Lymphoid Foci in Bone Marrow of Patients with Chronic Myeloid Leukaemia Treated with Imatinib.

Imatinib treatment of CML is successful but long term. In spite of reported inhibition of T lymphocyte proliferation and activation, we noticed multiple lymphoid foci occurring in BM trephines from CML patients on Imatinib.

Method: Patients with chronic phase CML were monitored with BM biopsies (generally 3 monthly) for 1 to 4 years on Imatinib (34 patients) and for 1.5 to 12 years on Interferon (22 patients). Three hundred and thirty-one trephine biopsies were assessed for the occurrence of lymphoid foci. Selected trephines with foci on recut sections were examined by immunocytochemistry with CD3 and CD20, and available aspirates were tested by flow cytometry and PCR for evidence of monoclonality.

Results: Lymphoid foci in bone marrow trephines of patients with CML chronic phase occurred more frequently in Imatinib-treated patients (28/34 patients; 82%) than in Interferon-treated patients (9/22 patients; 41%) (p =0.001). Of 175 trephine biopsies from Imatinib-treated patients 68 (39%) contained lymphoid foci, compared to 18 of 156 (12%) trephines from Interferon-treated patients (p= 0.001). In 13/34 Imatinib-treated patients the BM trephine was positive on only one occasion, with 15/34 having multiple positive biopsies. In comparison BM trephine biopsies from random patients with various diagnoses have been described to have lymphoid foci in 3% of cases (Thiele et al, J Clin Pathology 1999,52,294). The majority of foci were interstitial but there were occasional paratrabecular foci. There was no difference between the incidence of foci in Imatinib-treated patients who had previously been treated with Interferon (11/14) and those who had Imatinib as first-line therapy (17/20). Lymphocyte numbers in BM aspirates were above normal in 32/175 aspirates and not coincident with the presence of foci in the corresponding trephines.

Foci in the trephines examined by immunocytochemistry showed that the foci were a mixture of CD3 and CD20 positive cells. Flow cytometric immunophenotyping of available BM aspirates of patients with lymphoid foci showed no monoclonality, apart from 1 patient who developed monoclonal Non-Hodgkins lymphoma confined to the bone marrow during treatment with Imatinib. Only 2 patients had foci present at diagnosis of CML and one of these Imatinib-treated patients was the one who later developed NHL. Response to treatment as assessed by cytogenetic response could not be correlated with the development of lymphoid foci in the BM during treatment, as all Imatinib treated patients achieved complete cytogenetic remission. However patients with multiple positive trephine biopsies showed a trend (p=0.095) towards better molecular response as measured by a greater than 4 log reduction in BCR/ABL (8/14) than those with no lymphoid foci (1/6).

Conclusion: Lymphoid foci occur frequently in the BM trephines of Imatinib- treated chronic phase CML patients; more commonly than in Interferon-treated CML patients. Both these patient groups have a higher number of lymphoid foci than is reported in random BM biopsies. This finding seems in contradiction to in vitro findings of Inatimib suppression of lymphocytic activation and proliferation. The occurrence of multiple foci suggests that the BM trephines and aspirates should continue to be monitored in Imatinib-treated patients. This early data also suggests that there may be a correlation of molecular response to Imatinib with the development of multiple lymphoid foci in the bone marrow.