Real-world outcomes following venetoclax therapy in patients with chronic lymphocytic leukemia or Richter syndrome: a FILO study of the French compassionate use cohort

Bouclet, Florian; Calleja, Anne; Dilhuydy, Marie-Sarah; Véronèse, Lauren; Pereira, Bruno; Amorim, Sandy; Cymbalista, Florence; Herbaux, Charles; Guibert, Sophie de; Roos‐Weil, Damien; Hivert, Bénédicte; Aurran, Thérèse; Dupuis, Jehan; Blouet, Anaise; Tchernonog, Emmanuelle; Laribi, Kamel; Dmytruck, Nataliya; Morel, Pierre; Michallet, Anne‐Sophie; Dartigeas, Caroline; Tournilhac, Olivier; Nguyen‐Khac, Florence; Delmer, Alain; Feugier, Pierre; Ysebaert, Loïc; Guièze, Romain

doi:10.1007/s00277-021-04419-w

Cited by 27 publications

(26 citation statements)

References 13 publications

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“…Although venetoclax in first line has recently been approved, cumulated clinical experience with the Bcl-2 antagonist mostly regards heavily pre-treated diseases. 32 – 36 This is consistent with a population of patients of advanced age, often presenting with multiple comorbidities, assuming concomitant medications and deep immunosuppression. To assess whether any clinical baseline condition may predict venetoclax tolerance and influence drug management, thus avoiding both the bias of a co-administered anticancer drug and fixed duration schedule, we chose to analyze patients treated with continuous monotherapy.…”

Section: Discussionsupporting

confidence: 84%

“…There are not many studies exploring venetoclax tolerability outside of clinical trials, with the majority focused mostly on the role of age and renal function in respect to TLS and dose adjustments. 14 , 15 , 32 – 34 Furthermore, outcomes have been analyzed only in relation to age without considering the possible interference of other patient-related factors.…”

Section: Discussionmentioning

confidence: 99%

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Coexisting conditions and concomitant medications do not affect venetoclax management and survival in chronic lymphocytic leukemia

Frustaci

Poeta

Visentin

et al. 2022

Therapeutic Advances in Hematology

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Background: The question of which parameters may be informative on venetoclax outcome in chronic lymphocytic leukemia (CLL) is still unclear. Furthermore, the choice to treat with venetoclax can be challenging in patients with baseline characteristics or comorbidities that may potentially favor some specific adverse events. Objectives: This study was aimed to evaluate whether age, fitness status, patients’/disease characteristics, or concomitant medications may predict outcomes in CLL patients receiving venetoclax. Design: Retrospective observational study. Methods: Impact of age, presence of Cumulative Illness Rating Scale (CIRS) >6 or severe organ impairment (CIRS3+), Eastern Cooperative Oncology Group–Performance Status (ECOG-PS), renal function, and concomitant medications were retrospectively analyzed on treatment management (definitive discontinuation due to toxicity, discontinuation due to toxicity, Tox-DTD; permanent dose reduction, PDR) and survival [progression free survival (PFS), event free survival (EFS), overall survival (OS)] in unselected patients receiving venetoclax monotherapy in common practice. Results: A total of 221 relapsed/refractory patients were included. Tox-DTD and PDR were reported in 5.9% and 21.7%, respectively, and were not influenced by any fitness parameter, age, number or type of concomitant medication, baseline neutropenia, or impaired renal function. None of these factors were associated with tumor lysis syndrome (TLS) development. Age and coexisting conditions had no influence on PFS and EFS. At univariate analysis, OS was significantly shorter only in patients with ECOG-PS >1 ( p < 0.0001) and elderly (⩾65 years) with CIRS >6 ( p = 0.014) or CIRS3+ ( p = 0.031). ECOG-PS >1 retained an independent role only for EFS and OS. While Tox-DTD affected all survival outcomes, no differences in PFS were reported among patients permanently reducing dose or interrupting venetoclax for > 7 days. Conclusion: Clinical outcome with venetoclax is not influenced by comorbidities, patients’ clinical characteristics, or concomitant medications. Differently from other targeted therapies, this demonstrates that, except ECOG-PS, none of the parameters generally considered for treatment choice, including baseline neutropenia or impaired renal function, should rule the decision process with this agent. Anyway, if clinically needed, a correct drug management does not compromise treatment efficacy and may avoid toxicity-driven discontinuations. Plain Language Summary Chapter 1: Why was this study done? Chapter 2: Which are the main findings of the study? Chapter 3: How these findings may impact on clinical practice? Coexisting conditions and concomitant medications do not affect venetoclax management and survival in chronic lymphocytic leukemia • The question of which parameters may be informative on venetoclax outcome in chronic lymphocytic leukemia is still unclear. Furthermore, the choice to treat with venetoclax can be challenging in patients with baseline characteristics or comorbidities that may potentially favor some specific adverse events (e.g. compromised renal function or baseline neutropenia). • In our large series of patients treated outside of clinical trials, we demonstrated that neither age, fitness, comorbidities nor concomitant medications impact on venetoclax management and survival. Importantly, patients presenting with baseline neutropenia or impaired renal function did not have a higher rate of dose reductions or toxicity-driven discontinuations, thus further underlining that venetoclax may be safely administered even in those categories with no preclusions. • Differently from other targeted agents, our data demonstrate that none of the baseline factors commonly considered in treatment decision process retains a role with venetoclax. Finally, permanent dose reductions and temporary interruptions did not adversely impact PFS suggesting that, if clinically needed, a correct drug management should be adopted with no risk of compromising venetoclax efficacy.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Coexisting conditions and concomitant medications do not affect venetoclax management and survival in chronic lymphocytic leukemia

