Bispecific antibodies and dual-targeting CAR-T cells for multiple myeloma: latest updates from the 2023 ASCO annual meeting.

Bispecific antibodies (BsAbs) and dual-targeted chimeric antigen receptor T (CAR T) cells have been employed in relapsed/refractory multiple myeloma (RRMM) patients over the past few years, as an increasing number of patients were ineffectively treated by ≥ 3 prior lines of therapy. BCMA/CD3 and GPRC5D/CD3 are the most popular combinations. Clinical findings indicated that patients exhibit a greater susceptibility to stronger and more enduring responses. Here, we summarize the latest data from the 2023 ASCO annual meeting on BsAbs targeting BCMA/CD3, GPRC5D/CD3 and BCMA/CD19 CAR T cells.

A short report of novel RARG-HNRNPM fusion gene in resembling acute promyelocytic leukemia.

BACKGROUND: Resembling acute promyelocytic leukemia (APL) is a unique subtype of APL who sharing clinical, morphological, and immunophenotypic features with typical APL, but lacking evidence of PML-RARA fusion gene and usually insensitive to arsenic trioxide (ATO) and all-trans retinoic acid (ATRA). For years, RARA, RARB and RARG rearrangement were found in resembling APL continually. The confirmed partner genes of RARG rearrangement included CPSF6, NUP98, NPM1, PML, and HNRNPC. These patients were a group of resembling APL with rare molecular genetic abnormality and unfavorable prognosis. They usually were resistant to ATO and ATRA but partially sensitive to anthracycline-based chemotherapy. CASE PRESENTATION: We reported a 25-year-old female patient with a novel fusion gene RARG-HNRNPM (RARG chr12:53606869: -; HNRNPM chr19: 8527413: + based on GRCh37/hg19 Assembly) through RNA-seq as resembling APL. The patient with RARG-HNRNPM was benefited from a combined chemotherapy homoharringtonine, cytarabine, and aclacinomycin (HAA) regimen with no relapse. DISCUSSION AND CONCLUSIONS: RARG rearrangement resembling APL are various. The treatment should be switched from ATRA/ATO to AML combined chemotherapy regimen early.

[NPM1 High Mutant Allele Burden is an Adverse Prognostic Factor for AML Patients with Mutated NPM1].

OBJECTIVE: To investigate the clinical features, accompanying gene mutation characteristics and prognostic factors of adult patients with acute myeloid leukemia with mutated NPM1 (NPM1+AML). METHODS: Seventy-three patients with newly diagnosed adult NPM1+AML were selected. The mutations of 22 genes were detected by second generation sequencing and 43 fusion genes of AML were detected by real-time fluorescent quantitative PCR. The Kaplan-Meier survival curve and Cox multivariate regression analysis were used to study the prognostic factors. RESULTS: A total of 74 NPM1 site mutations were detected in 73 patients with NPM1+AML. The incidence rates were 92.0% L287fs, 2.7% Q289fs and W288fs, 1.4% L258fs and Q289H, among which 1 patient had 2 NPM1 mutations; the different mutation sites had no effect on the prognosis of NPM1+AML. The median value of NPM1 variant allele frequency (VAF) was 35.4% (1.8%-56.6%). Based on the uppermost quartile of 38.4%, the patients were classified as NPM1 VAF>38.4% (NPM1highAML) and NPM1 VAF≤38.4% (NPM1lowAML). Compared with NPM1lowAML, the early mortality rate was statistically significantly higher (33.3% vs 7.3%, P<0.05), and median EFS (148 d，95%CI 58-238 d vs 372 d，95%CI 264-480 d) (P<0.01) and median OS (179 d 95%CI 6-352 d vs 444 d) (P<0.01) were significantly shorter in NPM1high AML. A total of 126 accompanying gene mutation sites were detected in 87.7% of patients with NPM1+AML. The patients with NRAS gene mutation displayed a higher rate of complete remission (100% vs 58%) (P<0.05) and longer median OS (not reached to 320 d, 95%CI 150-490 d) (P<0.05). The 43 fusion genes were examined in 65 out of 73 cases of NPM1+AML, and in all the patients the fusion gene test was negative. Multivariate analysis showed that NPM1 VAF>38.4% was an independent prognostic factor for EFS (HR=3.1, 95% CI 1.6-6.4, P<0.01) and OS (HR=3.0, 95% CI 1.4-6.2, P<0.01). CONCLUSION: The NPM1 gene mutation in AML patients often is accompanied by other gene mutations, while the coexistence of fusion genes is rare; high NPM1 mutant allele burden is an independent prognostic factor for adult AML patients with mutated NPM1.