Impact of granulocyte colony-stimulating factor use during induction for acute myelogenous leukemia in children: a report from the Children's Cancer Group

PURPOSE: To determine whether granulocyte colony-stimulating factor (G-CSF) administered during acute myelogenous leukemia (AML) induction affects hematopoietic and nonhematopoietic toxicity, length and outcome of induction therapy, event-free survival, overall survival, and prognostic significance of the day 7 bone marrow. PATIENTS AND METHODS: In Children's Cancer Group study 2891, patients were given intensively timed induction with G-CSF (n = 254) after accrual for the regimen without G-CSF (n = 258) was met. RESULTS: Time to neutropenic recovery after induction courses 1 and 2 was significantly shorter for patients who received G-CSF. Times to platelet recovery were similar regardless of G-CSF use. Effects on incidence of grades 3 and 4 toxicities, infections, or fatal infections were not observed. Use of G-CSF reduced the median length of induction by 9 days and hospital stay by 6 days. Induction remission rates, overall survival, and event-free survival were similar with and without G-CSF. Day 7 bone marrow was prognostic of better long-term outcome. Patients with hypercellular day 7 marrow who received G-CSF had a higher remission rate and event-free survival than patients who did not receive G-CSF. CONCLUSIONS: The incidence of severe toxic event and infection, induction remission rate, overall survival, and event-free survival were comparable regardless of G-CSF use. Use of G-CSF decreased neutropenia duration, hospital stay, and length of induction. Patients with hypercellular day 7 bone marrow who received G-CSF had an induction remission rate and event-free survival superior to those of patients who did not receive G-CSF.     

米托蒽醌治疗小儿难治复发的急性非淋巴细胞白血病的临床研究

为探讨小儿难治复发的急性非淋巴细胞白血病的治疗方法 ,临床上观察了 2 7例病人 ,经米托蒽酯 6mg/m2 × 3天 ,Ara c 1 50mg/m2 × 7天 ,VP166 0mg/m2 × 5天的联合化疗疗效。结果治疗后CR 37% ( 1 0 /2 7) ,PR 30 % ( 8/2 7) ,总有效率 6 7% ,化疗后骨髓造血功能抑制明显 ,感染发生率较高为 73% ,结果显示 :以米托蒽醌为主的化疗治疗小儿难治及复发的急性非淋巴细胞白血病有较好疗效。     

超大剂量阿糖胞苷在小儿急性髓细胞白血病的治疗探讨

目的应用超大剂量阿糖胞苷(SHDAra-C)对急性髓细胞白血病(AML)患儿进行缓解后治疗,探讨其疗效及安全性。方法在患者取得骨髓缓解后应用SHDAra-C共五个疗程,第一疗程Ara-C总剂量达36 g/m2,其后每疗程Ara-C总剂量18 g/m2,累计Ara-C总剂量达108 g/m2。结果8例AML患儿有7例完成了5个疗程HDAra-C化疗(1例只完成4疗程),除1例骨髓复发放弃治疗外,余7例均获CCR至今,CCR时间6~76月,无一例化疗相关性死亡。结论SHDAra-C是小儿AML化疗获得长期无病生存的重要治疗方法,有效且相对安全,其治疗效果值得更大规模的临床病例观察,治疗机理有待更深入的实验研究。     

Toxicity and effectiveness of high-dose idarubicin during AML induction therapy: results of a pilot study in children

BACKGROUND: Idarubicin (IDR) is one of the most effective, but also toxic drugs in the treatment of AML. The standard dose used in children and adults is 8-12 mg/m2 during induction. PATIENTS AND METHODS: To improve outcome, we increased the IDR dose from 12 mg/m2 (standard dose in study AML-BFM 93), applied over three days during induction therapy (AIE = Ara-C, Idarubicin, Etoposide) to 14 mg/m2 in a pilot study including 17 patients (16 with de novo AML, one with secondary AML). Outcome and toxicities were compared with the other patients of study AML-BFM 93, treated with 3 x 12 mg/m2 IDR or 6 x 30 mg/m2 daunorubicin (DNR). RESULTS: Patients of the pilot study achieved a good blast cell reduction in the bone marrow on day 15, a high CR rate of 94% and a low relapse rate (3/17 pts.), however, not significantly different to the IDR (12 mg/m2) group. Hematological toxicity was high, median duration until neutrophil recovery > 500/microliter was 25.0 (12-66) days, and similar to the IDR (12 mg/m2) and DNR groups. Duration of thrombocytopenia (time to > 20,000/microliter) was 21 (10-66) days in the pilot study compared to 19 (7-26) days in DNR patients (p = 0.08). Four of 17 pilot patients presented with severe WHO grades 3/4 of mucositis during induction. One patient died in long-lasting aplasia after the 3rd treatment block. CONCLUSION: Results of this pilot study show that the IDR 14 mg/m2 regimen was effective but also toxic. According to our results which, however, are based on small patient numbers, an improved outcome compared to the IDR 12 mg/m2 regimen seems to be unlikely, therefore the possibly increased toxicity might not be acceptable.     

Usefulness of cytosine arabinoside (NSC-63878) and prednisone (NSC-10023) in refractory childhood lymphoblastic leukemia.

One hundred forty-three children with refractory lymphoblastic and undifferentiated leukemia (ALL/AUL) were treated with cytosine arabinoside (Ara-C) and prednisone (Pred). The dose and duration of Ara-C was escalated during induction depending on the response seen in the peripheral blood and/or bone marrow. For those achieving a remission, Ara-C was also used to determine its maintenance capabilities. Of the 143 children, 79 attained a clinical remission, 45 having a complete bone marrow remission and 34 having a partial remission. Maintenance of remission with twice weekly Ara-C was short and did not appear to depend on the amount of Ara-C given during induction. The major toxicity of Ara-C was myelosuppression.     

Usefulness of cytosine arabinoside (NSC-63878) and prednisone (NSC-10023) in refractory childhood lymphoblastic leukemia

One hundred forty-three children with refractory lymphoblastic and undifferentiated leukemia (ALL/AUL) were treated with cytosine arabinoside (Ara-C) and prednisone (Pred). The dose and duration of Ara-C was escalated during induction depending on the response seen in the peripheral blood and/or bone marrow. For those achieving a remission, Ara-C was also used to determine its maintenance capabilities. Of the 143 children, 79 attained a clinical remission, 45 having a complete bone marrow remission and 34 having a partial remission. Maintenance of remission with twice weekly Ara-C was short and did not appear to depend on the amount of Ara-C given during induction. The major toxicity of Ara-C was myelosuppression.     

A NOVEL APPROACH TO TREATMENT WITH HIGH-DOSE STEROID AS A DIFFERENTIATION INDUCER IN CHILDREN WITH ACUTE MYELOBLASTIC LEUKEMIA

Several experimental studies have demonstrated that certain steroid hormones can induce differentiation of mouse myeloid leukemic cells to macrophages and granulocytes. We have shown that high-dose methylprednisolone treatment (HDMP, 20-30 mg/kg/day) can induce differentiation of leukemic cells to mature granulocytes in children with different morphological subtypes of acute myeloblastic leukemia (FAB AML M1, M2, M3, M4). In addition, apoptosis can also be induced in vivo and in vitro in AML blast by HDMP treatment. Short-course (3 to 5 days) HDMP treatment increases the hematopoietic CD34- positive progenitor cells in both bone marrow and peripheral blood in children with AML. Acceleration of leukocyte and neutrophil recovery has been obtained by the administration of short-course HDMP in chemotherapy-induced neutropenic children with AML. The addition of HDMP to anti leukemic chemotherapy increased the complete remission rate and prolonged the duration of remission in children with AML and significantly improved the outcome of AML children who presented with extramedullary infiltration. We suggest that the possibility of HDMP-induced differentiation and apoptosis should be evaluated in patients with other malignant diseases.     

Treatment of recurrence of acute myeloid leukemia in childhood. A retrospective analysis of recurrence in the AML-BFM-83 study]

Complete remission (CR) rates of 80% are achieved with the AML-BFM protocols but one third of patients relapse within the first three years. There are few reports of treatment of relapsed childhood AML, and these deal with the evaluation of new drugs for frontline therapy. We performed a retrospective analysis to investigate how patients previously treated with the AML-BFM-83 protocol were treated after relapse and how many long term remissions were achieved. 48 of 139 patients relapsed after having achieved complete remission with the AML-BFM-83 protocol which consists of continous infusion of ARA-C 100 mg/m2 day 1-2, ARA-C 200 mg/m2 day 3-8, Daunorubicin 60 mg/m2 day 3, 4, and 5, and VP-16 150 mg/m2 day 6, 7, and 8, and an 8 week consolidation therapy consisting of Prednisolone, Thioguanine, Vincristine, ADR, ARA-C, Cyclophosphamide, intrathecal ARA-C and cranial irradiation followed by maintenance therapy. Duration of first remission ranged from 1.5 months to 66.3 months. Excluding 5 children with either isolated or combined extramedullary relapses and another 4 patients for missing data, 39 children were evaluable. 20 children received no therapy or palliative therapy while 16 patients received chemotherapy and another 3 children were transplanted in relapse. Although 9 different intensive chemotherapy regimens were used for reinduction, a high number (12 of 16 = 75%) of second complete remissions was achieved. Several therapeutic options were used to maintain a second remission: regular maintenance therapy (7 patients), allogeneous bone marrow transplantation (BMT) (2 patients), autologous BMT (3 patients).(ABSTRACT TRUNCATED AT 250 WORDS)     

