Complex Variant Translocations Research Articles

Cytogenetic and epidemiological profile of chronic myeloid leukemia in Morocco.

Chronic myeloid leukemia (CML) is a neoplastic disease of genetic origin resulting from clonal proliferation of hematopoietic stem cells (HSCs). The reciprocal translocation t(9;22)(q34;q11) is the main chromosomal abnormality involved in this pathology, usually detected by conventional cytogenetics. This article aims to investigate the epidemiological, cytogenetic, therapeutic, and clinical characteristics of Moroccan patients with CML. This research represents the first large-scale study of CML patients in Morocco and was carried out at Institut Pasteur of Morocco. Bone marrow samples were processed for cytogenetic analysis, and karyotypes were described according to an international system of human cytogenetic nomenclature (ISCN 2016). Patients were studied according to their epidemiological characteristics, clinical information and cytogenetic results. For statistical calculations, R version 4.3.1 was used to analyze the data and calculate the statistical parameters. RStudio and Power BI were used for data visualization. The National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) method of incidence estimation was used to calculate our incidence. We received 826 patients (from 1992 to 2023) who were referred for suspected CML or who were undergoing treatment. Only 650 patients with confirmed CML were included in the study, all of whom underwent their first cytogenetic test. The median age of our patients was 45 years and the sex ratio was 1.03. At the time of diagnosis, 147 (30%) of the patients had clinical manifestations. Most patients were diagnosed in the chronic phase (94.5%). Nineteen complex variant translocations of the Philadelphia (Ph) chromosome were detected. At the time of diagnosis, 55 (11.5%) patients had ACAs, of which 30 (54.5%) were high-risk ACAs. Based on data from 174 patients treated with imatinib, the median time to complete cytogenetic response (CCyR) was 11 months, and at the last cytogenetic follow-up, 81 patients (46.6%) achieved CCyR, while 64 patients (36.8%) showed no response to treatment. Regarding adherence to European LeukemiaNet (ELN) guidelines, 58 patients (33%) were followed according to these guidelines, with optimal treatment in 8.6%, suboptimal treatment in 7% and treatment failure in 18%. The estimated incidence of chronic myeloid leukemia calculated is 0.6 cases per 100,000 in the Casablanca region. This study provides a detailed overview of CML in Morocco, highlighting important clinical, cytogenetic and therapeutic aspects despite some limitations. It also highlights the need to deepen our understanding of this complex disease for disease management in our specific context.

Three-way Complex Variant Translocation Involving Long Arm of Chromosome 1 in a Chronic Myeloid Leukemia Patient

Clinical presentation of chronic myeloid leukemia (CML) with classic translocation is similar to those with variant translocations. However, the disease course, outcome and prognosis differs to a large extent. Therefore, it is important to identify and report variant cytogenetic findings. The case is being reported to improve awareness regarding such cases.
 Case Presentation: Herein we present a case study of 55-year-old male who presented with abdominal pain and fever. The initial complete blood count showed hyperleukocytosis with features suggestive of chronic myeloproliferative leukemia (CML). Bone marrow biopsy and cytogenetic studies were performed for confirmation. Cytogenetic analysis showed presence of complex, three-way (1;9;22)(q12;q34;q11.2) translocation involving chromosomes 1, 9 and 22. The Fluorescence in situ hybridization (FISH) studies further confirmed BCR-ABL fusion gene and its atypical pattern was in concordance with aberrations observed in karyotype. The variant translocation we reported herein is unique and rarely reported in literature.
 Discussion: We presented a complex variant case of three-way translocation with characteristic hematological and immunophenotypic findings of CML in chronic phase. To the best of our knowledge, only few cases have been documented so far involving such complex translocation. The initial response to cytoreduction was encouraging while imatinib response has to be followed in present case.
 Conclusion: It is important to highlight the variant translocations since such findings may influence the disease course hence play a significant role to predict outcome.

A complex KMT2A::AFF3 fusion resulting from a three-way chromosomal rearrangement in pediatric B lymphoblastic leukemia

The KMT2A::AFF3 fusion, t(2;11)(q11.2;q23.2), is a very rare fusion occurring in pediatric B-cell acute lymphoblastic leukemia (B-ALL). Our patient is a 2-year-old male who presented with three weeks of intermittent fever. Bone marrow biopsy showed 82% blasts and cytogenetic analysis demonstrated a complex 3-way chromosomal rearrangement involving KMT2A and an unknown fusion partner. Molecular testing identified the fusion partner as AFF3, a FLT3-TKD non-D835 mutation, and an NF1 mutation. This case demonstrates a highly complex three-way variant translocation resulting in the rare KMT2A::AFF3 fusion with only a few cases previously described in the literature.

Molecular, Cytogenetic, and Hematological Analysis of Chronic Myeloid Leukemia Patients and Discovery of Two Novel Translocations.

Chronic myeloid leukemia (CML) is a disease of hematopoietic stem cells and is caused by the balanced translocations among the long arms of chromosomes 9 and 22, which are called the Philadelphia (Ph) chromosome. In this study, 131 CML patients were enrolled. Complete blood cell count was performed at the time of diagnosis for all the patients. Cytogenetic (karyotyping) examination using bone marrow samples was conducted on 76 CML patients for the confirmation of Ph-positive (9;22)(q34;q11) standard translocation, complex variant translocation, and additional chromosome abnormalities. FISH was performed on 38 patients for diagnostic purposes and on 39 patients for monitoring purposes. Twenty-two samples of CML patients were evaluated by reverse transcriptase PCR and real-time PCR for the patients who failed to respond against imatinib mesylate. In this study, 72 (54.96%) were males and 59 (45.03%) were females with a median age of 38.5 years. CBC values in the diagnosis process showed that 75 patients had high values of WBC being >100 × 103/μl, while 71 (58.01) patients exhibited reduced values of hemoglobin, i.e., <10.00 mg/dl, and high values of PLTs > 100 were observed in 40 (30.53%) patients. Cytogenetic results show that standard translocation was developed in 63 (82.89%), development of complex variant translocations in 4 (5.32%), additional chromosomal abnormalities (ACAs) in 3 (3.94%), and ACAs together with complex variant translocations in 1 (1.31%) patient. At the time of diagnosis, 61 (92.95%) patients were in the chronic phase, 4 (5.63%) were in the accelerated phase, and only 1 (1.40%) was in the blast crisis. Out of twenty-two patients, only 6 CML patients who were shifted from imatinib mesylate to nilotinib showed BCR-ABL-positive amplification. However, only 7 out of twenty-one patients exhibit BCR-ABL gene values ≥ 1 after three months of follow-up when analyzed by the quantitative real-time PCR. In conclusion, we found a novel five-way translocation 46XX,t(1;2;2;17;9;22)(p36.3,q21;q11.2,q21,q34,q11.2) and a novel four-way complex variant translocation 48XY,+8(8;17)(9;22),+der(22)(q11.2;q23)(q34;q11.2) in the accelerated phase.

A unique three-way Philadelphia chromosome variant t(4;9;22)(q21;q34;q11.2) in a newly diagnosed patient with chronic phase chronic myeloid leukemia: a case report and review of the\xa0literature

BackgroundChronic myeloid leukemia is a hematologic malignancy associated with the fusion of two genes: BCR and ABL1. This fusion results from a translocation between chromosomes 9 and 22, which is called the Philadelphia chromosome. Although the Philadelphia chromosome is present in more than 90% of patients with chronic myeloid leukemia, 5–8% of patients with chronic myeloid leukemia show complex variant translocations. Herein, we report a unique case of a three-way translocation variant in chronic phase chronic myeloid leukemia.Case presentationA 40-year-old Asian male who presented with leukocytosis was diagnosed with chronic phase chronic myeloid leukemia. Cytogenetic karyotyping analysis showed 46,XY,t(4;9;22)(q21;q34;q11.2). He was treated with bosutinib and then changed to dasatinib because of intolerance, and MR4.5 (BCR-ABL/ABL ≦ 0.0032%, international scale) was achieved after 17 months of continuous treatment.ConclusionThis was the 14th case of t(4;9;22), in particular, a new variant Ph translocation involved in chromosome 4q21 and the first successful case treated with tyrosine kinase inhibitors in the world. We summarize previous case reports regarding three-way variant chromosome translocation, t(4;9;22) and discuss how this rare translocation is linked to prognosis.

Characterization of acute promyelocytic leukemia cases lacking the classic t(15;17): results of the European Working Party

AbstractAcute promyelocytic leukemia (APL) is typified by the t(15;17), generating the PML-RARα fusion and predicting a beneficial response to retinoids. However, a sizeable minority of APL cases lack the classic t(15;17), prompting the establishment of the European Working Party to further characterize this group. Such cases were referred to a workshop held in Monza, Italy and subjected to morphologic, cytogenetic, and molecular review, yielding 60 evaluable patients. In the majority (42 of 60), molecular analyses revealed underlying PML/RARα rearrangements due to insertions (28 of 42) or more complex mechanisms, including 3-way and simple variant translocations (14 of 42). Metaphase fluorescence in situ hybridization (FISH) demonstrated that insertions most commonly led to formation of the PML-RARα fusion gene on 15q. In 11 of 60 workshop patients, PLZF/RARα rearrangements were identified, including 2 patients lacking the t(11;17)(q23;q21). In one case with a normal karyotype, FISH analysis revealed insertion ofRARα into 11q23, and PLZF-RARα was the sole fusion gene formed. Two patients were found to have t(5;17), one with a diffuse nuclear NPM staining pattern and with NPM-RARαand RARα-NPM transcripts detected. In the other with an unbalanced der(5)t(5;17)(q13;q21) and a nucleolar NPM localization pattern, an NPM/RARα rearrangement was excluded, and FISH revealed deletion of one RARα allele. In the remaining 5 workshop patients, no evidence was found for a rearrangement ofRARα, indicating that in rare instances, alternative mechanisms could mediate the differentiation block that typifies this disease. This study highlights the importance of combining morphologic, cytogenetic, and molecular analyses for optimal management of APL patients and better understanding of the pathogenesis of the disease.

Do Not Miss Karyotyping at Chronic Myeloid Leukemia Diagnosis: An Italian Campus CML Study on the Role of Complex Variant Translocations

