The Upper Age Limit for a Pediatric-Inspired Therapy in Younger Adults with Ph-Negative Acute Lymphoblastic Leukemia (ALL)? Analysis of the Graall-2005 Study
Authors: Huguet Françoise , Leguay Thibaut , Thomas Xavier , Boissel Nicolas , Escoffre-Barbe Martine , Chevallier Patrice , Hunault Mathilde , Vey Norbert , Bonmati Caroline , Leprêtre Stéphane , Marolleau Jean-Pierre , Pabst Thomas , Rousselot Philippe , Buzyn Agnès , Cahn Jean-Yves , Lhéritier Véronique , Béné Marie C , Asnafi Vahid , Delabesse Eric , Macintyre Elizabeth , Chalandon Yves , Ifrah Norbert , Dombret Hervé 
Published: October 2019

Abstract

Background: Treatment of younger adults with Ph-negative ALL has markedly evolved since the early 2000s. Survivals have substantially improved using pediatric or pediatric-inspired protocols with higher doses of steroids, vincristine (VCR), methotrexate (MTX) and L-asparaginase (L-Aspa), as was done in the GRAALL-2003 trial (Huguet et al. JCO 2009). However, the upper age limit for a pediatric-like strategy remained undetermined. In the GRAALL-2005 study (NCT00327678), we aimed to address this age issue in a larger trial and to randomly evaluate a reinforced hyper-fractionated (hyperC) vs standard (standardC) dose of cyclophosphamide (CPM) during induction and late intensification. Patients with CD20-positive B-cell precursor (BCP) ALL were also randomized in the rituximab GRAALL-2005/R study, as specifically reported last year (Maury et al. ASH 2015).
Patients and Methods: Patients aged 18-59 years old with newly-diagnosed Ph-negative ALL were eligible. Chemotherapy comprised a steroid prephase, a 5-drug induction, two 3-block dose-dense consolidation phases, a late intensification, a third consolidation phase, CNS irradiation, and a 2-year maintenance (Beldjord et al. Blood 2014). Allogeneic transplantation was offered in first complete remission (CR) to patients with conventional high-risk factors (Dhédin et al. Blood 2015). During induction and late intensification, CPM was given at 750 mg/m2 on day 1 followed by 750 mg/m2 on day 15 (standardC) or 300 mg/m2/12h on day 15 to 17 (hyperC), according to randomization arm. The primary endpoint was event-free survival (EFS). Secondary endpoints were cumulative incidences of failure (CIF, including primary refractoriness and relapse) and CI of non-refractoriness/relapse mortality (CINRM, including toxic death during induction and death in first CR), overall survival (OS), compliance and safety. Compliance was assessed by comparing the median doses of specific drugs actually received by patients who completed specific treatment phases.
Results: Between 2006 and 2014, 787 evaluable patients were randomized (398 standardC, 389 hyperC; 525 BCP-ALL, 262 T-ALL). Median age was 36y, with 200, 172, 171, 151 and 93 patients in the 18-24y, 25-34y, 35-44y, 45-54y and 55y+ age subgroups, respectively. Overall CR rate was 91.9% and 278 patients were transplanted in first CR. With a median follow-up of 5.2 years, 5y-EFS and OS were 52% (48-56) and 58% (55-62), respectively, confirming previous GRAALL-2003 results. No difference in outcome was observed in T- vs BCP-ALL patients. At 5 years, EFS was 60%, 58%, 54%, 50% and 26% in the youngest to the oldest age subgroup, respectively (HR, 2.2 [1.7-2.8]; p<0.001 for 55y+ vs younger patients; Figure 1). The worse EFS in 55y+ patients (best age cutoff) came predominantly from a higher CINRM (40% vs 14% at 5y; HR, 3.4 [2.3-5.0]; p<0.001) while CIF was not significantly higher (33% vs 30% at 5y; p=0.77). Overall, hyperC treatment had no impact on EFS (HR, 0.89 [0.7-1.1]; p=0.26). However, post-hoc subgroup analyses revealed that patients aged 55y+ significantly benefited from hyperC (5y-EFS, 38% vs 12%; HR, 0.51 [0.3-0.8]; p=0.007) while younger patients did not (5y-EFS, 57% vs 55% at 5y; HR, 0.95 [0.8-1.2]; p=0.66), with a significant interaction (p=0.029; Figure 2). A higher 40% 5y-CIF was observed in 55y+ patients treated in thestandardC arm, while it was only 27% in those treated in thehyperC arm, closer to the 31% and 30% 5y-CIF observed in <55y patients treated in thestandardC andhyperC arm, respectively. This observation might be related to the inferior treatment compliance observed in patients aged 55y+ at each treatment phase, suggesting that the benefit associated withhyperC reinforcement became apparent since these patients could not tolerate the planned pediatric-inspired therapy. For instance, 55y+ patients received significantly less L-aspa during induction, lessAraC, MTX and CPM during each consolidation phase, and less VCR, prednisone anddaunorubicin during late intensification.
Conclusions: Taken together, these results indicate that 55 years is likely to be the upper age limit for a pediatric-like strategy in younger adults with ALL, because of excessive toxicity and worse treatment compliance observed above this age. Older adults could probably benefit from alternative front-line approaches such as hyper-fractionated CPM or new agents such asinotuzumabozogamicin.

Disclosures
Rousselot: BMS: Research Funding; Ariad: Research Funding; Pfizer: Research Funding.