Donor Stem Cell Transplant in Treating Patients With Relapsed Hematologic Cancer

Non-Myeloablative Allogeneic Hematopoietic Cell Transplantation For Patients With Disease Relapse Or Myelodysplasia After Prior Autologous Transplantation

RATIONALE: Giving low doses of chemotherapy, such as fludarabine and busulfan, before a donor bone marrow or peripheral blood stem cell transplant helps stop the growth of cancer cells. It also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune system and help destroy any remaining cancer cells (graft-versus-tumor effect). Giving an infusion of the donor's T cells (donor lymphocyte infusion) after the transplant may help increase this effect. Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving immunosuppressive therapy after the transplant may stop this from happening.

PURPOSE: This phase II trial is studying how well donor bone marrow or peripheral stem cell transplant works in treating patients with relapsed hematologic cancer after treatment with chemotherapy and autologous stem cell transplant.

Study Overview

• Status: Completed
• Conditions: Lymphoma; Myelodysplastic Syndromes; Leukemia; Multiple Myeloma; Plasma Cell Neoplasm; Myeloproliferative Neoplasms
• Intervention / Treatment: Biological: anti-thymocyte globulin; Biological: G-CSF; Drug: busulfan; Drug: fludarabine phosphate; Drug: methotrexate; Drug: mycophenolate mofetil; Drug: tacrolimus; Procedure: allogeneic cell transplantation; Drug: allopurinol

Detailed Description

OBJECTIVES:

• Determine the feasibility of non-myeloablative allogeneic hematopoietic stem cell transplantation by demonstrating that the risk of treatment-related mortality during the first 6 months is an acceptable rate of less than 40% in patients with relapsed hematologic malignancies after prior high-dose chemotherapy and autologous stem cell transplantation.
• Determine the response rates (disease-specific partial and complete response) in patients treated with this regimen.
• Determine the 6-month and 12-month probabilities of response in patients treated with this regimen.
• Determine the distribution of time-to-progression in patients responding to this regimen.
• Determine the percent donor chimerism in patients treated with this regimen.
• Determine the risk of acute and chronic graft-vs-host disease in patients treated with this regimen.
• Determine the toxic effects of this regimen in these patients.
• Determine the disease-free and overall survival of patients treated with this regimen.

OUTLINE: This is an open-label study.

• Preparative Regimen: Patients receive fludarabine IV over 30 minutes on days -7 to -3 and busulfan IV over 2 hours every 6 hours (for a total of 8 doses) on days -4 and -3.
• Graft vs Host Disease (GVHD) Prophylaxis: Patients who have an HLA-identical donor receive oral (or IV if unable to tolerate oral administration) tacrolimus twice daily on days -1 to 90 followed by a taper^* until day 150 and methotrexate IV on days 1, 3, and 6. Patients with a matched related or matched unrelated donor receive oral (or IV if unable to tolerate oral administration) tacrolimus twice daily on days -1 to 180 followed by a taper^* as tolerated; methotrexate IV on days 1, 3, 6, and 11; oral mycophenolate mofetil twice daily on days -2 to 60 followed by a taper; and rabbit anti-thymocyte globulin IV over 4-6 hours on days -4 to -1 (for a total of 4 doses).

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

• Allogeneic Stem Cell Transplantation: Patients undergo allogeneic bone marrow or peripheral blood stem cell transplantation on days 0 and 1. Patients then receive filgrastim (G-CSF) 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.

Patients are followed within 2-3 months, every 3 months for 2 years, and then every 6 months for 3 years.

• Study Type: Interventional
• Enrollment (Actual): 82
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • La Jolla, California, United States, 92093-0658
      • Rebecca and John Moores UCSD Cancer Center
  • Delaware
    • Lewes, Delaware, United States, 19958
      • Beebe Medical Center
    • Newark, Delaware, United States, 19713
      • CCOP - Christiana Care Health Services
    • Wilmington, Delaware, United States, 19805
      • St. Francis Hospital
  • Maryland
    • Elkton MD, Maryland, United States, 21921
      • Union Hospital Cancer Center at Union Hospital
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Siteman Cancer Center at Barnes-Jewish Hospital
  • New Jersey
    • Voorhees, New Jersey, United States, 08043
      • Cancer Institute of New Jersey at the Cooper University Hospital - Voorhees
  • New York
    • Buffalo, New York, United States, 14263-0001
      • Roswell Park Cancer Institute
  • 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 Solove Research Institute at Ohio State University
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224-1791
      • Western Pennsylvania Cancer Institute at Western Pennsylvania Hospital
  • Virginia
    • Richmond, Virginia, United States, 23298-0037
      • Massey Cancer Center at Virginia Commonwealth University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 69 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed hematologic malignancy, including one of the following:

