IntroductionDPP-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.ObjectiveConduct 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.MethodsPatients 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.ResultsThirty-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).ConclusionCD26/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.

Hypogammaglobulinemia is a poorly described complication of chemotherapy in adolescents and young adults (AYAs, 15-39 years) with acute lymphoblastic leukemia (ALL). The majority of AYAs treated on a Berlin-Frankfurt-Munster-based ALL regimen experienced hypogammaglobulinemia (65.0% [13/20]). Febrile neutropenia episodes (throughout the treatment course) and infectious events during maintenance occurred more frequently in hypogammaglobulinemic patients compared with patients with normal immunoglobulin G levels (n = 7) (median 1.0 vs. 0.0,p = 0.02; 7.0 vs. 3.0,p = 0.02, respectively). Hypogammaglobulinemia did not impact overall or event-free survival. Further studies are needed to elucidate the etiology of hypogammaglobulinemia and to establish criteria for immunoglobulin replacement in these patients.

Sinusoidal obstruction syndrome (SOS) is a serious complication of hematopoietic stem cell transplantation (HSCT). Sirolimus plus tacrolimus is an accepted regimen for graft-versus-host disease (GVHD) prophylaxis, with both agents implicated as risk factors for SOS. We analyzed 260 consecutive patients who underwent allogeneic HSCT following myeloablative conditioning using total body irradiation (TBI)-based (n = 151) or chemotherapy only (n = 109) regimens, with sirolimus plus tacrolimus for GVHD prophylaxis. SOS occurred in 28 patients at a median of 22 (range, 12–58) days. Mean sirolimus trough levels were higher between days 11 and 20 following transplant in patients who developed SOS (10.3 vs. 8.5 ng/ml, P = 0.008), with no significant difference in mean trough levels between days 0 and 10 (P = 0.67) and days 21–30 (P = 0.37). No differences in mean tacrolimus trough levels during the same time intervals were observed between those developing SOS and others. On multivariable analysis, a mean sirolimus trough level ≥ 9 ng/ml between days 11 and 20 increased the risk of SOS (hazard ratio 3.68, 95% CI: 1.57–8.67, P = 0.003), together with a longer time from diagnosis to transplant (P = 0.004) and use of TBI (P = 0.006). Our results suggest that mean trough sirolimus levels ≥ 9 ng/mL between days 11 and 20 post transplant may increase the risk of SOS and should be avoided.

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.

Study Objective Basiliximab is an immunosuppressive monoclonal antibody used for rejection prevention following solid organ transplantation; the pharmacokinetics (PK) of basiliximab in this setting are known. Basiliximab may also be used for prophylaxis and treatment of graft-versus-host disease (GVHD) in patients undergoing allogeneic hematopoietic cell transplantation (HCT); however, the PK of basiliximab in this setting are not known. Clinical transplant providers expect variation in the volume of distribution and clearance after nonmyeloablative allogeneic transplantation (NMAT) compared with solid organ transplantation. Blood loss, organ site-specific antibody accumulation, and differences in blood product use during the two transplantation approaches may generate differences in basiliximab PK. Therefore, the objective of this study was to describe the PK of basiliximab after its addition to a minimally intense NMAT regimen, in conjunction with cyclosporine, for GVHD prophylaxis in patients with hematologic malignancies. Design Population PK analysis of a single-center, single-arm, phase II clinical trial. Setting Academic cancer research center. Patients Fourteen adults with hematologic malignancies (acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myelodysplastic syndrome, non-Hodgkin's lymphoma, Hodgkin's lymphoma, myelofibrosis, or severe aplastic anemia) and undergoing NMAT with a fully HLA-matched (10 of 10 antigen matched) related or unrelated donor. Measurements and Main Results Basiliximab was used in conjunction with cyclosporine to deplete activated T cells in vivo as GVHD prophylaxis. We developed a novel competitive enzyme-linked immunosorbent assay (ELISA) method using recombinant interleukin-2 receptor alpha-chain (IL-2Ra) and a commercially available soluble sIL-2R ELISA kit to permit the quantification of serum basiliximab concentrations and characterization of the PK properties of the drug in this patient population. Using a nonlinear mixed effects model with NONMEM software, a one-compartment model with first-order elimination best described the PK, as covariate analysis using stepwise covariate modeling did not improve the base model. Conclusion We suggest a one-compartment population model with first-order elimination to capture the PK profile for basiliximab for this patient population.

BackgroundTT/Cy has been reported as a well-tolerated conditioning regimen in patients with a variety of advanced leukemias undergoing allogeneic HCT (Blood 1996, 88:353-7). While other TT-containing regimens have been investigated, outcomes with TT/Cy, specifically, in a more uniform population have not been reported. Here, we report the outcome of TT/Cy in patients with myeloid malignancies undergoing allogeneic HCT, and compare the results with TBI/Cy.MethodsWe retrospectively analyzed 149 consecutive patients with AML (n=101), advanced CML (n=29), and high-grade MDS with >5% blasts (n=19) who received either TBI/Cy (TBI >13.5 Gy; Cy 120 mg/kg) or TT/Cy (TT 15 mg/kg; Cy 120 mg/kg) and allogeneic HCT from HLA-matched sibling or 10/10 or 9/10 HLA-matched volunteer unrelated donors (VUD) between 2007-2016 at Indiana University.ResultsSixty-seven patients received TBI/Cy and 82 received TT/Cy. Baseline characteristics were not significantly different. TBI/Cy resulted in significantly higher grades 3-4 toxicity, including mucositis (64% vs. 48%, P=0.048), acute respiratory failure (22% vs. 10%, P=0.04), transaminase elevation (24% vs. 9%, P=0.01), acute renal failure (16% vs. 5%, P=0.02), and sinusoidal obstruction syndrome (16% vs. 0%, P=0.0001). Cumulative incidence of 100-day grades 2-4 acute GVHD (TBI/Cy 15.0% ± 4.4%, TT/Cy 20.7% ± 4.5%; P=0.15) and extensive stage chronic GVHD at 1-year (TBI/Cy 35.3% ± 6%, TT/Cy 43.6% ± 5.6%; P=0.27) were not significantly different. The cumulative incidence (CI) of non-relapse mortality (NRM) was higher following TBI/Cy (Fig 1A, P<0.001); at 1 year NRM was 31.5% ± 5.8% for TBI/Cy and 12.2% ± 3.6% for TT/Cy. There was no significant difference in the CI of relapse (CIR) (Fig 1B, P=0.49); the 3-year CIR was 21.2% ± 5.1% with TBI/Cy and 28.7% ± 5.6% with TT/Cy. The overall survival (OS) was significantly higher with TT/Cy compared with TBI/Cy at 1 year (79.3% ± 4.5% versus 52.2% ± 6.1%) and 3 years (57.3% ± 5.9% versus 35% ± 5.9%) (Fig 1C, P=0.001). On multivariable analysis, TT/Cy was associated with a significantly lower risk of death (HR 0.42; 95% CI: 0.27-0.68, P<0.001), while 9/10 HLA-matched VUD and Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) >5 were both associated with a higher hazard of death (P=0.02 and P=0.004).ConclusionTT/Cy is an effective conditioning regimen in patients with myeloid malignancies undergoing allogeneic HCT and is associated with lower NRM compared with TBI/Cy. Future studies should assess whether addition of other agents to TT and Cy improve outcomes or simply increase toxicity. TT/Cy has been reported as a well-tolerated conditioning regimen in patients with a variety of advanced leukemias undergoing allogeneic HCT (Blood 1996, 88:353-7). While other TT-containing regimens have been investigated, outcomes with TT/Cy, specifically, in a more uniform population have not been reported. Here, we report the outcome of TT/Cy in patients with myeloid malignancies undergoing allogeneic HCT, and compare the results with TBI/Cy. We retrospectively analyzed 149 consecutive patients with AML (n=101), advanced CML (n=29), and high-grade MDS with >5% blasts (n=19) who received either TBI/Cy (TBI >13.5 Gy; Cy 120 mg/kg) or TT/Cy (TT 15 mg/kg; Cy 120 mg/kg) and allogeneic HCT from HLA-matched sibling or 10/10 or 9/10 HLA-matched volunteer unrelated donors (VUD) between 2007-2016 at Indiana University. Sixty-seven patients received TBI/Cy and 82 received TT/Cy. Baseline characteristics were not significantly different. TBI/Cy resulted in significantly higher grades 3-4 toxicity, including mucositis (64% vs. 48%, P=0.048), acute respiratory failure (22% vs. 10%, P=0.04), transaminase elevation (24% vs. 9%, P=0.01), acute renal failure (16% vs. 5%, P=0.02), and sinusoidal obstruction syndrome (16% vs. 0%, P=0.0001). Cumulative incidence of 100-day grades 2-4 acute GVHD (TBI/Cy 15.0% ± 4.4%, TT/Cy 20.7% ± 4.5%; P=0.15) and extensive stage chronic GVHD at 1-year (TBI/Cy 35.3% ± 6%, TT/Cy 43.6% ± 5.6%; P=0.27) were not significantly different. The cumulative incidence (CI) of non-relapse mortality (NRM) was higher following TBI/Cy (Fig 1A, P<0.001); at 1 year NRM was 31.5% ± 5.8% for TBI/Cy and 12.2% ± 3.6% for TT/Cy. There was no significant difference in the CI of relapse (CIR) (Fig 1B, P=0.49); the 3-year CIR was 21.2% ± 5.1% with TBI/Cy and 28.7% ± 5.6% with TT/Cy. The overall survival (OS) was significantly higher with TT/Cy compared with TBI/Cy at 1 year (79.3% ± 4.5% versus 52.2% ± 6.1%) and 3 years (57.3% ± 5.9% versus 35% ± 5.9%) (Fig 1C, P=0.001). On multivariable analysis, TT/Cy was associated with a significantly lower risk of death (HR 0.42; 95% CI: 0.27-0.68, P<0.001), while 9/10 HLA-matched VUD and Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) >5 were both associated with a higher hazard of death (P=0.02 and P=0.004). TT/Cy is an effective conditioning regimen in patients with myeloid malignancies undergoing allogeneic HCT and is associated with lower NRM compared with TBI/Cy. Future studies should assess whether addition of other agents to TT and Cy improve outcomes or simply increase toxicity.

