Role of Age, Fitness and Concomitant Medications in CLL Patients Treated with Venetoclax
Authors: Frustaci Anna Maria , Biagi Annalisa , Chiarenza Annalisa , Coscia Marta , Ciolli Stefania , Laurenti Luca , Sportoletti Paolo , Reda Gianluigi , Varettoni Marzia , Mauro Francesca Romana , Murru Roberta , Baratè Claudia , Greco Antonino , Borella Chiara , Zamprogna Giulia , Martino Enrica Antonia , Vitale Candida , Morelli Francesca , Fresa Alberto , Guarente Valerio , Noto Alessandro , Postorino Massimiliano , Cairoli Roberto , Montillo Marco , Del Poeta Giovanni , Tedeschi Alessandra 
Published: November 2020

Background
The provision of effective and tolerable therapy in elderly and unfit patients is a clear priority in CLL. The BCL2 inhibitor venetoclax has shown remarkable efficacy in relapsed/refractory population and recently, in unfit untreated patients receiving a fixed duration schedule combined with obinutuzumab. Large retrospective real word experiences confirmed the efficacy and survival outcomes previously seen in trials. Although toxicity analysis including rates of tumor lysis syndrome (TLS), dose interruptions and discontinuations have been assessed in a recent cohort (Eyre et al. BJH 2020), the question of whether age and fitness may affect efficacy and survival on venetoclax treatment is still open.
Methods
This is a multicenter retrospective analysis evaluating 158 patiens in 14 Italian centers treated with venetoclax from February 2017 to May 2020. For each patient we analyzed the impact of age (&lt;65y, versus ≥ 65y) , CIRS (≤6 versus &gt;6), major CIRS comorbidity (at least one organ with a CIRS score ≥3, CIRS3+), ECOG-PS (0-1 versus &gt;1) and CCI (&lt;2 versus ≥2) in definitive treatment discontinuation due to toxicity (tox-DTD); permanent dose reduction (PDR); EFS (event: tox-DTD, progression, death); PFS and OS. Medical conditions that were deemed to be complications of CLL as well as the diagnosis of CLL itself, were not included in CIRS score calculation.
The survival functions for the time-to-event variables were estimated by Kaplan-Meier method and the related strata compared using the log-rank test. Multivariate analyses were performed too using the Cox regression.
Results
Patients characteristics are shown in table 1. Median time of observation for the whole population was 11.9 months (2.1 - 40.2). Median months of venetoclax treatment were 9.4 (range 2.1 - 40.2). Overall, 111 (70.3%) patients are continuing with therapy. A total of 42 (26.6%) patients permanently discontinued venetoclax: 7 (4.4%) due to toxicity; 25 (15.8%) due to progressive disease and/or Richter Transformation; 16 (10.1%) for other reasons. Among 158 patients, 41 (25.9%) discontinued treatment for ≥7 days with a median of 8 days/patient interruption. At least one dose reduction episode occurred in 36 patients (22.8%) and in 21 (13.3%) venetoclax was permanently administered at a lower dosage. Concomitant medications were reported in 134 (84.8%) patients, 75 of whom took ≥4 drugs in addition to venetoclax. In 32 cases (20.3%) venetoclax was administered concomitantly with CYP3A4 inhibitors/inducers.
Patients age did not influence tox-DTD and PDR as well as patients outcomes in terms of EFS PFS and OS. In the elderly CIRS &gt; 6 significantly influenced PDR (p 0.012) but not tox-DTD. In younger patients CIRS &gt;6 did not show effect on treatment management; CIRS3+ instead, led to higher rate of tox-DTD (p 0.044). Progression free survival, EFS and OS were not affected by CIRS3+ and CIRS&gt;6 even when patients were stratified according to age. Patients with an ECOG &gt;1 experienced more tox-DTD (P 0.003) and a significantly shorter PFS (p &lt;0.0001), EFS (p &lt;0.0001) and OS (p&lt;0.0001). CCI had an impact on PDR but not on patients outcome. Table 2 reports the parameters influencing management and outcome at the Cox regression analysis. Presence of del(17p) and/or TP53 mutation was associated with shorter PFS, EFS and OS, furthermore ECOG &gt; 1 was independently associated with shortened PFS. While baseline neutropenia and concomitant treatment with CYP3A4 inhibitors/inducers led to a significant PDR, the presence of a compromised renal function did not influence patients management.
Conclusions
To our knowledge this is the first analysis assessing whether age, ECOG-PS and comorbidities retain a predictive value with venetoclax and if number and types of concomitant medications may interfere on treatment outcome. Age, CIRS and CIRS3+ did not affect patients management and outcomes; however, ECOG was the only significant factor related to fitness independently influencing outcome at the multivariate analysis.

Disclosures
Coscia: Abbvie: Honoraria, 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, Research Funding, Speakers Bureau; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Research Funding. Ciolli:Abbvie: Research Funding; Janssen: Honoraria. Laurenti:Janssen: Honoraria; Gilead: Honoraria; AbbVie: Honoraria; Roche: Honoraria. Sportoletti:AbbVie: Honoraria; Janssen: Honoraria. Reda:Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Varettoni:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel/accommodations/expenses; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Other: Travel/accommodations/expenses. Mauro:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octopharma: Consultancy; Shire-Takeda: Membership on an entity's Board of Directors or advisory committees. Murru: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; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vitale:Janssen: Honoraria. Montillo:Gilead: Honoraria, Speakers Bureau; Verastem: Honoraria; Astra Zeneca: Honoraria; Janssen: Honoraria, Speakers Bureau; AbbVie: Honoraria, Speakers Bureau; F. Hoffmann-La Roche: Honoraria, Research Funding. Tedeschi:Janssen: Honoraria, Speakers Bureau; Acerta: Honoraria, Speakers Bureau; Sunesis: Honoraria, Speakers Bureau; Beigene: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau.