Stage Chronic Lymphocytic Leukemia Research Articles

#2991 Two cases of chronic lymphocytic leukemia associated immunotactoid glomerulopathy: variable clinical presentation, close hematological collaboration

Abstract Background and Aims Immunotactoid glomerulopathy (ITG) is a very rare disease, observable in less than 0.1% of native kidney biopsy samples. It is most often associated with hematological diseases. We confirmed ITG in two cases among our 850 kidney biopsy patients in the past 9 years. In both patients, chronic lymphocytic leukemia (CLL) was the underlying cause. Method Case 1, a 56-year-old man was admitted due to severely increased proteinuria (2 g/day) with preserved renal function, while case 2, a 57-year-old-man was referred with rapidly decreasing eGFR (20 ml/min/1.73m2) with nephrotic syndrome (serum albumin level was 24 g/l). In case 1, no previous history of hematological disease was known, in case 2, CLL - that did not require treatment - was diagnosed half a year before admission. He still had no kidney involvement even 3 months after the CLL diagnosis. We performed kidney biopsy. Light microscopy revealed mesangial proliferative-atypical membranous pattern in case 1, and membranoproliferative pattern in case 2. Immunofluorescence microscopy showed IgG1-lambda deposition, electron microscopy confirmed the organised deposits, microtubular structures with a diameter of 44 nanometers in both cases. Neither monoclonal gammopathy nor systemic immune disease was confirmed. In case 2, low titer ANA positivity, low C3 and high anti-C1q antibody titer was detected, lupus nephritis was ruled out. Previously, lymphocyte count was slightly increased in case 1, CLL was confirmed after kidney biopsy. The immunoglobulin heavy chain variable region gene somatic hypermutation status was borderline in case 1, while in the other case it was unmutated. Fluorescein in situ hybridisation revealed trisomy 12 in both cases. In case 1, chemotherapy was not used due to Rai stage 0, and with appropriate antihypertensive treatment, we could preserve kidney function, and proteinuria was persistently low (below 1 g/day). In case 2, due to Rai stage 1, and progressive renal and lymph node involvement, immunochemotherapy was started (obinutuzumab-venetoclax). Three months later eGFR stabilized at 27 ml/min/1.73 m2, proteinuria decreased below 1 g/day, the C3 level normalized. Conclusion ITG can develop in the early stages of CLL, but it can also indicate CLL progression. The light microscopy histological pattern and, in parallel, the clinical appearance can be of varying severity. Immunochemotherapy resulting reduction of CLL tumor burden and cessation of complement damage, both play a role of improving renal status. Our cases also draw attention to the need for close collaboration with hematologists.

Abstract CT174: A phase 1 study of JBH492, an anti C-C chemokine receptor 7 antibody-drug conjugate (anti-CCR7 ADC), assessing safety and efficacy in lymphoid malignancies

Abstract Background: CCR7 is overexpressed in lymphoid malignancies. JBH492 is a first-in-class CCR7-targeting ADC, comprising a humanized, Fc-silenced anti-CCR7 IgG1 antibody conjugated to maytansinoid microtubule inhibitor DM4 via a cleavable linker. Preclinical studies support avidity-driven differential binding in CCR7-high tumor cells compared to CCR7-low healthy immune cells, and in vivo animal studies demonstrated robust and durable efficacy in multiple clinically relevant lymphoma models (Dang et al. 2022). Methods: This is an ongoing first-in-human, open-label, phase I/Ib, multi-center study in patients (pts) with relapsed/refractory (r/r) chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma (NHL) (NCT04240704), which completed enrollment for dose-escalation phase. Five dose levels of JBH492 monotherapy ranging from 0.4 to 3.6 mg/kg (intravenous administration every 3 weeks [q3W]) were tested with 3 - 7 pts enrolled per dose level. Preclinical data from xenografts predicted tumor stasis at 1.6 mg/kg q3W. The objective of dose escalation was to assess safety, tolerability, pharmacokinetics (PK), immunogenicity, and preliminary efficacy of JBH492 and to determine maximum tolerated and recommended doses. Pts with r/r CLL and NHL, who failed standard of care therapy (at least 2 prior regimens) and who were intolerant/ineligible to approved therapies, were included; CCR7 expression confirmation was not required prior enrollment. Results: Total 25 pts with r/r stage II-IV NHL (n = 24, [adult T cell leukemia-lymphoma, 3; cutaneous T cell lymphoma, 4; diffuse large B cell lymphoma, 7; follicular lymphoma, 1; Mantle cell lymphoma, 1; marginal zone lymphoma, 2; peripheral T cell lymphoma, 3; others, 3]) and CLL (n = 1) with median age 69.0 y (43 - 85) were enrolled. Mean duration of exposure was 13.5 wks. One pt had dose-limiting toxicity — grade (G) 3 thrombocytopenia lasting for 13 d. Overall, 23 (92%) pts had at least 1 adverse event (AE) (G ≥ 3, n = 11). Treatment-related AEs (TRAEs) were reported in 15 (60%) pts (G ≥ 3, n = 3). Of 6 (24%) pts who had serious AEs (SAEs) (G ≥ 3, n = 3), 2 (8%) had TRSAE. The most frequent AEs (≥ 20%) included anemia (32%), thrombocytopenia (28%), neutropenia and dry eye (20% each). Two deaths due to underlying disease were reported. PK for total ADC was roughly dose proportional. Four NHL pts (2 T-NHL and 2 B-NHL) had partial response (PR) and 2 had stable disease, with PRs observed at doses between 2.4 and 3.6 mg/kg q3W. Post data-cut-off, 1 pt with T-NHL achieved CR following 4 cycles of treatment. No correlation between CCR7 expression and response could be drawn (CCR7 expression was observed in all samples from 14 pts). Conclusions: The data from this phase I study suggest that targeting CCR7 with JBH492 is a promising therapeutic strategy for lymphoid malignancies with manageable hematological and non-hematological safety profile. [K.I. and S.L. contributed equally to this study.] Citation Format: Pau Abrisqueta, Reinhard Marks, Irit Avivi, Martin Wermke, Francesca Lim, Tae Min Kim, Alba Cabirta Touzon, Kristiina Karihtala, Shinichi Makita, Lillian Werner, Chiaki Tanaka, Anhthu Dang, Anwesha Chaudhury, Seth Rice, Rowshan Chowdhury, Deborah Knee, Belén Gomezcarrillo, Elissa Furutani, Koji Izutsu, Sirpa Leppä. A phase 1 study of JBH492, an anti C-C chemokine receptor 7 antibody-drug conjugate (anti-CCR7 ADC), assessing safety and efficacy in lymphoid malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT174.

