Non Hodgkin Lymphoma Clinical Trial
Chemotherapy Before Autologous Stem Cell Transplantation +/- Rituximab in Relapsed or Refractory Aggressive Non-Hodgkin’s Lymphoma
RATIONALE: Drugs used in chemotherapy, such as dexamethasone, cisplatin, gemcitabine, and cytarabine, work in different ways to stop cancer cells from dividing so they stop growing or die. Combining chemotherapy with autologous stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more cancer cells. Monoclonal antibodies, such as rituximab, can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. Giving rituximab as maintenance therapy after stem cell transplantation may kill any remaining cancer cells. It is not yet known which salvage chemotherapy regimen is more effective before autologous stem cell transplantation in treating relapsed or refractory non-Hodgkin's lymphoma.
PURPOSE: This randomized phase III trial is studying salvage chemotherapy using dexamethasone, cisplatin, and gemcitabine to see how well it works compared to dexamethasone, cisplatin, and cytarabine given before autologous stem cell transplantation in treating patients with relapsed or refractory aggressive non-Hodgkin's lymphoma. This trial also is studying giving rituximab as maintenance therapy to see how well it works compared to no further therapy after stem cell transplantation. Rituximab was added to both salvage treatment arms for CD20+ patients in a protocol amendment in 2005.
Compare the response rate and transplantation rate in patients with relapsed or refractory aggressive non-Hodgkin's lymphoma when treated with salvage chemotherapy comprising dexamethasone, cisplatin, and gemcitabine with or without rituximab vs a standard platinum-based regimen (dexamethasone, cisplatin, and high-dose cytarabine with or without rituximab).
To compare the transplantation rates of the two protocol salvage regimens.
Compare the event-free and overall survival of patients treated with these regimens.
Compare the success rate of these regimens, in terms of getting patients to autologous stem cell transplantation and successful mobilization after high-dose chemotherapy.
Compare the quality of life of patients treated with these salvage regimens.
Compare the toxic effects of these salvage regimens in these patients.
Compare resource utilization for patients treated with these salvage regimens.
Compare relative medical and societal costs of these salvage regimens with outcomes in these patients.
Compare the 2-year event-free survival of patients with CD20+ B-cell lymphoma treated with maintenance rituximab after these salvage regimens and autologous stem cell transplantation to those patients who received no further treatment.
Compare the 2-year survival of patients treated with or without maintenance rituximab.
Compare the toxic effects of rituximab vs observation alone in these patients.
OUTLINE: This is a randomized, multicenter study. For salvage therapy, patients are stratified according to participating center, International Prognostic Index score at relapse/study entry (0 or 1 vs 2 vs â‰¥ 3), immunophenotype (B cell vs T cell), response to or response duration after initial chemotherapy (no response or progressive disease vs > 1 year vs â‰¤ 1 year), and prior rituximab (yes vs no). For maintenance therapy, patients are stratified according to participating center, salvage therapy treatment randomization (with or without rituximab, cisplatin, dexamethasone, and gemcitabine vs with or without rituximab, cisplatin, dexamethasone, and cytarabine), response to salvage therapy (complete response [CR] and CR unconfirmed [CRu] vs partial response [PR] vs stable disease [SD]), and prior rituximab (yes vs no).
Salvage therapy: Patients are randomized to 1 of 2 treatment arms.
Arm I: Patients receive cisplatin IV over 60 minutes on day 1, dexamethasone IV or orally on days 1-4, and gemcitabine IV over 30 minutes on days 1 and 8. Patients with CD20+ B cell lymphoma receive rituximab IV over 1.5-6 hours on day 1.
Arm II: Patients receive cisplatin IV over 24 hours on day 1, dexamethasone as in arm I, and cytarabine IV over 3 hours every 12 hours for a total of 2 doses on day 2. Patients with CD20+ B cell lymphoma receive rituximab IV over 1.5-6 hours on day 1.
In both arms, treatment repeats every 21 days for at least 2 courses in the absence of disease progression or unacceptable toxicity.
Patients are reassessed after 2 courses. Patients with progressive disease are removed from study. Patients with a CR, CRu, or PR proceed to autologous stem cell transplantation (ASCT). Patients with SD may proceed to ASCT or receive 1 additional course of salvage therapy at the discretion of the investigator. Patients receiving an additional course of salvage therapy are then reassessed after the completion of therapy. Patients with progressive disease are removed from study. Patients with a PR proceed to ASCT. Patients with SD may proceed to ASCT or be followed off study at the discretion of the investigator.
ASCT: Responding patients (or those with stable disease, if that is the center's policy)undergo mobilization, stem cell harvest, and subsequent ASCT. Patients with CD20+ B-cell disease are randomized to maintenance therapy or observation.
Maintenance therapy: Patients are randomized to 1 of 2 treatment arms.
Arm I: Beginning on day 28 posttransplantation, patients receive rituximab IV once every 2 months for 6 doses (a total of 12 months) in the absence of disease progression or unacceptable toxicity.
Arm II: Patients undergo observation only. Quality of life is assessed at baseline, days 1 and 10 of course 2, day 1 of course 3 (if given), on the last day of salvage therapy (or the first day of mobilization, if given), and at 1 month posttransplantation.
Patients who undergo ASCT are followed at months 1, 3, 7, 13, 19, and 25 and then annually thereafter. Patients who complete salvage therapy, but do not undergo ASCT are followed at months 4, 8, 14, 20, and 26 and then annually thereafter. Patients who relapse or progress are followed every 6 months until 25 months from ASCT or 26 months from completion of salvage therapy and then annually thereafter.
PROJECTED ACCRUAL: A total of 637 patients will be accrued for this study within 3-4 years for the first randomization, and 240 transplanted CD20+ patients will be needed for the second randomization.
Histologically confirmed aggressive non-Hodgkin's lymphoma of 1 of the following subtypes:
Diffuse large cell lymphoma (includes primary mediastinal B-cell lymphoma and T-cell-rich B-cell lymphoma)
Prior indolent lymphoma (e.g., follicular center cell lymphoma; marginal zone lymphoma, including extranodal mucosa-associated lymphoid tissue [MALT] lymphoma; and lymphoplasmacytoid lymphoma) with transformation to diffuse large B-cell lymphoma at relapse
Must be histologically confirmed
No transformed lymphoma at diagnosis with subsequent indolent histology without transformation at relapse
Peripheral T-cell lymphoma
Anaplastic large cell lymphoma
Small noncleaved Burkitt-like lymphoma
T-cell or B-cell lineage confirmed by immunohistochemistry
Clinically or radiologically documented disease meeting either of the following criteria:
Measurable disease, defined as at least 1 bidimensionally measurable site of disease using clinical exam, CT scan, or MRI
Lymph nodes must be > 1.5 cm by physical exam or CT scan
Other non-nodal lesions must be â‰¥ 1.0 cm by physical exam, CT scan, or MRI
Bone lesions are not considered measurable
Evaluable disease, defined as only nonmeasurable disease, including any of the following:
Cytology-confirmed ascites or effusions
Enlarged liver or spleen
Unidimensionally measurable intrathoracic or abdominal masses
Previously treated with 1, and only 1, chemotherapy regimen including an anthracycline and excluding cisplatin, cytarabine, and gemcitabine
No uncontrolled CNS involvement by lymphoma
No CNS disease at time of relapse
CNS disease diagnosed at initial presentation allowed provided a complete response for CNS disease was achieved and maintained
16 to 65
At least 12 weeks
Absolute granulocyte count â‰¥ 1,000/mm^3
Platelet count â‰¥ 75,000/mm^3
Bilirubin â‰¤ 1.5 times upper limit of normal (ULN)
AST or ALT â‰¤ 2.5 times ULN (5 times ULN if liver involvement with lymphoma)
Hepatitis B status known (for patients with a history of hepatitis B or who are at high risk of hepatitis B infection)
Creatinine â‰¤ 1.5 times ULN
No significant cardiac dysfunction or cardiovascular disease
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
Willing to complete quality of life questionnaires
No active, uncontrolled bacterial, fungal, or viral infection
No other malignancy within the past 5 years except adequately treated basal cell skin cancer or carcinoma in situ of the cervix
No other concurrent serious illness or medical condition that would preclude study participation
PRIOR CONCURRENT THERAPY:
Prior rituximab allowed
See Disease Characteristics
At least 4 weeks since prior IV chemotherapy
No prior high-dose chemotherapy with stem cell transplantation
No concurrent corticosteroids except for physiologic replacement
At least 4 weeks since prior radiotherapy and recovered
Exceptions may be made for low-dose, non-myelosuppressive radiotherapy
No prior radiotherapy to more than 25% of functioning bone marrow
Involved-field radiotherapy may be given to areas of bulky disease at relapse (â‰¥ 5 cm) after stem cell transplantation, according to the center's policy
At least 2 weeks since prior major surgery
No other concurrent anticancer therapy
No other concurrent experimental agents
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There are 27 Locations for this study
Chicago Illinois, 60612, United States
Indianapolis Indiana, 46202, United States
Hackensack New Jersey, 07601, United States
Cincinnati Ohio, 45219, United States
Pittsburgh Pennsylvania, 15232, United States
Woodville South Australia, 5011, Australia
Calgary Alberta, T2N 4, Canada
Edmonton Alberta, T6G 1, Canada
Winnipeg Manitoba, R3E 0, Canada
Moncton New Brunswick, E1C 6, Canada
St. John's Newfoundland and Labrador, AIB 3, Canada
Halifax Nova Scotia, B3H 1, Canada
Hamilton Ontario, L8V 5, Canada
Kingston Ontario, K7L 5, Canada
London Ontario, N6A 4, Canada
Mississauga Ontario, L5M 2, Canada
Thunder Bay Ontario, P7B 6, Canada
Toronto Ontario, M4N 3, Canada
Toronto Ontario, M5B 1, Canada
Toronto Ontario, M5G 2, Canada
Greenfield Park Quebec, J4V 2, Canada
Montreal Quebec, H2L 4, Canada
Quebec City Quebec, G1R 2, Canada
Quebec City Quebec, G1S 4, Canada
Sherbrooke Quebec, J1H 5, Canada
Regina Saskatchewan, S4T 7, Canada
Saskatoon Saskatchewan, S7N 4, Canada
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