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.
- 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
- 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 are followed periodically post-transplant.
PROJECTED ACCRUAL: At least 405 patients will be accrued for this study within 5 years.
- 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
- Acute myeloid leukemia (AML) (antecedent myelodysplastic syndromes
[MDS], secondary AML, or high-risk cytogenetic abnormalities)
- Acute lymphoblastic leukemia (ALL) (high-risk cytogenetic
- Chronic myeloid leukemia (CML)
- Chronic phase, accelerated phase, or blast phase
- Myeloproliferative disorders or MDS, including any of the following:
- 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
- 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
- Resistant or recurrent disease after combination chemotherapy with one
- 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
- 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
- 4 to 70
- Zubrod 0-2 OR
- Karnofsky 70-100%
- Not specified
- See Disease Characteristics
- 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
- Creatinine normal
- Creatinine clearance ≥ 50 mL/min
- No severe renal disease that would preclude study participation
- 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)
- DLCO or DLVA ≥ 50% predicted (corrected for hemoglobin or alveolar ventilation)
- No serious concurrent medical or psychiatric illness
- No other serious organ dysfunction (unless due to underlying disease), including the
- Uncontrolled bacterial, viral, or fungal infection
- Uncontrolled peptic ulcer disease
- Uncontrolled diabetes mellitus
- HIV negative
- Cytomegalovirus status known
- Not pregnant
PRIOR CONCURRENT THERAPY:
- Not specified
- See Disease Characteristics
- Pretransplant cytoreductive chemotherapy allowed for patients with relapsed or
- Not specified
- Not eligible for total-body irradiation if prior radiotherapy exceeded the following
- 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
- Not specified