Summary
Chemokines and their receptors play a pivotal role in the regulation of B‐lymphocyte trafficking. This study was aimed at investigating the pattern of chemokine receptor expression, including ...CCR1 to CCR3, CCR5 to CCR7, CXCR1 to CXCR5, and the migration ability of multiple myeloma (MM) plasma cells (PC). PC were recovered from the bone marrow (BM) of 29 MM patients, extramedullary sites of 10 patients and the BM of five controls. Flow cytometry analysis showed that the receptors mainly expressed on malignant BM PC were represented by CXCR4 (70% of patients), CCR1 (25%), CCR2 (25%), CCR5 (17%) and CXCR3 (20%), while other receptors were commonly lacking. The analysis performed on extramedullary (peripheral blood and pleural effusion) malignant PC demonstrated that the most represented receptors were CXCR4 (100%), CCR2 (66%) and CXCR1 (60%). The migratory capability of malignant PC at resting conditions identified three groups of patients with different migration (low, intermediate and high). As CXCR4 was the relevant chemokine receptor expressed by MM PC, its ligand CXCL12 induced their migration. These data suggest that malignant PC from MM display different chemokine receptor profiles and that CXCR4 is fully functional and might play a role in the spreading of the disease.
Introduction. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for coronavirus disease 19 (COVID-19), has led to a significant increase of morbidity worldwide. A recent ...meta-analysis showed a high case fatality rate in hospitalized patients with hematological malignancies and published reports indicated high rates also in chronic lymphocytic leukemia patients (CLL) patients. The aim of our study was to evaluate the impact of COVID-19 in CLL patients treated with venetoclax. Methods. The retrospective multicenter study included CLL patients treated since 2017 with venetoclax single agent until progression or toxicity or venetoclax plus anti-CD20 antibody (mainly rituximab as part of VR protocol for 24 months in relapsed/refractory patients or obinutuzumab as part of VO protocol for 12 months in untreated patients). Results. We found 128 infections from SARS-CoV-2 in 104 patients out of 287 patients with CLL who received venetoclax. Basal characteristics of the 104 patients who experienced COVID-19 were compared to those of the 183 patients who did not experience the infection (Table 1). Patients of the first group did not show more comorbidities in terms of CIRS, nor renal and pulmonary impairment. Unexpectedly patients without COVID-19 experienced more previous infections in the 12 months before the beginning of venetoclax but a similar low rate of previous SARS-CoV-2 infection. They received a median of 2 different previous lines of treatment whereas patients with COVID-19 were exposed to a median of a single line of therapy. No significant differences were noted for prophylaxis with immunoglobulin, antiviral and antibacterial drugs. In the group of COVID-19 a higher rate of patients received venetoclax plus anti-CD20 antibody (62.9% vs 38.5% of the group without COVID-19, p<0.001). The rate of vaccination was higher than 66% in both the groups with a median of 3 doses each. Prophylaxis with tixagevimab/cilgavimab was administered in less than 20% of the patients. Analyzing the characteristics of the 128 infections we distinguished 73 grade 1-2 COVID-19 and 55 grade 3-4 COVID-19. Patients with grade 1-2 COVID-19 were positive for a median time of 10 days (range 5-97). No treatment was administered in 29.1% of the cases, nirmatrelvir/ritonavir was used in 23.6%, remdesivir in 18.2%. Regarding patients with grade 3-4 COVID-19 resulted positive for a median time of 21 days (range 5-120). Remdesivir was chosen as treatment in 48.9%, nirmatrelvir/ritonavir in 21.3%. Univariate and multivariate analysis found that association to anti-CD20 was a risk factor for COVID-19 of any grade (OR 1.93) and of grade 3-4 (OR 2.96), conversely previous infection in the 12 months before the beginning of venetoclax was a protective factor for COVID-19 any grade (OR 0.42) and grade 1-2 (OR 0.32). During COVID-19 Venetoclax was withdrawn in 38 (36.5%) patients, in 32 of whom venetoclax was administered together to anti-CD20 antibody; in 25/38 the discontinuation was only temporary. Thirty-five (33.6%) patients required hospitalization due to COVID-19, the median time of recovery was 15 days, and 8 (7.7%) patients needed intensive care unit admission. Among the 104 patients with COVID-19, 18 patients died, 10 deaths were due to COVID-19: 7 were exposed to anti-CD20 antibody, 3 had a previous grade 1-2 COVID-19, but none experienced a SARS-CoV-2 infection before treatment with venetoclax. All were vaccinated with at least 3 doses except one patient who was not vaccinated but was infected and died in 2020. The rate of mortality due to COVID-19 was 9.6% considering patients who were infected by SARS-CoV-2, but 18.2% among patients with severe grade 3-4 COVID-19. Conclusions. This is a real-life study on 287 patients affected by CLL treated with venetoclax with the aim to describe COVID-19 in this cohort. The analysis found over a third of patients infected by SARS-CoV-2, in 57% of the cases the infection was grade 1-2 with a mortality rate of almost 10%, but higher if COVID-19 was of grade 3-4 (18.2%). We confirmed the association of anti-CD20 antibody to venetoclax as a risk factor for SARS-CoV-2 infection and mortality rate in patients with CLL and severe COVID-19.
Introduction. Infections are a major source of morbidity and mortality in patients with Chronic Lymphocytic Leukemia (CLL). The development of targeted agents decreased the rate of these ...complications in comparison to standard chemoimmunotherapy regimens. However, these patients often elderly, with other comorbidities, heavily treated, experienced serious infections. The aim of our study was to evaluate the incidence of clinically or microbiologically documented bacterial, fungal and viral infectious complications in CLL patients treated with venetoclax. Methods. The retrospective multicenter study included CLL patients treated since 2017 with venetoclax single agent until progression or toxicity or venetoclax plus anti-CD20 antibody (mainly rituximab as part of VR protocol for 24 months or obinutuzumab as part of VO protocol for 12 months). Results. A total of 287 patients with CLL received venetoclax during the study period from 16 different institutions: 151 patients (52.6%) as monotherapy and 136 (47.4%) associated to anti-CD20 antibody. Basal characteristics of the whole population and of the two groups are summarized in Table 1. Patients of the first group were older, more frequently had del17/TP53mut, renal impairment and lower basal levels of IgG. They also showed more previous infections in the 12 months before the beginning of the treatment with venetoclax. We registered 284 infections of any grade. When comparing time of first infection between the patients treated with venetoclax and those treated with venetoclax plus anti-CD20 antibody, we registered a trend toward a higher rate of infection in the latter group after the first year (p=0.066). This difference was not confirmed when we focused on infections of grade 3-4 (p=0.521). One-hundred eighty-one infections of grade 1-2 developed in 114 patients (39.7%) during the study. Most of the infections involved the respiratory tract (106 events, 58.6%), followed by genitourinary tract (23, 12.7%) and gastrointestinal one (16, 8.8%). Pathogens implicated in the infections were isolated only in 57 (31.5%) cases: 36 viral, 18 bacterial and 3 fungal. We recorded 103 episodes of infections of grade 3-4, occurred in 73 patients (25.4%). The most common site of infection involved the respiratory tract (71 events, 68.9%), then we registered sepsis (13, 12.6%) and gastrointestinal tract infections (7 events, 6.8%). Of 103 severe infections, 64 (62.1%) were microbiologically proven, of whom 40 were viral, 21 bacterial and 3 fungal. When comparing patients with and without infection, COPD (p<0.001, OR 3.75), previous infections in the last 12 months (p<0.001, OR 3.15), renal impairment CrCl<70 (p = 0.049, OR 1.62), previous treatments (p=0.023; OR 1.196) and stage A (p=0.001; OR 0.2) were more frequently associated with infection in univariate analysis. In multivariate analysis COPD (p <0.001, OR 5.39) and previous infections (p=0.001, OR 2.57) resulted significant. Stratifying patients according to COPD and previous infections in the last 12 months we obtained 3 groups significantly different in terms of infective risk (p <0.001; figure 1). When considering only grade 3-4 infections, risk factors significant in the univariate analysis were COPD (p <0.001, OR 3.23), smoke (p=0.033, OR 1.98) and previous infections (p=0.020, OR 1.91). COPD was the unique significant variable in multivariate analysis (p=0.008, OR 2.62). Treatment was withdrawn for infections in 80 patients (27.9%): in 58 (20.2%) treatment was temporarily discontinued, while in 22 (7.7%) discontinuation was permanent. The infections that caused definitive withdrawals were mainly pneumonia (12 cases, 6 of whom from SarS-CoV2 infection) and sepsis (8 cases, 5 of whom after a SarS-CoV2 infection). A total of 83 patients (28.9%) died and the median OS was 55 months. The main causes of death were CLL progression in 36 cases and infection in 22 cases. Conclusions. This is a real-life study on 287 patients affected by LLC treated with venetoclax with the aim to describe the infectious complications in such population in routine clinical practice. The analysis found a significant rate of infections, most of grade 1-2: 39.7% of the patients experienced a grade 1-2 infection; 25.4% a grade 3-4 infection. The identification of additional infectious risk factors found a role of comorbidities such as COPD and previous infections; COPD resulted a risk factor also for infections of grade 3-4.
BACKGROUND Hairy cell leukemia (HCL) is a BRAFV600E-mutated indolent B-cell neoplasm (Tiacci et al., NEJM 2011) often relapsing after chemotherapy with purine analogs. BRAF inhibition is very active ...in relapsed/refractory (R/R) HCL, but produces mostly partial remissions (PR) and never clears minimal residual disease (MRD) (Tiacci, Park, et al., NEJM 2015). In a recent phase-2 single-center study on 30 R/R patients (pts) with a median of 3 prior therapies, a short chemotherapy-free regimen of the BRAF inhibitor vemurafenib (V) + rituximab (R; Mabthera) led to 87% complete remissions (CR), 60% MRD-negativity and 85% relapse-free survival (RFS) at a median follow-up of 34 months, with a favorable toxicity profile (Tiacci et al., NEJM 2021). METHODS A multi-center retrospective study was conducted to validate in a real-world setting the off-label use of V+R in R/R HCL needing therapy due to cytopenia(s). RESULTS From 6/2019 to 12/2021, 35 pts (median age 56 years, range 42-80) were treated at 14 Italian centers with VR (V: 960 mg bid for 8 weeks; R: 375 mg/m2 every 2 weeks for 8 doses); biosimilar R was used in 89% of pts. Prior therapies (median 2; range 0-11) included chemotherapy with cladribine or pentostatin (94% of pts), interferon-alpha (29%), rituximab (31%), splenectomy (6%), BRAF inhibitor monotherapy (6%) and zanubrutinib (3%). Median blood counts across the 35 pts were: platelets 69000/mmc, neutrophils 860/mmc and hemoglobin 11.6 g/dl (with 20% of pts, i.e. 7/35, requiring transfusions). Eleven pts (31%) had active (n=3) or latent (n=8) infections, including: ongoing systemic atypical mycobacteriosis (n=1); ongoing miliary tuberculosis (n=1; a 80-year old pt who was the only one receiving V+R as first-line therapy); ongoing large cerebral abscess (n=1); HIV infection controlled by anti-viral therapy (n=1); and latent tuberculosis (n=1) or HBV (n=6) infections requiring anti-microbial prophylaxis. Toxicity was as expected, mostly of grade 1-2 and always reversible (Table), allowing high relative dose intensities (RDI) for both drugs (V, median 97%; interquartile range/IQR 73-100%; R, 100% in 85% of pts). Similarly, among the 33/35 (94%) pts who received V for a substantial duration (≥35 days), and were thus evaluable for dose density, 20 pts (61%) completed V without ever suspending the drug, including 14/33 pts (42%) without any dose reduction. Vemurafenib toxicities were mainly represented by cutaneous rash, asymptomatic liver and pancreatic laboratory abnormalities, arthralgia, warts and photosensitivity. Three pts (9%) were not evaluable for response as they died prematurely due to atypical mycobacteriosis, complications of neurosurgery for cerebral abscess and sudden death unrelated to study drugs. Recovery of platelets (≥100000/mmc), neutrophils (≥1500/mmc) and hemoglobin (≥ 11 g/dl) occurred quickly, after a median of 2, 4 and 7 weeks after starting treatment, respectively. A CR was observed in 30/32 evaluable cases (94%; or 86%, 30/35 pts, by intention to treat/ITT). CR was obtained in all evaluable cases refractory to chemotherapy (n=8) or rituximab (n=3), or previously splenectomized (n=2) or unable to reach CR with a prior BRAF inhibitor (n=2). The only 2 evaluable pts not achieving a CR (1 PR; 1 short-lived resolution of cytopenias) received V at only 16%/50% RDI and R at only 13%/34% RDI due to drug toxicities. Analysis of MRD by allele-specific PCR for BRAF-V600E in the bone marrow aspirate was performed in 30 pts and showed MRD clearance (<0.05% mutant alleles) at a high rate: 79% (22/28 CR pts; or 65%, 22/35 pts, by ITT), which raised to 82% (66% by ITT) when including 1 additional CR case untested by PCR which had negative bone marrow flow cytometry. At a median follow-up of 21 months after the end of treatment, RFS was high among the 31 responding pts, with just 1 relapse (3%) in the only case obtaining a PR post-therapy (Figure). CONCLUSIONS This study validates in a real-life context the high efficacy and tolerability of the V+R chemo-free regimen delivered to R/R HCL pts, including the cost-saving use of biosimilar rituximab.
