Impact of Additional Intensive L-Asparaginase Therapy during Consolidation Phase for High-Risk Acute Lymphoblastic Leukemia: Results of a Randomized Controlled Trial in the AIEOP-BFM ALL 2009 Protocol

Introduction Treatment of childhood Acute Lymphoblastic Leukemia (ALL) with unfavorable features remains a major challenge. An earlier intervention, aiming at lowering Minimal Residual Disease (MRD) levels, might reduce the risk of relapse and the indication to allogeneic hematopoietic stem cell transplantation (HSCT) in 1^st complete remission (CR). The AIEOP-BFM ALL 2009 protocol included a randomized study for patients with high-risk (HR) features, to investigate if an intensive and continuous exposure to pegylated L-Asparaginase (Peg-L-ASP), given on top of BFM consolidation phase IB, could decrease the levels of MRD and to influence long term outcome.

Patients and methods From June 1, 2010 to February 28, 2017, 6136 patients with Ph’ negative ALL, aged between 1-17 years, were enrolled in the AIEOP-BFM ALL 2009 Study (Eudract number 2007-004270-43). Participating study centers were in Australia, Austria, Czech Republic, Germany, Israel, Italy and Switzerland.1097 were classified as HR at the end of induction phase IA (day 33), on the basis of evidence ofKMT2A-AFF1 rearrangement, hypodiploidy (<45 chromosomes, or DNA-index <0.8), prednisone poor response (PPR), poor bone marrow (BM) response at day 15 (i.e. ≥10% blasts by MFC), failure to achieve morphological CR.

Treatment consisted of a 7-day prephase with prednisone and 1 intrathecal dose of methotrexate (ITMTX), an induction protocol IA with prednisone or dexamethasone, vincristine, daunomycin, Peg-L-ASP (2 doses), ITMTX and, only in PPR T-ALL cyclophosphamide. Patients eligible were randomized to receive or not 4 weekly doses of Peg-L-ASP (2500 IU/sqm x 4) on top of consolidation phase IB, which included 6-MP, cyclophosphamide, cytosine arabinoside and ITMTX. Thereafter, patients received 3 blocks of non-cross-resistant drugs, 3 reinduction phases with or without cranial radiotherapy (12 Gys), and maintenance therapy till 24 months from diagnosis. The primary endpoint was PCR-MRD reduction to less than 5x10^-4at the end of phase IB; secondary endpoint was Event-Free Survival (EFS).

Results Overall, 1097 patients were at HR at the end of induction phase IA and 809 (79.2%) were randomized to receive (404) or not (405) 4 doses of Peg-L-Asp during consolidation phase IB. The primary endpoint could be assessed in 732 patients (90.5%). By ITT analysis, the proportion of patients with PCR MRD ≥ 5x10^-4 at the end of consolidation phase IB in the experimental arm (EA) vs the control arm (CA) was 13.9% vs 17.0% with no significant difference (p-value=0.25).There were more toxic deaths during consolidation phase IB among patients randomized to Peg-L-Asp (n=14, 12 of them due to infections), vs controls (n=1): 7 of them, all in the EA, however, occurred before starting the randomized treatment. Deaths in CR after phase IB were 24 vs 24 in the EA vs CA (of whom 10 vs 12 were after HSCT in CR1, performed in 87 and 90 patients respectively). In the EA and CA the overall 5-year EFS by ITT was 70.4% (2.3) and 75.0% (2.2) (p-value=0.18), the 5-year cumulative incidence of death in CR was 9.5% (1.5) vs 5.7% (1.2) (p-value=0.08) and that of relapse was 17.7% (1.9) vs 17.2% (1.9), respectively (p-value=0.94). Non HSCT related deaths were due to infections in 23/28 in the EA, and in 10/13 in CA patients. The 5-year overall survival probability was 81.5% (2.0) and 84.0% (1.9) respectively (p-value=0.25).

Discussion In this randomized study, results (ITT analysis) show a very modest, not significant decrease in the percentage of patients with high MRD in the EA, and no significant difference in EFS between the two arms. The trial results suggest that the additional administration of intensive Peg-L-Asp in phase IB is associated with higher, although not statistically significant, mortality in CR and very similar relapse incidence. However, some fatal events in phase IB occurred very early after randomization, before the start of the planned treatment with Peg-L-Asp. Importantly, in both analyses, by ITT and by treatment given, there is no evidence of benefit on reduction of relapses by the additional therapy with Peg-L-ASP in phase IB. These findings indicate that an early intensification of chemotherapy with Peg-L-Asp in patients defined as HR does not improve the outcome of children with HR ALL treated according to AIEOP-BFM regimen, thus suggesting that further improvements with conventional chemotherapy might be difficult in the context of intensive treatment protocols.

Conter:Shire: Honoraria, Research Funding; SigmaTau: Honoraria, Research Funding; Medac: Research Funding. Attarbaschi:Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: compensation of travel expenses; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Elitzur:Amgen: Consultancy; Novartis: Honoraria; Medison Pharma: Honoraria. Locatelli:TAKEDA: Speakers Bureau; GILEAD: Speakers Bureau; MEDAC: Speakers Bureau; MILTENYI: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SANOFI: Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NEOVII: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AMGEN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BLUEBIRD BIO: Speakers Bureau; SOBI: Speakers Bureau; JAZZ PHARMACEUTICALS: Speakers Bureau; PFIZER: Membership on an entity's Board of Directors or advisory committees. Moericke:Clinigen: Consultancy, Honoraria; BTG: Consultancy, Honoraria. Rizzari:Servier: Consultancy, Honoraria, Research Funding. Boos:Servier: Research Funding; Jazz: Research Funding. Lanvers-Kaminsky:Clinigen: Honoraria; Servier: Other: travel grants. Gruhn:Amgen GmbH: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel costs; Jazz Pharmaceuticals: Honoraria, Other: Travel costs; Novartis Pharma GmbH: Honoraria, Other: Travel costs; EUSA Pharma GmbH: Membership on an entity's Board of Directors or advisory committees; Pfizer Pharma GmbH: Honoraria; Servier GmbH: Honoraria, Other: Travel costs; Bellicum Pharma GmbH: Membership on an entity's Board of Directors or advisory committees, Other: Travel costs; medac GmbH: Other: Travel costs; Neovii Biotech GmbH: Other: Travel costs. Biondi:Amgen: Consultancy, Honoraria; CoImmune: Honoraria, Research Funding; CoImmune: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Schrappe:SHIRE: Research Funding; Novartis: Honoraria, Research Funding; Amgen: Research Funding; Servier: Honoraria, Research Funding; JazzPharma: Consultancy, Honoraria, Research Funding; SigmaTau: Research Funding.