At present, there are no approved targeted therapies for KMT2Ar acute myeloid leukaemia (AML) which carries a poor prognosis with an OS of approximately 6 months.1 The interaction between menin and KMT2A is a key driver of leukemogenesis. Revumenib, a menin inhibitor, has previously shown a manageable safety profile and clinically meaningful responses in a phase I study.2 Based on this, the phase II AUGMENT-101 study enrolled patients aged ≥30 days with relapsed/refractory (R/R) KMT2Ar AML who then received revumenib q12h with a strong CYP3A4i in 28-day cycles.1
These patients were heavily pre-treated or resistant to standard therapy. At a median follow up of 6.1 months, the interim analysis reported an overall response rate (ORR) of 63% in the efficacy population. The primary endpoint of CR with complete haematologic response (CR+CRh) was met with a rate of 23%. This CR+CRh rate was similar for patients aged above and below 18 years of age (23% [95% CI: 12-38] vs. 23% [5-54]). Of note, the number of patients per subgroup was low and this study was not powered to look at differences between subgroups. The median OS was 8 months and the median time to CR+CRh was 1.87 months [0.9-4.6]. In terms of safety, 10% of patients had a dose reduction, and 13% discontinued due to treatment-emergent adverse events (TEAE), only 6% of which were due to treatment-related adverse events (TRAE). Febrile neutropenia was the most common grade ≥3 adverse event (AE) (37%). Overall, revumenib led to a high remission rate with a manageable safety profile in both paediatric and adult patients with R/R KMT2Ar AML and this study was concluded early due to meeting the primary efficacy endpoint.
Venetoclax (VEN) and azacitidine (AZA) are responsible for a paradigm shift in treating older patients with AML. However, long-term outcomes are still poor with a 2-year OS of approximately 38% and high relapse rates.3 The potential of the menin-KMT2A inhibitor revumenib in combination with VEN + AZA was investigated in 24 patients with untreated AML aged ≥60 years (median age 70 years) with NPM1mut or KMT2Ar who were ineligible for intensive induction therapy.3 Here, a dose escalation based on dose-limiting toxicities (113 mg Q12h + strong CYP3A4 inhibitor azole or 163 mg Q12h + strong CYP3A4 inhibitor azole) and dose expansion were performed.
At the time of the update at EHA 2024, one haematologic dose-limiting toxicity was noted in the 113 mg group (thrombocytopenia). The median duration of induction until initiation of the continuation phase was 36 days, with 80% of patients experiencing a delay due to cytopenia. However, notably there was no time difference to this initiation between the doses, suggesting that the cytopenias were related to the VEN + AZA combination. Thirteen total dose reductions were implemented (six revumenib, five VEN, two AZA). Furthermore, 96% of patients achieved a composite CR with 88% of patients achieving remission following one induction. From this study it is evident that revumenib can be dosed safely with VEN + AZA and is highly active in this patient population. A randomised phase III trial is currently being planned.
Another study investigated the menin-KMT2A inhibitor bleximenib, in combination with VEN and AZA, in R/R KMT2A/NPM1 AML.4 This builds on a previous phase I study reporting the efficacy of bleximenib in patients with R/R KMT2A/NPM1 AML.5 While this was a multi-arm trial, the dose escalation results of the cohort of patients with R/R KMT2A/NPM1 AML who received bleximenib (15 mg-100 mg BID) + VEN + AZA (28-day cycle) were presented at EHA 2024. Importantly, in this cohort 48% of patients had received prior VEN therapy. Of the patients enrolled, 50% had KMT2A alteration and 50% had NPM1 alteration. In terms of safety, the most common grade ≥3 AE was febrile neutropenia (37%). Only one patient had a dose-limiting toxicity (50 mg dose; grade 5 differentiation syndrome), while two patients had differentiation syndrome (100 mg dose; grade 3, 50 mg dose; grade 5) and only one patient had grade 3 tumour lysis syndrome during VEN ramp up. Of note, the recommended phase II dose is still being determined as dose escalation is ongoing.
For the efficacy cohort, only patients receiving 50 mg BID or more and who had KMT2Ar/NPM1m were included (n= 34). In total, 93% of patients had at least a 50% reduction in bone marrow blasts and an ORR of 79%. Median time to first response was 0.8 months (0.5-1.9). In patients who had received prior VEN therapy (n= 17), an ORR of 65% was seen. This study demonstrated the ability to combine bleximenib with standard doses of VEN and AZA in this patient population.
