A Phase 2 Study of Ibrutinib Maintenance After Reduced-Intensity Conditioning and Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia
Phase: PHASE2
Conditions: Acute Biphenotypic Leukemia, Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Hematopoietic Cell Transplantation Recipient
Sponsor: Andrew Rezvani

A Phase 2 Study of Ibrutinib Maintenance After Reduced-Intensity Conditioning and Allogeneic 
Hematopoietic Cell Transplantation for Acute Leukemia 
 
IRB-38934 
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A Phase 2 Study of Ibrutinib Maintenance After Reduced-Intensity Conditioning 
and Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia 
Coordinating Center 
Stanford Cancer Institute 
875 Blake Wilbur Dr 
Stanford, CA 94305 
Protocol Director and Lead Principal Investigator   
Andrew R Rezvani, MD  
Stanford University 
300 Pasteur Dr, 
 
Stanford, CA 94305 
Telephone:  650-725-4077;  Fax:  650-725-8950 
arezvani@stanford.edu  
Coordinating Center Sub-Investigators 
David Miklos, MD, PhD  
Stanford University 
300 Pasteur Dr, 
 
Stanford, CA 94305 
Tel:   650-725-4959;  Fax:  650-498-6159 
Email:  dmiklos@stanford.edu 
Principal Investigators 
Leyla Shune, MD  
The University of Kansas Medical Center 
 
Westwood, KS 66205 
Tel:  
 
Email: lshune@kumc.edu 
Biostatistician 
, PhD  
Stanford University 
HRP Redwood Building, 
 
150 Governor's Lane 
Stanford, CA 94305 
Tel:  
;  Fax:  
 
Email:  
@stanford.edu  
Lead Study Coordinator 
, RN  
Stanford University 
300 Pasteur Dr, 
 
Stanford, CA 94305 
Tel:  
;  Fax:  
 
@stanford.edu   
Version Date:  23 November 2020 
 
NCT03267186 

A Phase 2 Study of Ibrutinib Maintenance After Reduced-Intensity Conditioning and Allogeneic 
Hematopoietic Cell Transplantation for Acute Leukemia 
 
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TABLE OF CONTENTS 
 
PROTOCOL SYNOPSIS ................................................................................................. 4 
SCHEMA ......................................................................................................................... 6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  ......................................... 7 
1. OBJECTIVES ........................................................................................................... 8 
1.1. PRIMARY OBJECTIVE ............................................................................................. 8 
1.2. SECONDARY OBJECTIVES ...................................................................................... 8 
2. BACKGROUND ........................................................................................................ 8 
2.1 STUDY DISEASE ..................................................................................................... 8 
2.2 STUDY AGENT/DEVICE/PROCEDURE ........................................................................ 8 
2.3 RATIONALE .......................................................................................................... 10 
2.4 STUDY DESIGN .................................................................................................... 10 
3. PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES ...................... 10 
3.1 INCLUSION CRITERIA ............................................................................................ 10 
3.2 EXCLUSION CRITERIA ........................................................................................... 12 
3.3 INFORMED CONSENT PROCESS ............................................................................. 13 
3.4 STUDY TIMELINE .................................................................................................. 13 
4. TREATMENT PLAN ............................................................................................... 14 
4.1 GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ............. 15 
4.2 CRITERIA FOR REMOVAL FROM STUDY ................................................................... 18 
4.3 ALTERNATIVES ..................................................................................................... 18 
5. INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION.................. 18 
5.1  INVESTIGATIONAL AGENT/DEVICE/PROCEDURE ...................................................... 18 
5.2 AVAILABILITY ....................................................................................................... 23 
5.3 AGENT ORDERING ................................................................................................ 23 
5.4 AGENT ACCOUNTABILITY ...................................................................................... 23 
6. DOSE MODIFICATIONS ........................................................................................ 24 
6.1 TREATMENT DISCONTINUATION ............................................................................. 23 
7. ADVERSE EVENTS AND REPORTING PROCEDURES ...................................... 26 
7.1 POTENTIAL ADVERSE EVENTS ............................................................................... 27 
7.2 ADVERSE EVENT REPORTING ................................................................................ 27 
8. CORRELATIVE/SPECIAL STUDIES ..................................................................... 32 
9. STUDY CALENDAR ............................................................................................... 36 
10. MEASUREMENT .................................................................................................. 37 
10.1  PRIMARY AND SECONDARY OUTCOME MEASURES ................................................ 37 
11. REGULATORY CONSIDERATIONS .................................................................... 38 
11.1 INSTITUTIONAL REVIEW OF PROTOCOL ................................................................. 38 
11.2 DATA AND SAFETY MONITORING PLAN ................................................................. 38 

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11.3 DATA MANAGEMENT PLAN .................................................................................. 38 
11.4 CONFIDENTIALITY ............................................................................................... 39 
11.5 REPORTING MECHANISMS ................................................................................... 40 
12. STATISTICAL CONSIDERATIONS...................................................................... 40 
12.1 STATISTICAL DESIGN .......................................................................................... 40 
12.2 INTERIM ANALYSES ............................................................................................. 41 
12.3 ANALYSIS POPULATION ....................................................................................... 41 
12.4 ACCRUAL ESTIMATES ......................................................................................... 41 
13. REFERENCES ...................................................................................................... 43 
APPENDICES ............................................................................................................... 45 
APPENDIX A:  PRE-TRANSPLANT ELIGIBLITY CHECKLIST .................................................. 45 
APPENDIX B:  SECONDARY CRITERIA TO CONTINUE TO IBRUTINIB TREATMENT .................. 47 
APPENDIX C:  GRADING OF ACUTE GRAFT-VS-HOST DISEASE ......................................... 50 
APPENDIX D:  ASSESSMENT OF CHRONIC GRAFT-VS-HOST DISEASE ............................... 51 
APPENDIX E:  INHIBITORS AND INDUCERS OF CYP3A ...................................................... 57 
APPENDIX F:  CHILD-PUGH SCORING CRITERIA .............................................................. 59 
 
Table of Tables 
Table 1:  Most frequently reported treatment-emergent adverse events (TEAEs)  .. 21 
Table 2:  Ibrutinib Dose Modifications ...................................................................... 25 
Table 3:  Schedule of correlative laboratory studies ................................................ 33 
 
 

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PROTOCOL SYNOPSIS 
TITLE 
A Phase 2 Study of Ibrutinib Maintenance After 
Reduced-Intensity Conditioning and Allogeneic 
Hematopoietic Cell Transplantation for Acute Leukemia 
STUDY PHASE 
Phase 2 
INDICATION 
Prevention of relapse in subjects with acute leukemias 
undergoing reduced-intensity conditioning and allogeneic 
hematopoietic cell transplantation 
INVESTIGATIONAL 
PRODUCT 
Ibrutinib 
PRIMARY 
OBJECTIVE(S) 
To reduce the incidence of relapse at 18 months after RIC 
and allogeneic HCT for AML, ALL, and CML in blast crisis 
from 45% to 25% 
SECONDARY 
OBJECTIVE(S) 
• To study the incidence and severity of post-transplant 
complications in subjects receiving ibrutinib maintenance 
after allogeneic HCT. 
• To study the incidence of infectious complications in 
subjects receiving maintenance ibrutinib after allogeneic 
HCT. 
• To study the impact of ibrutinib maintenance on minimal 
residual disease after RIC and allogeneic HCT. 
• To study the impact of maintenance ibrutinib on immune 
reconstitution and alloreactivity after allogeneic HCT, 
specifically on Th1/Th2 polarization, T follicular cell 
number, T- and B-cell repertoire, serum immunoglobulin 
levels, and alloantibody formation. 
INCLUSION CRITERIA • Diagnosis of acute myeloid leukemia (AML), acute 
biphenotypic leukemia, or acute lymphoblastic leukemia 
(ALL).  CML transformed to blast crisis is eligible. 
• Planned allogeneic HCT using FLU/MEL or FLU/BU 
conditioning (regimens defined in protocol). 
• Planned GvHD prophylaxis consisting of TAC/MTX or 
TAC/SRL (regimens defined in protocol). 
• HLA-identical sibling donor, HLA-matched unrelated 
donor, or donor mismatched at 1 HLA allele or antigen. 
• Less than or equal to 5% blasts on bone marrow 
examination within 60 days of starting conditioning. 
• Age ≥ 18 years and ≤ 70 years. 
• Able to give informed consent. 

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EXCLUSION 
CRITERIA 
• Active involvement of the central nervous system with 
malignancy (previous CNS involvement is allowed if 
clearance of CNS disease has been documented prior to 
enrollment) 
• Pregnant or breastfeeding 
• Karnofsky Performance Status < 60% 
• Active leukemia (> 5% leukemic blasts in peripheral 
blood or bone marrow) 
• Non-hematologic malignancy with a life expectancy of 
< 5 years 
• Known history of human immunodeficiency virus (HIV) or 
active hepatitis C virus (HCV) or hepatitis B virus (HBV) 
infection.  Subjects who are positive for hepatitis B core 
antibody or hepatitis B surface antigen must have a 
negative polymerase chain reaction (PCR) result before 
enrollment.  Those who are PCR-positive will be 
excluded. 
• Known bleeding disorders (eg, von Willebrand’s disease) 
or hemophilia. 
• History of other malignancies, except:  
o Malignancy treated with curative intent and with no 
known active disease present for ≥ 3 years before the 
first dose of study drug and felt to be at low risk for 
recurrence by treating physician. 
o Adequately treated non-melanoma skin cancer or 
lentigo maligna without evidence of disease. 
o Adequately treated carcinoma in situ without evidence 
of disease.  
TREATMENT 
SUMMARY 
Subjects will be treated with ibrutinib 420 mg orally once 
daily, starting between Day +60 and Day +90 after 
allogeneic HCT and continuing until 18 months 
post-transplant 
SAMPLE SIZE  
50 subjects enrolled and treated 
STATISTICAL 
CONSIDERATIONS 
Screening and enrollment of 50 subjects will provide 
84% power to detect a decrease in the incidence of relapse 
at 18 months post-transplant from 45% to 25% 
 

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SCHEMA 
 
 
 
Reduced-Intensity Conditioning Regimens: 
Fludarabine/Busulfan (FLU/BU) 
- 
Fludarabine (120 to 180 mg/m2) 
- 
Busulfan (≤ 8 mg/kg PO or 6.4 mg/kg IV) 
 
Fludarabine/Melphalan (FLU/MEL) 
- 
Fludarabine (120 to 180 mg/mg2) 
- 
Melphalan (≤ 150 mg/m2) 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ALL 
Acute lymphoblastic leukemia 
AE 
Adverse event 
AML 
Acute myeloid leukemia 
BCR 
B-cell receptor 
BTK 
Bruton’s tyrosine kinase 
BU 
Busulfan 
CBC 
Complete blood count 
CLL 
Chronic lymphocytic leukemia 
CNS 
Central nervous system 
CRF 
Case report/Record form 
CR 
Complete response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMB 
Data Safety Monitoring Board 
FLU 
Fludarabine 
GvHD 
Graft-vs-host disease 
GI 
Gastrointestinal 
HCT 
Hematopoietic cell transplantation 
Hgb 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 
HTN 
Hypertensions 
IRB 
Institutional Review Board 
ITK 
Interleukin-2-inducible T-cell kinase 
IV 
Intravenous 
MCL 
Mantle cell lymphoma 
MEL 
Melphalan 
MTX 
Methotrexate 
NRM 
Non-relapse mortality 
OS 
Overall survival  
PLT 
Platelet 
PFS 
Progression-free survival  
PR 
Partial response 
RIC 
Reduced-intensity conditioning 
RR 
Response rate 
SAE 
Serious adverse event 
SRL 
Sirolimus 
TAC 
Tacrolimus 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WHO 
World Health Organization 
 

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1. 
OBJECTIVES 
1.1 
Primary Objective  
• To reduce the incidence of relapse at 18 months after RIC and allogeneic HCT 
for AML, ALL, and CML in blast crisis from a historical baseline of 45% to 25%, 
using ibrutinib maintenance therapy. 
1.2 
Secondary Objectives 
 
• To study the incidence and severity of post-transplant complications in subjects 
receiving ibrutinib maintenance after allogeneic HCT. 
• To study the incidence of infectious complications in subjects receiving 
maintenance ibrutinib after allogeneic HCT. 
• To study the impact of ibrutinib maintenance on minimal residual disease after 
RIC and allogeneic HCT. 
• To study the impact of maintenance ibrutinib on immune reconstitution and 
alloreactivity after allogeneic HCT, specifically on Th1/Th2 polarization, T 
follicular cell number, T- and B-cell repertoire, serum immunoglobulin levels, and 
alloantibody formation. 
2. 
BACKGROUND 
2.1 
Allogeneic hematopoietic cell transplantation in acute leukemia 
Allogeneic HCT is frequently performed with curative intent in patients with AML and 
ALL.  Reduced-intensity conditioning is utilized in older patients, or in those with 
significant medical comorbidities, in order to reduce the risk of regimen-related toxicity 
and mortality.  However, leukemia relapse after RIC and allogeneic HCT is the most 
common cause of treatment failure in this patient population.  Patients receiving RIC are 
generally thought to have a higher risk of relapse compared to those receiving 
high-dose conditioning (1, 2).  The incidence of post-transplant relapse in this setting is 
approximately 45% with current transplant approaches (1-6).  
2.2 
Ibrutinib 
Ibrutinib is a first-in-class, potent, orally-administered, covalently-binding inhibitor of 
Bruton’s tyrosine kinase (BTK).  Inhibition of BTK blocks downstream B-cell receptor 
(BCR) signaling pathways and thus prevents B-cell proliferation.  In vitro, ibrutinib 
inhibits purified BTK and selected members of the kinase family with 10-fold specificity 
compared with non-BTK kinases Ibrutinib (Imbruvica) is approved by the U S Food and 
Drug Administration (FDA) for the treatment of:  1) mantle cell lymphoma (MCL) in 
patients who have received at least one prior therapy based on overall response rate;   
2) chronic lymphocytic leukemia (CLL) in patients who have received at least one prior 
therapy;   3) CLL in patients with 17p deletion;  and 4) Waldenström macroglobulinemia.  
Ibrutinib is currently under investigation in various indications.  It is not currently 
approved as a maintenance therapy for acute leukemia following allogeneic HCT, so 
this clinical trial requires an Investigational New Drug (IND) application. 
B-cells are lymphocytes with multiple functions in the immune response, including 
antigen presentation, antibody production, and cytokine release.  B-cells express cell 

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surface immunoglobulins comprising the B-cell receptor (BCR), which is activated by 
binding to antigen.  Antigen binding induces receptor aggregation and the clustering and 
activation of multiple tyrosine kinases, which in turn activate further downstream 
signaling pathways (7).  
The process of B-cell maturation, including immunoglobulin chain rearrangement and 
somatic mutation, is tightly regulated.  It is thought that B-cell lymphomas and CLL 
result from mutations and translocations acquired during normal B-cell development (8).  
Several lines of evidence suggest that signaling through the BCR is necessary to 
sustain the viability of B-cell malignancies.   
The role of BTK in BCR signal transduction is demonstrated by the human genetic 
immunodeficiency disease X-linked agammaglobulinemia and the mouse genetic 
disease X-linked immunodeficiency, both caused by a mutation in the BTK gene.  These 
genetic diseases are characterized by reduced BCR signaling and a failure to generate 
mature B-cells.  The BTK protein is expressed in most hematopoietic cells with the 
exception of T-cells and natural killer cells, but the selective effect of BTK mutations 
suggests that its primary functional role is in antigen receptor signaling in B-cells (9).  
Data from Study PCYC-04753 demonstrate that although ibrutinib is rapidly eliminated 
from the plasma after oral administration, once daily dosing with ibrutinib is adequate to 
sustain maximal pharmacodynamic activity for 24 hours post-dose at dose levels 
≥ 2.5 mg/kg.  In Study PCYC-04753, the BTK occupancies for the 2.5 mg/kg/day to 
12.5 mg/kg/day cohorts and for the 560 mg continuous dosing cohort, were all above 
90% at either 4 or 24 hours after drug administration. 
Pre-clinical data suggest that ibrutinib may have direct anti-tumor activity in AML.  The 
drug’s target, BTK, is constitutively activated in many forms of AML, and BTK inhibition 
with ibrutinib prevents AML blast proliferation in pre-clinical studies (10).  Ibrutinib has 
also been shown to inhibit SDF1/CXCR4 interactions, thus interfering with the migration 
of leukemic cells and potentially rendering them more vulnerable to cytotoxic 
chemotherapy or graft--vs-leukemia effects by separating the leukemic cells from their 
protected niche (11).  Given the activity of ibrutinib against B-cells, this compound is 
also under active investigation for its anti-tumor effects in acute B-lymphoblastic 
leukemias (12). 
Recent studies show that B-cells are key mediators of chronic GvHD.  Dysfunctional 
B-cells have been identified in chronic GvHD, where patients have a relatively higher 
number of activated memory B-cells, higher levels of B-cell-activating factor of the tumor 
necrosis family (BAFF), and donor-derived alloantibodies (13).  It has been 
demonstrated that pathogenic antibody deposition occurs in human chronic GvHD, and 
a network of alloreactive T-helper cells, including Th1, Th2, Th17 and Tfh (T-follicular 
helper) cells infiltrate tissues and produce effector cytokines thereby causing antibody 
deposition and tissue fibrosis, similar to autoimmunity.  In addition, genetic studies 
confirmed that ITK and BTK are independently critical for chronic GvHD.  Ibrutinib, 
which hits both targets, showed effectiveness in both T-cell-driven and 
alloantibody-driven chronic GvHD models.  Ibrutinib treatment delayed progression, 
improved survival and ameliorated clinical and pathological manifestations in mouse 
models of sclerodermatous and alloantibody-driven chronic GvHD (14). 

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2.3 
Rationale 
This study is designed to test the hypothesis that ibrutinib maintenance therapy will 
reduce the incidence of post-transplant relapse in subjects receiving RIC and allogeneic 
HCT for AML and ALL.  The rationale for the use of ibrutinib in this setting is twofold:  
ibrutinib may have direct anti-tumor effects against both AML and ALL, as described 
above; and ibrutinib may potentiate the immunologic graft--vs-leukemia effect driven by 
donor T-cells after allogeneic HCT.  In addition to the BTK-mediated effects of ibrutinib, 
the compound is known to inhibit ITK, a tyrosine kinase which plays a central role in 
T-cell differentiation (15).  By inhibiting ITK, ibrutinib may drive donor T-cells toward a 
Th1 phenotype, which is hypothesized to generate more effective graft--vs-leukemia 
reactions. 
2.4 
Study Design 
This is a treatment, single-group, single-intervention, open-label, non-randomized 
efficacy trial. 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
Refer to the Participant Eligibility Checklists in Appendices A & B.  Eligibility will 
be assessed initially before allogeneic HCT, and second confirmation of eligibility 
will be assessed prior to the administration of ibrutinib, between Day +60 and 
Day +90 after allogeneic HCT. 
3.1 
Inclusion Criteria  
3.1.1 Inclusion Criteria for enrollment (pre-transplant) 
• Diagnosis of acute myeloid leukemia (AML), acute biphenotypic leukemia, or 
acute lymphoblastic leukemia (ALL).  CML transformed to blast crisis is eligible. 
• Planned allogeneic HCT using FLU/MEL or FLU/BU conditioning (regimens 
defined below). 
• Planned GvHD prophylaxis consisting of TAC/MTX or TAC/SRL (regimens 
defined below). 
• HLA-identical sibling donor, HLA-matched unrelated donor, or donor mismatched 
at 1 HLA allele or antigen. 
• Less than or equal to 5% blasts on bone marrow examination within 60 days of 
starting conditioning. 
• Age ≥ 18 years and ≤ 70 years. 
• Able to give informed consent. 
Subjects will be eligible if their planned conditioning regimen for allogeneic HCT 
consists of one of the two following standard reduced-intensity conditioning regimens: 
• FLU/MEL:  Fludarabine 120 to 180 mg/m2;  melphalan ≤ 150 mg/m2 
• FLU/BU:  Fludarabine 120 to 180 mg/m2;  busulfan ≤ 8 mg/kg orally or 
≤ 6.4 mg/kg intravenously 

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Subjects will be eligible if their planned post-grafting immunosuppression consists of 
one of the two following regimens: 
• TAC/MTX:  Tacrolimus (oral or intravenous) and intravenous methotrexate 
administered according to institutional standard practice. 
• TAC/SRL:  Tacrolimus (oral or intravenous) and oral sirolimus, administered 
according to institutional standards of care. 
These two regimens of post-grafting immunosuppression have been shown to produce 
equivalent rates of GvHD, relapse-free survival, and GvHD-free survival in a 
prospective, randomized controlled trial (16), and we thus view them as equivalent for 
the purposes of this clinical trial.  Immunosuppressant doses and taper schedules will 
be adjusted based on institutional standard practice and clinical factors, at the discretion 
of the attending physician, as in previous clinical trials of these regimens (16). 
3.1.2 Inclusion criteria (prior to ibrutinib administration) 
• Age ≥ 18 years 
• Adequate hematologic function, defined as ANC > 0.75 x 109/L;  platelet count 
> 50 x 109/L;  and hemoglobin > 8.0 g/dL without transfusion or growth-factor 
support for at least 7 days prior to screening (with the exception of pegylated 
G-CSF and darbopoietin, which require at least 14 days of abstinence prior to 
screening) 
• Adequate hepatic and renal function, as defined by serum AST and ALT 
≤ 3.0 x upper limit of normal (ULN);  estimated creatinine clearance ≥ 30 mL/min 
via Cockroft-Gault formula;  nd bilirubin ≤ 1.5 x ULN (unless elevated bilirubin is 
due to Gilbert’s syndrome or of non-hepatic origin) 
• Adequate coagulation studies, defined as PT/INR and PTT (aPTT) ≤ 1.5 x ULN 
• Female subjects who are of non-reproductive potential (ie, post-menopausal by 
history - no menses for ≥ 1 year;  OR history of hysterectomy;  OR history of 
bilateral tubal ligation; OR history of bilateral oophorectomy).  Female subjects of 
childbearing potential must have a negative serum pregnancy test upon 
screening. 
• Male and female subjects who agree to use both a highly effective method of 
birth control (eg, implants;  injectables;  combined oral contraceptives;  some 
intrauterine devices [IUDs];  sexual abstinence;  or sterilized partner) and a 
barrier method (eg, condoms;  vaginal ring;  sponge;  etc) during the period of 
therapy and for 30 days after the last dose of study drug for females and 90 days 
after the last dose of the study drug for males. 
• Between Day +60 and Day +90 after allogeneic HCT 

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3.2 
Exclusion Criteria  
3.2.1 Exclusion Criteria for enrollment (pre-transplant) 
• Active involvement of the central nervous system with malignancy (previous CNS 
involvement is allowed if clearance of CNS disease has been documented prior 
to enrollment) 
• Pregnant or breastfeeding 
• Karnofsky Performance Status < 60% 
• Active leukemia (> 5% leukemic blasts in peripheral blood or bone marrow) 
• Non-hematologic malignancy with a life expectancy of < 5 years 
• Known history of human immunodeficiency virus (HIV) or active hepatitis C virus 
(HCV) or hepatitis B virus (HBV) infection.  Subjects who are positive for 
hepatitis B core antibody or hepatitis B surface antigen must have a negative 
polymerase chain reaction (PCR) result before enrollment.  Those who are 
PCR-positive will be excluded. 
• Known bleeding disorders (eg, von Willebrand’s disease) or hemophilia. 
• History of other malignancies, except:  
o Malignancy treated with curative intent and with no known active disease 
present for ≥ 3 years before the first dose of study drug and felt to be at low 
risk for recurrence by treating physician. 
o Adequately treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease. 
o Adequately treated carcinoma in situ without evidence of disease.  
3.2.2 Exclusion Criteria (prior to ibrutinib administration) 
• Active and uncontrolled acute GvHD Grades III or IV 
• Use of secondary therapy for acute GvHD at any time (defined as any systemic 
therapy intended to treat acute GvHD besides corticosteroids) 
• Requirement for anticoagulation with warfarin or other Vitamin K antagonists 
(concomitant use of other anticoagulants is permitted) 
• Relapsed leukemia (> 5% leukemic blasts in peripheral blood or bone marrow 
after allogeneic HCT) 
• Karnofsky Performance Status < 60% 
• Chemotherapy ≤ 21 days prior to first administration of study treatment and/or 
monoclonal antibody ≤ 6 weeks prior to first administration of study treatment 
• Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study 
drug. 
• Currently active, clinically significant cardiovascular disease, such as 
uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by the 
New York Heart Association Functional Classification; or a history of myocardial 
infarction, unstable angina, or acute coronary syndrome within 6 months prior to 
randomization. 

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• History of stroke or intracranial hemorrhage within 6 months prior to screening 
• Any life-threatening illness, medical condition, or organ system dysfunction that, 
in the investigator’s opinion, could compromise the subject’s safety or put the 
study outcomes at undue risk. 
• Major surgery within 4 weeks of first dose of study drug. 
• Any uncontrolled active systemic infection. 
• Unresolved toxicities from prior anti-cancer therapy, defined as having not 
resolved to Common Terminology Criteria for Adverse Event (CTCAE, version 4), 
Grade ≤ 1, or to the levels dictated in the inclusion/exclusion criteria with the 
exception of alopecia 
• Unable to swallow capsules or malabsorption syndrome, disease significantly 
affecting gastrointestinal function, or resection of the stomach or small bowel, 
symptomatic inflammatory bowel disease or ulcerative colitis, or partial or 
complete bowel obstruction 
• Requires treatment with a strong cytochrome P450 (CYP) 3A4/5 inhibitor 
(see Appendix E). 
• Unwilling or unable to participate in all required study evaluations and 
procedures. 
• Unable to understand the purpose and risks of the study and to provide a signed 
and dated informed consent form (ICF) and authorization to use protected health 
information (in accordance with national and local subject privacy regulations). 
• Currently active, clinically significant hepatic impairment 
(Child-Pugh Class B or C) 
• Lactating or pregnant 
• Uncontrolled cardiac arrhythmias 
3.3 
Informed Consent Process 
All participants must be provided a consent form describing the study with sufficient 
information for participants to make an informed decision regarding their participation.  
Participants must sign the IRB approved informed consent prior to participation in any 
study specific procedure.  The participant must receive a copy of the signed and dated 
consent document.  The original signed copy of the consent document must be retained 
in the medical record or research file.  
3.4 
Study Timeline 
Primary Completion: 
The study is expected to complete accrual within 1 year, and to complete treatment 
within 2 years of opening. 
Study Completion: 
The study is expected to be completed within 2.5 years of opening. 

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4. 
TREATMENT PLAN 
Subjects will be assessed for eligibility and enrolled prior to allogeneic HCT, using the 
pre-transplant inclusion and exclusion criteria above.  Eligible and enrolled subjects will 
then be reassessed prior to the administration of ibrutinib, which may begin at any point 
between Day +60 and Day +90 after allogeneic HCT, using the pre-ibrutinib inclusion 
and exclusion criteria above.  Ibrutinib will not be initiated until the enrollment checklist 
has been reviewed by the coordinating center; a minimum of 48 hours’ notice is 
required. 
If subjects are deemed ineligible prior to beginning ibrutinib therapy, they may be 
reassessed for eligibility at any point until Day +90 after allogeneic HCT, and ibrutinib 
may be initiated if they meet all relevant criteria at any point between Day +60 and 
Day +90 after allogeneic HCT.  Subjects beyond Day +90 will not be eligible to initiate 
ibrutinib if they have not already done so. 
Pre-transplant screening:  all studies to be completed within 60 days of beginning 
conditioning therapy, unless otherwise indicated: 
• History and physical examination, including Karnofsky Performance Status 
(standard of care) 
• Serologic and/or nucleic-acid testing for HIV, hepatitis B, and hepatitis C 
according to institutional standard practice (standard of care) 
• Serum pregnancy testing, for women of childbearing potential (standard of care) 
• Bone marrow examination, including assessment of minimal residual disease by 
multiparameter flow cytometry or high-throughput sequencing (standard of care) 
• Disease assessment (standard of care):  Data forms for CIBMTR will be made 
available to the coordinating center.  Alternatively, detailed disease assessment 
data will be entered directly into the electronic database. 
• Complete enrollment checklist and submit to coordinating center for review prior 
to enrollment.  Preparative regimen for HCT should not begin until enrollment 
checklist has been reviewed by coordinating center (research). 
Start of preparative regimen through Day +60 to Day +90: 
• Pre-conditioning blood sample from HCT recipient for high-throughput 
sequencing, flow cytometry, and CyTOF (research) 
• Blood sample from HCT donor (related only), as a baseline to investigate 
development of post-transplant GVL effects (research) 
• Disease reassessment between Day +28 and Day +60, including bone marrow 
examination and assessment of minimal residual disease as described above 
(standard of care) 
Prior to administration of ibrutinib (Day +60 to Day +90; all studies should be 
done within 2 weeks of starting ibrutinib): 
• Laboratory assessment of hepatic and renal function (standard of care) 
• Assessment of acute GvHD presence, severity, and therapy history 
(standard of care) 

