Venetoclax adverse event monitoring: a safety meta-analysis of randomized controlled trials and a retrospective evaluation of the FAERS.

Concerns persist about venetoclax's long-term safety in larger populations, with limited evidence of infrequent and delayed adverse events (AEs). The study integrated safety data on venetoclax in leukemia patients from randomized controlled trials (RCTs) and FDA adverse event monitoring system (FAERS). We systematically reviewed RCTs reporting safety outcomes of venetoclax in adult leukemia patients of any gender, either monotherapy or in combination, applying advanced search on databases like PubMed, EMBASE, and ClinicalTrial.gov. The quality assessment was done using the Cochrane Risk of Bias Tool. We utilized a random effect meta-analysis to calculate risk ratio (RR) with 95% confidence intervals (CI). The Open Vigil 2.1 MedDRAv24 was used to search the FAERS database, with data available until September 2023. The disproportionality was calculated using the proportional reporting ratio and the reporting odds ratio. The study protocol for meta-analysis was registered with PROSPERO; CRD42022378006. For the safety meta-analysis, seven RCTs with available AEs were examined. A total of 942 AEs were found associated with the venetoclax group; 79% of them were in grade three or above. Venetoclax significantly increased the risk of neutropenia grade three or above (RR = 1.34, 95% CI: 1.10-1.64, p: 0.0033) compared with the control group. In FAERS, 26,436 patients were reported with AEs associated with venetoclax. Significant signal scores were observed in hematological, cardiac, vascular, and gastrointestinal disorders. 11 out of 30 generated signals, failed to meet the signal criteria upon refinement. The current study updated and improved the safety profile of venetoclax in the post-marketing period, assisting in risk evaluation and mitigation for the best possible patient health care.

Pharmacogenetic guided versus standard warfarin dosing for routine clinical care with its pharmacoeconomic impact: a randomized controlled clinical trial.

BACKGROUND: Empirical use of pharmacogenetic test(PGT) is advocated for many drugs, and resource-rich setting hospitals are using the same commonly. The clinical translation of pharmacogenetic tests in terms of cost and clinical utility is yet to be examined in hospitals of low middle income countries (LMICs). AIM: The present study assessed the clinical utility of PGT by comparing the pharmacogenetically(PGT) guided- versus standard of care(SOC)- warfarin therapy, including the health economics of the two warfarin therapies. METHODS: An open-label, randomized, controlled clinical trial recruited warfarin-receiving patients in pharmacogenetically(PGT) guided- versus standard of care(SOC)- study arms. Pharmacogenetic analysis of CYP2C9*2(rs1799853), CYP2C9*3(rs1057910) and VKORC1(rs9923231) was performed for patients recruited to the PGT-guided arm. PT(Prothrombin Time)-INR(international normalized ratio) testing and dose titrations were allowed as per routine clinical practice. The primary endpoint was the percent time spent in the therapeutic INR range(TTR) during the 90-day observation period. Secondary endpoints were time to reach therapeutic INR(TRT), the proportion of adverse events, and economic comparison between two modes of therapy in a Markov model built for the commonest warfarin indication- atrial fibrillation. RESULTS: The study enrolled 168 patients, 84 in each arm. Per-protocol analysis showed a significantly high median time spent in therapeutic INR in the genotype-guided arm(42.85%; CI 21.4-66.75) as compared to the SOC arm(8.8%; CI 0-27.2)(p < 0.00001). The TRT was less in the PG-guided warfarin dosing group than the standard-of-care dosing warfarin group (17.85 vs. 33.92 days) (p = 0.002). Bleeding and thromboembolic events were similar in the two study groups. Lifetime expenditure was ₹1,26,830 in the PGT arm compared to ₹1,17,907 in the SOC arm. The QALY gain did not differ in the two groups(3.9 vs. 3.65). Compared to SOC, the incremental cost-utility ratio was ₹35,962 per QALY gain with PGT test opting. In deterministic and probabilistic sensitivity analysis, the base case results were found to be insensitive to the variation in model parameters. In the cost-effectiveness-acceptability curve analysis, a 90% probability of cost-effectiveness was reached at a willingness-to-pay(WTP) of ₹ 71,630 well below one time GDP threshold of WTP used. CONCLUSION: Clinical efficacy and the cost-effectiveness of the warfarin pharmacogenetic test suggest its routine use as a point of care investigation for patient care in LMICs.

How Do We Manage Chronic Lymphocytic Leukemia in India.

