Complex karyotype with double Philadelphia chromosome and T315I mutation results in blastic phase and extensive extramedullary infiltration in a chronic myeloid leukemia patient


      Chronic myeloid leukemia (CML) is a common hematological malignancy originating from bone marrow stem cells. Chromosomal abnormalities can be seen in almost all cases, the most known anomaly being Philadelphia (Ph) chromosome, a derivative chromosome resulting from a translocation between 9. and 22. chromosome. Other chromosomal abnormalities may be present in 10% of patients at diagnosis, although they emerge frequently during the acute transformation and can be associated with unfavorable significance. Also, point mutations like T315I in BCR-ABL fusion gene may arise during the course of the disease and thereby cause tyrosine kinase inhibitors (TKI) resistance. Here, we report a BCR-ABL positive CML patient who was followed for 6 years in major molecular response (MMR), complete cytogenetic response (CCR), and complete hematological response (CHR). He had a sudden loss of hematological, cytogenetic, and molecular response with a very aggressive blastic course and extensive extramedullary infiltration, with T315I mutation, complex translocations, an extra Ph chromosome, and additional chromosomes. The patient who received intensive cytotoxic chemotherapy together with ponatinib treatment, which is effective for the T315I mutation, never went into remission, and there was no chance of transplantation because a suitable donor for HLA could not be found. Although these findings are not very rare individually, coexistence of complex karyotype and T315I mutation is not frequent and complicates clinical management. Our patient is the first case in literature with all disclosed findings together and indicates the importance of early detection of these chromosomal and molecular abnormalities.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Cancer Genetics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Cortes J
        • Pavlovsky C
        • Saußele S.
        Chronic myeloid leukaemia.
        Lancet. 2021 Nov 20; 398 (Epub 2021 Aug 20PMID34425075): 1914-1926
        • myeloid Kronik
        • ve kronik lösemi
        myeloproliferative neoplaziler tanı ve tedavi kılavuzu.
        Türk Hematoloji Derneği. Sürüm. 2016; 1 (03 - Ekim)
        • Vardiman JW
        • Harris NL
        Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms.
        Blood. 2002; 100: 2292
        • Torii Y
        • Nanjo K
        • Toubai T
        • Hosokawa M
        • Sato R
        • Yamada A
        • Aizawa K
        • Himuro M
        • Ito S
        • Yamamoto M
        • Magenau J
        • Wilcox R
        • Ishizawa K.
        A unique three-way Philadelphia chromosome variant t(4;9;22)(q21;q34;q11.2) in a newly diagnosed patient with chronic phase chronic myeloid leukemia: a case report and review of the literature.
        J Med Case Rep. 2021 May 25; 15 (PMID34030730PMCIDPMC8146239): 285
        • Clark RE
        • Apperley JF
        • Copland M
        • Cicconi S.
        Additional chromosomal abnormalities at chronic myeloid leukemia diagnosis predict an increased risk of progression.
        Blood Adv. 2021 Feb 23; 5 (PMID33616651PMCIDPMC7903225): 1102-1109
        • Cortes JE
        • Kim DW
        • Pinilla-Ibarz J
        • le Coutre P
        • Paquette R
        • Chuah C
        • Nicolini FE
        • Apperley JF
        • Khoury HJ
        • Talpaz M
        • DiPersio J
        • DeAngelo DJ
        • Abruzzese E
        • Rea D
        • Baccarani M
        • Müller MC
        • Gambacorti-Passerini C
        • Wong S
        • Lustgarten S
        • Rivera VM
        • Clackson T
        • Turner CD
        • Haluska FG
        • Guilhot F
        • Deininger MW
        • Hochhaus A
        • Hughes T
        • Goldman JM
        • Shah NP
        • Kantarjian H
        • Investigators PACE
        A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias.
        N Engl J Med. 2013 Nov 7; 369: 1783-1796
        • Asnafi AA
        • Deris Zayeri Z
        • Shahrabi S
        • Zibara K
        • Vosughi T
        Chronic myeloid leukemia with complex karyotypes: Prognosis and therapeutic approaches.
        J Cell Physiol. May 2019; 234 (Epub 2018 Nov 14PMID30430567): 5798-5806
        • O'Hare T
        • Shakespeare WC
        • Zhu X
        • Eide CA
        • Rivera VM
        • Wang F
        • Adrian LT
        • Zhou T
        • Huang WS
        • Xu Q
        • Metcalf CA
        • Tyner JW
        • Loriaux MM
        • Corbin AS
        • Wardwell S
        • Ning Y
        • Keats JA
        • Wang Y
        • Sundaramoorthi R
        • Thomas M
        • Zhou D
        • Snodgrass J
        • Commodore L
        • Sawyer TK
        • Dalgarno DC
        • Deininger MW
        • Druker BJ
        • Clackson T.
        AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance.
        Cancer Cell. 2009 Nov 6; 16 (3rd) (PMID19878872PMCIDPMC2804470): 401-412
        • Massaro F
        • Molica M
        • Breccia M.
        Ponatinib: A Review of Efficacy and Safety.
        Curr Cancer Drug Targets. 2018; 18 (PMID28969556): 847-856
      1. National Comprehensive Cancer Network. Chronic Myeloid Leukemia (Version 2.2020). Accessed September 27, 2019.

