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Modified Hopkins conditioning may improve donor engraftment for sickle cell disease
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SALT LAKE CITY — An altered version of the Hopkins conditioning regimen may lead to more stable donor engraftment without severe toxicity among patients with sickle cell disease who undergo haploidentical hematopoietic stem cell transplantation, according to study data presented at the BMT Tandem Meetings.
Lack of HLA-matched sibling donors has limited allogeneic HSCT among patients with sickle cell disease. Although a haploidentical donor for HSCT may increase access to transplant, long-term EFS rates are low.
“Less than 20% of sickle cell disease patients will have an HLA-matched donor and alternative stem cell sources, such as haploidentical donors, can expand the donor pool,” Santosh Saraf, MD, assistant professor of medicine at University of Illinois at Chicago, told HemOnc Today. “Current haploidentical transplantation regimens in adults with sickle cell disease have demonstrated stable long-term engraftment in only approximately 50% of cases.”
Saraf and colleagues evaluated 10 adults with sickle cell disease (median age, 27 years; range, 20-52) who underwent haploidentical HSCT. Two patients received a conditioning regimen of alemtuzumab (Campath/Lemtrada, Genzyme) and 3 Gy total body irradiation, followed by posttransplant cyclophosphamide. However, both patients failed to engraft and recovered autologous neutrophils on day 39 and day 34.
The other eight patients received a modified version of the Hopkins protocol — 30 mg/m2, fludarabine, 14.5 mg/kg cyclophosphamide, 3 Gy total body irradiation, 0.5 mg/kg antithymocyte globulin, 50 mg/kg posttransplant cyclophosphamide and infused mobilized peripheral blood stem cells. Patients underwent HSCT between September 2015 and March 2017.
At day 12 posttransplant, neutropenic patients with sickle hemoglobin less than 30% received 5 µg/kg granulocyte-colony stimulating factor. The median time to neutrophil engraftment was 22 days (range, 18-23).
All patients engrafted donor cells at first, then one developed secondary graft failure. The other seven patients maintained a stable donor cell engraftment.
Transplant-related toxicities observed in the modified Hopkins regimen group included neutropenic fever (n = 8), grade 2 or higher mucositis (n = 3), cytomegalovirus reactivation (n = 2) and small intracranial hemorrhages (n = 2).
Grade 2 or higher acute graft-versus-host disease occurred among two patients; one patient had complete resolution after steroid therapy and the other experienced transformation into chronic GVHD.
The researchers noted that no other cases of chronic GVHD had been observed at the time of the presentation.
At a median follow-up of 11 months (range, 6-24), all eight patients remained alive. Seven maintained donor cell chimerism greater than 90% and improved median hemoglobin concentration from 8.8 g/dL (range, 6.4-12.8) to 13.3 g/dL (range, 9.9-15.3).
“Our findings demonstrate the real-life experience of screening and transplanting adults with sickle cell disease using haploidentical donors and identifies donor-specific antibodies and patient concerns about the safety of the regimen as major barriers to haploidentical transplantation in sickle cell disease,” Saraf said. “It also demonstrates that modifications to the Hopkins protocol leads to stable engraftment in adult sickle cell disease patients with low morbidity.” – by Melinda Stevens
Reference:
Saraf S, et al. Abstract 52. Presented at: BMT Tandem Meetings; Feb. 21-25, 2018; Salt Lake City.
Disclosures: HemOnc Today could not confirm the authors’ relevant financial disclosures at the time of reporting.
Perspective
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Edward A. Copelan, MD, FACP
EFS without GVHD can be achieved in approximately nine of 10 patients with sickle cell disease who undergo allogeneic HSCT from healthy HLA-identical sibling donors, with the best results achieved in children. Unfortunately, HLA-identical sibling or matched unrelated donors are available for less than one-third of patients with sickle cell disease. Efforts to extend transplantation to patients lacking HLA-identical donors are critical to wider application of this curative therapy.
Reduced-intensity conditioning — with fludarabine, cyclophosphamide and 2 Gy total body irradiation — with posttransplant cyclophosphamide has proven a safe and effective treatment for patients with hematologic malignancies and extends the effective application of HSCT to patients with haploidentical donors. This regimen, even with the addition of antithymocyte globulin, has been associated with a high incidence of graft failure, however, in patients with sickle cell disease receiving haploidentical marrow grafts.
Despite the modest number of patients in this trial, the results suggest that using 3 Gy total body irradiation — instead of 2 Gy — and peripheral blood cells, in place of marrow, is safe and ensures more consistent engraftment, a vital step in developing better approaches for these patients.
An alternate modification which incorporates hydroxyurea prior to conditioning and thiotepa in the conditioning regimen is currently being evaluated in a phase 2 single arm multicenter trial performed by the BMT-CTN. It is crucial that this multicenter trial be completed in a timely manner to determine whether this approach is sufficiently safe and immunosuppressive to become a standard curative approach for this deadly disorder.
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