Objective: To explore the clinical features and prognostic factors of Ph-positive and/or BCR-ABL positive acute lymphoblastic leukemia (Ph+ ALL) in children. Methods: The clinical data of 68 Ph+ ALL children who were treated at Peking University People's Hospital from December 2006 to December 2016 was retrospectively reviewed. Survival analysis were estimated by Kaplan-Meier method. Univariate analysis was estimated by Log-rank test and Chi-square, and multivariate analysis was estimated by Cox proportional hazards regression model. Results: In the 68 cases, the proportion of male to female was 2.1∶1, with a median age of 8 (1-16) years, and the median overall survival (OS) and disease free survival (DFS) were 16.8 months and 13.5 months, respectively. The early response rate to treatment was 43.9%, with myeloid-antigens-expression group lower than the non-expression group (29.6% vs 61.3%, χ2=5.814, P=0.020); The complete remission (CR) rate after one-course induction therapy was 86.2% (56/65), with good-response group higher than the poor-response group (100.0% vs 74.2%, χ2=6.680, P=0.003);The CR rate after induction in patients receiving imatinib plus chemotherapy was higher than the patients receiving chemotherapy only (94.9% vs 73.1%, χ2=5.185, P=0.024). The 2-and 5-year OS were (61.4±7.0)% and (50.8±8.1)%, respectively. The 2-and 5-year DFS were (54.6±6.8)% and (48.6±7.3)%, respectively. Univariate analysis showed that the initial WBC, LDH, spleen size, liver size, with-myeloid-antigens-expression, early response to treatment, MRD (BCR-ABL) after one-course induction, application of imatinib and different treatment options affected 2-year OS rate (all P<0.05). LDH, spleen size, liver size, with-myeloid-antigens-expression, early response to treatment, MRD (BCR-ABL) after one-course induction, application of imatinib and different treatment options affected 2-year DFS rate (all P<0.05). Multivariate prognostic analysis for OS (RR=45.7, 95% CI 1.4-1 528.2, P=0.033) and DFS (RR=52.3, 95% CI 1.6-1 725.9, P=0.026) showed that the spleen ≥ 3 cm was the independent risk factor. Conclusions: Pediatric Ph+ ALL is a special condition with unique clinical and biological features. The early response to treatment was poor in patients with myeloid-antigens-expression, which resulted in a low CR rate after one-course induction and the administration of imatinib can remarkably improve the CR rate. Initial spleen ≥ 3 cm is an independent prognostic factor. The efficacy of chemotherapy alone is poor, and imatinib combined with chemotherapy is applauded in the aim of improving outcomes.目的： 探讨儿童Ph染色体阳性和（或）BCR-ABL融合基因阳性急性淋巴细胞白血病（Ph+ ALL）的临床特征及预后影响因素。 方法： 回顾性分析北京大学人民医院儿科2006年12月至2016年12月收治的68例初治Ph+ ALL患儿的临床资料。采用Kaplan-Meier法进行生存分析，χ2检验及Log-rank检验评估各因素对预后的影响，多因素分析采用Cox回归模型。 结果： 68例Ph+ ALL患儿男女比为2.1∶1，中位年龄8（1~16）岁，中位总生存（OS）时间16.8个月，中位无病生存（DFS）时间13.5个月。早期治疗反应良好率为43.9%（29/66），伴髓系抗原表达组与不伴髓系抗原表达组的早期治疗反应良好率分别为29.6%和61.3%（χ2=5.814, P=0.020）。1个疗程完全缓解（CR）率为86.2%（56/65），早期治疗反应良好组与不良组的1个疗程CR率分别为100.0%和74.2%（χ2=6.680, P=0.003）。诱导化疗期加用伊马替尼组与单纯化疗组的1个疗程CR率分别为94.9%和73.1%（χ2=5.185, P=0.024）。2年和5年的OS率分别为（61.4±7.0）%和（50.8±8.1）%，2年和5年的DFS率分别为（54.6±6.8）%和（48.6±7.3）%。单因素分析显示，Ph+ ALL患儿的2年OS率与初诊WBC、LDH水平、脾脏大小、肝脏大小、是否伴髓系抗原表达、早期治疗反应、1个疗程后流式细胞术检测的MRD水平（或BCR-ABL）、是否应用伊马替尼及不同治疗方案等因素有关（P值均<0.05），2年DFS率与LDH水平、脾脏大小、肝脏大小、是否伴髓系抗原表达、早期治疗反应、1个疗程后流式细胞术检测的MRD水平（或BCR-ABL）、是否应用伊马替尼及不同治疗方案等因素有关（P值均<0.05）。多因素分析显示脾脏肋缘下≥3 cm是影响患者OS（RR=45.7, 95% CI 1.4~1 528.2, P=0.033）及DFS（RR=52.3, 95% CI 1.6~1 725.9, P=0.026）的独立预后危险因素。 结论： 儿童Ph+ ALL具有独特的临床和生物学特征。免疫分型中伴髓系抗原表达患儿的早期治疗反应差。早期治疗反应差的患儿1个疗程CR率低，诱导化疗期加用伊马替尼可明显提高1个疗程CR率。脾脏肋缘下≥3 cm是影响患者预后的独立危险因素。单纯化疗疗效差，化疗联合伊马替尼可以明显提高疗效。.
Highlights•Hematologic response at the induction end and BCR-ABL levels at 3 months are likely to be useful for identifying pediatric Ph+ ALL patients at a high risk of relapse in the TKI era.•Children with Ph+ ALL in first CR may benefit from allo-HSCT, particularly those at high risk.•Haplo-HSCT can be an alternative approach for high-risk Ph+ ALL patients.AbstractThe role of allogeneic hematopoietic stem cell transplantation (allo-HSCT), particularly haploidentical (haplo)-HSCT, in pediatric patients with Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) in the tyrosine kinase inhibitor (TKI) era is unclear. This study aimed to identify prognostic factors and explore the role of haplo-HSCT in the treatment of Ph+ ALL in the TKI era. We analyzed clinical data of Ph+ ALL patients aged 1 to 18 years who received imatinib added to intensive chemotherapy at the start of induction therapy. Among the 68 patients who completed at least 2 consolidation cycles, 44 underwent transplantation (transplant arm) and 24 received continuous TKI with chemotherapy (nontransplant arm). At the 3-year follow-up the cumulative incidence of relapse (CIR), event-free survival (EFS), and overall survival (OS) were 23.5%, 73.4%, and 80.3%, respectively. Multivariate analysis showed that hematologic response (whether complete remission [CR] was achieved) at the induction end, BCR-ABL levels (whether major molecular response [MMR] was achieved) at 3 months, and transplantation were independent affecting factors for CIR, EFS, and OS. In the risk stratification analysis based on the first 2 prognostic factors mentioned above, no significant difference existed between the transplant and nontransplant arms for the probabilities of 3-year OS, EFS, and CIR in the standard-risk group (no poor prognostic factors). Meanwhile, OS, EFS, and CIR rates were significantly better in the transplant arm in the high-risk group (≥1 poor prognostic factor). Among the 44 patients in the transplant arm, 37 underwent haplo-HSCT. Achieving CR at the induction end, MMR at 3 months, and haplo-transplant were also independent favorable factors of CIR, EFS, and OS in the nontransplant and haplo-HSCT arms. Haplo-HSCT showed a significant survival advantage in the high-risk group only. Hematologic response at the induction end and BCR-ABL levels at 3 months are likely to be useful for identifying pediatric Ph+ ALL patients at a high risk of relapse in the TKI era. Children with Ph+ ALL in first CR may benefit from allo-HSCT, particularly those at high risk. Haplo-HSCT could achieve good long-term survival for pediatric Ph+ ALL. Thus, haplo-HSCT can be an alternative approach for high-risk Ph+ ALL patients.
To assess the prognostic effect of different levels of IKZF1 gene deletions in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). IKZF1 Δ2-8/ALB deletions were quantified using multiplex real-time quantitative PCR in newly diagnosed pediatric BCP-ALL patients. Seventy-four patients with IKZF1 deletions ≥ 0.01% were included. Clinical characteristics, laboratory data, and treatment outcomes were analyzed. The patients were divided into two groups: IKZF1 deletions <1% (group A) and ≥1% (group B). Group B patients had a higher BCR-ABL1 positive rate than group A patients. The proportions of patients who had an age at onset ≥10 years old, and white blood cell count ≥50 × 109/L were significantly higher in group B than in group A. The 3-year overall survival (OS) and 3-year event-free survival (EFS) rates in group B were 79 ± 8.8% and 62.4 ± 9.7%, respectively, being significantly lower than those in group A (97.7 ± 2.2% and 83.2 ± 5.8%, respectively). The level of IKZF1 deletions ≥1% and the central nervous system leukemia were independent risk factors of EFS. Pediatric BCP-ALL patients with high levels of IKZF1 gene deletions have a poorer prognosis than those with low levels.
Abstract Trial design The design of this study is to compare the effectiveness of two analgesic drugs in the intervention of pain events for patients on mechanical ventilation. Methods 414 patients from three hospitals with respiratory failure requiring mechanical ventilation were randomly assigned to oxycodone hydrochloride or flurbiprofen axetil. The primary endpoints is the difference in the proportion of patients with a Behavioral Pain Scale (BPS) score > 5 within 48 hours. The secondary endpoints is to compare the dosage of sedative drugs (midazolam, propofol, dexmedetomidine) and to assess the clinical outcomes such as duration of mechanical ventilation. Results T here was no significant difference in BPS scores between the two groups at enrollment, and BPS scores in oxycodone group were significantly lower than those in flurbiprofen axetil group at 24 and 48 hours of enrollment. The proportion of patients with BPS less than 5 points in the Oxycodone hydrochloride group was also significantly lower than that in the flurbiprofen axetil group. For patients with Acute Physiology and Chronic Health Evaluation II (APACHE II )score greater than 10, subgroup analysis showed that the mechanical ventilation time of oxycodone hydrochloride group was significantly lower than that of flurbiprofen axetil group with statistical significance, and the dosage of midazolam was significantly lower than that of flurbiprofen axetil group. The length of ICU stay was significantly lower than that of flurbiprofen axetil group. Conclusion Oxycodone hydrochloride was more potent than flurbiprofen axetil for analgesia for patients with respiratory failure requiring mechanical ventilation.
Abstract Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal disorders and is rare in children. Allogeneic hematopoietic stem cell transplantation (HSCT) is commonly used in children with MDS with excess blasts and in patients with refractory cytopenia of childhood (RCC) associated with monosomy 7, complex karyotype, severe neutropenia, or transfusion dependence. We recruited 27 children with MDS who received haploidentical hematopoietic stem cell transplantation (haplo‐HSCT). At transplantation, 10 patients had RCC, 12 patients had advanced MDS (RAEB and RAEB‐T), and 5 patients had myelodysplasia‐related acute myeloid leukemia (MDR‐AML). All patients received granulocyte colony‐stimulating factor (G‐CSF)–mobilized bone marrow cells and peripheral blood stem cells. At a median follow‐up of 24.1 months (range: 2.0‐74.5 months) after HSCT, the estimated probabilities of 3‐year disease‐free survival (DFS) and overall survival (OS) were both 81.9% (95% CI, 66.8‐100.0%). The estimated 3‐year incidences of relapse (CIR) and non‐relapse mortality (NRM) were both 7.4% (95% CI, 1.2%‐21.4%). The 100‐day cumulative incidence of grade II–IV aGVHD was 52.6% (95% CI, 42.9‐62.3%), while that of grade III–IV aGVHD was 11.1% (95% CI, 5.1‐17.1%). The 3‐year cumulative incidences of overall and extensive cGVHD were 42.3% (95% CI, 19.8%‐57.5%) and 21.1% (95% CI, 2.5%‐63.2%), respectively. Univariate analysis showed that chronic GVHD significantly affected OS and DFS. Haploidentical HSCT may be an effective treatment option with easier donor availability for pediatric patients with MDS.
The design of this study is to compare the effectiveness of two analgesic drugs in the intervention of pain events for patients on mechanical ventilation. 414 patients from three hospitals with respiratory failure requiring mechanical ventilation were randomly assigned to oxycodone hydrochloride or flurbiprofen axetil. The primary endpoints is the difference in the proportion of patients with a Behavioral Pain Scale (BPS) score > 5 within 48 h. The secondary endpoints is to compare the dosage of sedative drugs (midazolam, propofol, dexmedetomidine) and to assess the clinical outcomes such as duration of mechanical ventilation. There was no significant difference in BPS scores between the two groups at enrollment, and BPS scores in oxycodone group were significantly lower than those in flurbiprofen axetil group at 24 and 48 h of enrollment. The proportion of patients with BPS less than 5 points in the Oxycodone hydrochloride group was also significantly lower than that in the flurbiprofen axetil group. For patients with Acute Physiology and Chronic Health Evaluation II (APACHE II) score greater than 10, subgroup analysis showed that the mechanical ventilation time of oxycodone hydrochloride group was significantly lower than that of flurbiprofen axetil group with statistical significance, and the dosage of midazolam was significantly lower than that of flurbiprofen axetil group. The length of ICU stay was significantly lower than that of flurbiprofen axetil group. Oxycodone hydrochloride was more potent than flurbiprofen axetil for analgesia for patients with respiratory failure requiring mechanical ventilation.
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