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.

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

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

Phase I Clinical Trial Evaluating Abatacept in Patient with Steroid-Refractory Chronic Graft Versus Host Disease

Introduction: Chronic graft versus host disease (cGVHD) remains a major source of morbidity and mortality following allogeneic transplantation. While corticosteroids remain first line therapy for cGVHD, they are associated with significant toxicity, and a substantial proportion of patients fail to completely respond. Treatments for steroid-refractory cGVHD are limited. While the pathophysiology of chronic GVHD is complex, activated T cells play a critical role, driven by allo-antigen stimulation. As such, inhibition of T cell activation via blockade of co-stimulation has potential as a therapeutic target in cGVHD. Abatacept is a recombinant fusion protein consisting of the extracellular domain of human CTLA-4 and a fragment of the Fc domain of human IgG1 that has been modified to prevent complement fixation and antibody-dependent cellular cytotoxicity. Abatacept is the first drug in a class of agents termed "selective co-stimulation modulators." The CTLA-4 moiety of Abatacept binds specifically to CD80 and CD86 and down-modulates the CD28-mediated co-stimulation of T cells. We conducted a phase I clinical trial was conducted to evaluate the safety, clinical and immune effects of Abatacept in patients with steroid-refractory cGVHD. Methods: The study followed a 3+3 design with two escalating doses of Abatacept to determine the maximum tolerated dose (MTD): 3 mg/kg and 10 mg/kg. Dose-limiting toxicities (DLTs) were defined as Grade 3 or 4 toxicities judged to be probably or definitely related to Abatacept. Infection was not considered a DLT. Abatacept was administered for a total of 6 doses. Doses 1-3 were administered at two-week intervals. One month following Dose 3, Abatacept was given at four-week intervals for three doses (Doses 4-6). Inclusion criteria included recipients of allogeneic bone marrow or stem cell transplantation with myeloablative or reduced intensity conditioning, with cGVHD defined by NIH consensus criteria. Patients must have had treatment with ≥ 0.5 mg/kg/day of prednisone for at least 4 weeks. Patients with active malignant disease relapse or other active malignancy and patients with uncontrolled infection were excluded. Peripheral blood was drawn prior to each dose of Abatacept and following completion of therapy to assess the effect of treatment on circulating T cells. PD-1 expression on circulating T cells, and T cell expression of interferon gamma versus IL-10 was assessed by multichannel FACS analysis. Results: 17 subjects were treated. Three patients were treated at a dose of 3 mg/kg without DLT. Three evaluable patients completed treatment on cohort 2, at a dose of 10mg/kg without DLT. A forth participant withdrew consent following one dose of treatment and therefore is not evaluable. Ten patients were treated on an expansion cohort at a dose of 10mg/kg. We observed one grade 4 pulmonary infection, and three grade 3 pulmonary infections which resolved. Other Abatacept related adverse events included grade 2 gastritis (n=1), grade 2 pain (n=1), and grade 1 diarrhea (n=2), fatigue (n=2), rash (n=1), and skin pain (n=1). Of the 16 evaluable patients, 7 (44%) achieved a clinical partial response as defined by improvement of two disease systems based on the 2011 NIH consensus criteria. Abatacept resulted in a 51.3% reduction in prednisone usage in clinical responders with a mean baseline dose of 27mg compared to a mean dose of 14mg 1 month following the 6th dose of Abatacept (p = 0.01). PD-1 expression on circulating CD4+ and CD8+ T cells increased from a mean of 3.4% and 2.7% respectively at baseline to a mean of 8.9% and 7.6% respectively at one month following the 6thdose of Abatacept in clinical responders (n=3; p<0.05). In contrast, no change in T cell expression of PD-1 was observed in non-responders. A shift from Th1 to Th2 cytokine secretion was observed in clinical responders, with a mean 2.8 fold decrease in interferon gamma and a mean 2.5 fold increase in IL-10 secretion by circulating T cell populations (n=4). Conclusion: Abatacept is well-tolerated in the treatment of steroid-refractory cGVHD. Abatacept resulted in the improvement in NIH cGVHD scores in 44% of patients with steroid-refractory GVHD with a significant decrease in prednisone dose. An increase in PD-1 expression and a skewing toward Th2 cytokines was observed in clinical responders. Based on this promising data, a phase II trial is being initiated. Disclosures Soiffer: GentiumSpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Arnason:Gilead: Consultancy. Avigan:Astex: Research Funding; DCPrime: Research Funding. Rosenblatt:Astex: Research Funding; BMS: Research Funding; DCPrime: Research Funding.

Coping with moderate to severe chronic graft-versus-host disease (cGVHD) among hematopoietic stem cell transplant (HCT) survivors: A qualitative analysis.

257 Background: HCT survivors with moderate to severe cGVHD experience substantial symptoms, which negatively impact their quality of life. However, data are lacking on how patients cope with their illness. We aimed to achieve a deeper understanding of patients’ illness perception and how they cope with their cGVHD. Methods: We conducted qualitative interviews with 14 HCT survivors with moderate to severe cGVHD as defined by NIH Consensus Criteria. We used a semi-structured interview guide to elicit patients’ illness perception and coping strategies. Two raters coded interviews independently. We used content analysis to identify themes. Results: Patients highlighted two key themes in their efforts to cope with what they perceived as a “full time job” dealing with their cGVHD: personal transformation and empowerment. With respect to transformation, patients expressed the importance of (1) changing the goal of care from recovery to coping with a chronic condition, and (2) seeking new sources of support and connectedness specifically from other patients and caregivers affected by cGVHD. With respect to empowerment, patients sought more information and understanding about cGVHD in order to gain more control over their symptoms and illness experiences. Patients also noted the importance of knowledge and control in coping with their disease. By seeking knowledge and a greater understanding of their disease, patients explained that they felt that they were gaining control and feeling more empowered. Through the lens of change, it is clear that all patients sought an evolution in their care perspective by increasing care motivation, creating active support webs, and seeking further involvement in their own care. Conclusions: The diagnosis and course of cGVHD is psychologically transformative for patients. Although patients demonstrated an understanding of how they cope with the psychological and physical burden, they also expressed a wish for more education, support and a method of connecting with other HCT survivors. Future interventions should focus on enhancing patients’ coping strategies, knowledge of their illness and connections with other HCT survivors.

Prolonged Duration of Systemic Immunosuppression after Allogeneic Hematopoietic Cell Transplantation Associates with the Use of Peripheral Blood Stem Cells, Severe Grade of Chronic Gvhd, Progressive Type Onset of Chronic Gvhd, Grade 2-4 Acute Gvhd and Older Age, but Not with T-Cell Depletion or Conditioning Regimen

Background: Prolongedsystemic immunosuppression (SIS) post allogeneic hematopoietic cell transplantation (HCT) results in increased unnecessary complications. In our previous study of avascular necrosis (AVN; ASBMT 2015), one of common complications occurring after allogeneic HCT related to the use of prolonged immunosuppression including corticosteroids, we demonstrated a strong correlation between the duration of SIS and the risk of AVN. The probability of remaining on SIS was higher in the group developed AVN than those without episode of AVN (46.4% vs 11.7% at 4 years post-HCT). The question remains what are the risk factors related to prolonged SIS after allogeneic HCT. The present study attempted to evaluate potential risk factors for prolonged SIS. Methods: A retrospective review of 845 consecutive patients ≥18 years of age who underwent alloHCT at Princess Margaret Cancer Centre from 2002 to 2013 was conducted to determine the probability of SIS discontinuation considering death and relapse as competing risks. Univariate and multivariate analyses were conducted using cumulative incidence method considering competing risk to identify the risk factors for failure from SIS discontinuation. Results: Out of 845 patients, the probability of remaining on SIS, SIS discontinuation and death at 4 years is 19.6%, 30.5%, 49.9%, respectively. The median follow up duration among survivors was 3.5 years. Univariate analysis for successful SIS cessation revealed following risk factors: aGVHD grade 2-4 (p<0.001, HR 0.53), cGVHD by NIH consensus criteria (p<0.001, HR 0.52), cGVHD severity (p<0.001,HR 0.44), progressive type onset of cGVHD (p<0.001, HR 0.62), stem cell source (p<0.001,HR 0.54 for PBSC), T cell depletion (p<0.001, HR 1.42), donor type (p=0.0028, HR 1.45 for matched related donor), HLA match (p=0.0039, HR 0.30 for mismatched) and age (p<0.001, HR 0.98). Multivariate analysis confirmed that younger age (p<0.001, HR 0.97), aGVHD grade 2-4 (p<0.001, HR 0.51), progressive type of cGVHD (p<0.001, HR 0.53), cGVHD by NIH consensus criteria (p<0.001, HR 0.53), stem cell source (p<0.001, HR 0.51 for PBSC) and use of matched related donor (p<0.001, HR 1.68) were significant risk factors. ROC analysis was performed which revealed an age ≤ 50 to be a categorical risk factor for SIS discontinuation. A risk score model was generated assigning a score to each risk factor. A score of 1 was assigned to aGVHD grade 2-4, younger patient of age ≤50 years, progressive type of cGVHD, cGVHD by NIH consensus criteria, PBSC stem cell source and the use of matched related donor. Total score was calculated with risk score 0 (n=16, 2%), risk score 1 (n=55, 7%), risk score 2 (n=109, 14%), risk score 3 (n=215, 28%), risk score 4 (n=232, 30 %), risk score 5 (n=119, 16%), risk score 6 (n=14, 1%). Three risk groups were created: low (score 0-2, n=181, 21.4%), intermediate (score 3, n=216, 25.6%) and high (score 4-6, n=365, 47%). This risk score group could stratify the patients according to their success rate of SIS cessation (p<0.0001): 48.0% in low vs. 40.8% in intermediate vs. 28.5% in high risk group for SIS discontinuation rate at 4 yrs. Conclusions: Younger age, aGVHD grade 2-4, progressive type of cGVHD, cGVHD by NIH consensus criteria, peripheral stem cell source and use of matched sibling donor predicts for prolonged immunosuppression use post allogeneic transplant. Figure 1. Figure 1. Disclosures Kim: Novartis Pharmaceuticals: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding.

Incidence and Risk Factors for Vzv Infection after Allogeneic Hematopoietic Cell Transplantation in 1,045 Patients: Younger Age Less Than or Equal to 45, Occurrence of Cgvhd By NIH Consensus Criteria, and No T-Cell Depletion

Introduction: Varicella zoster (VZV) infection is a common complication post allogeneic hematopoietic stem cell transplantation (HCT) associated with significant morbidity, such as post herpetic neuralgia and secondary bacterial infection. Strategies to diminish the incidence of VZV infection include the use of prophylactic antivirals with some controversy. Our previous studies have explored risk factors associated with the incidence of VZV infection in 192 patients (Kim, Transplant Infectious Diseases, 2007). We attempted to determine the incidence of VZV infection and to explore risk factors leading to the development of VZV infection in an extended cohort of 1,045 patients receiving alloHCT. Methods: A retrospective single center study was conducted at Princess Margaret Cancer Centre, Toronto, Canada. Medical record review was performed for 1,045 consecutive patients who had undergone an alloHCT from 2001 to 2013. VZV infection was determined by clinical features and/or microbiologic determination. The incidence of VZV infection was calculated using cumulative incidence method considering death and relapse as competing risks. Univariate and multivariate analyses were conducted using EZR to identify the risk factors for VZV infection. Results: Out of 1,045 patients, 142 cases were identified with VZV infection (13.6%) with 14.4% of VZV incidence at 5 years (95% CI, 12.3-16.8%). The median days to the diagnosis of VZV post allogeneic transplantation was 231 days (range, 27-1488 days). 86.6% of patients were diagnosed as having VZV within 2 years post transplantation. 52.1% of those who developed VZV developed post-herpetic neuralgia, while 14.8% developed disseminated VZV. A univariate analysis was conducted including the following risk factors: aGVHD grade 2-4, aGVHD grade 3-4, occurrence of cGVHD, cGVHD severity by NIH consensus criteria, diagnosis (lymphoid v. others), T-cell depletion for GVHD prophylaxis, donor (related v. unrelated), HLA (matched v. mismatched) and donor type (matched related v. matched unrelated v. mismatched). Risk factors that were significant on univariate analysis were cGVHD occurrence by NIH criteria (p<0.001, HR 3.441), progressive type onset of GVHD (p=0.001, HR 1.89,), and age (p=0.006, HR 0.98,). T cell depletion (p=0.002, HR 0.67) and matched related donor (p=0.005, HR 1.86) were also significant. Multivariate analysis confirmed that age (p=0.007, HR 0.98), occurrence of cGVHD by NIH consensus criteria (p<0.001, HR 3.07), and T-cell depletion (p=0.032, HR 0.55) were significant risk factors. ROC analysis was performed which revealed an age less than or equal to 45 to be a categorical risk factor for VZV infection. A risk score model was generated assigning a score to each risk factor. A score of 1 was assigned to younger patient with age less than or equal to 45, occurrence of cGVHD by NIH consensus criteria, and no T-cell depletion. Total score was calculated with risk score 0 (n=82, 10%), risk score 1 (n=264, 31%), risk score 2 (n=334, 40%), risk score 3 (n=163, 19%)(843 patients were used for risk score analysis from 845 patients due to missing information). Three risk groups were created: low (score 0-1, n=346, 41%), intermediate (score 2, n=334, 40%) and high (score 3, n=163, 19%). This risk score group could stratify the patients according to VZV infection (p<0.0001): 5.9% in low vs. 14.3% in intermediate vs. 25.8% in high-risk group for VZV infection at 5 yrs. Conclusions: The incidence of VZV infection was substantial at 14.4% at 5 yrs. The occurrence of cGVHD by NIH consensus criteria increases the risk of VZV infection. Of interest, younger age was also associated with increasing risk of VZV infection, while T-cell depletion was protective from VZV infection. Strategies to prevent VZV infection should be considered in the high risk group of patients for VZV infection. Further study is strongly warranted to confirm these risk factors in other cohorts. Figure 1. Figure 1. Disclosures Lipton: Pfizer: Consultancy, Research Funding; Teva: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Research Funding. Kim:Novartis Pharmaceuticals: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding.

