Twenty years of Polish experience with three consecutive protocols for treatment of childhood acute myelogenous leukemia

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1 (2005) 19, & 2005 Nature Publishing Group All rights reserved /05 $ Twenty years of Polish experience with three consecutive protocols for treatment of childhood acute myelogenous leukemia A Dluzniewska 1, W Balwierz 1, J Armata 1, A Balcerska 2, A Chybicka 3, J Kowalczyk 4, M Matysiak 5, M Ochocka 5, U Radwanska 6, R Rokicka-Milewska 5, D Sonta-Jakimczyk 7, J Wachowiak 6 and M Wysocki 8, for the Polish Pediatric /Lymphoma Study Group (PPLLSG) 1 Department of Pediatric Oncology/Hematology, Institute of Pediatrics, Medical College Jagiellonian University, Krakow, Poland; 2 Department of Pediatrics, Hematology, Oncology and Endocrinology, Medical Academy, Gdansk, Poland; 3 Department of Pediatric Hematology/Oncology, Medical Academy, Wroclaw, Poland; 4 Department of Pediatric Hematology/Oncology, Medical Academy, Lublin, Poland; 5 Department of Pediatrics, Hematology and Oncology, Medical Academy, Warsaw, Poland; 6 Department of Pediatric Hematology/Oncology, Medical Academy, Poznan, Poland; 7 Department of Pediatric Hematology and Chemotherapy, Silesian Medical Academy, Zabrze, Poland; and 8 Department of Pediatrics, Hematology and Oncology, Medical Academy, Bydgoszcz, Poland Until 1983, results of treatment of acute myelogenous leukemia (AML) in Poland with different regimens were very poor. In 1983, the Polish Pediatric /Lymphoma Study Group introduced a unified treatment protocol a modified version of BFM- 83 protocol. This led to an increase in the curability of AML from 15% to approximately 32%. In 1994, a modification was made: the high-risk patients (45% blasts in bone marrow on day 15 of therapy and all M5 cases) received two additional cycles with intermediate-dose cytarabine (ID-ARAC). This led to a nonsignificant improvement in the 5-year event-free survival (EFS) rate from 32 to 36%. A new treatment protocol employing idarubicin in place of daunorubicin was introduced in 1998 and produced better initial responses, increase in the number of patients attaining remission after induction therapy and proportional increase of standard-risk patients.the probability of 5-year EFS (pefs) for the whole group of patients increased from 36 to 47%. In standard- and high-risk groups, the 5-year pefs was 62 and 33%, respectively. The probability of 5-year disease-free survival was 58% in the whole group, and there were no differences between risk groups. Unsatisfactory treatment results in children classified into the high-risk group are principally due to the low remission rate. (2005) 19, doi: /sj.leu ; published online 29 September 2005 Keywords: acute myelogenous leukemia; risk factors; treatment results Introduction The Polish Pediatric /Lymphoma Study Group (PPLLSG) was established in Initially, Hodgkin s disease and acute lymphoblastic leukemia were the focus of interest, and improvement of treatment results by implementing unified protocols with standardized diagnostic criteria and therapy regimens was the main goal. Gradually, the prospects were widened and a unified approach was introduced for non- Hodgkin s lymphomas, and finally acute myelogenous leukemia (AML) in Background and treatment strategy of PPLLSG AML trials Before 1983, results of treatment of AML using various regimens were very poor, with 5-year event-free survival (EFS) below 15%. 1 Correspondence: Dr A Dluzniewska, Department of Pediatric Oncology/Hematology, Polish-American Institute of Pediatrics, Jagiellonian University, Wielicka Str 265, Krakow, Poland; Fax: þ ; balwierz@mp.pl Received 9 December 2004; accepted 2 June 2005; published online 29 September 2005 Since 1983, the PPLLSG introduced three consecutive unified protocols for the treatment of AML (Table 1), which led to a gradual increase in the 5-year EFS from less than 15% before 1983 to 47% after In 1983 we introduced the BFM-83 protocol (thanks to courtesy of Professor Schellong) as an attempt to improve our results. Our goal was to check the feasibility of this intensive protocol in our conditions, and to develop nationwide diagnostic and treatment standards. The protocol allowed us to increase the 5-year EFS to 32%, which was a remarkable progress compared to our previous results, but was significantly worse than the original BFM results. 