Shortened-duration Tacrolimus Following Nonmyeloablative, Related Donor BMT With High-dose Posttransplantation Cyclophosphamide
Phase: PHASE1
Conditions: Hodgkin's Lymphoma, Leukemia, Myelodysplastic Syndrome(MDS), Multiple Myeloma, Non Hodgkin's Lymphoma
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Version date: 5/1/12 
 
1 
Shortened-duration tacrolimus following nonmyeloablative, related donor BMT with high-dose 
posttransplantation cyclophosphamide  
 
PI:  
Yvette Kasamon 
 
CRB 388, 1650 Orleans St 
 
Baltimore, MD 21231 
 
Phone 410-955-8839 
 
Fax 410-955-0960 
Pager 410-283-9945 
ykasamo1@jhmi.edu 
 
Co-investigators: Ephraim Fuchs, Richard Jones, Leo Luznik, Javier Bolaños-Meade, Allen Chen, Kieren 
Marr 
 
Statisticians: Gary Rosner, Marianna Zahurak 
 
Version date: 5/1/12 (Amendment 5) 
 
Protocol history: 
Original IRB approval (version date 5/5/11): 6/28/11  
Amendment 1 (version date 7/5/11): approved 7/26/11 
Amendment 2 (version date 8/2/11): approved 8/16/11 
Amendment 3 (version date 9/28/11): approved 10/18/11 
Amendment 4 (version date 10/26/11): approved 11/15/11 
 

Version date: 5/1/12 
 
2 
INDEX 
 
Schema 
 
1.0 
Introduction 
 
1.1 Rationale for shortened-duration immunosuppression 
 
1.2 High-dose posttransplantation cyclophosphamide 
1.3 Nonmyeloablative BMT with fludarabine, TBI, and posttransplantation cyclophosphamide 
1.4 Shortened-course immunosuppression 
2.0 
Objectives  
 
2.1 Primary objective 
 
2.2 Secondary objectives 
3.0 
Selection of Patients and Donors 
 
3.1 Eligibility for transplantation 
 
3.2 Donor eligibility 
 
3.3 Donor prioritization 
 
4.0 
Registration Procedures 
4.1 Registration requirements 
4.2 Accrual goal 
5.0 
Treatment Plan 
 
5.1 Evaluations and procedures 
 
5.2 Transplantation regimen 
 
 
5.21 
Fludarabine 
 
 
5.22 
Pretransplantation cyclophosphamide 
 
 
5.23 
Total body irradiation 
 
 
5.24 
Day of rest 
 
 
5.25 
Bone marrow transplantation 
 
 
5.26 
Posttransplantation cyclophosphamide 
 
 
5.27 
Mycophenolate mofetil 
 
 
5.28 
Tacrolimus 
 
 
 
5.281 Tacrolimus initiation and dosing 
 
 
 
5.282 Tacrolimus duration 
 
 
 
5.283 Eligibility for protocol-driven, early cessation of tacrolimus 
 
 
 
5.284 Tacrolimus cessation in the context of pending evaluations 
 
 
 
5.285 Changes in planned tacrolimus duration 
 
 
 
5.286 Evaluability for the primary endpoint 
 
 
5.29 
Growth factors 
 
5.3 Supportive care   
 
 
5.31 
Anti-ovulatory treatment 
 
 
5.32 
Intravenous access 
 
 
5.33 
Infection prophylaxis 
 
 
5.34 
Antiemetics 
 
5.4 Posttransplantation therapies 
 
 
5.41 
Donor lymphocyte infusion 
 
 
5.42 
Posttransplantation systemic therapy 
 
 
5.43 
Posttransplantation radiation 
 
5.5 Posttransplantation follow-up 
6.0 
Measurement of Effect and Endpoints 
6.1 Hematologic parameters 
6.11 
Neutrophil recovery 
6.12 
Platelet recovery 
6.13 
Donor chimerism 

Version date: 5/1/12 
 
3 
6.14 
Graft failure 
6.2 Graft-versus-host disease 
6.21 
Acute GVHD 
6.22 
Chronic GVHD 
6.3 Disease and survival endpoints 
6.31 
Progression-free survival 
6.32 
Event-free survival 
6.33 
Overall survival 
6.34 
Nonrelapse mortality 
6.35 
Relapse or progression 
6.36 
Minimal residual disease 
 
6.4 Correlative studies 
7.0 
Study Parameters 
8.0 
Risks and Reporting Requirements 
 
8.1 Drug information 
 
 
8.11 
Cyclophosphamide 
 
 
8.12 
Mesna 
 
 
8.13 
Fludarabine 
 
 
8.14 
Total body irradiation 
 
 
8.15 
Mycophenolate mofetil 
 
 
8.16 
Tacrolimus 
 
8.2 Toxicity grading 
 
8.3 Toxicity reporting 
 
8.4 Monitoring plan 
 
8.5 Risks and benefits 
9.0 
Statistical Considerations 
 
9.1 Primary endpoint and design 
 
 
9.11  
Sequence of study 
 
 
9.12 
Criteria for feasibility and safety 
 
 
9.13 
Operating characteristics of design 
 
9.2 Secondary endpoints 
10.0 
Pathology Review 
11.0 
Records to be Kept 
12.0 
Patient Consent and Peer Judgment 
13.0 
References 
 
Appendix 
A. Acute GVHD Grading 
B. Statistical Supplement 
 

Version date: 5/1/12 
 
4 
SCHEMA a 
 
Days –6, –5                           Fludarabine 30 mg/m2 IV daily (adjusted for renal function) 
 
Cyclophosphamide 14.5 mg/kg IV daily   
            
Days –4, –3, –2 
Fludarabine 30 mg/m2 IV daily 
 
 
Day –1 
TBI 200 cGy        
 
 
 
 
Day 0 
Infuse T-cell replete bone marrow 
 
Begin antibiotic prophylaxis 
 
 
Days 3, 4 
Cyclophosphamide 50 mg/kg IV QD 
 
Mesna 40 mg/kg IV QD in divided doses 
                              
 
Day 5   Begin tacrolimus (1 mg IV QD for pts > 18 y), with planned duration as below b 
                
MMF 15 mg/kg PO TID (maximum 3 g/day) 
(Immunosuppression must begin at least 24 hours after Cy completion) 
 
 
Begin GCSF 5 g/kg/d SC or IV, continue until ANC > 1000/mm3 over 3 days 
  
 
Day 28 (+/- 3 d) 
Assess chimerism 
 
   
Day 35  
          Discontinue MMF (optional if GVHD has occurred) 
 
 
Day 56 (+/- 3 d) 
Assess chimerism, GVHD  
Day 56 (+/- 3 d) 
Evaluate disease  
 
 
Day 84 (+/- 5 d) 
Assess chimerism, GVHD 
 
 
Day 112 (+/- 7 d)  
Assess chimerism, GVHD  
 
 
Day 180 (+/- 7 d) 
Assess chimerism, GVHD  
 
Evaluate disease 
 
 
Day 270 (+/- 21 d) 
Assess chimerism, GVHD 
 
 
1 yr (+/- 30 d) 
Assess chimerism 
 
1 yr (+/- 30 d) and beyond 
Evaluate disease, GVHD  
 
 
Shortened-course tacrolimus if eligible: up through Day 90 (starting regimen), Day 60, or Day 120 c 
If ineligible: continue tacrolimus up through Day 180 d  
 
a See Section 5.2 for complete dosing instructions, and Section 7.0 for required evaluations. 
b See Section 5.281 for tacrolimus dosing in younger patients. 
c See Section 5.283 for eligibility. 
d Per Section 5.282. 

Version date: 5/1/12 
 
5 
1.0 
INTRODUCTION 
Recent advances in allogeneic blood or marrow transplant (BMT) platforms for hematologic malignancies 
have substantially lowered transplant-related morbidity both in the HLA-matched and partially HLA-
mismatched settings.  One of these major advances is the incorporation of high-dose posttransplantation 
cyclophosphamide (Cy) for prophylaxis of graft-versus-host-disease (GVHD) and graft rejection, as 
developed at Johns Hopkins.1  For nonmyeloablative, related donor, HLA haploidentical or matched BMT, 
our postgrafting immunosuppression has standardly consisted of two doses of high-dose Cy, mycophenolate 
mofetil (MMF) for one month, and tacrolimus without taper until Day 180.  However, there are several 
potential advantages to shorter-duration pharmacologic immunosuppression. The current study builds on our 
transplantation platform that incorporates high-dose posttransplantation Cy, by investigating the feasibility 
and safety of shorter planned durations of pharmacologic immunosuppression with tacrolimus.    
 
1.1  
Rationale for shorter-duration immunosuppression 
With the advent of posttransplantation high-dose Cy, our nonmyeloablative allogeneic BMT platforms have 
been associated with acceptable rates of acute GVHD, graft failure, and nonrelapse mortality (NRM) that are 
similar to those seen with HLA-matched transplants.2,3  However, relapse remains a major problem, and 
approaches that augment the anti-tumor efficacy of the transplant procedure are needed.  Transplantation 
platforms that minimize the amount of pharmacologic immunosuppression, but that carry acceptable rates of 
severe GVHD and graft failure, are desirable for a number of reasons.  Less pharmacologic 
immunosuppression has the potential to a) lower the risk of relapse by facilitating a graft-versus-tumor 
effect, and b) facilitate the development of immunotherapies in the transplant setting, including tumor 
vaccines.  In addition, it has the potential to lower the risk of opportunistic infections, and to lower the 
likelihood or severity of drug toxicities. 
 
Extensive published data demonstrate that allogeneic BMT can be associated with a clinically significant 
graft-versus-tumor (GVT) effect mediated by donor T cells specific for host histocompatibility antigens.  
Yet, the T cells that mediate a GVT effect may also cause clinically significant GVHD.   
Tacrolimus, a calcineurin inhibitor (CNI), blocks T cell activation and the production of interleukin-2, a 
critical growth factor for T cells including regulatory T cells that control autoimmunity.  CNI’s are used to 
prevent acute GVHD, but they are associated with an increased incidence of renal dysfunction, hypertension, 
opportunistic infection, and other complications.  Importantly, CNI’s block T cell development in the 
thymus16,17 resulting in delayed immunologic reconstitution, and by suppressing T cell activation may block 
the GVT effect and increase the risk of disease relapse after allogeneic BMT.18-20   
 
Posttransplantation immunotherapy in order to augment the anti-tumor efficacy of the transplant is an area of 
ongoing research.  In addition, pretransplantation vaccination of donor T cells against tumor-associated 
antigens has the potential to augment the anti-tumor effect of allogeneic BMT without increasing the 
incidence or severity of GVHD.  A number of antigens specific to or highly expressed by hematologic 
malignancies have been identified, including myeloma idiotype,4 the Wilms Tumor 1 antigen, PRAME, and 
proteinase-3 5 in AML, and the bcr-abl fusion protein of CML.6,7  Clinical trials of peptide-based tumor 
vaccines in the non-BMT setting have been conducted, with some promising immunologic and clinical 
outcomes.8  The major obstacles to obtaining clinical responses to tumor vaccines are pre-existing T cell 
tolerance 9,10 as well as tumor 11- or therapy-induced immunosuppression.   
 
1.2 
High-dose posttransplantation cyclophosphamide 
The immunologic rationale for administering high-dose Cy after transplantation is that recently activated, 
alloreactive T cells (the cells most responsible for GVHD) are selectively sensitive to the toxic effects of this 
drug.12  High-dose Cy, when administered in a narrow window after transplantation, depletes alloreactive T 
cells from the donor and host and can inhibit both GVHD and graft rejection.12-17  As a form of drug-induced 
immunologic tolerance,18 the strategy of giving high-dose Cy after transplantation takes advantage of the 
heightened cytotoxic sensitivity of proliferating, alloreactive T cells over non-alloreactive, resting T cells to 
being killed by a DNA-damaging agent.19 Pre-clinical studies demonstrated that engraftment of major 

Version date: 5/1/12 
 
6 
histocompatibility complex (MHC)-mismatched bone marrow could be achieved by conditioning mice with 
pretransplantation fludarabine and low dose (200 cGy) total body irradiation (TBI), with posttransplantation 
Cy.14  Additional studies demonstrated that posttransplantation Cy reduced the incidence and severity of 
GVHD in the setting of MHC-mismatched allogeneic BMT after myeloablative conditioning.13  
After allogeneic BMT, standard regimens of GVHD prophylaxis consist of a CNI (cyclosporine or 
tacrolimus) in combination with either methotrexate, MMF, or sirolimus.  However, a nonmyeloablative, 
partially HLA-mismatched (haploidentical), related donor BMT platform with high-dose posttransplantation 
Cy, MMF, and tacrolimus for GVHD and graft rejection prophylaxis has produced encouraging results 3.  
This approach has been associated with rapid and stable engraftment in most patients.3  Most importantly, 
this approach has carried acceptable rates of GVHD and NRM that parallel those seen with nonmyeloablative 
HLA-matched transplants (Figure 1).2,3,20,21  Cy, when administered at high doses after myeloablative, HLA-
matched, related or unrelated donor BMT, notably has been found to be effective single-agent prophylaxis 
against GVHD, obviating the need for CNI’s in this setting (Figure 1).22   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1. Acute GVHD after BMT incorporating high-dose posttransplantation Cy. A) 
nonmyeloablative BMT.3  B) myeloablative, HLA-matched, related or unrelated donor BMT, with Cy as 
single-agent prophylaxis.22 
 
1.3 
Nonmyeloablative BMT with fludarabine, TBI, and posttransplantation cyclophosphamide 
Independent clinical trials have evaluated or are evaluating a nonmyeloablative, partially HLA-mismatched 
(haploidentical), related donor BMT platform with high-dose posttransplantation Cy, tacrolimus, and MMF 
for GVHD and graft rejection prophylaxis.  Conditioning in these studies has historically consisted of 
fludarabine, low-dose Cy, and 200 cGy TBI.  The postgrafting immunosuppression regimen that underlies 
recent and ongoing research efforts at Johns Hopkins has been published.3,21  A combined analysis of two 
independent clinical trials for poor-risk hematologic malignancies was originally reported in 2008 (40 
patients at Johns Hopkins, 28 at Fred Hutchinson Cancer Research Center), evaluating the safety and efficacy 
of a high-dose posttransplantation Cy platform after outpatient nonmyeloablative conditioning and T-cell-
replete BMT from partially HLA-mismatched, related donors (Figure 2).3  Following transplantation, high-
dose (50 mg/kg) Cy was administered on Day 3 (Seattle group), or on Days 3 and 4 (Hopkins).  
Pharmacologic prophylaxis of GVHD was initiated on the day following completion of posttransplantation 
Cy with MMF until Day 35, and tacrolimus which was tapered to off by Day 180 (Seattle) or continued at 
full dose until Day 180 (Hopkins).  Filgrastim 5 g/kg/day was administered until recovery of neutrophils to 
>1000/L: 
 
A
B

Version date: 5/1/12 
 
7 
 
Figure 2. Treatment Schema in Previous Studies 
 
Median times to recovery of neutrophils and platelets were 15 and 24 days, respectively.  Graft failure 
occurred in 9 of 66 evaluable patients (12%); all but one patient with graft failure had recovery of autologous 
hematopoiesis with median times to neutrophil and platelet recovery of 15 days (range, 11-42) and 28 days 
(range, 0 – 395 days) respectively.  Engrafting patients achieved full donor chimerism rapidly; with few 
exceptions, donor chimerism in patients with sustained engraftment was virtually complete (>95%) by 2 
months after transplantation.  The cumulative incidences of acute grade II-IV GVHD and acute grade III-IV 
GVHD by Day 200 were <35% and <10%, respectively, on competing-risk analysis.  The groups did not 
differ significantly in the incidence of acute grade II-IV or III-IV GVHD, although the risk of chronic GVHD 
appeared to be lower with two doses of Cy. The cumulative incidence of extensive chronic GVHD by 1 year 
was only 5% in the group with two doses of Cy. The cumulative incidences of relapse and NRM at 1 year 
were 51% and 15% respectively on competing-risk analysis; however the event-free survival (EFS) 
probability at 1 year was only 34%.  Similar outcomes were seen in a recent analysis of 185 patients treated 
on these trials including follow-up phase II trial (J0457) of this approach.21  Interestingly, although 
increasing degrees of HLA mismatch between donor and recipient have historically been associated with 
greater GVHD and inferior survival after allogeneic BMT, that analysis retrospectively found no such 
adverse effect of HLA mismatching using this approach in the haploidentical setting.21   
 
On an updated analysis of 212 patients with advanced hematologic malignancies, uniformly treated at Johns 
Hopkins with related donor, partially HLA-mismatched BMT with fludarabine/Cy/TBI conditioning and 
postgrafting immunosuppression with 2 doses of Cy, MMF on Days 5-35, and full-dose tacrolimus on Days 
5-180, the 1-year EFS was 44%, and cumulative incidence of NRM by competing risk analysis was 8% by 
Day 100 and 14% at 1 year.  The cumulative incidence of acute grade II-IV GVHD was 28% by Day 200, 
cumulative incidence of severe GVHD was only 4%, and the cumulative incidence of chronic GVHD was 
14% by competing risk analysis (unpublished data).    
 
The same approach to nonmyeloablative BMT using partially HLA-mismatched, related donors has been 
adopted at Johns Hopkins for HLA-identical donor BMT.  In a phase I trial (J0169) of nonmyeloablative, 
matched sibling donor BMT, Cy alone on Day 3, Cy alone on Days 3 and 4, or Cy on Days 3 and 4 with 
MMF was investigated with the latter being favored.  Although the optimal postgrafting immunosuppression 
after high-dose Cy is not defined, MMF plus a CNI is the industry-standard GVHD prophylaxis for 
nonmyeloablative conditioning (i.e. omission of a CNI is nonstandard).  At Johns Hopkins we have used the 
approach developed in over 200 nonmyeloablative haploidentical transplants described above in our 
nonmyeloablative matched unrelated donor (MUD) transplants, and have recently adopted this for our 
nonmyeloablative matched sibling transplants as well.  This is similar to most centers that use the same 
nonmyeloablative conditioning and GVHD prophylaxis for matched sibs and MUDs.  
 
In summary, HLA-haploidentical BMT after non-myeloablative conditioning and using 2 doses of 
posttransplantation Cy followed by MMF for one month and tacrolimus for up to 6 months is a generally 
well-tolerated procedure that can be administered largely in an intensified outpatient setting.  The toxicity of 

Version date: 5/1/12 
 
8 
the procedure compares favorably to the toxicity of non-myeloablative transplantation using unrelated or 
even HLA-identical sibling donors.2 The major cause of treatment failure in this high-risk population is 
relapse, occurring in approximately 50% of patients by 1 year.  Therefore, investigations of strategies that 
may lower the risk of relapse are needed.  Towards this end, a strategy of reduced-duration pharmacologic 
immunosuppression is herein investigated. 
 
1.4 
Shortened-course immunosuppression 
MMF plus a CNI (i.e. tacrolimus or cyclosporine) is an industry-standard GVHD prophylaxis for 
nonmyeloablative conditioning.  However, optimal postgrafting immunosuppression after high-dose Cy is 
not defined, nor is the optimal type or duration of postgrafting immunosuppression fully defined in 
allogeneic BMT in general.   
 
For example, in nonmyeloablative, HLA-matched BMT with postgrafting immunosuppression consisting 
solely of MMF + cyclosporine, investigators at the Fred Hutchinson retrospectively evaluated three durations 
of cyclosporine: taper from Days 35 to 56, Days 56 to 77, or Days 56 to 180.23  Grafts were derived from 
peripheral blood stem cells.  There was no significant association between cyclosporine duration and the 
rates of acute grade II-IV GVHD (57%, 43%, and 49% respectively), extensive chronic GVHD, or NRM; 
however, longer duration of cyclosporine was associated with a lower risk of acute severe (grade III-IV) 
GVHD and lower incidence of discontinuation of all systemic immunosuppression by 24 months (an indirect 
marker of the prevention and successful treatment of GVHD).   
 
In an older randomized trial of myeloablative, HLA-identical or one-antigen mismatched BMT, where 
postgrafting immunosuppression consisted of methotrexate and cyclosporine with or without 
methylprednisolone, results suggested that cyclosporine could be stopped earlier (by Day 60) in patients 
without prior acute GVHD, whereas those with prior acute GVHD appeared to benefit from a longer course 
24.  In another randomized trial of myeloablative, HLA-matched related or unrelated donor BMT, the risk of 
clinically extensive chronic GVHD and transplant-related mortality did not significantly differ in patients 
assigned to 6 months versus 24 months of cyclosporine.25  Other nonrandomized studies of myeloablative, 
HLA-matched sibling transplant have suggested a benefit to longer duration cyclosporine in chronic GVHD 
prevention.26  However, some studies have found an increased risk of relapse associated with higher doses of 
cyclosporine.27,28  
 
The experiences with immunosuppression duration with other allogeneic BMT platforms cannot be directly 
extrapolated to the high-dose posttransplantation Cy platform.  Immunosuppression must be sufficient to 
prevent graft failure and to prevent excessive rates of GVHD including severe GVHD; yet extended-course 
immunosuppression may increase the risk of infection, drug toxicity, and relapse.  There are presently no 
published data on the minimum required duration of tacrolimus after nonmyeloablative BMT that includes 
high-dose Cy as part of postgrafting immunosuppression.  The effectiveness of high-dose posttransplantation 
Cy in GVHD prevention, however, permits the investigation of this question. 
 
2.0 
OBJECTIVES 
 
2.1 
Primary objective  
In nonmyeloablative, related donor, partially HLA-mismatched or HLA-matched BMT with post-
grafting immunosuppression that includes high-dose cyclophosphamide and MMF, evaluate the 
safety and feasibility of reduced-duration tacrolimus (from Day 5 through either Day 90, Day 60, or 
Day 120). 
 
2.2 
Secondary objectives 
1. In patients eligible for reduced-duration tacrolimus, estimate the incidences of acute grade II-IV 
GVHD, acute grade III or higher GVHD, chronic GVHD (overall and by extent), graft failure, 

Version date: 5/1/12 
 
9 
relapse, and NRM between the date of early tacrolimus cessation and Day 180, and beyond Day 
180. 
2. Estimate the cumulative incidence of acute grade II-IV GVHD, acute grade III-IV GVHD, 
chronic GVHD, relapse/progression, and NRM for the group overall. 
3. Estimate the cumulative incidence of systemic steroid initiation, the cumulative incidence of 
non-steroid immunosuppression use, and the cumulative incidence of discontinuation of 
systemic immunosuppression for GVHD treatment by 1 year and 2 years after BMT for the 
group overall and for patients with shortened-duration tacrolimus; and describe the number and 
types of systemic immunosuppression used for GVHD treatment. 
4. Estimate the event-free survival, progression-free survival, and overall survival after 
transplantation. 
5. Describe the graft failure frequency, kinetics of neutrophil and platelet recovery, and kinetics of 
donor chimerism in unsorted and CD3+ sorted peripheral blood. 
6. Characterize immune reconstitution after transplantation and its relationship to duration of 
pharmacologic immunosuppression and clinical outcomes. 
7. Describe major toxicities and complications associated with the transplantation procedure.  
8. Evaluate selected patient and transplant characteristics in relation to transplantation outcomes. 
 
 
3.0 
SELECTION OF PATIENTS AND DONORS   
 
3.1 
Eligibility for transplantation 
The following are eligibility for study entry and transplantation.  Eligibility criteria for protocol-
driven, early cessation of tacrolimus are designated in Section 5.283. 
1. Patient age 0.5-75 years  
2. Presence of a suitable first-degree related, HLA-haploidentical or HLA-matched bone marrow 
donor.  
a. The donor and recipient must be identical at at least one allele of each of the following 
genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB1.  A minimum 
match of 5/10 is therefore required, and will be considered sufficient evidence that the 
donor and recipient share one HLA haplotype.  
3. Eligible diagnoses:  
a. Low-grade non-Hodgkin’s lymphoma or plasma cell neoplasm with either of the 
following, and with stable disease or better prior to transplantation: 
i. Progressed during multiagent therapy, failed at least two prior therapies 
(excluding single agent rituximab), or there is evidence of prior transformation 
ii. SLL or CLL with 11q or 17p deletion or with progression < 6 months after a 
purine analog-containing regimen 
b. Relapsed, refractory, or progressive aggressive non Hodgkin’s lymphoma (including 
mantle cell lymphoma), with PR or better prior to transplantation, and autologous BMT 
is not recommended. 
Note: Patients with Burkitt’s, atypical Burkitt’s, or acute lymphoblastic lymphoma 
must be in CR. 
c. Relapsed, refractory, or progressive Hodgkin’s lymphoma meeting one of the following 
criteria, and autologous BMT is not recommend: 
i. 
PR or better prior to transplantation. 
ii. Stable disease prior to transplantation, provided that the disease is low-volume 
and disease control is regarded as sufficient to proceed with BMT.  Eligibility of 
such patients will be determined on a case-by-case basis with the PI or co-PI. 
d. One of the following poor-risk lymphomas or plasma cell neoplasms, in PR or better prior 
to transplantation: 
i. Transformed lymphoma 
ii. T-cell PLL 

Version date: 5/1/12 
 
10
iii. Peripheral T-cell lymphoma 
iv. NK or NK/T-cell lymphoma  
v. Blastic/blastoid mantle cell lymphoma 
vi. Plasma cell leukemia  
e. For patients with SLL, CLL, or PLL, < 20% of bone marrow cellularity involved by this 
process (to lower risk of graft rejection). 
f. Relapsed, refractory, or progressive acute leukemia in second or subsequent remission, 
with remission defined as <5% bone marrow blasts morphologically. 
g. Poor-risk acute leukemia in first remission, with remission defined as <5% bone marrow 
blasts morphologically: 
i. AML with at least one of the following:  
 
AML arising from MDS or a myeloproliferative disorder, or secondary 
AML 
 
Presence of Flt3 internal tandem duplications 
 
Poor-risk cytogenetics 
 
Primary refractory disease 
ii. ALL (leukemia and/or lymphoma) with at least one of the following: 
 
Poor-risk cytogenetics 
 
Clear evidence of hypodiploidy 
 
Primary refractory disease  
iii. Biphenotypic leukemia 
h. MDS with at least one of the following poor-risk features: 
i. Poor-risk cytogenetics 
ii. IPSS score of INT-2 or greater 
iii. Treatment-related or secondary MDS 
iv. MDS diagnosed before age 21 years 
v. Progression on or lack of response to standard DNA-methyltransferase inhibitor 
therapy 
vi. Life-threatening cytopenias, including those requiring frequent transfusions 
i.  Interferon- or imatinib-refractory CML in first chronic phase, or CML in second or 
subsequent chronic phase 
j. 
Philadelphia chromosome negative myeloproliferative disease (including myelofibrosis) 
k. Chronic myelomonocytic leukemia 
l. 
Juvenile myelomonocytic leukemia 
4. One of the following, to lower risk of graft rejection: 
a. Cytotoxic chemotherapy, alemtuzumab, or an adequate course of 5-azacitidine or 
decitabine within 3 months prior to start of conditioning; or 
b. Previous BMT within 6 months prior to start of conditioning 
Note: Patients who have received treatment outside of these windows may be 
eligible if it is deemed sufficient to reduce graft rejection risk; this will be decided 
on a case-by-case basis by the PI or co-PI. 
5. No active extramedullary leukemia or known active CNS involvement by malignancy.  Such 
disease treated into remission is permitted. 
6. Any previous BMT must have occurred at least 3 months prior to start of conditioning. 
7. No previous allogeneic BMT (syngeneic BMT permissible). 
8. Adequate end-organ function as measured by: 
a. Left ventricular ejection fraction  35% or shortening fraction > 25% 
b. Bilirubin ≤ 3.0 mg/dL (unless due to Gilbert’s syndrome or hemolysis), and ALT and 
AST < 5 x ULN 
c. FEV1 and FVC > 40% of predicted; or if unable to perform pulmonary function tests due 
to young age, oxygen saturation >92% on room air  

Version date: 5/1/12 
 
11
9. ECOG performance status < 2 or Karnofsky or Lansky score > 60. 
10. Not pregnant or breast-feeding. 
11. No uncontrolled infection.  
Note:  Infection is permitted if there is evidence of response to medication. 
Eligibility of HIV infected patients will be determined on a case-by-case basis.   
 
3.2 
Donor eligibility 
1. Donors must be HLA-haploidentical or HLA-identical, first-degree relatives of the patient based 
on allele or allele group level typing as defined in Section 3.1.  Half-siblings are not permitted. 
2. Medically fit to and willing to donate 
3. Lack of recipient anti-donor HLA antibody 
Note: In some instances, low level, non-cytotoxic HLA specific antibodies may be 
permissible if they are found to be at a level well below that detectable by flow cytometry.  
This will be decided on a case-by-case basis by the PI and one of the immunogenetics 
directors. Pheresis to reduce anti-HLA antibodies is permissible; however eligibility to 
proceed with the transplant regimen would be contingent upon the success of the 
desensitization.  
4. Has not donated blood products to patient 
 
3.3 
Donor prioritization  
Donors will be prioritized in the following order:   
1. Fit to donate 
2. HLA-matched prioritized over HLA-mismatched  
3. Lack of major ABO incompatibility  
In order of priority: 
 
 
a.   Compatible 
 
 
b.   Minor incompatibility 
 
 
c.   Major incompatibility  
4. CMV serostatus: CMV negative donor preferred, if the patient is CMV negative; CMV positive 
donor preferred, if the patient is CMV is positive. 
 
Other factors such as donor age and health history will be integrated into the donor selection process 
per standard practice and may be prioritized over HLA, ABO and CMV status.   
 
4.0 
REGISTRATION PROCEDURES 
 
4.1 
Registration requirements  
Patients will be registered in the CRMS.  The following are additionally required: 
1. Signed and dated informed consent  
2. Patient eligibility checklist(s) 
 
A registration may be cancelled, provided that protocol treatment has not been begun.   
 
4.2 
Accrual goal 
The goal is to transplant up to 55 patients per planned duration of immunosuppression (per Section 
9.0), with up to 5 additional patients transplanted per regimen to replace unevaluable patients (per 
Section 5.286).  Contingent on feasibility and safety outcomes, up to two reduced durations of 
tacrolimus will be investigated and thus a targeted maximum of 110 patients will be transplanted. 
The cap is 140 transplanted patients, to account for inevaluable patients or patients who are assigned 
to the Day 120 arm pending full evaluation of the Day 90 arm (per Section 9.11) .  Additional 
patients may be screened, consented, and registered, in order to reach accrual goals. 
 

Version date: 5/1/12 
 
12
Every effort will be made to recruit women and minorities to this study. 
 
5.0 
TREATMENT PLAN 
 
5.1   
Evaluations and procedures 
Required evaluations are designated in Section 7.0.   
 
5.2 
Transplantation regimen 
The preparative regimen in each case consists of fludarabine, Cy, and TBI, with posttransplantation 
high-dose Cy, MMF, and tacrolimus. 
5.21 
Fludarabine 
Fludarabine 30 mg/m2/day (adjusted for renal function) is administered over a 30-60 minute IV 
infusion on Days –6 through –2 (maximum cumulative dose, 150 mg/m2). 
 
The body surface area (BSA) for fludarabine dosing is based on actual body weight.   
 
For decreased creatinine clearance (CrCl), fludarabine dosage is reduced as follows: 
 
 
CrCl  46-60 mL/min, fludarabine = 24 mg/m2 
 
 
CrCl 31-45 mL/min, fludarabine = 22.5 mg/m2 
 
 
CrCl 21-30 mL/min, fludarabine = 19.5 mg/m2 
 
 
CrCl < 20 mL/min, fludarabine  = 15 mg/m2 
 
For patients > 18 years old, CrCl will be estimated by the Cockcroft Formula, based on ideal body 
weight (IBW):  
 
 
CrCl = (140 – age) x IBW (kg)   x   0.85 for females 
 
 
                       PCr x 72 
For patients <18 years old, CrCl will be estimated by the Schwartz equation: 
Schwartz equation: CrCl (mL/min/1.73m2)= [length (cm) x k] / serum creatinine 
 
k = 0.45 for infants 1 to 52 weeks old 
k = 0.55 for children 1 to 13 years old 
k = 0.55 for adolescent females 13-18 years old 
k = 0.7 for adolescent males 13-18 years old 
A measured CrCl or a glomerular filtration rate may be substituted to determine CrCl. 
CrCl  may change during the days fludarabine is given.  The dose should be adjusted accordingly; 
however a fludarabine dose may be given based on the preceding day’s estimated CrCl .  
             
 
5.22 
Pretransplantation cyclophosphamide  
Cy 14.5 mg/kg/day is administered as a 1-2 hour IV infusion on Days –6 and –5 after hydration.  
Mesna 11.6 mg/kg IV daily on Days –6 and –5 is not required, but may be given.   
 
Cy and mesna are dosed according to IBW, unless the patient weighs less than IBW, in which case 
dose drug according to actual weight.   
 
 
5.23  
Total body irradiation  

Version date: 5/1/12 
 
13
200 cGy TBI is administered in a single fraction on Day –1.  Radiation sources, dose rates, and 
shielding follow institutional practice.   
 
 
5.24 
Day of rest 
A day of rest, i.e. after preparative regimen completion and prior to bone marrow infusion, is not 
routinely scheduled.  Up to two days of rest may be added in this window based on logistical 
considerations or clinically as indicated.  For one day of rest, fludarabine would be administered on 
Days –7 through –3, pretransplantation Cy on Day –7 and Day –6, and TBI on Day –2.  For two days 
of rest, fludarabine would be administered on Days –8 through –4, pretransplantation Cy on Day –8 
and Day –7, and TBI on Day –3. 
 
 
5.25  
Bone marrow transplantation 
On Day 0, bone marrow is infused.  Donor bone marrow will be harvested with a target yield of 4 x 
108 nucleated cells/kg recipient IBW.  Peripheral stem cell harvest is not permitted because of the 
increased risk of GVHD.  Sample of the product to be infused will be sent for flow cytometry to 
determine the content of CD34+ and CD3+ cells.  Graft dose including total nucleated cells 
infused/kg, CD34+ cells infused/kg, and CD3+ cells infused/kg will be recorded.   
 
The graft will not be manipulated to deplete T cells.  Processing for ABO incompatibility follows 
institutional practices.  Guidelines for bone marrow infusion are established and outlined in the ABO 
compatible/minor mismatched allogeneic BMT or the ABO incompatible allogeneic BMT standing 
orders.   
 
5.26 
Posttransplantation cyclophosphamide  
Hydration prior to Cy, management of volume status, and monitoring for hemorrhagic cystitis will 
follow institutional standards.  Intravenous hydration will be started at least 2 hours prior to Cy and 
continued for at least 8 hours post-Cy.  Urine output should be at least 3 mg/kg (actual body weight) 
before Cy is administered. 
 
Mesna is given in divided doses IV 30 minutes pre- and at 3, 6, and 8 hours post-Cy, unless patients 
are treated in the Children’s Center in which case mesna is dosed per pediatric oncology standard 
(e.g., divided doses IV 30 minutes pre- and at 3, 6 and 9 hours post-Cy).  The total daily dose of 
mesna is equal to 80% of the total daily dose of Cy. 
 
Cy and mesna are dosed according to IBW, unless the actual body weight is less, in which case dose 
drugs according to actual body weight.   
 
Cy 50 mg/kg IV, over approximately 1-2 hours (depending on volume), is given on Day 3 
posttransplantation (ideally between 60 and 72 hours after marrow infusion) and on Day 4 
(approximately 24 hours after Day 3 Cy).   
 
It is crucial that no systemic immunosuppressive agents are given from Day 0 until at least 24 
hours after the completion of the posttransplantation Cy.  This includes corticosteroids as anti-
emetics.  
 
5.27 
Mycophenolate mofetil  
MMF begins on Day 5, at least 24 hours after completion of posttransplantation Cy.  The MMF dose 
is 15 mg/kg PO TID (actual body weight) with total daily dose not to exceed 3 grams (i.e. maximum 
1 g PO TID).  Doses are rounded to the nearest strength tablets.  Equivalent IV dosing (1:1 
conversion) may instead be given.  Guidelines for dose modification are provided in Section 8.15. 
MMF prophylaxis is discontinued after the last dose on Day 35, or may be continued if there is 
GVHD.  

Version date: 5/1/12 
 
14
 
5.28 
Tacrolimus  
 
 
5.281 Tacrolimus initiation and dosing 
Tacrolimus begins on Day 5, at least 24 hours after completion of posttransplantation Cy.  
Duration of tacrolimus is designated in Section 5.282. 
 
For patients > 18 years old, the tacrolimus starting dose is 1 mg IV QD.  Tacrolimus can be 
changed to a PO BID dosing schedule once a stable therapeutic level is achieved and the 
patient can tolerate PO medications.  Dose is adjusted to maintain a serum trough level of 10 
– 15 ng/mL, with a minimum acceptable trough level of 5 ng/mL.  
 
For patients < 18 years old, the starting dose of tacrolimus is 0.015 mg/kg IV Q12 hours, 
based on IBW unless the actual body weight is less. Tacrolimus can be changed to a PO BID 
dosing schedule once a stable therapeutic level is achieved and the patient can tolerate PO 
medications.  Dose is adjusted to maintain a serum trough level of 10 – 15 ng/mL, with a 
minimum acceptable trough level of 5 ng/mL.  
 
In the case of prohibitive toxicities to calcineurin inhibitors (e.g., PRES), other 
immunosuppression may be given after case-by-case discussion with the PI or co-PI.   
 
 
 
 
 
5.282 Tacrolimus duration 
The tacrolimus duration is assigned prospectively in cohorts of patients before initiation of 
the preparative regimen.  Up to two of the following three regimens of shortened-duration 
tacrolimus will be investigated, beginning with tacrolimus up through and including Day 90.  
The sequence and evaluation of regimens is specified in Section 9.0. 
 
 
Stop tacrolimus after last dose on Day 90 
 
or  
Stop tacrolimus after last dose on Day 60  
 
or 
Stop tacrolimus after last dose on Day 120  
 
Eligibility for protocol-driven, early tacrolimus discontinuation is provided in Section 5.283.  
All of these eligibility criteria must be met in order to stop tacrolimus at the prespecified 
time point.   
 
In patients ineligible for protocol-specified early tacrolimus cessation, tacrolimus is 
discontinued after the last dose on Day 180; however in these patients, tacrolimus may be 
continued beyond Day 180 if GVHD has occurred or may be discontinued earlier in the 
context of relapse, progression, graft failure, or prohibitive toxicity.  Patients with suspected 
graft failure should remain on tacrolimus until at least the ~Day 56 chimerism assessment, 
although earlier discontinuation is permissible after discussion with the PI or co-PI.  
 
5.283 Eligibility for protocol-driven, early cessation of tacrolimus 
In order to be eligible for protocol-specified shortened-course tacrolimus, patients must meet 
all of the following criteria by the scheduled date of tacrolimus cessation:  
a. No documented graft failure 
b. Presence of at least 5% donor T cell chimerism in peripheral blood and/or bone  
marrow at ~Day 56 evaluations and beyond 
c. No acute, clinical grade II-IV GVHD, whether active or resolved 

Version date: 5/1/12 
 
15
Note: Eligible patients with acute grade I GVHD by the time of scheduled 
tacrolimus discontinuation will stop tacrolimus early as planned. 
d. No chronic GVHD, whether active or resolved, with the exception of 
asymptomatic or minimally symptomatic chronic GVHD limited to the oral 
mucosa.  
e. No documented disease progression or relapse 
f. No receipt of prohibited preemptive posttransplantation therapy (per Section 
5.4) 
 
Evaluations that are required before the protocol-driven, early cessation of tacrolimus are 
provided in Section 7.0.  Early cessation of tacrolimus when required evaluations for 
eligibility are pending is discussed in Section 5.284.   
 
5.284 Early tacrolimus cessation in the context of pending evaluations  
If results of scheduled evaluations are pending at the time tacrolimus is due to stop early, 
tacrolimus should be stopped according to schedule and the duration of tacrolimus 
reevaluated when results become available.  
 
For logistical reasons, stopping tacrolimus up to 5 days after the scheduled stop date is 
permissible in patients for whom early, protocol-specified tacrolimus cessation is planned.   
Stopping tacrolimus more than 5 days later than the scheduled stop date constitutes a 
protocol violation and is further discussed in Section 5.286. 
 
5.285 Changes in planned tacrolimus duration 
If a patient begins study treatment but, prior to the planned tacrolimus discontinuation date, 
the target number of patients have been evaluated for safety or stopping criteria are met, the 
assigned tacrolimus duration for that patient may be changed as appropriate.   
 
5.286 Evaluability for the primary endpoint 
For protocol-driven, early cessation of tacrolimus, stopping tacrolimus up to 5 days after the 
scheduled stop date is permissible for logistical reasons.  Such patients will be considered 
evaluable for both the safety and feasibility of early tacrolimus cessation. 
 
Patients who should stop tacrolimus within this time frame (per protocol-driven criteria), but 
do not for logistical reasons, are unevaluable for safety; whether they remain evaluable for 
feasibility depends on the cause.  If tacrolimus is not stopped in the allowable window 
because of pending evaluations, feasibility will be based on the results of those evaluations, 
provided they were done no later than 5 days past the prespecified date of tacrolimus 
cessation. Cases in which eligible patients do not stop tacrolimus early because of physician 
discretion will count against feasibility.  If there are other logistical reasons for not stopping 
tacrolimus in the designated time frame, or if eligibility evaluations for early tacrolimus 
cessation are performed more than 5 days past the planned stop date, patients will be 
considered unevaluable for safety and feasibility. 
 
Patients who develop a prohibitive toxicity to tacrolimus resulting in its earlier than 
scheduled discontinuation will be considered unevaluable for the primary endpoint. Patients 
who receive preemptive posttransplantation therapy that is not permitted on this study 
(Section 5.4) may be unevaluable for the primary endpoint.  
 
Patients who are not evaluable for the primary endpoint may, if needed, be replaced but will 
continue on study unless consent is withdrawn. 
 

Version date: 5/1/12 
 
16
5.29 
Growth factors 
GCSF (filgrastim) begins on Day 5 at a dose of 5 mcg/kg/day (actual body weight) IV or 
subcutaneously (rounding to the nearest vial dose is allowed), until the absolute neutrophil count 
(ANC) is ≥ 1,000/mm3 over the course of three days.  Additional GCSF may be administered as 
warranted.  Pegfilgrastim (Neulasta®) and GM-CSF are not permitted. 
 
5.3 
Supportive care  
Patients will receive transfusions, nutritional support, infection prophylaxis and treatment, and other 
supportive care according to standard of care and institutional guidelines.  
 
5.31 
Anti-ovulatory treatment 
Menstruating females should begin an anti-ovulatory agent before starting the preparative regimen. 
 
5.32 
Intravenous access 
 
A double lumen central venous catheter is required for administration of IV medications and blood 
products. 
 
5.33 
Infection prophylaxis  
Patients will receive infection prophylaxis and treatment according to institutional guidelines.  
Infection prophylaxis should include agents or strategies to prevent herpes simplex, CMV (e.g., 
CMV PCR screening and preemptive therapy), Pneumocystis jirovecii, fungal infections, and 
infections from oral flora secondary to mucositis.  Posttransplantation immunizations will be given 
per institutional standard. 
 
5.34  Antiemetics 
Note that steroids should not be used as an antiemetic agent after the graft is infused, until at least 24 
hours after the completion of all posttransplantation Cy. The use of steroids as antiemetics after this 
time frame is discouraged in the absence of relapsed/progressive disease. 
 
5.4 
Posttransplantation therapies 
 
5.41 
Donor lymphocyte infusion (DLI) 
Prophylactic posttransplantation DLI (e.g., for persistent detectable malignancy, prophylaxis in the 
absence of detectable malignancy, or mixed donor chimerism) is not permitted before Day 200, as 
this carries a high risk of GVHD.  The use of DLI will be recorded and such patients will be 
censored for analysis of disease and graft failure outcomes, GVHD, and related transplant-related 
toxicity outcomes.  Analysis of outcomes without such censoring is also planned. 
 
5.42 
Posttransplantation systemic therapy 
Preemptive systemic chemotherapy or biologic therapy (e.g., DNA-methyltransferase inhibitor for 
MDS, tyrosine kinase inhibitor for Philadelphia chromosome + malignancy, flt3 inhibitor for AML) 
is permitted after transplantation, with the exception of anti-CD20 antibody therapy such as 
rituximab.  The latter is not permitted because phase II data suggest that posttransplantation 
rituximab may increase the incidence of acute GVHD (unpublished data). Intrathecal chemotherapy 
is permitted.   
 
5.43 
Posttransplantation radiation 
Consolidative radiation therapy is permitted after transplantation. 
 
The use of preemptive therapy will be recorded. Patients who receive such therapies will not be 
censored for analysis of disease outcomes at that time, except as stated in Section 5.41.  
 

Version date: 5/1/12 
 
17
5.5 
Posttransplantation follow-up 
Required evaluations are designated in Section 7.0. 
 
More frequent monitoring of disease status, vital status, and toxicities may be performed for study 
purposes including through collection of outside records and patient and physician contact.  Patients 
who relapse or progress will continue to be followed on study unless consent is withdrawn.   
 
Patients will be followed primarily at Johns Hopkins at least until the ~ Day 56 evaluations, then 
periodically thereafter as designated in Section 7.0.  In the event that it is not possible or practical for 
a patient to come back to Johns Hopkins for required evaluations, clinical and laboratory evaluations 
performed though a local oncologist may fulfill study requirements. This will be decided on a case-
by-case basis by the PI or co-PI; however chimerism assessments must be performed at Johns 
Hopkins.     
 
6.0 
MEASUREMENT OF EFFECT AND ENDPOINTS 
 
6.1 
Hematologic parameters 
 
 
 
6.11 
Neutrophil recovery: Post-nadir ANC > 500/mm3 for three consecutive measurements on 
different days.  The first of the three days will be designated as the day of neutrophil 
recovery.   
 
6.12 
Platelet recovery:  Sustained platelet count > 20,000/mm3 or > 50,000/mm3 with no platelet 
transfusions in the preceding seven days.  The first of three consecutive measurements on 
different days will be designated as the day of initial platelet recovery.  
 
 
6.13 
Donor chimerism: Mixed donor chimerism is defined as > 5%, but < 95%, donor.  Full 
donor chimerism is defined as > 95% donor.  
 
Prior to transplantation, a sample of peripheral blood from the patient, and either harvested 
bone marrow or blood from the donor, are collected for genetic studies to establish a 
baseline for subsequent chimerism assays.   
 
Chimerism determinations from T cells (CD3+ sorted) and whole blood (total nucleated 
cells) will be made from peripheral blood per Section 7.0, and more frequently as indicated.  
Methods may include (i) PCR analysis of variable number of tandem repeats (VNTR) in 
PBMC if informative, (ii) restriction fragment length polymorphism (RFLP) if the donor and 
recipient RFLPs are informative, (iii) fluorescence in-situ hybridization (FISH) for Y-
chromosome markers on PBMC if the donor is male and patient is female, (iv) cytogenetic 
analysis, (v) flow cytometric analysis of HLA-A, B or DR on lymphocytes in the peripheral 
blood if haploidentical and suitable reagents exist.  Chimerism may also be determined from 
the bone marrow. 
 
 
 
6.14 
Graft failure: < 5% donor chimerism in blood and/or bone marrow on ~Day 28 or after and 
on all subsequent measurements.   
 
Primary graft failure: < 5% donor chimerism in blood and/or bone marrow by ~ 
Day 56  
 
Secondary graft failure: achievement of > 5% donor chimerism, followed by 
sustained <5% donor chimerism in blood and/or bone marrow. 
 
< 5% donor T cell chimerism, but with > 5 % donor chimerism in total leukocytes, is not 
considered graft failure. 

Version date: 5/1/12 
 
18
 
6.2 
Graft-versus-host disease 
 
6.21 
Acute GVHD:  Acute GVHD is graded by standard criteria (Appendix).29 All suspected 
cases of acute GVHD must be confirmed histologically by biopsy of an affected organ (e.g., 
skin, liver, or gastrointestinal tract).  Date of symptom onset, date of biopsy confirmation of 
GVHD, maximum clinical grade, sites affected, and dates and types of treatment will be 
recorded.  Dates of symptom onset of grade II or higher GVHD and grade III-IV GVHD will 
be recorded.   
 
The cumulative incidences of acute grade II-IV and grade III-IV GVHD will be determined 
through competing risk analysis.  Treatment of relapse/progression, graft failure, and death 
are considered competing risks for GVHD for study purposes.  In addition, GVHD will be 
reported with only graft failure and death regarded as competing risks. 
 
 
6.22 
Chronic GVHD:  Chronic GVHD is graded by both NIH consensus criteria30 and Seattle 
criteria.31  Date of onset, date of biopsy confirmation (if any), dates and types of treatment, 
and extent will be recorded. The cumulative incidence of chronic GVHD (overall and 
according to extent) will be determined through competing risk analysis.   
 
6.3 
Disease and survival endpoints 
 
6.31 
Progression-free survival: Interval from Day 0 to date of first objective disease progression 
or relapse, death from any cause, or last patient evaluation.  Patients who have not 
progressed or died will be censored at the last date they were assessed and deemed free of 
relapse or progression.  Disease persistence in the absence of progression is not included in 
this analysis.  
 
6.32 
Event-free survival: Interval from Day 0 to date of first objective disease progression or 
relapse, an unplanned therapeutic maneuver for disease persistence, death from any cause, or 
last patient evaluation.  Patients without events will be censored at the last date they were 
assessed and deemed event-free.   
 
6.33 
Overall survival: Interval from Day 0 to date of death from any cause or last patient contact.   
 
6.34 
Nonrelapse mortality: Death without evidence of disease progression or relapse. 
Relapse/progression is a competing risk for NRM.   
 
6.35 
Relapse or progression: Defined per the following response criteria:  
a. Lymphoma: 2007 International Working Group (IWG) criteria for lymphoma 32  
b. CLL: 2008 International Workshop criteria 33 
c. Multiple myeloma:  International Myeloma Working Group uniform response criteria 34 
d. Acute leukemia: 2010 European LeukemiaNet criteria,35 based on 2003 IWG criteria 36 
e. MDS: 2006 IWG criteria 37 
 
Designation of disease status in other histologies will also follow standard criteria.  NRM is 
a competing risk for relapse/progression. 
 
6.35 
Minimal residual disease (MRD): MRD is defined by the sole evidence of malignant cells 
by flow cytometry, FISH, PCR or other techniques, in absence of morphological or 
cytogenetic evidence of disease in blood or marrow. Since the frequency and sensitivity of 
testing for MRD are variable, evidence of MRD will not be sufficient to meet the definition 

Version date: 5/1/12 
 
19
of relapse or progression in this study, but will be captured in the case report forms along 
with data on changing management in response to MRD detection.   
 
6.4 
Correlative studies 
Patients’ peripheral blood specimens will be collected per Section 7.0 and banked for future research 
on immune reconstitution and on clinical outcomes including GVHD.  Planned studies include but 
are not limited to characterization of humoral and cellular immune reconstitution at ~ 2 months and ~ 
6 months posttransplantation, and analysis of cellular immunity including T regulatory cell 
subpopulations in relation to the development of GVHD.  
 
7.0 
STUDY PARAMETERS 
The following table summarizes the minimum testing and clinical assessments required for study purposes.  
This is in addition to other testing and assessments indicated as standard of care, which may be collected for 
study purposes.   

Version date: 5/1/12 
 
20
 
Table: Study Parameters 
 
Baseline 
1,2 
D28      
+/- 3 d 
D56 
 +/- 3 d 
D84  
+/- 5 d    
D112 
+/- 5 d   
D180       
+/- 7 d 
D270       
+/- 21 d 
D365   
+/- 30 d c 
Standard pre/post transplant 
evaluations a, b 
 
 
 
 
 
 
 
 
History and physical exam  
X 
  
X 
X m 
X m 
X 
X m 
X 
Performance status 
X 
 
 
 
 
 
 
 
CBC / differential d 
X 
X 
X 
X  m 
X  m 
X m  
X  m 
X  m  
Comprehensive metabolic 
panel (CMP) e 
X 
  
X 
X l 
X l 
X l 
X l 
X l 
Infectious disease evaluations f 
X 
 
 
 
 
 
 
 
Serum HCG (if applicable) 
X 
 
 
 
 
 
 
 
LV ejection fraction  
X 
 
 
 
 
 
 
 
Pulmonary function tests  
X 
 
 
 
 
 
 
 
Bone marrow biopsy and 
aspirate with flow cytometry 
and relevant cytogenetic and 
molecular studies g  
X 
 
X, with 
chimerism 
analysis h 
  
 
X, with 
chimerism 
analysis h 
 
X, with 
chimerism 
analysis h 
CT of sinuses 
X 
 
 
 
 
 
 
 
CT, PET/CT, or MRI of chest, 
abdomen, and pelvis 
(lymphoma and CLL only) 
X 
 
X 
 
 
X m 
 
X m 
Response assessment to last 
therapy  i 
X 
 
 
 
 
 
 
 
HLA typing 
X 
 
 
 
 
 
 
 
Lymphocytotoxic antibody 
screen 
X 
 
 
 
 
 
 
 
Donor marrow or blood for 
VNTR or RFLP analysis j 
X 
 
 
 
 
 
 
 
Patient blood for baseline 
VNTR or RFLP analysis j 
X 
 
 
 
 
 
 
 
Peripheral blood chimerism, 
both total leukocyte (unsorted) 
and T-cell sorted  j 
  
X 
X 
X l 
X l 
X l 
X l 
X l 
GVHD and other morbidity 
assessments k 
 
   
X 
X l 
X l 
X l 
X l 
X l 
Additional evaluations 
 
 
 
 
 
 
 
 
Patient research blood 
 
 
X n 
 
 
X n 
 
 
 
a Baseline evaluations should occur < 1 month before initiation of conditioning therapy, with the exception of 
the following: cardiac and pulmonary evaluations may occur < 8 weeks prior, and the HLA typing and 
baseline studies for chimerism determinations may occur at any point prior. Results of evaluations performed 
before study entry as standard of care may be used for research purposes and to fulfill study requirements. 
b Demographics and baseline characteristics will be captured.  Characteristics to be recorded include: age, 
gender, race/ethnicity, performance status, disease type, remission status, prior treatments including prior 
transplantation and type, donor age, donor relationship to patient, donor gender, type of transplant (HLA-
matched or mismatched), CMV serostatus of patient and donor, ABO compatibility. 
c Patients should continue to follow-up at Johns Hopkins at least yearly on study, per institutional standard of care.  
Follow-up data may be captured more frequently for study purposes.  Data that will continue to be recorded beyond 1 
year include disease status until first relapse/progression, vital status, major transplant-related toxicities, and GVHD.   

Version date: 5/1/12 
 
21
d At minimum, CBC/differential should also be performed twice a week from start of preparative regimen, 
until ANC is >1000/uL over course of 3 days, then weekly until 12 weeks posttransplantation, and 
periodically thereafter; those need not be captured in the CRF. 
e CMP includes: BUN, creatinine, sodium, potassium, chloride, AST, ALT, total bilirubin, alkaline phosphatase. At 
minimum, these should be performed weekly until 12 weeks posttransplantation, then periodically until off 
immunosuppression; those need not be captured in the CRF. 
f Infectious disease evaluations follow institutional standard of care.  Minimum evaluations are CMV IgG, HSV IgG, 
VZV IgG, hepatitis panel (Hep B surface antigen, Hep B core antibody, Hep C antibody), HIV antibody (unless 
known to be HIV positive).   
g Flow cytometry in diseases other than Hodgkin’s lymphoma. Follow-up studies should include relevant cytogenetics 
and molecular markers to detect residual disease, i.e. repeat of studies found to be positive at baseline. 
h For leukemia (including CLL), MDS, myeloproliferative disease, and myeloma; for lymphoma patients, required if 
bone marrow was positive on baseline (pretransplantation) evaluation. May be omitted if there is documented disease 
progression or relapse before scheduled assessment. 
i Include comparison of pre- and post-treatment scans with bidimensional measurements where relevant. 
j Collect 10 cc lavender top.  
k GVHD and other morbidity assessments are also standardly performed weekly at Johns Hopkins until at least ~Day 
60.  Results of these and subsequent assessments may be collected for research purposes.  Patients may be asked to 
complete GVHD questionnaires. 
l Day 84 and later CMP, chimerism, and GVHD evaluations may be omitted in patients with documented graft 
failure. CBC/differential, H & P, and morbidity assessment at these time points will be obtained. 
m May be omitted in patients who receive treatment for disease progression or relapse. The dates of treatment 
initiation and DLI will be recorded.  
n Collect 60 cc in green top (heparinized) tubes. Deliver at room temperature to Human Immunology Core for 
cryopreservation. May be omitted at PI or co-PI discretion. 
 
8.0 
RISKS AND REPORTING REQUIREMENTS 
 
8.1 
Drug information 
 
8.11  
Cyclophosphamide (Cytoxan®) 
Cyclophosphamide is an alkylating agent whose metabolites form cross-links with DNA resulting in 
cell cycle-nonspecific inhibition of DNA synthesis and function.  Cyclophosphamide side effects 
include: nausea, vomiting, diarrhea, headache, dizziness, hemorrhagic cystitis, fluid weight 
gain/edema, SIADH, transaminitis, cardiomyopathy, pericarditis, rash, mucositis, alopecia, 
cytopenias, sterility, and rarely, secondary myelodysplastic syndrome and anaphylaxis. 
 
Dose adjustments for cyclophosphamide will not be made. 
 
8.12  
Mesna (sodium-2-mercapto ethane sulphonate) 
Mesna is a prophylactic agent used to prevent hemorrhagic cystitis induced by the 
oxasophosphorines (cyclophosphamide and ifosphamide).  It has no intrinsic cytotoxicity and no 
antagonistic effects on chemotherapy.  Mesna binds with acrolein, the urotoxic metabolite produced 
by the oxasophosphorines, to produce a non-toxic thioether and slows the rate of acrolein formation 
by combining with 4-hydroxy metabolites of oxasophosphorines. 
 
The total daily dose of mesna is equal to 80% of the total daily dose of cyclophosphamide. 
At the doses used for uroprotection, mesna is virtually non-toxic.  However, potential adverse effects 
include nausea and vomiting, diarrhea, abdominal pain, altered taste, rash, urticaria, headache, joint 
or limb pain, hypotension, and fatigue. 
 
8.13 
Fludarabine (Fludara) 

Version date: 5/1/12 
 
22
Fludarabine is a purine analog antimetabolite.  Side effects of fludarabine include: 
a. Neurotoxicity: Agitation or confusion, blurred vision, loss of hearing, peripheral neuropathy or 
weakness have been reported.  Severe neurologic effects, including blindness, coma, and death 
may occur; severe CNS toxicity is rarely seen with doses in the recommended range for 
nontransplant therapy. The dose used in this study is approximately 1.5 times the usual one-
course dose given in non-transplant settings.  Doses and schedules similar to those used in this 
study have been used in adult and pediatric patients without observed increase in neurotoxicity. 
 
b. Anemia: Life-threatening and sometimes fatal autoimmune hemolytic anemia has been reported 
after one or more cycles of therapy in patients with or without a previous history of autoimmune 
hemolytic anemia or a positive Coombs’ test and who may or may not be in remission.  
Corticosteroids may or may not be effective in controlling these episodes.  The majority of 
patients re-challenged developed a recurrence of the hemolytic process.  
 
c. Cardiovascular: Deep venous thrombosis, phlebitis, transient ischemic attack, and aneurysm 
(1%) are reported.    
 
d. Fever: 60% develop fever. 
 
e. Rash: 15% develop a rash, which may be pruritic.  
 
f. Digestive: Gastrointestinal side effects include: nausea/vomiting (36%), diarrhea (15%), 
stomatitis (9%), anorexia (7%), GI bleeding and esophagitis (3%), mucositis (2%), liver failure, 
abnormal liver function test, constipation, dysphagia (1%) and mouth sores.  
 
g. Some other effects include: Chills (11%), peripheral edema (8%), myalgias (4%), osteoporosis 
(2%), pancytopenia, arthralgias (1%), dysuria (4%), urinary tract infection and hematuria (2%); 
renal failure, abnormal renal function test, and proteinuria (1%); and, very rarely, hemorrhagic 
cystitis and pulmonary toxicity.  
 
Dose adjustments of fludarabine are required for renal insufficiency (see Section 5.21). 
 
8.14 
Total Body Irradiation (TBI) 
TBI can cause: nausea and vomiting, diarrhea, parotitis (rapid onset within 24-48 hours, usually self-
limited), generalized mild erythema (usually within 24 hours, resolving in 48-72 hours) , 
hyperpigmentation, fever, mucositis, alopecia, and pancytopenia. Late effects include: cataracts (10-
20%), hypothyroidism, nephropathy, interstitial pneumonitis, veno-occlusive disease, carcinogenesis, 
and sterility.  
 
8.15 
Mycophenolate Mofetil (MMF, Cellcept®) 
MMF is an ester prodrug of the active immunosuppressant mycophenolic acid (MPA).  
Side effects include: pancytopenia, infection (including sepsis, CMV, HSV, VZV, and Candida), 
nausea, vomiting, diarrhea, allergic reactions, hypertension, headache, dizziness, insomnia, 
hyperglycemia, electrolyte imbalances, rash, and leg cramps/bone pain.  
 
Drug interactions: MMF activity is decreased with oral antacids and cholestyramine. There are no 
pharmacokinetic interactions with cotrimoxazole, oral contraceptives, or cyclosporine.  Acyclovir or 
ganciclovir blood levels may increase due to competition for tubular secretion. High doses of 
salicylates or other highly protein-bound drugs may increase the free fraction of MPA and 
exaggerate the potential for myelosuppression. 
 
Dose adjustments: No dose adjustments are required for liver dysfunction.  For renal insufficiency, 

Version date: 5/1/12 
 
23
MMF dosing should not be modified unless dialysis is needed, in which case MMF can be reduced 
to 25-50% of the starting dose. 
 
8.16 
Tacrolimus (FK-506, Prograf®) 
Tacrolimus is a macrolide immunosuppressant that inhibits lymphocytes through calcineurin 
inhibition.   
 
Toxicities: There is a spectrum of well-described toxicities of tacrolimus. Toxicities include renal 
insufficiency, hypertension, hyperglycemia, hypomagnesemia, hypokalemia, nausea, diarrhea, 
headache, neurologic toxicity including tremor and leukoencephalopathy, infection, and rarely 
thrombotic thrombocytopenic purpura (TTP). 
 
Drug interactions: Tacrolimus is well absorbed orally.  Tacrolimus is extensively metabolized by the 
cytochrome P-450 (CYP3A4) system and metabolized products are excreted in the urine.  Drugs that 
may increase tacrolimus levels include tri-azole drugs (especially voriconazole and posaconazole), 
nephrotoxic drugs, calcium channel blockers, cimetidine and omeprazole, metoclopramide, 
macrolide antibiotics, quinupristin/dalfopristin, danazol, ethinyl estradiol, methylprednisolone, and 
HIV protease inhibitors.  Drugs that may decrease tacrolimus levels include some anticonvulsants 
(phenobarbital, phenytoin, carbamezepine), caspofungin, rifamycins, and St. John’s wort.   
 
Dose adjustments: The tacrolimus dose is adjusted to maintain a serum trough level of 5-15 ng/mL, 
with a target of 10-15 ng/mL.  Patients with hepatic or renal insufficiency should receive doses at the 
lower end of therapeutic concentrations.  No dose adjustments are required in patients undergoing 
hemodialysis. 
 
Due to extreme interactions with voriconazole and posaconazole, the tacrolimus dose 
should be empirically lowered when these azoles are initiated at steady state levels of 
tacrolimus.  Guidelines are provided in the table below.  Dose adjustments for therapy with other 
azoles may be indicated.  However, the initial tacrolimus dose (on Day 5) remains fixed.  
 
Dosing considerations with concurrent azole therapy: Triazole antifungal medications are expected 
to increase serum CNI levels; therefore dosages of CNI’s should be adjusted accordingly. Guidelines 
are provided in the table below.  Of note, reversal of azole-mediated inhibition of CYP3A4 (and 
others) and P-glycoprotein is gradual when azoles are stopped.  Therefore, immediate significant 
dose increases in tacrolimus are not advised when azoles are stopped. Rather, tacrolimus dose 
increases should be cautious and based on more frequent monitoring of levels as appropriate. 
 
Table: Suggested preemptive dose reduction of tacrolimus when azoles are initiated at steady 
state levels of tacrolimus  
Antifungal 
Tacrolimus 
 
Dose ↓ 
 
Comment 
Voriconazole  
67% 
Strongly advised 
Posaconazole 
67% 
Advised 
Itraconazole 
50% 
Advised 
Fluconazole 
25%  
Consider 
 
8.2 
Toxicity grading 
Toxicities are graded using the NCI’s Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.0. (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm) 
 
8.3 
Toxicity reporting 

Version date: 5/1/12 
 
24
The agents being used in the study are used extensively in the BMT setting and have well-defined 
toxicity profiles.  In addition, there are many expected toxicities of allogeneic BMT.  The following 
are examples of toxicities that are serious but not unexpected: Grade 4 cytopenias; neutropenic fever 
and sepsis; bacterial, fungal, or viral (including CMV, BK virus) infection; severe mucositis; severe 
GVHD; hepatic veno-occlusive disease; pulmonary toxicities; hemorrhagic cystitis; bleeding without 
hemodynamic compromise. 
 
For study purposes, the following will be recorded and reported in accordance with IRB 
requirements: 
a. Any hospitalization and its reason in the first year of transplant, with the exception of 
hospitalizations related to relapsed disease or second BMTs. 
b. Neutropenic fever is an expected, common complication; as such, hospitalizations for grade 
4 neutropenic fever will be reported in real-time to the IRB with hospitalizations for lesser 
grade neutropenic fever routinely reported on a yearly basis. 
c. Any death before Day 200, and any later death which is potentially transplant-related. 
d. Any unexpected, serious events deemed significant by the PI. 
 
 
In addition, the following toxicities will be tracked for study purposes and reported on a yearly basis 
to the IRB, or earlier if warranted:  
a. Clinically significant infections during the first year of transplant, with the exception of 
uncomplicated, culture-negative neutropenic fever. This includes CMV disease, other 
clinically significant documented viral infections, bacterial infections, and proven or 
probable invasive fungal infections. 
b. CMV reactivation (including asymptomatic reactivation) 
c. Hepatic veno-occlusive disease 
d. Grade 3 or greater pulmonary toxicity during the first year of transplant that is potentially 
transplant-related 
 
Additional complications and toxicities may be tracked. This is in addition to evaluating hematologic 
parameters, GVHD, and disease and survival endpoints outlined in Section 6.0.  
 
8.4 
Monitoring plan  
This is a Level I study under the SKCCC at Johns Hopkins Data and Safety Monitoring Plan.  The 
protocol will be monitored internally by the PI.  Data and safety monitoring oversight will be 
conducted by the SKCCC at Johns Hopkins Safety Monitoring Committee. An audit will be 
performed early in the study, and then audits will be performed periodically thereafter.   
 
8.5 
Risks and benefits   
Allogeneic BMT carries risk for major morbidity and mortality.  Major toxicities and risks of the 
transplant procedure include acute and chronic GVHD, severe infection, immunosuppression which 
may be prolonged, graft failure, end-organ damage, and death.  High-dose posttransplantation Cy 
appears to significantly lower the risk of GVHD.  Shorter-duration immunosuppression may be 
associated with increased risk of GVHD, increased severity of GVHD, and graft failure. 
The potential benefits of this trial are palliation of disease-related symptoms and 
prolongation of overall or event-free survival, including the possibility of long-term disease-free 
survival and cure.  Potential benefits also include fewer infectious and other complications and lower 
risk of relapse because of the shorter duration of immunosuppression.  
 
