Non-myeloablative allogeneic HSCT shows promise for adults with sickle cell disease

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.

Researchers observed the benefits in patients with or without thalassemia.

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.

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, 0.00-0.45) 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.

Allison King, MD 

Allison A. King

“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 all 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.”

For more information:

  • Hsieh MM. JAMA. 2014;doi:10.1001/jama.2014.7192.
  • King AA. JAMA. 2014;312:33-34.

Disclosure: The researchers report no relevant financial disclosures. King and DiPersio report no relevant financial disclosures.

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.

Researchers observed the benefits in patients with or without thalassemia.

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.

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, 0.00-0.45) 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.

Allison King, MD 

Allison A. King

“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 all 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.”

For more information:

  • Hsieh MM. JAMA. 2014;doi:10.1001/jama.2014.7192.
  • King AA. JAMA. 2014;312:33-34.

Disclosure: The researchers report no relevant financial disclosures. King and DiPersio report no relevant financial disclosures.