Pioneering research led by Johns Hopkins scientists on the use of partially matched bone marrow transplants to wipe out sickle cell disease has been selected as one of the Top 10 Clinical Research Achievements of 2012 by the Clinical Research Forum. The success of a preliminary clinical trial of the so-called haploidentical transplants has the potential to bring curative transplants to a majority of sickle cell patients who need them, eliminating painful and debilitating symptoms and the need for a lifetime of pain medications and blood transfusions.
On behalf of the research team, Robert A. Brodsky, M.D., the Johns Hopkins Family Professor of Medicine in Oncology and director of the Division of Hematology at the Johns Hopkins University School of Medicine, will receive the award and an additional honor, the Distinguished Clinical Research Achievement Award, at a ceremony on April 18 during the Clinical Research Forum annual meeting in Washington, D.C.
Comprised of academic medical centers, professional organizations, and industry partners, the Clinical Research Forum selects 10 scientists each year whose clinical research improves human health and alleviates suffering from disease. All research projects honored this year were published in 2012 and funded by various federal agencies, foundations, and corporations. In addition to Brodsky's work, others on the Top 10 list in 2012 included studies of a treatment that restores sight, the use of sophisticated prosthetic devices to alleviate paralysis from neurological illnesses, and replacement of defective heart valves without open heart surgery.
Brodsky's study, reported online September 6, 2012 in the journal Blood, showed that, of 17 sickle cell disease patients offered bone marrow transplants (BMT), 11 transplants were successful. Eight of those successful transplants involved patients who received half-matched, rather than fully matched donor marrow. Three received fully matched transplants. All 11 patients are now free of painful sickle cell crises. Six of the patients successfully transplanted received half-matched bone marrow and are no longer taking the sickle cell-related immunosuppressive drugs they needed before their transplants.
"This clinical research study constitutes a major advance in the potential curative treatment for sickle cell disease, which affects one out of 400 African-Americans in the United States," says Myron L. Weisfeldt, M.D., who nominated Brodsky's research for the award and who is the William Osler Professor of Medicine at Johns Hopkins and Director of Medicine for Johns Hopkins Medicine.
"Sickle cell patients have overwhelming symptoms and physical impairments due to strokes, myocardial infarction, kidney failure, and a wide variety of other chronic disabilities," Weisfeldt adds. "The clinical improvement of successful patients in this study has been truly remarkable."
Sickle cell disease is a hereditary illness in which a genetic defect in hemoglobin causes misshapen red blood cells and other defects that ultimately restrict oxygen-rich blood flow into various organs. The condition often results in life-long debilitating pain, organ damage, and a shortened life span.
Until recently, bone marrow transplants were successful in curing some cases of sickle cell disease, but were rarely done because fully matched, eligible donors are exceedingly rare and, even when a match is found, the transplants pose risks.
To overcome the lack of matched donors, Brodsky and colleagues developed techniques that enable sickle cell patients to receive transplants that are only half-identical, or "haploidentical," to their tissue type. The half-matched bone marrow, extracted by needle from a donor's hip bone, can be obtained from a patient's parents, children, and most siblings.
Normally, patients' bodies would reject bone marrow that was not identical to their own. But the Johns Hopkins investigators also developed a protocol that prepared patients for the donor marrow by administering low-dose immunosuppression drugs, low toxicity-chemotherapy, and low-dose total body irradiation. This "gentler" approach, Brodsky says, makes the process more tolerable for patients whose tissues and organs have been compromised by sickle cell disease. Post-transplant, patients received high doses of chemotherapy to kill off any remaining original blood cells (including diseased sickled cells), while preserving the stem cells that make new, healthy blood cells.
Brodsky also sees the potential for using the half-matched donor approach for people with autoimmune disorders such as lupus and multiple sclerosis. It makes sense, he says, that a brand-new immune system would resolve the underlying problem causing their medical condition. "I think you're going to see newer indications [for these half-match BMTs] more often for nonmalignant diseases than malignant ones, for which bone marrow transplants were first developed," Brodsky says. "That's really the next new frontier."