Final Analysis of the Italian Campus ALL Observational Study on 476 Older Patients with Philadelphia-Negative Acute Lymphoblastic Leukemia
Authors: Cerrano Marco , Davide Lazzarotto , Boscaro Eleonora , Borlenghi Erika , Tanasi Ilaria , Chiusolo Patrizia , Minetto Paola , Grimaldi Francesco , Dargenio Michelina , Leoncin Matteo , Trappolini Silvia , Papayannidis Cristina , Forghieri Fabio , Gurrieri Carmela , Zappasodi Patrizia , La Starza Roberta , Fracchiolla Nicola , Di Biase Federica , Del Principe Maria Ilaria , Defina Marzia , Pasciolla Crescenza , Cambò Benedetta , Mosna Federico , Pietrasanta Daniela , Mariani Sabrina , Mancini Valentina , Guolo Fabio , Lussana Federico , Todisco Elisabetta , Annunziata Mario , Calafiore Valeria , Ciccone Maria , Piccini Matteo , Dragani Matteo Emidio , Sani Beatrice , Mauro Endri , Basilico Claudia , De Marco Beatrice , Antonacci Marco , Forlani Laura , Fumagalli Monica , Trastulli Fabio , Lunghi Monia , Salutari Prassede , Mastaglio Sara , Chiaretti Sabina , Candoni Anna , Ferrara Felicetto , Pizzolo Giovanni , Foà Robin , Bonifacio Massimiliano 
Published: December 2024

BACKGROUND
The prognosis of younger Philadelphia (Ph)-negative acute lymphoblastic leukemia (ALL) patients (pts) has significantly improved in recent years, but older adults still experience poor outcomes with standard chemotherapy. Recent GMALL data suggested that dose-reduced regimens including asparaginase (ASP) are feasible in older pts with encouraging survival, warranting confirmation. Immunotherapy has changed the treatment landscape of B-ALL, but long-term overall survival (OS) remains poor when these therapies are employed in the relapsed/refractory setting. Indeed, these agents are being moved front-line, but they are not widely available in this setting yet.
METHODS
In the context of the Campus ALL national framework, we retrospectively collected data on Ph-negative ALL pts aged ≥55y diagnosed between January 2013 and December 2023 in Italy. Kaplan-Meier, Cox proportional hazard methods and competitive risk analyses were performed with STATA 12.1 to estimate survival outcomes and cumulative incidence functions.
RESULTS
We included 476 pts (female 52%), with a median age of 66y (range 55-91y), 31% &gt; 70y. 78% of the cases were B-lineage, 39% were very high risk (VHR) according to LAL1913 classification, 5% showed central nervous system (CNS) infiltration and 33% had an ECOG performance status (PS) ≥2.
Eight pts received palliative care only (not analyzed for outcomes) while most pts (98%) started an active treatment according to different regimes with frequent dose adaptations: 53% LAL1913/NILG10.07, 17% LAL1104, 8% EWALL/GMALL, 6% Hyper-CVAD/mini-HyperCVD, 2% vincristine and steroids, 14% others. During the disease course, 31% of the pts received immunotherapy and 23% an allogeneic stem cell transplant.
After a median follow up of 42.9m, median OS was 21.3m, with a 3y-OS rate of 40%. 30- and 60-day mortality rates were 4% and 9%, respectively. After induction (course I or II) complete remission (CR)/CR with incomplete count recovery (CRi) rate was 76%, in 35% of the cases with a negative measurable residual disease (MRD), while 8% of the pts died before response assessment. After achieving remission, 47% of the pts relapsed and 13% died in remission, with a median relapse free survival (RFS) of 17.1m and a 3y-RFS rate of 40%. 3y-cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 50% and 10%.
Over time, a modest improvement of survival was observed, with pts diagnosed after 2017 showing superior OS (median 23.1 vs 18.1m, P=0.045), mostly in B-ALL (median 26.4 vs 18m, P=0.058, compared to 14.9 vs 18.1m, P=0.64, for T-ALL).
Age was a strong prognostic factor (HR 1.05, P&lt;0.001), with pts aged 55-70y showing significant superior OS compared to those &gt;70y (median 27.9 vs 11.2m, P&lt;0.001) and a higher CR/CRi rate (81% vs 66%, P&lt;0.001).
After adjusting for age and PS, treatment regimens including ASP (LAL1913/NILG10.07 and EWALL/GMALL) were superior to other approaches (HR 0.58, P&lt;0.0001). However, this benefit was not significant in pts aged &gt;70y (HR 0.65, P=0.09).
At multivariate analysis, age (HR 1.04, P&lt;0.001), VHR group (HR 1.43, P=0.007), and CNS positivity (HR 2.9, P&lt;0.001) were significantly associated with worse survival, while ASP-containing regimens with better outcome (HR 0.63, P=0.003).
MRD negativity was independently associated with improved RFS (HR 0.51, P&lt;0.001) and reduced CIR (sHR 0.48, P&lt;0.001). However, relapses were quite frequent (27% of the pts). Considering the 71 MRD-negative B-ALL pts up to 70y, our results were comparable to those observed in the standard arm of the E1910 clinical trial (3y-RFS 54% vs 57%).
CONCLUSION
In this large real-life cohort of older Ph-negative ALL pts, ASP-containing regimens appeared superior to other approaches after accounting for age and PS, but this benefit was markedly reduced above 70y. Only modest survival improvements were observed in recent years and restricted to B-ALL, possibly due to the increasing availability of salvage immunotherapies. MRD negativity was associated with better prognosis, but relapses were rather frequent, confirming the need of new drugs also in this setting. Different front-line therapeutic strategies, such as immunotherapy combined with minimal/no chemotherapy, are currently being tested in clinical trials for older B-ALL pts and are especially warranted in those above 70y. Hopefully, innovative trials will be starting soon in T-ALL, in which new drugs are currently lacking.