Venetoclax and Cytarabine in AML Transformed from Myelofibrosis
Authors: McKay John , Gayhart Matthew , Al-Juhaishi Taha , Yazbeck Victor , Perkins Edward B. 
Published: November 2019

Background
Acute myeloid leukemia (AML) accounts for 1% of all newly diagnosed cancers with a mean age at diagnosis of 68. Although the majority present de novo, AML can be secondary to conditions such as myelodysplastic syndrome (MDS) and myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF). The subset of patients with AML transformed from MPN continues to remain a therapeutic challenge with little data to support clinical efficacy. A large retrospective review of 273 patients revealed no significant improvement in overall survival in this patient population for those diagnosed between 1989 and 2016. Prognosis remains dismal with an overall survival of 5-7 months. Treatment options are limited and often with little proven clinical utility. Even the addition of hypomethylating agents to treatment options has failed to show any improvement in survival necessitating the investigation of new treatment options (Chihara et al, ASH 2016). In this case series, we present two AML cases that have transformed from myelofibrosis and were successfully treated with the combination of cytarabine and venetoclax.
Objective
Our primary objective was to determine the clinical efficacy of the combination of cytarabine and venetoclax in patients with myelofibrosis with leukemic transformation.
Methods
This is an observational, retrospective case series of two patients that were treated with cytarabine and venetoclax at Virginia Commonwealth University from 2018 to 2019. Both patients had previously been confirmed as meeting WHO criteria for myelofibrosis on bone marrow examination. Upon transformation to acute myeloid leukemia, again confirmed on bone marrow biopsy, both patients were transitioned to the following regimen: cytarabine 20 mg/m2 on days 1-10 of 28-day cycle in combination with venetoclax with rapid dose escalation to goal of 600mg daily with dose adjustments for medication interactions. The patient's response to therapy and side effect monitoring were performed at regular intervals in the outpatient clinic.
Results
Our study consisted of two females, age 65 (patient 1) and 71 (patient 2) with a median age of 68 and bone marrow biopsy confirmed diagnosis of myelofibrosis. Both females had grade 3+ fibrosis on marrow examination and both harbored JAK2 mutations on initial diagnosis of myelofibrosis. Patient 2 also demonstrated a 20q deletion. Neither female was deemed a suitable candidate for transplantation due to their age and considerable comorbidities. On transformation to leukemia, blast count burden was 27% and 23%, respectively. Patient 1 had received decitabine prior to the cytarabine/venetoclax regiment while the other had no previous therapy for her myelofibrosis or leukemia.
Patient 1 was maintained on the regiment with for 10 months and nearly completed 9 cycles before patient decompensated and was transitioned to comfort care and eventually died. Complications during her treatment course included an elevated uric acid requiring a dose of rasburicase, neutropenic fever and subdural hematoma that resolved without any intervention.
Patient 2 has completed 6 cycles of therapy and is now 8 months post initiation of therapy. Her most recent bone marrow biopsy showed a hypocellular bone marrow (20-30% cellularity) and severe myelofibrosis (reticulin 3/3+) with less than 1% blasts. She remains independent of transfusions.
Conclusions
Our case series demonstrates that the combination of cytarabine and venetoclax can be effectively used in patients with AML transformed from myelofibrosis. In a disease historically with an overall survival of 6 months, one patient survived 10 months and the other is 8 months out and currently in remission from her AML on her most recent bone marrow biopsy, and independent of transfusions. Overall, therapy has been well tolerated with manageable adverse events. Although future prospective studies are needed, the combination of cytarabine and venetoclax offers a reasonable treatment option for secondary AML transformed from myelofibrosis.

Disclosures
Yazbeck: Gilead Sciences: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.