Lymphocytosis Following First-Line Treatment for CML In Chronic Phase with Dasatinib Is Associated with Improved Responses: A Comparison with Imatinib

Persistent expansion of clonal cytotoxic T cells or NK cells has been described in patients with chronic myeloid leukemia (CML) and Ph+ acute lymphoblastic leukemia (ALL) receiving dasatinib. These small studies have suggested a relationship between the development of T/NK lymphocytosis with both toxicity and improved response. A recent analysis of CML patients who were resistant to or intolerant of imatinib indicated that lymphocytosis occurs in ∼30% of patients in all stages of CML after treatment with dasatinib (Schiffer 2010 ASCO abstract #6553). In addition, lymphocytosis was associated with improved cytogenetic response and an increased incidence of pleural effusions. The DASISION study (CA180-056) compared dasatinib with imatinib in patients with newly diagnosed, previously untreated chronic phase CML. This subanalysis of the DASISION data was undertaken to determine the safety profile, responses, and outcomes in those patients with sustained lymphocytosis.

Patients enrolled in the DASISION study were retrospectively evaluated for lymphocytosis (N=516). Lymphocytosis was defined as lymphocytes >3.6 × 10⁹/L on ≥2 occasions after 28 days of treatment. Immunophenotyping was not done as part of these studies. Rates of major cytogenetic response (MCyR) and complete cytogenetic response (CCyR), overall survival (OS), progression-free survival (PFS), and adverse events (AEs) were measured in those with and without lymphocytosis. The median follow-up was 14.0 and 14.3 months for dasatinib and imatinib, respectively.

Lymphocytosis occurred more frequently and sooner in patients treated with dasatinib compared with imatinib (23.6% vs 5.4% and 3.0 months vs 4.7 months, respectively). Dasatinib-treated patients who developed lymphocytosis had lower baseline Hasford risk scores, whereas imatinib-treated patients who developed lymphocytosis had high Hasford risk scores. In the presence or absence of lymphocytosis, MCyR and CCyR occurred more frequently with dasatinib as compared with imatinib. In dasatinib treated patients, lymphocytosis was associated with a higher MCyR rate (91.8% with vs 83.3% without) and CCyR rate (83.6% with vs 75.1% without). In imatinib-treated patients, lymphocytosis was associated with a lower MCyR rate (50.0% with vs 82.8% without) and CCyR rate (50.0% with vs 69.7% without). Patients with lymphocytosis, compared with those without it, had higher rates of pleural effusion (any grade) on dasatinib (18.0% vs 7.6%, respectively). Only 1 patient treated with imatinib, who did not have lymphocytosis, experienced pleural effusion. Dasatinib-treated patients with lymphocytosis, compared with those without it, had higher rates of fatigue (16.4% vs 9.1%,); this trend was reversed for imatinib-treated patients (7.1% vs 11.9%). Patients with lymphocytosis, compared with those without it had lower rates of myalgias and arthralgias (all grades) on both the dasatinib arm (11.5% vs 18.8%) and the imatinib arm (7.1% vs 24.2%).

Lymphocytosis occurred much more frequently and sooner in patients treated with dasatinib than with imatinib. Lymphocytosis was associated with improved responses (MCyR and CCyR) in dasatinib-treated patients. An apparent inverse relationship was observed in imatinib-treated patients, although the number of patients with lymphocytosis was small. It remains to be determined how lymphocytosis, baseline Hasford risk score, and response are correlated. It is possible that some of the antileukemic effects of dasatinib are produced by an immunomodulatory mechanism. Lymphocytosis in dasatinib-treated patients was associated with an increased rate of pleural effusion and a possible decrease in myalgias and arthralgias. Longer follow-up is needed to assess whether lymphocytosis has an effect on PFS.

Schiffer:Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Cellgenix: Consultancy; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding. Cortes:Bristol-Myers Squibb: Research Funding. Saglio:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. le Coutre:Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria. Guilhot:Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Bahceci:Bristol-Myers Squibb: Employment. Dejardin:Bristol-Myers Squibb: Employment. Shah:Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Ariad: Consultancy.