9.0 
STATISTICAL CONSIDERATIONS 
 
9.1 
Primary endpoint and design 

Version date: 5/1/12 
 
25
The primary goal of this study is to determine whether one can shorten the duration of 
immunosuppression with tacrolimus following nonmyeloablative, related donor BMT that 
incorporates high-dose posttransplantation Cy.   
 
To be relevant, an immunosuppression regimen must not only be safe, but be applicable to a 
sufficient number of patients.  Therefore, both safety and feasibility are incorporated in the primary 
analysis. Feasibility is herein defined as the proportion of patients, measured from Day 0, who meet 
criteria for protocol-driven, early tacrolimus cessation (as defined in Section 5.283) and have 
tacrolimus stopped at the prespecified time point.  Monitoring rules for feasibility (based on the 
proportion of patients who are able to stop tacrolimus at a prespecified time point) and safety (i.e. 
complications do not exceed cause-specific thresholds defined below) will be implemented to guide 
the choice of tacrolimus duration (tacrolimus until Day 60, 90, 120 or the historical standard, Day 
180).  The planned duration of tacrolimus will be assigned prior to the start of the preparative 
regimen.   
 
It is possible that longer durations of immunosuppression are more safe (e.g., lower risk of GVHD), 
but less feasible (e.g., greater possibility of NRM or another event that would prevent protocol-
driven early cessation of immunosuppression, as defined in Section 5.283).  Conversely, shorter 
durations of immunosuppression may be more feasible but unsafe (e.g., excessive GVHD).   Based 
on historical information, we expect that it will be feasible to reduce the duration of tacrolimus from 
the current standard (until Day 180) to until Day 90.  We hypothesize that stopping tacrolimus on 
Day 90 will not carry excess risk of GVHD or graft failure (potential manifestations of inadequate 
immunosuppression).  
 
9.11 
 Sequence of study 
The duration of tacrolimus will be evaluated in the following order, with monitoring rules (specified 
in Section 9.12) based on feasibility and safety.  A maximum of two reduced durations of tacrolimus 
will be evaluated, and based on this, a decision made in favor of a particular tacrolimus duration 
(until Day 60, 90, 120, or 180).  
 
a. Begin with tacrolimus until Day 90.  
 
b. If tacrolimus until Day 90 appears feasible but unsafe, evaluate tacrolimus until Day 120 
with analogous monitoring rules.  
 If tacrolimus until Day 120 appears both feasible and safe, we will decide in favor of 
this regimen.  Otherwise, we will decide in favor of tacrolimus until Day 180. 
 If accrual to the tacrolimus until Day 90 arm is complete, subsequent patients can be 
assigned to tacrolimus until Day 120 while evaluation of the Day 90 arm is pending.   
  
c. If tacrolimus until Day 90 appears both safe and feasible, evaluate tacrolimus until Day 60 
with analogous monitoring rules.   
 If tacrolimus until Day 60 appears both safe and feasible, we will decide in favor of 
this regimen.  Otherwise, we will decide in favor of tacrolimus until Day 90. 
 
d. If tacrolimus until Day 90 does not appear feasible (such that less than the minimum target 
proportion of patients are able to discontinue tacrolimus), and this is due to high rates of 
GVHD or graft failure (or low donor T cell chimerism) or both, tacrolimus until Day 60 will 
not be evaluated and we will decide in favor of tacrolimus until Day 180.  Otherwise, 
tacrolimus until Day 60 will be studied as this may be more feasible than tacrolimus until 
Day 90 (i.e., less time to develop an event that would preclude early cessation of 
immunosuppression), and may be associated with frequencies of GVHD, graft failure, NRM, 

Version date: 5/1/12 
 
26
and relapse/progression that do not exceed the cause-specific thresholds defined below 
(Section 9.12).  
 
9.12 
 Criteria for feasibility and safety 
This study considers it “feasible” to stop tacrolimus early (e.g., Day 90) if at least one-third (33%) of 
all evaluable transplanted patients have not had any of the events (defined in Section 5.283) that 
would render them ineligible to stop at the prespecified time point and who have tacrolimus stopped 
accordingly.  A Bayesian stopping rule will be implemented to declare a particular shortened 
duration of tacrolimus not feasible, if there is 80% or more certainty that fewer than 33% of patients 
could have tacrolimus stopped early.  The Bayesian rule begins with a Beta (3, 3) prior probability 
distribution that tacrolimus until Day 90 is feasible. This prior distribution is based on historical 
information below and has mean 50% and 90% probability that the fraction of patients who will be 
available to have tacrolimus stopped is between 32% and 68%.  For a particular planned duration of 
tacrolimus, up to 55 patients will be transplanted in order to identify at least 15 who are evaluable for 
the safety of early tacrolimus cessation.  Up to 5 additional patients may be transplanted per regimen 
to replace unevaluable patients (per Sections 4.1 and 5.286).   
 
Historical estimates were derived from 212 uniformly treated patients with hematologic 
malignancies (fludarabine/Cy/TBI conditioning, with partially HLA-mismatched BMT, 
posttransplantation high-dose Cy, MMF on Days 5-35, and tacrolimus on Days 5-180). Event-
specific risks were calculated within 4 intervals: Days 1-60, 61-90, 91-120, and 121-180.  (Note that 
these probabilities are specific to the time interval indicated for each row and conditional on reaching 
the interval.)  
 
Days 
Graft Failure 
NRM 
Relapse 
GVHDa 
No Event 
1-60 
0.1133  
0.0191  
0.0803  
0.2217  
0.5656 
61-90 
0.0254  
0.0337  
0.0337  
0.0586  
0.8486 
91-120 
0.0005  
0.0005  
0.0983  
0.0494  
0.8513 
121-180 
0.0006  
0.0120  
0.1610  
0.0235  
0.8029 
 
 
 
 
 
 
 
 
a acute grade II or higher or chronic GVHD 
 
Separate stopping rules will be implemented for each of 4 events occurring between the date of 
tacrolimus discontinuation and the Day 180 evaluation (Day 180 evaluations are +/- 7 days for 
logistical reasons): acute, clinical grade II or higher GVHD or severe chronic GVHD; graft failure; 
NRM; and disease relapse or progression.  The latter is incorporated so as to have a sufficient 
number of patients evaluable for safety.  For the stopping rules, the prior precision of these event-
specific risks within each interval corresponds to a prior sample size of 53 patients, one-fourth of the 
212 historical sample size.  We discounted the historical data to avoid having the prior information 
dominate the inference from the current study’s data. 
 
The table above shows risks for acute grade II-IV and chronic GVHD combined.  Of the 61 GVHD 
events, 3 were chronic.  We combined these three events with the 58 acute GVHD events to be more 
conservative in our stopping rules.  Given the discounting of the prior data, these three events 
contribute very little influence on the performance of the stopping rules, relative to the acute GVHD 
events in the historical data.  The simulation results below reveal that these stopping rules perform 
well and provide reasonable protection of patients against unexpectedly elevated risks.   
 
The estimated historical cause-specific (cumulative) risks between Day 91 and 180 are 7% (GVHD), 
<1% (graft failure), 1.3% (NRM), and 26% (relapse).  For monitoring, we will compute the posterior 
probability of each of four events, given the data and a historical prior distribution, and evaluate 
whether to stop throughout the study.  The stopping rule declares a particular duration of tacrolimus 

Version date: 5/1/12 
 
27
unsafe if the posterior probability is 67% or higher that the risk of that adverse event between the day 
tacrolimus stops and ~ Day 180 overly exceeds the following cause-specific probabilities: stopping 
for > 20% combined of acute, clinical grade II or higher GVHD and severe chronic GVHD, > 10% 
NRM, or > 5% graft failure in this window, or stopping for a > 50% incidence of disease relapse or 
progression in this window.  
 
Although chronic GVHD usually manifests later than Day 180, the window chosen for the primary 
monitoring rule is justifiable for several reasons:  a) In our haploidentical BMT experience, the 
majority of patients who develop chronic GVHD will have had acute GVHD; 3 b) A more extended 
observation window for stopping rule purposes would make timely completion of the trial difficult; 
and c) In the setting of myeloablative, matched, related or unrelated donor BMT that utilizes high-
dose posttransplantation Cy as the sole agent for GVHD prophylaxis (i.e., no mycophenolate mofetil 
or CNI’s), the rate of chronic GVHD has been very low.22 
 
Patients who develop both acute and chronic GVHD will be regarded as having one adverse GVHD 
event for stopping rule purposes.  Patients who develop GVHD after treatment for 
relapse/progression will be regarded as having a competing risk for GVHD.  However, patients who 
have relapse/progression then develop either acute grade II-IV GVHD or severe chronic GVHD by 
~Day 180, before treatment of that relapse/progression, will be regarded as having both 
relapse/progression and an adverse GVHD event for stopping rule purposes.   
 
Monitoring will occur in groups of 5 assessable patients, beginning after 18 assessable patients have 
 
been transplanted.  
 
In deciding upon the safety of a particular duration of tacrolimus, the stopping rule(s) met will be 
considered.  Excess GVHD or graft failure is a potential manifestation of inadequate 
immunosuppression, thus would lead one to favor a longer course of tacrolimus.  NRM may or may 
not be due to less immunosuppression; thus if only the NRM rate exceeds the predefined threshold, 
the recommended duration of tacrolimus will be contingent on the causes of NRM (whether they are 
unrelated or possibly related to reduced immunosuppression).  On the other hand, excess 
relapse/progression is not an expected manifestation of inadequate immunosuppression, since 
shorter-course or lower-dose CNI’s may lower the relapse risk.27,28 If only this stopping criterion is 
met, the length of time that the relapsed patients are evaluable for safety endpoints will be assessed 
and a decision rendered whether to increase the accrual goal.   
 
It is possible that with the combined analysis of HLA-matched and HLA-mismatched transplants, an 
increased risk of graft failure, GVHD, or NRM with shortened-course immunosuppression, as 
compared to the historical outcomes with HLA-mismatched BMT, may be less readily identified.  
However, most of the transplants will be HLA-mismatched, and the potential benefits to shortened-
duration immunosuppression are not specific to the type of transplant.  Inclusion of HLA matched 
transplants is justified because a) there will be continual monitoring for safety as described above; b) 
with postgrafting immunosuppression that includes high-dose Cy, our rates of graft failure and 
GVHD appear to be similar in the HLA-matched and -mismatched settings (Burroughs LM et al, 
BBMT 2008;14(11):1279-87),2 and c) with such postgrafting immunosuppression, increasing 
degrees of HLA mismatch have not been found to be associated with inferior outcomes in 
haploidentical BMT (Kasamon YL et al, BBMT16(4):482-9).21   
 
 
9.13 
Operating characteristics of design 
We carried out simulations of possible risks of each of four events among simulated groups of 
patients enrolling in the study.  The four events of interest are a) graft failure, b) relapse/progression, 
c) NRM, and d) GVHD.  We used historical information to derive a prior distribution for the risks of 
each of these four events within each of the following time intervals (days) following the transplant: 

Version date: 5/1/12 
 
28
1-60, 61-90, 91-120, and 121-180.  Monitoring in groups of 5 patients started after 18 patients 
entered the study.  The following table shows results for the first scenario when tacrolimus is to stop 
at Day 90 and the simulated risks are the same as those seen historically.  Other scenarios are given 
in the appendix.  Each scenario is shown with operating characteristics based on 1000 simulations. 
 
Scenario #1: Historical risks of events within each interval  
Days 
Graft Failure 
NRM 
Relapse 
GVHD 
No Event 
1-60 
0.1133  
0.0191  
0.0803  
0.2217  
0.5656 
61-90 
0.0254  
0.0337  
0.0337  
0.0586  
0.8486 
91-120 
0.0005  
0.0005  
0.0983  
0.0494  
0.8513 
121-180 
0.0006  
0.0120  
0.1610  
0.0235  
0.8029 
 
After 1000 simulations with the historical probabilities of events and a stopping criterion for each 
event's risk between days 91 and 180 of:  Graft Failure = 0.05, NRM = 0.10, relapse/progression = 
0.50, GVHD = 0.20: 
        Stopped for lack of feasibility 8 (0.8%) times. 
        Stopped for lack of feasibility at first look 0 (0%) times. 
        Safety or relapse problem declared 0 (0%) times. 
        Safety or relapse problem by reason (% of times): 
        GraftFail     NRM   Relapse      GVHD   No Event  
        0                   0              0                0             0  
 
Number of patients transplanted to reach 15: 
Min.   1st Qu.  Median   Mean    3rd Qu.   Max.  
  18.00   28.00     33.00      32.74     38.00     53.00  
 
9.2 
Secondary endpoints 
 
a. In patients eligible for reduced-duration tacrolimus, estimate the incidences of acute grade II-IV 
GVHD, acute grade III or higher GVHD, chronic GVHD, graft failure, relapse, and NRM 
between the date of early tacrolimus cessation and Day 180, and beyond Day 180. 
Cumulative incidences of GVHD, relapse and NRM will be computed in these time frames 
using Fine and Gray’s method for competing risks.38,39  Treatment of relapse/progression, 
graft failure, and death are considered competing risks for GVHD; relapse/progression is a 
competing risk for NRM; and death before relapse/progression is a competing risk for 
relapse/progression. In addition, we plan to report GVHD incidences with only graft failure 
and death regarded as competing risks.  
 
The graft failure frequency in evaluable patients will be reported with 90% confidence 
intervals. 
 
