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Note: the green color indicates higer sucra values with a greater probability ofbeing the more effective (c) or the safer (d) treatment and the red color indicates lower sucra values with a lower probability of being the best (c) or the safest treatment. gl When we analyzed safety outcomes, reduced toxicity was associated with increased SUCRA values. 7 Molica S, Giannarelli D, Montserrat E. Comparison between Venetoclax-based and Bruton tyrosine kinase inhibitor-based therapy as upfront treatment of chronic lymphocytic leukemia (CLL): a systematic review and network meta-analysis. To the Editor, The current shift in the treatment paradigm from chemoimmunotherapy to targeted agent (TA) therapy has rapidly changed the therapeutic landscape of chronic lymphocytic leukemia (CLL).[1] Current European and US guidelines recommend continuous first-generation or second-generation Bruton tyrosine kinase inhibitors (BTKis) and time-limited venetoclax-based therapy in the setting of previously untreated or relapsed-refractory CLL.[[2]] However, the lack of head-to-head randomized clinical trials, especially in the upfront setting, limits the potential of guidelines to address questions related to the choice of TA. Of note, adverse events lead to lower adherence to therapy, compromising the chosen treatment's clinical efficacy and need to be considered in treatment selection.[19] This study has some limitations. [Extracted from the article]

Editor The association between immune thrombocytopenia (ITP) and chronic lymphocytic leukemia (CLL) is well-described with a prevalence of 2.3% [[1]]. In contrast CLL-directed treatment should be offered to persons with ITP that is unresponsive to ITP-directed therapy, even in the absence of overt CLL progression [[4]]. [Extracted from the article]

In the non-inferiority designed ELEVATE RR study, which directly compared ibrutinib and acalabrutinib in R/R CLL patients, treatment discontinuations related to adverse events occurred less frequently in acalabrutinib-treated patients (15%) than in ibrutinib-treated patients (21%) [[19]]. More than twenty years ago, the tyrosine kinase inhibitor imatinib, used in the treatment of chronic-phase chronic myeloid leukemia (CML), heralded a new era of targeted oral treatments in hematology [[1]]. Current oncology practices should continue to develop standard procedures for patient education, the development, and sharing of treatment plans, and routine monitoring of patient adherence to oral antineoplastic therapies. We should also be mindful that good communication between healthcare professionals and patients is crucial to enable our CLL patients to obtain maximal benefit from therapy whilst toxicities are minimized [[21]]. [Extracted from the article]

Simple Summary: In a comprehensive analysis of phase 3 clinical trials, including the two FLAIR sub-studies, ECOG1912, and the CLL13 trials, we assessed the impact of first-line treatments with targeted agents (TAs), or fludarabine, cyclophosphamide, and rituximab (FCR)-based chemo-immunotherapy (CIT), on overall survival (OS) compared to age- and sex-matched individuals in the general population. TAs demonstrated a higher 5-year restricted mean survival time (RMST) (58.1 months; 95% CI: 57.4 to 58.8) compared to CIT (5-year RMST, 56.9 months; 95% CI: 56.7–58.2). Moreover, the comparison with age- and gender-matched general populations (AGMGP) suggested that TAs may mitigate CLL's impact on OS during the first five years post-treatment initiation. In contrast, CLL patients treated with FCR exhibited sustained OS differences compared to both the Italian and US AGMGP cohorts. These results support TAs as the preferred first-line treatment for younger/fit CLL patients but imply the need for a careful interpretation due to variations in patient selection criteria and clinical profiles across trials. Longer follow-up is essential to assess the survival improvement of younger CLL patients treated with TAs relative to the AGMGP. To assess the impact of first-line treatment with targeted agents (TAs) or fludarabine, cyclophosphamide, and rituximab (FCR)-based chemo-immunotherapy (CIT) on overall survival (OS) compared to age- and sex-matched individuals in the general population, we conducted an aggregated analysis of phase 3 clinical trials, including the two FLAIR sub-studies, ECOG1912, and CLL13 trials. The restricted mean survival time (RMST), an alternative measure in outcome analyses capturing OS changes over the entire history of the disease, was used to minimize biases associated with the short follow-up time of trials. Patients treated with TAs demonstrated a higher 5-year RMST (58.1 months; 95% CI: 57.4 to 58.8) compared to those treated with CIT (5-year RMST, 56.9 months; 95% CI: 56.7–58.2). Furthermore, the OS comparison of treatment groups with the AGMGP suggests that TAs may mitigate the impact of CLL on OS during the first five years post-treatment initiation. In summary, the 5-year RMST difference was −0.4 months (95% CI: −0.8 to 0.2; p = 0.10) when comparing CLL patients treated with TAs to the Italian age- and gender-matched general population (AGMGP). A similar trend was observed when CLL patients treated with TAs were compared to the US AGMGP (5-year RMST difference, 0.3 months; 95% CI: −0.1 to 0.9; p = 0.12). In contrast, CLL patients treated with FCR exhibited sustained OS differences when compared to both the Italian cohort (5-year RMST difference: −1.6 months; 95% CI: −2.4 to −0.9; p < 0.0001) and the US AGMGP cohort (5-year RMST difference: −0.9 months; 95% CI: −1.7 to −0.2; p = 0.015). Although these results support TAs as the preferred first-line treatment for younger CLL patients, it is crucial to acknowledge that variations in patient selection criteria and clinical profiles across clinical trials necessitate a cautious interpretation of these findings that should be viewed as directional and hypothesis-generating. A longer follow-up is needed to assess the survival improvement of younger CLL patients treated with TAs relative to the AGMGP. [ABSTRACT FROM AUTHOR]

