Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial

Abstract

SummaryBackgroundAlthough survival of children with acute lymphoblastic leukaemia has improved greatly in the past two decades, the outcome of those who relapse has remained static. We investigated the outcome of children with acute lymphoblastic leukaemia who relapsed on present therapeutic regimens.MethodsThis open-label randomised trial was undertaken in 22 centres in the UK and Ireland and nine in Australia and New Zealand. Patients aged 1–18 years with first relapse of acute lymphoblastic leukaemia were stratified into high-risk, intermediate-risk, and standard-risk groups on the basis of duration of first complete remission, site of relapse, and immunophenotype. All patients were allocated to receive either idarubicin or mitoxantrone in induction by stratified concealed randomisation. Neither patients nor those giving interventions were masked. After three blocks of therapy, all high-risk group patients and those from the intermediate group with postinduction high minimal residual disease (≥10−4 cells) received an allogenic stem-cell transplant. Standard-risk and intermediate-risk patients with postinduction low minimal residual disease (<10−4 cells) continued chemotherapy. The primary outcome was progression-free survival and the method of analysis was intention-to-treat. Randomisation was stopped in December, 2007 because of differences in progression-free and overall survival between the two groups. This trial is registered, reference number ISCRTN45724312.FindingsOf 239 registered patients, 216 were randomly assigned to either idarubicin (109 analysed) or mitoxantrone (103 analysed). Estimated 3-year progression-free survival was 35·9% (95% CI 25·9–45·9) in the idarubicin group versus 64·6% (54·2–73·2) in the mitoxantrone group (p=0·0004), and 3-year overall survival was 45·2% (34·5–55·3) versus 69·0% (58·5–77·3; p=0·004). Differences in progression-free survival between groups were mainly related to a decrease in disease events (progression, second relapse, disease-related deaths; HR 0·56, 0·34–0·92, p=0·007) rather than an increase in adverse treatment effects (treatment death, second malignancy; HR 0·52, 0·24–1·11, p=0·11).InterpretationAs compared with idarubicin, mitoxantrone conferred a significant benefit in progression-free and overall survival in children with relapsed acute lymphobastic leukaemia, a potentially useful clinical finding that warrants further investigation.FundingCancer Research UK, Leukaemia and Lymphoma Research, Cancer Council NSW, and Sporting Chance Cancer Foundation.

Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia

“…RR ALL samples were generally more resistant to agents used for induction in ALL such as dexamethasone (10 of 12 patients), cytarabine (9 of 12 patients), and doxorubicin (9 of 12 patients) compared with other diagnostic and relapse ALL patients ( Figure 4A). In contrast, individual samples were highly sensitive to dexamethasone, idarubicin, and mitoxantrone, which are included in the standard of care for relapsed ALL, 38 and to new agents from different classes, such as venetoclax, dasatinib, bortezomib, nutlin, JQ1, and panobinostat. Again, we noticed unexpected responses to venetoclax and dasatinib in a few patients, which we discuss later in this article.…”

“…Currently, most investigational agents will be tested in combination with a standard-of-care antileukemic regimen that includes 2 to 4 drugs such as vincristine, dexamethasone, asparaginase, and an anthracycline typically used for reinduction chemotherapy at relapse. 38 We detected synergy in vitro by using co-titration experiments, but this assay is challenging when assessing a drug with such strong in vitro activity as venetoclax 43 (supplemental Figure 9; supplemental Table 4). Because it is impossible to provide supportive care to mice after myelotoxic chemotherapy in vivo, we next tested the combination of venetoclax, dexamethasone, and vincristine without anthracyclines ( Figure 5A).…”

The assessment and appraisal of regenerative medicines and cell therapy products: an exploration of methods for review, economic evaluation and appraisal

“…However, results from the UKALL R3 trial, which compared different chemotherapy treatments for children in first relapse, showed that the longer-term outcome of having MRD-negative status in patients who have already had one relapse may well vary according to how the status was achieved. 115 There is, therefore, some uncertainty in how MRD negativity correlates to long-term outcomes in relapsed populations.…”

“…This definition is based on the criteria used in the UK ALL study. 115 State occupancy in the model was derived using the partitioned survival technique. This involved the direct extrapolation of EFS and OS curves, which were then used to estimate the proportion of patients occupying each of the three states using the following equations:…”

“…This was modelled based on data from the UK ALL study. 115 The proportional relationship between EFS and OS is not expected to continue indefinitely, given the potential for cure of disease and the expectation that after a finite period of time all patients alive in the simulation would also be free of relapsed disease (EFS = OS). This is equivalent to saying that, at some point in time, all patients who are alive are long-term survivors of ALL.…”