ALBERT

Description: Background: Patients with relapsed or refractory aggressive B-cell lymphoma, or transformed indolent lymphoma can achieve long-term survival with high dose therapy and autologous stem cell transplant (HDT/ASCT), provided their disease is sensitive to salvage chemotherapy. Unfortunately, approximately 50% of patients are insensitive to standard salvage regimens. Objectives: This trial investigated whether adding Rituximab to ESHAP (etoposide, solumedrol, cytosine arabinoside, cisplatin) induction improved chemosensitivity. The primary outcome was overall response rate (CR + CRu + PR) to R-ESHAP. Secondary outcomes were toxicity, ability to undergo ASCT, progression free survival (PFS) and overall survival (OS). Methods: The protocol was approved by the local ethics review board and all patients provided informed consent. Eligible patients received ESHAP every 28 days with GCSF support until 〈 15% bone marrow involvement was achieved (2–4 cycles). Rituximab was given weekly x 8 weeks concurrent with the first 2 cycles of ESHAP. GCSF mobilized stems cells were collected on day 10–11 of cycle 1 or 2. Results: The trial was stopped early after the complete response (CR) rate at a planned interim analysis exceeded 40% (a pre-specified criteria for stopping the trial). Final results of 26 patients are presented. Median age was 55.5 years (range 42–64). Twelve patients had relapsed aggressive lymphoma, 2 had refractory disease and 12 had transformed indolent lymphoma. Twenty-two of 26 patients were stage III/IV. The overall response rate to R-ESHAP was 92% (95% CI 82% to 100%). Twelve patients (46%; 95% CI 27% to 65%) had a CR or unconfirmed CR. Grade 3–4 thrombocytopenia, neutropenia, and anemia occurred in 57%, 40%, and 15% of R-ESHAP cycles respectively. Grade 3–4 infections complicated 7% of cycles. Median follow-up was 17 months (range 2.9 to 43.2) from enrollment. Twenty-three of 26 patients (88%) were transplanted. Notable post-transplant toxicity included 5 cases of herpes zoster, 2 cases of bacterial pneumonia, 1 case of pulmonary aspergillosis, and 1 fatal case of pneumocystis carnii pneumonia (PCP). Three patients did not proceed to HDT/ASCT; 2 were refractory to R-ESHAP and 1 died of a myocardial infarction after induction chemotherapy but prior to ASCT. Fifteen of 23 patients who received ASCT remain in remission, 6 have relapsed. Seven patients have died, 4 of progressive disease, 1 of myocardial infarction, 1 of PCP, and 1 of accelerated Parkinson’s Disease. Median PFS and median OS have not yet been reached. Conclusions: In this single-arm, phase II study of relapsed or refractory aggressive B-cell lymphoma and transformed indolent B-cell lymphoma, R-ESHAP induction therapy resulted in a very high ORR (92%) and enabled a large percentage of patients (88%) to proceed to HDT/ASCT. Toxicity of the R-ESHAP regimen was acceptable, and its efficacy compared favorably with other salvage regimens reported in the literature, including R-ICE.

Description: High-dose therapy and autologous stem cell transplantation (HDT/ASCT) and rituximab immunotherapy have been increasingly applied in the management of non-Hodgkin’s lymphomas (NHL). Although both approaches have been individually associated with B-cell depletion and hypogammaglobulinemia, the incidence, time course, and predictors of prolonged deficiencies following a combined treatment approach is unknown. Methods: We completed a series of prospective phase II studies of HDT/ASCT combined with rituximab for patients with relapsed follicular lymphoma (FL) or diffuse large B cell lymphoma (DLBCL). In two phase II trials of patients with FL (R/Tx and R-IFN/Tx), patients received 9 infusions of rituximab 375mg/m2 as both an in vivo purge and as maintenance post HDT/ASCT. In a trial with relapsed DLBCL or transformed lymphoma, patients received 8 infusions with rituximab 375mg/m2 only as part of the salvage chemotherapy regimen (R-ESHAP/Tx). Immunoglobulin levels were expressed as percentages with 100% representing the lower limit of normal at the institutional lab. Hypogammaglobulinemia was defined as 3 months) infections included herpes zoster reactivation (n=7) and pneumonia (n=8). One individual in the R-ESHAP/Tx study died of PCP pneumonia 4 months post HDT/ASCT. A relationship between grade III-IV infections and prolonged hypogammaglobulinemia was not evident on univariate analysis (data not shown). Conclusions: Patients with follicular lymphoma undergoing high dose therapy and stem cell transplantation together with rituximab maintenance are likely to experience a prolonged hypogammaglobulinemia whereas this is less likely with patients with aggressive-histology lymphoma undergoing similar doses of rituximab as part of their salvage therapy. Further research is required to elucidate the relative contributions of disease histology, bone marrow involvement, baseline hypogammaglobulinemia, timing of rituximab infusions or other factors not yet identified. Figure Figure Figure Figure

Description: High-dose therapy and autologous stem cell transplantation (HDT/ASCT) are associated with prolonged remissions in relapsed follicular lymphoma (FL). Maintenance rituximab (R) has an accepted role in extending remissions and preclinical evidence suggests that its effects may be enhanced by the immunomodulatory capacity of interferon alpha (IFN-α). We designed a phase II study to incorporate in-vivo purging (with R) and post-transplant maintenance immunotherapy (with combined R and IFN-α) to prolong the remissions attained by HDT/ASCT. We present a planned analysis of 30 patients age ≤65 with 1–2 relapses of FL. Individuals received salvage CHOP or DHAP and proceeded with stem cell mobilization and HDT/ASCT with cyclophosphamide/carmustine/etoposide if they achieved ≥75% reduction in bulk and