Clinical trial NCT00003816: Combination Chemotherapy and Donor Stem Cell Transplant in Treating Patients With Aplastic Anemia or Hematologic Cancer
Official title: Allogeneic Blood or Marrow Transplantation for Hematologic Malignancy and Aplastic Anemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Chronic Myeloproliferative Disorders
Leukemia
Lymphoma
Myelodysplastic Syndromes
Myelodysplastic/Myeloproliferative Diseases
Nonmalignant Neoplasm
Unspecified Adult Solid Tumor, Protocol Specific
Unspecified Childhood Solid Tumor, Protocol Specific
Keywords: recurrent childhood acute lymphoblastic leukemia
recurrent cutaneous T-cell non-Hodgkin lymphoma
Burkitt lymphoma
Waldenstrom macroglobulinemia
recurrent childhood lymphoblastic lymphoma
recurrent childhood acute myeloid leukemia
recurrent adult acute myeloid leukemia
recurrent adult acute lymphoblastic leukemia
relapsing chronic myelogenous leukemia
refractory chronic lymphocytic leukemia
chronic phase chronic myelogenous leukemia
accelerated phase chronic myelogenous leukemia
blastic phase chronic myelogenous leukemia
adult acute myeloid leukemia in remission
adult acute lymphoblastic leukemia in remission
childhood acute myeloid leukemia in remission
childhood acute lymphoblastic leukemia in remission
polycythemia vera
essential thrombocythemia
refractory anemia
refractory anemia with excess blasts
refractory anemia with excess blasts in transformation
chronic myelomonocytic leukemia
T-cell large granular lymphocyte leukemia
acute undifferentiated leukemia
recurrent grade 1 follicular lymphoma
recurrent grade 2 follicular lymphoma
recurrent grade 3 follicular lymphoma
recurrent adult diffuse small cleaved cell lymphoma
recurrent adult diffuse mixed cell lymphoma
recurrent adult diffuse large cell lymphoma
recurrent adult immunoblastic large cell lymphoma
recurrent adult lymphoblastic lymphoma
recurrent adult Burkitt lymphoma
recurrent adult T-cell leukemia/lymphoma
secondary acute myeloid leukemia
de novo myelodysplastic syndromes
previously treated myelodysplastic syndromes
secondary myelodysplastic syndromes
prolymphocytic leukemia
intraocular lymphoma
recurrent childhood small noncleaved cell lymphoma
recurrent childhood large cell lymphoma
recurrent mantle cell lymphoma
angioimmunoblastic T-cell lymphoma
anaplastic large cell lymphoma
recurrent mycosis fungoides/Sezary syndrome
primary myelofibrosis
childhood chronic myelogenous leukemia
atypical chronic myeloid leukemia
myelodysplastic/myeloproliferative disease, unclassifiable
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
adult acute myeloid leukemia with t(8;21)(q22;q22)
adult acute myeloid leukemia with t(16;16)(p13;q22)
adult acute myeloid leukemia with inv(16)(p13;q22)
adult acute myeloid leukemia with 11q23 (MLL) abnormalities
adult acute myeloid leukemia with t(15;17)(q22;q12)
childhood myelodysplastic syndromes
aplastic anemia
unspecified adult solid tumor, protocol specific
unspecified childhood solid tumor, protocol specific
Lead sponsor: Roswell Park Cancer Institute
Sponsor class: OTHER
First posted: 2003-01-27
Enrollment: 361
Sex: ALL
Minimum age (years): 4
Maximum age (years): 70
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility 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/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

Primary outcomes:
measure: CR Rate
timeFrame: day 100
Secondary outcomes:
measure: Toxicity/TRM at Day 100
timeFrame: Day +100
measure: 4 Year PFS
timeFrame: 4 years
measure: 4 yr OS
timeFrame: 4-year
Other outcomes:
Locations:
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
Study officials:
affiliation: Roswell Park Cancer Institute
name: Philip L. McCarthy, MD
role: STUDY_CHAIR
References: