Chronic Malignancies Research Articles

The SF3B1 K666 Hotspot Mutation Confers Unfavourable Disease Risk across Major Myeloid Neoplasm Subgroups

SF3B1 is the most prevalent splicing factor mutated in myeloid neoplasms, detected in 20-30% of patients with myelodysplasia (MDS) and associated with a milder disease phenotype. SF3B1 mutations are typically single nucleotide variations occurring in hotspots in the HEAT domain. Disease-specific SF3B1 hotspot predilection is observed; for example, K700E is most common in MDS and R625 in uveal melanoma. The K666 hotspot has been associated with increased risk of MDS disease progression to acute myeloid leukemia (AML). However, the prognostic impact across all myeloid neoplasms inclusive of myeloproliferative neoplasms (MPN) and MDS/MPN overlap syndromes has not been established. Mutation information was collated from available datasets inclusive of unpublished clinical trial cohorts across patients with myeloid neoplasms (MDS, MPN, MDS/MPN, AML) and patients with solid malignancies and clonal hematopoiesis (CH). SF3B1 hotspot mutations were correlated with additional somatic mutations, disease type and other clinical parameters. Overall, 11,744 patients with myeloid neoplasms; MDS (n=4275), AML (n=3526), MDS/MPN (n=192), MPN (n=3751) and 24,146 patients with solid malignancies and CH were included in this analysis. SF3B1 mutations were present in 11.1% of patients; 21.3% MDS, 4.1% AML, 51% MDS/MPN and 3.7% MPN. In MDS, SF3B1 mutations were predominantly present in low risk MDS (23.8%) as compared with 4.1% in intermediate to high risk MDS. This contrasts with MPN where SF3B1 mutations were present at a higher frequency in more advanced MPN (5.5% in treatment-resistant ET, 8.8% in all MF cases and further augmented at 14% in JAK inhibitor resistant high-risk thrombocytopenic MF) as compared with earlier phase MPN (2.1% and 1.3% in ET and PV respectively). In MPN SF3B1-mutant cases, JAK-STAT signaling driver mutation frequency and distribution were in line with published data; 65.6% JAK2V617F-mutated, 18.8% CALR-mutated, 8.5% MPL-mutated and 7% triple negative. As previously described, SF3B1 K700E hotspot mutations were most prevalent (frequency 49.1%), followed by K666, H622 and R625 hotspot mutations at 20.6%, 7.6% and 6.1% respectively. K700E was enriched as expected in MDS cohorts and K666 hotspot mutations were enriched in AML (42%). Although less common in MDS (11.6 - 17.8%), the frequency of K666 mutation correlated with higher IPSS-M risk category in MDS (p=0.001; chi-squared test). In contrast to MDS, SF3B1 K666 was the dominant hotspot in MPN ranging 46-70% in frequency across subtypes from earlier to more advanced MPN such as MF (Fig 1A). SF3B1 K700E mutations were more often co-mutated with epigenetic mutations such as in DNMT3A, TET2, EZH2 and KMT2C genes (Fig 1B) whereas SF3B1 K666 mutations were significantly co-mutated with NPM1 and FLT3 in AML cases (odds ratio, OR, 25.6 and 4.2 respectively, p-value <0.0001) and JAK2V617F in MPN cases (OR 3.2, p<0.0001). SF3B1 K666 mutations also showed a trend towards significant co-occurrence with adverse prognostic mutations in AML; PHF6, PTPN11 and RUNX1. No differences were observed for SF3B1 hotspots for CALR or MPL-mutated MPN but numbers were too few to draw conclusions. In patients with SF3B1 mutations, 58% were male and K666 hotspot was more frequent in males (21% as compared with 11% in females, p<0.001, chi-squared test). There were no hotspot differences observed in age, ethnicity, bloods counts or karyotype where data was available for this analysis. In CH, SF3B1 mutations were detected in 0.5% with K700E (34.2%) and K666 (26.7%) frequencies equivalent (p=0.24). In summary, this large multi-cohort myeloid neoplasm analysis reveals myeloid disease-specific SF3B1 hotspot propensity. The K666 hotspot was frequent in MPN, particularly in persons with advanced disease where SF3B1 mutations are more prevalent than earlier phase MPN. We conclude that different SF3B1 hotspots are associated with distinct clinical phenotypes and in chronic myeloid malignancies; K666 SF3B1 mutation is associated with adverse clinical course. Additional studies to elucidate the distinct biological effects of different SF3B1 mutations are warranted.

The Efficacy and Safety of Selinexor in Combination with Ruxolitinib in Ruxolitinib-Treated Myelofibrosis Patients： the Interim Analysis of a Prospective, Open-Label, Multicenter, Parallel-Cohort, Phase 2 Study

Background: Myelofibrosis is a chronic hematologic malignancy characterized by constitutional symptoms, bone marrow fibrosis, extramedullary hematopoiesis resulting in splenomegaly and a propensity toward leukemic progression. Although JAK inhibitors have improved patients' splenomegaly and symptom burden, the clinical management of MF is still challenging for its limited treatment options, especially when patients become less responsive or intolerable to Ruxolitinib (RUX) treatment. Selinexor (SEL) is a novel, first-in-class, oral selective inhibitor of nuclear export agent that binds the karyopherin protein exportin 1 (XPO1). Preclinical studies showed SEL decreased viable cells and colony formation both in newly diagnosed and RUX-exposed MF cells. ESSENTIAL trial showed SEL's sustained spleen responses as a single agent in JAKi refractory MF. Besides, a phase I study reported, with SEL plus RUX in treatment-Naïve MF, 92% patients(pts) achieved SVR35, 69% had symptom response and 65% had stable or improved Hgb levels. We have presented promising efficacy and safety data in real-world setting of SEL plus RUX regimen in MF patients in 2023 EHA. Here we are to report the efficacy and safety of the regimen in RUX-treated patients in a prospective clinical trial. Methods: This is a prospective, open-label, multi-center, parallel-cohort phase 2 study, examining SEL plus RUX regimen in RUX-treated MF pts. The study includes MF pts with suboptimal RUX responses or intolerable to RUX treatment. Pts are given SEL 40mg or 60mg QW plus RUX (dosage per investigator judgement, RUX intolerable pts will receive reduced dose of RUX). A total of 40 pts will be included into the study. The primary endpoint is spleen response assessed by palpation or CT/MRI scan per IWG-MRT and ELN response criteria. Key secondary endpoints include anemia response, symptom response defined as symptom resolution or alleviation according to TSS or physician's judgement, and safety. Results: Characteristics As of July 2023, 28 pts had received at least one dose of oral weekly SEL, including 12 suboptimal RUX responses pts and 16 RUX intolerable pts. The median age was 65 years old. Mean duration of prior RUX treatment was 24.5 months (range: 4-77). 18 pts had primary MF, 4 had post-PV MF, and 6 had post-ET MF. Median time from MF diagnosis to study enrollment was 5 years (0.25-29). JAK2, CALR and MPL mutations were present in 18 (64.28%), 5 (17.85%) and 1 (3.57%) pts respectively. All pts presented constitutional symptoms, 25 (89.29%) had splenomegaly, and 7 (25.00%) had packed red blood cell (PRBC) transfusion-dependent anemia. DIPSS risk category was intermediate 23 (82.14%), high risk 3 (10.71%) and unknown 2 (7.14%). Median treatment duration was 134 days (14-525) (Table 1). 15 pts (53.57%) discontinued SEL. Reasons for treatment discontinuation were death in 4 pts (3 from covid-19, 1 sepsis), participation in clinical trial in 2 pts, unsatisfactory response in 2, transplantation in 1, toxicity in 2, economic burden in 1 patient and lost to follow-up in 3. Efficacy Analysis The analysis of spleen response included 21 pts with spleen length assessment data by either palpation or CT/MRI. Spleen response is defined as length reduction more than 50% per IWG-MRT and ELN response criteria. 15 (71.42%) pts had a reduction in spleen volume and 8 (38.09%) achieved spleen response ( Figure 1). For symptom response, 27 pts are with available data. 23 (85.18%) pts had symptom alleviation, 9 (33.33%) achieved ≥50% reduction in TSS or symptom response assessed by physician, of which 1 achieved symptom resolution. There are 12 pts with PRBC transfusion-independent anemia (Hgb≤100g/L) at baseline and had received study treatment for at least 28 days. 10 (83.33%) pts had maintained stable or improved Hgb levels at the last follow up. 5/7 (71.42%) PRBC transfusion-dependent pts became transfusion independent (1 pt) or had reduced transfusion frequency (4 pts), and 2 pts remained stable. Safety The most common TEAEs were nausea 14 (50.00%), vomiting 9 (32.14%), decreased appetite 8 (28.57%), and anemia 7 (25.00%). The most frequent TEAEs ≥ Grade 3 were anemia 3(10.71%) and thrombocytopenia 2(7.14%). Conclusion: In this preliminary analysis, the combination of SEL and RUX showed encouraging efficacy and manageable safety in RUX-treated pts with myelofibrosis.

Cryopreserved Versus Non-Cryopreserved Peripheral Blood Haematopoietic Stem Cells for Autologous Stem Cell Transplantation in Multiple Myeloma: A Comparative Analysis from the Chronic Malignancies Working Party of EBMT and WBMT

Introduction: Globally, most transplant centres cryopreserve peripheral blood haematopoietic stem cells (PBSC) for use in a subsequent autologous haematopoietic cell transplant (AHCT), utilizing Dimethyl sulfoxide (DMSO) as a cryoprotectant. In contrast, non-vryopreserved PBSC are used in autologous transplants for multiple myeloma (MM) in some countries with more limited resources. We therefor compared standard MM AHCT outcomes between a large transplant centre in Algeria and EBMT registry data. Patients and Methods: This was a retrospective, international, multi-centre, matched-pair analysis between a tertiary transplant center in Algeria and EBMT-affiliated centres in 23 countries. A total of 437 consecutive adult patients undergoing a first MM AHCT in Oran, Algeria, between 2009 and 2020 using non-cryopreserved PBSC. All patients had given informed consent for approved research. PBSC mobilization was performed using G-CSF alone (10µg/kg) for 5 days. Stem cell collection was performed on either the Cobe Spectra or Optia using standard protocols. PBSCs were stored in a 4°C refrigerator immediatly post-collection. PBSC viability was calculated by standard Trypan Blue and flow cytometric techniques. The conditioning regimen was either Melphalan 140 mg/m 2 or 200 mg/m 2. PBSCs were infused 24 hours following Melphalan administration. Patients from Oran were matched to a maximum of 4 patients from an overall cohort of 64,030 patients from 420 EBMT-affiliated centres receiving cryopreserved stem cells over the same time-period. Pair matching was based on the following criteria: (1) patient gender (M,F), (2) MM sub-classification (IgG, IgA, light-chain only), (3) disease status at AHCT (CR, VGPR, PR, relapse/progression), (4) Melphalan conditioning dosage (140 or 200), (5) interval from diagnosis to AHCT, (6) date of AHCT, and (7) age at AHCT. Exact matching was used for the first four variables; propensity score matching was used for the remaining three. Primary endpoints were neutrophil and platelet engraftment as defined by standard EBMT criteria. Secondary endpoints included non-relapse mortality (NRM). The cumulative incidence of neutrophil and platelet engraftment was estimated using the crude cumulative incidence estimator with death was as competing event. The same method was used to estimate NRM as a competing event. Groups were compared using Gray's test. Results: In Oran, 437 MM patients were autografted between 2009 and 2020. Induction regimens (available in 436/437) were heterogeneous (VAD (11.2%), VD (13.3%), CTD (1.4%), VTD (43.1%), VRD (1.4%), VCD (28.0%), TD (0.5%), PAD (0.5%) or others (0.7%)) reflective of local practice. Most patients had one line of induction therapy (n=333 (76.4%); 98 patients (22.5%) had a second line of therapy prior to mobilization. The mean number of collection procedures was two (range (r), 1-3). The average PBSC viability was 95% (r, 93.8-98.5%). Complete matching variable data was available in 405 Oran patients (93%) and 19/405 (4.7%) could not be matched to EBMT patients. These were mostly younger patients (16/19<50 years at AHCT) who received low dose melphalan (17/19 received 140 mg/m 2 melphalan). Of the 386 patients, 357 patients had the required matches of 4 patients from the EBMT database and were used in this analysis. For the patients from Oran, the median dose of PBSCs collected was 3.2x10 6 CD34+ cells/kg (interquartile range (IQR, 2.4-4.5); for EBMT patients (available in 12%), it was 3.7x10 6CD34+ cells/kg (IQR, 2.8-4.9) (p=0.22). Regarding engraftment kinetics, the median times to neutrophil engraftment for the non-cryopreserved and EBMT cryopreserved cohorts were 12 (IQR, 11 to 14) days, and 12 (IQR, 11 to 13) days, respectively (p=0.11). Moreover, no significant difference was evident in the median time to platelet engraftment>20x10 9/L: non-cryopreserved 12 (r, 11 to 14) days and EBMT cryopreserved 12 (r, 11 to 14) (p=0.39) (Figure 1). Non-relapse mortality at day 100 (NRM) rate was 1%(0-2%) in Oran and 1% (1-1%) in EBMT (p=0.4). Conclusion: This large co-operative study between Oran and EBMT found that neutrophil and platelet engraftment rates were similar in the cryopreserved and non-cryopreserved matched cohorts. Moreover, there was no difference in NRM. The use of non-cryopreserved PBSC for MM AHCT in countries with limited resources is more straighforward and less costly.

Treosulfan Compared to Busulfan in Allogeneic Haematopoietic Stem Cell Transplantation for Myelofibrosis: A Registry-Based Study from the Chronic Malignancies Working Party of the EBMT

Background The optimal conditioning prior to allogeneic stem cell transplantation (HSCT) for myelofibrosis (MF) remains an ongoing matter of debate. There is a paucity of randomized trials robustly showing superiority of one over another. Registry studies comparing reduced intensity conditioning (RIC) versus myeloablative conditioning (MAC) regimens did not show significant differences in overall survival (OS). Recently, a multi-center phase 3 trial in MDS-AML reported an advantage of fludarabine-treosulfan (TREO) over fludarabine-busuflan (BU) RIC (Lancet Haematol Beelen et al 2020). The role of this large EBMT registry study was to compare outcomes of MF HSCT following TREO and BU based MAC or RIC regimens. Methods Patients with MF transplanted from a T-cell replete graft between 2010-2018 following BUMAC, BURIC or TREO were identified in the EBMT registry. Patients who were transformed into AML were excluded. Centers were contacted to participate in additional data collection. 63 centers included a total of 536 patients of whom 6 patients were excluded due to missing data for major endpoints (relapse or regimen). The role of TREO was tested in multi-variable models adjusted on major prognostic factors especially those who were not well balanced between groups and using multiple imputation for missing values. Results Most TREO (n=73) patients received it in combination with FLUDARABINE (95%) and most BU (n=457) received FLUDARABINE +/- other (93%). Median total dose received of TREO was 42 g/m2 and median dose of BU was 8mg/kg. Main differences between the 3 groups were: 1) Recipient age; patients were the oldest in the RIC group (median age 61 years, (IQR: 55-65), the youngest in BUMAC (56 years, (IQR: 51-62)), and intermediate in the TREO group (59 years, (IQR: 54-64); 2) Performance status; Karnofsky score was < 80 in 20%, 30%, 42% in the TREO, BUMAC and BURIC groups, respectively; 3) Comorbidity score (HCT-CI) was lowest in the MAC group (HCT-CT ‘low’ in 56%, 45% and 37% of BUMAC, BURIC and TREO groups); 4) Disease status; patients in the TREO group were more often transplanted with progressive disease (58% vs 30% in BUMAC and 34% in BURIC); 5) JAK inhibitor prior to HSCT; a higher proportion of patients in the TREO group were treated with a JAK inhibitor before HSCT (61% vs 50% in BUMAC and 42% in BURIC); 6) Cytomegalovirus (CMV) donor/ recipient status; CMV combinations were more frequently donor recipient -/- in the TREO cohort (41% vs 28% in MAC and 36% in RIC); 7) an HLA matched sibling donor was less frequently used in TREO group (18% vs. 28% in BURIC and 36% in BUMAC). The 3 groups were well balanced regarding period of transplantation, MF classification (primary versus secondary), splenomegaly at time of transplantation, chromosome abnormalities, MF related symptoms, DIPSS score, GVHD prophylaxis and use of ATG. Median time to neutrophil recovery was 17 days (range: 6-54), with no differences between the 3 groups. Cumulative incidence of engraftment at day 30 was 91.5% (95%CI: 89.1-93.9), with no differences between the 3 groups. Cumulative incidence of grade 2-4 acute GVHD at 120 days for the entire cohort was 23% (95%CI: 19-26%); similar in the 3 groups. Three-year OS was 62% (95% CI 58 -66), 3-year PFS was 49% (45-53). At 3 years, cumulative incidence of relapse was 26% (22-29) and NRM was 25% (21-29). Figure 1 shows OS, PFS, NRM and cumulative incidence of relapse (CIR) according to regimen. Multiple variables Cox models after selection are shown in Table 1. TREO group had a significantly better OS than BUMAC (HR: 0.61, 95%CI: 0.39-0.93), BURIC had similar OS to BUMAC (HR: 0.92, 95%CI: 0.68-1.26) and there was a trend for a better OS with TREO over BURIC (HR: 0.66, 95%CI: 0.41-1.05). The same trend was also observed for PFS with a significant advantage of TREO over BUMAC (HR: 0.57, 95%CI: 0.38-0.84) and BURIC (HR: 0.60, 95%CI: 0.39-0.91) while BURIC had a similar risk to BUMAC (HR: 1.05, 95%CI: 0.80-1.39). The improvement of OS and PFS was related to a lower NRM (HR: 0.44, 95%CI: 0.24-0.80 TREO vs BUMAC; HR: 0.54, 95%CI: 0.28-1.04 TREO vs BURIC) and same relapse risk with TREO over BU (TREO vs BUMAC, HR: 0.71, 95%CI: 0.42-1.20; TREO vs BURIC, HR: 0.63, 95%CI: 0.36-1.11). Conclusion TREO based regimens compared to BU based shows better PFS in MF HSCT. This advantage was also confirmed for OS and NRM when compared to BUMAC. More specific prospective studies are needed to confirm findings from this registry based study.

Post-Transplant Cyclophosphamide (PTCY) Compared to ATG in Patients with Myelodysplastic Neoplasms Allografted with an Unrelated Donor: A Registry Study of the Chronic Malignancies Working Party of the EBMT

Background Prospective randomized trials have reported a benefit for ATG-based GVHD prophylaxis in the setting of allogeneic hematopoietic stem cell transplantation (alloHSCT) with an unrelated donor (UD). However, the best GVHD prophylaxis has been recently challenged by the use of PTCY, first in haplo-identical transplant and then in HLA mismatched or matched unrelated transplantation. We here present the outcomes of PTCY vs ATG as GVHD prophylaxis in MDS patients from the EBMT registry transplanted with an unrelated donor. Method A total of 969 patients transplanted from 2012 to 2019 in 92 participating centers, receiving either PTCY or ATG, were included in this study. The primary outcomes were progression free survival (PFS) and overall survival (OS). Competing risks analyses were performed to analyze non-relapse mortality (NRM) with competing event relapse, and acute GvHD grade II-IV, chronic GvHD and neutrophil engraftment with competing events relapse and death. Cox proportional hazards regression with a predefined covariate constellation (age, IPSS-R cytogenetics, donor HLA matching, age, hypomethylating agents (HMA) prior to transplantation, comorbidity score and MDS classification (MDS with or without excess blast, EB) was used to obtain adjusted effect estimates of ATG compared to PTCY for OS and PFS. Results Overall, 214 patients received PTCY and 755 received ATG as GVHD prophylaxis for UD alloHSCT. Patients of the ATG group were older (60.1 year-old [IQR: 50.6-65.2] vs 57.2 year-old [IQR: 46.4-61.1], p=0.008). Disease characteristics were similar in both group: there were a total of 583 MDS with EB at diagnosis, 510 MDS-EB at transplantation, and 207 patients transformed into AML. Among patients with available data for IPSS-R at MDS diagnosis (n=760) 44 (5.8%) were Very Low, 114 (15%) Low, 209 (27.5%) Intermediate, 232 (30.5%) High and 161 (21.2%) Very High. Patients of the PTCY group received more frequently HMA before transplantation (72.4% vs 57.3%, p=0.001) and were preferentially transplanted from an HLA mismatched 9/10 donor (37.9% vs 21.6%, p<0.001). Conditioning regimen was more frequently myeloablative in the PTCY group (55.4% vs 38.7%, p<0.001). Neutrophil engraftment at 28 days was significantly better with ATG (93% vs 84%, p<0.001). With a median follow-up of 4.4 (95% CI 4.2 - 4.8) years, five-year OS was 57% (49-64) with PCTY and 49% (95% 46-53%) in ATG group, p=0.127. Five-year cumulative incidence of relapse was similar in both groups (22%, 95%CI 16-29 in PTCY vs 25%, 95%CI 22-28 in ATG; p=0.28). Notably, 5-year PFS was marginally higher for PTCY with 52% (95%CI 44-59) vs 44% (95%CI 40-48) for ATG, p=0.075, whereas 5-year NRM was 26% (95% CI 20-32%) vs 31% (95% CI 27-34) in PTCY and ATG, respectively, p=0.28. Grade II-IV acute GVHD incidence was lower using PTCY (22% [95% CI 17-28%] vs 30% [95% CI 26-33%]), p=0.035 while there was no difference for chronic GVHD (36% (29-43% with PTCY vs 38% (34-41%) in ATG at 5 years). Multivariable analyses confirmed a better OS and PFS for PTCY, with a HR of ATG of 1.34 (95% CI 1.02-1.76), p=0.04, and a better PFS for PTCY with a HR for ATG of 1.31 (95%CI 1.01-1.69) (Table 1). There was no apparent interaction between GvHD prophylaxis and IPSS-R or HLA matching, suggesting an effect exclusive to the type of GVHD prophylaxis used. Conclusion: This EBMT registry study suggests that MDS patients who received a transplant from an unrelated donor had a better OS and PFS using PTCY compared to ATG. This confirms that PTCY instead of ATG in this setting is a valid option.

Clinical Characteristics and Prognostic Factors of Patients With Stenotrophomonas maltophilia Pneumonia: 10-Year Experience From a Single Center.

Stenotrophomonas maltophilia infection is gaining importance as an important cause of nosocomial pneumonia. S. maltophilia infection occurs especially in patients with a history of immunosuppression, comorbidity, or multiple antibiotherapy uses. A retrospective 10-year study was carried out to determine the clinical characteristics of all patients with S. maltophilia pneumonia, antibiotic resistance pattern, and risk factors associated with hospital mortality. Hospitalized pneumonia patients with S. maltophilia culture positivity were identified, and their medical records were reviewed. Risk factors associated with hospital mortality were analyzed. Any variable with a significant association with mortality in the univariate analysis was entered in a multivariate forward stepwise logistic regression model to identify independent risk factors for death. Seventy-two patients (mean age: 67.3 years, 65.2% males) with S. maltophilia pneumonia were included in the study. All patients had at least one comorbidity. The most common comorbidities were chronic obstructive pulmonary disease, diabetes mellitus, chronic renal failure, malignancy, and cardiac diseases. Percentage resistance to trimethoprim-sulfamethoxazole (5.5%) was lower than that for fluoroquinolones (12.5%). By using multivariate analysis, respiratory insufficiency needed mechanical ventilation, low hemoglobin level, age>65 years, previous antibiotic usage, and hypotension were the independent prognostic factors for mortality. S. maltophilia is emerging as an important pathogen with an increased risk of mortality in patients with respiratory insufficiency who need mechanical ventilation, a low hemoglobin level, >65 years of age, previous antibiotic usage, and hypotension. Empiric therapy should include agents active against S. maltophilia, such as newer fluoroquinolones and trimethoprim-sulfamethoxazole.

Medullary Infarction of Bilateral Tibia - A Rare Presentation of Tuberculosis: A Case Report with Review of Literature

Background: Bony infarction or osteonecrosis is a rare, painful condition, reported in the setting of trauma, chronic steroid exposure, radiation, malignancies, and sickle cell anemia, diagnosed radiologically by its characteristic features in magnetic resonance imaging (MRI). The present case highlights the challenges in the diagnosis and management of an adolescent boy, who presented with medullary infarction of bilateral tibia. Clinical Description: A 15-year-old boy presented with severe pain in bilateral lower limbs, restricting his ability to stand and walk independently. There were no signs of inflammation or restriction of movements at the joints of the lower limb. Routine investigations were largely normal. The MRI of left tibia showed bone infarct in the middle shaft. Further investigations for the known causes of bone infarct were noncontributory. Considering a remote possibility that tuberculous endarteritis may cause such an infarct, tuberculin test was done which was positive. The chest X-ray was normal. Management and Outcome: Therapeutic trial of antitubercular drugs (2HRZE+10HRE) was given. The child showed a significant improvement in leg pain by 2 weeks of the start of therapy. On follow-up, he demonstrated complete resolution of the disease in X-ray and MRI. Conclusion: Tuberculosis endarteritis leading to bony infarction is an extremely rare phenomenon but biologically plausible. By reporting this case, we would like to convey that clinicians may consider bone infarct as a rare cause of unexplained, incapacitating limb pain in children, which, in the absence of known contributory factors, may be due to tuberculosis.

Graft-versus-Host Disease Prophylaxis with Post- Transplantation Cyclophosphamide in Chronic Myeloid Leukemia Patients Undergoing Allogeneic Hematopoietic Cell Transplantation from an Unrelated or Mismatched Related Donor: A Comparative Study from the Chronic Malignancies Working Party of the EBMT (CMWP-EBMT)

Outcomes following allogeneic hematopoietic cell transplantation (allo-HCT) for chronic myeloid leukemia (CML) with post-transplantation cyclophosphamide (PTCy) using an unrelated donor (UD) or a mismatched related donor (MMRD) remain unknown. We report a retrospective comparison of PTCy-based allo-HCT from a UD, non-PTCy allo-HCT from a UD, and PTCy allo-HCT from an MMRD. Inclusion criteria were adult patients with CML undergoing first allo-HCT between 2012 and 2019 from a UD with either PTCy or non-PTCy graft-versus-host disease (GVHD) prophylaxis or from an MMRD using PTCy. The primary endpoint was GVHD-free/relapse-free survival (GRFS). A total of 1341 patients were included (82% in the non-PTCy UD cohort). With a median follow-up of 34.9 months, the 3-year GRFS was 43% in the non-PTCy cohort, 37% in the PTCy-UD cohort, and 39% PTCy-MMRD cohort (P=.15). Multivariable analyses revealed no significant differences among the 3 cohorts in terms of overall survival (OS), progression-free survival, RI, and nonrelapse mortality. Factors independently associated with worse OS in the overall cohort were Karnofsky Performance Status <90 (hazard ratio [HR], 1.86; 95% confidence interval [CI], 1.41 to 2.45; P < .001), older age (HR, 1.24, 95% CI, 1.11 to 1.38; P < .001), and disease stage (compared to chronic phase [CP] 1): blast phase (HR, 2.25; 95% CI, 1.60 to 3.16; P < .001), accelerated phase (HR, 1.63; 95% CI, 1.05 to 2.54; P=.03), and CP >2 (HR, 1.58; 95% CI, 1.15 to 2.17; P=.005). These results suggest that allo-HCT in patients with CML using either a UD or an MMRD with PTCy-based GVHD prophylaxis are feasible transplantation, platforms and that the disease stage at allo-HCT remains a major prognostic factor, highlighting the importance of closely monitoring CML patients and proposing transplantation when indicated when still in CP1.

