An easy-to-handle DPD deficiency test in saliva to identify patients at high-risk for life-threatening toxicity due to fluoropyrimidine therapy.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14019-e14019
Author(s):  
Gilberto Schwartsmann ◽  
Marina Venzon Antunes ◽  
Andres Galarza ◽  
Roberta Zilles Hahn ◽  
Suziane Raymundo ◽  
...  
Keyword(s):  
High Risk ◽  
Dihydropyrimidine Dehydrogenase ◽  
Metabolic Ratio ◽  
Sample Population ◽  
Allele Carrier ◽  
Severe Toxicity ◽  
Medical Oncologists ◽  
Risk Patients ◽  
Life Threatening ◽  
Grade 3

e14019 Background: Severe dihydropyrimidine dehydrogenase (DPD) deficiency can be lethal in 0.5-3.0% of patients receiving fluoropyrimidines. Unfortunately, there is no routine test in medical practice to identify high-risk patients. Here, we evaluated the use of plasma and saliva uracil (U) to dihydrouracil (UH2) metabolic ratio and DPYD genotyping, as a means to identify patients with DPD deficiency and fluoropyrimidine toxicity. In addition, we report on a functional test using UH2/U metabolic ratio in dried saliva spots (DSS). Methods: Prior to fluoropyrimidine therapy, plasma and saliva samples were obtained from 60 patients with GI cancer. U and UH2 levels were measured by LC-MS/MS in plasma and saliva. Patients were also genotyped for DPYD (*7/*2A/*13/Y186C). WHO grading were used to report treatment toxicity. Results: In 21 patients (35%) toxicity was documented. For those, no variant allele carrier for DPYD was identified. The UH2/U metabolic ratios were 0.1-26.7 in plasma and 0.1-24.0 in saliva, with a higher correlation with toxicity grade in saliva as compared to plasma (rs 0.52 vs 0.28). Median metabolic ratios were lower in patients with severe toxicity as compared to those with no toxicity (0.59 vs 2.83 saliva; 1.62 vs 6.75 plasma, P < 0.01). A cut-off of 1.16 for the salivary UH2/U ratio was set (AUC 0.84) with 86% sensitivity and 77% specificity for the identification of grade 3-4 toxicity. A plasma cut-off of 4.0 (AUC 0.75) revealed a 71% sensitivity and 76% specificity. Moreover, saliva of 21 patients were applied to filter paper to obtain DSS and sent to the laboratory by regular mail. U and UH2 were stable in DSS stored at 45°C up to 7 days. In this set of patients, grade 3-4 toxicity was documented in 3/21 cases (14%), all three cases had metabolic ratios below 1.16 in DSS, confirming our prior results. Conclusions: DPYD genotyping failed to identify severe DPD deficiency, but the UH2/U metabolic ratios in saliva showed enough sensitivity and specificity to deserve further evaluation. DSS samples allowed medical oncologists working at distant sites to send us samples by post, with results available within a week. This test is being validated in a larger sample population.

Behavioral Emergencies and Crises

2010 ◽  
pp. 739-762
Author(s):  
Phillip M. Kleespies ◽  
Justin M. Hill
Keyword(s):  
Mental Health ◽  
Risk Factors ◽  
High Risk ◽  
Work Environment ◽  
Emotional Impact ◽  
High Risk Patients ◽  
Risk Patients ◽  
Life Threatening ◽  
Behavioral Emergencies ◽  
And Training

This chapter illustrates the mental health clinician’s relationship with behavioral emergencies. The chapter begins by distinguishing the terms behavioral emergency and behavioral crisis, and underlying themes among all behavioral emergencies are identified. Given that most clinicians will face a behavioral emergency in their careers, the importance of enhancing the process of educating and training practitioners for such situations far beyond the minimal training that currently exists is highlighted. The chapter continues by exploring various aspects of evaluating and managing high-risk patients (i.e., those who exhibit violent tendencies toward themselves or others, and those at risk for victimization). It includes a discussion of the benefits and limitations to estimating life-threatening risk factors and specific protective factors. The chapter concludes by discussing the emotional impact that working with high-risk patients has on clinicians, and an emphasis is placed on the importance of creating a supportive work environment.