Prognostication in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in Western countries. CLL is a highly heterogeneous disease: some patients may never require therapy and others relapse several times after different therapeutic strategies. Therefore, in CLL, prognostic markers are essential to capture high-risk patients for different clinical endpoints including early treatment requirement, early progression after BTK or BCL2 inhibitors and Richter transformation. In early stage CLL, different biological and clinical biomarkers have been identified to predict time to treatment requirement that could be used to identify the most appropriate population for early intervention clinical trial. However, at the moment, the standard of care for early stage CLL remains watch & wait since no survival benefit has been identified in clinical trials with chemoimmunotherapy and with BTK inhibitors. In patients requiring treatment TP53 disruptions identify high-risk patients who benefit the most from long-term continuous therapy with BTKi. On the opposite side of the spectrum, IGHV mutated patients devoid of TP53 disruption benefit the most from fixed-duration therapy with venetoclax-obinutuzumab. In between, the highly heterogenous subgroup of patients with IGHV unmutated genes represents the group in which further efforts are needed to identify additional prognostic biomarkers aimed at selecting patients who can benefit from fixed-duration and patients who can benefit from long term BTKi therapy. In the context of the aggressive transformation of CLL, namely Richter syndrome, the clonal relationship to the CLL counterpart represents the strongest prognostic biomarker. Clonally related Richter syndrome still represents an unmet clinical need which requires further efforts to identify new therapeutic strategies.

Expression of ZAP 70 in Chronic Lymphocytic Leukemia (CLL) and its Correlation with Clinical Stages

Objective: To ascertain the levels of ZAP-70 expression within the context of Chronic Lymphocytic Leukemia (CLL) patients and to subsequently analyze the potential correlations between ZAP-70 expression and the clinical staging of the disease. Study Design & Setting: Cross-sectional, descriptive study. Department of Hematology, Armed Forces Institute of Pathology (AFIP), Rawalpindi from July 2021 to December 2021. Methodology: We included 73 CLL patients of various ages and both genders. and patients having lymphoproliferative disorders other than CLL were excluded. Sysmex XN-3000 was used to do complete blood counts. Diagnosis of CLL was confirmed immunophenotypically by flow cytometry. Samples were processed by standard methods for ZAP70 analysis. Descriptive statistics were expressed in terms of mean ± standard deviation (SD). A Chi-square test was conducted, with a significance level of p-value =0.05 being considered significant. Results: Among 73 patients, 24 were females (32.9%) and 49 were males (67.1%). Females had a mean age of 69.00±9.47 years, whereas males had a mean age of 65.73±11.12 years. ZAP-70 expression was positive in 8 (11%) and negative in 65 (89.0%) cases. The expression of ZAP-70 in CLL and its correlation with Binet Stages was significant (p=0.002). ZAP- 70 expression in males and females showed no significant difference (p 0.059). ZAP-70 analysis showed no significant difference in patients with age more than 60 years from = 60 years of age (p= 0.275) Conclusion: ZAP-70 gene expression should be used in routine laboratory settings and can be correlated with the clinical stages of CLL

PD-1 and LAG-3 as early prognostic markers in the treatment of patients with chronic lymphocytic leukemia

Background. Recently, studies have been conducted all over the world to study the role of immune checkpoints in the pathogenesis of chronic lymphocytic leukemia (CLL) and the possibility of their use as prognostic markers. Of greatest interest are PD-1 (programmed cell death-1) and LAG-3 protein (lymphocyte-activation gene 3).Aim. To study the features of PD-1 (CD279) and LAG-3 (CD223) expression on blood B-cells of CLL patients and the possibility of their use as early markers for predicting the hematological response to therapy.Materials and methods. The blood of 30 patients with CLL in stage C according to Binet and 20 healthy individuals was studied by 10-color flow cytometry.Results. In patients with CLL, there were significant differences in the initial lymphocytes level, PD-1 and LAG-3 expression on B-lymphocytes, both with persons in the control group and among themselves with different hematological responses to therapy with rituximab according to the results of minimal residual disease monitoring.Conclusion. PD-1 and LAG-3 can be used as early markers for predicting the response of CLL patients to therapy. The combined use of initial lymphocytes level and PD-1 and LAG-3 expression on CD19+ blood cells has a greater prognostic value. New data obtained from the study of immune checkpoints PD-1 and LAG-3 may be useful in the development of targeted therapeutic agents.

Omission of Anti-CD20 Antibody in Chronic Lymphocytic Leukemia during COVID-19 Pandemic: Twelve Month Course of Venetoclax Is a Safe and Effective Alternative Regimen

Introduction The current treatment for patients with advanced stages of Chronic Lymphocytic Leukemia (CLL) is the combination of the Rituximab - an Anti-CD 20 Antibody and Venetoclax - a BCL-2 inhibitor. However, during COVID-19 Pandemic, we were concerned that the immunodeficiency state induced by anti-CD20 antibody infusions would increase the risk of COVID-19 complications. Also, we were concerned about exposing cancer patients to long term anti-neoplastic treatments when there were so many unknowns about the new Sar-CoV-2 virus. Thus, in order to minimize these deleterious effects, and long exposure to cancer treatment, the CLL treatment was modified through omitting Rituximab, and using a 12-month course of Venetoclax as a single agent, with the goal of preventing COVID complications, but still achieving durable remissions. Methods Between February 2020 and September 2022, 13 patients with advanced stage CLL who met the treatment criteria, were treated with single agent Venetoclax with the mean age of 77 ranging from ages 56-99 and a Male to Female ratio of 10:3. Indications of treatment were as follows: bulky lymphadenopathy (8), markedly elevated lymphocyte count (3), and bone marrow failure (2). Among these 13 patients, there were 7 treatment naive patients and 6 had previously received between 1 to 3 treatments. These treatments included: Chlorambucil-Obinutuzumab, Ibrutinib, Fludarabine-Cyclophosphamide-Rituximab, and Bendamustine-Rituximab. Following are the FISH analysis results of these patients: 13Q14, 12+, TP53- , 11Q22-. Single agent venetoclax was administered to patients as a 5 week ramp up schedule per standard dosing guidelines, with the goal being to achieve 400 mg by week 5 of the treatment. The 400 mg dosage was continued for another 11 months and patients were monitored monthly for treatment response and toxicity. After the conclusion of 12 months of treatment, patients were followed up clinically at regular intervals to monitor durability of treatment response. Patients were informed that if there was progression noted during Venetoclax treatment, a new regimen that included Anti-CD20 Antibody will be started. Results Eleven out of 13 patients achieved full dosage escalation to 400 mg by week 5. Of the 2 patients that did not escalate the full dose, one patient - age 99- only achieved dosage up to 100 mg due to physician discretion, and the other patient achieved dosage up to 200 mg due to extreme fatigue. Common side effects amongst the patients were fatigue and mild cytopenia whilst the toxicity overall was manageable. One patient required treatment interruption for Autoimmune Hemolytic Anemia (AIHA) and only one patient contracted COVID-19. This patient recovered, however, quickly with no complications and treatment of Venetoclax was resumed at full dosage. Temporary increase in absolute lymphocyte count was noted in 8 patients. Mild persistent anemia was shown in 2 patients at the completion of treatment and mild thrombocytopenia was present in 7 patients. Neutropenia was not observed in any patients. Overall, treatment response was noted in 12 out of 13 patients with 11 complete remission (CR) and 1 partial remission (PR). Time to response was 3 months from the start of treatment for all responding patients. All patients who achieved CR and PR remain in remission during follow up with a median remission duration of 15 months. One patient had stable disease while on treatment but progressed immediately after discontinuation of Venetoclax. This patient then received the combination of Obinutuzumab-Acalabrutinib and achieved complete remission. Conclusion Thus, we can conclude that a 12-month course of Venetoclax administered without anti-CD 20 antibody, is an effective treatment regimen in advanced stage CLL. The avoidance of the anti-CD 20 antibody resulted in preservation of the immunity as noted in the one patient who contracted COVID-19 during treatment but recovered quickly from infection without any COVID-19 associated complication. We believe that although Rituximab with Venetoclax remains the standard of care in advanced stage CLL, but in unusual circumstances such as during the COVID-19 pandemic, short, limited course of single agent Venetoclax is a viable option of treatment to achieve durable remission.

