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Reduction of leukemia cell burden and restoration of normal hematopoiesis at 3 months of crizotinib treatment in RAN-binding protein 2 (RANBP2)–anaplastic lymphoma kinase (ALK) acute myeloid leukemia

Leukemia volume 28, pages 1935–1937 (2014)Cite this article

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Since the ALK gene was first discovered to be rearranged with the nucleophosmin gene in anaplastic large cell lymphoma (ALCL) carrying t(2;5)(p23;q35), rearrangement of ALK has been recognized in a wide variety of tumors.1 These include non-small cell lung cancer (NSCLC), a subset of diffuse large B-cell lymphoma, inflammatory myofibroblastic tumor (IMT)2 and a small proportion of cancers that develop in the kidney, colon, breast, ovary and esophagus.1 As the rearrangements invariably generate chimeric protein that leads to activation of the ALK tyrosine kinase, molecular targeting therapy for ALK has been developed.

We tapered and stopped crizotinib for 2 weeks, and resumed it at a dose of 200 mg daily on day 35 with the intermittent administration of granulocyte colony-stimulating factor (G-CSF) (Figure 2). Around 6 weeks after the initiation of crizotinib, platelet counts began to increase. Blasts finally disappeared from the blood on day 72, and neutrophils in the blood lost their dysplastic morphology but showed a normal appearance. Bone marrow examination on day 82 of crizotinib treatment showed 10% cellularity with normal erythroid and myeloid precursors/mature cells and megakaryocytes, even though the blasts made up 1.4% of nucleated cells. There were many macrophages showing marked phagocytosis (Supplementary Figures S1d–h). The percentage of blasts with the leukemia cell phenotype determined by flow cytometry was around 1%. G-banding was normal in all 10 metaphase cells analyzed. FISH for ALK rearrangement and monosomy 7 revealed 0.8% and 2.3% positivity of >1000 and >300 nuclei of the bone marrow, respectively. Both values were below the cut-off level of each FISH test; however, large nuclei representing leukemia cells that carried ALK rearrangement or −7 remained (Figures 1b and d). The RANBP2–ALK fusion mRNA in the blood was detectable with the reverse transcriptase PCR,3 whereas the copy number of Wilms’ tumor-1 mRNA decreased below the level of detection (Supplementary Figure S2 and Supplementary Table S1). The hemoglobin level on day 96 was 8.9 g/dl with macrocytic red cells, the platelet count was 172 × 103/μl and white cell count was 2.33 × 103/μl with a normal differential. The patient was free from transfusion and the administration of G-CSF at that time (Figure 2), although she had grade 1 peripheral edema. Unfortunately, however, blasts reappeared in the blood on day 135, and the leukemia, again showing ALK rearrangement and −7 by FISH, no longer responded to an increased dose (250 mg twice daily) of crizotinib.

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Authors and Affiliations

  1. Department of Hematology, Tenri Hospital, Tenri, Japan

    Y Maesako, K Izumi, Y Kamoda, F Iioka, T Akasaka & H Ohno

  2. Tenri Institute of Medical Research, Tenri, Japan

    A Okumura, K Takeoka, C Kishimori & H Ohno

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Maesako, Y., Okumura, A., Takeoka, K. et al. Reduction of leukemia cell burden and restoration of normal hematopoiesis at 3 months of crizotinib treatment in RAN-binding protein 2 (RANBP2)–anaplastic lymphoma kinase (ALK) acute myeloid leukemia. Leukemia 28, 1935–1937 (2014). https://doi.org/10.1038/leu.2014.166

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