Chronic Myeloid Leukemia with a Rare Philadelphia Chromosome Variant Involving Chromosome 16

Introduction

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.