Molecular profile at CML diagnosis predicts survival - ASH abstract

[Guest guest]

Here's an interesting ASH Abstract/poster session, from the folks in

Goldman's lab in London.

The object of their study was to find out whether any molecular markers at

the time of diagnosis can predict which patients will have aggressive vs.

slow moving disease. To answer this question, they went back and looked at

marrow samples frozen at the time of diagnosis from one group of patients

whose CML progressed to blast phase rapidly (in less than three years); and

another whose CML progressed more slowly (to blast phase in seven years or

more).

Needless to say, given their nasty outcomes, all these patients were from

the pre-Gleevec era, so it's not clear what relevance their findings have

for us fortunate folks. Still, the results were interesting, in that

microarray gene expression profiling (GEP) showed highly significant

differences between the two groups (specifically, patients whose cells at

diagnosis expressed minimal CD7 and high Proteinase 3 or elastase lived a

long time, while those whose cells showed the opposite pattern progressed to

blast phase quickly).

Hopefully these folks will repeat the experiment using bone marrow from

patients diagnosed in the IM era - the obvious question being whether these

GEP patterns predict anything about response to and survival on Gleevec (or

any of the newer STIs). Other studies are underway to try to predict the

same thing, which would help clinicians decide when to start with a higher

dose, try a different drug, drugs in combo, or recommend early transplant.

I came across a couple of these studies (all still in early stages) and will

report on them when I find my notes.

R

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[1984] Molecular Profiling of CD34+ Cells from Diagnosis in CML Patients

Identifies Low Expression of CD7 with High Expression of Proteinase 3 or

Elastase as Predictors of Longer Survival. Session Type: Poster Session

188-II

Agnes S.M. Yong, M. Szydlo, M. Goldman, Jane F. Apperley, Junia

V. Melo . Department of Haematology, Hammersmith Hospital, Du Cane Road,

Imperial College London, London, United Kingdom; Hematology Branch,

NHLBI/NIH, Bethesda, MD, USA

Although most patients with chronic myeloid leukemia (CML) have the same

initial molecular abnormality, the BCR-ABL fusion gene, the duration of

chronic phase (CP) varies widely. To identify the possible molecular basis

of this heterogeneity, we studied CD34+ cells collected at diagnosis from 68

CML-CP patients. In all cases the Philadelphia chromosome was the only

cytogenetic abnormality identified. Cryopreserved cells had all been

collected by leukapheresis within 3 months of diagnosis, when the patients

still had high leukocyte counts prior to definitive treatment. Although the

majority of patients were diagnosed in the pre-imatinib era and treated with

hydroxyurea and/or interferon-£\, 32 (47%) received imatinib during the

course of their disease. The median age at diagnosis was 45.2 years (range

17.6-68.3), and the male: female ratio was 1.8: 1 (44 males, 24 females).

Total RNA was extracted from CD34+ purified cells. Gene expression profiling

using Affymetrix HG-U133A microarrays was performed on two subsets of

patients, one comprising patients with an 'aggressive disease' who developed

blastic transformation (BT) within 3 years of diagnosis (n=10) and, at the

other extreme, patients with an 'indolent disease' whose BT occurred 7 or

more years from diagnosis (n=9). There was no difference in the proportion

of the CD34+ subsets of CD38+ Lin+, CD38+ Lin¡V or CD38¡V Lin¡V cells between

patients in the indolent as compared to the aggressive CML groups.

Microarray data were analysed using a combination of MAS 5.0, dChip, RMA and

GeneSpring 5.0 software, and revealed 20 genes differentially expressed in

patients with aggressive and indolent disease, which were validated by

quantitative real-time polymerase chain reaction (qPCR). The correlation

between microarray and qPCR expression measures was highly significant for

18/20 genes (p<0.005, Spearman's Rho). In the complete cohort of 68

patients, a multivariate regression model identified the combination of

low CD7 expression with high expression of proteinase 3 (PR-3) or elastase

as associated with longer survival (p=0.0004 and p=0.0006, respectively).

The levels of cytoplasmic PR-3 and surface CD7 protein expression by

flowcytometry were also of prognostic value (p=0.029 and p=0.031,

respectively). Patients who had more than 11% CD34+ cells expressing surface

CD7 protein at diagnosis had a poor survival. Conversely, patients with more

than 2% CD34+ cells expressing cytoplasmic PR-3 had a superior survival.

This differential pattern of gene expression probably reflects the intrinsic

heterogeneity of the disease; if so, assessing expression levels of selected

genes at diagnosis may be valuable in predicting duration of survival in

patients treated upfront with imatinib and the newer tyrosine kinase

inhibitors.