The Incidence of Pleural Effusion on Dasatinib Treatment Is Associated with CD56 Positive Cell Values One Month after Commencing Dasatinib and Achievement of an Early Molecular Response in Newly Diagnosed Chronic Myeloid Leukemia Patients: Results of a D-First Study
Authors: Iriyama Noriyoshi , Fujisawa Shin , Hagihara Maki , Yoshida Chikashi , Wakita Hisashi , Chiba Shigeru , Okamoto Shinichiro , Kimihiro Kawakami , Takezako Naoki , Kumagai Takashi , Inokuchi Koiti , Ohyashiki Kazuma , Taguchi Jun , Yano Shingo , Igarashi Tadahiko , Kouzai Yasuji , Morita Satoshi , Sakamoto Junichi , Sakamaki Hisashi 
Published: November 2019

Abstract

Background: The introduction of the tyrosine kinase inhibitor (TKI) imatinib has dramatically improved the outcomes for patients diagnosed with chronic myeloid leukemia (CML). Furthermore, second-generation TKIs nilotinib and dasatinib, approved as initial treatment agents for patients with chronic myeloid leukemia-chronic phase (CML-CP), are now available clinically. Although the DASISION study demonstrated that in comparison to imatinib treatment dasatinib significantly improves both the major molecular response (MMR) and complete molecular response (CMR) rates; there remains serious concern about the adverse effects associated with it such as pleural effusion (PE). Further, the clinical significance of the mechanism underlying the development of PE is still elusive, especially in the upfront setting. Thus, we analyzed the clinical significance of PE incidence and the association of immunoprofiles based on records derived from the prospective D-First study (ClinicalTrials.gov NCT01464411). The present study sought to investigate the efficacy and safety profile of dasatinib treatment (100 mg QD) among newly diagnosed CML-CP patients in Japan.
Patients and Methods: Fifty-two patients with newly diagnosed CML-CP were enrolled in the study. All patients in the present study were followed for at least 18 months. Chest radiographs, and molecular assessments for detecting and quantifying BCR-ABL transcript levels, were performed routinely (at 1, 3, 6, 9, 12, 15, and 18 months) after initiation of dasatinib treatment. An MMR was defined as <731 copies/μg RNA of real-time quantitative polymerase chain reaction (RQ-PCR) value (equivalent to BCR-ABLIS <0.1%). A CMR was defined by an undetectable value of RQ-PCR (<50 copies/μg RNA, equivalent to BCR-ABLIS <0.0069%). A single case with an undetectable BCR-ABL transcript level was excluded from the molecular assessment results. Pearson’s chi-squared test and Student’s t-test were used to compare differences between the two groups. Receiver operating characteristic (ROC) curves were generated to investigate the correlation of factors and to determine optimal threshold values. Statistical analyses were performed using JMP software, version 11 (SAS Institute Inc., Cary, NC, USA).
Results: Of the patients enrolled into the study, 17 (33%) developed PE but all were moderate (Grade 1, 10 and Grade 2, 7). In examining patients at diagnosis with or without PE (PE+ or PE-), a significant difference was observed by patient age (median 63 and 41 years, P = 0.00075); however other characteristics including sex, Sokal risk, BCR-ABL transcript value, body weight, or performance status, did not differ. The MMR rate by 3 months in the PE+ group was significantly higher than that in the PE- group (59% vs 24%, P = 0.013); however, the MMR rates by 12 months and CMR rates by 18 months did not differ by group (MMR rates 82% vs 74%, P = 0.48; CMR rates 71% vs 53%, P = 0.23). Because the incidence of PE was associated with an early response to dasatinib, we investigated the immunoprofiles of patients at 1, 2, and 3 months after treatment with dasatinib according to the presence or absence of PE by 18 months. We found that the lymphocyte value at 1 month significantly affected the incidence of PE by 18 months (area-under-the-curve [AUC] 0.64, 48% vs 21% in lymphocytes ≥1,550/μL and <1,550/μL groups, P = 0.038, odds ratio 3.51, 95% confidence interval [CI] 1.04–11.8). According to immunoprofile, the value of CD56-positive cells at 1 month was more significantly associated with the incidence of PE (AUC 0.65, 50% vs 25% in CD56+ cells ≥427/μL and <427/μL groups, P = 0.026, odds ratio 4.00, 95% CI 1.14–14.0) than that of CD3+/CD8+ cells (AUC 0.56, 45% vs 23% in CD3+/CD8+ cells ≥360/μL and <360/μL groups, P = 0.108, odds ratio 2.69, 95% CI 0.79–9.12).
Conclusion: The incidence of PE on dasatinib treatment is associated with advanced patient age, lymphocyte value at 1 month (especially in the CD56-positive fraction), and achievement of an early molecular response. These results suggest that the incidence of PE until 18 months may be due to an immune-mediated mechanism involving NK-cells, with the underlying mechanism contributing to a transient tumor decline that is probably not retained over a long period in patients newly diagnosed with CML-CP.

Disclosures
Iriyama: Bristol: Honoraria. Yoshida:Bristol: Honoraria. Chiba:Bristol: Honoraria. Ohyashiki:Bristol: Honoraria. Morita:Bristol: Honoraria. Sakamaki:Bristol: Honoraria, Research Funding.