Myeloablative Haploidentical BMT With Post-transplant Cyclophosphamide for Pediatric Patients With Hematologic Malignancies

Pediatric Blood & Marrow Transplant Consortium (PBMTC) Phase II Myeloablative Haploidentical BMT With Post-transplantation Cyclophosphamide for Pediatric Patients With Hematologic Malignancies

This is a multi-institutional phase II haploidentical T cell replete bone marrow transplant (BMT) study in children with high-risk leukemia. The myeloablative conditioning regimen prescribed will be Total body irradiation (TBI)-based for lymphoid leukemia and busulfan-based for myeloid leukemia. Our goal is to establish an easily exportable, inexpensive platform for haplotransplantation that has a safety profile equivalent to matched related and unrelated BMTs. The primary objective will be to estimate the incidence of 6-month non-relapse mortality (NRM), hypothesizing that NRM is < 18%.

Study Overview

• Status: Completed
• Conditions: Myeloablative Conditioning; HLA-mismatched Bone Marrow Transplantation; Graft Survival; Transplantation, Bone Marrow
• Intervention / Treatment: Drug: Cyclophosphamide; Radiation: TBI; Drug: Busulfan; Other: Unmanipulated Bone Marrow; Drug: Tacrolimus; Drug: Mycophenolate mofetil

Detailed Description

This is a phase II prospective study designed to evaluate the incidence of 6 month non- relapse mortality, safety, and feasibility of haploidentical bone marrow transplantation (BMT) after myeloablative conditioning with post-transplant Cy. Conditioning regimens include a total body irradiation (TBI)-based prep for lymphoid leukemias and a chemotherapy based prep for myeloid leukemias.

To estimate the incidence of non-relapse mortality at 180 days following myeloablative haploidentical BMT for children and young adults with high risk hematologic malignancies.

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3V4
      • British Columbia Children's Hospital
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for Sick Children
• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital of Colorado
  • Delaware
    • Wilmington, Delaware, United States, 19803
      • Nemours Alfred I. Dupont Hospital for Children
  • Florida
    • Saint Petersburg, Florida, United States, 33701
      • All Children's Hospital Johns Hopkins Medicine
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University in St. Louis
  • North Carolina
    • Charlotte, North Carolina, United States, 28203
      • Levine Cancer Center
  • South Carolina
    • Charleston, South Carolina, United States, 29423
      • Medical University of South Carolina

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patient age 0.5-25years
• Patients must have a first-degree related donor or half-sibling who is at minimum HLA haploidentical. The donor and recipient must be identical at at least one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB1. A minimum match of 5/10 is therefore required, and will be considered sufficient evidence that the donor and recipient share one HLA haplotype.
• An unrelated donor search is not required for a patient to be eligible for this protocol, or a donor search and donor mobilization may be abandoned if the clinical situation dictates an urgent transplant. Clinical urgency is defined as 6-8 weeks from referral to transplant or a low-likelihood of finding a matched, unrelated donor. Patients with an eligible HLA-matched RELATED should not be enrolled on this trial.
• Patients must have at least one of the following high-risk conditions listed below:
• Acute lymphocytic leukemia (ALL) in CR1* as defined by at least one of the following:

hypodiploidy, induction failure,Minimal residual disease (MRD) after consolidation

- Acute myeloid leukemia (AML) in CR1 with high risk features defined as: High allelic ratio FLT3/ITD+, Monosomy 7, Del (5q), Standard risk cytogenetics with positive minimal residual disease at the end of Induction I chemotherapy (for patients being treated on or according to Children's Oncology Group (COG) AAML1031 study who have had MRD studies sent to Seattle or performed at their local institution where the flow assay is sensitive enough to detect > 0.1% blasts)

• Acute Leukemia in 2nd or subsequent CR (CR>2)
• Mixed phenotype/Undifferentiated Leukemia in 1st or subsequent CR*
• Secondary or therapy related leukemia in CR > 1
• Natural Killer (NK) cell lymphoblastic leukemia CR > 1
• Myelodysplastic syndrome (MDS)
• Juvenile myelomonocytic leukemia (JMML) (patients are eligible if they are not eligible for COG1221 study)
• Prior transplant eligible if < 18yo, >6 months has elapsed since BMT, and patient is off immunosuppression for > 3 months with no Graft versus host disease (GVHD)
• No known active Central nervous system (CNS) involvement or extramedullary involvement by malignancy. Such disease treated into remission is permitted.
• Acute Leukemia - Remission is defined as morphology with < 5% blasts with no morphological characteristics of acute leukemia (e.g., Auer Rods) in a bone marrow with > 20% cellularity.

Exclusion Criteria:

• Poor cardiac function: left ventricular ejection fraction <45% as determined by Multigated acquisition scan (MUGA) or Echocardiogram (ECHO). For pediatric patients Left ventricular ejection fraction (LVEF) <45% or a shortening fraction below normal limits for age.
• Symptomatic pulmonary disease. Poor pulmonary function: Forced expiratory volume (FEV1), Forced vital capacity (FVC), and Diffusing capacity for carbon monoxide (DLCO) <50% predicted (corrected for hemoglobin) for patients who have not received thoracic or mantle irradiation. For patients who have received thoracic or mantle irradiation, FEV1 and FVC <70% predicted or DLCO < 50 of predicted. For children unable to perform Pulmonary function tests (PFTs) because of developmental stage pulse oximetry < 92% on Room air (RA).
• Poor liver function: bilirubin >2 mg/dl (not due to hemolysis, Gilbert's or primary malignancy). Alanine aminotransferase (ALT) or Aspartate transaminase (AST) > 3 x laboratory upper normal limits.
• Poor renal function: Creatinine >2.0mg/dl or creatinine clearance (calculated creatinine clearance is permitted) < 60 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) Multiply by another factor of 0.85 if female Intended for ages 18-110, serum creatinine 0.6-7 mg/dl For patients <18 years: creatinine clearance (CrCl) will be estimated by the Schwartz formula. A measured CrCl or a Glomerular filtration rate (GFR) may be substituted to determine the subject's CrCl.
• Schwartz equation: CrCl (ml/min/1.73m2)=[length (cm) x k] /serum creatinine K = 0.45 for infants 1 to 52 weeks old k = 0.55 for children 1 to 13 years old k = 0.55 for adolescent females 13-18 years old k = 0.7 for adolescent males 13-18 years old
• HIV-positive
• Positive leukocytotoxic crossmatch Specifically, complement dependent cytotoxicity and flow cytometric crossmatch assays must be negative, and the mean fluorescence intensity (MFI) of any anti-donor HLA antibody by solid phase immunoassay should be <3000. Consult with PI for the clinical significance of any anti-donor antibody.
• Women of childbearing potential who currently are pregnant (HCG+) or who are not practicing adequate contraception or who are breastfeeding
• Uncontrolled viral, bacterial, or fungal infections (currently taking medication and have progression of clinical symptoms)
• Patients with symptoms consistent with Respiratory syncytial virus (RSV), influenza A, B, or parainfluenza at the time of enrollment will be assayed for the above viruses and if positive are not eligible for the trial until they are no longer symptomatic (patients may have continued assay positivity for a period of time post resolution of symptoms secondary to the nature of the assay

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Haploidentical BMT with PTCy for acute leukemias and MDS; Patients with AML and MDS: Days -6 through -3: Busulfan q 5-6h IV q24h x 4 days Days -2 and -1: Cyclophosphamide 50mg/kg/day IV x 2 days+ Mesna 40 mg/kg/day IV For patients with ALL and lymphoblastic lymphoma: Days -5 through -4: Cyclophosphamide 50mg/kg/day IV q24h x 2 days+Mesna 40 mg/kg/day IV Days -3 through -1: TBI 200 Centigray (cGy) twice a day for 3 days All patients Day 0: Infuse unmanipulated bone marrow Day +3 and +4: Cyclophosphamide 50 mg/kg/day IV + Mesna 40 mg/kg IBW/day IV Day +5: Begin tacrolimus 0.015mg/kg IBW/dose IV over 4 hours q 12h and mycophenolate mofetil (MMF)15mg/kg po/IV tid with maximum daily dose 3 gm/day Day +30: Assess chimerism and disease status in bone marrow Day +35: Discontinue MMF Day +60: Assess chimerism and disease status in bone marrow Day 180: Discontinue tacrolimus

Drug: Cyclophosphamide; Chemotherapy administration; Other Names: Cy; Radiation: TBI; Radiation Therapy; Drug: Busulfan; Chemotherapy Administered; Other Names: Bu; Other: Unmanipulated Bone Marrow; Bone Marrow Transplant; Drug: Tacrolimus; Immunosuppressive Drug Administered; Other Names: tacro; Drug: Mycophenolate mofetil; Immunosuppressive Drug Administered; Other Names: MMF

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative Incidence of Non-relapse Mortality	Cumulative incidence (measured as a percentage) of non-relapse mortality at 180 days following myeloablative, Human Leukocyte Antigen (HLA)-mismatched bone marrow transplant (BMT) for patients with high risk hematologic malignancies.	Day 180

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Donor Cell Engraftment	Number of Participants with Donor Cell Engraftment at Day 60 following myeloablative, HLA-mismatched BMT.	Day 60
Cumulative Incidence of Acute Graft Versus Host Disease (GVHD) Grades 2-4 and Grades 3-4	Cumulative incidence (measured as a percentage) of acute GVHD grades 2-4 (overall) and grades 3-4 (severe).	100 days
Cumulative Incidence of Chronic GVHD	Cumulative incidence (measured as a percentage) of chronic graft versus host disease (GVHD).	2 years
Primary and Secondary Graft Failure	Incidence (measured as a percentage) of primary and secondary graft failure.	2 years
Steroid and Non-steroid Immunosuppressants	Number of participants who used steroid and non-steroid immunosuppressants to treat GVHD.	Two Years
Steroid and Non-steroid Immunosuppressants Use Duration	Duration of use of steroid and non-steroid immunosuppressants (in months) to treat GVHD.	Two Years
Survival	Estimate incidence of overall survival (OS), progression-free survival (PFS), disease-free survival (DFS), event-free survival, and relapse-free GVHD-free survival (GRFS) in patients receiving myeloablative, HLA-mismatched BMT for patients with high risk hematologic malignancies at 1 year. Incidence as a percentage.	up to 1 years
Survival	Estimate incidence of overall survival (OS), progression-free survival (PFS), disease-free survival (DFS), event-free survival, and relapse-free GVHD-free survival (GRFS) in patients receiving myeloablative, HLA-mismatched BMT for patients with high risk hematologic malignancies at 2 years. Incidence as a percentage.	up to 2 years
Immune Reconstitution	Characterize immune reconstitution post myeloablative haploidentical BMT with Post transplantation cyclophosphamide (PT/Cy).	Two Years
Time to Neutrophil and Platelet Recovery	Time to neutrophil and platelet recovery in median days	100 days
Incidence of Donor Cell Engraftment	Incidence of donor cell engraftment measured as the percentage of donor cell engraftment.	60 days

Collaborators and Investigators

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Investigators: Principal Investigator: Heather Symons, MD, MHS, SKCCC Johns Hopkins Hospital

Study record dates

Study Major Dates

• Study Start (Actual): July 2, 2015
• Primary Completion (Actual): June 15, 2018
• Study Completion (Actual): October 1, 2020

Study Registration Dates

• First Submitted: April 16, 2014
• First Submitted That Met QC Criteria: April 18, 2014
• First Posted (Estimate): April 22, 2014

Study Record Updates

• Last Update Posted (Actual): November 26, 2021
• Last Update Submitted That Met QC Criteria: November 23, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: Acute myeloid leukemia; Acute lymphoblastic leukemia; Biphenotypic leukemia; Juvenile myelomonocytic leukemia; Treatment related leukemia
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Hematologic Diseases; Hematologic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Cyclophosphamide; Tacrolimus; Mycophenolic Acid; Busulfan
• Other Study ID Numbers: J13161; NA_00091665 (Other Identifier: JHM IRB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No