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JAK2 V617F Genetic Biomarker Used in Differential Diagnosis for BCR-ABL1 Negative Myeloproliferative Neoplasms
Abstracts coefficients (cc) were as follows: 0.37 for absenteeism, 0.70 for presenteeism, 0.70 for work impairment, and 0.70 for activity impairment (all P<0.001; Table 2). Considerably high correlation was observed between WPAI scores and each of the ten symptoms in MPN TSS, with problems with concentration, inactivity, and fatigue showing the strongest correlation. Conclusion: Work productivity and daily activities of patients with MPNs were substantially impaired by their disease. A greater detrimental impact was observed in patients with higher symptom burden.
MPN-166 Are Patients with High-Risk Polycythemia Vera (PV) Receiving Cytoreductive Medications? A Retrospective Analysis of Real-World Data Dilan Paranagama ,1 Jingbo Yu,1 Philomena Colucci,1 Kristin Evans,2 Machaon Bonafede,2 Shreekant Parasuraman1 1 Incyte Corporation, Wilmington, United States; 2Truven Health Analytics, an IBM Company, Cambridge, United States
Context: Risk-adapted therapy in PV is aimed at preventing thrombotic events (TE). Under current treatment recommendations (including European LeukemiaNet), high-risk patients (age 60 y and/or history of TE) should be managed with cytoreductive medications in addition to phlebotomy and low-dose aspirin. Objective: The objective of this study was to describe cytoreductive medication usage in patients with high-risk PV. Design: Retrospective cohort analysis of claims from the Truven Health MarketScanÒ Database. Setting: US clinical practice. Patients: Inclusion criteria were 2 non-diagnostic claims for PV >30 days apart, age 18 y, continuous enrollment during pre-index (1/ 1/2012e12/31/2012), and continuous enrollment through or death during the study period (1/1/2013e12/31/2014). Patients with claims for myelodysplastic syndrome, myelofibrosis, acute myelogenous leukemia, or secondary polycythemia were excluded. Descriptive statistics were used. Intervention: This study is noninterventional. Main Outcome Measures: The primary outcome of this analysis is to report the occurrence of cytoreductive medication use among adult patients with high-risk PV in the United States. Results: The study included 2856 patients. Mean (SD) age was 62.5 (13.5) y, 65.9% of patients were male, and 63.8% were highrisk. Comorbid conditions of interest were reported more frequently in high-risk patients than low-risk patients: hypertension (65.0% vs 43.1%), diabetes (21.7% vs 10.1%), and congestive heart failure (6.6% vs 0.6%). In low- and high-risk patients, the most commonly used cytoreductive medications were hydroxyurea (93.6%), anagrelide (7.6%), and interferon (2.4%). Low-risk patients received cytoreductive medications less often than high-risk patients (Table). However, only 42% of the high-risk patients received treatment with a cytoreductive medication by the end of the study. Conclusions: Despite higher cardiovascular risk and current treatment recommendations, less than half of the high-risk PV patients
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Clinical Lymphoma, Myeloma & Leukemia September 2017
Table Cytoreductive medication usage by risk category Risk Category (N[2856)
Ever Received Cytoreductive Medication, n (%)
High Risk (n¼1823) Age <60 with TE (n¼165)
766 (42.0) 54 (32.7)
Age S60 without TE (n¼1145)
474 (41.4)
Age S60 with TE (n¼513)
238 (46.4)
Low-risk (n¼1033)
195 (18.9)
received cytoreductive medications. Furthermore, less than a third of younger patients with a prior TE received cytoreductive medications.
MPN-177 JAK2 V617F Genetic Biomarker Used in Differential Diagnosis for BCRABL1 Negative Myeloproliferative Neoplasms Rodica Talmaci ,1,2,3 Natalia Cucu,3,4 Mihaela Dragomir,2 Silvia Aposteanu,2 D. Coriu1,2 1 Department of Hematology-Fundeni Clinical Institute, University of Medicine and Pharmacy “Carol Davila”, Bucharest, Romania; 2Center
of Hematology and Bone Marrow Transplantation, Fundeni Clinical Institute, Bucharest, Romania; 3Association for Epigenetics and Metabolomics, Bucharest, Romania; 4Department of Genetics, University of Bucharest, Bucharest, Romania
Context: V617F mutation in Januss kinase 2 (JAK2) gene is detected in more than 60% of patients with BCR-ABL1 negative myeloproliferative neoplasms (MPNs), such as: polycythemia vera (PV), essential trombocythemia (ET) and primary myelofibrosis (PMF). This mutation results in self inhibition of the JAK2 activity from cytoplasm, an enzyme with a role of signal transduction from growth factor receptors, resulting in increased cell proliferation in hematopoietic bone marrow and periphereal blood. Objective: The possibility that the burden of JAK2 mutation has an influence on disease phenotype through the level of activation of downstream JAK/STAT signalling pathways is supported by several experimental and clinical observations. Is it necessary to take into account the low level positivity for MPN patients and start the medication therapy in order to receive the best respons to therapy? Design: We have analyzed 527 DNA samples from patients diagnosed with BCR-ABL1 negative MPNs in Department of Hematology, Fundeni Clinical Institute, Bucharest. Amplification Refractory Mutation System (ARMS-PCR), described by Baxter et al, has been re-designed and optimized in our laboratory for the concomitant detection of the mutant allele and the wild type gene. Setting: For confirmation, some low level pozitive samples were sequenced by Next Generation Sequencing (MiSeq - illumina) method with sensitivity 1-5%. The results were confirmed the presence of V617F mutation in exon 14 of JAK2 gene. For allele burden
Abstracts determination, a semiquantitative evaluation by High Resolution Melting temperature based system (i-densy - Arkray) was performed. Results: Our observations show substantial differences in the V617F allele burden in peripheral blood granulocytes among individual MPNs; the highest levels are found in PV and the lowest in ET patients and intermediate levels in PMF. These findings correlate very well allele burden of V617F mutation at diagnosis with confirmed diagnosis: PV 25%-100%, PMF 1025% and ET 1-10%. Conclusions: In conclusion, the allele burden of JAK2 V617F was significantly lower for ET than that for PV or PMF in DNA samples. The JAK2 V617F allele burden is a diagnostic tool for differentiating PV or PMF from ET at the time of diagnosis and for a high professional therapeutic decision.
MPN-222 Low Mean Corpuscular Volume Retains Ability to Predict Inferior Outcome in Polycythemia Vera Victor Garcia ,1 Hussein Hamad,2 Yellapragada Sarvari,2,3 Gustavo Rivero1,2,3
independent prognostic value independent from WBC, platelets, hemoglobin and FER. Conclusions: MCV <89 fL predicts inferior outcome in P.vera. Despite MCV <89 pt exhibited higher platelet count, lower MCV conferred inferior survival independently variables with known adverse effect on P.vera. Lower MCV possibly segregate subgroup with aggressive behavior. We currently seek to validate our observation in larger pt cohort with precise cytogenetic and molecular characterization.
MPN-225 Monocytosis in myelofibrosis is associated with clinical outcome, hematologic abnormalities and somatic mutations Daniel Kerr, II ,1 Andrew Kuykendall,1 Chetasi Talati,1 Najla Al-Ali,2 David Sallman,2 Kendra Sweet,2 Jeffrey Lancet,2 Alan List,2 Eric Padron,2 Rami Komrokji2 1
H. Lee Moffitt Cancer Center/University of South Florida, Tampa,
United States; 2H. Lee Moffitt Cancer Center & Research Institute, Tampa, United States
1
Baylor St Luke Medical Center, Houston, United States; 2The Dan L.
Duncan Comprehensive Cancer, Houston, United States; 3Michael E. DeBakey VA Houston Medical Center, Houston, Texas, 77030, Houston, United States
Context: Lower than expected MCV reflects Iron deficiency (ID) aggravates cardiovascular (CV) disease in Polycythemia Vera (P.vera). Our study is first and novel to investigate proof of concept for MCV as potential predictor for disease inferior outcome. Objective: To evaluate whether MCV detected at diagnosis retains ability to predict outcome in P.vera patients (pt). Design: Prior IRB approval, a retrospective single institution study aimed at evaluating MCV impact on survival in 49 pt with P.vera was conducted from 2000 to 2016. Setting: Pt were selected from cancer register at the Michael E. DeBakey Houston VA. Patients or Other Participants: 20/49 (40.8%) pt had confirmed Jak2617F mutation. Before 2005, 29 pt were diagnosed after secondary erythrocytosis was ruled out and presented with low EPO and ferritin, respectively. Intervention: None. Main Outcomes Measures: Median MCV was estimated and censored survivals were plotted in PRISM5. To control for potential factors that impact MCV, pt with GI bleed, thalassemia, B12 and folate deficiency were excluded. Multivariate analysis including WBC, Hb, platelets, and ferritin was performed. Results: Median MCV was 89 fL. 24/49 (48.9%) and 25/49 (51.1%) pt were MCV < and > 89 fL. For those pt with MCV < 89fL, median age was 61 y (33-86) vs 58 y (35-89) for MCV >89fL, p¼0.10. Hemoglobin, WBC, platelets and ferritin (FER) were 16.7 g /dL (10.3-20.9) vs 18.5 g/dL (14.8- 20.2),10.75 (5.6-24.8) vs 7.6 (4.2-16.3), p¼ 0.08, 317 (121-761) vs 199.5 (78-625), p¼0.01, 28.7 ng/ml (7204.2) vs 50.6 ng/ml (23-1056.55), p¼ 0.10, for MCV < or > 89fL, respectively. Median survival was 5364 d and 8842 d for pt with MCV < or > 89 fL, p¼0.006 (95% CI¼0.34-0.86). Multivariate analysis revealed that MCV <89 fL retains
Background: Myelofibrosis is a chronic myeloproliferative neoplasm that has a heterogenous clinical phenotype and prognosis. Current prognostic models use a variety of clinical and laboratory characteristics to define risk groups whose median survivals can differ by nearly a decade. Prior investigations have suggested a negative prognostic role of absolute monocytosis in this disease. Methods: We retrospectively reviewed an institutional database of 180 MF patients who presented to Moffitt Cancer Center between 4/26/2005 and 12/31/2016. We selected patients with available clinical, pathologic and longitudinal data as well as genomic sequencing analyses (NGS). We identified a cohort of MF patients with both absolute (AMC > 800/L) and relative (>10%) monocytosis at time of diagnosis or first presentation. Laboratory values and prognostic scores were determined at first presentation. Overall survival (OS) was measured from diagnosis until date of death/ censored at last follow-up. Leukemia-free survival (LFS) was measured from diagnosis to development of AML. Results: Our total cohort of 180 MF patients had a median age at diagnosis of 69.7 (range 19-90) and included 28 patients with monocytosis. A positive correlation was observed between monocytosis and WBC, absolute lymphocyte count, percentage of peripheral blasts and marrow myeloblasts (p < 0.04) as well as a negative correlation with platelet count (p ¼ 0.03). Monocytosis was also associated with increased IPSS, DIPSS and DIPSS+ scores (p < 0.02) indicating a higher incidence of monocytosis in higher risk disease. Comparing NGS data, we found an increased incidence of somatic mutations in TET2, ASXL1, SRSF2 and KRAS within the monocytosis cohort (p < 0.04). The monocytosis cohort had significantly shorter OS (median 26.2 months vs 161 months, p < 0.001) as well as LFS (median 40.5 months vs undefined, p ¼ 0.03). Summary/ Conclusion: We classified monocytosis by using absolute and relative cutoffs accounting for patients with higher WBC without a relative increase in monocytes. We have confirmed previous data
Clinical Lymphoma, Myeloma & Leukemia September 2017
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MPN-166 Are Patients with High-Risk Polycythemia Vera (PV) Receiving Cytoreductive Medications? A Retrospective Analysis of Real-World Data Dilan Paranagama ,1 Jingbo Yu,1 Philomena Colucci,1 Kristin Evans,2 Machaon Bonafede,2 Shreekant Parasuraman1 1 Incyte Corporation, Wilmington, United States; 2Truven Health Analytics, an IBM Company, Cambridge, United States
Context: Risk-adapted therapy in PV is aimed at preventing thrombotic events (TE). Under current treatment recommendations (including European LeukemiaNet), high-risk patients (age 60 y and/or history of TE) should be managed with cytoreductive medications in addition to phlebotomy and low-dose aspirin. Objective: The objective of this study was to describe cytoreductive medication usage in patients with high-risk PV. Design: Retrospective cohort analysis of claims from the Truven Health MarketScanÒ Database. Setting: US clinical practice. Patients: Inclusion criteria were 2 non-diagnostic claims for PV >30 days apart, age 18 y, continuous enrollment during pre-index (1/ 1/2012e12/31/2012), and continuous enrollment through or death during the study period (1/1/2013e12/31/2014). Patients with claims for myelodysplastic syndrome, myelofibrosis, acute myelogenous leukemia, or secondary polycythemia were excluded. Descriptive statistics were used. Intervention: This study is noninterventional. Main Outcome Measures: The primary outcome of this analysis is to report the occurrence of cytoreductive medication use among adult patients with high-risk PV in the United States. Results: The study included 2856 patients. Mean (SD) age was 62.5 (13.5) y, 65.9% of patients were male, and 63.8% were highrisk. Comorbid conditions of interest were reported more frequently in high-risk patients than low-risk patients: hypertension (65.0% vs 43.1%), diabetes (21.7% vs 10.1%), and congestive heart failure (6.6% vs 0.6%). In low- and high-risk patients, the most commonly used cytoreductive medications were hydroxyurea (93.6%), anagrelide (7.6%), and interferon (2.4%). Low-risk patients received cytoreductive medications less often than high-risk patients (Table). However, only 42% of the high-risk patients received treatment with a cytoreductive medication by the end of the study. Conclusions: Despite higher cardiovascular risk and current treatment recommendations, less than half of the high-risk PV patients
S356
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Clinical Lymphoma, Myeloma & Leukemia September 2017
Table Cytoreductive medication usage by risk category Risk Category (N[2856)
Ever Received Cytoreductive Medication, n (%)
High Risk (n¼1823) Age <60 with TE (n¼165)
766 (42.0) 54 (32.7)
Age S60 without TE (n¼1145)
474 (41.4)
Age S60 with TE (n¼513)
238 (46.4)
Low-risk (n¼1033)
195 (18.9)
received cytoreductive medications. Furthermore, less than a third of younger patients with a prior TE received cytoreductive medications.
MPN-177 JAK2 V617F Genetic Biomarker Used in Differential Diagnosis for BCRABL1 Negative Myeloproliferative Neoplasms Rodica Talmaci ,1,2,3 Natalia Cucu,3,4 Mihaela Dragomir,2 Silvia Aposteanu,2 D. Coriu1,2 1 Department of Hematology-Fundeni Clinical Institute, University of Medicine and Pharmacy “Carol Davila”, Bucharest, Romania; 2Center
of Hematology and Bone Marrow Transplantation, Fundeni Clinical Institute, Bucharest, Romania; 3Association for Epigenetics and Metabolomics, Bucharest, Romania; 4Department of Genetics, University of Bucharest, Bucharest, Romania
Context: V617F mutation in Januss kinase 2 (JAK2) gene is detected in more than 60% of patients with BCR-ABL1 negative myeloproliferative neoplasms (MPNs), such as: polycythemia vera (PV), essential trombocythemia (ET) and primary myelofibrosis (PMF). This mutation results in self inhibition of the JAK2 activity from cytoplasm, an enzyme with a role of signal transduction from growth factor receptors, resulting in increased cell proliferation in hematopoietic bone marrow and periphereal blood. Objective: The possibility that the burden of JAK2 mutation has an influence on disease phenotype through the level of activation of downstream JAK/STAT signalling pathways is supported by several experimental and clinical observations. Is it necessary to take into account the low level positivity for MPN patients and start the medication therapy in order to receive the best respons to therapy? Design: We have analyzed 527 DNA samples from patients diagnosed with BCR-ABL1 negative MPNs in Department of Hematology, Fundeni Clinical Institute, Bucharest. Amplification Refractory Mutation System (ARMS-PCR), described by Baxter et al, has been re-designed and optimized in our laboratory for the concomitant detection of the mutant allele and the wild type gene. Setting: For confirmation, some low level pozitive samples were sequenced by Next Generation Sequencing (MiSeq - illumina) method with sensitivity 1-5%. The results were confirmed the presence of V617F mutation in exon 14 of JAK2 gene. For allele burden
Abstracts determination, a semiquantitative evaluation by High Resolution Melting temperature based system (i-densy - Arkray) was performed. Results: Our observations show substantial differences in the V617F allele burden in peripheral blood granulocytes among individual MPNs; the highest levels are found in PV and the lowest in ET patients and intermediate levels in PMF. These findings correlate very well allele burden of V617F mutation at diagnosis with confirmed diagnosis: PV 25%-100%, PMF 1025% and ET 1-10%. Conclusions: In conclusion, the allele burden of JAK2 V617F was significantly lower for ET than that for PV or PMF in DNA samples. The JAK2 V617F allele burden is a diagnostic tool for differentiating PV or PMF from ET at the time of diagnosis and for a high professional therapeutic decision.
MPN-222 Low Mean Corpuscular Volume Retains Ability to Predict Inferior Outcome in Polycythemia Vera Victor Garcia ,1 Hussein Hamad,2 Yellapragada Sarvari,2,3 Gustavo Rivero1,2,3
independent prognostic value independent from WBC, platelets, hemoglobin and FER. Conclusions: MCV <89 fL predicts inferior outcome in P.vera. Despite MCV <89 pt exhibited higher platelet count, lower MCV conferred inferior survival independently variables with known adverse effect on P.vera. Lower MCV possibly segregate subgroup with aggressive behavior. We currently seek to validate our observation in larger pt cohort with precise cytogenetic and molecular characterization.
MPN-225 Monocytosis in myelofibrosis is associated with clinical outcome, hematologic abnormalities and somatic mutations Daniel Kerr, II ,1 Andrew Kuykendall,1 Chetasi Talati,1 Najla Al-Ali,2 David Sallman,2 Kendra Sweet,2 Jeffrey Lancet,2 Alan List,2 Eric Padron,2 Rami Komrokji2 1
H. Lee Moffitt Cancer Center/University of South Florida, Tampa,
United States; 2H. Lee Moffitt Cancer Center & Research Institute, Tampa, United States
1
Baylor St Luke Medical Center, Houston, United States; 2The Dan L.
Duncan Comprehensive Cancer, Houston, United States; 3Michael E. DeBakey VA Houston Medical Center, Houston, Texas, 77030, Houston, United States
Context: Lower than expected MCV reflects Iron deficiency (ID) aggravates cardiovascular (CV) disease in Polycythemia Vera (P.vera). Our study is first and novel to investigate proof of concept for MCV as potential predictor for disease inferior outcome. Objective: To evaluate whether MCV detected at diagnosis retains ability to predict outcome in P.vera patients (pt). Design: Prior IRB approval, a retrospective single institution study aimed at evaluating MCV impact on survival in 49 pt with P.vera was conducted from 2000 to 2016. Setting: Pt were selected from cancer register at the Michael E. DeBakey Houston VA. Patients or Other Participants: 20/49 (40.8%) pt had confirmed Jak2617F mutation. Before 2005, 29 pt were diagnosed after secondary erythrocytosis was ruled out and presented with low EPO and ferritin, respectively. Intervention: None. Main Outcomes Measures: Median MCV was estimated and censored survivals were plotted in PRISM5. To control for potential factors that impact MCV, pt with GI bleed, thalassemia, B12 and folate deficiency were excluded. Multivariate analysis including WBC, Hb, platelets, and ferritin was performed. Results: Median MCV was 89 fL. 24/49 (48.9%) and 25/49 (51.1%) pt were MCV < and > 89 fL. For those pt with MCV < 89fL, median age was 61 y (33-86) vs 58 y (35-89) for MCV >89fL, p¼0.10. Hemoglobin, WBC, platelets and ferritin (FER) were 16.7 g /dL (10.3-20.9) vs 18.5 g/dL (14.8- 20.2),10.75 (5.6-24.8) vs 7.6 (4.2-16.3), p¼ 0.08, 317 (121-761) vs 199.5 (78-625), p¼0.01, 28.7 ng/ml (7204.2) vs 50.6 ng/ml (23-1056.55), p¼ 0.10, for MCV < or > 89fL, respectively. Median survival was 5364 d and 8842 d for pt with MCV < or > 89 fL, p¼0.006 (95% CI¼0.34-0.86). Multivariate analysis revealed that MCV <89 fL retains
Background: Myelofibrosis is a chronic myeloproliferative neoplasm that has a heterogenous clinical phenotype and prognosis. Current prognostic models use a variety of clinical and laboratory characteristics to define risk groups whose median survivals can differ by nearly a decade. Prior investigations have suggested a negative prognostic role of absolute monocytosis in this disease. Methods: We retrospectively reviewed an institutional database of 180 MF patients who presented to Moffitt Cancer Center between 4/26/2005 and 12/31/2016. We selected patients with available clinical, pathologic and longitudinal data as well as genomic sequencing analyses (NGS). We identified a cohort of MF patients with both absolute (AMC > 800/L) and relative (>10%) monocytosis at time of diagnosis or first presentation. Laboratory values and prognostic scores were determined at first presentation. Overall survival (OS) was measured from diagnosis until date of death/ censored at last follow-up. Leukemia-free survival (LFS) was measured from diagnosis to development of AML. Results: Our total cohort of 180 MF patients had a median age at diagnosis of 69.7 (range 19-90) and included 28 patients with monocytosis. A positive correlation was observed between monocytosis and WBC, absolute lymphocyte count, percentage of peripheral blasts and marrow myeloblasts (p < 0.04) as well as a negative correlation with platelet count (p ¼ 0.03). Monocytosis was also associated with increased IPSS, DIPSS and DIPSS+ scores (p < 0.02) indicating a higher incidence of monocytosis in higher risk disease. Comparing NGS data, we found an increased incidence of somatic mutations in TET2, ASXL1, SRSF2 and KRAS within the monocytosis cohort (p < 0.04). The monocytosis cohort had significantly shorter OS (median 26.2 months vs 161 months, p < 0.001) as well as LFS (median 40.5 months vs undefined, p ¼ 0.03). Summary/ Conclusion: We classified monocytosis by using absolute and relative cutoffs accounting for patients with higher WBC without a relative increase in monocytes. We have confirmed previous data
Clinical Lymphoma, Myeloma & Leukemia September 2017
- S357