An acute myeloid leukemia case with concurrent 11q23 anomaly and D13S319 deficiency diagnosed by combined inter- and metaphase fluorescence in situ hybridization / 中华医学遗传学杂志

Objective@#To carry out multipath cytogenetic analysis of a rare case of acute myeloid leukemia (AML) with 11q23 aberration and D13S319 deletion.@*Methods@#G+ R banding technique was used to analyze the chromosomal karyotype of the patient after 24 h of cell culture. Combined interphase and metaphase fluorescence in situ hybridization (FISH) was used to detect specific chromosomal sites for complex translocations and minor missing fragments.@*Results@#The patient was found to harbor MLL-AF10 fusion gene due to rearrangement of the mixed lineage leukemia (MLL) gene in conjunct with deletion of the D13S319 locus on chromosome 13.@*Conclusion@#Whether MLL gene rearrangement and absence of D13S319 locus has a double impact on AML should attract more attention. For AML patient with clonal abnormalities such as 13q-, del (13)(q14), -13 or der (13), FISH assay should be proof and considered to determine the size of missing fragment so as targeted therapy may be implemented.

Clinical characteristics and prognosis of 34 cases of acute myeloid leukemia with FLT3 internal tandem duplication and MLL gene rearrangement / 中华血液学杂志

Objective@#To analyze the clinical characteristics and prognosis of 34 cases of acute myeloid leukemia (AML) with FLT3 internal tandem duplication (FLT3-ITD) and MLL gene rearrangement.@*Methods@#The clinical data of 34 AML patients with FLT3-ITD and MLL gene rearrangement was compared and analyzed for the therapeutic efficacy, prognostic factors when treated with chemotherapy, chemotherapy combined with targeted therapy or allogenic hematopoietic stem cell transplantation (allo-HSCT).@*Results@#Of the thirty-four cases with median age 41 (4-71) years old, 63.6% presented with white blood cells (WBC) greater than 30×109/L, 39.4% greater than 50 × 109/L respectively on admission. M5 (35.3%) made up the highest proportion. The cytogenetic abnormality reached 61.8%, of which the complex cytogenetic abnormality accounted for 11.8%. Eleven patients (32.35%) had both FLT3-ITD and MLL gene abnormalities. In addition to FLT3 and MLL abnormalities, 23 patients (67.6%) had one or more other gene abnormalities (multiple gene abnormalities). Of the 34 cases, 29.4% patients went into complete remission (CR) after two courses of chemotherapy. 20.6% (7 patients) went into CR after 3 or more courses of chemotherapy. The rate of early relapse in the CR group was 52.9%. Patients with WBC>50×109/L or multiple gene abnormalities had a lower remission rate (7.7%, 5.4%) after two courses of chemotherapy. CR rate for the patients with more than three gene abnormalities was 0. The total 2-year overall survival (OS) in the 34 patients was 28.8% (95% CI 13.5%-46.0%) and the disease-free survival (DFS) was 27.1% (95% CI 12.5%-44.0%). Of the 18 patients treated with chemotherapy alone or chemotherapy combined with targeted therapy, 17 cases died within 2 years and 1 lost follow-up after giving up treatment. For the 16 patients received allo-HSCT, the 3-year OS was 43.4% (95% CI 13.7%-70.4%) and DFS 42.7% (95% CI 13.4%-69.7%).@*Conclusion@#AML patients with FLT3-ITD and MLL gene rearrangement often presented with M5, accompanied by hyperleukocytosis, cytogenetic or multiple gene abnormalities. Those patients were observed to have low response rate and high early relapse when treated with chemotherapy without allo-HSCT. Patients had multiple gene abnormalities may be an important poor prognostic factor. Allo-HSCT is an effective treatment which could significantly improve the prognosis and survival of AML patients with FLT3-ITD and MLL gene abnormalities.

Clinical characteristics and prognosis of 34 cases of acute myeloid leukemia with FLT3 internal tandem duplication and MLL gene rearrangement / 中华血液学杂志

Objective: To analyze the clinical characteristics and prognosis of 34 cases of acute myeloid leukemia (AML) with FLT3 internal tandem duplication (FLT3-ITD) and MLL gene rearrangement. Methods: The clinical data of 34 AML patients with FLT3-ITD and MLL gene rearrangement was compared and analyzed for the therapeutic efficacy, prognostic factors when treated with chemotherapy, chemotherapy combined with targeted therapy or allogenic hematopoietic stem cell transplantation (allo-HSCT). Results: Of the thirty-four cases with median age 41 (4-71) years old, 63.6% presented with white blood cells (WBC) greater than 30×10(9)/L, 39.4% greater than 50 × 10(9)/L respectively on admission. M(5) (35.3%) made up the highest proportion. The cytogenetic abnormality reached 61.8%, of which the complex cytogenetic abnormality accounted for 11.8%. Eleven patients (32.35%) had both FLT3-ITD and MLL gene abnormalities. In addition to FLT3 and MLL abnormalities, 23 patients (67.6%) had one or more other gene abnormalities (multiple gene abnormalities). Of the 34 cases, 29.4% patients went into complete remission (CR) after two courses of chemotherapy. 20.6% (7 patients) went into CR after 3 or more courses of chemotherapy. The rate of early relapse in the CR group was 52.9%. Patients with WBC>50×10(9)/L or multiple gene abnormalities had a lower remission rate (7.7%, 5.4%) after two courses of chemotherapy. CR rate for the patients with more than three gene abnormalities was 0. The total 2-year overall survival (OS) in the 34 patients was 28.8% (95% CI 13.5%-46.0%) and the disease-free survival (DFS) was 27.1% (95% CI 12.5%-44.0%). Of the 18 patients treated with chemotherapy alone or chemotherapy combined with targeted therapy, 17 cases died within 2 years and 1 lost follow-up after giving up treatment. For the 16 patients received allo-HSCT, the 3-year OS was 43.4% (95% CI 13.7%-70.4%) and DFS 42.7% (95% CI 13.4%-69.7%). Conclusion: AML patients with FLT3-ITD and MLL gene rearrangement often presented with M(5), accompanied by hyperleukocytosis, cytogenetic or multiple gene abnormalities. Those patients were observed to have low response rate and high early relapse when treated with chemotherapy without allo-HSCT. Patients had multiple gene abnormalities may be an important poor prognostic factor. Allo-HSCT is an effective treatment which could significantly improve the prognosis and survival of AML patients with FLT3-ITD and MLL gene abnormalities.

Detection of rearrangements of mixed lineage leukemia gene in acute leukemia patients / 白血病·淋巴瘤

Objective To explore the value of fluorescence in situ hybridization (FISH) and multiplex RT-PCR in the detection of mixed lineage leukemia (MLL) gene rearrangement in acute leukemia (AL) patients. Methods Dual-color MLL probe, multiplex RT-PCR and R or G banding techniques were used to detect the MLL gene rearrangement in 189 cases of AL.Results MLL gene rearrangements were detected in 9 cases (5.03 ％) by FISH,and 16 cases (8.47 ％) by multiplex RT-PCR,including MLL/AF9,MLL/AF10,MLL/AF6, MLL/AF7, MLL/ELL, MLL/PTD. R or G banding techniques could find 11q23 in 5 out of 189 patients (2.65 ％). There was no statistic difference in the incidence of 6 common MLL gene rearrangements between ALL (73 cases) and AML patients (116 cases) (P ＞ 0.05).Conclusion Multiplex RT-PCR is a powerful technique in the detection of MLL gene rearrangement for tentatively diagnosed AL.It could not only confirm translocation detected by conventional cytogenetic method, but also detect MLL partial tandem duplication which could not been detected by cytogenetic examination or FISH. It plays an important role in guiding therapy and predicting prognosis for AL.

Survival Benefit of Hematopoietic Stem Cell Transplantation in Infant Acute Lymphoblastic Leukemia, According to Classification of High Risk Group / 임상소아혈액종양

BACKGROUND: In comparison to older children, acute leukemia in infants has a dismal outcome, despite introduction of intensive multi-agent chemotherapy. Patients with age under 1 year and mixed-lineage leukemia (MLL) gene rearrangements are the most high risk group. In this study, we investigate the outcome of more intensive chemotherapy and the role of hematopoietic stem cell transplantation (HSCT) in high risk group of infant leukemia. METHODS: This study analyzed on 9 infants with acute lymphoblastic leukemia (ALL) who were diagnosed and treated between 1998 and 2008 at Severance hospital. We classified high risk group with age at diagnosis is under 6 months or white blood cell at diagnosis are over 50,000/microL or presence of MLL gene rearrangements. Patients in high risk group were treated on a protocol of intensive chemotherapy followed by HSCT. RESULTS: In this study, the 3-years EFS rate for 9 infant ALL patients was 66.7+/-15.7%. Both of 2 patients younger than 6 months of age at diagnosis did not survive. 3yr-EFS rate for the 7 patients categorized in high risk group out of 9 infant ALL patients was 57.1+/-18.7%, and 3 yr EFS of the 6 patients in the high risk group who received HSCT was 60+/-21.9%. We did not experience relapse in 6 patients treated with HSCT. CONCLUSION: This study showed promising results and lesser risks in high risk group infant ALL treated with intensive chemotherapy and HSCT. We suggest early HSCT with intensive chemotherapy for infant leukemia patients in high risk group.

A Case of Therapy-related Acute Lymphoblastic Leukemia with t(11;19)(q23;p13.3) and MLL/MLLT1 Gene Rearrangement / 대한진단검사의학회지

Therapy-related ALL (t-ALL) is a rare secondary leukemia that develops after chemotherapy and/or radiotherapy for primary malignancies. Chromosomal 11q23 abnormalities are the most common karyotypic alterations in t-ALL. The t(11;19)(q23;p13) aberration is extremely rare and has not been confirmed at the molecular genetic level. Here, we report a case of t-ALL with t(11;19)(q23;p13.3) and MLL-MLLT1 (alias ENL) gene rearrangement confirmed by cytogenetic analysis, multiplex reverse transcription-PCR (multiplex RT-PCR), and DNA sequencing in a patient who had undergone treatment for breast cancer. A 40-yr-old woman developed acute leukemia 15 months after undergoing 6 cycles of adjuvant chemotherapy (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2), radiation therapy (dose, 5,900 cGy), and anticancer endocrine therapy with tamoxifen. The complete blood cell counts and bone marrow examination showed increased blasts and the blasts showed B lineage immunophenotype (positive for CD19, CD34, and cytoplasmic CD79a). Cytogenetic analysis revealed the karyotype 47,XX,+X,t(11;19)(q23;p13.3)[4]/46,XX[16]. FISH analyses, multiplex RT-PCR, and DNA sequencing confirmed the MLL-MLLT1 gene rearrangement. The patient underwent induction chemotherapy with fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD) and achieved complete remission. Subsequently, she underwent consolidation chemotherapy, but died of brain ischemia in the pons and the region of the middle cerebral artery. To our knowledge, this is the first case report of t-ALL with t(11;19)(q23;p13.3) and the MLL-MLLT1 gene rearrangement.

Survival Benefit of Hematopoietic Stem Cell Transplantation in Infant Acute Lymphoblastic Leukemia, According to Classification of High Risk Group / 임상소아혈액종양

BACKGROUND: In comparison to older children, acute leukemia in infants has a dismal outcome, despite introduction of intensive multi-agent chemotherapy. Patients with age under 1 year and mixed-lineage leukemia (MLL) gene rearrangements are the most high risk group. In this study, we investigate the outcome of more intensive chemotherapy and the role of hematopoietic stem cell transplantation (HSCT) in high risk group of infant leukemia.METHODS: This study analyzed on 9 infants with acute lymphoblastic leukemia (ALL) who were diagnosed and treated between 1998 and 2008 at Severance hospital. We classified high risk group with age at diagnosis is under 6 months or white blood cell at diagnosis are over 50,000/microL or presence of MLL gene rearrangements. Patients in high risk group were treated on a protocol of intensive chemotherapy followed by HSCT.RESULTS: In this study, the 3-years EFS rate for 9 infant ALL patients was 66.7+/-15.7%. Both of 2 patients younger than 6 months of age at diagnosis did not survive. 3yr-EFS rate for the 7 patients categorized in high risk group out of 9 infant ALL patients was 57.1+/-18.7%, and 3 yr EFS of the 6 patients in the high risk group who received HSCT was 60+/-21.9%. We did not experience relapse in 6 patients treated with HSCT.CONCLUSION: This study showed promising results and lesser risks in high risk group infant ALL treated with intensive chemotherapy and HSCT. We suggest early HSCT with intensive chemotherapy for infant leukemia patients in high risk group.

A Case of Therapy-related ALL with MLL Gene Rearrangement Following Treatment of Breast Cancer / 대한진단검사의학회지

ALL with MLL gene rearrangement secondary to chemotherapy has been rarely reported. We report a case of therapy-related ALL (t-ALL) with MLL gene rearrangement in a patient who had undergone treatment for breast cancer. A 60-yr-old woman with breast cancer underwent breast-conserving surgery followed by 6 cycles of adjuvant chemotherapy (cyclophosphamide, epirubicin, and fluorouracil) and radiation therapy (dose, 5,040 cGy to the left breast and a 1,000 cGy boost to the tumor bed). A follow-up examination performed 14 months after the chemotherapy revealed no evidence of breast malignancy. However, the patient's complete blood cell count indicated acute leukemia: white blood cell count, 174.1x10(9)/L with 88% blasts; Hb level, 12.5 g/dL; and platelet count, 103.0x10(9)/L. Examination of the bone marrow aspirate smear revealed a high percentage of blasts (85.1% of all nucleated cells); the blasts showed a pro-B immunophenotype and were positive for CD19, CD79a, HLA-DR, CD34, and terminal deoxynucleotidyl transferase (TdT). Cytogenetic and FISH analyses revealed t(4;11)(q21;q23) and MLL gene rearrangement, respectively. The patient received induction chemotherapy with cyclophosphamide, vincristine, doxorubicin, and dexamethasone and achieved complete remission. Following consolidation chemotherapy, she underwent allogenic peripheral blood stem cell transplantation and has been clinically stable. To our knowledge, this is the first reported case of t-ALL with MLL gene rearrangement following treatment of breast cancer in Korea.