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Sustained major molecular response in the absence of any antileukaemic therapy after dasatinib treatment and autologous peripheral blood stem cell transplantation in a patient with imatinib-resistant myeloblastic-phase chronic myeloid leukaemia

Leukemia volume 23, pages 1158–1159 (2009)Cite this article

Dasatinib, a dual Src and abl tyrosine kinase inhibitor, has recently been approved in Philadelphia (Ph) chromosome, Ph-positive chronic myeloid leukaemia (CML) and Ph-positive acute lymphoblastic leukaemia with resistance or intolerance to imatinib mesylate.1 Until now, discontinuation of imatinib in CML patients has always been associated with further disease recurrence, except in a few patients with undetectable bcr–abl transcripts.2 For the first time, we report on a CML patient treated with dasatinib after imatinib resistance, who maintained low levels of bcr–abl transcripts despite dasatinib discontinuation.

In December 2004, a relapse of myeloblastic-phase CML occurred. Karyotype analysis revealed abnormalities identical to those observed at the time of the first blast crisis. The bcr–abl rearrangement was present in 100% of interphase cells by fluorescent in situ hydridization, and the bcr–abl/abl IS transcript ratio increased to 42% (Figure 1). A mutational analysis of the tyrosine kinase domain of abl performed by PCR and direct sequencing revealed an Y253H mutation located in the adenosine triphosphate-binding loop (P-Loop) of the bcr–abl oncoprotein that confers a high degree of resistance to imatinib.3 Imatinib was stopped and the patient was started on single-agent dasatinib at 70 mg twice daily in January 2005. The dosage of dasatinib was decreased rapidly to 50 mg twice daily due to a grade 2 pleural effusion and gastrointestinal intolerance. A complete haematological response, a normal karyotype and a major molecular response (bcr–abl/abl IS ratio ⩽0.1%) were obtained after 2 months of dasatinib treatment. After 10 months of continuous treatment, major molecular response proved to be stable with a bcr–abl/abl IS transcript ratio down to 0.04% (Figure 1). The decision was made to collect an autologous peripheral blood stem cell graft and the patient was administered with 5 μg/kg of granulocyte colony-stimulating factor twice a day for five consecutive days under dasatinib therapy. On day 5, the peripheral blood CD34+ cell concentration was 54.8/mm3. Apheresis was carried out using a Cobe Spectra cell separator (Gambro BCT, Stokholm, Sweden), and a cellular product containing 6.86 × 108 nucleated cells/kg, 5.55 × 106 CD34+ cells/kg and 173.3 × 104 granulocyte-macrophage colony-forming unit/kg was harvested and cryopreserved, the bcr–abl/abl IS ratio in the graft being 0.09%. The decision to proceed to an autologous stem cell transplantation was thus taken. Dasatinib treatment ceased at the start of the conditioning regimen consisting of intravenous busulfan and cyclophosphamide. Autologous peripheral blood stem cell transplantation was carried out in January 2006. After thawing, cell viability was 92% and the infused product contained 4.6 × 108 viable nucleated cells/kg and 4.6 × 106 viable CD34+ cells/kg. Neutrophil and platelet recovery was obtained within 17 days without any granulocyte colony-stimulating factor treatment and no severe documented infection occurred. Dasatinib was not reintroduced. At the last follow-up in June 2008, the patient remained in complete haematological response with a normal karyotype and a stable residual disease measured at 0.01%, in the absence of any tyrosine kinase inhibitor therapy (Figure 1).

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Authors and Affiliations

  1. Service des Maladies du Sang, Hôpital Saint-Louis, AP-HP, Paris, France

    D Rea, E Raffoux & H Dombret

  2. Unité de Thérapie Cellulaire, Hôpital Saint-Louis, AP-HP, Paris, France

    D Rea

  3. Laboratoire Central d’Hématologie, Hôpital Saint-Louis, AP-HP, Paris, France

    J-M Cayuela & O Maarek

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  1. D Rea
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Correspondence to D Rea.

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Rea, D., Raffoux, E., Cayuela, JM. et al. Sustained major molecular response in the absence of any antileukaemic therapy after dasatinib treatment and autologous peripheral blood stem cell transplantation in a patient with imatinib-resistant myeloblastic-phase chronic myeloid leukaemia. Leukemia 23, 1158–1159 (2009). https://doi.org/10.1038/leu.2008.376

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