A search of the literature found limited evidence to support the use of intensive paediatric-inspired regimens in the treatment of acute lymphoblastic leukaemia (ALL) in older adolescents and young adults. The expert reference committee supported publication of the protocol on the basis of the information summarised below. The committee was most strongly influenced by data from the ALL06 phase II trial.r
Intensive paediatric regimens have been extensively used for the treatment of ALL in children and young adolescents. A French retrospective studyr of 177 adolescent patients (15-20 years) compared outcomes of patients treated with either a paediatric regimen (FRALLE-93) or an adult regimen (LALA-94). Patients who received the paediatric regimen were more likely to reach complete remission (CR; 94% vs 83%, p=0.04) and had improved 5-year event-free survival (EFS; 67% vs 41%, p < 0.0001).
When compared to children and adolescents, adults with ALL tend to have poorer outcomes. This may be in part due to differences in the biology of ALL in adults, the increased prevalence of poor risk cytogenetic changes such as presence of the Philadelphia chromosome (9;22 translocation) and reduced prevalence of good risk cytogenetic changes such as hyperdiploidy.r
The use of paediatric protocols in adults with ALL is promising. A retrospective study by the PETHEMA groupr compared the outcomes of adolescents (age 15-18) and young adults (age 19-30) treated with a paediatric regimen (ALL-96). There was no significant difference in overall survival (OS; 77% vs 63%, p=0.44) or 6-year EFS (60% vs 63%, p=0.97) between the two groups.
The GRAALL 2003 studyr treated 225 Philadelphia negative ALL patients aged 15–60 with a paediatric-inspired regimen. The CR rate was 93.5%, with an EFS rate of 55% and OS rate of 60%. Results were compared with the LALA-94 study of 712 patients treated with an adult regimen: the CR rate, EFS and OS rate were more favourable in patients treated with the GRAALL 2003 protocol.
The current ALL06 protocol is a BFM 2000-derived protocol developed for the ALL06 study of adults with ALL. The efficacy data from ALL06 is presented below.r
Source |
Study & Year Published |
Supports Use |
Is the dose and regimen consistent with the protocol? |
Comments |
Phase II trials |
ALL06 (2021)r |
Yes |
Yes |
|
PETHEMA (2008)r |
Yes |
No |
|
GRAALL (2009)r |
Yes |
No |
|
Efficacy
The ALL06 regimen, a BFM 2000-derived protocol, was used by Greenwood et al.rr in a phase II trial of 82 patients between 15-40 years with newly diagnosed Philadelphia-negative ALL. The primary outcome was the proportion of patients that commenced protocol M or High Risk (HR) Block 1 by day 94. The results were as follows:
Outcomer |
ALL06 |
Total patients |
82 |
Proportion receiving protocol M by day 94 |
34 (41.5%, p=0.77) |
Median time to commencement of protocol M |
97 days (IQR 87.5 - 103) |
Induction mortality |
3.6% |
Complete response (CR) |
79 (96.3%) |
3-year overall survival (OS) |
74.9% (95% CI: 65.3 - 84.5%) |
3-year disease-free survival (DFS) |
72.8% (95% CI: 62.8 - 82.7%) |
Figure 1: Disease-free survival (DFS) and overall survival (OS) in the ALL06 Studyrr
© EHA 2019
© Blood Advances 2021
Role of Minimal Residual Disease Testing
Minimal residual disease (MRD) testing has commonly been used in a research setting in order to stratify risk, and is increasingly used in clinical practice for this purpose.
In the ALL06 studyrr, those who achieved a negative MRD at day 79 had improved 3-year DFS (HR 0.35, p=0.034) and OS (HR 0.19, p=0.006) when compared to those whose day 79 MRD was positive.
Figure 2: Role of MRD testingr
© Blood Advances 2021
Toxicity
In the ALL06 study,r the most frequent grade 3 and grade 4 toxicities in the 34 patients who achieved protocol M / HR by day 94 were neutropenia (100%), anaemia (94%) and thrombocytopenia (91%).
The most common non-haematological toxicities were hepatic of which the most common were mild elevation of transaminases, cholestatic enzymes and bilirubin. 6% of patients experienced grade 4 non-haematological toxicities.
Neutropenic fevers and related infections were the most commonly seen infectious toxicities.