Clinical trial NCT02145039
Conditions: Acute Leukemias Burkitt's Lymphoma Chronic Myelogenous Leukemia
Keywords: Acute Lymphoblastic Leukemia (ALL) Acute Myelogenous Leukemia (AML) Burkitt's lymphoma Natural killer cell malignancies Chronic myelogenous leukemia Myelodysplastic syndrome Large-cell lymphoma Hodgkin lymphoma Multiple myeloma Chronic lymphocytic leukemia (CLL) Small lymphocytic lymphoma (SLL) Marginal zone B-cell lymphoma Follicular lymphoma Lymphoplasmacytic lymphoma Mantle-cell lymphoma Prolymphocytic leukemia Refractory leukemia Myelodysplastic syndrome (MDS) Bone marrow failure syndromes Myeloproliferative syndromes
Sponsor: Masonic Cancer Center, University of Minnesota
Start date: 2014-10-01; Completion date: 2019-01-01
Enrollment: 2 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a treatment guideline for HLA-Haploidentical hematopoietic stem cell transplant (HSCT) using a reduced intensity conditioning (RIC) regimen. This regimen, consisting of fludarabine, cyclophosphamide and low dose total body irradiation (TBI), is designed for the treatment of patients with advanced and/or high risk diseases.

Detailed description:

Arms: arm 1: This is a treatment guideline for HLA-Haploidentical hematopoietic stem cell transplant (HSCT) using a reduced intensity conditioning (RIC) regimen. This regimen consists of fludarabine, cyclophosphamide and low dose total body irradiation (TBI).
Interventions: intervention 1: Fludarabine intervention 2: Cyclophosphamide intervention 3: Total Body Irradiation intervention 4: Haploidentical stem cell transplant
Intervention descriptions: intervention 1: Fludarabine 30 mg/m2 IV over 30-60 minutes on days -6 through -2 before transplant. intervention 2: Cyclophosphamide 14.5 mg/kg IV over 1-2 hours on days -6 and -5 before transplant and Cyclophosphamide 50 mg/kg IV on days 3 and 4 post-transplant. intervention 3: TBI 200cGy on day -1 before transplant. intervention 4: Non-T-cell depleted bone marrow infusion

Protocol documents:
Prot_SAP_000.pdf: 
Masonic Cancer Center, University of Minnesota 
Blood and Marrow Transplant Program 
 
 
Reduced Intensity Conditioning (RIC) and Transplantation of HLA-
Haploidentical Related Bone Marrow (Haplo-BM) For Patients  
With Hematologic Diseases 
MT2013-33C 
CPRC #2013OC116 
 
Investigators 
Nelli Bejanyan, MD (Principal Investigator) 
Claudio Brunstein, MD, PhD 
Mukta Arora, MD 
John E. Wagner, MD 
Daniel J. Weisdorf, MD 
 
Study Statistician 
Todd E. DeFor, MS 
 
 
Version Date 
September 29, 2016 
 
 
 
 
 
 
 
 
 
 
 
 
Confidential 
 


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CPRC# 2013OC116 
Revision History 
Revision 
# 
Version 
Date 
Detail of Changes 
Consent 
change?  
 
12/03/13 
Original to CPRC/IRB 
 
1 
09/12/2016 
Updated disease eligibility and general study inclusion 
/exclusion criteria to match institutional standard language 
Updated with current protocol template language  
no 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PI Contact Information: 
Nelli Bejanyan, MD 
Hematology Oncology Transplant 
MMC 480 Mayo  
420 Delaware St SE 
Minneapolis, MN 55455 
Phone:  612-624-6982 
Email: nbejanya@umn.edu 
 
 


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Table of Contents 
Synopsis ..................................................................................................................................... 4 
Schema ....................................................................................................................................... 5 
1.0 
Introduction ..................................................................................................................... 6 
2.0 
Background and Rationale ............................................................................................... 6 
2.1 
Patient Characteristics Receiving Haplo-BM per BMT-CTN0603 .............................................. 8 
2.2 
Hematopoietic Recovery and Chimerism ..................................................................................... 9 
2.3 
Graft-Versus-Host Disease ......................................................................................................... 10 
2.4 
Treatment-Related-Mortality, Relapse, and Survival ................................................................. 10 
3.0 
Patient Selection ..............................................................................................................11 
3.1 
Age, Graft Cell Dose and Graft HLA Criteria ............................................................................ 11 
3.2 
Eligible Diseases ......................................................................................................................... 12 
3.5 
Exclusion Criteria ....................................................................................................................... 15 
4.0 
Registration in OnCore ...................................................................................................15 
5.0 
Treatment Plan ...............................................................................................................15 
5.1 
Transplant Preparative Therapy (day -6 through day -1) ............................................................ 16 
5.2 
Transplant (day 0) ....................................................................................................................... 17 
5.3 
Post-Transplant Cyclophosphamide (days 3 and 4) .................................................................... 18 
5.4 
Immunosuppressive Therapy (begin day 5) ................................................................................ 18 
5.5 
Growth Factor Support (begin day 5) ......................................................................................... 18 
5.6 
Supportive Care .......................................................................................................................... 19 
5.7 
Follow-Up ................................................................................................................................... 19 
6.0 
Clinical Evaluations ........................................................................................................19 
7.0 
Event Reporting ..............................................................................................................21 
8.0 
Data Collection and Statistical Plan .................................................................................21 
8.1 
Trial Size Justification ................................................................................................................ 21 
8.2 
Enrollment Plan .......................................................................................................................... 22 
8.3 
Analysis of Primary and Secondary Endpoints ........................................................................... 22 
8.4 
Safety Monitoring ....................................................................................................................... 22 
9.0 
References ......................................................................................................................22 
Appendix I – Appendix I – Performance Status Scales.................................................................26 
Appendix II - Expected Risks of the Preparative Regimen, GVHD Prophylaxis and Transplant ...27 


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Synopsis 
Reduced Intensity Conditioning (RIC) and Transplantation of HLA-Haploidentical 
Related Bone Marrow (Haplo-BM) For Patients With Hematologic Diseases 
MT2013-33C 
CPRC #2013OC116 
 
 
This is a treatment guideline to allow routine clinical data to be collected and maintained in OnCore and the University 
Of Minnesota Blood and Marrow Database as part of the historical database maintained by the department. 
 
Design: 
This is a treatment guideline for HLA-Haploidentical hematopoietic stem cell transplant (HSCT) using 
a reduced intensity conditioning (RIC) regimen.  This regimen, consisting of fludarabine, 
cyclophosphamide and low dose total body irradiation (TBI), is designed for the treatment of  patients 
with advanced and/or high risk diseases 
 
Eligibility: 
• Diagnosis of a hematologic disease for which a transplant is indicated but without a 7/8 or 8/8 HLA-
matched sibling donor or appropriate UCB unit(s) 
• Meets the disease specific criteria found in section 3.2 
• Age < 75 years of age 
• Available related haploidentical bone marrow donor  
 
Treatment 
Plan 
 
 
 
treatment day 
treatment 
protocol section 
Day –6, -5 
Fludarabine 30 mg/m2 IV  
Cyclophosphamide 14.5 mg/kg IV  
section 5.1 
Day –4, -3, -2 
Fludarabine 30 mg/m2 IV over 30-60 minutes 
Day –1 
TBI 200 cGy 
Day 0 
Non-T-cell depleted bone marrow infusion 
section 5.2 
Day 3 
Cyclophosphamide 50 mg/kg IV 
section 5.3 
Day 4 
Cyclophosphamide 50 mg/kg IV 
Day 5 
Begin tacrolimus (or cyclosporine), mycophenolate mofetil, 
and G-CSF 
sections 5.4 and 
5.5 
Endpoints: 
Endpoints include survival at 2 years post- transplant, hematopoietic engraftment, chimerism at day 
100, 6 months and 1 year, acute GVHD at 100 days, chronic GVHD at 1 year, and  transplant related 
mortality (TRM) at 6 months.    
 
Enrollment: 
4 to 5 patients per year 
 
 
 
 


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Schema 
 
 
 
 


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1.0 
Introduction 
This is a treatment guideline for a haploidentical bone marrow transplant (Haplo-BM) 
using reduced intensity conditioning (RIC) for patients with a hematologic disease for 
whom a matched donor or umbilical cord blood is not available.  There is no research 
element except the collection of routine clinical data. 
Patients will consent to allow routine clinical data to be collected and maintained in 
OnCore, the Masonic Cancer Center’s (MCC) clinical database, and specific transplant 
related endpoints in the University Of Minnesota Blood and Bone Marrow Database as 
part of the historical database maintained by the department.   
Endpoints include survival at 2 years post-transplant, hematopoietic engraftment, 
chimerism at day 100, 6 months and 1 year, acute GVHD at 100 days, chronic GVHD at 
1 year, and transplant related mortality (TRM) at 6 months.    
 
2.0 
Background and Rationale 
Allogeneic hematopoietic cell transplantation (HCT) is widely used as a curative therapy 
for number of hematological diseases. Reduced intensity conditioning (RIC) opened 
opportunities for older patients and those with comorbid conditions to be eligible for 
potentially curable transplantation.1-5 However, donor availability still remains significant 
challenge for large number of patients as HLA-identical matched sibling (MSD) or adult 
unrelated donor (MUD) is available only for about 60% of the patients.6 In addition, the 
data from the National Marrow Donor Program (NMDP) indicate that median time from 
donor search to adult MUD transplant is about 3-4 months, this time delay infrequently 
increases the risk of malignancy relapse in some patients with aggressive diseases.1,2 
Since adult MUD is generally not readily available for many patients with hematological 
malignancies who are in need for urgent HCT, recent years number of transplant centers 
widely expended the use of alternative graft sources such as umbilical cord blood (UCB) 
or haploidentical grafts. 1-5,7-11 Although UCB is timely available for most of the 
Caucasian patients, its availability is significantly less for ethnic minorities such as 
African Americans or Asians. Furthermore, significantly high cost of UCB as compared 
to other donor sources remains an additional limitation. In contrast, lower cost and easy 
accessibility of haploidentical transplantation (haploHCT) makes it an attractive 
alternative graft source. First-degree relative haploidentical donor is available for more 
than 95% of individuals with an average of 2.7 such donors number per patient.6,12 Initial 
experience with haploidentical transplantation using T-cell replete allograft was 
disappointing with unacceptably high incidence of severe graft versus host disease 
(GVHD) and non relapse mortality (NRM) in about half of the patients.1314,15 However, 
when T-cells were depleted and non-myeloablative (NMA) preparative regimen was used 


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there was an excessive risk of graft failure. Engraftment was improved with the infusion 
of mega-doses of CD34 + cells (over 10x106 cells/kg) and/or when myeloablative 
conditioning regimens were used.9,12,16 On the other hand T-cell depleted myeloablative 
regimens were associated with significantly increased mortality from serious infections 
and poor immune reconstitution as reported by the European Group for Blood and 
Marrow Transplantation (EBMT) 16 Several strategies are still under development to 
promote T-cell tolerance and reduce the risk of GVHD without affecting immune 
reconstitution. These approaches include the adoptive therapy of pathogen-specific T-
cells,17-21  T-cells engineered to express suicide genes,22-24 regulatory T-cells (Tregs),25,26 
alloreactive donor T-cell ex-vivo photodepletion.27,28, ex vivo anergy induction by 
costimulation blockade,29,30 ex vivo selective depletion of T-cells,31-33 and more recently 
the administration of high-dose post-transplant cyclophosphamide (PT-Cy).10,34-37  
PT-Cy approach has become more widely used by many transplant centers in recent years 
given its ease of administration and low cost. PT-Cy leads to in vivo depletion of 
alloreactive T-cells that helps reducing both graft rejection and GVHD rates.38 Recent 
study by Munchel and colleagues reported 87% sustained engraftment, 27% grades II-IV 
acute GVHD and 13% chronic GVHD rates among 210 haploHCT recipients with 5-year 
non-relapse mortality (NRM) of only 18%, relapse incidence of 55% and overall survival 
(OS) of 35%.34 Another study by Ciurea and colleagues compared the clinical outcomes 
of 65 haploHCT recipients with T-cell replete BMT/PT-Cy versus T-cell depleted 
peripheral blood HCT. They demonstrated superiority of T-cell replete BMT/PT-Cy with 
significant lower 1-year NRM (16% vs.42%, p=0.03), chronic GVHD rate (8% vs. 18%, 
p=0.03), and superior progression free (PFS) (45% vs. 21%, p=0.03) and OS (66% vs. 
30%, p=0.02).35 Several recent studies suggest improvement of immune reconstitution 
with preserved memory T-cells when PT-Cy is used in T-cell replete haploHCT.34,36 
Bashey and colleagues identified comparable relapse rate, DFS and OS were identified 
between haploHCT/PT-Cy and MSD or adult MUD transplant.10 Another group of 
investigators from China retrospectively compared the outcome of 117 patients with 
various hematological malignancies receiving MSD (n=36) and haploidentical bone 
marrow transplant (haplo-BM, n=81). They showed higher incidence of grade II-IV acute 
GVHD in haploHCT group as compared to MSD group (49% v. 24%, p=0.014), but 
lower 2-year relapse rate (26% vs. 49%, p=0.008), which resulted to better 3-year 
probability of OS among haploHCT recipients (42% vs. 20%, p=0.048).39 Brunstein and 
colleagues reported the outcomes of patients with haplo-BM/PT-Cy (BMT CTN 0603, 
n=50) and UCB transplantation (BMT CTN 0604, n=50) after RIC in Blood and Marrow 
Transplant Clinical trials Network (BMT-CTN) 2 parallel multicenter phase 2 trials.8 
Eligibility criteria for the two trials were the identical. The target accrual of 50 patients 
per trial was achieved in just 20 months (16 months faster than expected).  Recipients of 
haplo-BM were conditioned with Flu 30 mg/m2/day IV daily from Days  -6 to -2 (total 
dose of 150 mg/m2), Cy 14.5 mg/kg IV on Day -6 and -5, and 2 Gy TBI in a single 


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fraction on Day -1 (Figure 1).  GVHD prophylaxis consisted of Cy 50 mg/kg IV on Days 
3 and 4 followed by MMF and tacrolimus beginning on Day 5, with CsA as an acceptable 
substitution for tacrolimus.  Filgrastim 5 mcg/kg/day was initiated on post-transplantation 
Day 5 and continued until the ANC was ≥ 1000/µL for three consecutive days. 
2.1 
Patient Characteristics Receiving Haplo-BM per BMT-CTN0603  
Characteristics of the patients enrolled in haploHCT are summarized in Table 1 
(BMT CT 0603).  
Fifty patients were treated according to the protocol and included in the report.  
Seventeen donors were siblings of the recipient, 15 were parents and 18 were 
children.  More than three quarters of the HLA-haploidentical related donors were 
mismatched for four or more HLA loci using high-resolution typing (HLA-A, -B, 
-C, -DRB1, and –DQB1) in both the graft-versus-host and host-versus-graft 
directions.  


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Table 1. Patient characteristics receiving haplo-BM 
2.2 
Hematopoietic Recovery and Chimerism 
After haplo-BM the cumulative incidence of neutrophil recovery >500/µL at Day 
56 was 96% (95%CI, 90-100%) with a median time to recovery of 16 days (range, 
12-83).  The cumulative incidence of platelet recovery ≥ 20,000/µL at Day 100 
was 98% (95%CI, 93-100%) with a median time to recovery of 24 days (range, 1-
92).  The corresponding probability for platelets ≥ 50,000/µL was 76% (95%CI, 
64-88%) with a median time to recovery of 26 days (range, 1-126).  There was 
one case of primary graft failure.  This patient did not receive a second transplant 
and died on Day 67.  Median donor chimerism in marrow or peripheral blood was 
100% (range 72-100%) on Day 28 and 100% (range 0-100%) on Day 56 after 
transplantation.  


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2.3 
Graft-Versus-Host Disease 
After haplo-BM transplantation, the cumulative incidence of grade II-IV acute 
GVHD at Day +100 were 32% (95% CI, 19-45%).  There were no reported cases 
of grade III-IV acute GVHD.  The cumulative incidence of chronic GVHD at 1 
year was 13% (95% CI, 3-23%). 
2.4 
Treatment-Related-Mortality, Relapse, and Survival 
After haplo-BM, the median follow-up of surviving patients was 357 days (range 
103-441).  The 1-year cumulative incidence of TRM was 7% (95% CI, 0-15%) 
and of relapse/progression was 45% (95% CI, 30-61%; Figure 2A).  Sixteen 
patients have died: 13 from relapse, 2 from infection, and 1 from graft failure. 
Six-month survival, which was the primary endpoint, was 84% (95%CI, 70-92%).  
The 1-year probability of progression-free survival was 48% (95% CI, 32-62%) 
and overall survival 62% (95% CI, 44-76%; Figure 2B). 
The BMT CTN haplo-BM results (0603) may even be a little better than those 
initially reported by Johns Hopkins,11 probably because of inclusion of somewhat 
better-risk 
patients 
in 
the 
BMT CTN trial. 
These results of 
the RIC followed 
by haploidentical 
related 
(0603) 
transplantation in 
multicenter Phase 
II trials are quite 
encouraging. This 
set the stage for 
current 
ongoing 
BMT-CTN 1101 
a 
multicenter, 
randomized phase 
III trial that aims 
to compare 2-year 
PFS 
of 
two 
standard of care 
alternative donor 
platforms; haplo BM with PT-Cy and double UCB grafts. The reproducible 
outcomes of haploHCT, in particular haplo BM with PT-Cy,  has made it yet 
another viable and effective graft source that is readily and extends allogeneic 
 
Figure 2.  Relapse, NRM (A), overall survival, and event-free 
survival (B) after RIC and transplantation of Haplo-marrow. 
A
B


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transplantation to almost all patients lacking an HLA-identical donor and for 
those requiring potentially curative urgent transplantation. 
   
3.0 
Patient Selection  
3.1 
Age, Graft Cell Dose and Graft HLA Criteria 
Must be <75 years old with no 7/8 or 8/8 HLA-matched sibling donor.  Patients ≥ 
70 and ≤ 75 years of age may be eligible if they have a Co-Morbidity score ≤ 2 
(http://www.qxmd.com/calculate-online/hematology/hct-ci) 
One or more potential related mismatched donors (e.g. biologic parent (s) or 
siblings (full or half) or children).  Low resolution using DNA based typing at 
HLA-A, -B and –DRB1 for potential haploidentical donors is required. 
Patients and donor must be HLA typed at high resolution using DNA based 
typing at the following HLA-loci: HLA-A, -B, -C and DRB1 and have available: 
A related haploidentical BM donor with 2, 3, or 4 HLA-mismatches.  A 
unidirectional mismatch in either the graft versus host or host versus graft 
direction is considered a mismatch.  The donor and recipient must be HLA 
identical for at least one antigen (using high resolution DNA based typing) at the 
following genetic loci: HLA-A, HLA-B, HLA-C, and HLA-DRB1.  Fulfillment of 
this criterion shall be considered sufficient evidence that the donor and recipient 
share one HLA haplotype, and typing of additional family members is not 
required.   
Donors will consent to and be enrolled in the University of Minnesota 
Procedure Guidelines For Related Hematopoietic Stem Cell Donors 
(MT2012-14C).  Refer to that document for donor related eligibility and 
procedures. 
Donor Prioritization: 
In the event that two or more eligible donors are identified, the following order of 
priority is suggested but NOT mandated: 
• For cytomegalovirus (CMV) seronegative recipients, a CMV seronegative 
donor 
• Red blood cell compatibility 
• RBC cross-match compatible 
• Minor ABO incompatibility 
• Major ABO incompatibility 
 
 


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3.2 
Eligible Diseases  
Acute Leukemias:  Must be in remission by morphology (≤5% blasts).  Also a 
small percentage of blasts that is equivocal between marrow regeneration vs. early 
relapse are acceptable provided there are no associated cytogenetic markers 
consistent with relapse.  
Acute lymphoblastic leukemia (ALL)/lymphoma: second or greater CR; CR1 
unable to tolerate consolidation chemotherapy due to chemotherapy-related 
toxicities; CR1 high-risk ALL.    
High risk ALL is defined as having one of the following:: 
• Adverse cytogenetics such as t(9;22), t(1;19), t(4;11), other MLL 
rearrangements, IKZF1 
• White blood cell counts of >30,000/mcL (B-ALL) or >100,000/mcL (T-
ALL) at diagnosis, 
• 30 years of age or older at diagnosis, 
• Slow cytologic response (>10% lymphoblasts in bone marrow on Day 14 
of induction therapy) 
• Evidence of persistent immonophenotypic or molecular minimal residual 
disease (MRD) at the end of induction and consolidation therapy 
 
Acute Myelogenous Leukemia (AML) and related precursor neoplasms:  2nd or 
greater complete remission (CR); first complete remission (CR1) in patients > 60 
years old; CR1 in ≤ 60 years old that is NOT considered as favorable-risk. 
Favorable risk is defined as having one of the following: 
• t(8,21) without cKIT mutation 
• inv(16) or t(16;16) without cKIT mutation 
• Normal karyotype with mutated NPM1 and wild type FLT-ITD 
• Normal karyotype with double mutated CEBPA 
• Acute prolymphocytic leukemia (APL) in first molecular remission at end 
of consolidation 
 
Acute Leukemias in 2nd or subsequent CR  
Biphenotypic/Undifferentiated/Prolymphocytic Leukemias in first or subsequent 
CR, adult T-cell leukemia/lymphoma in first or subsequent CR 
Burkitt’s Lymphoma in CR2 or subsequent CR 
 
Natural Killer Cell Malignancies  
 


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Chronic Myelogenous Leukemia (CML): in chronic or accelerated phase, or CML 
blast crisis in morphological remission (<5% blasts).  Chronic phase patients must 
have failed at least two different TKIs, been intolerant to all available TKIs or 
have T315I mutation  
 
MRD positive leukemia (AML, ALL or accelerated/blast phase CML). Selected 
patients in morphologic CR, but with positive immunophenotypic (flow 
cytometry) or molecular evidence of MRD may be eligible if recent 
chemotherapy has not resulted in MRD negative status. 
 
Myelodysplastic Syndrome: IPSS INT-2 or High Risk; R-IPSS High or Very 
High; WHO classification: RAEB-1, RAEB-2; Severe Cytopenias: ANC < 0.8, 
Anemia or thrombocytopenia requiring transfusion; Poor or very poor risk 
cytogenetics based on IPSS or R-IPSS definitions; therapy-related MDS. Blasts 
must be < 5% by bone marrow aspirate morphology. If >5% blasts, patient 
requires chemotherapy for cytoreduction to <5% blasts prior to transplantation. 
 
Relapsed Large-Cell Lymphoma, Mantle-Cell Lymphoma and Hodgkin 
Lymphoma that is chemotherapy sensitive and has failed or ineligible for an 
autologous transplant. 
 
Lymphoplasmacytic Lymphoma is eligible after initial therapy if chemotherapy 
sensitive. 
 
Relapsed Multiple Myeloma that is chemotherapy sensitive and has failed or 
ineligible for an autologous transplant.  
 
Plasma cell leukemia after initial therapy if achieved at least in partial remission; 
or relapsed and achieved subsequent remission (CR/PR).  
 
Relapsed 
chronic 
lymphocytic 
leukemia/small 
lymphocytic 
lymphoma 
(CLL/SLL), marginal zone B-cell lymphoma, follicular lymphoma, which have 
progressed within 12 months of achieving a partial or complete remission. 
Patients who had remissions lasting > 12 months, are eligible after at least two 
prior therapies. Patients with bulky disease should be considered for de-bulking 
chemotherapy before transplant.  Patients with refractory disease are eligible, 
unless has bulky disease and an estimated tumor doubling time of less than one 
month.  
 


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Refractory leukemia or MDS in aplasia.  These patients may be taken to 
transplant if after induction therapy they remain with aplastic bone marrow and no 
morphological or flow-cytometry evidence of disease ≥ 28 days post-therapy. 
These high risk patients will be analyzed separately.  
 
Acquired bone marrow failure syndromes 
 
Myeloproliferative neoplasms/myelofibrosis  
Relapsed T-Cell Lymphoma that is chemotherapy sensitive in CR/PR that has 
failed or ineligible for an autologous transplant. 
Other Leukemia Subtypes:  A major effort in the field of hematology is to identify 
patients who are of high risk for treatment failure so that patients can be 
appropriately stratified to either more (or less) intensive therapy.  This effort is 
continually ongoing and retrospective studies identify new disease features or 
characteristics that are associated with treatment outcomes.  Therefore, if new 
features are identified after the writing of this protocol, patients can be enrolled 
with the approval of two members of the study committee.  
3.3 
Organ Function and Performance Status Criteria  
Adequate organ function is defined as:  
Cardiac: Absence of decompensated congestive heart failure, or uncontrolled 
arrhythmia and left ventricular ejection fraction ≥40%.  For children that are not 
able to cooperate with MUGA and echocardiography, such should be clearly 
stated in the physician’s note 
Pulmonary: DLCO, FEV1, FVC ≥ 40% predicted, and absence of O2 
requirements. For children that are not able to cooperate with PFTs, a pulse 
oximetry with exercise should be attempted.  If nether test can be obtained it 
should be clearly stated in the provider’s note.  
Liver: Transaminases ≤ 5 x upper limit of normal and total bilirubin ≤ 2.5 mg/dL 
except for patients with Gilbert’s syndrome or hemolysis 
Renal: serum creatinine ≤2.0 mg/dl (adults) or glomerular filtration rate (GFR) ≥ 
40 mL/min/1.73m2 (peds). Patients with a creatinine > 1.2 mg/dl or a history of 
renal dysfunction must have glomerular filtration rate (GFR) ≥ 40 
mL/min/1.73m2. 


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Adequate performance status is defined as Karnofsky score ≥ 70% (≥ 16 years of 
age) or Lansky score ≥ 50 (pediatrics < 16 years of age) (Appendix I) 
3.4 
Other Inclusion Criteria  
Sexually active females of childbearing potential and males with partners of 
child-bearing potential must agree to use adequate birth control during study 
treatment.   
Voluntary written consent (adult or parent/guardian with presentation of the minor 
information sheet, if appropriate) 
3.5 
Exclusion Criteria 
• 
Available and clinically suitable 5-6/6 HLA-A, B, DRB1 matched sibling 
donor 
• 
Pregnant or breast feeding. The agents used in this study include Pregnancy 
Category D: known to cause harm to a fetus.  Females of childbearing 
potential must have a negative pregnancy test prior to starting therapy  
• 
Evidence of HIV infection or known HIV positive serology 
• 
Untreated active infection 
• Less than 3 months since prior myeloablative transplant (if applicable); less 
than 6 months since prior autologous transplant (if applicable). 
• Evidence of progressive disease by imaging modalities or biopsy - persistent 
PET activity, though possibly related to lymphoma, is not an exclusion 
criterion in the absence of CT changes indicating progression 
• 
CML in refractory blast crisis 
• 
Large cell lymphoma, mantle cell lymphoma and Hodgkin disease that is 
progressive on salvage therapy.   
• 
active central nervous system malignancy 
 
4.0 
Registration in OnCore 
Patients will be registered in OnCore after providing written consent.   
 
5.0 
Treatment Plan 
The information provided in this section is to serve as a guideline for treatment and 
maybe altered as clinically appropriate on a per patient basis.   
 


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In order to provide optimal patient care and to account for individual medical conditions, 
investigator discretion may be used in the prescribing of all supportive care therapy (i.e. 
acetaminophen, diphenhydramine, G-CSF, antimicrobials, etc.).    
 
Corticosteroids may not be used as an anti-emetic agent and should not be administered 
until 24 hours after the completion of post-transplantation cyclophosphamide, unless used 
for adrenal support or during a medical emergency (e.g. treatment of anaphylaxis). 
 
treatment day 
treatment 
protocol section 
Day –6 
Fludarabine 30 mg/m2 IV over 30-60 minutes, then 
Cyclophosphamide 14.5 mg/kg IV over 1-2 hours 
section 5.1 
Day –5 
Fludarabine 30 mg/m2 IV over 30-60 minutes, then 
Cyclophosphamide 14.5 mg/kg IV over 1-2 hours 
Day –4 
Fludarabine 30 mg/m2 IV over 30-60 minutes 
Day -3 
Fludarabine 30 mg/m2 IV over 30-60 minutes 
Day -2 
Fludarabine 30 mg/m2 IV over 30-60 minutes 
Day –1 
TBI 200 cGy 
Day 0 
Non-T-cell depleted bone marrow infusion 
section 5.2 
Day 3 
Cyclophosphamide 50 mg/kg IV 
Mesna 40 mg/kg IV 
section 5.3 
Day 4 
Cyclophosphamide 50 mg/kg IV 
Mesna 40 mg/kg IV 
Day 5 
Begin tacrolimus (or cyclosporine), mycophenolate 
mofetil, and G-CSF 
sections 5.4 and 5.5 
Refer to appendix II for the risks associated with the treatment plan. 
5.1 
Transplant Preparative Therapy (day -6 through day -1) 
All drugs will be prepared and administered per institutional guidelines, with the 
drugs, doses and scheduled modified as clinically indicated.   
Fludarabine  
Fludarabine 30 mg/m2/day will be administered over 30-60 minutes intravenous 
infusion on Days –6 through –2 for a total dose of 150 mg/m2.   
Fludarabine will be dosed according to the recipient’s actual body weight.  For 
patients who have an estimated or measured GFR < 70 ml/min/1.73 m2, prior 


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CNS disease, prior brain radiation, or prior intrathecal chemotherapy, the 
fludarabine dose should be reduced by 20%.  The fludarabine dose should be the 
same on Days -6 to -2, even if the patient’s creatinine changes.   
Fludarabine must be administered before cyclophosphamide on Days -6 and -5. 
Pre-Transplantation Cyclophosphamide 
Hydration prior to cyclophosphamide may be given according to institutional 
standards.  A recommended approach is as follows: Patients are instructed to 
increase fluids overnight before cyclophosphamide administration.  Hydration 
with normal saline at 3 ml/kg/hr IV will be started 2 hours prior to 
cyclophosphamide, then the rate will be reduced to 2 ml/kg/hr for 1 hour pre-
cyclophosphamide and continued at 2 ml/kg/hour for 8 hours post-
cyclophosphamide.   
 
Uroprotection is administered according to institutional guidelines.  Mesna is 
recommended to accompany pre-transplantation cyclophosphamide, but is not 
required.  The mesna dose will be based on the cyclophosphamide dose being 
given.  A suggested approach is as follows: divided doses IV 30 min pre- and at 3, 
6, and 8 hours post-cyclophosphamide.  The total daily dose of mesna should be ≥ 
80% of the total daily dose of cyclophosphamide.   
 
Cyclophosphamide 14.5 mg/kg/day will be administered as a 1-2 hour 
intravenous infusion on Days –6 and –5.  Cyclophosphamide will be dosed 
according to the recipient’s ideal body weight (IBW), unless the patient weighs 
more than 125% of IBW, in which case the drug will be dosed according to the 
adjusted IBW.   
 
Total Body Irradiation (TBI) 
200 cGy TBI will be administered in a single fraction on Day –1 per institutional 
standards.   
5.2 
Transplant (day 0) 
On Day 0, patients will receive unprocessed marrow unless there is a major ABO 
incompatibility, in which case red blood cells will be depleted from the donor 
marrow using institutional practices.  Institutional practices will determine if there 
will be processing for minor ABO incompatibilities.   
Donor bone marrow will be harvested with a target yield of 4 x 108 nucleated 
cells/kg recipient IBW, and a recommended minimum yield of 2.5 x 108 nucleated 
cells/kg of recipient IBW.  It is recommended not to take more than 10 mL per 
aspirate.   


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In addition to calculating the total nucleated cell dose /kg, a sample of the product 
to be infused will be sent for flow cytometry to determine the content of 
CD34+cells.   
The use of cryopreserved marrow is not recommended.   
5.3 
Post-Transplant Cyclophosphamide (days 3 and 4) 
Hydration and uroprotection may be given according to institutional standards.  
See Section 5.1 for a recommended strategy. 
Cyclophosphamide 50mg/kg will be given as an IV infusion over 1-2 hours 
(depending on volume) on Days 3 post-transplant (between 60 and 72 hours after 
marrow infusion) and on Day 4 post-transplant (approximately 24 hours after Day 
3 cyclophosphamide).  Cyclophosphamide will be dosed according to the 
recipient’s ideal body weight (IBW), unless the patient weighs more than 125% of 
IBW, in which case the drug will be dosed according to the adjusted IBW.  
5.4 
Immunosuppressive Therapy (begin day 5) 
Tacrolimus will be given at a dose of 1 mg IV daily or 1 mg PO bid, and then 
will be changed to a PO dosing schedule once a therapeutic level is achieved or as 
per institutional standards.  Tacrolimus prophylaxis will begin on Day 5 post-
transplant.  Serum levels of tacrolimus will be measured around Day 7 and then 
should be checked weekly thereafter and the dose adjusted accordingly to 
maintain a trough level of 5-15 ng/mL.  Tacrolimus will be discontinued after the 
last dose around Day 180, or may be continued if active GVHD is present.   
Cyclosporine (trough level of 200-400 ng/ml) may be substituted for tacrolimus if 
the patient is intolerant of tacrolimus or per institutional practice.   
Mycophenolate mofetil (MMF) 
MMF will be given at a dose of 15 mg/kg PO TID (based upon actual body 
weight) with the maximum total daily dose not to exceed 3 grams (1 g PO TID).  
MMF prophylaxis will begin on Day 5 post-transplant and will be discontinued 
after the last dose on Day 35, or may be continued if active GVHD is present.  
5.5 
Growth Factor Support (begin day 5) 
G-CSF will be given beginning on Day 5 at a dose of 5 mcg/kg/day (rounding to 
the nearest vial dose is allowed), until absolute neutrophil count (ANC) is ≥ 
1,500/mm3 for three consecutive measurements on two different days.  G-CSF 
may be restarted to maintain ANC > 1,000/mm3.  G-CSF may be given by IV or 
subcutaneously.  


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5.6 
Supportive Care 
Patients will receive standard supportive disease and transplant related care, 
including antibacterial/antifungal/antiviral prophylaxis according to institutional 
guidelines or as modified based on clinical parameters. 
 
Patients will be eligible for any supportive care studies regarding infectious 
disease prophylaxis and management, immunoglobulin support, etc. as 
appropriate. 
5.7 
Follow-Up 
Follow-up will be according to the current University Of Minnesota BMT follow-
up guidelines as outlined in section 6. 
 