In addition to the European Society for Medical Oncology (ESMO) and National Comprehensive Cancer Network (NCCN) guidelines that are reference standards for the treatment of chronic lymphocytic leukemia (CLL) in Europe and the USA, several consensus statements, formulated by independent, multidisciplinary panels of specialists, have been developed to provide region-specific guidance for the management of CLL. [ABSTRACT FROM AUTHOR]

Simple Summary: Due to improved selectivity and favorable toxicity profiles, the next-generation Bruton's tyrosine kinase inhibitors (BTKis) are replacing ibrutinib in the treatment of B-cell malignancies including chronic lymphocytic leukemia (CLL). While efficacy between different BTKi agents is probably similar, there are important differences in toxicity profiles (including lower incidences of cardiovascular complications) that favor the choice of second-generation BTKis such as zanubrutinib. Updates in the National Comprehensive Cancer Network (NCCN) guidelines and German CLL treatment algorithm and approvals from both the Food and Drug Administration (FDA) and European Medicines Agency (EMA) support zanubrutinib as a preferred option for the treatment of both treatment-naïve and relapsed/refractory CLL patients irrespective of patient fitness. Ibrutinib, the first-in-class Bruton's tyrosine kinase inhibitor (BTKi), is a commonly deployed therapeutic option for previously untreated and relapsed/refractory (R/R) patients with chronic lymphocytic leukemia (CLL). The use of ibrutinib is, however, partially limited by off-target side effects. Zanubrutinib (zanu) is a second-generation BTKi with enhanced target selectivity and occupancy of the kinase binding site. The SEQUOIA study showed that zanu significantly prolonged progression-free survival (PFS) when compared to bendamustine–rituximab (BR) in treatment-naive CLL patients. More recently, data from the phase III ALPINE trial, which directly compared zanu with ibrutinib, demonstrated that zanu's advantages include an improved safety profile as well as enhanced clinical efficacy. Based on the results of the SEQUOIA and ALPINE pivotal trials, the Food and Drug Administration (FDA) and European Medicines Agency (EMA) licensed zanu for the treatment of patients with CLL or small lymphocytic lymphoma (SLL) in January 2023. The updated (v2.2023) National Comprehensive Cancer Network (NCCN) guidelines and the most recent German CLL algorithm suggest that zanu may replace first-generation BTKis as a preferred therapeutic option for patients with CLL/SLL due to its increased selectivity for the kinase binding site, improved therapeutic efficacy, and favorable toxicity profile. Some drug class-related characteristics such as drug resistance, low complete remission (CR) rates, and indefinite treatment duration still remain with zanu, and the results from recently completed and ongoing fixed-duration clinical trials, combining zanu with an anti-BCL2 agent, are eagerly awaited with the possible promise of a reduced treatment duration and lower financial burden. [ABSTRACT FROM AUTHOR]

