LMC

FASEINIZIALE

FASEACCELLERATA

FASECRONICA

(Fase blastica)

•PVTE

LEUCEMIALEUCEMIAACUTAACUTA

•TE

•PMF

Porf AM Vannucchi‐AA2009‐10

LMC: eziopatogenesiLMC: eziopatogenesi•Radiazioni ionizzanti (incidenza >9 volte nei medici radiologi, >13 volte nei

paz. con spondiloidite anchilosante trattati, 40% delle leucemiep p ,dopo bomba atomica

LMC: segni clinici all’esordio

• Astenia, anoressia, perdita di peso

• Leucocitosiperdita di peso

• Splenomegalia• Piastrinosi (30‐50% casi)

• Basofilia• Epatomegalia

• ≈40% asintomatici• ⇓ PAL• Mielemia con minimaMielemia con minima blastosi

Porf AM Vannucchi‐AA2009‐10

LMC: segni di progressione

A t i i dit L it i i t• Astenia, anoressia, perdita di peso ingravescenti

• Splenomegalia

• Leucocitosi ingravescente, anemia, piastrinopenia

• Spiccata trombocitosi• Splenomegalia progressiva, non responsiva alla terapia

• Spiccata trombocitosi

• Basofilia >20%

• Blasti periferici >15%p p

• Febbre non infettiva

• Dolori ossei

• Blasti periferici >15%

• Blasti+promielociti >30%

A li it ti hDolori ossei

• Ridotta sensibilità ai farmaci

• Anomalie citogenetiche aggiuntive

-- fase acuta: blasti >30%Porf AM Vannucchi‐AA2009‐10

Porf AM Vannucchi‐AA2009‐10

DIAGNOSI e MONITORAGGIO:

• Esame cariotipico convenzionale• FISH• RT-PCR & TaqMan• RT-PCR & TaqMan

Porf AM Vannucchi‐AA2009‐10

The Translocation of t(9;22)(q34;q11) in CML

Porf AM Vannucchi‐AA2009‐10

Porf AM Vannucchi‐AA2009‐10

Mechanism of Action of BCR-ABL and of Its Inhibition by Imatinib

Porf AM Vannucchi‐AA2009‐10

Figure 1 Disease burden and tests

Radich J P Blood 2009;114:3376 3381

Copyright ©2009 American Society of Hematology. Copyright restrictions may apply.

Radich, J. P. Blood 2009;114:3376-3381

Porf AM Vannucchi‐AA2009‐10

Table 1 Methods to detect minimal residual disease in CMLTable 1.. Methods to detect minimal residual disease in CML

Method Target Sensitivity, percentage

Advantages Disadvantages

Morphology Cellular morphology 5 Standard Poor sensitivity

Cytogenetics Chromosome structure

1‐5 Widely available Low sensitivity, bone marrow only

FISH Specific genetic marker(s)

0.1‐5 Fast (1‐2 days) Does not look for other clonal events

QPCR RNA sequence 0.001‐0.01 Very sensitive Poor standardization, laboratory‐intensive

Porf AM Vannucchi‐AA2009‐10

Table 2.. Response criteria in CML

Level of response Definition

Complete hematologic response

Normal complete blood count and differential

Mi t ti 35% 90% Ph+ t hMinor cytogenetic response 35%‐90% Ph+ metaphasesPartial cytogenetic response 1%‐34% Ph+ metaphasesComplete cytogenetic response 0% Ph+ metaphasesMajor molecular response 3 log reduction of BCR ABLMajor molecular response 3‐log reduction of BCR‐ABL

mRNAComplete molecular remission Negativity by QPCR

Note that all cytogenetic response categories require the analysis of at least 20 metaphases.

Porf AM Vannucchi‐AA2009‐10

Porf AM Vannucchi‐AA2009‐10

Schematic of point mutations in the ABL kinase domain. Mutations in the ABL kinase domain (amino acids 240 to 500) cluster in 4 distinct regions theABL kinase domain (amino acids 240 to 500) cluster in 4 distinct regions, the ATP-binding domain (amino acid 248-255, green), mutations of T315 (red), which form a hydrogen bond with imatinib, M351 (turquoise), which interacts with the SH2 domain and participates in autoregulation of kinase activity and thethe SH2 domain and participates in autoregulation of kinase activity, and the activation loop (amino acids 379-398, magenta).

Porf AM Vannucchi‐AA2009‐10