6.0 
Clinical Evaluations 
All clinical evaluations are standard of care and will be done according to current institutional 
guidelines or as clinically indicated.  The table below contains suggested guidelines and may be 
tailored as appropriate for individual patient’s clinical case. 
ACTIVITY 
PRE-BMT 
WORK-UP 
DAY 1 TO 
ENGRAFTMENT* 
FOLLOW-UP 
DAYS 31-100 
FOLLOW-UP  
(6 months, 1 and 2 years) 
Consent 
X 
 
 
 
Medical History 
X 
daily 
weekly 
X 
Physical Exam 
X 
daily 
weekly 
X 
Karnofsky/Lansky 
X 
 
day 100 
X 
GVHD Assessment 
 
weekly 
weekly, day 100 
X (day 180, 360) 
CBC/diff/plt 
X 
daily 
weekly 
X 
PT/PTT 
X 
weekly 
 
 
basic metabolic panel 
(BMP) 
 
daily 
 
 
comprehensive metabolic 
panel 
X 
weekly (0mit BMP on 
these days) 
weekly 
X 
Viral Screen 
X 
 
 
 
testing for anti-HLA 
antibodies 
X# 
 
 
 
Urinalysis 
X 
 
 
 
GFR for peds or adults 
with creat > 1.2 or hx or 
renal dysfunction 
X 
 
 
 
Pregnancy test for 
FOCBP 
X 
 
 
 
BM Biopsy chimerism  
X (on BM or 
blood) 
BM (day 21) 
BM (day 100) 
X 
Blood chimerism  
PB (day 21) 
PB (day 60) 
 
PFT 
X 
 
 
 


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MUGA or Echo 
X 
 
 
 
Chest CT 
X** 
 
 
 
Disease Evaluation 
X 
X (day 28) 
X (day 100) 
X  
# obtain as soon as possible once the patient is determined to be a candidate for Haplo-BM transplantation in order 
to guide donor selection 
* engraftment defined as absolute neutrophil count (ANC) ≥ 5 X 108/L for 3 consecutive measurements  
**Patients with a history of MDS or a history of 2 or more consecutive inductions/re-inductions to treat acute 
leukemia or CML blast crisis or prolonged neutropenia of at least 2 months immediately preceding transplant should 
have a chest CT without contrast to exclude occult fungal infection prior to transplant. 
 
 


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7.0 
Event Reporting 
Toxicity and adverse events will be classified according to NCI's Common Terminology 
Criteria for Adverse Events V 4.0 (CTCAE).  A copy of the CTCAE can be downloaded 
from the CTEP home page http://evs.nci.nih.gov/ftp1/CTCAE/About.html  
Transplant related outcomes and events will be recorded in the Blood and Marrow 
Transplantation (BMT) database.   
Events requiring prompt reporting to the University of Minnesota Institutional Review 
Board (IRB) and protocol deviations will be documented in OnCore.  
 
8.0 
Data Collection and Statistical Plan  
Specific transplant related endpoints include: 
• 2 year survival 
• Incidence of hematopoietic engraftment  
• Incidence of chimerism at day 100, 6 months and 1 year 
• Incidence of acute GVHD at 100 days 
• Incidence of chronic GVHD at 1 year 
• Incidence of transplant related mortality (TRM) at 6 months 
 
All endpoint data will be recorded in the University Of Minnesota Blood and Bone 
Marrow Database as part of the historical database maintained by the department.   
8.1 
Trial Size Justification 
The primary objective is to record outcomes and patient characteristics in the 
BMT database for patients who are treated in a standard manner. Based on prior 
enrollment it is expected this study will accrue 4 to 5 patients per year.  Since this 
treatment plan among these patients has been studied over the last several years, 
this is now a standard of care protocol.  No trial size justification is needed. Safety 
was closely monitored and assessed in the prior CTN trial as described in section 
Agency 
Criteria for reporting 
Timeframe 
Form to 
Use 
Submission 
address/ fax 
numbers 
U of MN 
IRB 
Events requiring prompt reporting including, but not limited to 
unanticipated death of a locally enrolled subject(s); new or 
increased risk; any adverse event  that require a change to the 
protocol or consent form or any protocol deviation that resulting 
in harm  For a complete list refer to 
http://www.research.umn.edu/irb/guidance/ae.html#.VC7xraI0-
sh  
Within 5 
business 
days of 
event 
discovery 
 
Report 
Form 
irb@umn.edu 
 


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2.0 using the same preparative regimen and GVHD prophylaxis. The treatment 
was shown to be safe and efficacious. 
8.2 
Enrollment Plan 
4-5 patients per year 
8.3 
Analysis of Primary and Secondary Endpoints  
Cumulative incidence will be used to estimate TRM, neutrophil engraftment, 
GVHD and graft failure treating non-events as competing risks. Kaplan-Meier 
curves will be used to estimate disease-free survival and overall survival. 
Chimerism will be plotted with box-plots and described over time. 
8.4 
Safety Monitoring  
This regimen has been studied for patients with these diagnoses for the past 
several years and it has been shown to be safe. Continuous stopping rules are no 
longer needed.  Safety parameters will be monitored on a yearly basis. 
 
9.0 
References 
1. 
Grewal SS, Barker JN, Davies SM, Wagner JE. Unrelated donor hematopoietic cell 
transplantation: marrow or umbilical cord blood? Blood. 2003;101:4233-4244. 
2. 
Confer D, Robinett P. The US National Marrow Donor Program role in unrelated donor 
hematopoietic cell transplantation. Bone Marrow Transplant. 2008;42 Suppl 1:S3-S5. 
3. 
Ballen KK, Spitzer TR, Yeap BY, et al. Double unrelated reduced-intensity umbilical cord blood 
transplantation in adults. Biol Blood Marrow Transplant. 2007;13:82-89. 
4. 
Barker JN, Weisdorf DJ, DeFor TE, Blazar BR, Miller JS, Wagner JE. Rapid and complete donor 
chimerism in adult recipients of unrelated donor umbilical cord blood transplantation after reduced-
intensity conditioning. Blood. 2003;102:1915-1919. 
5. 
Brunstein CG, Barker JN, Weisdorf DJ, et al. Umbilical cord blood transplantation after 
nonmyeloablative conditioning: impact on transplantation outcomes in 110 adults with hematologic 
disease. Blood. 2007;110:3064-3070. 
6. 
Gladstone DE, Zachary AA, Fuchs EJ, et al. Partially mismatched transplantation and human 
leukocyte antigen donor-specific antibodies. Biol Blood Marrow Transplant;19:647-652. 
7. 
Misawa M, Kai S, Okada M, et al. Reduced-intensity conditioning followed by unrelated 
umbilical cord blood transplantation for advanced hematologic malignancies: rapid engraftment in bone 
marrow. Int J Hematol. 2006;83:74-79. 


MT2013-33C – RIC and Haplo-BM for Patients with Hematologic Diseases 
 
 
 
