Real‐world evidence on venetoclax in chronic lymphocytic leukemia: The Italian experience

Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in the western world. In Italy, venetoclax was approved for use in patients with CLL as monotherapy in 2017 and in combinations in 2019. As a result of this delayed approval, there are relatively few real‐world studies from Italian clinical practice and much of the data are in heavily pretreated patients. We have collected the available studies in Italian routine practice. Three studies confirm the effectiveness and tolerability of this agent in patients with relapsed/refractory CLL and high‐risk disease characteristics, many of whom had received prior B‐cell receptor signaling treatment. Addition of rituximab to venetoclax produced more complete responses in patients with relapsed/refractory CLL, while higher disease burden and progression while receiving a prior Bruton's tyrosine kinase inhibitor were both associated with poorer outcomes in patients treated with venetoclax. Venetoclax was well‐tolerated with low discontinuation rates. No studies of venetoclax plus obinutuzumab for the first‐line treatment of patients with CLL were available due to the short time since approval in Italy. Several cohorts addressed the impact of COVID‐19 on patient management and outcomes, suggesting that treated patients and those in clinical observation had similar rates of COVID‐19‐related hospital admission, intensive care unit admission, and mortality. Overall, the responses and tolerance to venetoclax observed in the Italian real‐world setting confirm the tolerability and effectiveness of venetoclax regimens in high‐risk patients.

shorter overall survival (OS). 3,4The CLL International Prognostic Index (CLL-IPI) 5 predicts progression-fee survival (PFS) and OS in patients receiving CIT as first-line treatment. 6However, the CLL-IPI does not perform as well with targeted therapies, where the presence of TP53 mutations or del(17p) have a less relevant impact. 7][10][11][12] CLL is an incurable condition and physicians need to identify the optimal treatment strategy for each patient to improve PFS and OS, and maintain good quality of life.
In Italy, approval of venetoclax for use in patients with CLL came later than in other European countries, both as monotherapy (August 2017) and in combination (December 2019).As a result, there are relatively few real-world studies from Italian clinical practice and much of the real-world experience involves heavily pretreated patients.We have collected the available studies in Italian routine practice and discuss them in the context of patient management.

| Recent progress in CLL therapy
Until recently, time-limited CIT with fludarabine, cyclophosphamide, and rituximab (FCR) was the standard of care for young, fit patients with CLL requiring treatment 13,14 ; however, such an intensive combination is often associated with myelosuppression, infections, and can increase the long-term risk of myeloid disorders, including myelodysplastic syndrome and acute myeloid leukemia. 15,16The use of FCR is now mainly limited to the first-line treatment of fit patients with favorable biologic factors (mutated IGHV, no 17p-or 11q-), where long-term benefits have been obtained with this combination. 17CLL treatment has evolved with the approval of novel agents targeting either B-cell receptor signaling (BCRi) through Bruton's tyrosine kinase inhibitors (BTKis; ibrutinib, acalabrutinib) or phosphoinositide 3-kinase delta inhibitors (idelalisib), or by antagonizing the anti-apoptotic B-cell lymphoma 2 protein (BCL2) using venetoclax. 18These molecules are better tolerated than CIT.
Unlike CIT, BCRi therapy is administered until progression or unacceptable toxicity occurs, 19 and interruption or discontinuation of BCRi therapy in patients with progressive disease can be associated with disease flares and relapse. 20These agents effectively suppress the proliferation of CLL cells, but they are usually less effective in achieving complete responses and responses with undetectable minimal residual disease (uMRD). 213][24] This is an important treatment result, as uMRD was shown to be an independent prognostic marker of PFS and OS in patients receiving CIT for CLL. 25 Moreover, time-limited therapy provides a substantial benefit for patients and their caregivers in terms of improved quality of life associated with the reduced time of treatment, hospital visits, and management of side effects.In addition, limiting treatment duration may potentially improve adherence, and reduced selective pressure and clonal evolution.
7][28] The ongoing CLL17 trial (NCT04608318) is comparing continuous monotherapy with ibrutinib versus time-limited treatment comprising either venetoclax plus obinutuzumab or venetoclax plus ibrutinib in the first-line CLL setting.

| Venetoclax
Several characteristics make BCL2 an important target in the treatment of CLL. 29 BCL2 is highly expressed in CLL, and CLL cells are dependent on BCL2 for survival. 30Venetoclax is a BCL2-selective, orally bioavailable BH3 mimetic that bypasses p53 and disrupts the anti-apoptotic function of BCL2. 31BCR is increase the dependence of CLL cells on BCL2, 32,33 providing a rationale for combination therapy.
In the US, venetoclax is indicated for the treatment of adult patients with CLL or small lymphocytic lymphoma. 34In Europe since December 2016, venetoclax has been approved in combination with obinutuzumab for the treatment of adult patients with previously untreated CLL, and in combination with rituximab for the treatment of adult patients with CLL who have received at least one prior therapy.
Venetoclax monotherapy is indicated for the treatment of CLL in adult patients with a del(17p) or TP53 mutation who are unsuitable for or have failed a BCRi, or in adult patients without a del(17p) or TP53 mutation who have failed both CIT and a BCRi. 35In Italy, venetoclax has been eligible for reimbursement by the Health Care System for CLL as monotherapy since August 2017, 36 in combination with rituximab in pretreated patients since December 2019, 37 and in combination with obinutuzumab in the first line since May 2022. 38netoclax was granted approval for treating CLL with TP53 aberrations based on the results of the phase 2, open-label, single-arm M13-982 study, which enrolled 158 patients with relapsed/refractory (R/R) CLL and confirmed del(17p). 39Approval for use in combination with rituximab was based on the results from the phase 3, randomized MURANO study in patients with R/R CLL, 40 which compared the venetoclax plus rituximab combination versus the bendamustine plus rituximab combination.This study demonstrated that a time-limited chemotherapy-free regimen with venetoclax and rituximab was more effective than CIT in patients with R/R CLL, including those with high-risk disease.At the end of combination treatment (9 months), venetoclax plus rituximab had resulted in uMRD in peripheral blood in 62.4% of patients versus 13.3% with bendamustine plus rituximab.Five-year follow-up of patients from the MURANO study showed that responses with venetoclax plus rituximab were durable, with sustained benefits in terms of PFS and OS. 41 the first-line setting, the CLL14 trial demonstrated that the 1year, fixed-duration therapy with venetoclax plus obinutuzumab provided longer PFS than chlorambucil plus obinutuzumab in unfit patients with CLL. 42The results of this study led to the approval of this combination for first-line treatment of CLL. 34After extended follow-up of median 52.4 months, a significant PFS improvement was maintained in the venetoclax-obinutuzumab arm compared with the chlorambucil-

| Real-world evidence in CLL
Randomized controlled trials are necessary to establish efficacy, but they focus on selected and homogeneous populations and usually report limited outcome data. 44Sources of real-world evidence (RWE) include administrative healthcare databases, patient registries, medical records, as well as case reports.RWE studies provide data in unselected patients, and the results of these studies provide useful information in underrepresented patient populations, address important clinical issues, and provide feedback on the implementation of data from controlled trials. 45,46 eal-world studies investigate long-term safety and the impact of adverse events (AEs) on dose reductions and treatment discontinuations, 47 and provide important information on healthcare system costs. 48Moreover, these studies are used to assess prognostic testing and treatment patterns, 49 and to collect data on specific CLL patient populations. 50Other important information that can be obtained from RWE studies includes comparing real-world response rates to those described in clinical trials, 51 assessing the effectiveness of treatments in heavily pretreated high-risk patients with CLL, 52 or in different age groups, 53 evaluating the sequencing of targeted therapies in CLL, 54,55 as well as defining the impact of specific AEs. 56garding venetoclax for CLL, Eyre et al. 53 assessed the effectiveness of venetoclax according to age in a retrospective cohort of 342 patients with R/R CLL in the US and UK real-world setting, reporting equivalent efficacy and safety among patients ≥75 and < 75 years of age.This finding confirmed aggregated safety data from three early-phase trials showing similar toxicity profiles in these age groups. 57Further analysis of this cohort by Roeker et al. 56 assessed the rates of selected AEs in 297 patients, confirming the low tumor lysis syndrome (TLS) rates observed in clinical trials after the introduction of a ramp-up dosing schedule and TLS prophylaxis. 58,59to et al. 51 assessed discontinuation rates in a retrospective realworld cohort of 141 patients with R/R CLL treated with venetoclax, reporting after a median 7 months of follow-up that 39 (28%) patients discontinued, mostly because of progression (21/39; 53.8%), whereas relatively few discontinued due to toxicity (8/39; 20.5%), confirming the clinical trial results. 58cently, Thompson et al. 60 conducted an international retrospective study investigated the feasibility of venetoclax re-treatment in 46 patients with CLL who had initially responded to time-limited venetoclax-based regimens (64.2% had uMRD).The most frequent reasons for stopping treatment had been completing planned treatment (39.1%) or discontinuation due to toxicity (21.7%).Most patients were re-treated because of disease progression and retreatment was started after a median 16-month interval.The observed overall response rate (ORR) on re-treatment was 79.5%.
The limitations of real-world studies in general include missing data and the intrinsic bias associated with retrospective data collection. 44It is also important to note that the results of real-world studies may differ between countries due to the different time of drug approval and local guidelines for treatment approaches.For this reason, we reviewed clinical insights on venetoclax for CLL in the Italian context.

| METHODS
We searched Embase and PubMed databases with the terms: "chronic lymphocytic leukemia" [title/abstract] AND "venetoclax" (title/abstract) AND "Italy."We then hand-sorted the results to identify real-world studies.We searched the reference lists of identified reports, as well as published congress proceedings for additional studies (Figure 1).

| REAL-WORLD EVIDENCE ON VENETOCLAX IN CLL IN ITALY
The real-world experience with venetoclax developed in Italy has been described in three studies that confirm the effectiveness and tolerability of this agent in patients with R/R CLL and high-risk disease characteristics, many of whom had received prior BCRi treatment.The combination of venetoclax with obinutuzumab for the first-line treatment of patients with CLL has only recently been approved in Italy; we did not identify any real-world studies in this patient setting.

| Effectiveness of venetoclax
An ongoing retrospective/prospective cohort study (NCT04282811) conducted by Scarfò et al. 61 on behalf of the Italian Adult Hematological Diseases Group (GIMEMA) is assessing the outcomes of 124 Italian patients with R/R CLL treated with venetoclax-based regimens outside of clinical trials (Table 1).The planned follow-up of this study is 48 months from start of venetoclax treatment, and quality of life will be assessed in the prospective cohort.
In another Italian real-world study, Morelli et al. 62 conducted a retrospective analysis of the safety and efficacy of venetoclax monotherapy in 38 patients (median age 66 years, median follow-up 20 months).Two-thirds of these patients had high-risk genotypes; one-third had a high comorbidity burden (Cumulative Illness Rating Scale [CIRS] >6); two-thirds had received more than two treatments before venetoclax.After 12 months, PFS and OS were 62% and 63%, respectively.The ORR was 75%, of which 25% were complete responses.[63][64][65][66][67][68][69][70][71][72] T A B L E 1 Outcomes with venetoclax in previously treated patients with CLL in the Italian real-world setting.

| Safety
In the study by Scarfò et al., 61

| Patient profile: The evolving concept of fitness
The mean age at diagnosis of CLL is 72 years 1 ; therefore, patient fitness may influence the ability to tolerate the full-dose treatment required for optimal outcomes.Comorbidities and advanced age can present a challenge to treating CLL with a chemotherapy-containing regimen such as CIT.Older adults may tolerate combinations with less intense chemotherapy components better 73 ; however, these combinations may be less effective in the long term.Regarding targeted therapy, the role of patient fitness in treatment decisions is evolving. 74BTKi and BCL2i, while not devoid of adverse effects, are better tolerated than chemotherapy-containing regimens.In addition, targeted agents are more effective than CIT, 40,42,75,76 and also for treating unfit patients. 42In a retrospective cohort of 158 patients treated with venetoclax monotherapy at 14 Italian centers, Frustaci et al. 64 analyzed the influence of age (<65 years vs. ≥65 years) and fitness on patient management and outcomes.Fitness was defined in terms of CIRS score (≤6 vs. >6), presence of major comorbidities, Eastern Cooperative Oncology Group performance status (ECOG PS; 0-1 vs. >1), renal function (creatinine clearance <30 mL/min vs. ≥30 mL/min), Charlson Comorbidity Index (<2 vs. ≥2), the presence of baseline neutropenia, and concomitant medications.Outcomes included treatment discontinuation due to toxicity, permanent dose reductions, PFS, and OS.
None of the baseline parameters considered had an influence on TLS development or treatment management.Performance status (ECOG PS > 1), was the only pretreatment factor significantly associated with survival while on venetoclax at univariate analysis, confirming its independent role only on event-free survival (EFS) and OS.Although permanent discontinuation due to toxicity was detrimental for all survival outcomes, neither permanent dose reduction nor venetoclax interruption >7 days led to worse PFS, EFS, or OS.
Age and comorbidities were not predictive factors, and the number and types of concomitant medications did not influence treatment outcomes.In multivariate analysis, ECOG PS was the only fitnessrelated factor that independently influenced outcomes.Thus, none of the parameters that traditionally influence treatment choices appeared to influence outcomes with venetoclax.

| Impact of COVID-19 on patients with CLL
The COVID-19 pandemic has created enormous challenges for healthcare professionals, especially in the management of patients with hematological disorders associated with immunodeficiency. 77ltiple immune defects are present in CLL patients and are associated with an increased risk of infections, 78 and a reduced response to vaccines. 79The two largest studies that have evaluated the clinical impact of COVID-19 on patients with CLL analyzed the outcomes of nearly 400 patients.

| Other real-world cases in CLL
Several real-world case reports have been described that demonstrated the efficacy of venetoclax in CLL and concomitant diseases.

| Central nervous system involvement
Central nervous system (CNS) involvement is rare in CLL, occurring in <1% of patients, and most reported CNS symptoms have other etiologies 81 ; however, Reda et al. 70  Therapeutic concentrations of venetoclax were detected in CSF during treatment, with peak and trough concentrations of 2.8 and 1.5 ng/mL, respectively.Suggesting that venetoclax may be effective in CLL cases with CNS involvement.

| Acquired von Willebrand syndrome
Acquired von Willebrand syndrome is a rare condition that has been observed in patients with autoimmune or neoplastic disorders, including CLL. 82 Innocenti et al. 71 described a heavily pretreated patient with CLL with no medical or family history of bleeding disorders who developed acquired von Willebrand syndrome.The patient achieved a complete (uMRD) response with venetoclax that was associated with normalization of coagulation parameters.

| Polyneuropathy with anti-MAG antibodies
Briani et al. 72 recently reported that venetoclax plus rituximab was active in a patient with wild-type MYD88 polyneuropathy and antibodies to myelin-associated glycoprotein (MAG).A 62-year-old woman with CLL and monoclonal IgM/K protein had experienced anti-MAG antibody neuropathy for several years.Anti-MAG antibody neuropathy is the most common IgM paraproteinemic neuropathy, and is characterized by sensory ataxic gait and upper limbs tremor, with motor involvement occurring late in the disease course. 72After 12 months of treatment, IgM levels decreased, paraprotein became undetectable and the anti-MAG antibody titer decreased.The patient regained the ability to walk independently.

| Experience addressing hematological complications of CLL in the Italian setting
Other autoimmune conditions associated with CLL include autoimmune hemolytic anemia, 83 and autoimmune cytopenias (AICs). 84In Italy, Vitale et al. 85 venetoclax-based regimens were well tolerated, with the most frequent AE of any grade being neutropenia, which occurred in 80% of patients and was grade 3-4 in 62% of cases.Of 113 AEs of any grade, 52 were grade 3, and 28 were grade 4. Seven patients discontinued venetoclax due to AEs, and 11 patients due to disease progression, including three cases of Richter's transformations.The median time to discontinuation was 4.1 months (range: 0.4-10.8).During the dose-escalation phase, one patient experienced clinical TLS that resolved without sequelae, while two had laboratory TLS.In the study by Morelli et al., 62 hematological toxicity requiring a dose reduction had occurred in 5 of 38 patients at a median followup of 20 months.There were no reported instances of extrahematological toxicities and no instances of TLS during the doseescalation phase.
described a heavily pretreated CLL patient with CNS involvement characterized by atypical lymphocytes in the cerebrospinal fluid (CSF), periventricular lesions, and meningeal involvement at L4-L5.The authors demonstrated that venetoclax crosses the blood-brain barrier and penetrates CSF.The patient responded after 1 month to treatment with oral venetoclax plus intrathecal chemotherapy with cytarabine plus methotrexate.

Innocenti et al. 2019 63 venetoclax Morelli et al. 2020 62 venetoclax Scarfo et al. 2021 61 venetoclax + rituximab
80,80Most of the treated patients were receiving BCRi (105/388) at the time of COVID-19, and 26/388 patients were on venetoclax-based regimens.In the study by Mato et al.,80previ- 86sessed the incidence and management of preexisting and treatment-emergent AICs during therapy with targeted drugs in a large retrospective series of patients with CLL (n = 100 treated with venetoclax; median age 70 years [range:44-  84]; median number of previous treatments two [range: 0-8]).Venetoclax was administered as monotherapy in 88% and in association with an anti-CD20 agent in the rest, most patients were heavily pretreated.After a median follow-up of 14 months (range: 1-70 months) in the venetoclax group, the ORR was 78%, with a partial response rate of 67% and a complete response rate of 11%.Consistent with previous reports,86most treatment-emergent AICs occurred in patients with high-risk disease characteristics.
87eatment-emergent AICs occurred in about 7% of patients who received venetoclax, a rate higher than that observed in patients treated with other CLL-targeted therapies (7% vs. 1%; p ≤ 0.001), likely due to patient characteristics.The results suggest that targeted treatments may not increase the risk of AIC.87626-LAURENTI ET AL.