Advani, Ranjana H.

3084 Background: Homologous recombination (HR) is an essential, high-fidelity mechanism to repair DNA double strand breaks (DSBs) in cancer cells. CYT-0851 inhibits HR leading to an accumulation of unrepaired DSBs and tumor cell death. We are reporting the completed Phase 1 dose-escalation results and RP2D selection to support ongoing development of CYT-0851. Methods: Patients (pts) with advanced hematologic and solid tumors were treated with continuous 28-day cycles of increasing doses of CYT-0851 following a 3+3 design. The primary objective was determining the maximum tolerated dose. Secondary objectives included safety, pharmacokinetics, and anti-tumor activity. Results: As of a 15 Nov 2021 data cutoff (DCO), 73 pts with advanced cancers (NHL n = 18; Sarcoma n = 16; Pancreas n = 11; Breast n = 8; HNSCC n = 6; Ovarian n = 4; SCLC n = 4; Other n = 4; Myeloma n = 2) were treated in 12 cohorts (total daily doses: 30 mg to 1200 mg). One pt experienced a dose-limiting toxicity (DLT) of reversible metabolic acidosis at 1200 mg. Two of 3 pts at 800 mg experienced reversible DLT-like events in Cycle 2 of Gr3 dry skin and Gr3 myalgia and polyarthritis, respectively. Three of 10 pts treated at 600 mg experienced DLT-like events in Cycle 1: 1 pt experienced an SAE of Gr3 anorexia with Gr3 stomatitis, vomiting, and dehydration and 2 pts had Gr3 fatigue. No DLTs occurred at 400 mg daily which was selected as the RP2D. 42 pts (57.5%) experienced a CYT-0851-related adverse event (AE), including 12 (16.4%) with a Gr3/4 AE. There were no treatment-related deaths. AE leading to CYT-0851 withdrawal were reported in 2 pts (2.7%) treated with 600 and 800 mg. The most common CYT-0851-related AEs were primarily Gr1/2 and included fatigue (20.5%), hyperuricemia (11%), nausea (11%), alopecia (9.6%), constipation (8.2%) and headache (8.2%). CYT-0851 exposure was approximately dose-proportional across the evaluated doses with an effective half-life of ̃3 days. Exposure at 400 mg daily was consistent with efficacy in preclinical models. 46 pts were evaluable for response at the DCO. 12 pts with NHL were evaluable by Lugano and included 1 CR in FL and 1 PR in DLBCL treated for 393+ and 244 days respectively. 34 pts with solid tumors were evaluable by RECIST v1.1 with 1 PR in a pt with myxofibrosarcoma treated for 313 days and 16 pts with stable disease. Fifteen pts were treated for 100+ days and 5 for 180+ days. Conclusions: CYT-0851 has demonstrated promising and broad clinical activity in a Ph 1 population of pts with advanced cancers. The safety profile is favorable as characterized by events that were infrequent, primarily Gr1/2, and reversible. Six expansion cohorts (DLBCL, Follicular Lymphoma, Myeloma, Pancreatic, Ovarian and Sarcoma) are enrolling to characterize activity at the RP2D. Ph 1 evaluation of CYT-0851 in combination with 3 chemotherapy backbones is also ongoing. Clinical trial information: NCT03997968.

