Coleen Bejot

Addition of lenalidomide to rituximab, ifosfamide, carboplatin, etoposide (RICER) in first-relapse/primary refractory diffuse large B-cell lymphoma

Relapsed/refractory diffuse large B‐cell lymphoma (DLBCL) is associated with a poor prognosis. Outcomes are particularly poor following immunochemotherapy failure or relapse within 12 months of induction. We conducted a Phase I/II trial of lenalidomide plus RICE (rituximab, ifosfamide, carboplatin, and etoposide) (RICER) as a salvage regimen for first‐relapse or primary refractory DLBCL. Dose‐escalated lenalidomide was combined with RICE every 14 d. After three cycles of RICER, patients with chemosensitive disease underwent stem cell collection and consolidation with BEAM [BCNU (carmustine), etoposide, cytarabine, melphalan] followed by autologous stem cell transplantation (autoSCT). Patients who recovered from autoSCT toxicities within 90 d initiated maintenance treatment with lenalidomide 25 mg daily for 21 d every 28 d for 12 months. No dose‐limiting or unexpected toxicities occurred with lenalidomide 25 mg plus RICE. Grade 3/4 haematological toxicities resolved appropriately, and planned dose density and dose intensity of RICER were preserved. No lenalidomide or RICE dose reductions were required in any of the three cycles. After two cycles of RICER, nine of 15 patients (60%) achieved a complete response, and two achieved a partial response (13%). Combining lenalidomide with RICE is feasible, and results in promising response rates (particularly complete response rates) in high‐risk DLBCL patients.

Reduced‐dose fludarabine, cyclophosphamide, and rituximab (FCR‐Lite) plus lenalidomide, followed by lenalidomide consolidation/maintenance, in previously untreated chronic lymphocytic leukemia

Fludarabine, cyclophosphamide, and rituximab (FCR) remains the standard of care for fit chronic lymphocytic leukemia (CLL) patients requiring first therapy. However, side effects can be significant, and patients with poor risk features have inferior outcomes. The purpose of this study was to evaluate reduced‐dose FCR (FCR‐Lite) plus lenalidomide (FCR2) followed by lenalidomide maintenance as a strategy to shorten immunochemotherapy in untreated CLL. Patients received four to six cycles of FCR2. Patients who were minimal residual disease (MRD) negative in peripheral blood (PB) and bone marrow (BM) initiated 12 months of lenalidomide maintenance after either four or six cycles (based on MRD status). The primary study endpoint was the complete response (CR) rate after four cycles of FCR2. Twenty patients were evaluable. After four cycles of FCR2, response rates were: CR, 45.0%; CR with incomplete blood count recovery (CRi), 5.0%; partial response (PR), 45.0%; and stable disease (SD), 5.0%. BM and PB samples from 27.8% and 52.9% of patients, respectively, were MRD negative. After six cycles, response rates were: CR, 58.3%; CRi, 16.7%; and PR, 25.0%. BM and PB samples from 50.0% and 72.7% of patients, respectively, were MRD negative. Overall, 75% of evaluable patients achieved a CR or CRi following FCR2. After 17.4 months of median follow‐up, one progression and one death occurred. Our findings suggest that FCR2 combines encouraging clinical activity with acceptable toxicity in previously untreated CLL. Lenalidomide can be safely added to FCR and may reduce chemotherapy exposure without compromising outcomes. Am. J. Hematol. 90:487–492, 2015.

Targeting indolent non-Hodgkin lymphoma

ABSTRACT Introduction: Due to recent advancements in the understanding of the molecular pathogenesis of B-cell malignancies, there has been an explosion of innovative agents in development. The purpose of this review is to efficiently summarize novel therapies with activity in indolent non-Hodgkin lymphoma (iNHL) targeting surface antigens, signaling pathways, and the tumor microenvironment. Areas covered: A literature search was performed to identify preclinical data and clinical trials focused on the use of targeted therapies in iNHL subtypes including follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, and lymphoplasmacytic lymphoma/Waldenström macroglobulinemia. Classes reviewed include monoclonal antibodies, antibody-drug conjugates, immunomodulatory agents, B-cell receptor pathway inhibitors, Bcl-2 inhibitors, checkpoint inhibitors, chromatin and epigenetic modulating agents, and CAR T-cells. Expert commentary: Opinions regarding strategies to address the prioritization of novel agents entering clinical development, the determination of rational combination therapy, the development of novel endpoints to expedite clinical development, and the movement towards novel consolidative approaches with immuno- and cellular therapy in an attempt to provide curative treatment options are provided. Also, the economic impact of indefinite therapy is discussed.

The association between the GOELAMS MCL-PET prognostic index and survival in patients treated with rituximab-hypercvad (R-HyCVAD) or high-dose therapy with autologous stem cell rescue (HDT/ASCT).

8050 Background: Prognostic models in MCL are still debated particularly in dose-intensive treatment approaches (R-HyCVAD or HDT/ASCT) since they include both age (med age dx, mid 60s) and performance status. Additional prognostic factors have been looked at including Ki-67 (MIB-1) and more recently PET scan. The GOELAMS group proposed a model to predict OS and PFS in MCL in the 1st-line setting based on a dichotomized SUV max (≤ 6 vs. >6 = 1 point) + IPI score (≤ 2 vs. >2 = 1 point) in 44 heterogeneously treated pts (3 groups: score 0-2). We sought to validate this approach in MCL pts treated in the 1st-line setting. METHODS Single center retrospective study to assess the clinical utility of the GOELAMS MCL-PET prognostic index in newly diagnosed MCL pts treated with R-HCVAD or HDT/ASCT using PFS and OS as 1° endpoints. PET-CT images were centrally reviewed to determine SUV max at diagnosis and response (International Harmonization Project in Lymphoma criteria) by 3 radiologists blinded to outcomes. RESULTS 83 pts (median age 58, range 35-74) with advanced stage (98% stage IV) MCL treated with 1st line R-HyCVAD (60%) or HDT/ASCT (40%) were indentified for this analysis. Overall treatment response (IWG) was 93% (76% CR + 17% PR). 60 pts had clinical and radiologic data available for the validation study. Median baseline characteristics: WBC 7.75 (range 2.5-918), Ki-67 30% (range 5-90%), IPI 3 (52% ≥3), MIPI 3.5 (40% int+high risk), SUV Max 7.8 (range 2.4-36.7). Estimated 3 year OS and PFS were 82% and 76% (med follow-up 35 months). Using Cox regression and Kaplan Meir survival analyses, the MCL-IPI-PET model did not stratify pts into 3 groups with distinct PFS (HR 1.3, p=.24 LR test) or OS (HR 3.1, p .13 LR test). Baseline SUV max was not an independent predictor of outcome in multivariate analysis (PFS: HR 1.4, p=.71, OS: HR 2.3, p=.29) when added to IPI. CONCLUSIONS The MCL-IPI-PET model was not validated in our series of newly diagnosed MCL pts treated with intensive approaches. This study highlights the need to develop and validate models to identify pts at risk for inferior survival treated with dose-intensive approaches.