Outcome of Younger Adults with Philadelphia Chromosome (Ph)-Negative Acute Lymphoblastic Leukemia (ALL) in First Relapse: A Graall Study

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.