Hairy-cell leukemia is characterised by a marked sensitivity of the malignant cells to the cytotoxic effects of therapeutically administered interferon-α. The aim of this study was to assess the role of protein tyrosine phosphatases in the maintenance of hairy-cell (HC) viability and their sensitivity to interferon-α. The selective tyrosine phosphatase inhibitor mpV(pic) killed HCs, but not normal B lymphocytes or chronic lymphotic leukemia (CLL) cells. HCs displayed increased expression of the phosphatases SHP-1 and SHP-2 when compared with normal B lymphocytes. Phosphatase inhibition also enhanced the cytotoxic effect of interferon-α against HCs in four of the five cases tested. Therefore, HCs, but not normal B cells or CLL-cells, require tyrosine phosphatase activity for preservation of their viability. In addition, HC sensitivity to interferon is down-regulated by this activity. [ABSTRACT FROM AUTHOR]

Abstract: Venous thromboembolism (VTE) is a major cause of morbidity and mortality in cancer patients. The literature is sparse on the incidence in the most common lymphoid malignancy, chronic lymphocytic leukaemia (CLL). We calculated the incidence rates for VTE in an unselected UK CLL clinic population at 1.45% per patient year. This represents a tenfold increase over previously published estimates of incidence in the general population and a twofold increase over that of the local hospital inpatient population. In our cohort, the risk of VTE was related to stage C disease. Clinicians should be aware that CLL patients are at risk of VTE. [Copyright &y& Elsevier]

Background: Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to COVID-19 related poor outcomes, including thrombosis and death, due to the advanced age, the presence of comorbidities, and the disease and treatment-related immune deficiency. The aim of this study was to assess the risk of thrombosis and bleeding in patients with CLL affected by severe COVID-19. Methods: This is a retrospective multicenter study conducted by ERIC, the European Research Initiative on CLL, including patients from 79 centers across 22 countries. Data collection was conducted between April and May 2021. The COVID-19 diagnosis was confirmed by the real-time polymerase chain reaction (RT-PCR) assay for SARS-CoV-2 on nasal or pharyngeal swabs. Severe cases of COVID-19 were defined by hospitalization and the need of oxygen or admission into ICU. Development and type of thrombotic events, presence and severity of bleeding complications were reported during treatment for COVID-19. Bleeding events were classified using ISTH definition. STROBE recommendations were used in order to enhance reporting. Results: A total of 793 patients from 79 centers were included in the study with 593 being hospitalized (74.8%). Among these, 511 were defined as having severe COVID: 162 were admitted to the ICU while 349 received oxygen supplementation outside the ICU. Most patients (90.5%) were receiving thromboprophylaxis. During COVID-19 treatment, 11.1% developed a thromboembolic event, while 5.0% experienced bleeding. Thrombosis developed in 21.6% of patients who were not receiving thromboprophylaxis, in contrast to 10.6% of patients who were on thromboprophylaxis. Bleeding episodes were more frequent in patients receiving intermediate/therapeutic versus prophylactic doses of low-molecular-weight heparin (LWMH) (8.1% vs. 3.8%, respectively) and in elderly. In multivariate analysis, peak D-dimer level and C-reactive protein to albumin ratio were poor prognostic factors for thrombosis occurrence (OR = 1.022, 95%CI 1.007‒1.038 and OR = 1.025, 95%CI 1.001‒1.051, respectively), while thromboprophylaxis use was protective (OR = 0.199, 95%CI 0.061‒0.645). Age and LMWH intermediate/therapeutic dose administration were prognostic factors in multivariate model for bleeding (OR = 1.062, 95%CI 1.017–1.109 and OR = 2.438, 95%CI 1.023–5.813, respectively). Conclusions: Patients with CLL affected by severe COVID-19 are at a high risk of thrombosis if thromboprophylaxis is not used, but also at increased risk of bleeding under the LMWH intermediate/therapeutic dose administration. [ABSTRACT FROM AUTHOR]

