Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III, Phase II	Treatment	Active	4 to 70	Other	RPCI-RP-9815 NCI-V99-1527, NCT00003816, RP 98-15

Objectives

1. 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.
2. 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.
3. Ensure that patients with uncommon diagnoses will be treated in a uniform fashion with the best therapy available.

Entry Criteria

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/mm³
      • Neutrophil count < 500/mm³
  • 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.]

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

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

Expected Enrollment

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

Outcomes

Activity of allogeneic stem cell transplant

Influence of donor histocompatibility on outcome

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 are followed periodically post-transplant.

Trial Contact Information

Trial Lead Organizations

Roswell Park Cancer Institute

Philip McCarthy, MD, Protocol chair		Ph: 716-845-4074; 800-685-6825 Email: philip.mccarthy@roswellpark.org

U.S.A.
New York
	Buffalo
	Roswell Park Cancer Institute
		Clinical Trials Office - Roswell Park Cancer Institute	Ph:  877-275-7724

Registry Information
Official Title		Allogeneic Blood or Marrow Transplantation for Hematologic Malignancy and Aplastic Anemia
Trial Start Date		1998-10-19
Trial Completion Date		2012-07-28 (estimated)
Registered in ClinicalTrials.gov		NCT00003816
Date Submitted to PDQ		1999-03-12
Information Last Verified		2008-11-30
NCI Grant/Contract Number		CA16056