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• History and physical, including Karnofsky Performance Status 
(standard of care) 
• Assessment of concomitant medications (standard of care) 
• Collection of peripheral blood samples for mixed lymphocyte reactions, Th1/Th2 
assays, and other correlative science endpoints (research) 
Ibrutinib will be initiated between Day +60 and Day +90, after confirmation that the 
subject meets all relevant eligibility criteria.  The drug will be dosed, and doses 
modified, as described below.  The following assessments will be performed after 
initiation of ibrutinib: 
After start of ibrutinib until 2 years post-transplant (tests should be performed 
+/- 2 weeks of given time points through Day +180, and +/- 4 weeks of given timepoints 
after Day +180): 
• History, physical examination, and laboratory assessment of hematologic and 
chemistry tests per institutional standard practice (standard of care) 
• Acute GvHD assessment weekly through Day +100 (standard of care) 
• Chronic GvHD assessment at 6 months, 9 months, 12 months, 15 months, 
18 months, and 2 years post-transplant (standard of care) 
• Toxicity assessment at baseline (before starting ibrutinib), weekly through 
Day +100, monthly until Day +180, and then at 9 months, 12 months, 15 months, 
and 18 months post-transplant (research), unless ibrutinib has been 
permanently discontinued 
• In subjects with AML, myeloid blast crisis, or biphenotypic leukemia:  bone 
marrow examination, including assessment of minimal residual disease by 
multiparameter flow cytometry, at Day +90;  Day +180;  and 1 year 
post-transplant (standard of care).  Please note:  Okay to omit Day +90 MRD 
testing and Day +90 biopsy if previous biopsy (between Day +28 and Day +60) 
showed no evidence of disease.   
• In subjects with ALL or lymphoid blast crisis:  minimal residual disease 
testing by peripheral-blood high-throughput sequencing (ClonoSEQ) at Day +90; 
Day +180; 1 year;  1.5 years;  and 2 years post-transplant (standard of care) 
• Peripheral blood draw for mixed lymphocyte reactions, Th1/Th2 assays, and 
other correlative science at Day +90;  Day +180;  1 year;  1.5 years;  and 2 years 
post-transplant (research) 
4.1 
General Concomitant Medication and Supportive Care Guidelines 
Permitted Concomitant Medications 
Supportive medications in accordance with standard practice (such as for emesis, 
diarrhea, etc) are permitted.  Use of neutrophil growth factors (filgrastim and 
pegfilgrastim) or red blood cell growth factors (erythropoietin) is permitted per 
institutional policy and in accordance with the ASCO guidelines.  Transfusions may be 
given in accordance with institutional policy.  

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Medications to be Used with Caution 
CYP3A Inhibitors/Inducers 
Ibrutinib is metabolized primarily by CYP3A.  Avoid co-administration with strong 
CYP3A4 or moderate CYP3A inhibitors and consider alternative agents with less 
CYP3A inhibition. 
• If a strong CYP3A inhibitor (eg, ketoconazole;  indinavir;  nelfinavir;  ritonavir;  
saquinavir;  clarithromycin;  telithromycin;  itraconazole;  nefazadone;  or 
cobicistat) must be used, reduce ibrutinib dose to 140 mg or withhold treatment 
for the duration of inhibitor use.  Subjects should be monitored for signs of 
ibrutinib toxicity.  
• If a moderate CYP3A inhibitor (eg, voriconazole;  erythromycin;  amprenavir;  
aprepitant;  atazanavir;  ciprofloxacin;  crizotinib;  darunavir/ritonavir;  diltiazem;  
fluconazole;  fosamprenavir;  imatinib;  verapamil;  amiodarone;  or dronedarone) 
must be used, reduce ibrutinib to 140 mg (for 840 mg/day dose, reduce to 
280 mg) for the duration of the inhibitor use.  Avoid grapefruit and Seville 
oranges during ibrutinib/placebo treatment, as these contain moderate inhibitors 
of CYP3A (see Appendix E Inhibitors and Inducers of CYP3A). 
• No dose adjustment is required in combination with mild inhibitors.  
Avoid concomitant use of strong CYP3A inducers (eg, carbamazepine, rifampin, 
phenytoin, and St John’s Wort).  Consider alternative agents with less CYP3A induction. 
A list of common CYP3A inhibitors and inducers is provided in Appendix E.  A 
comprehensive list of inhibitors, inducers, and substrates may be found at 
http://medicine.iupui.edu/clinpharm/ddis/main-table/.  This website is continually revised 
and should be checked frequently for updates.  
Drugs That May Have Their Plasma Levels Altered by Ibrutinib 
In vitro studies indicated that ibrutinib is not a substrate of P-glycoprotein (P-gp), but is a 
mild inhibitor (with an IC50 of 2.15 μg/mL).  Ibrutinib is not expected to have systemic 
drug-drug interactions with P-gp substrates.  However, it cannot be excluded that 
ibrutinib could inhibit intestinal P-gp after a therapeutic dose.  There is no clinical data 
available; therefore, to avoid a potential interaction in the GI tract, narrow therapeutic 
range P-gp substrates such as digoxin, should be taken at least 6 hours before or after 
ibrutinib. 
QT-prolonging Agents 
Any medications known to cause QT prolongation should be used with caution; periodic 
ECG and electrolyte monitoring should be considered.  
Antiplatelet Agents and Anticoagulants 
Fatal bleeding events have occurred in subjects treated with ibrutinib.  Grade 3 or 
higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria and 
post procedural hemorrhage) have occurred in up to 6% of subjects.  Bleeding events of 

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any grade, including bruising and petechiae, occurred in approximately half of subjects 
treated with ibrutinib.  The mechanism for the bleeding events is not well understood. 
Ibrutinib may increase the risk of hemorrhage in subjects receiving antiplatelet or 
anticoagulant therapies.  See Section 6 (Dose Modification) for recommendations 
regarding ibrutinib dosing in subjects undergoing surgery or other invasive procedures. 
Warfarin or vitamin K antagonists should not be administered concomitantly with 
ibrutinib.  Supplements such as fish oil and vitamin E preparations should be avoided.  
Use ibrutinib with caution in subjects requiring other anticoagulants or medications that 
inhibit platelet function.  Subjects with congenital bleeding diathesis have not been 
studied.  Ibrutinib should be held at least 3 to 7 days pre- and post-surgery depending 
upon the type of surgery and the risk of bleeding. 
Subjects requiring the initiation of therapeutic anticoagulation therapy (other than 
warfarin or a vitamin K antagonist) during the course of the study should have treatment 
with ibrutinib held, and ibrutinib should not be restarted until the subject is clinically 
stable and has no signs of bleeding.  Subjects should be observed closely for signs and 
symptoms of bleeding.  No dose reduction is required when study drug is restarted. 
Prohibited Concomitant Medications 
Any chemotherapy, anticancer immunotherapy, experimental therapy, or radiotherapy is 
prohibited while the subject is receiving study treatment with ibrutinib.  Localized, 
hormonal, or bone-sparing treatment for non-hematologic may be considered with 
approval of the PI.  
The Sponsor-investigator must be notified in advance (or as soon as possible 
thereafter) of any instances in which prohibited therapies are administered. 
Permitted Concomitant Medications 
Supportive medications in accordance with standard practice (such as for emesis, 
diarrhea, etc) are permitted.  Use of neutrophil growth factors (filgrastim and 
pegfilgrastim) or red blood cell growth factors (erythropoietin) is permitted per 
institutional policy and in accordance with relevant institutional and national guidelines.  
Transfusions may be given in accordance with institutional policy. 
Antimicrobial prophylaxis 
All subjects should receive antimicrobial prophylaxis appropriate for allogeneic HCT 
recipients, according to institutional standard practice.  If no institutional standard 
practice exists, one recommended (although not required) approach is as follows: 
• Acyclovir 400 mg TID for 1 year after allogeneic HCT or until discontinuation of 
all systemic immunosuppressive medication, whichever occurs later. 
• Bactrim SS 1 tablet daily for 6 months after allogeneic HCT or until 
discontinuation of all systemic immunosuppression, whichever occurs later. 
• Fluconazole 400 mg daily from start of transplant conditioning until Day +75 after 
allogeneic HCT. 

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Antimicrobial prophylaxis should be adjusted according to subject-specific risks, 
infectious history, institutional susceptibility data, and subjects’ clinical condition. 
4.2 
Criteria for Removal from Study 
Ibrutinib will be continued until 18 months post-transplant, or until one of the following 
occurs:  disease relapse; or discontinuation due to adverse events.  Subjects with 
leukemia relapse after allogeneic HCT will discontinue the study drug, and may be 
treated with any and all appropriate therapies, including investigational agents, at the 
discretion of the treating physician. 
Subjects will be withdrawn from study treatment if one of the following occurs:  leukemia 
relapse; unacceptable toxicity requiring interruption of ibrutinib for more than 28 
continuous days; investigator decision; withdrawal of consent by the subject for further 
treatment and/or follow-up; pregnancy; or study termination.  All enrolled subjects, 
regardless of discontinuation of study treatment, will be followed for leukemia relapse 
and survival until 18 months after allogeneic HCT unless the subject withdraws consent 
for follow-up. 
Withdrawal from the study will occur under the following conditions:  withdrawal of 
consent for follow-up observation by the subject; loss to follow-up; study termination; or 
death.  When an enrolled subject withdraws from the study, the reason for withdrawal 
should be documented, as should the subject’s willingness to participate in follow-up 
visits or assessments. 
4.3 
Alternatives 
The alternative to participation on this study is to receive allogeneic HCT on other 
clinical protocols or treatment plans without the use of maintenance ibrutinib.  This 
alternative will be discussed with subjects during the informed consent process. 
5. 
INVESTIGATIONAL AGENT INFORMATION 
5.1 
 Investigational Agent  
The investigational agent utilized in this clinical trial is ibrutinib, administered at a dose 
of 420 mg orally once-a-day (with dose adjustments for concomitant medications or 
toxicity as described elsewhere in this protocol) and continued for 1 year, until disease 
progression, or until discontinuation due to adverse events.  EXCEPTION:  The starting 
dose for subjects with mild liver impairment (Child-Pugh Class A) is defined to be 
140 mg/day. 
Ibrutinib capsules are size 0, hard gelatin capsules for oral administration and contain 
140 mg of micronized ibrutinib (content may be adjusted for water content and purity) 
and the following compendial excipients (National Formulary, Pharmacopoeia Europe, 
Japan Pharmacopoeia):  microcrystalline cellulose; croscarmellose sodium; sodium 
lauryl sulfate; and magnesium stearate.  Capsules are packaged in high-density 
polyethylene bottles with an induction seal and a child resistant screw-top cap.  The 
number of capsules per bottle is indicated on the label. 

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Ibrutinib capsules should be stored according to the storage conditions indicated on the 
label.  The recommended storage condition for ibrutinib capsules is 15° C to 25° C (59° 
F to 77° F) with excursions permitted to 30° C (86° F).  Ibrutinib should be administered 
orally once daily with a glass of water at approximately the same time each day.  The 
capsules should be swallowed whole with water and should not be opened, broken, or 
chewed.  Ibrutinib must not be taken with grapefruit juice. 
There are limited data on the effects of ibrutinib overdose.  No maximum tolerated dose 
(MTD) was reached in the Phase 1 study in which subjects received up to 
12.5 mg/kg/day (1400 mg).  In a separate study, one healthy subject who received a 
dose of 1680 mg experienced reversible Grade 4 hepatic enzyme increases (AST and 
ALT).  There is no specific antidote for ibrutinib.  Subjects who ingested more than the 
recommended dosage should be closely monitored and given appropriate supportive 
treatment. 
For the most comprehensive information regarding ibrutinib, refer to the current version 
of the Investigator's Brochure. 
Pharmacology  
Ibrutinib was designed as a selective and covalent inhibitor of Bruton’s tyrosine kinase 
(17).  In vitro, ibrutinib is a potent inhibitor of Btk activity (IC50 = 0.39 nM).  The 
irreversible binding of ibrutinib to cysteine-481 in the active site of Btk results in 
sustained inhibition of Btk catalytic activity and enhanced selectivity over other kinases 
that do not contain a cysteine at this position.  When added directly to human whole 
blood, ibrutinib inhibits signal transduction from the B-cell receptor and blocks primary 
B-cell activation (IC50 = 80 nM) as assayed by anti-IgM stimulation followed by CD69 
expression (18). 
Ibrutinib arrested cell growth and induced apoptosis in human B-cell lymphoma cell 
lines in vitro and inhibited tumor growth in vivo in xenograft models (18).  Ibrutinib also 
inhibited adhesion and migration of mantle cell lymphoma (MCL) cells in co-culture and 
reduced tumor burden in lymph node and bone marrow in a murine model of MCL 
dissemination and progression (19). 
Toxicology 
In safety pharmacology assessments, no treatment-related effects were observed in the 
central nervous system or respiratory system in rats at any dose tested.  Further, no 
treatment-related corrected QT interval (QTc) prolongation effect was observed at any 
tested dose in a cardiovascular study using telemetry-monitored dogs.  
Based on data from rat and dog including general toxicity studies up to 13 weeks 
duration, the greatest potential for human toxicity with ibrutinib is predicted to be in 
lymphoid tissues (lymphoid depletion) and the gastrointestinal tract (soft feces/diarrhea 
with or without inflammation).  Additional toxicity findings seen in only one species with 
no observed human correlate in clinical studies to date include pancreatic acinar cell 

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atrophy (rat), minimally decreased trabecular and cortical bone (rat) and corneal 
dystrophy (dog).   
In vitro and in vivo genetic toxicity studies showed that ibrutinib is not genotoxic.  In a rat 
embryo-fetal toxicity study ibrutinib administration was associated with fetal loss and 
malformations (teratogenicity) at ibrutinib doses that result in approximately 6 times and 
14 times the exposure (AUC) in subjects administered the dose of 420 and 560 mg 
daily, respectively.  
Carcinogenesis, Mutagenesis, Impairment of Fertility 
Carcinogenicity studies have not been conducted with ibrutinib.  Ibrutinib was not 
mutagenic in a bacterial mutagenicity (Ames) assay, was not clastogenic in a 
chromosome aberration assay in mammalian (CHO) cells, nor was it clastogenic in an 
in vivo bone marrow micronucleus assay in mice at doses up to 2000 mg/kg.  Fertility 
studies with ibrutinib have not been conducted in animals.  In the general toxicology 
studies conducted in rats and dogs, orally administered ibrutinib did not result in 
adverse effects on reproductive organs. 
Pharmacokinetics and Metabolism 
Following oral administration of ibrutinib at doses ranging from 1.25 to 12.5 mg/kg/day 
as well as fixed dose levels of 420, 560, and 840 mg/day, exposure to ibrutinib 
increased as doses increased with substantial intersubject variability.  The mean 
half-life (t1/2) of ibrutinib across 3 clinical studies ranged from 4 to 9 hours, with a median 
time to maximum plasma concentration (Tmax) of 2 hours.  Administration of 420 mg 
ibrutinib with a high-fat breakfast in subjects with CLL approximately doubled the mean 
systemic exposure compared to intake after overnight fasting with median time to Tmax 
delayed from 2 to 4 hours.  Ibrutinib was extensively metabolized to the dihydrodiol 
metabolite PCI-45227, a reversible inhibitor of Btk, with approximately 15-times lower 
inhibitory potency compared to ibrutinib.  The metabolite-to-parent AUC ratio ranged 
from 0.7 to 3.4.  Steady-state exposure of ibrutinib and PCI-45227 was less than 2-fold 
of first dose exposure. 
The results of human mass balance study of [14C]-ibrutinib conducted in six healthy 
male subjects demonstrated that less than 10% of the total dose of [14C]-ibrutinib is 
renally excreted, whereas approximately 80% is recovered in feces.  Subjects with mild 
and moderate renal insufficiency (creatinine clearance > 30 mL/min) were eligible to 
enroll in Study PCYC-1102-CA in which pharmacokinetic (PK) assessments were 
included.  No dose adjustment is needed for mild or moderate renal impairment (greater 
than 30 mL/min creatinine clearance).  There is no data in subjects with severe renal 
impairment or subjects on dialysis.  The study of ibrutinib in hepatic impaired subjects is 
currently in progress. 

