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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.

The results of the addition of gemtuzumab ozogamicin, an anti-CD33 antibody conjugate, to the standard treatment for patients with acute myeloid leukaemia in phase 3 trials were contradictory. We investigated whether the addition of low fractionated-dose gemtuzumab ozogamicin to standard front-line chemotherapy would improve the outcome of patients with this leukaemia without causing excessive toxicity. In a phase 3, open-label study, undertaken in 26 haematology centres in France, patients aged 50–70 years with previously untreated de novo acute myeloid leukaemia were randomly assigned with a computer-generated sequence in a 1:1 ratio with block sizes of four to standard treatment (control group) with or without five doses of intravenous gemtuzumab ozogamicin (3 mg/m2 on days 1, 4, and 7 during induction and day 1 of each of the two consolidation chemotherapy courses). The primary endpoint was event-free survival (EFS). Secondary endpoints were relapse-free (RFS), overall survival (OS), and safety. Analysis was by intention to treat. This study is registered with EudraCT, number 2007-002933-36. 280 patients were randomly assigned to the control (n=140) and gemtuzumab ozogamicin groups (n=140), and 139 patients were analysed in each group. Complete response with or without incomplete platelet recovery to induction was 104 (75%) in the control group and 113 (81%) in the gemtuzumab ozogamicin group (odds ratio 1·46, 95% CI 0·20–2·59; p=0·25). At 2 years, EFS was estimated as 17·1% (10·8–27·1) in the control group versus 40·8% (32·8–50·8) in the gemtuzumab ozogamicin group (hazard ratio 0·58, 0·43–0·78; p=0·0003), OS 41·9% (33·1–53·1) versus 53·2% (44·6–63·5), respectively (0·69, 0·49–0·98; p=0·0368), and RFS 22·7% (14·5–35·7) versus 50·3% (41·0–61·6), respectively (0·52, 0·36–0·75; p=0·0003). Haematological toxicity, particularly persistent thrombocytopenia, was more common in the gemtuzumab ozogamicin group than in the control group (22 [16%] vs 4 [3%]; p<0·0001), without an increase in the risk of death from toxicity. The use of fractionated lower doses of gemtuzumab ozogamicin allows the safe delivery of higher cumulative doses and substantially improves outcomes in patients with acute myeloid leukaemia. The findings warrant reassessment of gemtuzumab ozogamicin as front-line therapy for acute myeloid leukaemia. Wyeth (Pfizer).

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.

FLT3 internal tandem duplications (FLT3-ITDs) are present in nearly 25% of patients with AML and have been associated with poor response to conventional therapy and poor outcome. We retrospectively evaluated the effect of reinforced courses of chemotherapy on the prognostic value of FLT3-ITDs in 159 AML patients prospectively enrolled in the ALFA-9000 trial, which randomly compared three reinforced induction regimens (standard 3+7 including high-dose daunorubicin, double induction, and timed-sequential therapy). FLT3-ITD was present in 40/159 (25%) blast samples and associated with high WBC (P = 0.002) and cytogenetics (P < 0.001) with a higher incidence (35%) in patients with a normal karyotype. There was no difference in CR rate between FLT3-wt and FLT3-ITD patients (80% vs 78%). Relapse-free survival (RFS) was similar in both groups (5-year RFS, 33% vs 32%; P = 0.41), even after adjustment for age, sex, WBC, cytogenetics, and treatment arm. A trend to a worse survival was observed in the FLT3-ITD group (estimated 5-year OS, 23% vs 37%; P = 0.09), mainly in patients with a normal karyotype. This was associated with a dramatic outcome in relapsing FLT3-ITD patients (estimated 3-year post-relapse survival, 0% vs 27%; P = 0.04). These results suggest that the bad prognosis associated with FLT3-ITDs in AML might be partly overcome using reinforced chemotherapy. Early detection of FLT3 mutations might thus be useful to intensify induction as well as post-remission therapy in FLT3-ITD patients.

To determine the maximum-tolerated dose (MTD), dose-limiting toxicities and pharmacokinetic of semisynthetic homoharringtonine (ssHHT), given as a twice daily subcutaneous (s.c.) injections for 9 days, in patients with advanced acute leukaemia, 18 patients with advanced acute myeloid leukaemia were included in this sequential Bayesian phase I dose-finding trial. A starting dose of 0.5 mg m −2  day −1 was explored with subsequent dose escalations of 1, 3, 5 and 6 mg m −2  day −1 . Myelosuppression was constant. The MTD was estimated as the dose level of 5 mg m −2  day −1 for 9 consecutive days by s.c. route. Dose-limiting toxicities were hyperglycaemia with hyperosmolar coma at 3 mg m −2 , and (i) one anasarque and haematemesis, (ii) one life-threatening pulmonary aspergillosis, (iii) one skin rash and (iv) one scalp pain at dose level of 5 mg m −2  day −1 . The mean half-life of ssHHT was 11.01±3.4 h, the volume of distribution at steady state was 2±1.4 l kg −1 and the plasma clearance was 11.6±10.4 l h −1 . Eleven of the 12 patients with circulating leukaemic cells had blood blast clearance, two achieved complete remission and one with blast crisis of CMML returned in chronic phase. The recommended daily dose of ssHHT on the 9-day schedule is 5 mg m −2  day −1 .

In a multicenter trial, 259 young adults (15-49 years) with newly diagnosed acute myeloid leukemia (AML) were first randomized to receive a timed-sequential induction regimen given either alone (135 patients) or concomitantly with granulocyte-macrophage colony-stimulating factor (GM-CSF) (124 patients). Patients reaching complete remission (CR) were then randomized to compare a timed-sequential consolidation to a postremission chemotherapy including four cycles of high-dose cytarabine followed by maintenance courses. In the appropriate arm, GM-CSF was given concurrently with chemotherapy during all cycles of consolidation. CR rates were significantly better in the GM-CSF arm (88 vs 78%, P<0.04), but did not differ after salvage. Patients receiving GM-CSF had a higher 3-year event-free survival (EFS) estimate (42 vs 34%), but GM-CSF did not impact on overall survival. Patients with intermediate-risk cytogenetics benefited more from GM-CSF therapy (P=0.05) in terms of EFS than patients with other cytogenetics. This was also confirmed when considering only patients following the second randomization, or subgroups defined by a prognostic index based on cytogenetics and the number of courses required for achieving CR. Priming of leukemic cells with hematopoietic growth factors is a means of enhancing the efficacy of chemotherapy in younger adults with AML.