PURPOSE OF REVIEW: Chronic lymphocytic leukemia was an ignored leukemia in India until a decade back, given its low prevalence and absence of novel drugs to treat it. Healthcare in India is heterogeneous, with variations in population, health systems, and reimbursement options. We have focused on opinions from three hemato-oncologists incorporating an opinion poll from 44 hemato-oncologists across India on the common issues in CLL to give an idea of the practice pan-India. RECENT FINDINGS: More CLL patients are being diagnosed in their early stages. There is an attempt to use prognostic and predictive markers in making shared decisions for managing CLL. There is still a role for chemoimmunotherapy (CIT) in India, given limited health insurance coverage. But with the availability of inexpensive generics, the patient preference for non-CIT options like Bruton's tyrosine kinase (BTK) inhibitors is palpable. The CLL scene in India is changing rapidly. With the wide availability of economical generic small molecule inhibitors, monoclonal antibodies, and coverage by social health insurance schemes, India is poised to cater to most CLL patient needs.

Management of pain in the inpatient and non-surgical outpatient dermatology settings: A narrative review.

Pain is frequently encountered in dermatology practice, which impairs the activities of daily living, adds to psychological morbidity, and therefore compromises the quality of life. It ranges from mild to severe in intensity across various dermatoses and requires prompt addressal and treatment. Diseases such as extensive pemphigus vulgaris and Stevens-Johnson syndrome are especially painful and require a multidisciplinary approach with the involvement of a pain specialist in their management. The main pathogenic types of pain include visceral nociceptive, somatic nociceptive, and neuropathic types, the latter two being most relevant in dermatological disorders. Somatic nociceptive pain is often seen in patients of Stevens-Johnson syndrome/ Toxic epidermal necrolysis, epidermolysis bullosa, pemphigus vulgaris, erythema nodosum, and hidradenitis suppurativa, while neuropathic pain is part of the disease process in dermatoses like leprosy, herpes zoster, and dysesthesia syndromes. Therapeutic approaches to pain management include the use of non-opioids (acetaminophen, non-steroidal anti-inflammatory agents), opioids, and non-pharmacological therapies, along with appropriate management of the underlying dermatosis. World Health Organisation (WHO) analgesic ladder remains the most commonly employed guideline for the management of pain, although treatment needs individualisation depending on the nature and severity of pain (acute/chronic), type of dermatosis, and patient factors. There is a paucity of literature pertaining to pain management in dermatology and this topic is often neglected due to a lack of awareness and knowledge of the topic. The present review aims to discuss the pain pathway, various painful conditions in the setting of medical dermatology practice, and their management along with relevant pharmacology of the commonly used analgesics.

Bridging the gap: understanding contemporary autopsies in acute leukemia by comparing ante-mortem and post-mortem profiles.

This study investigates acute myeloid leukemia/lymphoblastic leukemia (AML/ALL) through a 14-year analysis (2009-2022) of 46 autopsied cases (age >12 years). B-ALL was the dominant subtype (34.8%). Liver and spleen were the common sites of active leukemia (63% cases). Symptoms like dyspnea and altered sensorium associated significantly with heart (p = .031) and brain leukostasis (p = .006). Measurable residual disease (MRD) negativity correlated with disease-free status outside the bone marrow, while MRD-positive cases displayed leukemic infiltrates. Infections were identified in 23 autopsied cases, notably linked to post-induction and post-transplant fatalities. Surprisingly, 18 of these 23 cases had unexpected infections mainly fungal (13 cases) with Aspergillus species as the most common. Diagnostic discrepancies were identified in 48% of cases. Malignant infiltration (46%) and infections (25%) were the leading causes of death. This research sheds light on leukemia in extra-medullary tissues, uncovers novel clinical-pathological associations, and highlights overlooked therapy side effects, offering insights for future case management.

Comparable outcomes with low-dose and standard-dose horse anti-thymocyte globulin in the treatment of severe aplastic anemia.

