemotherapy +/- radiation therapy of the 
conditioning regimen. For some subjects in this study, allogeneic transplantation will be 
considered. 
 
The following criteria will be used to determine whether subjects will proceed to  
autologous or allogeneic transplantation: 
 
Autologous transplantation 
 Subjects with relapsed lymphoma who have at least a partial response to their 
prior salvage regimen defined as: 
 PET positivity with SUV ≤ 8and > 50% bidimensional decrease in lymphoma 
masses.  
 
Allogeneic transplantation 
 Subjects with lymphoma who had a prior autologous transplant 
or 
 Subjects with refractory lymphoma who did not achieve a partial response to 
salvage therapy as defined above. 
 
NOTE: The response definitions are outlined in the Cheson criteria (Appendix C)..20 
 
2.2.4 Treatment Justification 
 
1) The subjects included in this protocol have a low likelihood of durable response 
to standard salvage therapy and arein great need of new curative options. 
 
2) The protocol is formally designed to assess the toxicity of the entire treatment 
sequence. But the secondary endpoints include an effort to assess benefits  and 
toxicity of every component (drug and transplant) individually.   
 
3) In some respects this study mirrors current clinical practice and 
codifiesmanagement that is routinely performed in desperate cases.  
 
3. 
STUDY DESIGN 
 
Step 1: Bendamustine  
 
Step 2A: BEAM (plus Rituximab if applicable) conditioning and autologous transplant. 
 
OR 
 


11 
 
Step 2B: BEAM (plus Rituximab if applicable) conditioning and allogeneic transplant. 
 
This pilot study will enroll a total of 30 subjects. With 15 subjects assigned to the 
autologous transplant cohort (according to disease status and eligibility) and 15 subjects 
to the allogeneic transplant cohort (according to diseases status and eligibility). 
 
Subjects who do not undergo transplantation will be replaced until both cohorts are filled 
with 15 allogeneic and 15 autologous subjects. The subjects who do not undergo 
transplant will be evaluable for toxicity if they underwent the bendamustine 
chemotherapy.  
 
Once the pilot is completed with reasonable safety and efficacy as reviewed by the 
DSMB, an expansion phase 2 study will be done to validate the results of the pilot. This 
will involve enrolling another 60 patients to follow the above algorithm. Patients who do 
not undergo transplant will be replaced but will be evaluable for bendamustine toxicity. 
 
4. SUBJECT SELECTION 
 
4.1 
Inclusion Criteria 
 
 Subjects must have histologically or cytologically confirmed relapsed or primary 
refractory lymphoma (including Hodgkin’s Lymphoma) staged with PET scan to 
have 
 Allogeneic arm: 
o Progressive diseaseor  
o No response to salvage therapyor 
o Partial response to salvage therapy defined as>50% reduction in 
bidirectional area of masses but SUV remains ≥8 in at least some 
PET avid areas 
o Prior autologous transplant 
 
 Autologous arm: 
o Partial response of >50% reduction in bidirectional area  of masses 
and SUV reduction to <8 in PET avid areas  
 
Patients with complete response to salvage therapy (i.e. complete resolution of previous 
lesions and PET consistent with complete response (CR) by Cheson Criteria) are not 
eligible.  
 
 Subjects must have evaluable disease.  
 Subjects must have received at least one induction therapy and one line of 
salvage therapy that each incorporate at least two drugs that are standard of 
care for lymphoma  
 Age >18 years. 
 KPS (Karnofsky Performance Score) ≥ 50% 
 For autologous transplants: Subjects must have an adequate number of CD34+ 
stem cells collected to allow for transplantation.  This number is defined as ≥ 
2x106 CD34+ cells / kg body weight. If not previously collected and stored, the 


12 
 
subject must be willing to undergo stem cell mobilization and collection as per 
standard practice. If sufficient cells cannot be collected, subjects will be offered 
the option to proceed with the allogeneic arm of the study.  
 Male and female subjects must use an effective contraceptive method during the 
study and for a minimum of 6 months after study treatment. Female subjects of 
childbearing potential must have a negative serum pregnancy test within 2 weeks 
prior to enrollment. 
 Ability to understand and the willingness to sign a written informed consent 
document. 
 
4.2 
Exclusion Criteria  
 
 Known to be positive for HIV  
 Subjects may not be receiving any other investigational agents (defined as non 
FDA-approved agents) at the time of initiating bendamustine regimen. However, 
the salvage therapy for lymphoma can be part of an ongoing clinical trial with an 
investigational agent.  
 Women who are pregnant or breast feeding. Women of childbearing age must 
use adequate contraception and have a negative pregnancy test. 
 The risks to an unborn fetus or potential risks in nursing infants are unknown. 
 History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to any medications listed in the protocol. 
 Subject with severely decreased Left Ventricular Ejection Fraction (LVEF) or 
severely impaired pulmonary function tests (PFT’s) 
 Uncontrolled illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements.  
 
4.3 
 Donor Selection and Stem Cell Source 
 
Institutional policies regarding criteria and selection of the donor will be followed. 
Related and unrelated donors will be allowed. 
 
4.4 
Hematopoietic Progenitor Cell Source (HPC) 
 
Storage, stem cell source, and handling of HPC will be in accordance with 
institutional policy. 
 
5.  
REGISTRATION PROCEDURES 
 
5.1 
Central Patient Registration 
 
Subjects will be centrally registered with Weill Cornell Medicine (WCM), Joint 
Clinical Trials Office (JCTO).To register a subject, fax the following documents to 
the Clinical Research Office at (646) 962-1610: 
 
 
WCMC Subject registration form 


13 
 
 
First and last page of the fully executed informed consent form, plus 
additional pages if checkboxes for correlative studies are required. 
 
Fully executed HIPAA research authorization form 
 
Eligibility checklist signed and dated by investigator and research nurse 
 
Documentation of any eligibility waivers granted  
 
Confirmation of sponsor registration, when applicable 
 
For inpatients, signed consent documentation template 
 
Central registration information is reviewed and entered into the HemOnc centralized 
research database.   
 
6.  ASSESSMENTS  
 
6.1 
Pre-Transplant Evaluation  
 
6.1.1 Evaluation at Enrollment-before bendamustine bridge 
 
 
The following observations are considered standard evaluations for transplant eligibility 
and should be determined as close to conditioning as possible.  
1. Medical history, physical examination, height and weight.1,2 
2. KPS (Karnofsky Performance Score) ≥ 50%1,2 
3. Complete blood count (CBC) with differential and platelet count, serum 
creatinine, BUN, electrolytes, uric acid, Ca, PO4 , bilirubin, alkaline phosphatase, 
AL T, AST, LDH, glucose, Mg, protein, albumin, PT, PTT, estimated GFR1,2 
4. Dental evaluation 
5. Sinus imaging, which can include x-rays, CT, PET or MRI scans 
6. Cytomegalovirus (CMV) antibody test 
7. Infectious disease and hepatitis panel (HepAAb, HepB Sab, HepB Sag, HepB 
Core Ab, HepCAb), herpes simplex, syphilis, HIV and HTLV 1 antibody, & 
varicella zoster virus. 
8. High resolution HLA typing, if not already performed.⁰ 
9. Electrocardiogram (ECG) < 6 weeks before initiation of conditioning therapy. 
10. Left ventricular ejection fraction, before initiation of conditioning therapy. It would 
be necessary to do LVEF testing after completion of any prior cardio toxic drugs.  
11. Diffusing capacity the lung for carbon monoxide (DLCO), Forced Expiratory 
Volume in One Second (FEVI), and Forced Vital Capacity (FVC) or O2 saturation 
before initiation of conditioning therapy.2 It would be necessary to do the 
pulmonary testing after completion of any prior lung toxic drugs.  
12. Bone marrow aspirates and / or biopsies for pathology and cytogenetics1,2 
13. Beta -HCG serum pregnancy test for females of childbearing potential. 
14.  Whole body PET/CT scanprior to enrollment.1,2 It would be necessary to the the 
PET/ CT after any prior lymphoma therapy has been completed.  
15.  Chimerism:  Peripheral blood for pre-transplant RFLP analysis to establish a 
reference profile of host hematopoiesis.⁰,2 
16. Diagnostic Lumbar Puncture as clinically indicated (High grade lymphoma). 
 


14 
 
⁰ These evaluations will occur for allogeneic transplants, only 
 
6.1.2. Evaluation after bendamustine but before Transplant conditioning 
 
 Medical history, physical examination, height and weight.1,2 
 KPS (Karnofsky Performance Score) ≥ 50%1,2 
 Complete blood count (CBC) with differential and platelet count, serum 
creatinine, BUN, electrolytes, uric acid, Ca, PO4 , bilirubin, alkaline 
phosphatase, AL T, AST, LDH, glucose, Mg, protein, albumin, PT, PTT, 
estimated GFR1,2 
 Whole body PET/CT scan 
 
6.2 
Post-Transplant Evaluation 
 
The follow-up schedule for scheduled study visits is outlined in Table 1 below. 
 
Table 1 
 
Study Visit 
Target Day Post-Transplant 
1 week 
7 + 4 days  
2 week 
14 + 4 days 
3 week 
21 + 4 days 
4 week 
Weeks 5 – 8 
28 + 4 days 
At least 2 visits 
Day 100 visit 
100 +/- 30days 
6 month 
180 +/-  30 days 
12  month 
365 +30 days 
 
The following evaluations are considered standard evaluations for allogeneic transplant 
recipients. These tests may be adjusted as warranted by clinical circumstances and 
evolving transplant policy. Please also refer to institutional transplant work up 
guidelines. 
 
1. History and physical exam to assess GVHD and other morbidity at each visit. 
CBC at least three times a week from Day 0 until ANC > 500 mm3 for 3 days 
after nadir reached. Thereafter, CBC at each visit.  
2. Creatinine, bilirubin, alkaline phosphatase, AL T, AST, LDH, sodium, 
magnesium, potassium, and chloride tests twice a week until Day 28 (or four 
weeks) and then at each visit.  
3. Peripheral blood on Days 28, 56, 100, 180, and 365 (or as close to those time 
frames as possible) for post-transplant chimerism assay 
4. Immunizations will be given per institutional guidelines and will follow CDC 
guidelines.  
5. Toxicity assessments post-transplant on Days 28, 100, 180, and 360 or as close 
to those days as possible.  
6. Disease status (PET) evaluation required post-transplant on Days 28, 100, 180 
and 1 year post-transplant (or as close to those days as possible).  
 


15 
 
Testing to determine disease status with PET scans should follow pre-transplant 
evaluation process. The follow-up schedule for scheduled study visits is outlined in 
Table 2. 
 
