ALBERT

Description: Background: The impact of prior salvage therapy with brentuximab vedotin (BV) for relapsed/ refractory Hodgkin lymphoma (HL) on long-term outcomes after reduced intensity conditioned (RIC) allogeneic hematopoietic cell transplantation (allo-HCT) is unknown. Early studies (Chen et al Biol Blood Marrow Transplant 2014; 20: 1864-1868) suggested an improved 2-year progression free survival (PFS) with BV salvage given before allo-HCT compared to patients without prior BV treatment. In the current study, we analyzed the impact of prior therapy on the incidence of chronic graft-versus-host disease (cGVHD) and other major outcomes in patients, who received an RIC allo-HCT for relapsed HL. Methods: This is a retrospective study of relapsed/refractory HL patients who had RIC allo-HCT between 2005-2014 at the Fred Hutchison Cancer Research Center. Patients were grouped according to prior history of salvage therapy with or without BV pre allo-HCT. Baseline patient characteristics are shown in the Table. Results: Of the 62 consecutive allo-HCT recipients in this study, 25 had prior therapy with BV (BV group) and 37 received other chemotherapy alone (No BV group) for relapsed HL before allo-HCT. More patients in the BV group were in complete remission at allo-HCT (Table). The 100 day acute GVHD and 5 year cGVHD incidence for the BV vs. no BV group were 58% (95% confidence intervals [CI]: 39%-78%) vs. 65% (95% CI: 50%-80%), p=0.6 and 46% (95% CI: 26%-67%) vs. 51% (95% CI: 35%-68%), p=0.66, respectively. The 5 year non-relapse mortality and relapse/ progression for the BV vs. no BV group were 8% (95% CI: 1%-19%) vs. 25% (95% CI: 11%-38%), p=0.13 and 46% (95% CI: 24%-67%) vs. 38% (95% CI: 22%-53%), p0.98. The 5 year PFS and overall survival for BV vs. no BV group were 46% (95% CI: 25%-68%) vs. 38% (95% CI: 22%-53%), p=0.44 and 78% (95% CI: 60%-95%) vs. 56% (95% CI: 40%-72%), p=0.14. The major cause of death in both groups was relapsed HL. Conclusion: With longer follow-up, similar incidences of cGVHD, PFS and OS were observed in patients who received salvage therapy for relapsed/refractory HL prior to allo-HCT with or without BV. Any potential differences in cGVHD and other major outcomes need to be tested in a larger population. Table 1. Characteristics Prior treatment with Brentuximab vedotin Yes N=25 No N=37 Median age, years (range) 27 (14-47) 32 (17-64) Disease stage at diagnosis, n (%) I II III IV 2 (8)11 (44)7 (28)5 (20) 0 (0)15 (41)12 (32)10 (27) Prior history of local radiation pre allo-HCT 20 (80) 29 (78) No. of prior lines of therapies pre allo-HCT 4 (2 - 10) 3 (2 - 7 ) Prior autologous HCT, n (%) 0 1 2 (tandem auto) 1 (4) 21 (84) 3 (12) 0 (0) 35 (96) 2 (4) Disease status at allo-HCT, n (%) Complete remission Partial remission Progressive disease 9 (36) 13 (52) 3 (12) 7 (19)20 (54)10 (27) Median interval from diagnosis to allo-HCT, months (range) 33 (10.7-222) 30.7 (5-292) Graft type, n (%) Bone Marrow Peripheral blood stem cells 9 (36) 16 (64) 15 (41) 22 (59) Donor type, n (%) Haploidentical Matched related Matched unrelated Mismatch unrelated 16 (64) 5 (20) 4 (16) 0 (0) 17 (46) 14 (38) 5 (14) 1 (2) Conditioning for allo-HCT, n (%) FLU/CY/TBI (2 Gy) FLU/TBI (2 Gy) FLU/TBI (3 Gy) TBI (2 Gy) 16 (64) 6 (24) 1 (4) 2 (8) 17 (46) 15 (40) 0 (0) 5 (14) GVHD prophylaxis, n (%) CNI/MMF/post transplant CY CNI+MMF+/- other 16 (64) 9 (36) 17 (46)20 (54) Median follow-up, months (range) 34 (4 - 99) 84 (34 - 121) Abbrev: FLU fludarabine, CY cyclophosphamide, TBI total body irradiation,CNI calcineurin inhibitor, MMF mycophenolate mofetil Disclosures Maloney: Seattle Genetics: Honoraria; Roche/Genentech: Honoraria; Janssen Scientific Affairs: Honoraria; Juno Therapeutics: Research Funding. Gopal:Gilead, Spectrum, Pfizer, Janssen, Seattle Genetics: Consultancy; Spectrum, Pfizer, BioMarin, Cephalon/Teva, Emergent/Abbott. Gilead, Janssen., Merck, Milennium, Piramal, Seattle Genetics, Giogen Idec, BMS: Research Funding; Millennium, Seattle Genetics, Sanofi-Aventis: Honoraria. Cassaday:Seattle Genetics: Research Funding; Pfizer: Research Funding. Sandmaier:Gilliad: Honoraria; ArevaMed: Honoraria; Jazz Pharmaceutical: Honoraria; Seattle Genetics: Honoraria; Abmit: Research Funding; Bellicum: Research Funding.

