L-asparaginase for adult CD20 positive B-cell precursor acute lymphoblastic leukemia

The letter by Chang et al. raises the interesting question of discrepant results regarding the prognostic impact of CD20 expression in adults with B-cell precursor acute lymphoblastic leukemia. Recently, we evidenced an adverse prognostic impact of CD20 expression on the cumulative incidence of relapse in a multivariate analysis including: (i) CD20 positivity; (ii) age over 45; and (iii) leukocyte count over 30 G/L.1 Using the same cumulative incidence of relapse endpoint and co-variables but a different statistical model (Kaplan-Meier instead of cumulative incidence curves taking into account deaths in first complete remission as a competing risk), Chang et al. found no significant influence of CD20 expression. This conclusion was made in a series of 119 patients apparently treated similarly to a smaller cohort of 85 BCR-ABL negative B-cell precursor acute lymphoblastic leukemia patients reported by the same Canadian group.2 However, one must note that the clinical results reported in this last study2 were far better than those reported by Chang et al. in their letter. Of note, we incorporated the cut-off of 45 years of age in our analysis since it had been previously identified as the best one to illustrate the negative impact of advanced age in our cohort.3 Since a cutoff of 35 years of age rather than 45 was previously identified as a significant adverse predictor for overall survival in the published experience of this Canadian group,2 it might be preferentially included in their multivariate analyses.

Despite these analytical differences, Chang et al. show, in contrast to our results, no evidence of any adverse effect associated with CD20 expression in a similarly sized cohort, apparently treated with a quite similar pediatric-inspired protocol. We compared precisely these chemotherapy regimens in order to put forward hypotheses explaining this discrepancy and evidenced two main differences. First, our regimen included cyclophosphamide at different steps of treatment (induction, consolidations, late intensification) while this drug was not used in the schedule mentioned by Chang et al. However, one would not easily argue that the use of cyclophosphamide would emphasize the negative impact of CD20 expression in our cohort. In contrast, we observed in the schedule mentioned by Chang et al. that around 3-fold higher cumulative doses of L-asparaginase were used in comparison with our protocol (400,000 UI/m vs. 144,000 UI/m). We hypothesize that this increased use of L-asparaginase may have annihilated the negative impact of CD20 expression. Interestingly, Thomas et al. previously reported the same adverse prognostic impact of CD20 expression in adult B-cell precursor acute lymphoblastic leukemia in a series of 110 patients treated with the VAD/CVAD regimen and 143 patients treated with the hyper-CVAD protocol.4 In their study, CD20 positivity was associated with a higher incidence of relapse (65% vs. 42%, P<0.001), lower 3-year complete remission duration rate (20% vs. 50%, P<0.001) and lower 3-year overall survival rate (27% vs. 40%, P=0.03). Thomas et al. further evaluated the significance of CD20 expression with their two sequential regimens of increasing intensity (VAD/CVAD then hyper-CVAD). Whereas intensifying the chemotherapy (from VAD/CVAD to hyper-CVAD) significantly improved the outcome for the CD20 negative group, the outcome for the CD20 positive group was similar regardless of chemotherapy regimen. They suggested that “further intensifying the chemotherapy for CD20 positive precursor B-cell acute lymphoblastic leukemia in a manner other than incorporating monoclonal antibodies (e.g. rituximab) or other targeted agents would be unlikely to improve outcome”, but also that “the one potential caveat is the incorporation of asparaginase since it was not a substantial component of either regimen”. Indeed, L-asparaginase cumulative doses were 80,000 UI/m in the VAD/CVAD regimen and patients received 2 doses of pegylated asparaginase (2,500 UI/m) at the maintenance phase in the hyper-CVAD regimen. In regard to these results obtained from 3 different protocols with their specific chemotherapy components, we fully agree with Chang et al. that differences in chemotherapy regimens might account for much of the observed differences of CD20 significance. Further investigations are certainly warranted to determine whether L-asparaginase would be specially needed for adult CD20 positive BCP acute lymphoblastic leukemia.