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Allogeneic hematopoietic stem cell transplantation (HSCT) is considered the only a curative treatment in patients with higher risk myelodysplastic syndrome (MDS), although demethylating agents (DMA) have been reported to improve survival. The advantage of HSCT over other treatment comes from retrospective studies and the aim of the current study was to prospectively test this hypothesis, analyzing in particular patients from the pre-transplant period to avoid the selection bias of performing transplantation. This study was conducted to compare overall survival in MDS patients candidates to transplantation according to donor availability. The majority of patients (76%) received a treatment with DMA after registration, 69% had a human leukocyte antigen (HLA)-identical donor, 70% of whom were transplanted. Baseline patient and disease characteristics were similar according to donor availability. Four-year overall survival was significantly better in patients with an HLA matched donor (37%) compared to patients without donor (15%). There was also evidence that this overall survival advantage was because of transplantation. Mortality risk was decreased after transplantation but it became significant only after the second year post transplant, because of early transplant-related mortality. Our results appear to justify, in higher risk MDS, a transplantation approach in all potential candidates who have an HLA identical donor.

In core binding factors (CBF) acute myeloid leukemia (AML), the disruption of CBFalpha/beta genes impairs normal hematopoietic differentiation and is supposed to cooperate with additional mutations promoting proliferation. The incidence and the prognosis of receptor tyrosine kinase (RTK) c-Kit and FLT3 mutations and Ras mutations were evaluated in 103 pediatric and adult patients with CBF-AML. c-Kit mutations were present in 17% patients. c-Kit exon 8 mutations were more frequent in inv(16) than in t(8;21) subset (20 versus 6%). Only one patient had FLT3-ITD but FLT3-D835 was as frequent as reported in AML population (7%). Ras mutations were significantly more frequent in inv(16) than in t(8;21) subset (36 versus 8%, P=0.001). RTK mutations were associated with a higher white blood cell count (WBC) (36 versus 21 G/L, P=0.05). FLT3 mutations were significantly associated with a shorter EFS and survival (P<0.0001 and P=0.0002) owing to an excess of early events. c-Kit mutations were associated with a shorter EFS and RFS (P=0.002 and P=0.003) in t(8;21) but not inv(16) patients. As previously observed, Ras mutations did not affect prognosis. Screening for RTK mutations may help to identify patients with a more adverse outcome and thus susceptible to benefit from intensified protocols or RTK inhibitors.

BackgroundAutoimmune and inflammatory diseases (AID) are associated with myeloid malignancies[1], and include both organ-specific diseases and systemic inflammatory disorders. While the occurrence of associated AID reaches up to 15-20% in myelodysplastic neoplasms (MDS) patients[2,3], its prevalence in the context of myeloproliferative neoplasm (MPN) remains unknown. In patients with a history of AID, the risk of developing MPN was increased[4], suggesting a correlative link between the two disorders, but data regarding the characterization of AID in MPN patients remain scarce and the lack of studies prevents from identifying potential risk traits that may underline a common physiopathology.ObjectivesWe conducted a single center retrospective study to describe the prevalence, clinical and biological features of AID in MPN patients. We also reported the mutational landscape of MPN with associated AID, along with its prognostic impact.MethodsAll patients with a diagnosis of Philadelphia-negative MPN according to the World Health Organization’s criteria, followed between January 2011 and January 2021 in our center were included. Clinical and biological characteristics at the time of diagnosis and follow-up were collected. Next-generation targeted sequencing was performed targeting a panel of 36 genes involved in myeloid malignancies. AID diagnosis was based on recommended international criteria specific to each AID. Patients with interferon-alpha-induced AID were excluded from this study.ResultsA total of 1541 MPN patients were included, including 95 (6%) patients with AID who were compared to the remaining 1446 (94%) patients without AID. Median age was 51.6 [6.6; 98.3] years at MPN diagnosis in the whole cohort. Female patients were predominant within the AID group (62 (65%) versus 773 (54%), p=0.03). Within the AID cohort, a total of 103 diagnoses of AID were reported in 95 patients, including 48 organ-specific AID (47%) (autoimmune hypothyroidism (n=33), inflammatory bowel diseases (IBD, n=7), neuroinflammatory disorders (n=4), autoimmune cytopenia (n=2), glomerulonephritis (n=1) and pernicious anemia (n=1)), 13 inflammatory arthritis (13%), 9 connective tissue diseases (9%), 9 dermatosis (9%), 6 systemic vasculitis (6%) and 18 unclassified AID (17%). Molecular sequencing was performed in 998/1541 (65%) patients and the prevalence of driver and additional mutations did not differ between the MPN with or without AID. The prevalence of TET2 mutations was higher in the AID cohort (21/65, 32% versus 208/993, 22%), although not reaching statistical significance (p=0.08). After a median follow-up of 8.3 IQR[3.7-14.3] years, the association with AID did not impact overall survival (p= 0.67), MDS/AML transformation free survival (p=0.37) or secondary myelofibrosis-free survival (p=0.91).ConclusionOur data suggest that the prevalence of AID is similar in MPN patients to that of the general population, and that the distribution and presentation of AID in MPN patients is also similar. TET2 mutations are highly prevalent in MPN patients with AID suggesting a shared physiopathology. Additional mechanistic studies are needed to further decipher a potential TET2-mediated common physiopathology. The association with AID did not impact MPN patients’ outcome.References[1]Barcellini, W. et al. Increased prevalence of autoimmune phenomena in myelofibrosis: Relationship with clinical and morphological characteristics, and with immunoregulatory cytokine patterns. Leukemia Research 37, 1509–1515 (2013).[2]Mekinian, A. et al. Systemic inflammatory and autoimmune manifestations associated with myelodysplastic syndromes and chronic myelomonocytic leukaemia: a French multicentre retrospective study. Rheumatology (Oxford) 55, 291–300 (2016).[3]Zhao, L.-P. et al. Genomic landscape of MDS/CMML associated with systemic inflammatory and autoimmune disease. Leukemia (2021).[4]Kristinsson, S. Y. et al. Autoimmunity and the risk of myeloproliferative neoplasms. Haematologica 95, 1216–1220 (2010).AcknowledgementsThe authors thank the clinical care team of the Comprehensive Myeloproliferative neoplasms Center for samples and data collection, and the staff of the cellular biology laboratory for excellent technical assistance. The authors also thank the French Intergroup for Myeloproliferative neoplasms (FIM) for insightful discussions.Disclosure of InterestsNone Declared.

