Steroid-refractory Chronic Graft-versus-host Disease Research Articles

Ruxolitinib Pharmacokinetics and Pharmacodynamics in Children with Acute and Chronic Graft-versus-Host Disease

IntroductionWe report pharmacokinetics of oral ruxolitinib in children with steroid refractory acute graft versus host disease (GVHD) (<12y) and chronic GVHD (≤18y) using our published pediatric dosing. MethodsPK sampling before and +2 hours after ruxolitinib was performed in patients with established chronic GVHD. More extensive PK analysis was evaluated in patients with newly diagnosed acute or chronic GVHD before, +0.5, 1, 2, 4 and 6 hours after ruxolitinib in patients >10kg, and before, +3 and +6 hours in children <10kg. We measured pSTAT1, 3 and 5 expression on CD4+ and CD8+ T-cells before and 2 hours after ruxolitinib as a pharmacodynamic marker of JAK/STAT inhibition. ResultsThirteen patients were prospectively enrolled (0-≤18y with existing chronic GVHD(n=8), 0-<12y with new onset steroid refractory acute GVHD(n=4) and newly diagnosed steroid-refractory chronic GVHD(n=1). A large variability in PK was seen. Mean oral clearance (CL/F) was 7.76 ± 4.09 L/h (±SD 4.4; range: 3.1-15.3). The average elimination half-life was 2.32 hours (±SD 1.0). Ruxolitinib clearance was higher in children <2 years versus >2 years (12.1 ± 3.0, vs 5.7 ± 2.8 L/h, p=0.005) and was reduced with concurrent azoles and azithromycin. We saw a variable reduction in pSTAT1/3/5 expression on T-cells at time of peak ruxolitinib absorption (2 hours after dose). ConclusionsChildren<10 kg have lower ruxolitinib exposure, possibly due to inherent increased drug clearance or variabilities in dosing methods leading to decreased drug absorption.

Role of abatacept in the prevention of graft-versus-host disease: current perspectives.

Administration of abatacept following transplantation has been reported to inhibit graft rejection and graft-versus-host-disease (GvHD) in mouse models associated with allogeneic hematopoietic stem cell transplant (HSCT). This strategy has recently been adopted in clinical practice for GvHD prevention in human allogeneic HSCT and offers a unique approach to optimizing GvHD prophylaxis following alternative donor HSCTs. When combined with calcineurin inhibitors and methotrexate, abatacept had shown to be safe and effective in preventing moderate to severe acute GvHD in myeloablative HSCT using human leukocyte antigen (HLA) unrelated donors. Equivalent results are being reported in recent studies using alternative donors, in reduced-intensity conditioning HSCT and nonmalignant disorders. These observations have led to hypothesizing that even in the setting of increasing donor HLA disparity, abatacept when given with traditional GvHD prophylaxis does not worsen general outcomes. In addition, in limited studies, abatacept have being protective against the development of chronic GvHD through extended dosing and in the treatment of steroid-refractory chronic GvHD. This review summarized all the limited reports of this novels approach in the HSCT setting.

Immune Ablation and Stem Cell Rescue in Two Pediatric Patients with Progressive Severe Chronic Graft-Versus-Host Disease

Transplantation of allogeneic hematopoietic stem cells represents an established treatment for children with high-risk leukemia. However, steroid-refractory chronic graft-versus-host disease (SR-cGvHD) represents a severe life-threatening complication, for which there is no standard therapy. After failing several lines of immunosuppressive and biological treatment, we applied an immunoablative therapy with re-transplantation of purified CD34+ donor stem cells to reset the aberrant immune system. Two pediatric patients, who had been transplanted for high-risk acute lymphoblastic leukemia, underwent the procedure. Interestingly, enough stem cells could be mobilized, harvested, and purified to be used as grafts more than one year after allogeneic transplantation under intensive immunosuppressive therapy and ongoing SR-cGvHD. With a follow-up of 8 and 22 months, respectively, both patients are without immunosuppressive therapy and do not show signs of active disease. Regeneration of skin manifestations started promptly, other damaged organs did not progress and continue to show recovery from severe fibrotic transformation. Bone marrow function is robust and T cell receptor repertoires showed polyclonal immune reconstitution. In conclusion, stem cell harvest and re-transplantation of human CD34+-selected allogeneic stem cells is possible and represents a new therapeutic option in SR-cGvHD by resetting a profoundly disturbed immune network.

Tyrosine Kinase Inhibitors in the Treatment of Steroid Refractory Chronic Graft Versus Host Disease

Introduction: Different novel drugs have been investigated for steroid-refractory chronic graft versus host disease (SR-cGVHD). Despite Rixulotinib approval, the need for more therapeutic options is still warranted. Tyrosine kinase (TK) inhibitors are known to inhibit pathways involved in cGVHD pathophysiology, including transforming growth factor (TGF)-β and platelet-derived growth factor receptor (PDGF-r) signaling pathways. Therefore, this drug class is currently under investigation in treating SR cGVHD. Methods: A comprehensive search was conducted across various data sets, including PubMed, Cochrane, and Embase. A review of the most recent data is summarized in this abstract. Results: Results from a randomized single-arm multicenter study highlighted the efficacy of Bruton's TK inhibitor ibrutinib with an acceptable safety profile. Similarly, multiple pilot studies show Imatinib, BCR/ABL TK inhibitor, as a suitable alternative treatment for steroid-refractory cGVHD. One study shows higher efficacy of Imatinib when combined with mycophenolate. A single phase I/II study highlighted the potential role of nilotinib. A list of complete and partial response rates of these studies with their most common adverse effects are listed in the table. 1. A cumulative analysis of these studies showed that overall these three tyrosine kinase inhibitors showed a median complete response (CR) rate of 3.85% with ranges from 0 to 36.80% and a median partial response (PR) rate of 55.50% with ranges of 25-80%. These results, although not groundbreaking but still are encouraging. Conclusion Tyrosine kinase inhibitors are promising results in treating patients with SR cGVHD with a good side effect profile. More research is warranted to explore this drug class in this patient population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Organ-specific response after low-dose interleukin-2 therapy for steroid-refractory chronic graft-versus-host disease

AbstractDespite new therapeutic options, treatment of steroid-refractory chronic graft-versus-host disease (SR-cGVHD) remains challenging as organ involvement and clinical manifestations are highly variable. In previous trials of low-dose interleukin-2 (LD IL-2), we established the safety and efficacy of LD IL-2 for the treatment of SR-cGVHD. In the present report, we combined five phase 1 or 2 clinical trials conducted at our center to investigate organ-specific response rate, coinvolvement of organs, predictors of organ-specific response, and its possible association with immune response. For the 105 adult patients included in this report, the overall response rate after 8 or 12 weeks of LD IL-2 was 48.6% and 53.3%, including late responses in patients who continued treatment for extended periods. Skin was the most frequent organ involved (84%). The organ-specific response rate was highest in liver (66.7%) followed by the gastrointestinal tract (62.5%), skin (36.4%), joint/muscle/fascia (34.2%), and lung (19.2%). In multivariable analysis, shorter time from diagnosis of cGVHD to IL-2 initiation, shorter time from transplant to IL-2 initiation, and fewer prior therapies were associated with overall response as well as skin response. For immunologic correlates, the ratio of regulatory T cells:conventional T cells (ie, CD4Treg:CD4Tcon) ratio at 1 week was significantly higher in patients with overall and skin response; skin response was significantly associated with lower number of total CD3 T cells, CD4Tcon cells, and CD8 T cells and a higher number of B cells. For lung responders, terminal effector memory cell counts were lower within all T-cell populations compared with nonresponders. Organ-specific mechanisms of injury should be investigated, and organ-specific targeted therapies need to be developed.

Efficiency and Toxicity of Ruxolitinib as a Salvage Treatment for Steroid-Refractory Chronic Graft-Versus-Host Disease.

Graft-versus-host disease (GVHD), especially steroid-refractory GVHD, remains a life-threatening complication after hematopoietic stem cell transplantation (HSCT). The effect of the JAK1/2 kinase inhibitor ruxolitinib on treating steroid-refractory acute GVHD has been verified by the REACH1/2 study; however, its safety and efficacy in patients with steroid-refractory chronic GVHD (SR-cGVHD) remain unclear. In this retrospective study, 70 patients received ruxolitinib as a salvage therapy for SR-cGVHD. Twenty-four weeks after ruxolitinib treatment, the overall response rate (ORR) was 74.3% (52/70), including 34 patients who achieved complete remission (CR) and 18 who achieved partial remission (PR). The main adverse event was cytopenia, which occurred in 51.4% (36/70) of patients. After ruxolitinib treatment, the percentage of CD4 cells increased from 18.20% to 23.22% (P<0.001), while the percentages of NK (CD16+CD56+) cells and regulatory T cells (CD4+CD127 ± CD25+) decreased (P<0.001, P<0.001). Among the B cell subsets, the proportion of total B cells approximately tripled from 3.69% to 11.16% (P<0.001). Moreover, we observed a significant increase in IL-10 levels after ruxolitinib treatment (P=0.025) and a remarkable decrease in levels of suppression of tumorigenicity 2 (ST2) from 229.90 ng/ml to 72.65 ng/ml. The median follow-up after the initiation of ruxolitinib treatment was 401 (6-1076) days. The estimated one-year overall survival rate of the whole group was 66.0% (54.4–77.6%, 95% CI), and the one-year overall survival rate of patients with mild and moderate cGVHD was 69.6% (57.4–81.8%, 95% CI), which was better than that of patients with severe cGVHD (31.3%, 0.0–66.2%, 95% CI) (P=0.002). Patients who achieved a CR and PR achieved better survival outcomes (84.5%, 73.9–95.1%, 95% CI) than those who showed NR to ruxolitinib treatments (16.7%, 0–34.3%, 95% CI) (P<0.001). At the final follow-up, cGVHD relapse occurred in six patients after they reduced or continued their ruxolitinib doses. Collectively, our results suggest that ruxolitinib is potentially a safe and effective treatment for SR-cGVHD.

Venous Thromboembolism in Patients with Steroid-Refractory Chronic Graft-Versus-Host Disease Receiving Synthetic Retinoid Am80

Chronic graft-versus-host disease (GVHD) remains a major cause of late death and morbidity after allogeneic hematopoietic cell transplantation, and the treatment of chronic GVHD remains challenging. All-trans retinoic acid (ATRA), a potent vitamin A derivative, can regulate immune responses. Synthetic retinoid Am80, which shows biological activity approximately 10 times more potent than that of ATRA, directly inhibits Th1 cytokine production. We previously reported in an experimental mouse model that Am80 down-regulated both Th1 and Th17 differentiation in donor T cells, resulting in attenuation of chronic GVHD (Nishimori H. et al. Blood 2012). Based on this background, we conducted an open-labeled, multicenter phase II study of Am80 in patients with steroid-refractory chronic GVHD (Maeda Y. et al. Acta Med. Okayama. 2016). Six facilities are participating in this study. Patients take Am80 orally (4 mg/day) for 24 weeks. If any unexpected adverse events with Grade 2 or expected adverse events with Grade 3 develop, the daily dose will be decreased to 2 mg/day, 2 mg every other day, or discontinued.Eighteen patients were enrolled and 5 out of 18 (27.8%) patients experienced venous thromboembolism (VTE). Table 1 shows the patient characteristics of those developed VTEs.It is controversial whether retinoid would enhance the incidence of VTE. Only one patient reported thrombosis when Am80 orally (6 mg/m2) for 2-8 weeks was administrated to approximately 800 patients with acute promyelocytic leukemia. In this study, 5 out of 18 (27.8%) patients experienced thrombosis and the safety committee in this study has stopped the trial due to safety concerns. Recently, a meta-analysis reported the incidence of VTE in chronic GVHD was 35 % (20-54 %). Further studies are needed to confirm the causal relationship between Am80 orally (4 mg/day) for 24 weeks and VTE. And also, alternative treatment schedule in addition to anticoagulants for the prevention of VTE will be investigated in subsequent studies. [Display omitted] DisclosuresNishimori:Toko Pharmaceutical Industries: Other: Investigational drug is provided free of charge.. Maeda:Toko Pharmaceutical Industries: Other: Investigational drug is provided free of charge.

Effect of Ruxolitinib on Lung Function after Allogeneic Stem Cell Transplantation.

Ruxolitinib, a selective Janus kinase (JAK)1/2 inhibitor, has recently been proposed for steroid-refractory chronic graft-versus host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT), particularly in severe skin cGVHD. Lung function impairment is common in severe skin cGVHD through concomitant bronchiolitis obliterans syndrome (BOS) or restrictive lung disease (RLD) from skin sclerosis. To date, no treatment has shown a benefit on lung function in this context. We retrospectively assessed the effect of ruxolitinib on lung function in a cohort of 70 patients diagnosed with sclerotic-type skin cGVHD between March 2015 and April 2018. Among these patients, 36 received ruxolitinib. To handle confounding by indication bias, exposure groups were matched on the propensity score to receive ruxolitinib, incorporating age, myeloablative conditioning, total body irradiation, BOS, forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and tobacco use at the time of cohort entry, as well as the time from transplantation. The 1:1 matching used a greedy-matching algorithm with replacement, with a caliper of 0.10. FVC and FEV1 trajectories during follow-up were compared in the matched samples, using linear mixed-effects models. The median duration of follow-up of the 46 matched patients was 58 months (interquartile range, 32 to 84 months). Ten patients had an RLD (6 exposed, 4 unexposed), and 13 patients were diagnosed with BOS (8 exposed, 5 unexposed). FEV1 decreased significantly over time independent of exposure to ruxolitinib (P < .0001). The FEV1 trajectory was similar in the exposed patients and the unexposed patients (P = .11). In conclusion, ruxolitinib administration did not demonstrate any improvement in the course of respiratory function in allogeneic HSCT recipients with sclerotic-type skin cGVHD.

Higher response rates in patients with severe chronic skin graft-versus-host disease treated with extracorporeal photopheresis.

IntroductionDifferent forms of graft-versus-host disease (GVHD) remain a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). The prognosis for steroid-refractory chronic GVHD (cGVHD) remains poor. Our aim was to evaluate extracorporeal photopheresis (ECP) treatment in cGVHD patients with different organ involvement to detect subgroups of patients with the best response.Material and methodsThirty-four patients who underwent HSCT and developed moderate (n = 7) or severe (n = 27) steroid-refractory or steroid-dependent cGVHD treated with ECP were included in the analysis. A matched cGVHD control patient group untreated with ECP was collected for comparison.ResultsCompared to the control group and the stable/progressive disease (SD/PD) patients, individuals with complete/partial remission have higher overall survival and lower transplant-related mortality. Furthermore, patients with complete and partial remission (CR/PR) had significantly higher levels of albumin and platelets after ECP treatment compared to patients with stable or progressive cGVHD (SD/PD). Corticosteroid treatment and other immunosuppressive agents could successfully be tapered in the CR/PR group compared to the SD/PD patients. In this study patients with skin cGVHD are those with the highest rate of CR/PR after ECP treatment.ConclusionsOur results suggest that ECP treatment is safe and effective for patients with predominantly skin, oral and liver cGVHD.

Early initiation of extracorporeal photochemotherapy increases response for chronic graft versus host disease following steroid failure

ObjectivesChronic graft versus host disease (GVHD) is one of the major obstacles to achieve success in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Extracorporeal photochemotherapy (ECP) has been demonstrated to be an effective modality for the treatment of GVHD in previous studies but they vary in terms of initiation and duration. Our aim is to demonstrate the characteristics of our patients who received ECP for chronic GVHD to clarify the best treatment scheme. Material and methodsIn this study, we retrospectively evaluated 34 patients with steroid refractory chronic GVHD (n=34) who were treated with ECP between 2001 and 2015. The initiation of ECP was determined according to patient status and the physician's preference. ResultsECP was initiated early (≤3months) as the preferred second-line treatment after failure of methylprednisolone treatment in 12 patients (35%), 22 steroid refractory patients (65%) received ECP later. In all cohorts, 10 (29%) and 14 (41%) of 34 patients achieved complete response (CR) and partial response (PR), respectively, with an overall response rate (ORR) of 70. Early initiation of ECP after chronic GVHD diagnosis (≤3months vs more than 3months) was associated with increased rates of response (92% vs 59%, P=0.046) in which the severity of diseases were similar. Patients with skin involvement in early treatment group had statistically better response. Mild side effects were detected in only 6 patients (16%). ConclusionECP is a safe treatment modality and particularly effective when initiated soon after steroid failure in chronic GVHD.

A Phase I Study of Donor Regulatory T Cells As Treatment for Steroid Dependent/Refractory Chronic Graft Versus Host Disease

Background: Chronic graft versus host disease (CGVHD) remains a notable cause of post transplant morbidity and mortality, limiting quality of life and survival in the allogeneic transplant survivor. CD4+CD25+CD127dimFoxP3+ regulatory T cells (Treg) are a naturally occurring cell population isolatable in the peripheral blood (PB) with key immune regulatory function. Treg have been shown to protect against GVHD in a number of murine models and in patients. Further, clinical correlations have been observed between the presence of CGVHD and a decreased frequency of Treg post allogeneic hematopoietic cell transplant (HCT) as well as the use of low dose IL-2 resulting in clinical responses with an associated increase in Treg. Based on these observations we embarked on a phase I safety and tolerability trial of the treatment of steroid-refractory or dependent CGVHD with infusion of donor Treg in matched related donor recipients.Methods: Eligible patients were ³ 18 years of age with steroid refractory or dependent CGVHD with a matched related HCT donor. All patients were on systemic immunosuppression at the time of enrollment. Donor derived Treg were enriched from a non-mobilized PB apheresis product over 2 days of apheresis. The fresh apheresis product underwent enrichment by CD25+ immunomagnetic selection on the CliniMACS¨ Cell Selection System (Miltenyi Biotec) and Treg were purified by high-speed flow cytometry and gated on the CD4+CD127dim population. The functional activity of the Treg product was assessed via a mixed lymphocyte reaction (MLR). The trial dosing was through a 3+3 dose escalation design with three Treg dose cohorts: 1 x 10E5 Treg/kg, 5 x 10E5 Treg cells/kg and 1.5 x 10E6 Treg cells/kg.Results: Ten patients were enrolled and received donor Treg cell infusions. Isolation of highly purified Treg was successful from all donors. A median of 1.9x10E8 (range 0.9-2.78x10E8) Treg were collected with a purity that ranged from 87.1-99.3% FoxP3+ (Table 1). Function of the Treg enriched apheresis product confirmed Treg suppressive activity with a median suppression of 69.1% (48.7-77.2%) at a ratio of responder cells:CD4+/CD8+:Treg cells of 1:2:1, with sustained suppression to a ratio of 1:2:0.1. All 10 pateints were treated with three patients treated on all three dose cohorts and an additional patient was treated on the third cohort due to the planned cell dose being not reached with the third patient-donor pair. There were no adverse toxicities with the Treg infusion and no incidence of acute GVHD or acute exacerbation of CGVHD. The ratio of Treg/CD4+ cells in the patients’ PB ranged from 2-4.4% at the time of the infusion and remained stable <3 months post infusion. Six of 10 patients have had stable to improved CGVHD with one of these patients having had a flare of CGVHD in the setting of a lapse in immunosuppressive medication and response with reinstitution of immunosuppression. Four patients have had unresponsive or progressive disease requiring the addition of new immunosuppressive agents <2 months post Treg cell infusion. All enrolled patients remain alive at a follow up of >150 days post Treg cell infusion.Summary: This study is the first clinical experience utilizing highly purified donor derived Treg isolated through clinical scale high speed cell sorting. Donor Treg cell therapy for the treatment of steroid refractory or dependent CGVHD at doses of 1.5x10E5-1.5x10E6 Treg/kg were administered without toxicity including absence of AGVHD or exacerbation of CGVHD. The Treg dose of 1.5 x 10E6/kg of recipient weight may be the maximum feasible dose attainable without ex vivo Treg cell expansion. Treg mediated suppression in the MLR documented the in vitro suppressive capability of the Treg cells with investigations ongoing to characterize the functionality of the Treg cells infused. Although this trial was designed to describe the feasibility, safety and tolerability of Treg cell infusions in patients with active CGVHD, the preliminary outcomes of clinical responses and survival are encouraging and comparable to other therapies for steroid refractory/dependent CGVHD with only a single infusion of cells. Further strategies such as multiple infusions or the addition of low dose IL-2 could be considered to attempt to augment the clinical efficacy of Treg based cellular immunotherapy. [Display omitted] DisclosuresMeyer:Stanford University: Patents & Royalties. Negrin:Stanford University: Patents & Royalties.

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.

AML Relapse after Rituximab Treatment for Graft-Versus-Host Disease: Crucial Role for B Cells in Graft-Versus-Host and Graft-Versus-Leukemia

Patients with hematologic malignancies that develop graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HSCT) have a reduced risk of disease relapse compared to patients that do not develop GvHD, suggesting that GvHD and graft-versus-leukemia (GvL) responses are co-dependent. T cells are important in these processes, as T cell depletion from the graft reduces the risk of GvHD at the expense of disease relapse. Much less is known about the effect of B cell depletion on GvHD and GvL responses. Small patient series have demonstrated variable efficacy of Rituximab in the treatment of steroid-refractory chronic GvHD but the effect of depleting allo-reactive B cells on disease relapse remains to be determined. We here report on a patient with steroid-refractory GvHD whose AML relapsed after Rituximab treatment.This 39-year old male received an allogeneic HSCT for chemotherapy-related AML (AML-t) that however relapsed 8 weeks after the transplantation. Upon rapid cessation of immunosuppressive therapy (cyclosporine, mycophenolic acid) and without additional chemotherapy he obtained full remission, at the expense of severe GvHD of the skin, liver and intestine that was corticosteroid-refractory. B cell depletion with Rituximab was successful as second-line treatment for GvHD but eliminated the GvL response and the patient died of AML relapse several months after.To evaluate the B cell repertoire of this patient at the moment of maximal GvH and GvL responses, we isolated peripheral blood B lymphocytes that were transduced with Bcl-xL and Bcl-6 to create clonal B cell lines. These B cells were screened for binding to AML and host tissues. One clone was retrieved that specifically bound to AML cell lines and AML blasts freshly isolated from newly diagnosed AML patients. Antibodies from this clone induced antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity of AML cells in vitro. Several other clones were retrieved that were specific for host tissues such as liver (HepG2 and H69 cell lines), skin (primary fibroblasts) and/or colon (CaCo cell line).These data demonstrate the pivotal role of B lymphocytes in anti-leukemia and anti-host immune responses in an allogeneic HSCT recipient with relapsed AML-t. DisclosuresNo relevant conflicts of interest to declare.

Consensus recommendations for improvement of unmet clinical needs—the example of chronic graft-versus-host disease: a systematic review and meta-analysis

Consensus recommendations are used to improve the methodology of research about rare disorders, but their uptake is unknown. We studied the uptake of consensus recommendations in steroid-refractory chronic graft-versus-host disease (SR-cGVHD). Although in 2006 the National Institutes of Health (NIH) cGVHD consensus project produced recommendations for clinical trials, guidelines have emphasised the scarcity of valuable evidence for all tested interventions. We searched Medline (PubMed) between Jan 1, 1998, and Oct 1, 2013, for non-randomised studies of systemic treatment for SR-cGVHD. To measure adherence to NIH recommendations, we applied a 61 item checklist derived from the NIH consensus document. We did a meta-analysis to measure pooled effect size for overall response rate (ORR) and meta-regression analyses to measure the effect of deviations from NIH recommendations on pooled effect size. We included 82 studies related to nine interventions. Conformity to NIH recommendations was evenly low across the analysed timeframe (1998-2013), and did not change significantly after publication of NIH recommendations. The pooled effect size for ORR for systemic treatment of SR-cGVHD was 0.66 (95% CI 0.62-0.70). Increased adherence to NIH recommendations in a score of items defining correct response assessment was associated with a significant reduction in ORR (-4.2%, 95% CI -6.6 to -1.9; p=0.001). We recorded no significant association between ORR and sets of items related to correct diagnostic definition of SR-cGVHD (change in ORR -3.1%, 95% CI -7.7 to 1.5), specification of primary intervention (0, -3.8 to 3.6), or concomitant treatments (-1.6%, -5.4 to 2.3). The score of items defining correct response assessment increased after publication of NIH recommendations. Our findings show evidence of bias in the reported efficacy of treatment of SR-cGVHD. The overall effect of NIH recommendations in scientific literature is scarce; however, NIH recommendations improved assessment of response, possibly reducing the overestimation bias. Better implementation of NIH recommendations might reduce false expectations about new interventions, and thus prevent clinical studies with ineffective treatments. None.

Extracorporeal photopheresis for chronic graft-versus-host disease: a systematic review and meta-analysis.

BackgroundThe safety of extracorporeal photopheresis (ECP) in steroid-refractory chronic graft-versus-host disease (SR-cGVHD) has been explored in multiple studies but reported response rates (RR) vary significantly across studies.MethodsWe conducted a meta-analysis to assess the efficacy of ECP for SR-cGVHD. A search of electronic databases for studies published between 1984 and 2012 was conducted. End points included RR: complete response (CR), overall response rates (ORR), and organ-specific RR. The initial search generated 312 studies, of which 18 met the selection criteria (N=595). A random effects model was used for pooled rates.ResultsPooled CR rates and ORR were 29% (confidence interval [CI], 19-42%) and 64% (CI, 65-82%), respectively. One-year overall survival was available for 4 studies only and was 49% (CI, 29-70%). The pooled RR for skin, liver, ocular, oral, lung, gastrointestinal and musculoskeletal SR-cGVHD was 74%, 68%, 60%, 72%, 48%, 53%, and 64%, respectively. There was a significant heterogeneity among studies due to differences in ECP schedules and duration. No significant differences in responses to ECP for pediatric and adult populations were found. Sensitivity analysis could not be undertaken due to a limited number of prospective studies.ConclusionECP is an effective therapy for oral, skin, and liver SR-cGVHD, with modest activity in lung and gastrointestinal SR-cGVHD.

Long-term outcome and prospective validation of NIH response criteria in 39 patients receiving imatinib for steroid-refractory chronic GVHD

AbstractForty adults aged 28 to 73 years were entered into a prospective trial of imatinib for the treatment of steroid-refractory chronic graft-versus-host disease (SR-cGVHD). After 6 months, intention-to-treat (ITT) analysis of 39 patients who received the drug, regardless of the duration of treatment, revealed 14 partial responses (PR), 4 minor responses (MR) with relevant steroid sparing (46%) according to Couriel criteria, and 20 ≥ PR (51.3%), as per the National Institutes of Health (NIH) criteria and NIH severity score changes. The best responses were seen in the lungs, gut, and skin (35%, 50%, and 32%, respectively). After a median follow-up of 40 months, 28 patients were alive, with a 3-year overall survival (OS) and event-free survival of 72% and 46%, respectively. The 3-year OS was 94% for patients responding at 6 months and 58% for nonresponders according to NIH response, suggesting that these criteria represent a reliable tool for predicting OS after second-line treatment. Monitoring of anti–platelet-derived growth factor receptor (PDGF-R) antibodies showed a significant decrease in PDGF-R stimulatory activity in 7 responders, whereas it remained high in 4 nonresponders. This study confirms the efficacy of imatinib against SR-cGVHD and suggests that the response at 6 months significantly predicts long-term survival. This study is registered at https://eudract.ema.europa.eu/ (EUDRACT number: 2009-012927-27).

Chronic graft-versus-host disease: disease biology and novel therapeutic strategies.

Graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation. Chronic GVHD often presents with clinical manifestations that resemble those observed in autoimmune diseases. Standard treatment is 1-2mg/kg/day of prednisone or an equivalent dose of methylprednisolone, with continued administration of a calcineurin inhibitor for steroid sparing. However, the prognosis of steroid-refractory chronic GVHD remains poor. Classically, chronic GVHD was said to involve predominantly Th2 responses. We are now faced with a more complex picture, involving possible roles for thymic dysfunction, transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF), B cells and autoantibodies, and Th1/Th2/Th17 cytokines, as well as regulatory T cells (Tregs), in chronic GVHD. More detailed research on the pathophysiology of chronic GVHD may facilitate the establishment of novel strategies for its prevention and treatment.

Mesenchymal stromal cell therapy for steroid-refractory acute and chronic graft versus host disease: a phase 1 study

Steroid-refractory acute graft versus host disease (AGVHD) and chronic graft versus host disease (CGVHD) after allogeneic haematopoietic stem cell transplantation are major causes of morbidity and mortality. We undertook a phase I trial in patients with steroid-refractory AGVHD and CGVHD utilising bone marrow-derived mesenchymal stromal cells (MSC). Additionally, all refractory patients were treated with etanercept concomitantly. The primary end point was safety, and secondary end points were best response achieved and overall survival. A median of two infusions per patient were administered. The response rate overall for AGVHD was complete in seven, partial in four and no response in one patient. Of the seven patients who achieved a complete response, six are alive. The actuarial survival for the overall group of AGVHD was 55% at 30 months. Two patients with CGVHD achieved complete response with two partial responses and three with no response. The survival for those with AGVHD who achieved a complete response compared with those who did not was significant (p = 0.03). We identified no early or late safety issues in the nineteen patients. In view of the poor outlook for steroid-refractory AGVHD, further trials are warranted of MSC with steroid therapy, at the onset of AGVHD before steroid resistance.

