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.

The optimal schedule of pneumococcal vaccination after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains controversial. The objective of this study was to investigate the immunogenicity of a 5-dose pneumococcal vaccination schedule in adult allo-HSCT recipients with and without immunosuppressive therapy.In this prospective cohort study, allo-HSCT recipients received four doses of the 13-valent pneumococcal conjugate vaccine (PCV13) and one dose of the 23-valent pneumococcal polysaccharide vaccine (PPSV23) starting 4-6 months after allo-HSCT.

Chronic GVHD (cGVHD) complicating allo-SCT commonly presents as sclerotic skin changes resembling systemic sclerosis (SSc), suggesting a common pathophysiological pathway. Damage to capillaries is considered an early event in the pathogenesis of SSc, and is associated with characteristic nailfold capillary abnormalities. Whether such nailfold capillary abnormalities occur in sclerodermatous cGVHD is unknown. Nailfold videocapillaroscopy (NVC) was used to evaluate capillary morphology, density and loop dimensions in 14 patients with sclerodermatous cGVHD, 14 sex-and age-matched SSc patients, and 14 healthy controls. It was shown that none of the cGVHD patients and controls, whereas all SSc patients showed severe capillary abnormalities. cGVHD patients and controls showed no differences in capillary density (9.05 vs 9.16 loops/mm, respectively, P ¼ 0.84), and capillary loop dimensions (total loop width 44.36 vs 45.56 mm, respectively, P ¼ 0.84). Compared with cGVHD patients, SSc patients had a reduced capillary density (9.05 vs 5.25 loops/mm, respectively, Po0.001), and an increase in capillary loop dimensions (total loop width 44.36 vs 99.97 mm, respectively, P ¼ o0.001). In conclusion sclerodermatous cGVHD patients do not show the characteristic microvascular abnormalities seen in SSc, suggesting that capillary damage does not contribute to the pathophysiology of sclerodermatous cGVHD, and making NVC unsuitable for early identification.

Introduction Chronic Graft Versus Host Disease (cGVHD) has a large impact on morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Therapeutic approaches for cGVHD are limited. Affected patients require long-term use of immunosuppressive drugs, mainly corticosteroids combined with a calcineurin inhibitor, which lead to severe side effects. Options for second line therapy are numerous but no consensus on the most favourable choice of agents has been reached. Both monotherapy with rituximab (Cutler, Miklos et al. 2006, Kharfan-Dabaja, Mhaskar et al. 2009, van Dorp, Resemann et al. 2011) and monotherapy with tyrosine kinase inhibition (Magro, Mohty et al. 2009, Olivieri, Locatelli et al. 2009) have shown to be effective in reducing cGVHD symptoms. Materials and Methods We performed a prospective study to test whether the sequential therapy of the anti-CD20 antibody rituximab followed by a 6 month treatment period with nilotinib, a tyrosine kinase inhibitor, is a favorable treatment strategy for patients with sclerotic cGVHD (EudraCT nr 2008-004125-42). All patients were evaluated monthly according to NIH cGVHD consensus response criteria working group recommendations from 2005. Serial blood sampling was performed every other month. Results We included 29 patients, 5 patients went offstudy (1 with side effects rituximab, 2 with gastro-intestinal side effects nilotinib, 1 patient had progression of M. Hodgkin, 1 patient due to viral encephalitis with cognitive impairment), 24 are available for analysis. Baseline characteristics are depicted in table 1. We observed a response in 71% (2 patients CR, 15 patients PR). Only 1 patient showed progressive disease (PD) and the remaining 6 patients showed stable disease (SD). Moreover, 2 out of 5 patients who suffered from severe ulcerations at the start of the study had a complete resolution of ulcers at the end of the treatment period. Responding patients show a significant decrease in cGVHD affected body surface area (Figure 1) mostly explained by a significant reduction in nonmoveable sclerosis. Patients with a (partial) response also show a clinically relevant decrease in self attributed severity of cGVHD. On a scale of 10 points their self-attributed cGVHD severity decreased in the PD+SD group with a mean of 0,3 points whilst in the PR+CR group there was a mean decrease of 2,4 points. Fifty percent of responding patients could taper >50% of their daily prednisolone dose at the end of the study period. Other immunosuppressive drugs (ciclosporin, MMF) could also be tapered. Rituximab was well tolerated except for 1 patient who showed a neurological syndrome resembling Guillain Barre after 2 infusions and therefor went offstudy. Nilotinib was dosed 300mg b.i.d. however only 9 patients tolerated this dose without side effects. For the remaining patients the dose was decreased to 200mg b.i.d. which was well tolerated for the majority. Most encountered side effects included fatigue, nausea, pain in extremities and prolonged QT-interval on standard ECG monitoring. Conclusions The combination of B-cell depletion and tyrosine kinase inhibition provides a new and interesting alternative treatment option for this difficult and heavily pretreated patient category. Approximately 70% of patients achieve a (partial) response with a decrease of sclerosis, an improved quality of life and a significant reduction in the use of corticosteroids. Two patients reached a complete resolution of all cGVHD related symptoms which is seldom achieved. How to prospectively designate which patients will benefit from this treatment strategy is currently under investigation. Figure 1 Percentage of body surface area (BSA) affected by cGVHD during the study period. From month 7 onwards there was a significant difference between PD+SD patients and PR+CR patients (t-test corrected for multiple testing by means of Sidak-Bonferroni method). Comparing start and end of the study PR+CR patients show a significant reduction in BSA affected by cGVHD (paired Wilcoxon matched pairs signed rank test). Mean and s.e.m. are depicted. BSA: Body Surface Area, CR: complete response, PD: progressive disease, PR: partial response, RTX: rituximab, SD: stable disease. Figure 1. Percentage of body surface area (BSA) affected by cGVHD during the study period. From month 7 onwards there was a significant difference between PD+SD patients and PR+CR patients (t-test corrected for multiple testing by means of Sidak-Bonferroni method). Comparing start and end of the study PR+CR patients show a significant reduction in BSA affected by cGVHD (paired Wilcoxon matched pairs signed rank test). Mean and s.e.m. are depicted. BSA: Body Surface Area, CR: complete response, PD: progressive disease, PR: partial response, RTX: rituximab, SD: stable disease. Disclosures Kuball: Gadeta B.V,: Membership on an entity's Board of Directors or advisory committees.

Chronic Graft Versus Host Disease (cGVHD) affects about 60% of all patients receiving an allogeneic hematopoietic stem cell transplantation (HSCT) and surviving beyond day 100. Incidence of cGVHD is rising because of the widespread use of Peripheral Blood Stem Cells (PBSC) as stemcell source. Chronic GVHD accounts for high morbidity and mortality rates. Affected patients require long term use of immunosuppressive drugs, mainly corticosteroids, which lead to development of severe side effects. Both the manifestations of cGVHD as the side effects from immune suppressive drugs account for a decrease in quality of life when cGVHD develops. Therefor new therapeutic strategies are urgently needed. Therapeutic approaches for cGVHD are limited. Generally recommended first line therapy consists of glucocorticoid therapy combined with a calcineurin inhibitor. Options for second line therapy are numerous but no consensus on the most favourable choice of agents has been reached. However as both monotherapy with rituximab and monotherapy with tyrosine kinase inhibition have shown to be effective in reducing cGVHD symptoms . We aimed to test whether the sequential therapy of the anti CD20 antibody rituximab followed by a 6 month treatment period with the tyrosine kinase inhibitor nilotinib is a good treatment strategy for patients with sclerotic cGVHD (EudraCT nr 2008-004125-42). We treated 26 patients with a combination of 4 weekly infusions of rituximab followed by a 6 month period of treatment with nilotinib (300mg b.i.d.). Patients were evaluated monthly for 13 months and sequential blood samples and skin biopsies were analyzed. All patients gave informed consent before enrollment. 3 patients experienced severe side effects from either rituximab or nilotinib treatment and therefor were taken off study. Of the remaining 13 patients who thus far have completed the study protocol, 60% showed a (partial) response (3 patients went from NIH scoring 'severe' to 'moderate', 1 patient went from NIH scoring 'moderate' to 'no cGVHD'). There is also a significant decrease in cGVHD affected body surface area (Figure 1). Moreover, two out of four patients who suffered from severe ulcerations at the start of the study had a complete resolution of ulcers at the end of the treatment period. Patients with a (partial) response also showed a decrease in self attributed severity of cGVHD and their immunosuppressive drugs could be tapered. The sequential therapy of B-cell depletion and tyrosine kinase inhibition provides a new and interesting alternative treatment option for this difficult and heavily pretreated patient category. Table 1. Baseline characteristics of participants. Patients 26 Male sex 20 Mean age in years (range) 47,5 21-70 Primary diagnosis AML 7 Multiple myeloma 5 ALL 4 Lymphoma 4 MDS 2 CLL 1 Myeloproliferative disorder 2 aplastic anemia 1 Mean days after allo SCT (range) 1368 411-3820 Ulcerative chronic GvHD at start 5 NIH grade severity cGVHD at start severe 20 moderate 6 Figure 1. Percentage of total body surface area affected by chronic Graft versus Host Disease is plotted against time in months after start of the study. Each dot represents 1 patient. P-values are calculated by means of Wilcoxon matched-pairs signed rank test. Figure 1. Percentage of total body surface area affected by chronic Graft versus Host Disease is plotted against time in months after start of the study. Each dot represents 1 patient. P-values are calculated by means of Wilcoxon matched-pairs signed rank test. Disclosures Off Label Use: Anti CD20 antibody rituximab is used for sclerotic chronic GVHD. Tyrosine kinase inhibitor nilotinib is used for sclerotic chronic GVHD..