Improved outcome for children with non-high risk acute lymphoblastic leukaemia after using an ALL IC-BFM 2002-based protocol in Shanghai, China

Authors


Correspondence: Yi-Jin Gao, MD, Children's Hospital, Shanghai Medical College, Fudan University, Shanghai 201102, China.

E-mail: gaoyijin@hotmail.com

Summary

We report the outcome of 92 non-high risk children with acute lymphoblastic leukaemia (ALL) following a Berlin-Frankfürt-Münster (BFM) Intercontinental ALL -based protocol. Compared with a matched historical control group, we found a lower incidence of treatment-related early death (1·2% vs. 10·9%, = 0·015), a higher 6-year event-free survival (75·4 ± 4·9% vs. 58·2 ± 6·7%, = 0·02), reduced total in-hospital costs per person (US $) (10267·0 vs. 18331·0, < 0·001) and fewer total in-hospital days (164 vs. 296, < 0·001). This ALL-BFM based protocol was quite tolerable in our institution and will be extended to high-risk patients.

The cure rate of childhood acute lymphoblastic leukaemia (ALL) has reached 80% in many developed countries. In mainland China, the outcome for this group remains poor when patients with treatment abandonment are included (Gu et al, 2008; Tang et al, 2008; Luo et al, 2008; Huang et al, 2009; Luo et al, 2009). In our previous study, we found that patients treated with a national ALL China-98 protocol between January 1998 and June 2003 had a lower remission rate, a lower 5-year event-free survival (EFS) and a higher mortality from sepsis compared with industrialized countries (Gao et al, 2006). Those results prompted us to change our protocol to an ALL Intercontinental - Berlin-Frankfurt-Münster (ALL IC-BFM) 2002- (BFM)-based protocol. This study reports the outcome in non-high risk (non-HR) ALL children following this protocol and discusses the plausible explanations for the improvement.

Patients and methods

Patients

Between July 2003 and March 2008, 111 newly diagnosed ALL paediatric patients were admitted to our hospital for treatment. The study was approved by our institutional review board. Informed consent was obtained from the guardians of all patients. The date of last follow-up was 30 July 2012.

Diagnosis

The diagnosis was established when at least 25% lymphoblasts were present in the bone marrow (BM). Central nervous system (CNS) disease (CNS3) was diagnosed the presence of ≥5 cells/μl and morphologically identifiable lymphoblasts in the cerebrospinal fluid (CSF) on cytospin preparations, or cerebral infiltrations on cranial computed tomography/magnetic resonance imaging, or cranial nerve palsy. CNS status was classified as CNS2 when CSF cell count was ≤5 cells/μl and lymphoblasts were identified in CSF cytospin preparations, or in the case of traumatic lumber puncture.

Response and relapse criteria

Prednisone response was assessed by the absolute blast count (ABC) in the peripheral blood (PB) on day 8 after seven days of prednisone prephase and one intrathecal (IT) dose of methotrexate (MTX) on day 1. Patients with a day-8 ABC <1 × 109/l PB were designated as ‘prednisone-good responders’ (PGR). Patients with a day-8 ABC ≥1 × 109/l PB were designated as ‘prednisone-poor responders’ (PPR). The BM status was assessed on day 15 and day 33 of induction treatment. Complete remission (CR) was defined as M1 marrow (<5% blasts) with regenerating haematopoiesis, the absence of leukaemic blasts in CSF, and no localized leukaemic infiltrates. Relapse was defined as recurrence of 25% or more lymphoblasts in BM smears or localized leukaemic infiltrates at any sites.

Stratification

Patients were stratified into 3 risk groups according to the following criteria: (i) Standard-risk group (SR): PGR, age at diagnosis ≥1–<6 years, initial white blood cell count (WBC) <20 × 109/l, M1 or M2 marrow (≥5%–<25% blasts) on day 15, and M1 marrow on day 33. (ii) Intermediate-risk group (IR): PGR, age at diagnosis <1 year or ≥6 years and/or WBC ≥20 × 109/l, M1 or M2 marrow on day 15, and M1 marrow on day 33; or fulfilling SR criteria, but with M3 marrow (>25% blasts) on day 15 and M1 marrow on day 33. (iii) High-risk group (HR): PPR, and/or M2 or M3 marrow on day 33, or fulfilling IR criteria with M3 marrow on day 15.

Treatment

Treatment was based on a modification of the ALL IC-BFM 2002 based protocol. In brief, all patients received a standard induction protocol I/I', consolidation/extracompartmental protocol mM, delayed intensification protocol III with interim maintenance phase and maintenance therapy. For all patients, the duration of therapy was 104 weeks. T-ALL patients ≥1 year old received prophylactic cranial radiotherapy with 12 Gy. Patients ≥2 years old with CNS3 received 18 Gy therapeutic cranial radiotherapy (12 Gy if aged ≥1–<2 years). Patients with CNS2 received 2 additional IT MTX doses in induction.

Total in-hospital costs and days

The in-hospital costs and days for each patient were collected from the in-patient electronic database. Because there was no computerized database for out-patients, the clinic costs were excluded. Costs were calculated with Renminbi (RMB) Yuan due to fluctuating exchange rates in the past decade.

Historical control group

Patients of our previous study ALL China-98 (Gao et al, 2006) were reclassified using the ALL IC-BFM 2002 based stratification criteria. The resulting ‘non-HR group’ subsets from the study ALL China-98 constituted the historical control group for evaluating the impact of the present BFM-based protocol.

Statistical analysis

EFS was calculated from the day of diagnosis to any event (remission failure, death for any reason in CR, relapse, abandonment of treatment in CR, second malignancy) or the date of last follow-up. EFS was determined using the Kaplan-Meier method, with differences compared by the log-test. Differences in the distribution of individual parameters among patient subgroups were analysed using the chi-square test or Fisher exact test. Patients lost to follow-up were censored at the time of their last follow-up examination. Statistical significance was defined as < 0·05. Statistical analysis was performed using the statistical package for the social sciences (SPSS) software, version 18.0 (SPSS Inc., Chicago, IL, USA).

Results

Patient characteristics

Of the 111 patients, 19 HR patients were excluded from this analysis. The remaining 92 patients (41 SR, 51 IR; 58 males and 34 females) were evaluable for this study, with a median age of 4·2 years (range, 1·2–12·1 years).

Estimated overall abandonment rate

Seven of 92 patients refused treatment during therapy. Including the 36 highly suspicious ALL cases in the out-patient clinic and the 19 HR patients who were excluded from the study, the abandonment rate for ALL patients was estimated to be around 29·2% (43/147) between July 2003 and March 2008. Compared with our previous study during January 1998 and June 2003 (51·3%, 61/119), the overall abandonment rate was significantly lower in this study (51·3% vs. 29·2%, < 0·001).

Event-free survival

The median follow-up was 72 months (range, 53–109 months) for continuous complete remission patients. The 5-year EFS was 71·7 ± 4·7% in all 92 patients, 75·6 ± 6·7% in SR group, and 68·6 ± 6·5% in IR group, respectively. When the seven patients who refused treatment during therapy were eliminated from the analysis, the 5-year EFS was 77·6 ± 4·5% in all 85 patients, 83·8 ± 6·1% in SR group, and 72·9 ± 6·4% in IR group, respectively.

Events

Only 2 of the 92 patients did not achieve CR, one died of treatment-related causes (sepsis), and 1 abandoned treatment and was lost to follow-up on day 9 in induction. The CR rate of this non-HR ALL study was 97·8%. Seven patients (7·6%) died after achievement of CR because of treatment-related complications. Relapse occurred in 12 patients (13·0%), 6 in SR group (6/41, 14·6%), 6 in IR group (6/51, 11·8%). The site of relapse was BM in all patients. The median time from diagnosis to relapse was 29 months (range: 9–72 months). At the time of evaluation (July 30, 2012), second malignancy was not observed.

Evaluation of the BFM based protocol

Patients who abandoned treatment were excluded from the analysis. Lower incidence of treatment-related early death (1·2% vs. 10·9%, = 0·015), lower total in-hospital costs per person (RMB Yuan) (78029·0 vs. 150314·1, < 0·001) and fewer total in-hospital days (164 vs. 296, < 0·001) were noted among patients treated with the BFM-based protocol (Table 1). There was statistically significant difference between 6-year EFS of patients treated with the BFM-based protocol compared to the China-98 protocol (75·4 ± 4·9% vs. 58·2 ± 6·7%, = 0·02) (Fig 1).

Table 1. Comparison of treatment results and adverse events: patients in present study and the historical control ‘non-HR group’ from previous study ALL China-98 (Gao et al, 2006)
 ALL-BFM 2002 based present studyALL China-98 ‘non-HR group’P value
  1. CR, complete remission; EFS, event-free survival; s.e., standard error.

  2. a

    Patients who abandoned treatment were excluded from the analysis.

  3. b

    1 US dollar = 8·2 RMB Yuan during 1998–2005; 1 US dollar = 8·0 RMB Yuan in 2006; 1 US dollar = 7·6 RMB Yuan in 2007; 1 US dollar = 7·0 RMB Yuan in 2008.

Duration of studyJuly 2003–March 2008January 1998–June 2003 
Number of patients85a55a 
Follow-up time (months)70116 
Median (Range)(1–109)(1–166) 
Remission failure
Early death related to treatment160·015
Induction failure 
Abandonment of treatment 
Death in CR741·000
Relapse12130·178
Abandonment of treatment in CR 
Second malignancy01 
EFS (%±s.e.)
at 4 years77·6 ± 4·5%63·6 ± 6·5% 
at 5 years77·6 ± 4·5%60·0 ± 6·6% 
at 6 years75·4 ± 4·9%58·2 ± 6·7%0·020
Total in-hospital costs per patient (RMB Yuanb)
Median78029·0150314·1<0·001
Range44213·3–276236·894779·0–438283·6 
Total in-hospital days per patient
Median164296<0·001
Range115–258191–547 
Figure 1.

EFS at 6 years for non-high risk patients in the two consecutive studies ALL IC-BFM 2002 based protocol ((BFM2002, = 85) and ALL China-98 protocol (= 55). Patients who abandoned treatment were excluded from the analysis.

Discussion

Compared with the historical control group from our previous study, the 6-year EFS achieved in this study was higher. Fewer early deaths related to treatment contributed to this improvement. At least three factors contributed to this lower incidence of treatment-related early death. First, more specialists and nurses received overseas training. Second, we set up supportive guidelines according to BFM protocol requirements (therapy of neutropenic fever, infection prophylaxis, etc.) before we launched this study. Third, supportive infrastructures and facilities in our hospital were gradually improving. However, the EFS was still 5–10% lower than that of ALL-BFM series conducted in European countries (Schrappe et al, 2000; Möricke et al, 2008). The higher rate of treatment-related mortality in first CR was responsible for the difference (1–3% in the reports from developed countries: Schrappe et al, 2000; Silverman et al, 2010; Gaynon et al, 2010; Christensen et al, 2005; Slats et al, 2005; Rubnitz et al, 2004). Adequate supportive care is particularly relevant to the ultimate outcome of anti-ALL treatment in our institution.

In China, treatment refusal was the most common cause of treatment failure. Financial difficulties and the belief that ALL is incurable were the main reasons given for abandonment (Tang et al, 2008; Wang et al, 2011). The abandonment rates varied, from 12·2% to 64·4%, for total ALL patients in different treatment centres according to recent reports published in English (Gao et al, 2006; Tang et al, 2008; Liu et al, 2009; Huang et al, 2009; Liu et al, 2009; Wang et al, 2011). In our institution, the number of overall cases of abandonment seemed to be reduced considerably during the period of this study. The results suggest two key reasons for the reduction. First, Shanghai and surrounding area are more developed than other regions in the Chinese Mainland. The annual per capita disposable income in Shanghai and surrounding area increased from US $1000 in 1998 to US $3500 in 2008. Moreover, for local children from Shanghai, the government welfare system and a non-profit childhood medical insurance cover 90% of all medical costs for catastrophic diseases, such as leukaemia. In recent years, this system has gradually expanded to involve children from other provinces who have a Shanghai long-term residence permit together with their parents. Second, we adopted a well-documented effective protocol and set up supportive guidelines according to BFM protocol requirements. This BFM-based protocol resulted in a higher CR rate, a lower mortality from sepsis, fewer total in-hospital days and lower total in-hospital costs per person compared with our previous study. This combination of changes had a positive effect on patients and their guardians leading them to complete the full treatment protocol.

Due to the success in non-HR group during this protocol change, we conclude that this ALL IC-BFM 2002-based protocol is quite tolerable in our institution. The protocol has been extended to HR patients since March 2008.

Funding

None.

Ethical approval

Approval of the retrospective study was obtained from the ethnical committee of the hospitals. Informed consent from study participants were waived because the data analyses were from spread sheets.

Competing interest

None declared.

Contributors

Yi-Jin Gao and Xiao-Wen Qian are co-first authors. Yi-Jin Gao contributed patients to the study and helped in designing the study, collecting the data, writing and revising the manuscript. Xiao-Wen Qian helped in writing the article, collecting and analysing the data. Lu FJ, Zhai XW, Wang HS and Li J contributed patients to the study.

Ancillary