Correspondence

Complete Molecular Remission in Chronic Myelogenous Leukemia after Imatinib Therapy

N Engl J Med 2002; 347:539-540August 15, 2002

Article

To the Editor:

The tyrosine kinase inhibitor imatinib mesylate specifically inhibits the BCR-ABL kinase, and has shown promising results in phase 1 and 2 trials in patients with chronic myelogenous leukemia at various stages of the disease.1,2 We describe a patient in whom a complete molecular response was achieved with no evidence of BCR-ABL messenger RNA (mRNA) six months after treatment with imatinib began.

A 58-year-old man with Philadelphia chromosome (Ph)–positive chronic myelogenous leukemia in chronic phase was initially treated with interferon alfa followed by intensive chemotherapy plus granulocyte colony-stimulating factor, which allowed the successful collection of Ph-negative blood stem cells. Subsequently, he underwent autologous blood stem-cell transplantation. Thirty-four months after transplantation, a cytogenetic relapse (35 percent Ph-positive cells in metaphase) was detected in a routine bone marrow examination, although the bone marrow was morphologically normal. Treatment with 3 million units of interferon alfa once daily was reinstated but had to be discontinued after five months because of side effects (depression) with no signs of a cytogenetic response. Treatment with 400 mg of imatinib once daily was initiated. Three months after imatinib therapy began, the patient had a complete cytogenetic response as well as a molecular response in peripheral blood (Table 1Table 1Cytogenetic and Molecular Follow-up Data.).3 In subsequent studies, performed 6, 8, 12, and 14 months after the initiation of imatinib therapy, the patient had no detectable disease in the bone marrow or peripheral blood (Table 1). The patient had no side effects attributable to imatinib.

We describe a sustained, complete molecular remission, as defined by repeatedly negative results on real-time quantitative polymerase chain reaction (RQ-PCR) for BCR-ABL mRNA after treatment with imatinib. Occasional case reports of isolated negative results on PCR have been published, but missing information on expression of a reference gene prevents evaluation of the sensitivity of the PCR assay used on those particular samples.2,4 Preliminary evidence suggests that patients with chronic myelogenous leukemia who have a complete cytogenetic response after short-term treatment with imatinib still have detectable amounts of BCR-ABL transcripts in peripheral blood.5 At the time imatinib therapy began, our patient had had a purely cytogenetic relapse after autologous blood stem-cell transplantation.

Ongoing studies with a large number of patients and with longer follow-up will determine the prognostic importance of molecular remission after imatinib therapy. In the meantime, it can be asked whether treatment with imatinib should be interrupted after molecular remission has been achieved and whether the patient should then be monitored by RQ-PCR for BCR-ABL mRNA. Although imatinib is well tolerated in most cases, the drug is expensive and carries an inherent risk of development of drug resistance.

Gisela Barbany, M.D., Ph.D.
Martin Höglund, M.D., Ph.D.
Bengt Simonsson, M.D., Ph.D.
University Hospital, 751 85 Uppsala, Sweden
gisela.barbany@medsci.uu.se

for the Swedish CML Group

5 References

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   M Suttorp. (2008) Innovative approaches of targeted therapy for CML of childhood in combination with paediatric haematopoietic SCT. Bone Marrow Transplantation 42, S40-S46
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   Jerald P Radich, Eduardo Olavarria, Jane F Apperley. (2004) Allogeneic hematopoietic stem cell transplantation for chronic myeloid leukemia. Hematology/Oncology Clinics of North America 18:3, 685-702
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