We categorized the relapse treatment into four groups: ALL-REZ BFM protocols ( 90, 95/96 and ), NOPHO ALL and ALL HR arms. In a prospective and blinded study, the ALL-REZ BFM Study Group .. In the subsequent trial ALL-REZ BFM , this level of MRD after. n = 46; ALL-REZ BFM 95/96, n = 46; ALL-REZ BFM , n = 9). Six/ (3%) cases received palliative treatment for first relapse, and 71/

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Recurrent acute lymphoblastic leukaemia ALL is a common disease for pediatric oncologists and accounts for more alo from cancer in children than any other malignancy. Treatment must be tailored after relapse of ALL, since outcome will be influenced by well-established prognostic features, including the timing and site of disease recurrence, the disease immunophenotype, and early response to retrieval therapy in terms of minimal residual disease MRD.

After reinduction chemotherapy, high risk HR patients are clear candidates for allogeneic stem cell transplantation Al, while standard risk patients do better with conventional chemotherapy and local therapy. Early MRD response assessment is currently applied to identify those patients within the sll heterogeneous intermediate risk group who should undergo SCT as consolidation therapy. Recent evidence suggests distinct biological mechanisms for early vs 200 relapse and the recognition of the involvement of certain treatment resistance related genes as well cell cycle regulation and B-cell development genes at relapse, provides the opportunity to search for novel target therapies.

Selected recent publications regarding the current management of childhood relapsed acute lymophoblastic leukemia have been reviewed. Controversies, current lines of investigation and possible future directions are discussed. Slow early response was also associated with a higher risk of relapse.

By contrast, there was no significant difference in the distribution of the immunophenotype B-precursor or T-cell between the patients who relapsed vs those who bm not[ 16 ].

Recurrent ALL is a relatively common disease for pediatric oncologists, and given the relatively high prevalence of newly diagnosed ALL, relapsed ALL still has a higher incidence than the new diagnoses of many of the most common pediatric malignancies and represents one of the most common childhood cancer. The number of children with ALL who experience treatment failure each year is similar to the number of children with newly diagnosed acute myeloid leukemia or rhabdomyosarcoma[ 218 ].

Moreover, relapsed ALL accounts for tez deaths from cancer in children than any other malignancy and represents a major cause of death among children[ 1719 – 23 ]. In the bf s, ALL relapse was regarded as bf almost incurable disease[ 24 ]. Today, most patients achieve 202 second remission.

Despite substantial second remission rates and a wide availability of haematopoietic stem cell transplantation SCTmost children with relapse die[ 2 ].

After remission reinduction, recommendations for continuation therapy include ongoing intensive chemotherapy with or without radiation therapy or SCT.

As in newly diagnosed patients, treatment must be tailored after relapse of ALL, since outcome will be influenced by several risk factors. Decisions regarding optimal postremission therapy in relapsed ALL are frequently based on well-established prognostic features, including the timing and site of disease recurrence, the disease immunophenotype, and, more recently, on evaluation of early response in terms of 20022 residual disease MRD at the end of the reinduction phase[ 202628 – 31 ].

Though slightly different variables were measured, results from different study groups showed similar poor outcomes for patients in second complete remission CR2 [ 1620 – 22242532 – 34 ]. Thus, there is a relative lack of success in the induction of durable second remissions using conventional chemotherapy combinations and the benefits of SCT vs aggressive chemotherapy for different patient groups remain unclear. Although the best treatment approach for relapsed ALL remains uncertain, there is agreement that when relapse occurs early, leukemia-free survival remains dismal; most children still die despite aggressive chemo-radiotherapy approaches, including transplantation, and novel salvage regimens are needed[ 1821243536 ].

Relapsed ALL represents the focus of considerable pediatric research and alternative treatment options exploring distinct mechanisms of action are being pursued[ 1737 ]. New studies clearly need to address how to effectively treat relapsed patients and maintain durable remissions[ 16 ]. Site of relapse and length of first remission are the major criteria for the classification of patients after first relapse.

According to the site of relapse, patients are commonly classified as isolated marrow, concurrent marrow, isolated central nervous system CNSisolated testicular and other extramedullary relapses with or without CNS involvement Table 2 [ 16 ]. Some studies require the demonstration of the presence of leukemic cells in the cerebrospinal fluid CSF in two consecutive CSF samples taken with an interval of at least 24 h[ 3840 ]. In some studies, testicular relapse was diagnosed in case of uni- or bilateral painless enlargement of the testicles[ 2233 ].

In the case of unilateral testicular relapse, it is recommended to rule out a subclinical involvement of the contralateral testis[ 24 ]. Although completion of primary therapy often corresponds to the end of the maintenance therapy, in a few patients, it may correspond to the end of a short and intensive first line treatment, or to the end of an inadequately short primary treatment.

For the BFM group, the end of frontline therapy is as much or even rex important than the duration of the first remission. Reinduction treatment not resulting in CR is generally termed reinduction failure and surviving patients are termed refractory[ 19 ].

Relapses and reinduction failures are collectively termed treatment failures within most studies. Treatment failures, the development of a second malignant neoplasm, or death from any cause are generally considered events for DFS analysis[ 19 ]. Risk factors predicting CNS relapse after the first CR include T-cell al, hyperleukocytosis, high-risk genetic abnormalities, and the presence of leukemic cells in the CSF at the time of diagnosis[ 44 ].


Understanding the biological factors contributing to relapse will probably contribute rea identify new agents able to increase the chances of a sustained second remission and cure. Studying the biology of these diseases at diagnosis, in minimal residual disease states after selection by chemotherapy, and at relapse, provides a unique opportunity to dissect pathways and identify potential therapeutic strategies for relapsed childhood ALL and may improve our understanding of how to use current therapy as well as identifying new targets[ 163745 ].

It has generally been assumed that relapse is the consequence of the emergence of a drug-resistant leukemia subclone which was already present at diagnosis and that was selected during frontline therapy. During initial therapy, this minor population would exhibit only eez reduction relative to the bulk aol the diagnostic leukemic cells but would rapidly expand before clinical relapse[ 45 ]. Although most relapsed patients achieve a second CR2 with drug combinations involving the same agents used at primary diagnosis, those patients who fail to enter in remission are not likely to be salvaged using different drug combinations, suggesting intrinsic drug resistance[ 45 ].

The equivalent post-relapse survival for patients undergoing different intensity regimens as first line therapy, suggests that the malignant cells responsible for relapse are present at diagnosis and mutate to a resistant phenotype through the acquisition of spontaneous mutations that are dependent on intrinsic genomic instability rather than treatment exposures[ 17 ]. Lesion specific backtracking studies revealed that in most cases the relapse clone existed as a minor sub-clone within the diagnostic sample prior to the initiation of therapy suggesting that the relapse clone was selected for during treatment.

These findings indicate that the diagnosis and relapse clones originated from a common ancestral clone and acquired distinct copy number abnormalities CNAs before emerging as the predominant clones at diagnosis or relapse. In this model, relapse emerges from a drug-resistant subclone present at initial diagnosis that is selected during treatment regardless of btm nature of the frontline therapy delivered[ 17 ].

This data support the hypothesis that many relapses may be the result of the selection of a relatively resistant clone already present at initial diagnosis rather than the generation of a novel clone by mutation[ 18 gez, 47 ]. Resistant leukemia subclones are probably present at primary diagnosis in those patients destined for early relapse.

Early-relapse mechanisms appear to be more homogeneous and are suggestive of the selection bbfm a resistant, more proliferative clone Table 3 [ 48 ]. Alternatively, the acquisition of resistance-conferring mutations induced by initial treatment might be responsible for the relative drug resistance noted at relapse[ 45 ].

For subsequent relapses bfk treatment attempts a significant decrease in CR rates is expected[ 19 ], which suggests the emergence of new mechanisms of resistance. According to this model, genomic studies carried out in samples from children at diagnosis and relapse demonstrated the acquisition of new genetic alterations at relapse, often involving cell proliferation and B-cell development pathways[ 45464849 ]. By contrast, late relapses may represent de novo development of a second leukemia from a common premalignant clone.

Although SR patients receive less intense therapy, these data suggest that intrinsic differences in the biology of the leukemic blasts are correlated with different mechanisms and the timing of relapse[ 16 ]. Distinct gene expression profiles were revealed for pediatric relapsed ALL patients at both early and alk time points[ 49 ].

Paired samples from patients experiencing early relapse are more similar in expression patterns than paired samples from those reez later[ 48 ]. Staal et al[ 52 aall using genome-wide expression array on purified leukemic cells, found that genes involved in a late or an early relapse identified clearly distinct pathways.

Analyses of the TCR gene rearrangement status, pattern of NOTCH1 mutations, and genome-wide copy number showed a common clonal origin between diagnosis and early relapses of T-cell ALL but not for the aol cases of T-cell ALL late relapses, suggesting that these recurrences should be considered as a second T-ALL rather than a resurgence of the original clone[ 53 ].

These findings are suggestive of a model whereby late relapse is due to the acquisition of diverse secondary events that might occur in a distinct subpopulation such as a leukemic stem cell[ 48 ].

By contrast, some of the genes down-regulated at relapse compared with initial diagnosis included proapoptotic genes, antiproliferative genes and a putative tumor 20022 gene[ 48 ]. Time to relapse length of first remissionsite of relapse and ALL-immunophenotype are well-established risk factors that can predict survival and constitute the most important prognostic determinants that can be used to alp patients with a alll relapse into different treatment groups[ 216172025 – 2732343557 ].

Before relapse, the median duration of the first complete remission CR1 has been reported to be around 2.

ALL-REZ BFM–the consecutive trials for children with relapsed acute lymphoblastic leukemia.

Most ALL relapses occur during treatment or within the first 2 years after treatment completion, although relapses have been reported to occur even 10 years after diagnosis[ 218 ]. In a retrospective analysis of relapsed patients registered within 10 consecutive CCG studies, the duration of the CR1 for patients who relapsed varied according to NCI risk group at primary diagnosis, with shorter duration of remission coinciding largely with higher risk features at diagnosis[ 16 ]. The duration of the CR1 has been reported to vary with the site of relapse[ 343541 ].

In re study reported by Malempati et al[ 34 ], the mean interval between day 28 of primary induction and relapse for all patients was Re of relapse has emerged as the most significant predictor of outcome and the most important factor for a second relapse is the duration of the first remission. Early relapse has worse prognoses than late relapse[ 161720222532 – 353857 ].


Some late relapses are thought to arise from a common precursor that retains the chemosensitivity of the original clone, which could explain the high cure rates achieved with chemotherapy alone in late relapses[ 30 ].

These outcomes have been remarkably consistent over recent decades, irrespective of differences in the components of salvage regimens[ 212428 ]. Isolated CNS or testicular relapse or, much less frequently, relapse involving other extramedullary sites may also occur Table 4 [ 20223234 ]. In extramedullary relapses, a clear distinction also has to be made for early relapses vs late relapses.

Regarding early relapse, survival rates are higher for rrez with isolated CNS relapse than for patients with either isolated or combined BM relapse, and this is also true for intermediate and late relapsing patients.

Current approach to relapsed acute lymphoblastic leukemia in children

Survival rates were also significantly higher for patients with concurrent marrow relapses compared to those with isolated marrow relapses[ 1624 ]. Thus, involvement of an extramedullary site in patients with BM relapse has been identified as a favourable prognostic feature compared to patients without extramedullary involvement.

Thus, relapses in extramedullary sites are often considered as relapses from malignant cells treated with suboptimal drug levels; due to their homing on these sanctuaries.

Therefore, bf, may be more sensitive to chemotherapy than clones originating directly from the BM[ 24 ]. Five-year survival rates for isolated CNS range between In a report by investigators at St. Thus, apart from the fact that T-cell recurrences tend to occur early, T-cell immunophenotype itself is associated with a very poor outcome after relapse regardless of site and time to relapse[ 1620 – 2224 – 262832 ]. Minimal residual fez MRDmeasured either by flow cytometry or real-time polymerase chain reaction PCRmay supplement morphologic response[ 295859 ].

The prognostic significance of Alll response at relapse has been assessed in several studies[ 283160 ]. The absence of MRD at the end of the first month of reinduction therapy portended better outcomes in all patients, and separately in early and late relapse patients. The combination of timing of relapse and MRD appeared to identify three groups of patients.

Early relapse patients who were MRD positive had a dismal outcome, while late relapse patients who were MRD negative had an excellent outcome, approaching that seen in newly diagnosed patients. MRD-negative early relapse patients and MRD-positive late relapse patients appeared to form an intermediate group.

MRD positivity was also correlated strongly with the duration of initial remission; those patients experiencing relapse at less than 18 mo from initial diagnosis had the highest proportion of MRD positivity[ 2829 ]. Multivariate analysis revealed that MRD 20022 the second induction course was the only parameter independently predicting the occurrence of subsequent adverse events[ 31 ].

Conflicting results, however, were observed in the Medical Research Council MRC UKR3 trial, in which reinduction therapy with mitoxantrone was superior to that with idarubicin, yet no differences in the end of reinduction MRD were observed[ 30 ].

MRD proved to be the most important determinant for subsequent relapse and survival after transplantation in univariate and multivariate analysis. According to these findings, patients classified as being intermediate risk with conventional clinical parameters could be further classified into a very HR subgroup if MRD proves to persist at a high level until transplantation[ 61 ]. In 22002 study, classical risk factors such as immunophenotype, site of relapse, time to relapse, and others were only significant in patients who bmf chemotherapy in CR2.

These factors lost their relevance in patients undergoing SCT, and MRD remained the only independent prognostic variable in this setting[ 42 ]. Thus, MRD of leukemia both during second CR and before transplantation, has been reported to be a very strong prognostic factor for the ultimate outcome[ 61 ].

ALL-REZ BFM–the consecutive trials for children with relapsed acute lymphoblastic leukemia.

However, the Saint Jude group reported that, although MRD before transplantation was an independent predictor of survival, patients with high levels of MRD 0. Given its power as a prognostic factor, quantification of MRD at diagnosis of ALL relapse and regularly during therapy has become an essential tool to characterize the responsiveness of the disease and to allocate the patients to a risk adapted treatment. It is currently being incorporated for relapsed patients into a risk-classification algorithm for the management of relapsed ALL within the COG Table 2 [ 2829 ].

Although study designs are incorporating the use of MRD in order to quickly assess responses in patients with relapsed ALL who are treated with novel agents, at present MRD remains an unvalidated surrogate marker for this purpose[ 2829 ]. To this regard, even when a clear superiority from one arm to the other was obtained regarding the primary outcome i. There is some debate in the literature on the prognostic factor of the white blood cell WBC count and the presence of blasts in the peripheral blood at the time of relapse[ 253233 ].

Age at primary diagnosis might influence outcome after relapse. In a recent analysis of patients aged years registered in four consecutive Austrian ALL-BFM trials, prognosis of relapsed leukaemia was significantly better for younger patients patients aged years at primary diagnosis than for adolescent i.