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.

Bullous Sweet syndrome as a presentation of chronic myelogenous leukaemia.

A woman in her 40s presented with a 3-month-long history of fever and tender erythematous bullous skin lesions not responsive to antibiotics. There had been no previous gastrointestinal, respiratory or urinary infection, nor did she have any history of autoimmune disease, drug reaction or vasculitis.Histological evaluation of skin biopsy showed diffuse dense neutrophilic infiltrates located in dermis diagnostic of Sweet syndrome. Haematological investigations showed leucocytosis with circulating immature cells, which on further investigations with bone marrow biopsy, were evident of chronic myelogenous leukaemia in the accelerated phase. Sweet syndrome was the presenting characteristic of chronic myelogenous leukaemia in this case, which is a rare association. Investigating unusual skin lesions can aid in the suspicion of underlying cancer, allowing for prompt action.

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.

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.

Diagnosis and Management of Diffuse Large B-Cell Lymphoma: Society of Medical Oncology, Pakistan Society of Hematology, and Pakistan Society of Clinical Oncology Joint Clinical Practice Guideline.

Diffuse large B-cell lymphoma (DLBCL) is the commonest non-Hodgkin lymphoma encountered by hematopathologists and oncologists. Management guidelines for DLBCL are developed and published by countries with high income and do not cater for practical challenges faced in resource-constrained settings. This report by a multidisciplinary panel of experts from Pakistan is on behalf of three major national cancer societies: Society of Medical Oncology Pakistan, Pakistan Society of Hematology, and Pakistan Society of Clinical Oncology. The aim is to develop a practical and standardized guideline for managing DLBCL in Pakistan, keeping in view local challenges, which are similar across most of the low- and middle-income countries across the globe. Modified Delphi methodology was used to develop consensus guidelines. Guidelines questions were drafted, and meetings were convened by a steering committee to develop initial recommendations on the basis of local challenges and review of the literature. A consensus panel reviewed the initial draft recommendations and rated the guidelines on a five-point Likert scale; recommendations achieving more than 75% consensus were accepted. Resource grouping initially suggested by Breast Health Global Initiative was applied for resource stratification into basic, limited, and enhanced resource settings. The panel generated consensus ratings for 35 questions of interest and concluded that diagnosis and treatment recommendations in resource-constrained settings need to be based on available resources and management expertise.

Transplant in Aplastic Anemia Using Combined Granulocyte Colony-Stimulating Factor Primed Blood and Bone Marrow Stem Cells: A Retrospective Analysis.

INTRODUCTION: Aplastic anemia (AA) is characterized by diminished hematopoietic precursors in the bone marrow, most often due to injury to the pluripotent stem cell. In Pakistan, AA is not uncommon, and allogeneic hematopoietic stem cell transplant remains the only curative option for these patients. OBJECTIVE: The objective of this study was to determine the transplant outcome of combined granulocyte colony-stimulating factor (G-CSF) primed blood and bone marrow grafts in adult and pediatric patients with AA. METHODS: We retrospectively collected the data of all transplant procedures performed from 2004 to 2019 at Aga Khan University in Karachi, Pakistan. Variables analyzed included age, sex, type of stem cells used, conditioning regimens, and overall survival for patients undergoing transplant in AA. RESULTS: A total of 351 transplants were performed during the study period. Out of these, 239 were allogeneic transplants, whereas 112 were autologous procedures. We performed 70 transplants for AA during the study period, of which 52 were male patients and 18 were female patients. The median age ± standard deviation (SD) was 17.5 ± 9.4 years (range, 2-43 years). Cyclophosphamide/antithymocyte globulin (ATG) was used as a conditioning regimen in 65 patients, while ATG/cyclophosphamide/fludarabine was used in 5 patients. In 60 patients, a combination of G-CSF primed blood and bone marrow stem cells were used. The mean CD34 count was 5.2 × 106/kg. Graft-vs-host disease (GVHD) prophylaxis was done with cyclosporine and methotrexate. All patients received standard infection prophylaxis. Engraftment was achieved in 86% of patients. The median day of myeloid engraftment was 15 (range, 10-22 days). Chronic GVHD was present in 3 patients while 4 had acute GVHD. The overall survival was 71.2% (median duration of 80 months). The main cause of mortality was gram-negative sepsis. CONCLUSION: A combination of blood and bone marrow stem cells results in early engraftment with decreased frequency of GVHD in AA. The overall survival was comparable to international literature.

