ALBERT

Description: The phase II CAVALLI (NCT02055820) study assessed efficacy and safety of venetoclax, a selective, B-cell lymphoma-2 (Bcl-2) inhibitor, with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in first-line (1L) diffuse large B-cell lymphoma (DLBCL), including patients demonstrating Bcl-2 protein overexpression by immunohistochemistry (Bcl-2 IHC-positive). Eligible patients ≥18 years with previously untreated DLBCL, Eastern Cooperative Oncology Group performance status ≤2, and International Prognostic Index 2-5. Venetoclax 800 mg (days 4-10, cycle 1 and days 1-10, cycles 2-8) was administered with rituximab (8 cycles) and CHOP (6-8 cycles); 21-day cycles. Primary endpoints: safety, tolerability, and complete response (CR) at end of treatment (EOT). Secondary endpoints: progression-free survival (PFS) and overall survival. Comparative analyses used covariate-adjusted R-CHOP controls from the GOYA/BO21005 study, an appropriate contemporary benchmark for safety and efficacy. Safety and efficacy analyses included 206 patients. CR rate at EOT was 69% in the overall population and was maintained across Bcl-2 IHC-positive subgroups. With median follow-up of 32.2 months, trends were observed for improved investigator-assessed PFS for venetoclax plus R-CHOP in the overall population (Hazard ratio [HR] = 0.61, 95% confidence interval [CI], 0.43-0.87) and Bcl-2 IHC-positive subgroups (HR = 0.55, 95% CI, 0.34-0.89), versus R-CHOP. Despite a higher incidence of grade 3/4 hematologic adverse events (86%), related mortality was not increased (2%). Chemotherapy dose intensity was similar in CAVALLI versus GOYA. The addition of venetoclax to R-CHOP in 1L DLBCL demonstrates increased but manageable myelosuppression and the potential of improved efficacy particularly in high-risk, Bcl-2 IHC-positive patient subgroups.

Description: Background: Venetoclax (Ven), an orally bioavailable BCL2 inhibitor, is approved as monotherapy (Ven-mono) and in combination with rituximab (R; VenR) for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) and combined with obinutuzumab in 1L CLL. Herein, we present the long-term efficacy data, including durability of response of continuous and fixed-duration therapy, from the initial phase 1b study (Seymour, et al. Lancet Oncol. 2017) of VenR in R/R CLL with median follow-up on study of 4.9 yrs. Methods: Pts with relapsed CLL received Ven daily (200 - 600 mg) and 6 - 9 doses of R over 6 mo, then Ven-mono (NCT01682616). Minimal residual disease (MRD) was assessed in bone marrow (BM) using multicolor flow cytometry (1 pt were pneumonia (n=2) and osteoarthritis (n=2). Thirty-three pts (67%) achieved CR or BM uMRD by 12 mo and opted to remain on Ven-mono (n=15) or stopped therapy with Ven due to good response (n=18) and stayed on study; DOR and PFS estimates using Kaplan-Meier methodology are presented in the Table. Of the 16 pts not achieving CR or uMRD by 12 mo and continuing therapy, all subsequently discontinued the trial (withdrew consent [n = 2], AEs [n = 2], progressive disease [PD] with CLL [n = 7], or Richter transformation [n = 5]). One pt (1/16) had PD at 36.9 mo (best response on therapy was partial response [PR]) and received an additional round of R treatment starting at 51.9 mo, but the disease did not respond to intensified treatment and the pt came off Ven at 58.4 mo. Of the 15 pts (CR or BM uMRD by 12 mo) who remained on Ven-mono long-term, PD occurred in 5 pts and 1 pt died in ongoing response due to myocardial ischemia (unrelated) (Figure). Two pts received an additional round of R treatment after PD, one at 55.3 mo (achieved uMRD CR [DOR post-R, 11.3+ mo]) and the other at 70.5 mo (recently restarted R). At data cut-off, 10 pts were in remission: 6 in CR (including 1 pt retreated with R and 1 pt who recently stopped Ven after 4.3 yr due to being disease-free) and 4 in uMRD PR. Response for the last pt post-R retreatment is pending. Of the 18 pts who stopped Ven in deep response (14 uMRD CR, 2 MRD-positive CR, 2 uMRD PR [Figure]), the median time on Ven prior to cessation was 16 mo (5 - 40) and median time off Ven is 40.3 mo (1.1 - 70.0) to date. Four have discontinued study without progression (withdrew consent [n = 2], elected for stem cell transplant [n = 1], lost to follow-up [n = 1]). Four pts (2 MRD-positive CR and 2 uMRD CR) had PD after stopping Ven (all asymptomatic) at 25.5, 29.0, 33.3 and 42.0 mo off Ven and have been re-treated with VenR or Ven-mono, and 3 have been re-evaluated for response. All achieved at least PR (2 without BM assessment so unevaluable for CR), with 2 having ongoing response. One pt with PR but residual BM infiltrate had subsequent PD 18 mo later. The fourth pt was recently re-treated with Ven-mono; response is pending. Two additional pts had PD off Ven and had not been re-treated as of the data cutoff; both remain on study. Conclusions: In