Imatinib’s Potential Effects on Fertility, Immunity and Pulmonary Function: A Prospective Study in Patients with Previously Untreated CML.

Imatinib therapy was rapidly introduced for CML because of its efficacy and tolerability, so ongoing scrutiny is warranted to elucidate any effects not seen in registration trials. Imatinib strongly inhibits several tyrosine kinases (abl, arg, kit, and pdgfr’s) with functions in normal tissues. Mice lacking these genes have impaired male fertility (abl or kit knockouts), B- and T- cell lymphopenia (abl), emphysema (pdgf) and glomerular dysfunction (pdgf). Hence, we prospectively analysed chronic-phase CML patients on higher-dose imatinib (Hughes TP et al. Abstract #95 ASH 2003) for fertility, immunoglobulin levels, lymphocyte sub-sets and pulmonary function over 1 year. 39/103 patients participated in the safety sub-study, with median age 50 (range 28–75), on median daily imatinib doses of 558–575mg.

In 20 males tested, median serum testosterone (in nmol/L) changed little, from 12.8 at baseline to 14.7 at 6 months, to 11.4 at 1 year (Wilcoxon p=0.05). Serum LH, FSH and oestradiol were unchanged. Only 2 patients had repeat sperm counts: one recovered from azoospermia to have low counts; the other had normal counts at baseline and 6 months. In 20 females, there were no changes in median serum progesterone, oestradiol or LH. FSH (in U/L) fell from 25 to 5 at 6 months, but rose to 21 at 1 year (p=0.03). Median serum IgG levels (in g/L; n=34) fell from 10.5 to 9.8 at 6 months, to 8.6 at 1 year (p<0.0001). Serum IgM (in g/L) also fell from 1.4 to 0.8 at 6 months, to 0.9 at 1 year (p=0.0003). Serum IgA declined from 1.6 to 1.5g/L (p=0.002). There were no consistent changes in median B−, NK− or CD8+ T-cell counts (n=26). T-cell counts declined, with falls in CD4+ cells (x10^9/L) from 1.0 to 0.7 at 6 months, to 0.6 at 1 year (p=0.003). 3 of 39 patients had Grade 3–4 infections; in all 3, lower IgM’s were noted (with one below normal) at 6 months; in one case IgG and IgA also fell below normal. Pulmonary function tests (n=32) showed no consistent changes. Median FEV1 (in L) fell from 3.64 to 3.22 at 6 months (p=0.03), but rose to 3.52 at 1 year. Vital Capacity (in L) also fell from 4.89 to 4.12 at 6 months (p=0.02), but rose to 4.60 at 1 year. DLCO improved marginally. PEFR (in L/sec) trended down from 8.79 to 7.37 at 6 months, to 7.68 at 1 year. There was no evidence of glomerular dysfunction, measured by 24-hour urinary protein. In summary, in patients with chronic-phase CML treated with imatinib at a median dose of ~600mg/day for 1 year, changes in hormonal, immune and pulmonary parameters were recorded. Declines in serum IgG and IgM were highly significant, but were not associated with lower B-cell numbers. These data reveal novel and potentially clinically relevant effects in CML patients on imatinib.