Genetic markers and ibrutinib vs placebo treatment in early stage chronic lymphocytic leukemia -results from the GCLLSG CLL12 trial

Background: Watch and wait is standard of care in patients with early stage chronic lymphocytic leukemia (CLL). In the CLL12 trial, 515 stage Binet-A patients were risk stratified and randomized 1:1 to ibrutinib (ibr, n=182) or placebo (pcb, n=181) when assigned to (very) high or intermediate risk, while low risk patients were only observed (w&w, n=152). Treatment with ibr was associated with longer progression-free survival (PFS) (event defined as progression or death) and event-free survival (EFS) (event defined as death, symptomatic progression or initiation of CLL treatment) but not overall survival (OS) when compared to pcb (Langerbeins et al. EHA 2023). However, it is unclear if specific subgroups defined by genetic markers may derive particular benefit from early ibr treatment. Methods: Genetic markers were analyzed in all 515 patients at study entry. Genomic aberrations were assessed by FISH, IGHV mutational status by sequencing with a threshold of 98% homology and gene mutations via targeted NGS for TP53, FBXW7, NOTCH1, SF3B1, NRAS, KRAS, BRAF, BIRC3, MYD88, NFKBIE, EGR2 and XPO1. Results: The prevalence of genomic aberrations and gene mutations is shown in the table 1. At a median follow up of 69.3 months, there were 166 events for EFS and 32 for OS respectively. EFS was shorter with del(17p) (compared to del(13q): Hazard ratio (HR) 2.89, 95%CI 1.14-7.37, p<0.05), del(11q) (HR 4.39, 95%CI 2.48-7.76, p<0.001); +(12) (HR 1.78, 95%CI 1.01-3.13, p<0.05) in the pcb arm, while with ibr only del(17p) (HR 5.07, 95%CI 1.70-15.17 p<0.01) was associated with shorter EFS. IGHV mutation status had an impact on EFS with pcb (U-IGHV vs. M-IGHV, HR 4.44, 95%CI 2.88-6.85, p<0.001) but not with ibr (HR 1.52, 95%CI 0.81-2.85, p=0.19). In the pcb arm, mutations in NOTCH1 (HR 2.26, 95%CI 1.35-3.76, p<0.01), NRAS/KRAS/BRAF, (HR 5.38, 95%CI 1.92-15.03, p<0.01) and NFKBIE (HR 4.12, 95%CI 1.97-8.64, p<0.001) but not TP53 (HR 1.24, 95%CI 0.57-2.68, p=0.59) were significantly associated with a shorter EFS. In contrast, with ibr treatment, only TP53 (HR 2.88, 95%CI 1.31-6.32, p<0.01) and NFKBIE (HR 2.45, 95%CI 1.03-5.87, p=0.04) were associated with shorter EFS. Notably, in the full trial population (i.e. including the w&w cohort) TP53 mutations were associated with shorter EFS only when combined with U-IGHV (HR 2.37, 95%CI 1.22-4.63, p<0.05) but not with M-IGHV (HR 0.53, 95%CI 0.26-1.10. p=0.09). In the w&w cohort high risk markers were rare and only +(12) (compared to del(13q)(HR 4.66, 95%CI 1.4-15.51, p<0.05) and mutations in TP53 (HR 4.88, 95%CI 1.49-16.04, p<0.01), SF3B1 (HR 5.01, 95%CI 1.53-16.45, p<0.01), BIRC3 (HR 3.43, 95%CI 1.05-11.23, p<0.05) and NFKBIE (HR 12.58, 95%CI 3.68-42.99, p<0.001) were significantly associated with shorter EFS. Significant EFS benefit from ibr as compared to pcb with HR<0.2 was observed in subgroups with U-IGHV (HR 0.18, 95%CI 0.1-0.3, p<0.001); del(11q) (HR 0.10, 95%CI 0.04-0.29, p<0.001) and cases with mutations in NOTCH1 (HR 0.18, 95%CI 0.06-0.55, p<0.01) and NFKBIE (HR 0.15, 95%CI 0.04-0.53, p<0.01), while no significant benefit was observed with del(17p) (HR 0.68, 95%CI 0.16-2.85, p=0.59) and mutated TP53 (HR 0.69, 95%CI 0.25-1.92, p=0.48, figure 1). Regarding OS none of the subgroups defined by genetic markers derived significant benefit from ibr as compared to pcb. In multivariable analysis for EFS including treatment arms, clinical disease characteristics and genetic markers as variables, ibr treatment was an independent favorable factor (HR 0.25, 95%CI 0.16-0.37, p<0.001), while U-IGHV (HR 3.38, 95%CI 2.29-4.98 p<0.001), del(17p) (HR 3.53, 95%CI 1.76-7.06, p<0.001), +(12) (HR 1.58, 95%CI 1.01-2.45 p<0.05) and mutated NFKBIE (HR 2.22, 95%CI 1.23-4.01, p<0.01) were independent adverse prognostic factors. Conclusion: In addition to the well-known prognostic factors, also mutated SF3B1, NFKBIE and BIRC3 are associated with shorter EFS in low risk early stage CLL. While some genetic subgroups derived particular EFS benefit from ibr, patients with high-risk TP53 aberration and/or del(17p) did not. In summary, the CLL12 trial fails to demonstrate survival superiority by early ibr treatment, including genetic subgroups and w&w remains the standard of care for all patients with Binet stage A CLL.

Chronic lymphocytic leukemia patient-derived xenografts recapitulate clonal evolution to Richter transformation

Chronic lymphocytic leukemia (CLL) is a B-cell neoplasm with a heterogeneous clinical behavior. In 5–10% of patients the disease transforms into a diffuse large-B cell lymphoma known as Richter transformation (RT), which is associated with dismal prognosis. Here, we aimed to establish patient-derived xenograft (PDX) models to study the molecular features and evolution of CLL and RT. We generated two PDXs by injecting CLL (PDX12) and RT (PDX19) cells into immunocompromised NSG mice. Both PDXs were morphologically and phenotypically similar to RT. Whole-genome sequencing analysis at different time points of the PDX evolution revealed a genomic landscape similar to RT tumors from both patients and uncovered an unprecedented RT subclonal heterogeneity and clonal evolution during PDX generation. In PDX12, the transformed cells expanded from a very small subclone already present at the CLL stage. Transcriptomic analysis of PDXs showed a high oxidative phosphorylation (OXPHOS) and low B-cell receptor (BCR) signaling similar to the RT in the patients. IACS-010759, an OXPHOS inhibitor, reduced proliferation, and circumvented resistance to venetoclax. In summary, we have generated new RT-PDX models, one of them from CLL cells that mimicked the evolution of CLL to RT uncovering intrinsic features of RT cells of therapeutical value.

Gut Microbiome Links to Disease Stage and Immune Microenvironment in Patients with Chronic Lymphocytic Leukemia

Background Recent studies have shown extensive crosstalk between our immune system and the gut microbiome (GM). The host immune system plays a vital role in the maintenance of GM homeostasis by establishing a balance between eliminating invading pathogens and promoting the growth of beneficial microbes, whereas GM can modulate the immune system by cytokine production. As chronic lymphocytic leukemia (CLL) is characterized by a high rate of infectious complications and an altered immune microenvironment, it is warranted to uncover the link between microbiome composition and immune dysregulation in CLL patients. Thus, we investigated the microbiome pattern and potential connections to disease characteristics and phenotypes and distribution within the immune microenvironment in CLL patients requiring treatment. Methods Blood and feces samples were collected from 17 patients with CLL prior to targeted treatment with acalabrutinib or ibrutinib+venetoclax in clinical trials. T-cell maturation subsets, Treg/Th17 subsets, and activation- and exhaustion profiles were assessed in fresh blood samples by an 8-tube, 10 color flow cytometry panel (DuraClone), including one tube containing beads for calculating absolute concentrations. Fecal samples were subjected to shotgun sequencing using Illumina HiSeq and taxonomical profiling was done using an in-house bioinformatics pipeline. The bioinformatics analysis involved microbial species abundances comparison and co-occurrence identification across patient clusters. Electronic health records provided data on clinical baseline characteristics. Case report forms and data on use of antimicrobial drugs will be assessed at a later stage to investigate potential associations with infections or toxicity related adverse events. All patients provided written informed consent and the study was approved by the National Ethics Committee and the Data Protections Agency. Results Unsupervised clustering analyses based on GM composition data revealed two GM clusters, where we found an overlap constituting approximately 40% of the cohort between Binet stage C (7/10 patients) and GM cluster 2 (7/10 patients) (Figure 1A). GM cluster 2 was characterized by differentially abundant species such as Bacteroides fragilis and Eggerthela lenta, demonstrating the two highest fold change and elevated relative abundances (Figure 1B). Closer examination of the taxonomic composition characteristic for the 7 patients revealed a small set of indicator microbiome species, where Clostridium innocuum together with Clostridiales sp., Bacteroides fragilis and Escherichia coli, were the most significantly abundant co-occurring species for CLL patients with Binet C. Preliminary examination of T-cell subset data showed generally lower concentrations of T-cells in patients from GM cluster 2 compared to GM cluster 1, where the 7 patients overlapping with Binet C furthermore had decreased levels of Th17 CD4+ and Tc17 CD8+ cells compared to both the normal reference level and the rest of the cohort (Figure 1C). Conclusion Our preliminary results suggest a link between CLL stage at time of needing treatment, gut microbiome composition, represented by a subset of highly abundant bacterial species, and T-cell distribution with reduced Th17 and Tc17 subsets, to be further investigated. To our knowledge, we are thus among the first to present data connecting the gut microbiome to tumor microenvironmental changes in patients with CLL. Moving forward we will further explore microbiome-microenvironment interactions with focus on the production of short-chain fatty acids (bacterial metabolites which play crucial roles as immunomodulatory molecules) to investigate connections between microbiome, immune phenotypes, and clinical outcomes including infections, treatment-related toxicity, and disease progression, to light on novel avenues for therapeutic interventions in CLL.

Extended Follow up of a Phase 2 Study of Early Intervention with Lenalidomide in Patients with High-Risk Chronic Lymphocytic Leukemia

