Real-World Outcomes in Transplant-Ineligible Patients With Newly Diagnosed Multiple Myeloma Treated With Bortezomib/Cyclophosphamide/Dexamethasone and Bortezomib/Lenalidomide/Dexamethasone as Upfront Treatment.

Introduction Multiple myeloma (MM) is a hematological disorder characterized by aberrant multiplication of malignant plasma cells in the bone marrow. The current mainstay of treatment for patients with newly diagnosed MM (NDMM) is a triplet regimen with a proteasome inhibitor, immunomodulatory imide, and dexamethasone. The two most common of these triplet regimens are VLD (bortezomib/lenalidomide/dexamethasone) and VCD (bortezomib/cyclophosphamide/dexamethasone). This study aims to compare the outcomes between these two therapies in transplant-ineligible patients with NDMM. Methods We conducted a retrospective study at the Aga Khan University Hospital in Karachi, Pakistan. All NDMM transplant-ineligible patients either receiving VLD or VCD therapy between January 2015 and December 2022 were included in our study. Hematological parameters before and after treatment were obtained from hospital records. Response to treatment was classified according to the International Myeloma Working Group (IMWG) response criteria as either complete response (CR), very good partial response (VGPR), partial response (PR), minimal response (MR), stable disease (SD), or progressive disease (PD). The response to treatment as well as overall survival (OS) and progression-free survival (PFS) was compared between VCD and VLD therapy. A p-value of 0.05 or less was taken to be statistically significant. Results Twenty (23.8%) patients in the VCD group and 20 (23.0%) in the VLD group underwent complete remission. Seven (8.3%) patients experienced disease progression in the VCD group, while the figure stood at three (3.4%) in the VLD group. There was no statistically significant difference in the overall response rate between the VCD (58; 69.0%) and VLD (70; 80.5%) groups (p=0.086), a difference that was not statistically significant on the Chi-square test. OS was comparable between VCD (69.1 months, 95%CI: 61.3-77.0) and VLD (76.9 months, 95%CI: 69.0-85.0) therapies. Conclusions The study did not identify any statistically significant distinction in the treatment outcomes between the VCD and VLD regimens among NDMM patients ineligible for transplantation. Nevertheless, the study highlights the positive outcomes observed with both treatments in this specific patient cohort. This implies that either regimen could be deemed suitable as a treatment option for patients in low- and middle-income countries. Since both regimens demonstrate comparable effectiveness, assessing the cost-effectiveness of these regimens is crucial. Future research should also explore the economic aspects of the two treatment options.

Dexamethasone treatment for COVID-19 is related to increased mortality in hematologic malignancy patients: results from the EPICOVIDEHA Registry.

Not available.

A Journey of Innovation: 40 years of Pioneering Medical Education at the Aga Khan University Medical College in Karachi, Pakistan.

This article presents an overview of Aga Khan University's (AKU) pioneering medical education initiatives over the past 40 years, exploring its impact on healthcare in the region and its commitment to advancing medical education and research in the developing world. Established in 1983 as the first private university in Pakistan, AKU has evolved into a global institution with a focus on improving healthcare standards and addressing healthcare needs in the developing world. The article also discusses the undergraduate and postgraduate medical education programs at AKU Medical College, Pakistan, highlighting their unique features and pioneering approaches to medical education. The institution's journey highlights its ability to adapt to the evolving healthcare landscape while maintaining a focus on quality and excellence, offering a model for other institutions striving to meet healthcare needs in low- and middle-income countries.

Humoral and T cell responses to SARS-CoV-2 reveal insights into immunity during the early pandemic period in Pakistan.

