Mutational profile and benefit of gemtuzumab ozogamicin in acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) is a highly heterogeneous disease both in terms of genetic background and response to chemotherapy. Although molecular aberrations are routinely used to stratify AML patients into prognostic subgroups when receiving standard chemotherapy, the predictive value of the genetic background and co-occurring mutations remains to be assessed when using newly approved antileukemic drugs. In the present study, we retrospectively addressed the question of the predictive value of molecular events on the benefit of the addition of gemtuzumab ozogamicin (GO) to standard front-line chemotherapy. Using the more recent European LeukemiaNet (ELN) 2017 risk classification, we confirmed that the benefit of GO was restricted to the favorable (hazard ratio [HR], 0.54, 95% confidence interval [CI], 0.30-0.98) and intermediate (HR, 0.57; 95% CI, 0.33-1.00) risk categories, whereas it did not influence the outcome of patients within the adverse risk subgroup (HR, 0.93; 95% CI, 0.61-1.43). Interestingly, the benefit of GO was significant for patients with activating signaling mutations (HR, 0.43; 95% CI, 0.28-0.65), which correlated with higher CD33 expression levels. These results suggest that molecular aberrations could be critical for future differentially tailored treatments based on integrated genetic profiles that are able to predict the benefit of GO on outcome.

AML Risk Stratification Models Utilizing ELN-2017 Guidelines and Additional Prognostic Factors: A SWOG Report

“…Thus, the results may not be generalizable to patients receiving therapy outside of evaluated clinical trials, low-intensity regimens (e.g., azacytidine), or targeted agents (e.g., midostaurin). Nonetheless, some recent biomarker studies suggest that previously recognized prognostic factors remain highly informative and predictive for responses to more "targeted' agents (54)(55)(56), and as such, there likely remains some role for the identification of prognostic biomarkers that are applicable across a variety of therapies.…”

Biomarkers of Gemtuzumab Ozogamicin Response for Acute Myeloid Leukemia Treatment

“…Mutations have become strong prognostic factors and have been integrated in the latest European LeukemiaNet (ELN) 2017 risk stratification [83]. A retrospective analysis from the ALFA-0701 showed a benefit of the addition of GO on EFS in patients from the ELN favorable-risk (HR: 0.54, 95% CI: 0.30-0.98, p = 0.04) and intermediate-risk groups (HR: 0.57, 95% CI: 0.33-1.00, p = 0.05), but not in patients from the ELN adverse-risk group (HR: 0.93, 95% CI: 0.61-1.43, p = 0.74) [84]. In particular, considering mutations by functional group as previously described [82], GO predominantly improved EFS of patients harboring signaling mutations, (HR: 0.43, 95% CI: 0.28-0.65) [84].…”

Acute myeloid leukemia: 2021 update on risk‐stratification and management

“…Table 1 summarizes scenarios in which the recently approved FDA drugs should be considered “standard of care”. These conform to FDA's bases for approval, supplemented by data published since approval in the cases of midostaurin [27] and gemtuzumab 32 . The table also notes some remaining issues.…”

“…Given the prognostic information added by incorporation of molecular data, 30 Fournier et al 32 compared results in the 7 + 3+/− GO arms of their randomized study (one of the five included in the above meta‐analysis) according to mutational pattern as summarized in the ELN2017 guidelines below 30 and according to individual mutations. They found addition of GO was beneficial in the ELN2017 “favorable” group and the ELN 2017 intermediate group, but not in the ELN2017 adverse group (Figure 6).…”

“…EFS (D) and OS (E) according to protocol arm and the existence of signaling mutations (SIGN+). See reference 32…”