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Aplastic anemia is a relatively rare but potentially fatal disorder, with a reported higher incidence in developing countries in comparison to the West. There are significant variations in epidemiological as well as etiological factors of bone marrow failure syndromes in the developing countries in comparison to the developed world. Furthermore, the management of bone marrow failure syndromes in resource constraint settings has significant challenges including delayed diagnosis and referral, limited accessibility to healthcare facilities, treatment modalities as well as limitations related to patients who require allogeneic stem cell transplantation. Here we will provide a review of the available evidence related to specific issues of aplastic anemia in the developing countries and we summarize suggested recommendations from the Eastern Mediterranean blood and bone marrow transplantation (EMBMT) group and the severe aplastic anemia working party of the European Society of blood and marrow transplantation (SAAWP of EBMT) related to the diagnosis and therapeutic options in countries with restricted resources.

Cyclosporine (CsA) combined with short-course methotrexate is considered standard-of-care graft-versus-host disease (GVHD) prophylaxis for patients with severe aplastic anemia (AA) who undergo transplantation using cyclophosphamide (Cy) plus anti-thymocyte globulin (ATG) conditioning. However, there is no consensus on optimal post-transplant GVHD prophylaxis for patients undergoing matched related donor (MRD) transplantation using fludarabine (Flu)-based conditioning. We conducted a single-center retrospective analysis of patients with acquired AA (n = 106) undergoing MRD transplantation from July 2007 through January 2019. All patients received Flu-Cy-ATG conditioning and single-agent CsA as GVHD prophylaxis. Median age of the study cohort was 20 years (range, 3 to 52) and male to female ratio was 3.8:1. Median time from diagnosis to transplant was 11.5 months (range, 2.8 to 62). Graft source was bone marrow harvest in 71 (68%), combined bone marrow and peripheral blood stem cells in 34 (31%), and peripheral blood alone in 1 (1%) patient. Cumulative incidence of neutrophil engraftment at day 28 was 93.4% (95% confidence interval [CI], 87.3% to 97.1%) while that of platelet engraftment at day 100 was 90.5% (95% CI, 84% to 96%). Cumulative incidence of primary graft failure at day 28 was 6.6% (95% CI, 4% to 8%) while secondary graft failure occurred at a median of 190 days (range, 90 to 415) at a cumulative incidence of 3.7% (95% CI, 2% to 5%). Cumulative incidence of grade II to IV acute GVHD at day 100 was 3.8% (95% CI, 1.4% to 9.9%), while a 1-year probability of chronic GVHD was calculated as 7.5% (95% CI, 2.6% to 15%). Median follow-up post-transplant was 61 months (range, 6 to 144). Overall survival was 84.9%, disease-free survival was 80.2%, and GVHD-free relapse-free survival was 76.3%. This study indicates that single-agent cyclosporine is a feasible option for GVHD prophylaxis in MRD hematopoietic stem cell transplantation using Flu-Cy-ATG conditioning and is associated with very low rates of acute and chronic GVHD.

Objective: Prevalence of aplastic anemia (AA) is high in the Asian population. This study was done to explore the etiology and association of AA with various socio-economic and environmental factor...

