Ruxolitinib in children with steroid-refractory acute graft-versus-host disease: A retrospective multicenter study of the pediatric group of SFGM-TC.

BACKGROUND: We conducted a national multicenter retrospective study in France to evaluate the efficacy and tolerance of ruxolitinib in children with steroid-refractory acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplant. PROCEDURE: Patients were recruited from the 15 pediatric transplantation centers. Transplanted patients were eligible if they met the following criteria: aged ≤ 18 years at transplantation, receiving a myeloablative allogeneic hematopoietic stem cell transplant, having an aGVHD of grade ≥2, and treated with ruxolitinib for steroid-refractory aGVHD. RESULTS: Twenty-nine patients received ruxolitinib for steroid-refractory aGVHD. Six patients achieved a complete response at day 28 after the start of treatment but finally 19 patients (65.5%) achieved a complete response (CR) with a median delay of 41 days (5-93 days). Two patients had a partial response. All patients who achieved CR or partial response discontinued corticosteroid treatment. Eight patients showed treatment failure. The overall response rate was 72.4%. Twenty-three of 29 patients were alive at a median follow-up of 685 days (177-1042 days) after the hematopoietic stem cell transplantation. Viral replication was observed in 41.4% of cases. We did not observe severe hematological adverse events and cytopenia requiring a modification of ruxolitinib doses always resolved. The median initial dose of ruxolitinib was 12.6 mg/m2 /day with an important range. We could not demonstrate any relationship between initial dose and effectiveness. CONCLUSION: Ruxolitinib may constitute a promising second-line treatment for children with steroid-refractory aGVHD that should be validated in a prospective large-scale pharmacokinetic and efficacy trial.

Allogeneic hematopoietic stem cell transplantation in two brothers with DNA ligase IV deficiency: a case report and review of the literature.

BACKGROUND: DNA ligase IV deficiency is a rare autosomal recessive disorder caused by hypomorphic mutations in the DNA ligase IV (LIG4) gene. DNA ligase IV is an essential protein for the development of a healthy immune system as well as for the protection of genomic integrity. Apart from typical stigmata, patients with DNA ligase IV deficiency are characterized by progressive bone marrow failure and a predisposition to malignancy. To our knowledge this reported case is the first description of two brothers with ligase IV deficiency who are treated with different hematopoietic stem cell transplantation (HSCT) regimens resulting in vastly divergent outcomes. CASE PRESENTATION: The cases of two brothers suffering from severe recurrent infections and growth retardation are described. The laboratory findings showed pancytopenia with significant lymphopenia. The two boys were diagnosed with DNA ligase IV deficiency, associated with severe combined immunodeficiency (SCID). Both patients received HSCT from two different matched unrelated donors (MUD) at the age of 33 and 18 months. The older brother succumbed post-transplant due to fatal side-effects 143 days after allogeneic HSCT. The younger brother - conditioned with a different regimen - received a T cell depleted graft 4 months later. No severe side-effects occurred, neither post-transplant nor in the following years. Ten years after HSCT the patient is well off, living a normal life and attending a regular high school. His immune system is fully reconstituted, resulting in a maximum of T cell receptor (TCR) diversity, which is a prerequisite for immune competence. However, he still suffers from microcephaly, dwarfism and dystrophy. CONCLUSIONS: This case report gives an example of a successful HSCT as a treatment option in a genetic disorder such as ligase IV deficiency, using a rather mild conditioning regimen. Further studies are required to determine the viability and efficacy of this treatment option.

Immunological effects in patients with steroid-refractory graft-versus-host disease following treatment with basiliximab, a CD25 monoclonal antibody.

Steroid-refractory graft-versus-host disease (GvHD) is a complication following an allogeneic stem cell transplantation with limited therapeutic options. Studies have shown a response in up to 80% of patients with this condition after treatment with the CD25 monoclonal antibody, basiliximab. Despite the good responses to treatment, around 50% of the patients experience recurrence of their GvHD symptoms 4-6 wk following cessation of therapy. The in vivo changes in the following treatment with this antibody have not been elucidated so far. We treated 14 patients with severe steroid-refractory GvHD with basiliximab weekly for 4 wk and monitored the changes in the T-, B-, NK- and dendritic cell subsets over this time period. The overall response to treatment was 92% (13/14) with 50% (7/14) achieving a complete response. Fifty four percentage (7/13) of the patients who responded showed recurrence of their GvHD symptoms. Contrary to expectations, our observations showed a significant depletion of the regulatory T-cell subset following treatment. Our findings suggest that the undesirable depletion of the regulatory T cells along with the CD25(+) acute inflammatory cells might be responsible for the high incidence of GvHD recurrence in this cohort of patients.

Graft-versus-host disease management.

Graft-versus-host disease (GVHD) remains a major problem of allogeneic hematopoietic-stem cell transplantation (HSCT) and an obstacle for successful outcome. Clinically significant acute GVHD (grade II or higher) developed in 20 to 65 percent of the patients. Death due to this complication accounts for approximately 50 percent of the deaths that are not due to a relapse of the neoplasm. Up to 70 % of patients who survive beyond day 100 develop chronic GVHD and it is the leading cause of nonrelapse mortality more than 2 years after allogeneic HSCT. In addition, chronic GVHD is associated with decreased quality of life, impaired functional status, and ongoing need for immunosuppressive medications. The incidence of chronic GVHD is increasing because of expansion of the donor population beyond HLA-identical siblings, older recipient age, use of peripheral blood cells as the graft source, and infusion of donor lymphocytes for treatment of recurrent malignancy after HSCT. With the current rush in new findings related to GVHD, we see a significant advancement in its management. Given these various new options and challenges, it is important to identify the minimal requirements for diagnosis and treatment of GVHD, as access to the most sophisticated advances may vary depending on local circumstances (Tab. 4, Fig. 1, Ref. 51).

Treatment of graft versus host disease with mesenchymal stromal cells: a phase I study on 40 adult and pediatric patients.

This phase I multicenter study was aimed at assessing the feasibility and safety of intravenous administration of third party bone marrow-derived mesenchymal stromal cells (MSC) expanded in platelet lysate in 40 patients (15 children and 25 adults), experiencing steroid-resistant grade II to IV graft-versus-host disease (GVHD). Patients received a median of 3 MSC infusions after having failed conventional immunosuppressive therapy. A median cell dose of 1.5 × 10(6)/kg per infusion was administered. No acute toxicity was reported. Overall, 86 adverse events and serious adverse events were reported in the study, most of which (72.1%) were of infectious nature. Overall response rate, measured at 28 days after the last MSC injection, was 67.5%, with 27.5% complete response. The latter was significantly more frequent in patients exhibiting grade II GVHD as compared with higher grades (61.5% versus 11.1%, P = .002) and was borderline significant in children as compared with adults (46.7 versus 16.0%, P = .065). Overall survival at 1 and 2 years from the first MSC administration was 50.0% and 38.6%, with a median survival time of 1.1 years. In conclusion, MSC can be safely administered on top of conventional immunosuppression for steroid resistant GVHD treatment. Eudract Number 2008-007869-23, NCT01764100.

The black swan: a case of central nervous system graft-versus-host disease.

OBJECTIVES: Graft-versus-host disease (GVHD) of central nervous system is an atypical and rare manifestation of chronic GVHD, presenting with a heterogeneous spectrum of signs and symptoms. Diagnosis of neurological manifestations of GVHD can be highly challenging and remain associated with dismal prognosis, significant morbidity, and reduced quality of life. CASE PRESENTATION: In this report, we describe a 39-year-old woman developing neurological signs and symptoms 8 months after allogeneic HSCT magnetic resonance imaging showed multifocal hyperintense lesions involving the periventricular region and frontal subcortical white matter. There was no laboratory evidence of infective or malignant etiology, and the case was diagnosed as CNS-GVHD. The patient was treated with intravenous methylprednisolone pulse therapy and the clinical conditions gradually improved. After few months, patient symptoms progressed despite the addition of high-dose intravenous immunoglobulin, tacrolimus, and a new course of high dose steroids. To engage targeted therapy, the patient underwent brain biopsy that revealed a loss of myelin fibers, perivascular and diffuse infiltration of T cells, and macrophages associated with reactive gliosis, representing a demyelinating disease. We intensified treatment with cyclophosphamide and subsequently introduced ibrutinib as salvage strategy. Despite a magnetic resonance imaging showing great regression of the demyelinating lesions, patient's conditions deteriorated and she died 16 months after HSCT. CONCLUSIONS: CNS-GVHD is a rare complication of HSCT that is difficult to diagnose. Based on our experience, brain biopsy may represent a useful diagnostic tool when the clinical features of neurological symptoms are ambiguous or in patients without evidence of preceding chronic GVHD.

Clinical Features, Treatment, and Outcome of Pediatric Steroid Refractory Acute Graft-Versus-Host Disease: A Multicenter Study.

