Myeloproliferative Neoplasms (MPNs): Diagnosis, Treatment .
3/23/2020Myeloproliferative Neoplasms (MPNs):Diagnosis, Treatment, andSide Effects Management1LEARNING OBJECTIVES Describe the types of myeloproliferative neoplasms, includingmyelofibrosis, polycythemia vera, and essential thrombocythemia Identify tests used to diagnose disease and monitor treatment Explain the overarching goals of treatment for the various types ofmyeloproliferative neoplasms Explain approved and emerging treatment options for all myeloproliferativeneoplasms, including stem cell transplantation, and the role of clinical trials Describe strategies to manage treatment side effects as well as potentiallong-term and late effects of treatments Identify resources for patients, caregivers and healthcare providers21
3/23/2020FACULTYMichael Mauro, MDProfessor of MedicineLeader, Myeloproliferative Neoplasms ProgramLeukemia ServiceMemorial Sloan Kettering Cancer CenterNew York, NYCharlene Kabel, PharmD, BCOPCarolanne Carini, BSN, RN, BMTCNClinical Pharmacy SpecialistLeukemia Service, Department of PharmacyMemorial Sloan Kettering Cancer CenterNew York, NYOffice Practice Nurse, Medical OncologyMemorial Sloan Kettering Cancer CenterNew York, NY3Myeloproliferative Neoplasms:Diagnosis, Treatment, and Side Effects ManagementMichael Mauro, MDLeader, Myeloproliferative Neoplasms ProgramLeukemia ServiceMemorial Sloan Kettering Cancer CenterCharlene Kabel, PharmD, BCOPClinical Pharmacy Specialist, LeukemiaMemorial Sloan Kettering Cancer Center42
3/23/2020MPN Overview: TimeframesOvert PMFPost ET/PV MFPVETEarly PMFShort term: mictransformationLead time: Typicallyyears ( 10)Time: Variable;3-5 years commonPrematuredeathEMH, extramedullary hematopoiesis; ET, essential thrombocythemia; MF, myelofibrosis; PMF, primary myelofibrosis, PV, polycythemia veraPinilla-Ibarz J et al. (2016). Onco Targets Ther, 9:4937-4957; Lichtman M et al. (2011).Williams Manual of Hematology (8th ed). New York: McGraw Hill Medical.5JAK2 V617F Mutation Discovery in MPNs: “The Other BCR-ABL”March 18, 2005March 24, 2005April 28, 200563
3/23/2020JAK2 Signaling in MPNs: Finding the “Driver”Wild-type JAK2: Normal signalingJAK2 V617F: Enthusiastic signalingDiseaseFrequencyPV 95%ET 50-60%PMF 50-60%Stein B. JAMA. 2010;303(24):2513-2518.7Frequency and Distributionof “Driver” and OtherMutations in Patients WithMPNsCourtesy of J. Mascarenhas, modified from Lundbertg P et al. Blood. 2014;123(14):2220-8.84
3/23/2020MULTIVARIATE ANALYSISVariablesAge 60 yrsWeightedvalueHR (95% CI)P3.8 (2.60-5.51) 0.00011.5Hgb 100 g/L1.4 (1.01-1.99)0.040.5Constitutional Symptoms1.5 .(1.13-2.16)0.0070.5PLT 200x109/L2.5 (1.77-3.42) 0.00011.0Triple Negativity3.9 (2.20-6.80) 0.00011.5JAK2/MPL mutation1.8 (1.11-2.90)0.0160.5ASXL1 mutation1.4 (1.06-1.99)0.020.5SRSF2 mutation1.7 (1.08-2.58)0.020.5Molecular International PrognosticScoring System1 in Myelofibrosis*, IPSS Median SurvivalIPSS - LOWIPSS - INT-1* 23.4y §* 17.7yIPSS - INT-2*4.5yRefines prognostic stratificationwithin the IPSS categories P .005M§ I P S SEstimatedP .040Low24.9y Low 15.3y§§P .001 Int-1 17.7y Int-2 6.2y Int-1 8.1y Int-2 1.9y1 Mutation-Enhanced International Prognostic Scoring SystemVannucchi A et al. Blood. 2014;124:405.9Molecular Prognosis in MyelofibrosisNCCN Guidelines v3.2019. Myeloproliferative Neoplasms. Accessed November 6, 2019.105
3/23/2020Molecular Prognosis in Polycythemia VeraNCCN Guidelines v3.2019. Myeloproliferative Neoplasms. Accessed November 6, 2019.11Molecular Prognosis in Essential ThrombocythemiaNCCN Guidelines v3.2019. Myeloproliferative Neoplasms. Accessed November 6, 2019.126
3/23/2020Assessing MPN Patient Risk: Prognostic ModelsIPSET(ET—3 groups)Survivalthrombosis riskPVRisk (4 groups)Survivalleukemia ratesDIPSS(PMF—4 groups)SurvivalAge, years 60 (2 points) vs 60 67 (5 points)57-66 (2 points), 60 (0) 65 (1 point) vs 65Leukocytes 11 (1 point) vs 11 x 109/L 15 (1 point) vs 15 x 109/L 25 (1 point) vs 25 x 109/LHemoglobin 10 (2 points) vs 10 g/dLPresenta (1 point) vs absentConstitutional symptomsBlastsPrior thrombosisRisk group point cutoffs 1% (1 point) vs 1%Yes (1 point) vs NoYes (1 Point) vs No0; 1-2; 3-4 points0; 1-2; 3; 4 points0; 1-2; 3-4; 4 pointsIPSET, International Prognostic Score of Thrombosis for Essential Thrombocythemia; DIPSS, Dynamic International Prognostic Scoring SystemBose & Verstovsek. (2016). Cancer. 122:681-692.13147
3/23/2020Formally Assessing MPN Symptom Burden:Symptom Assessment FormVascular and Ψ Sx9 ItemsConstitutional Sx5 ItemsSpleen Sx4 ItemsBrief FatigueInventory(BFI) – 9 ItemsQOL 1 ItemMF–SAF2009(19 items)MF-SAF 2.0(7 items 2011)JCO 2012MPN–SAF2011(27 items)Blood 2011MPN-SAF TSSMPN10(10 items 2012)JCO 2013 MPN-SAF lianPortugueseMandarinJapaneseHebrewCzechCourtesy of R. Mesa, Mayo Clinic.15Signs and Symptoms of MPNs: Often Under-Queried Geyer HL et al. Blood. 2014;124:3529-3537.168
3/23/2020MPN Symptom AssessmentNCCN Guidelines v3.2019. Myeloproliferative Neoplasms. Accessed November 6, 2019.17Myelofibrosis189
3/23/2020Clinical Features of Myelofibrosis Bone marrow fibrosis Splenomegaly– Splenomegaly-associated symptoms include abdominalpain/discomfort, early satiety Cytopenias– Anemia, thrombocytopenia Constitutional symptoms– Include fatigue, night sweats, pruritus (itching), boneaches, weight lossCervantes F. Blood. 2014;124(17):2635-42.19WHO Criteria for Diagnosis of Overt Primary Myelofibrosis ALL 3 major criteria plus at least 1 minor criteriaMajor Criteria1. Presence of megakaryocytic proliferation andatypia, accompanied by either reticulin and/orcollagen fibrosis grades 2 or 32. Not meeting WHO criteria for ET, PV, BCRABL1 CML, MDS, or other myeloid neoplasms3. Presence of JAK2, CALR, or MPL mutation or inthe absence of these mutations, presence ofanother clonal marker, or absence of reactivemyelofibrosisMinor CriteriaAt least 1 of the following, confirmed in 2consecutive determinations:1. Anemia not attributed to a comorbid condition2. Leukocytosis 11 109/L3. Palpable splenomegaly4. LDH increased to above upper normal limit ofinstitutional reference range5. LeukoerythroblastosisArber D et al. Blood. 2016;127:2391-2405.2010
3/23/2020MPN Fibrosis GradingNCCN Guidelines v3.2019. Myeloproliferative Neoplasms. Accessed November 6, 2019.21The “Driver” Mutation and Other Alterations Affect Outcome in MFThe mutational status of JAK2, MPL and CALR and the presence and number of other relevant mutations(ASXL1, SRSF2, EZH2, IDH1/2) provide IPSS/DIPSS-plus independent prognostic informationCALR mutantJAK2 mutantMPL mutantTriplenegativeHR 2.29 (P .0001)Hazard Ratio:2.3 for JAK2V617F (P .001)2.6 for MPL (P .009)6.2 for Triple Negative (P .001)High risk:any mutation in ASXL1, EZH2, SRSF2, IDH1/2Rumi E et al. Blood. 2014;124:1062-9.Vannucchi AM et al. Leukemia. 2013;27:1861-9.2211
3/23/2020PatientspecificvariableRisk Stratification in MyelofibrosisLille(1996)Prognostic scoring systemIPSSDIPSSDIPSS MIPSS(2009) lsymptomslaboratoryHemoglobin 10 g/dLPeripheral bloodblasts 1%Platelet countRBC TransfusionalsupportgeneticDisease specific variablesWBCKaryotype (-8, -7, -5,i17q, 12p-, inv3, 11q23or complex)MutationalstatusMascarenhas J. Hematology Am Soc Hematol Educ Program. 2015.232008 IWG-MRT Diagnostic Criteria for Post-PV MF and Post-ET MFDiagnostic criteria for post-PV MFDiagnostic criteria for post-ET MFREQUIRED CRITERIA1. Documentation of a previous diagnosis of ET or PV as defined by the WHO criteria2. Bone marrow fibrosis grade 2/3 (on a 0-3 scale) or grade 3/4 (on a 0-4 scale)ADDITIONAL CRITERIA (2 are required)ADDITIONAL CRITERIA (2 are required)1. Anemia or sustained loss of requirement for either phlebotomy(in the absence of cytoreductive therapy) or forcytoreductive treatment for erythrocytosis1. Anemia and a 2 mg/mL decrease from baseline hemoglobinlevel2. A leukoerythroblastic peripheral blood picture3. Increasing splenomegaly of 5 cm (distance of the tip of thespleen from the left costal margin) or the appearance of newlypalpable splenomegaly3. Increasing splenomegaly of 5 cm (distance of the tip of thespleen from the left costal margin) or the appearance of anewly palpable splenomegaly4. Increased lactate dehydrogenase (above reference level)4. Development of 1 of 3 constitutional symptoms: 10%weight loss in 6 months, night sweats, unexplained fever( 37.5 C)5. Development of 1 of 3 constitutional symptoms: 10%weight loss in 6 months, night sweats, unexplained fever( 37.5 C)2. A leukoerythroblastic peripheral blood pictureBarosi G et al. Leukemia. 2008;22:437-438.2412
3/23/2020Risk-Adapted Treatment of MyelofibrosisLow Risk Asymptomatic: Observation or clinical trial Symptomatic: JAK2 inhibitor, interferon, or clinical trial Observation, JAK2 inhibitor, AlloSCT, anemia treatment, or clinical trialINT-1INT-2 & Transplant candidates: AlloSCT Non-transplant candidate: Clinical trial or JAK2 inhibitor /- anemia treatmentHigh RiskAnemia treatment may include: Immunomodulatory imide drugs (IMID), androgens, erythropoiesis stimulating agents; clinical trial, splenectomyMesa RA. Leuk Lymphoma. 2013;54:242-51.Geyer HL, Mesa RA. Hematol.2014 277-86.NCCN Guidelines v3.2019. Myeloproliferative Neoplasms. Accessed November 6, 2019.25Interferon for the Treatment of MyelofibrosisAuthor, Year, study designNInterventionCR/PR/ORRGrade 3 – 4 ADRsJabbour E et al. 2007,Prospective11PEG-INF-α-2b (Peg-Intron ) 2-3 mcg/kg SCweekly(median dose: 1.5 mcg/kg weekly)9%/0%/NRFatigue, myalgias, weakness,thrombocytopeniaSilver RT et al. 2013,Prospective single-armtrial32rIFN-α-2b (Intron A ) 500,000 – 1 million units SCthrice weeklyPEG-INF-α-2a (Pegasys ) 45 mcg SC weekly9.4%/37.5%/78%ThrombocytopeniaIanotto JC et al. 2013,Retrospective62PEG-INF-α-2a (Pegasys ) 45 mcg SC weeklyORR: 69 – 83%Spleen reduction: 46.5%Anemia, thrombocytopenia,leukopeniaPEG-INF-α-2b (Peg-Intron ): Pegylated Interferon-alpha-2b (Peg-Intron )rIFN-α-2b (Intron A ): Interferon-alpha 2bPEG-INF-α-2a (Pegasys ): Pegylated Interferon-alpha-2b (Peg-Intron )Jabbour E et al. Cancer. 2007;110:2012-2018.Silver RT et al. ASH 2013. Abstract 4053.Ianotto JC et al. Br J Haematol. 2013;162(6):783-91.2613
3/23/2020Interferon From a Pharmacist’s Perspective Data supporting the use of 3 differentformulations–PEG-INF-α-2b (Peg-Intron ), rIFN-α-2b(Intron A ), PEG-INF-α-2a (Pegasys ) Initial dosing Administration– SC injection Dosage forms– Pre-filled syringes and solution forinjection– Dependent on formulation Dose adjustments Storage– Renal impairment– Hematologic toxicity– Store in the refrigerator Cost Drug interactions– 3,600 – 4,500/month– No major interactions Warnings and precautions– Cytopenias, cognitive impairment,cutaneous reactions, GI hemorrhage,hepatotoxicity, hypersensitivityreactions, new or worsening depression,ophthalmic effects, pancreatitis, andpulmonary effects Drug acquisition– Not FDA approved for any MPN– Will likely require prior authorization Disposal– Sharps container– Adhere to state laws27Ruxolitinib (Jakafi ) in MyelofibrosisCOMFORT-I (N 309)Ruxolitinib (Jakafi ) vs. placebo in ptswith intermediate- or high-risk MFCOMFORT-II (N 219)Ruxolitinib (Jakafi ) vs. best availabletherapy (BAT) in pts with intermediate- orhigh-risk MF 41.9% (ruxolitinib [Jakafi ]) vs 0.7% (placebo) had 35%reduction in spleen volume at week 24 (P 0.001) 32% (ruxolitinib [Jakafi ]) vs 0% (BAT) had 35% reduction inspleen volume at week 24(P 0.001)Verstovsek S et al. N Engl J Med. 2012;366:799-807.Harrison C et al. N Engl J Med. 2012;366:787-798.2814
3/23/2020Effect of Spleen Volume Reduction on MF-Related Symptoms, QoLMean % Change FromBaseline SEM5030(n 20)P .00110(n 46)P .001(n 60)P .001(n 99)-10-30-50-70AllPlacebo 10%10%- 35%Improvement WorseningMean % Change FromBaseline SEM3020100(n 46)P .001(n 64)P .001-10-20 35%(n 22)P .4176(n 98)Ruxolitinib (Jakafi )Spleen Volume ReductionAllPlacebo 10%10%- 35%Worsening ImprovementGlobal Health Status/QoL ScoreTotal Symptom Score70 35%Ruxolitinib (Jakafi )Spleen Volume ReductionMesa RA et al. J Clin Oncol. 2013;31(10):1285-1292.29Mean % Change From BaselineCOMFORT-II: Mean Percentage Change in Spleen Volume OverTimeRuxolitinib(Jakafi )20100-10BAT (excluding crossover)BAT (including 2144156WeekCervantes F et al. Blood. 2013;122(25):4047-53.3015
3/23/2020COMFORT-I: Non-Hematologic Adverse Events in 10%Ruxolitinib (Jakafi ), n 155% With Adverse EventAdverse EventPlacebo, n 151% With Adverse EventAll GradesGrade 3/4All GradesGrade rheaPeripheral ipationVomitingPain in extremityInsomniaArthralgiaPyrexiaAbdominal painVerstovsek S et al. N Engl J Med. 2012;366:799-807.31Ruxolitinib (Jakafi ): Survival DataCOMFORT-ICOMFORT-IIRUX (n 155) vs Placebo (n 154)Median follow-upRUX (n 146) vs Best available therapy (n 73)HR (95% CI)P value*OS at 1 year0.50 (0.25–0.98)0.04Median follow-upOS at 1 yearHR (95% CI)P value*OS at 2 years0.58 (0.36–0.95)0.03OS at 2 years0.51 (0.27–0.99)0.041OS at 3 years0.69 (0.46–1.03)0.067OS at 3 years0.48 (0.28–0.85)0.0090.70 (0.20–2.49)Combined Survival Data for COMFORT-I and COMFORT-IIMedian follow-upOS at 5 yearsHR (95% CI)P value*0.70 (0.54-0.91)0.0065Harrison C et al. N Engl J Med. 2012;366(9):787–98.Cervantes F et al. Haematologica. 2013;98(2):160–2.Cervantes F et al. Blood. 2013;122(25):4047-53.Verstovsek S et al. N Engl J Med. 2012;366(9):799–807.Verstovsek S et al. Haematologica. 2013;98(12):1865–71.Verstovsek S et al. Haematologica. 2015;100(4):479-88.Verstovsek S et al. J Hematol Oncol. 2017;10:156.3216
3/23/2020Summary: Ruxolitinib (Jakafi ) in Patients With Myelofibrosis COMFORT-I and COMFORT-II phase III trials:– Efficacy Spleen size reduction, significant improvement in symptoms, quality of life,performance status Not selective for JAK2V617F (i.e., benefits patients with and without JAK2 mutation) Possible prolongation of life in patients with advanced disease– Safety Myelosuppression Infection risk33Ruxolitinib (Jakafi ) From a Pharmacist’s Perspective Initial dosing Administration– Dependent on platelet count and renal/hepaticfunction Dose adjustments– Renal impairment– Hepatic impairment– Hematologic toxicity Drug interactions– CYP3A4 and CYP2C9– Regardless of food– Via nasogastric tube Dosage forms– 5, 10, 15, 20, and 25 mg tablets Cost– 12,703.20/month Drug acquisition Warnings and precautions– Specialty pharmacies only– Cytopenias, infection, discontinuation syndrome,non-melanoma skin cancers,& lipid elevations; Following discontinuation of Jakafi,symptoms from myeloproliferative neoplasms mayreturn to pretreatment levels over a period ofapproximately one week. Some patients with MF haveexperienced one or more of the following adverseevents after discontinuing Jakafi: fever respiratory distress hypotension DIC multi-organ failureJakafi (Ruxolitinib [package insert]. Wilmington, DE; 2016.3417
3/23/2020Fedratinib (Inrebic ): The SecondApproved JAK Inhibitor for MF Phase II study of primary and secondary MFpreviously exposed to ruxolitinib (Jakafi ;n 97)––––DIPSS INT-1 with constitutional symptomsINT/High RiskSplenomegaly 5cm below left CMPlatelets 50,000 1o endpoint: 35% reduction in spleen volumeat 24 weeks 2o endpoint: 50% reduction in totalsymptom score at 24 weeks Fedratinib (Inrebic ) 400 mg QDPrior RUX(Jakafi )Response:Fedratinib(Inrebic )Response:Harrison CN et al. Lancet Haematol. 2017;4:e317-24.35Fedratinib (Inrebic ): TheSecond Approved JAK Inhibitorfor MF Toxicity raised distinct novel AEs– 39% 1 dose reduction; most common for GI– 19% discontinuation for AEs– Most common AEs anemia, thrombocytopenia During study concern over risk of Wernickeencephalopathy (WE): acute neurologicalcondition characterized by a clinical triad ofophthalmoparesis with nystagmus, ataxia, andconfusion, generally caused by thiaminedeficiency Grade 3 encephalopathy in one patient,adjudicated to be hepatic not WernickeFDA Label:Harrison CN et al. Lancet Haematol. 2017;4:e317-24.3618
3/23/2020Fedratinib (Inrebic ) From a Pharmacist’s Perspective Initial dosing Administration– 400 mg PO daily– Baseline PLT 50– Regardless of food– Take with high fatty meal toreduce N/V Dose adjustments– Renal impairment– Hematologic toxicity– Non-hematologic toxicity Dosage forms– 100 mg tablets Cost– 25,200/month Drug interactions Drug acquisition– CYP3A4 and CYP2C19 Warnings and precautions– Encephalopathy (Wernicke’s),GI toxicity (N/V/D), cytopenias,hepatotoxicity– Specialty pharmacies onlyCheck thiamine level prior to initiatingtreatment. Replete thiamine BEFOREstarting fedratinib (Inrebic )Inrebic (fedratinib [package insert]). Summit, NJ; 2019.37Patient Case: BP 60-year-old male with no major past medical history Presentation: Fatigue, pruritus, abdominal discomfort, 15-lb weight loss Physical exam: Splenomegaly by palpation (extends 8 cm below the left costal margin)DiagnosticsWBC55x 109/L (reference range: 4.3-10.5 x 109/L)Peripheral blasts3%Hgb8.1 g/dL (reference range: Male, 13.8 to 17.2 g/dL)Platelets130 x 109/L (reference range: 150-400 x 109/L)LDH1000 IU/L (reference range: 105 - 333 IU/L)Bone marrowAtypical megakaryocytes and proliferation; grade 3 reticulin fibrosisCytogeneticsNormal karyotypeDiagnostic molecular pathology BCR-ABL negative, JAK2V617F mutation3819
3/23/2020Patient Case: BP Based on the patient’s presentation, laboratory, and bone marrow biopsy findings, does the patientmeet the criteria for PMF?– Yes– No ALL 3 major criteria plus at least 1 minor criteriaMajor CriteriaMinor Criteria1. Presence of megakaryocytic proliferation andatypia, accompanied by either reticulin and/orcollagen fibrosis grades 2 or 32. Not meeting WHO criteria for ET, PV,BCR-ABL1 CML, MDS, or other myeloidneoplasms3. Presence of JAK2, CALR, or MPL mutation orin the absence of these mutations, presence ofanother clonal marker, or absence of reactivemyelofibrosisAt least 1 of the following, confirmed in 2consecutive determinations:1. Anemia not attributed to a comorbid condition2. Leukocytosis 11 109/L3. Palpable splenomegaly4. LDH increased to above upper normal limit ofinstitutional reference range5. Leukoerythroblastosis39BP’s Risk StatusPatient Review: This 60-year-old man presented with constitutional symptoms and splenomegaly, WBC 55 x 10 9/L,peripheral blasts 3%, Hgb 8.1 g/dL, platelets 130 x 109/L, megakaryocyte atypia and grade 3 reticulin fibrosis, andJAK2V617F mutation.What is the IPSS risk status of this newly-diagnosed PMF patient?A. LowB. Intermediate-1C. Intermediate-2D. HighIPSS Risk Assessment for PMFRisk FactorsNo. of Risk FactorsRisk LevelMedian OS, mo. Age 65 yrs0Low Constitutional symptoms1Intermediate-195 Hgb 10 g/dL2Intermediate-248High27 WBC count 25 x 109/L 3135 Blood blasts 1%Cervantes F et al. Blood. 2009;113:2895-2901.4020
3/23/2020Treatment Options for BP Patient Review: 60-year-old man presented with constitutional symptoms and splenomegaly, WBC 55x 109/L, peripheral blasts 3%, Hgb 8.1 g/dL, platelets 130 x 109/L, megakaryocyte atypia and grade 3reticulin fibrosis, a JAK2V617F mutation, and an IPSS score of 4What is/are the best treatment options for BP?A. Rituximab (Rituxan )B. Allogeneic stem cell transplantC. Ruxolitinib (Jakafi )D. InterferonE. Both B and CF. None of the above41Treatment for BP While allogeneic SCT would be a potentially curative option, BP opted against proceeding withtransplant. As such, his hematologist would like to prescribe ruxolitinib (Jakafi ) and comes to you asthe ph
Williams Manual of Hematology (8th ed). New York: McGraw Hill Medical. EMH, extramedullary hematopoiesis; ET, essential thrombocythemia; MF, myelofibrosis; PMF, primary myelofibrosis, PV, polycythemia vera JAK2V Y _F Mutation Discovery in MPNs: “The Other
Coding of Neoplasms in ICD-10-CM Presented by Brenda Edwards, CPC, CPB, CPMA, CPC-I, CEMC AAPC ICD-10 Training Expert AAPCCA Board of Directors 1 Coding of Neoplasms in ICD-10-CM No part of this presentation may be reproduced or transmitted in any form or by any means (graphically, electronically, or mechanically,
Chronic Myloid Leukemia (CML) Acute Myeloid Leukemia (AML), Myelodysplastic Syndromes (MDS), Myeloproliferative Neoplasms (MPD) New Diagnosis Workup and Evaluation 1:00 Break 1:15 Acute Myeloid Leukemia (AML): Treatment of Good and Poor Risk AML in Elderly and Young Patients 2:00 Acute Promyelocytic Leukemia (APL):
MPN.37,38 Mutant IDH was documented in the presence or ab-sence of JAK2, MPL, and TET2 mutations. IDH mutations are MPN AML MDS MDS/MPN 2008 WHO classification of myeloid malignancies CML PV ET PMF BCR-ABL JAK2 V617F KIT D816V JAK2 Exon 12 MPL W515 Classic Non-classic MPN-eos FGFR1 rearranged PDGFR rearranged CNL CEL-NOS SM MPN-U CMML JMML aCML .
Abstract: CALR mutations are a revolutionary discovery and represent an important hallmark of myeloproliferative neoplasms (MPN), especially essential thrombocythemia and primary myelofi-brosis. To date, several CALR mutations were identified, with only frameshift mut
–Uncommon –Sign of transformation to a more acute phase –LN may be diffusely infiltrated by myeloid blasts . CMML: Classification . hypogranularity are common WBC count usually increased Severe anemia and thrombocytopenia . aC
Other Parts of Central Nervous System Intracranial Gland Hodgkin and non-Hodgkin Lymphoma Excludes cases collected in the following schemas: Lymphoma Ocular Adnexa, Primary Cutaneous Lymphomas and Mycosis Fungoides . Hematopoietic, Reticuloendothelial, Immunoproliferative and Myeloproliferative Neoplasms Myeloma and Plasma Cell Disorders .
Project 5: Molecular characterisation of Myeloproliferative Neoplasms (MPN) MPN are a group of late onset and progressive malignancies characterised by the clonal hyper-proliferation of stem and progenitor cells, increased output of mature cells of one or more myeloid lineages, and disease progression to bone marrow fibrosis and AML.
Abrasive jet Machining consists of 1. Gas propulsion system 2. Abrasive feeder 3. Machining Chamber 4. AJM Nozzle 5. Abrasives Gas Propulsion System Supplies clean and dry air. Air, Nitrogen and carbon dioxide to propel the abrasive particles. Gas may be supplied either from a compressor or a cylinder. In case of a compressor, air filter cum drier should be used to avoid water or oil .
