Session: 615. Acute Myeloid Leukemia: Commercially Available Therapy, excluding Transplantation: Targeted Therapy For Adults Diagnosed With Acute Myeloid Leukemia
Hematology Disease Topics & Pathways:
Adult, Therapies, Non-Biological, Study Population, Clinically relevant
Methods: We searched for cases of DS in Study AG120-C-001 for IVO and Study AG221-C-001 for ENA using PTs and laboratory data within the first 90 days of treatment, grouped per the Montesinos criteria. Patients were included in the analysis if they had been treated for R/R AML using the approved dose of IVO (n=179) or ENA (n=214). We reviewed case narratives and laboratory data for algorithmically-identified cases of DS to adjudicate whether cases were DS or unlikely DS, due to an alternative explanation (e.g., infection, disease progression). An additional query for the DS cases was performed for concomitant leukocytosis, defined using PTs Leukocytosis, Hyperleukocytosis, or White blood cell count increased, or laboratory results showing leukocyte count > 10 Gi/L within 7 days of clinical signs/symptoms.
Results: The algorithm identified 72/179 (40%) cases of potential DS for IVO and 86/214 (40%) for ENA. FDA reviewer adjudication revealed that roughly half of the cases identified by the algorithm were DS for IVO (34/179, 19%) and ENA (41/214, 19%). This contrasts with the DS incidence of 11% (19/179) for IVO (DiNardo et al. NEJM 2018) and 12% (26/214) for ENA (Fathi et al. JAMA Oncol 2018) reported by investigators and review committee determination, respectively. Characteristics of FDA-identified DS cases in patients treated with IVO and ENA and FDA-adjudicated complete remission (CR) + CR with partial hematologic recovery (CRh) responses to the respective drugs in patients with DS are presented in the Table. For both IVO and ENA, CR+CRh rate in patients with DS was numerically lower than that for patients without DS (IVO: 18% [95% CI 7-35%] vs. 36% [95% CI 28-45%]; ENA: 18% [95% CI 7-33%] vs. 25% [95% CI 18-32%]). Age, demographics, and cytogenetic risk of patients with FDA-identified DS were similar to those of patients without DS.
Conclusions: An algorithmic analysis of AEs and laboratory tests using the Montesinos criteria led to recognition of additional cases of DS not identified by investigators for patients treated with IDH inhibitors IVO and ENA. DS occurred in roughly one in five patients treated with both drugs and grade 3 or higher adverse reactions were present in over half of cases. Leukocytosis was not always present. Patients with DS had numerically lower response rates, but firm conclusions regarding the impact on response cannot be inferred based on this post-hoc subgroup analysis. Increased recognition of signs and symptoms of DS through the framework of the Montesinos criteria may lead to earlier diagnosis and treatment, which may decrease severe complications and mortality. Furthermore, integration of the algorithmic approach into clinical trials of differentiating therapies may help to prospectively monitor the incidence and severity of DS.
Disclosures: No relevant conflicts of interest to declare.
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