Allogeneic hematopoietic cell transplantation in patients with CALR-mutated myelofibrosis: a study of the Chronic Malignancies Working Party of EBMT.

Allogeneic hematopoietic cell transplantation (allo-HCT) is curative for myelofibrosis (MF) but assessing risk-benefit in individual patients is challenging. This complexity is amplified in CALR-mutated MF patients, as they live longer with conventional treatments compared to other molecular subtypes. We analyzed outcomes of 346 CALR-mutated MF patients who underwent allo-HCT in 123 EBMT centers between 2005 and 2019. After a median follow-up of 40 months, the estimated overall survival (OS) rates at 1, 3, and 5 years were 81%, 71%, and 63%, respectively. Patients receiving busulfan-containing regimens achieved a 5-year OS rate of 71%. Non-relapse mortality (NRM) at 1, 3, and 5 years was 16%, 22%, and 26%, respectively, while the incidence of relapse/progression was 11%, 15%, and 17%, respectively. Multivariate analysis showed that older age correlated with worse OS, while primary MF and HLA mismatched transplants had a near-to-significant trend to decreased OS. Comparative analysis between CALR- and JAK2-mutated MF patients adjusting for confounding factors revealed better OS, lower NRM, lower relapse, and improved graft-versus-host disease-free and relapse-free survival (GRFS) in CALR-mutated patients. These findings confirm the improved prognosis associated with CALR mutation in allo-HCT and support molecular profiling in prognostic scoring systems to predict OS after transplantation in MF.

Efficacy of sunscreen gel infused with giant tiger prawn (Penaeus monodon) head extract

Excessive sunlight exposure can lead to various minor skin disorders, including sunburn and the development of chronic skin malignancies. One effective preventive measure against these adverse effects is the use of sunscreen. Sunscreen can be derived from natural sources, such as the astaxanthin compound in giant tiger prawns (Penaeus monodon). This study aimed to formulate a sunscreen gel from giant tiger prawn head extract that meets good physical gel standards. Additionally, the study sought to determine the sun protection factor (SPF), erythema transmission level (%TE), and pigmentation transmission level (%TP) through in-vitro testing. The extraction process involved using coconut oil as a solvent using the maceration method. The resultant extract was then evaluated for SPF, %TE, and %TP values and subsequently formulated into gel variants with extract concentrations ranging from 1% to 10%. The findings of this investigation revealed that the giant tiger prawn head extract exhibited SPF, %TE, and %TP values of 8.0±0.11, 18.8±0.25%, and 21.7±0.73%, respectively, categorizing it as providing maximum protection, facilitating fast tanning, and acting as a sunblock. The gel formula containing 8% giant tiger prawn head extract demonstrated the highest sunscreen potential. In conclusion, this study highlights the promising potential of giant tiger prawn head extract as a natural sunscreen ingredient and identifies the optimal gel formula for effective sun protection.

Hemophagocytic lymphohistiocytosis associated with sodium valproate

Hemophagocytic lymphohistiocytosis(HLH) is known to have numerous causes, such as chronic inflammation, infection, malignancy, drug use, and primary or familial HLH. HLH triggered by valproate (VPA) has rarely been reported in the literature. Here we describe a pediatric patient with HLH induced by VPA. A 5-years-old girl presented to our center with recurrent fever accompanied by diffuse generalized rash after 2 weeks of taking oral VPA. Physical examination revealed hepatosplenomegaly; laboratory findings showed bicytopenia (hemoglobin and platelet), hemophagocytic cells on the bone marrow smear, hypofibrinogenaemia and hypertriglyceridaemia, and a high ferritin level. She was diagnosed to have HLH associated with VPA. She was treated with intravenous immunoglobulin, glucocorticoid and withdrawal of the sodium valproate, and she completely recovered. In conclusion, VPA can trigger HLH, a potentially fatal condition.

Long-term management and outcome of lung transplantation in Japan.

The long-term survival after lung transplantation (LT) is favorable in Japan. However, long-term survivors after LT are subject to late complications, including chronic lung allograft dysfunction (CLAD), malignancy, infection, and chronic kidney disease (CKD) because of the need for lifelong immunosuppression. The rates of single cadaveric LT (CLT) and living-donor lobar LT (LDLLT) are higher than that of bilateral CLT in Japan. Here, we will describe the management of late complications and long-term outcome after LT in Japan. Attention should be paid to not only the phenotype of CLAD but also the difference in CLAD after CLT and after LDLLT as well as the timing of lung re-transplantation for advanced CLAD, especially after single CLT. Since post-transplant lymphoproliferative disorder is the most common malignancy after LT, infection monitoring for infection-related malignancies and appropriate screening are keys to the early diagnosis and treatment of malignancy after LT. The long-term management of infection after LT is also important, especially with regard to community-acquired pathogens, Aspergillus, and cytomegalovirus. When providing long-term care after LT, physicians should be aware of CKD and the timing of renal replacement therapy in cases with severe CKD. The widespread use of computed tomography and dialysis in Japan are beneficial for long-term survivors of LT. The similar survival outcomes of single CLT and LDLLT, compared with bilateral CLT, might contribute to improved long-term survival in Japan. Pulmonologists are encouraged to become further involved in long-term management after LT in Japan.

Mortality Prediction in Patients With or Without Heart Failure Using a Machine Learning Model

BackgroundMost risk prediction models are confined to specific medical conditions, thus limiting their application to general medical populations. ObjectivesThe MARKER-HF (Machine learning Assessment of RisK and EaRly mortality in Heart Failure) risk model was developed in heart failure (HF) patients. We assessed the ability of MARKER-HF to predict 1-year mortality in a large community-based hospital registry database including patients with and without HF. MethodsThis study included 41,749 consecutive patients who underwent echocardiography in a tertiary referral hospital (4,640 patients with and 37,109 without HF). Patients without HF were further subdivided into those with (n = 22,946) and without cardiovascular disease (n = 14,163) and also into cohorts based on recent acute coronary syndrome or history of atrial fibrillation, chronic obstructive pulmonary disease, chronic kidney disease, diabetes mellitus, hypertension, or malignancy. ResultsThe median age of the 41,749 patients was 65 years, and 56.2% were male. The receiver operated area under the curves for MARKER-HF prediction of 1-year mortality of patients with HF was 0.729 (95% CI: 0.706-0.752) and for patients without HF was 0.770 (95% CI: 0.760-0.780). MARKER-HF prediction of mortality was consistent across subgroups with and without cardiovascular disease and in patients diagnosed with acute coronary syndrome, atrial fibrillation, chronic obstructive pulmonary disease, chronic kidney disease, diabetes mellitus, or hypertension. Patients with malignancy demonstrated higher mortality at a given MARKER-HF score than did patients in the other groups. ConclusionsMARKER-HF predicts mortality for patients with HF as well as for patients suffering from a variety of diseases.

Ayurvedic Principles to Prevent Lifestyle Disorders

In India, almost 61 percent of all death in India is due to lifestyle disorders and non-communicable diseases WHO identifies prime risk factors for LSD. These are alcohol and tobacco intake, poor diet intake, lack of physical activities, mental stress, etc. According to sustainable development goal l3.4, which mandates a 1/3rd reduction in premature death due to lifestyle disorder by 2030.&#x0D; An individual or group of people who have a lifestyle disorder (LSD) are essentially inviting themselves to develop any number of ailments that are mostly based on how they live. These include conditions including chronic bronchitis, hypertension, heart disease, stroke, obesity, diabetes, and malignancies brought on by diet and cigarette use. Ayurveda describes several principles to prevent LSD like Dincharya (daily routine), Ritucharya (seasonal routine), Sadvratta (code of conduct), etc but seven principles are essential to follow to lead a healthy life. These are 1. Tri-upstairs (Ahara, Vihara, Brahmacharya) which is the main pillar of health, 2. Dincharya, 3. Ritucharya, 4. Avoidance of Vegadharana (suppression of natural urges), 5. Avoidance of Prajnapradha (renunciation) 6. Sadvratta (good code of conduct), 7. Yoga (to avoid mental stress). This article mainly emphasizes the preventive aspect of Lifestyle disorder by using the Ayurveda principle.

T-cell dysfunction by pseudohypoxia and autocrine purinergic signaling in chronic lymphocytic leukemia

AbstractAcquired T-cell dysfunction is common in chronic B-cell malignancies. Given the strong connection between T-cell metabolism and function, we investigated metabolic alterations as the basis of T-cell dysfunction induced by malignant cells. Using B-cell malignant cell lines and human peripheral blood mononuclear cells, we first established a model that recapitulates major aspects of cancer-induced T-cell dysfunction. Cell lines derived from chronic lymphocytic leukemia (CLL) (PGA-1, CII, and Mec-1), but not from other B-cell malignancies, altered the T-cell metabolome by generating a pseudohypoxic state. T cells were retained in aerobic glycolysis and were not able to switch to oxidative phosphorylation (OXPHOS). Moreover, T cells produced immunosuppressive adenosine that negatively affected function by dampening the activation, which could be restored by the blocking of adenosine receptors. Subsequently, we uncovered a similar hypoxic-like signature in autologous T cells from primary CLL samples. Pseudohypoxia was reversible upon depletion of CLL cells ex vivo and, importantly, after the in vivo reduction of the leukemic burden with combination therapy (venetoclax and obinutuzumab), restoring T-cell function. In conclusion, we uncovered a pseudohypoxic program connected with T-cell dysfunction in CLL. Modulation of hypoxia and the purinergic pathway might contribute to therapeutic restoration of T-cell function.

Carfilzomib, lenalidomide and dexamethasone followed by a second ASCT is an effective strategy in first relapse multiple myeloma: a study on behalf of the Chronic malignancies working party of the EBMT.

In the setting of a first relapse of multiple myeloma (MM), a second autologous stem cell transplant (ASCT) following carfilzomib-lenalidomide-dexamethasone (KRd) is an option, although there is scarce data concerning this approach.We performed a retrospective study involving 22 EBMT-affiliated centers. Eligible MM patients had received a second-line treatment with KRd induction followed by a second ASCT between 2016 and 2018.Primary objective was to estimate progression-free survival (PFS) and overall survival (OS). Secondary objectives were to assess the response rate and identify significant variables affecting PFS and OS. Fifty-one patients were identified, with a median age of 62 years. Median PFS after ASCT was 29.5 months while 24- and 36-months OS rates were 92.1% and 84.5%, respectively. Variables affecting PFS were an interval over four years between transplants and the achievement of a very good partial response (VGPR) or better before the relapse ASCT. Our study suggests that a relapse treatment with ASCT after KRd induction is an effective strategy for patients with a lenalidomide-sensitive first relapse. Patients with at least four years of remission after a frontline ASCT and who achieved at least a VGPR after KRd induction appear to benefit the most from this approach.

