Clinical trial NCT00006379: Non-Ablative Allo HSCT For Hematologic Malignancies or SAA
Official title: Purine-Analog-Containing Non-Myeloablative Allogeneic Stem Cell Transplantation for Treatment of Hematologic Malignancies and Severe Aplastic Anemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Myeloproliferative Disorders
Leukemia
Lymphoma
Multiple Myeloma and Plasma Cell Neoplasm
Myelodysplastic Syndromes
Myelodysplastic/Myeloproliferative Diseases
Precancerous/Nonmalignant Condition
Small Intestine Cancer
Keywords: monoclonal gammopathy of undetermined significance
recurrent childhood acute lymphoblastic leukemia
recurrent adult Hodgkin lymphoma
recurrent cutaneous T-cell non-Hodgkin lymphoma
isolated plasmacytoma of bone
extramedullary plasmacytoma
refractory multiple myeloma
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
small intestine lymphoma
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
chronic idiopathic myelofibrosis
essential thrombocythemia
adult acute erythroid leukemia (M6)
adult acute megakaryoblastic leukemia (M7)
childhood acute erythroleukemia (M6)
childhood acute megakaryocytic leukemia (M7)
recurrent/refractory childhood Hodgkin lymphoma
refractory anemia with excess blasts
refractory anemia with excess blasts in transformation
chronic myelomonocytic 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
primary systemic amyloidosis
adult acute minimally differentiated myeloid leukemia (M0)
childhood acute minimally differentiated myeloid leukemia (M0)
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
childhood chronic myelogenous leukemia
chronic eosinophilic leukemia
chronic neutrophilic leukemia
atypical chronic myeloid leukemia
myelodysplastic/myeloproliferative disease, unclassifiable
juvenile myelomonocytic leukemia
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
Lead sponsor: Case Comprehensive Cancer Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2003-01-27
Enrollment: 58
Sex: ALL
Maximum age (years): 70
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Peripheral stem cell transplantation may be able to replace immune cells that were destroyed by chemotherapy used to kill cancer cells.

PURPOSE: Phase II trial to study the effectiveness of combination chemotherapy followed by peripheral stem cell transplantation in treating patients who have hematologic cancer or aplastic anemia.

Detailed description: OBJECTIVES:

* Determine the rates of durable full donor hematologic engraftment in patients with high-risk hematologic malignancies or severe aplastic anemia treated with non-myeloablative conditioning using fludarabine, cyclophosphamide, and anti-thymocyte globulin followed by allogeneic peripheral blood stem cell transplantation.
* Determine the acute and delayed toxic effects of this non-myeloablative conditioning regimen in this patient population.
* Determine the event-free and overall survival of patients treated with this regimen.
* Determine the incidence and severity of acute and chronic graft-versus-host disease in patients treated with this regimen.
* Determine the rate and quality of immune reconstitution in patients treated with this regimen.
* Determine the rate of disease relapse and incidence of post-transplantation lymphoproliferative disease in these patients.

OUTLINE: Patients are stratified according to disease category (malignant vs non-malignant) and graft source (unrelated vs HLA-matched sibling).

Beginning at least 4 weeks after conventional-dose chemotherapy, patients receive non-myeloablative conditioning comprising fludarabine IV over 30 minutes on days -8 to -4, cyclophosphamide IV over 2 hours on days -3 to -2, and anti-thymocyte globulin IV over at least 4 hours on days -2 and -1. Patients undergo filgrastim (G-CSF)-mobilized allogeneic peripheral blood stem cell transplantation on day 0.

Patients are followed weekly for 3 months, every 2 weeks for 3 months, monthly for 6 months, and then every 2 months thereafter.

PROJECTED ACCRUAL: A minimum of 30 patients will be accrued for this study within 4 years.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically proven high-risk hematologic malignancy

  * Acute non-lymphocytic leukemia (ANLL) after induction failure, or in first complete remission (CR) with high-risk features, including any of the following:

    * Stem cell or biphenotypic classification (AML-M0)
    * Erythroleukemia (AML-M6)
    * Acute megakaryocytic leukemia (AML-M7)
    * Cytogenetic markers indicative of poor prognosis
    * Failure to achieve CR after standard induction therapy
  * Acute lymphocytic leukemia (ALL) or ANLL in relapse or second or subsequent remission
  * Chronic myelogenous leukemia (CML) in chronic or accelerated phase

    * Patients with CML in blast crisis are eligible after reinduction chemotherapy places them in chronic phase
  * High-risk ALL in first CR with high risk defined by presence of t(4;11), t(9;22) translocation, hyperleukocytosis (initial WBC greater than 30,000/mm\^3), or failure to achieve CR by day 28 after standard induction

    * No T-cell ALL or t(8;14) positive B-cell ALL in first remission with hyperleukocytosis
  * Myelodysplastic syndrome by peripheral blood smear and bone marrow examination

    * Refractory to medical management OR
    * Cytogenetic abnormalities predictive of transformation into acute leukemia including 5q-, 7q-, monosomy 7, and trisomy 8 OR
    * Evidence of evolution to AML (e.g., refractory anemia with excess blasts (RAEB) or RAEB in transformation)
  * Multiple myeloma, non-Hodgkin's lymphoma (NHL), ANLL, or ALL with recurrent disease after autologous stem cell transplantation (SCT)

    * At least 3 months since prior autologous SCT
  * Hodgkin's lymphoma, NHL, or multiple myeloma beyond first CR or primary induction failures whose disease has demonstrated sensitivity to pre-transplantation cytoreduction (defined as greater than 50% reduction in tumor burden)

    * Mantle zone NHL allowed after induction therapy
  * Myeloproliferative disorder that is non-responsive to medical management and requires allografting, unless evidence of grade 3 or worse myelofibrosis on marrow biopsy OR
* Histologically proven acquired severe aplastic anemia (SAA) that is recurrent or unresponsive after anti-thymocyte globulin and/or cyclosporine

  * SAA defined by at least 2 of the following conditions:

    * Granulocyte count less than 500/mm\^3
    * Platelet count less than 20,000/mm\^3
    * Absolute reticulocyte count less than 20,000/mm\^3 after correction for hematocrit
* Ineligible for full ablative conditioning due to any of the following conditions:

  * Prior extensive therapy (more than 2 salvage chemotherapy regimens and/or autologous transplantation)
  * Over age 55 OR
  * Under age 55 with comorbid disease (e.g., suboptimal cardiac, pulmonary, or renal function and/or prior life-threatening infection)
* HLA-A, B, and DR phenotypically identical sibling donor OR
* HLA-A, B, and DR identical genetically matched unrelated donor
* No ANLL in first CR (less than 5% blasts in marrow) with translocations t(8;21) and inv(16) unless failed first-line induction therapy OR
* No ANLL in first CR (less than 5% blasts in marrow) with translocations t(15;17) abnormality unless failed first-line induction therapy OR molecular evidence of persistent disease
* No active CNS disease

PATIENT CHARACTERISTICS:

Age:

* 0 to 70

Performance status:

* Zubrod 0-1
* Karnofsky 80-100%

Life expectancy:

* At least 3 months

Hematopoietic:

* See Disease Characteristics

Hepatic:

* ALT/AST no greater than 4 times normal
* Bilirubin no greater than 2.0 mg/dL

Renal:

* See Disease Characteristics
* Creatinine clearance at least 50 mL/min

Cardiovascular:

* See Disease Characteristics
* Shortening fraction or ejection fraction at least 40% of normal for age by echocardiogram or radionuclide scan
* No clinically significant comorbid illnesses (e.g., myocardial infarction or cerebrovascular accident)

Pulmonary:

* See Disease Characteristics
* FVC and FEV_1 at least 60% of predicted for age
* DLCO at least 60% of predicted for adults

Other:

* No severe neurosensory symptoms (i.e., peripheral neuropathy)
* HIV negative
* Active infection allowed if controlled by appropriate drug therapy
* Not pregnant or nursing
* Negative pregnancy test

PRIOR CONCURRENT THERAPY:

Biologic therapy:

* See Disease Characteristics

Chemotherapy:

* See Disease Characteristics

Endocrine therapy:

* Not specified

Radiotherapy:

* Not specified

Surgery:

* Not specified

Other:

* Recovered from prior therapy
* No concurrent investigational agents unless approved by protocol investigators

Primary outcomes:
measure: Evaluation of Donor Engraftment
timeFrame: at 28 days
Secondary outcomes:
measure: Stable donor hematopoietic chimerism
timeFrame: at day 100
measure: Event free and overall survival
timeFrame: to progression/death
Other outcomes:
Locations:
city: Cleveland
country: United States
facility: Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center
state: Ohio
Study officials:
affiliation: Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center
name: Tamila Kindwall-Keller, DO
role: PRINCIPAL_INVESTIGATOR
References: