Tocilizumab in the Treatment of Pediatric Chronic Gvhd

Beebe, Kristen; Miller, Holly; Ngwube, Alexander; Salzberg, Dana; Stahlecker, Jennifer; McNulty, Annmarie; Magee, Kyrie; Adams, Roberta H.

doi:10.1016/j.bbmt.2017.12.174

Cited by 6 publications

(5 citation statements)

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“…Depressive symptoms constitute a significant prognostic risk variable for poorer clinical outcomes among HCT recipients, including early mortality and increased occurrence of graft-versus-host disease (GVHD) 27,28 . IL-6 is dysregulated during GVHD [29][30][31] , with IL-6 antagonists demonstrating promise for GVHD prevention [32][33][34][35] . HCT patients are a clinically relevant population to address the larger question of whether IL-6 antagonism might offer a viable antidepressant strategy among medically ill patients experiencing elevated inflammatory activity.…”

Section: Introductionmentioning

confidence: 99%

The IL-6 antagonist tocilizumab is associated with worse depression and related symptoms in the medically ill

et al. 2021

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Because medical illness is associated with increased inflammation and an increased risk for treatment-resistant major depressive disorder, anti-cytokine therapy may represent a novel, and especially efficacious, treatment for depression. We hypothesized that blockade of the interleukin (IL)-6 signaling pathway with tocilizumab would decrease depression and related symptomatology in a longitudinal cohort of allogeneic hematopoietic stem cell transplantation (HCT) patients, a medically ill population with a significant inflammation and psychopathology. Patients undergoing allogeneic HCT received either a single dose of tocilizumab one day prior to HCT (n = 25), or HCT alone (n = 62). The primary outcome included depressive symptoms at 28 days post HCT; anxiety, fatigue, sleep, and pain were assessed at pretreatment baseline and days +28, +100, and +180 post HCT as secondary outcomes. Multivariate regression demonstrated that preemptive treatment with tocilizumab was associated with significantly higher depression scores at D28 vs. the comparison group (β = 5.74; 95% CI 0.75, 10.73; P = 0.03). Even after adjustment for baseline depressive symptoms, propensity score, and presence of acute graft-versus-host disease (grades II–IV) and other baseline covariates, the tocilizumab-exposed group continued to have significantly higher depression scores compared to the nonexposed group at D28 (β = 4.73; 95% CI 0.64, 8.81; P = 0.02). Despite evidence that IL-6 antagonism would be beneficial, blockade of the IL-6 receptor with tocilizumab among medically ill patients resulted in significantly more—not less—depressive symptoms.

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Section: Introductionmentioning

confidence: 99%

The IL-6 antagonist tocilizumab is associated with worse depression and related symptoms in the medically ill

et al. 2021

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“…However, in the latter analyses, only two patients with cGvHD were included-one showed partial response and the other stable disease. In another more recent pediatric study in patients with cGvHD, tocilizumab led to subjective improvement in cGvHD to some degree in all patients, 4/5 patients improved by at least one grade in one organ score, and a reduction of immunosuppression was possible in all patients, even in non-responders [18]. In our study, concomitant immunosuppression with prednisolone was also reduced by 50% in average of all patients at 3-and 6-month follow-up and by another 25% in responders between 6-and 12-month follow-up.…”

Section: Discussionmentioning

confidence: 82%

“…In murine models, IL-6 promotes donor B cellderived IgG-induced Th17 cell infiltration and germinal center formation and thereby contributes to GVHD pathogenesis [13,14], as also seen in solid organ transplant models [15,16]. However, there are few studies describing the effects of tocilizumab on the development and treatment of cGvHD in patients after alloHSCT [17,18]. We retrospectively analyzed the efficacy and safety of tocilizumab for the treatment of advanced cGvHD at our center between the years 2015 and 2019.…”

Section: Introductionmentioning

confidence: 99%

IL6-receptor antibody tocilizumab as salvage therapy in severe chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation: a retrospective analysis

Kattner

Holler

et al. 2020

Ann Hematol

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Chronic graft-versus-host disease (cGvHD) remains the most relevant factor affecting survival after allogeneic hematopoietic stem cell transplantation (alloHSCT). Besides corticosteroids (and ibrutinib in the USA), there is no established therapy for cGvHD. Tocilizumab, a humanized IgG1 IL6-receptor antibody, has shown efficacy in acute GvHD and cGvHD. We retrospectively analyzed the efficacy and safety of tocilizumab for the treatment of advanced cGvHD. Eleven patients with severe steroid refractory cGvHD (median age 49; range 21-62 years) that received at least two prior lines of therapy for cGvHD (range 2-8 regimens) were treated with tocilizumab (q4w, dosage 8 mg/kg IV) with a median number of 15 cycles (range 2-31). NIH consensus criteria grading for cGvHD were recorded prior to tocilizumab administration and after 3, 6, and 12 months of therapy. All patients received additional concomitant immunosuppression (IS) but no new IS within the last 4 weeks before start of tocilizumab and response assessment was terminated before start of any new IS. The median number of days between alloHSCT and initiation of tocilizumab therapy was 1033 days. Organs involved at initiation of tocilizumab therapy were skin (100%, all grade 3), eyes (82%), fascia (82%), mouth (64%), lungs (55%), and genitals (18%). Overall, 7/10 patients (70%) showed partial remission, 2/10 patients (20%) showed progressive cGvHD, 1/10 patient (10%) showed mixed response, and 1 patient died due to sepsis before first response assessment 1.5 months after initiation of treatment. Four patients required subsequent new immunosuppressive treatment. Two patients developed bacterial sepsis, one of whom died. The overall survival and relapse-free survival were 82% with an average follow-up of 22 months (range 1.5-52 months). Tocilizumab seems a promising treatment option in advanced cGvHD but further evaluation within a phase II trial is required.

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“…Treatment was affected by mild infections. Interestingly, four patients had normal IL-6 levels prior to starting treatment ( 103 , 104 ) ( Table 3 ).…”

Section: Monoclonal Antibodiesmentioning

confidence: 99%

Treatment of steroid-refractory graft versus host disease in children

Gottardi,

Leardini,

Muratore

et al. 2023

Front. Transplant.

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Systemic steroids are still the first-line approach in acute graft-versus-host disease (aGvHD), and the backbone of chronic GvHD management. Refractoriness to steroid represent a major cause of morbidity and non-relapse mortality after hematopoietic stem cell transplantation (HSCT). In both backgrounds, several second-line immunosuppressive agents have been tested with variable results in terms of efficacy and toxicity. Solid evidence regarding these approaches is still lacking in the pediatric setting where results are mainly derived from adult experiences. Furthermore, the number of treated patients is limited and the incidence of acute and chronic GvHD is lower, resulting in a very heterogeneous approach to this complication by pediatric hematologists. Some conventional therapies and anti-cytokine monoclonal antibodies used in the adult setting have been evaluated in children. In recent years, the increasing understanding of the biological mechanisms underpinning the pathogenesis of GvHD justified the efforts toward the adoption of targeted therapies and non-pharmacologic approaches, with higher response rates and lower immunosuppressive effects. Moreover, many questions regarding the precise timing and setting in which to integrate these new approaches remain unanswered. This Review aims to critically explore the current evidence regarding novel approaches to treat SR-GvHD in pediatric HSCT recipients.

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Tocilizumab in the Treatment of Pediatric Chronic Gvhd

Cited by 6 publications

References 0 publications

The IL-6 antagonist tocilizumab is associated with worse depression and related symptoms in the medically ill

The IL-6 antagonist tocilizumab is associated with worse depression and related symptoms in the medically ill

IL6-receptor antibody tocilizumab as salvage therapy in severe chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation: a retrospective analysis

Treatment of steroid-refractory graft versus host disease in children

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