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Leukemia Research 34 (2010) e237–e239

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Leukemia Research

journa l homepage: www.e lsev ier .com/ locate / leukres

etter to the Editor

uccessful treatment using low-dose dasatinib for chronicyelogenous leukemia in a patient with megakaryoblas-

ic transformation concomitant with myelofibrosis and anxtramedullary tumor

. Introduction

Imatinib mesylate (IM) has been shown to be very beneficial forhe treatment of Philadelphia chromosome-positive (Ph-positive)hronic myelogenous leukemia (CML) in chronic phase (CP) [1].lthough IM may be effective at all disease stages, the probabilityf a response decreases and the duration of the response becomeshorter as the disease progresses [2]. Megakaryoblastic crisis of CMLs extremely rare, and has a dismal prognosis [3,4]. The progno-is of patients with CML who develop extramedullary disease [5]r myelofibrosis (MF) [6] is also poor. Dasatinib induces hemato-ogic and cytogenetic responses in patients with CML or Ph-positivecute lymphoblastic leukemia who cannot tolerate or are resistanto IM [7].

. Case report

A 70-year-old man with CML began to complain of a rightemoral pain in April 2008. He was diagnosed as Ph-positive CML-P in 2000. He had been treated with IM since July 2004, at whichime his bone marrow (BM) findings were consistent with CML-P without MF or the additional chromosomal abnormalities otherhan Ph. IM was started at a dosage of 400 mg/day. However, theosage was gradually reduced because of adverse effects (AEs). Itas fixed at 100 mg and 200 mg on alternate days in April 2005.e exhibited only a partial cytogenetic response at best with IM

herapy.Because the right femoral pain was reinforced, the patient was

dmitted to our hospital in July 2008 (Fig. 1). On admission noemarkable findings were obtained on a physical examination. Theatient’s laboratory data showed anemia (Hb 10.8 g/dl) and throm-ocytosis (PLT 405 × 109/l). The WBC count was 8.83 × 109/l withnormal hemogram. Magnetic resonance imaging (MRI) findings

evealed tumor involvement extending from his right femoral heado his right femoral neck. A needle biopsy of the tumor showed

F and the proliferation of blastoid cells without a definite diag-osis. A BM sample, which was easily aspirated from his sternum

n August 2008, showed normocellularity with neutrophils in dif-erent stages of maturation and a blast component of 0.8%. TheM cells were 97% positive for BCR–ABL fusion genes, as deter-ining using a fluorescence in situ hybridization (FISH) analysis,

ith the additional complex chromosomal abnormalities other

han t(9;22)(q34; q11.2) in all of the tested 20 BM cells. Becauset became impossible to take IM orally, the administration of IFN-

was begun. Because his general condition worsened, his rightemoral bone tumor was removed in September 2008. The patho-

145-2126/$ – see front matter © 2010 Elsevier Ltd. All rights reserved.oi:10.1016/j.leukres.2010.03.024

logical findings from the removed tumor showed that the blasts hadinfiltrated the bone and destroyed the bone trabeculae. The BM inthe removed tumor showed signs of severe MF and hypercellular-ity with blasts that tended to differentiate into megakaryocytes.Immunohistochemical analysis revealed that the blasts were pos-itive for CD42b and CD34 and negative for CD3, CD7, CD20, andTdT. The pathological diagnosis was CML with megakaryoblastictransformation and MF. His femoral pain was alleviated soon aftersurgery. Because he declined to undergo chemotherapy, IM wasstarted again in addition to IFN-� in October 2008. BM aspirationsat the sternum and iliac in November 2008 were unsuccessful bydry tapping. A BM biopsy of the iliac showed MF and megakary-oblastosis.

His condition until March 2009 was relatively good. There-after, he once again began to complain of a right femoral pain.A PET-CT scan and MRI examination showed that his tumor hadrelapsed around the replaced right artificial femoral head. He washospitalized once again in April 2009, at which time he showedanemia (Hb 6.0 g/dl) and thrombocytopenia (PLT 66 × 109/l). TheWBC count was 3.68 × 109/l with a normal hemogram. Since hisdisease had become resistant to combination therapy with IFN-�and IM, which were discontinued, treatment with dasatinib at adosage of 80 mg once daily was initiated in April 2009. The dose ofdasatinib was reduced to 60 mg/day after 1 month of treatmentand 40 mg/day after 2 months because of hematologic AEs. Hisright femoral pain was gradually alleviated after the commence-ment of dasatinib. After 2 months of treatment with dasatinibfindings of PET-CT and MRI revealed that the relapsed femoraltumor had almost disappeared, and a BM aspiration and biopsyshowed hypocellular marrow without megakaryoblastosis or MF.At that time a FISH test of BM cells was 4.0% positive for BCR–ABLfusion genes, and complex chromosome abnormalities includingt(9;22)(q34; q11.2) were only seen in one of the 20 tested BMcells. Although he still has anemia and thrombocytopenia, he hasnot required any transfusions since August 2009. A FISH test hasshown a complete cytogenetic response (CCyR) since August 2009.The BCR–ABL transcript level in the peripheral blood, as quantifiedusing a transcription-mediated amplification assay was more thanthe maximum detection level before starting dasatinib therapy.This level gradually decreased with dasatinib therapy and a majormolecular response was achieved in October 2009. The patientis re-evaluated for disease progression and AEs every 2 weeks,and currently in good condition at 10 months after the start ofdasatinib.

