Recent approaches in acute lymphoblastic leukemia in adults

Abstract

In the last decades outcome of adult acute lymphoblastic leukemia (ALL) has improved considerably. In large multicenter studies remission rates range from 75% to 89%, and long-term leukemia-free survival (LFS) from 28% to 39%. Major progress has also been made regarding better characterization of subtypes of ALL. Complete diagnostic procedures are essential to identify these subtypes which have significant differences in clinical and laboratory features and prognosis. LFS of > 50% can be expected in favorable subtypes such as T-ALL or mature B-ALL, while LFS of < 20% is expected in Ph/BCR-ABL positive ALL. Prognostic factors can be used for risk stratification and selection of treatment strategies can be adapted to the subtype and relapse risk. This includes measurement of minimal residual disease (MRD) to evaluate individualized treatment strategies adapted to the molecular response. Several new approaches for improvement in chemotherapy and stem cell transplantation (SCT) are under investigation. They include the use of intensified anthracyclines, asparaginase, cyclophosphamide or high-dose cytarabine during induction and intensive rotational chemotherapy during consolidation. Also SCT - mainly from sibling donors - is now part of standard treatment of de novo ALL, although it remains open whether indications should be based on prognostic factors or whether SCT should be offered to all patients with sibling donor. However, substantial progress can only be achieved by new, experimental strategies. These include new approaches for SCT, such as nonmyeloablative SCT, measurement of MRD, causal treatment with molecular targeting, e.g. with kinase inhibitors, and antibody therapy.

Influence of detection of pretreatment cytogenetic abnormalities on first complete remission and survival in adult acute lymphoblastic leukemia

“…The time to CR was the shortest (1 month), despite the presence of markers of poor prognosis (high WBC count and myeloid co-expression). These findings highlight the difficulty in confirming the independent prognostic importance of relatively small cytogenetic subgroups that are strongly correlated with other risk factors, such as the WBC count and age [20,23,[32][33][34]. In the present study the frequency of 8q24 translocations and/or rearrangements of the C-MYC proto-oncogene was high 28.6% in the highrisk group and 12% in all 33 patients.…”

“…Cytogenetic abnormalities were classified into 2 groups, as follows: 1) high risk: t(11q23)/MLL, t(9;22)/bcr-abl, hypodiploidy (<45 chromosomes), t(1;19), t(8q24)/C-MYC, and complex karyotype; 2) standard risk: normal karyotype, hyperdiploidy, and other structural aberrations. The parameters were selected according to internationally accepted prognostic factors in ALL [7,11,[19][20][21]. As a prognostic factor, cytogenetics was considered a binomial variable (high-risk group versus standard-risk group).…”

Dexamethasone compared to prednisolone for adults with acute lymphoblastic leukemia or lymphoblastic lymphoma: final results of the ALL-4 randomized, phase III trial of the EORTC Leukemia Group

“…[1][2][3] Corticosteroids are also part of the induction and the maintenance therapy in adults. 4,5 Dexamethasone is 6.5 times more potent than prednisolone as measured by conventional glucocorticoid activity, but it shows a 16-fold gain in potency against lymphoblasts in vitro, suggesting that it might be a more active corticosteroid in the treatment of ALL. 6,7 The better penetration in the central nervous system (CNS) 8 and the enhanced lymphoblastic cytotoxicity might explain the lower bone marrow relapse rate, the lower CNS relapse rate and the advantage in event-free survival recorded in children receiving dexamethasone .…”

The mTOR inhibitor CCI-779 induces apoptosis and inhibits growth in preclinical models of primary adult human ALL

“…Even with aggressive therapy, these patient groups have 5-year diseasefree survival rates of only 28% to 39%. 1 Thus, the development of novel therapeutic agents is crucial.…”