ISTORIC

barbat, 50 ani astenie fizica progresiva, satietate precoce - debut 2-3 luni

Examenul fizicAfebrilTegumente normal colorate , fara sindrom hemoragipar cutaneo-mucos Fara adenopatii periferice palpabile Respirator - in limite normale CV: normalAbdomen: mobil, nedureros spontan si la palpare;Fara hepatomegalie Splina - suprafata neteda, marita de volum - pol splenic inferior palpabil la 5 cm de RC stg Examen Neurologic : normal

Hemoleucograma Formula leucocitara:L - 75.000 /LHb -14 g/dLHct - 42%MCV -- 88 flPLT -550.000/LBl 2%, Mi 20% Mt 4%N 1%S 43%Eo 6%B 14%Ly 4% Mo 6%,

LeucocitozaTrombocitozaFormula leucocitara deviata la stg, desfasurata Bazofilie

COMMENT: Basophils are granulocytes with large purple cytoplasmic granules. They mediate allergic and inflammatory reactions and are increased in these situations as well as with viral infections, chronic infections such as tuberculosis, malignancies and, for reasons that are unclear, in the myeloproliferative disorders. Basophilia is the term for the presence of increased numbers of basophils in the peripheral blood).

Probe inflamatoriiVSH 2mm/hFibrinogen 250mg/dl PCR - N

BiochimieNa- 143 mmoli/LK- 4.1 mmoli/LCL- 106 mmoli/Luree- 12 mg/dl creatinine- 0.7 mg/dlglucoza- 87 mg/dllactat dehidrogenaza (LDH) - 397 U/LAcid uric 5.3 mg/dl.

Aspecte clinice si biologice ---- diagnosticul posibil este ?? Leucemie acuta mieloblastica Policitemia vera Trombocitemie esentiala Leucemie mieloida cronica Leucemie mielomonocitara cronicaTrombocitoza, leucocitoza reactive , secundare unui proces infectios

Teste suplimentare necesare stabilirii unui diagnostic de certitudine ? Punctie medulara aspirativa Biopsie osteomedulara Examen citogenetic aspirat medularFISH - BCR-ABL Ex molecular RT PCR - calitativ, cantitativ - gena hibrida BCR-ABL +/- Imunofenotipare

Apirat medular Hipercelularitate celularaMK mici hipolobulate, dispuse in cuiburi

Clusters of megakaryocytes may be appreciated in the spicules

Seria granulocitar crescut cantitativ (89%) cu maturaie prezent, granulocite hipersegmentate, 1% mieloblati, 15% eozinofile, 7% bazofileSeria eritroblastic sczut cantitativ 9% de tip mixt mormoblastic i megaloblastic. Rari eritroblati cu punctaii bazofileSeria limfoplasmocitar sczut cantitativ 2%, limfocite mature

Aspiratul medular:Aspectele morfologice ale aspiratului medular - mieloproliferare cronica (fara a face intotdeauna o diferenta intre acestea, cu exc posibila a LGC) ; exclude dg de leucemie acuta Prezenta de MK atipice (mici, hipolobulate, dispuse in cuiburi) - nu apare in conditiile asociate cu trombocitoza (reactiva)

BOM - HP: fragment bioptic osteomedular cu mduv hematogen hipercelular, compact prin hiperplazie mieloid predominant granulocitar, cu moderat deviere la stg, maturaie prezent, numeroase segmentate, CD 34+ < 5%MK - hiperplazie pe seria MK, mici, hipolobulateSerie Er redusa cantitativFibroza reticulinica - absenta (Impregnare argentic Gomori)

Examen citogenetic aspirat medular Translocatie reciproca : bratele lungi ale cromoz 9 si 22 cromozomulPhiladelphiaIdentificat in 100% metafazele analizate

Fluorescence in situ hybridization (FISH) - BCR-ABL rearrangement

Translocatia intre crom 9 si 22 determina fuzionarea oncogenei celulare c-abl (crom 9) cu gene bcr (breakpoint cluster region) (crom 22) ---- gena hibrida --- da nastere unui ARN mesager , responsabil de sinteza unei proteine cu activitate tirozin kinazica.

Gena de fuziune bcr/abl - FISH

fluorescence in situ hybridization (FISH) - transcripul BCR-ABLFlourescence In Situ Hybridization: Interphase (non-dividing) bone marrow cells stained with flourescein labeled probes for bcr and abl genes. FISH analysis using labeled probes for abl (red) and bcr (green) loci shows the presence of non fused genes in a normal cell and a bcr-abl fused signal (yellow) in an abnormal cell.

Polymerase chain reaction (PCR) - gena bcr-ablPozitiv (% bcr-abl/abl: 8.1)The assay shows the presence of bcr-abl transcriptsThe result is usually expressed as the ratio of bcr-abl transcripts to normal abl transcripts It is a quantitative assay that is extremely sensitive and can detect one Philadelphia chromosome positive cell in 105 to 106 normal cells It is now routinely used to monitor response to tyrosine kinase inhibitor therapy. Treatment monitoring rising transcript levels may signal the development of resistance to treatment and warrant change in therapy.

Diagnosticul de certitudine Leucemie acuta mieloblasticaLeucemie mieloida cronicaTrombocitemie esentiala Policitemia vera Leucemie mielomonocitara cronicaLeucocitoza / trombocitoza reactiva

Testele - necesare stabilirii unui astfel de dg????

Leucemia mieloida cronica

citogenetica FISHRT- PCR

LMC - ce faza ?

Faza cronicaFaza accelerataPuseu blastic

Faza cronica - Corect!

Deseori asimptomaticeLeucocitoza identificata in timpul unui control de rutina simptomatologie prezenta --- secundare statusului hipermetabolic (astenie, febra, transpiratii nocturne,scadere ponderala)> cz splenomegalie si hepatomegalie la dgcriteriile de dg

Accelerated Phase IncorectDebut agresiv, febra, dureri osoaseCresterea numarului de blasti in SP si MO, dar

Puseu blastic Incorect!!Hiatus leucemic > 20% blasti SP, MO - majoritatea Mi, 25-30% cz LySuprav medie - 3-6 luni.

Tratamentul adecvat pentru acest pacient?

Monitorizarea lui??Observare Incorect. Fara tratament adecvat, eficient toti pac. dg LMC in faza cronica evolueaza spre faza accelerata/ puseu blastic

Incorect. 1. Hydroxyurea inhibitor de ribonucleotid reductaza (inhiba sinteza DNA) 2. Indic. de tratament: f hiperleucocitoza (>250,000)---- Hydroxyurea ---- pt reducerea rapida a nr de Leuc, controlul simptomatologiei 3. Hydroxyurea nu elimina cromoz Ph si nu intarzie progresia catre fz accelerata sau puseu blastic Hydroxyuree

Incorect. Interferon alpha nu mai reprezinta indicatie de electie prima linie terapeutica LMC glicoproteine cu efecte anti-virale, anti-proliferative, imunomodulatorii si inducerea diferentieriiInduce raspuns hematologic complet in majoritatea cazurilor ( criteriile de RHC) RCyC in nr mic de cazuri max 25% Toxicitate astenie fizica, prurit, rash, depresie, mialgii, scadere ponderala etcInterferon alpha

Incorect. Nu reprezinta I linie terapeutica.Indisponibilitatea donator HLA inrudit , varsta de dg T 315I Allo transplant medular cel STEM

Imatinib mesylate (Gleevec)- Corect!

Inhibitor tirozin-kinazic ( interfera cu leg ATP la domeniul tirozin kinazei BCR-ABL ce codifica prot the bcr-abl) ---- intreruperea semnaletor oncogenice catre nc celRCyC (eradicarea cr Ph) ~ 80% RMM ~ 40% Risc intoleranta/ rezistenta la Imatinib

ITK gen II ~~~~ (dasatinib, nilotinib)

Hematologic RemissionDefinition:Complete HR:Platelet count

Cytogenetic ResponseComplete: Ph+ 0% Partial: Ph+ 1%-35% Minor: Ph+ 36%-65%Minimal: Ph+ 66%-95% None: Ph+ >95%Every 6 months until complete response achieved, every 12 months thereafterDefinition:Monitoring:

Molecular ResponseComplete: BCR-ABL transcripts not detectableMajor:BCR-ABL to control gene ratio 0.1Every 3 months; mutational analysis in case of failure, suboptimal response or increase of transcript levelsDefinition:Monitoring:

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