Graft-versus-host Disease In Children Research Articles

P1327: RUXOLITINIB COMBINED WITH GLUCOCORTICOID IN THE FIRST-LINE TREATMENT OF GRAFT-VERSUS-HOST DISEASE IN CHILDREN: A SINGLE CENTER RETROSPECTIVE STUDY

Background: Ruxolitinib has certain advantages and potential in the treatment of GVHD. It can inhibit the secretion of inflammatory factors by T cells, increase the number of regulatory T cells（Tregs）in the recipient, and then mediate immune tolerance. It can also reduce T cell surface related chemokines or chemokine receptors, and then change T cell migration. A multicenter retrospective study showed that the effective rate of ruxolitinib on glucocorticoid resistant aGVHD was 81.5%, and the effective rate of glucocorticoid resistant cGVHD was 85.4%. At present, there is no report on the first-line treatment of GVHD in children with glucocorticoid combined with glucocorticoid.Our center tried to use this combined scheme as the first-line treatment option in the early stage, in order to reduce the application time of glucocorticoid and reduce glucocorticoid related complications. Aims: To investigate the efficacy and safety of ruxolitinib combined with glucocorticoid in the treatment of graft-versus-host disease (GVHD) in children. Methods: A retrospective analysis of 17 cases of graft-versus-host disease（GVHD） after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in our center was conducted. The clinical efficacy and adverse reactions of early application of ruxolitinib combined with glucocorticoid were observed. Results: The median treatment time of 17 children was 47 (24-380) days, and the median onset time was 7 (4-90) days. The overall effective rate was 94.1% (16/17), the complete remission rate was 58.8% (10/17), the partial remission rate was 35.3% (6/17). The incidence of hemocytopenia during the combination therapy was 41.1% (7 /17).The incidence of EBV infection was 35.2% (6 /17), and the incidence infection of CMV was 29.4% (5/17).The incidence of hemorrhagic cystitis was 11.8% (2/17). The median follow-up time was 230 (74-545) days. One child died of grade IV acute graft versus host disease (aGVHD), and the other 16 children survived. The 6-month overall survival rate was 94.1%. Summary/Conclusion: Ruxolitinib combined with corticosteroid is effective and safe in the treatment of children with GVHD. It is expected to become a first-line anti GVHD therapy.

Mesenchymal Stromal Cells for Enhancing Hematopoietic Engraftment and Treatment of Graft-Versus-Host Disease, Hemorrhages and Acute Respiratory Distress Syndrome.

Mesenchymal stromal cells (MSCs) possess profound immunomodulatory and regenerative properties that are of clinical use in numerous clinical indications with unmet medical need. Common sources of MSCs include among others, bone marrow (BM), fat, umbilical cord, and placenta-derived decidua stromal cells (DSCs). We here summarize our more than 20-years of scientific experience in the clinical use of MSCs and DSCs in different clinical settings. BM-MSCs were first explored to enhance the engraftment of autografts in hematopoietic cell transplantation (HCT) and osteogenesis imperfecta around 30 years ago. In 2004, our group reported the first anti-inflammatory use of BM-MSCs in a child with grade IV acute graft-versus-host disease (GvHD). Subsequent studies have shown that MSCs appear to be more effective in acute than chronic GvHD. Today BM-MSC-therapy is registered for acute GvHD in Japan and for GvHD in children in Canada and New Zeeland. MSCs first home to the lung following intravenous injection and exert strong local and systemic immunomodulatory effects on the host immune system. Thus, they were studied for ameliorating the cytokine storm in acute respiratory distress syndrome (ARDS). Both, MSCs and DSCs were used to treat SARS-CoV-2 coronavirus-induced disease 2019 (COVID-19)-induced ARDS. In addition, they were also used for other novel indications, such as pneumomediastinum, colon perforation, and radiculomyelopathy. MSC and DSCs trigger coagulation and were thus explored to stop hemorrhages. DSCs appear to be more effective for acute GvHD, ARDS, and hemorrhages, but randomized studies are needed to prove superiority. Stromal cell infusion is safe, well tolerated, and only gives rise to a slight fever in a limited number of patients, but no major side effects have been reported in multiple safety studies and metaanalysis. In this review we summarize current evidence from in vitro studies, animal models, and importantly our clinical experience, to support stromal cell therapy in multiple clinical indications. This encloses MSC’s effects on the immune system, coagulation, and their safety and efficacy, which are discussed in relation to prominent clinical trials within the field.

Association of Donor and Recipient Interleukin-1 Gene Single Nucleotide Polymorphisms with Outcome after Allogeneic Hematopoietic Stem Cell Transplantation in Childhood

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment approach for hematological malignancies, genetic diseases, and severe immune deficiencies. Despite the matching of the human leucocyte antigens (HLA), HSCT is still associated with a considerable rate of morbidity and mortality caused by infections, relapse, and graft-versus-host disease (GVHD). Therefore, non-HLA polymorphisms like cytokines and their receptors are considered as important contributing factors. Interleukin-1 (IL-1) is a cytokine that initiates and maintains the immune response as well as the development of GVHD in the recipient. Single nucleotide polymorphisms (SNPs) of the IL-1 gene are associated with a higher risk of malignancies, an elevated death rate because of infections, and a higher chance to suffer from autoimmune or chronic diseases. This study aimed to analyze the association of IL-1 gene SNPs with outcome in a pediatric population undergoing allogeneic HSCT.Methods: We included 270 pediatric patients with a median age of 9 years who underwent an allogeneic HSCT and their respective donors. We used TaqMan real-time polymerase chain reaction to analyze the SNPs IL-1-alpha rs1800587 (-889, A/T), IL-1-beta rs1143627 (-31, A/T), and IL-1-beta rs16944 (-511, A/T). The underlying diseases were acute lymphoblastic leukemia (n=89), acute myeloid leukemia (n=63), chronic myeloid leukemia (n=10), juvenile myelomonocytic leukemia (n=9), myelodysplastic syndrome (n=29), lymphoma (n=7), solid tumor (n=11), genetic disease (n=41), and aplastic anemia (n=11). The stem cell sources were bone marrow (n=178), peripheral blood (n=90) or umbilical cord blood (n=2). Two hundred donors were HLA-matched, and 70 donors were HLA-mismatched. Conditioning regimen was myeloablative in all cases and based on chemotherapy in 180 children or total body irradiation in 90 children. The predominant post-transplant immunosuppression was cyclosporine A and methotrexate in 148 patients or cyclosporine A alone in 55 patients. The genotyped SNPs were compared using the Kaplan-Meier method for event-free survival (EFS) and overall survival (OS) and the Gray test for acute GVHD, chronic GVHD, relapse rate (RR), and transplant-related mortality (TRM).Results: We observed a significant association between the SNP IL-1-alpha rs1800587 (-889, A/T) of the donor and the rate of acute GVHD. The genotypes of IL-1-alpha rs1800587 had the following distributions in the donor: CC genotype n=132 (49%), CT genotype n=114 (42%), and TT genotype n=24 (9%). Overall, 63 children (23%) suffered from moderate to severe acute GVHD (grade II-IV). We found a significantly increased incidence of moderate to severe acute GVHD (grade II-IV) if the patient was transplanted from a donor with the CC/CT genotype compared to the TT genotype (25% versus 4%; p=0.028). We found no significant associations of the SNP IL-1-alpha rs1800587 (-889, A/T) for chronic GVHD, RR, TRM, EFS, and OS. In addition, we observed no significant associations of the other studied genotypes IL-1-beta rs16944 (-511, A/T) and rs1143627 (-31, A/T) in either donors or recipients for acute and chronic GVHD, RR, TRM, EFS, and OS.Conclusion: Our study identified the IL-1-alpha rs1800587 CC/CT genotype of the donor as a genetic risk factor for the development of moderate to severe acute GVHD (grade II-IV) in pediatric allogeneic HSCT recipients. After confirmation in further studies, these findings could implicate the adjustment of prophylactic measures to reduce the risk of acute GVHD in children. DisclosuresGruhn: AmgenGmbh: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel costs; Bellicum Pharma Gmbh: Membership on an entity's Board of Directors or advisory committees, Other: travel costs; EUSA Pharma Gmbh: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Other: travel costs; Novartis Pharma Inc.: Honoraria, Other: travel costs; pfizer: Honoraria; servier: Honoraria, Other: travel costs; Neovii Biotech GmbH: Other: travel costs; medac GmbH: Other: travel costs.

Impact of decontamination therapy on gastrointestinal acute graft-versus-host disease after allogeneic hematopoietic cell transplantation in children: Decontamination therapy in allo-HCT

Introduction: Gut colonization with antibiotic-resistant bacteria (ARB) is associated with a significantly decreased overall survival in adult patients undergoing allo-HCT because of an increased treatment-related mortality.Objective: The objective of this multicenter study was the analysis of impact of gut colonization status and the use of antibiotics on development of gastro-intestinal (GI) graft-versus-host disease (GVHD) of allo-HCT in children.Methods: All consecutive patients who underwent allo-HCT over a period of three years in all pediatric HCT centers in Poland were analyzed for the impact of gut colonization on GI GVHD, with respect to standard of care including prophylaxis of infections and supportive therapy.Results: At the time of allo-HCT, 44.2% of pediatric patients were colonized by ARB. Decontamination therapy with antibiotics was applied in 78% of children. Gut decontamination prophylactic therapy with antibiotics decreased the risk of acute GI GVHD. The use of gentamicin contributed to decreased rate of GVHD, while the use of ciprofloxacin and colistin contributed to increased incidence of GVHD after allo-HCT in children. Sepsis with ARB and non-MFD transplant contributed significantly to worse survival, while neither colonization nor gut decontamination had an impact on overall survival.Conclusions: Gut decontamination therapy contributed to lower incidence of acute GI GVHD in children undergoing allo-HCT, and the use of specific antibiotics might be responsible for this effect.

Prospective pilot trial of calcipotriene as a novel topical treatment for acute skin graft versus host disease

Skin graft versus host disease (GVHD) can affect quality of life in hematopoietic stem cell transplant recipients. Therapeutic options for steroid-refractory GVHD are limited. We report the first prospective pilot study evaluating the topical vitamin D3 analog Calcipotriene (DOVONEX 0.005% cream) for acute skin GVHD in children, with associated analyses of target organ chemokine CXCL10 changes in response to therapy. We observed that Calcipotriene applications were safe and well tolerated. There were no symptom progression nor new symptoms requiring GVHD therapy escalation during study period. The most consistent response observed by study subjects was resolution of pruritus in eight patients and significant improvement in pruritus in two study subjects. Nine of ten patients had improvement or resolution of skin rash. In addition, we documented reduction of CXCL10 levels in the skin of seven subjects with GVHD after Calcipotriene course using non-invasive D-Squame® disc application to the skin for chemokine analysis. Our pilot study shows promising observation that topical Calcipotriene could be a novel therapeutic option for acute skin GVHD, especially in patients presenting with pruritus and should be studied in larger prospective studies.

