Diagnosis Of Chronic Lymphocytic Leukemia Research Articles

Abstract 3795: Early seeding of Richter transformation in chronic lymphocytic leukemia

Abstract Introduction: Clonal evolution drives cancer development due to the emergence and/or selection of proliferatively advantageous subclones. Its understanding may facilitate the design of anticipation-based management strategies. Richter transformation (RT) is a paradigmatic tumor evolution in which chronic lymphocytic leukemia (CLL), an indolent neoplasia of mature B-cells, transforms into a high-grade lymphoma, usually diffuse large B-cell lymphoma (DLBCL), conferring a dismal prognosis. The evolutionary trajectories of RT and its driving (epi)genomic mechanisms remain largely unknown. Aims: To reconstruct the evolutionary history of RT and to reveal the molecular processes underlying this transformation. Methods: We characterized the whole genome (WGS), epigenome (DNA methylation, H3K27ac, ATAC-seq), and transcriptome (RNA-seq), combined with single-cell DNA and RNA sequencing analyses, of 19 CLL patients developing RT before (n=3) or after treatment with chemoimmunotherapy (n=6) and targeted therapies (BCR or BCL2 inhibitors, n=10). We analyzed 54 longitudinal samples covering up to 19 years of disease course. Results: Our WGS analyses uncovered that RT is characterized by a remarkable structural complexity. We also identified a novel treatment-independent RT-specific mutational process, which we named SBS-RT. The genetic driver landscape of RT is a compendium of alterations in genes involved in cell cycle, MYC, and NF-κB pathways, frequently targeted in single catastrophic events including chromothripsis and chromoplexy. The WGS-based phylogenic reconstruction and single-cell DNA/RNA-seq analyses identified a very early diversification of CLL leading to emergence of RT-cells carrying specific genetic drivers and transcriptomic profiles of RT already at CLL diagnosis. These small subclones were dormant for 6-19 years until rapid expansion associated with the clinical transformation. While the DNA methylome kept track of the cell of origin and proliferative history of RT cells, their chromatin configuration and transcriptional program converged into the overexpression of cell cycle regulators, Toll-like receptors, MYC, MTORC1, and OXPHOS related transcripts, as well as downregulation of BCR pathway. This phenotypic shift was related to de novo activation of key transcription factors. In vitro experiments confirmed that RT cells have a 4-fold higher oxygen consumption at routine respiration and electron transfer system capacity compared to CLL. The resistance of RT to BCR inhibition is consistent with its high OXPHOS and low BCR signaling, which mimics de novo DLBCL-OXPHOS insensitive to BCR inhibition. This OXPHOShigh-BCRlow transcriptional axis of RT can be exploited therapeutically. Conclusions: These findings demonstrate the early seeding of subclones driving advanced stages of cancer evolution and uncover therapeutic targets for the, once expanded, lethal Richter transformation. Citation Format: Ferran Nadeu, Romina Royo, Ramon Massoni-Badosa, Beatriz Garcia-Torre, Martí Duran-Ferrer, Kevin J. Dawson, Marta Kulis, Ander Diaz-Navarro, Neus Villamor, Juan L. Melero, Vicente Chapaprieta, Ana Dueso-Barroso, Julio Delgado, Riccardo Moia, Sara Ruiz-Gil, Domenica Marchese, Núria Verdaguer-Dot, Mónica Romo, Maria Rozman, Gerard Frigola, Alfredo Rivas-Delgado, Tycho Baumann, Miguel Alcoceba, Marcos González, Fina Climent, Pau Abrisqueta, Josep Castellví, Francesc Bosch, Marta Aymerich, Anna Enjuanes, Sílvia Ruiz-Gaspà, Armando López-Guillermo, Pedro Jares, Sílvia Beà, Dolors Colomer, Núria López-Bigas, Josep LlGelpí, David Torrents, Peter J. Campbell, Ivo Gut, Pablo M. Garcia-Roves, Davide Rossi, Gianluca Gaidano, Xose S. Puente, Holger Heyn, Francesco Maura, José I. Martín-Subero, Elías Campo. Early seeding of Richter transformation in chronic lymphocytic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3795.

Flow Cytometric Expression of CD49d in Newly Diagnosed Chronic Lymphocytic Leukemia and Its Correlation with Established Prognostic Markers.

Introduction Chronic lymphocytic leukemia (CLL) is the commonest hematological malignancy in the West but is relatively uncommon in India. The prognosis of CLL is determined by well-established prognostic markers. CD49d has been emerging as a promising prognostic marker in CLL. CD49d expression in CLL has been found to have an aggressive clinical course, shorter time to first treatment, and poorer prognosis. The aim of this study was to analyze the flow cytometric expression of CD49d in newly diagnosed CLL and to correlate its expression with clinico-hematological parameters. Materials and Methods Twenty-five consecutive patients of CLL, diagnosed on flow cytometry, were included in the study. Patients on treatment or those with relapse were excluded. The panel for flow cytometry included the routine markers used for CLL diagnosis along with CD49d. The expression of CD49d was correlated with clinico-hematological parameters in all patients. "R" software was used for the statistical analysis. Fisher's exact test and Wilcox test were used to assess the correlation of CD49d to categorical and continuous data, respectively. Results The mean age of the patients was 62.6 ± 12.5 years, and 80% were symptomatic at diagnosis. CD49d expression was found in 44% cases, with a higher proportion being male patients. CD49d and prolymphocyte percentage showed a statistically significant correlation ( p = 0.0007). We found a statistically significant correlation between CD49d expression and lymphadenopathy and splenomegaly with p -values of 0.033 and 0.0472, respectively. CD49d positivity correlated significantly with a higher Rai stage ( p = 0.0196) and intermediate and high-risk cases according to Binet staging ( p = 0.033). Conclusion CD49d expression in the present study correlated with a higher prolymphocyte percentage, lymphadenopathy, splenomegaly, and higher Rai and Binet stages. CD49d expression on flow cytometry was reproducible and easy to interpret.

Safety and efficacy of Ibrutinib in Indian patients with chronic lymphocytic leukemia.

e19585 Background: Ibrutinib, an oral Bruton's tyrosine kinase inhibitor, is approved for the treatment of chronic lymphocytic leukemia (CLL) in both upfront and relapsed/refractory. The prevalence of CLL is very low in India compared to western countries. Hence, the real-world data regarding efficacy and safety of Ibrutinib among the Indian population is very scarce. In this study, we aim to examine the toxicity profile, treatment response, and survival outcomes among Indian patients with CLL treated with Ibrutinib. Methods: In this retrospective study, we recruited all consecutive patients diagnosed with CLL, both treatment naïve (TN) and relapsed/refractory (R/R) CLL, on Ibrutinib (daily dose of 420 mg), registered at the Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India between April 2016 and December 2021. Diagnosis of CLL, an indication of treatment, and response assessment were based on the recent guidelines (2018) from the International Workshop on CLL (iwCLL). Results: A total of 90 patients were recruited in this study, of which 33 were newly diagnosed and 57 had R/R CLL. Median age of the cohort was 60 years (range, 35–80 years) and male to female ratio was 3:1. The median total leukocyte count was 55x109/L and Del 17p was detected in 18% of cases. The R/R cases had received a median of 1(1-3) prior line of therapy. Overall response rate was observed in 76(84.4%), complete response was in 18 (20%) cases, partial response (PR) was in 49 (54.4%) cases, and in 9 (10%) cases PR with lymphocytosis (PR-L) was observed. With a median follow-up period of 15 months (4-60), 2-year progression-free survival (PFS) was 80% for the whole cohort. The median PFS was not reached in TN cases and was 18 months in R/R cases. Grade-3/4 adverse events (A/E) were seen in 17 (29.8%, n = 57) of R/R cases and in 3 (9.1%,n = 33) of TN cases. The most common Grade-3/4 A/E were infections in 19 (21.1%), (Varicella: 7, Pneumocystis: 6, Aspergilosis: 2, Mucormycosis: 1, Disseminated tuberculosis: 1, Encephalitis: 1, Others: 1) and cytopenias in 9 (10%) of cases. Other A/E were fatigue in 6 cases, arthralgia in 3, bleeding in 2, cutaneous rash in 2, reactivation of hepatitis-B in 2, diarrhea in 2, arrhythmia in 2, and autoimmune hemolytic anemia in one case. Ten patients (11.1%) had a dose reduction due to AE. The discontinuation rate was 27 (30%), due to progressive disease in 18 patients and due to adverse events in 9 patients. Twenty patients died, 14 due to disease progression or Richter's transformation, 5 due to infections, and 2 due to other reasons. Conclusions: This is the largest study of ibrutinib from India. Ibrutinib is safe and effective in upfront and R/R cases of CLL. Infections are the most common adverse event in R/R cases. Acyclovir and Co-trimoxazole prophylaxis can be considered in R/R cases of CLL in routine clinical practice . Arrhythmias were rare A/E as compared with the available literature.

Survival trends among patients diagnosed with both melanoma and chronic lymphocytic leukemia.

e19527 Background: Patients previously diagnosed with melanoma have a higher risk of developing subsequent chronic lymphocytic leukemia (CLL). Similarly, melanoma risk has been observed to be elevated among patients with a history of CLL. However, previous studies have reported inconsistent results on whether being diagnosed with both cancers significantly reduces patient survival. Additional research is needed to assess the potential reduction in survival among this unique cohort of patients diagnosed with both melanoma and CLL. In addition, the timing of the cancer development needs to be assessed to further explore unique patient characteristics. Methods: A retrospective cohort study was conducted using data from adult patients who were diagnosed and/or treated for melanoma (n = 5,511) or chronic lymphocytic leukemia (CLL, n = 571) at Moffitt Cancer Center (MCC) in 2008-2020. Clinical characteristics and survival information were obtained from the MCC Cancer Registry including, date of diagnosis, vital status, time of death or last contact, and tumor stage at diagnosis. The Kaplan-Meier method was used to estimate survival for three patient groups: patients diagnosed with only melanoma, patients diagnosed with only CLL, and patients who were diagnosed with both cancers. The timing of the two cancer diagnoses were assessed among the 17 patients diagnosed with both melanoma and CLL. Results: The estimated 5-year survival was 78.5% and 82.9% among patients diagnosed with only melanoma and only CLL, respectively. Among patients who were diagnosed with both cancers, the 5-year survival since melanoma diagnosis was 61.4% whereas the 5-year survival since the CLL diagnosis further reduced to 60.2%. When analyzing the timing of the diagnoses of the two cancers, 13 out of 17 patients were diagnosed with melanoma prior to CLL. Further, among these 13 patients, 12 patients had CLL diagnosed within 100 days after the melanoma diagnosis. Conclusions: Patients diagnosed with both melanoma and CLL experienced poorer survival outcomes as compared to patients who were diagnosed with only one of these cancers. Among patients who were diagnosed with both cancers, more than 70% of the patients were diagnosed with CLL shortly after their melanoma diagnosis. Additional research using larger national cancer registry databases can help to advance the understanding of the underlying disease mechanism and confirm the observed timing of diagnoses is due to the CLL being diagnosed incidentally as result of node biopsies for melanoma.

Self-reported financial difficulties among patients with multiple myeloma and chronic lymphocytic leukemia: An Alliance for Clinical Trials in Oncology study.

6602 Background: Treatment advances have greatly improved survival and quality of life among blood cancer patients, yet significant financial costs are a growing concern. Methods: We conducted an observational, prospective survey in 2019-2020 to estimate the self-reported prevalence of financial difficulty among multiple myeloma (MM) and chronic lymphocytic leukemia (CLL) patients and identify sociodemographic correlates of financial difficulty. Patients with an MM or CLL diagnosis >/= 18 years of age were recruited from NCI NCORP sites of care. Financial difficulty was measured in a previously validated single question from the EORTC QLQ C30 and a composite measure of five questions from the EORTC QLQ C30. Results: 521 MM and CLL patients were registered to the study, 416 patients were administered all or part of the patient survey, for an overall response rate of 79.8%. 16.8% of respondents reported experiencing financial difficulty in response to the single item question and 58.6% reported experiencing financial difficulty in response to the composite measure. Respondents reporting financial difficulty to both measures had reported household incomes of less than $60,000, identified their highest education levels as a high school diploma or GED, had more than one medical comorbidity and used an expensive oral chemotherapeutic agent to treat their blood cancer. Conclusions: Blood cancer patients treated at NCI NCORP sites are experiencing financial difficulties. Results of this study aim to inform physician, site of care and policy efforts to improve access among cancer patients. Clinical trial information: NCT03870633. [Table: see text]

Features of the course of chronic lymphocytic leukemia in the presence of a genetic mutation of leukemia cells: 17p13 deletion and its impact on disease prognosis.

