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Patients receive ruxolitinib PO BID from day -1 to day +100, tacrolimus IV on day -1, and methotrexate IV on days +1, +3, +6, and +11, and undergo HCT on day 0. Patients also undergo chest CT and ECHO/MUGA at screening and undergo collection of blood samples throughout the trial.

Biospecimen Collection

Chest Computed Tomography

Echocardiography

Hematopoietic Cell Transplantation

Multigated Acquisition Scan

Ruxolitinib Phosphate

Haris Ali

This phase II trial tests how well ruxolitinib with tacrolimus and methotrexate work to prevent the development of graft versus host disease in pediatric and young adult patients undergoing allogeneic hematopoietic cell transplant for acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome. Ruxolitinib is a type of medication called a kinase inhibitor. It works by blocking the signals of cells that cause inflammation and cell proliferation, which may help prevent graft versus host disease (GVHD). Tacrolimus is a drug used to help reduce the risk of rejection by the body of organ and bone marrow transplants by suppressing the immune system. Methotrexate stops cells from making DNA, may kill cancer cells, and also suppress the immune system, which may reduce the risk of GVHD. Giving ruxolitinib with tacrolimus and methotrexate may prevent GVHD in pediatric and young adults undergoing allogeneic hematopoietic cell transplants.

PRIMARY OBJECTIVES:

I. Determine if the addition of ruxolitinib phosphate (ruxolitinib) to tacrolimus and methotrexate as graft-versus-host disease (GVHD) prophylaxis, is safe in pediatric and young adult patients with hematologic malignancies who are eligible to undergo allogeneic hematopoietic cell transplantation (HCT) from a matched donor. (Safety lead-in segment) II. Following a patient safety lead-in, evaluate the efficacy of ruxolitinib, when given as part of reduced intensity HCT from a matched related/unrelated donor, as assessed by 1 year graft-versus-host disease-free and relapse-free (GRFS) rates in pediatric and young adult patients. (Phase II segment)

SECONDARY OBJECTIVES:

I. Estimate the cumulative incidence of acute GVHD (aGVHD) and non-relapse mortality (NRM) at 100-days after transplant.

II. Estimate the cumulative incidence of chronic GVHD (cGVHD) at 1- and 2-years after transplant.

III. Estimate the probabilities of overall and progression-free survival (OS/PFS) at 1- and 2-years after transplant.

IV. Estimate the relapse/progression rate. V. Estimate rate of infection and development of second malignancies including lymphoproliferative disorders at 1- and 2-years post-transplant.

VI. Further evaluate the safety of this regimen by assessing:

VIa. Adverse event type, frequency, severity, attribution, time-course, and duration; VIb. Complications including: infection, and delayed engraftment.

EXPLORATORY OBJECTIVES:

I. Characterize and evaluate hematologic recovery, donor cell engraftment and immune reconstitution by cell count and flow cytometry of lymphocyte subsets.

II. Characterize changes in aGVHD biomarkers (Reg-3alpha, sTNF RI, IL2Ralpha), JAK-regulated pro-inflammatory cytokines (i.e. IL-6, TNFalpha, C-reactive protein \[CRP\], beta2Microglubuolin) and STAT3 phosphorylation (downstream of JAK signaling) over time and by aGVHD status/grade.

III. Evaluate the pharmacokinetics of ruxolitinib in pediatric and young adult patients.

OUTLINE:

Patients receive ruxolitinib orally (PO) twice daily (BID) from day -1 to day +100, tacrolimus intravenously (IV) on day -1, and methotrexate IV on days +1, +3, +6, and +11, and undergo HCT on day 0. Patients also undergo chest computed tomography (CT) and echocardiography (ECHO)/multigated acquisition scan (MUGA) at screening and undergo collection of blood samples throughout the trial.

After completion of study treatment, patients are followed up at 30 days after the last dose of ruxolitinib and at 1 and 2 years post transplant.

Ruxolitinib With Tacrolimus and Methotrexate for the Prevention of Graft Versus Host Disease in Pediatric and Young Adult Patients Undergoing Allogeneic Hematopoietic Cell Transplant for Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or Myelodysplastic Syndrome

Phase 2a Study of Adding Ruxolitinib With Tacrolimus/Methotrexate Regimen for Graft-versus-Host Disease Prophylaxis in Myeloablative Conditioning Hematopoietic Cell Transplantation in Pediatric and Young Adult Patients

Defined using the modified Bearman Scale and the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 scale.

Will be estimated using the product-limit method of Kaplan and Meier.

Patients who have received at least 80% of planned doses of ruxolitinib are deemed to meet feasibility criteria.

Will be graded and staged according to Mount Sinai Acute GVHD International Consortium criteria. Will be estimated using the method described by Gooley et al (1999).

Defined as death occurring in a patient from causes other than relapse or progression. Will be estimated using the method described by Gooley et al (1999).

Will be evaluated and scored according to National Institutes of Health Consensus Staging. Will be estimated using the method described by Gooley et al (1999).

Will be estimated using the method described by Gooley et al (1999).

Will be reported by site of disease, date of onset, severity and resolution, if any.

Assessed using: absolute neutrophil count ≥ 0.5 x 10\^3/uL achieved and sustained for 3 consecutive lab values on different days with no subsequent decline; platelets ≥ 20 K/uL independent of platelet transfusion support; immune reconstitution studies done by flow cytometry.

National Cancer Institute (NCI)

City of Hope Medical Center

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Ruxolitinib With Tacrolimus and Methotrexate for the Prevention of Graft Versus Host Disease in Pediatric and Young Adult Patients Undergoing Allogeneic Hematopoietic Cell Transplant for Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or Myelodysplastic Syndrome	NCT06128070	Acute Lymphobla... Acute Myeloid L... Myelodysplastic...	Biospecimen Col... Chest Computed ... Echocardiograph... Hematopoietic C... Methotrexate Multigated Acqu... Ruxolitinib Pho... Tacrolimus	2 Years - 22 Years	City of Hope Medical Center
Ruxolitinib With Tacrolimus and Methotrexate for the Prevention of Graft Versus Host Disease in Pediatric and Young Adult Patients Undergoing Allogeneic Hematopoietic Cell Transplant for Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or Myelodysplastic Syndrome	NCT06128070	Acute Lymphobla... Acute Myeloid L... Myelodysplastic...	Biospecimen Col... Chest Computed ... Echocardiograph... Hematopoietic C... Methotrexate Multigated Acqu... Ruxolitinib Pho... Tacrolimus	2 Years - 22 Years	City of Hope Medical Center

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