ABSTRACT
ABSTRACT: We evaluated the chronic lymphocytic leukemia International Prognostic Index (CLL-IPI) in patients with CLL treated first line with targeted drugs (n = 991) or chemoimmunotherapy (n = 1256). With a median observation time of 40.5 months, the 3-year progression-free survival (PFS) rates for targeted drug-treated patients varied by CLL-IPI risk group: 96.5% (low), 87.6% (intermediate), 82.4% (high), and 78.7% (very high). Differences between consecutive CLL-IPI risk groups were observed for intermediate vs low and high vs intermediate, but not very high vs high. CLL-IPI factors ß2-microglobulin, immunoglobulin heavy variable (IGHV) status, and TP53 status each retained prognostic value for PFS. The 3-year overall survival (OS) rates by CLL-IPI risk groups were 100%, 96%, 93.9%, and 89.4%, respectively, with no differences between consecutive risk groups. Age, Binet stage, ß2-microglobulin, and TP53 status each retained prognostic value for OS. In chemoimmunotherapy patients (median observation time, 66.9 months), 3-year PFS rates for CLL-IPI risk groups were 78.1%, 51.4%, 40.1%, and 16.5%, respectively; corresponding 3-year OS rates were 97.4%, 93.1%, 81.8%, and 57.3%. In a matched-pair analysis, PFS differences in targeted therapies (n = 812) vs chemoimmunotherapy (n = 812) across all risk groups and OS differences in all but patients at low risk were demonstrated. The CLL-IPI maintains its prognostic value in predicting PFS outcomes with targeted drugs, but its impact in predicting survival appears diminished. Targeted therapies showed enhanced outcomes over chemoimmunotherapy, highlighting their effectiveness across various risk groups. Our findings support ongoing assessment of prognostic tools in CLL treatment evolution. These trials were registered at www.ClinicalTrials.gov as #NCT02345863, #NCT02401503, #NCT02689141, #NCT02445131, #NCT02758665, #NCT02950051, #NCT02242942, #NCT00262782, #NCT00281918, and #NCT01010061.
Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell , Molecular Targeted Therapy , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis , Female , Male , Aged , Middle Aged , Prognosis , Aged, 80 and over , Adult , beta 2-Microglobulin , Survival RateABSTRACT
Venetoclax-obinutuzumab (Ven-Obi) is a standard-of-care for patients with previously untreated chronic lymphocytic leukemia (CLL). In the CLL14 study, patients with previously untreated CLL and coexisting conditions were randomized to 12 cycles of Ven-Obi (n=216) or chlorambucil-obinutuzumab (Clb-Obi, n=216). Progression-free survival (PFS) was the primary endpoint. Key secondary endpoints included time-to-next-treatment (TTNT), rates of undetectable minimal residual disease (uMRD), overall survival (OS) and rates of adverse events. Patient reported outcomes (PROs) of time until definitive deterioration (TUDD) in quality of life (QoL) were analyzed. At a median observation time of 76.4 months, PFS remained superior for Ven-Obi compared to Clb-Obi (median 76.2 vs 36.4 months; HR 0.40[95%CI 0.31-0.52], p<0.0001). Likewise, TTNT was longer after Ven-Obi (6-year-TTNT 65.2% vs 37.1%; HR 0.44, 95%CI 0.33-0.58, p<0.0001). In the Ven-Obi arm, presence of del(17p), unmutated-IGHV and lymph node size ≥5 cm were independent prognostic factors for shorter PFS. Five years after treatment, 17 patients (7.9% of intention-to-treat-population) in the Ven-Obi arm had uMRD (<10-4 in peripheral blood) compared to 4 (1.9%) in the Clb-Obi arm. 6-year-OS rate was 78.7% in the Ven-Obi and 69.2% in the Clb-Obi arm (HR 0.69[95%CI 0.48-1.01], p=0.052). A significantly longer TUDD in global health status/QoL was observed in the Ven-Obi compared to the Clb-Obi arm (median 82.1 vs 65.1 months; HR 0.70[95%CI 0.51-0.97]). Follow-up adjusted SPM incidence rates were 2.3 and 1.4/1000 patient-months in the Ven-Obi and Clb-Obi arm, respectively. The sustained long-term survival, uMRD and QoL benefits support the use of one-year fixed-duration Ven-Obi in CLL. NCT02242942, EudraCT 2014-001810-24.
ABSTRACT
INTRODUCTION: Overweight and obesity are linked to increased hospitalization and mortality in COVID-19 patients. This study aimed to characterize induced immune responses and deep immune cell profiles stratified by BMI in hospitalized COVID-19 patients. METHODS AND RESULTS: This observational multicenter cohort pilot study included 122 adult patients with PCR-confirmed COVID-19 in Denmark, stratified by BMI (normal weight, overweight, obese). Inflammation was assessed using TruCulture® and immune cell profiles by flow cytometry with a customized antibody panel (DuraClone®). Patients with obesity had a more pro-inflammatory phenotype with increased TNF-α, IL-8, IL-17, and IL-10 levels post-T cell stimulation, and altered B cell profiles. Patients with obesity showed higher concentrations of naïve, transitional, and non-isotype switched memory B cells, and plasmablasts compared to normal weight patients and healthy controls. CONCLUSIONS: Obesity in hospitalized COVID-19 patients may correlate with elevated pro-inflammatory cytokines, anti-inflammatory IL-10, and increased B cell subset activation, highlighting the need for further studies.
ABSTRACT
BACKGROUND: Chronic lymphocytic leukemia (CLL) is a hematological malignancy characterized by immune dysfunction, which significantly contributes to increased morbidity and mortality due to infections. SUMMARY: Advancement in therapeutic strategies based on combination chemoimmunotherapy and targeted treatment have increased life expectancy for patients affected by CLL. However, mortality and morbidity due to infection showed no improvement over the last decades. Although therapy options are highly efficient in targeting leukemic cells, several studies highlighted the interactions of different treatments with the tumor microenvironment immune components, significantly impacting their clinical efficacy and fostering increased risk of infections. KEY MESSAGES: Given the profound immune dysfunction caused by CLL itself, treatment can thus represent a double-edged sword. Thus, it is essential to increase our understanding and awareness on how conventional therapies affect the disease-microenvironment-infection axis to ensure the best personalized strategy for each patient. This requires careful consideration of the advantages and disadvantages of efficient treatments, whether chemoimmunotherapy or targeted combinations, leading to risk of infectious complications. To this regard, our machine learning-based algorithm CLL Treatment-Infection Model, currently implemented into the local electronic health record system for Eastern Denmark, aims at early identification of patients at high risk of serious infections (PreVent-ACaLL; NCT03868722). We here review strategies for management of immune dysfunction and infections in CLL.
Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Immunotherapy/adverse effects , Tumor MicroenvironmentABSTRACT
Overall survival (OS) for patients with a hematological cancer may differ between immigrant and Danish-born patients due to disparities in socioeconomic status, health literacy, and language proficiency. This cohort study aimed to investigate survival and hospitalization according to immigrant status while controlling for confounders. Patients with newly diagnosed hematological cancer in 2000-2020 were identified in the Danish nationwide hematological registers and stratified into Danish-born, Western, and non-Western patients. Patients were followed from diagnosis until death, 31st December 2021, or emigration, whichever came first. Crude OS, standardized OS, and 5-years OS differences were computed using flexible parametric models and hazard ratios using Cox regression. Number of hospitalization days in the year before and after diagnosis, respectively, were calculated using Poisson regression. A total of 2,241 immigrants and 41,519 Danish-born patients with a hematological cancer were included. Standardized 5-years OS was similar between groups with 58% (95% confidence interval 57-58%) for Danish-born patients, 57% (55-60%) for Western, and 56% (53-58%) for non-Western immigrant patients. Subgroup analyses identified OS differences in selected subgroups. Non-Western immigrant patients had 1.3 (0.5-2.1) more hospitalization days in the year before diagnosis and an adjusted incidence rate ratio of hospitalization days of 1.14 (1.13-1.15) in the year after diagnosis compared with Danish-born patients. In conclusion, there were no overall differences in survival when comparing immigrant patients to Danish-born patients after controlling for relevant confounders. Healthcare utilization was slightly higher among non-Western immigrant patients before and after diagnosis, but differences were small on an individual patient level.
