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Previous studies have shown that patients with chronic lymphocytic leukemia (CLL) and coronavirus disease 2019 (COVID-19) have high mortality rates. Infection with the Omicron variant has been described as a milder disease course in the general population. However, the outcome for immunocompromised patients has not previously been reported. In a cohort of patients with CLL tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at hospital test sites in the time periods before and after dominance of the Omicron variant, rates of hospitalizations and intensive care unit admissions declined significantly, whereas 30-day mortality remained as high as 23% in the period with dominance of the Omicron sublineage BA.2 variant. However, for a larger population-based cohort of patients with CLL (including the hospital cohort), 30-day mortality was 2%. Thus, patients with CLL with close hospital contacts and, in particular, those >70 years of age with 1 or more comorbidities should be considered for closer monitoring and preemptive antiviral therapy upon a positive SARS-CoV-2 test.

BACKGROUNDRandomized trials of venetoclax plus anti-CD20 antibodies as first-line treatment in fit patients (i.e., those with a low burden of coexisting conditions) with advanced chronic lymphocytic leukemia (CLL) have been lacking.METHODSIn a phase 3, open-label trial, we randomly assigned, in a 1:1:1:1 ratio, fit patients with CLL who did not have TP53 aberrations to receive six cycles of chemoimmunotherapy (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab) or 12 cycles of venetoclax-rituximab, venetoclax-obinutuzumab, or venetoclax-obinutuzumab-ibrutinib. Ibrutinib was discontinued after two consecutive measurements of undetectable minimal residual disease or could be extended. The primary end points were undetectable minimal residual disease (sensitivity, RESULTSA total of 926 patients were assigned to one of the four treatment regimens (229 to chemoimmunotherapy, 237 to venetoclax-rituximab, 229 to venetoclax-obinutuzumab, and 231 to venetoclax-obinutuzumab-ibrutinib). At month 15, the percentage of patients with undetectable minimal residual disease was significantly higher in the venetoclax-obinutuzumab group (86.5%; 97.5% confidence interval [CI], 80.6 to 91.1) and the venetoclax-obinutuzumab-ibrutinib group (92.2%; 97.5% CI, 87.3 to 95.7) than in the chemoimmunotherapy group (52.0%; 97.5% CI, 44.4 to 59.5; PCONCLUSIONSVenetoclax-obinutuzumab with or without ibrutinib was superior to chemoimmunotherapy as first-line treatment in fit patients with CLL. (Funded by AbbVie and others; GAIA-CLL13 ClinicalTrials.gov number, NCT02950051; EudraCT number, 2015-004936-36.) BACKGROUNDRandomized trials of venetoclax plus anti-CD20 antibodies as first-line treatment in fit patients (i.e., those with a low burden of coexisting conditions) with advanced chronic lymphocytic leukemia (CLL) have been lacking.METHODSIn a phase 3, open-label trial, we randomly assigned, in a 1:1:1:1 ratio, fit patients with CLL who did not have TP53 aberrations to receive six cycles of chemoimmunotherapy (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab) or 12 cycles of venetoclax-rituximab, venetoclax-obinutuzumab, or venetoclax-obinutuzumab-ibrutinib. Ibrutinib was discontinued after two consecutive measurements of undetectable minimal residual disease or could be extended. The primary end points were undetectable minimal residual disease (sensitivity, RESULTSA total of 926 patients were assigned to one of the four treatment regimens (229 to chemoimmunotherapy, 237 to venetoclax-rituximab, 229 to venetoclax-obinutuzumab, and 231 to venetoclax-obinutuzumab-ibrutinib). At month 15, the percentage of patients with undetectable minimal residual disease was significantly higher in the venetoclax-obinutuzumab group (86.5%; 97.5% confidence interval [CI], 80.6 to 91.1) and the venetoclax-obinutuzumab-ibrutinib group (92.2%; 97.5% CI, 87.3 to 95.7) than in the chemoimmunotherapy group (52.0%; 97.5% CI, 44.4 to 59.5; PCONCLUSIONSVenetoclax-obinutuzumab with or without ibrutinib was superior to chemoimmunotherapy as first-line treatment in fit patients with CLL. (Funded by AbbVie and others; GAIA-CLL13 ClinicalTrials.gov number, NCT02950051; EudraCT number, 2015-004936-36.)

Patients with chronic lymphocytic leukaemia (CLL) have an increased risk of new malignancies. However, limited data have been published about the impact of CLL treatment on this risk. Here we followed a Danish population-based cohort of CLL patients for risks of new malignancies. Patients in the Danish CLL registry (2008–2017) were included. Up to 50 CLL-free matched comparators were identified. First-line treatment was categorized into four groups; bendamustine, chlorambucil, fludarabine or other. Patients were followed from CLL diagnosis for individual types of malignancy. Adjusted hazard ratios (HR) for new malignancies and 95% confidence intervals (95% CI) were calculated. Overall, 4286 CLL patients and 214 150 controls developed 594 and 20 565 new malignancies respectively. Risk of new malignancies was increased for CLL patients. Chemotherapy treatment was registered for 1064 (25%) patients with CLL. Chemotherapy was associated with increased HR (1·51, 95% CI: 1·3–1·8) of any new malignancy. Specifically, fludarabine was associated with an increased risk of myelodysplastic syndrome (MDS) (HR 4·93, 95% CI: 1·2–19·8). Patients with CLL are at increased risk of other haematological and solid malignancies compared to the general population. Chemotherapy exposure is associated with increased risk of second malignancies and fludarabine is associated with increased risk of MDS.

Previous studies have shown that patients with chronic lymphocytic leukemia (CLL) and coronavirus disease 2019 (COVID-19) have high mortality rates. The omicron variant has been reported to give milder disease in the general population, but outcomes of infections with the omicron variant among immunocompromised patients have not previously been reported. In a population-based cohort we assessed rates of hospitalizations, ICU-admissions, and 30-day all-cause mortality among all patients with CLL from Eastern Denmark testing positive for severe adult respiratory syndrome coronavirus 2 (SARS-CoV-2) in time periods before and after dominance of the omicron variant. Rates of hospitalizations and ICU-admissions declined significantly, whereas 30-day mortality remained as high as 23% in the period with dominance of the omicron sublineage BA.2 variant. Thus, patients with CLL in general and in particular those above 70 years of age with one or more comorbidities should be considered for closer monitoring and pre-emptive antiviral therapy upon a positive SARS-CoV-2 test.Key pointsThe omicron variant of COVID-19 leads to high fatality rates in CLL, despite milder disease in the background populationPatients with CLL who test positive for SARS-CoV-2 in the era of the omicron variant should be considered for pre-emptive antiviral therapyExplanation of noveltyThe omicron variant has been reported to give milder disease in the general population, but outcomes of infections with the omicron variant among immunocompromised patients have not previously been reported. These population-based data on outcome for patients with CLL upon infection with the omicron variant of SARS-CoV-2 warrants closer monitoring and pre-emptive antiviral therapy upon a positive SARS-CoV-2 test for patients with CLL.

Purpose: Investigation of signaling pathways altered by recurrent gene mutations and their clinical impact in a consecutive cohort of patients with newly diagnosed chronic lymphocytic leukemia (CLL). The heterogeneous clinical course and genetic complexity of CLL warrant improved molecular prognostication. However, the prognostic value of recurrent mutations at the time of diagnosis remains unclear. Experimental Design: We sequenced samples from 314 consecutive, newly diagnosed patients with CLL to investigate the clinical impact of 56 recurrently mutated genes assessed by next-generation sequencing. Results: Mutations were identified in 70% of patients with enrichment among IGHV unmutated cases. With 6.5 years of follow-up, 15 mutated genes investigated at the time of diagnosis demonstrated significant impact on time to first treatment (TTFT). Carrying driver mutations was associated with shorter TTFT and poor overall survival. For outcome from CLL diagnosis, the number of signaling pathways altered by driver mutations stratified patients better than the number of driver mutations. Moreover, we demonstrated gradual impact on TTFT with increasing number of altered pathways independent of CLL-IPI risk. Thus, a 25-gene, pathway-based biomarker assessing recurrent mutations refines prognostication in CLL, in particular for CLL-IPI low- and intermediate-risk patients. External validation emphasized that a broad gene panel including low burden mutations was key for the biomarker based on altered pathways. Conclusions: We propose to include the number of pathways altered by driver mutations as a biomarker together with CLL-IPI in prospective studies of CLL from time of diagnosis for incorporation into clinical care and personalized follow-up and treatment.

Emelie C Rotbain,1– 5 Klaus Rostgaard,3,5 Michael A Andersen,2,3 Caspar Da Cunha-Bang,2 Carsten U Niemann,2 Henrik Frederiksen,1,4,6 Henrik Hjalgrim2,3,5,7 1Department of Hematology, Odense University Hospital, Odense, Denmark; 2Department of Hematology, Rigshospitalet, Denmark; 3Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark; 4Department of Clinical Research, University of Southern Denmark, Odense, Denmark; 5Danish Cancer Society Research Center, Hematology Research Group, Copenhagen, Denmark; 6Academy of Geriatric Cancer Research (AGECARE), Odense University Hospital, Odense, Denmark; 7Department of Clinical Medicine, Copenhagen University, Copenhagen, DenmarkCorrespondence: Emelie C RotbainDepartment of Hematology, Odense University Hospital, Kløvervænget 6, Odense, DK-5000, DenmarkTel +45 5369 0201Email erot0006@regionh.dkPurpose: Age-related comorbidity is highly prevalent in chronic lymphocytic leukemia (CLL). The purpose of this study was to provide information on current patterns of healthcare utilization in CLL.Patients and Methods: We used data from Danish nation-wide registers to study healthcare utilization the year before and the year after CLL diagnosis and in relation to first-line treatment. Patients diagnosed with CLL between 1997 and 2018 were included and stratified on number of comorbidities, presence of specific comorbidities, and fitness status, respectively. Healthcare utilization was studied in terms of hospital admissions, in-hospital bed days, out-patient visits, emergency room visits, and prescription drugs. Odds ratios with 95% confidence intervals were calculated using multivariable logistic regression analyses adjusting for age, sex, and calendar year.Results: The study comprised 9170 patients with CLL with a median age of 71 years, of whom 35% had ≥ 1 comorbidity. Healthcare utilization increased markedly upon CLL diagnosis both in patients with and without comorbidities. During the year after CLL diagnosis, 39% were hospitalized, 16% visited an emergency room, 88% visited an out-patient clinic, and 93% received prescription drugs. Both individual comorbidities and the total number of comorbidities were associated with increased healthcare utilization of all types, except for contacts to hematological departments.Conclusion: Our results suggest that CLL diagnosis may unveil incipient diseases and aggravate comorbidities and thereby have considerably wider health implications than those directly related to CLL. These findings may be used by clinicians and decisions makers to guide planning of multidisciplinary care for cancer patients.Keywords: chronic lymphocytic leukemia, hematology, epidemiology, real-world data

Patients with Chronic Lymphocytic Leukemia (CLL) have increased morbidity and mortality following infection with Covid19. Insight into serological response following vaccination is crucial for pati...

Background: For fit CLL patients (pts), continuous BTK inhibitor treatment is replacing CIT as standard of care in frontline setting, particularly in pts with unfavorable prognostic factors. The time limited combinations venetoclax plus obinutuzumab (GVe) and venetoclax plus rituximab (RVe) have produced high rates of undetectable minimal residual disease (uMRD), which strongly associates with long progression-free survival (PFS) both in frontline and relapsed setting. For frontline therapy GVe is approved in this setting based on data from the CLL14 trial in an unfit population. However, data from a fit cohort are not yet available. The GAIA (CLL13) trial evaluated the efficacy and safety of three Ven+CD20 antibody-based regimens in comparison to CIT as a frontline treatment for fit pts with CLL and without TP53 mutation/deletion. Methods: Treatment-naïve fit (CIRS ≤6, normal creatinine clearance with ≥ 70ml/min) CLL pts requiring therapy were eligible. Based on known poor response to CIT, pts with TP53 aberrations were excluded. Pts were randomized in a 1:1:1:1 ratio to receive six courses of CIT (FCR for pt ≤65 years: fludarabine 25 mg/m² d1-3, cyclophosphamide 250 mg/m² d1-3, rituximab 375 mg/m² d1 cycle 1 and 500 mg/m² d1 cycle 2-6; BR for pt >65 years: bendamustine 90mg/m² d1-2, rituximab) or one of three venetoclax (V) combinations (standard ramp-up from cycle 1 d22, 400 mg/d cycle 2-12): V and rituximab (375/500mg/m² d1 cycle 1-6) [RVe], V and obinutuzumab (1000 mg d1, 8, 15 cycle 1 and d1 cycle 2-6) [GVe], or V, obinutuzumab and ibrutinib (420 mg/d cycle 1-12, if MRD-detectable continued until cycle 36) [GIVe] . Pts were stratified according to country, Binet stage and age (≤ 65/> 65 years). The co-primary endpoints of the trial are (1) the rate of uMRD ( Trial is registered at ClinicalTrials.gov (NCT02950051). Results: A total of 926 pts (CIT: 229 (150 FCR, 79 BR), RVe: 237, GVe: 229, GIVe: 231) with a median age of 61 years (range 27-84) were accrued between 12/2016 and 09/2019. The majority of pts were in advanced Binet stage (B: 37.8%, C: 35.6%) and unmutated IGHV status was present in 56%. Fourteen pts did not receive study treatment (13 FCR, 1 GVe) and were not included in the safety population. The data cut for the first co-primary endpoint analysis was February 28, 2021. The median observation time was 27.9 months. The co-primary endpoint uMRD in PB at MO15 was met as the rate of uMRD in ITT population was significantly higher in GVe compared to CIT: 86.5% (97.5% CI 80.6-91.1) vs 52.0% (CI 44.4-59.5; p The most common grade 3-5 treatment-emergent AE were neutropenia (50.5% of all pts), thrombocytopenia (12.2%), tumor lysis syndrome (7.5%), infusion-related reaction (7.2%), febrile neutropenia (6.5%) and pneumonia (5.3%)). Atrial fibrillation and bleeding events occurred more frequently in GIVe while infusion-related reactions were most common in the GVe arm (Table 1). The absolute numbers of second malignancies were 33, 19, 22 and 21 for CIT, RVe, GVe and GIVe. Fatal AEs occurred in 5, 7, 6 and 9 of the patients. Conclusions: The time-limited therapies of GVe and GIVe provided superior uMRD rates in PB at MO 15 compared to CIT. In addition, uMRD rates in BM and CRR were higher in GVe and GIVe in particular than in CIT. All arms showed a good safety profile in this fit pt population. Figure 1 Figure 1. Disclosures Eichhorst: AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Speakers Bureau; Adaptive Biotechnologies: Speakers Bureau; Hexal: Speakers Bureau; ArQule: Membership on an entity's Board of Directors or advisory committees; Oxford Biomedica (UK): Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; Consultant Department I for Internal Medicine: Consultancy; University Hospital of Cologne: Current Employment. Kater: Genmab, LAVA: Other: Ad Board, Steering Committee; Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding; Abbvie: Honoraria, Other: Ad Board, Research Funding; BMS, Roche/Genentech: Other: Ad Board, , Research Funding. Von Tresckow: Celgene: Other: travel grant; AstraZeneca: Honoraria, Other; Roche: Honoraria, Other: Reasearch support, travel grant; Janssen: Honoraria, Other: Reasearch support, travel grant; AbbVie: Honoraria, Other: advisory board, travel grant. Staber: Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Takeda: Consultancy, Research Funding; MSD: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria. Tadmor: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Poulsen: Janssen: Consultancy; Abbvie: Consultancy. Janssens: Sanofi: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Beigene, AstraZeneca: Consultancy, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Trael Grant, Speakers Bureau; Abbvie, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Noesslinger: Roche: Speakers Bureau; Abbvie,: Speakers Bureau; Janssen: Speakers Bureau; AstraZeneca: Honoraria; Gilead: Honoraria; Celgene: Honoraria. Jaeger: Norvartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Frederiksen: Abbvie: Research Funding; Gilead: Research Funding; Alexion: Research Funding; Novartis: Research Funding; Janssen Pharmaceuticals: Research Funding. Hebart: Roche: Honoraria; BMS: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Janssen: Honoraria. Simon: Gilead: Other: Travel support. Fink: AbbVie: Other: travel grant; Janssen: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Celgene: Research Funding. Fischer: Abbvie: Honoraria; Roche: Honoraria, Other: Travel Grants. Kreuzer: Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Abbvie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Honoraria, Research Funding, Speakers Bureau. Ritgen: Abbvie: Consultancy, Other: Travel support, Research Funding; Chugai: Consultancy; MSD: Consultancy, Other: Travel support; Roche: Consultancy, Other: Travel support, Research Funding; Celgene: Other: Travel support. Brüggemann: Amgen: Other: Advisory Board, Travel support, Research Funding, Speakers Bureau; Incyte: Other: Advisory Board; Janssen: Speakers Bureau. Levin: Roche, Janssen, Abbvie: Other: Travel Expenses, Ad-Board. Stilgenbauer: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Other: Research Support; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Consultancy; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Honoraria; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Research Funding. Hallek: Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Abbvie: Consultancy, Research Funding, Speakers Bureau. OffLabel Disclosure: Ibrutinib in combaintion with Venetoclax + Obinutuzumab is not approved.