7503 Background: To date, an overall survival (OS) benefit from upfront treatment for new treatment combinations over existing approaches has rarely been shown in first-line classical Hodgkin lymphoma (cHL). With the introduction of newer active therapies for relapsed/refractory disease, demonstration of improved OS with first-line therapy has been challenging. In ECHELON-1 (NCT01712490), 5-year follow-up analyses supported the long-term progression-free survival (PFS) benefit with first-line brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) vs doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in patients (pts) with stage III/IV cHL, independent of interim positron emission tomography status. A+AVD had a manageable long-term safety profile, with numerically fewer second malignancies and a greater number of pregnancies reported vs ABVD (Connors et al, NEJM 2018; Straus et al, Lancet Haematol 2021). We report a prespecified OS analysis after approximately 6 years’ follow-up (cut-off, June 1, 2021). Methods: Pts were randomized 1:1 to receive up to 6 cycles of A+AVD (n = 664) or ABVD (n = 670) on day 1 and 15 every 28 days. OS was the key secondary endpoint and was an event-driven, pre-specified, alpha-controlled analysis in the intention to treat population. Results: At a median follow-up of 73 months, 39 and 64 OS events occurred in A+AVD and ABVD arms, respectively: OS significantly favored A+AVD vs ABVD (HR 0.590; 95% confidence interval [CI] 0.396–0.879; p = 0.009). Estimated 6-year OS rates (95% CI) were 93.9% (91.6–95.5) vs 89.4% (86.6–91.7) with A+AVD vs ABVD, respectively. There was a consistent OS benefit for A+AVD vs ABVD across prespecified subgroups. The 6-year PFS estimate was 82.3% (79.1–85.0) vs 74.5% (70.8–77.7) with A+AVD vs ABVD, respectively (HR 0.678 [95% CI 0.532–0.863]). Overall, A+AVD had a comparable long-term safety profile to ABVD. Treatment-emergent peripheral neuropathy continued to resolve or improve in both arms, with 86% (379/443) and 87% (249/286) of cases in the A+AVD and ABVD arms either completely resolving (72% vs 79%) or improving (14% vs 8%) by last follow-up. Fewer second malignancies were reported in the A+AVD vs ABVD arm (23 vs 32). More female patients reported pregnancy (49 vs 28) or live births (42 vs 19 in females) in the A+AVD vs the ABVD arm; no stillbirths were reported. No new safety signals were identified. Conclusions: A+AVD treatment resulted in a statistically significant 41% reduction in the risk of death vs ABVD, with a manageable safety profile consistent with prior reports. These outcomes confirm A+AVD as a preferred option for pts with previously untreated stage III/IV cHL. Clinical trial information: NCT01712490.

Abstract Since the publication of the Revised European-American Classification of Lymphoid Neoplasms in 1994, subsequent updates of the classification of lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress has recently been made in the characterization of malignancies of the immune system, with many new insights provided by genomic studies. They have led to this proposal. We have followed the same process that was successfully used for the third and fourth editions of the World Health Organization Classification of Hematologic Neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional have now been upgraded to definite entities. Terminology for some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification of mature lymphoid, histiocytic, and dendritic cell tumors.

Hodgkin lymphoma (HL) is an uncommon malignancy of B-cell origin. Classical HL (cHL) and nodular lymphocyte–predominant HL are the 2 main types of HL. The cure rates for HL have increased so markedly with the advent of modern treatment options that overriding treatment considerations often relate to long-term toxicity. These NCCN Guidelines Insights discuss the recent updates to the NCCN Guidelines for HL focusing on (1) radiation therapy dose constraints in the management of patients with HL, and (2) the management of advanced-stage and relapsed or refractory cHL.

Abstract The T-cell non-Hodgkin lymphomas continue to be an area of unmet need for new therapies that offer novel mechanisms of action. Tipifarnib is a potent and selective inhibitor of the enzyme farnesyltransferase (FT). Tipifarnib inhibits farnesylation of key regulatory proteins involved in CXCL12 production (Gualberto et al, EHA 2019). CXCL12 is a chemokine that is essential for T-cell homing to lymphoid organs and bone marrow, and for the maintenance of immune cell progenitors via its receptor CXCR4 (Susek et al, Front Immunology, 2018). Angioimmunoblastic T-cell lymphoma (AITL) is associated with high levels of CXCL12 expression, which is also a negative prognostic factor (Witzig et al, Blood, 2019). Additionally, Peripheral T-Cell lymphoma Not Otherwise Specified (PTCL-NOS) patients with the CXCL12 rs2839695 A/A wildtype genotype (PTCL-CXCL12+) have also been found to have elevated levels of CXCL12. Therefore, there is strong rationale for targeting these subsets of PTCL with tipifarnib. This Phase 2 study (NCT02464228) was a multi-institutional, single-arm, open-label trial determining the efficacy, safety, and potential predictive biomarkers for tipifarnib in adult patients with relapsed or refractory (R/R) PTCL. Patients received tipifarnib 300 mg orally twice daily on Days 1-21 of 28-day treatment cycles until progression of disease or unacceptable toxicity. The primary objective of the study was to determine the antitumor activity by overall response rate (ORR) per Lugano Classification. Secondary objectives included safety, duration of response (DoR) and progression-free survival (PFS), and exploratory analyses included overall survival (OS) and identification of potential biomarkers associated with tipifarnib activity. Sixty-five R/R PTCL patients (38 AITL, 14 PTCL-NOS, 11 PTCL-CXCL12+, 2 other (1 ALCL-ALK negative, 1 PTCL-subtype not specified) were treated with tipifarnib. The population was heavily pretreated with a median of 3 prior regimens (range 1-8). All patients had at least one treatment-emergent adverse event (TEAE); most patients (87.7%) had at least one treatment-related TEAE, and 18 (27.7%) patients had at least one treatment-related serious TEAE. The most frequently observed (≥20%) treatment-related TEAEs (all grades) were hematological (neutropenia, thrombocytopenia, anemia,) and gastrointestinal (nausea, diarrhea), as well as fatigue, which is consistent with the known safety profile of tipifarnib. Fifty-eight patients were efficacy evaluable and had an associated ORR of 39.7% (23/58) with most responses observed in the AITL and PTCL-CXCL12+ cohorts. In the 32 patients with AITL, the ORR was 56.3% (18/32), including 9 complete responses (CR) and 9 partial responses (PR). In the 10 patients with PTCL-CXCL12+, the ORR was 40.0% (4/10), including 1 CR and 3 PR. The median OS for patients with AITL was 32.8 months, and the median OS had not been reached for patients with PTCL-CXCL12+. Previously, a strong association between KIR3DL2 C336R/Q386E mutation and the activity of tipifarnib was observed and reported in AITL patients (Witzig et al, EHA 2020). Extensive gene expression and gene variant analyses of samples from the study population is currently ongoing to evaluate this correlation and explore other potential predictors of response. Final data will be presented at the time of the conference. Overall, the results from this Phase 2 study with tipifarnib demonstrated very encouraging efficacy in patients with CXCL12-expressing subtypes of PTCL (AITL and PTCL-CXCL12+) and showed a tolerable safety profile. Disclosures Witzig: Karyopharm Therapeutics, Abbvie/Genentech, Seattle Genetics, Celgene/BMS, Incyte, Epizyme, Cellectar, Tessa Therapeutics, Portola Pharmaceuticals, MorphoSys, ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS, Acerta Pharma, Kura Oncology, Acrotech Biopharma, Karyopharm Therapeutics: Research Funding. Sokol: Dren Bio: Membership on an entity's Board of Directors or advisory committees; Kyowa-Kirin: Membership on an entity's Board of Directors or advisory committees. Kim: IGM Biosciences: Research Funding; Kyowa Kirin: Research Funding; Roche: Research Funding; Sanofi: Research Funding; Celltrion: Research Funding; Dong-A Pharmaceutical: Research Funding; Johnson & Johnson: Research Funding; Eisai: Research Funding. de la Cruz Vicente: Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Advani: Astellas/Agensys: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Bristol Myer Squibb: Membership on an entity's Board of Directors or advisory committees; Cell Medica: Membership on an entity's Board of Directors or advisory committees; Forty Seven: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genetech Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceutical: Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding; Kyowa: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Millenium: Research Funding; Pharmacyclics: Consultancy, Research Funding; Portola Pharmaceuticals: Consultancy; Regeneron: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees. Marin Niebla: Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kiowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; Amgen: Speakers Bureau. Terol: BMS: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Hospital Clinico Valencia: Current Employment; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Roche: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding. Eva: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bendris: Kura Oncology: Current Employment, Current equity holder in publicly-traded company. Ahsan: Gilead: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Kura Oncology: Current Employment, Current equity holder in publicly-traded company. Leoni: Kura Oncology: Current Employment. Foss: Daiichi Sankyo: Honoraria; Mallinckrodt: Honoraria; Acrotech: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Kyowa: Honoraria; Kura: Honoraria.

Abstract Introduction: Clinical trials of novel salvage therapies (ST) have encouraging outcomes for relapsed/refractory classic Hodgkin lymphoma (R/R cHL) after autologous stem cell transplant (ASCT); yet studies comparing novel ST with conventional salvage chemotherapy are lacking. In a single center cohort, we demonstrated that bendamustine/brentuximab (BBV) had higher overall response rates (ORR) and complete response (CR) rates in ASCT-eligible R/R cHL (Desai et al JCO, 2021). Herein we report comparative outcomes of novel and conventional ST in R/R cHL who undergo ASCT, in a large multicenter retrospective cohort. Methods: Consecutive R/R cHL pts who underwent ASCT at 12 institutions across United States were included. Demographics and clinical variables at relapse including age, sex, B symptoms, stage, bulky disease (BD, single mass > 6 cm) extra nodal disease (END), primary refractory disease (PRD) and early relapse (ER, within 1 year) were recorded by electronic health records review. Study objectives were ORR, CR to first ST, post-ASCT PFS and OS by final ST. Time to event endpoints were defined from date of ASCT. Results: From 12 participating institutions, 853 pts of R/R cHL who underwent ASCT were eligible for this study. Median age was 33 (14-72) years, 457 (54%) were male, 446 (52%) had BD, 257 (30%) had advanced stage, 271 (32%) had END, 369 (43%) had B symptoms, 142 (17%) had PRD and 307 (36%) had ER. All 853 received at least 1 ST, 245 received 2 ST, 71 received 3 ST and 26 received 4 ST. Seven groups of ST were identified: 1. Conventional platinum-based chemotherapy (PBC) group including ICE, DHAP and ESHAP 2. BBV 3. Brentuximab Vedotin and nivolumab (BV/Nivo) 4. BV alone (BV) 5. gemcitabine-based chemotherapy (Gem) 6. checkpoint inhibitors (CPI) and 7. other miscellaneous agents (Misc). 1st ST was as follows: 553 had PBC; 69 had BBV; 48 had BV/Nivo; 65 had BV; 49 had Gem; 4 had CPI and 63 had Misc. There was no significant difference in the baseline characteristics by type of 1 st ST (data not shown). BBV had significantly higher ORR (92% vs 79%, p<0.001) and CR rate (80% vs 49%, p <0.001) compared to PBC. BV/Nivo had significantly higher CR rate (67% vs 49%, p <0.001) and a trend towards higher ORR (86% vs 79%, p = 0.1) compared to PBC. BV had significantly lower ORR (62% vs 79%, p <0.001) and CR rate (34% vs 49%, p <0.001) compared to PBC. There was no difference in ORR and CR rate of PBC, Gem, CPI and Misc agents. Final ST prior to ASCT was PBC in 451, BBV in 76, BV/Nivo in 48, BV in 87, CPI in 24, Gem in 90 and Misc in 64. Table 1 lists K-M estimates of 2-year survival probabilities for different Final ST groups. Median follow up was 3 (range 0.1-13) years. BV/Nivo group had significantly higher proportion of patients with PRD and BD than PBC, no other differences in baseline characteristics were identified amongst ST groups (data not shown). BV/Nivo (HR: 0.1 (CI 95:0.02-0.4), p<0.01) and CPI (HR: 0.12 (CI 95:0.03-0.5), p<0.01) had significantly higher PFS than PBC. There was no significant difference in PFS between other ST groups (Figure 1a). Type of ST was not significantly associated with difference in OS (Figure 1b). 536 pts underwent ASCT in CR, 273 underwent ASCT in partial response (PR) and 31 underwent ASCT with progressive disease (PD). Pre-ASCT PR (HR 1.6 (CI 95:1.3-2.6), p<0.001) and PD (HR: 4.1 (CI 95: 2.5-6.8), p<0.001) predicted significantly lower PFS compared to CR (Figure 2a). OS was also significantly lower in pts with pre-ASCT PR (HR 1.7 (CI 95: 1.2-1.6), p<0.001) and PD (HR 5.3 (CI 95: 2.8-10), p<0.001) (Figure 2b). Higher number of pre-ASCT ST predicted lower PFS (HR 1.3 (CI 95: 1.1-1.6), p<0.001) and OS (HR 1.5 (CI 95: 1.2-1.8), p<0.001). In pts with pre-ASCT CR, all 36 who had pre-ASCT CR after BV/Nivo were alive and relapse free for follow up of 0.1-5 yrs. BV/Nivo was associated with significantly higher PFS (HR 0.1 (CI 95: 0.01-0.7), p <0.05) but not OS compared to PBC in this subgroup. Increasing number of pre-ASCT ST predicted worse PFS (HR 1.5 (CI 95: 1.2-2.0), p<0.01) and OS (HR 2.2 (CI 95: 1.4-3.4), p<0.001) in this subgroup as well. Conclusions: BV/Nivo has a higher CR rate and better post-ASCT PFS compared to conventional chemotherapy and can lead to durable remissions in pts with pre-ASCT CR. BBV had a higher response rate and similar post-ASCT survival to conventional chemotherapy. BV had lower response rates compared to chemotherapy. Novel ST such as BV/Nivo and BBV may be preferable to conventional chemotherapy in R/R cHL. Figure 1 Figure 1. Disclosures Spinner: Notable Labs: Honoraria. Bachanova: FATE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; KaryoPharma: Membership on an entity's Board of Directors or advisory committees; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dorritie: SITC presentation: Honoraria; Genmab: Research Funding; University of Pittsburgh/UPMC Hillman Cancer Center: Current Employment; Janssen: Research Funding; F. Hoffman-La Roche Ltd: Research Funding; Juno/BMS: Research Funding; Kite, a Gilead Company: Research Funding; OncLive/Institutional Perspectives on Cancer presentation: Honoraria. Arai: Magenta Therapeutics: Research Funding. Maurer: Nanostring: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Celgene: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Diefenbach: Genentech, Inc./ F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; IMab: Research Funding; Morphosys: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Merck Sharp & Dohme: Consultancy, Honoraria, Research Funding; Perlmutter Cancer Center at NYU Langone Health: Current Employment; AbbVie: Research Funding; IGM Biosciences: Research Funding; Incyte: Research Funding; Trillium: Research Funding; Gilead: Current equity holder in publicly-traded company; MEI: Consultancy, Research Funding. Nowakowski: Kyte Pharma: Consultancy; Ryvu Therapeutics: Consultancy; Selvita: Consultancy; Curis: Consultancy; Karyopharm Therapeutics: Consultancy; Celgene/Bristol Myers Squibb: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; MorphoSys: Consultancy; Bantham Pharmaceutical: Consultancy; Daiichi Sankyo: Consultancy; Zai Labolatory: Consultancy; Incyte: Consultancy; Kymera Therapeutics: Consultancy; TG Therapeutics: Consultancy; Blueprint Medicines: Consultancy; Nanostrings: Research Funding. Advani: Astellas/Agensys: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Bristol Myer Squibb: Membership on an entity's Board of Directors or advisory committees; Cell Medica: Membership on an entity's Board of Directors or advisory committees; Forty Seven: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genetech Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceutical: Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding; Kyowa: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Millenium: Research Funding; Pharmacyclics: Consultancy, Research Funding; Portola Pharmaceuticals: Consultancy; Regeneron: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees.

In the last decade, a better understanding of the molecular pathogenesis of B-cell non-Hodgkin lymphomas has resulted in the development of novel targeted therapies, such as small molecule inhibitors of select kinases in the B-cell receptor pathway, antibody–drug conjugates, and small molecules that target a variety of proteins (eg, CD-19, EZH2, and XPO-1–mediated nuclear export). Anti-CD19 CAR T-cell therapy, first approved for relapsed/refractory (R/R) diffuse large B-cell lymphoma, has also emerged as a novel treatment option for R/R follicular lymphoma and mantle cell lymphoma. These NCCN Guideline Insights highlight the new targeted therapy options included in the NCCN Guidelines for B-Cell Lymphomas for the treatment of R/R disease.

Abstract We performed a multicenter retrospective analysis across 10 US academic medical centers to evaluate treatment patterns and outcomes in patients age ≥60 years with classic Hodgkin lymphoma (cHL) from 2010-2018. Among 244 eligible patients, median age was 68, 63% had advanced stage (III/IV), 96% had Eastern Cooperative Oncology Group performance status (PS) 0-2, and 12% had documented loss of ≥1 activity of daily living (ADL). Medical comorbidities were assessed by the Cumulative Illness Rating Scale–Geriatric (CIRS-G), where n = 44 (18%) had total scores ≥10. Using multivariable Cox models, only ADL loss predicted shorter progression-free (PFS; hazard ratio [HR] 2.13, P = .007) and overall survival (OS; HR 2.52, P = .02). Most patients (n = 203, 83%) received conventional chemotherapy regimens, including doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD; 56%), AVD (14%), and AVD with brentuximab vedotin (BV; 9%). Compared to alternative therapies, conventional regimens significantly improved PFS (HR 0.46, P = .0007) and OS (HR 0.31, P = .0003). Survival was similar following conventional chemotherapy in those ages 60-69 vs ≥70: PFS HR 0.88, P = .63; OS HR 0.73, P = .55. Early treatment discontinuation due to toxicity was more common with CIRS-G ≥10 (28% vs 12%, P = .016) or documented geriatric syndrome (28% vs 13%, P = .02). A competing risk analysis demonstrated improved disease-related survival with conventional therapy (HR 0.29, P = .02) and higher mortality from causes other than disease or treatment with high CIRS-G or geriatric syndromes. This study suggests conventional chemotherapy regimens remain a standard of care in fit older patients with cHL, and highlights the importance of geriatric assessments in defining fitness for cHL therapy going forward.

AbstractThis phase 1-2 study evaluated brentuximab vedotin (BV) combined with nivolumab (Nivo) as first salvage therapy in patients with relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL). In parts 1 and 2, patients received staggered dosing of BV and Nivo in cycle 1, followed by same-day dosing in cycles 2 to 4. In part 3, both study drugs were dosed, same day, for all 4 cycles. At end of study treatment, patients could undergo autologous stem cell transplantation (ASCT) per investigator discretion. The objective response rate (ORR; N = 91) was 85%, with 67% achieving a complete response (CR). At a median follow-up of 34.3 months, the estimated progression-free survival (PFS) rate at 3 years was 77% (95% confidence interval [CI], 65% to 86%) and 91% (95% CI, 79% to 96%) for patients undergoing ASCT directly after study treatment. Overall survival at 3 years was 93% (95% CI, 85% to 97%). The most common adverse events (AEs) prior to ASCT were nausea (52%) and infusion-related reactions (43%), all grade 1 or 2. A total of 16 patients (18%) had immune-related AEs that required systemic corticosteroid treatment. Peripheral blood immune signatures were consistent with an activated T-cell response. Median gene expression of CD30 in tumors was higher in patients who responded compared with those who did not. Longer-term follow-up of BV and Nivo as a first salvage regimen shows durable efficacy and impressive PFS, especially in patients who proceeded directly to transplant, without additional toxicity concerns. This trial was registered at www.clinicaltrials.gov as #NCT02572167.

Abstract Introduction Brentuximab vedotin (BV) is an ADC directed against CD30, a receptor expressed by malignant Reed-Sternberg (RS) cells present in the inflammatory/immune cell microenvironment of classical Hodgkin lymphomas (cHL). Through induction of immunogenic cell death, BV may prime an antitumor immune response via microtubule disruption of CD30-expressing RS cells (Gardai 2015). Tumor cells expressing PD-1 ligands use the PD-1 pathway to evade an immune response. Nivolumab (Nivo) blocks the PD-1 receptor, inhibits binding of PD-1 ligands, and restores an effective antitumor immune response. Targeted killing of CD30-expressing RS cells, concurrent with restoration of the immune response, may lead to higher complete response (CR) rates in patients (pts) with relapsed or refractory cHL (R/R HL), as well as improved durability of responses post autologous stem cell transplant (ASCT). Here we present updated results from the phase 1/2 study of BV + Nivo in pts with R/R HL. Methods BV + Nivo was evaluated in cHL that had relapsed or was refractory to frontline (FL) chemotherapy in adult pts (NCT02572167). Pts were excluded if they had received prior salvage therapy, BV or immuno-oncology therapy, or allogeneic SCT or ASCT. Pts were treated in 21-day cycles for up to 4 cycles. In Parts 1 and 2 of the trial, BV (1.8 mg/kg) was given on Cycle 1 Day 1 and Nivo (3 mg/kg) on Cycle 1 Day 8. For Cycles 2-4, BV and Nivo were given on Day 1. After the Cycle 4 response assessment, pts were eligible to undergo ASCT. The investigators assessed response per the Lugano Classification (Cheson 2014). Results 62 pts with R/R HL were enrolled in Parts 1 and 2; 61 pts received BV + Nivo, of whom 58 completed treatment (tx). 4 pts discontinued the study due to pt decision (2), AE (1), and investigator decision (1). Median age was 36 years, 52% were female, and 90% had received FL ABVD. 45% of pts had primary refractory disease and 31% experienced relapse within 1 year of FL therapy. Infusion-related reactions (IRRs) occurred in 41% of pts. Tx emergent AEs occurred in 98% of pts prior to ASCT (33% G3, 5% G4). Excluding IRRs, potential immune-related AEs (IrAEs) occurred in 84% of pts (10% G3, 3% G4) with 5 pts (8%) treated with systemic steroids for G4 pneumonitis, G4 pneumonitis and colitis, G2 pneumonitis, G3 diarrhea and G2 colitis, and G3 AST elevation. Among the 60 efficacy-evaluable pts, the CR rate was 62%, (48% of CR pts had Deauville ≤ 2) with an objective response rate of 85%; 5 pts (8%) had stable disease and 4 pts (7%) progressed on tx. At the time of this analysis, 39 pts had initiated ASCT with a median 5.1x106 CD34+ cells/kg (range; 3-60) collected. Median times to neutrophil and platelet engraftment were 12 and 15 days, respectively. Pts were followed for a median of 3 months from ASCT (N=39, range; 0-12) and 5.7 months from first dose (N=61, range; 1-17). BV and Nivo effects on the immune system were evaluated by peripheral blood immunophenotyping, serum cytokine/chemokine analyses, T-cell receptor sequencing, and intracellular cytokine staining. The first dose of BV resulted in elevation of pro-inflammatory cytokines and chemokines and concurrent reduction in serum TARC levels, with these results maintained post Nivo. We observed a reduction in Tregs and other T cell subsets after the first dose of BV with an elevation of T cell subsets post BV + Nivo. While TCR clonality in the periphery did not change over the course of the trial, T cell clonal expansion was observed post BV + Nivo, concurrent with T cell elevation measured by flow cytometry. Ex vivo peptide stimulation of PBMCs isolated from blood revealed the enhanced ability of T cell subsets to respond to MHC I and MHC II antigens following BV + Nivo compared to baseline: e.g., effector memory CD8+ T cells from some pts displayed increased intracellular IL-2, and TNFa after stimulation with MHCI and MHCII peptide pools compared to baseline, potentially indicating elevated activation status of the immune system following combination tx. Conclusion R/R HL remains an unmet clinical need despite recent medical advances. These data suggest the combination BV + Nivo is a well tolerated and an active salvage therapy with a high rate of CR (62%) that has no adverse impact on stem cell collection. The safety and activity of this novel combination support further exploration in an ongoing pivotal phase 3 trial in pts with R/R HL who have either already received or are considered ineligible for ASCT (NCT03138499). Disclosures Herrera: Seattle Genetics: Research Funding; Merck: Consultancy; Genentech: Consultancy; BMS: Consultancy; Pharmacyclics: Consultancy. Moskowitz: Seattle Genetics: Honoraria, Research Funding; Takeda: Honoraria; Incyte: Research Funding; ADC Therapeutics: Research Funding; Bristol Myers-Squibb: Consultancy, Research Funding. Bartlett: Novartis: Research Funding; ImaginAB: Research Funding; Astra Zeneca: Research Funding; Millenium: Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; Affimed: Research Funding; Forty Seven: Research Funding; Immune Design: Research Funding; Bristol-Meyers Squibb: Research Funding; Merck & Co: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Vose: Merck: Research Funding; Kite: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Allos Therapeutics: Research Funding; Acerta: Research Funding; Incyte: Research Funding; Onyx: Research Funding; Seattle Genetics: Research Funding; US Biotest: Research Funding; Bristol-Myers Squibb: Research Funding. Ramchandren: Seattle Genetics: Consultancy; MERCK: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding. Feldman: AbbVie: Speakers Bureau; Janssen: Speakers Bureau; Kite Pharma: Speakers Bureau; Celgene: Speakers Bureau; Pharmacyclics: Speakers Bureau; Seattle Genetics: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy. LaCasce: BMS: Consultancy; Forty Seven: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Research Funding. Ansell: Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Celldex: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding. Moskowitz: Celgene: Consultancy; Seattle Genetics: Consultancy, Other: Ad Board, Research Funding; Genentech BioOncology: Consultancy; Pharmacyclics: Research Funding; Merck: Consultancy, Research Funding. Fenton: Seattle Genetics: Employment, Equity Ownership. Ogden: Seattle Genetics: Employment, Equity Ownership. Taft: Seattle Genetics: Employment, Research Funding. Zhang: Seattle Genetics: Employment, Research Funding. Kato: Bristol-Myers Squibb: Employment, Equity Ownership; Seattle Genetic: Research Funding. Campbell: Seattle Genetics: Employment, Equity Ownership; CTI BioPharma: Employment, Equity Ownership. Advani: Agensys: Research Funding; Pharmacyclics: Research Funding; Regeneron: Research Funding; FortySeven: Research Funding; Nanostring: Consultancy; Celgene: Research Funding; Pharmacyclics: Consultancy; Merck: Research Funding; Juno Therapeutics: Consultancy; Kura: Research Funding; Janssen: Research Funding; Millennium: Research Funding; Seattle Genetics: Research Funding; Gilead: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Spectrum: Consultancy; Bayer Healthcare Pharmaceuticals: Research Funding; Infinity: Research Funding; Genentech: Research Funding; Cell Medica: Research Funding; Sutro: Consultancy.