# The penny has dropped for sickle cell disease

Ronit Elhasid

In this issue of Blood, Gluckman et al confirm the role of HLA identical sibling transplantation in sickle cell disease (SCD) with a 5-year overall survival of 95% when performed at an early age (<16 years) and using bone marrow as the source of stem cells.1

Although SCD is the most common inherited hemoglobinopathy worldwide, and most patients suffer from life-threatening complications, fewer transplants have been performed compared with the number carried out for thalassemia major. Past indications for stem cell transplantation (SCT) reserved this procedure for patients with significant sickle-related morbidity, such as recurrent pain crises leading to multiple hospitalizations, stroke or acute chest syndrome, sickle lung disease, and sickle nephropathy. By following those recommendations for transplant in SCD, only severely affected children had been included, such as those with established end-organ involvement (kidney, lung, brain) that further jeopardized transplant success through increasing the risk for toxicity. New recommendations have been recently published by an international expert panel.2 These state that young patients with symptomatic SCD who have an HLA-matched sibling donor should be transplanted as early as possible, preferably before school age. The importance of early transplantation has long been well recognized in thalassemia major, which is the second most common hemoglobinopathy. Transplant in thalassemia major is performed when there is a matched sibling donor as soon as the child initiates regular blood transfusions.3 The excellent outcome reported by Gluckman et al in patients with SCD transplanted between 1986 and 2013 and following the old SCT indications confirmed that patient age at transplant is important, supporting the earlier notion that early transplant before end organ damage occurs is fundamental to treatment success.

One may argue that although SCT is currently the only curative treatment, preventive measures such as newborn screening, penicillin prophylaxis, pneumococcus vaccinations, and chronic treatment with hydroxyurea and regular transfusion can help the child reach adulthood. The question that arises, however, is: At what price? How good is the quality of life of those children? Their survival is 20 years shorter than that of the general population, and this is the best-case scenario for patients with good compliance who receive treatment in industrialized countries.4 In a survey of 30 adults with SCD on their feelings toward receiving a reduced-intensity bone marrow transplantation for the management of their disease, 50% were willing to accept infertility, and 62% were ready to accept a transplant-related mortality greater than 10%.5 Although that was a small study, among select individuals, it gave an idea of the quality of life of patients with SCD who had reached adulthood. Another report described post-SCT quality of life and demonstrated results identical to those of unaffected siblings.6

SCD is recognized as a global public health issue with an average lifetime cost of care of $460 151 per patient.7 However, taking into consideration disease chronicity, recurrent hospital admissions, surgical and nonsurgical treatment of complications, use of intensive care facilities, and multidisciplinary approach to management, the actual cost estimation is closer to$9 million for 50 years of life expectancy per patient.7 In terms of economics, the earlier the transplantation, the greater the savings.

Another evolving field that offers a cure is gene therapy, using various exciting techniques, from gene addition by lentiviral vector to gene correction or reactivation of fetal hemoglobin.8 Although very attractive and having the potential of proving utility in the future, these techniques are not yet common practice and cannot offer an immediate solution for patients with SCD.

Historically, it took 32 years and many small series between the time of the first successful transplant in a patient with SCD in 19849 and the appearance of this important article by Gluckman et al, summarizing 1000 patients. Those authors revealed that early intervention with transplantation in patients with SCD using a matched sibling donor can save the patient from years of chronic treatment and significant incapacities. A similar conclusion was reached many years ago for patients with thalassemia major. The first transplantation performed in thalassemia major took place in 1981, and by 2001, the group in Pesaro had already transplanted about 900 patients with homozygous β thalassemia, using marrow as the stem cell source, learning and understanding the pitfalls associated with transplantation in thalassemia, including the importance of age and associated comorbidities.3 This led to a survival rate of above 90% in patients with class I thalassemia.

The importance of the paper by Gluckman et al is the collaboration among the European Blood and Marrow Transplant Group, Eurocord, and the Center for International Blood and Marrow Transplant Research to report the results of 1000 patients who had undergone transplant for SCD and to arrive at concrete conclusions that can help physicians benefit their patients. It takes a leader in the field to promote treatment progress. Yet, in the real world, most patients do not have a sibling donor. As in other nonmalignant disorders, it is time to move forward using matched unrelated donor (MUD) for SCT. The data regarding MUD transplants in SCD are sparse. The largest study treated 29 patients with reduced-intensity conditioning with good engraftment but with high incidence of chronic graft-versus-host disease.10 Eligible patients had a median age of 14 years and severe SCD. Learning from matched sibling SCT, age and disease severity are important and should be taken into account when suggesting MUD SCT to a patient with SCD.

Pediatric hemato-oncologists often encounter reluctance on the part of hematologists to refer their patients with SCD for transplantation. With an overall survival rate of 95% among young patients with SCD using matched sibling donor, there is no need to perform controlled clinical trials for comparing chronic transfusions, hydroxyurea, and SCT. Planning controlled prospective clinical trials to explore the best conditioning regimen, either myeloablative or reduced intensity, in the setting of matched unrelated donor is the next challenge that needs to be faced.

## Footnotes

• Conflict-of-interest disclosure: The author declares no competing financial interests.

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