GVHD relapse-free survival after peripheral blood hematopoietic cell transplantation for hematologic malignancies.

The preferred choice for hematopoietic cell transplantation (HCT) donors in India is a matched related donor (MRD) followed by a haploidentical (haplo) donor for patients with hematological malignancies. International data in the haplo-HCT setting is mainly using bone marrow as a source. Almost all HCTs in India use peripheral blood stem cells (PBSC), which increases the risk of graft-versus-host disease (GVHD). In this single-center prospective study from 2017 to 2021, we sought to compare these outcomes prospectively in adult patients with hematological malignancies. Patient, disease, donor, and HCT details were prospectively recorded. GVHD prophylaxis included cyclosporine + methotrexate in MRD-HCT and post-transplant cyclophosphamide (PTCy) based in haplo-HCT. The primary endpoint GVHD relapse-free survival (GRFS) was defined as the time post-HCT without any of the following events: grade III-IV acute GVHD, chronic GVHD requiring systemic immunosuppressive treatment, disease relapse, or death from any cause. A total of 41 MRD and 33 haplo-HCT recipients were included in the study. Both cohorts were matched for age, sex, diagnosis, disease risk index, donor age, sex and CMV mismatches, and CD34 counts. A lower proportion of MRD-HCT recipients than haplo-HCT received myeloablative conditioning (39% vs. 76%, p = 0.002). There was no difference in the cumulative incidence of grade III-IV acute GVHD (16% vs. 27%, p = 0.2) or moderate-to-severe chronic GVHD (58% vs. 71%, p = 0.5). The one-year GRFS was not significantly different (53% vs. 38%, p = 0.2), with median GRFS of 420 and 274 days. The relapse incidence (22% vs. 19%, p = 0.6) and non-relapse mortality (25% vs. 35%, p = 0.4) did not differ. There was no difference in overall survival at one year (60% vs. 52%, p = 0.3). Despite a higher proportion of myeloablative conditioning in the haplo-HCT cohort, all outcomes, including GRFS, were comparable to those of the MRD-HCT cohort. This should encourage patients without an MRD to undergo haplo-HCT.

Dose-dependent renoprotection efficacy of sglt2 inhibitors in type 2 diabetes: systematic review and network meta-analysis.

AIM: To compare the relative effects of different dosages of sodium-glucose cotransport inhibitors (SGLT2i) for renoprotection in Type 2 diabetes mellitus. METHODS: The study searched different databases (PubMed, Embase, Scopus, and Web of Science) for studies comparing dose-dependent renoprotective efficacy defined as a decline in eGFR with the different "-flozins namely Empagliflozin, Canagliflozin, Dapagliflozin, Ertugliflozin, Ipragliflozin, Luseogliflozin, Remogliflozin and Sotagliflozin. The studies were compared with the Bayesian approach of network meta-analysis coupled with the random-effect model using the Cochrane risk of bias tool (RoB 2.0), and the surface under the cumulative ranking curve (SUCRA) score was allotted to each dosage of different SGLT-2i. RESULTS: A total of 43,434 citations were identified, out of which forty-five randomized trials with 48,067 patients, mentioning the flozin dose and eGFR as an endpoint, were found to be eligible for further analysis. The median duration of the follow-up in the trials was 12 months (IQR 5.5-16 months). Canagliflozin 100 mg demonstrated distinct eGFR benefit with an odds ratio of 2.3 (CI 0.72-3.9) compared to placebo. A statistically non-significant eGFR benefit was observed with all other "-flozins." Canagliflozin 100 mg drug dose category showed the highest sucra rank probability score of 93%, followed by the Canagliflozin 300 mg and Dapagliflozin 5 mg with sucra rank probability scores of 69% and 65%, respectively. The Flozin-dose assessment against eGFR was similar to the albumin-creatinine ratios as the secondary endpoint in the SUCRA ranking. CONCLUSION: The renoprotective efficacy of SGLT2i is independent of the incremental doses suggesting lower doses may suffice for renal outcomes.

Utility of eGVHD App for bedside GVHD assessment in a high-volume BMT center.

