Matched Unrelated Donor (MUD) Versus HLA-Haploidentical Related (Haplo) Myeloablative Hematopoietic Cell Transplantation for Children, Adolescents, and Young Adults (AYA) With Acute Leukemia or Myelodysplastic Syndrome (MDS)
Study Details
Study Description
Brief Summary
This trial will determine whether haploHCT should replace the current standard of MUD HCT. Additionally, this trial creates opportunities to explore health disparities between non-Hispanic White and minority patients by controlling for donor source. Finally, this trial will also provide insight into whether there are differences in key outcomes between post-transplant cyclophosphamide and TCRαβ+ T cell depletion, the two most frequently used strategies of haploHCT.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Detailed Description
PRIMARY OBJECTIVES:
- To compare the 1-year cumulative incidence of severe GVHD (from day of HCT) defined as Grade III-IV acute GVHD (aGVHD) and/or chronic GVHD (cGVHD) that requires systemic immunosuppression and to compare the disease free survival (DFS) (from time of randomization) in children and young adults (AYA) with acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), and Myelodysplastic Syndrome (MDS) who are randomly assigned to haploHCT or to an 8/8 adult MUD HCT.
SECONDARY OBJECTIVES:
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To compare overall survival (OS) between children and AYA with AML/ALL/MDS randomly assigned to haploHCT and MUD HCT.
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To compare differences in health-related quality of life (HRQOL) between haploHCT and MUD HCT from baseline (pre-transplant), at 6 months, 1 year and 2 years post-transplant.
EXPLORATORY OBJECTIVES:
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To compare the median time to engraftment and cumulative incidences of neutrophil engraftment at 30 and 100 days post transplant and platelet engraftment at 60 and 100 days post transplant, primary graft failure by 60 days, secondary graft failure at 1 year post transplant, Grade II-IV and III-IV acute graft versus host disease (aGVHD) requiring systemic immunosuppression at 100 days and 6 months, and cumulative incidences of non-relapse mortality (NRM), relapse, and moderate and severe chronic graft versus host disease (cGVHD) at 6 months, 1 and 2 years after haploHCT and MUD HCT.
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To estimate 1 year, 18-month and 2-year cumulative incidence of graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) with events defined as occurrence of any of the following from Day 0 of HCT: Grade III-IV acute GVHD, chronic GVHD requiring systemic immunosuppressive treatment, disease relapse or progression, and death from any cause.
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To evaluate the influence of key clinical variables: age (<13 years and 13-21.99 years), disease (ALL vs. AML vs. AML/MDS), haploHCT approach (TCRαβ+ T cell depletion vs. post-transplant cyclophosphamide(PTCy)); donor age (by ten-year increments), donor sex (maternal vs. paternal for parental donation), pre-HCT minimal residual disease status (MRD + vs MRD -); pediatric disease risk index (low, intermediate, and high, impact on OS and DFS only), conditioning regimen (chemotherapy based versus TBI based), immunosuppressive regimen (ATG exposure according to the weight and ALC dependent dosing approach vs no ATG exposure) time to transplant (interval between diagnosis/relapse and date of stem cell infusion) graft cell dose, use of relapse prevention therapy (yes or no) and weight on engraftment, OS, DFS, GRFS, relapse, transplant related mortality (TRM), aGvHD and cGvHD at 1 and 2 years after haplo and MUD HCT by performing stratified and multivariate analyses.
IV. To compare other important transplant related outcomes after haplo and MUD HCT, such as:
V. To compare immune recovery after haplo PTCy, haplo αβ T cell depletion, and MUD HCT via:
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Biobanking whole blood or serum to measure rabbit antithymocyte globulin (rATG) exposure when dosed according to weight and absolute lymphocyte count (ALC) using established pharmacokinetic and pharmacodynamics assays (after last infusion, Day -4, Day 0, Day +7)
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To compare resource utilization after haplo and MUD HCT.
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To describe and compare outcomes (neutrophil and platelet engraftment, graft failure, OS, DFS, GRFS, NRM, relapse, GvHD and HRQOL post HCT) by recipient race/ethnicity, area-based socioeconomic (SES) status, annual household income, primary spoken language and conserved transcriptional response to adversity (CTRA).
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To describe HRQoL outcomes in racial/ethnic minorities and compare HRQoL outcomes between White patients receiving haploHCT and racial/ethnic minority patients receiving haploHCT.
