Infliximab and Low Dose Alemtuzumab in Patients with Steroid-Refractory Acute Graft-Versus-Host Disease

Introduction:

Steroid-refractory grade IV acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT) carries a mortality rate of approximately 80%. Trials of novel therapies including antibodies directed against the T-cell immune response have generally failed to improve outcomes although may lead to responses. Infliximab, a chimeric monoclonal antibody to TNF alpha, and alemtuzumab another monoclonal antibody targeting CD52, an antigen expressed on T and B lymphocytes and other antigen presenting cells (APCs) both have produced response rates in the 50-75% range. However, few are long-term survivors as the majority die of opportunistic infections (OI). While steroids are ineffective in many series, they are continued when novel agents are employed. We have approached steroid-refractory aGVHD with a combination of rapid steroid discontinuation, standard doses of infliximab and short course low dose alemtuzumab with the hope for aGVHD control without early deaths from OIs.

Methods:

We identified all patients who were treated for steroid-refractory aGVHD between January 1, 2014 and March 1, 2016 at Loyola University Medical Center. The diagnosis of aGVHD was made by clinical criteria per the National Institutes of Health guidelines. The diagnosis was confirmed by endoscopic evaluation and biopsy of the affected organ. All patients received methylprednisolone 2 mg/kg/day IV given in twice daily dosing for at least 7 days prior to being considered steroid-refractory. Patients received infliximab 10 mg/kg IV infusion weekly x 2 then every other week until remission and alemtuzumab 3 mg IV test dose on day 1, followed by 10 mg IV daily for 4 days. At the same time steroids were reduced by 50% and further reductions of 50% were made every 4 days. Responses were assessed by daily grading of aGVHD per Glucksberg criteria after dosing of infliximab and alemtuzumab. A complete response (CR) was defined as full resolution of abdominal pain, diarrhea, rectal bleeding, liver function test abnormalities, or skin involvement. A partial response (PR) was defined as a 50% improvement in diarrhea, liver function abnormalities, or skin involvement with a decrease in 1 or more grade levels of aGVHD per Glucksberg criteria.

Results:

To date 6 patients have been treated for steroid-refractory aGVHD after matched related donor (MRD) or matched unrelated donor (MUD) HSCT. Patient characteristics are shown in Table 1. There were 5 patients who underwent a MRD or MUD HSCT for myelodysplastic syndrome (MDS), and 1 patient who underwent a MUD HSCT for B-cell acute lymphoblastic leukemia (B-ALL). Median age at treatment was 64 years. All patients had Glucksberg grade 4 aGVHD (Table 1). The overall response rate (ORR) was 83% with 4 patients achieving a PR, 1 patient achieving CR, and 1 patient with no response to treatment. Day 100 survival after dosing of alemtuzumab was 50% with deaths due to aGVHD in 2 patients and death due to septic shock in 1 patient. CMV reactivation occurred in 4 patients and EBV reactivation occurred in 1 patient.

Conclusion:

In our single institution analysis, the combination of infliximab and alemtuzumab with rapid steroid withdrawal achieved a high ORR of 83% in treatment of steroid-refractory aGVHD after MRD or MUD HSCT with an encouraging 50% survival at day 100. This approach will be continued to further define its efficacy and safety for the treatment of steroid-refractory aGVHD.

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