Crizotinib treatment for refractory pediatric acute myeloid leukemia with ran-binding protein 2-anaplastic lymphoma kinase fusion gene

Crizotinib is an anaplastic lymphoma kinase (ALK) inhibitor, which has brought marked clinical benefits to patients with adult non-small cell lung cancer with _ALK_ rearrangement.1 The _ALK_

gene is located on chromosome 2p23 and its rearrangements with variable fusion partners have been identified in various malignant diseases such as anaplastic large cell lymphoma,

inflammatory myofibroblastic tumors and neuroblastoma.2 The potential efficacy of crizotinib for these diseases has been reported.2, 3, 4 Myeloid neoplasms with _ALK_ rearrangement are

uncommon but several reports indicate that crizotinib is effective for these diseases.5, 6 The efficacy of an ALK inhibitor on leukemia cells with _ALK_ rearrangement has been shown _in

vitro_.6 Furthermore, crizotinib reduced leukemia cells in acute myeloid leukemia (AML) with _ALK_ rearrangement.5 Here we report a pediatric patient with relapsed and refractory AML with

RAN-binding protein 2 (_RANBP2_)-_ALK_ fusion with monosomy 7, who achieved complete remission (CR) after treatment with crizotinib and allogeneic hematopoietic cell transplantation

(allo-HCT). A previously healthy 2-year-old female developed fatigue and a respiratory disorder. Her blood tests showed marked leukocytosis and anemia, and she was referred to our

department. Her laboratory results were as follows: hemoglobin level 3.5 g/dl, platelet count 10 × 103/μl and leukocyte count 159 × 103/μl with 39% blast cells. A bone marrow aspirate showed

hypercellularity with leukemia cells. The patient was diagnosed as acute myelomonocytic leukemia. The karyotype determined by G-banding was 45,XX,inv(2)(p23q13), which indicates _ALK_

rearrangement, in all 20 cells analyzed. Other gene abnormalities, including monosomy 7, were not detected. The patient was treated in accordance with Japanese Pediatric Leukemia/Lymphoma

Study Group AML-05 protocol.7 After induction therapy, hematological CR was achieved and further G-banding analysis revealed a normal karyotype. The first relapse occurred 6 months after

diagnosis, during consolidation therapy. In addition to inv(2)(p23q13), monosomy 7 was identified by fluorescence _in situ_ hybridization. The patient received IDA-FLAG (Idarubicin, 10 

mg/m2, on days 1 and 2; fludarabine, 30 mg/m2, on days 1–5; and cytarabine, 2 g/m2, once daily on days 1–5. Granulocyte colony-stimulating factor, 300 mg/m2, was administered daily beginning

1 day before the commencement of chemotherapy and continued until a neutrophil count of >500/μl), and azacitidine as salvage therapy; however, these proved ineffective. Because the

patient’s leukemia cells carried _ALK_ rearrangement and were refractory to conventional salvage therapy, we decided to administer crizotinib based upon its potential efficacy for the

disease.5 After the approval of an institutional review board and written informed consent from her guardians, the patient received crizotinib, 280 mg/m2, twice a day, without concomitant

chemotherapy except for intrathecal therapy (12 mg methotrexate, 25 mg cytarabine and 10 mg hydrocortisone). The dose of crizotinib used was determined based on phase I clinical trials by

the Children's Oncology Group.4 Complete cytogenetic remission (disappearance of monosomy 7 in fluorescence _in situ_ hybridization of bone marrow aspirate) was confirmed 51 days after

the initiation of crizotinib. Severe adverse reactions did not occur except for nausea and vomiting. Subsequently the patient underwent allo-HCT from the 5/8 HLA-matched mother. Crizotinib

was administrated for 55 days in total and discontinued 6 days before the initiation of a conditioning regimen, with total body irradiation of 12 Gy and 90 mg/m2 melphalan for 2 days. HCT

was well tolerated, and neutrophil engraftment was achieved on day 29. Complete donor chimerism and the absence of monosomy 7 in a bone marrow aspirate was confirmed on day 28. CR has

remained for more than 1 year after the HCT. The presence of _RANBP2-ALK_ fusion gene was confirmed by PCR with reverse transcription of a bone marrow sample at diagnosis and a relapse

