Treatment of Adolescents and Young Adults with Acute Lymphoblastic Leukemia (ALL): An Update of the GIMEMA Experience

Backgound: Adolescent and young (<30y) adults (AYAs) ALL represent a distinct population from both children and older adults. Recently it has been demonstrated that if AYA are treated according to pediatric schedules, Event Free Survival and Overall Survival (OS) can significantly improve (Ribera et al. 2008, Huguet et al. 2009). Nevertheless, which therapeutic strategy, a pediatric or an adult one, can, indeed, be the best approach in this cohort of pts it is still a matter of debate. (Usvasalo et al. 2008). We retrospectively reviewed the disease outcome of AYAs entered in a period over than 25 y in the 6 consecutive GIMEMA adult ALL trials in order to analyze the impact on Disease Free Survival(DFS) and OS of the different treatment strategies applied. Patients: Between 1982-2008, 1218 pts - median age 20.2 ys (range 12.0-30.0y)- were enrolled in the 6 GIMEMA studies; 30.4% of pts were 18y old, initial median WBC was 15.0x109/L (range 0.3-848.0), 72.9% of pts and 27.1% of pts were classified as B-lineage and T-ALL respectively, and 84 pts (13.1%) were Ph and/or BCR/ABL+ve. Results: Overall Remission Rate was 85.1% with no significant difference in terms of CR between the different protocols. From 1990, Ph and/or BCR/ABL+ve patients received a post-CR treatment including transplant and, since 2000, TKIs were also added. Comparing the studies, ALL0288 vs. ALL0183 and ALL0904, ALL2000 vs. ALL0183 and ALL0904, long-term DFS rate resulted significantly associated to protocol: (p=0.0078, p=0.0051, respectively) and (p=0.0044, p=0.0136, respectively), while OS resulted trend-associated to protocol (p=0.0891). One of the older study - ALL0288 - demonstrated a significantly lower Cumulative Incidence of Relapse (CIR) not only compared with the oldest ALL0183 (p<0.00001), but also with the following ALL0496 (p=0.0009), ALL2000 (0.0022) and ALL0904 (p=0.00002). Whether this was related to a more intensified treatment with reinduction cycles, both in consolidation and maintenance, foreseen in the ALL0288 study remains an open question; however, probably due to the less effective supportive care and, in particular, to the lack of growth factors, non-relapse mortality in CR was higher and the final outcome of ALL0288 did not significantly differed in terms of overall survival from other studies. Table 1 Protocol PDN Pretreat Induction Consolidation Maintenance pts. N. %OS (C.I. 95%) %DFS (C.I. 95%) %CIR (C.I. 95%) -------------------------------------------------------------------------------- ALL0183 - PVD + L-Asp PVD/L-VAMP/ VM-26+CA Standard (12 mths) 169 6y 35.6% (33.1-38.2) 6y 25.7% (23.9-27.6) 6y 69.4% (69.2-69.7) ALL0288 YES PVD + L-Asp ± Cy PV+Nov/L-VAMP/VM-26+CA Intensive vs. standard (24 mths) 456 6y 39.1% (37.4-41) 6y 37% (35.2-38.9) 6y 44.2% (44.1-44.3) ALL0394 - PV + Myeloid-like + L-Asp L-VAMP/VM-26+CA Standard (12 mths) 76 4y 50% (44.4-56.2) 4y 45.6% (40.1-51.9) 4y 45.9% (45-46.8) ALL0496 - PV + HD DNR + L-Asp VP-16+CA + Cy Standard + V-Cy/V-DNR Reinduction (36 mths) 231 6y 40.4% (37.8-43.2) 6y 36.1% (33.6-38.7) 6y 57.3% (57-57.6) ALL2000 YES PV + HD DNR + L-Asp VP-16+CA Standard + V-Cy/V-DN Reinduction (36 mths) 209 6y 44.4% (40.7-48.4) 6y 41.6% (38.3-45.2) 6y 55.9% (55.6-56.3) ALL0904 YES PV + HD DNR + L-Asp VP-16+CA Standard + V-Cy/V-DNR Reinduction (36 mths) 77 3y 47.6% (40.1-56.5) 3y 28.2% (23.9-33.4) 3y 66.4% (64.7-68.1) In conclusion, the overall results of the consecutive GIMEMA adult ALL trials conducted over the past 25 years show that only slight advances for specific subgroup of patients – i.e. Ph+ - have been obtained, mainly thanks to the introduction of targeted agents like TKIs. Also in the AYAs subgroup, the outcome remains dismal, and new approaches, possibly with more intensive pediatric-like regimens must be explored.