PURPOSE In previous analyses of the MURANO study, fixed-duration venetoclax plus rituximab (VenR) resulted in improved progression-free survival (PFS) compared with bendamustine plus rituximab (BR) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). At the 4-year follow-up, we report long-term outcomes, response to subsequent therapies, and the predictive value of molecular and genetic characteristics. PATIENTS AND METHODS Patients with CLL were randomly assigned to 2 years of venetoclax (VenR for the first six cycles) or six cycles of BR. PFS, overall survival (OS), peripheral-blood minimal residual disease (MRD) status, genomic complexity (GC), and gene mutations were assessed. RESULTS Of 389 patients, 194 were assigned to VenR and 195 to BR. Four-year PFS and OS rates were higher with VenR than BR, at 57.3% and 4.6% (hazard ratio [HR], 0.19; 95% CI, 0.14 to 0.25), and 85.3% and 66.8% (HR, 0.41; 95% CI, 0.26 to 0.65), respectively. Undetectable MRD (uMRD) at end of combination therapy (EOCT) was associated with superior PFS compared with low MRD positivity (HR, 0.50) and high MRD positivity (HR, 0.15). Patients in the VenR arm who received ibrutinib as their first therapy after progression (n = 12) had a reported response rate of 100% (10 of 10 evaluable patients); patients subsequently treated with a venetoclax-based regimen (n = 14) had a reported response rate of 55% (six of 11 evaluable patients). With VenR, the uMRD rate at end of treatment (EOT) was lower in patients with GC than in those without GC ( P = .042); higher GC was associated with shorter PFS. Higher MRD positivity rates were seen with BIRC3 and BRAF mutations at EOCT and with TP53, NOTCH1, XPO1, and BRAF mutations at EOT. CONCLUSION Efficacy benefits with fixed-duration VenR are sustained and particularly durable in patients who achieve uMRD. Salvage therapy with ibrutinib after VenR achieved high response rates. Genetic mutations and GC affected MRD rates and PFS.

Background: Asymmetrical distribution of specific phospholipids between the two leaflets of biological membranes is generated and maintained by transporters. Results: A mutation in murine Atp11c results in altered morphology and shortened life span of erythrocytes. Conclusion: Phospholipid transport by ATP11C maintains phospholipid asymmetry in erythrocytes. Significance: Defects in phospholipid transport across the cell membrane can lead to anemia.

The MURANO trial (ClinicalTrials.gov identifier, NCT02005471) demonstrated superior progression-free survival (PFS) and overall survival (OS) with venetoclax-rituximab treatment vs bendamustine-rituximab in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Patients were randomized to 2 years venetoclax-rituximab (n = 194; rituximab for the first 6 months) or 6 months bendamustine-rituximab (n = 195). Although undetectable minimal residual disease (uMRD) was achieved more often with venetoclax-rituximab, long-term implications of uMRD with this fixed-duration, chemotherapy-free regimen have not been explored. We report MRD kinetics and updated outcomes with 5-years' follow-up. Survival benefits with venetoclax-rituximab vs bendamustine-rituximab were sustained (median PFS [95% confidence interval]: 53.6 [48.4, 57.0] vs 17.0 [15.5, 21.7] months, respectively, P < .0001; 5-year OS [95% confidence interval]: 82.1% [76.4, 87.8] vs 62.2% [54.8, 69.6], respectively, P < .0001). Venetoclax-rituximab was superior to bendamustine-rituximab, regardless of cytogenetic category. Venetoclax-rituximab-treated patients with uMRD at end of treatment (EOT; n = 83) had superior OS vs those with high-MRD+ (n = 12): 3-year post-EOT survival rates were 95.3% vs 72.9%, respectively (P = .039). In those with uMRD at EOT, median time to MRD conversion was 19.4 months. Of 47 patients with documented MRD conversion, 19 developed progressive disease (PD); median time from conversion to PD was 25.2 months. A population-based logistic growth model indicated slower MRD median doubling time post-EOT with venetoclax-rituximab (93 days) vs bendamustine-rituximab (53 days; P = 1.2 x 10−7). No new safety signals were identified. Sustained survival, uMRD benefits and durable responses support 2-year fixed-duration venetoclax-rituximab treatment in R/R CLL.

Introduction: The randomized Phase III MURANO study (NCT02005471) compared fixed-duration VenR with standard bendamustine-rituximab (BR) in R/R CLL. Deep responses with uMRD were associated with superior progression-free survival (PFS) of VenR vs BR with 48 months (mo) follow-up (f/u). We now report long-term MRD kinetics and updated efficacy outcomes, including re-exposure to VenR (to be presented), with a 5 year (yr) median follow-up (clinical cutoff date May 8, 2020). Methods: As published, pts were randomized to VenR (Ven 400 mg daily for 2 yrs + standard dose R for the first 6 mo) or B (70 mg/m2)R (6 mo). A sub-study was introduced in 2018, allowing pts who developed progressive disease (PD) following Tx with BR or VenR to receive the MURANO VenR regimen. PFS was based on investigator assessment. Peripheral blood MRD was analyzed centrally by allele-specific oligonucleotide polymerase chain reaction and/or flow cytometry. Pts were categorized by MRD status as previously reported, using <10-4 threshold for uMRD. MRD conversion was defined as 2 consecutive assays detecting MRD or PD in pts who previously had uMRD. Genomic complexity (GC) and del(17p) status were assessed by array comparative genomic hybridization. GC was defined as ≥3 copy number variations (CNV). All p-values are descriptive. Results: 389 pts were enrolled (VenR, n=194; BR, n=195). With a median f/u of 59.2 (range, 0-71.5) mo, the PFS benefit with VenR over BR was sustained (HR, 0.19 [95% CI: 0.15-0.26]; p<0.0001). Median PFS was 53.6 (95% CI: 48.4-57.0) mo for VenR and 17.0 (95% CI: 15.5-21.7) mo for BR. For pts who completed the full 2 yrs of Ven Tx (n=130), PFS estimates 36 mo post-end of treatment (EOT) were ~51.1% (95% CI: 40.2-61.9). Overall survival (OS) benefit was maintained for pts treated with VenR vs BR (HR, 0.40 [95% CI: 0.26-0.62]; p<0.0001), with 5-yr OS estimates of 82.1% (95% CI: 76.4-87.8) for VenR and 62.2% (95% CI: 54.8-69.6) for BR. Improved OS outcome was observed among the VenR pts that reached EOT without PD and had uMRD (83/118) compared with those with MRD (35/118), with 3-yr post-EOT survival estimates of 95.3% (95% CI: 90.0-100.0) vs 85.0% (95% CI: 72.8-97.2), respectively (Figure 1). Of the pts with uMRD at EOT, 32/83 had not shown PD and remained uMRD at the 5-yr update, 4/83 had PD without prior confirmed MRD conversion and 47/83 had MRD conversion. Median time to MRD conversion from EOT was 19.4 (95% CI: 8.7-28.3) mo. Of the 47/83 pts with confirmed MRD conversion, 19 subsequently developed PD by International Workshop on CLL criteria with a median time to PD from MRD conversion of 25.2 (95% CI: 19.4-30.4) mo. These 19 pts exhibited more rapidly increasing rates of MRD post-EOT than pts that had MRD conversion but were PD-free (Figure 2). Among pts that were uMRD at EOT, the baseline presence of del(17p), GC and unmutated immunoglobulin heavy chain gene (IGVH) were each associated with increased risk of MRD conversion and subsequent PD post-EOT (Table 1). All 4 pts with del(17p) experienced MRD conversion with subsequent PD. 8/18 (44%) pts with GC vs 8/40 (20%) pts without GC eventually converted to MRD and developed PD. The rate of MRD conversion with eventual PD was also higher among those with unmutated IGVH (21/56; 37%) than those without (1/23; 4%). Once uMRD at EOT was achieved, pts without del(17p) or GC, or with mutated IGVH, were more likely to maintain uMRD or experience MRD conversion without subsequent PD at this follow-up (Table 1). No new safety signals were identified. Excluding non-melanoma skin cancers, 2 second primary malignancies (VenR [acute myeloid leukemia and multiple myeloma]) were reported since the previous update. Rates of Richter transformation remained balanced between treatment arms (7 on VenR, 6 on BR). Following PD on the main study, 29 pts were enrolled in the sub-study (re-treatment; n=21, crossover; n=8). Further data on their biologic profile, updated response rates, and MRD in the re-treatment cohort will be presented. Conclusions: Five-yr data from MURANO demonstrate sustained PFS and OS benefit with VenR vs BR. In the VenR cohort, uMRD at EOT is associated with improved OS. Unmutated IGVH, del(17p) and GC (≥3 CNV) are associated with higher rates of MRD conversion and subsequent PD after attaining uMRD at EOT. Overall, a substantial proportion of pts who completed Ven Tx retained uMRD 36 mo after treatment cessation, displaying durable response following 2-yr fixed-duration VenR. Disclosures Kater: Janssen: Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Roche: Research Funding; Genentech: Research Funding. Kipps:Pharmacyclics/ AbbVie, Breast Cancer Research Foundation, MD Anderson Cancer Center, Oncternal Therapeutics, Inc., Specialized Center of Research (SCOR) - The Leukemia and Lymphoma Society (LLS), California Institute for Regenerative Medicine (CIRM): Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Oncternal Therapeutics, Inc.: Other: Cirmtuzumab was developed by Thomas J. Kipps in the Thomas J. Kipps laboratory and licensed by the University of California to Oncternal Therapeutics, Inc., which provided stock options and research funding to the Thomas J. Kipps laboratory, Research