Could intensified treatment in childhood acute ...

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Copyright Blackwell Munksgaard 2005

Eur J Haematol 2005: 75: 361–369 All rights reserved

EUROPEAN JOURNAL OF HAEMATOLOGY

Could intensiﬁed treatment in childhood acute lymphoblastic leukemia improve outcome independently of risk factors? Tzortzatou-Stathopoulou F, Moschovi MA, Papadopoulou AL, Barbounaki IG, Lambrou GI, Balafouta M, Syriopoulou V. Could intensiﬁed treatment in childhood acute lymphoblastic leukemia improve outcome independently of risk factors? Eur J Haematol 2005: 75: 361–369. Blackwell Munksgaard 2005. Abstract: Purpose: Many risk-directed therapeutic protocols have been proposed in acute lymphoblastic leukemia (ALL). However, the relapse rates remain high. The eﬀectiveness of each protocol depends on how quickly the clearance of blast cells is achieved. In an attempt to improve survival, by minimizing treatment toxicity and relapse rate, diﬀerent therapeutic protocols were used every 3 yr in our Unit. Patients and Methods: During 1991–2000, 132 children with ALL were diagnosed in our Unit. Modiﬁed and intensiﬁed NY II and BFM protocols, in three consecutive periods [(Hematology/Oncology Pediatric Department of the University of Athens) HOPDA-91, HOPDA-94, HOPDA-97] were used. Results: At a median follow-up time of 96 months, the 8-year overall survival (OS) was 88% ± 3%, whereas the event-free survival (EFS) was 85% ± 3%. There was a signiﬁcant increase of the 5-year EFS of the high-risk (HR) group through time (65% in HOPDA-91 vs. 80% in HOPDA-97), whereas EFS of the low risk (LR) group in HOPDA-97 was 96%. Five cases relapsed (3.8%), four of which underwent successful bone marrow transplantation. Fifteen children died (13 diagnosed by 1996, two in the last 4 yr). Conclusion: Modiﬁcation of the protocols signiﬁcantly improved survival in both HR and LR groups. The intensiﬁed regimen in the LR group did not increase the adverse toxic events, but on the contrary was extremely eﬀective.

In childhood acute lymphoblastic leukemia (ALL), prognostic factors traditionally used as indicators for modiﬁcation of therapy and disease control tend to lose their ﬁrst line value. Their signiﬁcant role is undoubted but inadequate to predict which children are at risk of relapse. Many relapses continue to occur in patients labeled as Ôstandard riskÕ who do not have any speciﬁc adverse prognostic biologic or clinical characteristics. Nowadays, the combination of immunological, cytogenetic and molecular genetic information can more precisely deﬁne the case risk group and the risk-adapted therapy but obviously many unknown factors are eventually involved in prognosis. Consequently, relapse risk remains unclear and randomized trials need to be conducted to clarify more aspects of the disease.

Fotini Tzortzatou-Stathopoulou, Maria A. Moschovi, Athina L. Papadopoulou, Ioanna G. Barbounaki, George I. Lambrou, Myrsini Balafouta, Vassiliki Syriopoulou Hematology/Oncology Unit, First Department of Pediatrics, University of Athens, ÔAghia SophiaÕ Children's Hospital, Athens, Greece

Key words: childhood; acute lymphoblastic leukemia; risk factors; intensified protocol; outcome Correspondence: Prof. Fotini Tzortzatou-Stathopoulou MD, PhD, Hematology/Oncology Unit, University of Athens, ÔAghia SophiaÕ Children's Hospital, 11527 Athens, Greece Tel: 0030 210 746 7890 Fax: 0030 210 779 5538 e-mail: [email protected] Accepted for publication 24 May 2005

Recent ALL studies mostly focus on relating the relapse risk with the initial poor reduction of the leukemic clone. Early response to therapy after a multi-agent induction regimen seems to be the cornerstone of cure success (1–3). The clearance of blast cells in the bone marrow (BM) and the peripheral blood is predictive of the outcome in childhood ALL and is considered as the strongest prognostic factor (4–7). The basic strategy is to rapidly achieve the maximum cell kill, in order to prohibit the acquisition of drug resistance, which seems to be responsible for treatment failure. However, in some large studies, cases considered as high risk (HR) paradoxically had less or similar relapses than medium or low risk (LR) who received less intensive protocols (8–12). Therefore, would it be wiser to use the same intensive prime 361

Tzortzatou-Stathopoulou et al. regimen in all cases regardless of the diagnostic characteristics, thus focusing on the therapy burden and response? With this new aspect of view, diﬀerent protocols in three distinct therapeutic periods were used to treat children diagnosed with ALL in a 10-year period in the Hematology/Oncology Pediatric Department of the University of Athens (HOPDA). The aim of this prospective study is to present the skepticism concerning HR features and regimen modiﬁcation and to discuss the resulting outcome. Patients and methods Patients

From January 1991 to December 2000, 138 consecutive children younger than 15-year old with newly diagnosed ALL enrolled in the prospective study of our Unit. Six patients were excluded from the study; three who had been diagnosed and received initial treatment in foreign countries, a case with neonatal ALL, a boy with Li-Fraumeni syndrome and a girl who presented with a vascular necrosis of the femoral bone during early induction and continued with modiﬁed treatment without steroids. Thus, 132 patients were eligible and evaluable. All patients were followed-up throughout the study. The diagnosis was based on morphologic, immunophenotypical and cytochemical evaluation of leukemic cells in BM smears. Central nervous system (CNS) disease was diagnosed by investigating the number of blasts found in the CNS ﬂuid obtained (>5 blast per lL denoted positive diagnosis). A panel of monoclonal antibodies was used to characterize cases so that they were classiﬁed as pre-pre-B, common, B or T and unclassiﬁed ALL. Risk group

Cases were divided into low and HR groups according to the following prognostic factors: age, WBC count, morphology (L1, L2, and L3) in BM, immunophenotype classiﬁcation, and CNS leukemia at diagnosis. Until 1996, low-risk were the patients aged ‡2 and £ 10 yr, with WBC <50000/ lL and L2 £ 20% without CNS disease or T ALL. On the other hand, patients were classiﬁed as HR when one or more of these factors presented: aged <2 or > 10 yr, WBC ‡50000/lL, L2 >20%, T ALL and/or CNS disease. During 1997–2000, age classiﬁcation and L2 blast criteria were modiﬁed: cases <1 or >10 yr were considered as HR whereas cases with L2 blasts in BM as the only adverse factor were not classiﬁed as HR. All other risk factors remained the same. 362

Treatment plan

The study was approved from the University of Athens. All parents of the children were informed and agreed to participate in the study. During 1991– 2000, three therapeutic periods were employed. Protocols were modiﬁed in an attempt to reduce acute treatment toxicity and improve outcome. In HOPDA-91 (1991–1993, Table 1), LR patients received a combination of UKALL XI (induction) and R blocks of ALL-REZ BFM-87 (intensiﬁcation) whereas HR patients received the NY II regimen (13). However, four cases, all in the HR group, died during the consolidation phase due to complications (three septicemias, one Aspergillus fumigatus infection) (14). Furthermore, a boy with LR leukemia had an early relapse but achieved a second remission. Thus, modiﬁcation of the protocol was carried out during the next years. In HOPDA-94 (1994–1996), the therapeutic protocol was modiﬁed for both groups (LR, HR) and consisted of induction, milder consolidation, intensiﬁcation and maintenance. The induction phase remained as in HOPDA-91 according to risk group. Then, both groups had the same consolidation phase in which cytarabine was restricted to four doses with 3 g/m2 in two consecutive days (total 12 g/m2) and methotrexate was removed. The intensiﬁed treatment of the LR group remained the same. The intensiﬁcation of the HR group was the BB block of the NHL-BFM-90 (15, 16) protocol reducing the dose of methotrexate to 2 g/m2. In addition, during maintenance, daunomycin was replaced by VP-16 300 mg/m2 (when the cumulative dose of daunomycin was up to 300 mg/m2). These modiﬁcations resulted in the reduction of the toxicity rate. No relapse was observed except for one boy in the LR group who developed MDS/AML. In HOPDA-97 (1997–2000, Table 2), considering that the most important objective of the ﬁrst line protocol is to kill the leukemic burden and avoid drug resistance, LR and HR patients received the same drug-combination (induction, consolidation and intensiﬁcation). Maintenance phase was also the same but shorter in LR cases. Extra therapy with high dose Ara-C and BB block of the NHLBFM-90 was applied in eight patients who experienced very HR features as WBC >300 000/ lL (two cases), T ALL (three cases), infantile ALL (two cases) or expressed positive myeloid markers (one case). No relapse or second malignancy occurred. During the three trials, cranial prophylactic radiotherapy (18 Gy) was applied only in HR cases (52 cases). Prophylaxis was not given in 18 HR children who were younger than 3-year old, in seven cases who died early and in two cases who never

