Clinical and Economic Implications of Hydroxyurea Intolerance in Polycythemia Vera in Routine Clinical Practice.

Background/Objectives: Polycythemia vera (PV) is a chronic hematologic neoplasm commonly treated with hydroxyurea (HU). We utilized the advanced digitalized database of Maccabi Healthcare Services to retrospectively investigate the clinical and economic implications of HU intolerance in the routine clinical care of PV patients in Israel. Methods: We collected data on demographics, physician visits, hospitalizations, laboratory results, medication purchases, cardiovascular and thrombotic events, mental health, economic outcomes, and mortality. Outcomes included cardiovascular and other thrombotic events, disease progression, mental health events, economic outcomes, and overall mortality. Results: Of the 830 patients studied, 3 (0.4%) were resistant to HU treatment, 318 (38.3%) were intolerant to HU treatment, and 509 (61.3%) were stable on HU treatment. The venous thrombosis rate was significantly higher among HU-intolerant compared to HU-stable patients (1.58 vs. 0.47 per 100 person-years [PY], respectively; p < 0.001). The rate of progression to myelofibrosis was 6 vs. 0.9 per 100 PY in HU-intolerant patients vs. HU-stable patients, respectively (p < 0.001), and the rate of progression to acute myeloid leukemia (AML) was 1.16 vs. 0.2 per 100 PY in HU-intolerant patients vs. HU-stable patients, respectively (p < 0.001). The phlebotomy requirement, mortality rate, and total hospitalization days among HU-intolerant patients were significantly higher than in HU-stable patients (p = 0.049, p < 0.001, p < 0.001, respectively). More mental health-related events were noted in HU-intolerant patients vs. HU-stable patients (p = 0.007), and the total healthcare cost ratio was 2.65 for the HU-intolerant patients compared with HU-stable patients. Conclusions: This study suggests that HU-intolerant patients are more likely to have worse outcomes than HU-stable patients, highlighting the need for the close monitoring of these patients for disease-related complications or progression.

Vitamin D supplement for patients with early-stage chronic lymphocytic leukemia is associated with a longer time to first treatment.

ABSTRACT: Low levels of vitamin D are associated with a shorter time to first treatment (TTFT) and inferior overall survival in patients with chronic lymphocytic leukemia (CLL). But whether vitamin D supplement affects the clinical course of patients with CLL, remains an open question. In this study, we aimed to retrospectively explore the clinical benefit of vitamin D supplement or one of its analogs, on TTFT and treatment-free survival (TFS) in a large cohort of patients with asymptomatic CLL, who were under watch-and-wait approach. Among the 3474 patients included in the study, 931 patients (26.8%) received either vitamin D supplement or its analog, for a minimum of 6 months. We found that vitamin D supplement was statistically significant for longer TTFT in the young cohort (age ≤65) and was associated with a longer TFS for all ages (P = .004). Among non-vitamin-D users, the median TFS was found to be 84 months, whereas among vitamin D supplement users the median TFS extended to 169 months. In conclusion, our long-term retrospective study demonstrates that the administration of vitamin D to patients with CLL in a watch-and-wait active surveillance is significantly associated with a longer TFS (in any age) and a longer TTFT among young patients (age ≤65). A prospective clinical trial is needed to validate results.

First-line venetoclax combinations versus chemoimmunotherapy in fit patients with chronic lymphocytic leukaemia (GAIA/CLL13): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: In the primary analysis report of the GAIA/CLL13 trial, we found that venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib improved undetectable measurable residual disease (MRD) rates and progression-free survival compared with chemoimmunotherapy in patients with previously untreated chronic lymphocytic leukaemia. However, to our knowledge, no data on direct comparisons of different venetoclax-based combinations are available. METHODS: GAIA/CLL13 is an open-label, randomised, phase 3 study conducted at 159 sites in ten countries in Europe and the Middle East. Eligible patients were aged 18 years or older, with a life expectancy of at least 6 months, an Eastern Cooperative Oncology group performance status of 0-2, a cumulative illness rating scale score of 6 or lower or a single score of 4 or lower, and no TP53 aberrations. Patients were randomly assigned (1:1:1:1), with a computer-generated list stratified by age, Binet stage, and regional study group, to either chemoimmunotherapy, venetoclax-rituximab, venetoclax-obinutuzumab, or venetoclax-obinutuzumab-ibrutinib. All treatments were administered in 28-day cycles. Patients in the chemoimmunotherapy group received six cycles of treatment, with patients older than 65 years receiving intravenous bendamustine (90 mg/m2, days 1-2), whereas patients aged 65 years or younger received intravenous fludarabine (25 mg/m2, days 1-3) and intravenous cyclophosphamide (250 mg/m2, days 1-3). Intravenous rituximab (375 mg/m2, day 1 of cycle 1; 500 mg/m2, day 1 of cycles 2-6) was added to chemotherapy. In the experimental groups, patients received daily venetoclax (400 mg orally) for ten cycles after a 5-week ramp-up phase starting on day 22 of cycle 1. In the venetoclax-rituximab group, intravenous rituximab (375 mg/m2, day 1 of cycle 1; 500 mg/m2, day 1 of cycles 2-6) was added. In the obinutuzumab-containing groups, obinutuzumab was added (cycle 1: 100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8 and 15; cycles 2-6: 1000 mg on day 1). In the venetoclax-obinutuzumab-ibrutinib group, daily ibrutinib (420 mg orally, from day 1 of cycle 1) was added until undetectable MRD was reached in two consecutive measurements (3 months apart) or until cycle 36. The planned treatment duration was six cycles in the chemoimmunotherapy group, 12 cycles in the venetoclax-rituximab and the venetoclax-obinutuzumab group and between 12 and 36 cycles in the venetoclax-obinutuzumab-ibrutinib group. Coprimary endpoints were the undetectable MRD rate in peripheral blood at month 15 for the comparison of venetoclax-obinutuzumab versus standard chemoimmunotherapy and investigator-assessed progression-free survival for the comparison of venetoclax-obinutuzumab-ibrutinib versus standard chemoimmunotherapy, both analysed in the intention-to-treat population (ie, all patients randomly assigned to treatment) with a split α of 0·025 for each coprimary endpoint. Both coprimary endpoints have been reported elsewhere. Here we report a post-hoc exploratory analysis of updated progression-free survival results after a 4-year follow-up of our study population. Safety analyses included all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT02950051, recruitment is complete, and all patients are off study treatment. FINDINGS: Between Dec 13, 2016, and Oct 13, 2019, 1080 patients were screened and 926 were randomly assigned to treatment (chemoimmunotherapy group n=229; venetoclax-rituximab group n=237; venetoclax-obinutuzumab group n=229; and venetoclax-obinutuzumab-ibrutinib group n=231); mean age 60·8 years (SD 10·2), 259 (28%) of 926 patients were female, and 667 (72%) were male (data on race and ethnicity are not reported). At data cutoff for this exploratory follow-up analysis (Jan 31, 2023; median follow-up 50·7 months [IQR 44·6-57·9]), patients in the venetoclax-obinutuzumab group had significantly longer progression-free survival than those in the chemoimmunotherapy group (hazard ratio [HR] 0·47 [97·5% CI 0·32-0·69], p<0·0001) and the venetoclax-rituximab group (0·57 [0·38-0·84], p=0·0011). The venetoclax-obinutuzumab-ibrutinib group also had a significantly longer progression-free survival than the chemoimmunotherapy group (0·30 [0·19-0·47]; p<0·0001) and the venetoclax-rituximab group (0·38 [0·24-0·59]; p<0·0001). There was no difference in progression-free survival between the venetoclax-obinutuzumab-ibrutinib and venetoclax-obinutuzumab groups (0·63 [0·39-1·02]; p=0·031), and the proportional hazards assumption was not met for the comparison between the venetoclax-rituximab group versus the chemoimmunotherapy group (log-rank p=0·10). The estimated 4-year progression-free survival rate was 85·5% (97·5% CI 79·9-91·1; 37 [16%] events) in the venetoclax-obinutuzumab-ibrutinib group, 81·8% (75·8-87·8; 55 [24%] events) in the venetoclax-obinutuzumab group, 70·1% (63·0-77·3; 84 [35%] events) in the venetoclax-rituximab group, and 62·0% (54·4-69·7; 90 [39%] events) in the chemoimmunotherapy group. The most common grade 3 or worse treatment-related adverse event was neutropenia (114 [53%] of 216 patients in the chemoimmunotherapy group, 109 [46%] of 237 in the venetoclax-rituximab group, 127 [56%] of 228 in the venetoclax-obinutuzumab group, and 112 [48%] of 231 in the venetoclax-obinutuzumab-ibrutinib group). Deaths determined to be associated with study treatment by the investigator occurred in three (1%) patients in the chemoimmunotherapy group (n=1 due to each of sepsis, metastatic squamous cell carcinoma, and Richter's syndrome), none in the venetoclax-rituximab and venetoclax-obinutuzumab groups, and four (2%) in the venetoclax-obinutuzumab-ibrutinib group (n=1 due to each of acute myeloid leukaemia, fungal encephalitis, small-cell lung cancer, and toxic leukoencephalopathy). INTERPRETATION: With more than 4 years of follow-up, venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib significantly extended progression-free survival compared with both chemoimmunotherapy and venetoclax-rituximab in previously untreated, fit patients with chronic lymphocytic leukaemia, thereby supporting their use and further evaluation in this patient group, while still considering the higher toxicities observed with the triple combination. FUNDING: AbbVie, Janssen, and F Hoffmann-La Roche.