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Age-related comorbid conditions are exceedingly common in patients with chronic lymphocytic leukemia (CLL). As the prevalence of type 2 diabetes (T2D) is predicted to double during the next two decades, a better understanding of the interplay between CLL and T2D is of increasing importance. In this study, analyses were performed in parallel in two separate cohorts, based on Danish national registers and the Mayo Clinic CLL Resource. The primary outcomes were overall survival (OS) from time of CLL diagnosis, OS from time of treatment, and time to first treatment (TTFT), studied using Cox proportional hazard regression analysis and Fine-Gray regression analysis. In the Danish CLL cohort, the prevalence of T2D was 11%, in the Mayo CLL cohort, it was 12%. Patients with CLL and T2D had shorter OS both from time of diagnosis and from first-line treatment for were less likely to receive treatment for CLL compared with patients with CLL and without T2D. The increased mortality was largely driven by an increased risk of death due to infections, especially in the Danish cohort. The findings of this study emphasize a substantial subgroup of CLL patients with co-occurring T2D with an inferior prognosis and a possible unmet treatment need requiring additional interventions and further research.
Subject(s)
Diabetes Mellitus, Type 2 , Leukemia, Lymphocytic, Chronic, B-Cell , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/complications , Leukemia, Lymphocytic, Chronic, B-Cell/therapy , Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis , Diabetes Mellitus, Type 2/complications , Cause of Death , PrognosisABSTRACT
BACKGROUND: Cancer treatments suppress immune function and are associated with increased risk of infections, but the overall burden of serious infectious diseases in treated patients has not been clearly elucidated. METHODS: All patients treated for solid malignant tumours with radiotherapy (RT) and/or standard first-line chemotherapy (C) at the Department of Oncology at Rigshospitalet between 01/1/2010 and 31/12/2016 were included. Patients were followed from treatment initiation until the first of new cancer treatment, 1 year after treatment initiation, end of follow-up or death. Incidence rates (IR) of positive blood culture (PBC) per 1000 person-years follow-up (PYFU) were calculated. FINDINGS: 12,433 individuals were included, 3582 (29%), 6349 (51%), and 2502 (20%) treated with RT, C, or both RT & C, respectively, contributing 8182 PYFU. 429 (3%) individuals experienced 502 unique episodes of PBC, incidence rate (95% CI) 52.43 (47.7, 57.6) per 1000 PYFU. The 30-day mortality rate after PBC was 24% independent of treatment modality. Adjusted incidence rate ratios in the first 3 months (95% CI) after PBC significantly varied by treatment: 2.89 (1.83, 4.55) and 2.52 (1.53, 4.14) for C and RT & C compared to RT. Escherichia coli (n = 127, 25%) was the top microorganism identified. INTERPRETATION: PBCs are not common, but when they occur, mortality is high.
Subject(s)
Blood Culture , Neoplasms , Humans , Incidence , Neoplasms/drug therapy , Neoplasms/epidemiology , Neoplasms/radiotherapyABSTRACT
BACKGROUND: Patients with hematological malignancies (HM) are known to carry an increased risk of invasive pneumococcal disease (IPD). However, temporal variations in IPD risks following a cancer diagnosis remain poorly characterized. To inform vaccine guidelines and patient management, we assessed the IPD incidence among patients with HM and other malignancies. METHODS: The study population included all individuals agedâ ≥15 years during 2000-2016 in Denmark. Variations in incidences of IPD over time and between different types of hematological malignancies and diagnoses were assessed by Poisson regression. RESULTS: During 85â 002 224 person-years of observation, 13â 332 episodes of a first IPD were observed, of which 765 (5.7%) occurred among individuals with HM. Among HM patients, the IPD incidence rate decreased continuously during the study period (rate ratio per year,â 0.91; 95% confidence interval, .90-.92). The risk of IPD in patients with HM was up to 39 times higher when compared to the background population and was highest for multiple myeloma, acute lymphoblastic leukemia, and chronic lymphocytic leukemia. Unlike other malignancies, the increased IPD risk did not wane with the time since HM diagnosis. We found a vaccination uptake of only ≤2% in patients with HM and ≤1% for those with other types of malignancies. CONCLUSIONS: Adults with HM in general and patients with lymphoid malignancies in particular have an increased risk for IPD, compared with patients with other types of cancer and with individuals free of cancer. The pneumococcal vaccination uptake is extremely low in this at risk-population. Efforts to prevent IPD in HM patients are continuously warranted.
