In the Journals

Incidence of lymphocytosis linked to higher dasatinib response rate in CML

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June 14, 2016

Lymphocytosis occurs in approximately one-third of patients with chronic myeloid leukemia treated with dasatinib and is associated with longer duration of response and improved OS and PFS, according to study results published in Cancer.

“We demonstrate . . . that lymphocytosis commonly occurs after treatment with dasatinib [Sprycel; Bristol-Myers Squibb, Otsuka], but not imatinib [Gleevec, Novartis],” Charles A. Schiffer, MD, professor of medicine and oncology and the leader of the multidisciplinary leukemia/lymphoma group at the Barbara Ann Karmanos Cancer Institute at Wayne State University in Detroit, and colleagues wrote. “Lymphocytosis develops in a minimum of 32% of patients and persists for 1 year or more in at least 50% of such patients.”

Charles Schiffer

Charles A. Schiffer

Preclinical analyses have shown dasatinib inhibits lymphocyte proliferation and function without inducing apoptosis. However, small studies of CML also have shown initiation of dasatinib therapy leads to clonal expansion of cytotoxic T cells and natural killer cells, which has been associated with higher-than-expected response rates.

To further evaluate the association between the development of lymphocytosis and initial response, long-term outcome and the development of pleural effusions, Schiffer and colleagues retrospectively analyzed data from 1,402 dasatinib-treated patients (median age, 46-56 years) from three phase 3 clinical trials.

The data from these trials included:

  • 5-year, long-term data from patients newly diagnosed with CML in chronic phase (CML-CP) treated with dasatinib or imatinib in the DASISION trial;
  • 7-year, long-term data from patients with resistant CML-CP or who were intolerant of imatinib in a dose-optimization trial (CA180-034); and
  • 5-year, long-term data from patients with CML in accelerated phase (CML-AP) or CML in myeloid-blast phase (CML-MBP) who were resistant to, or intolerant of, imatinib in a dose-optimization trial for advanced-phase CML (CA180-035).

Across the three studies, the baseline median lymphocyte counts ranged from 1.7 x 109/L to 3 x 109/L.

The cumulative incidence of lymphocytosis — defined as lymphocyte counts greater than 3.6 x 109/L on two or more consecutive occasions after 28 treatment days — ranged from 32% to 35% and appeared comparable across all phases of CML.

In the DASISION trial, more patients treated with dasatinib than imatinib experienced lymphocytosis (35% vs. 8%), and the occurrence of lymphocytosis in imatinib-treated patients appeared transient.

The median time to lymphocytosis detection after dasatinib initiation was 3 to 5 months, but the duration of lymphocytosis ranged from 1.4 months to 33.8 months across the different phases of CML. Lymphocytosis persisted for 12 months or longer in 52% to 77% of patients with CML-CP.

Lymphocytosis appeared associated with statistically significantly higher rates of complete cytogenetic response in all phases of CML, including newly diagnosed CML-CP (P = .0166), resistant/intolerant CML-CP (P = .0011), CMP-AP (P = .0004) and CML-MBP (P = .003).

Data also showed significantly increased rates of major molecular response (MMR) and molecular response (MR) associated with lymphocytosis among patients newly diagnosed with CML-CP (MMR, P = .0438; MR P = .0253) and among imatinib-resistant or -intolerant patients (MMR, P = .0010; MR, P = .0068).

PFS (P = .0110) and OS (P = .0349) were significantly longer in patients with lymphocytosis from the CA180-034 trial, which had the longest follow-up. However, researchers observed no significant difference in PFS or OS in patients with more advanced phases of CML, irrespective of lymphocytosis.

Researchers also evaluated pleural effusion, a common nonhematologic toxicity associated with dasatinib that has been linked to elevated T-cell and natural killer lymphocytes.

Pleural effusion occurred in more patients with than without lymphocytosis, regardless of the phase of CML. Specifically, the incidence of pleural effusion was significantly more common in patients with CML-AP (P = .0003).

The researchers acknowledged that the lymphocytosis definition used in the study may have led to an underestimation of the incidence rate. Still, despite this limitation, the results clearly show a correlation between dasatinib and lymphocytosis, pleural effusion, OS, PFS and response rate in respective cases of CML, according to the researchers.

However, the pharmacological mechanism that causes this association remains unclear.

“Lymphocytosis has not been noted after CML treatment with other TKIs, and we convincingly confirm this observation here through analysis of patients with CML-CP who were treated on a randomized study of dasatinib versus imatinib,” researchers wrote. “... Lymphocytosis occurs frequently with dasatinib treatment, persists for 1 year or more and is associated with higher response rates, increased PFS and OS in patients with CML-CP who are refractory to, or intolerant of, imatinib and the development of pleural effusions.” – by Nick Andrews

Disclosure: The study was funded by Bristol-Meyers Squibb. Schiffer reports consultant roles with and received institutional research funding from Bristol-Meyers Squibb, Celgene, Cephied, MEI Pharma, Micromedix, Novartis, Onconova, Pfizer, Pharmacyclics, Takeda and Teva. Other study researchers report consultant roles with; stock/other ownership interest in; and honoraria, research funding and travel compensation from Bristol Meyers Squibb; however, no researcher received financial compensation from Bristol-Myers Squibb for writing this article. Please see the study for a full list of the researchers’ relevant financial disclosures.

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