Appearance of Bone Marrow Lymphocytosis as a Sign of Immunoactivation Is Associated with a Good Response to Imatinib Therapy in Patients with Chronic Myeloid Leukemia.

Abstract

In addition to potent BCR-ABL -mediated anti-leukemia effects, growing evidence suggests that imatinib mesylate (IM) also acts as an immunomodulatory agent. IM modulates both innate and adaptive immunity with impact on dendritic, NK, and T cell activation. Current data implies an immunostimulatory effect of IM, which could be a factor in the long-term control of chronic myeloid leukemia (CML). Modest increase in BM lymphocyte count has often been observed during imatinib therapy. We speculated that this increase may be related to the immunoactivation induced by IM and studied the relation of lymphocyte counts in BM aspirates to therapeutic response to IM.A total of 147 BM aspirates were studied from 28 CML patients in chronic phase and on imatinib therapy (28 diagnostic/pretreatment and 119 follow-up samples taken generally 3 monthly). The samples were analyzed blinded to the imatinib response. The patient was classified as having BM lymphocytosis if the BM lymphocyte count was above normal (>25%) in more than one BM sample during IM therapy. Patients were treated according to clinical protocols and response to treatment was assessed according to recent guidelines (Baccarani et al, 2006). Lymphocyte immunophenotyping was done from BM and peripheral blood samples, when available.The median follow-up time for IM response was 18 months. During the IM treatment 45 of 119 samples (38%) had an increase in lymphocyte count in BM aspirates, whereas only 1 of 28 (4%) samples at diagnosis had a minor increase in lymphocyte count. The increase in lymphocyte count was related to the IM therapy response; patients with good response had more often lymphocytosis in BM aspirates.Response to IMBM lymphocytosisYesNoGood (n=13 patients)9 (69%)4 (31%)Suboptimal (n=7 patients)2 (29%)5 (71%)Failure (n=8 patients)1 (13%)7 (87%)p=0.036 (Fisher's Exact test)In the good response group most patients (7/9) had an increase in lymphocyte count already at 3 months after the start of therapy and the same phenomenon usually continued throughout the therapy. In the failure and suboptimal groups the BM lymphocyte increases occurred only in sporadic samples (median value for positive lymphocytosis samples per patient was 6%, 13%, and 80% in failure, suboptimal, and good therapy response groups, respectively).Peripheral blood leukopenia was more common in the failure group (69%) compared to good (14%) and suboptimal (26%) groups, but BM samples were not hypoplastic and the blood leukocyte/lymphocyte counts were not related to BM lymphocyte counts.Preliminary data on immunophenotyping indicated that the BM lymphocytes were a mixture of T- (normal CD4/CD8 ratio), NK-, and B-cells (T-cells predominating). B-cells were polyclonal and a minor percentage of B-cells were immature (CD10 positive). In conclusion, we found a clear association between an increased BM lymphocyte count and a good IM response. In patients responding to IM, increases in BM lymphocyte count could already be seen at 3 months. The observed lymphocyte proliferation in good-responding patients may reflect the concerted action of various types of lymphocytes mediating putative immunological anti-tumor effect of IM treatment.