T-Cell Replete Peripheral Blood Haploidentical Donor Transplant Is Frequently Associated with Cytokine Release Syndrome Which Responds to Anti-IL-6 Therapy

Introduction: Allogeneic hematopoietic cell transplantation is a cornerstone of therapy for hematologic malignancies and often a patient’s only curative intent treatment.  Traditionally reserved for patients with an HLA-matched donor, advances in graft versus host disease (GVHD) prophylaxis utilizing post-transplant cyclophosphamide (PTCy) have expanded the use of haploidentical hematopoietic cell transplantation (haplo-HCT).  While overall outcomes for haplo-HCT appear to be excellent, its novel approach brings toxicities that are particular to its biological and clinical milieu. 

The immediate post-transplant course in T cell replete haplo-HCT is often complicated by symptoms including fever, hypoxia, hypotension and organ dysfunction resembling the cytokine release syndrome (CRS) previously described in recipients of targeted cellular therapeutics such as CAR T-Cells.   IL-6 is thought to be a key mediator of CRS in patients receiving novel T-cell engaging therapies, and tocilizumab has been used with success in this setting.

Here we aim to describe the nature and incidence of CRS in haplo-HCT recipients, as well as its potential implications on clinical outcomes.  Additionally, prospective analysis of cytokine profiles of haplo-HCT recipients and clinical responses to tocilizumab therapy are presented.

Patients and Methods: We performed a retrospective review of patients who underwent haplo-HCT transplantation at our institution from July 2009 through April 2015.  Patients were scored for symptoms of CRS based on established grading criteria (Lee et al, Blood 2014). Patients were stratified into three categories by grade of CRS experienced: none (grade 0), mild (grade 1-2) and severe (grade 3-4).  Outcomes were assessed. 

A total of 84 patients were identified, 55% (46) were male, with a median age at transplant of 49 (19-73), and 49% (41) had active disease at the time of transplant.  The most common diagnosis was AML (55 pts), followed by ALL (9 pts), MDS (5 pts) and NHL (2 pts).  Among the patients, 26% (22 pts) had undergone prior transplant.

In addition to the retrospective review, baseline and post- transplant cytokine levels were prospectively drawn in 10 patients who underwent haplo-HCT. A total of 7 additional patients who met criteria for CRS were treated prospectively with tocilizumab (dose: 4mg/kg-bw) and clinical responses were recorded.  We recorded CRP levels in selected patients as part of clinical monitoring.

Results:  We found a high incidence, 85%, of CRS in our haplo-HCT patients.  Among a total of 84 patients, 12 (14%) experienced severe CRS, 60 (72%) had mild CRS, and 12 (14%) patients had no evidence of CRS. The most common manifestations of severe CRS included: fever (100%), respiratory failure (75%), hypotension (83.3%), hepatic failure (25%) and renal failure (33.3%). The median maximum CRP (during post-transplant days 0 to 8) in all patients suffering from CRS was 155 mg/L.

Of the twelve patients who suffered from severe CRS, nine (75%) died. Predicted median survival was 0.72 months for severe CRS, 12.7 months for patients with no CRS and was not reached for patients with mild CRS (fig 1).  Rates of acute and chronic graft-versus-host disease did not differ by CRS status. The incidence of mild and severe CRS did not differ by ABO mismatch, age, CMV status, donor sex, T-cell or CD34 cell dose. There was no difference in rates of CRS for patients in remission versus active disease at time of transplant.  There were no differences in engraftment.

Cytokine profiles in haplo-HCT recipients showed significant elevation in serum IL-6 levels, most significant in patients who suffered from severe CRS (fig 2). We administered tocilizumab to 7 patients with severe CRS symptoms early after haplo-HCT (median day of treatment was day +3) resulting in the resolution of their CRS symptoms within 48-72 hours.  Over the same time period CRP levels dropped below 50% of the peak value.

Summary:

CRS is common after T-cell replete haplo-HCT and severe CRS is potentially associated with high risk of early mortality after transplant. Cytokine profiles suggest IL-6 is a key mediator of CRS in haplo-HCT patients. Tocilizumab appears to be an effective treatment for patients who develop severe CRS early after T-cell replete haplo-HCT. Future prospective studies are warranted in studying the role of tocilizumab in the treatment and potentially prevention of severe CRS in haplo-HCT patients.