Twenty years of Polish experience with three consecutive ... - Nature

Leukemia (2005) 19, 2117–2124 & 2005 Nature Publishing Group All rights reserved 0887-6924/05 $30.00 www.nature.com/leu

Twenty years of Polish experience with three consecutive protocols for treatment of childhood acute myelogenous leukemia A Dluzniewska1, W Balwierz1, J Armata1, A Balcerska2, A Chybicka3, J Kowalczyk4, M Matysiak5, M Ochocka5, U Radwanska6, R Rokicka-Milewska5, D Sonta-Jakimczyk7, J Wachowiak6 and M Wysocki8, for the Polish Pediatric Leukemia/Lymphoma Study Group (PPLLSG) 1

Department of Pediatric Oncology/Hematology, Institute of Pediatrics, Medical College Jagiellonian University, Krakow, Poland; Department of Pediatrics, Hematology, Oncology and Endocrinology, Medical Academy, Gdansk, Poland; 3Department of Pediatric Hematology/Oncology, Medical Academy, Wroclaw, Poland; 4Department of Pediatric Hematology/Oncology, Medical Academy, Lublin, Poland; 5Department of Pediatrics, Hematology and Oncology, Medical Academy, Warsaw, Poland; 6 Department of Pediatric Hematology/Oncology, Medical Academy, Poznan, Poland; 7Department of Pediatric Hematology and Chemotherapy, Silesian Medical Academy, Zabrze, Poland; and 8Department of Pediatrics, Hematology and Oncology, Medical Academy, Bydgoszcz, Poland 2

Until 1983, results of treatment of acute myelogenous leukemia (AML) in Poland with different regimens were very poor. In 1983, the Polish Pediatric Leukemia/Lymphoma Study Group introduced a unified treatment protocol – a modified version of BFM83 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. Leukemia (2005) 19, 2117–2124. doi:10.1038/sj.leu.2403892; published online 29 September 2005 Keywords: acute myelogenous leukemia; risk factors; treatment results

Introduction The Polish Pediatric Leukemia/Lymphoma Study Group (PPLLSG) was established in 1974. 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 nonHodgkin’s lymphomas, and finally acute myelogenous leukemia (AML) in 1983.

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, 30-663 Krakow, Poland; Fax: þ 48 12 6580261; E-mail: [email protected] 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 1998.1–4 In 1983 we introduced the AML-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 AML-94 protocol was in use from 1994 to 1997. 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 AML-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 reports6–12 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

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Leukemia

Table 1

Treatment elements in three consecutive AML-PPLLSG protocols

Schedule elements

AML-PPLLSG 83

AML-PPLLSG 94 SRG

Induction (A)

SR

HR

ADE as in BFM 83 Cytarabine 100 mg/m2/day continuous infusion on days 1 and 2 followed by 30 min infusion every 12 h on days 3–8 Daunorubicin 60 mg/m2, 30 min infusion on days 3–5 Etoposide 150 mg/m2, 60 min infusion on days 6–8

ADE as in BFM 83 Cytarabine and etoposide as before

AIE Cytarabine and etoposide as before

Daunorubicin 30 mg/m2 30 min infusion every 12 h on days 3, 4 and 5

Idarubicin 12 mg/m2, 30 min infusion days 3, 4 and 5

As in BFM 83

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/m2, 30 min infusion on days 1, 8, 15 and 22 instead of adriamycin in both risk groups

6-thioguanine 60 mg/m2/day, days 1–28, orally Prednisone 60 mg/m2, days 1–28, orally Cytarabine 75 mg/m2, days 3–6, 10–13, 17–20, 24–27, i.v. or s.c. Vincristine 1.5 mg/m2/day, days 1, 8, 15 and 22 Adriamycin 30 mg/m2/day, days 1, 8, 15 and 22 Consolidation phase 2 (C)

6-thioguanine 60 mg/m2, days 29–57 orally Cytarabine 75 mg/m2, days 31–34, 38–41, 45–48 and 52–55, i.v or s.c. Cyclophosphamide 500 mg/m2/day, 60 min infusion on days 29 and 57

As in protocol AML-PPLLSG 83

Not given


Not given

ID-ARAC-Dauno (D)

Not given

Not given

Not given

ID-ARAC-VP (E)