Although historically, most cases acute GVHD develop before Day 90 and graft failure after 
Day 60 is rare, the time course for these events in patients treated with less than 6 months of 
immunosuppression is not well defined.  The observation time for the primary safety 
monitoring rule varies according to tacrolimus duration, and it is possible though not 
expected that excess GVHD (acute or chronic), graft failure, or NRM will develop after Day 
180.  Although these events are not incorporated in the primary monitoring rule, their 
incidences will be continually monitored, and the trial will pause pending IRB review should 
these incidences appear prohibitive.  
 

Version date: 5/1/12 
 
29
These outcomes and the outcomes in points b through f below will be described with HLA-
mismatched and HLA-matched transplants combined, and individually where appropriate. 
 
b. Estimate the cumulative incidences of acute grade II-IV GVHD, acute grade III-IV GVHD, 
chronic GVHD, relapse and NRM for the group overall. 
The cumulative incidence of each of these events will be calculated from Day 0 using Fine 
and Gray’s method for competing risks.  
 
c. Estimate the cumulative incidence of systemic steroid initiation, the cumulative incidence of 
non-steroid immunosuppression use, and the cumulative incidence of discontinuation of 
systemic immunosuppression for GVHD treatment by 1 year and 2 years after BMT for the 
group overall and for patients with shortened-duration tacrolimus; and describe the number and 
types of systemic immunosuppression used for GVHD treatment. 
These cumulative incidences will be similarly estimated using competing-risk analyses, 
wherein graft failure and death, or graft failure, death and treatment of relapse/progression, 
are considered competing risks.  The number and types of systemic immunosuppression used 
for GVHD treatment will be reported descriptively. 
 
d. Estimate event-free survival, progression-free survival, and overall survival after transplantation. 
Using the Kaplan-Meier method, the probabilities of 1-year and longer-term event-free 
survival, progression-free survival, and overall survival will be estimated and reported with 
90% confidence intervals.  The proportions of patients who are event-free at 1 year and who 
are alive at 1 year will also be estimated with a 90% exact binomial confidence interval.   
 
e. Describe the graft failure frequency, kinetics of neutrophil and platelet recovery, and kinetics of 
donor chimerism in unsorted and CD3+ sorted peripheral blood. 
The graft failure frequency in evaluable patients (those having chimerism results at least at 
~Day 28) will be described, with 90% confidence intervals.  Times to neutrophil and platelet 
recovery will be described with medians and ranges, and with cumulative incidence 
functions with death before count recovery as a competing risk.  The degree of donor 
chimerism in unsorted and CD3+ sorted peripheral blood at predefined time points (per 
Section 7.0) will be summarized with medians and ranges, and the proportion reaching full 
donor chimerism (total leukocyte, T cell)  by ~ Day 28 and ~ Day 56 will be estimated with 
90% confidence intervals.  The proportion achieving >50% T cell donor chimerism at ~ Day 
28 and ~ Day 56 will similarly be estimated.   
 
The association between the amount of donor T cell chimerism at ~ Day 28 and patient/graft 
characteristics (e.g., prior therapies, graft cell dose) and transplantation outcomes (sustained 
engraftment, relapse or progression, GVHD) will be investigated.  Because of the limited 
sample size these investigations will be exploratory.   
 
f. Characterize immune reconstitution after transplantation and its relationship to duration of 
pharmacologic immunosuppression and clinical outcomes. 
Patterns of immune reconstitution at ~ 2 months and ~ 6 months after transplantation, 
including peripheral blood concentrations of T cells, B cells, and natural killer cells, in 
relation to tacrolimus duration will be described using summary statistics.  Descriptive 
comparisons of immune reconstitution in patients treated with shortened-duration tacrolimus 
will be made to that of historical patients who did not experience GVHD, graft failure, or 
relapse and were treated with tacrolimus until Day 180.  In addition, the association of 
cellular immune reconstitution, including frequencies of T regulatory cell subpopulations 
and early changes in these populations, with the development of GVHD will be described 
with boxplots and logistic or GEE (generalized estimating equations) regression models. 

Version date: 5/1/12 
 
30
 
g. Describe major toxicities and complications associated with the transplantation procedure.  
Selected toxicities will be reported descriptively. 
 
h. Evaluate selected patient and transplant characteristics in relation to transplantation outcomes. 
The association between selected baseline patient and transplant characteristics and event-
free survival, overall survival, relapse, and GVHD will be investigated using Cox 
proportional hazard models or proportional hazard models for competing risk.  Planned 
variables include donor-recipient HLA mismatch status and models of NK alloreactivity; 
however because of limited sample size, it is anticipated that outcomes in this regard will be 
analyzed with those of other studies. 
 
10.0 
PATHOLOGY REVIEW 
Specimens diagnostic of the malignancy (from the original diagnosis and/or relapse) must be reviewed by the 
Johns Hopkins department of pathology prior to starting protocol therapy.  In cases diagnosed solely by 
peripheral blood flow cytometry, the diagnostic flow cytometry report must be reviewed. 
 
11.0 
RECORDS TO BE KEPT 
Records to be filed include the following:  
a. Patient consent form 
b. Registration form 
c. Eligibility checklist(s) 
d. Case report forms 
e. Adverse event report form(s) 
f. Follow-up assessments 
 
The principal investigator will review case report forms on a regular basis.  Case report forms will be 
supported by primary source documents. 
 
12.0 
PATIENT CONSENT AND PEER JUDGMENT 
Current federal, NCI, state, and institutional regulations regarding informed consent will be followed. 
 
13.0  
REFERENCES  
 
1. 
Luznik L, Jones RJ, Fuchs EJ: High-dose cyclophosphamide for graft-versus-host disease 
prevention. Curr Opin Hematol 17:493-9, 2010 
 
2. 
Burroughs LM, O'Donnell PV, Sandmaier BM, et al: Comparison of outcomes of HLA-
matched related, unrelated, or HLA-haploidentical related hematopoietic cell transplantation following 
nonmyeloablative conditioning for relapsed or refractory Hodgkin lymphoma. Biol Blood Marrow 
Transplant 14:1279-87, 2008 
 
3. 
Luznik L, O'Donnell PV, Symons HJ, et al: HLA-haploidentical bone marrow 
transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, 
posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 14:641-50, 2008 
 
4. 
Lynch RG, Graff RJ, Sirisinha S, et al: Myeloma proteins as tumor-specific transplantation 
antigens. Proc Natl Acad Sci U S A 69:1540-4, 1972 
 
5. 
Molldrem J, Dermime S, Parker K, et al: Targeted T-cell therapy for human leukemia: 
cytotoxic T lymphocytes specific for a peptide derived from proteinase 3 preferentially lyse human myeloid 
leukemia cells. Blood 88:2450-7, 1996 
 
6. 
Bocchia M, Wentworth PA, Southwood S, et al: Specific binding of leukemia oncogene 
fusion protein peptides to HLA class I molecules. Blood 85:2680-4, 1995 

Version date: 5/1/12 
 
31
 
7. 
Pinilla-Ibarz J, Cathcart K, Korontsvit T, et al: Vaccination of patients with chronic 
myelogenous leukemia with bcr-abl oncogene breakpoint fusion peptides generates specific immune 
responses. Blood 95:1781-7, 2000 
 
8. 
Dao T, Scheinberg DA: Peptide vaccines for myeloid leukaemias. Best Pract Res Clin 
Haematol 21:391-404, 2008 
 
9. 
Staveley-O' Carroll K, Sotomayor E, Montgomery J, et al: Induction of antigen-specific T 
cell anergy: An early event in the course of tumor progression. Proc Natl Acad Sci U S A 95:1178-83, 1998 
 
10. 
Willimsky G, Blankenstein T: Sporadic immunogenic tumours avoid destruction by inducing 
T-cell tolerance. Nature 437:141-6, 2005 
 
11. 
Gabrilovich DI, Chen HL, Girgis KR, et al: Production of vascular endothelial growth factor 
by human tumors inhibits the functional maturation of dendritic cells. Nat Med 2:1096-103, 1996 
 
12. 
Mayumi H, Umesue M, Nomoto K: Cyclophosphamide-induced immunological tolerance: 
an overview. Immunobiology 195:129-39, 1996 
 
13. 
Luznik L, Engstrom LW, Iannone R, et al: Posttransplantation cyclophosphamide facilitates 
engraftment of major histocompatibility complex-identical allogeneic marrow in mice conditioned with low-
dose total body irradiation. Biol Blood Marrow Transplant 8:131-8, 2002 
 
14. 
Luznik L, Jalla S, Engstrom LW, et al: Durable engraftment of major histocompatibility 
complex-incompatible cells after nonmyeloablative conditioning with fludarabine, low-dose total body 
irradiation, and posttransplantation cyclophosphamide. Blood 98:3456-64, 2001 
 
15. 
Mayumi H, Himeno K, Tanaka K, et al: Drug-induced tolerance to allografts in mice. XII. 
The relationships between tolerance, chimerism, and graft-versus-host disease. Transplantation 44:286-90, 
1987 
 
16. 
Glucksberg H, Fefer A: Chemotherapy of established graft-versus-host disease in mice. 
Transplantation 13:300-5, 1972 
 
17. 
Owens AH, Jr., Santos GW: The effect of cytotoxic drugs on graft-versus-host disease in 
mice. Transplantation 11:378-82, 1971 
 
18. 
Schwartz R, Dameshek W: Drug-induced immunological tolerance. Nature 183:1682-3, 
1959 
 
19. 
Luznik L, Fuchs EJ: High-dose, post-transplantation cyclophosphamide to promote graft-
host tolerance after allogeneic hematopoietic stem cell transplantation. Immunol Res, 2010 
 
20. 
O'Donnell PV, Luznik L, Jones RJ, et al: Nonmyeloablative bone marrow transplantation 
from partially HLA-mismatched related donors using posttransplantation cyclophosphamide. Biol Blood 
Marrow Transplant 8:377-86, 2002 
 
21. 
Kasamon YL, Luznik L, Leffell MS, et al: Nonmyeloablative HLA-haploidentical bone 
marrow transplantation with high-dose posttransplantation cyclophosphamide: effect of HLA disparity on 
outcome. Biol Blood Marrow Transplant 16:482-9, 2010 
 
22. 
Luznik L, Bolanos-Meade J, Zahurak M, et al: High-dose cyclophosphamide as single agent, 
short-course prophylaxis of graft-versus-host disease. Blood 115:3224-3230, 2010 
 
23. 
Burroughs L, Mielcarek M, Leisenring W, et al: Extending postgrafting cyclosporine 
decreases the risk of severe graft-versus-host disease after nonmyeloablative hematopoietic cell 
transplantation. Transplantation 81:818-25, 2006 
 
24. 
Storb R, Leisenring W, Anasetti C, et al: Methotrexate and cyclosporine for graft-vs.-host 
disease prevention: what length of therapy with cyclosporine? Biol Blood Marrow Transplant 3:194-201, 
1997 
 
25. 
Kansu E, Gooley T, Flowers ME, et al: Administration of cyclosporine for 24 months 
compared with 6 months for prevention of chronic graft-versus-host disease: a prospective randomized 
clinical trial. Blood 98:3868-70, 2001 
 
26. 
Mengarelli A, Iori AP, Romano A, et al: One-year cyclosporine prophylaxis reduces the risk 
of developing extensive chronic graft-versus-host disease after allogeneic peripheral blood stem cell 
transplantation. Haematologica 88:315-23, 2003 
 
27. 
Bacigalupo A, Van Lint MT, Occhini D, et al: Increased risk of leukemia relapse with high-
dose cyclosporine A after allogeneic marrow transplantation for acute leukemia. Blood 77:1423-8, 1991 

Version date: 5/1/12 
 
32
 
28. 
Carlens S, Aschan J, Remberger M, et al: Low-dose cyclosporine of short duration increases 
the risk of mild and moderate GVHD and reduces the risk of relapse in HLA-identical sibling marrow 
transplant recipients with leukaemia. Bone Marrow Transplant 24:629-35, 1999 
 
29. 
Przepiorka D, Weisdorf D, Martin P, et al: 1994 Consensus Conference on Acute GVHD 
Grading. Bone Marrow Transplant 15:825-8, 1995 
 
30. 
Filipovich AH, Weisdorf D, Pavletic S, et al: National Institutes of Health consensus 
development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and 
staging working group report. Biol Blood Marrow Transplant 11:945-56, 2005 
 
31. 
Shulman HM, Sullivan KM, Weiden PL, et al: Chronic graft-versus-host syndrome in man. 
A long-term clinicopathologic study of 20 Seattle patients. Am J Med 69:204-17, 1980 
 
32. 
Cheson BD, Pfistner B, Juweid ME, et al: Revised response criteria for malignant 
lymphoma. J Clin Oncol 25:579-86, 2007 
 
33. 
Hallek M, Cheson BD, Catovsky D, et al: Guidelines for the diagnosis and treatment of 
chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia 
updating the National Cancer Institute-Working Group 1996 guidelines. Blood 111:5446-56, 2008 
 
34. 
Durie BG, Harousseau JL, Miguel JS, et al: International uniform response criteria for 
multiple myeloma. Leukemia 20:1467-73, 2006 
 
35. 
Dohner H, Estey EH, Amadori S, et al: Diagnosis and management of acute myeloid 
leukemia in adults: recommendations from an international expert panel, on behalf of the European 
LeukemiaNet. Blood 115:453-74, 2010 
 
36. 
Cheson BD, Bennett JM, Kopecky KJ, et al: Revised recommendations of the International 
Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting 
Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol 21:4642-9, 2003 
 
37. 
Cheson BD, Greenberg PL, Bennett JM, et al: Clinical application and proposal for 
modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood 108:419-
25, 2006 
 
38. 
Gray RJ: A class of k-sample tests for comparing the cumulative incidence of a competing 
risk. Ann Stat 16:1141-1154, 1988 
 
39. 
Fine JP, Gray RJ: A proportional hazards model for the subdistribution of a competing risk. 
JASA 94:496-509, 1999 
 
 

Version date: 5/1/12 
 
33
APPENDIX A                 
Acute GVHD Grading 
 
 
 
From Przepiorka D et al. 1994 Consensus Conference on Acute GVHD Grading. BMT 1995; 15: 825-828. 
 
 

Version date: 5/1/12 
 
34
APPENDIX B  
 
 
Statistical Supplement 
 
 
The following are operating characteristics of the statistical design, with varying simulated risks, and 
planned cessation of tacrolimus on Day 90.  In each scenario, the stopping criteria between Days 91 
and 180 are as follows:  Graft Failure = 0.05, nonrelapse mortality (NRM) = 0.10, 
relapse/progression = 0.50, GVHD (acute grade II-IV or severe chronic GVHD) = 0.20.  Each 
scenario is shown with operating characteristics based on 1000 simulations.   
 
Scenario #2: Increased risk of graft failure in first 60 days:  
After 1000 simulations with probabilities: 
Days 
Graft Failure 
NRM 
Relapse 
GVHD 
No Event 
1-60 
0.50 
0.05 
0.05 
0.10 
0.30 
61-90 
0.01 
0.05 
0.05 
0.10 
0.79 
91-120 
0.01 
0.05 
0.05 
0.10 
0.79 
121-180 
0.05 
0.05 
0.05 
0.10 
0.75 
 
        Stopped for lack of feasibility 768 (76.8%) times. 
        Stopped for lack of feasibility at first look 441 (44.1%) times. 
        Safety or relapse problem declared 15 (1.5%) times. 
        Safety or relapse problem by reason (% of times): 
        GraftFail   NRM 
 Relapse   GVHD   No Event  
     
  1.1       0.4          0.0            0.0         0.0  
        Number of patients transplanted to reach 15: 
   
Min.   1st Qu.  Median   Mean    3rd Qu.    Max.  
18.00   18.00    28.00       32.64    48.00      58.00  
 
Scenario #3: Increased risk of graft failure in first 60 days and of GVHD between Days 91 and 120:  
After 1000 simulations with probabilities: 
Days 
Graft Failure 
NRM 
Relapse 
GVHD 
No Event 
1-60 
0.50 
0.05 
0.05 
0.10 
0.30 
61-90 
0.01 
0.05 
0.05 
0.10 
0.79 
91-120 
0.01 
0.05 
0.05 
0.30 
0.59 
121-180 
0.05 
0.05 
0.05 
0.10 
0.75 
 
        Stopped for lack of feasibility 774 (77.4%) times. 
        Stopped for lack of feasibility at first look 421 (42.1%) times. 
        Safety or relapse problem declared 41 (4.1%) times. 
        Percent of times safety or relapse problem by reason (%): 
        GraftFail     NRM   Relapse      GVHD   No Event  
      
 0.3          0.0       0.0        
3.8        0.0  
        Number of patients transplanted to reach 15: 
  
 Min.  1st Qu.  Median   Mean   3rd Qu.  Max.  
   
18.00   18.00    28.00      31.49    43.00   58.00  
 
 

Version date: 5/1/12 
 
35
Scenario #4: Increased risk of graft failure in first 90 days 
After 1000 simulations with probabilities: 
Days 
Graft Failure 
NRM 
Relapse 
GVHD 
No Event 
1-60 
0.50 
0.05 
0.05 
0.10 
0.30 
61-90 
0.20 
0.05 
0.05 
0.10 
0.60 
91-120 
0.01 
0.05 
0.05 
0.10 
0.79 
121-180 
0.05 
0.05 
0.05 
0.10 
0.75 
 
        Stopped for lack of feasibility 958 (95.8%) times. 
        Stopped for lack of feasibility at first look 369 (36.9%) times. 
        Safety or relapse problem declared 8 (0.8%) times. 
        Percent of times safety or relapse problem by reason (%): 
        GraftFail     NRM   Relapse    GVHD   No Event  
     
  0.6         0.2       0.0             0.0     
0.0  
        Number of patients transplanted to reach 15: 
  Min.  1st Qu.  Median   Mean   3rd Qu.   Max.  
   
  18.00   18.00   18.00     24.61    28.00      58.00  
 
Scenario #5: Increased risk of graft failure and GVHD in first 60 days and after Day 90  
After 1000 simulations with probabilities: 
Days 
Graft Failure 
NRM 
Relapse 
GVHD 
No Event 
1-60 
0.15 
0.02 
0.12 
0.25 
0.46 
61-90 
0.01 
0.02 
0.05 
0.10 
0.82 
91-120 
0.01 
0.01 
0.12 
0.35 
0.51 
121-180 
0.05 
0.05 
0.16 
0.35 
0.39 
 
        Stopped for lack of feasibility 113 (11.3%) times. 
        Stopped for lack of feasibility at first look 54 (5.4%) times. 
        Safety or relapse problem declared 578 (57.8%) times. 
        Percent of times safety or relapse problem by reason (%): 
        GraftFail     NRM   Relapse  GVHD   No Event  
       
1.1    
    0.0       0.0         56.7       0.0  
        Number of patients transplanted to reach 15: 
  
 Min.  1st Qu.  Median    Mean   3rd Qu.   Max.  
   
 18.00   28.00    33.00      33.51    43.00     58.00  
 

Version date: 5/1/12 
 
36
Scenario #6: Increased risk of GVHD   
After 1000 simulations with probabilities: 
Days 
Graft Failure 
  NRM 
Relapse 
GVHD 
No Event 
1-60 
0.15 
0.02 
0.12 
0.25 
0.46 
61-90 
0.01 
0.02 
0.05 
0.10 
0.82 
91-120 
0.01 
0.01 
0.20 
0.30 
0.48 
121-180 
0.01 
0.05 
0.25 
0.35 
0.34 
 
        Stopped for lack of feasibility 118 (11.8%) times. 
        Stopped for lack of feasibility at first look 63 (6.3%) times. 
        Safety or relapse problem declared 395 (39.5%) times. 
        Percent of times safety or relapse problem by reason (%): 
        GraftFail     NRM   Relapse     GVHD   No Event  
      
 0.3        0.0          0.0         39.2       0.0  
        Number of patients transplanted to reach 15: 
   
Min.   1st Qu.  Median   Mean   3rd Qu.   Max.  
   
18.00   28.00    38.00      35.96    43.00     58.00  
 
Scenario #7: Increased risk of GVHD and relapse   
After 1000 simulations with probabilities: 
Days 
Graft Failure 
NRM 
Relapse 
GVHD 
No Event 
1-60 
0.15 
0.02 
0.12 
0.35 
0.36 
61-90 
0.01 
0.02 
0.25 
0.20 
0.52 
91-120 
0.01 
0.01 
0.50 
0.40 
0.08 
121-180 
0.01 
0.05 
0.25 
0.30 
0.39 
 
        Stopped for lack of feasibility 940 (94%) times. 
        Stopped for lack of feasibility at first look 384 (38.4%) times. 
        Safety or relapse problem declared 28 (2.8%) times. 
        Percent of times safety or relapse problem by reason (%): 
        GraftFail     NRM   Relapse     GVHD   No Event  
       
0.0    
    0.0       0.0             2.8          0.0  
        Number of patients transplanted to reach 15: 
  
Min.  
1st Qu.  Median   Mean    3rd Qu.   Max.  
   
18.00    18.00     18.00      25.04     28.00    58.00  
 
 

Version date: 5/1/12 
 
37
Scenario #8: Increased risk of GVHD and relapse with very few graft failures  
After 1000 simulations with probabilities: 
Days 
Graft Failure 
NRM 
Relapse 
GVHD 
No Event 
1-60 
0.01 
0.02 
0.12 
0.35 
0.50 
61-90 
0.01 
0.02 
0.25 
0.20 
0.52 
91-120 
0.01 
0.01 
0.50 
0.40 
0.08 
121-180 
0.01 
0.05 
0.25 
0.30 
0.39 
 
        Stopped for lack of feasibility 632 (63.2%) times. 
        Stopped for lack of feasibility at first look 354 (35.4%) times. 
        Safety or relapse problem declared 126 (12.6%) times. 
        Percent of times safety or relapse problem by reason (%): 
         
GraftFail     NRM   Relapse   GVHD   No Event  
      
 0.0              0.0       0.0          12.6         0.0  
        Number of patients transplanted to reach 15: 
  
Min.   1st Qu.  Median   Mean    3rd Qu.   Max.  
   
18.00   18.00    33.00     33.58     43.00     58.00  
 
Scenario #9:  High probability of relapse after Day 90  
After 1000 simulations with probabilities: 
Days 
Graft Failure 
NRM 
Relapse 
GVHD 
No Event 
1-60 
0.01 
0.02 
0.05 
0.05 
0.87 
61-90 
0.01 
0.02 
0.10 
0.05 
0.82 
91-120 
0.01 
0.01 
0.60 
0.05 
0.33 
121-180 
0.01 
0.05 
0.85 
0.05 
0.04 
 
        Stopped for lack of feasibility 0 (0%) times. 
        Stopped for lack of feasibility at first look 0 (0%) times. 
        Safety or relapse problem declared 55 (5.5%) times. 
        Percent of times safety or relapse problem by reason (%): 
       
 GraftFail     NRM   Relapse   GVHD   No Event  
      
 0.0                0.0       5.5           0.0           0.0  
        Number of patients transplanted to reach 15: 
   
Min.   1st Qu.  Median   Mean   3rd Qu.   Max.  
   
18.00   23.00    23.00     23.07    23.00      33.00  
 

Version date: 5/1/12 
 
38
Scenario #10:  High probability of GVHD after Day 90  
After 1000 simulations with probabilities: 
Days 
Graft Failure 
NRM 
Relapse 
GVHD 
No Event 
1-60 
0.01 
0.02 
0.05 
0.05 
0.87 
61-90 
0.01 
0.02 
0.05 
0.10 
0.82 
91-120 
0.01 
0.01 
0.05 
0.40 
0.53 
121-180 
0.01 
0.05 
0.05 
0.60 
0.29 
 
        Stopped for lack of feasibility 0 (0%) times. 
        Stopped for lack of feasibility at first look 0 (0%) times. 
        Safety or relapse problem declared 983 (98.3%) times. 
        Percent of times safety or relapse problem by reason (%): 
         
GraftFail    NRM    Relapse   GVHD   No Event  
      
 0.3            0.0       0.0            98.2       0.0  
        Number of patients transplanted to reach 15: 
   
Min.  1st Qu.  Median   Mean   3rd Qu.  Max.  
  
18.0    18.0       18.0        18.7     18.0       33.0  
 
Scenario #11:  High probability of graft failure after Day 90  
After 1000 simulations with probabilities: 
Days 
Graft Failure 
NRM 
Relapse 
GVHD 
No Event 
1-60 
0.01 
0.02 
0.05 
0.05 
0.87 
61-90 
0.01 
0.02 
0.05 
0.10 
0.82 
91-120 
0.10 
0.01 
0.05 
0.10 
0.74 
121-180 
0.15 
0.05 
0.05 
0.10 
0.65 
 
        Stopped for lack of feasibility 0 (0%) times. 
        Stopped for lack of feasibility at first look 0 (0%) times. 
        Safety or relapse problem declared 635 (63.5%) times. 
        Percent of times safety or relapse problem by reason (%): 
         
GraftFail     NRM    Relapse    GVHD   No Event  
     
 63.3             0.0        0.0            0.2         0.0  
        Number of patients transplanted to reach 15: 
   
Min.    1st Qu.  Median   Mean   3rd Qu.  Max.  
   
18.00   18.00     18.00      20.54   23.00     38.00  
 
 

Version date: 5/1/12 
 
39
Scenario #12:  High probability of NRM after Day 90  
After 1000 simulations with probabilities: 
Days 
Graft Failure 
NRM 
Relapse 
GVHD 
No Event 
1-60 
0.01 
0.02 
0.05 
0.05 
0.87 
61-90 
0.01 
0.02 
0.05 
0.10 
0.82 
91-120 
0.01 
0.20 
0.05 
0.10 
0.64 
121-180 
0.01 
0.30 
0.05 
0.10 
0.54 
 
        Stopped for lack of feasibility 0 (0%) times. 
        Stopped for lack of feasibility at first look 0 (0%) times. 
        Safety or relapse problem declared 781 (78.1%) times. 
        Percent of times safety or relapse problem by reason (%): 
         
GraftFail     NRM   Relapse    GVHD   No Event  
      
 0.2              77.9       0.0          0.2         0.0  
        Number of patients transplanted to reach 15: 
  
 Min.   1st Qu.  Median   Mean   3rd Qu.  Max.  
  
 18.0     18.0       18.0        20.3      23.0      38.0  
 
Scenario #13:  Higher probability of relapse after Day 90  
After 1000 simulations with probabilities: 
Days 
Graft Failure 
NRM 
Relapse 
GVHD 
No Event 
1-60 
0.01 
0.02 
0.05 
0.05 
0.87 
61-90 
0.01 
0.02 
0.10 
0.10 
0.77 
91-120 
0.01 
0.01 
0.85 
0.10 
0.03 
121-180 
0.01 
0.01 
0.90 
0.05 
0.03 
 
        Stopped for lack of feasibility 0 (0%) times. 
        Stopped for lack of feasibility at first look 0 (0%) times. 
        Safety or relapse problem declared 40 (4%) times. 
        Percent of times safety or relapse problem by reason (%): 
         
GraftFail     NRM   Relapse    GVHD   No Event  
     
  0.1              0.0         3.9            0.0         0.0  
        Number of patients transplanted to reach 15: 
 Min.   1st Qu.  Median   Mean   3rd Qu.  Max.  
 18.00   23.00    23.00      24.37    28.00   38.00