Which steroids should we choose for the treatment of adult acute lymphoblastic leukemia?
Authors: Changcheng Zheng, Xin Liu, Jingsheng Wu, Xiaoyan Cai, Weibo Zhu, Zimin Sun
Journal: American Journal of Hematology (2010)

Corticosteroids are essential and one of the mainstays in the treatment of acute lymphoblastic leukemia (ALL). In vitro assays show that dexamethasone (DXM) is five to six times more cytotoxic to leukemic lymphoblasts than prednisolone (PDN) [1], and the use of DXM as an alternative drug for PDN is an important issue in the treatment of childhood ALL. The current randomized comparisons in childhood ALL indicated a statistically significant and clinically important decrease in rate of isolated central nervous system (CNS) relapses and an increase in event-free survival (EFS) with DXM. However, the data were limited in adult ALL. Recently, Labar et al. [2] reported their first investigation in comparison of the antileukemic activity and toxicity between DXM and PDN for adult patients with ALL and lymphoblastic lymphoma (LBL) through a randomized clinical trial (the ALL-4 trial of the EORTC Leukemia Group), and the author concluded that DXM as a steroid therapy for adult patients with ALL/LBL did not show any benefit compared with PDN, which did not support the experience from several other pediatric studies. In Labar's observation, about 70% of adult patients were high risk (HR) ALL. Most of the patients in pediatric trials were standard risk (SR) ALL. In our study, we also evaluate the role of DXM compared with PDN during induction or subsequent phases of therapy in adult ALL with emphasis on SR group. We designed a clinical trial to investigate the effectiveness of DXM compared with PDN in selected risk groups of adult ALL patients (=18 years of age), as the CCG-1922 study first indicated that children ALL with SR receiving DXM had a better outcome [3]. The study was approved by the Ethics Committee in Anhui Provincial Hospital, also all patients gave a signed informed consent. From June 2003 to January 2008, 42 SR and 63 HR or very high risk (VHR) newly diagnosed adult ALL patients entered the randomized comparison of DXM at 6 mg/m2/d versus PDN at 60 mg/m2/d with ALL treatment protocol as we described before [4]. HR ALL was defined as patients fulfilling at least one of the following criteria: age 35 years and older, WBC count greater than 30 × 109/L for B-lineage ALL or more than 100 × 109/L for T-lineage ALL at diagnosis, time to complete remission (CR) more than 4 weeks, or presence of extramedullary involvement. Patients who had none of these risk factors were considered as SR, and patients with cytogenetics of t (9; 22) or BCR-ABL fusion gene positive were considered as VHR. Burkitt and Burkitt-like lymphoma/leukemia were excluded from the study group. The median follow-up time was 3.5 years. Outcome according to risk groups is summarized in Table I. There were no significant differences in terms of CR between the PDN and DXM arms, no matter in SR group (86% vs. 88%, P = 0.73) or in HR + VHR group (76% vs. 79%, P = 0.57). In patients with SR, the cumulative incidence of isolated CNS relapse was lower for DXM patients than for PDN patients, with 3-year cumulative estimates of 6.5 and 11.3%, respectively (P = 0.01). The 3-year disease-free survival (DFS) and 3-year overall survival (OS) rates were 53 and 57% in SR patients who received DXM, which were significantly higher than 42 and 49% in SR patients who received PDN (P = 0.005, 0.012). For patients with HR + VHR, the isolated CNS relapse rate was similar for patients assigned to DXM compared with that of patients assigned to PDN (3-year cumulative estimates: 10.2% vs. 13.4%, P = 0.13), and there were no differences in the 3-year DFS rates (34% vs. 32%, P = 0.43) and 3-year OS rates (38% vs. 36%, P = 0.45) based on steroids type (DXM vs. PDN). During induction, the incidence of grade 3–4 infection was similar in the two arms (DXM 17.3% vs. PDN 14.6%, P = 0.15), and during postinduction consolidation, it was higher in the DXM arm (13.5% vs. 7.5%, P = 0.025). Reversible hyperglycemia and myopathy were higher in the DXM arm than in the PDN arm (5.5% vs. 4.7%, 3.8% vs. 2.7%) but the differences were not statistically significant (P = 0.5, 0.25). Only one patient received DXM was diagnosed with avascular necrosis of the femoral head in maintenance treatment. Until now, there are at least six prospective, randomized, controlled trials have been reported to evaluate whether DXM yields a better outcome than PDN for the treatment of childhood ALL. Four clinical trials, including CCG-1922 [3], UK-MRC-ALL 97/99 [5], AIEOP-BFM ALL 2000 [6] and DFCI-ALL 00-01 [7], indicated DXM to be more effective than PDN in providing a significant EFS benefit, and this benefit was greatest for patients with SR ALL, although a tendency of a higher incidence of complications in DXM arm. TCCSG L95-14 [8] and EORTC 58951 trials [9], most of SR and intermediate risk or average risk patients, failed to demonstrate a improved EFS when DXM was substituted for PDN but both obtained higher EFS rates. This may be attributed to the higher dosage of PDN and more aggressive chemotherapies including high-dose methotrexate and high-dose cytarabine used. Perhaps the superiority of steroids may be dependent on the setting of intensive induction and consolidation therapy. Although the number of patients is small, our results indicate that DXM might have benefit in adult SR ALL patients, as it was proved in children, especially concerning the long-term survival and the CNS relapse. The difference of DXM efficacy in above children ALL clinical trials and Labar's observation could be related to a different biology of the disease and a different intensity of treatment protocols used in children and adults. The greater frequency of HR subtypes of ALL in the adult population strongly interferes with any comparison of adult and pediatric therapeutic practices [10]. The data reported here were consistent with previous reports of childhood ALL steroids comparison which DXM could improve survival outcome of SR patients, but the advantages for DXM in SR patients were not realized in the HR or VHR patients. This was not contradictory to Labar's report, because the majority of HR patients (70%) participated in the ALL-4 trial determined the author's negative conclusion. For patients at HR of relapse, it is unlikely that only modification of steroids replacement would alter their dismal prognosis, and these patients should be treated with either more intensified chemotherapy or hematopoietic stem cell transplantation whenever possible. Changcheng Zheng*, Xin Liu*, Jingsheng Wu*, Xiaoyan Cai*, Weibo Zhu*, Zimin Sun*, * Department of Hematology, Anhui Provincial Hospital, Anhui Medical University, Hefei, China.