Mds n mps

MYELODYSPLASTIC SYNDROME(MDS)

&

MYELOPROLIFERATIVE DISORDERS

Dr ANIL KUMAR G ASST PROF

DEPT OF MEDICINE

MDS• Disorders of multipotent hemopoietic stem cell

• Heterogenous group

• Hemopoiesis is ineffective and morphological dysplastic ( Blood/ BM)

• Tendency to evolve into acute leukemia

• Elderly patient

Definition:• A group of clonal bone marrow stem cell

disorders, characterized by hypercellular marrows, peripheral cytopenias, and cell functional abnormalities–Ineffective hematopoiesis

• Highly variable natural history• High mortality rate

• Unless permanent control achieved (by alloBMT) death due to bone marrow failure, with or without conversion to AML

FAB (1982)• Refractory anemia (RA)• Refractory anemia with ring sideroblast (RARS)• Refractory anemia with excess blast (RAEB)• Refractory anemia with excess blast in• transformation (RAEBt)• Chronic myelomonocytic leukemia (CMML)

MDS: Limitations of FAB Classification

•Multilineage cytopenia with <5% BM blasts

•Rough prediction of prognosis

•Cytogenetics not given importance

• Immunophenotyping and genetic techniques not included

Comparison of MDS ClassificationsFAB classification

1982WHO Classification 2008

RA Refractory cytopenia with unilineage dyplasia• Refractory anemia• Refractory neutropenia• Refractory thrombocytopenia

RARS Refractory anemia with ring sideroblasts (RARS)

RCMD(Refractory cytopenia with multilineage dysplasia)

RCMD-RS

RAEB RAEB I and 2(excess blast)

RAEB-T RAEB II/ AML

CMML MDS-UC

MDS associated with isolated del(5q)

Childhood myelodysplastic syndrome• Refractory cytopenia of childhood

Predisposition: Acquired:Mutagen/Genotoxic Stress Therapeutic alkylators, Topo-II agents, -emitters (32P), autoSCT Environmental/occupational

(benzene) Tobacco

Aplastic anemiaPNH

List AF, et al. The Myelodysplastic Syndromes. In: Wintrobe’s Hematology 2003.

Heritable:Constitutional genetic disorders Trisomy 8 mosaicism Familial monosomy 7

Neurofibromatosis 1Embryonal dysgenesis (del12p)Congenital Neutropenia Kostmann, Schwachman-Diamond

DNA repair deficiencies Fanconi anemia, AT, Bloom syndrome

Pharmacogenomic polymorphisms (GSTq1-null)

Clinical Overlap / Associations:• AML • Aplastic anemia• Myeloproliferative disease• leukemia• Autoimmune diseases

AML

PRCA

PNH MDS

AA

LGL MPD

With Permission of J Maciejewski,M.D. Taussig Cancer Center/ Cleveland Clinic FoundationWith Permission of American College of Physicians from Young NS. Ann Intern Med. 2002 Apr 2;136(7):534-46 (ACP not responsible for accuracy of figure translation).

Diagnosis and Classification

Basic Diagnostic Evaluation:

• Peripheral blood counts + reticulocyte count

• Bone marrow biopsy and aspiration – Cytogenetics

• Auxiliary tests – FISH– Flow cytometry in indeterminate cases – Iron saturation, ferritin – B12, folate levels – EPO level

Establish diagnosis Assess – FAB/WHO classification – IPSS score (if applicable)

http:// www.NCCN.org MDS Guidelineshttp://www.hmds.org.uk/mds.html

Epling-Burnett and List. Curr Opin Hematol 2009;16:70

Advances in ManagementImproved prognostic scores

Disease related variablesHost factors

Appropriate clinical decisionDisease eradication/ controlProlonging overall survivalManaging complications of disease and therapyImproving quality of life

2012 Revised IPSS

Schanz J, et al. J Clin Oncol. 2012;30:820-829. Greenberg PL, et al. Blood. 2012;120:2454-2465.

Prognostic Subgroup

Cytogenetic Abnormality

Very good del(11q), -Y

Good Normal, del(20q), del(5q) alone or double, del(12p)

Intermediate +8, del(7q), i(17q), +19, any other single or double, independent clones

Poor inv(3)/t(3q)/del(eq), -7, double including del(7q), complex (3)

Very poor complex (≥ 3)

Fine tune the prognostic impact of •Cytogenetic abnormalities•Depth of cytopenia

IPSS-R

Risk Category Risk Score

Very low ≤ 1.5

Low >1.5 - 3

Intermediate >3 – 4.5

High >4.5 - 6

Very High >6

Variable 0 0.5 1 1.5 2 3 4Cytogenetics V. good - Good - Int Poor V. poorBM blast% ≤2 - >2 - <5 - 5-10 >10 -Hgb ≥10 - 8-<10 <8 - - -Platelets ≥100 50-100 <50 - - - -ANC ≥0.8 <0.8 - - - - -

Tools to treat MDS

• Observation• Supportive therapy (Transfusions)• Hematopoietic growth factors• Iron chelation• Lenalidomide (Revlimid 2005)• Hypomethylating agents

▫ Azacitidine (Vidaza 2004)▫ Decitabine (Dacogen 2006)

• Immunosuppression• Allogeneic stem cell transplantation• Newer agents

Role of Growth Factors

GCSF Support improves ANC (75% patients)Has no impact on overall survival.Not recommended for routine infection prophylaxis

Thrombopoietic agents

Most have no significant impact on transfusion needs:Main utility

– Fewer dose modifications of disease modifying agents– Romiplostim: weekly– Eltrombopag: under study

Erythropoiesis stimulating agents (ESA)

– First line therapy for IPSS low or Int-1 risk MDS with EPO <500U/L (NCCN guidelines)

– Response rates; 20-30%, – Epoeitin alpha: 60,000-80,000 U once per week– Darbopoietin alpha: 500mcg once 3 weekly

Most widely prescribed class of medications for MDS (55%)

Biological response modifiersspecial case of Del 5q syndrome

Eligibility: •del(5q)•IPSS low or Int-1•platelets > 50K/mm3

•neutrophils > 500/mm3

• transfusion dependent

Hypomethylating agents

Hypomethylating agents

•

• Azacytidine and decitabine are potent DNMT inhibitors

• This leads to hypomethylation of dinucleotides in gene promoters and reactivation of previously silent genes

Hypomethylating agentsWhen to start

– Int/ high risk MDS (IPSS)– Transfusion dependent/ EPO failure– Not yet known if early treatment is better than late treatment in MDS

Which drug– NCCN recommends Azacitidine preference over Decitabine– EORTC study failed to show survival benefit.– MDACC regimen (5 day 20mg/m2/d) highest CR

Duration– Optimal duration- not known– To treat responding pts till disease progression, as long as tolerated– At least 4 cycles recommended for adequate response

Steensma et al. Hematol Oncol clin N Am 2010

MDSLow risk

(low or Int 1, BM blasts <10%)

Any age

Iron ChelationGrowth factorsDMT InhibitorsLenolidamide

Progression/ failure

HSCT

High Risk(Int 2, High risk, blasts>10%)

Age <60 Age≥60

Intensive chemoDMTI

DMTIIntensive Chemo

FailureFailure

MYELOPROLIFERATIVE DISORDERS

The myeloproliferative diseases (MPDs) are clonal stem cell disorders characterised by leukocytosis, thrombocytosis, erythrocytosis, splenomegaly, and bone marrow hypercelularity

Myeloproliferative Disorders(old classification)

a group of disease characterized by overgrowth of one or more hematologic cell lines in BM

1. chronic myelogenous leukemia (CML)2. polycythemia vera (PV)3. essential thrombocythemia4. agnogenic myeloid metaplasia/myelofibrosis

www.freelivedoctor.com

Myeloproliferative Disorders(2008 WHO classification)

1. polycythemia vera2. chronic idiopathic myelofibrosis3. essential thrombocytosis4. chronic myeloid leukemia (CML)5. [chronic neutrophilic leukemia]6. [chronic eosinophilic leukemia]7. [hypereosinophilic syndrome]8.Mast cell disease

“myelodysplastic/myeloproliferative diseases”juvenile myelomonocytic leukemiaatypical chronic myeloid leukemia (lacking t(9;22))chronic myelomocytic leukemia


Polycythemia Vera(lots of red cells - for real)

An uncommon disorder - distinguish from other causes of erythrocytosisDiagnosis depends on knowledge of erythropoeisisComplications most commonly from thrombosis and vascular incidentsLong natural history with treatment

Definition of Erythrocytosis

Normal hematocrit : Male 47 5 percent Female 42 5 percent

Normal hemoglobin : Male 15 2 gm/dl Female 13.5 1.5 gm/dl

Absolute vs. Relative Erythrocytosis

Normal Spurious Polycythemia

Plasma VolRBC

Pathophysiology of Polycythemia

Secondary Polycythemia

Inappropriate EPO (ectopic production) Tumors (hepatoma, renal carcinoma,

leiomyoma, hamartoma) Renal disorders (transplantation, cysts) hemangiomas Androgen abuse EPO abuse Familial polycythemia

