Ho, Vincent T.

Abstract Introduction: Relapse is the primary cause of death after reduced intensity conditioning (RIC) hematopoietic cell transplantation (HCT). Documented responses have been reported after combination chemotherapy, hypomethylating agents, donor lymphocyte infusions, and second transplants. For patients with early relapse after RIC HCT while still on immunosuppression (IS), IS taper alone may induce significant graft-versus-tumor (GVT) activity. We describe the clinical characteristics and subsequent course of 48 patients with disease recurrence that responsed to IS taper alone without any additional chemotherapy, radiation, or donor lymphocyte infusion. Methods: We reviewed medical records of all patients with frank histologic or radiographic evidence of relapse (n=477) and those with impending relapse defined by development of cytopenias with a fall in donor derived hematopoietic cell chimerism (n=87) within one year of allogeneic RIC HCT who were on IS at time of relapse between January 1, 2004 and December 31, 2013 at Dana Farber Cancer Institute/Brigham and Women's Hospital. Complete response after IS taper was defined as complete recovery of peripheral blood counts, bone marrow biopsy with absence of disease, negative radiologic imaging, or chimerism recovery to above 90 percent. Partial response was defined as improvement in disease burden in bone marrow or by imaging. Survival probabilities were calculated using the Kaplan Meier method. Results: Forty-eight patients (37 male, 11 female) who relapsed within one year of HCT responded to IS taper alone. Of these, 14 had impending relapse and 34 had frank relapse at time of IS taper. The median age of patients was 62 years at time of transplant. The most frequent indication for transplant was MDS (n=14) followed by AML (n=11), non-Hodgkin's lymphoma (n=8), CLL (n=6), Hodgkin's disease (n=4), CML (n=3) and multiple myeloma (n= 2). At time of transplant, 9 patients had standard risk disease and 39 had high risk disease. All patients except one underwent conditioning with busulfan (≤ 6.4 mg/kg) and fludarabine. Five patients had graft versus host disease (GVHD) prior to relapse. The median time to frank or impending relapse was 105 days (range 57-360) after HCT. The median interval between starting and completing IS taper was 30 days (range 0-251), but 13 patients could not come off IS completely due to GVHD. The median time to documented response after initiation of IS taper was 77 days (range 14-189). Thirty-five patients had a complete response and the remaining 13 patients had a partial response. Nine patients subsequently relapsed late after initial response to IS taper at a median time of 2.38 years (range 0.88-3.95). Forty-five of the 48 patients developed or had a flare of previous GVHD as a consequence of IS taper. Of these, 26 patients had grade II-IV acute GVHD and 19 had chronic GVHD. The median time to developing GVHD after starting IS taper was 39 days (range 7-261 days). Twenty-five patients died during follow-up (10 from GVHD, 6 from disease, 7 from infection, 1 from congestive heart failure and 1 unknown). The median follow-up time among survivors was 4 years (range 1.6, 9.4). The median overall survival (OS) time from IS taper was 4.78 years (95% CI 2.93-7.35, see figure). The 4 year overall survival was 56%. There was no difference in survival for those with frank or impending relapse. Conclusion: Immunosuppression taper alone in patients who relapse early after RIC HCT can produce durable remissions but is almost always associated with development of GVHD. Understanding the clinical, molecular and immunologic characteristics of underlying disease will allow us to better predict who will respond to this manipulation. When feasible, this strategy should be given sufficient time to allow for a GVT response to develop in order to possibly avoid the adverse effects of more aggressive therapies. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 3069 Disease relapse remains a major obstacle to the success of allogeneic hematopoietic stem cell transplantation (HSCT) for patients with hematologic malignancies (HM), and the principal cause of failure after reduced intensity conditioning HSCT. Much work has focused on identifying the risk factors for relapse and devising strategies for its prevention, but comparatively little is known about the outcome of patients who relapse and the relevant prognostic factors in this setting. We conducted a retrospective study of 1080 consecutive adult patients with HM transplanted at our institution between 2004 and 2008. 351 (33%) relapsed at a median of 4.5 months after HSCT. The 4-year post-relapse overall survival (pr-OS) was 15%, with a median post-relapse follow-up of 39 months. Significant risk factors for post-relapse mortality included shorter time to relapse, higher disease risk index1 at HSCT, myeloablative conditioning, and high HCT-CI2 at HSCT. While being on immunosuppression at the time of relapse did not significantly affect outcome in multivariable models, a history of acute or chronic graft-versus host disease (GVHD) prior to relapse conferred a higher risk for death after relapse. Based on those 5 factors and their hazard ratio for mortality in the Cox models, we constructed a simple risk score that stratified patients into 4 groups, with 4-year pr-OS ranging from 64% in patients with fewer than 3 points (13% of the cohort, among whom over one third had myeloid diseases) to 0% in those with greater than 6 points (p<0.0001) (Figure). This score performed similarly in a historical validation cohort of 276 relapsed patients who were transplanted between 1998 and 2003. An analysis of the impact of post-relapse treatment on outcome showed that immune manipulation, through either donor lymphocyte infusion or repeat HSCT, was associated with significantly better pr-OS (4-year pr-OS 28% versus 9%, p<0.0001). Even though this likely reflects in part selection bias, the difference remained significant in models that accounted for other post-relapse prognostic factors, in landmark analyses of patients who survived at least 2 months from relapse, and in patients with active GVHD at the time of relapse. The results of this study may aid with prognostication and management of patients who relapse after HSCT, as well as motivate the design of clinical trials aimed at relapse prevention or treatment in the higher-risk groups. Figure. Post-Relapse Overall Survival by risk score. Figure. Post-Relapse Overall Survival by risk score. Risk factors are: Disease Risk Index (0 points for low risk, 1 point for intermediate, 2 points for high or very high)1Time to relapse (0 points for >24 months, 1 point for 6–24 months, 2 points for 3–6 months, 3 points for <3 months)HCT-CI (0 points for index of 0–2, 1 point for index of 3+)2Myeloablative conditioning (1 point)Prior GVHD (1 point) Disclosures: No relevant conflicts of interest to declare.

Abstract Background: Chronic GVHD contributes to morbidity and mortality after allogeneic transplantation. Several phase 2 and 3 open label studies suggested that ATLG (formerly referred to as ATG-F) reduces cGVHD without impacting relapse or survival. This report describes the first prospective randomized double blind phase 3 trial to assess the effect of ATLG (Neovii) when added to tacrolimus / methotrexate prophylaxis on cGVHD free survival. Patients and Methods: This study was conducted at 27 sites in the United States and Australia. 260 patients were randomized (132 placebo, 128 ATLG). 6 patients who were randomized never received ATLG/placebo (4 placebo and 2 ATLG). Data presented include the 128 placebo and 126 ATLG patients who underwent treatment and transplant. Patients were ages 18-65 years with a diagnosis of acute myeloid (AML, 64%) or lymphoblastic (ALL, 21%) leukemia in first or subsequent complete remission or myelodysplastic syndrome (MDS, 15%) with less than 10% marrow blasts. Median age was 48 years (18-65) with 55% males. All patients received 8/8 HLA (A, B, C, DR) allele matched unrelated products (80% mobilized peripheral blood, 20% bone marrow). Myeloablative conditioning was with cyclophosphamide and total body irradiation (Cy/TBI, 27%), busulfan and cyclophosphamide (Bu/Cy, 33%), or busulfan and fludarabine (Bu/Flu, 40%). All patients received tacrolimus starting on Day -1 and standard mtx on days 1, 3, 6, and 11 for GVHD prophylaxis. Patients received ATLG or placebo on Days -3, -2, -1 at an ATLG dose of 20 mg/kg per day (60 mg/kg total). The primary endpoint of the study was moderate/severe chronic GVHD free survival. cGVHD was scored by the investigator and then confirmed or overturned by an independent adjudication committee. Secondary endpoints included engraftment, acute GVHD , moderate/severe cGVHD, non-relapse mortality, GVHD and relapse free survival (GRFS), progression free (PFS) and overall survival (OS). The impact of ATLG on immune reconstitution was assessed in 91 patients. Results: Treatment arms were balanced with respect to age, diagnosis, remission status, cytogenetics, graft source (PB or BM), CMV serostatus and conditioning regimen. Median follow up of survivors was 745 days (61, 1425). Regarding the primary endpoint, there was no difference in 2 year moderate/severe cGVHD free survival between ATLG and placebo (48 vs 44%, p = 0.57), nor was there a difference in GRFS (Table 1). Neutrophil engraftment at Day 30 was less in the ATLG arm (85% vs 95%, p=0.00001). Grade 2 or higher infusion reactions were higher in the ATLG arm (16% vs 2.3%, p=0.0001). Reactivation of CMV was similar (27% vs 31%, p=0.58). The Day 180 cumulative incidence of grades 2-4 acute GVHD was lower in the ATLG arm (23 vs 40%, p = 0.003) as was the 2-year cumulative incidence of moderate/severe cGVHD (12 vs 33%, p = 0.000006). However, both 2-year OS and PFS were lower in ATLG treated patients (58 v 76% and 47 vs 67%, respectively) due in part to a higher incidence of relapse (32 vs 19%, p=0.068). Multivariable models confirmed that ATLG was associated with inferior OS, HR 1.85 (1.1-2.9, p=.0075) and PFS, HR 1.63 (1.1-2.41, p=0.015). We then conducted an unplanned post-hoc analysis and discovered a striking influence of conditioning regimen on outcomes. There were no differences in OS or PFS between ATLG and placebo arms in patients receiving Bu/Cy or Bu/Flu but a dramatic difference in patients receiving Cy/TBI conditioning (OS, 88% vs 48% p =0.006 and PFS, 75 vs 29%, p=0.007 in placebo and ATLG arms, respectively). 91 patients (44 ATLG, 47 placebo) participated in the immune reconstitution study. ATLG treatment was associated with lower CD3, CD4, and CD8 counts at Days 30, 100, and 360, respectively. In turn lower CD3, CD4, and CD8 counts assessed as time dependent variables were all associated with inferior OS and PFS as well as higher NRM (data not shown). Conclusion: In this first ever prospective, randomized, double blind trial of ATLG added to tacrolimus /methotrexate in recipients of matched unrelated donor grafts after myeloablative conditioning, there was no significant difference in 2 year moderate/severe cGVHD free survival or GRFS. ATLG did significantly reduce grades 2-4 acute and moderate/severe chronic GVHD. However, overall survival was higher in the placebo arm, driven mainly by patients who received Cy/TBI conditioning. Further analyses are needed to understand the proper role for ATLG in HCT. Disclosures Soiffer: Juno: Membership on an entity's Board of Directors or advisory committees; Kiadis: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Porter:Genentech: Employment; Novartis: Patents & Royalties, Research Funding. Jagasia:Therakos: Consultancy. Szer:Alnylam: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ra Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ritz:Kiadis: Membership on an entity's Board of Directors or advisory committees. Glavin:Neovii Biotech: Employment. Chen:Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding.

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 Over the last decade, allogeneic HCT has been increasingly administered in the United States to adults aged 70 and older with hematologic malignancies. Allogeneic transplant outcomes were reasonable; high comorbidity and ablative conditioning regimens were associated with inferior outcomes.

Abstract Rationale The natural history of lung function in patients with bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic cell transplant is poorly characterized. Understanding the trajectory of lung function is necessary for prompt clinical recognition and treatment and also for the rational design of prospective studies. Objectives To describe the longitudinal trajectory of lung function parameters, including FEV1, in patients with BOS after hematopoietic cell transplant. Methods Subjects with BOS defined by National Institutes of Health consensus guidelines criteria from a recent multicenter prospective trial of combination treatment with fluticasone, azithromycin and montelukast and a retrospective cohort from Fred Hutchinson Cancer Research Center were included. Longitudinal change in FEV1 for each patient was calculated on the basis of available pulmonary function tests in three periods: pre-BOS, from BOS diagnosis to 6 months, and 6–18 months after diagnosis. The effect of treatment on FEV1 trajectory was analyzed by univariate and multivariate linear regression. The Kaplan-Meier method was used to estimate survival. Measurements and Main Results: The FEV1 percent predicted value at diagnosis was 46% (interquartile range, 35–57%) for trial participants and 53% (interquartile range, 41–64%) for the retrospective cohort. There was a concomitant mild reduction in FVC, as well as a marked reduction in forced expiratory flow, midexpiratory phase, at diagnosis. While there was individual heterogeneity, the overall FEV1 trajectory was characterized by a marked decline within 6 months prior to BOS diagnosis, followed by stability of FEV1 early after diagnosis and a slow rate of decline beyond 6 months. The effect of the trial medications on FEV1 trajectory after BOS diagnosis was a mean rate of change of 0.92% predicted per month (95% confidence interval, −0.53 to 2.37) compared with the retrospective cohort, but this was not statistically significant. Two-year overall survival rates were 76% and 72% for the study participants and the retrospective cohort patients, respectively. Earlier time to diagnosis after hematopoietic cell transplant and severity of FVC at diagnosis were significantly associated with reduced survival. Conclusions The FEV1 trajectory in patients with BOS after hematopoietic cell transplant in a contemporary era of management follows a predominant pattern of rapid FEV1 decline in the 6 months prior to diagnosis, followed by FEV1 stabilization after diagnosis.