(Figure 1a).8 The _RANBP2-ALK_ fusion gene disappeared after 51 days of administration of crizotinib and remained negative after HCT (Figure 1b). This is the first pediatric case suggesting

the effectiveness of crizotinib and HCT for relapsed and refractory AML with _ALK_ rearrangement. The potential efficacy of crizotinib for hematological malignancies with _ALK_ rearrangement

has been reported previously. In a pediatric phase I trial, seven out of eight patients with _ALK_-positive anaplastic large cell lymphoma achieved a CR after treatment with crizotinib.4

Maesako _et al._5 reported the efficacy of crizotinib in reducing leukemia cells in AML with _ALK_ rearrangement. However, resistance to crizotinib due to a secondary ALK kinase domain

mutation occurred.5, 9 The authors consequently suggested the necessity of consolidation therapy using cytotoxic agents to achieve long-term remission.5 Allogeneic HCT is also a tolerable

and curative option after crizotinib therapy, as reported in a case of refractory anaplastic large cell lymphoma.3 Our case achieved CR by crizotinib administration only and then

successfully underwent subsequent HCT. A _RANBP2-ALK_ fusion gene combined with monosomy 7 may be responsible for a certain type of hematologic disorder, such as acute myelomonocytic

leukemia, and be related to a poor prognosis.10, 11 Clinical data for our patient and five other previously reported patients5, 10, 11 showing a myeloid neoplasm with _ALK_ rearrangement are

summarized in Table 1. The neoplasms of all patients, including our case, were accompanied by monosomy 7 and were resistant to multidrug cytotoxic chemotherapy. Maxson _et al._6 identified

an oncogenic _ALK_ point mutation in adult AML and pediatric B-cell acute lymphoblastic leukemia, and suggested that _ALK_ mutations likely require other cooperating mutations for

progression to leukemia. Monosomy 7, a potentially unfavorable prognostic factor in AML and juvenile myelomonocytic leukemia, may, in our patient, have a role as the cooperating mutation,

together with _ALK_ rearrangement, which leads to resistance to standard cytotoxic chemotherapy. The prognosis of AML with monosomy 7 is dismal; however, our patient successfully achieved

molecular CR by crizotinib monotherapy treatment and maintained CR for more than a year after HCT. Crizotinib can be viewed as a promising treatment option for those high-risk patients with

_ALK_ rearrangement. Therefore, we suggest examining _ALK_ rearrangement and using crizotinib in patients with a refractory or relapsed myeloid neoplasm and chromosome 2p23 aberration.

Further studies of the use of crizotinib in AML with _RANBP2-ALK_ fusion gene are required to enhance our understanding of the contribution of crizotinib to the successful treatment of this

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Google Scholar  Download references ACKNOWLEDGEMENTS This study was funded by basic research expenditures of Yokohama City University. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS *

Department of Pediatrics, Yokohama City University, Yokohama, Japan A Hayashi, R Tanoshima, S-I Tsujimoto, M Yanagimachi, M Takeuchi, K Sasaki, J Ikeda, R Kajiwara & S Ito * Department

of Pediatrics, Toho University School of Medicine, Tokyo, Japan H Takahashi Authors * A Hayashi View author publications You can also search for this author inPubMed Google Scholar * R

Tanoshima View author publications You can also search for this author inPubMed Google Scholar * S-I Tsujimoto View author publications You can also search for this author inPubMed Google

Scholar * M Yanagimachi View author publications You can also search for this author inPubMed Google Scholar * M Takeuchi View author publications You can also search for this author

inPubMed Google Scholar * K Sasaki View author publications You can also search for this author inPubMed Google Scholar * J Ikeda View author publications You can also search for this author

inPubMed Google Scholar * R Kajiwara View author publications You can also search for this author inPubMed Google Scholar * S Ito View author publications You can also search for this

author inPubMed Google Scholar * H Takahashi View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to R Tanoshima. ETHICS

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http://creativecommons.org/licenses/by/4.0/ Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Hayashi, A., Tanoshima, R., Tsujimoto, SI. _et al._ Crizotinib treatment for

refractory pediatric acute myeloid leukemia with RAN-binding protein 2-anaplastic lymphoma kinase fusion gene. _Blood Cancer Journal_ 6, e456 (2016). https://doi.org/10.1038/bcj.2016.52

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