Abstract：
BACKGROUND: Paediatric patients with acute lymphoblastic leukaemia or lymphoma are at increased risk of venous thromboembolism resulting in increased mortality and morbidity. We hypothesised that apixaban, a direct oral anticoagulant, would safely reduce venous thromboembolism in this patient population.
METHODS: PREVAPIX-ALL was a phase 3, open-label, randomised, controlled trial conducted in 74 paediatric hospitals in 9 countries. Participants aged 1 year or older to younger than 18 years with newly diagnosed acute lymphoblastic leukaemia (pre-B cell or T cell) or lymphoblastic lymphoma (B cell or T cell immunophenotype) and a central venous line in place throughout induction were randomly assigned 1:1 to standard of care (SOC, ie, no systemic anticoagulation) or weight-adjusted twice-daily apixaban during induction. Randomisation was performed centrally and stratified by age (those <10 years or those ≥10 years). Participants weighing 35 kg or less were administered 2·5 mg twice daily of apixaban as a 2·5 mg tablet, 0·5 mg tablets, or 0·4 mg/mL oral solution, while those weighing more than 35 kg were administered weight-adjusted prophylactic doses using 0·5 mg tablets or the 0·4 mg/mL oral solution twice daily. Primary outcomes were assessed by a blinded central adjudication committee. The primary efficacy outcome for the intention to treat population was the composite of symptomatic or clinically unsuspected venous thromboembolism, the primary safety outcome was major bleeding, and secondary safety outcomes included clinically relevant non-major (CRNM) bleeding. Patients were screened for venous thromboembolism by ultrasound and echocardiogram at the end of induction. The trial was registered with ClinicalTrials.gov (NCT02369653) and is now complete.
RESULTS: Between Oct 22, 2015, and June 4, 2021, 512 participants were randomly assigned and included in analyses (222 [43%] female and 290 [57%] male; 388 [76%] White, 52 [10%] Asian, 24 [5%] Black or African American, and 48 [9%] other races; and 122 [24%] Hispanic or Latino ethnicity). During a median follow-up period of 27 days (IQR 26-28), 31 (12%) of 256 patients on apixaban had a composite venous thromboembolism compared with 45 (18%) of 256 participants receiving SOC (relative risk [RR] 0·69, 95% CI 0·45-1·05; p=0·080). Two major bleeding events occurred in each group (RR 1·0, 95% CI 0·14-7·01; p=1·0). A higher incidence of CRNM bleeding, primarily grade 1 or 2 epistaxis, occurred in the apixaban group (11 [4%] of 256 participants) compared with the SOC group (3 [1%] of 256; RR 3·67, 95% CI 1·04-12·97, p=0·030). The most frequent grade 3-5 adverse events in both groups were thrombocytopenia (n=28 for the apixaban group and n=20 for the SOC group) or platelet count decreased (n=49 and n=45), anaemia (n=77 and n=74), febrile neutropenia (n=27 and n=20), and neutropenia (n=16 and n=17) or neutrophil count decreased (n=22 and n=25). Five deaths occurred, which were due to infection (n=3 in the SOC group), cardiac arrest (n=1 in apixaban group), and haemorrhagic cerebral sinus vein thrombosis (n=1 in the SOC group). There was one apixaban-related death (coagulopathy and haemorrhage after cardiac arrest of unknown cause).
CONCLUSIONS: PREVAPIX-ALL is, to our knowledge, the first trial assessing primary thromboprophylaxis using a direct oral anticoagulant in paediatric patients with acute lymphoblastic leukaemia or lymphoma. No statistically significant treatment benefit was identified in participants receiving apixaban. Major and CRNM bleeding were infrequent overall, but a higher incidence of CRNM bleeding (primarily epistaxis in younger children) occurred in participants receiving apixaban. For patients deemed to be at particularly high risk of thrombosis, PREVAPIX-ALL provides encouraging safety data for the use of apixaban in clinical settings in which the potential benefits are thought to outweigh the risk of bleeding.
BACKGROUND: Bristol Myers Squibb-Pfizer Alliance.
METHODS: PREVAPIX-ALL was a phase 3, open-label, randomised, controlled trial conducted in 74 paediatric hospitals in 9 countries. Participants aged 1 year or older to younger than 18 years with newly diagnosed acute lymphoblastic leukaemia (pre-B cell or T cell) or lymphoblastic lymphoma (B cell or T cell immunophenotype) and a central venous line in place throughout induction were randomly assigned 1:1 to standard of care (SOC, ie, no systemic anticoagulation) or weight-adjusted twice-daily apixaban during induction. Randomisation was performed centrally and stratified by age (those <10 years or those ≥10 years). Participants weighing 35 kg or less were administered 2·5 mg twice daily of apixaban as a 2·5 mg tablet, 0·5 mg tablets, or 0·4 mg/mL oral solution, while those weighing more than 35 kg were administered weight-adjusted prophylactic doses using 0·5 mg tablets or the 0·4 mg/mL oral solution twice daily. Primary outcomes were assessed by a blinded central adjudication committee. The primary efficacy outcome for the intention to treat population was the composite of symptomatic or clinically unsuspected venous thromboembolism, the primary safety outcome was major bleeding, and secondary safety outcomes included clinically relevant non-major (CRNM) bleeding. Patients were screened for venous thromboembolism by ultrasound and echocardiogram at the end of induction. The trial was registered with ClinicalTrials.gov (NCT02369653) and is now complete.
RESULTS: Between Oct 22, 2015, and June 4, 2021, 512 participants were randomly assigned and included in analyses (222 [43%] female and 290 [57%] male; 388 [76%] White, 52 [10%] Asian, 24 [5%] Black or African American, and 48 [9%] other races; and 122 [24%] Hispanic or Latino ethnicity). During a median follow-up period of 27 days (IQR 26-28), 31 (12%) of 256 patients on apixaban had a composite venous thromboembolism compared with 45 (18%) of 256 participants receiving SOC (relative risk [RR] 0·69, 95% CI 0·45-1·05; p=0·080). Two major bleeding events occurred in each group (RR 1·0, 95% CI 0·14-7·01; p=1·0). A higher incidence of CRNM bleeding, primarily grade 1 or 2 epistaxis, occurred in the apixaban group (11 [4%] of 256 participants) compared with the SOC group (3 [1%] of 256; RR 3·67, 95% CI 1·04-12·97, p=0·030). The most frequent grade 3-5 adverse events in both groups were thrombocytopenia (n=28 for the apixaban group and n=20 for the SOC group) or platelet count decreased (n=49 and n=45), anaemia (n=77 and n=74), febrile neutropenia (n=27 and n=20), and neutropenia (n=16 and n=17) or neutrophil count decreased (n=22 and n=25). Five deaths occurred, which were due to infection (n=3 in the SOC group), cardiac arrest (n=1 in apixaban group), and haemorrhagic cerebral sinus vein thrombosis (n=1 in the SOC group). There was one apixaban-related death (coagulopathy and haemorrhage after cardiac arrest of unknown cause).
CONCLUSIONS: PREVAPIX-ALL is, to our knowledge, the first trial assessing primary thromboprophylaxis using a direct oral anticoagulant in paediatric patients with acute lymphoblastic leukaemia or lymphoma. No statistically significant treatment benefit was identified in participants receiving apixaban. Major and CRNM bleeding were infrequent overall, but a higher incidence of CRNM bleeding (primarily epistaxis in younger children) occurred in participants receiving apixaban. For patients deemed to be at particularly high risk of thrombosis, PREVAPIX-ALL provides encouraging safety data for the use of apixaban in clinical settings in which the potential benefits are thought to outweigh the risk of bleeding.
BACKGROUND: Bristol Myers Squibb-Pfizer Alliance.
摘要：
背景：患有急性淋巴细胞白血病或淋巴瘤的儿科患者静脉血栓栓塞的风险增加，导致死亡率和发病率增加。我们假设阿哌沙班，直接口服抗凝剂,将安全地减少该患者人群的静脉血栓栓塞。
方法：PREVAPIX-ALL是第3阶段，开放标签，随机化，在9个国家的74家儿科医院进行的对照试验。年龄在1岁或以上至18岁以下的新诊断急性淋巴细胞白血病（前B细胞或T细胞）或淋巴母细胞淋巴瘤（B细胞或T细胞免疫表型）和整个诱导过程中的中心静脉线的参与者被随机分配1：1到标准护理（SOC，ie,没有全身抗凝）或在诱导期间每天两次调整体重的阿哌沙班。按年龄（<10岁或≥10岁）集中进行随机分组。体重35公斤或以下的参与者每天两次服用2·5毫克的阿哌沙班2·5毫克片剂，0·5毫克片剂，或0·4mg/mL口服溶液，而体重超过35kg的患者则使用每日两次0·5mg片剂或0·4mg/mL口服溶液给予体重调整后的预防剂量。主要结果由一个盲目的中央裁决委员会评估。意向治疗人群的主要疗效结果是有症状或临床上未怀疑的静脉血栓栓塞的复合结果。主要安全结局是大出血,次要安全性结局包括临床相关非大出血(CRNM).在诱导结束时通过超声和超声心动图筛查患者的静脉血栓栓塞。该试验已在ClinicalTrials.gov（NCT02369653）注册，现已完成。
结果：在2015年10月22日至2021年6月4日之间，512名参与者被随机分配并纳入分析（222[43％]女性和290[57％]男性;388[76％]白人，52[10%]亚洲人，24[5%]黑人或非洲裔美国人，和48[9%]其他种族；和122[24%]西班牙裔或拉丁裔）。在27天的中位随访期间（IQR26-28），256例接受阿哌沙班治疗的患者中有31例(12%)出现复合静脉血栓栓塞，而接受SOC治疗的患者中有45例(18%)出现复合静脉血栓栓塞(相对危险度[RR]0·69,95%CI0·45-1·05;p=0·080)。每组发生2起主要出血事件（RR1·0，95％CI0·14-7·01；p=1·0）。CRNM出血的发生率较高，主要是1级或2级鼻出血，与SOC组(256例参与者中的3例[1%];RR3·67,95%CI1·04-12·97,p=0·030)相比,阿哌沙班组(256例参与者中的11例[4%])发生.两组中最常见的3-5级不良事件是血小板减少症（阿哌沙班组n=28，SOC组n=20）或血小板计数降低（n=49和n=45），贫血（n=77和n=74），发热性中性粒细胞减少症（n=27和n=20），中性粒细胞减少症（n=16和n=17）或中性粒细胞计数减少（n=22和n=25）。发生了5人死亡,这是由于感染（SOC组n=3），心脏骤停（阿哌沙班组n=1），和出血性脑窦静脉血栓形成（SOC组n=1）。有1例阿哌沙班相关死亡（不明原因心脏骤停后凝血障碍和出血）。
结论：PREVAPIX-ALL是，根据我们的知识，第一项试验评估急性淋巴细胞白血病或淋巴瘤儿科患者使用直接口服抗凝剂预防血栓形成.在接受阿哌沙班的参与者中没有发现统计学上显著的治疗益处。大出血和CRNM出血总体上很少见，但接受阿哌沙班治疗的参与者发生CRNM出血(主要是年幼儿童的鼻出血)的发生率较高.对于被认为血栓形成风险特别高的患者，PREVAPIX-ALL为在临床环境中使用阿哌沙班提供了令人鼓舞的安全性数据，在这些环境中，潜在的益处被认为大于出血风险。
背景：百时美施贵宝-辉瑞联盟。
方法：PREVAPIX-ALL是第3阶段，开放标签，随机化，在9个国家的74家儿科医院进行的对照试验。年龄在1岁或以上至18岁以下的新诊断急性淋巴细胞白血病（前B细胞或T细胞）或淋巴母细胞淋巴瘤（B细胞或T细胞免疫表型）和整个诱导过程中的中心静脉线的参与者被随机分配1：1到标准护理（SOC，ie,没有全身抗凝）或在诱导期间每天两次调整体重的阿哌沙班。按年龄（<10岁或≥10岁）集中进行随机分组。体重35公斤或以下的参与者每天两次服用2·5毫克的阿哌沙班2·5毫克片剂，0·5毫克片剂，或0·4mg/mL口服溶液，而体重超过35kg的患者则使用每日两次0·5mg片剂或0·4mg/mL口服溶液给予体重调整后的预防剂量。主要结果由一个盲目的中央裁决委员会评估。意向治疗人群的主要疗效结果是有症状或临床上未怀疑的静脉血栓栓塞的复合结果。主要安全结局是大出血,次要安全性结局包括临床相关非大出血(CRNM).在诱导结束时通过超声和超声心动图筛查患者的静脉血栓栓塞。该试验已在ClinicalTrials.gov（NCT02369653）注册，现已完成。
结果：在2015年10月22日至2021年6月4日之间，512名参与者被随机分配并纳入分析（222[43％]女性和290[57％]男性;388[76％]白人，52[10%]亚洲人，24[5%]黑人或非洲裔美国人，和48[9%]其他种族；和122[24%]西班牙裔或拉丁裔）。在27天的中位随访期间（IQR26-28），256例接受阿哌沙班治疗的患者中有31例(12%)出现复合静脉血栓栓塞，而接受SOC治疗的患者中有45例(18%)出现复合静脉血栓栓塞(相对危险度[RR]0·69,95%CI0·45-1·05;p=0·080)。每组发生2起主要出血事件（RR1·0，95％CI0·14-7·01；p=1·0）。CRNM出血的发生率较高，主要是1级或2级鼻出血，与SOC组(256例参与者中的3例[1%];RR3·67,95%CI1·04-12·97,p=0·030)相比,阿哌沙班组(256例参与者中的11例[4%])发生.两组中最常见的3-5级不良事件是血小板减少症（阿哌沙班组n=28，SOC组n=20）或血小板计数降低（n=49和n=45），贫血（n=77和n=74），发热性中性粒细胞减少症（n=27和n=20），中性粒细胞减少症（n=16和n=17）或中性粒细胞计数减少（n=22和n=25）。发生了5人死亡,这是由于感染（SOC组n=3），心脏骤停（阿哌沙班组n=1），和出血性脑窦静脉血栓形成（SOC组n=1）。有1例阿哌沙班相关死亡（不明原因心脏骤停后凝血障碍和出血）。
结论：PREVAPIX-ALL是，根据我们的知识，第一项试验评估急性淋巴细胞白血病或淋巴瘤儿科患者使用直接口服抗凝剂预防血栓形成.在接受阿哌沙班的参与者中没有发现统计学上显著的治疗益处。大出血和CRNM出血总体上很少见，但接受阿哌沙班治疗的参与者发生CRNM出血(主要是年幼儿童的鼻出血)的发生率较高.对于被认为血栓形成风险特别高的患者，PREVAPIX-ALL为在临床环境中使用阿哌沙班提供了令人鼓舞的安全性数据，在这些环境中，潜在的益处被认为大于出血风险。
背景：百时美施贵宝-辉瑞联盟。
