Abstract: Patients with indolent B-cell non-Hodgkin lymphoma (iNHL) generally require treatment but experience normal survival, emphasizing the need for simpler, safer therapies. Proteasome inhibitors target aberrant signaling pathways within iNHL and have manageable toxicities. We evaluated the oral proteasome inhibitor ixazomib as initial monotherapy, and combined with rituximab, for first-line treatment of iNHL. Treatment-naïve patients with iNHL needing therapy received oral ixazomib 4 mg weekly until progressive disease or unacceptable adverse events. A 4-week course of rituximab was added during month 7. The primary end point was overall response rate (ORR) during the ixazomib monotherapy window. Correlations included gene expression profiling and response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. Thirty-three patients with follicular lymphoma (FL) (n = 20), marginal zone lymphoma (n = 7), and other iNHL were treated with a median follow-up of 30.3 months. During the 6-month ixazomib window, the ORR was 24%, including 35% in FL. The best ORR over the entire study period was 52% overall and 65% in FL; complete response was achieved in 33% and 45%, respectively. The median duration of response was 25.8 months (range, 0-49.7), and the 24-month progression-free and overall survival rates were 51% (95% confidence interval [CI], 32-67) and 91% (95% CI, 74-97), respectively. Ixazomib was well tolerated. Baseline downregulation of proteasome genes, PSMB9 (P = .03) and PSMB8 (P = .007), were associated with response. All evaluated patients generated anti-S antibodies to SARS-CoV-2 vaccination, with a median of 254.9 binding arbitrary unit per mL. Ixazomib demonstrated efficacy alone and with short-course rituximab in untreated iNHL while exhibiting favorable toxicity, convenience, and retention of the B-cell immune response. This trial is registered at www.clinicaltrials.gov as NCT02339922.

Abstract: Background: Window of opportunity studies are rarely conducted in lymphoma, but permit evaluation of novel therapies before resistance mechanisms emerge. Identification of a minimum acceptable response rate in the first-line setting may expedite drug development and is most attractive for testing relatively nontoxic, oral targeted agents that may offer substantial logistical and clinical benefits (1). Ixazomib, an orally bioavailable proteasome inhibitor, showed promising activity in a single small study that included relapsed/refractory indolent B-cell NHL (i-NHL) (2). We designed a frontline "window" study to assess the activity of ixazomib monotherapy in patients with i-NHL. Methods: This single-arm, open-label investigator-initiated phase II trial (NCT 02339922) is being conducted at the University of Washington / Fred Hutch Cancer Research Center. Patients must have a diagnosis of i-NHL and a clinical indication for treatment per NCCN guidelines. Other criteria are ECOG ≤ 2, and no prior systemic anti-neoplastic treatment except in cases of mucosa-associated marginal zone lymphoma relapsed after or refractory to antibiotics. Ixazomib is administered at 4 mg orally once a week on consecutive 28-day cycles until disease progression or unacceptable toxicity. The window period closes after 6 cycles, with four doses of weekly rituximab added during the 7th cycle to test the safety and efficacy of this combination. The primary endpoint is investigator-assessed response rate performed every 2 cycles. An overall response rate of ≥ 19 of 36 is required to conclude promising efficacy. Secondary endpoints include duration of response, progression free survival, time