Serum IgG level between4-5 g/L was noted in 11 of 28 patients (39%), very low IgG (<4 g/L) in 8 of 28 patients (29%) and 2 patients had completely undetectable IgG <0.75 g/L (7%). Survival plots of CLL patients with (a) documented infections on ibrutinib therapy and (b) serum IgG level before start of ibrutinib therapy. Patient characteristics with CLL genetics, treatments received, immunoglobulin levels, infections and deaths on ibrutinib therapy. We report a retrospective analysis on 26 ibrutinib-treated relapsed/refractory CLL patients and 3 CLL patients who received ibrutinib as first line therapy from January 2016 to May 2020. [Extracted from the article]

Background: Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia. Combination immunochemotherapy such as fludarabine, cyclophosphamide and rituximab is the standard first line therapy in fit patients, but there is limited evidence regarding the optimal treatment of patients after relapse. Ofatumumab as monotherapy has been proven to be effective in the treatment of relapsed, refractory CLL, and as it is not myelotoxic, it is an ideal drug to combine with chemotherapy. However, the optimal dose of ofatumumab in this setting is not known. The Chemotherapy plus Ofatumumab at Standard or Mega dose in relapsed CLL (COSMIC) trial will assess the efficacy and safety of standard and high (mega) doses of ofatumumab combined with bendamustine or a combination of fludarabine and cyclophosphamide to determine which, if either, schedule should progress to a phase III trial.Methods/design: COSMIC is a phase II, multi-centre, randomised, open, parallel group trial for patients with relapsed CLL who are not refractory to fludarabine-based chemotherapy. Participants will be randomised to receive either standard dose or mega dose ofatumumab. Both doses will be given in combination with either bendamustine or fludarabine and cyclophosphamide chemotherapy backbone. The primary objective is to assess the proportion of participants achieving a complete remission following therapy with the two treatment arms (mega versus standard), as assessed at 3 months post treatment. The treatment groups will be assessed independently to determine whether the level of response is acceptable in relation to pre-specified criteria. If both treatment groups show an acceptable level of response, selection criteria will be used to determine which to take forward to a confirmatory phase III trial. A key secondary objective is to assess the dynamics of minimal residual disease (MRD) levels in relapsed disease. Eighty-two participants are planned to be recruited from 18 research centres in the UK.Discussion: Currently there is limited evidence regarding the optimal treatment of patients with relapsed or refractory CLL, and so suitable therapies are urgently needed. The COSMIC trial will identify whether ofatumumab given in combination with chemotherapy is safe and effective in this population, and will identify the optimal doses for further investigation.Trial Registration: ISRCTN51382468 . Registered on 21 September 2011. [ABSTRACT FROM AUTHOR]

Defining the prognosis of individual cancer sufferers remains a significant clinical challenge. Here we assessed the ability of high-resolution single telomere length analysis ( STELA), combined with an experimentally derived definition of telomere dysfunction, to predict the clinical outcome of patients with chronic lymphocytic leukaemia ( CLL). We defined the upper telomere length threshold at which telomere fusions occur and then used the mean of the telomere 'fusogenic' range as a prognostic tool. Patients with telomeres within the fusogenic range had a significantly shorter overall survival ( P < 0·0001; Hazard ratio [ HR] = 13·2, 95% confidence interval [ CI] = 11·6-106·4) and this was preserved in early-stage disease patients ( P < 0·0001, HR=19·3, 95% CI = 17·8-802·5). Indeed, our assay allowed the accurate stratification of Binet stage A patients into those with indolent disease (91% survival at 10 years) and those with poor prognosis (13% survival at 10 years). Furthermore, patients with telomeres above the fusogenic mean showed superior prognosis regardless of their IGHV mutation status or cytogenetic risk group. In keeping with this finding, telomere dysfunction was the dominant variable in multivariate analysis. Taken together, this study provides compelling evidence for the use of high-resolution telomere length analysis coupled with a definition of telomere dysfunction in the prognostic assessment of CLL. [ABSTRACT FROM AUTHOR]