HLA-Mismatched Unrelated Donor Bone Marrow Transplantation With Post-Transplantation Cyclophosphamide

Phase 2

Completed

Conditions: Myelodysplastic Syndrome (MDS)
Chronic Lymphocytic Leukemia (CLL)
Chemotherapy-sensitive Lymphoma
Acute Lymphoblastic Leukemia (ALL)/T Lymphoblastic Lymphoma
Acute Myelogenous Leukemia (AML)
Acute Biphenotypic Leukemia (ABL)
Acute Undifferentiated Leukemia (AUL)

Interventions: Drug: Fludarabine
Drug: Cyclophosphamide 14.5 mg/kg/day IV on Days -6, -5
Drug: Cyclophosphamide 50mg/kg/day IV on Days -5,-4
Radiation: Total Body Irradiation (TBI) 200cGy on Day -1
Drug: Cyclophosphamide 50mg/kg/day IV on Days -2,-1
Drug: Busulfan
Radiation: Total Body Irradiation (TBI) 200cGy twice a day on Days -3, -2, -1
Procedure: Infusion of non-T-cell depleted bone marrow on Day 0
Drug: Post-HCT Cyclophosphamide 50mg/kg IV on Day+3, +4
Drug: Sirolimus
Drug: Mycophenolate mofetil
Drug: G-CSF
Drug: Pre-HCT Mesna on Days -2 and -1
Drug: Pre-HCT Mesna on Days -5 and -4
Drug: Pre-HCT Mesna on Days -6 and -5
Drug: Post-HCT Mesna

Registration Number: NCT02793544

Lead Sponsor: Center for International Blood and Marrow Transplant Research

Brief Summary: This is a multi-center, single arm Phase II study of hematopoietic cell transplantation (HCT) using human leukocyte antigen (HLA)-mismatched unrelated bone marrow transplantation donors and post-transplantation cyclophosphamide (PTCy), sirolimus and mycophenolate mofetil (MMF) for graft versus host disease (GVHD) prophylaxis in patients with hematologic malignancies.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 80

Inclusion Criteria

Age ≥ 15 years and < 71 years at the time of signing the informed consent form
Partially HLA-mismatched unrelated donor: HLA typing will be performed at high resolution (allele level) for the HLA-A, -B, -C, and -DRB1 loci; a minimum match of 4/8 at HLA-A, -B, -C, and -DRB1 is required
Product planned for infusion is bone marrow
Disease and disease status:
1. Acute Leukemias or T lymphoblastic lymphoma in 1st or subsequent complete remission (CR): Acute lymphoblastic leukemia (ALL)/T lymphoblastic lymphoma; acute myelogenous leukemia (AML); acute biphenotypic leukemia (ABL); acute undifferentiated leukemia (AUL)
2. Myelodysplastic Syndrome (MDS), fulfilling the following criteria: Subjects with de novo MDS who have or have previously had Intermediate-2 or High risk disease as determined by the International Prognostic Scoring System (IPSS). Current Intermediate-2 or High risk disease is not a requirement; Subjects must have < 20% bone marrow blasts, assessed within 60 days of informed consent; Subjects may have received prior therapy for the treatment of MDS prior to enrollment
3. Chronic Lymphocytic Leukemia (CLL) in CR if RIC is to be used; in CR or partial response (PR) if FIC is to be used
4. Chronic myeloid leukemia (CML) in 1st or subsequent chronic phase characterized by <10% blasts in the blood or bone marrow.
5. Chemotherapy-sensitive lymphoma in status other than 1st CR
Performance status: Karnofsky or Lansky score ≥ 60% (Appendix A)
Adequate organ function defined as:
1. Cardiac: left ventricular ejection fraction (LVEF) at rest ≥ 35% (RIC cohort) or LVEF at rest ≥ 40% (FIC cohort), or left ventricular shortening fraction (LVFS) ≥ 25%
2. Pulmonary: diffusing capacity of the lungs for carbon monoxide (DLCO), forced expiratory volume (FEV1), forced vital capacity (FVC) ≥ 50% predicted by pulmonary function tests (PFTs)
3. Hepatic: total bilirubin ≤ 2.5 mg/dL, and alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) < 5 x upper limit of (ULN) (unless disease related)
4. Renal: serum creatinine (SCr) within normal range for age (see table 2.3). If SCr is outside normal range for age, creatinine clearance (CrCl) > 40 mL/min/1.73m2 must be obtained (measured by 24-hour (hr) urine specimen or nuclear glomerular filtration rate (GFR), or calculated GFR (by Cockcroft-Gault formula for those aged ≥ 18 years; by Original Schwartz estimate for those < 18 years))
Subjects ≥ 18 years of age must have the ability to give informed consent according to applicable regulatory and local institutional requirements. Legal guardian permission must be obtained for subjects < 18 years of age. Pediatric subjects will be included in age appropriate discussion in order to obtain assent.
Subjects with documentation of confirmed HIV-1 infection (i.e. HIV-positive), and a hematologic malignancy who meets all other eligibility requirements must:
1. Receive only RIC regimen (i.e. Regimen A)
2. Be willing to comply with effective antiretroviral therapy (ARV)
3. Have achieved a sustained virologic response for 12 weeks after cessation of hepatitis C antiviral treatment (in HIV-positive subjects with hepatitis C)

Exclusion Criteria

HLA-matched related or 8/8 allele matched (HLA-A, -B, -C, -DRB1) unrelated donor available. This exclusion does not apply to HIV-positive subjects who have a CCR5delta32 homozygous donor.
Autologous HCT < 3 months prior to the time of signing the informed consent form
Females who are breast-feeding or pregnant
HIV-positive subjects:
1. Acquired immunodeficiency syndrome (AIDS) related syndromes or symptoms that may pose an excessive risk for transplantation-related morbidity as determined by the Treatment Review Committee (see Appendix D).
2. Untreatable HIV infection due to multidrug ARV resistance. Subjects with a detectable or standard viral load > 750 copies/mL should be evaluated with an HIV drug resistance test (HIV-1 genotype). The results should be included as part of the ARV review (described in Appendix D).
3. May not be currently prescribed ritonavir, cobacistat and/or zidovudine
Current uncontrolled bacterial, viral or fungal infection (currently taking medication with evidence of progression of clinical symptoms or radiologic findings)
Prior allogeneic HCT
History of primary idiopathic myelofibrosis
MDS subjects may not receive RIC and must be < 50 years of age at the time of signing the informed consent form

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Regimen A (RIC: Flu/Cy/TBI)	Cyclophosphamide 14.5 mg/kg/day IV on Days -6, -5	1. Fludarabine 30 mg/m2/day IV on Days -6, -5, -4, -3, -2 2. Cyclophosphamide 14.5 mg/kg/day IV on Days -6, -5 3. Total Body Irradiation (TBI) 200cGy on Day -1 4. Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.
Regimen A (RIC: Flu/Cy/TBI)	Post-HCT Mesna	1. Fludarabine 30 mg/m2/day IV on Days -6, -5, -4, -3, -2 2. Cyclophosphamide 14.5 mg/kg/day IV on Days -6, -5 3. Total Body Irradiation (TBI) 200cGy on Day -1 4. Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.
Regimen A (RIC: Flu/Cy/TBI)	Fludarabine	1. Fludarabine 30 mg/m2/day IV on Days -6, -5, -4, -3, -2 2. Cyclophosphamide 14.5 mg/kg/day IV on Days -6, -5 3. Total Body Irradiation (TBI) 200cGy on Day -1 4. Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.
Regimen A (RIC: Flu/Cy/TBI)	Total Body Irradiation (TBI) 200cGy on Day -1	1. Fludarabine 30 mg/m2/day IV on Days -6, -5, -4, -3, -2 2. Cyclophosphamide 14.5 mg/kg/day IV on Days -6, -5 3. Total Body Irradiation (TBI) 200cGy on Day -1 4. Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.
Regimen A (RIC: Flu/Cy/TBI)	Infusion of non-T-cell depleted bone marrow on Day 0	1. Fludarabine 30 mg/m2/day IV on Days -6, -5, -4, -3, -2 2. Cyclophosphamide 14.5 mg/kg/day IV on Days -6, -5 3. Total Body Irradiation (TBI) 200cGy on Day -1 4. Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.
Regimen A (RIC: Flu/Cy/TBI)	G-CSF	1. Fludarabine 30 mg/m2/day IV on Days -6, -5, -4, -3, -2 2. Cyclophosphamide 14.5 mg/kg/day IV on Days -6, -5 3. Total Body Irradiation (TBI) 200cGy on Day -1 4. Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.
Regimen A (RIC: Flu/Cy/TBI)	Pre-HCT Mesna on Days -6 and -5	1. Fludarabine 30 mg/m2/day IV on Days -6, -5, -4, -3, -2 2. Cyclophosphamide 14.5 mg/kg/day IV on Days -6, -5 3. Total Body Irradiation (TBI) 200cGy on Day -1 4. Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.
Regimen B 2a (FIC: Bu/Cy)	Infusion of non-T-cell depleted bone marrow on Day 0	1. Busulfan ≥ 9mg/kg total dose on Days -6, -5, -4, -3 (IV or PO) 2. Cyclophosphamide 50mg/kg/day IV on Days -2,-1 3. Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.
Regimen B 2a (FIC: Bu/Cy)	Cyclophosphamide 50mg/kg/day IV on Days -2,-1	1. Busulfan ≥ 9mg/kg total dose on Days -6, -5, -4, -3 (IV or PO) 2. Cyclophosphamide 50mg/kg/day IV on Days -2,-1 3. Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.
Regimen B 2a (FIC: Bu/Cy)	Pre-HCT Mesna on Days -2 and -1	1. Busulfan ≥ 9mg/kg total dose on Days -6, -5, -4, -3 (IV or PO) 2. Cyclophosphamide 50mg/kg/day IV on Days -2,-1 3. Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.
Regimen B 2a (FIC: Bu/Cy)	Post-HCT Mesna	1. Busulfan ≥ 9mg/kg total dose on Days -6, -5, -4, -3 (IV or PO) 2. Cyclophosphamide 50mg/kg/day IV on Days -2,-1 3. Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.
Regimen B 2b (FIC: Bu/Flu)	Fludarabine	1. Busulfan ≥ 9mg/kg total dose on Days -6, -5, -4, -3 (IV or PO) 2. Fludarabine 30 mg/m2/day IV on Days -6, -5, -4, -3, -2 3. Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.
Regimen B 2a (FIC: Bu/Cy)	Post-HCT Cyclophosphamide 50mg/kg IV on Day+3, +4	1. Busulfan ≥ 9mg/kg total dose on Days -6, -5, -4, -3 (IV or PO) 2. Cyclophosphamide 50mg/kg/day IV on Days -2,-1 3. Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.
Regimen B 2b (FIC: Bu/Flu)	Infusion of non-T-cell depleted bone marrow on Day 0	1. Busulfan ≥ 9mg/kg total dose on Days -6, -5, -4, -3 (IV or PO) 2. Fludarabine 30 mg/m2/day IV on Days -6, -5, -4, -3, -2 3. Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.
Regimen B 2b (FIC: Bu/Flu)	Busulfan	1. Busulfan ≥ 9mg/kg total dose on Days -6, -5, -4, -3 (IV or PO) 2. Fludarabine 30 mg/m2/day IV on Days -6, -5, -4, -3, -2 3. Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.
Regimen B 2b (FIC: Bu/Flu)	Post-HCT Mesna	1. Busulfan ≥ 9mg/kg total dose on Days -6, -5, -4, -3 (IV or PO) 2. Fludarabine 30 mg/m2/day IV on Days -6, -5, -4, -3, -2 3. Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.
Regimen C (FIC: Cy/TBI)	Infusion of non-T-cell depleted bone marrow on Day 0	1. Cyclophosphamide 50mg/kg/day IV on Days -5,-4 2. Total Body Irradiation (TBI) 200cGy twice a day on Days -3, -2, -1 3. Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.
Regimen C (FIC: Cy/TBI)	Cyclophosphamide 50mg/kg/day IV on Days -5,-4	1. Cyclophosphamide 50mg/kg/day IV on Days -5,-4 2. Total Body Irradiation (TBI) 200cGy twice a day on Days -3, -2, -1 3. Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.
Regimen C (FIC: Cy/TBI)	Total Body Irradiation (TBI) 200cGy twice a day on Days -3, -2, -1	1. Cyclophosphamide 50mg/kg/day IV on Days -5,-4 2. Total Body Irradiation (TBI) 200cGy twice a day on Days -3, -2, -1 3. Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.
Regimen C (FIC: Cy/TBI)	Sirolimus	1. Cyclophosphamide 50mg/kg/day IV on Days -5,-4 2. Total Body Irradiation (TBI) 200cGy twice a day on Days -3, -2, -1 3. Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.
Regimen C (FIC: Cy/TBI)	Post-HCT Mesna	1. Cyclophosphamide 50mg/kg/day IV on Days -5,-4 2. Total Body Irradiation (TBI) 200cGy twice a day on Days -3, -2, -1 3. Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.
Regimen C (FIC: Cy/TBI)	Mycophenolate mofetil	1. Cyclophosphamide 50mg/kg/day IV on Days -5,-4 2. Total Body Irradiation (TBI) 200cGy twice a day on Days -3, -2, -1 3. Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.
Regimen C (FIC: Cy/TBI)	Pre-HCT Mesna on Days -5 and -4	1. Cyclophosphamide 50mg/kg/day IV on Days -5,-4 2. Total Body Irradiation (TBI) 200cGy twice a day on Days -3, -2, -1 3. Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.
Regimen A (RIC: Flu/Cy/TBI)	Post-HCT Cyclophosphamide 50mg/kg IV on Day+3, +4	1. Fludarabine 30 mg/m2/day IV on Days -6, -5, -4, -3, -2 2. Cyclophosphamide 14.5 mg/kg/day IV on Days -6, -5 3. Total Body Irradiation (TBI) 200cGy on Day -1 4. Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.
Regimen B 2b (FIC: Bu/Flu)	Post-HCT Cyclophosphamide 50mg/kg IV on Day+3, +4	1. Busulfan ≥ 9mg/kg total dose on Days -6, -5, -4, -3 (IV or PO) 2. Fludarabine 30 mg/m2/day IV on Days -6, -5, -4, -3, -2 3. Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.
Regimen C (FIC: Cy/TBI)	Post-HCT Cyclophosphamide 50mg/kg IV on Day+3, +4	1. Cyclophosphamide 50mg/kg/day IV on Days -5,-4 2. Total Body Irradiation (TBI) 200cGy twice a day on Days -3, -2, -1 3. Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.
Regimen A (RIC: Flu/Cy/TBI)	Sirolimus	1. Fludarabine 30 mg/m2/day IV on Days -6, -5, -4, -3, -2 2. Cyclophosphamide 14.5 mg/kg/day IV on Days -6, -5 3. Total Body Irradiation (TBI) 200cGy on Day -1 4. Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.
Regimen A (RIC: Flu/Cy/TBI)	Mycophenolate mofetil	1. Fludarabine 30 mg/m2/day IV on Days -6, -5, -4, -3, -2 2. Cyclophosphamide 14.5 mg/kg/day IV on Days -6, -5 3. Total Body Irradiation (TBI) 200cGy on Day -1 4. Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.
Regimen B 2a (FIC: Bu/Cy)	Busulfan	1. Busulfan ≥ 9mg/kg total dose on Days -6, -5, -4, -3 (IV or PO) 2. Cyclophosphamide 50mg/kg/day IV on Days -2,-1 3. Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.
Regimen B 2a (FIC: Bu/Cy)	Sirolimus	1. Busulfan ≥ 9mg/kg total dose on Days -6, -5, -4, -3 (IV or PO) 2. Cyclophosphamide 50mg/kg/day IV on Days -2,-1 3. Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.
Regimen B 2a (FIC: Bu/Cy)	Mycophenolate mofetil	1. Busulfan ≥ 9mg/kg total dose on Days -6, -5, -4, -3 (IV or PO) 2. Cyclophosphamide 50mg/kg/day IV on Days -2,-1 3. Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.
Regimen B 2a (FIC: Bu/Cy)	G-CSF	1. Busulfan ≥ 9mg/kg total dose on Days -6, -5, -4, -3 (IV or PO) 2. Cyclophosphamide 50mg/kg/day IV on Days -2,-1 3. Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.
Regimen B 2b (FIC: Bu/Flu)	Mycophenolate mofetil	1. Busulfan ≥ 9mg/kg total dose on Days -6, -5, -4, -3 (IV or PO) 2. Fludarabine 30 mg/m2/day IV on Days -6, -5, -4, -3, -2 3. Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.
Regimen B 2b (FIC: Bu/Flu)	Sirolimus	1. Busulfan ≥ 9mg/kg total dose on Days -6, -5, -4, -3 (IV or PO) 2. Fludarabine 30 mg/m2/day IV on Days -6, -5, -4, -3, -2 3. Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.
Regimen B 2b (FIC: Bu/Flu)	G-CSF	1. Busulfan ≥ 9mg/kg total dose on Days -6, -5, -4, -3 (IV or PO) 2. Fludarabine 30 mg/m2/day IV on Days -6, -5, -4, -3, -2 3. Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.
Regimen C (FIC: Cy/TBI)	G-CSF	1. Cyclophosphamide 50mg/kg/day IV on Days -5,-4 2. Total Body Irradiation (TBI) 200cGy twice a day on Days -3, -2, -1 3. Infusion of non-T-cell depleted bone marrow on Day 0 Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.

Primary Outcome Measures

Name	Time	Method
Overall Survival	365 days post transplant	Death from any cause. The time to this event is the time from HCT to death, loss to follow-up, or end of study (whichever comes first). The overall survival probability and 90% CI will be calculated by the Kaplan Meier product limit estimator.

Secondary Outcome Measures

Name	Time	Method
Progression-free Survival	180 days and 365 days post-transplant	Time from HCT until the documentation of disease progression / relapse or death due to any cause, whichever occurs first. Progression-free survival probability and 90% CI will be calculated by the Kaplan Meier product limit estimator.
Transplant-related Mortality	100 days, 180 days, and 365 days post-transplant	Death without evidence of disease progression or recurrence. A cumulative incidence will be computed along with a 90% CI.
Cumulative Incidence of Neutrophil Recovery	100 days and 365 days post transplant	Achieving a donor derived ANC ≥ 500/mm3 for 3 consecutive laboratory values on different days. A cumulative incidence will be computed along with a 90% CI.
Cumulative Incidence of Platelet Recovery	100 days and 365 days post transplant	Achieving a platelet count ≥ 20,000/μL for 3 consecutive laboratory values on different days (with no platelet transfusions in the preceding seven days). A cumulative incidence will be computed along with a 90% CI.
Cumulative Incidence of Acute GVHD	100 days post-transplant	Any skin, gastrointestinal or liver abnormalities fulfilling the BMT CTN Manual of Operations (2013) criteria of grades II-IV acute GVHD. A cumulative incidence will be computed along with a 90% CI. Any skin, gastrointestinal or liver abnormalities fulfilling the BMT CTN Manual of Operations (2013) criteria of grades III-IV acute GVHD. A cumulative incidence will be computed along with a 90% CI.
Grades II-IV Acute GVHD	100 days	Any skin, gastrointestinal or liver abnormalities fulfilling the BMT CTN Manual of Operations (2013) criteria of grades II-IV acute GVHD. A cumulative incidence will be computed along with a 90% CI.
Grades III-IV Acute GVHD	100 days	Any skin, gastrointestinal or liver abnormalities fulfilling the BMT CTN Manual of Operations (2013) criteria of grades III-IV acute GVHD. A cumulative incidence will be computed along with a 90% CI.
Cumulative Incidence of Chronic GVHD	180 days and 365 days post-transplant	Per National Institutes of Health (NIH) Consensus Criteria and includes organ involvement and severity, and overall global composite score (mild/moderate/severe). A cumulative incidence will be computed along with a 90% CI. Death from any cause. The time to this event is the time from HCT to death, loss to follow-up, or end of study (whichever comes first). The overall survival probability and 90% CI will be calculated by the Kaplan Meier product limit estimator.
Cumulative Incidences of Viral Reactivations and Infections: Grade 2-3 CMV Reactivation or Infection	100 days, 180 days, and 365 days	Grade 2: Clinically active CMV infection (e.g. symptoms, cytopenias) or CMV Viremia not decreasing by at least 2/3 of the baseline value after 2 weeks of therapy; Grade 3: CMV end-organ involvement (pneumonitis, enteritis, retinitis). A cumulative incidence will be computed along with a 90% CI. Death from any cause. The time to this event is the time from HCT to death, loss to follow-up, or end of study (whichever comes first). The overall survival probability and 90% CI will be calculated by the Kaplan Meier product limit estimator.
Cumulative Incidences of Viral Reactivations and Infections: Grade 3 CMV Infection	100 days, 180 days, and 365 days	CMV end-organ involvement (pneumonitis, enteritis, retinitis) ). A cumulative incidence will be computed along with a 90% CI. Death from any cause. The time to this event is the time from HCT to death, loss to follow-up, or end of study (whichever comes first). The overall survival probability and 90% CI will be calculated by the Kaplan Meier product limit estimator.
Cumulative Incidences of Viral Reactivations and Infections: Grade 2-3 EBV Infection	100 days, 180 days, and 365 days	Grade 2: EBV reactivation requiring institution of therapy with rituximab; Grade 3: EBV post-transplant lymphoproliferative disorder). A cumulative incidence will be computed along with a 90% CI. Death from any cause. The time to this event is the time from HCT to death, loss to follow-up, or end of study (whichever comes first). The overall survival probability and 90% CI will be calculated by the Kaplan Meier product limit estimator.
Cumulative Incidences of Viral Reactivations and Infections: Grade 2 BK Virus Infection	100 days, 180 days, 365 days	BK viremia or viruria with clinical consequence requiring prolonged therapy and/or surgical intervention). A cumulative incidence will be computed along with a 90% CI.
Cumulative Incidences of Viral Reactivations and Infections: Grade 2-3 Adenovirus Infection	100 days, 180 days, and 365 days	Grade 2: Adenoviral URI, viremia, or symptomatic viruria requiring treatment; Grade 3: ADV with end-organ involvement (except conjunctivitis and upper respiratory tract) ). A cumulative incidence will be computed along with a 90% CI. Death from any cause. The time to this event is the time from HCT to death, loss to follow-up, or end of study (whichever comes first). The overall survival probability and 90% CI will be calculated by the Kaplan Meier product limit estimator.
Cumulative Incidences of Viral Reactivations and Infections: Grade 2 HHV-6 Infection	100 days, 180 days, 365 days	Clinically active HHV-6 infection (e.g. symptoms, cytopenias) or HHV-6 viremia without viral load decline 0.5 log after 2 weeks of therapy). A cumulative incidence will be computed along with a 90% CI.
Cumulative Incidence of Relapse/Progression	180 days and 365 days post-transplant	Defined by either morphological, cytogenetic/molecular or radiological evidence of disease consistent with pre-HCT features. A cumulative incidence will be computed along with a 90% CI. Death from any cause. The time to this event is the time from HCT to death, loss to follow-up, or end of study (whichever comes first). The overall survival probability and 90% CI will be calculated by the Kaplan Meier product limit estimator.
Cumulative Incidences of Thrombotic Microangiopathy (TMA) and Hepatic Veno-occlusive Disease (VOD)/Sinusoidal Obstruction Syndrome (SOS)	365 days post transplant	TMA is defined as (Ho et al., 2005): 1. RBC fragmentation and \>2 schistocytes per high-power field on peripheral smear 2. Concurrent increased serum LDH above institutional baseline 3. Concurrent renal and/or neurologic dysfunction without other explanation 4. Negative direct and indirect Coombs test results A cumulative incidence will be computed along with a 90% CI. VOD/SOS is defined as: In the first 20 days after HCT, the presence of ≥2 of the following: 1. Bilirubin \>2 mg/Dl, 2. Hepatomegaly or pain in right upper quadrant, 3. Weight gain (\>2% basal weight). A cumulative incidence will be computed along with a 90% CI.
Cumulative Incidence of Primary Graft Failure	56 days post-transplant	Lack of donor-derived neutrophil engraftment. The frequency of subjects experiencing primary graft failure by 56 days will be described.
Donor Chimerism	28 days, 56 days, 100 days, 180 days, and 365 days post-transplant	Peripheral blood chimerism (% of donor chimerism) in whole blood (unsorted). The degree of donor chimerism will be summarized using descriptive statistics.
Peripheral Blood Chimerism	56 days post-transplant	The frequency of subjects with Peripheral blood (unsorted) chimerism\>95% at 56 days will be described.
Proportion of Subjects Proceeding to Transplant	Pre-HCT	The proportion of subjects proceeding to HCT after informed consent.
Time From Search to Donor Identification	Pre-HCT	Time from search to donor identification Time from preliminary search to formal donor activation.
Donor Selection Characteristics: HLA Match	Pre-HCT	Number of matched donor and recipient HLA allele pairs. A matched donor would have 8/8 HLA allele pairs matching; mismatched donors listed below have one to four mismatched HLA allele pairs at HLA-A, -B, -C, or -DRB1.
Donor Selection Characteristics: Donor Age	Pre-HCT	Donor age
Donor Selection Characteristics: Donor Age, Categorical	Pre-HCT	Donor age, categorical
Donor Selection Characteristics: Donor Weight	Pre-HCT	Donor weight
Donor Selection Characteristics: Donor Sex	Pre-HCT	Donor sex
Donor Selection Characteristics: Donor and Recipient Sex	Pre-HCT	Donor-recipient sex match
Donor Selection Characteristics: Donor and Recipient CMV Serostatus	Pre-HCT	Donor-recipient Cytomegalovirus (CMV) serostatus match
Donor Selection Characteristics: Donor and Recipient ABO Blood Match	Pre-HCT	Donor-recipient ABO group match
Donor Clonal Hematopoiesis	100 days and 365 days post-transplant	The proportion of subjects developing donor clonal hematopoiesis
Subgroup Analysis of HIV-positive Subjects	365 days post transplant	If CCR5delta32 homozygous donors are successfully found and used for one or more HIV-positive subjects, a descriptive analysis of baseline characteristics and outcomes for those HIV-positive subjects will be conducted, including the viral load detected over time obtained from collected samples.

Trial Locations

Locations (11): Shands HealthCare & University of Florida
🇺🇸
Gainesville, Florida, United States
University of Miami
🇺🇸
Miami, Florida, United States
H. Lee Moffitt Cancer Center and Research Institute
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Tampa, Florida, United States
University of Maryland Greenebaum Cancer Center
🇺🇸
Baltimore, Maryland, United States
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
🇺🇸
Baltimore, Maryland, United States
Karmanos Cancer Institute
🇺🇸
Detroit, Michigan, United States
Memorial Sloan Kettering Cancer Center - Adults
🇺🇸
New York, New York, United States
University of North Carolina Hospitals
🇺🇸
Chapel Hill, North Carolina, United States
Ohio State Medical Center, James Cancer Center
🇺🇸
Columbus, Ohio, United States
Virginia Commonwealth University Massey Cancer Center Bone Marrow Transplant Program
🇺🇸
Richmond, Virginia, United States
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Shands HealthCare & University of Florida
🇺🇸Gainesville, Florida, United States