New treatment strategies are highly sought after and there is some evidence supporting the addition of VEN to less intensive regimens to improve patient outcomes.6,7 A phase II trial in patients with newly diagnosed or R/R AML who were fit for intensive therapy investigated the potential of the addition of VEN to FLAG-IDA.8 Patients were excluded if they had received prior therapy with VEN. Induction comprised of filgrastim (5 mcg/kg; d1-7), fludarabine (30 mg/m2; d2-6), cytarabine (1.5 g/m2; d2-6), idarubicin (8 mg/m2 for newly diagnosed, and 6 mg/m2 for R/R; d4-6) (FLAG-IDA), with VEN (start at 100 mg d1, 200 mg d2, 400 mg d3; d1-7). CYP3A inhibitors should be avoided during VEN treatment, however, if necessary, the dose of VEN may be adjusted accordingly (moderate inhibitor: 200 mg; strong inhibitor: 100 mg; posaconazole: 50-70 mg). Consolidation therapy consisted of filgrastim (5 mcg/kg; d1-7), fludarabine (30 mg/m2; d2-4), cytarabine (1.5 g/m2; d2-4), idarubicin (6 mg/m2; d3-4), and VEN (400 mg; d1-7).
For patients with newly diagnosed AML, there was an ORR of 99% with a CR of 82%. At a median follow up of 30 months, neither the median OS nor the median EFS were reached. Further, 57% of newly diagnosed AML patients proceeded to SCT, which improves outcomes, with two-year OS rates of 80% and 44% in those who did and did not undergo SCT, respectively (p= 0.03). In the R/R population, the ORR was 68% with 41% achieving CR. At a median follow up of 27 months, the median OS was 12 months and median EFS was 7 months. The median time to SCT in the R/R population was 3.2 months and the one-year OS was 74% vs. 6% in those who did or did not proceed to SCT, respectively. Patients with newly diagnosed AML with KMT2Ar responded better than those with R/R AML with KMT2Ar (CR 67% vs. 17%), highlighting the need for novel treatment strategies for this patient population. The most observed grade ≥3 AE was infection (80%), followed by gastrointestinal toxicities (16%). Overall, FLAG-IDA +VEN displays good activity in both newly diagnosed and R/R AML. In newly diagnosed AML, it demonstrates efficacy across ELN risk groups, whereas in the R/R setting, it is particularly effective in first salvage, TP53WT patients.
The ENHANCE-3 study is a randomised phase III study investigating the potential of magrolimab, an mAb targeting CD47, in combination with VEN + AZA vs. placebo + VEN + AZA in patients with previously untreated AML ineligible for intensive chemotherapy.9 In total, 178 patients (median age 75 years) were randomised 1:1 to receive either magrolimab + VEN + AZA or placebo + VEN + AZA. This study was stopped early at a prespecified interim due to futility. After a median follow-up of 7.6 months in the magrolimab arm and 7.4 months in the placebo arm, no significant difference in OS was noted (10.7 months [8.7-14.9] vs.14.1 months [9.7-NE], HR[95% CI]: 1.178 [0.848-1.637], p= 0.3276, respectively). The CR rate within six cycles of treatment was 41.3% vs. 46.0% in magrolimab and the placebo arm, respectively. In total, 5.8% of patients in the magrolimab arm and 6.9% in the placebo arm continued to SCT. Grade ≥3 AEs were observed in 97.4% of patients in the treatment arm vs. 97.3% in the placebo arm, however, the incidence of TEAE’s leading to death were higher in the treatment arm (19% vs. 11.4%). The main cause of these TEAE deaths was infection (11.1% vs. 6.5% in placebo arm). This study does not support the use of magrolimab in this treatment population.
The QUANTUM-FIRST trial assessed the impact of continuation therapy on quizartinib, which has received approval in the US, EU, UK, and Japan for use in combination with chemotherapy or as continuation monotherapy for patients with newly diagnosed FLT3-ITD-positive AML.10 In this study, 539 patients were randomised 1:1 to receive either quizartinib (40 mg; d8-21) + cytarabine (d1-7) + daunorubicin or idarubicin (d1-3), or placebo with cytarabine (d1-7) + daunorubicin or idarubicin (d1-3) for induction. This was followed by consolidation with quizartinib or placebo with HiDAC (d1,3,5) and/or allo-HCT and continuation with quizartinib or placebo. The 36-months relapse-free survival (RFS) for the quizartinib group was 67.1% vs. 59.6%, while the median RFS was NR in the placebo group (48.6 months in quizartinib group). The cumulative incidence of relapse at 36 months was 25.9% vs. 34.4% in the placebo arm. While the median OS was NR in either group (HR[95% CI]: 0.683[0.395-1.183]), the 48-month OS was 76.3% vs. 67.9% for quizartinib vs. placebo, respectively. For patients who had prior allo-HCT and received continuation therapy (quizartinib n= 70 vs. placebo n=49), the median OS was NR in both groups (HR[95% CI]: 1.622[0.623-4.220]). In patients who had not received allo-HCT, the median OS was NR in the quizartinib arm vs. 42.5 months (HR[95%]: 0.401[0.192-0.838]). In terms of grade ≥3 TEAE’s, there was a rate of 78.4% vs. 57.6% in the placebo arm with TEAE’s leading to dose reduction also being higher in the quizartinib arm (36.2% vs. 15.2%). The most commonly observed grade ≥3 TEAE was neutropenia (31% in quizartinib arm vs. 4.3% in the placebo arm). In conclusion, the QUANTUM-FIRST trial reported a numerically superior OS, higher RFS rates, and lower cumulative incidence of relapse rates in the quizartinib arm.
Finally, at EHA 2024, the final 5-year results from the pivotal cohort of the phase II trial NCT02719574 were presented.11 This study investigated safety and efficacy of olutasidenib (150 mg BID) in patients with R/R mIDH1 AML (n= 153). The primary endpoint (CR/CRh) was 35% (p< 0.001) and 32% of patients achieved CR with a median time to CR of 2.8 months. An ORR of 48% was observed. The duration of response for patients who achieved CR/CRh was at least 12 months for approximately 66% of patients. Platelet transfusion independence (for >56 days) was achieved in 41% of patients who were transfusion dependent at baseline. The median OS was 11.6 months in the overall population but was NR in patients who achieved CR/CRh. Furthermore, 11% of patients continued to receive SCT following treatment with olutasidenib. In patients with prior VEN treatment (n= 12), CR/CRh was achieved in 33% and an ORR of 50% was observed along with a median OS of 16.2 months. At 5-years follow up, the most common AE was nausea (39%). This study further demonstrates and supports the safety and efficacy of olutasidenib in heavily pretreated patients with mIDH1 AML.
References
1. Issa GC, et al. Revumenib monotherapy in patients with relapsed/refractory KMT2Ar acute leukemia: topline efficacy and safety results from the pivotal AUGMENT-101 phase 2 study. Presented at EHA 2024; Abstract S131.
2. Issa GC, et al. The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia. Nature. 2023;615:920-4.
3. Zeidner J, et al. Phase 1b study of azacitidine, venetoclax and revumenib in newly diagnosed older adults with NPM1 mutated or KMT2A rearranged AML: interim results of dose escalation from the BEATAML consortium. Presented at EHA 2024; Abstract S134.
4. Wei AH, et al. A phase 1b study of the MENIN-KMT2A inhibitor JNJ-75276617 in combination with venetoclax and azacitidine in relapsed/refractory acute myeloid leukemia with alterations in KMT2A or NPM1. Presented at EHA 2024; Abstract S133.
5. Jabbour E, et al. A First-in-Human Phase 1 Study of the Menin-KMT2A (MLL1) Inhibitor JNJ-75276617 in Adult Patients with Relapsed/Refractory Acute Leukemia Harboring KMT2A or NPM1 Alterations. Presented at ASH 2023; Abstract 57.
6. DiNardo CD, et al. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N Engl J Med. 2020;383:617-29.
7. Chua CC, et al. Chemotherapy and Venetoclax in Elderly Acute Myeloid Leukemia Trial (CAVEAT): A Phase Ib Dose-Escalation Study of Venetoclax Combined With Modified Intensive Chemotherapy. J Clin Oncol. 2020;38:3506-18.
8. Wei-Ying J, et al. FLAG-IDA + venetoclax (ven) in newly diagnosed (ND) or relapsed / refractory (RR) AML. Presented at EHA 2024; Abstract S136.
9. Naval D, et al. Magrolimab vs placebo in combination with venetoclax and azacitidine in previously untreated patients with acute myeloid leukemia who are ineligible for intensive chemotherapy: the ENHANCE-3 study. Presented at EHA 2024; Abstract S138.
10. Sekeres MA, et al. QUANTUM-FIRST: Efficacy in newly diagnosed patients with FMS-like tyrosine kinase 3-internal tandem duplication–positive (FLT3-ITD+) acute myeloid leukemia (AML) who received continuation therapy. Presented at EHA 2024; Abstract S142.
11. Cortes J, et al. Olutasidenib for mutated IDH1 acute myeloid leukemia: final five-year results from the phase 2 pivotal cohort. Presented at EHA 2024; Abstract S144.
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