Donor Stem Cell Transplant in Treating Patients With Relapsed Hematologic Malignancies or Secondary Myelodysplasia Previously Treated With High-Dose Chemotherapy and Autologous Stem Cell Transplant

February 6, 2017 updated by: Alliance for Clinical Trials in Oncology

Reduced-Intensity Allogeneic Hematopoietic Cell Transplantation as Second Transplantation for Patients With Disease Relapse or Myelodysplasia After Prior Autologous Transplantation

RATIONALE: Giving chemotherapy, such as busulfan and fludarabine phosphate, before a peripheral blood stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving methotrexate, tacrolimus, and antithymocyte globulin before and after the transplant may stop this from happening. Once the donated stem cells begin working, the patient's immune system may see the remaining cancer cells as not belonging in the patient's body and destroy them (called graft-versus-tumor effect). Giving an infusion of the donor's white blood cells (donor lymphocyte infusion) may boost this effect.

PURPOSE: This phase II trial is studying how well donor stem cell transplant works in treating patients with relapsed hematologic malignancies or secondary myelodysplasia previously treated with high-dose chemotherapy and autologous stem cell transplant .

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

OBJECTIVES:

Primary

  • To demonstrate the efficacy of performing reduced-intensity conditioning allogeneic hematopoietic cell transplantation in patients with relapsed hematologic malignancies or secondary myelodysplasia after completion of prior high-dose chemotherapy and autologous hematopoietic stem cell transplantation.
  • To compare the strategy of this regimen with the strategy used in CALGB-100002.

Secondary

  • To describe the response rate at 6 and 12 months in patients treated with this regimen.
  • To describe the time-to-progression in patients treated with this regimen.
  • To determine the ability to use pharmacokinetic-directed busulfan to achieve AUC within 20% of target AUC in > 80% of patients.
  • To determine percent of donor chimerism in T-cell, myeloid and B-cell populations achieved with this regimen compared with CALGB-100002.
  • To determine the risk of acute and chronic graft-versus-host disease and other toxicities of this regimen in these patients.
  • To describe the overall survival and disease-free survival of patients treated on this regimen.
  • To determine the rate of viral, bacterial, and fungal opportunistic infections occurring in the first year after transplantation compared with CALGB-100002.

OUTLINE: This is a multicenter study.

  • Preparative Regimen:

    • Busulfan test dose: Patients receive busulfan IV over 45 minutes once during days -14 and -9.
    • Busulfan treatment dose: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3 and busulfan IV over 3 hours on days -6 to -3.

  • Graft-vs-Host Disease (GVHD) Prophylaxis:

    • HLA-identical donor: Patients receive antithymocyte globulin IV over 6-10 hours on days -6 to -5; oral tacrolimus twice daily on days -2 to 90 followed by a taper* as tolerated until day 150 or 180; and methotrexate IV on days 1, 3, and 6.

NOTE: * Tacrolimus may be tapered on days 60-90 if donor chimerism of CD3+ cells is < 50% at day 60 or patient has progressive disease.

  • Matched-unrelated donor: Patients receive antithymocyte globulin, tacrolimus, and methotrexate as in HLA-identical donor regimen. Patients also receive oral mycophenolate mofetil twice daily on days 0 to 60.

    • Allogeneic Stem Cell Transplantation: Patients undergo allogeneic peripheral blood stem cell transplantation on days 0 and 1. Patients then receive filgrastim subcutaneously daily beginning on day 7 and continuing until blood counts recover.
    • Donor Lymphocyte Infusion (DLI): After day 180 (or day 210 for patients without an HLA-identical donor), patients with stable or progressive disease and no active GVHD may receive up to 3 DLIs every 8 weeks.

Blood samples are collected at baseline and then periodically during study therapy for pharmacokinetic studies.

After completion of study therapy, patients are followed up every 3 months for 2 years and then every 6 months for up to 5½ years.

Study Type

Interventional

Enrollment (Actual)

6

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
    • Delaware
      • Lewes, Delaware, United States, 19958
        • Tunnell Cancer Center at Beebe Medical Center
      • Newark, Delaware, United States, 19713
        • CCOP - Christiana Care Health Services
    • Florida
      • Orlando, Florida, United States, 32803-1273
        • Florida Hospital Cancer Institute at Florida Hospital Orlando
    • Maryland
      • Baltimore, Maryland, United States, 21201
        • Greenebaum Cancer Center at University of Maryland Medical Center
      • Elkton MD, Maryland, United States, 21921
        • Union Hospital of Cecil County
    • Missouri
      • Saint Louis, Missouri, United States, 63110
        • Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
    • New Jersey
      • Voorhees, New Jersey, United States, 08043
        • Cancer Institute of New Jersey at Cooper - Voorhees
    • New York
      • New York, New York, United States, 10021
        • New York Weill Cornell Cancer Center at Cornell University
    • North Carolina
      • Winston-Salem, North Carolina, United States, 27157-1096
        • Wake Forest University Comprehensive Cancer Center
    • Ohio
      • Columbus, Ohio, United States, 43210-1240
        • Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center

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 69 years (ADULT, OLDER_ADULT, CHILD)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

DISEASE CHARACTERISTICS:

  • Histologically confirmed hematologic malignancies:

    • Chronic lymphocytic leukemia (CLL) or prolymphocytic leukemia (PLL)

      • Absolute lymphocytosis of > 5,000/μL

      • Lymphocytes must appear morphologically mature with < 55% prolymphocytes (CLL)

        • Patients with > 55% prolymphocytes are considered as having PLL
      • Lymphocyte phenotype with expression of CD20, CD19, and CD5 (CLL)

    • Non-Hodgkin lymphoma

      • Any WHO classification of histologic subtype
      • Core biopsies acceptable for primary diagnosis and immunophenotyping
      • Bone marrow biopsies as sole means of diagnosis not allowed for follicular lymphoma

    • Hodgkin lymphoma

      • Any WHO classification of histologic subtype
      • Core biopsies acceptable for primary diagnosis and immunophenotyping
      • Bone marrow biopsy is required

    • Multiple myeloma

      • Patients must have active disease requiring treatment (Durie-Salmon stage I-III)

    • Acute myeloid leukemia

      • Must have < 10% bone marrow blasts and no circulating blasts

    • Myelodysplastic syndrome (MDS)

      • MDS as define by WHO criteria
      • Must have < 10% marrow blasts

  • Relapsed or progressive disease or myelodysplasia ≥ 6 months after prior high-dose chemotherapy with autologous hematopoietic cell support

    • Prior syngeneic transplantation allowed

  • Healthy donor meeting one of the following criteria:

    • HLA-identical sibling (6/6)

      • Serologic typing for class I (A, B) and molecular typing for class II (DRB1) required

    • 8/8 matched-unrelated donor

      • Molecular identity at HLA A, B, C, and DRB1 by high-resolution typing required
    • No syngeneic donors

PATIENT CHARACTERISTICS:

  • Creatinine clearance ≥ 40 mL/min
  • Total bilirubin ≤ 2 mg/dL
  • AST ≤ 3 times upper limit of normal
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • DLCO ≥ 40% with no symptomatic pulmonary disease
  • LVEF ≥ 30% by MUGA or ECHO
  • No uncontrolled diabetes mellitus or active serious infection
  • No known hypersensitivity to E.coli-derived products
  • No HIV infection

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics
  • At least 4 weeks should elapse between prior standard cytotoxic chemotherapy, radiation therapy, or surgery and the planned start of the preparative regimen on day -7

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: NA
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Treatment

Matched-unrelated donor: Patients receive antithymocyte globulin, tacrolimus, and methotrexate as in HLA-identical donor regimen. Patients also receive oral mycophenolate mofetil twice daily on days 0 to 60.

Allogeneic Stem Cell Transplantation: Patients undergo allogeneic peripheral blood stem cell transplantation on days 0 and 1. Patients then receive filgrastim subcutaneously daily beginning on day 7 and continuing until blood counts recover.

Donor Lymphocyte Infusion (DLI): After day 180 (or day 210 for patients without an HLA-identical donor), patients with stable or progressive disease and no active GVHD may receive up to 3 DLIs every 8 weeks.

Blood samples are collected at baseline and then periodically during study therapy for pharmacokinetic studies.

After completion of study therapy, patients are followed up every 3 months for 2 years and then every 6 months for up to 5½ years.
Drug: methotrexate
Biological: anti-thymocyte globulin
Biological: therapeutic allogeneic lymphocytes
Drug: fludarabine phosphate
Procedure: allogeneic hematopoietic stem cell transplantation
Drug: busulfan
Procedure: peripheral blood stem cell transplantation
Biological: filgrastim
Drug: tacrolimus
Drug: mycophenolate mofetil
Biological: donor lymphocytes
Other: reduced-intensity transplant conditioning procedure

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Event-free Survival (EFS)
Time Frame: Duration of study (up to 5.5 years)
EFS was defined as the date of transplant to date of progression or develop myelodysplasia after autologous transplant. EFS was estimated using the Kaplan Meier method.
Duration of study (up to 5.5 years)
Comparison of EFS Distribution to That of CALGB-100002
Time Frame: 2 years
EFS distributions between CALGB-100002 and this study will be compared using the two-sample log-rank test.
2 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Complete Response Rate
Time Frame: Up to 5.5 years
Complete response (CR) rate is reported as the percentage of participants who achieved a CR.
Up to 5.5 years
Overall Survival
Time Frame: Up to 5.5 years
Overall survival (OS) was defined as the transplant from registration to death of any cause. Surviving patients were censored at the date of last follow-up. The median OS with 95% confidence interval (CI) was estimated using the Kaplan Meier method.
Up to 5.5 years
Rate of Opportunistic Infections
Time Frame: 1 year post transplant
Percent of participants who have an opportunistic (viral, bacterial and fungal) infection in the first year following transplant.
1 year post transplant

Collaborators and Investigators

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

Sponsor

Alliance for Clinical Trials in Oncology

Collaborators

National Cancer Institute (NCI)

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

December 1, 2010

Primary Completion (ACTUAL)

March 1, 2012

Study Completion (ACTUAL)

August 1, 2013

Study Registration Dates

First Submitted

May 5, 2010

First Submitted That Met QC Criteria

May 5, 2010

First Posted (ESTIMATE)

May 6, 2010

Study Record Updates

Last Update Posted (ACTUAL)

March 24, 2017

Last Update Submitted That Met QC Criteria

February 6, 2017

Last Verified

February 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CALGB-100601
  • CDR0000667954 (REGISTRY: NCI Physician Data Query)

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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