Intensified Therapy of Acute Lymphoblastic Leukemia in Adults: Report of the Randomized GRAALL-2005 Clinical Trial
- Study type
- Clinical trial
- Study name
- GRAALL-2005
- Phase
- Phase 3
- Design
- Randomised, open-label, multicentre trial of the Group for Research on Adult ALL (GRAALL) using a paediatric-inspired protocol; part of the GRAALL-2005 umbrella programme
- Sample size
- 787 evaluable patients (525 B-lineage and 262 T-lineage)
- Source
- J Clin Oncol · 2018
- Trial registration
- NCT00327678
In plain words
In this large study, 787 adults (median age 36 years) with acute lymphoblastic leukaemia without the Philadelphia chromosome were all treated with a programme inspired by children's treatment, and half of them received an intensified dose of one of the drugs (cyclophosphamide). The intensified dose gave no overall benefit. About 9 in every 10 patients went into remission, and about 6 in every 10 were alive 5 years later. At 55 and older, the intensive treatment was tolerated less well and the results were poorer.
Key results
Treatment arms and regimens
Paediatric-inspired protocol: the same corticosteroid prephase for all patients, induction with 4-drug, 4-week chemotherapy, consolidation, late intensification and maintenance; allogeneic transplant according to unfavourable risk factors (ClinicalTrials.gov). In this arm, cyclophosphamide was given at the standard dose during first induction and late intensification. Dose details in the full text of the paper.
The same protocol, with hyperfractionated cyclophosphamide (hyper-C) instead of the standard dose during first induction and late intensification. Dose details in the full text of the paper.
Source of the regimen details: ClinicalTrials.gov NCT00327678 (protocol structure and randomisation, without doses); doses in the full text of the paper
Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.
Study population
Adults with newly diagnosed Philadelphia chromosome-negative acute lymphoblastic leukaemia (B or T lineage); median age 36.1 years. According to the ClinicalTrials.gov record: age 18 to 59 years; lymphoblastic lymphoma, ALL3 (Burkitt type), CML and severe organ failure were excluded.
Endpoints
According to ClinicalTrials.gov, the primary endpoint was event-free survival; secondary endpoints included complete remission after 1 or 2 courses, induction death, death in first remission, relapse, relapse-free survival, overall survival and treatment-related adverse events. Compliance with chemotherapy was assessed by the median doses actually received in each phase.
Safety and side effects
Because of worse treatment tolerance, increasing age steadily affected complete remission, event-free survival and overall survival, with 55 years as the best age cut-off; patients aged 55 and older showed lower compliance with the whole planned chemotherapy. Details of adverse events are in the full text of the paper.
Clinical significance and place in guidelines
This large trial showed the results of a paediatric-inspired protocol in adults under 60 (5-year overall survival 58.5%), showed that adding hyper-C gives no overall benefit, and identified 55 years as the age beyond which this intensive treatment is poorly tolerated; this finding shows the importance of age in choosing the intensity of treatment for adult ALL.
Limitations
The main randomised question (hyper-C) was negative, and the benefit in patients aged 55 and older was seen in a subgroup. Philadelphia-positive patients were not included in this part (they were studied in GRAAPH-2005). In CD20-positive B-ALL, a separate randomisation of rituximab was also performed (GRAALL-2005/R; ClinicalTrials.gov). Exact doses are not given in the abstract.
This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.