Kurzfassung: Primary mediastinal large B‐cell lymphoma (PMBL) is a distinct subtype of diffuse large B‐cell lymphoma (DLBCL) that shows overlap with classical Hodgkin lymphoma (CHL) and a favorable prognosis compared to mediastinal gray‐zone lymphoma (MGZL). We performed immunohistochemistry on initial diagnostic specimens of 49 cases of uniformly treated PMBL to determine the frequency and clinical significance of expression of antigens commonly seen in CHL and MGZL, along with markers previously shown to be prognostic in DLBCL, not otherwise specified. The median age was 37 years with a female:male ratio of 2.3. After a median follow‐up of 78 months, 24% of patients had relapsed or refractory disease and 22% had died; the 5‐year PFS was 70%. Variable CD15 expression was seen in 31% of cases, but was not associated with adverse outcome. Hans cell‐of‐origin, proliferation index, and MYC/BCL2 coexpression were not associated with outcome, while low PDL1 ( P  = 0.011) and high MUM1 ( P  = 0.065) staining were each associated with shorter PFS. A biologic risk score (one point each for low PDL1 and high MUM1) stratified patients into three prognostic risk groups for PFS ( P  = 0.001) and OS ( P  = 0.032). On separate multivariate models, low PDL1 was independent of R‐IPI risk group for PFS (HR 6.0, P  = 0.023), as was a biologic risk score of 2 (HR 5.6, P  = 0.011). Incorporation of the biologic risk score sub‐stratified patients within R‐IPI groups for both PFS ( P   〈  0.001) and OS ( P   〈  0.001). In summary, we characterize the immunophenotypic spectrum of PMBL and identify PDL1 and MUM1 as prognostic biomarkers for high‐risk disease. Am. J. Hematol. 91:E436–E441, 2016. © 2016 Wiley Periodicals, Inc.

Kurzfassung: Background: Venetoclax (Ven; BH3 mimetic) and Obinutuzumab (O; CD20 antibody) is an approved, fixed-duration regimen (one year) that induces undetectable minimum residual disease (uMRD) and durable remissions in treatment naïve patients (pts) with chronic lymphocytic leukemia (CLL; Fischer NEJM 2019). In the CLARITY trial of venetoclax-ibrutinib (BTK inhibitor; BTKi) in relapsed or refractory CLL, peripheral blood (PB) MRD response kinetics predicted bone marrow (BM) uMRD and were associated with progression-free survival (Rawstron EHA 2020). We explored MRD as a biomarker to direct treatment duration in an investigator-initiated phase 2 trial of Zanubrutinib (BTKi) and O-Ven (BOVen). We hypothesize that early MRD kinetics will identify a defined cohort of pts with delayed BM MRD clearance, and early recurrent detectable MRD after discontinuation of treatment in pts attaining uMRD. Methods: In this multicenter, phase 2 trial (NCT03824483), eligible pts had previously untreated CLL requiring treatment (iwCLL), ECOG PS ≤2, absolute neutrophil count (ANC) ≥1,000/ul, platelets (PLT) ≥75,000/ul (ANC ≥0/ul, PLT ≥20,000/ul if due to CLL). Informed consent was obtained from all pts. BOVen was administered in 28-day (D) cycles (C): Zanubrutinib 160 mg by mouth (PO) twice daily starting D1; Obinutuzumab 1000 mg IV D1 (split D1-2 if lymphocyte count ≥25,000/ul or lymph node ≥5cm), D8, D15 of C1, and D1 of C2-8; Venetoclax ramp up initiated C3D1 (target 400 mg PO daily). MRD was evaluated by flow cytometry (MRD-FC) and immunosequencing (MRD-IS; Adaptive ClonoSEQ) with uMRD defined as ≤10 -4 for flow and ≤10 -5 for IS. Treatment consisted of 8-24 cycles with duration determined by prespecified MRD criteria. Beginning on C7D1 then every 2 cycles, pts with PB uMRD-FC had BM within 14 days. If BM uMRD, PB MRD was repeated after two additional cycles. Pts with confirmed uMRD-FC in PB and BM discontinued therapy and entered posttreatment surveillance. Response was assessed per iwCLL. Adverse events (AE) were assessed per CTCAE v5. MRD-IS failure free survival (FFS) was calculated from end-of-treatment (EOT) to the date of detectable MRD-IS (≥10 -5) using the Kaplan-Meier method. Results: The study accrued 39 pts (03/19-10/19): median age 59 years (23-73), 3:1 male predominance, 28/39 (72%) IGHV unmutated, 5/39 (12.8%) del(17p)/TP53M. All pts