Not given

Not given

Cytarabine 500 mg/m2, 60 min infusion every 12 h on days 1–5 (10 doses) daunorubicin 30 mg/m2, 30 min infusion on days 1, 3 and 5 Cytarabine 500 mg/m2, 60 min infusion every 12 h on days 1–5 (10 doses) etoposide 100 mg/m2, 60 min infusion on days 1–5

As in protocol AML- PPLLSG 94 but idarubicin 12 mg/m2, 30 min infusion on days 1,3 and 5 instead of daunorubicin after first phase of consolidation (B) As in previous period but after cycle with ID-ARAC-Ida

Short postremission block (F)

Not given

Not given

6-thioguanine 60 mg/m2 on days 1–15 orally cytarabine 75 mg/m2 on days 3–6, 10–13 i.v. or s.c. cyclophosphamide 500 mg/m2/day, 60 min infusion on day 1

Not given

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

Not given


Treatment results of AML-PPLLSG protocols A Dluzniewska et al

Consolidation phase 1 (B)

HRG

AML-PPLLSG 98


950 mg/m2

600 mg/m2

15120 mg/m2

Recommended in HR


390 mg/m2

950 mg/m2

300 mg/m2

450 mg/m2

450 mg/m2

7000 mg/m2 15120 mg/m2 7000 mg/m2

420 mg/m2

Not recommended Recommended but limited access Not given (very limited access)

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

450 mg/m2

400 mg/m2

7640 mg/m2

Cause of exclusion

Stem cell transplant Cumulative doses of Cytarabine Anthracyclines Adriamycin equivalent dose Etoposide

Therapy for 1 year (about 18 months of therapy together with intensive courses) Maintenance

Intrathecal therapy

As in protocol AML-PPLLSG 94 Without adriamycin up to 2 years Daily thioguanine 40 mg/m2 orally, Cytarabine 40 mg/m2 i.v./s.c. 4 days every 4 weeks for 2 years; adriamycin 25 mg/m2 every 8 weeks during first year

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 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

SR HRG

AML-PPLLSG 94 AML-PPLLSG 83 Schedule elements

Continued Table 1

As in SR during induction and 1st consolidation; further treatment as in previous protocol

HR

Materials and methods

SRG

AML-PPLLSG 98

2119 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 AML-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.

Transformation of MDS or CML Biphenotypic leukemia Down’s syndrome Other concomitant disease Secondary leukemia Death before treatment Pretreatment Other protocol Lack of data Together

Number of patients (%) AMLPPLLSG 83

AMLPPLLSG 94

AMLPPLLSG 98

0

6 (32)

11 (26)

0 1 (6) 1 (6)

1 (5) 4 (21) 0

3 (7) 10 (23) 0

1 (6) 7 (39) 0 4 (22) 4 (22) 18 (100)

0 5 (27) 3 (16) 0 0 19 (100)

4 9 1 5

(9) (21) (2) (12) 0 43 (100)

Leukemia


2120 Table 3

Initial patient data in consecutive treatment AML-PPLLSG protocols

Parameters

AML-PPLLSG 83 n

Number of eligible patients

208

Gender Male Female

106 102

Age (years) Median Range o2 2p10 410 Leukocytes ( 109/l) Median Range o20 X20–o100 4100

%

AML-PPLLSG 94 n

AML-PPLLSG 98

%

83 51 49

27 102 79

48 52

58 46

9.2 0.6–16.6 13 49 38

6 38 39

12.0 0.6–264

%

104

40 43

8.3 0.1–16.6

n

56 44 9.3 0.1–17.8

7 46 47

11 44 49

14.7 1–587

11 42 47 16.5 0.5–516

123 60 24

59 29 12

48 22 13

58 27 16

55 24 21

53 23 20

CSN involvement

10

5

5

6

6

6

Extramedullary involvement (CSN incl.)

44

21

16

19

18

17

FAB M0 M1 M2 M3 M4 M5 M6 M7

0 44 53 22 50 30 8 1

21 26 11 24 14 4 0.5

3 12 24 9 18 11 3 1

4 15 30 11 22 14 4 1

7 18 26 14 17 10 6 2

7 17 25 16 16 10 6 2

208

ND

29

67

3 2 0 1

6 3 3 0 10 21

Karyotypes nd Cytogenetic favorable t(8;21) t(15;17) inv(16) Normal Other

ND ND

ND ND

18 11

BM blasts day15a p5% 45%

ND ND

ND ND

38 34

51 41

72 25

68 24

SRa HRa

ND ND

ND ND

36 39

44 47

57 40

55 39

ND: no data. a 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). Leukemia

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.


2121 Table 4

Results of three consecutive AML-PPLLSG treatment protocols

Parameters

AML-PPLLSG 83

Number of patients Median follow-up of patients in CCR (years, range) Early deaths (total)a Nonresponse CR achieved Death in CCR Relapse

AML-PPLLSG 94

AML-PPLLSG 98

n

% (s.e.)

n

% (s.e.)

n

% (s.e.)

208 10.9 46 13 150 20 62

(3.9–18) 22 6 71 10 42

83 6.1 12 15 56 9 17

(2.75–8.3) 15 18 68 10 30.

104 3.25 8 13 83 10 25

(0.45–6.2) 8 13 80 10 24

pOS 5-years 8-years 10-years

33 (3) 33 (3) 33 (3)

38 (5) 38 (5) NE

50 (5) NE NE

pEFS 5-years 8-years 10-years

32 (3) 32 (3) 32 (3)

36 (5) 36 (5) NE

47 (5) NE NE

pDFS 5-years 8-years 10-years

45 (4) 45 (4) 45 (4)

53 (7) 53 (7) NE

58 (6) NE NE

SCT in first CR Allogeneic (all types) Autologous

6 6

13 8 5

22 14 8

CCR: continuous complete remission; CR: complete remission; NE: not established, SCT: stem cell transplantation. Early deaths are defined as death until day 42.

a

Table 5

Results according to different risk parameters in studies AML-PPLLSG 83–98 (5-year EFS (%), only for subgroup nX5)

Parameters

AML-PPLLSG 83

AML-PPLLSG 94

AML-PPLLSG 98

Total number of patients

EFS (s.e.)

P-value


EFS (s.e.)

P-value


EFS (s.e.)

P–value

Age (years) o2 2–10 410

27 102 79

7 (75) 29 (75) 46 (76)

0.0001

6 38 39

17 (715) 40 (78) 35 (78)

NS

11 44 49

36 (715) 42 (78) 53 (77)

NS

Gender Male Female

106 102

28 (75) 37 (75)

NS

40 43

54 (78) 18 (76)

0.0004

58 46

50 (77) 42 (77)

NS

0.0001

3 12 24 9 18 11 3 1

NS

7 18 26 14 17 10 6 2

43 39 73 64 29 20 33

FAB M0 M1 M2 M3 M4 M5 M6 M7

0 44 53 22 50 30 8 1

33 48 48 35

(77) (77) (711) (77) 0

48 33 56 28 36

0 (715) (710) (717) (711) (715)

NS

Leukocytes ( 109/l) o20 20–100 4100

123 60 24

33 (74) 32 (76) 25 (79)

Risk groupa SR HR

ND ND

ND ND

Total

208

32 (73)

ND

(719) (712) (79) (713) (711) (713) (19)

0.090 trend 48 22 13

35 (74) 33 (75) 22 (77)

36 39

37 (78) 41 (78)

83

36 (75)

NS

0.018

0.008 55 24 21

47 (77) 71 (79) 24 (79)

57 40

63 (77) 32 (77)

104

47 (75)

0.001

s.e.: standard error. a Death before day 15 not qualified to risk groups. Leukemia


2122 Table 6 Distribution of causes of deaths in consecutive AMLPPLLSG protocols

1.0 0.9

Type of death

Number of patients (%) 0.8

Ineligible patients Death before treatment Eligible patients Death before day 15 (without establishing of early response) Death between 15 and 42 days (aplasia death)

18 7 208 14 (7)

AMLPPLLSG 94 19 5 83 8 (10)

AMLPPLLSG 98 43 9 104 7 (7)

0.6 0.5 0.4 0.3

32 (16)

4 (5)

1 (1)

0.2

p=0.015 (Mantel-Cox)

0.1

Death between 43 days and 6 months Nonresponse Relapse Death in remission Infection Bleeding

11 9 13 10 3

After 6 months In remission SCT complications Nonresponse Relapse

60 (29) 7 0 1 52

25 (30) 2 3 7 13

25 (24) 0 2 3 20

139 (67)

51 (61)

51 (49)

Total

0.7 Probability

AMLPPLLSG 93

33 (16)

14 (17) 7 3 4 3 1

18 (17) 8 2 8 7 1

0.0

0

5

10 Time (years)

15

AML-PPLLSG 83. 5-year OS=0.33. SE=0.33 (N=208. 139 events) AML-PPLLSG 94. 5-year OS=0.38. SE=0.05 (N=83. 51 events) AML-PPLLSG 98. 5-year OS=0.50. SE=0.05 (N=104. 51 events)

Figure 1 Estimated probability of overall survival for patients treated according to three consecutive AML-PLLSG protocols.