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in the world with approximately 450 new cases yearly in Denmark. The disease is highly heterogeneous, and half of the patients will never require treatment. The standard treatment is chemoimmunotherapy, but highly effective targeted therapies are approved for patients with high-risk disease or relapse as summarised in this review. The Danish CLL guidelines are continuously updated based on results from ongoing clinical trials and international guidelines.

Comorbid conditions are highly prevalent in chronic lymphocytic leukemia (CLL), nevertheless, detailed information on the association of specific comorbidities with CLL prognosis is missing. Using Danish, nation-wide registers, we followed consecutive patients from CLL-diagnosis in 1997–2018, until death or end of follow-up. Sub-grouping of comorbidities was defined using a modified Charlson comorbidity index. Patients were matched on sex, date of birth (±1 month), and region of residency with up to ten comparators from the general population. In total, 9170 patients with CLL were included in the study, with a median of 5.0 years of follow-up. All comorbid conditions studied were individually associated with increased mortality, and many also with increased cause-specific mortality, related or unrelated to CLL. Comorbidity correlated with increased mortality from infections and cardiovascular disease. CLL patients, particularly older, had a significant loss of lifetime compared with the general population. This study highlights a large subgroup of comorbid CLL patients with an unmet treatment-need and missing efficacy and safety data on treatment, who are under-prioritized in clinical trials. Also, studies assessing interventions that may provide better tolerability of treatment in older or comorbid patients, with cancer in general, and CLL in particular, are warranted.

Comorbid conditions are highly prevalent in chronic lymphocytic leukemia (CLL), nevertheless, detailed information on the association of specific comorbidities with CLL prognosis is missing. Using Danish, nation-wide registers, we followed consecutive patients from CLL-diagnosis in 1997-2018, until death or end of follow-up. Sub-grouping of comorbidities was defined using a modified Charlson comorbidity index. Patients were matched on sex, date of birth (±1 month), and region of residency with up to ten comparators from the general population. In total, 9170 patients with CLL were included in the study, with a median of 5.0 years of follow-up. All comorbid conditions studied were individually associated with increased mortality, and many also with increased cause-specific mortality, related or unrelated to CLL. Comorbidity correlated with increased mortality from infections and cardiovascular disease. CLL patients, particularly older, had a significant loss of lifetime compared with the general population. This study highlights a large subgroup of comorbid CLL patients with an unmet treatment-need and missing efficacy and safety data on treatment, who are under-prioritized in clinical trials. Also, studies assessing interventions that may provide better tolerability of treatment in older or comorbid patients, with cancer in general, and CLL in particular, are warranted.

BACKGROUND Cytomegalovirus (CMV) infection is common among solid organ transplant (SOT) recipients and may cause CMV disease. To optimize the implementation of existing prevention strategies, the Management of Post-transplant Infections in Collaborating Hospitals (MATCH) program was developed. Two key performances of MATCH (diagnosing CMV infection at low viral load (VL) and before the onset of CMV disease) were assessed prior to, during and after the implementation of MATCH. METHODS The MATCH program included a personalized surveillance plan, prophylaxis and preemptive therapy determined by the recipient's risk of CMV infection. The plan was composed through predefined algorithms and implemented through harvesting of real-time data from medical records. Risk of CMV disease was compared for recipients transplanted during and after vs prior to the implementation of MATCH. Lung and non-lung transplants were analyzed separately. RESULTS A total of 593, 349, 520, and 360 SOT recipients were transplanted before (2007-2010), during (2011-2012), early after (2013-2015), and late after (2016-2017) implementation of MATCH with an observed reduction of diagnostic VL (P

Richter’s transformation (RT) refers to the development of an aggressive lymphoma in patients with chronic lymphocytic leukemia (CLL). Approximately, 2–10% of patients with CLL develop RT, most often as diffuse large B-cell lymphoma. To assess the incidence of RT, we examined risk factors for RT and death among patients with RT in a nationwide CLL cohort (from 2008 to 2016). Among 3772 patients, 113 had biopsy-proven RT. With a median follow-up of 4.3 years, the 5-year cumulative incidence of RT was 2.8%. Advanced Binet stage (B/C) (p

PURPOSE: Solid organ (SOT) and allogeneic haematopoietic stem cell (HSCT) transplant recipients have elevated risks of de novo or secondary cancer. We explored risk factors hereof.METHODS: Among SOT and HSCT between January 2004 and December 2014, standardised incidence ratio (SIR) of de novo/secondary cancer compared with the Danish population was determined and risk factors were identified using Poisson regression.RESULTS: During a median of 3.4 (IQR 1.3-6.4) and 2.6 (0.8-5.4) person-years (PY) after SOT and HSCT, a total of 212/1656 (13%) and 75/992 (8%) persons developed cancer; SIR 3.61 (3.0-4.3) and 2.2 (1.6-3.0), resp.). SIR correlated with younger age and was highest for skin and haematological cancers for both types of transplantation. Within the cohort, cancer was associated with older age (adjusted incidence rate ratio > 50 vs ≤ 19 years, among SOT and HSCT: 9.4 (3.4-25.7) and 25.4 (5.1-126.0), resp.) and current elevated C-reactive protein (CRP) (≥ 10 vs CONCLUSION: Rates of de novo or secondary cancers are elevated in both SOT and HSCT compared with the general population and mainly for skin and haematological cancers. Among transplant recipients, older age and current elevated CRP are risk factors.

Emerging EBV DNAemia in plasma is considered an early sign of post-transplant lymphoproliferative disorder (PTLD). The aim of this study was to quantify the extent of benefit from screening for EBV DNAemia to detect emerging PTLD among solid organ (SOT) or hematopoietic stem cell transplant recipients (HSCT). We used receiver operating characteristic (ROC) curves for assessing ability of models to predict PTLD. Among 2642 recipients transplanted between January 2004 and December 2014, 79 (3%) developed PTLD. EBV DNAemia was observed in 331/1784 recipients (18.6%, 95% CI 16.8–20.4) with measured EBV DNA. The area under the curve (AUC) of the ROC of EBV DNAemia to identify persons with subsequent PTLD was 72% (95% CI, 64–79%) among SOT and 59% (51–68%) among HSCT. Including clinical predictors such as age, gender, transplant year and type, high-risk EBV serostatus, and routine biochemistry in addition to EBV DNAemia increased AUC to 83% (75–90%) among SOT and 84% (79–89%) among HSCT. Among HSCT, including additional factors such as T-cell-depleting treatment, acute graft vs. host disease and donor match increased AUC to 85% (78–91%). We constructed a model to better predict PTLD compared to EBV DNA screening alone which could have clinical implications.

Background: In early studies of venetoclax (ven) in CLL, severe tumor lysis syndromes (TLS) were observed leading to the implementation of multiple safety measures including a 5-week ramp up schedule. Since then, studies have consistently reported low rates of TLS in ven-treated patients (pts), most likely as a result of strict prophylactic and laboratory monitoring measures. Various lead-in regimens prior to the administration of ven were shown to be feasible and effective in reducing the risk of TLS in pts with CLL. However, no comparison of different pretreatment regimens has been performed so far in a prospective randomized trial. Using the set-up of the GAIA trial, we compared TLS incidence and formal TLS risk reduction between 3 different ven-based combinations. Methods: The phase 3 GAIA (CLL13) trial compared 3 different time-limited ven-based combinations against standard chemoimmunotherapy (CIT) in fit, treatment-naïve pts with CLL. Pts were randomized to receive CIT (FCR in pts ≤65 years; BR in pts >65 years), ven and rituximab (RVe), ven and obinutuzumab (GVe), or ven, obinutuzumab and ibrutinib (GIVe). In RVe, GVe and GIVe, ven was added at cycle 1 day 22 (ramp up day 1) after a 21-day pretreatment with rituximab (1 dose), obinutuzumab (3 doses) or obinutuzumab (3 doses) plus ibrutinib (continuous) (Figure 1A). The safety population (i.e. all pts who received study treatment) of the ven-containing arms was used for this analysis. TLS was reported according to Cairo-Bishop criteria (Cairo M, Bishop M. Br J Haematol. 2004). For TLS risk evaluation, the most recent available CT/MRI and absolute lymphocyte count (ALC) were used. TLS risk was evaluated at baseline and at ramp up day 1, before the first dose of ven. The patients were categorized retrospectively according to the following TLS risk categories: high (any lymph node [LN] with largest diameter ≥10 cm or any LN with largest diameter ≥5 cm and ALC ≥25 G/L), intermediate (any LN ≥5 cm to Results: The safety population of all ven-containing arms comprised of 696 pts (RVe: 237, GVe: 228, GIVe: 231). Baseline TLS risk was high in 22%, 23% and 19% of pts in the RVe, GVe and GIVe arm, intermediate in 62%, 65%, 67% and low in 10.5%, 14.7% and 12.4% of pts, respectively. After the first 21 days of treatment (i.e. at ramp up day 1), the fraction of pts with a reduction in TLS risk varied between the treatment arms with 31.7% (RVe), 71.4% (GVe) and 47.3% (GIVe) of pts decreasing by at least one TLS risk category (Figure 1B). With regard to TLS risk reduction, GVe was superior to RVe (p In total, 36, 30 and 19 cases of TLS occurred in 29 (12.2%), 26 (11.4%) and 19 (8.2%) pts in the RVe, GVe and GIVe arm. The majority of TLS cases were categorized as CTC grade 3 (28 [RVe], 19 [GVe], 12 [GIVe]), only few CTC grade 4 TLS were reported (1 [RVe], 2 [GVe], 3 [GIVe]). There were no cases of fatal TLS and no pts requiring dialysis due to TLS. In the obinutuzumab arms the majority of TLS cases occurred before ramp up day 1 (GVe: 76.7%, GIVe: 68.4%), i.e. before any venetoclax intake, in contrast 80.6% of TLS cases in the RVe arm were reported during ven ramp up (Figure 2). While there was no significant difference in the cumulative TLS incidence between the treatment arms (p=0.334), there was an increase in TLS occurring after ramp up day 1 in the RVe arm compared to GVe (p Conclusions: This analysis represents the first comparison of the formal TLS risk reduction and actual TLS incidence of different ven-based combinations in a randomized trial. GVe led to the highest TLS risk reduction, while the lowest number of TLS cases occurred in the GIVe arm. Most TLS cases in the GVe and GIVe arms occurred before the start of ven. RVe was least effective in reducing TLS risk and in contrast to the obinutuzumab-containing arms, the vast majority of TLS cases was reported during the ven ramp up. The relatively high incidence of TLS in comparison to other trials might partly be a consequence of using different reporting criteria (Cairo-Bishop vs Howard criteria). No fatal TLS occurred in any of the treatment arms. Figure 1 Figure 1. Disclosures Von Tresckow: AbbVie: Honoraria, Other: advisory board, travel grant; Celgene: Other: travel grant; AstraZeneca: Honoraria, Other; Roche: Honoraria, Other: Reasearch support, travel grant; Janssen: Honoraria, Other: Reasearch support, travel grant. Niemann: Novo Nordisk Foundation: Research Funding; CSL Behring, Genmab, Takeda, Octapharma: Consultancy; Abbvie, AstraZeneca, Janssen: Consultancy, Research Funding. Kater: Abbvie: Honoraria, Other: Ad Board, Research Funding; Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding; Genmab, LAVA: Other: Ad Board, Steering Committee; BMS, Roche/Genentech: Other: Ad Board, , Research Funding. Staber: Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Takeda: Consultancy, Research Funding; MSD: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria. Tadmor: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Levin: Roche, Janssen, Abbvie: Other: Travel Expenses, Ad-Board. Poulsen: Janssen: Consultancy; Abbvie: Consultancy. Janssens: Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Trael Grant, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Beigene, AstraZeneca: Consultancy, Speakers Bureau; Abbvie, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Noesslinger: AbbVie: Honoraria; Celgene: Honoraria; Roche: Honoraria; Jansen: Honoraria; AstraZeneca: Honoraria; Gilead: Honoraria. Simon: Gilead: Other: Travel support. Fink: AbbVie: Other: travel grant; Janssen: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Celgene: Research Funding. Fischer: Abbvie: Honoraria; Roche: Honoraria, Other: Travel Grants. Wendtner: Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding. Ritgen: MSD: Consultancy, Other: Travel support; Chugai: Consultancy; Abbvie: Consultancy, Other: Travel support, Research Funding; Roche: Consultancy, Other: Travel support, Research Funding; Celgene: Other: Travel support. Brüggemann: Amgen: Other: Advisory Board, Travel support, Research Funding, Speakers Bureau; Incyte: Other: Advisory Board; Janssen: Speakers Bureau. Stilgenbauer: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Honoraria; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Other: Research Support; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Research Funding; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Consultancy. Hallek: Roche: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Mundipharma: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Speakers Bureau. Eichhorst: Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Speakers Bureau; Adaptive Biotechnologies: Speakers Bureau; Hexal: Speakers Bureau; ArQule: Membership on an entity's Board of Directors or advisory committees; Oxford Biomedica (UK): Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; Consultant Department I for Internal Medicine: Consultancy; University Hospital of Cologne: Current Employment. OffLabel Disclosure: The combination of obinutuzumab, venetoclax and ibrutinib is not approved for the treatment of CLL

Background: Venetoclax (ven)-based time-limited combination treatments have yielded high rates of undetectable MRD (uMRD) in patients (pts) with CLL. In correlative analyses, attainment of uMRD status was associated with longer progression-free survival (PFS), making uMRD a robust surrogate parameter for remission duration particularly after time-limited therapy. While MRD is usually assessed by conventional 4-color flow cytometry (FCM) defining uMRD as less than 1 CLL cell in 10 000 leukocytes ( Methods: The phase 3 GAIA (CLL13) trial compared 3 different time-limited ven-based combinations against chemoimmunotherapy (CIT) in fit, treatment-naïve pts with CLL. Pts were randomized to receive CIT for 6 cycles of 28 days each (FCR for pts ≤65 years; BR for pts >65 years), ven and rituximab (RVe), ven and obinutuzumab (GVe), or ven, obinutuzumab and ibrutinib (GIVe), all for 12 cycles with the option for ibrutinib continuation until cycle 36 for pts not obtaining uMRD4. The co-primary endpoints were the rate of uMRD4 at month (MO) 15 (GVe vs CIT) and PFS (GIVe vs CIT). MRD was centrally assessed by FCM at MO2, MO9, MO12 and MO15 in peripheral blood (PB) and at final restaging (RE, two months after the end of treatment) in bone marrow (BM). The following categories were used: high (≥10 -2), intermediate (≥10 -4 to Results: In total, 926 pts were randomized (CIT: 229, RVe: 237, GVe: 229, GIVe: 231). Based on the intention-to-treat (ITT) population, rates of uMRD4 in PB by FCM were 62.0% (CIT), 73.0% (RVe), 88.6% (GVe) and 88.3% (GIVe) at MO9 and 52.0% (CIT), 57.0 (RVe), 86.5% (GVe) and 92.2% (GIVe) at MO15. BM uMRD4 results at RE were 37.1% (CIT), 43.0 (RVe), 72.5% (GVe) and 77.9% (GIVe). HsFCM samples were available for 844 (MO9 PB), 863 (MO15 PB) and 744 (RE BM) pts with median limits of detection (LOD) of 1.6x10 -5 (MO9 PB), 1.4x10 -5 (MO15 PB) and 9.9x10 -6 (RE BM) that were similar between the treatment arms. With hsFCM a lower limit of detection (LOD) of ≤10 -5 was achieved in 364 (MO9) and 477 (MO15) PB samples and in 580 BM samples at RE. 480 (MO9 PB), 386 (MO15 PB) and 164 (RE BM) samples did not reach a LOD of ≤10 -5 and were thus not included in the MRD5-evaluable populations (Figure 1). Among pts with samples evaluable for MRD5 in PB at MO15, 26 of 82 (31.7%, CIT), 45 of 132 (34.1%, RVe), 81 of 131 (61.8%, GVe) and 93 of 132 (70.5%, GIVe) achieved uMRD5. BM uMRD5 rates at RE were 24.2% (23 of 95 pts), 16.1% (27 of 168 pts), 41.7% (65 of 156 pts) and 53.4% (86 of 161 pts), respectively (Figure 2A). The median MRD level at MO9 was lower in CIT, GVe, GIVe (all 1x 10 -5) compared with RVe (2x 10 -5) by hsFCM (Figure 2B). While the obinutuzumab-containing arms stayed at this low level between MO9 and MO15, median MRD levels in CIT and RVe increased to 8.9x 10 -5 (CIT) and 3.1x 10 -5 (RVe) in the same period. The different treatment arms showed distinct patterns of differential clearance of CLL in BM and PB. While the fraction of concordant MRD results between PB and BM at RE was lower in the CIT arm with 14/34 (41.2%), the ven-containing arms showed a similar compartment effect with a proportion of concordant results of 67/108 (62.0%, RVe), 70/101 (69.3%, GVe) and 71/104 (68.3%, GIVe). In 9/16 (56.3%, CIT), 23/36 (63.9%, RVe), 22/63 (34.9%, GVe) and 23/73 (31.5%,GIVe) pts who achieved uMRD5 in PB (RE) MRD was still measurable in BM. More sensitive NGS analyses and detailed correlative analyses are pending and will be presented at the conference. Conclusions: HsFCM improves MRD detection in CLL below 10 -4 in PB and BM by capturing low levels of MRD (≥10 -5 to Figure 1 Figure 1. Disclosures Von Tresckow: Celgene: Other: travel grant; AstraZeneca: Honoraria, Other; Roche: Honoraria, Other: Reasearch support, travel grant; Janssen: Honoraria, Other: Reasearch support, travel grant; AbbVie: Honoraria, Other: advisory board, travel grant. Niemann: CSL Behring, Genmab, Takeda, Octapharma: Consultancy; Abbvie, AstraZeneca, Janssen: Consultancy, Research Funding; Novo Nordisk Foundation: Research Funding. Kater: Genmab, LAVA: Other: Ad Board, Steering Committee; Abbvie: Honoraria, Other: Ad Board, Research Funding; BMS, Roche/Genentech: Other: Ad Board, , Research Funding; Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding. Simon: Gilead: Other: Travel support. Fink: AbbVie: Other: travel grant; Janssen: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Celgene: Research Funding. Fischer: Abbvie: Honoraria; Roche: Honoraria, Other: Travel Grants. Wendtner: Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding. Staber: Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Takeda: Consultancy, Research Funding; MSD: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria. Tadmor: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Levin: Roche, Janssen, Abbvie: Other: Travel Expenses, Ad-Board. Stilgenbauer: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Honoraria; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Other: Research Support; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Research Funding; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Consultancy. Brüggemann: Amgen: Other: Advisory Board, Travel support, Research Funding, Speakers Bureau; Incyte: Other: Advisory Board; Janssen: Speakers Bureau. Hallek: Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Abbvie: Consultancy, Research Funding, Speakers Bureau. Ritgen: MSD: Consultancy, Other: Travel support; Chugai: Consultancy; Abbvie: Consultancy, Other: Travel support, Research Funding; Roche: Consultancy, Other: Travel support, Research Funding; Celgene: Other: Travel support. Eichhorst: AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Speakers Bureau; Adaptive Biotechnologies: Speakers Bureau; Hexal: Speakers Bureau; ArQule: Membership on an entity's Board of Directors or advisory committees; Oxford Biomedica (UK): Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; Consultant Department I for Internal Medicine: Consultancy; University Hospital of Cologne: Current Employment. OffLabel Disclosure: The combination of obinutuzumab, venetoclax and ibrutinib is not approved for treatment of CLL

Patients with chronic lymphocytic leukemia and unmutated immunoglobulin heavy-chain variable region gene (IGHV) have inferior survival from time of treatment in clinical studies. We assessed real-world outcomes based on mutational status and treatment regimen in a nationwide population-based cohort, comprising all 4,135 patients from the Danish chronic lymphocytic leukemia registry diagnosed between 2008 and 2017. In total, 850 patients with known mutational status received treatment: 42% of patients received intensive chemoimmunotherapy consisting of fludarabine, cyclophosphamide plus rituximab, or bendamustine plus rituximab; 27% received chlorambucil in combination with anti-CD20 antibodies or as monotherapy, and 31% received other, less common treatments. No difference in overall survival from time of first treatment according to mutational status was observed, while treatment-free survival from start of first treatment was inferior for patients with unmutated IGHV. The median treatment-free survival was 2.5 years for patients treated with chlorambucil plus anti-CD20, and 1 year for those who received chlorambucil monotherapy. The 3-year treatment-free survival rates for patients treated with fludarabine, cyclophosphamide plus rituximab, and bendamustine plus rituximab were 90% and 91% for those with mutated IGHV, and 76% and 53% for those with unmutated IGHV, respectively, and the 3-year overall survival rates were similar for the two regimens (86-88%). Thus, it appears that, in the real-world setting, patients progressing after intensive chemoimmunotherapy as first-line therapy can be rescued by subsequent treatment, without jeopardizing their long overall survival. Intensive chemoimmunotherapy remains a legitimate option alongside targeted agents, and part of a personalized treatment landscape in chronic lymphocytic leukemia, while improved supportive care and treatment options are warranted for unfit patients.

IntroductionRichter’s transformation (RT) refers to the development of an aggressive lymphoma in patients with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma. Studies have shown that 2–10% of patients with CLL develop RT including diffuse large B-cell lymphoma (DLBCL) and less common Hodgkin lymphoma (HL). This study aims to assess the risk factors for RT of CLL in a nationwide cohort. Additionally, we want to examine prognostic factors in patients with RT. These findings may guide management of treated as well as untreated patients with CLL in the risk of RT.MethodsClinical data for patients diagnosed with CLL between 2008 and 2016 will be retrieved from the Danish National CLL registry (DCLLR). Using the Danish unique person identification number, clinical data will be merged with histologically verified DLBCL and/or HL diagnoses retrieved from the Danish National Pathology Data Bank. This will ensure complete follow-up for all patients.The DCLLR includes data from more than 4000 patients with CLL ensuring a median follow-up of 3 years. With the reported incidences (2-10%) of RT, we expect to identify 80–200 CLL patients with RT enabling analysis of overall survival following RT. From time of CLL diagnosis, estimates of cumulative incidence of RT will be calculated using the Aalen-Johansen estimator. From time of RT diagnosis, survival analysis will be performed by Kaplan-Meier method. Cox proportional hazards models will be used for multivariable survival analysis.Ethics and disseminationApprovals for data collection and analysis was obtained from the Danish Data Protection Agency and the Danish Health Authorities. All data will be managed confidentially according to guidelines and legislation. The dissemination will include a publication of scientific papers and/or presentations of the study findings at international conferences.

Bruton's tyrosine kinase (BTK) is crucial in B-cell development and survival. The role of BTK as a downstream kinase in the B-cell receptor (BCR) signaling pathway is well described. As a key player in the pathogenesis of B-cell malignancies, targeting of dysregulated BCR signaling has been explored by development of inhibitors of downstream mediators. Discovery of the biological function of BTK and the development of covalent inhibitors for clinical use, ibrutinib as the lead agent and acalabrutinib as the second clinically approved BTK inhibitor, have revolutionized the treatment options for B-cell malignancies. Currently, ibrutinib is approved for mantle cell lymphoma, chronic lymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, small lymphocytic lymphoma, marginal zone lymphoma and chronic graft versus host disease, while acalabrutinib is approved for mantle cell lymphoma. Potential expansion of indications in other diseases is under investigation in several clinical trials, while combination of BTK inhibitors with either chemoimmunotherapy or other targeted agents is being systematically explored in B-cell malignancies.

Background Patients with Chronic Lymphocytic Leukemia (CLL) have an increased risk of infections both prior to and upon treatment. Infections are the major cause of death for these patients, the 5-year incidence of severe infection prior to treatment is approximately 32 % with a 30-day mortality of 10 % (Andersen et al., Haematologica, 2018). Chemoimmunotherapy is still 1st line standard of treatment for patients without del17p or TP53 mutation despite association with neutropenia, immunesuppression and infections. The combination of BTK inhibitors and the bcl-2 inhibitor venetoclax has demonstrated synergy in vitro and in vivo, while translational data indicate that the CLL-related immune dysfunction can be improved on treatment with reduced risk of infections. Employing the Machine-Learning based CLL treatment infection model (CLL-TIM) that we have developed, patients with a high (>65%) risk of infection and/or need of CLL treatment within 2 years of diagnosis can be identified (CLL-TIM.org). The significant morbidity and mortality due to infections in treatment-naïve CLL warrants trials that challenge the dogma of only treating symptomatic CLL. Thus, we initiated the randomized phase 2 PreVent-ACall trial of 12 weeks acalabrutinib + venetoclax to reduce risk of infections. Methods Design and statistics A phase 2, randomized, open label, multi-center clinical trial for newly diagnosed patients with CLL. Based on the CLL-TIM algorithm, patients with high risk of severe infection and/or treatment within 2 years from diagnosis can be identified. Approximately 20% of newly diagnosed CLL patients will fall into this high-risk group. First patient in trial planned for September 2019, primary outcome expected in 2021. Only patients identified as at high risk, who do not currently fulfil IWCLL treatment criteria are eligible. Patients will be randomized between observation in terms of watch&wait according to IWCLL guidelines or treatment. Primary endpoint Grade ≥3-Infection-free survival in the treatment arm compared to the observation arm after 24 weeks (12 weeks after end of treatment). Study treatment Acalabrutinib 100 mg BID from cycle 1 day 1 for 12 weeks. Venetoclax, ramp up during the first five weeks starting cycle 1 day 1, thereafter 400 mg once daily for a total of 12 weeks counted from cycle 1 day 1. Patients A sample size of 25 patients in each arm, 50 patients in total. Major inclusion criteria CLL according to IWCLL criteria ≤1 year prior to randomizationHigh risk of infection and/or progressive treatment within 2 years according to CLL-TIM algorithmIWCLL treatment indication not fulfilledAdequate bone marrow functionCreatinine clearance above 30 mL/min.ECOG performance status 0-2. Major exclusion criteria Prior CLL treatmentRichter's transformationPrevious autoimmune disease treated with immune suppressionMalignancies other than CLL requiring systemic therapies or considered to impact survivalRequirement of therapy with strong CYP3A4 and CYP3A5 inhibitors/inducers or anticoagulant therapy with vitamin K antagonistsHistory of bleeding disorders, current platelet inhibitors / anticoagulant therapyHistory of stroke or intracranial hemorrhage within 6 months Trial registry number EUDRACT NUMBER: 2019-000270-29 Clinicaltrials.gov number: NCT03868722 Perspectives: As infections is a major cause of morbidity and mortality for patients with CLL prior to any treatment, we aim at changing the natural history of immune dysfunction in CLL. The PreVent-ACaLL trial includes an optional extension into a phase 3 part with the primary outcome of grade ≥3 infection-free, CLL treatment-free survival two years after enrollment to address the unmet need of improved immune function in CLL for the first time. Figure Disclosures Da Cunha-Bang: AstraZeneca: Consultancy; Janssen: Consultancy; Abbvie: Consultancy, Other: Travel Grant; Roche: Other: Travel Grant. Levin:Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Educational grant ; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Educational grant . Österborg:BeiGene: Research Funding; Gilead: Research Funding; Janssen: Research Funding; Abbvie: Research Funding; Kancera AB: Research Funding. Niemann:Novo Nordisk Foundation: Research Funding; Gilead: Other: Travel grant; Janssen: Consultancy, Other: Travel grant, Research Funding; Roche: Other: Travel grant; CSL Behring: Consultancy; Acerta: Consultancy, Research Funding; Sunesis: Consultancy; Astra Zeneca: Consultancy, Research Funding; Abbvie: Consultancy, Other: Travel grant, Research Funding. OffLabel Disclosure: acalabrutinib and venetoclax in combination for CLL.

Introduction In chronic lymphocytic leukemia (CLL), few randomized clinical trials include patients who are older or have significant comorbidity, despite constituting a large proportion of the CLL-population. Therefore, detailed data on the association of specific comorbidities with CLL-prognosis are missing and decisions on treatment and follow-up are poorly informed in comorbid patients. We present data on the association of comorbidity with prognostic factors, treatment patterns and causes of death in patients from the world's largest cohort of unselected CLL-patients. Methods All patients diagnosed with CLL in the CLL-registry (2008-2017) or the Danish Cancer Register (1997-2017) were followed through the Civil Registration System from 1 month after CLL-diagnosis until death, emigration or January 2017. Data from Danish nationwide population-based health registers were linked through personal unique identification numbers. Data on comorbidities based on the modified Charlson Comorbidity Index was attained from the Danish National Patient Register, from 20 years prior to the CLL-diagnosis and until 1 month after. Multimorbidity was defined as ≥ 2 comorbidities. Prognostic baseline data such as Binet Stage, IGHV-status, cytogenetics and β2-microglobuline (B2M) level were available through the CLL-registry. Causes of death were ascertained through the National Register of Causes of Death, further sub-categorized as CLL-related (including CLL, all other malignancies and infections) and CLL-unrelated death. Hazard ratios (HR) for mortality were calculated using Cox regression models, adjusting for age, sex, calendar period (5-year intervals) and internally for all other comorbidities. The association between IGHV-status and overall survival (OS) and treatment-free survival (TFS) was assessed by means of Kaplan-Meier and fully adjusted Cox models, stratifying for age and comorbidity-burden. Results The study included 8055 patients with a median follow-up time of 4.2 years; 59 % were male and the median age at diagnosis was 71 years. Overall 2816 patients (35%) were comorbid and 965 (12%) multimorbid. At diagnosis 818 (10%) patients had a history of chronic heart failure or myocardial infarction, 672 (8%) cerebrovascular disease, 626 (8%) diabetes (type 1 or 2), 620 (8%) chronic pulmonary disease, 399 (5%) peripheral vascular disease, 307 (4%) peptic ulcer, 264 (3%) connective tissue disease, 172 (2%) psychiatric disease, 148 (2%) renal disease, 87 (1%) dementia and 86 (1%) hepatic disease. Elevated B2M (>4.0 mg/L) was more common in comorbid (20%) and multimorbid (24%) patients compared with non-comorbid (11%), while Binet Stage B/C, unmutated IGHV-status and del(17p) were evenly distributed across the groups (18-20%, 31-33% and 6-8%, respectively). Among comorbid patients, 56% died during follow-up, compared with 42% among non-comorbid patients. For comorbid patients, death was more commonly caused by cardiovascular disease (14% vs 6%) or other causes (14% vs 10%), while hematological malignancy was less common (25% vs 34%) compared with non-comorbid patients. Other malignancies (11% vs 13%), infection (34% vs 35%) and cerebrovascular disease (2% vs 2%) were equally common causes of death in the two groups. All individual comorbidities were associated with increased all-cause mortality. Except for connective tissue disease, dementia and chronic pulmonary disease, all comorbidities were associated with increased CLL-related mortality (Fig 1A) and as for CLL-unrelated mortality, only ulcer disease, psychiatric disease, renal disease and connective tissue were not associated with an increase. Unmutated IGHV status was associated with inferior TFS for all patients regardless of age and comorbidity burden (range of HRs 1.47-3.70), while IGHV status was associated with inferior OS for non-comorbid patients only (range of HRs 1.43-1.66). Of comorbid patients who died from CLL-related causes, 59% had not received treatment for CLL, compared with 43% among non-comorbid patients. Conclusions All individual types of comorbidity were associated with increased all-cause mortality and most also with higher CLL-related mortality. Improved management is warranted for comorbid CLL-patients, who should be prioritized in clinical trials of agents with high tolerability to further inform treatment guidelines and reduce CLL-related mortality for these patients. Disclosures Curovic Rotbain: Abbvie: Other: Travel Grant; AstraZeneca: Consultancy, Research Funding; Janssen: Research Funding. Niemann:Novo Nordisk Foundation: Research Funding; AstraZeneca: Consultancy, Other: Travel Grant, Research Funding; Sunesis: Consultancy; Acerta: Consultancy; CSL Behring: Consultancy; Roche: Other: Travel Grant; Janssen: Consultancy, Other: Travel Grant, Research Funding; Abbvie: Consultancy, Other: Travel Grant, Research Funding; Gilead: Other: Travel Grant. Da Cunha-Bang:Janssen: Consultancy; Abbvie: Consultancy, Other: Travel Grant; AstraZeneca: Consultancy; Roche: Other: Travel Grant. Frederiksen:Gilead: Research Funding; Abbvie: Research Funding; Janssen Pharmaceuticals: Research Funding; Novartis: Research Funding; Alexion: Research Funding.

Supplemental Digital Content is available in the text, Correct classification of death causes is an important component of transplant trials. We aimed to develop and validate a system to classify causes of death in hematopoietic stem cell (HSCT) and solid organ (SOT) transplant recipients. Case record forms (CRF) of fatal cases were completed, including investigator-designated cause of death. Deaths occurring in 2010 to 2013 were used for derivation; and were validated by deaths occurring in 2013 to 2015. Underlying cause of death (referred to as recorded underlying cause) was determined through a central adjudication process involving 2 external reviewers, and subsequently compared with the Danish National Death Cause Registry. Three hundred eighty-eight recipients died 2010 to 2015 (196 [51%] SOT and 192 [49%] HSCT). The main recorded underlying causes of death among SOT and HSCT were classified as cancer (20%, 48%), graft rejection/failure/graft-versus-host-disease (35%, 28%), and infections (20%, 11%). Kappa between the investigator-designated and the recorded underlying cause of death was 0.74 (95% CI 0.69–0.80) in derivation and comparable in the validation cohort. Death causes were concordant with the Danish National Death Cause Registry in 37.2% (95% CI 31.5–42.9) and 38.4% (95% CI 28.8–48.0) in the derivation and validation cohorts, respectively. We developed and validated a method to systematically and reliably classify the underlying cause of death among transplant recipients. There was a high degree of discordance between this classification and that in the Danish National Death Cause Registry.

In chronic lymphocytic leukemia, TP53 mutations and deletion of chromosome 17p are well-characterized biomarkers associated with poor progression-free and overall survival following chemoimmunotherapy. Patients harboring low burden TP53 mutations with variant allele frequencies of 0.3-15% have been shown to have similar dismal outcome as those with high burden mutations. We here describe a highly sensitive deep targeted next-generation sequencing assay allowing for the detection of TP53 mutations as low as 0.2% variant allele frequency. Within a consecutive, single center cohort of 290 newly diagnosed patients with chronic lymphocytic leukemia, deletion of chromosome 17p was the only TP53 aberration significantly associated with shorter overall survival and treatment-free survival. We were unable to demonstrate any impact of TP53 mutations, whether high burden (variant allele frequency >10%) or low burden (variant allele frequency ≤10%), in the absence of deletion of chromosome 17p. In addition, the impact of high burden TP53 aberration (deletion of chromosome 17p and/or TP53 mutation with variant allele frequency >10%) was only evident for patients with IGHV unmutated status; no impact of TP53 aberrations on outcome was seen for patients with IGHV mutated status. In 61 patients at time of treatment, the prognostic impact of TP53 mutations over 1% variant allele frequency could be confirmed. This study furthers the identification of a clinical significant limit of detection for robust TP53 mutation analysis in chronic lymphocytic leukemia. Multicenter studies are needed for validation of ultra-sensitive TP53 mutation assays in order to define and implement a technical as well as a clinical lower limit of detection.

Supplemental digital content is available in the text., Background Viral blips reflecting polymerase chain reaction (PCR) artefacts or transient low-level replication are well described in the human immunodeficiency virus setting. However, the epidemiology of such blips in transplant recipients screened for cytomegalovirus (CMV) with PCR remains uncertain and was investigated in a cohort of solid organ and hematopoietic stem cell recipients. Methods Eligible recipients had known donor/recipient CMV IgG serostatus, and 3 CMV PCRs ≥. The CMV PCR triplicates (3 consecutive CMV PCRs) were defined; the first CMV PCR was always negative, and the time between the second and third samples was 7 days ≤. A positive second but negative third sample represented a blip. Odds ratio (OR) for factors associated with a triplicate being a blip was estimated by binomial regression adjusted for repeated measurements. Whether blips affected the hazard ratio (HR) for subsequent CMV infection was determined with a Cox model. Results 851 recipients generated 3883 CMV PCR triplicates. The OR of a triplicate representing a blip decreased with increasing viral load of the second sample (vs 273 IU/mL; >273-910 IU/mL: odds ratio [OR], 0.2; 95% confidence interval [CI], 0.1-0.5; >910 IU/mL: OR, 0.08; 95% CI, 0.02-0.2; P ≤ 0.0002) and increased with intermediary-/low-risk serostatus (vs high risk) (OR, 2.8; 95% CI, 1.2-5.5; P = 0.01). Cumulative exposure to DNAemia in the CMV blips greater than 910 IU/mL indicated increased HR of subsequent CMV infection (HR, 4.6; 95% CI, 1.2-17.2; P = 0.02). Conclusions Cytomegalovirus blips are frequent; particularly when the viral load of the first positive PCR is < 910 IU/mL, and serostatus risk is intermediary/low. Accumulating blips suggest intermittent low-level replication. If blips are suspected, confirmation of ongoing replication before initiation of treatment is prudent.

Background Richter's transformation (RT) refers to the development of an aggressive lymphoma in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL). Roughly, 2-10 % of patients with CLL develop RT most often as diffuse large B-cell lymphoma (DLBCL) or Hodgkin lymphoma (HL). Aim This study aimed to assess the incidence rate and risk factors for RT for patients with CLL in a nationwide cohort. Furthermore, we want to assess prognostic risk factors for patients with RT. Methods All patients diagnosed with CLL in Denmark between 2008 and 2016 were included in this study. Clinical data was retrieved from the Danish National CLL Registry (DCLLR), whereas all histologically verified DLBCL, HL and/or transformation diagnoses for patients with CLL were retrieved from the Danish National Pathology Registry. Patients were followed from date of CLL diagnosis until date of RT, death or end of follow-up, whichever came first. The time to RT was estimated as cumulative incidence considering death as a competing risk. Stepwise Cox analysis with backward elimination was applied to identify independent risk factors for RT in patients with CLL. Results A total of 3771 CLL patients were identified, and followed for 14165 person-years. With a median follow-up of 4.3 (IQR (2.4;6.6)) years, 120 (3%) CLL patients had a transformation diagnosis, of which 4 patients were excluded due to misdiagnosis. DLBCL accounted for 78/116 (67%) cases, HL for 15/116 (13%) cases and one patient presented with both DLBCL and HL. In the remaining 22/116 (19%) cases the subtype of the transformation was either unspecified or unclassified RT. The median time to RT was 3.4 (IQR (1.8;5.7)) years from CLL diagnosis and the median overall survival (OS) after development of RT was 4.9 (IQR (0.7;8.4)) years. The cumulative incidence of RT, calculated by Aalen-Johansen estimator, at 5 and 8 years post-CLL diagnosis were 3.3% and 7.9% respectively (Figure 1). The annual crude incidence rate of RT was approximately 0.7% per year for all CLL patients. In all, 918 (24%) patients received CLL-related treatment, of whom 59 (6.4%) patients developed RT, resulting in a cumulative incidence of RT of 7% after 5 years and 11% after 8 years. At the time of CLL diagnosis, patients treated for CLL prior to RT diagnosis had a worse median OS (1.49 years) compared to RT patients who were untreated for CLL (6.16 years). In the univariate analysis, RT was significantly associated with male gender, advanced Binet stage (B or C), unmutated IGHV status (CLL-U), elevated beta-2-microglobulin (>3.5 mg/L) and elevated lactate dehydrogenase (>205 U/L). Of cytogenic aberration, deletion 13q (del(13q)) had a protective effect on the risk of RT, whereas deletion 11q (del(11q)) and deletion 17p (del(17p)) increased the risk. In the multivariable model, advanced Binet stage (HR 2.86 (1.82;4.51), p Conclusions To the best of our knowledge, we here report the largest study on RT assessing nationwide data of consecutive patients diagnosed with CLL. The incidence of RT in this unselected population was 3.3% after 5 years while the median OS for patients from time of RT was 4.9 years. Advanced Binet stage, del(17p) and CLL-U were significantly and independently associated with an increased risk of RT. Del(17p) at CLL diagnosis and PS≥1 at RT diagnosis were significant predictors for death for patients with RT. For patients diagnosed with RT prior to any CLL treatment, a less severe disease course with a median OS of 6.16 years was demonstrated. Contrary, the median OS for patients receiving prior CLL treatment was 1.49 years. Thus, assessment of different treatment options for patients developing RT based on whether they have received prior CLL treatment or not is warranted. Figure 1. Figure 1. Disclosures Ben-Dali: Rigshospitalet: Research Funding. Hleuhel:Rigshospitalet: Research Funding. Brieghel:Arvid Nilson's Fund: Research Funding; Rigshospitalet, Denmark: Research Funding. Niemann:Danish Cancer Society: Research Funding; Novo Nordisk Foundation: Research Funding; Janssen: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy; Gilead: Consultancy; AstraZeneca: Consultancy; CSL Behring: Consultancy.

To the editor: The rapid development in treatment options for patients with chronic lymphocytic leukemia (CLL) in parallel with a much more detailed understanding of the underlying pathogenesis has warranted the development of novel prognostic indices for patients with CLL to replace the clinical