Despite excellent transplant outcomes of aplastic anemia (AA) in developed countries, management in developing countries is challenging because of delay in the diagnosis, use of family donors for transfusions, and higher infection risk pretransplant. These factors can lead to allo-immunization, increased risk of graft failure, graft-versus-host disease (GVHD), and transplant-related mortality, leading to unfavorable outcomes. Conventional cyclophosphamide (Cy) and antithymocyte globulin (ATG) are associated with inferior overall survival in such high-risk patients. We conducted single-center retrospective analysis of high-risk AA patients (N = 147) enrolled consecutively and undergoing matched related donor transplant from March 2002 through October 2018. We included high-risk AA patients receiving fludarabine (Flu)-based conditioning. Median patient age was 20 years (range, 3 to 52). The median time from diagnosis to transplant was 11 months (range, 3 to 63). High-risk features included age ≥ 20 years in 55.8% of patients (n = 82), disease duration more than 3 months in 95 % (n = 140), RBC concentrates transfusions > 20 in 79.6% (n = 117), random donor platelet transfusion > 50 in 64.6% of patients (n = 95), and second hematopoietic stem cell transplant (HSCT) in 7.4% (11). We divided patients into 2 groups based on different conditioning regimens. Flu group 1 (Flu1) received Flu 120 to 150 mg/m2, Cy 120 to 200 mg/kg, and ATG 20 mg/kg, and Flu group 2 (Flu2) was given Flu 150 mg/m2, Cy 300 mg/m2, and ATG 20 mg/kg. Bone marrow stem cells were used as graft source in 97% of patients (n = 144) (alone in 52% and with peripheral blood stem cells in 45%). Cyclosporine alone was used for GVHD prophylaxis in 75% (n = 110) and cyclosporine plus methotrexate in 25% (n = 37). Median total nucleated cell dose was 5 × 108/kg. Median days for neutrophil engraftment was 13 (range, 10 to 20) and platelet engraftment 20 (range, 14 to 43). Day 100 mortality was 7.5% (n = 11). Sustained successful engraftment was achieved in 87.8% of patients (n = 129). Most graft failures (40%) occurred in Flu2 conditioning (P = .000) and in patients with >2 risk factors (P = .000). Overall incidence of acute and chronic GVHD was 11.6% (n = 17) and 12.9% (n = 19), respectively, in Flu1 and Flu2 groups. Overall survival (OS), disease-free survival (DFS), and GVHD-free relapse-free survival (GRFS) was 83.7%, 78.2%, and 70.7%, respectively. A trend toward improved OS was observed in patients receiving Flu1 conditioning but was statistically nonsignificant (P = .256), whereas DFS and GRFS were significantly better in Flu1 versus Flu2 (P = .004 and .001, respectively). When stratified per number of risk factors (age > 20, RBC concentrate > 20 or platelet > 50 random, duration > 3 months, previous HSCT), OS and DFS decreased significantly with increasing number of risk factors (P = .000 and .001, respectively). Patients are able to tolerate Flu-based conditioning well with lower rates of rejection and excellent long-term survival in high-risk AA patients. Cyclosporine alone as GVHD prophylaxis and marrow source stem cells as graft source are preferable options. Use of Flu plus low-dose Cy conditioning is associated with inferior survival outcomes. A randomized trial of Flu-based versus conventional Cy-containing conditioning would be helpful in establishing a standard of care conditioning regimen in high-risk AA patients.

Post‐transplant lymphoproliferative disorder (PTLD) is rarely reported in matched sibling donor (MSD) transplants of aplastic anemia (AA), and occurrence of Hodgkin lymphoma in this subgroup is extremely uncommon. Our patient, a 7‐year‐old girl, underwent MSD transplant for AA and developed EBV‐driven Hodgkin lymphoma after tapering of immunosuppression. Post‐transplant lymphoproliferative disorders (PTLDs) represent heterogenous groups of clonal disorders occurring after solid organ and hematopoietic stem cell transplantation. Most of PTLDs are EBV driven and have a frequency of 3.2% in stem cell transplant recipients and 1.1% in matched sibling donor (MSD) transplants.1 Risk factors of PTLD include unrelated donor and haploidentical transplants, use of T‐cell depleting conditioning and higher recipient age. The underlying mechanism is failure of newly instituted donor immune system to control EBV‐infected host cells due to profound T‐cell immune suppression. Epstein‐Barr Virus (EBV) DNA monitoring is done in these high‐risk patients to detect reactivation of EBV and institution of pre‐emptive measures like reduction of immunosuppression and treatment with rituximab. There are only few case reports of PTLD in patients of AA undergoing MSD transplant2 but to our knowledge this is first reported case of EBV‐driven Hodgkin lymphoma occurring after tapering of immunosuppression in patient undergoing MSD HSCT for AA.