 
September 29, 2016 
Page 23 of 30 
CPRC# 2013OC116 
8. 
Brunstein CG, Fuchs EJ, Carter SL, et al. Alternative donor transplantation after reduced intensity 
conditioning: results of parallel phase 2 trials using partially HLA-mismatched related bone marrow or 
unrelated double umbilical cord blood grafts. Blood;118:282-288. 
9. 
Chang YJ, Xu LP, Liu DH, et al. Platelet engraftment in patients with hematologic malignancies 
following unmanipulated haploidentical blood and marrow transplantation: effects of CD34+ cell dose 
and disease status. Biol Blood Marrow Transplant. 2009;15:632-638. 
10. 
Bashey A, Zhang X, Sizemore CA, et al. T-cell-replete HLA-haploidentical hematopoietic 
transplantation for hematologic malignancies using post-transplantation cyclophosphamide results in 
outcomes equivalent to those of contemporaneous HLA-matched related and unrelated donor 
transplantation. J Clin Oncol;31:1310-1316. 
11. 
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;16:482-489. 
12. 
Chang YJ, Xu LP, Liu DH, et al. The impact of CD34+ cell dose on platelet engraftment in 
pediatric patients following unmanipulated haploidentical blood and marrow transplantation. Pediatr 
Blood Cancer. 2009;53:1100-1106. 
13. 
Powles RL, Morgenstern GR, Kay HE, et al. Mismatched family donors for bone-marrow 
transplantation as treatment for acute leukaemia. Lancet. 1983;1:612-615. 
14. 
Beatty PG, Clift RA, Mickelson EM, et al. Marrow transplantation from related donors other than 
HLA-identical siblings. N Engl J Med. 1985;313:765-771. 
15. 
Szydlo R, Goldman JM, Klein JP, et al. Results of allogeneic bone marrow transplants for 
leukemia using donors other than HLA-identical siblings. J Clin Oncol. 1997;15:1767-1777. 
16. 
Ciceri F, Labopin M, Aversa F, et al. A survey of fully haploidentical hematopoietic stem cell 
transplantation in adults with high-risk acute leukemia: a risk factor analysis of outcomes for patients in 
remission at transplantation. Blood. 2008;112:3574-3581. 
17. 
Perruccio K, Tosti A, Burchielli E, et al. Transferring functional immune responses to pathogens 
after haploidentical hematopoietic transplantation. Blood. 2005;106:4397-4406. 
18. 
Feuchtinger T, Opherk K, Bethge WA, et al. Adoptive transfer of pp65-specific T cells for the 
treatment of chemorefractory cytomegalovirus disease or reactivation after haploidentical and matched 
unrelated stem cell transplantation. Blood;116:4360-4367. 
19. 
Comoli P, Basso S, Zecca M, et al. Preemptive therapy of EBV-related lymphoproliferative 
disease after pediatric haploidentical stem cell transplantation. Am J Transplant. 2007;7:1648-1655. 
20. 
Comoli P, Schilham MW, Basso S, et al. T-cell lines specific for peptides of adenovirus hexon 
protein and devoid of alloreactivity against recipient cells can be obtained from HLA-haploidentical 
donors. J Immunother. 2008;31:529-536. 


MT2013-33C – RIC and Haplo-BM for Patients with Hematologic Diseases 
 
 
 
 
September 29, 2016 
Page 24 of 30 
CPRC# 2013OC116 
21. 
Leen AM, Christin A, Myers GD, et al. Cytotoxic T lymphocyte therapy with donor T cells 
prevents and treats adenovirus and Epstein-Barr virus infections after haploidentical and matched 
unrelated stem cell transplantation. Blood. 2009;114:4283-4292. 
22. 
Ciceri F, Bonini C, Stanghellini MT, et al. Infusion of suicide-gene-engineered donor 
lymphocytes after family haploidentical haemopoietic stem-cell transplantation for leukaemia (the TK007 
trial): a non-randomised phase I-II study. Lancet Oncol. 2009;10:489-500. 
23. 
Vago L, Oliveira G, Bondanza A, et al. T-cell suicide gene therapy prompts thymic renewal in 
adults after hematopoietic stem cell transplantation. Blood;120:1820-1830. 
24. 
Di Stasi A, Tey SK, Dotti G, et al. Inducible apoptosis as a safety switch for adoptive cell 
therapy. N Engl J Med;365:1673-1683. 
25. 
Nguyen VH, Shashidhar S, Chang DS, et al. The impact of regulatory T cells on T-cell immunity 
following hematopoietic cell transplantation. Blood. 2008;111:945-953. 
26. 
Di Ianni M, Falzetti F, Carotti A, et al. Tregs prevent GVHD and promote immune reconstitution 
in HLA-haploidentical transplantation. Blood;117:3921-3928. 
27. 
Mielke S, Nunes R, Rezvani K, et al. A clinical-scale selective allodepletion approach for the 
treatment of HLA-mismatched and matched donor-recipient pairs using expanded T lymphocytes as 
antigen-presenting cells and a TH9402-based photodepletion technique. Blood. 2008;111:4392-4402. 
28. 
Bastien JP, Krosl G, Therien C, et al. Photodepletion differentially affects CD4+ Tregs versus 
CD4+ effector T cells from patients with chronic graft-versus-host disease. Blood;116:4859-4869. 
29. 
Lafferty KJ, Cunningham AJ. A new analysis of allogeneic interactions. Aust J Exp Biol Med 
Sci. 1975;53:27-42. 
30. 
Guinan EC, Boussiotis VA, Neuberg D, et al. Transplantation of anergic histoincompatible bone 
marrow allografts. N Engl J Med. 1999;340:1704-1714. 
31. 
Federmann B, Bornhauser M, Meisner C, et al. Haploidentical allogeneic hematopoietic cell 
transplantation in adults using CD3/CD19 depletion and reduced intensity conditioning: a phase II study. 
Haematologica;97:1523-1531. 
32. 
Godder KT, Henslee-Downey PJ, Mehta J, et al. Long term disease-free survival in acute 
leukemia patients recovering with increased gammadelta T cells after partially mismatched related donor 
bone marrow transplantation. Bone Marrow Transplant. 2007;39:751-757. 
33. 
Federmann B, Hagele M, Pfeiffer M, et al. Immune reconstitution after haploidentical 
hematopoietic cell transplantation: impact of reduced intensity conditioning and CD3/CD19 depleted 
grafts. Leukemia;25:121-129. 
34. 
Munchel A, Kesserwan C, Symons HJ, et al. Nonmyeloablative, HLA-haploidentical bone 
marrow transplantation with high dose, post-transplantation cyclophosphamide. Pediatr Rep;3 Suppl 
2:e15. 


MT2013-33C – RIC and Haplo-BM for Patients with Hematologic Diseases 
 
 
 
 
September 29, 2016 
Page 25 of 30 
CPRC# 2013OC116 
35. 
Ciurea SO, Mulanovich V, Saliba RM, et al. Improved early outcomes using a T cell replete graft 
compared with T cell depleted haploidentical hematopoietic stem cell transplantation. Biol Blood Marrow 
Transplant;18:1835-1844. 
36. 
Raiola AM, Dominietto A, Ghiso A, et al. Unmanipulated haploidentical bone marrow 
transplantation and posttransplantation cyclophosphamide for hematologic malignancies after 
myeloablative conditioning. Biol Blood Marrow Transplant;19:117-122. 
37. 
Solomon SR, Sizemore CA, Sanacore M, et al. Haploidentical transplantation using T cell replete 
peripheral blood stem cells and myeloablative conditioning in patients with high-risk hematologic 
malignancies who lack conventional donors is well tolerated and produces excellent relapse-free survival: 
results of a prospective phase II trial. Biol Blood Marrow Transplant;18:1859-1866. 
38. 
Luznik L, Fuchs EJ. High-dose, post-transplantation cyclophosphamide to promote graft-host 
tolerance after allogeneic hematopoietic stem cell transplantation. Immunol Res;47:65-77. 
39. 
Wang Y, Liu DH, Xu LP, et al. Superior graft-versus-leukemia effect associated with 
transplantation of haploidentical compared with HLA-identical sibling donor grafts for high-risk acute 
leukemia: an historic comparison. Biol Blood Marrow Transplant;17:821-830. 
 
