Clinical trial NCT00281879: Donor Stem Cell Transplant or Donor White Blood Cell Infusions in Treating Patients With Hematologic Cancer
Official title: Transplantation of Unrelated Donor Hematopoietic Stem Cells for the Treatment of Hematological Malignancies
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Chronic Myeloproliferative Disorders
Leukemia
Lymphoma
Multiple Myeloma and Plasma Cell Neoplasm
Myelodysplastic Syndromes
Myelodysplastic/Myeloproliferative Neoplasms
Unusual Cancers of Childhood
Keywords: adult acute lymphoblastic leukemia in remission
L1 adult acute lymphoblastic leukemia
L2 adult acute lymphoblastic leukemia
L3 adult acute lymphoblastic leukemia
recurrent adult acute lymphoblastic leukemia
accelerated phase chronic myelogenous leukemia
blastic phase chronic myelogenous leukemia
chronic phase chronic myelogenous leukemia
relapsing chronic myelogenous leukemia
childhood acute lymphoblastic leukemia in remission
L1 childhood acute lymphoblastic leukemia
L2 childhood acute lymphoblastic leukemia
L3 childhood acute lymphoblastic leukemia
recurrent childhood acute lymphoblastic leukemia
recurrent adult Hodgkin lymphoma
recurrent/refractory childhood Hodgkin lymphoma
stage IV adult Hodgkin lymphoma
stage IV childhood Hodgkin lymphoma
adult acute myeloid leukemia in remission
adult acute myeloid leukemia with 11q23 (MLL) abnormalities
adult acute myeloid leukemia with t(15;17)(q22;q12)
adult acute myeloid leukemia with t(16;16)(p13;q22)
childhood acute myeloid leukemia in remission
recurrent adult acute myeloid leukemia
recurrent childhood acute myeloid leukemia
myelodysplastic/myeloproliferative neoplasm, unclassifiable
previously treated myelodysplastic syndromes
secondary myelodysplastic syndromes
secondary acute myeloid leukemia
refractory anemia with excess blasts in transformation
refractory anemia with excess blasts
refractory anemia
chronic myelomonocytic leukemia
childhood chronic myelogenous leukemia
chronic eosinophilic leukemia
primary myelofibrosis
chronic neutrophilic leukemia
de novo myelodysplastic syndromes
atypical chronic myeloid leukemia, BCR-ABL negative
extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
juvenile myelomonocytic leukemia
nodal marginal zone B-cell lymphoma
noncontiguous stage II adult Burkitt lymphoma
noncontiguous stage II adult diffuse large cell lymphoma
noncontiguous stage II adult diffuse mixed cell lymphoma
noncontiguous stage II adult diffuse small cleaved cell lymphoma
noncontiguous stage II adult immunoblastic large cell lymphoma
noncontiguous stage II adult lymphoblastic lymphoma
noncontiguous stage II grade 1 follicular lymphoma
noncontiguous stage II grade 2 follicular lymphoma
noncontiguous stage II grade 3 follicular lymphoma
noncontiguous stage II mantle cell lymphoma
noncontiguous stage II marginal zone lymphoma
noncontiguous stage II small lymphocytic lymphoma
recurrent adult Burkitt lymphoma
recurrent adult diffuse large cell lymphoma
recurrent adult diffuse mixed cell lymphoma
recurrent adult diffuse small cleaved cell lymphoma
recurrent adult immunoblastic large cell lymphoma
recurrent adult lymphoblastic lymphoma
recurrent childhood large cell lymphoma
recurrent childhood lymphoblastic lymphoma
recurrent childhood small noncleaved cell lymphoma
recurrent grade 1 follicular lymphoma
recurrent grade 2 follicular lymphoma
recurrent grade 3 follicular lymphoma
recurrent mantle cell lymphoma
recurrent marginal zone lymphoma
recurrent small lymphocytic lymphoma
refractory chronic lymphocytic leukemia
refractory hairy cell leukemia
refractory multiple myeloma
splenic marginal zone lymphoma
stage I multiple myeloma
stage II multiple myeloma
stage III adult Burkitt lymphoma
stage III adult Hodgkin lymphoma
stage III adult diffuse large cell lymphoma
stage III adult diffuse mixed cell lymphoma
stage III adult diffuse small cleaved cell lymphoma
stage III adult immunoblastic large cell lymphoma
stage III adult lymphoblastic lymphoma
stage III chronic lymphocytic leukemia
stage III grade 1 follicular lymphoma
stage III grade 2 follicular lymphoma
stage III grade 3 follicular lymphoma
stage III mantle cell lymphoma
stage III marginal zone lymphoma
stage III multiple myeloma
stage III small lymphocytic lymphoma
stage IV adult Burkitt lymphoma
stage IV adult diffuse large cell lymphoma
stage IV adult diffuse mixed cell lymphoma
stage IV adult diffuse small cleaved cell lymphoma
stage IV adult immunoblastic large cell lymphoma
stage IV adult lymphoblastic lymphoma
stage IV chronic lymphocytic leukemia
stage IV grade 1 follicular lymphoma
stage IV grade 2 follicular lymphoma
stage IV grade 3 follicular lymphoma
stage IV mantle cell lymphoma
stage IV marginal zone lymphoma
stage IV small lymphocytic lymphoma
stage III childhood Hodgkin lymphoma
stage III childhood large cell lymphoma
stage III childhood lymphoblastic lymphoma
stage III childhood small noncleaved cell lymphoma
stage IV childhood large cell lymphoma
stage IV childhood lymphoblastic lymphoma
stage IV childhood small noncleaved cell lymphoma
unusual cancers of childhood
childhood myelodysplastic syndromes
Lead sponsor: OHSU Knight Cancer Institute
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2006-01-25
Enrollment: 200
Sex: ALL
Maximum age (years): 60
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: RATIONALE: A peripheral stem cell transplant or an umbilical cord blood transplant from a donor may be able to replace blood-forming cells that were destroyed by chemotherapy or radiation therapy. Giving an infusion of the donor's white blood cells (donor lymphocyte infusion) after the transplant may help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells can make an immune response against the body's normal cells. Methotrexate, cyclosporine, tacrolimus, or methylprednisolone may stop this from happening.

PURPOSE: This clinical trial is studying how well a donor stem cell transplant or donor white blood cell infusions work in treating patients with hematologic cancer.

Detailed description: OBJECTIVES:

Primary

* Determine the effectiveness of unrelated donor allogeneic hematopoietic stem cells for transplantation after conditioning for the treatment of patients with high-risk hematologic malignancies.
* Compare survival, disease-free survival (DFS), response rate, and toxicity rates in these patients with historical controls.
* Compare the rate and severity of acute and chronic GVHD after allogeneic hematopoietic stem cell transplantation in patients with hematopoietic malignancies with historical controls transplanted with stem cells from related sibling donors
* Assess engraftment, long-term hematopoietic recovery, relapse rate, and disease-free survival when allogeneic hematopoietic stem cells are used as a source of stem cells for transplantation in patients with high-risk hematological malignancies.
* Assess engraftment, long-term hematopoietic recovery, and overall survival when allogeneic hematopoietic stem cells are used as a source of stem cells for transplantation in patients who have graft failure or graft rejection.
* Compare engraftment, long-term hematopoietic recovery, rate of GVHD, rate of relapse, toxicity rates, overall disease-free survival and overall survival when donor leukocyte infusions (DLI) are given for patients who have disease recurrence, progression, or low donor chimerisms after unrelated stem cell transplantation or before DLI with historical controls of other donor leukocyte infusions.

Secondary

* Determine the quality of life of patients undergoing hematopoietic stem cell transplantation or donor leukocyte infusions from unrelated HLA genotypically-identical donors.

