Advani, Ranjana H

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 Autologous stem cell transplantation (ASCT) can be curative for patients with relapsed/refractory Hodgkin lymphoma (HL). Based on studies suggesting that anti-PD-1 monoclonal antibodies (mAbs) can sensitize patients to subsequent chemotherapy, we hypothesized that anti-PD-1 therapy before ASCT would result in acceptable outcomes among high-risk patients who progressed on or responded insufficiently to ≥1 salvage regimen, including chemorefractory patients who are traditionally considered poor ASCT candidates. We retrospectively identified 78 HL patients who underwent ASCT after receiving an anti-PD-1 mAb (alone or in combination) as third-line or later therapy across 22 centers. Chemorefractory disease was common, including 42 patients (54%) refractory to ≥2 consecutive systemic therapies immediately before anti-PD-1 treatment. Fifty-eight (74%) patients underwent ASCT after anti-PD-1 treatment, while 20 patients (26%) received additional therapy after PD-1 blockade and before ASCT. Patients received a median of 4 systemic therapies (range, 3-7) before ASCT, and 31 patients (41%) had a positive pre-ASCT positron emission tomography (PET) result. After a median post-ASCT follow-up of 19.6 months, the 18-month progression-free survival (PFS) and overall survival were 81% (95% CI, 69-89) and 96% (95% confidence interval [CI], 87-99), respectively. Favorable outcomes were observed for patients who were refractory to 2 consecutive therapies immediately before PD-1 blockade (18-month PFS, 78%), had a positive pre-ASCT PET (18-month PFS, 75%), or received ≥4 systemic therapies before ASCT (18-month PFS, 73%), while PD-1 nonresponders had inferior outcomes (18-month PFS, 51%). In this high-risk cohort, ASCT after anti-PD-1 therapy was associated with excellent outcomes, even among heavily pretreated, previously chemorefractory patients.

SummaryIbrutinib is associated with durable responses in patients with Waldenström macroglobulinaemia (WM). We hypothesized that response depth is predictive of progression‐free survival (PFS) in WM patients treated with ibrutinib. Using landmark analyses, we evaluated response depth in two cohorts of WM patients treated with ibrutinib monotherapy. The learning cohort was composed of 93 participants from two clinical trials, and the validation cohort of 190 consecutive patients treated off clinical trial. Rates of partial response (PR) or better at six months in learning and validation cohorts were 64% and 71% respectively (P = 0·29). In the learning cohort, three‐year PFS rates for patients who attained PR or better at six monthsversusnot were 81% and 57% respectively (P = 0·009). In the validation cohort, three‐year PFS rates for patients who attained PR or better at six monthsversusnot were 83% and 54% respectively (P = 0·008). In multivariate analyses, attaining PR or better at six months was associated with superior PFS in the learning [hazard ratio (HR) 0·38;P = 0·01] and validation cohorts (HR 0·18;P = 0·004). Attaining PR at six months on ibrutinib emerges as an intermediate outcome of interest and should be validated as surrogate for PFS in clinical trials evaluating Bruton tyrosine kinase inhibitors in WM.

Abstract Purpose: We sought to improve upon frontline bendamustine/rituximab (BR) induction therapy followed by rituximab maintenance in untreated high-risk follicular lymphoma (FL). Patients and Methods: Patients were randomized to BR induction followed by 2-year rituximab maintenance (BR-R), BR with bortezomib and rituximab maintenance (BVR-R), or BR followed by lenalidomide (1 year) with rituximab maintenance (BR-LR). Dual primary objectives were complete remission (CR) rate and 1-year disease-free survival (DFS); 289 patients enrolled (NCT01216683). Results: For induction, 92%, 87%, and 86% of patients randomized to BR-R, BVR-R, or BR-LR received six cycles, respectively. CR rate with BR versus BVR induction was 62% versus 75%, respectively (P = 0.04). One-year DFS rates with BR-R versus BR-LR were 85% versus 67%, respectively (P = 0.0009). This was due to an imbalance in CR rates post-BR induction and discontinuation due to adverse events (AEs). The most common grade 3–4 AEs for BVR versus BR were neutropenia and sensory neuropathy (12% vs <1%); 83% of the latter occurred with intravenous bortezomib. The most common grade 3–4 AEs related to LR versus rituximab maintenance were neutropenia 66% versus 21%, respectively (P < 0.0001), and febrile neutropenia 10% versus 2%, respectively (P = 0.05). The overall treatment-related mortality was 1.4%. With 5-year median follow-up, 3-year PFS rates for BR-R, BVR-R, and BR-LR were 77%, 82%, and 76%, respectively (P = 0.36) with OS rates of 87%, 90%, and 84%, respectively (P = 0.79). For prognostication, CR rate and POD-24 were associated with survival. Conclusions: Altogether, neither bortezomib added to BR induction nor lenalidomide added to rituximab maintenance immediately post-BR induction is recommended in untreated FL.

The NCCN Clinical Practice Guidelines in Oncology for Hodgkin Lymphoma (HL) provide recommendations for the management of adult patients with HL. The NCCN panel meets at least annually to review comments from reviewers within their institutions, examine relevant data, and reevaluate and update their recommendations. Current management of classic HL involves initial treatment with chemotherapy alone or combined modality therapy followed by restaging with PET/CT to assess treatment response. Overall, the introduction of less toxic and more effective regimens has significantly advanced HL cure rates. This portion of the NCCN Guidelines focuses on the management of classic HL.

Abstract Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is an uncommon histologic variant, and the optimal treatment of stage I-II NLPHL is undefined. We conducted a multicenter retrospective study including patients ≥16 years of age with stage I-II NLPHL diagnosed from 1995 through 2018 who underwent all forms of management, including radiotherapy (RT), combined modality therapy (CMT; RT+chemotherapy [CT]), CT, observation after excision, rituximab and RT, and single-agent rituximab. End points were progression-free survival (PFS), freedom from transformation, and overall survival (OS) without statistical comparison between management groups. We identified 559 patients with median age of 39 years: 72.3% were men, and 54.9% had stage I disease. Median follow-up was 5.5 years (interquartile range, 3.1-10.1). Five-year PFS and OS in the entire cohort were 87.1% and 98.3%, respectively. Primary management was RT alone (n = 257; 46.0%), CMT (n = 184; 32.9%), CT alone (n = 47; 8.4%), observation (n = 37; 6.6%), rituximab and RT (n = 19; 3.4%), and rituximab alone (n = 15; 2.7%). The 5-year PFS rates were 91.1% after RT, 90.5% after CMT, 77.8% after CT, 73.5% after observation, 80.8% after rituximab and RT, and 38.5% after rituximab alone. In the RT cohort, but not the CMT cohort, variant immunoarchitectural pattern and number of sites >2 were associated with worse PFS (P < .05). Overall, 21 patients (3.8%) developed large-cell transformation, with a significantly higher transformation rate in those with variant immunoarchitectural pattern (P = .049) and number of involved sites >2 (P = .0006). OS for patients with stage I-II NLPHL was excellent after all treatments.