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The maximum tolerated dose (MTD) of quisinostat + bortezomib + dexamethasone in patients with relapsed multiple myeloma was evaluated in a phase-1b, open-label, multicenter, '3 + 3' dose-escalation study. Patients received escalating doses of oral quisinostat (6 mg [n = 3], 8 mg [n = 3], 10 mg [n = 6], and 12 mg [n = 6] on days 1, 3, and 5/week) plus subcutaneous bortezomib (1.3 mg/m(2)) and oral dexamethasone (20 mg) in cycles of 21 (cycles 1-8) or 35 d (cycles 9-11) until MTD was determined. No dose-limiting toxicities were reported in 6/8 mg groups except ventricular fibrillation (Grade 4 cardiac arrest, n = 1 [10 mg] cycle 6) and clinically significant cardiac toxicities (Grade 3 QTc prolongation, Grade 3 atrial fibrillation, n = 2 [12 mg]). Thrombocytopenia (n = 11), asthenia (n = 10), and diarrhea (n = 12) were most common adverse events. Overall, 88.2% patients achieved treatment response, median duration of response, and median progression-free survival were 9.4 and 8.2 months, respectively. The MTD of quisinostat was established as 10 mg thrice weekly oral dose with bortezomib + dexamethasone.

Background Diabetes and myelodysplastic syndrome are two conditions that may coexist in a single patient, since both diseases are prevalent in the elderly. The pathophysiology of myelodysplastic syndrome involves recurrent genetic mutations, especially in genes controlling epigenetic regulation. Although the pathophysiology of diabetes is not well understood, several studies suggest a role of epigenetics in type 2 diabetes. Case presentation We report here for the first time the case of a 75-year-old Caucasian man who was treated for both diabetes and acute myeloid leukemia secondary to myelodysplastic syndrome, with a temporal association between glycemic dysregulation and the intake of 5-azacitidine. In fact, 2–3 days after starting each 7-day cycle of 5-azacitidine, he reported higher blood glucose levels, requiring an increased dose of self-administered insulin. Conclusion This observation could help to understand the pathophysiology of these two conditions and could encourage physicians to monitor blood glucose levels in patients under hypomethylating agent with a history of diabetes.

Purpose Elderly patients with acute myeloid leukemia (AML) have a poor prognosis, and innovative maintenance therapy could improve their outcomes. Androgens, used in the treatment of aplastic anemia, have been reported to block proliferation of and initiate differentiation in AML cells. We report the results of a multicenter, phase III, randomized open-label trial exploring the benefit of adding androgens to maintenance therapy in patients 60 years of age or older. Patients and Methods A total of 330 patients with AML de novo or secondary to chemotherapy or radiotherapy were enrolled in the study. Induction therapy included idarubicin 8 mg/m2 on days 1 to 5, cytarabine 100 mg/m2 on days 1 to 7, and lomustine 200 mg/m2 on day 1. Patients in complete remission or partial remission received six reinduction courses, alternating idarubicin 8 mg/m2 on day 1, cytarabine 100 mg/m2 on days 1 to 5, and a regimen of methotrexate and mercaptopurine. Patients were randomly assigned to receive norethandrolone 10 or 20 mg/day, according to body weight, or no norethandrolone for a 2-year maintenance therapy regimen. The primary end point was disease-free survival by intention to treat. Secondary end points were event-free survival, overall survival, and safety. This trial was registered at www.ClinicalTrials.gov identifier NCT00700544. Results Random assignment allotted 165 patients to each arm; arm A received norethandrolone, and arm B did not receive norethandrolone. Complete remission or partial remission was achieved in 247 patients (76%). The Schoenfeld time-dependent model showed that norethandrolone significantly improved survival for patients still in remission at 1 year after induction. In arms A and B, respectively, 5-year disease-free survival was 31.2% and 16.2%, event-free survival was 21.5% and 12.9%, and overall survival was 26.3% and 17.2%. Norethandrolone improved outcomes irrelevant to all prognosis factors. Only patients with baseline leukocytes > 30 × 109/L did not benefit from norethandrolone. Conclusion This study demonstrates that maintenance therapy with norethandrolone significantly improves survival in elderly patients with AML without increasing toxicity.

Maintenance interferon alpha (IFN-α) immunotherapy after induction chemotherapy prolongs progression-free survival (PFS) in untreated follicular lymphoma (FL). Little information is available about IFN-α use in relapsed FL. This study aims to evaluate the benefit of IFN-α as a treatment of low-burden FL relapse. This single-centre retrospective study identified 20 patients treated in 27 cases with IFN-α. We analysed all cases of IFN-α treatment in patients with low-burden FL in clinical relapse (11), partial response (5) or only with molecular minimal residual disease (MRD; 5). The treatment schedule was 3MIU IFN-α three times a week alone (16) or combined with four weekly rituximab (R; 11), according to the institution's policy. Except for the molecular relapses, responses were evaluated according to the IWG 1999 criteria. MRD was defined as a repeatedly detectable BCL2-IgH rearrangement in peripheral blood or bone marrow. In 22 cases of clinical relapses or partial responders, overall response rate was 68 %, with 55 % complete responses. Median PFS was 20.9 months (95 % confidence interval (95 % CI), 0-64.9) with 20.9 and 48.7 months in the IFN and R-IFN groups, respectively (p = 0.4). The median PFS of the five MRD cases was 133 months (95 % CI, 103-165). The Follicular Lymphoma International Prognostic Index score calculated at initiation of IFN-α treatment was predictive of time to relapse (p = 0.036). These results compare favourably with previous reports of the efficacy of R alone, and of R with IFN-α in relapse. Further research is required to explore the role of IFN-α in the management of FL.

Introduction Frontline treatment of patients in chronic phase of chronic myeloid leukemia(CP-CML) is classically based on tyrosine kinase inhibitors (TKI). Imatinib was introduced in 1998, then second- and third-generation TKIs have been developed. This therapeutic arsenal suggest a possible personalized treatment. The choice of TKI could be guided on the one hand by the potential adverse effects depending on the co-morbidities and on the other hand, the efficiency of treatment since an optimal response during the first year is a therapeutic goal (Baccarani M et al. A review of the European LeukemiaNet recommendations for the management of CML. Ann Hematol 2015, 94 Suppl 2:S141-7). Treatment inefficacy may be related to the persistence of quiescent leukemic cells, characterized by a decreased metabolic activity and redox metabolism inducing a low proliferation rate athough the BCR-ABL mutation is present. The level of reactive oxygen species (ROS) being regulated by antioxidant enzymes, we hypothesized that scoring gene expression levels of major antioxidant enzymes could be of clinical interest when considering the response to imatinib. By combining the gene expression profiles of CP-CML patients at the time of diagnosis and their molecular response (BCR-ABL1/ABL1 ratio) at one-year, we determined a theranostic Imatinib-Response Score (IRS) potentially useful to optimize therapeutic decisions (patent # WO2016083742). Methods The expression of antioxidant genes was quantified from blood samples collected from 122 CP-CML patients at diagnosis and 102 healthy volunteers (HealthOx protocol, ClinicalTrials.gov # NCT02789839). Sokal-scores were calculated and all patients were treated with imatinib for at least one year. Quantification of the BCR-ABL1/ABL1 ratio allowed to determine of the one-year response according to the ELN definition (optimal: BCR-ABL1/ABL1 ≤ 0.1%, warning: BCR-ABL1/ABL1 0.1-1%, failure: BCR-ABL1/ABL1 > 1%). RNA extraction was performed after red blood cell lysis and RNA quality was checked with a 2100 Bioanalyzer (Agilent). The expression of antioxidant genes (SOD1, SOD2, SOD3, CAT, TXN, TXN2, GLRX, GLRX2, GLRX3, GLRX5, GPX1, GPX2, GPX3, GPX4, GPX7, GSR, PRDX1, PRDX2, PRDX3, PRDX4, PRDX5, PRDX6) and 3 housekeeping genes (ACTB, B2M, RPL13A) was quantified by RT-qPCR (LightCycler® 480 and UPL technology, Roche). All targets were concomitantly analyzed in triplicates and average values from patients and aged-matched healthy controls were used to determine Relative Quantification (RQ) values by the 2-ΔΔCt method. Mutations in the ABL kinase domain were studied by direct sequencing. IRS were determined by logarithmic logistic regression performed thanks to the glm() function of the stats package (R v3.2.2 software). The generalized linear model was obtained by logistic regression with weighted RQ and was validated by split-sample strategy (10,000 repeats). Samples were divided into two groups ("learning" and "test" groups) randomly mixing optimal responses and failures. Results and conclusion None of the patients had a mutation in the BCR-ABL kinase domain. The expression levels of numerous antioxidant genes were different when considering optimal response and failure to imatinib treatment. A multifactorial strategy by linear combination of normalized RQ values was used to calculate IRS, which allowed for an efficient discrimination between optimal response(IRS = -3.42±1.44) and failure (IRS = 1.76±0.64) (p-value = 1.4 10-9). The probability of one-year response to imatinib was assessed by empirical cumulative distribution function. This function allowed the prediction of optimal response and failure. As expected, the IRS values of patients with a warning response, not used to build the mathematical model (external validation), were located between those of optimal response and failure. Interestingly, the IRS was not correlated with Sokal-score of CP-CML patients (R2= 0.0333), reinforcing its potential usefulness for clinical management. Altogether, this retrospective multicentric study allowed the determination of a molecular score to predict imatinib response. This simple biological strategy using diagnosis blood sample of CP-CML patients will benefit from prospective studies to adapt therapy. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

Tandem versus single autologous peripheral blood stem cell transplantation as post-remission therapy in adult acute myeloid leukemia patients under 60 in first complete remission: results of the multicenter prospective phase III GOELAMS LAM-2001 trial

Background The 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.Design and Methods This was a retrospective analysis of 214 patients treated with L-asparaginase (7500 IU/m2 x 6) for acute lymphoblastic leukemia or lymphoblastic lymphoma. Between day 1 of the induction course and discharge, clinical events, and biological and therapeutic modifications were reviewed.Results Antithrombin and fibrinogen levels were lower than 60% and 1 g/L in 71% and 73% of patients, respectively. Twenty thromboses occurred in 9.3% of the patients; these patients had a median antithrombin level of 53% (range, 21–111) at the time of the event. Forty-two episodes of bleeding occurred in 31 patients with a median fibrinogen level of 1.3 g/L. Infusions of L-asparaginase were reduced or delayed in 64% of patients due to low fibrinogen and/or antithrombin levels. Fresh-frozen plasma, antithrombin and fibrinogen were infused in 31%, 41% and 52% of patients, respectively. The mean antithrombin and fibrinogen levels increased from 61% to 88% and from 1 to 1.4 g/L after infusion of antithrombin or fibrinogen respectively, while both levels remained unchanged after the infusion of fresh-frozen plasma. In patients who received antithrombin concentrates L-asparaginase injections were less frequently omitted or delayed (53% vs. 72%, p=0.005), the rate of thrombosis was lower (4.8% vs. 12.2%, p=0.04) and the disease-free survival was also reduced (p=0.05).Conclusions This retrospective study suggests that antithrombin concentrates may have a beneficial effect on the outcome of adults treated for acute lymphoblastic leukemia with L-asparaginase; prospective studies are essential to confirm this hypothesis.

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.

Background Treatment with interferon prolongs survival in chronic myelogenous leukemia. We conducted a clinical trial to assess the efficacy of treatment with a combination of interferon and cytarabine. Methods Previously untreated patients with chronic myelogenous leukemia were randomly assigned to receive either hydroxyurea (50 mg per kilogram of body weight per day) and interferon alfa-2b (5 million units per square meter of body-surface area per day), or hydroxyurea and interferon in the same dosages plus monthly courses of cytarabine (20 mg per square meter per day, for 10 days). The end points were overall survival, complete hematologic remission at 6 months, and major cytogenetic response (less than 35 percent Philadelphia chromosome–positive cells in the bone marrow) at 12 months. Results The trial was stopped when a sequential analysis showed a benefit of interferon and cytarabine. A significant improvement in survival was observed in the interferon–cytarabine group (360 patients) as compared wit...

We conducted a randomized multicenter study to compare the efficacy and safety of two antibiotic regimens (cefepime [2 g b.i.d.] plus amikacin or ceftazidime [2 g t.i.d.] plus amikacin) as first-line therapy for fever in patients with hematologic malignancies and neutropenia. A total of 353 patients were randomized according to a 2:1 (cefepime:ceftazidime) ratio. Two hundred-twelve patients in the cefepime group and 107 in the ceftazidime group (90% of all patients) were evaluable for efficacy. The polymorphonuclear neutrophil count was

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.

In a retrospective analysis of T cell depleted bone marrow transplantation, we have looked at different parameters in order to determine risk-factors of graft-failure after allogeneic bone marrow transplantation for leukemia. Fifty-one patients with acute leukemia or chronic myeloid leukemia have been analysed. For 33 of them, the pretransplant conditioning regimen consisted of fractionated total body irradiation (TBI) at 12 Gy prior to cyclophosphamide (120 mg/kg). The other patients received various reinforced preparative regimens. T-cell depletion consisted of treating marrow cells with pan-T monoclonal antibodies (CD2+CD3 or CD2-CD5-CD7) followed by complement mediated cytolysis. No post-transplant immunosuppressive prophylaxis was administered except for the first nine patients who received Methotrexate alone. In this group of 51 patients, 12 died within 3 months from graft-related complications and 10 developed graft failure (no engraftment or rejection). Among the possible risk factors associated with this failure, two graft-related parameters appeared significant: the number of CFU-GM progenitors and the number of viable T cells injected with the marrow inoculum. No correlation with graft failure was found with other parameters including diagnosis, disease status at transplant, conditioning regimen, age, sex, and CMV status of donor/host pairs. However, the interpretation must remain cautious because of the relatively small samples in each group.

A 56-year-old man with refractory B-cell lymphocytic non-Hodgkin's lymphoma was treated in a Phase II study with interleukin-2 (IL-2) (Roussel-Uclaf, Romainville, France). The patient had involvement of multiple lymph nodes and medullary and peripheral blood (3.6 x 10(9) monoclonal CD19-positive [CD19+] B-lymphocytes/l). After a 5-day cycle of IL-2 treatment, an eightfold increase of the monoclonal CD19+ population was observed (27 x 10(9) monoclonal CD19+ cells). The lymphocytosis decreased dramatically during the second cycle (days 15 to 19) of IL-2 treatment, resulting in 6 x 10(9)/l peripheral lymphocytes, with 5.5 x 10(9) B-lymphocytes. As soon as day 20, peripheral B-cells again increased considerably, with 32 x 10(9) CD19+ cells/l at day 27. The CD19+ population remained monoclonal as assessed by kappa/lambda cell-surface phenotyping and kappa gene rearrangement evaluation. Kinetics of the monoclonal B-lymphocyte response to IL-2 paralleled the natural killer/lymphokine-activated killer and T-cell response, with a 4-day latency period, suggesting an indirect enhancing effect of IL-2. Before and during IL-2 treatment, peripheral B-lymphocytes never expressed detectable levels of the p55 IL-2 receptor. However, the p75 IL-2 receptor was expressed significantly in the IL-2-responsive monoclonal B-cell population. Tumor necrosis factor alpha, a known (in vitro) B-cell tumor growth factor, reached high serum levels during IL-2 treatment. Response evaluation at day 45 showed stability of the lymph node involvement and the marrow lymphocyte infiltrate. At day 45, peripheral B-cell lymphocytosis was 7.5 x 10(9)/l. To the knowledge of the authors, this is the first report of an in vivo IL-2-induced reversible increase of peripheral monoclonal B-cell lymphocytosis.

Various 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 x 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-alpha 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.

The present study was designed to compare directly the frequency of circulating LTC-IC and E-LTC-IC mobilized in peripheral blood (PB) after chemotherapy supported by either G-CSF (PB-G) or GM-CSF (PB-GM) in comparison to steady-state bone marrow (BM) and PB (PB-ST) values in the same patients.Long-term cultures (LTC) were performed from 20 patients with malignant lymphoma at saturating cell concentrations to assess bulk progenitor cell production and by limiting dilution assay (LDA) to measure both frequency of LTC-IC and their proliferative and differentiation capacities.While CFC production in bulk LTC was higher at weeks 3-5 with PB-G than with PB-GM samples, week-5 LTC-IC and week-10 LTC-IC (E-LTC-IC) frequencies were not different using a LDA. However, the number of CFC derived from a single LTC-IC was higher in PB-G patients than in PB-GM patients (p = 0.01). Interestingly, the frequency of LTC-IC per 1 x 10(5) MNC in mobilized PB positively correlated with one-year marrow progenitor cell recovery, in contrast to the number of autografted CD34(+) cells and CFU-GM per kg.Both G-CSF and GM-CSF resulted in similar increases in LTC-IC and E-LTC-IC in PB at comparable levels to those present in BM. However, the differentiation capacity of LTC-IC was higher after mobilization with G-CSF than with GM-CSF, suggesting qualitative differences in LTC-IC mobilized with these growth factors.

Cytarabine ocfosfate (YNK01) is a prodrug analogue of cytarabine which is resistant to systemic deamination after oral administration. Following initial studies indicating significant anti-tumour activity of YNK01 a phase II trial was initiated in order to assess the tolerability and efficacy of a combination of this agent with interferon alpha-2b (IFN-alpha2b) in recently diagnosed chronic phase CML patients (n = 98). The treatment was subdivided into cycles consisting of 4 weeks of continuous administration of IFN-alpha-2b (3 MU/m(2)/day 1st week and then 5 MU/m(2)/day) and 14 days of oral YNK01 (600 mg/day 1st cycle). At the end of each cycle the dose of YNK01 was adjusted according to the blood count observed during the previous 4 weeks. The median time from diagnosis to inclusion in the trial was 2 months (range 6 days to 7.5 months). At 12 weeks, 62 patients (63%; 95% CI, 54-73) achieved a complete hematological response. At 24 weeks, of 98 patients, two achieved a complete cytogenetic response, 14 a partial response (16% major cytogenetic response rate; 95% CI, 9-24) and 34 a minor response; 19 patients were not evaluable for cytogenetic response. During the trial, 20 patients progressed to accelerated (6) or blastic phases (14). The median time to progression was 15 months (range 2-38 months). At 3 years the overall survival was 79% (95% CI, 70-88). Although the complete hematological response rate compared favorably with the 40% response rate previously obtained with the subcutaneous formulation of Ara-c, the cytogenetic response rate was less than expected. Most of the patients experienced side-effects and all permanently stopped YNK01. Although the combination seems attractive the initial dose of 600 mg per day is probably too high and should be reconsidered in further trials.

We report the first randomized study assessing the efficacy and safety of daunorubicin (DNR) continuous infusion (CI) compared to the more conventional 30-min infusion (i.v.) in newly diagnosed adult acute lymphoblastic leukemia (ALL). Seventy-seven patients were initially randomized to receive either a 24-h CI DNR (60 mg/m2 days 2-4) (40 patients) or bolus DNR at the same dosage (37 patients) with vincristine (2 mg i.v. days 1, 8, 15) and oral prednisone (60 mg/m2 days 1-15), without hematopoietic growth factor support, as an induction regimen. The distribution of adverse prognostic factors was comparable in the two-induction arm. Acute toxicity was more important in the CI arm. Gram negative infection (9 vs 1 gram negative septicemia, P = 0.01) and infection-related deaths (6 vs 1 deaths, P = NS) occurred more frequently in the CI arm during the induction treatment than in the i.v. arm, leading to the study interruption. Neutropenia but not thrombopenia duration was significantly longer in the CI arm than in the i.v. arm (18 days vs 14 days, P > 0.05 and 16 days vs 12 days, P > 0.05, respectively). Despite a similar CR rate according to the method of DNR administration (68% in the CI DNR arm vs 76% in the i.v. arm after the first course), there was a trend toward higher freedom from relapse (FFR) after DNR CI (48% vs 28% in the i.v. arm at 5 years, P = NS), suggesting that despite this high toxicity, DNR CI may improve the CR quality and decrease further the residual disease.

