Arora, Mukta

Abstract Standard initial therapy of chronic graft vs. host disease (cGVHD) with glucocorticoids results in suboptimal response. Safety and feasibility of therapy with ofatumumab (1000 mg IV on days 0 and 14) and prednisone (1 mg/kg/day) was previously established in our phase I trial (n = 12). We now report the mature results of the phase II expansion of the trial (n = 38). The overall NIH severity of cGVHD was moderate (63%) or severe (37%) with 74% of all patients affected by the overlap subtype of cGVHD and 82% by prior acute cGVHD. The observed 6 month clinician-reported and 2014 NIH-defined overall response rates (ORR = complete + partial response [CR/PR]) of 62.5% (1-sided lower 90% confidence interval=51.5%) were not superior to pre-specified historic benchmark of 60%. Post-hoc comparison of 6 month NIH response suggested benefit compared to more contemporaneous NIH-based benchmark of 48.6% with frontline sirolimus/prednisone (CTN 0801 trial). Baseline cGVHD features (organ involvement, severity, initial immune suppression agents) were not significantly associated with 6-month ORR. The median time to initiation of second-line therapy was 5.4 months (range 0.9-15.1 months). Failure-free survival (FFS) was 64.2% (95% CI 46.5-77.4%) at 6 months and 53.1% (95% CI 35.8-67.7%) at 12 months, whereas FFS with CR/PR at 12 months of 33.5% exceeded a benchmark of 15% in post-hoc analysis, and was associated with greater success in steroid discontinuation by 24 months (odds ratio 8 (95% CI 1.21-52.7). This single-arm phase II trial demonstrated acceptable safety and potential efficacy of the upfront use of ofatumumab in combination with prednisone in cGVHD. This trial was registered at www.clinicaltrials.gov as #NCT01680965.

Abstract Introduction: Amphiregulin (AREG) is an epidermal growth factor receptor (EGFR) ligand that can restore integrity to damaged intestinal mucosa in murine models of acute graft-versus-host disease (aGVHD). We previously described AREG as a circulating biomarker of late-onset aGVHD, but its relevance combined with clinical risk factors has not yet been tested in a large cohort of patients with aGVHD occurring prior to day 100 post-transplant. We therefore tested samples from two aGVHD first-line treatment trials, Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0302 and 0802, and identified a clinically relevant threshold level of circulating AREG at aGVHD onset. We then investigated whether incorporating AREG into the refined Minnesota Risk Score could further risk-stratify patients. Patients and Methods: Blood samples were obtained at the onset of systemic aGVHD treatment within BMT CTN 0302 (serum) and BMT CTN 0802 (plasma). All patients with response data and samples for analysis from both trials were included (N=251). We determined the association of AREG with clinical outcomes, including risk stratification by the refined Minnesota criteria, day 28 complete/partial response (CR/PR) to first-line therapy, 2-year overall survival (OS) and 6-month and 2-year non-relapse mortality (NRM). We investigated the effect of AREG on clinical endpoints per a doubling in the value of AREG, defined a clinically relevant threshold level in the AREG values using two-fold cross-validation, and confirmed the clinical relevance of this cut-point in independent samples (N=92) from pooled from drawn from the Chronic GVHD Consortium and the Mount Sinai Acute GVHD International Consortium (MAGIC). Results: In patients enrolled in BMT CTN 0302/0802, AREG levels were 1.7-fold higher in patients with Minnesota high-risk (HR) compared to standard-risk (SR) aGVHD (HR median 53.4 vs SR 31 pg/ml, p<0.01). Every 2-fold increase in AREG was associated with a 33% decrease in the likelihood of day 28 CR/PR (odds ratio [OR] 0.67, p<0.01, table). Clinical factors alone, as determined by the refined Minnesota Risk Score, were associated with day 28 CR/PR (p=0.02, table). Adding AREG to the Minnesota Risk Score could further risk-stratify patients. Minnesota SR patients with elevated AREG ≥ 33 pg/mL showed a 59% lower odds of day 28 CR/PR than SR patients with low AREG (OR 0.41, p=0.02). Patients with Minnesota HR aGVHD with AREG ≥ 33 pg/mL had the worst outcomes, with an 82% lower odds of day 28 CR/PR in comparison to HR with low AREG (OR 0.18, p<0.01). High AREG was associated with worse OS and NRM in both Minnesota SR (hazard ratios 2-year OS 2.3, p<0.01 and 6 month NRM 2.95, p=0.01, respectively) and HR patients (hazard ratios 2-year OS 3.35, p<0.01 and 6-month NRM 9.38, p<0.01 respectively, figure). Finally, in independent samples from the Chronic GVHD Consortium/MAGIC we confirmed that high AREG was associated with worse day 28 CR/PR (55.2% vs. 79.4%, p=0.02) and significantly worse 6-month survival after the onset of aGVHD (57.1% vs. 82.5%, p=0.01). Conclusion: AREG is elevated in patients with poor aGVHD outcomes and adds to the accuracy of risk stratification when combined with the refined Minnesota Risk Score. AREG ≥33 pg/mL at aGVHD onset is associated with lower day 28 CR/PR and higher mortality in samples from 4 multicenter cohorts. The mechanism of elevated circulating AREG in severe aGVHD is not yet known, although we hypothesize the degree of AREG elevation reflects the intensity of immune-mediated tissue injury resulting in AREG release. With accumulating evidence of altered EGFR ligands in aGVHD, further investigation into epithelial repair pathways involving AREG may lead to new adjunctive therapies to overcome poor steroid response in high-risk aGVHD. Disclosures Holtan: Incyte: Other: One-time advisory board member. Khera: Novartis: Consultancy. Lee: Mallinckrodt: Honoraria; Amgen: Other: One-time advisory board member; Bristol-Myers-Squibb: Other: One-time advisory board member; Kadmon: Other: One-time advisory board member. Chen: Immudex: Research Funding. Arora: Takeda Oncology: Consultancy. Flowers: Pharmacyclics: Consultancy. Cutler: Pfizer: Consultancy; Kite: Consultancy; Incyte: Consultancy; Bristol-Myers Squibb: Consultancy; Pharmacyclics: Consultancy; Astellas: Consultancy. Jagasia: Janssen: Consultancy, Research Funding; Therakos: Consultancy, Research Funding; Mallinckrodt: Consultancy. Hexner: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Levine: Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees. MacMillan: Magenta Therapeutics: Research Funding.

PURPOSE There is no consensus on the best choice of an alternative donor (umbilical cord blood [UCB], haploidentical, one-antigen mismatched [7/8]–bone marrow [BM], or 7/8-peripheral blood [PB]) for hematopoietic cell transplantation (HCT) for patients lacking an HLA-matched related or unrelated donor. METHODS We report composite end points of graft-versus-host disease (GVHD)–free relapse-free survival (GRFS) and chronic GVHD (cGVHD)–free relapse-free survival (CRFS) in 2,198 patients who underwent UCB (n = 838), haploidentical (n = 159), 7/8-BM (n = 241), or 7/8-PB (n = 960) HCT. All groups were divided by myeloablative conditioning (MAC) intensity or reduced intensity conditioning (RIC), except haploidentical group in which most received RIC. To account for multiple testing, P < .0071 in multivariable analysis and P < .00025 in direct pairwise comparisons were considered statistically significant. RESULTS In multivariable analysis, haploidentical group had the best GRFS, CRFS, and overall survival (OS). In the direct pairwise comparison of other groups, among those who received MAC, there was no difference in GRFS or CRFS among UCB, 7/8-BM, and 7/8-PB with serotherapy (alemtuzumab or antithymocyte globulin) groups. In contrast, the 7/8-PB without serotherapy group had significantly inferior GRFS, higher cGVHD, and a trend toward worse CRFS (hazard ratio [HR], 1.38; 95% CI, 1.13 to 1.69; P = .002) than the 7/8-BM group and higher cGVHD and trend toward inferior CRFS (HR, 1.36; 95% CI, 1.14 to 1.63; P = .0006) than the UCB group. Among patients with RIC, all groups had significantly inferior GRFS and CRFS compared with the haploidentical group. CONCLUSION Recognizing the limitations of a registry retrospective analysis and the possibility of center selection bias in choosing donors, our data support the use of UCB, 7/8-BM, or 7/8-PB (with serotherapy) grafts for patients undergoing MAC HCT and haploidentical grafts for patients undergoing RIC HCT. The haploidentical group had the best GRFS, CRFS, and OS of all groups.

Abstract Background: Conflicting data exists on whether T-cell dose of allogeneic stem cell product influences transplant outcome. Methods: Using CIBMTR database, we identified 2,736 adult patients who underwent first allogeneic HCT for AML/ALL/MDS (between 2008-2014) with PBSC from an HLA-identical sibling donor (MSD) or 8/8-matched unrelated donor (MUD). This cohort excluded ex-vivo and in-vivo T-cell depletion transplants. Correlative analysis was done between CD3 cell dose and risk of GVHD, relapse, NRM, DFS and OS. Results: T-cell dose cutoff values were identified (using maximum likelihood estimation method) to identify differential risk of aGVHD (grade II-IV) in both MSD and MUD groups. A CD3 cell dose cutoff of 14 x107 cells/kg identified MSD/low CD3 (n=223) and MSD/high CD3 (n=1214) and a dose of 15 x107 cells/kg identified MUD/low CD3 (n=197) and MUD/high CD3 (n=1102). CD3 and CD34 cell doses did not correlate. Median CD3 cell dose were 11 and 29 in the MSD/Low and MSD/High groups, respectively, and 10 and 28 in the MUD/Low and MUD/High groups, respectively. In MSD/high CD3, cumulative incidence (CI) of D100-aGVHD (GII-IV) was higher (33% vs 25%) (P value =0.009) without influence on engraftment, severe aGVHD (GIII-IV), cGVHD, NRM, relapse, DFS, or OS. In MUD/high CD3, CI of D100-aGVHD (GII-IV) was higher (50% vs 40%) (p value=0.009) and so was the CI of 6-month-cGVHD (31% vs23%) (p value = 0.02) with no influence on engraftment, severe aGVHD, 2-year-GVHD, NRM, relapse, DFS, or OS. On multivariate analysis, both MSD (table 1) and MUD (table 2) groups failed to show a correlation between CD3 cell dose and aGVHD (GII-IV) (p value =0.1 and 0.07), cGVHD (p value=0.8 and 0.3) for both groups respectviely. Sub-analysis of CD4, CD8 and CD4/CD8 ratio failed to identify cutoff values predictive of transplant outcome. Using log-rank test, the sample size was, however, suboptimal to identify difference (with 80% power at 0.05% significant level) at these cutoff cell dose. Conclusion: In this relatively small registry study, the CD3 cell dose in the PBSCT product did not influence the risk of acute or chronic GVHD or other transplant outcome when using matched sibling or 8/8 unrelated donors. Disclosures Saad: Actinium: Consultancy. Lamb:Incysus Therapeutics Inc.: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Abstract 3094 The HLA class II DRB1 antigen DR15 is an important immunobiologic marker in immune mediated marrow failure states. DR15 has also been reported in small studies to be associated with favorable outcomes (reduction in acute GVHD and reduced relapse resulting in improved overall survival) after allogeneic hematopoietic cell transplant. To elucidate the impact of DR15 on major transplant outcomes, we conducted a retrospective study of 2, 891 recipients of first marrow or mobilized peripheral blood stem cell transplantation for the treatment of acute myeloid leukemia (n=1038), acute lymphoblastic leukemia (n=700), chronic myeloid leukemia (n=948), or myelodysplastic syndrome (n=205) between 1990–2008 and reported to the CIBMTR registry. Selection was confined to HLA-identical sibling transplantation to avoid HLA-disparity as a driving force for observed differences. All patients received conventional myeloablative conditioning, T-replete grafts and cyclosporine plus methotrexate- based GVHD prophylaxis. DNA-based HLA typing allowed categorization of 732 (25.3%) patients as positive and 2159 (74.7%) patients as negative for DRB1*15 :01 or *15 :02 (DR15). There were no significant differences in baseline characteristics between the HLA DR15-positive and -negative groups. In univariate analysis, HLA-DR15 status had no impact on neutrophil engraftment, acute graft-versus-host disease (GvHD) II-IV or III-IV, chronic GVHD, treatment related mortality, relapse, disease-free survival or overall survival. Confining the univariate analysis to myeloid malignancies did not alter these findings. Multivariate analysis models were constructed with DR15 status forced into the models in all steps of model building and the final model regardless of its statistical significance. Other variables tested included: donor/recipient age, CMV status, disease, disease stage, graft source, Karnofsky score, race and year of transplant. Variables that attained a p-value ≤0.05 were held in the final multivariate models. In multivariate analysis, DR15 status showed no significant difference in the primary outcomes of acute GVHD II-IV or III-IV, chronic GVHD, overall survival, or relapse. In conclusion, DR15 status had no impact on major HLA-matched sibling donor hematopoietic cell transplantation outcomes in this large and homogenous cohort of leukemia and MDS patients. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 897 Recent changes in allogeneic hematopoietic cell transplantation (HCT) including increased use of reduced-intensity conditioning, peripheral blood cells as the graft source (PB) and unrelated donors (URD) warrant re-evaluation of risk factors for acute graft-versus-host disease (aGVHD) and its impact on overall survival (OS). Risk factors for these outcomes were analyzed using more recent data from CIBMTR observational database. Methods: The cohort included adult patients ≥ 20 y transplanted from an HLA-identical sibling (SD) (n=3191) or URD (N=2370) for acute myelogenous leukemia (AML), acute lymphoid leukemia (ALL), chronic myeloid leukemia (CML), or myelodsyplastic syndrome (MDS) using a T-cell replete graft from 1999–2005. Six groups were created to evaluate the impact of conditioning [(myeloablative (MA) and reduced-intensity or non-myeloablative (RIC)], total-body irradiation (TBI) and graft source [(bone marrow (BM) or PB] as follows: MA+TBI+PB (group 1), MA+TBI+BM (group 2) MA+ no TBI+PB (group 3), MA+ no-TBI+BM (group 4), RIC+PB (group 5) and RIC+BM (group 6). Separate analyses were performed for SD and URD. IBMTR grade was used to classify aGVHD. A p-value of ≤ 0.01 was considered significant. Results: Among the SD cohort, the probability of aGVHD grade B-D and grade C-D at 100 days was 39% (95% CI, 37–41%) and 16% (95% CI, 14–17%). In multivariate analyses, non-TBI based MA regimens with a BM graft (group 4), RIC conditioning with PB (group 5) and tacrolimus plus methotrexate aGVHD prophylaxis were associated with lower odds ratio of grade B-D aGVHD (Table 1). The probability of OS was 51% (95% CI: 49–53%) at 3 y and 46% (95% CI: 44–49%) at 5 y. In multivariate analyses, grade B-D aGVHD was associated with a higher risk of death. Other independent risk factors for OS are shown in Table 2. Among the URD cohort, the probability of aGVHD grade B-D and C-D at 100 days was 59% (95%, CI 57–61%) and 32% (30-34%). In multivariate analysis, BM with MA (TBI and no TBI) or RIC conditioning (groups 2, 4 and 6) were significantly associated with lower odds ratio of grade B-D aGVHD (Table 1). Other independent risk factors included a diagnosis of CML. HCT from a 7/8 HLA-mismatched URD showed a trend for higher incidence of aGVHD (p=0.02). The probability of OS was 38% (95% CI: 35–40%) at 3 y and 33% (95% CI: 31–35%) at 5 y. In multivariate analysis, grade B-D aGVHD was associated with a higher mortality. Table 2 shows other independent risk factors for OS. Conclusion: Intensity of the conditioning regimen, TBI and the graft source has a combined effect on the risk of aGVHD. In both SD and URD cohorts, BM with MA, non-TBI regimens were associated with lower risk of aGVHD. In URD cohort, BM after a RIC also was associated with a reduced risk of aGVHD. Modulation of these risk factors is needed to reduce acute GVHD incidence and death after allogeneic transplantation. Disclosures: No relevant conflicts of interest to declare.

