Repeat Transplantation for Relapsed or Refractory Hematologic Malignancies Following Prior Transplantation

Study Overview
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Brief Summary
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This pilot phase II trial studies how well a new reduced intensity conditioning regimen that includes haploidentical donor NK cells followed by the infusion of selectively T-cell depleted progenitor cell grafts work in treating younger patients with hematologic malignancies that have returned after or did not respond to treatment with a prior transplant. Giving chemotherapy and natural killer cells before a donor progenitor cell transplant may help stop the growth of cells in the bone marrow, including normal blood-forming cells (progenitor cells) and cancer cells. It may also stop the patient's immune system from rejecting the donor's cells. When the healthy progenitor cells from a related donor are infused into the patient they make red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells (called graft-versus-host disease). Removing specific T cells from the donor cells before the transplant may prevent this.

Detailed Description
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PRIMARY OBJECTIVE: To estimate engraftment by day +42 post-transplant in patients who receive CD45RA-depleted haploidentical donor progenitor cell transplantation following reduced intensity conditioning regimen that includes haploidentical natural killer (NK) cells. SECONDARY OBJECTIVES: Estimate the incidence of malignant relapse, event-free survival, and overall survival 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. Blood progenitor cells will be collected from adult donors to be used for transplantation. Donor cells will be processed and filtered in a laboratory at St. Jude using a machine called the CliniMACS™ device, and later infused (transplanted) into the participant through his/her veins. Participants undergo a conditioning regimen beginning Day 21 prior to progenitor cell transplantation that includes chemotherapy medications and natural killer cells in preparation for transplantation. They will then receive T-cell depleted HPC transplant followed by CD45RA-depleted HPC transplant the following day.

Official Title
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CD45A-Depleted Haploidentical Hematopoietic Progenitor Cell and Natural Killer Cell Transplantation for Hematologic Malignancies Relapsed or Refractory Despite Prior Transplantation

Conditions
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Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Myeloid Sarcoma, Chronic Myelogenous Leukemia (CML), Juvenile Myelomonocytic Leukemia (JMML), Myelodysplastic Syndrome (MDS), Non-Hodgkin Lymphoma (NHL)

Intervention / Treatment
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* Drug: Cyclophosphamide
* Drug: Fludarabine
* Biological: G-CSF
* Biological: Interleukin-2
* Drug: Melphalan
* Drug: Thiotepa
* Drug: Rituximab
* Biological: Natural killer cell therapy
* Biological: T-cell depleted HPC transplant
* Biological: CD45RA-depleted HPC transplant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age less than or equal to 21 years. One of the following hematologic malignancies that has relapsed or remains refractory after prior allogeneic hematopoietic cell transplant (HCT): ALL, AML, Myeloid Sarcoma, CML, Juvenile myelomonocytic leukemia (JMML), myelodysplastic syndrome (MDS), 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 in CNS complete remission (CR) Does not have current uncontrolled bacterial, fungal, or viral infection. Patient must fulfill pre-transplant evaluation: Left ventricular ejection fraction > 40%, or shortening fraction ≥ 25%. Creatinine clearance (CrCl) or glomerular filtration rate (GFR) ≥ 50 ml/min/1.73m2. 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 (See Appendix A). Bilirubin ≤ 3 times the upper limit of normal for age. Alanine aminotransferase (ALT) ≤ 5 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 DONOR: At least single haplotype matched (≥ 3 of 6) family member DONOR: At least 18 years of age. DONOR: HIV negative. DONOR: Not pregnant as confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment (if female). DONOR: Not breast feeding. DONOR: Regarding donation eligibility, is identified as either: 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.

Ages Eligible for Study
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Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Participants<br>Participants undergo a conditioning regimen with cyclophosphamide, fludarabine, aldesleukin (interleukin-2), natural killer cell therapy, anti-thymocyte globulin, rituximab, thiotepa, and melphalan prior to transplantation of T-cell depleted HPC transplant on day 0 and CD45RA-depleted HPC transplant on day 1. Beginning Day 6 post-transplant, patients receive G-CSF daily until ANC recovers to normal level. | Drug: Cyclophosphamide<br>* Given intravenously (IV)<br>* Other names: Cytoxan;Drug: Fludarabine<br>* Given IV<br>* Other names: Fludarabine monophosphate;Biological: G-CSF<br>* Given IV or subcutaneously (SQ)<br>* Other names: Neupogen®;Biological: Interleukin-2<br>* Given SQ<br>* Other names: Aldesleukin;Drug: Melphalan<br>* Given IV<br>* Other names: Alkeran®;Drug: Thiotepa<br>* Given IV<br>* Other names: TSPA;Drug: Rituximab<br>* Given IV<br>* Other names: Rituxan™;Biological: Natural killer cell therapy<br>* Given IV<br>* Other names: NK cell therapy;Biological: T-cell depleted HPC transplant<br>* T-cell depleted hematopoietic stem cells will be infused on day 0.<br>* Other names: HPC,A Infusion(ɑ/β T cell depleted);Biological: CD45RA-depleted HPC transplant<br>* CD45RA depleted stem cells will be infused on day 1.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Engrafted by Day 42 Post-transplant | To estimate engraftment by day +42 post-transplant in patients who receive CD45RA-depleted haploidentical donor progenitor cell transplantation following reduced intensity conditioning regimen that includes haploidentical NK cells. Engraftment is defined as the first of 3 consecutive tests performed on different days of an ANC ≥ 500/mm^3 with evidence of donor cell engraftment. | Day 42 post transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Malignant Relapse | The estimate of cumulative incidence of relapse will be estimated using Kalbfleisch-Prentice method. Death is the competing risk event. The number of participants with incidence of malignant relapse is given. Relapse was evaluated using standard WHO criteria for each disease. | one year post transplantation | 
| Event-free Survival (EFS) | The Kaplan-Meier estimate of event-free survival (EFS) along with their standard errors will be calculated using the SAS macro (bmacro251-Excel2007\kme) available in the Department of Biostatistics at St. Jude, where EFS = min (date of last follow-up, date of relapse, date of graft failure, date of death due to any cause) - date of transplant, and all participants surviving at the time of analysis without events will be censored. The number of participants who did not experience any of these events through one year post-transplant is given. | one year post transplantation | 
| Overall Survival (OS) | The Kaplan-Meier estimate of OS along with their standard errors will be calculated using the SAS macro (bmacro251-Excel2007\kme) available in the Department of Biostatistics at St. Jude, where OS = min (date of last follow-up, date of death) - date of transplant and all participants surviving at the time of analysis without events will be censored. The number of participants surviving to one-year post-transplantation is given. | one year post transplantation | 
| Incidence and Severity of Acute GvHD | The cumulative incidence of acute GvHD will be estimated using Kalbfleisch-Prentice method. Death is the competing risk event. The severity of acute GvHD. The number of participants with incidence by grade is given. Participants are graded on a scale from 1 to 4, with 1 being mild and 4 being severe. | 100 days post transplantation | 
| Incidence and Severity of Chronic GvHD | The cumulative incidence of chronic GvHD will be estimated using Kalbfleisch-Prentice method. Death is the competing risk event. The severity of chronic GvHD will be described. Chronic GvHD was evaluated using NIH Consensus Global Severity Scoring. The number of participants with incidence by severity is given. | one year post transplantation | 
| Rate of Transplant-related Mortality (TRM) | The cumulative incidence of transplant related mortality will be estimated using Kalbfleisch-Prentice method. Deaths before day 100 because of other reasons are the competing risk events. | 100 days post transplantation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hematological malignancies, Allogeneic hematopoietic cell transplant, Refractory hematologic malignancy, Relapsed hematologic malignancy