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］     

Improved remission induction rate with D-ZAPO but unimproved remission duration with addition of immunotherapy to chemotherapy in previously untreated children with ANLL.

In 163 children with acute nonlymphocytic leukemia (ANLL), a D-ZAPO induction program consisting of daunomycin, 5-azacytidine, cytosine arabinoside, prednisone, and vincristine resulted in a remission rate of 71.8%. Immunologic therapy was employed during maintenance with the aim of prolonging remission and improving survival. The administration of immunotherapy consisting of a mixture of bacillus Calmette-Guérin (BCG) and allogenic acute myelomonocytic leukemic cells injected intradermally on day 14 of each of the first three monthly cycles of 6-thioguanine for ten days, 5-azacytidine and cytosine arabinoside for four days, and vincristine for one day did not improve remission duration or survival compared to that due to chemotherapy alone. Important prognostic factors identified in this study included a remission induction rate significantly better for females than males (P = 0.04), for children between the ages of 5 and 10 years compared to those greater than this age group (P = 0.01), and a prolonged remission duration (P = 0.04), and survival (P less than 0.01) for patients with initial white blood counts of less than 20 x 10(9)/liter.     

Treatment of Childhood Acute Nonlymphocytic Leukemia with High-Dose Cytosine Arabinoside, 6-Thioguanine, and Doxorubicin without Maintenance Therapy: Pilot Study ANLL-80 of the Dutch Childhood Leukemia Study Group (DCLSG)

A pilot study was undertaken to determine the efficacy of remission induction therapy with 1000 mg/ m² high-dose cytosine-arabinoside (one i.v. push injection every 24 h, days 1-12), 65 mg/m² 6-thioguanine (orally, days 1-12), and 40 mg/m² doxorubicin (i.v., days 13 and 14) without maintenance or consolidation therapy as a possible cure of childhood acute nonlymphocytic leukemia. Children in first remission with a suitable donor were offered the opportunity of allogeneic bone marrow transplantation (BMT). Between March 1980 and June 1981, 24 of 27 consecutive, newly diagnosed children entered the pilot study. Complete remission was achieved in 15 (71.4%) of 21 treated patients. Eleven children received no further therapy: 9 relapsed within 5 months (all hematologically), 2 have been in longstanding continuous complete remission (CCR)for 70+ and 77+ months. Four children underwent allogeneic BMT: 2 have been in CCR for 68+ and 75+ months, 1 child died of graft-versus-host disease, and 1 child relapsed 60 months after BMT. Although the remission rate (71.4 %) was satisfactory, only a minority (18%) of the patients who received no further therapy seem to be cured.     

AML1-ETO阳性的儿童急性髓系白血病疗效分析

目的探讨儿童急性髓系白血病m2型伴AML1-ETO阳性患儿的疗效及预后相关因素。方法2003年1月至2008年12月收住AML1-ETO阳性儿童m233例,并对患儿进行总结分析、随访。了解患儿临床特征,免疫分型,染色体核型治疗及疗效,生存情况及影响治疗的因素。结果33例AML1-ETO阳性儿童第一疗程诱导缓解率为63.5%,中位随访时间32个月,目前仍处于CR状态25例占75.5%,5例患儿骨髓复发,复发率为15.1%,高白细胞数,多脏器受累,免疫表型CD5＋6以及第一疗程诱导治疗未达缓解者预后不良,并伴有较低的生存率。结论儿童急性髓系白血病M2伴有AML1-ETO阳性患儿预后是好的。强烈化疗高剂量阿糖胞苷能帮助提高疗效。提高生存率。高白细胞计数,累及多脏器以及CD56标记阳性和初次诱导治疗的缓解不佳,影响总的生存率。     

Liposomal daunorubicine combined with cytarabine in the treatment of relapsed/refractory acute myeloid leukemia in children

BACKGROUND: First-line treatment in AML commonly included high cumulative doses of anthracyclines with an increasing risk of cardiotoxicity. Liposomal daunorubicin (L-DNR) is thought to be less cardiotoxic without impairment of efficacy. METHODS: The AML-BFM REZ 97 study included two reinduction blocks with L-DNR (2 x 60 mg/m (2) n = 38, since 2/1999 3 x 60 mg/m (2) n = 31) combined with cytarabine (500 mg/m (2) 4 d). Children who achieved a second blast clearance were allocated to allogeneic stem cell transplantation either from a matched related (MRD) or a matched unrelated donor (MUD). Lack of a donor justified haploidentical SCT in early relapse (1st remission < 1 year) and autologous SCT in late relapse. PATIENTS: Between 1/1997 and 9/2001, 69 children were enrolled in the AML-BFM 97 relapse study. The median duration of first remission was 0.9 years. Forty-one patients had a remission of less than one year, 28 of more than a year. RESULTS: 46 children (67 %) achieved a second remission, defined as clearance of blasts in bone marrow and at least a partial hematological reconstitution. Seventeen of these children are alive (12 of 25 children receiving allogeneic SCT (MFD/MUD); 1 of 8 children after haploidentical SCT; 1 of 4 patients after autologous SCT and 3 of 9 patients treated with chemotherapy only). Further three children without 2nd remission survived after MFD-SCT (n = 2) or chemotherapy (n = 1; follow-up 0.3 to 0.7 years). Duration of first remission remains a significant prognostic factor. The pharmacokinetic investigation showed a high overall AUC of 234.6 mg/l h at a dose of 60 mg/m (2), and a volume of distribution of 1.98 l/m (2), which is much lower in comparison to conventional Daunorubicin. Regarding toxicity, the combination of L-DNR and cytarabine followed by SCT was feasible in experienced centers, however, acute complications like infection or septicemia in aplasia, mucositis and GvHD were common. By contrast, no clinical relevant cardiotoxicity was seen so far, but definitive results in long-term cardiotoxicity await a longer follow-up. In conclusion, L-DNR/cytarabine treatment induced a 2nd remission in most of the children with relapsed or refractory AML. It has to be followed by allogeneic SCT which enables long-term survival.     

Intensive consolidation chemotherapy for acute lymphoblastic leukaemia (UKALL X pilot study).

Eighty two children with acute lymphoblastic leukaemia presenting at this hospital received one or two modules of intensive chemotherapy to consolidate remission. Modules were given after four and roughly 19 weeks on treatment. Each included two doses of daunorubicin (45 mg/m2/day), cytosine arabinoside (100 mg/m2 twice daily X 5), etoposide (100 mg/m2/day X 5), and 6-thioguanine (80 mg/m2/day X 5). A total of 132 courses were given. This study included all new patients except girls aged 1-14 years with presenting leucocyte count less than 20 X 10(9)/l. Twenty patients with recurrent disease were also included. The first 32 patients were given cytosine as a 24 hour infusion, but combined with the other agents this was associated with severe intestinal toxicity, which necessitated a change to a less toxic 12 hourly bolus regimen. The complications of the module are reviewed in terms of myelosuppression, enterotoxicity, infection, and other clinical problems encountered. All patients became profoundly neutropenic and thrombocytopenic. The latter was significantly more severe after cytosine infusion. Overall, 64% received platelet transfusions and 85% were re-admitted with fevers requiring intravenous antibiotics for between four and 56 days. Gastrointestinal toxicity with the modified module occurred in 38% of patients and was severe in 13%. This intensification module has been adopted by the Medical Research Council Working Party on Childhood Leukaemia for use in a multicentre study (UKALL X) and the details of the problems encountered in the pilot study may be of value to other centres now using this protocol.     

Chemotherapy for myeloid malignancy in children with Fanconi anemia

BACKGROUND: Children with Fanconi anemia (FA) have a markedly increased risk of developing myeloid malignancies. Historically, patients with FA and myeloid malignancy have extremely poor outcomes. There are currently no clinical trials or case series addressing the use of chemotherapy for children with FA, except in the context of preparative regimens for stem cell transplantation (SCT). In this report we describe the toxicity of a chemotherapy approach for patients with FA and myeloid malignancy to achieve cytoreduction prior to SCT. PATIENTS AND METHODS: Four patients with FA and myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) were treated with chemotherapy (fludarabine 30 mg/m(2) and cytosine arabinoside 300 mg/m(2) each on days 2-4 and granulocyte-colony stimulating factor (G-CSF) 5 microg/kg on days 1-5), termed reduced intensity FLAG prior to SCT. RESULTS: The chemotherapy was well tolerated with expected hematologic toxicity and no measurable toxicity in other organs. Two of the three patients with AML cleared blasts from their bone marrow. Reduction in marrow cellularity was also achieved in one patient with hypercellular MDS. CONCLUSION: These data indicate that children with FA and myeloid malignancy can tolerate chemotherapy and achieve clearance of disease. It remains unclear whether pre-SCT chemotherapy improves currently poor survival rates for SCT in FA patients with myeloid malignancies and further studies are needed to determine if there is a clinical role for this strategy.     

Very intensive, short-term chemotherapy for children and adolescents with metastatic sarcomas

BACKGROUND: To improve the prognosis for pediatric patients with metastatic sarcomas, including the Ewing sarcoma family of tumors (ESFT), rhabdomyosarcoma (RMS), and undifferentiated sarcoma (UDS), we tested the feasibility of a brief, intensive regimen of chemotherapy that maximizes dose intensity. PROCEDURE: Twenty-four children and adolescents with metastatic sarcomas received VACIME chemotherapy, consisting of eight courses of vincristine 2 mg/m(2) on day 0; doxorubicin 20 mg/m(2)/day on days 0-3; cyclophosphamide 360 mg/m(2)/day on days 0-4; ifosfamide 1,800 mg/m(2)/day on days 0-4; mesna 2,400 mg/m(2)/day; and etoposide 100 mg/m(2)/day on days 0-4. Doxorubicin was omitted in courses 7 and 8. Granulocyte colony-stimulating factor (G-CSF) was used routinely following each course of therapy. Courses of therapy were repeated every 21 days or as soon as hematopoietic recovery and resolution of nonhematopoietic toxicities permitted. Surgical resection followed course 6, and radiotherapy followed the completion of all therapy. RESULTS: Thirteen patients achieved a complete response (CR) with chemotherapy alone, and seven more achieved a CR following surgical resection after course 6 (overall CR rate 83%). There was one toxic death. Thirteen patients developed progressive disease, with 2- and 4-year event-free survivals (95% confidence interval) of 50% (30-70%) and 45% (25-65%), respectively. Myelosuppression was severe and cumulative, leading to dose reductions and chemotherapy interval delays. Mucositis was the most common nonhematopoietic toxicity. CONCLUSIONS: VACIME chemotherapy was a feasible dose-intensive regimen for pediatric patients with metastatic sarcomas. Cumulative hematopoietic toxicity and severe mucositis limited the delivery of chemotherapy as prescribed. The CR and 2-year event-free survival rates were superior to those of most previously reported regimens.     

Fludarabine, cytarabine, G-CSF and idarubicin (FLAG-IDA) for the treatment of relapsed or poor risk childhood acute leukemia

The prognosis of relapsed acute leukemia or chronic leukemia in acute blast crisis is poor and new chemotherapeutic regimens could be useful for these patients. Six relapsed acute lymphoblastic leukemia (ALL), nine relapsed acute myeloblastic leukemia (AML), one chronic myelomonocytic leukemia (CMML) and one chronic myeloid leukemia (CML) in acute blast crisis between three to 18 years (median 10 years) received fludarabine, cytarabine, G-CSF and idarubicin (FLAG-IDA) chemotherapy (CT). Five of the AML relapses were after bone marrow transplantation (BMT) and four were recurrent relapses. At the end of the second course only three patients (2 AML, 1 ALL) were in complete remission (CR). Of the three patients in CR, one patient with AML had her first donor lymphocyte transfusion (DLT) on the 7th day of the second FLAG-IDA course and she is disease-free on the 30th month of the second remission. The remaining two patients were transplanted from unrelated donors in a BMT center abroad on the 5th and 8th month of the last remission and both died with BMT-related complications. Out of 25 courses, seven resulted in fatal infections. The regimen was ineffective in B-cell ALL as in acute blastic crisis of CMML and CML. We could not evaluate the remission-inducing effect accurately in most of the patients due to induction failure. FLAG-IDA appears to be a myelotoxic therapy for relapsed or poor risk leukemia in a developing country. It is not cost-effective; dose modifications or a regimen without IDA may be tried if there is an available marrow donor.     

急性髓系白血病患儿骨髓细胞中血管内皮生长因子及其受体的变化

目的探讨儿童急性髓系白血病(AML)骨髓细胞中血管内皮生长因子(VEGF)及其受体(VEGFR)的表达差异,分析其与儿童急性髓系白血病临床特征的关系,以及化疗前后的变化。方法采用SP免疫组化方法检测20例AML患儿治疗前后以及对照组骨髓中VEGF/VEGFR(Flt-1和KDR)的表达情况。结果VEGF、Flt-1、KDR在AML患儿骨髓中表达水平高于对照组。化疗后获得完全缓解(CR)14例患儿的VEGF、Flt-1、KDR表达在化疗后比化疗前显著降低;化疗后未获得CR的6例患儿的表达化疗前后差异无统计学意义。AML患儿的VEGF表达与骨髓中幼稚细胞百分比、外周血中幼稚细胞百分比呈正相关。骨髓中VEGF、Flt-1、KDR的表达水平在不同年龄、不同性别、有无髓外浸润差异无统计学意义。高表达的VEGF组缓解率低于低表达组。结论VEGF、Flt-1、KDR在AML患儿中呈高表达,提示可能与儿童急性白血病发生过程与预后有关。     

Improved treatment results in children with AML: Results of study AML-BFM 93

BACKGROUND: In the multicenter trial AML-BFM 93 daunorubicin or idarubicin was randomly applied in all patients during induction in combination with cytarabine and etoposide. After induction all patients were stratified to the standard or high risk group. To improve outcome in high risk patients high dose cytarabine and mitoxantrone (HAM) was introduced. The placing of HAM as either the 2nd or 3rd therapy block was randomized to evaluate the efficacy and toxicity accordingly. PATIENTS AND METHODS: 471 children with de novo AML entered the trial AML-BFM 93 (161 standard risk, 310 high risk). RESULTS: Overall, 387 of 471 (82 %) patients achieved remission, 5-year survival, event free survival (EFS), and disease free survival were 60 % SE 3 %, 51 % SE 2 % and 62 % SE 3 %, respectively. Idarubicin-based induction resulted in a significantly better blast cell reduction in the bone marrow on day 15 (25 of 144=17 % patients with > 5 % blasts compared to 46 of 149=31 % patients after daunorubicin, pchi(2)=0.01). This was, however, mainly seen in high risk patients treated with idarubicin (19 % vs. 38 %, pchi(2)=0.007). Cardiotoxicity, WHO grade 1 - 3 shortening fraction reduction after induction occurred in 6 % patients in both arms. In the total group of patients probabilities of five years event-free survival and disease-free survival were similar for patients treated with daunorubicin or idarubicin. However, in patients presenting with more than 5 % blasts on day 15 there was a trend for a better outcome after treatment with idarubicin (p logrank 0.06). Outcome in high risk patients was superior in study 93 compared to study 87 (remission rate and 5-year pEFS in study AML-BFM 93 vs. study 87: 78 % vs. 68 %, p=0.007, and 44 % vs. 31 %, p logrank=0.01). The placing of HAM as the 2nd or 3rd therapy block was of minor importance. However, patients who received the daunorubicin treatment during induction benefited from early HAM. CONCLUSION: Compared to study AML-BFM 87 treatment results in study AML 93 improved significantly in high risk patients. This can partly be contributed to the better response on day 15 after idarubicin induction but is mainly due to the introduction of HAM.     

Determination of the maximum tolerated dose of idarubicin when used in a combination chemotherapy program of reinduction of childhood ALL at first marrow relapse and a preliminary assessment of toxicity compared to that of daunorubicin: a report from the Childrens Cancer Study Group.

An escalating-dose trial of idarubicin, used weekly for 3 doses in combination with vincristine, prednisone, and L-asparaginase (VPLI), to reinduce remission of childhood ALL at first bone marrow relapse was conducted by the Childrens Cancer Study Group (CCSG). The maximum tolerated dose (MTD) of idarubicin, used in the manner, was determined to be 12.5 mg/m2/dose. Twelve of 16 (75%) evaluable patients in first marrow relapse of ALL treated at a dose of 10 or 12.5 mg/m2 entered a second complete remission, compared to 41 of 69 evaluable patients (59%) treated in a comparable way with daunorubicin (30 mg/m2) (VPLD). Prolonged myelosuppression was observed in both groups, but the frequency of documented bacterial sepsis and the duration of required hospitalization were greater among patients treated with idarubicin. No additional toxicity, specifically attributable to idarubicin, was observed at these doses.