Haplo-HSCT regimen can cure SCD, team says

Jenny Fontaine

A haploidentical transplant regimen has led to long-term engraftment in adults with sickle cell disease (SCD), according to researchers.

Seven of 8 patients treated with this regimen were still alive at last follow-up, and 6 of them maintained engraftment.

Two patients developed graft-versus-host disease (GVHD). One of them had acute and chronic GVHD and died about 400 days after transplant. The other had acute GVHD that resolved with treatment.

Damiano Rondelli, MD, of the University of Illinois at Chicago, and his colleagues reported these results in Biology of Blood and Marrow Transplantation.

The researchers initially screened 50 adult SCD patients as candidates for haploidentical hematopoietic stem cell transplant (haplo-HSCT) between January 2014 and March 2017. Most patients were ineligible or declined the procedure.

Ultimately, 10 patients received a haplo-HSCT. Unfortunately, the first 2 patients failed to engraft. These patients had received conditioning with alemtuzumab and 3 Gy total body irradiation (TBI) as well as post-transplant cyclophosphamide.

Because of this failure, the researchers used the following regimen for the remaining 8 patients. It’s a modified version of the regimen described in Blood in 2012.

“We modified the transplant protocol by increasing the dose of radiation used before the transplant and by infusing growth factor-mobilized peripheral blood stem cells instead of bone marrow cells,” Dr Rondelli said. “These two modifications helped ensure the patient’s body could accept the healthy donor cells.”

Modified regimen

Patients received growth-factor-mobilized peripheral blood stem cells after conditioning with rabbit antithymocyte globulin (0.5 mg/kg on day -9, 2 mg/kg on day -8 and -7), cyclophosphamide (14.5 mg/kg on day -6 and -5), fludarabine (30 mg/m² on day -6 to -2), and single-dose TBI (3 Gy on day -1).

For GVHD prophylaxis, patients received intravenous cyclophosphamide (50 mg/kg on day 3 and 4), oral mycophenolate mofetil (15 mg/kg 3 times daily from day 5 to 35), and sirolimus (from day 5 dosed for a target trough of 5 to 15 ng/mL). In patients who had T-cell chimerism greater than 50% at 1 year after HSCT and did not have signs of GVHD, sirolimus was tapered off over 3 months.

Patients stopped taking hydroxyurea on day -9. They received red blood cell exchange transfusion on day -10 (with the goal of getting hemoglobin S below 30%) and received platelet transfusions to maintain platelet counts greater than 50 x 10⁹ cells/L.

Patients also received penicillin V (250 mg twice daily) in addition to standard antimicrobial prophylaxis.

Results

All 8 patients on the modified regimen engrafted. The median time to neutrophil engraftment was 22 days (range, 18 to 23 days). One patient experienced secondary graft failure on day 90.

Seven neutropenic patients with hemoglobin S less than 30% received G-CSF after transplant. They received a median of 7 doses (range, 3 to 14) at 5 μg/kg, starting at day 12 post-HSCT. One of these patients experienced mild bone pain in the lower extremities.

Two patients developed GVHD. At day 83, one patient developed acute or chronic GVHD involving the skin, liver, and eyes. Steroids and sirolimus improved eye and liver symptoms, but the patient died at home on day 407.

The other patient had grade 2, gastrointestinal, acute GVHD that resolved with steroid therapy.

Three patients had grade 2 or higher mucositis, and 2 had cytomegalovirus (CMV) reactivation without CMV infection.

Two patients had small subarachnoid hemorrhages. One of these patients had a history of multiple red blood cell antibodies, became refractory to platelet transfusions, and developed small subarachnoid hemorrhages day 10. The patient’s symptoms and brain imaging resolved after platelet counts were maintained above 50 x 10⁹ cells/L with cross-matched platelets.

The second patient had a history of stroke, experienced a seizure when the platelet count was 68 x 10⁹ cells/L, and was found to have a subarachnoid hemorrhage on day 12. Symptoms and imaging results improved once the patient began levetiracetam and platelet levels were maintained above 100 x 10⁹ cells/L.

At a median follow-up of 17 months (range, 12 to 30), 7 of the 8 patients were still alive.

Six patients had maintained greater than 95% stable donor engraftment with improvements in their hemoglobin concentrations. Three of these patients have stopped immunosuppression, and 3 are being tapered off it.

“These patients are cured of sickle cell disease,” Dr Rondelli said. “The takeaway message is two-fold. First, this transplant protocol may cure many more adult patients with advanced sickle cell disease.”

“Second, despite the increasing safety of the transplant protocols and new compatibility of HLA half-matched donors, many sickle cell patients still face barriers to care. Of the patients we screened, only 20% underwent a transplant.”

Dr Rondelli noted that 20% of the patients screened could not undergo transplant because of insurance denial. Other patients were ineligible because they had high rates of donor-specific antigens, and still others declined transplant.

