Faculty Bibliography

This phase 2 study evaluated brentuximab vedotin monotherapy in CD30-expressing DLBCL; after several patients with little to no CD30 achieved a complete remission (CR), the study evaluated treatment of DLBCL with undetectable CD30 (CD30u) by local visual immunohistochemistry (vIHC). Sixteen of 52 CD30u DLBCL patients (31%) had an objective response (6 CRs [12%]). Median progression-free survival (PFS) was 1.4 months (range, 0.4-15.6) and median overall survival (OS) was 7.5 months (range, 0.7-18.6+). Subsequent CD30 expression quantitated by computer-assisted digital image analysis (cIHC) showed that 11 of 16 CD30u DLBCL responders had >/=1% CD30. Correlative analyses of CD30u and CD30-expressing DLBCL combined demonstrated that >/=1% CD30 expression by cIHC resulted in a trend toward a higher response rate and significantly longer median PFS and OS. A minimum CD30 expression threshold appears to be required for antitumor activity in DLBCL; however, other factors also likely contribute to activity. (NCT01421667).

Background: Survival outcomes for older patients with aggressive NHL are disproportionally inferior to those of younger patients. While differences in tumor biology may play a role, older patients are often frail with comorbidities, polypharmacy, and use potentially inappropriate medications (PIM) such as anticholinergics and benzodiazepines. Methods: Using Cox proportional hazard and logistic regression models, we analyzed all aggressive NHL patients age >= 60 treated at our two affiliated hospitals from 2009-2014 to examine the association of polypharmacy and PIM use with progression-free survival (PFS), overall survival (OS), and treatment-related toxicities. Results: In this updated and final analysis, we included 171 patients with complete records from these two hospitals. They share similar demographic, clinical, and laboratory characteristics except for higher International Prognostic Index (IPI) in patients from one hospital. The median age was 70 years (range 65-77). At the time of diagnosis, 46% of patients used more than 4 medications (polypharmacy) and 47% used at least one PIM. Only 43% of patients received first-line chemotherapy of adequate relative dose intensity (>85% dosage), and 65% experienced >= grade 3 toxicities. Polypharmacy and PIM use were associated with shortened PFS and OS by log-rank test. Most importantly, PIM use remained an independent predictor of PFS, OS, and >= grade 3 toxicities in multivariable analyses (Table). Conclusions: This is the first report of significantly adverse survival impacts of polypharmacy and PIM use in older patients with aggressive NHL, presumably from drug-drug interactions that increase toxicities and impair the delivery of adequate chemotherapy dosage. Our findings support the use of evidence-based geriatric principles to guide meticulous medication management to improve outcome disparity for these patients. (Table presented)

The National Clinical Trials Network lymphoid malignancies Clinical Trials Planning Meeting (CTPM) occurred in November of 2014. The scope of the CTPM was to prioritize across the lymphoid tumors clinically significant questions and to foster strategies leading to biologically informed and potentially practice changing clinical trials. This review from the Hodgkin lymphoma (HL) subcommittee of the CTPM discusses the ongoing clinical challenges in HL, outlines the current standard of care for HL patients from early to advanced stage, and surveys the current science with respect to biomarkers and the landscape of ongoing clinical trials. Finally, we suggest areas of unmet need in HL and elucidate promising therapeutic strategies to guide future HL clinical trials planning across the NCTN.

Hodgkin lymphoma is a unique disease entity characterized by a low number of neoplastic tumor cells surrounded by an inflammatory microenvironment composed of dysfunctional immune cells. Recent molecular and genetic studies have revealed that upregulation of the immune checkpoint pathway programmed death 1/programmed death ligand 1 is a key oncogenic driver of Hodgkin lymphoma. Corroborating these mechanistic studies, early-phase clinical trials using the checkpoint inhibitors nivolumab and pembrolizumab in treatment regimens for relapsed and/or refractory Hodgkin lymphoma have demonstrated impressive response rates, a promising durability of response, and a favorable side-effect profile. Given its targeted mechanism of action, acceptable safety, and clinically meaningful activity, the checkpoint inhibitor nivolumab was recently approved by the US Food and Drug Administration as therapy for classical Hodgkin lymphoma that has relapsed or progressed after autologous stem cell transplantation (ASCT) and post-ASCT consolidation therapy with brentuximab vedotin. In this article we review the scientific rationale, preclinical evidence, and most recent clinical data for the use of checkpoint inhibitor therapy in patients with relapsed Hodgkin lymphoma.

PURPOSE: Evaluate the safety, pharmacokinetic profile, pharmacodynamic effects, and antitumor activity of the first-in-class investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) in patients with relapsed/refractory lymphoma or multiple myeloma. EXPERIMENTAL DESIGN: Patients with relapsed/refractory myeloma (n = 17) or lymphoma (n = 27) received intravenous pevonedistat 25 to 147 mg/m2 on days 1, 2, 8, 9 (schedule A; n = 27) or 100 to 261 mg/m2 on days 1, 4, 8, 11 (schedule B; n = 17) of 21-day cycles. RESULTS: Maximum tolerated doses were 110 mg/m2 (schedule A) and 196 mg/m2 (schedule B). Dose-limiting toxicities included febrile neutropenia, transaminase elevations, muscle cramps (schedule A), and thrombocytopenia (schedule B). Common adverse events included fatigue and nausea. Common grade >/=3 events were anemia (19%; schedule A), and neutropenia and pneumonia (12%; schedule B). Clinically significant myelosuppression was uncommon. There were no treatment-related deaths. Pevonedistat pharmacokinetics exhibited a biphasic disposition phase and approximate dose-proportional increases in systemic exposure. Consistent with the short mean elimination half-life of approximately 8.5 hours, little-to-no drug accumulation in plasma was seen after multiple dosing. Pharmacodynamic evidence of NAE inhibition included increased skin levels of CDT-1 and NRF-2 (substrates of NAE-dependent ubiquitin ligases), and increased NRF-2-regulated gene transcript levels in whole blood. Pevonedistat-NEDD8 adduct was detected in bone marrow aspirates, indicating pevonedistat target engagement in the bone marrow compartment. Three lymphoma patients had partial responses; 30 patients achieved stable disease. CONCLUSIONS: Pevonedistat demonstrated anticipated pharmacodynamic effects in the clinical setting, a tolerable safety profile, and some preliminary evidence that may be suggestive of the potential for activity in relapsed/refractory lymphoma. Clin Cancer Res; 1-10. (c)2015 AACR.

The International Prognostic Score (IPS-7) is the most commonly used risk stratification tool for advanced Hodgkin lymphoma (HL), however recent studies suggest the IPS-7 is less discriminating due to improved outcomes with contemporary therapy. We evaluated the seven variables for IPS-7 recorded at study entry for 854 patients enrolled on Eastern Cooperative Oncology Group 2496 trial. Univariate and multivariate Cox models were used to assess their prognostic ability for freedom from progression (FFP) and overall survival (OS). The IPS-7 remained prognostic however its prognostic range has narrowed. On multivariate analysis, two factors (age, stage) remained significant for FFP and three factors (age, stage, haemoglobin level) for OS. An alternative prognostic index, the IPS-3, was constructed using age, stage and haemoglobin level, which provided four distinct risk groups [FFP (P = 0.0001) and OS (P < 0.0001)]. IPS-3 outperformed the IPS-7 on risk prediction for both FFP and OS by model fit and discrimination criteria. Using reclassification calibration, 18% of IPS-7 low risk patients were re-classified as intermediate risk and 13% of IPS-7 intermediate risk patients as low risk. For patients with advanced HL, the IPS-3 may provide a simpler and more accurate framework for risk assessment in the modern era. Validation of these findings in other large data sets is planned.

Over the past decade, new biologic insights have revealed the key role of the tumor microenvironment in the pathogenesis of classical Hodgkin lymphoma (cHL). The primary Hodgkin Reed-Sternberg (HRS) tumor cells normally constitute less than 1% of the tumor cellularity in cHL, and are surrounded by an abundant and heterogeneous inflammatory infiltrate. The cross talk between the HRS cells and the cells of the cHL microenvironment sustains tumor growth and survival. An improved understanding of this phenomenon has led to the development of novel antitumor strategies that alter the cHL microenvironment, changing it from protective to cytotoxic. Developing new strategies remains a high priority because-despite the curability of cHL-as many as one-third of advanced-stage patients will relapse after first-line therapy. Furthermore, only half of relapsed patients will obtain long-term disease control through autologous stem cell transplant. In this review, we will provide an overview of the role of the cHL microenvironment in disease biology, the agents currently available or under investigation targeting the cHL microenvironment, and the most promising and innovative treatment platforms being evaluated in clinical trials.

Introduction: Based on early evidence of cumulative toxicity of polatuzumab vedotin (PoV; anti-CD79b antibody-drug conjugate) at a dose of 2.4 mg/kg (Morschhauser ASH 2014; NCT01691898), a dose of 1.8 mg/kg was explored. We report updated results of the dose comparison. Safety and efficacy of PoV after 8 treatment cycles were also analysed. Methods: Patients (pts) with R/R FL received PoV at 2.4 or 1.8 mg/kg with rituximab (R) 375 mg/m², q21d until progression or unacceptable toxicity. Five pts with R/R FL from the Phase 1 study (Palanca-Wessels ASH 2013) treated with PoV 2.4 mg/kg were included in the analysis. Data at completion of PoV treatment were compared with data after 8 cycles. Results: Forty-five pts received PoV + R (25, 2.4 mg/kg; 20, 1.8 mg/kg). Median follow-up was 14 mo. in the 2.4 mg/kg group versus 8 mo. in the 1.8 mg/kg group. When limited to the first 8 treatment cycles, median follow-up was similar at 6 mo. for both groups. Baseline characteristics were balanced between the two cohorts, except for age (median 68 y 2.4 mg/kg; 62 y 1.8 mg/kg) and tumour volume (SPD 1824 mm² at 2.4 mg/kg, 2655 mm² at 1.8 mg/kg). Forty per cent (10/25, 2.4 mg/ kg) and 50% (10/20, 1.8 mg/kg) pts were refractory to their last treatment. At data cut-off for this analysis, pts received a median of 10 and 9.5 treatment cycles in the 2.4 and 1.8 mg/kg groups, respectively, with median dose intensities through cycle 8 of 88% and 99%, respectively. Safety is shown in the Table. Peripheral neuropathy (PN) was more frequent with PoV 2.4 mg/kg, and discontinuation (d/c) rates due to all causes were 56% versus 30% with the 1.8 mg/kg dose. After 8 treatment cycles, d/c rates were similar for both doses (28% vs 25%). An 84-year old pt in the 2.4 mg/kg cohort died 2 mo. after cycle 12 due to pulmonary congestion. Safety profiles of PoV + R for all treatment cycles and truncated after cycle 8 ORR was similar for both levels: 19/25 (76%) at 2.4 mg/kg and 15/20 (75%) at 1.8 mg/kg. CRs were achieved in 11/25 (44%) patients at 2.4 mg/kg and 2/20 (10%) patients at 1.8 mg/kg. Duration of response was 12 mo. for 2.4 mg/kg and not estimable for 1.8 mg/kg group. After 8 cycles, ORR remained similar (64% for 2.4 mg/kg and 60% for 1.8 mg/kg). Median PFS was 15 mo. at 2.4 mg/kg and not reached in the 1.8 mg/kg group. Conclusions: PoV + R in R/R FL showed high ORR at both doses, with higher CR at 2.4 mg/kg. D/c rates, mostly due to cumulative PN, were high. AEs and d/c rates were reduced at both doses if only the first 8 cycles are considered versus those through study completion. The safety of PoV can be improved by shorter treatment and/or lower dose. Updated PFS will be presented. (Table Presented)