Abstract B-cell maturation antigen (BCMA)– and G protein–coupled receptor class C group 5 member D (GPRC5D)–directed therapies have shown high efficacy in the treatment of relapsed or refractory multiple myeloma, with multiple new immune therapies now approved. Preclinical studies have shown that the expression of BCMA and GPRC5D is heterogeneous in malignant plasma cells. We conducted a phase 1 dose-escalation trial of the BCMA chimeric antigen receptor (CAR) T-cell therapy MCARH125 alone or in combination with the GPRC5D CAR T-cell therapy MCARH109 in patients with relapsed or refractory multiple myeloma. Patients were treated across 3 dose levels, with the primary objective of establishing the safety of concurrent infusion. We treated 15 patients across 3 dose levels, including 6 patients who received MCARH125 alone and 9 patients treated with the concurrent infusion of MCARH125 and MCARH109. One patient each with MCARH 125 alone and the coinfusion of MCARH125 and MCARH109 developed immune effector cell–associated hemophagocytic syndrome. There were no instances of grade ≥3 cytokine release syndrome or immune effector cell–associated neurologic syndrome. The overall response for coinfusion was 78%, with a median progression-free survival of 18.2 months. Correlative analysis suggests that antigen loss may be an important mechanism of resistance even with dual-antigen targeting, and we show, to our knowledge for the first time that expansion of 1 CAR population may limit expansion of the second population because patients treated with dual CARs had significantly less BCMA CAR expansion compared with patients treated with BCMA CAR alone, despite equivalent BCMA CAR T-cell doses at infusion. This trial was registered at www.clinicaltrials.gov as NCT05431608.
In randomized studies, addition of FLT3 inhibitors failed to improve survival in older patients with FLT3-ITD AML unfit for intensive chemotherapy. Although hypomethylating agents or low-dose cytarabine combined with venetoclax is standard, FLT3-ITD is an important mechanism of resistance and a barrier to improved survival. Recent studies show promise for the addition of gilteritinib or quizartinib to less intensive venetoclax-based therapy, however resulting marrow toxicity requires substantial reductions to administered treatment. The INTERVENE study (Investigating Novel Triplets to Extend Remission with VENetoclax in Elderly AML) (ACTRN12619001655134) examined the role of midostaurin (M) administered sequentially after low-dose cytarabine (L) combined with venetoclax (V) in patients with newly diagnosed AML ≥60 years with non-adverse karyotype. After a run-in phase (n=18) established that LDAC combined with venetoclax from days 1-28 and midostaurin from days 11-28 was tolerable, 120 patients were randomized 2:1 to receive either LVM or LV. For the primary endpoint, LVM did not improve composite complete remission (CRc), compared to LV (72% vs 68%). Combining midostaurin with LV enhanced CRc among the sub-group of patients (n=29) with FLT3-ITD (82% vs 57%, difference = 25%, 0.85 posterior probability true difference > 5%, 95% CrI: -10 to 59%) and improved FLT3-ITD clearance as measured by ultrasensitive NGS (65% vs 0%), resulting in longer OS (median 24.2 vs 8.8 months, HR=0.34, 95% CrI: 0.071 to 0.960), compared to LV. In conclusion, midostaurin combined with low-dose cytarabine and venetoclax is well-tolerated and may have a role in newly diagnosed FLT3-ITD AML unfit for intensive chemotherapy.
Gene therapy for hemophilia A (HA) aims to provide durable hemostatic control and reduce treatment burden, but AAV-based products to date have limitations: inconsistent peak expression, declining factor levels, and immunogenicity causing transaminitis and expression loss. ASC618 (ASC Therapeutics, Milpitas, CA, USA) was developed as a second-generation gene therapy product to overcome some of these limitations, using ET3, a bioengineered chimeric human/porcine B-domain-deleted FVIII transgene, paired with a minimal liver promoter and liver codon optimization. In a phase 1/2 trial (NCT04676048), two patients received ASC618. Despite initial factor expression, both developed high-titer FVIII inhibitors and are now maintained on emicizumab prophylaxis. Although inhibitor titers have declined, both remain high-titer nearly two years after a single infusion. The best explanation for inhibitor formation is that the novel FVIII with the human-porcine hybrid construct (ET3) contained epitopes for which these patients had not developed tolerance despite both having more than 1000 exposure days to exogenous FVIII in the past. Although this trial has been halted, these cases provide important lessons for the development of future hemophilia gene therapies. They highlight the need for careful immunogenicity assessment when using bioengineered transgenes, even in previously treated patients with extensive factor VIII exposure.
RAS mutations are recurrent in acute myeloid leukemia (AML); yet, their genomic and clinical landscape remain poorly characterized. We analyzed centralized molecular profiling data in 8,553 patients with newly diagnosed AML. Of these, 1,775 (21%) harbored RAS mutations: NRAS in 1,103 (13%), KRAS in 445 (5%), and both in 227 (3%). RAS mutations primarily clustered in P-loop hotspots (G12/G13, 70%), with NRAS showing higher Q61 mutation prevalence (24% vs. 9%) and KRAS showing additional K117/A146 hotspots. Multiple RAS mutations occurred in 23% of patients. Convergent evolution of RAS signaling mutations emerged as a key feature of RASmut AML. RTK/RAS pathway mutations were non-uniformly enriched: PTPN11, KIT and FLT3-TKD mutations were positively associated, CBL mutations showed no association, and FLT3-ITD mutations were negatively associated. The prognostic impact of RAS mutations was dependent on the genomic background and treatment. In multivariate analyses in intensively treated patients, NRAS mutations showed opposing associations with overall survival (OS): adverse in patients with AML, myelodysplasia-related (HR=1.32, p=0.036) and favorable in those with NPM1 (HR=0.61, p=0.036) or FLT3-ITD (HR=0.63, p=0.048) mutations, among others. KRAS mutations predicted inferior OS (HR=1.41; p=0.003). In patients treated with non-intensive, venetoclax-based regimens, RAS mutations were associated with markedly inferior OS in patients with NPM1 (HR=2.98, p=0.007) or IDH1/2 mutations (HR=4.06, p<0.001). These data inform risk stratification and development of RAS-targeting strategies in AML.
