A Phase I Clinical Trial to Evaluate the Maximally Tolerated Dose (MTD), Dose Limiting Toxicities (DLTs) and Safety Profiles of Increasing Doses of Lenalidomide After Allo-HCT in AML and MDS Subjects With Minimal Residual Disease (MRD) Detected by the CD34+ Mixed Chimerism Analysis (UF-BMT-MRD-101)
Phase: PHASE1
Conditions: Leukemia, Myeloid, Myelodysplastic Syndromes
Sponsor: University of Florida

Clinical Study Protocol 
 
A phase I clinical trial to evaluate the maximally tolerated dose (MTD), dose limiting toxicities 
(DLTs) and safety profiles of increasing doses of lenalidomide after allo-HCT in AML and MDS 
subjects with minimal residual disease (MRD) detected by the CD34+ mixed chimerism 
analysis. 
 
 
Protocol Number: 
 
UF-BMT-MRD-101 
 
Celgene Protocol Number: 
RV-CL-AML-PI-002987 
 
Protocol Version Date: 
8/25/2017 
 
Amendment Version:  
5 
 
 
Principal Investigator:  
Maxim N. Norkin, MD, PhD 
 
 
 
 
University of Florida 
 
 
 
 
1600 SW Archer Road, Box 100278 
 
 
 
 
Gainesville, FL 32610-0278 
 
 
 
 
Phone: (248) 756-4524 
Email: norkinm@ufl.edu 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
Page 
Table of Contents ......................................................................................................................... 2 
Abbreviations ............................................................................................................................... 7 
Protocol Synopsis ....................................................................................................................... 10 
Schedule of Events ..................................................................................................................... 17 
1. 
Background ........................................................................................................................ 18 
1.1 
Acute Myelogenous Leukemia ................................................................................ 18 
1.2 
Myelodysplastic Syndromes .................................................................................... 18 
1.3 
Experience with Revlimid after allo-HCT in patients with Multiple Myeloma ...... 19 
1.4 
CD34+ mixed chimerism analysis ........................................................................... 19 
2. 
Study Agent ........................................................................................................................ 22 
2.1 
Lenalidomide............................................................................................................ 22 
2.1.1 Background ...................................................................................... 22 
2.1.2 Adverse Events................................................................................. 22 
2.1.3 Second New Cancers........................................................................ 23 
2.1.4 Lenalidomide Description ................................................................ 23 
2.1.5 Clinical Pharmacology ..................................................................... 24 
2.1.6 Pharmacokinetics and Drug Metabolism ......................................... 24 
2.1.7 Pharmacokinetic Parameters ............................................................ 24 
2.1.8 Metabolism and Excretion ............................................................... 24 
2.1.9 Supplier(s) ........................................................................................ 24 
2.1.10 Dosage form ..................................................................................... 25 
2.1.11 Packaging ......................................................................................... 25 
2.1.12 Labeling............................................................................................ 25 
2.1.13 Special Handling Instructions .......................................................... 25 
2.1.14 Prescribing Information ................................................................... 25 
2.1.15 Pregnancy Testing ............................................................................ 25 
3. 
Objectives ........................................................................................................................... 25 
3.1 
Primary ..................................................................................................................... 25 
3.2 
Secondary ................................................................................................................. 25 
4. 
Study Design ...................................................................................................................... 26 

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4.1 
Overall Study Design ............................................................................................... 26 
4.2 
Dose Escalation ........................................................................................................ 26 
4.3 
Dose Limiting Toxicity ............................................................................................ 27 
4.4 
Study Duration and Dates ........................................................................................ 27 
4.5 
Correlative Studies ................................................................................................... 28 
5. 
Selection of Subjects .......................................................................................................... 28 
5.1 
Number of Subjects .................................................................................................. 28 
5.2 
Inclusion Criteria ...................................................................................................... 28 
5.3 
Exclusion criteria ..................................................................................................... 29 
6. 
Study Treatment ................................................................................................................. 29 
6.1 
Treatments to be Administered ................................................................................ 29 
6.2 
Instructions for initiation of lenalidomide................................................................ 30 
6.3 
Management of Toxicity .......................................................................................... 30 
6.3.1 Hematopoietic Supportive Care ....................................................... 30 
6.4 
Method of Treatment Assignment ........................................................................... 30 
6.5 
Record of Administration ......................................................................................... 31 
7. 
Concomitant Medications .................................................................................................. 31 
7.1 
Concomitant Medications and Therapy ................................................................... 31 
7.2 
Excluded Medications .............................................................................................. 31 
7.3 
Immunosuppression ................................................................................................. 31 
8. 
Study Procedures ................................................................................................................ 31 
8.1 
Protocol Procedures ................................................................................................. 31 
9. 
Data Measurements and Methods of Collection ................................................................ 32 
9.1 
Data Measurements .................................................................................................. 32 
9.1.1 Safety Data ....................................................................................... 32 
9.1.2 Correlative Studies ........................................................................... 32 
9.2 
Methods of Collection .............................................................................................. 32 
9.2.1 Sample Collection for Correlative Studies ....................................... 32 
9.2.2 Safety Measurements ....................................................................... 32 
10. Adverse Events ................................................................................................................... 34 

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10.1 
Definitions ................................................................................................................ 34 
10.1.1 Adverse Event (AE) ......................................................................... 34 
10.1.2 Serious Adverse Event (SAE) .......................................................... 34 
10.1.3 Events not considered to be SAEs are hospitalizations for: ............. 35 
10.1.4 Non-Serious Adverse Event ............................................................. 36 
10.1.5 Abnormal Laboratory Values ........................................................... 36 
10.2 
Period of Observation .............................................................................................. 36 
10.3 
Documenting and Reporting of Adverse Events by the Investigator ....................... 36 
10.3.1 Assessment of Causal Relationship of Study Drug ......................... 37 
10.3.2 Intensity of Adverse Events ............................................................. 38 
10.3.3 Action Taken with Study Drug ........................................................ 38 
10.3.4 Definition of Outcome ..................................................................... 39 
10.4 
Immediately Reportable Events ............................................................................... 39 
10.4.1 Serious Adverse Events.................................................................... 39 
10.4.2 Other Events Requiring Immediate Reporting ................................. 40 
10.5 
Second Primary Malignancies.................................................................................. 40 
10.6 
Pregnancies .............................................................................................................. 40 
10.6.1 Male Subjects ................................................................................... 41 
10.7 
Investigator Reporting Responsibilities ................................................................... 41 
10.7.1 IND Annual Reports ........................................................................ 41 
10.7.2 Investigator Reporting to the FDA ................................................... 41 
10.7.3 Adverse event updates/IND safety reports ....................................... 41 
11. Discontinuations ................................................................................................................. 42 
11.1 
Discontinuation of Subjects ..................................................................................... 42 
11.2 
Replacement of Subjects .......................................................................................... 42 
11.3 
Study Stopping Rules ............................................................................................... 42 
12. Data and Safety Monitoring ............................................................................................... 42 
12.1 
Summary .................................................................................................................. 42 
13. Statistical Methods ............................................................................................................. 43 
13.1 
Determinations of Sample Size ................................................................................ 43 

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13.2 
Analysis Populations ................................................................................................ 43 
13.2.1 Safety Population ............................................................................. 43 
13.2.2 Dose Limiting Toxicity Evaluable Population ................................. 44 
13.2.3 Efficacy Evaluable Population ......................................................... 44 
13.3 
Analysis Methods ..................................................................................................... 44 
13.3.1 Safety................................................................................................ 44 
13.3.2 Efficacy ............................................................................................ 44 
14. Emergency Procedures ....................................................................................................... 44 
14.1 
Emergency Contact .................................................................................................. 44 
14.2 
Emergency Identification of Investigational Products ............................................. 45 
14.3 
Emergency Treatment .............................................................................................. 45 
15. Administrative Considerations ........................................................................................... 45 
15.1 
Good Clinical Practice ............................................................................................. 45 
15.2 
Delegation of Investigator Responsibilities ............................................................. 45 
15.3 
Subject Information and Informed Consent ............................................................. 45 
15.4 
Confidentiality ......................................................................................................... 45 
15.5 
Protocol Amendments .............................................................................................. 46 
15.6 
Record Retention ...................................................................................................... 46 
16. Appendices ......................................................................................................................... 47 
16.1 
Appendix A: AML WHO 2008 Classification System3 .......................................... 47 
16.2 
Appendix B: MDS WHO 2008 Classification System34 ......................................... 48 
16.3 
Appendix C: AML Response Criteria According to IWG35 .................................... 49 
16.4 
Appendix D: MDS Response Criteria According to IWG36 .................................... 50 
16.5 
Appendix E: Karnofsky Performance Status ........................................................... 51 
16.6 
Appendix F: Graft-versus-host-disease scales ......................................................... 52 
16.7 
Appendix G: Statistical Characteristics of the “3+3” Design .................................. 53 
16.8 
Appendix H: RBC Transfusion Independence ......................................................... 54 
16.9 
Appendix I: Cockcroft-Gault Creatinine Clearance Calculation ............................. 55 
17. References .......................................................................................................................... 56 
 

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Page 
Figure 1. CD34+ Chimerism cells ............................................................................................. 20 
Figure 2. Conventional and CD34+ donor chimerism monitoring in patients with (left column) 
and without (right column) hematologic relapse ............................................ 20 
Figure 3. Chemical Structure of Lenalidomide .......................................................................... 23 
Figure 4. Dose Limiting Toxicity Flow Diagram ...................................................................... 27 
 
 
 
 
 

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ABBREVIATIONS 
AE 
Adverse Event 
aGVHD 
Acute Graft-Versus-Host-Disease 
ALT 
Alanine Transaminase (also SGPT) 
AML 
Acute Myelogenous Leukemia 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Transaminase (also SGOT) 
AUC 
Area Under Curve 
AUC(0-t)
Area Under the Plasma Concentration-time curve from time zero to time t 
AUC(0-∞)
Area Under the Plasma Concentration-time curve from time zero to infinity 
AUC(0-Tlast)
Area Under the Plasma Concentration-time curve from time zero to the last 
measurable time point 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CIBMTR 
Center for International Blood and Marrow Transplant Research 
Cmax
Maximum Plasma Concentration 
CR 
Complete Remission 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DFS 
Disease-free Survival 
DLT 
Dose-Limiting Toxicity 
DNA 
Deoxyribonucleic Acid 
DISC 
Data Integrity and Safety Committee 

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eCRF 
Electronic Case Report Form 
FCBP 
Female of Child-Bearing Potential 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GVHD 
Graft-Versus-Host-Disease 
GVL 
Graft-Versus-Leukemia 
HCT 
Hematopoietic Cell Transplant 
HI 
Hematologic Improvement (see Appendix D) 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug 
IP 
Investigational Product 
IPSS 
International Prognostic Scoring System 
IRB 
Institutional Review Board 
IWG 
International Working Group 
MDS 
Myelodysplastic syndromes 
MG 
Milligram 
MRD 
Minimal Residual Disease 
MTD 
Maximum Tolerated Dose 
NIH 
National Institutes of Health 
NK 
Natural Killer 
OS  
Overall Survival 
PD 
Pharmacodynamics 

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PI 
Principal investigator 
PML 
Promyelocytic Leukemia 
PO 
By Mouth 
PR 
Partial Remission 
QD 
Every Day 
QOD 
Every Other Day 
RBC 
Red Blood Cells 
REMS 
Risk Evaluation and Mitigation Strategy 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase (also AST) 
SGPT 
Serum Glutamic Pyruvate Transaminase (also ALT) 
SPM 
Second Primary Malignancy 
STR 
Short Tandem Repeat 
UFHCC 
University of Florida Health Cancer Center 
US 
United States 
WBC 
White Blood Cell  
WHO 
World Health Organization 
 
 
 
 
 

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PROTOCOL SYNOPSIS 
Title: 
A phase I clinical trial to evaluate the maximally tolerated dose (MTD), 
dose limiting toxicities (DLTs) and safety profiles of escalating doses of 
lenalidomide after allo-HCT in AML and MDS subjects with minimal 
residual disease (MRD) detected by the CD34+ mixed chimerism analysis 
Rationale: 
Prognosis of high risk AML and MDS remains poor and less than 30% of 
these patients achieve long term survival. Allogeneic transplant (allo-
HCT) is an effective therapy for high risk AML and MDS, however, post-
transplant disease relapse continues to be a major obstacle to treatment 
success and cure. Therefore, there is an urgent need to develop novel 
therapeutic strategies to effectively prevent disease relapse in AML and 
MDS patients after allo-HCT.  
This phase I clinical trial is designed to evaluate the maximally tolerated 
dose (MTD), dose limiting toxicities (DLTs) and safety profiles of 
increasing doses of lenalidomide after allo-HCT in AML and MDS 
subjects with minimal residual disease (MRD) detected by the CD34+ 
mixed chimerism analysis.  
Lenalidomide has a potent immunomodulatory activity and is capable of 
activating T- and natural killer (NK)-cells. T- and NK-cells mediated 
immunity plays a critical role in host defense against progression of 
myeloid malignances, therefore restoration of impaired cytotoxic activity 
of T- and NK cells with lenalidomide could have significant clinical 
implications in patients with relapsing MDS and AML after allo-HCT 
because alloreactive T- and NK-cells play a crucial role in the GVL effect, 
which is considered to be a key mechanism preventing disease relapse 
after allo-HCT. Treatment of relapsed disease is more successful if 
initiated early when tumor burden is minimal. Previous studies evaluating 
the role of lenalidomide in patients with relapsed myeloid malignances 
showed its efficacy only in patients with low blast count. For this purpose, 
monitoring of MRD allows timely therapeutic interventions before the 
hematologic relapse becomes clinically apparent and while tumor burden 
is minimal. However, in AML and MDS patients monitoring of MRD is 
technically difficult and is not routinely implemented in clinical practice. 
For these purposes, new approaches for MRD detection are currently 
being explored.  
Lineage-specific chimerism analysis of CD34+ cells is a novel approach, 
which has better sensitivity and specificity for early MRD detection after 
allo-HCT. It was demonstrated that monitoring of CD34+ chimerism in 
patients with AML and MDS after allo-HCT is a very sensitive technique, 
which is capable to early identify patients at a very high risk for a 
hematologic relapse. Our preliminary data showed that of 10 enrolled 
patients 4 patients had hematologic relapse confirmed by a bone marrow 

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evaluation. In each patient with relapsed disease there was a significant 
decline in CD34+ specific chimerism, which was detected for at least a 
month prior to confirmed hematologic relapse. The CD34+ specific STR 
analysis is superior to conventional chimerism analysis for MRD 
monitoring and identification of early relapse after allo-HCT. More 
importantly, drop of CD34+ specific chimerism occurred significantly 
earlier that decrease in chimerism assessed by conventional STR-based 
techniques. Therefore, the use of highly sensitive and specific MRD 
monitoring by the CD34+ chimerism analysis substantially increases the 
reliability of early MRD detection after allo-HCT allowing early 
therapeutic interventions and is potentially practice changing.  
Therefore, the proposed research project is highly significant because it 
seeks to develop a novel therapeutic strategy to effectively delay or 
prevent AML and MDS relapse in allo-HCT recipients.  Successful 
completion of  this phase I study will build the foundation for a subsequent 
phase II trial of pre-emptive lenalidomide administration to prevent or 
delay an imminent hematological relapse after allo- HCT in subjects with 
MDS and AML with minimal residual disease (MRD) detected by the 
CD34+ mixed chimerism analysis, which would likely impact the clinical 
care of allo-HCT recipients with high risk AML and MDS and will give 
valuable insights into mechanisms of action of lenalidomide after allo-
HCT. 
Primary Objective: 
To determine safety and the maximum tolerated dose of lenalidomide after 
allo-HCT in AML and MDS subjects with MRD detected by the CD34+ 
mixed chimerism analysis. 
Secondary Objective: To monitor changes in the CD34+ mixed chimerism after allo-HCT in 
AML and MDS subjects with detectable MRD in response to escalating 
doses of lenalidomide. 
Study Design: 
This is an open-label, phase I dose escalation study of lenalidomide after 
allo-HCT in AML and MDS subjects with MRD detected by the CD34+ 
mixed chimerism analysis.  The study is designed to evaluate the safety 
profile, MTD and biologic  activity of lenalidomide after allo-HCT in 
patients with AML and MDS  
The dose levels of lenalidomide will be as follows: 
Dose Level 1:  2.5 mg PO QOD Day 1-21 for 28 day cycle X 2 cycles 
Dose Level 2:  2.5 mg PO QD Day 1-21 for 28 day cycle X 2 cycles 
Dose Level 3:  5 mg PO QD Day 1-21 for 28 day cycle X 2 cycles 
Dose Level 4:  7.5 mg PO QD Day 1-21 for 28 day cycle X 2 cycles 
Subjects will be enrolled in cohorts of three (3). Lenalidomide will be 
administered for 21 consecutive days in a 28 day cycle X 2 cycles. The 
starting dose will be 2.5 mg given orally every other day for 21 days. 

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Subjects will be individually assessed for safety and dose limiting toxicity 
(DLT) for the purpose of determining the MTD .Three eligible subjects 
will be enrolled in sequential cohorts at increasing dose levels until at least 
one DLT is seen between the first dose and 14 days after the last dose of 
lenalidomide. For this study, MTD will be defined as the highest dose 
which no more than 34% of the subjects observed at a given dose level 
experience a DLT. The following dose escalation rules will be used and 
applied:  
1. Three subjects are initially studied at each dose level. 
2. If none of these 3 subjects experience DLT, then the dose is 
escalated to the next dose level in 3 subsequent subjects.  
3. If 1 of these 3 subjects experiences DLT at current dose, then up to 
3 more subjects are accrued at the same level. 
a) If none of these 3 additional subjects experience DLT, then 
the dose is escalated to the next dose level in 3 subsequent 
subjects. 
b) If 1 or more of these 3 additional subjects experiences 
DLT, then the MTD is considered to have been exceeded 
and the previous dose level will be the MTD. 
4. If 2 or more of the initial 3 subjects at a dose level experience 
DLT, then the MTD is considered to have been exceeded and dose 
escalation will be stopped. Up to 3 more subjects are treated at the 
next lower dose.  
A subject must meet one of the following 3 criteria to be evaluable for 
subsequent  dose-escalation decisions: 
1. Complete at least 21 days of lenalidomide without a DLT by 14 
days after the last dose of lenalidomide;  
2. Experienced a DLT between the first dose and 14 days after the 
last dose of lenalidomide; or 
3. Withdrawn from the study after at least 14 days of lenalidomide 
administration.  
If a subject does not meet any of these criteria, the subject is not evaluable 
for dose escalation decisions and will be replaced in that cohort. No more 
than 3 subjects will be added simultaneously to a dose cohort during dose 
escalation.   
The study ends when there is a maximum dose where 2 or more subjects 
out of 6 have a DLT, or when the maximum sample size of twenty four 
(24) subjects has been reached. 
Dose Limiting Toxicity 
DLT will be defined as any of the following adverse events that are not 
clearly unrelated to drug administration or treatment-emergent from 
lenalidomide and constitute a change from baseline irrespective of 
outcome. For the purpose of dose-escalation decisions and MTD 

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determination, only DLTs that occur within 14 days after the last dose of 
lenalidomide administration will be taken into account. 
1. Grade 3 or greater nausea, diarrhea, or vomiting despite the use of 
maximal medical intervention; 
2. Grade 3 or greater acute GVHD despite the use of maximal 
medical intervention; 
3. Any other clinically significant non-hematologic toxicity of grade 
3 or greater considered not related to the underlying disease or 
intercurrent illness; 
4. Grade 3 or greater neutropenia;  
5. Grade 4 thrombocytopenia or platelet count  ≤ 50 thou/mm3 by day 
28 of lenalidomide administration; or    
6. Any treatment-related effect leading to a subject missing 3 or more 
doses of lenalidomide. 
Correlative Studies:  
Peripheral blood will be collected to examine the CD34+ specific 
chimerism. 
Inclusion/ 
Exclusion  
Criteria: 
Inclusion Criteria:  
1. Subjects must be at least 18 years of age; 
2. Subjects must be 60 (+/- 7) days post-allogeneic transplant from 
any donor source; 
3. Subjects must have either: 
a) High risk CD34+ AML (de novo or secondary, and any WHO 
2008 classification excluding acute promyelocytic leukemia, see 
Appendix A). High risk AML is defined as (a) disease status 
beyond complete remission (CR) #1 at transplant or (b) 
treatment related AML or (c) presence of adverse cytogenetics 
including inv(3); t(3;3); t(6;9); t(v;11); -5 or del(5q); -7; 
abnl(17p) or complex karyotype; or 
b) High risk CD34+ MDS (WHO 2008 classification, see Appendix 
B). High risk is defined as (a) blast count ≥5% at the time of 
transplant or (b) treatment related MD or (c) presence of adverse 
cytogenetics including -7/del7q or complex karyotype; 
4. For AML subjects, they must have a documented CR within 45 
days prior to allo-HCT; 
5. For MDS subjects, they must have < 20% myeloblasts in the bone 
marrow within 45 days prior to allo-HCT;  
6. Subject Karnofsky performance status must be ≥ 70; 
7. Subjects must be platelet transfusion independent (Platelet 
transfusion independence is defined as 7 days or greater without a 
platelet transfusion);   
8. Neutrophil count ≥ 1.0 thou/mm3 and platelet count ≥ 30 
thou/mm3;  

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9. Subjects must have total bilirubin ≤ 2 mg/dL; 
10. Subjects must have serum AST and ALT levels ≤ 2.5 times upper 
limit of normal; 
11. Subjects must have serum creatinine < 2.5 times upper limit of 
normal and a calculated creatinine clearance > 30 ml/min by 
Cockcroft-Gault formula (see Appendix I: Cockcroft-Gault 
Creatinine Clearance Calculation); 
12. All study participants who will receive lenalidomide based on the 
CD34+ chimerism testing must be registered into the mandatory 
Revlimid REMS® program, and be willing and able to comply with 
the requirements of the REMS® program;  
13. Females of child-bearing potential (i.e., women who are pre-
menopausal or not surgically sterile) may participate, provided 
they meet the following conditions: 
a) Females of reproductive potential must adhere to the scheduled 
pregnancy testing as required in the Revlimid REMS® program; 
and   
14. Written, voluntary informed consent, willingness, and ability to 
comply with all study procedures. 
Exclusion Criteria:  
1. CD34- AML or MDS; 
2. Subjects with peripheral blasts or progressive cytopenias will be 
excluded unless a CR or CRi confirmed by a bone marrow biopsy 
within two weeks post of the allo-HCT; 
3. Inability to give informed consent;  
4. Uncontrolled active infection(s) requiring intravenous antibiotics;  
5. Known or suspected hypersensitivity to lenalidomide; 
6. Grade II-IV acute GVHD or extensive GVHD;  
7. Not able to swallow the lenalidomide capsule as a whole; or  
8. Female subjects who are pregnant or nursing; 
Accrual: 
The sample size for the study is based on incidence of DLT; however, it is 
not to exceed 24 subjects. The accrual period will be three years. 
Study Duration 
and Dates: 
The subject recruitment period is approximately 36 months, starting last 
quarter 2015. The study duration encompasses the following: 
• Screening period of up to 14 days (+/-7 days from Day +60); and 
• The CD34+ donor chimerism will be performed on days +60 and 
+90 (± 7 days) post-transplant until the CD34+ donor chimerism 
drops to < 90%.  If the CD34+ donor chimerism continues to be > 
90% by day +90 (± 7 days) post-transplant the patient will be 
removed from the study; 
• Treatment with lenalidomide will start within 10 days after 
detection of the CD34+ donor chimerism ≤ 90%  and be continued 

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for 21 days in a 28 day cycle X 2 cycles or until terminating event 
occurs;  
• In subjects receiving lenalidomide, the CD34+ donor chimerism 
will be performed at Days +60 and +120 (± 7 days) of 
lenalidomide therapy. 
Safety 
Assessments: 
 
Subjects will be examined weekly per institutional standard of care. 
Examinations will consist of vital sign measurements, physical 
examinations, laboratory assessments (hematology, serum chemistries) 
and assessment of acute GVHD. NCI Common Terminology Criteria for 
Adverse Events (CTCAE), Version 4.0 will be used to grade toxicity and 
adverse events. 
GVHD assessment: Acute GVHD will be evaluated as per institutional 
practice guidelines using established staging criteria (see Appendix F). 
GVHD severity will be determined clinically; however, biopsies of 
affected organs are encouraged whenever possible. GVHD assessments 
will be performed at screening and Days +60 & +90.  If lenalidomide is 
initiated, GVHD assessments will be performed weekly during scheduled 
visits and continuing until 30 days after the last dose of lenalidomide. 
GVHD assessments will also be documented at Days +60 and Day +120 
after the initiation of lenalidomide. 
Overall grading and response to GVHD therapy will be measured through 
the use of the consensus and IBMTR GVHD severity indices based on 
physical exam and laboratory serum values (see Appendix F). Individual 
organ stages will be scored by the attending physician or other trained 
provider. 
Immunosuppression: 
All patients should receive standard GVHD prophylaxis per institutional 
guidelines per the treating physician. 
Efficacy 
Assessments: 
The efficacy outcome of interest will be reversal of the decreased CD34+ 
specific donor chimerism by day 60 of lenalidomide administration. 
Statistical 
Procedures: 
This study is descriptive in nature and not designed to provide analytical 
inferential results regarding primary or secondary endpoints. The sample 
size is based primarily on clinical considerations and not on statistical 
power calculations. Statistical characteristics of the “3 + 3” design are 
described in Appendix G. Descriptive statistics will be used to summarize 
baseline subject characteristics, treatment administration, and safety 
variables. All subjects who receive at least 5 doses of lenalidomide and 
have one post-dose safety assessment will comprise the safety population. 
The efficacy evaluable population will comprise all subjects who complete 

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at least 15 days of lenalidomide and have at least one post-therapy CD34+ 
specific chimerism assessment. 
 

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Schedule of Events 
Assessment 
Screening 
(+/-7 days 
from Day 
+60) 
Post-
Transplant 
Monitoring 
Days +60 & 
90 
( ± 7 days) 
Revlimid 
C1D1, C2D1 
End of 
Treatment 
30 Days post- 
last Revlimid 
Dose 
( ± 2 days) 
Post-
Revlimid 
Monitoring 
Days +60 & 
+120 
( ± 7 days) 
Survival 
Every  
3-months for 
1 year 
Signed Informed Consent 
X 
 
 
 
 
 
Demographics, Medical /Treatment History 
X 
 
 
 
 
 
MDS and AML WHO Classification 
X 
 
 
 
 
 
Weight, Height 
X 
 
 
 
 
 
Physical Examination 
X 
X 
X 
X 
X 
 
GVHD Assessment A 
X 
X 
X 
X 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
 
Karnofsky Performance Score 
X 
X 
X 
X 
X 
 
CBC + Differential 
X 
X 
X 
X 
X 
 
Serum Chemistry 
X 
X 
X 
X 
X 
 
Serum Pregnancy Test (females) B 
X 
 
X 
 
 
 
Bone Marrow Aspiration and Biopsy C 
X 
 
 
 
 
 
Peripheral Blood Chimerism 
 
X 
 
 
 
 
Peripheral blood CD34+ donor chimerism D 
 
X 
 
 
X 
 
Dispense Revlimid (21-day supply) 
 
 
X 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
 
 
Adverse Events Assessments 
X 
X 
X 
X 
 
 
Concomitant Blood Products 
X 
X 
X 
X 
 
 
Disease Response Assessment C 
X 
X 
 
 
 
X 
Survival Assessment 
 
 
 
X 
 
X 
A. Overall grading and response to GVHD therapy will be measured through the use of the consensus and IBMTR GVHD 
severity indices. GVHD assessments will be performed at screening and Days +60 &+ 90.  If lenalidomide is initiated, 
GVHD assessments will be performed weekly during scheduled visits and continuing until 30 days after the last dose of 
lenalidomide.  GVHD assessments will also be documented at Days +60, and Day +120  after the initiation of lenalidomide. 
B. 
Females of reproductive potential must have 2 negative pregnancy tests prior to initiating therapy. The first test should be 
performed within 10-14 days, and the second test within 24 hours prior to prescribing REVLIMID therapy and then weekly 
during the first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with 
irregular menstrual cycles. 
C. 
All disease assessments which occur during routine care of the subject will be recorded in the CRF. Bone marrow 
procedures or other disease assessments will be performed according to institutional guidelines or physician discretion. 
D. The peripheral blood CD34+ donor chimerism will be performed on days +60 and +90 (± 7 days) post-transplant until the 
CD34+ donor chimerism drops to ≤ 90%. In subjects receiving lenalidomide, the CD34+ donor chimerism will be 
performed at Days +60 and +120 (± 7 days) of lenalidomide therapy. Additional CD34+ donor chimerism testing will be 
performed at the discretion of the clinical investigator (e.g., when a subject develops peripheral blasts, worsening 
pancytopenia, or extramedullary relapse).  

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1. BACKGROUND 
This clinical trial provides an investigational therapeutic option to prevent disease relapse in 
patients with high risk AML and MDS after allo-HCT. 
1.1 
Acute Myelogenous Leukemia 
Acute myelogenous leukemia (AML) is a hematologic malignancy arising from a clonal 
hematopoietic stem cell and characterized by accumulation of malignant myeloblasts in the 
bone marrow and resulting in ineffective hematopoiesis. AML is the most common type of 
acute leukemia in adults in the United States, with over 11,000 new cases reported each 
year. 1   It is widely known that AML remits initially to conventional cytotoxic 
chemotherapy, but often relapses due to (1) genetic and epigenetic abnormalities conferring 
insensitivity to conventional cytotoxic agents, and (2) protective microenvironments that 
support leukemia cell survival and proliferation. 2,3 Whereas initial remission rates are 50-
80%, long-term disease-free survival is 20% in patients achieving a complete remission and 
less than 10% overall.1 Relapsed and refractory disease are major challenges. 
The prognosis for patients with AML relapsing after allo-HCT is very poor. The duration of 
first remission in relapsed patients is the most important prognostic factor correlating with 
the probability of second CR and survival.4 Patients with primary refractory and early 
relapsed disease with a CR duration < 6 months have a significantly poorer response to 
therapy and OS than do patients who relapsed after a first CR lasting ≥ 6 months (CR rate 
10%–30% vs. 40%–60%, respectively).5-8 The optimum strategy at the time of relapse for 
patients with resistant disease remains uncertain.  
1.2 
Myelodysplastic Syndromes 
The myelodysplastic syndromes (MDS) are a heterogeneous group of clonal neoplastic 
hematopoietic stem cell disorders. They are characterized by a hypercellular bone marrow, 
with dysplastic ineffective hematopoiesis resulting in peripheral blood cytopenias. MDS 
most often affects elderly people. The incidence of MDS is 50 per 100,000 in the population 
over age of 60, and it is the most common hematological malignancy in this age group.9 
Thirty to fifty percent of cases of MDS eventually evolve into AML, therefore this 
syndrome historically has been called oligoblastic leukemia, smoldering acute leukemia, or 
preleukemia.10 
The decision to treat MDS is generally based on age of the patient, performance status, and 
International Prognostic Scoring System (IPSS) score.11-13 While some patients with low 
risk disease and stable blood counts do not need immediate treatment and can be followed 
without therapy, others with Low and Intermediate-1 risk IPSS scores may require treatment 
to alleviate cytopenias and improve quality of life. Such patients are usually treated with low 
intensity approaches such as supportive care, including antibiotics, blood product 
transfusion, hematopoietic growth factors, immunosuppressants, immunomodulators, and 
inhibitors of angiogenesis. Epigenetic modulators, farnesyltransferase and tyrosine kinase 
inhibitors target molecular aberrations seen in later stages of MDS. Higher intensity 
therapies which aim at changing the natural history of disease are usually reserved for 
patients with excess myeloblasts (RAEB-1 and RAEB-2 disease) and Intermediate-2 and 
High risk IPSS scores. 

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Despite significant progress in treatment of advanced disease MDS (RAEB-1, RAEB-2, 
Intermediate-2 IPSS, High IPSS), the only curative therapy is allogeneic hematopoietic cell 
transplant, which is risky.14-19 In addition, few MDS patients are eligible for transplant due 
to co-morbidities and lack of suitable donors. Standard induction therapy for patients with 
advanced MDS include azanucleosides such as azacitidine (Vidaza®) and decitabine 
(Dacogen®), which exhibit dual properties as pyrimidine analogues and hypomethylating 
agents.20,21 These agents change the natural history of MDS, reduce transfusion 
requirements, extend survival, and delay progression to acute leukemia.20,22-25 However, 
only 20% of patients achieve complete and partial bone marrow remissions (CR+PR) and 
only 50% of patients achieve hematologic improvements. Moreover, in spite of any 
improvement nearly all MDS patients suffer from disease relapse and progression. 
Treatment for relapsed MDS after allo-HCT is poor. There is no standard therapy. Most 
patients are referred to clinical trials for investigational therapy. 13 If no clinical trial is 
available, best supportive care and hospice services are recommended. 
1.3 
Experience with Revlimid after allo-HCT in patients with Multiple Myeloma 
There is a limited amount of published data available about the feasibility of lenalidomide 
administration after allo-HCT in patients with multiple myeloma.  
Coman et al. showed that administration of lenalidomide at 25 mg/day (alone or in 
combination with dexamethasone) after allo-HSCT in patients with multiple myeloma was 
associated with high response rate, however led to the development or worsening of aGVHD 
in 31% patients. Importantly development of aGVHD was significantly associated with a 
stronger anti-myeloma response126. Alsina et al. reported similar findings demonstrating that 
maintenance therapy with lenalidomide in myeloma patients after allo-HSC is feasible. In 
this study lenalidomide was started at 10 mg/day and the doses were further escalated. The 
median time from allo-HSCT to lenalidomide initiation was 96 days and aGVHD developed 
in 37% patients with a cumulative incidence of grades III to IV aGVHD of 17% 2 27. 
However, Kneppers et al reported that even low doses of lenalidomide at 10 mg given for 21 
days of a 28-day schedule led to relatively high rates of its discontinuation, mainly because 
of aGVHD, which developed in 43%3 28. 
1.4 
 CD34+ mixed chimerism analysis  
The CD34+ chimerism analysis allows early identification of patients at a very high risk for 
relapse. Our preliminary data showed the ability of the CD34+ specific chimerism analysis 
to monitor MRD and identify of AML and MDS patients at a very high risk for hematologic 
relapse after allo-HCT. To obtain the CD34+ specific chimerism analysis, CD34+ cells from 
12 subjects were positively selected by immunomagnetic isolation from peripheral blood 
and processed by fluorescence-activated cell sorting. Purified CD34+ cells were 
subsequently evaluated for percentage of donor DNA contribution by short tandem repeat 
(STR) analysis. We were able to isolate CD34+ cells from peripheral blood with a very high 
purity (Figure 1) and in sufficient amount for a reliable STR testing analysis in all 12 study 
patients. The CD34+ specific donor chimerism analysis was repeated monthly until 
hematologic relapse or death occurred.  Simultaneously, conventional donor chimerism 
analysis was measured in the subpopulations of peripheral blood cells. Out of 12 enrolled 
subjects 6 subjects had hematologic relapse confirmed by a bone marrow evaluation. In 5 

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out of 6 patients with relapsed disease CD34+ specific chimerism dropped to <10% prior to 
confirmed hematologic relapse, whereas routine STR analysis in subpopulations of 
peripheral blood cells failed to convincingly demonstrate a significant decrease in 
donor/recipient chimerism (Figure 2). One patient (pt#7) with hematologic relapse steadily 
dropped the CD34+ specific donor chimerism down to 52%, however was lost to follow up 
with no further chimerism testing for the period of 3 months preceding hematologic relapse.   
Figure 1. CD34+ Chimerism cells 
 
Figure 2. Conventional and CD34+ donor chimerism monitoring in patients with (left 
column) and without (right column) hematologic relapse 
 
 
0
20
40
60
80
100
D30
D60
Donor/Recepient Chimersim %
Pt #2 
STR Gran
STR T-
cells
STR B-
cells
STR
CD34+
Relaspe
0
20
40
60
80
100
D30
D60
D90
D120
D150
Donor/Recepient Chimersim %
Pt #5 
STR
Gran
STR T-
cells
STR B-
cells
STR
CD34+
0
20
40
60
80
100
D30
D60
D90
Donor/Recepient Chimersim %
Pt # 3 
STR
Gran
STR T-
cells
STR B-
cells
STR
CD34+
Relaspe
0
20
40
60
80
100
D30
D60
D90
D120
D150
D180
D210
Donor/Recepient Chimersim %
Pt #10 
STR Gran
STR T-
cells
STR B-
cells
STR
CD34+
Purity of 
CD34+ cells - 
98.5% 

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21 
 
 
 
0
20
40
60
80
100
D30
D60
D90
Donor/Recepient Chimersim %
Pt # 4 
STR
Gran
STR T-
cells
STR B-
cells
STR
CD34+
Relaspe
0
20
40
60
80
100
D30
D60
D90
Donor/Recepient Chimersim %
Pt #13 
STR
Gran
STR T-
cells
STR B-
cells
STR
CD34+
0
20
40
60
80
100
D30
D60
D90 D120 D150 D180 D210 D240 D270 D300 D330 D360
Donor/Recepient Chimersim %
Pt # 7 
STR
Gran
STR T-
cells
STR B-
cells
STR
CD34+
Relaspe
Lost to 
follow 
up 
0
20
40
60
80
100
D30 D60 D90 D120D150D180D210D240D270D300D330D360D390D420D450
Donor/Recepient Chimersim %
Pt #6 
STR
Gran
STR T-
cells
STR B-
cells
STR
CD34+
0
20
40
60
80
100
D30
D60
D90
D120
D150
Donor/Recepient Chimersim %
Pt # 9 
STR
Gran
STR T-
cells
STR B-
cells
STR
CD34+
Relaspe
0
20
40
60
80
100
D30
D60
D90
D120 D150 D180 D210 D240 D270 D300 D330 D360
Donor/Recepient Chimersim %
Pt #8 
STR Gran
STR T-cells
STR B-cells
STR CD34+
0
20
40
60
80
100
D30
D60
Donor/Recepient Chimersim %
Pt # 11 
STR Gran
STR T-
cells
STR B-
cells
STR
CD34+
Relaspe
0
20
40
60
80
100
D30
D60
D90
D120
D150
D180
Donor/Recepient Chimersim %
Pt #12 
STR
Gran
STR T-
cells
STR B-
cells
STR
CD34+
? Relapse

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These results demonstrated the feasibility of using the CD34+ specific chimerism analysis to 
monitor MRD and timely detect an imminent hematologic relapse. The CD34+ specific STR 
analysis is superior to conventional chimerism analysis for MRD monitoring and 
identification of early relapse after allo-HCT. More importantly, drop of CD34+ specific 
chimerism occurred significantly earlier that decrease in chimerism assessed by 
conventional STR-based techniques. Therefore, the use of highly sensitive and specific 
MRD monitoring by the CD34+ chimerism analysis substantially increases the reliability 
of early MRD detection after allo-HCT allowing early therapeutic interventions and is 
potentially practice changing.  
2. STUDY AGENT 
2.1 
Lenalidomide 
2.1.1 Background  
Lenalidomide has both immunomodulatory and anti-angiogenic properties which could 
confer antitumor and antimetastatic effects.  Lenalidomide has been demonstrated to possess 
anti-angiogenic activity through inhibition of bFGF, VEGF and TNF-alpha induced 
endothelial cell migration, due at least in part to inhibition of Akt phosphorylation response 
to bFGF.29  In addition, lenalidomide has a variety of immunomodulatory effects.  
Lenalidomide stimulates T cell proliferation, and the production of IL-2, IL-10 and IFN-
gamma, inhibits IL-1 beta and IL-6 and modulates IL-12 production.30  Upregulation of T 
cell derived IL-2 production is achieved at least in part through increased AP-1 activity.31  
Although the exact antitumor mechanism of action of lenalidomide is unknown, a number of 
mechanisms are postulated to be responsible for lenalidomide’s activity against multiple 
myeloma.  Lenalidomide has been shown to increase T cell proliferation, which leads to an 
increase in IL-2 and IFN-gamma secretion.  The increased level of these circulating 
cytokines augment natural killer cell number and function, and enhance natural killer cell 
activity to yield an increase in multiple myeloma cell lysis.32 In addition, lenalidomide has 
direct activity against multiple myeloma and induces apoptosis or G1growth arrest in 
multiple myeloma cell lines and in multiple myeloma cells of patients resistant to 
melphalan, doxorubicin and dexamethasone.33  
2.1.1.1 Indications and Usage: 
Revlimid® (lenalidomide) is indicated for the treatment of patients with transfusion-
dependent anemia due to Low- or Intermediate-1-risk myelodysplastic syndromes associated 
with a deletion 5q cytogenetic abnormality with or without additional cytogenetic 
abnormalities.  Revlimid® is also approved in combination with dexamethasone for the 
treatment of patients with multiple myeloma that have received at least one prior therapy.  
2.1.2 Adverse Events 
Most frequently reported adverse events reported during clinical studies with lenalidomide 
in oncologic and non-oncologic indications, regardless of presumed relationship to study 
medication include: anemia, neutropenia, thrombocytopenia and pancytopenia, abdominal 
pain, nausea, vomiting and diarrhea, dehydration, rash, itching, infections, sepsis, 
pneumonia, urinary tract infection, upper respiratory infection, atrial fibrillation, congestive 

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heart failure, myocardial infarction, chest pain, weakness, hypotension, hypercalcemia, 
hyperglycemia, back pain, bone pain, generalized pain, dizziness, mental status changes, 
syncope, renal failure, dyspnea, pleural effusion, pulmonary embolism, deep vein 
thrombosis, cerebrovascular accident, convulsions, dizziness, spinal cord compression, 
syncope, disease progression, death not specified and fractures. 
2.1.3 Second New Cancers 
According to researchers, patients with cancer have a higher risk of developing a second 
new cancer when compared to people without cancer. In clinical studies of patients with 
newly diagnosed multiple myeloma, a higher number of second cancers were reported in 
patients treated with lenalidomide as induction therapy (treatment for several cycles to 
reduce number of cancer cells) and/or bone marrow transplant followed by lenalidomide for 
a long period of time compared to patients treated with induction therapy and/or bone 
marrow transplant then placebo (a capsule containing no lenalidomide). Patients should 
make their doctors aware of their medical history and any concerns they may have regarding 
their own increased risk of other cancers.  
Complete and updated adverse events are available in the Investigational Drug Brochure and 
the IND Safety Letters. 
2.1.4 Lenalidomide Description 
REVLIMID® (lenalidomide), a thalidomide analogue, is an immunomodulatory agent with 
anti-angiogenic properties.  The chemical name is 3-(4-amino-1-oxo 1,3-dihydro -2H-
isoindol-2-yl) piperidine-2,6-dione and it has the following chemical structure:  
Figure 3. Chemical Structure of Lenalidomide 
 
3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione 
The empirical formula for lenalidomide is C13H13N3O3, and the gram molecular weight is 
259.3.  
Lenalidomide is an off-white to pale-yellow solid powder. It is soluble in organic 
solvent/water mixtures, and buffered aqueous solvents. Lenalidomide is more soluble in 
organic solvents and low pH solutions. Solubility was significantly lower in less acidic 
buffers, ranging from about 0.4 to 0.5 mg/ml. Lenalidomide has an asymmetric carbon atom 
and can exist as the optically active forms S(-) and R(+), and is produced as a racemic 
mixture with a net optical rotation of zero. 
N
N
H
O
O
O
NH2

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2.1.5 Clinical Pharmacology 
2.1.5.1 Mechanism of Action:  
The mechanism of action of lenalidomide remains to be fully characterized. Lenalidomide 
possesses immunomodulatory and antiangiogenic properties.  Lenalidomide inhibited the 
secretion of pro-inflammatory cytokines and increased the secretion of anti-inflammatory 
cytokines from peripheral blood mononuclear cells.  Lenalidomide inhibited cell 
proliferation with varying effectiveness (IC50s) in some but not all cell lines.  Of cell lines 
tested, lenalidomide was effective in inhibiting growth of Namalwa cells (a human B cell 
lymphoma cell line with a deletion of one chromosome 5) but was much less effective in 
inhibiting growth of KG-1 cells (human myeloblastic cell line, also with a deletion of one 
chromosome 5) and other cell lines without chromosome 5 deletions.  Lenalidomide 
inhibited the expression of cyclooxygenase-2 (COX-2) but not COX-1 in vitro.   
2.1.6 Pharmacokinetics and Drug Metabolism 
2.1.6.1 Absorption: 
Lenalidomide, in healthy volunteers, is rapidly absorbed following oral administration with 
maximum plasma concentrations occurring between 0.625 and 1.5 hours post-dose. 
Co-administration with food does not alter the extent of absorption (AUC) but does reduce 
the maximal plasma concentration (Cmax) by 36%. The pharmacokinetic disposition of 
lenalidomide is linear. Cmax and AUC increase proportionately with increases in dose. 
Multiple dosing at the recommended dose-regimen does not result in drug accumulation. 
Pharmacokinetic analyses were performed on 15 multiple myeloma patients treated in the 
phase I studies.  Absorption was found to be rapid on both Day 1 and Day 28 with time to 
maximum blood levels ranging from 0.7 to 2.0 hours at all dose levels (5mg, 10mg, 25mg, 
and 50mg).  No plasma accumulation was observed with multiple daily dosing.  Plasma 
lenalidomide declined in a monophasic manner with elimination half-life ranging from 2.8 
to 6.1 hours on both Day 1 and 28 at all 4 doses.  Peak and overall plasma concentrations 
were dose proportional over the dosing range of 5mg to 50mg.33  Exposure (AUC) in 
multiple myeloma patients is 57% higher than in healthy male volunteers.  
2.1.7 Pharmacokinetic Parameters 
2.1.7.1 Distribution 
In vitro (14C)-lenalidomide binding to plasma proteins is approximately 30%. 
2.1.8 Metabolism and Excretion 
The metabolic profile of lenalidomide in humans has not been studied. In healthy volunteers, 
approximately two-thirds of lenalidomide is eliminated unchanged through urinary 
excretion. The process exceeds the glomerular filtration rate and therefore is partially or 
entirely active.  Half-life of elimination is approximately 3 hours.  
2.1.9 Supplier(s) 
Celgene Corporation will supply lenalidomide (Revlimid®) to study participants at no charge 
through Celgene’s Revlimid Risk Evaluation and Mitigation Strategy™ (REMS) (formerly 
known as RevAssist® Program).   

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2.1.10 Dosage form 
Lenalidomide will be supplied as capsules for oral administration.   
2.1.11 Packaging 
Lenalidomide will be shipped directly to the clinical site. Bottles will contain a sufficient 
number of capsules for one cycle of dosing.    
2.1.12 Labeling 
Lenalidomide supplies are dispensed in individual bottles of capsules.  Each bottle will 
identify the contents as study medication.  In addition, the label will bear Celgene’s name, 
quantity contained and the standard caution statement as follows:  “Caution: New drug - 
Limited by Federal law to investigational use.” Lenalidomide should not be handled by 
FCBP unless wearing gloves.  
The study drug label must be clearly visible.  Additional labels must not cover the Celgene 
label. 
2.1.13 Special Handling Instructions 
Females of childbearing potential should not handle or administer lenalidomide unless they 
are wearing gloves. 
2.1.14 Prescribing Information  
Lenalidomide (Revlimid®) will be provided to research subjects for the duration of their 
participation in this trial at no charge to them or their insurance providers.  Lenalidomide 
will be provided in accordance with the Celgene Corporation’s Revlimid REMS® program.  
Per standard Revlimid REMS® program requirements,  all physicians who prescribe 
lenalidomide for research subjects enrolled into this trial, and all research subjects enrolled 
into this trial, must be registered in, and must comply with, all requirements of the Revlimid 
REMS® program.   
Drug will be shipped on a per patient basis by the contract pharmacy to the clinic site for 
IND studies. Only enough lenalidomide for one cycle of therapy will be supplied to the 
patient each cycle. 
2.1.15 Pregnancy Testing    
Females must follow pregnancy testing requirements as outlined in the Revlimid REMS® 
program material.  
3. OBJECTIVES 
3.1 
Primary 
To determine safety and the maximum tolerated dose of lenalidomide after allo-HCT in 
AML and MDS subjects with MRD detected by the CD34+ mixed chimerism analysis. 
3.2 
Secondary 
To monitor changes in the CD34+ mixed chimerism after allo-HCT in AML and MDS 
subjects with detectable MRD in response to escalating doses of lenalidomide. 

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4. STUDY DESIGN 
4.1 
Overall Study Design 
This is an open-label, phase I study of lenalidomide in after allo-HCT in AML and MDS 
subjects with MRD detected by the CD34+ mixed chimerism analysis. The study is designed 
to evaluate the safety profile, maximum tolerated dose and biologic activity of lenalidomide 
in patients with AML and MDS after allo-HCT. Subjects will be recruited in cohorts of 3. 
Each subject will receive lenalidomide daily for 21 days per cycle for 2 cycles (42 days). 
Duration of each cycle is 28 days. The starting dose will be 2.5 mg given orally every other 
day. Subjects will be evaluated for DLTs from the first dose and until 14 days after the last 
dose of lenalidomide.   
4.2 
Dose Escalation 
The dose levels of lenalidomide will be as follows: 
• Dose Level 1:  2.5 mg PO QOD Day 1-21 for 28-day cycle X 2 cycles 
• Dose Level 2: 2.5 mg PO QD Day 1-21 for 28-day cycle X 2 cycles 
• Dose Level 3:  5 mg PO QD Day 1-21 for 28-day cycle X 2 cycles 
• Dose Level 4: 7.5 mg PO QD Day 1-21 for 28-day cycle X 2 cycles 
The dose escalation phase of the study will utilize a standard “3 + 3” design to estimate the 
MTD for lenalidomide. A description of the statistical characteristics (probabilities of 
halting or continuing dose escalation) of this design is provided in Appendix G: Statistical 
Characteristics of the “3+3” Design. For this study, MTD will be defined as the highest dose 
at which no more than 34% of the subjects observed at a given dose level experience a DLT. 
Subjects will be individually assessed for safety and DLTs for the purpose of determining 
the MTD. Three eligible subjects will be enrolled in sequential cohorts at increasing dose 
levels until at least one (1) DLT is seen between the first dose and 14 days after the last dose 
of lenalidomide. The following dose escalation rules will be used and applied:  
1. Three subjects are initially studied at each dose level. 
2. If none of these 3 subjects experience DLT, then the dose is escalated to the next 
dose level in 3 subsequent subjects. 
3. If 1 of these 3 subjects experiences DLT at the current dose, then up to 3 more 
subjects are recruited at the same dose level. 
a) If none of these 3 additional subjects experience DLT, then the dose is 
escalated to the next dose level in 3 subsequent subjects. 
b) If 1 or more of these 3 additional subjects experiences DLT, then the MTD is 
considered to have been exceeded and the previous dose level will be the 
MTD. 
4. If 2 or more of the initial 3 subjects at a dose level experience DLT, then the MTD is 
considered to have been exceeded and dose escalation will be stopped. Up to 3 more 
subjects are treated at the next lower dose.  
A subject must meet one of the following 3 criteria to be evaluable for dose-escalation 
decisions: 
1. Completed at least 21 days of lenalidomide without a DLT by 14 days after the last 
dose of lenalidomide;  

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2. Experienced a DLT between the first dose and 14 days after the last dose of 
lenalidomide; or 
3. Withdrawn from the study after at least 14 days of lenalidomide administration.  
The study ends when there is a maximum dose where 2 or more subjects out of 6 have a 
DLT, or when the maximum sample size of twenty-four (24) subjects has been reached. 
Figure 4 provides an example of how the MTD will be determined in Cycle 1. 
Figure 4. Dose Limiting Toxicity Flow Diagram 
 
 
 
Dose 1 
 
 
Dose 2 
Exceeded 
MTD ← 
DLT 
2/3 
3 Subjects 
DLT 
0/3 → 
3 Subjects 
 
 
 
DLT 
1/3 
 
 
 
 
 
 
↓ 
 
 
 
 
 
