|Year : 2017 | Volume
| Issue : 4 | Page : 152-155
Optimal response to imatinib therapy in a case of chronic myeloid leukemia with a concurrent loss of distal 22q
Bayan Alqahtany1, Fatma S Alqahtani2, Osamah Khojah2, Abdurahman Almaeen3, Aamer Aleem4
1 Medical Intern, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia
2 Department of Pathology, Hematology Unit, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia
3 Department of Pathology, College of Medicine, Al-Jouf University, Sakakah, Kingdom of Saudi Arabia
4 Department of Medicine, Hematology and Oncology Unit, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia
|Date of Web Publication||12-Jan-2018|
Dr. Bayan Alqahtany
College of Medicine, King Saud University, P.O. Box 9822, Riyadh 11492
Kingdom of Saudi Arabia
Source of Support: None, Conflict of Interest: None
The hallmark of diagnosing classical chronic myelogenous leukemia (CML) is the identification of Philadelphia (Ph) chromosome (Chr). However, some CML cases show additional structural/numerical chromosomal abnormalities involving either Ph Chr or more frequently other Chrs. Genetic alterations sparing Ph Chr are commonly called “additional chromosomal abnormalities (ACAs)” which have been extensively analyzed in recent large studies. In contrast, the presence of additional genetic abnormalities in Ph Chr has been anecdotally reported with an ambiguity of their impact on treatment response. In our case, we report a newly diagnosed CML patient with the rarest additional chromosomal aberration affecting Ph Chr which has revealed an optimal response over a period of 2 years of follow-up. This report underlines the importance of re-examining CML cases for any ACAs, especially those occurring in Ph Chr, which might be overlooked easily. Moreover, their possible role in disease prognostication should be sought, as well.
Keywords: Additional chromosomal abnormality, chronic myelogenous leukemia, Philadelphia chromosome
|How to cite this article:|
Alqahtany B, Alqahtani FS, Khojah O, Almaeen A, Aleem A. Optimal response to imatinib therapy in a case of chronic myeloid leukemia with a concurrent loss of distal 22q. J Appl Hematol 2017;8:152-5
|How to cite this URL:|
Alqahtany B, Alqahtani FS, Khojah O, Almaeen A, Aleem A. Optimal response to imatinib therapy in a case of chronic myeloid leukemia with a concurrent loss of distal 22q. J Appl Hematol [serial online] 2017 [cited 2022 Aug 19];8:152-5. Available from: https://www.jahjournal.org/text.asp?2017/8/4/152/223174
| Introduction|| |
Chronic myelogenous leukemia (CML) is a classical myeloproliferative neoplasm which typically harbors a Philadelphia (Ph) chromosome (Chr) with an incidence of 1–2 cases per 100,000 adults, comprising about 15% of newly diagnosed cases of leukemia in adults. Ph Chr was the first genetic structural abnormality linked to developing a cancer. It results from a balanced translocation (t) between an oncogene, Abelson (ABL1), at Chr 9q34 and a breakpoint cluster region (BCR) gene at Chr 22q11.2 forming a fusion gene (BCR-ABL1). In the current World Health Organization (WHO) classification of hematological neoplasms, CML must show an evidence of Ph Chr, t(9;22)(q34;q11.2), or BCR-ABL1 fusion gene. Otherwise, an alternative diagnosis should be considered., An approximately 5%–10% of CML cases have a cryptic t(9;22) resulting in a normal conventional karyotypic analysis. However, these cases reveal BCR/ABL1 rearrangement by molecular methods including fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR).,, Identification of Ph Chr and BCR-ABL1 fusion gene are crucial for CML diagnosis, assessing therapy efficacy and monitoring disease progression.,
In several occasions, an additional genetic abnormality/ies is/are frequently detected at diagnosis or during therapy course which might reclassify the CML phase.,, These genetic alterations could occur in pathogenic Ph Chr or in another Chr. However, the majority of studies were largely focused on the additional abnormality/ies not affecting the Ph Chr. These abnormalities are known as “additional chromosomal abnormalities (ACAs)” which are classified exclusively based on their occurrence at diagnosis to “major” and “minor” route abnormalities. However, a clear relationship between these ACAs and CML progression and management is still uncertain and under evaluation., On the other hand, a few reports explored the presence of a concurrent alteration affecting the Ph Chr and its partner, Chr 9. This is usually visualized as an abnormal signal by FISH, yet sometimes can be discovered by classical karyotyping or implied from unexpected result of a real-time (RT) PCR. When it is detected by FISH, it is referred to as an “atypical pattern” of Ph Chr that includes diverse genetic aberrations such as loss of one or both residual parts of Chr 9q and Chr 22q, supernumerary Ph Chr, and complex translocations.,, The European LeukemiaNet Recommendations 2013 stated that Chr 9 deletions and variant translocations have no value for prognosis, whereas Chr 22 deletions were not mentioned as a ACA with determined significant. In this case, a full description of a classical CML patient showed atypical pattern by FISH analysis including distal deletion involving Chr 22q that seldom has been reported.
| Case Report|| |
A 33-year-old female presented to the emergency department with a mild fever, recent weight loss, lassitude, and night sweats. On examination, she looked pale and had a moderately enlarged spleen. Urgent initial investigations showed marked elevation in white blood cell (WBC) and platelet counts: 126.96 × 109/L and 1,589 × 109/L, respectively. Profound anemia was evident, hemoglobin (Hb): Seventy-two g/L. Peripheral blood film revealed a moderate leukoerythroblastic blood picture. Red blood cell morphology revealed hypochromic/microcytic picture along with some teardrop poikilocytes and target cells, a few elliptocytes and polychromatic cells and occasional nucleated erythrocytes. Marked leukocytosis with left shift, basophilia (7%), eosinophilia (4%), and blastemia (4%) without Auer rods More Details were seen. Remarkable increase in the neutrophilic (63%) and myelocytic (13%) stages was noticeable. Severe thrombocytosis and frequent platelet clumps were evident. No significant dysplasia was discernible. Neutrophil alkaline phosphatase score was very low (only 3, a feature seen usually in a classical CML case). These findings were likely consistent with CML in chronic phase. The Sokal relative risk (RR), Euro Hasford RR, and EUTOS score are 1.6 (high), 1304 (intermediate), and 65 (low risk), respectively.,, Thus, testing for BCR-ABL1 fusion gene on peripheral blood and bone marrow specimens was requested to confirm the diagnosis and stage of the disease. Bone marrow aspirate showed markedly hypercellular particles (of almost 100% cellularity) along with plentiful megakaryocytes, markedly overactive granulopoiesis, and 3%–4% blasts of all nucleated cells. The trephine biopsy was fully packed with granulopoietic components and no collection of immature cells could be identified. Moreover, the BCR-ABL1 fusion gene turned out to be positive, in keeping with CML in chronic phase. She was started on imatinib 400 mg orally once daily. A week later, the results of bone marrow karyotyping and FISH analysis were released revealing a positive classical CML case with t(9;22) (q34;q11.2). Unfortunately, G-banded karyotyping failed to catch any metaphases. Interestingly, a dual color, dual fusion (DF)-FISH translocation probe showed atypical pattern of t(9;22) (q34;11.2) in 70% of 100 analyzed nuclei. This atypical pattern was represented by a single fusion signal, instead of two fusion signals, with one green and two red signals. These findings primarily meant an existence of Ph Chr with a concurrent loss of distal 22q that usually occurs as a balanced translocation with derivative (der) of Chr 9 [Figure 1] and [Figure 2]. The patient showed an optimal response to imatinib after 3 months of therapy. The Hb level improved reaching 103 g/L and both WBC and platelet counts were normalized (i.e., 5.8 × 109/L and 178 × 109/L, respectively). Later at 12-month follow-up, the conventional karyotyping, FISH, and molecular studies showed a complete cytogenetic and major molecular (MR4) responses with lack of distal deletion of Chr 22q. This optimal response has been maintained for a period of 22 months till the last follow-up.
|Figure 1: FISH study using LSI BCR/ABL1, dual color, dual fusion probe (Vysis Inc., IL, USA). Yellow (y) color: representing BCR-ABL1 fusion gene. Red (r) color: representing ABL1 gene at Chr 9q. Green (g) color: representing BCR gene at Chr 22q. In this case, 1Y, 2R, and 1G signals stated developing Ph Chr with a deletion of distal derivative of Chr 22q. FISH = Fluorescence in situ hybridization; BCR = Breakpoint cluster region; Chr = Chromosome|
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|Figure 2: Illustration of t(9;22)(q34;q11.2), BCR-ABL1 fusion gene by FISH study. (a) Normal cell pattern, (b) Classical CML cell pattern, (c) Atypical pattern in this case with additional deletion in distal Chr 22q. FISH = Fluorescence in situ hybridization; BCR = Breakpoint cluster region; CML = Chronic myelogenous leukemia; Chr = Chromosome; Der = Derivative; F = Fusion signal; R = Red signal; G = Green signal (courtesy to Dr. P. Tavares, CGC Genetics, Porto, Portugal)|
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| Discussion|| |
This CML case exhibited an abnormal DF-FISH pattern represented by an additional genetic aberration (i.e., distal loss of Chr 22q11.2 at BCR gene level) which has not deleteriously affected the outcome so far. Infrequent studies investigated the atypical pattern of Ph Chr. In 2005, Lim et al. published a large study of 27 Ph-positive cases with five different atypical FISH patterns. Ph Chr accompanied with loss of residual proximal 9q and distal 22q was observed in 10 (37%) cases while only 2 (7%) out of 27 cases showed Ph Chr with a distal loss of der Chr 22q. Other abnormalities coexisting with Ph Chr included complex translocations, additional Ph Chr/s, and proximal loss of Chr 9q were observed in 9 (33%), 3 (11%), and 3 (11%) cases, respectively. However, these cases were primarily treated before the targeted therapy era and drawing a conclusion of the impact of these additional alterations is not possible. Unfortunately, no recent data reported the frequency or the outcome of distal deletion of BCR as an additional abnormality to Ph Chr.
In contrast, the ACAs have been recognized in depth in the recent years. The current WHO 2008 “blue book” monograph of hematological neoplasms only defined a clonal cytogenetic evolution occurring after the initial diagnostic karyotype as a warning sign for accelerated phase (AP) in CML. However, the updated revision of WHO 2016 classification of myeloid neoplasm recognized eight criteria for defining AP of CML, two of which are related to cytogenetic abnormalities. The first criterion is any additional clonal chromosomal abnormalities in Ph-positive cells at diagnosis that include “major route” abnormalities (i.e., second Ph, trisomy 8, isochromosome [iso] 17q, and trisomy 19), complex karyotype, or abnormalities of 3q26.2. The other criterion is an occurrence of any new clonal chromosomal abnormality in Ph-positive cells during therapy. In addition, the updated classification added provisional criteria for molecular testing of BCR-ABL1 fusion gene by RT-PCR. Recently, a large study was published which divided the most common six ACAs into two groups. The first group, including trisomy 8, deletion (-) Y, and an extra copy of Ph Chr, had a relatively good prognosis and did not affect the overall survival compared to patients without ACAs. The iso 17q10, −7/del7q, and 3q26.2 rearrangements/abnormalities constituted the second group with inferior survival rate and poorer prognosis. This study also illustrated that presence of two or more ACAs conferred an inferior survival and can be categorized into the poor prognostic group regardless of the individual types of ACAs.
In summary, classical CML cases occasionally harbor a concurrent alteration in Ph Chr or its counterpart Chr which has undetermined significance. The rarest reported abnormality of atypical pattern is loss of der Chr 22q which appears innocuous in this case, at least so far. Whether the patient will develop resistance to imatinib and have progression of disease remains to be seen. A large multicenter study should be undertaken to examine the impact of such abnormalities on CML patients. This report emphasizes the urgency for implementation of a better reporting protocol of the findings of conventional and molecular cytogenetic CML studies to reduce missing such concurrent abnormalities that might affect the disease management and outcome.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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