MIELOPROLIFERATIVE DISORDERS INSTITUTUL REGIONAL DE ONCOLOGIE IASI CLINICA HEMATOLOGIE 2012-2013.
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Transcript of MIELOPROLIFERATIVE DISORDERS INSTITUTUL REGIONAL DE ONCOLOGIE IASI CLINICA HEMATOLOGIE 2012-2013.
MIELOPROLIFERATIVE MIELOPROLIFERATIVE DISORDERSDISORDERS
INSTITUTUL REGIONAL DE INSTITUTUL REGIONAL DE ONCOLOGIE IASIONCOLOGIE IASI
CLINICA HEMATOLOGIECLINICA HEMATOLOGIE
2012-20132012-2013
CHRONIC MYELOPROLIFERATIVE CHRONIC MYELOPROLIFERATIVE DISORDERS (MPD)DISORDERS (MPD)
MPD are clonal diseases originating in MPD are clonal diseases originating in pluripotential haematopoieticpluripotential haematopoietic stem cell. stem cell.
The clonal expansion results in increased and The clonal expansion results in increased and abnormal haematopoiesis and produces a abnormal haematopoiesis and produces a group of interrelated syndromes, classified group of interrelated syndromes, classified according to the predominant phenotypic according to the predominant phenotypic expression of the myeloproliferative clone.expression of the myeloproliferative clone.
CHRONIC MYELOPROLIFERATIVE CHRONIC MYELOPROLIFERATIVE DISORDERS (MPD)DISORDERS (MPD)
Neoplastic (clonal) disorders of hemopoietic stem cells
Over-production of all cell lines, with usually one line in particular
Fibrosis is a secondary event
Acute Myeloid Leukemia may occur
HAEMATOPOIESISHAEMATOPOIESIS
HEMATOPOIETIC PROGENITORSHEMATOPOIETIC PROGENITORS
GeneticMutation
National Cancer Institute
GENERALITIESGENERALITIES
Hemopoietic stem cell disorderHemopoietic stem cell disorder– ClonalClonal– Characterized by proliferationCharacterized by proliferation
– GranulocyticGranulocytic
– ErythroidErythroid
– MegakaryocyticMegakaryocytic
Interrelationship betweenInterrelationship between– PolycythaemiaPolycythaemia– Essential thrombocythaemiaEssential thrombocythaemia– myelofibrosismyelofibrosis
GENERALITIESGENERALITIES
Normal maturation (effective)Normal maturation (effective)Increased number ofIncreased number of
Red cellsRed cellsGranulocytesGranulocytesPlateletsPlatelets
(Note: myeloproliferation in myelodysplastic syndrome is ineffective)(Note: myeloproliferation in myelodysplastic syndrome is ineffective)
Frequent overlap of the clinical, laboratory & morphologic Frequent overlap of the clinical, laboratory & morphologic findingsfindings
Leucocytosis, thrombocytosis, increased Leucocytosis, thrombocytosis, increased megakaeryocytes, fibrosis & organomegaly blurs the megakaeryocytes, fibrosis & organomegaly blurs the boundariesboundaries
Hepatosplenomegaly Hepatosplenomegaly Sequestration of excess bloodSequestration of excess bloodExtramedullary haematopoiesisExtramedullary haematopoiesisLeukaemic infiltrationLeukaemic infiltration
Rationale for classificationRationale for classification
Classification is based on the lineage of the Classification is based on the lineage of the predominant proliferationpredominant proliferation
Level of marrow fibrosisLevel of marrow fibrosis
Clinical and laboratory data (FBP, BM, Clinical and laboratory data (FBP, BM, cytogenetic & molecular genetic)cytogenetic & molecular genetic)
CHRONIC MYELOPROLIFERATIVE CHRONIC MYELOPROLIFERATIVE DISORDERSDISORDERS
WHO Classification of CMPDWHO Classification of CMPD
Ch Myeloid leukemiaCh Myeloid leukemiaCh Neutrophillic leukemiaCh Neutrophillic leukemiaCh Eosinophillic leukemia / Hyper Eo SyndCh Eosinophillic leukemia / Hyper Eo SyndPolycythemia VeraPolycythemia VeraEssential ThrombocythemiaEssential ThrombocythemiaMyelofibrosisMyelofibrosisCMPD unclassifiableCMPD unclassifiable
MYELOPROLIFERATIVE MYELOPROLIFERATIVE DISORDERSDISORDERS
MPD•PRV•ET•MF
AML
MDS•RA•RARS•RAEB I•RAEB II
CMML
CML
CHRONIC MYELOPROLIFERATIVE CHRONIC MYELOPROLIFERATIVE DISORDERSDISORDERS
Chronic Myeloid leukemia (Chronic Myeloid leukemia (BCR-ABL positive)BCR-ABL positive)Polycythemia VeraPolycythemia VeraEssential ThrombocythemiaEssential ThrombocythemiaMyelofibrosisMyelofibrosis
– Specific clincopathologic criteria for diagnosis and Specific clincopathologic criteria for diagnosis and distinct diseases, have common featuresdistinct diseases, have common features
– Increased number of one or more myeloid cellsIncreased number of one or more myeloid cells– HepatosplenomegalyHepatosplenomegaly– HypercatabolismHypercatabolism– Clonal marrow hyperplasia without dysplasiaClonal marrow hyperplasia without dysplasia– Predisposition to evolvePredisposition to evolve
Bone marrow stem cell
Clonal abnormality
Granulocyte precursors
Red cell precursors
Megakaryocytes Reactive fibrosis
Essentialthrombocytosis
(ET)
Polycythaemia rubra vera
(PRV)
Myelofibrosis
AML
Chronic myeloid leukemia
70%
10% 10%
30%
CHRONIC CHRONIC MYELOGENOUS MYELOGENOUS LEUKEMIA (CML)LEUKEMIA (CML)
CML - INTRODUCTIONCML - INTRODUCTION
Clonal malignant myeloproliferative disorder Clonal malignant myeloproliferative disorder characterized by increased proliferation of the characterized by increased proliferation of the granulocytic cell line without the loss of their granulocytic cell line without the loss of their capacity to differentiate capacity to differentiate
Results in increases in myeloid cells, erythroid cells Results in increases in myeloid cells, erythroid cells and platelets in peripheral blood and marked myeloid and platelets in peripheral blood and marked myeloid hyperplasia in the bone marrow hyperplasia in the bone marrow
Originate in a single abnormal haemopoietic stem cellOriginate in a single abnormal haemopoietic stem cell
CML - BACKGROUNDCML - BACKGROUND
CML was the first human malignancyCML was the first human malignancy to be to be associated with a specific genetic lesion, the associated with a specific genetic lesion, the PhiladelphiaPhiladelphia chromosome, harboring the chromosome, harboring the BCR-BCR-ABLABL oncogene. Since then, it has oncogene. Since then, it has become a become a paradigm for the discovery of molecular paradigm for the discovery of molecular mechanismsmechanisms and targeted therapeutic and targeted therapeutic approaches in the field of hematologicapproaches in the field of hematologic
neoplasias.neoplasias.
CML - EPIDEMIOLOGYCML - EPIDEMIOLOGYCML accounts for 20% of all leukemias CML accounts for 20% of all leukemias affecting adultsaffecting adults..
Frequency - 10-15 new cases, each year, Frequency - 10-15 new cases, each year, for one million population. for one million population.
In general, this disease occurs in the In general, this disease occurs in the fourth and fifth decades of life. fourth and fifth decades of life.
Younger patients aged 20-29 years may Younger patients aged 20-29 years may be affected and may present with a more be affected and may present with a more aggressive form, such as in accelerated aggressive form, such as in accelerated phase or blast crisis. phase or blast crisis.
Sex ratioSex ratio is 1,4-2,2 (m/f). is 1,4-2,2 (m/f).