Hypoosmolar and hyperosmolar COVID-19 patients are predisposed to dismal clinical outcomes

We aimed to investigate the associations of hypo- and hyperosmolarity at hospital admission with clinical characteristics and outcomes in 5645 consecutive hospitalized COVID-19 patients treated at a tertiary-level institution. Serum osmolarity was calculated as 2x Na (mmol/L) + urea (mmol/L) + glucose (mmol/L), with normal range from 275 to 295 mOsm/L. Median serum osmolarity was 292.9 mOsm/L with 51.8% normoosmolar, 5.3% hypoosmolar and 42.9% hyperosmolar patients present at the time of hospital admission. Hypoosmolarity was driven by hyponatremia, and was associated with the presence of chronic liver disease, liver cirrhosis, active malignancy and epilepsy. Hyperosmolarity was driven by an increase in urea and glucose and was associated with the presence of chronic metabolic and cardiovascular comorbidities. Both hypo- and hyperosmolar patients presented with more severe COVID-19 symptoms, higher inflammatory status, and experienced higher mortality in comparison to normoosmolar patients. In multivariate analysis, hypoosmolarity (adjusted odds ratio (aOR)=1.39, p = 0.024) and hyperosmolarity (aOR = 1.9, p < 0.001) remained significantly associated with higher mortality independently of older age, male sex, higher Charlson Comorbidity Index and more severe COVID-19. Disruptions in serum osmolarity are frequent in COVID-19 patients, may be easy to detect and target therapeutically, and thus potentially moderate associateds poor prognosis.

Diagnosis and treatment of glomerular diseases with a membranoproliferative glomerulonephritis (MPGN) pattern of injury

Membranoproliferative glomerulonephritis (MPGN) represents aheterogeneous group of diseases. The common feature of amembranoproliferative lesion pattern in the kidney biopsy can either be idiopathic/primary or-much more frequently-have asecondary cause. The historical classification into MPGN typesI toIII has largely been abandoned and replaced in recent years by apathogenesis-oriented classification. AMPGN with C1q, C3 and/or C4 deposits on light microscopy is referred to as immune complex GN (IC-GN), while aMPGN with dominant C3 deposits is referred to as C3 glomerulopathy (C3G). C3G is further divided into C3 glomerulonephritis (C3GN) and dense deposit disease (DDD). These diagnoses can only be made by akidney biopsy. Possible causes of MPGN are chronic infections (especially hepatitisB andC, bacterial infections, infections with protozoa), autoimmune diseases (especially lupus, rheumatoid arthritis) or malignancies (especially hematological malignancies). Particularly in the case of C3G acomprehensive analysis of the complement system components is strongly recommended. Due to the low incidence and the heterogeneous clinical appearance of MPGN therapeutic decisions must be made individually; an optimal general therapy is unknown, except that supportive treatment as with other glomerular diseases should be optimized. In the case of asecondary MPGN it is generally recommended to treat the potential cause of the MPGN. If significant proteinuria persists and eGFR remains > 30 ml/min/1.73 m2, treatment with systemic steroids and mycophenolate mofetil is recommended. Other treatment options on an individual level after evaluation and discussion of the risk-benefit ratio with the patient are rituximab and eculizumab. Rapidly progressive MPGN should be treated like ANCA-associated vasculitis. The recurrence rates after kidney transplantation are very high and treatment is challenging.

Investigating the association of acute kidney injury (AKI) with COVID-19 mortality using data-mining scheme

COVID-19 has caused significant challenges in kidney research and disease management. Data mining techniques such as logistic regression (LR) and decision tree (DT) were used to model data. All analyses were performed using SPSS 25 and Python 3. The incidence of acute kidney injury (AKI) was 14.1% and the overall mortality risk was 13% among COVID-19 patients. The mortality was associated with, AKI, age, marital status, smoking status, heart failure, chronic obstructive pulmonary disease, malignancy, and SPO2 level using LR. The accuracy, sensitivity, specificity, and area under the curve of the DT (and LR) classifier were 70% (85%), 73% (75%), 78% (79%), and 77% (81%), respectively. Based on the DT model, the variable most significantly associated with COVID-19 mortality was AKI followed by age, high WBC count, BMI, and lymphocyte count. It was concluded that the incidence of AKI was high, and AKI was identified as one of the important factors that played an effective role in mortality due to COVID-19.

Targeting PP2A-dependent autophagy enhances sensitivity to ruxolitinib in JAK2V617F myeloproliferative neoplasms

The Janus kinase 2 (JAK2)-driven myeloproliferative neoplasms (MPNs) are chronic malignancies associated with high-risk complications and suboptimal responses to JAK inhibitors such as ruxolitinib. A better understanding of cellular changes induced by ruxolitinib is required to develop new combinatory therapies to improve treatment efficacy. Here, we demonstrate that ruxolitinib induced autophagy in JAK2V617F cell lines and primary MPN patient cells through the activation of protein phosphatase 2A (PP2A). Inhibition of autophagy or PP2A activity along with ruxolitinib treatment reduced proliferation and increased the death of JAK2V617F cells. Accordingly, proliferation and clonogenic potential of JAK2V617F-driven primary MPN patient cells, but not of normal hematopoietic cells, were markedly impaired by ruxolitinib treatment with autophagy or PP2A inhibitor. Finally, preventing ruxolitinib-induced autophagy with a novel potent autophagy inhibitor Lys05 improved leukemia burden reduction and significantly prolonged the mice’s overall survival compared with ruxolitinib alone. This study demonstrates that PP2A-dependent autophagy mediated by JAK2 activity inhibition contributes to resistance to ruxolitinib. Altogether, our data support that targeting autophagy or its identified regulator PP2A could enhance sensitivity to ruxolitinib of JAK2V617F MPN cells and improve MPN patient care.