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Introduction Multiple myeloma (MM) patients with renal impairment (RI), especially dialysis-dependent (DD) RI, have poorer outcomes than MM patients with normal renal function. Autologous stem cell transplantation (ASCT) is a treatment option, but there is concern at a perceived higher risk of complications which may be limiting consideration of the use of ASCT in this population. The evidence is inconsistent among studies and interpretation is complicated by heterogeneous datasets, some dating to before the availability of novel agents. Finally, the reversibility of RI following ASCT is an important prognostic factor for both survival and quality of life. Aim To evaluate the safety and efficacy of ASCT in MM patients with DD RI transplanted in EBMT centres between 1997 and 2017. Methods Baseline characteristics at diagnosis, patient treatment regimens and clinical outcomes were collected using standardised report forms. OS was defined as the period between the date of ASCT and the date of death or the date of last observation. PFS was defined as the period between the date of ASCT and date of progression/relapse or death of any causes or the date of the last observation. Cox proportional hazard regression analysis was applied to assess risk factors for progression and death. Survival curves were plotted by the Kaplan-Meier method and compared using log-rank test. P Results A total of 109,959 adult MM patients are registered in the EBMT database as having undergone ASCT between 1997 and 2017. We further analysed 118 DD MM patients who had a first ASCT during this period. The median (range) age was 57 (27-71) years. Seventy (59%) patients were males. Forty nine patients (49/94 patients, 52%) had Karnofsky score ≥90. One hundred and ten patients were treated with hemodialysis and eight with peritoneal dialysis. A total of 68 (58%) patients had Light Chain MM, 43 kappa and 25 Lambda. In first-line induction therapy, 47/76 (62%) patients received bortezomib-based regimens. Forty-four (37%) patients achieved at least VGPR pre-ASCT. The median time from diagnosis to ASCT was 0.7 years (0.3-4.9). Melphalan doses were as follows: 140 mg/m2 (n=55, 67%), 70-100 mg/m2 (n=15, 18%), and >140 mg/m2 (n=12, 15%). The times to Neutrophil (>0.5) and Platelet (>20) engraftment were 12 (10-37) and 14 (4-128) days, respectively. The 30-day and 100-day transplant-related mortality (TRM) rates were 0.0% and 0.9%, respectively. ASCT was associated with a significant deepening of response (at least VGPR pre- vs post-ASCT: 36/93 (39%) vs 48/93 (52%), p < 0.001). The median PFS was 37 months (95% CI: 24-43) and 5-year PFS was 31% (95% CI: 20-41). The median OS was 102 months (95% CI: 67-129). Five-year OS post-ASCT was 62% (52-72) and 10-year OS 36% (17-55). Thirty-one (26%) DD MM patients achieved dialysis independence. There were no differences in PFS or OS when comparing the 1997-2007 and 2008-2017 cohorts: 5-year PFS - 28% (6-49) vs 31% (19-43) (p=0.7) and 5-year OS - 61% (38-84) vs 63% (51-74) (p=0.9), respectively. On univariate analysis of factors affecting PFS, achievement of an Overall Response Rate (ORR) (CR+VGPR+PR vs. Other) pre-ASCT was associated with a lower risk (HR 0.467, p=0.032) and older age (>55 years) with a higher risk (HR 1.786, p=0.035) of post-ASCT progression. Age higher than 55 (HR 2.033, 95%CI: 0.992 - 4.166, p=0.053) increased and achievement of at least VGPR pre-transplant (HR 0.494, 95%CI: 0.224 - 1.091, p=0.081, on the verge of statistical significance) decreased the risk of death. Conclusion To the best of our knowledge, the DIADEM study is the largest analysis of ASCT in DD MM pts to date. This cohort of 118 unselected patients had an OS comparable to patients without RI. This may reflect patient selection based on younger age, Karnofsky scores and pre-ASCT response. The low TRM and excellent outcomes support consideration of the use of ASCT in pts with DD RI. Notably, more than a quarter of patients became dialysis independent, an outcome likely to confer an improved Quality-of-Life.. These results can also inform the debate around the role of renal transplantation in younger DD MM patients who do not achieve dialysis independence. Disclosures Snowden: IDMC: Honoraria; Kiadis: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Mallinckrodt: Honoraria; Jazz: Honoraria; Gilead: Honoraria. Dreger:MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, Roche: Consultancy; AbbVie, Gilead, Novartis, Riemser, Roche: Speakers Bureau; Neovii, Riemser: Research Funding. Illés:Takeda, Seattle: Research Funding; Janssen, Celgene, Novartis, Takeda, Roche, Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Basak:Teva: Honoraria; Celgene: Honoraria. Gyan:Pfizer: Honoraria. Hayden:Alnylam: Honoraria; Amgen: Honoraria. Beksac:Amgen: Consultancy; Celgene: Consultancy; Janssen&Janssen: Consultancy; Takeda: Consultancy. Schönland:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Medac: Other: Travel Grant; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Venetoclax in combination with obinutuzumab has significantly improved efficacy versus immunochemotherapy (progression-free survival) in patients with chronic lymphocytic leukaemia who have not received prior treatment. The objective of this study was to evaluate its efficiency in Spain using a cost-utility analysis.Using a partitioned-survival analysis model adapted to the Spanish context and based on three health states (progression-free survival, survival after progression, and death), a simulation of the evolution of patients who were candidates for initiating first-line treatment was conducted for a lifetime time horizon. Venetoclax in combination with obinutuzumab was compared to the most commonly used therapeutic options for these patients at the time of study design: chlorambucil in combination with obinutuzumab, ibrutinib, fludarabine in combination with cyclophosphamide and rituximab, and bendamustine in combination with rituximab. In order to estimate survival curves, efficacy data were derived from the CLL14 trial and a network meta- analysis. The analysis was conducted from the perspective of the Spanish National Healthcare System and included direct healthcare costs (i.e. pharmacological costs and their administration), and those associated with the management of the disease and adverse events. The resource use was validated by an expert group. Quality of life data were used to estimate the quality-adjusted life years obtained for each alternative. A threshold of €25,000/quality-adjusted life years was used. The robustness of the model was evaluated using deterministic and probabilistic sensitivity analyses.Venetoclax in combination with obinutuzumab was shown to be a dominant alternative compared to the rest of the treatment alternatives, with a lower cost per patient (€-67,869 compared to chlorambucil in combination with obinutuzumab, €-375,952 compared to ibrutinib, €-61,996 compared to fludarabine in combination with cyclophosphamide and rituximab, and €- 77,398 compared to bendamustine in combination with rituximab). It also had a greater gain in quality-adjusted life years (0.551 quality-adjusted life years gained compared to chlorambucil in combination with obinutuzumab and ibrutinib, 1.639 quality-adjusted life years gained compared to fludarabine in combination with cyclophosphamide and rituximab, and 1.186 quality-adjusted life years gained compared to bendamustine in combination with rituximab). Between 68% and 85% of the simulations performed in the sensitivity analysis showed that venetoclax in combination with obinutuzumab had lower costs and more quality-adjusted life years gained.Venetoclax in combination with obinutuzumab is an efficient and dominant alternative for treating previously untreated patients with chronic lymphocytic leukaemia compared to the available alternatives and from the perspective of the Spanish National Health System.Venetoclax en combinación con obinutuzumab ha mostrado frente a la inmunoquimioterapia mejoras significativas en términos de eficacia (supervivencia libre de progresión) en pacientes con leucemia infocítica crónica que no han recibido tratamiento previo. El objetivo de este estudio fue evaluar su eficiencia en España a partir de un análisis de coste- utilidad.Método: A partir de un modelo de análisis de la supervivencia adaptado al contexto español y basado en tres estados de salud (supervivencia libre de progresión, supervivencia tras progresión y muerte), se llevó a cabo una simulación de la evolución de los pacientes candidatos a iniciar una primera línea de tratamiento para un horizonte temporal de toda la vida. Venetoclax en combinación con obinutuzumab se comparó frente a las opciones terapéuticas más utilizadas para estos pacientes en el momento del diseño del estudio: clorambucilo en combinación con obinutuzumab, ibrutinib, fludarabina en combinación con ciclofosfamida y rituximab, y bendamustina en combinación con rituximab. Los datos de eficacia para estimar las curvas de supervivencia fueron derivados del estudio CLL14 y de un metaanálisis en red. El análisis consideró la perspectiva del Sistema Nacional de Salud incluyendo los costes sanitarios directos, en concreto los farmacológicos y su administración, y los asociados al manejo de la enfermedad y acontecimientos adversos. El uso de recursos fue validado por un grupo de expertos. Se emplearon datos de calidad de vida para estimar los años de vida ajustados por calidad obtenidos para cada alternativa. Se consideró un umbral de 25.000 €/años de vida ajustados por calidad. La robustez del modelo se evaluó mediante análisis de sensibilidad determinísticos y probabilísticos.Venetoclax en combinación con obinutuzumab se mostró como una alternativa dominante frente al resto de alternativas de tratamiento, con un menor coste por paciente (–67.869 € frente a clorambucilo en combinación con obinutuzumab, –375.952 € frente a ibrutinib, –61.996 € frente a ludarabina en combinación con ciclofosfamida y rituximab, y –77.398 € frente a bendamustina en combinación con rituximab) y una mayor ganancia en años de vida ajustados por calidad (0,551 años de vida ajustados por calidad ganados frente a clorambucilo en combinación con obinutuzumab e ibrutinib, 1,639 años de vida ajustados por calidad ganados frente a fludarabina en combinación con ciclofosfamida y rituximab, y 1,186 años de vida ajustados por calidad ganados frente a bendamustina en combinación con rituximab). Entre el 68% y el 85% de las simulaciones realizadas en el análisis de sensibilidad mostraban a venetoclax en combinación con obinutuzumab con un menor coste y un mayor número de años de vida ajustados por calidad ganados.Venetoclax en combinación con obinutuzumab se muestra como una alternativa eficiente y dominante como tratamiento de pacientes con leucemia linfocítica crónica no tratados previamente frente a las alternativas disponibles y desde la perspectiva del Sistema Nacional de Salud.