CONCLUSIONS Lenalidomide (LEN) is an effective therapy for chronic lymphocytic leukemia (CLL) and has immunomodulatory effects that were hypothesized to improve immune function in patients (pts) with untreated early stage CLL. A NCI/CTEP sponsored phase 2 study (NCT01351896) randomized asymptomatic pts with high-risk CLL to receive LEN either concurrent with or delayed from (3 months after 1st dose) two doses of 13-valent protein-conjugated pneumococcal vaccine (PCV13). The primary endpoint was the proportion of pts who achieve an antibody response to the 2nd PCV13 vaccine and was not significantly different between groups (Thangavadivel et al., Clinical Cancer Research 2020). Despite this, many pts experienced effective CLL disease control with LEN. Here we report long-term results from this trial to examine the impact of LEN early treatment on CLL disease course, complicating infections (INF), and second neoplasms (SN). Pts ≥18 and <80 years-old who had CLL with a high-risk feature, defined as FISH positive for del(17)(p13.1) and/or del(11)(q22.3), complex karyotype (≥3 abnormalities), or unmutated IGHV status, no prior treatment, and no iwCLL 2008 criteria for treatment were eligible. LEN was started at 2.5mg daily and increased to 5mg as tolerated. Data on INF and SN was determined from study adverse events and graded (gr) using CTCAE v4.0 and 5.0. Overall survival (OS) and progression-free survival (PFS) were calculated from the start of LEN and discontinuation of LEN, and analyzed using the Kaplan-Meier method. Time to next therapy (TTNT) was calculated from start or discontinuation of LEN to the initiation of next therapy treating death without new therapy as a competing risk. Data cut for analysis was 6/12/2023. A total of 49 pts were enrolled between 11/2011 and 7/2014. The median age was 59 (range 40-70) years, 69% were men, and 96% were Caucasian. In terms of CLL features, 94% (46/49) were IGHV unmutated, 47% (23/49) had complex karyotype, 14% (7/49) had del(17)(p13.1), and 31% (15/49) had del(11q)(q22.2). The median follow-up from LEN start was 4.6 (range 0.4-11.2) years and median time on LEN treatment was 3.7 (range 0.02-10.1) years with 2 pts remaining on LEN at 9.7 and 10.1 years. The median PFS after starting LEN was 5.7 (95% CI: 3.2-6.4) years with an estimated 8-year PFS of 25.9% (95% CI: 13.9%-39.6%) (Figure). Eleven pts had progressive disease (PD) at the time of LEN discontinuation and their median time from first dose of LEN to PD was 3.7 (range 0.3-6.0) years. For those who discontinued without PD, the median PFS from discontinuation was 1.5 (95% CI: 0.6-2.6) years. For those who initiated a subsequent therapy, the median TTNT from starting LEN was 4.4 (range 0.3-9.1) years and from discontinuing LEN was 1.1 (range 0.1-7.8) years. There were 7 deaths, and the median OS was not reached with an estimated 8-year OS of 73.9% (95% CI: 51.6%-87.2%). There were 217 episodes of INF that occurred in 88% (43/49) of pts. Patients experienced multiple INF: 24 (49%) pts had 1-3 INFs and 19 (39%) had ≥3 INFs with 5 of those having >10 INFs. The most frequent INFs were upper respiratory (n=71), sinus (n=37), skin and soft tissue (n=27), and lower respiratory (n=22) (Table). INFs were gr 1-2 in 95% of cases. Gr ≥3 INF were experienced by 18% (9/49) of patients with 10 events. There were 9 gr 3 INFs (lower respiratory tract n=4, kidney n=1, urinary tract n=1, appendix n=1, joint n=1, meninges n=1) and 1 gr 5 COVID-19 INF which occurred in a pt who discontinued LEN >2 years prior. The rate of gr ≥3 INF was 3.8 (95% CI: 1.8-7.0) per 100-person-years. SN were experienced by 8 pts who had 19 SNs. The most common SN were non-melanoma skin cancers (n=15). Other SN were lung adenocarcinoma (n=2 in 1 pt), melanoma in situ (n=1), and squamous cell carcinoma in a parotid lymph node from a skin SCC (n=1). The rate SN was 7.2 (95% CI 4.3-11.3) per 100-person-years. There were no cases of acute leukemia. In this population of pts with CLL with high-risk disease features predictive of need for earlier treatment, LEN resulted in a prolonged time to subsequent therapy, even in cases of LEN discontinuation. The incidence of gr ≥3 INFs and SN were as expected for this population supporting that LEN does not increase risk for these complications.

Whole Genome Classification of Pre-Malignant B-Cells Disorder of the Oxplored Study

Background. Chronic lymphocytic leukaemia (CLL) is always preceded by preclinical clonal B-cell disorders such as monoclonal B-cell lymphocytosis (MBL). Pre-malignant clonal B-cells are identifiable in asymptomatic individuals, a minority of whom will progress to symptomatic CLL. While some people remain at pre-cancerous or asymptomatic early stage CLL, others experience clinically aggressive disease. There is currently no method to effectively stratify individuals at higher risk of developing symptomatic CLL. Despite recent advances in treatment options available, the disease remains incurable. Therefore, we need to expand our knowledge and improve current classification methods. Here, we propose a molecular classifier using whole genome sequencing (WGS). This classifier was obtained by performing genomic characterization in pre-malignancy / early stages of the disease and comparing the genomic subgroups with those of symptomatic CLL. Methods. Individuals with newly diagnosed monoclonal B-cell lymphocytosis and early asymptomatic chronic lymphocytic leukaemia were enrolled in the OXPLORED clinical trial (Oxford Pre-cancerous Lymphoproliferative Disorders: Analysis and Interception study). We performed WGS in 400 samples from 200 individuals (sorted CD19+ B-cells as tumour, and matched salivary DNA as germline) to detect somatic alterations. We derived immunoglobulin heavy chain variable (IGHV) mutational status, stereotype and an additional 186 genomic features as previously described (Robbe*, Ridout* et al. Nature Genetics 2022) including known and recently discovered candidate drivers of CLL, recurrent structural variants, mutational signatures, genomic complexity measures, mutational burden, and pathway alterations. All the data was compiled into a matrix to extract meaningful sets of features to cluster patients' genomes using non-negative matrix factorization (NMF). Genomic findings were compared to the largest CLL whole genome cohort of symptomatic patients requiring frontline treatment (n=443). Results. The IGHV mutational status was found unmutated in 31% of individuals and hypermutated in 69% (excluding missing data for 6 genomes). Next, we considered mutations and CNAs in 58 common CLL drivers and 34 regions with recurrent CNAs. Although numbers were lower than in frontline CLL, most individuals presented at least one driver (86%) or more (57%) (by comparison, the CLL frontline cohort presented at least one CLL driver in 98% of patients). Genomic complexity, defined as 4 or more CNAs was detected in 12%, and complex genome defined as the presence of both CN gains and CN losses in 22%, indicating that newly diagnosed monoclonal B-cell lymphocytosis and early asymptomatic CLL present a relatively high degree of genomic complexity similar to what was observed in frontline CLL. The most common driver was del13q (60%), including as a sole driver in a third of these genomes. Other recurrent alterations were IGLL5 mutations (20%), trisomy 12 (9%), and mutations in MYD88 (8%), CREBBP (5%), NOTCH1 (5%), and SPEN (5%). Noncoding elements were also found mutated, including 30 promoters (including BIRC3 in 7%), five UTRs and eight enhancers, including BCL6 and PAX5 enhancers in 18% and 3.4% of individuals, respectively. When comparing this cohort with CLL genomes, we found that alterations in the main cancer pathways were depleted in OXPLORED, including known drivers such as ATM, NOTCH1, SF3B1. Finally, moving away from single-alteration grouping, we clustered the 643 genomes (443 CLL + 200 OXPLORED) using 186 genomic features by applying NMF. Importantly, we found distinct genomic profiles in the early disease cohort, including a subgroup like symptomatic CLL at frontline and another distinct subgroup, hinting towards identifying a genomic subgroup at higher risk of progressing to CLL. Conclusion: The comprehensive characterisation of genomic events that determine progression to malignancy are essential to understand the mechanisms of disease progression. Our study opens new horizons towards identifying individuals at higher risk and might pinpoint to individuals who need early intervention with curative intent. Therefore, we propose to analyse newly generated whole-genome sequencing (WGS) data to establish genomic subgroups in early CLL / pre-malignancy stages.

ZMYM3 Mutations Cooperate with NOTCH1 Alterations, Reduce Histone H4 Acetylation and Promote Apoptosis Evasion in Chronic Lymphocytic Leukemia

Introduction: Recent next-generation sequencing (NGS) studies have identified up to 200 recurrently mutated genes in chronic lymphocytic leukemia (CLL), the vast majority of which appear mutated in <5% of CLL cases. Among the long list of CLL candidate driver genes is ZMYM3, a gene mutated in 2-4% of CLL patients. Since the impact of ZMYM3 mutations is unknown, we aimed to identify their clinical and biological consequences in CLL. Methods: 487 CLL patients were analyzed by targeted NGS using a customized panel of 54 CLL-related genes to characterize the mutational profile of ZMYM3 mutated patients ( ZMYM3 MUT) and the clinical impact of these variants. In addition, we introduced ZMYM3 truncating mutations into the CLL-derived HG3 cell line with two genetic backgrounds: wild-type (WT), and NOTCH1 mutated cells ( NOTCH1 MUT), to generate cells with either single ZMYM3 MUT, NOTCH1 MUT or combined ZMYM3 MUT NOTCH1 MUT. In these CLL models, we evaluated the impact of these alterations in gene expression, apoptosis, growth and DNA damage response (DDR). Results: A total of 32 ZMYM3 variants were identified in 30 CLL patients, most of which were loss-of-function mutations (24/32; 75%). These variants were distributed throughout the protein sequence, with a particular recurrent frameshift mutation occurring in 6 patients (p.P48fs) that was subsequently reproduced in our CLL model. Attending to their mutational profile, we identified that 70% (21/30) of ZMYM3 MUT patients harbored mutations in the NOTCH pathway, either in NOTCH1 (60%) or in negative regulators such as MED12, FBXW7 and SPEN, suggesting a cooperation between ZMYM3 dysfunction and NOTCH1 signaling mutations in CLL evolution. Interestingly, ZMYM3 MUT patients exhibited significantly shorter time to first treatment (TFT) than ZMYM3 WT cases (median: 35 vs 52 months; p=0.010). Furthermore, ZMYM3 mutations shortened TFT of early stage CLL patients, including Binet A (48 vs 108 months, p=0.002) or Rai 0/1 (48 vs 91 months, p=0.016), as well as in low-risk cytogenetics del(13q) patients (median: 45 vs 93 months; p=0.033). We next addressed the biological implications of ZMYM3 mutations and their co-occurrence with NOTCH1 mutations in HG3 cells. First, we performed RNA-sequencing and analyzed the number of differentially expressed genes (DEGs) (|fold change|>2, adjusted p-value<0.05). Comparing with WT cells, we detected 155 DEGs in ZMYM3 MUT and 83 DEGs in NOTCH1 MUT, whereas ZMYM3 MUT NOTCH1 MUT cells showed 690 DEGs,indicating that the combination of both mutations profoundly dysregulate gene expression. Immune regulation, apoptosis and DNA damage response were some of the biological processes dysregulated by ZMYM3 mutations (p<0.05). Furthermore, considering the suggested role of ZMYM3 in chromatin remodeling (Puente et al, Nature. 2015) and that ZMYM3 MUT cells showed altered expression of histone acetylation related genes (p<0.05), we identified that ZMYM3 mutations reduced global acetylation levels of histone H4 (p<0.05), which may underlie the ZMYM3-related changes in gene expression. To further define the functional effects of ZMYM3 mutations, we assessed in vitro their impact in the main dysregulated pathways identified by RNA-seq. First, we identified that ZMYM3 mutations impair DNA damage response, as reflected by the difficulties to arrest cell cycle in G2/M phase after irradiation. Moreover, we detected more γH2AX foci (p<0.05) in ZMYM3 MUTcells, indicating persistent DNA damage; and fewer RAD51 and BRCA1 foci than WT cells (p<0.001) after irradiation, suggesting defective DNA damage response. In parallel, we identified that ZMYM3 mutations promote apoptosis evasion, especially in the context of NOTCH1 mutations (p<0.001), which led to enhanced growth of ZMYM3 MUT NOTCH1 MUT cells (p<0.05). Of note, ZMYM3 MUT cells showed down-expression of caspases (-8, -7 and -3) and slightly higher levels of anti-apoptotic proteins (BCL2, MCL1 and BCL-XL), which may explain this apoptosis resistance. Conclusions: Mutations in ZMYM3 are mainly loss-of-function, associate with NOTCH1 signaling mutations and shorten TFT in CLL patients, suggesting that ZMYM3 mutational status may be a useful marker in the management of early stage CLL patients. Moreover, ZMYM3 mutations reduce histone H4 acetylation and cooperate with NOTCH1 mutations to dysregulate gene-expression, leading to impair DNA damage response and apoptosis evasion.

IGLV3-21 R110 Is a Prognostic Marker for Early Stage CLL Patients Under Ibrutinib Treatment or Watch & Wait: Results from the Double-Blind, Randomized, Placebo-Controlled GCLLSG CLL12 Trial