to next treatment, and safety / tolerability. Correlative studies are being performed on tumor tissue samples collected pre-treatment and paired with biopsies obtained, as able, within 2 months after initiation of ixazomib and with clinically suspected disease progression to gain insight into potential molecular predictors of response. Correlates under investigation include gene expression profiling using the Nanostring platform and immunohistochemical evaluation of pathways associated with lymphoma proliferation and proteasome inhibition. The study opened in May 2016 and as of June 2019, 32 patients were screened. Of 23 patients treated the median age is 64 (range 41 to 85) and 15 (65%) are male. Fifteen (65%) patients had follicular lymphoma, 4 (17%) mantle cell lymphoma, 3 (13%) marginal zone lymphoma, and 1 (4%) chronic lymphocytic leukemia. No unexpected toxicities have emerged to date. The study is supported by Takeda Oncology. Glimelius B, Lahn M. Window-of-opportunity trials to evaluate clinical activity of new molecular entities in oncology. Ann Oncol. 2011;22(8):1717-25.Assouline SE, Chang J, Cheson BD, Rifkin R, Hamburg S, Reyes R, et al. Phase 1 dose-escalation study of IV ixazomib, an investigational proteasome inhibitor, in patients with relapsed/refractory lymphoma. Blood Cancer J. 2014;4:e251. Disclosures Graf: BeiGene: Research Funding; AstraZeneca: Research Funding; TG Therapeutics: Research Funding. Lynch:Johnson Graffe Keay Moniz & Wick LLP: Consultancy; Incyte Corporation: Research Funding; Juno Therapeutics: Research Funding; T.G. Therapeutics: Research Funding; Rhizen Pharmaceuticals S.A: Research Funding; Takeda Pharmaceuticals: Research Funding. Ujjani:Gilead: Consultancy; Astrazeneca: Consultancy; Atara: Consultancy; Genentech: Honoraria; AbbVie: Honoraria, Research Funding; Pharmacyclics: Honoraria; PCYC: Research Funding. Cowan:Abbvie: Research Funding; Celgene: Consultancy, Research Funding; Sanofi: Consultancy; Cellectar: Consultancy; Juno: Research Funding; Janssen: Consultancy, Research Funding. Smith:Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Portola Pharmaceuticals: Research Funding; Genentech: Research Funding; Ayala (spouse): Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Denovo Biopharma: Research Funding; Ignyta (spouse): Research Funding; Merck Sharp & Dohme Corp: Consultancy, Research Funding; Incyte Corporation: Research Funding; Acerta Pharma BV: Research Funding; Bristol-Myers Squibb (spouse): Research Funding. Shadman:BeiGene: Research Funding; Sound Biologics: Consultancy; Celgene: Research Funding; Gilead: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; TG Therapeutic: Research Funding; Sunesis: Research Funding; Astra Zeneca: Consultancy; Atara Biotherapeutics: Consultancy; Mustang Bio: Research Funding; ADC Therapeutics: Consultancy; Verastem: Consultancy; AbbVie: Consultancy, Research Funding; Acerta Pharma: Research Funding. Libby:Alnylam: Consultancy; Abbvie: Consultancy; Pharmacyclics and Janssen: Consultancy; Akcea: Consultancy. Cassaday:Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Kite/Gilead: Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Other: Spouse's disclosure: employment, stock and other ownership interests. Fromm:Merck, Inc.: Research Funding. Gopal:Teva, Bristol-Myers Squibb, Merck, Takeda, Seattle Genetics, Pfizer, Janssen, Takeda, and Effector: Research Funding; Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte: Honoraria; Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte.: Consultancy. OffLabel Disclosure: Ixazomib is not approved for use in indolent B-NHL.

Abstract: Background: Frontline treatment of indolent B-cell non-Hodgkin lymphoma (iB-NHL) typically involves intravenously administered anti-CD20 monoclonal antibodies with or without cytotoxic chemotherapy. Effective and low-toxicity therapies with improved convenience of administration are sought. We hypothesized that ixazomib (Ix) could safely and conveniently induce remissions in patients with untreated iB-NHL. Here we present the first data on frontline use of Ix in untreated iB-NHL. Methods: This single-arm, open-label phase II "window" trial for patients with untreated iB-NHL (NCT02339922) opened to enrollment in May 2016. Eligibility included histopathologically confirmed iB-NHL, measurable disease, a clinical indication for treatment based on NCCN guidelines, and no prior systemic treatment. Ix was administered at 4 mg orally once a week on consecutive 28-day cycles until disease progression or unacceptable toxicity and four doses of weekly rituximab (R) were added during the 7th cycle, after the initial window period. The primary endpoint was investigator-assessed response rate after independent radiology review. Response assessment occurred at every 2 cycles and using standard (Lugano) criteria. Tumor tissue was collected for gene expression profiling and immunohistochemical evaluation of molecular pathways associated with proteasome inhibition. Results: As of July 1, 2018, 15 patients were treated. The median age was 64 years (range, 47 to 81) and 53% were men. Disease histologies included follicular lymphoma (FL, n = 10), mantle cell lymphoma (MCL, n = 2), marginal zone lymphoma (MZL, n = 2), and small lymphocytic lymphoma (SLL, n = 1). At the start of therapy, all had stage III/IV disease and B-symptoms were present in 40%. For patients with FL, 80% had poor risk by FLIPI. Overall, the indication for treatment included symptoms due to disease (40%), steady progression of disease (33%), and cytopenia due to disease (27%). To date, 14 patients were evaluable for response and 13 experienced tumor burden reduction during the Ix-only window (Figure 1). Of patients with FL, 6 completed the Ix-only window phase and, of these, 5 achieved PR. An additional 4 patients with FL have not completed all 6 cycles of Ix monotherapy. Of these, 1 patient achieved a PR after 4 cycles and continues on treatment, 1 patient came off study with stable disease after 4 cycles, and 2 patients have experienced tumor reduction without meeting formal response criteria and continue on treatment (after 2 and 4 cycles, respectively). Of those patients with FL that received R, all achieved formal remission (3 CR, 3 PR). Median progression free survival has not been reached with a median follow up of 7.4 months. No patient with non-FL histology had yet achieved a PR during the Ix-only window or had undergone response assessment after receiving R at the time of the data cut. The most common adverse events (AEs) for all pts were grade 1-2 and included nausea (53%), diarrhea (53%), rash (40%), and fatigue (33%). Peripheral neuropathy occurred in 20% patients (grade 2 in 7%). A single grade ≥ 3 AE occurred (syncope, grade 3). Conclusions: Data from this interim analysis suggest that Ix monotherapy is well tolerated and highly active in the frontline treatment of FL with all patients demonstrating tumor reduction to date and augmented responses following the addition of R. Non-FL histologies of B-NHL appear less responsive to Ix, but numbers are small. Accrual on study continues. Correlative analyses are underway to determine if Ix or Ix-R may represent a viable frontline option for some patients with iB-NHL. Figure 1. Waterfall plot of response. Number of cycles of treatment received to date indicated for each subject. Four weekly doses of rituximab are added, per protocol, with the 7th cycle of ixazomib. Asterisk indicates treatment on study ongoing. Disclosures Graf: Acerta: Research Funding; TG Therapeutics: Research Funding; Beigene: Research Funding. Lynch:T.G. Therapeutics: Research Funding; Takeda Pharmaceuticals: Research Funding; Rhizen Pharmaceuticals S.A.: Research Funding; Incyte Corporation: Research Funding; Johnson Graffe Keay Moniz & Wick LLP: Consultancy. Shadman:Genentech: Consultancy; Genentech: Research Funding; Verastem: Consultancy; AbbVie: Consultancy; Gilead Sciences: Research Funding; Beigene: Research Funding; Qilu Puget Sound Biotherapeutics: Consultancy; AstraZeneca: Consultancy; TG Therapeutics: Research Funding; Mustang Biopharma: Research Funding; Pharmacyclics: Research Funding; Acerta Pharma: Research Funding; Celgene: Research Funding. Gopal:Pfizer: Research Funding; Aptevo: Consultancy; BMS: Research Funding; Brim: Consultancy; Asana: Consultancy; Seattle Genetics: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Takeda: Research Funding; Merck: Research Funding; Janssen: Consultancy, Research Funding; Spectrum: Research Funding; Incyte: Consultancy; Teva: Research Funding.

Abstract: Background High dose therapy and autologous stem cell transplantation (ASCT) can improve outcomes for patients with mantle cell lymphoma (MCL), yet relapse ultimately occurs in the majority of patients. Maintenance rituximab (MR) administered after induction chemotherapy has been shown to improve overall survival (OS), but limited comparative data are available regarding the impact of MR following ASCT. We report the impact of MR on outcomes following ASCT in a large series of patients with MCL. Methods One hundred sixty four consecutive patients with MCL that underwent ASCT for MCL at our center between November 1995 and May 2011 were included in this retrospective analysis. Patients that received MR after ASCT were compared to patients that did not receive maintenance rituximab after ASCT (no-MR). Two patients underwent tandem autologous/allogeneic stem cell transplants and were excluded from analysis; inadequate follow-up data precluded the evaluation of MR administration in an additional 5 patients. MR was treated as a time-dependent covariate to account for the variability in the time to initiation after ASCT. Statistical significance of differences in event rates between the MR and no-MR groups was evaluated with the Cox proportional hazards regression model. Two-sided p-values less than 0.05 were considered statistically significant. Results A total of 157 patients met the above criteria and were evaluated in this study. MR was administered to 50 (32%) patients and the remaining 107 (68%) patients received no MR after ASCT. Median age at the time of ASCT was 58 (range 35–71). All patients in the MR group had received rituximab prior to ASCT, whereas 13 of the 107 patients in the no-MR group had no prior rituximab (p = 0.01). Patients in the MR group were more likely to have had chemo-sensitive disease (p = 0.05) and to have undergone ASCT during first remission (p = 0.0001) and in complete remission (CR) (p = 0.0003). Patients in the no-MR group were more likely to have received radio-immunotherapy based conditioning (p 〈 0.0001). The groups were well matched for simplified MIPI score (sMIPI) at the time of diagnosis (p = 0.50) and at ASCT (p = 0.88). A median of 8 (range 1 to 16) doses of MR was administered at a dose of 375 mg/m2. MR was initiated at a median of 77 days after ASCT (range 27 to 287) and the last dose was administered at a median of 271 days after ASCT (range 55 to 1074). The most common dosing schedules included weekly dosing for 4 weeks for two cycles separated by 6 months (n = 15), monthly dosing (n = 8), and every 3-month dosing (n = 7); a variety of dosing schedules were used in the remaining cases (n = 20). Grade 4 neutropenia was observed in 16 of 47 evaluable patients (34%) in the MR group, and 16 of 87 evaluable patients (18%) in the no-MR group (p = 0.04). Granulocyte colony stimulating factor (GCSF) was administered for neutropenia in 15 of 47 evaluable patients (32%) in the MR group, and 10 of 85 evaluable patients (12%) in the no-MR group (p = 0.005). MR was associated with a significantly prolonged PFS (HR 0.33, p = 0.0005) and OS (HR 0.40, p = 0.01) following a multivariate adjustment (Table 1) with a median follow up of 4.75 years. Likewise, in a landmark analysis limited to patients alive and without progression at day 100 after ASCT (n = 147), 3-year PFS and OS were 78% and 86%, respectively, in the MR group and 59% and 71%, respectively, in the no-MR group (Figure 1). Conclusion These data suggest that MR administered following ASCT improves both PFS and OS for patients with MCL with an associated increase in the risk of severe neutropenia and consequent use of GCSF. Randomized, prospective trials are needed to confirm these findings and establish post-ASCT MR as standard of care in treating MCL. Table 1. Multivariate Cox proportional hazards modeling using maintenance rituximab as a time-dependent covariate Progression Free Survival1 Overall Survival2 HR p-value HR p-value Maintenance rituximab 0.33 (0.18 – 0.62) 0.0005 0.40 (0.20 – 0.81) 0.01 1Adjusted for: Age, B-symptoms, MIPI at time of ASCT, disease status at ASCT, chemo-sensitivity, ASCT in first remission, conditioning regimen 2Adjusted for: Age, disease status at ASCT, chemo-sensitivity, ASCT in first remission, conditioning regimen Figure 1. Kaplan-Meier plots using landmark of day 100 after ASCT for (A) progression free survival and (B) overall survival Figure 1. Kaplan-Meier plots using landmark of day 100 after ASCT for (A) progression free survival and (B) overall survival Disclosures Off Label Use: Rituximab as maintenance therapy after autologous stem cell transplantation for mantle cell lymphoma.