Optimal Thalassemia Free Survival and Minimal Regimen Related Toxicity in 50 Consecutive Transplants of High Risk Beta Thalassemia Pediatric Patients Using Myelablative Therapy with Intravenous Busulphan.
Authors: Marktel Sarah , Chiesa Robert , Cappelli Barbara , Roccia Tito , Frugnoli Ilaria , Noè Anna , Biral Erika , Crocchiolo Roberto , Evangelio Costanza , Fossati Marco , Napolitano Sara , Soliman Clara , Cursi Laura , Cattaneo Federica , Zito Laura , Fiori Rossana , Fleischhauer Katharina , Miniero Roberto , Ciceri Fabio , Roncarolo Maria Grazia 
Published: October 2019

Abstract
In the developed world, the survival and quality of life of patients with beta thalassemia (Bthal) has dramatically improved with optimization of blood transfusions and iron chelation. By contrast, in countries with limited resources most affected children die before the age of 20 because of the unavailability of safe blood products, expensive iron chelating drugs and inadequate management of co-morbidities. For these patients allogeneic stem cell transplantation (SCT) from matched donors offers a cure with low morbidity and mortality. Between June 2005 and May 2008, 47 consecutive Bthal patients underwent SCT from an HLA identical sibling in our center, among these, 3 patients underwent 2 SCTs. Median age was 8 years (2–15), country of origin: Lebanon (9), Iraq (19), Palestine (3), Syria (16). One pt was classified as Lucarelli class I, 24 as class II and 22 as class III. Most patients had severe iron overload evidenced by irregular iron chelation (83%), median ferritin 2973 (956–14280), median liver iron concentration 22 mg Fe/g (6.9–95.7). Most patients had liver toxicity due to iron overload and hepatitis evidenced by median ALT 71 (12–545), AST 59 (18–371), liver fibrosis Ishak 3 (0–5), HepC pos 16/47 (34%). Patients had inadequate transfusional management evidence by a median pre-transfusion Hb of 8 g/dL and anti HLA antibodies in 81% pts. Class I-II patients were conditioned with a regimen based on iv busulphan (iv Bu, Busilvex®, dosage according to weight, adjusted from the 5th dose to a target AUC 1200 umol/min) and cyclophosphamide (Cy) 200mg/kg (n19) with the addition of thiotepa (TT 10mg/kg) if <4 years (n6). Class III pts received a preconditioning based on hydroxiurea and azathioprine followed by fludarabine (Flu) 100mg/m2, iv Bu and Cy 160mg/kg (n6) or, from April 2007, Flu 150mg/m2, iv Bu, Cy 160 mg/kg and Atg (Thymoglobuline®) 7,5mg/kg (n16); patients receiving a 2nd SCT following graft rejection (n3) received preconditioning followed by Flu 150mg/m2, iv Bu, Cy 200 mg/kg, TT 10 mg/kg and Atg Sangstat 7,5mg/kg. Anti seizure prophylaxis consisted of clonazepam; due to liver disease all patients received anti VOD/SOS prophylaxis with oral defibrotide 40 mg/kg. GVHD prophylaxis consisted of cyclosporine A (CyA) and short course methotrexate, in addition methylprednisolone for 30 days was given to pts not receiving ATG. Thirtythree patients (66%) achieved Bu AUC in the expected range of 900–1500 umol/min following the 1st dose. Seventeen patients (34%) required dose adjusted because either above (n9) or below (n8) the expected range. The source of stem cells was unmanipulated bone marrow from an HLA identical sibling; median CD34 cells were 8x10^6/kg (3.3–19), CD3+ cells 73x10^6/kg (36–117). Fourtyseven patients engrafted with donor cells with median ANC take on day 19 (12–39) and median PLT take on day 17 (13–54). Three class III patients had primary graft failure, among these 2 reconstituted with autologous cells and 1 died in aplasia. Post transplant toxicity was mild and characterized by: hemorrhagic cystitis (n4), reversible CyA related posterior encephalopaty (n3), VOD/SOS (n1), grade II-IV stomatitis (n7), reversible lung infiltrates of unknown origin (n4), CMV reactivation requiring preemptive treatment (n23), FUO in aplasia (n33), MOF and death (n1). The incidence of acute GvHD II-IV was 5/47 evaluable patients (4 grade II, 1 grade III). Limited chronic GvHD was observed in 3/47. At a median follow-up of 528 days (112–936), 46/47 patients (98 %) are alive with a 100% Lansky score. Current thalassemia free survival is 94% of which 100% in class I-II pts and 86% in class III. In conclusion, in this population of high risk thalassemic it is recommended to perform Bu pharmacokinetic studies to avoid excessive toxicity or ineffective myeloablation. With appropriate dose adjustment, a myeloablative conditioning based on iv Bu resulted in limited regimen related toxicity and excellent thalassemia free survival in patients affected by Bthal coming from countries with limited resources.