Jenny Fontaine

A haploidentical transplant regimen has led to long-term engraftment in adults with sickle cell disease (SCD), according to researchers.

Seven of 8 patients treated with this regimen were still alive at last follow-up, and 6 of them maintained engraftment.

Two patients developed graft-versus-host disease (GVHD). One of them had acute and chronic GVHD and died about 400 days after transplant. The other had acute GVHD that resolved with treatment.

Damiano Rondelli, MD, of the University of Illinois at Chicago, and his colleagues reported these results in Biology of Blood and Marrow Transplantation.

The researchers initially screened 50 adult SCD patients as candidates for haploidentical hematopoietic stem cell transplant (haplo-HSCT) between January 2014 and March 2017. Most patients were ineligible or declined the procedure.

Ultimately, 10 patients received a haplo-HSCT. Unfortunately, the first 2 patients failed to engraft. These patients had received conditioning with alemtuzumab and 3 Gy total body irradiation (TBI) as well as post-transplant cyclophosphamide.

Because of this failure, the researchers used the following regimen for the remaining 8 patients. It’s a modified version of the regimen described in Blood in 2012.

“We modified the transplant protocol by increasing the dose of radiation used before the transplant and by infusing growth factor-mobilized peripheral blood stem cells instead of bone marrow cells,” Dr Rondelli said. “These two modifications helped ensure the patient’s body could accept the healthy donor cells.”

Modified regimen

Patients received growth-factor-mobilized peripheral blood stem cells after conditioning with rabbit antithymocyte globulin (0.5 mg/kg on day -9, 2 mg/kg on day -8 and -7), cyclophosphamide (14.5 mg/kg on day -6 and -5), fludarabine (30 mg/m² on day -6 to -2), and single-dose TBI (3 Gy on day -1).

For GVHD prophylaxis, patients received intravenous cyclophosphamide (50 mg/kg on day 3 and 4), oral mycophenolate mofetil (15 mg/kg 3 times daily from day 5 to 35), and sirolimus (from day 5 dosed for a target trough of 5 to 15 ng/mL). In patients who had T-cell chimerism greater than 50% at 1 year after HSCT and did not have signs of GVHD, sirolimus was tapered off over 3 months.

Patients stopped taking hydroxyurea on day -9. They received red blood cell exchange transfusion on day -10 (with the goal of getting hemoglobin S below 30%) and received platelet transfusions to maintain platelet counts greater than 50 x 10⁹ cells/L.

Patients also received penicillin V (250 mg twice daily) in addition to standard antimicrobial prophylaxis.

Results

All 8 patients on the modified regimen engrafted. The median time to neutrophil engraftment was 22 days (range, 18 to 23 days). One patient experienced secondary graft failure on day 90.

Seven neutropenic patients with hemoglobin S less than 30% received G-CSF after transplant. They received a median of 7 doses (range, 3 to 14) at 5 μg/kg, starting at day 12 post-HSCT. One of these patients experienced mild bone pain in the lower extremities.

Two patients developed GVHD. At day 83, one patient developed acute or chronic GVHD involving the skin, liver, and eyes. Steroids and sirolimus improved eye and liver symptoms, but the patient died at home on day 407.

The other patient had grade 2, gastrointestinal, acute GVHD that resolved with steroid therapy.

Three patients had grade 2 or higher mucositis, and 2 had cytomegalovirus (CMV) reactivation without CMV infection.

Two patients had small subarachnoid hemorrhages. One of these patients had a history of multiple red blood cell antibodies, became refractory to platelet transfusions, and developed small subarachnoid hemorrhages day 10. The patient’s symptoms and brain imaging resolved after platelet counts were maintained above 50 x 10⁹ cells/L with cross-matched platelets.

The second patient had a history of stroke, experienced a seizure when the platelet count was 68 x 10⁹ cells/L, and was found to have a subarachnoid hemorrhage on day 12. Symptoms and imaging results improved once the patient began levetiracetam and platelet levels were maintained above 100 x 10⁹ cells/L.

At a median follow-up of 17 months (range, 12 to 30), 7 of the 8 patients were still alive.

Six patients had maintained greater than 95% stable donor engraftment with improvements in their hemoglobin concentrations. Three of these patients have stopped immunosuppression, and 3 are being tapered off it.

“These patients are cured of sickle cell disease,” Dr Rondelli said. “The takeaway message is two-fold. First, this transplant protocol may cure many more adult patients with advanced sickle cell disease.”

“Second, despite the increasing safety of the transplant protocols and new compatibility of HLA half-matched donors, many sickle cell patients still face barriers to care. Of the patients we screened, only 20% underwent a transplant.”

Dr Rondelli noted that 20% of the patients screened could not undergo transplant because of insurance denial. Other patients were ineligible because they had high rates of donor-specific antigens, and still others declined transplant.

Jenny Fontaine

A haploidentical transplant regimen has led to long-term engraftment in adults with sickle cell disease (SCD), according to researchers.

Seven of 8 patients treated with this regimen were still alive at last follow-up, and 6 of them maintained engraftment.

Two patients developed graft-versus-host disease (GVHD). One of them had acute and chronic GVHD and died about 400 days after transplant. The other had acute GVHD that resolved with treatment.

Damiano Rondelli, MD, of the University of Illinois at Chicago, and his colleagues reported these results in Biology of Blood and Marrow Transplantation.

The researchers initially screened 50 adult SCD patients as candidates for haploidentical hematopoietic stem cell transplant (haplo-HSCT) between January 2014 and March 2017. Most patients were ineligible or declined the procedure.

Ultimately, 10 patients received a haplo-HSCT. Unfortunately, the first 2 patients failed to engraft. These patients had received conditioning with alemtuzumab and 3 Gy total body irradiation (TBI) as well as post-transplant cyclophosphamide.

Because of this failure, the researchers used the following regimen for the remaining 8 patients. It’s a modified version of the regimen described in Blood in 2012.

“We modified the transplant protocol by increasing the dose of radiation used before the transplant and by infusing growth factor-mobilized peripheral blood stem cells instead of bone marrow cells,” Dr Rondelli said. “These two modifications helped ensure the patient’s body could accept the healthy donor cells.”

Modified regimen

Patients received growth-factor-mobilized peripheral blood stem cells after conditioning with rabbit antithymocyte globulin (0.5 mg/kg on day -9, 2 mg/kg on day -8 and -7), cyclophosphamide (14.5 mg/kg on day -6 and -5), fludarabine (30 mg/m² on day -6 to -2), and single-dose TBI (3 Gy on day -1).

For GVHD prophylaxis, patients received intravenous cyclophosphamide (50 mg/kg on day 3 and 4), oral mycophenolate mofetil (15 mg/kg 3 times daily from day 5 to 35), and sirolimus (from day 5 dosed for a target trough of 5 to 15 ng/mL). In patients who had T-cell chimerism greater than 50% at 1 year after HSCT and did not have signs of GVHD, sirolimus was tapered off over 3 months.

Patients stopped taking hydroxyurea on day -9. They received red blood cell exchange transfusion on day -10 (with the goal of getting hemoglobin S below 30%) and received platelet transfusions to maintain platelet counts greater than 50 x 10⁹ cells/L.

Patients also received penicillin V (250 mg twice daily) in addition to standard antimicrobial prophylaxis.

Results

All 8 patients on the modified regimen engrafted. The median time to neutrophil engraftment was 22 days (range, 18 to 23 days). One patient experienced secondary graft failure on day 90.

Seven neutropenic patients with hemoglobin S less than 30% received G-CSF after transplant. They received a median of 7 doses (range, 3 to 14) at 5 μg/kg, starting at day 12 post-HSCT. One of these patients experienced mild bone pain in the lower extremities.

Two patients developed GVHD. At day 83, one patient developed acute or chronic GVHD involving the skin, liver, and eyes. Steroids and sirolimus improved eye and liver symptoms, but the patient died at home on day 407.

The other patient had grade 2, gastrointestinal, acute GVHD that resolved with steroid therapy.

Three patients had grade 2 or higher mucositis, and 2 had cytomegalovirus (CMV) reactivation without CMV infection.

Two patients had small subarachnoid hemorrhages. One of these patients had a history of multiple red blood cell antibodies, became refractory to platelet transfusions, and developed small subarachnoid hemorrhages day 10. The patient’s symptoms and brain imaging resolved after platelet counts were maintained above 50 x 10⁹ cells/L with cross-matched platelets.

The second patient had a history of stroke, experienced a seizure when the platelet count was 68 x 10⁹ cells/L, and was found to have a subarachnoid hemorrhage on day 12. Symptoms and imaging results improved once the patient began levetiracetam and platelet levels were maintained above 100 x 10⁹ cells/L.

At a median follow-up of 17 months (range, 12 to 30), 7 of the 8 patients were still alive.

Six patients had maintained greater than 95% stable donor engraftment with improvements in their hemoglobin concentrations. Three of these patients have stopped immunosuppression, and 3 are being tapered off it.

“These patients are cured of sickle cell disease,” Dr Rondelli said. “The takeaway message is two-fold. First, this transplant protocol may cure many more adult patients with advanced sickle cell disease.”

“Second, despite the increasing safety of the transplant protocols and new compatibility of HLA half-matched donors, many sickle cell patients still face barriers to care. Of the patients we screened, only 20% underwent a transplant.”

Dr Rondelli noted that 20% of the patients screened could not undergo transplant because of insurance denial. Other patients were ineligible because they had high rates of donor-specific antigens, and still others declined transplant.