relapsed CLL, VenR induces deep responses within 12 mo in 67% of pts. These responses are highly durable whether on continuous or limited duration therapy, with treatment-free remissions of 〉4 yr now being observed. Re-treatment of pts with Ven or VenR re-exposure has resulted in response in some pts. In addition to long PFS, which represents time to first PD or death, pts who cease Ven in deep response have the opportunity for further disease control through reintroduction of Ven. Disclosures Brander: AstraZeneca: Consultancy, Research Funding; Novartis: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Research Funding; MEI: Research Funding; Acerta: Research Funding; Tolero: Research Funding; BeiGene: Research Funding; DTRM Biopharma: Research Funding. Seymour:Acerta: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy. Kipps:Genentech, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Velos-Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jannsen Pharmaceutical Companies of Johnson & Johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca, Inc.: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees. Ma:Abbvie: Research Funding; Beigene: Research Funding; Janssen: Consultancy, Speakers Bureau; Astra Zeneca: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Acerta: Research Funding; Kite: Consultancy; Bioverativ: Consultancy; Incyte: Research Funding; Juno: Research Funding; Gilead: Research Funding; Novartis: Research Funding; Xeme: Research Funding. Anderson:Walter and Eliza Hall Institute: Employment, Patents & Royalties: Institute receives royalties for venetoclax, and I receive a fraction of these.. Choi:Oncternal: Research Funding; Gilead: Consultancy, Speakers Bureau; Rigel: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Abbvie: Consultancy, Research Funding, Speakers Bureau. Humphrey:F. Hoffmann-La Roche Ltd: Employment. Masud:AbbVie: Employment, Other: Stock/stock options. Nandam:AbbVie: Employment, Other: Stock/stock options. Jacobson:AbbVie: Employment, Other: Stock or options. Roberts:Australasian Leukaemia and Lymphoma Group: Membership on an entity's Board of Directors or advisory committees; Walter and Eliza Hall Institute: Patents & Royalties: Institute receives royalties for venetoclax, and I receive a fraction of these.; AbbVie: Other: Unremunerated speaker for AbbVie, Research Funding; Janssen: Research Funding; BeiGene: Research Funding.

Description: BACKGROUND The evaluation of response to therapy in CLL is widely assessed according to the iwCLL guidelines which define progressive disease (PD) as advancing lymphocytosis, lymphadenopathy, organomegaly, cytopenias or histological transformation (Hallek, Blood, 2008). At the time of PD, considerable heterogeneity exists; patients (pts) with asymptomatic lymphocytosis seem to have a more indolent clinical course than those who progress by other means. On this basis, we hypothesized that the type of PD might impact on subsequent post-progression pt outcomes including the time to next treatment (TTNT) and overall survival (OS). METHODS All analyses were performed on data collected from pts enrolled in the CLL11 trial (NCT01010061), an open-label, randomized, pivotal phase III study comparing the efficacy and safety of obinutuzumab (GA101; GAZYVA) plus chlorambucil (Clb) with rituximab and Clb or Clb alone in treatment-naïve pts with CLL and pre-existing comorbidities (Goede, NEJM, 2014). Pts with defined PD, excluding death, were identified and assigned to 1 of 2 groups according to whether PD was by absolute lymphocyte count (ALC), or other, (non-ALC) causes, as per iwCLL criteria. Individuals could be allocated to only 1 group. To test whether subgroups were balanced at baseline (BL), characteristics between groups were compared for proportional differences using a Pearson chi-square test. Post-progression Kaplan-Meier survival curves for TTNT and OS were plotted by PD type. The log-rank test was used to detect significant differences in the treatment timings and survival distributions between groups, respectively. Group differences in the proportion of pts with cytopenia due to bone marrow (BM) infiltration (excluding autoimmune causes) were tested at BL and the time of PD. Similarly, B symptoms were calculated as the proportion of pts reporting disease-attributable fevers, night sweats or weight loss. Health-related quality of life (HRQoL) data were extracted from the EORTC QLQ-C30 and -CLL16 questionnaires. The mean and mean change scores by progression type were derived from BL and PD assessments. RESULTSOf the 781 pts enrolled in CLL11, progression data were available for 507 (64.9%) subjects. Of these, a total of 329 (64.9%) pts progressed by ALC, while the remaining 178 (35.1%) had PD from an alternative, non-ALC cause. At study BL, there were no differences in the demographics or disease characteristics between groups. The median post-progression TTNT for the ALC group was 373 days (95% CI [320, 449]) versus 120 days (95% CI [101, 209]) for the non-ALC group, (p 〈 0.0001) (Fig 1). Type of PD was also associated with a better OS in the ALC group (p = 0.0014) but the median time could not be accurately estimated due to insufficient events (Fig 2). A higher proportion of non-ALC pts demonstrated evidence of disease-related BM infiltration at PD (0.38 vs 0.24, p = 0.0013) with anemia (0.24 vs 0.10, p 〈 0.001) and neutropenia (0.16 vs 0.06, p 〈 0.001) representing the greatest differences between groups (Fig 3). Despite a trend towards a higher proportion of B symptoms in the non-ALC group at PD, significance was not achieved (p = 0.0624). Mean absolute HRQoL scores at BL, highlighted trends towards a higher level of functioning (higher scores) and milder physical symptoms (lower scores) in the ALC group. At the time of PD, those progressing by ALC reported clinically meaningful (6 point) higher role and physical functioning and measurably less fatigue, insomnia, dyspnea and pain. Within-group, mean score changes between BL and PD highlighted an overall trend towards improved functioning (QLQ-C30) over the course of treatment in the ALC group and a decline in function in the non-ALC group although differences were small. In general, both groups reported milder disease-related symptoms (QLQ-C30 and -CLL16) at PD with pts in the ALC group showing clinically meaningful improvements in fatigue and appetite. CONCLUSION These data provide the first comprehensive outcome analysis in CLL based on the mode of first progression for pts receiving upfront chemoimmunotherapy. We have shown that progression by ALC is consistently associated with a favourable clinical profile but whether our findings apply to pts in the relapsed setting or to those receiving other novel therapies is yet to be determined. An accurate estimate of survival by PD type might guide physician choice/timing of next treatments. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures Bazeos: Roche: Employment. Gower:Roche Products Ltd: Employment. Swann:Roche: Employment. Trask:Genentech, Inc.: Employment, Equity Ownership. Dixon:Roche Products Limited: Employment, Equity Ownership. Crompton:Roche: Employment. Kinnersley:Roche-Genentech: Employment, Equity Ownership. Al-Sawaf:Gilead: Other: Travel grants. Goede:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria; Roche: Consultancy, Honoraria, Other: Travel grant, Research Funding. Fingerle-Rowson:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Humphrey:Genentech, Inc.: Employment.

Description: INTRODUCTION The Bcl-2 inhibitor venetoclax (GDC-0199/ABT-199) has yielded promising results in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), both as monotherapy and in combination with rituximab. The CLL11 trial demonstrated that combining obinutuzumab, a type 2, glycoengineered anti-CD20-antibody, with chlorambucil resulted in improved overall survival compared to chlorambucil alone in patients with previously untreated CLL and coexisting medical conditions. Prior to opening the randomized phase of the current CLL14 trial, the successor trial to CLL11, a safety run-in phase of previously untreated patients with CLL and coexisting medical conditions was performed to assess the tolerability of obinutuzumab and venetoclax. Here, we report preliminary results of this safety run-in phase after completion of recruitment. METHODS The protocol specified to enroll 12 previously untreated patients with confirmed CLL and with coexisting medical conditions assessed by cumulative illness rating scale (CIRS) total score 〉 6 and/or estimated creatinine clearance (CrCl) 〈 70 mL/min requiring treatment (according to NCI/iwCLL criteria into the safety run-in phase of the CLL14 trial. All patients received 6 cycles of obinutuzumab and venetoclax followed by 6 additional cycles of venetoclax. Obinutuzumab was administered intravenously with 100 mg on day 1, 900 mg on day 2 (option to deliver 1000 mg on day 1), 1000 mg on day 8 and day 15 of cycle 1 and 1000 mg on day1 for cycles 2-6. A gradual weekly dose ramp-up of venetoclax with 20 mg, 50 mg, 100 mg, 200 mg up to 400 mg was administered starting at day 22 of cycle 1. Risk assessment for tumor lysis syndrome (TLS) based on absolute lymphocyte count and the largest diameter of measurable lymph nodes was performed before treatment in order to direct prophylactic measures. Study defined stopping criteria for all 12 patients included: one treatment-related death or one grade 4 adverse event related to a clinical TLS despite protocol-specified prophylaxis. Adverse events were graded per the NCI CTCAE v.4 criteria. RESULTS Between December 2014 and April 2015, 13 previously untreated patients from Australia, Canada, Germany, New Zealand, United States and Spain were enrolled; baseline patient characteristics are summarized in Figure 1. The median age was 75 years (range 59 - 88) and 54% of the patients were classified as Binet stage C; six patients were assessed medium risk and 7 patients high risk for TLS. At the timepoint of data cut-off, 12 of 13 patients have been on treatment for at least 4 weeks and completed the venetoclax dose ramp up. The median time on treatment with venetoclax is 64.5 days (range 34-153 days). One patient developed a grade 4 infusion related reaction (IRR) during the first dose of obinutuzumab and was therefore withdrawn from the trial according to the protocol requirements. All patients experienced at least 1 adverse event. Adverse events are summarized in Figure 2. Of note, 1 patient developed a self-limited grade 4 elevation of transaminases secondary to obinutuzumab. No clinical TLS was reported. Two patients developed laboratory TLS. One patient was classified as medium risk for TLS and developed hyperkalemia and hyperuricemia after the 100 mg infusion of obinutuzumab on day 1 of cycle 1. The second patient was classified as high risk for TLS (including a lymph node measuring 110 mm in diameter) and developed hypocalcemia, hyperphosphatemia and hyperuricemia after receiving 200 mg of venetoclax on day 15 of cycle 2. Neither event resulted in interruption or dose modification of study treatment. Rapid reduction in the peripheral lymphocyte count was observed in all 12 patients treated with the combination regimen. Initial response data is anticipated for all 12 patients in the next 6 months per the protocol schedule. CONCLUSIONS The treatment regimen developed for the experimental arm of the CLL14 trial comprising obinutuzumab monotherapy for one cycle followed by venetoclax and obinutuzumab in previously untreated, elderly patients with CLL and coexisting medical conditions appears tolerable. The majority of enrolled patients were older than 70 years of age and many of them had clinically meaningful comorbidities in addition to CLL. None of the protocol defined stopping criteria for the safety run-in phase of the study were met. The randomized phase of the CLL14 trial was opened in August 2015. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Fischer: Roche: Other: Travel Grants. Off Label Use: GAZYVA (obinutuzumab) is a CD20-directed cytolytic antibody and is indicated, in combination with chlorambucil, for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL). This abstract reports on obinutuzumab in combination with venetoclax for previously untreated CLL. Venetoclax is an investigational drug that is not yet approved in this indication. Fink:Roche: Honoraria, Other: travel grant. Bishop:Roche: Employment. Dixon:Roche: Employment, Equity Ownership. Choi:Gilead: Consultancy, Other: Advisory Board, Speakers Bureau; AbbVie: Consultancy, Other: Advisory Board, Research Funding. Weinkove:Avalia Immunotherapies: Consultancy; Janssen New Zealand: Consultancy; Roche New Zealand: Other: Travel support for conference. Robinson:Lundbeck: Other: Advisory boards; Novartis: Other: Advisory boards; CSL: Other: Advisory boards; Bering: Other: Advisory boards; Roche: Honoraria, Other: Advisory boards; Bayer: Other: Advisory boards; Pfizer: Other: Advisory boards; Celgene: Other: Advisory boards; Biogen Idec: Other: Advisory boards; Gilead: Other: Advisory boards; Janssen: Other: Advisory boards; Baxter: Other: Advisory boards. Dreyling:Roche: Honoraria, Research Funding. Opat:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Subsidised drug. Owen:Gilead: Honoraria; Lundbeck: Honoraria; Janssen: Honoraria; Roche: Honoraria. Tausch:Gilead: Other: Travel support. Ritgen:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Humerickhouse:AbbVie: Employment, Equity Ownership. Humphrey:Roche: Employment. Wenger:Genentech, Inc.: Employment. Goede:Bristol-Myers Squibb: Honoraria; Mundipharma: Honoraria; GSK: Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding. Eichhorst:AbbVie: Consultancy; Roche: Consultancy, Research Funding, Speakers Bureau; MundiPharma: Consultancy, Research Funding, Speakers Bureau. Wendtner:AbbVie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Genentech, Inc.: Consultancy, Honoraria, Research Funding. Stilgenbauer:Roche: Honoraria, Research Funding. Kipps:Pharmacyclics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Speakers Bureau. Hallek:Mundipharma: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; Celgene: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; Roche: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; AbbVie: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; Boehringher Ingelheim: Honoraria, Other: Speakers Bureau and/or Advisory Board; Pharmacyclics: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; Janssen: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; Gilead: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding.