were evaluable for toxicity with 37 evaluable for efficacy. At a median follow up of 26+ months (mo; 4.5-30.5+), 95% (35/37) pts achieved uMRD-FC in PB, among whom 33 (94%) also achieved uMRD-IS. BM uMRD-FC was seen in 89% (33/37) at a median time of 8 mo (6-16), all of whom met prespecified MRD criteria and discontinued therapy after a median of 10 mo (8-18). Three pts discontinued therapy with persistent detectable BM MRD after 24 cycles. The most common AEs were neutropenia (51%), thrombocytopenia (44%), diarrhea (44%), infusion related reaction (41%) and bruising (41%). The most common grade ≥3 AE was neutropenia (15%). No laboratory or clinical TLS occurred (Howard definition). A ≥400-fold reduction in PB MRD-IS after 4 cycles (ΔMRD400) was selected using the Youden Index and was highly predictive of attaining BM uMRD in ≤8mo (sensitivity 88% [21/24], specificity 100% [11/11] , PPV 100% [21/21], NPV 79% [11/14] . As a result, the median duration of therapy was shorter among patients who achieved ΔMRD400 (8 vs 13 mo). Of 33 pts who met prespecified uMRD criteria and stopped therapy, 31 (94%) remain uMRD-FC following a median 15 mo (0-20) from EOT, and 2 pts had recurrent MRD (1 with PD recaptured PB uMRD with retreatment). Of 33 pts who discontinued therapy after achieving the prespecified MRD endpoint, MRD-IS was evaluated every 3 months in 31 pts for a median of 12 mo (range, 3-18) from EOT. MRD-IS FFS was longer in pts who achieved ΔMRD400 (log rank p & lt;0.001; Figure) despite shorter treatment duration. We did not observe differences in posttreatment MRD kinetics based on IGHV status or high-risk genetics. Conclusion: BOVen achieved frequent, durable uMRD. All pts completed therapy (median 10 mo treatment), including 89% (33/37) who met the prespecified PB/BM uMRD endpoint. With a median posttreatment follow-up of 15 mo, 31 (94%) remain uMRD-FC. ΔMRD400 identified a cohort of pts (40%) with delayed BM MRD clearance and earlier MRD recurrence, despite longer treatment duration. ΔMRD400 warrants further study as a predictive biomarker for treatment duration. Figure 1 Figure 1. Disclosures Soumerai: Seattle Genetics: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy, Research Funding; BMS: Consultancy; Adaptive Biotechnologies: Consultancy, Research Funding; AbbVie: Consultancy; TG Therapeutics: Consultancy, Research Funding; BostonGene: Research Funding; GlaxoSmithKline: Research Funding. Mato: Janssen: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; Johnson and Johnson: Consultancy, Research Funding; Acerta/AstraZeneca: Consultancy, Research Funding; DTRM BioPharma: Consultancy, Research Funding; Genmab: Research Funding; AstraZeneca: Consultancy; MSKCC: Current Employment; Genentech: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Nurix: Research Funding; AbbVie: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; BeiGene: Consultancy, Research Funding. Dogan: Seattle Genetics: Consultancy; Peer View: Honoraria; Takeda: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Physicians' Education Resource: Honoraria; EUSA Pharma: Consultancy. Joffe: Epizyme: Consultancy; AstraZeneca: Consultancy. Hochberg: Leuko: Consultancy; Intervention Insights: Consultancy. Abramson: Bluebird Bio: Consultancy; Morphosys: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; Kymera: Consultancy; BeiGene: Consultancy; Novartis: Consultancy; C4 Therapeutics: Consultancy; Genmab: Consultancy; EMD Serono: Consultancy; Kite Pharma: Consultancy; Incyte Corporation: Consultancy; Astra-Zeneca: Consultancy; Allogene Therapeutics: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. Batlevi: TouchIME: Honoraria; BMS: Current holder of individual stocks in a privately-held company; Medscape: Honoraria; GLG Pharma: Consultancy; Dava Oncology: Honoraria; Kite Pharma: Consultancy; Juno/Celgene: Consultancy; ADC Therapeutics: Consultancy; Life Sciences: Consultancy; Moderna: Current holder of individual stocks in a privately-held company; Regeneron: Current holder of individual stocks in a privately-held company; Viatris: Current holder