Graft Survival, HLA-mismatched Bone Marrow Transplantation, Myeloablative Conditioning, Transplantation, Bone Marrow
Conditions
Keywords
Acute lymphoblastic leukemia, Acute myeloid leukemia, Juvenile myelomonocytic leukemia, Treatment related leukemia, Biphenotypic leukemia
Brief summary
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%.
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.
Interventions
DRUGCyclophosphamide
Chemotherapy administration
RADIATIONTBI
Radiation Therapy
DRUGBusulfan
Chemotherapy Administered
OTHERUnmanipulated Bone Marrow
Bone Marrow Transplant
DRUGTacrolimus
Immunosuppressive Drug Administered
DRUGMycophenolate mofetil
Immunosuppressive Drug Administered
Sponsors
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Months to 25 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative Incidence of Non-relapse Mortality | Day 180 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative Incidence of Acute Graft Versus Host Disease (GVHD) Grades 2-4 and Grades 3-4 | 100 days | Cumulative incidence (measured as a percentage) of acute GVHD grades 2-4 (overall) and grades 3-4 (severe). |
| Cumulative Incidence of Chronic GVHD | 2 years | Cumulative incidence (measured as a percentage) of chronic graft versus host disease (GVHD). |
| Primary and Secondary Graft Failure | 2 years | Incidence (measured as a percentage) of primary and secondary graft failure. |
| Steroid and Non-steroid Immunosuppressants | Two Years | Number of participants who used steroid and non-steroid immunosuppressants to treat GVHD. |
| Number of Participants With Donor Cell Engraftment | Day 60 | Number of Participants with Donor Cell Engraftment at Day 60 following myeloablative, HLA-mismatched BMT. |
| Survival | up to 1 years | 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. |
| Immune Reconstitution | Two Years | Characterize immune reconstitution post myeloablative haploidentical BMT with Post transplantation cyclophosphamide (PT/Cy). |
| Time to Neutrophil and Platelet Recovery | 100 days | Time to neutrophil and platelet recovery in median days |
| Incidence of Donor Cell Engraftment | 60 days | Incidence of donor cell engraftment measured as the percentage of donor cell engraftment. |
| Steroid and Non-steroid Immunosuppressants Use Duration | Two Years | Duration of use of steroid and non-steroid immunosuppressants (in months) to treat GVHD. |
Countries
Canada, United States
Participant flow
Pre-assignment details
Three patients screen failed due to: One patient could not report on whether the marrow is cellular or at least 20 percent cellularity, one patient had poor liver function, and the one patient's Alanine aminotransferase (ALT) was over the study limit.
Participants by arm
| Arm | Count |
|---|---|
| Haploidentical BMT With PTCy for Acute Leukemias and MDS Patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (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 acute lymphocytic leukemia (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: total body irradiation (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 Cyclophosphamide: Chemotherapy administration TBI: Radiation Therapy Busulfan: Chemotherapy Administered Unmanipulated Bone Marrow: Bone Marrow Transplant Tacrolimus: Immunosuppressive Drug Administered Mycophenolate mofetil: Immunosuppressive Drug Administered | 32 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 8 |
Baseline characteristics
| Characteristic | Haploidentical BMT With PTCy for Acute Leukemias and MDS |
|---|---|
| Age, Continuous | 12 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants |
| Race (NIH/OMB) More than one race | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 18 Participants |
| Region of Enrollment Canada | 7 Participants |
| Region of Enrollment United States | 25 Participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 8 / 32 |
| other Total, other adverse events | 13 / 32 |
| serious Total, serious adverse events | 14 / 32 |
Outcome results
Primary
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.
Time frame: Day 180
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Haploidentical BMT With PTCy for Acute Leukemias and MDS | Cumulative Incidence of Non-relapse Mortality | 0 percent |
Secondary
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).
Time frame: 100 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Haploidentical BMT With PTCy for Acute Leukemias and MDS | Cumulative Incidence of Acute Graft Versus Host Disease (GVHD) Grades 2-4 and Grades 3-4 | Grades 2-4 | 10 percent |
| Haploidentical BMT With PTCy for Acute Leukemias and MDS | Cumulative Incidence of Acute Graft Versus Host Disease (GVHD) Grades 2-4 and Grades 3-4 | Grades 3-4 | 0 percent |
Secondary
Cumulative Incidence of Chronic GVHD
Cumulative incidence (measured as a percentage) of chronic graft versus host disease (GVHD).
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Haploidentical BMT With PTCy for Acute Leukemias and MDS | Cumulative Incidence of Chronic GVHD | 11 percent |
Secondary
Immune Reconstitution
Characterize immune reconstitution post myeloablative haploidentical BMT with Post transplantation cyclophosphamide (PT/Cy).
Time frame: Two Years
Population: Blood samples collected were not analyzed due to lack of funding. No data was generated.
Secondary
Incidence of Donor Cell Engraftment
Incidence of donor cell engraftment measured as the percentage of donor cell engraftment.
Time frame: 60 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Haploidentical BMT With PTCy for Acute Leukemias and MDS | Incidence of Donor Cell Engraftment | 84 percentage of donor cell engraftment |
Secondary
Number of Participants With Donor Cell Engraftment
Number of Participants with Donor Cell Engraftment at Day 60 following myeloablative, HLA-mismatched BMT.
Time frame: Day 60
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Haploidentical BMT With PTCy for Acute Leukemias and MDS | Number of Participants With Donor Cell Engraftment | 27 Participants |
Secondary
Primary and Secondary Graft Failure
Incidence (measured as a percentage) of primary and secondary graft failure.
Time frame: 2 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Haploidentical BMT With PTCy for Acute Leukemias and MDS | Primary and Secondary Graft Failure | Primary | 16 percentage of graft failure |
| Haploidentical BMT With PTCy for Acute Leukemias and MDS | Primary and Secondary Graft Failure | Secondary | 0 percentage of graft failure |
Secondary
Steroid and Non-steroid Immunosuppressants
Number of participants who used steroid and non-steroid immunosuppressants to treat GVHD.
Time frame: Two Years
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Haploidentical BMT With PTCy for Acute Leukemias and MDS | Steroid and Non-steroid Immunosuppressants | Steroid immunosuppressants | 4 Participants |
| Haploidentical BMT With PTCy for Acute Leukemias and MDS | Steroid and Non-steroid Immunosuppressants | Non-steroid immunosuppressants | 2 Participants |
Secondary
Steroid and Non-steroid Immunosuppressants Use Duration
Duration of use of steroid and non-steroid immunosuppressants (in months) to treat GVHD.
Time frame: Two Years
Population: Four participants used immunosuppressants. Four used steroids and 2 of the 4 also used non-steroid. Duration of use for 3 participants using steroids was not recorded. One participant using non-steroid was not recorded.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Haploidentical BMT With PTCy for Acute Leukemias and MDS | Steroid and Non-steroid Immunosuppressants Use Duration | Steroid immunosuppressants | 18 months |
| Haploidentical BMT With PTCy for Acute Leukemias and MDS | Steroid and Non-steroid Immunosuppressants Use Duration | Non-steroid immunosuppressants | 19 months |
Secondary
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.
Time frame: up to 2 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Haploidentical BMT With PTCy for Acute Leukemias and MDS | Survival | Relapse-free GVHD-free survival (GRFS) | 52 percent |
| Haploidentical BMT With PTCy for Acute Leukemias and MDS | Survival | overall survival (OS) | 73 percent |
| Haploidentical BMT With PTCy for Acute Leukemias and MDS | Survival | progression-free survival (PFS) | 64 percent |
| Haploidentical BMT With PTCy for Acute Leukemias and MDS | Survival | disease-free survival (DFS) | 64 percent |
| Haploidentical BMT With PTCy for Acute Leukemias and MDS | Survival | event-free survival | 64 percent |
Secondary
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.
Time frame: up to 1 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Haploidentical BMT With PTCy for Acute Leukemias and MDS | Survival | overall survival (OS) | 77 percent |
| Haploidentical BMT With PTCy for Acute Leukemias and MDS | Survival | progression-free survival (PFS) | 68 percent |
| Haploidentical BMT With PTCy for Acute Leukemias and MDS | Survival | disease-free survival (DFS) | 68 percent |
| Haploidentical BMT With PTCy for Acute Leukemias and MDS | Survival | event-free survival | 68 percent |
| Haploidentical BMT With PTCy for Acute Leukemias and MDS | Survival | Relapse-free GVHD-free survival (GRFS) | 65 percent |
Secondary
Time to Neutrophil and Platelet Recovery
Time to neutrophil and platelet recovery in median days
Time frame: 100 days
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Haploidentical BMT With PTCy for Acute Leukemias and MDS | Time to Neutrophil and Platelet Recovery | neutrophil | 22 days |
| Haploidentical BMT With PTCy for Acute Leukemias and MDS | Time to Neutrophil and Platelet Recovery | platelet | 21 days |