HLA alleles, haplotypes frequencies, and their association with hematological disorders: a report from 1550 families whose patients underwent allogeneic bone marrow transplantation in Egypt.

HLA alleles are representative of ethnicities and may play important roles in predisposition to hematological disorders. We analyzed DNA samples for HLA-A, -B, -C, -DRB1, and -DQB1 loci, from 1550 patients and 4450 potential related donors by PCR-SSO (Polymerase chain reaction sequence-specific oligonucleotides) and estimated allele frequencies in donors and patients from 1550 families who underwent bone marrow transplantation (BMT) in Egypt. We also studied the association between HLA allele frequencies and incidence of acute myeloid leukemia, acute lymphoblastic leukemia, and severe aplastic anemia. The most frequently observed HLA class I alleles were HLA- A*01:01 (16.9%), A*02:01 (16.1%), B*41:01 (8.7%), B*49:01 (7.3%), C*06:02 (25.1%), and C*07:01 (25.1%), and the most frequently observed class II alleles were HLA-DRB1*11:01 (11.8%), DRB1*03:01 (11.6%), DQB1*03:01 (27.5%), and DQB1*05:01 (18.9%). The most frequently observed haplotypes were A*33:01~B*14:02 ~ DRB1*01:02 (2.35%) and A*01:01~B*52:01~DRB1*15:01 (2.11%). HLA-DRB1*07:01 was associated with higher AML odds (OR, 1.26; 95% CI, 1.02-1.55; p = 0.030). Only HLA-B38 antigen showed a trend towards increased odds of ALL (OR, 1.52; 95% CI, 1.00-2.30; p = 0.049) HLA-A*02:01, -B*14:02, and -DRB1*15:01 were associated with higher odds of SAA (A*02:01: OR, 1.35; 95% CI, 1.07-1.70; p = 0.010; B*14:02: OR, 1.43; 95% CI, 1.06-1.93; p = 0.020; DRB1*15:01: OR, 1.32; 95% CI, 1.07-1.64; p = 0.011). This study provides estimates of HLA allele and haplotype frequencies and their association with hematological disorders in an Egyptian population.

The Use of Post-transplantation Cyclophosphamide in Peripheral Blood HLA-matched Stem Cell Transplantation as Graft-versus-host Disease Prophylaxis in Patients With Malignant or Non-malignant Hematologic Disorders: A Single-center Experience of 52 Patients.

INTRODUCTION: Studies addressing the utilization of post-transplant cyclophosphamide (CY) as graft-versus-host disease (GVHD) prophylaxis in allogeneic hemopoietic stem cell transplantation from matched sibling donors are limited and with controversial results. Chronic GVHD incidence necessitating systemic treatment is around 35% in peripheral blood stem cell transplantation (PBSCT) from human leukocyte antigen-matched sibling donors. PATIENTS AND METHODS: In this study, high-dose CY was added to PBSCT aiming to reduce the incidence of GVHD to reach a lower figure compared with standard GVHD prophylaxis. Fifty-two patients with either benign or malignant hematologic disorders who underwent stem cell transplantation at Nasser Institute Hospital in Egypt from November 2017 to October 2018 were enrolled in this study. Fifty patients had fully human leukocyte antigen-matched siblings, whereas the remaining 2 patients had 1 locus class I mismatched donors. Pre-transplant conditioning regimen was fludarabine and busulfan (FLU/BU) in malignant cases (73.1%) and FLU/CY in benign hematologic disorders (26.9%) and 1 patient with hypocellular myelodysplastic syndrome. For GVHD prophylaxis, CY was given at a dose of 50 mg/kg/day on days 3 and 4 post-transplantation, and cyclosporine (CSA) starting day 5 in 96.1% of patients. For the 1-locus mismatched patients, both CSA and mycophenolate mofetil were administered starting day 5. RESULTS: The 1-year incidence of acute GVHD (aGVHD) was 15.3% and for chronic GVHD (cGVHD) was 13.4%. Historical data of GVHD prophylaxis at our center using CSA and methotrexate showed an incidence of 37% for aGVHD and 33.9% for cGVHD. CONCLUSIONS: Post-transplant CY GVHD prophylaxis led to significantly less aGVHD (P = .03) and cGVHD (P = .04).

MPN10 score and survival of molecularly annotated myeloproliferative neoplasm patients.

JAK2, CALR, MPL and triple-negative mutational status has a direct impact on symptom severity and disease burden assessed by MPN10 score in myeloproliferative neoplasms (MPNs). Among 93 patients; median MPN10 score was 48 (5-76) in JAK2 mutants versus 25 (4-80) in JAK2 negative (p < .001); 22.5 (4-65) in CALR mutants versus 35 (5-80) in CALR negative (p < .050) and 21 (10-48) in triple negative versus 40 (4-80) in JAK2/CALR/MPL mutants (p < .001). At three years, progression free and overall survival of JAK2-positive versus JAK2-negative patients were 62% versus 100% (p < .001); 85% versus 100% (p = .011) and were 100% versus 78% (p = .067); 100% versus 92% (p = .197) in CALR-positive versus CALR-negative patients and 100% versus 75% (p = .004); 100% versus 90% (p = .015) in triple negative versus mutant patients, respectively. MPN10 score in association with driver gene mutations can be used as a predictor of survival in MPN patients.