      2. Xu P, Guo D, Shao X, Peng M, Chen B. Characteristics and mutation analysis of Ph-positive leukemia patients with T315I mutation receiving tyrosine kinase inhibitors. Onco Targets Ther. 2017 Sep 25;10:4731-4738. doi:10.2147/OTT.S142482. PMID: 29026321; PMCID: PMC5626416.

        • Al-Achkar W
        • Moassass F
        • Ikhtiar A
        • Liehr T
        • Othman MA
        • Wafa A
        Hyperdiploidy associated with T315I mutation in BCR-ABL kinase domain in an accelerated phase-chronic myeloid leukemia case.
        Mol Cytogenet. 2014 Nov 29; 7: 89
        • Anastasi J
        • Feng J
        • Le Beau MM
        • Larson RA
        • Rowley JD
        • Vardiman JW
        The relationship between secondary chromosomal abnormalities and blast transformation in chronic myelogenous leukemia.
        Leukemia. 1995; 9 (Apr): 628-633
        • Swolin B
        • Weinfeld A
        • Westin J
        • Waldenström J
        • Magnusson B.
        Karyotypic evolution in Ph-positive chronic myeloid leukemia in relation to management and disease progression.
        Cancer Genet Cytogenet. 1985; 18 (Sep): 65-79
        • Sokal JE
        • Gomez GA
        • Baccarani M
        • Tura S
        • Clarkson BD
        • Cervantes F
        • Rozman C
        • Carbonell F
        • Anger B
        • Heimpel H
        • et al.
        Prognostic significance of additional cytogenetic abnormalities at diagnosis of Philadelphia chromosome-positive chronic granulocytic leukemia.
        Blood. 1988; 72 (Jul): 294-298
        • Cerny J
        • Yu H
        • Ramanathan M
        • Raffel GD
        • Walsh WV
        • Fortier N
        • Shanahan L
        • O'Rourke E
        • Bednarik J
        • Barton B
        • Kroll-Desrosiers A
        • Hao S
        • Woda B
        • Hutchinson L
        • Evens AM
        • Rosmarin AG
        • Nath R.
        Expression of CD25 independently predicts early treatment failure of acute myeloid leukaemia (AML).
        Br J Haematol. 2013; 160 (Jan): 262-266
        • Gönen M
        • Sun Z
        • Figueroa ME
        • Patel JP
        • Abdel-Wahab O
        • Racevskis J
        • Ketterling RP
        • Fernandez H
        • Rowe JM
        • Tallman MS
        • Melnick A
        • Levine RL
        • Paietta E
        CD25 expression status improves prognostic risk classification in AML independent of established biomarkers: ECOG phase 3 trial, E1900.
        Blood. 2012 Sep 13; 120: 2297-2306
        • Fujiwara SI
        • Muroi K
        • Yamamoto C
        • Hatano K
        • Okazuka K
        • Sato K
        • Oh I
        • Ohmine K
        • Suzuki T
        • Ozawa K.
        CD25 as an adverse prognostic factor in elderly patients with acute myeloid leukemia.
        Hematology. 2017; 22 (Jul): 347-353