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Summary of Clinical Safety  
Pooled safety data for a total of 1071 subjects treated with ibrutinib monotherapy from 9 
studies in B-cell malignancies, which includes subjects from 2 randomized-control 
studies who crossed over from comparator treatment or placebo to receive ibrutinib 
monotherapy, are summarized below in Table 1.  
Table 1.  Most frequently reported treatment-emergent adverse events (TEAEs)  
in subjects receiving ibrutinib as monotherapy (N=1071): 
Most frequently reported 
TEAEs > 10% 
Most frequently reported 
Grade 3 or 4 TEAEs > 2% 
Most frequently reported 
Serious TEAEs > 1% 
Diarrhea 
Neutropenia 
Pneumonia 
Fatigue 
Pneumonia 
Atrial fibrillation 
Nausea 
Thrombocytopenia 
Febrile neutropenia 
Cough 
Anemia 
Pyrexia 
Anemia 
Hypertension 
 
Pyrexia 
Atrial fibrillation 
 
Neutropenia 
 
 
For more detailed information refer to the current version of the IB. 
Risks 
Bleeding-related events 
There have been reports of hemorrhagic events in subjects treated with ibrutinib both 
with and without thrombocytopenia.  These include primarily minor hemorrhagic events 
such as contusion;  epistaxis;  and petechiae; and some major hemorrhagic events 
including gastrointestinal bleeding;  intracranial hemorrhage;  and hematuria. Use of 
ibrutinib in subjects requiring other anticoagulants or medications that inhibit platelet 
function may increase the risk of bleeding. 
Leukostasis 
There were isolated cases of leukostasis reported in subjects treated with ibrutinib.  A 
high number of circulating lymphocytes (> 400,000/µL) may confer increased risk.  
Consider temporarily holding ibrutinib.  Subjects should be closely monitored.  
Administer supportive care including hydration and/or cytoreduction as indicated.  
Lymphocytosis 
Upon initiation of treatment, a reversible increase in lymphocyte counts (ie, ≥ 50% 
increase from baseline and an absolute count > 5000/µL), often associated with 
reduction of lymphadenopathy, has been observed in most subjects with chronic 
lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) treated with ibrutinib.  
This effect has also been observed in some subjects with mantle cell lymphoma (MCL) 

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treated with ibrutinib.  This observed lymphocytosis is a pharmacodynamic effect and 
should not be considered progressive disease in the absence of other clinical findings.  
In both disease types, lymphocytosis typically occurs during the first few weeks of 
ibrutinib therapy (median time 1.1 weeks) and typically resolves within a median of 
8.0 weeks in subjects with MCL and 18.7 weeks in subjects with CLL/SLL.  
A large increase in the number of circulating lymphocytes (eg, > 400,000/µL) has been 
observed in some subjects.  Lymphocytosis was not commonly observed in subjects 
with Waldenström’s macroglobulinemia treated with ibrutinib.  Lymphocytosis appeared 
to occur in lower incidence and at lesser magnitude in subjects with CLL/SLL receiving 
ibrutinib in combination with chemoimmunotherapy. 
Atrial Fibrillation  
Atrial fibrillation and atrial flutter have been reported in subjects treated with ibrutinib, 
particularly in subjects with cardiac risk factors, hypertension, acute infections, and a 
previous history of atrial fibrillation.  For atrial fibrillation which persists, consider the 
risks and benefits of ibrutinib treatment and follow the protocol dose modification 
guidelines (see Section 6). 
Cytopenias 
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and 
anemia) were reported in subjects treated with ibrutinib.  
Diarrhea 
Diarrhea is the most frequently reported non-hematologic AE with ibrutinib monotherapy 
and combination therapy.  Other frequently reported gastrointestinal events include 
nausea, vomiting, and constipation.  These events are rarely severe.  Should symptoms 
be severe or prolonged follow the protocol dose modification guidelines (see Section 6).  
Infections 
Fatal and non-fatal infections have occurred with ibrutinib therapy.  At least 25% of 
subjects with MCL and 35% of subjects with CLL had Grade 3 or greater infections per 
NCI Common Terminology Criteria for Adverse Events (CTCAE v4.0).  The most 
commonly reported infections include pneumonia, cellulitis, urinary tract infection and 
sepsis.  Although causality has not been established, cases of progressive multifocal 
leukoencephalopathy (PML) have occurred in subjects treated with ibrutinib.  Cases of 
hepatitis E, which may be chronic, have occurred in patients treated with ibrutinib. 
Subjects should be monitored for signs and symptoms (such as fever, chills, weakness, 
confusion, vomiting and jaundice, and abnormal liver function tests) and appropriate 
therapy should be instituted as indicated. 
Lymphocytosis 
Upon initiation of treatment, a reversible increase in lymphocyte counts (ie, ≥ 50% 
increase from baseline and an absolute count > 5,000/µL), often associated with 
reduction of lymphadenopathy, has been observed in most subjects with CLL/SLL 

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treated with ibrutinib.  This effect has also been observed in some subjects with MCL 
treated with ibrutinib.  This observed lymphocytosis is a pharmacodynamic effect and 
should not be considered progressive disease in the absence of other clinical findings.  
In both disease types, lymphocytosis typically occurs during the first few weeks of 
ibrutinib therapy (median time 1.1 weeks) and typically resolves within a median of 
8.0 weeks in subjects with MCL and 18.7 weeks in subjects with CLL/SLL.  
A large increase in the number of circulating lymphocytes (eg, > 400,000/µL) has been 
observed in some subjects.  Lymphocytosis was not observed in subjects with WM 
treated with ibrutinib.  Lymphocytosis appeared to occur in lower incidence and at lesser 
magnitude in subjects with CLL/SLL receiving ibrutinib in combination with 
chemoimmunotherapy. 
Non-Melanoma Skin Cancer 
Non-melanoma skin cancers have occurred in subjects treated with ibrutinib.  Monitor 
subjects for the appearance of non-melanoma skin cancer. 
Rash 
Rash has been commonly reported in subjects treated with either single-agent ibrutinib 
or in combination with chemotherapy.  Rash occurred at a higher rate in the ibrutinib 
arm than in the ofatumumab arm in Study 1112.  Most rashes were mild to moderate in 
severity. 
Tumor lysis syndrome (TLS) 
There have been reports of tumor lysis syndrome (TLS) events in subjects treated with 
single-agent ibrutinib or in combination with chemotherapy.  Subjects at risk of tumor 
lysis syndrome are those with comorbidities and/or risk factors such as high tumor 
burden prior to treatment, increased uric acid (hyperuricemia), elevated lactate 
dehydrogenase (LDH), bulky disease at baseline, and pre‐existing kidney abnormalities 
Interstitial Lung Disease (ILD) 
Cases of interstitial lung disease (ILD) have been reported in subjects treated with 
ibrutinib.  Monitor subjects for pulmonary symptoms indicative of ILD.  Should 
symptoms develop, follow the protocol dose modification guidelines (see Section 6). 
5.2 
Availability 
Ibrutinib will be provided for this clinical trial by its manufacturer, Pharmacyclics.  
5.3 
Agent Ordering 
Each study site will order their drug stock through Pharmacyclics.  Ibrutinib will be 
requested from the research pharmacy at each study site. 
5.4 
Agent Accountability 
Ibrutinib will be kept secure according to institutional guidelines and will be processed 
and dispensed by Investigational Drug Services at Stanford University and by 
analogous services at outside collaborating centers.  

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Overdose 
Any dose of study drug in excess of that specified in this protocol is considered to be an 
overdose.  Signs and symptoms of an overdose that meet any Serious Adverse Event 
criterion must be reported as a Serious Adverse Event in the appropriate time frame 
and documented as clinical sequelae to an overdose.  
There is no specific experience in the management of ibrutinib overdose in subjects.  
No maximum tolerated dose (MTD) was reached in the Phase 1 study, in which 
subjects received up to 12.5 mg/kg/day (1,400 mg/day).  Healthy subjects were 
exposed up to single dose of 1,680 mg.  One healthy subject experienced reversible 
Grade 4 hepatic enzyme increases (AST and ALT) after a dose of 1,680 mg.  Subjects 
who ingest more than the recommended dosage should be closely monitored and given 
appropriate supportive treatment. 
Refer to Section 7.2 for further information regarding AE reporting.  
6. 
DOSE MODIFICATIONS 
The study dose levels of ibrutinib are defined as follows. 
Dose level 0:  420 mg orally once a day. 
Dose level -1:  280 mg orally once a day. 
Dose level -2:  140 mg orally once a day. 
Dose level -3:  Discontinue ibrutinib. 
The dose of ibrutinib should be modified according to the dose modification guidelines 
in Table 2 if any of the following toxicities occur and are considered to be due to 
ibrutinib. 
Hematologic Adverse Events  
• Grade 3 ANC (< 1,000/ µL) with an associated temperature ≥ 38.5°C 
• Grade 4 ANC (< 500/µL) for more than 7 days 
• Grade 3 thrombocytopenia (< 50,000/µL) in the presence of Grade ≥ 2 bleeding 
events 
• Grade 4 thrombocytopenia (< 25,000/µL) 
Non-Hematologic Adverse Events 
• Grade 3 or 4 nausea, vomiting, or diarrhea if persistent, despite optimal anti-emetic 
and/or anti-diarrheal therapy  
• Any other Grade 4 or unmanageable Grade 3 toxicity attributed to ibrutinib 

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Table 2:  Ibrutinib Dose Modifications 
Hematologic Adverse Events  
Occurrence Action to be Taken 
First 
Withhold ibrutinib until recovery to an ANC ≥ 750 or platelets > 25,000 with 
no evidence of Grade ≥ 2 bleeding;  may restart at original dose level 
Second 
Withhold ibrutinib until recovery to an ANC ≥ 750 or platelets > 25,000 with 
no evidence of Grade ≥ 2 bleeding;  may restart at 1 dose level lower  
Third 
Withhold ibrutinib until recovery to an ANC ≥ 750 or platelets > 25,000 with 
no evidence of Grade ≥ 2 bleeding;  may restart at 1 dose level lower  
Fourth 
Discontinue ibrutinib a 
Non-Hematologic Adverse Events 
First 
Withhold ibrutinib until recovery to Grade ≤ 1 or baseline;  may restart at original 
dose level 
Second 
Withhold ibrutinib until recovery to Grade ≤ 1 or baseline;  may restart at 1 dose 
level lower  
Third 
Withhold ibrutinib until recovery to Grade ≤ 1 or baseline;  may restart at 1 dose 
level lower  
Fourth 
Discontinue ibrutinib a 
a  If ibrutinib is discontinued for toxicity, subject will end the Treatment Phase of the 
study. 
Dose changes must be recorded.  At the Investigator’s discretion, the dose of ibrutinib 
may be re-escalated after 8 weeks of a dose reduction in the absence of a recurrence of 
the toxicity that led to the reduction. 
Dose modifications for use with CYP3A inhibitors 
Concomitant use of strong CYP3A inhibitors which would be taken chronically 
(eg, ritonavir;  indinavir nelfinavir;  saquinavir;  boceprevir;  telaprevir;  nefazodone) is 
not recommended.  For short-term use (treatment for 7 days or less) of strong CYP3A 
inhibitors (eg, antifungals and antibiotics) either reduce ibrutinib dose to 140 mg daily or 
withhold ibrutinib therapy until the CYP3A inhibitor is no longer needed.  
Reduce ibrutinib dose to 140 mg orally once daily if a moderate CYP3A inhibitor must 
be used (eg, fluconazole;  darunavir;  erythromycin;  diltiazem;  atazanavir;  aprepitant;  
amprenavir;  fosamprevir;  crizotinib;  imatinib;  verapamil;  and ciprofloxacin).  Subjects 
taking concomitant strong or moderate CYP3A inhibitors should be monitored more 
closely for signs of ibrutinib toxicity. 
As most study subjects are expected to be receiving azoles (fluconazole;  
voriconazole;  posaconazole) until at least Day +75 after allogeneic HCT, the dose 
of ibrutinib will be 140 orally once daily while on such medications.  Once these 
agents are stopped, the dose may be escalated to 420 mg once daily. 

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Dose modifications for hepatic impairment 
Ibrutinib is metabolized in the liver and therefore subjects with clinically significant 
hepatic impairment at the time of screening (Child-Pugh Class B or C) are excluded 
from study participation.  For subjects who develop mild liver impairment while on study 
(Child-Pugh Class A), the recommended dose reduction for ibrutinib is to 140 mg daily 
(1 capsule).  Subjects who develop moderate or severe hepatic impairment 
(Child-Pugh Class B or C) will have study drug withheld until resolved to mild 
impairment (Child-Pugh Class A) or better.  Subjects who completely resolve liver 
impairment may re-initiate ibrutinib treatment according to Table 2.  Subjects who 
resolve liver impairment to mild (Child-Pugh Class A) may re-start ibrutinib treatment at 
140 mg daily (1 capsule).  Continue to monitor subjects for signs of toxicity and follow 
dose modification guidance as needed (Refer to Table 2). 
Dose modifications for planned surgery or invasive procedures 
The following recommendations should be considered during the perioperative period 
for subjects who require surgical intervention or an invasive procedure while receiving 
ibrutinib: 
a. For any planned major surgery or invasive procedure requiring sutures or staples 
for closure, ibrutinib should be held at least 7 days prior to the intervention and 
should be held at least 7 days after the procedure, and restarted at the discretion 
of the investigator when the surgical site is reasonably healed without 
serosanguineous drainage or the need for drainage tubes.  
b. For planned minor procedures (such as a central line placement, needle biopsy, 
thoracentesis, or paracentesis) ibrutinib should be held for at least 3 days prior to 
the procedure and should not be restarted for at least 3 days after the procedure.  
For bone marrow biopsies that are performed while the subject is on ibrutinib, it is 
not necessary to hold ibrutinib for these procedures. 
c. For emergency procedures, ibrutinib should be held after the procedure until the 
surgical site is reasonably healed, for at least 7 days after the urgent surgical 
procedure, or at the discretion of the investigator. 
Ultimately, the management of ibrutinib in conjunction with invasive procedures 
depends upon the perceived bleeding risk, the subject’s clinical situation, and the 
urgency of the procedure. 
6.1 
Treatment Discontinuation  
Study treatment with ibrutinib will be permanently discontinued for any subject if any of 
the following occur. 
• Grade 4 treatment related (ie, possibly-, probably-, or definitely-related) 
non-hematologic toxicity 
• Grade 4 neutropenia lasting > 21 days  
• Grade 4 thrombocytopenia lasting > 21 days or associated with clinically 
significant bleeding (requiring > 3 units of packed red blood cells within 24 hours 

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to replace loss OR bleeding from a site which in the Investigator’s opinion is a 
potential life-threatening source irrespective of blood loss) 
7. 
ADVERSE EVENTS AND REPORTING PROCEDURES 
7.1 
Potential Adverse Events 
Please see “Risks” in Section 5.1 above for a full description of known risks and 
toxicities associated with ibrutinib. 
7.2 
Adverse Event Reporting 
Adverse events will be graded according to CTCAE v4.03.  Both Serious and 
Non-Serious Adverse Events will be clearly noted in source documentation and listed on 
study specific Case Report Forms (CRFs).  The Protocol Director (PD) or designee will 
assess each Adverse Event (AE) to determine whether it is unexpected according to the 
Informed Consent, Protocol Document, or Investigator’s Brochure, and related to the 
investigation.  All Serious Adverse Events (SAEs) will be tracked until resolution, or until 
30 days after the last dose of the study treatment.  
An adverse event (AE) will be defined as any medical change in the subject’s baseline 
or pre-treatment condition (occurring during the course of the clinical study) after 
receiving the study drug (ibrutinib), whether considered treatment-related or not.  
Adverse events will be monitored spontaneously by the subject or will be discovered as 
a result of general questioning by the investigator or by physical examination.  All 
adverse events will be recorded.  As far as possible, each adverse event will be 
described by its duration (start and end dates), frequency (single episode, intermittent, 
continuous), severity (mild, moderate, severe) and assessment of its cause (the 
underlying study indication, co-existing disease, concomitant medication, investigational 
drug, or other), relationship to investigational drug (unrelated, unlikely, possibly, 
probably, definitely), whether it influenced the course of treatment, whether it required 
specific therapy and what is expected or unexpected.  All adverse events will be graded 
on a three point scale of increasing severity.  Serious adverse events will be reported to 
the IRB and appropriate regulatory agencies. 
An adverse event is any significant medical occurrence in a subject treated on this 
protocol both during treatment and follow-up period, regardless of causality 
assessment.  This includes adverse clinical or laboratory findings, inter-current illness, 
or an exacerbation or progression of a condition present at the time of study initiation.  
An adverse event is considered serious if it fulfills one of the following criteria: 
a. Results in death 
b. Life-threatening (subject at risk of death at the time of the event) 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
d. Results in persistent or significant disability 
e. Other medical events that may not be immediately life-threatening or result in 
death or hospitalization by may jeopardize the subject or require intervention to 
prevent one of the outcomes listed above 

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Study subjects will be instructed to report any adverse events to investigators and 
subjects will be evaluated for adverse events at every clinic visit.  All adverse events will 
be documented by investigators and will contain the following information, if known: 
a. Medical diagnosis of the event 
b. Date and time of onset of event 
c. Date and time of resolution of event 
d. Severity of the event according to the National Cancer Institute (NCI) Common 
Toxicity Criteria and Adverse Events (CTCAE) criteria, version 4.0 
e. Frequency of the event 
f. Intervention 
g. Outcome 
h. Likelihood of association between the event and the study drug 
The following are NOT considered AEs: 
• Pre-existing condition:  A pre-existing condition (documented on the medical 
history CRF) is not considered an AE unless the severity, frequency, or character 
of the event worsens during the study period. 
• Pre-planned or elective hospitalization:  A hospitalization planned before 
signing the informed consent form is not considered an SAE, but rather a 
therapeutic intervention.  However, if during the pre-planned hospitalization an 
event occurs, which prolongs the hospitalization or meets any other SAE criteria, 
the event will be considered an SAE.  Surgeries or interventions that were under 
consideration, but not performed before enrollment in the study, will not be 
considered serious if they are performed after enrollment in the study for a 
condition that has not changed from its baseline level.  Elective hospitalizations 
for social reasons, solely for the administration of chemotherapy, or due to long 
travel distances are also not SAEs. 
• Diagnostic Testing and Procedures:  Testing and procedures should not to be 
reported as AEs or SAEs, but rather the cause for the test or procedure should 
be reported. 
Serious adverse events (SAEs) CTCAE Grade 3 and above, and all subsequent 
follow-up reports will be reported to the Stanford Cancer Center Data and Safety 
Monitoring Committee (DSMC) using the study specific CRF regardless of the event’s 
relatedness to the investigation.  Following review by the DSMC, events meeting the 
IRB definition of ‘Unanticipated Problem’ will be reported to the IRB using eProtocol 
within 10 working days of DSMC review, or within 5 working days for deaths or 
life-threatening experiences.  If complete information is not available at the time, the 
investigator must provide follow-up information as soon as it is known. 
Adverse events that are serious and unexpected suspected adverse reactions, and are 
possibly, probably, or definitely related to the study drug ibrutinib (SUSAR per 
21CFR§312.32), will be reported to the FDA via IND Safety Report [21CFR§312.32] 

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within 14 calendar days, or within 7 calendar days if the event is an unexpected fatal or 
life-threatening suspected adverse reaction. 
In addition, all serious adverse events (initial and follow-up information) will be reported 
on the Serious Adverse Event Report Form from Pharmacyclics and sent via email or 
fax to Pharmacyclics Drug Safety or designee within 24 hours of the discovery of the 
event or information.  Pharmacyclics may request follow-up and other additional 
information from the Investigator (for instance, hospital admission/discharge notes and 
laboratory results).  The contact information (phone, email and fax) for Pharmacyclics 
Drug Safety can be found on the Serious Adverse Event Report Form and instructions. 
Hematopoietic cell transplantation (HCT) is an aggressive therapy for the treatment of a 
number of life-threatening malignant and non-malignant disorders.  Individuals 
considered for HCT have generally exhausted other avenues of effective therapy.  The 
non-relapse mortality (NRM) associated with a sibling-donor myeloablative allogeneic 
transplant is approximately 20% and the NRM for an unrelated-donor myeloablative 
allogeneic transplant ranges from 20-50%.  In the setting of reduced-intensity 
conditioning and allogeneic HCT, the NRM is approximately 10% with a sibling donor 
and 20% with an unrelated donor. 
As an aggressive therapy, HCT is associated with a large number of AEs and SAEs.  
The toxicities associated with HCT are related to the following:  1) the underlying 
disease;  2) therapy antecedent to HCT;  3) the health status of the transplant recipient, 
including co-existing conditions;  4) the preparative regimen employed before 
transplant;  5) therapies directed at reducing transplant-related complications 
(eg, immunosuppressants for the prevention of GvHD);  and 6) the treatment of 
complications of HCT.  
The use of toxicity grading scales such as the NCI CTC is a standard in the medical 
community for the reporting of AEs and SAEs in the investigation of new drugs or 
devices.  The use of this type of scale is less helpful in the evaluation of AEs and SAEs 
associated with a treatment, such as HCT.  In an effort to report to regulatory agencies 
the toxicities that are relevant and meaningful for the evaluation of risks and benefits to 
potential HCT recipients, the following guidelines will serve to determine which events 
are reported as AEs and SAEs. 
The following SAEs require reporting to the Stanford Cancer Institute Data Safety 
Monitoring Board for subjects on research protocols.  If the event is unexpected, 
serious, and harmful, then it will also require reporting to the IRB: 
1) Deaths  
All deaths: 
• while the subject is receiving treatment on a protocol  
• up to 60 days (autologous) or 90 days (allogeneic) after last dose of protocol 
treatment 
• or any death that occurs more than 60 days (autologous) or 90 days (allogeneic) 
after protocol treatment has ended that is felt to be treatment related. 

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Reports will include deaths from the common and expected Grade 4 toxicities noted 
below.  Deaths that occur outside of Stanford will be reported whenever possible.  It 
must be noted that obtaining detailed information on the cause and circumstances of a 
death occurring at another institution can be difficult.  Excludes deaths related to 
relapse of underlying disease, which will reported to the IRB at the time of protocol 
renewal.  
2) All serious and unexpected toxicities 
Defined as those toxicities not identified in the transplant literature, product inserts, or 
study consent form. 
The following will be recorded, but generally will not be reported as AEs or SAEs, 
unless also considered related to the study drug.   
1) Hospitalizations  
Approximately 50% of allogeneic transplant recipients will be readmitted to the 
hospital.  The most common indications for readmission of an allogeneic HCT 
recipient are fever, failure to maintain nutritional status, and GvHD.  NOTE:  Events 
that result in hospitalization or extend hospitalization will still be considered SAEs.  
2) Relapse of disease 
Relapse unfortunately remains a significant problem following both autologous and 
allogeneic HCT.  The risk of relapse is influenced by both subject and disease 
variables.  The risk of relapse following allogeneic transplant is extremely dependent 
on the disease being treated but ranges from 10% (for subjects with severe aplastic 
anemia) to 80% (for subjects with refractory acute leukemia). 
3) Common and expected toxicities of HCT ≤ Grade 4 that are well-described in 
transplant literature, the product inserts, or study consent form and do not 
result in death. 
In general, these toxicities are considered reversible.  The specific reporting 
requirements are found in the protocol.  These Grade 4 toxicities include, but are not 
limited to, alopecia, anemia, anorexia, bleeding requiring transfusions, cardiac 
arrhythmias , central venous catheter infections, constipation, diarrhea, edema, 
fatigue, febrile episodes, gastritis, graft failure, graft versus host disease, hematuria , 
hypertension, hypotension, hypoxia, incontinence, infections, insomnia, laboratory 
abnormalities, mental status changes, mood alterations, mucositis, nausea , 
neutropenia, pain, pleural effusion, pneumonitis, rash, seizures, sepsis, sinusoidal 
obstructive syndrome, tachycardia, thrombocytopenia, thrombotic microangiopathy, 
tremor, vomiting.  For IND studies, SAEs that are SUSARs per 21CFR§312.32 will 
be reported as IND Safety Reports (see above).  
4) Acute and chronic GvHD 
Acute and chronic GvHD are major complications of HCT and account for most 
non-relapse mortality.  The incidence of GvHD will be reported as part of the 
secondary outcomes and to the IRB at the time of the protocol annual review. 

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5) Secondary Malignancies 
The occurrence of secondary malignancies and associated mortality is a known risk 
of cancer therapies.  The occurrence of secondary malignancies will be reported to 
the IRB at the time of the protocol annual review. 
6) Special reporting situations which may require expedited reporting and/or 
safety evaluation include, but are not limited to: 
• Overdose of any study drug 
• Suspected abuse/misuse of a study drug 
• Inadvertent or accidental exposure to a study drug 
• Medication error involving a product (with or without subject exposure to the 
study drug) 
Occurrence of any special reporting situation should be recorded in the CRF.  If any 
special reporting situation meets the criteria for an adverse event, it should be 
recorded on the adverse events CRF.  If the adverse event is considered serious, it 
should be recorded on the adverse events CRF as serious and should be reported 
on the Serious Adverse Event Report Form.  The SAE Report Form should be sent 
via email or fax to Pharmacyclics Drug Safety or designee within 15 days of 
awareness. 
Adverse Events of Special Interest (AESI) 
Specific adverse events, or groups of adverse events, will be followed as part of 
standard safety monitoring activities.  The following events (regardless of seriousness) 
will be reported to Pharmacyclics Drug Safety per SAE reporting timelines.  
Major Hemorrhage 
Major hemorrhage is defined as any of the following: 
• Any treatment-emergent hemorrhagic adverse events of Grade 3 or higher*.  Any 
treatment-emergent serious adverse events of bleeding of any grade 
• Any treatment-emergent central nervous system hemorrhage/hematoma of any 
grade 
*All hemorrhagic events requiring transfusion of red blood cells should be reported 
as Grade 3 or higher AE per CTCAE v4.0. 
Events meeting the definition of major hemorrhage will be captured as an event of 
special interest. 
Expediting Reporting Requirements for Serious Adverse Events 
All serious adverse events and AESIs (initial and follow-up information) will be 
reported on FDA Medwatch (Form 3500A) or Suspect Adverse Event Report 
(CIOMS Form 1) IRB Reporting Form and sent via email (
@pcyc.com) 
or fax (408-215-3500) to Pharmacyclics Drug Safety, or designee, within 15 days of 

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the event.  Pharmacyclics may request follow-up and other additional information 
from the Sponsor Investigator.  
All serious adverse events that have not resolved by the end of the study, or that 
have not resolved upon discontinuation of the subject's participation in the study, 
must be followed until any of the following occurs: 
• The event resolves 
• The event stabilizes 
• The event returns to baseline, if a baseline value/status is available 
• The event can be attributed to agents other than the study drug or to factors 
unrelated to study conduct 
• It becomes unlikely that any additional information can be obtained (subject or 
health care practitioner refusal to provide additional information, lost to follow up 
after demonstration of due diligence with follow-up efforts) 
8. 
CORRELATIVE/SPECIAL STUDIES  
We propose a series of correlative laboratory studies using blood samples collected 
from study participants, with the aim of elucidating the impact of ibrutinib on immune 
reconstitution after allogeneic HCT and on the development of alloreactivity, 
graft--vs-tumor effects, and GvHD. 
Background 
Alloreactive T- and B-cells play a crucial role in development of both beneficial 
graft-vs-tumor effects and harmful GvHD after allogeneic HCT.  In chronic GvHD, 
T follicular helper cells (TFH), Th2, and Th17 T-cells activate B-cells and elicit fibrotic 
cascades underpinned by alloantibody production and collagen deposition.  To 
understand the impact of ibrutinib on alloreactivity after allogeneic HCT, we will perform 
global B- and T-cell immune phenotype analysis using multiplexed CyTOF analysis, 
focused on quantifying Th2 subversion and cytotoxic T-cell preservation, T follicular cell 
composition, and T-cell functional activation.  These laboratory assays will be correlated 
with clinical evidence of GvHD and GVL effects (quantified by measuring minimal 
residual disease via sequencing of T- and B-cell immune receptors with clonoSEQ 
technology (in subjects with ALL) and via multi-parameter flow cytometry (in subjects 
with AML).  
T- and B-cell repertoire reconstitution will be monitored via immune receptor 
high-throughput sequencing (HTS) and H-Y alloreactive B-cell phenotyping.  We will 
determine the effect of ibrutinib on serum immunoglobulin levels, cytokine quantification, 
protective anti-EBV and anti-tetanus immunity, and allogeneic H-Y antibody responses 
after allogeneic HCT. 
Minor histocompatibility antigens expressed on the Y chromosome are called H-Y 
antigens and are frequently targeted by female donor lymphocytes when male subjects 
undergo sex-mismatched transplantation (FM HCT).  Dr Miklos’ lab has demonstrated 
that H-Y specific B-cells and antibodies are associated with chronic GvHD following 
FM HCT.  We hypothesize that ibrutinib will preferentially target and deplete 

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alloreactive B-cell.  While H-Y antigen provides a model system to study 
antigen-specific alloimmunity, H-Y can only be studied in male subjects with female 
donors (FM HCT).  Recognizing this limitation for H-Y antigen studies, as well as 
limitations in the number of PBMC available for research per subject, we have decided 
to dedicate FM HCT subject samples to H-Y B-cell analyses while using samples from 
all other donor and recipient sex combinations (not FM) for T-helper cell and 
functional T-cell analyses as shown in Table 3 below.  Historically, FM allotransplants 
account for 35-40% of cases of chronic GvHD. 
Sample collection 
As in the PCYC 1129 protocol, 50 mL of blood will be collected in five 10 mL 
heparinized green-top tubes before the start of conditioning therapy; before ibrutinib 
intiation; and then again at Day +180, 1 year, and 1.5 years after allogeneic HCT.  We 
will also obtain blood samples from the HCT donor.  The 50 mL aliquots of recipient 
blood will be processed on-site at Stanford University, providing three vials of 1.5 mL 
plasma and five 1 mL vials of viably frozen peripheral blood mononuclear cells (PBMC) 
separated by Ficoll gradient centrifugation as described in the PCYC1129 laboratory 
manual.  PBMC cell yields will be recorded and evenly distributed into five vials 
irrespective of cell quantity.  Plasma will be stored at -80° C and PBMC will be stored in 
liquid nitrogen on-site.  Comprehensive multiplexed B- and T-cell phenotype analysis 
will be performed on all samples at all time points using CyTOF.  In addition, B- and 
T-cell repertoire analyses will be determined using immune receptor high-throughput 
sequencing (HTS).  We plan to reserve a single vial of PBMC and 1 mL plasma per 
subject in central storage, in case trial investigators identify additional informative 
studies later. 
Table 3.  Schedule of correlative laboratory studies. 
 
 
Pre- 
HCT 
Pre- 
Ibrut. 
6 m 
12 m 
18 m 
CyTOF B- and T-cell phenotyping (PBMC 1) 
Res. 
All 
All 
All 
All 
All 
T-cell repertoire analysis by immune receptor 
sequencing (PBMC 2) 
Res. 
All 
All 
All 
All 
All 
B-cell repertoire analysis by immune receptor 
sequencing (PBMC 2) 
ALL SOC 
AML Res 
 
 
 
 
All 
IgG & IgM quantification 
SOC 
All 
All 
All 
All 
All 
Cytokine Analysis and BAFF (plasma 1) 
Res. 
All 
--- 
--- 
All 
All 
T-Follicular quantification (PBMC 3) 
Res. 
All but 
FM 
All but 
FM 
All but 
FM 
All but 
FM 
All but 
FM 
H-Y alloreactive Antibodies (Plasma 2) 
Res. 
FM 
only 
FM 
only 
FM 
only 
FM 
only 
FM 
only 
H-Y specific B-cell characterization (PBMC 4) 
Res. 
FM 
only 
FM 
only 
FM 
only 
FM 
only 
FM 
only 
Abbreviations:  HCT, hematopoietic cell transplantation;  Ibrut, ibrutinib;  m, months;  Res, research;  
SOC, standard of care;  AML, acute myeloid leukemia;  ALL, acute lymphoblastic leukemia;  
F->M, female-donor-to-male-recipient;  PBMC, peripheral blood mononuclear cells 

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Preliminary data
We performed immune phenotyping on peripheral blood samples collected from 
12 subjects who underwent allogeneic HCT for chronic lymphocytic leukemia and who 
were treated with ibrutinib for post-transplant relapse.  In these subjects, ibrutinib rapidly 
depleted pre-germinal-center B-cells (CD19+CD38+CD27+IgD+), which have previously 
been associated with development of chronic GvHD.  In contrast, memory B-cells 
(CD19+CD27+IgD-CD38-) persisted, and total serum IgG levels were maintained despite 
ibrutinib treatment.  Subset analysis of T-cells showed a 75% reduction in 
GATA3-expressing Th2 cells, while Tbet-expressing Th1 cells remained unaffected.  
T follicular cells (CD4+CXCR5+BCL6+) were likewise depleted rapidly from the 
circulation by ibrutinib treatment (Figure 1).  Taken together, these preliminary results 
support the hypothesis that ibrutinib treatment after allogeneic HCT will result in Th1 
polarization of the T-cell repertoire, preservation of CD8+ T-cells, and depletion of T 
follicular cells, all of which would be expected to reduce GvHD risk while maintaining 
beneficial anti-tumor alloreactivity.  Of note, these preliminary data were obtained in 
subjects treated with ibrutinib for relapse, while the proposed study herein attempts to 
elucidate the role of maintenance ibrutinib on immune reconstitution and GvHD.
Figure 1.  Changes in peripheral B-cell and T-cell subsets after treatment with ibrutinib 
in subjects with relapsed CLL after allogeneic HCT
Correlative science aims
1. Perform immunophenotyping of peripheral-blood B- and T-cells before and after 
initiation of maintenance ibrutinib.
a. Evaluate Th1 polarization, effect on T follicular cells, and CD8+ cytotoxic T 
lymphocytes
b. Evaluate B-cell reconstitution by quantifying transitional, naïve, memory, and 
activated plasmablast fractions
CD19+ B Cells
CD3+ T Cells

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c.  Determine concentrations of Th1 and Th2 cytokines in plasma 
2. Characterize the B- and T-cell repertoire during and after ibrutinib maintenance 
using immune receptor high-throughput sequencing to assess clonal expansion of 
donor cytotoxic T-cells and follicular T-cells. 
a.  Compare to results from patients transplanted at our institution without 
maintenance ibrutinib 
b.  Quantify EBV-specific T-cell reconstitution 
3. Assess B-cell function before and after initiation of maintenance ibrutinib 
a.  Evaluate for presence of alloreactive B-cells and H-Y antibodies in F->M 
allogeneic HCT 
b.  Quantify total serum immunoglobulin levels 
c.  Quantify protective anti-EBV and anti-tetanus antibodies 
d.  Assess levels of BAFF before, during, and after ibrutinib maintenance treatment 
These laboratory studies will be correlated with clinical data (including onset, severity, 
and response of chronic GvHD and minimal residual disease detection of leukemia). 

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9. 
STUDY CALENDAR 
Studies shown in italics are research studies, while evaluations shown in black 
represent clinical standard of care. 
 
Within 
60 days of 
starting 
conditioning 
Between 
Day +28 
and 
Day +60 
Start of 
ibrutinib 
(between 
Day +60 
and 
Day +90) 
Day 
+90 
Day 
+180 
9 
months 1 year 
15 
months  
18 
months 
2 
years 
Off 
Study 
Eligibility determination 
X 
X 
 
 
 
 
 
 
 
 
 
History & physical 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
KPS assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory testing of 
hepatic and renal function 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Transplant evaluation per 
institutional criteria 
X 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram (ECG)  
X 
 
 
 
 
 
 
 
 
 
 
Hepatitis and HIV testing 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (for women 
of childbearing potential) 
X 
 
 
 
 
 
 
 
 
 
 
Bone marrow aspiration 
and/or biopsy with 
assessment of minimal 
residual disease  
X 
X 
 
AML 
only* 
AML 
only 
 
AML 
only 
 
 
 
 
Minimal residual disease 
detection by 
peripheral-blood 
high-throughput 
sequencing (ClonoSEQ) 
X 
X 
 
X* 
X 
 
X 
 
X 
X 
 
Assessment of 
concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Acute GvHD assessment 
 
X 
 
X 
 
 
 
 
 
 
 
Chronic GvHD assessment 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Ibrutinib (study drug) 
 
 
 
X ------------------------------------------------------X 
Adverse event evaluation 
 
 
 
X-------------------------------------------------------X 
Blood draw for biological 
studies 
X 
 
X 
X 
X 
 
X 
 
X 
X 
 
Blood sample from HCT 
donor (related only) 
X 
 
 
 
 
 
 
 
 
 
 
For the Day +90 and Day +180 timepoints, the relevant evaluations may be performed within +/- 2 weeks 
of the specified timepoint.  For the 9-month, 1-year, 15-month, and 18-month timepoints, the relevant 
evaluations should be performed within +/- 4 weeks of the specified timepoint.   
* Please note:  Okay to omit Day +90 MRD testing and Day +90 biopsy if previous biopsy (between 
Day +28 and Day +60) showed no evidence of disease.   

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10. 
MEASUREMENTS 
10.1  Primary and Secondary Outcome measures 
The primary outcome measure is the incidence of relapsed leukemia at 18 months after 
allogeneic HCT.  This is an efficacy endpoint. 
Secondary endpoints include the incidence of acute GvHD Grades II–IV and III–IV at 
Day +180 after allogeneic HCT, the incidence of chronic GvHD at 18 months after 
allogeneic HCT, and the incidence of detectable minimal residual disease at 1 year after 
allogeneic HCT. 
10.1.1 Relevant Subsets 
The primary and secondary outcomes will be measured on all enrolled subjects. 
10.1.2 Measurement Definition 
For the primary outcome measure, relapsed leukemia is defined as > 5% leukemic 
blasts detected in bone marrow or peripheral blood.  Subjects will also be considered to 
have relapsed leukemia if they receive any active treatment for progressive leukemia 
after allogeneic HCT, even if they have <5% leukemic blasts.  Withdrawal of 
immunosuppression alone is not considered an active treatment for progressive 
disease. 
For the secondary outcome measures, acute GvHD will be graded and scored 
according to standard criteria (Appendix C).  Chronic GvHD will be graded and scored 
according to the 2014 NIH consensus criteria (Appendix D).  Minimal residual disease 
will be assessed by high-throughput sequencing (ClonoSEQ) for subjects with ALL, and 
by high-sensitivity flow cytometry for subjects with AML or acute biphenotypic leukemia.  
Minimal residual disease will be considered present if > 1 x 10-6 leukemic clones are 
detected by ClonoSEQ (20), or if any aberrant blasts matching the original leukemic 
immunophenotype are detected by high-sensitivity flow cytometry (21). 
10.1.3 Measurement Methods and Time Points 
The primary outcome will be measured by bone marrow examination at Day +90;  
Day +180;  and 1 year after allogeneic HCT in subjects with AML or myeloid leukemias, 
and by peripheral-blood high-throughput sequencing on Day +90;  Day +180;  1 year;  
18 months;  and 2 years post-transplant in subjects with ALL.  Minimal residual disease 
detection by high-throughput sequencing is not itself diagnostic of relapse, but should 
prompt a bone marrow examination to assess definitively for relapse.  Routine 
monitoring of peripheral blood counts and differential will also be performed according 
to clinical standards of care, with bone marrow examination performed in response to 
any concerning findings to assess for relapse. 
The secondary outcomes will be measured as follows:  acute GvHD will be scored 
weekly (if returning to the transplant center that frequently) from initiation of ibrutinib 
through Day +100 using the criteria described above.  Chronic GvHD will be assessed 
at Day +180, at 9 months, at 1 year, at 15 months, and at 18 months after allogeneic 

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HCT, using the criteria described above. Minimal residual disease will be assessed as 
described above on Day +90;  Day +180;  1 year;  and 18 months after allogeneic HCT. 
For the Day +100 and Day +180 timepoints, the relevant evaluations may be performed 
within +/- 2 weeks of the specified timepoint.  For the 9-month; 1-year; 15-month;  and 
18-month timepoints, the relevant evaluations should be performed within +/- 4 weeks of 
the specified timepoint. 
11. 
REGULATORY CONSIDERATIONS 
11.1 Institutional Review of Protocol 
The protocol, the proposed informed consent and all forms of participant information 
related to the study (eg, advertisements used to recruit participants) will be reviewed 
and approved by the Stanford IRB and Stanford Cancer Institute Scientific Review 
Committee (SRC).  Any changes made to the protocol will be submitted as a 
modification and will be approved by the IRB prior to implementation.  The Protocol 
Director will disseminate the protocol amendment information to all participating 
investigators. 
11.2 Data and Safety Monitoring Plan 
Primary internal data monitoring will be performed by the Overall Protocol Director at 
Stanford and site investigators and their research staff.  The Protocol Director will 
review data to assure the validity of data, as well as the safety of the subjects.  The 
Protocol Director will also monitor the progress of the trial.  The Protocol Director will be 
responsible for maintaining the clinical protocol, reporting adverse event, assuring the 
consent is obtained and documented, reporting of unexpected outcomes and reporting 
the status of the trial in the continuing renewal report submitted annually to the IRB and 
SRC. 
A safety monitoring committee (SMC) will be composed of the Protocol Director and 
research staff, including other site principal investigators.  The SMC will conduct regular 
teleconferences on at least a quarterly basis or more frequent communication between 
the Protocol Director and research staff may occur via email or teleconference as 
necessary. 
The data will be monitored continuously over the accrual and follow up periods by the 
investigators and the study coordinators.  The Protocol Director will be responsible for 
maintaining the clinical protocol, reporting adverse event, assuring the consent is 
obtained and documented, reporting of unexpected outcomes and reporting the status 
of the trial to the IRB and the Stanford University Cancer Center Data Safety Monitoring 
Board (DSMB). 
11.3 Data Management Plan 
The Protocol Director, or his/her designee, will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study.  
Study-specific electronic Case Report Forms (eCRFs) will document treatment 
outcomes for data analysis.  The RedCAP database system will be used and 
maintained by the PI and/or his designees.  The eCRFs will be secured via confidential 
username and password access to the research team. 

