Ibrutinib, a highly effective inhibitor of the Bruton tyrosine kinase, has significantly transformed the therapeutic approach in chronic lymphocytic leukemia (CLL). Despite these advancements, the ...disease continues to be characterized by immune dysfunction and increased susceptibility to infections, with mortality rates from infections showing no significant improvement over the past few decades. Therefore, timely prevention, recognition, and treatment of infections remains an important aspect of the standard management of a patient with CLL. A panel of hematologists with expertise in CLL met to discuss existing literature and clinical insights for the management of infectious in CLL undergoing ibrutinib treatment. Despite not being a fully comprehensive review on the topic, this work provides a set of practical recommendations that can serve as a guide to healthcare professionals who manage these patients in their daily clinical practice.
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.
Venetoclax is the first BCL-2 inhibitor approved for the treatment of patients with chronic lymphocytic leukemia (CLL) alone or in combination with anti-CD20 monoclonal antibodies (MoAbs). Initial ...studies have shown high efficacy of venetoclax monotherapy or in combination with rituximab with an overall response rate of 79-92% in patients with relapsed/refractory (R/R) CLL.
To investigate the use of venetoclax combinations in a real-world population, we designed this observational retrospective and prospective study aimed at defining the outcome of patients with R/R CLL treated with venetoclax-based regimens outside clinical trials in Italy. Efficacy (progression-free survival -PFS-, overall response rate -ORR-, complete response -CR-, measurable residual disease -MRD-) and safety (most frequent adverse events -AE-, grade 3-4 AE, laboratory and clinical tumor lysis syndrome -TLS-) data were collected within the study through a web-based platform after patients signed written informed consent.
As of July 8 th, 2021 124 subjects (85 males, 39 females) were enrolled into the study (Table 1). Median age at venetoclax initiation was 70 years (44-91), median CIRS score 4 (0-14), median creatinine clearance 70 ml/min (22-123). A relevant proportion of patients presented adverse prognostic features, including TP53 aberrations 32% TP53 mutation and/or del(17p), unmutated IGHV (77%). At the time of venetoclax initiation, patients had received a median of 2 previous therapies (1-8), with 57% previously exposed to BTK and/or PI3K inhibitors. 67/117 (57%) patients received venetoclax alone, while 50 were treated with a combination of venetoclax + rituximab (VenR), information on treatment plan was missing in 7 patients. Patients on venetoclax monotherapy compared to those receiving VenR showed a higher percentage of elevated LDH at baseline (64% vs 38%), were more heavily pretreated (median lines of therapy 3 vs 1), and had more frequently received treatment with ibrutinib (66% vs 27%) and/or idelalisib + rituximab (29% vs 4%). After a median follow-up of 13.7 months (0-41.9), the estimated 12m-PFS was 82% (CI 74-90%) (Figure 1), and the estimated 12m-overall survival (OS) was 83% (CI 76-91%). The best ORR in the whole cohort was 85% (CI 95% 76-91%) with a CR rate of 40%; best response was reached after a median of 3.9 months of treatment (range 0.6-30.5). The best ORR was not different in patients receiving VenR vs venetoclax alone (83% vs 88% respectively, p = n.s.), while the CR rate was significantly higher in those receiving VenR vs venetoclax alone (57% vs 30%, p=0.011). The ORR and CR rate in patients previously exposed to BTK and/or PI3K inhibitors were significantly lower (77% and 29% respectively), and the 12m-PFS was shorter in patients previously treated with ibrutinib compared to ibrutinib-naïve (75% vs 89%, p=0.005). Twenty subjects discontinued venetoclax (median time to discontinuation 4.1 months, range 0.4-10.8), 8 due to disease progression, 3 Richter's transformation, 7 AEs, 1 was lost to follow-up and 1 underwent planned allogeneic stem cell transplantation.
Venetoclax-based regimens were well tolerated, with the most frequent AE of any grade related to venetoclax being neutropenia (79.6%), grade 3-4 in 61.9% (Table 2). In the whole cohort one grade 3 clinical TLS occurred and resolved without sequelae, and only 2/124 patients experienced laboratory TLS during ramp-up phase (both grade 1). No treatment-related death was reported. In conclusion, this analysis presents the results of one of the largest cohort of patients with R/R CLL treated with venetoclax-based regimens outside clinical trials and confirms the favourable efficacy and safety profile of the drug. In this patient population highly enriched for unfavorable disease features (1 out of 3 carrying TP53 aberrations, almost 80% with unmutated IGHV) venetoclax-based regimens were able to obtain a response in a high proportion of cases, with a very short time to best response (less than 4 months). As expected, response duration was shorter in patients previously exposed to BTKi/PI3Ki. When we compared the outcome of patients treated with venetoclax monotherapy vs VenR, the addition of anti-CD20 MoAb allowed to reach deeper responses by significantly increasing the CR rate. As the study and its data collection are still ongoing, the updated analysis of an expanded cohort with longer follow-up will be presented at the meeting.
Display omitted
Scarfo: Janssen: Honoraria, Other: Travel grants; Astra Zeneca: Honoraria; Abbvie: Honoraria. Quaglia: Roche: Other: Travel grants; Janssen: Honoraria, Other: Travel grants, Speakers Bureau; Sandoz: Consultancy; AstraZeneca: Honoraria. Marasca: AbbVie: Honoraria, Other: Travel grants; AstraZeneca: Honoraria; Janssen: Honoraria, Other: Travel grants. Sanna: Astra Zeneca: Consultancy; Abbvie: Consultancy; Janssen: Consultancy. Murru: Abbvie: Consultancy, Honoraria, Other: travel and accommodation; Janssen: Consultancy, Honoraria. Laurenti: Roche: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Honoraria; BeiGene: Honoraria. Gaidano: Incyte: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Reda: Beigene: Consultancy; Astra Zeneca: Consultancy; Abbvie: Consultancy; Janssen: Consultancy. Molica: Astrazeneca: Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Sportoletti: AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria. Galimberti: AbbVie, Janssen: Honoraria, Other: Travel grants; Incyte: Speakers Bureau. Mauro: AbbVie: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Gilead: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Speakers Bureau. Cuneo: Janssen: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau. Ghia: AstraZeneca: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Research Funding; BeiGene: Consultancy, Honoraria; Celgene/Juno/BMS: Consultancy, Honoraria; ArQule/MSD: Consultancy, Honoraria; Sunesis: Research Funding.
Novel therapies targeting BTK (ibrutinib), PI3Kδ (idelalisib) and BCL2 (venetoclax) are active in poor-risk chronic lymphocytic leukemia (CLL) and are widely administered to patients with ...relapsed/refractory (R/R)-CLL. Given the activity of ibrutinib in high-risk CLL patients, including those with del17p/TP53 mutation or germline IGHV genes, we assumed that this drug could diminish the prognostic utility of the CLL-IPI, because the outcome of patients with high- and very high-risk CLL-IPI scores may improve. Recently, Soumerai et al (Lancet Hematology, 2019) proposed a new risk score for overall survival (OS) based on four accessible markers, called BALL (β2-microglobulin, anemia, LDH, last therapy), in the setting of R/R-CLL patients receiving chemo-immunotherapy or targeted therapies in clinical trials. This model segregates CLL patients into three groups with significantly different OS. This multicenter, observational retrospective study aimed at validating the proposed BALL score for R/R-CLL real-world patients treated with ibrutinib. The primary objectives were to determine whether: i) the BALL score is of prognostic value for ibrutinib R/R-CLL patients, ii) the BALL score is predictive of progression-free survival (PFS); and iii) the CLL-IPI retains its prognostic power also in R/R patients treated with ibrutinib.
This study, from an institutional Italian multicenter working group on CLL (‘Campus CLL‘), included CLL patients collected from 18 Italian centers and 1 Israeli center, who received ibrutinib 420 mg/day outside of clinical trials as salvage therapy with available data for the calculation of the BALL and CLL-IPI scores at the time of the start of treatment. OS was estimated for all subgroups according to both scores. Additionally, risk-specific PFS was assessed. Kaplan-Meier curve, log-rank test and Cox regression analyses were performed. The prognostic accuracy of the predictive model was assessed by the Harrell's C-index.
Overall, 541 CLL patients were included in this analysis. The majority of patients were Binet stages B and C (87.2%). The median age was 70.4 years (range 37 - 88) and 353 cases (65.2%) were male. The median number of previous therapies was 2 (range 1-9). The baseline patients' features are listed in Table 1. After a median follow-up of 1.8 years (range 1 month to 5.8 years), 101 patients had died and 206 experienced an event (death or progression). According to the BALL score, 372 patients (68.8%) were classified as low-risk, 132 (24.4%) as intermediate-risk and 37 (6.8%) as high-risk. Stratification of patients according to the BALL score predicted significant differences in terms of OS. Thus, low-risk patients had a 2-year OS probability of 89.2% (HR=1), intermediate-risk of 79.9% (HR=2.8, 95%CI 1.8-4.4, P<0.0001) and high-risk of 48.2% (HR=6.6, 95%CI 3.9-11, P<0.0001) (Figure 1). The C-statistic was 0.66 (P<0.001) for OS prediction. The CLL-IPI score indicated that 32 patients (5.9%) were classified as low-risk, 123 (22.7%) as intermediate-risk, 252 (46.6%) as high-risk and 134 (24.8%) as very high-risk. Stratification of patients according to the CLL-IPI score did not allow to predict significant differences in OS. Indeed, low-risk patients had a 2-year OS probability of 92.7% (HR=1), intermediate-risk patients of 88.4% (HR=2.3, 95%CI 0.5-9.9, P=0.26), high-risk of 84% (HR=3.3, 95%CI 0.8-13.7, P=0.1) and very high-risk of 76.4% (HR=4.3, 95%CI 1.038-17, P=0.046). Both the BALL and CLL-IPI scores failed to stratify patients significantly in terms of PFS.
Our multicenter retrospective study confirms the prognostic power of the BALL score in this real-world series of R/R-CLL patients treated with ibrutinib, as previously reported in the setting of clinical trials (Soumerai et al, Lancet Hematology 2019). Furthermore, the CLL-IPI did not retain a discriminative power in the current retrospective study of ibrutinib-treated patients, possibly due to i) the well-known activity of ibrutinib in high-risk CLL patients, i.e. those with TP53 disruption and/or germline IGHV genes, which represent the most heavily weighted adverse risk factors contributing to the CLL-IPI, and to ii) the fact that the CLL-IPI was designed for patients receiving front-line chemo-immunotherapy. Conversely, the BALL score may identify higher risk R/R-CLL patients potentially requiring alternative and more effective therapeutic strategies.
Display omitted
Mauro:Jannsen: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Shire: Consultancy, Research Funding; Roche: Consultancy, Research Funding. Coscia:Gilead: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees. Herishanu:Roche: Honoraria; Janssen: Honoraria; AbbVie: Honoraria. Varettoni:ABBVIE: Other: travel expenses; Roche: Consultancy; Gilead: Other: travel expenses; Janssen: Consultancy. Rigolin:AbbVie: Speakers Bureau; Gilead: Speakers Bureau; Gilead: Research Funding. Rossi:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Other: Scientific advisory board; Janseen: Honoraria, Other: Scientific advisory board; Roche: Honoraria, Other: Scientific advisory board; Astra Zeneca: Honoraria, Other: Scientific advisory board. Gaidano:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sunesys: Consultancy, Honoraria; Astra-Zeneca: Consultancy, Honoraria. Cuneo:Amgen: Honoraria; Abbvie: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau. Foà:Roche: Consultancy, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees.
Objectives
To compare the capacity of ibrutinib (IB) and idelalisib‐rituximab (IDELA‐R) of prolonging overall survival (OS) as in CLL patients, previously treated with chemotherapy only.
Methods
A ...real‐life cohort of 675 cases has been identified and investigated in the database of the groups participating in the study.
Results
At an unadjusted univariate analysis, a significant death risk reduction was observed favoring IB (IDELA‐R vs IB HR = 0.5, 95% CI = 0.36‐0.71) although with some limitations due to the non‐randomized and retrospective nature of the study and to the lower number of patients in the IDELA‐R group (112 cases) related to the current prescribing practice. To overcome the potential problem of confounding by indication, we adjusted the association between the type of therapy and mortality for all variables significantly associated with OS at Cox univariate analysis. Furthermore, those variables, differently distributed between the two study groups, were introduced into the multivariate Cox model to improve the effectiveness of the analysis. By introducing all these variables into the multiple Cox regression model, we confirmed the protective effect of IB vs IDELA‐R (HR = 0.67, 95% CI = 0.45‐0.98, P = .04) independent of potential confounders.
Conclusions
Although our analysis presents some constraints, that is, the unavailability of additional potential confounders, and the retrospective nature of the study, this observation may be of help for the daily clinical practice, particularly in the absence of randomized trials comparing the two schedules.
PDF
