Page 471 - Clinical Hematology_ Theory _ Procedures ( PDFDrive )

CHAPTER 23 ■ Myeloproliferative Neoplasms 455

(LAP) proce ure is use to i erenti te between CML n Treatment Drugs in Chronic

leukemoid reaction. A leuke oi re ction is pro uce by TABLE 23.3 Myelogenous Leukemia

severe in ection or in tion n requently rese bles

leuke i on bone rrow or bloo s e rs. In CML, the LAP Generic Name Trade Name Genetic Target

score is ecre se s co p re with leuke oi re ction, in

which high score is usu l. An incre se LAP score y be Imatinib Gleevec BCR-ABL, c-KIT, PDGFR

encountere in CML bec use o subsequent secon ry in ec- Lapatinib Tykerb HER2/neu, EGFR

tions or in tion. A ition lly, uring re ission ph ses Nilotinib Tasigna BCR-ABL, c-KIT, PDGFR

o CML, the LAP score y return to nor l li its.

In the LAP or neutrophilic lk line phosph t se (NAP)

re ction, solution o n phthol AS-MX phosph te lk line Sorafenib Nexavar BRAF, VEGFR, EGFR,

n either st blue RR or st re violet LB s lt is incub te PDGFR

with icroscopic s e r o peripher l bloo or bone r-

row. Positive re ctions re in ic te by the eposition o blue cell cycle. T e Ks re ABL, BCR-ABL, AARG, PDGFRα n

or violet pig ent t the cellul r sites o lk line phosph te PDGFRβ, n c-KI .

ctivity within either b n or or seg ente neutrophils. T e intro uction o i tinib un ent lly ltere

Following st ining, 100 b n s or seg ente neutro- the n ge ent o p tients with CML in chronic ph se

phils re counte . E ch cell is r te ccor ing to the istri- (Fig. 23.7). It is reco en e s the best single gent or

bution n intensity o st ining. T e possible r nge is 0 to newly i gnose p tients who re not eligible or initi l tre t-

400, lthough the nor l r nge is ro 20 to 100. Incre se ent by allogeneic stem cell transplantation. T ere is no con-

scores re ssoci te with leuke oi re ctions, severe b cte- sensus on whether i tinib shoul be inistere lone or

ri l in ections, n PRV. Decre se scores c n be oun in in conjunction with IFN-α, cyt r bine, hy roxyure , or rse-

vir l in ections n CML. nic trioxi e. I tinib now see s to be the initi l tre t ent

o choice or p tients with CML who o not h ve suit ble

Cytogenetic Studies bone rrow onor or who re not c n i tes or tr nspl n-
t tion. It is now wi ely ccepte th t i tinib esyl te (pre-
Cytogenetic stu ies re the st n r i gnostic test or CML. viously S 1571) is the best single gent or n ging newly

Other i gnostic proce ures inclu e geno ic poly er se i gnose p tients with CML in chronic ph se who re not

ch in re ction (PCR) n Southern blot n lysis th t c n eter- cle rly c n i tes or llogeneic ste cell tr nspl nt tion.

ine the ex ct bre kpoints o DNA usion pro ucts. Reverse Pri ry resist nce to i tinib see s to be r re in chronic-

tr nscript se PCR (R -PCR) n Northern blot n lysis llow ph se p tients, but the jority o v nce -ph se p tients

etection o BCR-ABL tr nscripts t the RNA level. T e BCR- beco e resist nt to i tinib.

ABL protein c n be e onstr te by using ntibo ies g inst Constitutive ctiv tion o these Ks ocu ents in CML,

the N-ter in l region o BCR n the C-ter in l region o Ph + ALL, n yeloproli er tive isor ers is ue to chro-

ABL in i unoprecipit tion or Western blot n lysis. oso l re rr nge ent. Although i tinib is e ective in

Detecting gene re rr nge ents involving the BCR n Ph pos leuke i s, rel pses o occur inly s result to

c-ABL genes is clinic lly use ul or: the outgrowth o leuke ic subclones with i tinib-resist nt

1. Conf r tion o Ph -positive c ses o CML BCR-ABL ut tions. T e e i n surviv l ti e ro the
1
2. Di gnosis o Ph -neg tive c ses o CML ti e o i gnosis is pproxi tely 1 ye r in p tients l cking
1
1
1
3. Di gnosis o CML presenting in bl st crisis Ph . T ose p tients with Ph h ve better prognosis, with
4. Monitoring o p tients with CML uring n er ther py e i n surviv l ti e o 3 to 4 ye rs. A er progression to

or etection o ini l resi u l ise se the bl st crisis ph se, the prognosis is poor, with p tient sur-

5. Conf r tion o re ission viv l ti e usu lly being less th n 6 onths. Molecul r tech-

6. E rly etection o rel pse niques (e.g., PCR o BCR-ABL, RNA tr nscripts) c n gui e
ther py by istinguishing p tients who re oing well with

i tinib ro those who will experience rel pse n thus
Prognosis and Treatment
require ltern tive ther py (e.g., ste cell tr nspl nt tion).

Bec use chronic-ph se CML is highly responsive to tre t- In the uture, gene expression icro rr y stu ies ight help

ent, ny p tients experience t le st one re ission. T ese pre ict respon ers to specif c ther py.

re issions c n l st ro sever l weeks to onths, with 60% I tinib esyl te h s l rgely suppl nte llogeneic

o p tients beco ing sy pto tic. he topoietic ste cell tr nspl nt tion s f rst-line ther py

I tinib (Gleevec, Nov rtis Ph r ceutic ls, B sel, or CML. M ny CML p tients eventu lly un ergo ste cell

Switzerl n ) w s the f rst o the f ve s ll olecule selective tr nspl nt tion r ising question o whether prior ther py

inhibitors ( ble 23.3) o the BCR-ABL K th t re now i p cts tr nspl nt tion success. Surviv l r tes re high

v il ble, which occupies the A P-bin ing site o sever l ong chronic-ph se p tients receiving i tinib esyl te.

K olecules (BCR-ABL oncoprotein) n prevents phos- He tologic l response y be ssoci te with sy pto -

phoryl tion o substr tes th t re involve in regul ting the tic i prove ent in CML.