Sclerotic chronic graft vs. host disease (cGVHD) still has a large impact on morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). We performed the first prospective study to test whether sequential therapy of the anti-CD20 antibody rituximab followed by 6 months treatment with tyrosine kinase inhibitor nilotinib is a favorable treatment strategy for patients with sclerotic cGVHD. Twenty-nine patients were included, 24 were available for analysis. We observed objective responses in 71% of patients (two patients CR, 15 patients PR). Moreover, two out of five patients suffering from severe ulcerations showed complete resolution of ulcers. Observed responses lasted until the end of study follow-up. The majority of responding patients could reduce daily corticosteroid dose with more than 50%. Furthermore, CD5+ B-cells are significantly lower (p = 0.007) in responding patients at baseline, proposing a new biomarker predictive for response. In conclusion, sequential treatment of rituximab followed by nilotinib associates with a very high response rate in this difficult to treat patient population. CD5+ B-cells could assist in guiding treatment choices and might be a first step toward more personalized cGVHD treatment. This trial was registered at the Dutch clinical trial registry as NTR1222.
Chronic graft vs. host disease (cGVHD) is a devastating complication affecting approximately 60% of patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Despite novel low GVHD platforms [1,2,3,4,5] and more individualized ATG applications , the number of patients suffering from cGVHD is still rising. Major reasons are increased use of allo-HSCT in older recipients, improvements made in treatments post allo-HSCT prolonging survival, and the increased administration of pre-emptive or prophylactic donor lymphocyte infusions . A major hurdle for the treatment of cGVHD remains the poor understanding of the diverse pathophysiology of cGVHD complicating treatment decisions and the development of new therapeutic strategies. Generally recommended first-line therapy consists of glucocorticoid therapy combined with calcineurin inhibition. Affected patients require long term use of these immunosuppressive drugs associated with the development of severe side effects and hampered quality of life. Options for second-line therapy are numerous but consensus on the most favorable choice of agent(s) has not been reached. B-cell depletion has shown to have a beneficial effect on fibrosis with reported response rates between 66% and 86% [8,9,10,11,12]. Tyrosine kinase inhibition (TKI) with imatinib also showed response rates ranging from 22% to 79% [13,14,15,16]. In patients with cGVHD with cutaneous sclerosis response rates to both monotherapy with rituximab (RTX) and monotherapy with imatinib seem to be worse, 27% and 26%, respectively . Also, monotherapy with either B-cell depletion or TKI almost never leads to a complete resolution of cGVHD symptoms. We speculate that combining B-cell depletion with RTX and TKI with nilotinib would result in more profound and durable responses in patients with sclerotic cGVHD. We chose nilotinib due to higher cellular uptake and possible decreased cellular efflux compared to imatinib [18, 19]. Both drugs block the intracellular tyrosine kinase c-abl, a downstream target of pro-fibrotic TGF-β signaling, and both drugs are inhibitors of the PDGF receptor that can directly and indirectly, through activation of Src kinases and c-abl, promote extracellular matrix formation . In this light, we performed a prospective phase II clinical study in which we treated 29 patients with the combination of RTX and nilotinib. Also patients with ulcerative skin lesions, known to barely respond to monotherapies, were included. In addition, we tested whether our previously identified biomarker , which suggests responsiveness to RTX treatment, can also predict responsiveness to the combination therapy, as many published biomarkers for responsiveness to cGVHD treatment could often not be confirmed in independent prospective cohorts .
The clinical trial (amendment to NTR1222, trial registry The Netherlands) with treatment with RTX and nilotinib was approved by the Institutional Review Board of the University Medical Center Utrecht and is in accordance with the Declaration of Helsinki. All patients gave written informed consent before enrollment.
Patients were eligible when diagnosed with cGVHD with skin localization refractory to or dependent on first-line treatment with steroids (SR-cGVHD) and/or calcineurin inhibitors and ≥18 years old. Patients were ineligible to participate with WHO performance score >2, life expectancy of <6 months, active systemic (viral) infections, treatment with RTX or TKI in the previous year, inadequate renal or liver function, low neutrophil counts (<1.5 × 109/l), low hemoglobin (<6.2 mmol/l) or low platelets (<75 × 109/l), a history of pancreatitis, a known impaired cardiac function, or were pregnant or breastfeeding.
Study visits were scheduled monthly for the duration of 13 months. At each study visit, the patients were evaluated according to 2005 NIH cGVHD consensus response criteria working group recommendations  as the study was set up before the updated response criteria from 2014 . Serial blood sampling was performed every other month. Peripheral blood mononuclear cells (PBMCs) were isolated and lymphocyte numbers were directly measured by Trucount (manufacturers protocol, BD Biosciences). PBMCs were frozen and stored in liquid nitrogen until further analysis. Plasma and serum samples were stored at −80 °C.
Evaluation of response
Complete overall response (CR) was defined as resolution of all reversible manifestations in each organ or site. Partial response (PR) was defined as an improvement of more than 50% in at least one cGVHD manifestation without progression in any other organ. Stable disease (SD) was defined by no change in the extent or severity of the disease in any organ. Deterioration of symptoms in a specific organ by a 25% increase in the scale used to measure disease manifestations related to cGVHD was termed progressive disease (PD). Patients were evaluated monthly however final response scoring took place at 13 months after start of the study. Response evaluation was based on NIH response criteria working group report from 2006 .
Treatment with RTX and nilotinib
RTX (MabThera®, F. Hoffmann-La Roche Ltd., Basel, Switzerland) was administered intravenously with 4 weekly infusions at a dose of 375 mg/m2. Approximately 1 week after the last RTX infusion, nilotinib (Tasigna®, Novartis Pharmaceuticals Corporation) was started b.i.d. 300 mg. When patients experienced side effects, nilotinib could be reduced to either b.i.d. 200 mg or q.d. 400 mg or stopped if dose reduction was not sufficient. No dose adjustments were made for grade 1 or 2 toxicity. Any toxicity should be resolved within 28 days in order to resume study drug at the reduced dose.
All flow cytometry was performed on an LSR Fortessa (BD, 4 lasers) flow cytometer and data analysis was performed using FACS Diva Software (BD Biosciences). Fluorescent labeled beads (CS&T beads, Becton Dickinson) were used to check the performance and verify optical path and stream flow of the flow cytometer. This procedure enables controlled standardized results and allows the determination of long-term drifts and incidental changes within the flow cytometer. No changes were observed which could affect the results during the study period. Antibodies used for flow cytometry: CD38-PerCP-Cy5.5, CD27-APC, IgM-BrilliantViolet421, CD1d-BrilliantViolet510, CD21-BrilliantViolet711, CD24-PE-CF594, CD10-PE-Cy7, CD70-FITC, CD43-APC, CD27-BrilliantViolet510, CD86-PE-Cy7, CD4-PerCP-Cy5.5, CD28-BrilliantViolet421, TCRγδ-PE, CD8-PE-Cy7, CD127-BrilliantViolet421, CD25-PE, CD16-BrilliantViolet510, CD56-PE-Cy7 (BD), CD3-AlexaFluor700, CD5-PE, HLA-DR-PerCP-Cy5.5, CD20-BrilliantViolet421, CD45RO-BrilliantViolet711 (BioLegend), CD19-eFluor780, FoxP3-APC (eBioscience), CCR7-APC (R&D Systems), and TCRVβ11-FITC, TCRVα24 (Beckman Coultier).
Power calculation was performed with an α value of 0.05 and a power of 80% to show a response rate of 30% in 24 patients. Statistical analyses of patient data, construction of Receiver Operating Curves (ROC), and probability of survival by means of Kaplan–Meier estimates were performed using SPSS (IBM Statistics, version 21, Amsterdam, The Netherlands). Data from flow cytometry experiments and multiplex immune assays were performed using GraphPad Prism 6 for Windows (GraphPad Software, La Jolla, CA, USA). Gaussian-distributed groups were compared using Student’s t-test. Data not normally distributed were compared using Mann–Whitney U test. Paired comparisons were calculated using Wilcoxon matched-pairs signed rank test. In all cases, a probability level of 5% (p < 0.05) was considered significant.
Study cohort and clinical response rates
We prospectively tested clinical efficacy of anti-CD20 treatment in combination with TKI in SR-cGVHD patients with skin involvement. We hypothesized this combination would have an additive beneficial effect in this patient category. Between January 2012 and November 2015, 29 adult patients with moderate or severe cGVHD were enrolled. We screened 35 patients and six patients could not be enrolled due to mainly prolonged QT interval (Fig. 1), suggesting we included a representative cohort of heavily pretreated patients (Supp. Figure 1) seen during daily clinical practice. Patient baseline characteristics are depicted in Table 1. In short, the majority of patients were male and the median age was 49 years. All patients had received several lines of treatment (range 1–5, Supp. Figure 1) before enrollment and were found to be steroid refractory. Two patients had received RTX prior to study inclusion, their last RTX doses were administered 27 and 31 months before study entry. Five patients went off study for different reasons (Fig. 1), therefore 24 patients were eligible for analysis. We observed an overall response in 71% of patients (two patients CR, 15 patients PR, 95% CI interval for ORR 51–90%). From the two patients who have been treated previously with RTX, one patient did not tolerate nilotinib and went off study before any response could be evaluated. The other had a SD after treatment with RTX and nilotinib. In order to avoid overestimation of response by early dropouts, we calculated also total response rate including patients that went off study after receiving RTX and nilotinib. Then response rate remains 69%. Only one patient showed PD and the remaining six patients showed SD. Moreover, two out of five patients suffering from severe ulcerations at baseline had a complete resolution of ulcers at the end of the treatment period. Responding patients show a significant decrease (Fig. 2, p = 0.0012) in cGVHD affected body surface area (BSA) at month 13 of the study compared to baseline. This is mostly explained by a significant reduction in non-moveable sclerosis. From month 7 onward, there was a significant difference between affected BSA in responders vs. non-responders (Fig. 2). Not only skin manifestations of cGVHD improved but we also observed responses in other affected organs, mainly oral and gastrointestinal tract, less in genital cGVHD (Fig. 3). Differences between baseline and end of study follow-up at 13 months are depicted. Interestingly, we also observed an improvement in lung cGVHD in 33% of affected patients; however, this was not our primary outcome measure and therefore lung function tests were only performed by discretion of the treating physician. No patients fulfilled response criteria at evaluation at 1 month after only receiving RTX, all showed SD.
Impact on immune-suppressive drugs
We assessed impact of objective clinical responses on usage of immune-suppressive drugs. There was no significant difference in corticosteroid use between PR + CR patients vs. SD + PD patients at baseline (data not shown). Corticosteroid dose could be tapered in responding patients (PR and CR, p = 0.0131) but not in non-responding patients (Fig. 4a). The majority (57%) of responding patients could reduce their daily prednisolone dose with >50%. Also other immunosuppressive drugs (ciclosporin and mycophenolate) could be tapered in the majority of responding patients and to a lesser extent in some patients with SD (Fig. 4b).
Side effects and dose reductions
RTX was well tolerated except for one patient who showed a neurological syndrome resembling Guillain Barre after 2 infusions and therefore went off study. The patient recovered completely without sequelae. Nilotinib in a starting dose of 300 mg b.i.d. was only tolerated by 10 patients without side effects (Supp. Figure 2). Remaining patients needed dose reductions to 200 mg b.i.d. which was well tolerated by the majority. Side effects included fatigue, nausea, pain in extremities, and prolonged QT interval on standard ECG monitoring. About 38% of patients experienced a serious adverse event (SAE) during the study (Fig. 5). We observed no neutropenia, only leukopenia grade 3 in one patient within the context of a viral infection. One patient died due to progressive osteomyelitis with multiresistant bacteria (1-year OS entire cohort 96.5%).
Prospective analysis of biomarker and prediction model
In our earlier study  on SR-cGVHD patients treated with monotherapy RTX, we identified a B-cell subset that seemed predictive of clinical response. By analyzing immune subsets (indicated panels in Methods), lower absolute number of CD20+CD5+ B-cells was the only significant predictive parameter (p-value 0.007) at baseline in responding patients (Fig. 6). This finding is consistent with the results from our earlier study . In particular, we observed no significant differences at baseline in either total B-cells, memory or naïve B-cell subsets as opposed to other reports [10, 17]. Absolute T-cell numbers in cGVHD patients were lower compared to healthy donors (n = 5) and no GVHD controls (n = 5); however, this was not significant. Responding cGVHD patients did not have significantly different T-cell numbers either at baseline or during follow-up. Also regulatory T-cells did not differ between the groups at baseline or during follow-up.
To allow upfront decision-making with our cellular biomarker on which patients might benefit most from treatment containing RTX, we constructed an ROC curve for the absolute number of CD20+CD5+ B-cells with an area under the curve (AUC) of 84.9% (p-value 0.008). With a threshold at 11 cells/µl the positive predictive value is 93.8%. In univariate logistic regression analysis on outcome response, the number of CD5+ B-cells was the only significant variable (p-value 0.004, Supp. Table 1).
We performed a prospective phase II clinical trial in SR-cGVHD patients whom we treated with a combination of RTX and nilotinib. We observed a clinical response in 71% of patients with two patients even reaching a CR. Immune suppression could be tapered in this heavily pretreated patient group. The observed responses were durable and lasted until the end of study follow-up when patients had already discontinued the study medication for 6 months. Toxicity was manageable but dose reductions for nilotinib were needed regularly. The majority of responding patients could reduce their daily corticosteroid dose with more than 50%. Interestingly, also in patients with SD immune suppression could be tapered without causing deterioration of cGVHD symptoms. Intriguingly, we found a low number of CD5+ B-cells as positive predictor for therapeutic responses in this study, as we also identified in our previous RTX-only based study . Validation of this cellular biomarker in other patient cohorts could show if this B-cell subset could identify patients with a high likelihood of response and thus provide a possibility for personalized cGVHD therapy.
Our data suggest that combining RTX with nilotinib might have two major advantages when compared to other treatments. Firstly, responses of patients with ulcerative cGVHD can be expected, as indicated by the response observed in two patients with severe ulcers. This is important since ulcerative cGVHD is considered very difficult to treat. Secondly, we found that clinical responses were durable throughout the study follow-up period and often even improving further during this period. Response rates up to 70% have also been reported with RTX monotherapy, questioning the true additive value of nilotinib in our study [8,9,10,11]. However, these favorable outcomes might be a consequence of mainly including good risk patients as evidenced by the recent observation that first-line therapy of cGVHD associates with an overall response rate of 83% . Outcomes in cGVHD with cutaneous sclerosis response rates to both monotherapy with RTX and monotherapy with imatinib have been reported to be substantially lower . In this light, our data demonstrate that also severely affected patient cohorts (76% NIH score severe) with sclerotic skin disease at a mean of 45 months after allogeneic HSCT, which is substantially longer than many other studies [8, 12] including a recent cohort reported to receive ibrutinib . Thus patients even at this late stage of disease benefit most likely substantially from combination therapy with B-cell depletion and TKI. Side effects caused by nilotinib may be a possible limitation and showed not to be less than earlier reported with the use of imatinib in cGVHD [13, 15]. The number of patients in our study did not allow for subgroup analysis and therefore we cannot comment on the possible differences in clinical outcome between patients that were treated according to the study protocol and patients that had a dose reduction because of side effects. As several patients still showed improvement of symptoms after 6 months of treatment, maintenance therapy with a TKI seems appealing. However, maintenance therapy in these patients might come at the cost of more severe side effects. Prospective clinical data are needed to obtain more information regarding optimal treatment duration.
