Heidi Móciková

PURPOSE Patients with the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) historically showed inferior survival with standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Phase II studies demonstrated that adding the immunomodulatory agent lenalidomide to R-CHOP improved outcomes in ABC-type DLBCL. The goal of the global, phase III ROBUST study was to compare lenalidomide plus R-CHOP (R2-CHOP) with placebo/R-CHOP in previously untreated, ABC-type DLBCL. METHODS Histology and cell-of-origin type were prospectively analyzed by central pathology prior to random assignment and study treatment. Patients with ABC-DLBCL received lenalidomide oral 15 mg/d, days 1-14/21 plus standard R-CHOP21 versus placebo/R-CHOP21 for six cycles. The primary end point was progression-free survival (PFS) per independent central radiology review. RESULTS A total of 570 patients with ABC-DLBCL (n = 285 per arm) were stratified by International Prognostic Index score, age, and bulky disease, and randomly assigned to R2-CHOP or placebo/R-CHOP. Baseline demographics were similar between arms. Most patients completed six cycles of treatment: 74% R2-CHOP and 84% placebo/R-CHOP. The most common grade 3/4 adverse events for R2-CHOP versus placebo/R-CHOP were neutropenia (60% v 48%), anemia (22% v 14%), thrombocytopenia (17% v 11%), and leukopenia (14% v 15%). The primary end point of PFS was not met, with a hazard ratio of 0.85 (95% CI, 0.63 to 1.14) and P = .29; median PFS has not been reached for either arm. PFS trends favoring R2-CHOP over placebo/R-CHOP were seen in patients with higher-risk disease. CONCLUSION ROBUST is the first DLBCL phase III study to integrate biomarker-driven identification of eligible ABC patients. Although the ROBUST trial did not meet the primary end point of PFS in all patients, the safety profile of R2-CHOP was consistent with individual treatments with no new safety signals.

Introduction: The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) continues to convey inferior survival despite efforts to enhance outcomes with novel R-CHOP combinations. Phase II studies have suggested that the addition of the immunomodulatory agent lenalidomide to R-CHOP could ameliorate the poor prognostic effect of the ABC phenotype and improve treatment outcome in this subgroup of patients. Methods: The global phase III ROBUST trial (NCT02285062) is the first to compare lenalidomide/R-CHOP (R2-CHOP) vs placebo/R-CHOP in previously untreated, prospectively selected, CD20+ ABC-type DLBCL. Patients included adults with Ann Arbor stage II-IV disease, IPI score ≥ 2, and ECOG PS ≤ 2. Confirmation of histology and cell-of-origin type were prospectively analyzed from formalin-fixed, paraffin-embedded excisional/surgical or core needle biopsy samples by central pathology using the NanoString Lymphoma Subtyping Test (LST), based on the Lymph2Cx GEP assay (Scott, Blood 2014). ABC-DLBCL patients were stratified by IPI score (2 vs ≥ 3), bulky disease (< 7 vs ≥ 7 cm) and age (< 65 vs ≥ 65 y), and randomized 1:1 to lenalidomide PO 15 mg/d, d1-14/21 + standard R-CHOP21 vs placebo/R-CHOP21 for 6 cycles, with 2 additional, optional doses of rituximab per local practice. The primary endpoint was progression-free survival (PFS) assessed by independent central radiology per 2014 NHL IWG criteria, and defined as time from randomization to PD or death from any cause. Results: A total of 570 ABC-DLBCL patients met eligibility criteria and were enrolled in ROBUST (n = 285 per arm). Baseline demographics were similar between arms, with a median age for all patients of 65 y (52% ≥ 65 y), 42% IPI 2 score/58% IPI ≥ 3 score, 88% stage III/IV disease, and 34% bulky disease. The primary endpoint of PFS was not met with an HR = 0.85 (95% CI, 0.63-1.14) and P = 0.29; median PFS was not reached for either arm (Figure). Positive PFS trends favoring R2-CHOP over placebo/R-CHOP were observed with disease stage III/IV (HR = 0.81 [95% CI, 0.60-1.10]) and IPI score ≥ 3 (HR = 0.74 [95% CI, 0.53-1.05]). Median EFS was not reached for either arm (HR = 1.04; 95% CI, 0.80-1.34; P = 0.73). At a median follow-up of 27.1 mo (range, 0-47) for survivors, 2-y OS was 79% for R2-CHOP and 80% for placebo/R-CHOP (medians not reached). ORR was 91% for both arms, with 69% vs 65% CR for R2-CHOP vs placebo/R-CHOP, respectively. 74% R2-CHOP and 84% placebo/R-CHOP patients completed 6 cycles of treatment; AEs (mainly neutropenia) were the most common reason for treatment discontinuation. The most common grade 3/4 AEs (≥ 10%) for R2-CHOP vs placebo/R-CHOP were neutropenia (60% vs 48%), anemia (22% vs 14%), thrombocytopenia (17% vs 11%), leukopenia (14% vs 15%), febrile neutropenia (14% vs 9%), and lymphopenia (11% vs 8%).

Follicular lymphoma (FL) is a common indolent B-cell malignancy with a variable clinical course. An unfavorable event in its course is histological transformation to a high-grade lymphoma, typically diffuse large B-cell lymphoma. Recent studies show that genetic aberrations of MYC or its overexpression are associated with FL transformation (tFL). However, the precise molecular mechanisms underlying tFL are unclear. Here we performed the first profiling of expression of microRNAs (miRNAs) in paired samples of FL and tFL and identified 5 miRNAs as being differentially expressed. We focused on one of these miRNAs, namely miR-150, which was uniformly downmodulated in all examined tFLs (∼3.5-fold), and observed that high levels of MYC are responsible for repressing miR-150 in tFL by binding in its upstream region. This MYC-mediated repression of miR-150 in B cells is not dependent on LIN28A/B proteins, which influence the maturation of miR-150 precursor (pri-miR-150) in myeloid cells. We also demonstrated that low miR-150 levels in tFL lead to upregulation of its target, namely FOXP1 protein, which is a known positive regulator of cell survival, as well as B-cell receptor and NF-κB signaling in malignant B cells. We revealed that low levels of miR-150 and high levels of its target, FOXP1, are associated with shorter overall survival in FL and suggest that miR-150 could serve as a good biomarker measurable in formalin-fixed paraffin-embedded tissue. Overall, our study demonstrates the role of the MYC/miR-150/FOXP1 axis in malignant B cells as a determinant of FL aggressiveness and its high-grade transformation.

This retrospective study evaluated the secondary clinical risk score at relapse, the prognostic significance of pre-transplant positron emission tomography (PET), and complete remission (CR) assessed by computed tomography (CT) after salvage chemotherapy before autologous stem cell transplant (ASCT) in 76 patients with relapsed/refractory Hodgkin lymphoma (HL). Median follow-up after ASCT was 23 months. Overall 11/20 PET-positive and 14/56 PET-negative patients relapsed after ASCT. In univariate analysis, only PET negativity before ASCT was significantly associated with better 2-year progression-free survival (PFS) (72.7 ± 6.3% vs. 36.1 ± 11.6%, p = 0.01) and 2-year overall survival (OS) (90.3 ± 4.1% vs. 61.4 ± 11.6%, p = 0.009). Other factors were not significant. In multivariate analysis, none of the evaluated factors were significant for PFS and OS. However, positive pre-transplant PET identified a population with worse PFS and OS at least in univariate analysis.