A Case of Atypical Delayed and Prolonged Hematologic Toxicity With Azacitidine in Chronic Myelomonocytic Leukemia (CMML) and Review of Literature

Hypomethylating drugs are useful and have been approved for the treatment of myelodysplastic syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML). However, phase 2 and 3 studies that assessed these agents in MDS, have included only a small number of patients with CMML, and there are just a few specific reports on CMML patients. The Azacitidine is actually authorised for the treatment of CMML patients with 10–29% marrow blasts without myeloproliferative disorder, who are not eligible for haematopoietic stem cell transplantation. This hypomethylating agent in MDS is known for causing transient cytopenias, most often occurring during the first 2 cycles. Here we report a case of an atypical delayed and prolonged hematologic toxicity during Azacitidine treatment in a CMML patient; furthermore we also reviewed the literature regarding the efficacy of the drug and the management of hematologic adverse effects, in term of dose adjustments or alternative schedule of administration, in specific CMML setting

A sex-informed approach to improve the personalised decision making process in myelodysplastic syndromes: a multicentre, observational cohort study

Background Sex is a major source of diversity among patients and a sex-informed approach is becoming a new paradigm in precision medicine. We aimed to describe sex diversity in myelodysplastic syndromes in terms of disease genotype, phenotype, and clinical outcome. Moreover, we sought to incorporate sex information into the clinical decision-making process as a fundamental component of patient individuality. Methods In this multicentre, observational cohort study, we retrospectively analysed 13 284 patients aged 18 years or older with a diagnosis of myelodysplastic syndrome according to 2016 WHO criteria included in the EuroMDS network (n=2025), International Working Group for Prognosis in MDS (IWG-PM; n=2387), the Spanish Group of Myelodysplastic Syndromes registry (GESMD; n=7687), or the Dusseldorf MDS registry (n=1185). Recruitment periods for these cohorts were between 1990 and 2016. The correlation between sex and genomic features was analysed in the EuroMDS cohort and validated in the IWG-PM cohort. The effect of sex on clinical outcome, with overall survival as the main endpoint, was analysed in the EuroMDS population and validated in the other three cohorts. Finally, novel prognostic models incorporating sex and genomic information were built and validated, and compared to the widely used revised International Prognostic Scoring System (IPSS-R). This study is registered with ClinicalTrials.gov, NCT04889729. Findings The study included 7792 (58middot7%) men and 5492 (41middot3%) women. 10 906 (82middot1%) patients were White, and race was not reported for 2378 (17middot9%) patients. Sex biases were observed at the single-gene level with mutations in seven genes enriched in men (ASXL1, SRSF2, and ZRSR2 p<0middot0001 in both cohorts; DDX41 not available in the EuroMDS cohort vs p=0middot0062 in the IWG-PM cohort; IDH2 p<0middot0001 in EuroMDS vs p=0middot042 in IWG-PM; TET2 p=0middot031 vs p=0middot035; U2AF1 p=0middot033 vs p<0middot0001) and mutations in two genes were enriched in women (DNMT3A p<0middot0001 in EuroMDS vs p=0middot011 in IWG-PM; TP53 p=0middot030 vs p=0middot037). Additionally, sex biases were observed in co-mutational pathways of founding genomic lesions (splicing-related genes, predominantly in men, p<0middot0001 in both the EuroMDS and IWG-PM cohorts), in DNA methylation (predominantly in men, p=0middot046 in EuroMDS vs p<0middot0001 in IWG-PM), and TP53 mutational pathways (predominantly in women, p=0middot0073 in EuroMDS vs p<0middot0001 in IWG-PM). In the retrospective EuroMDS cohort, men had worse median overall survival (81middot3 months, 95% CI 70middot4-95middot0 in men vs 123middot5 months, 104middot5-127middot5 in women; hazard ratio [HR] 1middot40, 95% CI 1middot26-1middot52; p<0middot0001). This result was confirmed in the prospective validation cohorts (median overall survival was 54middot7 months, 95% CI 52middot4-59middot1 in men vs 74middot4 months, 69middot3-81middot2 in women; HR 1middot30, 95% CI 1middot23-1middot35; p<0middot0001 in the GEMSD MDS registry; 40middot0 months, 95% CI 33middot4-43middot7 in men vs 54middot2 months, 38middot6-63middot8 in women; HR 1middot23, 95% CI 1middot08-1middot36; p<0middot0001 in the Dusseldorf MDS registry). We developed new personalised prognostic tools that included sex information (the sex-informed prognostic scoring system and the sex-informed genomic scoring system). Sex maintained independent prognostic power in all prognostic systems; the highest performance was observed in the model that included both sex and genomic information. A five-to-five mapping between the IPSS-R and new score categories resulted in the re-stratification of 871 (43middot0%) of 2025 patients from the EuroMDS cohort and 1003 (42middot0%) of 2387 patients from the IWG-PM cohort by using the sex-informed prognostic scoring system, and of 1134 (56middot0%) patients from the EuroMDS cohort and 1265 (53middot0%) patients from the IWG-PM cohort by using the sex-informed genomic scoring system. We created a web portal that enables outcome predictions based on a sex-informed personalised approach. Interpretation Our results suggest that a sex-informed approach can improve the personalised decision making process in patients with myelodysplastic syndromes and should be considered in the design of clinical trials including low-risk patients. Copyright (c) 2022 Published by Elsevier Ltd. All rights reserved