BACKGROUND: Protection against SARS-CoV-2 is mediated by humoral and T cell responses. Pakistan faced relatively low morbidity and mortality from COVID-19 through the pandemic. To examine the role of prior immunity in the population, we studied IgG antibody response levels, virus neutralizing activity and T cell reactivity to Spike protein in a healthy control group (HG) as compared with COVID-19 cases and individuals from the pre-pandemic period (PP). METHODS: HG and COVID-19 participants were recruited between October 2020 and May 2021. Pre-pandemic sera was collected before 2018. IgG antibodies against Spike and its Receptor Binding Domain (RBD) were determined by ELISA. Virus neutralization activity was determined using a PCR-based micro-neutralization assay. T cell - IFN-γ activation was assessed by ELISpot. RESULTS: Overall, the magnitude of anti-Spike IgG antibody levels as well as seropositivity was greatest in COVID-19 cases (90%) as compared with HG (39.8%) and PP (12.2%). During the study period, Pakistan experienced three COVID-19 waves. We observed that IgG seropositivity to Spike in HG increased from 10.3 to 83.5% during the study, whilst seropositivity to RBD increased from 7.5 to 33.3%. IgG antibodies to Spike and RBD were correlated positively in all three study groups. Virus neutralizing activity was identified in sera of COVID-19, HG and PP. Spike reactive T cells were present in COVID-19, HG and PP groups. Individuals with reactive T cells included those with and without IgG antibodies to Spike. CONCLUSIONS: Antibody and T cell responses to Spike protein in individuals from the pre-pandemic period suggest prior immunity against SARS-CoV-2, most likely from cross-reactive responses. The rising seroprevalence observed in healthy individuals through the pandemic without known COVID-19 may be due to the activation of adaptive immunity from cross-reactive memory B and T cells. This may explain the more favourable COVID-19 outcomes observed in this population.

Outcome of patients with primary and secondary hemophagocytic lymphohistiocytosis: A retrospective analysis from a tertiary care center.

Hemophagocytic lymphohistiocytosis (HLH) is a progressive and potentially life-threatening disorder. It is classified into primary and secondary HLH. The objective of our study was to determine the outcome of primary and secondary HLH in pediatric and adult patients based on HScore and treatment modality. We conducted a retrospective analysis done from July 2010 to June 2020. Variables analyzed included age, gender and history of death in siblings. HScore was used for disease classification while clinical and laboratory findings which were required to fulfill the HScore diagnostic criteria were also recorded. Continuous variables were summarized as median and categorical variables as frequencies and percentages. Categorical variables were compared using chi-square test and Fisher Exact test. Significance of different variables between primary and secondary HLH was calculated using independent-samples t test. A P value of < .05 was taken as significant. A total of 51 patients were included in the analysis (41 in primary and 10 in secondary HLH group). In primary HLH, 36 patients were in the pediatric age group and 12.2% had a history of death in sibling. All 41 patients had increased ferritin and decreased fibrinogen levels. The overall survival in primary HLH was 44%. In the secondary HLH group, viral infections were the most common etiology and ferritin was increased as well. The overall survival in secondary HLH was 60%. The median survival was 15 ± 4.8 months. The overall survival of both groups combined was 53%. Primary HLH should be considered in pediatric patients who present with pancytopenia and hepatosplenomegaly. In centers where genetic testing is not available, HScore along with serum ferritin and fibrinogen is a good substitute for disease classification.

Haematopoietic Stem Cell Transplant Trends in Pakistan: Activity Survey from Pakistan Bone Marrow Transplant Group.

Pakistan is the fifth most populous country with a population of 225 million and has health expenditure accounting for only 2.8 percent of gross domestic product (GDP). Accordingly, there are a limited number of haematology-oncology and transplant centers in the country. The Pakistan Blood and Marrow Transplant (PBMT) group was established in 2020, and this report is the first activity survey from January 2021 to December 2022 focusing on the trends of matched-related donor, haploidentical, and autologous transplants in a developing country. A total of 12 transplant centers contributed data on the modified PBMT survey form retrospectively and 806 haematopoietic stem cell transplants (HSCTs) were carried out during the study duration. Allogeneic HSCT constituted 595 (73.8%) of all the transplants; this is in stark contrast to Western data, where autologous HSCT accounts for the majority of transplants. ß-thalassemia major and aplastic anemia were the commonest indications for allogeneic HSCT, in contrast to Western data, where acute leukemia is the leading transplant indication. Autologous transplants were more frequently performed for Hodgkin's lymphoma as compared to non-Hodgkin's lymphoma and multiple myeloma. The use of peripheral and bone marrow stem cells was comparable. A myeloablative conditioning regimen was routinely used in patients with acute leukemia. This report provides an insight of HSCT trends in Pakistan which are different from those of Western centers contributing to transplant data from South Asia.

Response to ifosfamide, carboplatin, etoposide (ICE) vs. dexamethasone, cytarabine cisplatin (DHAP) as salvage chemotherapy in patients with relapsed/refractory lymphoma.

Background: Non-Hodgkin's lymphomas are the eighth-most prevalent malignancy in females and the eleventh in males. No research has been conducted comparing dexamethasone, cytarabine cisplatin (DHAP) vs. ifosfamide, carboplatin, etoposide (ICE) as salvage chemotherapy regimens for relapsed or refractory lymphomas in Pakistan. This study aims to compare the response of ICE vs. DHAP as salvage chemotherapy in patients with relapsed/refractory lymphomas. Methods: A prospective follow-up study was conducted at the tertiary care hospital in Karachi, Pakistan, from 2019 to 2020. A total of 58 lymphoma patients after first-line chemotherapy were included in the study. The treatment response was evaluated after two cycles of salvage chemotherapy using WHO assessment criteria, and Cox regression was used to determine the hazard ratios considering the P value ≤0.05 significant. Results: Of 58 patients, 19 (32.8%) patients achieved complete response (CR), and 8 (13.8%) patients achieved partial response (PR), with an overall response rate of overall response rate of 46.6%. In the ICE group, the response was assessed in 19 patients. Overall response was 42.1%, CR was 31.6% and PR was 10.5%. In the DHAP group, response was evaluated in 39 patients, the overall response rate was 48.7%, CR was 33.3% and PR was 15.4%. The hazard ratio for survival in patients with relapsed/refractory lymphomas who received DHAP was 1.40 times (95% CI: 1.27-3.63, P=0.001) compared to patients who received ICE as salvage chemotherapy. Conclusion: DHAP seems to have a marginally better overall response rate than the ICE regimen in patients with refractory or relapsed lymphoma. However, the toxicity profile of patients in both groups was similar.

Primary Cutaneous B-Cell Lymphoma in a Young Female.

Primary cutaneous lymphomas are a group of lymphomas that originate in the skin at the time of diagnosis. We report a case of a 45-year-old female who presented with cutaneous lesions that were unresponsive to conservative management. A biopsy was performed, which was consistent with primary cutaneous B-cell lymphoma. She received four cycles of chemotherapy and her end-of-treatment positron emission tomography (PET)-computed tomography (CT) scan showed a complete metabolic response.

Outcomes of Patients with FLT3 Positive Acute Myeloid Leukaemia; an Experience from a Tertiary Care Hospital in Karachi, Pakistan.

Introduction: Molecular genetic abnormalities in acute myeloid leukaemia (AML) are essential for disease diagnosis and determining prognosis and clinical course. Mutations in FLT3 and nucleophosmin (NPM) genes are the most frequent genetic abnormalities, which are also known to impact disease outcomes. FLT3 mutations have been identified in approximately 30% of de novo AML patients and are associated with poor prognoses. This study aimed to determine the response to induction chemotherapy, overall survival (OS) and relapse rate (RR) in patients with FLT3-positive AML. Materials and Methods: In this study, a retrospective analysis was performed of 75 newly diagnosed patients with AML registered between January 2015 and July 2022. Patient demographics and clinical-haematological parameters were noted and molecular analysis for FLT3 ITD/TKD and NPM mutations was performed. All the patients received standard induction chemotherapy and their response to treatment, OS and RR were assessed. Results: A total of 75 cases of AML were analysed. The mean age of the sample was 34.9 years, of which 65.3% were males and 34.7% were females. The patients were stratified into two groups: Those who were positive for FLT3 while negative for NPM (FLT3+/NPM-), representing 17.3% and those who were negative for both FLT3 and NPM (FLT3-/NPM-), representing 82.7% of cases. On day 28 post-induction, the complete remission rate was 69.2% in the FLT3 positive group and 77.4% in the FLT3 negative group. In the FLT3+/NPM- group, 55.6% of cases who were in remission at day 28 subsequently relapsed, compared to 50.0% of FLT3-/NPM- cases. The overall median survival time for the cohort and FLT3+ group was 1467 days, while that of the FLT3-group could not be estimated due to the very high survival rate. Conclusion: No significant differences in outcomes were observed in patients who were FLT3 positive compared to those who were FLT3 negative.