e19515 Background: In order to identify the features of the course of the disease in patients with chronic lymphocytic leukemia (CLL) when prescribing standard polychemotherapy (PCT) according to the RFC scheme (rituximab, fludarabine, cyclophosphamide) we investigated chromosomal aberrations in leukemia cells. Methods: We observed 190 patients (aged 57.4±23.7 years, 87 men, 103 women). Cytogenetic studies were conducted. Clinical and hematological remission was evaluated. Results: 52% of patients had single chromosomal aberrations, 25% - double, 23% - complex. A deletion of 17p13 (del (17p13)) with a level on leukemia cells from 2 to 98% in the period from the moment of CLL diagnosis of 11.8±7.2 months was found in 85 people (44.7%), with a level of more than 15% - in 24 (12.6%), of which with a level of 21% - 98% - in 12 (6.3%). During standard PCT according to the RFC scheme, among 44 patients with a level of cells with del (17р13) less than 15%, when controlled after 12 months, 12 (37.5%) showed an increase in the number of these cells to an average of 22.5%, which correlated (p < 0.1) with early relapses of the disease and the formation of secondary resistance to cytostatic treatment; in 20, there was no correlation between an increase in the number of cells and progression (partial remission (PR) was achieved); in 12 patients, cells with del (17p13) were not detected, and patients were characterized by the achievement of complete clinical and hematological remission (CR), which indicates the effectiveness of the FCR scheme in most patients. In 12 patients with the level of cells with del (17p13) 21% - 98%, no statistically significant increase in them was detected after 12±3 months (p > 0.15), however, remission was not achieved. They were treated with ibrutinib. Among the 8 patients with a recurrent course while taking ibrutinib at a dose of 420 mg per day for 2 to 4 years, severe infections were observed in the first months of therapy; in 4 patients the number of infectious episodes reduced later. 4 achieved PR (50%), 3 - PR (37.5%), 1 - stabilization. Conclusions: Thus, the level of blood cells with del (17p13) less than 15% in patients with CLL does not determine the severity of the disease and sensitivity to cytostatic treatment. These patients in the first line of chemotherapy are indicated for R, which, as a rule, does not cause irreversible elimination of cells with del (17p13), but slows down the growth of the tumor clone. This may determine the achievement of longer CR and PR and lead to a significant improvement in the long-term prognosis of the disease, and therefore the widely used RFC chemotherapy for B-CLL remains effective in most primary and pretreated patients. The detection of forms with a 17p13 deletion in an amount of more than 15% among tumor leukemia cells makes it possible to select a group of patients for prescribing ibrutinib, the overall response rate in which was 87.5%.

Real-world evidence of impact of atrial fibrillation (AF) on clinical and economic outcomes in patients with chronic lymphocytic leukemia (CLL).

e18729 Background: While the incidence of AF in CLL has been increasing, the implications of AF in real-world CLL patients remain understudied. This study aimed to assess the impact of AF on clinical and economic outcomes in CLL patients. Methods: This retrospective observational study used the US IBM MarketScan® commercial claims/Medicare supplement database (2017-2020) to identify newly diagnosed CLL patients (≥18 years) and incidence of AF after index date, defined as the first CLL diagnosis date. Patients were followed for ≥3-months pre-index, and from index to last follow-up or death. In addition to patient characteristics, clinical outcomes (incidence of heart failure [HF], bleeding and stroke) and economic outcomes (costs and healthcare resource utilization [HRU]) were compared between CLL patients with AF (CLL+AF) and CLL patients without AF (CLL-AF). HRU was evaluated by inpatient, outpatient, ER, and pharmacy visits. Multivariable regression analyses were conducted to examine the association between AF and clinical outcomes. Results: Among a total of 16,800 newly diagnosed CLL patients included in the study, 20% developed AF. CLL+AF were significantly older than CLL-AF (median: 77 vs 62 years; P < .001). Compared to CLL-AF, CLL+AF also had significantly more comorbidities at baseline, as shown by higher Charlson comorbidity index (CCI) (median: 1.0 vs 3.0; P < .001) and more patients with previous AF history (0.3% vs 8.4%; P < .001). Further assessing clinical outcomes in CLL+AF vs CLL-AF, significantly higher incidence of HF (26.3% vs 3.0%; P < .001), bleeding (12.2% vs 4.8%; P < .001) and stroke (6.6% vs 1.2%; P < .001) were observed. For HRU, CLL+AF were reported to have significantly higher rates of ER visits (29.4% vs 12.9%; P < .001) and hospitalizations (42.2% vs 14.5%; P < .001) than CLL-AF. In CLL+AF, the average total AF-related costs were $13,520.21 within 30 days after AF diagnosis, and $22,304.82 within 60 days after AF diagnosis. Controlling for demographics and comorbidities, multivariable regressions reported statistically significant associations between AF and HF, as well as AF and stroke (Table). Conclusions: This real-world study reported significantly higher incidence of HF, bleeding and stroke incurred by CLL patients who developed AF compared with those who did not. The presence of HF, bleeding and stroke further increased HRU and costs. These findings highlight the importance of better disease management and treatment selection to prevent AF in CLL patients.[Table: see text]

Outcomes of Hodgkin variant Richter transformation in chronic lymphocytic leukaemia and small lymphocytic lymphoma in British Columbia.

Hodgkin variant Richter transformation (HvRT) is a rare and challenging complication of chronic lymphocytic leukaemia (CLL) for which information on prognostic factors and treatment approaches remain limited. We analysed characteristics and survival outcomes of a population-based cohort of 32 patients with HvRT identified in British Columbia over a 40-year period. Median interval from CLL diagnosis to HvRT was 5.6 years (range, 0-33.6), with five cases diagnosed concurrently. Most patients (80%) had treatment for CLL prior to HvRT. Median age at HvRT was 71 years (range, 51-86) and the majority of patients had high-risk disease, including stage 3-4 in 87% and International Prognostic Score (IPS) ≥ 4 in 65%. Two-year progression-free (PFS) and overall survival (OS) from HvRT were 47% (95% CI: 29%-64%) and 57% (95% CI: 38%-72%), respectively. OS from HvRT was significantly worse in those with anaemia (p= 0.02), elevated lactate dehydrogenase (p= 0.04), high IPS (p= 0.04), and worse performance status (p= 0.001). For those treated with curative-intent ABVD/ABVD-like therapy, 2-year PFS and OS were 70% (95% CI: 45%-85%) and 74% (95% CI: 49%-89%), respectively. In this real-world population-based cohort, HvRT was associated with poor clinical outcomes overall; however, those able to tolerate curative-intent therapy had similar survival to older patients with de novo HL.

Distinct Age-Related Clinical Features and Risk Assessment in Chinese With Chronic Lymphocytic Leukemia.

The biological and clinical features of chronic lymphocytic leukemia (CLL) exhibited profound heterogeneity across Chinese and patients of predominately European descent. However, the age-related peculiarities and risk assessment of Chinese CLL patients remained ill-defined. The present study demonstrated that CLL patients were characterized by the earlier age at onset in China (median age at diagnosis: 63 years old) than in the United States (median age at diagnosis: 69 years old). Young patients from Shandong Provincial Hospital CLL database displayed prolonged overall survival than the Surveillance, Epidemiology, and End Results cohort. Furthermore, among Chinese CLL patients, young patients showed an increased relapse rate compared with elderly patients. To optimize the risk assessment of CLL patients, novel risk score models named PR-Score and HBG-Score were developed for predicting the outcomes of young and elderly CLL patients respectively. The neonatal survival prediction systems were superior to international prognostic index for CLL (CLL-IPI) and Binet stage in assessing the overall survival and progression free survival of CLL patients. The analyses highlighted refinement of risk evaluation for CLL patients in different age groups, providing insights into individualized diagnosis and treatment of CLL.

Invasive Fungal Disease in Patients with Chronic Lymphocytic Leukemia in Japan: A Retrospective Database Study.

Invasive fungal disease (IFD) is an important cause of morbidity and mortality in patients with hematological malignancies. As chronic lymphocytic leukemia (CLL) is a rare hematological malignancy in Japan, IFD incidence in Japanese patients with CLL is unclear. This study aimed to investigate IFD incidence in Japanese patients with CLL. This retrospective cohort study used data of patients with CLL registered between April 2008 and December 2019 in the Medical Data Vision database (n = 3484). IFD incidence after CLL diagnosis in the watch-and-wait (WW) and drug therapy (DT) groups was 1.5% and 9.2%, respectively. The most common type of IFD was invasive aspergillosis (28.1%). Cox proportional hazards multivariate analysis revealed that DT (hazard ratio [HR]: 2.13) and steroid use (HR: 4.19) were significantly associated with IFD occurrence. IFD incidence was significantly higher in the DT group than in the WW group (log-rank p < 0.001); however, there was no significant between-group difference in the time to IFD onset or the type of IFD (p = 0.09). This study determined the incidence of IFD in patients with CLL during WW. Physicians should monitor for IFD, even among patients with CLL undergoing the WW protocol.

Prediction of clinical outcome in CLL based on recurrent gene mutations, CLL-IPI variables, and (para)clinical data

