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Small-molecule inhibitors of PD-L1 are postulated to control immune evasion in tumors similar to antibodies that target the PD-L1/PD-1 immune checkpoint axis. However, the identity of targetable PD-L1 inducers is required to develop small-molecule PD-L1 inhibitors. In this study, using chromatin immunoprecipitation (ChIP) assay and siRNA, we demonstrate that vitamin D/VDR regulates PD-L1 expression in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) cells. We have examined whether a VDR antagonist, MeTC7, can inhibit PD-L1. To ensure that MeTC7 inhibits VDR/PD-L1 without off-target effects, we examined competitive inhibition of VDR by MeTC7, utilizing ligand-dependent dimerization of VDR-RXR, RXR-RXR, and VDR-coactivators in a mammalian 2-hybrid (M2H) assay. MeTC7 inhibits VDR selectively, suppresses PD-L1 expression sparing PD-L2, and inhibits the cell viability, clonogenicity, and xenograft growth of AML cells. MeTC7 blocks AML/mesenchymal stem cells (MSCs) adhesion and increases the efferocytotic efficiency of THP-1 AML cells. Additionally, utilizing a syngeneic colorectal cancer model in which VDR/PD-L1 co-upregulation occurs in vivo under radiation therapy (RT), MeTC7 inhibits PD-L1 and enhances intra-tumoral CD8+T cells expressing lymphoid activation antigen-CD69. Taken together, MeTC7 is a promising small-molecule inhibitor of PD-L1 with clinical potential.

The utilization of hematopoietic stem cell transplantation (HSCT) has been rapidly growing due to multiple factors, including better availability of donors and improved supportive care. Hyperbaric oxygen has been associated with the improvement of hematopoietic stem cell (HSC) homing at the time of transplant through lowering erythropoietin levels in preclinical studies. We studied the role of hyperbaric oxygen (HBO) in the enhancement of engraftment of HSC when utilized prior to umbilical cord HSCT and autologous HSCT in two pilot clinical trials with excellent safety profiles. In these two pilot studies, we observed an uncommon phenomenon post-transplant, particularly a significant peripheral blood lymphocytosis and lymphocyte infiltration of different tissues in 3/34 of HBO-treated patients. This peripheral blood lymphocyte expansion was associated with various clinical manifestations that can be confused with infections, inflammatory conditions, or disease relapse. We hypothesize that this observation is related to different immune reconstitution dynamics related to the use of HBO. While the incidence is ~9%, this may have implications as HBO is being investigated in larger clinical trials. This case series highlights the clinical presentation, course, outcome, and potential implications of this significant rise in lymphocytes when utilizing HBO before HSCT.

Introduction Myelofibrosis (MF) is a bone marrow neoplasm characterized by marrow fibrosis/failure and splenomegaly, causing pain, early satiety, and cytopenia. The only curative option is allogeneic hematopoietic stem cell transplant (allo-HSCT); however, its use is limited due to donor availability and patient age, functional status, and comorbidities. Umbilical cord blood (UCB) has been explored in this population for this reason with variable success, partly related to splenomegaly, which might influence engraftment in MF patients. Objective The objective was to report the successful use of UCB transplantation in conjunction with splenic irradiation to treat a patient with advanced MF and massive splenomegaly. Methods A 71-year-old male with post-essential thrombocythemia MF was treated with ruxolitinib for 2 years but developed worsening cytopenia and transfusion dependence. Splenomegaly (19.1×7.1×20.8 cm) was identified. Allo-HSCT was recommended on the basis of high-risk disease (DIPSS Plus score: 4) and few alternative options. Although suitable HLA-matched donors were unattainable, two cord blood units were available. A reduced intensity conditioning regimen of fludarabine, cyclophosphamide, and TBI 300 was chosen. Given the primary resistance to ruxolitinib, the spleen was irradiated with 450 cGy prior to transplant. Results Neutrophil and platelet engraftment occurred on days +30 and +49, respectively. The patient developed engraftment syndrome and acute graft versus host disease (GVHD) that resolved with methylprednisolone and early introduction of ruxolitinib. His immunosuppressive medications were discontinued by 6-months without evidence of chronic GVHD thereafter. He is now 1 year post-transplant with 100% donor chimerism and no clinical evidence of MF or GVHD. Discussion We present a novel therapeutic approach combining the use of splenic irradiation and a double unit UCB HSCT in a patient with MF and massive splenomegaly. UCB transplant should be considered in patients with MF who do not have an HLA-matched donor with the additional benefit of less chronic GvHD. Massive splenomegaly can negatively impact transplant outcomes due to entrapment of donor stem cells, delayed engraftment, and prolonged cytopenia. Splenic irradiation before UCB transplant can potentially reduce these complications, as it did in this case, and in turn decrease transplant-related mortality. Our future aim is to develop a clinical trial to study this approach.

Adequate hematopoietic progenitor cell (HPC) collection is critical for patients undergoing autologous HPC transplant (AHPCT). Historically, 15 - 30% of patients failed HPC mobilization with granulocyte-colony stimulating factor (G-CSF) alone. Bortezomib, a proteasome inhibitor, has been shown to down regulate very late antigen-4 (VLA-4), an adhesion molecule expressed on HPCs. In this pilot study, bortezomib was administered on days -11 and -8 at a dose of 1.3 mg/m

A 47-year-old male had bilateral upper extremity thrombophlebitis after use of intravenous amiodarone for sustained ventricular tachycardia complicating myocardial infarction. Intravenous amiodarone has been widely used since it was introduced 20 years ago for severe intractable arrhythmias. Superficial thrombophlebitis was frequently noted in the early case reports when high-dose intravenous amiodarone was used. Superficial thrombophlebitis could extend hospitalization and become a significant source of distress to our patients. Some authors recommend insertion of a central line to administer intravenous amiodarone especially with expected extended use of therapy. The treating physician should be vigilant and switch from intravenous therapy to oral therapy as soon as the patient's condition stabilizes and oral therapy can be started.

Abstract 4525 High dose therapy and autologous transplantation is considered a standard of care procedure in symptomatic, transplant eligible multiple myeloma patients. The chemotherapy of choice in this situation is high dose melphalan. The later has marginal solubility and limited chemical stability upon reconstitution and dilution. The marginal stability of this compound has limited the use of regimens utilizing higher absolute dosages and/or longer infusions (> 60 minutes) that could potentially lead to improved outcomes. Accordingly, co-solvents are used in the marketed formulation, which are believed to contribute to the side effects of the therapy. A co-solvent used in Alkeran for Injection is propylene glycol, which has been reported to cause renal dysfunction, arrhythmias, hyperosmolality, increased anion gap metabolic acidosis, and sepsis-like syndrome. On the other hand, Melphalan HCl for Injection (Propylene Glycol-Free), a reformulation of Alkeran for Injection, incorporates the Captisol® brand of β-cyclodextrin sulfobutyl ethers, sodium salts (also known as [SBE]7m-β-CD) into a freeze-dried product developed by CyDex Pharmaceuticals, Inc. (CyDex). Captisol improves stability allowing for potentially longer infusion times. Study Design/Goals: In this phase IIa, open-label, randomized, cross-over design, the PK of Melphalan HCl for Injection (Propylene Glycol-Free) and Alkeran for Injection are assessed in the same MM patients undergoing transplantation. Furthermore, the rates of myeloablation and subsequent engraftment are determined, and any difference in expected safety and tolerability due to high-dose Melphalan HCl for Injection (Propylene Glycol-Free) is assessed in transplanted patients. Results: Seven patients of the planned 24 patients have already enrolled in the study at the University of Kansas Medical Center. All patients achieved myeloablation followed by successful engraftment. Median time to myeloablation, defined as number of days from the start of chemotherapy until absolute neutrophil count dropped below 500/Ul, was 6.4 days (range 5–7 days). Median time to neutrophil engraftment, defined as first day of three consecutive days where ANC was higher than 500/Ul following their nadir, was day +9. Beside expected grade 2–3 toxicities related to high dose melphalan, no additional toxicities were reported. In specific, no renal insufficiency was noted. Preliminary PK analysis has been performed on five patients. Preliminiary parameter estimates (Mean± SEM) are presented in the Table. The mean bioavailability was 113%. The mean half-lifes for the Melphalan HCl for Injection (Propylene Glycol-Free) and Alkeran for Injection were 70 and 75 min. Following Melphalan HCL for Injection (PropyleneGlycol-Free) and Alkeran for Injection, the distribution volumes were 0.23 and 0.35 L/kg and clearances were 0.29 and 0.34 L/hr per kg, respectively. Conclusion: Melphalan HCl for Injection (Propylene Glycol-Free), administered as half of a high-dose conditioning regimen, appears to result in successful myeloablation and subsequent engraftment at no extra-toxicity, and trending toward higher bio-availability compared to Alkeran. Future studies that are designed to expose patients exclusively to the propylene glycol-free formulation will delineate potential safety and efficacy advantages over the current therapy.ProductN=Cmax (μ g/mL)t½α(min)t½ β(min)Vc (L)Vdss (L)AUC (μ g* min/mL)CL (mL/min)Melphalan HCl for Injection55.5 ± 2.112.9 ± 2.769.6 ± 2.825.5 ± 11.042.0 ± 15.4424 ± 146529 ± 187Alkeran54.4 ± 2.624.2 ± 19.774.8 ± 14.039.3 ± 25.752.3 ± 22.1375 ± 167631 ± 209 Disclosures: Aljitawi: CyDex Pharmaceuticals, Inc.: Research Funding. Off Label Use: Melphalan use in high dose therapy and autologous transplantation. Robinson:CyDex Pharmaceuticals, Inc.: Consultancy. Pipkin:CyDex Pharmaceuticals, Inc.: Employment.