  • Chronic lymphocytic leukemia (CLL)

    • Absolute lymphocytosis greater than 5,000/mm^3
    • Lymphocytes must appear morphologically mature with less than 55% prolymphocytes
    • Lymphocyte phenotype with expression of CD19 and CD5

  • Prolymphocytic leukemia (PLL)

    • Morphologically confirmed
    • Absolute lymphocytosis greater than 5,000/mm^3
    • More than 55% prolymphocytes

  • Non-Hodgkin's lymphoma or Hodgkin's lymphoma

    • Any WHO histologic subtype allowed except mantle cell lymphoma
    • Core biopsies allowed if they contain adequate tissue for primary diagnosis and immunophenotyping
    • No bone marrow biopsy as the sole diagnostic means for follicular lymphoma

  • Multiple myeloma

    • Active disease requiring treatment
    • Durie-Salmon stage I, II, or III

  • Acute myeloid leukemia

    • Documented control (i.e., less than 10% bone marrow blasts and no circulating blasts)

  • Myelodysplastic syndromes

    • Documented disease by WHO criteria
• Must have evidence of relapse/progression at least 6 months after prior high-dose chemotherapy with autologous hematopoietic stem cell support
• Absence of CD23 expression for CLL or PLL allowed provided there is no morphologic evidence of mantle cell lymphoma

• Availability of any of the following donor types:

  • HLA-identical sibling (6/6)

  • 9/10 matched related donor by high-resolution molecular typing at HLA A, B, C, DRB1, and DQB1 loci

    • Only a single mismatch at one class I or II allele allowed
  • 10/10 matched unrelated donor by high-resolution molecular typing at HLA A, B, C, DRB1, and DQB1 loci
• No syngeneic donors

PATIENT CHARACTERISTICS:

Age

• Under 70

Performance status

• Not specified

Life expectancy

• Not specified

Hematopoietic

• See Disease Characteristics

Hepatic

• Bilirubin no greater than 3 times upper limit of normal (ULN)
• AST no greater than 3 times ULN

Renal

• Creatinine clearance at least 40 mL/min

Cardiovascular

• LVEF at least 30% by MUGA

Pulmonary

• DLCO greater than 40%
• No symptomatic pulmonary disease

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• HIV negative
• No uncontrolled diabetes mellitus
• No active serious infection
• No known hypersensitivity to E. coli-derived products

PRIOR CONCURRENT THERAPY:

Biologic therapy

• See Disease Characteristics

Chemotherapy

• See Disease Characteristics
• More than 4 weeks since prior chemotherapy

Endocrine therapy

• Not specified

Radiotherapy

• More than 4 weeks since prior radiotherapy

Surgery

• More than 4 weeks since prior surgery

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Non myeloblative allogeneic transplant; Non myeloblative allogeneic hematopoietic cell transplantation after prior autologous transplantation

Biological: anti-thymocyte globulin; 2.5mg/kg/day IV infusion over 6 hrs x 4 doses Days -4 to -1 (for MUD and 9/10 related donor transplants only); Biological: G-CSF; 5 ug/kg/day subQ injection Day 7 until ANC> 1000/uL for 3 consec days; Other Names: filgrastim; Drug: busulfan; 0.8mg/kg IV infusion over 2 hrs q 6 hrs x 8 doses Days -4 thru -3; Drug: fludarabine phosphate; 30 mg/sq m/day IVBP over 30 min Days -7 thru -3; Drug: methotrexate; 5 mg/sq m/day IV infusion Days 1, 3, & 6 for HLA-identical donor transplants and Days 1, 3, 6, & 11 for MUD & 9/10 related donor transplants; Drug: mycophenolate mofetil; 15mg/kg PO bid Day -2 to Day 60, then taper as tolerated (for MUD and 9/10 related donor transplants only); Drug: tacrolimus; target serum level is 5-10 ng/mL. Start with 0.03mg/kg PO bid Day -1 to Day 90, then taper thru Day 150 for HLA identical donor transplants and Day -1 to Day 180 then taper for MUD and 9/10 related donor transplants; Procedure: allogeneic cell transplantation; 2,000,000-8,000,000 CD34+ cells total via infusion Days 0 and 1; Drug: allopurinol; 300 mg/day PO Days -8 thru -1

