Combination Chemotherapy with or without Autologous Stem Cell Transplant in Treating Patients with Central Nervous System B-cell Lymphoma
This phase II trial studies how well combination chemotherapy given together with autologous stem cell transplant works compared to combination chemotherapy alone in treating patients with central nervous system B-cell lymphoma. Giving chemotherapy before an autologous stem cell transplant helps kill cancer cells in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. After treatment, stem cells are collected from the patient's blood and stored. More chemotherapy is then given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy.
Inclusion Criteria
- Diagnosis of primary central nervous system (CNS) diffuse large B-cell lymphoma confirmed by one of the following: * Brain biopsy or resection * Cerebrospinal fluid * Vitreous fluid
- Karnofsky performance scale >= 30 (>= 50 for patients ages 60-70 years)
- Patients must be non-pregnant and non-nursing; due to the unknown teratogenic potential of this regimen, pregnant or nursing patients may not be enrolled; women of childbearing potential must have a negative serum or urine pregnancy test 10-14 days prior to registration; in addition, women and men of childbearing potential must commit to use an effective form of contraception throughout their participation in this study due to the teratogenic potential of the therapy utilized in this trial; appropriate methods of birth control include abstinence, oral contraceptives, implantable hormonal contraceptives, or double barrier method (diaphragm plus condom)
- Patients must have negative human immunodeficiency virus (HIV) serology
- Patients must have negative hepatitis C virus (HCV) serology; all patients must be screened for hepatitis B infection before starting treatment; those patients who test positive for hepatitis B should be closely monitored for evidence of active hepatitis B virus (HBV) infection and hepatitis during and for several months after rituximab treatment; PCNSL patients with a history of hepatitis B infection should be treated with entecavir or lamivudine (physician discretion for choice of drug) as antiviral prophylaxis to prevent hepatitis B reactivation
- Absolute neutrophil count (ANC) >= 1500/mcL
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2 x upper limit of normal (ULN)
- Total bilirubin =< 3 mg/dL
- Creatinine clearance >= 50 mL/min
- Platelet count >= 100,000/mcL
Exclusion Criteria
- Patients must have no evidence or history of non-Hodgkin lymphoma (NHL) outside of CNS
- Patients must have no prior chemotherapy or radiation therapy for lymphoma
- Patient must have no history of organ transplantation or ongoing immunosuppressant therapy
Additional locations may be listed on ClinicalTrials.gov for NCT01511562.
See trial information on ClinicalTrials.gov for a list of participating sites.
PRIMARY OBJECTIVE:
I. To compare the two-year progression-free survival (PFS) of patients treated with the myeloablative consolidation treatment strategy of high-dose therapy (HDT)/autologous stem cell transplant (ASCT) versus those treated with non-myeloablative consolidation chemotherapy with cytarabine and etoposide.
SECONDARY OBJECTIVES:
I. To compare the two-year event-free survival (EFS) of patients treated with consolidation HDT/ASCT versus those treated with consolidation chemotherapy consisting of etoposide and cytarabine.
II. To compare the overall survival (OS) of patients treated with the consolidation HDT/ASCT versus those treated with consolidation chemotherapy consisting of etoposide and cytarabine.
III. To assess the toxicities associated with consolidation HDT/ASCT versus consolidation consisting of etoposide and cytarabine.
IV. To determine diffusion magnetic resonance imaging (MRI) metrics (apparent diffusion coefficient [ADC]mini, ADC25%, and ADCmean) prior to induction chemotherapy, after one full induction chemotherapy cycle, and at the end of induction chemotherapy as a predictor of response and outcome (Cancer and Leukemia Group B [CALGB] 581101).
V. To determine brain fludeoxyglucose F 18 (FDG)-positron emission tomography (PET) metrics (tumor standardized uptake value [SUV] and tumor versus background SUV) prior to induction chemotherapy, after one full induction chemotherapy cycle, and at the end of induction chemotherapy as a predictor of response and outcome (CALGB 581101).
VI. To determine whether low baseline ADC measurements are associated with shorter PFS and OS (CALGB 581101).
VII. To determine whether reduction in SUV by > 25% on brain FDG-PET/computed tomography (CT) after one cycle of induction therapy is associated with improved PFS and OS (CALGB 581101).
VIII. To determine which immunohistochemistry (IHC)-based biomarkers are predictive of an adverse prognosis (CALGB 151113).
IX. To determine which IHC-based biomarkers are predictive of a favorable prognosis (CALGB 151113) for BCL6 (B-cell CLL/lymphoma 6), and STAT 6 (signal transducer and activator of transcription 6, interleukin-4 induced).
X. To analyze tumor tissue for gene mutational analysis via whole exome sequencing, copy number aberrations, and expression profiles, and to correlate these profiles with treatment outcomes (CALGB 151113).
XI. To determine whether cerebrospinal fluid (CSF) proteome is a predictor of outcomes (prognostic marker) irrespective of treatment arm (CALGB 151113) for (IL-10 [interleukin-10] and C3 [complement component 3]).
XII. To assess the neurocognitive function of patients treated with consolidation HDT/ASCT versus those treated with consolidation chemotherapy (etoposide and cytarabine) as measured by serial administration of the International Primary Central Nervous System Lymphoma (PCNSL) Collaborative Group (IPCG) neurocognitive battery and evaluate the long-term survivorship differences between the two arms (CALGB 71105).
XIII. To assess the quality of life of patients treated with consolidation HDT/ASCT versus those treated with consolidation etoposide and cytarabine as measured by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30/Brain Cancer Module-20 (EORTC-QLQ30/BCM20), and to evaluate the long-term survivorship differences between the two arms (CALGB 71105).
OUTLINE:
INDUCTION CHEMOTHERAPY: Patients receive methotrexate intravenously (IV) over 4 hours on days 1 and 15 (cycles 1-4); leucovorin IV every 6 hours beginning 24 hours after each methotrexate dose (cycles 1-4); rituximab IV on days 3, 10, 17, and 24 (cycle 1), and days 3 and 10 (cycle 2); temozolomide orally (PO) on days 7-11 (cycles 1-4); and cytarabine IV over 2 hours twice daily (BID) on days 1 and 2 (cycle 5 only). Treatment repeats every 28 days for 5 cycles in the absence of disease progression or unacceptable toxicity. Patients achieving a complete response, complete response unconfirmed, partial response, or stable disease proceed to consolidation therapy.
CONSOLIDATION THERAPY: Patients are randomized to 1 of 2 arms.
ARM I: Between 3-5 weeks after induction therapy patients undergo stem cell mobilization per participating institution guidelines.
CONSOLIDATION THERAPY: Beginning 2-4 weeks after stem cell mobilization, patients receive high-dose therapy comprising carmustine IV over 2 hours on day -6 and thiotepa IV over 2 hours every 12 hours on days -5 to -4. Beginning on day 4, patients also receive filgrastim subcutaneously (SC) once a day and continuing until absolute neutrophil count recovers.
STEM CELL RESCUE: Patients then undergo autologous peripheral blood stem cell transplantation (PBSCT) on day 0.
ARM II: Beginning no earlier than 4 weeks and no later than 12 weeks after day 1 of cycle 5 of induction therapy, patients receive cytarabine IV over 2 hours every 12 hours on days 1-4, and etoposide IV continuously over 96 hours on days 1-4. Beginning on day 4, patients also receive filgrastim SC once a day and continuing until absolute neutrophil count recovers.
After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then yearly for 5 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationAlliance for Clinical Trials in Oncology
Principal InvestigatorTracy T. Batchelor
- Primary IDCALGB-51101
- Secondary IDsNCI-2012-00110, CDR0000721927
- ClinicalTrials.gov IDNCT01511562