Cytokine release syndrome after GVHD prophylaxis with posttransplant bendamustine
2 Laboratory of Autoimmune Diagnostics, Pavlov First St. Petersburg State Medical University, St. Petersburg, Russian Federation
Hematopoietic stem cells transplantation is an effective method of treatment of many cancer diseases and the number of transplants is increasing worldwide. There are many clinical trials under way to improve and develop more effective conditioning methods, the main task is to reduce graft-versushost disease and to induce graft versus leukemia response. For this goal posttransplant bendamustine (PTB) was used at the R. M. Gorbacheva Memorial Institute of Hematology, Oncology and Transplantation in the setting of a clinical trial. One of the adverse reactions of this conditioning regimen was development of a life-threatening complication – cytokine release syndrome (CRS). Understanding dynamics of cytokines in the development of this syndrome allows to predict its development and to conduct relevant therapy.
Materials and methods
We carried out a prospective study (NCT02799147), which included 12 patients: 8 with acute myeloid leukemia, 4 with acute lymphoblastic leukemia. All patients had chemorefractory disease and absence of hematologic remission at the start of the conditioning. The median age was 38 years (from 24 to 54 years old). All patients received a prophylaxis of GVHD with bendamustine 100-140 mg/m2 per day +3, +4. Myeloablative conditioning regimen with fludarabine and busulfan was applied in all patients. Blood sampling with subsequent analysis of the level of cytokines (IFN-γ, IL-1, IL-10, IL-6, IL-17) was performed on day -7, 0, +7, +14. The cytokine release syndrome developed in 8/12 patients.
High cytokine level was determined starting from the first blood sample in all patients. However, after engraftment, a further increase was detected in IFN-γ level (18 vs 197 ng/ml, p=0.037), IL-10 (6.3 vs 110 ng/ml, p=0.23), IL-6 (96 vs 105 ng/ml, p=0.23). The frequency of CRS was 66.7% (n=8) in study group, but positive association with the CRS was detected only for IL-6 (74 vs 8 ng/ml, p=0.036). The level of IL-6 wasn’t a predictor of mortality from complications (76 vs 19 ng/ml, р=0.21). The frequency of CRS grades 1-2 was 33.3% (n=4), grades 3-4 was 33.3% (n=4). The most frequent clinical manifestations of CRS were fever (100%), increase in creatinine (90%), CRP (100%), bilirubin and transaminases (67%), acute kidney injury (56%), hypotension (50%), CNS toxicity (33%), disseminated intravascular coagulation syndrome (22%) and others.
The prophylaxis of GVHD with posttransplant bendamustine is associated with the increase of IFN-γ, IL-10, IL-6, however, only the increase of IL-6 was associated with CRS. These results confirmed the rationality of using anti-IL6 therapy.
Graft-versus-host disease, cytokine release syndrome (CRS), posttransplant bendamustine (PTB).