ORLANDO, Fla. — Hematopoietic stem cell transplantation from human leukocyte antigen-matched siblings was successful among more than 90% of patients with severe sickle cell disease, according to results of an international registry-based study presented at the ASH Annual Meeting and Exposition.
Further, limited transplant-related complications, such as rejection and graft-versus-host disease (GVHD), occurred in this population, results showed.
“These results show that OS and EFS are very good as compared with treatment of sickle cell patients without transplant,” Barbara Cappelli, MD, a research physician of the Centre Scientifique de Monaco and the Eurocord International Registry of Paris, said at a press conference. “If a human leukocyte antigen-matched sibling is present, it is probably worth it to consider undergoing transplant.”
Although hematopoietic stem cell transplantation (HSCT) is the only curative therapy for sickle cell disease, it is not frequently offered to these patients because few patients have suitable human leukocyte antigen (HLA)-matched donors and there is a lack of consensus on indications for HSCT. Further, the procedure had previously been associated with a risk for GVHD and high mortality rates, according to study background.
Cappelli and colleagues reported the outcomes after HLA–matched sibling HSCT among patients from two registries: The Eurocord-Monacord/European Group for Blood and Marrow Transplantation (EBMT) and Center for International Blood and Marrow Transplantation Research (CIBMTR).
The researchers used these registries to identify 1,000 patients with sickle cell disease who underwent HLA–matched sibling HSCT between 1991 and 2013 — 53% of the transplants occurred after 2007.
The median age at the time of transplant was 9 years (range, 1-54 years) and 85% of the population was aged younger than 16 years. Ninety-four percent of the patients were homozygotes for hemoglobin S (HbS genotype).
The most common indication for HSCT was stroke. Other indications included a central nervous system event that lasted longer than 24 hours, an elevated cerebral arterial velocity, acute chest syndrome or a vaso-occlusive event that required hospitalization.
Of the 510 evaluable patients, 93% received red blood cell transfusions and 56% received hydroxyurea.
Eighty-seven percent of the patients received myeloablative-conditioning regimens, most of which contained busulfan with cyclophosphamide (82%) or fludarabine (9%). Thirteen percent of patients received reduced-intensity conditioning regimens, the most common of which was cyclophosphamide and fludarabine (38%).
Seventy-one percent of the regimens included in vivo T-cell depletion with either anti-thymocyte globulin (n = 630) or alemtuzumab (Campath, Genzyme; n = 76).
GVHD prophylaxis regimens used included cyclosporine alone (19%) or with methotrexate (56%).
Stem cells were most commonly derived from the bone barrow (84%), followed by cord blood (9%) and peripheral blood (7%).
Median follow-up was 45 months (range, 1.1-324.6 months).
The cumulative incidence of neutrophil engraftment 60+ days after transplantation was 98% (cord blood, 96.6%; bone marrow, 98.3%; peripheral blood, 95.2%), with a median time to recovery of 19 days.
The rate of platelet engraftment was 98% (cord blood, 96% ± 2%; bone marrow, 99% ± 1%; peripheral blood, 98% ± 9%), with a median time to recovery of 25 days.
Overall, 26 patients experienced primary graft failure and 47 patients experienced secondary graft failure.
Sixty-seven patients died, mostly of GVHD or infection. The rate of 3-year OS was 94% (95% CI, 92-95) and 3-year EFS was 90% (95% CI, 68-82). The 3-year rates of OS significantly differed based on stem cell source, ranging from 99% for cord blood, 94% with bone marrow and 80% with peripheral blood (P ˂ .0001).
Results of a multivariate analysis showed risk for mortality increased with older age (HR for every year in age increment = 1.1; 95% CI, 1.07-1.14) and use of peripheral blood (HR = 3.43; 95% CI, 1.49-7.88).
Further, a greater proportion of patients who received myeloablative vs. reduced-intensity conditioning achieved 3-year EFS (91% ± 1% vs. 82% ± 1%; P ˂ .001).
Results of a multivariate analysis showed poorer EFS was linked to every year in age increment (HR = 1.05; 95% CI, 1.02-1.07), peripheral blood grafts (HR = 1.83; 95% CI, 1.07-3.15) and HSCT prior to 2000 (HR = 0.77; 95% CI, 0.64-0.92).
The cumulative incidence of acute grade 2 to grade 4 GVHD was 14.4% (95% CI, 12.2-16.7), and incidence of chronic GHVD was 13.3% (95% CI, 11-15.8). The risk for GVHD increased with older age (HR = 1.04; 95% CI, 1.01-1.07); however, none of the variables had an association with chronic GVHD.
Despite these results, eligible patients still may not receive this therapy.
“Several barriers include lack of a suitable donor, lack of information and limited understanding of transplantation by primary care physicians and families,” study researcher Eliane Gluckman, MD, PhD, head of the department of bone marrow transplantation at the Hôpital Saint-Louis in Paris, told HemOnc Today. “The cost of the procedure [is also prohibitive], especially in emerging countries.”
Gluckman — who is part of the International Sickle Cell Disease Observatory — said that they are trying to coordinate better patient care by establishing a worldwide network for exchanging data on HSCT, developing new methods for pre- and postnatal diagnosis, providing recommendations for pre- and postnatal care, performing cost efficiency studies, publishing recommendations for HSCT, and disseminating information to the general public and medical professionals in association with other international associations. – by Anthony SanFilippo
Cappelli B, et al. Abstract 541. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.
Disclosure: The researchers report consultant/advisory roles with, research funding from, and other relationships with Amgen, ERYTECH Pharma, Fresenius, Jazz Pharmaceuticals, Medac, Novartis, Pierre-Fabre, Pfizer, Sanofi, and ViaCord and AllCells Inc.