Description: Introduction The BCL-2 inhibitor venetoclax has yielded promising results in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), both as monotherapy and in combination with rituximab. The CLL14 trial is a prospective, open-label, multicenter randomized phase III trial to compare the efficacy and safety of obinutuzumab and venetoclax with obinutuzumab and chlorambucil in patients with previously untreated CLL and coexisting medical conditions. Prior to opening the randomized phase, a run-in phase was performed to assess the tolerability of obinutuzumab and venetoclax in this particular patient population. Here, we report the final results on safety and efficacy of this run-in phase. Method The protocol specified to enroll 12 previously untreated patients with confirmed CLL and with coexisting medical conditions assessed by cumulative illness rating scale (CIRS) total score 〉 6 and/or estimated creatinine clearance (CrCl) 〈 70 mL/min requiring treatment according to iwCLL criteria into the run-in phase. All patients received 6 cycles of obinutuzumab and venetoclax followed by 6 additional cycles of venetoclax. Obinutuzumab was administered intravenously with 100 mg on day 1, 900 mg on day 2 (option to deliver 1000 mg on day 1), 1000 mg on day 8 and day 15 of cycle 1 and 1000 mg on day1 for cycles 2-6. A gradual weekly dose ramp-up of venetoclax with 20 mg, 50 mg, 100 mg, 200 mg up to 400 mg was administered starting at day 22 of cycle 1. Risk assessment for tumor lysis syndrome (TLS) based on absolute lymphocyte count and tumor burden was performed before treatment in order to direct prophylactic measures. Study defined stopping criteria for all 12 patients included: one treatment-related death or one grade 4 adverse event related to a clinical tumor lysis syndrome (TLS) despite protocol-specified prophylaxis. Adverse events were graded per the NCI CTCAE v.4 criteria. Final response to treatment including assessment for minimal residual disease (MRD) in peripheral blood by ASO-PCR was assessed per the iwCLL guidelines 3 months after the end of treatment, at month 15. Results Between December 2014 and April 2015, 13 previously untreated patients from Australia, Canada, Germany, New Zealand, United States and Spain were enrolled into the trial. Baseline patient characteristics are summarized in Table 1. The median age was 75 years (range 59 - 88) and 62% of the patients were classified as Binet stage C; 38% of the patients were assessed at medium risk and 62% at high risk for TLS. One patient developed a grade-4 infusion related reaction (IRR) during the first dose of obinutuzumab and was therefore withdrawn from the trial according to the protocol requirements. Eleven of 12 patients completed treatment. One patient discontinued treatment after 6 cycles of obinutuzumab and venetoclax and 2 additional cycles of venetoclax due to patient´s wish. All patients experienced at least one adverse event. The commonest adverse events are summarized in Table 2. No clinical TLS was reported. At month 15, 11 of 12 patients were evaluable for final response assessment. All patients responded to therapy. Complete remissions occurred in 7 of the 12 patients including one complete remission with incomplete bone marrow recovery. Ten of 12 patients had no detectable (

Description: Introduction Although CLL minimal residual disease (MRD) status is used in contemporary clinical trials aimed at maximizing response or determining treatment duration, its role as a predictive factor for PFS has only been established following chemoimmunotherapy. In contrast, whether MRD is a valuable tool for treatment choice in the era of novel targeted agents for CLL is unknown. Unlike kinase inhibitors, the BCL2 inhibitor venetoclax does result in undetectable MRD (uMRD). MURANO demonstrated significant PFS benefit for venetoclax + rituximab (VenR) given for a fixed duration vs bendamustine + rituximab (BR) in relapsed/refractory (R/R) CLL. Here we present analysis of peripheral blood (PB) MRD kinetics in relation to PFS in MURANO with long follow up, when all pts have completed therapy. Methods Pts were randomized to VenR (Ven 400mg/d for 2 yrs + R for first 6 mo) or BR (6 mo). Response was assessed clinically using complete blood count and physical exam at follow-up visits. PB MRD was analysed centrally by ASO-PCR and/or flow cytometry at Cycle 4, end of combination therapy (EOCT; mo 9) and every 3 mo thereafter until 3 yrs, then every 6 mo. As strong concordance between PB and bone marrow (BM) MRD with VenR was previously shown (Hillmen et al. ASCO 2018), we focus on PB MRD. Pts were categorized into uMRD (

