2005 i3 dln myelodysplastic syndromes and myeloproliferative disorders jaya v.juturi md 4/24/08

2005 i3 dln

MYELODYSPLASTIC SYNDROMES MYELODYSPLASTIC SYNDROMES AND MYELOPROLIFERATIVE AND MYELOPROLIFERATIVE

DISORDERSDISORDERS

Jaya V.Juturi MDJaya V.Juturi MD4/24/084/24/08

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OBJECTIVESOBJECTIVES

CASECASE

DEFINITIONDEFINITION

EPIDEMIOLOGYEPIDEMIOLOGY

OVERLAP SYNDROMESOVERLAP SYNDROMES

CLASSIFICATIONCLASSIFICATION

IPSS IPSS

GOALS OF THERAPYGOALS OF THERAPY

TREATMENT OVERVIEWTREATMENT OVERVIEW

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Pathologic Classification of MDS:Pathologic Classification of MDS:FAB vs WHOFAB vs WHO

FAB Classification of MDS WHO MDS Classification

Refractory anemia (RA) RA Refractory cytopenias with multilineage

dysplasia (RCMD) MDS-unclassified (MDS-U) MDS with isolated del(5q)

Refractory anemia with ringedsideroblasts (RARS)

RARS RCMD with ringed sideroblasts (RCMD-

RS)

Refractory anemia with excess blasts (RAEB)

RAEB—Type 1 (RAEB-1) RAEB—Type 2 (RAEB-2)

Chronic myelomonocytic leukemia (CMML) MDS/myeloproliferative disorders (MPD)

RAEB-in-transformation AML

Vardiman JW, et al. Blood 2002;100:2292-2302.

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IPSS Risk Score: IPSS Risk Score: De NovoDe Novo MDS MDS

VariableWeighted Score

0 0.5 1.0 1.5 2.0

Marrow blasts, % < 5 5-10 -- 11-20 21-30

Karyotype* Good Int Poor

Cytopenias,† n 0-1 2-3

Risk Group Weighted Score

Low 0

Intermediate-1 0.5-1

Intermediate-2 1.5-2

High > 2.5

Greenberg P, et al. Blood. 1997;89:2079-2088.

*Good: normal, del 5q, del 20q, -Y; intermediate: other; poor: complex (> 3 abnormalities), chromosome 7 abnormalities

†Cytopenias: Hb < 10 g/dL, platelets < 100,000/µL, neutrophils < 1800/µL

2006 i3 dlnCopyright ©2006 American Society of Hematology. Copyright restrictions may apply.

Fukumoto, J. et al. ASH Image Bank 2006;2006:6-00022

Figure 1. Ringed sideroblast, myelodysplastic syndromes (MDS), shown with a Prussian blue stain at low power


Fukumoto, J. et al. ASH Image Bank 2006;2006:6-00022

Figure 2. Ringed sideroblasts, myelodysplastic syndromes (MDS), shown with a Prussian blue stain at high power


Maslak, P. ASH Image Bank 2004;2004:101041

Figure 2. Myeloid maturation is arrested



Figure 1. Pictured is a blast from a patient with AML



Figure 1. Auer rods are distinctive cytoplasmic inclusion bodies which are found in MDS and AML



Figure 2. Myeloid blast with an auer rod



Figure 5. In the peripheral blood, some of the myeloid blasts appear with prominent nucleoli

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Goals of MDS TherapyGoals of MDS Therapy

Select best treatmentSelect best treatment– Response according to predictive variablesResponse according to predictive variables– Consider type and severity of cytopenia(s), Consider type and severity of cytopenia(s),

age, and possible comorbiditiesage, and possible comorbidities IPSS intermediate-1/low riskIPSS intermediate-1/low risk

– Improve blood counts, quality of life; Improve blood counts, quality of life; decrease infectionsdecrease infections

– Decrease transfusion requirement, Decrease transfusion requirement, potentially improve survivalpotentially improve survival

Intermediate-2/high-risk IPSSIntermediate-2/high-risk IPSS– Prolong survival, delay progression to AMLProlong survival, delay progression to AML

Cheson BD, et al. Blood. 2000;96:3671-3674.MDS Guidelines. Available at: http:// www.NCCN.org.

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Myeloproliferative disordersMyeloproliferative disorders

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OBJECTIVESOBJECTIVES

DEFINITIONDEFINITION

CLASSIFICATIONCLASSIFICATION

OVERLAP SYNDROMESOVERLAP SYNDROMES

BIOLOGYBIOLOGY

CMLCML

P.VERAP.VERA

ETET

MFMF

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Clonal haematopoeitic disordersClonal haematopoeitic disorders

Proliferation of one of myeloid lineagesProliferation of one of myeloid lineages

– GranulocyticGranulocytic

– ErythroidErythroid

– MegakaryocyticMegakaryocytic

Relatively normal maturationRelatively normal maturation

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Myeloproliferative disordersMyeloproliferative disordersCh Myeloid leukemia (Ch Myeloid leukemia (BCR-ABL positive)BCR-ABL positive)

Polycythemia VeraPolycythemia Vera

Essential ThrombocythemiaEssential Thrombocythemia

MyelofibrosisMyelofibrosis– 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 cell linesIncreased number of one or more myeloid cell lines

– HepatosplenomegalyHepatosplenomegaly

– HypercatabolismHypercatabolism

– Clonal marrow hyperplasia without dysplasiaClonal marrow hyperplasia without dysplasia

– Predisposition to evolvePredisposition to evolve

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MPD•PRV•ET•MF

AML

MDS•RA•RARS•RAEB I•RAEB

II

CMML

CML

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Bone marrow stem cellClonal

abnormality

Granulocyte precursors

Red cell precursors

Megakaryocytes Reactive fibrosis

Essentialthrombocytosis

(ET)

Polycythemia rubra vera

(PRV)

Myelofibrosis

AML

Chronic myeloid leukemia

70%10% 10%

30%

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Understanding of biology (JAK-2 gene)Understanding of biology (JAK-2 gene)

JAK-2 is a tyrosine kinase (cytoplasmic) critical for the JAK-2 is a tyrosine kinase (cytoplasmic) critical for the initiation of the intracellular signalling by the receptors initiation of the intracellular signalling by the receptors for erythropoietin, thrombopoietin, IL-3, G-CSF and GM-for erythropoietin, thrombopoietin, IL-3, G-CSF and GM-CSFCSF

Substitution of phenyl-alanine for Valine at position 617 Substitution of phenyl-alanine for Valine at position 617 of the JAK protein (V617F)of the JAK protein (V617F)

This is the patho-physiology of cytokine independent This is the patho-physiology of cytokine independent activation of the JAK-STAT, AKT, PI3 K pathways as well activation of the JAK-STAT, AKT, PI3 K pathways as well as the MAP-K and ERK pathwayas the MAP-K and ERK pathway

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Campbell P and Green A. N Engl J Med 2006;355:2452-2466

Role of JAK2 in Pathway Signaling and Erythropoietin Binding, Stem-Cell Differentiation, and Development of Homozygosity for the V617F Mutation

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Incidence of the JAK-2 V617F Incidence of the JAK-2 V617F mutationmutation

65-95% patients with P.Vera65-95% patients with P.Vera

50% patients with myelofibrosis50% patients with myelofibrosis

25-60% patients with essential 25-60% patients with essential thrombocythemiathrombocythemia

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Campbell P and Green A. N Engl J Med 2006;355:2452-2466

Classification of the Myeloproliferative Disorders on the Basis of Molecular Pathogenetic Characteristics

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Epidemiology of CMLEpidemiology of CML

Median age range at presentation: 45 to 55 yearsMedian age range at presentation: 45 to 55 years

• 12% - 30% of patients are >60 years old12% - 30% of patients are >60 years old

At presentationAt presentation

– 50% diagnosed by routine laboratory tests50% diagnosed by routine laboratory tests

– 85% diagnosed during chronic phase85% diagnosed during chronic phase

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Presentation

Insidious onset

Anorexia and weight loss

Symptoms of anemia

Splenomegaly –maybe massive

Pt . maybe asymptomatic

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The Philadelphia Chromosome: t(9;22) The Philadelphia Chromosome: t(9;22) TranslocationTranslocation

bcr-abl

Fusion proteinwith tyrosine

kinase activity

22

bcr

abl

Ph

9 9+

Philadelphia chromosome

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Figure 1. Numerous platelets are noted in the peipheral blood smear from a patient with CML

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Clinical Course: Phases of CMLClinical Course: Phases of CML

Chronic phase

Median 4–6 yearsstabilization

Accelerated phase

Median durationup to 1 year

Blastic phase (blast crisis)

Median survival3–6 months

Terminal phase

Advanced phases

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Treatment of Chronic Myeloid leukemia

Arsenic Lissauer, 1865

Radiotherapy Pusey, 1902

Busulfan Galton, 1953

Hydroxyurea Fishbein et al, 1964

Autografting Buckner et al, 1974

Allogeneic BMT (SD) Doney et al, 1978

Interferon Talpaz et al, 1983

Allogeneic BMT (UD) Beatty et al, 1989

Donor Leukocytes Kolb et al, 1990

Imatinib Druker et al, 1998

Imatinib/Combination therapy O’Brien et al, 200……

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The Ideal Target for Molecular TherapyThe Ideal Target for Molecular Therapy

Present in the majority of patients with a Present in the majority of patients with a specific diseasespecific disease

Determined to be the causative abnormalityDetermined to be the causative abnormality

Has unique activity that isHas unique activity that is

- Required for disease induction- Required for disease induction

- Dispensable for normal cellular function- Dispensable for normal cellular function

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Mechanism of Action of ImatinibMechanism of Action of Imatinib

Goldman JM. Lancet. 2000;355:1031-1032.

Bcr-Abl

ATP

Substrate

Imatinib

Y = TyrosineP = Phosphate

Bcr-Abl

Substrate

PPP

P

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O'Brien S et al. N Engl J Med 2003;348:994-1004

Kaplan-Meier Estimate of the Time to a Major Cytogenetic Response

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CMLCML

Diagnosis

Young with a well-matched donor

Start Imatinib at400mg/day

Cosider for Allograft

Allo SCT

Poor response or Initial response

Followed byLoss of response

Add or substituteOther agents

Allo-SCTAuto

Good response maintained

Continue Imatinib indefinitely

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Issues related to Imatinib

• Very few molecular responses (5-10%)

• Resistance in some patients

• Lack of response in some patients

• Expensive

• Long term toxicity/side effects unknown

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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

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Causes of secondary polycythemiaCauses of secondary polycythemia ERYTHROPOIETIN (EPO)-MEDIATEDERYTHROPOIETIN (EPO)-MEDIATED

– Hypoxia-DrivenHypoxia-Driven• Chronic lung diseaseChronic lung disease• Right-to-left cardiopulmonary vascular shuntsRight-to-left cardiopulmonary vascular shunts• High-altitude habitatHigh-altitude habitat• Chronic carbon monoxide exposure (e.g., smoking)Chronic carbon monoxide exposure (e.g., smoking)• Hypoventilation syndromes including sleep apneaHypoventilation syndromes including sleep apnea• Renal artery stenosis or an equivalent renal pathologyRenal artery stenosis or an equivalent renal pathology

– Hypoxia-Independent (Pathologic EPO Production)Hypoxia-Independent (Pathologic EPO Production)• Malignant tumorsMalignant tumors

– Hepatocellular carcinomaHepatocellular carcinoma– Renal cell cancerRenal cell cancer– Cerebellar hemangioblastomaCerebellar hemangioblastoma

• Nonmalignant conditionsNonmalignant conditions– Uterine leiomyomasUterine leiomyomas– Renal cystsRenal cysts– Postrenal transplantationPostrenal transplantation– Adrenal tumorsAdrenal tumors

DRUG-ASSOCIATEDDRUG-ASSOCIATED– EPO DopingEPO Doping– Treatment with Androgen PreparationsTreatment with Androgen Preparations

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POLYCYTHEMIA VERAPOLYCYTHEMIA VERAChronic, clonal myeloproliferative disorder Chronic, clonal myeloproliferative disorder

characterized by an absolute increase in characterized by an absolute increase in number of RBCsnumber of RBCs

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

Hct > 60% for men and 56% for women in Hct > 60% for men and 56% for women in the absence of secondary causesthe absence of secondary causes

65-95% with a JAK-2 (V617F) mutation65-95% with a JAK-2 (V617F) mutation

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Clinical featuresClinical features

Headache, pruritus, dyspnea, blurred vision, facial Headache, pruritus, dyspnea, blurred vision, facial

plethoraplethora

Persistent leukocytosis and or thrombocytosisPersistent leukocytosis and or thrombocytosis

Microcytosis secondary to iron deficiencyMicrocytosis secondary to iron deficiency

SplenomegalySplenomegaly

Unusual thrombosis (e.g., Budd-Chiari syndrome)Unusual thrombosis (e.g., Budd-Chiari syndrome)

Erythromelalgia (acral dysesthesia and erythema)Erythromelalgia (acral dysesthesia and erythema)

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WHO--Diagnostic CriteriaWHO--Diagnostic CriteriaA1A1 Raised red cell mass hgb>18.5 in men or Raised red cell mass hgb>18.5 in men or

>16.6g/dl in women>16.6g/dl in women

A2A2 Normal O2 sats and EPONormal O2 sats and EPO

A3A3 Palpable spleen Palpable spleen

A4A4 No BCR-ABL fusionNo BCR-ABL fusion

B1B1 Thrombocytosis >400 x 109/LThrombocytosis >400 x 109/L

B2B2 Hyper cellular Bone marrow Hyper cellular Bone marrow

B3B3 Neutrophilia >12 x 10 Neutrophilia >12 x 1099/L/L

B4B4 Low serum EPO levelsLow serum EPO levels

A1+A2+either another A or two B establishes PVA1+A2+either another A or two B establishes PV

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TreatmentTreatment The mainstay of therapy in PV remains phlebotomy to keep the The mainstay of therapy in PV remains phlebotomy to keep the

hematocrit below 45 percent in men and 42 percent in womenhematocrit below 45 percent in men and 42 percent in women

Additional hydroxyurea in high-risk pts for thrombosis (age over Additional hydroxyurea in high-risk pts for thrombosis (age over 70, prior thrombosis, platelet count >400,000/microL, presence of 70, prior thrombosis, platelet count >400,000/microL, presence of cardiovascular risk factors)cardiovascular risk factors)

Aspirin (75-100 mg/d) if no contraindication, reduces thrombosesAspirin (75-100 mg/d) if no contraindication, reduces thromboses

IFNa (3mu three times per week) in patients with refractory IFNa (3mu three times per week) in patients with refractory pruritus, pregnancypruritus, pregnancy

Normalize hematocrit values for several days prior to any elective Normalize hematocrit values for several days prior to any elective surgerysurgery

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Landolfi R et al. N Engl J Med 2004;350:114-124

Probability of Survival Free of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes (Panel A) and Probability of Survival Free of Myocardial Infarction, Stroke, Death from

Cardiovascular Causes, Pulmonary Embolism, and Deep Venous Thrombosis (Panel B)

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Essential Thrombocythemia (ET)Essential Thrombocythemia (ET)

Most common clonal MPDMost common clonal MPD

Persistent elevation of Plt>600 /microLPersistent elevation of Plt>600 /microL

Lack of positive diagnostic criteriaLack of positive diagnostic criteria

Median age at diagnosis: 60, however 20% cases <40yrsMedian age at diagnosis: 60, however 20% cases <40yrs

JAK-2 mtation found upto 50% of the ptsJAK-2 mtation found upto 50% of the pts

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Clinical FeaturesClinical Features VasomotorVasomotor

– Headache Headache

– Lightheadedness Lightheadedness

– Syncope Syncope

– Erythromelalgia (burning pain of the hands or feet Erythromelalgia (burning pain of the hands or feet associated with erythema and warmth) associated with erythema and warmth)

– Transient visual disturbances (eg, amaurosis fujax, Transient visual disturbances (eg, amaurosis fujax, scintillating scotomata, ocular migraine) scintillating scotomata, ocular migraine)

– Livedo reticularisLivedo reticularis

Thrombosis and HemorrhageThrombosis and Hemorrhage

Transformation rareTransformation rare

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InvestigationsInvestigationsET is a diagnosis of exclusionET is a diagnosis of exclusion

Rule out other causes of elevated platelet countRule out other causes of elevated platelet count

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Diagnostic criteria for ETDiagnostic criteria for ET Platelet count >600 x 109/L for at least 2 months Platelet count >600 x 109/L for at least 2 months

Megakaryocytic hyperplasia on bone marrow Megakaryocytic hyperplasia on bone marrow aspiration and biopsy aspiration and biopsy

No cause for reactive thrombocytosisNo cause for reactive thrombocytosis

Absence of the Philadelphia chromosomeAbsence of the Philadelphia chromosome

Normal red blood cell (RBC) mass or a HCT <0.48Normal red blood cell (RBC) mass or a HCT <0.48

Presence of stainable iron in a bone marrow aspiration Presence of stainable iron in a bone marrow aspiration

No evidence of myelofibrosisNo evidence of myelofibrosis

No evidence of MDSNo evidence of MDS

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Hydroxyurea Compared with Anagrelide in High-Risk Essential Thrombocythemia

Hydroxyurea plus low-dose aspirin is superior Hydroxyurea plus low-dose aspirin is superior to anagrelide plus low-dose aspirin for patients to anagrelide plus low-dose aspirin for patients with essential thrombocythemia at high risk for with essential thrombocythemia at high risk for vascular events. vascular events.

N Engl J Med 2005; 353:33-45

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Harrison C et al. N Engl J Med 2005;353:33-45

Kaplan-Meier Estimates of Survival Free of the Primary End Point of Arterial or Venous Thrombosis, Serious Hemorrhage, or Death from Any of These Causes

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Therapy of ET based on the risk of Therapy of ET based on the risk of thrombosisthrombosis

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Myelofibrosis with myeloid Myelofibrosis with myeloid metaplasiametaplasia

Clonal abnormal hematopoietic stem cells that release fibrosis Clonal abnormal hematopoietic stem cells that release fibrosis promoting cytokines in the bone marrowpromoting cytokines in the bone marrow

Splenomegaly and Hepatomegaly (extramedullary Splenomegaly and Hepatomegaly (extramedullary hematopoiesis)hematopoiesis)

Leukoerythroblastic picture, Teardrop cellsLeukoerythroblastic picture, Teardrop cells

Median survival is 3-5 yearsMedian survival is 3-5 years

Death from marrow failure, transformation or complications of Death from marrow failure, transformation or complications of portal HTNportal HTN

Low dose thalidomide with or without steroids, Allogenic Low dose thalidomide with or without steroids, Allogenic transplant in young patientstransplant in young patients

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Figure 1. Blasts are increased in this bone marrow aspirate

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CaseCase

50 year old man with pruritus while showering50 year old man with pruritus while showering

Otherwise excellent state of healthOtherwise excellent state of health

Non smoker and a palpable spleen tip on examNon smoker and a palpable spleen tip on exam

FOB screen negative, normal O2 satFOB screen negative, normal O2 sat

Hct 61%, wbc 11k, MCV 79, Plt count 550, Hct 61%, wbc 11k, MCV 79, Plt count 550, ferritin 12, GI screen Okayferritin 12, GI screen Okay

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Most appropriate therapyMost appropriate therapy

Phlebotomy and anagrelidePhlebotomy and anagrelide

Oral iron and AsaOral iron and Asa

Hydroxyurea and asaHydroxyurea and asa

Phlebotomy and low dose asaPhlebotomy and low dose asa

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CaseCase

56 year old male with fatigue, fever and nose 56 year old male with fatigue, fever and nose bleedsbleeds

RAEB-1 diagnosed 5 months agoRAEB-1 diagnosed 5 months ago

Supportive care with PRBC’s and EPO to dateSupportive care with PRBC’s and EPO to date

Fever 103 F, ecchymoses and petechiae, no Fever 103 F, ecchymoses and petechiae, no organomegaly or adenopathyorganomegaly or adenopathy

HgB 6 wbc 1.2, plts 7KHgB 6 wbc 1.2, plts 7K

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In addition to a transfusion and a bone marrow In addition to a transfusion and a bone marrow aspirateaspirate

Plasma exchangePlasma exchange

Allogeneic stem cell transplantAllogeneic stem cell transplant

AzacytidineAzacytidine

Combination induction chemotherapyCombination induction chemotherapy

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CaseCase

76 year old man with extreme fatigue, dyspnea, 76 year old man with extreme fatigue, dyspnea, early satiety and night sweatsearly satiety and night sweats

Lost 10% of baseline weightLost 10% of baseline weight

large spleen, HgB 7.6, WBC 4.2, plts 1.2 Mlarge spleen, HgB 7.6, WBC 4.2, plts 1.2 M

Bone marrow “dry tap”, PH chromosome negBone marrow “dry tap”, PH chromosome neg

Improves with a transfusionImproves with a transfusion

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OPTIONSOPTIONS

Chronic transfusionsChronic transfusions

SplenectomySplenectomy

Daily Imatinib MesylateDaily Imatinib Mesylate

Allogeneic stem cell transplantAllogeneic stem cell transplant

2005 i3 dln myelodysplastic syndromes and myeloproliferative disorders jaya v.juturi md 4/24/08

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