Lou Jy

CD19-positive acute myeloblastic leukemia with trisomy 21 as a sole acquired karyotypic abnormality

We report that a 63-year-old Chinese female had acute myeloblastic leukemia (AML) in which trisomy 21 (+21) was found as the sole acquired karyotypic abnormality. The blasts were positive for myeloperoxidase, and the immunophenotype was positive for cluster of differentiation 19 (CD19), CD33, CD34, and human leukocyte antigens (HLA)-DR. The chromosomal analysis of bone marrow showed 47,XX,+21[2]/46,XX[18]. Fluorescent in situ hybridization (FISH) showed that three copies of AML1 were situated in separate chromosomes, and that t(8;21) was negative. The patient did not have any features of Down syndrome. A diagnosis of CD19-positive AML-M5 was established with trisomy 21 as a sole acquired karyotypic abnormality. The patient did not respond well to chemotherapy and died three months after the diagnosis. This is the first reported case of CD19-positive AML with trisomy 21 as the sole cytogenetic abnormality. The possible prognostic significance of the finding in AML with +21 as the sole acquired karyotypic abnormality was discussed.

Efficacy and safety of the HAA regimen as induction chemotherapy in 236 de novo acute myeloid leukemia

OBJECTIVE To evaluate the efficacy and safety of the HAA regimen (homoharringtonine, cytarabine and aclarubicin) as induction chemotherapy in de novo acute myeloid leukemia (AML). METHODS The efficacy and safety of 236 de novo AML patients who received the HAA regimen as induction chemotherapy were retrospectively analyzed. The complete remission (CR) rate was assayed. Kaplan-Meier method was used to estimate overall survival (OS) and relapse free survival (RFS), and the differences were compared by Log-rank test. RESULTS The overall CR rate was 78.0%, and 65.7% of the patients attained CR in the first induction cycle. The early death rate was 4.7%. The median followup time was 41(1-161) months. The estimated 5-year OS and 5-year RFS rates were 44.9% and 45.5%, respectively. The CR rates of patients with favorable, intermediate and unfavorable cytogenetics were 92.9%,78.6%and 41.7%, respectively. The 5-year OS of favorable and intermediate group were 61.1% and 45.1%, respectively. The 5- year RFS of favorable and intermediate group were 49.0% and 45.4%, respectively. The median survival time of unfavorable group was only 5 months. The side effects associated with the HAA regimen were tolerable, in which the most common toxicities were myelosuppression and infection. CONCLUSION The HAA regimen is associated with a higher rate of CR and longer survival time and its toxicity could be tolerated.

Additional rearrangements affecting the derivative chromosome 9 involved in the standard Philadelphia translocation after imatinib therapy in a patient with chronic myeloid leukemia

Imatinib is a selective BCR-ABL tyrosine kinase inhibitor that has shown significant activity against Philadelphiapositive chronic myeloid leukemia (CML). Although the majority of CML patients in chronic phase have durable hematologic and cytogenetic responses to imatinib, a subset of CML patients lose their best response despite continued treatment. Some of these patients progress to accelerated phase or blast crisis, but some relapse [1]. Here, we describe the novel case of a patient with CML, in which a standard Ph translocation transformed into a second translocation between chromosomes der(9) and der(21) accompanied by relapse and resistance after a brief disappearance of Ph chromosome subsequent to imatinib therapy. A 25-year-old man was referred to our hospital because of suspected acute leukemia in August 2004. His full blood counts were as follows: hemoglobin 13.9 g/dL, platelets 671 10/L, and white blood cells 27.1 10/L. The bone marrow aspirate showed hypercellularity and granulocytic hyperplasia. No blasts were seen. Rbanded karyotype analysis revealed 46,XY,t(9;22) (q34;q11.2)[9]/46,XY[1] (Fig. 1a). Reverse transcriptase polymerase chain reaction (RT-PCR) showed the p210(b3a2) fusion transcript. Thus, he was diagnosed as having CML in chronic phase. Imatinib therapy (400 mg daily) was started. The patient was sensitive to imatinib and soon gained complete cytogenetic response. The Philadelphia chromosome and the b3a2 fusion transcript were no longer detected. In April 2006, however, when his disease relapsed and he showed resistance to imatinib, the karyotype was determined to be 46,XY,der(9)(9pter/ 9q34::21p11.2/21pter),der(22)t(9;22) (Fig. 1b). The RT-PCR showed the b3a2 transcript as before. Dualcolor, dual-fusion fluorescence in situ hybridization (D-FISH) using the LSI BCR-ABL probe (Abbott Molecular/Vysis, Des Plaines, IL) showed a yellow fusion signal, one red signal (ABL), and one green signal (BCR) in interphase nuclei (Fig. 2a). On metaphase spreads, this yellow fusion signal for the BCR-ABL fusion gene could be defined to the Ph chromosome, with a red signal (ABL) located on der(9q) and a green signal (BCR) on der(21p) (Fig. 2b).