Efficacy of BMMSCs on aGVHD and Its Correlation with SerumInflammatory Cytokines in Pediatric Patients with Severe Refractory Acute Graft-Versus-Host Disease

To investigate the efficacy of bone marrow mesenchymal stem cells (BMMSC) on children with refractory graft-versus-host disease (GVHD) and to judge the efficacy of BMMSC by dynamically monitoring the changes of cytokines in children with GVHD before and after infusion of BMMSC, so as to provide a theoretical basis for clarifying the mechanism of BMMSC. 17 children with refractory aGVHD including 7 of grade II, 6 cases of grade III and 4 cases of grade IV after allo-HSCT were enrolled. All the children with aGVHD, who received routine immunosuppressive therapy, but the state of disease not improved, were treated with immunosuppressive drugs combined with BMMSC infusion. Study endpoints included safety of BMMSC infusion, response to BMMSC, and overall response of aGVHD. The serum levels of IL-2α, IL-6, IL-10, IL-8 and TNF-α in aGVHD patients were measured by chemiluminescence before infusion of BMMSCs and Day 7, Day 14 after infusion of BMMSCs. The cumulative median dose of BMMSCs was 5.5 (3.4-11.1) × 106/kg for average of 3.7 times, and the median time of 16.5 (4-95) days for the first infusion of MSCs. In 17 cases of refractory GVHD, 14 responded to treatment, whereas 3 patients failed. The total effective rate was 82.4% and no adverse reactions occurred. Of the 14 survived cases (82.4%), the median follow-up time was 944 (559-1245) days from the first infusion of MSCs. The levels of TNF-α in children with grade II, III and IV GVHD before treatment were 9.5±4.3 pg/ml, 16.3±10.9 pg/ml and 35.8±21.2 pg/ml respectively. The difference between grade II and IV, III and IV was statistically significant (P<0.05). Compared with the ineffective group of BMMSC infusion, the serum TNF-αlevel in the BMMSCs treatment effective group was 10.8±5.6 pg/ml vs 40.6±14.8 pg/ml (t=-3.901, P<0.05) before treatment. In the effective group of BMMSCs infusion, IL-10 20±17.4 pg/ml of day 14 was significantly higher than that 7.3±3.1 pg/ml before the treatment (t=-2.850, P<0.05), while , the serum levels of IL-2α, IL-6, IL-8, TNF-α were not statistically significantly different (P＞0.05). The infusion of BMMSC is safe and effective in the treatment of refractory GVHD in children. TNF-αlevel relates with the severity of GVHD. BMMSC may play an anti-GVHD role by up regulating the level of cytokine IL-10 in vivo.

Pediatric Late-Onset Acute and Chronic Graft-Versus-Host Disease: A Single Center Cohort Study 2007-2017

<h3>Objectives</h3> Late acute graft-versus-host-disease (GVHD) in children is not well described. The 2014 NIH Chronic GVHD Consensus Criteria have not been studied in pediatric populations. We examined the incidence, organ involvement, severity by 2014 NIH criteria, and outcomes of late acute GVHD (L-aGVHD), overlap cGVHD, (O-cGVHD) and classic-chronic GVHD (C-cGVHD) in children. <h3>Methods</h3> We retrospectively reviewed 573 children, median age 7 (range 0.1-17.9) years who underwent first allogeneic hematopoietic cell transplant (HCT) at the University of Minnesota (2007-2017). 377 (66%) had a non-malignant disease. Graft sources included bone marrow (47%), peripheral blood (2%) and cord blood (51%). The majority (76%) received myeloablative regimens. GVHD prophylaxis was calcineurin-based (93%), sirolimus-based (2%) or ex vivo T-cell depletion (5%). <h3>Results</h3> While 79 patients (14%; 95%CI: 11–17) developed early onset (ie, ≤ day +100 after HCT) acute GVHD by 3 years, 9 patients had developed L-aGVHD (> day +100; cumulative incidence 2%, 95%CI: 1–3), 16 patients developed O-cGVHD (3%; 95%CI: 1–4) and 6 patients C-cGVHD (1%; 95%CI: 0–2) (Figure 1). Patients with prior grade II–IV early onset acute GVHD had a higher incidence of O-cGVHD or C-cGVHD (8% vs. 3%, p=0.02). No other patients or graft characteristics were associated with the 32 patients with L-aGVHD, O-cGVHD, or C-cGVHD. Skin was the most common involved organ at GVHD diagnosis across all the GVHD subtypes (Figure 2). No cases with joint or genitourinary chronic GVHD were reported. 6 patients had mild, 4 moderate and 13 severe chronic GVHD. 24/32 patients with L-aGVHD, O-cGVHD, or C-cGVHD received systemic therapy as initial treatment. Systemic therapies included steroids alone (17%, 4/24), steroids and sirolimus (8%, 2/24), steroids and cyclosporine (58%, 14/24), and CSA alone (17%, 4/24). At 6 months, CR/PR was achieved in 78% L-aGVHD patients, 44% O-cGVHD patients, and 43% C-cGVHD patients. 2 year CR/PR was achieved in 89% L-aGVHD patients, 63% O-cGVHD patients, and 71% C-cGVHD patients. The 1-year non-relapse mortality (NRM) was 11% (95%CI: 0–30) for L-aGVHD, 13% (95%CI: 0–29) for O-cGVHD, and 14% (95%CI: 1–28) for C-cGVHD as compared to 34% (95%CI: 23–47) for early onset acute GVHD. Patients with L-aGVHD, O-cGVHD and/or C-cGVHD had higher 2-year NRM than those without (Hazard Ratio: 2.8, 95%CI: 1.0–7.9, p=0.049). <h3>Conclusion</h3> Patients with L-aGVHD, O-cGVHD, and/or C-cGVHD had a higher likelihood of poor NRM. These data suggest that pediatric patients with L-aGVHD may respond better to treatment than those with O-cGVHD or C-cGVHD. Future research should further investigate the risks and nature of L-aGVHD, O-cGVHD and C-cGVHD to better understand how to prevent and treat GVHD in children.

Abatacept Decreases the Rate of Acute and Chronic Gvhd in Children with Sickle Cell Disease Undergoing Matched Sibling Transplants

<h3>Introduction</h3> We wanted to study the role of abatacept on the incidence of graft versus host disease (GVHD) in patients with sickle cell disease (SCD) undergoing allogeneic hematopoietic stem cell transplant (HSCT). <h3>Methods</h3> We conducted a retrospective chart review of patients who received an allogeneic HSCT for SCD at Cincinnati Children's Hospital Medical Center and compared various transplant characteristics between patients with and without abatacept for acute GVHD prophylaxis. <h3>Results</h3> Sixteen patients were transplanted for SCD at our center. Nine patients received a calcineurin inhibitor, methotrexate and abatacept at 10 mg/kg intravenously on days -1, +5, +14 and +28 while 7 patients received a calcineurin inhibitor with methotrexate and methylprednisolone for acute GVHD prophylaxis (table 1). No abatacept infusion related adverse effects were observed. Neutrophil engraftment was comparable at a median of 12.5 days (range 11-21) in patients without abatacept versus 13 days (range 12-16 days) in the abatacept cohort. Incidence of grade 2-4 GVHD was 0/9 in the abatacept cohort versus 3/7 patients in the no-abatacept cohort. Two of the 3 acute GVHD patients in the no-abatacept cohort had visceral involvement. One patient in the abatacept cohort had mild chronic GVHD compared to 3 patients in the no-abatacept cohort with mild (n=1) and moderate (n=2) chronic GVHD. Six patients in the no-abatacept cohort had viral reactivation compared to 8/9 patients in the abatacept cohort. No patient in either cohort had viral disease. One patient in the abatacept cohort had secondary graft loss and was transplanted again with the same donor and conditioning regimen successfully. There was no graft loss in patients who did not receive abatacept. The disease-free survival was 100% in both groups at last follow up of 1925 days (range 837-8164 days) in the no-abatacept group and 770 days (range 112-1634 days) after HSCT in the abatacept cohort. <h3>Conclusions</h3> Abatacept is well tolerated and decreases the incidence of acute and chronic GVHD in children with SCD undergoing fully matched sibling transplants. Larger studies are needed to definitively determine the impact of abatacept in GVHD prophylaxis in the matched sibling donor setting.

Low Levels of Plasmacytoid Dendritic Cells at the Time of Engraftment Are a Valuable Severe aGVHD Indicator in Children Undergoing Allogeneic Stem Cell Transplantation

