Carlson, Robert H.
ORLANDO, FL—A subanalysis of the Phase III DASISION study reported here at the ASH Annual Meeting has shown that patients with chronic myeloid leukemia in chronic phase (CML-CP) treated with the second-generation tyrosine kinase inhibitor dasatinib develop lymphocytosis much more frequently and sooner than patients treated with imatinib (Abstract 358).
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But it also showed that patients receiving dasatinib who developed lymphocytosis had higher rates of cumulative complete cytogenetic response and major cytogenetic response at 12 months compared with both those receiving imatinib and the dasatinib group who did not develop lymphocytosis.
The dasatinib 100 mg study arm included 258 patients, 24% (61) of whom developed lymphocytosis. That compared with only about 5% (14) of the 258 patients in the imatinib 400 mg arm, reported lead author Charles A. Schiffer, MD, Professor of Medicine and Oncology and Head of the Multidisciplinary Leukemia/Lymphoma Team at the Barbara Ann Karmanos Cancer Institute, Wayne State University.
Lymphocytosis also occurred sooner in patients treated with dasatinib compared with imatinib, he said, 3.0 versus 4.7 months, respectively.
In the dasatinib-treated patients, lymphocytosis was associated with a higher cumulative major cytogenetic response rate (92% of patients with lymphocytosis vs 83% without) and a higher cumulative complete cytogenetic response rate (84% of patients with lymphocytosis vs 75% without).
In the imatinib-treated patients, lymphocytosis was associated with a lower cumulative major cytogenetic response rate (50% of patients with lymphocytosis vs 83% without) and a lower cumulative complete cytogenetic response rate (50% of patients with lymphocytosis vs 70% without).
At 12 months, 82% (50 of 61) of dasatinib patients who had lymphocytosis and were still on treatment had a complete cytogenetic response, as did 73% (143 of 197) of dasatinib patients without lymphocytosis still on treatment.
In contrast, at 12 months, 50% (seven of 14) imatinib patients still on treatment who had lymphocytosis had complete cytogenetic responses, as did 66% (160 of 244) imatinib patients still on treatment who did not have lymphocytosis.
Possible Immunomodulatory Mechanism
In an interview after his presentation, Dr. Schiffer said data from this and other studies suggest a relationship between the development of T/NK lymphocytosis and both toxicity and improved response.
“It is possible that some of the antileukemic effects of dasatinib are produced by an immunomodulatory mechanism”—most likely NK cell proliferation, he said, noting that persistent expansion of clonal cytotoxic T cells or NK cells has been described in patients with CML and Ph+ ALL receiving dasatinib.
Dr. Schiffer said dasatinib-treated patients who developed lymphocytosis had lower baseline Hasford risk scores, whereas imatinib-treated patients who developed lymphocytosis had high Hasford risk scores. It remains to be determined, he said, how lymphocytosis, baseline Hasford risk score and response are correlated in newly diagnosed CML-CP.
And longer follow-up is needed to assess whether lymphocytosis has an effect on progression-free survival, he said.
The DASISION trial (CA180-056), comparing dasatinib with imatinib in patients with newly diagnosed, previously CML-CP, showed that first-line dasatinib was associated with significantly higher and faster response rates than imatinib (Kantarjian et al: NEJM 2010;362:2260-2270).
Lymphocytosis was defined as a lymphocyte count greater than 3.6 x 109/L on two or more occasions after 28 days of treatment.
In an earlier study by Dr. Schiffer, reported at the 2010 ASCO Annual Meeting (Abstract 6553) of CML patients resistant to or intolerant of imatinib, lymphocytosis occurred in approximately 30% of patients in all stages of CML after second-line treatment with dasatinib.
The incidence and development pattern of lymphocytosis in that study were identical to this DASISION subanalysis, Dr. Schiffer noted.
“There could be an important immunomodulatory effect, and we have to pick up on this and study it carefully. It‘s very exciting—anything that happens 30% of the time is a big deal.”
Other Adverse Events
In the subanalysis, patients with lymphocytosis, compared with those without it, had higher rates of any grade pleural effusion on dasatinib, 18.0% vs 7.6%, respectively. Only one patient treated with imatinib who did not have lymphocytosis experienced pleural effusion.
Dasatinib-treated patients with lymphocytosis, compared with those without it, also had higher rates of fatigue (16.4% vs 9.1%,), but this trend was reversed for imatinib-treated patients (7.1% vs 11.9%).
And patients with lymphocytosis, compared with those without it, had lower rates of all grades of myalgias and arthralgias on both the dasatinib arm (11.5% vs 18.8%) and the imatinib arm (7.1% vs 24.2%).
© 2011 Lippincott Williams & Wilkins, Inc.