Clinical trial NCT02581007
Conditions: Chronic Myelogenous Leukemia Acute Myelogenous Leukemia Myelodysplastic Syndrome Acute Lymphocytic Leukemia Chronic Lymphocytic Leukemia Hodgkin's Lymphoma Non-Hodgkin's Lymphoma Myelofibrosis CMML Multiple Myeloma
Keywords: CML AML MDS ALL CLL/CPL HD NHL MPS CMML MM
Sponsor: Northside Hospital, Inc.
Start date: 2015-10-26; Completion date: 2020-12-28
Enrollment: 25 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This trial will evaluate the safety and efficacy of a reduced intensity allogeneic HSCT from partially HLA-mismatched first-degree relatives utilizing PBSC as the stem cell source. The primary objective of the study is to estimate the incidence of graft rejection and acute GVHD. A secondary objective will be to estimate the incidence of the relapse, NRM, OS, chronic GVHD and EFS.

Detailed description:
Patients will receive a haploidentical transpalnt using a fludarabine melphalan prepartive regimen. Patients will get cyclophosphamide on days 3 \& 4 post-transplant.

Arms: arm 1: Fludarabine, Melphalan \& Post-transplant cyclophosphamide
Interventions: intervention 1: Fludarabine intervention 2: Melphalan intervention 3: Cyclophosphamide intervention 4: peripheral blood stem cell transplant
Intervention descriptions: intervention 1: fludarabine (30mg/m2) given every day starting on Day -6 through Day -2; intervention 2: None intervention 3: cyclophosphamide (50mg/kg) given every day starting on Day 3 through Day 4. intervention 4: None

Protocol documents:
Prot_SAP_000.pdf: 
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NORTHSIDE HOSPITAL 
 
 
 
A 
PHASE 
II 
TRIAL 
OF 
REDUCED 
INTENSITY 
CONDITIONING 
AND 
TRANSPLANTATION OF PARTIALLY HLA-MISMATCHED PERIPHERAL BLOOD 
STEM CELLS FOR PATIENTS WITH HEMATOLOGIC MALIGNANCIES 
 
 
 
 
Principal Investigators:  
Melhem Solh MD 
 
  
 
 
Scott R. Solomon MD 
 
 
H. Kent Holland, MD 
                                                                
Lawrence E. Morris, MD 
 
 
 
 
 
 
Asad Bashey, MD, PhD  
 
 
 
 
Version:   10/28/16 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
 
SCHEMA………………………………………………………. 
3 
 
1.0 
OBJECTIVES…………………………………………………. 
4 
 
2.0 
BACKGROUND AND RATIONALE……………………….. 
4 
 
3.0 
DRUG INFORMATION……………………………………… 
6 
 
4.0 
PATIENT SELECTION……………………………………… 
8 
 
5.0 
TREATMENT PLAN………………………………………… 
11 
 
6.0 
ADVERSE EVENT REPORTING…………...……………… 
14 
 
7.0 
RISKS AND TOXICITIES…………………………………….. 15 
 
8.0 
STUDY PARAMETERS…………..…………………………… 16 
 
9.0 
FOLLOW UP/OFF STUDY CRITERIA……………………… 17 
 
10.0 
STATISTICAL CONSIDERATIONS………………………… 18 
 
11.0 
REFERENCES…………………………………………………. 20 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Treatment Schema  
 
 
 
Days –6   –2 Fludarabine 30 mg/M2 IV qd x 5 days (day -6 to -2) 
 
 
 

 
Day –1 
Melphalan 140 mg/M2 IV x 1 dose (day -1) 
 
 
 
 

Day 0 
Infuse unmanipulated PBSCs 
(Begin antibiotic prophylaxis) 
 
 
 

Days 3, 4 
Cyclophosphamide 50 mg/kg IV q d 
 
(hydration/Mesna) 
 
(First dose of Cyclophosphamide must be administered 48-72 hr after infusion of PBSCs) 
 
 
 
 
Day 5    
Begin Tacrolimus (target plasma level 5-15)  
                
MMF 15 mg/kg po tid with maximum daily dose 3 gm/d 
 
 
 
 
Day 35    
 
 
 
Discontinue  MMF 
 
 
 
  
Day 180 
Discontinue Tacrolimus 
 
 
 
 


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1. OBJECTIVES: 
 
Primary Objectives: 
 
1.1. To estimate the incidence of graft rejection following reduced intensity, human 
leukocyte antigen (HLA)-mismatched hematopoietic stem cell transplantation (HSCT) in 
patients with high risk hematologic malignancies.  
 
Secondary Objectives: 
 
1.2. To obtain estimates of overall survival (OS), relapse, graft versus host disease (GVHD),  
non-relapse mortality (NRM), and event-free survival (EFS) in patients receiving 
reduced intensity conditioning and transplantation of partially human leukocyte antigen 
(HLA)-mismatched peripheral blood stem cells (PBSC) from first-degree relatives. 
 
1.3. Characterize additional hematologic and non-hematologic toxicities of reduced intensity 
haploidentical HSCT. 
 
1.4. Identify the incidence of BK virus cystitis in patients receiving reduced intensity 
conditioning and transplantation of partially human leukocyte antigen (HLA)-
mismatched peripheral blood stem cells (PBSC) from first-degree relatives. 
 
 
 
2. BACKGROUND 
 
Allogeneic HSCT is considered a curative modality for many patients with high risk hematologic 
malignancies. Transplantation using a matched related sibling if available leads to improved 
outcomes when compared to other graft sources1. Unfortunately, only about a third of candidates 
for HSCT have HLA-matched siblings.  For patients who lack HLA-matched siblings, there are 
other alternative sources of stem cells for HSCT: 1) volunteer unrelated donors; 2) umbilical 
cord blood; and 3) partially HLA-mismatched, or haploidentical, related donors.  Haploidentical 
HSCT has been historically associated with significant risks of graft rejection and severe 
GVHD2, which are manifestations of excessive alloreactivity by host and donor T cells3, 
respectively.  Earlier study of T cell depletion in the setting of haploidentical HSCT were 
associated with prolonged immune compromise and increase risk of mortality from infections4. 
Recently, the use of cyclophosphamide (Cy) post infusion of stem cells has become a new 
standard to reduce the incidence of GVHD without significantly increasing the risk of infections 
seen with T cell depleted haploidentical transplantation5. 
 


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Post-transplant Cy (PTCY) was studied by the group from Johns Hopkins in a non-ablative 
conditioning regimen of non-T cell-depleted marrow from haploidentical first degree relatives6.  
This study showed that optimally dosed and timed PTCY, after a conditioning regimen of 
fludarabine and low dose total body irradiation had an acceptably low risk of graft rejection and 
GVHD, the two major complications of haploidentical HSCT.  All patients received 
mycophenolate mofetil (MMF) and tacrolimus, beginning 24 hours after PTCY administration 
for GVHD prophylaxis. The median times to neutrophil and platelet recovery for all patients 
were 15 and 24 days, respectively. Graft failure occurred in a total of 15/84 patients (18%). All 
but two patients with graft failure experienced recovery of autologous hematopoiesis with 
median times to neutrophil and platelet engraftment of 24 days (range 11-48 days) and 44 days 
(range 15-395 days), respectively. 
 
The cumulative incidences of grades II-IV and III-IV acute GVHD were 35% and 10%. 
The cumulative incidence of chronic and extensive chronic GVHD in the first year after 
transplantation for the entire population was 22% and 14%, respectively. The cumulative 
incidences of NRM at 180 days and 1 year after transplantation were 13% and 19%, respectively. 
The cumulative incidences of relapse at 1 and 2 years after transplantation were 50% and 57%, 
respectively. At a median follow-up of survivors of 817 days (range, 112-1808 days), the 
actuarial overall survival at 1 and 2 years were 45% and 35%, respectively.  
 
  
From these results, it was concluded that a combination of PTCY, tacrolimus, and MMF 
were associated with an acceptably low incidence of graft rejection, severe acute GVHD, and 
extensive chronic GVHD. There was effective clinical immune reconstitution as demonstrated by 
the low incidence of severe opportunistic infections. Relapse represented the major cause of 
treatment failure in this poor risk patient population.  One explanation for the high rate of 
relapse, as in other nonmyeloablative HSCT trials, is that the transplantation conditioning was 
not intense enough to achieve sufficient tumor cytoreduction.    
 
 
Given that relapse remains the largest impediment to success after nonmyeloablative 
bone marrow transplantation utilizing PTCY, efforts to reduce relapse remain an important area 
of clinical investigation. We have recently published 2 studies on the use of myeloablative 
conditioning with PTCY. The first study with busulfan based conditioning established that 
myeloablative haploidentical transplantation can yield full donor chimerism at day 30, grade III-
IV acute GVHD rate of 10%, and a 1 year OS of 69% and DFS of 50%7. The second 
myeloablative study with total body irradiation (TBI) based conditioning showed full donor 
chimerism at day 30, and a 2 year DFS of 73%8. The limitation of myeloablative regimens is that 
they cannot be safely administered for elderly patients or patients with poor organ function, 
increased comorbidities and poor performance status. The need of a more intense regimen than 
the non-ablative (Fludarabine/low dose TBI) but less intensive than the full myeloablative 


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conditioning regimens in an effort to decrease relapse among HSCT patients remains an area of 
clinical investigation. 
 
 
This trial will evaluate the safety and efficacy of a reduced intensity allogeneic HSCT 
from partially HLA-mismatched first-degree relatives utilizing PBSC as the stem cell source.  
The primary objective of the study is to estimate the incidence of graft rejection and acute 
GVHD. A secondary objective will be to estimate the incidence of the relapse, NRM, OS, 
chronic GVHD and EFS.  
 
 
3. Drug Information 
 
3.1 Cyclophosphamide (Cytoxan®) 
 
Cyclophosphamide is an alkylating agent which prevents cell division primarily by cross-linking 
DNA strands. Cyclophosphamide is cell cycle nonspecific. Cyclophosphamide for injection is 
available in 2000 mg vials which are reconstituted with 100 ml sterile water for injection. The 
concentration of the reconstituted product is 20 mg/ml. The calculated dose will be diluted 
further in 250-500 ml of Dextrose 5% in water. Each dose will be infused over 1-2 hr (depending 
on the total volume). Clinical toxicities of cyclophosphamide include alopecia, nausea and 
vomiting, headache and dizziness, hemorrhagic cystitis, cardiotoxicity, immunosuppression, 
myelosuppression, pulmonary fibrosis, increased hepatic enzymes and syndrome of 
inappropriate anti-diuretic hormone (SIADH). 
 
