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Abstract 685 Background: In 2004 we have shown that first-line intensive therapy plus transplantation of autologous hematopoietic stem cells lead to an improved EFS and OS over standard CHOP regimen in adults with disseminated aggressive lymphomas (NEJM 2004; 350: 1287). Then the rituximab era came. We have shown that the addition of R to the intensive therapy was feasible and might further improve the results (BBMT 2010; 16: 672). We present here the preliminary analysis of a multicenter randomized trial aiming at comparing the results of R- CHOP every 14 days to R- HDT in adults with untreated confirmed DLBCL (clinical trial.gov: NCT 00561379). Methods: The patients were 18 to 60 y.o. with CD20 + DLBCL Ann Arbor stage 1 or 2 with bulk >/= 7 cm or 3 and 4 were randomized at diagnosis (with a stratification according to age adjusted IPI) between R-CHOP every 14 days at standard doses (8 consecutive courses if a response was observed after the first 4 courses) and R-HDT. This program consisted of 2 courses of high-dose CHOP-like regimen, 15 days apart, with rituximab (375/mg/m2) on day 1 of each course, followed by rituximab on d 22, harvest of G-CSF mobilised peripheral blood stem cells on d 28,29, then rituximab on d 36 followed by a course of high-dose methotrexate with cytarabin. For patients who achieved at least a partial response after these 3 courses, a BEAM regimen started on d 66 to 80 followed by the infusion of stem cells. In each arm, the intermediate evaluation of response was assessed by means of standard CT Scan and PET. Patients not achieving a PR or a negative PET were proposed a salvage Tx followed in case of response by an autologous transplantation. The main objective of the study was the EFS with an event defined as insufficient intermediate response, progression, relapse or death. Analysis was performed on intent to treat basis. Results: 331 pts were included from 01/2005 to 05/2010. 305 patients were found eligible and 286 are fully evaluable at time of this abstract, 143 in each arm. The main characteristics of the pts in the 2 arms are strictly super imposable. Overall 56% had a bulk as defined, 72% had a 3 or 4 AA stage and 58% had an aa IPI 2 or 3. The treatment as scheduled in the protocol was completed in 71% in the R-CHOP arm and 60% in the R-HDT arm. The intermediate evaluation showed exactly the same rate of response with Standard CT scan (CR + CRu: 65% and 62% following 4 courses R-CHOP and first 3 courses of R-HDT respectively). PET remained significantly more often + after the first 3 courses of R-HDT (43% vs 30% following 4xR-CHOP; p=0.03). The ORR (CR + Cru) was 78% and 71% in the R-CHOP and R-HDT arms respectively (p=0.8). With a med FU of surviving patients of 25 m, the probability of survival for the whole group of patients is 88% and 74% at 2 and 5 years. There is no significant difference according to the treatment arm in any of the aaIPI strata. The EFS with the standard CT Scan as an intermediate evaluation is 74% and 66% at 2y and 5 y with no difference according to the treatment arm in any aaIPI strata. The EFS with PET scan as an intermediate evaluation is 49% and 45% at 2y and 5 y and is statistically worse with R-HDT for aaIPI 2 and 3 pts (p=0.01). Conclusion: Based on these results, one cannot recommend first-line R-HDT as performed in that trial for adult patients with DLBCL. R-CHOP 14 is as efficient, less toxic and spares resources. Disclosures: Milpied: Roche: Membership on an entity's Board of Directors or advisory committees.

The French group, GOELAMS, performed a multicenter phase III randomized open trial to evaluate whether adding androgens to post-remission induction therapy was associated with an improved outcome in elderly pts with de novo AML. All patients received the ICL induction protocol (idarubicin 8mg/m2 day1–5, cytarabine 100mg/m2 day1–7 & lomustine 200mg/m2 day1). Patients in complete or partial remission received maintenance therapy consisting in 6 reinduction courses (idarubicin 8mg/m2 day1, cytarabine 100mg/m2 day1–5.), once every 3 months, with a continuous regimen of methotrexate and 6-mercaptopurine in-between these. At diagnosis, patients were randomized to receive (AndroG arm) or not (Control arm) norethandrolone 10 to 20 mg per day, according to body weight. Androgen was started after recovery from aplasia, between day-20 and day-30 following induction chemotherapy, and was to be continued during the 2-year maintenance therapy period if a complete or partial remission was achieved following induction chemotherapy. The two arms were well-balanced for known prognostic factors. Between June 2002 and January 2005, 330 patients with de novo AML and age 60 y (median 70, range 60–86) were included. Pts with acute promyelocytic leukemia were not included. At diagnosis, ECOG was 0–1, 2, 3–4 in 270, 55, and 5 cases; WBC count was < 4 G/L, > 30 G/L, > 100 G/L in 141, 85, and 33 pts. Of note, 61% of the pts with a WBC count < 4 G/L were males, and 52% of males had a low WBC count vs 33% of females (p Results: Crude univariate analyses regarding the effect of androgen randomization on 5-year relapse incidence, LFS, EFS and OS are listed in Table 1. Table 1 Full time period from diagnosis HR, hazard ratio; CI, confidence interval; Cox p-val, p-value of Cox regression model. Endpoints Control AndroG Gray test p-val HR; 95%CI Cox p-val Relapse 66% 54% 0.21 -- -- LFS 23% 33% -- 0.79; 0.58–1.09 0.15 EFS 16% 22% -- 0.95; 0.75–1.22 0.69 OS 19% 26% -- 0.96; 0.74–1.23 0.72 Of note, the effect of norethandrolone on relapse incidence, LFS, EFS, and OS, was violating the proportional hazards assumption (scaled Schoenfeld residuals analysis). Since the 2 hazards rate functions crossed each other, which would result in ineffective comparisons if using log-rank tests, time-dependent models were considered. For all these endpoints, as estimates for the 2 arms were not significantly different during the first year, but diverged during the following years, favoring the AndroG arm (Table 2, Figure 1), a step-function at 1 year from diagnosis was considered. Table 2 Time period starting 1 year from diagnosis Endpoints Control AndroG Gray test p-val HR; 95%CI Cox p-val Relapse 55% 33% < 0.01 -- -- LFS 37% 54% -- 0.56; 0.33–0.94 0.028 EFS 32% 52% -- 0.57; 0.36–0.89 0.013 OS 37% 60% -- 0.63; 0.41–0.96 0.034 Figure Figure Thus, for pts alive and in complete remission at 1 year from diagnosis, relapse incidence was lower, while LFS, EFS and OS were higher in the AndroG arm, even after adjusting for other significant covariates (p=0.029 Relapse; p=0.038 LFS; p=0.028 EFS; p=0.029 OS). Moreover, the beneficial effect of norethandrolone was more pronounced in males, and in pts having WBC count < 4 G/L as shown in Figure 2 for the LFS. Figure Figure Conclusion: addition of low-dose norethandrolone to maintenance chemotherapy is associated with an improved outcome in elderly pts with AML; especially in those achieving CR and remaining in remission for at least a year. Improved outcome was observed with androgen in males and/or in pts with low proliferative disease.

In an attempt to improve the outcome of acute myeloid leukemia in older patients, we performed a multicenter randomized trial evaluating the possible benefit of androgens during post remission therapy. All patients received the ICL regimen as induction (Idarubicin, 8mg/m2 d1–5; Cytarabine, 100mg/m2 d1–7 and Lomustine, 200mg/m2 d1). All patients were randomized at the time of diagnosis to receive, after achieving CR or PR, a maintenance therapy including or not androgens. Maintenance therapy consisted of 6 courses of reinduction with idarubicin (8mg/m2 d1) and cytarabine (100mg/m2d1–5, subcutaneously) every 3 months, and, between these courses, a continuous regimen of methotrexate and 6-mercaptopurine. Patients randomized with androgens additionally received 10 to 20 mg according to body weigh of norethandrolone daily from CR/PR on, for up to 2 years. Between June 2002 and January 2005, 330 patients aged ≥ 60 years (median 70 yrs, range 60–86) were included. CR, PR, failure and death rates after induction were 69 %, 6%, 9% and 15% respectively. The median follow-up for the 330 patients was 26 months. Among the 249 patients who achieved remission, 119 had been randomized with norethandrolone and 130 without. The 2 arms were balanced according to age, sex-ratio, performance status, FAB, WBC as well as platelets counts, peripheral blood and bone marrow blasts counts and cytogenetic groups (low risk: t(8;21), inv(16); high risk: del(5), del(7), del(11q), complex karyotype; standard-risk: normal karyotype and other aberrations). Differences in CR rates were only related to the latter parameter of cytogenetic features (P = 0.005). For the whole cohort of patients DFS at 3-years was 23±3% (median 13 months) and OS at 3 years was 29±3% (median 15 months). For patients who achieved CR or PR and had been randomized, the addition of androgens did not influence either DFS (P = 0.6) or OS (P = 0. 9), even when considering age groups, high/low WBC, or cytogenetic features. In conclusion, the ICL regimen followed by six reinductions and two years maintenance therapy induce high CR rates and improve OS and DFS. However the addition of androgens did not decrease the relapse rate.