Chronic myelogenous leukemia showing biphenotypic blast crisis ...

Leukemia Research 33 (2009) e195–e198

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Case report

Chronic myelogenous leukemia showing biphenotypic blast crisis followed by lineage switch to B lymphoblastic leukemia Seung Hwan Oh a , Tae Sung Park b , Hye Ran Kim a , Ja Young Lee a , Jae Hyun Kim a , Jeong Hwan Shin a , Jeong Nyeo Lee a,∗ a Department of Laboratory Medicine, Inje University College of Medicine, GaeGeum-dong, Busanjin-gu, Busan 614-735, Republic of Korea b Department of Laboratory Medicine, Kyung Hee University College of Medicine, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-702, Republic of Korea

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Article history: Received 30 March 2009 Received in revised form 16 April 2009 Accepted 18 April 2009 Available online 17 May 2009

a b s t r a c t Lineage switch is a very rare event in blastic crisis of chronic myelogenous leukemia (CML-BC). To our knowledge, only three cases of lineage switch between lymphoid and myeloid/myelomonocytic lineages have been reported in the literature. Here, we report a novel case of imatinib-resistant CML-BC, in which the blast lineage switched from biphenotypic to B-lymphoid. © 2009 Elsevier Ltd. All rights reserved.

Keywords: Chronic myelogenous leukemia Biphenotypic blast crisis Lineage switch B lymphoblastic leukemia

1. Introduction Chronic myelogenous leukemia (CML) is a common myeloproliferative disease that is characterized by the clonal expansion of marrow stem cells, and is associated with the Philadelphia chromosome [1]. As the disease progresses, the indolent chronic phase may convert to a more aggressive accelerated phase or, finally, blast crisis (BC). In this final stage (BC), the marrow is infiltrated by blasts, which are more frequently of myeloid lineage than of lymphoid lineage [2]. Due to its heterogeneity, bilineage crisis is sometimes found in the blastic phase of CML [3,4], and biphenotypic crisis has also been reported to account for 14% of BC [5]. Treatment options have been selected according to the phenotype of blasts and recently renewed by the introduction of the Abl kinase inhibitor imatinib mesylate (IM) [6,7]. Here, we report a novel case of imatinib-resistant CML-BC, in which the blast lineage switched from biphenotypic to B-lymphoid. 2. Case report A 14-year-old boy was admitted to our hospital in July 2007 because of persistent epistaxis for 5 days. His initial complete

∗ Corresponding author. Tel.: +82 52 890 6862; fax: +82 52 893 1562. E-mail address: [email protected] (J.N. Lee). 0145-2126/$ – see front matter © 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2009.04.026

blood count (CBC) showed a hemoglobin level of 8.9 g/dL, a platelet count of 676,000/␮L, and a WBC count of 263,200/␮L, with 4% blasts. A bone marrow study revealed hypercellular marrow, with 5.2% blasts (Fig. 1). A chromosome study revealed a 46,XY,t(9;22)(q34;q11.2) in all 20 cells analyzed. A fluorescence in situ hybridization (FISH) study using a BCR/ABL1 probe (Abbott Molecular/Vysis, Des Plaines, IL) showed two fusion signals in 89% of the cells analyzed, consistent with the result of “nuc ish (ABLx3)(BCRx3)(ABL con BCRx2)[178/200].” Reverse transcriptasepolymerase chain reaction (RT-PCR) analysis identified the p210 isoform of the BCR/ABL1 fusion transcript (b2a2 type). The patient was diagnosed with CML in the chronic phase; however, treatment with IM was delayed due to economic reason. Instead, hydroxyurea was started and he responded well. After 6 months, his peripheral blood showed an increased leukocyte count, with 13% blasts and 4% basophils. His marrow showed hypercellularity and was infiltrated by medium-to-large sized blasts, with fine nuclear chromatin, distinct nucleoli, and limited basophilic cytoplasms. Immunophenotyping by flow cytometry revealed that the blasts were positive for myeloperoxidase (MPO), CD13, CD19, CD20, CD10, CD22, and TdT (Fig. 2). A diagnosis of biphenotypic blast crisis (myeloid and B-lineage) from CML was made. Despite chemotherapy with cytarabine and fludarabine, in combination with IM, he did not achieve complete remission. After receiving continuous administration of IM for 4 months, his marrow was replaced by lymphoblastic leukemic cells showing CD19, CD20,

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S.H. Oh et al. / Leukemia Research 33 (2009) e195–e198

Fig. 1. Bone marrow aspirate (1000×) and FISH findings. (A) Chronic myelogenous leukemia at the initial diagnosis. (B) Acute biphenotypic leukemia at the blastic phase. (C) Acute lymphocytic leukemia at the relapse. (D) FISH using BCR/ABL probe showed dual fusion signals: nuc ish (ABLx3)(BCRx3)(ABL con BCRx2)[178/200].

CD10, CD22, and TdT, but not CD13 or MPO. During the patient’s clinical course, no additional chromosome aberration other than the Philadelphia chromosome was detected. After being diagnosed with lymphoid BC, he is now awaiting allogeneic hematopoietic stem cell transplantation after ALL-type induction chemotherapy. 3. Discussion There are several previous reports of lineage switch in acute leukemia [8–10]. Many cases of lineage switch have occurred in Philadelphia chromosome-positive acute leukemia [11–15]. Blast lineage switch was characterized by clonal selection or transformation of multipotential progenitor cells during intensive chemotherapy [9]. However, lineage switch is a very rare event in CML-BC. To our knowledge, only three cases of lineage switch between lymphoid and myeloid/myelomonocytic lineages have been reported [16–18]. Only one case of lineage switch from mixed (myeloid/B-lineage) to myeloid was reported [19]. On the other hand, our case underwent a lineage switch from biphenotypic to lymphoid. In the previous cases, lineage switch occurred during the

course of treatment with conventional chemotherapeutic agents, but our patient’s switch occurred during the administration of imatinib. The biphenotypic and bilineage presentation of blasts suggested that the origin was multipotent progenitor cells [12]. Thus, our case suggests that blasts in CML-BC have the potential to commit to other phenotypes, which may be subject to factors such as treatment modality. To our knowledge, this is the first case report of biphenotypic blast crisis with successive lymphoblastic lineage switch in CML. Further studies are needed to survey the frequency, prognosis, and treatment response of such lineage switching CML patients. Contributions Drs. Seung Hwan Oh and Tae Sung Park conducted study design and preparation of the manuscript. These two authors contributed equally to this work as first authors. Dr. Hae Ran Kim interpreted chromosome study and Drs. Ja Young Lee, Jae Hyun Kim, and Jeong Hwan Shin reviewed the case and the manuscript. Dr. Jeong Nyeo Lee, as the corresponding author, interpreted bone marrow pathology, and she reviewed the manuscript.


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Fig. 2. Immunophenotype results of the present study. (A) It showed a positive result for MPO and CD13 markers (biphenotypic blast crisis). (B) It showed a negative result for MPO and CD13 at relapse (lineage switch to lymphoid leukemia).