Background. The Philadelphia (Ph) chromosome (chr.) is the hallmark of chronic myeloid leukemia (CML) and typically results from the reciprocal translocation t(9;22)(q34;11.2). Complex variant translocations (CVT) involving one or more additional chr. are identified in less than 5% of newly diagnosed CML. There are conflicting reports about the prognostic impact of CVT in the achievement of optimal response to tyrosine kinase inhibitor (TKI), and very few studies addressed the role of frontline treatment with imatinib or second generation (2G)-TKI in patients with CVT. Aims. To assess the response to imatinib or 2G-TKI in a large cohort of newly diagnosed CML with CVT, and to explore the impact of the different chr. translocations on outcome. Methods. This observational retrospective study was conducted in 19 hematologic centers in the framework of Campus CML, a network of Italian physicians involved in the management of CML patients. All newly diagnosed CML from 2000 to 2019 were evaluated and patients with CVT were selected for the present analysis. Karyotypes were defined according to the 2016 International System for Human Cytogenetic Nomenclature. Responses to frontline treatment were retrospectively categorized according to the 2013 ELN recommendations, as they include cytogenetic milestones. Deep molecular response (DMR, i.e. MR4or better) was defined as BCR-ABLIS ratio ≤0.01% or undetectable disease with ≥10,000 ABL copies. Patients with DMR lasting ≥2 years and at least a Q-PCR test every 6 months were defined as stable DMR responders. Failure-free survival (FFS) was calculated from the start of frontline TKI treatment to progression to advanced phase, death, or switch to other treatments for resistance. For FFS calculation, patients were censored at TKI stop for treatment-free remission (TFR) or in case of switch for intolerance only. Differences between subgroups according to the partner chr. were presented for descriptive purposes. Results. CVT were identified in 109 (3.2%) patients from a whole population of 3,361 subjects with newly diagnosed CML. Ninety-five out of 109 patients (87%) exhibited three-way translocations, with chr. 1, 4, 6, 10, 11, 12, 14, 15 and 17 representing the most common additional partners (figure). Four- and five-way translocations were identified in 13 and 1 patients, respectively. Additional chr. abnormalities (ACA) in the Ph+ cells were observed in 15/109 (13.8%) patients and were more common in older individuals (p=0.018). Overall, median age at diagnosis was 50.6 years (range 20-90). Risk distribution according to the ELTS score was 54%, 28% and 8% for L, I and H risk, respectively (10% missing). Cytogenetic result was available before the choice of frontline treatment in 45% of cases and represented a decisive factor in 28% of them (i.e. clinicians selected a 2G-TKI or high-dose imatinib, according to the available options). Frontline TKI treatment was imatinib in 80 cases (73%) and 2G-TKI (nilotinib n=22, dasatinib n=6, bosutinib n=1) in the remaining cases. The frequency of optimal response at 3, 6 and 12 months was 48%, 45% and 53%, respectively, for imatinib-treated patients, and 76%, 83% and 76%, respectively, for the 2G-TKI cohort (p&amp;lt;0.05 for all comparisons). Stable DMR was achieved by 39% of patients and 42% of them attempted a TFR. After a median follow-up of 91.3 months (range 1-236), 5-year FFS was 66% (95%CI: 53.4-76.4) and 84% (95%CI: 62.4-93.6) for imatinib and 2G-TKI treated patients, respectively (p=ns). The estimated 10-year OS for the entire cohort was 84.4% (95%CI: 73.6-91). The subtype of CVT had an impact on response and long-term outcome. Patients with CVT involving chr. 1, 4, 6, 11 or 12 had a higher frequency of MMR at 12 months than patients with CVT involving chr. 10, 14, 15 or 17 (75.8% vs 30.4%, respectively, p=0.001), higher frequency of stable DMR (48.7% vs 22.2%, respectively; p=0.04) and tended to have better median FFS (p=0.07), regardless of the type of frontline TKI and of the ELTS score. Conclusions. Due to its retrospective nature, this study does not allow to define which is the optimal therapy for CML harboring CVT at diagnosis. However, our data reinforce the usefulness of bone marrow karyotyping in CML. The observed differences between partner chr. may also depend on the breaking points, which are variable. Further dissection of CVT will help to identify which are associated to a poor response to TKIs. Figure Disclosures D'Adda: Incyte: Other: Advisory board; Novartis: Other: Advisory board; Pfizer: Other: Advisory board. Galimberti:Novartis: Speakers Bureau; Incyte: Honoraria. Crugnola:Celgene: Honoraria; Janssen: Honoraria; BMS: Honoraria; Novartis: Honoraria. Bocchia:Incyte: Honoraria; CELGENE: Honoraria. Krampera:Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Breccia:Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Abbvie: Consultancy; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Saglio:Novartis: Research Funding; Ariad: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Research Funding; Incyte: Research Funding; Roche: Research Funding.

Złożona translokacja wariantowa t(9;22;6;17;1) w przebiegu leczenia przypadku przewlekłej białaczki szpikowej.

The presence of the Philadelphia chromosome (Ph) in chronic myelogenous leukaemia (CML) is a specific cytogenetic change resulting from a reciprocal translocation between chromosomes 9 and 22. In 5–10% of newly diagnosed cases there are variant translocations (vPh) involving more chromosomes. This paper presents the case of a CML patient with a complex variant translocation involving chromosomes 1, 6, 9, 17 and 22. A molecular analysis did not reveal any muta­tion in the kinase domain of BCR-ABL1 gene or the mutation of TP53 gene. After the first-line treatment with imatinib no cytogenetic or molecular response was obtained. The change of treatment to dasatinib resulted in a minimal cytogenetic response (minCyR) followed by a minor cytogenetic response (mCyR). The application of nilotinib in the third-line treatment resulted in a complete molecular response (CMolR) and therapy success. The likely reason for the failure of the first- and second-line treatment was the loss of a fragment of the 17p13 region as a result of a variant translocation. The change can be a functional equivalent of the loss of one copy of TP53 . The analysis of presented case confirms the significance of the detailed evaluation of the composition of vPh complex variant translocations as well as importance of combination cytogenetic and molecular diagnostics in CML treatment monitoring. It makes possible to adequate diagnose higher-risk patients and apply effective treatment strategies if an aberration is identified.

PB1954 DETECTION OF COMPLEX VARIANT T(9;22) CHROMOSOME TRANSLOCATIONS IN NEWLY DIAGNOSED CASES OF CHRONIC MYELOID LEUKAEMIA

Background:Chronic myeloid leukemia (CML) is a stem cell clonal disease characterized by the acquisition of a fusion protein, BCR‐ABL1 oncogene, which leads to uncontrolled proliferation of myeloid elements in all stages of differentiation. However, a small proportion of patients with CML have simple or complex variants of this translocation, involving various breakpoints in addition to 9q34 and 22q11.Aims:Detection of complex variant t(9;22) chromosome translocations in newly diagnosed cases of Chronic Myeloid Leukaemia which help us to choose therapy modalities.Methods:This study was conducted for a time period of 05 years from 2012 to 2017 in the department of Oncology/ Hematology of Civil hospital, Karachi. Between April 2012 and April 2017, 88 CML patients were diagnosed in our Department. Informed consent was obtained from the patient in accordance with the Declaration of Helsinki. Diagnosis was done on the morphological basis and BCR‐ABL mutation by PCR/FISH. Conventional cytogenetic analysis was performed on unstimulated 24‐hour culture of a bone marrow (BM) specimen. The cells were cultured and processed by conventional methods, and the chromosomes were stained with trypsin‐Giemsa banding (GTG‐banding).Results:A total of 88 patients were Philadelphia‐positive CML, out of which 53(60.2%) were males &amp; 35(39.7%) were females. Mean age was 48 yrs ± 11.43. Out of them, the group of 9 (10.2%) patients with complex cytogenetics were consisted of 5 females and 4 males, ranging in age at diagnosis from 32 to 66 yrs. All the patients were in chronic phase at presentation. Cytogenetic analysis by G‐banding revealed the presence of 9 reciprocal three‐way variant translocations of the classical t(9;22)(q34;q11). The chromosome breakpoints involved in these complex variant translocations were the following: 1p13, 1q21, 1p22, 2q31, 3q21, 3p21, 11q13, 15q24 and Xp11.2Summary/Conclusion:In our study 09 patients had complex variants of t(9;22).The presence of these complex variants at diagnosis and during the TKI treatment may announce treatment failure and/ or transformation to advanced stage (accelerated or blast). Early identification of these abnormalities may help in choosing therapy modalities.

Conventional and molecular cytogenetic studies to characterize 32 complex variant Philadelphia translocations in patients with chronic myeloid leukemia.

BCR/ABL1 gene fusion is the hallmark of chronic myeloid leukemia (CML), and is generated in 5-10% of patients by a variant translocation involving 9q34, 22q11.2 and one or more additional genomic regions. The objective of the present study was to characterize, by conventional and molecular cytogenetics, 32 complex variant Philadelphia (Ph) translocations present at diagnosis in patients with CML. The chromosomes most frequently involved were 1 and 5, and the breakpoint most frequently involved was 12p13. The q-chromosome arm was more frequently involved (60%) than the p-arm. The breakpoints were located in the G-light bands in the majority of cases (85%). Additional chromosomal abnormalities were observed in 6 out of 32 (19%) patients. In conclusion, the combination of conventional and molecular cytogenetics studies has allowed us to: i) Detect and quantify the BCR/ABL1 fusion gene; ii) characterize the complex variant translocations and detect cryptic translocations; iii) confirm that the breakpoints are commonly localized in the G-light bands; (iv) confirm that the genesis of variant translocations could be via either the one-step or two-step mechanisms; and v) to report new cases of complex variant translocations.

The novel three-way variant t(6;17;15)(p21;q21;q22) in acute promyelocytic leukemia with an FLT3-ITD mutation: A case report.

Acute promyelocytic leukemia (APL) is characterized by the reciprocal translocation t(15;17)(q22;q21), resulting in the fusion of the promyelocytic leukemia gene at 15q22 with the retinoic acid receptor α at 17q21. Additionally, all patients with APL who have additional chromosome abnormalities (ACA) and gene mutations are resistant to all-trans retinoic acid (ATRA), the drug that causes disease regression specifically in patients with APL globally. The present study describes a case of a 19-year-old female with APL carrying a novel complex variant translocation t(6;17;15)(p21;q21;q22), add(7)(q32) and an FMS-related tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation. Complete remission was attained following a course of chemotherapy with ATRA and arsenic trioxide. To the best of our knowledge, this is the first report of a novel three-way translocation of 6p21 and a FLT3-ITD mutation involved with APL.

The molecular-cytogenetic characterization and tyrosine kinase inhibitors efficacy in newly diagnosed chronic phase CML patients with variant Philadelphia chromosomes

目的探究伴Ph染色体变异易位（vPh）初诊慢性髓性白血病慢性期（CML-CP）患者的分子、细胞遗传学特征及酪氨酸激酶抑制剂（TKI）的疗效。方法收集32例伴vPh且一线应用伊马替尼（IM）治疗、BCR-ABL转录本为P210的初诊CML-CP患者临床资料，并与同期相同条件的703例伴典型Ph染色体的患者进行对比分析。结果两组人口统计学与初诊时血液学特征比较差异均无统计学意义（P值均>0.05）。32例vPh组患者中3例（9.4%）为简单变异易位，29例为复杂变异易位。29例复杂变异易位患者中，28例（87.5%）累及3条染色体，1例（3.1%）累及4条染色体，除8、15、18及X、Y染色体外，其余染色体均被累及，其中12q（15.5%）与1p（12.1%）累及频率较高。FISH信号以2绿2红1黄（2G2R1Y）（74.1%）为主，其次为1G1R2F（14.8%）、2G1R1Y（3.7%）、1G2R1Y（3.7%）、1G1R1Y（3.7%），简单机制型与复杂机制型亚组比较，完全细胞遗传学反应（CCyR）率（P=0.269）、主要分子学反应（MMR）率（P=0.391）差异无统计学意义。与典型Ph组相比，vPh组具有更高的原发IM耐药率（χ2=3.978，P=0.046），尤其是原发血液学耐药率（χ2=7.870，P=0.005）；但两组CCyR（χ2=0.192，P=0.661）、MMR（χ2=0.822，P=0. 365）、无事件生存（χ2=0.509，P=0.476）、总生存（χ2=3.485，P=0.062）比较差异均无统计学意义。通过多因素分析显示vPh的存在并不影响患者总生存（RR=0.692，95%CI 0.393~1.765，P=0.658）、无事件生存（RR=0.893，95%CI 0.347~2.132，P=0.126）及无进展生存（RR=1.176，95%CI 0.643~2.682，P=0.703）。结论CML-CP vPh患者与典型Ph患者具有相似的人口学及血液学特征，除22q11、9q34外，vPh累及的染色体以12q、1p较多，FISH信号类型以2G2R1Y为主，不同的形成机制对TKI疗效无明显影响。vPh与较高的IM原发耐药率，尤其是与原发血液学耐药率相关，但换用二代TKI后患者能迅速获得深层次分子学反应，长期疗效并不受影响。

Co-existence of isodicentric Ph chromosomes and the three-way Ph chromosome variant t(3;9;22)(p21;q34;q11) in a rare case of chronic myeloid leukemia.

More than 90% of patients with chronic myeloid leukemia (CML) have the chromosomal translocation t(9;22)(q34;q11), while 5-8% of patients have complex variant translocations that have previously been thought not to affect the efficacy of imatinib therapy. The present study reports a patient with CML in B-lymphoid blast crisis who had a rare three-way Philadelphia (Ph) variant t(3;9;22)(p21;q34;q11), in addition to isodicentric Ph chromosomes. The patient was initially treated with imatinib for >2 months with a very poor response. When no T315I or F317L mutations in the ABL proto-oncogene 1 region were detected, the patient received dasatinib treatment (140 mg daily) and achieved a complete hematologic response. Following allo-hematopoietic stem cell transplantation, the patient displayed clinical, hematological and cytogenetic remission, with complete molecular response and complete donor chimerism, and stopped taking dasatinib at the last follow-up. The present data suggest that BCR-ABL gene amplification may be associated with imatinib resistance, which can be overcome with dasatinib. The present analysis suggests an alternative therapy strategy for CML involving isodicentric Ph chromosomes.

A leukemic double-hit follicular lymphoma associated with a complex variant translocation, t(8;14;18)(q24;q32;q21), involving BCL2, MYC, and IGH

Double-hit lymphoma (DHL) is defined as lymphoma with concurrent BCL2 and MYC translocations. While the most common histological subtype of DHL is diffuse large B-cell lymphoma, the present patient had leukemic follicular lymphoma (FL). A 52-year-old man was admitted to our hospital due to general fatigue and cervical and inguinal lymph node swelling. The patient was leukemic and the pathological diagnosis of the inguinal lymph node was FL grade 1. Chromosomal analysis revealed a complex karyotype including a rare three-way translocation t(8;14;18)(q24;q32;q21) involving the BCL2, MYC, and IGH genes. Based on a combination of fluorescence in situ hybridization (FISH), using BCL2, MYC and IGH, and spectral karyotyping (SKY), the karyotype was interpreted as being the result of a multistep mechanism in which the precursor B-cell gained t(14;18) in the bone marrow and acquired a translocation between der(14)t(14;18) and chromosome 8 in the germinal center, resulting in t(8;14;18). The pathological diagnosis was consistently FL, not only at presentation but even after a second relapse. The patient responded well to standard chemotherapies but relapsed after a short remission. This patient is a unique case of leukemic DH-FL with t(8;14;18) that remained in FL even at a second relapse.

A rare case of three-way complex variant translocation in chronic myeloid leukemia t(6;9;22)(p21;q34;q11): A case report.

Philadelphia (Ph)-positive chromosome or Ph translocation has been recognized in 90-95 chronic myeloid leukemia (CML) cases worldwide. However, only 5-8% CML patients show complex variant translocations. In the present study, hematological tests for a 47-year-old female CML patient were performed to determine the hemoglobin, platelets and total leukocyte values. A FISH test was carried out to recognize the BCR/ABL gene fusion, and a cytogenetic analysis was performed. The hematological results showed an increase in WBC (414000/mm3) and a decrease in hemoglobin (8.9 mg/dl), indicating the anemic condition in the CML patient. Furthermore, cytogenetic karyotyping results showed 46,XX,t(6;9;22)(p21;q34;q11) and positive for Ph chromosome. In conclusion, in the present study, we report a rare three-way complex variant translocation in a CML patient.

A rare case of a three way complex variant positive Philadelphia translocation involving chromosome (9;11;22)(q34;p15;q11) in chronic myeloid leukemia: A case report.

The t(9;22)(q34;q11) translocation is present in 90-95% of patients with chronic myeloid leukemia (CML). Variant complex translocations have been observed in 5-8% of CML patients, in which a third chromosome other than (9;22) is involved. Imatinib mesylate is the first line breakpoint cluster region-Abelson gene (BCR/ABL)-targeted oral therapy for CML, and may produce a complete response in 70-80% of CML patients in the chronic phase. In the present study, a bone marrow sample was used for conventional cytogenetic analysis, and the fluorescence in situ hybridization (FISH) test was used for BCR/ABL gene detection. A hematological analysis was also performed to determine the white blood cell (WBC) count, red blood cell count, hemoglobin levels, packed and mean cell volumes, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration and platelet values of the patient. The hematological analysis of the patient indicated the increased WBC of 186.5×103 cells/µl, and decreased hemoglobin levels of 11.1 g/dl. The FISH test revealed that 67% cells demonstrated BCR/ABL gene translocation. The patient was treated with 400 mg imatinib mesylate daily, and was monitored at various intervals over a 6-month period. The present study reports the rare case of a patient that demonstrates a three-way Philadelphia chromosome-positive translocation involving 46XY,t(9;11;22)(q34;p15;q11)[10], alongside CML in the chronic phase. The translocation was analyzed using cytogenetic and FISH tests.

Cytogenetics abnormalities in acute leukemias of ambiguous lineage: First report of complex variant philadelphia translocations

Cytogenetics abnormalities in acute leukemias of ambiguous lineage: First report of complex variant philadelphia translocations

Coexistence of t(15;17) and t(15;16;17) detected by fluorescence in situ hybridization in a patient with acute promyelocytic leukemia: A case report and literature review.

Acute promyelocytic leukemia (APL) is characterized by the t(15;17)(q22;q21), which results in the fusion of the promyelocytic leukemia (PML) gene at 15q22 with the retinoic acid α-receptor (RARA) gene at 17q21. The current study presents the case of a 54-year-old female with APL carrying the atypical PML/RARA fusion signal due to a novel complex variant translocation t(15;16;17)(q22;q24;q21), as well as the classical PML/RARA fusion signal. Subsequent array comparative genomic hybridization revealed somatic, cryptic deletions on 3p25.3, 8q23.1 and 12p13.2-p13.1, and a duplication on 8q11.2; however, no genetic material loss or gain was observed in the breakpoint regions of chromosomes 15, 16 or 17. To the best of our knowledge, this is the first report of the coexistence of two abnormal clones, one classical and one variant, presenting simultaneously in addition to cryptic chromosome segmental imbalances in an adult APL patient.

Complex variant of Philadelphia translocation involving chromosomes 9, 12, and 22 in a case with chronic myeloid leukaemia.

Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder included in the broader diagnostic category of myeloproliferative neoplasms, associated with fusion by BCR gene at chromosome 22q11 to ABL1 gene at chromosome 9q34 with the formation of the Philadelphia (Ph) chromosome. In 2–10% of CML cases, the fusion gene arises in connection with a variant translocation, involving chromosomes 9, 22, and one or more different chromosomes; consequently, the Ph chromosome could be masked within a complex chromosome rearrangement. In cases with variant Ph translocation a deletion on der(9) may be more frequently observed than in cases with the classical one. Herein we describe a novel case of CML with complex variant Ph translocation involving chromosomes 9, 12, and 22. We present the hematologic response and cytogenetic response after Imatinib treatment. We also speculated the mechanism which had originated the chromosome rearrangement.

Double-hit lymphomas and complex variant translocations of t(14;18)(q32;q21.3)

Double-hit lymphomas and complex variant translocations of t(14;18)(q32;q21.3)