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.

Обзор

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.

Вмешательства

• Препарат 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.
• Препарат 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.
• Препарат 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
• Препарат 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.
• Лучевая терапия 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.
• Биопрепарат Cell Infusion
  On day 0 the cells will be infused per cell source specific institutional guidelines.
• Препарат 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.
• Препарат 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.
• Препарат 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 1

Первичные конечные точки

• Incidence of grade 3-4 acute GvHD [Срок оценки: 1 year post HCT]
• Incidence of chronic GvHD-free, failure-free survival (GFFS) [Срок оценки: 1 year post HCT]
• Incidence of chronic GvHD-free survival [Срок оценки: 1 year post HCT]

Вторичные конечные точки (7)

• Incidence of failure-free survival (GFFS) [Срок оценки: 2 years post HCT]
• Incidence of neutrophil recovery [Срок оценки: Day 42 post HCT]
• Incidence of platelet recovery [Срок оценки: 6 months post HCT]
• Incidence of grade 3-4 acute GvHD [Срок оценки: 100 days post HCT]
• Incidence of any chronic GvHD [Срок оценки: 1 year post HCT]
• Overall survival [Срок оценки: 1 and 2 years post HCT]
• Incidence of chronic GvHD-free survival [Срок оценки: 2 years post HCT]

Критерии участия

Критерии включения

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

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

• Platelets <20,000/uL or transfusion dependent
• Absolute neutrophil count <500/uL without hematopoietic growth factor support
• Absolute reticulocyte count <60,000/uL AND bone marrow cellularity <50% (with < 30% residual hematopoietic cells)
• Early myelodysplastic features (bone marrow (BM) blasts <5%), without history of MDS/AML pre-treatment.
• 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:

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

• Platelets <20,000/uL or transfusion dependent
• Absolute neutrophil count <500/uL without hematopoietic growth factor support
• 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%
• Early myelodysplastic features (bone marrow (BM) blasts <5%) without history of MDS/AML pre-treatment.
• 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

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 1 центр

• University of Minnesota Masonic Cancer Center — Minneapolis

Идентификаторы

NCT: NCT06412497 · 2023LS101

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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