Drug cross-resistance and therapy-induced resistance in chronic lymphocytic
leukaemia by an enhanced method of individualised tumour response testing.
Andrew G Bosanquet, Sue M Richards, Rachel Wade, Monica Else, Estella Matutes,
Martin J S Dyer, Saad M B Rassam, Justin Durant, Sheila M Scadding, Steve L
Raper, Claire E Dearden, and Daniel Catovsky
Br J Haematol, June 22, 2009;

Bath Cancer Research, Royal United Hospital, Bath.

Previous results with individualised tumour response testing (ITRT) in vitro in
chronic lymphocytic leukaemia (CLL) have consistently shown good correlation
with patient response and survival. We describe here an improved test and report
its use with samples from the Leukaemia Research Fund CLL4 randomised clinical
trial and previously treated patients. ITRT was performed by the tumour response
to anti-neoplastic compounds (TRAC) assay, a modification of the differential
staining cytotoxicity (DiSC) assay. Improvements included drying drugs into
wells before assay and using the Octospot system to cytocentrifuge eight spots
of cells onto one microscope slide. We successfully tested 765/782 (98%)
cellular blood samples received within 48 h of phlebotomy. Cross-resistance
(Pearson's r > 0.7) in untreated CLL was found between similar drugs.
Mitoxantrone (r = 0.31), cyclophosphamide (r = 0.35) and pentostatin (r = 0.29)
had low cross-resistance with fludarabine. Treatment resulted in increased
resistance to chlorambucil, cyclophosphamide, doxorubicin, mitoxantrone,
corticosteroids, cladribine and fludarabine (P < 0.01) but not to pentostatin.
These results provide further rationale for standard drug combinations such as
fludarabine-mitoxantrone and fludarabine-mitoxantrone-cyclophosphamide and
suggest possible pentostatin salvage in fludarabine-resistant patients. ITRT
results could assist both in determining the best treatment for individual
patients and in the design and rationale of future clinical trials.
PMID: 19552723

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