Key Points• Initial imatinib-based therapy of Ph1 adult ALL is associated with lower early mortality and higher CR rate.• In adults with Ph1 ALL, allogeneic SCT in first CR prolongs relapse-free survival and OS.In this study, we randomly compared high doses of the tyrosine kinase inhibitor imatinib combined with reduced-intensity chemotherapy (arm A) to standard imatinib/hyperCVAD (cyclophosphamide/vincristine/doxorubicin/dexamethasone) therapy (arm B) in 268 adults (median age, 47 years) with Philadelphia chromosome-positive (Ph1) acute lymphoblastic leukemia (ALL). The primary objective was the major molecular response (MMolR) rate after cycle 2, patients being then eligible for allogeneic stem cell transplantation (SCT) if they had a donor, or autologous SCT if in MMolR and no donor. With fewer induction deaths, the complete remission (CR) rate was higher in arm A than in arm B (98% vs 91%; P 5 .006), whereas the MMolR rate was similar in both arms (66% vs 64%). With a median follow-up of 4.8 years, 5-year event-free survival and overall survival (OS) rates were estimated at 37.1% and 45.6%, respectively, without difference between the arms. Allogeneic transplantation was associated with a significant benefit in relapse-free survival (hazard ratio [HR], 0.69; P 5 .036) and OS (HR, 0.64; P 5 .02), with initial white blood cell count being the only factor significantly interacting with this SCT effect. In patients achieving MMolR, outcome was similar after autologous and allogeneic transplantation. This study validates an induction regimen combining reduced-intensity chemotherapy and imatinib in Ph1 ALL adult patients and suggests that SCT in first CR is still a good option for Ph1 ALL adult patients. This trial was registered at www.clinicaltrials.gov as #NCT00327678. (Blood. 2015;125(24):3711-3719)

Fifty-four percent of adults with acute lymphoblastic leukemia (ALL) who entered the LALA-94 trial experienced a first relapse. We examined the outcome of these 421 adult patients. One hundred and eighty-seven patients (44%) achieved a second complete remission (CR). The median disease-free survival (DFS) was 5.2 months with a 5-year DFS at 12%. Factors predicting a better outcome after relapse were any transplant performed in second CR (Po0.0001), a first CR duration 41 year (P ¼ 0.04) and platelet level 4100 Â 10 9 /l at relapse (P ¼ 0.04). Risk groups defined at diagnosis and treatment received in first CR did not influence the outcome after relapse. The best results were obtained in a subset of patients who were eligible for allogeneic stem cell transplantation (SCT). Genoidentical allogeneic SCT was performed in 55 patients, and 3 patients received donor lymphocyte infusions. Forty-four transplantations were performed from an unrelated donor (of which four were cord blood). We conclude that most adult patients with recurring ALL could not be rescued using current available therapies, although allogeneic SCT remains the best therapeutic option.

Many somatic genetic abnormalities have been identified in T-cell acute lymphoblastic leukemia (T-ALL) but each individual

Because of a high CR rate, induction chemotherapy should be considered systematically for elderly patients who have AML with t(8;21) or inv(16). The high risk of relapse suggests that alternative strategies of postremission therapy are warranted.

The 90-kDa heat shock protein (HSP90) is implicated in the conformational maturation and stabilization of a variety of client proteins with receptor and signal transduction functions. The objective of this study was to assess its expression in primary acute myeloid leukemia (AML) cells and to evaluate its biological and clinical significance. The in vitro effects of 17-AAG, a selective inhibitor of HSP90, was also evaluated. Cells from 65 patients with newly diagnosed AML were studied. The expression of HSP90 correlated with that of CD34, p170, and bcl-2 proteins but not with white cell counts, FAB or WHO subtype, or cytogenetics. HSP90 levels were also higher in samples exhibiting an autonomous growth in liquid culture or forming spontaneous colonies. A concomitant constitutive activation of the extracellular signal-regulated kinase and phosphatidylinositol 3-kinase/AKT pathways was observed in a majority of samples and was significantly correlated with HSP90 expression. All patients received induction chemotherapy. The percentages of HSP90-, CD34-, bcl-2-, and p170-positive cells were higher in patients who did not attain complete remission. Survival was also shorter in patients with high levels of HSP90. In vitro exposure of leukemic cells to 17-allylamino-demethoxy geldanamycin (17-AAG) resulted in inhibition of growth in liquid and clonogeneic cultures and in apoptosis, at concentrations which in most cases were not toxic for normal CD34-positive or progenitor cells. The concentration inhibiting 50% growth at 72 h in liquid culture correlated with HSP90 expression. Our study suggests that HSP90 is overexpressed in poor-prognosis AML cells and plays a role in cell survival and resistance to chemotherapy. Targeted therapy with 17-AAG represents a promising antileukemic strategy in adult AML.