CML - ETIOLOGYCML - ETIOLOGY
EtiologyEtiology– Not clearNot clear– Little evidence of genetic factors linked to the Little evidence of genetic factors linked to the
diseasedisease– Increased incidence Increased incidence
Survivors of the atomic disasters at Nagasaki & Survivors of the atomic disasters at Nagasaki & HiroshimaHiroshima
Post radiation therapyPost radiation therapy
LEUKEMOGENESISLEUKEMOGENESIS
Philadelphia chromosome is an Philadelphia chromosome is an acquired cytogenetic anomaly acquired cytogenetic anomaly that is characterizes in all that is characterizes in all leukaemic cells in CMLleukaemic cells in CML
90-95% of CML pts have Ph 90-95% of CML pts have Ph chromosomechromosome
Reciprocal translocation of Reciprocal translocation of chromosome 22 and chromosome 22 and chromosome 9chromosome 9
CML - Ph CHROMOSOMECML - Ph CHROMOSOME
LEUKEMOGENESISLEUKEMOGENESIS
BCR (breakpoint cluster region)BCR (breakpoint cluster region) gene on gene on chromosome 22 fused to the chromosome 22 fused to the ABL (Ableson ABL (Ableson leukemia virus)leukemia virus) gene on chromosome 9 gene on chromosome 9
Ph chromosome is found on myeloid, Ph chromosome is found on myeloid, monocytic, erythroid, megakaryocytic, B-cells monocytic, erythroid, megakaryocytic, B-cells and sometimes T-cell proof that CML derived and sometimes T-cell proof that CML derived from pluripotent stem cellfrom pluripotent stem cell
LMC - CROMOZOMUL PhLMC - CROMOZOMUL Ph
a11
5’ 3’
Ib Ia a2 a3
Gena ABL – Crs 9
5’ 3’ e1 e1’ e2’ e6 b2 b3 e19
m-bcr M-bcr μ-bcr
Gena BCR – Crs 22
P190
P210
P230
BCR
ABL
Consequences of p210Consequences of p210BCR-ABLBCR-ABL
Molecular consequence of the t(9;22) is the fusion Molecular consequence of the t(9;22) is the fusion protein BCR–ABL, which has increased in tyrosine protein BCR–ABL, which has increased in tyrosine kinase activitykinase activityBCR-ABL protein transform hematopoietic cells so that BCR-ABL protein transform hematopoietic cells so that their growth and survival become independent of their growth and survival become independent of cytokinescytokinesIt protects hematopoietic cells from programmed cell It protects hematopoietic cells from programmed cell death (apoptosis) death (apoptosis)
– deregulated cellular proliferation,deregulated cellular proliferation,
– decreased adherence of leukemia cells to the bone marrow stroma decreased adherence of leukemia cells to the bone marrow stroma
– reduced apoptotic response to mutagenic stimuli reduced apoptotic response to mutagenic stimuli
LMC - CROMOZOMUL PhLMC - CROMOZOMUL Ph
CML – HISTORY (I)CML – HISTORY (I)
Disease is biphasic, sometimes triphasicDisease is biphasic, sometimes triphasicThe clinical manifestations of CML are insidious and The clinical manifestations of CML are insidious and are often discovered incidentally are often discovered incidentally - - 40% 40% asymptomaticasymptomaticChronic phaseChronic phaseSplenomegaly often massiveSplenomegaly often massiveSymptoms related to hypermetabolismSymptoms related to hypermetabolism– Weight lossWeight loss– AnorexiaAnorexia– LassitudeLassitude– Night sweatsNight sweats
CML – HISTORY (II)CML – HISTORY (II)
Features of anaemiaFeatures of anaemia– Pallor, dyspnoea, tachycardiaPallor, dyspnoea, tachycardia
Abnormal platelet functionAbnormal platelet function– Bruising, epistaxis, menorrhagiaBruising, epistaxis, menorrhagia
Hyperleukocytosis Hyperleukocytosis – thrombosisthrombosis– Increased purine breakdown : goutIncreased purine breakdown : gout– Visual disturbancesVisual disturbances– PriapismPriapism
Some patients may present with complications – Some patients may present with complications – spleen infarction, spleen fracture, peptic ulcer with spleen infarction, spleen fracture, peptic ulcer with hemorrhagia. hemorrhagia.
CML – PHYSICAL (I)CML – PHYSICAL (I)
SplenomegalySplenomegaly ( (70–85%70–85%) - ) - is the most is the most common physical finding in patients with common physical finding in patients with CML.CML.– The size of the spleen correlates with the The size of the spleen correlates with the
peripheral blood granulocyte countsperipheral blood granulocyte counts– A very large spleen is usually a harbinger of the A very large spleen is usually a harbinger of the
transformation into an acute blast crisis form of the transformation into an acute blast crisis form of the diseasedisease
HepatomegalyHepatomegaly also occurs, although less also occurs, although less commonly than splenomegalycommonly than splenomegaly , in , in 20–45%20–45%,,LymphadehopatiesLymphadehopaties - signifie the evolution to - signifie the evolution to the accelerated/blastic phase.the accelerated/blastic phase.
CML – PHYSICAL (II)CML – PHYSICAL (II)Fever, purpura.Fever, purpura.Physical findings of Physical findings of leukostasisleukostasis and and hyperviscosityhyperviscosity can occur in some patients, can occur in some patients, with extraordinary elevation of their WBC with extraordinary elevation of their WBC counts, exceeding 300,000-600,000 counts, exceeding 300,000-600,000 cells/mmccells/mmc :: – headache, headache, – dizziness, dizziness, – vertigo, vertigo, – tinnitus, tinnitus, – visual disturbances, visual disturbances, – angina pectoris, or angina pectoris, or – intermittent claudications.intermittent claudications.
CML – CML – PERIPHERAL BLOODPERIPHERAL BLOOD LeucocytosisLeucocytosis ( (a total WBC count of 20,000-over a total WBC count of 20,000-over 100.000 cells/100.000 cells/L) with circulating immature cells L) with circulating immature cells from the bone marrow, such as myeloblasts, from the bone marrow, such as myeloblasts, myelocytes, metamyelocytes, and nucleated red blood myelocytes, metamyelocytes, and nucleated red blood cells, mimicking the findings in the bone marrow. cells, mimicking the findings in the bone marrow. BasophiliaBasophilia - 2-4%, over 7% in 10 – 15 % patients - 2-4%, over 7% in 10 – 15 % patientsEosinophiliaEosinophiliaMild-to-moderate Mild-to-moderate anemiaanemia usually normochromic and usually normochromic and normocyticnormocytic ThrombocitosisThrombocitosis - 500.000–600.000/mm - 500.000–600.000/mm33, to 1–2 , to 1–2 million/mmmillion/mm33..
CML – CML – PERIPHERAL BLOODPERIPHERAL BLOOD
CML – CML – PERIPHERAL BLOODPERIPHERAL BLOOD
CML – BONE MARROWCML – BONE MARROW
Marrow aspirateMarrow aspirate - - Bone marrow isBone marrow is– Hypercellular (reduced fat spaces)Hypercellular (reduced fat spaces)
– Myeloid:erythroid ratio – 10:1 to 30:1 (N : 2:1)Myeloid:erythroid ratio – 10:1 to 30:1 (N : 2:1)
– Myelocyte predominant cell, blasts less 10%Myelocyte predominant cell, blasts less 10%
– Megakaryocytes increased & dysplasticMegakaryocytes increased & dysplastic
– Increase reticulin fibrosis in 30-40%Increase reticulin fibrosis in 30-40%
BOMBOM - confirm - confirmss the hyperplasia of the hyperplasia of hematopoietic tissue. hematopoietic tissue. Mild fibrosis is often Mild fibrosis is often seen in the reticulin stain.seen in the reticulin stain.
CML – BONE MARROWCML – BONE MARROW
CML – BONE MARROWCML – BONE MARROW
CML – BIOLOGYCML – BIOLOGY
the the leukocyte alkaline phosphataseleukocyte alkaline phosphatase stains very low stains very low to absent in most cells, resulting in a low scoreto absent in most cells, resulting in a low score ..markedly elevatedmarkedly elevated serum vitamin B-12–binding serum vitamin B-12–binding proteinprotein (TC-I) (TC-I);;hemostasishemostasis thrombocytopathia with prolonged thrombocytopathia with prolonged bleeding time bleeding time andand decreased platelet decreased platelet aggregability. aggregability. hyperuricemiahyperuricemia andand hyperuricuriahyperuricuria, elevated , elevated LDHLDH;;hyperhistaminemiahyperhistaminemia;;
CML - EVOLUTIONCML - EVOLUTIONChronic phaseChronic phaseAccelerated phaseAccelerated phaseAcute phase (blastic phase)Acute phase (blastic phase)ComplicationsComplications– anemia, infecanemia, infectionstions, , – bleeding or thrombosis (priapism), bleeding or thrombosis (priapism), – spleen infarction or fracture, spleen infarction or fracture, – pulmonary (infarction, infecpulmonary (infarction, infectionstions), ), – bone (pains, distrucbone (pains, distructiontion, hypercalcemia), , hypercalcemia), – neurologic (leucostasis, hemorragia, thrombosis), neurologic (leucostasis, hemorragia, thrombosis), – metabolic (gout)metabolic (gout)
LMC – ACCELERATED PHASELMC – ACCELERATED PHASEMedian duration is 3.5 – 5 yrs before evolving to Median duration is 3.5 – 5 yrs before evolving to more aggressive phasesmore aggressive phasesMay last for several months.May last for several months.– Clinical featuresClinical features
Increasing splenomegaly refractory to chemoIncreasing splenomegaly refractory to chemoIncreasing chemotherapy requirementIncreasing chemotherapy requirement
– Lab featuresLab featuresBlasts>15% in bloodBlasts>15% in bloodBlast & promyelocyte > 30% in bloodBlast & promyelocyte > 30% in bloodBasophil 20% in bloodBasophil 20% in bloodThrombocytopeniaThrombocytopeniaCytogenetic: clonal evolutionCytogenetic: clonal evolution
CML – BLASTIC PHASECML – BLASTIC PHASE
Criteria :Criteria :– Resembles acute leukaemiaResembles acute leukaemia
– Diagnosis requires > 30% blast in marrowDiagnosis requires > 30% blast in marrow
– 2/3 transform to myeloid blastic phase and 1/3 to lymphoid 2/3 transform to myeloid blastic phase and 1/3 to lymphoid blastic phaseblastic phase
– Survival : 9 mos vs 3 mos (lym vs myeloid)Survival : 9 mos vs 3 mos (lym vs myeloid)
BCR-ABL – detection techniquesBCR-ABL – detection techniques
Conventional cytogeneticConventional cytogenetic analysisanalysisFluorescece in situu hybridisation (FISH)Fluorescece in situu hybridisation (FISH)Polymerase chain reaction (PCR)Polymerase chain reaction (PCR)Reverse transcriptase – PCR (RT-PCR)Reverse transcriptase – PCR (RT-PCR)Real-time quantitative PCR (RQ-PCR) for BCR-Real-time quantitative PCR (RQ-PCR) for BCR-ABLABL mRNAmRNAUtility :Utility :– Diagnosis positif and differentialDiagnosis positif and differential– Monitorising drug therapyMonitorising drug therapy– Assesment of minimal residual disease (MRD)Assesment of minimal residual disease (MRD)
Diagnostic Considerations in Diagnostic Considerations in Chronic Myeloid LeukemiaChronic Myeloid Leukemia
Karyotyping in CML
1) Allows for the diagnosis of CML
2) Requires a bone marrow aspirate for optimal metaphases
3) Allows for evaluation of clonal evolution as well as additional chromosomal abnormalities in the non-Ph+ clones
4) Occasional cryptic and complex karyotypes can result in the missed identification of the t(9;22)
Demonstrating the presence of the t(9;22) or its gene product is absolutely essential in diagnosing a patient with CML
Source Undetermined
Diagnostic Considerations in Diagnostic Considerations in Chronic Myeloid LeukemiaChronic Myeloid Leukemia
Fluorescence in-situ hybridization(FISH) in CML:
1) Allows for the diagnosis of CML2) Does not require a bone marrow aspirate for optimal results3) Allows for the identification of potential duplications of the Ph chromosome 4) Allows for the identification of the loss of the der (9) chromsome5) Allows for the identification of cryptic translocations involving Bcr-Abl
Bcr- Ch 22
Abl – Ch 9
Bcr-Abl Fusion
Source Undetermined
LMC - FISHLMC - FISH
Diagnostic Considerations in Diagnostic Considerations in Chronic Myeloid LeukemiaChronic Myeloid Leukemia
Bcr-Abl
Bcr
Abl
cDNA
Quantitative RT-PCR for Bcr-Abl in CML
1) Allows for the diagnosis of CML
2) Does not require a bone marrow aspirate for optimal results
3) Can quantify the amount of disease
4) Allows for the identification of cryptic translocations involving Bcr-Abl
5) Many primers sets only detect the p190 and/or the p210 translocation and may miss the p230 or alternative translocations
Source Undetermined
CML – PROGNOSTICCML – PROGNOSTICPoor prognosis features in patients with CML Poor prognosis features in patients with CML include :include :– older ageolder age – symptomatic presentationsymptomatic presentation – poor performance statuspoor performance status – Hepatomegaly,Hepatomegaly, splenomegalysplenomegaly – negative Ph chromosome or negative Ph chromosome or bcr-ablbcr-abl – anemiaanemia – thrombocytopenia/thrombocytosis, thrombocytopenia/thrombocytosis, – basophilia, or myelofibrosis (increased reticulin or basophilia, or myelofibrosis (increased reticulin or
collagen) collagen) – longer time to hematologic remission with longer time to hematologic remission with
myelosuppression therapy myelosuppression therapy
CML – PROGNOSTICCML – PROGNOSTIC Sokal Score Sokal Score
(+)/(+)/0(t) = Exp 0,0116 (0(t) = Exp 0,0116 (AgeAge - 43,4) + - 43,4) + 0,0345 (0,0345 (spleenspleen - 7,51)+ 0,188 - 7,51)+ 0,188 ((PtPt/700)/700)22 - -
0,5630,563 + 0,0887 ( + 0,0887 (blablasststs - 2,10) - 2,10)
ScoreScore Median survivalMedian survival Survival at 48 months Survival at 48 months
– IS = < 0,8IS = < 0,8 60 months60 months 62%62%– IS = 0,8 - 1,2IS = 0,8 - 1,2 44 months 44 months 43%43%– IS = >1,2IS = >1,2 32 months32 months 33%33%
CML – GENERAL CML – GENERAL MANAGEMENTMANAGEMENT
Discussion with familyDiscussion with family– The disease & diagnosisThe disease & diagnosis– Prognosis Prognosis – Choices of treatmentChoices of treatment
Cytotoxic drug vs bone marrow transplantCytotoxic drug vs bone marrow transplant
Side effectSide effect
CML – PRINCIPLES OF CML – PRINCIPLES OF TREATMENTTREATMENT
Relieve symptoms of hyperleukocytosis, Relieve symptoms of hyperleukocytosis, splenomegaly and thrombocytosissplenomegaly and thrombocytosis– HydrationHydration
– Chemotherapy (bulsuphan, Hydoxyurea)Chemotherapy (bulsuphan, Hydoxyurea)
Control and prolong chronic phase (non-curative)Control and prolong chronic phase (non-curative)– alpha interferon+chemotherapyalpha interferon+chemotherapy
– imatinib mesylate imatinib mesylate
– chemotherapy (hydroxyurea)chemotherapy (hydroxyurea)
CML – PRINCIPLES OF CML – PRINCIPLES OF TREATMENTTREATMENT
Treatment cont…Treatment cont…
Eradicate malignant clone (curative)Eradicate malignant clone (curative)– allogeneic transplantationallogeneic transplantation– alpha interferon ?alpha interferon ?– imatinib mesylate/STI 571 ?(Thyrosine kinase imatinib mesylate/STI 571 ?(Thyrosine kinase
inhibitor)inhibitor)
LMC – MEDICAL CARELMC – MEDICAL CARE
Myelosupresive drugsMyelosupresive drugs
InterferonInterferon
ImatinibImatinib
Allogenic hematopoietic stem cell Allogenic hematopoietic stem cell transplantation transplantation
Autologous hematopoietic stem cell Autologous hematopoietic stem cell transplantationtransplantation
Experimental drugsExperimental drugs
CHEMOTHERAPYCHEMOTHERAPY
BusulphanBusulphan– Alkylating agentAlkylating agent– Preferred in older pts (not candidate for transplant)Preferred in older pts (not candidate for transplant)– Side effect :Side effect :
prolonged myelosuppressionprolonged myelosuppressionPulmonary fibrosisPulmonary fibrosisSkin pigmentationSkin pigmentationinfertilityinfertility
CHEMOTHERAPYCHEMOTHERAPY
HydoxyuresHydoxyures– Fewer side effectFewer side effect
– Acts by inhibiting the enzyme ribonucleotide reductaseActs by inhibiting the enzyme ribonucleotide reductase
Haematological remissions obtain in 80% for both Haematological remissions obtain in 80% for both drugs drugs
However disease progression not altered and However disease progression not altered and persistence of Ph chromosome containing clonepersistence of Ph chromosome containing clone
CHEMOTHERAPYCHEMOTHERAPY
Recombinant human α- InterferonRecombinant human α- Interferon– Optimal dose : Optimal dose : 3-5 MUI/m3-5 MUI/m22/d/d– Prolong chronic phase and increase survivalProlong chronic phase and increase survival– Haematogical and cytogenetic remissionHaematogical and cytogenetic remission– Side effect Side effect
Flu like symptomsFlu like symptoms
Fever and chillsFever and chills
AnorexiaAnorexia
DepressionDepression
CML – THERAPEUTICAL AIMCML – THERAPEUTICAL AIM
Therapeutic responseTherapeutic response– Hematologic responseHematologic response– Cytogenetic responseCytogenetic response– Molecular responseMolecular response
SurvivalSurvival– Overall survival (OS)Overall survival (OS)– Progression-free survival (PFS)Progression-free survival (PFS)– Disease free survival (DFS)Disease free survival (DFS)– Time to progression (TTP)Time to progression (TTP)
HEMATOLOGIC RHEMATOLOGIC REESPONSESPONSEComplete hematologic Complete hematologic responseresponseWBC count normalised (under 10.000/mmWBC count normalised (under 10.000/mm33))Disapearance of immature cells of peripheral blood Disapearance of immature cells of peripheral blood Platelets count normalised (under 350.000/mmPlatelets count normalised (under 350.000/mm33))Disapearance of all signs and symptoms of diseaseDisapearance of all signs and symptoms of diseaseSpleen normalisedSpleen normalised
Partial hematologic responsePartial hematologic responseDecreasing with at least 50% of leucocytosis (10.000 si Decreasing with at least 50% of leucocytosis (10.000 si
20.000/mm20.000/mm33 ) )or completor completee hematologic response with persistent hematologic response with persistent
splenomegalysplenomegaly
CYTOGENETIC RESPONSECYTOGENETIC RESPONSE
% cells Ph+ in bone marrow% cells Ph+ in bone marrow
Complete :Complete : 00ParParttial :ial : < 35< 35Major :Major : complet + parcomplet + parţţialialMinor :Minor : 35 - 9535 - 95Minimal :Minimal : > 95> 95EEşşec :ec : 100100
MOLECULAR RMOLECULAR REESPONSESPONSE
Major molecularMajor molecular response (MajMR)response (MajMR) = a = a 3 log reduction in3 log reduction in BCR-ABL/BCRBCR-ABL/BCR level level when compared to the median when compared to the median pretreatment level.pretreatment level.
Major molecularMajor molecular response(MajMR)response(MajMR) = = BCR-ABL/BCR 0.045%BCR-ABL/BCR 0.045%
Complete molecularComplete molecular response(CMR)response(CMR) = = BCR-ABL unedetectable or reduction BCR-ABL unedetectable or reduction BCR-ABL/BCR with > 4.5 logBCR-ABL/BCR with > 4.5 log
Normal Bcr-Abl Signaling*Normal Bcr-Abl Signaling*
The kinase domain The kinase domain activates a substrate activates a substrate protein, eg, PI3 kinase, protein, eg, PI3 kinase, by phosphorylationby phosphorylation
This activated substrate This activated substrate initiates a signaling initiates a signaling cascade culminating in cascade culminating in cell proliferation and cell proliferation and survivalsurvival PP P
ADP P
P
PP P
ATP
SIGNALING
Bcr-Abl
Substrate
Effector
ADP = adenosine diphosphate; ATP = adenosine triphosphate; P = phosphate.Savage and Antman. N Engl J Med. 2002;346:683Scheijen and Griffin. Oncogene. 2002;21:3314.
Imatinib Mesylate: Imatinib Mesylate: Mechanism of Action*Mechanism of Action*
Imatinib mesylate Imatinib mesylate occupies the ATP occupies the ATP binding pocket of the binding pocket of the Abl kinase domainAbl kinase domain
This prevents This prevents substrate substrate phosphorylation and phosphorylation and signalingsignaling
A lack of signaling A lack of signaling inhibits proliferation inhibits proliferation and survivaland survival
P
PP P
ATP
SIGNALING
Imatinib mesylate
Bcr-Abl
Savage and Antman. N Engl J Med. 2002;346:683.
Imatinib Mesylate in Chronic Phase Imatinib Mesylate in Chronic Phase CML Following IFN-CML Following IFN- Failure: Overall Failure: Overall
Survival*Survival*
Kantarjian et al. Blood. 2004;104;1979. Copyright American Society of Hematology, used with permission.
0 24 48 72 96
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Months
Su
rviv
al p
rob
abili
ty
Total Dead
261 31
251 193
Imatinib mesylate
Others
(P<0.0001)
Imatinib - schema terapeuticaImatinib - schema terapeutica
Recomendede dose : Recomendede dose : – 400 mg/d for patients in chronic phase 400 mg/d for patients in chronic phase – 600 – 800 mg/d for patients in accelerated 600 – 800 mg/d for patients in accelerated
phase or in blastic phase. phase or in blastic phase.
The daily dose is administred in one dose, The daily dose is administred in one dose, with lunch, associated withat least 250 ml with lunch, associated withat least 250 ml waterwater
Allogenic hematopoietic stem cell Allogenic hematopoietic stem cell transplantation (AHSCT)transplantation (AHSCT)
““For the momentFor the moment a allogeneic bone marrow or llogeneic bone marrow or stem cell transplantation is the best and only stem cell transplantation is the best and only one treatment for cure of this disease.one treatment for cure of this disease. ” ”
ButBut
The procedure is limited by the existance of a The procedure is limited by the existance of a potential donor and the high toxicity which limits potential donor and the high toxicity which limits the age of the patients with potential indication the age of the patients with potential indication for transplantation.for transplantation.
Source of HSCSource of HSC
Source :Source :Bone marrow – bone marrow transplantationBone marrow – bone marrow transplantation
Peripheral blood – peripheral blood HSC Peripheral blood – peripheral blood HSC transplantationtransplantation
Peripheral blood source is preferred - Peripheral blood source is preferred - becausebecause
Quicker engraftmentQuicker engraftment
Less regimen related toxicityLess regimen related toxicity
Shorter post-therapeutic aplasiaShorter post-therapeutic aplasia
Longer disease free – GvL effect is strongerLonger disease free – GvL effect is stronger
POLYCYTHEMIA VERAPOLYCYTHEMIA VERA
POLYCYTHEMIA VERA (PV) POLYCYTHEMIA VERA (PV) (Polycythaemia rubra vera)(Polycythaemia rubra vera)
Definition of polycythemiaDefinition of polycythemiaRaised packed cell volume (PCV / HCT)Raised packed cell volume (PCV / HCT)Male > 0.51 (50%)Male > 0.51 (50%)Female > 0.48 (48%)Female > 0.48 (48%)
ClassificationClassificationAbsoluteAbsolute
Primary proliferative polycythaemia (polycythaemia vera)Primary proliferative polycythaemia (polycythaemia vera)Secondary polycythaemiaSecondary polycythaemiaIdiopathic erythrocytosisIdiopathic erythrocytosis
ApparentApparentPlasma volume or red cell mass changesPlasma volume or red cell mass changes
POLYCYTHEMIAPOLYCYTHEMIA
True / AbsoluteTrue / Absolute– Primary PolycythemiaPrimary Polycythemia– Secondary PolycythemiaSecondary Polycythemia
Epo dependentEpo dependent– Hypoxia dependentHypoxia dependent– Hypoxia independentHypoxia independent
Epo independentEpo independent
Apparent / RelativeApparent / Relative– Reduction in plasma volumeReduction in plasma volume
6767
ERYTHROCYTOSIS ERYTHROCYTOSIS (Classification)(Classification) (1)(1)
I. Absolute erythrocytosis (Polycythemia):I. Absolute erythrocytosis (Polycythemia):A. Secondary erythrocytosis (abnormal increase of serumA. Secondary erythrocytosis (abnormal increase of serum erythropoietin erythropoietin level)level)
1. Erythrocytosis secondary to decreased tissue oxygenation:1. Erythrocytosis secondary to decreased tissue oxygenation:a) chronic lung diseasesa) chronic lung diseasesb) cyanotic congenital heart diseasesb) cyanotic congenital heart diseasesc) high-altitude erythrocytosis (Monge disease)c) high-altitude erythrocytosis (Monge disease)d) hypoventilation syndromes (Sleep apnoe)d) hypoventilation syndromes (Sleep apnoe)e) hemoglobin-oxygen dissociation abnormalitiese) hemoglobin-oxygen dissociation abnormalities- hemoglobinopathies associated with high oxygen affinity- hemoglobinopathies associated with high oxygen affinity- carboxyhemoglobin in „smoker’s polycythemia”- carboxyhemoglobin in „smoker’s polycythemia”
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ERYTHROCYTOSIS (Classification)ERYTHROCYTOSIS (Classification) (2)(2)
I.I. Absolute erythrocytosis (Polycythemia):Absolute erythrocytosis (Polycythemia):
A. Secondary erythrocytosis (abnormal increase of serumA. Secondary erythrocytosis (abnormal increase of serum erythropoietin level)erythropoietin level) 2. Secondary to aberrant erythropoietin production or response: 2. Secondary to aberrant erythropoietin production or response: a) Erythropoietin-producting tumors: hepatoma, uterine leiomyoma,a) Erythropoietin-producting tumors: hepatoma, uterine leiomyoma,
cerebellar hemangioblastoma, ovarian carcinoma, pheochromocytoma cerebellar hemangioblastoma, ovarian carcinoma, pheochromocytoma b) Renal diseases: renal cell carcinoma, kidney cysts andb) Renal diseases: renal cell carcinoma, kidney cysts and
hydronephrosis, renal transplantation. hydronephrosis, renal transplantation. c) Androgen abuse: adrenal cortical hypersecretion, exogenous c) Androgen abuse: adrenal cortical hypersecretion, exogenous
androgensandrogensB. Primery erythrocytosisB. Primery erythrocytosis
1. Polycythemia vera1. Polycythemia vera2. Familial erythrocytosis2. Familial erythrocytosis
II. Relative erythrocytosis (pseudopolycythemia):II. Relative erythrocytosis (pseudopolycythemia):1. Hemoconcentration1. Hemoconcentration2. Spurious polycythemia (Gaisboek syndrome)2. Spurious polycythemia (Gaisboek syndrome)
POLYCYTHEMIA VERA (PV)POLYCYTHEMIA VERA (PV)
Polycythaemia vera is a clonal stem cell disorder Polycythaemia vera is a clonal stem cell disorder characterised by increased red cell productioncharacterised by increased red cell production
Abnormal clones behave autonomousAbnormal clones behave autonomous
Same abnormal stem cell give rise to granulocytes and plateletsSame abnormal stem cell give rise to granulocytes and platelets
Disease phaseDisease phaseProliferative phaseProliferative phase
““Spent” post-polycythaemic phaseSpent” post-polycythaemic phase
Rarely transformed into acute leukemiaRarely transformed into acute leukemia
EpidemiologyEpidemiology– 2-3 / 1000002-3 / 100000
– Median age at presentation: 55-60Median age at presentation: 55-60
– M/F: 0.8:1.2 M/F: 0.8:1.2
POLYCYTHEMIA VERA (PV)POLYCYTHEMIA VERA (PV)
Clinical featuresClinical features
AgeAge– 55-60 years55-60 years– May occur in young adults and rare in childhoodMay occur in young adults and rare in childhood
Symptoms common to all erythrocytosisSymptoms common to all erythrocytosis– Headache, Headache, mental acuity, weaknessmental acuity, weakness
Symptoms more specific to P vera and myeloproliferative Symptoms more specific to P vera and myeloproliferative diseases.diseases.– Pruritis Pruritis after bathingafter bathing– ErythromelalgiaErythromelalgia– Hypermetabolic symptomsHypermetabolic symptoms– ThrombosisThrombosis (arterial or venous) (arterial or venous)– HemorrhageHemorrhage
POLYCYTHEMIA VERAPOLYCYTHEMIA VERA physical examinationphysical examination
1.1. Splenomegaly – is present in 75% of patients at the Splenomegaly – is present in 75% of patients at the time of diagnosis.time of diagnosis.
2.2. Hepatomegaly - is present in approximately 30% of Hepatomegaly - is present in approximately 30% of patients at the time of diagnosis. patients at the time of diagnosis.
3.3. HypertensionHypertension
4.4. On examination of the eye grounds, the vessels may be On examination of the eye grounds, the vessels may be engorged, tortuous, and irregular in diameter; the veins engorged, tortuous, and irregular in diameter; the veins may be dark purple.( fundus policythaemicus)may be dark purple.( fundus policythaemicus)
Facial plethoraFacial plethora
POLYCYTHEMIA VERAPOLYCYTHEMIA VERA physical examinationphysical examination
HepatosplenomegalyHepatosplenomegaly
ErythromelalgiaErythromelalgia
– Increased skin tempIncreased skin temp
– Burning sensationBurning sensation
– RednessRedness
Liver40%
Spleen70%
Erythromelalgia
POLYCYTHEMIA VERAPOLYCYTHEMIA VERA Lab FindingsLab Findings
CBCCBC Hgb/HctHgb/Hct WBC in 45%WBC in 45% Plts in 65%Plts in 65%– BasophiliaBasophilia (seen in all MPDs) (seen in all MPDs)
Uric acid (can lead to gout) and B12Uric acid (can lead to gout) and B12 Leukocyte alkaline phosphatase scoreLeukocyte alkaline phosphatase scoreLow epo levelsLow epo levelsPositive JAK2 V617FPositive JAK2 V617F
PV - typical blood countPV - typical blood countWBC x 109/L 18.0 [4-11]
Hb g/L 200 [140-180]
HCt 0.62 [.42-.51]
MCV fl 75 [80-100]
Platelets x 109/L 850 [150-450]
Neuts x 109/L 14.6 [2-7.5]
Lymphs x 109/L 2.0 [1.5-4]
Monos x 109/L 0.8 [0.2-0.8]
Eos x 109/L 0.1 [0-0.7]
Basos x 109/L 0.5 [0-0.1]
Film: microcytosis: large and abnormal platelets present
PRV - DIAGNOSISPRV - DIAGNOSIS
exclude secondary polycythemia
look for features of primary polycythemia
measure erythropoietin
JAK-2 mutation analysis
SECONDARY POLYCYTHEMIASECONDARY POLYCYTHEMIA
Arterial blood gasArterial blood gasHb electrophoresisHb electrophoresisOxygen dissociation curveOxygen dissociation curveEPO levelEPO levelUltrasound abdomenUltrasound abdomenChest X rayChest X rayTotal red cell volume(51Cr)Total red cell volume(51Cr)Total plasma volume(125 I-albumin)Total plasma volume(125 I-albumin)
Diagnostic Criteria for Primary PVDiagnostic Criteria for Primary PV
2008 WHO Diagnostic Criteria for Primary Polycythemia Vera
Major Criteria▪ Elevated RBC mass
>36 cc/kg in men >32 cc/kg in women
▪ Oxygen saturation >92%▪ Splenomegaly
Minor Criteria▪ Plt count > 400,000▪ WBC > 12,000▪ Elevated LAP score (>100)▪ Serum vitamin B12 >900 pg/mL or serum unbound B12 binding capacity >2,200 pg/mL
→ All 3 major criteria OR the first 2 major and any 2 minor criteria ←
Polycythemia Vera Study Group (PVSG) Criteria for PV
Major Criteria1) Hgb > 18.5g/dl (♂) or 16.5g/dl (♀) or Hgb or Hct > 99% or Hgb > 17g/dl (♂) or 15 g/dl (♀) and a documented increase of 2 g/dl or RBC mass > 25% of mean normal
2) Presence of a JAK2 V617F or similar mutation
Minor Criteria1) Bone marrow trilineage expansion2) Subnormal EPO level3) Endogenous erytyhroid colony growth
→ two major or first major and two minor criteria ←
Tefferi et al. Leukemia (2008) 22, 14–22
PV - TREATMENTPV - TREATMENT
PhlebotomyPhlebotomy
Myelosuppressive agentsMyelosuppressive agents– HydroxyureaHydroxyurea– Alkylating agents such as busulfanAlkylating agents such as busulfan– 3232PP
Interferon alphaInterferon alpha
PV - PHLEBOTOMYPV - PHLEBOTOMY
Generally, the best initial treatment for P veraGenerally, the best initial treatment for P vera– No increase in progression to AMLNo increase in progression to AML– Rapid onsetRapid onset– No BM suppressionNo BM suppression
Remove 500 cc blood 1-2x/wk to target Hct 45%, Remove 500 cc blood 1-2x/wk to target Hct 45%, then maintainthen maintainDownsides:Downsides:– Increased risk of thrombosisIncreased risk of thrombosis– No effect on progression to spent phaseNo effect on progression to spent phase– May be insufficient to control diseaseMay be insufficient to control disease
PV - MYELOSUPPRETIONPV - MYELOSUPPRETION
Hydroxyurea Hydroxyurea – can be used in conjunction with phlebotomycan be used in conjunction with phlebotomy– May increase the risk of leukemic transformation from 1-May increase the risk of leukemic transformation from 1-
2% to 4-5%2% to 4-5%3232PP– increase the risk of leukemic transformation from 1-2% to increase the risk of leukemic transformation from 1-2% to
11%11%– May be appropriate for pts intolerant of medications or for May be appropriate for pts intolerant of medications or for
elderly patientselderly patients– Single injection may control hemoglobin and platelet count Single injection may control hemoglobin and platelet count
for a year or more.for a year or more.
PV – INTERFERON ALPHAPV – INTERFERON ALPHABenefitsBenefits– No myelosuppressionNo myelosuppression– No increase in progression to AMLNo increase in progression to AML– No increase in thrombosis riskNo increase in thrombosis risk– OK in pregnancyOK in pregnancy
DrawbacksDrawbacks– Must be given by injectionMust be given by injection– Side effects may be intolerable in many pts, Side effects may be intolerable in many pts,
include flu-like symptoms, fatigue, fever, include flu-like symptoms, fatigue, fever, myalgias, malaisemyalgias, malaise
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POLYCYTHEMIA VERAPOLYCYTHEMIA VERA
I. I. Patients under the age of 50 with no history of thrombosis and without Patients under the age of 50 with no history of thrombosis and without severe thrombocytosis (greater than 1000G/L)-severe thrombocytosis (greater than 1000G/L)-phlebotomy alonephlebotomy alone
- initially 450-500 ml phlebotomy every every other day until the - initially 450-500 ml phlebotomy every every other day until the
hematocrit is less than 46%hematocrit is less than 46%
- older patients or these with underlying cardiovascular disase - older patients or these with underlying cardiovascular disase shouldshould
undergo smaller phlebotomies 200-300mL twice weekly orundergo smaller phlebotomies 200-300mL twice weekly or
100-150mLevery day until Ht<46% 100-150mLevery day until Ht<46%
- subsequently, Ht should be mainted between 42-46%- subsequently, Ht should be mainted between 42-46%
- fluid replacement so that the patients remains isovolemic- fluid replacement so that the patients remains isovolemic
II. Patients over the age of 70, or with history of thrombosis and with severe II. Patients over the age of 70, or with history of thrombosis and with severe thrombocytosis (greater than 1000G/L)-thrombocytosis (greater than 1000G/L)-myelosuppresive agentmyelosuppresive agent
- Hydroxyurea 15-30mg/kg- Hydroxyurea 15-30mg/kg
III. Patients 50-70 years with no history of thrombosis and without severe III. Patients 50-70 years with no history of thrombosis and without severe thrombocytosis (greater than 1000G/L)thrombocytosis (greater than 1000G/L) individualize therapy I or II individualize therapy I or II
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POLYCYTHEMIA VERAPOLYCYTHEMIA VERA
IV. Antiplatelets agentsIV. Antiplatelets agents
Aspirin initially 150-300mg/d, Aspirin initially 150-300mg/d,
maintence therapy 75-100 mgmaintence therapy 75-100 mg
Tiklid 2x1Tiklid 2x1
DipyridamolDipyridamol
Anagrelide 2-2,5 mg/dAnagrelide 2-2,5 mg/d
V. Other modalitiesV. Other modalities
1. Radioactive phosphorus (in older than 75 years)1. Radioactive phosphorus (in older than 75 years)
2. Interferon alpha 3 million units 3 times weekly2. Interferon alpha 3 million units 3 times weekly
VI. Special TopicsVI. Special Topics
1. Pruritus:antihistaminic agent, cyproheptadine-4mg three times per day 1. Pruritus:antihistaminic agent, cyproheptadine-4mg three times per day
2. Hyperuricemia-allopurinol 300mg/day2. Hyperuricemia-allopurinol 300mg/day
ESSENTIAL ESSENTIAL THROMBOCYTHEMIA (ET)THROMBOCYTHEMIA (ET)
THROMBOCYTOSISTHROMBOCYTOSIS
Etiology of ThrombocytosisEtiology of Thrombocytosis PrimaryPrimary - if the thrombocytosis is caused by a myeloproliferative neoplasm, the - if the thrombocytosis is caused by a myeloproliferative neoplasm, the
platelets are frequently abnormal and the patient may be prone to both bleeding and platelets are frequently abnormal and the patient may be prone to both bleeding and clotting events.clotting events.
Secondary Secondary - if thrombocytosis is secondary to another disorder (reactive), even - if thrombocytosis is secondary to another disorder (reactive), even patients with extremely high platelet counts (e.g., > 1,000,000 cells/patients with extremely high platelet counts (e.g., > 1,000,000 cells/μμl) are usually l) are usually asymptomatic.asymptomatic.
Differential Diagnosis of secondary thrombocytosis:Differential Diagnosis of secondary thrombocytosis: 1.1. MalignanciesMalignancies 2. Infections and inflammatory disorders (e.g., Crohn’s disease)2. Infections and inflammatory disorders (e.g., Crohn’s disease) 3. Post surgical status3. Post surgical status 4.4. Connective tissue disordersConnective tissue disorders 5.5. Iron deficiency anemiaIron deficiency anemia 6.6. SplenectomySplenectomy 7. Recovery of the bone marrow from a stress (chemotherapy or alcohol)7. Recovery of the bone marrow from a stress (chemotherapy or alcohol) 8. Essential Thrombocythemia8. Essential Thrombocythemia
Definition: thrombocytosis is defined as a platelet count > 450,000 cells/μL
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ESSENTIAL THROMBOCYTHEMIA ESSENTIAL THROMBOCYTHEMIA (ET)(ET)
ET is a clonal myeloproliferative disorder ET is a clonal myeloproliferative disorder characterized by bone marrow hyperplasia characterized by bone marrow hyperplasia with excessive proliferation of with excessive proliferation of megakaryocytes and sustained elevation of megakaryocytes and sustained elevation of the platelet count. the platelet count.
ESSENTIAL ESSENTIAL THROMBOCYTHEMIA (ET)THROMBOCYTHEMIA (ET)
Neoplastic stem cell disorder causing dysregulated production of large numbers of abnormal platelets
Some cases non-clonal (esp young women)
Abnormal platelets aggregate in vivo, causing thrombosis
Abnormal platelets also cause bleeding
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ESSENTIAL THROMBOCYTHEMIAESSENTIAL THROMBOCYTHEMIA clinical pictureclinical picture
1. 1. Thrombotic complications (intermittent or permanent occlusion of small Thrombotic complications (intermittent or permanent occlusion of small blood vessels)blood vessels)
transient cerebral and ocular ischemic episodes that maytransient cerebral and ocular ischemic episodes that may progress to progress to infarction infarction
peripheral arterial occlusive disease associated with peripheral arterial occlusive disease associated with „erythromelalgia”„erythromelalgia” (intermittent, painful errythema and(intermittent, painful errythema and cyanosis of cyanosis of the fingers and toes the fingers and toes
2. Hemorrhagic complications - bleeding after surgery and spontaneus upper 2. Hemorrhagic complications - bleeding after surgery and spontaneus upper gastrointestinal bleeding (the hemorrhagic tendency is worsened if gastrointestinal bleeding (the hemorrhagic tendency is worsened if nonsteroidal anti-inflammatory agent are administerednonsteroidal anti-inflammatory agent are administered
3. Splenomegaly - 20-50% patients3. Splenomegaly - 20-50% patients
4. Hepatomegaly - rarely4. Hepatomegaly - rarely
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ESSENTIAL THROMBOCYTHEMIAESSENTIAL THROMBOCYTHEMIA laboratory findingslaboratory findings
Thrombocytosis (in most patients patients>1000 G/l)Thrombocytosis (in most patients patients>1000 G/l)
Numerous thrombocyte aggregates in peripheral blood Numerous thrombocyte aggregates in peripheral blood smearsmear
Leukocytosis, usually less than 20G/lLeukocytosis, usually less than 20G/l
Neutrophilia and a mild shift to the left(usually toNeutrophilia and a mild shift to the left(usually to
metamyelocyte)metamyelocyte)
Slight eosinophilia and basophiliaSlight eosinophilia and basophilia
Marked hyperplasia of the megakaryocytes in the boneMarked hyperplasia of the megakaryocytes in the bone
marrowmarrow
ET-ET-Typical Blood CountTypical Blood CountWBC x 109/L 10.0 [4-11]Hb g/L 156 [140-180]MCV fl 85 [80-100]Platelets x 109/L 1560 [150-450]
Neuts x 109/L 7.0 [2-7.5]Lymphs x 109/L 2.0 [1.5-4]Monos x 109/L 0.8 [0.2-0.8]Eos x 109/L 0.1 [0-0.7]Basos x 109/L 0.1 [0-0.1]
Film Comment: many large and abnormal platelets present
ET – DIAGNOSTIC CRITERIAET – DIAGNOSTIC CRITERIA
→ Diagnosis of essential thrombocythemia requires meeting all four major criteria ←
Teferri et al. Leukemia (2008) 22, 14–22
2008 WHO Diagnostic Criteria for Essential Thrombocytosis
1. Platelet count > 450,0002. Megakaryocytic proliferation with large, mature morphology and with little granulocytic or erythroid expansion3. Not meeting WHO criteria for CML, PV, PMF, MDS or other myeloid neoplasm4. Demonstration of the JAK2V617F or other clonal marker or lack of evidence of a secondary (reactive thrombocytosis)
ET - DIAGNOSISET - DIAGNOSIS
Criteria of exclusionCriteria of exclusion– No evidence of Polycythaemia veraNo evidence of Polycythaemia vera– No evidence of CMLNo evidence of CML– No evidence of myelofibrosis (CIMF)No evidence of myelofibrosis (CIMF)– No evidence of myelodysplastic syndromeNo evidence of myelodysplastic syndrome– No evidence of reactive thrombocytosisNo evidence of reactive thrombocytosis
BleedingBleedingTraumaTraumaPost operationPost operationChronic iron defChronic iron defMalignancyMalignancyChronic infectionChronic infectionConnective tissue disordersConnective tissue disordersPost splenectomyPost splenectomy
ET - OUTCOMESET - OUTCOMES
Most patients with ET enjoy a normal life expectancy Most patients with ET enjoy a normal life expectancy
Like PV, the major risks are secondary to thrombosis and disease Like PV, the major risks are secondary to thrombosis and disease transformation:transformation:
▪▪ 15-year cumulative risks: 15-year cumulative risks: ▪▪ thrombosis - 17% riskthrombosis - 17% risk
▪▪ clonal evolution into either myelofibrosis (4%) or AML (2%)clonal evolution into either myelofibrosis (4%) or AML (2%)
High risk for thrombosis: High risk for thrombosis: ▪ ▪ age ≥ 60age ≥ 60 ▪ ▪ prior thrombosisprior thrombosis ▪ ▪ long-term exposure to a plt count of > 1,000,000long-term exposure to a plt count of > 1,000,000
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ESSENTIAL THROMBOCYTHEMIAESSENTIAL THROMBOCYTHEMIA -THERAPY-THERAPY
1. No treatment- asymptomatic( without thrombotic and bleeding1. No treatment- asymptomatic( without thrombotic and bleeding
complications), young (< 60 r.ż.) patients with platelet count<1000G/Lcomplications), young (< 60 r.ż.) patients with platelet count<1000G/L
2. 2. Cytoreductive therapy Cytoreductive therapy – patients with platelet count>1000 G/L, especially– patients with platelet count>1000 G/L, especially for these with previous thrombotic or bleeding problems for these with previous thrombotic or bleeding problems
- hydroxyurea at doses 15-30mg/kg,, to maintein platelet count - hydroxyurea at doses 15-30mg/kg,, to maintein platelet count
between 400-600 G/lbetween 400-600 G/l
3. Anti-aggregating therapy: 3. Anti-aggregating therapy: AspirinAspirin 75-150mg/d 75-150mg/d dipyridamol for older dipyridamol for older
patients and/or with a cardiovascular risk patients and/or with a cardiovascular risk
4. 4. Anagrelide (Agrylin)- Anagrelide (Agrylin)- drug that produces selective platelet cytoreduction, drug that produces selective platelet cytoreduction,
and it also inhibits platelet activation and it also inhibits platelet activation doses from 0,5mg every 6 hours, doses from 0,5mg every 6 hours,
to max. 10 mg/d ) to max. 10 mg/d )
5. Interferon-5. Interferon-: 3 million units/d s.c.: 3 million units/d s.c.
ESSENTIAL THROMBOCYTHEMIA ESSENTIAL THROMBOCYTHEMIA -THERAPY -THERAPY
Low Risk:Low Risk: ▪▪ Age <60 years Age <60 years ▪▪ No previous history of thrombosis No previous history of thrombosis ▪▪ Platelet count <1 million/Platelet count <1 million/μμll → → aspirin (81 mg daily) if vasomotor Sx or other medical need for ASAaspirin (81 mg daily) if vasomotor Sx or other medical need for ASA → → if otherwise low risk and plt >1.5 X 10if otherwise low risk and plt >1.5 X 1066, screen for an acquired von Willebrand , screen for an acquired von Willebrand
disease before instituting ASAdisease before instituting ASA
High Risk:High Risk: ▪▪ Age ≥60 years Age ≥60 years ▪▪ A previous history of thrombosis A previous history of thrombosis → → hydroxyurea + aspirin (81 mg daily)hydroxyurea + aspirin (81 mg daily) → → if plt >1.5 X 10if plt >1.5 X 1066, screen for an acquired von Willebrand disease before instituting , screen for an acquired von Willebrand disease before instituting
ASAASA → → anagrelide is an option, but when c/w hydroxyurea, it was assn with an increased anagrelide is an option, but when c/w hydroxyurea, it was assn with an increased
risk of arterial thrombosis, venous thrombosis, serious risk of arterial thrombosis, venous thrombosis, serious hemorrhage, or death from vascular causes hemorrhage, or death from vascular causes
MYELOFIBROSISMYELOFIBROSIS
MYELOFIBROSISMYELOFIBROSIS
AKA: agnogenic myeloid metaplasia with myelofibrosisAKA: agnogenic myeloid metaplasia with myelofibrosis
Clonal stem cell disorder affecting megakaryocytes Clonal stem cell disorder affecting megakaryocytes predominantlypredominantly
All myeloproliferative disorders can result in a spent phase All myeloproliferative disorders can result in a spent phase which can be difficult to distinguish from primary MFwhich can be difficult to distinguish from primary MF
Myeloid metaplasia refers to earlier proliferative phase where Myeloid metaplasia refers to earlier proliferative phase where extramedullary hematopoiesis predominates.extramedullary hematopoiesis predominates.
MYELOFIBROSISMYELOFIBROSISMyelofibrosis is a chronic myeloproliferative disease with Myelofibrosis is a chronic myeloproliferative disease with clonal hematopoesis and secondary(non-clonal) clonal hematopoesis and secondary(non-clonal) hyperproliferation of fibroblasts (stimulated by PDGF, EGF, hyperproliferation of fibroblasts (stimulated by PDGF, EGF, TGF-TGF- released from myeloid cells, mainly from neoplastic released from myeloid cells, mainly from neoplastic megakaryocytes) with increased collagen synthesis. It megakaryocytes) with increased collagen synthesis. It produces bone marrow fibrosis and to extramedullary produces bone marrow fibrosis and to extramedullary hematopoesis in the spleen or in multiple organshematopoesis in the spleen or in multiple organs
Other terms – agnogenic myeloid metaplasia
– primary myelofibrosis,
– osteomyelofibrosis,
– idiopathic myelofibrosis,
– myelofibrosis with myeloid metaplasia
MYELOFIBROSISMYELOFIBROSISInsidious onset in older peopleInsidious onset in older people– asymptomatic (15% - 30%)asymptomatic (15% - 30%)
– severe fatiguesevere fatigueSplenomegaly- massiveSplenomegaly- massiveHepatomegalyHepatomegalyHypermetabolic symptomsHypermetabolic symptoms– Loss of weight, fever and night Loss of weight, fever and night
sweatssweats
Bleeding problemsBleeding problemsBone painBone painGoutGoutCan transform to acute Can transform to acute leukaemia in 10-20% of casesleukaemia in 10-20% of cases
MYELOFIBROSISMYELOFIBROSISAnaemiaAnaemiaHigh WBC at presentationHigh WBC at presentationLater leucopenia and Later leucopenia and thrombocytopeniathrombocytopeniaLeucoerythroblastic blood filmLeucoerythroblastic blood filmTear drops red cellsTear drops red cellsBone marrow aspiration- Failed Bone marrow aspiration- Failed due to fibrosisdue to fibrosisTrephine biopsy- fibrotic Trephine biopsy- fibrotic hypercellular marrowhypercellular marrowIncrease in NAP scoreIncrease in NAP scoreJAK2JAK2++ (V617F) in (V617F) in approximately 50% of casesapproximately 50% of cases
Tefferi A. N Engl J Med 2000;342:1255-1265
Pathological Features of Peripheral Blood and Bone Marrow in Patients with Myelofibrosis with Myeloid
Metaplasia
MF – DIAGNOSTIC CRITERIAMF – DIAGNOSTIC CRITERIA
→ Diagnosis of primary myelofibrosis (PMF) requires meeting all three major criteria and two minor criteria ←
Teferri et al. Leukemia (2008) 22, 14–22
2008 WHO Diagnostic Criteria for Primary Myelofibrosis
Major:1. Megakaryocytic proliferation and atypia with either reticulin or collagen fibrosis or If no fibrosis, mekakaryocytic expansion must be assn. w/increased BM
cellularity2. Does not meet WHO criteria for CML, PV, MDS, or other myeloid neoplasm3. Demonstration of the JAK2 V617F mutation or other clonal marker or no other evidence of a reactive marrow fibrosisMinor: 1. Leukoerythroblastosis (immature RBCs and WBCs in the PB) 2. Increased LDH 3. Anemia 4. splenomegaly
MF - OUTCOMEMF - OUTCOME As fibrosis progresses, cytopenias worsen leading to a transfusion As fibrosis progresses, cytopenias worsen leading to a transfusion
dependencydependency
▪▪ symptoms related to extrmedullary hematopoiesis increase (worsening symptoms related to extrmedullary hematopoiesis increase (worsening splenomegaly and ‘B’ symptoms) also are frequently identifiedsplenomegaly and ‘B’ symptoms) also are frequently identified
Rarely do patients transform to Acute Leukemia (~ 4%)Rarely do patients transform to Acute Leukemia (~ 4%)
▪▪ clonal evolution was common in these patientsclonal evolution was common in these patients
▪▪ some evidence that in all MPNs, cases of JAK2 some evidence that in all MPNs, cases of JAK2 (-)(-) Acute Leukemia arise Acute Leukemia arise out of a JAKout of a JAK++ MPN, causing speculation that there are additional genetic MPN, causing speculation that there are additional genetic changes that either initiate and/or propagate these diseaseschanges that either initiate and/or propagate these diseases
Despite the lack of transformation to leukemia, three-year survival rate is Despite the lack of transformation to leukemia, three-year survival rate is approximately 52%approximately 52%
MF – RISK ASSASSEMENTMF – RISK ASSASSEMENT
Mayo Scoring System
(pts age < 60)
Score Median Survival
0 173 mo
1 61 mo
≥ 2 26 mo
Risk Factors: Hemoglobin <10 g/dL White blood cell count <4000/μl or >30,000/ μl Absolute monocyte count >1000 μL Platelet count <100,000/ μL
Transplant Scoring System
(pts age < 55)
Score Median Survival
0 or 1 15 yrs
≥ 2 3 yrs
Risk factors: Hemoglobin <10 g/dL ‘B’ symptoms present (eg, fever, NS, weight loss) Circulating blasts >1 percent
Elliott et al. Leuk Res. 2007;31(11):1503-9. Dupriez et al. Blood 1996 Aug 1;88(3):1013-8.
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MYELOFIBROSIS - MYELOFIBROSIS - TREATMENTTREATMENT
AndrogensAndrogens(oxymetholone 2-4mg/kg) in anemia from decreased red cell (oxymetholone 2-4mg/kg) in anemia from decreased red cell production -overall response is about 40%production -overall response is about 40%
CortykosteroidsCortykosteroids(prednisone 1mg/kg)(prednisone 1mg/kg) in anemia with shortened red cell in anemia with shortened red cell life-span-response in 25-50% of patientslife-span-response in 25-50% of patients
Hydroksyurea Hydroksyurea (15- 20mg/kg) for the control of leukocytosis, (15- 20mg/kg) for the control of leukocytosis, thrombocytosis, or organomegalythrombocytosis, or organomegaly
Allopurinol-Allopurinol-to prevent hyperuricaemiato prevent hyperuricaemia
Vit. DVit. D33-analogues-analogues(1,25-dihydroxycholecalciferol-1ug/d ((1,25-dihydroxycholecalciferol-1ug/d (?)?)
Transfusions of packed red cells Transfusions of packed red cells for anemia or for anemia or platelets platelets for for thrombocytopenia with bleeding thrombocytopenia with bleeding
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MYELOFIBROSIS - MYELOFIBROSIS - TREATMENTTREATMENT
Splenectomy should be considered for: Splenectomy should be considered for: portal hypertension, painful portal hypertension, painful splenomegaly, refractory anemia and thrombocytopenia, or splenomegaly, refractory anemia and thrombocytopenia, or exccessive transfusion requirement. However,the procedere is exccessive transfusion requirement. However,the procedere is hazardous (an operative mortality is up to 38%). hazardous (an operative mortality is up to 38%).
Splenic irradiation: Splenic irradiation: when there is a contrindication to splenectomywhen there is a contrindication to splenectomy
Allogeneic stem-cell transplantation:Allogeneic stem-cell transplantation: for young patients who have for young patients who have a poor prognosis and have a suitable donor identified. a poor prognosis and have a suitable donor identified.
Experimental therapies:Experimental therapies: Interferon- Interferon-, antifibrotic and , antifibrotic and antiangiogenic drugs (anagrelide, suramin, pirfenidone, antiangiogenic drugs (anagrelide, suramin, pirfenidone, thalidomide,)thalidomide,)
MF - TREATMENTMF - TREATMENT
Risk stratification is critical in deciding on therapeutic options Risk stratification is critical in deciding on therapeutic options
(see previous scoring systems)(see previous scoring systems)
‘‘Low Risk’ without symptoms – expectant managementLow Risk’ without symptoms – expectant management
‘‘Low Risk’ with symptoms – hydroxyureaLow Risk’ with symptoms – hydroxyurea
androgenic and corticosteroidsandrogenic and corticosteroids
splenectomy if adequate BM hematopoiesissplenectomy if adequate BM hematopoiesis
splenic irradiationsplenic irradiation
thalidomide or lenalidomide thalidomide or lenalidomide
‘‘High Risk’ and age < 55(?) – consider a reduced intensity allogeneic BMTHigh Risk’ and age < 55(?) – consider a reduced intensity allogeneic BMT
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MYELOFIBROSISMYELOFIBROSIS- prognosis- prognosis
- - a median survival of 3,5 to 5,5 yearsa median survival of 3,5 to 5,5 years
- the principal causes of death are infections, - the principal causes of death are infections, thrombohemorrhagic events, heart failure, and thrombohemorrhagic events, heart failure, and leukemic transformationleukemic transformation
- leukemic transformation occurs in - leukemic transformation occurs in approximately 20% of patients during first 10 approximately 20% of patients during first 10 years years