Sickle Cell Disease Cured With Partial-Match Bone Marrow

Ricki Lewis, PhD

September 24, 2012

September 24, 2012 — Full and haploidentical bone marrow transplant can cure sickle cell disease (SCD) in adults if combined with high-dose cyclophosphamide after the procedure, according to a preliminary study published online September 6 in Blood.

The organs of adults with severe SCD are typically too damaged to withstand the myeloablative conditioning regimen typically used for an allogeneic bone marrow transplant. Moreover, the likelihood of success is greater if the bone marrow is a complete HLA match, but finding compatible donors in the black community, where 1 in 400 individuals has SCD, is challenging.

Taking cues from work on hematopoietic malignancies, Javier Bolaños-Meade, MD, associate professor of oncology at the Hematologic Malignancies and Bone Marrow Transplantation Program, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center and Johns Hopkins University School of Medicine, Baltimore, Maryland, and colleagues conducted a small clinical trial that exposed adults with severe SCD to a gentler pretransplant conditioning regimen, followed by posttransplant high-dose cyclophosphamide to reduce risk for graft-versus-host-disease (GVHD). Their hypothesis was that results with haploidentical bone marrow could be as good as fully matched marrow if the patients receive cyclophosphamide posttransplant.

SCD is the result of a point mutation at amino acid position 6 in the beta globin gene, causing erythrocytes to sickle under low-oxygen conditions, obstructing microcirculation. Prophylactic antibiotics from infancy, blood transfusions, narcotics, and hydroxyurea to increase the population of unsickled cells have extended life and have prevented or treated painful crises. Repeated blood transfusions, however, have led to antibody responses against many blood types, which complicates finding a match. Despite these advances, most patients die from organ damage that elevates risk for stroke, avascular necrosis, infections, lung diseases, kidney failure, and deep-vein thrombosis.

"Finding well-matched donors for all patients who might benefit remains a challenge, and this issue is particularly acute for minorities, who may be underrepresented on marrow registries. Most patients will have mismatched or half-matched family members, but historically, toxicity, particularly from GVHD, has been limiting, making haploidentical transplant impractical for many patients," David Porter, MD, professor in the Division of Hematology-Oncology and director of Blood and Marrow Transplantation in the Abramson Cancer Center at the University of Pennsylvania, Philadelphia, told Medscape Medical News. Dr. Porter was not involved in the study.

The researchers screened 19 patients with severe disease for haploidentical or fully matched first-degree relatives willing to donate bone marrow. Two patients did not find matches, 3 had fully matched siblings, and 11 had haploidentical relatives. Recipient ages ranged from 15 to 46 years.

The pretransplant "non-myeloablative bone marrow transplant platform" consisted of low-dose antithymocyte globulin, low-toxicity fludarabine and cyclophosphamide, and low-dose total body irradiation.

Patients received GVHD prophylaxis and an antirejection regimen on days 3 and 4 posttransplant, consisting of high-dose cyclophosphamide, mycophenolate mofetil, and tacrolimus or sirolimus. Cyclophosphamide destroys the recipient's erythrocytes while sparing donor hematopoietic stem cells.

Eleven of the 17 patients responded: Three of the 11 had fully matched transplants and 8 had haploidentical transplants. All 11 had no pain crises, and 10 had no anemia.

Median follow-up was 711 days (range, 224 - 1981 days). The investigators measured chimerism in peripheral blood at days 30, 60, 180, and 360. Five patients with haploidentical transplants had become full donor chimeras requiring no immunosuppression. A sixth haploidentical patient was a >95% donor chimera at 6 months.

Five patients were mixed chimeras, yet they, similar to the full chimeras, experienced fewer pain crises, had less hemolysis, and required fewer transfusions. The graft did not become established in 6 of the patients, as indicated by absence of donor DNA in 2 consecutive checks more than a week apart.

There were no deaths or unexpected toxicities in the study population, although all patients experienced pain. A few participants contracted infections, and a single patient developed GVHD in facial skin, but that resolved on its own. Three patients developed posterior reversible encephalopathy syndrome, which resolved without neurologic damage.

"[W]e confirmed that full donor chimerism is not required to improve symptoms, since patients with mixed chimerism demonstrated improvement in disease-related symptoms," the researchers write. Future experiments will attempt to increase engraftment rate by transplanting more stem cells and using different immunosuppressants.

"This approach has the potential to be widely applicable to any disease where patients may benefit from allogeneic transplants and well-matched donors are not readily available," Dr. Porter told Medscape Medical News.

Four coauthors are inventors on a patent application for "use of high-dose, post-transplantation oxazaphosphorine drugs for reduction of transplant rejection." One coauthor served in a scientific advisory board for Hemaquest. The other authors and Dr. David Porter have disclosed no relevant financial relationships.

Blood. Published online September 6, 2012. Abstract