Received: 9 August 2018 | Accepted: 10 September 2018

DOI: 10.1002/jcp.27505

REVIEW ARTICLE

Chronic myeloid leukemia with complex karyotypes:

Prognosis and therapeutic approaches

Ali Amin Asnafi1 | Zeinab Deris Zayeri2 | Saeid Shahrabi3 | Kazem Zibara4 |
1
Tina Vosughi

1
Research Center of Thalassemia &
Hemoglobinopathy, Health Research Institute, Abstract
Ahvaz Jundishapur University of Medical Objective and Background: Chronic myeloid leukemia (CML) is a neoplastic disease
Sciences, Ahvaz, Iran
2 whose genetic and cytogenetic changes play important roles in prognosis and
Golestan Hospital Clinical Research
Development Unit, Ahvaz Jundishapur treatment strategies. Philadelphia (Ph) translocation t(9;22)(q34;q11) is a diagnostic
University of Medical Sciences, Ahvaz, Iran
and prognostic biomarker in CML.
3
Department of Biochemistry and
Hematology, Faculty of Medicine, Semnan Methods: Pubmed and Google Scholar databases were searched for English language
University of Medical Sciences, Semnan, Iran articles from 1975 to 2017 containing the terms CML; Additional chromosomal
4
ER045, Laboratory of Stem Cells, DSST,
abnormalities; Philadelphia translocation; Prognosis; and Treatment.
Biology Department, Faculty of Sciences,
Lebanese University, Beirut, Lebanon Discussion: Approximately 10–12% of CML patients exhibit additional chromosomal
aberrations (ACAs) in chronic phase and blast crisis. ACAs emergence may cause
Correspondence
Zeinab Deris Zayeri, Golestan Hospital Clinical different features in CML patients according to Ph pattern. For instance, deletion of
Research Development Unit, Ahvaz
chromosome 9 derivation is associated to patient’s bad survival, whereas monosomy
Jundishapur University of Medical Sciences,
Ahvaz 15794-61357, Iran. 7 develops myeloid dysplastic syndrome (MDS) or acute myeloid leukemia (AML) in
Email: [email protected]
CML patients with Ph‐negative pattern. And ACAs in Ph‐positive CML is considered
as a failure in the management of CML with imatinib.
Conclusion: CML classification using different features such as Ph and ACAs can play
a decisive role in the evaluation of treatment responses in patients, for example, CML
patients with Ph negative and monosomy 7 develop MDS or CML patient –Y and
extra copy of Ph have a good response to tyrosine kinase inhibitors, therefore,
classifications according to Ph and ACAs play an important role in choosing better
treatment protocols and therapeutic strategies. Karyotype analysis in CML patients
with complex karyotype shows unrandom pattern so ACAs can be great clue in
medical guidelines.

KEYWORDS
chromosome aberration, chronic myeloid leukemia, complex karyotype, genetic, prognosis

1 | INTRODUCTION breakpoint cluster region (bcr) and Abelson (abl) genes. Clinical symptoms
associated to this translocation include hypercellular bone marrow,
Chronic myeloid leukemia (CML) is a neoplastic disease whose genetic anemia, platelet dysfunction, and an increase in the number of leukocytes,
and cytogenetic changes play important roles in prognosis and treatment especially neutrophils and immature myeloid cells. Ph translocation plays
process (Hehlmann, Hochhaus, & Baccarani, 2007). Philadelphia (Ph) an important role not only in CML pathogenesis, but also in diagnosis
translocation t(9;22)(q34;q11), known as Philadelphia chromosome, is an since it is considered as a prognostic biomarker in this disease (Huntly
important characteristic in CML (Apperley, 2015) which derives from et al., 2001; Seghatoleslami et al., 2016). Approximately 10–12% of CML
J Cell Physiol. 2018;1–9. wileyonlinelibrary.com/journal/jcp © 2018 Wiley Periodicals, Inc. | 1
2 | ASNAFI ET AL.

patients exhibit additional chromosomal aberrations (ACAs) in chronic protecting vital organs such as heart in cancer treatment (Haybar,
phase and 80% in blast crisis (Sgherza et al., 2017). These ACAs include Shahrabi, Deris Zayeri, & Pezeshki, 2018). Understanding complex
monosomy 7, trisomy 8, trisomy 21 (Molica, Massaro, & Breccia, 2017), karyotypes, cancer genetic and their treatment approaches is essential
loss of chromosome X in women, and loss of chromosome Y in men, and can be lifesaving. Scientists found different results in their treatment
which indicate poor prognosis and predict hematological and pathological options to the various types of complex karyotypes in CML. In this
changes (Molica et al., 2017; Shahrabi, Khodadi, Saba, Shahjahani, & Saki, review, to present an insight about complex karyotypes in CML,
2017). Researchers classified ACAs into major and minor route changes. prognostic, and therapeutic responses of complex karyotypes were
Major route changes include trisomy 8, extra Ph derivation (1der(22)t reviewed according to Ph translocation (positive or negative) and the
(9;22)(q34;q11)), isochromosome 17 (i(17)(q10)), trisomy 19, isochromo- possible interaction between Ph and ACAs. New treatment protocols
some derivation and Ph translocation (ider(22)(q10)t(9;22)(q34;q11)) could be suggested based on Ph and ACAs interaction.
(Sgherza et al., 2017). Chromosome 9 deletions, but not deletion variant
translocations, are strong prognostic markers in CML (Huntly et al.,
2001). Indeed, deletion of chromosome 9 derivation is associated with 2 | THE A CAS
patient’s bad survival (Sinclair et al., 2000). On the other hand, CML
patients with Ph negative and monosomy 7 develop myeloid dysplastic ACAs are bad symptoms indicating the disease progression and Ph
syndrome (MDS) or acute myeloid leukemia (AML; Jawad et al., 2016). coincidence with ACAs is a ringing bell of more than one pathway
Development of the latter diseases is due to various events such as activation with different cytogenetic origin so we should expect
inactivation of tumor suppressor genes such as CDKN2A, which is ominous result (Mitelman, 1993), but it is not correct all the time as
located, interestingly, in 9p21 (Heidari et al., 2017). ACAs affect we clarify in the next paragraphs. According to Bozkurt et al. (2013)
treatment responses too (Yokota, Nakamura, & Bessho, 2012; study only all of the Ph‐negative patients who carried ACAs showed
Figure 1). Cytogenetic abnormalities such as karyotype aberrations, gene optimal response to tyrosine kinase inhibitors (TKIs) therapy, in this
mutations, and gene expression abnormalities are important tools in study only 25% of the Ph‐positive patients with ACAs showed
diagnosis and classification of neoplastic disease such as leukemia optimal response to the treatment. These results reflects genetic
(Shahjahani et al., 2015). Genetic studies in cancer filed can be useful in instability in Ph‐positive patients and predicts poor prognosis. A
finding a therapeutic targets, however; our knowledge is very limited cohort study by Wang et al. (2013) on CML patients in the era of TKI
(Rasras, Zibara, Vosughi, & Zayeri, 2018). Genetic and cytogenetic have therapy showed patients with chromosome 3q26.2 abnormalities in
many benefits in several aspects of cancer and cancer therapy side chronic or accelerated phase had poorer response to TKI and
effects such as cardiotoxicity (Haybar, Jalali, Zibara, & Zayeri, 2017), in transformed to blast phase faster in comparison with other ACAs so
other word genetic studies present several ideas in diagnosis, prognosis, these changes reflect worse prognosis in CML patients (W. Wang,
cancer treatment, studding the side effects, and the mechanisms of Cortes, Lin, Beaty, et al., 2015). The emergence of ACAs such as

F I G U R E 1 Genetic analysis in CML patient can present us a great guide lines. CML: chronic myeloid leukemia; INF‐α: interferon‐α; TKI:
tyrosine kinase inhibitor [Color figure can be viewed at wileyonlinelibrary.com]
ASNAFI ET AL. | 3

trisomy 8 affects TKI treatment response and prognosis, a cohort development of TKI resistance as a result of point mutation in abl1
study by W. Wang, Cortes, Lin, Khoury, et al. (2015) showed trisomy kinase domain, which decreases TKI binding to this domain
8 associated with a good response to TKI treatment in this study 30 (Apperley, 2015). On the other hand, approximately 10% of CML
CML patients received TKI treatment after emergence of trisomy 8 patients show a Ph‐negative profile, however, one‐third of them
and 22 patients who had evaluated for cytogenetic and molecular display BCR‐positive with a treatment approach similar to
response 55% achieved complete cytogenetic response also they Ph‐positive CML (Cortes et al., 1995). Ph‐negative CML patients
reported that the most common cytogenetic alteration associated typically show different cytogenetic abnormalities with poor re-
with trisomy 8 was an extra Ph. Isochromosome 17q (i17q) reflects a sponse to TKIs therapy and highly frequent thrombocytopenia.
high risk for aggressive disease progression and its association with Ph‐negative CML with normal cytogenetic profile and emerging bcr
poor prognosis confirmed in a study by El Gendi, Fouad, Mohamed, rearrangement might be the only indicator of developing malignant
Eissa, and Mostafa (2016). A study by Issa et al. (2017) discussed the disease in CML patients in other word CML patient with Ph‐negative
subject of ACAs in Ph‐negative CML patients; they reported the and normal cytogenetic profile and emerging bcr rearrangement
emerging of ACAs in non –Y Ph‐negative CML patients are might have poorer prognosis and shorter survival time (Epstein,
associated with decreased survival time in chronic phase of the Kurzrock, Gutterman, & Talpaz, 1988). JAK2 mutation 1849G>T,
CML. ACAs mostly appear in the final stages of CML and these might which affect treatment response, is detectable in 19% of Ph‐negative
leads to diagnosis of new characteristics of CML in final stages and CML (Jelinek et al., 2005). Studies have shown that ACAs can also
classify the CML to different variants which leads to focus on better affect treatment responses in both Ph‐positive and Ph‐negative CML.
understanding of the effect of ACAs in the patient and the prognosis Scientists suggest that ACAs can lead to genome instability and can
effects of them (Fleischman et al., 1981). ACAs and karyotypic be clonal evolution markers. A group of Italian scientists showed the
changes can also be as an alarm for drug resistant in CML because effect of CML treatment with IM mesylate in variant translocations,
chromosomal balance changes affect protein production and finally which exist in approximately 5% of CML (Marzocchi et al., 2011).
multidrug resistance probably means the change of transcriptomes, Indeed, approximately 30% of patients in accelerate phase and
which leads to resistance against specific drugs such as imatinib (IM; 70–80% in blast crisis exhibit ACAs in their karyotypes (Mu et al.,
Duesberg et al., 2007). Karyotype analysis in CML patients with 2012; W. Wang, Chen, et al., 2016). Two cytogenetic pathways are
complex karyotype shows unrandom pattern so ACAs can be great involved: major versus minor route changes. The former includes
clue in making therapeutic decisions and predicting the results, trisomy 8, i(17q), trisomy 19, and an extra Ph chromosome, and one
however, our knowledge is not complete in matching these clues of these major routes appears in approximately 10–12% of Ph
(Mitelman, Levan, Nilsson, & Brandt, 1976), and spread the theory of positive. However, minor route changes include deletions in
ACAs bases in CML patients. chromosomes 7 or 17, trisomy 17 or 21, and deletion of sex
chromosome, whereas at less one of these minor routes occur in 15%
of all Ph‐positive CML cases (Mitelman, 1993). ACAs in Ph‐positive
3 | PH TRANSL OCAT ION AN D A CAS CML can also reveal disease progression (Medina et al., 2003). On
IN CML the other hand, ACAs in Ph‐negative CML display better prognosis
and response to IM mesylate, if they do not show MDS morphology
Ph translocation generates bcr‐abl tyrosine kinase activity, which (Deininger et al., 2007). Indeed, these ACAs in Ph‐negative CML may
plays an important role in CML development (Druker et al., 2001). indicate new malignant clone development (Jabbour et al., 2007).
Targeted therapy of Ph‐positive CML patients using IM changed our Numerous studies have investigated IM‐induced ACA in Ph‐negative
vision in treatment of CML and increased the survival of patients CML patients. Interestingly, prognosis seems to be associated to
specially in recent years (Norozi et al., 2016). Indeed, bcr‐abl fusion specific ACAs (Loriaux & Deininger, 2004). ACAs play an important
bcr‐abl
protein P210 is considered a good target for CML treatment role in IM‐resistant patients, whereas emerging ACAs during
using TKIs (Druker, 2008). In fact, most Ph‐positive CML patients treatment indicate poor prognosis (Luatti et al., 2012). In summary,
respond clearly to TKIs such as IM mesylate, dastatinib, and nilotinib. ACAs are involved in evaluating the prognosis of CML patients,
IM is a standard treatment of chronic phase; however, these therefore, awareness about them can be useful in CML management
chemotherapy agents can activate pathological hypertrophic signal- in both Ph‐positive and Ph‐negative cases (Z. Wang, Zen, et al., 2015;
ing pathways and lead to side effects such as chemotherapy‐induced Figure 2).
cardiotoxicity (Haybar et al., 2017), in other hand IM‐resistant
patients are another point of view in cancer treatment and in some
cases given interferon‐α which is a better treatment option for early 4 | P H‐POSITIVE COMP LEX KARYOT YP E
stage of chronic phase (Hehlmann et al., 2007). IM‐resistant profiles IN CML
in Ph‐positive CML patients could be a result of mutations or ACAs
(Bellodi et al., 2009). Ph‐positive CML patients in blast crisis have Ph‐positive and complex karyotype are important risk factors in
poor prognosis; however, the effect of IM mesylate on this phase is patients with ABL domain point mutations where cytogenetic
very promising (Kantarjian et al., 2002). Recent studies showed the responses are higher in patients treated with allogenic
4 | ASNAFI ET AL.

F I G U R E 2 Classifying CML patients according to ph and ACA can be helpful. Ph is a marker which indicates several results. ACA: additional
chromosomal aberration; AML: acute myeloid leukemia; BM: bone marrow; CML: chronic myeloid leukemia; MDS: myeloid dysplastic syndrome;
Ph: Philadelphia [Color figure can be viewed at wileyonlinelibrary.com]

hematopoietic stem cell transplantation (allo‐HSCT) compared The most common ACAs that can be found in Ph‐negative CML
with those treated with second generation TKIs or chemotherapy treated with IM, dastatinib, and nilotinib is trisomy 8 (J. Wang, Zhang,
agents (Gao et al., 2014). The status and class of break point in et al., 2016). A Ph‐negative CML patient with normal karyotype
BCR gene leads to the generation of various BCR‐ABL gene showed good prognosis and good response to hydroxyurea
fusions which may lead to the production of three protein types, (Hagemeijer et al., 1993). Other studies reported that ACAs can
P210, in most of the cases, P190 and less frequently P230 protein develop during the treatment in Ph‐negative CML (Issa et al., 2017).
(Shahrabi et al., 2014). BCR‐ABL1 activity affects important ACAs and complex karyotypes which appeared in Ph‐negative CML
signaling pathways such as Ras, which is the main signaling patients are summarized in Table 2.
pathway in apoptosis, proliferation, and differentiation. In
addition, Ras‐associated pathways play important roles in CML,
especially in advanced stages (Bertacchini et al., 2015). Point 6 | ROLE OF A CA S IN P ROGNOSIS A ND
mutations in ABL domain such as Y253H, E255K/V, F359V/C/I, or TREATMENT R ESPONSE
T315I cause relapse in patients receiving nilotinib, whereas those
in V299L, F317L/V/I/C, T315A, or T315I result into relapse in ACAs reveal the rise in genetic instability in Ph‐positive CML patients
patients receiving dastatinib. However, point mutations in T315I and can be a predictive phenomenon for estimating the increase in
lead to bosutinib resistance. Therefore, point mutations in ABL malignant phenotypes (Luzi et al., 2007). The incidence of additional
domain are important factors for choosing an efficient treatment chromosome and variant translocation is higher in blast crisis of
(Baccarani et al., 2013). On the other hand, numerous studies CML. Indeed, structural abnormalities such as i(17q) and additional
have shown that patients with complex karyotypes exhibit poor chromosomes such as chromosomes 8, 21, and ph are detected in
prognosis, even with IM mesylate treatment (Syed, Usman, Adil, & different patients during this phase, whereas patients with trisomy
Khurshid, 2008). Indeed, according to the guidelines of European do not have good response to therapies (Qiu et al., 2009). Complex
Leukemia Net (ELN), ACAs in Ph‐positive CML is considered as a karyotype is a negative prognostic factor for patients survival,
failure in the management of IM‐treated CML (Baccarani et al., especially in blast crisis (Pérez‐Jacobo et al., 2015). Appearance of
2009). Finally, rare cases of CML with ACAs such as inv(3)/t(3;3) ACAs during the treatment announces transformation to the next
reflect poor prognosis (Z. Wang, Zen, et al., 2015). Other ACAs phase and getting closer to advanced stages of CML (Crisan, Coriu,
and complex karyotypes, which were found in various ph‐positive Arion, Colita, & Jardan, 2015). ACAs emergence in CML metaphase
CML patients are summarized in Table 1. karyotype is considered as an alarm for the development of MDS
or AML (Issa et al., 2015). Different rearrangements of 9q34 and
22q11 regions indicate that CML has heterogeneous subgroups
5 | PH‐ NEGATIVE COMP LEX KARYOT YP E which can affect CML features and treatment responses (Virgili et al.,
IN CML 2008). Among ACAs, an extra copy of Ph chromosome would have a
negative effect on treatment responses and disease outcome
Prognosis of Ph‐negative CML is different from that of Ph‐positive (Palandri et al., 2009). Isochromosome 17q (i(17q)) predicts CML
CML; however, molecular evidence for BCR‐ABL gene fusion is used with bad clinical and pathologic features and higher risk for disease
as a diagnostic marker for classical CML (Van der Plas et al., 1989). progression and metastasis (El Gendi et al., 2016). Recent studies
ASNAFI ET AL. | 5

T A B L E 1 Therapeutic approaches and prognosis in Ph‐positive CML with ACAs

ACAs Therapeutic response Prognosis References

SCL Poor Poor Shahrabi et al. (2017)
Del(7)(p12) Good, 6 Month INF‐α – Christodoulidou, Silver, Macera, and
Verma (1992)
Monosomy 7 – Poor Molica et al. (2017)
t(7;11;9;22;9)(q22;q13;q34;q11.2;q34) Good, imatinib Good Yokota et al. (2012)
t(11;14)(q13;q32) Poor to imatinib and dasatinib, more than a – Manda‐Mapalo, Khalili, Quintana,
year on dasatinib hematologic response Rabinowitz, and Zhang (2016)
inv(3)(q21q26.2)/t(3;3)(q21;q26.2) Poor to TKIs Poor W. Wang, Cortes, Lin, Beaty,
et al. (2015)
t(3;21)(q26.2;q22) Poor to TKIs Poor W. Wang, Cortes, Lin, Beaty,
et al. (2015)
Trisomy 8 Good to TKIs Intermediate W. Wang, Cortes, Lin, Khoury,
et al. (2015)
−Y, extra copy of Ph Good to TKIs Good W. Wang, Cortes, et al. (2016)
i(17)(q10), −7/del7q, 3q26.2 rearrangement Intermediate to TKIs Poor W. Wang, Cortes, et al. (2016)
+der(22)(9;22) Good to dastatinib – Ikeda et al. (2014)
inv(3)(q21q26.2) Good to TKIs – Lewen et al. (2016)
t(6;9;22)(p21;q34;q11) Good to imatinib – Asif et al. (2017)
t(1;11)(q21;q23) Good to nilotinib Intermediate Gutiérrez et al. (2017)
ins (22;9) (q11;q21q34) Good to flumatinib Good W. Wang, Cortes, Lin, Khoury,
et al. (2015)
t(9;12;19;22)(q34.1;p11.2;q13.3;q11.2) and Good to hydroxyurea – Achkar, Wafa, ALi, Manvelyan, and
trisomy 8 and + der(12) Liehr (2010)
54XY with chromosome gain at positions 6, Poor to imatinib Poor Belurkar, Manohar, and Kurien (2013)
9, 10, 13, 14, 15, 19, and 21.
t(7;11)(p15;p15) Poor to hydroxyurea followed by Poor Yamamoto, Nakamura, Nakamura,
interferon a‐2b Saito, and Furusawa (2000)
t(9:15:22) (q34.1q34.3?:q26.1:qllq13) Poor to hydroxyurea Poor Palumbo et al. (1989)

Abbreviations: ACAs: additional chromosomal aberrations; CML: chronic myeloid leukemia; Del: deletion; der: derivation; INF‐α: interferon‐α; inv:
inversion; ins: insertion; SCL: sex chromosomal loss; T: translocation; −: loss; +: additional.

showed that ACAs have different impacts on CML prognosis, for CML and in the management of CML with complex karyotype.
outcome and survival and that ACAs can be used as a rationale for However, ACAs of major route are important factors that can cause
treatment in CML patients in both Ph‐positive and Ph‐negative CML treatment failure and therapeutic resistance responses. In fact,
patients (W. Wang, Chen, et al., 2016). IM is used as a golden therapy screening ACAs and ABL1 domain mutations can be very useful in

T A B L E 2 Therapeutic approaches and prognosis in Ph‐negative CML with ACAs

ACAs Therapeutic response Prognosis References

Monosomy 7 Good to nilotinib – Zeidan, Kakati, Anderson, Barcos, and
Wetzler (2007)
del(5)(q21q33) Poor to hydroxyurea Poor Heller et al. (2002)
t(9;12;15)(q34;12;q21) Intermediate to allopurinol and hydroxyurea – Shanske, Grunwald, Cook, Heisterkamp, and
Groffen (1998)
t(8;9;22)(q22;q34;q11) Hydroxyurea – Botti, Silver, Macera, Benn, and Verman (1988)
t(6;9)(p21;q34.1) Good to hydroxyurea and cytosine arabinoside Good Todorić‐Zivanović et al. (2006)
47,XY, +mar Good to leukapheresis and hydroxyurea Poor Hagemeijer et al. (1993)
Trisomy 8 Poor to interferon‐α, intermediate to imatinib – Cannella et al. (2012)
t(11,17)(q23;q25) Poor to clofarabine, idarubicin and cytarabine Poor Jaitly, Wang, and Hu (2015)

Abbreviations: CML: chronic myeloid leukemia; +mar: extra marker

6 | ASNAFI ET AL.

ordering efficient regimens for CML treatment (Amare et al., 2016), CON F LI CTS OF I NTERE ST
where ACAs can play a role as a predictor for failure in the treatment
The authors declare that there are no conflicts of interest.
with IM (Lekovic et al., 2017). Numerous studies proposed that
emergence of ACAs and development of genome instability may
reflect kinase domain mutation in CML and could be a reason for AU TH ORS ’ CO NTRIBUTIO N
TKIs resistance response (Sweet et al., 2014). Other studies showed
that patients with minor route have a better outcome than patients Z. D. Z. designed the structure and the tables and wrote the abstract,
with major route (Chen et al., 2017). Recent studies suggested that introduction, Ph translocation and ACAs in CML and revised the
ACAs existence in childhood CML is not significantly related to conclusion; A. A. A. wrote the Ph translocation and ACAs in CML and
prognosis; however, ACAs can play an important role in adult CML. revised the abstract and the conclusion; S. S. and T. V. wrote Role of
Hence, age could be an effective factor in deciding whether the ACAs in prognosis and treatment response and Ph‐negative complex
changes are meaningful or not (Millot et al., 2017). Cytogenetic and karyotype in CML; and K. Z. edited the whole manuscript grammar
molecular responses appear in chronic phase of most CML patients and revised it generally.
receiving TKIs therapy. Therefore, monitoring of additional changes
such as ACAs is useful for identifying patients at higher risk of ORCI D
treatment failure (Oehler, 2013). Definition of CML according to
hematologic, cytogenetic, and molecular changes can be useful in Zeinab Deris Zayeri http://orcid.org/0000-0002-8621-5904
predicting treatment responses and in organizing guidelines for CML
treatment, especially in the chronic phase (Rohon et al., 2013). R E F E R E N CE S

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