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11.4 Confidentiality 
Subjects may be referred to this clinical trial from outside of Stanford.  Therefore, study 
subjects will be assigned a unique study identification (ID) number.  Referring 
physicians will be sent letters by the BMT physicians updating them on their subject's 
status, including information regarding the expected side effects of the treatment, 
necessary precautions and also the appropriate follow-up.  Specific information 
regarding the study would not be routinely shared with the referring physician. 
Subjects will be assigned a study-specific identification number (a unique number) and 
their data are entered into a secure database.  Access to the database is 
password-restricted and limited to study personnel.  
Research records will be maintained in a secure BMT office, and electronic data will be 
maintained in a study-specific, secure database.  In addition, information from the main 
Stanford BMT database may be uploaded into the study-specific database.  
All study staff will be required to complete HIPAA training.  All research staff must 
complete the IRB human subjects research training.  The study subject data are 
identified by a unique study ID number in the research documents.  Access to the 
research database is limited to approved clinical and research staff.  The code is 
maintained by the Stanford’s BMT Database System Administrator, and kept in a secure 
location.  
Study subjects will not be directly identified in any publications, presentations or 
correspondence. 
Private Health Information (PHI) is collected and recorded at the time of the subject’s 
first consultation with the BMT program.  Additional information is collected when the 
subject is enrolled in a clinical trial.  PHI may include some or all of the following: 
1. Names and initials 
2. Telephone numbers  
3. Addresses including ZIP code 
4. Dates, including date of birth 
5. Age;  sex;  race;  and ethnicity 
6. Email addresses  
7. Identification numbers, including Medical record numbers (MRNs) and Stanford 
Patient Number (SPN) 
8. Relevant medical history as it pertains to their BMT history, malignancy for which 
they received their BMT, acute and chronic GvHD history, past treatments for 
GvHD, vital signs, diagnostic test results, laboratory values, physical exam 
findings, past medical history, including relevant family medical history 
(eg, coronary heart disease, diabetes, hypertension, etc) that may place them at 
risk for side effects, medication history/current medications, interval history since 
last clinic visit, current health complaints, GvHD assessment, and treatment plan. 
Other outside agencies that may receive information include:  
• 
Pharmacyclics LLC, its affiliates or collaborators (eg, Janssen Biotech, Inc.) or 
their representatives  

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• 
The Office for Human Research Protections (OHRP) in the US Department of 
Health and Human Services (DHHS)  
• 
The Food and Drug Administration 
• 
The US Centers for Medicare & Medicaid Services (CMS), the agency 
responsible for administration of the Medicare program  
• 
Other federal and/or regulatory agencies as required 
• 
Center for International Blood and Marrow Transplant Research (CIBMTR)  
• 
The National Institutes of Health (NIH) / National Cancer Institute (NCI) / National 
Heart, Lung, and Blood Institute (NHLBI) 
• 
Stanford Data Safety Monitoring Board 
• 
Other Stanford investigators with IRB-approved projects (researchers outside of 
the BMT program will not have access to subject’s identity or personal protected 
health information (PHI).  The data will be managed using a database program.  
Data sets may be generated to share with investigators outside the program by 
de-identifying the data). 
Samples will be identified by the Subject ID number.  Research records are kept in a 
locked office.  Access to the office is limited to key access.  Only study personnel within 
the research program have access to the electronic database, the research records, or 
the code linking the samples to subject’s identifying information.  
11.5 Reporting Mechanisms 
The study Protocol Director (or designee) will be responsible for the coordination and 
development of all protocol amendments.  Any changes to the protocol or consent will 
be made in the form of an eProtocol modification, and will be approved prior to 
implementation.  Any amendments to the Protocol or Informed Consent Form protocol 
must be sent to Pharmacyclics for review and approval prior to submission to the IRB.  
This process will be included in the monitoring plan.  Changes or amendments to the 
protocol or consent will be reported to the IRB, FDA and NHLBI.  All IRB actions will be 
reported to the DSMC, NHLBI and FDA.  
12. 
STATISTICAL CONSIDERATIONS 
12.1 Statistical Design, Effect Size, and Sample Size 
This study is designed as a single-arm efficacy trial using historical published controls.  
This study’s primary endpoint is the incidence of relapse at 18 months after allogeneic 
HCT for AML/ALL.  Baseline relapse rates after reduced-intensity conditioning for these 
diseases in the published literature vary from 40–60% (1-6).  For the purposes of study 
design, we will use a relatively conservative baseline relapse risk of 45%.  This study is 
designed to detect a decrease in relapse rate from 45% to 25%.  Therefore, in the 
power analysis we will assume that the true relapse rate in the study population is 25%, 
while the null hypothesis holds that the relapse rate is 45%.  Under these conditions, 
using intent-to-treat analysis, a sample size of 50 enrolled subjects will provide 84% 
power to conclude that the relapse rate is lower than 45% at the two-sided significance 
level of 0.05.  Conservatively assuming that 45 of these 50 subjects meet the secondary 
criteria to continue to ibrutinib treatment (Appendix B) and are treated with ibrutinib, a 
subgroup analysis restricted to these 45 subjects will have 78% power to conclude that 
the relapse rate is < 45% with a significance level of 0.05. 

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12.2 Interim analyses 
We will monitor major adverse event rates as described above, in particular serious 
bleeding complications (hemorrhage Grade 3 or 4, as defined by CTCAE v4.0).  We will 
monitor and estimate the incidence rate of serious bleeding in study participants, and 
report all occurrences and corresponding analytic summaries (such as the estimated 
incidence rate with 95% confidence intervals) to the DSMB to assist in decision-making 
regarding early termination for safety. 
Allogeneic HCT is an intensive therapy with many associated side effects and toxicities 
related to the transplant conditioning regimen;  the ensuing immunosuppressed status;  
adverse effects of standard post-transplant medications;  and graft-vs-host interactions 
or GvHD.  Toxicities, including Grade 4 toxicities, are relatively common.  Non-relapse 
mortality (NRM) is a definitive endpoint which captures fatal effects of any aspect of the 
transplant process outside of disease relapse, and thus represents the most accurate 
and reproducible measure of the toxicity and safety of the allogeneic HCT process.  
The baseline cumulative incidence of NRM after allogeneic HCT for acute leukemia with 
FLU/MEL conditioning was estimated in a recent large cohort study at 20% (22).  
In order to ensure that patients are not harmed by the study intervention, the formal 
stopping rule below monitors that the study intervention does not increase the risk of 
NRM in participants.  
The stopping rule is based on the incidence of NRM at 1 year after allogeneic HCT.  
Patients will be evaluable with regard to the stopping rule if they die or if they reach 
1 year post-transplant, whichever occurs first.  The stopping rule will be tested every 
increment of 5 evaluable patients.  The stopping rule will be triggered if any of the 
following conditions are met:  
Number of 
evaluable patients 
Number of patients 
with NRM 
5 
3 
10 
5 
15 
6 
20 
8 
25 
9 
30 
10 
35 
12 
40 
13 
If the stopping rule is triggered, the study will be terminated, and FDA so notified.  This 
stopping rule provides 80% power to detect an increase in NRM with a type I error rate 
of 0.05.  The stopping rule was constructed using the Pocock boundary with the same 
significance level for all looks at the data.  The rule was created using R v.3.1.3 and the 
clinfun package.  

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12.3 Analysis Population 
Subjects who are enrolled but never treated with ibrutinib (eg, due to failure to meet the 
secondary criteria to continue to ibrutinib treatment) will be included in the primary 
analysis, which will be performed as an intention-to-treat analysis.  However, they will 
not be counted toward the overall accrual goal of 45 subjects.  A planned subset 
analysis will be performed testing the primary and secondary endpoints in the subset of 
subjects who receive at least 1 dose of ibrutinib on study. 
12.4  
Accrual estimates  
 
We performed 36 reduced-intensity allogeneic HCT for AML/ALL at Stanford in calendar 
year 2014.  We will also plan to open this study at UCSF (with Dr Aaron Logan) and City 
of Hope (with Dr Alex Herrera).  We anticipate accruing 10 to 15 subjects annually at 
UCSF and 20 subjects annually at City of Hope, based on their historical transplant 
patterns.  We therefore expect that study accrual will take 1 year to complete. 

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13. REFERENCES 
1. 
Aoudjhane M, Labopin M, Gorin NC, Shimoni A, Ruutu T, Kolb HJ, et al. Comparative 
outcome of reduced intensity and myeloablative conditioning regimen in HLA identical 
sibling allogeneic haematopoietic stem cell transplantation for patients older than 50 years 
of age with acute myeloblastic leukaemia:  a retrospective survey from the Acute Leukemia 
Working Party (ALWP) of the European group for Blood and Marrow Transplantation 
(EBMT). Leukemia. 2005;19(12):2304-12. 
2. 
Alyea EP, Kim HT, Ho V, Cutler C, DeAngelo DJ, Stone R, et al. Impact of conditioning 
regimen intensity on outcome of allogeneic hematopoietic cell transplantation for advanced 
acute myelogenous leukemia and myelodysplastic syndrome. Biology of blood and marrow 
transplantation :  journal of the American Society for Blood and Marrow Transplantation. 
2006;12(10):1047-55. 
3. 
Shimoni A, Hardan I, Shem-Tov N, Yerushalmi R, Nagler A. Allogeneic hematopoietic 
stem-cell transplantation in AML and MDS using myeloablative versus reduced-intensity 
conditioning:  long-term follow-up. Leukemia. 2010;24(5):1050-2. 
4. 
Shimoni A, Hardan I, Shem-Tov N, Rand A, Herscovici C, Yerushalmi R, et al. Comparison 
between two fludarabine-based reduced-intensity conditioning regimens before allogeneic 
hematopoietic stem-cell transplantation:  fludarabine/melphalan is associated with higher 
incidence of acute graft-versus-host disease and non-relapse mortality and lower incidence 
of relapse than fludarabine/busulfan. Leukemia. 2007;21(10):2109-16. 
5. 
Alyea EP, Kim HT, Ho V, Cutler C, Gribben J, DeAngelo DJ, et al. Comparative outcome of 
nonmyeloablative and myeloablative allogeneic hematopoietic cell transplantation for 
patients older than 50 years of age. Blood. 2005;105(4):1810-4. 
6. 
Mohty M, Labopin M, Volin L, Gratwohl A, Socie G, Esteve J, et al. Reduced-intensity 
versus conventional myeloablative conditioning allogeneic stem cell transplantation for 
patients with acute lymphoblastic leukemia:  a retrospective study from the European 
Group for Blood and Marrow Transplantation. Blood. 2010;116(22):4439-43. 
7. 
Bishop GA, Haxhinasto SA, Stunz LL, Hostager BS. Antigen-specific B-lymphocyte 
activation. Crit Rev Immunol. 2003;23(3):149-97. 
8. 
Shaffer AL, Rosenwald A, Staudt LM. Lymphoid malignancies:  the dark side of B-cell 
differentiation. Nat Rev Immunol. 2002;2(12):920-32. 
9. 
Satterthwaite AB, Witte ON. The role of Bruton's tyrosine kinase in B-cell development and 
function:  a genetic perspective. Immunological reviews. 2000;175:120-7. 
10. Rushworth SA, Murray MY, Zaitseva L, Bowles KM, MacEwan DJ. Identification of Bruton's 
tyrosine kinase as a therapeutic target in acute myeloid leukemia. Blood. 
2014;123(8):1229-38. 
11. Zaitseva L, Murray MY, Shafat MS, Lawes MJ, MacEwan DJ, Bowles KM, et al. Ibrutinib 
inhibits SDF1/CXCR4 mediated migration in AML. Oncotarget. 2014;5(20):9930-8. 
12. ClinicalTrials.gov. NCT02129062:  Ibrutinib in Treating Patients With Relapsed or 
Refractory B-cell Acute Lymphoblastic Leukemia:  National Institutes of Health;  [Available 
from:  https://clinicaltrials.gov/ct2/show/NCT02129062. 
13. Sarantopoulos S, Stevenson KE, Kim HT, Cutler CS, Bhuiya NS, Schowalter M, et al. 
Altered B-cell homeostasis and excess BAFF in human chronic graft-versus-host disease. 
Blood. 2009;113(16):3865-74. 
14. Dubovsky JA, Flynn R, Du J, Harrington BK, Zhong Y, Kaffenberger B, et al. Ibrutinib 
treatment ameliorates murine chronic graft-versus-host disease. The Journal of clinical 

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investigation. 2014;124(11):4867-76. 
15. Dubovsky JA, Beckwith KA, Natarajan G, Woyach JA, Jaglowski S, Zhong Y, et al. Ibrutinib 
is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T 
lymphocytes. Blood. 2013;122(15):2539-49. 
16. Cutler C, Logan B, Nakamura R, Johnston L, Choi S, Porter D, et al. Tacrolimus/sirolimus 
vs tacrolimus/methotrexate as GVHD prophylaxis after matched, related donor allogeneic 
HCT. Blood. 2014;124(8):1372-7. 
17. Pan Z, Scheerens H, Li SJ, Schultz BE, Sprengeler PA, Burrill LC, et al. Discovery of 
selective irreversible inhibitors for Bruton's tyrosine kinase. ChemMedChem. 
2007;2(1):58-61. 
18. Herman SE, Gordon AL, Hertlein E, Ramanunni A, Zhang X, Jaglowski S, et al. Bruton 
tyrosine kinase represents a promising therapeutic target for treatment of chronic 
lymphocytic leukemia and is effectively targeted by PCI-32765. Blood. 
2011;117(23):6287-96. 
19. Chang BY, Francesco M, De Rooij MF, Magadala P, Steggerda SM, Huang MM, et al. 
Egress of CD19(+)CD5(+) cells into peripheral blood following treatment with the Bruton 
tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma patients. Blood. 
2013;122(14):2412-24. 
20. Logan AC, Vashi N, Faham M, Carlton V, Kong K, Buno I, et al. Immunoglobulin and T cell 
receptor gene high-throughput sequencing quantifies minimal residual disease in acute 
lymphoblastic leukemia and predicts post-transplantation relapse and survival. Biology of 
blood and marrow transplantation:  journal of the American Society for Blood and Marrow 
Transplantation. 2014;20(9):1307-13. 
21. Walter RB, Gyurkocza B, Storer BE, Godwin CD, Pagel JM, Buckley SA, et al. Comparison 
of minimal residual disease as outcome predictor for AML patients in first complete 
remission undergoing myeloablative or nonmyeloablative allogeneic hematopoietic cell 
transplantation. Leukemia. 2014. 
22. Baron F, Labopin M, Peniket A, Jindra P, Afanasyev B, Sanz MA, et al. Reduced-intensity 
conditioning with fludarabine and busulfan versus fludarabine and melphalan for patients 
with acute myeloid leukemia:  a report from the Acute Leukemia Working Party of the 
European Group for Blood and Marrow Transplantation. Cancer. 2015;121(7):1048-55. 
23. Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, et al. National 
Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic 
Graft-versus-Host Disease:  I. The 2014 Diagnosis and Staging Working Group report. 
Biology of blood and marrow transplantation:  Journal of the American Society for Blood 
and Marrow Transplantation. 2015;21(3):389-401 e1. 
 