Description: Introduction Anti-apoptotic protein BCL2 is overexpressed in hematologic malignancies such as CLL. BCL2 inhibitor VEN has shown profound efficacy when combined with B and anti-CD20 antibodies G and R, all of which are established components of CLL therapy. Pre-clinical and early clinical data in R/R CLL suggest addition of VEN to BR or BG may improve efficacy. Here we present data from a Phase Ib study of VEN in combination with BR/BG evaluated for first line (1L) CLL patients (pts). Methods This single-arm, open-label study had dose-finding (3 + 3 design) and subsequent safety-expansion stages. 1L CLL pts with ECOG PS ≤1, adequate marrow and organ function, who were in need of treatment, were first enrolled to BR-VEN, then safety data were reviewed before initiation of the BG-VEN cohort and expansions. In dose finding, 2 dosing schedules were assessed: a) Cycle 1: VEN ramp up introduced before BR/BG or b) Cycle 1: BR/BG loading dose introduced before VEN ramp up, with 1 schedule to be chosen for expansion. Pts were to receive 6 (28-day) cycles of BR/BG-VEN followed by 6 mo of VEN single agent for an overall treatment duration of 1 yr. VEN single agent could be extended upon request of the treating physician if pts were bone marrow (BM) minimal residual disease (MRD) positive and/or had partial response. Objectives were maximum tolerated dose of BR/BG-VEN, safety/tolerability of the combinations and efficacy, including undetectable MRD (

Description: Background: The MYC proto-oncogene encodes a DNA-binding factor that can induce widespread changes in gene expression profiles (GEP). Activation of MYC is a hallmark of aggressive lymphomas and frequently observed in Richter transformation of CLL. In contrast, the role of MYC-related pathogenic networks is less clearly defined in untransformed CLL. Aims: We hypothesized that MYC activation in CLL could lead to specific GEP associated with aggressive disease. We combined the analysis of genomic copy number alterations (CNA) and GEP involved in MYC pathway activation on specimens from patients registered on the CLL8 trial (front line therapy FC vs. FCR). Methods: GEP were derived from CD19-enriched CLL samples (n=337, Human Exon 1.0 ST, Affymetrix) and analysis of CNA was performed based on availability of DNA (n=309, Human SNP Arrays 6.0, Affymetrix). Sample work-up upon trial registration included FISH and TP53 mutation analysis. Results: Genomic gains involving the MYC locus on 8q24.21 were observed in 4.5% of cases. To test the hypothesis of specific GEP associated with MYC activation, we explored the distribution of cases with MYC gain using an unsupervised approach on GEP. After consensus clustering (k=6 clusters) of variably expressed genes (SD〉0.5), cases with MYC gain were non-randomly distributed and showed a characteristic pattern. Preferential enrichment was observed in one cluster ("MYC-CNA" group, comprising 40% of all cases) with 64% of MYC gains. Gene set enrichment analysis (GSEA) confirmed overrepresentation of MYC target genes (gene set: HALLMARK_MYC_TARGETS_V1, FDR

Description: Abstract 1387 Introduction: Chemoimmunotherapy with purine analogues and the CD20-antibody rituximab is the standard of care in younger and physically fit patients with chronic lymphocytic leukemia (CLL). However, the majority of CLL patients are of advanced age and many of those are afflicted with comorbidity. To date, there is no established standard treatment for such patients and the alkylating drug chlorambucil remains a valuable treatment option. The addition of CD20-antibodies (including the novel type II antibody GA101) to chlorambucil (CLB) has been proposed to improve alkylator-based therapy in CLL. Whether these regimens are beneficial in CLL patients with comorbidity remains to be explored. The German CLL Study Group (GCLLSG) in collaboration with F. Hoffmann-La Roche Ltd has initiated the multicenter international 3-armed CLL11 trial comparing CLB alone with CLB plus rituximab (R-CLB) or GA101 (G-CLB) in comorbid CLL patients. Here, we present the results of six elderly and comorbid CLL patients having received G-CLB treatment within the CLL11 safety run-in phase. Patients: Prior to the opening of the randomized phase of the CLL11 trial, six patients with previously untreated CLL in need of treatment and with a cumulative illness rating scale (CIRS) total score 〉 6 and/or a creatinine clearance (CrCl) 〈 70 ml/min were enrolled to receive 6 cycles of G-CLB. Chlorambucil was given orally at 0.5 mg/kgBW on d1 and d15 of each cycle (QW 28d). GA101 was administered intravenously on d1, d8 and d15 of cycle 1 and on d1 for cycles 2–6. Occurrence of (i) one treatment-related death or (ii) three episodes of febrile neutropenia/infections requiring antibiotic therapy during the first cycle were defined as stopping criteria for the trial. Results: All patients (2 females, 4 males) had CD20-positive CLL and active disease according to NCI/IWCLL criteria. The patients' age, CrCl and CIRS total score ranged between 71 and 79 years (median: 76 years), 38 and 83 ml/min (median: 51 ml/min), and from 5 to 9 (median: 8), respectively. So far, 4 patients completed therapy while 2 patients are still on treatment (both due to treatment delays). Therapy had to be delayed in 3 patients, mainly due to neutropenic episodes but also caused by a mechanical ileus unrelated to treatment and requiring surgical intervention and by a psychotic disorder. None of the patients have been withdrawn from treatment to date. Infusion-related reactions occurred in 5 patients, but were mild (grade 1–2) in all cases. NCI CTC grade 3 or 4 neutropenias were seen in 5 patients; 3 patients received G-CSF with immediate response. One patient had grade 3–4 thrombocytopenia while none of the patients developed grade 3–4 anemia. No grade 3–4 infections were observed and there were no febrile neutropenias or infections in the presence of neutropenia requiring antibiotic therapy. All 6 patients showed rapid clearing of lymphocytes from their peripheral blood within a few days of first dosing with G-CLB (response rates at the end-of-treatment will be reported). Conclusion: Chemoimmunotherapy with CLB and GA101 appears to be feasible in CLL patients of advanced age and with high burden of comorbidity. However, neutropenia as well as complications associated with comorbidity need special consideration in this very fragile patient population. None of the stopping criteria defined for the CLL11 run-in phase were met. The CLL11 trial therefore was opened for randomization in April 2010. Disclosures: Goede: Roche: Honoraria, Travel Grants. Fischer:Roche: Travel Grants. Fink:Roche: Travel Grants. Bieska:Roche: Employment. Humphrey:Roche: Employment. Bishop:Roche: Employment. Wenger:Roche: Employment. Hallek:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Introduction Venetoclax (Ven) is a highly selective oral inhibitor of BCL2, a key regulator of the intrinsic apoptotic pathway, which is constitutively overexpressed in CLL. Efficacy and safety of VenR given for a fixed duration in R/R CLL was evaluated in the randomized Phase III MURANO study compared with standard bendamustine + rituximab (BR). A first pre-planned analysis, when the majority of patients (pts) were still on study treatment (median follow-up 23.8 mo), established a superior PFS of VenR over BR (Seymour et al. NEJM 2018). With all pts having completed therapy, we analysed long-term outcome with a median follow up of 36.0 mo. Methods Pts were randomized to receive 6 cycles of VenR followed by Ven 400mg once daily for a total of 2 yrs, or 6 cycles of BR. Disease status was assessed by CT scan at screening, Cycle (C) 4 and 2−3 mo after end of combination therapy (EOCT). During Ven single agent and at follow-up visits, response was determined by clinical assessment every 3 mo until 3 yrs of follow-up, then every 6 mo thereafter or until PD. PFS status was based on investigator assessment. Peripheral blood (PB) minimal residual disease (MRD) was analysed centrally by ASO-PCR and/or flow cytometry at C4, EOCT and every 3/6 mo thereafter. All p values are descriptive. Results In total, 389 pts were enrolled in VenR (n=194) or BR (n=195) arms. As of May 8 2018, all pts were off treatment. For BR, 154 (79%) had completed 6 cycles. In the VenR arm, 174 (90%) completed the VenR combination phase and 130 (67%) had completed 2 yrs of Ven. The remainder had PD (11%), died (1%), or withdrew due to AEs (15%) or other reason (6%). Median Ven exposure duration and relative dose intensity were 24.4 (range 0-27.9) mo and 97.4% (26-100%), respectively, overall and 17.7 (0.5-21.9) mo and 99% during Ven single-agent therapy. With a median time off Ven after 2 yrs treatment of 9.9 (1.4-22.5) mo, PFS with VenR remains superior to BR (HR, 0.16 [95% CI 0.12, 0.23]; p1% in PB at Mo 24 (when Ven single agent was scheduled to cease) and 10/16 pts had del(17p)/TP53 mutation at baseline. Clinical and cytogenetic risk factors in pts with and without PD after Mo 24 are in Table 1. In this analysis, OS improvement was seen with VenR over BR (HR, 0.50 [95% CI 0.30, 0.85]; p=0.0093; 3-yr rate: 87.9% vs 79.5%; Figure 4). Subsequent CLL-directed treatment was given after PD in 91 pts in the BR arm. 71/91 (78%) BR arm pts received novel targeted agents, including 45 who had ibrutinib and 7 who had Ven. 27/194 (14%) pts in the VenR arm received subsequent therapy: 13/27 (44%) had novel targeted agents as next treatment, including 8 pts who had ibrutinib and 3 who were re-treated with Ven. See Table 2 for a safety overview for VenR combination and Ven single-agent periods. During Ven single agent: 17/171 pts (10%) had an AE leading to drug withdrawal; 7/171 pts (4%) had an AE leading to dose reduction; 44/171 pts (26%) had a Ven dose interruption due to an AE; 7/171 pts (4%) had a fatal AE (4 other cancers, 2 cardiac, 1 pneumonia). Grade 3-4 AEs occurred in 59/171 pts (35%); the most frequent were neutropenia (20 pts, 12%), anemia (5 pts, 3%), and thrombocytopenia (3 pts, 2%). 12/171 (7%) pts had a grade 3-4 infection in the Ven single-agent phase. The total number of Richter transformation events was 7 with VenR and 6 with BR. Conclusions With all pts off treatment and 3 yrs' median follow-up, continued substantial benefit was observed with VenR, with PFS and OS superior to BR. There were no new safety signals; most pts were able to complete treatment. The rate of CLL progression in the first 12 mo after Ven completion was modest (13%), supporting the feasibility and safety of a time-limited VenR duration. The protocol has been amended to include assessment of response and durability of disease control with VenR reintroduction at PD. This updated analysis of this Phase III global randomized study demonstrates clinically meaningful benefit of the VenR chemotherapy-free regimen with a fixed duration in all pts with R/R CLL. Disclosures Seymour: AbbVie: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Consultancy. Kipps:Genentech Inc: Consultancy, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Celgene: Consultancy; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Eichhorst:AbbVie, Celgene, Gilead, Janssen, Mundipharma, Novartis, Roche: Honoraria, Other: Travel support, Research Funding. Hillmen:Alexion Pharmaceuticals, Inc: Consultancy, Honoraria; Gilead Sciences, Inc.: Honoraria, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Novartis: Research Funding; Celgene: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Assouline:Pfizer: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; BMS: Honoraria, Research Funding, Speakers Bureau. Owen:Teva: Honoraria; Celgene: Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Merck: Honoraria; AbbVie: Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics: Research Funding; AstraZeneca: Honoraria, Research Funding. Robak:Janssen: Consultancy, Honoraria; Gilead: Consultancy; AbbVie, Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria. de la Serna:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: 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; Janssen: 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. Jaeger:Takeda-Millenium: Membership on an entity's Board of Directors or advisory committees; Takeda-Millenium: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; MSD: Research Funding; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cartron:Gilead Sciences: Honoraria; Celgene: Consultancy, Honoraria; Janssen: Honoraria; Roche: Consultancy, Honoraria; Sanofi: Honoraria. Montillo:Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding. Lamanna:Acerta: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jannsen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Verdugo:AbbVie, Inc: Employment, Equity Ownership. Punnoose:Genentech Inc: Employment; Roche: Equity Ownership. Jiang:Genentech Inc: Employment, Equity Ownership. Wang:Genentech Inc: Employment; F. Hoffmann-La Roche Ltd: Equity Ownership. Boyer:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Humphrey:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Mobasher:F. Hoffmann-La Roche Ltd: Other: Ownership interests non-PLC; Genentech Inc: Employment. Kater:Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding.