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Patients receive a myeloablative conditioning regimen with PTCy or alpha beta T cell depletion at the discretion of the treating provider. Patients then undergo haploHCT on day 0. Patients undergoing myeloablative conditioning regimen with PTCy also receive GVHD prophylaxis on days 3-5. Patients undergo lumbar puncture, bone marrow aspiration, and ECHO or MUGA during screening. Patients also undergo collection of blood throughout the trial.

Patients receive a TBI-based or chemotherapy-based myeloablative conditioning regimen between days -9 and -2, followed by MUD-HCT on day 0. Patients then receive GVHD prophylaxis regimen on days 1-11. Patients undergo lumbar puncture, bone marrow aspiration, and ECHO or MUGA during screening. Patients also undergo collection of blood throughout the trial.

Patients who only have a haplo donor receive a myeloablative conditioning regimen with PTCy or alpha beta T cell depletion at the discretion of the treating provider. Patients then undergo haploHCT on day 0. Patients undergoing myeloablative conditioning regimen with PTCy also receive GVHD prophylaxis on days 3-5. Patients undergo lumbar puncture, bone marrow aspiration, and ECHO or MUGA during screening. Patients also undergo collection of blood throughout the trial.

Biospecimen Collection

Bone Marrow Aspiration

Echocardiography

Haploidentical Hematopoietic Cell Transplantation

Lapine T-Lymphocyte Immune Globulin

Lumbar Puncture

Matched Unrelated Donor Hematopoietic Cell Transplantation

Multigated Acquisition Scan

Mycophenolate Mofetil

Receive myeloablative conditioning regimen

Myeloablative Conditioning

Quality-of-Life Assessment

Questionnaire Administration

Undergo haploHCT with alpha beta T cell depletion

T-Cell Depletion Therapy

Total-Body Irradiation

Site Public Contact

Joseph H. Chewning

Mohamad G. Sinno

David L. Becton

Anna B. Pawlowska

Albert Kheradpour

Nahal R. Lalefar

Orly R. Klein

Lena E. Winestone

Michael R. Verneris

Aron Flagg

Emi H. Caywood

William B. Slayton

Julio C. Barredo

Jorge R. Galvez Silva

Fouad M. Hajjar

Natalie A. Booth

Sonali Chaudhury

Toshihiro Onishi

Rajat Sharma

William T. Tse

Lolie C. Yu

Heather J. Symons

Gregory A. Yanik

Sureyya Savasan

Kathleen J. Yost

Mira Kohorst

Dereck Davis

Ibrahim A. Ahmed

Shalini Shenoy

Christine Camacho-Bydume

Alice Lee

Clare J. Twist

Jonathan D. Fish

Gloria P. Contreras Yametti

Jeffrey R. Andolina

Jessica C. Hochberg

Jessica M. Sun

Rabi Hanna

Rene Y. McNall-Knapp

Lisa M. McGregor

Michelle P. Hudspeth

Jennifer A. Domm

Carrie L. Kitko

Stanton C. Goldman

Victor M. Aquino

Richard P. Howrey

Erin Doherty

Jose M. Esquilin

Joseph G. Dolan

Elizabeth Krieger

Kenneth B. De Santes

Bhavna Padhye

Ashley Chopek

Joerg A. Krueger

Henrique N. Bittencourt

Heather J Symons

This phase III trial compares hematopoietic (stem) cell transplantation (HCT) using mismatched related donors (haploidentical \[haplo\]) versus matched unrelated donors (MUD) in treating children, adolescents, and young adults with acute leukemia or myelodysplastic syndrome (MDS). HCT is considered standard of care treatment for patients with high-risk acute leukemia and MDS. In HCT, patients are given very high doses of chemotherapy and/or radiation therapy, which is intended to kill cancer cells that may be resistant to more standard doses of chemotherapy; unfortunately, this also destroys the normal cells in the bone marrow, including stem cells. After the treatment, patients must have a healthy supply of stem cells reintroduced or transplanted. The transplanted cells then reestablish the blood cell production process in the bone marrow. The healthy stem cells may come from the blood or bone marrow of a related or unrelated donor. If patients do not have a matched related donor, doctors do not know what the next best donor choice is. This trial may help researchers understand whether a haplo related donor or a MUD HCT for children with acute leukemia or MDS is better or if there is no difference at all.

PRIMARY OBJECTIVE:

I. To compare the 1-year cumulative incidence of severe Graft Versus Host Disease (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), mixed phenotype acute leukemia (MPAL), and myelodysplastic syndrome (MDS) who are randomly assigned to haploHCT or to an 8/8 adult MUD-HCT.

SECONDARY OBJECTIVES:

I. To compare overall survival (OS) between children and AYA with AML/ALL/MPAL/MDS randomly assigned to haploHCT and MUD HCT.

II. 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:

I. 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 transplant-related mortality (TRM), relapse, and moderate and severe chronic graft versus host disease (cGVHD) at 6 months, 1 and 2 years after haploHCT and MUD HCT.

II. 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.

IIa. To compare "chronic GVHD" (GRFS) after haploHCT and MUD HCT using landmark definitions.

IIb. To compare "current" GRFS is defined as the time to onset of any of the following events from Day 0 of HCT: Grade III-IV acute GVHD, chronic GVHD that is STILL requiring systemic immunosuppressive treatment, disease relapse or progression, death from any cause at 18 months and 2 years.

III. To evaluate the influence of key clinical variables: age (\<13 years and 13-21.99 years), disease (ALL/MPAL versus \[vs.\] AML/MDS), haploHCT approach (TCR alpha beta + 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 total-body irradiation \[TBI\] based), immunosuppressive regimen (anti-thymocyte globulin \[ATG\] exposure according to the weight and absolute lymphocyte count \[ALC\] 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:

IVa. Incidence of any significant fungal infections (defined as proven or probable fungal infection) through 1 year post HCT; IVb. Incidence of viremia with or without end organ disease (i.e. cytomegalovirus \[CMV\], adenovirus, Epstein-Barr virus \[EBV\], human herpesvirus 6 \[HHV-6\], BK) requiring hospitalization and/or systemic antiviral therapy and/or cell therapy through 1 year post HCT; IVc. Incidence of sinusoidal obstruction syndrome (SOS) through 100 days post HCT; IVd. As defined by the Cairo criteria; IVe. To compare the incidence and outcome of SOS when different criteria are used (European Bone Marrow Transplant \[EBMT\], Cairo, Baltimore, and modified Seattle criteria); IVf. Incidence of transplant-associated thrombotic microangiopathy (TA-TMA) through 100 days post HCT.

V. To compare immune recovery after haplo PTCy, haplo alpha-beta T cell depletion, and MUD HCT via:

Va. Pace of reconstitution of T, B, and natural killer (NK) cells and immunoglobulins at 30 days, 60 days, 100 days, 180 days and 365 days after HCT; Vb. Response to vaccinations as determined by vaccination-specific antibody titers at 12-18 months post hematopoietic stem cell transplant (HSCT); Vc. Biobanking blood or marrow to analyze the impact of graft composition on GvHD, relapse and viremia; Vd. Biobanking whole blood and serum to compare immune recovery using extended immune phenotyping and immune functional assessments.

VI. 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).

VII. To compare resource utilization after haplo and MUD HCT. VIIa. Length of HCT hospital stay from Day 0 and readmissions within the first 100 days (number of readmissions, duration, and reason).

VIIb. Inpatient costs within the first 100 days and at 2 years post HCT. VIII. To describe and compare outcomes (neutrophil and platelet engraftment, graft failure, OS, DFS, GRFS, NRM, relapse, GvHD and health-related quality of life \[HRQOL\] post HCT) by recipient race/ethnicity, annual household income, primary spoken language and conserved transcriptional response to adversity (CTRA).

IX. To describe HRQoL outcomes in racial/ethnic minorities and compare HRQoL outcomes between White patients receiving haploHCT and racial/ethnic minority patients receiving haploHCT.

X. To assess the feasibility of incorporating total body irradiation (TBI) delivered with volumetric modulated arc therapy (VMAT) or tomotherapy into a multi-institutional study, to describe the toxicities and oncologic outcomes (relapse, DFS, OS, and TRM) of the subgroup of patients treated with this approach, and to compare these outcomes to those of patients treated with conventional TBI.

OUTLINE: Patients who have both a MUD and haplo donor are randomized to Arm A or Arm B. Patients who only have a haplo donor are nonrandomly assigned to Arm C.

ARM A: Patients receive a haplo HCT following a TBI- based or chemotherapy-based myeloablative conditioning regimen with PTCy or alpha beta T cell depletion (center's choice). When PTCy is used, it Is administered on days 3 and 4 after HCT and additional immunsouppression is started on day 5 after SCT.

ARM B: Patients receive a MUD HCT following a TBI-based or chemotherapy-based myeloablative conditioning regimen between days -9 and -2 Patients then receive GVHD prophylaxis on days 1-11.

ARM C: Patients receive a haploHCT following a TBI-based or chemotherapy-based myeloablative conditioning regimen with PTCy or alpha beta T cell depletion (center's choice). When PTCy is used, it Is administered on days 3 and 4 after HCT and additional immunsouppression is started on day 5 after SCT.

Patients in all arms undergo standard HCT screening prior to transplant including disease evaluation (lumbar puncture, bone marrow aspiration), and organ function evaluation including but not limited to echocardiogram (ECHO) or multigated acquisition scan (MUGA), PFTS, and bloodwork.Patients also undergo collection of blood throughout the trial.

After completion of study treatment, patients are followed periodically for up to 5 years from HCT.

Mismatched Related Donor Versus Matched Unrelated Donor Stem Cell Transplantation for Children, Adolescents, and Young Adults With Acute Leukemia or Myelodysplastic Syndrome

A Multi-Center, Phase 3, Randomized Trial of 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)

We will estimate the cumulative incidences of neutrophil engraftment by Day 30 and Day 100 post-HCT and corresponding 95% confidence intervals among enrolled, eligible patients randomized to either the Haplo or MUD arm and who undergo HCT.

We will estimate cumulative incidences of platelet engraftment by Day 30 and Day 100 post-HCT and corresponding 95% confidence intervals among enrolled, eligible patients randomized to either the Haplo or MUD arms and who undergo HCT.

Primary (defined as lack of donor-derived neutrophil engraftment) and secondary graft failure (defined as initial donor-derived neutrophil engraftment followed by subsequent decline in ANC to \< 500/μL with loss of donor chimerism to \< 10% donor CD3 in peripheral blood or bone marrow). We will estimate cumulative incidences of primary and separately, secondary graft failure by Day 60 post-HCT and corresponding 95% confidence intervals among enrolled, eligible patients randomized to either Haplo or MUD arms and who undergo HCT.

We will estimate cumulative incidences of Grade II-IV aGVHD and separately, Grade III-IV aGVHD by Days 100 and 180 post-HCT and corresponding 95% confidence intervals among enrolled, eligible patients randomized to either Haplo or MUD arms and who undergo HCT.

We will estimate cumulative incidences of transplant-related mortality by 6-months, 1-year, and 2-years post-HCT and corresponding 95% confidence intervals among enrolled, eligible patients randomized to either Haplo or MUD arms and who undergo HCT.

We will estimate cumulative incidences of relapse by 6-months, 1-year, and 2-years post-HCT and corresponding 95% confidence intervals among enrolled, eligible patients randomized to either Haplo or MUD arms.

We will estimate cumulative incidences of GRFS events using all three definitions by 1-year, 18-months, and 2-years post-HCT and corresponding 95% confidence intervals among enrolled, eligible patients randomized to either Haplo or MUD arms and who undergo HCT.

We will estimate cumulative incidences of mild, moderate, and severe cGvHD by 6-months, 1-year, and 2-years post-HCT and corresponding 95% confidence intervals among enrolled, eligible patients randomized to either Haplo or MUD arms and who undergo HCT.

We will estimate the cumulative incidence of significant fungal infections by 1-year post-HCT and the corresponding 95% confidence interval among enrolled, eligible patients randomized to either Haplo or MUD arms.

We will estimate the cumulative incidence of viremia by 1-year post-HCT and the corresponding 95% confidence interval among enrolled, eligible patients randomized to either Haplo or MUD arms.

We will estimate the proportion of patients experiencing SOS under the separate definitions by 100-days post-HCT and the corresponding 95% confidence interval among enrolled, eligible patients randomized to either Haplo or MUD arms.

We will estimate the proportion of TA-TMA events up-to 100-days post-HCT and the corresponding 95% confidence interval among enrolled, eligible patients randomized to either Haplo or MUD arms and who undergo HCT.

We will estimate the median of the distribution of T, B, NK cells, and immunoglobulins among patients given each of three HCT methods (Haplo PTCy, Haplo alpha-beta T-cell depletion, and MUD).

We will estimate theedian antibody titer among patients given each of three HCT methods (haplo PTCy, haplo alpha-beta T-cell depletion, and MUD).

The average proportion of days spent hospitalized will be computed for patients randomized to the Haplo and MUD arms and corresponding 95% confidence intervals will be reported. The median inpatient PHIS adjusted costs by day 100 and 2-years post-HCT will be calculated for patients randomized to Haplo and MUD arms.

Will be assessed by quality assurance monitoring. Will review treatment plans along with treatment received using data submitted to IROC and will describe the proportion of patients whose planned and actual TBI treatments align among those who received VMAT or tomotherapy. Will quantify the proportion of patients receiving VMAT or tomotherapy TBI who experience serious adverse events (defined as any AE reported through CTEP-AERS) and, separately, who experience any unexpected AE. Will estimate the cumulative incidence of death or relapse (DFS as a composite event) as well as death and relapse separately, and TRM by 0.5, 1, and 2-years year post-transplant from the time of starting TBI among those who receive VMAT or tomotherapy. For relapse and TRM, competing risk analysis will be used, as described under 9.3.5.1. 95% confidence intervals for each of these point estimates will also be provided.

We will estimate the cumulative incidence of severe GVHD at 1-year post-HCT and corresponding 95% confidence interval among enrolled and eligible patients randomly assigned to either HAPLO or MUD arms who actually undergo HCT.

We will estimate the cumulative incidence at 1 year post randomization and the corresponding 95% confidence interval among all enrolled and eligible patients randomly assigned to either HAPLO or MUD arms.

We will estimate the cumulative incidence of all-cause mortality events up-to 1-year post-HCT and the corresponding 95% confidence interval among all enrolled, eligible, randomized patients.

For enrolled, eligible patients who consent to optional QoL studies, we will estimate the mean PedsQL score (excluding School Functioning) among patients randomized to the Haplo arm, the MUD arm, and among patients who enroll to arm C. For each, we will also calculate a corresponding 95% confidence interval.

For enrolled, eligible patients who consent to optional QoL studies, we will estimate the mean PedsQL Stem Cell Transplant module score among patients randomized to the Haplo arm and the MUD arm, and among patients who enroll to arm C. For each, we will calculate a corresponding 95% confidence interval.

Children's Oncology Group

Spots Global Cancer Trial Database for haploidentical hematopoietic cell transplantation