甲磺酸伊马替尼联合VDLD化疗方案治疗急性淋巴细胞白血病患儿的长期随访研究

目的探究甲磺酸伊马替尼联合VDLD化疗方案治疗急性淋巴细胞白血病(ALL)患儿的应用价值。方法选取2015年5月~2018年6月收治的74例ALL患儿,按照治疗方案不同分组。对照组(37例)实施VDLD方案治疗,联合组(37例)实施甲磺酸伊马替尼+VDLD化疗方案治疗。对比两组疗效、不良反应发生率、随访1年无复发生存率(RFS)及治疗前、治疗2个疗程后血清B淋巴细胞刺激因子(BAFF)、增殖诱导配体(APRIL)水平。结果联合组总有效率(91.89%)高于对照组(72.97%)(P<0.05);联合组治疗2个疗程后血清BAFF、APRIL水平低于对照组(P<0.05);两组不良反应发生率、随访1年RFS对比无显著差异(P>0.05)。结论甲磺酸伊马替尼联合VDLD化疗方案治疗ALL,疗效确切,能显著降低血清BAFF、APRIL水平,且安全性高。     

NUDT15 is a key genetic factor for prediction of hematotoxicity in pediatric patients who received a standard low dosage regimen of 6-mercaptopurine

6-Mercaptopurine (6-MP) is commonly used for treatment of acute lymphoblastic leukemia (ALL). The incidence of hematotoxicity caused by this drug is quite high in Asians even using a standard low dosage regimen. The present study was aimed to elucidate the impact of thiopurine S-methyltransferase (TPMT), a nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15), inosine triphosphatase (ITPA) and ATP Binding Cassette Subfamily C Member 4 (ABCC4) polymorphisms on hematotoxicity in pediatric patients who received a standard low starting dose of 6-MP. One hundred and sixty-nine pediatric patients were enrolled and their genotypes were determined. Patients who carried NUDT15¹3 and NUDT15¹2 genotypes were at a 10–15 fold higher risk of severe neutropenia than those of the wild-type during the early months of the maintenance phase. Risk of neutropenia was not significantly increased in patients with other NUDT15 variants as well as in patients with TPMT, ITPA or ABCC4 variants. These results suggest that NUDT15 polymorphisms particularly, NUDT15¹3 and NUDT15¹2, play major roles in 6-MP-induced severe hematotoxicity even when using a standard low dosage of 6-MP and genotyping of these variants is necessary in order to obtain precise tolerance doses and avoid severe hematotoxicity in pediatric patients.     

白血病细胞p16基因突变分析

目的探讨ｐ１６基因突变在白血病发生中的作用及基因突变的机制。方法利用点突变检测仪、水平和垂直板电泳对ｐ１６基因的外显子１、外显子２的ＰＣＲ扩增产物作缺失和点突变分析。结果在白血病３５例临床标本中有２２例发生缺失突变，６例发生点突变，突变率约８０％。在２２例缺失突变病例中，有１０例为不完全缺失突变即有低于外显子５０９ｂｐ的扩增产物。结论ｐ１６基因含有“ＧＣ”ＤＮＡ重复顺序，易发生ＤＮＡ重组及易位和重排。在白血病发生中起重要作用     

Acute lymphoblastic leukemia in children: correlation of musculoskeletal manifestations and immunophenotypes

Purpose Studies on musculoskeletal manifestations (MSM) of childhood acute lymphoblastic leukemia (ALL) have yielded variable findings with regard to their clinical impact. We investigated the significance for differential diagnosis, treatment and outcome of musculoskeletal complaints as presenting symptoms of ALL, and their correlation with leukemia immunophenotypes, for which data is lacking. Methods Data on 783 children in the national study for childhood ALL between 1984 and 2003 were reviewed retrospectively. Statistical analysis examined possible relationships between MSM at the time of diagnosis and demographic and clinical data, biological features of leukemia (peripheral blood counts, immunophenotype and main cytogenetic aberration), response to initial prednisone treatment, and outcome. Results Of 765 children with data on orthopaedic complaints, 240 presented with MSM (31.4%). Among these children, B cell precursor (BCP) was much more common (209/576, 36.3%) than T cell ALL (25/176, 14.2%). Patients with MSM had lower white blood cell counts (WBC) (median of 9 vs. 20 × 10⁹/L, P < 0.001) and percentage of blast cells in the peripheral blood at diagnosis compared to those without (median of 27 vs. 53%, P < 0.001). Hepatomegaly and splenomegaly were less common in MSM group (67 vs. 53% <3 cm, P < 0.001, and 63 vs. 50% <3 cm, P < 0.001, respectively). Poor response to initial treatment with prednisone was recorded in 7.1% of patients with MSM versus 11.5% of those without (P = 0.086). The analysis revealed no independent effect of MSM on event-free survival (EFS), after correcting for differences in EFS related to immunophenotype or initial WBC. Conclusions MSM occur mostly in children with BCP ALL who present with less involvement of extramedullary organs, low peripheral blood blasts and white blood cells counts. These findings highlight the importance of including ALL in the differential diagnosis of MSM even in the presence of an apparently normal peripheral blood count. Our study also suggests that MSM are caused by leukemic cells with enhanced biological propensity to remain relatively confined within the intramedullary bone-marrow space.     