BACKGROUND: The standard dose (SD) of horse anti-thymocyte globulin (hATG) ATGAM (Pfizer, USA) or its biosimilar thymogam (Bharat Serum, India) for the treatment of Aplastic Anemia (AA) is 40 mg/kg/day for 4 days in combination with cyclosporine. Data on the impact of hATG dose on long-term outcomes are limited. Here, we describe our comparative experience using 25 mg/kg/day (low-dose [LD]) hATG for 4 days with SD for the treatment of AA. METHODS: We retrospectively studied patients with AA (age > 12 years) who received two doses of hATG combined with cyclosporine. Among 93 AA patients who received hATG, 62 (66.7%) and 31 (33.3%) patients received LD and SD hATG with cyclosporine, respectively. Among these,seventeen(18.2%) patients also received eltrombopag with hATG and cyclosporine. Overall response rates [complete response (CR) and partial response (PR)] of LD and SD hATG groups at 3 months (50% vs. 48.4%; p = 0.88), 6 months (63.8% vs. 71.4%; p = 0.67), and 12 months (69.6% vs. 79.2%; p = 0.167) were comparable. The mean (Standard Deviation) 5-year Kaplan-Meier estimate of overall survival and event-free survival was 82.1 (4.6)% and 70.9 (5.5)% for the study population. The mean (standard deviation) 5-year Kaplan-Meier estimate of overall survival and event-free survival of those who received LD hATG versus SD hATG dose was 82.9 (5·3)% versus 74.8 (10·3)% (P = 0·439), and 75.2 (6.2)% versus 61.4(11.2)% (P = 0·441). CONCLUSION: Our study revealed that the response rates of patients with AA and LD were similar to those of patients with SD to hATG combined with cyclosporine in a real-world setting.

Challenges in Administering Salvage Therapy and Outcomes of Relapsed/Refractory Diffuse Large B-Cell Lymphoma Patients: A LMIC Real-World Study.

Standard therapy for patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (RR DLBCL) involves salvage chemotherapy followed by autologous hematopoietic stem cell transplant. However, information regarding the number of patients receiving salvage therapy and associated factors is not available from low/middle income countries (LMICs). All patients treated at our center with RR DLBCL from 2016 to 2021 were included in the study. Univariate and multivariate analyses was performed to find factors associated with the lack of receipt of salvage chemotherapy. Eighty-five patients were included in the study. Most patients had primary refractory disease (69.4%). Only 26 patients received standard salvage therapy, while the others (N = 59) received metronomic/palliative oral therapy. On univariate analysis, patients with an annual income below India's Gross National Income per capita (p = 0.014), an education level below Class XII (p = 0.025), Stage III/IV disease at relapse (p = 0.018) and CNS relapse (p = 0.027) were more likely to receive palliative therapy. Conversely, patients with a late relapse were more likely to receive salvage therapy (p = 0.001). On multivariate analysis, patients with Stage III/IV relapse (p = 0.030) and an education level less than Class XII (p = 0.012) were more likely to receive palliative therapy, while patients with a late relapse (p = 0.001) were more likely to receive salvage therapy. Patients who received salvage therapy had a longer Median OS than those who received palliative therapy (p < 0.001). Timing of relapse, stage at relapse and educational status of the patient are significant factors affecting access to effective therapy for patients with RR DLBCL in LMICs.

The frequency and clinical outcome of mono-hit and multi-hit TP53 aberrations in newly diagnosed multiple myeloma.

We investigated the frequency and outcome of mono-hit and multi-hit TP53 aberrations [biallelic or ≥1 TP53 mutations (TP53mut) or TP53mut with variant allele frequency (VAF) ≥55%] in an Indian cohort of newly diagnosed multiple myeloma (NDMM) patients. We employed fluorescence insitu hybridisation (FISH; n=457) and targeted next-generation sequencing (NGS; n=244) on plasma cell-enriched samples. We also studied the impact of TP53mut in cases with and without TP53 deletions (TP53del). In our cohort with a median age of 60 years, TP53del and TP53mut were seen in 12.9% (n=59/457; 14-95% cells) and 10.2% (n=25/244; 30 variants; VAF 3.4-98.2%; median 38.2%) respectively. Mono-hit and multi-hit-TP53 aberrations were observed in 10.2% and 7.8%, respectively. Compared to TP53-wild-type (TP53wt), mono-hit and multi-hit TP53 aberrations were associated with significantly poorer progression-free survival (PFS) (22.6 vs 12.1 vs 9.5 months; p=0.004) and overall survival (OS) [not reached (NR) vs 13.1 vs 15.6 months respectively; p=0.024]. However, multi-hit TP53 did not significantly differ in OS/PFS compared to mono-hit cases. Compared to TP53wt, PFS and OS were significantly poorer in patients with TP53mut only (9.5 vs 22.6 months and 12.1 months vs NR, respectively; p=0.020/0.004). TP53mut retained its significance even in the presence of any Revised International Staging System (HR 2.1; 95% CI 1.1-3.8; p=0.015) for OS. The detection of additional cases with TP53 aberrations, as well as poor survival associated with the presence of mutation alone, supports TP53mut testing in NDMM at least in patients without TP53del and other high-risk cytogenetic abnormalities.

Effectiveness of Lactoferrin in the Treatment of Anemia in Chronic Kidney Disease: A Single-Center Pilot Study.

Background: Anemia occurs in majority of patients with chronic kidney disease despite adequate dialysis and iron replete status. This study was done to evaluate the effects of lactoferrin with or without iron supplementation for the treatment of anemia in patients with chronic kidney disease (CKD). Materials and Methods: In this prospective, observational, single-center, single-arm pilot study, adult patients aged >18 years, having stage 5 CKD (estimated glomerular filtration rate [eGFR] <15 ml/min/1.73 m2), and who had anemia (hemoglobin [Hb] <10 g/dl; transferrin saturation [Tsat] >20%) were included. Patients were treated with 100 mg of oral lactoferrin twice a day for one month with or without iron supplementation. Patients had been on stable erythropoietin doses for ≥1 month prior to inclusion in the study. We report on the improvement in Hb levels and effect on inflammatory markers from baseline at four weeks. Results: A total of 46 CKD patients having anemia were included. Patients had a mean age of 39.3 years, and a majority were men (69.6%). Improvement in the mean (SD) Hb level (g/dl) was observed from baseline (8.18 [1.19]) to Week 2 (8.54 [1.57]), which attained significance at Week 4 (8.96 [1.93]; P < 0.001; mean difference: -0.76; 95% confidence interval [CI]: -1.291 to - 0.2383). The improvement in Hb was higher in women than in men (P = 0.48) and in patients receiving lactoferrin with iron supplementation than in those receiving lactoferrin alone (P = 0.14). There was a non-significant decrease in the erythrocyte sedimentation rate (P = 0.14) and a non-significant increase in C-reactive protein (P = 0.54) level. Conclusion: Oral lactoferrin therapy was effective in improving hemoglobin levels in patients with advanced CKD and anemia. The effects of lactoferrin therapy on inflammatory markers remain uncertain.

Donor types and outcomes of transplantation in myelofibrosis: a CIBMTR study.

ABSTRACT: We evaluate the impact of donor types on outcomes of hematopoietic cell transplantation (HCT) in myelofibrosis, using the Center for International Blood and Marrow Transplant Research registry data for HCTs done between 2013 and 2019. In all 1597 patients, the use of haploidentical donors increased from 3% in 2013 to 19% in 2019. In study-eligible 1032 patients who received peripheral blood grafts for chronic-phase myelofibrosis, 38% of recipients of haploidentical HCT were non-White/Caucasian. Matched sibling donor (MSD)-HCTs were associated with superior overall survival (OS) in the first 3 months (haploidentical hazard ratio [HR], 5.80 [95% confidence interval (CI), 2.52-13.35]; matched unrelated (MUD) HR, 4.50 [95% CI, 2.24-9.03]; mismatched unrelated HR, 5.13 [95% CI, 1.44-18.31]; P < .001). This difference in OS aligns with lower graft failure with MSD (haploidentical HR, 6.11 [95% CI, 2.98-12.54]; matched unrelated HR, 2.33 [95% CI, 1.20-4.51]; mismatched unrelated HR, 1.82 [95% CI, 0.58-5.72]). There was no significant difference in OS among haploidentical, MUD, and mismatched unrelated donor HCTs in the first 3 months. Donor type was not associated with differences in OS beyond 3 months after HCT, relapse, disease-free survival, or OS among patients who underwent HCT within 24 months of diagnosis. Patients who experienced graft failure had more advanced disease and commonly used nonmyeloablative conditioning. Although MSD-HCTs were superior, there is no significant difference in HCT outcomes from haploidentical and MUDs. These results establish haploidentical HCT with posttransplantation cyclophosphamide as a viable option in myelofibrosis, especially for ethnic minorities underrepresented in the donor registries.

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.

Factors Impacting Return to Work/School among Hematopoietic Cell Transplantation Survivors in India.

Introduction: While there are data about return to work after hematopoietic cell transplantation (HCT) in survivors from resource-rich regions, similar data from resource-challenged settings are scarce. This study assessed the incidence of and factors affecting return to work/school (RTW) among HCT survivors in India. Methods: This single-center cross-sectional study was conducted at the long-term follow-up (LTFU) clinic of a large-volume HCT center during 2022-2023. HCT survivors surviving beyond four months were included after obtaining informed consent. Patients' sociodemographic, disease, HCT, and work details were recorded. The factors affecting RTW were evaluated using univariate (ANOVA) and logistic regression analyses. Results: A total of 126 HCT survivors participated in the study. Of these, 34 (27%) did not RTW, 47 (37%) returned to part-time work, and 45 (36%) returned to full-time work at a median of more than three years post-HCT. The three groups did not significantly differ in age, sex, or marital status. The univariate analysis revealed that education, pre-HCT job status, income, and conditioning intensity were significantly associated with RTW. Logistic regression analysis revealed that survivors with a higher (taxable) income were more likely to RTW than those with a lower (non-taxable) income (OR 3.5; CI 1.2-10.2, p=0.01). Survivors with a desk job were more likely to RTW than those who were unemployed/retired or students (OR 4.5; CI 1.1-18.0, p=0.03). Conclusion: Socioeconomic factors, like pre-HCT job status and income, were significantly associated with post-HCT RTW. Therefore, there is a need to integrate multidisciplinary RTW programs for HCT survivors in India.

Autopsy findings of acute erythroid leukemia

ABSTRACT Acute erythroid leukemia (AEL) is an exceedingly uncommon but distinct hematological malignancy that shows neoplastic proliferation of erythroid precursors with maturation arrest and no significant myeloblasts. We describe an autopsy case of this rare entity in a 62-year-old man with co-morbidities. He underwent a bone marrow (BM) examination for pancytopenia during the first outpatient department visit, which revealed an increased number of erythroid precursors with dysmegakaryopoiesis suggesting the possibility of Myelodysplastic syndromes (MDS). Thereafter, his cytopenia got worsened, warranting blood and platelet transfusions. Four weeks later on the second BM examination, AEL was diagnosed based on morphology and immunophenotyping. Targeted resequencing for myeloid mutations revealed TP53 and DNMT3A mutations. He was initially managed along febrile neutropenia with the stepwise escalation of antibiotics. He developed hypoxia attributed to anemic heart failure. Subsequently, he had hypotension and respiratory fatigue pre-terminally and succumbed to his Illness. A complete autopsy showed infiltration of various organs by AEL and leukostasis. Besides, there was extramedullary hematopoiesis, arterionephrosclerosis, diabetic nephropathy (ISN-RPS class II), mixed dust pneumoconiosis, and pulmonary arteriopathy. The histomorphology of AEL was challenging, and the differential diagnoses were many. Thus, this case highlights the autopsy pathology of AEL, an uncommon entity with a strict definition, and its relevant differentials.

Feasibility of treatment-free remission with generic imatinib: Results of generic imatinib-free trial-in-chronic myeloid leukaemia chronic phase study

Background & objectives: Both innovator and generic imatinib are approved for the treatment of Chronic Myeloid Leukaemia-Chronic phase (CML-CP). Currently, there are no studies on the feasibility of treatment-free remission (TFR) with generic imatinib. This study attempted to determine the feasibility and efficacy of TFR in patients on generic Imatinib. Methods: In this single-centre prospective Generic Imatinib-Free Trial-in-CML-CP study, twenty six patients on generic imatinib for ?3 yr and in sustained deep molecular response (BCR ABLIS ?0.01% for more than two years) were included. After treatment discontinuation, patients were monitored with complete blood count and BCR ABLIS by real-time quantitative PCR monthly for one year and three monthly thereafter. Generic imatinib was restarted at single documented loss of major molecular response (BCR ABLIS>0.1%). Results: At a median follow up of 33 months (interquartile range 18.7-35), 42.3 per cent patients (n=11) continued to be in TFR. Estimated TFR at one year was 44 per cent. All patients restarted on generic imatinib regained major molecular response. On multivariate analysis, attainment of molecularly undetectable leukaemia (>MR5) prior to TFR was predictive of TFR [P=0.022, HR 0.284 (0.096-0.837)]. Interpretation & conclusions: The study adds to the growing literature that generic imatinib is effective and can be safely discontinued in CML-CP patients who are in deep molecular remission.

Development of an interview-based warfarin nomogram predicting the time spent in the therapeutic INR range: A cost-effective, and non-invasive strategy building from a cross sectional study in a low resource setting

A cross-sectional study was conducted to predict time in therapeutic range (TTR) using clinical history, examination, and socioeconomic data. Study included warfarin-receiving patients from outpatient-clinic. In 203 patients studied, mean warfarin start-dose was 2.55 mg/day and maintenance-dose/week was 30.79 mg. Body mass index (BMI) (p ¼ 0.03), warfarin maintenance dose/day (p ¼ 0.02), and comorbidity presence (p ¼ 0.04) were significantly associated with TTR. Occupation (p ¼ 0.53), income (p ¼ 0.83), education (p ¼ 0.55), and socioeconomic score (p ¼ 0.73) showed non-significant association with TTR. A TTR predicting nomogram was built from clinical history and examination findings.