3.2 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. Mesna is 
available in 200 mg, 400 mg and 1000 mg vials containing a 100 mg/ml solution. Each dose of 
mesna will be diluted further in 50 ml of normal saline to be infused over 15 min or as per 
institutional standards. Mesna dose will be based on the cyclophosphamide dose being given. 
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, adverse effects which may 
be attributable to mesna include nausea and vomiting, diarrhea, abdominal pain, altered taste, 
rash, urticaria, headache, joint or limb pain, hypotension and fatigue. Mesna will be dispensed by 
the Oncology Pharmacy and is produced by Mead Johnson Pharmaceuticals. 


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3.3 Melphalan 
 
 Melphalan is an alkylating agent that is commonly used in stem cell transplant due to its 
significant myelosuppressive effects. Melphalan will be infused as a single dose on day -1 prior 
to infusion of stem cells. Even with the use of hematopoietic growth factors, significant 
neutropenia is expected. Neutropenic infections and/or need for transfusions of red cells and/or 
platelets may result. Stomatitis, esophagitis and severe diarrhea are common with high dose 
melphalan: management with i.v. narcotics and potentially i.v. alimentation may be needed. 
Other less common toxicities reported include pulmonary fibrosis and interstitial pneumonitis, 
skin hypersensitivity, vasculitis, alopecia, hemolytic anemia and allergic reaction. 
 
3.4 Fludarabine (Fludara®) 
 
Fludarabine phosphate is purine antimetabolite that, after administration, undergoes rapid 
conversion in plasma to the nucleoside 2-fluoro ara-A (F-araA). F-araA subsequently enters cells 
where it is phosphorylated to F-araATP and the monophosphate F-araAMP.  Once activated, F-
araATP inhibits DNA polymerase and ribonucleotide reductase. The monophosphate F-araAMP, 
once incorporated into DNA, is an effective DNA chain terminator. Fludarabine monophosphate, 
50 mg/vial, is reconstituted with 2 ml of sterile water, resulting in a 25mg/ml solution. The 
desired dose is further diluted to concentrations of 0.04-1 mg/ml in normal saline or 5% dextrose 
(50-100ml) for injection and will be administered by IV infusion over 30 minutes or longer. 
Following IV administration, the drug is metabolized to 2-F-araA and widely distributed in 
tissues.  2-F-araA is excreted primarily in urine and has a terminal elimination half-life of 7 to 12 
hours. Clinical toxicities of fludarabine monophosphate include: myelosuppression, primarily 
lymphopenia and granulocytopenia, alopecia, rash, dermatitis, nausea, vomiting, anorexia, 
stomatitis, diarrhea, somnolence, fatigue, peripheral neuropathy, mental status changes, cortical 
blindness, hepatocellular toxicity with elevation in serum transaminases, and interstitial 
pneumonitis. These effects are reversible when the drug is discontinued. Fludarabine will be 
administered by IV infusion over 30 minutes in a dose of 40 mg/m2/day on days -5 to -2. 
Fludara® will be dispensed by the Oncology Pharmacy and is produced by Berlex 
Pharmaceuticals. 
 
3.5 Tacrolimus 
 
Tacrolimus, also known as FK-506, is a macrolide immunosuppressant. It inhibits lymphocytes 
by forming a complex with FKBP-12, calcium, and calmodulin, leading to the decrease in the 
phosphatase activity of calcineurin. This drug is used with corticosteroids for prophylaxis of 
organ rejection in patients receiving allogeneic liver transplants. Its use is also currently being 
investigated in kidney, bone marrow, cardiac, pancreas, pancreatic islet cell and small bowel 
transplantation. This drug is well-absorbed orally. It is metabolized in the liver by unknown 


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mechanisms, but demethylation and hydroxylation have been proposed based on in vitro studies. 
The metabolized products are excreted in the urine. Nephrotoxic drugs, antifungals, calcium 
channel blockers, cimetidine, danazol, erythromycin, methylprednisone and metoclopramide 
increase the bioavailabilty of FK-506. In contrast, phenobarbital, phenytoin, rifamycins and 
carbamazepine decrease FK-506 levels. Adverse reactions include tremor, headache, diarrhea, 
hypertension, nausea, and renal dysfunction. 
 
3.6 Mycophenolic Acid Mofetil (Cellcept®) 
 
Mycophenolate Mofetil is an ester prodrug of the active immunosuppressant mycophenolic acid 
(MPA). This active metabolite is a noncompetitive, reversible inhibitor of inosine 
monophosphate dehydrogenase (IMPDH). There are no pharmacokinetic interactions with 
ganciclovir, cotrimoxazole, oral contraceptives and cyclosporine. Side effect profiles include 
diarrhea, leukopenia, sepsis, allergic reactions, and vomiting. There is also an increase in certain 
types of infection mainly from the herpes virus family (CMV, HSV & VZV) and candida. 
3.7 Hematopoietic growth factor: G-CSF 
G-CSF may be associated with development of fevers, chills, skin rash, polyserositis, muscle 
aches, malaise and/or headache. It has also been reported to cause bone aches or pain in a 
minority of patients 
 
4. PATIENT SELECTION 
 
4.1 Criteria for recipient eligibility 
 
 
4.1.1 
No available matched related or unrelated donor, OR a matched related or 
unrelated donor will not be available in the time frame necessary to perform a 
potentially curative transplant. 
 
4.1.2 
Availability of a 3/6 – 5/6 matched (HLA-A, B, DR) related donor   
 
Donor must have negative HLA cross-match in the host vs. graft direction. 
 
 
4.1.3 
Age ≤75 years 
 
 
4.1.4 
Karnofsky status ≥70% 
 
 
4.1.5  
One of the following high-risk malignancies: 
 
 
 
4.1.5.1 
Chronic Myelogenous Leukemia 


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 Chronic myelogenous leukemia in chronic phase, resistant or intolerant to 
available tyrosine kinase inhibitors (OR) 
 Chronic myelogenous leukemia in accelerated phase (OR) 
 Chronic myelogenous leukemia with blast crisis that has entered into a 
second chronic phase following induction chemotherapy.   
 
 
 
4.1.5.2 
Acute Myelogenous Leukemia in first or greater remission 
 
 
 
4.1.5.3 
Myelodysplastic Syndrome at least one of the following:  
 Treatment-related 
 Monosomy 7, complex cytogenetics or other high risk karyotype 
 IPSS score of 1.0 or greater 
 Neutropenia or cytopenia requiring transfusion not responding to therapy   
 Peripheral or BM blast count of <10% 
 Chronic myelomonocytic leukemia (CMML)  
 
 
 
4.1.5.4 
Acute lymphocytic leukemia/lymphoblastic lymphoma 
 2nd or subsequent complete remission (OR) 
 First complete remission: 
Acute lymphocytic leukemia with poor-risk features: including but not 
limited to [t (9; 22) or bcr-abl fusion, t(4;11) or other MLL translocation]  
or hypodiploidy; WBC >20,000/µl at diagnosis, no CR by day 28 of initial 
induction therapy, extramedullary leukemia or age >30 at diagnosis 
 Marrow blasts <5%, but persistence of minimal residual disease by flow 
cytometry, cytogenetics or FISH 
 
 
 
4.1.5.5 
Chronic Lymphocytic Leukemia / Prolymphocytic Leukemia 
 Previously treated disease that has either relapsed or failed to respond 
adequately to conventional-dose therapy including purine analogs  
        
 
 
4.1.5.6 
Hodgkin’s or Non-Hodgkin’s Lymphoma (including low-grade, 
mantle cell, and intermediate-grade/diffuse) 
 Previously treated disease that has either relapsed or failed to respond 
adequately to conventional-dose therapy or autologous transplantation 
  
           
  4.1.5.7 Myeloproliferative diseases (myelofibrosis, CMML) 
 
  4.1.5.8 Multiple Myeloma with relapse after a prior autologous transplant or 
eligible for allogeneic HSCT based on other risk factors 
 


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4.2 Exclusion Criteria for recipient  
 
4.2.1 Patients will not be excluded on the basis of sex, racial or ethnic background.  
 
4.2.2 Poor cardiac function: left ventricular ejection fraction <40% 
 
4.2.3 Poor pulmonary function: FEV1 and FVC <50% predicted  
 
4.2.4 Poor liver function: bilirubin >2 mg/dl (not due to hemolysis, Gilbert’s or primary 
malignancy) 
 
4.2.5 Poor renal function: Creatinine >2.0mg/dl or creatinine clearance (calculated 
creatinine clearance is permitted) < 40 mL/min based on Traditional Cockcroft-Gault 
formula: 140 - age (yrs)  x Smaller of Actual Weight vs. Ideal Body Weight (kg)  / 72 x 
Serum creatinine (mg/dl) 
 
4.2.6  HIV-positive 
 
 
4.2.8 Women of childbearing potential who currently are pregnant or who are not 
practicing adequate contraception 
 
4.2.9 Patients who have any debilitating medical or psychiatric illness which would 
preclude their giving informed consent or their receiving optimal treatment and follow-
up.  
 
4.3 Criteria for donor selection 
 
4.3.1 Donors will be relatives (parent, child, sibling) of the recipient and be matched at 
3/6 – 5/6 loci (HLA-A, B, DR) with the recipient. 
 
4.3.2 Donors will be selected to avoid a positive HLA crossmatch in the host-versus-graft 
(HVG) direction or high titer donor specific antibodies as determined by the pre-
transplant panel reactive antibody (PRA) testing.  
 


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5. Treatment Plan  
 
Days –6 –2 
Fludarabine 30 mg/M2 IV qd x 5 days (day -6 to -2) 
 
 
 
 
 

 
Days –1 
Melphalan 140 mg/M2 IV qd x 1 dose (day -1) 
 
 
 

 
Day 0 
Infuse unmanipulated PBSCs 
(Begin antibiotic prophylaxis) 
 
 
 

Days 3, 4 
Cyclophosphamide 50 mg/kg IV q d 
 
(hydration/Mesna) 
 
(First dose of Cyclophosphamide must be administered 48-72 hr after infusion of PBSCs) 
 
 
 
 
Day 5    
Begin Tacrolimus (target plasma level 5-15)  
                
MMF 15 mg/kg po tid with maximum daily dose 3 gm/d 
 
 
 
 
Day 35 
 
 
 
Discontinue MMF 
 
 
 
  
Day 180 
Discontinue Tacrolimus 
 
 


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5.1 
 Peripheral Blood Stem Cell Collection  
Peripheral blood stem cells will be collected by institutional guidelines following 
standard G-CSF-based mobilization and infused on day 0.  Cryopreservation of the 
stem cell product prior to infusion is permissible. 
 
5.2    
Stem Cell Processing 
Minor ABO incompatible marrow or stem cell grafts will be plasma reduced and 
washed.  Major ABO incompatible stem cell products will not require 
manipulation.   
 
5.3 
Preparative Regimen  
5.3.1 Fludarabine 30 mg/m2 infused over 30 minutes once daily on five consecutive 
days (total dose, 150 mg/m2):  days -6, -5, -4, -3 and -2. 
 
5.3.2 Melphalan 140 mg/m2 infused on day -1.   
 
5.3.3 Veno-occlusive disease (VOD) prophylaxis will include: 
 Ursodiol 300mg PO bid starting 24 hours prior to starting the preparative 
regimen until day +30 post-transplant 
 
5.3.4 Stem Cell Infusion (Day of Transplant) day 0. 
 
 
5.4 Post-transplant Cyclophosphamide 
 
5.4.1 Cyclophosphamide 50mg/kg will be given on D+3 post-transplant (within 48-72 
hr of PBSC infusion) and on D+4 post-transplant. Cyclophosphamide will be 
given as an IV infusion over 1- 2 hr (depending on volume). Hydration and 
Mesna will be given according the institution’s standard of care.   
 
5.5 Chemotherapy Dosing:  All chemotherapy should be dosed based on the lesser of actual 
or  ideal body weight for patients who weigh less than or equal to 130% of their 
IBW.  For patients who weigh more than 130% of their IBW, dosing should be 
based on the adjusted ideal body weight (AIBW).   
 
1.  Ideal Body Weight (IBW) Formulas: 
 
 
Males IBW = 50 kg + 2.3 kg/inch over 5 feet 
 
 
Females IBW = 45.5 + 2.3 kg/inch over 5 feet 
 
 
For patients less than 5 feet, subtract 2.3 kg/inch 
2.  Adjusted Ideal Body Weight (AIBW) Formula: 


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AIBW = IBW + [(0.25) x (ABW – IBW)] 
Doses of Fludarabine and Cyclophosphamide will be adjusted as needed according to 
creatinine clearance: 
 
 
 
Creatinine Clearance = (140-Age) x IBW ( x 0.85 for females) 
 
 
 
 
 
 
 
72 x Serum Creatinine 
 
 
 
CHEMOTHERAPEUTIC 
AGENT 
 
Calculated 
Creatinine 
Clearance 
51-60 
 
Calculated 
Creatinine 
Clearance  
30-50 
 
Fludarabine 
 
80% of total dose 
 
80% of total dose 
 
Cyclophosphamide 
 
100% of total dose 
 
75% of total dose 
 
 
5.6 Antibiotic prophylaxis and other supportive care measures will be implemented 
according to institutional guidelines.  
 
5.7 Post-transplant immunosuppression: 
 
5.7.1 No immunosuppressive agents are given until 24 hours after the completion of 
PTCY.  This includes steroids as anti-emetics 
 
5.7.2 Tacrolimus 0.03mg/kg/day infuse over 24 hours starting on day+5 (adjusted to 
maintain a trough level of 5-15 ng/ml) and switched to oral (twice-daily divided 
dose) on day 21 or when able to tolerate p.o.  Tacrolimus will be discontinued on 
day +180, in the absence of clinically significant GVHD.  
 
5.7.3 Mycophenolate Mofetil (MMF) 15 mg/kg po tid with maximum daily dose 3 
gm/d, starting on day+5.  MMF will be discontinued on day +35 in the absence of 
clinically significant GVHD. 
 
5.8 Chimerism testing 
 


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5.8.1 Quantitation of chimerism: PCR-based analysis of DNA to detect short tandem 
repeats (STRs) will be used for quantitative chimerism of post-transplant 
peripheral blood T-lymphocytes and myeloid cells.  The level of chimerism in 
each of these populations is represented by the percentage of the cells that are of 
donor origin.  Chimerism will be assessed beginning at day +30.  If full donor 
chimerism is reached by day +30, it will be assessed per institutional guidelines 
for restaging.  If full donor chimerism is not reached by day +30, additional 
assessments will be done at day +60, +90 and then every four weeks (+/- 3 days) 
until the goal of full donor chimerism is achieved. For the purposes of this 
protocol mixed chimerism will be defined as the detection of > 5% and < 95% 
cells of donor origin and full donor chimerism will be defined as 95% cells of 
donor origin.  
 
5.9 
Graft-versus-host disease will be evaluated, graded and managed by current BMT 
of Georgia GVHD standards found in the BMT of Georgia Supportive Care 
Manual. 
 
5.10 
Restaging evaluations will occur per institutional standards at day +100, at 6 
months, 12 months, 18 months, 24 months, and 36 months. 
 
5.11 
Treatment failure:  
 
5.11.1 Treatment failure is defined as (1) patients that develop disease relapse and 
progression in spite of grade II-IV acute GVHD or extensive chronic GVHD, (2) 
patients with graft failure, or (3) patients with impending graft rejection as 
defined by low (<20%) or dropping T cell chimerism. 
 
5.11.2 Such patients will be considered a treatment failure and receive any additional 
treatment off-study according to physician discretion. 
 
 
6. Adverse Event /Serious Adverse Event Reporting  
6.1 
Patients will be monitored by the investigators and data maintained by the 
Clinical Research Program.  All Adverse Events will be graded with the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0.  Adverse events 
will be monitored for a period of three (3) months post HSCT (approximately 
D100 restaging) and for study purposes will be defined as 
 
 Grade 2, 3 and 4 unexpected reactions that are deemed related to study. 
 


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6.2 
Serious adverse events will be reported by telephone or email to the Institutional 
Review Board within 24 hours of notification.  Written report will follow within 
10 working days.  Serious adverse events will be reported for a period of six (6) 
months post HSCT (180 days)  
 
 
6.2.1 Procedure for reporting Serious and Unexpected Adverse Events 
Serious Adverse Events will be reported by telephone or email to the Institutional Review 
Board within 24 hours of notification of event.  Written report will follow within 10 
working days.  Serious adverse events will be reported for a period of 6 months post-
transplant.   
Routine hospital admissions for expected side effects/complications of stem cell 
transplant such as fever, infection, mucositis or GVHD will not be reported to the IRB 
but will be recorded in the BMT database. Only hospitalizations that are for unexpected 
side effects of the transplant procedure will be reported to IRB as serious adverse events. 
 
 
 
6.2.2  Definition of Serious and Unexpected Adverse Events: 
Serious Adverse Events are defined as one of the following: 
a. Death  
b. Life-Threatening  
c. Hospitalization (initial or prolonged)  
d. Disability 
e. Congenital Anomaly  
f. Requires Intervention to Prevent Permanent Impairment or Damage 
 
Unexpected is defined as: 
Not previously reported with the agents/devices or procedures being undertaken. 
Symptomatically and pathophysiologically related to known toxicity but differs because of 
greater severity than previously reported. 
 
7. 
Risks and Toxicities 
7.1    
Cyclophosphamide after graft infusion 
 
The major risk of participating in this research protocol is that shifting part of the standard 
HSCT dose of cyclophosphamide after the graft infusion may damage the graft. The 


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consequences of damaging the graft may include delayed hematologic recovery, graft failure, 
or treatment-related malignancy in donor cells. The risk of delayed hematologic recovery 
does not appear to be severe, because patients who have engrafted with donor cells in the 
setting of a nonmyeloablative preparative regimen incorporating the same post-HSCT dose 
of cyclophosphamide experienced only approximately two weeks of neutropenia. This 
protocol is more intense than the non-ablative regimens and if patients fail to engraft, this can 
be fatal . However, we expect this to be a rare complication for several reasons. First, 
hematopoietic stem cells express high levels of aldehyde dehydrogenase that detoxifies the 
active metabolite of cyclophosphamide, 4 hydroxycyclophospamide. Second, patients with 
acute hematologic malignancies who received a much less intensive preparative regimen that 
incorporated the same dose of cyclophosphamide after HSCT all engrafted, and 
intensification of the preparative regimen reduces the likelihood of graft rejection. The risk of 
treatment-related malignancy in donor cells is difficult to estimate, but is likely to be similar 
to the 1% risk estimated after limited exposure to cyclophosphamide. 
 
7.2  
Acute and Chronic GVHD 
 
The second major risk in participating in this research protocol is the risk of developing acute 
and/or chronic GVHD given the use of a reduced intensity preparative regimen followed by 
the infusion of PBSC from haploidentical donors. The degree of GVHD varies from mild 
cutaneous reactions to extensive widespread and systemic involvement of skin, liver, and 
gastrointestinal tract.  The incidence of fatal infection is greater in patients developing 
GVHD due to the immunosuppressive nature of GVHD and its associated treatments. The 
development of grade 3 or higher acute GVHD is considered clinically significant and 
associated with increased morbidity and non-relapse mortality. The likelihood of surviving 
severe GVHD is to a large part dependent on the age of the patient and the patient’s overall 
condition. For the majority of the patients eligible for this trial who have high-risk 
hematologic malignancies, a moderate increase in GVHD may be accompanied by an 
increased graft-versus-malignancy (GVM) benefit, so that the same long-term relapse free 
survival is maintained.  
 
7.3 
Regimen-related toxicities  
 
Toxicities directly related to the administration of high-dose chemotherapy include 
gastrointestinal toxicity (nausea, vomiting, mucositis), alopecia, infertility (which may be 
permanent), interstitial pneumonitis, idiopathic cardiomyopathy, hemorrhagic cystitis, 
hepatic venoocclusive disease, or multi-organ failure which may be fatal. 
Toxicities related to individual chemotherapy drugs are described in section 3.0. 


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7.4             Infection 
 
Infection is a major cause of morbidity in allo HSCT and is a major concern in these patients.  
Infections may be bacterial, viral, parasitic, or fungal.  Often, these infections are life-
threatening, particularly when caused by viral or fungal organisms, and are associated with 
high mortality in the transplant population. 
 
7.5  
Aplasia/Graft Failure 
Pancytopenia is an expected side effect of allogeneic HSCT with the use of reduced intensity 
preparative regimens. Given the previous experience with post-transplant cyclophosphamide 
in other trials, we would expect the duration of aplasia to be relatively short. Prolonged 
aplasia can result from the failure of donor PBSC to engraft and is usually fatal. 
  
 
8. STUDY PARAMETERS 
 
8.1  
Non-relapse mortality 
 
Non-relapse mortality, which is defined as death in the absence of relapse or progression, 
will be characterized at 100 days and at one year after HSCT. 
 
8.2  
Relapse 
 
The secondary objective of this protocol is to characterize overall and progression free 
survival following reduced intensity conditioning and transplantation of PBSCs from 
partially HLA-mismatched related donors. High clinical suspicion of relapse will most likely 
lead to a disease-specific evaluation. Cytogenetic studies or decreasing donor chimerism also 
increase the suspicion of relapse as well and can sometimes detect asymptomatic relapse in 
routine protocol-related marrow samples. If there is evidence of early relapse and no 
evidence of GVHD following HSCT, immunosuppressive therapy may be discontinued 
earlier than indicated in Section 5.7. If there is evidence of low donor chimerism and no 
evidence of GVHD, patients may be eligible for subsequent donor lymphocyte infusions. 
 
8.3  
Hematologic recovery 
 
A secondary endpoint of this Phase II trial is time to recovery of circulating neutrophils and 
platelets (following chemotherapy). Neutrophil recovery is defined as the first day of three 
consecutive lab values on different days, after the conditioning regimen-induced nadir of 
blood counts, that the absolute neutrophil count is > 500/μL. Platelet recovery is defined as 
the first day of three consecutive lab values on different days, after the conditioning regimen-


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induced nadir of blood counts, that the platelet count is ≥ 20,000/μL without platelet 
transfusion support in the seven days prior. 
 
8.4  
Donor chimerism 
 
Chimerism will be assessed beginning at day +30.  If full donor chimerism is reached by day 
+30, it will be assessed per institutional guidelines for restaging.  If full donor chimerism is 
not reached by day +30, additional assessments will be done at day  +60, +90 and then every 
four weeks (+/- 3 days) until the goal of full donor chimerism is achieved. For the purposes 
of this protocol mixed chimerism will be defined as the detection of > 5% and < 95% cells of 
donor origin and full donor chimerism will be defined as 95% cells of donor origin. 
 
8.5  
GVHD 
 
Patients will be followed for development of acute and chronic GVHD using standard 
criteria.  
 
9. 
FOLLOW UP/OFF STUDY CRITERIA 
 
9.1  
Patients will be considered to be off study if disease relapse occurs and additional 
treatment is received.  No subsequent adverse or serious adverse event reporting will be 
done.  Further follow up off study will be according to institutional requirements.  (For 
purposes of the study, donor lymphocyte infusions will not be considered “additional 
treatment.”)  
 
9.2  
Patients will be considered to have completed study follow up at 6 months post 
HSCT and will be removed from “on study” status.  Further off study follow up will be 
according to institutional requirements. 
 
10 STATISTICAL CONSIDERATIONS 
 
The primary objective of this phase II clinical trial is to estimate the incidence of graft rejection 
and severe graft versus-host disease (GVHD) following reduced intensity, HLA-mismatched 
HSCT for patients with high risk hematologic malignancies. A secondary objective is to obtain 
estimates of overall survival (OS), relapse, non-relapse mortality (NRM), and event-free survival 
(EFS) in patients receiving myeloablative conditioning and transplantation of partially human 
leukocyte antigen (HLA)-mismatched bone marrow from first-degree relatives.  
 
We will plan to accrue 30 patients that will be enough to test the following hypothesis: For the 
graft failure endpoint we will test the hypotheses H0: p=10% versus Ha: p<10% using a one-
sided exact Binomial test. Assume that none of patients undergoing the proposed regimen will 


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have graft failure, the power for confirming p less than 15% is always 100% if the null 
hypothesis is rejected. The size of at least 29 patients is needed to achieve rejection of the null 
hypothesis at the 5% significance level. 
 
Stopping criterion:  
 
10.1  
NRM: As outlined in Section 2.0 (Background), the overall nonrelapse mortality 
on the phase I nonmyeloablative haploidentical HSCT trial utilizing 2 doses of post-
transplantation Cy, MMF and tacrolimus was approximately 19% at one year. Other 
haploidentical HSCT trials, both nonmyeloablative and ablative have shown NRM in the 
range of 30-40%, mostly from infectious causes. The working hypothesis of this trial is 
that the overall toxicity of reduced intensity haploidentical HSCT is less than that of 
haploidentical HSCT after myeloablative conditioning utilizing PTCY. Therefore we 
adopt the stopping rule that a NRM incidence is greater than 30% after a minimum 
enrollment of 5 patients. The stopping boundaries are presented in the following table.  
 
 
Number of enrollment 
5 
6 
7 
8 
9 
10 
11 
15 
Suspend trial if NRM 
occurs in r patients 
r ≥ 2 
r ≥ 2 
r ≥ 3 
r ≥ 3 
r ≥ 3 
r ≥ 4 
r ≥ 4 
r ≥ 5 
 
 
 
 
10.2   
Severe acute GVHD: The incidence of severe aGVHD (Grades III-IV)) on the 
myeloablative haploidentical HSCT trial utilizing 2 doses of PTCY, MMF and tacrolimus 
was approximately 23%. The working hypothesis of this trial is that the overall toxicity of 
reduced intensity conditioning should not be significantly more than that seen with 
myeloablative conditioning utilizing post-transplantation Cy. Therefore we adopt the 
stopping rule that an incidence of III-IV aGVHD is greater than 35% after a minimum 
enrollment of 5 patients. The stopping boundaries are presented in the following table.  
 
 
Number of enrollment 
5 
6 
7 
8 
9 
10 
11 
15 
Suspend trial if severe acute 
GVHD occurs in r patients 
r ≥ 2 
r ≥ 3 
r ≥ 3 
r ≥ 3 
r ≥ 4 
r ≥ 4 
r ≥ 4 
r ≥ 6 
 
10.3   
Engraftment Failure:  As outlined in Section 2.0 (Background), the incidence of 
engraftment failure on the phase I nonmyeloablative haploidentical HSCT trial utilizing 2 doses 
of post-transplantation Cy, MMF and tacrolimus was approximately 18%. All patients in the two 


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myeloablative studies at our center engrafted. It is concerning that with the intensity of flu/mel, 
patients are not going to recover their own count if they fail to engraft. The working hypothesis 
of this trial is that the overall toxicity of reduced intensity haplo HSCT is not significantly 
greater than haploidentical HSCT after nonmyeloablative conditioning utilizing PTCY. 
Therefore we adopt the stopping rule that an incidence of engraftment failure is greater than 30% 
after a minimum enrollment of 5 patients. The stopping boundaries are presented in the 
following table.  
 
 
Number of enrollment 
5 
6 
7 
8 
9 
10 
11 
15 
Suspend trial if engraftment 
failure occurs in r patients 
r ≥ 2 
r ≥ 2 
r ≥ 3 
r ≥ 3 
r ≥ 3 
r ≥ 4 
r ≥ 4 
r ≥ 5 
 
 
If any of the above stopping criteria is met, accrual to the trial will be temporarily halted, until a 
decision regarding either modification or termination of the trial could be made.  
 


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11. REFERENCES 
 
1. 
Szydlo R, Goldman JM, Klein JP, Gale RP, Ash RC, Bach FH, et al. Results of 
allogeneic bone marrow transplants for leukemia using donors other than HLA-identical siblings. 
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 
1997;15(5):1767-77. 
2. 
Anasetti C, Amos D, Beatty PG, Appelbaum FR, Bensinger W, Buckner CD, et al. Effect 
of HLA compatibility on engraftment of bone marrow transplants in patients with leukemia or 
lymphoma. The New England journal of medicine. 1989;320(4):197-204. 
3. 
Kernan NA, Flomenberg N, Dupont B, O'Reilly RJ. Graft rejection in recipients of T-
cell-depleted HLA-nonidentical marrow transplants for leukemia. Identification of host-derived 
antidonor allocytotoxic T lymphocytes. Transplantation. 1987;43(6):842-7. 
4. 
Aversa F, Terenzi A, Tabilio A, Falzetti F, Carotti A, Ballanti S, et al. Full haplotype-
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5. 
Bashey A, Solomon SR. T-cell replete haploidentical donor transplantation using post-
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sibling donor. Bone marrow transplantation. 2014;49(8):999-1008. 
6. 
O'Donnell PV, Luznik L, Jones RJ, Vogelsang GB, Leffell MS, Phelps M, et al. 
Nonmyeloablative bone marrow transplantation from partially HLA-mismatched related donors 
using posttransplantation cyclophosphamide. Biology of blood and marrow transplantation : 
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7. 
Solomon SR, Sizemore CA, Sanacore M, Zhang X, Brown S, Holland HK, 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. Biology of blood and marrow transplantation : journal of the American Society for Blood 
and Marrow Transplantation. 2012;18(12):1859-66. 
8. 
Solomon SR, Sizemore CA, Sanacore M, Zhang X, Brown S, Holland HK, et al. Total 
Body Irradiation-Based Myeloablative Haploidentical Stem Cell Transplantation Is a Safe and 
Effective Alternative to Unrelated Donor Transplantation in Patients Without Matched Sibling 
Donors. Biology of blood and marrow transplantation : journal of the American Society for 
Blood and Marrow Transplantation. 2015.