Marked improvement of delayed methotrexate-induced leukoencephalopathy treated with high-dose folinic acid

We report the case of a patient with delayed methotrexate (MTX)-induced leukoencephalopathy who showed a marked improvement both in clinical and neuroimaging findings after a high-dose of the active form of folinic acid (leucovorin) treatment. The patient developed progressive affective impairment accompanied by headache, nausea and vomiting after treatment with MTX during the chemotherapy for acute lymphoblastic leukemia, and diagnosed as delayed type MTX-induced leukoencephalopathy. After an intravenous injection of high-dose folinic acid (total 1920 mg), neurological deficits and white matter changes dramatically improved in a few weeks. Although delayed MTX-induced leukoencephalopathy may cause irreversible brain damage, an early treatment with high dose leucovorin may thus facilitate the marked improvement of clinical findings and white matter abnormalities.     

慢粒白血病abl癌基因表达的研究

选择分别位于ｂｃｒ／ａｂｌ嵌合基因的Ｍｂｃｒｌ第二外显子和ａｂｌ的第二外显子上的两条引物，对１８例慢粒白血病及２例急淋白血病标本进行逆转录ＰＣＲ（ＲＴ－ＰＣＲ）检测。结果：在１８例包括ｐｈ（＋）和ｐｈ（－）不同病期的慢粒白血病患者血中均检出ｂｃｒ／ａｂｌ嵌合基因的表达，其中１４例为Ｋ－２８型表达，１例为Ｌ－６型表达，３例为Ｋ－２８型，Ｌ－６型同时表达；２例急淋白血病标本中１例为Ｋ－２８型表达。研究结果表明，１．ｂｃｒ／ａｂｌ嵌合基因是慢粒白血病的一个重要分子生物学特征；２．ｐｈ（＋）和ｐｈ（－）慢粒白血病的分子生物学基础相同，即均有ｂｃｒ／ａｂｌ嵌合基因；３．至少部分急淋白血病与慢粒白血病有相同的分子生物学基础；４．ｂｃｒ的断裂点位置可能有一定的临床意义，但有待进一步研究；５．同时表达Ｌ－６型和Ｋ－２８型的情况多见于急变区，此现象提示体内可能同时有两类不同嵌合的白血病细胞或白血病急变期ｂｃｒ出现新的重排。     

糖皮质激素受体高、低亲和力位点在急性淋巴细胞性白血病治疗中的意义

研究了１０例正常人和２９例急性淋巴细胞性白血病（急淋）患者外周血糖皮质激素受体高、低亲和力结合位，或（ＧＣＲＨ、ＧＣＲＬ），利用Ｒｕ３８４８６对ＧＣＲＬ进行封闭，对部分患者ＧＣＲＨ、ＧＣＲＬ在激素联合化疗前后水平的变化进行了动态观察。结果表明，正常对照组ＧＣＲＨ、ＧＣＲＬ分别为４６０８±１８８９位点／细胞和１３５２３８±８８５０９位点／细胞，两者相关良好。急淋患者ＧＣＲＨ、ＧＣＲＬ分别为６０５２±３８８８位点／细胞和１２６４０５±１０２１３３位点／细胞，经过糖皮质激素药物联合化疗后，其水平分别为３６１６±１９６２位点／细胞和１４３５９７±１１２２８９位点／细胞，ＧＣＲＨ下降明显（Ｐ＜０．０１），下降率为４０．３％；而ＧＣＲＬ化疗前后差异不显著（Ｐ＞０．０５）。提示ＧＣＲＬ在介导糖皮质激素联合化疗疗效的维持中起重要的作用。