The Association Of Dasatinib-Induced Lymphocytosis With Treatment Outcome In Patients With Chronic Myeloid Leukemia (CML)
Authors: Schiffer Charles A. , Cortes Jorge E. , Saglio Giuseppe , le Coutre Philipp D. , Porkka Kimmo , Mustjoki Satu , Mohamed Hesham , Shah Neil P. 
Published: October 2019

Abstract

Background
Clonal proliferation of T/NK cells has been noted after the treatment of CML patients with dasatinib. Previous reports have suggested that persistent expansion of clonal cytotoxic T cells or NK cells in dasatinib-treated patients may be associated with higher response rates and increased occurrence of pleural effusions. This retrospective study analyzed the incidence of lymphocytosis and its association with response, progression-free survival (PFS) and overall survival (OS), and pleural effusion in a large sample of dasatinib-treated patients.

Methods
Analyses were conducted using dasatinib-treated patients from three large studies with ≥3 years of follow-up: CA180-056 (DASISION), which included 258 dasatinib-treated patients with newly diagnosed CML in chronic phase (CML-CP); CA180-034, which included 662 dasatinib-treated patients with CML-CP who were previously treated with imatinib; and CA180-035, which included 316 dasatinib-treated patients with CML in accelerated phase (CML-AP) and 148 dasatinib-treated patients with CML in myeloid blast phase (CML-MBP) who were previously treated with imatinib.

Results
Lymphocytosis, as defined by ≥2 consecutive lymphocyte counts > 3600/µl after 28 days of treatment, was present in 33% of patients (85/258) with newly diagnosed CML-CP in DASISION (median time to onset, 4.6 months) and 31% of patients (206/662) with imatinib-resistant or -intolerant CML-CP in CA180-034 (median time to onset, 3.0 months). The median on-treatment follow-up times were 36.8 months and 29.3 months for DASISION and CA180-034, respectively. For CA180-035, the median on-treatment follow-up time was 6.1 months, and lymphocytosis developed in 35% of patients (110/316) with CML-AP and 34% of patients (51/148) with CML-MBP. Lymphocytosis persisted for >12 months in 64% of patients (54/85) with newly diagnosed CML-CP, in 52% of patients (107/206) with imatinib-resistant or -intolerant CML-CP, in 42% (46/110) with CML-AP, and in 18% (9/51) with CML-MBP. The proportion of newly diagnosed patients with complete cytogenetic response (CCyR) or major molecular response (MMR) at any time was higher among those with vs. without lymphocytosis: 89% (76/85) vs. 80% (138/173) for confirmed CCyR and 74% (63/85) vs. 67% (116/173) for MMR. Patients who developed lymphocytosis during treatment with second-line dasatinib were more likely to achieve CCyR, regardless of disease phase; the proportion of patients who achieved CCyR with vs. without lymphocytosis was 62% (127/206) vs. 49% (222/456) for CML-CP, 46% (51/110) vs. 27% (55/206) for CML-AP, and 31% (16/51) vs. 14% (14/97) for CML-MBP. In landmark analyses of patients with CML-CP in DASISION who were still on first-line dasatinib at 3 or 8 months, lymphocytosis status did not significantly affect PFS or OS. Similar results were found in the second-line studies, when considering patients with CML-CP, -AP, or -MBP who were still on study treatment (second-line dasatinib) at 3 months. Pleural effusions (all grades) developed more often in newly diagnosed patients with lymphocytosis (28% [24/85] vs. 16% [27/173] without lymphocytosis) and in imatinib-resistant or -intolerant patients with CML-CP (38% [79/206] vs. 30% [136/456]) or CML-AP (53% [58/110] vs. 31% [64/206]). The proportion of patients with CML-MBP developing pleural effusions was 27%, regardless of the presence of lymphocytosis (14/51 with lymphocytosis and 26/97 without lymphocytosis).

Conclusions
Lymphocytosis develops very commonly after treatment with dasatinib and persists for >1 year in an appreciable fraction of patients. Immunophenotyping was not done, but it can be presumed that this represents a large granular lymphocyte proliferation in most patients, based on other studies. Lymphocytosis was associated with higher CCyR rates in all stages of CML, as well as higher rates of pleural effusions in CML-CP and -AP. Lymphocytosis was also associated with higher MMR rates in patients with CML-CP receiving first-line dasatinib. There appears to be no significant association, however, between lymphocytosis and PFS or OS in this analysis. Prospective studies are warranted to more carefully characterize the functional activity of these cells and to help assess whether an immunologic effect against CML is detectable in some patients, particularly advanced phase patients with unexpected long responses to treatment with dasatinib alone.

Disclosures:
Schiffer: Novartis: Consultancy, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Teva: Consultancy; Eisai: Consultancy; Ariad: Research Funding; Pfizer: Research Funding. Cortes:Ariad: Consultancy, Grant to institution Other, Honoraria; BMS: Grant to institution, Grant to institution Other; Novartis: Grant to institution, Grant to institution Other; Pfizer: Consultancy, Grant to institution, Grant to institution Other, Honoraria; Teva: Consultancy, Grant to institution Other, Honoraria; Tragara: Membership on an entity’s Board of Directors or advisory committees; Ambit: Grants/grants pending for institution Other; Astellas: Grants/grants pending for institution, Grants/grants pending for institution Other; Incyte: Grants/grants pending for institution, Grants/grants pending for institution Other; Arog: Grants/grants pending for institution Other; Celgene: Grants/grants pending for institution, Grants/grants pending for institution Other; sanofi: Grants/grants pending for institution, Grants/grants pending for institution Other. Saglio:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. le Coutre:Novartis: Honoraria, Research Funding; BMS: Honoraria; Pfizer: Honoraria. Porkka:BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Mustjoki:BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Mohamed:BMS: Employment, Stock/stock options; travel/accommodations/meeting expenses unrelated to activities listed Other. Shah:BMS: Consultancy, Grants/grants pending to institution for costs related to clinical research Other; Ariad: Consultancy, Grants/grants pending to institution for costs related to clinical research, Grants/grants pending to institution for costs related to clinical research Other.