Combination Chemotherapy and Donor Stem Cell Transplant in Treating Patients With Aplastic Anemia or Hematologic Cancer

Allogeneic Blood or Marrow Transplantation for Hematologic Malignancy and Aplastic Anemia

RATIONALE: Giving chemotherapy drugs and total-body irradiation before a donor stem cell helps stop the growth of cancer or abnormal cells. It may also 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. It is not yet known which combination chemotherapy regimen is most effective when given before a donor stem cell transplant in treating aplastic anemia or hematologic cancer.

PURPOSE: This phase II/III trial is studying different combination chemotherapy regimens to compare how well they work when given before donor stem cell transplant in treating patients with aplastic anemia or hematologic cancer.

Study Overview

• Status: Completed
• Conditions: Lymphoma; Unspecified Childhood Solid Tumor, Protocol Specific; Myelodysplastic Syndromes; Leukemia; Chronic Myeloproliferative Disorders; Unspecified Adult Solid Tumor, Protocol Specific; Myelodysplastic/Myeloproliferative Diseases; Nonmalignant Neoplasm
• Intervention / Treatment: Drug: fludarabine phosphate; Drug: cyclophosphamide; Drug: etoposide; Drug: melphalan; Drug: carboplatin; Drug: thiotepa; Drug: busulfan; Biological: anti-thymocyte globulin; Radiation: total-body irradiation

Detailed Description

OBJECTIVES:

• Compare the morbidity, mortality, and overall outcome of patients with severe aplastic anemia or hematologic malignancy treated with standard vs novel conditioning regimens followed by allogeneic stem cell transplantation.
• Examine the influence of donor histocompatibility on outcome by comparing matched/related, mismatched/related (with or without T-cell depletion), and matched/unrelated transplants with stratification for type of preparative regimen.
• Ensure that patients with uncommon diagnoses will be treated in a uniform fashion with the best therapy available.

OUTLINE: Patients are stratified according to risk of relapse (standard-risk: acute leukemia in first complete remission, chronic myelogenous leukemia in first chronic phase, lymphoma in sensitive first relapse or second remission, primary or untreated myelodysplastic syndromes, or untreated severe aplastic anemia vs high-risk: all others).

Patients are assigned to one of the following conditioning regimens based on diagnosis, risk of relapse, and donor relatedness:

• Regimen 1: Patients receive busulfan IV over 2 hours every 6 hours on days -7 to -4 and cyclophosphamide IV over 2 hours on days -3 and -2.
• Regimen 2: Patients receive cyclophosphamide IV over 2 hours on days -5 to -2 and anti-thymocyte globulin IV over 4-8 hours on days -5 to -3.
• Regimen 3: Patients receive cyclophosphamide IV over 2 hours on days -5 and -4 and total-body irradiation (TBI) twice daily on days -3 to -1.
• Regimen 4: Patients receive fludarabine IV over 30 minutes on days -6 to -2 and melphalan IV over 1 hour on days -3 and -2.
• Regimen 5: Patients receive etoposide IV over 26 hours beginning on day -5, cyclophosphamide IV over 2 hours on day -4, and TBI twice daily on days -3 to -1.
• Regimen 6: Patients receive cyclophosphamide IV over 24 hours, carboplatin IV over 24 hours, and thiotepa IV over 24 hours on days -7 to -4.
• Regimen 7: Patients receive fludarabine IV over 30 minutes on days -5 to -1 and anti-thymocyte globulin IV over 4-8 hours on days -5 to -2.
• Regimen 8: Patients receive cyclophosphamide IV over 2 hours on days -5 and -4, TBI twice daily on days -3 to -1, and anti-thymocyte globulin IV over 4-8 hours on days -3 to -1.
• Regimen 9: Patients receive busulfan IV over 2 hours every 6 hours and anti-thymocyte globulin IV over 4-8 hours on days -7 to -4 and cyclophosphamide IV over 2 hours on days -3 and -2.

All patients then receive donor stem cell infusions on day 0. Some patients may undergo involved-field radiotherapy 4-8 weeks after transplant.

Patients will be taken off study after a minimum of 4 years of follow up.

PROJECTED ACCRUAL: At least 405 patients will be accrued for this study within 5 years.

• Study Type: Interventional
• Enrollment (Actual): 361
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • New York
    • Buffalo, New York, United States, 14263-0001
      • Roswell Park Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 68 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Diagnosis of one of the following:

  • Severe aplastic anemia as defined by either of the following:

    • Marrow cellularity (< 25% [or 25-50% cellularity with < 30% of remaining cells hematopoietic in origin])

    • At least 2 of the following abnormal peripheral blood counts:

      • Reticulocyte count < 1% (corrected for hematocrit)
      • Platelet count < 20,000/mm^3
      • Neutrophil count < 500/mm^3

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

    • Acute leukemia

      • Resistant or recurrent disease after combination chemotherapy with at least one standard regimen OR in first remission and at high risk of relapse
      • Acute myeloid leukemia (AML) (antecedent myelodysplastic syndromes [MDS], secondary AML, or high-risk cytogenetic abnormalities)
      • Acute lymphoblastic leukemia (ALL) (high-risk cytogenetic abnormalities)

    • Chronic myeloid leukemia (CML)

      • Chronic phase, accelerated phase, or blast phase

    • Myeloproliferative disorders or MDS, including any of the following:

      • Myelofibrosis
      • Polycythemia vera*
      • Essential thrombocythemia*
      • Refractory anemia
      • Refractory anemia with excess blasts
      • Refractory anemia with excess blasts in transformation
      • Chronic myelomonocytic leukemia NOTE: * Only if transformed to AML or MDS

    • Lymphoproliferative disease

      • Recurrent or persistent, symptomatic disease after first-line chemotherapy, including any of the following:

        • Chronic lymphocytic leukemia (CLL) (≥ 20% marrow involvement)
        • Waldenstrom macroglobulinemia
        • Low-grade non-Hodgkin lymphoma

    • Intermediate or high-grade non-Hodgkin lymphoma, meeting 1 of the following criteria:

      • Resistant or recurrent disease after combination chemotherapy with one standard regimen
      • Lymphoblastic lymphoma or small noncleaved cell lymphoma in first remission and at high risk of relapse
      • CNS disease
      • Bone marrow disease and LDH greater than 300
  • Solid tumor that would otherwise be treated on RPCI-DS-9115 (or equivalent autologous stem transplant protocol) AND has a syngeneic donor

• Autologous bone marrow transplant not possible (or desirable) due to 1 of the following:

  • History of marrow tumor
  • Inadequate marrow dose
  • Abnormal marrow histology or function prior to storage
  • Thrombocytopenia or leukopenia
  • Marrow cellularity < 20%

• Histocompatible donor identified

  • Well-matched donor, as defined by 1 of the following:

    • Family member matched for 5 or 6 HLA specificities (A, B, DR)*
    • Unrelated donor meeting compatibility criteria of the National Marrow Donor Program (matched for HLA A, B, and DRB1 antigens)*
    • Identical twin sibling
  • If a compatible cord blood donor is identified and there is no suitable unrelated donor available, patient may receive cord blood transplant NOTE: *Patients ≤ 25 years of age may be singly mismatched at the A or B loci

NOTE: A new classification scheme for adult non-Hodgkin's lymphoma has been adopted by PDQ. The terminology of "indolent" or "aggressive" lymphoma will replace the former terminology of "low", "intermediate", or "high" grade lymphoma. However, this protocol uses the former terminology.

PATIENT CHARACTERISTICS:

Age:

• 4 to 70

Performance status:

• Zubrod 0-2 OR
• Karnofsky 70-100%

Life expectancy:

• Not specified

Hematopoietic:

• See Disease Characteristics

Hepatic:

• Bilirubin < 3 times normal (unless due to disease)
• Alkaline phosphatase < 3 times normal (unless due to disease)
• SGOT < 3 times normal (unless due to disease)
• Hepatitis B surface antigen negative
• No severe hepatic disease that would preclude study participation

Renal:

• Creatinine normal
• Creatinine clearance ≥ 50 mL/min
• No severe renal disease that would preclude study participation

Cardiovascular:

• Cardiac ventricular ejection fraction ≥ 50% by MUGA or echocardiogram
• No uncontrolled or severe cardiovascular disease (e.g., myocardial infarction, congestive heart failure, symptomatic angina, life threatening arrhythmia, or hypertension within the past 6 months)

Pulmonary:

• DLCO or DLVA ≥ 50% predicted (corrected for hemoglobin or alveolar ventilation)

Other:

• No serious concurrent medical or psychiatric illness

• No other serious organ dysfunction (unless due to underlying disease), including the following:

  • Uncontrolled bacterial, viral, or fungal infection
  • Uncontrolled peptic ulcer disease
  • Uncontrolled diabetes mellitus
• HIV negative
• Cytomegalovirus status known
• Not pregnant

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• See Disease Characteristics
• Pretransplant cytoreductive chemotherapy allowed for patients with relapsed or refractory disease

Endocrine therapy:

• Not specified

Radiotherapy:

• Not eligible for total-body irradiation if prior radiotherapy exceeded the following limits:

  • Mediastinum: 3,600 cGy
  • Heart: 3,600 cGy
  • Whole lungs: 1,200 cGy
  • Small bowel: 3,600 cGy
  • Kidneys: 1,200 cGy
  • Whole liver: 1,600 cGy
  • Cranial spinal: 3,600 cGy
  • Brain: 4,000 cGy
  • Retina: 4,000 cGy

Surgery:

• Not specified

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

9

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Regimen 1; Patients receive busulfan IV over 2 hours every 6 hours on days -7 to -4 and cyclophosphamide IV over 2 hours on days -3 and -2.	Drug: cyclophosphamide; Given IV; Drug: busulfan; Given IV
Experimental: Regimen 2; Patients receive cyclophosphamide IV over 2 hours on days -5 to -2 and anti-thymocyte globulin IV over 4-8 hours on days -5 to -3.	Drug: cyclophosphamide; Given IV; Biological: anti-thymocyte globulin; Given IV
Experimental: Regimen 3; Patients receive cyclophosphamide IV over 2 hours on days -5 and -4 and total-body irradiation (TBI) twice daily on days -3 to -1.	Drug: cyclophosphamide; Given IV; Radiation: total-body irradiation; Given twice daily for 3 days
Experimental: Regimen 4; Patients receive fludarabine IV over 30 minutes on days -6 to -2 and melphalan IV over 1 hour on days -3 and -2.	Drug: fludarabine phosphate; Given IV; Drug: melphalan; Given IV
Experimental: Regimen 5; Patients receive etoposide IV over 26 hours beginning on day -5, cyclophosphamide IV over 2 hours on day -4, and TBI twice daily on days -3 to -1.	Drug: cyclophosphamide; Given IV; Drug: etoposide; Given IV; Radiation: total-body irradiation; Given twice daily for 3 days
Experimental: Regimen 6; Patients receive cyclophosphamide IV over 24 hours, carboplatin IV over 24 hours, and thiotepa IV over 24 hours on days -7 to -4.	Drug: cyclophosphamide; Given IV; Drug: carboplatin; Given IV; Drug: thiotepa; Given IV
Experimental: Regimen 7; Patients receive fludarabine IV over 30 minutes on days -5 to -1 and anti-thymocyte globulin IV over 4-8 hours on days -5 to -2.	Drug: fludarabine phosphate; Given IV; Biological: anti-thymocyte globulin; Given IV
Experimental: Regimen 8; Patients receive cyclophosphamide IV over 2 hours on days -5 and -4, TBI twice daily on days -3 to -1, and anti-thymocyte globulin IV over 4-8 hours on days -3 to -1.	Drug: cyclophosphamide; Given IV; Biological: anti-thymocyte globulin; Given IV; Radiation: total-body irradiation; Given twice daily for 3 days
Experimental: Regimen 9; Patients receive busulfan IV over 2 hours every 6 hours and anti-thymocyte globulin IV over 4-8 hours on days -7 to -4 and cyclophosphamide IV over 2 hours on days -3 and -2.	Drug: cyclophosphamide; Given IV; Drug: busulfan; Given IV; Biological: anti-thymocyte globulin; Given IV

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CR Rate	Rate of Complete Remission by Day +100	day 100

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity/TRM at Day 100	Death due to treatment related causes before day +100 after BMT	Day +100
4 Year PFS	progression free survival estimate at 4 years post BMT (events are disease progression/relapse and death due to any cause)	4 years
4 yr OS	Overall survival estimate at 4 years post BMT	4-year

Collaborators and Investigators

• Sponsor: Roswell Park Cancer Institute
• Investigators: Study Chair: Philip L. McCarthy, MD, Roswell Park Cancer Institute

Study record dates

Study Major Dates

• Study Start (Actual): October 19, 1998
• Primary Completion (Actual): July 12, 2019
• Study Completion (Actual): July 12, 2019

Study Registration Dates

• First Submitted: November 1, 1999
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Actual): August 13, 2021
• Last Update Submitted That Met QC Criteria: July 19, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: unspecified childhood solid tumor, protocol specific; unspecified adult solid tumor, protocol specific; primary myelofibrosis; 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; 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; chronic phase chronic myelogenous leukemia; childhood chronic myelogenous leukemia; childhood myelodysplastic syndromes; recurrent adult acute myeloid leukemia; atypical chronic myeloid leukemia; myelodysplastic/myeloproliferative disease, unclassifiable; adult acute myeloid leukemia in remission; recurrent adult diffuse small cleaved cell lymphoma; recurrent adult diffuse mixed cell lymphoma; blastic phase chronic myelogenous leukemia; relapsing chronic myelogenous leukemia; Waldenstrom macroglobulinemia; 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; intraocular lymphoma; angioimmunoblastic T-cell lymphoma; anaplastic large cell lymphoma; recurrent mycosis fungoides/Sezary syndrome; recurrent adult acute lymphoblastic leukemia; polycythemia vera; essential thrombocythemia; prolymphocytic leukemia; recurrent childhood acute lymphoblastic leukemia; accelerated phase chronic myelogenous leukemia; adult acute lymphoblastic leukemia in remission; recurrent childhood acute myeloid leukemia; recurrent childhood lymphoblastic lymphoma; acute undifferentiated leukemia; T-cell large granular lymphocyte leukemia; Burkitt lymphoma
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Bone Marrow Failure Disorders; Neoplasms; Lymphoma; Syndrome; Myelodysplastic Syndromes; Leukemia; Preleukemia; Anemia; Myeloproliferative Disorders; Myelodysplastic-Myeloproliferative Diseases; Anemia, Aplastic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; 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; Cyclophosphamide; Carboplatin; Etoposide; Melphalan; Fludarabine; Fludarabine phosphate; Thiotepa; Busulfan; Antilymphocyte Serum
• Other Study ID Numbers: RP 98-15 (Other Identifier: Roswell Park Cancer Institute)