Haematologica最新文献

Erythropoiesis-stimulating agents (ESA) achieve hematological improvement-erythroid (HI-E) in only 30% of ESA-naïve lower- risk myelodysplastic syndrome (LR-MDS) patients with anemia, highlighting the need for developing novel drugs or new treatment strategies to improve the outcome of these patients. We conducted this multicenter, single-arm trial to investigate the efficacy and safety of a triple regimen consisting of recombinant human erythropoietin (rhEPO), all-trans retinoic acid (ATRA) and testosterone undecanoate in patients with anemia due to lower-risk MDS based on Revised International Prognostic Scoring System. Eligible patients received rhEPO 10,000 IU/day, oral ATRA 25 mg/m2/day and oral testosterone undecanoate 80 mg twice daily for 12 weeks. The primary endpoint was the proportion of patients achieving HI-E during 12 weeks of treatment. Of 52 eligible patients, 32 (61.5%, 95% confidence interval [CI]: 48.0-73.5%) achieved HI-E, meeting the primary endpoint. Fifteen patients (65.2% [15/23]) with baseline serum erythropoietin (EPO) ≤500 IU/L had HI-E versus 58.6% of those (17/29) with baseline serum EPO >500 IU/L. More patients with very low or low risk had HI-E than those with intermediate risk (73.3% vs. 45.5%; P=0.041) and fewer patients with mutated ASXL1 had HI-E than those with wild-type ASXL1 (33.3% vs. 70.0%; P=0.040). The regimen had an acceptable safety profile compatible with individual agents. In conclusion, the triple regimen of rhEPO combined with ATRA and testosterone undecanoate attained HI-E in approximately 61.5% of patients regardless of baseline serum EPO levels, supporting further development of this regimen for LR-MDS patients with anemia. This study was registered at http://www.chictr.org.cn (Identifier: ChiCTR2000032845).

Various drug classes target B-cell maturation antigen (BCMA) including chimeric antigen receptor T-cell (CAR T) therapies, bispecific antibodies (bsAb), and antibody-drug conjugates (ADC). Outcomes with CAR T and bsAb therapies in multiple myeloma (MM) have been affected by T-cell exhaustion, and abrogated expression/mutation of the BCMA target has been observed with anti-BCMA therapies. Optimal anti-BCMA sequencing strategies are needed to improve long-term clinical outcomes. We used data from multiple clinical studies of the ADC belantamab mafodotin (as monotherapy and combination regimens) to explore its impact on BCMA levels and binding (using electrochemiluminescence methodology) and T-cell/ natural killer (NK) cell fitness (including cell counts, expression of functional markers), to determine whether belantamab mafodotin could be sequenced ahead of other BCMA-targeting therapies for MM. Levels of free soluble BCMA (sBCMA), measured at the best-confirmed response (BCR) and at progression, dropped at BCR but returned to near baseline at time of disease progression. There was no apparent impact on the binding epitope of BCMA, as indicated by the retention of belantamab mafodotin binding to sBCMA. No significant changes in cell counts or expression of T-cell exhaustion markers (PD-1, TIGIT, TIM-3 [except NK cells], or CTLA-4) and co-stimulatory markers (ICOS [except CD4+ T cells], OX40, 4-1BB) were observed at relevant time points (up to 4 or 21+ months depending on the marker). No negative impact was observed on expression of proliferation (Ki67) and antitumor activity (granzyme B, CD107a) markers. Pending confirmatory studies, our results indicate potential for utilizing belantamab mafodotin ahead of other anti-BCMA therapies in MM.