Graft-versus-host-disease (GVHD) remains a leading cause of transplant-related mortality (TRM) in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Patients who do not respond to GVHD therapy are at high risk for death without relapse. Strategies that can predict the development of severe GVHD in transplant patients may improve risk stratification for steroids treatment refractory GVHD and TRM. Dendritic cells (DCs) play nonredundant roles in regulating both immunity and tolerance. Clinical and pre-clinical studies suggest that GVHD causes dysregulated development of functional DCs and impaired reconstitution of donor DCs is associated with increased risk of severe GVHD. We demonstrate that donor plasmacytoid DC (pDC) reconstitution around the engraftment time is a useful predictor for the development of severe GVHD in children after allo-HSCT. We examined reconstitution of donor DCs, including total DCs (lineage-negative (LIN-)HLADR+), pDCs (LIN-HLADR+CD123+CD1c-) and CD1c+DCs (LIN-HLADR+CD123-CD1c+), in peripheral blood of patients undergoing allo-HSCT, using age-matched healthy children as controls. The median time for engraftment was 14 days (range, 13.0~17 days), whereas clinical signs of GVHD occurred approximately 10 days later (median time, 24 days;range, 18~35 days). Thus, measuring the number and frequency of circulating blood DCs early at the engraftment time allowed us to evaluate the subsequent occurrence of GVHD. Transplant patients were followed up for 6 months after allo-HSCT. Of evaluable 45 transplant patients, 27 patients had no GVHD (grade 0) or mild GVHD (grade I), and 18 patients developed severe GVHD (grade II-IV GVHD). Patients who developed grade II-IV GVHD had no significant difference in frequency ( median, 0.2%; range, 0.04~0.35%) and number (median, 1.6 cell/ml; range, 1~3.8 cell/ml) of total DCs than patients with grade 0-I GVHD (median frequency, 0.41%; range, 0.15~0.63%, P&lt;0.05; and median number, 2.6 cell/ml , range, 1~6.7 cell/ml,Figure1A,1B). Both pDCs and CD1c+DCs represent the major DC populations in human peripheral blood. Patients with grade II-IV GVHD showed significantly lower frequency and number of pDCs (median frequency, 3.4%; range, 0.64~14%, median number, 0.06/ml, range, 0.02~0.25 cell/ml) than patients with grade 0-I GVHD median frequency, 29.1%, range, 20.3%~39.2%, P&lt;0.01; mediate number, 0.5 cell/ml, range, 0.2~1.9 cell /ml, P&lt;0.01Figure1A,1B). In contrast, there was no significant difference in frequency and number of CD1c+DC between the two groups. These data suggest that the reconstitution of donor pDCs is linked to the occurrence of severe GVHD. Using Receiver operating characteristic (ROC) curve analysis, we explored thresholds of pDCs as a discriminator for grade II-IV GVHD patients versus grade 0-I GVHD patients. The median pDC level in all tested patients was 0.25 cell/ml (range, 0.1~0.9 cell/ml,Figure1C) at the engraftment time. We chose the threshold of pDC level at 0.3 cell/ml to evaluate the difference in patients with high (above the threshold) versus low (below the threshold) pDC levels. Of these 45 patients, 21 (46.7%) patients had high pDCs and 24 (53.3%) were low pDCs. Patients with low pDCs had a significantly higher probability of developing grade II-IV GVHD (p&lt;0.01). The sensitivity of discriminating severe GVHD versus no/mild GVHD was 75% and the specificity was 94%. In addition, low engraftment pDC patients had higher TRM compared to high pDC patients (12.5% versus 0%) for median follow-up time 300 days (range, 210-465 days) after transplantation. However, there was no significant difference in overall survival rate between high pDC- and low pDC-group. Furthermore, the serum level of REG3α and ST2 at the engraftment time was not associated with the incidence of severe GVHD in these patients. Collectively, our findings identify that quantitation of pDCs at the engraftment time is a valuable prognostic predicator for severe GVHD in patients undergoing allo-HSCT. Given the importance of pDCs in modulating GVH reactions, it will be important to further determine whether impaired reconstitution of donor DCs may contribute to dysregulated immune tolerance against host tissues after allo-HSCT. Disclosures No relevant conflicts of interest to declare.

«Graft-Versus-Host» Disease after Haploidentical Hematopoietic Stem Cell Transplantation from Relative Donors in Children with Cancer, Prophylaxis Regimens and Correlation with «Graft-Versus-Tumor» Effect: a Retrospective Cohort Study

Background. «Graft-versus-host» disease (GVHD) is a major complication of allogeneic Hematopoietic Stem Cell Transplantation (HSCT), the main cause of non-relapse mortality. The actual problems of alternative donors HSCTs are GVHD prophylaxis and its distinction from «graft-versus-tumor» (GVT) effect. Objective. Assessment of incidence and severity of GVHD in children with very high-risk cancer after non-T-depleted haplo-HSCT; searching some correlation between controlled chronic GVHD (chGVHD) and GVT effect after HSCT, compare cyclosporine (CSA) and tacrolimus based GVHD prophylaxis. Methods. We provided the GVHD assessment in 74 recipients of haplo-HSCs from relatives since 2001 till 2018 in retrospective cohort study. Effect of chGVHD on the HSCT results was assessed in 23 patients with acute myeloid leukemia (AML) and 15 patients with solid tumors. We analyzed the incidence of severe acute and chronic GVHD in patients who received CSA or tacrolimus-based prophylaxis. Results. The incidence of severe aGHVD in our study was 15%, chGVHD — 12%. Switch CSA to tacrolimus resulted in reduction of severe aGVHD from 21% to 9% and full elimination of severe extensive chGVHD. Controlled chGVHD after haplo-HSCT was associated with relapse reduction from 48.7% to 30% and improvement of overall survival (OS) from 46.5% to 80.8% in patients with AML. We haven’t seen any clinically significant antitumor effect of graft in patients with solid tumors. Conclusion. In our study the incidence of severe GVHD corresponds to world data after HSCTs from alternative donors, it went down after switch from CSA to tacrolimus. We found some correlation between controlled chGVHD development and HSCT results improvement in patients with AML. The GVT effect of haplo-graft in solid tumors is almost absent.

Benefits and challenges with diagnosing chronic and late acute GVHD in children using the NIH consensus criteria

AbstractChronic graft-versus-host disease (cGVHD) and late acute graft-versus-host disease (L-aGVHD) are understudied complications of allogeneic hematopoietic stem cell transplantation in children. The National Institutes of Health Consensus Criteria (NIH-CC) were designed to improve the diagnostic accuracy of cGVHD and to better classify graft-versus-host disease (GVHD) syndromes but have not been validated in patients <18 years of age. The objectives of this prospective multi-institution study were to determine: (1) whether the NIH-CC could be used to diagnose pediatric cGVHD and whether the criteria operationalize well in a multi-institution study; (2) the frequency of cGVHD and L-aGVHD in children using the NIH-CC; and (3) the clinical features and risk factors for cGVHD and L-aGVHD using the NIH-CC. Twenty-seven transplant centers enrolled 302 patients <18 years of age before conditioning and prospectively followed them for 1 year posttransplant for development of cGVHD. Centers justified their cGVHD diagnosis according to the NIH-CC using central review and a study adjudication committee. A total of 28.2% of reported cGVHD cases was reclassified, usually as L-aGVHD, following study committee review. Similar incidence of cGVHD and L-aGVHD was found (21% and 24.7%, respectively). The most common organs involved with diagnostic or distinctive manifestations of cGVHD in children include the mouth, skin, eyes, and lungs. Importantly, the 2014 NIH-CC for bronchiolitis obliterans syndrome perform poorly in children. Past acute GVHD and peripheral blood grafts are major risk factors for cGVHD and L-aGVHD, with recipients ≥12 years of age being at risk for cGVHD. Applying the NIH-CC in pediatrics is feasible and reliable; however, further refinement of the criteria specifically for children is needed.

Coronary artery involvement in chronic graft‐versus‐host disease presenting as sudden cardiac arrest

Graft-versus-host disease (GVHD) is related to considerable morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Cardiac complications associated with GVHD are uncommon, and coronary artery involvement is even more unusual. We report on a male pediatric patient with chronic GVHD who developed a fatal ventricular arrhythmia caused by coronary artery obstruction after HSCT. At 30months after HSCT, he suddenly collapsed with ventricular fibrillation. After resuscitation, electrocardiography showed abnormal q-wave and ST changes in the inferior leads, suggesting a coronary event. Coronary angiography revealed complete obstruction of the proximal left anterior descending artery, subtotal obstruction of the mid left circumflex artery, and mild narrowing at the right coronary artery. This boy had none of the risk factors for coronary artery disease, and the only possible explanation for the cardiac event is GVHD. Coronary artery disease only rarely occurs as a cardiac event in children. However, coronary artery involvement should be recognized as one of the important manifestations of chronic GVHD in children.

Steroid-Refractory Acute Gvhd in Children: Retrospective Analysis of the AIEOP HSCT Registry

Introduction. Severe acute graft-versus-host disease (GVHD) remains the most relevant complication after allogeneic HSCT. Although its incidence in the pediatric population is lower than in adults, children with severe acute GVHD and who do not respond to first-line treatment with systemic steroids still have a poor prognosis. The exact incidence of steroid-refractory acute GVHD in children is still not precisely defined, as well as the risk of non-relapse mortality (NRM) due to steroid-refractory acute GVHD. Aim of our study was to analyze the frequency of acute GVHD unresponsive to first-line steroid treatment in children and adolescents given allogenic HSCT, to describe the second line treatment employed, and the outcome of patient with this complication.Patients and methods. This retrospective study included patients younger than 18 years at the time of transplantation and given a first allogeneic HSCT between 2010 and 2015 in one of the HSCT Centers of the Italian Association for Pediatric Hematology / Oncology (AIEOP). Overall, 1608 patients (59% M and 41% F) were analyzed. Median age at HSCT was 8 years (range 0.2 - 18) 1084 (67%) were affected by malignant diseases and 524 (33%) by non-malignant disorders. The donor was an HLA-matched family donor (MFD) in 28% of cases, an unrelated donor (UD) in 52% and an HLA-haploidentical family donor in 20%. In MFD transplants Cyclosporine (CSA) was used as GVHD prophylaxis in 30% of cases and the combination of CSA + short-term methotrexate (MTX) in 48%. 75% of UD transplant recipients received CSA + MTX + anti-thymocyte globulin (ATG) as GVHD prophylaxis, and 25% other drug combinations. Ex vivo T-cell depletion of the graft was employed in most patients given a HLA-haploidentical HSCT (79% of transplants), and high-dose post-transplant cyclophosphamide in 11% of cases.Results. The cumulative incidence (CI) of grade II-IV acute GVHD was 31%, while that of grade III-IV acute GVHD was 10%. The overall incidence of chronic GVHD was 13% and that of extensive chronic GVHD was 6%. The CI of NRM was 14% for grade 0 acute GVHD patients, 9% for grade I, 11% for grade II, 26% for grade III and 68% for grade IV (P < 0.001). Of the 491 patients with grade II-IV acute GVHD, 250 (51%) required a second-line treatment after first-line steroid therapy (30% of grade II, of 75% grade III and 83% of grade IV patients). Acute GVHD requiring second-line treatment was more frequent in UD transplant recipients (21% of patients) than in matched sibling or haploidentical donor recipients (7% and 13% respectively, P < 0.01), while age at HSCT and diagnosis (malignant vs. non-malignant disease) were not associated with this complication. Second-line treatment was extracorporeal photochemotherapy in 60% of patients, mofetil mycophenolate (MMF) in 46%, mesenchymal stromal cells (MSC) in 12%, monoclonal antibodies (MoAbs) in 5% and other treatments in 28%; 32% of patients received more than one second line treatment. Overall NRM was 13% for patients with grade 0-I acute GVHD, 15% for grade II-IV responding to steroids, and 25% for grade II-IV patients requiring second-line therapy (P < 0.001). The addition of a second-line treatment partially decreased NRM only in patients with grade IV acute GVHD, but the difference was not statistically significant (66% vs. 78%; P = 0.313). In multivariable analysis, grade III (HR = 1.84; P = 0.044) and grade IV acute GVHD (HR = 7.07; P < 0.001), and the use of an UD (HR = 1.63; P = 0.007) were associated with an increased NRM, while the use of a second-line treatment did not decrease this risk (HR = 0.80; P = 0.368).Conclusions. Despite being less frequent than in adults, severe steroid-refractory acute GVHD is still associated with a very high NRM also in pediatric patients. Second or third-line treatments adopted so far have not been effective in improving control of the complication and in decreasing NRM. The prospective evaluation of acute GVHD biomarkers (such as ST2 and REG3α) could help in identifying patients at higher risk of NRM. Prospective studies are warranted to define new treatment modalities that could decrease the mortality rate associated with the most severe form of disease. DisclosuresZecca:Chimerix: Honoraria. Locatelli:bluebird bio: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria.

Influence of Age on Acute and Chronic GVHD in Children Undergoing HLA-Identical Sibling Bone Marrow Transplantation for Acute Leukemia: Implications for Prophylaxis

Relapse remains the major cause of mortality after hematopoietic cell transplantation (HCT) for pediatric acute leukemia. Previous research has suggested that reducing the intensity of calcineurin inhibitor-based graft-versus-host disease (GVHD) prophylaxis may be an effective strategy for abrogating the risk of relapse in pediatric patients undergoing matched sibling donor (MSD) HCT. We reasoned that the benefits of this strategy could be maximized by selectively applying it to those patients least likely to develop GVHD. We conducted a study of risk factors for GVHD, to risk-stratify patients based on age. Patients age <18 years with leukemia who received myeloablative, T cell-replete MSD bone marrow transplantation and calcineurin inhibitor-based GVHD prophylaxis between 2000 and 2013 and were entered into the Center for International Blood and Marrow Transplant Research registry were included. The cumulative incidence of grade II-IV acute GVHD (aGVHD) was 19%, that of grade II-IV aGVHD 7%, and that of chronic GVHD (cGVHD) was 16%. Compared with age 13 to 18 years, age 2 to 12 years was associated with a lower risk of grade II-IV aGVHD (hazard ratio [HR], .42; 95% confidence interval [CI], .26 to .70; P = .0008), grade II-IV aGVHD (HR, .24; 95% CI, .10 to .56; P = .001), and cGVHD (HR, .32; 95% CI, .19 to .54; P < .001). Compared with 2000-2004, the risk of grade II-IV aGVHD was lower in children undergoing transplantation in 2005-2008 (HR, .36; 95% CI, .20 to .65; P = .0007) and in 2009-2013 (HR, .24; 95% CI. .11 to .53; P = .0004). Similarly, the risk of grade III-IV aGVHD was lower in children undergoing transplantation in 2005-2008 (HR, .23; 95% CI, .08 to .65; P = .0056) and 2009-2013 (HR, .16; 95% CI, .04 to .67; P = .0126) compared with those doing so in 2000-2004. We conclude that aGVHD rates have decreased significantly over time, and that children age 2 to 12 years are at very low risk for aGVHD and cGVHD. These results should be validated in an independent analysis, because these patients with high-risk malignancies may be good candidates for trials of reduced GVHD prophylaxis.

Early blood stream infection following allogeneic hematopoietic stem cell transplantation is a risk factor for acute grade III-IV GVHD in children and adolescents.

Graft-versus-host disease (GVHD) remains a major cause of mortality and morbidity in allogeneic hematopoietic stem cell transplantation (HSCT). In adults, early blood stream infection (BSI) and acute GVHD (AGVHD) have been reported to be related. The impact of BSI on risk for AGVHD, however, has not been assessed in pediatric patients. We conducted a retrospective analysis to test the hypothesis that early BSI (before day +30) predisposes allogeneic pediatric transplant patients to severe AGVHD. We analyzed 293 allogeneic HSCT performed at Children's Healthcare of Atlanta between 2005 and 2014 that met eligibility criteria. The cumulative incidence of acute grade III-IV GVHD at 100 days after HSCT was 17.1%. In multivariate analysis, risk for acute grade III-IV GVHD was associated with HLA-mismatched donor (hazard ratio [HR]=4.870, P<0.001), and BSI between day 0 and +30 prior to AGVHD (HR=3.010, P=0.001). These results indicate that early BSI appears to be a risk factor for acute grade III-IV GVHD. Further research is needed to determine if the link is causal.

Calcineurin inhibitor-free strategies for prophylaxis and treatment of GVHD in children with posterior reversible encephalopathy syndrome after stem cell transplantation.

Posterior reversible encephalopathy syndrome (PRES) is a distinct clinico-radiologic entity that can occur following allogeneic hematopoietic stem cell transplantation, often in the context of treatment with calcineurin inhibitors (CNIs). We describe the results of CNI-free management of 14 children with PRES and review the clinical and radiologic manifestations of their presentation. Discontinuation of CNIs usually resulted in remission of PRES, but patients with established graft versus host disease (GVHD) at the time when treatment was changed often experienced progressive GVHD despite administration of immune suppressive and modulating treatments. All but three patients experienced full neurologic recovery. Nine children died as a result of either GVHD, disease relapse, or severe infection. Discontinuation of CNIs results in neurologic improvement in most cases, but superior alternative immune modulatory treatment is needed to prevent progression of established GVHD.

