Results of the Full Pediatric, Minimal Residual Disease (MRD)-Oriented Trial LAL-RI/2008 for Adolescents and Young Adults (AYA) with Standard Risk (SR), Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia (ALL)

Background and objective. Full pediatric or pediatric-derived trials constitute the treatment of choice for AYA with SR-ALL. In the MRD era, patients (pts) with SR factors at baseline with poor MRD clearance should be considered as HR patients. The objectives of the full pediatric LAL-RI/2008 trial (NCT02036489) from the Spanish PETHEMA group were to assess the proportion of AYA with SR-ALL at baseline who have HR features based on poor early cytological response and/or poor MRD clearance, and to compare their prognosis with that from those pts who achieve good early cytological response and good MRD clearance.

Patients and methods. SR ALL was defined in adolescents (age 15 to 18 years) and young adults (age 19 to 29 years) fulfilling all the following criteria: WBC count ≤30 × 10⁹/L, and absence of t(9;22), t(1;19), t(4;11) or any other 11q23 rearrangements. Induction therapy included vincristine (VCR), prednisone (PDN), daunorubicin (DNR) and native E. coli asparaginase (ASP) for 4 weeks. Pts who achieved complete remission (CR) and MRD<0.1% proceeded to consolidation-1 (high-dose methotrexate [MTX], intermediate-dose ARA-C, etoposide and mercaptopurine [MP]), consolidation-2/reinduction (VCR, dexamethasone, DNR, cyclophosphamide and ASP), maintenance-1 (MP and MTX with monthly reinductions with VCR, PDN and ASP until the end of the 1st year) and maintenance-2 (MP and MTX without reinductions until the end of the 2nd year). CNS prophylaxis consisted of triple intrathecal therapy (MTX, ARA-C and hydrocortisone, 16 doses throughout the treatment). Pts with poor early cytological response (BM blast cells >10% on day 14 of induction), MRD level >0.1% (assessed by flow cytometry) at CR or MRD level >0.05% at any time after CR were considered as high risk (HR) pts and received the ALL-HR trial consisting of intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation (alloHSCT) (Ribera JM et al. J Clin Oncol 2014; 32:1595-604).

Results. Between 2008 and 2017, 79 eligible pts were treated according to the ALL-RI-08 protocol. Median age (range) was 20 years (15-29), 34 (43%) were adolescents and 45 (57%) YA. The mean (SD) WBC count was 10 (9) x10⁹/L, and 73 patients (94%) had B-cell precursor ALL. Two patients are on treatment and 74 out of the remaining 77 (96%) achieved the CR. From the 77 pts, 15 had poor early cytological response, 3 had MRD >0.1% at the time of CR and 1 pt showed reappearance of MRD level >0.05% during maintenance. In all, 19 patients were considered as HR. Of the 58 patients who remained SR and followed the LAL-RI/2008 protocol, 14 relapsed (7 during treatment and 7 off therapy), whereas in the HR group, 3 were resistant, 4 relapsed and 2 died by toxicity (transplant-related in 1 out of 4 pts submitted to alloHSCT). Table 1 shows the DFS, OS and cumulative incidence of relapse (CIR) at 5-yrs for the whole series, the patients remaining SR and those who turned HR. Of note, OS was lower in the HR pts (Figure 1). On comparison with the results of the ALL-RI-96 trial (same inclusion criteria, same treatment but no follow-up by MRD, Ribera JM et al. J Clin Oncol 2008; 26:1843-9), no differences were observed in DFS, OS and CIR (Table 1).

Conclusions

Twenty-five percent of AYA pts with SR ALL at baseline are in fact HR based on slow early cytological response to therapy and/or poor MRD clearance. High-risk pts showed lower OS despite being moved to a HR protocol.

Supported in part by grants RD12/0036/0029 (RTICC, FEDER), PI14/01971 FIS, Instituto Carlos III, and SGR225 (GRE), Spain.

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