PHARMAWRITE AT THE 13TH ANNUAL HOPA CONFERENCE
The Curative Potential of Hematopoietic Stem Cell Transplantation for Sickle Cell DiseaseCompiled for you by PharmaWrite.
Presented by Missy Sricherz, PharmD, BCOP
University of Minnesota Masonic Children's Hospital, Minneapolis, MN
- Hematopoietic stem cell transplant (HSCT) is the only curative option for sickle cell disease (SCD)
- A significant barrier to HSCT for SCD patients is the lack of donor availability
- While myeloablative (MA) HSCT offers more stable engraftment, non-myeloablative (NMA) HSCT and the use of reduced-intensity conditioning (RIC) regimens with HSCT appear to be safe and effective alternatives
- Haploidentical transplants offer the potential to expand the donor pool
Sickle cell disease (SCD), a type of inherited blood disorder, is caused by poor hemoglobin production resulting in deformed red blood cells that are unable to carry adequate supplies of oxygen. An estimated 3.2 million people worldwide have SCD, including about 100,000 people in the US. Only about 50% of SCD patients survive past the 5th decade of life (Platt 1995).
Patients with SCD are at risk for multiple complications. Due to the sickle/crescent shape of the hemoglobin, the tissues and organs can be deprived of adequate oxygen supply. Patients with SCD are thus at risk for sudden painful episodes, known as pain crises, that can result in hospitalization. These patients are also at high risk for infections because they are considered to be functionally asplenic. Other complications can include strokes or acute chest syndromes.
Due to significant advances in supportive care, mortality rates in SCD have improved. Monitoring for SCD has become a common part of newborn screening in the US, for example, which allows for early identification of patients who would benefit from early interventions to prevent complications associated with SCD.
The mainstay of therapy for SCD has been treatment with hydroxyurea, which has been shown to reduce pain episodes, the need for transfusions, and hospitalizations. While hydroxyurea has helped to improve outcomes, SCD is still a significant burden on the health care system, with an estimated annual cost of $475 million in the US.
The use of hematopoietic stem cell transplant (HSCT) is the only option to offer a potential cure. With HSCT, donor-derived erythropoiesis can stabilize and restore function to the affected organs. Current indications for the use of HSCT for SCD include one or more of the following:
- Stroke or central nervous system (CNS) event lasting longer than 24 hours
- Impaired neuropsychological function with abnormal cerebral MRI and angiography
- Recurrent acute chest syndrome
- Stage I or II sickle lung disease
- Recurrent vaso-occlusive pain or recurrent priapism
- Sickle nephropathy (glomerular filtration rate 30%-50% of predicted normal)
Allogeneic HSCT with the use of a human leukocyte antigen (HLA) identical sibling offers overall survival (OS) rates of 90% or more and event free survival rates (EFS) of 80% or more, with low amounts of treatment-related mortality. However, the number of patients being offered transplant is very low due to several barriers, including lack of a sibling donor (primary barrier), poor financial or psychosocial support, parent refusal, and physician refusal (Walters 1996).
Novel methods to identify donors have been undertaken as have studies exploring the use of umbilical cord blood (UCB), which found that UCB with myeloablative (MA) regimens (vs treatment with HLA identical sibling bone marrow) had significantly lower incidences of graft-vs-host disease (GvHD) with no difference in OS, EFS, or disease free survival (DFS).
In a study by Ruggeri and colleagues, however, the use of unrelated UCB was disappointing, with DFS at only 50%. Of 16 patients, 7 had primary graft failure. Kamari and colleagues evaluated the use of UCB or bone marrow in the setting of reduced-intensity conditioning regimens (RIC). The UCB arm was ultimately suspended due to a high incidence of graft failure. In the BM arm results were better, but chronic GvHD at 1 year was extensive at 62%. From this study the regimen was deemed unsafe without better GvHD prophylaxis. While UCB provided a means to identify more donor options, there was still a large gap for patients. The best stem cell source was unclear as was which conditioning regimen and what type of GvHD prophylaxis was needed.
The benefit of using RIC or non-myeloablative (NMA) regimens is that they allow for decreased toxicity from MA regimens and minimize acute and delayed organ toxicities yet provide a mixed chimerism to allow for cure. The use of RIC and NMA would also allow increased eligibility for adult patients with SCD to undergo transplant. Several studies by Bhatia et al, King et al, and Hsieh et al demonstrated the feasibility of using RIC or NMA regimens for SCD transplant. Results from OS and EFS were comparable to transplant done using MA regimens. Although MA transplants tend to provide more stable engraftment, these studies demonstrated that RIC and NMA transplant were safe and effective in patients with SCD.
However, there is still a portion of the population without a donor, and less than 20% of African American patients will have a fully unrelated matched donor. The use of familial haploidentical donors can increase the donor pool significantly, although this carries a large risk of GvHD.
In the study published by Bolaņos-Meade and colleagues, 57% of patients had long-term engraftment, which resulted in reversal of their sickle cell phenotype and pain crises. There was a high rate of graft rejection in the UCB patients undergoing haploidentical transplant. However, there was no acute or chronic GvHD. The authors concluded that graft failure may be an obstacle but it may be acceptable if patients can be cured with limited serious toxicities.
This session summary was prepared by Maribel A. Pereiras, PharmD, BCPS, BCOP, a member of the PharmaWrite Oncology Working Group.
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