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Contains fulltext : 88800.pdf (Publisher’s version ) (Open Access) BACKGROUND: Corticosteroids are a standard component of the treatment of acute lymphoblastic leukemia and lymphoblastic lymphoma. Our aim was to determine whether dexamethasone results in a better outcome than prednisolone. DESIGN AND METHODS: Adult patients with acute lymphoblastic leukemia or lymphoblastic lymphoma were randomized to receive, as part of their induction therapy on days 1-8 and 15-22, either dexamethasone 8 mg/m(2) or prednisolone 60 mg/m(2). Those who reached complete remission were given two courses of consolidation therapy with high-dose cytarabine and mitoxantrone and methotrexate and asparaginase. Subsequently patients younger than 50 years, with a suitable donor, were to undergo allogeneic stem cell transplantation, whereas the others were planned to receive either an autologous stem cell transplant or high-dose maintenance chemotherapy with prophylactic central nervous system irradiation. Randomization was done with a minimization technique. The primary endpoint was event-free survival and the analyses was conducted on an intention-to-treat basis. RESULTS: Between August 1995 and October 2003, 325 patients between 15 to 72 years of age were randomized to receive either dexamethasone (163 patients) or prednisolone (162 patients). After induction and the course of first consolidation therapy, 131 (80.4%) patients in the dexamethasone group and 124 (76.5%) in the prednisolone group achieved complete remission. No significant difference was observed between the two treatment groups with regards to 6-year event-free survival rates (+/-SE) which were 25.9% (3.6%) and 28.7% (3.5%) in the dexamethasone and prednisolone groups, respectively (P=0.82, hazard ratio 0.97; 95% confidence interval, 0.75-1.25). Disease-free survival after complete remission was also similar in the dexamethasone and prednisolone groups, the 6-year rates being 32.3% and 37.5%, respectively (hazard ratio 1.03; 95% confidence interval 0.76-1.40). The 6-year cumulative incidences of relapse were 49.8% and 53.5% (Gray's test: P=0.30) while the 6-year cumulative incidences of death were 18% and 9% (Gray's test: P=0.07). CONCLUSIONS: In the ALL-4 trial in adult patients with acute lymphoblastic leukemia or lymphoblastic lymphoma, treatment with dexamethasone did not show any advantage over treatment with prednisolone. 01 september 2010

Corticosteroids are a standard component of the treatment of acute lymphoblastic leukemia and lymphoblastic lymphoma. Our aim was to determine whether dexamethasone results in a better outcome than prednisolone. Adult patients with acute lymphoblastic leukemia or lymphoblastic lymphoma were randomized to receive, as part of their induction therapy on days 1–8 and 15–22, either dexamethasone 8 mg/m2 or prednisolone 60 mg/m2. Those who reached complete remission were given two courses of consolidation therapy with high-dose cytarabine and mitoxantrone and methotrexate and asparaginase. Subsequently patients younger than 50 years, with a suitable donor, were to undergo allogeneic stem cell transplantation, whereas the others were planned to receive either an autologous stem cell transplant or high-dose maintenance chemotherapy with prophylactic central nervous system irradiation. Randomization was done with a minimization technique. The primary endpoint was event-free survival and the analyses was conducted on an intention-to-treat basis. Between August 1995 and October 2003, 325 patients between 15 to 72 years of age were randomized to receive either dexamethasone (163 patients) or prednisolone (162 patients). After induction and the course of first consolidation therapy, 131 (80.4%) patients in the dexamethasone group and 124 (76.5%) in the prednisolone group achieved complete remission. No significant difference was observed between the two treatment groups with regards to 6-year event-free survival rates (±SE) which were 25.9% (3.6%) and 28.7% (3.5%) in the dexamethasone and prednisolone groups, respectively (P=0.82, hazard ratio 0.97 ; 95% confidence interval, 0.75–1.25). Disease-free survival after complete remission was also similar in the dexamethasone and prednisolone groups, the 6-year rates being 32.3% and 37.5%, respectively (hazard ratio 1.03 ; 95% confidence interval 0.76–1.40). The 6-year cumulative incidences of relapse were 49.8% and 53.5% (Gray’s test: P=0.30) while the 6-year cumulative incidences of death were 18% and 9% (Gray’s test: P=0.07). In the ALL-4 trial in adult patients with acute lymphoblastic leukemia or lymphoblastic lymphoma, treatment with dexamethasone did not show any advantage over treatment with prednisolone.

Background and Objectives. In the EORTC ALL-3 trial, the efficacy of allogeneic transplantation was compared with that of autologous marrow transplantation and maintenance chemotherapy in patients less than or equal to 50 years who reached CR. Design and Methods. Among 340 patients who entered the study, 279 were less than or equal to 50 years old. Out of these, 220 reached CR, 184 patients started consolidation and were HLA typed ; 68 had a donor and 116 had no sibling donor. The median follow-up was 9.5 years ; 93 patients relapsed, 26 died in CR, and overall 116 patients died. Allogeneic transplantation was performed in 47 (68%) patients with a donor while autologous transplantation or maintenance chemotherapy was given to 84 (72%) patients without a sibling donor. Results. The 6-year disease-free survival rate was similar in the groups with and without donor [38.2% (SE=5.9%) vs. 36.8% (SE=4.6%), hazard ratio 1.01, 95% CI 0.67-1.53]. Comparing the donor group with the no donor group, the former had a lower relapse incidence (38.2% vs. 56.3%, p=0.001), but a higher cumulative incidence of death in CR (23.5% vs. 6.9%, p=0.0004). The 6-year survival rates were similar [41.2% (SE=6.0%) vs. 38.8% (SE=4.6%)]. Interpretation and Conclusions. This trial did not show that allogeneic transplantation, when a sibling donor is available, produces a better outcome than the policy of offering autotransplantation or chemotherapy in the absence of a donor.

B-cell chronic lymphocytic leukemia (B-CLL) is generally considered as a malignant disorder characterized by an accumulation of resting clonal B lymphocytes related to defective apoptosis. The cyclin dependent kinase inhibitor p27kip1 is known to play an important role in G0/G1 cell cycle arrest. We reported recently that high p27 expression was strongly correlated with a shorter doubling time and associated with a poorer prognosis in B-CLL (Blood, 91, 4694, 1998). In vitro, we observed an increased spontaneous survival of B-CLL cells expressing high p27 levels in contrast to cells that expressed low p27 levels. Interleukin-4 (IL4), which promotes B cell survival, was found to upregulate p27 in B-CLL cells in vitro. Conversely, after a 5 day exposure to fludarabine, which induces apoptosis, there was a decrease in p27 expression. When considering earlier times of culture, before any significant decrease of p27 protein level, we noticed the expression of a protein running at approximately 23 kDa. This protein was detected on Western blot analysis when using an antibody against p27 N terminus, but an antibody against the C terminus of p27 failed to detect it. Therefore p23 was likely to correspond to a p27 molecule truncated at the C terminus. The p23 was undetectable in samples studied before culture or in the presence of IL4. In these conditions, percentage of apoptotic cells, as assessed by TUNEL method and by FITC-annexin V staining, was less than 5%. Expression of p23 was not specific of fludarabine, as p23 was detected in samples exposed to other proapoptotic drugs such as etoposide or corticosteroids. This proteolytic cleavage was associated with the apoptotic process and appeared as soon as after a 6 hours drug exposure. Recently, caspases (cysteine aspartate specific proteases) were shown to play a central role in apoptosis. Recent studies report that cleavage of cell cycle regulator proteins may contribute to the apoptosis process. We found that p23 results from the proteolytic cleavage of p27 by caspases: a site of potential cleavage for CPP32 is present in the C terminal region of p27, and 2 inhibitors of these caspases (i.e. z-VAD-fmk and ac-DEVD-CHO) prevented truncation of p27 as well as apoptosis in B-CLL cells exposed to fludarabine. The p23 protein lacks the C terminal region of p27 which contains a nuclear localization signal and Western blot analysis on nuclear and cytoplasmic extracts revealed that p23 was strictly intracytoplasmic. Conversely, the cdk binding site, located in the amino-terminal region, is unaffected. This could suggest a putative role for p23 in cell cycle control and apoptosis. In samples exposed to fludarabine, we found a substantial cdk-4 activity contrasting with undetectable activity in untreated cells. As cdk-4 in B-CLL appears mostly cytoplasmic, p23 is likely to prevent p27 access to cdk-4 and subsequently its inhibition. Therefore, we hypothesize that, after proapoptotic drug exposure, p23 might actively contribute to the onset of apoptosis.