Hypomethylating Agent Therapy plus Venetoclax plus FLT3 Inhibitor Was Active in Older/Unfit Patients with FLT3-Mutated AML

A single-institution retrospective study analyzed outcomes with addition of venetoclax (VEN) to low-intensity chemotherapy (LIC) + FLT3 inhibitors (triplet regimen) versus LIC + FLT3 inhibitor (doublet regimen) in newly diagnosed older/unfit patients with FLT3-mutated acute myeloid leukemia (AML) enrolled in clinical trials.

This study identified older or unfit adult patients with newly diagnosed FLT3-mutated AML who received FLT3 inhibitor–based LIC treatment in clinical trials between June 2012 and March 2021. Eligible patients must also have had ≥2 bone marrow assessments, including at baseline, end of the first cycle of therapy, and/or later during therapy. Minimal residual disease (MRD) assessments were performed using multicolor flow cytometry (MFC; sensitivity threshold of 10-4) and multiplex polymerase chain reaction (PCR; sensitivity of 10-2-10-3).

A total of 87 patients were identified; of these, 60 (69%) patients received doublet and 27 (31%) received triplet regimens. Baseline clinical characteristics were generally similar between the 2 cohorts.

In the doublet group (n = 60), 83% of LIC was hypomethylating agent (HMA)-based and 17% was low-dose cytarabine (LDAC)-based; 44 (73%) received a first-generation FLT3 inhibitor (34 sorafenib, 16 midostaurin) and 16 (27%) received a second-generation FLT3 inhibitor (quizartinib). Among patients treated with first- or second-generation FLT3 inhibitor─based doublets, there was no statistically significant difference in complete response (CR)/CR with incomplete hematologic recovery (CRi; 88% vs 64%) or MRD negativity rates (by either FLT3-PCR or MFC).

In the triplet group (n = 27), 12 (44%) patients received gilteritinib, 10 (37%) received sorafenib, 4 (15%) received quizartinib, and 1 (4%) patient received midostaurin combined with HMA-VEN. Compared with patients who received the doublet regimen, those who received the triplet regimen achieved significantly higher CR/CRi rates (93% vs 70%; P = .02) and MRD rates by FLT3-PCR (96% vs 54%; P <.01) and MFC negativity (83% vs 38%; P <.01) rates. The triplet HMA-VEN-FLT3 inhibitor regimen (follow-up time of 12 months) was associated with significant OS improvement compared with the HMA-VEN doublet regimen (follow-up time of 50 months), with median OS not reached versus 9.5 months (P <.01). The 60-day mortality rate was comparable between the 2 cohorts (7% vs 10%).

A higher proportion of patients underwent allogeneic stem-cell transplantation (allo-SCT) following the triplet regimen versus the doublet regimen (29% vs 10%). In a landmark analysis at 4 months (n = 50), patients who received allo-SCT in their first CR had superior OS versus patients who did not (not reached vs 19.5 months; P = .01). Moreover, patients who received doublet regimen derived OS benefit from allo-SCT.

Based on these results, it was concluded that the triplet regimen of HMA-VEN-FLT3 inhibitor led to significant improvement in CR/CRi rates, MRD rates, and OS in older/unfit patients with FLT3-mutated AML, without increase in early mortality.

Source: Yilmaz M, et al. ASH 2021; abstr 798.

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