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Am J Case Rep
Am J Case Rep
amjcaserep
The American Journal of Case Reports
1941-5923
International Scientific Literature, Inc.

39215452
10.12659/AJCR.944641
944641
Articles
Chronic Myeloid Leukemia with a Rare Philadelphia Chromosome Variant Involving Chromosome 16
Bahashwan Salem M. A B D E F 1 2
1 Department of Hematology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
2 Hematology Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
Corresponding Author: Salem M. Bahashwan, e-mail: Smbahashwan1@kau.edu.sa
Authors’ Contribution:

A Study Design

B Data Collection

C Statistical Analysis

D Data Interpretation

E Manuscript Preparation

F Literature Search

G Funds Collection

Financial support: None declared

Conflict of interest: None declared

2024
31 8 2024
25 e944641-1e944641-5
06 3 2024
17 7 2024
25 7 2024
© Am J Case Rep, 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Patient: Female, 34-year-old

Final Diagnosis: Chronic myeloid leukaemia

Symptoms: Left upper quadrant abdominal pain

Clinical Procedure: —

Specialty: Hematology

Objective:

Rare coexistence of disease or pathology

Background:

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the presence of the Philadelphia (Ph) chromosome, which results from the fusion of the translocation of the ABL1 gene from chromosome 9 to the BCR gene located in chromosome 22, forming the BCR-ABL gene on chromosome number 22, which accounts for approximately 95% of CML cases. Complex translocation involving other chromosomes can occur.

Case Report:

We present a rare case of CML with a variant Ph chromosome, in which chromosome 16 was involved with the usual translocation. A 34-year-old woman presented with a history of left upper quadrant pain and excessive sweating, with no hepatosplenomegaly on examination. She was found to have leukocytosis, with elevated neutrophils (34 000/mm3), basophils (1460/mm3), and eosinophils (2650/mm3). Karyotyping showed a translocation (16;22) (q24,q11.2), and FISH analysis showed BCR-ABL fusion as a result of (9,22) translocation, with a third chromosome (chromosome 16) involved and fused with chromosome 22, with a different breakpoint, which has never been reported in the literature, affecting the long arm of chromosome 16. The patient was treated with a first-generation tyrosine kinase inhibitor (imatinib) and achieved a deep molecular remission. The repeated FISH analysis confirmed the disappearance of both translocations (9,22) and (16,22).

Conclusions:

The impact of the additional chromosomal aberration in CML is widely heterogeneous, and the outcome is dependent on multiple factors. Larger studies are needed to clarify the outcome in CML with variant Ph chromosomes, as most of the available data come from reported cases.

Keywords:

Imatinib Mesylate
Karyotyping
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Philadelphia Chromosome
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pmcIntroduction

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the presence of the Philadelphia (Ph) chromosome, which results from the fusion of the translocation of the ABL1 gene from chromosome 9 to the BCR gene located in chromosome 22, resulting in the BCR-ABL gene on chromosome number 22 [1]. This reciprocal t(9;22) accounts for around 95% of CML cases. In a minority of cases, complex translocation involving other chromosomes in addition to chromosomes 9 and 22 can occur [2,3].

Two previous cases of CML with variant Ph chromosome in which chromosome 16 was involved were reported, and the short arm of chromosome 16 was affected in both cases (16 p13) [4,5].

Here, we report and discuss a rare case of CML with a variant of the Ph chromosome, in which chromosome 16 was involved with the usual translocation of chromosomes 9 and 22. This is the first case in which the breakpoint on chromo-some 16 is different and the long arm of chromosome 16 is affected (16 q24).

Case Report

A 34-year-old woman, known to have hypertension, presented in 2019 with a history of progressive left upper quadrant abdominal pain over a couple of days and with a long-term history of excessive sweating over the last year. There was no history of fever or weight loss, or other remarkable concerns.

On physical examination, tenderness without rigidity was found over the left upper quadrant area, with no palpable hepatomegaly or splenomegaly. Physical examinations of the central nervous system, respiratory system, and cardiovascular system were normal.

Abdominal ultrasound was done and showed no hepatosplenomegaly, with no focal lesions.

The cause of this left upper quadrant pain was unidentified by physical examination and imaging.

The laboratory examination (Table 1) showed a white blood cell count of 48 000/mm3 (reference range: 4000–1000/mm3), with elevated neutrophil count of 34 000/mm3, basophil count of 1460/mm3, eosinophil count of 2650/mm3, and monocyte count of 4130/mm3. The lymphocyte count was 6000/mm³, hemoglobin level was 10.3 g/dL, mean corpuscular volume was 82.9, and platelet count was 366 000/mm3. Peripheral blood film showed only left shifting with no abnormal cells. There was no family history of hematological malignancy or similar clinical picture.

We used the European Treatment and Outcome Study (EUTOS) score as a risk stratification score, which is calculated based on the percentage of basophils in the peripheral blood and the spleen size below the costal margin in centimeters. The patient had an EUTOS score of 21, which considered as low risk of not achieving a complete cytogenetic remission by 18 months after treatment initiation [6].

Bone marrow aspiration and biopsy showed hypercellular marrow with less than 5% of blast cells and marked granulocytic hyperplasia with variable stages of maturation (Figure 1). Megakaryocytes were significantly increased, and reticulin fibrosis was mildly increased. Findings were consistent with CML in the chronic phase.

Karyotyping from bone marrow was sent and showed a female karyotype with translocation between the long arm of chromosome 16 at a breakpoint q24 and chromosome 22 at a breakpoint q11.2 (46, XX, t (16;22) (q24; q11.2) [20]) (Figure 2).