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Treatment-related mortality	6 months post transplant

Secondary Outcome Measures

Outcome Measure	Time Frame
Per cent donor chimerism	30, 60, 90, 180 days post transplant
Disease-free survival	12 months up to 5 years post study entry
Graft-versus-host disease incidence	6 months post transplant
Response Rates	6 and 12 months

Collaborators and Investigators

• Sponsor: Alliance for Clinical Trials in Oncology
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Asad Bashey, MD, PhD, University of California, San Diego

Publications and helpful links

General Publications

• Bashey A, Owzar K, Johnson JL, Edwards PS, Kelly M, Baxter-Lowe LA, Devine S, Farag S, Hurd D, Ball E, McCarthy P, Lister J, Shea TC, Linker C. Reduced-intensity conditioning allogeneic hematopoietic cell transplantation for patients with hematologic malignancies who relapse following autologous transplantation: a multi-institutional prospective study from the Cancer and Leukemia Group B (CALGB trial 100002). Biol Blood Marrow Transplant. 2011 Apr;17(4):558-65. doi: 10.1016/j.bbmt.2010.07.015. Epub 2010 Jul 30.
• Bashey A, Owzar K, Johnson JL, et al.: Reduced-intensity allogeneic transplantation after failure of autologous transplantation: a prospective multi-center CALGB study. [Abstract] Blood 108 (11): A-3122, 2006.

Study record dates

Study Major Dates

• Study Start: December 1, 2002
• Primary Completion (Actual): November 1, 2006
• Study Completion (Actual): August 1, 2010

Study Registration Dates

• First Submitted: January 27, 2003
• First Submitted That Met QC Criteria: January 27, 2003
• First Posted (Estimate): January 28, 2003

Study Record Updates

• Last Update Posted (Estimate): July 1, 2016
• Last Update Submitted That Met QC Criteria: June 30, 2016
• Last Verified: June 1, 2016

More Information

Terms related to this study

• Keywords: recurrent grade 3 follicular lymphoma; recurrent adult diffuse large cell lymphoma; recurrent adult immunoblastic large cell lymphoma; recurrent adult Burkitt lymphoma; recurrent childhood small noncleaved cell lymphoma; recurrent childhood large cell lymphoma; de novo myelodysplastic syndromes; previously treated myelodysplastic syndromes; secondary myelodysplastic syndromes; adult acute myeloid leukemia with 11q23 (MLL) abnormalities; adult acute myeloid leukemia with inv(16)(p13;q22); adult acute myeloid leukemia with t(15;17)(q22;q12); adult acute myeloid leukemia with t(16;16)(p13;q22); adult acute myeloid leukemia with t(8;21)(q22;q22); childhood myelodysplastic syndromes; recurrent adult acute myeloid leukemia; recurrent adult Hodgkin lymphoma; recurrent/refractory childhood Hodgkin lymphoma; recurrent adult diffuse small cleaved cell lymphoma; recurrent adult diffuse mixed cell lymphoma; stage II multiple myeloma; stage III multiple myeloma; recurrent grade 1 follicular lymphoma; recurrent grade 2 follicular lymphoma; recurrent marginal zone lymphoma; recurrent small lymphocytic lymphoma; extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue; nodal marginal zone B-cell lymphoma; splenic marginal zone lymphoma; stage I multiple myeloma; refractory chronic lymphocytic leukemia; refractory multiple myeloma; prolymphocytic leukemia; recurrent childhood acute myeloid leukemia; myelodysplastic/myeloproliferative neoplasm, unclassifiable; atypical chronic myeloid leukemia, BCR-ABL negative; recurrent childhood lymphoblastic lymphoma
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease; Bone Marrow Diseases; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Precancerous Conditions; Neoplasms; Lymphoma; Syndrome; Myelodysplastic Syndromes; Multiple Myeloma; Neoplasms, Plasma Cell; Leukemia; Preleukemia; Plasmacytoma; Myeloproliferative Disorders; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Dermatologic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Reproductive Control Agents; Antioxidants; Antitubercular Agents; Free Radical Scavengers; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Gout Suppressants; Antibiotics, Antitubercular; Calcineurin Inhibitors; Fludarabine; Fludarabine phosphate; Methotrexate; Tacrolimus; Mycophenolic Acid; Busulfan; Allopurinol; Antilymphocyte Serum
• Other Study ID Numbers: CALGB-100002; U10CA031946 (U.S. NIH Grant/Contract); CDR0000269301 (Registry Identifier: NCI Physician Data Query)