Assessing acute and chronic graft-versus-host disease (GVHD) is challenging because there are several classification systems. The European Society for Blood and Marrow Transplantation and the Center for International Bone Marrow Transplantation Registry task force recommends using the eGVHD application (App) to score acute GVHD according to the Mount Sinai Acute GvHD International Consortium (MAGIC) criteria and chronic GVHD according to the National Institutes of Health 2014 criteria. We prospectively used the eGVHD App at each follow-up visit in a large-volume bone-marrow transplant center in India from 2017 to 2021. We retrospectively evaluated the discrepancy in scoring GVHD severity by physicians not using the App from the same patient charts. The App user satisfaction and experience were recorded using the technology acceptance model (TAM) and the Post-Study System Usability Questionnaire (PSSUQ). In 100 consecutive allogeneic hematopoietic cell transplantation recipients, there was more discrepancy in scoring the severity of chronic GVHD (38%) than acute GVHD (9%) without using the App. The median TAM and PSSUQ scores were six (IQR:1) and two (IQR:1), respectively, indicating high perceived usefulness and user satisfaction. The eGVHD App is an excellent learning tool for hematology/BMT fellows and helps manage GVHD in high-volume BMT centers.

Role of fluoroquinolone prophylaxis in allogeneic hematopoietic cell transplantation in regions with a high prevalence of fluoroquinolone resistance.

Introduction: The role of fluoroquinolone (FQ) prophylaxis in preventing gram-negative bacilli (GNB) bacteremia, graft-versus-host disease (GVHD), and overall survival (OS) after allogeneic hematopoietic cell transplantation (allo-HCT) is debatable and may differ in settings with low and high prevalences of FQ resistance. In this study, we aimed to answer this question in regions with high FQ resistance. Methods: This single-center retrospective study included all consecutive allo-HCT recipients aged ≥12 years from 2012 to 2021. Allo-HCT recipients until 2016 were administered FQ prophylaxis (levofloxacin). After 2016, the institutional protocol was modified to no antibiotic prophylaxis. Data were retrieved from patient records for disease and transplant characteristics, the incidence of GNB bacteremia, duration of parenteral antibiotics, hospitalization duration, acute GVHD, and OS. Results: A total of 135 allo-HCT recipients (43 in the FQ-prophylaxis cohort and 92 in the no-antibiotic prophylaxis cohort) were analyzed in this study. The two cohorts were matched for age (median, 26 vs. 24.5 years; p = 0.8). The no-antibiotic prophylaxis cohort had a higher proportion of malignant diagnoses (80% vs. 58%, p = 0.01), haploidentical transplants (46% vs. 14%, p = 0.004), and posttransplant cyclophosphamide exposure (46% vs. 14%, p = 0.003) than did the FQ cohort. Despite this, the incidence of GNB bacteremia was not significantly different between the two cohorts (37% vs. 34%, p = 0.6). There were no differences in parenteral antibiotic use or hospitalization duration, as well as the incidence of acute GVHD (53% vs. 53%, p = 0.3). The 1-year OS was similar between the two cohorts (66% vs. 67%, p = 0.6). Conclusion: This study shows that FQ prophylaxis did not affect the incidence of GNB bacteremia, parenteral antibiotic use, hospitalization duration, acute GVHD, and OS post-allo-HCT.

Post-transplant cyclophosphamide pharmacokinetics and haploidentical hematopoietic cell transplantation outcomes: an exploratory study.

Pharmacokinetics of cyclophosphamide has been explored to optimize conditioning dosing. We hypothesized that post-transplant cyclophosphamide (PTCy) metabolite carboxy-ethyl phosphoramide mustard (CEPM) pharmacokinetics might impact haploidentical transplantation (haplo-HCT) outcomes. CEPM area under the curve (AUC0-48) was determined by eleven sampling timepoints on day +3/+4 using LC-MS/MS. The median CEPM AUC0-48 in a cohort of 30 patients was 14.2 (14) mg·hr/L. The incidence of severe chronic graft-versus-host disease (GVHD) (73% vs. 11%, p = 0.02), and GVHD-/relapse-free survival (GRFS) was significantly inferior in the CEPM AUC0-48 < 14 mg·hr/L group (54 days vs. 344 days, p = 0.02). There was, however, no difference in grade III-IV acute GVHD (38% vs. 14%, p = 0.12) and overall survival (295 days vs. not reached, p = 0.2). CEPM AUC0-48, is associated with severe chronic GVHD and GRFS post-haplo-HCT in this exploratory study. There is scope for personalizing day + 4 PTCy dose based on day + 3 CEPM AUC0-8.

