Single-center experience using anakinra for steroid-refractory immune effector cell-associated neurotoxicity syndrome (ICANS)

In addition to remarkable antitumor activity, chimeric antigen receptor (CAR) T-cell therapy is associated with acute toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Current treatment guidelines for CRS and ICANS include use of tocilizumab, a monoclonal antibody that blocks the interleukin (IL)-6 receptor, and corticosteroids. In patients with refractory CRS, use of several other agents as third-line therapy (including siltuximab, ruxolitinib, anakinra, dasatinib, and cyclophosphamide) has been reported on an anecdotal basis. At our institution, anakinra has become the standard treatment for the management of steroid-refractory ICANS with or without CRS, based on recent animal data demonstrating the role of IL-1 in the pathogenesis of ICANS/CRS. Here, we retrospectively analyzed clinical and laboratory parameters, including serum cytokines, in 14 patients at our center treated with anakinra for steroid-refractory ICANS with or without CRS after standard treatment with tisagenlecleucel (Kymriah) or axicabtagene ciloleucel (Yescarta) CD19-targeting CAR T. We observed statistically significant and rapid reductions in fever, inflammatory cytokines, and biomarkers associated with ICANS/CRS after anakinra treatment. With three daily subcutaneous doses, anakinra did not have a clear, clinically dramatic effect on neurotoxicity, and its use did not result in rapid tapering of corticosteroids; although neutropenia and thrombocytopenia were common at the time of anakinra dosing, there were no clear delays in hematopoietic recovery or infections that were directly attributable to anakinra. Anakinra may be useful adjunct to steroids and tocilizumab in the management of CRS and/or steroid-refractory ICANs resulting from CAR T-cell therapies, but prospective studies are needed to determine its efficacy in these settings.

Intrathecal Chemotherapy As a Potential Alternative Treatment for Steroid-Refractory Immune Effector Cell-Associated Neurotoxicity Syndrome

Introduction Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment paradigm for patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and other hematologic malignancies. However, its use is associated with serious adverse effects including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Severe ICANS can present with aphasia, mutism, somnolence, seizures, signs of increased intracranial pressure and rarely cerebral edema. Corticosteroids (CS) and IL-6 inhibitors are first line treatment for CRS and ICANS. Prolonged CS use has been associated with decreased over-all survival in CAR T-cell treated patients. Data on effective treatments for CART T-cell induced neurotoxicity is limited, especially in steroid-refractory ICANS. Blood-brain barrier (BBB) disruption and infiltration of myeloid and immune effector cells into the central nervous system are implicated in the pathogenesis of ICANS. This likely explains the role of intrathecal chemotherapy, which has been described in literature for treatment of steroid-refractory ICANS. Here, we report the outcomes of two patients with refractory DLBCL who developed severe ICANS after receiving axicabtagene ciloleucel (axi cel) and treated with intrathecal (IT) chemotherapy. Case Presentation Our first case is of a 66 year old male with diagnosis of R/R DLBCL, who was treated with R-CHOP, followed by R-GemOx, with no response then received axi cel. Patient developed grade 2 CRS and grade 1 ICANS (National Cancer Institute Common Terminology Criteria for Adverse Effects v4.03) on day +2 post infusion, treated with tocilizumab and dexamethasone with good response initially. While tapering dexamethasone on day +5, he developed grade 3 CRS and grade 3 ICANS. Brain MRI did not show any intracranial abnormality and EEG showed no seizure activity. Lumbar puncture (LP) was done on day +7 and showed opening pressure of 32 cm H2O, and 12 lymphocytes. He was started on IV solumedrol and tocilizumab was resumed. CRS improved while neurotoxicity progressed to grade 4 prompting intubation and mechanical ventilation on day +8. On day +9, patient received intrathecal methotrexate 12 mg and hydrocortisone 50 mg. On day +12, neurotoxicity improved to grade 1 and patient was extubated on day +13. Steroid taper stopped on +17. Despite disease response, patient remained hospitalized at day +45 for deconditioning and vocal cord paralysis related to a lengthy hospital stay and intubation. He was eventually discharged, however passed away on day +49 from complications of prolonged hospitalization. Our second case is of a 69 year old female with a diagnosis of R/R DLBCL with CNS involvement, treated with RCHOP x6 followed by salvage chemotherapy with refractory disease, She then received axi cel. Patient developed grade 1 CRS on day +4, treated with tocilizumab and dexamethasone, and patient responded well. On day +9, she developed grade 2 CRS and grade 3 ICANS. At that time, dexamethasone was switched to pulse dose solumedrol and tocilizumab was continued. CT head showed no acute intracranial abnormality and EEG did not show any epileptiform activity. LP showed opening pressure of 21, and 84 lymphocytes. On day +11, patient's CRS resolved, however ICANS developed to grade 4 and patient received 12 mg intrathecal methotrexate and hydrocortisone 50 mg for steroid-refractory ICANS. The very next day, patient showed significant neurological improvement. Steroid taper was initiated and patient's ICANS resolved on day +16. MRI brain showed decrease in size of nodular enhancement along periventricular white matter and left occipital area corresponding to treatment response. She was discharged on day +28 and continues to do well one year out of axi cel infusion Conclusion Our abstract adds to the sparse literature about the use IT chemotherapy in cases with severe ICANS. It also highlights its importance as an alternative potential therapy to high doses and prolonged courses of corticosteroids which is associated with increased morbidity and mortality. Steroid-refractory ICANS has limited treatment options and further evaluation of the use of IT chemotherapy in large scale studies is warranted. Disclosures Kahn: Abbvie: Research Funding, Speakers Bureau; Astrazeneca: Research Funding, Speakers Bureau; Beigene: Research Funding, Speakers Bureau; Epizyme: Research Funding, Speakers Bureau; Genetech: Research Funding, Speakers Bureau; GSK: Speakers Bureau; Karyopharm: Speakers Bureau; Kite: Speakers Bureau; Morphosys: Speakers Bureau; Sanofi: Speakers Bureau; SeaGen: Speakers Bureau. Fazal: Agios: Consultancy, Honoraria, Speakers Bureau; AMGEN: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; Glaxo Smith Kline: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Janssen Oncology: Consultancy, Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Karyopharm Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Sanofi Genzyme: Consultancy, Honoraria, Speakers Bureau; Stemline Therapeutics: Consultancy, Honoraria, Speakers Bureau; Taiho Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau. Lister: Oncology Analytics: Other: Academic Board.

Efficacy and Safety of Fecal Microbiota Transplantation in the Treatment of Acute and Chronic Steroid-Refractory Graft-Versus-Host Disease after Hematopoietic Stem Cell Transplantation

Despite major improvements in allogeneic hematopoietic stem cell transplantation over the last decades, steroid-refractory (SR) acute (a) and chronic (c) graft-versus-host disease (GVHD) cause high mortality. SR-GVHD is a therapeutic challenge. Increasing evidence reveals that gut microbiota play a significant role in GVHD. Several small sample clinical trials indicates fecal microbiota transplantation (FMT) is the viable solution for SR-GVHD.In this retrospective survey, we reported outcome data from 29 patients aged 16-61 years who had underwent a total of 44 FMTs (range, 1-3) as salvage-therapy for SR-GVHD. Patients were classified as having SR-aGVHD (n=18, all grade II or III, all gastrointestinal tract involvement) or SR-cGVHD (n=11, all moderate or severe, progressive involvement of the gastrointestinal tract, lungs, liver, skin and mouth). The median number of prior systemic GVHD-therapies was 3 for both SR-aGVHD (range, 1-4) and SR-cGVHD (range, 1-5). The overall response rate (ORR) was 55.6% (10/18) in SR-aGVHD including 7 CRs (38.9%), while for SR-cGVHD the ORR was 54.5% (6/11, all partial responses). Among the complications of FMT with a possible cause-effect relationship there were: 11 fever, 3 fecal bacterial culture positive, 2 constipation. No serious adverse events clearly related to FMT occurred.FMT may constitute a promising new treatment option for SR-aGVHD and SR-cGVHD that should be validated in a prospective trial. Disclosures No relevant conflicts of interest to declare.

Multicenter Phase II Study to Evaluate Therapeutic Efficacy of Imatinib Mesylate in Patients with Steroid-Refractory Chronic Graft-Versus-Host Disease

Background Graft-versus-host disease (GVHD), where T- and B-cells derived from the graft attack host, is still a vital hurdle to overcome for successful allogeneic stem cell transplantation (allo-SCT). In particular, chronic GVHD (cGVHD) occurs approximately 30-70% of the patients and it is the most relevant cause of non-relapse morbidity (NRM) after allo-SCT. This multicenter, phase II study evaluated the safety and efficacy of imatinib mesylate in patients with steroid-resistant cGVHD. In addition, we scored the quality of life of the enrolled patients using Short Form Health Survey Questionnaire (SF-36). Patients and methods A total of 36 patients who diagnosed with steroid-refractory cGVHD participated in this study and treated with imatinib from March 2013 to February 2019. Enrolled patients received 100mg of imatinib daily for 2 weeks. Every 2 weeks, imatinib dosage was increased up to 400 mg/day if the patients did not have any grade 3-4 adverse event. Patients who showed stable disease (SD), partial remission (PR) and complete remission (CR) in the 3-month response evaluation continued the imatinib up to 6 months. Treatment response was evaluated every 2 weeks for 6 months according to the NIH global scoring system. Survival outcomes of the enrolled patients were followed up to 2 years. Quality of life was also evaluated using SF-36 at 1, 3, and 6 months after starting imatinib treatment. Response of cGVHD was evaluated based on the NIH response criteria by scoring each involved organ sites with four-point scale (0-3). CR was defined as resolution of all reversible manifestations related to cGVHD. Partial response (PR) of cGVHD was defined clinical score reduction of at least one point in one or more affected organs. Disease progression or treatment failure was defined as increased score at least one point in one or more organs or occurrence of any new symptoms or signs of c GVHD. Failure-free survival (FFS) and overall survival (OS) were calculated from the day of starting imatinib. Result Median age was 47.5 years (23-63). Majority of the patients were diagnosed with acute leukemia (75%) and myelodysplastic syndrome (16.9%), and underwent allo-SCT in CR disease status (69.5%). Twenty-five (69.4%) patients experienced acute GVHD. Most of the patients presented overlap symptoms. Skin GVHD was identified in 23 (63.9%) patients. Lung, mouth, and eye involvement were found in 16 (44.4%), 14 (38.9%), and 14 (38.9%) patients, respectively. All of the enrolled patients had been treated with steroid due to moderate (55.6%), and severe (44.4%) grade cGVHD. Overall, median duration of imatinib therapy was 5.4 months and no severe adverse effect over grade 3 was reported. The last therapeutic mean dosage of imatinib was 305.6 mg/day. Three patients (8.3%) achieved CR, and 18 (50%) and 12 patients (33.3%) were reported as PR and SD. Treatment failure was identified in three patients (8.3%). Overall response rate (ORR) of imatinib was 58.3% and 25 patients (69.4%) could reduce the steroid. According to the each involved organ site, ORR of the gastrointestinal (GI) and liver cGHVD were 70.5% and 66.7%, while skin and lung were 34.8% and 25.0%, respectively. The efficacy of imatinib was better in GI, liver, and mouth than skin and lung in the current clinical study. With the median follow-up duration of 28.5 months, two-year FFS and OS rate were 76% and 88.5%. Responders to the imatinib therapy showed a superior tendency in OS than non-responders (p = 0.066). In the patients-reported QOL evaluation with SF-36, both physical and mental component score were improved. Particularly, a factor representing emotional well-being was significantly improved (p = 0.002). Conclusion This multicenter clinical study showed that imatinib is an effective option not only for skin GVHD but also for GI and liver involvement. Moreover, QOL of the patients tended to improve during imatinib treatment with steroid dose reduction. Figure 1 Figure 1. Disclosures Lee: Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board; AbbVie: Honoraria, Other: Advisory board; Korean Society of Hematology: Membership on an entity's Board of Directors or advisory committees.

Ruxolitinib for Steroid-Refractory Acute Graft-Versus-Host Disease: A Single Centre Retrospective Study

Background Acute graft-versus-host disease (aGVHD) is the major cause of non-relapse morbidity and mortality after allogeneic hematopoietic stem cell transplantation(allo-HSCT). But only 40% of the patients will respond to first-line therapies Corticosteroids. Ruxolitinib, a selective Janus kinase (JAK) 1/2 inhibitor, reduces the incidence and severity of GVHD while preserving graft-versus-leukemia effects in preclinical models. The retrospective study evaluated the efficacy of ruxolitinib compared with other second-line therapies for steroid-refractory aGVHD (SR-aGVHD) in a single-center. Methods A total of 90 patients who developed SR-aGVHD after HSCT were evaluated in this retrospective study.They were treated with ruxolitinib (n=45) or other salvage-therapies (n=45) including MTX, basiliximab, etanercept and MSC at our institution. The primary endpoint was the overall response rate (ORR) at Day 28. Additional endpoints included overall survival (OS), cumulative incidence rates of failure-free survival (FFS), relapse, non-relapse mortality (NRM) and cGVHD. Treatment failure was defined as 1) addition of new systemic therapy for aGVHD, 2) NRM, 3) relapse, 4) progression of hematologic disease. FFS and OS were calculated from the day of starting the use of second-line treatments for aGVHD. Results The median age was 34 years (range 14-69). At the time of enrollment 25 patients had grade Ⅱ disease, 39 with grade Ⅲ disease, 26 with grade IV disease. The skin was involved in 54.4%, lower gastrointestinal (GI) tract in 78.9% and liver in 20.2%. With a median follow-up of 1.33 years, the ORR at day 28 was higher in ruxolitinib group than non-ruxolitinib group (62.2% [95% CI, 47.5%-77.0%] vs. 26.7% [95% CI, 13.2%-40.1%], P=0.001) (Table 1). The 1-year OS was 64.4 % and 45.5% in the two groups, respectively (P=0.0382). Ruxolitinib treatment also improved the 1-year cumulative incidence of FFS (57.8% vs. 26.6%, P=0.002), while the 1-year cumulative incidence of relapse did not differ significantly (9.6% vs. 20.0%, P=0.195). The 1-year cumulative incidence of NRM was lower in the ruxolitinib group than the non-ruxolitinib group (24.4% vs. 45.3%, P=0.023). The 1-year and 3-year cumulative incidence of cGVHD were 17.8% vs. 33.3% and 26.8% vs. 44.4% between the ruxolitinib group and non-ruxolitinib group (P=0.10 and P=0.04). Conclusions Our study demonstrated that ruxolitinib is effective than other second-line treatments in patients with SR-aGVHD due to the higher response rates and the improvement of prognosis. Furthermore, ruxolitinib could reduce the incidence and severity of chronic GVHD in aGVHD patients. Keywords: Ruxolitinib; Steroid-refractory; Acute graft-versus-host disease; Haploidentical hematopoietic stem cell transplantation Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.