•PV

•TE

LEUCEMIA

ACUTA

•PMF

LMC

FASE

INIZIALE

FASE

ACCELLERATA

FASE

CRONICA

(Fase blastica)

Porf AM Vannucchi-AA2009-10

LMC: segni clinici all’esordio

• Astenia, anoressia, perdita di peso

• Splenomegalia

• Epatomegalia

• 40% asintomatici

• Leucocitosi

• Piastrinosi (30-50% casi)

• Basofilia

• PAL

• Mielemia con minima blastosi

LMC: eziopatogenesi

•Radiazioni ionizzanti (incidenza >9 volte nei medici radiologi, >13 volte nei

paz. con spondiloidite anchilosante trattati, 40% delle leucemie

dopo bomba atomica

Porf AM Vannucchi-AA2009-10

LMC: segni di progressione

• Astenia, anoressia, perdita di peso ingravescenti

• Splenomegalia progressiva, non responsiva alla terapia

• Febbre non infettiva

• Dolori ossei

• Ridotta sensibilità ai farmaci

• Leucocitosi ingravescente, anemia, piastrinopenia

• Spiccata trombocitosi

• Basofilia >20%

• Blasti periferici >15%

• Blasti+promielociti >30%

• 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

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

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

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

Figure 1 Disease burden and tests

Porf AM Vannucchi-AA2009-10

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

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

Porf AM Vannucchi-AA2009-10

Level of response Definition

Complete hematologic response

Normal complete blood count and differential

Minor cytogenetic response 35%-90% Ph+ metaphasesPartial cytogenetic response 1%-34% Ph+ metaphasesComplete cytogenetic response 0% Ph+ metaphasesMajor molecular response 3-log reduction of BCR-ABL

mRNAComplete molecular remission Negativity by QPCR

Table 2.. Response criteria in CML

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, 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 the

activation loop (amino acids 379-398, magenta).

Porf AM Vannucchi-AA2009-10