Sickle cell anemia is an inherited blood disorder caused by a genetic defect that alters the structure of hemoglobin, the oxygen-carrying protein found in red blood cells.
The defective hemoglobin (also called hemoglobin S) causes red blood cells to become stiff, sticky, and sickle-shaped. These deformed cells can block blood flow, causing symptoms ranging from severe pain to organ damage and stroke.
Stem cell transplant (SCT), or replacing the stem (precursor) cells that give rise to red blood cells, is the only treatment currently available to cure the disorder. Stem cells can be obtained from a donor’s bone marrow (the site within the bones where stem cells are produced), peripheral blood (blood in the veins), or umbilical cord (the cord that transports oxygen and nutrients from a mother to her baby) at the time of birth.
SCT is complex, however, and like all treatments, carries particular requirements and risks.
How stem cell transplant works
Stem cell transplant involves replacing the patient’s bone marrow with the bone marrow from a healthy donor. If the transplant is successful, the sickle cell patient may well be cured.
The procedure has two major requirements: identification of a best-suitable donor, and the pre-transplant evaluations of both patient’s and donor’s major organs (heart, lungs, kidney etc.).
There are three main types of stem cell donors: matched and related, matched and unrelated, and partly matched and related.
A matched-related donor is typically a sibling who has the same bone marrow type and the same mother and father. The patient and donor are matched through special blood tests called HLA typing. Match siblings are often preferred donors and, for this reason, this potentially curative treatment is still a somewhat limited treatment.
A matched but unrelated donor is an individual who has the same bone marrow type as the patient, but is not a family member or relative. Such donors are usually matched through national organizations.
Partly matched and related donors, also called haploidentical donors, are family members other than siblings, usually a mother or a father.
Studies have shown that transplants from siblings or other matched-related donors have a potential 85 percent chance of cure; a report by the National Institutes of Health showed that in 30 patients who went through such transplants, 87 percent — or 26 of the 30 — had their disease “reversed.”
Prior to stem cell transplant, recipients now typically need to take strong doses of chemotherapy for an extended period. Chemotherapies are used to weaken or destroy the patient’s own bone marrow, stem cells, and immune system, in an attempt to prevent their body from rejecting their donor’s blood cells.
Other means of avoiding rejection, short of chemotherapy, are being explored in clinical trials, including a Phase 2 trial detailed below.
The patient’s bone marrow is then replaced with blood-forming stem cells from a healthy donor. The new bone marrow, if accepted, will produce normal red blood cells.
Stem cell transplant in clinical trials
Ongoing trials are exploring the use of stem cells derived from bone marrow, peripheral blood, and umbilical cord from a related newborn baby in sickle cell anemia patients.
Matched-related donor transplantation
Interestingly, this study used a non-chemotherapy treatment to prevent rejection: low-dose radiation combined with two immunosuppressive drugs (alemtuzumab and sirolimus). Results showed that the treatment reversed the disease in 87 percent of patients, or 26 of the 30 in the trial. At a median follow-up of 3.4 years, successfully treated patients did not show any signs of graft-versus-host disease (GVHD) — a disease in which donor’s cells attack the recipient’s. Fifteen patients were able to stop taking immunosuppressants a year after the transplant.
Several clinical trials (NCT02776202, NCT01499888, NCT02038478, NCT02105766, NCT03214354, NCT01877837) are ongoing, studying the safety and efficacy of stem cell transplantation from a matched-related donor. Some use chemotherapy as pre-treatment, others radiotherapy and immunosuppression.
Matched unrelated donor transplantation
A Phase 2 trial (NCT00745420) called SCURT, trial evaluated the safety and efficacy of a bone marrow transplant from an unrelated donor in 29 children with severe sickle cell anemia after reduced-intensity chemotherapy. The results showed a high incidence of graft-versus-host disease (GVHD) and associated death, suggesting that the regimen was not sufficiently safe.
A similar study (NCT01565616), called STRIDE , evaluated the safety and efficacy of a bone marrow transplant from matched-related (sibling) donors as well as matched-unrelated donors following chemotherapy in 22 teenagers and adults, ages 16 to 40. At one-year post-transplant, 20 patients were alive and 19 showed event-free survival, without any signs of graft rejection or disease recurrence.
Several studies evaluating the use of matched but unrelated donors in sickle cell anemia and, occasionally, other patients — NCT02678143, NCT02435901, NCT02065596, NCT01966367, NCT01962415) — are ongoing.
Unrelated cord blood transplantation
A study that evaluated the use of cord blood from unrelated donors to treat sickle cell anemia and a similar disease reported treatment failed due to graft failure. Another similar study was suspended after recipients experienced a high rate of graft failure.
A pilot study (NCT01590628) is evaluating the safety and efficacy of co-transplantation using modified and unmodified cord blood cells in patients, including those with sickle cell anemia.
Haploidentical donor transplantation
Several clinical trials (NCT03279094, NCT03240731, NCT03263559, NCT02757885, NCT01461837, NCT03298399, NCT03077542, NCT03121001, NCT03249831) are studying the safety and efficacy of a stem cell transplant from haploidentical donors (half-matched family members).
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