Alemtuzumab Plus Myeloablative Conditioning Reduces Post-Transplant GVHD Risk

For younger patients with sickle cell disease (SCD) who are eligible for a hematopoietic cell transplantation (HCT), adding alemtuzumab lowered the risk of graft-versus-host disease (GVHD), without increasing the risk of graft rejection, according to results from a single-center study presented at the 2019 Transplantation & Cellular Therapy Meeting.

“Alemtuzumab is associated with low rates of GVHD, but also severe immune suppression,” lead author and presenter Tami John, MD, from Baylor College of Medicine and Texas Children’s Hospital, told ASH Clinical News.

To explore the use of myeloablative chemotherapy with alemtuzumab to prevent GVHD and promote durable engraftment, the authors retrospectively reviewed outcomes for 38 patients who underwent HCT with a matched related donor at Texas Children’s Hospital between 2003 and 2017. Participants underwent transplant at a median age of 8.6 years (range = 2.9-18.4 years). Three patients had a non-sibling donor and 35 had a sibling donor; bone marrow grafts served as the stem cell source for all patients.

All patients received myeloablative conditioning with intravenous busulfan every six hours for four days (with a target area under the curve of 800-1,200 μM/min) and cyclophosphamide 50 mg/kg daily for four days.

GVHD prophylaxis included methotrexate, a calcineurin inhibitor, and alemtuzumab (administered daily in 3-4 doses starting at 5 days prior to HCT). Alemtuzumab was administered according to patient weight (5-15 kg = 3 mg; 15-30 kg = 5 mg; >30 kg = 10 mg).

Donor chimerism was evaluated periodically via fluorescence in situ hybridization in patients’ peripheral blood. Persistent mixed donor chimerism was defined as the presence of recipient cells on two consecutive evaluations, without return to full donor chimerism at last follow-up.

All patients achieved neutrophil engraftment at a median of 19 days post-HCT (range = 13-24 days). No patient experienced graft rejection or recurrence of SCD-related symptoms.

The incidence of persistent mixed donor chimerism was high, at 60.5 percent, Dr. John reported, although chimerism stabilized at greater than 50 percent donor cells in most patients. At last follow-up, the median chimerism among all patients was 94 percent donor cells (range = 24-100%).

“Only two patients had persistent severe mixed donor chimerism (<50% donor cells),” she added. One of these patients had mixed donor chimerism of less than 25 percent; however, mixed donor chimerism stabilized at 24 percent donor cells at two years after HCT and electrophoresis demonstrated concurrent hemoglobin S, which reflected the presence of sickle cell trait in the donor.

“We saw very low rates of severe acute and chronic GVHD,” Dr. John reported. Two patients experienced “significant” grade II to IV acute GVHD, and one patient developed chronic extensive GVHD. The single patient with grade IV GVHD had a matched father as a donor, as opposed to a sibling donor, she noted.

At a median follow-up of 2.9 years (range = 90-4,627 days), the overall survival rate was 94.7 percent. Two patient deaths occurred during study follow-up, both of which were attributed to transplant-related complications; one death occurred within 100 days of HCT due to disseminated Mycobacterium tuberculosis and the other occurred 318 days after HCT due to hemophagocytic syndrome. No deaths were attributed to viral-associated infection, “which typically is a significant concern with alemtuzumab,” Dr. John added. Most patients had viral reactivations, but only three had viral disease (adenovirus), and most responded to standard antiviral therapy.

Although the researchers concluded that the alemtuzumab plus myeloablative conditioning regimen “may be a promising approach” for patients with SCD who can tolerate myeloablative chemotherapy, Dr. John noted that the findings of the study are limited by its small sample size and the single-center design. Longer follow-up also is necessary to determine the long-term stability of the grafts.

Future research could focus on optimal dosing of alemtuzumab to improve rates of mixed donor chimerism. “With new data regarding alemtuzumab pharmacokinetic targeting, we could potentially tailor dosing based on pharmacokinetic data, though our data show that weight-based dosing of alemtuzumab near the time of HCT prevents GVHD very effectively in this group,” she concluded.

The authors report no relevant conflicts of interest.

Reference

John T, Yassine K, Naik S, et al. Myeloablative conditioning with alemtuzumab in matched related donor hematopoietic cell transplant for sickle cell disease prevents graft-versus-host disease without compromising engraftment. Abstract #49. Presented at the Transplantation & Cellular Therapy Meetings of ASBMT and CIBMTR, February 22, 2019; Houston, TX.

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