ABSTRACT:Central nervous system involvement (CNSi) of chronic lymphocytic leukemia (CLL) is a rare condition with no consensus on diagnostic criteria and limited evidence for management and outcome. Here, we report an international, multicenter, retrospective study conducted by the European Research Initiative on CLL. The study defined CNSi of CLL by the following: (1) detection of CLL cells in the cerebrospinal fluid or confirmation of CLL infiltration of the CNS based on a tissue biopsy, (2) clinical or radiographic evidence of neurologic disease, and (3) the absence of other explanations for the neurologic findings. A total of 48 patients from 26 centers in 15 countries met all 3 diagnostic criteria of CLL-CNSi. Median age at diagnosis of CNSi was 64 years. Most patients were males (73%), had Binet stage A at CLL diagnosis (61%), and had untreated CLL at the time of CNSi (63%). Motor impairment was the most common symptom (38%) followed by visual impairment (32%). Of 47 patients who received treatment for CNSi, half (51%) received targeted agents, most often a Bruton tyrosine kinase inhibitor (BTKi), and 34% received chemoimmunotherapy. Initial treatment was highly effective, leading to a reduction (83%) or complete resolution (71%) of neurologic symptoms and imaging findings in most patients. The estimated 5-year overall survival (OS) from the CNSi diagnosis was 77.1%. The 5-year time to next treatment or death was 94% for patients treated with BTKi compared with 64% for those treated with CIT. Treatment-sensitive disease, represented by attainment of CNS complete response after initial therapy, was associated with longer OS.

ABSTRACT:Octogenarians represent a significant fraction of patients with chronic lymphocytic leukemia (CLL) but, despite the prevalence of the disease in this age group, limited data are available on the safety and efficacy of novel drugs in this subgroup. We conducted a multicenter retrospective study enrolling 120 octogenarian patients who received venetoclax (Ven) regimens in any line. Regarding efficacy, we found Ven to perform similarly to what is reported in younger patients with CLL, with an overall response rate of 91%, a complete response rate of 44%, and median progression-free survival of 44 months. Concerning safety, we report a toxicity profile that is consistent with previous reports, with most high-grade adverse events being of hematologic or infectious nature, given that 37% and 22% of patients experienced neutropenia or infections of grade 3 or higher. As part of our study, we compared the safety and efficacy data we collected with those obtained in a comparable Bruton tyrosine kinase inhibitor (BTKi)-treated population. We found that these 2 treatments were comparable in terms of overall efficacy, barring a higher rate of complete responses with Ven; safety profiles were different among the 2 groups given that BTKi-treated patients had more cardiovascular toxicities (26% vs 4%) and Ven-treated subjects experienced more infectious events (82% vs 49%). Our data point out that Ven-based regimens are safe and effective in octogenarian patients with CLL despite their higher clinical complexity and comorbidity burden and should provide some basis for the design of prospective studies to further evaluate the optimal treatment regimen in this patient population.

Background. Clinical trials have documented the efficacy of ibrutinib in combination with venetoclax in CLL. Indeed, Ibrutinib plus venetoclax (I+V) is the first all oral fixed duration treatment approved for treatment naive patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) based on the results of the Captivate (phase II) and GLOW (phase III) trials. Discontinuation rates due to adverse events (AEs) were 5% in the Captivate trial, which enrolled patients with ≤70 yrs, and 10.4% in the GLOW trial, which included older and comorbid patients without del(17p). We hypothesized that, when appropriately selected, patients of all ages can tolerate and benefit from I+V. Methods. This is the interim analysis of a retrospective multicenter study aiming at investigating the safety and efficacy of I+V in the real-world setting. Patients with previously untreated CLL/SLL, 18 years or older, who have completed 3 cycles of I and started V were eligible for the study. Patients treated with I+V in clinical trials were excluded. All patients were scheduled to receive fixed-duration I+V. After 3 lead-in cycles of I (420mg once daily), V was added for 12 cycles with the standard weekly ramp-up (20-50-100-200-400mg). The primary objective of this study was to determine the rate of discontinuation due to toxicity of I+V. Secondary objectives included overall response (ORR), safety, baseline characteristics associated with treatment discontinuation, and survival analysis. Results. We gathered data from 220 patients (intention-to-treat population) from 45 institutions in 11 countries. At the time of data cut-off, 14 patients were still receiving I lead-in, and 4 discontinued I before initiating V [reasons for discontinuation: 2 atrial fibrillation (AF), 1 diarrhea, and 1 grade 5 infection]. Overall, 202 patients were included in the analysis (treated population). The median age at I+V initiation was 65 years [interquartile range (IQR) 56-70]. Most patients were males (121, 59.9%), and 24 (12.3%) had an ECOG performance status of 2 or higher. Regarding prognostic markers, 112/179 (62.6%) patients carried unmutated IGHV genes, and 29/148 (16.4%) and 7/192 (3.6%) had del(11q) and del(17p) (determined by fluorescence in situ hybridization), respectively. TP53 mutations were present in 7/171 (4.1%) cases. At the data cut-off (30 June 2025), 201 (99.5%) patients were alive, and 151 (82.1%) were still on treatment. Among the 190 with at least 6 months of follow-up available for response assessment, the overall response rate was 95.6%. AEs of any grade were present in 122 (61.6%) patients. Specifically, 86 (43.4%) experienced non-hematological AEs, of which 23 (11.3%) were grade 3 or higher (including, 9 infective events, including 2 febrile neutropenia; 4 arterial hypertension; 3 AF; 1 rash; 1 diarrhea; 1 ventricular arrhythmia). No fatal treatment-related AEs have been reported to date. Seven (3.6%) patients developed laboratory tumor lysis syndrome (TLS), but no clinical TLS occurred. One patient developed Richter transformation (large B-cell lymphoma variant). Regarding hematological AEs, grade 3 or higher neutropenia, anemia and thrombocytopenia occurred in 48 (64.8%), 9 (20.9%), and 6 (15%) of patients, respectively. One patient died after being diagnosed with lung cancer. Seven (3.4%) patients discontinued I+V due to toxicity. Reasons for discontinuation included: acute generalized exanthematous pustulosis; AF; ventricular arrhythmia; heart failure (I was discontinued but V was completed as per treatment plan); neutropenia and heart failure; recurrent urinary tract infections and diarrhea; AF and stroke. The median age of patients who discontinued I+V treatment was 64.5 years (IQR 64-74). Five (71.4%) had at least one comorbidity: the most common was arterial hypertension (3/7, 43%). The discontinuation rates for patients in a Captivate-like (aged ≤ 70 years) and Glow-like (≥ 65 years without del17p) subgroups were 3.2% (5/153) and 4.9% (5/102), respectively. Conclusions. We herein confirm the efficacy and tolerability of I+V in the real-world setting. Notably, the discontinuation rate of I+V in our study compares favorably with the discontinuation rate in pivotal clinical trials, even in elderly patients, suggesting that I+V is an appropriate treatment option in a broad patient population. Longer follow-up will allow the assessment of real-world progression-free survival and time to next treatment after I+V.

The concept of fitness to receive treatment with novel agents in chronic lymphocytic leukemia (CLL) remains debated. Comorbidities and treatment-related logistics are increasingly recognized as key factors in treatment feasibility. Venetoclax- obinutuzumab (VO) has demonstrated efficacy in both fit and unfit patients in clinical trials, yet real-world data remain limited. This retrospective, multicenter study analyzed disease- and patient-related factors affecting VO management and outcomes in 271 patients. Fitness was assessed using comorbidity indices (CLL-CI, CIRS, CCI), Eastern Cooperative Oncology Group performance status, and caregiver need. Adverse events (AE) and treatment modifications were evaluated across four treatment phases. The median age of the patients was 66 years (19% ≥75 years old); 83% had comorbidities, 34% required polypharmacy, and 10% needed caregiver support. Overall, 96% completed debulking, 89% the full regimen, while 11% discontinued due to toxicity (Tox-DTD). Grade ≥3 AE occurred in 55%, tumor lysis syndrome in 6%, severe infusion-related reactions in 5%. Overall, 3.3% of the patients died during treatment. Unfit patients did not show a significantly higher risk of treatment modifications due to AE. Dose adjustments were more frequent during debulking. None of the validated fitness scores predicted treatment feasibility or Tox-DTD. Global feasibility was impacted by age (P=0.002), prior malignancies (P=0.003), prolonged steroid pre-treatment (P<0.001), and baseline thrombocytopenia (P=0.013). Tox-DTD correlated with caregiver need (P=0.029), endocrine comorbidities (P=0.025), prior malignancies (P=0.002), hypogammaglobulinemia (P=0.003), high lymphocyte count (P=0.034), and prolonged steroid pre-treatment (P=0.006). In conclusion, this study confirms the feasibility of VO treatment in CLL clinical practice, highlighting the role of traditionally overlooked factors that ultimately do have an impact.

Fixed duration venetoclax-obinutuzumab (VO) is approved in treatment naïve (TN) chronic lymphocytic leukemia (CLL), based on CLL14 study addressed to patients (pts) with coexisting conditions. The combinations showed also to be effective and well tolerated in the younger population enrolled in the randomized CLL13 trial. The aim of this retrospective, multicenter Italian study is to evaluate the feasibility and tolerability of this combination in TN CLL in common clinical practice as well as reasons for choosing fixed-duration VO instead of continuous BTKi. Consecutive pts receiving first-line therapy after VO approval/reimbursement in Italy (May 2022) were considered. Reasons for choosing the fixed duration treatment were recorded. The impact of clinical, biological, and demographic characteristics on VO feasibility (definitive treatment discontinuation and/or schedule modifications due to toxicity) and tolerability were analyzed. Debulking (Deb) phase (D1-D56) was separately evaluated to better understand its influence on treatment management. From May 2022 to June 2023, 790 treatment naïve continuous pts were treated with targeted agents in 49 centers. Treatment choice consisted of: continuous BTKi in 558 pts and fixed-duration VO in 232 (the latter representing the population of our analysis). The main reasons given by physicians for choosing VO instead of BTKi were: disease biology 46% (mutated IgHV status), fixed duration 33%, comorbidities 15%, patient choice 6%. Pts' characteristics are shown in Table 1. When considering Deb-phase (232 pts), VO was regularly administered according to the investigator brochure in 150 (64.7%). In 22 cases (9.5%) the schedule was a priori modified by clinicians: 12 pts started with V led-in and postponed O infusion at C2D1; in 10 planned O D8 and D15 infusions were omitted. Overall, 12 pts (5.2%) permanently discontinued VO due to toxicity. 3 of them dying due to: COVID pneumonia, invasive aspergillosis, VO-unrelated cachexia. In the remaining 48 (20.7%) schedule was adjusted due to AEs. Treatment modifications, overlapping in some cases were: 42 extended the Deb-phase (median days to completion 63, range 59-130); 14, never reached the full V dose; 31 did not perform the planned 5 O infusions (median 3 infusions, range 1-4). No age, neither coexisting conditions influenced treatment feasibility. The only parameters having an impact on Deb-phase discontinuation or schedule modifications due to toxicity were: baseline ANC<1500/mmc (OR 3.1, p=.035), hypogammaglobulinemia (OR 2.2, p=.018), concomitant use of anticoagulants (3.13, p=.029). Overall 23 pts (9.9%), including 7 categorized as high risk TLS, were hospitalized for treatment initiation. During Deb-phase grade 3-4 AEs occurred in 69 pts (30%): neutropenia (18%); thrombocytopenia (14%); infections (5%); IRR (5%). Development of any severe AE was influenced by: upper GI disorder, baseline neutropenia or thrombocytopenia. TLS was recorded in 13 pts (6%): 11 O-related and 4 V-related. All 4 clinical TLS were considered as secondary to O. Only high CLL-CI risk was associated with TLS. None of the baseline factors nor type of steroids premedication predicted IRR. At the present follow-up of the 232 pts considered: 142 completed the 6 cycles of combinations treatment, 75 are still ongoing, 15 definitively discontinued treatment for AEs. Overall, 42 pts received VO with an adjusted schedule for toxicities: 22 are receiving V at reduced dose, 39 pts did not complete the planned O infusions (treatment modifications overlapping in some cases). G 3-4 toxicity developed in 78 pts being neutropenia and infections the most common reported. At univariate analysis factors affecting treatment feasibility were: presence of endocrine comorbidity; intermediate/high CLL-CI and hypogammaglobulinemia. To our knowledge this is the first real-world study on clinical factors that may influence VO feasibility. Despite this setting of unselected population, most clinicians were adherent to VO schedule. A low rate of pts permanently discontinued therapy during Deb-phase with no impact of age or comorbidities on feasibility. Furthermore, TLS and IRR were in line with clinical trials. Longer follow-up data will be reported at the meeting allowing by multivariate analysis to better clarify the role of comorbidities on treatment management and the reproducibility of VO tolerability in common clinical practice.

In this retrospective international multicenter study, we describe the clinical characteristics and outcomes of patients with chronic lymphocytic leukemia (CLL) and related disorders (small lymphocytic lymphoma and high-count monoclonal B lymphocytosis) infected by SARS-CoV-2, including the development of post-COVID condition. Data from 1540 patients with CLL infected by SARS-CoV-2 from January 2020 to May 2022 were included in the analysis and assigned to four phases based on cases disposition and SARS-CoV-2 variants emergence. Post-COVID condition was defined according to the WHO criteria. Patients infected during the most recent phases of the pandemic, though carrying a higher comorbidity burden, were less often hospitalized, rarely needed intensive care unit admission, or died compared to patients infected during the initial phases. The 4-month overall survival (OS) improved through the phases, from 68% to 83%, p = .0015. Age, comorbidity, CLL-directed treatment, but not vaccination status, emerged as risk factors for mortality. Among survivors, 6.65% patients had a reinfection, usually milder than the initial one, and 16.5% developed post-COVID condition. The latter was characterized by fatigue, dyspnea, lasting cough, and impaired concentration. Infection severity was the only risk factor for developing post-COVID. The median time to resolution of the post-COVID condition was 4.7 months. OS in patients with CLL improved during the different phases of the pandemic, likely due to the improvement of prophylactic and therapeutic measures against SARS-CoV-2 as well as the emergence of milder variants. However, mortality remained relevant and a significant number of patients developed post-COVID conditions, warranting further investigations.

Introduction: Although Waldenstrom Macroglobulinemia (WM) typically affects the elderly, no studies so far have specifically addressed the impact of age, comorbidities, ECOG-PS and concomitant medications on treatment outcomes. Data on WM receiving ibrutinib outside of clinical trials are sparse, showing 18-20% and 8-35% of pts requiring permanent dose reduction (PDR) and toxicity-related definitive treatment discontinuation (Tox-DTD). Furthermore, the impact of polypharmacy and drug interference while on ibrutinib is still unexplored. The aim of this study is to evaluate which fitness parameters are significant for treatment outcome and management in patients with WM receiving ibrutinib in clinical practice. Methods: This is a multicenter retrospective study analyzing the impact of age (≥75y), CIRS (>6), major CIRS comorbidity (at least one organ with a CIRS score ≥3, CIRS3+), ECOG-PS (>1), polypharmacy (>3 concomitant medications), type of concomitant medications, CrCl (<30; <50 ml/min), baseline nephropathy, cardiopathy, hypertension, neuropathy, neutropenia and disease characteristics on tox-DTD; PDR; PFS, EFS (event: tox-DTD, PDR, progression, death) and OS. Medical conditions that were deemed to be complications of WM and WM diagnosis itself, were not included in CIRS score calculation. Results: From Aug 2016 to Apr 2022, 206 pts were included in the analysis. Pts' characteristics are reported in table 1. After a median follow up of 26.6 mo (range 0.5-70.5 mo), 139 pts (67.5%) are still on ibrutinib. Treatment temporary interruption occurred in 60 pts (29.6%) for a median of 18 consecutive days. Overall, 67 pts discontinued ibrutinib due to: PD in 30 (14.6%); toxicity in 23 (11.2%, Tox-DTD); other reasons in 14 (6.8%). Median time to Tox-DTD was 7.5 mo with recurrent atrial fibrillation (AF) in 10/23 pts being the most common recorded toxicity. Fifty-three pts (25.7%) required ibrutinib dose reduction at least once, followed by PDR in 40 (19.4%) of them. AF and diarrhea were the most common reasons for PDR both occurring in 7 pts. Median time to PDR was 7.1 mo. Pts with very-high revised-IPSSWM and CrCl<50 showed higher risk of Tox-DTD, that was confirmed also at multivariate analysis (p .002 and p .025, respectively). While ECOG-PS>1, CIRS>6 and cardiocomorbidity significantly influenced PDR at univariate analysis, only ECOG-PS maintained its independent role (p <.001). Number and type of concomitant medications had no impact on ibrutinib management. Median PFS, EFS and OS for the whole population were not reached and resulted 73.3%, 54.1% and 85.3% at 2 years, respectively. Age, ECOG-PS, CrCl>50 and nephropathy negatively predicted all survival outcomes at univariate analysis. The presence of major comorbidities, but not CIRS>6 impacted on OS. At Cox proportional regression hazard model, only ECOG-PS>1 confirmed its role on PFS, EFS and OS (p <.001), while CrCl<50 was significant for EFS (p .007) and OS (p .003). Among baseline disease characteristics CXCR4 mutation was the only factor independently associated with progression (p .023). Results from univariate analysis are summarized in Table 2. PFS was significantly impacted by PDR (p<.0001), also showing a trend in pts temporarily interrupting ibrutinib (p .053). Conclusions: To our knowledge this is the first series analyzing the role of age, comorbidities and concomitant medications in patients with WM receiving ibrutinib. Poor ECOG-PS and compromised renal function emerged as significant prognostic baseline parameters on both treatment management and survival. High comorbidity burden (CIRS>6) but not presence of major comorbidity shows to associate with schedule modifications. Age per se did not result as a risk factor for toxicity-related discontinuations or dose reductions, nevertheless pts with very-high revised-IPSSWM, that includes age in its score calculation, were at higher risk of Tox-DTD. Importantly, as per our data neither polypharmacy, nor type of concomitant medication interfere with ibrutinib management. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

BACKGROUND. Infection by SARS-CoV2 remains a worldwide health burden. Previous studies by the ERIC (European Research Initiative on CLL) showed that patients with chronic lymphocytic leukemia (CLL) have a very-high risk of severe Coronavirus disease 19 (COVID19). In particular, age, CLL-directed treatment, and cardiac failure were identified as significant risk factors of overall survival (OS). Since the beginning of 2020 different treatment strategies have been used to fight COVID19 and different SARS-CoV2 variants alternated during the pandemic, however very few studies analyzed their impact on patients with CLL. AIMS. The aims of this study were to investigate different manifestations, treatments and outcome of COVID19 in patients with CLL/SLL (small lymphocytic lymphoma), and MBL (monoclonal B-cell lymphocytosis). METHODS. This is a retrospective international multicenter ERIC study from Jan 2020 till May 2022. CLL diagnosis, COVID-19 management, review of medical history, and assessment of patient status were performed by local investigators following international guidelines. Ninety institutions participated in the study. Statistical analyses were conducted using R software. During the pandemic we identified 4 phases: 1st Jan 2020 - Jun 2020, 2nd Jul 2020 - Feb 2021, 3rd Mar 2021 - Dec 2021 and 4th Jan 2022 - May 2022. RESULTS. We gathered data from 1540 patients (93.8% CLL, 4.1% SLL and 2.1% MBL), 65% males, the median age at COVID19 was 69 years, median CIRS score was 4 (IQR 2-7), 49.6% were treated in the last 12 months before COVID19, 38.8% was on treatment at COVID19 onset (BTK inhibitor-based 51.1%, BCL2 inhibitor-based 20.7%, chemo/chemoimmunotherapy 21.5%, 6.7% others). Overall, 34.4% of patients was managed at home, 49.9% needed hospitalization and 15.7% was admitted to the intensive care unit (ICU). After a median follow-up of 2.7 months, the infection was resolved in 1124/1540 (73%) cases, while 23% died and 3.6% were still under medical observation. Distribution of patients among time is shown in Fig. 1A. Three hundred and four (19.8%) patients were infected during the 1st, 737 (48%) during the 2nd, 137 (8.9%) during the 3rd and 357 (23.3%) during the last 4th phase. Comparing the features of patients infected in different phases, age at COVID19 and distribution of biological markers were similar, but more patients in the latter phases suffered from arrhythmias (8.2% vs 10.5% vs 16.1% vs 14.2%, p=0.01), chronic renal disease (3.9% vs 5.9% vs 8.9% and 11.1%, p=0.003) and other malignancies (0.3% vs 1.8% vs 2.2% vs 3.6%, p=0.04). Vaccinated patients (0% vs 0.4% vs 45.7% vs 89.1%, p<0.001) and those treated for CLL in the last 12 months (44.1% vs 44.1% vs 55.7% vs 66.1%, p<0.001) were also more common in the last phases. COVID19 signs and symptoms differed between early and late phases, with less fever (p<0.001) and dyspnea (p=0.028) but more fatigue (p<0.001), cough (p<0.001), headache (p<0.001), anosmia/ageusia (p<0.001) and myalgia/arthralgia (p<0.001) in the later phases. COVID19 management also changed over time, with less patients receiving a SARS-CoV2 therapy (87.6% vs 74.7% vs 78.1% vs 67.9%, p<0.001). In particular, hydroxychloroquine, azithromycin, steroids and anti-IL6/IL6R were more commonly used in the first 2 phases while antiviral and monoclonal antibodies (mAb) were mainly employed in the last 2 phases. Less patients were hospitalized (84.5% vs 67.3% vs 60.3% vs 45.8%, p<0.001), needed ICU admission (20.6% vs 17.2% vs 13.3% vs 8.1%, p<0.001) or died (29.8% vs 25.5% vs 21.8% vs 15.8%, p=0.002) through these phases. These improvements in patients' management led to an increase of OS, with 2-month OS of 70%, 74%, 81% and 83% for patients diagnosed during the 1st, 2nd,3rd and 4th phase (p=0.0015, Fig. 1B). CONCLUSION. We analyzed one of the largest series of patients with CLL infected by SARS-CoV2 over more than 2 years of COVID19 pandemic. Patients infected during the most recent phases, though carrying a higher comorbidity burden, were less frequently hospitalized, only rarely needed ICU admission and died due to the SARS-CoV2 infection in a lower proportion compared to initial phases. The improvement in COVID-19 management with effective antiviral drugs, mAb and the high rate of vaccination together with the change in SARS-CoV2 variants over time may have played an important role in this outcome. AV, LS, TC, AK, CD and GK equally contributed. KS and PG are both last authors. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to Coronavirus disease 2019 (COVID-19) due to age, disease, and treatment-related immunosuppression. We aimed to assess risk factors of outcome and elucidate the impact of CLL-directed treatments on the course of COVID-19. We conducted a retrospective, international study, collectively including 941 patients with CLL and confirmed COVID-19. Data from the beginning of the pandemic until March 16, 2021, were collected from 91 centers. The risk factors of case fatality rate (CFR), disease severity, and overall survival (OS) were investigated. OS analysis was restricted to patients with severe COVID-19 (definition: hospitalization with need of oxygen or admission into an intensive care unit). CFR in patients with severe COVID-19 was 38.4%. OS was inferior for patients in all treatment categories compared to untreated ( p < 0.001). Untreated patients had a lower risk of death (HR = 0.54, 95% CI:0.41–0.72). The risk of death was higher for older patients and those suffering from cardiac failure (HR = 1.03, 95% CI:1.02–1.04; HR = 1.79, 95% CI:1.04–3.07, respectively). Age, CLL-directed treatment, and cardiac failure were significant risk factors of OS. Untreated patients had a better chance of survival than those on treatment or recently treated.