Intensiﬁed treatment in childhood ALL Table 1. Therapy of LR and HR patients treated with the HOPDA-91 protocols Induction

Consolidation

LR

VCR 1.5 mg/m2 (1, 8, 15, 21, 28), DNM 45 mg/m2 (1, 2, 28, 29), PRED 40 mg/m2 (1–28), L-ASP 6000 U/m2 (3/w for 3 w), Ara-C 100 mg/m2 · 2 (28–32), VP-16 100 mg/m2 (28–32), 6 TG 80 mg/m2 pos (28–32), IT MTX 6–12 mg1 (1, 8, 15, 21, 28)

–

HR

IT Ara C 20–701 mg (1), CPM 1200 mg/m2 iv (1), VCR 1.5 mg/m2 (1, 8, 15, 22), PRED 60 mg/m2 :3 (1–22), DNM 60 mg/m2 (2, 3), L-ASP 6000 U/m2 (3/w for 3–5 w), IT MTX 6–12 mg1 (82, 15, 22)

Ara-C 3 g/m2 · 2 (28, 29, 35, 36), VCR 1.5 mg/m2 (28), PRED 100 mg/m2 :3 pos (28–32), MTX 150–200 mg (31, 38), L-ASP 10000 U/m2 im (30, 31)

Intensification PRED 100 mg/m2 :3 pos (1–5), 6 MP 100 mg/m2 pos (1–5), VCR 1.5 mg/m2 (1), MTX-HD 1 g/m2 (1), IT MTX 6–12 mg1 (1, 5), IT Ara C 16–301 mg (1, 5), IT D-medrol 0.1 mL (1, 5), Ara-C 300 mg/m2 (5), VP-16 165 mg/m2 (5), L-ASP 10000 U/m2 im (6–8), DEX 20 mg/m2 :3 (21–25), 6 TG 100 mg/m2 pos (21–25), MTX-HD 1 g/m2 (21), IT MTX 6–12 mg1 (21, 25), IT Ara C 16–301 mg (21, 25), IT D-medrol 0.1 mL (21, 25), IFO 400 mg/m2 (21, 25), DNM 50 mg/m2 (25). After 2 wk of DNM, the intensification regimen was repeated four times DEX 10 mg/m2 :3 (1–5), VCR 1.5 mg/m2 (1), MTX-HD 2 g/m2 (1), IT MTX 6–12 mg1 (1, 5), IT Ara C 16–301 mg (1, 5), IT D-medrol 0.1 mL (1, 5), CPM 200 mg/m2 (1–5), ADM 25 mg/m2 (4, 5). 3 wk after: IT MTX 6–12 mg1 (1, 8, 15, 22), PRED 15 mg/m2 :3 pos(1–13)3, CPM 600 mg/m2 (4), L-ASP 25000 U im (5, 12, 19, 26), MTX 150 mg/m2 (26), CR 18 Gy

Maintenance PRED 40 mg/m2 (1–8), VCR 1.5 mg/m2 every 28 days, 6 MP 75 mg/m2 pos daily, MTX 20 mg/m2 pos once a week, it was continued until 2 yr were completed

IT MTX 6–12 mg1 (1), 6 MP 300 mg/m2 pos (1–4), CPM 1200 mg/m2 (5), VCR 1.5 mg/m2 (12, 19, 26), PRED 100 mg/m2 :3 pos (12–19), MTX 150–200 mg/m2 (26), DNM 20 mg/m2 (40, 41), Ara-C 100 mg/m2 cont. infusion (42–44), 6 TG 40 mg/m2 · 2 pos (42–44). At day 60, start again, it was repeated until 2 yr were completed

1

According to age. Only if CNS disease is present. 3 During radiotherapy only. HR, high risk; LR, low risk; VCR, Vincristine; DNM, Daunomycin (Daunorubicin); PRED, Prednisone; L-ASP, L-Asparaginase; Ara-C, Cytarabine; VP-16, Etoposide; 6TG, Thioguanine; IT, Intrathecal; MTX, Methotrexate; MTX-HD, High dose MTX; 6MP, 6-Mercaptopurine; DEX, Dexamethasone; IFO, Ifosfamide; CPM, Cyclophosphamide ADM, Adriamycin (Doxorubicine). 2

achieved remission. The cumulative dose of anthracyclins did not exceed the dose of 300 mg/m2. Since 1994, supportive care has changed with the early use of broad-spectrum antibiotics and antifungal therapy when severe neutropenia develops. Toxicity and remission evaluation

Toxicity was evaluated for each period according to the WHO grading system. Response status was assessed by examination of the peripheral blood, BM and CSF on days 25–28 and every 2 months thereafter. Statistical analysis

Event-free survival (EFS) and overall survival (OS) rates were calculated according to the method of

Kaplan–Meier Estimator. All children of the three protocols were followed-up until June 2004 or the date of death. EFS was measured from the date of study entry (diagnosis/ﬁrst day of induction) to the ﬁrst occurrence of any one of the following events: relapse, toxicity deaths, and deaths from resistant disease, second malignancy or the last follow-up examination. Gehan’s modiﬁcation of a generalized Wilcoxon’s test was used to evaluate the diﬀerence between the subgroups. This test is sensitive to early diﬀerences between survival rates and it was considered appropriate to analyze this study in which all events (deaths or relapses), except two, occurred during the ﬁrst 2 yr after diagnosis. The estimation of the median survival time and median event-free time is not possible since almost all deaths occurred during the ﬁrst 20 months and all relapses were noted during the ﬁrst 49 months after diagnosis. 363

Tzortzatou-Stathopoulou et al.

Table 2. Therapy of LR and HR patients treated with the HOPDA-97 protocols Induction IT Ara C 20–701 mg (1), CPM 1200 mg/m2 iv (1), VCR 1.5 mg/m2 (1, 8, 15, 22), PRED 60 mg/m2 :3 (1–22), DNM 60 mg/m2 (2, 3), L-ASP 6000 U/m2 (3/w for 3–5 w), IT MTX 6–12 mg1 (82, 15, 22)

Consolidation

Intensification

Maintenance

Ara-C 3 g/m2 · 2 (28, 29), VCR 1.5 mg/m2 (28), PRED 100 mg/m2 :3 pos (28–32), L-ASP 10000 U/m2 im (30–31)

Day 50: DEX 10 mg/m2 :3 (1–5), VCR 1.5 mg/m2 (1), MTX-HD 2 g/m2 (1), IT MTX 6–12 mg1 (1, 5), IT Ara C 16–301 mg (1, 5), IT D-medrol 0.1 mL (1, 5), CPM 200 mg/m2 (1–5), ADM 25 mg/m2 (4, 5). After 3 wk: IT MTX 6–12 mg1 (1, 8, 15, 22), PRED 15 mg/m2.3 pos (1–13)3, CPM 600 mg/m2 (4), L-ASP 25000 U im (5, 12, 19, 26), MTX 150 mg/m2 (26), HR: CR 18 Gy

IT MTX 6–12 mg1 (1), 6 MP 300 mg/m2 pos (1–4), CPM 1200 mg/m2 (5), VCR 1.5 mg/m2 (12, 19, 26), PRED 100 mg/m2 :3 pos (12–19), MTX 150–200 mg/m2 (26), DNM 20 mg/m2 (40, 41), Ara-C 100 mg/m2 cont. infusion (42–44), 6 TG 40 mg/m2 · 2 pos (42–44). At day 60, start again. LR: it was repeated seven times. Then: 6-mp 75 mg/m2 pos daily, MTX 20 mg/m2 pos once a week. HR: it was repeated 10 times

HR, high risk; LR, low risk; VCR, Vincristine; DNM, Daunomycin (Daunorubicin); PRED, Prednisone; L-ASP, L-Asparaginase; Ara-C, Cytarabine; VP-16, Etoposide; 6TG, Thioguanine; IT, Intrathecal; MTX, Methotrexate; MTX-HD, High dose MTX; 6MP, 6-Mercaptopurine; DEX, Dexamethasone; IFO, Ifosfamide; CPM, Cyclophosphamide ADM, Adriamycin (Doxorubicine). 1 According to age. 2 Only if CNS disease is present. 3 During radiotherapy only.