Fluorescence in situ hybridization (FISH) analysis was done and showed atypical BCR-ABL fusion of 90% of the cells. The ABL gene showed 3 signals: 2 of them were normal and the third was fused with the BCR gene. On the BCR gene, which is located on chromosome 22, three signals were observed. One signal was normal, one was fused with the BCR gene, and the other was translocated to chromosome 16 (Figure 3).

Qualitative real-time PCR was performed on the ration BCRABL/ABL and was 3.7%.

The patient was started on the first-generation tyrosine kinase inhibitor (TKI) imatinib mesylate at a dose of 400 mg daily. The treatment was well tolerated, and the patient achieved a complete hematological remission by 3 months after the initiation of imatinib. By 6 months, karyotyping and FISH analysis from peripheral blood were normal, and the patient achieved a major molecular response by 12 months, when quantitative PCR showed undetectable BCR-ABL translocation. The patient continued to have a major molecular response 5 years after treatment initiation.

Consent was taken from the patient to publish this case.

Discussion

This case represents and describes a rare case of CML with a variant Ph chromosome translocation involving chromo-some 16. The breakpoint observed in this case affected the long arm of chromosome 16, which has never been reported in the literature.

Additional chromosomal abnormalities are found in less than 5% of the newly diagnosed cases of CML with variant Ph chromosome, and the risk of getting an additional chromosomal abnormality during the course of the disease rises and can reach to approximately 80% in the blast crisis phase [7,8].

The impact of the additional chromosomal abnormalities in CML cases with variant Ph chromosome is not well recognized and could be dependent on multiple factors, such as the type of the chromosomal abnormality and the time of the appearance of this abnormality. Additional chromosomal abnormalities developed during the course of the disease are thought to be associated with a worse outcome [7–10].

Different prognostic scores are used for assessing the risk of progression and survival in CML, and the most recent and accurate method is the EUTOS score, which was developed after the era of TKI and showed higher accuracy in predicting survival in a real world clinical setting, as other scores were developed before the era of TKI [11].

The accuracy of diagnosis in CML has significantly improved in the past decade, and FISH has played an important role in the detection of the chromosomal rearrangement and can sometimes detect chromosomal rearrangement not seen or detected by karyotyping, especially if the number of metaphase is insufficient in karyotyping [12,13].

Limited evidence is available in the literature regarding the efficacy of the first generation TKI on CML with variant Ph chromosome. Some investigations showed a lower response rate to imatinib [9,14]. Other studies showed a similar outcome in those with variant Ph chromosome treated with imatinib as in those with standard translocation. Based on the available evidence in the literature [15,16], the European Leukemia Net classified the presence of an additional chromosomal abnormalities at the time of diagnosis as a warning sign [17]. The appearance of the additional chromosomal abnormalities during the course of the treatment is related to the development of imatinib resistance and failure and is associated with a poor outcome [18].

A large observational study including 1151 patients with CML showed that, for those patients with variant Ph chromosome with an additional minor route chromosomal aberration, the chromosomal abnormalities could disappear with imatinib [7], which was concurrent with the present reported case.

Over the last decade, second- and third-generation TKIs were introduced and showed great efficacy in treating CML, especially in those patients with resistance or intolerance to prior TKIs. They were then incorporated in the recommendation as a first-line treatment for the group of patients with high-risk disease progression and transformation, including those with additional chromosomal aberration [19].

Newly emerged and approved treatment by the FDA to treat relapsed and resistant cases of CML with asciminib could be a good alternative to the TKIs, as it acts differently as an allosteric inhibitor of BCR-ABL1 kinase; however, trials are needed to prove the efficacy [20].

Conclusions

The impact of the additional chromosomal aberration in CML is widely heterogeneous, and the outcome is dependent on multiple factors. Multiple studies have been conducted and describe some of the additional chromosomal aberration associated with CML, such as t(1;9;22;16)(q32;q34.1;q11.2;p13), t(9;22;1;13)(q34.1;q11.2;p12;q34), t(9;22;4)(q34.1;q11.2;p16), and t(9;22;7)(q34.1;q11.2;p22). The outcomes of these studies were either similar to CML with the Ph chromosome with no other additional chromosomal aberration or were associated with a poor outcome [21,22]. Additional research is needed to clarify the outcome in CML with variant Ph chromosomes, as most of the data come from reported cases.

Figure 1. A bone marrow aspiration showing granulocytic hyperplasia with eosinophilia and basophilia (high power).

Figure 2. Karyotyping showing a female karyotype with translocation between the long arm of chromosome 16 at a break point q24 and chromosome 22 at a break point q11.2 (46, XX, t (16;22) (q24; q11.2) [20].

Figure 3. BCR-ABL fusion as a result of (9,22) translocation, with a third chromosome (chromosome 16) involved and fused with chromosome 22.

Table 1. Complete blood count with differentials.

Parameter	Result	Reference range	
White blood cells	48 000/mm3	4000–1000/mm3	
Neutrophils	34 000/mm3	2500–7000/mm3	
Eosinophils	2650/mm3	50–500/mm3	
Basophils	1460/mm3	25–100/mm3	
Monocytes	4130/mm3	100–700/mm3	
Lymphocytes	6000/mm3	1000–4000/mm3	
Hemoglobin	10.3 g/dL	12–16 g/dL	
Mean corpuscular volume	82.9 fL	80–100 fL	
Platelets	366 000/mm3	150–450/mm3	

Publisher’s note: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher

Department and Institution Where Work Was Performed

The full work was done at King Abdulaziz University, Hematology Department, Faculty of Medicine, Jeddah, Saudi Arabia.

Declaration of Figures; Authenticity

All figures submitted have been created by the authors who confirm that the images are original with no duplication and have not been previously published in whole or in part.
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