Selected Articles from This Issue

Chronic myelomonocytic leukemia (CMML) is a rare clonal myeloid neoplasm. Preclinical studies have shown CMML to be sensitive to GM-GSF signaling and JAK inhibition. To this end, Hunter and colleagues conducted a phase I and II clinical trial testing ruxolitinib, a JAK1/2 inhibitor that downregulates GM-CSF signaling, in patients with CMML. Ruxolitinib was well tolerated in this patient population, and an overall response rate of 38% was observed. A parallel study of patient-derived xenografts from patients enrolled on the clinical trial corroborated the in-human findings. These results support further clinical study of ruxolitinib for the treatment of CMML.

In tumors with BRCA1/2 mutations, homologous repair deficiency causes inability to repair DNA double-strand breaks. PARP inhibitors (PARPi), such as olaparib, have proven to be effective in BRCA-mutated ovarian, breast, pancreatic and prostate cancer. van der Wijngaart and colleagues conducted a clinical trial of olaparib in patients with tumors harboring BRCA1/2 mutations regardless of histological subtype. Of 24 evaluable patients with 9 different tumor types, 58% had clinical benefit from olaparib. Clinical benefit was observed in patients with complete loss of function of BRCA1/2, as well as in patients with biallelic BRCA loss of function. These data indicate that PARp. is a promising treatment strategy for patients with non-BRCA-associated cancer subtypes harboring biallelic BRCA loss of function, although further clinical trials are needed.

Tafasitamab, a humanized anti-CD19 monoclonal antibody, demonstrated efficacy in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who were ineligible for transplant (L-MIND) in combination with lenalidomide (LEN). However, the lack of a control arm in this trial prevented the evaluation of the contribution of tafasitamab to the efficacy of this combination. To address this question, Zinzani and colleagues conducted a retrospective observational study to establish a historical control for the L-MIND dataset. The investigators collected data from 140 patients treated with LEN monotherapy who qualified for matching with the L-MIND cohort. LEN monotherapy led to poorer objective response rates (34.2%) and complete response rates (13.2%) compared with combination therapy (67.1% and 39.5%, respectively). These analyses reveal the benefit of the addition of tafasitamab to LEN in DLBCL and support further study of this combination.

RAF-targeted therapy is generally effective in patients with BRAF^V600E-mutated glioma, although resistance occurs via heretofore unidentified mechanisms. To address this open question, Schreck and colleagues assessed RAF-mutant gliomas via genomic analysis of paired tissue from before and after RAF inhibitor (RAFi) treatment. Alterations conferring putative resistance were identified, including mutations in ERRFI1, BAP1, ANKHD1, and MAP2K1, and in vitro experiments confirmed the relationship between these mutations and RAFi resistance. These data highlight the utility of genomic profiling to identify resistance mechanisms and appropriate targeted therapy at the time of progression. Further clinical assessment of this personalized approach in glioma is warranted.