Many patients with primary immunodeficiency (PID) require immunoglobulin G (IgG) replacement therapy, delivered as intravenous IgG (IVIG) or subcutaneous IgG (SCIG). We aim to identify trends in efficacy and safety that would not be evident in individual studies of small patient numbers. Seven open-label, Phase 3, prospective, multicenter studies of the efficacy and safety of Hizentra® (a SCIG), conducted in Japan, Europe, and the US were summarized. Overall, 125 unique patients received 15,013 weekly infusions during a total observation period of 250.9 patient-years. Mean weekly doses of Hizentra® were 83.22–221.3 mg/kg body weight; infusion rates per patient (total body rate) were 25.2–49.3 mL/h across studies. The rates of infections and serious bacterial infections were 3.10 and 0.03 events per patient/year, respectively. Annualized rates of days hospitalized due to infection, out of work/school, and prophylactic antibiotic use were 0.95, 5.14, and 36.78 per patient, respectively. For the equivalent monthly dose, weekly Hizentra® SCIG administration resulted in expectedly-increased serum IgG trough levels in patients switching from IVIG, and maintained levels in patients switching from previous SCIG. Adverse events (AEs) totaled 5039 (events/infusion 0.094–0.773), almost all of which were mild/moderate. Three thousand one hundred ninety-seven were considered treatment-related, the most common of which were injection site reactions (2919 events; 0.001–0.592 AEs per infusion). Systemic AEs were very uncommon. The results from these seven studies indicate that Hizentra® therapy was both efficacious and well tolerated during long-term treatment. This is particularly important in patients with PID, who may require lifelong IgG replacement therapy.

Abstract Background: The optimal setting to treat AYA patients remains a complex decision involving access to different treatment regimens, clinical trial availability, and appropriate psychosocial support. There are data to support that AYA patients with acute lymphoblastic leukemia (ALL) have better outcomes and improved overall survival when treated on pediatric inspired treatment protocols. However, limited data exist for similar patients with AML. We, therefore, sought to assess the variation in outcomes between AML patients within the AYA population treated in our pediatric setting versus adult setting. Methods: A retrospective review of patients with newly diagnosed AML aged 17-25 years old (n=33) treated at either the Indiana University Simon Cancer Center (n=20) or Riley Hospital for Children at Indiana University Health (n=13) between 2006 and 2018 was completed. All patients in the adult setting received standard induction therapy with the 7+3 (standard-dose cytarabine, anthracycline) regimen, while patients in the pediatric setting received an ADE (daunorubicin, cytarabine, etoposide) backbone +/- investigational agents per clinical trial protocols. Data were analyzed with t-tests using IBM SPSS v25 software. This study was approved by the Indiana University Institutional Review Board. Results: Median age was 23 years in patients treated in the adult setting (range 19-25) compared with 17 years (range 17-20) in the pediatric setting. As per the most recent NCCN risk classification for AML, patients in the adult setting were classified as 55% poor risk, 35% intermediate risk, and 10% favorable risk; in the pediatric setting, risk classification was 15% poor risk, 62% intermediate risk, and 23% favorable risk. The incidence of FLT3 mutations was n=4 (20%) in the adult setting and none in the pediatric setting. Clinical trial enrollment was markedly lower in the adult setting with no patients enrolled compared with 54% (7/13) enrolled in the pediatric setting. Complete response (CR) was achieved in 85% of patients treated in the adult setting, but only 62% of patients treated in the pediatric setting. Relapse post induction was higher in the pediatric setting (n=6, 46%) compared to the adult setting (n=5, 40%), and median time to relapse was shorter in the pediatric setting (275 days vs. 344 days). During induction, no statistically significant differences in toxicities were found as measured by ICU interventions (dialysis, mechanical ventilation/NIPPV, and/or use of vasopressors) and identified infections (bacteremia, pneumonia, and/or clostridium difficile). Clostridium difficile infections were increased in the adult setting (15% vs. 0%), but identified bacteremia was higher in the pediatric setting (38% vs. 20%). The median time to allogeneic stem cell transplantation in the adult setting was 117.5 days compared to a median of 223 days seen in the pediatric setting. Incidence of relapse post stem cell transplantation was higher in the adult setting (36% vs. 17%). Proportion of overall survival was 50% (n=10) in the adult setting and 28% (n=8) in the pediatric setting. The highest mortality was seen in poor-risk patients (90%) in the adult setting and intermediate risk patients (62.5%) in the pediatric setting. A trend was seen towards improved overall survival in the adult setting with median overall survival of 739.5 days in the adult setting compared to 415 days in the pediatric setting (p=0.11). In both settings, patients that proceeded to stem cell transplantation had conferred survival benefit: median 1128 vs. 414.5 days in the adult setting and median 530.5 vs. 486.5 days in the pediatric setting. Conclusion: Despite having a higher risk population and lower clinical trial enrollment, we found a trend towards higher complete response rate after induction, reduced relapse rate after induction, shorter time to transplant, longer time to relapse post-transplant, improved survival in the transplant population, and improved median overall survival without a clear increase in toxicity in patients treated in our adult setting. This is in contrast to data in ALL, which suggests improved patient outcomes in AYA patients treated with pediatric based regimens. Our data is limited by a small sample size and a single institution experience. Larger, multicenter studies are needed to understand the optimal AML treatment strategy in the AYA population. Table. Table. Disclosures No relevant conflicts of interest to declare.

Introduction: Nonmyeloablative (NMA) regimens allow HSCT for many otherwise ineligible patients with Acute Myeloid Leukemia (AML). NMA regimens are generally better tolerated with lower rates of toxicity than Myeloablative (MA) regimens and have comparable outcomes(S M Luger et al 2012.). Our institutional practice has been to offer NMA conditioning regimens to patients > 60 and patients up to 75 years of age. Previous studies have combined various agents with Fludarabine as part of NMA conditioning (Bacigalupo et al . 2009). In the absence of prospective randomized studies, head to head comparison between various regimens have been largely limited to retrospective studies and included heterogenous groups of patients. Methods: We retrospectively analyzed 80 consecutive AML patients who underwent non myeloablative Fludarabine/Cyclophosphamide (n=38) or myeloablative Thiotepa/ Cyclophosphamide (n=42) conditioning followed by allogeneic HSCT between March 2010 and July 2016. Analysis was conducted using proportional hazards regression accounting for competing risk for disease free survival (DFS), Transplant related mortality (TRM) and overall survival (OS) with different variables as a covariate. Results: The median age at transplant was 53.2 years, median duration of follow up was 25 months, 95% (n=76) patients had high risk features defined as disease in 2nd or 3rd Complete remission, adverse risk disease, secondary AML or required >1 induction therapy, 46.2 % (n=37) patients were older than 55 and 53.1% (n=42) had adverse risk disease. The median age at transplant for NMA group was 60.3 years and that for MA group was 42.8 years. Remission was maintained in 60% patients (n=48) and 47% (n=37) patients remained alive during the study period. On survival analysis, relapse free survival and overall survival were comparable between two groups despite the disparity in median age between two groups by > 18 years (Figure 1 & 2). Transplant related mortality (TRM) increased with increasing age at transplant, was higher in patients with secondary AML (Hazards ratio 4.9, 95% Confidence Interval 1.4-17.1, p=0.01) and patients treated with Fludarabine/Cyclophosphamide (HR 8.7, 95% CI 1.1- 70.5, p=0.04). Conclusion: Within limits of this study, non-myeloablative conditioning regimen consisting of minimal intensity Fludarabine/Cyclophosphamide was comparable to myeloablative Cyclophosphamide/Thiotepa in terms of relapse free survival and overall survival in AML especially in elderly population. Transplant Related Mortality increased with increasing age at transplant. Download : Download high-res image (172KB) Download : Download full-size image Disclosures No relevant conflicts of interest to declare.

Human immunoglobulin preparations for intravenous or subcutaneous administration are the cornerstone of treatment in patients with primary immunodeficiency diseases affecting the humoral immune system. Intravenous preparations have a number of important uses in the treatment of other diseases in humans as well, some for which acceptable treatment alternatives do not exist. We provide an update of the evidence-based guideline on immunoglobulin therapy, last published in 2006. Given the potential risks and inherent scarcity of human immunoglobulin, careful consideration of its indications and administration is warranted. (J Allergy Clin Immunol 2017; 139: S1-46.)

Background: Acute myelogenous leukemia (AML) progresses uniquely in each patient. However, patients are typically treated with the same types of chemotherapy, despite biological differences that lead to differential responses to treatment.Results: Here we present a multi-lineage multi-compartment model of the hematopoietic system that captures patient-to-patient variation in both the concentration and rates of change of hematopoietic cell populations. By constraining the model against clinical hematopoietic cell recovery data derived from patients who have received induction chemotherapy, we identified trends for parameters that must be met by the model; for example, the mitosis rates and the probability of self-renewal of progenitor cells are inversely related. Within the data-consistent models, we found 22,796 parameter sets that meet chemotherapy response criteria. Simulations of these parameter sets display diverse dynamics in the cell populations. To identify large trends in these model outputs, we clustered the simulated cell population dynamics using k-means clustering and identified thirteen 'representative patient' dynamics. In each of these patient clusters, we simulated AML and found that clusters with the greatest mitotic capacity experience clinical cancer outcomes more likely to lead to shorter survival times. Conversely, other parameters, including lower death rates or mobilization rates, did not correlate with survival times.Conclusions: Using the multi-lineage model of hematopoiesis, we have identified several key features that determine leukocyte homeostasis, including self-renewal probabilities and mitosis rates, but not mobilization rates. Other influential parameters that regulate AMLmodel behavior are responses to cytokines/growth factors produced in peripheral blood that target the probability of self-renewal of neutrophil progenitors. Finally, our model predicts that the mitosis rate of cancer is the most predictive parameter for survival time, followed closely by parameters that affect the self-renewal of cancer stem cells; most current therapies target mitosis rate, but based on our results, we propose that additional therapeutic targeting of self-renewal of cancer stem cells will lead to even higher survival rates.

8574 Background: Paraneoplastic syndromes (PNS) are commonly associated with thymic epithelial tumors (TET), especially thymoma. The purpose of this analysis is to examine the clinical impact of PNS in TET. Methods: Patients with pathologically diagnosed TET at a single institution were reviewed retrospectively. The primary and second endpoints for this study were overall survival (OS) and recurrence rates. Clinical factors included age, gender, race, performance score, histology, WHO classification, Masaoka stage, post-operative status, tumor size and number of positive lymph nodes. Cox proportional hazards model was used to identify significant prognostic factors for OS between different PNS groups. Results: From 1975 to 2016, 733 patients with TET (thymoma (T) -71%, thymic carcinoma (TC) -26% and neuroendocrine tumor (NET)-3%) were seen at Indiana University. Of these, 203 (28%) had PNS including myasthenia gravis (n = 130), red cell aplasia (n = 20), hypogammaglobulinemia (n = 14), systemic lupus erythematosus (n = 12) or other PNS (n = 64). Among these, 37 (18%) had two or more types of PNS. PNS were seen in 35% (183/523) of T, 9% (16/187) of TC and 15% (3/20) of NET ( p < 0.001), respectively. Recurrence rates and mortality at 5 year were 8% and 10% in PNS (+) group compared to 13% and 16% in PNS (-) group ( p < 0.05). Intrathoracic recurrences were more common in PNS (+) patients (89% vs 77%; p = 0.016). In both groups, adverse factors for survival included: older age, advanced stage, number of positive lymph nodes and TC histology (all p-values < 0.05). However, post-operative R1/2 status was adverse prognostic factor only in the PNS (-) group ( p = 0.001). Conclusions: PNS is common in TETs. Patients with PNS have lower risk of recurrence and mortality compared to patients without PNS, but may have a higher risk of intrathoracic recurrence.

Background: Due to lack of randomized trials, the role of postoperative radiation therapy (PORT) in thymic epithelial tumors (TET) remains controversial. This study aimed to evaluate whether PORT improves treatment outcome in patients with resected TET in a large single institution database. Methods: This is a retrospective study of all TETs seen at Indiana University between 1975 and 2015. Patients with resected thymoma or thymic carcinoma were eligible disregarding their margin status or stage. Study endpoints were progression free survival (PFS) and overall survival (OS). Age, gender, race, tumor size, stage, pathology, grade, completeness of resection and adjuvant treatment modality were analyzed for significance on PFS and OS. Multivariate Cox model was used to identify significant factors for propensity score matching. Differences between the PORT and surgery alone group were estimated using stratified log-rank test. Results: A total of 478 patients with surgical resection of primary tumors were eligible. Masaoka stage was: (I) 86 (22%); (II) 87 (23%); (III) 107 (28%); and (IV) 106 (27%) respectively. Multivariate analysis demonstrated that gender (HR =1.4, P=0.03), stage (HR =1.3, P=3×10−3), thymic carcinoma (HR =1.6, P=0.03) and PORT (HR =1.6, P=0.002) were significantly associated with PFS. Age (HR =1.1, P=4×10−7), histology of thymic carcinoma (HR =3.2, P=3×10−5), stage (HR =1.4, P=0.003) were associated with OS. PORT was given to 126 (26%) patients. Propensity score matching based on independent prognostic factors of OS identified 99 patients for PORT, matched to 285 patients without. The 5­/10-year intra­thoracic progression free rates were 77%/69% and 85%/68%, for patients with and without PORT (P=0.009), respectively. The 5-/10-year PFS rates were 39%/18% and 61%/32%, for patients with and without PORT (P=0.002), respectively. The median survival, 5-/10-year OS rates for patients treated with PORT were 150 (95% CI, 111–277) months, 87%/57% and respectively, compared to 192 months (95% CI, 167–279), 88%/69% for patients receiving surgery alone (P=0.13). Subgroup analysis demonstrated that PORT significantly decreased PFS in thymoma (P<0.001), did not significantly change PFS in thymic carcinoma (P=0.137), or OS in thymoma (P=0.466) or OS in thymic carcinoma (P=0.719). For patients with stage II/III thymoma, PORT was neither significant for PFS nor OS, for either negative or positive margins (P ranged 0.134–0.461). Conclusions: In this series of patients, PORT did not improve OS in thymoma or thymic carcinoma disregarding the margin status, but significantly decreased PFS in patients with thymoma. Role of PORT deserves further study in TET.

Delayed engraftment remains a limitation of umbilical cord blood (UCB) transplantation. We previously showed that inhibition of dipeptidylpeptidase (DPP)-4 using sitagliptin 600 mg daily was safe with encouraging results on engraftment, but inhibition was not sustained. We evaluated the efficacy and feasibility of higher doses of sitagliptin to enhance engraftment of UCB in patients with hematological cancers. Fifteen patients, median age 41 (range, 18-59) years, received single UCB grafts matched at 4 (n=11) or 5 (n=4) of 6 HLA loci with median nucleated cell dose of 3.5 (range, 2.57-4.57) x107/kg. Sitagliptin 600 mg every 12 hours was administered days -1 to +2. All patients engrafted by day 30, with 12 (80%) engrafting by day 21. The median time to neutrophil engraftment was 19 (range, 12-30) days. Plasma DPP-4 activity was better inhibited with a mean residual trough DPP-4 activity of 70%±19%. Compared to patients previously treated with 600 mg/day, sitagliptin 600 mg every 12 hours appeared to improve engraftment, supporting the hypothesis that more sustained DPP-4 inhibition is required. In-vivo inhibition of DPP-4 using high-dose sitagliptin compares favorably with other approaches to enhance UCB engraftment with greater simplicity, and may show synergy in combination with other strategies.