of individual stocks in a privately-held company; Pfizer: Current holder of individual stocks in a privately-held company; Karyopharm: Consultancy; TG Therapeutics: Consultancy; Memorial Sloan Kettering Cancer Center: Current Employment; Seattle Genetics: Consultancy; Bayer: Research Funding; Xynomic: Research Funding; Roche/Genentech: Research Funding; Novartis: Research Funding; Epizyme: Research Funding; Janssen: Research Funding; Autolus: Research Funding. Matasar: Rocket Medical: Consultancy, Research Funding; Merck Sharp & Dohme: Current holder of individual stocks in a privately-held company; Juno Therapeutics: Consultancy; Merck: Consultancy; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; IGM Biosciences: Research Funding; GlaxoSmithKline: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Memorial Sloan Kettering Cancer Center: Current Employment; Teva: Consultancy; TG Therapeutics: Consultancy, Honoraria; Pharmacyclics: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; ImmunoVaccine Technologies: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy. Noy: Rafael Parhma: Research Funding; Morphosys: Consultancy; Targeted Oncology: Consultancy; Medscape: Consultancy; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Epizyme: Consultancy. Palomba: Ceramedix: Honoraria; Seres: Honoraria, Other: Stock, Patents & Royalties, Research Funding; Notch: Honoraria, Other: Stock; Novartis: Consultancy; Kite: Consultancy; PCYC: Consultancy; BeiGene: Consultancy; Lygenesis: Honoraria; Nektar: Honoraria; Juno: Patents & Royalties; Wolters Kluwer: Patents & Royalties; Rheos: Honoraria; Magenta: Honoraria; Pluto: Honoraria; WindMIL: Honoraria; Priothera: Honoraria. Kumar: Abbvie Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Kite Pharmaceuticals: Other: advisory board , Research Funding; Celgene: Honoraria, Other: advisory board, Research Funding; Astra Zeneca: Honoraria, Other: Advisory Board, Research Funding; Adaptive Biotechnologies, Celgene, Abbvie Pharmaceticals, Pharmacyclics, Seattle Genetics: Research Funding; Seattle Genetics: Research Funding. Roeker: AbbVie, AstraZeneca, Janssen, LOXO, Pharmacyclics, TG Therapeutics, Vaniam Group, Verastem: Consultancy; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy; TG Therapeutics: Consultancy; Loxo Oncology: Consultancy; Abbot Laboratories: Current equity holder in publicly-traded company. Thompson: VJHemOnc: Honoraria; MJH Life Sciences: Honoraria; Curio Science: Honoraria. Roshal: Physicians' Education Resource: Other: Provision of services; Auron Therapeutics: Other: Ownership / Equity interests; Provision of services; Celgene: Other: Provision of services. Huang: BeiGene: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months, Other: Travel, Accommodations, Expenses; Protara Therapeutics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Biondo: Roche: Current holder of individual stocks in a privately-held company; Genentech, Inc.: Current Employment. Wu: Genentech, Inc.: Current Employment; Roche/GNE: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Jacob: Adaptive Biotechnologies: Current Employment. Abdel-Wahab: H3B Biomedicine: Consultancy, Research Funding; Foundation Medicine Inc: Consultancy; Merck: Consultancy; Prelude Therapeutics: Consultancy; LOXO Oncology: Consultancy, Research Funding; Lilly: Consultancy; AIChemy: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Envisagenics Inc.: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Zelenetz: Novartis: Honoraria; Genentech/Roche: Honoraria, Research Funding; BMS/Celgene/JUNO: Honoraria, Other; AstraZeneca: Honoraria; MethylGene: Research Funding; Pharmacyclics: Honoraria; Amgen: Honoraria; MEI Pharma: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Verastem: Honoraria; Beigene: Honoraria, Other, Research Funding; Abbvie: Honoraria, Research Funding; SecuraBio: Honoraria; Janssen: Honoraria; Gilead: Honoraria; MorphoSys: Honoraria; NCCN: Other; LFR: Other. OffLabel Disclosure: Zanubrutinib is administered off-label in combination with venetoclax and obinutuzumab for patients with CLL/SLL.