OUTLINE: Patients are assigned to 1 of 8 treatment groups.

* Group 1\*: Patients undergo total body irradiation (TBI) twice a day on days -7 to -4. Patients then receive cyclophosphamide IV over 1 hour on days -3 and -2. On day 0 patients undergo stem cell transplantation (SCT). Beginning on day 7, patients receive filgrastim (G-CSF) IV once daily until blood counts recover.
* Group 2 (patients who have previously experienced dose-limiting radiotherapy): Patients receive oral busulfan 4 times daily on days -7 to -4 and cyclophosphamide IV over 1 hour on days -3 and -2. On day 0 patients undergo SCT. Beginning on day 7, patients receive G-CSF IV once daily until blood counts recover.
* Group 3 (pediatric patients only): Patients receive busulfan IV 4 times daily on days -9 to -6 and cyclophosphamide IV over 1 hour and fludarabine IV over 30 minutes on days -5 to -2. On day 0 patients undergo SCT. Beginning on day 7, patients may receive G-CSF IV once daily until blood counts recover.
* Group 4 (second SCT for patients who have experienced graft rejection or failure)\*: Patients receive low-dose fludarabine IV over 30 minutes on days -4 to -2. Patients then undergo low-dose TBI once followed by SCT on day 0. Beginning on day 7, patients may receive G-CSF IV once daily until blood counts recover.
* Group 5 (patients who developed grade 3 cystitis after prior cyclophosphamide-containing therapy): Patients receive carmustine IV over 2 hours on day -6, etoposide IV over 2 hours and cytarabine IV over 30 minutes on days -5 to -2, and melphalan IV over 30 minutes on day -1 (BEAM). On day 0, patients undergo SCT. Beginning on day 7, patients receive G-CSF IV once daily until blood counts recover.
* Group 6 (cord blood transplantation): Patients receive anti-thymocyte globulin IV once daily and methylprednisolone IV twice daily on days -3 to -1. On day 0, patients undergo an umbilical cord blood SCT.
* Group 7 (patients with relapsing or progressive disease after prior transplants or low donor chimerisms)\*: Patients must not have existing graft-versus-host disease (GVHD). Patients receive donor lymphocyte infusions with conditioning chemotherapy and/or radiotherapy at the discretion of the investigator.
* Group 8 (pediatric patients only)\*: Patients undergo TBI twice a day on days -7 to -5. Patients also receive etoposide IV over 24 hours on day -4 and cyclophosphamide IV over 1 hour on days -3 and -2. On day 0, patients undergo SCT. Beginning on day 7, patients may receive G-CSF IV once daily until blood counts recover.

NOTE: \*Patients who have received \> 3000 cGy to the central nervous system or \> 2000 cGy to the lung or liver may not receive any regimen containing total body irradiation (TBI)

All patients receive GVHD prophylaxis comprising methotrexate IV on days 1, 3, 6, and 11; cyclosporine and/or tacrolimus on days -2 to 100; and/or methylprednisolone IV on days 7 to 100.

Patients with an unrelated donor who experience a relapse prior to transplantation, may proceed directly to transplantation. However, if immediate transplantation from the unrelated donor is not possible, the patient must be re-induced into a complete hematological remission. Patients who experience graft failure or graft rejection after allogeneic transplantation are eligible for a second stem cell infusion from the original donor.

Quality of life is assessed at baseline and at 7 days, 3 months, and 1 year after transplantation.

After completion of study treatment, patients are followed periodically for survival.

PROJECTED ACCRUAL: A total of 43 patients will be accrued for this study.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Diagnosis of 1 of the following\*:

  * Acute lymphoblastic leukemia in any disease phase

    * Patients with any of the following high-risk features are encouraged to enroll:

      * Philadelphia chromosome positive disease
      * L3 morphology, especially in the presence of t(8;14), t(8;22), or t(2;8)
      * Patients not in remission at day 28 of first induction
      * High LDH (i.e., ≥ 300 IU/mL at presentation)
      * Pre-B-cell, mixed lineage, or Burkitt's markers
      * Relapsed in the marrow while receiving continuous chemotherapy
      * Within 6 months after stopping chemotherapy
      * Relapse in one organ or extramedullary relapses in more than one organ while still receiving chemotherapy
  * Hodgkin's or non-Hodgkin's lymphoma beyond first complete remission (CR) or in first CR with features of high-risk disease, including, but not limited to:

    * Lymphoma not in CR after 3 courses of primary therapy
    * Patients with bulky disease at presentation, especially bulky mediastinal disease
    * Patients with LDH ≥ 300 IU/mL at presentation
    * Patients with extranodal disease
    * Patients with first remission within less than 1 year
    * Stage IV disease at presentation, especially with marrow involvement
    * Patients with high-intermediate or high International Index Scores
  * Acute myeloid leukemia (AML) meeting the following criteria:

    * Beyond first remission or high-risk disease in first CR
    * Required multiple courses of induction therapy to achieve a remission
    * Had residual leukemia on day 14-28 bone marrow examination after initial induction
    * Patients with any cytogenetic abnormality except inv 16 or t(8;21)
  * Chronic myelogenous leukemia in the chronic or early accelerated phase of the disease

    * Patients with blast crisis that can be induced back into chronic phase may be transplanted in second chronic phase
  * Myelodysplastic syndromes (MDS) meeting the following requirements:

    * Transfusion-dependent refractory anemia (RA), RA with excess blasts (RAEB), RAEB in transformation, or chronic myelomonocytic leukemia (CMML)
    * Patients with MDS that present with or evolve to AML must be re-induced back to remission prior to initiating a search for an unrelated donor NOTE: \*Patients with other hematologic malignancies not listed above, including diseases such as chronic lymphocytic leukemia (CLL), multiple myeloma, or rare pediatric malignancies, or patients who are felt to be at high-risk for relapse but who do not have features listed, may be allowed at the discretion of the investigator.
* Must have failed prior stem cell transplantation
* Must have a suitable unrelated allogeneic hematopoietic stem cell donor

  * A 5/6 match degree is acceptable for unrelated bone marrow donors
  * A 4/6 match degree is acceptable for unrelated cord blood units

PATIENT CHARACTERISTICS:

* SWOG performance status (PS) 0-2 OR
* Karnofsky PS 50-100% OR
* Lansky PS 50-100%
* Creatinine clearance ≥ 45 mL/min
* Creatinine ≤ 2.5 mg/dL
* Bilirubin ≤ 2 mg/dL (abnormally high liver function tests allowed if the only source for the elevation is due to lymphoma of the liver)
* AST or ALT ≤ 2 times normal (abnormally high liver function tests allowed if the only source for the elevation is due to lymphoma of the liver)
* No patients at high risk of veno-occlusive disease
* Not pregnant or nursing
* Negative serum pregnancy test
* Fertile patients must use an effective contraceptive method
* DLCO ≥ 50% of predicted
* FEV_1/FVC ≥ 65% of predicted
* No current congestive heart failure (CHF) and/or LVEF ≥ 45%
* No myocardial infarction within the past 6 months
* No unstable angina within the past 6 months
* HIV negative
* Life expectancy must not be limited by disease other than malignancy
* No allergy to any chemotherapeutic agent included in the regimen

PRIOR CONCURRENT THERAPY:

* See Disease Characteristics

Primary outcomes:
measure: Number of Participants With Disease Free Survival (DFS).
timeFrame: Duration of the study; Up to 2 years
Secondary outcomes:
Other outcomes:
Locations:
city: Portland
country: United States
facility: OHSU Knight Cancer Institute
state: Oregon
Study officials:
affiliation: OHSU Knight Cancer Institute
name: Richard Maziarz, MD
role: STUDY_CHAIR
References: