In Chronic Lymphocytic Leukemia Females Survive for Longer Than Males Even in Patients with Unmutated Immunoglobulin Genes.
Authors: Hamblin Terry John , Orchard Jenny A. , Davies Zadie A. , Ibbotson Rachel E. , Gardiner Ann C. , Copplestone Adrian , Oscier David G. 
Published: October 2019

Abstract
Among the proposed prognostic factors for chronic lymphocytic leukemia (CLL), gender has been constant. In published trials females survive longer. With the new prognostic markers that relate to cell biology it seemed that an explanation was forthcoming. The sex ratio for patients with unmutated immunoglobulin variable region heavy chain (IgVH) genes is M:F=2:1 whereas for those with mutated IgVH genes it is close to unity. Females are less likely to have the more malignant subset. We have explored whether this is a sufficient explanation for the better outcome in females. 310 patients with CLL were studied. 260 were local patients representing the referral pattern of a district hospital and 50 were second-opinion referrals. 180 were male and 130 female. Overall, the median survival of females was 161 months compared to 119 months for males (p<0.005). 189 (101 males; 88 females) had mutated and 121 (79 males; 42 females) unmutated IgVH genes. As expected patients with mutated IgVH genes had longer median survivals (mutated 183 months, unmutated 95 months; p<0.0001). Thus males are more likely to belong to the shorter-lived subtype. However, this is not a complete explanation. Among those with unmutated IgVH genes, females also survived significantly longer (135 months versus 97 months; p<0.05), whereas among those with mutated IgVH genes there was no difference. Censoring for unrelated deaths did not affect the findings. We also looked at treatment-free survival. This was better for females than males (median time to treatment not yet reached versus 113 months; p=0.0097) but among those with unmutated IgVH genes there was no significant difference (49 months versus 31 months; p=0.57). However, survival following first treatment was significantly better for females than for males both for the whole group (127 months versus 70 months; p=0.0092) and for the unmutated subgroup (100 months versus 45 months; p=0.014), but there was no difference for the mutated group. This finding is consistent with the findings in clinical trials for which survival is calculated from date of entry into the trial, not date of diagnosis. There were other slight differences between males and females. Mean age at presentation was slightly greater for females (66.7 v 64.3; p=0.0063), and females who were treated were more likely to have received alkylating agents alone (20 males, 17 females; p=0.0015) but neither of these factors is likely to have led to greater longevity. 117 patients (86 males; 41 females) had required treatment. Apart from the group treated with alkylating agents alone there were no significant differences in how males and females were treated. 44 patients received an alkylating agent followed by fludarabine (30 males and 14 females), and 27 received a fludarabine containing regimen as first line (22 males and 5 females). Seven patients received monoclonal antibodies (5 male, 2 females) and there were 3 allografts (two male, one female) and 1 autograft (male). The prevalence of adverse chromosomal abnormalities as detected by FISH was 6.4% for 17p13 deletions and 12.3% for 11q23 deletions and not significantly different (separately or together) between the sexes. We conclude that females survive for longer following treatment for CLL for unknown reasons. We are aware that androgen receptors play a part in lymphopoiesis, but how this relates to the gender differences in CLL is unclear.