Ehab Atallah, MD
In a study by Trembely et al . sponsored by Pfizer, an indirect comparison of both studies was performed using a simulated treatment comparison to account for differences in patient characteristics. As expected, the overall response rates were higher in the venetoclax study compared to the glasdegib study (48% vs. 24%), but overall survival was similar (hazard ratio 0.75 vs. HR 0.46). This study demonstrates again that CR/CRi cannot be used as a surrogate endpoint for survival in AML. In addition, with the negative study of V-LDAC vs. LDAC and the improved overall survival of the combination of azacytidine + venetoclax (Aza-ven) vs. azacitdine, the current standard of care of newly diagnosed patients with AML unbale to tolerate intensive chemotherapy is Aza-ven and V-LDAC is rarely used.
The success of Aza-ven is not without side effects. This was demonstrated recently in a retrospective study by Feld et al. In that study 72 patients with newly diagnosed AML (26), relapsed refractory AML (39) and MDS (7) received azacitdine + venetoclax. The main side effect was myelosuppression with only 15% of patients who were transfusion dependent become transfusion independent. In addition, 46% of patients had a neutropenic fever and 43.7% of patients requiring admission. Most patients (54.9%) required treatment interruption and 35.2% stopped venetoclax for toxicity.
This study highlighted that the optimal dose and frequency of venetoclax remains unclear. A shorted duration or lower dose of venetoclax maybe more ideal, however that may lead to less efficacy. In addition, bone marrow evaluation to assess for cellularity on D21 to D28 of the first cycle may help guide dose adjustments. Finally with the high CR/CRi rates in AML and short duration of response further studies are ongoing to further define molecular abnormalities that may refine prognosis or guide therapy. Two of those studies recently reported identified a prognostic and possible therapeutic role for both EZH2 and the PI3 kinase mTOR pathway .