Sorafenib or placebo in patients with newly diagnosed acute myeloid leukaemia: long-term follow-up of the randomized controlled SORAML trial

Abstract Early results of the randomized placebo-controlled SORAML trial showed that, in patients with newly diagnosed acute myeloid leukaemia (AML), sorafenib led to a significant improvement in event-free (EFS) and relapse-free survival (RFS). In order to describe second-line treatments and their implications on overall survival (OS), we performed a study after a median follow-up time of 78 months. Newly diagnosed fit AML patients aged ≤60 years received sorafenib (n = 134) or placebo (n = 133) in addition to standard chemotherapy and as maintenance treatment. The 5-year EFS was 41 versus 27% (HR 0.68; p = 0.011) and 5-year RFS was 53 versus 36% (HR 0.64; p = 0.035). Allogeneic stem cell transplantation (allo SCT) was performed in 88% of the relapsed patients. Four years after salvage allo SCT, the cumulative incidence of relapse was 54 versus 35%, and OS was 32 versus 50%. The 5-year OS from randomization in all study patients was 61 versus 53% (HR 0.82; p = 0.282). In conclusion, the addition of sorafenib to chemotherapy led to a significant prolongation of EFS and RFS. Although the OS benefit did not reach statistical significance, these results confirm the antileukaemic activity of sorafenib

Impact of IDH1 and IDH2 mutational subgroups in AML patients after allogeneic stem cell transplantation

Background The role of allogeneic hematopoietic cell transplantation (alloHCT) in acute myeloid leukemia (AML) with mutated IDH1/2 has not been defined. Therefore, we analyzed a large cohort of 3234 AML patients in first complete remission (CR1) undergoing alloHCT or conventional chemo-consolidation and investigated outcome in respect to IDH1/2 mutational subgroups (IDH1 R132C, R132H and IDH2 R140Q, R172K). Methods Genomic DNA was extracted from bone marrow or peripheral blood samples at diagnosis and analyzed for IDH mutations with denaturing high-performance liquid chromatography, Sanger sequencing and targeted myeloid panel next-generation sequencing, respectively. Statistical as-treated analyses were performed using R and standard statistical methods (Kruskal–Wallis test for continuous variables, Chi-square test for categorical variables, Cox regression for univariate and multivariable models), incorporating alloHCT as a time-dependent covariate. Results Among 3234 patients achieving CR1, 7.8% harbored IDH1 mutations (36% R132C and 47% R132H) and 10.9% carried IDH2 mutations (77% R140Q and 19% R172K). 852 patients underwent alloHCT in CR1. Within the alloHCT group, 6.2% had an IDH1 mutation (43.4% R132C and 41.4% R132H) and 10% were characterized by an IDH2 mutation (71.8% R140Q and 24.7% R172K). Variants IDH1 R132C and IDH2 R172K showed a significant benefit from alloHCT for OS (p = .017 and p = .049) and RFS (HR = 0.42, p = .048 and p = .009) compared with chemotherapy only. AlloHCT in IDH2 R140Q mutated AML resulted in longer RFS (HR = 0.4, p = .002). Conclusion In this large as-treated analysis, we showed that alloHCT is able to overcome the negative prognostic impact of certain IDH mutational subclasses in first-line consolidation treatment and could pending prognostic validation, provide prognostic value for AML risk stratification and therapeutic decision making

JAK2-V617F mutation in a patient with Philadelphia-chromosome-positive chronic myeloid leukaemia13

In July, 2000, a 50-year-old man presented with leukocytosis and splenomegaly (21 cm). Leucocyte concentration was 93×109/L, haemoglobin 150 g/L, and platelets 345×109/L (figure 1). A differential blood count showed 54% neutrophils, 2% lymphocytes, 13% myelocytes, 7% metamyelocytes, 2% promyelocytes, 1% blasts, and 7% basophils. Lactate dehydrogenase (LDH) concentration was increased at 484 U/L. 17 months previously, the blood count had been in the normal range. Bone-marrow aspiration was dry and bone-marrow biopsy showed marked myeloid hyperplasia, increased megakaryopoiesis, and the beginning of fibrosis. Cytogenetic analysis revealed a chromosome translocation (t[9;22][q34;q11]) in all ten metaphases examined. Expression of B3A2 BCR-ABL mRNA was detected by reverse transcriptase polymerase chain reaction (RT-PCR) in peripheral-blood leucocytes

The 2022 Diadema antillarum die-off event: Comparisons with the 1983-1984 mass mortality

The 1983-1984 die-off of the long-spined sea urchin Diadema antillarum stands out as a catastrophic marine event because of its detrimental effects on Caribbean coral reefs. Without the grazing activities of this key herbivore, turf and macroalgae became the dominant benthic group, inhibiting coral recruitment and compromising coral reef recovery from other disturbances. In the decades that followed, recovery of D. antillarum populations was slow to non-existent. In late January 2022, a new mass mortality of D. antillarum was first observed in the U.S. Virgin Islands. We documented the spread and extent of this new die-off using an online survey. Infected individuals were closely monitored in the lab to record signs of illness, while a large population on Saba, Dutch Caribbean, was surveyed weekly before and during mortality to determine the lethality of this event. Within four months the die-off was distributed over 1,300 km from north to south and 2,500 km east to west. Whereas the 1983-1984 die-off advanced mostly with the currents, the 2022 event has appeared far more quickly in geographically distant areas. First die-off observations in each jurisdiction were often close to harbor areas, which, together with their rapid appearance, suggests that anthropogenic factors may have contributed to the spread of the causative agent. The signs of illness in sick D. antillarum were very similar to those recorded during the 1983-1984 die-off: lack of tube feet control, slow spine reaction followed by their loss, and necrosis of the epidermis were observed in both lab and wild urchins. Affected populations succumbed fast; within a month of the first signs of illness, a closely monitored population at Saba, Dutch Caribbean, had decreased from 4.05 individuals per m2 to 0.05 individuals per m2. Lethality can therefore be as high as 99%. The full extent of the 2022 D. antillarum die-off event is not currently known. The slower spread in the summer of 2022 might indicate that the die-off is coming to a (temporary) standstill. If this is the case, some populations will remain unaffected and potentially supply larvae to downstream areas and augment natural recovery processes. In addition, several D. antillarum rehabilitation approaches have been developed in the past decade and some are ready for large scale implementation. However, active conservation and restoration should not distract from the primary goal of identifying a cause and, if possible, implementing actions to decrease the likelihood of future D. antillarum die-off events