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Matched unrelated transplantation improves EFS, but ‘not sufficiently safe’ for sickle cell disease
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Bone marrow transplantation using unrelated donor marrow conferred promising rates of 1-year EFS for children with severe sickle cell disease, according to phase 2 study results published in Blood.
However, due to the excessive incidence of graft-versus-host disease (GVHD), the treatment strategy “cannot be considered sufficiently safe for widespread adoption,” the researchers wrote.
“The GVHD rates we saw were higher than those seen after matched-unrelated donor transplantation in other disorders,” Shalini Shenoy, MD, professor of pediatrics at Washington University School of Medicine and director of the pediatric stem cell transplant program at St. Louis Children’s Hospital, told HemOnc Today. “We believe this is multifactorial, and may be related to race or ethnicity, patient age among recipients who developed GVHD, the design of the conditioning regimen used to target engraftment, or the inflammatory nature of sickle cell disease itself.”
Children with severe sickle cell disease experience adverse outcomes in early childhood, including organ damage, diminished quality of life and premature death.
Bone marrow transplantation from an HLA–matched sibling can significantly improve EFS outcomes in this patient population; however, fewer than 20% of U.S. children with sickle cell disease have a suitable donor sibling.
Shenoy and colleagues studied the safety and efficacy of transplanting bone marrow grafts from unrelated adult donors. A study arm investigating the use of umbilical cord blood was closed early due to unacceptable graft rejection rates.
The study included data from 30 children (median age, 14 years; range, 6-19; 53% boys). Indications for transplant included stroke (n = 12), significant pain (n = 12), elevated transcranial Doppler velocity (n = 2) and recurrent acute chest syndrome (n = 4).
All children received a conditioning regimen consisting of alemtuzumab (Campath, Genzyme), fludarabine and melphalan.
For GVHD prophylaxis, patients received a calcineurin inhibitor after graft infusion, with methotrexate (7.5 mg/m2 on days 1, 3 and 6) and methylprednisolone (1 mg/kg on days 7-28, followed by a 20% weekly taper).
EFS at 1-year served as the primary outcome measure. The researchers hypothesized that a reduced-intensity conditioning regimen would be stable for engraftment after unrelated transplantation and confer 1-year EFS of at least 75%; they considered primary or secondary graft rejection, as well as death, to be events.
Secondary outcome measures included OS, hematopoietic recovery, and rates of acute and chronic GVHD.
Median follow-up was 26 months (range, 12-62).
The study met its primary endpoint, with a 1-year EFS rate of 76% (95% CI, 56-88) and OS rate of 86% (95% CI, 67-95). At 2 years, EFS was 69% (95% CI, 48-82) and OS was 79% (95% CI, 59-90).
The graft rejection rate was 10% (primary rejection, n = 2; secondary rejection, n = 1). Median time to neutrophil recovery was 12 days (range, 6-16) and median time to platelet recovery was 24 days (range, 7-90).
All patients who experienced graft rejection eventually recovered host hematopoiesis without marrow aplasia.
On day 100, the cumulative incidence of grade 2 to grade 4 acute GVHD was 28% (95% CI, 13-45), and the incidence of grade 3 to grade 4 acute GVHD was 17% (95% CI, 6-33).
At 1 year, the cumulative incidence of chronic GVHD was 62% (95% CI, 41-77), 38% of which the researchers classified as extensive.
Eight patients died, seven of whom died of GVHD complications. The remaining death was caused by infection and occurred in a patient with primary graft rejection.
Parent proxies (n = 21) reported significantly worse changes to self-esteem health-related quality of life at day 100 (P = .006); however, they also reported significantly improved general health perception scores (P = .0003). Patient-reported changes in health scores also significantly increased (P = .0013).
“We are now investigating newer ways of tackling GVHD in similar transplants,” Shenoy said. “These include novel approaches to GVHD prophylaxis, such as abatacept [Orencia, Bristol-Myers Squibb] and post-transplant cyclophosphamide, and manipulation of stem cell products to achieve selective T cell/T-cell subtype depletion prior to infusion.”
Despite setbacks, a modified version of this treatment regimen may eventually become feasible for patients with sickle cell disease, Shenoy said.
“Our long-term follow-up of patients who received this regimen for transplantations reveals very few serious late events,” Shenoy said. “We also have a number of patients who have had successful pregnancies after transplantation, suggesting that female fertility preservation may be possible. If GVHD is effectively tackled, this regimen could provide an effective method of transplantation in children.” – by Cameron Kelsall
For more information:
Shalini Shenoy , MD, can be reached at shenoy@wustl.edu.
Disclosure: The researchers report no relevant financial disclosures.
Perspective
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Gregory M. Vercellotti
Gene therapy and bone marrow transplantation are the only curative approaches for sickle cell disease. The former shows great promise by expressing hemoglobin A in autologous hematopoietic stem cells, and the latter has been most successful in children who have human leukocyte antigen (HLA)–identical siblings as stem cell donors with over 90% event free survival and minimal graft versus host disease. However, this is limiting, as only 18% of patients have HLA–matched sibling donors.
Finding alternative HLA–matched donors is challenging, and using matched unrelated bone marrow or umbilical cord blood donors increases risks for graft rejection and GVHD. Minimizing the toxicity of a myeloablative conditioning regimen using a reduced conditioning regimen potentially decreases treatment-related mortality, morbidity and possibly long-term adverse effects in survivors.
Shenoy and colleagues’ important study — conducted in 29 children aged 3 to 19 years with severe sickle cell disease — utilized reduced conditioning and bone marrow grafts from HLA-A, -, -C and -DRB1–matched unrelated adults. Unfortunately, the 2-year OS was 79%, with seven GVHD–related deaths.
Incidence of acute GVHD at day 100 was 28%, but incidence of chronic GVHD at 1 year was 62%. Posterior reversible encephalopathy syndrome was noted in 34% by 6 months. These results are sobering and suggest a re-evaluation of hematopoietic stem cell transplant protocols in sickle cell disease.
With improved survival in children with sickle cell disease — due to comprehensive care centers, antibiotics, screening for stroke risk with transcranial Doppler and hydroxyurea use — and the potential novel therapies focusing on adhesion, inflammation, hemoglobin S polymerization, hemolysis and more now being studied, how should we consider curative hematopoietic stem cell transplants in sickle cell disease?
First, studies that compare bone marrow transplant with standard of care in patients with sickle cell disease are needed. The Blood and Marrow Transplant Clinical Trials Network Protocol 1503 — chaired by Lakshmanan Krishnamurti, MD, and Mark C. Walters, MD, and designed to compare bone marrow transplant with standard of care in adolescents and young adults with severe sickle cell disease — is a step forward in addressing this question.
Minimizing toxicity of the preparative regimen, use of immunosuppressive agents to minimize GVHD, and assessment of patient risk factors — such as infection propensity, iron overload, cardiac and lung disease, CNS disease, allosensitization, etc — must be foremost in future studies.
It makes no sense to trade one chronic disease for another, such as chronic GVHD. Other studies using reduced-conditioning HLA–haploidentical bone marrow transplants may help expand the number of eligible patients with sickle cell disease and provide a potentially safer curative therapy than described in the study by Shenoy and colleagues.
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