Article

International Journal of Hematology

, 80:62

First online:

Existence of Leukemic Clones Resistant to Both Imatinib Mesylate and Rituximab before Drug Therapies in a Patient with Philadelphia Chromosome-Positive Acute Lymphocytic Leukemia

  • Takaaki HatoAffiliated withDivision of Blood Transfusion, Ehime University School of Medicine Email author 
  • , Jun YamanouchiAffiliated withDepartments of Internal Medicine 1, Ehime University School of Medicine
  • , Tatsushiro TamuraAffiliated withDepartments of Internal Medicine 1, Ehime University School of Medicine
  • , Norimasa HojoAffiliated withDepartments of Internal Medicine 1, Ehime University School of Medicine
  • , Yasunari NiiyaAffiliated withDepartments of Internal Medicine 1, Ehime University School of Medicine
  • , Masashi KohnoAffiliated withDepartments of Internal Medicine 1, Ehime University School of Medicine
  • , Shiro BandoAffiliated withDepartments of Laboratory Medicine, Ehime University School of Medicine
  • , Yoshihiro YakushijinAffiliated withDepartments of Internal Medicine 1, Ehime University School of Medicine
  • , Kiyonori TakadaAffiliated withDepartments of Internal Medicine 1, Ehime University School of Medicine
    • , Ikuya SakaiAffiliated withDepartments of Internal Medicine 1, Ehime University School of Medicine
    • , Masaki YasukawaAffiliated withDepartments of Internal Medicine 1, Ehime University School of Medicine
    • , Shigeru FujitaAffiliated withDepartments of Internal Medicine 1, Ehime University School of Medicine

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Abstract

Imatinib mesylate and rituximab are molecularly targeted drugs against the BCR-ABL fusion protein and the CD20 antigen, respectively. Although these drugs have excellent anticancer effects, a major concern is drug resistance. We have investigated the case of a patient with Philadelphia chromosome-positive and CD20+ acute lymphocytic leukemia who acquired resistance to imatinib and rituximab. Imatinib therapy resulted in prompt cytogenetic remission, but resistance developed shortly thereafter. Sequencing of the kinase domain of the ABL gene and allele-specific polymerase chain reaction analysis revealed a point mutation resulting in an E255V substitution that was present before the therapy. After the patient received mild chemotherapy followed by rituximab administration, hematologic and cytogenetic remission was sustained for 5.5 months. The recurrent leukemic cells after the rituximab therapy showed not only the E255V mutation in the ABL gene but also loss of the CD20 antigen due to impaired transcription of the CD20 gene. The results of 2-color flow cytometry analysis showed that a small population of CD20- leukemic cells existed before the imatinib therapy. These results suggest that leukemic subclones carrying a genetic perturbation of the targeted molecules for both imatinib and rituximab were present before the therapies. The preexistence of primary resistant clones suggests the inability of combination therapy with 2 molecularly targeted drugs to overcome drug resistance in leukemia.

Key words

Imatinib mesylate Rituximab Resistance Acute lymphocytic leukemia t(1:9)(q21:p13)