The MURANO trial (A Study to Evaluate the Benefit of Venetoclax Plus Rituximab Compared With Bendamustine Plus Rituximab in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia [CLL]; ClinicalTrials.gov identifier #NCT02005471) reported superior progression-free survival (PFS) and overall survival (OS) with venetoclax-rituximab (VenR) vs bendamustine-rituximab (BR) in relapsed/refractory (R/R) CLL. Patients were randomized to 2 years of VenR (n = 194; rituximab for the first 6 months) or 6 months of BR (n = 195). Although undetectable minimal residual disease (uMRD) was achieved more often with VenR, the 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 VenR vs BR 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], P < .0001). VenR was superior to BR, regardless of cytogenetic category. VenR-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% (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 VenR (93 days) vs BR (53 days; P = 1.2 × 10−7). No new safety signals were identified. Sustained survival, uMRD benefits, and durable responses support 2-year fixed-duration VenR treatment in R/R CLL.

The placebo controlled CLLM1 trial evaluated the efficacy of lenalidomide maintenance treatment in patients with high-risk chronic lymphocytic leukemia (CLL) in first remission after chemoimmunotherapy (CIT). Upon observation of three cases with acute lymphoblastic leukemia (ALL) in overall 56 lenalidomide treated patients (5.4%), the study treatment was prematurely stopped. Using next generation sequencing of B cell and T cell receptor (TR) rearrangements, we here report common clonal B cell ancestry between CLL and ALL in one of those three patients, in whom both diseases shared the same VDJ- as well as crosslineage TR rearrangements. Chromosomal/mutation analyses indicated that in this patient the ALL developed from a common B cell precursor which lacks genomic lesions acquired in the CLL subclone, but shares a BIRC3 frameshift deletion (p.L421fs*). In two cases we found independent IGH rearrangements indicating de novo ALL development from a different B cell clone. A retrospective cohort analysis of >1600 CLL patients treated with first-line CIT in previously reported phase 2-3 studies of the German CLL study group, yielded a significantly lower cumulative incidence of ALL at 12.6 cases/100,000 patient years, compared to 1345.5 cases/100,000 patient-years observed in the lenalidomide arm of the CLLM1 study. Given our results and increasing knowledge on the biological effects of lenalidomide in bone marrow precursor cells, we discuss the potential involvement of lenalidomide in the pathogenesis of ALL in CLL patients.

PURPOSE Acalabrutinib, a highly selective, potent, Bruton tyrosine kinase inhibitor, was evaluated in this global, multicenter, randomized, open-label, phase III study in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). METHODS Eligible patients, aged ≥ 18 years with R/R CLL, were randomly assigned 1:1 centrally and stratified by del(17p) status, Eastern Cooperative Oncology Group performance status score, and number of prior lines of therapy. Patients received acalabrutinib monotherapy or investigator’s choice (idelalisib plus rituximab [I-R] or bendamustine plus rituximab [B-R]). The primary end point was progression-free survival (PFS) assessed by an independent review committee (IRC) in the intent-to-treat population. Key secondary end points included IRC-assessed overall response rate, overall survival, and safety. RESULTS From February 21, 2017, to January 17, 2018, a total of 398 patients were assessed for eligibility; 310 patients were randomly assigned to acalabrutinib monotherapy (n = 155) or investigator’s choice (n = 155; I-R, n = 119; B-R, n = 36). Patients had received a median of two prior therapies (range, 1-10). After a median follow-up of 16.1 months (range, 0.03-22.4 months), median PFS was significantly longer with acalabrutinib monotherapy (PFS not reached) compared with investigator’s choice (16.5 months [95% CI, 14.0 to 17.1 months]; hazard ratio, 0.31 [95% CI, 0.20 to 0.49]; P < .0001). Estimated 12-month PFS was 88% (95% CI, 81% to 92%) for acalabrutinib and 68% (95% CI, 59% to 75%) for investigator’s choice. Serious adverse events occurred in 29% of patients (n = 44 of 154) treated with acalabrutinib monotherapy, 56% (n = 66 of 118) with I-R, and 26% (n = 9 of 35) with B-R. Deaths occurred in 10% (n = 15 of 154), 11% (n = 13 of 118), and 14% (n = 5 of 35) of patients receiving acalabrutinib monotherapy, I-R, and B-R, respectively. CONCLUSION Acalabrutinib significantly improved PFS compared with I-R or B-R and has an acceptable safety profile in patients with 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 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 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.

We investigate a sample of 6 Herbig Ae/Be stars belonging to the Orion OB1 association, as well as 73 low mass objects, members of the $\sigma$ Orionis cluster, in order to explore the angular momentum evolution at early stages of evolution, and its possible connection with main-sequence Ap/Bp magnetic stars. Using FIES and HECTOCHELLE spectra, we obtain projected rotational velocities through two independent methods. Individual masses, radii, and ages were computed using evolutionary models, distance, and cluster extinction. Under the assumption that similar physical processes operate in both, T Tauri and Herbig Ae/Be stars, we construct snapshots of the protostar's rotation against mass during the first 10 Myr with the aid of a rotational model that includes a variable disc lifetime, changes in the stellar moment of inertia, a dipolar magnetic field with variable strength, and angular momentum loss through stellar winds powered by accretion. We use these snapshots, as well as the rotational data, to infer a plausible scenario for the angular momentum evolution. We find that magnetic field strengths of a few k$G$ at 3 Myr are required to match the rotational velocities of both groups of stars. Models with masses between 2-3 $M_{\odot}$ display larger angular momentum by a factor of $\sim 3$, in comparison to stars of similar spectral types on the main-sequence. Even though some quantitative estimates on this dramatic decrease with age, for Ap/Bp magnetic main-sequence stars are presented, the results obtained for the angular momentum evolution do not explain their low rotation., Comment: 39 pages, 18 figures, Accepted for publication in AJ

Chronic Lymphocytic Leukemia (CLL) is the most prevalent leukemia in Western countries and is notable for its variable clinical course. This variability is partly reflected by the mutational status of IGHV genes. Many CLL samples have been studied in recent years by next-generation sequencing. These studies have identified recurrent somatic mutations in NOTCH1, SF3B1, ATM, TP53, BIRC3 and others genes that play roles in cell cycle, DNA repair, RNA metabolism and splicing. In this study, we have taken a deep-targeted massive sequencing approach to analyze the impact of mutations in the most frequently mutated genes in patients with CLL enrolled in the REM (rituximab en mantenimiento) clinical trial. The mutational status of our patients with CLL, except for the TP53 gene, does not seem to affect the good results obtained with maintenance therapy with rituximab after front-line FCR treatment.

PETHEMA, HOVON, PALG, GATLA cooperative groups., [Objective] The obesity/overweight may have an influence on APL outcomes., [Methods] This is the biggest multicentre analysis on 1320 APL patients treated with AIDA‐induction and risk‐adapted consolidation between 1996 and 2012. Patients body mass index (BMI) was classified as underweight (, [Results and conclusions] Relationship between male gender, older age, and other known laboratory abnormalities in overweight/obese patients was significant. The induction mortality rate was significantly higher in APL with BMI ≥25 vs BMI, This work was partially financed with FEDER funds (CIBERONC (CB16/12/00284)) and with Instituto de Investigación Sanitaria La Fe funds (2014/0368).

The PDS 70 system has been subject to many studies in the past year following the discovery of two accreting planets in the gap of its circumstellar disk. Nevertheless, the mass accretion rate onto the star is still not well known. Here we determined the stellar mass accretion rate and its variability based on TESS and HARPS observations. The stellar light curve shows a strong signal with a $3.03\pm0.06$ days period, which we attribute to stellar rotation. Our analysis of the HARPS spectra shows a rotational velocity of $v\sin\,i=16.0\pm0.5\,{\rm km\,s^{-1}}$, indicating that the inclination of the rotation axis is $50\pm8$ degrees. This implies that the rotation axes of the star and its circumstellar disk are parallel within the measurement error. We apply magnetospheric accretion models to fit the profiles of the H$\alpha$ line and derive mass accretion rates onto the star in the range of $0.6-2.2\times10^{-10}\,{\rm M_{\odot}yr^{-1}}$, varying over the rotation phase. The measured accretion rates are in agreement with those estimated from NUV fluxes using accretion shock models. The derived accretion rates are higher than expected from the disk mass and planets properties for the low values of the viscous parameter $\alpha$ suggested by recent studies, potentially pointing to an additional mass reservoir in the inner disk to feed the accretion, such as a dead zone. We find that the He I $\lambda$10830 line shows a blueshifted absorption feature, indicative of a wind. The mass-loss rate estimated from the line depth is consistent with an accretion-driven inner disk MHD wind., Comment: Accepted for publication in The Astrophysical Journal; 13 pages; 8 figures

The diagnostic criteria for CLL rely on morphology and immunophenotype. Current approaches have limitations affecting reproducibility and there is no consensus on the role of new markers. The aim o ...

Background: Bruton tyrosine kinase (BTK) inhibitors are a preferred treatment option in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Acalabrutinib (acala) is a next-generation, highly selective, covalent BTK inhibitor approved for the treatment of patients with CLL including those with R/R disease. In the primary analysis of the ASCEND study with a median follow-up duration of 16.1 months, acala monotherapy demonstrated superior progression-free survival (PFS) compared with idelalisib (Id) plus rituximab (R) (IdR) or bendamustine (B) plus R (BR) and favorable safety in patients with R/R CLL (Ghia et al. J Clin Oncol. 2020;38:2849-2861). Herein we report results of the ASCEND study at 3 years of follow-up. Methods: In this randomized, multicenter, open-label, phase 3 study (NCT02970318), patients with R/R CLL were randomized 1:1 to receive acala 100 mg orally (PO) twice daily or investigator's (INV) choice of IdR (Id: 150 mg PO twice daily; R: 375 x1 then 500 mg/m 2 intravenously [IV] for 8 total infusions) or BR (B: 70 mg/m 2 IV and R: 375 x1 then 500 mg/m 2 IV for 6 total cycles) until disease progression or unacceptable toxicity. Crossover to the acala monotherapy arm was permitted in patients who progressed on IdR or BR. Assessments included INV-assessed PFS, overall survival (OS), INV-assessed overall response rate (ORR), and safety. Results: A total of 310 patients (acala, n=155; IdR, n=119; BR, n=36) were enrolled (median age: 67 y; del(17p) 16%, unmutated IGHV 78%, Rai stage 3/4 42%). At a median (range) follow-up of 36.0 (0.5-44.0) and 35.2 (0.03-42.5) months (data cutoff: October 26, 2020) for acala and IdR/BR, respectively, acala significantly prolonged INV-assessed PFS vs IdR/BR (median: not reached [NR] vs 16.8 months, respectively; hazard ratio [HR]: 0.29; 95% confidence interval [CI]: 0.21, 0.41; P Adverse events (AEs) occurring in ≥15% of patients in any treatment arm are shown in the Table; the most commonly reported all-grade AEs (≥20%) with acala were headache (23%), neutropenia (23%), diarrhea (21%), and upper respiratory tract infection (20%); with IdR, diarrhea (53%) and neutropenia (47%); and with BR, neutropenia (34%), fatigue (23%), infusion-related reaction (23%), and nausea (20%). Serious AEs (SAEs) were reported in 38% of acala, 63% of IdR, and 26% of BR patients; SAEs reported in ≥5% of patients in any treatment arm were pneumonia (acala 8%, IdR 9%, BR 3%), pyrexia (acala 2%, IdR 7%, BR 3%), and diarrhea (acala 1%, IdR 15%, BR 0%). AEs led to drug discontinuation in 21% of acala, 65% of IdR, and 17% of BR patients. Events of clinical interest included all-grade atrial fibrillation/flutter (acala 6%, IdR/BR 3%), all-grade hypertension (acala 7%, IdR/BR 4%), all-grade major hemorrhage (acala 3%, IdR/BR 3%), grade ≥3 infections (acala 25%, IdR/BR 27%), and all-grade second primary malignancies excluding non-melanoma skin cancer (acala 7%, IdR/BR 3%). Conclusions: At 3 years of follow-up, the efficacy of acala monotherapy was maintained, showing a significant PFS benefit over standard-of-care regimens in patients with R/R CLL. Acala also maintained an acceptable tolerability profile with no new safety findings identified with longer-term follow-up. Figure 1 Figure 1. Disclosures Jurczak: AbbVie, AstraZeneca, Bayer, BeiGene, Celtrion, Celgene, Debbiopharm, Epizyme, Incyte, Janssen, Loxo Oncology, Merck, Mei Pharma, Morphosys, Novo Nordisk, Roche, Sandoz, Takeda, TG Therapeutics, Pharmacyclics, Affirmed, Gilead Sciences, Nordic Nanovecto: Research Funding; AstraZeneca, BeiGene, Janssen, Loxo Oncology, Sandoz, Roche: Membership on an entity's Board of Directors or advisory committees; European Medicines Agency, Sandoz-Novartis, Janssen China R&D, BeiGene, Epizyme, Acerta, AstraZeneca: Consultancy; Jagiellonian University: Ended employment in the past 24 months; Maria Sklodowska-Curie National Research Institute of Oncology: Current Employment. Pluta: Celgene, Servier, Takeda, Novartis: Honoraria; Celgene: Other: Travel, Accommodations, Expenses; Janssen-Cilag, Kartos Therapeutics, Iqvia, Roche, Acerta Pharma, Pharmacyclics, BeiGene, Takeda: Research Funding; National University of Sanok: Current Employment; Szpital Specjalistyczny w Brzozowie: Ended employment in the past 24 months. Lysak: Novartis, Janssen-Cilag, AbbVie; AstraZeneca: Honoraria, Research Funding. Šimkovič: AbbVie, AstraZeneca, Janssen-Cilag, Gilead, Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants. Kriachok: Takeda, Roche, Abbivie, Janssen, MSD: Consultancy; Takeda, Roche, Abbvie, Janssen, MSD, Pfizer: Honoraria, Speakers Bureau. Illes: Novartis, Janssen, Pfizer, Roche: Other: Travel, Accommodations, Expenses; Takeda, Seattle Genetics: Research Funding; Janssen, Celgene, Novartis, Pfizer, Takeda, Roche: Consultancy. de la Serna: ABBVIE, ASTRAZENECA,ROCHE: Research Funding; AbbVie, AstraZeneca, Beigene, Gilead, GSK, Janssen, Jazzpharma, Novartis, Roche: Consultancy; AbbVie, AstraZeneca, Roche: Speakers Bureau. Campbell: Novartis: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; CSL Behring: Consultancy; AstraZeneca: Consultancy; Amgen: Consultancy, Research Funding; BMS/Celgene: Research Funding; Roche: Consultancy, Research Funding. Musuraca: Janssen, Roche, Incyte: Honoraria; Janssen, Roche, Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen, Incyte, Roche: Consultancy. Jacob: Astrazeneca, GlaxoSmithKilne: Current equity holder in publicly-traded company; Horizon Discovery, Oxford Biomedica: Divested equity in a private or publicly-traded company in the past 24 months; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Clinical Haematology Services: Membership on an entity's Board of Directors or advisory committees; AbbVie, Astrazeneca: Honoraria. Avery: Macrogenics, Moderna: Divested equity in a private or publicly-traded company in the past 24 months. Wang: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Yu: AstraZeneca: Current Employment; EMD Serono Research Institute: Ended employment in the past 24 months; AstraZeneca, Johnson and Johnson, AbbVie, Abbott: Current equity holder in publicly-traded company; Merck KGaA: Divested equity in a private or publicly-traded company in the past 24 months. Ghia: AbbVie: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; ArQule/MSD: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Celgene/Juno/BMS: Consultancy, Honoraria; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Sunesis: Research Funding.

Introduction: The BCL-2 inhibitor venetoclax (Ven) has been approved on monotherapy or combined with rituximab in relapsed/refractory CLL patients (pts) and combined with obinutuzumab in previously untreated CLL pts. However, evidence from clinical trials can be difficult to generalize to real-world patient populations. The VENARES study assesses the real-world use of Ven following approval to inform of subpopulations underrepresented in clinical trials. Methods: This is Spanish non-interventional retrospective, multicenter post-marketing observational study. The main objective was to evaluate the effectiveness of Ven in adult CLL pts by the overall response rate (ORR) at 9 months (mo) after the first Ven dose administration. Secondary objective was to evaluate the effectiveness for the Ven monotherapy and the Ven combined with rituximab subpopulations. Consecutive adult pts with diagnosis of CLL who have initiated Ven at least 9 mo before the inclusion in the study were included. Data of pts are retrospectively reviewed until the date of last follow-up or death. Results: 125 pts diagnosed with CLL and who met the eligibility criteria were analyzed. The median age was 72 years (67 - 77) with 76.8% being older than 65 years. Most patients were male (68.8%), had a concurrent disease (65.6%). ECOG PS was recorded in 76 pts: 40 pts (32%) had PS 0, 30 pts (24%) PS 1 and 6 pts (4.8%) PS 2. Pts had received a median of 4 prior lines of therapy (range 1-13 lines). At baseline, among the 92 pts with known Binet stage, 31 (33.7%) had stage C and 38 (41.3%) had stage B; bulky nodes ≥ 5 cm were present in 20 of 87 pts; 49 pts (39.2%) had an absolute lymphocyte count ≥ 25 x 10 9/L and 33 of 54 pts (61%) baseline beta-2 microglobulin value above of 3500 ng/mL. In total, 29 of 90 patients (32%) assessed had Cr 17p deletion, 28 of 86 patients (32%) tested had TP53 mutations, and 46 of 56 patients (82%) who were tested had unmutated immunoglobulin heavy-chain variable (IGHV) status. Ven was administered as monotherapy in 71 pts (57.6%), combined with rituximab in 36 pts (28.8%), combined with obinutuzumab in 5 pts (4%) and combined with other drugs in 13 pts (10.4%). 83 of 125 patients included were evaluable for the primary objective of the study: the ORR at 9 mo was 84.3% (70 patients): CR/CRi in 44 (53%) pts, PR/nPR in 26 pts (31.3%), SD in 9 pts (10.8%) and PD in 4 pts (4.8%). By treatment, in the evaluable patients, ORR at 9 months were 79.2% (38 of 48 patients) in the Ven monotherapy group, with 45% of CR/CRi, and 92.3% (24 of 26 patients) in the Ven combined with rituximab, with 61% CR/Cri. The median duration of PFS was not reached at the time of the analysis (1-June-2021). Kaplan-Meier estimates of the probability of PFS at 24 mo was 75.4% (95% CI, 58.2 - 86.3). Disease progression occurred in 21 pts. Assessment of minimal residual disease (MRD) was available for 32 patients (25.6%) on the basis of peripheral-blood samples, bone marrow or both. Best undetectable MRD was reached in fourteen patients (43.8%). uMRD was more common in pts treated with Ven combined with R (83.3%, 5 of 6 pts) than in pts treated with Ven monotherapy (33.3%, 7 of 21 pts). Adverse events (AEs) were reported during Ven therapy in all 125 patients, 93 of these pts reported AEs related to Ven. Related to Ven, 67 patients (53.6%) experienced at least one AE: 52 pts (41.6%) had neutropenia being grade 3 and 4 in 22 (42.3%) and 9 (17.3%) pts, respectively. 9 pts (7.2%) had febrile neutropenia. Thrombocytopenia and anemia were less common occurring in 5.6% and 2.4%, respectively. Tumor lysis syndrome (TLS) occurred in 4 of 125 pts during ramp-up (3 laboratory and 1 clinical), 2 of them were related to Ven both lab TLS. None of the pts discontinued therapy due to TLS. Richter transformation was observed in 6 pts (4.8%). Other common AEs was diarrhea (10.4%), but most cases were mild. Conclusions: Our first real-world data show that Ven monotherapy or combined with rituximab is effective in highly pre-treated CLL patients, ORR at 9 mo was 84.3% in all population and PFS estimate at 24 mo was 75.4% with similar outcomes to those in the pivotal clinical trials. The safety profile of Ven was consistent with prior experience of Ven in monotherapy or combined with rituximab and no new safety signals were detected. Disclosures Baltasar: Janssen, Abbvie: Consultancy. Terol: Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel; BMS: Consultancy; Roche: Consultancy; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Hospital Clinico Valencia: Current Employment. Moreno: Janssen, Abbvie: Research Funding; Abbvie, Janssen, AstraZeneca: Speakers Bureau; Abbvie, Janssen, AstraZeneca, Beigene: Membership on an entity's Board of Directors or advisory committees. Osorio: Janssen, Abbvie, Roche: Consultancy. De la Cruz: Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Beigene: Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; JANSSEN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirkin: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. de la Serna: AbbVie, AstraZeneca, Roche: Speakers Bureau; ABBVIE, ASTRAZENECA,ROCHE: Research Funding; AbbVie, AstraZeneca, Beigene, Gilead, GSK, Janssen, Jazzpharma, Novartis, Roche: Consultancy. Arguiñano: Takeda, Sanofi, Janssen, BMS-Celgene, Abbvie: Speakers Bureau; Takeda, Sanofi, Janssen, BMS-Celgene, Abbvie: Consultancy. Loscertales: Janssen, Abbvie, Roche, Gilead: Speakers Bureau; Janssen, Abbvie, Astra-Zeneca, Beigene, Roche, Gilead: Consultancy. García: Janssen, Roche, Gilead, Celgene: Consultancy; Janssen, AbbVie: Research Funding; Janssen, Roche, Gilead, AbbVie, Celgene: Other: medical meetings funding. Pérez Persona: BMS/Celgene: Consultancy, Other: Support for attending meetings and/or travel, Speakers Bureau; Amgen: Consultancy, Other: Support for attending meetings and/or travel, Speakers Bureau; Takeda: Speakers Bureau; AbbVie: Other: Support for attending meetings and/or travel, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; GSK: Consultancy; Incyte: Consultancy. Pérez-Encinas: Janssen: Consultancy. Caballero: Celgene, Janssen, Novartis, Abbvie: Speakers Bureau; Celgene, Janssen, Amgen: Consultancy. Ruiz-Zorrilla: Abbvie: Current Employment. Moreno: abbvie: Current Employment. Ferrà: Janssen, Roche, Gilead, Takeda, Abbvie: Consultancy; Janssen, Roche, Gilead, AbbVie: Other: medical meetings funding.

APOGEE spectra offer $\lesssim$1 km s$^{-1}$ precision in the measurement of stellar radial velocities (RVs). This holds even when multiple stars are captured in the same spectrum, as happens most commonly with double-lined spectroscopic binaries (SB2s), although random line of sight alignments of unrelated stars can also occur. We develop a code that autonomously identifies SB2s and higher order multiples in the APOGEE spectra, resulting in 7273 candidate SB2s, 813 SB3s, and 19 SB4s. We estimate the mass ratios of binaries, and for a subset of these systems with sufficient number of measurements we perform a complete orbital fit, confirming that most systems with period $, Comment: Accepted to AJ. 23 pages, 17 figures

Introduction: Venetoclax (Ven) is an orally administered, highly selective inhibitor of B-cell lymphoma-2 (BCL-2). Fixed-duration VenR improved outcomes versus standard bendamustine-rituximab (BR) in the randomized Phase III MURANO study (NCT02005471; Seymour et al. N Engl J Med 2018) and is now a standard of care for the treatment of pts with R/R CLL. There are currently limited data to guide subsequent therapies when relapse occurs after fixed-duration VenR and uncertainty regarding the efficacy of repeated VenR treatment. Here, we report the response rates to follow-up therapy with Ven and Ven-based regimens, or exposure to Bruton tyrosine kinase inhibitor (BTKi) salvage therapy, following pts' participation in the MURANO trial. Methods: Pts were randomized to VenR (Ven 400 mg daily for 2 years [yrs] plus monthly R for the first 6 months [mo]) or BR (6 mo). The primary endpoint was investigator-assessed progression-free survival (PFS). Pts in either arm with disease progression were followed for overall survival (OS) and disease response to any subsequent anti-CLL therapeutic regimens. Pts who initiated new anti-CLL therapy, but who had not had a response assessment reported by the principal investigator, were considered unevaluable. Results: 389 pts were enrolled in MURANO (VenR, n=194; BR, n=195). At a clinical cutoff date of May 8, 2020, all main study pts had ceased treatment with a median follow-up of 59 mo (range 0-71.5). PFS and OS benefits were maintained at the 5-yr follow-up (Kater et al. Submitted to ASH 2020). Following disease progression, 67/87 (77.0%) VenR pts and 123/148 (83.1%) BR pts had received subsequent anti-CLL therapy. The time to next therapy (TTNT) from study entry was longer following VenR versus BR, with a median TTNT of 57.8 (95% CI: 55.1-NE) mo versus 23.9 (95% CI: 20.7-29.5) mo (HR, 0.26 [95% CI: 0.20-0.35]; p Of the BR pts receiving subsequent therapy; 99/123 (80.5%) pts received novel targeted therapy alone or in combination with other agents (BTKi, n=72; phosphoinositide 3-kinase inhibitors [PI3Ki], n=10; Ven, n=15; or other investigational medicinal products [IMP], n=2) while the remaining 24 pts received chemoimmunotherapy. Of pts previously treated with BR, the BOR rate to novel targeted agents was 84.4% among evaluable pts (83.9% for BTKi and 80.0% for Ven-based therapy; Table 1). Fifty two of 67 pts in the VenR arm received subsequent novel therapy (BTKi, n=18; PI3Ki, n=1; Ven [alone or in combination], n=32; IMP, n=1). The BOR rate to these targeted agents was 79.4% among evaluable pts. After a median treatment-free interval of 13.5 (range 0.0-41.3) mo, 18 VenR pts received a BTKi as their next line of therapy (all were BTKi naïve). These pts achieved high overall response rates (ORR): 14/14 (100% of pts with an evaluable assessment) at a median treatment duration of 21.9 (range 5.6-59.2) mo, with 10 pts continuing on BTKi therapy at this follow-up. After a median treatment-free interval of 23.7 (range 3.3-43.8) mo, 32 VenR pts were re-treated with Ven-based regimens; 21 were enrolled in the re-treatment arm of the MURANO sub-study and 11 were treated outside of the sub-study. The BOR to re-treatment with Ven or Ven-containing therapies was 72.2% of evaluable pts (Table 1). Among these pts, initial response to VenR at the main study end of combination treatment response visit was 100% (6 complete response [CR]/CR with incomplete hematologic recovery; 12 partial response), with 77.8% (14/18) achieving undetectable minimal residual disease and 15/18 completing the initial 2 yrs of Ven therapy without progression. Median treatment duration in evaluable pts re-treated with Ven-based regimens was 11.4 (range 0.7-37.6) mo with 50% of pts continuing on therapy. Conclusions: Five-yr data from MURANO demonstrated sustained TTNT benefit with VenR versus BR. Despite >80% of relapsed BR pts receiving salvage therapy with a novel agent, OS rates remain superior with VenR therapy. Relapsed VenR pts demonstrated high ORR to either subsequent BTKi therapy or re-exposure to Ven-based regimens. These data show early use of fixed-duration VenR in R/R CLL is an effective approach and does not compromise subsequent therapy response or OS. Disclosures Owen: AbbVie, F. Hoffmann-La Roche, Janssen, Astrazeneca, Merck, Servier, Novartis, Teva: Honoraria. D'Rozario:AbbVie: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Robak:GSK: Research Funding; Bristol Meyers Squibb: Research Funding; Medical University of Lodz: Current Employment; Morphosys: Research Funding; Takeda: Consultancy; UCB: Honoraria, Research Funding; Octapharma: Honoraria; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Acerta: Research Funding; Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Novartis: Honoraria, Research Funding; Sandoz: Consultancy, Honoraria; UTX-TGR: Research Funding; Momenta: Consultancy; Pfizer: Research Funding; AstraZeneca: Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; BioGene: Honoraria, Research Funding. Kater:Celgene, F. Hoffmann-La Roche/Genentech, Astra Zeneca, Janssen: Honoraria; Celgene, F. Hoffmann-La Roche/Genentech, Astra Zeneca, Janssen: Research Funding. Montillo:AbbVie: Honoraria, Speakers Bureau; F. Hoffmann-La Roche: Honoraria, Research Funding; Janssen: Honoraria, Speakers Bureau; Astra Zeneca: Honoraria; Gilead: Honoraria, Speakers Bureau; Verastem: Honoraria. de la Serna:Abbvie, AstraZeneca: Other: Travel, Accommodations, Expenses; Abbvie, Pharmacyclics, Novartis, Janssen, Acerta, AstraZeneca, BioGene, UCB, Sandoz: Honoraria; Gilead, AstraZeneca, Abbvie, Janssen, Sandoz, F. Hoffmann-La Roche: Consultancy; Abbvie, Janssen: Speakers Bureau; F. Hoffmann-La Roche, Abbvie, Pharmacyclics, Gilead, GlaxoSmithKline, Novartis, Janssen, Roche, Acerta, AstraZeneca, BioGene, UCB: Research Funding. Trněný:Bristol Meyers Squibb: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Incyte: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead Sciences: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Roche: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Celgene: Consultancy. Kim:AbbVie, Inc.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Other: may hold stock or other options. Bataillard:Imperial College Healthcare NHS Trust: Ended employment in the past 24 months; Roche Products Limited (temporary clinical fellowship as a fixed-term sabbatical from Hematology specialty training fellowship at Imperial College Healthcare NHS Trust): 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; F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy; Nurix: Honoraria; Morphosys: Consultancy, Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding.

Data on outcome in older (≥70 years) patients with acute promyelocytic leukemia after treatment with arsenic trioxide (ATO) compared with standard chemotherapy (CTX) is scarce. We evaluated 433 patients (median age, 73.4 years) treated either with ATO+ all-trans retinoic acid (ATO/ATRA; n = 26), CTX/ATRA + ATO during consolidation (CTX/ATRA/ATO; n = 148), or with CTX/ATRA (n = 259). Median follow-up for overall survival (OS) was 4.8 years. Complete remissions (CR) were achieved in 92% with ATO/ATRA and 82% with CTX/ATRA; induction death rates were 8% and 18%, respectively. For analysis of postremission outcomes we combined the ATO/ATRA and CTX/ATRA/ATO groups (ATO/ATRA ± CTX). Cumulative incidence of relapse (CIR) was significantly lower after ATO/ATRA ± CTX compared with CTX/ATRA (P P = 0.20). High (>10 × 109/l) white blood cell (WBC) counts at diagnosis were associated with higher CIR (P P = 0.48). ATO, when added to ATRA or CTX/ATRA is feasible and effective in elderly patients for remission induction and consolidation, particularly in patients with high WBC at diagnosis.

PETHEMA And PALG Groups., Acute promyelocytic leukemia is infrequent among patients aged ≥75 years old, a population that is rarely eligible for clinical protocols. This study aims to analyze the treatment strategies and clinical outcomes of very old APL patients reported to the international PETHEMA registry. Between 1997 and 2017, among 2501 APL cases registered 120 were ≥75 years old. Treatment approaches were: AIDA regimen, 79 patients; ATRA alone, 23; 16, supportive care (SC) and 2, other strategies. Patients treated with AIDA were younger, had better ECOG and lower leukocytes. Complete remission (CR) was achieved in 65% of AIDA-group vs. 45% in the ATRA-group, being infections followed by bleeding the most frequent causes of induction death. Patients in CR after AIDA showed 3-year DFS of 73%. Our real-life series of very old APL patients provides a reference basis for future treatment strategies aiming to improve clinical outcomes in this challenging population., This work was partially financed with FEDER Funds (CIBERONC (CB16/12/00284)).

Introduction. Despite the high proportion of prolonged remissions obtained with ibrutinib in patients with CLL, complete responses (CR) are rarely observed. For the purpose of increasing the deepness of response, ibrutinib has been tested in combination with other drugs that exert a different mechanism of action. Thus, monoclonal antibodies (mAbs) have been concomitantly combined with ibrutinib in untreated or R/R CLLs. Nonetheless, several data derived from both in vitro and clinical studies do not support a synergistic effect of the concomitant administration of ibrutinib with anti-CD20 mAbs. Herein, we present the preliminary results of a multi-center, non-randomized phase 2 study aimed to determine the efficacy and safety of the sequential treatment of CLL patients with ibrutinib followed, in those not attaining CR, by a consolidation phase with ofatumumab (GELLC-7, EudraCT number 2016-004937-26). Patients and methods. Patients aged ≥18 years, physically fit (CIRS score < 6) with treatment-naïve CLL were enrolled in this study. Patients received an induction phase consisting of 12 cycles (28-day) of ibrutinib in monotherapy at 420 mg once daily. Patients attaining a CR after this induction phase were kept on ibrutinib until progression. In contrast, patients not obtaining a CR also continued on ibrutinib but received a consolidation treatment with 7 doses of ofatumumab (300 mg D1 and 1000mg D8 of C13, 1000 mg D1 of C14-C18). The primary endpoint of the study was the CR rate assessed after 20 cycles of treatment (2 months after completing ofatumumab consolidation). Results. 84 patients with a median age 69 years (range 38-84 yrs), 71% male, were included in this study. At inclusion, 83.3% had Binet stage B/C, 61% unmutated IGHV status, and 19% high risk genetic aberrations (7.6% 17p deletion and/or TP53mut, and 11.4% 11q deletion). At the interim data cut-off (June 2019), 7 patients had discontinued the study (progression to Richter transformation, n=1; patient withdrawal, n=3; adverse events [AE], n=3, including one G5 AE), 5 of them during the first 12 cycles of treatment. Sixty-seven patients received the induction phase with 12 cycles of ibrutinib, whereas 22 patients completed 20 cycles of treatment and were evaluable for the primary endpoint of the study. After 12 cycles of ibrutinib, 3 patients (4.5%) were in CR, 54 patients (80.5%) in PR, 6 patients (9%) in PR with lymphocytosis, and 4 patients (6%) in SD. In 20 patients receiving the consolidation with ofatumumab an improvement in response was observed, with 8/20 patients (40%) attaining a CR (7 patients converted PR to CR, and one patient SD to CR), whereas the remaining 12 patients were classified as PR. Two patients that were already in CR at cycle 12 maintained the CR under ibrutinib monotherapy. MRD was undetectable in blood ( Grade ≥3 adverse events (AEs) were experienced by 26 patients (31%), whilst 22 serious AEs were observed in 16 patients (19%) (14 infections, 1 febrile neutropenia, 3 dyspnoea, 1 anemia, 1 edema/pleural effusion, 1 renal insufficiency, 1 squamous carcinoma). The most common G3/4 AEs were hematological toxicity (neutropenia [7.1%], anemia [4.5%], thrombocytopenia [2.4%]) and infections (8.5%). The Gr 5 AE consisted of a severe peripheral edema and pleural effusion leading to death. The great majority of SAEs (67%) and G3/4 AEs (66%) were observed during the first 12 cycles of treatment with ibrutinib monotherapy. Conclusions. The preliminary analysis of the GELLC7 trial showed that the addition of consolidation with ofatumumab after 12 cycles of prior treatment with ibrutinib was well tolerated and elicited a deeper response. These results support the potential role of a sequential therapeutic strategy in CLL, where the addition of a consolidation with mAbs in patients with low tumor burden might improve the quality of the response. Finally, more mature results will be further presented at the meeting. Disclosures Abrisqueta: Roche: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau. González-Barca:Kiowa: Consultancy; Celgene: Consultancy; Takeda: Honoraria; AbbVie: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celtrion: Consultancy. Terol:Roche: Consultancy; Janssen: Consultancy, Research Funding; Abbvie: Consultancy; Astra Zeneca: Consultancy; Gilead: Research Funding. Baltasar Tello:GILEAD: Honoraria; JANSSEN: Consultancy, Honoraria; ABBVIE: Honoraria; ROCHE: Honoraria. de la Serna:Roche, AbbVie, Gilead, Janssen, Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche, AbbVie, Janssen, Gilead: Speakers Bureau. Ramirez Payer:GILEAD SCIENCES: Research Funding. Cordoba:Janssen: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Speakers Bureau; Kyowa-Kirin: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Research Funding, Speakers Bureau; Roche: Honoraria, Speakers Bureau; FUNDACION JIMENEZ DIAZ UNIVERSITY HOSPITAL: Employment; Celgene: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy. Bosch:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. OffLabel Disclosure: Ibrutinib followed by Ofatumumab Consolidation

© 2018 The Authors., [Background]: The present prospective, multinational, noninterventional study aimed to document and describe real-world treatment regimens and disease progression in multiple myeloma (MM) patients. [Patients and Methods]: Adult patients initiating any new MM therapy from October 2010 to October 2012 were eligible. A multistage patient/site recruitment model was applied to minimize the selection bias; enrollment was stratified by country, region, and practice type. The patient medical and disease features, treatment history, and remission status were recorded at baseline, and prospective data on treatment, efficacy, and safety were collected electronically every 3 months., [Results]: A total of 2358 patients were enrolled. Of these patients, 775 and 1583 did and did not undergo stem cell transplantation (SCT) at any time during treatment, respectively. Of the patients in the SCT and non-SCT groups, 49%, 21%, 14%, and 15% and 57%, 20%, 12% and 10% were enrolled at treatment line 1, 2, 3, and ≥ 4, respectively. In the SCT and non-SCT groups, 45% and 54% of the patients had received bortezomib-based therapy without thalidomide/lenalidomide, 12% and 18% had received thalidomide/lenalidomide-based therapy without bortezomib, and 30% and 4% had received bortezomib plus thalidomide/lenalidomide-based therapy as frontline treatment, respectively. The corresponding proportions of SCT and non-SCT patients in lines 2, 3, and ≥ 4 were 45% and 37%, 30% and 37%, and 12% and 3%, 33% and 27%, 35% and 32%, and 8% and 2%, and 27% and 27%, 27% and 23%, and 6% and 4%, respectively. In the SCT and non-SCT patients, the overall response rate was 86% to 97% and 64% to 85% in line 1, 74% to 78% and 59% to 68% in line 2, 55% to 83% and 48% to 60% in line 3, and 49% to 65% and 36% and 45% in line 4, respectively, for regimens that included bortezomib and/or thalidomide/lenalidomide., [Conclusion]: The results of our prospective study have revealed great diversity in the treatment regimens used to manage MM in real-life practice. This diversity was linked to factors such as novel agent accessibility and evolving treatment recommendations. Our results provide insight into associated clinical benefits., Writing support during the development of our report was provided by Laura Mulcahy and Catherine Crookes of FireKite, an Ashfield company, a part of UDG Healthcare plc, which was funded by Millennium Pharmaceuticals, Inc, and Janssen Global Services, LLC. The EMMOS study was supported by research funding from Janssen Pharmaceutical NV and Millennium Pharmaceuticals, Inc.

International audience; BACKGROUND: Venetoclax inhibits BCL2, an antiapoptotic protein that is pathologically overexpressed and that is central to the survival of chronic lymphocytic leukemia cells. We evaluated the efficacy of venetoclax in combination with rituximab in patients with relapsed or refractory chronic lymphocytic leukemia. METHODS: In this randomized, open-label, phase 3 trial, we randomly assigned 389 patients to receive venetoclax for up to 2 years (from day 1 of cycle 1) plus rituximab for the first 6 months (venetoclax-rituximab group) or bendamustine plus rituximab for 6 months (bendamustine-rituximab group). The trial design did not include crossover to venetoclax plus rituximab for patients in the bendamustine-rituximab group in whom progression occurred. The primary end point was investigator-assessed progression-free survival. RESULTS: After a median follow-up period of 23.8 months, the rate of investigator-assessed progression-free survival was significantly higher in the venetoclax-rituximab group (32 events of progression or death in 194 patients) than in the bendamustine-rituximab group (114 events in 195 patients); the 2-year rates of progression-free survival were 84.9% and 36.3%, respectively (hazard ratio for progression or death, 0.17; 95% confidence interval [CI], 0.11 to 0.25; P\textless0.001 by the stratified log-rank test). The benefit was maintained across all clinical and biologic subgroups, including the subgroup of patients with chromosome 17p deletion; the 2-year rate of progression-free survival among patients with chromosome 17p deletion was 81.5% in the venetoclax-rituximab group versus 27.8% in the bendamustine-rituximab group (hazard ratio, 0.13; 95% CI, 0.05 to 0.29), and the 2-year rate among those without chromosome 17p deletion was 85.9% versus 41.0% (hazard ratio, 0.19; 95% CI, 0.12 to 0.32). The benefit of venetoclax plus rituximab over bendamustine plus rituximab was confirmed by an independent review committee assessment of progression-free survival and other secondary efficacy end points. The rate of grade 3 or 4 neutropenia was higher in the venetoclax-rituximab group than in the bendamustine-rituximab group, but the rates of grade 3 or 4 febrile neutropenia and infections or infestations were lower with venetoclax than with bendamustine. The rate of grade 3 or 4 tumor lysis syndrome in the venetoclax-rituximab group was 3.1% (6 of 194 patients). CONCLUSIONS: Among patients with relapsed or refractory chronic lymphocytic leukemia, venetoclax plus rituximab resulted in significantly higher rates of progression-free survival than bendamustine plus rituximab. (Funded by Genentech and AbbVie; ClinicalTrials.gov number, NCT02005471 .).

We report data from a prospective, observational study (ZAGAL) evaluating miglustat 100mg three times daily orally. in treatment-naïve patients and patients with type 1 Gaucher Disease (GD1) switched from previous enzyme replacement therapy (ERT). Clinical evolution, changes in organ size, blood counts, disease biomarkers, bone marrow infiltration (S-MRI), bone mineral density by broadband ultrasound densitometry (BMD), safety and tolerability annual reports were analysed. Between May 2004 and April 2016, 63 patients received miglustat therapy; 20 (32%) untreated and 43 (68%) switched. At the time of this report 39 patients (14 [36%] treatment-naïve; 25 [64%] switch) remain on miglustat. With over 12-year follow-up, hematologic counts, liver and spleen volumes remained stable. In total, 80% of patients achieved current GD1 therapeutic goals. Plasma chitotriosidase activity and CCL-18/PARC concentration showed a trend towards a slight increase. Reductions on S-MRI (p=0.042) with an increase in BMD (p

PI3Kδ (idelalisib) and BTK (ibrutinib) inhibitors have demonstrated significant clinical activity in chronic lymphocytic leukemia (CLL) interfering with the cross-talk between CLL cells and the lymph node microenviroment, yet their mechanism of action remains to be fully elucidated. Here, we developed an ex vivo model with the aim of reproducing the effects of the microenvironment that would help shed light on the in vivo mechanism of action of idelalisib and ibrutinib and predict their clinical efficacy in individual patients. First we explored the effects of various cell-extrinsic elements on CLL apoptosis and proliferation and found that the combination of CpG+IL2+HS5 stromal cell line + human serum +CLL plasma and erythrocyte fractions represented the best co-culture conditions to test the effects of the novel inhibitors. Then, using this assay, we investigated the impact of idelalisib and ibrutinib on both survival and proliferation in 30 CLL patients. While both drugs had a limited direct pro-apoptotic activity, a potent inhibition of proliferation was achieved at clinically achievable concentrations. Notably, up to 10% of CLL cells still proliferated even at the highest concentrations, likely mirroring the known difficulty to achieve complete responses in vivo. Altogether, this novel assay represents an appropriate ex vivo drug testing system to potentially predict the clinical response to novel inhibitors in particular by quantifying the antiproliferative effect., This work was supported in part by H2020 “MEDGENET, Medical Genomics and Epigenomics Network” (Grant 692298), funded by the European Union; the Swedish Cancer Society, the Swedish Research Council, and Lion’s Cancer Research Foundation; Associazione Italiana per la Ricerca sul Cancro AIRC (Investigator Grant #20246 to PG and Special Program Molecular Clinical Oncology - 5 per mille #9965), Milano, Italy, Ricerca; ERA-NET TRANSCAN-2 JTC 2016, GCH-CLL. Vivia has received unrestricted research support from Gilead.

Background Patients with hematologic malignancies treated with anticancer immunosuppressive therapies (ITs) are at increased risk of herpes zoster (HZ). In a previous report of this phase 3, observer-blind, multicenter trial (NCT01767467), the adjuvanted recombinant zoster vaccine (RZV) was shown to be immunogenic and well-tolerated in ≥18 years of age patients with hematologic malignancies who completed or were undergoing anticancer IT.1 Here we report end-of-study results from the same trial. Methods Participants were randomized 1:1 to receive 2 doses of RZV or placebo (PL) 1–2 months apart, either ≥10 days before or after a cancer therapy cycle, or 10 days to 6 months after cancer therapy ended. Humoral and cell-mediated immune (CMI) responses were evaluated at 1 month and 12 months post-dose 2 (month 2 and month 13, respectively). Confirmatory objectives were to evaluate humoral response rate to RZV and to compare humoral immune responses to RZV and PL at month 2 excluding either subjects with chronic lymphocytic leukemia and non-Hodgkin B-cell lymphoma (NHBCL), or only those with NHBCL. Efficacy against HZ was explored in a post-hoc analysis of confirmed HZ cases. Solicited and unsolicited adverse events (AEs) were recorded for 7 and 30 days after each dose, respectively. Serious AEs (SAEs) and potential immune-mediated diseases (pIMDs) were recorded throughout the study. Results Of the 562 (RZV: 283, PL: 279) treated participants, 415 (RZV: 217, PL: 198)/310 (RZV: 168, PL: 142) were included in the according-to-protocol (ATP) cohort for humoral immunogenicity/immune persistence. The ATP sub-cohort for CMI included 132 (RZV: 69, PL: 63) participants at month 2 and 100 (RZV: 54, PL: 46) at month 13. All confirmatory immunogenicity objectives were met (Table 1). RZV efficacy against HZ, assessed post-hoc, was 87.2% (Table 2). RZV was more reactogenic than PL. The occurrence of unsolicited AEs, SAEs, and pIMDs was similar between the study groups (Table 3). Conclusion RZV induced robust humoral and cellular immune responses and showed an effect in the reduction of HZ incidence in patients with hematologic malignancies who completed or were undergoing anticancer IT. No safety concerns were identified. Reference 1. Oostvogels et al. IDWeek2017, abs 1344. Funding. GlaxoSmithKline Biologicals SA. Disclosures A. F. Dagnew, GSK: Employee and Shareholder, Salary. J. Murphy, GSK: Investigator, Research support. S. A. McNeil, GSK group of companies: Grant Investigator, Research grant and Research support. B. Salaun, GSK group of companies: Employee and Shareholder, Salary. E. Di Paolo, GSK group of companies: Employee, Salary. L. Campora, GSK group of companies: Employee and Shareholder, Salary. M. López-Fauqued, GSK group of companies: Employee, Salary. M. El Idrissi, GSK group of companies: Employee, Salary. A. Schuind, GSK: Employee, Salary. T. C. Heineman, GSK group of companies: Consultant, Employee and Shareholder, Consulting fee and Salary. P. Van Den Steen, GSK: Employee and Shareholder, Restricted shares and Salary. L. Oostvogels, GSK: Employee, Salary and Stock and stock options.

ResumenObjetivosEvaluar el coste-efectividad del esquema de rituximab, fludarabina y ciclofosfamida (R-FC) en comparación con el de fludarabina y ciclofosfamida (FC) en dos tipos de pacientes con leucemia linfática crónica (LLC): no tratados previamente o bien en recidiva/resistentes al tratamiento previo.MétodosDos modelos de Markov, utilizando los resultados publicados de superviviencia libre de progresión (SLP) de pacientes con LLC tratados con R-FC o FC en primera o segunda línea, las tasas de progresión de la enfermedad y las tasas de mortalidad en España. A los estados de SLP y progresión se les asignaron utilidades obtenidas en un estudio sobre LLC. Los costes de los medicamentos y de los tratamientos de soporte, así como los años de vida ajustados por calidad (AVAC), se estimaron para un periodo de 10 años. Se efectuaron análisis de sensibilidad univariados y probabilísticos (Monte Carlo).ResultadosLa adición de rituximab a la quimioterapia con FC aumentó los años de vida ganados (AVG) y los AVAC tanto en primera como en segunda línea de tratamiento. La razón de coste-eficacia incremental fue de 20.703 € por AVG y de 19.343 € por AVAC con la primera línea de tratamiento, y de 23.183 € por AVG y 24.781 € por AVAC con la segunda línea de tratamiento.ConclusionesEn los pacientes con LLC no tratados previamente y en aquellos en recaída o resistentes al tratamiento previo, la adición de rituximab al esquema FC aumentó la esperanza de vida y los AVAC, y en ambos casos resultó ser un tratamiento coste-efectivo.AbstractObjectivesWe evaluated the cost-effectiveness of rituximab added to the chemotherapy regimen of fludarabine plus cyclophosphamide (R-FC) versus fludarabine plus cyclophosphamide (FC) for the treatment of patients with previously untreated or relapsed/refractory chronic lymphocytic leukemia (CLL).MethodsTwo Markov models were built, using published results on progression-free survival (PFS) in patients receiving first- or second-line therapy with R-FC vs FC, rates of disease progression and mortality rates in Spain. Patient-elicited utilities were applied to PFS and progressed health states. The cost of drugs, supportive care, and quality-adjusted life years (QALY) were estimated over a 10-year period. Univariate and probabilistic (Monte Carlo) sensitivity analyses were performed.ResultsThe addition of rituximab to chemotherapy in first- and second-line therapy increased life-years gained (LYG) and QALYs compared with chemotherapy. The incremental cost per LYG and QALY gained was €20,703 and €19,343 for first-line treatment and was €23,183 and €24,781 for second-line treatment.ConclusionIn patients with previously untreated or relapsed/refractory CLL, the addition of rituximab to the FC regimen increased life expectancy and quality-adjusted life expectancy. In both types of patient, the treatment was cost-effective.

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.

Introduction: In the CLL11 study, obinutuzumab (G) plus chlorambucil (Clb; G-Clb) significantly improved outcomes relative to rituximab plus Clb and Clb alone in previously untreated patients (pts) with chronic lymphocytic leukemia (CLL) and comorbidities, but was associated with an increased incidence and severity of infusion-related reactions (IRRs), cytopenias and treatment discontinuations (Goede et al. N Engl J Med 2014; Goede et al. EHA 2018). IRRs have been associated with the release of pro-inflammatory cytokines, including interleukin-6 (IL-6; Freeman et al. Blood 2015). Tocilizumab (TCZ) is a monoclonal antibody that blocks downstream signaling by IL-6. It has regulatory approval (FDA/EMA) for the treatment of chimeric antigen receptor T-cell induced cytokine release syndrome, and could potentially be used to limit the IRRs associated with G administration. GALACTA was a randomized, double-blind, Phase Ib trial in previously untreated pts with CLL and co-morbidities (NCT02336048). Its primary objective was to determine the safety and tolerability of TCZ prior to G-Clb. Secondary endpoints included pharmacokinetics and pharmacodynamics of TCZ in this population, and impact on the efficacy of the G-CIb combination. Methods: Previously untreated CLL pts who were unsuitable for more intensive therapy (CIRS score >6 or creatinine clearance 50x109/L) and mean fluorescence intensity of CD20 on CLL-gated cells. G-CIb was administered as: G 1000mg IV on D1/D2 (100mg/900mg), D8 and D15 of C1, and D1 of C2-6; Clb 0.5mg/kg PO on D1 and D15 of C1-6. Prior to the first G dose in C1, standard premedication (antipyretic, antihistamine, corticosteroids) was administered in addition to TCZ or PLB. IRR was defined as any adverse event (AE) occurring during or within 24 hours of G infusion and judged by the investigator as related to G. Results: A total of 38 pts were enrolled between June 26, 2015 and Jan 22, 2018; 25 were randomized to TCZ and 13 to PLB. Median age was 74 years (range 54-87), 63% were male, 95% had ECOG PS 0-1, and 95% had Binet stage B/C disease. Baseline characteristics were well balanced, with the exception of more males in the TCZ arm (72%) than the PLB arm (46%). Despite a similar proportion of baseline ALC ≤50 versus >50x109/L in the two treatment arms, more pts in the TCZ arm had levels which were >100x109/L (15% in PLB vs 28% in TCZ). At the time of analysis, 25 pts had completed all 6 cycles, 6 remained on treatment, and 7 had discontinued. IRRs occurred in 18/25 (72%) pts in the TCZ arm and 10/13 (77%) in the PLB arm. Grade ≥3 IRRs occurred in 11/25 (44%) pts in the TCZ arm and 4/13 (31%) pts in the PLB arm. Four pts discontinued treatment due to IRRs: 3 (12%) in the TCZ arm and 1 (8%) in the PLB arm. Similar to previous reports, cytokine levels peaked on D1 after 100mg G had been administered. Serum amyloid A (Figure 1) and C-reactive protein (CRP) (Figure 2) were sub-optimally reduced in the TCZ arm. Of the 19 pts with measurable TCZ levels, no marked differences in exposure were seen based on IRR intensity. However, TCZ exposure was lower on average than in rheumatoid arthritis pts of equivalent weight treated with the same dose (mean Cmax 154 vs 193µg/mL), and TCZ-treated pts that developed IRRs had comparatively less suppression of CRP than those who did not. Conclusions: Preliminary results suggest that use of a single 8mg/kg dose of TCZ prior to the first dose of G was feasible, but did not appear to prevent IRRs in this pt population. The study was primarily designed to assess the safety of the combination, and was underpowered to detect meaningful differences between groups in IRR severity. TCZ-treated pts who developed IRRs had higher baseline risk than those who did not, and the TCZ dose may have been insufficient, resulting in the lack of efficacy. Whether inhibition of this pro-survival cytokine enhances the cytotoxic potential of the regimen is not yet determined; updated results will be presented at the meeting. Disclosures Freeman: Seattle Genetics: Honoraria; Abbvie: Honoraria. Böttcher:Celgene: Research Funding; Genentech: Research Funding; AbbVie: Honoraria, Research Funding; Janssen: Honoraria; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. 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. Gobbi:Novartis: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Janssen: Consultancy; Pfister: Membership on an entity's Board of Directors or advisory committees. Di Bernardo:Roche: Employment. Mallalieu:Roche: Employment, Equity Ownership. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Other: Ownership interests PLC. Knapp:Roche: Employment. Gribben:Janssen: Honoraria, Research Funding; Abbvie: Honoraria; Acerta Pharma: Honoraria, Research Funding; TG Therapeutics: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Medical Research Council: Research Funding; Novartis: Honoraria; Kite: Honoraria; Cancer Research UK: Research Funding; Pharmacyclics: Honoraria; Unum: Equity Ownership; Roche: Honoraria; Wellcome Trust: Research Funding; NIH: Research Funding.

Background: Characteristics and outcome of older patients (pts) with acute promyelocytic leukemia (APL) are unclear due to lack of clinical data. Aims: To describe a large series of older APL pts and compare outcome according to treatment strategy. Methods: We retrospectively studied 475 APL pts (median age, 73.8 yrs; range, 70-90.3 yrs), treated between 1990 and 2018 within four study groups/institutions of the US and Europe (Acute Leukemia French Association, n=228; Programa Espanol de Tratamientos en Hematologia, n=211; Study Alliance Leukemia, n=28; Johns Hopkins School of Medicine, Baltimore, n=8). APL was confirmed either by cytogenetics, fluorescence in situ hybridization and/or polymerase chain reaction. For analysis, pts were grouped according to treatment: i) chemotherapy/all-trans retinoic acid (CTX/ATRA, n=260; consisting of daunorubicin/idarubicin and ATRA for induction and different CTXs+ATRA for consolidation), ii) ATO/ATRA±CTX, n=177 (according to Lo-Coco F, et al. NEJM, 2013, n=23 or CTX/ATO/ATRA, n=154), iii) less intensive therapy, n=26 (reduced CTX, n=2 or ATRA only, n=24) and iv) no treatment/unknown, n=12. Results: Median white blood cell (WBC) and platelet counts at diagnosis were 1.5/nl (range, 0.1-242/nl) and 37/nl (range, 2-261/nl), respectively. Two-hundred twenty-nine pts (48%) were female. Cytogenetic analysis was available in 408 pts and 85 (21%) had additional abnormalities. BCR3 was positive in 138 (44%) of 316 available pts. Only 15 (22%) of 69 tested pts were FLT3-ITD positive. One hundred (22%) of 464 pts had a WBC count >10/nl. Median WBC was significantly lower (P Complete remission (CR) after induction therapy was achieved in 75% (194/259) of the CTX/ATRA group, in 93% (162/174) of the ATO/ATRA±CTX group, and in 50% (13/26) of the less intensive group. Two pts of the CTX/ATRA group and one patient after ATRA only were refractory. Early death rates were 24% (n=63) after CTX/ATRA, 7% (n=12) after ATO/ATRA±CTX and 46% (n=12) in the less intensive group. A logistic regression model revealed age above 75 yrs (odds ratio [OR], 0.53; P=0.02) higher WBC (OR, 0.35; P10/nl) was associated with an inferior RFS in CTX/ATRA (P10/nl; hazard ratio [HR], 2.36; P75 yrs (HR, 2.07; P Conclusions: The ATO-based regimen for first line treatment of elderly APL pts was associated with excellent and sustained response rates. Our data demonstrate the important potential of ATO/ATRA in the primary management of older APL pts. Disclosures Fenaux: Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Jazz: Honoraria, Research Funding. Schlenk:Pfizer: Research Funding, Speakers Bureau. Platzbecker:Celgene: Research Funding. Montesinos:Novartis: Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Speakers Bureau.

