International Journal of Hematology

, Volume 91, Issue 5, pp 799–807 | Cite as

Clinical features of dasatinib-induced large granular lymphocytosis and pleural effusion

  • Yasunobu Nagata
  • Kazuteru OhashiEmail author
  • Shiomi Fukuda
  • Noriko Kamata
  • Hideki Akiyama
  • Hisashi Sakamaki
Original Article


During follow-up of leukocyte counts in 20 consecutive patients (age range 29–81 years) treated with dasatinib, 9 patients (7 chronic myeloid leukemia in chronic phase, 2 Philadelphia chromosome-positive acute lymphoid leukemia in complete remission) developed lymphocytosis (>3,000/μl). Peripheral blood smears revealed a population of large granular lymphocytes. Large granular lymphocytosis (LGL) was first noted between 1 and 8 months after initiation of dasatinib, and it has persisted up to 33 months from the onset of LGL in one patient. Peak numbers of large granular lymphocytes ranged from 2,915 to 17,425/μl. The occurrence of LGL might interfere with achieving molecular response (MR, real-time quantification of major BCR-ABL1 mRNA less than 50 copies/μg RNA) in our small cohort; 8 (89%) of 9 patients with LGL attained MR, while only 6 (55%) of 11 patients without LGL eventually achieved MR. With respect to the relationship between LGL and pleural effusion (PE), 3 (27%) of 11 patients without LGL developed PE, while 5 (56%) of 9 patients with LGL developed PE. Moreover, the mean peak number of LGL was 9,215/μl, which was much higher than the mean peak number (4,635/μl) of LGL in patients without PE. These results may suggest possible association of both events in our cohorts.


Dasatinib Philadelphia chromosome Adverse effects Large granular lymphocytosis Pleural effusion 



This study was supported in part by a grant for clinical cancer research from the Ministry of Health, Labor and Welfare of Japan. The authors would like to thank the nursing staff at Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, for their assistance in the collection of samples from patients included in this study. We are also grateful to the staff of the Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center at Komagome Hospital for their excellent patient care.


  1. 1.
    Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J, Paquette R, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006;354:2531–41.CrossRefPubMedGoogle Scholar
  2. 2.
    Hochhaus A, Baccarani M, Kantarjian HM, Apperley JF, Lipton JH, Goldberg SL, et al. Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia. 2008;22:1200–6.CrossRefPubMedGoogle Scholar
  3. 3.
    Lombardo LJ, Lee FY, Chen P, Norris D, Barrish JC, Behnia K, et al. Discovery of N-(2-chloro-6-methyl-phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)-thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem. 2004;47:6658–61.CrossRefPubMedGoogle Scholar
  4. 4.
    McKenzie SE, Reilly MP. The clot thickens (or not). Blood. 2009;114:1722–3.CrossRefPubMedGoogle Scholar
  5. 5.
    Khoury HJ, Guilhot F, Hughes TP, Kim DW, Cortes JE. Dasatinib treatment for Philadelphia chromosome-positive leukemias: practical considerations. Cancer. 2009;115:1381–94.CrossRefPubMedGoogle Scholar
  6. 6.
    Porkka K, Khoury HJ, Paquette RL, Matloub Y, Sinha R, Cortes JE. Dasatinib 100 mg once daily minimizes the occurrence of pleural effusion in patients with chronic myeloid leukemia in chronic phase and efficacy is unaffected in patients who develop pleural effusion. Cancer. 2010;116:377–86.CrossRefPubMedGoogle Scholar
  7. 7.
    Bergeron A, Réa D, Rousselot P, Picard C, Meignin V, Tamburini J, et al. Lung abnormalities after dasatinib treatment for chronic myeloid leukemia: a case series. Am J Respir Crit Care Med. 2007;176:814–8.CrossRefPubMedGoogle Scholar
  8. 8.
    Mustjoki S, Ekblom M, Arstila TP, Dybedal I, Epling-Burnette PK, Guilhot F, et al. Clonal expansion of T/NK-cells during tyrosine kinase inhibitor dasatinib therapy. Leukemia. 2009;23:1398–405.CrossRefPubMedGoogle Scholar
  9. 9.
    Kim DH, Kamel-Reid S, Lipton JH, Sutherland R, Jung CW, Kim HJ, et al. Natural killer or natural killer/T cell lineage large granular lymphocytosis associated dasatinib therapy for Philadelphia chromosome positive leukemia. Haematologica. 2009;94:135–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Yamamoto M, Kakihana K, Ohashi K, Yamaguchi T, Tadokoro K, Akiyama H, et al. Serial monitoring of T315I BCR-ABL mutation by invader assay combined with RT-PCR. Int J Hematol. 2009;89:482–8.CrossRefPubMedGoogle Scholar
  11. 11.
    Gruber F, Mustjoki S, Porkka K. Impact of tyrosine kinase inhibitors on patient outcomes in Philadelphia chromosome-positive acute lymphoblastic leukaemia. Br J Haematol. 2009;145:581–97.CrossRefPubMedGoogle Scholar
  12. 12.
    Wong SF. Dasatinib dosing strategies in Philadelphia chromosome-positive leukemia. J Oncol Pharm Pract. 2009;15:17–27.CrossRefPubMedGoogle Scholar
  13. 13.
    Kelly K, Swords R, Mahalingam D, Padmanabhan S, Giles FJ. Serosal inflammation (pleural and pericardial effusions) related to tyrosine kinase inhibitors. Target Oncol. 2009;4:99–105.CrossRefPubMedGoogle Scholar
  14. 14.
    Quintás-Cardama A, Kantarjian H, O’brien S, Borthakur G, Bruzzi J, Munden R, et al. Pleural effusion in patients with chronic myelogenous leukemia treated with dasatinib after imatinib failure. J Clin Oncol. 2007;25:3908–14.CrossRefPubMedGoogle Scholar
  15. 15.
    de Lavallade H, Punnialingam S, Milojkovic D, Bua M, Khorashad JS, Gabriel IH, et al. Pleural effusions in patients with chronic myeloid leukaemia treated with dasatinib may have an immune-mediated pathogenesis. Br J Haematol. 2008;141:745–7.CrossRefPubMedGoogle Scholar
  16. 16.
    Giles FJ, O’Dwyer M, Swords R. Class effects of tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia. Leukemia. 2009;23:1698–707.CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2010

Authors and Affiliations

  • Yasunobu Nagata
    • 1
  • Kazuteru Ohashi
    • 1
    Email author
  • Shiomi Fukuda
    • 2
  • Noriko Kamata
    • 3
  • Hideki Akiyama
    • 1
  • Hisashi Sakamaki
    • 1
  1. 1.Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases CenterKomagome HospitalTokyoJapan
  2. 2.Clinical Laboratory Room, Tokyo Metropolitan Cancer and Infectious Diseases CenterKomagome HospitalTokyoJapan
  3. 3.Radiology Division, Tokyo Metropolitan Cancer and Infectious Diseases CenterKomagome HospitalTokyoJapan

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