RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining chemotherapy with bone marrow transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells. It is not yet known which regimen of combination chemotherapy followed by bone marrow transplantation is most effective for aplastic anemia or hematologic cancer.

PURPOSE: Phase II/III trial to determine the effectiveness of different regimens of combination chemotherapy followed by bone marrow transplantation in treating patients who have aplastic anemia or hematologic cancer.

Condition	Treatment or Intervention	Phase
childhood Hodgkin's lymphoma childhood non-Hodgkin's lymphoma hematopoietic and lymphoid cancer	Drug: anti-thymocyte globulin  Drug: busulfan  Drug: carmustine  Drug: cyclophosphamide  Drug: etoposide  Drug: fludarabine  Drug: melphalan  Procedure: allogeneic bone marrow transplantation  Procedure: biological response modifier therapy  Procedure: bone marrow ablation with stem cell support  Procedure: bone marrow transplantation  Procedure: chemotherapy  Procedure: non-specific immune-modulator therapy  Procedure: peripheral blood stem cell transplantation  Procedure: radiation therapy	Phase II Phase III

OBJECTIVES:

• Compare the morbidity, mortality, and overall outcome of standard vs novel conditioning regimens for allogeneic blood progenitor cell or bone marrow transplant in patients with severe aplastic anemia or hematologic malignancy.
• Examine 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.

OUTLINE: Patients are stratified according to risk of graft-vs-host disease (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 syndrome, and untreated severe aplastic anemia vs high-risk: all others) and donor relatedness, which determines the conditioning regimen used.

All patients receive donor stem cell infusions on day 0. Conditioning regimens are assigned as follows:

• Standard-risk except chronic myelogenous leukemia; related fully matched donor; all standard-risk with a 5/6 matched donor: Patients receive etoposide IV over 26 hours on days -5 and -4, cyclophosphamide IV over 2 hours on day -4, and total body irradiation (TBI) on days -3 to -1.
• Hodgkin's lymphoma, any risk, related or unrelated donor: Patients receive etoposide IV over 34 hours on days -8 and -7, cyclophosphamide IV over 2 hours on days -7 to -4, and carmustine IV over 2 hours on day -3.
• Standard-risk chronic myelogenous leukemia; standard risk with fully matched donor and TBI not indicated: Patients receive oral busulfan every 6 hours on days -7 to -4 and cyclophosphamide IV over 2 hours on days -3 and -2.
• Standard-risk with unrelated donor or 5/6 donor, unable to receive TBI: Patients receive oral busulfan every 6 hours on days -7 to -4, cyclophosphamide IV over 2 hours on days -3 and -2, and anti-thymocyte globulin IV over 10 hours on days -7 to -5.
• Aplastic anemia: Patients receive cyclophosphamide IV over 2 hours on days -5 and -2, and anti-thymocyte globulin IV over 10 hours on days -5 to -3, 6-12 hours following cyclophosphamide.
• Any risk, related or unrelated donor: Patients receive melphalan IV over 1 hour on day -4 and TBI on days -3 to -1.
• Standard-risk with unrelated donor: Patients receive cyclophosphamide IV over 2 hours on days -5 and -4, and TBI on days -3 to -1.
• High-risk, related or unrelated donor; multiple myeloma: Patients receive fludarabine IV over 30 minutes on days -6 to -2 and melphalan IV over 1 hour on days -3 and -2. Some patients may undergo radiotherapy 4-8 weeks after the stem cell transplant. Patients are followed every 1-2 weeks for 6 months and then periodically for survival.

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

Ages Eligible for Study:  5 Years   -   59 Years,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Diagnosis of aplastic anemia
• Severe disease indicated by marrow cellularity less than 25% (or 25-50% cellularity with less than 30% of remaining cells hematopoietic in origin) accompanied by at least 2 of the following peripheral blood values: reticulocytes less than 1%; platelets less than 50,000/mm^3; neutrophils less than 500/mm^3
• Age under 40 OR
• Age over 40 and no response to immunosuppressive therapy with antithymocyte globulin OR
• Histologically confirmed hematologic malignancy
• Must have one of the following:
• Acute leukemia
• Resistant or recurrent disease after combination chemotherapy with at least one standard regimen OR
• High risk of relapse after first remission
• Acute myeloid leukemia (AML)
• Antecedent myelodysplastic syndrome, 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 and myelodysplastic syndromes
• Polycythemia vera
• Myelofibrosis
• Essential thrombocytosis
• Refractory anemia
• Refractory anemia with excess blasts
• Refractory anemia with excess blasts in transformation
• Chronic myelomonocytic leukemia
• Lymphoproliferative diseases
• Recurrent or persistent, symptomatic disease after first-line chemotherapy
• Chronic lymphocytic leukemia (CLL)
• Multiple myeloma
• Waldenstrom's macroglobulinemia
• Low-grade non-Hodgkin's lymphoma
• Intermediate or high-grade non-Hodgkin's lymphoma, meeting 1 of the following criteria:
• Resistant or recurrent disease after combination chemotherapy with one standard regimen
• First remission lymphoblastic or small, noncleaved cell lymphoma at high risk of relapse
• CNS disease
• Bone marrow disease and LDH greater than 300
• Hodgkin's lymphoma
• Resistant or recurrent disease after combination chemotherapy with at least one standard regimen
• Histocompatible donor identified
• Well-matched, as defined by 1 of the following:
• Family member matched for 5 or 6 human leukocyte antigen (HLA) specificities (A, B, DR)
• Unrelated donors meet compatibility criteria of the National Marrow Donor Program (matched for all 8 HLA A, B, and DR antigens)
• All other patients are considered too highly mismatched and will be entered on an appropriate cord blood study active at Roswell Park Cancer Institute, if compatible cord blood donor is identified
• Autologous marrow transplant not possible (or desirable) due to one of the following:
• History of marrow tumor
• Inadequate marrow dose
• Abnormal marrow histology or function prior to storage
• Thrombocytopenia or leukopenia
• Marrow cellularity less than 20%
• Not eligible for total body irradiation (TBI) if disease has progressed in previously irradiated areas 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:

• 5 to 59 (50 and under for unrelated transplants)

Performance status:

• Zubrod 0-2 OR
• Karnofsky 70-100%

Life expectancy:

• Not specified

Hematopoietic:

• See Disease Characteristics

Hepatic:

• Bilirubin less than 3 times normal unless due to disease
• Alkaline phosphatase less than 3 times normal unless due to disease
• SGOT less than 3 times normal
• Hepatitis B surface antigen negative

Renal:

• Creatinine no greater than normal
• Creatinine clearance greater than 50 mL/min

Cardiovascular:

• Cardiac ventricular ejection fraction at least 50% by MUGA or echocardiogram
• No uncontrolled or severe cardiovascular disease, including:
• At least 6 months since myocardial infarction, congestive heart failure, symptomatic angina, life threatening arrhythmia, or hypertension

Pulmonary:

• Pulmonary function tests (DLCO and spirometry) at least 50% predicted OR
• VO_2 at least 15 mL/min/kg on exercise studies

Other:

• No serious concurrent medical or psychiatric illness
• No other serious organ dysfunction (unless due to underlying disease), including:
• Active bacterial, viral, or fungal infection
• Active peptic ulcer disease
• Uncontrolled diabetes mellitus
• HIV negative
• Cytomegalovirus, hepatitis virus, and Epstein-Barr virus 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
• No prior cumulative doses of carmustine greater than 600 mg/m^2, bleomycin greater than 150 units/m^2, doxorubicin greater than 450 mg/m^2, or daunorubicin greater than 600 mg/m^2
• No prior doses of etoposide greater than 900 mg/m^2 per course if otherwise eligible for transplant regimens containing this agent

Endocrine therapy:

• No prior doses of cyproterone greater than 100 mg/m^2 per course if otherwise eligible for transplant regimens containing this agent

Radiotherapy:

• See Disease Characteristics
• Not eligible for TBI if prior radiotherapy exceeded the following limits:
• Mediastinum: 5000 cGy (3000 cGy to lung volume)
• Heart: 4000 cGy
• Whole lungs: 1800 cGy
• Small bowel: 4500 cGy
• Kidneys: 1800 cGy
• Whole liver: 2500 cGy
• Cranial spinal: 1800 cGy
• Brain: 4500 cGy
• Retina: 5000 cGy

Surgery:

• Not specified

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

Study chairs or principal investigators

Philip L. McCarthy, MD,  Study Chair,  Roswell Park Cancer Institute   

Study ID Numbers:  CDR0000066968; RPCI-RP-9815; NCI-V99-1527
Record last reviewed:  December 2002
Record first received:  November 1, 1999
ClinicalTrials.gov Identifier:  NCT00003816
Health Authority: Unspecified
ClinicalTrials.gov processed this record on 2004-11-19