Background Acute promyelocytic leukemia is a subtype of acute myeloid leukemia characterized by the t(15;17). The incidence and prognostic significance of additional chromosomal abnormalities in acute promyelocytic leukemia is still a controversial matter. Design and Methods Based on cytogenetic data available for 495 patients with acute promyelocytic leukemia enrolled in two consecutive PETHEMA trials (LPA96 and LPA99), we analyzed the incidence, characteristics, and outcome of patients with acute promyelocytic leukemia with and without additional chromosomal abnormalities who had been treated with all-trans retinoic acid plus anthracycline monochemotherapy for induction and consolidation. Results Additional chromosomal abnormalities were observed in 140 patients (28%). Trisomy 8 was the most frequent abnormality (36%), followed by abn(7q) (5%). Patients with additional chromosomal abnormalities more frequently had coagulopathy (P=0.03), lower platelet counts (P=0.02), and higher relapse-risk scores (P=0.02) than their counterparts without additional abnormalities. No significant association with FLT3/ITD or other clinicopathological characteristics was demonstrated. Patients with and without additional chromosomal abnormalities had similar complete remission rates (90% and 91%, respectively). Univariate analysis showed that additional chromosomal abnormalities were associated with a lower relapse-free survival in the LPA99 trial (P=0.04), but not in the LPA96 trial. However, neither additional chromosomal abnormalities overall nor any specific abnormality was identified as an independent risk factor for relapse in multivariate analysis. Conclusions The lack of independent prognostic value of additional chromosomal abnormalities in acute promyelocytic leukemia does not support the use of alternative therapeutic strategies when such abnormalities are found.

Purpose We analyzed the incidence, risk factors, and outcome of therapy-related myeloid neoplasms (t-MNs) in patients with acute promyelocytic leukemia (APL) in first complete remission (CR). Patients and Methods From 1996 to 2008, 1,025 patients with APL were enrolled onto three sequential trials (LPA96, LPA99, and LPA2005) of the Programa Español para el Tratamiento de Enfermedades Hematológicas and received induction and consolidation therapy with all-trans-retinoic acid (ATRA) and anthracycline-based chemotherapy. Results Seventeen of 918 patients who achieved CR developed t-MN (10 with < 20% and seven with ≥ 20% of bone marrow blasts) after a median of 43 months from CR. Partial and complete deletions of chromosomes 5 and 7 (nine patients) and 11q23 rearrangements (three patients) were the most common cytogenetic abnormalities. Overall, the 6-year cumulative incidence of t-MN was 2.2%, whereas in low-, intermediate-, and high-risk patients, the 6-year incidence was 5.2%, 2.1%, and 0%, respectively. Multivariate analysis identified age more than 35 years and lower relapse risk score as independent prognostic factors for t-MN. The median overall survival time after t-MN was 10 months. Conclusion t-MN is a relatively infrequent, long-term, and severe complication after first-line treatment for APL with ATRA and anthracycline-based regimens. Therapeutic strategies to reduce the incidence of t-MN are warranted.

Differentiation syndrome (DS) can be a life-threatening complication in patients with acute promyelocytic leukemia (APL) undergoing induction therapy with all-trans retinoic acid ( ATRA). Detailed knowledge about DS has remained limited. We present an analysis of the incidence, characteristics, prognostic factors, and outcome of 739 APL patients treated with ATRA plus idarubicin in 2 consecutive trials (Programa Espanol de Tratamientos en Hematologa [PETHEMA] LPA96 and LPA99). Overall, 183 patients (24.8%) experienced DS, 93 with a severe form (12.6%) and 90 with a moderate form (12.2%). Severe but not moderate DS was associated with an increase in mortality. A bimodal incidence of DS was observed, with peaks occurring in the first and third weeks after the start of ATRA therapy. A multivariate analysis indicated that a WBC count greater than 5 x 10(9)/L and an abnormal serum creatinine level correlated with an increased risk of developing severe DS. Patients receiving systematic prednisone prophylaxis (LPA99 trial) in contrast to those receiving selective prophylaxis with dexamethasone (LPA96 trial) had a lower incidence of severe DS. Patients developing severe DS showed a reduced 7-year relapse-free survival in the LPA96 trial (60% vs 85%, P = .003), but this difference was not apparent in the LPA99 trial (86% vs 88%). (Blood. 2009; 113: 775-783)

A previous report of the Programa de Estudio y Tratamiento de las Hemopatías Malignas (PETHEMA) Group showed that a risk-adapted strategy combining all-trans retinoic acid (ATRA) and anthracycline monochemotherapy for induction and consolidation in newly diagnosed acute promyelocytic leukemia results in an improved outcome. Here we analyze treatment outcome of an enlarged series of patients who have been followed up for a median of 65 months. From November 1999 through July 2005 (LPA99 trial), 560 patients received induction therapy with ATRA plus idarubicin. Patients achieving complete remission received 3 courses of consolidation followed by maintenance with ATRA and low-dose chemotherapy. The 5-year cumulative incidence of relapse and disease-free survival were 11% and 84%, respectively. These results compare favorably with those obtained in the previous LPA96 study (P = .019 and P = .04, respectively). This updated analysis confirms the high antileukemic efficacy, low toxicity, and high degree of compliance of a risk-adapted strategy combining ATRA and anthracycline monochemotherapy for consolidation therapy.

An understanding of the prognostic factors associated with the various forms of induction mortality in patients with acute promyelocytic leukemia (APL) has remained remarkably limited. This study reports the incidence, time of occurrence, and prognostic factors of the major categories of induction failure in a series of 732 patients of all ages (range, 2-83 years) with newly diagnosed APL who received all-trans retinoic acid (ATRA) plus idarubicin as induction therapy in 2 consecutive studies of the Programa de Estudio y Tratamiento de las Hemopatias Malignas (PETHEMA) Group. Complete remission was attained in 666 patients (91%). All the 66 induction failures were due to induction death. Hemorrhage was the most common cause of induction death (5%), followed by infection (2.3%) and differentiation syndrome (1.4%). Multivariate analysis identified specific and distinct pretreatment characteristics to correlate with an increased risk of death caused by hemorrhage (abnormal creatinine level, increased peripheral blast counts, and presence of coagulopathy), infection (age >60 years, male sex, and fever at presentation), and differentiation syndrome (Eastern Cooperative Oncology Group [ECOG] score >1 and low albumin levels), respectively. These data furnish clinically relevant information that might be useful for designing more appropriately risk-adapted treatment protocols aimed at reducing the considerable problem of induction mortality in APL.

A multicentre, cross-sectional epidemiological survey was conducted to describe the health status of patients with type 1 Gaucher disease (GD1) in Spain. Patient data were collected retrospectively from clinical records. Therapeutic goals for seven clinical parameters were chosen as primary outcome measures. 108 GD1 patients (mean age 44.8years; 53% male) were recruited from 28 hospitals. Ninety-five patients (88%) were receiving treatment for GD1. Hemoglobin concentration was the therapeutic goal with the highest level of achievement, being met by 105 of 108 patients (97%), followed by the goals for liver volume (86/98 patients; 88%), spleen volume (67/77 patients; 87%) and platelet count (81/108 patients; 75%). The goal for bone mineral density (BMD) was met by 48 of 75 patients (64%), and the goal for quality of life was met by 65 of 103 patients (63%). Bone pain was the parameter with the lowest level of achievement (goal met by 50/94 patients; 53%). The clinical information most often missing from patient records was the BMD Z-score (missing for 31% of patients). These data suggest that most Spanish GD1 patients have good control over hematological and visceral parameters, but there is a need to improve monitoring and treatment of GD-related bone disease.

Front-line treatment of acute promyelocytic leukaemia (APL) consists of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy. In this setting, a comparison of idarubicin and daunorubicin has never been carried out. Two similar clinical trials using ATRA and chemotherapy for newly diagnosed APL were compared using matched-pair analysis. One was conducted by the PETHEMA/HOVON group with idarubicin and the other by the International Consortium on APL (IC-APL) using daunorubicin. Three hundred and fifty patients from the PETHEMA/HOVON cohort were matched with 175 patients in the IC-APL cohort, adjusting for the significantly unbalanced presenting features of the two entire cohorts. Complete remission (CR) rate was significantly higher in the PETHEMA/HOVON (94 %) than in the IC-APL cohort (85 %) (P = 0.002). The distribution of causes of induction failure and the time to achieve CR were similar in both cohorts. Patients who achieved CR had comparable cumulative incidence of relapse and disease-free survival rates, but lower overall and event-free survivals were observed in the IC-APL cohort, which was mainly due to a higher death rate during induction therapy. A higher death rate during consolidation therapy was also observed in the IC-APL. These results show that daunorubicin and idarubicin have similar antileukaemic efficacy in terms of primary resistance, molecular persistence, as well as molecular and haematological relapse rates when combined with ATRA in treatment of APL. However, a higher toxic death rate during induction and consolidation therapy was observed in the IC-APL cohort. This trial was registered at www.clinicaltrials.gov as #NCT00408278 [ClinicalTrials.gov].