 


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Appendix I – Appendix I – Performance Status Scales 
 
 
For patients 16 years of age and older: 
Karnofsky Performance Scale 
Percent 
Description 
100 
Normal, no complaints, no evidence of disease. 
90 
Able to carry on normal activity; minor signs or symptoms of disease. 
80 
Normal activity with effort; some signs or symptoms of disease. 
70 
Cares for self, unable to carry on normal activity or to do active work. 
60 
Requires occasional assistance, but is able to care for most of his/her needs. 
50 
Requires considerable assistance and frequent medical care. 
40 
Disabled, requires special care and assistance. 
30 
Severely disabled, hospitalization indicated.  Death not imminent. 
20 
Very sick, hospitalization indicated. Death not imminent. 
10 
Moribund, fatal processes progressing rapidly. 
0 
Dead. 
 
 
For patients < 16 years of age: 
Lansky 
Score 
Play Score 
100 
Fully active, normal 
90 
Minor restrictions in physically strenuous activity 
80 
Active, but tires more quickly 
70 
Both greater restriction of and less time spent in play activity 
60 
Up and around, but minimal active play; keeps busy with quieter activities 
50 
Gets dressed but lies around much of the day, no active play but able to participate 
in all quiet play and activities 
40 
Mostly in bed; participates in quiet activities 
30 
In bed; needs assistance even for quiet play 
20 
Often sleeping; play entirely limited to very passive activities 
10 
No play; does not get out of bed 
0 
Unresponsive 
 
 


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Appendix II - Expected Risks of the Preparative Regimen, GVHD Prophylaxis and 
Transplant 
Preparative Regimen: 
Cyclophosphamide 
Common 
Less Common 
Rare, but may be serious 
• low white blood cell count 
with increased risk of 
infection  
• hair loss or thinning, 
including face and body hair 
(usually grows back after 
treatment)  
• nausea  
• vomiting  
• loss of appetite  
• sores in mouth or on lips  
• bleeding from bladder, with 
blood in urine  
• diarrhea  
• long-term or short-term 
infertility (inability to have 
children) in women and men 
• 
low platelet count (mild) 
with increased risk of 
bleeding  
• 
darkening of nail beds  
• 
acne  
• 
tiredness  
• 
infection 
• 
fetal changes if you become 
pregnant while taking 
cyclophosphamide  
 
• heart problems with high 
doses, with chest pain, 
shortness of breath, or swollen 
feet 
• severe allergic reactions 
• skin rash  
• scarring of bladder 
• kidney damage (renal tubular 
necrosis) which can lead to 
kidney failure 
• heart damage, with trouble 
getting your breath, swelling 
of feet, rapid weight gain 
• scarring of lung tissue, with 
cough and shortness of breath 
• second cancer, which can 
happen years after taking this 
drug 
• death from infection, 
bleeding, heart failure, 
allergic reaction, or other 
causes 
 
 
Fludarabine 
Common 
Less Common 
Rare, but may be serious 
• low white blood cell count 
with increased risk of 
infection  
• low platelet count with 
increased risk of bleeding  
• low red blood cell count 
(anemia) with tiredness and 
weakness 
• tiredness (fatigue)  
• nausea  
• vomiting  
• fever and chills 
• infection 
• 
pneumonia  
• 
diarrhea  
• 
loss of appetite 
• 
weakness 
• 
pain 
 
• numbness and tingling in 
hands and/or feet related to 
irritation of nerves  
• changes in vision  
• agitation  
• confusion 
• clumsiness 
• seizures 
• coma  
• cough  
• trouble breathing  
• intestinal bleeding 
• weakness  
• death due to effects on the 
brain, infection, bleeding, 
severe anemia, skin blistering, 


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Fludarabine 
Common 
Less Common 
Rare, but may be serious 
or other causes 
• death from infection, 
bleeding, heart failure, 
allergic reaction, or other 
causes 
 
Total Body Irradiation 
Common 
Less Common 
Rare, but may be serious 
• nausea and vomiting 
• diarrhea 
• cataracts 
• sterility 
• endocrinopathies 
• growth failure 
• intestinal cramps 
• mucositis 
• parotitis 
• interstitial pneumonitis 
• generalized mild erythema 
• veno-occlusive disease 
 
• dysphagia 
• vertebral deformities 
• nephropathy 
• risk of 2nd malignancy years 
later (when given along with 
chemotherapy) 
 
Risks of the Transplant Procedure (in general) 
The following problems may occur as a result of cord blood or marrow transplant.  
o Slow recovery of blood counts   
o Graft failure 
o Graft-Versus-Host Disease (GVHD)  
o Other complications. Other complications may include: 
a. Damage to the vital organs  
b. Serious infections  
c. Relapse of disease or a new blood cancer  
d. Risk to the unborn 
 
Risks of Using a Haploidentical Donor 
Based on previous experience at this instutition and others there is lower transplant related mortality 
(TRM), a greater chance of disease relapse but similar overall survival when compared with other 
transplants using a related or unrelated matched donor. 
 


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Supportive Care: 
Tacrolimus   
Common 
Less Common 
Rare, but may be serious 
 kidney problems 
 loss of magnesium, calcium, 
potassium 
 high blood pressure 
 tremors 
 increases in cholesterol and 
triglyceride 
 
 nausea 
 vomiting 
 liver problems 
 changes in how clearly 
one can think 
 insomnia 
 unwanted hair growth 
 confusion 
 
seizures 
 
changes in vision 
 
dizziness 
 
red blood cell destruction 
It is very important that grapefruit or drinks with grapefruit juice are consumed while taking 
Tacrolimus.  Grapefruit has an ingredient called bergamottin, which can affect some of the treatment 
drugs used in this study.  Common soft drinks that have bergamottin are Fresca, Squirt, and Sunny 
Delight.  
Mycophenolate mofetil (MMF) 
Common 
Less Common 
Rare, but may be serious 
• miscarriage 
• birth defects 
• diarrhea 
• damage to unborn baby 
• limited effectiveness of birth 
control 
• stomach pain 
• upset stomach 
• vomiting 
• headache 
• tremors 
• low white blood cell count 
with increased risk of 
infection 
• increased blood cholesterols 
• swelling of the hands, feet, 
ankles or lower legs 
• anemia 
• rash 
• difficulty falling asleep or 
staying asleep 
• dizziness 
• uncontrollable hand shakes 
• difficulty breathing 
• unusual bruising 
• fast heartbeat 
• excessive tiredness 
• weakness 
• blood in stool 
• bloody vomit 
• change in vision 
• secondary cancers, such as 
lymphoproliferative disease or 
lymphoma 
• Progressive Multifocal 
Leukoencephalopathy 
 
filgrastim (G-CSF) 
Common 
Less Common 
Rare, but may be serious 
• bone or muscle pain 
• increased levels of liver 
enzymes and uric acid in 
the blood 
• headache 
• tiredness 
• injection site reaction (redness, 
pain, or swelling) 
• nausea 
 
• allergic reaction 
• spleen enlargement or rupture 
–symptoms of an enlarged 
spleen include a feeling 
discomfort, fullness, or pain 
on the upper left side of the 
abdomen; this pain may 
spread to the left shoulder 


MT2013-33C – RIC and Haplo-BM for Patients with Hematologic Diseases 
 
 
 
 
September 29, 2016 
Page 30 of 30 
CPRC# 2013OC116 
filgrastim (G-CSF) 
Common 
Less Common 
Rare, but may be serious 
• serious lung problems 
(ARDS)  
• worsening of skin rashes