A Correction to this paper has been published: https://doi.org/10.1038/s41375-020-01112-1.

Pivotal phase II studies in acute myeloblastic leukemia (AML) patients in first relapse have used gemtuzumab ozogamicin (GO) (Mylotarg) at a dose of 9 mg/m(2) on days 1 and 14. These studies showed a 26% response rate (13% complete remission (CR) and 13% CRp (complete remission with incomplete platelet recovery)) but with high degree of hematological and liver toxicities. Based on in vitro studies showing a re-expression of CD33 antigenic sites on the cell surface of blasts cells after exposure to GO, we hypothesized that fractionated doses of GO may be efficient and better tolerated. Fifty-seven patients with AML in first relapse received GO at a dose of 3 mg/m(2) on days 1, 4 and 7 for one course. Fifteen patients (26%) achieved CR and four (7%) CRp. Remission rate correlated strongly with P-glycoprotein and MRP1 activities. The median relapse-free survival was 11 months, similar for CR or CRp patients. Median duration of neutropenia < 500/microl and thrombocytopenia < 50,000/microl were, respectively, 23 and 21 days. No grade 3 or 4 liver toxicity was observed. No veno-occlusive disease occurred after GO or after hematopoietic stem cell transplantation given after GO in seven patients. Mylotarg administered in fractionated doses demonstrated an excellent efficacy/safety profile.

A large proportion of lower-risk myelodysplastic syndromes (MDS) respond to erythropoiesis-stimulating agents (ESA), but most responses are transient. We updated a previously reported cohort of lower-risk MDS patients treated with ESA and analyzed outcomes after ESA failure. In 120 patients with primary resistance and 66 patients with relapse after an initial response to ESA, the 5-year cumulative incidence of acute myeloid leukemia (AML) after failure was 18.9% and 11.6%, respectively ( P =0.20). Median overall survival (OS) after failure was 40.1 and 44.9 months ( P =0.35), respectively. We further categorized patients as ‘early failures’ (including resistance and relapse after <6 months of response), or ‘later failures’ (that is, relapse after ⩾6 months). The 5-year cumulative incidence of AML and median OS after failure in early and later failure were 21.6% and 9% ( P =0.02) and 36.7 and 54.3 months ( P =0.02), respectively. Early failure to ESA and a baseline diagnosis of refractory anemia with excess blasts (RAEB)-1 were independent prognostic factors for AML progression and, along with trisomy 8, for shorter OS. Median OS from treatment onset was 40, 90.7 and 65.8 months in early failure, later failure and no relapse, respectively ( P =0.001). Lower-risk MDS with early failure to ESA have a relatively unfavorable outcome, and should be offered alternative treatments.