AbstractA highly variable clinical course, immune dysfunction, and a complex genetic blueprint pose challenges for treatment decisions and the management of risk of infection in patients with chronic lymphocytic leukemia (CLL). In recent years, the use of machine learning (ML) technologies has made it possible to attempt to untangle such heterogeneous disease entities. In this study, using 3 classes of variables (international prognostic index for CLL [CLL-IPI] variables, baseline [para]clinical data, and data on recurrent gene mutations), we built ML predictive models to identify the individual risk of 4 clinical outcomes: death, treatment, infection, and the combined outcome of treatment or infection. Using the predictive models, we assessed to what extent the different classes of variables are predictive of the 4 different outcomes, within both a short-term 2-year outlook and a long-term 5-year outlook after CLL diagnosis. By adding the baseline (para)clinical data to CLL-IPI variables, predictive performance was improved, whereas no further improvement was observed when including the data on recurrent genetic mutations. We discovered 2 main clusters of variables predictive of treatment and infection. Further emphasizing the high mortality resulting from infection in CLL, we found a close similarity between variables predictive of infection in the short-term outlook and those predictive of death in the long-term outlook. We conclude that at the time of CLL diagnosis, routine (para)clinical data are more predictive of patient outcome than recurrent mutations. Future studies on modeling genetics and clinical outcome should always consider the inclusion of several (para)clinical data to improve performance.

CD200 as a Valuable Marker for Differentiating between CLL and Other B-cell Lymph Proliferative Disorders

Chronic lymphocytic leukaemia (CLL) being the commonest subtype of mature B-cell lymphoid neoplasms need to be differentiated correctly from other B-chronic lymphoproliferative disorders (BCLPD). CD200 is being an essential marker for prognosis and diagnosis of CLL. Sixty patients diagnosed with BCLPD were evaluated for CD200 expression with eight-colour flow cytometry. An integration of modified Matutes score and CD200 were applied for CLL diagnosis. The overall immunophenotype of CLL patients in this study showed significant, frequent expression of CD5, CD22, CD23, CD43 and CD200. Atypical versus typical CLL patients’ phenotype comparison revealed significant lower expression of CD5 and CD43 with higher expression of CD79b in atypical CLL patients. CD200 was expressed significantly higher in CLL patients (typical and atypical) than in MCL patients who showed dim CD200 expression in only twenty-five percent of patients. The inclusion of CD200 within the diagnostic markers can empower the modified Matutes score accuracy for CLL.

Clonal haematopoiesis as a risk factor for therapy-related myeloid neoplasms in patients with chronic lymphocytic leukaemia treated with chemo-(immuno)therapy.

Clonal haematopoiesis of indeterminate potential (CHIP) may predispose for the development of therapy-related myeloid neoplasms (t-MN). Using target next-generation sequencing (t-NGS) panels and digital droplet polymerase chain reactions (ddPCR), we studied the myeloid gene mutation profiles of patients with chronic lymphocytic leukaemia (CLL) who developed a t-MN after treatment with chemo-(immuno)therapy. Using NGS, we detected a total of 30 pathogenic/likely pathogenic (P/LP) variants in 10 of 13 patients with a t-MN (77%, median number of variants for patient: 2, range 0-6). The prevalence of CHIP was then backtracked in paired samples taken at CLL diagnosis in eight of these patients. Six of them carried at least one CHIP-variant at the time of t-MN (median: 2, range: 1-5), and the same variants were present in the CLL sample in five cases. CHIP variants were present in 34 of 285 patients from a population-based CLL cohort, which translates into a significantly higher prevalence of CHIP in patients with a CLL who developed a t-MN, compared to the population-based cohort (5/8, 62.5% vs. 34/285, 12%, p=0.0001). Our data show that CHIP may be considered as a novel parameter affecting treatment algorithms in patients with CLL, and highlight the potential of using chemo-free therapies in CHIP-positive cases.

Atypical immunophenotype of chronic lymphocytic leukemia

Assessment of the immunophenotype plays a crucial role in the diagnostic process of chronic lymphocytic leukemia (CLL). The expression of CD5, CD19 and CD23 antigens with a concomitant reduction or lack of surface immunoglobulin expression as well as CD22 and CD79b antigens is the basic part of CLL diagnosis. A significant diagnostic challenge is atypical CLL with cells devoid of CD5 or CD23 antigens. The assessment of additional antigens in flow cytometry, especially the CD200 glycoprotein, may facilitate the process of differential diagnosis of atypical CLL from other B-cell lymphoproliferative neoplasms. The results of current studies analyzing the influence of atypical CLL on prognosis are inconclusive. The analysis of a large group of patients with atypical CLL is difficult because of the rare occurrence of CD5(–) or CD23(–) CLL and the misdiagnosis of this disease as other B-cell lymphoproliferative neoplasms. The following paper aims to show how important it is to include atypical CLL in the diagnostic process of this disease and to re-standardize the commonly used immunophenotypic scales for its diagnosis.

Frequency and timing of other primary cancers in patients with chronic lymphocytic leukemia (CLL): a 17-year longitudinal study

Patients with chronic lymphocytic leukemia (CLL) are known to be at a higher risk of developing other primary cancers (OPC). Identifying latency and risk factors associated with OPCs in CLL is of interest as select patients may potentially benefit from early treatment of CLL with targeted therapies to improve immune surveillance. In this single-center retrospective study, 16.9% of 969 patients with CLL were diagnosed with an OPC. Interestingly, 44% of OPCs were diagnosed prior to the CLL diagnosis, including 30% that were diagnosed >1 year prior. This included a majority of genitourinary cancers and melanoma skin cancers. Patients with CLL and an OPC were older than pts with no OPCs but no other risk factors for developing OPCs were identified. Our data suggest that not only are patients with CLL at higher risk of developing OPCs and warrant appropriate cancer surveillance, but the risk also precedes CLL diagnosis by several years.

Pembrolizumab plus dinaciclib in patients with hematologic malignancies: the phase 1b KEYNOTE-155 study

Preclinical data demonstrated that combining an anti–programmed cell death 1 (PD-1) inhibitor with a cyclin-dependent kinase 9 (CDK9) inhibitor provided enhanced antitumor activity with no significant toxicities, suggesting this combination may be a potential therapeutic option. The multicohort, phase 1 KEYNOTE-155 study evaluated the safety and antitumor activity of the PD-1 inhibitor pembrolizumab plus the CDK9 inhibitor dinaciclib in patients with relapsed or refractory (rr) chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM). Patients enrolled were ≥18 years of age with a confirmed diagnosis of CLL, DLBCL, or MM. The study included 2 phases: a dose-evaluation phase to determine dose-limiting toxicities and a signal-detection phase. Patients received pembrolizumab 200 mg every 3 weeks plus dinaciclib 7 mg/m2 on day 1 and 10 mg/m2 on day 8 of cycle 1 and 14 mg/m2 on days 1 and 8 of cycles 2 and later. Primary endpoint was safety, and a key secondary endpoint was objective response rate (ORR). Seventy-two patients were enrolled and received ≥1 dose of study treatment (CLL, n = 17; DLBCL, n = 38; MM, n = 17). Pembrolizumab plus dinaciclib was generally well tolerated and produced no unexpected toxicities. The ORRs were 29.4% (5/17, rrCLL), 21.1% (8/38, rrDLBCL), and 0% (0/17, rrMM), respectively. At data cutoff, all 72 patients had discontinued treatment, 38 (52.8%) because of progressive disease. These findings demonstrate activity with combination pembrolizumab plus dinaciclib and suggest that a careful and comprehensive approach to explore anti–PD-1 and CDK9 inhibitor combinations is warranted. This trial was registered at www.clinicaltrials.gov as NCT02684617.

ROR-1 Expression in the Diagnosis and Monitoring of Minimal Residual Disease in Chronic Lymphocytic Leukemia

Background. In view of similar morphological and phenotypic characteristics of some B-cell lymphoproliferative diseases and despite the known phenotype of tumor cells, a search is currently underway for new diagnostic markers, the expression of which remains stable during chronic lymphocytic leukemia (CLL) treatment and can be used for both diagnosis and assessment of residual tumor population. One of such markers is ROR-1. Aim. To assess the expression and feasibility of the ROR-1 marker using В-lymphocytes in minimal residual disease (MRD) dynamics and monitoring in CLL. Materials &amp; Methods. Hematological and immunophenotypic analyses were performed in 110 CLL patients (50 of them with newly diagnosed disease and 60 on therapy). In addition to that, 20 patients with reactive lymphocytosis and 32 donors were examined. The ROR-1 expression in В-lym-phocytes were measured with FACS Canto II flow cytometer using the following monoclonal antibody panel: CD45, CD19, CD20, and ROR-1. Results. The analysis showed that ROR-1 is essentially not expressed in normal and reactive В-lymphocytes and is detected in 100 % of CLL tumor cells both at disease onset and on therapy. The ROR-1 expression does not change during CLL treatment and can be used not only for CLL diagnosis but also for detection of MRD. Bone marrow aspirates (п = 64) and peripheral blood samples (п = 6) were analysed for MRD assessment by two methods: according to the standardized protocol, recommended by ERIC (European Research Initiative on CLL) in 2007, with FACS Canto II flow cytometer (BD Biosciences) and using DuraClone RE CLB Tube (Beckman Coulter) with Navious flow cytometer (Beckman Coulter).

Healthcare Utilization and Comorbidity in Chronic Lymphocytic Leukemia.

PurposeAge-related comorbidity is highly prevalent in chronic lymphocytic leukemia (CLL). The purpose of this study was to provide information on current patterns of healthcare utilization in CLL.Patients and MethodsWe used data from Danish nation-wide registers to study healthcare utilization the year before and the year after CLL diagnosis and in relation to first-line treatment. Patients diagnosed with CLL between 1997 and 2018 were included and stratified on number of comorbidities, presence of specific comorbidities, and fitness status, respectively. Healthcare utilization was studied in terms of hospital admissions, in-hospital bed days, out-patient visits, emergency room visits, and prescription drugs. Odds ratios with 95% confidence intervals were calculated using multivariable logistic regression analyses adjusting for age, sex, and calendar year.ResultsThe study comprised 9170 patients with CLL with a median age of 71 years, of whom 35% had ≥1 comorbidity. Healthcare utilization increased markedly upon CLL diagnosis both in patients with and without comorbidities. During the year after CLL diagnosis, 39% were hospitalized, 16% visited an emergency room, 88% visited an out-patient clinic, and 93% received prescription drugs. Both individual comorbidities and the total number of comorbidities were associated with increased healthcare utilization of all types, except for contacts to hematological departments.ConclusionOur results suggest that CLL diagnosis may unveil incipient diseases and aggravate comorbidities and thereby have considerably wider health implications than those directly related to CLL. These findings may be used by clinicians and decisions makers to guide planning of multidisciplinary care for cancer patients.

Outcome of treatment among chronic lymphocytic leukemia and its correlation to Rai staging system in Kurdistan region of Iraq

Background: Chronic lymphocytic leukemia is common adulthood leukemia with low incidence in Kurdistan region of Iraq. Staging of chronic lymphocytic leukemia is essential in treatment planning and the pattern of response is variable. Aim of study: To evaluate the Rai staging distribution of patients with chronic lymphocytic leukemia in Kurdistan region/Iraq and its correlation with the treatment outcome. Patients & Methods: A retrospective cross sectional review study conducted in three Hemato/oncology centers in Kurdistan for duration of eleven years through the period from 1st of January, 2010 to 31st of December, 2020 on convenient sample of 170chronic lymphocytic leukemia patients. Diagnosis of chronic lymphocytic leukemia was done according to the International Workshop on Chronic Lymphocytic Leukemia. The Rai staging was done by the clinical hematologist in Hemato/oncology center according to clinical evaluation and laboratory investigations. The pattern of the treatment response was determined according to the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Results: The Rai staging of our patients was 0 in 15.3% of them, stage I in 12.4%, stage II 30%, stage III 13.5% and stage IV 28.8%. The treatment response of studied sample was complete response (43.5%), partial response (17.6%), stable (14.1%), no response (21.8%) and progressive (2.9%).A highly significant association was observed between no response to treatment and advanced Rai staging and also a highly significant association was observed between death outcome of patients and advanced Rai staging. Conclusions: The treatment response of patients with chronic lymphocytic leukemia is directly related to Rai staging as patients with advanced Rai staging had lower treatment response rate.

Diagnostic and therapeutic recommendations of the Polish Society of Haematologists and Transfusiologists and Polish Adult Leukemia Group-CLL for chronic lymphocytic leukemia in 2021

Chronic lymphocytic leukemia (CLL) is a disease of the elderly, with a median age at diagnosis of approximately 70 years. The natural course of the disease varies greatly, and patients with nonprogressive and asymptomatic leukemia do not require treatment. The results of CLL treatment have improved significantly in recent years, mainly due to the introduction of new, more effective drugs, including BCR inhibitors and BCL2 inhibitors. The new drugs are used continuously, while venetoclax in combination with anti-CD20 antibodies is used for 24 (rituximab) or 12 (obinutuzumab) months, depending on the type of antibody and line of therapy. The choice of treatment protocol should largely depend on the assessment of 17p deletion/ TP53 mutation and immunoglobulin variable heavy chain (IGVH) mutation status, which correlate with a worse response to immunochemotherapy. The role of immunochemotherapy, which until recently was the mainstay of CLL treatment, has now significantly decreased. In the first-line, it is recommended only in patients without 17p deletion/ TP53 mutation, with mutated IGVH . Other patients should receive novel targeted therapies. However, at the time of the preparation of these recommendations, these therapies are not available in the firs-line of treatment in Poland. Novel targeted therapies play a major role in the treatment of refractory/relapsed CLL, and immunochemotherapy is recommended primarily in patients with a long-term response to first-line therapy. In this article, we present an update of the guidelines for the diagnosis and treatment of CLL, including the treatment of autoimmune complications, as well as the prophylaxis and treatment of infections, developed by the Polish Society of Haematologists and Transfusiologists and PALG-CLL Working Group.