Outcome of Younger Adults with Philadelphia Chromosome (Ph)-Negative Acute Lymphoblastic Leukemia (ALL) in First Relapse: A Graall Study
Authors: Desjonqueres Alexandre , Chevallier Patrice , Thomas Xavier , Huguet Françoise , Leguay Thibault , Bernard Marc , Bay Jacques-Olivier , Tavernier Emmanuelle , Charbonnier Aude , Isnard Françoise , Hunault Mathilde , Turlure Pascal , Renaud Marc , Bastie Jean-Noel M. , Himberlin Chantal , Lepretre Stephane , Lioure Bruno , Lhéritier Véronique , Asnafi Vahid , Beldjord Kheira , Lafage Marina , Ifrah Norbert , Dombret Herve 
Published: October 2019

Abstract
Purpose: Pediatric-like protocols have yielded significant advances in younger adults with Ph-negative ALL. Nonetheless, the 5-year cumulative incidence of relapse was still estimated at 32% in the GRAALL-2003/2005 trials, approximately 25% of the relapses occurring after allogeneic stem cell transplantation (SCT). We report here on the outcome of these relapsing patients.
Patients and Methods: Among 880 GRAALL-2003/2005 patients(18-60 years) with Ph-negative ALL in first complete remission (CR1), 264 relapsed. Data were available for 229 of them (151 B-cell precursor [BCP] ALL, 78 T-ALL; 45 standard-risk, 165 high-risk, and 19 unclassified ALL according to the risk classification used in these trials). Relapse site was bone marrow (BM), isolated CNS, combined BM/CNS and other in 181, 20, 17 and 11 patients, respectively. At relapse, median age was 35.7 years (range, 17-63). Median CR1 duration was 10 months (range, 0.5-74), 50 patients (22%) having CR1 > 18 months. Fifty-four patients (24%) had received allogeneic SCT during CR1. First salvage treatments were classified as follows: standard curative therapy, 194 (85%); low-intensity therapy, 21 (9%); allogeneic SCT, 6 (2.5%); and best supportive care (BSC), 8 (3.5%). Post-relapse allogeneic SCT was analyzed as a time-dependent event using Mantel-Byar estimations.
Results: A total of 121 patients (53%) achieved CR2, including 100/194 patients after standard salvage, 7/21 patients after low-intensity salvage, and 14 patients after SCT (6 as first salvage, 8 as subsequent salvage after standard salvage failure). Thus, 107/215 patients (50%) treated with standard or low-intensity first salvage achieved CR2 and in multivariable analysis (including age, ALL lineage, ALL risk classification, CR1 duration, prior SCT, relapse site and salvage type), a younger age and a longer CR1 duration were associated with CR2 achievement in these patients. Of note, few patients with t(4;11) BCP-ALL reached CR2 (19%). A total of 77 patients received allogeneic SCT after relapse, including 55 patients in CR2 after standard salvage (52 in CR2 at SCT time), 4 patients in CR2 after low-intensity salvage (all in CR2 at SCT time), the 6 patients transplanted as first salvage (all reaching CR2), and 12 patients transplanted as subsequent salvage (8 reaching CR2). The median time between relapse and SCT was 111 days (range, 5-311). With a median post-relapse follow-up of 3.1 years, post-relapse overall survival (OS) was 19.3% (14-25%) at 2 years and 13.3% (9-19%) at 5 years (median OS, 6.7 months). In landmark analysis, OS was significantly longer in patients who achieved CR2 (HR, 0.19; p<0.001). Post-relapse OS was also longer in patients aged < 45 years old (HR, 0.68; p=0.016), in those with CR1 > 18 months (HR, 0.43; p<0.001), as in those who received SCT after relapse (HR, 0.37; p<0.001). Neither ALL lineage, ALL risk classification, prior SCT, relapse site nor the type of salvage (if excluding the 8 BSC patients) significantly influenced post-relapse OS. A worse OS was nonetheless observed in BCP-ALL patients with t(4;11) (HR, 2.13; p=0.002) or low hypodiploidy / near triploidy (HR, 2.96; p=0.001), as in T-ALL patients with a complex karyotype (HR, 5.55; p<0.001). Neither focal IKZF1 gene deletion nor NOTCH1/FBXW7/RAS/PTENstatus at diagnosis influenced post-relapse outcome, in BCP- and T-ALL patients respectively. In multivariable analysis (including the covariates listed above and not considering the 8 BSC patients), CR1 > 18 months and SCT after relapse were associated with longer OS (HR, 0.49 and 0.39; p=0.001 and <0.001, respectively). Among the 107 patients who reached CR2 after standard or low-intensity salvage, 62 experienced a second relapse and 73 died, including 15 deaths in CR2. In these patients, disease-free survival (DFS) was 29.0% (21-38%) at 2 years and 26.3% (18-35%) at 5 years (median DFS, 10.2 months). Again, CR1 > 18 months and SCT after relapse were the two factors that independently predicted longer DFS (HR, 0.36 and 0.44; p=0.001 and 0.003) and OS (HR, 0.39 and 0.57; p=0.004 and 0.043, respectively) in these patients.
Conclusion: Adult patients relapsing after current ALL therapies still retain apoor outcome. Although a minority of them may be cured, especially if CR1 duration exceeds 18 months and if they may receive allogeneic SCT in CR2, new therapies are definitely needed for these patients.

Disclosures
No relevant conflicts of interest to declare.