1,2,5 The main cause of the difference was a significantly lower remission rate, due to a large number of early deaths. Problems with toxicities, or rather with supportive care, made us very cautious about the introduction of high doses of cytarabine and made us give up following strictly the BFM protocol (while still retaining its backbone) in our further protocols. The PPLLSG 94 protocol was in use from 1994 to In this protocol, stratification into risk groups was introduced and three therapeutic arms were active. The standard-risk (SR) group (FAB other than M5 and p5% blasts in bone marrow (BM) on day 15) was treated according to the BFM-83, and the high-risk (HR) group was divided into the M5-good early response group (FAB M5 and p5% blasts in BM on day 15) and HR-poor response group (any FAB and 45% blasts in BM on day 15): both HR groups were treated with intermediate doses of cytarabine (ID-ARAC). This protocol was not very successful except for the increase in EFS: more than two therapeutic arms proved impractical, especially the M5-good response group, which was small and difficult to compare with others. Moreover, the ID-ARAC courses after remission induction were not effective in producing remissions in late responders, and remission rate had not increased. 3 In our next, and the most recent, PPLLSG 98 protocol, we tried to develop a better and more useful stratification system, and to improve treatment results by introduction of a new drug idarubicin as several reports 6 12 stated its high activity in producing remissions. In this protocol, the SR was defined as follows: FAB other than M5, p5% blasts in BM on day 15, no increase in blast count after day 15. All other patients were qualified to the HR group. There were no special rules for FAB M3. The framework of all three protocols and cumulative doses of cytotoxic drugs are presented in Table 1. As the

2 2118 Table 1 Schedule elements Treatment elements in three consecutive PPLLSG protocols PPLLSG 83 PPLLSG 94 PPLLSG 98 SRG HRG SR HR Induction (A) ADE as in BFM 83 ADE as in BFM 83 AIE Cytarabine 100 mg/m 2 /day continuous Cytarabine and etoposide as before Cytarabine and etoposide as before infusion on days 1 and 2 followed by 30 min infusion every 12 h on days 3 8 Daunorubicin 60 mg/m 2, 30 min infusion Daunorubicin 30 mg/m 2 30 min infusion every 12 h Idarubicin 12 mg/m 2, 30 min infusion days 3, 4 and 5 on days 3 5 on days 3, 4 and 5 Etoposide 150 mg/m 2, 60 min infusion on days 6 8 Consolidation phase 1 (B) As in BFM 83 6-thioguanine 60 mg/m 2 /day, days 1 28, orally Prednisone 60 mg/m 2, days 1 28, orally Cytarabine 75 mg/m 2, days 3 6, 10 13, 17 20, 24 27, i.v. or s.c. Vincristine 1.5 mg/m 2 /day, days 1, 8, 15 and 22 Adriamycin 30 mg/m 2 /day, days 1, 8, 15 and 22 As in previous protocol As in previous protocol, but for FAB M5 good responders as second element of protocol, for other HR after ID-ARAC-Dauno and ID-ARAC-VP As in previous protocol but idarubicin 12 mg/m 2, 30 min infusion on days 1, 8, 15 and 22 instead of adriamycin in both risk groups Treatment results of PPLLSG protocols Consolidation phase 2 (C) 6-thioguanine 60 mg/m 2, days orally Cytarabine 75 mg/m 2, days 31 34, 38 41, and 52 55, i.v or s.c. Cyclophosphamide 500 mg/m 2 /day, 60 min infusion on days 29 and 57 As in protocol PPLLSG 83 Not given As in protocol PPLLSG 83 Not given ID-ARAC-Dauno (D) Not given Not given Cytarabine 500 mg/m 2,60min infusion every 12 h on days 1 5 (10 doses) daunorubicin 30 mg/m 2, 30 min infusion on days 1, 3 and 5 ID-ARAC-VP (E) Not given Not given Cytarabine 500 mg/m 2,60min infusion every 12 h on days 1 5 (10 doses) etoposide 100 mg/m 2, 60 min infusion on days 1 5 Not given As in protocol PPLLSG 94 but idarubicin 12 mg/m 2,30min infusion on days 1,3 and 5 instead of daunorubicin after first phase of consolidation (B) Not given As in previous period but after cycle with ID-ARAC-Ida Short postremission block (F) Not given Not given 6-thioguanine 60 mg/m 2 on days 1 15 orally cytarabine 75 mg/m 2 on days 3 6, i.v. or s.c. cyclophosphamide 500 mg/m 2 /day, 60 min infusion on day 1 Not given As in protocol PPLLSG 94 Cranial irradiation During second Phase consolidation (C) o1 year ¼ 12 Gy, 1 2 years ¼ 15 Gy, 42 years ¼ 18 Gy Timing and dose as before During short postremission block (F) doses as before As in previous protocol except, children o1 year ¼ no irradation

3 Treatment results of PPLLSG protocols Table 1 Continued PPLLSG 83 PPLLSG 94 PPLLSG 98 Schedule elements SRG HRG SR HR As in SR during induction and 1st consolidation; further treatment as in previous protocol Additional ith in AIE on days 3 and 7 Cytarabine: timing and doses as before additional doses during blocks ID-ARAC-Dauno and ID-ARAC-VP and on days 1, 8 and 15 block F Timing and dose as before Intrathecal therapy Cytarabine on days 31, 38, 45 and 51, (C) dose adjusted to age: o1 year ¼ 20 mg, 1 2 years ¼ 26 mg, 2 3 years ¼ 34 mg, 43 years ¼ 40 mg As in protocol PPLLSG 94 As in protocol PPLLSG 94 Therapy for 1 year (about 18 months of therapy together with intensive courses) Without adriamycin up to 2 years Maintenance Daily thioguanine 40 mg/m 2 orally, Cytarabine 40 mg/m 2 i.v./s.c. 4 days every 4 weeks for 2 years; adriamycin 25 mg/m 2 every 8 weeks during first year Not given (very limited access) Recommended but limited access Not recommended Recommended in HR Stem cell transplant Cumulative doses of Cytarabine 7640 mg/m mg/m mg/m mg/m mg/m 2 Anthracyclines Adriamycin 400 mg/m mg/m mg/m mg/m mg/m 2 equivalent dose Etoposide 450 mg/m mg/m mg/m mg/m mg/m 2 expected accrual was limited, randomized questions were not proposed. 4 Stem cell transplantation (SCT) became available in our country in 1989, but access to it was very limited till the late 1990s. This was the reason why we did not recommend SCT as a routine procedure in two former protocols. In PPLLSG 98 protocol, the SCT was recommended for HR patients, but was not a part of the protocol. Eventually, transplantations were performed at the discretion of individual centers and all forms of transplantation (autologous, matched familial and unrelated donors) were carried out in first remission. Materials and methods Between June 1993 and March 2002, 475 children with AML (226, 102 and 147 patients in consecutive periods) were registered at nine PPLLSG centers, and 395 (208, 83 and 104 patients in consecutive periods) were eligible for evaluation. The exclusion criteria were AML following chronic myeloid leukemia (CML) or myelodysplastic syndrome (MDS), AML as a secondary neoplasm, congenital malformations and severe comorbidities (including Down s syndrome), biphenotypic leukemia, pretreatment, death before treatment, treatment with other protocols or incomplete data of the patient (Table 2). The inclusion criteria were de novo diagnosed untreated AML (ie not secondary leukemia, MDS transformation, etc), no severe congenital malformations (including Down s syndrome) or comorbidities. In all children, the diagnosis was established after BM examination including cell morphology with FAB classification and cytochemistry. Immunophenotyping was recommended but became mandatory only in the last study; cytogenetic analysis was recommended in the last study, but results were obtained only in about half of the patients. All examinations were performed in local treatment centers. In all children we have also performed complete blood count, liver and renal function tests, lumbar puncture, chest X-ray, ECG and echocardiography. Patient characteristics in all three periods are presented in Table 3. Ineligible patients and reasons for exclusion are presented in Table 2. The fact that the number and percent of ineligible patients is increasing in time is most probably an effect of better registration, better diagnosis of MDS preceding AML and biphenotypic leukemia, and implementation of the protocol in children with Down s syndrome. Treatment protocols are presented in Table 1. Table 2 Ineligible patients: reasons of exclusion Cause of exclusion Number of patients (%) PPLLSG 83 PPLLSG 94 PPLLSG 98 Transformation of MDS 0 6 (32) 11 (26) or CML Biphenotypic leukemia 0 1 (5) 3 (7) Down s syndrome 1 (6) 4 (21) 10 (23) Other concomitant 1 (6) 0 0 disease Secondary leukemia 1 (6) 0 4 (9) Death before treatment 7 (39) 5 (27) 9 (21) Pretreatment 0 3 (16) 1 (2) Other protocol 4 (22) 0 5 (12) Lack of data 4 (22) 0 0 Together 18 (100) 19 (100) 43 (100) 2119

4 2120 Table 3 Treatment results of PPLLSG protocols Initial patient data in consecutive treatment PPLLSG protocols Parameters PPLLSG 83 PPLLSG 94 PPLLSG 98 n % n % n % Number of eligible patients Gender Male Female Age (years) Median Range o p Leukocytes ( 10 9 /l) Median Range o X20 o CSN involvement Extramedullary involvement (CSN incl.) FAB M M M M M M M M Karyotypes nd 208 ND Cytogenetic favorable 3 6 t(8;21) 2 3 t(15;17) 0 3 inv(16) 1 0 Normal ND ND Other ND ND BM blasts day15 a p5% ND ND % ND ND SR a ND ND HR a ND ND ND: no data. Death before day 15 excluded. Definitions and statistics Complete remission (CR) was defined as no more than 5% blasts in BM of normal or only slightly decreased cellularity with signs of regeneration of normal hematopoiesis, regeneration of normal cell production in peripheral blood, no blasts in peripheral blood and disappearance of any extramedullary sites. The features of CR should have lasted for not less than 1 month; in case it was shorter, the child was registered as a nonresponder (NR). Deaths were classified as early if they occurred within 6 weeks from the beginning of treatment. They were divided into the following three subgroups: 1. Death before treatment induction treatment has not been started. These patients were not evaluated. 2. Death before day 15 induction treatment has been started but there was no estimation of early response and classification into risk group was impossible. 3. Death between days 15 and 42 in aplasia.

5 Table 4 Results of three consecutive PPLLSG treatment protocols Treatment results of PPLLSG protocols 2121 Parameters PPLLSG 83 PPLLSG 94 PPLLSG 98 n % (s.e.) n % (s.e.) n % (s.e.) Number of patients Median follow-up of patients in CCR (years, range) 10.9 (3.9 18) 6.1 ( ) 3.25 ( ) Early deaths (total) a Nonresponse CR achieved Death in CCR Relapse pos 5-years 33 (3) 38 (5) 50 (5) 8-years 33 (3) 38 (5) NE 10-years 33 (3) NE NE pefs 5-years 32 (3) 36 (5) 47 (5) 8-years 32 (3) 36 (5) NE 10-years 32 (3) NE NE pdfs 5-years 45 (4) 53 (7) 58 (6) 8-years 45 (4) 53 (7) NE 10-years 45 (4) NE NE SCT in first CR Allogeneic (all types) Autologous 5 8 CCR: continuous complete remission; CR: complete remission; NE: not established, SCT: stem cell transplantation. a Early deaths are defined as death until day 42. Table 5 Results according to different risk parameters in studies PPLLSG (5-year EFS (%), only for subgroup nx5) Parameters PPLLSG 83 PPLLSG 94 PPLLSG 98 Total number of patients EFS (s.e.) P-value Total number of patients EFS (s.e.) P-value Total number of patients EFS (s.e.) P value Age (years) o (75) (715) NS (715) NS (75) (78) (78) (76) (78) (77) Gender Male (75) NS (78) (77) NS Female (75) (76) (77) FAB M NS 7 43 (719) M (77) (715) (712) M (77) (710) (79) M (711) 9 56 (717) (713) M (77) (711) (711) M (715) (713) M (19) M Leukocytes ( 10 9 /l) NS trend o (74) (74) (77) (76) (75) (79) (79) (77) (79) Risk group a SR ND ND ND (78) NS (77) HR ND ND (78) (77) Total (73) (75) (75) s.e.: standard error. a Death before day 15 not qualified to risk groups.

6 2122 Type of death Number of patients (%) Table 6 Distribution of causes of deaths in consecutive PPLLSG protocols PPLLSG 93 Treatment results of PPLLSG protocols PPLLSG 94 PPLLSG 98 Ineligible patients Death before treatment Eligible patients Death before day (7) 8 (10) 7 (7) (without establishing of early response) Death between 15 and 42 days (aplasia death) 32 (16) 4 (5) 1 (1) Death between (16) 14 (17) 18 (17) days and 6 months Nonresponse Relapse Death in remission Infection Bleeding After 6 months 60 (29) 25 (30) 25 (24) In remission SCT complications Nonresponse Relapse Total 139 (67) 51 (61) 51 (49) Probability p=0.015 (Mantel-Cox) Time (years) PPLLSG year OS=0.33. SE=0.33 (N= events) PPLLSG year OS=0.38. SE=0.05 (N= events) PPLLSG year OS=0.50. SE=0.05 (N= events) Figure 1 Estimated probability of overall survival for patients treated according to three consecutive PLLSG protocols Patients who survived longer than 6 weeks and did not achieve remission on protocol were classified as NR. For patients who completed consolidation while still having active disease, second line protocols were recommended. The results were expressed by means of remission rates, EFS, overall survival (OS) and disease-free survival (DFS). The EFS was calculated from the date of diagnosis to last follow-up or event (failure to achieve remission, relapse and second malignancy or death of any cause), OS was calculated from the date of diagnosis to death of any cause and DFS of patients achieving remission was calculated from the date of remission to first event. Survival rates were estimated using the Kaplan Meier method and compared with the log rank and Mantel Cox tests. 13 For statistical analysis, we used BMDP New System and Statistica 6.0 StatSoft software packages. The observations were completed on March 31, 2002, for 83 and 94 protocols, and on March 31, 2004, for 98 protocol. Results The treatment results of 395 eligible children are presented in Tables 4 6 and on survival curves (Figures 1-3). The probabilities of 5-year OS (0.33, s.e. 0.03; 0.38, s.e and 0.50, s.e. 0.05), EFS (0.32, s.e. 0.03; 0.36, s.e and 0.47, s.e. 0.05) and DFS (0.45, s.e. 0.04; 0.53, s.e. 0.07and 0.58, s.e. 0.05) improved in time, but the difference was greater between 98 and 94 than between 94 and 83. We also observed a continuous increase in remission rates (Po0.05), decrease in early death incidence (Po0.001) Probability p=ns (Mantel -Cox) Time (years) PPLLSG year EFS=0.32. SE=0.03 (N= events) PPLLSG year EFS=0.36. SE=0.05 (N= events) PPLLSG year EFS=0.47. SE=0.05 (N= events) Figure 2 Estimated probability of event-free survival for patients treated according to three consecutive PLLSG protocols. and decrease in the number of deaths in remission (statistically nonsignificant), which had a greater impact on results than the decrease in relapse rates (Tables 4 6) (Po0.05). The greatest improvement was observed in SR (5-year EFS 0.62, s.e. 0.06) in the last period. The analysis of risk factors (Table 5) reveals that their relative importance changed over time. In the first period, the outcome was significantly worse in children below 2 years, while later this was not the case. This also reflects improvement of supportive care in time. On the other hand, the white blood cell count at presentation began to play a role as prognostic factor, and FAB remains constantly important (Table 5).

7 Probability Time (years) Children with Down s syndrome were rarely registered on protocols PPLLSG 83 and 94. Most probably, they were treated with less intensive protocols. In the last period, 10 children were registered and six of them remain in remission, three died due to complications and one due to relapse. These children are more prone to toxicities and special rules including reduced drug doses should be employed. In the past, while the access to SCT was very limited, we hoped that wider use of that treatment would improve the overall treatment results. With the last protocol, we found that it is not the case. Among 22 SCTs performed, there were eight failures (six relapses and two treatment-related deaths) and pos and pefs for transplanted and nontransplanted patients were similar while comparing patients achieving CR, which is a necessary prerequisite for SCT. Discussion p=0.006 (Mantel-Cox) PPLLSG 94 SR, 5-year EFS=0.37, SE=0.08 (N=36, 22 events) PPLLSG 94 HR, 5-year EFS=0.41, SE=0.08 (N=39, 23 events) PPLLSG 98 SR, 5-year EFS=0.62, SE=0.06 (N=57, 21 events) PPLLSG 98 HR, 5-year EFS=0.32, SE=0.07 (N=40, 27 events) Figure 3 Estimated probability of event-free survival for patients with AML according to the risk groups in two consecutive PPLLSG protocols. The results achieved by our group show continuous improvement of treatment results and are comparable with those achieved by others in respective time periods. 2 4,9,14 18 The first study allowed us to achieve our goals: improve EFS and OS rates and introduce a unified approach in all cooperating centers. Comparison with the BFM results showed that weakness of supportive care leading to as many as 46 (22.1%) early deaths and 20 (9.6%) deaths in remission was the main reason for poor treatment results. Still, we observed improvement in that field over time, which resulted in improvement of late results of the protocol in comparison with those presented, while the protocol was pending. 1,2,5 The second trial did not fulfill our expectations. The improvement of OS, EFS and DFS was nonsignificant, and remission rate was even lower than before, particularly in HR (61.5%). ID-ARAC courses administered immediately after induction were not effective in producing remissions, which led to unsatisfactory outcome in spite of the decrease in early deaths Treatment results of PPLLSG protocols to 14.5%. 3 The relapse rate decreased from 41.8 to 30.3%, so poor efficacy in achieving remission was the main drawback of this protocol and made us look for new drugs, more effective in early phases of therapy. 3,6 12 In the third period, our results improved mainly by increase in remission rate (Po0.05) achieved by decrease in both early death and nonresponse rate. Decrease in relapse rates between second and third periods was nonsignificant. As shown in Table 3, idarubicin used in the induction phase produced more early responses (no more than 5% blasts in BM on day 15; difference statistically significant, Po0.05) and put more patients into SR in spite of more restrictive criteria. Transfer of patients with increase in blast count after day 15 to HR (only four of 11 such patients achieved remission on protocol) allowed us to identify a group of patients with better prognosis, based on early and stable response as the most important factor (except for FAB M5 no other factor is taken into account). This corresponds with other reports, which state that achieving remission after first induction block is associated with better outcome. 3,9,14,17,19 Finding of new immunological or genetic risk factors may change our concept of risk groups in future In HR patients, achieving remission remains the main problem, and the low remission rate is responsible for worse outcome. Our future efforts will focus on looking for ways to overcome early resistance to treatment. Acknowledgements Investigators of the study: A Moryl-Bujakowska, M Mikolajczyk, W Strojny, T Klekawka, Department of Pediatric Oncology/ Hematology, Polish-American Institute of Pediatrics, Jagiellonian University, Krakow; M Stefaniak, U Malek, Department of Pediatric Hematology/Oncology, Medical Academy, Lublin; K Krenke, A Malinowska, Department of Pediatrics, Hematology and Oncology, Medical Academy, Warsaw; R. 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