Italian Observational Study on Real-Life Use of Venetoclax in Acute Myeloid Leukemia (AVALON study): Results of Interim Analysis on Relapsed/Refractory Patients
Authors: Todisco Elisabetta , Fracchiolla Nicola , Papayannidis Cristina , Martelli Maria Paola , Rizzuto Giuliana , Cignetti Alessandro , Di Renzo Nicola , Zappasodi Patrizia , Gottardi Michele , Audisio Ernesta , Lunghi Monia , Gigli Federica , Tarella Corrado , Zingaretti Chiara , Petracci Elisabetta , Volpi Roberta , Cangini Delia , Giannini Maria Benedetta , Sciumè Mariarita , Rossi Giuseppe , Group Avalon , Martinelli Giovanni , Cerchione Claudio 
Published: November 2020

Background
This non-interventional retrospective study, is intended to analyze toxicity and effectiveness of venetoclax of a large cohort of R/R and de novo AML patients treated in Italy since 2015 outside clinical trials with the ultimate goal of improving the knowledge related to venetoclax treatment in the real-life setting. Interim analysis on first 59 patients enrolled is presented here.
Aims
The aim of this study is to collect data on safety and efficacy of venetoclax in a large cohort of AML patients treated in Italy from 2015 to 2020 in a real-life setting (out of clinical trials).
Methods
This is a multicenter, retrospective, observational study. All patients with AML treated outside clinical trials with venetoclax as single agent or in combination with other drugs from 1 January 2015 to 1 April 2020 in 40 Italian Hematology Units will be considered for enrollment. Data are collected in accordance with GCP and Helsinky declaration. For this interim analysis data registered into eCRF at 30 June 2020 have been considered. Adverse events (AEs) are graded according to CTCAE v4.03. Survival is estimated with Kaplan-Meyer method.
Results
The study started on August 2019 and will be completed on August 2021. Up to 30 June 2020 (first data cut off) 30 sites have been activated and 59 AML patients have been registered, 27 males (46%) and 32 females (54%), with a median age of 64 years (range 35 - 83).
At the time of venetoclax initiation, 14/59 (24%) patients had a refractory disease, 31 (52.5%) had relapsed disease (14 first relapse and 17 a second or further relapse), eight patients (15%) were newly diagnosed and received venetoclax as first line therapy while in six patients disease status was missing at the time of data cut off.
At diagnosis, 52 patients (88%) had bone marrow involvement, of which four (7%) had extramedullary involvement (skin or subcutaneous and deep muscular localization) and one had CNS involvement. 35/59 (59%) patients were classified as fit for intensive chemotherapy, 16 (27%) unfit and two (3%) frail according to SIE, SIES and GITMO group. For six patients fitness status was missing at the time of data cut off.
45/59 (76%) patients had received previous therapy for AML, eight patients were treatment naïve at the time of venetoclax initiation. while for six patients data regarding previous AML therapy were missing at the time of data cut off.
In the R/R setting (n=45), the median number of previous therapy lines were 2 (range 1-7). Nine patients had relapse after stem cell transplantation (SCT) and one of them had received double transplant.
For 42/45 R/R AML patients the data regarding treatment with venetoclax were available at the time of data cut off.
Three out of 42(7%) patients received venetoclax as single agents, 32 (76%) in combination with HMAs (31 Azacitidine and 1 Decitabine), and six with high or intermediate dose ARA-C.
In the cohort of R/R patients treated with combination of venetoclax and HMA, in 29/32 patients venetoclax was started as a ramp up phase. The median number of venetoclax cycles was 2 (range 1-13) and the median dose administered was 400 mg daily (range 100-600).
Regarding toxicity, 72 adverse events (AEs) were recorded of which 49 were grade III-IV (39 hematologic toxicities, 4 pneumonia, 2 sepsis and 4 other) and 2 fatal (sepsis).
For 25 out of 32 patients treated with venetoclax and HMAs combination, a response evaluation was available at the time of data cut off. 15 patients had an evaluable response within 2 months, 7 within 4-months and for 3 the date was missing. 14 (56%) patients obtained composite complete remission (CR=9; 5 =CRi), three patients had a partial response (PR), one stable disease (SD) while seven patients were refractory. Overall, six out of 32 (19%) patients underwent allogenic transplantation after venetoclax-HMAs combination. Median OS of R/R patients treated with venetoclax plus HMA was 182 days (95% C.I 85-421.).
Conclusions
These preliminary data show that venetoclax in combination with HMAs has an acceptable toxicity profile and is effective in this setting of R/R patients with unfavorable prognosis. Data from more than 100 patients treated in real life setting with venetoclax in Italy since 2015 is expected by the end of 2020, and further analysis on RR patients is ongoing. Data on newly diagnosed patients treated with venetoclax alone or in combination with HMA or chemotherapy will be analyzed.
*G.M. and C.C. contributed equally as last author

Disclosures
Todisco: Jannsen, Abbvie, Jazz:Membership on an entity's Board of Directors or advisory committees.Fracchiolla:Amgen:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau;ABBVIE:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses;Gilead:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau;Pfizer:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau.Papayannidis:Abbvie, Janssen, Novartis, Amgen, Pfizer:Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.Martelli:Pfizer:Membership on an entity's Board of Directors or advisory committees;Novartis:Membership on an entity's Board of Directors or advisory committees;Celgene:Membership on an entity's Board of Directors or advisory committees;Janssen:Membership on an entity's Board of Directors or advisory committees;AbbVie:Membership on an entity's Board of Directors or advisory committees;Amgen:Membership on an entity's Board of Directors or advisory committees;Jazz Pharmaceuticals:Membership on an entity's Board of Directors or advisory committees.Di Renzo:BerGenBio ASA:Research Funding.Tarella:ADC Therapeutics:Membership on an entity's Board of Directors or advisory committees, Research Funding;ImmunoGen:Research Funding;TG-therapeutics:Research Funding.Rossi:Jazz:Membership on an entity's Board of Directors or advisory committees;Abbvie:Membership on an entity's Board of Directors or advisory committees;Astellas:Membership on an entity's Board of Directors or advisory committees;Novartis:Other: Advisory board;Amgen:Honoraria;Pfizer:Membership on an entity's Board of Directors or advisory committees;Janssen:Membership on an entity's Board of Directors or advisory committees;Daiichi Sankyo:Consultancy, Honoraria;Takeda:Honoraria, Membership on an entity's Board of Directors or advisory committees;Alexion:Membership on an entity's Board of Directors or advisory committees;Celgene:Membership on an entity's Board of Directors or advisory committees;Sanofi:Honoraria.