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Corticosteroid resistance after acute graft-versus-host disease (SR-aGVHD) results in high morbidity and mortality after allogeneic hematopoietic cell transplantation. Current immunosuppressive therapies for SR-aGVHD provide marginal effectiveness because of poor response or excessive toxicity, primarily from infection. α1-Antitrypsin (AAT), a naturally abundant serine protease inhibitor, is capable of suppressing experimental GVHD by downmodulating inflammation and increasing ratios of regulatory (Treg) to effector T cells (Teffs). In this prospective multicenter clinical study, we sought to determine the safety and response rate of AAT administration in SR-aGVHD. Forty patients with a median age of 59 years received intravenous AAT twice weekly for 4 weeks as first-line treatment of SR-aGVHD. The primary end point was overall response rate (ORR), the proportion of patients with SR-aGVHD in complete (CR) or partial response by day 28 without addition of further immunosuppression. Treatment was well tolerated without drug-related adverse events. A significant increase in serum levels of AAT was observed after treatment. The ORR and CR rates by day 28 were 65% and 35%, respectively, and included responses in all aGVHD target organs. At day 60, responses were sustained in 73% of patients without intervening immunosuppression. Infectious mortality was 10% at 6 months and 2.5% within 30 days of last AAT infusion. Consistent with preclinical data, correlative samples showed an increase in ratio of activated Tregs to Teffs after AAT treatment. These data suggest that AAT is safe and may be potentially efficacious in treating SR-aGVHD. This trial was registered at www.clinicaltrials.gov as #NCT01700036. [ABSTRACT FROM AUTHOR]

The relationship between regulatory T cells (Tregs) and acute graft-versus-host disease (aGVHD) in clinical allogeneic bone marrow transplantation (BMT) recipients is not well established. We conducted a prospective analysis of peripheral blood Tregs as determined by the frequency of CD4+CD25hiFOXP3+ lymphocytes in 215 BMT patients. Autologous BMT patients (N = 90) and allogeneic BMT patients without GVHD (N = 65) had similar Treg frequencies, whereas allogeneic patients with GVHD (N = 60) had Treg frequencies that were 40% less than those without GVHD. Treg frequencies decreased linearly with increasing grades of GVHD at onset, and correlated with eventual maximum grade of GVHD (P < .001). In addition, frequency of Tregs at onset of GVHD predicted the response to GVHD treatment (P = .003). Patients with Treg frequencies less than the median had higher nonrelapse mortality (NRM) than patients with Tregs greater than the median, but experienced equivalent relapse mortality, resulting in an inferior survival at 2 years (38% versus 63%, P = .03). Treg frequency may therefore have important prognostic value as a biomarker of aGVHD. [Copyright &y& Elsevier]

Danger-associated molecular patterns (DAMPs) released during conditioning have been shown to amplify experimental GVHD. CD24 fusion protein (CD24Fc; OncoImmune), a glycoprotein linked to human IgG 1 Fc, binds to Siglec-10 to negatively regulate host response to DAMPs. We have reported that infusion of CD24Fc prior to HCT significantly decreased GVHD-related mortality in murine models of HCT (Toubai, Blood 2015 & Toubai, JCI Insight 2017). We hypothesized that enhancing Siglec10-CD24 interactions by administration of CD24Fc would prevent acute GVHD. A randomized, prospective, multi-site, placebo controlled phase 2a clinical trial was initiated to investigate safety of three dose levels of CD24Fc (or blinded placebo) plus standard GVHD prophylaxis with tacrolimus and methotrexate (MTX) in matched unrelated donors. T cell replete PBSC or BMT was infused. Randomization (3:1 ratio of CD24Fc:Placebo) was in 3 cohorts of 8 pts: 240mg single dose on D -1, 480mg single dose on D -1, and a 480mg, 240mg, and 240mg multiple dose regimen on D -1, 14 and 28, respectively. The primary endpoint was safety and determination of a recommended dose. Pts were followed for secondary endpoints of aGVHD, relapse and survival at D180. The trial enrolled 24 pts (CD24Fc, n=18; Placebo, n=6) with minimum follow up on one year (Table1). All planned dosages were administered without reaching an MTD. There were no infusion-related toxicities or DLTs. In placebo treated pts, there was one DLT resulting in death from pneumonia. Between groups there were no overall differences in AEs, although CD24Fc was associated with fewer days of severe (≥ Grade III) mucositis. There was no infection-related mortality related to CD24Fc treatment. The CD24Fc pts achieved neutrophil and platelet engraftment at a median of D 13 (12-23) and D 13 (9-23), respectively. PK studies demonstrated sustained drug levels through D 100 in the multi-dosing cohort. The incidence of grade II-IV GVHD was 39% (18-62%) and III-IV GVHD was 6% (95% CI 0-20%) at D 180 among CD24Fc treated pts. Grade 3 involvement of the lower-GI tract was observed in 1/18 pts, while the remainder of acute GVHD involved the upper GI tract or skin. All pts receiving treatment for GVHD experienced response. At D 180, relapse occurred in 2/18 pts, and OS was 100%. The endpoint of grade 3-4 GVHD-free survival (AGFS) was 94% at D 180 in pts receiving treatment with CD24Fc versus 50% in pts receiving placebo (HR 0.1; 90% CI 0.0-0.7). AGFS in contemporaneous case matched controls (n=68; CIBMTR) receiving myeloablative 8/8 HLA matched unrelated donor HCT with tacrolimus + MTX was 68% (95% CI: 56-78). In this translational phase 2a trial administration of CD24Fc was safe and tolerable. Additional investigations are required determine efficacy for improving AGFS after HCT. This trial represents the first attempt to prevent GVHD by inhibiting host response to DAMPs. [ABSTRACT FROM AUTHOR]

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]

The article offers the authors comment on the study on the proteasome inhibition in the treatment of chronic graft-versus-host disease (cGVHD) conducted by C. Pai and colleagues. The authors say that the study implicate proteasome inhibition as a pathogenic pathway for targeting and ameliorating cGVHD for the first time. They also say that the authors of the study should be commended for their efforts.

BACKGROUND A recent U.S. Food and Drug Administration (FDA) safety communication (Aug 2018) warned prescribers of the risk of relapse in patients receiving azithromycin as prophylaxis for bronchiolitis obliterans syndrome (BOS) following hematopoietic cell transplant (HCT). However, the FDA warning was based upon a single multicenter trial, in which patients were randomized to receive azithromycin for 2 years, starting at the time of conditioning. We now examine relapse rates in a cohort of patients treated with azithromycin for management of moderate-severe CGVHD. PATIENT POPULATION A retrospective review of our HCT database (2010-2017) identified 239 patients (median age 55 years, range 4-72) with moderate-severe CGVHD following an allogeneic HCT for a primary hematologic malignancy. NIH consensus criteria (2015) were used for CGVHD grading. Patients were divided into 2 cohorts, a) those receiving an extended course of azithromycin (≥ 14 days) for CGVHD management (cohort 1, n=86) and b) those who did not (cohort 2, n=153). Patients in cohort 2 either did not receive any azithromycin (n=122) or had received an abbreviated (<14 day) course (n=31) of azithromycin post-HCT. For cohort 1, the median time to initiation of azithromycin therapy was 15 months post-HCT (range 3-68), with a 26 month median duration of azithromycin therapy (range 1-77). All patients in cohort 1 met NIH consensus criteria for BOS. Patients in cohort 2 did not exhibit BOS, but still met NIH criteria for moderate-severe CGVHD. Hematologic conditions included acute leukemia (n=139), MDS/MPD (n=44), malignant lymphomas (n=26), chronic leukemia (n=24), and multiple myeloma (n=6). Ninety-one patients exhibited moderate and 148 patients exhibited severe CGVHD. The two cohorts were balanced for CGVHD severity, with severe CGVHD noted in 69% and 63% of patients in cohorts 1 and 2 respectively. RESULTS Decreased rates of relapse and improved survival were noted for patients treated with azithromycin for CGVHD. At 2 years, the cumulative incidence of relapse was 2% (95% CI:1-9%) for patients in cohort 1 vs 16% (95% CI: 11-23%) in cohort 2, p=0.001. Overall survival (2-year OS) in cohort 1 was 93% (95%CI: 88-99%) vs 78% (95% CI:72-85%) for cohort 2, p=0.003. Overall, 7 of 86 (8.1%) CGVHD patients treated with an extended course of azithromycin (cohort 1) have relapsed, the median time to relapse 876 days (range 379-1303) post-HCT. In comparison, 28 of 153 (18.3%) in cohort 2 have relapsed, a median 371 days (range 98-1252) post-HCT. CONCLUSION The use of azithromycin for the management of moderate to severe CGVHD was not associated with an increased risk of relapse in patients undergoing HCT for a hematologic malignancy. Azithromycin therapy for patients with CGVHD should not be contra-indicated in this patient population. [ABSTRACT FROM AUTHOR]

Despite the ongoing advent of more effective immunomodulators and proteasome inhibitors, multiple myeloma (MM) remains incurable and no effective therapy is available for advanced aggressive disease. Although allogeneic (Allo) hematopoietic cell transplantation (HCT) has a curative potential, the outcomes remain poor because of high treatment-related mortality (TRM), mostly due to regimen-related toxicities and graft-versus-host disease (GVHD) in case of myeloablative conditionings, high relapse rate in case of reduced-intensity or nonmyeloablative regimens, and possibly other unknown MM-specific issues. In an attempt to improve TRM, without compromising conditioning intensity, we prospectively explored the feasibility and efficacy of a myeloablative but reduced-toxicity conditioning regimen, consisting of fludarabine and busulfan (FluBu4; fludarabine 40 mg/m 2 /day and busulfan 3.2 mg/kg/day i.v. × 4 days) in 22 patients with high-risk or advanced refractory MM. The majority (14 of 22, 64%) had prior autologous HCT. The median HCT-specific comorbidity index score was 3 (range, 0 to 6), with 46% having a Karnofsky performance score < 80%. Ten patients had unrelated donors, 3 of whom were 7/8 HLA–loci matched. GVHD prophylaxis was tacrolimus and methotrexate in 20 (91%). Most patients had active MM at transplantation, with a partial response in 12 of 22 (46%) and stable disease in 1 of 22 (4.5%). All 22 patients tolerated the FluBu4 conditioning well, without early toxic deaths or graft failure. Common regimen-related toxicities included mild to moderate mucositis (18 of 22, 82%) and mild transient liver function abnormality (9 of 22, 41%). There were no grade 4 toxicities but grade 3 mucositis occurred in 7 of 22 patients (32%). The cumulative incidence of severe, grades III and IV acute GVHD at day 180 was 23% (95% confidence interval [CI], 10% to 47%) and that of chronic GVHD was 68% (95% CI, 46% to 88%). The cumulative incidences of TRM at 100 days, 1 year, and 3 years were 9% (95% CI, 2% to 33%), 19% (95% CI, 7% to 44%), and 29% (95% CI, 13% to 55%), respectively. Two TRMs were due to idiopathic pneumonia syndrome and 1 was due to cirrhosis. They all had decreased pre-HCT corresponding organ function, with HCT-specific comorbidity index scores of > 3. With a median follow-up of 58.7 (range, 39 to 82) months, the cumulative incidences of relapse at 1 and 3 years were 37% (95% CI, 20% to 61%) and 50% (95% CI, 29% to 75%); those for 1-year and 3-year overall survival (OS) were 58% (95% CI, 40% to 83%) and 29% (95% CI, 15% to 57%), respectively, and those for the 1-year and 3-year progression-free survivals (PFS) were 40% (95% CI, 23% to 67%) and 15% (95% CI, 5% to 42%), respectively. In summary, the use of the myeloablative FluBu4 conditioning Allo-HCT for high-risk MM resulted in decreased TRM, compared with that of Allo-HCT using conventional myeloablative regimens; however, the relapse rate was high, including in those developing moderate-to-severe chronic GVHD. This suggested a less robust graft-versus-myeloma effect against high-risk MM, thus resulting in poor PFS and OS. Nonetheless, the FluBu4 regimen may be used as a lower-TRM platform to combine with other strategies, eg, addition of an MM-targeted agent and/or maintenance therapy with these agents, to decrease relapse or progression in patients with high-risk MM. [ABSTRACT FROM AUTHOR]

Clinical diagnosis of grade 1 acute graft-versus-host disease (GVHD) marks the beginning of a potentially progressive and fatal course of GVHD after hematopoietic stem cell transplantation (HSCT). However, interventional studies to treat early GVHD are lacking. We conducted a single-arm prospective phase II trial to test the hypothesis that treatment of newly diagnosed grade 1 acute GVHD with etanercept and topical corticosteroids would reduce progression to grade 2 to 4 within 28 days. Study patients (n = 34) had a median age of 51 years (range, 10 to 67 years) and had undergone unrelated (n = 22) or related (n = 12) donor HSCT. Study patients were treated with etanercept (.4 mg/kg, maximum 25 mg/dose) twice weekly for 4 to 8 weeks. Ten of 34 patients (29%) progressed to grade 2 to 4 acute GVHD within 28 days. The cumulative incidence of grade 2 to 4 and grade 3 to 4 acute GVHD at 1 year was 41% and 3%, respectively. Nonrelapse mortality was 19% and overall survival was 63% at 2 years. Among a contemporaneous control cohort of patients who were diagnosed with grade 1 acute GVHD and treated with topical corticosteroids but not etanercept during the study period, 12 of 28 patients (43%) progressed to grade 2 to 4 GVHD within 28 days, with a 1-year incidence of grade 2 to 4 GVHD and grade 3 to 4 GVHD of 61% (41% versus 61%, P = .08) and 18% (3% versus 18%, P = .05), respectively. Patients treated with etanercept also experienced less increase in GVHD plasma biomarkers suppression of tumorigenicity 2 (P = .06) and regenerating islet-derived 3-alpha (P = .01) 28 days after grade 1 acute GVHD diagnosis compared with contemporaneous control patients. This study was terminated early because of poor accrual. Future prospective studies are needed to identify patients with grade 1 acute GVHD at risk of swift progression to more severe GVHD and to establish consensus for the treatment of grade 1 acute GVHD. This trial is registered with ClinicalTrials.gov, number NCT00726375. [ABSTRACT FROM AUTHOR]

Engraftment syndrome (ES), characterized by fever, rash, pulmonary edema, weight gain, liver and renal dysfunction, and/or encephalopathy, occurs at the time of neutrophil recovery after hematopoietic cell transplantation (HCT). In this study, we evaluated the incidence, clinical features, risk factors, and outcomes of ES in children and adults undergoing first-time allogeneic HCT. Among 927 patients, 119 (13%) developed ES at a median of 10 days (interquartile range 9 to 12) after HCT. ES patients experienced significantly higher cumulative incidence of grade 2 to 4 acute GVHD at day 100 (75% versus 34%, P < .001) and higher nonrelapse mortality at 2 years (38% versus 19%, P < .001) compared with non-ES patients, resulting in lower overall survival at 2 years (38% versus 54%, P < .001). There was no significant difference in relapse at 2 years (26% versus 31%, P = .772). Suppression of tumorigenicity 2, interleukin 2 receptor alpha, and tumor necrosis factor receptor 1 plasma biomarker levels were significantly elevated in ES patients. Our results illustrate the clinical significance and prognostic impact of ES on allogeneic HCT outcomes. Despite early recognition of the syndrome and prompt institution of corticosteroid therapy, outcomes in ES patients were uniformly poor. This study suggests the need for a prospective approach of collecting clinical features combined with correlative laboratory analyses to better characterize ES. [ABSTRACT FROM AUTHOR]