Key Points• GO before transplant improves outcome of CBF-AML patients in first relapse.Although core-binding factor-acute myeloid leukemia (CBF-AML) (t[8;21] (range, 16-76). Median first complete remission duration was 12.1 months (range, 2.1-93.6). Overall, second complete remission (CR2) rate was 88%. With a median follow-up from relapse of 3.5 years, the estimated 5-year disease-free survival (DFS) was 50% and 5-year overall survival (OS) was 51%. Older age and shorter first complete remission duration was associated with a shorter OS. Patients treated with GO had similar CR2 rate but significantly higher 5-year DFS (68% vs 42%; P 5 .05) and OS (65% vs 44%; P 5 .02). In multivariate analysis, GO salvage was still associated with a significant benefit in DFS and OS. In the 78 patients who received allogeneic hematopoietic stem cell transplantation in CR2, GO before transplant significantly improved posttransplant DFS and OS without excess of treatment-related mortality. (Blood. 2014;124(8):1312-1319

Despite recent progress in the understanding of acute lymphoblastic leukemia (T-ALL) oncogenesis, few markers are sufficiently frequent in large subgroups to allow their use in therapeutic stratification. Low ERG and BAALC expression (E/B low ) and NOTCH1/FBXW7 (N/F) mutations have been proposed as powerful prognostic markers in large cohorts of adult T-ALL. We therefore compared the predictive prognostic value of N/F mutations versus E/B low in 232 adult T-ALLs enrolled in the LALA-94 and Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) protocols. The outcome of T-ALLs treated in the pediatricinspired GRAALL trials was significantly superior to the LALA-94 trial. Overall, 43% and 69% of adult T-ALL patients were classified as E/B low and N/F mutated, respectively. Strikingly, the good prognosis of N/F mutated patients was stronger in more intensively treated, pediatricinspired GRAALL patients. The E/B expression level did not influence the prognosis in any subgroup. N/F mutation status and the GRAALL trial were the only 2 independent factors that correlated with longer overall survival by multivariate analysis. This study demonstrates that the N/F mutational status and treatment protocol are major outcome determinants for adults with T-ALL, the benefit of pediatric inspired protocols being essentially restricted to the N/F mutated subgroup. (Blood. 2011;118(19):5099-5107) IntroductionThe outcome of acute lymphoblastic leukemia (ALL) has been considerably improved in pediatric cases, with 5-year overall survival (OS) rates now reaching Ͼ 80%. 1 In adults with Philadelphia chromosome (Ph)-negative ALLs, even if the complete remission (CR) rate reaches 90%, long-term therapeutic results remain less satisfactory, with a 5-year OS rate of 45%. 1 The Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) study group recently reported a significant improvement in the outcome of Ph-negative adult ALL using a pediatric-inspired, intensified treatment protocol. 2 T-ALL corresponds to a heterogeneous group of acute leukemias, which account for 35% of Ph-negative adult ALLs. The classic initial prognostic factors used for ALL therapeutic stratification are predominantly clinical: age, WBC count, and CNS involvement. 3 These undoubtedly identify prognostically distinct subgroups among patients with B lineage ALL, but they are less appropriate for the stratification of T-ALL.Although recent advances have led to spectacular progress in the understanding of T-ALL oncogenesis, 4 the large number of molecular markers identified in this process and the fact that most are only present in minor subgroups limit their use for therapeutic stratification. Recognized oncogenic pathways in T-ALL include transcriptional activation of several proto-oncogenes, submicroscopic deletions of tumor suppressor genes, and NOTCH1 and/or FBXW7 mutations. 5,6 The NOTCH1 signaling pathway has been shown to be an essential factor in normal and pathologic T lymphoid development. 7,8 In T-ALL, NOTCH1 abnormalities The online v...

2002 in one institution. We reviewed the clinical, surgical and histological charts of 151 such patients who had a RPLND after first-line platinum-based chemotherapy. The recommendations used to define conformity to RPLND standards were: the indication based on initial and residual lymph node size, shrinkage, extension of dissection and completeness of resection. RESULTSRPLND conformed to standard recommendations in 70 of the 151 (46%) patients. Conformity was complete for the surgeon who operated on 48 patients and was 26% of the others. Fifteen patients (10%) relapsed in the retroperitoneum, 14 of whom had initial lymph nodes of ≥ 5 cm. Two patients (3%) relapsed in the group of 70 patients with conformed and complete RPLND, vs 13 (16%) in the 81 with conformed but incomplete resection or with non-conformed and complete or incomplete RPLND. After a median (range) follow-up of 77 (1.3-186.5) months 132 patients were alive with no evidence of disease, 18 died and one was alive with progressive disease. The limitations of this study were the relatively few patients and that it was retrospective. CONCLUSIONThere was conformity of RLNPD to the recommendations, and completeness of resection, in half of the patients operated; this might have an effect on oncological outcome. Our data suggest that patients should be treated in tertiary centres.