Nucleoporin 98 rearrangements (NUP98r) are recurrent in myeloid neoplasms and are subtype-defining for acute myeloid leukemia (AML) in the World Health Organization Classification 5th edition (WHO5) and the International Consensus Classification (ICC). Identification of NUP98r is essential given the frequency of treatment resistance and possibility of sensitivity to targeted therapies. However, NUP98r is often cryptic on karyotype and has over 40 described partners. Therefore, it is underdiagnosed in the absence of dedicated testing that is not always routine practice, e.g., RNA-based next generation sequencing (NGS), NUP98 break-apart fluorescence in situ hybridization, or real-time-quantitative polymerase chain reaction for specific NUP98 fusions. Historically, AML with NUP98r has received the most attention in pediatric AML, where its incidence is highest, but has been increasingly characterized in adult AML. By contrast, the incidence and behavior of NUP98 fusions in myelodysplastic syndromes (MDS) is less understood and based predominantly on case reports. In this study, we describe our adult institutional experience with a clinically validated anchored multiplex PCR RNA-based targeted NGS assay, explore strategies for rational use of specific testing for NUP98r including a proof-of-principle based on WT1 and FLT3- ITD mutational status, and integrate our results with a review of the literature. In total, we identified 3 MDS and 15 AML patients with NUP98r as the genetic driver, including two novel fusion partners (FGF14 and LAMC3), thus highlighting the utility of NGS testing to detect NUP98 fusions. Recognition of NUP98r in myeloid neoplasms is crucial for accurate diagnosis and prognosis, with significant implications for therapy or enrollment in clinical trials.

Allogeneic hematopoietic stem cell transplantation (alloHSCT) from mismatched unrelated donors (MMUD) carries high risks of non-relapse mortality (NRM) and graft-versus-host disease (GvHD). Post-transplant cyclophosphamide (PTCY) has emerged as an alternative to antithymocyte globulin (ATG) for GvHD prophylaxis. This single-center retrospective study compared PTCY (N=41) to high-dose ATG and low-dose ATG in 155 MMUD alloHSCT recipients. PTCY was associated with better overall survival with a 1-year overall survival of 78.7% versus 56.5% in the PTCY and high-dose ATG groups (P=0.007) and 64.8% in the low-dose ATG group (P=0.059), driven by a significant reduction in NRM (P=0.008), with a 1-year NRM in the PTCY group of 7.7% versus 24.4% in the high-dose ATG group (P=0.031) and 29.8% in the low-dose group (P=0.026). The relapse incidence was similar between the groups (17.5% vs. 25.7% and 16.2% for the PTCY, high-dose ATG and low-dose ATG groups, respectively; P=0.830), despite a better progression-free survival in the PTCY group (P=0.034) with 1-year progression-free survival being 78.4% compared with 50.0% in the high-dose ATG group (P=0.002) and 54.0% in the low-dose group (P=0.041). Day-100 grade II-IV and grade III-IV acute GvHD, as well as 1-year chronic GvHD and moderate/severe chronic GvHD were not significantly different. However, 1-year GvHD-related mortality was lower in the PTCY group (2.6% vs. 14.4% and 14.9% in the high- and low-dose ATG groups, respectively; P=0.018). Infection-related mortality was similar across groups, but cytomegalovirus and Epstein-Barr virus infections were less frequent with PTCY, a finding potentially linked to differences in immune reconstitution. Compared to high-dose and low-dose ATG, PTCY prophylaxis was associated with improved overall survival and progression-free survival as well as lower NRM in MMUD alloHSCT.

Patients with myeloid neoplasms with loss-of-function TP53 mutations and erythroid differentiation have poor outcomes, and a better understanding of disease biology is required. Upregulation of interferon-γ (IFN-γ) signaling has been associated with acute myeloid leukemia (AML) progression, selection of TP53 mutated clones and chemotherapy resistance, but its drivers remain unclear. In this study, we found that the surface receptor C-C motif chemokine receptor-like 2 (CCRL2) is over-expressed in AML with erythroid differentiation and TP53 mutations compared to other AML subtypes and healthy hematopoietic cells. CCRL2 knockout (KO) suppressed erythroleukemia growth in vitro and in vivo. Further proteomics and transcriptomics analysis revealed IFN-γ signaling response as the top CCRL2-regulated pathway in erythroleukemia. Our mechanistic studies support direct CCRL2-driven IFN-γ signaling upregulation without a clear effect of exogenous IFN-γ, through phosphorylation of STAT1, which is partially mediated by JAK2. CCRL2/IFN-γ signaling is up-regulated in erythroid leukemias, and TP53 mutated AML and appears to be directly induced by TP53 KO. Finally, CCRL2/IFN-γ signaling is associated with the transformation of pre-leukemic single-hit TP53 clones to multi-hit TP53 mutated AML, increased resistance to venetoclax and worse survival in AML. Overall, our findings support the view that CCRL2 is an essential driver of cell-autonomous IFN-γ signaling response in myeloid neoplasms with erythroid differentiation and TP53 mutations, and highlight CCRL2 as a relevant novel target for these neoplasms.