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Venetoclax plus FLAG-IDA Induction/Consolidation in Newly Diagnosed AML

Conference Correspondent

This phase 1b/2 study (NCT03214562) evaluated the safety and antileukemic activity of the venetoclax (VEN) addition to multiagent induction chemotherapy with fludarabine/cytarabine/granulocyte colony-stimulating factor/idarubicin (FLAG-IDA) in patients with newly diagnosed and relapsed/refractory acute myeloid leukemia (AML) in a single large center in the United States. The phase 2 component of the phase 1b/2 trial enrolled patients into 2 distinct cohorts, 1 consisting of newly diagnosed patients and a second of relapsed/refractory patients. Communicated results from the data analysis in the former cohort are summarized here.

The primary end point was overall response rate (complete response [CR] + CR with incomplete hematologic recovery [CRi] + CR with partial hematologic recovery + morphologic leukemia-free state [MLFS] + partial response); secondary objectives include overall survival (OS), event-free survival (EFS), and duration of response (DOR).

A total of 45 patients with newly diagnosed AML were enrolled in the trial; of these, 33 patients had de novo AML, 7 had secondary AML, and 5 had therapy-related AML. The median age of the overall population was 44 years; 18% had favorable European LeukemiaNet (ELN) risk, 40% had intermediate risk, and 42% had adverse risk. Common genetic alterations included mutations in NRAS, IDH2, RUNX1, NPM1, and TP53.

In the overall cohort, the ORR was 98%, including a 73% CR rate, 11% CRh rate, 4% CRi, and 10% MLFS. The composite CR (CRc) was 89%; 92% of these patients achieved minimal residual disease (MRD) negativity by flow cytometry. Median time to best response was 28 days; median DOR was not reached (NR). With median follow-up of 19 months, median OS and EFS were not reached; 1-year OS rate was 94% and 1-year EFS rate was 77%. By genetic alterations, the 24-month survival rate was 100% in patients with KMT2A rearrangements and 75% in those with AXL1/RUNX1 mutations; patients with TP53 mutations showed significantly inferior OS (19 months vs NR; P = .03) and EFS (8 months vs NR; P <.001) compared with patients with wild-type TP53. At a median of 3.8 months, 67% (n = 30) of patients transitioned to allogeneic stem-cell transplantation. Compared with historical cohorts of intensive induction therapy (fludarabine/idarubicin/cytarabine, n = 74), the FLAG-IDA + VEN regimen was associated with significantly improved OS (12-month OS rate: 94% vs 76%; P = .007).

The most common adverse events included febrile neutropenia (39%), pneumonia (24%), and bacteremia (19%). Four deaths have occurred, all in the setting of relapsed disease. There was no early mortality at 30 or 60 days. A total of 9 patients relapsed, all with intermediate or adverse risk disease per ELN; all 4 patients with TP53 mutations at baseline relapsed.

Based on these results, it was concluded that addition of VEN to the FLAG-IDA regimen yielded high MRD-negative CRc rates in newly diagnosed patients with AML, accompanied by a favorable safety profile. Patients with TP53 mutations did not derive clinical benefit with FLAG-IDA + VEN compared with patients with wild-type TP53.

Source: Lachowiez C, et al. ASH 2021; abstr 701.

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