Page 16 - Haematologica July

Editorials
Complication free survival long-term after hemopoietic cell transplantation in thalassemia
Emanuele Angelucci
Hematology and Transplant Center, Ospedale Policlinico San Martino, IRCCS, Genoa, Italy
1094
E-mail: emnang@tin.it doi:10.3324/haematol.2018.196071
Thalassemia patients have witnessed and have been the protagonists of two extraordinary events in the progress of their treatment during recent decades. Medical therapy (transfusion and regular chelation) has dramatically changed their prognosis from a fatal disease in childhood to a chronic disease into adulthood with an open, undefined prognosis. Hematopoietic cell transplant has changed the paradigm of thalassemia, introducing for the first time in medical history the notion of a cure for this congenital disease.
Allogeneic hematopoietic cell transplantation (HCT) has become a standard of care for the cure of transfusion- dependent thalassemia patients, with thousands undergo- ing this curative approach worldwide. Transplant has expanded from the industrialized countries and is now performed in several parts of the world, including those where the disease is most prevalent.1
As transplantation is a curative approach usually per- formed in childhood, with a limited but not absent risk in a non-neoplastic disease in which prolonged survival (decades) can be achieved with conventional medical therapy, data on long-term real-life complications are essential. In this issue of the Journal, Rahal et al.2 and the French co-operative group2 report on these much needed data.
Of the over 134 patients transplanted in the period 1984-2012 (median age at transplant 5.9 years, interquar- tile range 3-11 years) in 21 French centers, 107 were alive and well two years after HCT; 2 subsequently died from chronic graft-versus-host disease (GvHD) and 6 were later lost to follow up. The remaining 99 patients were part of these detailed analyses on long-term complications. Almost all patients had been transplanted in childhood after a myeloablative conditioning and almost all had received hematopoietic cells from an HLA identical sib- ling.
After a median follow up of 12 years (interquartile range 7-19 years) 11% of these patients presented thyroid dysfunction, 5% diabetes, and 2% cardiac failure. Hypogonadism was present in 56% of females and 14% of males. As expected, females who experienced normal puberty were younger at transplant compared to those who experienced delayed puberty. Almost half of the females aged 20 years or over had spontaneous and suc- cessful pregnancy after transplantation, confirming anoth- er single center report.3
Interestingly, no secondary cancer, delayed graft failure with thalassemia recurrence or transplant-related mortali- ty were registered. As correctly reported by the Authors, and as also expressed in other recent reports,4 the issue of secondary cancers probably requires a longer follow up to be confirmed. However, the limited incidence of chronic GvHD allows for some slight optimism in this setting. The data regarding absence of long-term thalassemia
recurrence do not confirm recent isolated case reports (EP Alessandrino and C Giardini, 2018, personal communications), but even in this case, longer follow up would probably be necessary.
Most patients have been successfully treated for iron overload even if the suggested target of normal transferrin saturation has not been completely reached in all of them.5
The great strength of this report is that it includes 73% of the transplanted patients and 93% of the patients who have survived for at least two years in the multi-center (21 transplant centers) experience of an entire large nation and, therefore, provides reliable real-life data on a popula- tion judged suitable for transplantation in the years indi- cated without other forms of selection. Moreover, condi- tioning, age at transplant, and follow-up methods were substantially uniform for almost all the patients. This report provides the most uniform world-wide long-term analyses from the entire transplant activity of one coun- try.
Another great strength of this work is that the Authors successfully managed to separate iron overload tha- lassemia-related long-term complication from transplant- related complication. Because of the homogeneous donor selection, and the very limited incidence of chronic GvHD, the reported transplant-related complication could likely be related to the intensity of the conditioning regi- men, and mainly to the use of high doses of the alkylating agent busulfan. This makes this analysis likely predictive for long-term complication in gene therapy programs in hemoglobinopathies6 requiring myeloablative preparative regimens.
There are three unavoidable limitations to a general use of these data. One is that patients were transplanted at a very young age (following the indications of the Pesaro Group), and it is likely that patients transplanted at an older age would present many more long-term tha- lassemia-related complications.7,8 Moreover, patients reported here were transplanted more than a decade ago with a standard myeloablative regimen. Today, less toxic preparative regimens have been developed,9-11 and their long-term complications could be different and, hopefully, of a lower grade. Finally, 91% of patients transplanted in France were transplanted from an HLA identical sibling, and therefore long-term complications of transplants from different donor types could not be completely represented in this research.
Nevertheless, taking into account the above reported limitations, these data can be used to set up rational screening programs for patients transplanted in child- hood.
There are several important considerations arising from this article.
haematologica | 2018; 103(7)