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Conflict of interest No financial support or conflicts of interest are reported by the authors. References [1] Goldman JM, Melo JV. Bcr-abl in chronic myelogenous leukaemia—how does it work? Acta Haematol 2008;119:212–7. [2] Hernandez JM, Gonzalez-Sarmiento R, Martin C, Gonzalez M, Sanchez I, Corral J, et al. Immunophenotypic, genomic and clinical characteristics of blast crisis of chronic myelogenous leukaemia. Br J Haematol 1991;79:408–14. [3] Amemiya N, Yatomi Y, Yanagi M, Endo T, Ozaki Y. Mixed blast crisis of chronic myelogenous leukemia involving minimally differentiated myeloblast and megakaryoblast lineages. Lab Hematol 2004;10:254–5. [4] Tsuyuoka R, Takahashi T, Suzuki A, Sasaki Y, Nakamura K, Fukumoto M, et al. A newly established megakaryoblastic/erythroid cell line that differentiates to red cells in the presence of erythropoietin and produces platelet-like particles. Stem Cells 1995;13:54–64. [5] Yen CC, Liu JH, Wang WS, Fan FS, Chiou TJ, Tai CJ, et al. Immunophenotypic and genotypic characteristics of chronic myelogenous leukemia in blast crisis. Zhonghua Yi Xue Za Zhi (Taipei) 2000;63:785–91. [6] Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, et al. Activity of a specific inhibitor of the bcr-abl tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 2001;344:1038–42. [7] Goldman JM, Marin D, Olavarria E, Apperley JF. Clinical decisions for chronic myeloid leukemia in the imatinib era. Semin Hematol 2003;40:98–103, discussion 104-113. [8] Lee HR, Kang SH, Kang HJ, Shin HY, Ahn HS, Kim HK, et al. Lineage switch from acute myeloid leukemia to biphenotypic acute leukemia with acquisition of philadelphia chromosome. Cancer Genet Cytogenet 2008;184:124–6.

[9] Stass S, Mirro J, Melvin S, Pui CH, Murphy SB, Williams D. Lineage switch in acute leukemia. Blood 1984;64:701–6. [10] Lounici A, Cony-Makhoul P, Dubus P, Lacombe F, Merlio JP, Reiffers J. Lineage switch from acute myeloid leukemia to acute lymphoblastic leukemia: report of an adult case and review of the literature. Am J Hematol 2000;65:319–21. [11] Cuneo A, Balboni M, Piva N, Carli MG, Tomasi P, Previati R, et al. Lineage switch and multilineage involvement in two cases of ph chromosome-positive acute leukemia: evidence for a stem cell disease. Haematologica 1994;79:76–82. [12] Monma F, Nishii K, Ezuki S, Miyazaki T, Yamamori S, Usui E, et al. Molecular and phenotypic analysis of philadelphia chromosome-positive bilineage leukemia: possibility of a lineage switch from t-lymphoid leukemic progenitor to myeloid cells. Cancer Genet Cytogenet 2006;164:118–21. [13] Pane F, Frigeri F, Camera A, Sindona M, Brighel F, Martinelli V, et al. Complete phenotypic and genotypic lineage switch in a philadelphia chromosomepositive acute lymphoblastic leukemia. Leukemia 1996;10:741–5. [14] Reardon DA, Hanson CA, Roth MS, Castle VP. Lineage switch in philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer 1994;73: 1526–32. [15] Saso R, Zomas A, Hamblin M, Dunlop L, Swansbury GJ, Min T, et al. Sequential development of myelodysplasia and acute myeloid leukemia but with no karyotypic evolution after autografting in a patient with philadelphia positive acute lymphoblastic leukemia. Leuk Lymphoma 1997;26:625–8. [16] Jehn U, Mittermuller J, Greither L, Clemm C, Heinemann V, Lorenz T, et al. Repeated blast crisis (bc) of changing morphology, immunologic phenotype and cytogenetics in chronic myeloid leukemia (cml). Anticancer Res 1989;9:1721–3. [17] Shirai T, Hasegawa S, Niitani K, Nishimura T, Ishida H, Shinohara T. Chronic myelogenous leukemia characterized by successive lymphoid and myelomonocytic blast crises. Rinsho Ketsueki 1989;30:668–73. [18] Goto H, Tsurumi H, Hara T, Moriwaki H. Lymphoid blast crisis during interferonalpha therapy in a patient with chronic myelogenous leukemia in myeloid blast crisis. Int J Hematol 2000;72:474–6. [19] Callea V, Morabito F, Francia di Celle P, Ronco F, Carbone A, Nobile F, et al. Phenotypic and genotypic switch in philadelphia-positive, bcr-positive blast crisis of chronic myeloid leukemia. Eur J Haematol 1992;48:187–91.