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Background: Dipeptidyl peptidase 4 (DPP-4; also known as CD26), a transmembrane receptor expressed on T cells, has a costimulatory function in activating T cells. In a mouse model, down-regulation of CD26 prevented graft-versus-host disease (GVHD) but preserved graft-versus-tumor effects. Whether inhibition of DPP-4 with sitagliptin may prevent acute GVHD after allogeneic stem-cell transplantation is not known.Methods: We conducted a two-stage, phase 2 clinical trial to test whether sitagliptin plus tacrolimus and sirolimus would reduce the incidence of grade II to IV acute GVHD from 30% to no more than 15% by day 100. Patients received myeloablative conditioning followed by mobilized peripheral-blood stem-cell transplants. Sitagliptin was given orally at a dose of 600 mg every 12 hours starting the day before transplantation until day 14 after transplantation.Results: A total of 36 patients who could be evaluated, with a median age of 46 years (range, 20 to 59), received transplants from matched related or unrelated donors. Acute GVHD occurred in 2 of 36 patients by day 100; the incidence of grade II to IV GVHD was 5% (95% confidence interval [CI], 1 to 16), and the incidence of grade III or IV GVHD was 3% (95% CI, 0 to 12). Nonrelapse mortality was zero at 1 year. The 1-year cumulative incidences of relapse and chronic GVHD were 26% (95% CI, 13 to 41) and 37% (95% CI, 22 to 53), respectively. GVHD-free, relapse-free survival was 46% (95% CI, 29 to 62) at 1 year. Toxic effects were similar to those seen in patients undergoing allogeneic stem-cell transplantation.Conclusions: In this nonrandomized trial, sitagliptin in combination with tacrolimus and sirolimus resulted in a low incidence of grade II to IV acute GVHD by day 100 after myeloablative allogeneic hematopoietic stem-cell transplantation. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT02683525.). [ABSTRACT FROM AUTHOR]

DPP-IV is a homodimeric type II transmembrane receptor identical to the leucocyte surface antigen CD26. The interaction of CD26/DPP-IV on T cells with its ligand caveolin-1 on antigen-presenting cells (APC) enhances T cell activation, proliferation, and cytokine production. It also upregulates CD86 on APC resulting in co-stimulation. In a xenograft mouse model, reducing CD26 expression by a monoclonal antibody prevented aGVHD and preserved graft-versus-tumor effects (Hatano et al. BJH 2013). In a pilot trial testing sitagliptin for enhancement of cord blood engraftment, we observed a lower than expected rate of aGVHD (Farag et al. Stem Cell Dev 2013) and hypothesized that CD26/DPP-IV inhibition with sitagliptin may prevent aGVHD following allogeneic PBSC transplants. Conduct a prospective phase II trial to test if sitagliptin can reduce the rate of grade II-IV aGVHD by day +100 following myeloablative allogeneic PBSC transplants (ClinicalTrials.gov, NCT02683525). The primary endpoint was grade II-IV aGVHD by day +100. Patients received thiotepa (15 mg/kg) and cyclophosphamide (120 mg/kg), followed by G-CSF mobilized PBSC from matched related (6/6 HLA match) or unrelated (10/10 HLA match) donors. Sitagliptin (600 mg q12 hours) was given on days -1 to day +14, together with tacrolimus and sirolimus through day +100, then tapering until day +180. In a Simon two-stage design, <8 of a total of 36 patients developing grade II-IV aGVHD by day +100 would demonstrate a reduction of aGVHD from a historical rate of 30% to <15% with 80% power and type 1 error = 0.1. Thirty-six (17 M; 19 F) patients of median age 46 (20-59) years were enrolled. Patients had AML (n=19), ALL (n=9), MDS (n=4), and CML (n=4). Transplants were from matched related (13 patients) or unrelated (23 patients) donors. Acute GVHD occurred in 2 of 36 patients by day +100 (1 grade II; 1 grade IV), for cumulative incidences of 5.6% (95% confidence interval [CI], 0% - 13.2%) and 2.8% (95% CI, 0% - 8.2%) for grade II-IV aGVHD and grade III-IV aGVHD at day +100, respectively (Fig 1). An additional patient developed late-onset grade II aGVHD at day +140 following abrupt stopping of immunosuppression on day +100 for low donor chimerism in absence of relapse. Significant toxicities though day +30 included grades III-IV mucositis (n=15), acute kidney injury (4 with high tacrolimus levels, 1 sepsis), viral reactivation/infection (4 CMV, 2 BK, 1 EBV, 1 HHV6), and passenger lymphocyte syndrome (n=2). Non-relapse mortality was 0% at 12 months. With median follow-up of 699 (118-1312) days, the relapse-free survival was 77.2% (95% CI, 63.2% - 91.1%) and overall survival was 94.3% (95% CI, 86.7% - 100%) at 12 months (Fig 2a-b). CD26/DPP-IV inhibition with sitagliptin is well-tolerated and significantly reduced the rate of aGVHD by day +100 in patients undergoing myeloablative allogeneic PBSCT transplantation. [ABSTRACT FROM AUTHOR]

Aim The risk of graft failure or graft-versus-host disease (GvHD) after Hematopoietic cell transplantation (HCT) strictly depends the degree of matching of histocompatibility antigens between the donor and recipient. In some cases due to rare HLA alleles or clinical emergency, it is difficult or even impossible to find a perfectly matched donor. HLA minor (allelic) mismatched (MM) donors (for example, B∗35:02 vs B∗35:05) have been shown to be an option for such patients. The goal of this study was to retrospectively analyze how class I minor MM HLA affect HCT outcomes. Methods The study population included 18 adult patients with a variety of hematological diseases who underwent HCT from 2001 through 2011 using unrelated donors with MM at class I HLA region. The control group included 55 patients transplanted within the same period of time who received 10/10 (HLA-A, -B, -C, -DR, -DQB1) matched HCTs. The groups were matched according to sex, age, diagnosis and pre-transplant protocol. High resolution HLA typing was performed using sequence based typing. The variables tested included total number of amino acid substitutions (AAS), locations of the AAS ( α helix or β strand), affected pockets (A, B, C, D, E, F), TCR or peptide binding sites, and dissimilarity score (DSS). These parameters were estimated using the HISTOCHECK computer algorithm. Statistical analysis comparing HLA matching parameters with the incidence of acute (a) and chronic (c) GvHD was done by ANOVA. Results All donor-recipient combinations were allele matched for DRB1 and DQB1 loci. Allelic MM transplants with a non-myeloablative preparative regimen was associated with a higher incidence of cGvHD (p = 0.009) Allelic MM at any class I locus was associated with increased risk of grade III-IV aGvHD (p = 0.0425). Variables predictive of any grade aGvHD were AAS in any HLA pocket but C (p < 0.030). DSS more than 10.0 was associated with increased risk for aGvHD and cGvHD (p = 0.0450) provided the AAS was in A, D, or F pockets. No significant association was found between MM and relapse, transplant-related mortality and overall survival. Conclusions AAS in peptide binding pockets in the setting of HLA class I MM donor-recipient combinations are at higher risk for GvHD and as such provide additional insight into donor search strategies. [ABSTRACT FROM AUTHOR]

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]

Methotrexate (MTX) is a standard agent used in combination with calcineurin inhibitors for graft-versus-host disease (GVHD) prophylaxis in patients undergoing allogeneic hematopoietic cell (HCT) transplantation. We retrospectively compared the incidence of acute GVHD (aGVHD), transplant-related morbidity, and mortality in patients given sirolimus/tacrolimus ± antithymocyte globulin (ATG) versus MTX/tacrolimus or cyclosporine and allogeneic transplantation for hematologic malignancies. Between January 1, 2005, and April 30, 2009, 106 consecutive patients received peripheral blood HCT or bone marrow grafts after 1 of 6 myeloablative conditioning regimens. The incidence of grade II-IV aGVHD was 18.6% in patients who received sirolimus/tacrolimus compared to 48.9% who received MTX (P = .001). The incidence of grade III-IV aGVHD was 5% and 17% (P = .045), respectively. There was no difference in overall survival (OS) between the groups (P = .160). Chronic GVHD (cGVHD) occurred in 40.4% who received sirolimus and 41.9% receiving MTX (P = .89). The incidence of thrombotic microangiopathy or interstitial pneumonitis was not significantly different between groups. The reduction in the risk of severe aGVHD was offset by an increased (20% versus 4%, P = .015) incidence of and mortality from sinusoidal obstructive syndrome (SOS). Sirolimus/tacrolimus appears to reduce the incidence of aGVHD after conventional allotransplantion compared to MTX-calcineurin inhibitor prophylaxis; however, this did not improve survival. [ABSTRACT FROM AUTHOR]

Abstract: Results were analyzed for 48 consecutive patients with acute myeloid leukemia not in remission who underwent unrelated donor bone marrow or stem cell transplantation between 1991 and February 2003 at 2 transplant centers. Forty-six were adults with a median age of 32 years (range, 4-58 years). Forty-two were HLA-A, -B, and -DR matched with their respective donors, and 6 were mismatched at 1 of these loci. The conditioning regimen was myeloablative in all cases: busulfan/cyclophosphamide/etoposide in 34 patients, busulfan/cyclophosphamide in 10 patients, and total body irradiation based in 4 patients. Median follow-up for survivors was 540 days (range, 145-2716 days). Only patients with <5000 peripheral blood blasts per microliter at the time of transplantation survived 2 years (18% versus 0%; P = .003). Similarly, patients with <20% blasts in the marrow at the time of transplantation had superior 2-year survival compared with those who had ≥20% (33% versus 5%; P = .04). Patients with <20% blasts who had ≥3 prior therapies also fared poorly. Cause of death was more commonly treatment related rather than relapse related. This study confirms that patients with acute myeloid leukemia not in remission can achieve prolonged survival with myeloablative conditioning and unrelated donor cell transplantation. However, sustained survival occurs only in patients with a low disease burden at the time of unrelated donor stem cell transplantation, and patients with a high disease burden may benefit from added counseling regarding the high risk of death due to both treatment-related toxicities and disease relapse. [Copyright &y& Elsevier]

Corticosteroids are considered the standard first-line treatment for moderate/severe acute graft versus host disease (aGVHD), yet there is no consensus on the optimal management of patients that are steroid-refractory (SR). Infliximab is a chimeric monoclonal antibody with anti-TNF-α activity that has previously demonstrated efficacy in SR-aGVHD. We performed a retrospective review of 59 patients at Indiana University who underwent allogeneic stem cell transplantation and developed SR grade III-IV aGVHD from January 2007 to August 2018. Infliximab was administered 10 mg/kg weekly intravenously. Response criteria was in accordance with Martin et al (BBMT 2009; 12:777-784). Median age of treated patients was 49.5 years (range, 34.5-60) and median time from transplant to diagnosis of aGVHD was 106 days (range, 42-185) Patients received a median of 12 days (range, 8-20) of systemic steroids prior to infliximab. At the start of infliximab, 52 (88%) patients were on non-steroidal immunosupressants and 39 (66%) on non-absorbable steroids concurrently with systemic steroids. Patients received a median of 3 doses of infliximab with 37 (62.7%) patients receiving <4 doses. At 28 days after first infliximab dose, overall response was seen in 16 (27.1%) patients, with 8 patients achieving a complete response and 8 with a very good partial response. From the start of infliximab, the median overall survival was 104 days with 76.3% (n=45) non-relapse mortality and 5% (n=3) relapse mortality. Bacterial infections were seen in 41 (66%) patients treated with infliximab with median time to onset of 13 days (range, 6-24), and viral infections were seen in 31 (50%) of patients with median time to onset of 16 days (range, 9-43). There was no significant difference between responders (n=16) and non-responders (n=43) in baseline demographic, transplant-related characteristics, initial GVHD prophylaxis regimen, number of non-steroidal systemic immunosuppressants at time of aGVHD diagnosis, or use of non-absorbable steroids. There was no difference in time from diagnosis of aGVHD to start of infliximab (median 16 vs. 11 days, P =0.06). Responders were less likely to have liver aGVHD involvement vs. non-responders (18% vs. 53%, P =0.016) and had slower tapering of systemic steroids, both at median time to 50% steroid dose (18 vs. 12 days, P =0.02) and 25% steroid dose (36 vs. 24 days, P =0.01). Responders had lower incidence of bacterial infection (44% vs. 74%, P =0.04), but not viral infections (56% vs. 47%, P =0.57). Responders had a longer overall survival (median 20.3 vs. 2.8 months, P =0.01). Our single center report of 59 patients with SR-aGVHD treated with infliximab is among the largest reported. The outcomes of response to SR-aGVHD are poor and there is an unmet need for better agents. Additional studies with greater patient numbers are needed to identify factors associated with improved response to infliximab. [ABSTRACT FROM AUTHOR]

Hepatic SOS is a potentially life-threatening complication occurring in up to 14% following HCT. Sirolimus (Siro) plus tacrolimus (FK) is an accepted regimen for graft-versus-host disease (GvHD) prophylaxis, with target Siro trough levels 10-20 ng/mL suggested to prevent acute GvHD (Blood 2016 128:3429). We previously reported that higher trough Siro levels might increase the risk of SOS, although a small sample size precluded detailed analysis. (Pharmacotherapy 2012; 32:441-5). In this study, we investigated if Siro and FK levels at specified times post-transplant are associated with an increased risk of SOS following non-busulfan, myeloablative conditioning. We analyzed 260 consecutive patients with hematological malignancies treated at Indiana University from 2007 to 2016 who underwent allogeneic HCT following myeloablative conditioning using TBI-based (n=151) or non-busulfan chemotherapy only (n=109) regimens. Patients received Siro plus FK for GvHD prophylaxis. No prophylaxis for SOS was used. Trough levels of Siro (target 5-15 ng/mL) and FK (target 5-10 ng/mL) were obtained at least twice weekly through day 30. SOS occurred in 28 patients at a median of 22 (range, 12-58) days for a cumulative incidence of 10.8%. Nine patients died of other causes before day 40 and were excluded from further analysis. Siro and FK troughs were compared in patients who developed SOS (n=28) with those who did not (n=223). Baseline characteristics were similar between the two groups. Mean Siro trough levels were higher between days 11-20 following transplant in patients who developed SOS (10.3 vs 8.5 ng/mL, P =0.008), while there was no significant difference in mean trough levels between days 0-10 (P =0.67) and days 21-30 (P =0.37) (Fig. 1). Patients with mean Siro trough level >9 ng/mL had higher incidence of SOS compared with those with Siro ≤ 9 ng/ml (71.4% vs. 41.7%; P =0.003). No differences in mean FK levels during the same time intervals were observed between those developing SOS and others. On multivariable analysis, mean Siro trough level >9 ng/ml between days 11-20 post-transplant was associated with an increased risk of SOS (odds ratio [OR] 3.9, 95% CI: 1.6-9.8, P =0.003), together with a longer time from diagnosis to transplant (P =0.004) and use of a TBI-based regimen (P =0.006). Among patients who did not develop SOS, mean Siro trough levels ≤9 ng/ml between days 11-20 were not associated with an increased risk of grade II-IV acute GvHD at day 100 compared with levels >9 ng/mL (13.8% vs. 17.3%, P =0.99). We conclude that mean trough Siro levels >9 ng/mL between days 11-20 post-transplant significantly increase the risk of SOS. Targeting lower Siro trough levels (e.g., 5-10 ng/mL) may reduce the risk of SOS without increasing acute GvHD. By interfering with endothelial cell function and potential healing following damage caused by TBI and/or high-dose chemotherapy, higher Siro levels could lead to SOS. [ABSTRACT FROM AUTHOR]