scholarly journals Cost Implications of Reactive Versus Prospective Testing for Dihydropyrimidine Dehydrogenase Deficiency in Patients With Colorectal Cancer: A Single-Institution Experience

Dose-Response ◽  
2018 ◽  
Vol 16 (4) ◽  
pp. 155932581880304 ◽  
Author(s):  
Con Murphy ◽  
Stephen Byrne ◽  
Gul Ahmed ◽  
Andrew Kenny ◽  
James Gallagher ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dihydropyrimidine Dehydrogenase ◽  
Cost Savings ◽  
Cost Effective ◽  
Public Hospitals ◽  
Severe Toxicity ◽  
Care Payer ◽  
Input Variables ◽  
Grade 3 ◽  
The Cost

Background: Severe toxicity is experienced by a substantial minority of patients receiving fluoropyrimidine-based chemotherapy, with approximately 20% of these severe toxicities attributable to polymorphisms in the DPYD gene. The DPYD codes for the enzyme dihydropyrimidine dehydrogenase (DPD) important in the metabolism of fluoropyrimidine-based chemotherapy. We questioned whether prospective DPYD mutation analysis in all patients commencing such therapy would prove more cost-effective than reactive testing of patients experiencing severe toxicity. Methods: All patients experiencing severe toxicity from fluoropyrimidine-based chemotherapy for colorectal cancer in an Irish private hospital over a 3-year period were tested for 4 DPYD polymorphisms previously associated with toxicity. The costs associated with an index admission for toxicity in DPD-deficient patients were examined. A cost analysis was undertaken comparing the anticipated cost of implementing screening for DPYD mutations versus current usual care. One-way sensitivity analysis was conducted on known input variables. An alternative scenario analysis from the perspective of the Irish health-care payer (responsible for public hospitals) was also performed. Results: Of 134 patients commencing first-line fluoropyrimidine chemotherapy over 3 years, 30 (23%) patients developed grade 3/4 toxicity. Of these, 17% revealed heterozygote DPYD mutations. The cost of hospitalization for the DPYD-mutated patients was €232 061, while prospectively testing all 134 patients would have cost €23 718. Prospective testing would result in cost savings across all scenarios. Conclusions: The cost of hospital admission for severe chemotherapy-related toxicity is significantly higher than the cost of prospective DPYD testing of each patient commencing fluoropyrimidine chemotherapy.

Prognostic Model for Stratification of Radioresistant Nasopharynx Carcinoma to Curative Salvage Radiotherapy

2018 ◽  
Vol 36 (9) ◽  
pp. 891-899 ◽  
Author(s):  
You Quan Li ◽  
Yun Ming Tian ◽  
Sze Huey Tan ◽  
Ming Zhu Liu ◽  
Grace Kusumawidjaja ◽  
...  
Keyword(s):  
High Risk ◽  
Prognostic Index ◽  
Intensity Modulated Radiotherapy ◽  
Training Data ◽  
Cancer Center ◽  
Weight Discrimination ◽  
Data Set ◽  
Training Cohort ◽  
Risk Patients ◽  
Grade 3

Purpose To investigate for a prognostic index (PI) to personalize recommendations for salvage intensity-modulated radiotherapy (IMRT) in patients with locally recurrent nasopharyngeal carcinoma (lrNPC). Methods Patients with lrNPC from two academic institutions (Sun Yat-Sen University Cancer Center [SYSUCC-A; n = 251 (training cohort)] and National Cancer Centre Singapore [NCCS; n = 114] and SYSUCC-B [n = 193 (validation cohorts)]) underwent salvage treatment with IMRT from 2001 to 2015. Primary and secondary clinical end points were overall survival (OS) and grade 5 toxicity-free rate (G5-TFR), respectively. Covariate inclusion to the PIs was qualified by a multivariable two-sided P < .05. Discrimination and calibration of the PIs were assessed. Results The primary PI comprised covariates that were adversely associated with OS in the training cohort (gross tumor volumerecurrence hazard ratio [HR], 1.01/mL increase [ P < .001], agerecurrence HR, 1.02/year increase [ P = .008]; repeat IMRT equivalent dose in 2-Gy fractions [EQD2] ≥ 68 Gy HR, 1.42 [ P = .03]; prior radiotherapy-induced grade ≥ 3 toxicities HR, 1.90 [ P = .001]; recurrent tumor [rT]-category 3 to 4 HR, 1.96 [ P = .005]), in ascending order of weight. Discrimination of the PI for OS was comparable between training and both validation cohorts (Harrell’s C = 0.71 [SYSUCC-A], 0.72 [NCCS], and 0.69 [SYSUCC-B]); discretization by using a fixed PI score cutoff of 252 determined from the training data set yielded low- and high-risk subgroups with disparate OS in the validation cohorts (NCCS HR, 3.09 [95% CI, 1.95 to 4.89]; SYSUCC-B HR, 3.80 [95% CI, 2.55 to 5.66]). Our five-factor PI predicted OS and G5-TFR (predicted v observed 36-month OS and G5-TFR, 22% v 15% and 38% v 44% for high-risk NCCS and 26% v 31% and 45% v 46% for high-risk SYSUCC-B). Conclusion We present a validated PI for robust clinical stratification of radioresistant NPC. Low-risk patients represent ideal candidates for curative repeat IMRT, whereas novel clinical trials are needed in the unfavorable high-risk subgroup.

Efficacy and Toxicity of Rituximab and Brief Duration, High Intensity Chemotherapy with Filgrastim Support for Burkitt or Burkitt – Like Leukemia/Lymphoma: Cancer and Leukemia Group B (Calgb) Study 10002

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 858-858 ◽  
Author(s):  
David A. Rizzieri ◽  
Jeffrey L Johnson ◽  
John C. Byrd ◽  
Gerard Lozanski ◽  
Bayard L. Powell ◽  
...  
Keyword(s):  
High Risk ◽  
High Intensity ◽  
International Prognostic Index ◽  
Tumor Lysis Syndrome ◽  
Prognostic Index ◽  
Adult Patients ◽  
Term Survival ◽  
Risk Patients ◽  
Grade 3

Abstract Abstract 858 Prior studies have shown that combination chemotherapy using high doses of antimetabolites and alkylating agents over a short duration is effective treatment for Burkitt leukemia and lymphoma. Adults able to tolerate this therapy have had > 50% long term survival, although those with higher risk by the International Prognostic Index (IPI) have had inferior outcomes. Between 5/2002 and 9/2009, we enrolled 105 adults (19-79 yrs old) with untreated Burkitt leukemia/lymphoma onto a phase II study of a high intensity chemo-immunotherapy regimen to assess the benefit of adding rituximab plus growth factor support to the intensive chemotherapy regimen developed in CALGB 9251 and evaluated patterns of relapse when prophylactic cranial irradiation was not given. All subjects were HIV negative and had serum creatinine and bilirubin ≤1.5 × upper limit. Complete data are available on 105 patients for toxicity and 103 patients for efficacy. Methods: Treatment began with cyclophosphamide (CY) 200 mg/m2 × 5 days and prednisone 60 mg/m2 × 7 days. Cycle 2 was started on Day 8 after entry. Cycles 2, 4, and 6 consisted of ifosfamide 800 mg/m2 on days 1–5, methotrexate (MTX) 1.5 g/m2 infused over day 1 with leucovorin rescue, vincristine (VCR) 2 mg day 1, Ara-C 1 gm/m2 days 4 and 5, VP-16 80 mg/m2 days 4 and 5, and dexamethasone 10 mg/m2 on days 1–5. Cycles 3, 5, and 7 included the same doses of MTX, VCR, and dexamethasone, with CY 200 mg/m2 IV on days 1–5 and doxorubicin 25 mg/m2 days 4 and 5. Cycles were delivered every 21 days if blood counts had recovered. Filgrastim was given at 5μg/kg/day SC beginning day 7 of each cycle and continuing until the absolute neutrophil count recovered to > 5000/μL. Rituximab was initiated during cycle 2 on day 8 at 50 mg/m2 and on days 10 and 12 at 375 mg/m2. During cycles 3 through 7, rituximab was infused only on day 8 of each course at 375 mg/m2. Central nervous system (CNS) prophylaxis consisted of triple intrathecal therapy on day 1 of cycles 2–7 (6 total doses). Results: 27% of patients were ≥60 years old; 70% were male; 46% had intermediate or high risk disease by the IPI (Table). Overall, 75 of 105 subjects completed all 7 planned courses of therapy. 82% attained a complete response (CR), and 87% of these remain in CR at last follow up. 7% had a partial response. With median follow up of survivors of 3.2 years, 2 year event free survival (EFS) and overall survival (OS) were 77% and 79%, respectively, with a trend favoring those <60 years old (87% and 87%, respectively). There were clear differences in outcome based on IPI score with 2 year EFS and OS for low risk patients of 90% and 92% versus 55% and 55% for high risk patients, respectively (Figure). This protocol did not use prophylactic CNS radiation, and 4 pts had documented CNS relapses; 2 had intermediate and 1 high IPI disease; the 4th was unknown. Relapse after 2 years was rare. 7 subjects (6.8%) died from treatment related causes (1 CNS bleed, 4 infections, 2 respiratory failure). Nearly all subjects experienced the anticipated severe hematologic toxicities. The most common grade 3 and 4 non-hematologic toxicities included stomatitis/upper GI toxicity (∼ 66%), nausea/vomiting (20%), fatigue (26%), rash or erythema multiforme (10%), diarrhea (10%), pulmonary or CNS bleeding (11%), clinically documented infections (72%), neurologic disturbances (8%), and dyspnea (10%). 8 pts (8%) had tumor lysis syndrome (all grade 3). Conclusion: This regimen provides a high rate of durable remissions in adult patients with a manageable side effect profile. Chemoimmunotherapy should be the standard for adult patients with Burkitt leukemia/lymphoma. Disclosures: Off Label Use: Rituximab for use in Burkitt's. Cheson:Genentech: Consultancy.

University of Wisconsin experience treating adult ALL with the BFM regimen

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 16501-16501
Author(s):  
S. C. Medlin ◽  
B. Kahl ◽  
W. Longo ◽  
E. Williams ◽  
J. Lionberger ◽  
...  
Keyword(s):  
Overall Survival ◽  
Young Adults ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Case Series ◽  
Adult Patients ◽  
Entire Group ◽  
Severe Toxicity ◽  
Risk Patients ◽  
Children And Young Adults

16501 Background: Berlin-Frankfurt-Munster therapy (BFM) is an effective regimen for acute lymphoblastic leukemia (ALL) in children and young adults (Lancet 2:921–924,1988). Treating children and young adults at higher risk for relapse with an augmented BFM was shown to increase both event free and overall survival (NEJM 338:23,1663–1671,1998). Outcomes using standard BFM or augmented BFM in adults are unknown. Methods: This is a case-series of 29 adult patients treated with the BFM regimen. Patients were stratified into low, intermediate and high-risk groups based upon the following characteristics: age, white blood cell count, adverse cytogenetics and absence of CD 10. Low risk patients received the standard BFM regimen. Intermediate risk patients were given augmented BFM if less than 50 years old, standard BFM if older than age 50. High-risk patients received augmented BFM. Cranial irradiation was omitted in most patients (25/29). Events were defined as relapse, death from any cause, and stopping treatment for any reason. Results: Fifteen patients (median age 38, range 19–70) were treated with standard BFM and 14 patients (median age 37, range 21–72) with augmented BFM. Complete remission at day 28 was 93% (27/29). For the entire group, the 3-year overall survival was 60% with a 3-year event free survival of 45%. Patients treated with augmented BFM experienced a 3-year EFS, PFS, OS of 26%, 43%, and 48% respectively. Patients treated with standard BFM had a 3-year EFS, PFS, OS of 60%, 78%, and 78% respectively. Toxicity was common with significant neuropathy and neutropenic fever occurring in 83% and 48% respectively. Septic shock occurred in 17% of patients. Severe toxicity resulted in 1 death and discontinuation of BFM in 3 patients. The entire regimen was completed in 33 % of those treated with augmented BFM and 71% of those treated with standard BFM. Conclusion: Standard BFM is an effective and tolerable regimen for treatment of adult ALL. Augmented BFM is a difficult regimen for adult patients to complete. For both regimens, the 3-year PFS and OS compare favorably to other published regimens. No significant financial relationships to disclose.

Dihydropyrimidine dehydrogenase gene (DPYD) polymorphism among Caucasian patients (pts) with 5-FU and capecitabine (CAP)-related toxicity

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14588-e14588
Author(s):  
N. A. Podoltsev ◽  
M. W. Saif
Keyword(s):  
Dihydropyrimidine Dehydrogenase ◽  
White Blood Cells ◽  
Control Group ◽  
Deleterious Mutations ◽  
Testing Methods ◽  
Sequence Variations ◽  
Hand Foot Syndrome ◽  
Individualized Approach ◽  
Life Threatening ◽  
Grade 3

e14588 Background: As many as 1 in 3 pts receiving 5-FU/CAP experience dose-limiting toxicity including diarrhea, hand-foot syndrome (HFS), mucositis and myelosupression. Deficiency of DPD, a rate limiting enzyme in 5-FU catabolism can lead to life- threatening complications. DPD deficiency was found to be related to > 40 sequence variations in DPYD. Known deleterious mutations explain only a limited proportion of 5-FU's adverse events. Full sequence analysis of DPYD gene increases sensitivity by 20% vs. simple identification of two most common deleterious mutations (IVS14 +1 G>A, D949V). Pretreatment detection could prevent serious, potentially lethal side effects. We present analysis of DPYD genotyping in untreated Caucasian pts (control group) and Caucasian pts with 5-FU/CAP-related grade 3/4 toxicities (toxicity group) who underwent TheraGuide 5-FU testing. Methods: Full sequencing of DPYD was performed by Myriad Genetic Laboratories, Inc. as part of TheraGuide 5-FU test. DNA was extracted and purified from white blood cells. Genetic variants within pt's DPYD were detected by comparison with a consensus wild-type DPYD sequence. Results: Among 227 pts from toxicity group 27 (12%) had deleterious mutations in DPYD: 12 (5%) had IVS14 +1 G>A, 11 (5%) had D949V and 4 (2%) other mutations. Only 7/192 (4%) pts from control group had DPYD genotype abnormalities: 2 (1%) had IVS14 +1 G>A, 4 (2%) had D949V and 1 (1%) other mutation. Genotype abnormalities were seen more frequently in toxicity group (p=0.001). Among 49 pts with HFS 9/49 (18%) had mutated DPYD. 9/46 (20%) pts with myelosupression were found to have a deleterious mutation. Mutations were more frequent in both subgroups when compared to control group: p=0.001 and 0.0007 respectively. Among 65 pts with toxicities due to CAP 9 (14%) had mutated DPYD which was more frequent than in control group (p=0.006). Conclusions: Mutated DPYD is frequently observed in Caucasian pts who experience toxicities while receiving 5-FU/CAP. Screening pts for DPYD mutations prior to administration of 5-FU/CAP using new pharmacogenetic testing methods may help to identify those pts who are at greatest risk for adverse effects, allowing a more individualized approach to their chemotherapy management. [Table: see text]

scholarly journals Tegafur–uracil is a safe alternative for the treatment of colorectal cancer in patients with partial dihydropyrimidine dehydrogenase deficiency: a proof of principle

2012 ◽  
Vol 4 (4) ◽  
pp. 167-172 ◽  
Author(s):  
Daniel I.G. Cubero ◽  
Felipe Melo Cruz ◽  
Patrícia Santi ◽  
Ismael Dale C.G. Silva ◽  
Auro del Giglio
Keyword(s):  
Colorectal Cancer ◽  
Cancer Patients ◽  
Dehydrogenase Deficiency ◽  
Dihydropyrimidine Dehydrogenase ◽  
Gene Sequencing ◽  
Severe Toxicity ◽  
Safe Alternative ◽  
Grade 3 ◽  
Colorectal Cancer Patients ◽  
Proof Of Principle

Objective: The objective of this study was to evaluate the safety of using tegafur–uracil (UFT) in colorectal cancer patients with partial dihydropyrimidine dehydrogenase (DPD) deficiency. Patients and Methods: The study included five colorectal cancer patients who presented with acute toxicity (grades 3 and 4) after being given the first cycle of chemotherapy using 5-fluorouracil. The DPD deficiency was confirmed by gene sequencing. After a full recovery from all side effects, we changed the regimen to UFT (300 mg/m2/day) associated with leucovorin (90 mg/day) for 21 days, with an empirical dose reduction of at least 10% in the first cycle. Results: We prospectively analysed 22 UFT cycles in 5 patients. We did not observe any episodes of grade 3 or 4 toxicity. The predominant toxicities were of grades 1 and 2 (nausea, vomiting and diarrhoea). Conclusion: Here, we demonstrate a complete absence of severe toxicity in all patients and cycles analysed. We believe that UFT is a safe alternative for the treatment of patients with partial DPD deficiency.

scholarly journals Predictive Value of Clinical Toxicities to Chemotherapy with Fluoropyrimidines and Oxaliplatin in Colorectal Cancer by DPYD and GSTP1 Genes Polymorphisms

2020 ◽  
Author(s):  
Xunwei Deng ◽  
Jingyuan Hou ◽  
Qiaoting Deng ◽  
Zhixiong Zhong
Keyword(s):  
Colorectal Cancer ◽  
Adverse Events ◽  
Direct Sequencing ◽  
Dihydropyrimidine Dehydrogenase ◽  
Severe Neutropenia ◽  
Severe Toxicity ◽  
Nucleotide Polymorphisms ◽  
Significant Difference ◽  
Grade 3 ◽  
Colorectal Cancer Patients

Abstract Background: Fluoropyrimidines and platinum are still widely used for colorectal cancer (CRC) management. Several studies have reported that mutations of dihydropyrimidine dehydrogenase (DPYD) and glutathione S-transferase pi-1 (GSTP1) polymorphisms are related to Chemotherapy-related adverse events. The present study was aimed to determine the role of DPYD and GSTP1 variants on patient chemotherapy toxicity risk among the Hakka population, minimize adverse events and in order to maximize therapy outcome for individualized treatment.Methods: Genotyping was examined in 104 patients diagnosed with CRC cases and receiving fluoropyrimidine and platinum drugs based chemotherapy regimen by direct sequencing of DPYD and GSTP1 polymorphisms. Three DPYD variants including *2A, *5A, *9A and GSTP1 c.313A>G were analyzed and clinical outcomes were assessed. Results: The data suggest that the incidence of DPYD*5A, DPYD*9A and GSTP1 c.313A>G variants were 37.5%, 24% and 31.7%, respectively. DPYD*2A variant was not found. A total of 38 patients (36.5%) suffered severe neutropenia and 23 patients (22.1%) suffered severe vomiting. DPYD*5A polymorphism was found significantly associated with grade 3/4 ulceration (p = 0.001). GSTP1 was determined to be an independent risk factor for severe neutropenia and ulceration (p = 0.010 and p = 0.034, respectively). Patients with GSTP1 c.313A>G wild type contributed to higher risk for grade severe toxicity compared with A/G + G/G genotype (p = 0.024). However, there was no significant difference between patients with DPYD*9A T/T and T/C + C/C genotype for chemotherapeutic toxicity.Conclusions: The results demonstrated that DPYD*5A and GSTP1 polymorphisms were useful predictors for severe events. Screening of single nucleotide polymorphisms of DPYD and GSTP1 in colorectal cancer patients prior to chemotherapy may help to realize personalized therapy.

scholarly journals Burden of Disease and Clinical Responses in Low and Intermediate-1 Risk Myelofibrosis Patients Treated with Ruxolitinib

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1834-1834
Author(s):  
Ahmad Zarzour ◽  
Ali Tabarroki ◽  
Valeria Visconte ◽  
Rokana Taftaf ◽  
Heesun J. Rogers ◽  
...  
Keyword(s):  
High Risk ◽  
Adverse Events ◽  
Burden Of Disease ◽  
Costal Margin ◽  
Severe Toxicity ◽  
Spleen Size ◽  
High Burden ◽  
Clinical Responses ◽  
Grade 3

Abstract Myelofibrosis (MF) is a hematologic neoplasm characterized by variable degrees of cytopenias/ myeloproliferation, extramedullary hematopoiesis, disease-related constitutional symptoms and an increased risk for acute myeloid leukemia (AML) transformation. Ruxolitinib, a JAK1/2 inhibitor is FDA approved for the management of intermediate to high-risk MF. However, intermediate-2 and high-risk MF patients accounted for 99% of patients (pts) in the 2 pivotal trials that led to the approval of ruxolitinib in North America, Australia and Europe (COMFORT 1 and COMFORT 2 studies). However, even low and intermediate-1 (int-1) risk MF pts could have a high burden of disease. Here we report our experience of using ruxolitinib in MF pts stratified as low and int-1 risk by the Dynamic International Prognostic Scoring System (DIPSS). A total of 25 pts with low and Int-1 risk disease were treated with ruxolitinib at the Cleveland Clinic and Northwestern University. The median age of the cohort was 61 yrs (range=33-87; males=9, females=16). The median total symptom score (TSS) by Myeloproliferative Neoplasm Symptom Assessment Form (MPN SAF) was 20. The median pre-treatment spleen size by palpation was 13 cm below the left costal margin. Baseline median bone marrow (BM) fibrosis grading was 2 (on a scale 0-3; grade 1 N=3, grade 2 N=11, and grade 3 N=11). The indications for starting ruxolitinib were constitutional symptoms (fatigue N=20, night sweats N=4, pruritus N=1) and splenomegaly (N=13). The median starting dose was 5 mg twice daily, 10mg twice daily at 3 months and 6 months, and 5mg twice daily at 12 months. The median dose at last follow up was 10 mg twice daily. The median duration of treatment was 12 months. There was a median 73% reduction in the MPN SAF TSS compared to baseline (P< 0.001). There was improvement in each of the parameters of the TSS. The percentage of reduction in spleen size by palpation at 3, 6, 12 months was 49, 57, and 64%, respectively. In 5 patients who had a repeat BM biopsy, there was an improvement in their BM fibrosis by at least 1 grade (N=3), stable fibrosis (N=1) or increased fibrosis (N=1). Hematologic adverse events were reported at 3, 6, 12 months of treatment. Using Common Terminology Criteria for Adverse Events (CTCAEv4.0), there were seven with grade 3/4 anemia and six with grade 3/4 thrombocytopenia. Non-hematologic adverse events reported at 3, 6, 12 months of treatment included dizziness (N=1), headaches (N=1) and infections (pneumonia N=2, cellulitis N=2, perineal abscess N=1, Herpes Zoster N=2, and gluteal abscess after BM biopsy N=1; only one required hospitalization). Ruxolitinib was discontinued in 5 patients due to lack of clinical response (N=3) and grade 3/4 anemia/thrombocytopenia (N=2). The remaining 20 patients are still on treatment. None of the pts progressed to AML or died. The median follow up of our cohort was 27 months. Further, using a multi-Analyte ELISArray Kit, plasma concentrations of interleukins (IL):IL1A, IL1B, IL2, IL4, IL6, IL8, IL10, IL12, IL17A, INFg, TNFa and GM-CSF were measured in low/int-1 risk pts (N=3) and intermediate-2/high risk patients (N=4) and no statistically significant difference was found between the two risk groups (P>0.05) further supporting the high burden of disease observed even in low and int-1 risk MF patients. In conclusion, pts with low/int-1 risk MF have a high burden of disease and can achieve meaningful clinical responses to ruxolitinib similar to int-2/ high risk MF pts without severe toxicity. Larger studies are needed to further evaluate the safety and efficacy of ruxoltinib in this patient population. Disclosures No relevant conflicts of interest to declare.

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