Risk Factors, Treatment and Outcome of 2^nd Relapse of Acute Lymphoblastic Leukemia in Children. Results of the ALL-REZ BFM Registry

Children with second relapse of acute lymphoblastic leukemia (ALL) are largely considered as non-curable and eligible for early clinical phase I /II trials. Nearly no data are available on the outcome of this patient group with conventional intensive therapy, and there is lack of a reliable comparator for the efficacy of new agents.

Aim of the study was to define suitable prognostic factors for children with 2^ndALL relapse and to determine an effective standard therapy which could be recommended at least for curative subgroups. Furthermore we aimed to develop a rationale for a standard chemotherapy backbone for future phase I/II combination trials with new agents.

We retrospectively analysed treatment and outcome of patients with a first relapse of ALL registered at the ALL-REZ BFM trial centre since July 1995 until October 2010 who suffered a subsequent relapse. Out of these, we selected the patients who were re-registered for the treatment at second relapse. Patients were treated individually at the discretion of the treating centre. However, the ALL-REZ BFM study centre provided treatment recommendations including modified ALL-REZ BFM elements, replacing anthracyclines with liposomal daunorubicin (DNX) at equivalent doses. Allogeneic hematopoietic stem-cell transplantation (HSCT) was recommended if a 3^rdCR could be achieved. In case of non-response to induction therapy, individual interventional and intensified chemotherapy courses were recommended.

A total of 536 patients who had been registered and treated with a 1^st relapse of ALL within ALL-REZ BFM trials suffered a subsequent relapse, among those 385 after chemo/radiotherapy and 151 after HSCT. Of these, 258 patients (48%) were re-registered, 227 with 2^nd relapse after chemo/radiotherapy and 31 after allogeneic HSCT. The risk profile of the re-registered group was favourable compared to the total group with 2^nd relapse with respect to timepoint of the 2^nd relapse. Re-registered patients who relapsed after chemo/radiotherapy demonstrated significantly superior probability of 5-year overall survival (pOS=.27±.03) compared with those who relapsed after HSCT (pOS=.04±.04, p=.024). In univariate analysis, time-point (very early, n=110, pEFS=.06±.02; early, n=56, pEFS=.14±.05; late, n=92, pEFS=.39±.05, p<.001) of and age at 2^nd relapse were significantly associated to pEFS. In multivariate Cox Regression analysis, the time point of 2^ndrelapse and SCT as time dependent covariate were the only independent significant prognostic covariates. Comparing induction therapies of patients who relapsed after chemotherapy, those who received ALL-REZ BFM protocol like therapy (Protocol II-DNX or F1/F2 courses, n=120, pEFS=.33 ± .04) showed significantly better prognosis than patients who received intensive non-protocol like induction therapy (Clofarabine containing regimens, DNX-FLA, FLAMSA, HAM, others; n=67, pEFS=.02±.02) or non-curative induction therapy (maintenance therapy, HSCT without pre-treatment; n=24, pEFS =.04±.04; p<.001). Best fared 60 patients with protocol-like induction, protocol-like consolidation and HSCT in CR3 with pEFS of .46±.07.

Children with a 2^nd relapse of ALL post allogeneic HSCT or with very early 2^nd relapse post chemo/radiotherapy have a dismal prognosis with intensive conventional antileukemic treatment and may be considered as candidates for single drug phase I/II trials. Patients with early or late 2^nd relapse of ALL post chemo/radiotherapy have a curative perspective with conventional induction/consolidation therapy, if HSCT in CR3 is performed. For this patient group phase I/II trials should be integrated into a curative treatment strategy. Conventional 4-drug induction therapy with dexamethasone, vincristine, anthracycline, and asparaginase such as Protocol II-DNX, or with dexamethasone, vincristine, HD-MTX and HD-ARA-C (F1/F2) are effective induction elements for children with 2^nd ALL relapse that can be considered as a backbone for phase I/II combination trials or as comparators for randomized phase II/III trials with new agents.

No relevant conflicts of interest to declare.