Table 2 
 
Study 
Assess-
ments 
 
 
 
 
 
Days after Transplantation 
 
Baseline After 
Benda 
before 
SCT 
7 14 
21 
28 
Weeks 5- 
8 (SOC)7 
100 
180 
 
365 
History, 
physical 
exam, weight, 
height, and 
KPS 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
CBC1 , 
differential, 
platelet 
count, and 
blood 
chemistries2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Infectious 
disease  
 
X 
 
 
 
 
 
 
 
 
 
 
Dental exam 
 
X 
 
 
 
 
 
 
 
 
 
Lumbar 
puncture5 
X 
 
 
 
 
 
 
 
 
 
Sinus 
Imaging 
X 
 
 
 
 
 
 
 
 
 
ECG, LVEF, 
or shortening 
fraction 
 
X 
 
 
 
 
 
 
 
 
 
DLCO, FEV I 
and FVC or 
02-saturation 
 
X 
 
 
 
 
 
 
 
X 
 
 
Bone marrow 
biopsy and 
aspirate for 
pathology4 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
PET/CT 
X 
X 
 
 
 
X 
 
X 
X 
X 
B-HCG  
X 
 
 
 
 
 
 
 
 
 
GVHD and  
Toxicity 
assessments 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
Chimerism 
X 
 
 
 
 
X 
X 
X 
X 
 
X 
 
Notes (Table 2): 


16 
 
 
1. CBC performed at least three times a week from Day 0 until ANC >500 mcL for three 
days after nadir. CBC performed twice weekly until Day 28. CBC  performed weekly after 
Day 28 until 12 weeks post-transplant. 
2. Blood chemistries include: serum creatinine, bilirubin, alkaline phosphatase, AST, and 
ALT, LDH, sodium, magnesium, potassium, and chloride (where standard of care should 
be according to institutional guidelines). Blood chemistries performed twice weekly until 
Day 28. Blood chemistries performed weekly after Day 28 until 12 weeks post-transplant. 
3. Infectious disease titers include: CMV, Hepatitis panel (HepA, Ab, HepB SAb, HepB SAg, 
HepB Core Ab, HepC Ab), herpes simplex virus, syphilis, HIV and HTLV III antibody, and 
varicella zoster. 
4. Bone marrow biopsy and aspirates to pathology required at Day 21 if WBC < 500. Day 28 
only to be done if slow neutrophil recovery to evaluate for graft failure. Cytogenics and 
flow cytometry should be sent as clinically indicated by subject's diagnosis.  Pre-SCT 
bone marrow should only be repeated if previous bone marrow involvement was present. 
This should be done prior to the bendamustine. If positive, it should be done again prior 
to the transplant conditioning.  
Post SCT (d 28, d100 etc.) should only be repeated if previously positive, and after 
allogeneic transplant.   
5. If clinically indicated for high grade lymphoma. 
6. GVHD assessments only in allogeneic transplant recipients. 
7. SOC is standard of care 
 
 
7. TREATMENT PLAN 
 
7.1 
Agents Administration 
 
Treatment will be administered on an inpatient and/or outpatient basis.  Reported 
adverse events and potential risks are described in Section 7.  Appropriate dose 
modifications for   Investigational Agents are described in Section 7.  No investigational 
or commercial agents or therapies other than those described below may be 
administered with the intent to treat the subject’s malignancy. 
 
All drugs used in this protocol will be commercially available.  
 
Subjects maybe admitted to the hospital for a period of four to six weeks, sometimes 
more if necessary for subject care prior to transplant.  
 
7.1.1 Bendamustine Bridge 
 
Subjects on this protocol will receive bendamustine at a dose of 200 mg/ m2/ day over 
60 minutes, on Days – 24 and Day – 23 followed by a short break of 14 +/- 5 days. The 
number of days the break for each subject will be dependent on multiple factors 
including donor dates, availability of donor, and weekend infusions versus weekday 
infusions. 
 
7.1.2  Conditioning Regimen and Transplantation  
 
7.1.2.1 Regimen for Related Marrow or Peripheral Blood Stem Cell 
Transplantation 


17 
 
 
 
 
Drug 
Day -6  
Day -5 
Day -4 
Day -3 
Day -2 
Day-1 
Day 0 
Carmustine1 
300mg/ 
m2  
 
 
 
 
 
 
Stem cell 
 infusion 
Etoposide2 
 
 
 
100mg/m2  
 
100mg/m2  
100mg/m2  
 
100mg/m2  
 
 
 
Cytarabine3 
 
200mg/m2  
200mg/m2  
200mg/m2  
 
200mg/m2  
 
 
 
 
Melphalan 
 
 
    
140mg/m2 
 
 
Campath 
 
 
20 mg/m2 
20 mg/m2 
20 mg/m2 
 
 
*Pre-medications to prevent Campath toxicities are acetaminophen, Diphenhydramine, 
Methylprednisolone or Hydrocortisone will be given if necessary. 
1) Carmustine – administered over 6 hours 
2) Etoposide – administered every 12 hours Day -5 – Day -2 
3) Cytarabine – administered every 12 hours Day -5 – Day -2 
 
 
 
7.1.2.2 Regimen for Unrelated Marrow or Peripheral Blood Stem Cell 
Transplantation 
 
 
Day -6  
Day -5 
Day -4 
Day -3 
Day -2 
Day-1 
Day 0 
Carmustine
1 
 
300mg/m2 
 
 
 
 
 
 
Stem cell 
 infusion 
Etoposide2 
 
 
 
100mg/m2 
100mg/m2  
100mg/m2  
 
100mg/m2  
 
 
 
Cytarabine3 
 
200mg/m2  
 
200mg/m2  
200mg/m2  
 
200mg/m2  
 
 
 
Melphalan 
 
 
140mg/m2 
 
Campath 
20 mg/m2 
20mg/ m2 20 mg/m2 
20 mg/m2 
20 mg /m2 
 
 
*Pre-medications to prevent Campath toxicities are acetaminophen, Diphenhydramine, 
Methylprednisolone or Hydrocortisone will be given if necessary. 
 
1) Carmustine – administered over 6 hours 
2) Etoposide – administered every 12 hours Day -5 – Day -2 
3)Cytarabine – administered every 12 hours Day -5 – Day -2 
 
 
 
For patients who cannot receive BEAM conditioning therapy, alternative conditioning regimens 
may be utilized (including but not limited to: Flu Mel, Flu Mel TBI, Cy/ TBI, VP16/TBI). Such 


18 
 
decisions will be addressed within the BMT physician team. This is often the case in patients 
who had prior BEAM with an autologous transplant and now require a different regimen for an 
allogeneic transplant.  
 
For patients who do not have an HLA compatible related or unrelated donor, alternative donors 
may be used such as haplo/ cord or double cord transplants. In such cases, ATG will be 
substituted for Campath and Flu Mel +/- TBI will be substituted as the conditioning regimen. 
These regimens are standard of care regimens within the BMT program.  
 
 
Day 
-7 
Day -6  Day -5 
Day -4 
Day -3 
Day -2 
Day -1 
Day 0 
 Day 
1 or 
day 0 
Fludarabine 
 
30 
mg/
m2 
30 
mg/m2 
30 
mg/m2 
30 
mg/m2 
30mg/
m2 
 
 
Haplo 
Stem 
Cell 
UCB 
stem 
cell 
Melphalan 
 
 
 
 
 
 
140 
mg/m2 
 
 
 
rATG 
 
 
1.5 
mg/kg 
 
1.5 
mg/kg 
 
1.5 
mg/kg 
 
 
TBI* 
 
 
 
2 Grey 
2 Grey 
 
 
 
 
 
Fludarabine: Administer 30 mg/m2 /day intravenously x 5 days (Day -7 to Day -3) of a total dose 
of 150 mg/m2. Fludarabine will be dosed according to actual body weight.  
 
Melphalan: Administer 140mg/m2/day intravenously on day -2. Melphalan will be dosed 
according to actual body weight. Cryotherapy with ice chips will be administered to prevent 
mucositis. 
 
Rabbit ATG (rATG)-thymoglobulin: 1.5 mg/kg/day IV x3 days total for all patients. ATG will be 
dosed according to actual body weight. The first dose will be infused over at least six hours, and 
subsequent doses over at least 4 hours.  Pre-medications include acetaminophen 650 mg by 
mouth, diphenhydramine 25-50 mg by mouth or intravenously, and methylprednisolone 2 mg/kg 
(1 mg/ kg at the initiation and 1 mg/kg half-way through anti-thymocyte globulin administration). 
Circumstances may require minor changes in scheduling of chemotherapy. Variations of up to 
24 hours in scheduling will be acceptable. 
 
TBI*: Because of occasional cases of graft failure, conditioning has been intensified for certain 
groups of patients. Patients at high risk for CNS relapse (e.g ALL or Burkitt’s) or patients at high 
risk for graft rejection (i.e., donor-specific HLA antibodies, patients with severe aplastic anemia, 
or hemoglobinopathies) may receive 2 doses of TBI as part of the conditioning. In rare cases , 
full dose TBI (1200 Grey) will be part of the regimen if the other regimens cannot be used.  
 
 
 
 
 
 


19 
 
 
7.1.2.3 Regimen for Autologous Transplantation 
 
Day -6  
Day -5 
Day -4 
Day -3 
Day -2 
Day-1    Day 0 
Carmustine 
 
300 
mg/m2 
over 6 
hours 
 
 
 
 
 
Stem cell 
 infusion 
Etoposide 
 
100 
mg/m2  
q12h 
100 
mg/m2  
q12h 
100 
mg/m2  
q12h 
100 
mg/m2  
q12h 
 
 
Cytarabine 
 
200 
mg/m2  
q12h 
200 
mg/m2  
q12h 
200 
mg/m2  
q12h 
200 
mg/m2  
q12h  
 
 
Melphalan 
 
 
140  
mg/m2   
Autologous hematopoietic stem cells will be infused on day 0 using standard infusion 
technique. 
 
7.1.3 Rituximab 
 
Subjects with pathological confirmed B-cell malignancies will receive rituximab 375 
mg/m2 on Days + 1 and +8 post -transplant. Subjects with T-cell lymphoma will be 
enrolled in the study but will not receive rituximab.   
 
Rituximab is FDA approved for B cell malignancies at this dose and schedule. However, 
as stated earlier, the FDA does not approve transplant regimens. Using rituximab has 
been utilized in many transplant published studies.  
 
7.1.4 GVHD Prophylaxis for Related and Unrelated Transplants 
 
Subjects will receive the drug tacrolimus (Prograf ®) starting before transplant to reduce 
the risks of graft versus host disease and to promote the growth of the graft.   
 
Tacrolimus will be given at a dose of 0.03 mg/kg/day using continuous intravenous 
infusion over 24 hours from Day -2 until engraftment or when subject is able to take 
orally, then a tacrolimus dosage of (approximately) 0.09 mg/kg orally in 2 divided doses.  
Tacrolimus should be given at full dose to maintain levels of 5-15 ng/mL through Day 
100 for related transplants and through Day 180 for unrelated transplants, tapered by 
20% every week thereafter. In the presence of GVHD, a clinical decision by the 
Attending Physician will determine if tacrolimus can be tapered or should be continued. 
PO tacrolimus can be used in the pre-engraftment period when IV-access for tacrolimus 
is not available. 
 


20 
 
 
7.1.5 GVHD Prophylaxis for Alternative Donor Haplo/Cord  and Double Cord Transplants 
Patients undergoing haplo cord transplant in this protocol will receive the following 
GVHD prophylaxis in addition to ATG;  
 
Subjects will receive the drug tacrolimus (Prograf ®) and another immunosuppressant, 
mycophenolate mofetil (Cellcept ®), starting before transplant also to reduce the risks of 
graft versus host disease and to promote the growth of the graft.   
 
Tacrolimus: 0.03 mg/kg/day using continuous intravenous infusion over 24 hour time 
period from Day -2 until engraftment or when subject is able to take by mouth, then 
tacrolimus approximately 0.09 mg/kg by mouth in 2 divided doses.  Tacrolimus should 
be given at full dose to maintain levels of 5-15 ng/mL through approximately Day 180, 
tapered by 20% every week thereafter. Infection ,toxicity or other clinical circumstances 
may prompt earlier discontinuation. In the presence of GVHD, a clinical decision by the 
attending physician will determine if tacrolimus can be tapered or should be continued.  
PO tacrolimus can be used in the pre-engraftment period when IV access for tacrolimus 
is not available. 
 
Mycophenolate mofetil (MMF): will be started on Day -2 and given at a dose of 1000 mg 
every 8 hours until Day 28. Earlier discontinuation, dose adjustments or more prolonged 
administration may be required for clinical reasons. MMF may be given PO or IV. . 
Infection, toxicity, very low patient weight (<50kg) may prompt earlier discontinuation or 
adjustment of doses 
 
 
7.2 
Mobilization and Stem Cell Collection of Donors 
 
Pre-screened donors will receive filgrastim according to institutional guidelines prior to 
collection. Hematopoeitic stem cell collection will be done via temporary large bore 
catheters or via peripheral access for approximately 1 - 2 days for approximately 3 - 4 
hours per day. Goals for the collection are at least 2.5 x 10 6 CD 34 cells per kg of 
recipient’s weight.  There will be no T cell depletion. 
 
