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Risk and Prognosis of Central Nervous System Leukemia in Patients with Philadelphia Chromosome-Positive Acute Leukemias Treated with Imatinib Mesylate

Departments of Hematology and Oncology, Johann Wolfgang Goethe-Universität, 60590 Frankfurt [H. P., B. W., W-K. H., M. K., U. S., P. B., A. B., N. G., D. H., O. G. O.]; Departments of Hematology and Oncology, University Carl Gustav Carus, Dresden 01307 [E. S.]; Departments of Hematology and Oncology, Evangelisches Diakonie Krankenhaus, Bremen 28239 [T. W.]; Departments of Hematology and Oncology, Albert-Ludwigs Universität, Freiburg 79106 [M. L.]; Departments of Hematology and Oncology, Robert-Bosch Krankenhaus, Stuttgart 70376 [L. L.]; and Departments of Hematology and Oncology, Novartis Pharma AG, Nürnberg 90429 [H. G.], Germany

ABSTRACT

Purpose: In patients with acute leukemias, a lymphoid phenotype, the presence of a Philadelphia chromosome (Ph), and inadequate central nervous system (CNS)-directed prophylactic therapy are risk factors for CNS involvement. Imatinib mesylate has promising single-agent antileukemic activity in patients with advanced Ph⁺ acute leukemias. It was the aim of this analysis to determine the incidence of, and risk factors associated with, meningeal leukemia during imatinib monotherapy.

Study design: We analyzed 107 consecutive patients with relapsed or refractory Ph⁺ acute lymphoid leukemia (ALL; n = 65) or chronic myeloid leukemia blast crisis (n = 42) who were enrolled in successive Phase II trials of single-agent imatinib and who did not receive routine prophylactic intrathecal chemotherapy.

Results: CNS leukemia developed in 13 of 107 patients (12%) and was associated primarily with a lymphoid or bilineage phenotype (12 of 78; 15%) and with imatinib refractory Ph⁺ ALL (5 of 19; 26%). Meningeal leukemia did not occur among patients who received prior prophylactic cranial irradiation. The median survival with combined CNS and systemic disease was 108 days (range, 58–141), with no patient surviving long term. In contrast, two of three patients with exclusively meningeal leukemia achieved prolonged molecular remissions with intrathecal chemotherapy, cranial irradiation, and continued imatinib.

Conclusions: Patients with Ph⁺ ALL are at considerable risk of meningeal leukemia during imatinib monotherapy and should routinely receive CNS prophylaxis. Although the prognosis with combined meningeal and systemic relapse is dismal, patients with an isolated meningeal relapse may still achieve sustained remissions. The optimal type of CNS-directed treatment and the extent of protection afforded by prophylactic cranial irradiation remain to be defined.

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