Abstract Introduction Older patients undergoing allogeneic stem cell transplantation may experience a higher degree of morbidity and limitations from transplant related complications. Chronic graft-versus –host disease (GVHD) causes a significant reduction in patients’ quality of life (QOL), physical functioning, and functional status. However, it is not known if moderate to severe chronic GVHD has a worse impact on QOL, or survival outcomes for older patients. Methods We analyzed data of patients with moderate or severe chronic GVHD (N=522, 1661 follow-up visits, a total of 2,183 visits) from the Chronic GVHD Consortium, a prospective observational multicenter cohort. Moderate or severe chronic GVHD was defined by the National Institutes of Health global severity score at the time of enrollment. We examined the relationship between age group (adolescent and young adult “AYA” 18-40, “middle-aged” 41-59, and “older” ≥ 60 years) and clinical manifestations of chronic GVHD, patient-reported outcomes, functional status, non-relapse mortality and overall survival. Clinical manifestations of chronic GVHD were determined by the clinician-reported individual organ scores. Patient-reported outcomes included (1) QOL as measured by Functional Assessment of Cancer Therapy Bone Marrow Transplantation (FACT-BMT) and the Medical Outcome Short-Form Health Survey (SF-36) (2) chronic GVHD symptom burden as measured by the Lee Symptom Scale; and (3) physical fitness as measured by the Human Activity Profile (HAP). Functional status was assessed using the 2-minute walk test (2MWT). Because of multiple testing, p-values <0.01 were considered significant. Results There were 115 (22%) AYA, 279 (53%) middle-aged and 128 (25%) older patients with moderate (58%) or severe (42%) chronic GVHD included. At study enrollment, older patients (≥60) were similar to younger patients in sex, time from transplant (median 12 months), prior acute GVHD, percentage of severe chronic GVHD, and current co-morbidity scores but differed in disease distribution and conditioning regimen intensity. At enrollment, in unadjusted analyses using all available data, older patients had similar rates and severity of global and organ-specific manifestations of chronic GVHD compared to younger patients, except for genital involvement, which was more prevalent and severe in AYA patients. Although older patients reported worse physical functioning [SF-36 Physical Functioning (p=0.01)], shorter 2MWT (p=0.002), and lower HAP scores (p=0.001) than AYA and middle-aged patients suggesting they have more physical limitations, older patients had better QOL [FACT-BMT (p=0.01)] scores compared to middle-aged patients and similar to AYA patients. Older patients had better psychological [Lee Psychological Scale (p<0.001), SF-36 Mental Health (p=0.01)] and emotional functioning [FACT-Emotional Well-being (p=0.001)] and less pain [SF-36 Bodily Pain (p=0.006)] than AYA and middle-aged patients but similar chronic GVHD symptom burden [Lee Symptom Scale (p=0.47)]. In multivariable linear mixed models utilizing all visit data and adjusted for clinical covariates, older patients had QOL (FACT-BMT) that was comparable to AYA patients (estimate -0.04, p=0.99) and better than middle-aged patients (estimate 5.7, p=0.004), while the SF36 physical and mental component scores and symptom burden were not different between the groups. Non-relapse mortality and overall survival were similar between the age groups in unadjusted analyses (p=0.23, p=0.17) and after adjusting for clinical covariates (p=0.17, p=0.15) in Cox models. In a subgroup analysis, we found that there were no differences in overall and organ-specific chronic GVHD manifestations, QOL and survival between patients in the 60-64 (n=73), 65-70 (n=39), and >70 (n=16) age groups, except for more moderate-severe skin involvement in the 65-70 year olds. Conclusion Despite higher physical and functional limitations, older patients with moderate or severe chronic GVHD have preserved QOL, comparable disease manifestations and symptom burden, and similar overall survival and non-relapse mortality when compared to younger patients. Therefore we did not find evidence that older age itself is associated with worse QOL or survival in patients with moderate or severe chronic GVHD. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 1940 Background: Chronic graft-versus-host disease (GVHD) is a significant source of morbidity, mortality, impaired patient-reported quality of life (QOL), greater symptom burden, and prolonged duration of immune suppressive therapy following allogeneic hematopoietic cell transplantation (HCT). While available data support the adverse prognosis of overlap subtype of chronic GVHD, the relative importance of site of gastrointestinal (GI) and type of hepatic involvement is not known. Methods: We analyzed prospectively acquired observational cohort data to examine whether the site of GI involvement (esophageal, upper GI, lower GI) and type of hepatic laboratory test abnormality (bilirubin, alkaline phosphatase (AP), alanine aminotransferase (ALT) elevation over the upper limit of normal based on study site-specific laboratory reference ranges) among chronic GVHD-affected patients are associated with overall survival (OS) and non-relapse mortality (NRM), symptoms (Lee Symptom Scale), and quality of life (QOL) per SF-36 and FACT-BMT instruments. Results: This analysis included 567 individual subjects with baseline and 1548 follow up visits. The majority were incident cases (59%), adults (98%), and predominantly White/Non-Hispanic. Median time from HCT to cohort enrollment was 11.9 months (range 3–294 months). Overall NIH chronic GVHD severity was mild in 10%, moderate in 52%, and severe in 38% at enrollment. Prior acute GVHD was noted in 66%, KPS < 80% in 17%, and platelet count at chronic GVHD onset of < 100 K/uL in 23%. At enrollment, GI involvement was seen in 40% (upper GI 20%, esophagus 16%, lower GI 13%), and liver involvement was seen in 52% (AP 38%, ALT 38%, bilirubin 10%). Time from transplant to cGVHD onset was not different for patients with or without GI involvement or hepatic involvement. In multivariate analysis utilizing data from enrollment visits only and adjusting for patient and transplant variables, lower GI involvement (HR 1.7, p=0.03) and elevated bilirubin (HR 2.36, p=0.001) were associated with OS; both were also associated with NRM. In multivariable analysis using all visits (time-dependent covariates), GI score greater than zero (HR 1.7, p=0.01) and elevated bilirubin (HR 3.7, p<0.001) were associated with OS; results were similar for NRM. Separate models were constructed to examine the relationship of severity of GI and hepatic involvement (0–3 severity score per NIH consensus) and mortality: Increasing lower GI severity at enrollment was significantly associated with non-relapse mortality, with progressively increasing HR for greater severity levels (lower GI score 2/3 vs. 0: HR 5.5, 95% CI 2.3–13.1, p = 0.0001). Increasing bilirubin was also associated with NRM (bilirubin score 2/3 vs. 0: HR 3.3, 95% CI 1.3–8.4, p=0.01). A similar association was observed for bilirubin elevation and NRM in the time-dependent model (bilirubin 2/3 vs. 0: HR 8.9, 95% CI 3.3–24, p < 0.0001). When analyzing all visits, any esophageal involvement and GI score greater than zero were associated with both symptoms and QOL while elevated bilirubin was associated with QOL. We found no consistent evidence that upper GI involvement, AP, ALT, or NIH liver score add prognostic value for survival, overall symptom burden, or quality of life. Conclusion: These data support important differences in patient-reported outcomes according to GI and hepatic involvement among chronic GVHD affected patients, and identify those with elevated bilirubin or higher GI score at any time, or lower GI involvement at cohort enrollment, as patients at greater risk for mortality under current treatment approaches. Disclosures: No relevant conflicts of interest to declare.

Key PointsHigh-circulating AREG (≥33 pg/mL) reclassifies additional patients into HR categories and further refines the Minnesota aGVHD risk score. Patients with aGVHD and AREG ≥33 pg/mL have lower rates of steroid response, higher NRM, and poorer OS.

Key Points Compared with parous female sibling donors, male URDs confer more aGVHD in all patients and more cGVHD in females. There was no difference in survival, relapse, or transplant mortality between recipients of parous female sibling or male URD grafts.