On rare occasions, stem cells will be obtained using standard bone marrow harvesting 
techniques. Peripheral blood stem cell collection will be the preferred method of 
collection but ultimately it is the donor’s choice as to what type of stem cells collection is 
done 
 
7.3 
 General Concomitant Medication and Supportive Care Guidelines 
 
Subjects will receive supportive care according to institutional guidelines.   
 
All subjects will be offered Neulasta after the bendamustine to avoid neutropenia 
between the bendamustine and the conditioning regimen. The dose will be the standard 
FDA-approved dose of Neulasta.  
 


21 
 
All subjects, regardless of disease histology will receive filgrastim (G-CSF) to speed up 
the recovery of stem cells. 5 mcg/kg (rounded to 300 mcg or 480 mcg, depending on 
subject weight) of filgrastim will be administered subcutaneously daily, as per 
institutional standard of care practice  until Absolute Neutrophil Count (ANC) >5 
x10E9/L. 
 
Infectious Disease prophylaxis and management will be administered as per the 
institution’s standard of care. Chimerism will be evaluated in allogeneic transplants at 
Baseline, Days +28, +56, + 100, +180, and +365 or more frequently if there is concern 
re-graft loss/relapse.  
 
7.4 
Duration of Therapy and Criteria for Removal from Study 
 
Withdrawal from the trial must be fully documented. The documentation must include 
reasons for withdrawal and details of any adverse events followed until symptoms 
resolved. A Final Summary Statement must be completed.  
 
Criteria for discontinuing protocol therapy:  
• 
If the investigator feels that a change of therapy would be in the best interest of the 
subject 
• 
If the subject requests discontinuation provided that the subject has been counseled 
again regarding the danger of discontinuation prior to infusion of stem cells after the 
conditioning regimen. 
• 
If the study drug(s) exhibits unacceptable toxicity  
• 
Intercurrent illness that would interfere with the assessment of clinical status to a 
significant degree or would prevent further administration of treatment 
• 
Disease progression 
• 
Pregnancy or a positive pregnancy test 
 
7.5 
Duration of Follow Up 
 
Subjects will be followed up to 3 years after removal from study or until death, 
whichever occurs first.  Subjects removed from the study for unacceptable adverse 
event(s) will be followed until resolution or stabilization of the adverse event(s). 
 
8. DOSING DELAYS/DOSE MODIFICATIONS 
 
None applicable 
 
9. ADVERSE EVENT REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
investigator will be required to provide appropriate information concerning any findings 
that suggest significant hazards, contraindications, side effects, or precautions pertinent 
to the safe use of the drug under investigation.  Safety will be monitored by evaluation 
of adverse events reported by subjects or observed by investigators or research staff, 
as well as by other investigations such as clinical laboratory tests, x-rays, 
electrocardiographs, etc. 


22 
 
 
The principal investigator is responsible for monitoring the safety of subjects who enroll 
in the study. All AEs occurring after any administration of the study drug(s) will be 
followed until resolution 
 
9.1 
Study Agents Risks 
 
All risks for drugs given to subjects within this protocol will be outlined in the 
Investigator’s Brochure. Additional information is in Appendix C – Background Drug 
Information. Risks for each drug will be specifically listed for subjects in the informed 
consent form. 
 
9.2  
Adverse Event Characteristics 
 
 
CTCAE term (AE description) and grade:  The descriptions and grading 
scales found in the revised NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0 will be utilized for AE reporting.  A copy of the 
CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov). 
 
 
Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
 
 
9.3 
Recording of Adverse Events 
 
All Grade 3-4 adverse events which are possibly related to the study and 
unexpected will be recorded on a IRB’s adverse event log.  The AE log will be 
maintained by the research staff and kept in the subject’s research chart.  
Hematologic AE’s will not be tracked since they are an expected 
consequence of transplant. Some other grade 3-4 AE that are expected in 
stem cell transplant will not be collected (e.g. alopecia).   
 
 
9.4 Serious Adverse Event (SAE) Reporting 
 
9.4.1 Definition of SAE 
 
SERIOUS ADVERSE EVENTS include death, life threatening adverse 
experiences, hospitalization or prolongation of hospitalization, disability or 
incapacitation, overdose, congenital anomalies and any other serious events that 
may jeopardize the subject or require medical or surgical intervention to prevent 
one of the outcomes listed in this definition 
 


23 
 
A serious adverse event (SAE) is any adverse drug experience that occurs at any dose 
that results in any of the following outcomes: 
• 
Death. 
• 
Life‐threatening adverse drug experience.* 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization for 
deemed unexpected events. For the purpose of this study, hospitalizations for 
protocol‐scheduled procedures, blood product transfusions, social reasons (ie, 
awaiting transport home), or deemed expected events will not be considered 
SAEs. 
• 
Persistent or significant disability/incapacity.** 
• 
A congenital anomaly/birth defect. 
• 
Is an important medical event*** 
• 
Suspected positive pregnancy 
*“Life-threatening” means that the subject was at immediate risk of death at the time of 
the serious adverse event; it does not refer to a serious adverse event that 
hypothetically might have caused death if it were more severe. 
**“Persistent or significant disability or incapacity” means that there is a substantial 
disruption of a person’s ability to carry out normal life functions. 
***Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in situations where none of the outcomes listed above 
occurred.  Important medical events that may not be immediately life-threatening or 
result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above should 
also usually be considered serious.  
 
Examples of such events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse.  A new 
diagnosis of cancer during the course of a treatment should be considered as medically 
important.  
 
9.4.2 Reporting of SAE to IRB 
 
All SAEs occurring on this study will be reported to the IRB according to the IRB policy.  
The IRB requires immediate reporting of all unexpected and study-related (definite or 
probable) adverse events.  The following procedure will be followed for reporting SAE to 
the IRB: 
 
 
Complete the SAE Cover Sheet (See Appendix B) 
 
If the event is unexpected AND definitely or probably related to the study, 
complete the IRB Unexpected, Study-related Adverse Events, Incidents, and 
Information Reporting Form.  This form should be submitted within 24 
business hours of investigator notification of the event. 
 
 
If the event is expected OR possibly or unrelated to the study, only the SAE 
Cover Sheet must be completed.  These events will be reported to the IRB at 
the time of continuing renewal on the Adverse Event & IND Safety Reporting 
Cumulative Table. 


24 
 
 
Forms may also be downloaded from the IRB website at: 
http://www.med.cornell.edu/research/for pol/ins rev boa.html 
 
9.4.3 Reporting of SAE to FDA  
 
If an SAE occurs on this study, the event will be filed on a MedWatch form with the 
FDA. 
 
CBER INDs:  
Center for Biologics Evaluation and Research  
Food and Drug Administration  
Suite 200N 1401 Rockville Pike  
Rockville, MD 20852-1448  
 
The phone number of the CBER is: 800-835-4709 
 
10. 
DATA REPORTING AND COLLECTION 
 
10.1   Data Collection 
 
The data collection plan for this study is to utilize REDCap to capture all treatment, 
toxicity, and efficacy data for all enrolled subjects. This is a trial to assess the feasibility 
including both safety and possible efficacy of a total sequential approach to treating 
refractory and relapsed Non-Hodgkin’s and Hodgkin’s lymphoma subjects.  
 
10.2 Accuracy of Data Collection  
 
The Principal Investigator will be the final arbiter of toxicity should a difference of 
opinion exist. 
 
10.3     REDCap 
 
REDCap (Research Electronic Data Capture) is a free data management software 
system that is fully supported by the Weill-Cornell Medical Center CTSC.  It is a tool for 
the creation of customized, secure data management systems that include Web-based 
data-entry forms, reporting tools, and a full array of security features including user and 
group based privileges, authentication using institution LDAP system, with a full audit 
trail of data manipulation and export procedures.  REDCap is maintained on CTSC-
owned servers that are backed up nightly and support encrypted (SSL-based) 
connections.  Nationally, the software is developed, enhanced and supported through a 
multi-institutional consortium led by the Vanderbilt University CTSA. 
 
10.4  Protocol Compliance 
 
Subjects will be reviewed weekly during admission by the study investigators who will 
score the subject for standard endpoints. After discharge they will be reviewed at least 
once a month according to the protocol schedule. 


25 
 
 
11. STATISTICAL CONSIDERATIONS 
 
11.1 Study Endpoints 
 
Primary Endpoints:  
 Proportion of patients able to proceed to transplant within 14 days of 
starting bendamustine  and recover after transplant as determined by:   
 
1) Engraftment: This will be defined as a neutrophil count of 500 /mm3 
and a platelet count of 20,000 without platelet support for at least one 
week. 
 
2) Regimen related toxicity: This will be assessed using CTCAE version 4 
 
- Hematologic toxicity will not be taken into account. 
 
Secondary Endpoints:  
 Disease Response: This will be defined as complete response, partial 
response, no response, progression according to Cheson Criteria 
(Appendix C). Response will be assessed after the bendamustine and 
again after the transplant.  
 
 Progression – Free Survival: This will be defined as survival free of 
progression of disease starting from the  day bendamustine starts and also 
calculated from day 0 of the transplant.  
 
 Survival: This will be defined in days post initiation of bendamustine and 
also recalculated as the numbers of days post-transplant and will be 
specifically evaluated at Day 100, one year and overall survival. 
 
 Transplant Related Mortality (TRM): Death due to treatment within the first 
100 days.  
 
Note: Acute GVHD will be scored according to the criteria proposed by Przepiorka et al. 
(Appendix E). Chronic GVHD will be scored according to the NIH Consensus 
Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease 
(Appendix F). 
 
Subject will have toxicity assessments using the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.0 criteria and response assessments as per 
PET/CT after each stage of this multifaceted approach.  
 
11.2 Sample Size, Analysis Plan and Accrual Rate 
 
Because this is a pilot study, no formal sample size calculation is required and the 
primary endpoint will be assessed descriptively.  However, with 15 subjects completing 
protocol-based requirements on both the allogeneic arm and autologous arm of the 


26 
 
study, 95% confidence intervals for the proportion of subjects who are able to proceed 
to transplant and recover after transplant can be constructed to be within ± 20.2% of the 
true proportion of such patients in the allogeneic arm and within ± 11.0% of the true 
proportion of such patients in the autologous arm.  These calculations assume that the 
proportion of such subjects who are able to proceed to transplant and recover after 
transplant is 80% and 95% in the allogeneic and autologous arms, respectively. 
 
 
The proportion of subjects able to proceed to transplant within 14 days after starting 
bendamustine and recover after transplant (i.e., primary endpoint) will be calculated and 
a 95% confidence interval (95% CI) will be estimated via binomial proportions.  
Secondary endpoints of disease response and transplant-related mortality (i.e., 
proportions and 95% CI) will also be estimated via binomial proportions.  Secondary 
endpoints of progression-free and overall survival will be assessed by Kaplan-Meier 
survival analysis.Greenwood’s formula will be used to calculate 95% confidence 
intervals for the Kaplan-Meier survival estimates. 
 
 
The frequency of subjects experiencing toxicities will be tabulated.  Toxicities will be 
assessed and graded according to CTCAE v. 4.0 terminology.  Exact 95% confidence 
intervals around the toxicity proportions will be calculated to assess the precision of the 
obtained estimates. 
 
 
All p-values will be two-sided with statistical significance evaluated at the 0.05 alpha 
level (for exploratory analyses comparing secondary endpoints between arms).  All 
analyses will be performed in SAS Version 9.3 (SAS Institute, Inc., Cary, NC) and 
STATA Version 12.0 (StataCorp, College Station, TX). 
 
It is expected that the study will accrue 15 subjects per year and accrual will last 
approximately 24 months. The expansion phase of the additional 60 patients will accrue 
over 3 years.  
 
11.3   Toxicity Stopping Guidelines 
 
The following toxicity stopping guidelines serve as a trigger for additional review by the 
protocol team and Data Safety Monitoring Board (DSMB), and are not formal “stopping 
rules” that would mandate automatic closure of study enrollment.   
 
 
11.3.1Transplant-Related Mortality (TRM) 
 
Non-relapse deaths in the first 100 days will be monitored.  A TRM rate of > 20% of 
subjects in the first 6 months within the allogeneic cohort and > 5% of subjects in the 
autologous cohort would be unexpected.  This would be reported to the DSMB and, 
subsequently, the research team will immediately review the data and protocol should 
this rate be exceeded.  Entry of subjects into the trial will be stopped while the protocol 
and deaths are reviewed.  
11.3.2 Graft Failure 
 
Failure to engraft by Day 35 is expected to occur in <=10% of subjects with this 
approach.  A graft failure/graft rejection rate of > 10% would be unexpected and the 


27 
 
research team and DSMB will review the data and protocol should this rate be 
exceeded.  Failure to engraft will be defined as lack of evidence of hematopoietic 
recovery (ANC < 500/mm3 and platelet count < 20,000/mm3) by Day +35, confirmed by 
a biopsy revealing a marrow cellularity < 5%.  Secondary graft failure will be defined as 
initial myeloid engraftment by day +35, documented to be of donor origin, followed by a 
drop in the ANC to < 500/mm3 for more than three days, independent of any 
myelosuppressive drugs, severe GVHD, CMV, or other infection.  
 
Graft rejection will be defined as graft failure with documentation of return of recipient 
hematopoiesis as determined by cytogenetic and/or chimerism studies. If there is 
evidence that the Day 35 graft failure rate is more than 10%, entry of subjects into the 
trial will be stopped while the protocol and failures are reviewed.  
 
11. 4  Reporting 
 
11.4.1  
Evaluation of toxicity:  All subjects will be evaluable for toxicity from the 
time of their first treatment. 
 
11.4.2  
Evaluation of response:All subjects included in the study will be assessed 
for response to treatment. 
 
12. DATA SAFETY MONITORING BOARD 
 
The Data Safety Monitoring Board (DSMB) is being requested to review safety data and 
to make recommendations regarding continuation, termination, or modification to the 
study. The research team will report all adverse events to the DSMB per their reporting 
policies. The DSMB will be constituted at Weill Cornell Medical College and will be 
composed of medical and statistical independent reviewers and will meet to review the 
efficacy and safety data and determine a risk/benefit analysis in this subject population.   
 
The purpose of the DSMB is to advise on serious safety considerations, lack of efficacy 
and any other considerations within the charge to the Committee.  The DSMB may 
request additional meetings or safety reports as deemed necessary upon discussion 
with the research team.  The Principal Investigator, Dr. Tsiporah Shore will be the safety 
contact for all DSMB related analysis outcomes. 
 
Dr. Shore’s office is located at: 
NYPH-WCMC 
520 E 70th St., F364 
New York, NY  10021 
Phone 212-746-2646 
 
 
The research team will report all adverse events to the DSMB per their reporting 
policies. They will convene every six months to discuss outcomes of the ongoing trial.  
They will be informed of the results of the interim analysis and they will have the 
authority to close the study in the interest of subject safety if they feel that one of the 
arms is clearly inferior or for futility.  
 


28 
 
 
 
12.1 Interim Analysis 
 
The first 3 subjects in the autologous arm and the first 3 subjects in the allogeneic arm 
will be reviewed in order to determine if it is safe to continue enrolling on each arm. The 
DSMB may stop the study following review of results from each interim analysis.  Once 
the first 3 are reviewed, the DSMB will meet to monitor the study every six months to 
discuss outcomes of the ongoing trial. Appropriate efficacy and safety data summaries 
will be provided to the DSMB after each interim analysis. 
 
The binomial distribution will be used to establish pre-specified stopping/review 
guidelines for toxicity.  A binomal distribution probability greater than 10% (i.e., 
estimated based on xsubjects with toxicity among 3 enrolled subjects in each cohort) 
will be chosen as the threshold for initiating a DSMB stopping and review of the 
cohort(s).  As detailed above, a TRM rate of >20% in the allogeneic cohort would be 
unexpected.  Assuming a TRM rate of 20% in the allogeneic cohort and utilizing the 
binomial distribution, the probability that 1 out of 3 enrolled subjects will experience 
TRM is 0.38 (and thus >10%).  Therefore, if 1 or more of the first 3 enrolled subjects 
experience TRM in the allogeneic cohort, the study cohort will be halted and reviewed 
by the DSMB.  Similarly, a TRM rate of >5% in the autologous cohort would be 
unexpected.  Assuming a TRM rate of 5% in the autologous cohort and utilizing the 
binomial distribution, the probability that 1 out of 3 enrolled subjects will experience 
TRM is 0.14 (and thus >10%).  Therefore, if 1 or more of the first 3 enrolled subjects 
experience TRM in the autologous cohort, the study cohort will be halted and reviewed 
by the DSMB.  This process will repeat for each set of three enrolled subjects in the 
cohorts. 
 
As detailed above, a graft failure/graft rejection rate of >10% in the study would be 
unexpected.  Assuming a graft failure/graft rejection rate of 10% in the study and 
utilizing the binomial distribution, the probability that 1 out of 3 enrolled subjects will 
experience graft failure/graft rejection is 0.24 (and thus >10%).  Therefore, if 1 or more 
of the first 3 enrolled subjects experience graft failure/graft rejection in the study, the 
study will be halted and reviewed by the DSMB.  This process will repeat for each set of 
three enrolled subjects in the cohorts. 
 
13. REGULATORY CONSIDERATIONS 
 
13.1 Institutional Review Board/Ethics Committee Approval 
 
The protocol for this study has been designed in accordance with the general ethical 
principles outlined in the Declaration of Helsinki.  The review of this protocol by the 
IRB/EC and the performance of all aspects of the study, including the methods used for 
obtaining informed consent, must also be in accordance with principles enunciated in 
the declaration, as well as ICH Guidelines, Title 21 of the Code of Federal Regulations 
(CFR), Part 50 Protection of Human Subjects and Part 56 Institutional Review Boards. 
 


29 
 
The Investigator will be responsible for preparing documents for submission to the 
relevant IRB/EC and obtaining written approval for this study.  The approval will be 
obtained prior to the initiation of the study. 
 
The approval for both the protocol and informed consent must specify the date of 
approval, protocol number and version, or amendment number. 
 
The investigator is also responsible for notifying the IRB/EC of any serious deviations 
from the protocol, or anything else that may involve added risk to subjects. 
 
Any advertisements used to recruit subjects for the study must be reviewed and 
approved by the IRB/EC prior to use. 
 
13.2 Informed Consent Procedures 
 
The Investigator must obtain informed consent of a subject or his/her designee prior to 
any study related procedure as per GCP’s as set forth in the CFR and ICH guidelines. 
 
Documentation that informed consent occurred prior to the subject’s entry into the study 
and the informed consent process should be recorded in the subject’s source 
documents.  The original consent form signed and dated by the subject and by the 
person consenting the subject prior to the subject’s entry into the study, must be 
maintained in the Investigator’s study files.   At the pre-admission consultation, patients 
will be fully informed as to the purposes and potential risks and benefits involved in this 
study. Subjects will have ample opportunity to ask questions before consenting. Legal 
guardians will sign informed consent for legally incompetent patients in accordance with 
hospital policy. 
 
13.3 Protocol Amendments and Deviations 
 
Any amendment to this protocol must be agreed to by the Principal Investigator.  Written 
verification of IRB/EC approval will be obtained before any amendment, which affects 
subject safety or efficacy, is implemented.  Amendments that are administrative in 
nature do not require IRB/EC approval but will be submitted to the IRB/EC for 
information purposes. 
 
All protocol amendments and consent form modifications will be made by the Principal 
Investigator.   
 
13.4 Protecting Privacy and Confidentiality 
 
Confidentiality will be maintained within the limits of the law. Patient names or any other 
identifying information will not be used in reports or publications resulting from this 
study. Only qualified staff from New York Presbyterian Hospital, Weill Medical College 
of Cornell University, the Food and Drug Administration, will be able to review subject 
medical records. 
 


30 
 
Should direct access to medical records require a waiver or authorization separate from 
the subject’s statement of informed consent, it is the responsibility of the Investigator to 
obtain such permission in writing from the appropriate individual. 
 
13.5 Study records requirements 
 
The Investigator must ensure that the records and documents pertaining to the conduct 
of the study and the distribution of the study drug, that is copies of case report forms 
(CRF) and source documents (original documents, data, and records [e.g., hospital 
records; clinical and office charts; laboratory notes; memoranda; subject’s diaries or 
evaluation checklists; pharmacy dispensing records; recorded data from automated 
instruments; copies or transcriptions certified after verification as being accurate copies; 
microfiches; photographic negatives, microfilm, or magnetic media; x-rays; subject files; 
and records kept at the pharmacy, at the laboratories, and at medico-technical 
departments involved in the clinical study; documents regarding subject treatment and 
study drug accountability; original signed informed consents, etc.]) be retained by the 
Investigator for as long as needed to comply with national and international regulations 
(generally 2 years after discontinuing clinical development or after the last marketing 
approval).  The Investigator agrees to adhere to the document/records retention 
procedures by signing the protocol. 
 
 
13.6 Protection of Human Rights 
 
Participation in this trial is voluntary. All subjects will be required to sign a statement of 
informed consent, which must conform to Weill Cornell Medical College IRB guidelines.  
 
13.7 Premature Discontinuation of Study 
 
The responsible local clinical Investigator has the right to discontinue this study at any 
time for reasonable medical or administrative reasons in any single center.  Possible 
reasons for termination of the study could be but are not limited to: 
 
 Unsatisfactory enrollment with respect to quantity or quality. 
 Inaccurate or incomplete data collection. 
 Falsification of records. 
 Failure to adhere to the study protocol. 
 Serious adverse events, intolerability of drug regimen, or sudden/unexpected 
death in any of the early trial (up to three patients) participants 
 
The investigator reserves the right to terminate this clinical study at any time for 
reasonable medical or administrative reasons. 
 
Any possible premature discontinuation would be documented adequately with reasons 
being stated, and information would have to be issued according to local requirements 
(e.g. IRB/EC, regulatory authorities, etc.). 
 
 


31 
 
13.8 Benefits of the Protocol 
 
The potential benefit of this study is the development of a safe and effective treatment 
program for lymphoma patients who have relapsed/ refractory disease.  Knowledge will 
be acquired about this treatment program, its tolerability, and the effectiveness of high 
dose bendamustine in combination with BEAM conditioning prior to stem cell transplant 
and the benefit of maintenance lenalidomide in  the treatment of relapsed or refractory 
lymphoma.  If effective, this treatment plan may improve disease-free and overall 
survival in such lymphoma patients. 
 
13.9 Risks in Relation to Anticipated Benefit 
 
The risks associated with participation in this trial are commensurate with the expected 
risks of other potential therapies and are reasonable given the potential benefit to 
patients with newly aggressive lymphoma.  If this sequential approach is as effective 
against relapsed/ refractory lymphoma as anticipated, this regimen could become 
standard of care leading to improved survival.   
 
13.10 Alternative Treatments 
 
Subjects who refuse to participate in the study or decided to withdrawal from the study 
will be given the option to choose standard chemotherapy, other investigation studies, 
supportive care, or no anti-cancer treatment at all.  Therapy with an autologous stem 
cell transplant using standard BEAM conditioning alone may be of benefit. While the 
results of these therapies have resulted in a low percentage of durable long term 
remissions, few subjects are cured and none of the drugs used in these standard 
treatments are free of side effects.  We believe that this novel regimen will improve 
response rates and duration of remission. 
 
13.11 Incentives 
 
No incentives will be offered to subjects for participation in the study.  Participation is 
voluntary. 
 
13.12 Costs 
 
Subjects and/or their medical insurance coverage will be responsible for paying for their 
hospitalization, doctor visits, diagnostic tests, chemotherapy (commercially available) 
drugs, and other medicines used in their care directly. These costs are expected to be 
equivalent to those that are standard of care.   


 
 
 
32 
 
APPENDIX A 
 
Performance Status Criterias (ECOG and Karnofsky) 
 
 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


33 
 
APPENDIX B 
 
WCMC IRB SAE Reporting Forms 
 
http://www.med.cornell.edu/research/for pol/ins rev boa.html 
 
 




35 
 
APPENDIX D: PACKAGE INSERT FOR BENDAMUSTINE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


36 
 
 
APPENDIX E: BACKGROUND DRUG INFORMATION 
 
DRUG FORMULATION, AVAILABILITY, AND PREPARATION  
 
Qualified personnel who are familiar with procedures that minimize undue exposure to 
themselves and to the environment will undertake the preparation, handling and safe disposal of 
chemotherapeutic agents in a self-contained, protective environment. Unused portions of 
injectable chemotherapeutic agents that do not contain a bacteriostatic agent or are prepared 
with unpreserved diluents will be disposed ( 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.  
 
FILGRASTIM (G-CSF:  Granulocyte Colony Stimulating Factor, Neupogen)   
 
AVAILABILITY 
G-CSF is commercially available in 1.0 and 1.6 mL vials containing 300 mcg and 480 mcg G-CSF, and in 
prefilled syringes containing 300 mcg/0.5 mL and 480 mcg/0.8 mL. 
 
 
STORAGE & STABILITY 
Intact vials and prefilled syringes should be stored under refrigeration.  Do not allow the drug to freeze.  
 
ADMINISTRATION 
The daily dose of G-CSF should be injected subcutaneously in one or two sites.  The dose following 
peripheral blood stem cell infusion is 5 mcg/kg/day.  The dose of G-CSF may be rounded up to the 
nearest vial size. 
 
TOXICITY 
The most common side effect associated with G-CSF is bone pain.  Bone pain is usually reported as mild 
or moderate and, if necessary, may be treated with non-opiod or opiod analgesics. 
 
MELPHALAN(Alkeran) 
 
AVAILABILITY 
Melphalan for IV use is commercially available in sterile 50 mg vials.  The product is a lyophilized powder 
with 20 mg povidone per vial.  Also provided is 10 mL of special diluent for use in reconstituting the 
product.  The special diluent has 0.20 g sodium citrate, 6 mL propylene glycol, 0.5 mL 95% ethanol, and 
sterile water. 
 
 
STORAGE & STABILITY 
Intact vials should be stored at room temperature (15oC-30oC) and protected from light.  Reconstituted 
solutions are chemically and physically stable for at least 90 minutes at room temperature.  Solutions 
further diluted in 0.9% sodium chloride to a concentration of 0.1 mg/mL to 0.45 mg/mL are stable for at 
least 60 minutes.  Solutions diluted to 1 mg/mL are reported to be physically stable for at least 4 hours at 
room temperature-chemical stability of this dilution is not known.  Because of the relative instability of 
melphalan solutions, it is recommended that administration of the diluted solution be completed within 60 
minutes of reconstitution.  Reconstituted solutions should not be refrigerated. 
 
PREPARATION 
Melphalan should be prepared immediately before intended use.  Each vial is reconstituted with 10 mL of 
the special diluent to yield a concentration of 5 mg/mL.  The reconstituted solution may be diluted with 
0.9% sodium chloride to a concentration of 0.1 mg/mL to 0.45 mg/mL. 
 
ADMINISTRATION 


37 
 
The total dose of melphalan will be administered by short IV infusion over 30-60 minutes, as per 
institutional pharmacy guidelines. 
 
TOXICITY 
The major toxicity of melphalan is bone marrow suppression, usually lasting four to eight weeks.  Other 
toxicities include nausea, vomiting, diarrhea, and mucositis.  Less common toxicities include pulmonary 
fibrosis, interstitial pneumonitis, vasculitis, alopecia, hemolytic anemia, and allergic reactions.  Transient 
rises in BUN and creatinine have occurred with high dose melphalan and also acute renal failure. Tissue 
necrosis may result if infiltration occurs.    
 
TACROLIMUS (Prograf, FK506) 
 
AVAILABILITY 
Tacrolimus is commercially available as an injection (5 mg/mL; 1 mL ampuls) and as oral capsules (0.5 
mg, 1 mg, and 5 mg). 
 
 
STORAGE & STABILITY 
Store tacrolimus capsules and injection at controlled room temperature, 15oC-30oC (59oF-86oF). 
 
PREPARATION – FOR IV USE 
Tacrolimus injection must be diluted prior to IV infusion with 0.9% sodium chloride or 5% dextrose 
injection to a concentration of 4-20 mcg/mL.  Solutions should be prepared in non-PVC plastic or glass.  
Tacrolimus injection and diluted solutions of the drug should be inspected visually for particulate matter 
and discoloration prior to administration whenever solution and container permit. 
 
ADMINISTRATION 
Oral therapy should be started as soon as possible as per protocol and 8 to 12 hours after stopping 
intravenous therapy.  Oral doses will be administered twice a day.  The conversion from IV to oral therapy 
should take into account concomitant medications (such as voriconazole). 
 
TOXICITY 
In patients receiving tacrolimus, 5% to 47% experienced anemia, 8% to 32% experienced leukocytosis, 
and 14% to 24% experienced thrombocytopenia.  Rare cases of microangiopathic hemolytic anemia have 
been reported.  Chest pain was reported in 19%.  Mild to moderate hypertension is a common adverse 
effect associated with tacrolimus therapy.  Antihypertensive therapy may be required.  The most common 
adverse effects of tacrolimus have involved the central nervous system, and include headache (37% to 
64%), tremors (48% to 56%), insomnia (32% to 64%), paresthesia (17% to 40%), and dizziness (19%).  
Tremor and headache may respond to dosage reduction.  Visual changes, agitation, anxiety, confusion, 
seizures, depression, hallucinations, myoclonus, neuropathy, psychosis, incoordination, and abnormal 
dreams have been reported in 3% to 15%.  Hyperkalemia (13% to 45%), hypokalemia (13% to 29%) 
hypophosphatemia (49%) and hypomagnesemia (16% to 48%) have been associated with tacrolimus 
therapy.  Hyperuricemia has been reported in >3%.  Gastrointestinal adverse effects included nausea 
(32% to 46%), vomiting (14% to 29%), anorexia (7% to 34%), constipation (23% to 35%), and diarrhea 
(37% to 72%).  Nephrotoxicity was reported in 38% to 52% of liver and kidney transplant patients, 
respectively.  Hematuria has been reported in greater than 3%.  Abnormal liver function tests have been 
reported in 6% to 36% of patients; ascites in 7% to 27%.   
 
Other effects reported in clinical trials include pain, fever, asthenia, back pain, and peripheral edema.  
The incidence of hyperglycemia was 17% and may require therapy with insulin.  Other less frequently 
occurring effects include abscess, chills, peritonitis, and photosensitivity reactions.  Anaphylaxis has been 
reported in a few patients receiving intravenous tacrolimus.  Tacrolimus injection contains cremophor 
which in other drugs has been associated with anaphylaxis.  Because tacrolimus is an 
immunosuppressant, the risk of opportunistic infections is increased. 
 
DRUG INTERACTIONS   


38 
 
Tacrolimus is metabolized by cytochrome P450 3A4.  Drugs that are inhibitors (e.g. itraconazole) of 
inducers (e.g. phenytoin) of 3A4 might be expected to increase or decrease tacrolimus concentrations, 
respectively, possibly resulting in increased or decreased effects.  
 
ETOPOSIDE 
DESCRIPTION 
Etoposide (also commonly known as VP-16) is a semisynthetic derivative of podophyllotoxin used in the 
treatment of certain neoplastic diseases. It is 4'-demethylepipodophyllotoxin 9-[4,6-0-(R)-ethylidene-β-D-
glucopyranoside]. It is very soluble in methanol and chloroform, slightly soluble in ethanol and sparingly 
soluble in water and ether. It is made more miscible with water by means of organic solvents. It has a 
molecular weight of 588.58 and a molecular formula of C29H32O13. 
Etoposide Injection USP is administered intravenously. Etoposide Injection USP is available in 100 mg (5 
mL) and 250 mg (12.5 mL) sterile, multiple dose vials. The pH of the clear, colourless to pale yellow 
solution is 3 to 4. Each mL contains 20 mg Etoposide, 2 mg anhydrous citric acid, 30 mg benzyl alcohol, 
80 mg polysorbate 80/tween 80, 650 mg polyethylene glycol 300, and 30.5 percent (v/v) dehydrated 
alcohol. Vial headspace contains nitrogen. 
The structural formula is: 
 
CLINICAL PHARMACOLOGY 
Its main effect, however, appears to be at the G2 portion of the cell cycle in mammalian cells. The 
predominant macromolecular effect of Etoposide appears to be the induction of DNA strand breaks by an 
interaction with DNA topoisomerase II or the formation of free radicals. 
 
PHARMACOKINETICS 
On intravenous administration, the disposition of Etoposide is best described as a biphasic process with a 
distribution half-life of about 1.5 hours and terminal elimination half-life ranging from 4 to 11 hours. Total 
body clearance values range from 33 to 48 mL/min or 16 to 36 mL/min/m2 and, like the terminal 
elimination half-life, are independent of dose over a range of 100 to 600 mg/m2. Over the same dose 
range, the areas under the plasma concentration vs. time curves (AUC) and the maximum plasma 
concentration (Cmax) values increase linearly with dose.  
Etoposide enters the CSF poorly., Etoposide is highly protein bound (97%) to human plasma proteins.  
. 
There is no evidence of a first-pass effect for EtoposideIn adults, the total body clearance of Etoposide is 
correlated with creatinine clearance, serum albumin concentration, and nonrenal clearance. Patients with 
impaired renal function receiving Etoposide have exhibited reduced total body clearance, increased AUC 
and a lower volume of distribution at steady state.  
 
WARNINGS 
Patients being treated with Etoposide Injection USP must be frequently observed for myelosuppression 
both during and after therapy. Physicians should be aware of the possible occurrence of an anaphylactic 
reaction manifested by chills, fever, tachycardia, bronchospasm, dyspnea, and hypotension. The infusion 
should be terminated immediately, followed by the administration of pressor agents, corticosteroids, 
antihistamines, or volume expanders at the discretion of the physician. 
 
For parenteral administration, Etoposide Injection USP should be given only by slow intravenous infusion 
(usually over a 30- to 60-minute period), since hypotension has been reported as a possible side effectof 
rapid intravenous injection. Etoposide Injection USP should be considered a potential carcinogen in 
humans.  
 
ADVERSE REACTIONS 
The following data on adverse reactions are based on intravenous administration of Etoposide Injection 
USP as a single agent, using several different dose schedules for treatment of a wide variety of 
malignancies. 
 
Hematologic Toxicity 
 
Myelosuppression. . 
 
Gastrointestinal Toxicity 


39 
 
 
Nausea and vomiting are the major gastrointestinal toxicities. Mild to severe 
mucositis/esophagitis may occur. 
 
Hypotension 
 
Transient hypotension following rapid intravenous administration has been reported in 1% to 2% 
of patients. It has not been associated with cardiac toxicity or electrocardiographic changes. No 
delayed hypotension has been noted. To prevent this rare occurrence, it is recommended that 
Etoposide Injection USP be administered by slow intravenous infusion over a 30- to 60-minute 
period. If hypotension occurs, it usually responds to cessation of the infusion administration of 
fluids or other supportive therapy as appropriate. When restarting the infusion, a slower 
administration rate should be used. 
 
Allergic ReactionsAnaphylactic-like reactions characterized by chills, fever, tachycardia, 
bronchospasm, dyspnea, and/or hypotension have been reported to occur in 0.7% to 2% of 
patients receiving intravenous Etoposide Injection USP and in less than 1% of the patients 
treated with oral capsules. These reactions have usually responded promptly to the cessation of 
the infusion and administration of pressor agents, corticosteroids, antihistamines, or volume 
expanders as appropriate; however, the reactions can be fatal. Hypertension and/or flushing have 
also been reported. Blood pressure usually normalizes within a few hours after cessation of the 
infusion. Anaphylactic-like reactions have occurred during the initial infusion of Etoposide 
Injection USP. 
 
Facial/tongue swelling, coughing, diaphoresis, cyanosis, tightness in throat, laryngospasm, back 
pain, and/or loss of consciousness have sometimes occurred in association with the above 
reactions. In addition, an apparent hypersensitivity-associated apnea has been reported rarely. 
 
Rash, urticaria, and/or pruritus have infrequently been reported at recommended doses. At 
investigational doses, a generalized pruritic erythematous maculopapular rash, consistent with 
perivasculitis, has been reported. 
 
Alopecia, Reversible alopecia, sometimes progressing to total baldness was observed in up to 
66% of patients. 
 
OTHER TOXICITIES 
The following adverse reactions have been infrequently reported: abdominal pain, aftertaste, constipation, 
dysphagia, asthenia, fatigue, malaise, somnolence, transient cortical blindness, optic neuritis, interstitial 
pneumonitis/pulmonary fibrosis, fever, seizure (occasionally associated with allergic reactions), Stevens-
Johnson syndrome, and toxic epidermal necrolysis, pigmentation, and a single report of radiation recall 
dermatitis. 
 
Hepatic toxicity, generally in patients receiving higher doses of the drug than those recommended, has 
been reported with Etoposide Injection USP. Metabolic acidosis has also been reported in patients 
receiving higher doses. 
 
Reports of extravasation with swelling have been received postmarketing. Rarely extravasation has been 
associated with necrosis and venous induration. 
The incidences of adverse reactions in the table that follows are derived from multiple databases from 
studies in 2,081 patients when Etoposide Injection USP was used either orally or by injection as a single 
agent. 
 
DOSAGE AND ADMINISTRATION 
Note: Plastic devices made of acrylic or ABS (a polymer composed of acrylonitrile, butadiene, and 
styrene) have been reported to crack and leak when used with undilutedEtoposide Injection USP. 
 
ADMINISTRATION PRECAUTIONS 
As with other potentially toxic compounds, caution should be exercised in handling and preparing the 
solution of Etoposide Injection USP. Skin reactions associated with accidental exposure to Etoposide 
Injection USP may occur. The use of gloves is recommended. If Etoposide Injection USP solution 
contacts the skin or mucosa, immediately and thoroughly wash the skin with soap and water and flush the 
mucosa with water. 
 


40 
 
PREPARATION FOR INTRAVENOUS ADMINISTRATION 
Etoposide Injection USP must be diluted prior to use with either 5% Dextrose Injection, USP, or0.9% 
Sodium Chloride Injection, USP, to give a final concentration of 0.2 to 0.4 mg/mL. If solutions are 
prepared at concentrations above 0.4 mg/mL, precipitation may occur. Hypotension following rapid 
intravenous administration has been reported; hence, it is recommended that the Etoposide Injection USP 
solution be administered over a 30- to 60-minute period. A longer duration of administration may be used 
if the volume of fluid to be infused is a concern. Etoposide Injection USP should not be given by rapid 
intravenous injection.Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration whenever solution and container permit. 
 
STABILITY 
Unopened vials of Etoposide Injection USP are stable for 24 months at room temperature (25°C). Vials 
diluted as recommended to a concentration of 0.2 or 0.4 mg/mL are stable for 96 and 24 hours, 
respectively, at room temperature (25°C) under normal room fluorescent light in both glass and plastic 
containers. 
Procedures for proper handling and disposal of anticancer drugs should be considered. Several 
guidelines on this subject have been published.1–8 There is no general agreement that all of the 
procedures recommended in the guidelines are necessary or appropriate. 
 
HOW IS ETOPOSIDE SUPPLIED 
Etoposide Injection USP 
NDC 16729-114-31 100 mg/5 mL Sterile, Multiple Dose Vial 
NDC 16729-114-32 250 mg/12.5 mL Sterile, Multiple Dose Vial 
Store at 20° to 25°C (68° to 77°F). [See USP controlled room temperature]. 
 
CYTARABINE 
Antimetabolite antineoplastic agent; synthetic pyrimidine antagonist.dfi 
 
ADMINISTRATION 
Conventional cytarabine: Administer by rapid IV injection or continuous IV infusion, sub-Q injection, or 
intrathecal injection; abcj also has been administered by IM injection† and by continuous sub-Q 
infusion†.f 
 
RECONSTITUTION  
Add 5, 10, 10, or 20 mL of bacteriostatic water for injection containing 0.945% benzyl alcohol to a vial 
containing 100, 500, 1000, or 2000 mg cytarabine powder; resultant solutions contain 20, 50, 100, or 100 
mg of cytarabine per mL, respectively. Diluents containing benzyl alcohol should not be used in 
neonatesfj or in high-dose† regimens. The desired dose of reconstituted solution may be given by rapid 
IV injection or may be further diluted with 5% dextrose or 0.9% sodium chloride injection for IV infusion. 
 
Dilution Cytarabine injection solution (containing 20 or 100 mg/mL) may be diluted with a compatible IV 
solution (e.g., 5% dextrose injection, 0.9% sodium chloride injection) for direct IV injection, rapid IV 
injection, or IV infusion. Cytarabine injection in pharmacy bulk package solution (containing 20 mg/mL) 
should be diluted with a compatible IV solution (e.g., 5% dextrose injection, 0.9% sodium chloride 
injection) for IV infusion. Alternatively, desired dose of the solution reconstituted from powder may be 
further diluted with 5% dextrose or 0.9% sodium chloride injection for IV infusion  
 
RATE OF ADMINISTRATION  
Has been given over 1–3 hours when used for treatment of refractory or secondary acute leukemia and 
refractory non-Hodgkin’s lymphomas.Also administered by rapid IV injection or continuous IV infusion. 
 
RECONSTITUTION  
Add 5, 10, 10, or 20 mL of bacteriostatic water for injection containing 0.945% benzyl alcohol to a vial 
containing 100, 500, 1000, or 2000 mg cytarabine powder; resultant solutions contain 20, 50, 100, or 100 
mg of cytarabine per mL, respectively.j 
Diluents or drug solutions containing benzyl alcohol should not be used in neonates or in high-dose† 
regimens. 


41 
 
 
WARNINGS 
Hematologic EffectsConventional cytarabine: Potent myelosuppressant. High-dose Regimens with 
Conventional Cytarabine 
Severe and sometimes fatal CNS, GI, and pulmonary toxicities reported following experimental dosage 
regimens for refractory or secondary acute leukemia or refractory non-Hodgkin’s lymphomas; differ from 
reactions seen with regimens employing lower dosages.Cerebral and cerebellar dysfunction (e.g., 
somnolence, coma, personality changes) reported; usually reversible. Reversible, acute aseptic 
meningitis, combined with cerebellar dysfunction, reported in at least 1 patient.Peripheral motor and 
sensory neuropathies have occurred occasionally.Patients with renal or hepatic impairment may be at 
increased risk of CNS toxicity associated with high-dose cytarabine therapy. Monitor patients receiving 
high-dose therapy closely for signs of central or peripheral neurotoxicity Dosage schedule adjustment 
may be necessary to avoid irreversible neurologic toxicity. Severe GI ulceration (including pneumatosis 
cystoides intestinalis leading to peritonitis), bowel necrosis, necrotizing colitis, hepatic abscess or hepatic 
damage with increased hyperbilirubinemia reported. Pancreatitis reported in patients previously treated 
with asparaginase and those receiving high-dose cytarabine therapy.Pulmonary edema reported. Diffuse 
interstitial pneumonitis reported occasionally in patients receiving relatively high doses (e.g., 1 g/m2) of 
cytarabine alone or in combination with other antineoplastic agents.A syndrome of acute respiratory 
distress, rapidly progressing to pulmonary edema and radiographically pronounced cardiomegaly, which 
was sometimes fatal, has been reported in patients with refractory acute leukemia receiving high-dose 
therapy.Severe skin rash leading to desquamation has been reported rarely. Complete alopecia occurs 
more commonly with high-dose regimens.Fatal cardiomyopathy reported in patients receiving high-dose 
cytarabine in combination with cyclophosphamide in preparation for bone marrow transplantation; this 
cardiac toxicity may be schedule dependent.Hemorrhagic conjunctivitis and reversible corneal toxicity 
(e.g., keratitis) reported; may be minimized or Sensitivity Reactions. AnaphylaxisAt least one case of 
anaphylaxis that resulted in acute cardiopulmonary arrest and required resuscitation has been reported 
after IV administration of conventional cytarabine. 
 
GENERAL PRECAUTIONS 
 
Cytarabine (Ara-C) Syndrome 
 
Cytarabine syndrome reported; may manifest as fever, myalgia, bone pain, maculopapular rash, 
conjunctivitis, malaise, and occasionally chest pain..j Generally occurs 6–12 hours after 
administration of conventional cytarabine.. 
 
Corticosteroids are beneficial in treatment and prevention.If symptoms require treatment, 
consider administration of corticosteroids, as well as continuation of conventional cytarabine 
therapy.. 
 
GI Effects 
 
Nausea and vomiting are more frequent and severe following rapid IV administration of 
conventional cytarabine than with continuous IV infusion. 
 
Pancreatitis - Pancreatitis reported in patients receiving conventional cytarabine and in those 
previously treated with asparaginase.. 
 
Hyperuricemia - Hyperuricemia may occur in patients receiving conventional cytarabine because 
of extensive purine catabolism accompanying rapid cellular destruction.. 
 
Monitor serum uric acid concentrations in patients receiving conventional 
cytarabine..Hyperuricemia may be minimized or prevented by adequate hydration, alkalinization 
of urine, and/or administration of allopurinol. 
 
Hepatic Impairment, Use with caution; increased risk of CNS toxicity after high-dose therapy with 
conventional cytarabine because of decreased clearance. Assess hepatic function prior to and 
periodically during prolonged therapy. 
 
Renal Impairment, Use with caution; increased risk of CNS toxicity after high-dose therapy with 
conventional cytarabine because of decreased clearance Assess renal function prior to and 
periodically during prolonged therapy.  
 
COMMON ADVERSE EFFECTS 
 
IV, sub-Q, or IM administration of conventional cytarabine: Myelosuppression, anorexia, nausea, 
vomiting, diarrhea, oral and anal inflammation or ulceration, hepatic dysfunction, fever, rash, 


42 
 
thrombophlebitis, bleeding (all sites). 
 
INTERACTIONS FOR CYTARABINE 
No formal drug interaction studies conducted with liposomal cytarabine to date. 
 
PHARMACOKINETICS 
AbsorptionBioavailability 
Conventional cytarabine: <20% of dose is absorbed after oral administration; not effective when 
administered orally. Conventional cytarabine: Continuous IV infusions produce relatively constant plasma 
concentrations of the drug in 8–24 hours. 
 
Distribution Extent 
Conventional cytarabine: Rapidly and widely distributed into tissues and fluids, including liver, plasma, 
and peripheral granulocytes crosses blood-brain barrier to a limited extent.Conventional cytarabine: CSF 
concentrations are higher during continuous IV or sub-Q infusion than after rapid IV injection and are 
approximately 40–60% of plasma concentrations.Conventional cytarabine: Apparently crosses 
placenta;not known if distributed into milk.  
 
Half-life 
Conventional cytarabine: After rapid IV injection, plasma drug concentrations appear to decline in a 
biphasic manner with a half-life of about 10 minutes in the initial distributive phase and about 1–3 hours in 
the terminal elimination phase; .reportedly undergoes triphasic elimination in some patients.. 
Conventional or liposomal cytarabine: Liposomal cytarabine has a substantially longer half-life in the CSF 
than conventional formulations after intrathecal injection.Conventional or liposomal cytarabine: CSF 
concentrations reportedly decline in a biphasic manner after intrathecal injection.di CSF terminal half-life 
of conventional cytarabine is approximately 2–3.4 hours;.CSF terminal half-life was 100–263 hours after 
intrathecal liposomal cytarabine doses ranging from 12.5–75 mg. 
 
Stability  Storage  
Conventional Cytarabine Powder for Injection25°C (may be exposed to 15–30°C).. 
Conventional Cytarabine Injection15–30°C. Store in manufacturer’s carton and protect from light.  
 
 
BCNU (CARMUSTINE) 
 
PHARMACOLOGY 
Carmustine alkylates DNA and RNA and also inhibits several enzymes by carbamoylation of amino acids 
in proteins. Antineoplastic and toxic activities may be caused by metabolites. 
Pharmacokinetics 
 
ABSORPTION 
IV Vd is 3.25 L/kg. Crosses the blood-brain barrier. 
 
ELIMINATION 
The t ½ is 22 min. Cl is 56 mL/min/kg. Approximately 60% is excreted in the urine; 6% is expired as CO 2 
. 
GENERAL ADVICE 
Administer by IV infusion. Follow procedures for proper handling and disposal of chemotherapy drugs. 
Wear gloves and avoid skin exposure and inhalation of fumes. 
 
The reconstituted solution is administered by IV drip over 1 to 2 h. Shorter infusion times may produce 
intense pain and burning at the site of injection.Dissolve 1 vial with 3 mL of the dehydrated alcohol 
diluent, followed by 27 mL of sterile water for injection for a final concentration of 3.3 mg/mL in 10% 
alcohol. This solution may be further diluted with 5% dextrose for a concentration of 0.2 mg/mL in glass 
containers.Accidental contact of carmustine with skin can cause temporary severe burning and 
hyperpigmentation; wear gloves when handling. Double gloving is recommended. 
 


43 
 
When administered with polyvinyl chloride tubing, longer infusion times may result in unacceptable drug 
loss. To avoid drug loss, polyethylene tubing, such as nitroglycerin tubing, can be utilized for infusions of 
carmustine.Open the foil pouches containing the wafer in the operating room immediately prior to 
implantation.Unopened foil pouches are stable at room temperature for up to 6 h at a time. 
Wafers may be used if broken in half. Do not use if broken in more than 2 pieces; dispose of as a 
hazardous chemical waste.Use a dedicated surgical instrument for handling the wafers during 
implantation. 
 
STORAGE/STABILITY 
Store the unopened vials in a refrigerator (2° to 8°C; 3° to 46°F). After reconstitution, store at room 
temperature (25°C; 77°F) for up to 8 h. Protect from light. 
 
ADVERSE REACTIONS 
 
CNS - Depression (16%); intracranial hypertension (9%); anxiety, facial paralysis (7%); ataxia, 
hypesthesia (6%); dizziness, hallucinations, seizures (5%); headache (28%); meningitis; abscess; 
asthenia; confusion; somnolence; brain edema; intracranial infection. 
 
Dermatologic - Rash (wafer) (12%); local burning pain at the injection site; intense flushing of the 
skin. 
 
GI - Constipation (19%); abdominal pain, diarrhea (5%), (wafer); nausea (22%); vomiting (21%). 
 
Genitourinary - UTI (8%; wafer); amenorrhea; male infertility. 
 
Hematologic - Bone marrow suppression; myelosuppression. 
 
Hepatic - Transient LFT elevations; hepatic necrosis and veno-occlusive disease after bone 
marrow transplantation. 
 
Metabolic - Diabetes mellitus (wafer). 
 
Renal - Dose-related, delayed-onset, progressive renal failure. 
 
Respiratory - Early pulmonary toxicity; delayed pulmonary fibrosis. 
 
Special Senses - Retinitis; optic neuritis; suffusion of the conjunctiva. 
WARNINGS 
 
Bone marrow suppression (notably thrombocytopenia and leukopenia) May contribute to bleeding 
and infections. Toxicity is cumulative, thus adjust dose based on nadir counts from prior doses. 
Do not repeat doses more frequently than every 6 wk. Perform weekly complete blood cell counts 
for 6 wk postdose. 
 
Hematologic - The most frequent and serious toxic effect of injectable carmustine is delayed 
myelosuppression. 
 
Pulmonary fibrosis - Delayed onset pulmonary fibrosis has occurred up to 17 yr after treatment 
and has been reported in patients who received injectable carmustine in childhood and early 
adolescence. 
 
Pulmonary toxicity -Pulmonary toxicity from injectable carmustine appears to be dose-related. 
Patients receiving more than 1400 mg/m 2 cumulative dose are at significantly higher risk than 
those receiving less. Other risk factors include history of lung disease and duration of treatment. 
Cases of fatal pulmonary toxicity have occurred. 
 
Monitor liver and renal function tests periodically.Conduct baseline pulmonary function studies 
and frequent pulmonary function tests during treatment. Patients with a baseline less than 70% of 
predicted forced vital capacity (FVC) or carbon monoxide diffusing capacity (DL co ) are at 
particular risk. 
 
Long-term use of nitrosoureas has been reported to be associated with the development of 
secondary malignancies.There have been reports of persistent testicular damage causing 
infertility with injectable carmustine.  
 
Nausea and vomiting after IV administration. This dose-related toxicity appears within 2 h of 
dosing and lasts 4 to 6 h. Healing abnormalities - The majority of these events were mild to 
moderate in severity. 
 
Reversible hepatic toxicity, manifested by increased transaminase, alkaline phosphatase, and 
bilirubin levels, has occurred in a small percentage of patients using injectable carmustine. 
 
Ocular - Toxicity manifested as nerve fiber-layer infarcts and retinal hemorrhages has been 
associated with high dose injectable carmustine therapy. 


44 
 
 
Renal toxicity - Decrease in kidney size, progressive azotemia, and renal failure have occurred in 
patients. 
 
ALEMTUZOMAB (CAMPATH) 
CAMPATH DOSAGE AND ADMINISTRATION 
Premedication and Patient Monitoring 
To minimize risk of IV infusion-related reactions, administer diphenhydramine hydrochloride 50 mg and 
acetaminophen 500–1000 mg 30 minutes prior to first alemtuzumab infusion and when dosage is 
escalated.1 (See Infusion-related Effects under Cautions.) 
Monitor patients carefully during or shortly after infusion for manifestations of infusion reactions (e.g., 
rigors, fever, bronchospasm, chills, nausea, vomiting, rash, urticaria, dyspnea, hypotension).1 
 
To minimize risk of injection site reactions, administer an antihistamine and acetaminophen prior to sub-
Q† injections (e.g., 30 minutes before administration);343536 in one study, premedication was gradually 
withdrawn following resolution of any injection-related reactions.34 
 
Anti-infective Prophylaxis - To minimize risk of serious opportunistic infections, give prophylactic anti-
infectives upon initiation of alemtuzumab and continue for 2 months after completion of therapy or until 
CD4+ T-cell count ≥200/mm3 (whichever occurs later).1 (See Infectious Complications under Cautions.) 
Administer co-trimoxazole (sulfamethoxazole 800 mg and trimethoprim 160 mg per dose) twice daily 3 
times weekly (or equivalent) for prophylaxis of Pneumocystis jiroveci (formerly P. carinii) pneumonia.1 
Administer famciclovir 250 mg twice daily (or equivalent) for prophylaxis of herpesvirus infection.1 
 
ADMINISTRATION 
Administer by IV infusion.1 May be administered by sub-Q injection†.IV Administration 
For solution compatibility information, see Compatibility under Stability.Administer by IV infusion only.1 Do 
not administer by rapid IV injection (e.g., IV push or bolus). Do not mix with any other drug or administer 
any other drug simultaneously in the same IV line. Vials are for single use only.  
 
DILUTION 
Use strict aseptic technique since drug product contains no preservative. Do not shake vial prior to use.15 
Withdraw appropriate dose of alemtuzumab concentrate into a syringe calibrated in increments of 0.01 
mL when preparing a 3-mg dose or a 10-mg dose; for a 30-mg dose, use a syringe calibrated in 
increments of 0.1 mL.1 To prepare a 3-mg dose, withdraw 0.1 mL of alemtuzumab concentrate into a 1-
mL syringe; to prepare a 10-mg dose, withdraw 0.33 mL into a 1-mL syringe; and to prepare a 30-mg 
dose, withdraw 1 mL into either a 1- or 3-mL syringe.1 Discard vial, including any unused portion, after 
withdrawal of dose.1 
Add appropriate dose of alemtuzumab concentrate to 100 mL of 0.9% sodium chloride or 5% dextrose 
injection; gently invert bag to mix solution.1 
 
RATE OF ADMINISTRATION 
Administer dose over 2 hours. Hematologic Toxicities - Adjust dosage and/or temporarily discontinue 
therapy if severe cytopenias (except lymphopenia) occur; permanently discontinue drug in patients with 
evidence of autoimmune hematologic toxicity (i.e., autoimmune anemia or thrombocytopenia).  
No dosage modifications recommended for lymphopenia.  
 
INFUSION REACTIONS 
Withhold therapy in patients experiencing grade 3 or 4 infusion reactions.  
Infectious Complications - If serious infection occurs, temporarily discontinue therapy; may reinitiate 
therapy following resolution of infection. Withhold therapy during antiviral therapy for CMV infection or 
confirmed CMV viremia (defined as positive for CMV according to PCR in ≥2 consecutive samples 
obtained ≥1 week apart) and initiate anti-infective therapy (ganciclovir or equivalent).  
 
CONTRAINDICATIONS 
None.  
 


45 
 
WARNINGS/PRECAUTIONS 
Use under supervision of a qualified clinician experienced in therapy with antineoplastic agents.  
 
Hematologic Effects 
 
Risk of severe (sometimes fatal) autoimmune anemia, autoimmune thrombocytopenia, and 
prolonged myelosuppression. 
 
 Hemolytic anemia, pure red cell aplasia, bone marrow aplasia, and hypoplasia have occurred in 
patients receiving recommended dosage.1 Increased incidence of pancytopenia with higher than 
recommended dosages (i.e., single doses >30 mg or cumulative weekly doses >90 mg). 
 
Withhold alemtuzumab in patients who develop severe cytopenias (except lymphopenia).1 (See 
Dosage under Dosage and Administration.) 
 
Discontinue therapy permanently in patients with autoimmune hematologic toxicity (i.e., 
autoimmune anemia or thrombocytopenia) or recurrent or persistent severe cytopenias (except 
lymphopenia).1 Safety of reinitiating alemtuzumab in patients with autoimmune cytopenia or bone 
marrow aplasia not established. 
 
Severe idiopathic thrombocytopenic purpura (ITP), sometimes fatal, reported in 3 patients 
receiving alemtuzumab in a clinical trial evaluating the drug for treatment of multiple sclerosis.32 
Two of these patients received cumulative doses that exceeded the cumulative weekly dose limit. 
 
Infusion Reactions - Risk of acute infusion reactions, including rigors, fever, bronchospasm, chills, 
nausea, vomiting, rash, urticaria, dyspnea, and hypotension occurring during or shortly after IV 
infusion, particularly during first week of therapy. 
 
Serious, sometimes fatal, infusion-related reactions (e.g., syncope, pulmonary infiltrates, ARDS, 
respiratory arrest, cardiac arrhythmias, MI, acute cardiac insufficiency, cardiac arrest, 
angioedema, anaphylactoid shock) reported. Monitor closely for adverse reactions during and 
shortly after infusion.1 Withhold alemtuzumab in patients experiencing grade 3 or 4 infusion 
reactions.1 Initiate medical management (e.g., glucocorticoids, epinephrine, meperidine) as 
clinically indicated. 
 
Premedication and incremental dosage escalation used to prevent or ameliorate reactions. 
Acute systemic injection-related reactions, including fever and chills/rigors, also reported with 
sub-Q† injection of alemtuzumab, but appear to be more common with IV infusion 
Immunosuppression 
Risk of severe and profound lymphopenia, which increases the potential for tranfusion-associated 
graft versus host disease (TA-GVHD).12 Administer only irradiated blood products unless 
immediate transfusion is required because of emergency.1 
Infectious Complications -Risk of serious (sometimes fatal) opportunistic bacterial, viral, fungal, or 
protozoan infections resulting from severe and profound lymphopenia.1 
 
Administer prophylactic anti-infectives against Pneumocystis jiroveci (formerly Pneumocystis 
carinii) and herpesvirus infections during alemtuzumab therapy and for at least 2 months after the 
last dose of alemtuzumab.134 (See Anti-infective Prophylaxis under Dosage and Administration.) 
 
Risk of potentially serious or life-threatening CMV infection.1 Monitor patient closely for CMV 
infection during and for at least 2 months following completion of alemtuzumab therapy.1 
 
If serious infection occurs, temporarily discontinue alemtuzumab;1 reinitiate therapy following resolution 
of infection.  
 
 
FLUDARABINE (Fludara) 
 
 
AVAILABILITY 
Fludarabine is commercially available as a white, lyophilized powder.  Each vial contains 50 mg of 
fludarabine, 50 mg of mannitol and sodium hydroxide to adjust pH. 
 
STORAGE & STABILITY 
Intact vials should be stored under refrigeration.  Reconstituted vials are stable for 16 days at room 
temperature or under refrigeration.  Solutions diluted in D5W or NS are stable for 48 hours at room 
temperature or under refrigeration. 
 


46 
 
PREPARATION 
Fludarabine should be reconstituted with Sterile Water for Injection, USP or normal saline per institutional 
pharmacy guidelines.   
 
ADMINISTRATION 
Fludarabine will be administered as an IV infusion over 30 minutes. 
 
TOXICITY 
Myelosuppression, (dose-limiting toxicity), fever, mild nausea and/or vomiting, diarrhea, stomatitis, skin 
rashes, myalgia, headache, agitation, hearing loss, transient episodes of somnolence and fatigue, 
autoimmune hemolytic anemia (may be life-threatening), peripheral neuropathy, and pulmonary toxicity.  
(Both pneumonia and hypersensitivity reactions have been reported.  Fatal pulmonary toxicity has been 
described, especially when fludarabine was used in combination with pentostatin.  Severe, fatal CNS 
toxicity presenting with loss of vision and progressive deterioration of mental status was encountered 
almost exclusively after very high doses of fludarabine.  Such toxicity has only been rarely demonstrated 
at the 25-30 mg /m2 dosage of fludarabine.  Very rarely described complications include transfusion-
associated graft versus host disease.  Tumorlysis syndrome has been observed, especially in patients 
with advanced bulky disease.  Opportunistic infections (protozoan, viral, fungal, and bacterial) have been 
observed.     
 
MYCOPHENOLATE MOFETIL (CellceptÒ; MyforticÒ; MMF) 
 
 
AVAILABILITY 
Mycophenolatemofetil is available as a Capsule, as mofetil:  CellCept®: 250 mg;  
as Injection, powder for reconstitution, as mofetil hydrochloride:  CellCept®: 500 mg [contains polysorbate 
80]; as Powder for oral suspension, as mofetil: CellCept®: 200 mg/mL (225 mL) [provides 175 mL 
suspension following reconstitution; contains phenylalanine 0.56 mg/mL; mixed fruit flavor]; as a Tablet, 
as mofetil: CellCept®: 500 mg [may contain ethyl alcohol]; and as a Tablet, delayed release, as 
mycophenolic acid: Myfortic®: 180 mg, 360 mg [formulated as a sodium salt]. 
 
 
STORAGE & STABILITY 
Intact vials should be stored at room temperature 15ºC to 30ºC (59ºF to 86ºF).  Store solutions at 15ºC to 
30ºC (59ºF to 86ºF) and begin infusion within 4 hours of reconstitution.  Store capsules at room 
temperature of 15ºC to 39ºC (59ºF to 86ºF).  Tablets should be stored at room temperature of 15ºC to 
39ºC (59ºF to 86ºF) and protected from light.  Store powder for oral suspension at room temperature of 
15ºC to 39ºC (59ºF to 86ºF).  Once reconstituted, the oral solution may be stored at room temperature or 
under refrigeration. Do not freeze. The mixed suspension is stable for 60 days. 
 
PREPARATION 
Mycophenolatemofetil is stable in D5W should be reconstituted per institutional pharmacy guidelines.  
 
ADMINISTRATION 
Intravenous solutions of mycophenolatemofetil should be administered over at least 2 hours (either 
peripheral or central vein); do not administer intravenous solution by rapid or bolus injection.  Oral dosage 
formulations (tablet, capsule, suspension) should be administered on an empty stomach to avoid 
variability in MPA absorption. The oral solution may be administered via a nasogastric tube (minimum 8 
French, 1.7 mm interior diameter); oral suspension should not be mixed with other medications. Delayed 
release tablets should not be crushed, cut, or chewed. 
 
TOXICITY 
Pain, abdominal pain, fever, headache, infection, sepsis, asthenia, chest pain, back pain, hypertension, 
tremor, insomnia, dizziness, acne, rash, diarrhea, constipation, mild N/V, oral monoliasis, anemia, 
leukopenia, thrombocytopenia, hypochromic anemia, leukocytosis, peripheral edema, 
hypercholesterolemia, hypophosphatemia, edema, hypo or hyperkalemia, hyperglycemia, infection, 
dyspnea, cough increase, pharyngitis, bronchitis, pneumonia, UTI, hematuria, kidney tubular necrosis, 
urinary tract disorder. 


47 
 
 
RABBIT ANTITHYMOCYTE GLOBULIN(ThymoglobulinÒ, rATG) 
 
AVAILABILITY 
Antithymocyte globulin is commercially available.  Each package contains two vials:  the first vial contains 
25 mg antithymocyte globulin, and the second vial contains > 5 mL SWFI diluent. 
 
 
STORAGE & STABILITY 
Ampuls must be refrigerated (2oC-8oC/ 36oF-46oF),).  Do not freeze.   
 
PREPARATION 
Reconstitute 25 mg vial with diluent provided by manufacturer (SWFI > 5 mL).  Roll vial gently to dissolve 
powder.  Use contents of vial within 4 hours of reconstitution.  Dilute dosage to a final concentration of 0.5 
mg/mL in 0.9% sodium chloride injection or 5% dextrose injection.  Gently invert admixture 1-2 times to 
mix solution.  Use admixture solution immediately.  Final concentration must be 0.5 mg/mL. 
 
ADMINISTRATION 
Infuse the first dose over at least six hours, and subsequent doses over at least 4 hours.  Infuse through a 
0.22 micron in-line filter into a high-flow vein.  Premedications include acetaminophen 650 mg PO, 
diphenhydramine 25-50 mg PO/IV, and methylprednisolone 1 mg/kg (at the initiation and half-way 
through antithymocyte globulin administration). 
 
TOXICITY 
Infusion-related toxicities, including fevers, chills, rash, dyspnea, cardiovascular (hypo- or hypertension, 
tachycardia, edema, chest pain).  In rare cases, anaphylaxis has been reported in which case the infusion 
should be terminated immediately, and emergency treatment with epinephrine and other resuscitative 
measures should be instituted.  rATG should not be administered again to this patient.  
Immunosuppression is a common feature of rATG and can result in severe infections including sepsis, 
CMV, and urinary tract infections.  Serum sickness, neutropenia (57%), thrombocytopenia (37%), 
leucopenia (57%), pain (46%), headache (40%), nausea and diarrhea (37%), peripheral edema (34%), 
systemic infection, malaise, pain, stomatitis, GI bleed, swelling or redness at injection site, myalgia, back 
pain, development of human anti-rabbit antibodies (HARA).  
 
 
Neulasta (Pegfilgrastim) 
 
INDICATIONS AND USAGE 
Neulasta is a leukocyte growth factor indicated to: 
e incidence of infection, as manifested by febrileneutropenia, in patients with non-myeloid 
malignancies receiving myelosuppressive anti-cancer drugs associated with a clinicallysignificant 
incidence of febrile neutropenia. 
acutely exposed to myelosuppressive dosesof radiation (Hematopoietic 
Subsyndrome of Acute Radiation Syndrome). 
Neulasta is not indicated for the mobilization of peripheral blood progenitorcells for hematopoietic stem 
cell transplantation. 
 
DOSAGE AND ADMINISTRATION 
 
o 6 mg administered subcutaneously once per chemotherapy cycle. 
o Do not administer between 14 days before and 24 hours afteradministration of cytotoxic 
chemotherapy.  
o Use weight based dosing for pediatric patients weighing less than45 kg 
 
o Two doses, 6 mg each, administered subcutaneously one weekapart. Administer the first dose 
as soon as possible after suspectedor confirmed exposure to myelosuppressive doses of 
radiation, anda second dose one week after 
o Use weight based dosing for pediatric patients weighing less than 45 kg 


48 
 
 
 
DOSAGE FORMS AND STRENGTHS
-use prefilled syringe 
-packagedwith the On-
body Injector for Neulasta 
 
CONTRAINDICATIONS 
Patients with a history of serious allergic reactions to human granulocytecolony-stimulating factors such 
as pegfilgrastim or filgrastim 
 
WARNINGS AND PRECAUTIONS 
enlarged spleen or splenic rupture 
respiratory distress. DiscontinueNeulasta in patients with ARDS 
 in patients with 
serious allergic reactions 
-body Injector for Neulasta uses acrylic adhesive. For patientswho have reactions to acrylic 
adhesives, use of this product may result in a significant reaction 
 
-reduction orinterruption of Neulasta if causality is likely 
 
ADVERSE REACTIONS 
Most common adverse reactions (≥ 5% difference in incidence compared toplacebo) are bone pain and 
pain in extremity 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX E 
 
ACUTE GRAFT VERSUS HOST DISEASE GRADING 
 
Consensus grading of acute GVHD7 


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52 
 
 
 
 
 
 
 
 
 
 
 
 


53 
 
Organ scoring of chronic GVHD. *AP may be elevated in growing children, and not reflective of liver 
dysfunction. †Pulmonary scoring should be performed using both the symptom and pulmonary function 
testing (PFT) scale whenever possible. When discrepancy exists between pulmonary symptom or PFT 
scores the higher value should be used for final scoring. Scoring using the Lung Function Score (LFS) is 
preferred, but if DLCO is not available, grading using FEV1 should be used. The LFS is a global 
assessment of lung function after the diagnosis of bronchiolitis obliterans has already been established 
[29]. The percent predicted FEV1 and DLCO (adjusted for hematocrit but not alveolar volume) should be 
converted to a numeric score as follows: >80% = 1; 70-79% = 2; 60-69% = 3; 50-59% = 4; 40-49% = 5; 
<40% = 6. The LFS = FEV1 score + DLCO score, with a possible range of 2-12. GVHD indicates graft 
versus host disease; ECOG, Eastern Cooperative Oncology Group; KPS, Karnofsky Performance Status; 
LPS, Lansky Performance Status; BSA, body surface area; ADL, activities of daily living; LFTs, liver 
function tests; AP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; 
ULN, upper limit of normal. 
 
 
 
Mild chronic GVHD involves only 1 or 2 organs or sites (except the lung: see below), 
with no clinically significant functional impairment (maximum of score 1 in all affected 
organs or sites). Moderate chronic GVHD involves (1) at least 1 organ or site with 
clinically significant but no major disability (maximum score of 2 in any affected organ or 
site) or (2) 3 or more organs or sites with no clinically significant functional impairment 
(maximum score of 1 in all affected organs or sites). A lung score of 1 will also be 
considered moderate chronic GVHD. Severe chronic GVHD indicates major disability 
caused by chronic GVHD (score of 3 in any organ or site). A lung score of 2 or greater 
will also be considered severe chronic GVHD. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


54 
 
                                                          
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