T cell costimulation blockade for hyperacute steroid refractory graft versus-host disease in children undergoing haploidentical transplantation

The outcome of hyperacute grade 3–4 steroid-refractory graft-versus-host-disease (SR-GVHD) remains dismal despite a plethora of agents being tried alone or in combination. Following T replete haploidentical transplantation with post-transplantation cyclophosphamide on 75 patients, 10 patients (13%) aged 2–20years, developed hyperacute SR-GVHD. We report on the outcome of two different regimens for treatment of SR-GVHD on the outcome of these patients. Five patients were treated in Regimen A consisting of anti-thymocyte globulin, Etanercept and Basiliximab. The next 5 patients were treated combining T cell costimulation blockade with Abatacept along with Etanercept and Basiliximab. The overall response at days 29 and 56 were 40% and 0% with Regimen A and100% and 40% with Regimen B. The major cause of treatment failure was progression of GVHD and opportunistic infections. Two of the patients achieving a complete remission on Regimen B are long term disease free survivors off immunosuppression. Our study demonstrates the dismal outcome of early onset SR-GVHD in children following T replete haploidentical transplantation. However, the combination of Abatacept with anticytokine agents seems to produce encouraging early response and might warrant further investigation.

Extracorporeal Photopheresis (ECP) for Treatment of Refractory Acute Graft-Versus-Host Disease in Children (GVHD) after Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Extracorporeal Photopheresis (ECP) for Treatment of Refractory Acute Graft-Versus-Host Disease in Children (GVHD) after Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Extracorporeal photopheresis versus alternative treatment for chronic graft-versus-host disease after haematopoietic stem cell transplantation in paediatric patients.

Chronic graft-versus-host disease (GvHD) is a major cause of morbidity and mortality after haematopoietic stem cell transplantation occurring in 6% to 65% of the recipients. Currently, the therapeutic mainstay for chronic GvHD are corticosteroids that are frequently combined with other immunosuppressive agents in people with steroid-refractory manifestations. There is no established standard treatment for steroid-refractory chronic GvHD. The therapeutic options for these patients include extracorporeal photopheresis (ECP), an immunomodulatory treatment that involves ex vivo collection of mononuclear cells from peripheral blood, exposure to the photoactive agent 8-methoxypsoralen, ultravioletradiation and re-infusion of the processed cell product. The mechanisms of action of ECP are not completely understood. This is an updated version of a Cochrane review first published in 2014. To evaluate the effectiveness and safety of ECP for the management of chronic GvHD in children and adolescents after haematopoietic stem cell transplantation. We searched the Cochrane Register of Controlled Trials (CENTRAL) (Issue 9, 2015), MEDLINE and EMBASE databases from their inception to 23 September 2015. We searched the reference lists of potentially relevant studies without any language restriction. We searched eight trial registers and five conference proceedings on 29 September 2015. Randomised controlled trials (RCTs) comparing ECP with or without alternative treatment versus alternative treatment alone in paediatric patients with chronic GvHD after haematopoietic stem cell transplantation. Two review authors independently performed the study selection. We resolved disagreements in the selection of trials by consultation with a third review author. No additional studies were identified in this 2015 review update, in total leading to no studies meeting the criteria for inclusion in this review. The efficacy of ECP in the treatment of chronic GvHDin paediatric patients after haematopoietic stem cell transplantation based on RCTs cannot be evaluated since the original version of this review and the first review update found no RCTs. Current recommendations are based on retrospective or observational studies only. Thus, ideally, ECP should be applied in the context of controlled trials only. However, performing RCTs in this patient population will be challenging due to the limited number of patients, the variable disease presentation and the lack of well-defined response criteria. International collaboration, multicentre trials and appropriate funding for such trials will be needed. If treatment decisions based on clinical data are made in favour of ECP, patients should be carefully monitored for beneficial and harmful effects. In addition, efforts should be made to share this information with other clinicians, for example by setting up registries for paediatric patients that are treated with ECP.

Safety and Outcomes of Extracorporeal Photopheresis With the Therakos Cellex System for Graft-Versus-Host Disease in Pediatric Patients.

Extracorporeal photopheresis (ECP) is a difficult procedure to perform in the pediatric population. This is a retrospective review of 12 pediatric patients who underwent photopheresis with the Therakos Cellex system for graft-versus-host disease (GVHD). Acute GVHD (aGVHD) occurred in 6 patients, and overlap syndrome and chronic GVHD (cGVHD) occurred in 4 and 2 patients, respectively. The ECP regimen was the same for all aGVHD and cGVHD patients: initially, every week (2 sessions/wk) for 2 months; next, every 2 weeks for 2 months; and finally, every month for at least 1 year. Improvement was observed in 7 of 10 aGVHD patients (70%) and in 4 of 6 cGVHD patients (66%). Eleven patients had skin involvement before ECP; 9 of them responded to treatment (81%). Gastrointestinal involvement occurred in 8 patients; 5 of them experienced improvement during ECP treatment (62%). All 4 patients with liver involvement failed to respond. No serious adverse reactions occurred. In conclusion, our study demonstrates that ECP with the Therakos Cellex system is a safe treatment option for GVHD in children, allowing the tapering of immunosuppressants by at least half.