Graft-Versus-Host Disease after Haploidentical Stem Cell Transplantation in High Risk Haematological Diseases: A 10-Years Evaluation at San Raffaele Scientific Institute

Introduction Haematopoietic stem cell transplantation (HSCT) is the only curative option for patients (pts) affected by high-risk haematological diseases (HRHD). However, the availability of a match donor is still an unmet-medical need. Recently alternative donor transplantations have been broadly exploited, reaching results similar to transplants from a well match donor. Anyway, whoever the donor is, the most important complication remains Graft-versus-Host Disease (GvHD). Aim of the study We evaluated incidence, characterization, stratification, treatment, treatment response and outcome at medium and long-term follow-up for both acute (a-) and chronic (c-) GvHD in haploidentical setting. We also evaluated the impact of the NIH consensus criteria on GvHD in a routine clinical application to confirm their feasibility in daily practice and not only in clinical trials use. Methods A population of 257 pts was selected from our Institutional database on the basis of their having an HRHD with indication to allogeneic HSCT and having received a HSCT from an haploidentical family donor without exclusion. HSCT were performed between January 2004 and December 2013 at our Center. No distinction between first HSCT or subsequent one was made, all consecutive haploidentical HSCT were captured. Results Time of median follow-up was 10 months; 1-year overall-survival (OS) was 46%, with better outcome for pts transplanted in complete remission (p 0.0001) confirming disease status as the leading factor for overall outcome. Transplant related mortality was estimated to be 30% at 1 year and the leading cause of death was infections. The 6-months a-GvHD incidence was 45% (119/257) - median day of presentation 21 post HSCT (range 8-89). Late-onset a-GvHD was documented in 15 pts. Grade I GvHD was documented in 33 pts (27.7%), grade II in 44 (37%), grade III-IV in 36 (30.3%) – 6 not evaluable. Skin was the most frequently involved organ (77.3%), both as single manifestation or combined. One-hundred and five pts received a first line therapy based on high-dose prednisone (2mg/Kg) and 37/105 completely abrogated the a-GvHD. At a 3-months evaluation 46% of affected pts showed complete resolution of a-GvHD, while the mortality rate was 29%. C-GvHD affected 69/257 pts and 1-year risk of onset was 25% - median day of presentation was 139 post HSCT (range 40-809) and 36/69 pts were off immunosuppressive therapy (52.3%) at presentation. According to onset presentation 53.7% were de novo, 24.6% progressive and 18.8% quiescent GvHD. Forty-one pts (59.5%) presented at declaration with overlap features. The most frequent involved organ was skin (grade I to III), as reported in 53 pts (76.8%). Skin lesions were usually accompanied with mouth lesions (35 pts – 50.7%), liver (23 pts – 33.3%) or eyes (27 pts – 39.1%) dysfunctions. The median number of involved organs was 3 (range 1-7). Mild c-GvHD was diagnosed in 10 pts (14.5%), who received topical therapy. Fifty-nine pts – diagnosed with moderate (32, 46.4%) or severe (27, 39.1%) - received a systemic treatment for c-GvHD: prednisone 1 mg/Kg alone or 0,5 mg/kg plus mTOR- or calcineurin-inhibitor for pts that were not likely to tolerate high dose steroid due to comorbidity (namely active infections, diabetes, cardiovascular diseases). At a 12-months evaluation the overall response was 48% (complete resolution 25%, partial resolution 23%), while the mortality rate was 36%. The Landmark analysis of OS at 3 months after HSCT shows that a-GvHD affected pts had a worse outcome (p= 0,068), on the contrary the Landmark analysis of OS at 18 months shows that c-GvHD did not associate with a worse outcome (p ns) but the follow up is still short. Confirming previous reports, overlap c-GvHD was related to worse survival in comparison with classic c-GvHD (p 0.0098). Conclusion Haploidentical HSCT is a valid and feasible option for pts in need of a transplant. GvHD is manageable after haploidentical HSCT, as in full matched setting. Better knowledge and insight in a/c-GvHD are providing advance in improving pts outcome. The NIH-consensus criteria are manageable in daily clinical practice and able to translate in a tailored approach to GvHD with benefit on general outcome. Further advance in the development of specific biomarkers for GvHD will provide additional crucial information for management, diagnosis and prognostication in GvHD. Figure 1 Figure 1. Disclosures Bonini: MolMed S.p.A.: Consultancy. Bordignon:MolMed: Employment.

Low Incidence Of Severe Cgvhd and Late NRM In a Phase II Trial Of Thymoglobulin®, Tacrolimus and Sirolimus For Gvhd Prevention

Introduction Chronic graft-versus-host disease (cGVHD) is a major factor determining long term outcome and quality of life following allogeneic hematopoietic cell transplantation (AHSCT). In fact, cGVHD is the leading cause of late non-relapse mortality (NRM) and morbidity after AHSCT. The rates of severe cGVHD using NIH consensus criteria reported in the literature are 15-38%. Effective regimens are needed to reduce the severity of cGVHD and improve NRM. We analyzed and updated the long term outcomes of our phase 2 trial evaluating the efficacy of intermediate dose rabbit anti-thymocyte globulin (Thymo) in combination with tacrolimus and sirolimus for the prevention of acute and chronic GVHD after unrelated donor transplantation. Methods In a Phase II trial, 47 adult patients (pts) underwent AHSCT from unrelated donors using Thymo, tacrolimus, and sirolimus for GVHD prophylaxis. Thymo was given as follows: 0.5 mg/kg day -3, 1.5mg/kg day -2, and 2.5mg/kg day -1. Chronic GVHD was measured using NIH consensus criteria. Results Twenty-two pts received 8/8 and 25 received 7/8 HLA matched unrelated grafts. Thirteen pts received a reduced intensity preparative regimen, while 34 pts received a full intensity regimen. The median follow-up duration was 45.2 months (95% CI 37.7-48.8), with minimum follow up of 30 months. At 4 years of follow up, the cumulative incidence of NIH severe cGVHD a, was 6.4 % (95% CI 1.6-15.9), and overall cumulative incidence of cGVHD was 48.9% (95% CI 33.6-62.6). Of 20 pts who are alive and disease free, only 4 pts continue to need systemic immune suppression at the last follow up. At 4 years of follow-up, the cumulative incidence of NRM and disease relapse were 27.7% (95% CI 15.7- 41.0) and 30.0% (95% CI 17.5- 43.6), respectively. There has been one non relapse death beyond 12 months and none after 18 months of follow up. Only one pt died from cGVHD and bronchiolitis obliterans, while two other pts had minimal symptoms from bronchiolitis obliterans. Progression free survival (PFS) and overall survival (OS) at 2 years were 50% (95% CI 35-64) and 56% (95% CI 42-70). Median OS is 33.9 months [95% CI (9.8 -*) *the upper limit of the CI was not calculated due to the pattern of censoring] All patients were censored after 40 months, so PFS and OS could not be calculated at 48 months. The median karnofsky performance status at 2 years was 90%. Conclusion At long term follow up, the combination of Thymoglobulin, Tacrolimus, and Sirolimus was associated with low incidence of severe cGVHD, low incidence of late NRM, and good performance status. Further validation of these results in randomized phase III trials is needed. Disclosures: Al-Kadhimi: Genzyme: Research Funding. Off Label Use: The use of Thymoglobulin® for GVHD prevention.