Extramedullary relapse of multiple myeloma presenting as space-occupying lesion in liver treated with daratumumab, pomalidomide, dexamethasone and bendamustine.

Extramedullary relapse in patients with multiple myeloma (MM) is often associated with loss of biochemical response and the appearance of measurable residual disease in the bone marrow. Fever is an unusual presenting manifestation of MM. Treatment of extramedullary relapse in patients progressing on proteasome inhibitors, anti-CD38 monoclonal antibodies and immunomodulatory drugs is challenging, as access to chimeric antigen receptor T-cells and bispecific antibodies is limited. We report a case of relapsed MM who presented with fever and hepatic space-occupying lesion mimicking hepatocellular carcinoma. In this case report, we also present our experience of using a novel combination regimen comprising Dara-Pom-Benda-Dexa (daratumumab, pomalidomide, dexamethasone and bendamustine) for relapsed MM.

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.

Unearthing the genotype-inhibitor phenotype association in severe haemophilia A: A north Indian cohort study.

INTRODUCTION: Various risk factors for inhibitor development in haemophilia A (HA) have been described but Indian data remains scanty. AIM: We aimed to evaluate the genetic changes in Indian HA-patients that are associated with the development of inhibitors. METHODS: All HA-patients with inhibitors who availed coagulation-laboratory services from January-2015 till December-2021 and had their samples preserved for DNA extraction were included in this study. An equal number of severity-matched HA patients without inhibitors were also included as controls. Intron 22 and intron 1 inversions in Factor VIII gene were identified using inverse-shifting-PCR. Inversion-negative patients were further assessed by targeted NGS, MLPA. RESULTS: Thirty HA-patients with inhibitors were identified. All had severe-HA. Thirty severe-HA-patients without inhibitors were also included as controls. Intron 22 inversion (63.3%) and large deletions (15%) were the commonest variants identified. There was no difference in genetic variants in patients with low and high titre inhibitors. A3, A2 and C2 were the most common domains involved in inversion-negative patients with inhibitors. However, there was no significant difference in domain involvement among inversion-negative patients with and without inhibitors. Seven novel-variants were identified, including three large deletions, one large duplication and two nonsense variants in inhibitor-positive patients, and one frameshift variant in inhibitor-negative patient. After adjusting for clinical risk-factors, large deletions were independently associated with the presence of inhibitors [aOR:6.1 (1.41-56.3)]. CONCLUSION: Intron 22 inversions are the commonest variant in Indian patients with severe-HA. Large deletions predispose to inhibitor development independent of clinical risk factors.

The Utility of Quantitative D-Dimer Assay as a Biomarker in the Diagnosis and Exclusion of Cerebral Venous Sinus Thrombosis.

The utility and sensitivity of quantitative D-Dimer assay to rule out the diagnosis of deep vein thrombosis is well established. We extrapolated this principle to evaluate the utility of D-Dimer assay in exclusion of cerebral venous sinus thrombosis (CVST). As advanced imaging modalities required for the diagnosis of CVST might not be available everywhere, it is important to have a sensitive biomarker and a clinical decision rule which can assist in the diagnosis. Patients undergoing CT/MR Venography of the brain with the suspicion of CVST were enrolled. Quantitative D-Dimer assay was performed in those who had CVST on CT/MR Venography and was compared with those who did not. A Clinical decision rule for the diagnosis of CVST was formulated using logistic regression analysis. Receiver operating characteristic analysis evaluating the diagnostic accuracy of D Dimer for patients with CVST as compared to those who did not revealed an AUROC of 0.694. D-Dimer levels of < 300 ng/mL had a sensitivity of 90% for the exclusion of CVST. After logistic regression analysis, a clinical decision rule with a total score of 16 and individual components of Female gender (2 points), Headache (7 points), D-Dimer levels of ≥ 792 ng/mL (7 points) was proposed. D-Dimer had a poor diagnostic accuracy for differentiation of patients who had CVST from those who did not, however, had a high sensitivity at values < 300 ng/mL. The proposed clinical decision rule with a score of ≥ 9 had a good diagnostic accuracy in prediction of CVST (AUROC = 0.809).

Automated Knowledge Modeling for Cancer Clinical Practice Guidelines.

Clinical Practice Guidelines (CPGs) for cancer diseases evolve rapidly due to new evidence generated by active research. Currently, CPGs are primarily published in a document format that is ill-suited for managing this developing knowledge. A knowledge model of the guidelines document suitable for programmatic interaction is required. This work proposes an automated method for extraction of knowledge from National Comprehensive Cancer Network (NCCN) CPGs in Oncology and generating a structured model containing the retrieved knowledge. The proposed method was tested using two versions of NCCN Non-Small Cell Lung Cancer (NSCLC) CPG to demonstrate the effectiveness in faithful extraction and modeling of knowledge. Three enrichment strategies using Cancer staging information, Unified Medical Language System (UMLS) Metathesaurus & National Cancer Institute thesaurus (NCIt) concepts, and Node classification are also presented to enhance the model towards enabling programmatic traversal and querying of cancer care guidelines. The Node classification was performed using a Support Vector Machine (SVM) model, achieving a classification accuracy of 0.81 with 10-fold cross-validation.

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.

No role of common NOD2 gene variants in predicting sepsis related outcomes in Indian patients undergoing hematopoietic stem cell transplant.

Background: High-risk single nucleotide polymorphisms (SNPs) in nucleotide-binding oligomerization domain-2 (NOD2) gene are associated with high susceptibility for infections and inflammation due to risk of inappropriate cytokine production and NF-κB activation. We studied the incidence of three high-risk NOD2 gene SNPs (8, 12 and 13) among BM-transplant (BMT) recipients. Methods: Sequential patients undergoing BMT over 1-year period were prospectively studied. Patients were tested with MspI/HhaI or NlaIV restriction-endonucleases (Euryx, Gdansk, Poland) for NOD2 gene SNPs 8, 12, and 13, respectively. Regimen-related organ toxicity was graded using the Seattle-Bearman criteria. Results: Forty patients were enrolled, their median age was 38 years (range 3-64), and 52.5% were males. Twenty patients each (50%) underwent autologous and allogeneic BMT. Majority of the patients (n = 38, 95%) developed febrile-neutropenia in the post-transplant period and 4 patients died due to overwhelming sepsis within day +100. Acute graft-versus-host disease (GVHD) [grade I-II (n = 3) and grade III-IV (n = 6)] was observed in 9/20 allogeneic HSCT recipients. None of our 40 patients showed presence of any of the three NOD2 gene SNPs. Conclusion: The 3 commonly observed high risk SNPs (8,12, and 13) of NOD2 genes were not present in study population. It is quite likely that due to geographical and racial variations these polymorphisms are completely absent in North India. NOD2 gene is highly diverse and polymorphic variants can be absolutely different in various populations. Larger studies targeting sequencing of the whole NOD2 gene can convincingly rule out or confirm the role of NOD2 gene variants in Indian population.

Factors associated with thrombo-hemorrhagic deaths in patients with Acute Promyelocytic leukemia treated with Arsenic Trioxide and all-trans retinoic acid.

Acute Promyelocytic Leukemia (APL) is associated with excellent long-term outcomes. However, early mortality due to coagulopathy remains a challenge. In this study we examined the bleeding and thrombotic manifestations, as well as incidence of Early Death secondary to thrombosis/hemorrhage (ED-TH) in patients with APL. Early death (ED) was defined as death occurring within 30 days of induction therapy. Two-hundred forty-eight patients were included in the study. Overall, 57 patients had evidence of a major bleed/thrombosis at presentation or during induction therapy, including 44 patients with a major bleed, 8 patients with thrombosis and 5 patients with both evidence of thrombosis and a major bleed. Forty patients (16.1%) had ED, of which 21 had ED-TH. The cumulative incidence of death due to thrombo-hemorrhagic complications at 30 days was 8.4%. On univariate analysis, increasing Prothrombin time (PT)(p-<0.001), white blood cell count (p < 0.001) and activated Partial thromboplastin time (aPTT) (p < 0.001) were statistically significantly associated with increased risk of ED-TH. However, on multivariate analysis, only increasing PT (p-0.025) and aPTT (p-0.041) were significantly associated with increased risk of ED-TH.

Delayed Transfer of Critically Ill Patients from Emergency Department to Intensive Care Unit.

Background and aim: Delay in the transfer of critically ill patients from the emergency department (ED) to intensive care units (ICUs) may worsen clinical outcomes. This prospective, observational study was done to find the incidence of delayed transfer. Materials and methods: After approval from the institute ethics committee and written informed consent, all patients admitted to ICU from ED over 6 months were divided into groups I and II as patients getting transferred to ICU within 30 minutes of the decision or not, respectively. The factors affecting the immediate transfer and clinical outcome of all patients were noted. Monthly feedback was given to the ED team. Results: Out of 52 ICU admissions from ED, 35 (67.3%) patients were not transferred within 30 minutes, and the most frequent factor preventing immediate transfer was ED-related (54%). A statistically significant difference was found in acute physiology and chronic health evaluation (APACHE II) score, clinical deterioration during transfer, longer duration of mechanical ventilation and length of stay, and higher mortality with patients transferred immediately to ICU. A reduction of 42.6% was noted in transfer time from the first month to the last month of study. Conclusion: The incidence of delayed transfer of patients from ED to ICU was 67.3% with ED-related factors being the most frequent cause of delay (54.2%). How to cite this article: Bosco S, Sahni N, Jain A, Arora P, Raj V, Yaddanapudi L. Delayed Transfer of Critically Ill Patients from Emergency Department to Intensive Care Unit. Indian J Crit Care Med 2023;27(8):580-582.

Characteristics and outcome of infectious complications after autologous hematopoietic cell transplantation in multiple myeloma patients.

BACKGROUND: Infections are a significant cause of morbidity and mortality after autologous hematopoietic cell transplantation (AHCT) in multiple myeloma (MM) patients. There has been a rapid advancement and evolution in MM treatment landscape in the last decade. There is limited information on post-AHCT infectious complications among MM patients with or without levofloxacin prophylaxis from developing countries. MATERIALS AND METHODS: We performed a retrospective study to explore the incidence, pattern, and clinical outcome of infections following AHCT in MM patients from 2010 to 2019 at our center. Patient-specific, disease-specific, and transplant-specific details were retrieved from the case files. The characteristics of infectious complications (site, intensity, organism, treatment, and outcomes) were analyzed. All patients who underwent transplantation from 2010 to 2016 received levofloxacin antibiotic prophylaxis. Common terminology criteria for adverse events (CTCAE) criteria (v5.0) were used for the grading of infections and regimen-related toxicity. International Myeloma Working Group updated criteria were used for the assessment of disease response before transplant and at day +100. RESULTS: Ninety-five consecutive patients with newly diagnosed multiple myeloma (NDMM) (n = 85), RRMM (n = 7), plasma cell leukemia (n = 2), and Polyneuropathy, Orgaomegaly, Endocrinopathy, Monoclonal gammopathy, skin abnormalities (POEMS) syndrome (n = 1) underwent AHCT during the study period. Their median age was 55 years (range 33-68); 55.8% were males. Immunoglobulin IgG kappa was the most common monoclonal protein (32.6%), International Staging System stage III disease was present in 45.3%, and 84.2% of patients achieved more than very good partial response before AHCT. The median time from diagnosis to AHCT was 10 months (range 4-144). Eighty-nine patients (93.7%) developed fever after AHCT. Fever of unknown focus, microbiologically confirmed infections, and clinically suspected infections were found in 50.5%, 37.9%, and 5.3% of patients, respectively. Clostridiodes difficile-associated diarrhea was observed in eight patients (8.4%). Neutrophil and platelet engraftment occurred after a median of 11 days (range 9-14) and 12 days (range 9-23), respectively. The median duration of hospital stay was 16 days (range 9-29). Only two patients (2.1%) required readmission for infections within 100 days of AHCT. Transplant-related mortality (TRM) in the study population was 4.2% (n = 4). The levofloxacin prophylaxis group (n = 32, 33.7%) had earlier neutrophil engraftment (day +10 vs. day +11) and platelet engraftment (day +11 vs. day +12), but time to fever onset, duration of fever, hospital stay, TRM, and day +100 readmission rates were not significantly different from those of patients without levofloxacin prophylaxis. There was no significant difference in the spectrum of infections between patients with and without levofloxacin prophylaxis. The overall survival and progression-free survival of the study population at 5 years were 72.7% and 64.8%, respectively. CONCLUSION: This study shows that the incidence of infections and TRM are higher in MM patients from lower-middle income countries after AHCT than in those from developed countries. The majority of such patients lack clinical localization and microbiological proof of infection. There was no significant difference in the spectrum of infections and their outcomes in patients with and without levofloxacin prophylaxis.

Management of thromboembolic disorders during pregnancy in resource-constrained settings: An Indian perspective.

Venous thromboembolism (VTE) in pregnancy and resulting thrombotic disorders are increasingly being recognized as an important cause of maternal morbidity and mortality. The diagnosis of VTE during pregnancy has an impact on current as well as future foeto-maternal outcomes. Whereas algorithms to manage VTEs during pregnancy in developed countries exist, these are difficult to implement in resource-constraint settings. In this narrative review, we discuss strategies that can be applied in daily clinical practice by obstetricians and haematologists dealing with these disorders in the country.

Pregnancy and long-term outcomes of female patients with chronic myeloid leukemia on tyrosine kinase inhibitors who experienced unplanned pregnancies.

PURPOSE: Despite the general recommendation to avoid Tyrosine Kinase Inhibitors (TKIs) for Chronic Myeloid Leukemia (CML) during pregnancy, unplanned pregnancies still occur, particularly among female patients residing in low- and middle-income countries (LMICs). We aimed to investigate the outcomes of pregnancy, foetal development, and disease progression among female CML patients in chronic phase (CML-CP) undergoing TKI therapy who encountered unplanned pregnancies in a tertiary care hospital in northern India. METHODS: We conducted a retrospective analysis of all pregnancies in female CML-CP between January 2002 and December 2022 at our hospital. Patients were included if they had a confirmed diagnosis of CML-CP, were receiving TKI therapy during conception, and had available medical records. We analysed the data on pregnancy outcomes, foetal development, and disease progression through a review of medical records. RESULTS: We identified 36 pregnancies in female CML-CP patients on TKI therapy during the study period, with 33 (91.7%) being unplanned. Sixteen pregnancies (48.5%) were conceived at less than major molecular remission (MMR) status. Twelve pregnancies (36.4%) were electively terminated, 4 (12.1%) had miscarriages, and, 17 (51.5%) pregnancies resulted in childbirth. Out of the 17 childbirths, 10 were full-term deliveries, and 7 were preterm deliveries. Twin pregnancies had a high incidence (18.2%). Among the 21 pregnancies that were not electively terminated, TKI was stopped at the first pregnancy detection in 14 pregnancies, while imatinib was continued throughout 7 pregnancies. Patients who discontinued TKI had a higher but statistically non-significant incidence of adverse pregnancy outcomes compared to those who continued imatinib throughout pregnancy (64.2% vs. 28.6%, p = 0.18). Additionally, the risk of long-term disease progression among patients who discontinued TKI during pregnancy and those who continued imatinib throughout pregnancy was 21.4% and 16.7% (p = 0.9), respectively. The risk of long-term disease progression was significantly increased in those persistently at less than MMR pre- and post-gestation (p = 0.0002). CONCLUSION: Our findings suggest that continuing imatinib therapy during pregnancy, may be a reasonable option for CML patients residing in low- and middle-income countries to reduce the risk of disease progression and adverse pregnancy outcomes. Patients persistently at less than MMR levels pre- and post-gestation should be closely monitored for the risk of long-term disease progression. Further studies with larger sample sizes are needed to confirm these results.

A Well-Curated Cost-Effective Next-Generation Sequencing Panel Identifies a Diverse Landscape of Pathogenic and Novel Germline Variants in a Bone Marrow Failure Cohort in a Resource-Constraint Setting.

The current study is a 4-year experience in diagnosis and screening of inherited and immune bone marrow failure cases using a targeted sequencing panel. A total of 171 cases underwent targeted next-generation sequencing and were categorized as suspected inherited bone marrow failure syndrome (IBMFS) group (106; 62%) and immune/idiopathic aplastic anemia (IAA) group (65; 38%) based on clinical and laboratory criteria. A total of 110 (64%) were pediatric (aged 0 to 12 years) patients and 61 (36%) were adolescent and adult (aged 13 to 47 years) patients. In suspected IBMFS group, 47 (44%), and in IAA group, 8 (12%) revealed a likely germline pathogenic variation. Whole-exome sequencing performed in 15 of 59 suspected IBMFS group cases was negative on targeted panel, and revealed a clinically important variation in 3 (20%) cases. A total of 11 novel variants were identified. The targeted panel helped establish a diagnosis in 44% (27/61) of unclassified bone marrow failure syndrome cases and led to amendment of clinical diagnosis in 5 (4.7%) cases. Overall, diagnostic yield of this well-curated small panel was comparable to Western studies with larger gene panels. Moreover, this was achievable at a much lower cost, making it suitable for resource-constraint settings. In addition, high frequency (>10%) of cryptic pathogenic IBMFS gene variations in IAA cohort suggests routine incorporation of targeted next-generation sequencing screening in these cases.

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.