INTRODUCTION: IGLV3-21 R110 is a point mutation that can confer the ability for autonomous signaling to B cell receptors (BCR) using light chains encoded by the allele IGLV3-21 ∗ 01 or IGLV3-21 ∗ 04. Chronic lymphocytic leukemia (CLL) patients with IGLV3-21 R110 have a shorter time to first treatment and shorter overall survival, independent of their IGHV mutational status. However, outcomes of CLL patients using IGLV3-21 R110 have not been evaluated in clinical trials of BTK inhibitors. METHODS: The CLL12 trial was a prospective, double-blind, randomized phase 3 trial that compared ibrutinib (ibr, n=182) vs. placebo (pcb, n=181) in previously untreated Binet A CLL patients with intermediate to very high risk, while low risk patients were assigned to watch & wait (w&w, n=152). The primary endpoint of the study was event-free survival (EFS) (event defined as death, symptomatic progression or initiation of CLL treatment), while overall survival (OS) was a secondary endpoint. The IGLV3-21 locus was sequenced via amplicon-based targeted next generation sequencing (tNGS) in 514 of 515 samples collected at enrolment. IGLV rearrangements and point mutations were detected with ScanIndel as well as IgCaller and the results of the genetic analyses were correlated with outcome. RESULTS: IGHV was unmutated (U-IGHV) in 148 (28.3%) patients (w&w n=8, pcb n=70, ibr n=70) and 10 patients belonged to stereotyped B cell receptor (BCR) subset 2 (w&w n=2, pcb n=1, ibr n=7). IGLV3-21 rearrangement was found in 34 of 514 patients (6.6%) and was more frequent in the intermediate/high risk groups (pcb n=16, ibr n=13) than in the low risk group (w&w n=5). Twenty of 34 patients with IGLV3-21 rearrangement had an IGLV3-21 R110 mutation (w&w n=3/5, pcb n=10/16, ibr n=7/13). For 5 patients with IGLV3-21 (3 pcb, 2 ibr) the mutational status for IGLV3-21 R110 could not be determined by tNGS. In the total cohort, IGLV3-21 R110 often co-occurred with mutations in SF3B1 (odds ratio 8.54, p < 0.001), but not with mutations in TP53 or any of the other frequently mutated genes in CLL. Conversely, SF3B1 mutations were not enriched in subset 2 patients (p = 0.165). Also, there was no association of IGLV3-21 R110 or IGLV3-21 usage in general with IGHV mutational status. At a median follow-up of 69.3 months, there were 166 events for EFS and 32 for OS. CLL with IGLV3-21 had a shorter EFS in the pcb (HR 1.93, CI95% 1.05-3.55, p=0.033) and ibr (HR 3.71, CI95% 1.62-8.46, p=0.002) arm (Figure 1A). The estimated 5-year EFS rate was 51.0% without and 21.4% with IGLV3-21 rearrangementin the pcb group vs. 80.7% and 44.8% in the ibr group, respectively. Similarly, IGLV3-21 R110 associated with shorter EFS with ibr (HR 3.30, CI95% 1.17-9.31, p=0.024) while no impact was observed in the pcb group (HR 1.51, CI95% 0.66-3.46, p=0.332, Figure 1B). Patients with IGLV3-21 R110 mutation and ibr treatment had an estimated 5-year EFS rate similar to that of patients in the pcb group without IGLV3-21 R110 (50.0% vs. 49.8%). In low risk patients with w&w, both IGLV3-21 rearrangement and IGLV3-21 R110 were adverse markers for EFS (HR 4.99, CI95% 1.52-16.41, p=0.008 and HR 17.0, CI95% 4.99-58.13, p<0.001, respectively). For the full trial, we observed a prognostic impact of IGLV3-21 in the M-IGHV (HR 3.87, CI95% 2.14-6.99, p<0.001) but not in the U-IGHV (HR 1.61, CI95% 0.74-3.54, p=0.233) group. Multivariable analysis for the treatment arms including the IGLV3-21 R110 status and other variables associated significantly with EFS in univariate analyses (treatment arm, serum β2-microglobulin, IGHV status, del(17p), del(11q), +(12), mutations in XPO1, NOTCH1, SF3B1 and NFKBIE) revealed presence of IGLV3-21 R110 (HR 2.76, CI95% 1.32-5.80, p = 0.007) as an independent prognostic factor. OS was excellent in all genetic subgroups and in all arms of the trial. The estimated 5-year OS rate was between 92.9% and 95.8% for any of the 4 subgroups defined jointly by IGHV status and presence of IGLV3-21 R110. CONCLUSIONS: IGLV3-21 R110 was identified as an independent prognostic factor for shorter EFS in early stage CLL with intermediate/high risk score and was associated with reduced ibrutinib efficacy in the CLL12 trial.

Predicting the overall survival of patients with chronic lymphocytic leukemia in the dynamics of the disease

Relevance. The high prevalence of chronic lymphocytic leukemia (CLL) in elderly and senile patients of the European population dictates the need to find a publicly available solution to the problem of prognosis in this cohort of patients. Previously, a relationship was established between the survival of patients with CLL and the value of the glomerular filtration rate (GFR) at the time of diagnosis. The purpose of the study: to assess the relationship of GFR with the survival of CLL patients in the course of the disease. Materials and methods: 207 patients (98 men and 109 women) aged 45 to 80 years with CLL A-C according to Binet and known overall survival were studied. Annually from the 1st to the 5th year of the course of the disease, the maximum value of the patient's GFR was taken into account according to the CKD-EPI formula. The data was processed by data mining using a logical classification algorithm. Results. With a GFR value of more than 76 ml/min/1.73 m2 during the first year of the disease, more than 75 ml/min/1.73 m2 during the second year of the disease, more than 70 ml/min/1.73 m2 during the third year of the disease, more than 68 ml/min/1.73 m2 during the fourth and fifth years of the disease, the patient will overcome the calculated parameters of the median survival for the corresponding stage of CLL according to Binet. Otherwise, the overall survival of the patient will be less than the calculated median survival according to Binet. This article provides illustrative clinical examples. Conclusion. It was found that the value of GFR in CLL patients gradually decreases with the course of the disease, however, the value of this parameter in the dynamics of the disease can be considered as a significant factor in predicting the survival of patients with CLL. Based on the results, an application for an invention No. 2023108368 was filed.

LncRNA CRNDE is downregulated and associated with poor prognostic markers in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is characterized by a very heterogeneous clinical outcome. Thus, a plethora of prognostic factors and systems has been identified to place patients into different risk categories and to guide therapy decisions. The classic clinical staging models by Rai and Binet have been the cornerstone of patient management for several years. The greater insight into the molecular biology of CLL facilitated the advent of prognostic genetic biomarkers that are expected to impact clinical practice soon in the future. Therefore, we aimed to investigate the expression of long non-coding RNA (lncRNA) CRNDE in patients with CLL, and to analyze its relationship with the clinicopathological parameters of CLL. In this study, 40 untreated CLL patients and 30 age- and gender-matched controls were enrolled. The analysis of lncRNA CRNDE expression was determined using reverse transcription-quantitative polymerase chain reaction technique. Our result confirmed the downregulated expression of LncRNA CRNDE in CLL patients compared to controls (p < 0.001). The low expression of CRNDE was significantly associated with poor prognostic markers including advanced stage of CLL, high levels of serum beta-2 microglobulin and lactic dehydrogenase, and the presence of del17p (p = 0.029, p = 0.013, p = 0.003, p = 0.028; respectively). Our study demonstrated that LncRNA CRNDE is significantly downregulated and associated with poor prognostic markers in CLL. It provides a rationale to assess its biological and prognostic impact in CLL.

Evidence-Based Management of Chronic Lymphocytic Leukemia: Consensus Statements from the Gulf Region

Introduction: Despite recent advances in diagnosis, prognostication, and treatment options, chronic lymphocytic leukemia (CLL) is still a largely incurable disease. New concepts on diagnosis, staging, treatment, and follow-up on CLL have been incorporated throughout recent years. The lack of regional consensus guidelines has led to varying practices in the management of patients with CLL in the region. This manuscript aims to reach a consensus among expert hematologists regarding the definitions, classifications, and related practices of CLL. The experts developed a set of statements utilizing their personal experience together with the current literature on CLL management. This consensus aims to provide guidance for healthcare professionals involved in the management of CLL and serves as a step in developing regional guidelines. Methods: Eight experts responded to 50 statements regarding the diagnosis, staging, treatment, and prognosis of CLL with three potential answering alternatives ranging between agree, disagree, and abstain. This consensus adopted a modified Delphi consensus methodology. A consensus was reached when at least 75% of the agreement to the answer was reached. This manuscript presents the scientific insights of the participating attendees, panel discussions, and the supporting literature review. Results: Of the 50 statements, a consensus was reached on almost all statements. Statements covered CLL-related topics, including diagnostic evaluation, staging, risk assessment, different patient profiles, prognostic evaluation, treatment decisions, therapy sequences, response evaluation, complications, and CLL during the COVID-19 pandemic. Conclusion: In recent years, CLL management has progressed significantly, with many diagnostic tests and several novel treatments becoming available. This consensus gathers decades of consolidated principles, novel research, and promising prospects for the management of this disease.

Differential prognosis of single and multiple TP53 abnormalities inhigh-count MBL and untreated CLL.

TP53 aberrations, including mutations and deletion of 17p13, are important adverse prognostic markers in chronic lymphocytic leukemia (CLL) but are less studied in high count monoclonal B-cell lymphocytosis (HCMBL), an asymptomatic pre-malignant stage of CLL. Here we estimated the prevalence and impact of TP53 aberrations in 1,230 newly diagnosed treatment-naïve individuals (849 CLL, 381 HCMBL). We defined TP53 state as: wild-type (no TP53 mutations and normal 17p), single-hit (del(17p) or one TP53 mutation), or multi-hit (TP53 mutation and del(17p), TP53 mutation and loss of heterozygosity, or multiple TP53 mutations). Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for time to first treatment and overall survival by TP53 state. We found 64 (7.5%) CLL patients and 17 (4.5%) HCMBL individuals had TP53 mutations with variant allele fraction >10%. Del(17p) was present in 58 (6.8%) of CLL and 11 (2.9%) of HCMBL cases. Most individuals had wild-type (N=1,128, 91.7%) TP53 state, followed by multi-hit (N=55, 4.5%) and then single-hit (N=47, 3.8%) TP53 state. The risk of shorter time to therapy and death increased with the number of TP53 abnormalities. Compared to wild-type patients, multi-hit patients had 3-fold and single-hit patients had 1.5-fold increased risk of requiring therapy. Multi-hit patients also had 2.9-fold increased risk of death compared to wild-type. These results remained stable after accounting for other known poor prognostic factors. Both TP53 mutations and del(17p) may provide important prognostic information for HCMBL and CLL that would be missed if only one were measured.

Additional malignancies shorten overall survival in chronic lymphocytic leukemia irrespective of chromosomal aberrations: A retrospective cohort study.

The aim of this study was to determine the incidence of other malignancies (OMs) in patients with chronic lymphocytic leukemia (CLL) and to identify parameters associated with the occurrence of OMs in addition to CLL. This retrospective cohort study was conducted by examining the records of CLL patients who applied to a tertiary hospital between January 2013 and December 2021. The cases were divided into 2 groups, CLL (n = 107) and CLL + OM (n = 25), according to the presence of additional malignancy. Lymphocyte count (P = .014), white blood cell count (P = .006), and hemoglobin (P = .034) were significantly higher in the CLL group. Rai stage IV percentage (P = .015), Binet stage B percentage (P = .043), progression, and sepsis percentages (P = .008) were significantly higher in the CLL + OM group. Overall survival time was significantly lower in the CLL + OM group (P = .032). Most OMs had been diagnosed before CLL (63.64%) in the no-treatment group, while the majority of OMs were diagnosed after CLL (78.57%) in the treatment group (P = .032). CLL patients with OM had a more advanced CLL stage, and survival was significantly shorter in these patients. In addition, CLL-associated OM appears to occur more frequently in the post-treatment period.

How we approach the perioperative management of patients with chronic lymphocytic leukaemia receiving continuous cancer-directed therapies.

Historically, invasive procedures and surgeries were deferred in patients with haematological malignancies including advanced stage chronic lymphocytic leukaemia (CLL) because of limited life expectancy. However, novel, and often continuous, treatments have markedly improved outcomes in CLL. Some patients may expect years of treatment response and disease control, overcoming the short life expectancy that deters interventionalists. Such patients now often undergo various invasive procedures including major surgery. To inform peri-operative management, we summarize the relevant side effects and drug interactions of continuous CLL therapies, highlight potential surgical risks, and provide recommendations on withholding specific CLL drugs around invasive procedures.

Determinants of Time-to-Death of Chronic Lymphocytic Leukemia Patients at Felege Hiwot Referral Hospital, Bahir Dar, Ethiopia

Background: Leukemia is a group of cancers that usually begin in the bone marrow and results in a large number of abnormal white blood cells. Chronic Lymphocytic Leukemia is the most prevalent leukemia in Western countries, with an estimated incidence rate of less than 1 to 5.5 per 100 000 people, and average age at diagnosis of 64 to 72 years. It is more common in men among Chronic Lymphocytic Leukemia patients in Ethiopia’s hospitals at Felege Hiwot Referal Hospital. Methods: A retrospective cohort research design was employed to acquire critical information from patients’ medical records in order to achieve the study’s purpose. The study comprised the medical records of 312 Chronic Lymphocytic Leukemia who were followed from January 1, 2018 to December 31, 2020. A Cox proportional hazard model was used to determine the risk factors for time to death in Chronic Lymphocytic Leukemia patients. Results: Accordingly the Cox proportional hazard model, age (Hazard Ratio = 11.36; P &lt; .001), sex of male (Hazard Ratio = 1.04; P = .004), married status (Hazard Ratio = 0.03; P = .003), medium stages of Chronic Lymphocytic Leukemia (Hazard Ratio = 1.29; P = .024), high stages of Chronic Lymphocytic Leukemia (Hazard Ratio = 1.99; P &lt; .001), presence of anemia (Hazard Ratio =0.09; P = .005), platelets (Hazard Ratio = 2.11; P = .007), hemoglobin (Hazard Ratio = 0.02; P &lt; .001), lymphocytes (Hazard Ratio = 0.29; P = .006), red blood cell (Hazard Ratio = 0.02; P &lt; .001), which patients with Chronic Lymphocytic Leukemia had a significant relationship with time to death. Conclusions: Age, sex, Chronic Lymphocytic Leukemia stage, anemia, platelets, hemoglobin, lymphocytes, and red blood cells were all statistically significant determinants in the time to death of Chronic Lymphocytic Leukemia patients, according to the data. As a result, healthcare providers should pay particular attention to and emphasize the identified characteristics, as well as provide frequent counseling on how to enhance the health of Chronic Lymphocytic Leukemia patients.