Studying the impact of presence of alpha acid glycoprotein and protein glycoprotein in chronic myeloid leukemia patients treated with imatinib mesylate in the State of Qatar

Despite the efficacy of imatinib mesylate (IM) in treating chronic myeloid leukemia (CML), there is a high degree of resistance. Alpha- 1-acid glycoprotein may reduce drug efficacy through its ability to interact with IM and blocks it from reaching its target, while protein glycoprotein (PGP) may reduce the intracellular concentration of the drug via an active pump mechanism. We thus investigated the correlation between AGP and PGP levels and the resistance/response to treatment. A total of 26 CML patients were investigated for AGP and PGP levels at diagnosis and during treatment. There was no significant difference or correlation between AGP levels and the different groups of patients. There was also no significant difference in the fluorescence intensities of PGP levels among the different patient groups. The resistance observed in our CML patient population could not be correlated with AGP and PGP levels. There was no significant pattern of AGP and PGP expression, irrespective of the response or resistance to treatment

BAT2 and BAT3 polymorphisms as novel genetic risk factors for rejection after HLA-related SCT.

The genetic background of donor and recipient is an important factor determining the outcome of allogeneic hematopoietic SCT (allo-HSCT). We applied whole-genome analysis to investigate genetic variants - other than HLA class I and II - associated with negative outcome after HLA-identical sibling allo-HSCT in a cohort of 110 β-Thalassemic patients. We identified two single-nucleotide polymorphisms (SNPs) in BAT2 (A/G) and BAT3 (T/C) genes, SNP rs11538264 and SNP rs10484558, both located in the HLA class III region, in strong linkage disequilibrium between each other (R2 =0.92). When considered as single SNP, none of them reached a significant association with graft rejection (nominal P<0.00001 for BAT2 SNP rs11538264, and P<0.0001 for BAT3 SNP rs10484558), whereas the BAT2/BAT3 A/C haplotype was present at significantly higher frequency in patients who rejected as compared to those with functional graft (30.0% vs 2.6%, nominal P=1.15 × 10-8; and adjusted P=0.0071). The BAT2/BAT3 polymorphisms and specifically the A/C haplotype may represent a novel immunogenetic factor associated with graft rejection in patients undergoing allo-HSCT

Somatic Mutation Tracking in Hematopoietic Stem Cell Gene Therapy Reveals Absence of Clonal Hematopoiesis

In hematopoietic stem cell Gene Therapy (GT), patients’ Hematopoietic Stem and Progenitor Cells (HSPCs) are genetically corrected ex vivo and reinfused to reconstitute the entire hematopoietic system and provide therapeutic benefit. During this process, HSPCs are subjected to tremendous pressures to sustain high levels of proliferation until the hematopoietic reconstitution is complete. So far it is unknown if this likely stressful condition may result in the accumulation of somatic mutations which may trigger decay of the hematopoietic functions and increased risk of oncogenesis. The impact of prolonged and heightened HSPCs proliferation rates on cellular fitness and safety remains an open question in GT. Indeed, HSPCs are not comprehensively geno-protected from DNA damage accumulation in HSPCs during aging and/or in specific disease conditions as it has been observed in sickle cell disease and Fanconi Anemia.Here we performed an analysis of somatic mutations in exons of 40 genes involved in clonal hematopoiesis and myeloid cancer in 23 GT patients treated for metachromatic leukodystrophy (MLD, 15 30 years old). We used genomic DNA from HSPCs cells prior infusion and peripheral blood mononuclear cells harvested at 2 years after GT and at the last available time point (2.5-7.5 years after GT). Sequencing reads correctly aligned on the targeted exon panel resulted in an average coverage of 4,400 and 4,300 reads/base in β-Thal and MLD patients respectively.The average mutation rate in the adult β-Thal patients was &gt;2 fold higher than the rate measured in the pediatric patients (11.3 ± 11 vs 5.6 ± 3.5). Moreover, the average somatic mutation rates in adult and pediatric β-Thal patients were both significantly higher than in MLD patients (1.6 ± 0.72, p-value=0.0136 vs adult β-Thal, p-value=0.012 vs pediatric β-Thal, by Kruskal-Wallis test). None of the mutations were pathological or likely pathological. Most somatic mutations (85 out of 96) exhibited a Variant Allele Frequency of less than 2%. The average number of mutations in both the clinical trials remained consistent across all time points, showing no statistically significant variations. Considering that the sequenced genomic interval corresponds to 76,715 bps and that we analyzed a total of 8,100 equivalent genomes per patient, the resulting mutation rate in β-Thal patients was 1.21x10-8 mutations/bp, while MLD patients resulted in a mutation rate of 2.6x10-9 mutations/bp. Five mutations (4 in β-Thal and 1 in MLD) were found at more than one time point, but none showed a progressive increase in abundance, suggesting that these mutations did not confer a selective advantage to the mutated cell clones.Our work revealed that no somatic mutations known to drive clonal hematopoiesis or myeloid cancer, nor accumulation of somatic mutations, were found in our GT patients, indicating that the GT treatment was neutral in these conditions. However, the underlying disease in β-Thal patients resulted in a significantly higher mutation burden than MLD patients, a finding worth of deeper analysis and that supports long-term follow-up assessments of the clonal composition of the hematopoietic system in GT patients

Second hematopoietic SCT in patients with thalassemia recurrence following rejection of the first graft

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Effect of Related and Unrelated Donor Haematopoietic Stem-Cell Transplantation on Outcome in Adults With High Risk Hematological Disease: An intention-to-treat Analysis of 410 Patients at a Single Center Institution

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Early molecular diagnosis of aspergillosis in a patient with acute myeloid leukaemia

Diagnosis of invasive fungal infection remains challenging. Here we report a case of early diagnosis of invasive aspergillosis in a neutropenic patient affected by acute myeloid leukaemia, achieved through the detection of Aspergillus fumigatus species-specific ribonucleic acid sequences by a sensitive multiplex real-time polymerase chain reaction-based molecular assay. Thanks to the early diagnosis, targeted therapy was promptly established and the severe fungal infection controlled, allowing the patient to subsequently receive allogeneic hematopoietic stem cell transplantation from a haploidentical donor, her only curative option. Also in this instance, targeted secondary antifungal prophylaxis with voriconazole avoided any other fungal infection afterwards. This report suggests how the implementation of molecular assays in combination with routine diagnostic procedures, can improve microbiological diagnosis in sepsis, particularly in case of fungal infection, difficult to detect with standard microbiological culture methods

Case Report: Invasive Fungal Infection and Daratumumab: A Case Series and Review of Literature

Life expectancy of multiple myeloma (MM) patients has improved in last years due to the advent of anti-CD38 monoclonal antibodies in combination with immunomodulators and proteasome inhibitors. However, morbidity and mortality related to infections remain high and represent a major concern. This paper describes the “real life” risk of invasive fungal infections (IFI) in patients treated with daratumumab-based therapy and reviews the relevant literature. In a series of 75 patients we only observed three cases of fungal pneumonia. Unfortunately, the early signs and symptoms were not specific for fungal infection. Diagnostic imaging, microbiology and patient history, especially previous therapies, are critical in the decision to start antifungal treatment. Recognising the subgroup of MM patients with high risk of IFI can increase the rate of diagnosis, adequate treatment and MM-treatment recovery