Most acquired idiopathic bone marrow failure syndromes (BMFS) are thought to be cytotoxic T cell-mediated and are responsive to immunosuppressive therapies (IST) targeting T cells. However, in addition to frequent relapses, a proportion of cases remain refractory to first- and second-line agents due to a lack of clinical trials in the refractory and relapsed disease setting. Recently, the landscape of IST has expanded significantly, harnessing multiple molecular pathways that could be theoretically useful in the BMFS setting. In this manuscript, we retrospectively analyzed clinical responses to selected salvage IST, including sirolimus, tofacitinib, and subcutaneously administered abatacept and alemtuzumab, in a cohort of 151 patients with aplastic anemia, pure red cell aplasia, large granular lymphocytic leukemia, and other rare hypoproliferative BMFS. Our results indicate significant salvage rates with these agents and differential efficacy in specific clinical scenarios, showing differences in responses in affected lineages and in different disease states. We report that different modalities of IST may have lineage-restricted and overall responses in relapsed or refractory BMFS states, and durable response can be achieved in clinically difficult cases. These findings underscore the need for clinical trials to establish the safety and efficacy of alternative agents as substitute lines of therapy in BMFS.
Relcobatinib (ELVN-001) is a next-generation, investigational, BCR::ABL1 active-site tyrosine kinase inhibitor (TKI) with a unique P-loop folded-in binding mode designed to deliver best-in-class efficacy with an improved tolerability profile over that of other TKIs for the treatment of chronic myeloid leukemia (CML). We demonstrate that relcobatinib has marked selectivity for BCR::ABL1, without inhibition of off-target kinases implicated in toxicities related to other TKIs. Relcobatinib exhibited greater selectivity than other active-site TKIs and demonstrated robust activity in vitro against native BCR::ABL1 and a broad range of clinically relevant TKI-resistant mutants. A BCR::ABL1 mouse xenograft model of human CML showed marked anti-tumor activity with relcobatinib as monotherapy, and, in combination with asciminib, showed further durable tumor regression, supporting the complementary mechanism of action between an active-site TKI and an allosteric inhibitor. Collectively, the preclinical profile of relcobatinib, marked by selective BCR::ABL1 targeting, supports its potential to improve efficacy and tolerability in the treatment of CML and other BCR::ABL1-driven malignancies, as monotherapy and in combination with an allosteric inhibitor.
Myeloproliferative neoplasms (MPNs) are chronic diseases characterized by an excessive production of myeloid blood cells. Janus kinase (JAK2)V617F is the most common mutation in MPNs but a substantial proportion of patients harbour calreticulin (CALR) mutations—an attractive target for emerging immunotherapies. Natural killer (NK) cells have a central role in the elimination of malignant cells, but NK cells of MPN patients have reduced activity. Thus, reactivating their function might improve the disease outcome. Here, we demonstrate that NK cells from a CALR-mutant mouse model exhibit normal maturation but enhanced degranulation. Consistently, NK cells from CALR-mutant patients exhibit preserved degranulation ability, exceeding that observed in JAK2-mutant patients. Notably, NK cells from CALR-, but not JAK2-mutant patients express high levels of the immune checkpoint TIGIT possibly due to increased abundance of immunomodulatory proteins in the plasma. Moreover, CD34⁺ cells from MPN patients express elevated levels of the TIGIT ligand CD112. TIGIT blockade results in reduced platelet numbers in a transplant mouse model. These findings suggest that NK cells in CALR-mutant MPNs are activated but functionally constrained when encountering TIGIT ligand–expressing target cells, providing a strong rationale for exploring TIGIT blockade to restore NK-cell immunity in this disease subset.
