Clinical trial NCT00296023: Donor Stem Cell Transplant in Treating Older or Frail Patients With Hematologic Cancer
Official title: Low-Dose Allogeneic Peripheral Blood Stem Cell Transplantation for High-Risk Low Grade Hematologic Malignancies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Chronic Myeloproliferative Disorders
Leukemia
Lymphoma
Multiple Myeloma and Plasma Cell Neoplasm
Myelodysplastic Syndromes
Keywords: stage III chronic lymphocytic leukemia
stage IV chronic lymphocytic leukemia
stage III adult diffuse small cleaved cell lymphoma
stage IV adult diffuse small cleaved cell lymphoma
noncontiguous stage II grade 1 follicular lymphoma
noncontiguous stage II grade 2 follicular lymphoma
noncontiguous stage II grade 3 follicular lymphoma
stage III grade 1 follicular lymphoma
stage III grade 2 follicular lymphoma
stage III grade 3 follicular lymphoma
stage IV grade 1 follicular lymphoma
stage IV grade 2 follicular lymphoma
stage IV grade 3 follicular lymphoma
noncontiguous stage II marginal zone lymphoma
stage III marginal zone lymphoma
stage IV marginal zone lymphoma
noncontiguous stage II small lymphocytic lymphoma
stage III small lymphocytic lymphoma
stage IV small lymphocytic lymphoma
noncontiguous stage II adult Burkitt lymphoma
stage III adult Burkitt lymphoma
stage IV adult Burkitt lymphoma
stage III adult diffuse large cell lymphoma
stage IV adult diffuse large cell lymphoma
noncontiguous stage II adult diffuse mixed cell lymphoma
stage III adult diffuse mixed cell lymphoma
stage IV adult diffuse mixed cell lymphoma
noncontiguous stage II adult immunoblastic large cell lymphoma
stage III adult immunoblastic large cell lymphoma
stage IV adult immunoblastic large cell lymphoma
noncontiguous stage II adult lymphoblastic lymphoma
stage III adult lymphoblastic lymphoma
stage IV adult lymphoblastic lymphoma
noncontiguous stage II mantle cell lymphoma
stage III mantle cell lymphoma
stage IV mantle cell lymphoma
extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
nodal marginal zone B-cell lymphoma
splenic marginal zone lymphoma
stage II multiple myeloma
stage III multiple myeloma
chronic phase chronic myelogenous leukemia
primary myelofibrosis
polycythemia vera
prolymphocytic leukemia
stage II adult Hodgkin lymphoma
stage III adult Hodgkin lymphoma
stage IV adult Hodgkin lymphoma
de novo myelodysplastic syndromes
previously treated myelodysplastic syndromes
secondary myelodysplastic syndromes
refractory anemia with excess blasts in transformation
refractory anemia with excess blasts
chronic myelomonocytic leukemia
adult acute myeloid leukemia in remission
secondary acute myeloid leukemia
Waldenström macroglobulinemia
essential thrombocythemia
adult acute myeloid leukemia with 11q23 (MLL) abnormalities
adult acute myeloid leukemia with inv(16)(p13;q22)
adult acute myeloid leukemia with t(15;17)(q22;q12)
adult acute myeloid leukemia with t(16;16)(p13;q22)
adult acute myeloid leukemia with t(8;21)(q22;q22)
noncontiguous stage II adult diffuse large cell lymphoma
noncontiguous stage II adult diffuse small cleaved cell lymphoma
stage I multiple myeloma
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2006-02-24
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: RATIONALE: Giving low doses of chemotherapy, such as fludarabine and busulfan, before a donor bone marrow or peripheral blood stem cell transplant helps stop the growth of cancer cells. It also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune system and help destroy any remaining cancer cells (graft-versus-tumor effect). Giving an infusion of the donor's T cells (donor lymphocyte infusion) after the transplant may help increase this effect. Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving antithymocyte globulin before transplant and methotrexate and tacrolimus after the transplant may stop this from happening.

PURPOSE: This phase I trial is studying the side effects of donor stem cell transplant in treating older or frail patients with hematologic cancer.

Detailed description: OBJECTIVES:

Primary

* Determine the safety of non-myeloablative allogeneic peripheral blood stem cell transplantation, in terms of regimen-related organ toxicity and toxicity from acute graft-vs-host disease (GVHD), in older or medically frail patients with high-risk indolent hematologic malignancies.
* Determine overall survival, disease-free survival, and relapse risk at 1, 2, and 3 years post-transplantation in these patients.

Secondary

* Determine the engraftment of donor hematopoiesis at 6 weeks, 3 and 6 months, and 1 year post-transplantation in these patients.
* Determine the incidence and severity of chronic GVHD in older and medically infirm patients treated with this regimen.
* Determine the safety and efficacy of collecting peripheral blood stem cells from older donors (age \> 60 years).
* Determine the need and efficacy of donor lymphocyte infusions in patients with residual disease after transplant.

OUTLINE:

* Non-myeloablative preparative regimen:Patients receive fludarabine IV over 30 minutes on days -7 to -3, busulfan IV over 2 hours every 8 hours on days -4 and -3, and anti-thymocyte globulin IV over 8 hours on days -4 to -1.
* Transplantation: Patients undergo allogeneic peripheral blood stem cell transplantation on day 0. Patients receive filgrastim (G-CSF) subcutaneously beginning on day 6 and continuing until blood counts recover.
* Graft-vs-host disease (GVHD) prophylaxis: Patients receive tacrolimus orally every 12 hours or IV continuously beginning on day -2 and continuing until day 90, followed by a taper until day 180. Patients also receive methotrexate IV over 15-30 minutes on days 1, 3, 6, and 11.
* Donor lymphocyte infusions (DLIs): Patients with residual disease ≥ 6 months post-transplantation who are off immunosuppression for ≥ 30 days with no evidence of GVHD may receive DLIs. DLIs are administered ≥ 12 weeks apart in the presence of persistent disease, absence of severe (grade 3-4) GVHD, and absence of persistent GVHD after the first DLI.

After completion of study therapy, patients are followed periodically for 5 years.

PROJECTED ACCRUAL: A total of 30 patients will be accrued for this study.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Diagnosis of a high-risk indolent hematologic malignancy meeting the following criteria:

  * Chronic lymphocytic leukemia (CLL) meeting 1 of the following criteria:

    * In second or subsequent remission
    * Failed to achieve a complete remission (CR) after chemotherapy
  * Non-Hodgkin's lymphoma (NHL) meeting 1 of the following criteria:

    * Low-grade NHL meeting 1 of the following criteria:

      * Standard-risk disease in second or subsequent remission
      * Standard-risk disease and failed to achieve a CR after chemotherapy
      * In first or subsequent remission with adverse International Prognostic Index (IPI) prognostic features, as defined by the presence of ≥ 3 of the following:

        * Age \> 60 years
        * Tumor stage III or IV
        * Extranodal disease at \> 1 site
        * ECOG performance status ≥ 2
        * Serum lactic dehydrogenase (LDH) \> upper limit of normal (ULN)
    * Intermediate- or high-grade NHL meeting 1 of the following criteria:

      * In second or subsequent remission
      * Failed to achieve a CR after initial chemotherapy
  * Waldenstrom's macroglobulinemia meeting 1 of the following criteria:

    * In second or subsequent remission
    * Failed to achieve a CR after initial chemotherapy
  * Multiple myeloma meeting 1 of the following criteria:

    * In first or subsequent remission
    * Failed to achieve a CR after initial chemotherapy
  * Myeloproliferative disorders, including any of the following:

    * Chronic myelogenous leukemia in first or subsequent chronic phase
    * Myelofibrosis
    * Essential thrombocytopenia that is poorly responsive to standard therapy
    * Polycythemia vera that is poorly responsive to standard therapy or is in spent phase
  * Prolymphocytic leukemia meeting 1 of the following criteria:

    * In first or subsequent remission
    * Failed to achieve a CR after initial chemotherapy
  * Mantle cell lymphoma meeting 1 of the following criteria:

    * In first or subsequent remission
    * Failed to achieve a CR after initial chemotherapy
  * Hodgkin's lymphoma meeting the following criteria:

    * In second or subsequent remission

      * Prior remission duration \> 6 months
    * No radiation therapy as the only prior primary therapy
  * Myelodysplastic syndromes (MDS) meeting 1 of the following criteria:

    * Refractory anemia with excess blasts (RAEB)
    * RAEB in transformation
    * Chronic myelomonocytic leukemia
    * Any MDS with transfusion dependence
    * Any MDS with ≥ 2 significant infections
  * Acute myeloid leukemia in morphologic remission
* In CR or partial remission or stabilization of disease after standard chemotherapy

  * No progressive or refractory disease
* Not eligible for standard allogeneic bone marrow transplantation
* Meets 1 of the following criteria:

  * Age 60 to 75 years old AND no co-morbid illness
  * Younger patients with any of the following comorbidities:

    * Decreased cardiac ejection fraction
    * Pulmonary dysfunction
    * Elevated liver function tests
    * Hepatitis C infection
    * Poor performance status
* Sibling or related donor available

  * Matched ≥ 5/6 HLA loci (A, B, and DR) 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:

* See Disease Characteristics
* ECOG performance status 0-2
* Creatinine \< 2.0 mg/dL
* Creatinine clearance \> 40 mL/min
* Ejection fraction \> 30% by echocardiogram or MUGA
* Bilirubin \< 3.0 mg/dL (if total bilirubin is elevated and Gilbert's disease is suspected, direct bilirubin must be normal)
* Alkaline phosphatase \< 4 times ULN
* AST \< 4 times ULN
* HIV negative
* Hepatitis B and/or C virus allowed if a liver biopsy (performed within the past 3 months) shows ≤ grade 2 inflammation
* No active infection

PRIOR CONCURRENT THERAPY:

* See Disease Characteristics

Primary outcomes:
measure: Toxicity and survival
timeFrame: up to 36 months post transplant
Secondary outcomes:
Other outcomes:
Locations:
city: Berkeley
country: United States
facility: Alta Bates Comprehensive Cancer Center
state: California
city: San Francisco
country: United States
facility: UCSF Comprehensive Cancer Center
state: California
Study officials:
affiliation: University of California, San Francisco
name: Thomas G. Martin, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Francisco
name: Willis Navarro, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Francisco
name: Charles A. Linker, MD
role: PRINCIPAL_INVESTIGATOR
References: