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INTRODUCTION The composite endpoint of GVHD-free, relapse-free survival (GRFS), defined as survival free from grade 3–4 acute GVHD (aGVHD), chronic GVHD (cGVHD) requiring systemic immunosuppressive therapy (IST), or relapse has emerged as an outcome to capture clinically meaningful events. In the present study, we validated GRFS as a useful surrogate endpoint by examining the relative importance of individual events and the GRFS composite itself on overall survival (OS) at 5-years after allogeneic HCT. METHODS We conducted an IRB-approved retrospective cohort study on 565 consecutive patients (age ≥18 years) undergoing first-time allogeneic HCT for hematologic malignancy (January 2007–March 2013). Data abstraction of GRFS events was performed through chart review of the EHR. To determine the impact of each event of the GRFS composite endpoint, we accounted for competing risks using Fine and Gray methods, and correlated each event with OS using Kaplan-Meier methods. Using statistical simulations, the relative consequences of successfully modulating individual or composite endpoints on OS were examined to further elucidate the role of GRFS in clinical trials research. RESULTS The median age of the cohort was 54 years (18–73 years), comprised predominantly of males (58%) and Caucasians (94%). The most common indication for transplant was AML (41%), followed by lymphoma (21%) and MDS/MPD (14%). Patients received HLA-matched related (47%), and matched unrelated (53%) donors, and mostly peripheral blood stem cells (90%) and myeloablative conditioning (68%). Relapse conferred the greatest risk for death (HR 7.89; 95% CI:5.83–10.69). Grade 3–4 aGVHD was associated with HR 6.16 (95%CI:4.42–8.56), while cGVHD requiring IST was associated with lower HR 1.69 (95%CI:1.16–2.46). Indeed, the GRFS composite correlated with less HR 4.81 (95% CI:3.61–6.41) compared with either relapse or grade 3–4 aGVHD events. To determine the impact of hypothetical improvements on individual events or combined events (composite) on OS, we next performed Monte Carlo simulations. Compared with individual events, modulating composite endpoints predicted the greatest change in 5-year OS (Figure 1). The greatest gain in OS was seen by proportionally reducing both grade 3–4 aGVHD and relapse (modified GRFS). Reducing chronic GVHD requiring IST proportionally with grade 3–4 aGVHD and relapse events (conventional GRFS) did not change 5-year OS. CONCLUSION These findings highlight the importance of influencing OS by targeting the major early adverse post-HCT events (i.e., grade 3–4 acute GVHD and relapse). Moreover, the simulations herein suggest that GRFS as currently defined may be less optimal for predicting OS than using early grade 3–4 aGVHD and relapse as composite endpoints. Importantly, further refinement of these endpoints will depend on the a priori defined study population as well as intervention. [ABSTRACT FROM AUTHOR]

Introduction Relapse remains a significant challenge towards improving survival after allogeneic hematopoietic transplantation (HCT) for Acute Myeloid Leukemia (AML) not in remission or possessing poor cytogenetic/molecular features. Insights from murine pre-clinical studies demonstrate a central role for CD8+ dendritic cells in cross-presentation of leukemia associated antigens (LAA) in mediating GVL without aggravating acute Graft-versus-Host Disease (aGVHD)(Toubai, Blood 2013). We posited that enhancing LAA cross-presentation with exogenous Type I Interferon (pegIFNα) would promote GVL response and reduce rates of relapse after HCT. Methods We initiated a prospective, phase I/II, clinical trial of pegIFNα administration after myeloablative conditioning for prevention of relapse in pts with detectable AML at time of HCT (resistant to induction) or with cytogenetic/molecular features conferring high relapse risk and poor survival. Pts received up to four doses of 90mcg or 180mcg pegIFNα SubQ on d -1 and d 14, 28, 42 after PBSC or BMT. aGVHD prophy was tacrolimus + MTX or MMF. The primary endpoint was to determine the incidence of relapse in pts receiving the phase II dosage of pegIFNα. We hypothesized that 30 pts assigned to the same dose would provide 80% power to detect a difference between a promising day 180 relapse rate of 40% versus a rate of 60%. Results A total of 30 pts received study treatment at a median age of 60 years (17-72). Conditioning was myeloablative FluBu (n=9), CloBu (n=20) or FluCyTBI (n=1). At time of HCT, AML was detected in 28 pts and 2 pts enrolled for poor cytogenetic/molecular risk, complex/monosomal karyotype (n=1) and FLT3-ITD+ (n=1). There was no DLT at 90mcg (n=3) and one DLT (graft failure) after escalation to 180mcg (n=27). pegIFNα was well tolerated with ≥3 doses administered to 87% of pts. ≥Grade 3 SAEs during treatment include acute kidney injury(n=1), engraftment failure(n=1), bone pain/weakness(n=1), hypotension(n=1) and hypoxemia (n=1). 29 pts (97%) experienced primary engraftment and bone marrow exam at d 30 revealed CR in 100% of pts. Thirteen pts (43%) experienced infection. Grade II-IV aGVHD and grade III-IV aGVHD occurred in 35% (20 – 56%) and 11% (4 – 30%) by day 180. The incidence of TRM was 11% (3-30%) at day 180 and 19% (8-41%) at 1-yr. The day 180 (and 1-yr) incidence of relapse was 39% (24 – 60%) in the overall cohort and 36% (20 – 58%) in 27 pts treated at the phase II dose. At a median follow up of 19 months, the 1-yr OS was 42% (27 – 65%). Conclusion These data provide initial evidence of clinical translation for pegIFNα when administered prophylactically in an AML cohort at high risk for relapse. Type I Interferon did not significantly alter toxicity or aGVHD risk and produced relatively low rates of relapse suggesting a robust GVL response. The role of type 1 IFN in reducing clinical relapse and its underlying biological mechanisms warrants additional study. [ABSTRACT FROM AUTHOR]

Summary: Background: Acute graft-versus-host disease (GVHD) remains a barrier to more widespread application of allogeneic haemopoietic stem-cell transplantation. Vorinostat is an inhibitor of histone deacetylases and was shown to attenuate GVHD in preclinical models. We aimed to study the safety and activity of vorinostat, in combination with standard immunoprophylaxis, for prevention of GVHD in patients undergoing related-donor reduced-intensity conditioning haemopoietic stem-cell transplantation. Methods: Between March 31, 2009, and Feb 8, 2013, we did a prospective, single-arm, phase 1/2 study at two centres in the USA. We recruited adults (aged ≥18 years) with high-risk haematological malignant diseases who were candidates for reduced-intensity conditioning haemopoietic stem-cell transplantation and had an available 8/8 or 7/8 HLA-matched related donor. All patients received a conditioning regimen of fludarabine (40 mg/m2 daily for 4 days) and busulfan (3·2 mg/kg daily for 2 days) and GVHD immunoprophylaxis of mycophenolate mofetil (1 g three times a day, days 0–28) and tacrolimus (0·03 mg/kg a day, titrated to a goal level of 8–12 ng/mL, starting day −3 until day 180). Vorinostat (either 100 mg or 200 mg, twice a day) was initiated 10 days before haemopoietic stem-cell transplantation until day 100. The primary endpoint was the cumulative incidence of grade 2–4 acute GVHD by day 100. This trial is registered with ClinicalTrials.gov, number NCT00810602. Findings: 50 patients were assessable for both toxic effects and response; eight additional patients were included in the analysis of toxic effects. All patients engrafted neutrophils and platelets at expected times after haemopoietic stem-cell transplantation. The cumulative incidence of grade 2–4 acute GVHD by day 100 was 22% (95% CI 13–36). The most common non-haematological adverse events included electrolyte disturbances (n=15), hyperglycaemia (11), infections (six), mucositis (four), and increased activity of liver enzymes (three). Non-symptomatic thrombocytopenia after engraftment was the most common haematological grade 3–4 adverse event (nine) but was transient and all cases resolved swiftly. Interpretation: Administration of vorinostat in combination with standard GVHD prophylaxis after related-donor reduced-intensity conditioning haemopoietic stem-cell transplantation is safe and is associated with a lower than expected incidence of severe acute GVHD. Future studies are needed to assess the effect of vorinostat for prevention of GVHD in broader settings of haemopoietic stem-cell transplantation. Funding: Merck, Leukemia and Lymphoma Society, National Institutes of Health, St Baldrick's Foundation, Michigan Institute for Clinical and Health Research. [ABSTRACT FROM AUTHOR]

Allogeneic HCT is the only established curative therapy for high risk hematologic malignancies. The major challenges are leukemia relapse and high grade GVHD. We have developed the CD24Fc fusion protein to selectively inhibit danger-associated molecular pattern (DAMP)-induced inflammation and discovered that it effectively prevents GVHD without affecting the desirable GVL effect in preclinical models. With the support of SBIR awards from the NCI, we have completed a phase II randomized, double blind, multi-center, dose escalation trial comprised of 3 dosing cohorts of 8 patients (3:1 CD24Fc vs. placebo), with a total enrollment of 24 subjects. Notably, clinical data from this trial demonstrate that CD24Fc reduces the incidence of severe GVHD, resulting in statistically significant increases of acute 180-day GVHD-free survival (aGFS). A Phase II expansion cohort to enroll an additional 20 subject is ongoing (NCT02663622). Here we propose a phase III clinical trial with 180 patients (1:1 CD24Fc vs placebo) to test the hypothesis that CD24Fc prophylaxis can significantly improve 180 day acute GVHD-free survival (aGFS) over placebo control. A Randomized, Double-blind, Placebo-controlled, Multi-Center, Phase III Study of CD24Fc for the Prevention of Acute GVHD Following Myeloablative Allogeneic HCT (CATHY) (NCT04095858). This study will compare CD24Fc or Placebo with standard GVHD prophylaxis of tacrolimus and methotrexate in the setting of myeloablative conditioning (MAC), matched unrelated donor (MUD) allogeneic HCT in patients with AML/ALL or MDS. Patients will be randomized 1:1 to receive CD24Fc or placebo at the dose levels of 480mg, 240mg and 240mg on Days -1, +14 and +28, respectively. The primary endpoint is the rate of 180 days grade III-IV acute GVHD-free survival (aGFS). Secondary endpoints are 1 yr DFS, 1 yr OS, and D180 Gr II-IV aGFS. Other exploratory evaluations will be 1 yr chronic GVHD, 1 yr relapse, NRM at 1 year, incidence and rate of infection at 100 days, and rate of Gr III and above mucositis at 28 days. The study will enroll 180 patients, or 90 per arm, with an estimated accrual period of 24 months. The study will include one interim analysis for efficacy. Z test statistics for comparing the two arms will be compared to the critical values and results be reviewed by the independent DSMB. [ABSTRACT FROM AUTHOR]

Background Tisagenlecleucel, a chimeric antigen receptor T-cell therapy, has demonstrated efficacy and manageable safety in adult patients (pts) with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL) in the global, multicenter, pivotal, phase 2, JULIET trial (NCT02445248). The primary endpoint, overall response rate (ORR), was met at the interim analysis (ORR: 59% [CR, 43%; PR, 16%]). Here, we report an updated analysis with a median 19 mo follow-up. Methods Adult pts ≥18 y with r/r DLBCL that had progressed after ≥2 lines of therapy including rituximab and an anthracycline and who were ineligible for or failed autologous stem cell transplant (ASCT) were enrolled. Tisagenlecleucel was manufactured from autologous T cells at 2 facilities (Morris Plains, NJ, USA [main cohort]. and Leipzig, Germany [cohort A]) and provided to pts at 27 treatment centers in 10 countries across the globe. Efficacy analyses include all pts with ≥3 mo of follow-up or earlier discontinuation. Safety analyses include all infused pts. Results In the JULIET study, 115 pts (99 in main cohort; 16 in cohort A) received a single dose of tisagenlecleucel infusion as of 21 May 2018. Prior to infusion, 90% of infused pts received bridging chemotherapy and 93% received lymphodepletion chemotherapy. Pts were a median 56 y (range, 22-76 y); 77% of pts had stage III/IV and 17% had double/triple-hit disease at the time of entry. Approximately half (51%) of pts had received ≥3 prior lines of chemotherapy (range, 1-6); 49% received prior ASCT. ORR was 54% (40% CR, 13% PR; 95% CI, 43%-64%) with a median follow-up of 19.3 mo post-infusion. Median duration of response (DOR) was not reached. The relapse-free probability was 66% (95% CI, 51%-78%) at 6 mo and 64% (95% CI, 48%-76%) at 12 or 18 mo. Consistent ORR was reported across prognostic subgroups (eg, prior ASCT; double/triple-hit lymphoma) and DOR was similar among age groups and disease status (Figure). Median OS was not reached for pts in CR and was 11.1 mo (95% CI, 6.6 mo-NE) for all infused pts. The probability of OS was 48% (95% CI, 38%-57%) at 12 mo and 43% (95% CI, 33%-53%) at 18 mo (max follow-up, 29 mo). No pts proceeded to allogeneic SCT or ASCT while in remission. During the first 8 wks post-infusion, grade 3/4 adverse events of special interest were cytopenias lasting >28 days (34%), cytokine release syndrome (CRS; 23%, by the Penn scale), infections (19%), febrile neutropenia (15%), neurologic events (11%; 1 case of grade 2 cerebral edema), and tumor lysis syndrome (2%). Tocilizumab was administered to 16% of pts with CRS, and no treatment-related death was reported. Conclusions This updated analysis with longer follow-up confirms earlier findings. Tisagenlecleucel produced a durable high ORR, consistent efficacy across all predefined subgroups, and had a manageable safety profile in pts with r/r DLBCL. [ABSTRACT FROM AUTHOR]