Background: Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). It causes end-organ disease, multi-organ dysfunction syndrome, graft failure, increased susceptibility to infections and GVHD. According to the published western data greatest risk of CMV infection is the seropositivity of the recipient, however, in a high endemic population where seropositivity is up to 100%, risk factors for CMV reactivation are different and are analyzed in this study. Methods: It is a prospective descriptive study performed at Armed Forces Bone Marrow Transplant Center, Rawalpindi, Pakistan from January 2017 to March 2020. Consecutive patients who underwent allogeneic HSCT during this period were enrolled. All patients were prospectively monitored for CMV reactivation by weekly or two weekly CMV DNA quantitative PCR, from engraftment till day 100 post-transplant. CMV infection was diagnosed on detection of more than 200 copies/ml on PCR. Threshold for starting preemptive antiviral therapy was kept at 2000 copies/ml. Patients with past history of CMV infection, those who expired before day 14 post-transplant or those with less than 70% of required CMV tests were not included in the study. Factors associated with CMV reactivation, outcome of antiviral therapy and effect of CMV on post-transplant survival were studied. Results: Out of 319 transplants during this period, 230 patients fulfilled the inclusion criteria. Of these, 197 were HLA matched sibling, 18 were matched family donor and 15 were haploidentical transplants. There were 163 males and 67 females. Median age at transplant was 9.5 years (0.5-53). Eighty-three transplants were done in thalassemia, 55 in aplastic anemia, 14 in Fanconi anemia, 27 in acute leukemias, 8 in CML, 9 in MDS, 12 in HLH and 22 in other hematological disorders. All the patients and donor were CMV IgG seropositive when tested before transplantation. CMV reactivation was seen in 152 out of 230 patients (66.1%). Of 152, 95 patients had CMV viral load more than 2000 copies/ml and required antiviral treatment. Median time to reactivation since transplant was 35 days (13-90). In multivariate analysis using binary regression, risk factors for high viral load CMV reactivation included steroid administration (p=0.009), recipient age less than 10 years (p=0.003) and haploidentical transplant (p=0.048). No statistically significant association was found with the use of ATG, GVHD, underlying disease, ABO blood group or gender mismatch. Survival analysis using cox regression showed significant impact of high viral load CMV reactivation on post-transplant survival. Event-free survival (EFS) with and without CMV reactivation was 70.5 % and 89.7% respectively (p=0.004) and overall survival (OS) was 80.0 % and 97.4 % with and without CMV reactivation respectively (p=0.002). Valganciclovir was given in 89 patients and 6patients were treated with ganciclovir. Mean time to clear viremia was 19.8±9 days. Myelosuppression was seen in 41% of patients treated with valganciclovir. Renal impairment was seen in 25% of patients treated with valganciclovir. One patient had resistant disease. One patient had CMV pneumonia and she recovered. One patient died of suspected CMV pneumonia Conclusion: CMV reactivation was seen in 66.1% of the transplant recipients, this is higher compared to the western world due to high CMV seropositivity is this region. Steroids administration in post-transplant period significantly increase the risk of CMV reactivation. Preemptive therapy with valganciclovir effectively treats CMV reactivation. Viral threshold for treatment should be decided considering the regional endemicity. CMV adversely effects the transplant outcome in terms of EFS and OS. Disclosures No relevant conflicts of interest to declare.

Allogeneic stem cell transplant for high-risk aplastic anemia (AA) yields inferior results using conventional cyclophosphamide (CY)-based conditioning. The use of fludarabine (Flu)-based regimens has resulted in improved outcomes in high-risk patients. Limited data are available comparing these two conditioning regimens in such patients. We retrospectively analyzed 192 high-risk patients undergoing matched-related donor transplantation from July 2001 to December 2018. The median age was 19.5 (2–52) years. Patients were divided into 2 groups, Cy200 anti-thymocyte globulin (ATG)20 (Gp1 n = 79) or Flu120–150 Cy120–160 ATG20 (Gp2 n = 113). The risk of graft failure was significantly higher in Gp1, and the majority occurred in patients with >2 risk factors (p = 0.02). The incidence of grade II-IV acute graft versus host disease (GVHD) and chronic GVHD was not significantly different between the two groups. The overall survival (OS) of the study cohort was 81.3 %, disease-free survival (DFS) 76.6 % and GVHD-free relapse-free survival (GRFS) was 64.1%. DFS and GRFS were significantly higher in Gp2 as compared to Gp1: DFS 84.1% versus 68.4 % (p = 0.02), GRFS 77.9% versus 54.4% (p = 0.01), respectively. We conclude that Flu-based conditioning is associated with superior OS, DFS and GRFS as compared to the conventional Cy-based regimen in high-risk AA.

Aplastic anemia (AA) is the most serious non-malignant blood disorder in Pakistan, ranked second in prevalence, after thalassemia. We investigated various epidemiological, clinical, and genetic factors of AA in a Pakistani cohort of 214 patients reporting at our hospital between June 2014 and December 2015. A control group of 214 healthy subjects was included for comparison of epidemiological and clinical features. Epidemiological data revealed 2.75-fold higher frequency of AA among males. A single peak of disease onset was observed between ages 10 and 29 years followed by a steady decline. AA was strongly associated with lower socioeconomic profile, rural residence, and high rate of consanguineous marriages. Serum granulocyte colony-stimulating factor and thrombopoietin levels were significantly elevated in AA patients, compared to healthy controls (P

Objective: To compare outcome, disease-free survival and rejection in aplastic anaemia patients receiving: (A) ALG or ATG plus cyclophosphamide (CY) 200 mg/Kg ; (B) Fludarabine 120 mg/m2, ATG plus CY 300 mg/m2 and (C) Fludarabine 120 mg/m2, ATG plus CY 120 mg/Kg conditioning regimens. Patients & Methods: The study included 202 consecutive aplastic anaemia patients undergoing hematopoietic stem cell transplantation from HLA matched sibling donors at this centre from July 2001 to April 2014. Overall 122 had very severe aplastic anemia, 76 severe and 4 non-severe aplastic anemia. Group A, B and C were compared for outcome, disease free survival and rejection. The stem cell source was bone marrow (39.6%); PBSC (7.9%) or both bone marrow plus PBSC (51.5%). GVHD prophylaxis consisted of cyclosporine (51% cases) and cyclosporine plus methotrexate (45.5% case). Chi-square test was used to compare categorical variables. Two way ANOVA was used to compare group means. Kaplan Meier survival curves with log rank test was applied to compare the groups for survival analysis. Results: Group A included 99, group B 72 and group C 31 patients. Male to female ratio was 76/23 in group A; 56/16 in group B and 22/9 in group C. Median age of patients in group A, B and C were 16, 22 and 18 years respectively (p=0.001). At a median follow up of 1267 days the overall and disease free survival were 76.7% and 68.7% in group A, 70.8% and 69.4% in group B, 67.7% and 54.8% in group C (p=0.350, and p=0.412 respectively). The rejection rate was 11.1%, 9.7% and 35.5% in group A, B and C respectively (p=0.001). Frequency of chronic GVHD was 10%, 8% and 35.5 in respective groups (p Conclusion: Conditioning regimens using ALG or ATG with Cy 200 mg/kg; and Fludarabine 120 mg/m2, ATG plus Cy 120 mg/kg give comparable results while the regimen using Fludarabine 120 mg/m2, ATG plus Cy 300 mg/m2 is associated with high rejection rate and inferior survival in aplastic anemia following allogeneic stem cell transplantation. Disclosures No relevant conflicts of interest to declare.

Allogeneic stem cell transplantation (SCT) from HLA matched sibling donor is the standard treatment option in younger patients with severe aplastic anaemia (SAA). In the current study outcome of 70 patients with SAA undergoing allogeneic SCT at our institution from July 2001 to June 2007 is presented. Median follow up time was 727 days (range 100–2187). Three patients received 2nd SCT due to graft failure or rejection so actual number of SCT in the patients was 73. Median age of the patients was 16 years (range 5–38), 55 males, and 15 females. Seventeen had major ABO mismatch while sex mismatch in the form of female donor to male patient was present in 23 cases, 7 had both major ABO and sex mismatch. Sixty four patients were CMV positive while 6 had CMV negative status. Conditioning regimens included; cyclophosphamide (Cy) 200 mg/kg with either antilymphocyte globulin (ALG) 45 mg/kg (n=33) or antithymocyte globulin (rabbit ATG) 11.25 mg/kg (n=26); Cy plus Campath 100 mg (n=6), fludarabine 150 mg/m2 plus Cy 300 mg/m2 and ATG (n=8). All patient undergoing 2nd transplant received conditioning with Cy, fludarabine and ATG. GVHD prophylaxis was given with cyclosporin (CSA) plus prednisolone (41) with or without short course of methotrexate (29). Patients received PBSC (10) or bone marrow (12) alone or both (48). Mean mononuclear and CD34+ cell doses were 5.59 x 108/Kg and 4.8 x 106/Kg respectively. Median time to neutrophil recovery was 11 days (range 7–24). Neutropenic fever was seen in 60% cases, with mean duration of fever being 8 days. In majority (66%) no focus of infection could be found. Various isolates included gram negative rods (n=6), staphylococcus (n=2) and fungi (n=5). Other post-transplant infections were tuberculosis (n=2), herpes zoster (n=2) and transfusion associated falciparum malaria (n=2). Post-BMT non-infectious complications included acute GVHD (24%), chronic GVHD (08%), hemorrhagic cystitis (14%), seizures (5%), and VOD (3%). Graft rejection and primary graft failure was seen in 3 and 2 cases respectively. Three of them received 2nd transplant and had successful recovery while the other 2 died of septicemia. Six patients died during peri-transplant period, 3 at day 100, and 8 beyond day 100. One patient died of unrelated cause at 2 years post-transplant. Main causes of death were septicemia (n=4), conditioning regimen toxicity (n=3), VOD (n=2), GVHD (n=2) and disseminated aspergillosis (n=2). The overall and disease free survival was 76%. In univariate analysis using Logrank and Wilcoxon test factors correlated with better survival were patient’s age

Summary Objective To describe our experience of post-transplant infections in allogeneic stem cell transplants at the Armed Forces Bone Marrow Transplant Centre, Rawalpindi, Pakistan. Methods From July 2001 to September 2006, patients with malignant and non-malignant hematological disorders having human leukocyte antigen (HLA)-matched sibling donors were selected for transplant. Pre-transplant infection surveillance was carried out, and strict prophylaxis against infection was observed. After admission to the hospital, patients were kept in protective isolation rooms, equipped with a HEPA filter positive-pressure laminar airflow ventilation system. Bone marrow and/or peripheral blood stem cells were used as the stem cell source. Cyclosporin and prednisolone were used as prophylaxis against graft-versus-host disease (GVHD). The engraftment was monitored with cytogenetic/molecular analysis and change of blood group. Survival was calculated from the date of transplant to death or last follow-up. Results One hundred and fifty-four patients received allogeneic stem cell transplants from HLA-matched siblings for various hematological disorders at the Armed Forces Bone Marrow Transplant Centre, Rawalpindi, Pakistan between July 2001 and September 2006. Indications for transplant included aplastic anemia ( n =66), β-thalassemia major ( n =40), chronic myeloid leukemia ( n =33), acute leukemia ( n =8), and miscellaneous disorders ( n =7). One hundred and twenty patients were male and 34 were female. The median age of the patient cohort was 14 years (range 1 1 4 − 54 years). One hundred and thirty-six patients and 135 donors were cytomegalovirus (CMV) IgG-positive. One hundred and forty patients (90.9%) developed febrile episodes in different phases of post-transplant recovery. Infective organisms were isolated in 150 microbiological culture specimens out of 651 specimens from different sites of infections (23.0% culture positivity). Post-transplant infections were confirmed in 120 patients (77.9%) on the basis of clinical assessment and microbiological, virological, and histopathological examination. Mortality related to infections was 13.0%. Fatal infections included CMV disease (100% mortality, 6/6), disseminated aspergillosis (66.7% mortality, 4/6), pseudomonas septicemia (42.9% mortality, 9/21), and tuberculosis (25% mortality, 1/4). Conclusions More than 90% of our patients developed febrile episodes with relatively low culture yield. The majority of infections were treated effectively, however CMV, aspergillosis, and pseudomonas infections remained problematic with high mortality.