Abstract
Background: Approximately 30% of adult acute lymphoblastic leukemia (ALL) occurs after the age of 60. The improvements observed in the past decade in adults with pediatric-inspired regimen do not translate in this population with increase treatment related toxicity and early deaths. The European Working Group for Adult ALL (EWALL) backbone, adapted for elderly patients, reported a poor 3 year overall survival (3y-OS) of about 24% due to high relapse rates. Our center report the outcome of a regimen designed to improve the outcome of the EWALL backbone taking advantage of the favorable results of pediatric-inspired protocols in younger adults and retrospectively compared it to an historical cohort.
Methods: Since 2012, patients > 60 y-old with Ph-neg ALL were treated in our center according to the EWALL first induction backbone. Patients achieving complete response (CR) were eligible to receive a pediatric-inspired consolidation phase designed for younger patients. After two consolidations courses, patients received late intensification phase followed by a third consolidation course. Monthly maintenance course was then started for CR patients. CNS prophylaxis included intrathecal injections and cranial irradiation. Consolidations included 9 cycles alternating cytarabine (8000mg/m2) intermediate-dose methotrexate (1500mg/m2) and cyclophosphamide (1000mg/m2) plus VP-16 (150mg/m2). Patients aged more than 70 years received reduced doses of chemotherapy during consolidation. Treatments are detailed in the table. We retrospectively compared the outcomes with those observed in patients > 60 y-old treated according to the EWALL induction and consolidation backbone (Goekbuget et al. 2008) in our center between 2007 and 2011.
Results: Twenty-four patients were included in the study. Median age was 67 [IQR: 64-71]. Nineteen patients (79%) had B-phenotype ALL. Four (13%) patients had adverse cytogenetics, three (13%) had hyperleukocytosis, none had CNS involvement. Twenty nine percent of patients had a Charlson Comorbidity Index > 1. Twenty-one patients were included in the historical cohort treated according to the EWALL backbone from 2007 to 2011. Main baseline characteristics were well balanced between the two study cohorts. Complete remission (CR) rate was 81% in the experimental cohort versus 79% in the historical cohort. The induction deaths were 4% in the experimental cohort versus 14% in the historical cohort. All patients in CR (19) in the experimental group were eligible to intensive consolidations and late intensification. Two of these patients were unable to reach maintenance phase (1 deterioration of general status and 1 relapse) and 1 patients omitted late intensification because of renal failure. During late intensification, the median duration with neutrophils < 0.5 X 109/L was 8 days [IQR: 4-14]. Six patients (32%) developed an infection during consolidation courses and 3 patients during late intensification course. Major toxicities during pediatric-inspired consolidation courses included infections (9 patients, including three with bacteremia, two with pyelonephritis and one with pneumonia), grade 3-4 liver toxicity (6), acute kidney failure (3) and hyperglycemia requiring insulin (1). Eighty-one percent of patients eligible to late intensification received over 80% of the scheduled dose of L-ASP. No death was observed during consolidations or late intensification. The median follow up times were 2,6 years and 8,2 years for the experimental cohort and the historical cohort, respectively. The experimental regimen translated into a significantly longer two years disease-free survival (57% [IC95% 31-76] vs 29% [IC95% 11-51] p=0.007 by log-rank test) and a longer two years overall survival than the historical cohort (54% [CI95% 30-73] vs 24% [CI95% 12-47] p=0.01 by log-rank test). The OS and DFS of the experimental and historical cohorts are show in the figure.
Conclusion: Results presented here strongly suggest that an intensified pediatric-inspired protocol after an age-adapted induction course might yield significantly better results than former protocols in older adults with Ph-negative ALL. The intensity of this consolidation treatment was tolerable, and the low rate of relapse is promising in this population with an unmet medical need.
Forcade: Neovii: Other: Travel grant.
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