Second malignancy (a secondary MDS transformed to AML) occurred only in one case, 69 months after the ﬁrst diagnosis. That means that the estimated survivor function is greater than 0.5 for all values of t. Seventy percent of cases have been followed up for a minimum period of 68 months and half of the cases were out of therapy for more than 78 months. Analyzing all patients, the median Ôfollow-upÕ duration for overall and event-free time was 96 months (C.I. 95%: 82–97 months) and 92 months (C.I. 95%: 80–95 months) respectively, which complete a period of 8 yr. Consequently, we estimated an 8-year overall (OS) and EFS for all patients. On the other hand, the median follow-up time was 135, 104, and 64 m for HOPDA-91, HOPDA-94, and HOPDA-97, respectively. Thus, the 11, 8, and 5-year survival rates for the respective periods were estimated. However, comparisons among periods were computed using the lowest survival rates. All results of survival were quoted with standard error estimation. Stratiﬁcation was used to compare rates between risk groups. The analysis was done having as strata variable the risk groups and as factor the protocols applied during each therapeutic period. Clinical and biological features of children diagnosed before and after modiﬁcation were compared using the Mann– Whitney U and chi-square tests. The prognostic relevance of these variables in the whole group and in each period was examined with the use of a stepwise Cox regression model. Statistical analysis was done using SPSS software programs. 364

Results Patient characteristics

The mean age of the patients was 66 months (range: 7–168 months); 5.3% were infants up to 1 yr of age and 13.4% were adolescents. The mean hemoglobin and platelet count were 8.2 g/dL and 110 000/lL, respectively. The mean WBC was 34 000/lL (median: 13 000/lL) and 91% of the cases had blasts in the peripheral blood specimens. Clinical and biological characteristics of all patients in the three periods are summarized in Table 3. No signiﬁcant diﬀerence was detected among biological characteristics of the patients in the three periods. Treatment results

After a median observation time of 96 months (range: 1–149 months), 15 patients died (13 diagnosed between 1991 and 1996, 2 diagnosed in the last 4 yr). In detail, two cases (1.5%) died because of resistant disease, 12 (9%) due to complications of therapy (14, 17) and one case because MDS with transformation to AML developed 69 months after diagnosis. Five cases (3.8%) relapsed (three in BM and two in testes), four of which underwent BM transplantation successfully. The other case had a second BMT due to second relapse and was alive up until the last follow up of the study (Table 4). The 8-year OS and EFS were 88% ± 3% and 85% ± 3%. Kaplan–Meier plots (Fig. 1) showed the EFS of all patients. LR patients had a

Intensiﬁed treatment in childhood ALL Table 3. Presenting features of patients treated with the HOPDA-91, HOPDA-94 and HOPDA-97 protocols HOPDA-94

HOPDA-97

Total

38 63/37 18.4

47 60/40 17

47 53/47 15

132 58.3/41.7 16.4

68.4 13.2

72.3 10.6

68 17

70.1 13.4

73.7 26.3

83 17

78.7 21.3

78.4 21.6

60.5 39.5

66 34

46 54

57 43

79 13 8

85 2 11 2

5. 3 39.5 60.5 47

4. 3 38 62 65

85 – 10.5 – 4.5 2 57 43 64

83.3 4.5 9.8 0.8 1.5 3.7 45 55 62.5

0.9 0.8 0.7 Probability

No. Sex (boys/girls) (%) grid £ 2 yr Age (%) 2–10 yr ‡10 yr WBC (%) <50000/lL cgrid ‡50000/lL L2 (%) £ 20 >20% Immunophenotype (%) Common Pre-pre-B T B Undifferentiated CNS disease (%) LR (%) HR (%) PR in HR (%)

HOPDA-91

1.0

0.6 0.5

Protocol used 1997–2000

0.4

5-year EFS 0.91 0.3 0.2

0.0 0

38 (23) 115 135 31 (81.6) 7 2 3 1 1 – – – – 22 1 1 – 2.6 10.5 5.2

HOPDA-94 HOPDA-97

Total

47 (29) 96 104 41 (87.2) 6 – – 2 1 1 – – – –

132 92 96

13 2.1 4.2 4.2

47 (20) 63 64 45 (96) 2 – – – – – – 1 1 32 2 1 – – – 4

20

40

60 80 100 120 Months from diagnosis

140

160

Fig. 1. The EFS of all patients in trials HOPDA-91, HOPDA-94, and HOPDA-97.

Table 4. Treatment results in the HOPDA-91, HOPDA-94 and HOPDA-97 protocols

No. pts (HR cases) Mean follow-up time (months) Median follow-up time (months) Alive (%) Dead1 Resistant disease Infection Aspergillus GI hemorrhage Measles pneumonia Encephalopathy Venous thrombosis Enteroviral encephalitis Relapse BM Testes Second malignancy Cumulative mortality rate (%) Induction deaths Consolidation deaths Maintenance deaths

1991–1993 11-year EFS 0.76

0.1

HR, high risk; LR, low risk; PR, prophylactic radiotherapy; CNS, Central nervous system; HOPDA, Hematology/Oncology Pediatric Department of the University of Athens.

HOPDA-91

1994–1996 8-year EFS 0.87

15

HOPDA-91: 38 patients were diagnosed during this period and 23 children (60%) had HR–ALL (Table 4). The median follow up for the total of the cases diagnosed in this period was 135 months. The cumulative induction, consolidation and maintenance mortality rates were 2.6%, 10.5%, and 5.2%, respectively (Table 4). The 11-year OS and EFS for all the patients of this period were 82% ± 6% and 76% ± 7%, respectively (Table 5). Since all events occurred during the ﬁrst 49 months of diagnosis, the 11, 8, and 5-year EFS were equal. WBC proved to be the most adverse prognostic factor. The 11-year OS and EFS of the HR and LR groups are summarized in Table 5 and Figs 2 and 3. HOPDA-94: 47 cases were diagnosed during 1994–1996 and 29 (62%) had HR–ALL. The median

5

1 1.5 3.7 4.4

HR, high risk; LR, low risk; HOPDA, Hematology/Oncology Pediatric Department of the University of Athens; BM, bone marrow. 1 Deaths were due to resistant disease, toxicity of therapy and to the second malignancy. 2 4/5 had under went BMT successfully. 3 He eventually died.

91% ± 4% EFS and HR cases 80% ± 4%. The LR group had a signiﬁcantly better outcome than the HR group (P ¼ 0.04).

Table 5. OS and EFS of patients treated with the HOPDA-91, HOPDA-94 and HOPDA-97 protocols

%

HOPDA-91 (11 yr)

HR OS EFS LR OS EFS All patients OS EFS

HOPDA-94 (8 yr)

HOPDA-97 (5 yr)

P value*

All patients

70 € 9 65 € 10

90 € 5 90 € 5

95 € 5 80 € 8

0.02 0.04

85 € 4 80 € 4

100 93 € 6

83 € 9 83 € 9

96 € 3 96 € 3

0.1 0.3

92 € 4 91 € 4

82 € 6 76 € 7

87 € 4 87 € 4

96 € 3 91 € 4

0.02 0.04

88 € 3 85 € 3

HR, high risk; LR, low risk; HOPDA, Hematology/Oncology Pediatric Department of the University of Athens; OS, overall survival; EFS, event-free survival. *P values were assessed using the lowest EFS rate for each period.

365

Tzortzatou-Stathopoulou et al. HOPDA-97: 47 cases were diagnosed during 1997–2000 and 20 cases (43%) had a HR proﬁle (Table 4). The median follow-up time was 64 months. The 5-year OS and EFS for all patients were 96% ± 3% and 91% ± 4% (Table 5). The OS and EFS of the HR and LR groups are summarized in Table 5 and Figs 2 and 3. The EFS of the very HR cases was 89% ± 3%.

1.0 0.9 0.8

Probability

0.7 0.6 Protocol used 0.5 1997–2000 0.4

5-year EFS 0.96

Discussion

0.3

1994–1996 8-year EFS 0.83

The ultimate objective of this study was to deﬁne the cases with HR of relapsing and to develop the most eﬀective treatment for these cases. Experience has indicated that the deﬁnition of risk factors in ALL is inadequate and paradoxical results have been reported by some studies, showing better or similar outcome in the higher risk patients who received a more intensive regimen and less favorable outcome in the lower risk patients who were excluded from this intensiﬁcation (10–12). Many relapses occurred in cases, which did not have any speciﬁc poor prognostic biologic or clinical characteristic (18–21). Three therapeutic protocols were assessed in our Unit. Modiﬁcations were performed every 3–4 yr as this approach is adopted by many studies. During the ﬁrst years, treatment toxicity was signiﬁcantly high due to prolonged periods of myelosuppression. By altering the consolidation and intensiﬁcation phase, via reduction of cytarabine to four doses (instead of six) and introduction of early antibiotic and antifungal prophylaxis in the neutropenic phase, children appeared to better tolerate the regimen, while deaths due to toxicity were reduced by half. During the last period (HOPDA-97), therapeutic philosophy was based on a diﬀerent approach. As some LR cases unexpectedly relapse, all patients were considered as HR at diagnosis and received the same protocol. LR groups are usually excluded from intensive protocols, but could gain as much, if not more, from dose intensiﬁcation as HR patients. This was the reported reason for the paradoxical risk reversals observed by the US CCG group when putatively higher risk patients achieved a better outcome with more intensive regimen than lower risk patients who received less intensive risk-adjusted therapy (10). In other signiﬁcant studies, 50–65% of recurrences occurred in low to moderate risk cases and relapse rate ranged from 14% in the CCG 1891 trial (19) (in which double delayed intensiﬁcation therapy was used in the intermediate risk group) to 20% in BFM-90 (8) and 30% in CLCG-EORTC 58831/32 (20).

0.2 1991–1993 11-year EFS 0.93

0.1 0.0

0

20

40

60 80 100 120 Months from diagnosis

140

160

Fig. 2. The EFS of low risk (LR) patients in trials HOPDA91, HOPDA-94, and HOPDA-97.

1.0 0.9 0.8

Probability

0.7 0.6 Protocol used

0.5

1997–2000

0.4

5-year EFS 0.80

0.3

1994–1996 8-year EFS 0.90

0.2

1991–1993 11-year EFS 0.65

0.1 0.0

0

20

40

60 80 100 120 Months from diagnosis

140

160

Fig. 3. The EFS of high-risk (HR) patients in trials HOPDA-91, HOPDA-94, and HOPDA-97.

follow-up time was 104 months. The cumulative induction, consolidation and maintenance mortality rates were 2.1%, 4.2%, and 4.2%, respectively. A patient developed secondary MDS transformed to AML 69 months after the ﬁrst diagnosis and eventually died (Table 4). The 8-year OS and EFS for all patients diagnosed these years were both 87% ± 4% since no relapse occurred (Table 5). The HR group had 90% ± 5% and the LR 83% ± 9% OS and EFS (P ¼ 0.7) (Figs 2 and 3). 366

Intensiﬁed treatment in childhood ALL Drug resistance, either primary or after initiation of treatment, is now the major cause of relapse. The Goldie-Coldman hypothesis insists that drug resistance and eventually relapse may be the result of possible random mutation in any cell division (22, 23). Therefore, each trial must aim to avoid drug resistance, a task that can be achieved only if leukemic cells are rapidly killed. The longer it is needed to reduce the leukemic burden, the higher the probability of emerging drug resistance (24). However, a question arises: Are LR cases able to tolerate acute or long-term toxic events due to intensiﬁed treatment? Studies indicated that this group of favorable cases showed a better therapy toxicity tolerance than cases with unfavorable characteristics (5, 19, 21). This was also evidenced in our study. Although LR patients received a more intensive induction regimen, no toxicity was reported. In the last therapeutic period, the early toxicity burden was virtually none. The majority of toxic events in HR cases was mainly due to neutropenic phase bacterial and fungal infections and was minimized during the last years. The induction mortality rate was 1.5%, similar to other studies, 1% in BFM-90, 1.9% in the St. Jude Hospital Total Therapy Study XI, 0.4% in the Dana-Faber Cancer Institute study 85-01 and 2.5% in UKALL X (8, 24–26). Thus, the intensiﬁed regimen in LR cases did not increase the adverse toxic events but proved to be extremely eﬀective. Similarly, the consolidation mortality rate, which was high in the ﬁrst therapeutic period, reduced to half in the second and was zero in the last. In Table 4, it is clear that the induction and consolidation mortality rates were reduced because of the eﬀective modiﬁcation of the protocol and the supportive care. However, the overall mortality rate was high due to the ﬁrst period. In addition, the maintenance cumulative mortality rate remained stable. This is probably due to environmental (17, 27) and socioeconomic factors. Late complications were minimized as well. During the follow-up period, children were assessed for endocrine function, cardiac and growth problems, in all distinct therapy groups. It was observed that these children had osteopenic problems but thyroid function and glucose tolerance were not signiﬁcantly aﬀected, whereas cardiac function remained within normal (data not shown). One case (0.7%) with common ALL and a LR proﬁle that was treated with less intensive induction during 1994–1996, developed t-MDS/AML 69 months after diagnosis. No reference evidenced a higher incidence of second malignancy among more intensively treated patients. In the study of Kjeld Schmieglow (28) in which 3123 patients were enrolled, 0.7% cases developed t-MDS/AML and

0.2% a solid tumor in a median interval of 33 months. The cumulative risk for therapy-related secondary neoplasm is 1–4%. However, the individual risk depends not only on the type and duration of therapy, but also on speciﬁc host factors. Preventive cranial radiotherapy was applied in HR patients who were older than 3 yr. Although, 12 Gy was as eﬀective as 18 Gy in some studies (8), we used the higher dose in the three periods because our attempt was to evaluate the diﬀerent drug eﬃcacy so any change in radiotherapy might have produced conﬂicting results. It is also well known that HR children treated with 18 Gy show minimal late neurotoxicity (29–31). In the future it might be possible to avoid cranial irradiation and use only intensive intrathecal combination drugs even in HR cases if they show a rapid response to induction therapy (21). In our study the survival rates are high. The 8year EFS of 85% are comparable with that of the other major cooperative groups. The 8-year EFS of the ALL-BFM-90 study group were 75.9% in a German study while the 6-year EFS rate of the ALL-BFM-90 was 78% in a German-AustrianSwiss study (7, 8). In the Italian Association for Paediatric Haematology and Oncology (AIEOP) group study, the 5-year EFS were 87.3% (32). In UKALL XI the 8-year EFS was 61% and the OS was 81% (9). In CCG 1891, the 6-year EFS were 85% (19). The 5-year EFS in the Total therapy study XIIIB at St. Jude Children’s Research Hospital was 80.8% and the 8-year EFS rate was 78.6% (6). The 5-year EFS in the same study were 88.7% for the LR group and 73.8% for the HR group. The EFS of the LR group during the last period reached a high of 96%, emphasizing the role of intensive regimen through all phases of therapy even in patients with classical favorable variables. The 80% EFS of HR cases was even more surprising. In other studies, survival is almost 60– 70% (6, 24, 30) and only 1/3 of very HR patients survive. In our study the very HR cases with hyperleukocytosis (age <1 yr) or T-cell ALL received extra regimens and the 5-year EFS was even better (89% ± 1%). This re-intensiﬁcation pushed aside the particular increase risk of failure. Seven out of eight very HR patients are out of therapy and remain healthy (median survival time 65 months). In our study, even though HR cases received the same protocol during the last two therapeutic periods, they showed a non-signiﬁcant reduction in EFS rate, possibly due to the environmental factors as mentioned above. The studied population had a trend towards the younger ages. Children aged 1–10 yr consisted 81.3% of the study group compared to other studies in which the same age was 65–79.6% of 367

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