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APPENDICES 
APPENDIX A:  Pre-Transplant Eligibility Checklist  
Protocol Title: 
A Phase 2 Study of Ibrutinib After Reduced-Intensity 
Conditioning and Allogeneic Hematopoietic Cell 
Transplantation for Acute Leukemia 
Protocol Number: 
IRB-38934  /  BMT302 
Principal Investigator: 
Andrew R Rezvani, MD 
II.  Subject Information: 
Subject Name/ID: 
 
Gender:    
 Male     
 Female 
III.  Study Information: 
SRC-Approved 
 IRB-Approved 
 Contract signed 
 
IV.  Inclusion/Exclusion Criteria 
Pre-transplant screening:  all studies to be completed within 60 days of beginning 
conditioning therapy, unless otherwise indicated: 
 
Inclusion Criteria 
(From IRB-approved protocol) 
Yes 
No 
Supporting 
Documentation* 
1. Diagnosis of acute myeloid leukemia (AML), 
acute biphenotypic leukemia, or acute 
lymphoblastic leukemia (ALL).  (CML 
transformed to blast crisis is eligible). 
 
 
      
2. Planned allogeneic HCT using FLU/MEL or 
FLU/BU conditioning (as defined in protocol). 
 
 
      
3. Planned GvHD prophylaxis with TAC/MTX or 
TAC/SRL (regimens defined in protocol). 
 
 
      
4. HLA-identical sibling donor, HLA-matched 
unrelated donor, or donor mismatched at 1 HLA 
allele or antigen. 
 
 
      
5. Less than or equal to 5% blasts on bone marrow 
examination within 60 days of starting 
conditioning. 
 
 
      
6. Age ≥ 18 years and ≤ 70 years. 
 
 
      
7. Able to give informed consent. 
 
 
      
 

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Exclusion Criteria 
(From IRB-approved protocol) 
Yes 
No 
Supporting 
Documentation* 
1. Active involvement of the central nervous system 
with malignancy (previous CNS involvement is 
allowed if clearance of CNS disease has been 
documented prior to enrollment) 
 
 
      
2. Pregnant or breastfeeding 
 
 
      
3. Karnofsky Performance Status <60% 
 
 
      
4. Active leukemia (> 5% leukemic blasts in 
peripheral blood or bone marrow) 
 
 
      
5. Non-hematologic malignancy with life expectancy 
< 5 years 
 
 
      
6. HIV positivity, active hepatitis C virus infection, or 
active hepatitis B virus infection.  (Subjects positive 
for HBV surface antigen or HBV core antibody are 
eligible if they have a negative HBV PCR before 
enrollment.  Those who are PCR-positive are not 
eligible) 
 
 
      
7. Known bleeding disorder (eg, von Willebrand’s 
disease, hemophilia) 
 
 
      
8. History of other malignancies, except: 
o Malignancy treated with curative intent and with 
no known active disease for at least 3 years 
before the first dose of study drug, and felt to be 
at low risk of recurrence by treating physician 
o Adequately treated non-melanomatous skin 
cancer or lentigo maligna without evidence of 
disease 
o Adequately treated carcinoma in situ without 
evidence of invasive disease 
 
 
      
*All subject files must include supporting documentation to confirm subject eligibility.  The 
method of confirmation can include, but is not limited to, laboratory test results, radiology test 
results, subject self-report, and medical record review.  

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IV.  Statement of Eligibility 
By signing this form of this trial I verify that this subject is [
 eligible / 
 ineligible] for 
participation in the study.  This study is approved by the Stanford Cancer Institute 
Scientific Review Committee, the Stanford IRB, and has finalized financial and 
contractual agreements as required by Stanford School of Medicine’s Research 
Management Group.  
 
Treating Physician Signature: 
Date: 
Printed Name: 
 
Secondary Reviewer Signature: 
Date: 
Printed Name: 
 
Study Coordinator Signature: 
Date: 
Printed Name: 

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Appendix B:  Secondary criteria to continue to ibrutinib treatment 
Protocol Title: 
A Phase 2 Study of Ibrutinib After Reduced-Intensity 
Conditioning and Allogeneic Hematopoietic Cell 
Transplantation for Acute Leukemia 
Protocol Number: 
IRB-38934  /  BMT302 
Principal Investigator: 
Andrew R Rezvani, MD 
II.  Subject Information: 
Subject Name/ID: 
 
Gender:    
 Male     
 Female 
III.  Study Information: 
SRC-Approved 
 IRB-Approved 
 Contract signed 
 
IV.  Continuation Criteria 
 
Continuation Criteria 
(From IRB-approved protocol) 
Yes 
No 
Supporting 
Documentation* 
1. Between Day +60 and Day +90 after allogeneic 
HCT 
 
 
      
2. Age ≥ 18 years 
 
 
      
 
 
 
 
3. Adequate hematologic function, defined as ANC 
> 0.75 x 109/L, platelet count > 50 x 109/L, and 
hemoglobin > 8.0 g/dL without transfusion or 
growth-factor support for at least 7 days prior to 
screening (with the exception of pegylated G-CSF 
and darbepoietin, which require at least 14 days of 
abstinence before screening) 
 
 
      
4. Adequate hepatic and renal function, defined by 
serum AST and ALT ≤ 3x upper limit of 
normal (ULN); estimated creatinine clearance 
≥ 30 mL/min by Cockroft-Gault equation; and 
bilirubin ≤ 1.5 x ULN (unless elevated bilirubin is 
due to Gilbert’s syndrome or of non-hepatic origin) 
 
 
      
5. Adequate coagulation studies, defined as PT/INT 
and PTT (aPTT) ≤ 1.5 x upper limit of normal 
 
 
      
6. Female subjects who are of non-reproductive 
potential (ie, post-menopausal by history - no 
menses for ≥ 1 year; OR history of hysterectomy; 
OR history of bilateral tubal ligation; OR history of 
bilateral oophorectomy).  Female subjects of 
childbearing potential must have a negative serum 
pregnancy test upon screening. 
 
 
 
      

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Continuation Criteria 
(From IRB-approved protocol) 
Yes 
No 
Supporting 
Documentation* 
7. Male and female subjects who agree to use both a 
highly effective method of birth control 
(eg, implants, injectables, combined oral 
contraceptives, some intrauterine devices [IUDs], 
sexual abstinence, or sterilized partner) and a 
barrier method (eg, condoms, vaginal ring, sponge, 
etc) during the period of therapy and for 30 days 
after the last dose of study drug for females and 
90 days after the last dose of the study drug for 
males. 
 
 
 
      
 
Withdrawal Criteria 
(From IRB-approved protocol) 
Yes 
No 
Supporting 
Documentation* 
1. Active and uncontrolled acute GvHD Grades III or 
IV 
 
 
      
2. Use of secondary therapy for acute GvHD at any 
time (defined as any systemic therapy intended to 
treat acute GvHD besides corticosteroids) 
 
 
      
3. Requirement for anticoagulation with warfarin or 
other Vitamin K antagonists (concomitant use of 
other anticoagulants is permitted) 
 
 
      
4. Relapsed leukemia (> 5% leukemic blasts in 
peripheral blood or bone marrow at any point after 
allogeneic HCT) 
 
 
      
5. Karnofsky Performance Status <60% 
 
 
      
6. Chemotherapy ≤ 21 days prior to first study drug 
dose and/or monoclonal antibody ≤ 6 weeks prior 
to first study drug dose 
 
 
      
7. Vaccinated with live, attenuated vaccine within 
4 weeks of first study drug dose 
 
 
      
8. Currently active, clinically significant cardiovascular 
disease (eg, NYHA Class III or IV heart failure, 
uncontrolled arrhythmia, or acute coronary 
syndrome within 6 months of first study drug dose) 
 
 
      
9. History of stroke or intracranial hemorrhage within 
6 months of first study drug dose 
 
 
      
10. Any life-threatening illness, medical condition, or 
organ dysfunction that, in the investigator’s 
judgement, could compromise the subject’s safety 
or put the study outcomes at undue risk. 
 
 
      
11. Major surgery within 4 weeks of first study drug 
dose 
 
 
      
12. Active, uncontrolled systemic infection 
 
 
      

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Withdrawal Criteria 
(From IRB-approved protocol) 
Yes 
No 
Supporting 
Documentation* 
13. Unresolved toxicities from prior anti-cancer therapy 
(not resolved to CTCAE v4 Grade 1 or less, or to 
the levels described in these criteria, except 
alopecia) 
 
 
      
14. Unable to swallow capsules or malabsorption 
syndrome, disease significantly affecting 
gastrointestinal function, or resection of the 
stomach or small bowel, symptomatic inflammatory 
bowel disease or ulcerative colitis, or partial or 
complete bowel obstruction 
 
 
 
      
15. Requiring treatment with strong CYP3A inhibitor 
(see Appendix E) 
 
 
      
16. Unwilling or unable to participate in all required 
study evaluations and procedures 
 
 
      
17. Unable to understand the purpose and risks of the 
study and to provide a signed and dated informed 
consent form (ICF) and authorization to use 
protected health information (in accordance with 
national and local subject privacy regulations). 
 
 
      
18. Lactating or pregnant 
 
 
      
19. Uncontrolled cardiac arrhythmias 
 
 
 
      
*All subject files must include supporting documentation to confirm subject eligibility.  The 
method of confirmation can include, but is not limited to, laboratory test results, radiology test 
results, subject self-report, and medical record review.  

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IV.  Statement of Continuation Eligibility 
By signing this form of this trial I verify that this subject is [
 eligible / 
 ineligible] for 
participation in the study.  This study is approved by the Stanford Cancer Institute 
Scientific Review Committee, the Stanford IRB, and has finalized financial and 
contractual agreements as required by Stanford School of Medicine’s Research 
Management Group.  
 
Treating Physician Signature: 
Date: 
Printed Name: 
 
Secondary Reviewer Signature: 
Date: 
Printed Name: 
 
Study Coordinator Signature: 
Date: 
Printed Name: 

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Appendix C:  Grading of acute graft--vs-host disease  
Organ 
Stage 
Description 
Skin 
1 
Maculopapular rash over <25% of body area 
2 
Maculopapular rash over 25–50% percent of body area 
3 
Generalized erythroderma 
4 
Generalized erythroderma with bullous formation and often with 
desquamation 
Liver 
1 
Bilirubin 2.0–3.0 mg/dL; SGOT 150–750 IU 
2 
Bilirubin 3.1– 6.0 mg/dL 
3 
Bilirubin 6.1–15.0 mg/dL 
4 
Bilirubin > 15.0 mg/dL 
Gut 
1 
Diarrhea > 500 mL/day; or upper-gut symptoms with positive histology 
2 
Diarrhea > 1000 mL/day 
3 
Diarrhea > 1500 mL/day 
4 
Diarrhea > 2000 mL/day; or severe abdominal pain ± ileus 
Glucksberg Grade: 
I 
Stage 1 or 2 skin involvement; no liver or gut involvement; ECOG PS 0 
II 
Stage 1–3 skin involvement; Stage 1 liver or gut involvement; ECOG PS 1 
III 
Stage 2–3 skin, liver, or gut involvement; ECOG PS 2 
IV 
Stage 1–4 skin involvement; Stage 2–4 liver or gut involvement; ECOG PS 3 
 
Abbreviations:  SGOT:  serum glutamic oxaloacetic transaminase; ECOG:  Eastern 
Cooperative Oncology Group; PS:  performance status. 

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Appendix D:  Assessment of chronic graft--vs-host disease 
 
Assessment of chronic GvHD will be performed using the 2015 NIH consensus criteria 
(23).  The diagnosis of chronic GvHD requires at least 1 diagnostic manifestation of 
chronic GvHD or at least 1 distinctive manifestation plus a pertinent biopsy, laboratory, 
or other tests (eg, pulmonary function tests [PFT], Schirmer’s test), evaluation by a 
specialist (ophthalmologist, gynecologist), or radiographic imaging showing chronic 
GvHD in the same or another organ, unless stated otherwise. 
The follow table describes the diagnostic, distinctive, other features, or features 
common to both acute and chronic GvHD: 

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Assessment of chronic GvHD will be performed only if a subject has a diagnosis of 
chronic GvHD.  Organ systems will be scored as outlined in the following table: 
 
 
 

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Appendix E:  Inhibitors and Inducers of CYP3A 
Inhibitors of CYP3A are defined as follows.  A comprehensive list of inhibitors can be found at 
the following website:  http://medicine.iupui.edu/clinpharm/ddis/table.aspx.  The general 
categorization into strong, moderate, and weak inhibitors according to the website is displayed 
below.  Refer to Section 6 on instructions for concomitant use of CYP3A inhibitors and inducers 
with ibrutinib. 
 
Inhibitors of CYP3A 
Inducers of CYP3A 
Strong inhibitors: 
carbamazepine 
indinavir 
efavirenz 
nelfinavir 
nevirapine 
ritonavir 
barbiturates 
clarithromycin 
glucocorticoids 
itraconazole 
modafinil 
ketoconazole 
oxcarbarzepine 
nefazodone 
phenobarbital 
saquinavir 
phenytoin 
suboxone 
pioglitazone 
telithromycin 
rifabutin 
cobicistat 
rifampin 
boceprevir 
St John’s Wort 
mibefradil 
troglitazone 
telaprevir 
 
troleandomycin 
 
posaconazole 
 
Moderate inhibitors: 
 
aprepitant 
 
amprenavir 
 
amiodarone 
 
atazanavir 
 
ciprofloxacin 
 
crizotinib 
 
darunavir/ritonavir 
 
dronedarone 
 
erythromycin 
 
diltiazem  
 
fluconazole 
 
fosamprenavir 
 
grapefruit juice 
 
Seville orange juice 
 
verapamil 
 
voriconazole 
 
imatinib 
 

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Weak inhibitors: 
 
cimetidine 
 
fluvoxamine 
 
All other inhibitors: 
 
chloramphenicol 
 
delaviridine 
 
diethyl-dithiocarbamate 
 
gestodene 
 
mifepristone 
 
norfloxacin 
 
norfluoxetine 
 
star fruit 
 
 

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Appendix F.  Child-Pugh Score 
Measure 
1 point 
2 points 
3 points 
Total bilirubin, μmol/L (mg/dL) 
<34 (<2) 
34 to 50 (2 to 3) 
> 50 (> 3) 
Serum albumin, g/L (g/dL) 
> 35 
(> 3.5) 
28 to 35 (2.8 to 3.5) 
< 28 (< 2.8) 
PT INR 
<1.7 
1.71 to 2.30 
> 2.30 
Ascites 
None 
Mild 
Moderate to Severe 
Hepatic encephalopathy 
None 
Grade I or II (or 
suppressed with 
medication) 
Grade III or IV  
(or refractory) 
 
Points 
Class 
5-6 
A 
7-9 
B 
10-15 
C 
 
Source:  
1. Child CG, Turcotte JG.  “Surgery and portal hypertension”. In Child CG.  The liver 
and portal hypertension.  Philadelphia:Saunders. 1964. pp. 50-64.   
2. Pugh RN, Murray-Lyon IM, Dawson L, Pietroni MC, Williams R.  “Transection of 
the oesophagus for bleeding oesophageal varices”.  The British journal of 
surgery, 1973;60:646-649.