Interaction of all-trans-retinoic acid with fluconazole in acute promyelocytic leukemia

All-trans-retinoic acid (ATRA) has a dramatic antitumor effect in patients with acute promyelocytic leukemia (APL). It is hepatically metabolized by cytochrome P-450, and there are known toxicities associated with high levels of this drug. The effects of ATRA can be potentiated by inhibition of cytochrome P-450, which is known to occur with certain drugs. We report a case of a patient with ATRA toxicity thought to be secondary to interaction with fluconazole.     

Genital ulcers after treatment with all-trans-retinoic acid in a child with acute promyelocytic leukemia

All-trans-retinoic acid (ATRA) has been shown to improve the outcome of patients with acute promyelocytic leukemia (APL). However, various adverse effects of ATRA treatment have been noted, such as scrotal and genital ulcers in adult patients. The authors report genital ulcers that developed in a child with APL after ATRA treatment. An 8-year-old girl with APL was treated with ATRA for 21 days and after discontinuation of ATRA treatment she developed genital ulcers. Systemic and local antibiotic pomades were applied and the lesions improved within 15 days. In conclusion, genital ulcers may develop in children with APL as a complication of ATRA treatment and physicians should be alert to this possibility.     

Fournier's gangrene and scrotal ulcerations during all-trans-retinoic acid therapy for acute promyelocytic leukemia

Scrotal ulcers are a rare manifestation in patients with acute promyelocytic leukemia. Fournier's gangrene (FG) is even rarer. We describe three adolescents and young adults who developed scrotal ulcerations during induction with all-trans-retinoic acid. One patient developed FG. These lesions are predominantly seen in Asian population. A good outcome with supportive management occurred in all the cases.     

Thrombosis during all-trans-retinoic acid therapy in a child with acute promyelocytic leukemia and factor VQ 506 mutation

Acute promyelocytic leukemia (APL) is often associated with a severe hemostatic disorder, caused by the release of procoagulant and fibrinolytic substances from leukemic blasts. The coagulation profile may exhibit disseminated intravascular coagulation and fibrinolysis or proteolysis. Therefore, heparin and antifibrinolytic agents alone or in combination have been used to prevent severe bleedings. Remission induction with all-trans-retinoic acid (ATRA) is accompanied with rapid correction of hemostatic abnormalities. Thrombosis is a rare complication of APL and may be due to the alterations in hemostasis caused by the disease itself as well as ATRA and antifibrinolytics. Here, the occurrence of thrombosis during induction treatment with ATRA combined with aprotinin and chemotherapy is described in a patient who is homozygous for factor VQ 506 mutation.     

Childhood acute promyelocytic leukemia: no benefit of all-trans-retinoic acid administered in a short-course schedule

From January 1990 to August 1997, 29 consecutive patients were treated with newly diagnosed primary acute promyelocytic leukemia (APL) at the authors' Institution. Of these, 27 (16 boys and 11 girls) were evaluable. Median age at diagnosis was 6.3 (range: 1.9-15.7) years. This population was treated with two consecutive protocols: 13 patients were included in the AML-HPG90 protocol and 14 in the AML-HPG-95. The initial treatment was the same for both protocols: an induction 8-day phase with cytarabine, idarubicin, and etoposide was followed by a consolidation with cyclophosphamide, cytarabine, 6-mercaptopurine, vincristine, doxorubicin, and prednisone. Two courses of intensification with high-dose (HD) cytarabine and etoposide were given in the first study. Only one intensification course was administered in the second study, with HD cytarabine plus idarubicin or etoposide decided by randomization. Complete remission was achieved in 67% (18/27) of cases. Mortality on induction was quite high, 30% (8/27) mainly due to hemorrhages from disseminated intravascular coagulation (DIC). The event-free survival estimate for all patients was 0.47 (SE: 0.1). From April 1994, all-trans-retinoic acid (ATRA) was administered just during the first days of the induction phase (median: 9, range: 2-27) to stop or prevent DIC. Eighteen patients received ATRA and 9 did not. Three patients developed signs of ATRA syndrome during the first days of administration but no one died due to this toxicity. The impact of a short course of ATRA on early control of DIC was studied by analyzing the number of platelet, cryoprecipitate, and fresh frozen plasma transfusions during the induction phase in both groups. No statistical differences in complete remission rate, early mortality, need of transfusion of blood components for DIC, and survival estimates could be established between patients who received ATRA and those who did not. ATRA used in a short-course schedule during induction of APL did not stop early mortality due to DIC. Moreover, survival results did not improve with this method of ATRA usage. Longer periods of ATRA administration during APL therapy are strongly recommended.     

急性早幼粒细胞白血病治疗的远期疗效

目的评估儿童急性早幼粒细胞白血病(APL)治疗的远期疗效。方法诱导治疗均应用全反式维甲酸(ATRA),同时联合化疗或同时联合三氧化二砷(As2O3)和化疗,直至骨髓形态学缓解。完全缓解(CR)后给予3～5个疗程的巩固化疗,使分子生物学缓解后再予以ATRA As2O3 6巯基嘌呤(6MP)及氨甲喋呤(MTX)维持治疗,总疗程2年。所有患儿治疗前、治疗后每3个月及停药随访期间每3～6个月定期行骨髓形态学、染色体及PML-RARα融合基因检测。结果17例APL患儿,获CR 16例(94%),CCR 12例(70%),随访7～122个月,平均35个月。4例复发(25%)。其中2例曾获骨髓形态学和分子生物学缓解,另外2例曾获骨髓形态学缓解而分子生物学始终未缓解。结论系统性的ATRA As2O3联合化疗治疗方案使大部分APL患儿获得长期生存,PML-RARα融合基因定期监测是判断疗效及预后的重要指标。     

儿童急性早幼粒细胞白血病76例随访报告

目的 探讨儿童急性早幼粒细胞白血病(APL)的治疗及预后,并评估砷剂在儿童APL中的疗效.方法 对76例初治APL患儿进行疗效及预后相关因素分析.采用SPSS10.0软件进行统计学分析.结果 本组76例APL患儿,6例早期死亡.其余70例患儿依据诱导方案的不同分成3组:1组44例,单用全反式维甲酸(ATRA);2组7例,单用三氧化二砷(As_2O_3);3组19例,联合应用ATRA和As_2O_3.1组的完全缓解率为100%,2组+3组的完全缓解率为100%.6例临床复发,2例分子生物学复发,复发部位均为骨髓.5年累计复发率为13.8%,5年累积无事件生存(EFS)率、无病生存(DFS)率、总生存(OS)率分别为79.5%、86.3%和90.5%.在1组与2组+3组之间的5年EFS、DFS没有明显差异.初诊时白细胞计数可能是影响儿童预后最主要的因素.结论 ATRA治疗儿童APL疗效好.砷剂治疗儿童APL的疗效亦较好,耐受性好.砷剂可以用于不能耐受ATRA副作用的患儿,亦可用于初治和复发的儿童APL.     

儿童急性早幼粒细胞性白血病并发DIC的临床研究

目的 回顾性分析26例急性早幼粒细胞性白血病(APL)患儿合并DIC的发生率、临床特点及预后情况.方法 26例初诊APL患儿以骨髓形态学及免疫学分型确诊.应用三氧化二砷(As2O3)进行诱导缓解,监测血常规及DIC指标.结果 23例患儿发生DIC(88%),诊断时即发生DIC 12例(52%),As2O3治疗2周内发生DIC 9例(39%),2周后发生DIC 2例(9%).DIC出血19例(73%),以皮肤出血9例(47%)为著,颅内出血2例(11%)均死亡.DIC指标以血小板下降最为敏感(100%),凝血酶原时间及部分凝血酶原时间延长者22例(96%),也有较高敏感性.DIC指标转阴需4～46d.结论 儿童APL合并DIC发生率较高,出血风险大,以诊断及治疗2周内为危险期,需积极监测DIC指标,在治疗APL基础上抗DIC治疗,以度过DIC期,保证诱导缓解期治疗的安全性.     

Acute promyelocytic leukemia in children

Sixteen children (ages 2–17) with acute promyelocytic leukemia (APL) were studied retrospectively. Diagnosis was based on clinical features and morphological criteria of the FAB classification. Bleeding diathesis was the predominant presenting symptom (>85%), associated with laboratory findings of disseminated intravascular coagulation (DIC). Extramedullary manifestations included skin rash in six patients, gum infiltration in two, and meningeal leukemia in two. Induction therapy consisted of cytosine arabinoside and an anthracycline, with or without other agents. Prophylactic heparinization was given to 12 patients. Six patients (37.5%) failed to achieve remission and died, secondary to hemorrhage in three, and secondary to infection in the remaining three patients. The median duration of remission was 14 months, and the median survival for responders was 21 months. One meningeal leukemia preceded bone marrow relapse despite intermittent intrathecal chemotherapy for prophylaxis. Three patients remain in continuous complete remission 3 years after initial diagnosis. Although childhood APL shares many features of its adult counterpart, the high frequency of extramedullary manifestations and mortality secondary to neutropenia deserves separate attention.     

Isolated central nervous system recurrence of acute promyelocytic leukemia in children

The incidence of isolated central nervous system (iCNS) relapse in pediatric acute promyelocytic leukemia (APL) is debated. We analyzed the literature, focusing on clinical trials reported since the advent of ATRA use. Only 2/218 (0.92%) good risk patients (diagnostic WBC <10,000/microl) had truly iCNS relapse. This incidence does not support the use of intrathecal CNS prophylaxis for all children with APL. We also identified multiple deficiencies in these reports. Additional reporting of these events could provide insight into the true incidence and pathogenesis of iCNS relapse and might allow for identification of risk factors associated with such extramedullary relapse.     

儿童急性早幼粒细胞白血病46例长期随访及预后分析

目的：探讨儿童急性早幼粒细胞白血病（APL）的治疗、长期生存和预后因子。方法：对该院1998年4月至2005年10月收治的APL 患儿46例进行临床分析。诱导缓解采用全反式维甲酸(ATRA)＋柔红霉素（DNR）或吡柔吡星（THP），巩固治疗采用大剂量阿糖胞苷与DA(柔红霉素+阿糖胞苷)、HA（高三尖杉酯碱+阿糖胞苷）、EA（足叶乙甙+阿糖胞苷）方案交替给药，维持阶段ATRA与DA，HA，EA方案交替治疗，总疗程为2.5年。结果：39例患儿进行了正规治疗，36例（92.3％）获完全缓解（CR）。39例患儿1年、3年和5年总体生存率（OS）分别为（86.1±5.8）％，（76.1±7.5）％和（70.2±8.9）％，1年、3年、5年的无事件生存率（EFS）分别是（78.4±6.8）％，（63.6±8.7）％和（53.1±10.0）％。5年累积复发率（CIR）28.6％。其中WBC≤10.0×109/L者的5年OS［（81.4±10.3）％］明显高于WBC＞10.0×109/L者［（51.6±14.7）％，P<0.05］。获CR的PML/RARα融合基因短型（S型）的患儿5例最后全部死亡，而长型（L型）患儿13例无死亡发生，两者差异有统计学意义（P<0.01）。结论：ATRA＋DNR或THP诱导缓解治疗儿童APL安全、有效，可以作为初发儿童APL的标准诱导治疗方案。联合蒽环类及阿糖胞苷等药物化疗能明显改善长期生存率。高WBC和S型PML/RARα融合基因阳性的患儿预后不佳。［中国当代儿科杂志，2007，9（1）：28-33］     

儿童急性早幼粒细胞白血病PML-RARα融合基因的动态观察

目的 探讨儿童急性早幼粒细胞白血病（APL）PML-RARα融合基因转阴的速率与治疗方案的关系。方法 10例患儿给全反式维甲酸（ATRA）诱导分化，HOAP（三尖杉酯碱，长春新碱、阿糖胞苷，强的松）或DA（柔红霉素，全反式维甲酸）巩固治疗，三联序贯疗法维持强化，治疗琐阶段用RT/PCR法检测融合基因。结果 1、诱导缓解（CR）90%，持续缓解（CCR）80%，2、PML-RARα融合基因转阴情况；4/9例转阴CR后2-6个月；5/9例转阴CR后12-32个月，首次转阴的总平均时间为CR后14个月，结论 1、ATRA诱导分化有显著效果。但不能清除体内白血病细胞，复发率极高。2、联合化疗方案，融合基因转阴率增高，而转阴的速度与化疗方案的强度成正比。3、融合基因的暂时转阴，说明该病人对化疗敏感，可能预后较好，而持续转阴和足够治疗时间（CCR4年以上）可达到临床治愈。     

儿童急性早幼粒细胞白血病PML-RARα融合基因跟踪检测的临床意义(英文)

目的　探讨跟踪检测急性早幼粒细胞白血病 (APL)特有的PML RARα融合基因在发现APL早期复发和指导APL临床治疗方面的意义。方法　 1 0例APL患儿用全反式维甲酸 (ATRA)和 (或 )其它化疗药物进行诱导缓解、巩固治疗和维持治疗 ,并进行随访。在病程的不同阶段采集骨髓标本进行形态学检查 ,并应用RT PCR方法检测PML RARα融合基因。结果　随访时间为 1 4～ 1 5 6月 (中位时间 4 2月 ) ,5年无病生存率为 5 6 .0 %±1 6 .5 %。 1 0例APL患儿完全缓解 (CR)率为 90 % ,早期死亡 1例。 9例CR病人中 4例在CR后 1 4～ 4 2月复发 ,4例在连续完全缓解 4～ 5年后已停药 ,停止治疗时间为 1 8～ 96月。 1例CR ,仍在继续治疗中。 9例CR患儿中 ,8例在病程中PML RARα转为阴性 ,1例持续阳性。 4例复发病人中 ,2例复发前持续阳性 ,2例在病程中由阴性转为阳性。 5例仍生存的患儿中 ,1例在病程中PML RARα由阴性转为阳性 ,2例分别在持续完全缓解 36和 4 2月仍呈阳性 ,这 3例患儿经治疗干预后均转阴 ,且长期生存。结论　对APL患儿跟踪检测PML RARα可早期发现分子复发 ,及时干预治疗可避免血液学复发。