Severe Cytokine-Release Syndrome after T Cell–Replete Peripheral Blood Haploidentical Donor Transplantation Is Associated with Poor Survival and Anti–IL-6 Therapy Is Safe and Well Tolerated

Abstract

Use of high dose post-transplant cyclophosphamide for graft versus host disease (GVHD) prophylaxis has expanded the use of un-manipulated haploidentical hematopoietic cell transplantation. The immediate post-transplant course in T-cell replete peripheral blood haploidentical hematopoietic cell transplantation (haplo-HCT) is often complicated by symptoms resembling the cytokine release syndrome (CRS) previously described in recipients of targeted cellular therapeutics. However, we know little about the incidence and impact of CRS on outcomes in these patients. To understand this syndrome in haplo-HCT patients, we reviewed data from 75 consecutive patients who received G-CSF mobilized T-cell replete peripheral blood haplo-HCT at a single center. Using CRS criteria described in recipients of chimeric antigen receptor T-cell therapies, we found 65/75 (87%) who met criteria for CRS though most of these were only mild (grade 1-2). However, nine patients (12%) experienced severe (grade 3-4) CRS. Median survival was 2.6 months (95% C.I. 0.43 – 5.8) in patients with severe CRS, compared with 13.1 months (95% CI. 8.1-Not Reached) in patients with mild CRS. Transplant related mortality (TRM) was worse in the severe CRS cohort with a hazard ratio of 4.59 (95% CI. 1.43-14.67) compared to mild CRS. Severe CRS patients had a significant delay in median time for neutrophil engraftment. Serum IL-6 levels were measured in ten haplo-HCT patients and were elevated in the early post-transplant setting. Seven patients with CRS were treated with tocilizumab resulting in a complete resolution of their CRS symptoms. Severe CRS represents a potential complication of peripheral blood haplo-HCT, is associated with worse outcomes, and anti-IL-6 Receptor (IL-6R) therapy is associated with rapid resolution of the CRS symptoms.

Safety and efficacy of allogeneic hematopoietic stem cell transplant after PD-1 blockade in relapsed/refractory lymphoma

“…None of the 7 patients we report received PTCY after a haploidentical PBSC, and the onset of fevers is delayed in our cohort (median, 15 days; range, 6-47 days) compared with those reported with cytokine-release syndrome, which occurred within 72 hours of HSCT. 21 As many of these patients went on to develop GVHD, this febrile syndrome may lie on the same immunologic/inflammatory spectrum as GVHD. Prospective assessment with measurements of cytokines and immune activation is needed to better define this phenomenon.…”

Cellular therapy: Immune‐related complications

“…Cytokine Release Syndrome is not unique to CAR‐T, though its manifestations are generally more severe after CAR‐T infusion. CRS has previously been seen in other cellular and immunotherapies including haploidentical hematopoietic stem cell transplant, checkpoint inhibitors (PD‐1/PD‐L1), BiTEs and other therapies that activate the immune response . The severity of CRS after CAR‐T however has necessitated novel and unique approaches to treatment.…”

Rapid identification of cytokine release syndrome after haploidentical PBSC transplantation and successful therapy with tocilizumab

“…Details regarding the incidence, clinical presentation, and management of CRS including the use of tocilizumab during haploidentical PBSCT represents an important area for further discourse (5, 6). …”