Faculty Bibliography

Background: Rituximab (R) plus CHOP (R-CHOP) is standard of care for pts with previously untreated DLBCL. Although most pts have long-term responses, up to 40% relapse or fail to achieve a remission. Atezolizumab (atezo) is a fully humanised anti-programmed death-ligand 1 (PD-L1) antibody with a complementary mechanism of action to R. An ongoing phase I/II study (NCT02596971) is evaluating the safety and efficacy of atezo in combination with R-CHOP (R-CHOP-atezo) in DLBCL pts. We report interim data.
Aim(s): To assess the safety and preliminary efficacy of R-CHOP-atezo in previously untreated pts with DLBCL.
Method(s): Pts (aged >=18 years, ECOG PS 0-2) with advanced DLBCL (Ann Arbor stage III/IV, International Prognostic Index [IPI] score >=2 or stage II with bulky disease [at least one lesion >=7cm]) received 8 cycles (each 21 days) of induction treatment with R-CHOP-atezo (R 375 mg/m² IV on Day 1 [Cycles 1-8], atezo 1200 mg IV on Day 1 [Cycles 2-8], CHOP [6 or 8 cycles as determined by the investigator (INV)]). Pts who achieved a CR at end of induction (EOI) received consolidation treatment with atezo 1200 mg IV on Day 1 of Cycles 9-25, every 21 days for 12 months. The primary endpoints were safety, and efficacy as determined by CR rate at EOI by independent review committee (IRC) using modified Lugano 2014 criteria. Secondary endpoints included CR rate at EOI assessed by INV using modified Lugano 2014, and by IRC and INV using Cheson 2007. An interim analysis was pre-planned after 15 consecutive pts had completed the EOI response assessment. The data cut-off was 20 November 2017.
Result(s): In total, 42 pts were enrolled and received treatment (safety population). At the time of data cut-off, 20 pts were receiving ongoing induction treatment, 5 had discontinued (3 AEs, 1 protocol violation, 1 withdrawal) and 17 had completed induction, of whom 14 had entered consolidation. Median (range) observation time was 5.3 (0.7-7.2) months for induction and only 1.6 (0.7-5.1) months for consolidation. Therefore, this report focuses on preliminary data from the safety population during induction only. Pt demographics and disease characteristics are shown in Table 1. Among 15 pts evaluable for response (efficacy population), 13 (87%) achieved a CR, and 2 (13%) had PD according to IRC and INV using modified Lugano 2014. Response assessment using Cheson 2007 showed 11 (73%) CRs, 2 (13%) PRs and 2 (13%) pts with PD, consistent between INV and IRC review. Preliminary safety data from induction therapy showed that all pts had >=1 AE and 27/42 pts (64%) had a grade (gr) 3-4 AE. Regardless of causality, the most common gr 3-4 AEs were neutropenia (16 pts [38%], 6 received G-CSF prophylaxis) and febrile neutropenia (4 pts [9.5%], 3 received G-CSF prophylaxis). No deaths were reported. Serious AEs were reported in 13 pts (31%). AEs led to dose reduction in 8 pts (19%) (gr 4 neutropenia, gr 3 pancytopenia, gr 1-2 peripheral neuropathy) and withdrawal of any component in 3 pts (7%) (gr 3 neutropenia, gr 3 transaminase and asymptomatic lipase increases, gr 2 hyperthyroidism). Three pts had atezo-related AEs (gr 3 lipase and transaminase increases). Summary/Conclusion: Interim data demonstrate that first-line R-CHOPatezo shows encouraging efficacy and acceptable toxicity in untreated pts with DLBCL. Updated results, including minimal residual disease and cell of origin data, will be presented. (Table Presented)

Hodgkin lymphoma treatment continues to evolve as new means of assessing response to treatment, new appreciation of important risk factors, and more effective therapeutic agents become available. Treatment algorithms integrating functional imaging now provide the opportunity to modify therapy during its delivery, allowing adjustment of duration and intensity of chemotherapy and rationale identification of patients who may benefit from the addition of therapeutic irradiation. Novel agents, including the antibody drug conjugate brentuximab vedotin and checkpoint inhibitors such as nivolumab and pembrolizumab can improve the effectiveness of treatment while keeping toxicity within acceptable limits. Carefully designed clinical trials permit the identification of superior approaches in which efficacy is enhanced and toxicity minimized. Clinicians treating patients with Hodgkin lymphoma now have access to novel treatment approaches, which will require detailed assessment of each patient and careful discussion of the goals and risks of treatment at the time of planning primary treatment, again during delivery of that treatment as data indicating ongoing effectiveness become available, at the conclusion of initial intervention, and, when the need arises, at the time of recurrence of disease.

Survival outcomes for elderly lymphoma patients are disproportionally inferior to those of younger patients. We examined medication usage at diagnosis for 171 elderly patients (median age 70 years) with aggressive non-Hodgkin lymphoma treated between 2009 and 2014. At least one potentially inappropriate medication was used in 47% of patients according to the Beers Criteria, 59% experienced treatment delays and/or dose reduction and 65% experienced >/= grade 3 treatment-related toxicities. We report here for the first time that potentially inappropriate medication use was associated with reduced progression-free survival and overall survival, and increased >/= grade 3 treatment-related toxicities in multivariate analysis.

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.