Luspatercept is a recent breakthrough in the therapy of anemia in low-risk MDS.
From January 2021 to October 2023, 44 patients (median age 77, M/F 25/19, WHO 2016 classification: MDS-RS-MLD 28, ...MDS-MLD -4, RARS-T 8, CMML- 0 2, 5q- + RS 2, IPSS-R: very low 2, low 33, Intermediate 9, IPSS-M (35 pts): very low + low 18, moderate low 11, moderate high 2, high 2, very high 2) were treated with luspatercept. Median follow-up was 13 months (range 1-42). The median number of cycles was 15 (2-42). Transfusion dependency (TD) before luspatercept initiation ranged from 2 transfusion units (TU) to 12 TU/8 weeks. All patients were tested for SF3B1 mutation.
We evaluated 42 patients. Twenty-four (57 %) patients reached TI (>12weekes), 6 (14 %) patients have had a reduction in transfusion need (HI, according to IWG criteria 2006). There were differences in response according to transfusion burden. Significant more responders belonged to lower IPSS-R, IPSS-M categories. In 17 patients, we added ESA (± prednisone), which led to the improvement of response in 12 cases with 9 TI. Four patients died (2-disease progression, 2 for comorbidity). There were no adverse effects of Grade II or more.
We did observed better responses in patients bearing single mutation in SF3B1, in lower IPSS-R and IPSS-M risk categories, patients with LTB and lower initial baseline EPO levels. The higher response rate in our follow-up may be influenced by the combination with ESA and rapid dose escalation.
PU.1 downregulation within hematopoietic stem and progenitor cells (HSPCs) is the primary mechanism for the development of acute myeloid leukemia (AML) in mice with homozygous deletion of the ...upstream regulatory element (URE) of PU.1 gene. p53 is a well-known tumor suppressor that is often mutated in human hematologic malignancies including AML and adds to their aggressiveness; however, its genetic deletion does not cause AML in mouse. Deletion of p53 in the PU.1(ure/ure) mice (PU.1(ure/ure)p53(-/-)) results in more aggressive AML with shortened overall survival. PU.1(ure/ure)p53(-/-) progenitors express significantly lower PU.1 levels. In addition to URE deletion we searched for other mechanisms that in the absence of p53 contribute to decreased PU.1 levels in PU.1(ure/ure)p53(-/-) mice. We found involvement of Myb and miR-155 in downregulation of PU.1 in aggressive murine AML. Upon inhibition of either Myb or miR-155 in vitro the AML progenitors restore PU.1 levels and lose leukemic cell growth similarly to PU.1 rescue. The MYB/miR-155/PU.1 axis is a target of p53 and is activated early after p53 loss as indicated by transient p53 knockdown. Furthermore, deregulation of both MYB and miR-155 coupled with PU.1 downregulation was observed in human AML, suggesting that MYB/miR-155/PU.1 mechanism may be involved in the pathogenesis of AML and its aggressiveness characterized by p53 mutation.
Hereditary haemorrhagic telangiectasia (HHT) exhibits considerable phenotypic heterogeneity. Therefore, precise mutation screening and evaluation of patient risk must be determined in every HHT ...family. We present an HHT-2 case with an initial life-threatening bleeding episode that led to identification of a relatively large HHT family. Exome sequencing of the family members determined HHT-associated ACVRL1C1120T variant resulting in Arg374Trp substitution at the Ser/Thr-kinase domain region. The affected members display typical epistaxis symptomatology from early childhood resulting in sideropoenia. In addition, the HHT patients also displayed dermatology findings such as facial teleangiectasias and trunk/limb white spots representing post-inflammatory hypopigmentation. Interestingly, co-segregating with modifying cytochrome P450 (CYP2C) variant in the HHT patients led to NSAID intolerance marked by increased frequency of bleeding episodes. No arterial-venous malformation of the visceral organs and brain or association with cancer were observed. The heterogeneity of clinical presentation and the role of other variants support the need of regular patient monitoring and development of a nation-wide patient registry.
Epigenetic 5-azacitidine (AZA) therapy of high-risk myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML) represents a promising, albeit not fully understood, approach. Hematopoietic ...transcription factor PU.1 is dynamically regulated by upstream regulatory element (URE), whose deletion causes downregulation of PU.1 leading to AML in mouse. In this study a significant group of the high-risk MDS patients, as well as MDS cell lines, displayed downregulation of PU.1 expression within CD34+ cells, which was associated with DNA methylation of the URE. AZA treatment in vitro significantly demethylated URE, leading to upregulation of PU.1 followed by derepression of its transcriptional targets and onset of myeloid differentiation. Addition of colony-stimulating factors (CSFs; granulocyte-CSF, granulocyte-macrophage-CSF and macrophage-CSF) modulated AZA-mediated effects on reprogramming of histone modifications at the URE and cell differentiation outcome. Our data collectively support the importance of modifying the URE chromatin structure as a regulatory mechanism of AZA-mediated activation of PU.1 and induction of the myeloid program in MDS.
We report the full analysis of the COMMANDS trial assessing efficacy and safety of luspatercept versus epoetin alfa (EA) in ESA-naive patients with LR-MDS.
363 patients (aged ≥18 y, with ...transfusion-dependent LR-MDS, serum erythropoietin <500 U/L) were randomized 1:1 to luspatercept or EA. Primary endpoint was achievement of red blood cell transfusion independence (RBC-TI) ≥12 wk with concurrent mean hemoglobin increase ≥1.5 g/dL (wk 1–24). Secondary endpoints included achievement of RBC-TI ≥12 and 24 wk, hematologic improvement–erythroid (HI-E) ≥8 wk (wk 1–24), RBC-TI ≥12 wk duration, and safety.
As of 31Mar2023, 110/182 (60.4%) luspatercept-treated versus 63/181 (34.8%) EA-treated patients achieved the primary endpoint (P<0.0001). Primary endpoint achievement favored luspatercept in most subgroups including region. Median (range) treatment duration was 51.3 (3–196) and 37.0 (1–202) wk for luspatercept versus EA. 68.1% and 48.6% of luspatercept- versus EA-treated patients, respectively, achieved RBC-TI ≥12 wk; 47.8% and 30.9% achieved RBC-TI 24 wk; 74.4% and 53.0% achieved HI-E ≥8 wk. Median (95% CI) duration of RBC-TI ≥12 wk was 128.1 wk (108.3–not estimable NE) with luspatercept versus 89.7 wk (55.9–157.3) with EA (HR, 0.534; Figure). 2.7% and 3.3% of luspatercept- and EA-treated patients, respectively, progressed to AML; 97.8% and 92.2% reported any-grade treatment-emergent adverse events (TEAEs); 58.5% and 49.2% reported grade 3/4 TEAEs. Death rates on- and post-treatment were similar between arms.
RBC-TI duration and erythroid responses achieved with luspatercept were superior to EA. Luspatercept safety results were consistent with previous MDS studies.
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