Pharmacometabolomics-guided clozapine therapy in treatment resistant schizophrenia: Preliminary exploration of future too near.

AIM: To study the association of clozapine pharmacometabolomics and clozapine response in Asian patients with treatment-resistant schizophrenia (TRS). METHOD: A cross-sectional study was performed on 50 consecutive TRS patients following up in psychiatry department of the tertiary care hospital. Demographic details, response assessment, were collected on the case record form. A blood sample was also collected for trough concentration assessment of drug and its metabolites. Clozapine (CLZ) the parent drug and its two major metabolites - Clozapine N oxide (CNO) and N-Desmethyl clozapine (N-DSMC) levels were assessed using a high-performance liquid chromatography method. Clozapine responders and nonresponders patients were classified based upon Andreasen criteria. RESULTS: The average trough concentration of CNO, N-DSMC, and CLZ were 123 ± 76.04, 171.93 ± 93.24, 229.27 ± 124.25 ng/ml, respectively. The two patient subgroups did not differ for CLZ, CNO, and N-DSMC concentrations statistically. However, clozapine nonresponse was associated with a higher CLZ/N-DSMC ratio (p = 0.03) and clozapine dose (p = 0.01). The receiver operator characteristic curve showed that the cut-off CLZ/N-DSMC ratio of 1.54 with a sensitivity of 85% and a positive predictive value of 84% for identifying nonresponders. CONCLUSION: CLZ/N-DSMC ratio and clozapine dose were identified as significant variables for future dose optimization algorithms. Pharmacometabolomics-guided clozapine therapy has the potential to revolutionize TRS management.

Adherence to long-term follow-up preventive practices in allogeneic hematopoietic cell transplantation survivors from North India.

Introduction: There are existing international guidelines for long-term follow-up (LTFU) care of allogeneic hematopoietic cell transplantation (allo-HCT) survivors. However, implementing these guidelines represents a unique challenge in resource-challenged settings. Methods: This study aimed to evaluate adherence to recommended surveillance in allo-HCT survivors at an academic center in North India and study the incidence of late effects. This single-center, retrospective study analyzed records of allo-HCT recipients from 2016 to 2020. Survivors were screened in our LTFU clinic at day +100 and +365 using cardiometabolic parameters (screening for hypertension, dyslipidemia, hyperglycemia, 24-hour urine protein, thyroid function), pulmonary function test (PFT), bone mineral density (BMD), and initiation of revaccination. Results: A total of 40/80 (50%) allo-HCT survivors were alive at a median of 888 days (IQR 515-1,306). The adherence to home-based screening parameters such as blood pressure and blood glucose was highest (>75%), followed by lab-based parameters (45-70%), and lowest for specialized tests such as PFT (<50%) at both day +100 and +365 time points. Adherence to the initiation of revaccination was only 67%. At least one cardiometabolic parameter was out of range in 55% and 63% of survivors at day +100 and +365, respectively. Conclusion: The adherence to recommended surveillance measures for allo-HCT survivors in an academic LTFU clinic at one year was only 75% overall. Cardiometabolic abnormalities were noted in more than half of the survivors. This study emphasizes the need for a structured LTFU clinic in all centers performing HCT.

Impact of broad-spectrum antibiotic exposures and multidrug-resistant gram-negative bacteremia on hematopoietic cell transplantation outcomes.

INTRODUCTION: There is a close association between the use of broad-spectrum antibiotics, gut microbiome alteration, multidrug resistant (MDR) gram-negative bacilli (GNB) bacteremia, graft versus host disease (GVHD), and mortality post-allogeneic hematopoietic cell transplantation (allo-HCT). This study reports the impact of the high use of carbapenems and colistin and MDR bacteremia pre- and post-HCT on HCT outcomes. METHODS: This was a single-center, partial retrospective, and prospective study from 2016 to 2020. Both pre- and post-HCT antibiotic exposures and blood culture/sensitivity were recorded. MDR GNB was defined as either non-susceptibility to third-generation cephalosporin or carbapenems. In the absence of positive cultures, the treating physician escalated antibiotics from third-generation cephalosporins to carbapenem and/or colistin as per clinical discretion. De-escalation policy was not strictly enforced. RESULTS: MDR GNB bacteremia was seen in 29 of 76 (38%) of patients peri-HCT. The utilization rates for carbapenems and colistin was significantly higher in the cohort with MDR GNB bacteremia pre-HCT (70% vs. 32%, p = 0.002 and 31% vs. 6.4%, p = 0.007, respectively) and post-HCT (100% vs. 74.5%, p = 0.002, and 55.2% vs. 8.5%, p < 0.0001, respectively). The cohort with MDR GNB bacteremia had significantly more severe acute GVHD at day+100 (45% vs. 17.5%, p = 0.009). The median survival was 204 days compared to not reached in the cohort without any MDR GNB bacteremia (p = 0.005). CONCLUSION: This study shows pre- and post-HCT MDR GNB bacteremia is associated with an increased risk of severe acute GVHD and mortality. Patients with MDR GNB bacteremia had higher exposure to pre- and post-HCT carbapenems and colistin.

Prevalence of polymorphisms in thiopurine metabolism and association with adverse outcomes: a South Asian region-specific systematic review and meta-analysis.

Background: Prevalence and impact of thiopurine S-methyltransferase (TPMT) and Nudix hydrolase (NUDT15) minor allele frequencies in South Asian population is unclear.Methods: We searched PubMed and Embase with keywords-TPMT and NUDT15 combined with South Asian countries. We included studies reporting frequency of TPMT and NUDT15 polymorphisms. We estimated the pooled prevalence of TPMT and NUDT15 polymorphisms and their impact on pooled odds ratio of adverse events with thiopurines.Results: We included 26 studies in our analysis. The pooled prevalence of NUDT15 and TPMT polymorphisms was 16.5% (95% CI: 13.09-20.58) and 4.57% (95% CI: 3.66-5.68), respectively. In patients with adverse effects, the pooled prevalence of NUDT15 and TPMT polymorphism was 49.51% (95% C.I. 21.69-77.64) and 9.47% (95% C.I. 5.39-16.11), respectively. The odds ratio (OR) of adverse events with presence of TPMT polymorphisms was 3.65 (95% C.I., 1.43-9.28). The pooled OR for adverse events in presence of NUDT15 polymorphism was 12.63 (95% C.I., 3.68-43.26).Conclusion: NUDT15 were reported more frequently than the TPMT polymorphisms in South Asian population and were more frequently associated with adverse events. These findings may have implications for preemptive testing amongst South Asian population and immigrants prior to starting thiopurines.

Long-term outcomes of innovator versus generic melphalan formulation in autologous hematopoietic cell transplantation for multiple myeloma.

BACKGROUND: Most data on autologous hematopoietic cell transplantation (auto-HCT) in myeloma are based on the use of innovator formulation of melphalan. Comparative bioequivalence and efficacy studies of generic melphalan are lacking. METHODS: In this retrospective study, we report long-term outcomes of auto-HCT in myeloma using innovator (Alkeran, Aspen Pharma; n = 41) and generic melphalan (Alkacel, Celon Labs, India; n = 55) formulations. All consecutive patients at a single center from the period 2011-2018 were included. RESULTS: The median follow-up in the innovator and generic groups was 61.7 and 32.5 months, respectively. Both groups were matched for age, sex, stage, and myeloma response. There were significantly more patients in the innovator melphalan group who were administered melphalan at a reduced dose at physician discretion (26.8% vs. 3.6%, p = .001). There were significantly more patients with grade 3 or higher mucositis (68.3% vs. 38.1%, p < .0001) and grade 3 or higher diarrhea (85.4% vs. 50.1%, p < .0001) in the innovator group. The median duration of hospital stay was significantly longer in the innovator group (19 days vs. 15.5 days, p < .0001). There were significantly more patients in the generic group who received standard maintenance (94.5% vs. 34.1%, p < .0001). Despite the differences in the melphalan dose and post-transplant strategies, the 4-year progression-free survival and overall survival were not significantly different in the two groups (58% vs. 63%, p = .7, 71% vs. 72%, p = .4, respectively). CONCLUSION: Long-term efficacy comparison is helpful in the absence of postmarketing bioequivalence studies of generic melphalan.

Protective role of Convolvulus pluricaulis on lipid abnormalities in high-fat diet with low dose streptozotocin-induced experimental rat model.

BACKGROUND: The methanolic extract of Convolvulus pluricaulis had earlier shown lipid lowering activity in Triton induced reversible hyperlipidemia model, but, the hypolipidemic activity in irreversible models and hypoglycaemic activity are not investigated so far. OBJECTIVE: This study was designed to validate the lipid and glucose-lowering actions of C. pluricaulis methanolic extract (CPME) by using ingredients from the Indian diet for induction of hyperlipidemia and diabetes on experimental rats. MATERIALS AND METHODS: Experimental animals were divided into four groups having six animals in each group (n = 6). Animals of Group I II, III and IV received - no treatment, 0.9% NaCl, Glipizide (GPZ) 5 mg/kg and CPME 400 mg/kg once daily for two weeks respectively. Animals of all groups except group I were fed a high fat-based Indian diet for 21 days followed by a single STZ (35 mg/kg) i.p. administration in model induction phase. Afterwards, animals were sacrificed, and the pancreas was dissected for histological changes, and blood was collected for measuring lipid parameters, FBS, insulin levels, and HOMA scores. RESULTS: CPME significantly ameliorate the lipid abnormalities in HFD-STZ-treated experimental model (p < 0.001) but fails to reverse the hyperglycaemia developed in diabetic rats with no protective effect on islet architecture (p > 0.05) as compared to experimental group while, GPZ showed protective effect on both lipid abnormalities and hyperglycemia by modulating the levels of lipid parameters and insulin respectively. CONCLUSION: In conclusion, the study confirm that CPME possesses significant hypolipidemic activity but fails to reverse the hyperglycaemia developed in diabetic rats.

Impact of frailty, melphalan pharmacokinetics, and pharmacogenetics on outcomes post autologous hematopoietic cell transplantation for multiple myeloma.

Autologous hematopoietic cell transplantation (auto-HCT) using melphalan is the standard of care in the management of myeloma. Auto-HCT is a safe procedure with tolerable toxicity except in Asian-Indians. We hypothesized either one or a combination of factors: (1) frailty (assessed by IMWG frailty score), (2) generic melphalan pharmacokinetic area under the curve (AUC) assessed by high-performance liquid chromatography, and (3) pharmacogenetics of glutathione S-transferase (GSTP1) assessed by Sanger sequencing, to be associated with toxicity and survival outcomes post auto-HCT. Disease response was evaluated by IMWG response criteria at day +100 post auto-HCT. Gastrointestinal (GI) toxicity, infections, hospital stay, progression-free survival (PFS) were also recorded. A total of 35 patients were evaluated over 2 years (2016-2018). Frailty, not HCT-comorbidity index correlated with GI toxicity and infections. Overall there was an 11-fold variation in melphalan AUC with a median of 27.88 mg h/L (10.06-110.26). Patients with AUC more than the median had more GI toxicity and infections. Patients with wild-type GSTP1 polymorphism had more GI toxicity and infections. Frailty, AUC, or GSTP1 polymorphism did not impact hospitalization duration or PFS. A combination of the factors frailty, melphalan pharmacokinetics, and pharmacogenetics impacts GI toxicity and infections after auto-HCT in myeloma.

Naturalistic Evaluation of Pharmacotherapy Consultations Provided to Hospital Clinicians: A Developing Country's Perspective.

Background: Critical appraisal of published literature for hospital clinicians has never been taken as an initiative in developing countries. Objective: This study was aimed at evaluating the nature of pharmacotherapy consultations from the drug information center (DIC) of the Postgraduate Institute of Medical Education and Research, Chandigarh, India. Methods: The DIC received pharmacotherapy consultation requests from January 2016 to December 2017. Various aspects such as clinical queries, patient-related factors, and disease-related information in these requests were recorded and analyzed. Descriptive statistics and χ2 test were used for the analysis of the data and feedback evaluation, respectively. Results: During the study, a total of 179 consultation requests were documented. On 19 (10.61%) encounters, pharmacotherapy consultations occurred for emergency patient care. Of the 179 queries, 31 (17.3%) were answered immediately while 148 (82.68%) were answered within an average time of 1.6 hours. The most common type of query was the pharmacotherapy of disease, followed by dose calculation and dose modification. Communications with DIC staff took place for timely critical appraisal of the medical literature, followed by a judicious selection of higher antimicrobials and other drugs. The time taken for answering a query was found to be a statistically significant determinant of user satisfaction (P < .05). Conclusion: The evidence level-specific drug information service was established and catered to hospital clinicians through critical evaluation of offline and online resources. DIC services have the potential to revolutionize the pharmacy and pharmacology curriculum in developing countries.

Identification of unique proteins in vitreous fluid of patients with noninfectious uveitis.

PURPOSE: Uveitis is a cause for concern in the developing countries like India. Its poor diagnosis and lack of proper therapeutics often cause blindness in children and young adults. Moreover, the exact mechanism of pathogenesis of different types of uveitis is still elusive. Modern proteomic techniques are found to be advantageous for an in-depth understanding of the ocular physiology using proteomic diversity. Our aim was to identify unique proteins involved in the pathogenesis of autoimmune or noninfectious uveitis. METHODS: Vitreous fluid samples (n = 90) were obtained from infectious (N = 34) and noninfectious (N = 56) uveitis patients, and their protein profiles were compared by analysing sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and 2D electrophoresis. Unique proteins were identified through matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS) and further studied for pathway analysis. RESULTS: Protein spots having different molecular weights were observed in noninfectious vitreous fluid samples. Enzymatic digestion of these spots after MALDI-TOF MS analysis revealed different proteins. We identified 25 different proteins through SDS-PAGE and 22 through 2D electrophoresis. 50% of the proteins from SDS-PAGE were associated with heterotrimeric G-protein signalling pathway-rod outer segment phototransduction. 50% proteins from SDS-PAGE and 20% from 2D electrophoresis revealed association with de novo purine biosynthesis. Carbonic anhydrase 1 and serpin B3 were found to be common in both analyses. CONCLUSION: High-throughput proteomic and pathway analyses have exposed the potential association of these proteins with autoimmune pathogenesis in uveitis. The exact role of most of the proteins in autoimmune uveitis is yet to be unfurled.

Distribution of different genes responsible for invasive characteristics, detection of point mutations in capsular gene wchA and biofilm production among the invasive and non-invasive isolates of Streptococcus pneumoniae.

BACKGROUND: Streptococcus pneumoniae continues to cause morbidity and mortality across the globe, with developing countries bearing the brunt of the disease. It is mainly responsible for meningitis, pneumonia and septicaemia primarily in children, elderly and immunocompromised persons. Colonisation and persistence in the human nasopharynx occur during early childhood, and it appears to be prerequisite for invasive pneumococcal disease (IPD). Factors that help in persistent colonisation and subsequent invasion are ill understood. Several virulence factors have been incriminated for nasopharyngeal carriage (NC) as well as for the manifestation of the pathogenesis of IPD. MATERIALS AND METHODS: This study attempts to characterise the S. pneumoniae isolates through analysing the distribution of different virulence markers such as lytA, ply, pbpA, eno, psaA, amiA, ciaR and wchA among the isolates obtained from disease and NC. A total of 37 isolates which include 14 invasive and 23 non-invasive isolates were investigated by polymerase chain reaction to detect the genes. Eight representative isolates were investigated for mutations in wchA by DNA sequencing that may responsible for capsular variation. RESULTS: Ply, pbpA, amiA and eno were observed in a greater percentage of invasive isolates than non-invasive isolates though these differences are not statistically significant. Other two genes ciaH and psaA did not show any significant difference between two groups of isolates. Biofilm production was significantly higher in than non-invasive isolates when compared to invasive isolates. Sequence analysis of wchA revealed three significant point mutations or single-nucleotide polymorphisms (SNPs) among the isolates of one particular cluster (cluster III). These SNPs are responsible for a non-synonymous mutation in wchA bringing in an amino acid change in WchA protein, which is a part of the capsule of S. pneumoniae. Notably, all the three isolates present in cluster III had these SNPs and all of them were isolated from ocular infections. CONCLUSION: The results of our study implies a possible capsular variations among the isolates and this may have an impact on capsular typing.