Allo HSCT Using RIC for Hematological Diseases

Phase 2

Completed

• Conditions: Chronic Myelogenous Leukemia; Lymphoplasmacytic Lymphoma; Mantle-Cell Lymphoma; Lymphoblastic Lymphoma; Acute Myelogenous Leukemia; Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma; Burkitt's Lymphoma; Hematological Diseases; B-Cell Lymphoma
• Interventions: Drug: Allopurinol; Drug: Fludarabine; Drug: Cyclophosphamide; Drug: ATG; Radiation: TBI; Drug: Tacrolimus; Drug: MMF; Biological: Peripheral Blood Stem Cells; Biological: Related or Unrelated Bone Marrow Cells

• Registration Number: NCT02661035
• Lead Sponsor: Masonic Cancer Center, University of Minnesota

Brief Summary

This is a phase II trial using a non-myeloablative cyclophosphamide/ fludarabine/total body irradiation (TBI) preparative regimen followed by a related or unrelated donor stem cell infusion. The primary objective is to evaluate rates of acute graft-versus-host disease (GVHD) grades II-IV and chronic GVHD with an updated GVHD prophylaxis of tacrolimus and mycophenolate mofetil (MMF) with a non-myeloablative preparative regimen in persons with hematologic malignancies.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2016-01-19
• Study First Submitted QC: 2016-01-20
• Study First Posted: 2016-01-21
• Study Start: 2017-03-09
• Primary Completion: 2023-04-17
• Study Completion: 2023-05-29
• Status Verified: 2023-09
• Last Update Submitted: 2023-09-19
• Last Update Posted: 2023-09-21

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 156

Inclusion Criteria

• Age, Performance Status, and Graft Criteria

  • Age 0 to 70 years of age with Karnofsky score ≥ 70% (≥ 16 years) or Lansky score ≥ 50 (< 16 years)
  • Patients ≥ 70 and ≤ 75 years of age may be eligible if they have a HCT-CI Co-Morbidity score ≤ 2
  • Must be ≥ 3 months after prior myeloablative transplant, if applicable
  • 5/6 or 6/6 related donor match or a 7-8/8 HLA-A,B,C,DRB1 allele matched unrelated donor marrow and/or PBSC donor match per current institutional guidelines Related donors will be evaluated and collected per MT2012-14C; Unrelated donors will be identified and collected per usual procedures

• Eligible Diseases

  • Acute Myeloid Leukemia (AML): high risk CR1 (as evidenced by preceding MDS, high risk cytogenetics, ≥ 2 cycles to obtain CR, erythroblastic or megakaryocytic leukemia, FLT-3 ITD +; CR2+. All patients must be in CR as defined by hematological recovery, AND <5% blasts by light microscopy within the bone marrow with a cellularity of ≥15%.
  • Very high risk pediatric patients with AML: Patients <21 years, however, are eligible with (M2 marrow) with < 25% blasts in marrow after having failed one or more cycles of chemotherapy.
  • Acute Lymphocytic Leukemia (ALL): factor that define high risk CR1 include but are not limited to cytogenetics demonstrating t(9;22), t (1:19), t(4;11), other MLL rearrangements, hypodiploidy, or IKZF1 abnormalities), DNA index < 0.81, > 1 cycle to obtain CR or presence minimal residual disease (MRD). Patients in CR2+ are eligible. All patients must be in CR as defined by hematological recovery, AND <5% blasts by light microscopy within the bone marrow with a cellularity of ≥15%.
  • Very high risk pediatric patients with ALL: patients <21 years are also considered high risk CR1 if they had M2 or M3 marrow at day 42 from the initiation of induction or M3 marrow at the end of induction. They are eligible once they achieved a complete remission.
  • Chronic Myelogenous Leukemia excluding refractory blast crisis: To be eligible in first chronic phase (CP1) patient must have failed or be intolerant to imatinib mesylate.
  • Plasma Cell Leukemia after initial therapy, who achieved at least a partial remission
  • Myelodysplasia (MDS) requiring transplant as defined as: IPSS INT-2 or High Risk; R-IPSS High or Very High; WHO classification: RAEB-1, RAEB-2; Severe Cytopenias: ANC < 0.8, Anemia or thrombocytopenia requiring transfusion; Poor or very poor risk cytogenetics based on IPSS or R-IPSS definitions; therapy-related MDS. Blasts must be < 5% by bone marrow aspirate morphology.
  • Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL), Marginal Zone B-Cell Lymphoma or Follicular Lymphoma are eligible if there was disease progression/relapse within 12 of achieving a partial or complete remission. Patients who had remissions lasting > 12 months, are eligible after at least two prior therapies. Patients with bulky disease (nodal mass greater than 5 cm) should be considered for de-bulking chemotherapy before transplant.
  • Lymphoplasmacytic Lymphoma, Mantle-Cell Lymphoma, Prolymphocytic Leukemia, NK cell malignancies are eligible after initial therapy in CR1+ or PR1+.
  • Large Cell NHL > CR2/> PR2: Patients in CR2/PR2 with initial short remission (<6 months) are eligible.
  • Lymphoblastic Lymphoma, Burkitt's Lymphoma, and other high-grade NHL after initial therapy if stage III/IV in CR1/PR1 or after progression if stage I/II < 1 year.
  • Multiple Myeloma beyond PR2: Patients with chromosome 13 abnormalities, first response lasting less than 6 months, or β-2 microglobulin > 3 mg/L, may be considered for this protocol after initial therapy.
  • Myeloproliferative Syndromes

• Organ Function Criteria Adequate organ function is defined as:

  • Liver: AST and ALT < 5 x upper limit of normal and bilirubin < 3 x upper limit of normal
  • Renal: Creatinine ≤ 2.0 mg/dl (adults) and estimated glomerular filtration rate (GFR) ≥ 40 mL/min (pediatrics). Adults with a creatinine > 1.2 mg/dl or a history of renal dysfunction must have estimated glomerular filtration rate (GFR) > 40 mL/min.
  • Albumin > 2.5 g/dL
  • Cardiac: Absence of decompensated congestive heart failure, or uncontrolled arrhythmia and left ventricular ejection fraction > 35%.
  • Pulmonary: DLCOcorr ≥ 40% predicted, and absence of O2 requirements. For children that are not able to cooperate with PFTs, a pulse oximetry with or without exercise should be attempted. If neither test can be obtained it should be clearly stated in the physician's note.

• If recent mold infection (e.g. aspergillus) must have minimum of 30 days of therapy and responsive disease and be cleared by Infectious Disease

• Females of child bearing potential and sexually active males must agree to use adequate birth control during study treatment

• Voluntary written consent (adult or parent/guardian with presentation of the minor information sheet, if appropriate)

Exclusion Criteria

• Pregnant or breast feeding. The agents used in this study include Pregnancy Category D: known to cause harm to a fetus. Females of childbearing potential must have a blood test or urine study within 14 days prior to registration to rule out pregnancy.
• Untreated active infection
• Active CNS disease
• Active HIV infection or known HIV positive serology
• Congenital bone marrow failure syndrome
• Previous irradiation that precludes the safe administration of an additional dose of 200 cGy of TBI
• CML in refractory blast crisis
• Intermediate or high grade NHL, mantle cell NHL, and Hodgkin disease that is progressive on salvage therapy. Stable disease is acceptable to move forward provided it is non-bulky.
• Multiple myeloma progressive on salvage chemotherapy

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Reduced Intensity Conditioning	TBI	Non-myeloablative cyclophosphamide/ fludarabine/total body irradiation (TBI) preparative regimen followed by a related or unrelated donor stem cell infusion
Reduced Intensity Conditioning	Related or Unrelated Bone Marrow Cells	Non-myeloablative cyclophosphamide/ fludarabine/total body irradiation (TBI) preparative regimen followed by a related or unrelated donor stem cell infusion
Reduced Intensity Conditioning	Fludarabine	Non-myeloablative cyclophosphamide/ fludarabine/total body irradiation (TBI) preparative regimen followed by a related or unrelated donor stem cell infusion
Reduced Intensity Conditioning	Peripheral Blood Stem Cells	Non-myeloablative cyclophosphamide/ fludarabine/total body irradiation (TBI) preparative regimen followed by a related or unrelated donor stem cell infusion
Reduced Intensity Conditioning	Allopurinol	Non-myeloablative cyclophosphamide/ fludarabine/total body irradiation (TBI) preparative regimen followed by a related or unrelated donor stem cell infusion
Reduced Intensity Conditioning	ATG	Non-myeloablative cyclophosphamide/ fludarabine/total body irradiation (TBI) preparative regimen followed by a related or unrelated donor stem cell infusion
Reduced Intensity Conditioning	Cyclophosphamide	Non-myeloablative cyclophosphamide/ fludarabine/total body irradiation (TBI) preparative regimen followed by a related or unrelated donor stem cell infusion
Reduced Intensity Conditioning	Tacrolimus	Non-myeloablative cyclophosphamide/ fludarabine/total body irradiation (TBI) preparative regimen followed by a related or unrelated donor stem cell infusion
Reduced Intensity Conditioning	MMF	Non-myeloablative cyclophosphamide/ fludarabine/total body irradiation (TBI) preparative regimen followed by a related or unrelated donor stem cell infusion

Primary Outcome Measures

Name	Time	Method
Evaluate rates of acute graft-versus-host disease (GVHD) II-IV	Day 100 post transplant	Percent of subjects with grade II-IV acute GVHD

Secondary Outcome Measures

Name	Time	Method
Evaluate rates of chronic GVHD	1 year post transplant	Percent of subjects with chronic GVHD
Evaluate relapse with ATG (in unrelated donors) - 1 year	1 year post transplant	Percent of subjects who relapsed with ATG (in unrelated donors)
Evaluate relapse without ATG (in unrelated donors) - 1 year	1 year post transplant	Percent of subjects who relapsed without ATG (in unrelated donors)
Evaluate relapse without ATG (in unrelated donors) - 2 years	2 years post transplant	Percent of subjects who relapsed without ATG (in unrelated donors)
Overall survival	3 years post transplant	Percent of surviving subjects
Transplant related mortality (TRM)	1 year post transplant	Percent of subjects with TRM
Evaluate neutrophil engraftment without ATG (in siblings)	Day 42 post transplant	Percent of subjects with neutrophil engraftment without ATG (in siblings)
Evaluate neutrophil engraftment with ATG (in unrelated donors)	Day 42 post transplant	Percent of subjects with neutrophil engraftment with ATG (in unrelated donors)
Evaluate neutrophil engraftment without ATG (in unrelated donors)	Day 42 post transplant	Percent of subjects with neutrophil engraftment without ATG (in unrelated donors)
Evaluate relapse without ATG (in siblings) - 1 year	1 year post transplant	Percent of subjects who relapsed without ATG (in siblings)
Evaluate relapse with ATG (in unrelated donors) - 2 years	2 years post transplant	Percent of subjects who relapsed with ATG (in unrelated donors)
Evaluate relapse without ATG (in siblings) - 2 years	2 years post transplant	Percent of subjects who relapsed without ATG (in siblings)

Trial Locations

Locations (1)

Masonic Cancer Center at University of Minnesota; 🇺🇸 Minneapolis, Minnesota, United States