Donor Peripheral Stem Cell Transplant in Treating Patients With Advanced Hematologic Cancer or Other Disorders

A Phase II Trial of Allogeneic Peripheral Blood Stem Cell Transplantation From Matched Unrelated Donors in Patients With Advanced Hematologic Malignancies and Hematological Disorders

RATIONALE: Giving chemotherapy and total-body irradiation before a donor peripheral stem cell transplant helps stop the growth of cancer or abnormal cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving tacrolimus, methotrexate, cyclosporine, mycophenolate mofetil, and sirolimus before and after transplant may stop this from happening.

PURPOSE: This phase II trial is studying how well donor peripheral stem cell transplant works in treating patients with advanced hematologic cancer or other disorders.

Study Overview

• Status: Active, not recruiting
• Conditions: Lymphoma; Myelodysplastic Syndromes; Leukemia; Chronic Myeloproliferative Disorders; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic/Myeloproliferative Diseases; Graft Versus Host Disease; Precancerous/Nonmalignant Condition
• Intervention / Treatment: Drug: cyclophosphamide; Drug: etoposide; Drug: methotrexate; Drug: fludarabine phosphate; Procedure: allogeneic hematopoietic stem cell transplantation; Radiation: total-body irradiation; Drug: busulfan; Procedure: peripheral blood stem cell transplantation; Drug: melphalan; Drug: cyclosporine; Drug: tacrolimus; Drug: sirolimus; Drug: mycophenolate mofetil

Detailed Description

OBJECTIVES:

Primary

• To evaluate hematopoietic recovery, using neutrophil and platelet engraftment as the primary criterion, in patients with advanced hematologic malignancies or other disorders undergoing allogeneic peripheral blood stem cell (PBSC) transplantation from matched unrelated donors.
• To evaluate the incidence of acute and chronic graft-versus-host-disease (GVHD) in patients undergoing allogeneic PBSC transplantation from matched unrelated donors.

Secondary

• To evaluate the impact of HLA class I and class II allele-matching on the incidence of GVHD and on the survival outcome of these patients.
• To evaluate overall survival, disease-free survival, and relapse in these patients.

OUTLINE: Patients are stratified according to type of conditioning regimen (myeloablative vs reduced-intensity myeloablative). Patients are assigned to a conditioning regimen according to diagnosis, age, disease status, prior radiotherapy, and prior autologous stem cell transplantation.

• Conditioning regimen:

  • Regimen I: Patients undergo total body irradiation (TBI) on days -7 to -4 and receive cyclophosphamide IV on days -3 and -2. Alternatively, patients may receive cyclophosphamide on days -7 and -6 and undergo TBI on days -4 to -1.
  • Regimen II: Patients receive busulfan IV over 2 hours once on day -8 and then every 6 hours on days -7 to -4. Patients also receive cyclophosphamide IV on days -3 and -2.
  • Regimen III: Patients undergo TBI on days -7 to -4 and receive etoposide IV on day -3.
  • Regimen IV: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3 and melphalan IV on day -2.
  • Regimen V: Patients receive fludarabine phosphate IV over 30 minutes on days -4 to -2 and undergo TBI on day 0.
  • Regimen VI: Patients receive busulfan IV over 3 hours and fludarabine phosphate IV over 30 minutes on days -5 to -2.
• Allogeneic peripheral blood stem cell (PBSC) transplantation: All patients undergo allogeneic PBSC transplantation on day 0.

• Graft-versus-host disease (GVHD) prophylaxis: Patients receive one of the following GVHD prophylaxis regimens:

  • Regimen A: Patients receive tacrolimus IV or orally on days -1 to 180 and methotrexate IV on days 1, 3, 6, and 11.
  • Regimen B: Patients receive cyclosporine IV or orally twice daily on days -1 to 180, mycophenolate mofetil IV over 2 hours or orally twice daily on days 0-27, and methotrexate IV on days 1, 3, and 6.
  • Regimen C: Patients receive tacrolimus IV continuously or orally, and oral sirolimus beginning on day -3. Patients also receive methotrexate IV on days 1, 3, and 6.

After completion of study therapy, patients are followed periodically.

• Study Type: Interventional
• Enrollment (Actual): 260
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 second to 120 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

DISEASE CHARACTERISTICS:

• Diagnosis of one of the following:

  • Acute lymphocytic leukemia (ALL), meeting one of the following criteria:

    • In first relapse or beyond

    • High-risk ALL, defined by any of the following:

      • Hypoploidy (≤ 44 chromosomes)
      • Pseudodiploidy with translocations or molecular evidence of t(9;22), 11q23, or t(8;14), excluding B-cell ALL
      • Elevated WBC at presentation (WBC > 20,000/mm³ [for patients > 18 years of age]; WBC > 200,000/mm³ [for patients 12-18 years of age])

  • Acute myeloid leukemia (AML), meeting one of the following criteria:

    • In first complete remission
    • Failed to achieve remission
    • In first relapse or beyond

    • Secondary AML (> 30% blasts in marrow aspirate)

      • Should receive induction chemotherapy to obtain remission, if possible, before transplant

  • Chronic myelogenous leukemia, meeting one of the following criteria:

    • In first or second chronic phase or accelerated phase
    • In blast crisis, defined as > 30% promyelocytes plus blasts in the bone marrow

  • Myelodysplastic syndromes, including any of the following:

    • Refractory anemia with excess blasts (RAEB)
    • Chronic myelomonocytic leukemia
    • RAEB in transformation

  • Refractory non-Hodgkin lymphoma, chronic lymphocytic leukemia, Hodgkin lymphoma, or multiple myeloma

    • Received and failed front-line therapy, high-dose therapy and autologous stem cell transplantation, or salvage therapy
  • Myeloproliferative disorders/myelofibrosis may be allowed on a case by case basis
  • Severe aplastic anemia, paroxysmal nocturnal hemoglobinuria, or any other hematologic disorder requiring transplantation
• Patients > 55 years of age with hematologic diseases treatable by allogeneic stem cell transplantation who are not eligible for IRB 99190 are eligible
• No uncontrolled CNS involvement of disease
• No matched (6/6) related donor available

• HLA-identical unrelated donor available

  • HLA-phenotypically identical for HLA-A and HLA-B alleles and identical for DRB1 alleles by DNA typing for both class I and class II antigens

    • Allele mismatch for HLA class I (i.e., B 2701 vs B 2702) allowed if no alternative donors
    • Allele mismatch for class II (i.e., DRB1 0401 vs 0402) or minor mismatch for class I cross reactive group (CREG) (i.e., A 2 vs A 28) allowed in patients ≤ 35 years of age requiring urgent transplant

PATIENT CHARACTERISTICS:

• Karnofsky performance status 50-100%
• Life expectancy > 8 weeks
• LVEF ≥ 45% at rest
• AST ≤ 2 times normal (unless liver function abnormality is due to underlying disease)
• Total bilirubin < 1.5 times normal (unless liver function abnormality is due to underlying disease)
• Creatinine ≤ 1.5 times normal OR creatinine clearance ≥ 60 mL/min
• DLCO ≥ 40% of predicted (corrected for hemoglobin)
• No coexisting medical problem that would significantly increase the risk of the transplant procedure
• HIV negative
• Not pregnant

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

Study Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Regimen I; Patients undergo total body irradiation (TBI) on days -7 to -4 and receive cyclophosphamide IV on days -3 and -2. Alternatively, patients may receive cyclophosphamide on days -7 and -6 and undergo TBI on days -4 to -1.	Drug: cyclophosphamide; Drug: methotrexate; Procedure: allogeneic hematopoietic stem cell transplantation; Radiation: total-body irradiation; Procedure: peripheral blood stem cell transplantation; Drug: cyclosporine; Drug: tacrolimus; Drug: sirolimus; Drug: mycophenolate mofetil
Active Comparator: Regimen II; Patients receive busulfan IV over 2 hours once on day -8 and then every 6 hours on days -7 to -4. Patients also receive cyclophosphamide IV on days -3 and -2.	Drug: cyclophosphamide; Drug: methotrexate; Procedure: allogeneic hematopoietic stem cell transplantation; Drug: busulfan; Procedure: peripheral blood stem cell transplantation; Drug: cyclosporine; Drug: tacrolimus; Drug: sirolimus; Drug: mycophenolate mofetil
Active Comparator: Regimen III; Patients undergo TBI on days -7 to -4 and receive etoposide IV on day -3.	Drug: etoposide; Drug: methotrexate; Procedure: allogeneic hematopoietic stem cell transplantation; Radiation: total-body irradiation; Procedure: peripheral blood stem cell transplantation; Drug: cyclosporine; Drug: tacrolimus; Drug: sirolimus; Drug: mycophenolate mofetil
Active Comparator: Regimen IV; Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3 and melphalan IV on day -2.	Drug: methotrexate; Drug: fludarabine phosphate; Procedure: allogeneic hematopoietic stem cell transplantation; Procedure: peripheral blood stem cell transplantation; Drug: melphalan; Drug: cyclosporine; Drug: tacrolimus; Drug: sirolimus; Drug: mycophenolate mofetil
Active Comparator: Regimen V; Patients receive fludarabine phosphate IV over 30 minutes on days -4 to -2 and undergo TBI on day 0.	Drug: methotrexate; Drug: fludarabine phosphate; Procedure: allogeneic hematopoietic stem cell transplantation; Radiation: total-body irradiation; Procedure: peripheral blood stem cell transplantation; Drug: cyclosporine; Drug: tacrolimus; Drug: sirolimus; Drug: mycophenolate mofetil
Active Comparator: Regimen VI; Patients receive busulfan IV over 3 hours and fludarabine phosphate IV over 30 minutes on days -5 to -2.	Drug: methotrexate; Drug: fludarabine phosphate; Procedure: allogeneic hematopoietic stem cell transplantation; Drug: busulfan; Procedure: peripheral blood stem cell transplantation; Drug: cyclosporine; Drug: tacrolimus; Drug: sirolimus; Drug: mycophenolate mofetil

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neutrophil Engraftment - The Days Till ANC Recovery	The primary engraftment endpoint, neutrophil engraftment, is defined as the first of three consecutive days on which the absolute neutrophil count is > 500/µL. The duration and extent of neutrophil engraftment is the time from transplant to neutrophil engraftment.	Up to 180 days post transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Two-year Overall Survival	Overall survival (OS) was measured from peripheral stem cell infusion to death from any cause. It was estimated using the Kaplan-Meier method; the 95% confidence interval was calculated using Greenwood's formula. Participants were followed up to 2 years after transplant and Kaplan-Meier survival analysis was used to generate the two-year Overall Survival estimate presented.	Up to 2 years post transplant

Collaborators and Investigators

• Sponsor: City of Hope Medical Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Auayporn P. Nademanee, MD, City of Hope Comprehensive Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): October 16, 2001
• Primary Completion (Actual): March 13, 2007
• Study Completion (Estimated): December 30, 2024

Study Registration Dates

• First Submitted: October 13, 2007
• First Submitted That Met QC Criteria: October 13, 2007
• First Posted (Estimated): October 16, 2007

Study Record Updates

• Last Update Posted (Actual): April 2, 2024
• Last Update Submitted That Met QC Criteria: March 29, 2024
• Last Verified: March 1, 2024

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; refractory anemia with excess blasts; refractory anemia with excess blasts in transformation; chronic myelomonocytic leukemia; 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); secondary acute myeloid leukemia; childhood acute lymphoblastic leukemia in remission; childhood acute myeloid leukemia in remission; juvenile myelomonocytic leukemia; chronic phase chronic myelogenous leukemia; childhood chronic myelogenous leukemia; recurrent adult acute myeloid leukemia; atypical chronic myeloid leukemia; myelodysplastic/myeloproliferative disease, unclassifiable; untreated childhood acute lymphoblastic leukemia; adult acute myeloid leukemia in remission; recurrent adult Hodgkin lymphoma; childhood immunoblastic large cell lymphoma; recurrent/refractory childhood Hodgkin lymphoma; recurrent adult diffuse small cleaved cell lymphoma; recurrent adult diffuse mixed cell lymphoma; blastic phase chronic myelogenous leukemia; relapsing chronic myelogenous leukemia; Waldenstrom macroglobulinemia; 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; recurrent adult lymphoblastic lymphoma; recurrent mantle cell lymphoma; aplastic anemia; refractory chronic lymphocytic leukemia; recurrent cutaneous T-cell non-Hodgkin lymphoma; recurrent adult T-cell leukemia/lymphoma; angioimmunoblastic T-cell lymphoma; anaplastic large cell lymphoma; recurrent mycosis fungoides/Sezary syndrome; adult nasal type extranodal NK/T-cell lymphoma; recurrent adult grade III lymphomatoid granulomatosis; refractory multiple myeloma; recurrent adult acute lymphoblastic leukemia; polycythemia vera; essential thrombocythemia; recurrent childhood acute lymphoblastic leukemia; accelerated phase chronic myelogenous leukemia; adult acute lymphoblastic leukemia in remission; recurrent childhood acute myeloid leukemia; chronic eosinophilic leukemia; chronic neutrophilic leukemia; recurrent childhood lymphoblastic lymphoma; chronic idiopathic myelofibrosis; untreated adult acute lymphoblastic leukemia; childhood diffuse large cell lymphoma; recurrent childhood grade III lymphomatoid granulomatosis; Burkitt lymphoma; childhood nasal type extranodal NK/T-cell lymphoma; graft versus host disease; paroxysmal nocturnal hemoglobinuria
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease; Bone Marrow Diseases; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Lymphoma; Syndrome; Myelodysplastic Syndromes; Multiple Myeloma; Neoplasms, Plasma Cell; Leukemia; Preleukemia; Plasmacytoma; Myeloproliferative Disorders; Myelodysplastic-Myeloproliferative Diseases; Graft vs Host Disease; Precancerous Conditions; 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; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Dermatologic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Reproductive Control Agents; Antitubercular Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Antibiotics, Antitubercular; Calcineurin Inhibitors; Cyclophosphamide; Etoposide; Melphalan; Fludarabine; Fludarabine phosphate; Methotrexate; Tacrolimus; Mycophenolic Acid; Sirolimus; Busulfan; Cyclosporine; Cyclosporins
• Other Study ID Numbers: 01089; P30CA033572 (U.S. NIH Grant/Contract); CHNMC-01089; CDR0000566376 (Registry Identifier: NCI PDQ)