Allogeneic hematopoietic stem cell transplantation for non-malignant hematological disorders.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) from a geno-identical matched sibling (MSD) is one of the most successful therapies in patients with non-malignant hematological disorders. This study included 273 patients with severe aplastic anemia (SAA), 152 patients with B-Thalassemia major (BTM), 31 patients with Fanconi's anemia (FA), 20 patients with congenital immunodeficiency diseases (ID), and 13 patients with inherited metabolic disorders (IMD) allografted from a MSD. In SAA, the 8-year overall survival (OS) of the whole group patients was 74%. OS was significantly better in patients conditioned with fludarabine and cyclophosphamide (Flu/Cy) than in those who received cyclophosphamide and antithymocyte globulin (Cy/ATG) (p = 0.021). Acute graft-versus-host disease (aGVHD) grade II-IV occurred in 15% while chronic GVHD (cGVHD) occurred in 28%. In BTM, the 12-year disease-free survival (DFS) of the whole group of BTM patients was 72.4%. DFS was 74% for peripheral blood stem cell (PBSC) group compared to 64% in the BM stem cell group. The incidence of graft rejection was significantly lower in patients who received PBSC than in those who received BM (9% vs 25%) (p = 0.036). AGVHD grade II-IV and cGVHD occurred in 15% and 12% of the whole group of BTM patients respectively. In FA, the 5-year OS was 64.5%. Graft rejection occurred in 10% of patients. Grade II-IV aGVHD occurred in 16% while cGVHD occurred in 4%. In ID, the 5-year OS was 62%. Graft rejection occurred in two (10%) patients. Three patients (15%) developed grade II-IV aGVHD, 2 of them progressed to secondary cGVHD. In IMD, OS was 46% at 5 years. Graft rejection occurred in 8% of patients. AGVHD grade II-IV occurred in 15% while cGVHD occurred in 14%. In conclusion, Allo-HSCT provides a higher DFS rate over conventional therapies for patients with non-malignant hematological disorders with prolonged survival.

Liver disease is a major cause of mortality following allogeneic bone-marrow transplantation.

BACKGROUND: Liver disease is an important cause of morbidity and mortality among recipients of bone-marrow transplantation (BMT). The aim of this retrospective study was to determine the incidence, risk factors and clinical evolution of liver disease following allogeneic BMT. METHODS: A total of 103 patients (mean age 22.8 years (SD 10.9); 31.1% aged < 18 years; 66% males) transplanted in a single institution were enrolled. Data on donors and recipients were collected, including hematological disease, alanine transaminase, alkaline phosphatase, bilirubin, hepatitis B virus (HBV) and hepatitis C virus (HCV) markers (including HBV-DNA and HCV-RNA). RESULTS: Fifty six of 103 patients died, with liver disease the main cause of death (27 of 56, 48%). Overall the incidence of liver failure attributed to hepatic graft-versus-host-disease (GVHD) was 22.3% (23 of 103; 74% HBV/HCV infected) and veno-occlusive disease (VOD) was 9.7% (10 of 103; 80% HBV/HCV infected). Fourteen patients had hepatitis reactivations (four hepatic GVHD and three VOD). Donors' HCV-RNA status and serum bilirubin above 2 mg/dl were predictive of hepatic GVHD [adjusted odds ratio (AOR) 11.1, 95% confidence interval (CI) 0.99-33.12; AOR 3.93, 95% CI 1.09-14.62; P < 0.05, respectively] and an abnormal alkaline phosphatase could predict severe liver disease (AOR 2.78, 95% CI 1.01-7.54; P < 0.05). Development of severe liver disease (hepatic GVHD or VOD) was a significant predictor of mortality (AOR 4.57, 95% CI 1.09-20.32; P < 0.05) with a low probability of survival (19.3%, SD 7.9%) compared with those without liver disease (52.1%, SD 7.6%; log-rank P = 0.0003). CONCLUSIONS: Hepatic GVHD is a common complication following BMT and an important cause of liver-related mortality. The high prevalence of HCV and HBV may have contributed to the outcome of hepatic GVHD and VOD. Therefore, antiviral therapy should be considered early to prevent relentless progression of liver disease.

Modification and implementation of NCCN guidelines on lymphomas in the Middle East and North Africa region.

In the Middle East and North Africa (MENA) region, cancer has many epidemiologic and clinical features that are different from those in the rest of the world. Additionally, the region has a relatively young population and large disparities in the availability of resources at diagnostic and treatment levels. A critical need exists for regional guidelines on cancer care, including those for lymphoid malignancies. A panel of lymphoma experts from MENA reviewed the 2009 version of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) on Non-Hodgkin's Lymphoma and Hodgkin Lymphoma and suggested modifications for the region that were discussed with the United States NCCN Lymphoma Panels. This article presents the consensus recommendations.