Blood and Lymph Conditions

All Conditions

Symptoms and General Pathology

Neoplasms

Rare Diseases

Thrombocytopenia

Syndrome

Anemia

Anemia, Aplastic

Cytopenia

Preleukemia

Myelodysplastic Syndromes

Bone Marrow Failure Disorders

Pancytopenia

Bone Marrow Diseases

Hematologic Diseases

Precancerous Conditions

Blood Platelet Disorders

Aplastic Anemia

All Drugs and Chemicals

Antibodies

Immunoglobulins

Immunoglobulins, Intravenous

Arm A will include acquired bone marrow failure (BMF) disorders including aplastic anemia, refractory cytopenia of childhood/Myelodysplastic Syndrome(MDS) without monosomy 7 and 5q deletion abnormalities, toxin induced myelosuppression due to infection and inherited cytopenia with or without involvement of other cell lines who are transfusion dependent and or showing progression to bone marrow failure.

Arm A: Start at 5 microgram/kg/dose per week along with standard of care and escalate with 2.5 microgram/kg/dose increments (per week at physician's discretion depending on the clinical and laboratory response) (Maximum: 20 microgram/kg/dose) based on response for at least 24 weeks or until hematopoietic response is seen, whichever comes first. If patient shows response, therapy will be continued for a total of 52 weeks.

Arm B will include children with chemo and or radiotherapy induced thrombocytopenia/cytopenia and children undergoing stem cell transplantation (SCT).

Arm B: Starting dose 2 microgram/kg/dose per week with increments at 1 microgram/kg/dose (Maximum: 10 micrograms/kg/dose) depending on the laboratory response.

Nplate is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Romiplostim

Anjali A. Sharathkumar, MBBS, MD, MS

This is an open label, prospective Pilot interventional study will investigate the safety and efficacy of Romiplostim, thrombopoietin (TPO) mimetic, in children (ages: 0 to 21 years) with broad scope of bone marrow failure disorders including acquired and inherited conditions as a first line of therapy along with standard of care.

This investigator-initiated study will investigate the safety and efficacy of Romiplostim, thrombopoietin (TPO) mimetic, in children (ages: 0 to 21 years) with broad scope of bone marrow failure disorders (BMF) including acquired and inherited conditions as a first line of therapy along with standard of care.

Objectives: Primary objectives are to evaluate safety and preliminary efficacy of Romiplostim in children with BMF. Methods: This open label, prospective Pilot interventional study has two arms.

Arm A will include acquired bone marrow failure (BMF) disorders including aplastic anemia, refractory cytopenia of childhood without monosomy 7 and 5q deletion abnormalities, toxin induced myelosuppression due to infection and inherited cytopenia with or without involvement of other cell lines who are transfusion dependent and or showing progression to bone marrow failure. Arm B will include children with chemo and or radiotherapy induced thrombocytopenia/cytopenia and children undergoing stem cell transplantation (SCT). Children with cancer predisposition and other morbidities which are considered significant by the investigator will be excluded from the study.

TPO-Mimetic Use in Children for Hematopoietic Failure

Single Arm Prospective Open Label Pilot Study Evaluating Short-Term Safety and Efficacy of Romiplostim in Children With Inherited and Acquired Disorders of Hematopoietic Failure

Categorize and quantify AEs per CTCAE version 5.0

Improvement in at least one of the cell blood lineages by 24 weeks of therapy:

1. Platelet response (increase to 10 X 103/mL above baseline or stable platelet counts with transfusion independence for a minimum of 2 weeks in those who were transfusion dependent on entry into the protocol)
2. Erythroid response (when pretreatment hemoglobin was, below 7 g/dL, defined as an increase in hemoglobin by 1.5 g/dL or, in transfused patients, a reduction in the units of packed red blood cell transfusions by an absolute number of at least 4 transfusions for 8 consecutive weeks, compared with the pretreatment transfusion number in the previous 8 weeks)
3. Neutrophil response (when pretreatment absolute neutrophil count \[ANC\] of 0.5 x103 /mL as at least a 100% increase in ANC, or an ANC increase by 0.5 x103 /mL)

Time from Romiplostim initiation to response, as defined in Outcome 2, for each cell lineage

Change in blood counts from Romiplostim initiation until the end of treatment

Occurrences of bleeding as defined by the International Society of Haemostasis and Thrombosis Bleeding Assessment Tool (https://bleedingscore.certe.nl/)

Number of occurrences of neutropenic fever

Change in number of platelet and red call transfusions without active bleeding diathesis

Increase in bone marrow myelofibrosis as measured by reticulin staining of bone marrow biopsy at diagnosis and follow up bone marrow testing upon initiation of Romiplostim

Number of patients who are transfusion dependent or who require decreased platelet transfusion

Amgen

Anjali Sharathkumar

Clinical Professor

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Digestive System Diseases

Nutritional and Metabolic Diseases

Diseases and Abnormalities at or Before Birth

Skin and Connective Tissue Diseases

Hematologic Neoplasms

Hemoglobinuria

Red-Cell Aplasia, Pure

Anemia, Sideroblastic

Shwachman-Diamond Syndrome

Anemia, Diamond-Blackfan

Anemia, Hypochromic

Hemoglobinuria, Paroxysmal

Proteinuria

Urination Disorders

Urologic Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Male Urogenital Diseases

Urological Manifestations

Hemolysis

Anemia, Hemolytic

Exocrine Pancreatic Insufficiency

Pancreatic Diseases

Gastrointestinal Diseases

Congenital Bone Marrow Failure Syndromes

Metabolism, Inborn Errors

Lipid Metabolism, Inborn Errors

Metabolic Diseases

Lipid Metabolism Disorders

Lipomatosis

Lipomatosis, Multiple Symmetrical

Anemia, Hypoplastic, Congenital

Genetic Diseases, Inborn

Paroxysmal Nocturnal Hemoglobinuria

Pure Red Cell Aplasia

Diamond-Blackfan Anemia

Congenital Amegakaryocytic Thrombocytopenia

Multiple Symmetric Lipomatosis

Antineoplastic Agents

Antirheumatic Agents

Dermatologic Agents

Reproductive Control Agents

Micronutrients

Hematinics

Vitamins

Tacrolimus

Fludarabine

Fludarabine phosphate

Methotrexate

Thymoglobulin

gamma-Globulins

Rho(D) Immune Globulin

Antilymphocyte Serum

Treosulfan

Busulfan

Antimetabolites

Enzyme Inhibitors

Folic Acid

Vitamin B Complex

Folic Acid Antagonists

Immunosuppressive Agents

Immunologic Factors

Calcineurin Inhibitors

Antineoplastic Agents, Alkylating

Alkylating Agents

Folinic Acid

Folate

Vitamin B9

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
TPO-Mimetic Use in Children for Hematopoietic Failure	NCT04478227	Bone Marrow Fai... Aplastic Anemia Thrombocytopeni... Refractory Cyto... Myelodysplastic...	Romiplostim	0 Years - 21 Years	University of Iowa
Treosulfan-Based Conditioning Regimen Before a Blood or Bone Marrow Transplant for the Treatment of Bone Marrow Failure Diseases (BMT CTN 1904)	NCT04965597	Bone Marrow Fai... Congenital Ameg... Congenital Pure... Hereditary Side... Paroxysmal Noct... Shwachman-Diamo... Hematologic Neo... Hematologic Neo... Hematologic Neo...	Treosulfan Fludarabine Pho... Tacrolimus Methotrexate Lapine T-Lympho... Peripheral Bloo... Allogeneic Bone... Quality-of-Life... Echocardiograph... Multigated Acqu... Bone Marrow Bio... Bone Marrow Asp... Biospecimen Col...	1 Year - 49 Years	Fred Hutchinson Cancer Center

Spots Global Cancer Trial Database for bone marrow failure disorders