Mycophenolic acid trough level monitoring: relevance in acute and chronic graft versus host disease and its relation with albumin

Mycophenolate mofetil (MMF) is used to treat acute and chronic graft versus host disease (GvHD). There is scant evidence in the literature about mycophenolic acid (MPA) trough level monitoring in GvHD. We therefore reviewed 32 patients treated with MMF for acute (n = 19) or chronic GvHD (n = 13). Twelve (63%) of 19 patients with acute GvHD and nine (69%) of 13 with chronic GvHD showed a good response. In all 21 patients who responded to MMF, their mean total MPA levels were therapeutic (1-3.5 mg/L), whereas five of 11 patients who did not respond had sub-therapeutic mean MPA levels (p = 0.002). Sixteen (66%) of 24 steroid refractory or dependent patients responded to MMF. Associations between the mean total MPA level for each patient and the corresponding mean serum albumin concentration showed therapeutic mean total MPA levels for all 23 patients with mean albumin ≥ 31 g/L but sub-therapeutic mean total MPA levels in five of nine patients with mean albumin <31 g/L (p = 0.0006). In conclusion, MMF is efficacious in steroid refractory and dependent acute or chronic GvHD with statistically significant correlation between therapeutic plasma total MPA trough levels and clinical response. Serum albumin levels should be taken into account when considering MMF dose adjustments.

The role of B cells in acute graft-versus-host disease

TO THE EDITOR: Mounting evidences implicates B cells in the pathogenesis of chronic graft-versus-host disease (GVHD). The body of evidence includes findings such as correlation between chronic GVHD and antibody production against Y chromosome-encoded minor histocompatabilty antigens (mHA) generated after sex-mismatched allogeneic stem cell transplantation (SCT), the clinical response of steroid-refractory chronic GVHD to rituximab, and association between high serum B cell-activating factor (BAFF) levels and chronic GVHD [1]. However, the role of B cells in acute GVHD remains controversial. Some studies that showed the association of high B cell count in the grafts in SCT patients with acute GVHD and beneficial effects of rituximab (used for B cell lymphoma treatment before transplantation) in acute GVHD patients, have suggested the possible role of B cells in the development of acute GVHD. Kim et al. reported that the BAFF level/absolute lymphocyte count (ALC) ratio or that of APRIL (a proliferation-inducing ligand) level/ALC at the time of acute GVHD diagnosis was associated with disease severity [2]. In their study, patients with grade III-IV acute GVHD (6) had higher BAFF level/ALC or APRIL level/ALC ratio than the corresponding ratio observed in patients with grade II acute GVHD (9). These findings suggest that BAFF level/ALC or APRIL level/ALC ratio can help determine the severity of acute GVHD and need to be confirmed in large prospective studies. However, it would be somewhat unreasonable to conclude that B cells may play an important role in the development of acute GVHD on the basis of these findings alone. First, counting the number of B cells should be performed along with measurement of the BAFF or APRIL levels because higher serum BAFF levels may reflect relative B lymphopenia depending on the period after transplantation. Furthermore, comparison of the findings for patients with and without acute GVHD for the same period after allogeneic SCT is essential for investigating the relationship between B cells and acute GVHD. BAFF has a complex, dichotomous role in immunity, which is mediated by the differential regulation of T cell- and B cell-dependent immune responses [3]. BAFF, a critical regulator of normal B cell homeostasis in mice and humans, also promotes T cell activation and survival [4]; these T cells play a pivotal role in acute GVHD pathogenesis. However, recent studies have also demonstrated the negative regulatory role of BAFF in T cell function [3, 5]. Walters et al. found that BAFF-transgenic mice accepted islet allografts and showed delayed rejection of skin allografts. On the basis of these results, they proposed that BAFF plays an anti-inflammatory role in T cell biology by promoting the expansion of regulatory T cells [3]. We studied the potential protective effect of BAFF against acute GVHD during the peritransplantation period in the setting of allogeneic SCT in humans [5]. Thus, further experimental and clinical studies are needed to elucidate the role of B cells in the development of acute GVHD and gain more insight into the pathogenesis of acute GVHD by studying the association of BAFF with B cells and T cells.