In recent years the management of patients (pts) with chronic lymphocytic leukemia (CLL) has benefited from a deeper knowledge of the mechanisms underlying the disease and from the development of ...novel therapeutic approaches. That notwithstanding, local and national accessibility to drugs and tests may lead to distinct “real-world” practices in terms of management of pts that are worth of being recorded and compared to understand the degree of reproducibility and applicability of international guidelines. This could also be relevant for the design of future clinical trials, more tailored to the true patient's needs. To this end, within the GIMEMA cooperative study group the observational retrospective and prospective CLL2121 study (NCT04867915) has been designed with the objective of evaluating the diagnosis and management of CLL in all hematological centers in Italy through the assessment of: 1) the methods and the actual diagnostic/prognostic work-up capacity; 2) the algorithms applied to define disease progression and treatment requirements with respect to national and international guidelines; 3) the clinical and biological variables not strictly associated with CLL, but capable of influencing the clinical course and overall survival; 4) the true incidence of some rarer complications associated with CLL. The study consists of a collection of clinico-biological data from all pts with newly diagnosed CLL, small lymphocytic lymphoma (SLL) or CLL-like monoclonal B-cell lymphocytosis (MBL), according to the iwCLL 2018 criteria in Italy. The retrospective part aims at including all cases followed at the participating centers with a diagnosis between January 2010 and September 2021, while the prospective part will include all pts with a documented diagnosis of CLL, SLL or MBL between September 2021 and September 2025. In this pilot analysis of the study, we examined pts' demographics, diagnosis, treatment line and type. Data were collected using the REDCap electronic data capture platform, analyzed using the SAS software v.9.4 and reported as numbers and frequencies. Between 2 November 2021 and 28 June 2023, 3294 eligible pts were enrolled in 75 hematology centers (out of the total of 110 centers who will be activated during the study) across the entire Italian territory. At the time of the present report, 3033 pts had clinical data available for our preliminary analysis. The vast majority of pts registered (N=2599, 85.7%) belonged to the retrospective cohort while only a minority (N=434, 14.3%) to the prospective cohort. Pts had a median age of 68 years ranging from 29 to 97; 60% of pts were males. 2630 pts (86.8%) had a diagnosis of CLL, 187 (6.2%) of SLL and 214 (7.0%) of MBL (2 missing information). Among those with available results 112 pts (12.6%) were TP53 mutated, 526 (45.6%) del(13q) positive, 174 (14.9%) del(11q) positive, 142 (11.9%) del(17p) positive and 226 (20.4%) presented a trisomy 12. The majority of pts (57.6%) were untreated, while 42.4% have been treated. Within the latter subset, 67.3% of pts have received one line of therapy, 21.4% 2 lines of therapy, 11.3% ≥3 lines of therapy. The most common therapeutic regimens were the combination of chemotherapy with an anti-CD20 antibody (39.3%), mainly rituximab, and those based on BTK inhibitors (33.3%), mainly ibrutinib. Chemotherapy alone was used in 12% of pts. Only 5% of pts was treated with the BCL2 inhibitor venetoclax. In the remaining 10% of pts, other approaches were used. This is the initial report of a nation-based real-world data collection aimed at describing the biological and clinical features of pts diagnosed with CLL in virtually all Italian hematology centers starting from 2010. The pattern of treatments highlighted in our preliminary analysis, with a wide use of the watch & wait policy and of chemoimmunotherapy, will help understand how the introduction of novel therapies impacted treatment habits also in light of the timing of the local reimbursement policy. The different time of drug access in Italy, typically delayed after the EU approval, may also have affected the limited use of venetoclax-based treatment. The continuous accrual of pts in this study will allow to obtain a close-to-registry vision of CLL management in Italy over time, in terms of coverage of the entire country but enriched with the granularity of the data and flexibility of the collection typical of a real-world study.
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