MT2023-20: Hematopoietic Cell Transplant With Reduced Intensity Conditioning and Post-transplant Cyclophosphamide for Severe Aplastic Anemia and Other Forms of Acquired Bone Marrow Failure.

A phase II trial of a reduced intensity conditioned (RIC) allogeneic hematopoietic cell transplant (HCT) with post-transplant cyclophosphamide (PTCy) for idiopathic severe aplastic anemia (SAA), paroxysmal nocturnal hemoglobinuria (PNH), acquired pure red cell aplasia (aPRCA), or acquired amegakaryocytic thrombocytopenia (aAT) utilizing population pharmacokinetic (popPK)-guided individual dosing of pre-transplant conditioning and differential dosing of low dose total body irradiation based on age, presence of myelodysplasia and/or clonal hematopoiesis.

Study Overview

• Status: Not yet recruiting
• Conditions: Acquired Pure Red Cell Aplasia; Paroxysmal Nocturnal Hemoglobinuria; Severe Aplastic Anemia; Acquired Amegakaryocytic Thrombocytopenia
• Intervention / Treatment: Drug: Rituximab; Drug: Rabbit ATG; Drug: Cyclophosphamide; Drug: Fludarabine; Radiation: Total Body Irradiation; Biological: Cell Infusion; Drug: Post-Transplant G-CSF; Drug: Tacrolimus; Drug: Mycophenolate Mofetil

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Christen Ebens, MD, MPH; Phone Number: 612-624-1791; Email: ebens012@umn.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Idiopathic Severe Aplastic Anemia (SAA), characterized by one of the following:

  1. Refractory cytopenia(s), with 1+ of the following:

     1. Platelets <20,000/uL or transfusion dependent
     2. Absolute neutrophil count <500/uL without hematopoietic growth factor support
     3. Absolute reticulocyte count <60,000/uL AND bone marrow cellularity <50% (with < 30% residual hematopoietic cells)
  2. Early myelodysplastic features (bone marrow (BM) blasts <5%), without history of MDS/AML pre-treatment.
  3. Idiopathic SAA with post-HCT graft failure (blood/marrow donor chimerism <5%) requiring a 2nd allogeneic HCT

• Paroxysmal Nocturnal Hemoglobinuria (PNH), including AA-PNH overlap syndrome, acquired pure red cell aplasia (aPRCA), or acquired amegakaryocytic thrombocytopenia (aAT), characterized by one of the following:

  1. Refractory cytopenia(s), with 1+ of the following:

     1. Platelets <20,000/uL or transfusion dependent
     2. Absolute neutrophil count <500/uL without hematopoietic growth factor support
     3. Absolute reticulocyte count <60,000/uL or red cell transfusion dependent AND Bone marrow evidence of 1 to 3-lineage aplasia OR peripheral blood PNH clone >/= 10%
  2. Early myelodysplastic features (bone marrow (BM) blasts <5%) without history of MDS/AML pre-treatment.
  3. Idiopathic PNH, aPRCA, or aAT with post-HCT graft failure (blood/marrow donor chimerism <5%) requiring a 2nd allogeneic HCT
• Adequate organ function within 30 days of conditioning regimen

Exclusion Criteria:

• Pregnant, breastfeeding or intending to become pregnant during the study. Persons of childbearing potential must have a negative pregnancy test (serum or urine) within 7 days of the start of treatment
• Uncontrolled infection
• Evidence of moderate or severe portal fibrosis or cirrhosis on biopsy
• Known allergy to any of the study components
• Prior radiation therapy deemed excessive by radiation therapist for proposed low dose TBI exposure on this protocol
• Diagnosis of an inherited bone marrow failure disorder such as Fanconi anemia, Telomere biology disorder, or Schwachman-Diamond syndrome, unless reviewed by the principal investigator and deemed appropriate for this approach (e.g. GATA2 deficiency)
• Advanced myelodysplastic syndrome (MDS; BM blasts >5%) or acute myeloid leukemia
• Psychiatric illness/social situations that, in the judgement of the enrolling Investigator, would limit compliance with study requirements
• Other illness or a medical issue that, in the judgement of the enrolling Investigator, would exclude the patient from participating in this study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A: No clonal hematopoiesis; Participants 25 years of age and younger with no clonal hematopoiesis. Active study treatment includes the conditioning regimen followed by the stem cell infusion and GvHD prophylaxis through day +180. Supportive care and follow up activities continue through two years post HCT.	Drug: Rituximab; For patients with EBV IgG seropositivity or EBV PCR positivity on pre-transplant evaluations, Rituximab 375 mg/m2 is given IV once on day -14 (+/-2 day) in the outpatient setting. Pre-medicate 30 minutes prior to rituximab with methylprednisolone (1 mg/kg) IV, acetaminophen 15 mg/kg (maximum 650mg) IV or PO and diphenhydramine 1 mg/kg (maximum 50mg) IV or PO.; Drug: Rabbit ATG; Rabbit ATG will be administered at doses and days indicated above, infused through a 0.22 micrometer filter over 4-6 hours. Pre-medicate 30 minutes prior to ATG infusion with methylprednisolone 1 mg/kg IV, (max dose = 125 mg), acetaminophen 15 mg/kg dose (max dose = 650 mg) enterally and diphenhydramine 1 mg/kg/dose (max dose = 50 mg) enterally or IV.; Other Names: Thymoglobulin; Drug: Cyclophosphamide; Cyclophosphamide 14.5 mg/kg is be given as a 2-hour infusion on day -6. If the patient is obese (actual body weight (ABW) >/= 125% of the ideal body weight (IBW)), cyclophosphamide should be dosed using the adjusted body weight (AdjBW): 0.5(ABW-IBW) + IBW. Uroprotection with MESNA (14.5 mg/kg/day) in IV continuous infusion will be provided per institutional guidelines. Hyperhydration is not required for 14.5 mg/kg cyclophosphamide doses. Cyclophosphamide will be administered at 50 mg/kg using ABW over 2 hours on days +3 and +4. If the patient is obese (ABW >/= 125% of the ideal body weight (IBW)), cyclophosphamide should be dosed using the adjusted body weight (AdjBW): 0.5(ABW-IBW) + IBW. Uroprotection with MESNA (50 mg/kg/day) in IV continuous infusion as well as hyperhydration will be provided per institutional guidelines.; Drug: Fludarabine; For all patients, fludarabine dosing will be model-based using Bayesian methodology IV every 24 hours on days -6 to -3 with a cumulative area under the curve (cAUC) of 20 mg*hr/L.; Radiation: Total Body Irradiation; For patients age >/= 25 years, with myelodysplasia, or clonal hematopoiesis, total body irradiation will be 4 Gy, provided in two fractions on day -1. For all other patients, total body irradiation will be 2 Gy provided in a single fraction on day -1. Each dose of 2 Gy will be given at a dose rate between 1 and 1.9 Gy/minute prescribed to the midplane of the patient at the level of the umbilicus.; Other Names: TBI; Biological: Cell Infusion; On day 0 the cells will be infused per cell source specific institutional guidelines.; Drug: Post-Transplant G-CSF; Beginning on day +5, patients will receive G-CSF SQ or IV 5 micrograms/kg once daily until post-nadir ANC > 1500/μL for 3 consecutive days or >3000/μL for 1 day.; Other Names: Filgrastim; Drug: Tacrolimus; Tacrolimus will begin on day +5 at an initial dose of 0.03 mg/kg/day IV via continuous infusion. Goal trough levels will be 10-15 ug/mL until day +14 posttransplant, then decreased to a goal of 5-10 ng/mL thereafter. In the absence of GvHD, tacrolimus will discontinue at day +180 without a taper.; Drug: Mycophenolate Mofetil; Mycophenolate mofetil (MMF) therapy will begin on day +5. For pediatric service patients dosing of MMF will be 15 mg/kg/dose (max = 1000 mg) three times daily. For adult service patients dosing of MMF will be 15 mg/kg/dose (max = 1500 mg) twice daily. The same dosage is used orally or intravenously. Consider dose modification and/or pharmacokinetic measurements if renal and/or hepatic impairment (GFR<25 mL/minute corrected). Stop MMF at Day +35 or 7 days after engraftment achieved (ANC>500 x 106 neutrophils/L x 3 days) if later than day +35. If sufficient acute GvHD is observed to require systemic therapy, MMF should be continued for 7 days after initiation of systemic therapy. Afterward, use of MMF is at the discretion of the treating physician.; Other Names: MMF
Experimental: Arm B: Clonal hematopoiesis; Participants 25-75 years old and/or with clonal hematopoiesis. Active study treatment includes the conditioning regimen followed by the stem cell infusion and GvHD prophylaxis through day +180. Supportive care and follow up activities continue through two years post HCT.	Drug: Rituximab; For patients with EBV IgG seropositivity or EBV PCR positivity on pre-transplant evaluations, Rituximab 375 mg/m2 is given IV once on day -14 (+/-2 day) in the outpatient setting. Pre-medicate 30 minutes prior to rituximab with methylprednisolone (1 mg/kg) IV, acetaminophen 15 mg/kg (maximum 650mg) IV or PO and diphenhydramine 1 mg/kg (maximum 50mg) IV or PO.; Drug: Rabbit ATG; Rabbit ATG will be administered at doses and days indicated above, infused through a 0.22 micrometer filter over 4-6 hours. Pre-medicate 30 minutes prior to ATG infusion with methylprednisolone 1 mg/kg IV, (max dose = 125 mg), acetaminophen 15 mg/kg dose (max dose = 650 mg) enterally and diphenhydramine 1 mg/kg/dose (max dose = 50 mg) enterally or IV.; Other Names: Thymoglobulin; Drug: Cyclophosphamide; Cyclophosphamide 14.5 mg/kg is be given as a 2-hour infusion on day -6. If the patient is obese (actual body weight (ABW) >/= 125% of the ideal body weight (IBW)), cyclophosphamide should be dosed using the adjusted body weight (AdjBW): 0.5(ABW-IBW) + IBW. Uroprotection with MESNA (14.5 mg/kg/day) in IV continuous infusion will be provided per institutional guidelines. Hyperhydration is not required for 14.5 mg/kg cyclophosphamide doses. Cyclophosphamide will be administered at 50 mg/kg using ABW over 2 hours on days +3 and +4. If the patient is obese (ABW >/= 125% of the ideal body weight (IBW)), cyclophosphamide should be dosed using the adjusted body weight (AdjBW): 0.5(ABW-IBW) + IBW. Uroprotection with MESNA (50 mg/kg/day) in IV continuous infusion as well as hyperhydration will be provided per institutional guidelines.; Drug: Fludarabine; For all patients, fludarabine dosing will be model-based using Bayesian methodology IV every 24 hours on days -6 to -3 with a cumulative area under the curve (cAUC) of 20 mg*hr/L.; Radiation: Total Body Irradiation; For patients age >/= 25 years, with myelodysplasia, or clonal hematopoiesis, total body irradiation will be 4 Gy, provided in two fractions on day -1. For all other patients, total body irradiation will be 2 Gy provided in a single fraction on day -1. Each dose of 2 Gy will be given at a dose rate between 1 and 1.9 Gy/minute prescribed to the midplane of the patient at the level of the umbilicus.; Other Names: TBI; Biological: Cell Infusion; On day 0 the cells will be infused per cell source specific institutional guidelines.; Drug: Post-Transplant G-CSF; Beginning on day +5, patients will receive G-CSF SQ or IV 5 micrograms/kg once daily until post-nadir ANC > 1500/μL for 3 consecutive days or >3000/μL for 1 day.; Other Names: Filgrastim; Drug: Tacrolimus; Tacrolimus will begin on day +5 at an initial dose of 0.03 mg/kg/day IV via continuous infusion. Goal trough levels will be 10-15 ug/mL until day +14 posttransplant, then decreased to a goal of 5-10 ng/mL thereafter. In the absence of GvHD, tacrolimus will discontinue at day +180 without a taper.; Drug: Mycophenolate Mofetil; Mycophenolate mofetil (MMF) therapy will begin on day +5. For pediatric service patients dosing of MMF will be 15 mg/kg/dose (max = 1000 mg) three times daily. For adult service patients dosing of MMF will be 15 mg/kg/dose (max = 1500 mg) twice daily. The same dosage is used orally or intravenously. Consider dose modification and/or pharmacokinetic measurements if renal and/or hepatic impairment (GFR<25 mL/minute corrected). Stop MMF at Day +35 or 7 days after engraftment achieved (ANC>500 x 106 neutrophils/L x 3 days) if later than day +35. If sufficient acute GvHD is observed to require systemic therapy, MMF should be continued for 7 days after initiation of systemic therapy. Afterward, use of MMF is at the discretion of the treating physician.; Other Names: MMF

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of grade 3-4 acute GvHD	Incidence of grade 3-4 acute graft-versus host disease (GvHD) at 1 year post HCT.	1 year post HCT
Incidence of chronic GvHD-free, failure-free survival (GFFS)	Incidence of chronic GvHD-free, failure-free survival (GFFS) 1 year post HCT	1 year post HCT
Incidence of chronic GvHD-free survival	Incidence of chronic GvHD-free survival at 1 year post HCT	1 year post HCT

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of failure-free survival (GFFS)	Incidence of chronic GvHD-free, failure-free survival (GFFS) 2 years post HC	2 years post HCT
Incidence of neutrophil recovery	Incidence of neutrophil recovery at day 42 post HCT	Day 42 post HCT
Incidence of platelet recovery	Incidence of platelet recovery at 6 months post HCT	6 months post HCT
Incidence of grade 3-4 acute GvHD	Incidence of grade 3-4 acute GvHD at 100 days post HCT	100 days post HCT
Incidence of any chronic GvHD	Incidence of any chronic GvHD at 1 year post HCT	1 year post HCT
Overall survival	Overall survival at 1 and 2 years	1 and 2 years post HCT
Incidence of chronic GvHD-free survival	Incidence of chronic GvHD-free survival at 2 years post HCT	2 years post HCT

Collaborators and Investigators

• Sponsor: Masonic Cancer Center, University of Minnesota

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2024
• Primary Completion (Estimated): May 1, 2035
• Study Completion (Estimated): May 1, 2036

Study Registration Dates

• First Submitted: May 9, 2024
• First Submitted That Met QC Criteria: May 9, 2024
• First Posted (Actual): May 14, 2024

Study Record Updates

• Last Update Posted (Actual): May 14, 2024
• Last Update Submitted That Met QC Criteria: May 9, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: HCT; SAA; RIC; PTCy; aAT; aPRCA
• Additional Relevant MeSH Terms: Urologic Diseases; Urological Manifestations; Bone Marrow Diseases; Hematologic Diseases; Urination Disorders; Blood Platelet Disorders; Proteinuria; Anemia, Hemolytic; Myelodysplastic Syndromes; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Cytopenia; Anemia; Thrombocytopenia; Anemia, Aplastic; Red-Cell Aplasia, Pure; Bone Marrow Failure Disorders; Pancytopenia; Hemoglobinuria; Hemoglobinuria, Paroxysmal; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Cyclophosphamide; Rituximab; Fludarabine; Tacrolimus; Mycophenolic Acid; Thymoglobulin
• Other Study ID Numbers: 2023LS101

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No