Acute Lymphoblastic Leukemia, Acute Myelocytic Leukemia, Chronic Myelocytic Leukemia, Hodgkin or Non-Hodgkin Lymphoma, Juvenile Myelomonocytic Leukemia, Myelodysplastic Syndrome, Sarcoma, Myeloid
Conditions
Keywords
Hematologic malignancy, Hematopoietic cell transplant
Brief summary
The primary aim of this protocol is to evaluate if the one-year survival is significantly improved in the group of patients who receive a T-cell replete haploidentical donor hematopoietic cell transplant (HCT) with a novel reduced intensity conditioning regimen. Study population will consist of patients (21 years or under) with hematologic malignancies that have relapsed or are refractory after prior allogeneic transplant. Toxicity will be evaluated by the rate of transplant related mortality and the rates of moderate and severe graft-versus-host disease (GvHD) at day 100. The investigators will describe event-free, and disease-free survival at one year, as well as the rates of hematopoietic recovery and donor engraftment and study comprehensively immune reconstitution following T-cell replete haploidentical transplantation.
Detailed description
Patients with refractory hematologic malignancies, including those who develop recurrent disease after allogeneic hematopoietic cell transplantation, have a dismal prognosis. Historically, both regimen-related mortality and disease recurrence have been significant causes of treatment failure in this heavily pre-treated patient population. Our institution has utilized mismatched family member (haploidentical) donors for these patients for a number of years for the following reasons: (1) Only 30% of patients have matched related donors available; (2) transplantation can be performed more rapidly since the time to unrelated donor transplantation averages 3 to 4 months; (3) no other curative treatment options are available. These therapeutic interventions have been largely successful given the dismal prognosis in this patient group; however disease recurrence remains the most significant cause of treatment failure. To provide maximum benefit for this challenging population, the goals of a therapeutic transplant protocol should include: (1) a conditioning regimen that is well tolerated, even in a heavily pre-treated population; but it should also provide substantial antileukemia effects, and (2) should establish rapid immune recovery such that the patient may benefit from graft versus leukemia effect and early protection from life threatening infections while also limiting dangerous and counter-productive graft versus host disease. The primary aim of this protocol will be to evaluate if the one-year survival is significantly improved in the group of patients receiving T-cell replete haploidentical donor HCT with a novel clofarabine, cytarabine, busulfan, plerixafor, cyclophosphamide, and ATG based reduced intensity conditioning regimen whose hematologic malignancy has relapsed or is refractory after prior allogeneic transplant. Toxicity will be evaluated by the rate of transplant related mortality and the rates of moderate and severe graft versus host disease at day 100. The investigators will also describe event-free, and disease-free survival at one year, as well as the rates of hematopoietic recovery and donor engraftment. Additionally, the investigators will study comprehensively immune reconstitution following T-cell replete haploidentical transplantation. PRIMARY OBJECTIVE: * Evaluate if the one-year survival is significantly improved in a group of children receiving a therapeutic regimen for high-risk hematologic malignancy that is relapsed or refractory despite previous allogeneic hematopoietic cell transplantation (HCT) using a novel reduced intensity conditioning and T-cell replete haploidentical donor hematopoietic stem cell plus NK cell transplantation. SECONDARY OBJECTIVES: * Estimate the incidence of malignant relapse, event-free survival, and disease free survival (DFS) at one-year post-transplantation. * Estimate incidence and severity of acute and chronic (GVHD). * Estimate the rate of transplant related mortality (TRM) in the first 100 days after transplantation.
Interventions
DRUGclofarabine
Given on Day -9 and Day -8 (Day 0 is first stem cell infusion). Drug class: antineoplastic agent
DRUGcytarabine
Given on Day -9 and Day -8 (Day 0 is first stem cell infusion). Drug class: antineoplastic agent
DRUGbusulfan
Given on Day -7 and Day -6 (Day 0 is first stem cell infusion). Drug class: antineoplastic agent
DRUGPlerixafor
Given on Day -7 and Day -6 (Day 0 is first stem cell infusion). Drug class: Hematopoietic Stem Cell Mobilizer
DRUGcyclophosphamide
Given on Day -5 and Day +4 (Day 0 is first stem cell infusion). Drug class: antineoplastic agent; immunosuppressive agent.
Given on Day -4, Day -3, Day -2, and Day -1 (Day 0 is first stem cell infusion). Drug class: immunosuppressive agent.
BIOLOGICALstem cells
Patients undergo T cell replete Hematopoietic stem cell infusion on Day 0 and Day +1. Patients undergo natural killer (NK) cell transplantation on day +6 (Day 0 is first stem cell infusion).
DRUGTacrolimus
Given on Day +11 (Day 0 is first stem cell infusion). Drug class: immunosuppressive agent.
DRUGmycophenolate mofetil
Given on Day +11 (Day 0 is first stem cell infusion). Drug class: immunosuppressive agent.
Sponsors
Assisi Foundation
St. Jude Children's Research Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 21 Years
Healthy volunteers
No
Inclusion criteria
- for transplant recipient: * Age less than 21 years. * One of the following hematologic malignancies that has relapsed or remains refractory after prior allogeneic HCT: * Acute lymphoblastic leukemia (ALL) * Acute myeloid leukemia (AML) (including myeloid sarcoma) * Chronic myelogenous leukemia (CML), juvenile myelomonocytic leukemia (JMML), myelodysplastic syndrome (MDS), Hodgkin or non-Hodgkin lymphoma (NHL) * Has a suitable single haplotype matched (≥ 3 of 6) family member donor. * Does not have any other active malignancy other than the one for which this transplant is indicated. * If prior central nervous system (CNS) leukemia, it must be treated and have no evidence of CNS disease * Does not have current uncontrolled bacterial, fungal, or viral infection per the judgment of the principal investigator. * Patient must fulfill pre-transplant evaluation: * Left ventricular ejection fraction greater than 40%, or shortening fraction greater than or equal to 25%. * Creatinine clearance or Glomerular Filtration Rate of ≥70 ml/min/1.73m\^2. * Forced vital capacity (FVC) ≥ 40% of predicted value; or pulse oximetry ≥ 92% on room air if patient is unable to perform pulmonary function testing. * Karnofsky or Lansky (age-dependent) performance score ≥ 50. * Total bilirubin ≤ 1.5 times the upper limit of normal for age. * Alanine aminotransferase (ALT) ≤ 3 times the upper limit of normal for age. * Not pregnant. If female with child bearing potential, must be confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment. * Not breast feeding. * Does not have active acute bronchiolitis obliterans or bronchiolitis obliterans organizing pneumonia. Inclusion Criteria - for donor: * At least single haplotype matched (≥ 3 of 6) family member, * At least 18 years of age. * Human immunodeficiency virus (HIV) negative. * Not pregnant as confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment (if female). * Not breast feeding. * A suitable donor is identified as either: * Has completed the process of donor eligibility determination as outlined in 21 CFR 1271 and agency guidance; OR * Does not meet 21 CFR 1271 eligibility requirements, but has a declaration of urgent medical need completed by the principal investigator or physician sub-investigator per 21 CFR 1271.
Exclusion criteria
* Does not meet above inclusion criteria.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| One-year Survival (OS) | One year post transplant | Evaluate the number of participants alive at 1 year. The number of participants surviving to one-year post-transplantation is given. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Event-Free Survival (EFS) | one year post transplant | Estimate the EFS at one-year post-transplantation. The event is defined as relapse or death due to any cause. The number of participants who were alive without relapse at one year post-transplant is reported. |
| Disease-Free Survival (DFS) | one year post transplant | Estimate the DFS at one-year post-transplantation. The event is defined as relapse or death due to relapse. The number of participants who did not relapse up to one year post transplant is reported. |
| Incidence of Malignant Relapse | One year post transplantation. | Estimate the incidence of malignant relapse at one year post-transplant. The number of participants with malignant relapse or progressive disease is given. Relapse was evaluated using standard WHO criteria for each disease. |
| Incidence and Severity of Chronic Graft Versus Host Disease (GVHD) | 100 days post transplant | The severity of chronic GVHD will be described. Chronic GVHD was evaluated using NIH Consensus Global Severity Scoring. The number of participants with chronic GVHD is given, organized by severity. |
| Number of Participants With Transplant Related Mortality (TRM) | 100 days post transplant | The number of participants who died due to TRM in the first 100 days post-transplant is given. |
| Incidence and Severity of Acute Graft Versus Host Disease (GVHD) | 100 days post transplant | The number of participants with acute GVHD is given, organized by grade. Participants are graded on a scale from 1 to 4, with 1 being mild and 4 being severe. |
Countries
United States
Participant flow
Recruitment details
Thirty four participants were enrolled at St. Jude Children's Research Hospital between August 2012 and November 2014.
Pre-assignment details
Of the 34 participants enrolled on the study, 17 were donors. Donors did not receive treatment and are not followed for data collection to answer the study objectives. They are therefore not included in the results reported here.
Participants by arm
| Arm | Count |
|---|---|
| Treatment Study participants (excluding donors) who were enrolled and underwent transplant. Donors did not receive treatment and are not followed for data collection to answer the study objectives. They are therefore not included in the results reported here. | 17 |
| Total | 17 |
Baseline characteristics
| Characteristic | Treatment |
|---|---|
| Age, Continuous | 6.97 years |
| Gender Female | 9 Participants |
| Gender Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 17 / 17 |
| serious Total, serious adverse events | 10 / 17 |
Outcome results
Primary
One-year Survival (OS)
Evaluate the number of participants alive at 1 year. The number of participants surviving to one-year post-transplantation is given.
Time frame: One year post transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment | One-year Survival (OS) | 7 participants |
Secondary
Disease-Free Survival (DFS)
Estimate the DFS at one-year post-transplantation. The event is defined as relapse or death due to relapse. The number of participants who did not relapse up to one year post transplant is reported.
Time frame: one year post transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment | Disease-Free Survival (DFS) | 7 participants |
Secondary
Event-Free Survival (EFS)
Estimate the EFS at one-year post-transplantation. The event is defined as relapse or death due to any cause. The number of participants who were alive without relapse at one year post-transplant is reported.
Time frame: one year post transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment | Event-Free Survival (EFS) | 4 participants |
Secondary
Incidence and Severity of Acute Graft Versus Host Disease (GVHD)
The number of participants with acute GVHD is given, organized by grade. Participants are graded on a scale from 1 to 4, with 1 being mild and 4 being severe.
Time frame: 100 days post transplant
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment | Incidence and Severity of Acute Graft Versus Host Disease (GVHD) | No Acute GVHD | 9 participants |
| Treatment | Incidence and Severity of Acute Graft Versus Host Disease (GVHD) | Grade I | 3 participants |
| Treatment | Incidence and Severity of Acute Graft Versus Host Disease (GVHD) | Grade II | 1 participants |
| Treatment | Incidence and Severity of Acute Graft Versus Host Disease (GVHD) | Grade III | 3 participants |
| Treatment | Incidence and Severity of Acute Graft Versus Host Disease (GVHD) | Grade IV | 1 participants |
Secondary
Incidence and Severity of Chronic Graft Versus Host Disease (GVHD)
The severity of chronic GVHD will be described. Chronic GVHD was evaluated using NIH Consensus Global Severity Scoring. The number of participants with chronic GVHD is given, organized by severity.
Time frame: 100 days post transplant
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment | Incidence and Severity of Chronic Graft Versus Host Disease (GVHD) | No Chronic GVHD | 15 participants |
| Treatment | Incidence and Severity of Chronic Graft Versus Host Disease (GVHD) | Mild | 0 participants |
| Treatment | Incidence and Severity of Chronic Graft Versus Host Disease (GVHD) | Moderate | 2 participants |
| Treatment | Incidence and Severity of Chronic Graft Versus Host Disease (GVHD) | Severe | 0 participants |
Secondary
Incidence of Malignant Relapse
Estimate the incidence of malignant relapse at one year post-transplant. The number of participants with malignant relapse or progressive disease is given. Relapse was evaluated using standard WHO criteria for each disease.
Time frame: One year post transplantation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment | Incidence of Malignant Relapse | 10 participants |
Secondary
Number of Participants With Transplant Related Mortality (TRM)
The number of participants who died due to TRM in the first 100 days post-transplant is given.
Time frame: 100 days post transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment | Number of Participants With Transplant Related Mortality (TRM) | 2 participants |