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Fulltext Detection of bcr/abl gene in chronic myeloid leukaemia: comparison of fluorescence in situ hybridisation (fish), conventional cytogenetics and polymerase chain reaction (pcr) techniques

Siti Aishah Md Ali, Ilina Isahak, Dahlan Sabil, Fatimah Sahlan, Lokman Saim, Abdullah Sani Mohamed

Medicine & Health, 2006;1(1):5-13.
MyJurnal

The reciprocal translocation t(9;22)(q34;q11) which gives rise to the Philadelphia (Ph1) chromosome and BCR/ABL fusion gene, plays a pivotal role in the diagnosis and pathogenesis of chronic myeloid leukemia (CML). In this study, we evaluated the role of fluorescence in situ hybridisation (FISH) in detecting the BCR/ABL rearrangement in CML patients. The sensitivity, specificity and detection rate of BCR/ABL gene using FISH, PCR and conventional cytogenetics (karyotyping) methods were also compared. 18 bone marrow samples of patients with clinically diagnosed CML and suspected of CML were collected. The sensitivity, specificity and positive predictive values of FISH were altogether 100% while the sensitivity, specificity and positive predictive values for conventional cytogenetics (karyotyping) were 85%, 100% and 100% respectively. Convetional cytogenetics (karyotyping) detected an additional chromosomal aberration in addition to the Ph1 chromosome. In conclusion, FISH is a highly sensitive method in detecting the BCR/ABL gene. Conventional cytogenetics (karyotyping) remains an important investigation in the work up of suspected CML patients since there is a possibility of detecting chromosomal aberrations in addition to the Ph1 translocation. Therefore, conventional cytogenetics (karyotyping) and FISH are complementary techniques and their results should be interpreted together with clinical information.

Matched MeSH terms: Philadelphia Chromosome; Philadelphia
Management of classical Philadelphia chromosome-negative myeloproliferative neoplasms in Asia: consensus of the Asian Myeloid Working Group

Gill H, Leung GMK, Ooi MGM, Teo WZY, Wong CL, Choi CW, et al.

Clin Exp Med, 2023 Dec;23(8):4199-4217.
PMID: 37747591 DOI: 10.1007/s10238-023-01189-9

Myeloproliferative neoplasms (MPN) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized clinically by the proliferation of one or more hematopoietic lineage(s). The classical Philadelphia-chromosome (Ph)-negative MPNs include polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). The Asian Myeloid Working Group (AMWG) comprises representatives from fifteen Asian centers experienced in the management of MPN. This consensus from the AMWG aims to review the current evidence in the risk stratification and treatment of Ph-negative MPN, to identify management gaps for future improvement, and to offer pragmatic approaches for treatment commensurate with different levels of resources, drug availabilities and reimbursement policies in its constituent regions. The management of MPN should be patient-specific and based on accurate diagnostic and prognostic tools. In patients with PV, ET and early/prefibrotic PMF, symptoms and risk stratification will guide the need for early cytoreduction. In younger patients requiring cytoreduction and in those experiencing resistance or intolerance to hydroxyurea, recombinant interferon-α preparations (pegylated interferon-α 2A or ropeginterferon-α 2b) should be considered. In myelofibrosis, continuous risk assessment and symptom burden assessment are essential in guiding treatment selection. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) in MF should always be based on accurate risk stratification for disease-risk and post-HSCT outcome. Management of classical Ph-negative MPN entails accurate diagnosis, cytogenetic and molecular evaluation, risk stratification, and treatment strategies that are outcome-oriented (curative, disease modification, improvement of quality-of-life).

Matched MeSH terms: Philadelphia Chromosome
Fulltext Double Philadelphia chromosome-positive B acute lymphoblastic leukaemia in an elderly patient

Tang YL, Raja Sabudin RZ, Leong CF, Ko CC, Chia WK, Salwati S, et al.

Malays J Pathol, 2015 Dec;37(3):275-9.
PMID: 26712675 MyJurnal

A rare case of double Philadelphia chromosome-positive B Acute lymphoblastic Leukaemia (B-ALL) is reported here. A 60-year-old lady presented with one month history of fever, submandibular lymphadenopathy, loss of appetite and weight loss. Physical examination revealed multiple palpable cervical lymph nodes. Blood film showed leucocytosis with 72% blasts. Bone marrow assessment confirmed a diagnosis of B-ALL with presence of double Philadelphia (Ph) chromosomes. As she was very ill, she was initially treated with an attenuated regimen of induction chemotherapy consisting of rituximab, cyclophosphamide, vincristine and prednisolone (R-CVP) along with intrathecal chemotherapy comprising methotrexate, cytarabine and hydrocortisone. Bone marrow examination post-induction chemotherapy showed >5% blasts. She was subsequently re-induced with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) along with intrathecal chemotherapy, following which she went into complete remission. Consolidation chemotherapy consisting of methotrexate, methylprednisolone, cytarabine, intrathecal chemotherapy and imatinib was subsequently administered followed by maintenance chemotherapy consisting of vincristine, prednisolone and imatinib (IDEAMOP). She developed spontaneous bruises and relapsed four months into her maintenance chemotherapy with 90% blasts in the bone marrow which was treated with fludarabine, cytarabine and granulocyte colony stimulating factor (FLAG). Unfortunately she developed neutropenic sepsis which was complicated by invasive lung aspergillosis. Bone marrow examination post-FLAG showed 80% blasts. Despite aggressive antifungal therapy, her lung infection worsened and she finally succumbed to her illness 13 months after the initial diagnosis. We highlight a rare case of elderly B-ALL with double Ph chromosomes which carries a poor prognosis despite aggressive treatment for the disease and its complications.

Matched MeSH terms: Philadelphia Chromosome*
Mixed phenotype acute leukaemia with t(9,22), BCR-ABL1: A case report

Yong WL, Yusof N, Ithnin A, Shuib S, Tumian R, Yousuf R, et al.

Malays J Pathol, 2020 Dec;42(3):469-476.
PMID: 33361731

INTRODUCTION: Mixed phenotype acute leukaemia (MPAL) is a rare entity of acute leukaemia.
CASE REPORT: Here we report a case of a 39-year-old lady, with an incidental finding of hyperleukocytosis (white blood cells count: 139.2 x 109/L). Her peripheral blood film revealed 36% of blasts and a bone marrow aspiration showed 53% of blasts. Immunophenotyping showed a population of blasts exhibiting positivity of two lineages, myeloid lineage and B-lymphoid lineage with strong positivity of CD34 and terminal deoxynucleotidyl transferase (Tdt). A conventional karyotyping revealed the presence of Philadelphia chromosome. She was diagnosed with MPAL with t(9,22), BCR ABL1, which carried a poor prognosis. She was treated with acute lymphoblastic leukaemia (ALL) chemotherapy protocol coupled with a tyrosine kinase inhibitor and was planned for an allogeneic stem cells transplant.
CONCLUSION: This MPAL case was diagnosed incidentally in an asymptomatic patient during medical check-up. We highlight this rare case report to raise the awareness about this rare disease. Understanding the pathogenesis of the disease with the underlying genes responsible for triggering the disease, uniform protocols for diagnosis and targeted treatment will help for proper management of these patients.

Matched MeSH terms: Philadelphia Chromosome*
Fulltext Molecular rearrangements of chromosome 22 in chronic myeloid leukemia in a multi-ethnic Malaysian population

Bosco JJ, Dyck JA

Singapore Med J, 1989 Aug;30(4):363-7.
PMID: 2814539

Rearrangements in the DNA of chronic myelogenous leukemia patients of Chinese, Malay and Indian origin were detected in the breakpoint cluster region of chromosome 22 using molecular techniques. The DNA of fifty patients was examined using a 1.2 kb DNA probe. Rearrangements were detected in 46/50 patients. Karyotypic data were available in nine patients, all of whom were Philadelphia chromosome positive and exhibited DNA rearrangement. Detection of the Philadelphia translocation by molecular methods, at this institution, where cytogenetics is not routinely performed, confirms its diagnostic value. The rearrangement data obtained in this study is consistent with molecular features of chronic myelogenous leukemia patients of Western countries.

Matched MeSH terms: Philadelphia Chromosome*
Fulltext BCR-ABL positive essential thrombocythaemia: a variant of chronic myelogerous leukaemia or a distinct clinical entity: a special case report

Fadilah SA, Cheong SK

Singapore Med J, 2000 Dec;41(12):595-8.
PMID: 11296785

A 37-year-old Malay man presented initially with the clinical picture of essential thrombocythaemia (ET) without the extreme leukocytosis, marked splenomegaly and low neutrophil alkaline phosphatase characteristic of chronic myelogenous leukaemia (CML). Bone marrow examination showed massive megakaryocytic hyperplasia; cytogenetic studies showed the presence of Philadelphia chromosome. The patient was treated with hydroxyurea that resulted in reduction in the platelet count. Seventeen months later, he presented with fever associated with tender massive splenomegaly. Bone marrow finding was consistent with chronic phase CML. The presence of a rearrangement involving the major breakpoint cluster region (M-bcr) on chromosome 22 was confirmed by reverse transcriptase-polymerase chain reaction. The clinical importance of finding the Philadelphia chromosome in patients who seem to have ET is in assessing prognosis. ET generally follows a chronic, indolent course. However, this patient who had Philadelphia chromosome underwent clinical transition to chronic phase CML17 months and blast crisis 29 months after presentation.

Matched MeSH terms: Philadelphia Chromosome*
Systematic Review of Normal Subjects Harbouring BCR-ABL1 Fusion Gene

Kuan JW, Su AT, Leong CF, Osato M, Sashida G

Acta Haematol., 2020;143(2):96-111.
PMID: 31401626 DOI: 10.1159/000501146

The treatment of chronic myeloid leukaemia (CML) requires quantitative polymerase chain reaction (qPCR) to monitor BCR-ABL1 in International Scale (IS). Some normal subjects were found to harbour BCR-ABL1. We performed a systematic review on normal subjects harbouring BCR-ABL1. A literature search was done on July 16, 2017 using EBSCOhost Research Databases interface and Western Pacific Region Index Medicus. Two authors selected the studies, extracted the data, and evaluated the quality of studies using the modified Appraisal Tool for Cross-Sectional Studies independently. The outcomes were prevalence, level of BCR-ABL1IS, proportion, and time of progression to CML. The initial search returned 4,770 studies. Eleven studies, all having used convenient sampling, were included, with total of 1,360 subjects. Ten studies used qualitative PCR and one used qPCR (not IS). The mean prevalence of M-BCR was 5.9, 15.5, and 15.9% in cord blood/newborns/infants (CB/NB/I) (n = 170), children (n = 90), and adults (n = 454), respectively, while m-BCR was 15, 26.9, and 23.1% in CB/NB/I (n = 786), children (n = 67), and adults (n = 208), respectively. No study reported the proportion and time of progression to CML. Nine studies were graded as moderate quality, one study as poor quality, and one study as unacceptable. The result of the studies could neither be inferred to the general normal population nor compared. Follow-up data were scarce.

Matched MeSH terms: Philadelphia Chromosome
Clinical stage of chronic granulocytic leukaemia and BCR breakpoint location in South-East Asian patients

Dyck JA, Bosco JJ

Br J Haematol, 1989 May;72(1):64-7.
PMID: 2736243

Forty-six Malaysian patients with chronic granulocytic leukaemia were found to be rearranged in the breakpoint cluster region (BCR) of chromosome 22, molecular evidence of Philadelphia chromosome (t9.22) translocation. Through the use of a 1.2 kb 3' BCR probe and two restriction enzyme digests, patients' breakpoints could be localized either to 5' or 3' regions of the BCR. Breakpoint site localization at the time of DNA sampling did not show any positive statistical association to clinical status defined as chronic phase, chronic phase with less than 6 months to blast crisis, accelerated phase and blast crisis. This was in contrast to earlier reports which indicated that patients with breakpoint at 3' site were at a higher biologic risk for entering blast crisis.

Matched MeSH terms: Philadelphia Chromosome
Fulltext Biphenotypic acute leukemia: a report of two cases

Azma, R.Z., Hamidah, N.H., C-F, Leong, Ainoon, O., Fadilah, S.A.W., S-K, Cheong, et al.

Medicine & Health, 2006;1(1):53-60.
MyJurnal

We report two cases of biphenotypic acute leukaemia diagnosed in Hospital Universiti Kebangsaan Malaysia (HUKM), their clinical, haematological characteristics and response to chemotherapy. Both patients are middle-aged ladies who presented with hepatosplenomegaly and high white cell count, mainly composed of blast cells. Their bone marrow aspirations were hypercellular comprising of more than 90% heterogenous blast cells. Cytochemical analyses show more than 3% positivity towards peroxidase, with smaller blasts showing block positivity towards PAS. Immunophenotypically, the blasts showed dual expression of CD 33 and CD 19, CD 19 and CD34, intra CD22, intra TdT and intraMPO. One of the patients showed presence of the Philadelphia chromosome on cytogenetic analysis which was confirmed by Fluorecsence In Situ Hybridisation (FISH). Molecular analysis also showed presence of the BCR-ABL fusion protein. Both patients were given combination chemotherapy consisting of daunorubicin and cytosine arabinoside.However, the patient with positive Philadelphia chromosome BCR-ABL did not achieve morphological remission after induction chemotherapy. In view of the poor prognosis of this disease, both the patients were planned for upfront peripheral blood stem cell transplantation.

Matched MeSH terms: Philadelphia Chromosome