Chronic lymphocytic leukemia (CLL) is a disease of the elderly, characterized by immunodeficiency. Hence, patients with CLL might be considered more susceptible to severe complications from COVID-19. We undertook this retrospective international multicenter study to characterize the course of COVID-19 in patients with CLL and identify potential predictors of outcome. Of 190 patients with CLL and confirmed COVID-19 diagnosed between 28/03/2020 and 22/05/2020, 151 (79%) presented with severe COVID-19 (need of oxygen and/or intensive care admission). Severe COVID-19 was associated with more advanced age (≥65 years) (odds ratio 3.72 [95% CI 1.79–7.71]). Only 60 patients (39.7%) with severe COVID-19 were receiving or had recent (≤12 months) treatment for CLL at the time of COVID-19 versus 30/39 (76.9%) patients with mild disease. Hospitalization rate for severe COVID-19 was lower (p < 0.05) for patients on ibrutinib versus those on other regimens or off treatment. Of 151 patients with severe disease, 55 (36.4%) succumbed versus only 1/38 (2.6%) with mild disease; age and comorbidities did not impact on mortality. In CLL, (1) COVID-19 severity increases with age; (2) antileukemic treatment (particularly BTK inhibitors) appears to exert a protective effect; (3) age and comorbidities did not impact on mortality, alluding to a relevant role of CLL and immunodeficiency.

Introduction: Patients (pts) with CLL may be at particular risk of severe COVID-19 given advanced age and immune dysregulation. Two large series with limited follow-up have reported outcomes for pts with CLL and COVID-19 (Scarfò, et al. Leukemia 2020; Mato, et al. Blood 2020). To provide maximal clarity on outcomes for pts with CLL and COVID-19, we partnered in a worldwide effort to describe the clinical experience and validate predictors of survival, including potential treatment effects. Methods: This international collaboration represents a partnership between investigators at 141 centers. Data are presented in two cohorts. Cohort 1 (Co1) includes pts captured through efforts by European Research Initiative on CLL (ERIC), Italian CAMPUS CLL Program, and Grupo Español de Leucemia Linfática Crónica. The validation cohort, Cohort 2 (Co2), includes pts from US (66%), UK (23%), EU (7%), and other countries (4%). There is no overlap in cases between cohorts. CLL pts were included if COVID-19 was diagnosed by PCR detection of SARS-CoV-2 and they required inpatient hospitalization. Data were collected retrospectively 2/2020 - 5/2020 using standardized case report forms. Baseline characteristics, preexisting comorbidities (including cumulative illness rating scale (CIRS) score ≥6 vs. <6), CLL treatment history, details regarding COVID-19 course, management, and therapy, and vital status were collected. The primary endpoint of this study was to estimate the case fatality rate (CFR), defined as the proportion of pts who died among all pts hospitalized with COVID-19. Chi-squared test was used to compare frequencies; univariable and multivariable analyses utilized Cox regression. Predictors of inferior OS in both Co1 and Co2 were included in multivariable analyses. Kaplan-Meier method was used to estimate overall survival (OS) from time of COVID-19 diagnosis (dx). Results: 411 hospitalized, COVID-19 positive CLL pts were analyzed (Co1 n=281, Co2 n=130). Table 1 describes baseline characteristics. At COVID-19 dx, median age was 72 in Co1 (range 37-94) and 68 in Co2 (range 41-98); 31% (Co1) and 45% (Co2) had CIRS ≥6. In Co1, 48% were treatment-naïve and 26% were receiving CLL-directed therapy at COVID-19 dx (66% BTKi ± anti-CD20, 19% Venetoclax ± anti-CD20, 9.6% chemo/chemoimmunotherapy (CIT), 1.4% PI3Ki, 4% other). In Co2, 36% were never treated and 49% were receiving CLL-directed therapy (65% BTKi ± anti-CD20, 19% Venetoclax ± anti-CD20, 9.4% multi-novel agent combinations, 1.6% CIT, 1.6% PI3Ki, 1.6% anti-CD20 monotherapy, 1.6% other). Most pts receiving CLL-directed therapy had it held at COVID-19 diagnosis (93% in Co1 and 81% in Co2). Frequency of most COVID-19 symptoms/laboratory abnormalities were similar in the two cohorts including fever (88% in both), lymphocytosis (ALC ≥30 x 109/L; 27% vs. 21%), and lymphocytopenia (ALC < 1.0 x 109/L; 18% vs. 28%), while others varied between Co1 and Co2 (p<0.0001), including cough (61% vs. 93%), dyspnea (60% vs. 84%), fatigue (13% vs. 77%). Median follow-up was 24 days (range 2-86) in Co1 and 17 days (1-43) in Co2. CFRs were similar in Co1 and Co2, 30% and 34% (p=0.45). 54% and 43% were discharged while 16% and 23% remained admitted at last follow-up in Co1 and Co2, respectively. The proportion of pts requiring supplemental oxygen was similar (89% vs. 92%) while rate of ICU admission was higher in Co2 (20% vs. 48%, p<0.0001). Figure 1 depicts OS in each cohort. Univariable analyses demonstrated that age and CIRS ≥6 significantly predicted inferior OS in both cohorts, while only age remained an independent predictor of inferior OS in multivariable analyses (Table 2). Prior treatment for CLL (vs. observation) predicted inferior OS in Co1 but not Co2. Conclusions : In the largest cancer dx-specific cohort reported, pts with CLL hospitalized for COVID-19 had a CFR of 30-34%. Advanced patient age at COVID-19 diagnosis was an independent predictor of OS in two large cohorts. This CFR will serve as a benchmark for mortality for future outcomes studies, including therapeutic interventions for COVID-19 in this population. The effect of CLL treatment on OS was inconsistent across cohorts; COVID-19 may be severe regardless of treatment status. While there were no significant differences in distribution of current lines of therapy between cohorts, prior chemo exposure was more common in Co1 vs. Co2, which may account for difference in OS. Extended follow-up will be presented. Disclosures Roeker: American Society of Hematology: Research Funding; Abbott Laboratories: Other: spouse with minority ownership interest ; AbbVie: Other: spouse with minority ownership interest . Scarfo:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees. Abrisqueta:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau. Eyre:AbbVie: Consultancy, Honoraria, Other: travel support; Gilead: Consultancy, Honoraria, Other: travel support; Janssen: Consultancy, Honoraria, Other: travel support; KITE, AZ, Loxo Oncology at Lilly: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Muntañola Prat:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; participated in advisory boards; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; participated in advisory boards; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; participated in advisory boards. Villacampa:AstraZeneca: Other: advisory role; Merck Sharp & Dohme: Honoraria. Leslie:AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC therapeutics: 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; BeiGene: Speakers Bureau; KitePharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics/Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Speakers Bureau; Karyopharm: Speakers Bureau; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Allan:Acerta, Genentech, Abbvie, Sunesis, Ascentage, Pharmacyclics, Janssen, AstraZeneca, BeiGene: Consultancy; Celgene, Genentech, Janssen, TG Therapeutics: Research Funding; Abbvie, Janssen, AstraZeneca, Pharmacyclics: Honoraria. Furman:Incyte: Consultancy; Genentech: Consultancy; Sunesis: Consultancy; Pharmacyclics: Consultancy; Loxo Oncology: Consultancy; Oncotarget: Consultancy; Janssen: Consultancy, Speakers Bureau; TG Therapeutics: Consultancy, Research Funding; Abbvie: Consultancy; Beigene: Consultancy; AstraZeneca: Consultancy, Research Funding; Acerta: Consultancy; Verastem: Consultancy. Pagel:BeiGene, Astrazeneca, Loxo Oncology, Gilead: Consultancy. Hernandez-Rivas:Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Rovi: Membership on an entity's Board of Directors or advisory committees. Patel:Genentech: Consultancy, Speakers Bureau; Adaptive Biotechnologies: Consultancy; Janssen: Consultancy, Speakers Bureau; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy; Kite: Consultancy; Pharmacyclics: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau. Motta:Roche: Honoraria; Janssen: Honoraria. Lamanna:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Verastem: Research Funding; Bei-Gene: Research Funding; TG Therapeutics: Research Funding; Acerta: Research Funding; Celgene: 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; Janssen: Membership on an entity's Board of Directors or advisory committees. Vitale:Janssen: Honoraria. Kamdar:Roche: Research Funding. Österborg:BeiGene: Research Funding; Kancera: Current equity holder in publicly-traded company, Research Funding; Sanofi: Consultancy; Karolinska Univeristy Hospital, Stockholm, Sweden: Current Employment. Hanson:Janssen-Cilag: Research Funding; Gilead: Research Funding; AbbVie: Honoraria. Eichhorst:ArQule: Consultancy, Honoraria, Other: travel support, Research Funding; BeiGene: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: travel support, Research Funding; Oxford Biomedica: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding. Reda:Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Varettoni:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel/accommodations/expenses; AbbVie: Other: Travel/accommodations/expenses; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees. Marchetti:Gilead: Consultancy; Novartis: Speakers Bureau; Amgen: Speakers Bureau; AbbVie: Other: Sponsored meetings; Takeda: Other: Sponsored meetings; Pfeizer: Other: Sponsored meetings. Munir:F. Hoffmann-La Roche: Consultancy, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland; Alexion: Honoraria. Zabalza:Janssen: Honoraria, Other: travel grants; Roche: Other: travel grants; Novartis: Other: travel grants. Janssens:Amgen: Consultancy, Other: travel grants; speaker fees; Abbvie: Consultancy, Other: travel grants; speaker fees; Celgene: Consultancy, Other: travel grants; speaker fees; Janssen: Consultancy, Other: travel grants; speaker fees; Gilead: Consultancy, Other: travel grants; speaker fees; Novartis: Consultancy, Other: travel grants; speaker fees; Sanofi-Genzyme: Consultancy, Other: travel grants; speaker fees; Roche: Consultancy, Other: travel grants; speaker fees. Niemann:AstraZeneca: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Sunesis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Danish Cancer Society: Honoraria, Research Funding; Novo Nordisk Foundation: Honoraria, Research Funding. Perini:Takeda: Honoraria; Janssen: Honoraria, Speakers Bureau; Abbvie: Speakers Bureau. Patten:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Honoraria. Marasca:Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Honoraria. Iyengar:Janssen: Honoraria; Gilead: Honoraria. Ferrari:Abbvie: Honoraria. El-Sharkawi:Roche: Other: Conference fees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Itchaki:Abbvie Inc: Consultancy, Research Funding. Ma:Novartis: Research Funding; Juno: Research Funding; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Bioverativ: Consultancy, Honoraria; BeiGene: Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding; TG Therapeutics: Research Funding. Van Der Spek:AMGEN: Other: Teaching activities. Seymour:Seattle Genetics: Research Funding; Merck: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Genentech: Research Funding; Bristol-Myers Squibb: Research Funding. Rigolin:Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mauro:Roche: Other; Octopharma: Other; Takeda-Shire: Other; Gilead: Other; Janssen: Other; Abbvie: Other. Laurenti:Janssen: Honoraria; Gilead: Honoraria; AbbVie: Honoraria; Roche: Honoraria. Levin:Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; Roche: Membership on an entity's Board of Directors or advisory committees, Other: travel compensation. Špaček:Gilead: Honoraria; Abbvie: Honoraria; Janssen: Honoraria. Walewska:AbbVie: Other: sponsored for educational meetings, Speakers Bureau; Janssen: Other: sponsored for educational meetings, Speakers Bureau; Gilead: Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees. Wiestner:Pharmacyclics LLC, an AbbVie Company; Acerta, Merck, Nurix, Verastem, and Genmab: Research Funding; National Institutes of Health: Patents & Royalties: and other intellectual property. Broom:Gilead: Other: Travel support, Speakers Bureau. Kater:Abbvie: Research Funding; Roche: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Genentech: Research Funding. Ujjani:AstraZeneca: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Verastem Oncology: Consultancy, Honoraria; Gilead/Kite: Consultancy, Research Funding; Atara: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; MorphoSys: Consultancy. Vandenberghe:Celgene: Other: sponsorship to attend Lugano lymphoma meeting in 2019; Gilead: Other: travel grants, Research Funding; Abbvie: Other: travel grants, Research Funding; Janssen: Other: travel grants; Roche: Other: travel grants, Research Funding. Chong:Novartis: Membership on an entity's Board of Directors or advisory committees; Tessa: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; KITE Pharma: Membership on an entity's Board of Directors or advisory committees. Pu:Takeda Pharmaceuticals: Consultancy. Brown:Janssen, Teva: Speakers Bureau; Gilead, Loxo, Sun, Verastem: Research Funding; Abbvie, Acerta, AstraZeneca, Beigene, Invectys, Juno/Celgene, Kite, Morphosys, Novartis, Octapharma, Pharmacyclics, Sunesis, TG Therapeutics, Verastem: Consultancy. Trentin:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria. Farina:Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Sanchez:Abbvie: Other: travel grants; Amgem: Other: travel grants; Janssen: Other: travel grants; Celgene: Other: travel grants; Roche: Other: travel grants. Shadman:Abbvie, Genentech, Astra Zeneca, Sound Biologics , Pharmacyclics, Verastem, ADC therapeutics, Beigene, Cellectar, BMS, Morphosys and Atara Biotherapeutics: Consultancy; Mustang Bio, Celgene, Pharmacyclics, Gilead, Genentech, Abbvie, TG therapeutics, Beigene, Astra Zeneca, Sunesis, Beigene: Research Funding. Foglietta:Janssen: Honoraria; Gilead: Honoraria. Jaksic:Roche: Honoraria; Janssen: Honoraria; Abbvie: Honoraria. Sportoletti:AbbVie: Honoraria; Janssen: Honoraria. Barr:Morphosys: Consultancy; Gilead: Consultancy; AstraZeneca: Consultancy, Research Funding; Verastem: Consultancy; Seattle Genetics: Consultancy; TG therapeutics: Consultancy, Research Funding; Abbvie/Pharmacyclics: Consultancy, Research Funding; Celgene: Consultancy; Merck: Consultancy; Genentech: Consultancy; Janssen: Consultancy. Ruchlemer:Abbvie Inc: Consultancy, Research Funding. Kersting:Celgene: Other: travel grant; Janssen: Research Funding; Abbvie: Research Funding. Huntington:Pharmacyclics: Honoraria; AbbVie: Consultancy; Novartis: Consultancy; Genentech: Consultancy; DTRM: Research Funding; Celgene: Consultancy, Research Funding; Bayer: Consultancy, Honoraria; Astrazeneca: Honoraria; TG Therapeutics: Research Funding. Herishanu:Roche: Honoraria; Sanofi: Honoraria; Medison: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; AstraZeneca: Honoraria. Jacobs:TG Therapeutics, Inc.: Research Funding; Astra Zeneca: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Pharmacyclics: Research Funding, Speakers Bureau; Seattle Genetics: Consultancy; Verastem: Consultancy; Janssen: Consultancy, Speakers Bureau; Genentech: Speakers Bureau; Sanofi Genzyme: Speakers Bureau. Portell:BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy; TG Therapeutics: Research Funding; Infinity: Research Funding; Roche/Genentech: Consultancy, Research Funding; Xencor: Research Funding; Bayer: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding; AbbVie: Research Funding. Rambaldi:Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Astellas: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); BMS/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); University of Milan: Current Employment; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of parent study and funding of editorial support. Received travel support., Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support from Gilead.; Amgen: Consultancy, 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 grant from Amgen Inc.; Omeros: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Advisory board and speaker fees from Pfizer.. Brander:Verastem: Consultancy, Honoraria, Other, Research Funding; NCCN: Other; Novartis: Consultancy, Other; Teva: Consultancy, Honoraria; Tolero: Research Funding; NCCN: Other; Novartis: Consultancy, Other; Teva: Consultancy, Honoraria; Tolero: Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; ArQule: Consultancy, Other, Research Funding; Ascentage: Other, Research Funding; AstraZeneca: Consultancy, Honoraria, Other, Research Funding; BeiGene: Other, Research Funding; DTRM: Other, Research Funding; Genentech: Consultancy, Honoraria, Other, Research Funding; Juno/Celgene/BMS: Other, Research Funding; MEI Pharma: Other, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other, Research Funding; Pfizer: Consultancy, Other; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding. Rossi:Abbvie: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Advisory board; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Coscia:Karyopharm Therapeutics: Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Coombs:Abbvie: Consultancy, Honoraria; Genentech: Honoraria; AstraZeneca: Honoraria; MEI Pharma: Honoraria; LOXO Oncology: Honoraria; Octapharma: Honoraria; Novartis: Honoraria. Schuster:Novartis, Genentech, Inc./ F. Hoffmann-La Roche: Research Funding; AlloGene, AstraZeneca, BeiGene, Genentech, Inc./ F. Hoffmann-La Roche, Juno/Celgene, Loxo Oncology, Nordic Nanovector, Novartis, Tessa Therapeutics: Consultancy, Honoraria. Foà:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cuneo:Astra Zeneca: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bosch:Jansen: Honoraria; Abbvie: Honoraria; Novartis: Honoraria; Astra Zeneca: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Roche: Honoraria. Stamatopoulos:AstraZeneca: Honoraria; Janssen, Gilead, Abbvie: Honoraria, Research Funding. Ghia:Adaptive, Dynamo: Consultancy, Honoraria; Novartis: Research Funding; BeiGene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Celgene/Juno: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; MEI: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Gilead: Consultancy, Honoraria, Research Funding; ArQule: Consultancy, Honoraria; Acerta/AstraZeneca: Consultancy, Honoraria. Mato:Adaptive: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; BeiGene: Consultancy; LOXO: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding.

The complex karyotype (CK) is an established negative prognostic marker in a number of haematological malignancies. After the introduction of effective mitogens, a growing body of evidence has suggested that the presence of 3 or more aberrations by conventional banding analysis (CBA) is associated with an unfavorable outcome in chronic lymphocytic leukemia (CLL). Thus, the importance of CBA was recognized by the 2018 guidelines of the International Workshop on CLL, which proposed the introduction of CBA in clinical trials to validate the value of karyotype aberrations. Indeed, a number of observational studies showed that cytogenetic aberrations and, particularly, the CK may have a negative independent impact on objective outcome measures (i.e. time to first treatment, progression free survival, time to chemorefractoriness and overall survival) both in patients treated with chemoimmunotherapy and, possibly, in patients receiving novel mechanism-based treatment. Here, we set out to present the scientific evidence supporting the significance of CK as a prognostic marker in CLL and to discuss the biological basis showing that the CK is a consequence of genomic instability.

Complex karyotype (CK) is a negative prognostic factor in chronic lymphocytic leukaemia (CLL). However, CK is a heterogeneous cytogenetic category. Unbalanced rearrangements were present in 73·3% of 90 CLL patients with CK (i.e. ≥3 chromosome aberrations in the same clone), and were associated with a shorter overall survival (P = 0·025) and a shorter time to first treatment (P = 0·043) by multivariate analysis. Patients with unbalanced rearrangements presented a distinct mRNA expression profile. In conclusion, CLL patients with unbalanced rearrangements might represent a subset of very high-risk CLL patients with distinct clinical and biological characteristics.

To the editor: Chronic lymphocytic leukemia (CLL) represents the most common form of leukemia in Western countries.[1][1] The clinical course of the disease is quite heterogeneous with some patients living for years with asymptomatic disease and others experiencing early progression and requiring

We investigated whether karyotype analysis and mutational screening by next generation sequencing could predict outcome in 101 newly diagnosed chronic lymphocytic leukemia patients with high-risk features, as defined by the presence of unmutated IGHV gene and/or 11q22/17p13 deletion by FISH and/or TP53 mutations. Cytogenetic analysis showed favorable findings (normal karyotype and isolated 13q14 deletion) in 30 patients, unfavorable (complex karyotype and/or 17p13/11q22 deletion) in 34 cases and intermediate (all other abnormalities) in 36 cases. A complex karyotype was present in 21 patients. Mutations were detected in 56 cases and were associated with unmutated IGHV status (p = 0.040) and complex karyotype (p = 0.047). TP53 disruption (i.e. TP53 mutations and/or 17p13 deletion by FISH) correlated with the presence of ≥ 2 mutations (p = 0.001) and a complex karyotype (p = 0.012). By multivariate analysis, an advanced Binet stage (p < 0.001) and an unfavorable karyotype (p = 0.001) predicted a shorter time to first treatment. TP53 disruption (p = 0.019) and the unfavorable karyotype (p = 0.028) predicted a worse overall survival. A shorter time to chemorefractoriness was associated with TP53 disruption (p = 0.001) and unfavorable karyotype (p = 0.025). Patients with both unfavorable karyotype and TP53 disruption presented a dismal outcome (median overall survival and time to chemorefractoriness of 28.7 and 15.0 months, respectively). In conclusion, karyotype analysis refines risk stratification in high-risk CLL patients and could identify a subset of patients with highly unfavorable outcome requiring alternative treatments.

Autoimmune hemolytic anemia (AIHA) is one of the most common disease-specific complications of chronic lymphocytic leukemia (CLL), occurring in 3–10% of patients, with a higher incidence in advance...

In chronic lymphocytic leukemia (CLL), next-generation sequencing (NGS) analysis represents a sensitive, reproducible, and resource-efficient technique for routine screening of gene mutations.

Chronic lymphocytic leukemia (CLL) displays an extremely variable clinical behaviour. Accurate prognostication and prediction of response to treatment are important in an era of effective first-line regimens and novel molecules for high risk patients. Because a plethora of prognostic biomarkers were identified, but few of them were validated by multivariable analysis in comprehensive prospective studies, we applied in this survey stringent criteria to select papers from the literature in order to identify the most reproducible prognostic/predictive markers. Each biomarker was analysed in terms of reproducibility across the different studies with respect to its impact on time to first treatment (TTFT), progression free survival (PFS), overall survival (OS) and response to treatment. We were able to identify the following biomarkers as the most reliable in guiding risk stratification in the daily clinical practice: 17p-/TP53 mutations, IGHV unmutated configuration, short telomeres and 11q-. However, the method for measuring telomere length was not validated yet and 11q- was predictive of inferior OS only in those patients who did not receive FCR-like combinations. Stage and lymphocytosis were predictive of shorter TTFT and age, high serum thymidine kinase levels and poor performance status were predictive of shorter OS. Using our criteria no parameter was found to independently predict for inferior response to treatment.

To clarify whether karyotype aberrations (KA) involving regions not covered by the standard fluorescence in situ hybridization (FISH) panel have independent prognostic relevance, we evaluated KA by conventional cytogenetics in a learning cohort (LC; n = 166) and a validation cohort (VC; n = 250) of untreated chronic lymphocytic leukemia (CLL) patients. In the VC, novel mitogens were used to improve metaphase generation and TP53, NOTCH1, and SF3B1 mutations were assessed. KA undetected by FISH were found in 35 and 35% of the cases in the LC and VC, respectively. In addition to FISH, KA allowed reclassification of 23 and 26% of cases in the LC and VC, respectively, into a higher cytogenetic risk group. By multivariate analysis, both in the LC and VC, KA other than isolated 13q deletion correlated with a shorter time to first treatment (TFT; P < 0.001 and 0.003, respectively), while a complex karyotype predicted a worse overall survival (OS, P = 0.015 and 0.010, respectively). In the VC, where a comprehensive biologic assessment was performed, a shorter TFT was also predicted by stage (P < 0.001), IGHV mutational status (P = 0.05), and del(17p)/TP53 mutations (P = 0.033) while stage (P = 0.023) and del(17p)/TP53 mutations (P = 0.024) independently predicted a shorter OS. FISH results did not independently impact on TFT and OS, in the LC and VC cohorts; this was also the case for NOTCH1 and SF3B1 mutations in the VC. We suggest that in CLL, conventional karyotyping with novel mitogens could be more effective than FISH for the detection of KA allowing for a more precise refinement of prognosis. © 2015 Wiley Periodicals, Inc.