 
Dose 1 
 
 
Dose 2 
Exceeded 
MTD ← 
DLT 
≥ 2/6 
Add  
3 Subjects 
DLT 
1/6 → 
3 Subjects 
4.3 
Dose Limiting Toxicity 
DLT will be defined as any of the following adverse events that are not clearly unrelated to 
drug administration or treatment-emergent from lenalidomide and constitute a change from 
baseline irrespective of outcome. For the purpose of dose-escalation decisions and MTD 
determination, only DLTs that occur before 14 days after the last dose of lenalidomide 
administration will be taken into account. 
1. Grade 3 or greater nausea, diarrhea, or vomiting despite the use of maximal medical 
intervention; 
2. Grade 3 or greater acute GVHD despite the use of maximal medical intervention; 
3. Any other clinically significant nonhematologic toxicity of grade 3 or greater 
considered not related to the underlying disease or intercurrent illness; 
4. Grade 3 or greater neutropenia  
5. Grade 4 thrombocytopenia or platelet count  ≤50 thou/mm3 by day 28 of 
lenalidomide administration; or    
6. Any treatment-related effect leading to a subject missing 3 or more doses of 
lenalidomide. 
4.4 
Study Duration and Dates 
The subject recruitment period is approximately 36 months, starting last quarter 2015. The 
study duration encompasses the following: 
• Screening period of up to 14 days (+/- 7) days from Day +60; and 

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• The CD34+ donor chimerism will be performed on days +60 and +90 (± 7 days) 
post-transplant until the CD34+ donor chimerism drops to ≤ 90%. If the CD34+ 
donor chimerism continues to be > 90% by day +90 (± 7 days) post-transplant the 
patient will be removed from the study; 
• Treatment with lenalidomide will start within 10 days after detection of the CD34+ 
donor chimerism ≤ 90%  and be continued for 21 days in a 28-day cycle X 2 cycles 
or until terminating event occurs, whichever occurs first;  
• In subjects receiving lenalidomide, the CD34+ donor chimerism will be performed at 
Days +60 and +120 (± 7 days) of lenalidomide therapy. 
4.5 
Correlative Studies 
Peripheral blood will be collected to examine the CD34+ specific chimerism at the time-
points as described in the Schedule of Events. 
5. SELECTION OF SUBJECTS 
5.1 
Number of Subjects 
It is anticipated that up to 24 allo-HCT recipients with AML and MDS will receive 
lenalidomide in this study. Justification for sample size is provided in Section 13.1. Subjects 
in this study can be of any race, gender and ethnic group. 
5.2 
Inclusion Criteria 
1) Subjects must be at least 18 years of age; 
2) Subjects must be  60 (+/- 7) days post-allogeneic transplant from any donor source; 
3) Subjects must have either: 
a) High risk CD34+ AML (de novo or secondary, and any WHO 2008 
classification excluding acute promyelocytic leukemia, see Appendix A: 
AML WHO 2008 Classification System3). High risk AML is defined as (a) 
disease status beyond complete remission (CR) #1 at transplant or (b) 
treatment related AML or (c) presence of adverse cytogenetics including 
inv(3); t(3;3); t(6;9); t(v;11); -5 or del(5q); -7; abnl(17p) or complex 
karyotype; or 
b) High risk CD34+ MDS (WHO 2008 classification, see Appendix B: MDS 
WHO 2008 Classification System34). High risk is defined as (a) blast count 
≥5% at the time of transplant or (b) treatment related MD or (c) presence of 
adverse cytogenetics including -7/del7q or complex karyotype; 
4)  For AML subjects, they must have a documented CR within 45 days prior to allo-
HCT; 
5)  For MDS subjects, they must have < 20% myeloblasts in the bone marrow within 45 
days prior to allo-HCT; 
6) Subject Karnofsky performance status must be ≥ 70 (see Appendix E: Karnofsky 
Performance Status); 
7) Subjects must be platelet transfusion independent (Platelet transfusion independence 
is defined as 7 days  or greater without a platelet transfusion);   
8) Neutrophil count ≥ 1.0 thou/mm3 and platelet count ≥ 30 thou/mm3;  
9) Subjects must have total bilirubin ≤ 2 mg/dL; 

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10) Subjects must have serum AST and ALT levels ≤ 2.5 times upper limit of normal; 
11) Subjects must have serum creatinine < 2.5 times upper limit of normal and  a 
calculated creatinine clearance > 30 ml/min by Cockcroft-Gault formula (see 
Appendix I: Cockcroft-Gault Creatinine Clearance Calculation); 
12) All study participants who will receive lenalidomide based on the CD34+ chimerism 
testing must be registered into the mandatory Revlimid REMS® program, and be 
willing and able to comply with the requirements of the REMS® program; 
13) Females of child-bearing potential (i.e., women who are pre-menopausal or not 
surgically sterile) may participate, provided they meet the following conditions: 
a) Females of reproductive potential must adhere to the scheduled pregnancy 
testing as required in the Revlimid REMS® program; and   
14) Written, voluntary informed consent, willingness, and ability to comply with all 
study procedures. 
5.3 
Exclusion criteria 
1) CD34- AML or MDS; 
2) Subjects with peripheral blasts or progressive cytopenias will be excluded unless a 
CR or CRi confirmed by a bone marrow biopsy within two weeks post of the allo-
HCT; 
3) Inability to give informed consent; 
4) Uncontrolled active infection(s) requiring intravenous antibiotics;  
5) Known or suspected hypersensitivity to lenalidomide; 
6) Grade II-IV acute GVHD or extensive GVHD;  
7) Not able to swallow the lenalidomide capsule as a whole; or  
8) Female subjects who are pregnant or nursing.  
6. STUDY TREATMENT 
All subjects entering the screening phase will receive a unique subject number. This number 
will be used to identify the subject throughout the study. Subjects withdrawn from the study 
retain their subject number. New subjects will be assigned a new subject number.  
6.1 
Treatments to be Administered 
Lenalidomide will be administered for a total of 42 days. The starting dose will be 2.5 mg 
given orally every other day on days 1-21 of a 28-day cycle for 2 cycles.  Dose escalations 
and de-escalations will be made until the MTD is reached.  
To ensure subject safety in the dose-escalation portion of the study, an early stopping rule 
will be implemented in the event that a DLT rate of greater than 34% is observed at a dose 
level of 2.5 mg, the lowest dose level to be evaluated in this study. In the event a DLT rate 
of greater than 34% observed at the starting dose of 2.5 mg orally every other day, the study 
will be terminated. 
The dose levels of lenalidomide will be as follows: 
• Dose Level 1:  2.5 mg PO QOD Day 1-21 for 28-day cycle X 2 cycles 
• Dose Level 2:  2.5 mg PO QD Day 1-21 for 28-day cycle X 2 cycles 

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• Dose Level 3:  5 mg PO QD Day 1-21 for 28-day cycle X 2 cycles 
• Dose Level 4: 7.5 mg PO QD Day 1-21 for 28-day cycle X 2 cycles 
Doses should be taken at approximately the same time each day.   
Subjects must be instructed to swallow lenalidomide capsules whole with water at the same 
time each day.  Do not break, chew or open the capsules.   
If a dose of lenalidomide is missed, it should be taken as soon as possible on the same day.  
If it is missed for the entire day, it should not be made up. 
Subjects who take more than the prescribed dose of lenalidomide should be instructed to 
seek emergency medical care if needed and contact study staff immediately. 
6.2 
Instructions for initiation of lenalidomide   
Lenalidomide may begin if each of the following criteria are met: 
• The ANC is ≥ 1.0 thou/mm³;  
• The platelet count is ≥ 50 thou/mm³;  
• The CD34+ donor chimerism is < 90% at day +60 or +120 (± 7 days) post-
transplant.  
Lenalidomide dosing will continue as scheduled unless a DLT occurs. 
6.3 
Management of Toxicity 
Lenalidomide at higher doses can cause hematopoietic toxicities. Management of 
neutropenia, neutropenic fever, thrombocytopenia, anemia, bleeding, infection, nausea, 
vomiting, mucositis, enteritis, and/or diarrhea will follow standard guidelines within the 
institution. 
6.3.1 Hematopoietic Supportive Care 
Platelet transfusions should be given to maintain counts > 10,000/µL. Platelets should not be 
transfused electively on study if the patient has a platelet count ≥ 20,000/µL and has no 
other medical indication for platelet transfusion (for example, bleeding, surgical procedure). 
For patients with platelet count of < 20,000/µL, elective platelet transfusions will be given 
as necessary according to institutional guidelines (depending on the threshold level for 
transfusion at the institutions and individualized based on concurrent medical problems). 
All blood and platelet transfusions will be recorded on the CRF. 
6.4 
Method of Treatment Assignment 
The dose of lenalidomide will be assigned according to the dose escalation schedule in 
section 4.2 and the dose level description in section 6.1. 

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6.5 
Record of Administration 
Each subject will keep an accurate record of lenalidomide dosing on the Subject Dosing 
Diary. This diary will be kept in the research record as source documentation of 
lenalidomide dosing. Study personnel will review the dosing instructions with each subject 
at each study visit. Subjects will be asked to bring any unused drug and empty drug 
containers to the study site at the next visit for reconciliation with the Subject Dosing Diary.  
Any unused Revlimid® (lenalidomide) will be returned to the site for disposition in 
accordance with Celgene’s Revlimid Risk Evaluation and Mitigation Strategy™ (REMS) 
(formerly known as RevAssist® Program). 
7. CONCOMITANT MEDICATIONS 
7.1 
Concomitant Medications and Therapy 
Any therapy or medication (except study drug), administered from screening until 28 days 
after the last dose of study drug, is considered a concomitant therapy or medication. If the 
use of any concomitant treatments (medications or procedures) becomes necessary, the 
treatment must be recorded, including the name of the drug or treatment, dose, route, date, 
indication for use, and frequency of treatment. 
No other investigational drugs may be administered.  
Concomitant medications should be kept to a minimum during the study. However, if these 
are considered necessary for the study subject’s welfare and are unlikely to interfere with the 
study drug, they may be given at the discretion of the treating physician. Subjects may 
receive blood transfusions and ongoing supportive and palliative care (e.g., pain control) as 
clinically indicated throughout the study. Anti-emetics and other supportive medications 
such as antibiotics should be recorded on the CRF. The administration of prophylactic 
antimicrobials is left to the discretion of the treating physician. 
7.2 
Excluded Medications 
The following drugs are excluded: 
• azacitidine (Vidaza); 
• decitabine (Dacogen);  
• Other investigational drugs. 
7.3 
Immunosuppression 
All patients should receive standard GVHD prophylaxis per institutional guidelines per the 
treating physician. 
8. STUDY PROCEDURES 
8.1 
Protocol Procedures 
All subjects will have study-related procedures as described in the Schedule of Events table. 

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9. DATA MEASUREMENTS AND METHODS OF COLLECTION 
9.1 
Data Measurements 
9.1.1 Safety Data 
Safety variable for this study include the following: 
• DLTs; 
• Physical examinations including assessment of skin GVHD; 
• Vital signs; 
• Clinical laboratory measurements, including hematology and serum chemistry; and 
• Adverse events. 
9.1.2 Correlative Studies 
The CD34+ specific chimerism analysis from peripheral blood will be performed on days 
+60 and +90 (± 7 days) post-HCT until the CD34+ donor chimerism drops to < 90%  and/or 
on days +60 and +120 (± 7 days)  days after the initiation of lenalidomide. Additional 
CD34+ donor chimerism testing will be performed at the discretion of the clinical 
investigator (e.g., when a subject develops peripheral blasts, worsening pancytopenia, or 
extramedullary relapse). 
9.2 
Methods of Collection 
9.2.1 Sample Collection for Correlative Studies 
9.2.1.1 Blood Samples 
Peripheral blood samples will be obtained by venipuncture or from venous catheter (if in 
place) and will be collected at the same time as other laboratory assessments are drawn for 
necessary clinical care, if possible.  The risks of drawing blood from a vein include 
discomfort at the site of injection, bruising and/or swelling around the injection site, 
infection, or syncope from the procedure. 
Approximately 50 mL of blood will be collected at each time point for the CD34+ specific 
chimerism testing. 
9.2.2 Safety Measurements 
Safety measurements for this study include AEs, clinical laboratory measurements 
(hematology and blood chemistry), physical examination findings, GVHD assessments, and 
vital signs. 
9.2.2.1 Adverse Events 
Prior to initiation of lenalidomide therapy, only serious and non-serious adverse events 
deemed to be related or possibly related to study interventions will be recorded as adverse 
events for the study. Adverse events will be collected at each clinic visit based on 
observation and spontaneous reporting. 
9.2.2.2 Clinical Laboratory Measurements 
All clinical laboratory assessments are outlined in the Schedule of Events. 

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Hematology assessments will be performed at Screening and then weekly during 
lenalidomide administration and for 3 weeks after therapy is completed. The hematology 
assessments will include: 
• Complete blood count including hemoglobin, hematocrit, WBC absolute differential 
and platelet count. 
Blood chemistry assessments will be performed at screening and then weekly during 
lenalidomide administration. The chemistry assessments will include: 
• Electrolytes: (sodium, potassium, calcium, magnesium, phosphorous, bicarbonate, 
and chloride); 
• Renal function: (BUN, creatinine, and uric acid); 
• Liver function: SGOT (also known as AST), SGPT (also known as ALT), total 
bilirubin; and  
• Alkaline phosphatase. 
Serum pregnancy test for females of childbearing potential will be performed at Screening 
and must follow the pregnancy testing requirements as outlined in the Revlimid REMS® 
program material. 
Abnormal values and/or noteworthy changes will be graded according to the Common 
Terminology Criteria for Adverse Events v4.0 (CTCAE).  
Abnormalities of laboratory values: 
The Investigator shall classify laboratory values occurring outside of the normal range 
obtained for the safety assessment as: 
• “Abnormal, but not clinically significant” or 
• “Abnormal and clinically significant” 
Laboratory abnormalities should be judged as “clinically significant” if they lead to 
treatment modifications, therapeutic actions, or if additional diagnostic measures are 
required for their resolution and in the Investigator’s opinion is relevant for the clinical 
study. 
Each clinically relevant laboratory abnormality must be recorded as a separate AE if it fits 
within the AE criteria outlined in Section 10.1 of the protocol and is not already described 
by another documented AE. 
Hematology and serum chemistry assessments will be performed according to the standard 
operating procedures by the validated local laboratory. 
9.2.2.3 Physical Examination 
Targeted post-transplant physical examinations will also include vital signs (systolic and 
diastolic blood pressure, pulse rate, respiratory rate, and temperature) and aGVHD 
assessments. The aGVHD assessment will be assessed using established staging criteria (see 
Appendix F: Graft-versus-host-disease scales). Overall grading and response to GVHD 
therapy will be measured through the use of the consensus and IBMTR GVHD severity 
indices. GVHD assessments will be performed at screening and Days +60 & +90.  If 
lenalidomide is initiated, GVHD assessments will be performed weekly during scheduled 

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visits and continuing until 30 days after the last dose of lenalidomide.  GVHD assessments 
will also be documented at Day +60 and Day +120 after the initiation of lenalidomide 
10. ADVERSE EVENTS 
10.1 Definitions 
10.1.1 Adverse Event (AE) 
The term “adverse event” covers any sign, symptom, syndrome, or illness that appears or 
worsens in a subject during the period of observation in the clinical study and that may 
impair the wellbeing of the subject. The term also covers laboratory findings or results of 
other diagnostic procedures that are considered to be clinically significant (e.g., that requires 
unscheduled diagnostic procedures or treatment measures, or result in withdrawal from the 
study). 
The adverse event may be: 
• 
A new illness/condition; 
• 
Worsening of a sign or symptom of the condition under treatment, or of a 
concomitant illness/condition; 
• 
An effect of the study drug; or 
• 
A combination of 2 or more of these factors. 
No causal relationship with the study drug or with the clinical study itself is implied by the 
use of the term “adverse event.” 
Surgical procedures themselves are not adverse events; they are therapeutic measures for 
conditions that require surgery. The condition(s) for which the surgery is required may be an 
adverse event. Planned surgical measures permitted by the clinical study protocol and the 
condition(s) leading to these measures are not adverse events. 
When a clear diagnosis is available that explains the abnormal objective findings, this 
diagnosis will be recorded as an adverse event and not the abnormal objective findings (e.g., 
viral hepatitis will be recorded as the adverse event and not the transaminase elevation). If a 
definitive diagnosis is not available, then the sign(s) (e.g., clinically significant elevation of 
transaminase levels) or symptom(s) (e.g., abdominal pain) will be recorded as the adverse 
event. 
Adverse events fall into the categories “serious” and “nonserious.” 
10.1.2 Serious Adverse Event (SAE) 
A serious adverse event is one that at any dose of the study drug or at any time during the 
period of observation: 
• 
Results in death; 
• 
Is life-threatening; 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization; 
• 
Results in persistent or significant disability/incapacity; 
• 
Is a congenital anomaly/birth defect; or 
• 
Is medically important. 

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Life-threatening means 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 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 other adverse 
events may be considered serious because they jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. Examples of 
such events are: intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse. “Medically important” should be marked 
only if no other serious criteria are met. 
An “unexpected SAE” is any SAE for which the nature, specificity or severity is not 
consistent with the current Revlimid Investigator Brochure or in other risk information that 
has been given to the Investigator. 
Clarification of the difference in meaning between “severe” and “serious” 
The term “severe” is often used to describe the intensity (severity) of a specific event (as in 
mild, moderate, or severe myocardial infarction); the event itself, however, may be of 
relatively minor medical significance (such as severe headache). This is not the same as 
“serious,” which is based on the outcome or action criteria usually associated with events 
that pose a threat to life or functioning. Seriousness (not severity) serves as a guide for 
defining regulatory reporting obligations. 
10.1.3 Events not considered to be SAEs are hospitalizations for: 
• 
A standard procedure for protocol therapy administration. However, hospitalization 
or prolonged hospitalization for a complication of therapy administration will be 
reported as an SAE. 
• 
Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition. 
• 
The administration of blood or platelet transfusion as routine treatment of studied 
Indication.  However, hospitalization or prolonged hospitalization for a complication 
of such transfusion remains a reportable SAE. 
• 
A procedure for protocol/disease-related investigations (e.g., surgery, scans, 
endoscopy, sampling for laboratory tests, bone marrow sampling). However, 
hospitalization or prolonged hospitalization for a complication of such procedures 
remains a reportable SAE. 
• 
Hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE. 
• 
A procedure that is planned (i.e., planned prior to starting of treatment on study); 
must be documented in the source document and the CRF. Hospitalization or 
prolonged hospitalization for a complication remains a reportable SAE. 
• 
An elective treatment of or an elective procedure for a pre-existing condition 
unrelated to the studied indication. 

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• 
Emergency outpatient treatment or observation that does not result in admission, 
unless fulfilling other seriousness criteria above. 
If an AE is considered serious, both the AE CRF and the SAE Report Form must be 
completed.  For each SAE, the Investigator will provide information on severity, start and 
stop dates, relationship to investigational product (IP), action taken regarding IP, and 
outcome. 
10.1.4 Non-Serious Adverse Event 
A non-serious adverse event is any adverse event not meeting any of the serious adverse 
event criteria. 
10.1.5 Abnormal Laboratory Values 
The investigator must appraise all abnormal laboratory results for their clinical significance.  
If any abnormal laboratory result is considered clinically significant, the investigator must 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome. 
An abnormal laboratory value is considered to be an AE if the abnormality: 
• 
Results in discontinuation from the study; 
• 
Requires treatment, modification/ interruption of IP dose, or any other therapeutic 
intervention;  
• 
Or is judged to be of significant clinical importance. 
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as a SAE. If a laboratory abnormality is one component of a 
diagnosis or syndrome, then only the diagnosis or syndrome should be recorded on the AE 
CRF. If the abnormality was not a part of a diagnosis or syndrome, then the laboratory 
abnormality should be recorded as the AE. If possible, the laboratory abnormality should be 
recorded as a medical term and not simply as an abnormal laboratory result (e.g., record 
thrombocytopenia rather than decreased platelets). 
10.2 Period of Observation 
For the purpose of this study, the period of observation for adverse events starts on the day 
the subject signs informed consent. For subjects who fail screening, the period of 
observation ends on the date of screening failure. Treated subjects, including those who 
were prematurely discontinued from the study, will be followed for any adverse events that 
occur during the study from the time the subject signs the informed consent form until 28 
days (± 2 days) following the last dose of study treatment (i.e., the Follow-up Visit). 
However, if another course of anti-cancer therapy is initiated prior to the 28-day follow-up 
period visit, collection of adverse events will no longer be performed, with the exception of 
events that may be possibly, probably, or definitely related to the investigational agent or are 
clinically significant. 
10.3 Documenting and Reporting of Adverse Events by the Investigator 
Prior to initiation of the investigational agent, lenalidomide, only serious and non-serious 
adverse events deemed to be related or possibly related to study interventions will be 

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recorded and reported as adverse events for the study. Adverse events will be collected at 
each clinic visit based on observation and spontaneous reporting. 
Once lenalidomide is initiated, all adverse events that occur must be documented in the case 
report form.  
Toxicity will be scored using CTCAE Version 4.0 for toxicity and adverse event reporting.  
A copy of the CTCAE Version 4.0 can be downloaded from the CTEP homepage 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40).  All 
appropriate treatment areas should have access to a copy of the CTCAE Version 4.03.  All 
adverse clinical experiences, whether observed by the investigator or reported by the patient, 
must be recorded, with details about the duration and intensity of each episode, the action 
taken with respect to the test drug, and the patient’s outcome.  The investigator must 
evaluate each adverse experience for its relationship to the test drug and for its seriousness. 
The following approach will be taken for documentation and reporting: 
• 
All adverse events (whether serious or nonserious) must be documented on the 
“Adverse Event” page of the case report form. 
• 
For adverse events classified as serious (see Section 10.1.2) the Investigator must 
complete the “Serious Adverse Event” form at the time the SAE is detected. This 
form must be faxed to Celgene Drug Safety within 24 hours of discovery. All SAE's 
must also be reported to the IRB and DISC in accordance with the institution's 
policy. Serious and unexpected AE's must be reported to the appropriate regulatory 
agencies (e.g., FDA) by the sponsor to comply with regulatory requirements in 
accordance with 21 CFR parts 56 and 312.  
Every attempt should be made to describe the adverse event in terms of a diagnosis that 
encompasses the component signs and symptoms. If only nonspecific signs or symptoms are 
present, then these should be recorded as separate diagnoses on the pages of the case report 
form. 
All subjects who have adverse events, whether considered associated with the use of study 
drug or not, must be monitored to determine the outcome. The clinical course of the adverse 
event will be followed according to accepted standards of medical practice, even after the 
end of the period of observation, until a satisfactory explanation is found or the Principal 
Investigator considers it medically justifiable to terminate follow-up. Should the adverse 
event result in death, a full pathologist’s report should be supplied, if possible. 
10.3.1 Assessment of Causal Relationship of Study Drug 
The Investigator will provide an assessment of the potential causal relationship between 
adverse events and study medication by determining whether or not there is a reasonable 
possibility that the event was caused by the study medication. The relationship or 
association of the adverse event to the study medication will be characterized as not related, 
probably not related, possibly related, probably related, or related:   
Not Related: There is not a temporal relationship to the study drug administration or the 
adverse event is clearly due only to the progression of the underlying disease state, 
intercurrent illness, concomitant medication, concurrent therapy or other known cause. 

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Unlikely Related:  There is little or no chance that the study drug administration caused the 
adverse event; the event is most likely due to another competing cause, including 
intercurrent illness, progression or expression of the disease state, or a reaction to a 
concomitant medication or concurrent therapy appearing to explain the reported adverse 
event.  
Possibly Related:  The association of the adverse event with the study drug administration 
is unknown; however, the adverse event is not reasonably attributed to any other condition.  
Probably Related:  When a reasonable temporal relationship exists between the adverse 
event and the study drug administration; significant symptoms abate upon discontinuation of 
the study drug and there is a reasonable explanation based on known characteristics of the 
study drug and there is no clear association with preexisting disease or therapy, intercurrent 
illness, concurrent therapy or other factor(s). 
Related:  When the adverse event is a known side effect of the study drug or there is a 
temporal relationship to the administration of the study drug; or the adverse event reappears 
upon re-administration of the study drug (rechallenge); or the significant symptoms of the 
adverse event abate upon discontinuation of the study drug (dechallenge). 
10.3.2 Intensity of Adverse Events 
The intensity of adverse changes in physical signs or symptoms will be graded according to 
the CTCAE version 4. For all other adverse events not described in the CTCAE, the 
intensity will be assessed by the Investigator using the following categories: 
Mild (Grade 1) – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required. 
Moderate (Grade 2) – mild to moderate limitation in activity, some assistance may be 
needed; no or minimal medical intervention/therapy required. 
Severe (Grade 3) – marked limitation in activity, some assistance usually required; medical 
intervention/therapy required, hospitalization is possible. 
Life-threatening (Grade 4) – extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization or hospice care probable. 
Death (Grade 5) – the event resulted in death. 
10.3.3 Action Taken with Study Drug 
The action the Investigator took with study drug as a result of the event should be recorded 
as one of the following: 
None – No action was taken with regard to the study drug as a result of the adverse event. 
Interrupted – Study drug was stopped due to the adverse event, but was later resumed at 
the same dose. 
Dose decreased – The dose of study drug was decreased as a result of the adverse event. 
Permanently discontinued – The subject was withdrawn from the study due to the adverse 
event. 

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Only one item should be chosen. If multiple actions apply, the following “worst case” 
scenario hierarchy should be used to determine the preferred entry: 
Discontinued > dose decreased > therapy interrupted. 
10.3.4 Definition of Outcome 
The outcome of the AE should be recorded as 1 of the following: 
Resolved without sequelae – The subject fully recovered from the adverse event with no 
observable residual effects. 
Resolved with sequelae – The subject recovered from the adverse event with observable 
residual effects. 
Not resolved – The adverse event was present at the time of last observation. 
Death – The subject died as a result of the adverse event. 
10.4 Immediately Reportable Events 
10.4.1 Serious Adverse Events 
Serious adverse events (SAE) are defined above.  The investigator must inform Celgene in 
writing using a Celgene SAE form or MEDWATCH 3500A form of any SAE within 24 
hours of being aware of the event.  The written report must be completed and supplied to 
Celgene by facsimile within 24 hours/1 business day. All SAE's must also be reported to the 
IRB and DISC in accordance with the institution's policy per 21 CFR 56.  
The initial report must be as complete as possible, including an assessment of the causal 
relationship between the event and the investigational product(s).  Information not available 
at the time of the initial report (e.g., an end date for the adverse event or laboratory values 
received after the report) must be documented on a follow-up report.  A final report to 
document resolution of the SAE is required.  The Celgene tracking number RV-CL-AML-
PI-002987 and the institutional protocol number should be included on SAE reports (or on 
the fax cover letter) sent to Celgene.  A copy of the fax transmission confirmation of the 
SAE report to Celgene should be attached to the SAE and retained with the patient records. 
Serious and unexpected AEs that are at least possibly related to the study drug must be 
reported to the FDA in accordance with 21CFR 312.32 IND Safety Reports. 
Celgene Drug Safety Contact Information: 
Celgene Corporation      
Global Drug Safety and Risk Management    
Connell Corporate Park      
300 Connell Dr.  Suite 6000     
Berkeley Heights, NJ  07922        
Fax: (908) 673-9115 
E-mail: drugsafety@celgene.com 

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10.4.2 Other Events Requiring Immediate Reporting 
Any overdose of lenalidomide should be reported via an SAE form within 24 hours of being 
made aware of the event, regardless of association with an adverse event. In case the 
overdose did not result in any adverse event, the Investigator should report this as 
“overdose, no adverse event” on the SAE form and provide the intended amount, as well as 
the actual amount, of drug administered. In the event of overdose or exaggerated response, 
appropriate supportive measures should be employed. At this time, no specific additional 
measures or unique treatments are known or indicated for management of lenalidomide 
overdose. Actual treatment should depend on the severity of the clinical situation and the 
judgment and experience of the treating physician. 
10.5 Second Primary Malignancies 
Second Primary Malignancies (SPMs) are considered events of interest and should be 
included as part of the assessment of adverse events throughout the course of the study.  
Investigators are to report any second primary malignancies as serious adverse events 
regardless of causal relationship to lenalidomide, occurring at any time for the duration of 
the study   For all subjects who develop second primary malignancies, sites will be required 
to submit all diagnostic reports (e.g., pathology, cytogenetics, flow cytometry results) from 
the indication diagnostic confirmation samples submitted at screening and all reports for the 
tumor samples from the SPM diagnosis.  For SPMs diagnosed at another institution (outside 
the investigational site), sites are to make every effort to obtain these reports for the SPM 
confirmation. 
10.6 Pregnancies 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of 
age or disease state) of a female subject occurring while the subject is on lenalidomide, or 
within  28 days of the subject’s last dose of lenalidomide, are considered immediately 
reportable events. Lenalidomide is to be discontinued immediately. The pregnancy, 
suspected pregnancy, or positive pregnancy test must be reported to Celgene Drug Safety 
immediately by facsimile or email using the Pregnancy Initial Report Form. The female 
subject should be referred to an obstetrician-gynecologist, preferably one experienced in 
reproductive toxicity for further evaluation and counseling. 
The Investigator will follow the female subject until completion of the pregnancy, and must 
notify Celgene Drug Safety immediately about the outcome of the pregnancy (either normal 
or abnormal outcome) using the Pregnancy Follow-up Report Form.  If the outcome of the 
pregnancy was abnormal (e.g., spontaneous or therapeutic abortion), the Investigator should 
report the abnormal outcome as an AE. If the abnormal outcome meets any of the serious 
criteria, it must be reported as an SAE to Celgene Drug Safety immediately by facsimile, or 
other appropriate method, within 24 hours of the Investigator’s knowledge of the event 
using the SAE Report Form. 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 28 days that the Investigator suspects 
is related to the in utero exposure to the IP should also be reported to Celgene Drug Safety 
immediately by facsimile, or other appropriate method, within 24 hours of the Investigator’s 
knowledge of the event using the SAE Report Form.  

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10.6.1 Male Subjects 
If a female partner of a male subject taking investigational product becomes pregnant, the 
male subject taking lenalidomide should notify the Investigator, and the pregnant female 
partner should be advised to call their healthcare provider immediately. 
10.7 Investigator Reporting Responsibilities  
The conduct of the study will comply with all FDA safety reporting requirements.   
10.7.1 IND Annual Reports 
If the FDA has granted an IND number, it is a requirement of 21 CFR 312.33, that an annual 
report is provided to the FDA within 60-days of the IND anniversary date.  21 CRF 312.33 
provides the data elements that are to be submitted in the report.  The Annual Report should 
be filed in the study's Regulatory Binder, and a copy provided to Celgene Corporation as a 
supporter of this study as follows. 
 
Celgene Corporation 
 
Attn: Medical Affairs Operations 
 
Connell Corporate Park  
 
400 Connell Drive Suite 700 
 
Berkeley Heights, NJ  07922 
All adverse experience reports must include the patient number, age, sex, weight, severity of 
reaction (e.g., mild, moderate, severe), relationship to drug (e.g., probably related, unknown 
relationship, definitely not related), date and time of administration of test medications and 
all concomitant medications, and medical treatment provided.   The investigator is 
responsible for evaluating all adverse events to determine whether criteria for “serious” and 
as defined above are present.  The investigator is responsible for reporting adverse events to 
Celgene as described below. 
10.7.2 Investigator Reporting to the FDA 
Serious adverse events (SAEs) that are unlisted/unexpected, and at least possibly 
associated to the drug, and that have not previously been reported in the Investigators 
brochure, or reference safety information document should be reported promptly to the Food 
and Drug Administration (FDA) by telephone or by fax.  Fatal or life threatening SAEs that 
meet the criteria for reporting to the FDA must be reported to the FDA within 7 calendar 
days after awareness of the event.  All other SAEs that meet the criteria for reporting to the 
FDA must be reported to the FDA within 15 calendar days after awareness of the event.  A 
clear description of the suspected reaction should be provided along with an assessment as 
to whether the event is drug or disease related.    
10.7.3 Adverse event updates/IND safety reports 
Celgene shall notify the Investigator via an IND Safety Report of the following information: 
• Any AE associated with the use of drug in this study or in other studies that is both 
serious and unexpected. 
• Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity. 

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The Investigator shall notify his/her IRB/EC promptly of these new serious and unexpected 
AE(s) or significant risks to subjects. 
The Investigator must keep copies of all AE information, including correspondence with 
Celgene and the IRB/EC, on file (see Section 15.6 for records retention information). 
11. DISCONTINUATIONS 
11.1 Discontinuation of Subjects 
A subject must be discontinued from protocol-prescribed therapy under the following 
circumstances: 
• Consent withdrawal at the subject’s own request or at the request of their legally 
authorized representative; 
• Unacceptable toxicity or adverse event as determined by the Principal Investigator 
and/or subject; 
• Significant deviation from inclusion/exclusion criteria, in the opinion of the Principal 
Investigator; 
• If, in the Principal Investigator’s opinion, continuation in the study could be 
detrimental to the subject’s well-being; 
• Relapsed or progressive disease; 
• Initiation of chemotherapy for relapsed or progressive disease. 
If a female subject or the female partner of a male subject who is required to use defined 
contraceptive methods becomes pregnant after the study, the female subject or pregnant 
partner must be followed until the outcome of the pregnancy is known. 
As far as possible, all end-of-study examinations must be performed on all subjects who 
receive the study drug but do not complete the study according to protocol. All subjects who 
discontinue from protocol-prescribed therapy for any of the reasons above will be followed 
for a period of 30 days following the last day of study drug administration. 
11.2 Replacement of Subjects 
Subjects who are withdrawn prior to completion of 21 days of lenalidomide for any reason 
will be replaced.  
11.3 Study Stopping Rules 
To reduce the risk of exposing subjects to an excessively toxic dose level, a stopping rule 
will be implemented if more than 34% of subjects in a given lenalidomide dose cohort 
experience a DLT. The study ends when there is a dose where 2 or more subjects out of 6 
have a DLT, or when the maximum sample size of twenty-four (24) subjects has been 
reached. 
12. DATA AND SAFETY MONITORING 
12.1 Summary 
This protocol will be reviewed and monitored by the University of Florida Health Cancer 
Center (UFHCC) Data Integrity and Safety Committee (DISC).  This study will have at 
minimum semi-annual monitoring by the UFHCC DISC. Any adverse event fulfilling 

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expedited reporting requirements must be reported to the DISC coordinator within 5 
working days. The DISC coordinator will forward the report to the DISC Chairperson.  If 
there are any safety concerns, the chairperson will take appropriate action.  This may 
involve a request for additional information, or a request for an early, unscheduled meeting 
of the DISC. 
As part of the responsibilities assumed by conducting this study, the Principal Investigator 
(PI) agrees to maintain and have available for monitoring adequate case records (accurate 
source documents and CRFs) for the subjects treated under this protocol.  
The PI will be primarily responsible for monitoring of adverse events, protocol violations, 
and other immediate protocol issues. The study coordinator will collect information on 
subjects enrolled through the use of electronic or paper adverse event (AE) forms, CRFs, 
and Informed Consent forms.  
Identification of oversight responsibility: 
The PI has primary responsibility. 
The UFHCC DISC will meet at least semi-annually to review accrual, patterns and 
frequencies of all adverse events, protocol violations, and when applicable, internal audit 
results.  
Description of internal (PI) safety review and monitoring process: 
The PI and study team will meet biweekly to identify and review subject accrual, adverse 
events, and protocol violations.  
Adverse events will be reported along with all of the other collected data in the OnCore 
database. The PI or PI designee will report all adverse events to the UFHCC DISC and IRB 
per reporting guidelines.  
13. STATISTICAL METHODS 
The sections below provide an overview of the proposed statistical considerations and 
analyses. 
13.1 Determinations of Sample Size 
No formal sample size calculations were performed. It is estimated that up to 24 subjects 
will be enrolled in this study. Precise sample size cannot be defined, as it is dependent on the 
observed toxicity rate. A description of the statistical characteristics (probabilities of halting 
or continuing dose escalation) of the “3 + 3” design is provided in section 16.7 (Appendix 
G: Statistical Characteristics of the “3+3” Design). Cohorts of 3 to 6 subjects will be treated 
at each lenalidomide dose level until the MTD is reached or a total of 24 subjects have been 
evaluated. 
13.2 Analysis Populations 
13.2.1 Safety Population 
The safety population will consist of all subjects who received at least one dose of study 
drug and had at least one post-dose safety assessment. Safety summaries will include all 
subjects in the safety population. 

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13.2.2 Dose Limiting Toxicity Evaluable Population 
A subject is evaluable in dose-escalation decisions provided the subject has received at least 
five doses without a DLT, has experienced a DLT, or has been withdrawn from the study 
prior to completing of 21 days of lenalidomide due to a DLT. If a subject withdraws from 
the study without meeting these criteria, the subject will be replaced in that cohort. 
Tabulations of DLTs will only include the DLT-evaluable population.  
13.2.3 Efficacy Evaluable Population 
The efficacy population will include all subjects who receive at least 21 days of study drug 
and had at least one post-cycle efficacy assessment. 
13.3 Analysis Methods 
13.3.1 Safety 
Safety evaluation will include monitoring for adverse events, scheduled laboratory 
assessments, vital sign measurements, and physical examinations. The intensity of adverse 
changes in physical signs or symptoms will be graded according to the CTCAE version 4. 
For all other adverse events not listed in the CTCAE, the intensity of these events will be 
assessed by the Investigator using a 5-point scale as described in Section 10.3.2. 
The number of adverse events and the incidence of adverse events will be summarized. 
Adverse events will be summarized by maximum intensity (as described in Section 10.3.2) 
and relationship to study drug for each treatment group. Separate summaries will be 
provided for all adverse events, serious adverse events, treatment-related adverse events, and 
other significant adverse events (e.g., adverse events leading to study discontinuation). 
Clinical laboratory results will be listed by subject or, as appropriate, summarized 
descriptively by treatment group, which will include a display of change from baseline. 
Laboratory values outside of the normal ranges will be identified. Clinically significant 
hematologic laboratory abnormalities (i.e., meet Grade 3, 4, or 5 criteria according to 
CTCAE v.4) will be listed and summarized. 
Physical examination, vital sign, and GVHD data will be listed for each subject at each 
study visit. If appropriate, descriptive statistics for vital signs, both observed values and 
changes from baseline, will be summarized by treatment group. 
13.3.2 Efficacy 
All efficacy endpoints will be summarized descriptively using frequency distributions. In 
addition, 95% confidence intervals will be provided for the proportion of each 
response/improvement. 
14. EMERGENCY PROCEDURES 
14.1 Emergency Contact 
In emergency situations, the treating physician should contact the Principal Investigator by 
telephone at the number listed on the title page of the protocol. 

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14.2 Emergency Identification of Investigational Products 
This is an open-label study; therefore, study drug will be identified on the package labeling. 
14.3 Emergency Treatment 
During and following a subject’s participation in the study, the treating physician and/or 
institution should ensure that adequate medical care is provided to a subject for any adverse 
events, including clinically significant laboratory values, related to the study. 
15. ADMINISTRATIVE CONSIDERATIONS 
15.1 Good Clinical Practice 
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that the Principal Investigator and Co-
Investigators abide by Good Clinical Practice (GCP), as described in International 
Conference on Harmonization (ICH) Guideline E6, the US Code of Federal Regulations 
(CFR), and in accordance with the general ethical principles outlined in the Declaration of 
Helsinki. The study will receive approval from an Institutional Review Board (IRB) prior to 
commencement. The Principal Investigator will conduct all aspects of this study in 
accordance with applicable national, state, and local laws of the pertinent regulatory 
authorities. 
15.2 Delegation of Investigator Responsibilities 
The Principal Investigator will ensure that all persons assisting with the study are adequately 
informed about the protocol, any amendments to the protocol, the study treatments, and their 
study-related duties and functions. The Principal Investigator will maintain a list of Sub-
Investigators and other appropriately qualified persons to whom he has delegated significant 
study-related duties. 
15.3 Subject Information and Informed Consent 
The Principal Investigator or designee must obtain valid informed consent of a subject prior 
to any study related procedures occur as per GCP 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 will be recorded in the subject’s source documents. The 
original informed consent form will be signed and dated by the subject and by the person 
conducting the consent discussion prior to entry into the study. An informed consent 
document that includes information about the study and investigational drug will be 
prepared and given to each potential subject. This document will contain all ICH, GCP, and 
locally required regulatory elements. The document must be in a language understandable to 
the subject and must specify who informed the subject. The original informed consent form 
must be maintained in the Investigator’s study files. A copy of the informed consent 
document must be given to the subject.   
15.4 Confidentiality 
Each subject will be assigned a unique acrostic that will contain no protected health 
information. The Principal Investigator will retain a copy of the acrostic key in a locked 
office. Study files stored on a computer will be stored in accordance with local data 

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protection laws. Subjects will be told that the IRB, Data Integrity and Safety Committee, or 
regulatory authorities may inspect their medical records to verify the information collected, 
and that all personal information made available for inspection will be handled in strictest 
confidence and in accordance with local data protection law. 
15.5 Protocol Amendments 
Once the study has started, amendments should be made only in exceptional cases. The 
changes then become part of the study protocol. 
15.6 Record Retention 
Essential documents will be retained by the Principal Investigator for a minimum of 5 years 
have elapsed since study closure. Essential documents include the following: 
• Signed informed consent documents for all subjects; 
• Subject identification code list, screening log, and enrollment log; 
• Record of all communications between the Principal Investigator and the IRB; 
• Composition of the IRB; 
• Record of all communications between the Principal Investigator and the DISC; 
• Composition of the DISC; 
• List of Sub-Investigators and other appropriately qualified persons to whom the 
Principal Investigator has delegated significant study-related duties, together with 
their roles in the study, curriculum vitae, start/stop date(s) of participation, and their 
signatures; 
• Copies of CRFs and of documentation of corrections for all subjects (for electronic 
case report forms [eCRF], electronic files of the eCRF and audit trails will be utilized 
and provided to the site, as necessary); 
• Drug accountability records; 
• Record of any blood samples retained; and 
• Other source documents (subject records, hospital records, laboratory records, etc.). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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16. APPENDICES 
16.1 Appendix A: AML WHO 2008 Classification System3 
• Acute myeloid leukemia with recurrent genetic abnormalities 
o AML with t(8;21)(q22;q22); RUNX1-RUNX1T1 
o AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 
o APL with t(15;17)(q22;q12); PML-RARA 
o AML with t(9;11)(p22;q23); MLLT3-MLL 
o AML with t(6;9)(p23;q34); DEK-NUP214 
o AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1 
o AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1 
• Acute myeloid leukemia with myelodysplasia-related changes 
• Therapy-related myeloid neoplasms 
• Acute myeloid leukemia, not otherwise specified 
o AML with minimal differentiation 
o AML without maturation 
o AML with maturation 
o Acute myelomonocytic leukemia 
o Acute monoblastic/monocytic leukemia 
o Acute erythroid leukemia 
 Pure erythroid leukemia 
 Erythroleukemia, erythroid/myeloid 
o Acute megakaryoblastic leukemia 
o Acute basophilic leukemia 
o Acute panmyelosis with myelofibrosis 
• Myeloid sarcoma 
• Myeloid leukemia associated with Down syndrome 
 
 
 
 
 
 
 

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16.2 Appendix B: MDS WHO 2008 Classification System34 
Disease 
Blood 
Bone Marrow 
Refractory Cytopenia with 
Unilineage Dysplasia (RCUD): 
• 
Refractory Anemia (RA) 
• 
Refractory Neutropenia (RN) 
• 
Refractory Thrombocytopenia 
(RT) 
Unicytopenia or Bicytopenia 
No or rare blasts (< 1%) 
Unilineage dysplasia ≥ 10% 
< 5% blasts 
< 15% of erythroid are RS 
Refractory Anemia with Ringed 
Sideroblasts (RARS) 
Anemia 
No blasts 
≥ 15% of erythroid are RS 
Erythroid dysplasia only 
< 5% blasts 
Refractory Cytopenia with 
Multilineage Dysplasia (RCMD) 
Cytopenia(s) 
No or rare blasts (< 1%) 
No Auer rods 
Absolute monocyte count < 
1000 
Dysplasia in ≥ 10% of cells 
in ≥ 2 lineages 
< 5% blasts 
No Auer rods 
± 15% of erythroid are RS 
Refractory Anemia with Excess 
Blasts 1  
(RAEB-1) 
Cytopenia(s) 
< 5% blasts 
No Auer rods 
Absolute monocytes count < 
1000 
Unilineage or multilineage 
dysplasia 
5% - 9% blasts 
No Auer rods 
Refractory Anemia with Excess 
Blasts 2  
(RAEB-2) 
Cytopenia(s) 
5% - 9% blasts 
Auer rods ± 
Absolute monocytes count < 
1000 
Unilineage or multilineage 
dysplasia 
10% - 19% blasts 
Auer rods ± 
Myelodysplastic Syndromes 
Unclassifiable  
(MDS-U) 
Cytopenias 
< 1% blasts 
Dysplasia < 10% 
Cytogenetic abnl c/w MDS 
< 5% blasts 
MDS associated with del(5q) 
Anemia 
Platelets: normal or increased 
No or rare blasts (< 1%) 
Megas:  normal to increased 
< 5% blasts 
Isolated del(5q) 
No Auer rods 
 
 

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16.3 Appendix C: AML Response Criteria According to IWG35 
Hematologic Response According to IWG Criteria for AML 
Response Criterion 
Time of Assessment 
Neutrophils  
(µL) 
Platelets 
(µL) 
Bone 
Marrow 
Blasts (%) 
Other 
Early treatment 
assessment  
7-10 days after therapy 
NA  
NA  
<5  
 
Morphologic leukemia-
free state  
Varies by protocol  
NA  
NA  
<5 
Flow cytometry EMD  
Morphologic CR  
Varies by protocol  
>1,000  
>100,000  
<5  
Transfusion EMD  
Cytogenetic CR  
Varies by protocol  
>1,000  
>100,000  
<5  
Cytogenics—normal, 
EMD  
Molecular CR  
Varies by protocol  
>1,000  
>100,000  
<5  
Molecular—negative, 
EMD  
Partial remission  
Varies by protocol  
>1,000  
>100,000  
>50 or 
decrease to 
5-25  
Blasts <5% if Auer rod 
positive  
Key: AML=acute myelogenous leukemia; CR=complete remission; EMD=extramedullary disease; IWG=International Working 
Group; NA=not applicable 
 
 
 

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16.4 Appendix D: MDS Response Criteria According to IWG36 
Disease Remission 
 
Hematologic Improvements (HI) 
Category 
Response (at least 4 weeks) 
 
Category 
Response (at least 8 
weeks) 
CR 
BM ≤ 5% blasts, may have 
persistent dysplastic 
changes in marrow, normal 
CBC 
 
Erythroid 
Response 
(pre-rx Hgb < 
11) 
Hgb increase by ≥ 1.5, 
RBC tx reduction by 4 
units/8 wks 
PR 
Blasts decreased by ≥ 50%, 
but BM still has > 5% 
blasts 
 
Platelet 
Response 
(pre-rx PLT < 
100K) 
If starting with > 20K, 
then increase  
by ≥ 30K;  
If starting with < 20K, 
then > 100% increase 
(and over 20K) 
Marrow CR 
BM blasts ≤ 5% and 
decreased by ≥ 50%, if HI 
then noted individually 
 
SD 
No PR, but progression in 
> 8 wk 
 
Failure 
Progression to a more 
advanced class, worsened 
counts, death due to MDS 
 
Neutrophil 
Response 
(pre-rx ANC < 
100) 
At least 100% increase 
and absolute increase of 
500 
Relapse 
Return to pre-rx blasts, 
grans or plts decrease by ≥ 
50%, Hgb decrease by ≥ 
1.5 or tx dependent 
 
Progression or 
Relapse after 
HI 
 
At least 1 of the 
following: 
• 
At least 50% decrease 
from max response 
(ANC and PLTS) 
• 
Reduction of Hgb by 
1.5 
• 
Transfusion 
dependence 
Cytogenetic 
Response 
Complete: Disappearance 
of abnormality 
Partial: at least 50% 
reduction in abnormality 
 
Disease 
Progression 
≥ 50% increase in blasts, 
decreased counts by ≥ 50%, 
tx dependent 
 
Survival 
Endpoints:  
• 
Overall: death from 
any cause  
• 
Event free: failure or 
death from any cause  
• 
PFS: disease 
progression or death 
from MDS  
• 
DFS: time to relapse  
• 
Cause-specific death: 
death related to MDS 

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16.5 Appendix E: Karnofsky Performance Status 
Karnofsky Score 
Activity 
100 
Normal; no complaints; no evidence of disease. 
90 
Able to carry on normal activity; minor signs or symptoms of 
disease. 
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. 
60 
Requires occasional assistance, but is able to care for most of his 
personal needs. 
50 
Requires considerable assistance and frequent medical care. 
40 
Disabled; requires special care and assistance. 
30 
Severely disabled; hospital admission is indicated although death 
not imminent. 
20 
Very sick; hospital admission necessary; active supportive 
treatment necessary. 
10 
Moribund; fatal processes progressing rapidly. 
0 
Dead 
 
 

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16.6 Appendix F: Graft-versus-host-disease scales 
GVHD Staging 
Stage 
Skin 
GI 
Liver 
1 
< 25% rash 
Diarrhea > 500 mL/day 
or persistent nausea 
Bilirubin 2-3 mg/dL 
2 
25-50% 
> 1000 mL/day 
Bilirubin 3-6 mg/dL 
3 
> 50% 
> 1500 mL/day 
Bilirubin 6-15 mg/dL 
4 
Generalized 
erythroderma with bullae 
Large volume diarrhea 
and severe abdominal 
pain ± ileus 
Bilirubin > 15 mg/dL 
Consensus GVHD Grading  
Grade 
Skin 
GI 
Liver 
I 
Stage 1-2 
0 
0 
II 
Stage 3 or 
Stage 1 or 
Stage 1 
III 
----- 
Stage 2-4 
Stage 2-3 
IV 
Stage 4 
----- 
Stage 4 
 (Przepiorka, et. al., 1995)37 
 
CIBMTR GVHD Index  
Stage 
Skin 
GI 
Liver 
A 
Stage 1 
0 
0 
B 
Stage 0-2 or 
Stage 0-2 or 
Stage 0-2 
C 
Stage 3 or 
Stage 3 or 
Stage 3 
D 
Stage 4 or 
Stage 4 or 
Stage 4 
(Rowlings, et. al., 1997)38 

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16.7 Appendix G: Statistical Characteristics of the “3+3” Design 
Probabilities of Stopping or Continuing Dose Escalation for Given Probabilities of DLT 
Associated with the Dose Level 
 
True Probability of 
DLT at a Dose Level 
0.05 0.1 
0.2 
0.33 0.4 
0.5 
0.6 
0.67 0.7 
0.8 
Probability of Dose 
Escalation Based on 3  
or 6 Subjects (2 or 
more DLTs) 
0.97 0.91 0.71 0.43 0.31 0.17 0.08 0.04 0.03 0.01 
Probability of Ceasing 
Dose Escalation Based 
on 3 or 6 Subjects (2 
or more DLTs) 
0.03 0.09 0.29 0.57 0.69 0.83 0.92 0.96 0.97 0.99 
Probability Based on 
only 3 Subjects (0 
DLT) 
0.86 0.73 0.51 0.30 0.22 0.13 0.06 0.04 0.03 0.01 
Key: DLT = dose limiting toxicity 
The probability that dose escalation will cease is at least 92% when the DLT probability is > 
60%. If the true probability of DLT for a dose level is at least 34%, the probability of 
stopping dose escalation is at least 57%. If the true probability of DLT for a dose level is 
less than 10%, the probability of stopping dose escalation is less than 10%. The probability 
of dose escalation continuing is at least 91% when the DLT probability is < 10%. 
 
 
 
 

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16.8 Appendix H: RBC Transfusion Independence  
RBC transfusion independence and RBC transfusion dependence are defined according to 
modified IWG criteria,36 as described below: 
Definitions of RBC transfusion status at screening: 
• RBC transfusion independence: 
o Subjects with hemoglobin > 90 g/L (9.0 g/dL); 
o Subjects who received ≤ 1 RBC transfusion during the previous 8 weeks 
(56 days). 
• RBC transfusion dependence: 
o Subjects with hemoglobin ≤ 90 g/L (9.0 g/dL); 
o Subjects who received ≥ 2 RBC transfusions during the previous 8 weeks 
(56 days). 
 
 

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16.9 Appendix I: Cockcroft-Gault Creatinine Clearance Calculation 
For purposes of determining eligibility, creatinine clearance will be estimated using the 
Cockcroft-Gault formula as follows: 
 
Creatinine Clearance  = 
(140 – Age) x Weight (kg) x [0.85 if Female] 
72 x Serum Creatinine (mg/dL) 
 
 
 
 
 
 

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