Introduction Primary refractory Diffuse Large B-Cell Lymphoma (DLBCL) as well as relapse after salvage therapy displays a poor prognosis. Salvage radiation therapy alone does not provide sufficient disease control on locally chemoresistant DLBCL. Autologous stem cell transplantation (ASCT) provides the best progression-free survival when salvaged patients are transplanted in Complete Response (CR). The objective of this study was to assess the effectiveness of CCR in locally relapsed or refractory DLBCL, followed by ASCT in responding patients. Material and methods We report the outcome of consecutive patients with locally relapsed or refractory lymphoma for which a decision of CRC was taken in a single institution. Each patient has been assessed by CT or PET-scan. The CRC regimen consisted in 3 cycles of Rituximab (375 mg/m² day 1), CDDP (30 mg/m² 3 days 1-3) and VP16 (120 mg/m² days 1-3) at 21 days intervals, with concomitant radiotherapy delivered to the residual disease sites, administrated in 2 Gy fractions per day to a total dose of 30 Gy, starting on day 1 of the second cycle. Responding patients received ASCT with a BEAM conditioning at the end of the procedure. Extra-hematological toxicity was ranked according to the Common Terminology Criteria for Adverse Events. Tumor response was evaluated according to IWG 1999 at 1 month after the last cycle of CRC, three months after ASCT if performed and during a quarterly follow-up. Results We identified 13 patients with localized chemoresistant DLBCL from January 2002 to April 2011 including 12 primary refractory forms. The median age was 56 years (20-76), 12 of 13 patients had received at least two lines of chemotherapy before inclusion with anthracycline and cisplatin. 11 patients achieved a partial response (85%) and 4 of them (31%) a complete response after the CRC. 8 (61.5%) patients were transplanted 1 month after the last cycle of CRC. 7 patients have relapsed within 6 months after the end of treatment. After a median follow-up of 37 months (range 21-125) for the surviving patients, 7 patients are alive and free of disease. The overall survival is 54%, and all surviving patients had been transplanted. No severe toxicity was reported. Conclusion CRC should be considered as an option in the therapeutic arsenal in refractory or locally relapsed DLBCL, especially in patients eligible for ASCT. Further research on CRC is warranted. Disclosures: No relevant conflicts of interest to declare.

Background HDACi inhibits aggresome function by acetylation of the tubulin-dynein complex that transports unfolded proteins via aggresomes to lysosomes for degradation, thereby serving as a mechanism for reversal of resistance to proteasome inhibitors. In vivo data have shown that quisinostat, a new oral pan HDACi, has a synergistic activity with bortezomib in preclinical models of MM. Methods Patients were treated with: quisinostat (Q) at escalated doses from 6 to 8 to 10 to 12 mg on days 1, 3, and 5 weekly, subcutaneous VELCADE (V) at 1.3 mg/m2 on days 1, 4, 8, and 11 of a 3-week cycle, and oral dexamethasone (D) at 20 mg on the day of and the day after VELCADE dosing. The primary endpoint was the maximum tolerated dose (MTD) of Q in the combination (Q+V+D). The secondary endpoints included safety, overall response rate, and pharmacodynamics and pharmacokinetics. Results The study has completed enrollment and eighteen patients with relapsed MM (3, 3, 6, and 6 in the 6, 8, 10 and 12 mgQ+D+V cohorts, respectively) were enrolled: 56% male; median age of 69 (range 50-82) years; all subjects received 1 to 3 prior lines of therapy (39% received 1, 50% received 2 and 11% received 3 prior lines) and half of the patients were previously exposed and sensitive to bortezomib. To date, 17 out of 18 patients (94%) discontinued treatment, among which 5 completed 11 cycles of therapy. One patient is currently ongoing. At the highest dose level (i.e., 12 mg), 2 of 6 (33%) patients experienced dose-limiting toxicity (DLT): QTc prolongation and atrial fibrillation. The MTD was therefore established at 10 mg Q for the Q+V+D regimen. Quisinostat oral absorption was rapid, with maximum plasma concentrations achieved approximately between 1 and 3 hours after drug intake. The estimated effective half-life was between 2.5 to 15 hours. Quisinostat Cmaxand AUC were comparable to previous clinical observations and increased approximately proportional with increased dose. VELCADE exposure was in line with previous clinical observations. Most common (≥15% of patients) drug related adverse events were asthenia (56%), thrombocytopenia (56%), diarrhea (44%), oedema peripheral (39%), peripheral sensory neuropathy (39%), constipation (33%), insomnia (28%), neuralgia (28%), vomiting (28%) and nausea (28%); most of them were grade 2 or lower in toxicity. The most common (≥10% of patients) grade ≥3 drug related events included thrombocytopenia (39%), QT prolongation (11%), asthenia (11%) and insomnia (11%). Dose reduction for myelosuppression (thrombocytopenia ≥G3) was required for VELCADE in 4 patients in the 10 and 12 mg cohorts. Quisinostat dose reductions were required for asthenia G2 and G3 in 2 patients (dose level 8 and 10mg). The overall response rate was 88.2% (15 of 17 patients, 95% CI: 63.6% to 98.5%), including 1 complete response, 3 very good partial responses, and 11 partial responses. The median duration of response was 6.8 months, ranging between 2.8 and 19.6 months. The observed pharmacokinetic profiles of quisinostat and bortezomib were in line with historical data. Two of 5 patients showed an increase in acetylated histone 3 from baseline as measured in peripheral blood mononuclear cells. Conclusion Preliminary results indicate that the MTD is 10 mg quisinostat in combination with standard doses of VELCADE and dexamethasone. The combination is active in the treatment of relapsed multiple myeloma with a high response rate and has an acceptable safety profile. Disclosures: Moreau: Janssen: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Facon:Janssen: Consultancy; Millennium: Consultancy; Celgene: Consultancy. Benboubker:Celgene: Consultancy. Badamo-Dotzis:Quintiles: Employment. Phelps:Janssen: Employment, Equity Ownership. Doty:Janssen: Employment. Smit:Janssen: Employment, Equity Ownership. Fourneau:Janssen: Employment, Equity Ownership. Forslund:Janssen: Employment. Hellemans:Janssen: Employment, Equity Ownership. Leleu:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; Leopharma: Consultancy, Honoraria; Millennium : Honoraria; Amgen: Honoraria; Novartis: Honoraria.

Background Maintenance interferon-alpha (IFNa) immunotherapy after induction chemotherapy prolongs progression-free survival (PFS) in untreated follicular lymphoma (FL). Little information is available about IFNa use in relapsed FL. Objectives To evaluate the benefit of IFNa as treatment for low-burden FL relapse. Methods In this single-centre retrospective study, we analysed all patients with molecular or clinical relapsed low- burden FL who received 3MIU IFNa three times a week alone (16 times) or in combination with 4-weekly rituximab (R) (11 times), without chemotherapy, according to the institution’s policy. All responses were evaluated according to the IWG 1999 criteria, except for molecular relapses which are described separately. Results 20 patients (13 men, 7 women), treated for a total of 27 times with IFNa were identified, with a median follow-up of 85 months. At diagnosis, 17 patients had advanced III-IV stage and 5 of them a high tumour burden, according to GELA criteria. 5 patients were treated for molecular IGH-BCL2 relapses. The FLIPI score was intermediate or high risk in 37% of patients. The median age of patients at the first IFNa +/- R treatment was 51 years (range: 30-65). Patients had previously received a median of three lines of treatment (range: 1-6) and 59% had received anthracycline-based chemotherapy. In the 22 situations with measurable disease, the overall response rate (OR) was 70%, with 59% complete responses (CR). For patients with only detectable molecular disease (n=5), IFNa was used alone for a median duration of 15 months (range: 12- 21 months), MRD becoming negative in 4 patients. The only factor significantly correlated with maximum response was low FLIPI score calculated at study entry (p=0.02). Median PFS was 56.9 months, (95% CI: 0.8-113). The R-IFNa and IFNa subgroup outcomes did not statistically differ in response or PFS. The FLIPI score calculated at initiation of IFNa treatment was predictive of time to relapse (P=0.014). The overall survival at 5 years was 95 % (95%CI: 91-99): 100% in the IFNa group and 91% (95%CI: 82-100) in the R-IFNa group. Reported toxicity was low. Conclusion Interferon alpha with or without rituximab achieve high response rates in relapsed low burden follicular lymphoma. These results compare favorably with previous reports of the efficacy of R alone, and of R with IFNa in relapse. Further research is required to explore the role of IFNa in the management of FL. Disclosures: Gyan: Roche: Research Funding.

Abstract 2841 Introduction: Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) characterized by bone marrow fibrosis, splenomegaly, cytopenias and constitutional symptoms. Ruxolitinib was recently approved by the FDA for the treatment of MF in the USA; its approval in Europe is still pending. However, EU patients may access to ruxolitinib through compassionate programs. In France, health authorities opened a compassionate patient-named program (Authorization for Temporary Utilization [ATU] program. Methods: 241 French patients (pts) with MF, including primary (PMF), post-polycythemia vera (PPV) and post-essential thrombocythemia (PET) MF were granted ruxolitinib therapy through ATU program, independently of their JAK2 mutational status, between April 15, 2011 and May 31, 2012. Physicians were asked to provide information on disease characteristics, treatment history, constitutional symptoms, spleen size, platelet and neutrophils count, as well as the ruxolitinib dose prescribed and adverse events (AE). Request forms had to be submitted at the time of initial application and every 3 months upon drug resupply or in case of treatment discontinuation. This analysis has been performed based on data available at baseline (n= 241), after 3 months (n= 101), 6 months (n= 57), 9 months (n= 21) and 12 months (n= 4). Results: In the entire cohort, 138 pts were men and 103 women. Median age was 68.3 years. 51.5% of pts had PMF, 22.8% PPV-MF and 23.8% PET-MF. 99.2% of pts had received ≥1 lines of therapy for MF prior to ruxolitinib (hydroxyurea: 56%; pipobroman: 15.4%; iMIDs: 13.7%; interferons: 13.7%; erythropoietins: 6.6%; spleen irradiation: 6.6%; anagrelide: 5.8%; corticosteroids: 4.9%). Despite these therapies, 93.7% had constitutional symptoms and 94.2% of patients presented a palpable splenomegaly (median 15 cm below costal margin) at inclusion. Efficacy: According to the baseline platelet count, ruxolitinib therapy was initiated at 15 mg BID in 132 pts (54.8%) or 20 mg BID in 103 pts (42.7%), or other doses in a minority of pts (n=6). Among the pts who were evaluable after 3 and 6 months of therapy, 96.5% and 90% presented a mean reduction in the spleen size (by palpation) by 47.2% and 46% from baseline, respectively. Constitutional symptoms resolved in 65.3% and 70.2% of pts at the aforementioned time points, respectively. In pts who completed 9 months follow-up (n=21), benefits in spleen size reduction and symptoms resolution were durable (95% and 71.4%). Safety: Since the beginning of the ruxolitinib ATU program, 83 pts presented at least one AE, including 27 pts with serious AE (SAE), with or without causal relationship to ruxolitinib therapy. AE, all grades, were essentially hematologic abnormalities (51.6%), gastro-intestinal 6.3%, cardiac 3.1%, musculoskeletal 3.1%, hepatic 2.3%, infection 2.3%. Dose adjustments were reported in 60 pts, mainly due to thrombocytopenia (n=36) and anemia (n=13). However, no patient discontinued ruxolitinib therapy because of cytopenia. Treatment was discontinued in 11 patients after a median duration of 2.6 months (range 0.3–7.9 months). Reasons for discontinuation were death (n=6), AE (n=2), inefficacy (n=2), and patient decision (n= 1). Conclusion: In this large, unselected population of heavily pretreated MF pts, ruxolitinib therapy appeared to be effective in treating both constitutional symptoms and splenomegaly, in line with previously reported efficacy in clinical trials. The safety profile seems also comparable. Comprehensive data and updated follow-up of the cohort will be presented. Disclosures: Off Label Use: compassionate use of ruxolitinib for myélofibrosis in France (indication not yet approved by EMEA). Rey:Novartis: Consultancy. Nicolini:novartis, Bristol myers Squibb, Pfizer, Ariad and Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Recher:Celgène, Genzyme, Sunesis, Jansen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel to ASH Other. Ranta:Novartis: Membership on an entity's Board of Directors or advisory committees. Legros:Novartis, Bristol Myers-Squibb: Research Funding, Speakers Bureau, Travel to meeting Other. Viallard:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dupriez:novartis: Membership on an entity's Board of Directors or advisory committees. Coiteux:Novartis, Bristol Myers-Squibb: Speakers Bureau. Demory:Novartis: Honoraria. Giraudier:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ugo:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Travel to ASH Other. Kiladjian:Incyte: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Roy:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel to ASH Other.

Serial determination of soluble CD8 (sCD8), soluble IL-2 receptors (sIL-2R), and tumor necrosis factor-alpha serum levels were performed in bone marrow transplant patients upon initiation, day 0 (D0) and at D10 of an anti-IL-2 receptor (alpha chain) monoclonal antibody (B-B10) in vivo treatment for steroid-resistant grade greater than or equal to 2 acute graft-versus-host disease (aGVHD). D0 and D10 sCD8 serum levels correlated strongly with response to B-B10 treatment (p = .003 and .001, respectively); 76% of the patients with D0 sCD8 levels less than 500 U/ml responded favorably to B-B10 treatment, versus only a 30% response if the sCD8 levels were greater than 500 U/ml (p = .02). Likewise, D0 tumor necrosis factor-alpha levels significantly correlated with subsequent response to B-B10 treatment (p = .03). D0 sIL-2R levels were not significantly different in B-B10-responsive and nonresponsive aGVHD patients. These results suggest that the serial determination of sCD8 and TNF serum levels could provide valuable predictive information as to steroid-resistant aGVHD responsiveness to anti-IL-2R treatment.

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

From 11/2001 until 04/2005, 832 patients (median age 46, 18–60) with AML (previous diagnosis of myelodysplasia or myeloproliferative disorder, and M3 excluded) were 1st randomized to received induction with continuous IV ARAC (200 mg/m2, x 7d) and Daunorubicin (D: 60 mg/m2 x 3d) OR Idarubicin (I: 8 mg/m2 x 5d). If marrow blasts > 5% on D15, 2nd induction course was applied (D: 35 mg/m2 x 2d OR I: 8 mg/m2 x 2d plus ARAC 1 g/m2 x 4 doses over 2d). After achieving CR, all patients received low dose consolidation (D: 60 mg/m2 x 2d OR I: 12 mg/m2 x 2d plus SC ARAC 100 mg/m2 x 7d). Patients with HLA-identical sibling receive a T-replete alloSCT: either conventional (bone marrow graft, TBI-cyclophosphamide, ciclosporin-methotrexate) if age ≤ 50 = arm M; or non myeloablative (NST: peripheral blood, Busulfan (Bu)-Fludarabin-Thymoglobulin®, ciclosporin alone), AFTER intensive consolidation (idem below) if age 51–60 = arm m. A small subgroup of patients (3 % patients in CR) with a donor but low-risk prognostic features (favorable cytogenetics, no hyperleucocytosis, CR after 1 induction) did not receive 1st line alloSCT but intensive consolidation then a 2nd HD ARAC course; alloSCT was therefore considered for relapse = arm C. Other patients proceed to 2nd randomization: intensive consolidation (D: 60 mg/m2 x 2d OR I: 12 mg/m2 x 2d plus ARAC 3 g/m2 x 8 doses over 4d) PLUS 1 autoSCT (Bu 16 mg/kg over 4d + HDM 140 mg/m2) = arm A; or intensive consolidation PLUS 2 autoSCT (HDM 200 mg/m2 THEN Bu 16 mg/kg over 4d + HDM 140 mg/m2) = arm B. After 1st randomization (D vs I), no difference was observed between 2 arms regarding age, leukocytosis or cytogenetic subgroups: favorable (t8;21) or inv16: D = I 13%), intermediate (D 66%, I 59%), defavorable (5, 7, complex, 11q23 except t(9;11) or 3q; D 21%, I 28%). Use of both anthracyclins results in same CR rate (D 83% vs I 85%); early death (3%); projected EFS (D 46% vs I 50%, p = 0,28) and OS (D 61% vs I 64%) at 2 years. Noteworthy was the more frequent use of 2nd induction course to obtain CR with D (30%) as compared with I (22%). 78% of all patients in CR proceeded to 2nd randomization or were assigned to alloSCT arms (33 % of them). Actual results concern 550 patients with 15 months follow-up. No benefit was observed with addition of HDM 200 for 2y projected DFS (A 53% vs B 49%) or OS (A = B 68%). Toxic death rate was higher in arm B, accounting for 18% total deaths vs 6% in arm A. Conventional alloSCT results in better 2y DFS than combined arms A+B (M 71% vs A+B 52%, p=0,007) thought 2y OS advantage remains non significant (M 77% vs A+B 68%, p=0,06). No significant difference was observed between conventional and NST (2y DFS 62%, OS 68%). Advantage for NST over autoSCT arms was non significant for DFS (p=0,24) and OS. Same results are obtained if considering only patients aged > 50 : 2y EFS (m 62% vs A+B 50%, p=0,27) and OS (m 68% vs A+B 65%). In conclusion: conventional alloSCT remains the best consolidation treatment for patients ≤ 50 with AML in CR1; NST after intensive consolidation seems promising for older patients and may extend use of alternative sources of alloSCT; HDM course adds no benefit for these patients. Data with more than 2 years follow-up will be presented.

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

Ph+ ALL accounts for approximately one third of ALL cases in patients aged 55 years or older. The median survival of older Ph+ ALL patients is one year, with practically no long-term survivors (Blood, 98, Supp1 p319a, 2001). Imatinib has demonstrated remarkable, although transient, activity in relapsed and refractory Ph+ ALL, which prompted the GRAALL to implement a treatment protocol alternating chemotherapy and imatinib in previously untreated elderly patients: ALL patients aged 55 years or older were treated with steroids during one week and Ph+ cases were then offered a specific therapy including an induction treatment with steroids, cyclophosphamide, daunorubicin and vincristine, followed, irrespective of response to induction chemotherapy, by imatinib, 600 mg daily, combined with intermittent steroids during 2 months. Patients in complete response (CR) were then given 10 blocks of alternating chemotherapy, including 2 additional two-month blocks of imatinib, for a total treatment duration of 2 years. Therapy of occult central nervous system leukemia included 5 intrathecal injections of methotrexate and cranial irradiation. Results are compared with those obtained in 21 Ph+ ALL elderly patients treated according to our previous protocol. From January 2003 to November 2004, 30 patients aged 58 to 78 years (median: 65.8 years) were included in the present study. The median follow-up of surviving patients is 15 months. 20/29 assessable patients were in complete response after induction chemotherapy vs 6/21 in the historical controls given similar induction regimen but with no steroids before chemotherapy (p=0.009). Two patients died during induction treatment vs none in the control group. Out of 6 patients alive with disease at completion of induction, 5 were in CR after salvage with imatinib. The projected overall survival is 71% at 1 year vs 43% in the control group (p=0.008, log-rank test). The 1 year projected relapse-free survival is 58% vs 11% (p=0.003) and the projected 1 year event-free survival (defined as failure to obtain a CR, death or relapse) is 57% vs 5% (p

Imatinib (IM) at 400 mg daily has emerged as the preferred therapy for newly diagnosed CML pts. Despite impressive results, only a minority of pts treated with IM achieved a molecular remission. To improve upon these results, the CML French Group designed a phase III, multicentre, open-label, prospective randomized trial. The experimental arms are IM 400mg daily in combination with Peg-IFN-α2a (Peg-IFNα2a, 90 μg weekly) or IM 400mg daily in combination with Ara-C, (20 mg/m2/day, days 15–28 of 28-day cycles) or IM 600mg daily. The reference arm is IM 400mg daily. All pts (over 18 years of age with Bcr-Abl positive CML in chronic phase within 3 months of diagnosis) receive IM 400 mg/day as monotherapy days 1–14 and then start the assigned randomized regimen. Treatment continues at least 12 months or until treatment failure (disease progression by hematologic criteria) or major toxicity. The primary endpoint will be the overall survival. Other endpoints will be: rate and duration of hematologic and cytogenetic responses, major (MCyR) and complete (CCyR), molecular response and the tolerability. Using treatment allocation ratio 1.1.1.1, randomization is stratified according to Sokal risk groups. An interim analysis of the first 636 patients (α=0.85%, β=10%) at 1 year from randomization will allow evaluation of molecular response rates, one of the experimental arm being selected for further comparison with IM 400. The increased dose of IM or a combination regimen would be considered as promising if it increased the 4 log reduction response rate by at least 20 percentage points, e.g. from 15% to 35%, with an acceptable tolerability. Evaluation of molecular response up to 12 months is centralized and blinded. This evaluation is based on a cohort of 315 pts with a median time of observation of 12 months, recruited between 9/2003 and 6/2005.[median age 53 yrs (18–78), 60% of pts were male; Sokal risk distribution: 39% of pts low risk, 38% intermediate risk, and 23% high risk]. At 3 months 82% of pts achieved complete hematologic response. Cytogenetic data are available from 154 pts. At 6 months, 135 pts (87%) achieved a MCyR, being complete in 105 pts (68%). Grade 3/4 neutropenia and thrombocytopenia occurred in 5% and 0% of IM400 pts, in 5% and 1% of IM600 pts, in 30% and 4% of IM+IFN pts and in 24% and 13% of IM+Ara-c pts respectively. Dose of Peg IFN was reduced in 16% of pts, 45 μg per week being well tolerated. Grade 3/4 non hematological toxicity occurred in 6% of IM400 pts (mainly skin rash and muscle cramps), in 10% of IM600 pts, in 5% of IM+IFN pts (maily skin rash) and in 13% of IM+Ara-c pts (mainly diarrhea). Discontinuation of experimental treatment occurred in 15% of IM600 pts, 28% of IM+IFN pts and in 13% of IM+Ara-c pts. This first analysis of a randomized trial has proven feasibility of IM combinations in addition to high response rates. However a substantial hematological toxicity was recorded with IFN or Ara-c combination, which requires a careful assessment during the first 6 months of treatment. Long-term observation will demonstrate whether these promising results will have the potential to improve survival of CML pts.

The incidence of AT and Fg deficiency and of thrombotic and bleeding events after Asp has been well evaluated in children with ALL, but little is known in adults. In this study, the incidence of these events and the use of coagulation supportive treatments was evaluated in 214 adult patients with ALL (n= 191) or LBL (n=23) included in the GOELAL02 trial (Blood 2004, in press). The induction therapy included steroids (40 mg/m2/d d1-21), vincristine (2 mg d1, 8, 15, 22), idarubicine (5 mg/m2 d1, 8,15, 22) and Asp (7500 UI/m2 d10, 13, 16, 19, 22, 25) delivered through a central venous access. Fresh frozen plasma (FFP), Fg (Clottagen®) and AT (Aclotine®) concentrates were recommended to maintain their levels > 1 g/l and 60%, respectively. If no transfusion, Asp infusion was delayed for 48 hours. Platelets were transfused when < 20 x 109/l. Heparin prophylaxis was left to institutional guidelines. Symptomatic thromboses and significant bleedings were systematically recorded. Active DIC was present in 10.3% of patients on d1. Fg and AT levels were measured 4098 times (20/patient, von Clauss assay) and 1718 times (8/patient, chromogenic assay) respectively, and evolved between d1 and d35 as shown below (mean ± sd). AT nadir was < 60% in 71% of patients with values < 40% in 26% of cases. Fg levels were < 1g/l in 73% of patients with values < 0.5g/l in 9%.Twenty-one thromboses occurred two to 35d after the first Asp infusion (median = 14d) in 20 patients (9.3%), with cerebral vein thrombosis (5), pulmonary embolism (3), upper (5) or lower (8) limb deep vein thrombosis. At the time of event, the median AT level was 48% (mean 60.7) with 12 of 21 thromboses (57%) occurring with AT < 60%. Fourty-two bleedings occurred one to 45d after the first Asp infusion (median = 8d) in 31 patients, with CNS hemorrhage (1), epistaxis (24), central venous access bleeding (8), GI bleeding (1), and large ecchymoses (8). At the time of event, median Fg level was 1.3 g/l. Asp infusions were reduced or delayed in 64% of all patients due to low Fg and/or AT levels. FFP, AT and Fg were infused in 31%, 41% and 52% of patients at mean doses of 5.3 ml/kg/infusion, 31UI/kg/infusion and 7.9 g respectively. AT level increased from 58%±16 (n=79) to 86%±23.2 (n=57) after the first AT infusion but was unchanged after FFP. Fg level increased from 0.9g/l ± 0.3 (n=85) to 1.4g/l ±0.5 (n=69) after Fg infusion but was unmodified after FFP. In conclusion, Fg and AT levels are frequently decreased in adults treated by Asp, with often a less than optimal chemotherapy. Bleeding events were not associated with severe Fg deficiency, but thrombotic events could be favored in some patients by acquired AT deficiency. The benefit of AT concentrates to prevent thrombosis and to reduce delay in Asp infusions could therefore be prospectively assessed in adults treated by Asp. d1 (n) d10-Asp 1 (n) d13-Asp2 (n) d19-Asp 4 (n) d25-Asp 6 (n) AT % - 121±16 (79) 83±16 (125) 65±20 (111) 65±22 (77) Fg g/l 3.2±1.7 (142) 1.9±1.0 (159) 1.4±0.7 (195) 1.1±0.4 (169) 1.4±0.6 (118)

Ph+ ALL accounts for approximately one third of ALL cases in patients aged 55 years or older. The median survival of older Ph+ ALL patients is one year, with practically no long-term survivor (Blood, 98, Supp1 p319a, 2001). Imatinib has demonstrated remarkable, although transient, activity in relapsed and refractory Ph+ ALL, which prompted the GRAALL to implement a treatment protocol associating imatinib and chemotherapy in previously untreated elderly patients: ALL patients aged 55 years or older are treated with steroids during one week and Ph+ve cases are then offered a specific therapy including an induction treatment with steroids, cyclophosphamide, daunorubicin and vincristine, followed, irrespective of response to induction chemotherapy, by imatinib, 600 mg daily, combined with intermittent steroids during 2 months. Patients in complete response are then given 10 blocks of alternating chemotherapy, including 2 additional two-month blocks of imatinib, for a total treatment duration of 2 years. Therapy of occult central nervous system leukemia includes 5 intrathecal injections of methotrexate and cranial irradiation. The study is intended to include 30 patients and its main objective is to improve overall one-year survival to 70%. Results are compared with those obtained in 21 Ph+ ALL elderly patients treated according to our previous protocol. Since January 2003, 21 patients aged 58 to 78 years (median: 64.7 years) were included in the AFR09 protocol. Their median follow-up is 3 months. 15/19 patients are in complete response after induction chemotherapy vs 6/21 in the historical controls given similar induction regimen but with no steroids before chemotherapy (p=0.002). The projected overall survival is 95% at 9 months vs 62% in the control group (p=0.08, log-rank test). The 9-month projected event-free survival is 83% vs 10% (p

This phase II study investigated the efficacy and safety of alemtuzumab (Campath-1H), as treatment to achieve a second minimal residual disease (MRD) negative complete remission, in patients with relapsed B-cell chronic lymphocytic leukemia (B-CLL) after autologous stem cell transplantation (ASCT). Only patients who had experienced a posttransplantation MRD negative status and with a low tumour burden at relapse were eligible for the study. Eleven patients were treated. Nine patients were Binet Stage A and two patients had converted to an MRD positive status. The median time from ASCT was 36 months (range, 15–66 months). Alemtuzumab was administered as a 30 mg intravenous injection three times weekly for a maximum of 12 weeks. All patients received valacyclovir and trimethoprim/sulfamethoxazole as infection prophylaxis during therapy and 6 months after. Cytomegalovirus (CMV) reactivation was monitored weekly using a blood antigen test. Patients with Binet stage A were evaluated according to National Cancer Institute (NCI) criteria. MRD assessment was performed in complete responders and the two MRD relapses in blood and bone marrow using sensitive techniques as MRD Flow (Rawstron et al, Blood 2001, 98: 35) and nonspecific allele IgH PCR. Among nine patients assessed for disease response by NCI criteria, two (22%) achieved a partial response and five (55%) a complete remission (overall response rate [ORR], 77%). The overall median response duration was 9 months (range, 4–18+ months) and 12 months (range, 6–18+ months) for complete responders. Five patients (45%) converted to a phenotypic and molecular complete remission, with a median response duration of 6 months (range, 4–18+ months). Two patients remained in MRD negative complete remission after therapy at 18+ and 12+ months, respectively. The treatment-free median survival has not been reached for complete responders, with a median follow-up of 14 months. All patients were evaluable for toxicity. WHO grade 1–2 infusion-related reactions were observed in up to 90% of patients with the initial escalating dose. A moderate hematological toxicity was reported, except for platelets. Frequency of grade 3–4 events during therapy were as follows: 27% of anemia, 18% of neutropenia and 54% of thrombocytopenia. A delayed-onset neutropenia occured in three patients, up to 2 months after completion of treatment. Grade 2 infections were observed in six patients (54%). Only one patient experienced a major infection. Two patients (18%) developed CMV reactivation, CMV disease was successfully prevented by treatment with oral ganciclovir, without discontinuing alemtuzumab therapy. Alemtuzumab has demonstrated activity and safety in relapsed B-CLL patients after ASCT with an ORR of 77% and an MRD negativity of 45%. However, the question of maintaining a durable MRD negative complete response remains posed.

PURPOSE: Ten years after the first clinical studies, the clinical impact of myeloid growth factors in acute myeloid leukemia is still unclear. One of the objectives of the Groupe Ouest-Est Leucémies Aigues Myeloblastiques (GOELAM) 2 trial was to evaluate the benefit of granulocyte colony-stimulating factor (GCSF) given only after the two courses of intensive consolidation chemotherapy (ICC) used to maintain complete remission (CR). PATIENTS AND METHODS: One hundred ninety-four patients who were in CR after induction treatment were randomly assigned to receive G-CSF (100 patients) or no G-CSF (94 patients) after two courses of ICC (ICC 1, high-dose cytarabine plus mitoxantrone; ICC 2, amsacrine plus etoposide). G-CSF (filgrastim) was administered from the day after chemotherapy until granulocyte recovery at a daily dose of 5 μg/kg. RESULTS: In the G-CSF group, the median duration of neutropenia (< 0.5 × 109/L) was dramatically reduced, both after ICC 1 (12 v 19 days, P < .001) and after ICC 2 (20 v 28 days, P < .001). The median duration of hospitalization was also significantly shorter in the G-CSF group (24 v 27 days after ICC 1, P < .001; 29 v 34 days after ICC 2, P < .001). The median duration of intravenous antibiotics was significantly reduced after ICC 1 and ICC 2, and the median duration of antifungal therapy was significantly reduced after ICC 1. However, the incidence of microbiologically documented infections, the toxic death rate, the 2-year disease-free survival, and the 2-year overall survival were not affected by G-CSF administration. Moreover, the median interval between ICC1 and ICC2 was reduced by only 2 days, and the number of patients undergoing ICC2 was not increased in the G-CSF arm. CONCLUSION: 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.

To improve the results in the treatment of adult acute lymphoblastic leukemia patients, different strategies have been proposed. The intensification could concern the induction and early consolidation phases, the conditioning regimen before allogeneic bone marrow transplantation (alloBMT), or both. We analyzed 2 consecutive trials for adult patients in first remission and with the same prognostic features. The Leucemie Aigue Lymphoblastique Paris-Ouest-France (LALPOF) protocol proposed alloBMT with standard conditioning after a classic induction and intensified consolidation scheme; the Groupe Ouest Est des Leucemies Aigues Lymphoblastiques (GOLEAL1) protocol tested an intensified induction and consolidation course before alloBMT with a reinforced conditioning regimen. The 4-year survival rates after alloBMT for LALPOF and GOELAL1 were, respectively, 71% +/- 12% and 36% +/- 13% ( P = .009). The 4-year disease-free survival reached 75% +/- 11% in the LALPOF study and 69% +/- 13% in the GOELAL1 study ( P = .30). The toxic death rate was significantly lower in the LALPOF (2/18) than in the GOELAL1 (6/15) group. Event-free survival at 4 years was significantly higher in LALPOF than in GOELAL1: 66% +/- 11% and 35% +/- 11%, respectively ( P = .02). For adult acute lymphoblastic leukemia patients in first remission, the intensification of chemotherapy before a reinforced conditioning regimen before alloBMT may lead to an increased toxic death rate.

Background and aim of the study: Autologous stem cell transplant (ASCT) has been shown to be an effective treatment for first-line and relapsed follicular lymphomas (FL). But no long term molecular remission was described. The aim of this retrospective study was to determine the clinical and molecular outcome of patients with FL who received ASCT during a 12-year period. Method: All patients who underwent ASCT for first-line or relapsed FL between January 1992 and December 2004 were included. Overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier method and cumulative incidence of nonrelapse mortality (NRM), with relapse as a competing event, by Fine and Gray method. Patient characteristics: Seventy-one patients with a median age of 45 years and a median follow-up of 108 months were analysed. The majority were of the subtype grade 1 (57 %), had a high tumour burden (50 %) and were treated in firstline (52 %). After an anthracyclin-based induction regimen, 12 patients were in first complete remission (CR), 25 in first very good partial response (VGPR), 8 in second CR and 26 in second VGPR. They received BCNU, Etoposide, Aracytine, Melphalan (BEAM in 58 %) or Cyclophosphamide, total body irradiation (42 %) as conditioning for the ASCT. The majority of them received an unpurged graft (58%). Results : Thirty-eight patients were alive, 24 without progression between 4 and 12 years; 31 patients had died, 7 without progression. A total of 38 patients (55 %) developed recurrent lymphoma. Median OS was estimated at 8 years and 4 months. The ten-year PFS and the ten-year OS were 33 % and 47 %, respectively and the tenyear molecular PFS was 37 %. There was an apparent plateau on the remission duration curve at 32 % at 72 months and on the molecular remission duration curve at 37 % at 80 months. A plateau on the OS curve seemed to emerge at 41 % from the tenth year. Patients who received a purged graft had better OS and better PFS (median OS not reached versus 50 months, p = 0.08; median PFS not reached versus 22 months, p = 0.035) Three patients developed a secondary neoplasm and two a secondary myelodysplastic syndrome. The 10-year non-relapse mortality (NRM) was 20 %. Conclusion : This long follow-up study showed a plateau on the PFS and on the molecular PFS curves, suggesting that a selected group of patients might be cured by ASCT.