Chromosomal abnormalities in Ph- cells - second try.

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Hey Folks, ASH time again. For a change of pace, I think I'll report on

poster sessions for a while. The first is one out of MD , by H.

Cortes, et. al., on the occurrence of chromosomal abnormalities in Ph-

cells, in CML patients on IM. The full abstract is below and is largely

self-explanatory, but there are a couple of points worth emphasizing.

First, the fact that these were newly diagnosed patients who were treated

right off with IM, so the changes can't be attributed to, say, Ara-C, as

some had previously thought. This doesn't mean that IM caused them, but the

fact that a higher frequency of abnormalities occurred in patients on 600 or

800mg of IM vs those on 400mg (this was in the poster session, but not in

the abstract), suggests that IM may, in fact, play a causative role.

Secondly, only three chromosomal changes accounted for the majority of those

found: loss of Y chromosome was the most frequent (33%), followed by

trisomy 8 (14%), and deletion of chromosome 7 (10%). Why certain mutations

should predominate, I have no idea, but it's interesting.

Thirdly, it is reassuring to note that almost all of these Ph- chromosomal

changes were transient, lasting a median of 4 months.

Finally, of 19 patients with the changes, 17 were still alive after a median

30 month follow period. One died of a heart attack. The death related to

CML was from a stem cell transplant; so much for SCT being the only

" cure... "

Cheers,

R

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[1090] Chromosomal Abnormalities in Philadelphia Chromosome (Ph)-Negative

Metaphases Appearing during Imatinib Mesylate (IM) Therapy in Patients (pts)

with Newly Diagnosed Chronic Myeloid Leukemia (CML) in Chronic Phase.

Session Type: Poster Session 248-I

Elias Jabbour, Hagop Kantarjian, O'Brien, Srdan Verstovsek, Guillermo

-Manero, Beth Rios, Cortes . Leukemia, University of Texas

M.D. Cancer Center, Houston, TX, USA

The development of chromosomal abnormalities in the Ph-negative metaphases

during IM therapy of CML has been recognized mostly in pts who failed prior

therapy. Prior exposure to cytarabine has been suggested to be a

predisposing factor. This phenomenon has not been yet assessed to date in

patients with newly diagnosed CML and treated with IM. This is different

from clonal evolution where the abnormalities are observed in the

Ph-positive metaphases. We assessed the frequency and the significance of

this event among 258 newly diagnosed pts with CML receiving IM (800 mg/d

n=207, 400 mg/d n=51) as first line of therapy between March 2001 and April

2005. After a median follow-up of 30 months (range, 6-48 months), 19 pts

(7%) developed 21 chromosomal abnormalities in Ph-negative metaphases.

Thirteen (62%) of these abnormalities have been seen in 2 or more

metaphases. The median time from the start of IM to appearance of

abnormalities was 18 months (range, 3-36 months). The most common

cytogenetic abnormalities were: loss of chromosome Y (n=7, 33%), trisomy 8

(n=3, 14%), and deletion of chromosome 7 (n=2, 10%). Excluding loss of

chromosome Y abnormalities, the incidence was 5%. All pts achieved a major

(Ph < 35%) cytogenetic (CG) response (complete cytogenetic response [CCGR]

in 17 [89%] pts). Major molecular response (BCR-ABL/ABL ratio <0.05) was

observed in 13 (68%) pts (including 2 with complete molecular response). In

all but 4 pts these events have been transient and disappeared after a

median of 4 months (range, 3-9 months). In 4 pts (loss of chromosome Y n=3,

trisomy 8 n=1), they persisted for a median of 13+ months (range, 6+-24+

months). One pt developed acute myeloid leukemia (associated with ­7); none

of the other pts has any feature of myelodysplasia. After a median follow-up

of 13 months (range, 1-42 months), 17 of the 19 pts are alive. One pt died

after allogeneic stem cell transplantation, and one died after 6 months of

CCGR from myocardial infarction. One pt lost response to IM. The remaining

16 pts are in major CG response at the last follow-up. We conclude that: 1)

cytogenetic abnormalities occur in Ph-negative cells in a small fraction of

patients (7%; 5% if loss of Y excluded) in newly diagnosed CML on IM; 2) in

the majority of cases, they are transient with no clear clinical

consequences; 3) in rare instances (loss of chromosome 7 only in our study)

they could reflect the emergence of a new malignant clone necessitating and

a close follow-up.