3. Discussion

Hirose et al. [8] reported the case of a CML patient witha megakaryoblastic crisis and severe MF who was successfullytreated with IM at a dosage of 400 mg/day and who achieved aCCyR, together with a marked regression of the MF, after 1 month

e238 Letter to the Editor / Leukemia Research 34 (2010) e237–e239

Fig. 1. Clinical course.Abbreviations: IM, imatinib mesilate; IFN-�, interferon-�; MU, million unit; WBC, white blood cell; Hb, hemoglobin; PLT, platelet; FISH, fluorescence in situ hybridization;P entras

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B, peripheral blood; BM, bone marrow; RCC, red cell concentrate; PC, platelet conchows the days on which the BCR–ABL transcript levels were determined.

f therapy. However, our patient developed a megakaryoblastic cri-is with MF despite IM therapy. Because of thrombocytopenia, heas only able to take a low dose of IM (100–200 mg/day) prior to

he development of blastic crisis (BC). An IM dosage of 400 mg/dayr more might have delayed disease progression. Point mutationsn the ATP-binding region of BCR–ABL kinase are frequently foundn patients with CML who develop IM resistance [9]. However, we

ere unable to investigate the possibility of BCR–ABL mutations inur patient prior to the start of dasatinib treatment. Considering thedditional complex chromosomal abnormalities that were foundn his BM cells when he was being treated with 200 mg/day of IM,lonal evolution might involve resistance to IM. As far as we couldearch, this is the first case report showing that dasatinib improvedML with megakaryoblastic crisis and MF which was resistant to

M.We started dasatinib at a dosage of 80 mg once daily because of

nemia and thrombocytopenia although the conventional dosages 70 mg twice daily for the treatment of CML-BC. So far, in theresent patient low-dose dasatinib therapy at a dose of 40 mg onceaily seems to be sufficient for treating the megakaryoblastic crisisnd MF, and AEs other than myelosuppression was only a transientlight pleural effusion. In some patients with CML, relatively low-ose dasatinib treatment might be sufficiently effective and couldinimize AEs.

onflict of interest

None of the authors have any conflict of interest.

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Acknowledgment

We thank Dr. Masafumi Ito (Department of Pathology, JapaneseRed Cross Nagoya First Hospital) for his review of the bone marrowpathology.

References

1] Kantarjian HM, Sawyers C, Hochhaus A, et al. Hematologic and cytogeneticresponses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med2002;346:645–52.

2] Sawyers CL, Hochhaus A, Feldman E, et al. Imatinib induces hematologicand cytogenetic responses in patients with chronic myelogenous leukemia inmyeloid blast crisis: results of a phase II study. Blood 2002;99:3530–9.

3] Faderl S, Talpaz M, Estrov Z, Kantarjian HM. Chronic myelogenous leukemia:biology and therapy. Ann Intern Med 1999;131:207–19.

4] Bourantas KL, Repousis P, Tsiara S, Christou L, Konstantinidou P, Bai M. Chronicmyelogenous leukemia terminating in acute megakaryoblastic leukemia. Casereport. J Exp Clin Cancer Res 1998;17:243–5.

5] Inverardi D, Lazzarino M, Morra E, et al. Extramedullary disease in Ph-positivechronic myelogenous leukemia: frequency, clinical features and prognostic sig-nificance. Haematologica 1990;75:146–8.

6] Kvasnicka HM, Thiele J, Schmitt-Graeff A, et al. Bone marrow featuresimprove prognostic efficiency in multivariate risk classification of chronic-phase Ph1+ chronic myelogenous leukemia: a multicenter trial. J Clin Oncol2001;19:2994–3009.

7] Talpaz M, Shah NP, Kantarjian HM, et al. Dasatinib in imatinib-resistant Philadel-phia chromosome-positive leukemias. N Engl J Med 2006;354:2531–41.

8] Hirose Y, Kiyoi H, Iwai M, Yokozawa T, Ito M, Naoe T. Successful treatment

with imatinib mesylate of a CML patient in megakaryoblastic crisis with severefibrosis. Int J Hematol 2002;76:349–53.

9] Branford S, Rudzki Z, Walsh S, et al. High frequency of point mutations clus-tered within the adenosine triphosphate-binding region of BCR/ABL in patientswith chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemiawho develop imatinib (STI571) resistance. Blood 2002;99:3472–5.

ia Res

Letter to the Editor / Leukem

Masaki Yamaguchi ∗

Saori MunemotoAtsuo Kasada

Ryoichi MurataMikio Ueda

Department of Hematology, Ishikawa PrefecturalCentral Hospital, Kanazawa,

Japan

earch 34 (2010) e237–e239 e239

∗ Corresponding author at: Department ofHematology, Ishikawa Prefectural Central Hospital,

2-1 Kuratsukihigashi, Kanazawa 920-8530, Japan.

Tel.: +81 76 237 8211; fax: +81 76 238 2337.

E-mail address: myjody@ipch.jp (M. Yamaguchi)

1 February 2010Available online 3 April 2010