Kurzfassung: Background: WM is an incurable low-grade lymphoplasmacytic lymphoma with limited options of therapy. Proteasome inhibition has been shown to induce components of the proapoptotic/terminal unfolded protein response (UPR), a signaling pathway activated by accumulation of misfolded proteins within the endoplasmic reticulum (ER). We previously found that UPR gene expression is related to disease activity in WM with a particular role for GRP78/Bip as a prognostic factor. We therefore examined tunicamycin (Sigma, St Louis, MO), a potent inducer of ER stress, for potential anti-tumor effects in WM. Methods: WM cell lines (BCWM.1 and WSU-WM), IgM secreting low-grade lymphoma cell lines (MEC1, RL) and primary CD19+ selected LPC cells from WM patients were incubated with tunicamycin (0.01–10 uM) for 24–72 hours and evaluated by MTT, thymidine uptake, and Apo2.7/PI staining for effects on proliferation and survival. Since bone marrow stromal cells (BMSC) confer growth and resistance to conventional treatments, we also tested the effect of tunicamycin on WM cells co-cultured with BMSC. Immunoblotting for caspases was also performed and expression of UPR genes determined using relative quantitative RT-PCR reaction following (0.5–16 hrs) culture with tunicamycin. Results: WM cells inherently expressed the ER chaperones GRP78/Bip and GRP94/gp96. Tunicamycin rapidly induced components of the proapoptotic/terminal UPR, including PERK, the ER stress-specific eIF-2alpha kinase; ATF6, an ER stress-induced transcription factor; and its proapoptotic target, CHOP/GADD153. Tunicamycin also induced significant cytotoxicity, and inhibited DNA synthesis with an IC50 of 0.5–1 ug/mL in all cell lines, as well as primary LPC from 3/3 WM patients. Furthermore, tunicamycin induced apoptosis in WM cells, with an increase in the sub-G1 population notable at 12 hrs. Tunicamycin induced apoptosis was preceded by caspase-12 cleavage, followed then by caspase-8, -9 and PARP cleavage. Importantly, co-culture of WM cells with the survival factors IL-6, IGF-1 as well as BMSC did not inhibit tunicamycin induced cytotoxicity. Lastly, tunicamycin did not induce cytotoxicity in healthy donor peripheral blood mononuclear or hematopoietic stem cells. Conclusion: These pre-clinical studies provide a framework for further evaluation of ER stress inducing agents as therapeutic agents in WM.

Kurzfassung: In previous studies, we demonstrated that Rituximab and Bortezomib are active agents as monotherapy in patients with Waldenstrom’s macroglobulinemia (WM), producing response rates of 40–80%. Moreover, we and others have demonstrated synergistic activity for these agents together, and with steroids in preclinical studies. As such, we examined the activity of combined bortezomib, dexamethasone and rituximab in patients with the consensus panel diagnosis of WM. Intended therapy consisted of IV bortezomib at 1.3 mg/m2 and IV dexamethasone 40 mg on days 1,4,8, and 11, and Rituximab at 375 mg/m2 on day 11 which constituted one cycle of therapy. Patients received four consecutive cycles, followed by a three month pause, and then 4 more cycles, each given three months apart. Ten patients are eligible for evaluation at interim analysis. Following a median of 4 cycles of therapy, median serum IgM levels for all evaluable patients declined from 5,095 (range 700–8030 mg/dL) to 2,850 (range 280–3660 mg/dL) (p=0.001). The overall response rate was 100%, with 5 and 5 patients achieving a minor (≥25% decrease in IgM) and major (≥50% decrease in IgM) response, respectively. Responses were prompt, and occurred at a median of 1.1 months. Therapy was well tolerated with III/IV toxicities consisting of sepsis (n=1), pneumonia (n=1), and thrombocytopenia (n=1). Four patients developed herpes zoster while on treatment, resulting in the implementation of prophylaxis for all patients with valcyclovir. At a median of 4 cycles, no sensory or motor neuropathies have occurred. The interim results of this study demonstrate that BDR is a highly active, and well-tolerated regimen in the primary therapy of WM.

Kurzfassung: INTRODUCTION: Previous studies have demonstrated the clinical activity of bortezomib as a single agent in patients with Waldenstrom Macroglobulinemia (WM). We performed preclinical studies that demonstrated synergistic activity of bortezomib with the anti-CD20 antibody rituximab in WM cell lines. This phase II study aimed to determine safety and activity of weekly bortezomib in combination with rituximab in patients with relapsed/refractory WM. METHODS: Patients who had at least one previous therapy for WM, symptomatic, and who had relapsed or refractory disease were eligible. NCI CTCAE v3.0 was used for toxicity assessment. Response was assessed by criteria established at the second consensus panel for WM. All patients received bortezomib IV weekly at 1.6mg/m2 on days 1, 8, 15 q 28 days x 6 cycles and rituximab 375 mg/m2 at days 1, 8, 15, 22 on cycles 1 and 4. RESULTS: 17 pts (10 men and 7 women, median age 62 years, range 43 – 81) have been treated to date. The median number of lines of prior treatment was 3 (range 1 – 5) including prior bortezomib and prior rituximab in some of those patients. The median IgM at baseline was 4070 mg/dL (range 1370– 10,800); median M-spike at baseline was 2.48 g/dL (range 1.5 – 4.87); and median hemoglobin was 11.0 g/dL (6.3–15.2). The median follow up was 5 months (range 1 – 11 months). Prior therapy included rituximab, nucleoside analogues (fludarabine and 2-CDA), combination chemotherapy (e.g CHOP, CVP), chlorambucil, and bortezomib. 13 pts are currently evaluable for response, best response to bortezomib and rituximab after 2 cycles are presented in Table 1. Median duration of response has not been reached. None of the patients progressed while on therapy with bortezomib and rituximab. Patients tolerated therapy well without significant toxicities: grade 3 peripheral neuropathy occurred in only 1 patient at cycle 6 and improved to grade 1 within 2 weeks of holding therapy. Other grade 3 and 4 toxicities included neutropenia in 3 patients, and anemia and hyponatremia in 1 patient. One patient discontinued therapy on study after 1 cycle because of inability to travel to study site and completed similar treatment off study and was unevaluable on this study. Attributable toxicities otherwise proved manageable with appropriate supportive care and the combination was generally well tolerated. CONCLUSIONS: The combination of weekly bortezomib and rituximab has been well tolerated and demonstrates exciting activity achieving CR+ PR + MR in 85%, and/or stabilization of disease in 15% of evaluable patients with relapsed WM. No significant peripheral neuropathy was observed with this regimen. Updated data will be presented at the meeting. Response N=13; ORR (CR+PR+MR)= 85% Median time to best response (months) Complete Response 1 (8%) 6 Partial Response 3 (23%) 3.5 (3–4) Minimal Response 7 (54%) 4 (2–6) Stable Disease 2 (15%) NA Progressive Disease 0

Kurzfassung: Treon et al provide early clinical data supporting a theoretical rationale for continuing ibrutinib in patients receiving the drug during COVID-19 illness.

Kurzfassung: Fludarabine and rituximab are commonly used in combination in the treatment of Waldenstrom’s macroglobulinemia (WM), though long term outcome of this regimen remains to be defined. We therefore examined the outcome of 43 WM patients treated on a clinical trial whose eligibility included & lt; 2 prior therapies, and no previous nucleoside analogue or rituximab treatment. Therapy consisted of 6 cycles (25 mg/m2/day for 5 days) of fludarabine and 8 infusions (375 mg/m2/week) of rituximab over 31 weeks. 43 patients were enrolled with a median age of 61, and median prior therapies of 0. Responses were: CR (n=2); VGPR (n=14); PR (n=21); MR (n=4); for an overall and major response rate of 95.3% and 86.0%, respectively. At best response, median bone marrow disease involvement declined from 55% to 5% (p & lt;0.00001), while serum IgM decreased from 3,840 to 443 mg/dL (p & lt;0.00001), and hematocrit rose from 31.2% to 38.0% (p & lt;0.0008). The median time to progression for all patients was 51.2 months, and was longer for untreated versus previously treated patients (77.6 vs. 38.4 months; p=0.017), as well as for those patients who achieved ≥ VGPR versus & lt;VGPR ( & gt;88.3 vs. 36.9 months; p=0.049). Grade ≥ 3 toxicities included neutropenia (n=27); thrombocytopenia (n=7); pneumonia (n=6), including two patients who succumbed to non-PCP interstitial pneumonia; peripheral neuropathy (n=2); limbic encephalitis (n=1); hemolytic anemia (n=1). With a median follow-up of 40.3 months, we observed transformation to aggressive lymphoma (n=3); myelodysplasia (n=1); acute myelogenous leukemia (n=2); bladder carcinoma (n=1); and carcinoma of unknown primary (n=1) among 8 patients. The results of this study demonstrate that fludarabine and rituximab is an active regimen in WM, though short and long term toxicities need to be carefully weighed against other available treatment options.

Kurzfassung: Background: ME-401, a potent and selective oral PI3kδ inhibitor, achieved a high rate of early and durable responses in patients with follicular lymphoma (FL), chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) when administered once daily in 28-day cycles on a continuous schedule (CS) in a dose escalation Phase 1b study (Soumerai et al, ASCO 2018:#7519). The most common adverse events (AEs) were the delayed onset (beyond Cycle 2) of grade 3 diarrhea and rash, which were reversible with drug interruption and/or corticosteroids. These delayed AEs were thought to be due to pathway inhibition in regulatory T cells (Treg) leading to a disruption in immune homeostasis. We hypothesized that an intermittent schedule (IS) beyond Cycle 2 might mitigate or reduce the incidence of significant delayed AEs. The IS tested was selected based on the kinetics of Treg repopulation, and consists of ME-401 administered on days 1-7 of a 28-day cycle. We report preliminary results of this strategy. Methods: Group 1 included 31 patients with relapsed FL (n = 22) or CLL/SLL (n = 9) who received ME-401 on a CS at doses ≥60 mg per day. 11/29 patients (38%) who received 〉 2 cycles of therapy had developed delayed grade 3 AEs on CS and could be re-challenged with either the CS or IS (from December 2017 onward) following recovery from toxicity. The other 18/29 patients (62%) had not developed a grade 3 AEs of interest on CS and, beginning in December 2017, were switched to IS after a median of 26 weeks (range, 8-49) of daily dosing. Group 2 included 15 patients with relapsed FL (n = 9), diffuse large B-cell lymphoma (n = 4), marginal zone lymphoma (MZL, n = 1), and CLL (n = 1) who received rituximab 375 mg/m2 x 8 doses over 6 months and ME-401 at 60 mg daily x 2 cycles then switched to the IS. Group 3 includes 30 patients with relapsed FL/CLL/SLL enrolling in an expansion cohort of ME-401 alone at 60 mg daily x 2 cycles then switching to IS. Results: Group 1: Of the 11 patients who developed a delayed grade 3 AE on CS, 6 were never re-challenged, 2 were re-challenged with CS with recurrence of their AE, and 3 were re-challenged with IS without recurrence of their AE. Of the 18 patients switched to the IS, and with a median follow-up of 5.2 months (range, 2.3-6.6) on IS, 3 developed grade 3 diarrhea on IS, 2 in the first cycle and 1 in the second cycle after the switch to IS, of whom 2 have been re-treated with IS for 1+ and 5+ months without recurrence of the AE. One patient was not evaluable for response due to discontinuation on Day 28 for personal reasons and 27/30 (90%) evaluable patients achieved an objective response. With a median follow-up of 9.4 months (range, 2.2-17.5) from enrollment, only 2/27 (7%) responders had disease progression (PD) on CS and were discontinued. Of the 18 patients who were switched to IS, only 1 SLL patient with a partial response (PR) achieved on CS developed PD on IS and was successfully rescued with switch back to CS. Another CLL patient in PR on CS had 10% increase in SPD from nadir in Cycle 5 on the IS and was switched back to CS. Group 2: 10/15 patients have completed 2 cycles of daily dosing at the time of analysis and were systematically switched to IS. With a median follow-up of 3.4 months (range, 1.5-5.7) on IS, only 1/10 patients developed delayed grade 3 diarrhea in the first cycle after switch to IS. 7/10 patients (70%) with FL/MZL achieved an objective response and no PD was reported with a median follow-up of 5.2 months (range, 3.1-7.5) from enrollment. Conclusions: Preliminary data suggest that switching to an intermittent schedule consisting of ME-401 administered on days 1-7 of a 28-day cycle following 2 cycles of continuous daily dosing was associated with a low rate of delayed grade 3 AEs and was associated with preservation of response in the vast majority of patients. All delayed grade 3 AEs of interest on IS occurred within 1-2 cycles of switching from CS to IS, suggesting that these might have represented a delayed effect of daily dosing. IS may also be a suitable re-treatment strategy in patients with delayed AEs on CS. Safety and efficacy data for the expansion cohort of 30 patients treated with ME-401 at 60 mg for 2 cycles then switched to IS will be presented at the meeting. A randomized study comparing CS and IS in FL is planned. Disclosures Zelenetz: Abbvie: Research Funding; Celgene: Consultancy; AstraZeneca: Consultancy; Novartis/Sandoz: Consultancy; Amgen: Consultancy; Gilead: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding. Reddy:MEI Pharma: Research Funding. Stathis:Oncology Therapeutic Development: Research Funding. Ghalie:MEI Pharma: Employment, Equity Ownership; Viracta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Pagel:Pharmacyclics, an AbbVie Company: Consultancy; Gilead: Consultancy.