Description: A randomized 3-arm Phase II trial involving 208 older or medically infirm patients (pts) with hematological malignancies given unrelated HCT after minimal intensity conditioning demonstrated that adding sirolimus to tacrolimus and MMF resulted in less grades II-IV GVHD, less steroid use, and less CMV reactivation (Hematologica 2014; 99(10); 1624). Based on this trial we designed a Phase III multi-site trial comparing triple therapy with sirolimus/MMF/CSP (Arm2) to the standard immunosuppressive regimen of MMF/CSP (Arm1). The primary objective of the trial was to compare the respective incidences of grades II-IV acute GVHD. Secondary objectives included comparing non-relapse mortality, survival, and progression-free survival. Pts in both Arms received CSP 5 mg/kg bid starting on day -3 through day 96 with a taper through day 150. In the first 28 days after HCT CSP was targeted to 400 and 350ng/ml in Arm1 and Arm2, respectively and 120-360ng/ml after day 28 in both arms. Arm 1: MMF was given daily at 15 mg/kg Q8 hours until day +30, reduced to 15 mg/kg Q12 hours until day 150, then tapered through day 180. Arm 2: MMF was given daily at 15 mg/kg Q8 hours until day +30, reduced to 15 mg/kg Q12 hours until day 40, then discontinued (no taper). In addition to the MMF/CSP, sirolimus was administered starting on day -3 at 2.0 mg/day through day 150 with a target level of 3-12ng/ml, with tapering off by day 180. The target enrollment was 300 pts with a built-in interim analysis for futility. At the time of the interim analysis, 158 pts ineligible for high-dose conditioning had been enrolled (Nov. 2010 to Jan. 2016: Arm1 n=74, Arm2 n=84) Their median age was 62 (range 18-79) yrs. The median HCT comorbidity index (HCT-CI) was 3 (range 0-10). Five pts had 6 previous allogeneic HCT and 32 pts (20%) had 36 previous autologous HCT. All pts were matched for HLA-DRB1 and -DQB1 at the allele level: 8 had single allele mismatches at HLA-A, -B or -C and the remainder (n=150) were fully HLA-matched. Diagnoses included AML (n=64), MDS/MPD (n=30), NHL (n=23), MM (n=13), CLL (n=13), ALL (n=11), HL (n=2), and CML (n=2). Randomization was stratified by transplant center. Unmodified PBSC grafts contained a median of 8.0 ×106 CD34 and 2.9 × 108 CD3 cells/kg. Conditioning consisted of fludarabine 90mg/m2 and 2-3 Gy TBI. Sustained donor engraftment occurred in 99% of pts. The median follow-up of surviving pts was 24 (range, 1-65) months. Table 1 and Figures 1 and 2 summarize results. The day-100 cumulative incidences of grades II-IV acute GVHD were in Arm1: 53%, and Arm2: 25% (p=0.0001) and the grades III-IV acute GVHD were in Arm1: 8%, Arm2: 2% (p=0.04). The 1-year cumulative incidence of chronic extensive GVHD was similar between Arm1: 49%, and Arm2: 48% (p=0.94). The 1-year cumulative incidence of non-relapse mortality was lower in Arm2 (Arm1: 15% and Arm2: 5%; p=0.007), while relapse/progression was similar at 1 year for Arm1: 21%, and Arm2: 19% (p=0.86). The 1-year overall and progression-free survivals for Arm1 vs. Arm2 were: 72% vs. 85% (p=0.03), and 65% vs. 77% (p=0.08); respectively. T-cell (CD3) donor chimerism was lower in Arm 2 on day 28 (median, Arm1 85%; Arm2 80%; p=0.05) with no differences seen in granulocyte (CD33: Arm1 98%, Arm2 95%) or NK cell (CD56: Arm1 96%, Arm2 97%) donor chimerisms. In summary, the interim analysis showed that adding sirolimus to MMF and CSP not only reduced the risks of grades II-IV but also of grades III-IV acute GVHD and of non-relapse mortality without increasing the risk of relapse or progressive malignancy. Based on these findings and the significantly improved survival, the DSMB recommended the trial be closed. This triple immunosuppressive regimen should, therefore, be considered in the future as the standard of care in pts given unrelated donor grafts after minimal intensity conditioning. Disclosures Pulsipher: Novartis: Consultancy, Other: Study Steering Committee; Chimerix: Consultancy; Jazz Pharmaceutical: Consultancy; Medac: Other: Housing support for conference.

Description: Introduction: Allogeneic Hematopoietic-cell transplantation (allo-HCT) may elicit immunological graft versus-tumor effects against tumor cells. However, these immune responses can be misdirected towards normal host organs, resulting in graft-versus host disease (GVHD). Acute GVHD (aGVHD) develops after activation and maturation of antigen-presenting cells, which then leads to donor T-cell activation, expansion, and destruction of host tissue by effector cells. The programmed death (PD) pathway serves as a checkpoint to limit T-cell-mediated immune responses. Blocking the PD1 receptor results in T-cell activation, proliferation, and can induce a potent immunotherapeutic antitumor effect. In the post-allogeneic HCT setting there is concern that activating T-cells via PD1 blockade may induce GVHD (Blazar, J Immunol 2003). While there have been several cases of severe and even fatal transplant-related complications, including GVHD, when nivolumab was given for disease control prior to allo-HCT, less is known about its use in managing relapse after HCT. A few case reports suggest it may be safe (Herbeaux, ASH 2015; Angenendt, BMT 2015; Yared, BMT 2016). Methods:With IRB approval, we conducted a multicenter, retrospective analysis of lymphoma patients (pts) who received monoclonal antibodies against PD1 after allo-HCT. We contacted 10 U.S. transplant programs with the highest volumes of lymphoma pts undergoing HCT, as provided by the Center for International Bone Marrow Transplant Registry (CIBMTR), to derive an estimate of the safety and toxicity of PD1 blockade post allograft. Additional sites were surveyed based on recommendation from these initial 10 sites. Descriptive statistics were used to summarize patient characteristics and clinical outcomes. Response assessments were defined according to revised Lugano criteria (Cheson, 2014). GVHD stage/grade was recorded according to Consensus scoring severity index. PD1 and PDL1 immunohistochemical (IHC) stains were performed on 2 pts' liver biopsies treated at University of Colorado (CU). Results:We surveyed 23 sites with 21 replies to date. 8 sites reported no experience using anti-PD1 after allo-HCT. 13 sites identified 27 lymphoma pts (26 classical Hodgkin lymphoma) who received a monoclonal antibody against PD1 for relapsed disease after allo-HCT (24 nivolumab, 3 pembrolizumab). Table 1 highlights patient characteristics prior to treatment with anti-PD1. At a median follow up of 217 days (range 26-560) after the first dose of PD1 blockade, 22 of 27 (81%) remain alive. 3 pts died from GVHD and 2 died from lymphoma progression complicated by GVHD. Overall response rate (ORR) to anti-PD1 was 79% (CR+PR) in 24 assessable pts (13 CR, 6 PR, 2 SD, 3 PD). 10 of 27 pts (37%) developed aGVHD and in 19% it was severe (5 grade IV, 3 grade II, & 2 grade I) after PD1 blockade. 9 of 10 experienced liver aGVHD (4 stage IV, 1 stage III, 4 stage I). 3 of 4 cases with stage IV liver aGVHD were biopsy proven and distinct from typical hepatopathy associated with PD1 blockade. In the 2 cases with PD1 IHC stains, PD1+ lymphocytes were more frequently involved in the endotheliitis rather than the cholangitis component of GVHD. 8 of 10 experienced skin aGVHD (1 stage IV, 5 stage III, 1 stage II, & 1 stage I). Only 2 experienced gut aGVHD (1 stage IV, 1 stage III). The 10 who developed aGVHD received a total of 1-3 doses (median 1) of anti-PD1. Median day of aGVHD onset from first dose of anti-PD1 was 15 (range 8-28). Of the 10 pts who developed aGVHD, 4 of 10 (40%) responded to treatment (2 CR, 2 PR). Only 1 patient responded to steroids alone. An additional 4 pts who did not experience aGVHD had new or worsening classic chronic GVHD (cGVHD) after anti-PD1. Overall 52% (14/27) of the pts in this analysis developed new or worsening acute or chronic GVHD after PD1 blockade (10 aGVHD, 4 cGVHD). Discussion/Conclusion: PD1 blockade was associated with a high ORR (79%) in heavily pretreated Hodgkin lymphoma patients relapsing following allo-HCT, suggesting a strong graft versus tumor effect. However, some patients developed severe and treatment refractory GVHD in this setting. Prospective study of PD1 blockade after allo-HCT is warranted. Potential risks and benefits of PD1 blockade after allo-HCT should be discussed with each patient, and they should be carefully monitored for aGVHD after PD1 blockade. Disclosures Kamdar: Seattle Genetics: Speakers Bureau. Saad:Astellas: Research Funding; American Porphyria foundation: Research Funding; Alexion: Honoraria; Spectrum: Honoraria. Ganguly:Janssen: Research Funding; Onyx: Speakers Bureau; Seattle Genetics: Speakers Bureau. Hari:Merck: Research Funding; BMS: Honoraria. Hamadani:Celgene: Honoraria, Research Funding; Takeda: Research Funding; Pharmacyclics: Consultancy; Merck: Research Funding. Jagasia:Therakos: Consultancy. Armand:Sequenta Inc: Research Funding; Merck: Consultancy, Research Funding; Pfizer: Research Funding; Roche: Research Funding; Infinity Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding.