Abatacept as salvage therapy in chronic graft-versus-host disease-a retrospective analysis.

The immunomodulatory fusion protein abatacept has recently been investigated for the treatment of steroid-refractory chronic graft-versus-host disease (cGvHD) in a phase 1 clinical trial. We analyzed the safety and efficacy of abatacept for cGvHD therapy in a retrospective study with 15 patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) and received abatacept for cGvHD with a median age of 49 years. Grading was performed as part of the clinical routine according to the National Institute of Health's (NIH) consensus criteria at initiation of abatacept and 1, 3, 6, 9 and 12 months thereafter. The median time of follow-up was 191 days (range 55-393 days). Best overall response rate (ORR) was 40%. In particular, patients with bronchiolitis obliterans syndrome showed significant clinical improvement and durable responses following abatacept treatment with a response rate of 89% based on improvement in lung severity score (n = 6) or stabilized lung function (n = 4) or both (n = 3). Infectious complications CTCAE °III or higher were observed in 3/15 patients. None of the patients relapsed from the underlying malignancy. Thus, abatacept appears to be a promising treatment option for cGvHD, in particular for patients with lung involvement. However, further evaluation within a phase 2 clinical trial is required.

Cyclophosphamide for salvage therapy of chronic graft-versus-host disease: a retrospective analysis.

We retrospectively analyzed the safety and efficacy of cyclophosphamide (cyclo) for salvage treatment of chronic graft-versus-host disease (cGvHD) and cGvHD-associated (glomerulo-)nephritis at our center between 01/2010 and 11/2019. We identified 13 patients (pts) receiving cyclo for treatment of moderate (3/13) and severe (6/13) steroid-refractory cGvHD, cGvHD-associated (glomerulo-)nephritis (3/13), or vasculitis-like CNS manifestation of cGvHD (1/13). Cyclo was started on median day 509 (range 42-8193) after cGvHD onset; the median duration of application was 153 days (range 14-486) with 2/13 currently continuing treatment. The National Institute of Health organ grading and the intensity of immunosuppression (IS) were assessed at cyclo start and repeated after 3, 6, and 12 months. Response assessment was stopped at the start of any additional new IS. The median time of follow up was 407 days (range 86-1534). Best response was 1/13 CR, 6/13 PR, 4/13 SD, 1/13 MR, and 1/13 PD (ORR 54%). Significant and durable response was observed especially in cGvHD-associated (glomerulo-)nephritis (3/3). Infectious complications > CTCAE grade III were observed in 3/12 pts. During cyclo therapy, none of the pts suffered from recurrence of underlying malignancy. Overall, cyclo was relatively well tolerated and showed responses in heavily pretreated patients but requires further evaluation within clinical trials.

IL6-receptor antibody tocilizumab as salvage therapy in severe chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation: a retrospective analysis.

Chronic graft-versus-host disease (cGvHD) remains the most relevant factor affecting survival after allogeneic hematopoietic stem cell transplantation (alloHSCT). Besides corticosteroids (and ibrutinib in the USA), there is no established therapy for cGvHD. Tocilizumab, a humanized IgG1 IL6-receptor antibody, has shown efficacy in acute GvHD and cGvHD. We retrospectively analyzed the efficacy and safety of tocilizumab for the treatment of advanced cGvHD. Eleven patients with severe steroid refractory cGvHD (median age 49; range 21-62 years) that received at least two prior lines of therapy for cGvHD (range 2-8 regimens) were treated with tocilizumab (q4w, dosage 8 mg/kg IV) with a median number of 15 cycles (range 2-31). NIH consensus criteria grading for cGvHD were recorded prior to tocilizumab administration and after 3, 6, and 12 months of therapy. All patients received additional concomitant immunosuppression (IS) but no new IS within the last 4 weeks before start of tocilizumab and response assessment was terminated before start of any new IS. The median number of days between alloHSCT and initiation of tocilizumab therapy was 1033 days. Organs involved at initiation of tocilizumab therapy were skin (100%, all grade 3), eyes (82%), fascia (82%), mouth (64%), lungs (55%), and genitals (18%). Overall, 7/10 patients (70%) showed partial remission, 2/10 patients (20%) showed progressive cGvHD, 1/10 patient (10%) showed mixed response, and 1 patient died due to sepsis before first response assessment 1.5 months after initiation of treatment. Four patients required subsequent new immunosuppressive treatment. Two patients developed bacterial sepsis, one of whom died. The overall survival and relapse-free survival were 82% with an average follow-up of 22 months (range 1.5-52 months). Tocilizumab seems a promising treatment option in advanced cGvHD but further evaluation within a phase II trial is required.

Long-term follow-up of rituximab in treatment of chronic graft-versus-host disease-single center experience.

Rituximab was recently described also as first-line therapy of chronic graft-versus-host disease (cGvHD). We retrospectively analyzed the efficacy and safety of all patients receiving rituximab for treatment of cGvHD between 2005 and 2016 at the Regensburg University transplant center with a median follow-up after rituximab therapy of 2.8 years. Responses of 29 allogeneic stem cell-transplanted patients (median age 49) with previous failure of response to steroids including one patient after donor lymphocyte infusion were assessed. Three months after rituximab application, the overall response rate was 31% (7% complete (n = 2) and 24% partial remission (n = 7)). At 12 months, overall survival was 72% (n = 21) and failure-free survival was 24% (n = 7). We further analyzed associations of rituximab response with clinical characteristics showing a higher response rate in steroid-dependent cGvHD patients (89% of 9 responding compared to steroid refractory patients (11% responding)). However, this difference was not statistically significant. Seven patients (24%) (including four lethal infectious complications) developed serious infections requiring hospitalization within 1-9 months after rituximab therapy exclusively in patients failing to respond to rituximab. In conclusion, rituximab appears to be an effective treatment of cGvHD especially in steroid dependent patients, but identification of biomarker predicting response will be crucial to avoid long-term infectious morbidity and mortality in non-responders.

Risk Factors and Outcome of Chronic Graft-versus-Host Disease after Allogeneic Stem Cell Transplantation-Results from a Single-Center Observational Study.

Chronic graft versus host disease (cGVHD) is the most frequent long-term complication after allogeneic stem cell transplantation (allo-SCT) and results in impaired quality of life and increased long-term morbidity and mortality. We analyzed 243 patients with cGVHD, documented according to the 2005 revised National Institutes of Health consensus criteria, to identify risk factors for the occurrence of cGVHD and outcomes for the patients with cGVHD. Patients without evidence of cGVHD (n = 147) were used as controls. Performing univariate and multivariate Cox regression analyses, we identified prior acute GVHD grades III or IV (hazard ratio [HR], 2.01; P = .005), use of peripheral blood stem cell graft (HR, 2.10; P = .03), and HLA-mismatched allo-SCT from unrelated donor (HR, 1.57; P = .02) as independent risk factors for cGVHD. Performing Kaplan-Meier analyses, progressive compared with de novo and quiescent onset of cGVHD and a platelet count of less than 100/nL compared with more than 100/nL at the time of cGVHD onset were associated with a significantly increased cumulative incidence of transplantation-related mortality (TRM) and significantly decreased overall survival. Furthermore, we found a significantly higher incidence of TRM in patients with severe cGVHD compared with patients without cGVHD (58% versus 11%, P < .0001). However, in subgroup analysis, patients with severe cGVHD and involvement of the lung, liver, or gastrointestinal (GI) tract had a 6.5-fold significantly higher incidence of TRM (72%), whereas patients with severe cGVHD lacking lung, liver, or GI involvement had only a 2.8-fold significantly higher incidence of TRM (31%) compared with patients without cGVHD (11%; P < .0001 and P = .03). Patients without lung, liver, or GI involvement did not have a significantly different TRM compared with patients with moderate cGVHD (31% versus 25%, P = .52). In conclusion, we confirm prior known risk factors for the occurrence of cGVHD and subsequent mortality and we provide evidence that the presence of lung, liver, or GI involvement in patients with severe cGVHD defines a subgroup with high mortality after allo-SCT; however, in the absence of these risk factors, the outcome appears not to be impaired compared with moderate cGVHD.

Verification of the new grading scale for ocular chronic graft-versus-host disease developed by the German-Austrian-Swiss consensus conference on chronic GVHD.

The purpose of the study was to validate a recently proposed new grading system for ocular manifestations of chronic graft-versus-host disease (cGVHD). Diagnosis of cGVHD was based on the NIH consensus criteria. In addition, a grading scale was applied, which has been developed by the German-Austrian-Swiss Consensus Conference on Clinical Practice in cGVHD. Sixty-six patients (male n = 46, female n = 20, mean age 48 years) with ocular cGVHD were included. Application of the proposed Consensus Conference grading revealed inflammatory activity in all patients with mild (33 %), moderate (44 %), or severe inflammation (23 %). Clinical scoring by the NIH scoring system showed that 6 % of patients had mild symptoms; 59 % of patients had moderate dry eye symptoms partially affecting activities of daily living, without vision impairment; and 35 % of patients had severe dry eye symptoms significantly affecting daily activities. Clinical characterization and grading by the Consensus Conference grading scale revealed that ocular cGVHD (1) frequently leads to severe ocular surface disease based on impaired function of the lacrimal glands and involvement of cornea, conjunctiva, and lids; (2) is mostly associated with ongoing inflammatory activity; (3) often leads to functional impairment and reduced quality of life; and (4) is associated with an increased risk for severe, sight-threatening complications.

The lung function score and its components as predictors of overall survival and chronic graft-vs-host disease after allogeneic stem cell transplantation.

AIM: To retrospectively assess if the modified lung function score (LFS) and/or its components, forced expiratory volume within the first second (FEV1) and diffusion capacity for carbon monoxide corrected for hemoglobin level (cDLCO), predict overall survival (OS) and chronic graft-vs-host-disease (cGvHD). METHODS: We evaluated 241 patients receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT) at the University of Regensburg Transplant Center between June 1998 and July 2005 in relation to their LFS, FEV1 and cDLCO, before and after HSCT. RESULTS: Decreased OS after allo-HSCT was related to decreased pre-transplantation values of FEV1<60% (P=0.040), cDLCO<50% of predicted value (P=0.025), and LFS≥III (P=0.037). It was also related to decreased FEV1 at 3 and 12 months after HSCT (P<0.001 and P=0.001, respectively) and increased LFS at 3 and 12 months after HSCT (P=.028 and P=0.002, respectively), but not to changes of cDLCO. A higher incidence of cGvHD was related to decreased FEV1 at 6, 12, and 18 months (P=0.069, P=0.054, and P=0.009, respectively) and increased LFS at 12 months (P=0.002), but not to changes in cDLCO. CONCLUSIONS: OS was related to both LFS and FEV1, but cGvHD had a stronger relation to FEV1 than to cDLCO or LFS. FEV1 alone offered more information on the outcome after allo-HSCT than LFS or cDLCO, suggesting limited value of LFS for the patients' assessment after allo-HSCT.

Metagenomic analysis of the stool microbiome in patients receiving allogeneic stem cell transplantation: loss of diversity is associated with use of systemic antibiotics and more pronounced in gastrointestinal graft-versus-host disease.

Next-generation sequencing of the hypervariable V3 region of the 16s rRNA gene isolated from serial stool specimens collected from 31 patients receiving allogeneic stem cell transplantation (SCT) was performed to elucidate variations in the composition of the intestinal microbiome in the course of allogeneic SCT. Metagenomic analysis was complemented by strain-specific enterococcal PCR and indirect assessment of bacterial load by liquid chromatography-tandem mass spectrometry of urinary indoxyl sulfate. At the time of admission, patients showed a predominance of commensal bacteria. After transplantation, a relative shift toward enterococci was observed, which was more pronounced under antibiotic prophylaxis and treatment of neutropenic infections. The shift was particularly prominent in patients that developed subsequently or suffered from active gastrointestinal (GI) graft-versus-host disease (GVHD). The mean proportion of enterococci in post-transplant stool specimens was 21% in patients who did not develop GI GVHD as compared with 46% in those that subsequently developed GI GVHD and 74% at the time of active GVHD. Enterococcal PCR confirmed predominance of Enterococcus faecium or both E. faecium and Enterococcus faecalis in these specimens. As a consequence of the loss of bacterial diversity, mean urinary indoxyl sulfate levels dropped from 42.5 ± 11 µmol/L to 11.8 ± 2.8 µmol/L in all post-transplant samples and to 3.5 ± 3 µmol/L in samples from patients with active GVHD. Our study reveals major microbiome shifts in the course of allogeneic SCT that occur in the period of antibiotic treatment but are more prominent in association with GI GVHD. Our data indicate early microbiome shifts and a loss of diversity of the intestinal microbiome that may affect intestinal inflammation in the setting of allogeneic SCT.

Tryptophan catabolism is associated with acute GVHD after human allogeneic stem cell transplantation and indicates activation of indoleamine 2,3-dioxygenase.

Induction of indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme in tryptophan degradation along the kynurenine pathway, acts as a potent immunoregulatory loop. To address its role in human allogeneic stem cell transplantation, we measured major tryptophan metabolites, such as quinolinic acid and kynurenine, in serial urine specimens from 51 patients by liquid chromatography-tandem mass spectrometry. Samples were collected between admission and day 90 after transplantation, and metabolite levels were correlated with early clinical events and outcome. In selected patients, IDO gene expression was assessed by quantitative RT-PCR in intestinal biopsies. Surviving patients had significantly lower metabolite levels on days 28, 42, and 90, respectively, compared with patients dying of GVHD and associated complications (n = 10). Kynurenine levels were directly correlated with severity and clinical course of GVHD: Mean urinary quinolinic acid levels were 4.5 ± 0.3 µmol/mmol creatinine in the absence of acute GVHD, 8.0 ± 1.1 µmol/mmol creatinine for GVHD grade 1 or 2, and 13.5 ± 2.7 µmol/mmol creatinine for GVHD grade 3 or 4 (P < .001), respectively. GVHD-dependent induction of IDO was further suggested by increased expression of IDO mRNA in intestinal biopsies from patients with severe GVHD. Our data indicate reactive release of kynurenines in GVHD-associated inflammation.

Primary vaccination in adult patients after allogeneic hematopoietic stem cell transplantation - A single center retrospective efficacy analysis.

Allogeneic hematopoietic stem cell transplantation (alloHSCT) results in a loss of humoral immunity and subsequent risk for severe infections. Thus, re-vaccination is required but may fail due to incomplete immune reconstitution. We retrospectively analyzed predictors of immune response to primary vaccination applied according to the EBMT (European Blood and Marrow Transplantation Group) recommendations. Serologic response to vaccination against diphtheria (D), tetanus (T), Bordetella pertussis (aP) and Haemophilus influenzae (Hib) (administrated as combined DTaP-Hib-IPV vaccination) was studied in 84 alloHSCT patients transplanted between 2008 and 2015 (age at alloHSCT: 18.6-70.6 years). All patients with a relapse-free survival of ≥9 months, at least 3 consecutive vaccinations and absence of intravenous immunoglobulin administration within 3 months before and after vaccination met the primary inclusion criteria. Additionally, immunological response to a pneumococcal conjugate vaccine was analyzed in a subgroup of 67 patients. Patients' characteristics at the time of first vaccination were recorded. Responses were measured as vaccine-specific antibody titers. Regarding DTaP-Hib-IPV vaccination, 89.3% (n = 75) of all patients achieved protective titers to at least 3 of the 4 vaccine components and were thus considered responders. 10.7% (n = 9) of the patients were classified as non-responders with positive immune response to less than 3 components. Highest response was observed for Hib (97.4%), tetanus (95.2%) and pneumococcal vaccination (83.6%) while only 68.3% responded to vaccination against Bordetella pertussis. Significant risk factors for failure of vaccination response included low B cell counts (p < 0.001; cut-off: 0.05 B cells/nl) and low IgG levels (p = 0.026; mean IgG of responders 816 mg/dl vs. 475 mg/dl of non-responders). Further, a trend was observed that prior cGvHD impairs vaccination response as 88.9% of the non-responders but only 54.7% of the responders had prior cGvHD (p = 0.073). The results demonstrate, that the currently proposed vaccination strategy leads to seroprotection in the majority of alloHSCT patients.

Potential Role of the PD-1/PD-L1 Axis in the Immune Regulation of Chronic GVHD.

BACKGROUND: Antibodies blocking the PD-1/PD-L1 axis have been shown to have substantial antitumor effects also in the treatment of Hodgkin's lymphoma (HL) relapsing after conventional chemotherapy or even autologous hematopoietic stem cell transplantation (autoHSCT). In the case of allogeneic HSCT (alloHSCT), this treatment bears the risk of inducing graft-versus-host disease (GVHD). So far, only a small number of patients who developed acute GVHD after PD-1 antibody administration are described in the literature. CASE REPORTS: We herein report the cases of 2 HL patients after alloHSCT who both responded well to the therapy; however, 1 patient developed chronic GVHD (cGVHD) within 3 days of administration of nivolumab. This patient already had a history of cGVHD and interestingly showed manifestations at the very same sites. The other patient never showed any signs of cGVHD, even with the administration of 13 cycles of anti-PD-1 therapy and large doses of donor lymphocytes. CONCLUSION: The rapid reappearance of cGVHD after blockade of PD-1 implies an important role of PD-1/PD-L1 in peripheral immune tolerance in cGVHD after alloHSCT and warrants further investigation.

Total nodal irradiation in patients with severe treatment-refractory chronic graft-versus-host disease after allogeneic stem cell transplantation: Response rates and immunomodulatory effects.

BACKGROUND AND PURPOSE: The use of total nodal irradiation (TNI) has been reported as an immunomodulatory therapy for different diseases including chronic graft-versus-host disease (cGVHD). MATERIAL AND METHODS: We retrospectively analyzed 13 patients with treatment-refractory cGVHD receiving TNI with 1×1Gy from 2001 to 2014. In 10 of 13 patients immunomodulatory effects of TNI were measured. RESULTS: At time of TNI all patients had severe cGVHD (involving the skin: n=12), fascia (n=6), oral mucosa (n=8), eye (n=8), and lung (n=5). Nine of 13 patients had corticosteroid-refractory cGVHD. In 7 of 13 patients (54%) a partial response (PR) could be achieved. In 3 patients (23%) cGVHD manifestations remained stable, 2 patients progressed. One patient was not evaluable due to follow-up <1 month. At 3 months after TNI, best responses could be achieved in skin, and oral involvement including steroid sparing activity. TNI was well tolerated with adverse effects limited to reversible thrombocytopenia and neutropenia. Immunomodulatory effects on peripheral blood cells could be demonstrated including an increase of CD4+ T cells in the group of responders. CONCLUSIONS: TNI represents an effective immunomodulating therapy in treatment-refractory cGVHD.