Kurzfassung: BACKGROUND: Recent prospective randomized phase III studies that include targeted agents in first-line (1L) chronic lymphocytic leukemia (CLL) all demonstrate major improvements in progression-free survival (PFS) compared to chemoimmunotherapy, with no or minimal impact on overall survival (OS). PFS has generally been a poor predictor of OS in indolent lymphoma and CLL. The clinical trial results with 1L targeted therapy including ibrutinib and venetoclax (in combination with obinutuzumab) may raise questions regarding the role of chemoimmunotherapy (bendamustine-rituximab and fludarabine-cyclophosphamide-rituximab) in the management of CLL. However, high cost of 1L targeted therapy limits its global availability. We recently found that time to second treatment (TT2T), rather than time to first treatment (TT1T), was a good predictor of OS in patients with follicular lymphoma. We sought to test the hypothesis that TT2T is correlated with OS in CLL and determine if there are pre-treatment variables that help determine which patients would benefit more from early use of targeted agents, and which patients can be managed with time-limited, relatively cost-effective chemoimmunotherapy. METHODS: We retrospectively identified 1974 patients with CLL diagnosed at MSKCC between January 1998 and December 2014. To undertake this analysis, we examined a subset of 298 patients with CLL/SLL who had complete data to determine the CLL-International Prognostic Index (CLL-IPI). The 298 patients with complete data had outcomes similar to that of patients in the CLL-IPI cohort. TT1T and TT2T were calculated from time of disease diagnosis to start of first and second treatments, respectively. Median time to event was calculated using the Kaplan-Meier method for each event: TT1T, TT2T and OS. Univariate and multivariate ordinal logistic regression models were constructed to identify risk factors (RF) for requiring systemic therapy. Patients were characterized by the number of CLL-directed treatments: 0 vs 1 vs ≥2 treatments. We then evaluated OS and TT2T based on the identified RF, using the log rank test to compare outcomes. RESULTS: We identified 298 patients with CLL/SLL that had complete data to determine the CLL-IPI. Patient characteristics are shown in Table 1. There was a male predominance (1.89:1), 28% were above age 65 with a median age of 61 years (range 24-87), and CLL-IPI score was Low and Intermediate to Very High in 43.6% (130/298) and 56.4% (168/298), respectively. At a median follow-up of 6.6 years: median TT1T was 6.5 years, median TT2T was not reached, and median OS was 13.8 years. TT2T was superior to TT1T for predicting OS. After univariate and multivariate analyses, 3 clinical factors were found to independently predict the requirement for systemic therapy: IGHV unmutated (OR 5.331, 95% CI 3.09 - 9.20, p 〈 0.001), elevated B2M (OR 3.70, 95% CI 1.40 - 9.77, p=0.008) and advanced Rai staging (OR 11.36, 95% CI 1.97 - 65.46, p=0.007). Overlapping 95% confidence intervals allowed for these 3 RF to be combined to create a simple prognostic model, defined as 0 vs 1 vs ≥2 of the 3 predictive RF. This model was predictive for both TT2T and OS. Patients with 0 RF had superior OS (p 〈 0.001) and had a longer time before needing 2L therapy (p 〈 0.001), Figure 2. DISCUSSION: These data support the conclusion that TT2T is a surrogate for OS in CLL/SLL in this group of patients treated largely with 1L chemoimmunotherapy. Patients with 0 or 1 RF have a significantly longer TT2T and OS compared to patients with 2 or more RF, suggesting that 1L chemoimmunotherapy provides more durable responses for patients with 0 and 1 RF than for patients with 2 or more RFs. For patients with durable responses, chemoimmunotherapy provides a time limited strategy with prolonged treatment-free period prior to the initiation of 2L therapy. The absence of an OS benefit with targeted 1L therapy in the ALLIANCE A041202, CLL14 and iLLUMINATE trials supports delaying targeted therapy to 2L. In contrast, patients with ≥2 RF have a median TT2T of 5.7 years, significantly shorter than that of patients with 0-1 RF (median not reached). Given the limited benefit of 1L therapy in patients with ≥2 RF in this predominantly chemo treated group, it would be appropriate to evaluate if utilizing 1L targeted therapy would be superior to chemoimmunotherapy. Additional analyses are ongoing to determine if these findings can be validated in an independent cohort. Disclosures Soumerai: TG therapeutics: Research Funding; BeiGene: Research Funding; BostonGene: Research Funding; AbbVie: Consultancy; Verastem: Consultancy; Genentech/Roche: Research Funding. Roeker:AbbVie: Equity Ownership; Abbott Laboratories: Equity Ownership. Mato:DTRM Biopharma: Research Funding; Genentech: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Gilead: Research Funding; LOXO: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB member , Research Funding; Celgene: Consultancy; AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Acerta: Consultancy; Janssen: Consultancy. Zelenetz:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees.