To define the efficacy of venetoclax with extended follow-up and identify clinical or biological treatment effect modifiers, updated data for previously treated patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) enrolled in 4 early-phase trials were pooled. Rates of response, complete remission (CR/CRi), and undetectable minimal residual disease (U-MRD) were analyzed for all patients (n = 436) and for those patients who were planned to receive 400 mg/day monotherapy (n = 347). Univariate and multiple regression analyses were performed to identify the pretreatment factors associated with response rates and duration of response (DoR). Objective responses were documented in 75% of all patients, including 22% CR/CRi. Overall, 27% and 16% of the patients achieved U-MRD in blood and marrow, respectively. Estimated median progression-free survival (PFS), DoR, and time to progression were 30.2, 38.4, and 36.9 months, respectively. Similar efficacy outcomes were observed within the 400 mg/day monotherapy subset. For those who achieved CR/CRi, the 3-year PFS estimate was 83%. DoR was superior for patients achieving CR/CRi or U-MRD in landmark analyses. In multiple regression analyses, bulky lymphadenopathy (≥5 cm) and refractoriness to B-cell receptor inhibitor (BCRi) therapy were significantly associated with lower CR rate and shorter DoR. Fewer prior therapies were associated with higher CR rate, but not DoR. Chromosome 17p deletion and/or TP53 mutation and NOTCH1 mutation were consistently associated with shorter DoR, but not probability of response. Thus, both pretreatment factors and depth of response correlated with DoR with venetoclax. Patients without bulky lymphadenopathy, BCRi-refractory CLL, or an adverse mutation profile had the most durable benefit.

The authors report eight otherwise normal children who presented with transient dystonic postures and/or movements in infancy. The anomalies appeared during the first months of life, progressed during a period then gradually disappeared at follow-up (from 3 months to 5 years). Differential diagnosis with primary orthopedic problems, cerebral palsy and early progressive CNS disease may be difficult at onset of the symptoms. Transient dystonia is probably one of the numerous mechanisms responsible for some abnormalities of tone, posture and movement in infancy and may account for some of the cases labeled as "transient cerebral palsy". Our cases resemble those described by Willemse (19) as "benign idiopathic dystonia in the first year of life".

Introduction: Undetectable minimal residual disease at <10-4 sensitivity (uMRD4 ) and intermediate MRD (<10-2 to ≥10-4) status in both peripheral blood (PB) and bone marrow (BM) are correlated with progression-free survival (PFS) and overall survival in patients treated with chemoimmunotherapy. However, the prognostic significance of uMRD4 in the setting of targeted agents has not been established, primarily due to the rare achievement of uMRD4 with B-cell receptor signaling pathway inhibitors (BCRi). Additionally, the multi-compartmental nature of CLL and differential effects of each therapy on these compartments could lead to differences in MRD level between PB and BM; therefore, relationship between PB and BM must be defined for each new treatment approach. Venetoclax is a targeted BCL-2 inhibitor approved for treatment of relapsed/refractory (R/R) CLL, and has achieved PB uMRD4 rates of 30% as monotherapy (Stilgenbauer, et al. J Clin Oncol. 2018; 36(19):1973-1980). In this post-hoc analysis we assess the concordance between MRD status in PB and BM and the prognostic significance of MRD levels achieved with venetoclax monotherapy. Methods: MRD and PFS data from two phase 2 studies of venetoclax monotherapy in patients with R/R CLL were pooled: Study M14-032 (NCT02141282) of patients with R/R CLL who failed BCRi therapy and Study M13-982 (NCT01889186) of patients with R/R CLL (and 5 previously untreated) with del(17p). In both studies, venetoclax was administered at a final dose of 400mg/day after dose ramp-up until disease progression or prohibitive toxicity. Patients with informative PB or BM MRD data available were included in the analysis. MRD was evaluated by multi-color flow cytometry, with the majority of patients assessed at regional reference centers using assays based on the standardized method published by the European Research Initiative on CLL (ERIC) consortium (4-color in the EU; 6-color in Australia and North America). Quantitative MRD results were categorized as uMRD4, intermediate MRD, or high MRD (≥10-2). For the correlation analysis between PB and BM MRD, only patients with matched time points (same day) were included. The concordance of MRD between PB and BM was evaluated by linear correlation coefficient. PFS was evaluated using Kaplan-Meier estimates and hazard ratios between best PB MRD status, and estimated by the Cox proportional hazards regression. Results: Of the 285 patients from the two trials, 176 had informative MRD data in either PB or BM and were included in the analyses. For the PB and BM comparison, there were 42 samples with matched time points from 38 patients. PB MRD level correlated with BM MRD level (Figure 1; R2 = .96; P<0.001); no patients with uMRD4 in BM had contemporaneous detectable MRD in PB. Out of 174 and 80 patients with PB and BM MRD data respectively, uMRD4 and intermediate MRD were achieved across iwCLL 2008 response categories (Table; all CRs were confirmed in BM). Median times to attainment of PB uMRD4 (n=46) and PB intermediate MRD (n=40) were 14 (range: 3.5-37) and 8 (range: 3.5-28) months, respectively. Best PB MRD status was associated with PFS; outcomes were superior for patients who achieved uMRD4 (HR 0.20; 95% CI 0.09, 0.44; P<0.001) or intermediate MRD (HR 0.29; 95% CI 0.12, 0.68; P=0.005) vs high MRD. PFS rates at 24 months from commencement of therapy were 92.8%, 84.3%, and 63.2% for PB uMRD4, intermediate MRD, and high MRD patients, respectively (Figure 2). Conclusions: Venetoclax monotherapy induced high rates of PB uMRD4 and intermediate MRD in both CR and PR iwCLL categories. PB and BM MRD levels achieved with venetoclax were highly concordant. Achievement of either uMRD4 or intermediate MRD in PB with venetoclax was associated with longer PFS. Disclosures Wierda: AbbVie, Inc: Research Funding; Genentech: Research Funding. Roberts:Walter and Eliza Hall: Employment, Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone and royalty payments related to venetoclax; AbbVie: Research Funding; Genentech: Research Funding; Janssen: Research Funding. Ghia:AbbVie, Inc: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Sunesis: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Acerta: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding. Brown:Janssen: Consultancy; Abbvie: Consultancy; Acerta / Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Sun Pharmaceutical Industries: Research Funding; Loxo: Consultancy; Beigene: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Morphosys: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; Invectys: Membership on an entity's Board of Directors or advisory committees; Sunesis: Consultancy; Roche/Genentech: Consultancy; Pharmacyclics: Consultancy; Boehringer: Consultancy; Celgene: Consultancy; Verastem: Consultancy, Research Funding; Gilead: Consultancy, Research Funding. Stilgenbauer:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, 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; Hoffmann La-Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmcyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cymbalista:Gilead: Honoraria; Janssen: Honoraria; AbbVie, Inc: Honoraria; Sunesis: Research Funding. Lamanna:Verastem: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding; AstraZeneca: 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; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jannsen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Seymour:Celgene: Consultancy; 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. Böttcher:Celgene: Research Funding; Genentech: Research Funding; AbbVie, INc: Honoraria, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria. Breuleux:Roche: Employment, Equity Ownership; Gilead: Equity Ownership; Basilea: Patents & Royalties; Novartis: Patents & Royalties. Chyla:AbbVie, Inc: Employment, Equity Ownership. Zhou:AbbVie, Inc: Employment, Equity Ownership. Nielsen:AbbVie, Inc: Employment, Equity Ownership. Kim:Abbvie: Employment, Equity Ownership. Potluri:AbbVie: Employment, Equity Ownership. Maher:AbbVie, Inc: Employment, Equity Ownership. Hillmen:Alexion Pharmaceuticals, Inc: Consultancy, Honoraria; F. Hoffmann-La Roche Ltd: Research Funding; Novartis: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences, Inc.: Honoraria, Research Funding.

No abstract

BACKGROUND: Venetoclax is an effective oral agent for frontline treatment of patients with chronic lymphocytic leukemia (CLL). Due to the rapid induction of cell death caused by the targeted activity of venetoclax, some patients require inpatient monitoring for tumor lysis syndrome (TLS) at initiation of therapy. In the recent CLL14 study, 64% and 22% of venetoclax-treated patients were medium and high risk for TLS, respectively. This study used disease re-staging every two cycles to explore the efficacy of using of obinutuzumab, with or without bendamustine prior to initiation of venetoclax, to reduce tumor burden and thus eliminate the need for hospitalizations, as well as reduce the risk for TLS at the initiation of venetoclax therapy. METHODS: This is a single arm open-label, phase 3b trial (NCT03406156). Patients had previously untreated CLL/SLL (excluding those with 17p deletion), an Eastern Cooperative Oncology Group (ECOG) performance score of ≤1, and a medium (any lymph node 5 - <10 cm or absolute lymphocyte count [ALC] ≥25 × 109 /L) or high (any lymph node ≥10 cm or ALC ≥25 × 109 /L and any lymph node ≥5 cm) tumor burden. Patients had tumor debulking (with obinutuzumab or obinutuzumab plus bendamustine) for a maximum of six 28-day cycles until low tumor burden (ALC <25 × 109 /L and all lymph nodes <5 cm) was achieved, at which point treatment with venetoclax plus obinutuzumab was initiated. The primary endpoints of the study were (1) the percentage of patients achieving low tumor burden after 2, 4, and 6 cycles of obinutuzumab, with or without bendamustine; and (2) the response rates of patients treated with venetoclax. RESULTS: A majority of patients were <75 years old (87%, 60/69) with ALC ≥25 × 109 /L (81%, 56/69), medium TLS risk (81%, 56/69), and RAI stage 1/2 (52%, 36/69; 32% had RAI stage 3/4). Of 69 patients treated, 50 had debulking with obinutuzumab alone, and 19 with added bendamustine (11% [2/19] added bendamustine at cycle 3+); 51 patients completed debulking and 18 are ongoing. After two cycles of debulking, 77% (40/52) of evaluable patients achieved low tumor burden; after four cycles, 94% (45/48); and after six cycles, 98% (46/47) [Figure]. ALC was reduced to less than 25 × 109 /L in 98% (50/51) of evaluable patients after two cycles of obinutuzumab, without (100%; 43/43) or with bendamustine (7/8). Amongst those that received obintuzumab alone, 4 of 5 evaluable patients with lymph nodes 5-10 cm were debulked to <5 cm by 4 cycles of therapy. For patients started with obinutuzumab plus bendamustine, all 4 evaluable patients with lymph nodes 5-10 cm were debulked to <5 cm within 2 cycles, and 3 of 4 evaluable patients with nodes >10 cm were debulked to <5 cm by 4 cycles of therapy. Safety signals were consistent with the known profiles of bendamustine, obinutuzumab and venetoclax; the most frequently reported any-grade AEs (>30%) were infusion-related reactions (71%; all grade 1-2), nausea (39%), headache (35%) and fatigue (32%). Neutropenia (28%) and thrombocytopenia (10%) were the most frequently reported Grade 3+ AEs. AEs of TLS were reported in the debulking phase in 7% (5/69) of patients. A retrospective analysis using Howard criteria for TLS identified three additional patients with laboratory TLS: two occurred during the debulking phase and one during the venetoclax phase, all driven by phosphate and uric acid. Uric acid levels were below the institutional upper limit of normal for the patient with TLS during venetoclax treatment and did not require management. No patients were hospitalized during venetoclax ramp up. CONCLUSIONS: Two cycles of obinutuzumab prior to initiation of venetoclax was an effective debulking strategy for patients with ALC >25 × 109 /L and lymph nodes <5 cm, with over 98% success rate; the addition of bendamustine increased effective debulking for patients with nodes 5-10 cm. Patients with nodes >5 cm treated with obinutuzumab or >10 cm treated with obinutuzumab plus bendamustine may need >2 cycles to achieve low tumor burden. Debulking via obinutuzumab, with or without bendamustine, may allow more patients to be administered venetoclax in the outpatient setting, eliminating the need for hospitalization during venetoclax initiation. Figure Disclosures Sharman: AstraZeneca: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Andorsky:Genetech: Research Funding; Gilead: Research Funding; Celgene: Research Funding; AstraZeneca: Consultancy; CTI: Research Funding. Melear:Texas Oncology: Employment; DARA: Speakers Bureau. Kolibaba:Atara Bio: Consultancy; AbbVie, Acerta, Celgene, Genentech, Gilead, Janssen, Novartis, Pharmacyclics, Seattle Genetics, TG Therapeutics: Research Funding; Verastem: Honoraria. Yimer:Clovis Oncology: Equity Ownership; Celgene: Honoraria; Seattle Genetics: Honoraria; Janssen: Speakers Bureau; AstraZeneca: Speakers Bureau; Amgen: Consultancy; Puma Biotechnology: Equity Ownership. Burke:Celgene: Consultancy; Roche/Genentech: Consultancy; Gilead: Consultancy. Fanning:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Masud:AbbVie: Employment, Other: Stock/stock options. Zimmerman:AbbVie: Employment, Other: stock or options. Nielsen:AbbVie: Employment, Other: and may hold stock or stock options. Vizkelety:AbbVie: Employment, Other: stock or options. Jiang:AbbVie: Employment, Other: stock or options. Flinn:AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding.