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gamma-Globulins

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CONDITIONING REGIMEN: Patients receive treosulfan IV over 120 minutes on days -6 to -4, fludarabine phosphate IV over 60 minutes on days -6 to -2, and rATG IV over 4-6 hours on days -4 to -2.

TRANSPLANTATION: Patients undergo bone marrow or peripheral blood stem cell transplant on day 0.

GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously beginning on day -2 and a taper beginning on day 180. Patients may also receive tacrolimus PO. Patients also receive methotrexate IV on days 1, 3, 6, and 11.

Patients undergo ECHO or MUGA during screening and undergo bone marrow biopsy and aspiration at baseline and follow up. Patients may optionally undergo blood sample collection throughout the trial.

Fludarabine Phosphate

Lapine T-Lymphocyte Immune Globulin

Peripheral Blood Stem Cell Transplantation

Allogeneic Bone Marrow Transplantation

Quality-of-Life Assessment

Echocardiography

Multigated Acquisition Scan

Undergo bone marrow biopsy and aspiration

Bone Marrow Biopsy

Bone Marrow Aspiration

Biospecimen Collection

Megan Scott

Adam Mendizabal, PhD

Kimberly Arieli

Paibel Aguayo-Hiraldo, MD

Mehrzad Milburn

Sheila Medina-Torne

Nicholas Gloude, MD

Kevin Magruder

Kristin Shimano, MD

Courtney Newbold

Jessica Knight-Perry, MD

Judson Russell

Kathryn Leung, MD

Jennifer Courneya

Kenneth Cooke, MD

Brandi Bratrude

Leslie Lehmann, MD

Connie Varner

Mark Vander Lugt, MD

Merve Tekmen

Margaret MacMillan, MD

Lisa Murray

Shalini Shenoy, MD

Rachel Carter

Nataliya Buxbaum, MD

Kirsten Fuller

Maria Cancio, MD

Amelia Halac

Jonathan Fish, MD

Erin Arbuckle

Joanne Kurtzberg, MD

Samantha (Sam) McBride

Kasiani Myers, MD

Lori Jewell

Rajinder Bajwa, MD

Rebecca Hulme

Evan Shereck, MD

Patricia Hankins

Timothy Olson, MD

Delia Darst

Jim Connelly, MD

Marissa Rose

Demetrios Petropoulous, MD

Emily Jobe

Jay Read, MD

Rebecca Stoffel

Michael Pulsipher, MD

Courtney Vandervlugt

Lauri Burroughs, MD

Emily Ruskiewicz

Julie Talano, MD

This phase II trial tests whether treosulfan, fludarabine, and rabbit antithymocyte globulin (rATG) work when given before a blood or bone marrow transplant (conditioning regimen) to cause fewer complications for patients with bone marrow failure diseases. Chemotherapy drugs, such as treosulfan, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Fludarabine may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. rATG is used to decrease the body's immune response and may improve bone marrow function and increase blood cell counts. Adding treosulfan to a conditioning regimen with fludarabine and rATG may result in patients having less severe complications after a blood or bone marrow transplant.

OUTLINE:

CONDITIONING REGIMEN: Patients receive treosulfan intravenously (IV) over 120 minutes on days -6 to -4, fludarabine phosphate IV over 60 minutes on days -6 to -2, and lapine T-lymphocyte immune globulin (rATG) IV over 4-6 hours on days -4 to -2.

TRANSPLANTATION: Patients undergo bone marrow or peripheral blood stem cell transplant on day 0.

GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously beginning on day -2 and a taper beginning on day 180. Patients may also receive tacrolimus orally (PO). Patients also receive methotrexate IV on days 1, 3, 6, and 11.

Patients undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) during screening and undergo bone marrow biopsy and aspiration at baseline and follow up. Patients may optionally undergo blood sample collection throughout the trial.

After completion of study treatment, patients are followed up at 1 year from transplant.

Treosulfan-Based Conditioning Regimen Before a Blood or Bone Marrow Transplant for the Treatment of Bone Marrow Failure Diseases (BMT CTN 1904)

Hematopoietic Cell Transplantation Using Treosulfan-Based Conditioning for the Treatment of Bone Marrow Failure Diseases

The primary endpoint is the incidence of 1-year GVHD free, EFS (GEFS). An event is defined as death due to any cause, graft rejection/failure, or 2nd HCT whichever occurs first. Grade III-IV acute GVHD and chronic GVHD (using NIH consensus criteria) requiring systemic immune suppression will be considered in this estimate

Event-free survival will be estimated at 12 months after HCT. Grade III-IV acute GVHD and chronic GVHD requiring systemic immune suppression will be considered in this estimate. An event is defined as death due to any cause, primary or secondary graft failure/rejection, or 2nd HCT whichever occurs first

Hematologic recovery will be assessed according to neutrophil recovery after transplant. Neutrophil recovery is defined as achieving an absolute neutrophil count (ANC) ≥ to 500/mm3 for 3 consecutive measurements on 3 different days. The first of the three days will be designated the day of neutrophil recovery. The competing event is death without neutrophil recovery.

Hematologic recovery will be assessed according to platelet counts recovery after transplant. Platelet recovery is defined as the first day of a minimum of 3 days that the patient has a sustained platelet count ≥ 20,000/mm3 with no platelet transfusions in the preceding 7 days. The first day of sustained platelet count above these thresholds will be designated the day of platelet engraftment.

Proportions of patients with full (\>95%), mixed (5-95%), or rejection (\<5%) myeloid

Defined as never achieving ANC ≥ 500/μL or never achieving ≥ 5% donor myeloid chimerism assessed by peripheral blood chimerism assays by day +42 post-HCT. Second infusion of hematopoietic cells is also considered indicative of primary graft failure by day +42 post-HCT

Defined as \< 5% donor myeloid chimerism in peripheral blood beyond day +42 post-HCT in patients with prior documentation of hematopoietic recovery with ≥ 5% donor cells by day +42 post-HCT. Second infusion of hematopoietic cells is also considered indicative of secondary graft failure.

The cumulative incidences of acute grade II-IV and III-IV GVHD at day 100 after HCT will be determined.

The cumulative incidence of chronic GVHD (using NIH consensus criteria) requiring systemic immune suppression at 1 year after HCT will be determined. Data will be collected directly from providers and chart review as defined by the NIH Consensus Conference Criteria

Grade 3-5 toxicities by day 100 after HCT

All microbiologically documented infections or significant infections requiring antibiotic/antifungal therapy occurring up to 6 months after HCT

The incidence of EBV reactivation requiring therapy in the first 180 days after HCT, and of EBV-associated lymphoproliferative disorder in the first 180 days after HCT will be evaluated.

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