Secondary involvement of gallbladder by acute lymphoblastic leukemia presenting clinically as cholecystitis in a young patient: a case report.

BACKGROUND: Primary lymphoma of the liver, gallbladder, and extrahepatic bile ducts or secondary involvement of these organs by leukemia is exceedingly rare. Patients with primary lymphoma or leukemic involvement of the biliary tract and liver often present with symptoms and signs of biliary tract obstruction or inflammation. CASE PRESENTATION: We present a case of a 24-year-old male with biliary tract symptoms who underwent laparoscopic cholecystectomy. His precholecystectomy complete blood count performed on the same morning showed 72% lymphocytes while peripheral blood smears showed approximately 15% blasts. Surgeon went ahead with the procedure. Imaging done prior to surgery showed thickened gallbladder, while the liver, biliary tract, and pancreas did not show any thickening or mass lesion. However, the liver was enlarged. Grossly, the gallbladder wall did not show any stones or discrete mass involving the wall. Instead, there was subtle thickening of the gallbladder wall due to diffuse infiltration by the leukemic infiltrate. This lymphoid population reacted with PAX-5 and TdT immunohistochemical antibodies in a diffuse manner confirming precursor B-cell origin. This patient was found to have B-lymphoblastic leukemia involving his bone marrow on further clinical and diagnostic workup. Patient responded well to chemotherapy and is currently on maintenance treatment. He is well 1.5 years after his diagnosis. CONCLUSION: This case highlights a unique and rare scenario where a previously undiagnosed and unsuspected hematologic malignancy initially presented with clinical features of a chronic inflammatory condition involving an abdominal organ owing to secondary involvement by the malignant infiltrate.

Current Practice of Oral Care for Hematopoietic Stem Cell Transplant Patients: A Survey of the Eastern Mediterranean Blood and Marrow Transplantation Group.

INTRODUCTION: The oral cavity is one of the most common sites impacted by hematopoietic stem cell transplantation (HSCT) with acute complications including mucositis, bleeding, salivary gland dysfunction, infection, and taste alteration. These complications may result in significant morbidity and can negatively impact outcomes such as length of stay and overall costs. As such, oral care during HSCT for prevention and management of oral toxicities is a standard component of transplant protocols at all centers. The objective of this study was to evaluate the current oral care practices for patients during HSCT at different transplant centers within the Eastern Mediterranean region. MATERIAL AND METHODS: An internet-based survey was directed to 30 transplant centers in the Eastern Mediterranean region. The survey included five sections asking questions related to (1) transplant center demographics; (2) current oral care protocol used at the center and type of collaboration (if any) with a dental service; (3) use of standardized oral assessment tools and grading systems for mucositis; (4) consultations for management of oral complications; and (5) oral health needs at each center. Data are presented as averages and percentages. RESULTS: A total of 16 responses from 11 countries were collected and analyzed, indicating a response rate of 53%. Eight centers reported that a dentist was part of the HSCT team, with four reporting oral medicine specialists specifically being part of the team. Almost all centers (15/16; 93%) had an affiliated dental service to facilitate pre-HSCT dental clearance with an established dental clearance protocol at 14 centers (87%). Dental extraction was associated with the highest concern for bleeding and the need for platelet transfusion. With respect to infection risk, antibiotic prophylaxis was considered in the setting of low neutrophil counts with restorative dentistry and extraction. All centers provide daily reinforcement of oral hygiene regimen. The most frequently used mouth oral rinses included sodium bicarbonate (68%) and chlorhexidine gluconate (62%), in addition to ice chips for dry mouth (62%). The most frequently used mucositis assessment tools were the World Health Organization scale (7/16; 43%) and visual analogue scale for pain (6/16; 37%). Mucositis pain was managed with lidocaine solution (68.8%), magic mouth wash (68.8%) and/or systemic pain medications (75%). CONCLUSIONS: Scope and implementation of oral care protocols prior to and during HSCT varied between transplant centers. The lack of a universal protocol may contribute to gaps in oral healthcare needs and management for this group of patients. Further dissemination of and education around available oral care guidelines is warranted. CLINICAL RELEVANCE: Considering oral care during HSCT a standard component of transplant protocols, the current study highlights the common oral care practices for patients at centers within the Eastern Mediterranean region.

Establishment of Population Specific Reference Intervals in Healthy Pakistani Adults for 21 Routine and Special Haematology Analytes.

Background: The reference interval (RI) is an interval between two limits derived from distribution of the results obtained from a sample of the reference population. These population based RIs are of paramount significance for the accurate clinical understanding of the patient's health status. Haematological RIs are heavily influenced by a variety of geographical and environmental factors. Therefore, accrediting bodies also mandate that each laboratory should establish its own RIs in its own population. Methods: This cross-sectional study was conducted at the Department of Pathology and Laboratory Medicine, the Aga Khan University Hospital, Pakistan.Twenty-one routine and special quantitative analytes were measured in adults aged 18-60 years who passed the initial health screening questionnaire. All samples were handled strictly following standard operating procedures. Microsoft Excel and EP Evaluator software were used for statistical analysis. Nonparametric CLSI EP28-A3C method was used to establish upper and lower confidence limits at 90% significance. Results: A total of 323 participants passed the questionnaire and were short-listed for blood collection. There were 147 males and 176 females. Reference intervals were established in 297 participants after exclusion of 26 outliers with grossly abnormal test results. Analytes included: 8 red, and 12 white blood cell parameters, platelet count, immature platelet fraction, erythrocyte sedimentation levels, haemoglobin A and A2 levels and glucose-6-phosphatase dehydrogenase levels. Conclusion: Routine and special haematology RIs established in this study reflect significant differences from RIs in Caucasian population. For meaningful interpretation of test results, each haematology laboratory should establish or verify RIs in the population it serves.

Simultaneous Onset of Haematological Malignancy and COVID: An Epicovideha Survey.

Background: The outcome of patients with simultaneous diagnosis of haematological malignancies (HM) and COVID-19 is unknown and there are no specific treatment guidelines. Methods: We describe the clinical features and outcome of a cohort of 450 patients with simultaneous diagnosis of HM and COVID-19 registered in the EPICOVIDEHA registry between March 2020 to February 2022. Results: Acute leukaemia and lymphoma were the most frequent HM (35.8% and 35.1%, respectively). Overall, 343 (76.2%) patients received treatment for HM, which was delayed for longer than one month since diagnosis in 57 (16.6%). An overall response rate was observed in 140 (40.8%) patients after the first line of treatment. After a median follow-up of 35 days, overall mortality was 177/450 (39.3%); 30-day mortality was significantly higher in patients not receiving HM treatment (42.1%) than in those receiving treatment (27.4%, p = 0.004), either before and/or after COVID-19, or compared to patients receiving HM treatment at least after COVID-19 (15.2%, p < 0.001). Age, severe/critical COVID-19, ≥2 comorbidities, and lack of HM treatment were independent risk factors for mortality, whereas a lymphocyte count >500/mcl at COVID-19 onset was protective. Conclusions: HM treatment should be delivered as soon as possible for patients with simultaneous diagnosis of COVID-19 and HM requiring immediate therapy.

A scoping review of antibiotic use practices and drivers of inappropriate antibiotic use in animal farms in WHO Southeast Asia region.

Antibiotic use (ABU) plays an important role in the proliferation of antimicrobial resistance (AMR). Global antimicrobial consumption in food production is projected to rise by 67% from 2010 to 2030, but available estimates are limited by the scarcity of ABU data and absence of global surveillance systems. The WHO South-East Asia (WHO SEA) region is at high risk of emergence of AMR, likely driven by intensifying farm operations and worsening ABU hotspots. However, little is known about farm-level ABU practices in the region. To summarize emerging evidence and research gaps, we conducted a scoping review of ABU practices following the Arksey and O'Malley methodological framework. We included studies published between 2010 and 2021 on farm-level ABU/AMR in the 11 WHO SEA member states, and databases were last searched on 31 October 2021. Our search strategy identified 184 unique articles, and 25 publications underwent full-text eligibility assessment. Seventeen studies, reported in 18 publications, were included in the scoping review. We found heterogeneity in the categorizations, definitions, and ABU characterization methods used across studies and farm types. Most studies involved poultry, pig, and cattle farms, and only one study examined aquaculture. Most studies evaluated ABU prevalence by asking respondents about the presence or absence of ABU in the farm. Only two studies quantified antibiotic consumption, and sampling bias and lack of standardized data collection methods were identified as key limitations. Emerging evidence that farm workers had difficulty differentiating antibiotics from other substances contributed to the uncertainty about the reliability of self-reported data without other validation techniques. ABU for growth promotion and treatment were prevalent. We found a large overlap in the critically important antibiotics used in farm animals and humans. The ease of access to antibiotics compounded by the difficulties in accessing quality veterinary care and preventive services likely drive inappropriate ABU in complex ways.

IgG antibodies to SARS-CoV-2 in asymptomatic blood donors at two time points in Karachi.

INTRODUCTION: An estimated 1.5 million cases were reported in Pakistan until 23 March, 2022. However, SARS-CoV-2 PCR testing capacity has been limited and the incidence of COVID-19 infections is unknown. Volunteer healthy blood donors can be a control population for assessment of SARS-CoV-2 exposure in the population. We determined COVID-19 seroprevalence during the second pandemic wave in Karachi in donors without known infections or symptoms in 4 weeks prior to enrollment. MATERIALS AND METHODS: We enrolled 558 healthy blood donors at the Aga Khan University Hospital between December 2020 and February 2021. ABO blood groups were determined. Serum IgG reactivity were measured to spike and receptor binding domain (RBD) proteins. RESULTS: Study subjects were predominantly males (99.1%) with a mean age of 29.0±7.4 years. Blood groups were represented by; B (35.8%), O (33.3%), A (23.8%) and AB (7%). Positive IgG responses to spike were detected in 53.4% (95% CI, 49.3-37.5) of blood donors. Positive IgG antibodies to RBD were present in 16.7% (95% CI; 13.6-19.8) of individuals. No significant difference was found between the frequency of IgG antibodies to spike or RBD across age groups. Frequencies of IgG to Spike and RBD antibodies between December 2020 and February 2021 were found to be similar. Seropositivity to either antigen between individuals of different blood groups did not differ. Notably, 31.2% of individuals with IgG antibodies to spike also had IgG antibodies to RBD. Amongst donors who had previously confirmed COVID-19 and were seropositive to spike, 40% had IgG to RBD. CONCLUSIONS: Our study provides insights into the seroprevalence of antibodies to COVID-19 in a healthy cohort in Karachi. The differential dynamics of IgG to spike and RBD likely represent both exposure to SARS-CoV-2 and associate with protective immunity in the population.

Perspective on newborn screening (NBS): Evidence sharing on conditions to be included in NBS in Pakistan.

Newborn screening aims at detecting treatable disorders early so that the treatment can be initiated to prevent mortality and morbidity. Such programmes are well established in most developed countries, and all newborns are screened for selected metabolic, endocrine and other disorders based on disease epidemiology, testing and treatment availability, efficiency and cost-effectiveness. Even in developing countries, such screening programmes are initiated using heel prick capillary blood collected on filter paper. The current narrative review was planned to provide a perspective with evidence in favour of starting newborn screening for different disorders. The programme project should be initiated nationwide, taking one disorder, congenital hypothyroidism, as the prototype and a newborn screening panel can then be extended to include other disorders. A task force should be set up to recommend disorders to be included in the panel, develop the national plan policies, and define procedures to strengthen the testing.

Response of Eltrombopag in immune thrombocytopenia and acquired idiopathic aplastic anemia: A single-center experience.

Eltrombopag has been used in ITP and found its use in AA armamentarium recently. We retrospectively analyzed 61 patients at a tertiary care center in Pakistan from January 2015 to January 2021. They included patients with severe AA who were refractory to at least one course of immunosuppressive therapy and persistent/chronic ITP who have received at least one previous treatment for ITP. Responses to Eltrombopag in our population were comparable to real-world experiences while tolerable hepatotoxicity and GI issues were notable. We found Eltrombopag to be a safe and efficacious agent for treating patients with ITP and AA.

VITT with inactivated SARS-CoV-2 vaccine - index case.

We report a case of vaccine-induced immune thrombotic thrombocytopenia (VITT) in a 73-year-old gentleman who presented with pulmonary embolism and thrombocytopenia, two weeks after receiving inactivated COVID-19 vaccine. He responded well to nonheparin anticoagulation with complete resolution of symptoms and platelet count.