The combination of interferon and cytarabine, as compared with interferon alone, increases the rate of major cytogenetic response and prolongs survival in patients with the chronic phase of chronic myelogenous leukemia.

, for the GOELAMS (Groupe Ouest-Est des Leucé mies Aiguë s et Maladies du Sang) GroupVarious transplantation strategies have been designed to improve the poor prognosis of adult (ages 15 to 60 years) acute lymphoblastic leukemia (ALL). The GOELAL02 trial evaluated the impact of early allogeneic bone marrow transplantation (alloBMT) or delayed unpurged autologous stem cell transplantation (ASCT) for patients who had no human leukocyte antigen (HLA)-matched sibling donor or who were older than 50 years. Inclusion criteria included at least one of the following: age older than 35 years; non-T-ALL; leukocytosis greater than 30 ؋ 10 9 /L; t(9;22), t(4;11), or t(1; 19); or failure to achieve complete remission (CR) after one induction course. Among 198 patients, the median age was 33 years. The CR rate was 80% with vincristine, idarubicine, L-asparaginase, and randomized intravenous injection or oral steroids (P ‫؍‬ nonsignificant [ns]). AlloBMT was performed after 2 consolidation courses while ASCT was delayed after 1 additional reinduction. Intensified conditioning regimen before transplantation included etoposide, cyclophosphamide, and total body irradiation (TBI). Median follow-up was 5.1 years. The median overall survival (OS) was 29 months, with a 6-year OS of 41%. On an intent-to-treat analysis for patients younger than 50 years, alloBMT significantly improved the 6-year OS (75% versus 40% after ASCT; P ‫؍‬ .0027). Randomized interferon-␣ maintenance had no effect on relapse or survival after ASCT. In conclusion, the outcome of adult ALL is better after early alloBMT than after delayed ASCT. (Blood. 2004; 104:3028-3037)

BackgroundThe effects of L-asparaginase on hemostasis during induction chemotherapy are less defined in adults than in children. We, therefore, studied the effects of L-asparaginase in adult patients.

Acute lymphoblastic leukemia (ALL) in the elderly is characterized by its ominous prognosis. On the other hand, imatinib has demonstrated remarkable, although transient, activity in relapsed and refractory Philadelphia-positive acute lymphoblastic leukemia (Ph þ ALL), which prompted us to assess the use of imatinib in previously untreated elderly patients. ALL patients aged 55 years or older were given steroids during 1 week. Ph þ ve cases were then offered a chemotherapy-based induction followed by a consolidation phase with imatinib and steroids during 2 months. Patients in complete response (CR) after consolidation were given 10 maintenance blocks of alternating chemotherapy, including two additional 2-month blocks of imatinib. Thirty patients were included in this study and are compared with 21 historical controls. Out of 29 assessable patients, 21 (72%, confidence interval (CI): 53-87%) were in CR after induction chemotherapy vs 6/21 (29%, CI: 11-52%) in controls (P ¼ 0.003). Five additional CRs were obtained after salvage with imatinib and four after salvage with additional chemotherapy in the control group. Overall survival (OS) is 66% at 1 year vs 43% in the control group (P ¼ 0.005). The 1-year relapse-free survival is 58 vs 11% (P ¼ 0.0003). The use of imatinib in elderly patients with Ph þ ALL is very likely to improve outcome, including OS.

G-CSF should be administered routinely after ICC to reduce the duration of neutropenia and hospitalization. However, G-CSF did not seem to significantly increase the feasibility of this two-course program or modify overall outcome.

The LAM2001 phase 3 trial, involving 832 patients with acute myeloid leukemia (AML; median: 46 years) proposed HLAidentical sibling allograft HSCT for all patients with an identified donor. The trial compared reduced-intensity conditioning (RIC) for patients older than 50 years of age (N ‫؍‬ 47) and myeloablative conditioning for younger patients (N ‫؍‬ 117). BM HSCT was performed in the younger patients, while the older ones received a consolidation course, followed by peripheral blood allo-HSCT using RIC. The incidence of grade II-IV acute GVHD, was 51.9% (95% confidence interval [CI]: 42.1-61.8) and 11.3% (1.6-21.2) after myeloablative or RIC, respectively (P < .0001) and that of chronic GVHD 45.8% (95% CI: 34.8-56.7) and 41.7% (24.7-58.6; NS). Cumulative incidence of nonrelapse mortality at 108 months was 15.8% (95% CI: 9.8-23.2) for myeloablative, and 6.5% (0.2-16.2) for RIC (NS). CI of relapse at 108 months was 21.7% (95% CI: 13.9-28.6) and 28.6% (16.5-43.4; NS). Overall survival at 108 months was 63.4% (95% CI: 54.6-72.2) and 65.8% (52.2-72.2), respectively, after myeloablative or RIC (NS). RIC peripheral blood stem cell allo-HSCT is prospectively feasible for patients between the ages of 51 and 60 years without excess of relapse or nonrelapse mortality, and compares favorably with myeloablative marrow allo-HSCT proposed to younger patients. This study was registered at clinicaltrials.gov as no. NCT01015196. (Blood. 2012;119(12):2943-2948) IntroductionGreat progress has been achieved since the introduction of aracytine and anthracyclins in the initial management of patients with acute myeloid leukemia (AML); complete remission (CR) rates have considerably improved, most failures being attributable to early death rather than induction toxicity. 1 However, the rate of relapse remains unacceptable, and new strategies are required to improve the long-term outcome of AML patients. Part of the progress can be attributed to postremission chemotherapy, 2 but HSCT is another consideration, be it autologous or allogeneic, the latter with related or unrelated donors.In the recent years, the Groupe Ouest-Est d'étude des Leucémies Aiguës et autres Maladies du Sang (GOELAMS) group has indeed developed risk-adapted strategies to improve the outcome of patients with AML in first remission. The trial reported here, designed in 2001, tested different strategies in relation to HSCT. For patients lacking genoidentical donors, one aim was to compare intensive consolidation followed by 1 or 2 autologous peripheral stem cell transplantation(s) (SCT). 3 For patients with a sibling donor, the second aim proposed an early allo-HST with an age-adapted conditioning regimen. A myeloablative regimen was applied for patients younger than 50 years of age. For patients between 50 and 60 years of age, a reduced-intensity conditioning (RIC) regimen was applied after an early intensification and before allo-HSCT. The results of the allogeneic HSCT arm of this trial are presented here, showing that this strategy yielded similar results in th...

for the Groupe Ouest Est Leucé mies Aiguë s Myé loblastiques (GOELAMS)Based on our previous demonstration that quinine could be used clinically to reverse P-glycoprotein-mediated resistance, we designed a multicenter, randomized trial aiming to determine whether quinine would improve the survival of adult patients (15-60 years old) with de novo acute myelogenous leukemia (AML). These patients randomly received (n ‫؍‬ 213) or did not receive (n ‫؍‬ 212) a 30 mg/kg/day continuous intravenous infusion of quinine in combination with induction chemotherapy combining idarubicine and cytarabine and, depending on bone marrow examination at day 20, an additional course of cytarabine and mitoxantrone. The mean steady-state quinine concentration was 7.8 mg/L and the mean multidrug resistance reversing activity of serum was 1.96. Complete remission (CR) was obtained in 344 patients (80.9%) without significant influence of quinine. Of the patients in complete remission, 82 were assigned to receive HLA-matched bone marrow transplants, whereas 262 were assigned to 2 courses of intensive consolidation chemotherapy, with or without quinine, depending on initial randomization. The 4-year actuarial overall survival (OS) of the 425 eligible patients was 42.0% ؎ 2.5%, without significant influence of quinine. Of 160 patients who could be studied, 54 demonstrated rhodamine 123 efflux. In these patients, quinine significantly improved the CR rate from 12 of 25 (48.0%) to 24 of 29 (82.8%) (P ‫؍‬ .01). However, there was no significant difference in OS. Neither mdr1 gene nor P-glycoprotein expression influenced the outcome. We conclude that quinine does not improve the survival of adult patients with de novo AML, even though it improves CR rate in a small subgroup of patients defined by rhodamine 123 efflux.

decreased activity against HMC-1.2 cells (IC 50 ¼ 15 mM). Dasatinib inhibited proliferation of both cell lines, albeit with 2-3 log less potency against HMC-1.2 as compared to HMC-1.1 (IC 50 ¼ 308 and 1 nM, respectively).We found KIT and JAK2 to be constitutively phosphorylated in HMC-1.1 and HMC-1.2 cells, in the absence of exogenous cytokines (Figure 1). Consistent with observations from aforementioned in vitro enzyme assays, TG101348 did not inhibit phosphorylation of KITV560G or KITD816V within the context of the two HMC-1 clones at concentrations up to 25 mM (Figure 1, top panel). In contrast, imatinib mesylate potently inhibited the kinase activity of KITV560G, but not KITD816V, with IC 50 for receptor phosphorylation of o150 and 425 mM, respectively ( In summary, we have shown the viability of targeting JAK-STAT signaling downstream of KITD816V in human mast cell leukemia cells as a potentially novel therapeutic approach in SM. Our experience to date with currently available JAK2-selective drugs, such as TG101348, which are orally bioavailable and have a favorable safety profile, leads us to believe that clinical trials with such agents for SM therapy are warranted. Recent clinical experience with TG101348 has shown that it is feasible to achieve serum drug concentrations that are predicted, based on our data, to be therapeutically relevant in SM. The concurrent use TG101348 and dasatinib targets known signaling pathways of major pathogenetic relevance in SM, namely KIT, JAK-STAT and SRC; this approach is clinically feasible given the synergy between the two drugs that should permit therapeutic activity to be manifest at doses that are lower than those used as monotherapy, thereby preserving an overall favorable therapeutic safety profile.