Two Year Data from a Prospective Safety Study Analyzing the Consequences of Imatinib Mesylate Inhibition of Sensitive Kinases Other Than bcr-abl in Patients with Previously Untreated Chronic Phase CML.
Authors: Seymour John Francis , Grigg Andrew , Reynolds John , Schwarer Anthony P. , Hermann Richard , Taylor Kerry McDonald , Bradstock Kenneth Francis , Mills Anthony K. , Koelmeyer Rachel , Lynch Kevin , Hughes Timothy 
Published: October 2019

Imatinib Mesylate (IM) is a potent inhibitor of bcr-abl which also inhibits a number of other tyrosine kinases; c-abl, c-arg, PDGF-R, c-kit, and c-fms. IM inhibits these targets in vivo at clinically achievable concentrations, but the consequences of these actions in patients (pts) with CML are unknown. Gene knockout mice lacking these kinases have distinct phenotypes suggesting potential consequences of long-term inhibition (infertility, lymphopenia, emphysema, glomerular dysfunction). To determine if long-term IM therapy may lead to such features, we prospectively evaluated these parameters in a subset of pts with untreated chronic-phase CML enrolled on the ALLG trial of dose intensified IM. Analyses were performed at baseline, 6-, 12-, and 24-months. Results are presented as within patient comparisons of baseline and 24-month data as paired samples, unless stated otherwise. 103 pts were entered in the main study and 45 have consented to aspects of this sub-study, with ages ranging from 37–75 yrs (median 51), and average daily IM dose of at least 600 mg. There were minor but statistically significant declines in respiratory function (n=24); median vital capacity (4.9 to 4.4L; p=0.019), FEV1.0 (3.6 to 3.2L; p=0.007) and PEFR (9.0 to 7.2 L/sec; p=0.06), with no change in DLCO. There was no change in urinary protein excretion (p=0.45), male (testosterone / FSH / LH) (n=14; each p>0.08) or female hormone levels (oestradiol / progesterone / FSH / LH) (n=6; each p>0.16), but one of 3 men with serial analyses developed oligospermia. There were consistent falls (n=26) in all Ig classes, most evident for IgG and IgM with the greatest decline seen in the first year and stable levels thereafter. In the 20 pts analysed there were sustained and ongoing declines in CD3+, CD4+, and CD8+ cells, but no changes in CD19+ or CD56+ cells. Results are tabulated, with the change (Δ) from baseline to 24-months shown. There have been no instances of severe or opportunistic infections in these pts. Based on these data there have been no adverse effects of IM evident on male or female reproductive hormonal status, glomerular function, B- or NK-cell numbers, but one case of oligospermia, consistent and sustained effects on pulmonary function, T-cell subsets and all classes of Ig levels without any clinical consequences yet manifest. These effects of IM on sensitive kinases other than bcr-abl in pts with CML are important for both our understanding of the physiologic role of these kinases in humans and the delineation of the spectrum of potential adverse effects associated with long-term use of this class of drugs.

Median values IgG (g/L) IgA (g/L) IgM (g/L) CD3+ (109/L) CD4+ (109/L) CD8+ (109/L) CD19+ (109/L) Baseline 10.45 1.63 1.36 1.43 1.03 0.51 0.19 6 month 9.9 1.55 0.76 1.12 0.67 0.35 0.20 12 month 8.7 1.49 0.71 1.06 0.65 0.38 0.16 24 month 8.5 1.55 0.68 0.90 0.51 0.28 0.15 Δ −2.23 −0.2 −0.7 −0.46 −0.25 −0.17 −0.04 P-value <0.0001 0.018 <0.0001 0.0007 0.0003 0.004 0.33