Faculty Bibliography

PURPOSE/OBJECTIVE:Mantle cell lymphoma (MCL) is a B-cell lymphoma characterized by cyclin D1 expression. Autologous hematopoietic cell transplantation (AHCT) consolidation after induction chemotherapy is often used for eligible patients; however, the benefit remains uncertain in the rituximab era. Herein we retrospectively assessed the impact of AHCT consolidation on survival in a large cohort of transplantation-eligible patients age 65 years or younger. PATIENTS AND METHODS/METHODS:We retrospectively studied transplantation-eligible adults age 65 years or younger with newly diagnosed MCL treated between 2000 and 2015. The primary objective was to assess for improved progression-free survival (PFS) with AHCT consolidation and secondarily to assess for improved overall survival (OS). Cox multivariable regression analysis and propensity score-weighted (PSW) analysis were performed. RESULTS:Data were collected from 25 medical centers for 1,254 patients; 1,029 met inclusion criteria. Median follow-up for the cohort was 76 months. Median PFS and OS were 62 and 139 months, respectively. On unadjusted analysis, AHCT was associated with improved PFS (75 v 44 months with v without AHCT, respectively; P < .01) and OS (147 v 115 months with v without AHCT, respectively; P < .05). On multivariable regression analysis, AHCT was associated with improved PFS (hazard ratio [HR], 0.54; 95% CI, 0.44 to 0.66; P < .01) and a trend toward improved OS (HR, 0.77; 95% CI, 0.59 to 1.01; P = .06). After PSW analysis, AHCT remained associated with improved PFS (HR, 0.70; 95% CI, 0.59 to 0.84; P < .05) but not improved OS (HR, 0.87; 95% CI, 0.69 to 1.1; P = .2). CONCLUSION/CONCLUSIONS:In this large cohort of younger, transplantation-eligible patients with MCL, AHCT consolidation after induction was associated with significantly improved PFS but not OS after PSW analysis. Within the limitations of a retrospective analysis, our findings suggest that in younger, fit patients, AHCT consolidation may improve PFS.

While up to 80% of patients with Hodgkin's lymphoma (HL) are cured with first-line therapy, relapsed/refractory (R/R) disease remains a clinical challenge and is fatal for many young patients. HL is unique in that the tumor cells (Hodgkin Reed-Sternberg; HRS cells) are a small fraction (<1%) of the tumor bulk, with the remaining tumor composed of the cells of the tumor microenvironment (TME). The support and integrity of the TME is necessary for HRS cell growth and survival. Targeting the programmed death 1 pathway has shown exciting activity in relapsed HL and led to United States Food and Drug Administration approval of the checkpoint inhibitors, nivolumab and pembrolizumab, for R/R HL. Novel combinations with checkpoint blockade therapy (CBT), targeted approaches such as combinations of CBT with brentuximab vedotin or chemotherapy, chimeric antigen receptor T-cells, and the use of CBT to potentially sensitize to subsequent therapy are being investigated as treatment approaches. As understanding of the HL TME grows, hopefully this will increase the number of rational therapeutic targets.

The activity of T cell mediated immunotherapies in B cell lymphoma has been limited to date. The novel bi-specific antibody CD20-TCB, has a 2:1 antibody design to maximize T cell engagement, and demonstrates activity in preclinical models. This may represent a novel therapeutic approach for patients with relapsed/refractory NHL.

Because both phosphatidylinositol 3-kinase δ (PI3Kδ) and Janus kinase (JAK)-signal transducer and activator of transcription pathways contribute to tumor cell proliferation and survival in B-cell malignancies, their simultaneous inhibition may provide synergistic treatment efficacy. This phase 1 dose-escalation/expansion study assessed the safety, efficacy, pharmacokinetics, and pharmacodynamics of INCB040093, a selective PI3Kδ inhibitor, as monotherapy or combined with itacitinib (formerly INCB039110), a selective JAK1 inhibitor, in adult patients with relapsed or refractory (R/R) B-cell lymphomas. Final results are reported. Overall, 114 patients were treated (monotherapy, n = 49; combination therapy, n = 72 [7 patients crossed over from monotherapy to combination]). INCB040093 100 mg twice daily (monotherapy) and INCB040093 100 mg twice daily + itacitinib 300 mg once daily (combination) were the recommended phase 2 doses. One dose-limiting toxicity (gastrointestinal bleed secondary to gastric diffuse large B-cell lymphoma [DLBCL] regression) occurred with monotherapy. The most common serious adverse events with monotherapy were pneumonia (n = 5) and pyrexia (n = 4), and with combination Pneumocystis jiroveci pneumonia (n = 5), pneumonia (unrelated to P jiroveci; n = 5), and pyrexia (n = 4). Grade 3 or higher transaminase elevations were less common with combination. INCB040093 was active across the B-cell lymphomas; 63% of patients (5/8) with follicular lymphoma responded to monotherapy. Adding itacitinib provided promising activity in select subtypes, with responses of 67% (14/21) in classic Hodgkin lymphoma (vs 29% [5/17] with monotherapy) and 31% (4/13) in nongerminal center B-cell-like DLBCL. INCB040093 with/without itacitinib was tolerated and active in this study, and is a promising treatment strategy for patients with select R/R B-cell lymphomas. This trial was registered at www.clinicaltrials.gov as #NCT01905813.

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.