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Not all patients with core binding factor acute myeloid leukemia (CBF-AML) display a good outcome. Modern risk factors include KIT and/or FLT3 gene mutations and minimal residual disease (MRD) levels, but their respective values have never been prospectively assessed. A total of 198 CBF-AML patients were randomized between a reinforced and a standard induction course, followed by 3 high-dose cytarabine consolidation courses. MRD levels were monitored prospectively. Gene mutations were screened at diagnosis. Despite a more rapid MRD decrease after reinforced induction, induction arm did not influence relapse-free survival (RFS) (64% in both arms; P = .91). Higher WBC, KIT, and/or FLT3-ITD/TKD gene mutations, and a less than 3-log MRD reduction after first consolidation, were associated with a higher specific hazard of relapse, but MRD remained the sole prognostic factor in multivariate analysis. At 36 months, cumulative incidence of relapse and RFS were 22% vs 54% (P < .001) and 73% vs 44% (P < .001) in patients who achieved 3-log MRD reduction vs the others. These results suggest that MRD, rather than gene mutations, should be used for future treatment stratifications in CBF-AML patients. This trial was registered at EudraCT as #2006-005163-26 and at www.clinicaltrials.gov as #NCT 00428558.

International audience; We report here the results of the GRAAPH-2003 trial with long-term follow-up in 45 patients with de novo Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Imatinib-based strategy improved the 4-year overall survival (OS) up to 52% versus 20% in the pre-imatinib LALA-94 trial (P = .0001). Despite the selection in patients who actually underwent transplantation, these results suggest that allogeneic or autologous stem cell transplants (SCTs) still have a place in overcoming the poor prognosis of Ph+ ALL in the era of imatinib therapy. OS was 50% after allogeneic SCT (24 patients), 33% in patients without a transplantation (9 patients), and 80% after autologous SCT (10 patients without allogeneic donor or >55 years, including 7 patients in complete molecular response).

Background Allogeneic stem cell transplantation (alloSCT) is the only curative treatment for most patients with CN AML. It is now well established that some relevant molecular markers can allow for the definition of risk groups after conventional chemotherapy. However, the role of these markers among other factors influencing outcome after alloSCT remains to be defined. Hence, we conducted an EBMT registry-based analysis aiming to define the exact prognostic role of molecular subgroups in conjunction with other classical risk factors after alloSCT for CN-AML. Patients, Methods and Results 752 adults (375 males) fulfilled the inclusion criteria, i.e. first alloSCT for CN-AML between 2000 and 2011, matched sibling (MSD) or unrelated (MUD) donor, and known mutational status of FLT3-ITD and NPM1, the two most frequently observed molecular markers in CN-AML. Median age was 51y (range, 18-71), disease status at time of alloSCT was CR1 (n=554), CR2/3 (n=90), primary induction failure (PIF, n=39), relapsed disease (n=62) and unknown (n=7). Myeloablative and reduced-intensity conditioning regimens were used in 371 and 378 patients, respectively. 597 received allogeneic PBSCs. With a median follow-up of 27 months, The 2-year estimates of overall survival (OS) and leukemia-free survival (LFS) were respectively 68±2% and 61±6% after alloSCT in CR1, 63±2% and 53±6% in CR2/3, 36±7% and 33±8% in PIF, and 28±7% and 25±6% in relapsed disease. In 554 patients transplanted in CR1, OS, LFS, cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were calculated according to molecular subgroups. Whereas NPM1mut had no influence on outcome, FLT3-ITD was associated with increased CIR (p . A multivariate Cox model of predefined risk factors including age, WBC at diagnosis, time to reach CR1, donor type, conditioning type (reduced vs. standard), and presence of NPM1mut and FLT3-ITD, was performed. Age >=50 years was the only risk factor for NRM (HR= 2.40, 95%CI: 1.32-4.37), while the presence of FLT3-ITD was the only risk factor for CIR (HR=2.85; 95%CI; 1.76-4.60). Both age >=50 years and FLT3-ITD were associated with inferior LFS (HR=1.65, 95%CI: 1.14-2.39, p=0.01 for age, HR=2.08, 95%CI: 1.43-3.01, p=0.001 for FLT3-ITD) and, most importantly, OS (HR=1,76; 95%CI: 1.19-2.61, p=0.005 for age, and HR=2.19; 95%CI: 1.48-3.26, p=0.0001 for FLT3-ITD). The latter data allowed to identify 3 prognostic groups with 2-years OS of 83±4% (younger age and FLT3-ITDneg), 70±4% (older age OR FLT3-ITD) and 48±5% (older age and FLT3-ITD), p Conclusion In the largest study on CN-AML performed thus far, we identified age >=50 years and FLT3-ITD as the major risk factors for OS after alloSCT in CR1, independently from other risk factors such as type of donor or conditioning. In patients harboring FLT3-ITD, a limited protective role for NPM1 mutation could be observed. These results underscore the importance of post-transplant strategies to prevent relapse in AML with FLT3-ITD. Encouraging results were observed after SCT in PIF, relapse or advanced CR. Disclosures: Schmid: Novartis: Honoraria, Research Funding, travel grant Other; Roche: travel grant, travel grant Other; MSD: Honoraria. Rambaldi:Novartis: Honoraria; Sanofi: Honoraria; Italfarmaco: Honoraria.

International audience; IL-34 is a recently identified cytokine that signals via the M-CSF receptor and promotes monocyte survival. Depending on the environment, monocytes can differentiate into macrophages (MQ) or dendritic cells (DC). A wide spectrum of MQ and DC subsets, with distinct phenotypes and functions, has been described. To date, the phenotype of monocytes exposed to IL-34 remains unexplored. We report here that IL-34 induces the differentiation of monocytes into CD14 high CD163 high CD1a 2 MQ (IL-34-MQ). Upon LPS stimulation, IL-34-MQ exhibit an IL-10 high IL-12 low M2 profile and express low levels of the costimulatory molecules CD80 and CD86. IL-34-MQ exhibit poor T cell costimulatory properties, and have potent immunosuppressive properties (decrease of TCR-stimulated T cell proliferation). For all the parameters analyzed, IL-34-MQ are phenotypically and functionally similar to M-CSF-MQ. IL-34 appears as efficient as M-CSF in inducing the generation of immunosuppressive MQ. Moreover, the generation of IL-34-MQ is mediated through the M-CSF receptor, is independent of endogenous M-CSF consumption and is potentiated by IL-6. In an attempt to identify strategies to prevent a deleterious M2 cell accumulation in some pathological situations, we observed that IFNc and GM-CSF prevent the generation of immunosuppressive MQ induced by IL-34. IFNc also switches established IL-34-MQ into immunostimulatory MQ. In conclusion, we demonstrate that IL-34 drives the differentiation of monocytes into immunosuppressive M2, in a manner similar to M-CSF, and that IFNc and GM-CSF prevent this effect.

Purpose Myelodysplastic syndrome with chromosomal translocation t(5;12)(q31-33;p12-13) and eosinophilia is a new entity recently described. Nine cases have been described in adults. We report the first pediatric case with a long follow-up (7 years). Patients and methods An 8-year-old girl presented with hyperleukocytosis, eosinophilia, and no clinical symptoms. Bone marrow investigations revealed myeloid hyperplasia and clonal chromosomal translocation t(5;12)(q31;p12-13). No treatment was prescribed, but 4 years later the white blood cell count reached 144 X 10(9)/L with immature myeloid cells and splenic enlargement. Hydroxyurea chemotherapy led to a hematopoietic remission. The patient is now 16 years old and well, >7 years after the initial diagnosis. Results The association: myelodysplastic syndrome, eosinophilia and translocation t(5;12)(q31-33;p12-13), seems to be a specific hematologic disorder. Study of cases previously reported in the literature shows the most important characteristics of this disease. However, there are still a number of questions about the disease itself (especially its treatment) and the significance of the chromosomal abnormalities. Conclusion This case seems to be the first report of the disease in a child and has had the longest follow-up. Other data should be collected to improve our knowledge of this hematopoietic disorder.

Background The median survival of patients with myeloma after conventional chemotherapy is three years or less. Promising results have been reported with high-dose therapy supported by autologous bone marrow transplantation. We conducted a randomized study comparing conventional chemotherapy and high-dose therapy. Methods Two hundred previously untreated patients under the age of 65 years who had myeloma were randomly assigned at the time of diagnosis to receive either conventional chemotherapy or high-dose therapy and autologous bone marrow transplantation. Results The response rate among the patients who received high-dose therapy was 81 percent (including complete responses in 22 percent and very good partial responses in 16 percent), whereas it was 57 percent (complete responses in 5 percent and very good partial responses in 9 percent) in the group treated with conventional chemotherapy (P

International audience

A double-blind, placebo-controlled trial of BT563, including 13 European centers, was initiated in October 1989 to compare the efficacy of the combination of in vivo anti-CD25 mAb (BT 563), cyclosporine, and steroids versus placebo and CSA-steroids in the treatment of grade II and III acute graft-versus-host disease (GVHD). Sixty-nine patients participated in the study, which excluded non-genotypically identical allogeneic bone marrow transplant recipients. No statistically significant differences were observed, clinically or biologically, between the 2 groups before the onset of the treatment. Treatment responses were scored during and after the 3-week treatment period (mAb or placebo). Efficacy was evaluated on days 4, 10, 20, 30, and 60 or on any day the patient's condition was found to be deteriorating. Preceding and systemically untreated GVHD of grade I was observed in 59% of the cases. No statistically clinically significant differences between the 2 groups were observed during or upon completion of treatment in GVHD grade. Nine patients in the placebo group and 6 in the active group were withdrawn of the study. Thirteen of these 15 patients were withdrawn because of failure of GVHD therapy (9 in the placebo group and 4 in the BT563 group). At day 20 after onset of the treatment, the response rate was 63% and 70% for the placebo and BT563 groups, respectively (NS). Probability of survival at 1 year was 59% and 66% (NS) for the placebo and active groups, respectively. In conclusion, despite preliminary promising results in the treatment of steroid-resistant acute GVHD, the role of first-line treatment with an in vivo anti-interleukin-2 receptor mAb remains to be determined.

From March 1988 to March 1991, 19 French bone marrow transplant (BMT) centers participated in a prospective randomized trial comparing two conditioning regimens for patients with chronic myeloid leukemia transplanted in first chronic phase with an HLA identical sibling donor. A total of 120 consecutive patients were randomized to receive either 120 mg/kg of cyclophosphamide followed by total body irradiation (CY-TBI; n = 55) or 16 mg/kg of busulfan followed by 120 mg/kg of CY (BU-CY; n = 65). Two different TBI regimens were used. Thirteen patients received a 10-Gy single-dose TBI (SDTBI), and 42 received a fractionated TBI (FTBI). Median time between diagnosis and BMT was 315 days. Overall 5-year actuarial survival was 62.9% (65.8% +/- 12.5% for CY-TBI and 60.6 +/- 11.7% for BU-CY; P = .5), and overall disease-free survival was 55% (51% +/- 14% for CY-TBI and 59.1% +/- 11.8% for BU-CY; P = .75). All patients conditioned with CY-TBI experienced sustained engraftment; in contrast, 4 of 65 patients conditioned with BU-CY rejected the graft (P = .18). There was no significant statistical difference between the two groups regarding transplant-related mortality (29% for CY-TBI and 38% for BU-CY; P = .44). So far, with a median follow up of 42 months, 11 patients have relapsed; 9 relapses occurred after CY-TBI, mostly after FTBI (8 of 9) and 2 after BU-CY (P = .02). The actuarial risk of relapse was 4.4% +/- 6.7% after BU-CY, 11.1% +/- 20.8% after SDTBI, and 31.3% +/- 18.1% after FTBI (P = .039). In addition, independently of the conditioning regimen, the increase of posttransplant immunosuppression in 16 patients with an anti- interleukin-2 receptor monoclonal antibody (MoAb) in addition to a short course of methotrexate and cyclosporine was shown to increase the actuarial risk of relapse (57% +/- 30% with MoAb v 9% +/- 7.3% without MoAb; P = .001). We conclude that BU is an acceptable alternative to TBI for patients with chronic myeloid leukemia in first chronic phase receiving BMT from HLA identical sibling donors. Both BU-CY and CY-TBI regimens gave similar transplant-related mortality, and the antileukemic efficiency of BU-CY regimen was either similar or even higher than that of CY-TBI.

Minimal residual disease (MRD) quantification is widely used for therapeutic stratification in pediatric acute lymphoblastic leukemia (ALL). A robust, reproducible, sensitivity of at least 0.01% has been achieved for IG/TCR clonal rearrangements using allele-specific quantitative PCR (IG/TCR-QPCR) within the EuroMRD consortium. Whether multiparameter flow cytometry (MFC) can reach such inter-center performance in ALL MRD monitoring remains unclear. In a multicenter study, MRD was measured prospectively on 598 follow-up bone marrow samples from 102 high-risk children and 136 adult ALL patients, using IG/TCR-QPCR and 4/5 color MFC. At diagnosis, all 238 patients (100%) had at least one suitable MRD marker with 0.01% sensitivity, including 205/238 samples (86%) by using IG/TCR-QPCR and 223/238 samples (94%) by using MFC. QPCR and MFC were evaluable in 495/598 (83%) samples. Qualitative results (

Chromosomal translocations involving the TCR loci represent one of the most recurrent oncogenic hallmarks of T-cell acute lymphoblastic leukemia (T-ALL) and are generally believed to result from illegitimate V(D)J recombination events. However, molecular characterization and evaluation of the extent of recombinase involvement at the TCR-oncogene junction has not been fully evaluated. In the present study, screening for TCRβ and TCRα/δ translocations by FISH and ligation-mediated PCR in 280 T-ALLs allowed the identification of 4 previously unreported TCR-translocated oncogene partners: GNAG, LEF1, NKX2-4, and IL2RB. Molecular mapping of genomic junctions from TCR translocations showed that the majority of oncogenic partner breakpoints are not recombinase mediated and that the regulatory elements predominantly used to drive oncogene expression differ markedly in TCRβ (which are exclusively enhancer driven) and TCRα/δ (which use an enhancer-independent cryptic internal promoter) translocations. Our data also imply that oncogene activation takes place at a very immature stage of thymic development, when Dδ2-Dδ3/Dδ3-Jδ1 and Dβ-Jβ rearrangements occur, whereas the bulk leukemic maturation arrest occurs at a much later (cortical) stage. These observations have implications for T-ALL therapy, because the preleukemic early thymic clonogenic population needs to be eradicated and its disappearance monitored.

The choice of postremission therapy for acute myeloid leukemia (AML) patients is now based on the blasts' cytogenetic and molecular profile. However, the potential benefit of autologous hematopoietic stem cell transplantation (auto-HSCT) according to the NPM1/FLT3-ITD status has been poorly studied in AML patients with a normal karyotype (NK). Therefore, we evaluated the NPM1/FLT3-ITD molecular status in 135 NK-AML patients treated by allogeneic HSCT (allo-HSCT), auto-HSCT, or chemotherapy as consolidation therapy within the GOELAMS LAM-2001 trial. In univariate analyzes, 4-year leukemia-free survival (LFS) and overall survival (OS) were significantly higher for NPM1+/FLT3-ITD- patients compared with patients presenting another molecular profile (61 vs. 43% and 72 vs. 48%, P = 0.02 and P = 0.01, respectively). In the NPM1+/FLT3-ITD- subgroup, there was no benefit for allo-HSCT or auto-HSCT vs. chemotherapy (4-year LFS: 71, 56, and 60%; 4-year OS: 73, 71, and 60%, respectively; P = NS). For patients with other NPM1/FLT3-ITD molecular profiles, allo-HSCT was found to be the best consolidation therapy, whereas auto-HSCT was associated with a better outcome when compared with chemotherapy (allo-HSCT-, auto-HSCT-, and chemotherapy-related 4-year LFS: 68, 44, and 36%, P = 0.004; 4-year OS: 68, 52, and 29%, respectively, P = 0.02). Our study indicates that allo-HSCT and auto-HSCT provide similar outcomes compared with chemotherapy as consolidation for NPM1+/FLT3-ITD- NK-AML patients. For NK-AML patients with an adverse molecular profile, auto-HSCT could represent an alternative therapeutic approach when no human leukocyte antigen-matched allogeneic donor is available.

The LAM2001 phase 3 trial, involving 832 patients with acute myeloid leukemia (AML; median: 46 years) proposed HLA-identical 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.

Background Gene expression profiling has shown its ability to identify with high accuracy low cytogenetic risk acute myeloid leukemia such as acute promyelocytic leukemia and leukemias with t(8;21) or inv(16). The aim of this gene expression profiling study was to evaluate to what extent suboptimal samples with low leukemic blast load (range, 2-59%) and/or poor quality control criteria could also be correctly identified. Methods Specific signatures were first defined so that all 71 acute promyelocytic leukemia, leukemia with t(8;21) or inv(16)-AML as well as cytogenetically normal acute myeloid leukemia samples with at least 60% blasts and good quality control criteria were correctly classified (training set). The classifiers were then evaluated for their ability to assign to the expected class 111 samples considered as suboptimal because of a low leukemic blast load (n = 101) and/or poor quality control criteria (n = 10) (test set). Results With 10-marker classifiers, all training set samples as well as 97 of the 101 test samples with a low blast load, and all 10 samples with poor quality control criteria were correctly classified. Regarding test set samples, the overall error rate of the class prediction was below 4 percent, even though the leukemic blast load was as low as 2%. Sensitivity, specificity, negative and positive predictive values of the class assignments ranged from 91% to 100%. Of note, for acute promyelocytic leukemia and leukemias with t(8;21) or inv(16), the confidence level of the class assignment was influenced by the leukemic blast load. Conclusion Gene expression profiling and a supervised method requiring 10-marker classifiers enable the identification of favorable cytogenetic risk acute myeloid leukemia even when samples contain low leukemic blast loads or display poor quality control criterion.

The Sokal, Hasford and EUTOS scoring systems have been successively proposed to predict the outcome of CML patients in chronic phase (CP-CML), both in terms of disease response and survival. The EUTOS score, which is the only one developed for patients treated with tyrosine kinase inhibitors, considers 2 risk groups based on spleen size and peripheral blood basophil percentage. No clear link has been identified between the covariates used to calculate those scores and CML molecular pathophysiology. To better delineate the molecular mechanisms underlying those scoring systems, a gene expression profiling study was performed on 48 CP-CML patients included in the Novartis ENEST1st study, for whom good quality peripheral blood total RNA was available at diagnosis. First, patients with low-risk (n=21) and high-risk (n=12) Sokal scores were compared, leading to identify 13 genes differentially expressed between those groups (q Disclosures Gardembas: Novartis: Speakers Bureau. Spentchian:Novartis: Research Funding. Giles:Novartis: Consultancy, Honoraria, Research Funding. Hochhaus:Pfizer: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Radich:Gilliad: Consultancy; Incyte: Consultancy; Novartis: Consultancy, Research Funding; Ariad: Consultancy. Rousselot:Pfizer: Consultancy; BMS: Consultancy, Speakers Bureau; Novartis: Speakers Bureau.

Background: R-DHAP regimen (rituximab, cisplatin, dexamethasone, high dose cytarabine) based on the 1988 Velasquez's study is a standard scheme used to treat relapsed Non-Hodgkin lymphomas (NHL). Cisplatin is frequently substituted with oxaliplatin to avoid nephrotoxicity, resulting in R-DHAX that is currently prescribed in first or second line treatment for aggressive NHL. However data are scarce. We compared the nephrotoxicity of cisplatine to oxaliplatine in R-DHA-platinum in this setting. Methods: All consecutive patients with NHL treated by R-DHAP or R-DHAX in Angers hospital between the 1st January 2007 and the 31th December 2014 were included. Either cisplatin 100 mg/m2 during 24 hours (R-DHAP) or oxaliplatin 130 mg/m2 during 2 hours (R-DHAX) were associated at d1 with cytarabine (2000 mg/m2 during 3 hours, two doses, d 2), dexamethasone (40 mg, d 1-4) and rituximab (375mg/m2, d 1) (Details on table 1). Cisplatin dosage were reduced from 25% to 50% according to individual renal tolerance. Up to 6 courses were delivered. Serum creatinine was recorded before each course of chemotherapy and was checked between d3 and d15 after administration, allowing to trace individual profiles of trajectories for their levels. These trajectories were clusterized in order to detect the existence of homogeneous patterns of evolution. This is a classical, semiparametric group-based statistical approach (Ref 1). Concomitant nephrotoxic drugs and events (sepsis…) were recorded to identify potential bias. Results: 21 patients received R-DHAP and 32 received R-DHAX. 6 patients switched from R-DHAP to R-DHAX due to nephrotoxicity. 2 different homogeneous clusters appeared. Cluster A included a majority of R-DHAX: 31 R-DHAX (88.6%), 3 R-DHAP (8.6%), 1 R-DHAP who changed to R-DHAX (2.9%). Cluster B contained a majority of R-DHAP: 11 R-DHAP (64.7%), 1 R-DHAX (5.9%), 5 R-DHAP to R-DHAX (29.4%) (p = 7.5.10-9). Cluster A graphic profile appeared less toxic than cluster B according to average serum creatinine level (mean cluster A: 70.2 µmol/L; mean cluster B: 99.5 µmol/L (p = 2.2.10-16)). Patients treated with R-DHAP experienced more severe renal failure than patients treated with R-DHAX (Chi-square test: p = 2.9.10-8, table 2). Nephrotoxic concomitant treatments have no significant discriminant effect. No differences were observed between either R-DHAP versus R-DHAX or cluster A versus B patients, as regards to age, sex, malnutrition status, histology, stage of the lymphoma, performans status, comorbidities including renal comorbidities and the history of nephrotoxic therapy. No significant difference was shown in OS and EFS (respectively, p = 0.463 and p = 0.290). Conclusions: Although R-DHAX is now widely used in NHL treatment, our study is one of the first to evaluate efficacy and renal tolerance of this treatment. R-DHAX nephrotoxicity is not significant whereas most patients receiving R-DHAP had significant acute renal impairment. We found no difference as regards to survival. A prospective study should compare these schedules in NHL to adapt future practices and improve morbidity. Table 1. Patients characteristics Caractéristics DHAP DHAX Total Sex M 14 (66.7%) 23 (71.9%) 37 (69.8%) F 7 (33.3%) 9 (28.1%) 16 (30.2%) Age (years) Median (min-max) 61 (34-80) 61 (39-77) 61 (34-80) BMI < 18 0 0 0 18 to 25 9 (42.9%) 17 (53.1%) 26 (49.1%) > 25 12 (57.1%) 15 (46.9%) 27 (50.9%) Performans Status (N=49) PS > = 2 3 (17.6%) 2 (6.3%) 5 (10.2%) PS < 2 14 (82.4%) 30 (93.8%) 44 (89.8%) Comorbidities Renal 1 (4.8%) 3 (9.4%) 4 (7.5%) Cardiovascular 8 (38.1%) 13 (40.6%) 21 (39.6%) Other 12 (57.1%) 16 (50%) 28 (52.8%) More than 2 comorbidities 6 (28.6%) 9 (28.1%) 15 (28.3%) Histologie NHL low grade 5 (23.8%) 5 (15.6%) 10 (18.9%) NHL High grade 15 (71.4%) 25 (78.1%) 40 (75.5%) CLL 1 (4.8%) 2 (6.3%) 3 (5.6%) Ann Arbor Stage I 0 0 0 II 2 (9.5%) 2 (6.3%) 4 (7.5%) III 2 (9.5%) 2 (6.3%) 4 (7.5%) IV 16 (76.2%) 26 (81.3%) 42 (79.2%) Previous chemotherapy Nephrotoxic 2 (9.5%) 3 (9.3%) 5 (9.4%) Non nephrotoxic 17 (80.9%) 21 (65.6%) 38 (71.7%) Albumine blood level < = 30 5 (23.8%) 5 (15.6%) 10 (18.9%) LDH > N 11 (52.4%) 12 (37.5%) 23 (43.4%) Total 21 32 53 Table 2. Renal Failures grade R-DHAP R-DHAX No renal failure 13 (27.7%) 100 (74.6%) Renal Failure 34 (72.3%) 34 (25.4%) (Reference 1: Group-based trajectory modeling in clinical research, Nagin et al. Annu Rev Clin Psychol. 2010) Disclosures No relevant conflicts of interest to declare.

In elderly pts, the prognosis of AML associated with poor risk cytogenetics or secondary to either MDS or previous cancer is so bad that only supportive care or investigational studies are usually recommended. Fit patients may achieve CR after conventional induction, but early relapse appears to be nearly inescapable whatever classical consolidation or maintenance therapy is used. Therefore, the GOELAMS investigated the impact of a maintenance using two agents mainly used in MDS, ie AZA and Len. Between March 2011 and February 2013, 117 pts from 27 centers (median age 69 yrs; 60-80) with previously untreated poor prognosis AML were included. Poor Risk factors were either preceding MDS (n=52), previous cancer (n=37) or centrally reviewed (IL) poor risk cytogenetics (n=83) defined as complex karyotype (≥3 abnormalities, n=65), monosomal karyotypes (n=54), del or - 5 (n=61) or 7 (n=44), 3q abnormality (n=9) or MLL rearrangement except for t(9;11) (n=5). Median WBC was 2.9 G/L (0.5-160), 7 pts had WBC ≥ 30 G/L. Induction chemotherapy included Lomustine 200 mg/m² po d1, Idarubicine 8 mg/m²/d (d1-5), Cytarabine 100mg/m²/d CI (d1-7). Patients in CR received 12 maintenance cycles alternating every 28 days AZA (sc 75 mg/m²/d1-7) and Len (10mg/d1-21), which started if PMN and platelets were >1 G/L and 100 G/L respectively. After d42, subsequent cycles were reduced to 50 mg/m²/d and 5 mg/d. GCSF was allowed in case of PMN < 0.5 G/L after 7 days or febrile neutropenia. At the end of induction, CR was achieved in 56% (65 pts) without any predictive factor, 9% died from infection (n=6), cerebral hemorrhage (n=1) or MOF (n=4) and 35% (41pts including 5 CRp) failed to achieve CR. The 12 planned maintenance courses could be given to 21 pts (32%) (median: 6). Few toxicities were observed. AZA courses were slightly more toxic than Len courses (table 1). Table 1.AZA courses %Len courses %Gr 3/4 neutropenia46.8/ 27.339.7 /17.6Antibiotics for fever at home6.97Hospitalization for febrile neutropenia0.52.7RBC transfusions55.4Gr 3 Thrombopenia2016Platelets transfusion8.67.9Interval between courses > 35 days26.118.4Median time interval between courses31 d28 dCourses with doses reductions9.621.6 Maintenance courses were interrupted because of relapse (n= 34, 77%), alloSCT (n=4 %), count error (n=1 %) or toxicities (n =5, 11%) occurring after Len (depression, vascular purpura and pseudomembranous diarrhea, sudden death, all during cycle 1) or after Aza (atrial fibrillation and cardiac dysfunction). Twenty Gr3/4 AE were reported among 441 cycles (0.56%/courses). Median follow-up for survivors was 38 mo (26-47). Median OS was 10 mo, with 21% 2y OS. Median CR duration was 7 mo (1-30). Impact of prognostic factors on DFS is shown table 2. Within poor risk factors, Cytogenetic abnormalities appeared as even poorer than previous MDS or cancer. Table 2.CR %CR NDFS median moP VALUE1y DFS %2y DFS %All patients56657.941.512.3Age ≥ 7058.3288.6 vs 7.746.417.9WBC ≥ 3.3 G/L48.1267.0 vs12.423.111.5Previous MDS51.92713.8 vs 6.4.0551.922.2MDS only68.41316.8 vs 6.4.00869.230.8Previous cancer54207.5 vs 7.9355Cancer only80812.4 vs 7.755012.5Poor cytogenetic53445.1 vs 15.3.0429.56.8Complex caryotype49.2324.8 vs 12.9.012259.4Monosomal caryotype50274.6 vs 12.9.00218.57.4Chromosome 5 abnormality52.5325 vs 13.8.00218.86.3Chromosome 7 abnormality54.5243.6 vs 12.00120.84.23q55.6510.4 vs 7.740017p deletion48.5165.0 vs 10.52512.5MLL8043.4 vs 8.4250poor cytogenetic + MDS42.997.7 vs 7.944.422poor cytogenetic + cancer46.774.8 vs 7.928.90poor cytogenetic + cancer + MDS71.453.4 vs 8.4200cancer + MDS00---Poor cytogenetic only rev aza57.5236.3 vs 12.9.05521.74.3Poor cytogenetic only SA255436.430.220.9 In the previous GOELAMS SA2 trial, 78 pts with poor risk cytogenetics without secondary leukemia received the same LIA induction followed in CR by maintenance therapy with 6 mini-reinductions (Ida 10mg/m² d1, cytarabine 50 mg/m²x2/d d1-5) and 6MP-MTX for 2years. In the present study, the DFS of the group of pts with poor risk cytogenetics without previous cancer or MDS is very similar. This alternating azacitidine/lenalidomide maintenance improved DFS and OS of pts without poor risk cytogenetics (median 15.7 and 24 mo). In this setting, it could be randomly compared to conventional chemotherapy maintenance. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Introduction: Acute myeloid leukemia (AML) with 17p abnormalities (abn(17p)), usually affecting TP53 locus, carries a very poor prognosis due to high refractoriness to conventional chemotherapy, with long-term survival of less than 5%. Allogeneic stem cell transplantation (SCT) appears as the only potential curative option in high-risk AML. To specifically address outcomes after SCT in patients with abn(17), we retrospectively analysed data from the EBMT registry. Methods: De novo or secondary AML with abnormal karyotype transplanted between 2000 and 2013 have been allocated. From a dataset of 5495 patients with AML undergoing SCT, we included only those patients for whom data were sufficient to confirm the presence of abn(17p) resulting in a loss or a disruption of the TP53 locus. Results: One hundred thirty-nine patients have been selected including 125 patients (90%) in first remission (CR1) and 14 (10%) in second remission. For further analysis, we focused on the 125 patients in CR1. Median age was 54 (range, 18-69) year-old and the median follow-up was 21 (range, 3-146) months. Eighty-five percent of the patients had a de novo AML, while 15% had a secondary AML. Abn(17p) was associated to a monosomal karyotype in 83% of patients, complex karyotype in 91%, monosomy 5 or 5q deletion (-5/5q-) in 55%, monosmy 7 (-7) in 39% and both -5/5q and -7 in 27%, respectively. Median time from diagnosis to CR1 was 57 (range, 18-170) days. Fifty-one (41%) of the patients received a myeloablative conditioning regimen and 73 (59%) had a reduced-intensity conditioning regimen. The vast majority of patients (70%) had a karnofsky performance status of more than 90% at the time of SCT. The 2-year overall survival (OS) and leukemia-free survival (LFS) were 28% and 24%, respectively. The 2-year non-relapse mortality (NRM) was 15%, and 2-yr relapse incidence (RI) was 61%. The cumulative incidence of grade II to IV acute graft-versus-host disease (GvHD) was 24% and that of chronic GvHD was 21%. In multivariate analysis, the presence of a -5/5q- in addition to abn(17p) was significantly and independently associated with worse OS, LFS and higher RI. Age and donor type did not correlate with outcome. Conditioning intensity was not statistically associated with OS, LFS and NRM when adjusted for patients'age. Conclusion: In contrast to the dismal prognosis reported for AML patients harboring abn(17p) undergoing conventional chemotherapy, allogeneic SCT provides long-term responses in about 25% of a selected group of patients harboring this cytogenetic abnormality at diagnosis and transplanted in CR1. Post and pre transplant targeted therapy may further improve results. Disclosures Milpied: Celgene: Honoraria, Research Funding.

BACKROUND: The protein defective in type 1 hereditary hemochromatosis, called HFE, is similar to MHC class I-type proteins, associates with beta2-microglobulin and is implicated in membranous protein recycling. Gemtuzumab ozogamicin (GO), a monoclonal antibody directed against CD33 linked to a cytotoxic agent, has been used with controversial effects in acute myeloid leukemia (AML). Internalization of GO is required for its anti-leukemic effect. Therefore, we hypothesized that H63D or C282Y HFE gene mutations may impair GO activity by preventing its internalization. METHODS: Wild type, C282Y and H63D HFE leukemic cells and primary cell were used to assess effects of GO alone or in combination with cytarabine on cell proliferation and apoptosis. Flow cytometry, confocal and AMNIS stream analysis were used to evaluate GO internalization. HFE mutations were analyzed by PCR analysis on DNA from patients included in clinical studies. Post-hoc subgroup analysis was performed to assess in vivo the role of HFE status on GO efficacy and toxicity among the 280 patients of the ALFA-0701 study as a study cohort (patients aged 50-70 years; GO 3mg/m² on days 1, 4, and 7 of chemotherapy and on day 1 of the first and second induction ; total dose 15 mg/m² ) and then on the GOELAMS-LAM 2006 IR study (patients aged 18-60 years; GO 6 mg/m² on day 4 of chemotherapy during the induction and the first consolidation; total dose 12 mg/m²) and UK NCRI AML17 study (patients aged 18-81 years; GO 3 vs 6 mg/m² on day 1 of chemotherapy but not during consolidation) as validating cohorts. RESULTS: GO induced cell death by apoptosis in AML cell lines and primary cells in a dose-dependent manner and synergistically in combination with cytarabine. However, the IC5O of GO was significantly higher in HFE mutated cells (125 vs 10 ng/mL p HFE mutations were screened in 242 of the 280 ALFA-0701 patients with DNA available. There were 155 non-mutated patients (64%), 68 (28%) heterozygous for H63D, 11 (5%) heterozygous for C282Y, and 8 (3%) homozygous for H63D, which is consistent with the prevalence of the various mutations in the French population. Median age was 62 years (50-71) and the M/F ratio was 0.5, equally distributed among the different groups. No significant difference was observed with respect to the diagnosis of various hematological parameters, including white blood cell count, blasts number, cytogenetic subgroups, molecular mutation incidences (FLT3, NPM1, CEBPA, IDH, DNMT3A). In the ALFA-0701 study cohort, HFE wild-type (WT) patients had a higher overall survival (OS) when treated in the GO arm (median, not reached vs 19.5 months, p=0.0193). In contrast, OS was similar among patients with heterozygotes HFE mutations treated in the GO and the control arm (median, 19.9 vs 21.9, p=0.9675). In confirmatory cohorts, GO treatment led to a trend to increased OS in the GOELAMS-LAM 2006 IR cohort only in HFE WT patients (4-year OS with GO 62% vs 48%, p=0.08) but not in mutated patients (4-year OS with GO 73% vs 64%, p=0.45). Furthermore, in this cohort in the FLT3 WT patients subgroup, GO further improve OS in WT patients (4-year OS with GO 72% vs 50%, p=0.017), but not in patients with heterozygous HFE mutation (4-year OS with GO 80% vs 65%, p=0.23) In the UK NCRI AML17 cohort, which used GO only during induction, 245 patients were randomized between GO at 3mg/m2 and 6mg/m2 and evaluated for HFE status. Overall there was no effect of GO dose on outcomes, and no evidence of either any heterogeneity by HFE, nor any subgroup, which showed a differential effect of GO dose. CONCLUSIONS: Future studies should focus on optimising the fractionated schedule for GO at the 3mg/m2. Fractionated high doses (3x3mg/m2) during induction and single dose during consolidation seems to be the best schedule. Most importantly, the effect of GO treatment differed between HFE WT and heterozygote mutated AML patients. GO only increased OS among HFE WT patients. This is likely related to impaired internalization of the CD33 target. Our data suggest that HFE status should be used as a companion test to predict outcome of AML treated with GO. Disclosures No relevant conflicts of interest to declare.

Introduction: The presence of an internal tandem duplication of FLT3 (FLT3-ITD) confers a higher risk of relapse and is now a current indication of allogeneic stem cell transplantation (SCT) in patients with intermediate-risk cytogenetic acute myeloid leukemia (IRC-AML) in first complete remission (CR1). Most studies encouraging this strategy have been performed in patients below 60 year-old, after a myeloablative conditioning (MAC) and using a sibling donor. Because age remains associated with a worse outcome after SCT, we decided to analyse outcomes of SCT in patients aged 60 year-old or older with intermediate-risk AML and FLT3-ITD. Methods: Using the EBMT registry, we selected de novo acute myeloid leukemia (AML) harboring IRC-AML and FLT3-ITD in patients transplanted from a related or matched unrelated donor (9/10 or 10/10) between January 2000 and July 2014. Results: Two hundred and five patients have been allocated. Median age at the time of SCT was 64 (range, 60-75) year-old and median follow-up was 20 (range, 2-139) months. Ninety-four percent of the patients had a good performance status (Karnofsky at SCT ≥ 80%). Most patients had a normal karyotype at diagnosis (90% versus 10% with other intermediate-risk karyotype) and NPM1 status was reported in 131 patients out of which 100 (76%) were mutated. Thirty-four patients received a MAC, 142 had a reduced-intensity conditioning (RIC) and 29 a non-myeloablative conditioning (NMA). One hundred forty-six patients received their SCT in first remission (CR1), 24 in second remission (CR2) and 35 in more advanced stage of the disease, respectively. The 2-year leukemia-free survival (LFS) was 52% in patients in CR1, 17% in those in CR2 and 11% in patients with advanced disease, respectively (p In multivariate analysis, disease status at SCT was the most powerful predictor of worse LFS and OS. Age, as a continuous variable, was not significantly associated with outcomes. Donor type (unrelated versus sibling donor) and donor CMV positivity correlated with worse OS and higher NRM. Next, we performed a second analysis focusing on patients transplanted in CR1. A multivariate analysis performed in this subgroup showed that age, as a continuous variable, did not translate into worse LFS, OS or NRM. Interval from diagnosis to CR1 was significantly associated with LFS, being 63% in patients achieving CR1 in less than 43 days and 45% in patients achieving CR1 in more than 43 days, respectively (p Conclusion: Allogeneic SCT in elderly (≥60 up to 75 year-old) patients with IRC-AML harboring the FLT3-ITD mutation, similar to current strategy in younger patients, appears as a good treatment strategy if performed in CR1, independently of age, with somewhat inferior outcome in transplants from unrelated donors. Nevertheless, indication for transplantation should still be evaluated taking into account donor type, co-morbidities and performance status. Disclosures Craddock: Celgene: Consultancy, Honoraria, Research Funding; Pfizer: Speakers Bureau; Sunesis: Honoraria; Johnson and Johnson: Consultancy. Russell:Therakos: Other: shares.

Purpose: The use of rituximab, a chimeric monoclonal antibody to CD20, has led to significant improvement in the treatment of B-cell non-Hodgkin's lymphoma and mature B-cell ALL. CD20 is expressed in 30 to 50% of adult BCP-ALL patients. Although some single arm studies suggested that adding rituximab to chemotherapy could improve the outcome of these patients, no randomized study has been reported so far. Methods: To evaluate the potential benefit of adding rituximab, we conducted a multicenter randomized trial comparing the pediatric-inspired GRAALL protocol to the same regimen plus rituximab, in patients aged 18-59 years old with newly diagnosed CD20-positive Ph-negative BCP-ALL enrolled in the GRAALL 2005 trial. CD20 positivity was defined as expression of CD20 in more than 20% of leukemia blasts. Rituximab (375 mg/m2) was given during induction (day 1 and 7), salvage reinduction when needed (day 1 and 7), consolidation blocks (6 infusions), late intensification (day 1 and 7) and first year of maintenance (6 infusions) for a total of 16 to 18 infusions. Allogeneic stem cell transplantation (SCT) was offered in first complete remission (CR) to patients with one or more conventional high-risk criteria and a donor. The primary study objective was event-free survival (EFS). A study sample size of 220 patients was estimated in order to detect a 20% gain in EFS at 2 years (two-sided test, power 85%, type 1 error 5%). A sensitivity analysis was performed after censoring patients allografted in first CR at transplant time. This trial was registered at http://www.clinicaltrials.gov as #NCT00327678. Results: From 2005 to 2014, 220 patients from 56 centers were randomized. Eleven patients had non-eligibility criteria (n=5 Ph+ ALL; n=3 CD20-negative ALL; n=1 HIV infection) or withdrew their consent (n=2) and were accordingly excluded from this modified ITT analysis that dealt with 209 patients (105 in the rituximab arm and 104 in the control arm). Median age was 40 years. Both randomization arms were well balanced for pretreatment characteristics including age, ECOG status, WBC, and central nervous system (CNS) involvement (6% of the whole cohort). After induction ± salvage reinduction, CR rate was 92% and 91% in rituximab and control arm, respectively. In patients who reached CR after first induction and were evaluated for Ig/TCR minimal residual disease level (MRD), the rates of patients with MRD Conclusions: In adults with CD20-positive, Ph-negative, BCP-ALL, the addition of rituximab to the pediatric-inspired GRAALL protocol improves EFS; it also prolongs OS when ignoring patient's outcome after transplantation in first CR. Disclosures Off Label Use: Rituximab is not currently approved for this indication.. Chalandon:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees.

The serine/threonine kinase mammalian target of rapamycin (mTOR) is crucial for cell growth and proliferation, and is constitutively activated in primary acute myeloid leukemia (AML) cells, therefore representing a major target for drug development in this disease. We show here that the specific mTOR kinase inhibitor AZD8055 blocked mTORC1 and mTORC2 signaling in AML. Particularly, AZD8055 fully inhibited multisite eIF4E-binding protein 1 phosphorylation, subsequently blocking protein translation, which was in contrast to the effects of rapamycin. In addition, the mTORC1-dependent PI3K/Akt feedback activation was fully abrogated in AZD8055-treated AML cells. Significantly, AZD8055 decreased AML blast cell proliferation and cell cycle progression, reduced the clonogenic growth of leukemic progenitors and induced caspase-dependent apoptosis in leukemic cells but not in normal immature CD34+ cells. Interestingly, AZD8055 strongly induced autophagy, which may be either protective or cell death inducing, depending on concentration. Finally, AZD8055 markedly increased the survival of AML transplanted mice through a significant reduction of tumor growth, without apparent toxicity. Our current results strongly suggest that AZD8055 should be tested in AML patients in clinical trials.

Introduction Cryofibrinogenemia may be essential, or secondary to diseases such as neoplasia, infection, thrombosis, and collagen vascular diseases. In a previous study, we reported the occurrence of neoplasia in some essential cryofibrinogenemia patients after a short period of follow-up. Purpose We performed a prospective multi-center 5-year follow-up study in essential cryofibrinogenemia patients (2005–2009). Results 23 patients with essential cryofibrinogenemia were included, mean age 59 years (range: 33–79), 14 males. After a mean follow-up period of 24 months, 11/23 (47%) of cases that were initially diagnosed as essential cryofibrinogenemia were found to have an underlying lymphoma (6 T lymphoma and 5 B lymphoma). Conclusion This prospective study suggests that some cases of cryofibrinogenemia that are initially considered as essential, may have underlying lymphoma. Thus, we further suggest that regular follow-up should be performed in patients with essential cryofibrinogenemia.

The myelodysplastic syndromes are a group of heterogeneous acquired and clonal disorders that are characterized by the intramedullar, abnormal death of myeloid progenitors leading to peripheral variable cytopenias. Progressive, aregenerative anemia irresponsive to B12, folates or iron supplementation often constitutes the initial complaint. The diagnosis that may be difficut relies to a careful analysis of bone marrow aspirate morphology Classification system is based on cytogenetic abnormalities, and both the number of lineage involved, and bone marrow blasts. It is predictive for the risk of transformation in secondary acute myeloid leukemia.

International audience; Cytogenetic stratification remains insufficient for almost half of the acute myeloblastic leukemia (AML) cases, with AML patients requiring subsequent molecular investigation. In our study, we used mass spectrometry (MS)-based proteomic approaches to characterize de novo AML. Fifty-four samples (mononuclear cells from bone marrow or peripheral blood mononuclear cells collected and frozen before treatment) from two independent cohorts of newly diagnosed AML patients were analyzed. We showed that the protein signature of leukemic cells defined two clusters that displayed significant variation for overall and disease-free survival (P=0.001 and 0.0004, respectively). This proteomic classification refines the cytogenetic classes. AML patients with intermediate and unfavorable cytogenetic classifications could be subdivided according to their protein profiles into subgroups with significantly different survival rates. Among the proteins expressed by leukemic cells, we isolated a 10,800-Da marker that retained the highest discriminative value between living and deceased patients. The 10,800-Da marker was identified by MS peptide sequencing as S100A8 (also designated MRP8 or calgranulin A). Western blot analysis confirmed its expression mainly in AML patients with the worst prognosis, arguing for a selective deregulation associated with poor prognosis. These results suggest that the expression of S100A8 in leukemic cells is a predictor of low survival.

Background and Purpose— Large vessels are also affected in sickle cell disease. The aim of this study was to assess several parameters in adult patients with sickle cell disease compared with control subjects and in patients with sickle cell disease with stroke. Methods— Carotid arterial stiffness, intima-media thickness, and transcranial Doppler ultrasonography were measured. Results— Arterial stiffness and transcranial Doppler velocity were significantly increased in 49 patients with sickle cell disease compared with 47 control subjects ( P P Conclusions— These data suggest that transcranial Doppler and arterial stiffness might be associated to stroke in adult patients with sickle cell disease.

International audience; OBJECTIVE: The presence of systemic and/or immune manifestations in myelodysplasia has been currently reported. The influence of these manifestations on the natural outcome of myelodysplastic syndrome has to be considered. We present a multicenter retrospective study (2002-2009) of patients with myelodysplastic syndrome disclosing systemic and/or immune manifestations. METHODS: Forty-six patients with myelodysplasia presenting with systemic and/or immune manifestations were compared in terms of survival with 189 patients with myelodysplasia lacking these features. RESULTS: The clinical picture in these cases consisted of fever (13%), arthralgia or arthritis (13%), and cutaneous manifestations (67%). Four cases of systemic vasculitis have been reported in our series, and they have a worse prognosis. Immune anomalies were recorded in 29% of the cases, and the presence of cryoglobulins was also associated with a worse prognosis. CONCLUSION: A difference in survival between patients with myelodysplastic syndrome with systemic manifestations and patients lacking these manifestations has been observed in the presence of systemic vasculitis and/or cryoglobulins.

In 1992, we reported the results of the first randomized trial comparing the combination of cyclophosphamide (CY) (120 mg/kg) and total body irradiation (TBI) (CYTBI) versus CY and busulfan (BU) (BUCY) as preparation for an allogeneic bone marrow transplantation (BMT) for adult patients with acute

The FOXO transcription factors are involved in multiple signaling pathways and have tumor-suppressor functions. In acute myeloid leukemia (AML), deregulation of oncogenic kinases, including Akt, extra-signal–regulated kinase, or IκB kinase, is frequently observed, which may potentially inactivate FOXO activity. We therefore investigated the mechanism underlying the regulation of FOXO3a, the only FOXO protein constantly expressed in AML blast cells. We show that in both primary AML samples and in a MV4-11/FOXO3a-GFP cell line, FOXO3a is in a constant inactive state due to its cytoplasmic localization, and that neither PI3K/Akt nor extra-signal–regulated kinase–specific inhibition resulted in its nuclear translocation. In contrast, the anti-Nemo peptide that specifically inhibits IKK activity was found to induce FOXO3a nuclear localization in leukemic cells. Furthermore, an IKK-insensitive FOXO3a protein mutated at S644 translocated into the nucleus and activated the transcription of the Fas-L and p21Cip1 genes. This, in turn, inhibited leukemic cell proliferation and induced apoptosis. These results thus indicate that IKK activity maintains FOXO3a in the cytoplasm and establishes an important role of FOXO3a inactivation in the proliferation and survival of AML cells. The restoration of FOXO3a activity by interacting with its subcellular distribution may thus represent a new attractive therapeutic strategy for AML.

Purpose No significant improvement in treatment outcome has been seen in elderly patients with acute myeloid leukemia (AML) over the past 20 years. This retrospective analysis investigated the prognostic factors for complete remission (CR) and survival in older patients with AML. Patients and Methods The study involved 847 patients older than 60 years enrolled onto three trials carried out in France between 1995 and 2005. Induction therapy consisted of idarubicin (8 mg/m2, days 1 through 5) and cytarabine (100 mg/m2, days 1 through 7; group I, 339 patients) or the same drugs plus lomustine (200 mg/m2 orally on day 1; group II, 508 patients). Consolidation therapy consisted of anthracycline and cytarabine courses at lower doses, preceded or not by a first course of intermediate-dose cytarabine. Results The rate of CR was significantly higher in patients in group II compared with group I (68% v 58%; P = .002). The rate of toxic death was similar in the two groups. In multivariate analysis, two prognostic factors were linked to CR: nonadverse cytogenetic (P < .003) and addition of lomustine to induction chemotherapy (P = .002). Median overall survival was significantly improved in patients treated with lomustine (median and SE, 12.7 ± 2.2 months v 8.7 ± 2.7 months; P = .004). In multivariate analysis, five prognostic factors positively affected overall survival: addition of lomustine (P = .002), age ≤ 69 years (P < .001), Eastern Cooperative Oncology Group performance status lower than 2 (P = .002), French-American-British subgroup 1/2 (P = .02), and nonadverse cytogenetic (P < .001). Conclusion Lomustine improves the rate of CR and survival in elderly patients with de novo AML when added to standard induction therapy.

The prognostic significance of CD20 expression in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has been mostly studied in children and yielded conflicting results. In 143 adults with Philadelphia chromosome-negative BCP-ALL treated in the multicentric GRAALL 2003 trial, CD20 positivity over 20% was observed in 32% of patients. While not influencing complete remission achievement, CD20 expression was associated with a higher cumulative incidence of relapse (CIR) at 42 months (P=0.04), independently of the ALL high-risk subset (P=0.025). Notably, the negative impact of CD20 expression on CIR was only observed in patients with a white blood cell count (WBC) over 30x10(9)/L (P=0.006), while not in those with a lower WBC. In the former subgroup, this impact translated into lower event-free survival (15% vs. 59% at 42 months, P=0.003). CD20 expression thus appears to be associated with a worse outcome, which reinforces the interest of evaluating rituximab combined to chemotherapy in CD20-positive adult BCP-ALL. ClinicalTrials.gov ID, NCT00222027.

Purpose Allogeneic stem-cell transplantation (alloSCT) is a curative therapeutic option for patients with low-grade lymphoid malignancies. Information regarding alloSCT in Waldenström macroglobulinemia (WM) is limited. This study presents the long-term outcome of a large series of patients with WM treated with alloSCT. Patients and Methods A total of 86 patients received allograft by using either myeloablative (MAC; n = 37) or reduced-intensity conditioning (RIC; n = 49) regimens and were retrospectively studied. The median age was 49 years (range, 23 to 64 years); 47 patients had received three or more previous lines of therapy, and eight patients had experienced failure on a prior autologous stem-cell transplantation. A total of 59 patients (68.6%) had chemotherapy-sensitive disease at the time of alloSCT. Median follow-up of the surviving patients was 50 months (7 to 142 months). Results Nonrelapse mortality (NRM) at 3 years was 33% for MAC and 23% for RIC. The overall response rate was 75.6%. The relapse rates (RRs) at 3 years were 11% for MAC and 25% for RIC. Fourteen patients received donor lymphocyte infusions (DLIs) for disease relapse. PFS and OS at 5 years were 56% and 62% for MAC and 49% and 64% for RIC, respectively. The occurrence of chronic graft-versus-host disease (cGVHD) was associated with a higher NRM and a lower RR, leading to an improvement in PFS. Conclusion alloSCT can induce durable remissions in a selected population of young and heavily pretreated patients with WM. The low RR, the achievement of additional disease responses after DLIs, and the lower RR in patients developing cGVHD suggest the existence of a clinically relevant graft-versus-WM effect.

Finding an effective treatment for acute myeloid leukemia (AML) remains a challenge, and all cellular processes that are deregulated in AML cells should be considered in the design of targeted therapies. We show in our current study that the LKB1/AMPK/TSC tumor suppressor axis is functional in AML and can be activated by the biguanide molecule metformin, resulting in a specific inhibition of mammalian target of rapamycin (mTOR) catalytic activity. This induces a multisite dephosphorylation of the key translation regulator, 4E-BP1, which markedly inhibits the initiation step of mRNA translation. Consequently, metformin reduces the recruitment of mRNA molecules encoding oncogenic proteins to the polysomes, resulting in a strong antileukemic activity against primary AML cells while sparing normal hematopoiesis ex vivo and significantly reducing the growth of AML cells in nude mice. The induction of the LKB1/AMPK tumor-suppressor pathway thus represents a promising new strategy for AML therapy.

PURPOSE For patients with Hodgkin's disease (HD) who do not achieve complete response (CR), who experience a relapse within the first year of CR, and for those who have two or more relapses, the outcome is poor. Salvage chemotherapy regimens at conventional doses produce a CR rate that ranges from 10% to 50% and a 5-year disease-free survival (DFS) between 10% and 25%. On the other hand, high-dose chemotherapy regimens given in combination with bone marrow transplantation (BMT) produce a CR rate that ranges from 40% to 80% and a 3-year DFS of approximately 40%. We report the 5-year results of a prospective study in patients with refractory HD who were treated with three courses of intensive chemotherapy without BMT. PATIENTS AND METHODS Thirty-nine adult patients with refractory HD were treated with three courses of intensive chemotherapy. Each cycle of chemotherapy comprised vindesine 1 mg/m2/d in continuous intravenous (IV) infusion from day 1 to day 5; Adriamycin (doxorubicin; Roger Bellon Laboratories, Neuilly, France) 40 mg/m2/d in continuous IV infusion from day 1 to day 3; carmustine 140 mg/m2/d at day 3; etoposide 200 mg/m2/d from day 3 to day 5; and methylprednisolone 120 mg/m2/d from day 1 to day 5. After the third cycle of chemotherapy, irradiation (20 Gy) was performed whenever possible and depended on previous irradiation. RESULTS At the end of the treatment, 31 patients (79%) were in CR. Among these patients, 10 relapsed after a median time of 3 months. The overall 5-year survival rate was 46%. The freedom from progression (FFP) and the freedom from treatment failure (FFTF) rates were 48% and 43%, respectively. The main toxicities were hematologic (neutropenia and thrombocytopenia) and digestive. Four patients died due to treatment-related complications (two from septic shocks, one from respiratory insufficiency, and one from posttransfusional AIDS). CONCLUSION The results of this study seem to be comparable to those results obtained with high-dose chemotherapies with autologous BMT.

Adrenal involvement in the course of a non-Hodgkin's lymphoma (NHL) appears to occur relatively often, but only seven cases of NHL-induced adrenal insufficiency were found in a recent review of the literature. The authors report four cases of hypoadrenalism in 127 patients treated for NHL; the cases were staged and classified according to the Working Formulation and were investigated for endocrine function by the cosyntropin stimulation test. The involvement was bilateral in four patients; all of the patients had high grade, mostly widespread NHL. These observations suggest that adrenal insufficiency may be underestimated in NHL. Basal hormonal serum levels may be borderline; consequently, only stimulation tests can prove the hormonal failure. The authors suggest that such tests are essential if the staging of the NHL shows bilateral adrenal enlargement, and that the tests should be performed before chemotherapy begins because of the risk of acute adrenal insufficiency.

Acute promyelocytic leukemia (APL) is highly curable with the combination of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy (CT), but very long-term results of this treatment, when CT should be added to ATRA and the role of maintenance treatment, remain uncertain. In our APL93 trial that included 576 newly diagnosed APL patients, with a median follow-up of 10 years, 10-year survival was 77%. Maintenance treatment significantly reduced 10-year cumulative incidence of relapses, from 43.2% to 33%, 23.4%, and 13.4% with no maintenance, maintenance using intermittent ATRA, continuous 6 mercaptopurine plus methotrexate, and both treatments, respectively (P < .001). Maintenance particularly benefited patients with white blood cell (WBC) count higher than 5 × 109/L (5000/μL). Early addition of CT to ATRA significantly improved 10-year event-free survival (EFS), but without significant effect on overall survival (OS). The 10-year cumulative incidence of deaths in complete response (CR), resulting mainly from myelosuppression, was 5.7%, 15.4%, and 21.7% in patients younger than 55, 55 to 65, and older than 65 years, respectively, supporting the need for less myelosuppressive treatments, particularly for consolidation therapy. This study is registered at http://clinicaltrials.gov as NCT00599937.

Background Alterations in the PI3K/Akt pathway are found in a wide range of cancers and the development of PI3K inhibitors represents a promising approach to cancer therapy. Constitutive PI3K activation, reflecting an intrinsic oncogenic deregulation of primary blast cells, is detected in 50% of patients with acute myeloid leukemia. However, the mechanisms leading to this activation are currently unknown. As we previously reported IGF-1 autocriny in acute myeloid leukemia cells, we investigated whether IGF-1 signaling was involved in the constitutive activation of PI3K. Design and Methods We analyzed the IGF-1/IGF-1R signaling pathway and PI3K activity in 40 acute myeloid leukemia bone marrow samples. Specific inhibition of IGF-1/IGF-1R signaling was investigated using neutralizing anti-IGF-1R, anti-IGF-1 antibodies or IGF-1 short interfering RNA. The anti-leukemic activity of the neutralizing anti-IGF-1R was tested by analyzing its effects on leukemic progenitor clonogenicity, blast cell proliferation and survival. Results In all samples tested, we found that functional IGF-1R was constantly expressed in leukemic cells. In the acute myeloid leukemia samples with PI3K activation, we found that the IGF-1R was constitutively phosphorylated, although no IGF-1R activating mutation was detected. Specific inhibition of IGF-1R signaling with neutralizing anti-IGF-1R strongly inhibited the constitutive phosphorylation of both IGF-1R and Akt in 70% of the PI3K activated samples. Moreover, both incubation with anti-IGF-1 antibody and IGF-1 short interfering RNA inhibited Akt phosphorylation in leukemic cells. Finally, neutralizing anti-IGF-1R treatment decreased the clonogenicity of leukemic progenitors and the proliferation of PI3K activated acute myeloid leukemia cells. Conclusions Our current data indicate a critical role for IGF-1 autocriny in constitutive PI3K/Akt activation in primary acute myeloid leukemia cells and provide a strong rationale for targeting IGF-1R as a potential new therapy for this disease.

Background Acquired somatic deletions and loss-of-function mutations in one or several codons of the TET2 ( Ten-Eleven Translocation-2 ) gene were recently identified in hematopoietic cells from patients with myeloid malignancies, including myeloproliferative disorders and myelodys-plastic syndromes. The present study was designed to determine the prevalence of TET2 gene alterations in chronic myelomonocytic leukemias. Design and Methods Blood and bone marrow cells were collected from 88 patients with chronic phase chronic myelomonocytic leukemia and from 14 with acute transformation of a previously identified disease. Polymerase chain reaction analysis and direct sequencing were used to sequence exons 3 to 11 of the TET2 gene. Annotated single nucleotide polymorphisms were excluded. Survival curves were constructed by the Kaplan-Meier method. Results We detected TET2 mutations in 44 of 88 (50%) patients with chronic myelomonocytic leukemia, which suggests that TET2 gene mutations are especially frequent in this myeloid disease. A TET2 gene alteration was identified in 18 of the 43 patients studied at diagnosis and was associated with a trend to a lower overall survival rate; confining the analysis to the 29 patients with chronic myelomonocytic leukemia-1, according to the WHO classification, the difference in overall survival between patients with or without TET2 gene mutations became statistically significant. Conclusions TET2 gene alterations are more frequent in chronic myelomonocytic leukemia than in other subgroups of hematopoietic diseases studied so far and could negatively affect the patients’ outcome. The striking association between TET2 gene alterations and monocytosis, already observed in patients with systemic mastocytosis, could indicate a negative role of TET2 in the control of monocytic lineage determination.

The deregulation of translation markedly contributes to the malignant phenotype in cancers, and the assembly of the translation initiating complex eIF4F is the limiting step of this process. The mammalian Target of Rapamycin Complex 1 (mTORC1) is thought to positively regulate eIF4F assembly and subsequent oncogenic protein synthesis through 4E-BP1 phosphorylation. We showed here that the translation inhibitor 4EGI-1 decreased the clonogenic growth of leukemic progenitors and induced apoptosis of blast cells, with limited toxicity against normal hematopoiesis, which emphasize the importance of translation deregulation in acute myeloid leukemia (AML) biology. However, the mTORC1 inhibitor RAD001 (a rapamycin derivate) did not induce AML blast cell apoptosis. We herein demonstrated that mTORC1 disruption using raptor siRNA or RAD001 failed to inhibit 4E-BP1 phosphorylation in AML. Moreover, RAD001 failed to inhibit eIF4F assembly, to decrease the proportion of polysome-bound c-Myc mRNA, and to reduce the translation-dependent accumulation of oncogenic proteins. We identified the Pim-2 serine/threonine kinase as mainly responsible for 4E-BP1 phosphorylation on the S65 residue and subsequent translation control in AML. Our results strongly implicate an mTORC1-independent deregulation of oncogenic proteins synthesis in human myeloid leukemogenesis. Direct inhibition of the translation initiating complex thus represents an attractive option for the development of new therapies in AML.

Purpose Acute promyelocytic leukemia (APL) with pretreatment WBC counts greater than 10,000/μL is still considered to carry a poorer prognosis than APL with WBC lower than 10,000/mL. We evaluated outcome improvement in such patients in recent years. Patients and Methods Nine hundred two patients with APL, including 204 patients and 68 patients with WBC counts more than 10,000/μL and more than 50,000/μL, respectively, were enrolled between 1993 and 2005 in two successive randomized trials of the European APL group (APL 93 and APL 2000) that tested, in particular, the modalities of combination of all-trans retinoic acid (ATRA) and chemotherapy, maintenance treatment, escalating doses of cytarabine, early administration of dexamethasone, and CNS prophylaxis. Results Between the APL 93 and 2000 trials, the complete response (CR) rate increased from 89.6% to 93%, and the 5-year cumulative incidence of relapse (CIR) decreased from 40% to 9.5% in patients with WBC counts of 10,000 to 50,000/μL. In patients with WBC counts more than 50,000/μL, the CR rate increased from 82% to 91%, and 5-year CIR decreased from 59% to 24%. Whereas in the APL 93 trial, increased WBC counts were significantly associated with higher CIR and shorter survival, this was not the case in the APL 2000 trial. In patients with increased WBC counts, enrollment onto the APL 2000 trial (v APL 93) and combined maintenance with ATRA and chemotherapy were associated with significantly lower CIR and better survival. Conclusion Outcome of APL with high WBC count has markedly improved over the years as a result of fewer early deaths and fewer relapses. Better initial supportive care and combined maintenance treatment have contributed to this improvement.

Purpose Retrospective comparisons have suggested that adolescents or teenagers with acute lymphoblastic leukemia (ALL) benefit from pediatric rather than adult chemotherapy regimens. Thus, the aim of the present phase II study was to test a pediatric-inspired treatment, including intensified doses of nonmyelotoxic drugs, such as prednisone, vincristine, or l-asparaginase, in adult patients with ALL up to the age of 60 years. Patients and Methods Between 2003 and 2005, 225 adult patients (median age, 31 years; range, 15 to 60 years) with Philadelphia chromosome–negative ALL were enrolled onto the Group for Research on Adult Acute Lymphoblastic Leukemia 2003 protocol, which included several pediatric options. Some adult options, such as allogeneic stem-cell transplantation for patients with high-risk ALL, were nevertheless retained. Results were retrospectively compared with the historical France-Belgium Group for Lymphoblastic Acute Leukemia in Adults 94 (LALA-94) trial experience in 712 patients age 15 to 55 years. Results Complete remission rate was 93.5%. At 42 months, event-free survival (EFS) and overall survival (OS) rates were 55% (95% CI, 48% to 52%) and 60% (95% CI, 53% to 66%), respectively. Age remained an important bad prognostic factor, with 45 years of age as best cutoff. In older versus younger patients, there was a higher cumulative incidence of chemotherapy-related deaths (23% v 5%, respectively; P < .001) and deaths in first CR (22% v 5%, respectively; P < .001), whereas the incidence of relapse remained stable (30% v 32%, respectively). Complete remission rate (P = .02), EFS (P < .001), and OS (P < .001) compared favorably with the previous LALA-94 experience. Conclusion These results suggest that pediatric-inspired therapy markedly improves the outcome of adult patients with ALL, at least until the age of 45 years.

Adult and child B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) differ in terms of incidence and prognosis. These disparities are mainly due to the molecular abnormalities associated with these two clinical entities. A genome-wide analysis using oligo SNP arrays recently demonstrated that PAX5 (paired-box domain 5) is the main target of somatic mutations in childhood BCP-ALL being altered in 38.9% of the cases. We report here the most extensive analysis of alterations of PAX5 coding sequence in 117 adult BCP-ALL patients in the unique clinical protocol GRAALL-2003/GRAAPH-2003. Our study demonstrates that PAX5 is mutated in 34% of adult BCP-ALL, mutations being partial or complete deletion, partial or complete amplification, point mutation or fusion gene. PAX5 alterations are heterogeneous consisting in complete loss in 17%, focal deletions in 10%, point mutations in 7% and translocations in 1% of the cases. PAX5 complete loss and PAX5 point mutations differ. PAX5 complete loss seems to be a secondary event and is significantly associated with BCR-ABL1 or TCF3-PBX1 fusion genes and a lower white blood cell count.

Many somatic genetic abnormalities have been identified in T-cell acute lymphoblastic leukemia (T-ALL) but each individual abnormality accounts for a small proportion of cases; therapeutic stratification consequently still relies on classical clinical markers. NOTCH1 and/or FBXW7 mutations both lead to activation of the NOTCH1 pathway and are among the most frequent mutations in T-ALL. We screened 141 adult diagnostic T-ALL samples from patients treated on either the Lymphoblastic Acute Leukemia in Adults (LALA)-94 (n = 87) or the GRAALL-2003 (n = 54) trials. In 88 cases (62%) there were demonstrated NOTCH1 mutations (42% heterodimerization [HD], 10% HD+proline glutamate serine threonine [PEST], 6% PEST, 2% juxtamembrane mutations, 2% transactivation domain [TAD]) and 34 cases (24%) had FBXW7 mutations (21 cases had both NOTCH1 and FBXW7 mutations); 40 cases (28%) were wild type for both. There was no significant correlation between NOTCH1 and/or FBXW7 mutations and clinico-biologic features. Median event-free survival (EFS) and overall survival (OS) were 36 versus 17 months (P = .01) and not reached versus 32 months (P = .004) in patients with NOTCH1 and/or FBXW7 mutations versus other patients, respectively. Multivariate analysis showed that the presence of NOTCH1/FBXW7 mutations was an independent good prognostic factor for EFS and OS (P = .02 and P = .01, respectively). These data demonstrate that NOTCH1 pathway activation by either NOTCH1 or FBXW7 mutation identifies a large group of patients with a favorable outcome that could justify individual therapeutic stratification for T-ALL.

Purpose To determine the antitumor activity and safety of a combination of gemtuzumab ozogamicin (GO), intermediate-dose cytarabine, and mitoxantrone (MIDAM) in patients with refractory or relapsed CD33+ acute myeloid leukemia (AML). Patients and Methods We treated 62 patients with refractory (n = 18) or relapsed (n = 44) CD33+ AML. Median age was 55.5 years. Salvage regimen consisted of GO 9 mg/m2 on day 4, cytarabine 1 g/m2 every 12 hours on days 1 through 5, and mitoxantrone 12 mg/m2/d on days 1 through 3. Median follow-up time was 26.5 months. Results Thirty-one patients (50%) achieved complete remission (CR), and eight patients (13%) had CR with delayed platelet recovery (CRp); the overall response (OR; CR + CRp) rate was 63%. A significantly higher OR rate was achieved in patients who had relapsed versus refractory AML (73% v 39%, respectively; P = .007) and patients with CD33 expression more than 98% of the blast population versus less than 98% (79% v 52.3%, respectively; P = .03). The overall, event-free, and disease-free survival rates were 41%, 33%, and 53% at 2 years, respectively. Leukocytosis more than 20,000/μL at MIDAM therapy, high-risk cytogenetics, and absence of postremission therapy were adverse prognostic factors. Age, disease status, and/or CD33 expression did not influence survival parameters. Four early toxic deaths occurred; a grade 3 to 4 hyperbilirubinemia rate of 16% was observed, and two patients had veno-occlusive disease (3%). Conclusion The MIDAM regimen seems to be an effective salvage regimen for refractory/relapsed CD33+ AML patients. These encouraging results support the need for a randomized phase III trial before considering this combination of GO and chemotherapy as superior or the standard of care treatment for refractory/relapsed CD33+ AML patients.

The phosphatidylinositol 3-kinase (PI3K)/Akt and mammalian target of rapamycin complex 1 (mTORC1) signaling pathways are frequently activated in acute myelogenous leukemia (AML). mTORC1 inhibition with RAD001 induces PI3K/Akt activation and both pathways are activated independently, providing a rationale for dual inhibition of both pathways. PI-103 is a new potent PI3K/Akt and mTOR inhibitor. In human leukemic cell lines and in primary blast cells from AML patients, PI-103 inhibited constitutive and growth factor-induced PI3K/Akt and mTORC1 activation. PI-103 was essentially cytostatic for cell lines and induced cell cycle arrest in the G1 phase. In blast cells, PI-103 inhibited leukemic proliferation, the clonogenicity of leukemic progenitors and induced mitochondrial apoptosis, especially in the compartment containing leukemic stem cells. In contrast, apoptosis was not induced with RAD001 and IC87114 association, which specifically inhibits mTORC1 and p110delta activity, respectively. PI-103 had additive proapoptotic effects with etoposide in blast cells and in immature leukemic cells. Interestingly, PI-103 did not induce apoptosis in normal CD34(+) cells and had moderate effects on their clonogenic and proliferative properties. Here, we demonstrate that multitargeted therapy against PI3K/Akt and mTOR with PI-103 may be of therapeutic value in AML.

International audience; The purpose of this study was to find histological clues for reliable differentiation between monoclonal gammopathy of undetermined significance (MGUS) and myeloma when clinical parameters are controversial. Differential appearance of dendritic cells and osteoclasts, two cell types developing from the monocytic lineage upon distinct cytokine activation profile, might be a useful approach. Bone and bone-marrow biopsies performed in 105 patients were studied using histomorphometry after identification of osteoclasts (by histochemical identification of tartrate resistant acid phosphatase) and dendritic cells (by immunohistochemical detection of the S-100 protein). Patients were classified by the World Health Organization criteria but histopathological criteria were more adapted to identify MGUS (53 cases), myeloma (46), B-cell lymphoma (six) since six myeloma were not correctly classified. Histomorphometry was compared to 15 control cases. The number of marrow dendritic cell was significantly increased with B-cell lymphoma >MGUS >myeloma > controls. Dendritic cell were often mixed with lymphoma cells. Myeloma had increased bone resorption with a high osteoclast number and moderate increase in dendritic cells. B-cell lymphomas had a considerable increase in dendritic cell but presented mononucleated osteoclasts. These findings can help in the classification of MGUS in the early stages of the disease and could help to propose preventive treatments.

It has been reported that patients with chronic myeloid leukemia (CML) with 5' breakpoints within the major breakpoint cluster region (M-BCR) of the BCR gene have somewhat better prognoses than those with 3' breakpoints. We studied the position of the breakpoint in 67 patients with CML in chronic phase using conventional Southern blotting. Using restriction enzymes BglII, BamHI and HindIII and two genomic probes, a 0.6 kb (3' M-BCR) probe hybridizing to a part of the intron between exons b3 and b4 and a 2.0 kb (5' M-BCR) probe hybridizing to sequences including exon b1, we localized the breakpoint in M-BCR as occurring 5' (n = 38) or 3' (n = 28) of the HindIII restriction site located just downstream of exon b3. We failed to localize the breakpoint in one patient. The median durations of chronic phase (37 versus 44 months respectively) and of survival (50 versus 51 months respectively) for patients with 5' and 3' breakpoints were not significantly different. When we analysed only patients whose DNA was collected within 4 weeks of diagnosis (5' breakpoints, n = 30; 3' breakpoints, n = 19), there was again no significant difference in duration of chronic phase or survival. The median survivals of patients divided into good, intermediate and poor prognosis categories in accordance with the prognostic index developed by Sokal and colleagues were 54, 50 and 26 months respectively. This study confirms the value of the Sokal prognostic index but provides no support for the notion that the precise genomic position of the breakpoint in M-BCR correlates with prognosis.