Randomized clinical trials in adult acute lymphoblastic leukemia: which is the question?

This issue of Haematologica contains the results of a randomized clinical trial conducted by the Spanish Group PETHEMA (see Tables for acronyms), relative to the effects of late intensification therapy in adult acute lymphoblastic leukemia (ALL) [Ribera et al. Late intensification chemotherapy has not improved the results of intensive chemotherapy in adult acute lymphoblastic leukaemia. Results of a prospective multicenter randomized trial (PETHEMA ALL-89). Haematologica 1998; 83:222-230]. Mature results from randomized adult ALL trials have not been frequently published in the last years, contrary to the number of unsolved therapeutic questions , so this report is both informative to the readers as well as an indicator of the new editorial policy of the Journal. From my point of view, admittedly that of a non-trialist deeply involved in the management of this illness, it can be profitable to reconsider critically the information gathered from phase III trials and their impact within the scientific community. The problem of late intensification therapy was previously tackled by the members of the SEG, whose phase III study reached the same conclusions as the PETHEMA Group. Both studies strongly discourage the inception of yet another controlled trial on the same subject, although a criticism may be addressed to the small number of patients assigned to random-ization arms (24 and 29 in each arm in the PETHEMA and SEG trial, respectively), to the low-intermediate intensity of the scheduled late intensification regi-mens, and to the fact that, by definition, patients relapsing early were excluded from both treatment realization and evaluation. So, while the available evidence speaks against late intensification, none can exclude a different result in a larger patient cohort, using an increased-intensity regimen, or in distinct immunobiologic ALL subtypes, particularly in pre-B ALL that shows a consistent tendency to recur until relatively late. The patient number is absolutely crucial. In their most recently published study (Table 2), concerning a different aspect of postremission therapy , the MRC team calculated that the inclusion into the study of 450 patients gave a less than a 65% chance of detecting a 2p=0.05 significance level for the consolidation treatments employed, given the 13% maximal prognostic divergence observed in that study. Nonetheless, clinicians willing to embark on a new study are warned by SEG and PETHEMA study results that late intensification is unlikely to significantly add to the final outcome. They are also warned, from a practical standpoint, that reducing the exposure …