Frustaci

Poeta

Visentin

et al. 2022

Therapeutic Advances in Hematology

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“…When tested in RS-PDX models, venetoclax showed efficacy in Bcl-2-expressing cells, inducing apoptosis and prolonging mice survival [85]. However, clinical trials testing its efficacy in RS patients as monotherapy resulted only in partial responses [90,91].…”

Section: Small Molecules-targeted Therapymentioning

confidence: 99%

Novel Approaches for the Treatment of Patients with Richter’s Syndrome

Iannello

Deaglio

Vaisitti

2022

Curr. Treat. Options in Oncol.

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Opinion statementIn the last 10–15 years, the way to treat cancers has dramatically changed towards precision medicine approaches. These treatment options are mainly based on selective targeting against signaling pathways critical for or detrimentally activated in cancer cells in cancer cells, as well as exploiting molecules that are specifically expressed on neoplastic cells, also known as tumor-associated antigens. These considerations hold true also in the hematological field where a plethora of novel targeted agents have reached patients’ bedside, significantly improving clinical responses. Chronic lymphocytic leukemia (CLL) is an example of how targeted therapies, such as BTK, PI3K, or Bcl-2 inhibitors as well as anti-CD20 antibodies, have improved patients’ management, even when adopted as frontline treatment. However, these advancements do not apply to Richter’s syndrome (RS), the transformation of CLL into a very aggressive and fatal lymphoma, occurring in 2–10% of patients. RS is usually a fast-growing lymphoma of the diffuse large B cell or the Hodgkin’s variant, with a dismal prognosis. Despite advancements in depicting and understanding the genetic background of RS and its pathogenesis, no significant clinical results have been registered. In the last couple of years, several studies have started to investigate the impact of novel drugs or drug combinations and some of them have opened for clinical trials, currently in phase I or II, whose results will be soon available. This review will present an overview of current and most recent therapeutic options in RS, discussing also how results coming from xenograft models may help in designing and identifying novel treatment opportunities to overcome the lack of effective therapies.

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“…Further, a UK multicenter study (170 patients from 11 centers; venetoclax monotherapy, n = 99 [58%]; venetoclax–rituximab, n = 68 [40%]; and venetoclax–obinutuzumab, n = 3 [2%]) reported seven TLS events (three clinical and four biochemical, of which six occurred in high‐risk patients); however, there was no indication if these centers were the same as those in the UK CLL Forum [ 57 ]. TLS was observed in 14 (22%) patients receiving venetoclax monotherapy in a French Innovative Leukemia Organization (FILO) study of the French compassionate use cohort [ 58 ], 10 (12%) patients in an observational study conducted in Austria, Germany, and Switzerland (after receiving venetoclax–rituximab) [ 59 ], and three (6.3%) patients in a Spanish observational study where venetoclax was initiated at least 9 months before inclusion in the study (venetoclax monotherapy [81%]; venetoclax–rituximab [4%]; venetoclax–obinutuzumab [2%]; venetoclax and other agents [13%]) [ 60 ]. A total of 17 (51.5%) patients developed TLS by laboratory criteria at venetoclax doses from 20 to 400 mg, five patients developed TLS by clinical criteria, ranging from grade 0 to 3 in severity (per Cairo–Bishop definition) in the Koenig et al.…”

Section: Debulking For Reduction Of Tls Riskmentioning

confidence: 99%

A review of the incidence of tumor lysis syndrome in patients with chronic lymphocytic leukemia treated with venetoclax and debulking strategies

Sharman

Biondo²,

Boyer

et al. 2022

eJHaem

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We reviewed the literature (January 2010–June 2021) on the effectiveness of debulking strategies before venetoclax initiation in patients with chronic lymphocytic leukemia to reduce tumor burden, downgrade tumor lysis syndrome (TLS) risk, and avoid hospitalization. Low TLS incidence and reduced TLS risk based on tumor burden were reported following debulking in clinical trials. Real‐world observational studies reporting debulking regimens recorded no TLS events, and those without debulking strategies had greater TLS incidence. Debulking prior to venetoclax considerably reduces TLS incidence. Further clinical trials and real‐world studies may provide additional evidence on effectiveness of debulking in reducing TLS incidence and hospitalization need.

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Real-world outcomes following venetoclax therapy in patients with chronic lymphocytic leukemia or Richter syndrome: a FILO study of the French compassionate use cohort

Cited by 27 publications

References 13 publications

Coexisting conditions and concomitant medications do not affect venetoclax management and survival in chronic lymphocytic leukemia

Coexisting conditions and concomitant medications do not affect venetoclax management and survival in chronic lymphocytic leukemia

Novel Approaches for the Treatment of Patients with Richter’s Syndrome

A review of the incidence of tumor lysis syndrome in patients with chronic lymphocytic leukemia treated with venetoclax and debulking strategies

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