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Background: Invasive fungal disease (IFD) is a sinister complication encountered in patients with haematological disorders. When occurring in the central nervous system (CNS), IFDs can have catastrophic outcomes. Objectives: To study the clinical presentation, predisposing etiological factors, and prognosis of a CNS‐IFD in a patient with a haematological disorder. Patients and Methods: This is a retrospective study focusing on the clinical profile, diagnosis, treatment strategy and outcomes of 43 patients with an underlying haematological disorder, who were diagnosed with CNS‐IFD between 2018 and 2022. Results: Of the 43 patients, 18 were chemotherapy recipients, while 23 were stem cell transplant (SCT) recipients and 2 presented with CNS‐IFD at diagnosis. AML/MDS (37.2%) and ALL (18.6%) were the predominant underlying diagnoses. A sudden deterioration in sensorium (53.5%) was the earliest clinical sign, while T2 hyperintensities (26.8%), vascular involvement (26.8%) and ring‐enhancing lesions (16.3%) were the commonest radiological findings, with all patients exhibiting diffusion restriction in diffusion‐weighted images. Microbiological evidence of infection was obtained in all patients; however, culture positivity was established in only 25 patients. Rhizopus spp (23.2%) and Aspergillus spp (20.9%) were implicated in most cases. Overall survival of the cohort was 27.9% at a median follow‐up of 6 months. In patients who succumbed, the median time to death was 4 days (0–46). Conclusion: CNS‐IFD is associated with very poor survival in patients undergoing chemotherapy or an SCT, urging the need for prompt diagnosis and initiation of suitable antifungal therapy. [ABSTRACT FROM AUTHOR]

Introduction: During normal aging, telomeric DNA is gradually lost in dividing somatic cells, and critically short telomeres lead to replicative senescence, apoptosis, or chromosomal instability. We studied telomere length in bone marrow failure syndromes (BMFS) compared to normal healthy population. Methods: Peripheral blood was collected from the participants, and genomic DNA was extracted. Relative telomere length was measured using a quantitative polymerase chain reaction. Statistical analysis was performed using SPSS and GraphPad Prism 8.2 software. Results: The median age of normal Indian population was 31 (0–60) years. As expected, telomere length (TL) showed a decline with age and no difference in TL between males and females. The median age of 650 patients with aplastic anemia (AA) was 30 (1–60) years. TL was significantly shorter in patients with AA compared to healthy controls (p <.001). In FA and MDS patients, TL was significantly shorter than age‐matched healthy controls (p =.028; p <.001), respectively. There was no difference between the median TL in age‐matched AA and FA patients (p =.727). However, patients with MDS had shorter TL than age‐matched AA (p =.031). Conclusion: TL in BMF syndrome patients was significantly shorter than age‐matched healthy controls. [ABSTRACT FROM AUTHOR]

A toxicity‐reduced conditioning regimen with treosulfan, fludarabine, and thiotepa in patients with high‐risk β‐thalassemia major has significantly improved hematopoietic stem cell transplantation (HCT) outcomes. However, complications resulting from regimen‐related toxicities (RRTs), mixed chimerism, and graft rejection remain a challenge. We evaluated the dose–exposure‐response relationship of treosulfan and its active metabolite S, S‐EBDM, in a uniform cohort of patients with β‐thalassemia major to identify whether therapeutic drug monitoring (TDM) and dose adjustment of treosulfan is feasible. Plasma treosulfan/S, S‐EBDM levels were measured in 77 patients using a validated liquid chromatography with tandem mass spectrometry method, and the pharmacokinetic parameters were estimated using nlmixr2. The influence of treosulfan and S, S‐EBDM exposure, and GSTA1/NQO1 polymorphisms on graft rejection, RRTs, chimerism status, and 1‐year overall survival (OS), and thalassemia‐free survival (TFS) were assessed. We observed that treosulfan exposure was lower in patients with graft rejection than those without (1,655 vs. 2,037 mg•h/L, P = 0.07). Pharmacodynamic modeling analysis to identify therapeutic cutoff revealed that treosulfan exposure ≥1,660 mg•hour/L was significantly associated with better 1‐year TFS (97% vs. 81%, P = 0.02) and a trend to better 1‐year OS (90% vs. 69%, P = 0.07). Further, multivariate analysis adjusting for known pre‐HCT risk factors also revealed treosulfan exposure <1,660 mg•h/L (hazard ratio (HR) = 3.23; 95% confidence interval (CI) = 1.12–9.34; P = 0.03) and GSTA1*B variant genotype (HR = 3.75; 95% CI = 1.04–13.47; P = 0.04) to be independent predictors for inferior 1‐year TFS. We conclude that lower treosulfan exposure increases the risk of graft rejection and early transplant‐related mortality affecting TFS. As no RRTs were observed with increasing treosulfan exposure, TDM‐based dose adjustment could be feasible and beneficial. [ABSTRACT FROM AUTHOR]

Immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG) and Cyclosporine (CSA) in aplastic anaemia (AA) results in improvement of blood counts between 3 and 6 months for the majority of patients. Infection is the most lethal complication in aplastic anemia and may arise due to several factors. We performed this study to determine the prevalence and predictors of specific infection types before and after IST. Six hundred and seventy-seven (546 adults; 434 males) transplant ineligible patients received ATG and CSA between 1995 and 2017. All patients who were transplant ineligible and received IST in this period were included. Infections before IST was seen in 209 (30.9%) and in 430 (63.5%) patients post IST. There were 700 infective episodes in the six months post-IST, including 216 bacterial, 78 fungal, 33 viral, and 373 culture-negative febrile episodes. Infections were highest (98, 77.8%) in very severe aplastic anaemia as compared to Severe AA (SAA) and Non-Severe AA (NSAA) (p < 0.001). Infections were also significantly higher in those who did not respond to ATG (71.1% vs. 56.8%, p = 0.003). At six months post-IST were 545 (80.5%) alive, and there were 54 (7.9%) deaths due to infection. Significant predictors of mortality were paediatric AA, very severe aplastic anaemia, pre or post ATG infections, and lack of response to ATG. Mortality was highest in those with combined bacterial and fungal infections post IST (p < 0.001). We conclude that infections are a common complication (63.5%) of IST. Mortality was highest when both bacterial and fungal infections were present. Routine use of growth factors and prophylactic antifungal and antibacterial agents was not part of our protocol, despite which 80.5% of the cohort was alive at the end of six months. [ABSTRACT FROM AUTHOR]

Background: Hematopoietic stem cell transplantation (HSCT) is the only curative option for patients with Fanconi Anemia (FA) with hematological abnormalities. Materials and Methods: This is a retrospective analysis of patients with FA who underwent a matched-related donor HSCT. Results: Sixty patients underwent 65 transplants between 1999-2021 using a fludarabine-based low-intensity conditioning regimen. The median age at transplant was 11 years (range: 3-37). Aplastic anemia (AA) was the underlying diagnosis in 55 (84.6%), while 8 (12.4%) had myelodysplastic syndrome (MDS) and 2 (3%) had acute myeloid leukemia (AML). The conditioning regimen used was Fludarabine with low-dose Cyclophosphamide for aplastic anemia and Fludarabine with low-dose Busulfan for MDS/AML. Graft versus host disease (GVHD) prophylaxis consisted of Cyclosporine and methotrexate. Peripheral blood was the predominant stem cell graft source (86.2%). Engraftment occurred in all but one patient. The median time to neutrophil and platelet engraftment was 13 days (range: 9-29) & 13 days (range: 5-31), respectively. Day 28 chimerism analysis showed complete chimerism in 75.4 % and mixed chimerism in 18.5%. Secondary graft failure was encountered in 7.7%. Grade II-IV acute GVHD occurred in 29.2%, while Grade III-IV acute GVHD occurred in 9.2%. Chronic GVHD was seen in 58.5% and was limited in most patients. The median follow-up is 55 months (range: 2-144) & the 5-year estimated overall survival (OS) is 80.2 ± 5.1%. Secondary malignancies were noted in 4 patients. The 5-year OS was significantly higher in patients undergoing HSCT for AA (86.6 + 4.7%) as compared to MDS/AML (45.7+16.6%) (p= 0.001). Conclusion: SCT using a fully matched donor provides good outcomes with low-intensity conditioning regimens in patients with FA who have aplastic marrow. [ABSTRACT FROM AUTHOR]