Steroid-refractory acute graft-versus-host disease (SR-aGvHD) is a severe complication in pediatric allogeneic hematopoietic stem cell transplantation (HSCT). We aimed to assess clinical course and outcomes of pediatric SR-aGvHD. We performed a retrospective nationwide multicenter cohort study in the Netherlands. All patients aged 0 to 18 years who underwent transplantation between 2010 and 2020 with SR-aGvHD were included. For each patient, weekly clinical aGvHD grade and stage, immunosuppressive treatment and clinical outcomes were collected. The primary study endpoint was the clinical course of SR-aGvHD over time. As a secondary outcome, factors influencing overall survival and SR-aGvHD remission were identified using a multistate Cox model. 20% of transplanted children developed grade II-IV aGvHD, of which 51% (n = 81) was SR-aGvHD. In these patients, second-line therapy was started at a median of 8 days after initial aGvHD-diagnosis. Forty-nine percent of SR-aGvHD patients received 3 or more lines of therapy. One year after start of second-line therapy, 34 patients (42%) were alive and in remission of aGvHD, 14 patients (17%) had persistent GvHD, and 33 patients (41%) had died. SR-aGvHD remission rate was lower in cord blood graft recipients than in bone marrow (BM) or peripheral blood stem cell (PBSC) recipients (hazard ratio [HR] = 0.51, 0.27-0.94, P = .031). Older age was associated with higher mortality (HR = 2.62, 1.04-6.60, P = .04, fourth quartile [aged 13.9-17.9] versus first quartile [aged 0.175-3.01]). In BM/PBSC recipients older age was also associated with lower remission rates (HR = 0.9, 0.83-0.96, P = .004). Underlying diagnosis, donor matching or choice of second-line therapy were not associated with outcome. Respiratory insufficiency caused by pulmonary GvHD was a prominent cause of death (26% of deceased). Our study demonstrates that SR-aGvHD confers a high mortality risk in pediatric HSCT. Older age and use of CB grafts are associated with an unfavorable outcome. Multicenter studies investigating novel treatment strategies to prevent pediatric SR-aGvHD and inclusion of children in ongoing trials, together with timely initiation of second-line interventions are pivotal to further reduce GvHD-related mortality.

Steroid-Refractory Gut Graft-Versus-Host Disease: What We Have Learned From Basic Immunology and Experimental Mouse Model.

Intestinal graft-versus-host disease (Gut-GVHD) is one of the major causes of mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). While systemic glucocorticoids (GCs) comprise the first-line treatment option, the response rate for GCs varies from 30% to 50%. The prognosis for patients with steroid-refractory acute Gut-GVHD (SR-Gut-aGVHD) remains dismal. The mechanisms underlying steroid resistance are unclear, and apart from ruxolitinib, there are no approved treatments for SR-Gut-aGVHD. In this review, we provide an overview of the current biological understanding of experimental SR-Gut-aGVHD pathogenesis, the advanced technology that can be applied to the human SR-Gut-aGVHD studies, and the potential novel therapeutic options for patients with SR-Gut-aGVHD.

Durability of clinical and immunologic responses to extended low-dose interleukin-2 therapy in patients with refractory chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) remains a frequent cause of non-relapse morbidity and mortality after allogeneic hematopoietic stem cell transplantation. In our single center trials of low-dose interleukin-2 (LD IL-2), the immunomodulatory properties of regulatory T cells (Tregs) have been harnessed to treat steroid-refractory cGVHD (SR-cGVHD) safely and effectively in adults and children. In these trials, 50-60% of patients showed clinical improvement of their cGVHD manifestations with partial responses at the primary response endpoint of 8-12 weeks. Many patients continued extended duration LD IL-2 therapy and achieved deeper clinical responses, including some complete responses. However, the durability of the clinical and immunologic improvement following IL-2 discontinuation has not been reported previously. We examined 20 adult and 2 pediatric patients who received extended duration LD IL-2 for a median of 103 weeks (range, 21-258) and had stable improvement or resolution of their cGVHD symptoms before discontinuing LD IL-2 therapy. The median follow-up after stopping IL-2 was 203 weeks (range 92-599). During this time, 16 patients (73%) were able to wean off all systemic immunosuppression without disease flare or progression. Among 13 patients with available immune cell data, the median fold change in absolute Treg count was 0.58 between 1 to 10 weeks after stopping IL-2 whereas CD4+ conventional T-cell (Tcon) and CD8+ T-cell numbers remained stable. Despite a decline in Treg numbers after IL-2 discontinuation, Treg numbers remained above the pre-treatment baseline. In addition, many patients had sustained clinical improvement after stopping IL-2, suggesting that extended IL-2 therapy can lead to immune tolerance.

Tocilizumab as first-line therapy for steroid-refractory acute graft-versus-host-disease: analysis of a single-center experience.

Acute graft-versus-host-disease (aGVHD) is a complication after allogeneic stem cell transplant. After the failure of treatment with high dose corticosteroids, steroid-refractory aGVHD (SR aGVHD) is associated with high rates of mortality. Tocilizumab has evidence of activity in SR aGVHD. For patients ineligible for trials, the OSU James Comprehensive Cancer Center has been utilizing tocilizumab as first-line therapy for SR aGVHD. We retrospectively report on 15 patients who received tocilizumab. aGVHD grading and responses were based on consensus criteria. Median age at transplant was 49 years. Median time to tocilizumab administration was 9 days (range, 3-16). Six patients had complete responses (40%) with a resolution of aGVHD. From the last contact, median overall survival for responders was not yet reached vs. 31 days for non-responders (p = .0002). Patients with skin and/or GI aGVHD demonstrated the greatest benefit. Patients with liver aGVHD did not respond. Future studies are needed to evaluate tocilizumab prior to steroid failure.