OUTLINE:
A phase III randomized controlled trial. Patients with both available donor sources (MUD and haplo) to Arm A (haploHCT) or Arm B (MUD-HCT). The randomization will be stratified by patient age, CR status, and disease type. Patients enrolled on this study who DO NOT have BOTH an available MUD and haplo donor but DO have a haplo donor will be assigned to Arm C and receive a nonrandomized haploHCT.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Arm A: haploHCT Patients who have both a MUD and a haplo donor available undergo Haploidentical hematopoietic cell transplantation |
Procedure: Haploidentical hematopoietic cell transplantation (haploHCT)
Patients undergo Haploidentical hematopoietic cell transplantation (haploHCT)
|
| Experimental: Arm B: MUD-HCT Patients who have both a MUD and a haplo donor available undergo Matched unrelated donor hematopoietic cell transplantation |
Procedure: matched unrelated donor hematopoietic cell transplantation (MUD-HCT)
Patients undergo Matched unrelated donor hematopoietic cell transplantation
|
| Experimental: ARM C: nonrandomized haploHCT Patients who do not have both an available MUD and haplo donor but do have a haplo donor undergo a nonrandomized haploHCT. |
Procedure: Haploidentical hematopoietic cell transplantation (haploHCT)
Patients undergo Haploidentical hematopoietic cell transplantation (haploHCT)
|
Outcome Measures
Primary Outcome Measures
- Cumulative incidence of severe GVHD [From transplant to 1 year post HCT.]
A severe GVHD event is defined as any of the following from Day 0 of HCT: Grade III-IV acute GVHD or chronic GVHD requiring systemic immunosuppressive therapy. The cumulative incidence of GVHD comparison will be performed according to the mITT principle by assigned arm.
- DFS from randomization [12 weeks post randomization]
A DFS event is defined as death from any cause, disease relapse, or imminent relapse as defined in Section 10.2. The DFS comparison will be performed according to the intention to treat (ITT) principle by assigned arm. The Kaplan-Meier method will be used to estimate the DFS for patients randomized to the two arms.
Secondary Outcome Measures
- Overall survival (OS) between haploHCT and MUD HCT. [12 weeks post randomization]
OS is defined as the time from randomization to death due to any cause. The Kaplan Meier method will be used to estimate OS. A multivariate Cox regression model will be used to compare OS between the two randomized arms, considering the stratification factors and MRD status (MRD+ vs. MRD-, known prior to HCT but post randomization.
- Generic PedsQLTM: Compare differences in health-related quality of life (HRQOL) between haploHCT and MUD HCT at 6-month, 1 year and 2 years post-transplant. [6-month, 1 year and 2 years post-transplant.]
Summary score from the Generic PedsQLTM (excluding School Functioning assessed at baseline, 6 months, 1 year, and 2 years post-transplant.
- PedsQLTM Stem Cell Transplant: Compare differences in health-related quality of life (HRQOL) between haploHCT and MUD HCT at 6-month, 1 year and 2 years post-transplant. [6-month, 1 year and 2 years post-transplant.]
Summary score from the summary score from the PedsQLTM Stem Cell Transplant module assessed at baseline, 6 months, 1 year, and 2 years post-transplant.
Other Outcome Measures
- Cumulative incidences of neutrophil engraftment [Day 30 and Day 100 post-transplant]
Neutrophil recovery is defined as achieving a donor derived ANC ≥ 500/μL for three consecutive measurements on different days. The first of the three days will be used to calculate the time to neutrophil engraftment. Probabilities of neutrophil recovery by Day 30 and Day 100 post-transplant will be described with 95% confidence intervals for each treatment group using the cumulative incidence estimate, treating death, relapse, and imminent relapse as competing events. These cumulative incidence curves will be compared between treatment groups using Gray's test.
- Cumulative incidences of platelet engraftment [Day 30 and Day 100 post-transplant]
Time to platelet engraftment is defined as the first day of a minimum of three consecutive measurements on different days such that the patient has achieved a platelet count > 20,000/μL and > 50,000/μL with no platelet transfusions in the preceding seven days. Cumulative incidence of platelet engraftment by Day 30 and Day 100 post-transplant will be described with 95% confidence intervals for each treatment group treating death, relapse, and imminent relapse as competing events. These cumulative incidence curves will be compared between treatment groups using Gray's test.
- Primary and secondary graft failure [Day 60 after transplant.]
Primary graft failure is defined as lack of donor-derived neutrophil engraftment and will be determined by day +60 after transplant. Relapse, imminent relapse, and death prior to neutrophil engraftment are considered competing risks for the endpoint of primary graft failure. Cumulative incidence of primary graft failure at day 60 and its 95% CI will be estimated for each arm. These cumulative incidence curves will be compared between treatment groups using Gray's test.
- Acute graft versus host disease (aGVHD) Grades II-IV and III-IV [Day 100 and Day 180 post-transplant]
Incidence of acute GVHD grade II-IV and grade III-IV requiring systemic immunosuppression at Days 100 and 180 will be estimated with 95% confidence intervals for each treatment group using competing risk analysis. Death, relapse, and imminent relapse prior to aGVHD are treated as competing events. Comparison of cumulative incidence will be performed using Gray's test.
- Cumulative incidence of transplant related mortality (TRM) [0.5, 1, and 2 year post HCT]
Cumulative incidence of transplant-related mortality (TRM) at 0.5, 1, and 2 year post HCT will be estimated for each treatment group treating relapse or imminent relapse as competing events. Comparison of cumulative incidence will be done using Gray's test.
- Cumulative incidence of relapse [0.5, 1, and 2 year post HCT]
Cumulative incidence of disease relapse at 0.5, 1, and 2 year post HCT will be estimated with 95% confidence intervals for each treatment group treating death and imminent relapse prior to disease relapse as competing events. Comparison of cumulative incidence will be done using Gray's test.
- Cumulative incidences of mild, moderate, and severe chronic graft versus host disease (cGVHD) [0.5, 1, and 2 year post HCT]
Cumulative incidence of mild, moderate, and severe chronic GVHD requiring systemic immunosuppression at 0.5, 1, and 2 year will be estimated separately with 95% confidence intervals for each treatment group treating death, relapse, and imminent relapse prior to chronic GVHD as a competing event. Comparison of cumulative incidence will be done using Gray's test.
- Comparison of GRFS after haploHCT and MUD HCT [1 year, 18-months and 2-year post HCT]
GRFS as defined as the time from Day 0 of HCT to onset of any of the following events: Grade III-IV acute GvHD, chronic GvHD that is STILL requiring systemic immunosuppressive treatment, disease relapse, imminent relapse, or death from any cause at 1 year, 18 months and 2 years. The Kaplan Meier method will be used to estimate the probability of GRFS by 1 year, 18-month and 2-year post HCT and the log rank test will be used to compare GRFS outcome between arms.
- Evaluate the influence of potential risk factors at baseline on primary and secondary graft failure, OS, DFS, GRFS, relapse, aGVHD and cGVHD at 1 and 2 years after haplo and MUD HCT. [1 year or 2 years after haplo and post MUD HCT]
Multivariate Cox regression models will be used to assess the effect of potential risk factors on OS, DFS, and GRFS outcomes from date of HCT. Time interaction will be considered if proportional hazard assumption is not satisfied. Multivariate Fine and Gray models will be used for GVHD and relapse outcomes to account for competing events.
- Incidence of any significant fungal infections (defined as proven or probable fungal infection) through 1 year post HCT. [1 year post HCT]
Rate per 100 patient days of any significant fungal infections (defined as proven or probable fungal infection130 according to De-Pauw et al, Appendix XII) will be estimated by HCT arm. The observation days will be from transplant date through 1 year post HCT.
- Incidence of viremia with or without end organ disease (i.e., CMV, adenovirus, EBV, HHV-6, BK) requiring hospitalization and/or systemic antiviral therapy and/or cell therapy through 1 year post HCT. [1 year post HCT]
Rate per 100 patient days of any viremia with or without end organ disease (i.e., CMV, adenovirus, EBV, HHV-6, BK) requiring hospitalization and/or systemic antiviral therapy and/or cell therapy will be estimated by HCT arm. The observation days will be from transplant date through 1 year post HCT.
- Incidence of sinusoidal obstruction syndrome (SOS) [HCT date through 100 days post HCT]
Among patients who are eligible for HCT: the incidence of SOS will be summarized by HCT arm assuming a binomial distribution using 4 different criteria to define SOS (EBMT, Cairo, Baltimore, and modified Seattle criteria), separately. The observation window is from HCT date through 100 days post HCT. Patients who drop out early or die before having an SOS event are considered as not having an SOS endpoint for this analysis.
- Incidence of transplant-associated thrombotic microangiopathy (TA-TMA) [HCT date through 100 days post HCT]
Among patients who are eligible for HCT: the incidence of TA-TMA as diagnosed by the Jodele criteria reported by HCT arm assuming a binomial distribution. The observation window is from HCT date through 100 days post HCT. Patients who drop out early or die before having a TA-TMA event are considered as not having a TA-TMA endpoint for this analysis.
- Incidence of "imminent" relapses, treatments administered, and progression to relapse. [0.5, 1, and 2 year post HCT]
Cumulative incidence of imminent relapse at 0.5, 1, and 2 year post HCT will be estimated with 95% confidence intervals for each treatment group treating death and relapse prior to imminent relapse as competing events. Comparison of cumulative incidence will be done using Gray's test.
- Pace of reconstitution of T, B, and NK cells and immunoglobulins [At 30 days, 60 days, 100 days, 180 days, and 365 days after HCT.]
The distributions of T, B, and NK cells reconstitution and immunoglobulins (IgA, IgG, IgM) are likely to be skewed, therefore, we will use a Kruskal-Wallis test to compare the median of each outcome between HCT methods (haplo PTCy, haplo αβ T cell depletion, and MUD) among the patients who have the outcome measured by 30 days, 60 days, 100 days, 180 days and 365 days after HCT.
- Response to vaccinations as determined by vaccination-specific antibody titers measured once between 12-18 months post-HSCT [Between 12-18 months post-HSCT]
Vaccination specific antibody Titer distribution is expected to be skewed. Median antibody titer will be compared between HCT methods (haplo PTCy, haplo αβ T cell depletion, and MUD) using a Kruskal-Wallis test. Titers to include diphtheria, hemophilus influenza, hepatitis B and pneumococcus.
- The impact of graft composition on GvHD, relapse, and viremia [0.5, 1, and 2 year post HCT]
Descriptive statistics (median and range) of graft composition will be reported by GVHD (yes/no), relapse (yes/no), and viremia (yes/no) in this aim.
- Compare the post HCT outcomes (primary and secondary graft rejection, graft failure, OS, DFS, GRFS, NRM, relapse, GvHD) by subject race/ethnicity, area-based SES, area-based annual household income and primary spoken language. [1 year post-transplant.]
Comparison the DFS and severe GVHD outcomes, as defined in the primary aim, between Arm C (non-randomized haplo) vs. Arm A (randomized haplo). If there are differences in outcomes, then treatment arm (Arm A vs. Arm C) will be adjusted for in our analyses to look at the influence of potential risk factors on DFS and severe GVHD
- HRQoL outcomes in racial/ethnic minorities and compare HRQoL outcomes between White patients receiving haploHCT and racial/ethnic minority patients receiving haploHCT [1 year post-transplant.]
GEE model for the mean score with an intercept, stratification factors, a main effect for treatment group (Arm A vs. Arm C), a main effect for time (1df), and an interaction between treatment group and time. This GEE model will be used to examine the trajectory of summary scores over time and estimate the difference (95%CI) in slopes of scores over time between patients receiving HAPLO Arm A and HAPLO Arm C.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Diagnosed with ALL, AML, or MDS for which an allogeneic hematopoietic stem cell transplant is indicated. For disease eligibility to proceed to transplant
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Complete Remission (CR) status will not be confirmed at the time of enrollment. CR as defined in these sections is required to proceed with the actual HCT treatment plan.
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Has not received a prior allogeneic hematopoietic stem cell transplant.
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Does not have a suitable HLA-matched sibling donor available for stem cell donation.
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Has an eligible haploidentical related family donor based on at least intermediate resolution HLA typing.
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Patients who also have an eligible 8/8 MUD adult donor based on confirmatory high resolution HLA typing are eligible for randomization to Arm A or Arm B.
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Patients who do not have an eligible MUD donor are eligible for enrollment to Arm C.
Exclusion Criteria:
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Patients with genetic disorders (generally marrow failure syndromes) prone to secondary AML/ALL with known poor outcomes because of sensitivity to alkylator therapy and/or TBI are not eligible (Fanconi Anemia, Kostmann Syndrome, Dyskeratosis Congenita, etc). Patients with Downs syndrome because of increased toxicity with intensive conditioning regimens.
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Patients with any obvious contraindication to myeloablative HCT at the time of enrollment
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Female patients who are pregnant are ineligible as many of the medications used in this protocol could be harmful to unborn children and infants
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Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation.
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All patients and/or their parents or legal guardians must sign a written informed consent.
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All institutional, FDA, and NCI requirements for human studies must be met.
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Children's Oncology Group
- National Cancer Institute (NCI)
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- ASCT2031