Improved Survival of Patients With Chronic Lymphocytic Leukemia Between 1998-2022, Including the Era of Target Therapies With BCL2 and BTK Inhibitors.

BACKGROUND/AIM: The treatment for chronic lymphocytic leukemia (CLL) has changed dramatically over the last two decades. The current study aimed to investigate the impact on overall survival (OS) and time to next treatment (TTT) among CLL patients from 1998 to 2022. PATIENTS AND METHODS: The cohort was based on data obtained from electronic medical records of Maccabi, the second largest healthcare organization in Israel. All included patients were diagnosed with CLL based on the IWCLL criteria and complete clinical, laboratory, and treatment data were available. The study encompassed 3,964 patients diagnosed with CLL during the specified study period. RESULTS: Patients with CLL who required therapy were divided into three eras based on the dominant treatment approach: chemotherapy alone before 2010, therapy with chemotherapy and anti-CD20 between 2010 and 2017, and therapy with targeted agents between 2017 and 2022. Median OS was 4.1 years, 7.5 years, and not reached, respectively. The six-year OS rates were 40%, 55%, and 69%, respectively, (p=0.0001). The median time to the next treatment improved from 5.5 years before 2010, to 8.3 between 2010-2017, to not reached after 2017 (p=0.0021). CONCLUSION: Marked improvements in survival subsequent to fundamental changes in first-line therapy were found in patients with CLL from before 2010 to after 2017.

Efficacy of preexposure prophylaxis with monoclonal-antibody tixagevimab-cilgavimab against emerging SARS-CoV-2 resistant variants in patients with chronic lymphocytic leukemia.

Introduction Pre exposure prophylaxis with monoclonal antibodies (mAbs) were developed in addition to COVID19 vaccine for immunocompromised and those with insufficient immune response, among them patients with CLL. Omicron variant and its sublineages evolved mutations that escape mAbs neutralizing effect, yet the extent of which was not studied. Methods We evaluated anti-spike titters and neutralization activity of COVID-19 wild type (WT) , Delta , Omicron, BA2, BA4 and BA5 before and after tixagevimab-cilgavimab (TGM/CGM) dose of 150/150mg or 300/300mg in patients with CLL. Results 70 patients were tested 2 weeks before and 4 weeks after receiving TGM/CGM mAbs. After TGM/CGM anti-spike ab level increased 170 folds from 13.6 BAU/ml (IQR, 0.4-288) to 2328 BAU/ml (IQR, 1681-3500). Neutralization activity increased in all variants, and was 176 folds higher in WT and 55 folds higher in Delta compared to 10 folds higher in Omicron and its sublineages (BA2 x11, BA4 x4 , BA5 x18). Over follow-up period of 3 months, 20 patients (29%) with CLL acquired COVID-19 infection, all recovered uneventfully. In a multivariate analysis anti-spike antibody titer was found a significant predictor for post TGM/CGM COVID19 infection. Conclusion Efficacy of preexposure prophylaxis with TGM/CGM in patients with CLL is significantly reduced in era of Omicron and its sublineages BA2, BA4 and BA5.

Accelerated Chronic Lymphocytic Leukemia and Richter Transformation in the Era of Novel Agents.

BACKGROUND: Tremendous developments in the field of chronic lymphocytic leukemia (CLL) in recent years have led to a revolutionary change in the treatment approach, which today is based on targeted treatments with a good response and optimal prognosis. Nevertheless, CLL can present or progress to "accelerated CLL" (A-CLL) or to "Richter transformation" (RT) and these two entities have a more aggressive course and are still characterized by challenges in the fields of diagnosis and therapy. In the current review, we summarized the latest knowledge in terms of diagnostic approaches to A-CLL, available treatments and clinical trials, for both A-CLL and RT which still pose an unmet need and require additional basic and clinical investigations. SUMMARY: A-CLL is a rare and underdiagnosed entity that probably stands in the "gray zone" between CLL and RT, generally holding an intermediate prognosis. Its diagnosis is mainly based on histological findings including expanded proliferation centers, increased mitotic activity, and/or high Ki-67 index. Due to its rarity, its treatment approach has still not been defined, but it seems that novel agents, especially Bruton tyrosine kinase inhibitors (BTKi), are effective. As for RT, the standard therapy still consists of chemo-immunotherapy followed by stem-cell transplantation for fit responders with a dismal prognosis. New approaches are recently adopted including B-cell inhibition via novel agents (BTKi, venetoclax), T-cell engagers (checkpoint inhibitors, bispecific antibodies [BiTe] or the chimeric antigen receptor [CAR] technology), antibody-drug conjugates, or drug combinations. Although both CAR-T and BiTe seem promising, especially when combined with BTKi, evidence is still insufficient, and patients should generally be recruited in clinical trials. KEY MESSAGES: The field of CLL has been a subject of major advances in recent years, but A-CLL and RT remain topics of "unmet need" and require further studies to identify the best diagnostic approach and a more effective treatment.

Integrative Approaches in the Treatment of Patients Affected by Lymphoma.

PURPOSE OF REVIEW: Lymphoma is the most frequent hematological malignancy with wide disease spectrum of watchful waiting period, active treatment, survivorship, and palliative care. All these steps impose unmet needs in terms of prevention, symptom alleviation, or prognosis. Complementary and integrative medicine (CIM) is widely used by patients with lymphoma to cope with such issues. Here, we describe the different CIM modalities that may be effective and safe for the management of patients with lymphoma. RECENT FINDINGS: Low inflammatory diet and ginseng seem effective for lymphoma prevention. Pain and neuropathy may be improved using acupuncture, touch therapy and specific dietary supplements. Nausea/vomiting, fatigue, and insomnia may be relieved by acupuncture, mind-body, touch therapy, and certain dietary supplements. Vitamin D, curcumin, and some traditional medicine herbs may positively impact lymphoma prognosis. Finally, safety issues should be considered especially for the concomitant use of dietary supplements and lymphoma-directed therapies. CIM may be beneficial along the continuum of lymphoma management although safety concerns should be considered when used concomitantly with conventional therapy.

Timing of BNT162b2 vaccine prior to COVID-19 infection, influence disease severity in patients with hematologic malignancies: Results from a cohort study.

The COVID-19 pandemic continues to pose challenges to the treatment of hemato-oncology patients. Emergence of COVID-19 variants, availability of vaccine boosters and antiviral treatments could impact their outcome. We retrospectively studied patients with hematologic malignancies and confirmed COVID-19 during the Omicron outbreak. Of 116 evaluated patients, 16% developed severe or critical COVID-19. Diagnosis of chronic lymphocytic leukemia (CLL) was significantly associated with severe COVID-19 (p = 0.01). The vaccine effectiveness was related to the timing of the vaccine, with patients who received a mRNA vaccine within 7-90 days prior to COVID-19 being less likely to develop severe disease compared to all other patients (p = 0.019). There was no correlation between disease severity and antiviral therapies. Importantly, 45% of patients undergoing active hematological treatment had to interrupt their treatment due to COVID-19. In conclusion, patients with hematologic malignancies are at a considerable risk for severe COVID-19 during the Omicron outbreak, with patients with CLL being the most vulnerable. mRNA vaccines have the potential to protect hematological patients from severe COVID-19 if administered within the previous 3 months. Hematological treatment interruption is a frequent adverse outcome of COVID-19 infection.

The course of patients with hairy cell leukemia during the omicron surge of the Covid-19 pandemic.

In this study, we aim to explore the outcomes of Covid-19 infection in patients with Hairy cell leukemia (HCL). The cohort is based on data obtained from electronic medical records. It includes 218 consecutive patients diagnosed with HCL between 16 June 1998, and 20 September 2022, out of which the coronavirus has infected 85 patients during the Omicron surge. Out of 85 patients with HCL who were infected by Covid-19; 7 patients (8.2%) have been hospitalized, and the mortality rate was 2.3% (two patients). Thirteen of the 85 patients had been infected by Covid-19 in previous waves, including 9/13 after vaccination, and none of them developed a severe disease. Humoral immune response after three doses of the BNT162b2 mRNA vaccination regimen was evaluated in 40 patients and was attained in 67.5%. Based on multivariate analysis: unfavorable outcome was significantly more common in patients with HCL above 65 years old, who had at least one cytopenia, and with comorbidity of cardiovascular disease or asplenia. Our results indicates that the course of COVID-19 in patients with HCL during the Omicron wave has been improved relatively favorable.

Clinical Outcomes of COVID-19 in Mycosis Fungoides and Sezary Syndrome.

INTRODUCTION: Haemato-oncologic patients are more susceptible to severe infections with SARS-CoV-2. We aimed to assess the clinical outcomes of SARS-CoV-2 infection among patients with Mycosis Fungoides and Sezary Syndrome (MF/SS). METHODS: The data were retrieved from anonymized electronic medical records of Maccabi Healthcare Services (MHS), the second-largest healthcare organization in Israel. Patients diagnosed with MF/SS were included in the study. COVID-19 PCR test results together with sociodemographic and clinical data were extracted and analyzed to evaluate the association of COVID-19 with clinical outcomes. RESULTS: In the period of 2020-2022, 1,472 MF/SS patients were included in the study. Among them, 768 (52%) had SARS-CoV-2 infection. The hospitalization rate was 2.9% and infection by the Delta variant was associated with the highest hospitalization rate (7.7%). The hospitalization rate was lower among fully vaccinated patients (p = 0.032) but higher for patients older than 65 (p < 0.001) and patients with SS (vs. MF) (p < 0.001) or COPD (p = 0.024) diagnosis. There was a tendency for decreased hospitalization among patients treated with nirmatrelvir + ritonavir within 5 days of infection, with a 79% risk reduction, although it was not statistically significant (p = 0.164). CONCLUSION: Patients with MF/SS do not necessarily have worse COVID-19 outcomes compared to the general population.

The Effectiveness of Bivalent mRNA Omicron Containing Booster Vaccines Among Patients With Hematological Neoplasms.

BACKGROUND/AIM: Last year was characterized by the appearance of novel SARS-CoV-2 virus variants, mainly the omicron sub-lineages BA.2.12.1, BA.4, and BA.5, which have confirmed resistance to the acquired immune response developed following first-generation mRNA vaccines. Given the ability to use mRNA technology to respond quickly to variant strains, novel bivalent vaccines against novel omicron variants were generated. In the current work, we evaluated the efficacy and safety of novel bivalent mRNA Omicron-containing booster vaccines among patients with hematological neoplasms, including both lymphoproliferative and myeloid malignancies. PATIENTS AND METHODS: Cohort patients were obtained from electronic medical records of Maccabi Healthcare Services (MHS), the second-largest healthcare organization in Israel. We analyzed the outcome of all patients with hematological neoplasms, between September 21, 2022, and December 31, 2022, who were identified as having SARS-CoV-2 infection based on polymerase chain reaction (PCR) tests. The Kaplan-Meier method was used to compare the proportion of patients hospitalized for SARS-CoV-2 infection within 30 days among recipients and non-recipients of omicron vaccine. RESULTS: During the study period, 472 patients were infected with Omicron. We compared the outcome of 70 patients who received the bivalent mRNA booster to 402 who did not. Fewer bivalent recipients needed COVID-19-related hospitalization [2 of 70 (2.9%)] in comparison to the non-vaccinated cohort [42 of 402 (10.4%)] (p-value=0.0304). This represents an 89% relative risk reduction in COVID-19-related hospitalization in patients with hematological neoplasms. The median duration of hospitalization was 7 days for the non-vaccinated group and 4 for the vaccinated group. A statistically significant increase in ischemic stroke rates due to bivalent mRNA Omicron-containing booster vaccine was not observed. CONCLUSION: The bivalent Omicron-containing vaccine mRNA booster has a protective effect in preventing and shortening hospitalization in patients with hematological neoplasms with an acceptable safety profile.

Pregnancy Course of 10 Women Diagnosed with Chronic Lymphocytic Leukemia.

Pregnancies following diagnosis of chronic lymphocytic leukemia (CLL) are rare events, mainly because the disease is typically diagnosed in the elderly. Literature on the topic is based only on case reports, and limited data are available on the influence of pregnancy on CLL course. In this retrospective study, we aimed to summarize the clinical and laboratory course of 10 women with CLL who became pregnant. None of the patients had significant changes in blood count during or after pregnancy or had complications such as infection, autoimmune phenomenon, or preeclampsia. Four out of 10 pregnancies were terminated with an early miscarriage. Following labor, 1 patient started anti-CLL treatment due to preexisting anemia, but none of the women required therapy during CLL progression during the first 2 years of follow-up. We conclude that based on our serial, pregnancy does not negatively impact on CLL course.

First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia.

BACKGROUND: Randomized 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. METHODS: In 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, <10-4 [i.e., <1 CLL cell in 10,000 leukocytes]) as assessed by flow cytometry in peripheral blood at month 15 and progression-free survival. RESULTS: A 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; P<0.001 for both comparisons), but it was not significantly higher in the venetoclax-rituximab group (57.0%; 97.5% CI, 49.5 to 64.2; P = 0.32). Three-year progression-free survival was 90.5% in the venetoclax-obinutuzumab-ibrutinib group and 75.5% in the chemoimmunotherapy group (hazard ratio for disease progression or death, 0.32; 97.5% CI, 0.19 to 0.54; P<0.001). Progression-free survival at 3 years was also higher with venetoclax-obinutuzumab (87.7%; hazard ratio for disease progression or death, 0.42; 97.5% CI, 0.26 to 0.68; P<0.001), but not with venetoclax-rituximab (80.8%; hazard ratio, 0.79; 97.5% CI, 0.53 to 1.18; P = 0.18). Grade 3 and grade 4 infections were more common with chemoimmunotherapy (18.5%) and venetoclax-obinutuzumab-ibrutinib (21.2%) than with venetoclax-rituximab (10.5%) or venetoclax-obinutuzumab (13.2%). CONCLUSIONS: Venetoclax-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.).

High karyotypic complexity is an independent prognostic factor in patients with CLL treated with venetoclax combinations.

Complex karyotypes have been associated with inferior outcomes in chronic lymphocytic leukemia (CLL) treated with chemoimmunotherapy (CIT), whereas their prognostic impact in the context of venetoclax-based treatments is still debated. In this prospective analysis on karyotype complexity in CLL, we evaluated the impact of complex (≥3 chromosomal aberrations [CAs], CKTs) and highly complex karyotypes (≥5 CAs; hCKTs) as well as specific aberrations in previously untreated patients without TP53 aberrations undergoing either CIT or time-limited venetoclax-based therapies in the phase 3 GAIA/CLL13 trial. Karyotype analyses were available for 895 of 926 patients (96.7%), of whom 153 (17%) had a CKT and 43 (5%) hCKT. In the CIT arm, CKT was associated with shorter progression-free survival (PFS) (hazard ratio [HR] 2.58; 95% confidence interval [95% CI], 1.54-4.32; P < .001) and overall survival (HR, 3.25; 95% CI, 1.03-10.26; P = .044). In the pooled venetoclax arms, a multivariable analysis identified hCKTs (HR, 1.96; 95% CI, 1.03-3.72; P = .041), but not CKTs, as independent adverse prognosticators for PFS. The presence of translocations (unbalanced and/or balanced) was also independently associated with shorter PFSs in the venetoclax arms. CIT led to the acquisition of additional CAs (mean CAs, 2.0-3.4; from baseline to CLL progression), whereas karyotype complexity remained stable after venetoclax-based treatments (2.0, both time points). This analysis establishes highly complex karyotypes and translocations as adverse prognostic factors in the context of venetoclax-based combination treatments. The findings of this study support the incorporation of karyotyping into the standard diagnostic workup of CLL, because it identifies patients at high risk of poor treatment outcomes and thereby improves prognostication. This trial was registered at www.clinicaltrials.gov as #NCT02950051.