Clinical significance of TET2 gene expression in 157 adult acute myeloid leukemia patients with normal cytogenetics

OBJECTIVE To explore the clinical significance of ten-eleven-translocation methylcytosine dioxygenase 2 (TET2) mRNA expression levels in adult acute myeloid leukemia patients with normal cytogenetics (CN-AML). METHODS Expression levels of TET2 mRNA were measured by real-time PCR in 157 adult CN-AML, and its clinical impact in CN-AML was evaluated as well. RESULTS TET2 gene expression levels from bone marrow mononuclear cells (BMMNCs) [7.29(3.41-9.99)] and CD34+ cells [6.02(5.64-6.54)] in CN-AML were significantly lower than those [BMMNCs: 8.13(6.68-9.04), P=0.026; CD34+ cells: 6.48(5.97-7.12), P=0.034] in healthy control. And TET2 mRNA level at diagnosis [7.32(6.11-8.41)] was obviously lower than that at complete remission [8.39(7.76-8.79), P<0.01]. CN-AML patients with lower levels of TET2 mRNA showed worse survival rate [(32.7±5.9)%] at 18-month than those with higher levels [(48.6±6.9)%, P=0.041]. In multivariate analysis, lower level of TET2 mRNA was an independent prognostic factor for OS [hazard ratio(HR)2.032, 95% confidence interval (CI)1.272-3.247, P=0.003] and event-free survival [HR 1.532, 95% CI 1.014-2.314, P=0.043]. CONCLUSION The level of TET2 mRNA is significantly lower in patients with CN-AML and it is an independent negative prognostic factor. TET2 could be an important factor for the molecular-based risk stratification in CN-AML.

Clinical and cytogenetic study of chromosome 1 abnormality in myelodysplastic syndrome

OBJECTIVE To explore the incidence of chromosome 1 abnormality in myelodysplastic syndrome（MDS）to couple its association with clinical presentation and prognosis. METHODS R- band karyotype analyses were performed in 672 cases of MDS between 2010 and 2013. Clinical data of those with abnormal chromosome l were collected and then analyzed factors affecting the prognosis. RESULTS Of 672 cases of patients with MDS, chromosome 1 aberration［der（1）, dup（1）, －1 were most frequent］ were found in 41（6.1%）cases. 1q trisomy was found in 18/41（43.9%）cases, and the most common patterns were duplication of the long arm as well as unbalanced translocation with other chromosomes. Of 41 patients with chromosomal 1 abnormality, 32 cases were accompanied with other chromosomal aberration, usually involving 3 or more abnormal chromosomal karyotypes, e.g., chromosome 8, 7 abnormalities. According to IPSS-R scoring system, 19 patients were diagnosed with very high risk, 10 patients high risk, 10 patients intermediate risk and 2 patients low risk MDS. 9 patients transformed into acute leukemia with median transforming time of 7.18（0.56-54.28）months. Median survival of 36 cases after 2010 was 17.48（95% CI 14.38-20.58）months. There were significant differences on median survival between RAEB and non-RAEB groups（χ²=10.398, P=0.001）, and between with more than 3 chromosome abnormalities and with less than 3 groups（χ²=3.939, P=0.047）. RAEB was identified as an independent risk factor for the prognosis of MDS with chromosome 1 abnormality. CONCLUSION Chromosome 1 aberration was not rare in MDS. 1q trisomy was the most common abnormal karyotype in China, which often accompanied with other chromosomal abnormalities. The prognosis of MDS patients with chromosome 1 abnormality was poor, especially worse in those diagnosed with RAEB-1, RAEB-2 and with more than 3 chromosome abnormality. For patients whose percentage of bone marrow blasts less than 5%, the prognosis of patients with 1q trisomy was better than those without 1q trisomy. RAEB was identified as an independent risk factor for the prognosis of MDS with chromosome 1 abnormality.目的 观察1号染色体异常在骨髓增生异常综合征(MDS)中的发生率，并分析其临床及细胞遗传学特征。 方法 回顾性分析2010年至2013年672例MDS患者临床资料，研究伴l号染色体异常的发生率及其临床、细胞遗传学特征，分析影响预后的因素。 结果 672例MDS患者中伴1号染色体异常41例(6.1%)，其中难治性贫血(RA)6例、难治性贫血伴有环状铁粒幼红细胞(RARS)2例、难治性血细胞减少伴有多系发育异常(RCMD)9例、难治性贫血伴有原始细胞过多(RAEB)-1 10例、RAEB-2 13例、MDS不能分类(MDS-U)1例。1号染色体异常以der(1)、dup(1)、−1多见，1q三体18例(43.9%)，以1q片段重复和1q与其他染色体发生不平衡易位多见。32例合并有其他染色体异常，多涉及3个及以上异常核型。9例转变为急性白血病(转白)，中位转白时间为7.18(0.56~54.28)个月；36例患者纳入生存分析，中位生存时间为17.48 (95% CI 14.38~20.58)个月。RAEB组(RAEB-1、RAEB-2)、染色体异常>3种组中位生存时间分别短于非RAEB组(RA、RARS、RCMD、MDS-U)、染色体异常≤3种组(χ2=10.398，P=0.001；χ2=3.939，P=0.047)。RAEB是影响l号染色体异常MDS患者预后的独立危险因素。 结论 1号染色体异常在MDS中并不罕见，以1q三体最为常见，且常伴其他异常核型。伴1号染色体异常MDS患者总体预后较差，RAEB是伴1号染色体异常MDS患者独立预后因素。

Expression level of SET gene in acute myeloid leukemia and its clinical significance

OBJECTIVE To investigate the expression level of SET gene in patients with acute myeloid leukemia (AML) and evaluate its significance. METHODS The expression level of SET gene in 141 de novo AML patients was determined by real time quantitative PCR (RQ-PCR), and its relationship with the clinical features and outcomes of these patients were analyzed. RESULTS SET gene transcript level was detected in 141 AML patients with the median expression level of 0.86(range 0.02-15.69). AML patients with higher SET gene expression had a higher level of white blood cell (WBC ≥ 100 × 10⁹/L) count than of lower SET gene expression ones (31.0% vs 11.4%, P=0.005). In the 136 patients who received treatment after diagnosis, higher SET gene expression group had lower complete remission rate (50.0%) than of lower expression cohort (73.5%) after two cycles of chemotherapy (P=0.005). Survival analysis showed that patients with higher SET gene expression had significantly shorter overall survival(OS) (10 months vs 22 months, P=0.001) and event-free survival (EFS) (2 months vs 14 months, P=0.005) than of lower SET gene expression ones. Multivariate COX regression analysis showed SET overexpression was an independent prognostic factor for OS. In the patients with the normal karyotype, higher SET expression group also had significantly shorter OS (12 months vs 35 months, P=0.010) and EFS (4 months vs 14 months, P=0.026) than of lower SET expression ones. CONCLUSION High expression of SET gene was associated with poor prognosis and might be a prognostic molecular marker of AML.