Reproducibility of biomarkers in cGVHD is a challenge  and therefore biomarkers are currently not used in daily practice to help decide which treatment to choose. In this light, it is intriguing that we could confirm our earlier identified cellular biomarker in an independent cohort of SR-cGVHD patients. However, as the number of patients in our trial was limited, these results should be further explored in larger patient cohorts. We found the subset of B-cells that is identified by CD5 positivity to be significantly higher among non-responders to RTX and nilotinib. The optimal cutoff value was slightly different in the current cohort possibly explained by fully normalized and accredited flow cytometry measurements. The biological role of these CD5+ B-cells is still largely unknown although they are known to also produce autoreactive antibodies . In auto-immune diseases such as rheumatoid arthritis (RA), CD5 production is elevated and in ANCA + vasculitis the percentage of CD5+ B-cells can predict relapse . As cGVHD resembles auto-immune diseases in many aspects, it seems reasonable this subset is also involved in the complex pathophysiology of cGVHD.
One limitation of our study is that NIH 2005 response criteria were used as the study was initiated before 2014 and CRFs (Case Report Form) from the study did not include all necessary parameters for recalculations in line with current NIH guidelines. However, considering the rapid developments with several new promising treatment options for SR-cGVHD patients such as ruxolitinib [29, 30] and ibrutinib [26, 31], guidance on which patients might benefit from the one or other compound will be essential in order to wisely use restricted resources. Considering that prospective clinical studies comparing different compounds will be scarce and many compounds never enter phase III trials as they are no longer of great market value, utilizing a rational approach with biomarkers validated in different cohorts might provide a first rational for a personalized cGVHD therapy. We therefore propose to take the number of circulating CD20+CD5+ B-cells along in future clinical trials. Corticosteroid refractory patients with low circulating CD20+CD5+ B-cells could then be considered to be first treated with RTX and nilotinib or another TKI. In contrast, patients with high CD20+CD5+ B-cells could then immediately proceed to other possible treatment options. Unfortunately, no biomarkers have yet been identified that can predict clinical response with either ruxolitinib or ibrutinib. However, our observation that several patients not responding to RTX and nilotinib still responded to ruxolitinib  suggests that different modes of action are active during cGVHD. Future trials would benefit from an intensive biomarker monitoring, to better dissect responders from non-responders.
In summary, we provide evidence that combining RTX and nilotinib can generate long-lasting responses in severely affected patients and even allow complete resolution of ulcers as well as improvement of lung GVHD. We also show low circulating CD20+CD5+ B-cells to be a possible new biomarker to predict response. Including biomarkers into the decision on which compound is used for cGVHD treatment could be a first step toward a personalized and cost-effective cGVHD therapy.
Mielcarek M, Furlong T, O’Donnell PV, Storer BE, McCune JS, Storb R, et al. Posttransplantation cyclophosphamide for prevention of graft-versus-host disease after HLA-matched mobilized blood cell transplantation. Blood. 2016;127:1502–8.
Pasquini MC, Devine S, Mendizabal A, Baden LR, Wingard JR, Lazarus HM, et al. Comparative outcomes of donor graft CD34+ selection and immune suppressive therapy as graft-versus-host disease prophylaxis for patients with acute myeloid leukemia in complete remission undergoing HLA-matched sibling allogeneic hematopoietic cell transplantation. J Clin Oncol. 2012;30:3194–201.
Walker I, Panzarella T, Couban S, Couture F, Devins G, Elemary M, et al. Pretreatment with anti-thymocyte globulin versus no anti-thymocyte globulin in patients with haematological malignancies undergoing haemopoietic cell transplantation from unrelated donors: a randomised, controlled, open-label, phase 3, multicentre trial. Lancet Oncol. 2016;17:164–73.
Kroger N, Solano C, Wolschke C, Bandini G, Patriarca F, Pini M, et al. Antilymphocyte globulin for prevention of chronic graft-versus-host disease. N Engl J Med. 2016;374:43–53.
Finke J, Schmoor C, Bethge WA, Ottinger HD, Stelljes M, Zander AR, et al. Prognostic factors affecting outcome after allogeneic transplantation for hematological malignancies from unrelated donors: results from a randomized trial. Biol Blood Marrow Transplant. 2012;18:1716–26.
Admiraal R, Nierkens S, de Witte MA, Petersen EJ, Fleurke GJ, Verrest L, et al. Association between anti-thymocyte globulin exposure and survival outcomes in adult unrelated haemopoietic cell transplantation: a multicentre, retrospective, pharmacodynamic cohort analysis. Lancet Haematol. 2017;4:e183–e91.
Tsirigotis P, Byrne M, Schmid C, Baron F, Ciceri F, Esteve J, et al. Relapse of AML after hematopoietic stem cell transplantation: methods of monitoring and preventive strategies. A review from the ALWP of the EBMT. Bone Marrow Transplant. 2016;51:1431–8.
Cutler C, Miklos D, Kim HT, Treister N, Woo SB, Bienfang D, et al. Rituximab for steroid-refractory chronic graft-versus-host disease. Blood. 2006;108:756–62.
Kharfan-Dabaja MA, Mhaskar AR, Djulbegovic B, Cutler C, Mohty M, Kumar A. Efficacy of rituximab in the setting of steroid-refractory chronic graft-versus-host disease: a systematic review and meta-analysis. Biol Blood Marrow Transplant. 2009;15:1005–13.
van Dorp S, Resemann H, te Boome L, Pietersma F, van Baarle D, Gmelig-Meyling F, et al. The immunological phenotype of rituximab-sensitive chronic graft-versus-host disease: a phase II study. Haematologica. 2011;96:1380–4.
Canninga-van Dijk MR, van der Straaten HM, Fijnheer R, Sanders CJ, van den Tweel JG, Verdonck LF. Anti-CD20 monoclonal antibody treatment in 6 patients with therapy-refractory chronic graft-versus-host disease. Blood. 2004;104:2603–6.
Mohty M, Marchetti N, El-Cheikh J, Faucher C, Furst S, Blaise D. Rituximab as salvage therapy for refractory chronic GVHD. Bone Marrow Transplant. 2008;41:909–11.
Magro L, Mohty M, Catteau B, Coiteux V, Chevallier P, Terriou L, et al. Imatinib mesylate as salvage therapy for refractory sclerotic chronic graft-versus-host disease. Blood. 2009;114:719–22.
Magro L, Catteau B, Coiteux V, Bruno B, Jouet JP, Yakoub-Agha I. Efficacy of imatinib mesylate in the treatment of refractory sclerodermatous chronic GVHD. Bone Marrow Transplant. 2008;42:757–60.
Olivieri A, Locatelli F, Zecca M, Sanna A, Cimminiello M, Raimondi R, et al. Imatinib for refractory chronic graft-versus-host disease with fibrotic features. Blood. 2009;114:709–18.
de Masson A, Bouaziz JD, Peffault de Latour R, Wittnebel S, Ribaud P, Rubio MT, et al. Limited efficacy and tolerance of imatinib mesylate in steroid-refractory sclerodermatous chronic GVHD. Blood. 2012;120:5089–90.
Arai S, Pidala J, Pusic I, Chai X, Jaglowski S, Khera N, et al. A randomized phase II crossover study of imatinib or rituximab for cutaneous sclerosis after hematopoietic cell transplantation. Clin Cancer Res. 2015;22:319–27.
Weisberg E, Manley PW, Breitenstein W, Bruggen J, Cowan-Jacob SW, Ray A, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell. 2005;7:129–41.
Blay JY, von Mehren M. Nilotinib: a novel, selective tyrosine kinase inhibitor. Semin Oncol. 2011;38(Suppl 1):S3–9.
Beyer C, Distler JH, Distler O. Are tyrosine kinase inhibitors promising for the treatment of systemic sclerosis and other fibrotic diseases? Swiss Med Wkly. 2010;140:w13050.
Kariminia A, Holtan SG, Ivison S, Rozmus J, Hebert MJ, Martin PJ, et al. Heterogeneity of chronic graft-versus-host disease biomarkers: association with CXCL10 and CXCR3+ NK cells. Blood. 2016;127:3082–91.
Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005;11:945–56.
Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, et al. National Institutes of Health Consensus Development Project on criteria for clinical trials in chronic graft-versus-host disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant. 2015;21:389–401e1.
Pavletic SZ, Martin P, Lee SJ, Mitchell S, Jacobsohn D, Cowen EW, et al. Measuring therapeutic response in chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on criteria for clinical trials in chronic graft-versus-host disease: IV. Response Criteria Working Group report. Biol Blood Marrow Transplant. 2006;12:252–66.
Malard F, Labopin M, Yakoub-Agha I, Chantepie S, Guillaume T, Blaise D, et al. Rituximab-based first line treatment for chronic GVHD after allogeneic SCT: results of a phase 2 study. Blood. 2017;130:2186–95.
Miklos D, Cutler CS, Arora M, Waller EK, Jagasia M, Pusic I, et al. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy. Blood. 2017;130:2243–50.
Lydyard PM, Lamour A, MacKenzie LE, Jamin C, Mageed RA, Youinou P. CD5+ B cells and the immune system. Immunol Lett. 1993;38:159–66.
Bunch DO, McGregor JG, Khandoobhai NB, Aybar LT, Burkart ME, Hu Y, et al. Decreased CD5(+) B cells in active ANCA vasculitis and relapse after rituximab. Clin J Am Soc Nephrol. 2013;8:382–91.
Zeiser R, Burchert A, Lengerke C, Verbeek M, Maas-Bauer K, Metzelder SK, et al. Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey. Leukemia. 2015;29:2062–8.
Spoerl S, Mathew NR, Bscheider M, Schmitt-Graeff A, Chen S, Mueller T, et al. Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease. Blood. 2014;123:3832–42.
Dubovsky JA, Flynn R, Du J, Harrington BK, Zhong Y, Kaffenberger B, et al. Ibrutinib treatment ameliorates murine chronic graft-versus-host disease. J Clin Invest. 2014;124:4867–76.
We thank the Multiplex Core Facility UMC, Utrecht, for performing multiplex immunoassays; the Flow Cytometry Core Facility UMC, Utrecht, for support in performing FACS assays; Novartis and Roche for kindly providing study medication. This work was further supported in part by grants from the Dutch Cancer Society to LvdW: KWF-UU 2011-5250 and to JK KWF-UU 2010-4669, 2013-6426, 2014-6790, and 2015-7601.
LtB, EM, SvD, and JK designed the study. LvdW and MS performed the experiments. LvdW analyzed and interpreted the data. LvdW and JK wrote the manuscript. LtB, IN, SvD, MvD, and EM interpreted the data. LtB, IN, MS, RR, EP, MdW, NdJ, MB, BB, and EM provided the clinical data and commented on the manuscript. JK supervised the study.
Conflict of interest
JK is cofounder and chief scientific officer of GADETA. His work is partly supported by a grant from Novartis; however, Novartis had no part in the design, analysis, or interpretation of the data or the writing of the manuscript.
Electronic supplementary material
About this article
Cite this article
van der Wagen, L., te Boome, L., Schiffler, M. et al. Prospective evaluation of sequential treatment of sclerotic chronic graft versus host disease with rituximab and nilotinib. Bone Marrow Transplant 53, 1255–1262 (2018). https://doi.org/10.1038/s41409-018-0158-9
Expert Review of Hematology (2020)
New Approaches for the Treatment of Chronic Graft-Versus-Host Disease: Current Status and Future Directions
Frontiers in Immunology (2020)
The concurrent administration of imatinib with extracorporeal photopheresis leads to complete and durable responses in patients with refractory sclerotic type chronic graft-versus-host disease
Current Research in Translational Medicine (2020)
Bone Marrow Transplantation (2019)
Journal of Immunology Research (2019)