Introduction: Aplastic anemia is thought to occur most often because of an aberrant autoreactive cytotoxic T-cell response that destroys hematopoietic stem cells. Therefore, treatment involves either immunosuppressive therapy utilizing antithymocyte globulin and a calcineurin inhibitor, or bone marrow transplantation. General guidelines recommend stopping calcineurin therapy after 4-6 months. However, anecdotal delayed responses in patients treated with extended calcineurin inhibition (ECI), combined with the principle that solid organ transplant recipients routinely receive calcineurin inhibitor therapy for years, prompted this retrospective analysis of ECI. Such information will be particularly relevant to patients who do not have a matched sibling bone marrow donor, have relative contraindications to a second course of intensive immunosuppressive therapy, or are not able to access a promising investigational protocol. Objective: (1) To compare peripheral blood count and survival outcomes of severe aplastic anemia patients treated with extended calcineurin inhibitor therapy to patients treated with matched sibling-donor bone marrow transplantation (MRD-BMT). (2) To compare peripheral blood count improvement from 6 month values in the ECI cohort to quantify the effect of extending therapy. Design, Setting, and Patients: Patients were selected from a database of fifty-three patients with severe and very severe aplastic anemia treated between 1994 and 2017 at the Indiana University Melvin and Bren Simon Cancer Center. Treatment groups included extended calcineurin inhibitor (defined as treatment greater than six months; n=15) and matched sibling-donor bone marrow transplantation (n=9). Patients who received 6 months or less of calcineurin inhibition, matched unrelated transplantation, other second-line therapies, supportive care, or those with missing data were excluded from analysis. Methods: Patients in the ECI arm were initially treated with anti-thymocyte globulin, glucocorticoids, and calcineurin inhibitor (cyclosporine or tacrolimus) followed by continuous calcineurin inhibition for longer than 6 months. Immediate pre-treatment counts were those obtained at the time of admission for therapy. White blood cell (WBC), hemoglobin (Hb), and platelet (Plt) counts were monitored retrospectively and improvement from the pre-treatment values was analyzed using the Mann-Whitney nonparametric U test. The influence of transfusions was accounted for by excluding counts obtained within one week of transfusion. Results: Median follow-up time was 34mo and 54mo respectively for the ECI and BMT cohorts. Figure 1 compares median improvement in cell counts between the ECI and MRD-BMT treatment arms. Figure 2 compares median cell counts of the ECI cohort after 6 months compared to their 6 month values. Patients with severe aplastic anemia who received MRD-BMT had a statistically significant greater improvement in median WBC counts from their pre-treatment values for up to 15 months, hemoglobin for up to 7 months, and platelet counts for up to 48 months compared to those who received ECI. However, beyond these times the difference in outcomes was not significant. Survival for ECI group was 88% versus 89% for patients undergoing BMT, p-value 0.749. Patients with severe aplastic anemia who were treated with calcineurin inhibition beyond 6 months had a statistically significant improvement in their hemoglobin beginning at 30 months and an otherwise general non-significant improvement in their counts. Conclusion: In this population of patients with severe aplastic anemia, MRD-BMT demonstrated greater improvement of peripheral counts compared to ECI initially, but the difference eventually became consistently not significant. Patients who received extended calcineurin inhibition demonstrated a consistent but non-significant improvement in their counts, except for perhaps hemoglobin, when compared to their 6 month values. Disclosures No relevant conflicts of interest to declare.

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. 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. 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. 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.

Background: The cause of primary immunodeficiency has expanded to nearly 200 distinct disorders. An improved understanding of these disorders has resulted in decreased morbidity and mortality with reciprocal improved life expectancy. Obstetricians should have knowledge of primary immunodeficiency, as more women with these disorders will reach reproductive age. Case: 21-year-old G1P0 with purine nucleoside phosphorylase (PNP) deficiency delivered a viable infant vaginally at 37 weeks. Although the patient's diagnosis and pregnancy placed her at increased risk for infection, she remained asymptomatic and infection-free throughout pregnancy. Conclusion: The management of pregnancy complicated by PNP deficiency requires strict immune surveillance and regimented immunoglobulin replacement.

Recombination-activating genes 1 and 2 (RAG1 and RAG2) play a critical role in T and B cell development by initiating the recombination process that controls the expression of T cell receptor (TCR) and immunoglobulin genes. Mutations in the RAG1 and RAG2 genes in humans cause a broad spectrum of phenotypes, including severe combined immunodeficiency (SCID) with lack of T and B cells, Omenn syndrome, leaky SCID, and combined immunodeficiency with granulomas or autoimmunity (CID-G/AI). Using next-generation sequencing, we analyzed the TCR and B cell receptor (BCR) repertoire in 12 patients with RAG mutations presenting with Omenn syndrome (n = 5), leaky SCID (n = 3), or CID-G/AI (n = 4). Restriction of repertoire diversity skewed usage of variable (V), diversity (D), and joining (J) segment genes, and abnormalities of CDR3 length distribution were progressively more prominent in patients with a more severe phenotype. Skewed usage of V, D, and J segment genes was present also within unique sequences, indicating a primary restriction of repertoire. Patients with Omenn syndrome had a high proportion of class-switched immunoglobulin heavy chain transcripts and increased somatic hypermutation rate, suggesting in vivo activation of these B cells. These data provide a framework to better understand the phenotypic heterogeneity of RAG deficiency.