Improved outcome in early induction deaths in patients with acute promyelocytic leukemia after therapeutic and supportive interventions: a follow up study of seven-years' experience at a tertiary care center.

INTRODUCTION AND OBJECTIVES: Acute promyelocytic leukemia (APL) is a unique subtype of acute myeloid leukemia with characteristic morphology and clinical features. Early mortality rate of 30% has been reported in developed countries despite prompt initiation of treatment. We have previously reported an early induction mortality of approximately 62% in our cohort. Based on this mortality rate, we made changes in our treatment protocol. The objective of this follow-up study was to report the early induction mortality and overall survival of patients with APL after incorporating changes in chemotherapy and supportive care regimen. SUBJECTS AND METHODS: This was a prospective descriptive study conducted at Aga Khan University Karachi, Pakistan from October 2012 till October 2019. Data of patients included clinical features, morphological findings, cytogenetic and PCR studies, cytotoxic protocols, overall outcome and causes of early induction mortality. The changes in treatment protocol included prophylactic infusion of fresh frozen plasma, dexamethasone therapy and other changes in supportive care regimen. Results were recorded as frequencies and percentages. Statistical Package for the Social Sciences version 19.0 (SPSS Inc., Chicago, IL, USA) was used to analyze patient's data. Survival curves were calculated using the Kaplan-Meier method. RESULTS: During the study period, total of 447 patients presented with acute myeloid leukemia at our institution out of which 40 patients were diagnosed with acute promyelocytic leukemia (9%). Out of these 40 patients 24 were males and 16 were females. The median age was 37 years. Twenty-five patients were in low risk group whereas 15 were high-risk. Differentiation syndrome was seen in 14 patients. As a part of induction chemotherapy, 13 patients received only ATRA because they were not eligible for chemotherapy and 17 patients received a combination of ATRA and anthracycline. Among the remaining patients, four received ATRA, arsenic and anthracycline while two received ATRA and arsenic only. Four patients did not receive any treatment because of rapid deterioration of clinical condition and death. The overall survival was 65% and early induction mortality was 30%. CONCLUSION: The early induction mortality decreased to 30% from 62% in this study and the overall survival was 65%. With the introduction of prophylactic infusion of fresh frozen plasma, dexamethasone and appropriate supportive treatment during the induction chemotherapy, we were able to improve the induction mortality and overall survival of patients.

Compliance of hand written transfusion requisition form and improvement after online request - a clinical audit.

OBJECTIVE: To assess the compliance of healthcare personnel with regard to sending completely filled transfusion requisition forms. METHODS: The audit was conducted at Aga Khan University Hospital, Karachi, and comprised requisition slips received at the hospital blood bank from September 2014 to February 2015. The British Committee for Standards in Haematology guidelines was used as the standard. Percentage of each variable on the proforma was analsyed. Rating <50% for each form was defined as "needs improvement", 51-99% as "good compliance" and 100% as "excellent compliance". After implementing strategies to increase awareness and the launching of an online transfusion requisition form, a re-audit of physician compliance was done from February to April 2016 and the results were compared with the initial audit.. Data was analysed using SPSS 21. RESULTS: The audit and the re-audit both comprised 1000 transfusion requisition forms each. In the audit, The sum of total scores of all the transfusion requisition forms was 4911, indicating a compliance rate of 46.9%, while the corresponding numbers in the re-audit were 10000 and 100%. CONCLUSIONS: The implementation of online blood transfusion requisition system had a positive impact on compliance rate.

Outcome of donor and recipient sex match versus mismatch in stem cell transplant procedure.

AIM: We determined the frequency of graft-versus-host disease (GvHD) and overall survival (OS) in sex matched vs mismatched transplant. METHODS: Medical records were analyzed of patients undergoing transplant from 2004 to 2016. Variables included age, sex of patient and donor, indication, conditioning regimen, stem cell source, frequency of GvHD and OS. RESULTS: We performed n = 162 allogeneic stem cell transplants. The most common conditioning regimen was busulfan/cyclophosphamide (n = 64). There was no difference in the frequency of GvHD in both groups. The transplant related mortality was higher (8.7%) in sex-mismatched transplants. The OS in both groups was similar. CONCLUSION: Our study showed higher transplant-related mortality in sex-mismatched transplant. There was no difference in GvHD and OS in both groups.

Distribution of Chromosomal Abnormalities Commonly Observed in Adult Acute Myeloid Leukemia in Pakistan as Predictors of Prognosis

Objectives: The heterogenous response to treatment in acute myeloid leukemia (AML) can be attributed largely to the difference in cytogenetic features identified in between cases. Cytogenetic analysis in acute leukemia is now routinely used to assist patient management, particularly in terms of diagnosis, disease monitoring, prognosis and risk stratification. Knowing about cytogenetic profile at the time of diagnosis is important in order to take critical decisions in management of these patients. The study was conducted to determine the distribution of cytogenetic abnormalities in Pakistani adult patients with AML in order to have insights regarding behavior of the disease. Methods: A retrospective analysis of all the cases of AML (≥15years old) diagnosed at Aga Khan University from January 2011 to December 2016 was performed. Cytogenetic analysis was made for all cases using the trypsin-Giemsa banding technique. Karyotypes were interpreted using the International System for Human Cytogenetic Nomenclature (ISCN) criteria. Results: A total of 321 patients were diagnosed with AML during the study period, of which 288 samples successfully yielded metaphase chromosomes. The male to female ratio was 1.7:1. A normal karyotype was present in 61% (n=176) of the cases whereas, 39% (n=112) had an abnormal karyotype. Of the abnormal cases, t (8;21) (q22;q22) and t (15;17) (q22;q12) were identified in 8.3% and 4.9% cases respectively. Adverse prognostic cytogenetic subgroups including complex karyotype, monosomy 7 and t(6;9)(p23;q34) were identified in 9%, 1% and 0.7% patients respectively. Conclusions: This largest cytogenetic data in adult AML from Pakistan showed comparable prevalence of favorable prognostic karyotype to international data. The prevalence of specific adverse prognostic karyotype was low.

Pleural effusion as a manifestation of multiple myeloma.

Multiple myeloma is a clonal B-cell malignancy, characterised by proliferation of plasma cells and secretion of paraproteins. These plasma cells accumulate predominantly in the bone marrow; rarely, they invade other areas, especially the thorax. Myeloma presenting with a pleural effusion is rare and reported in only 6% of patients with myeloma. Such patients generally present late and have a poor prognosis. Here, we describe a patient presenting with a lung mass, renal failure and a massive unilateral pleural effusion due to multiple myeloma who was treated successfully.

Clinico-Pathological Profile And Outcomes Of Patients With Polycythaemia Vera, Essential Thrombocythaemia And Idiopathic Myelofibrosis: A Tertiary Care Center Experience From Southern Pakistan.

BACKGROUND: The "Philadelphia Negative Classic Myeloproliferative Neoplasms" include polycythaemia vera (PV), essential thrombocythaemia (ET) and idiopathic myelofibrosis (IMF). These three disorders share several clinical and laboratory features including JAK2 V617F mutation. Our objectives were to determine the clinico-pathological profile and outcomes of Pakistani patients with polycythaemia vera (PV), essential thrombocythaemia (ET) and idiopathic myelofibrosis (IMF) in order to have an insight regarding behaviour of these conditions. METHODS: A retrospective analysis of all the cases of PV, ET and IMF diagnosed at our institute from January 1995 to December 2013 was performed. Age, gender, clinical presentation, laboratory investigations, treatment provided and duration of follow-up were included for analysis. Appropriate statistics were utilized for calculation of data. RESULTS: A total of 58 patients were diagnosed as PV, ET or IMF during the study period. Male to female ratio was 1.1:1. Forty five percent (n=27) patients came to medical attention due to abnormal laboratory results, 3 had cerebrovascular events, 3 had pruritus, and 1 patient each with gangrene and Budd-Chiari syndrome. Haemorrhage was not seen in any patient. Sixty percent (n=35) patients were treated with phlebotomy, hydroxyurea and aspirin alone or in combination. None of the patients transformed to myelofibrosis (MF) or myelodysplasia (MDS) during the mean (±SD) follow-up period of 57.2±50 months. One patient with ET transformed to acute myeloid leukaemia 9 years after the diagnosis. CONCLUSIONS: This study demonstrated a relatively more benign form of PV, ET and IMF with lesser frequency of symptoms, good response to treatment and less likelihood of transformation to MF, MDS or AML.

Autologous Hematopoietic Stem Cell Transplantation-10 Years of Data From a Developing Country.

Intensive chemotherapy followed by autologous stem cell transplantation is the treatment of choice for patients with hematological malignancies. The objective of the present study was to evaluate the outcomes of patients with mainly lymphoma and multiple myeloma after autologous stem cell transplant. The pretransplant workup consisted of the complete blood count, an evaluation of the liver, kidney, lung, and infectious profile, chest radiographs, and a dental review. For lymphoma, all patients who achieved at least a 25% reduction in the disease after salvage therapy were included in the study. Mobilization was done with cyclophosphamide, followed by granulocyte colony-stimulating factor, 300 µg twice daily. The conditioning regimens included BEAM (carmustine, etoposide, cytarabine, melphalan) and high-dose melphalan. A total of 206 transplants were performed from April 2004 to December 2014. Of these, 137 were allogeneic transplants and 69 were autologous. Of the patients receiving an autologous transplant, 49 were male and 20 were female. Of the 69 patients, 26 underwent transplantation for Hodgkin's lymphoma, 23 for non-Hodgkin's lymphoma, and 15 for multiple myeloma and 4 and 1 for Ewing's sarcoma and neuroblastoma, respectively. The median age ± SD was 34 ± 13.1 years (range, 4-64). A mean of 4.7 × 108 ± 1.7 mononuclear cells per kilogram were infused. The median time to white blood cell recovery was 18.2 ± 5.34 days. Transplant-related mortality occurred in 10 patients. After a median follow-up period of 104 months, the overall survival rate was 86%. High-dose chemotherapy, followed by autologous stem cell transplant, is an effective treatment option for patients with hematological malignancies, allowing further consolidation of response.

Frequency of chromosomal abnormalities in Pakistani adults with acute lymphoblastic leukemia.

BACKGROUND: The difference in prognosis of adult and childhood acute lymphoblastic leukemia (ALL) can be attributed largely to variation in cytogenetic abnormalities with age groups. Cytogenetic analysis in acute leukemia is now routinely used to assist patient management, particularly in terms of diagnosis, disease monitoring, prognosis and risk stratification. Knowing about cytogenetic profile at the time of diagnosis is important in order to take critical decisions in management of the patients. AIM AND OBJECTIVES: To determine the frequency of cytogenetic abnormalities in Pakistani adult patients with ALL in order to have insights regarding behavior of the disease. MATERIALS AND METHODS: A retrospective analysis of all the cases of ALL (≥15years old) diagnosed at Aga Khan University from January 2006 to June 2014 was performed. Phenotype (B/T lineage) was confirmed in all cases by flow cytometry. Cytogenetic analysis was made for all cases using the trypsin-Giemsa banding technique. Karyotypes were interpreted using the International System for Human Cytogenetic Nomenclature (ISCN) criteria. RESULTS: A total of 166 patients were diagnosed as ALL during the study period, of which 151 samples successfully yielded metaphase chromosomes. The male to female ratio was 3.4:1. The majority (n=120, 72.3%) had a B-cell phenotype. A normal karyotype was present in 51% (n=77) of the cases whereas 49% (n=74) had an abnormal karyotype. Of the abnormal cases, 10% showed Philadelphia chromosome; t(9;22)(q34;q11.2). Other poor prognostic cytogenetic subgroups were t(4;11)(q21;q23), hypodiploidy (35-45 chromosomes) and complex karyotype. Hyperdiploidy (47-57 chromosomes) occurred in 6.6%; all of whom were younger than 30 years. CONCLUSIONS: This study showed a relatively low prevalence of Philadelphia chromosome in Pakistani adults with ALL with an increase in frequency with age (p=0.003). The cumulative prevalence of Philadelphia- negative poor cytogenetic aberrations in different age groups was not significant (p=0.6).

Outcome of allogeneic hematopoietic stem cell transplantation in patients with hematological malignancies.

INTRODUCTION: Allogeneic hematopoietic stem cell transplantation is a potentially curative treatment modality for hematological malignancies. We evaluated the outcome of patients suffering from hematological malignancies, including acute leukemias, chronic myeloid leukemia and myelodysplastic syndrome after allogeneic transplantation. METHODS: All patients having hematological malignancies with HLA identical sibling donors who underwent allogeneic transplantation were included. Pre-transplant workup consisted of complete blood counts, evaluation of liver, kidneys, lungs, infectious profile, chest X-ray, paranasal sinus roentgenograms and dental review. Donors were given G-CSF at a dose of 5-10 µg/kg/twice daily for five days prior to harvest. The conditioning regimens included cyclophosphamide, busulfan and total body irradiation. RESULTS: A total of 41 allogeneic transplants were performed for hematological malignancies from April 2004 to December 2012. There were 31 males and 10 females. Median age ± SD was 28 ± 11.7 years (range 8 - 54 years). A mean of 7.7×108±1.5 mononuclear cells/kg were infused (range:6.2-9.2×108/kg). The median time to white cell recovery was 19±4 days (range:15-23 days). Transplant related mortality was 19.5%. The median overall survival was 53.6 months. Overall survival at a median follow up of 37 months was 67%. CONCLUSION: Allogeneic stem cell transplantation is an effective treatment option in patients with hematological malignancies. Our outcomes are comparable with results from neighboring countries as well as the western world.

Frequency and Outcome of Graft versus Host Disease after Stem Cell Transplantation: A Six-Year Experience from a Tertiary Care Center in Pakistan.

Objective. The objective of this study was to evaluate the frequency and outcome of graft versus host disease after stem cell transplantation for various haematological disorders in Pakistan. Materials and Methods. Pretransplant workup of the patient and donor was performed. Mobilization was done with G-CSF 300 µ g twice daily for five day. Standard GvHD prophylaxis was done with methotrexate 15 mg/m(2) on day +1 followed by 10 mg/m(2) on days +3 and +6 and cyclosporine. Grading was done according to the Glucksberg classification. Results. A total of 153 transplants were done from April 2004 to December 2011. Out of these were allogeneic transplants. There were females and males. The overall frequency of any degree of graft versus host disease was 34%. Acute GvHD was present in patients while had chronic GvHD. Grade II GvHD was present in patients while grade III and IV GvHD was seen in patients each. Acute myeloid leukemia and chronic myeloid leukemia were most commonly associated with GvHD. The mortality in acute and chronic GvHD was 8.8% and 12% respectively. Conclusion. The frequency of graft versus host disease in this study was 34% which is lower compared to international literature. The decreased incidence can be attributed to reduced diversity of histocompatibility antigens in our population.

Outcome of match related allogeneic stem cell transplantation procedures performed from 2004 till 2011.

We present our initial experience of allogeneic stem cell transplant procedure performed between April 2004 and August 2011 for various haematological disorders. All patients with non-malignant and malignant haematological disorders with HLA matched donors were selected after pre-transplant workup. Ninety seven patients underwent the procedure. Most common indications for transplant were aplastic anaemia in n = 34 (35%), followed by ß-Thalassemia major in n = 21 (21.6%) and chronic myeloid leukemia in n = 11 patients (11.3%). Primary graft failure present was present in 2.06%. Incidence of graft versus host disease (GvHD) in our patients was 34%. After median follow-up of five years the overall survival was 71.3% with a mean survival time of 51.2 ± 3.3 months.

Allogeneic stem cell transplantation in acute myeloid leukemia.

We report a case series of 12 patients with acute myeloid leukemia who underwent allogeneic stem cell transplant with a matched related donor. Male to female ratio was 1:1. The main complication post-transplant was graft-versus-host disease (n=7 patients). Transplant-related mortality involved one patient; cause of death was multi-organ failure. After a median follow up of 36.0±11.3 months, overall survival was 16%.

BK Virus Associated Late Onset Haemorrhagic Cystitis After Allogeneic Peripheral Blood Stem Cell Transplant.

Haemorrhagic cystitis (HC) after allogeneic stem cell transplant is a clinical disorder with multiple etiologies. There is an inflammation of the bladder mucosa leading to painful haematuria. Early onset HC is mainly attributed to conditioning chemotherapy consisting of cyclophosphamide. Late onset HC is now being related to reactivation of latent polyoma BK virus (BKV). We describe the case of a 37 year old male with acute myeloid leukemia presenting with haematuria after allogeneic stem cell transplant.