Maurer, Matthew

Abstract Disease progression after frontline therapy for Diffuse large B‐cell lymphoma (DLBCL) is a clinically significant event. Patients who experience early progression or have refractory disease have especially poor outcomes. Simple, clinically applicable prognostic tools are needed for selecting patients for consideration for novel therapies and prognostication in the relapsed/refractory (R/R) setting. Model building was performed in patients from the Surrogate endpoints in aggressive lymphoma (SEAL) consortium with disease progression after frontline immunochemotherapy. The primary endpoint was overall survival (OS) measured from date of progression. Validation was performed in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER) and Danish National Lymphoma Register (LYFO) cohorts. Model performance was assessed using time‐dependent concordance indices (c‐statistic) and calibration with metrics evaluated at 2 years from progression. Note, 1234 of 5112 patients treated with frontline immunochemotherapy in the SEAL consortium developed progressive disease. Time to progression on immunochemotherapy and age at progression were strongly associated with post‐progression OS (both p < 0.001). A prognostic model was developed incorporating spline fit for both variables. The model had good concordance in the discovery (0.67) and validation sets (LYFO c = 0.64, MER c = 0.68) with generally good calibration. Time to progression on frontline therapy is strongly associated with post‐progression OS in DLBCL. We developed and validated a simple to apply clinical prognostic tool in the R/R setting. The useful prediction of expected outcomes in R/R DLBCL and can inform treatment decisions such as considerations for CAR‐T therapy as well as trial designs. The model is available in smartphone‐based point of care applications.

PURPOSE Exclusion of patients needing urgent treatment or requiring novel biomarkers before enrollment has impacted the ability to enroll real-world patients in frontline trials of diffuse large B-cell lymphoma (DLBCL). The impact of baseline organ function–based eligibility criteria on this effect and clinical trial exclusion is less well-understood. METHODS Consecutive patients with newly diagnosed lymphoma were enrolled from 2002 to 2015 into the Molecular Epidemiology Resource (MER) of the University of Iowa and Mayo Clinic Lymphoma Specialized Program of Research Excellence. The current analysis includes 1,265 patients with DLBCL receiving standard immunochemotherapy. Organ function parameters were identified from criteria for hemoglobin, absolute neutrophil count, platelet count, creatinine clearance, and bilirubin, as reported in frontline DLBCL trials. Abstracted laboratory values from MER were used to determine the percent (%) of patients excluded. Outcomes and cause-of-death analyses comparing ineligible and eligible groups in MER were conducted. An interactive online tool was developed to estimate exclusions based on organ function for future trial design. RESULTS Between 9% and 24% of MER patients with DLBCL receiving standard immunochemotherapy were excluded on the basis of baseline organ function alone. Ineligible patients based on organ function had significantly inferior event-free survival (hazard ratios, 1.67-2.16), overall survival (hazard ratios, 1.87-2.56), and event-free survival at 24 months (odds ratio, 1.71-2.16). Ineligible patients were more likely to die from lymphoma progression than increased therapy-related complications. CONCLUSION Current national and international trials exclude up to 24% of patients from participation on the basis of organ function alone. A significant difference in the outcomes, notably lymphoma-related death, suggests issues with generalization and potential exclusion of high-risk patients. These data will help future clinical trial development and meet US Food and Drug Administration and ASCO recommendations to increase trial accrual.

AbstractImmunochemotherapy followed by autologous transplant (ASCT) in CALGB/Alliance 59909 achieved a median progression‐free survival (PFS) in mantle cell lymphoma (MCL) of 5 years, but late recurrences occurred. We evaluated tolerability and efficacy of adding post‐transplant bortezomib consolidation (BC) or maintenance (BM) to this regimen in CALGB/Alliance 50403, a randomized phase II trial. Following augmented‐dose R‐CHOP/ methotrexate, high‐dose cytarabine‐based stem cell mobilization, cyclophosphamide/carmustine/etoposide (CBV) autotransplant, and rituximab, patients were randomized to BC (1.3 mg/m2 IV days 1, 4, 8, 11 of a 3‐week cycle for four cycles) or BM (1.6 mg/m2 IV once weekly × 4 every 8 weeks for 18 months) beginning day 90. The primary endpoint was PFS, measured from randomization for each arm. Proliferation signature, Ki67, and postinduction minimal residual disease (MRD) in bone marrow were assessed. Of 151 patients enrolled; 118 (80%) underwent ASCT, and 102 (68%) were randomized. Both arms met the primary endpoint, with median PFS significantly greater than 4 years (P < .001). The 8‐year PFS estimates in the BC and BM arms were 54.1% (95% CI 40.9%‐71.5%) and 64.4% (95% 51.8%‐79.0%), respectively. Progression‐free survival was significantly longer for transplanted patients on 50403 compared with those on 59909. Both the PFS and OS were significantly better for those who were MRD‐negative post‐induction. The high risk proliferation signature was associated with adverse outcome. Both BM and BC were efficacious and tolerable, although toxicity was significant. The comparison between studies 50403 and 59909 with long‐term follow up suggests a PFS benefit from the addition of BC or BM post‐ transplant.

Abstract Purpose: Clear cell ovarian carcinoma (CCOC) is an aggressive disease that often demonstrates resistance to standard chemotherapies. Approximately 25% of patients with CCOC show a strong APOBEC mutation signature. Here, we determine which APOBEC3 enzymes are expressed in CCOC, establish clinical correlates, and identify a new biomarker for detection and intervention. Experimental Designs: APOBEC3 expression was analyzed by IHC and qRT-PCR in a pilot set of CCOC specimens (n = 9 tumors). The IHC analysis of APOBEC3B was extended to a larger cohort to identify clinical correlates (n = 48). Dose-response experiments with platinum-based drugs in CCOC cell lines and carboplatin treatment of patient-derived xenografts (PDXs) were done to address mechanistic linkages. Results: One DNA deaminase, APOBEC3B, is overexpressed in a formidable subset of CCOC tumors and is low or absent in normal ovarian and fallopian tube epithelial tissues. High APOBEC3B expression associates with improved progression-free survival (P = 0.026) and moderately with overall survival (P = 0.057). Cell-based studies link APOBEC3B activity and subsequent uracil processing to sensitivity to cisplatin and carboplatin. PDX studies extend this mechanistic relationship to CCOC tissues. Conclusions: These studies demonstrate that APOBEC3B is overexpressed in a subset of CCOC and, contrary to initial expectations, associated with improved (not worse) clinical outcomes. A likely molecular explanation is that APOBEC3B-induced DNA damage sensitizes cells to additional genotoxic stress by cisplatin. Thus, APOBEC3B is a molecular determinant and a candidate predictive biomarker of the therapeutic response to platinum-based chemotherapy. These findings may have broader translational relevance, as APOBEC3B is overexpressed in many different cancer types.

Diffuse large B-cell lymphoma is a heterogeneous disease, commonly described by cell-of-origin (COO) molecular subtypes. We sought to identify novel patient subgroups through an unsupervised analysis of a large public dataset of gene expression profiles from newly diagnosed de novo DLBCL patients, yielding two biologically distinct subgroups characterized by differences in the tumor microenvironment. Pathway analysis and immune deconvolution algorithms identified higher B-cell content and a strong proliferative signal in subgroup A and enriched T-cell, macrophage, and immune/inflammatory signals in subgroup B, reflecting similar biology to published DLBCL stratification research. A gene expression classifier, featuring 26 gene expression scores, was derived from the public dataset to discriminate subgroup A (classifier-negative, immune-low) and subgroup B (classifier-positive, immune-high) patients. Subsequent application to an independent series of diagnostic biopsies and replicated the subgroups with immune cell composition confirmed via immunohistochemistry. Avadomide, a CRL4CRBN E3 ubiquitin ligase modulator, demonstrated clinical activity in relapsed/refractory DLBCL patients, independent of COO subtypes. Given the immunomodulatory activity of avadomide and need for a patient selection strategy, we applied the gene expression classifier to pretreatment biopsies from relapsed/refractory DLBCL patients receiving avadomide (NCT01421524). Classifier-positive patients demonstrated an enrichment in response rate and progression-free survival of 44% and 6.2 months versus 19% and 1.6 months for classifier-negative patients (HR=0.49 [0.280, 0.86]; P=.0096). The classifier was not prognostic for R-CHOP or salvage immunochemotherapy. The classifier described here discriminates DLBCL tumors based on tumor and non-tumor composition and has potential utility to enrich for clinical response to immunomodulatory agents including avadomide.

Abstract In this month's CME article, an analysis of over 1300 patients with diffuse large B-cell lymphoma (DLBCL), Wang et al demonstrate that the approximately 13% of patients with concurrent indolent lymphoma at diagnosis had the same prognosis as those patients with isolated DLBCL.