Myeloproliferative diseases BY Dr.Omar Alshaer

Myeloproliferative disease Clonal hematolopoietic stem cell diseases Characterized by overproduction of one/more blood cell lines 1st proposed in 1951 by William Dameshek not a malignant neoplasm, MPDs are classified within the “ Hematological neoplasms ”

Myeloproliferative disease arise from precursors of the "myeloid" lineage in the bone marrow Polycythemia vera (PV) 2. Essential thombocytosis (ET) 3. Myelofibrosis with myeloid metaplasia (MMM) 4. Chronic Myelomonocytic leukemia (CMML)

CML CMML PV ET BONE MARROW Hematopoiesis Pluripotent Stem Cell Baso. CBL? Myeloid Stem Cell Myeloblast Eos. CEL PMN CNL Erythro blast Megalo blast Mono. RBC Platelet CML CMML PV ET

Polycythemia vera 1892 : 1st described by Vaquez 1900 : Phlebotomy as treatment by Osler : Dameshek classified PV as a MPD 1967 : Wesserman defined of PV and treatment incidence : 2 per 100,000 etiology : unknown median age : 60 yrs. ( male )

Polycythemia vera Survival time 1.5 yrs untreated PV 3.5 yrs PV with phlebotomy 7-12 yrs PV with myelosuppression 10 – 20 %  abnormal cytogenetics ; Trisomy 8 , Trisomy 9 and deletion 20q

Clonal stem cell disorder with trilineage myeloid involvement Pathophysiology Clonal stem cell disorder with trilineage myeloid involvement Characterized by GF-independent erythroid proliferation producing an elevated red cell mass Extramedullary hematopoiesis ; Liver , Spleen Congenital PV : abnormal of truncated form of EPO receptor

Clinical Features Thrombosis  common cause of death HT Thrombosis  common cause of death Pruritis ( aggravated by bathing ) 50% Erythromelagia Digital ischemia ( palpable pulse ) Joint pain Weight loss Headache , vertigo Visual disturbance Conjunctival plethora Palpable splenomegaly 70%

Clinical Features 10% Budd-Chiari Synd. pts. have coexistent PV 33% PV pts. have “ Acquired VWD “ 20% Erythrocytosis alone 40 % Trilineage hyperplasia BMA : Hypercellularity atypical megakaryocyte & clustering decrease stainable iron

Clinical Features Lab : elevated leukocyte alkaline phosphatase ( LAP ) 70% elevated serum B12 40% Risk to transform to acute leukemia 1.5 % spent phase 10-25% ( Spent phase : normalization of red cell mass asso. with cytopenia , increasing splenomegaly (extramed.hemat.) & collagen fibrosis of BM )

WHO criteria for diagnosis of Polycythemia Vera A1. elevated RBC mass > 25% above mean normal predicted value,or Hb > 18.5g/dL ( Male ) Hb > 16.5 g/dL (female ) A2. No cause of 2nd erythrocytosis,including: Absence of familial erythrocytosis No elevation of EPO from - hypoxia ( PaO2 92 % ) - high O2 affinity Hb. - truncated EPO receptor - inappropiated EPO production by tumor A3. Splenomegaly A4. Clonal genetic abnormality other than Ph chromosome or BCR/ABL fusion gene in marrow cells A5. Endogenous erythroid colony formation in vitro

WHO criteria for diagnosis of Polycythemia Vera B1. Thrombocytosis > 400,000 B2. WBC > 12,000 B3. BM Biopsy showing panmyelosis with prominent erythroid & megakaryocytic proliferation B4. Low serum EPO levels Diagnosis : A1+A2 and any other of CAT. A or A1+A2 and any 2 of CAT. B or > 99th percentile of method specific reference range of age ,gender,altitude of residence

EPO Production secondary to hypoxia Lung disease High altitude Smoking Cyanotic Heart disease Methemoglobinemia High O2 affinity hemoglobin Cobalt

EPO Overproduction Tumors ; renal , brain , hepatoma , uterine fibroid , pheochromocytoma Renal artery stenosis inappropriate EPO secretion Bartter’s syndrome Renal cyst , hydronephrosis

EPO levels in PV LOW or NORMAL EPO Overproduction Tumors ; renal , brain , hepatoma , uterine fibroid , pheochromocytoma Renal artery stenosis inappropriate EPO secretion Bartter’s syndrome Renal cyst , hydronephrosis

PV & Secondary polycythemia Finding PV 2nd Polycythemia Splenomegaly Leukocytosis Thrombocytosis RBC volume arterial O2 sat B12 level LAP Bone Marrow EPO level Endogenous CFU-E growth + increased normal Panhyperplasia decreased -

Lab evaluation of erythrocytosis - ABG Iron study serum EPO level Liver & Kidney function Abdominal Ultrasound / CT BMA / BM biopsy Red cell mass

PCR for overexpression of PRV-1 ( CD 177 ) Lab evaluation of Erythrocytosis PCR for overexpression of PRV-1 ( CD 177 )

Staging & Prognosis Hct. > 45% risk to thrombosis  Death age > 70 yrs. & previous Hx. of thrombosis ; important predictor of recurrent thrombotic events

Treatment aim ; - reduce thrombotic risk & slow leukemic transformation - based on risk of thrombosis Low risk age < 60yr. no Hx thrombosis Plt. < 1,500,000 no CVD risk High risk -age > 60yr. -Previous Hx. thrombosis -CVD risk(smoking,DLD ) Intermediate risk

Treatment Treatment of choice is “ Phlebotomy “ Hct. < 45 % in men , < 42% in women “ Hydroxyurea “ is supplemented to decreased Hct. “ IFN –alfa “ use for cytoreduction in younger ( decreased risk to leukemic transformation of hydroxyurea )

Treatment Busulfan or P-32 in elderly pt. with hydroxyurea intolerated Low dose ASA ( 40 mg ) ; alleviate of microvascular sequelae ( headache, vertigo,visual disturbance , erythromelalgia ) Anagrelide ; used in all MPD to lowering platelet count

Treatment Pruritis ( 50% of cases ) ; Cold water , antihistamine Cholestyramine , PUVA , IFN-alfa Recently........SSRI ( Fluoxetine 20 mg OD) Elective Surgery : keep Hct. < 45 % ( more than 2 mo. )

; occur ~ 10 yrs. after 1st Dx. Transformation to spent phase ; develop Cytopenia & Splenomegaly ; Hydroxyurea and Interferon ; Splenectomy ; Low dose splenic irradiation  short term relief ; “ Stem Cell Transplantation “ for advanced PV ( Curative !! )

Essential Thrombocytosis In 1934 ; 1st described by Epstein & Goedel “ Hemorrhagic thrombocytopenia “ 1951 ; classified to MPD by Dameshek incidence : 1- 2.5 per 100,000 etiology : unknown median age : 50- 60 yrs. ( no gender ) survival time : > 10 yrs. ...... 5 % of clonal cytogenetic abnormality ....

Essential Thrombocytosis Pathophysiology - clonal disorder polyclonal hematopoiesis in some pts. Dx. by exclusion No defining cytogenetic or morphologic feature

Clinical Features 50% asymptomatic 40 % vasomotor symptoms ; visual disturbance , headache , palpitation , erythromelalgia , livedo reticularis, acral paresthesia 15 % thrombosis ; DVT , PE ,digital ischemia, portal vein thrombosis, stroke, MI - 5-10% major hemorrhage

Clinical Features others ; recurrent 1st trimester abortion , palpable splenomegaly risk of leukemia transformation is less than other MPD < 5 % transformation to spent phasee

Diagnostic Testing - Characterized by persistent nonreactive thrombocytosis DDx. of thrombocytosis 1. asplenia 2. acute hemorrhage 3. Hemolysis 4. Infection 5. Post thrombocytopenic rebound 6. CA 7. Inflam. state ( infection,collagenvascular dz. ) 8. Iron def. 9. Pregnancy 10. MPD

Diagnostic Testing Lab assist in Dx. 1. Iron study 2. CRP , ESR 3. PBS : HJ bodies 4. Bone marrow 5. Cytogenetic ; FISH or PCR for BCR/ABL ( exclude CML ) 6. decreased megakaryocyte c-mpl expression 7. increased granulocyte PRV-1 & endogenous erythroid colony formation

WHO diagnostic criteria of Essential Thrombocytopenia Positive Criteria - Sustained platelet count > or = 600,000 - BM biopsy specimen showing proliferation mainly of the megakaryocytic lineage with increased numbers of enlarged,mature megakaryocytes

WHO diagnostic criteria of Essential Thrombocytopenia Exclusion criteria - No evidence of PV Normal red cell mass or Hb. < 18.5 g/dL men , Hb. < 16.5 g/dL women Stainable iron in marrow, normal serum ferritin or normal MCV If the former condition is not met, failure of iron trial to increase red cell mass or Hb level to the PV range - No evidence of CML No Philadelphia chromosome and no BCR/ABL fusion gene - No evidence of chronic idiopathic myelofibrosis Collagen fibrosis absence Reticulin fibrosis minimal or absence

WHO diagnostic criteria of Essential Thrombocytopenia - No evidence of MDS - No evidence that thrombocytosis is reactive because of, Underlying inflammation or infection Underlying neoplasm Prior spleenectomy

Treatment - Based on risk-based management Life expectancy is nearly normal Low risk group age < 40 yr. no Hx. of thrombosis no CVD risk plt. < 1,500,000 High risk group age > 60 yr. Hx. of thrombosis Intermediated risk group

Therapeutic options - Plateletepheresis ( in acute situation ) Myelosuppressive agent ( alkylating agent, Hydroxyurea, radiophosphorus ) - Maturation modulators ( IFN-alfa , Anagrelide ) - Antiplatelet agents Goal : Platelet count < 400,000

Myelofibrosis with myeloid metaplasia In 1879 ; 1st described by G. Hueck 1951 ; classified to MPD incidence : 0.5- 1.5 per 100,000 (higher incidence  exposed to radiation) etiology : unknown median age : 65 yrs. ( no gender ) survival time : 3-5 yrs. .......develop in late stage of PV or ET ......often referred to Agnogenic myeloid metaplasia(AMM) or Idiopathic myelofibrosis

Myelofibrosis with myeloid metaplasia Pathophysiology - Marrow fibroblasts not derived from abnormal clone increased in PDGF,TGF-beta & Cytokines Marrow fibrosis - 50% cytogenetic abnormality ; 13q-,20q-,trisomy 8 ,trisomy9 - high level of CD 34+

Clinical Features 30% asymptomatic , most with fever & night sweats Marked splenomegaly is common  2nd splenic infarction other symptoms ; fatigue, anemia, abdominal pain, wt. loss bleeding , peripheral edema , bone pain (osteosclerosis) Classic blood smear : Leukoerythroblastic Bone marrow : mild to marked fibrosis Elevation of LDH , serum B12 , alkaline phosphatase 20% Transformation to acute leukemia

Diagnostic Testing No standard for Diagnosis ! Inaspirable marrow  “ Dry tap “ Classic blood smear : Tear drop , NRC , leukoerythroblastic DDX. ; metastatic CA , Granulomatous dz. , CNT dz. , Lymphoma - PV & ET can transform to MMM - Cytogenetics , FISH or PCR for BCR/ABL ( exclude CML )

Staging & Prognostic factor often progress to marrow failure ; - Advanced age - Hypercatabolic symptoms - Anemia ( Hb. < 10 ) - Leukopenia ( WBC < 4,000 ) /Leukocytosis ( >30,000) - Abnormal cytogenetic or presence of circulating blast Median survival in high risk < 2 yr but in low risk > 10 yrs

Treatment Palliation 30% anemia  Combination of Androgen ( Oxymethalone 50 mg qid ) and Prednisolone ( 30 mg/d ) ( EPO is ineffective ) Blood transfusion Hydroxyurea ,Busulfan , IFN or Melphalan : Thrombocytosis Leukocytosis Organomegaly - ongoing study ; Thalidomide

Treatment Allogeneic stem cell transplantation for poor prog. patient ( Curative !! ) Overall survival after transplant ~ 60%

Chronic Myelomonocytic Leukemia incidence : 4 per 100,000 etiology : unknown median age : 70 yrs. ( male 1-3 times ) survival time : 12-18 mo. WHO classified in myelodysplastic/myeloproliferative Most common extramedullary sites : Spleen , Liver & L.N. 20-40% Clonal cytogenetic abnormality ; trisomy8,deletion 7q and translocations invol. 5q31-35 ( activate PDGFR-beta :asso. eosinophilia )

Clinical Features Fatigue , Fever , Wt. loss or night sweats Risk of infection from neutropenia Bleeding from thrombocytopenia 50% normal or decreased WBC PBS ; Monocytosis 15 –30 % progress to acute leukemia

Diagnostic Testing WHO diagnostic criteria : - Persistent peripheral blood monocytosis ( > 1,000 ) for more than 3 mo. Absence of the Philadephia chromosome or BCR/ABL fusion gene Less than 20% blasts in blood or BM Dysplasia of one or more myeloid lineages Clonal cytogenetic abnormality

Staging & Prognostic factor Factors that shorter survival : - Hb. < 12 g/dL - Lymphocyte count > 2,500 - Medullary blast count 10 % - Presence circulating immature myeloid cells ....Median survival time 12 mo.

Treatment No effective treatment in modify natural course of disease Growth Factor used to treat cytopenia Low dose Chemotherapy used in preleukemic phase Hydroxyurea used in proliferative phase

Treatment Low dose CMT ; cytarabine ,topotecan,fludarabine,idarubicin etoposide  little success in long term ( rare to CR !! ) Imatinib mesylate effective in rare CMML ( PDGFR-B – translocation) Stem Cell transplantation proved successful in some cases

MCQS 1- An increase in the number of circulating RBCs above established normal limits? Thrombocythemia Reactive thrombocytosis Acute leukemia Polycythaemia

MCQS 1- An increase in the number of circulating RBCs above established normal limits? Thrombocythemia Reactive thrombocytosis Acute leukemia Polycythaemia

MCQS 2_ Which condition is the most likely treatment regiemefor?- hydroxyurea,alpha interferon,anagelide: Thrombocythemia Reactive thrombocytosis Acute leukemia Polycythaemia

MCQS 2_ Which condition is the most likely treatment regiemefor?- hydroxyurea,alpha interferon,anagelide: Thrombocythemia Reactive thrombocytosis Acute leukemia Polycythaemia

MCQS 2_ Which condition is the most likely treatment regiemefor?- venesection, hydroxyurea,p32(radioactivephosphorus): Thrombocythemia Reactive thrombocytosis Acute leukemia Polycythaemia

MCQS 2_ Which condition is the most likely treatment regiemefor?- venesection, hydroxyurea,p32(radioactivephosphorus): Thrombocythemia Reactive thrombocytosis Acute leukemia Polycythaemia

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