1.0 0.9 0.8

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 AML-83 and AML-94 protocols, and on March 31, 2004, for AML-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. 0.05 and 0.50, s.e. 0.05), EFS (0.32, s.e. 0.03; 0.36, s.e. 0.05 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 AML-98 and AML-94 than between AML-94 and AML-83. We also observed a continuous increase in remission rates (Po0.05), decrease in early death incidence (Po0.001) Leukemia

Probability

0.7 0.6 0.5 0.4 0.3 p=NS (Mantel -Cox)

0.2 0.1 0.0 0

5

10

15

Time (years) AML-PPLLSG 83. 5-year EFS=0.32. SE=0.03 (N=208. 139 events) AML-PPLLSG 94. 5-year EFS=0.36. SE=0.05 (N=83. 53 events) AML-PPLLSG 98. 5-year EFS=0.47. SE=0.05 (N=104. 55 events)

Figure 2 Estimated probability of event-free survival for patients treated according to three consecutive AML-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).


1.0 0.9 0.8

Probability

0.7 0.6 0.5 0.4 0.3 0.2

p = 0.006 (Mantel-Cox)

0.1 0.0

0

5

10 Time (years)

15

AML-PPLLSG 94 SR, 5-year EFS=0.37, SE=0.08 (N=36, 22 events) AML-PPLLSG 94 HR, 5-year EFS=0.41, SE=0.08 (N=39, 23 events) AML-PPLLSG 98 SR, 5-year EFS=0.62, SE=0.06 (N=57, 21 events) AML-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.

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.20–22 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.

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Acknowledgements Children with Down’s syndrome were rarely registered on protocols AML-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 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

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. Tomaszewska, Department of Pediatric Hematology and Chemotherapy, Silesian Medical Academy, Zabrze; D Januszewska-Lewandowska, L Lewandowska, Department of Pediatric Hematology/Oncology, Medical Academy, Poznan; G Dobaczewski, Department of Pediatric Hematology/Oncology, Medical Academy, Wroclaw; J Styczynski, Department of Pediatrics, Hematology and Oncology, Medical Academy, Bydgoszcz; J Niedzwiedzki, Department of Pediatrics, Hematology, Oncology and Endocrinology, Medical Academy, Gdansk Statistician: H Stanuch, Department of Biostatistics Jagiellonian University, Krakow.

References 1 Cyklis R, Armata J, Dluzniewska A, Boguslawska-Jaworska J, Pejcz J, Wolak D et al. The results of therapy of the acute myeloblastic leukemia in childhood with AML-BFM-83 regimen in the material of the Polish Group on Therapy of Leukemia in Childhood Preliminary report. Pol Tyg Lek 1988; 43: 376–379. 2 Cyklis R, Dluzniewska A, Armata J, Boguslawska -Jaworska J, Ochocka M, Januszkiewicz-Lewandowska D et al. Efficacy of AML-BFM-83 regimen in children with acute myeloblastic leukemia. Over 10 year experience of Polish Pediatric Leukemia/ Lymphoma Study Group. Acta Hematol Pol 1996; 27: 131–137. 3 Dluzniewska A, Balwierz W, Moryl-Bujakowska A, BoguslawskaJaworska J, Dobaczewski G, Januszkiewicz-Lewandowska D et al. Intermediate doses of cytarabine arabinoside in the treatment of acute non- lymphoblastic leukemia in children. Medycyna Wieku Rozwojowego 2000; 4 (Suppl 2): 33–41. 4 Dluzniewska A, Balwierz W, Balcerska A, Chybicka A, Dobaczewski G, Kowalczyk J et al. Efficacy of idarubicin in the treatment Leukemia


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5

6

7 8

9

10 11

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