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 panel supported publication of the protocol on the basis of the information summarised below. The committee was most strongly influenced by preliminary 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 present protocol, ALL06, is a BFM 2000-derived protocol developed for the ALL06 study of adults with ALL. While the full results have not yet been published, the efficacy results from the abstract are presented below.r
||Study & Year Published
||Is the dose and regimen consistent with the protocol?
|Phase II trials
||Abstract only with full results yet to be published
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:
|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)
|Complete response (CR)
|2-year overall survival (OS)
||79.3% (95% CI: 69.9 - 88.8%)
|2-year disease-free survival (DFS)
||76.4% (95% CI: 66.5 - 86.4%)
Disease-free survival (DFS) and overall survival (OS) ALL06r
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 two-year DFS (HR 4.36, p=0.008) and OS (HR 7.30, p=0.003) when compared to those whose day 79 MRD was positive.
Toxicity data for the ALL06 protocol is yet to be published.r As ALL06 is a BFM-derived protocol, it is expected that the toxicity profile would be similar between these protocols.
In a study of 13 adult ALL patients receiving an augmented (asparaginase-containing) BFM regimenr, the most frequent toxicities were hepatic and gastrointestinal events, followed by neurologic toxicity.
The most common hepatic toxicities were mild transaminase and bilirubin elevation. Nausea and constipation were the most common gastrointestinal events. Sensory neuropathy, and less commonly motor neuropathy, were the most frequently seen neurologic events, and encephalopathy was a rarely seen toxicity. Neutropenic fevers and related infections were the most commonly seen infectious toxicities.
Preliminary results from ALL06 presented at EHA displayed the following table of the causes of death of 18 patientsr:
|Cause of death
* 3 of the deaths occurred during induction (3.6%)