ALBERT

Description: Background: Next-generation sequencing (NGS) technologies have led to the discovery of recurrently-mutated genes in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). These mutations have proven useful in diagnosis, prognostication, and prediction of treatment response when used in conjunction with cytogenetics and other clinical characteristics known to influence patient outcome. NGS platforms that test for the presence of genetic mutations associated with myeloid malignancies are now widely available in clinical practice and are often utilized during initial diagnostic evaluation. However, there is considerable variability among hematologists in the use of such data, and it is still unclear whether physicians are using molecular data to properly prognosticate or make treatment decisions for their patients. Thus, the purpose of this study is to assess real-world practices of physicians caring for patients with AML or MDS at a large National Comprehensive Cancer Network (NCCN) Member Institution and to determine the degree to which molecular data is being utilized to prognosticate or alter clinical management. Methods: Patients presenting to the University of Wisconsin-Madison Hospital and Clinics with newly-diagnosed AML or MDS from 1/1/2014 through 12/31/2018 were included in the study. Data was collected retrospectively, including patient demographics, clinical characteristics, cytogenetic and mutational data, and treatment. The medical record was scrutinized for documentation regarding impact of molecular data on physician prognostication and decision-making. Results and Discussion: 102 patients were included in the analysis, including 54 patients with AML and 48 patients with MDS. For AML patients, 36% were classified as adverse risk, 34% as intermediate risk, and 30% as favorable risk based on ELN criteria. For MDS patients, 50% were classified as very high or high risk, 27% as intermediate risk, and 23% as low or very low risk by IPSS-R criteria. The proportion of AML and MDS patients having normal cytogenetics were comparable (37% versus 29% respectively, p=0.40). The type and frequency of molecular data utilized differed significantly according to diagnosis (p

Description: Background: Asparaginase may improve outcomes in chemotherapy resistant malignancy, especially of lymphoid origin. L-asparaginase (L-ASP) was introduced in 1992 and hence has been incorporated in multiple regimens. An effective regimen including steroid (dexamethasone), methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) was developed by the NK-Cell Tumor Study Group as a unique chemotherapeutic regimen to combat chemo-resistant NK-cell neoplasms (Yamaguchi et al. 2008) and later shown to have efficacy in relapsed and refractory lymphoblastic lymphoma (Chang et al. 2014). The pegylated-asparaginase (PEG-ASP) is the only readily available commercial product as the other forms either have limited availability due to shortages (Erwinia asparaginase) or are no longer available in the United States (E-coli asparaginase). We present retrospective data incorporating PEG-ASP into a modified SMILE (mSMILE) regimen. To our knowledge, no prior comparison between the PEG-ASP and L-ASP based SMILE regimen is available in the literature. Methods: All adult patients treated with mSMILE for either extranodal NK/T-cell leukemia and lymphoma (ENKTL), T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LBL), adult T-cell leukemia/lymphoma (ATLL), or peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) from 12/1/2009-6/30/2019 at Moffitt Cancer Center were included. PEG-ASP replaced L-ASP in SMILE regimen at a dose of 2500 units/m2/dose IV on Day 8 only (maximum dose of 3750 units). Cycles were repeated every 28 days until disease progression, excessive toxicity, or consolidation with hematopoietic cell transplantion (HCT). Patients received appropriate supportive care with peg-filgrastim or filgrastim (until absolute neutrophil count 〉 1000/ul x 3Days or 〉3,000/ul) as well as antimicrobial prophylaxis with acyclovir, ciprofloxacin, and fluconazole once methotrexate cleared and post-chemotherapy. Toxicity assessment was analyzed retrospectively and graded based upon Common Terminology Criteria for Adverse Events (CTCAE) version 5. Toxicity profiles of PEG-ASP-based mSMILE in present study were compared to profiles of L-ASP-based SMILE in the recently published literature (Pokrovsky & Vinnikov Expert Rev Anticancer Ther, 2019). Results: A total of 13 patients were treated with mSMILE during the 10-year period (Table 1). Of these patients, the median age was 46 years (range, 19-69), caucasians (46%) and males (70%). Most of the patients were treated for ENKTL (46%). mSMILE was the first line therapy in 3 patients, while the median number of prior therapies was 1 (range 0-3). Toxicity assessment for mSMILE focused on PEG-ASP-induced toxicity as no patients had any hemorrhagic cystitis, neurotoxicity, or renal dysfunction that could be associated with ifosfamide, methotrexate, or etoposide. mSMILE was comparatively associated with more hematologic toxicity, likely related to inclusion of patients with lymphoblastic leukemia (table 2). Grade 3/4 hepatotoxicity rates are low, possibly owing to inclusion of carnitine prophylaxis (Schulte et al. 2018). Thrombosis was not observed. Hypertriglyceridemia was observed in 15% with no cases of pancreatitis. Hypersensitivity and neurotoxicity were not observed. Of the two patients who discontinued therapy due to toxicity, one was related to grade 3 hypofibrinogenemia and the other grade 4 bleeding. Mortality was attributable to disease progression in all cases, with 0% treatment related mortality. Efficacy is comparable, with ORR 54% (7/13), including 30% (4/13) successfully bridged to HCT. Conclusion: In a non-Asian population, modified SMILE regimen with PEG-ASP is a safe alternative to L-ASP-based SMILE regimen. There is increased hematological toxicity, which did not seem to affect chemotherapy delivery. Disclosures Chavez: Genentech: Speakers Bureau; Janssen Pharmaceuticals, Inc.: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Bello:Celgene: Speakers Bureau. Pinilla Ibarz:Sanofi: Speakers Bureau; Bayer: Speakers Bureau; TG Therapeutics: Consultancy; Teva: Consultancy; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Sokol:EUSA: Consultancy. Shah:AstraZeneca: Honoraria; Spectrum/Astrotech: Honoraria; Novartis: Honoraria; Celgene/Juno: Honoraria; Kite/Gilead: Honoraria; Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Honoraria; Adaptive Biotechnologies: Honoraria.

Description: Background: Only a small subset of Lower risk (LR) MDS patients benefit from treatment with rhu-Erythropoietin (Epo). We previously reported that lenalidomide (LEN) restores sensitivity to Epo in MDS progenitors by inducing the formation of lipid rafts that are enriched for signaling competent, JAK2/Epo-receptor complexes (McGraw K, et. al. PLoS One 2014; Basiorka A, et. al. Cancer Res 2016). In the MDS-002 and MDS-005 trials, treatment with LEN monotherapy gave rise to RBC transfusion-independence (TI) in 26% of azanucleoside-naïve, transfusion-dependent (TD) LR, non-del(5q) MDS patients for a median of 10.2 and 7.75 months, respectively. In a pilot study of Epo-refractory LR-MDS patients, the addition of epoetin alfa (EA) to LEN treatment yielded erythroid responses in 28% of patients who were unresponsive to LEN alone, suggesting that LEN may overcome clinical resistance to augment response to rhEpo (Komrokji R, et. al. Blood 2012). To test this hypothesis, we performed a randomized phase III trial comparing treatment with LEN to LEN+EA in LR non-del(5q) MDS patients who were refractory to, or not candidates for treatment with rhEpo. Methods: Patients with Low or Intermediate-1 IPSS risk MDS with hemoglobin 2 units/month) with serum Epo 〉500mU/mL were eligible. Patients were stratified by serum Epo level and prior rhEpo (EA vs. darbepoetin vs. none) then randomized to treatment with LEN 10 mg/d x21d q4wk (Arm A) or LEN + EA 60,000U SC/wk (Arm B). The primary endpoint was major erythroid response (MER) at week 16 which was defined according to transfusion status at baseline: (1) achievement of RBC-TI for ≥ 8 consecutive weeks AND a sustained ≥1 g/dL hemoglobin rise compared to mean pre-transfusion baseline value in TD patients; and (2) a 〉2 g/dL rise in hemoglobin without transfusion for ≥ 8 consecutive weeks in non-TD patients (Grade 3, non-hematologic adverse events between treatment arms. Two patients progressed to AML while on study (Arm A), and no thromboembolic events were reported. Conclusions: LEN restores sensitivity to rhEpo in otherwise refractory, LR-non-del(5q) MDS patients to yield a significantly higher frequency of durable major erythroid responses compared to LEN alone. The addition of LEN to EA treatment is an effective strategy for the management of Epo-refractory patients with a potential duration of benefit extending to years. Disclosures List: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Verma:Janssen: Research Funding; BMS: Research Funding; Stelexis: Equity Ownership, Honoraria; Acceleron: Honoraria; Celgene: Honoraria. Maciejewski:Novartis: Consultancy; Alexion: Consultancy. Komrokji:JAZZ: Speakers Bureau; Novartis: Speakers Bureau; JAZZ: Consultancy; Agios: Consultancy; Incyte: Consultancy; DSI: Consultancy; celgene: Consultancy; pfizer: Consultancy. Luger:Onconova: Research Funding; Pfizer: Honoraria; Seattle Genetics: Research Funding; Cyslacel: Research Funding; Biosight: Research Funding; Ariad: Research Funding; Agios: Honoraria; Genetech: Research Funding; Jazz: Honoraria; Daichi Sankyo: Honoraria; Kura: Research Funding; Celgene: Research Funding. Mattison:Pfizer: Membership on an entity's Board of Directors or advisory committees. Altman:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Consultancy, Honoraria, Other: Data Safety and Monitoring Committee; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; France Foundation: Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; prIME Oncology: Speakers Bureau; PeerView: Speakers Bureau; Cancer Expert Now: Consultancy; Novartis: Consultancy; Biosight: Other: US Lead. Claxton:Astellas Pharma: Other: Pharma support of clinical studies; Merck Sharp & Dohme Corp.: Other: Pharma support of clinical studies; Cyclacel Pharmaceuticals, Inc.: Other: Pharma support of clinical studies; Medimmune Inc.: Other: Pharma support of clinical studies; Novartis Pharmaceuticals: Other: Pharma support of clinical studies; Celgene Corporation: Other: Pharma support of clinical studies; Incyte Corporation: Other: Cyclacel Pharmaceuticals, Inc; Daiichi Sankyo Co. and Ambit Biosciences Corp: Other: Pharma support of clinical studies. Artz:Miltenyi: Research Funding. Tallman:Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Lenalidomide used for treatment non-del 5q myelodysplastic syndromes.

Description: Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) is a polypeptide mediator, elaborated by certain tumors and other cell types, that exerts multiple effects on endothelium via interaction with a class of high-affinity binding sites. In this report, the interaction of VPF/VEGF with human mononuclear phagocytes (MPs) is characterized. Radioligand binding studies at 4 degrees C showed the presence of a single class of binding sites, kd approximately 300 to 500 pmol/L (approximately 20 times lower affinity than the high-affinity binding site on endothelial cells [ECs]), the occupancy of which correlated with VPF/VEGF-induced MP migration and expression of tissue factor. These binding results were paralleled by functional experiments which indicated that the same VPF/VEGF preparations were about an order of magnitude less effective in stimulating MP chemotaxis than in inducing EC proliferation. When MPs with surface-bound 125I-VPF/VEGF were warmed to 37 degrees C, endocytosis and degradation occurred. Occupancy of VPF/VEGF binding site resulted in subsequent activation of intracellular signal transduction mechanisms, as shown by an increase in MP intracellular calcium concentration. Cross-linking studies with 125I-VPF/VEGF showed a new high-molecular weight band (corresponding to putative 125I- VPF/VEGF-receptor complex), the appearance of which was blocked by excess unlabeled VPF/VEGF. Consistent with these results, immunoprecipitation of 32PO4-labeled MPs exposed to VPF/VEGF showed a single band of similar mobility, not seen in untreated controls. These results demonstrate that the interaction of VPF/VEGF with MPs, though of lower affinity than that observed with ECs, also results from interaction of the polypeptide with a specific cell-surface protein and leads to activation of intracellular transduction mechanisms.

Description: Key Points Coordinated BCR-ABL1 kinase-dependent and -independent mechanisms convert p27 from a nuclear tumor suppressor to a cytoplasmic oncogene. Oncogenic functions of p27 that persist despite effective BCR-ABL1 inhibition may contribute to resistance to tyrosine kinase inhibitors.

Description: Post-transplant lymphoproliferative disorders (PTLDs) are classified as early PTLDs (E-PTLD), polymorphic PTLDs (P-PTLD), monomorphic PTLDs (M-PTLD) and classical Hodgkin's Lymphoma PTLD (HL). These entities are felt to represent a disease continuum, with a precursor-product relationship, though they are morphologically and clinically distinct. However, this process remains poorly understood, and limited evidence exists to support this hypothesis. We report a series of nine cases extracted from a PTLD database, including both pediatric and adult solid organ transplant recipients, with recurrent disease episodes that evince an apparent evolution in their morphologic categorization between episodes. All patients identified were high risk for PTLD, with multiple identifiable predisposing factors. Presentations varied from isolated lymphadenopathy, to gastrointestinal involvement to pulmonary involvement. Four of the patients were deceased at the time of acquisition, though only one directly from PTLD. Eight of the nine identified patients developed E or P-PTLD lesions that preceded a subsequent M-PTLD or HL lesion at a similar tissue site. Two of the cases had metachronous P and M-PTLD lesions. The six M-PTLD subtypes were variable, including DLBCL, Burkitt, T-cell, and extramedullary plasmacytoma, in addition to the three cases of classical Hodgkin's lymphoma. These cases suggest that E and P-PTLD may act as common precursor lesions to the development of both the M-PTLD variants and HL type lesions, and that the PTLD classification schema represents different stages of a common underlying pathology. Disclosures Owen: Lundbeck: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Roche: Honoraria.

Description: Experiments were conducted to investigate the effects of intravenous immunoglobulin (IVIG) in a rat model of immune thrombocytopenia (ITP). Rats were pretreated with 0 to 2 g/kg IVIG and then challenged with an antiplatelet antibody (7E3, 8 mg/kg). IVIG effects on 7E3-induced thrombocytopenia and on 7E3 pharmacokinetics were determined. IVIG pretreatment led to significant changes in the degree and time-course of 7E3-induced thrombocytopenia (P = .031). Nadir percent platelet counts were 121% to 279% greater in animals treated with IVIG (0.4-2 g/kg) than in animals receiving 7E3 alone. IVIG treatment also led to dose-dependent increases in 7E3 clearance (P