Switch of Asparaginase Formulation Based on Antibody Monitoring in Adults with Philadelphia-Negative Adult Lymphoblastic Leukemia. Results of the Graall-2014 Trial

Introduction: For over two decades, asparaginase-based regimen have contributed to the improved outcome of young adults with Ph-negative (Ph-) acute lymphoblastic leukemia (ALL). The use of E. coli-derived asparaginase (ASPA) can be responsible for numerous adverse effects, including silent hypersensitivity, in up to 50% of patients (pts), which has been associated with enzyme inactivation. In the GRAALL-2014 trial, patients (pts) received ASPA in induction and late intensification (LI) phases, with activity monitoring and assessments for anti-ASPA antibodies. Those exhibiting low activity, any clinical allergy to ASPA, or the presence of anti-ASPA antibodies were considered for switching to Erwinase (ERW) during LI. Here we report on the results of this strategy.

Patients and methods: Between 2014 and 2020, the multicenter French-Belgian-Swiss GRAALL-2014 trial enrolled 743 adult pts with newly diagnosed Ph- ALL, including 489 with BCP-ALL and 254 with T-ALL. During induction and LI, ASPA was administered as follows: for pts <45y, ASPA was given at 6000 IU/m²/day for 8 infusions every two days (D8,10,12 then 20,22,24,26,28), and for pts 45y+, it was given for 6 infusions. Pts with initial central nervous system (CNS) involvement received only 5 infusions regardless of age during induction.

Therapeutic drug monitoring (TDM) included measurement of asparaginase activity 48 hours after the third (D14) and sixth infusions (D26), with low ASPA activity defined as <100 IU/L. Anti-ASPA antibodies (Abs) were detected using an ELISA test, and were measured at baseline, at the end of induction (week 6), and twice during consolidation (week 10, week 12). A switch for ERW 25.000 IU/m²/infusion on the same schedule as ASPA was recommended in the event of clinical allergy (any grade), ASPA activity < 100 UI/L, or Ab detection (any of the 3 post-induction time points).

Results: Median age was 35y (range: 18-59) with 239 pts 45y+. Initial median white blood cell count was 11x10⁹/L (range: 0-712) and 87 pts had CNS involvement (12%). Among the 574 pts who underwent TDM assessment on D14, the median asparaginase activity was 660 IU/L (range: 2-2545), with 97.0% achieving levels of ≥100 IU/L. On D26, among 573 assessed pts, the median asparaginase activity was 551 IU/L (range: 2-4741), with 93.4% achieving levels of ≥100 IU/L. The planned schedule of ASPA infusions was administered to 554/737 pts (75.2%). Multivariable analysis identified increased body mass index (OR 0.94, 95%CI[0.91-0.98]), CNS involvement (OR 0.70, 95%CI[0.53-0.93]), and B- versus T-cell phenotype (OR 0.58, 95%CI[0.39-0.67-]) as associated with incomplete ASPA schedule administration.

Anti-ASPA Abs (Ab+) were detected in 293/565 pts (51.9%) at the end of induction. This rate was stable at week 10 (49.8%) and week 12 (49.5%). In pts with clinical allergy during induction (n=19), anti-ASPA Abs were more frequently observed, in 79.0%, 89.5%, and 94.1% at week 6, 10, and 12, respectively (p<0.001 at week 12).

Among the 447 pts who started LI, anti-ASPA Abs were detected in 240/438 pts (54.8%). Among the 198 Ab- patients,168 (84.8%) started IR with ASPA. Among the 240 Ab+ pts, 163 (67.9%) started IR with ERW, including all pts with clinical allergy during induction, while 57 (23.8%) started IR with ASPA despite switch recommendations. At D14 of LI, median asparaginase activity was 428.5 UI/L (range: 0-2171) and 294/322 assessed pts (91.3%) achieved an activity ≥100 IU/L. Unexpectedly, no difference in asparaginase activity was observed in pts receiving ASPA between Ab+ (669 IU/L, range 42-1418) and Ab- (753.5 IU/L, range 0-2171, P=0.13). On the other hand, Ab+ pts had inferior asparaginase activity if they received ERW (227.5 IU/L, range 2-2037 IU/L, p<0.001). The rate of pts with asparaginase activity ≥100 IU/L was 98.3% for ASPA/Ab-, 95.4% for ASPA/Ab+, and 83.6% for ERW/Ab+. Finally, Ab+ pts who received ERW had a higher cumulative incidence of relapse than those exposed to ASPA (Fine-Gray subdistribution hazard ratio 2.0, 95%CI[1.03;3.97]) with no significant impact on disease-free or overall survival.

Conclusion: In the GRAALL-2014 study, about half of the pts exposed to ASPA developed anti-ASPA Abs rapidly after induction phase. In contrast to prior observation, the presence of Abs did not predict ASPA inactivation. Pts who switched to ERW during LI had a higher risk of relapse, possibly due the different pharmacology profile between both asparaginases.

Balsat:Incyte: Honoraria; AMGEN: Consultancy, Honoraria; Pfizer: Honoraria, Other: International congress; Novartis: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Servier: Consultancy, Honoraria. Huguet:Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Escoffre-Barbe:Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte Biosciences: Membership on an entity's Board of Directors or advisory committees. Cluzeau:Keros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Syros: Speakers Bureau; Servier: Consultancy, Speakers Bureau; Jazz Pharma: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Abbvie: Consultancy, Research Funding, Speakers Bureau; Incyte: Speakers Bureau; Takeda: Speakers Bureau; Pfizer: Other: International Congress. Chalandon:Pfizer: Other: advisory board and travel support, paid to the institution; Novartis: Other: advisory board and travel support, paid to the institution; Roche: Other: advisory board and travel support, paid to the institution; Sanofi: Other: travel support, paid to the institution; Janssen: Other: travel support, paid to the institution; Takeda: Other: advisory board paid to the institution; Medac: Other: advisory board paid to the institution; BMS: Other: advisory board and travel support, paid to the institution; Servier: Other: advisory board paid to the institution; Jazz: Other: advisory board and travel support, paid to the institution; Incyte: Other: advisory board and travel support, paid to the institution; Pierre Fabre: Other: advisory board and travel support, paid to the institution; Abbvie: Other: advisory board and travel support, paid to the institution; Astra-Zeneca: Other: advisory board and travel support, paid to the institution; MSD: Other: advisory board and travel support, paid to the institution; Amgen: Other: advisory board and travel support, paid to the institution; Gilead: Other: advisory board and travel support, paid to the institution. Dombret:Incyte: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiich Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; BMS-Celgene: Research Funding; Pfizer: Research Funding. Boissel:Sanofi: Other; Pfizer: Other; Amgen: Other; Adveysa: Other.