Journals | Policy | Permission

Journal of Hematology

Case Report

Volume 9, Number 1-2, April 2020, pages 23-29

Emergence of BCR-ABL1 Chronic Myeloid Leukemia in a JAK2-V617F Polycythemia Vera

Myeloproliferative neoplasms (MPNs) include a heterogeneous group of disorders. The most frequent are chronic myelogenous leukemia (CML), essential thrombocytosis (ET), polycythemia vera (PV), and primary myelofibrosis (PMF). CML is characterized by Philadelphia chromosome translocation between the long arms of chromosome 9 and 22, leading to the BCR-ABL1 fusion gene. Philadelphia negative disorders (Ph-MPN) are associated with driver mutations, such as JAK2, CALR, and MPL. JAK2-V617F mutation is present in more than 90% of patients with PV (or exon 12 mutation in V617F negative), and more than 50% of patients with ET or PMF [1]. CALR mutation is present in 20-25% of TE and PMF, and MPL mutation is found in 3% of TE and 7% of PMF. The rest of MPNs are “triple negative”, but a minority present somatic mutations in other genes [2].

Classically, BCR-ABL1 and JAK2 were considered mutually exclusive driver genetic lesions [3, 4]. Here we describe a case of emergence of BCR-ABL1 CML in the setting of JAK2-V617F PV.

In 2012 a 70-year-old female was admitted with hematocrit of 63.9%, hemoglobin 22 g/dL, normal platelets, and white blood cell (WBC) of 15.97 × 10⁹/L with neutrophilia without spleen enlarge. Her smear showed absence of leukoerythroblastic picture and presence of mature granulocytes.

Bone marrow aspirate showed granular hyperplasia without blast excess; and biopsy was not performed at that time. Molecular testing revealed V617F mutation in JAK2 gene. JAK2-PV was diagnosed and she was treated with phlebotomies, acetylsalicylic acid (ASA) and hydroxyurea. Her disease was controlled, without thrombotic or hemorrhagic complications.

Six years later, progressive leukocytosis and spleen enlargement were observed. Her WBC was 80 × 10⁹/L with normal hemoglobin and platelets counts. There was concern of progression to acute leukemia so she was re-evaluated. Her smear showed leukoerythroblastosis with no blasts excess. Bone marrow smear showed no leukemic progression and biopsy informed granulocyte hyperplasia, absence of fibrosis, and 5% of cluster of differentiation (CD)34/CD117 progenitors. Cytogenetic analysis had no evaluable metaphases, and fluorescence in situ hybridization (FISH) for BCR-ABL1 was positive in 99% of nucleus. Conventional reverse transcription polymerase chain reaction (RT-PCR) showed b2a2 BCR-ABL1 fusion gene.

At this point we had a patient with JAK2-PV who evolved to chronic phase of BCR-ABL1 CML. In order to asses if this was a progression of the same clone or was a second myeloproliferative clone, we performed JAK2 by allele specific oligonucleotide (ASO)-PCR (ASO-PCR) for V61F mutation, which was negative, suggesting two different clones. We also assessed the presence of BCR-ABL1 by FISH in marrow sample of her diagnosis in 2012, but it was not an evaluable sample.

She started imatinib 400 mg QD and ASA, and stopped hydroxyurea, achieving complete hematologic remission at the first month of treatment. Cutaneous and hematologic toxicity was detected required dose reduction to 300 mg QD. She achieved cytogenetic complete remission at 3 months despite dose adjustment, but minor molecular response at 6 months.

Six months after the diagnosis of BCR-ABL1 CML, the hematocrit rose to 48%, suggesting JAK2-PV clone recurrence, and indeed JAK2-V617F was confirmed by molecular testing, so phlebotomies were added in order to control both clones. Because of poor response and toxicities to imatinib, dasatinib was started at 9 months of BCR-ABL1 CML diagnosis achieving major molecular response. She stopped ASA for 1 month and developed a deep vein thrombosis, but with normal hematocrit.

Concomitance or emergence of a new chronic myeloid neoplasm is a rare event; however plenty of evidence is published. Tables 1, 2 and 3 [5-37] show the latest reports on the matter.

Click to view

Table 1. Clinical and Genetic Characteristics of Published Cases Including Initial Molecular Lesion JAK2 in Combination With Molecular Change of JAK2, BCR/ABL or JAK2 and BCR/ABL

Click to view

Table 2. Clinical and Genetic Characteristics of Published Cases Including Initial Molecular Lesion BCR/ABL in Combination With Molecular Change of JAK2, BCR/ABL or JAK2 and BCR/ABL

Click to view

Table 3. Clinical and Genetic Characteristics of Published Cases Including Initial Molecular Lesion JAK2 and BCR/ABL in Combination With Molecular Change of JAK2, BCR/ABL or JAK2 and BCR/ABL

The presence of driver mutations with concomitant phenotypes (CML and Ph-MPN) at the beginning of the disease has been reported. Treatment of this scenario is challenging, but concomitant ruxolitinib and tyrosine kinase inhibitor (TKI) were successfully used [5].

Coexistence of JAK2-V617F and BCR-ABL1 from the beginning in first blood sample of six patients studied for MPN was described in our country previously [38]. Additionally, Tabassum et al reported a surprisingly high frequency (44%) of JAK2-V617F and BCR-ABL1 in 25 CML patients in Pakistan [39].

JAK2 and BCR-ABL1 concomitance with a predominant phenotype has also been reported [40]. In fact, the presence of very low levels of BCR-ABL1 in Phi-MPN and even its disappearance without treatment could represent a clonal hematopoiesis of indeterminate potential (CHIP) abnormality [41].

There are also reports on transforming phenotypes with second genetic mutations. The appearance of JAK2 Phi-MPN phenotype in the course of a CML treated with TKI was observed [6, 23, 42]; and a diagnosis of CML in the course of a Phi-MPN like our patient was also described [5, 42]. This could represent a previous masked clone, or a new one because of selective pressure.

Whether these scenarios are a consequence of a single clone that acquires a “second hit” or emergence of a second clone, it is not well known. There are some reports that address this issue by progenitor colonies genotyping. Bocchia et al observed that JAK2-V617F and BCR-ABL1 transcript can co-exist in an early (erythroid-myeloid-committed) progenitor cell, but few colonies showed JAK2-V617F mutation alone, whereas none showed BCR-ABL1 transcript alone. Treatment with imatinib caused disappearance of BCR-ABL1 remaining JAK2 in most of colonies, suggesting that a subclone of pre-existing JAK2-V617F mutant hemopoietic progenitors at a certain point acquired BCR-ABL1 translocation [7]. Bornhauser reported concurrent JAK2-BCR-ABL1 in only two of 16 granulocytic colonies but in none of 15 erythroid colonies, suggesting that BCR-ABL1 occurred at a later stage of myelopoiesis [8]. Zhou described a patient with concurrent PV and CML where the majority of the myeloid colonies have JAK2-V617F or BCR-ABL1, but not both, confirming that the two disorders arose within distinct clones [5].

Wang et al observed in two patients with features like the one in this report, that the acquisition of BCR-ABL1 occurred after JAK2 mutation, and that the development of CML is a secondary event that may occur in either heterozygous or homozygous JAK2-V617F hematopoietic progenitor cells [9].

Molecular landscape of MPN is rapidly evolving, and many driver and secondary mutations are arising with next-generation sequencing (NGS). Some epigenetic regulators mutations or oncogenic mutations described in myelodysplastic syndromes and acute myeloid leukemia are common in myeloproliferative diseases [2]. Kandarpa et al recently described the molecular characteristics of eight patients with combined phenotypes (CML and MF) by exome/transcriptome sequencing. They found the presence of mutations in epigenetic regulators such as TET2, ASXL1/2, SRSF2, and IDH2 at different frequencies (1-47%). Some patients harbored oncogenic mutations in N/KRAS, TP53, BRAF, EZH2, and GNAS at low frequencies (0.5-39%). Subclonal frequencies of these mutations might indicate clonal evolution of the disease. Genomic instability might be a result of mutation in epigenetic regulators and probably hematopoietic stem cells accumulate multiple genetic variants with clonal dominance. Findings in this study suggest that CML in those patients might be a secondary disease arising from underlying genetic instability [43].

There is no enough information about which patients harbor both genetic mutations or will develop a second myeloproliferative disease, but at least those who have mixed phenotype or change phenotype and/or bone marrow histopathology are candidates for molecular testing. Recent reports of the concomitance of BCR-ABL1 and CALR in patients with CML and PMF suggest testing CALR in JAK2-negative patients [44].

Management of these cases could be complicated, especially if two phenotypes are expressed, but CML treatment with TKIs and Phi-MPN control with hydroxyurea and/or phlebotomies in case of PV in association with ASA has been used, like in our patient. Ruxolitinib and TKIs, either given together or in alternating schedule, have been successfully used with no major adverse events [5, 43].

In conclusion, we described a patient with JAK2-PV who developed a BCR-ABL1 CML, but with absence of JAK2-V617F at the time of switching. Then PV phenotype and JAK2 mutation reappeared during CML treatment with TKI. These could be a result of two clones with clonal predominance.

Acknowledgments

We acknowledge Carolina Otati, Ana Ines Catalan, and Dr. Daniela Lens from the Departamento Basico de Medicina, Hospital de Clinicas, Montevideo, Uruguay for their help.

Financial Disclosure

None to declare.

Conflict of Interest

None to declare.

Informed Consent

Not applicable.

Author Contributions

Mariana Lorenzo is the manuscript author; Sofia Grille and Mariana Stevenazzi are the reviewers.

Data Availability

The data supporting the findings of this study are available from the corresponding author upon reasonable request.

1. Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2017 update on diagnosis, risk-stratification, and management. Am J Hematol. 2017;92(1):94-108.
   doi pubmed
2. Grinfeld J, Nangalia J, Baxter EJ, Wedge DC, Angelopoulos N, Cantrill R, Godfrey AL, et al. Classification and personalized prognosis in myeloproliferative neoplasms. N Engl J Med. 2018;379(15):1416-1430.
   doi pubmed
3. Jelinek J, Oki Y, Gharibyan V, Bueso-Ramos C, Prchal JT, Verstovsek S, Beran M, et al. JAK2 mutation 1849G>T is rare in acute leukemias but can be found in CMML, Philadelphia chromosome-negative CML, and megakaryocytic leukemia. Blood. 2005;106(10):3370-3373.
   doi pubmed
4. Kronenwett R, Graf T, Neumann F, Pechtel S, Steidl U, Diaz-Blanco E, Haas R. Absence of the JAK2 mutation V617F in CD34+ hematopoietic stem and progenitor cells from patients with BCR-ABL-positive CML in chronic phase and blast crisis. Leuk Res. 2006;30(10):1323-1324.
   doi pubmed
5. Zhou A, Knoche EM, Engle EK, Fisher DA, Oh ST. Concomitant JAK2 V617F-positive polycythemia vera and BCR-ABL-positive chronic myelogenous leukemia treated with ruxolitinib and dasatinib. Blood Cancer J. 2015;5:e351.
   doi pubmed
6. Hummel JM, Kletecka MC, Sanks JK, Chiselite MD, Roulston D, Smith LB, Czuchlewski DR, et al. Concomitant BCR-ABL1 translocation and JAK2(V617F) mutation in three patients with myeloproliferative neoplasms. Diagn Mol Pathol. 2012;21(3):176-183.
   doi pubmed
7. Bocchia M, Vannucchi AM, Gozzetti A, Guglielmelli P, Poli G, Crupi R, Defina M, et al. Insights into JAK2-V617F mutation in CML. Lancet Oncol. 2007;8(10):864-866.
   doi
8. Bornhauser M, Mohr B, Oelschlaegel U, Bornhauser P, Jacki S, Ehninger G, Thiede C. Concurrent JAK2(V617F) mutation and BCR-ABL translocation within committed myeloid progenitors in myelofibrosis. Leukemia. 2007;21(8):1824-1826.
   doi pubmed
9. Wang X, Tripodi J, Kremyanskaya M, Blouin A, Roda P, Hoffman R, Najfeld V. BCR-ABL1 is a secondary event after JAK2V617F in patients with polycythemia vera who develop chronic myeloid leukemia. Blood. 2013;121(7):1238-1239.
   doi pubmed
10. Siricilla M, Nader K, Ferber A. A case report of chronic myelogenous leukemia with JAK2- and BCR / ABL- positive mutation. AJHO. 2017;13(2):24-30.
11. Swaminathan M, Patel KP, Huynh-Lu J, Tang G, Zuo Z, Miranda R, Verstovsek S. Unique case of myeloproliferative neoplasm with two rare clonal abnormalities: rare JAK2 exon 12 mutation and rare e14a3 (b3a3) BCR/ABL fusion transcript. Acta Haematol. 2019;141(1):23-27.
    doi pubmed
12. Ursuleac I, Colita A, Adam T, Jardan C, Ilea A, Coriu D. The concomitant occurrence of JAK2V617F mutation and BCR/ABL transcript with phenotypic expression - an overlapping myeloproliferative disorder or two distinct diseases? - case report. J Med Life. 2013;6(1):34-37.
13. Jallades L, Hayette S, Tigaud I, Johnston A, Coiffier B, Magaud JP, Ffrench M. Emergence of therapy-unrelated CML on a background of BCR-ABL-negative JAK2V617F-positive chronic idiopathic myelofibrosis. Leuk Res. 2008;32(10):1608-1610.
    doi pubmed
14. Pingali SR, Mathiason MA, Lovrich SD, Go RS. Emergence of chronic myelogenous leukemia from a background of myeloproliferative disorder: JAK2V617F as a potential risk factor for BCR-ABL translocation. Clin Lymphoma Myeloma. 2009;9(5):E25-29.
    doi pubmed
15. Yamada O, Mahfoudhi E, Plo I, Ozaki K, Nakatake M, Akiyama M, Yamada H, et al. Emergence of a BCR-ABL translocation in a patient with the JAK2V617F mutation: evidence for secondary acquisition of BCR-ABL in the JAK2V617F clone. J Clin Oncol. 2014;32(21):e76-79.
    doi pubmed
16. Mirza I, Frantz C, Clarke G, Voth AJ, Turner R. Transformation of polycythemia vera to chronic myelogenous leukemia. Arch Pathol Lab Med. 2007;131(11):1719-1724.
17. Hussein K, Bock O, Theophile K, Seegers A, Arps H, Basten O, Grips KH, et al. Chronic myeloproliferative diseases with concurrent BCR-ABL junction and JAK2V617F mutation. Leukemia. 2008;22(5):1059-1062.
    doi pubmed
18. Darling HS, Kumar R, Kapoor R, Singh J, Verma T. BCR-ABL and JAK2V617F mutation co-existence, rare or just unexplored. Indian J Hematol Blood Transfus. 2017;33(4):633-635.
    doi pubmed
19. Pagnano KB, Delamain MT, Magnus MM, Vassallo J, CA DES, D DEA, Lorand-Metze I. Concomitant essential thrombocythemia with JAK2 V617F mutation in a patient with chronic myeloid leukemia with major molecular response with imatinib and long-term follow-up. Oncol Lett. 2016;12(1):485-487.
    doi pubmed
20. Kim YK. Letters to the editor. Am J Hosp Palliat Med. 2006;15(6):311-312.
    doi
21. Bader G, Dreiling B. Concurrent JAK2-positive myeloproliferative disorder and chronic myelogenous leukemia: a novel entity? A case report with review of the literature. J Investig Med High Impact Case Rep. 2019;7:2324709619832322.
    doi pubmed
22. Curtin NJ, Campbell PJ, Green AR. The Philadelphia translocation and pre-existing myeloproliferative disorders. Br J Haematol. 2005;128(5):734-736.
    doi pubmed
23. Tefferi A, Levitt R, Lasho TL, Knudson RA, Ketterling RP. Postimatinib therapy emergence of a new JAK2V617F clone and subsequent development of overt polycythemia vera in a patient with chronic myelogenous leukaemia. Eur J Haematol. 2010;85(1):86-87.
    doi
24. Bee PC, Gan GG, Nadarajan VS, Latiff NA, Menaka N. A man with concomitant polycythaemia vera and chronic myeloid leukemia: the dynamics of the two disorders. Int J Hematol. 2010;91(1):136-139.
    doi pubmed
25. Payande Mehrdad SZF, Erfan Zare Mohammad, Haji Shure Saber Ghanbari. JAK2-V617 mutation combined with Philadephia chromosome-positive myeloi leukaemia: a case report. Int J Hematol Oncol Stem Cell Res. 2011;5(2):14-15.
26. Xu W, Chen B, Tong X. Chronic myeloid leukemia patient with co-occurrence of BCR-ABL junction and JAK2 V617F mutation. Int J Hematol. 2014;99(1):87-90.
    doi pubmed
27. Hassan A, Dogara LG, Babadoko AA, Awwalu S, Mamman AI. Coexistence of JAK2 and BCR-ABL mutation in patient with myeloproliferative neoplasm. Niger Med J. 2015;56(1):74-76.
    doi pubmed
28. Toogeh G, Ferdowsi S, Naadali F, Alimoghaddam K, Ghavamzadeh A, Shirkoohi R, Ghaffari SH. Concomitant presence of JAK2 V617F mutation and BCR-ABL translocation in a pregnant woman with polycythemia vera. Med Oncol. 2011;28(4):1555-1558.
    doi pubmed
29. Park SH, Chi HS, Cho YU, Jang S, Park CJ, Kim DY, Lee JH, et al. Two cases of myeloproliferative neoplasm with a concurrent JAK2 (V617F) mutation and BCR/ABL translocation without chronic myelogenous leukemia phenotype acquisition during hydroxyurea treatment. Ann Lab Med. 2013;33(3):229-232.
    doi pubmed
30. Qin YW, Yang YN, Li S, Wang C. Coexistence of JAK2V617F Mutation and BCR-ABL Translocation in a Pregnant Woman with Essential Thrombocythemia. Indian J Hematol Blood Transfus. 2014;30(Suppl 1):331-334.
    doi pubmed
31. Kramer A, Reiter A, Kruth J, Erben P, Hochhaus A, Muller M, Cross NC, et al. JAK2-V617F mutation in a patient with Philadelphia-chromosome-positive chronic myeloid leukaemia. Lancet Oncol. 2007;8(7):658-660.
    doi
32. Campiotti L, Appio L, Solbiati F, Ageno W, Venco A. JAK2-V617F mutation and Philadelphia positive chronic myeloid leukemia. Leuk Res. 2009;33(11):e212-213.
    doi pubmed
33. Pastore F, Schneider S, Christ O, Hiddemann W, Spiekermann K. Impressive thrombocytosis evolving in a patient with a BCR-ABL positive CML in major molecular response during dasatinib treatment unmasks an additional JAK2V617F. Exp Hematol Oncol. 2013;2(1):24.
    doi pubmed
34. Cambier N, Renneville A, Cazaentre T, Soenen V, Cossement C, Giraudier S, Grardel N, et al. JAK2V617F-positive polycythemia vera and Philadelphia chromosome-positive chronic myeloid leukemia: one patient with two distinct myeloproliferative disorders. Leukemia. 2008;22(7):1454-1455.
    doi pubmed
35. de Conchon MRM, Costa JL, Novaes MMY, Dorlhiac-Llacer PE, de Alencar Fischer Chamone D, Bendit I. Simultaneous detection of JAK2 V617F mutation and Bcr-Abl translocation in a patient with chronic myelogenous leukemia. Int J Hematol. 2008;88(2):243-245.
    doi pubmed
36. Inami M, Inokuchi K, Okabe M, Kosaka F, Mitamura Y, Yamaguchi H, Dan K. Polycythemia associated with the JAK2V617F mutation emerged during treatment of chronic myelogenous leukemia. Leukemia. 2007;21(5):1103-1104.
    doi pubmed
37. Gattenlohner S, Volker HU, Etschmann B, Einsele H, Muller-Hermelink HK. BCR-ABL positive chronic myeloid leukemia with concurrent JAK2(V617F) positive myelodysplastic syndrome/myeloproliferative neoplasm (RARS-T). Am J Hematol. 2009;84(5):306-307.
    doi pubmed
38. Cappetta M, Perez V, Zubillaga MN, Elizondo V, Manrique G, Prosper I, Boschi S, et al. Concomitant detection of BCR-ABL translocation and JAK2 V617F mutation in five patients with myeloproliferative neoplasm at diagnosis. Int J Lab Hematol. 2013;35(1):e4-5.
    doi pubmed
39. Tabassum N, Saboor M, Ghani R, Moinuddin M. Frequency of JAK2 V617F mutation in patients with Philadelphia positive Chronic Myeloid Leukemia in Pakistan. Pak J Med Sci. 2014;30(1):185-188.
40. Pahore ZA, Shamsi TS, Taj M, Farzana T, Ansari SH, Nadeem M, Ahmad M, et al. JAK2V617F mutation in chronic myeloid leukemia predicts early disease progression. J Coll Physicians Surg Pak. 2011;21(8):472-475.
41. Boddu P, Chihara D, Masarova L, Pemmaraju N, Patel KP, Verstovsek S. The co-occurrence of driver mutations in chronic myeloproliferative neoplasms. Ann Hematol. 2018;97(11):2071-2080.
    doi pubmed
42. Hussein K, Bock O, Seegers A, Flasshove M, Henneke F, Buesche G, Kreipe HH. Myelofibrosis evolving during imatinib treatment of a chronic myeloproliferative disease with coexisting BCR-ABL translocation and JAK2V617F mutation. Blood. 2007;109(9):4106-4107.
    doi pubmed
43. Kandarpa M, Wu YM, Robinson D, Burke PW, Chinnaiyan AM, Talpaz M. Clinical characteristics and whole exome/transcriptome sequencing of coexisting chronic myeloid leukemia and myelofibrosis. Am J Hematol. 2017;92(6):555-561.
    doi pubmed
44. Diamond JM, de Almeida AM, Belo HJ, da Costa MP, Cabecadas JM, Abecasis MM. CALR-mutated primary myelofibrosis evolving to chronic myeloid leukemia with both CALR mutation and BCR-ABL1 fusion gene. Ann Hematol. 2016;95(12):2101-2104.
    doi pubmed

This article is distributed under the terms of the Creative Commons Attribution Non-Commercial 4.0 International License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Journal of Hematology is published by Elmer Press Inc.