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Modified blood stem cell transplant reversed sickle cell disease in adults
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Adults with sickle cell phenotype achieved a high rate of stable mixed-donor chimerism and disease reversal after they underwent non-myeloablative human leukocyte antigen-matched sibling allogeneic hematopoietic stem cell transplantation, according to study results.
Half of the patients evaluated safely stopped immunosuppressant medication following the transplant. Researchers observed the benefits of the approach in patients with or without thalassemia.
“Typically, stem cell recipients must take immunosuppressants all their lives,” researcher Matthew Hsieh, MD, a staff clinician at NIH, said in a press release. “That the patients who discontinued this medication were able to do so safely points to the stability of the partial transplant regimen.”
The analysis included 30 patients with severe sickle cell disease. The median age of patients was 28.5 years (range, 17-65).
All patients received 1 mg/kg alemtuzumab (Campath, Ilex Pharmaceuticals), 300 cGy total-body irradiation and sirolimus (Rapamune, Pfizer), followed by an infusion of 5.5-31.7 x 106 cells/kg unmanipulated filgrastim-mobilized peripheral blood stem cells from HLA-matched siblings.
One patient died after relapse due to intracranial bleeding. Median survival among the other 29 patients was 3.4 years (range, 1-8.6).
Twenty-six patients (87%) achieved engrafted donor leukocytes without acute or chronic graft-versus-host disease (GVHD). Of these patients, 15 were able to discontinue immunosuppression without developing GVHD, while still maintaining continued stable donor chimerism.
John F. Tisdale
“Side effects caused by immunosuppressants can endanger patients already weakened by years of organ damage from sickle cell disease,” researcher John F. Tisdale, MD, a senior investigator at NIH, said in a press release. “Not having to permanently rely on this medication, along with use of the relatively less-toxic partial stem-cell transplant, means that even older patients and those with severe sickle cell disease may be able to reverse their condition.”
Overall, the mean T-cell level was 48% (95% CI, 34-62) and the mean myeloid chimerism level was 86% (95% CI, 70-100).
Researchers noted normalized hemoglobin and hemolysis resolution also resulted in brain imaging stabilization, reduced echocardiographic estimates of pulmonary pressure and allowed for phlebotomy to reduce hepatic iron.
The mean annual hospitalization rate per patient decreased from 3.23 (95% CI, 1.83-4.63) the year before HSCT to 0.63 (95% CI, 0.26-1.01) the year after, 0.19 (95% CI, 0-0.45) at 2 years post-HSCT and 0.11 (95% CI, 0.04-0.19) at 3 years after transplantation.
Mean narcotic use per week also decreased from 639 mg (95% CI, 220-1,058) the week of transplantation to 140 mg (95% CI, 56-225) at 6 months post-transplant.
Six patients experienced transplant-related infections such as Clostridium difficile and cytomegalovirus. Five patients experienced sirolimus-related toxicities, and researchers reported 15 serious adverse events related to pain.
“In this series of patients who underwent a simplified HSCT regimen to date, stable mixed-donor chimerism and reversal of sickle cell disease phenotype was achieved in the majority of patients,” the researchers concluded. “Further accrual and follow-up is required to assess longer-term clinical outcomes, adverse events and transplant tolerance.”
Only patients with HLA-matched donors were eligible for the trial, even though most patients with sickle cell disease — especially adults — do not have matched donors. Still, the lack of GVHD occurrence appears promising, Allison A. King, MD, MPH, and John F. DiPersio, MD, PhD, both of Siteman Cancer Center of Washington University School of Medicine in St. Louis, wrote in an invited commentary.
“The results of the trial by Hsieh et al support the acceptance of mixed T-cell chimerism for disease cure without GVHD,” King and DiPersio wrote. “In a population of relatively older adults with sickle cell disease, these findings offer hope. Based on these exciting results, the role of age as a contraindication for offering adults with sickle cell disease and a matched sibling the chance of curative allogeneic stem cell transplantation should be reconsidered.”
References:
Hsieh MM. JAMA. 2014;doi:10.1001/jama.2014.7192.
King AA. JAMA. 2014;312:33-34.
Perspective
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Sohail R. Rana, MD
This is the best report yet for adults with sickle cell disease who received bone marrow transplantation, and the results are very impressive. Looking at the same matched sibling donors over a period of time, there are a significant number of children and adults who get GVHD and other complications, but with the non-myeloablative regimen that Tisdale and colleagues used and fine-tuned over a period of time, what was most impressive was a relative lack of GVHD. Chronic GVHD is one of the scariest things for these patients. They are cured of the disease but now have serious problems with skin, eyes, lungs, intestinal tract and other organs. There was practically no GVHD observed in this trial, which is very impressive.The second thing that is impressive is the high engraftment rate and low mortality, even though this was an adult population with significant co-morbidities. One patient who died had pre-existing Moyamoya disease. Other patients are living, although there were a few who rejected the engraftment. Overall, this is a real advance. Tisdale and colleagues should be saluted for their meticulous work in fine-tuning the preparatory and post-transplant regimens for bone morrow transplantation for individuals with sickle cell disease.
However, only one out of 10 individuals who need a bone marrow transplant with sickle cell disease have a sibling donor who’s fully matched. That’s one concern. Number two is that using hydroxyurea as early as during infancy has markedly decreased the morbidity and the number of complications in sickle cell disease. We are very hopeful that we would not have many candidates for bone marrow transplant.
My third concern is that, even though the mortality was 3% to 5%, we must remember this is not a controlled study, and even though this mortality is less than the 10% mortality rate reported maybe 10 years ago, you’re imposing a mortality where you don’t know the baseline rate. In the scheme of things, they probably have a decent chance of living, yet you impose a 3% to 5% mortality by a very laborious procedure. Also, the study doesn’t address the cost of a bone marrow transplantation, nor whether there was real improvement in quality of life. Similar to studies for cancer patients, studying quality of life before, after and during transplant would be very meaningful in this patient population.
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