Outcome Of Bone Marrow Transplantation In Lebanese Children With β-Thalassemia Major
Authors: Inati Adlette , Gaziev Javid , Abbas Hussein A , Korjian Serge , Daaboul Yazan , Kahale Mario , Paciaroni Katia , de Angelis Gioia , Taher Ali T , Nasr Therese Abi , Koussa Suzan , Lucarelli Guido 
Published: October 2019

Abstract
Abstract 5505

Introduction
Bone marrow transplantation (BMT) represents the only curative modality for β-Thalassemia Major (β–TM). Best results are achieved in regularly transfused and chelated pediatric patients. Outcome of BMT in 36 Lebanese children who received treatment in the Mediterranean Institute of Hematology (IME) centers in Italy is presented.

Methods
36 children with β–TM treated at Chronic Care Center, Lebanon underwent BMT from HLA compatible donors in IME centers. Each was assigned a Pesaro risk category and underwent a percutaneous liver biopsy before BMT. Conditioning regimen consisted of busulfan, cyclophosphamide ± Thiotepa and ATG. GvHD prophylaxis included cyclosporine A, methotrexate and prednisolone. Engraftment was evaluated by fluorescence in situ hybridization. Transplant related mortality (TRM) and other complications were calculated as cumulative incidence. Analyses were performed using R software.

Results
36 hepatitis B and C negative children with β –TM (M/F 1:l), median age 8.5 years, underwent BMT from HLA identical donors. The most common β-globin mutation was homozygous IVS1.110 (39.29%). 20.5%, 55.9% and 23.5% had Pesaro risk class 1, 2 and 3, respectively. Mean injected CD34+ cells, total nucleated cells and CD3+ cells/recipient were 10.9x106 /Kg, 8.69x108/Kg and 66.3x106 /Kg. Absolute neutrophil count >0.5 x109 and platelet count >20 x 109 were reached in all patients within a mean of +19.44±4 and +19.15 ±6.5 days. Regular chimerism surveillance showed complete engraftment in 35/36 children (97.3%) up till+ 4.2 years median follow up. 1/36 (2.7%) had partial engraftment but continued to be transfusion independent with a mean Hb of 9g/dcl for +1155 days. Immune reconstitution was seen in all patients by + 12 -18 months. At a median follow up of + 6.20 years, 32/36 (89%) of children are alive and transfusion independent. Among those who died (11%), 1 had multi organ failure, 2 had grade 4 acute GvHD and 1 had fulminant interstitial pneumonitis. 47% had acute GvHD which was not correlated with donor relation, conditioning regimen, and pre-BMT hepatomegaly, splenomegaly and transfusion frequency. 8/36 (22%) had grade 2 to 4 acute GvHD of which 75% resolved on treatment while 25% (all grade 4) were fatal. 9/32 (28%) surviving children had chronic GvHD completely resolved on treatment and not correlated with any recipient, donor or treatment feature. Other transplant related complications included CMV reactivation, sepsis, EBV and candida infections, hemorrhagic cystitis, cerebral toxoplasmosis, tuberculosis and transient cyclosporine related renal and neurotoxicity, all completely resolved on treatment. Late effects of transplant were monitored in 27 children. Iron overload data utilizing magnetic resonance imaging at + 3.1 year median follow up showed that mean baseline LIC for 27 patients was 11.3 mg Fe/g dw but ranged as high as 36.6 mg Fe/g dw. Median serum ferritin was 1255 ng/mL, with a maximum of 5884 ng/mL. 9/27 (33.3%) children had significant iron overload defined as SF >2500 ng/ml, or LIC >15 mg Fe/g dw, or T2* <20 msec, levels known to be associated with increased risk of progressive organ dysfunction and death. Median ejection fraction was 68 % (range 58-75%). Up till + 6.20 years median follow up, serum immunoglobulins, alanine and aspartate aminotransferases, BUN, creatinine and creatinine clearance were normal in all 27 children. Hypothyroidism, growth retardation and diffuse persistent vitiligo were seen in 3/25 (12%), 4/25 (16%) and 1/25 (4%) survivors respectively.

Summary
Our results reflect an excellent outcome for Lebanese children with β –TM undergoing transplantation. TRM was low and associated complications were transient and manageable. Significant iron overload was, however, noted years after BMT underscoring the need for long term monitoring for iron overload and for iron removal to prevent associated negative outcomes. This study highlights the need for monitoring for late effects for years after transplant. It also demonstrates the effectiveness of international collaboration in facilitating cure for thalassemia in developing countries as Lebanon.

Disclosures:
No relevant conflicts of interest to declare.