Oral azacitidine maintenance therapy for acute myeloid leukemia in first remission

Background: Although induction chemotherapy results in remission in many older patients with acute myeloid leukemia (AML), relapse is common and overall survival is poor. Methods: We conducted a phase 3, randomized, double-blind, placebo-controlled trial of the oral formulation of azacitidine (CC-486, a hypomethylating agent that is not bioequivalent to injectable azacitidine), as maintenance therapy in patients with AML who were in first remission after intensive chemotherapy. Patients who were 55 years of age or older, were in complete remission with or without complete blood count recovery, and were not candidates for hematopoietic stem-cell transplantation were randomly assigned to receive CC-486 (300 mg) or placebo once daily for 14 days per 28-day cycle. The primary end point was overall survival. Secondary end points included relapse-free survival and health-related quality of life. Results: A total of 472 patients underwent randomization; 238 were assigned to the CC-486 group and 234 were assigned to the placebo group. The median age was 68 years (range, 55 to 86). Median overall survival from the time of randomization was significantly longer with CC-486 than with placebo (24.7 months and 14.8 months, respectively; P<0.001). Median relapse-free survival was also significantly longer with CC-486 than with placebo (10.2 months and 4.8 months, respectively; P<0.001). Benefits of CC-486 with respect to overall and relapse-free survival were shown in most subgroups defined according to baseline characteristics. The most common adverse events in both groups were grade 1 or 2 gastrointestinal events. Common grade 3 or 4 adverse events were neutropenia (in 41% of patients in the CC-486 group and 24% of patients in the placebo group) and thrombocytopenia (in 22% and 21%, respectively). Overall health-related quality of life was preserved during CC-486 treatment. Conclusions: CC-486 maintenance therapy was associated with significantly longer overall and relapse-free survival than placebo among older patients with AML who were in remission after chemotherapy. Side effects were mainly gastrointestinal symptoms and neutropenia. Quality-of-life measures were maintained throughout treatment

The stereo camera on the BepiColombo ESA/JAXA mission: a novel approach.

The stereo camera (STC) is one of three channels of the spectrometer and imagers for Mercury Planet Orbiter BepiColombo Integrated Observatory SYStem (SIMBIOSYS), which will be on board the Mercury Planetary Orbiter of the ESA mission BepiColombo. SIMBIOSYS includes also an high resolution imaging channel (HRIC), providing images at spatial resolution of 5m/pixel at the periherm, and the VIS-NIR spectrometer (VIHI) that will provide the global mapping of the Mercury\u2019s surface in the spectral range 400\u20132200 nm, with a spectral sampling of 6.25 nm, and the spatial resolution of 400m/pixel at the periherm. The main scientific objective of STC is the global mapping of the entire surface of the Mercury in 3D and colors with a scale factor of 50m/pixel at the periherm. It will allow to generate the digital terrain model (DTM) of the entire surface improving the interpretation of morphological features at different scales and topographic relationships. The harsh environment of the Mercury will strongly affect the functionalities and performance of the instruments reducing the resources allocated to the payload. Even for the stereo camera, as for most of the instrument on board BepiColombo, a novel design had to be considered. We have implemented an original optical design, modifying a classical configurations, and a new technique of acquiring the stereo pairs for generating the DTM of the surface. The new technique will have an impact on the software chain generating the DTM and on the observation strategy. The stereo camera consists of two channels, looking at the surface at \ub120\u25e6 from the nadir direction, converging on the same bidimensional focal plane assembly, with no mechanical movable parts. The configuration of the focal plane assembly allows to apply the push-frame technique to acquire the stereo images

OBSERVATIONAL STUDY TO DEVELOP A TREATMENT–RELATED PATIENT-REPORTED OUTCOME MEASURE IN GAUCHER DISEASE (QOL-ONE PRO1G).

Background Gaucher disease (GD) is a rare autosomal recessive lysosomal disorder that results in the accumulation of sphingolipids in the body’s tissues due to glucocerebrosidase enzyme deficiency. GD manifests with vast clinical heterogeneity. Type 1 is the most common form (non neurophatic) with a wide spectrum of signs and symptoms at presentation: some are very mild, others may present variably enlarged liver and spleen which may cause abdominal discomfort. Trombocytopenia and anemia are very common at diagnosis and may be associated with signs and symptoms (bruising and bleeding, tiredness, vertigo, dyspnea and reduced physical functioning). Over 20% of patients experience bone pain or fractures. Treatment is indicated for patients with type 1 GD who exhibit clinical signs and symptoms of the disease, including anemia, thrombocytopenia, skeletal disease, or visceromegaly. Assessment of the impact of illness on physical, mental, and social functioning is an essential element of clinical diagnosis, a major determinant of therapeutic choices and efficacy, and a guide to longer-term care. Furthermore, it is known that patient reported outcomes (PROs) may influence various changes in intervention. There are many generic instruments available to measure the impact of disease on patient’s health-related quality of life (HRQoL). However, there is no PRO measure that has been developed specifically for the use in GD. Such a measure would help clinicians to gain a more in-depth understanding of the impact of GD on patients and inform clinical decision making, leading to better patient care and compliance. Aims The aim of this study is to develop and validate an instrument designed to measure the impact of GD and treatment on individual patients’ PROs. Primary endpoints are the generation of items to construct a PRO instrument for patients with GD and its psychometric evaluation. Methods This is an observational multicentre study. Participants will be GD patients aged ≥ 18 years attending referral centers. The study will be divided in 6 stages: Stage 1 - conceptualisation of PROs in GD patients before the data collection, in order to lay a conceptual foundation for the new instrument; Stage 2 - qualitative interviews; Stage 3 - item generation; Stage 4 - pre-testing; Stage 5 - item reduction; Stage 6 - validation of the final questionnaire. The total number of patients estimated to be assessed is approximately 100. Results The results of first stages of the study will be presented. The issues related to PROs of patients with GD will be researched and conceptualized. The interview guidance on HRQoL and symptom issues related to disease and its treatment will be developed and the interviewer will conduct interviews in accordance with this guidance. Emerging themes on HRQoL and symptoms from the interviews will be reported and are expected to fall into the four main HRQoL domains - physical, social, environmental and psychological. Outcomes of qualitative interviews will be analyzed. Conclusion The user-friendly questionnaire to evaluate impact and symptoms of GD will meet the minimum standards set out by the FDA for PROs and HRQoL instruments that include intrinsic characteristics (reliability and validity), responsiveness, sensitivity to change in health states and adequate sample size (FDA Guidance, 2006; https://www.fda.gov/downloads/drugs/guidances/ucm193282.pdf). The instructions on the questionnaire will be easy to use, and the instrument will be short in length, self-explanatory, take a short time to complete, be easy to use and put minimal burden on the patient

Humoral and cellular immune response in patients with hematological disorders after two doses of BNT162b2 mRNA COVID‐19 vaccine: A single‐center prospective observational study (NCT05074706)

Abstract Hematological patients at higher risk of severe COVID‐19 were excluded from the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) vaccine trials. In this single‐center observational prospective study (NCT05074706), we evaluate immune response in the hematological patients followed at the Hematological Division of San Gerardo Hospital, Monza (Italy) deemed to be severely immunosuppressed after vaccination with two doses of the BNT162b2 vaccine. Anti‐SARS‐CoV‐2 immunoglobulin G titers above the cutoff value of 33.8 BAU/ml were detected in 303 (80.2%) out of the 378 patients enrolled. Patients with lymphoproliferative disorders had a significant lower probability of immunization (43.2% vs. 88.4%, p < 0.001). Patients treated with anti‐CD20 showed a significantly lower probability of immunization compared to all other treatments (21.4%, p < 0.0001). Among 69 patients who failed seroconversion, 15 patients (22.7%) showed a positive T‐cell response. Patients previously treated with anti‐CD20 were 2.4 times more likely to test positive for T‐cell responses (p = 0.014). Within a follow‐up of 9 months from the second COVID‐19 vaccination, symptomatic SARS‐CoV‐2 infections were reported by 20 patients (5.3%) and four of them required hospitalization. Successful serological or T‐cell‐mediated immunization conferred protection from symptomatic COVID‐19. Patients treated with anti‐CD20 who were not seroconverted after vaccination might still be protected from COVID‐19 due to the T‐cell immune response

Wide-transcriptome analysis and cellularity of bone marrow CD34+/lin- cells of patients with chronic-phase chronic myeloid leukemia at diagnosis vs. 12 months of first-line nilotinib treatment

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder with heterogeneous biological and clinical features. The biomolecular mechanisms of CML response to tyrosine-kinase inhibitors are not fully defined