In a preliminary clinical trial, investigators at Johns Hopkins have
shown that even partially-matched bone marrow transplants can eliminate
sickle cell disease in some patients, ridding them of painful and
debilitating symptoms, and the need for a lifetime of pain medications
and blood transfusions. The researchers say the use of such marrow could
potentially help make bone marrow transplants accessible to a majority
of sickle cell patients who need them.
After a median follow-up of two years, the transplants successfully
eliminated sickle cell disease in 11 of 17 patients. Three were fully
matched to their donors and eight received half-matched donor marrow.
All 11 patients are free of painful sickle cell crises and 10 no longer
have anemia. There were no deaths and no unexpected toxicities.
Six of the 11 patients (all half-matched) have stopped taking
immunosuppressive drugs, although some still require narcotics for
chronic pain because of sickle cell-related organ damage. Blood tests on
the six patients show that their red cells are now completely derived
from their donor's marrow.
Patients with severe sickle cell disease (SCD) face shortened life
spans, intractable pain and eventual organ damage as a result of their
disease, an inherited disorder caused by a mistake in the
oxygen-carrying hemoglobin molecules in red blood cells. The flawed
genetic code stiffens red cells, and shapes them into a pronged "sickle"
that clump and stick into blood vessel walls, cutting off blood and
oxygen to tissues and organs throughout the body.
SCD occurs in approximately one in 400 African Americans, and rarely
in Caucasians. An estimated 100,000 people are currently living with
sickle cell disease in the U.S.
Most patients die before age 50, and many suffer poor quality of life
with frequent episodes of "off-the-charts" pain, and an increased risk
for kidney failure, stroke, deep-vein thrombosis, and lung disease.
Treatments include blood transfusions and a drug, hydroxyurea. Many
patients use narcotics to control severe pain and have repeat
hospitalizations. Bone marrow transplants have been successful in curing
some cases, but matching donors are rare and the procedure itself poses
risk.
In the current study, 17 patients at the Johns Hopkins Hospital were
offered bone marrow transplant options, including the use of
half-matched donor marrow to try and replace their "sickled" blood cells
with new, healthy ones. The transplants were successful in 11 of the
patients, of whom eight were only half-matches. Results of the trial
were published in the Sept. 6 early online edition of Blood.
"We're trying to reformat the blood system and give patients new
blood cells to replace the diseased ones, much like you would replace a
computer's circuitry with an entirely new hard drive," says Robert
Brodsky, M.D., director of the Division of Hematology at Johns Hopkins
and The Johns Hopkins Family Professor of Medicine and Oncology. "While
bone marrow transplants have long been known to cure sickle cell
disease, only a small percentage of patients have fully matched,
eligible donors."
National registries often are of little help in finding donors for
sickle cell patients, because most of those in need are African American
and other minorities who are vastly underrepresented in registries, say
the Johns Hopkins researchers.
To overcome the shortage of donors, investigators at Johns Hopkins
developed techniques, recently tested in leukemia and lymphoma patients,
to transplant with bone marrow that is half-identical or
"haploidentical" to the patient's tissue type. Half-matched bone marrow
can be obtained from parents, children and most siblings, and is
extracted by needle from the hip bone.
For the study, the Johns Hopkins team screened 19 patients to find
bone marrow donors with either half-identical or fully matched tissue.
Each transplant candidate had experienced many severe pain crises,
significant organ problems, or had failed hydroxyruea, the only drug
known to curtail sickle cell symptoms. The team found donors for 17 of
the 19 patients: 14 were half-identical and three were fully matched
siblings. The youngest patient was 15; the oldest 46.
Before each transplant, sickle cell patients received a
"conditioning" regimen of low-dose immunosuppression drugs, low toxicity
chemotherapy, and low-dose total body irradiation. Brodsky says this
gentler approach to pre-transplant therapy has made transplant possible
for sickle cell patients whose tissues and organs have been ravaged by
the disease.
After the transplant, all patients received high doses of the
chemotherapy drug cyclophosphamide, which kills remaining blood cells,
including diseased sickled cells, and preserves the donor's stem cells
responsible for making new, healthy cells.
Of the 17 patients, six transplants were not successful; however,
because of the reduced intensity of the conditioning regimen, all of
these patients recovered their own blood cells.
There were no deaths, some infections, and only slight skin-related
graft versus host disease symptoms in one patient, which cleared without
therapy, the researchers reported. Some brain swelling occurred in
three patients during the conditioning period and resolved without
neurologic damage.
The Johns Hopkins doctors say that while the majority of patients in
the trial had successful transplants, about less than half did not.
"Sickle cell disease patients undergo multiple blood transfusions
throughout their lives and may have acquired antibodies against many
different blood types, making it more difficult than usual to give
patients donated bone marrow." says Javier Bolaños-Meade, M.D.,
associate professor of oncology at the Johns Hopkins Kimmel Cancer
Center and principal investigator of the study.
Improving the rate of engraftment in haploidentical transplants for
sickle cell disease remains a challenge, they say, but the researchers
are looking for additional ways to overcome it, including increasing the
number of stem cells transplanted and using other immunosuppressant
drugs during the transplant.
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