Background: Although patients with acute myeloid leukemia (AML) were shown to have an increased risk of thrombosis, no thrombosis risk assessment scoring system has been developed for AML patients. The Khorana Risk Score (KRS), which has been widely used for thrombosis risk assessment in the clinical setting, was developed on the basis of solid tumor data and has not been validated among AML patients. This study aims to validate the use of the KRS as a thrombosis risk-scoring system among patients with AML. Methods: Using data from H. Lee Moffitt Cancer Center and Research Institution's Total Cancer Care Research Study, we retrospectively identified patients who were histologically confirmed with AML from 2000 to 2018. Clinical and laboratory variables at the time of AML diagnosis were characterized and analyzed. The thrombotic event rate was estimated with the Kaplan-Meier method and compared using the log-rank test. Results: A total of 867 AML patients were included in the analysis. The median age at AML diagnosis was 75 years (range, 51-96), and the majority were male (65%, n = 565). A total of 22% (n = 191), 51% (n = 445), 24% (n = 207), and 3% (n = 24) of patients had a KRS of 0, 1, 2, and 3, respectively. A total of 42 thrombotic events (3% [n = 6/191] with a KRS of 1; 5% [n = 23/445] with a KRS of 2; 6.3% [n = 13/207] with a KRS of 3) were observed, with a median follow-up of 3 months (range, 0.1-307). There was no statistical difference in the risk of thrombosis between these groups (P = .1949). Conclusions: Although there was an increased risk of thrombosis associated with a higher KRS among AML patients with a KRS of 1 to 3, the difference was not statistically significant. Furthermore, only a few patients were found to have a KRS > 3, and this was largely due to pancytopenia, which is commonly associated with AML. These results indicate the need for a better thrombotic risk-scoring system for AML patients.
Introduction Chronic myelomonocytic leukemia (CMML) is an overlap syndrome with both myeloproliferative and myelodysplastic features. Clinical outcomes can be variable and risk stratification models such as GFM and Molecular Mayo Model (MMM) are useful. These models integrate age, WBC, anemia, thrombocytopenia, mutation status, monocyte count, and blast/promonocyte count, to segregate patients1. The presence of fibrosis in MDS (MF 2-3) is often associated with high grade disease, poor cytogenetics, and worse prognosis 2. The role of moderate to severe fibrosis in CMML (CMML-F) is not well studied. We investigated mutational landscape of CMML-F and whether CMML-F is associated with more aggressive disease thus warranting incorporation into risk models. Methods Total Cancer Care (TCC) and PathNet databases at Moffitt Cancer Center were queried for patients diagnosed with CMML between 2014 and 2017 with available Next Generation Sequencing (NGS) profiling (Genoptix 5-gene panel, Genoptix 21-gene panel, FoundationOne, Custom TrueSeq Myeloid). The cases were individually reviewed by a board-certified hematopathologist to confirm the diagnosis. The degree of reticulin fibrosis was manually collated from the pathology report and graded according to the World Health Organization (WHO) grading of bone marrow fibrosis (grade 0-3). Grade 1-2 or 2-3 fibrosis in the report were designated 1.5 and 2.5, respectively. CMML-F was defined as grade 2.5 or higher or collagen fibrosis. t-test and two tailed Fisher exact tests were performed for statistical analysis. Results Of 108 CMML patients (median age of 69.7 years), bone marrow fibrosis data was available for 91 individuals. The degree of fibrosis was as follows: Grade 0= 33, Grade 1= 34, Grade 1.5= 2, Grade 2= 15, Grade 2.5= 2, Grade 3=5 (of which 2 had collagen fibrosis). The CMML patients without fibrosis (MF<2.5) showed a longer median overall survival when compared to CMML-F (24.79 months versus 20.43 months; p=0.67), but it was not statistically significant. One of the 8 CMML-F patients had AML transformation (12.5%), similar to the 9 out of 82 CMML patients without fibrosis (11%). One of 2 patients (50%) with collagen fibrosis showed leukemic transformation, higher than the transformation rate in non-collagen fibrosis patients (11%; p=0.21). The most common mutations in CMML-F were: ASXL1 (25%), SRSF2 (25%), JAK2 (16.7%), and TET2 (16.7%). The most common mutations in non-CMML-F were: TET2 (60%), ASXL1 (45%), SRSF2 (38%), and RUNX1 (19%). Of note, TET2 mutations was less likely to occur in CMML-F (p=0.008). The average marrow blast percentage in CMML-F was 4.2% while in non-CMML-f was 8.6% (p=0.25). Conclusions: In this study we demonstrate that CMML-F is less likely to harbor TET2 mutations than CMML without fibrosis. However, unlike MDS, the presence of moderate-to-severe fibrosis does not correlate with worse prognosis in CMML. Large cohorts warranted to identify novel prognostic markers that could be incorporated into risk stratification schemas. Disclosures Kuykendall: Incyte: Honoraria, Speakers Bureau; Janssen: Consultancy; Abbvie: Honoraria; Celgene: Honoraria. Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Komrokji:JAZZ: Consultancy; Agios: Consultancy; Incyte: Consultancy; DSI: Consultancy; pfizer: Consultancy; celgene: Consultancy; Novartis: Speakers Bureau; JAZZ: Speakers Bureau.
Introduction: Multiple myeloma (MM) is an incurable malignancy of the plasma cell. While patients may initially respond to treatment, the development of acquired drug resistance (ADR) is a consistent feature of the disease. In order to understand the processes involved in ADR, proteomics is used to examine multiple phenotypic outcomes associated with drug resistance in cell line models. Both protein expression and phosphorylation data will be mined for biological mechanisms and candidate biomarkers for detection of ADR in MM patients. Experimental Procedures: Using cell line models of melphalan and doxorubicin resistance, protein expression is compared using spectral counts and extracted ion chromatograms from GeLC-MS/MS data. In addition, phosphorylation profiles are created using SCX peptide fractionation with IMAC phosphopeptide enrichment prior to LC-MS/MS cataloging. Additional hypothesis-driven experiments are conducted using liquid chromatography-multiple reaction monitoring mass spectrometry (LC-MRM) for targeted quantification. In addition to steady state comparisons between naïve and drug resistant cells, initial responses to therapy are also evaluated. Assays developed for interrogation of cell line models can be translated to patient specimens. Data Summary: GeLC-MS/MS expression measurements typically produce semi-quantitative data for > 2,000 proteins (2+ peptides per protein). Phosphorylation analysis has produced a catalog of > 1,000 sites across the entire group of cell lines. Data are manually evaluated for proteins relevant to MM and mapped to pathways using Metacore GeneGO. Because both melphalan and doxorubicin produce DNA damage, common processes include DNA damage repair, cell cycle regulation, and apoptosis. Each drug also produces unique phenotypes. For example, doxorubicin resistance is mediated in large part by multidrug resistance proteins; melphalan resistance is marked by increases in redox proteins. LC-MRM of heat shock proteins and Bcl-2 family apoptosis regulators supplements existing data. LC-MRM is also used to examine the response in the expression of proteins involved in ADR at the onset of treatment in naïve MM cells. Conclusions: Proteomics can further elucidate the biological processes involved with ADR in MM to generate candidate biomarkers. LC-MRM is used in cell line models to develop a platform for assessing panels of proteins related to ADR, which can ultimately be translated to assist in clinical decisions for tailoring therapy to the individual patient. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4809. doi:1538-7445.AM2012-4809
INTRODUCTION: Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic cell transplant (HCT) resulting in significant morbidity and mortality. The combination of tacrolimus and sirolimus (TAC/SIR) has emerged as a GVHD prophylaxis platform preferred by many institutions given its association with rapid engraftment and acceptable transplant-related toxicity. However, overlapping toxicities between the two drugs can lead to intolerance and premature discontinuation in some patients. There is limited literature describing outcomes and subsequent management of such patients. The goal of this study is to investigate the clinical outcomes of patients becoming intolerant to the combination of TAC/SIR prophylaxis. METHODS: We retrospectively evaluated consecutive adult patients (n=100) at the Moffitt Cancer Center who received allogeneic HCT with TAC/SIR for GVHD prophylaxis in 2018. TAC/SIR intolerance was defined as discontinuation due to the toxicity of either TAC or SIR before post-transplant day 100. Survival analyses were estimated from the time of transplant with the Kaplan-Meier method and compared using the log-rank test. Patients intolerant of this prophylaxis regimen were compared to patients who completed >100 days of therapy, using Mann-Whitney U test for continuous variables and Pearson Chi-square tests for categorical variables. All statistical analyses were performed using SPSS v25 and NCSS v11. RESULTS: Demographics and clinical characteristics of all patients are summarized in Table 1A. TAC/SIR intolerance occurred in 25% (24 discontinued TAC, 1 discontinued SIR) of patients at a median duration of therapy of 19 days (range 4-92). The most common TAC/SIR toxicity (Table 1B) was acute kidney injury (AKI, n=11, 44%), followed by thrombotic microangiopathy (TMA, n=3, 12%). Baseline metabolic and clinical variables including creatinine, liver function, and conditioning intensity were not predictive of TAC-SIR intolerance. At a median follow-up of 10 months, the median overall survival (OS) for patients intolerant of TAC/SIR was 10 months versus was not reached for the patients without intolerance (HR 5.42; 95% CI 1.71-17.14; p<0.001). The 1-year PFS was 16% (95% CI 0% - 42%) vs 75% (95% CI 65% - 86%) and OS was 35% (95% CI 8% - 63%) vs. 79% (95% CI 68% - 90%) for patients who were TAC/SIR-intolerant compared to those who were TAC/SIR-tolerant (p<0.01) (Figure 1A). The cumulative incidence (CuI) of non-relapse mortality (NRM) at 1 year in patients intolerant of TAC/SIR was 47% (95% CI: 28% - 81%) and in patients tolerant of TAC/SIR was 4.4% (95% CI: 1.5% - 14%), (p<0.001). The Cul of relapse at 1 year was 45% (95% CI: 20% - 100%) in patients who were TAC/SIR-intolerant compared to 18% (95% CI: 10% - 30%) in patients who tolerated TAC/SIR (p=0.07) (figure 1B). Overall, 31 patients (31%) developed grade II-IV acute GVHD (aGVHD). The Cul of grade II-IV aGVHD at 100 days in patients who were TAC/SIR-intolerant was 29% (95% CI 15% - 58%) compared to 17% (95% CI 10% - 29%) in patients who tolerated TAC/SIR, (p=0.38). The Cul of cGVHD at 1 year in patients who were TAC/SIR-intolerant was 44% (95% CI: 25% - 79%) compared to 52% (95% CI: 40% - 68%) in patients who were TAC/SIR-tolerant (p=0.89). CONCLUSIONS: Outcomes for patients completing over 100 days of TAC/SIR for GVHD prophylaxis following allogeneic HCT are favorable. However, early intolerance of TAC/SIR GVHD prophylaxis occurred in 25% of allogeneic HCT in 2018 alone and predicted a poor prognosis with increased NRM and overall mortality, largely from drug-related toxicities. Notably, premature discontinuation of TAC/SIR did not contribute to higher subsequent risks of GVHD. Strategies to mitigate the risks of TAC/SIR toxicity are warranted. Future studies are also needed to identify the optimal GVHD prophylactic regimen for patients after TAC/SIR intolerance. Disclosures Nishihori: Novartis: Research Funding; Karyopharm: Research Funding. Bejanyan:Kiadis Pharma: Other: advisory board.
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