Polycythemia VeraP. vera is a rare diseaseMedian age 60 - 65 yearsClinical features Attributed to increased blood viscosity and

poor oxygen delivery to organs (brain) Poor O2 delivery leads to ischemia and

thrombosis Expanded blood volume and viscosity

leads to increased cardiac work load

P. Vera - Symptoms & Signs

Symptoms Headache Weakness Pruritis

(aquagenic) Dizziness Diaphoresis Visual

disturbance Weight loss

Signs Splenomegaly

70% Skin plethora

67% Hepatomegaly

40% Conjunctival

plethora 59% Systolic

Hypertension 72%

P. Vera - Diagnosis (PVSG criteria)

Criteria RBC mass

elevated SaO2 > 92% Splenomegaly

(or)thrombocytosisLeukocytosishigh LAPhigh B12

Significance True vs. spurious R/O most 2

causes Evidence for MPD

False Positive 0.5% smokers, drinkers

Diagnosis of Polycythemia Vera

Major Criteria1. Hgb level > 18.5 g/dL in men, >16.5 g/dL in women2. Presence of the JAK2V617F mutation (in 95% of patients)

Minor Criteria3. Bone marrow biopsy showing hypercellularity4. Serum Epo level below normal range5. Endogenous erythroid colony formation in vitro

PV is likely if:A. Both major criteria and at least 1 minor criterion are met, orB. First major criterion and at least 2 minor criteria are met

Treatment of Polycythemia Vera (PV)

Control and maintain Hct levels <45%

Manage disease-related complications of PV

Phlebotomy to maintain Hct levels <45%

Low-dose aspirin in appropriate patients

Hydroxyurea or IFNα as first-line cytoreductive therapy at any age

Patients with inadequate response to or intolerance of HU use Ruxolitinib (Jakifi) JAK2 inhibitor

Anagrelide (0.5 mg qds/d) is used mainly to manage thrombocytosis in patients refractory to other treatments.

Essential Thrombocythemia


Rare disorder (1.5 per 100,000)proliferation of megakaryocytes causing marked increase in circulating platelets (>1 million)morphologically abnormal plateletssplenomegaly, mucosal hemorrhage, thromboses

arrow: macrothrombocyte



Incidence: 1.5 per 100,000Age at Dx: 60 y/o (~20% <40 y/o)F to M ratio: 1.6 : 1Social risk factor: 1. long-term use of dark hair dyes

2. living in tuff house3. electrician

Clinical features: - near normal life expectancy- frequent vasomotor and thrombo- hemorrhagic episodes

Treatment: low-dose acetylsalicylic acid


MyelofibrosisBone marrow fibrosis

• fibroblasts may be “innocent bystanders”• fibrosis probably driven by neoplastic megakaryocytes

Middle aged adults (50-60 y/o)

extramedullary hematopoiesis (spleen, liver)

May occur as an extension of CML or PV

Abnormal peripheral RBCs (“tear-drop” & nucleated RBCs)

Immature WBC and abnormal platelets

Infection, thrombosis and hemorrhage as a major complicationwww.freelivedoctor.com

Myelofibrosis

LARGE AND BIZARRE PLATELETS, LEUKOCYTOSIS

“naked” nuclear fragments


TREATMENT

1.SPLENECTOMY

2. CORRECT VITAMIN DEF

3. ALLOGENIC BONE MARROW TRANSPLANT

CHRONIC MYELOID LEUKEMIA

Definition• Chronic myelogenous leukemia is a pluripotent

stem cell disease characterized by anaemia,extreme blood granulocytosis with immaturity ,basophilia,thrombocytosis and splenomegaly.

• Occurs more often in men.

• Disease of firsts.

• High doses of ionising radiation can increase the occurrence of CML.

Pathophysiology• Genetic hallmark of CML is the presence of

BCR-ABLfusion gene product.• The fusion protein is a result of reciprocal

translocation between the abelson oncogene on chromosome 9 and break point cluster region on chromosome 22.

• Fusion genes are generated that encode 190,210,or 230 kda forms of the BCR-ABL tyrosine kinase.

Other genetic abnormalities• Trisomy 8,p53 loss.• Interleukin 1 b involved in the progression of

CML to the blastic phase.

CML Pathogenesis: Philadelphia (Ph) Chromosome

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CML first cancer demonstrated to have underlying genetic abnormality

• Associated with Ph chromosome Result of translocation between chromosomes 9

and 22 Detected in approx. 95% of patients with CML

Clinical presentation Symptoms• Fatigue,malaise• Weight loss• Early satiety • Left upper quadrant pain or mass• Easy bruising ,bleeding• FeverUncommon presentation• Acute gouty arthritis,priapism,myocardial

infarction,venous thrombosis,visual disturbances,sweet syndrome..