Funding; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; VelosBio: Research Funding; Ascerta/AstraZeneca, Celgene, Genentech/F. Hoffmann-La Roche, Gilead, Janssen, Loxo Oncology, Octernal Therapeutics, Pharmacyclics/AbbVie, TG Therapeutics, VelosBio, and Verastem: Membership on an entity's Board of Directors or advisory committees. Eichhorst:F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; ArQule: Consultancy, Honoraria, Other: travel support, Research Funding; Oxford Biomedica: Consultancy, Honoraria, Other: travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: travel support, Research Funding; BeiGene: Consultancy, Honoraria, Other: travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding. Hillmen:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Astra Zeneca: Honoraria; F. Hoffmann-La Roche: Honoraria, Research Funding; Pharmacyclics: Research Funding; Gilead: Research Funding. D'Rozario:F. Hoffmann-La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Owen:AbbVie, F. Hoffmann-La Roche, Janssen, Astrazeneca, Merck, Servier, Novartis, Teva: Honoraria. Assouline:AbbVie: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Research Funding. Lamanna:MingSight: Other: Institutional research grants, Research Funding; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Oncternal, Verastem, TG Therapeutics: Other: Institutional research grants, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Juno: Other: Institutional research grants, Research Funding; Loxo: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Gilead: 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; Bei-Gene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Octapharma: Research Funding; Columbia University Medical Center: Current Employment; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Robak:Abbvie, Pharmacyclics, Gilead, GlaxoSmithKline, Novartis, Janssen, Roche, Acerta, AstraZeneca, BioGene, UCB: Research Funding; Abbvie, Pharmacyclics, Novartis, Janssen, Acerta, AstraZeneca, BioGene, UCB, Sandoz: Honoraria; Sandoz, Janssen, AbbVie, Roche, Gilead: Consultancy. de la Serna:F. Hoffmann-La Roche, Abbvie, Pharmacyclics, Gilead, GlaxoSmithKline, Novartis, Janssen, Roche, Acerta, AstraZeneca, BioGene, UCB: Research Funding; Abbvie, AstraZeneca: Other: Travel, Accommodations, Expenses; Abbvie, Janssen: Speakers Bureau; Gilead, AstraZeneca, Abbvie, Janssen, Sandoz, F. Hoffmann-La Roche: Consultancy; Abbvie, Pharmacyclics, Novartis, Janssen, Acerta, AstraZeneca, BioGene, UCB, Sandoz: Honoraria. Jaeger:F. Hoffmann-La Roche: Honoraria, Research Funding. Cartron:Celgene: Consultancy, Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria; Sanofi: Honoraria; Gilead: Honoraria; Jansen: Honoraria; Abbvie: Honoraria. Montillo:Gilead: Honoraria, Speakers Bureau; AbbVie: Honoraria, Speakers Bureau; F. Hoffmann-La Roche: Honoraria, Research Funding; Janssen: Honoraria, Speakers Bureau; Astra Zeneca: Honoraria; Verastem: Honoraria. Mellink:Genentech, Inc: Research Funding; Amsterdam University Medical Centre: Current Employment. Chyla:AbbVie: Current Employment, Current equity holder in publicly-traded company. Wilson:Roche Products Limited: Current Employment. Wu:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Jiang:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Lefebure:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Boyer:Roche: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Seymour:Mei Pharma: Consultancy, Honoraria; Nurix: Honoraria; Morphosys: Consultancy, Honoraria; Gilead: Consultancy; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

The lymphoproliferative disorders (LDs) are a heterogeneous group of at least 70 conditions that result from the clonal proliferation of B, T, and NK cells. Inflammatory bowel disease (IBD)‐associated lymphomas are typically B‐cell LD, while T‐cell or Hodgkin's lymphomas are rare. In IBD patients not on immunosuppression, the risk of LD seems to be similar or slightly higher than the background population risk. Thiopurine therapy is associated with an increased risk: the relative risk is increased four‐ to sixfold and the absolute risk varies between 1 in 4000–5000 for those aged 20–29 to 1 in 300–400 in those over 70. It is difficult to quantify the risk of anti‐ tumor necrosis factor (TNF) therapy alone; however, it appears to be less than for thiopurines alone. There is particular concern regarding the development of post‐transplant‐like LD in those with latent epstein‐barr virus (EBV) infection exposed to immunosuppressives, the occurrence of hepatosplenic T cell lymphoma in patients treated with combination anti‐TNF and thiopurine therapy, and the development of hemophagocytic lymphohistiocytosis in those who acquire a primary EBV or other infections while on immunosuppressive medication. There are currently no guidelines for monitoring EBV (or other virus) status in patients on immunosuppression, although it could be used to monitor those who have a prior history of lymphoma and are about to start a thiopurine or anti‐TNF agent. In discussing the risks of lymphoproliferative disorders associated with agents used for the treatment of IBD, patients can often be reassured that the benefits of such therapy still outweigh the small, but real, risks.