Allo HSCT Using RIC for Hematological Diseases

September 19, 2023 updated by: Masonic Cancer Center, University of Minnesota

Allogeneic Hematopoietic Stem Cell Transplantation Using Reduced Intensity Conditioning (RIC) for the Treatment of Hematological Diseases [MT2015-32]

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

156

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Minnesota
      • Minneapolis, Minnesota, United States, 55455
        • Masonic Cancer Center at University of Minnesota

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 75 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Reduced Intensity Conditioning
Non-myeloablative cyclophosphamide/ fludarabine/total body irradiation (TBI) preparative regimen followed by a related or unrelated donor stem cell infusion
Drug: Allopurinol
300 mg/day (for peds -150 mg/m^2/day), day -6 and continue through day 0 or longer if clinically indicated
Other Names:
  • Zyloprim
Drug: Fludarabine
30 mg/m^2 IV over 1 hour, day -6, -5, -4, -3 and -2
Other Names:
  • Fludara
Drug: Cyclophosphamide
50 mg/kg IV over 2 hours, day -6
Other Names:
  • Cytoxan
Drug: ATG
Only for patients with an unrelated donor (URD) and NO multi-agent chemotherapy 3 months prior to transplant. ATG will be administered IV every 12 hours for 6 doses on days -6, -5, and -4 according to institutional guidelines. Methylprednisolone 1 mg/kg IV administered immediately prior to each dose of ATG (6 doses).
Other Names:
  • Anti-thymocyte globulin
Radiation: TBI
All patients who have had previous radiation therapy or TBI will be seen by Radiation Oncology prior to entrance on the protocol for approval for additional 200 cGy of TBI. TBI may be delivered by local guidelines provided the effective dose is equivalent to what is recommended in the TBI Guidelines. The dose of TBI will be 200 cGy given in a single fraction on day -1.
Other Names:
  • Total body irradiation
Drug: Tacrolimus

All patients will receive tacrolimus therapy beginning on day -3. Initial dosing of tacrolimus will be 0.03 - 0.05 mg/kg/day IV; if the recipient body weight is <40 kg, dosing will be 3 times daily, and if ≥ 40 kg, twice daily or per current institutional guidelines.

An attempt will be made to maintain a trough level of 5-10 ng/mL and subsequent dose modifications will be provided by the pharmacist.

Once the patient can tolerate oral medications and has a reasonable oral intake, tacrolimus will be converted to an oral form based on the current IV dose providing normal renal and hepatic function and no major drug interactions.

The timing of the tacrolimus taper will be at the discretion of the treating physician, but in general:

  • Taper begins at day +100 +/- 10 days, if the patient is stably engrafted and has no active GVHD.
  • Taper to zero by reducing dose by approximately 10% a week (rounded to nearest pill size), with a goal to discontinue by month 6 post-HCT.
Other Names:
  • Prograf
Drug: MMF

3 gram/day IV/PO for patients who are ≥ 40 kg divided in 2 or 3 doses. In obese patients (>125% IBW) 15 mg/kg every 12 hours may be considered. Pediatric patient (<40 kilograms) will receive MMF at the dose of 15 mg/kg/dose every 8 hours beginning day -3. MMF dosing will be monitored and altered as clinically appropriate based on institutional guidelines. Patients will be eligible for MMF dosing and pharmacokinetics studies.

MMF will stop at day +30 or 7 days after engraftment, whichever day is later, if no acute GVHD. (Definition of engraftment is 1st day of 3 consecutive days of absolute neutrophil count [ANC) ≥ 0.5 x 109 /L]). If no donor engraftment, MMF will continue as long as clinically indicated.

Other Names:
  • Mycophenolate Mofetil
Biological: Peripheral Blood Stem Cells
On day 0, patients will receive an allogeneic transplant using PBSC which are CD34+ selected as the donor graft. The graft will be infused over 15-60 minutes after premedication with acetaminophen 650 mg PO and diphenhydramine 25 mg PO/IV with doses adjusted for pediatric patients.
Biological: Related or Unrelated Bone Marrow Cells
On day 0, a target dose of 3 x 10^8 nucleated cells/kg recipient weight will be collected. The graft will be infused over 15-60 minutes after premedication with acetaminophen 650 mg PO and diphenhydramine 25 mg PO/IV with doses adjusted for pediatric patients.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Evaluate rates of acute graft-versus-host disease (GVHD) II-IV
Time Frame: Day 100 post transplant
Percent of subjects with grade II-IV acute GVHD
Day 100 post transplant

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Evaluate rates of chronic GVHD
Time Frame: 1 year post transplant
Percent of subjects with chronic GVHD
1 year post transplant
Evaluate neutrophil engraftment without ATG (in siblings)
Time Frame: Day 42 post transplant
Percent of subjects with neutrophil engraftment without ATG (in siblings)
Day 42 post transplant
Evaluate neutrophil engraftment with ATG (in unrelated donors)
Time Frame: Day 42 post transplant
Percent of subjects with neutrophil engraftment with ATG (in unrelated donors)
Day 42 post transplant
Evaluate neutrophil engraftment without ATG (in unrelated donors)
Time Frame: Day 42 post transplant
Percent of subjects with neutrophil engraftment without ATG (in unrelated donors)
Day 42 post transplant
Evaluate relapse without ATG (in siblings) - 1 year
Time Frame: 1 year post transplant
Percent of subjects who relapsed without ATG (in siblings)
1 year post transplant
Evaluate relapse without ATG (in siblings) - 2 years
Time Frame: 2 years post transplant
Percent of subjects who relapsed without ATG (in siblings)
2 years post transplant
Evaluate relapse with ATG (in unrelated donors) - 1 year
Time Frame: 1 year post transplant
Percent of subjects who relapsed with ATG (in unrelated donors)
1 year post transplant
Evaluate relapse with ATG (in unrelated donors) - 2 years
Time Frame: 2 years post transplant
Percent of subjects who relapsed with ATG (in unrelated donors)
2 years post transplant
Evaluate relapse without ATG (in unrelated donors) - 1 year
Time Frame: 1 year post transplant
Percent of subjects who relapsed without ATG (in unrelated donors)
1 year post transplant
Evaluate relapse without ATG (in unrelated donors) - 2 years
Time Frame: 2 years post transplant
Percent of subjects who relapsed without ATG (in unrelated donors)
2 years post transplant
Overall survival
Time Frame: Day 100 post transplant
Percent of surviving subjects
Day 100 post transplant
Overall survival
Time Frame: 1 year post transplant
Percent of surviving subjects
1 year post transplant
Overall survival
Time Frame: 3 years post transplant
Percent of surviving subjects
3 years post transplant
Transplant related mortality (TRM)
Time Frame: Day 100 post transplant
Percent of subjects with TRM
Day 100 post transplant
Transplant related mortality (TRM)
Time Frame: 1 year post transplant
Percent of subjects with TRM
1 year post transplant

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Masonic Cancer Center, University of Minnesota

Investigators

  • Principal Investigator: Erica Warlick, MD, Masonic Cancer Center, University of Minnesota

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 9, 2017

Primary Completion (Actual)

April 17, 2023

Study Completion (Actual)

May 29, 2023

Study Registration Dates

First Submitted

January 19, 2016

First Submitted That Met QC Criteria

January 20, 2016

First Posted (Estimated)

January 21, 2016

Study Record Updates

Last Update Posted (Actual)

September 21, 2023

Last Update Submitted That Met QC Criteria

September 19, 2023

Last Verified

September 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2015LS152

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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