Signs• pallor• Splenomegaly• Sternal tenderness• Lymhadenopathy• Hepatomegaly• Purpura• Retinal haemorrhage

Diagnostic approach to CMLPeripheral blood• Granulocytic leukocytosis>50*10p9/l• Predominance of neutrophils and increased %of

myelocytes.• Absolute basophilia.• Platelets are normal or increased in number.Bone marrow• Marrow is hypercellular with granulocytic

predominance.• Megakaryocytes are increased in number with

abnormal morphology.• Increase in reticulin fibrosis.• Blasts less than 5%.

Band forms

promyelocyte

myelocyte

metamyelocyte

Diagnosis of accelarated phase• Blasts 10-20% in peripheral blood and or

bone marrow.• Basophils >20% in peripheral blood.• Persistent thrombocytopenia.• Increasing spleen size and white blood

count despite therapy.• Cytogenetic evidence of clonal evolution.

ACCELERATED PHASE

MYELOBLAST

Blast crisis phase• Blast > 20%• Extramedullary blast proliferation.• Large aggregates or clusters of blast in

bone marrow.

Clinical Presentation of Ph+ CML

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Other abnormalities There is increase in • uric acid level• vitamin B12 level.• lactate dehydrogenase.• Increase in the level of angiogenic factors.• Decrease level of leukocyte alkaline

phosphatase.• Increase in histamine levels.

• Identification of philadelphia chromosome• Can be done by conventional cytogenetic

karyotyping,FISH,RT-PCR.Conventional cytogenetics• Entire chromosomal complement is

evaluated to identify philadelphia chromosome and other abnormalities.

• Can be done on both peripheral blood and bone marrow.

Disadvantage• Presence of cryptic or submicroscopic

BCR-ABL arrangement cannot be identified

Fluorescent insitu hybridisationAdvantage• Fast results,greater sensitivity than

conventional cytogenetics.• cryptic molecular alteration can be

detected.Reverse transciptase-PCR• Detects different length products

corresponding to chimeric BCR-ABL proteins of 190,210 and 230 kda.

• So helps in distinguishing CML from ALL.

Fluorescent insitu hybridisation

Prognostic factorsSokal index• Percentage of circulating blast,spleen

size,platelet count,age and cytogenetic clonal evolution.

• Was developed based on chemotherapy treated patients.

Hassford system• Developed on interferon alpha treated patients.• Includes% of circulating blast,spleen

size,platelet count,age,% of eosinophils and basophils.

Treatment • Drugs • Stem cell transplant.• Leukaphresis and splenectomy.drugs• Imatinib mesylate,dasatinib,nilotinib• Hydroxyurea• busulphan• Interferon-alpha• Homoharringtonine• Anagrelide.• Cytarabin.

Imatinib• It is an ABL specific tyrosine kinase

inhibitor.• Imatinib induces apoptosis in cells

expressing BCR/ABL.• Dose is 400mg/day.• It should achieve cytogenetic remission

by 6months and molecular remission by 18 months.

• Side effects-edema,pleural and pericardial effusion,nausea,vomiting,diarrhoea,muscle cramps,skin rash,bone pain and arthralgia.myelosuppression.

Imatinib Mechanism of Action

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Criteria for Extent of Imatinib Treatment

. Hematologic response -White cell count <10x109(platelet count <450 x 109/L, no immature myeloid cells in the blood, and disappearance of all signs and symptoms related to leukemia (including palpable splenomegaly) lasting for at least 4 weeks.

• Major cytogenetic response-Less than 35% of cells containing the Ph chromosome by cytogenetic analysis of marrow cells.

• Complete cytogenetic response-No cells containing the Ph chromosome by cytogenetic analysis of marrow cells.

• Major molecular response-Blood cell BCR-ABL ratio <0.05% (3-log reduction in PCR signal from mean pretreatment baseline value)

• .Complete molecular response-Blood cell BCR-ABL levels undetectable (usually by nested RT-PCR method).

Guidelines for response to imatinib treatment

Time of observation

unsatisfactory

Suboptimal response

Optimal response

3 MONTHS NoHR pHR CHR

6 No mcyR mcyR McyR

12 noMCYR McyR CcyR

18 noCcyR CcyR MMR

Newer tyrosine kinase inhibitorsDasatinib• Structurally unrelated to imatinib binds to

the ABL kinase domain.• Side effect-myelosuppression,pleural

effusion,prolongation of QT interval.Nilotinib• Structural derivative of imatinib binds to

ABL kinase domain.• Side effects-rashes,transient elevation of

indirect bilirubin levels and myelosuppression.

Hydroxy urea• Inhibitor of ribonucleotide reductase.• Lower the blood counts in 1-2 days.• Dose is 500-3000 mg/day.• Side effect-nausea and skin rash.• Given for patients intolerant to imatinib.Busulphan• Gradually lowers the blood counts.• Dose-6-10 mg/day.• Should not be used in patients expected to

undergo bonemarrow transplantation.

Interferon alpha• Causes complete haemotologic response

in >70% of patients.• Dose is 5 million units daily by

subcutaneous administration.• Hasford score was developed to predict

the survival of patients treated with interferon alpha.

Homoharringtonine• it is a plant alkaloid causes cytogenetic

response in patients in late chronic phase.

Anagrelide• It is used for treating elevated platelet

count in CML.especially in presence of thrombosis and bleeding

Leukapheresis• Control CMLonly temporarily.• Used in hyperleucocytic patients where

rapid cytoreduction can reverse the symptoms.

• Pregnant patient with CML can be controlled by leukaphresis.

Allogenic stem cell transplant• Outcome depends on patients age,phaseof

disease,type of donor,preparative regimen,graft vs host disease,post transplantation treatment.

• Patients age should be less than 70 years.transplantation from donor should be HLA matched.

• Peripheral blood can be used a source of haemotopoietic progenitor cells.preoperative regimen like cyclophosphamideplus total body irradiationis used.

• Complications-graft vs host disease.

Differential diagnosis• Chronic myelomonocytic leukemia• Juvenile myelomonocytic leukemia• Chronic neutophilic leukemia• Atypical CML• Diseases associated with

hypereosinophilia.

Chronic myelomonocytic leukemia• Anemia, monocytosis >1000/l; blood blasts <10%;

increased plasma and urine lysozyme; BCR rearrangement absent; uncommon cases with PDGFR- mutation respond to imatinib.

• Chronic eosinophilic leukemia• Blood eosinophil count >1500/l; cardiac and neurologic

manifestations common; a proportion of cases have PDGFR- mutations and are responsive to imatinib mesylate.

Chronic monocytic leukemia• Proportion of monocytes elevated; very rare form of

leukemia.Juvenile myelomonocytic leukemia• Infants and children <4 years; eczematoid or

maculopapular rash; anemia and thrombocytopenia; increased HgF in 70% of cases; neurofibromatosis in 10% of cases; BCR rearrangement absent .

THANK YOU

Most CML Patients Are Diagnosed in the Chronic Phase

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Chronic Phase 80% Blast Phase 10%

CML Pathogenesis: Philadelphia (Ph) Chromosome

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CML first cancer demonstrated to have underlying genetic abnormality

• Associated with Ph chromosome Result of translocation between chromosomes 9 and 22 Detected in approx. 95% of patients with CML

Clinical Presentation of Ph+ CML

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Treatment of CML • Imatinib (Gleevec), developed by Dr. Brian Druker at Oregon

Health & Sciences University and Novartis pharmaceutical company in mid-1990.

• Also found to be effective in other blood cancers and GIST by inhibiting different TK proteins.

• World-wide sales now $28 billion in the 10 years from 2001-2011.

• Now 4 drugs, second generation tyrosine kinase inhibitors available to treat CML.

• Drugs continue throughout life.

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Imatinib Mechanism of Action

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Treatment of CML• 4 Targeted drugs which block the action of tyrosine kinase

(TKIs): – Imatinib (Gleevec)– Dastinib (Sprycel)– Nilotinib (Tasigna)– Bosutinib (Bosulif)

• Side Effects– Skin rash– Fluid retention– Diarrhea– Vascular thrombosis

• Omacetaxine (Synribo) or Homoharringtonine (alkaloid) approved use when 2 TKIs have failed

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Event-Free Survival and Survival Without AP/BC on First-Line Imatinib

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Survival Rates for Stem Cell Transplantation

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‘Inverted Iceberg’ Schematic of CML burden and reduction over time.

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CML Treatment Cessation of TKIs• If relapse occurs, it develops within the first 6 months after

the treatment stopped• About 40%—50% of patients have no recurrence if their

initial leukemic burden was low and they had been on treatment for a long duration (> 10 years)

• Ongoing studies investigating second generation TKIs e.g. nilotinib and achieving more rapid MMR > 4 – 5 logs

• Current recommendation is to continue with TKI treatment for life

• Patients may not be able to tolerate TKI and alternative drug chosen

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THANK YOU

Mds n mps

Health & Medicine

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