Evaluating the Safety of Outpatient Ramp up of Venetoclax in Acute Myeloid Leukemia and Myelodysplastic Syndrome
Authors: Xiang Elaine , Cirrone Frank , Chin Jamie , Akerman Meredith , Saint Fleur-Lominy Shella , Abdul Hay Maher 
Published: November 2021

Abstract
Introduction
Venetoclax, a selective b-cell lymphoma 2 (BCL2) inhibitor, has changed the landscape of treatment in newly diagnosed acute myeloid leukemia (AML) elderly patients. In addition, it has shown promising efficacy in treatment-naive and relapsed/refractory (r/r) myelodysplastic syndrome (MDS) as well as r/r AML. Unique toxicities of venetoclax include tumor lysis syndrome (TLS) due to the rapid apoptotic effect by BCL2 inhibition. Although TLS is less frequently reported in AML, due to the fatalities from TLS reported in chronic lymphocytic leukemia patients, inpatient hospitalization during initial venetoclax dose ramp up is recommended. Hydroxyurea or leukapheresis can also be used to achieve a white blood cell (WBC) count of less than 25,000 prior to initiating venetoclax. At NYU Langone Health (NYULH), patients are initiated on venetoclax dose ramp up in the outpatient setting regardless of WBC count due to the low incidence of TLS. The aim of this study is to assess the safety of outpatient venetoclax dose escalation in our AML and MDS patients.
Methods/Results
This was an institutional review board approved, descriptive, retrospective medical chart review of 60 adult patients who received venetoclax dose ramp up in the outpatient setting at NYULH and NYU Long Island from March 1, 2017 to March 01, 2021. Patients were included if they were 18 years and older, received venetoclax in combination with either hypomethylating agents (HMA) or low-dose cytarabine in the outpatient setting, and had a documented diagnosis of either de novo AML, r/r AML, newly diagnosed high-risk MDS, or r/r MDS. The primary endpoint was the number of patients demonstrating laboratory or clinical TLS as defined by Cairo-Bishop Criteria described by Howard and colleagues. Secondary endpoints included hospital admission within two weeks of initiating venetoclax therapy. If patients did not have laboratory values obtained within one week of starting venetoclax, but had continued hematology follow-up with the NYU health system, it was assumed that these patients did not experience laboratory or clinical TLS.
One patient was counted as two individual patients because venetoclax was initiated as initial frontline AML treatment, followed by re-trial for relapsed disease. The median age was 74 years (IQR, 66-83). Most patients (24) had newly diagnosed AML (40%) followed by 17 patients (28.3%) with newly diagnosed MDS, 14 patients (23.3%) with r/r AML, and 5 patients (8.3%) with r/r MDS. The median total WBC count prior to initiating venetoclax was 2.25 x 10^3 cells/uL (IQR, 1.40-7) with a median blast count in the bone marrow of 25% (IQR, 11.5-53). Two patients had an initial WBC count of greater than 25. Thirty-six (60%) patients had a Carlson Comorbidity Index score of 5 or greater.
Decitabine was the most common combination agent used (50%), followed by azacitidine (48.3%), and low-dose cytarabine (1.7%). The majority of patients, 39 (65%) were prescribed the standard dosing ramp up schedule, with 15 patients (25%) had venetoclax initiated during cycle two or thereafter. Thirty-seven (61.7%) patients ramped up to the full venetoclax dose (either 400mg or 600mg). The most common reasons for dose reductions included drug-drug interactions (7 patients), neutropenia or anemia (7 patients), and general tolerance (5 patients). Thirty-seven (61.7%) patients were prescribed allopurinol prophylaxis. No patients received rasburicase prior to initiating venetoclax.
Only 1 patient (1.67%) experienced both laboratory and clinical tumor lysis and required intravenous hydration in outpatient clinic. Three additional patients (5%) required TLS directed treatment, but did not meet TLS definition. Of note, 8 patients (13.3%) did not have any laboratory values checked between days 1-7 of starting venetoclax. No patients were hospitalized within two weeks of venetoclax initiation due to TLS.
Conclusion
Administering venetoclax dose ramp up in the outpatient setting avoids need for hospitalization and appears to be safe in patients with AML and MDS. Limitations of this study include the heterogeneous population and the retrospective nature of the study. Although 35% of our patients were not prescribed the standard venetoclax ramp up dose, this highlights the existing challenges of treating elderly AML and MDS patients.

Disclosures
Abdul Hay: Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Speakers Bureau.

OffLabel Disclosure:
To assess the safety of outpatient venetoclax ramp up in both newly diagnosed & relapsed/refractory acute myeloid leukemia & myelodysplastic syndrome