Donor Stem Cell Transplant in Treating Patients With High-Risk Hematologic Cancer

October 28, 2013 updated by: Northside Hospital, Inc.

Reduced Intensity Allogeneic Stem Cell Transplantation With Matched Unrelated Donors for Patients With Hematologic Malignancies

RATIONALE: Giving low doses of chemotherapy before a donor 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. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving a monoclonal antibody, such as alemtuzumab, before transplant and tacrolimus and methotrexate after transplant may stop this from happening.

PURPOSE: This phase II trial is studying the side effects of donor stem cell transplant and to see how well it works in treating patients with high-risk hematologic cancer.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

OBJECTIVES:

  • To evaluate the safety and toxicity of a reduced-intensity conditioning regimen followed by allogeneic bone marrow or peripheral blood stem cell transplantation from an HLA-matched unrelated donor in patients with high-risk hematologic malignancies.
  • To evaluate engraftment by peripheral blood chimerism analysis.
  • To determine the incidence and severity of acute and chronic graft-versus-host disease following the transplant.
  • To examine the possibility of controlling hematologic malignancies by induction of a graft-versus-leukemia/tumor effect.
  • To determine the disease-free survival, relapse, transplant-related mortality, and death from all causes.

OUTLINE:

  • Reduced-intensity conditioning regimen: Patients receive 1 of 2 conditioning regimens according to diagnosis.

    • Regimen 1 (acute leukemia, myelodysplastic syndromes, myeloproliferative syndrome, or chronic myelogenous leukemia): Patients receive fludarabine phosphate IV over 30 minutes and busulfan IV over 3 hours on days -6 to -3 or orally 4 times daily on days -7 to -3.
    • Regimen 2 (lymphoproliferative malignancies): Patients receive fludarabine phosphate IV over 30 minutes and cyclophosphamide IV over 1 hour on days -5 to -3. Patients with CD20+ malignancies also receive rituximab IV over 4-6 hours on days -13, -6, 1, and 8.
  • Transplantation: Patients undergo allogeneic bone marrow or peripheral blood stem cell transplantation on day 0.
  • Graft-versus-host disease (GVHD) prophylaxis: Patients receive low-dose alemtuzumab subcutaneously on days -11 to -9 and tacrolimus IV over 24 hours beginning on day -3 and then orally twice daily beginning on day 14 and continuing until day 60, followed by a taper until day 180 in the absence of clinically significant GVHD. Patients also receive methotrexate on days 1, 3, and 6.

Patients who exhibit persistent mixed chimerism or disease relapse/progression despite full withdrawal of immunosuppression may receive up to 3 donor lymphocyte infusions.

Blood samples are taken on days 30, 60, and 100 and then every 4 weeks thereafter for chimerism studies by PCR analysis.

After completion of study therapy, patients are followed periodically for up to 60 months.

Study Type

Interventional

Enrollment (Actual)

36

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
    • Georgia
      • Atlanta, Georgia, United States, 30342
        • Blood and Marrow Transplant Group of Georgia

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

40 years to 72 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

  • Diagnosis of one of the following hematological malignancies:

    • CML, with 1 of the following:

      • In first CP AND failed imatinib mesylate therapy, defined as failure to obtain a hematologic remission at 3 months or a major cytogenetic response (i.e., Ph+ cells < 35%) at 6 months or demonstrated clonal evolution or disease progression during therapy
      • In accelerated phase with < 15% blasts
      • In blast crisis that has entered into a second CP following induction chemotherapy

    • AML, with 1 of the following:

      • In second or subsequent complete remission (CR) (i.e., < 5% blasts by morphology, no residual leukemia by flow cytometry, and absence of cytogenetic abnormalities)
      • Failed primary induction chemotherapy, but subsequently entered into a CR with ≤ 2 subsequent re-induction chemotherapy treatment(s)
      • In first CR with intermediate-risk or poor-risk cytogenetics

    • ALL with 1 of the following:

      • In second or subsequent CR
      • In first CR AND presence of t(9;22)

    • MDS, with the following:

      • High-risk disease, defined by IPSS score of ≥ 1.5 at diagnosis AND meets 1 of the following criteria:

        • ≤ 10% blasts at diagnosis
        • In morphologic CR (< 5% blasts) following cytoreductive chemotherapy

    • CMML, with 1 of the following:

      • ≤ 10% blasts at diagnosis
      • In morphologic CR (< 5% blasts) following cytoreductive chemotherapy

    • CLL/PLL with the following:

      • Rai stage I-IV disease
      • Failed ≥ 1 prior chemotherapy regimen (including fludarabine phosphate) or ASCT
      • Documented chemosensitive or stable, non-bulky disease prior to transplant, defined as < 20% bone marrow involvement AND lymph node size < 3 cm in axial diameter
      • No bulky tumor masses, elevated lactate dehydrogenase (LDH), B symptoms, or progressive disease prior to transplant

    • Low-grade non-Hodgkin lymphoma (NHL) (i.e., small lymphocytic lymphoma, follicular center lymphoma [grade 1 or 2], marginal zone lymphoma, or B-cell lymphoma), with the following criteria:

      • Failed ≥ 1 prior chemotherapy regimen or ASCT
      • Documented chemosensitive or stable, non-bulky disease prior to transplant, defined as < 20% bone marrow involvement AND lymph node size < 3 cm in axial diameter
      • Received ≤ 3 prior chemotherapy regimens (monoclonal antibody therapy and involved-field radiotherapy are not considered a prior regimen)
      • No bulky tumor masses, elevated LDH, B symptoms, or progressive disease prior to transplant

    • Mantle cell lymphoma, with the following:

      • Failed to achieve remission or recurred after either conventional chemotherapy or ASCT
      • Responsive or stable disease to most recent prior therapy
      • No bulky tumor masses, elevated LDH, B symptoms, or progressive disease prior to transplant

    • Intermediate-grade NHL (i.e., follicular center lymphoma [grade 3] or diffuse large cell lymphoma), meeting the following criteria:

      • Failed to achieve remission or recurred after either conventional chemotherapy or ASCT
      • Documented chemosensitive, non-bulky disease prior to transplant, defined as at least a partial remission to salvage chemotherapy (≥ 50% reduction in diameter of all disease sites)
      • No bulky tumor masses, elevated LDH, B symptoms, or progressive disease prior to transplant

    • Hodgkin lymphoma, with the following:

      • Relapsed after prior ASCT OR after ≥ 2 combination chemotherapy regimens and ineligible for ASCT
      • Documented chemosensitive, non-bulky disease prior to transplant, defined as at least a partial remission to salvage chemotherapy (≥ 50% reduction in diameter of all disease sites)
      • No bulky tumor masses, elevated LDH, B symptoms, or progressive disease prior to transplant

    • Peripheral T-cell NHL, with the following:

      • Failed to achieve remission or recurred after either conventional chemotherapy or ASCT
      • Documented chemosensitive, non-bulky disease prior to transplant, defined as at least a partial remission to salvage chemotherapy (≥ 50% reduction in diameter of all disease sites)
      • No bulky tumor masses, elevated LDH, B symptoms, or progressive disease prior to transplant

  • Myeloproliferative syndrome with poor risk features, meeting 1 of the following criteria:

    • < 55 years old AND Lille score of 1
    • Lille score of 2
    • HgB < 10 g/dL AND abnormal karyotype

  • High-risk disease, with 1 of the following:

    • Age 40-72 years
    • Any age AND deemed to be at significantly increased risk of morbidity and death following a standard, myeloablative unrelated donor stem cell transplant (e.g., received extensive prior therapy, including ASCT)

  • HLA-matched unrelated donor available, with 1 of the following:

    • 8/8 match at HLA-A, B, C, or DR loci by high-resolution genotyping

    • Single allelic mismatch at either the HLA-B or HLA-C loci donor by high-resolution molecular typing

      • No single allelic mismatch at HLA-A or HLA-DR loci
  • KPS 80-100%
  • Adapted weighted Charlson Comorbidity Index < 3
  • Serum creatinine ≤ 2.0 mg/dL
  • AST or ALT < 3 times upper limit of normal (ULN)
  • Total bilirubin < 1.5 times ULN
  • LVEF ≥ 45%
  • DLCO > 50%
  • No hypoxia at rest with oxygen saturation < 92% on room air (corrected with bronchodilator therapy)
  • No other severe pulmonary function abnormalities
  • No HIV infection
  • No active hepatitis B or C infection that, in the opinion of a gastroenterologist or the transplant committee, places the patient at moderate to high risk for developing severe hepatic disease
  • No active opportunistic infection (e.g., fungal pneumonia, tuberculosis, or viral infection)

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
Other: Hematopoietic Stem Cell Transplantation
All patients receive a hematopoietic stem cell transplant using one of two chemotherapy regimens based on donor type
Biological: alemtuzumab
43 mg subcutaneously over 3 days (3 mg on day -11, 10 mg on day -10, 30 mg on day -9)
Other Names:
  • Campath
Biological: graft-versus-tumor induction therapy
curative potential of allogeneic transplant results from the immune anti-tumor effect of donor cells or GVT/GVL
Biological: rituximab
in patients with Cd20+ malignancies: rituximab 375 mg/m*2 day -13. rituximab 1000 mg/m*2 on days, -6, +1, +8.
Other Names:
  • Rituxan
Drug: busulfan
For patients with AML, CML, MDS, MPS and ALL only: IV or oral busulfan may be given IV busulfan: 130 mg/m2 over 3 hours once daily on days -6, -5, -4 and -3 Oral busulfan: taken every 6 hours x 15 doses beginning on day -7 at 6pm and continuing through day -3 at 6am. 1 mg/kg test dose will be given prior to day -7 and PK samples will be drawn to calculate AUC.
Drug: cyclophosphamide
750 mg/m2 infused over 1 hour once daily on days -5, -4 and -3. Cyclophosphamide will be started approximately 4 hours after the start of Fludarabine
Other Names:
  • Cytoxan
Drug: fludarabine phosphate
For patients with CLL, NHL & HD: 30 mg/m2 infused over 30 minutes once daily on days -5, -4 and -3 For patients with AML, CML, MDS, MPS and ALL: 40 mg/m2 infused over 30 minutes once daily on days -6, -5, -4 and -3.
Other Names:
  • Fludara
Drug: methotrexate
5 mg/m2 administered on days +1, +3 and +6
Drug: tacrolimus
0.03mg/kg/day infused over 24 hours starting on day -1 and switched to oral (twice daily divided dose) on day 14 or when able to tolerate PO
Other Names:
  • Prograf; FK506
Procedure: allogeneic bone marrow transplantation
Recipients will receive an allogeneic transplant on day 0 after receiving high-dose chemotherapy. This trial uses matched unrelated donor stem cells.
Other Names:
  • HSCT, allo transplant

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Survival at Day 100
Time Frame: 100 day
Survival at Day 100
100 day

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall Survival at 1 Year
Time Frame: 1 year
Evaluation of overall survival at 1 year (# of patients who are alive at 1 year post-transplant)
1 year
Non-relapse Mortality at Day 100
Time Frame: Day 100
patients are evaluable for their cause of death at Day 100
Day 100
Non-relapse Mortality at 1 Year Post-transplant
Time Frame: 1 year
Number of patients who died of non-relapse causes at one year. this is in clusive of all patients who were transplanted on study even though only 10 patients died at by 1 year time point. This outcome will be referenced in the donor chimerism outcome. Only 26/36 patients were eligible for this time point as that is all that were alive.
1 year
Complete Donor Chimerism
Time Frame: 2 years
Complete donor chimerism (defined as >/= 95% donor cells in peripheral blood CD3+ and CD33+ was measured.
2 years
Neutrophil Recovery
Time Frame: Day 100
The number of patients experiencing neutrophil recovery post transplant
Day 100
Platelet Engraftment
Time Frame: Day 100
The number of patients experiencing platelet engraftment post-transplant
Day 100
Number of Patients Requiring the Use of Donor Leukocyte Infusion (DLI) for Early Mixed T-cell Chimerism
Time Frame: Day 100
DLI is used for patients with mixed chimerism following transplant
Day 100
Number of Patients Experiencing Grade 2-4 Acute Graft-versus-host Disease Post-transplant
Time Frame: patients were followed for 2 years
patients experiencing acute graft versus host disease post-transplant
patients were followed for 2 years
Number of Patients Experiencing Chronic Graft Versus Host Disease
Time Frame: >100 days post-transplant
>100 days post-transplant
Number of Patients Experiencing Veno-occlusive Disease (VOD) Post-transplant
Time Frame: 4 years
Patients will be evaluated up to 4 years post transplant
4 years

Collaborators and Investigators

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

Sponsor

Northside Hospital, Inc.

Collaborators

Blood and Marrow Transplant Group of Georgia

Investigators

  • Principal Investigator: Scott R. Solomon, MD, Blood and Marrow Transplant Group of Georgia

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

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

May 1, 2005

Primary Completion (Actual)

March 1, 2011

Study Completion (Actual)

March 1, 2012

Study Registration Dates

First Submitted

January 7, 2009

First Submitted That Met QC Criteria

January 7, 2009

First Posted (Estimate)

January 8, 2009

Study Record Updates

Last Update Posted (Estimate)

December 18, 2013

Last Update Submitted That Met QC Criteria

October 28, 2013

Last Verified

October 1, 2013

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CDR0000630617
  • BMTGG-NSH-756 (Other Identifier: Northside Hospital, Inc)

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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