Subject(s)
Hematologic Neoplasms , Pneumococcal Infections , Adult , Aged , Cohort Studies , Hematologic Neoplasms/complications , Hematologic Neoplasms/epidemiology , Humans , Incidence , Infant , Pneumococcal Infections/epidemiology , Pneumococcal Vaccines , Streptococcus pneumoniaeABSTRACT
The antiviral drug remdesivir has been shown clinically effective for treatment of COVID-19. We here demonstrate suppressive but not curative effect of remdesivir in an immunocompromised patient. A man in his fifties treated with chemoimmunotherapy for chronic lymphocytic leukemia experienced a 9-week course of COVID-19 with high fever and severe viral pneumonia. During two 10-day courses of remdesivir starting 24 and 45 days after fever onset, pneumonia and spiking fevers remitted, but relapsed after discontinuation. Kinetics of temperature, C-reactive protein, and lymphocyte counts mirrored the remitting/relapsing SARS-CoV-2 infection. Combination therapy or longer treatment duration may be needed in immunocompromised patients.
Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/complications , Pneumonia, Viral/drug therapy , Severe Acute Respiratory Syndrome/drug therapy , Adenosine Monophosphate/therapeutic use , Alanine/therapeutic use , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/virology , Fever/drug therapy , Fever/virology , Humans , Immunocompromised Host , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Male , Middle Aged , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/virology , SARS-CoV-2 , Severe Acute Respiratory Syndrome/virology , Time Factors , Treatment Outcome , COVID-19 Drug TreatmentABSTRACT
Patients with chronic lymphocytic leukemia and unmutated immunoglobulin heavy-chain variable region gene (IGHV) have inferior survival from time of treatment in clinical studies. We assessed real-world outcomes based on mutational status and treatment regimen in a nationwide population-based cohort, comprising all 4,135 patients from the Danish chronic lymphocytic leukemia registry diagnosed between 2008 and 2017. In total, 850 patients with known mutational status received treatment: 42% of patients received intensive chemoimmunotherapy consisting of fludarabine, cyclophosphamide plus rituximab, or bendamustine plus rituximab; 27% received chlorambucil in combination with anti-CD20 antibodies or as monotherapy, and 31% received other, less common treatments. No difference in overall survival from time of first treatment according to mutational status was observed, while treatment-free survival from start of first treatment was inferior for patients with unmutated IGHV. The median treatment-free survival was 2.5 years for patients treated with chlorambucil plus anti-CD20, and 1 year for those who received chlorambucil monotherapy. The 3-year treatment-free survival rates for patients treated with fludarabine, cyclophosphamide plus rituximab, and bendamustine plus rituximab were 90% and 91% for those with mutated IGHV, and 76% and 53% for those with unmutated IGHV, respectively, and the 3-year overall survival rates were similar for the two regimens (86-88%). Thus, it appears that, in the real-world setting, patients progressing after intensive chemoimmunotherapy as first-line therapy can be rescued by subsequent treatment, without jeopardizing their long overall survival. Intensive chemoimmunotherapy remains a legitimate option alongside targeted agents, and part of a personalized treatment landscape in chronic lymphocytic leukemia, while improved supportive care and treatment options are warranted for unfit patients.
Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bendamustine Hydrochloride , Denmark/epidemiology , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Rituximab/therapeutic use , Treatment OutcomeABSTRACT
Ibrutinib has now been approved for treatment of chronic lymphocytic leukemia (CLL) in both front-line setting and as later-line treatment. However, knowledge about the outcomes and adverse events (AE) among patients at a population-based level is still limited. OBJECTIVES: To report outcomes and AEs in a population-based cohort treated with ibrutinib outside clinical trials. METHODS: We conducted a multicenter, retrospective cohort study including all patients with CLL treated with ibrutinib. RESULTS: In total, 205 patients were included of whom 39 (19%) were treatment-naïve. The median follow-up was 21.4 months (interquartile range (IQR), 11.9,32.8), the estimated overall survival at 12 months was 88.8% (95% confidence interval (CI); 84.3%, 93.3%), and the estimated progression-free survival at 12 months was 86.3% (95% CI; 81.3%, 91.2%). During follow-up, 200 (97.6%) patients had at least one AE and 100 (48.8%) patients had at least one grade ≥3 AE. Eighty-six patients (42.0%) discontinued ibrutinib, hereof 47 (54.7%) due to AEs and 19 (22.1%) had progression of CLL or Richter transformation. CONCLUSIONS: In our study, we find comparable, though slightly inferior, overall, and progression-free survival, and discontinuation due to toxicity was higher compared with clinical trials. Patient training and information may improve treatment adherence outside clinical trials.
Subject(s)
Adenine/analogs & derivatives , Antineoplastic Agents/therapeutic use , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/epidemiology , Piperidines/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Adenine/administration & dosage , Adenine/adverse effects , Adenine/therapeutic use , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis , Molecular Targeted Therapy , Piperidines/administration & dosage , Piperidines/adverse effects , Prognosis , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Public Health Surveillance , Retrospective Studies , Treatment OutcomeSubject(s)
Antineoplastic Combined Chemotherapy Protocols , Leukemia, Lymphocytic, Chronic, B-Cell , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/complications , Male , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Female , Aged , Infections/etiology , Infections/chemically induced , Middle AgedSubject(s)
Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis , Leukocyte Count , Aged , Eosinophils/cytology , Female , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/blood , Leukemia, Lymphocytic, Chronic, B-Cell/epidemiology , Leukemia, Lymphocytic, Chronic, B-Cell/therapy , Male , Middle Aged , Prognosis , Survival AnalysisABSTRACT
We report on markedly different frequencies of genetic lesions within subsets of chronic lymphocytic leukemia patients carrying mutated or unmutated stereotyped B-cell receptor immunoglobulins in the largest cohort (n=565) studied for this purpose. By combining data on recurrent gene mutations (BIRC3, MYD88, NOTCH1, SF3B1 and TP53) and cytogenetic aberrations, we reveal a subset-biased acquisition of gene mutations. More specifically, the frequency of NOTCH1 mutations was found to be enriched in subsets expressing unmutated immunoglobulin genes, i.e. #1, #6, #8 and #59 (22-34%), often in association with trisomy 12, and was significantly different (P<0.001) to the frequency observed in subset #2 (4%, aggressive disease, variable somatic hypermutation status) and subset #4 (1%, indolent disease, mutated immunoglobulin genes). Interestingly, subsets harboring a high frequency of NOTCH1 mutations were found to carry few (if any) SF3B1 mutations. This starkly contrasts with subsets #2 and #3 where, despite their immunogenetic differences, SF3B1 mutations occurred in 45% and 46% of cases, respectively. In addition, mutations within TP53, whilst enriched in subset #1 (16%), were rare in subsets #2 and #8 (both 2%), despite all being clinically aggressive. All subsets were negative for MYD88 mutations, whereas BIRC3 mutations were infrequent. Collectively, this striking bias and skewed distribution of mutations and cytogenetic aberrations within specific chronic lymphocytic leukemia subsets implies that the mechanisms underlying clinical aggressiveness are not uniform, but rather support the existence of distinct genetic pathways of clonal evolution governed by a particular stereotyped B-cell receptor selecting a certain molecular lesion(s).