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The H97-I trial (1997-2004) for Hodgkin lymphoma at intermediate stage (HL-I) included 269 patients who were randomized to receive three or four cycles of doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD). The 197 patients who reached complete remission (CR) (73.2%, p = 0.41 between arms) received radiotherapy (RT); their 10-year progression-free survival (PFS) rate was 87.7 ± 3.0%, similar to that of the 180 patients of a historical control group (HCG) in CR after three ABVD cycles before RT. The 59 patients who reached post-ABVD partial remission (PR) received one course of intensive chemotherapy (i.v., mg/m(2), vindesine 5, adriamycin 90, BCNU 140, etoposide 600, methylprednisolone 600) before RT. In spite of this additional intensive chemotherapy, their PFS rate (78.4 ± 6.3%) remained significantly lower (p = 0.03) than that of the 197 patients who reached post-ABVD CR, and was similar to that of the 60 patients of the HCG in PR after three ABVD cycles who did not receive additional chemotherapy before RT.

This multicentre prospective randomised trial compared the efficacy and safety of two doses of thalidomide in patients with relapsed or refractory myeloma. The study was designed to test the non-inferior efficacy and to confirm the better tolerability of low-dose thalidomide as compared to a higher dose. Four hundred patients were randomly assigned to receive either 100 or 400 mg/day of thalidomide. Dexamethasone treatment was added in both arms for patients with stable disease or treatment failure at 12 weeks. The primary endpoint was 1-year overall survival (OS). Thalidomide 100 mg/day was better tolerated than 400 mg/day with less high-grade somnolence, constipation, nausea/vomiting and peripheral neuropathy (P < 0.001, P = 0.007, P = 0.03 and P = 0.007, respectively). In the per-protocol population (PP), the estimated 1-year OS rates were of 74.5% (n = 149) and 67.3% (n = 156) in the 400 and 100 groups, respectively. The upper limit of the difference between these rates was of 15.6% higher than the non-inferiority acceptable limit of 12.75%, and the hypothesis of non-inferiority of 100 could not be established (P = 0.14). On the other hand, when intent-to-treat (ITT) population was analysed, the non-inferiority was demonstrated because the 1-year OS rates were of 72.8% (n = 195) and 68.8% (n = 205) in the same groups, leading to an upper limit of the difference of 11.49% lower than the non-inferiority acceptable limit. In addition, in patients alive 12 weeks postrandomisation and those who received thalidomide plus dexamethasone, there were no significant differences in response rates, time to progression, progression-free survival and OS between the two groups. Collectively, low-dose thalidomide 100 mg/day has significant activity in advanced myeloma with an improved safety profile and can be a good salvage therapy in combination with dexamethasone.

Purpose To compare efficacy and safety of bortezomib plus dexamethasone and vincristine plus doxorubicin plus dexamethasone (VAD) as induction before stem-cell transplantation in previously untreated myeloma. Patients and Methods Four hundred eighty-two patients were randomly assigned to VAD (n = 121), VAD plus dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP) consolidation (n = 121), bortezomib plus dexamethasone (n = 121), or bortezomib plus dexamethasone plus DCEP (n = 119), followed by autologous stem-cell transplantation. Patients not achieving very good partial response (VGPR) required a second transplantation. The primary end point was postinduction complete response/near complete response (CR/nCR) rate. Results Postinduction CR/nCR (14.8% v 6.4%), at least VGPR (37.7% v 15.1%), and overall response (78.5% v 62.8%) rates were significantly higher with bortezomib plus dexamethasone versus VAD; CR/nCR and at least VGPR rates were higher regardless of disease stage or adverse cytogenetic abnormalities. Response rates were similar in patients who did and did not receive DCEP. Post first transplantation, CR/nCR (35.0% v 18.4%) and at least VGPR (54.3% v 37.2%) rates remained significantly higher with bortezomib plus dexamethasone. Median progression-free survival (PFS) was 36.0 months versus 29.7 months (P = .064) with bortezomib plus dexamethasone versus VAD; respective 3-year survival rates were 81.4% and 77.4% (median follow-up, 32.2 months). The incidence of severe adverse events appeared similar between groups, but hematologic toxicity and deaths related to toxicity (zero v seven) were more frequent with VAD. Conversely, rates of grade 2 (20.5% v 10.5%) and grades 3 to 4 (9.2% v 2.5%) peripheral neuropathy during induction through first transplantation were significantly higher with bortezomib plus dexamethasone. Conclusion Bortezomib plus dexamethasone significantly improved postinduction and post-transplantation CR/nCR and at least VGPR rates compared with VAD and resulted in a trend for longer PFS. Bortezomib plus dexamethasone should therefore be considered a standard of care in this setting.

Peripheral T-Cell lymphomas (PTCL) are relatively rare diseases but appear to be highly aggressive and display worse remission and survival rates than B-cell lymphomas. Despite unsatisfactory results with the cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) regimen, it remains the reference front-line therapy in these diseases, but has not been challenged in phase III trials. The Groupe Ouest Est d'Etude des Leucémies et Autres Maladies du Sang (GOELAMS) devised an alternative therapeutic schedule including etoposide, ifosfamide, cisplatin alternating with doxorubicin, bleomycin, vinblastine, dacarbazine (VIP-reinforced-ABVD; VIP-rABVD) and compared it to CHOP/21 as front-line treatment in non-cutaneous PTCL. All newly diagnosed patients were eligible. The primary objective was to improve the 2-year event-free survival (EFS) rate. Secondary objectives were to compare the response rate, overall survival, and toxicities as well as identify prognostic factors. Eighty-eight patients were identified between 1996 and 2002. Both arms were well balanced for patients' characteristics in terms of histological and clinical presentation. No significant difference was observed between the two arms in terms of 2-year EFS. Anaplastic large cell lymphoma type and Ann Arbor stage I-II were identified as two independent favourable prognostic factors influencing survival. VIP-rABVD was not superior to CHOP/21 in terms of EFS as first-line treatment of PTCL, confirming that CHOP/21 remains the reference regimen in these lymphomas.

International audience; To evaluate the effect of rituximab in poor-prognosis patients with diffuse large B-cell lymphoma (DLBCL), a multicenter phase II trial combining rituximab with chemotherapy followed by high-dose therapy (HDT) with autologous stem cell transplant was conducted by the Groupe Ouest-Est des Leucémies et des Autres Maladies du Sang (GOELAMS). Patients were aged 18 to 60 years, with newly diagnosed CD20-expressing DLBCL, and at least 2 adverse risk factors as defined by the age-adjusted International Prognostic Index (aa-IPI). The treatment consisted of 2 courses of high-dose CHOP-like regimen on day 1 and 15 and 1 course of methotrexate and cytarabine on day 36. Four doses of rituximab (375 mg/m(2)) were infused on days 1, 15, 22, and 36. For patients who achieved at least a partial remission (PR), HDT followed by autologous stem cell transplant was performed on day 66. From April 2002 to May 2003, 42 patients were eligible. Half were high aa-IPI risk patients. Thirty-eight patients (90%) completed the treatment. Treatment-related mortality was 7% and no toxic death was related to rituximab. Complete response rate after the end of the full treatment was 67%. With a median follow-up of 66 months, event-free survival and overall survival rates were 55% and 74%, respectively. Median survival was not reached. First-line HDT with rituximab offers promising results for young adults with intermediate high or high aa-IPI high-grade lymphoma. Immediate and late toxicities were low. This treatment is being randomly compared prospectively with CHOP-14-rituximab in young adults with DLBCL (GOELAMS 075 trial).

Stem cell collection in patients with de novo multiple myeloma treated with the combination of bortezomib and dexamethasone before autologous stem cell transplantation according to IFM 2005–01 trial

International audience; Background There is currently no international consensus for first-line treatment (prior to autologous stem cell transplantation) in mantle cell lymphoma patients. Here, we investigated the efficacy and tolerance of VAD associated with chlorambucil (VAD+C) and rituximab or not before autologous stem cell transplantation. DESIGN AND METHODS: Between 1996 and 2005, 113 previously untreated mantle cell lymphoma patients were enrolled in two consecutive prospective phase II studies. Responses and response factors to the (R)VAD+C regimen were evaluated. The survival prognostic value of the MIPI score and Ki67 were also analyzed. RESULTS: The induction phase of 4 courses of (R)VAD+C showed very low hematologic and extra-hematologic toxicity (grade 3-4 thrombopenia and neutropenia, 9% and 2.7%, respectively and grade 3-4 extra-hematologic toxicities, 1.6%). Overall and complete response rates were 73% and 46%, respectively, and rose to 83% and 51% for the 70% of patients with less than two independent response factors (LDH, B symptoms and lymphocytosis). At the end of treatment, 65% of patients were in complete remission. Progression free and overall survival were significantly better in the transplanted population. The MIPI score was confirmed as a predictor of survival. Ki67, serum LDH, Performance Status (PS) and B symptoms were identified as independent prognostic factors of survival. A prognostic scoring system could stratify patients into three risk groups with markedly different median overall survival of 112, 44 and 11 months, respectively. Conclusions The (R)VAD+C is an effective regimen with very low toxicity. In addition to the MIPI score, Ki67 expression provides additional independent prognostic information for the prediction of overall survival (ClinicalTrials.gov Identifier: NCT00285389).

Treatment options for patients suffering from indolent forms of mastocytosis remain inadequate with the hyperactivation of mast cells responsible for many of the disease's systemic manifestations. Masitinib is a potent and highly selective oral tyrosine kinase inhibitor. A combined inhibition of c-Kit and Lyn make it particularly efficient in controlling the activity of mast cells and therefore, of potential therapeutic benefit in mastocytosis. Masitinib was administered to 25 patients diagnosed as having systemic or cutaneous mastocytosis with related handicap (i.e., disabilities associated with flushes, depression, pruritus and quality-of-life) at the initial dose levels of 3 or 6 mg/kg/day over 12 weeks. In accordance with the AFIRMM study, response was based upon change of clinical symptoms associated with patient handicap at week 12 relative to baseline, regardless of disease subtype. Improvement was observed in all primary endpoints at week 12 including a reduction of flushes, Hamilton rating, and pruritus as compared with baseline by 64% (P = 0.0005), 43% (P = 0.0049), and 36% (P = 0.0077), respectively. An overall clinical response was observed in 14/25 patients (56%; [95%CI = 37%-75%]), with sustainable improvement observed throughout an extension phase (>60 weeks). Common adverse events were edema (44%), nausea (44%), muscle spasms (28%), and rash (28%), the majority of which were of mild or moderate severity with a significant decline in frequency observed after 12 weeks of treatment. One patient experienced a serious adverse event of reversible agranulocytosis. Masitinib is a promising treatment for indolent forms of mastocytosis with handicap and indicates acceptable tolerability for long-term treatment regimens.

Repeated cycles of intravenous immunoglobulins (IVIG) have been reported to be successful in a few patients with idiopathic pure red cell aplasia (PRCA) or associated with another pathology. The efficacy of this treatment for PRCA with thymoma has not been reported previously. We describe here the case of a 75-yr-old man who presented with PRCA associated with a benign thymoma. After failure of thymectomy, corticosteroids and octreotide, a complete durable remission was obtained after a single 5-d cycle of IVIG.

International audience; Adult's mastocytosis is usually associated with persistent systemic involvement and c-kit 816 mutation, while pediatrics disease is mostly limited to the skin and often resolves spontaneously. We prospectively included 142 adult patients with histologically proven mastocytosis. We compared phenotypic and genotypic features of adults patients whose disease started during childhood (Group 1, n = 28) with those of patients whose disease started at adult's age (Group 2, n = 114). Genotypic analysis was performed on skin biopsy by sequencing of c-kit exons 17 and 8 to 13. According to WHO classification, the percentage of systemic disease was similar (75 vs. 73%) in 2 groups. C-kit 816 mutation was found in 42% and 77% of patients in groups 1 and 2, respectively (p

Background In multiple myeloma, combination chemotherapy with melphalan plus prednisone is still regarded as the standard of care in elderly patients. We assessed whether the addition of thalidomide to this combination, or reduced-intensity stem cell transplantation, would improve survival. Methods Between May 22, 2000, and Aug 8, 2005, 447 previously untreated patients with multiple myeloma, who were aged between 65 and 75 years, were randomly assigned to receive either melphalan and prednisone (MP; n=196), melphalan and prednisone plus thalidomide (MPT, n=125), or reduced-intensity stem cell transplantation using melphalan 100 mg/m(2) (MEL100; n=126). The primary endpoint was overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00367185. Findings After a median follow-up of 51.5 months (IQR 34.4-63.2), median overall survival times were 33.2 months (13.8-54.8) for MP, 51.6 months (26.6-not reached) for MPT, and 38.3 months (13.0-61.6) for MEL100. The MPT regimen was associated with a significantly better overall survival than was the MP regimen (hazard ratio 0.59, 95% CI 0.46-0.81, p=0.0006) or MEL100 regimen (0.69, 0.49-0.96, p=0.027). No difference was seen for MEL100 versus MP (0.86, 0.65-1.15, p=0.32). Interpretation The results of our trial provide strong evidence to indicate that the use of thalidomide in combination with melphalan and prednisone should, at present, be the reference treatment for previously untreated elderly patients with multiple myeloma.

Acquired genomic aberrations have been shown to significantly impact survival in several hematologic malignancies. We analyzed the prognostic value of the most frequent chromosomal changes in a large series of patients with newly diagnosed symptomatic myeloma prospectively enrolled in homogeneous therapeutic trials. All the 1064 patients enrolled in the IFM99 trials conducted by the Intergroupe Francophone du Myélome benefited from an interphase fluorescence in situ hybridization analysis performed on purified bone marrow plasma cells. They were systematically screened for the following genomic aberrations: del(13), t(11;14), t(4;14), hyperdiploidy, MYC translocations, and del(17p). Chromosomal changes were observed in 90% of the patients. The del(13), t(11;14), t(4;14), hyperdiploidy, MYC translocations, and del(17p) were present in 48%, 21%, 14%, 39%, 13%, and 11% of the patients, respectively. After a median follow-up of 41 months, univariate statistical analyses revealed that del(13), t(4;14), nonhyperdiploidy, and del(17p) negatively impacted both the event-free survival and the overall survival, whereas t(11;14) and MYC translocations did not influence the prognosis. Multivariate analyses on 513 patients annotated for all the parameters showed that only t(4;14) and del(17p) retained prognostic value for both the event-free and overall survivals. When compared with the currently used International Staging System, this prognostic model compares favorably. In myeloma, the genomic aberrations t(4;14) and del(17p), together with β2-microglobulin level, are important independent predictors of survival. These findings have implications for the design of risk-adapted treatment strategies.

In non-randomized studies, thalidomide appeared to be effective in myeloid metaplasia with myelofibrosis (MMM). We compared thalidomide to placebo for treatment of anemia in MMM.A prospective phase II B, randomized double-blind multicenter trial comparing thalidomide 400 mg/d with placebo for 180 days was conducted in 52 anemic patients (hemoglobin pounds Sterling 9 g/dL or transfused). The main outcome measure was a 2 g/L increase in hemoglobin or 20% reduction in transfusions.In the thalidomide group only 10 patients completed 6 months of treatment. At 180 days, in an intention-to-treat analysis, no difference was observed between the thalidomide and placebo groups as regards improvement of hemoglobin levels (one patient in each group) or reduction of red blood cell transfusions (three vs five patients, respectively). The spleen size, determined by ultrasonography, increased significantly less in the thalidomide group than in the placebo group (p0.05). Thalidomide had no apparent benefit on the Dupriez score, the severity score, survival, death, or any other clinical or biological parameter. Somnolence, gastro-intestinal signs, weight gain, and edema were significantly more frequent in the thalidomide group. Outpatient discontinuation of thalidomide was significantly correlated with a high severity score4 (odds ratio, OR = 16; p0.01), and g-glutamyl transferase levels40 IU/L (OR = 12; p0.05).Thalidomide (200-400 mg/d) does not demonstrate substantial efficacy in anemic MMM patients. The natural history of disease in the placebo group revealed spontaneous periods of remission of anemia. Tolerance of thalidomide was significantly correlated wih the severity and liver involvement of the disease.

Background: We conducted a phase II study to evaluate in 72 adult patients the efficacy of the intensive LMB chemotherapy regimen, previously reported by the Societe Francaise d'Oncologie Pediatrique for children with Burkitt lymphoma and L3 acute lymphoblastic leukemia. Patients and methods: Treatment began with a prephase (low-dose steroids, vincristine and cyclophosphamide), except in patients with low tumor burden. Group A (resected stage I and abdominal stage II disease) received three courses of vincristine, cyclophosphamide, doxorubicin and prednisone. Group B (not eligible for groups A or C) received five courses of chemotherapy comprising high-dose methotrexate, infusional cytarabine and intrathecal (IT) methotrexate. Group C (patients with central nervous system and/or bone marrow involvement with

Background This randomized study compared the efficacy and safety of fludarabine–mitoxantrone (FM) with mini-CHVP (cyclophosphamide, doxorubicin, vindesine, prednisone) in elderly patients with advanced, low-grade non-Hodgkin's lymphoma. Patients and methods End points were remission rates [overall response (OR) and complete response (CR)], failure-free survival (FFS), survival and toxicity. One hundred and fifty-five patients were randomized, 144 were evaluable for safety and 142 for response. Each treatment arm was given as six monthly cycles, followed by three bimonthly cycles. FM comprised fludarabine (20 mg/m2 i.v.), days 1–5, plus mitoxantrone (10 mg/m2 i.v.), day 1. CHVP cycles comprised cyclophosphamide (750 mg/m2 i.v. infusion), doxorubicin (25 mg/m2 i.v.) and vindesine (3 mg/m2 i.v.) on day 1, and prednisone (50 mg/m2) on days 1–5. Results FM therapy resulted in superior remission rates (OR 81% versus 64%, CR 49% versus 17%; P = 0.0004). Median FFS for FM patients was 36 months, compared with 19 months for CHVP patients, and has not yet been reached for early CR patients at 53 months. Treatment arm was the major risk factor influencing survival. Both treatments were well tolerated, with only few infectious complications. Conclusion FM was more effective than CHVP in achieving OR and CR, and favorably affected the outcome.

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.

Lymphocyte-predominant Hodgkin lymphoma (LPHL), according to the Revised European-American Lymphoma classification, was considered on a retrospective basis as a specific clinical entity with a large majority of patients at clinical stage (CS) IA or IIA. Of the 500 patients with CS IA/IIA Hodgkin lymphoma (HL) prospectively treated between 1981 and 1996 by one or 3 courses of anthracycline-based chemotherapies combined with high-dose extended irradiation, disease in 42 patients was reclassified as LPHL. These 42 patients, none of whom had mediastinal involvement (MI), were compared with the 458 patients with classical HL (cHL), 144 without MI and 314 with MI. Surprisingly, the male-female ratio, age, first site involved, hemoglobin level, lymphocyte count, and sedimentation rate of patients with LPHL and cHL without MI were identical and significantly different from those of patients with cHL with MI. Moreover, 15-year HL mortality rates were similarly low in patients with LPHL (2.4%) and cHL without MI (0.7%). Overall survival rates were also similar (86% and 82%) and as high as 100% and 95% in patients treated before the age of 40 years. This study demonstrated that LPHL and cHL without MI shared the same presenting characteristics and the same excellent long-term prognosis after a brief anthracycline-based chemotherapy plus high-dose extended irradiation.

From 1990 to 1996, a total of 386 adult patients with early/intermediate Hodgkin disease (HD) were randomly assigned to receive 3 cycles of adriamycin, bleomycin, vinblastine, dacarbazine (an alkylating agent), and methylprednisolone (ABVDm, arm A) or epirubicin, bleomycin, vinblastine, methotrexate, and methylprednisolone (EBVMm, arm E), a combination without alkylating agent. Responding patients received extended field radiation therapy (RT). Postchemotherapy complete remission and 10-year freedom from progression rates were higher in arm A (79.5% and 91.4%) than in arm E (70.4%, P = .04, and 80%, P < .002). HD mortality (HDM), treatment-related mortality (TRM), and overall survival (OS) were similar in both arms (A, 2.1%, 7.5%, and 90.4%; B, 3.9%, 5.5%, and 90.3%). However TRM and OS rates were lower in patients aged 40 years or older ( P < .005), reflecting the increasing incidence of background fatal events with increasing age. Finally, event-free survival (EFS) was higher in arm A (84.6%) than in arm E (74.9%, P < .02). In patients aged younger than 40 years in arm A (74%), 10-year EFS and OS rates were 88.9% and 95.4% with HDM and TRM rates as low as 0.7% and 3%. Three courses of ABVDm plus RT are the best available option for treating early or intermediate HD.

Limited data exist on infective endocarditis (IE) due to Streptococcus milleri (Sm) or beta-hemolytic streptococci (BHS). Because BHS and Sm share some physiologic and pathogenic properties, we wondered whether IE caused by these streptococci might present similarities.Through a nationwide retrospective study in France, the medical and microbiologic charts of adults with definite Sm or BHS IE observed between January 1, 1991, and December 31, 1996, in university and general hospitals were reviewed.Fifty-six patients had BHS IE (33 men and 23 women; median age, 59 years; range, 18-91 years) and 29 had Sm IE (18 men and 11 women; median age, 66 years; range, 37-97 years). The BHS group tended to have more underlying medical conditions (46%) and fewer previous cardiopathies (48%) than the Sm group (28% and 71%, respectively). Multivariate analysis showed that a longer median time of IE evolution before diagnosis and identification of the presumed portal of entry were independently associated with Sm IE (P.01). Extracardiac complications were more frequent in the BHS group (55%) than in the Sm group (39%). Comparison of echocardiographic findings between the 2 groups did not establish any statistically significant difference. Thirty-six patients (64%) in the BHS group and 18 (62%) in the Sm group underwent valve replacement. Overall, mortality was 27% for the BHS group and 14% for the Sm group. For all patients, multivariate analysis retained older age as the only significant risk factor for death (P =.01).Compared with Sm IE, BHS IE occurs in younger patients with more underlying diseases and fewer underlying cardiopathies and has a more aggressive presentation and evolution.

OBJECTIVES—To describe infectious complications and analyse their risk factors and prognostic role in adults with systemic lupus erythematosus (SLE). METHODS—A monocentric cohort of 87 adults with SLE (1960-1997) was studied to determine the risk factors for infection (disease activity evaluated by SLAM and SLEDAI scores, type of organ(s) involved or any biological abnormality, specific treatments) by comparing patients who had suffered at least one infectious episode (n=35; 40%) with non-infected patients (n=52; 60%). Prognostic indicators were assessed by comparing survivors at 10 years with non-survivors. RESULTS—Of the 57 infectious episodes, 47 (82%) were of bacterial origin, 16 (28%) were pneumonia, and 46 (81%) were community acquired. According to univariate analysis, significant risk factors for infection were: severe flares, lupus glomerulonephritis, oral or intravenous corticosteroids, pulse cyclophosphamide, and/or plasmapheresis. No predictors were identified at the time of SLE diagnosis. Multivariate analyses retained intravenous corticosteroids (p

This retrospective study compares high-dose therapy (HDT) with autologous stem cell transplantation and combined-modality treatment (CT) as a first-line therapy for Hodgkin's disease (HD) for patients with both a clinical stage (CS) IV and/or a mediastinal massor =0.45 of the thoracic diameter (MMor =0.45) at diagnosis, and an incomplete response after the first-line chemotherapy. Data on 42 grafted patients (GP) in Nantes Hospital, France and on 108 combined-modality treated patients (CTP) from two protocols of the GOELAMS group, France (POF 81 and H90) was analyzed. Both groups were comparable except for pulmonary disease in excess in the grafted group (P = 0.01). Among GP, 95% were in complete response at the end of first-line treatment and 77% among CTP. Median follow-up was 53 months (range, 7 to 128 months) for GP and 88 months (range, 25 to 181 months) for CTP. The 5-year freedom from progression (FFP) and event-free survival (EFS) rates were better for GP (87% vs 55% for FFP: P = 0.0004 and 81% vs 51% for EFS: P = 0.0004) whereas the overall survival (OS) rates did not differ significantly (85% for GP vs 71% for CTP: P = 0.06). Similar results were obtained for the groups with a responseor =50% after initial chemotherapy: 91% vs 65% for FFP, P = 0.01; 87% vs 61% for EFS, P = 0.02; and 92% vs 77% for OS, P = 0.2; and for the groups with a response50%: 80% vs 22% for FFP, P = 0.0003; 72% vs 13% for EFS, P = 0.0001; and 76% vs 46% for OS, P = 0.04. This study shows a better control of the disease with HDT.

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.

The treatment of Hodgkin's disease (HD) at advanced stages relies mainly upon multi-agent chemotherapies (CT), while the role of radiation therapy has not been definitely identified. The aim of this report is to analyze the 10-year results of a prospective study including 133 patients with HD clinical stages (CS) IIIA to IVB treated by three monthly courses of ABVD (adriamycin, bleomycin, vinblastin, and dacarbazine) followed by high-dose subtotal or total lymphoid irradiation [(S)TLI].From 1 October 1981 to 30 September 1988, 133 adult patients with HD CS IIIA (45), IIIB (33), IVA (seven) and IVB (48) were entered in the non-randomized multicentric prospective trial POF81/34. The number of involved nodal areas (NINA), and the number of visceral sites (NVIS) involved were registered in all patients; patients with bulky mediastinal tumor (BuMT) (mediastinal mass ratioor = 0.45) were also identified. All patients received three monthly cycles of ABVD. Patients in complete remission (CR) or partial remission (PR) after completion of CT received a (S)TLI including the spleen (involved sites 40 Gy, non-involved 30 Gy); initially involved lung(s) and liver received 18 and 20 Gy, respectively; and patients not in CR or PR after CT or RT received salvage treatments. Univariate and multivariate analyses were performed to identify the factors contributing significantly to the prognosis; initial characteristics, as well as status after the three cycles of CT, were entered in the model.Of the 133 patients, 74 (55.6%) entered in CR after CT and 116 (87.2%) after completion of radiation therapy. Ten-year freedom from progression (FFP), freedom from tumor mortality (FFTM) and survival rates were 70.4%, 78.9% and 70.6%, respectively. According to univariate analysis the NVIS (or = one vs.or = two) was the only initial factor simultaneously influencing 10-year FFP (73.9% vs. 38.2%) FFTM (82.5 vs. 34.1%) and survival (73.5% vs. 17.3%) rates; on the other hand, the NINA (or = four vs.or = five) influenced FFP (81.4% vs. 60.7%) and FFTM rates (87.3% vs. 71.4%) while symptoms (A vs. B) influenced FFP (80.7% vs. 63.3%) and survival (82.8% vs, 61.2%) rates. Finally, age (40 vs.or = 40) influenced survival rate only (79.2% vs. 50%). According to multivariate analysis, NVIS and NINA had an independent impact on FFP and FFTM, while survival was modified by the NVIS and age. The post-CT status (CR vs. no CR) had a major impact on FFP (85.3% vs. 64.9%) FFTM (92.1% vs. 63.3%) as well as on survival (78.6% vs. 54.7%) rates in both univariate and multivariate analyses. Complications of therapy were mainly due to RT: 11 patients acquired second malignancies, six developed lung fibrosis or severe pulmonary infections, three developed intestinal obstructions and six developed angina pectoris or carotid stenosis.Tumor burden (identified by the number of involved nodal areas and the number of visceral sites) and the response to initial CT were the two independent factors influencing the outcome of this group of 133 patients with HD, CSIII and IV treated by three cycles of ABVD followed by high-dose [(S)TLI].

Once-daily (o.d.) administration of 20 mg of amikacin per kg of body weight to neutropenic patients has been validated by clinical studies, but amikacin pharmacokinetics have been documented only for the 7.5-mg/kg twice-daily (b.i.d.) regimen in this population. In order to determine in neutropenic patients (i) the influence of the dosing regimen on the kinetics of amikacin, (ii) the linearity of kinetics of amikacin in the range of 7.5 to 20 mg/kg, and (iii) the influence of patient characteristics on the disposition of amikacin and (iv) to provide a rationale for dosing recommendations, we evaluated the population pharmacokinetics of amikacin administered to 57 febrile neutropenic adults (neutrophil count, 3 ) being treated for a hematological disorder and receiving amikacin at 7.5 mg/kg b.i.d. ( n = 29) or 20 mg/kg o.d. ( n = 28) and administered intravenously over 0.5 h. A total of 278 blood samples were obtained (1 to 14 samples per patient) during one or several administration intervals (1 to 47). Serum amikacin levels were measured by the enzyme-multiplied immunoassay technique. A mixed-effect modeling approach was used to fit a bicompartmental model to the data (NONMEM software). The influences of the dosing regimen and the demographic and biological indices on the pharmacokinetic parameters of amikacin were evaluated by the maximum-likelihood ratio test on the population model. The dosing regimen had no influence on amikacin pharmacokinetic parameters, i.e., the kinetics of amikacin were linear over the range of 7.5 to 20 mg/kg. Amikacin elimination clearance (CL) was only correlated with creatinine clearance or its covariates, namely, sex, age, body weight, and serum creatinine level. The interindividual variability of CL was 21%, while those of the central volume of distribution, the distribution clearance, and the tissue volume of distribution were 15, 30, and 25%, respectively. On the basis of the expected distribution of amikacin concentrations in this population, dosing recommendations as a function of creatinine clearance (CL CR ) are proposed: for patients with normal renal function (CL CR of 80 to 130 ml/min), 20 mg/kg o.d. is recommended, whereas for patients with severe renal impairment (CL CR , 10 to 20 ml/min), a dosage of 17 mg/kg every 48 h is recommended.

We report a case of aspergillus pericarditis with tamponade complicating invasive pulmonary aspergillosis in a patient treated for acute lymphocytic leukemia. Prolonged antifungal therapy and aggressive surgical treatment cured the pericarditis, without relapse, despite the fact that the patient underwent autologous bone marrow transplantation. In a review of 28 other cases of aspergillus pericarditis, we found that this condition usually had occurred in severely immunocompromised patients and was always the result of contiguous dissemination of Aspergillus from the lung or myocardium. Tamponade was present in eight of 29 patients. Aspergillus antigen was detected in the pericardial fluid of all three patients whose fluid specimens were tested. Aspergillus pericarditis was diagnosed before death in 10 of 29 patients, all of whom had established premortem diagnoses of invasive aspergillosis at other sites and had received antifungal therapy. Three of the four survivors received combined medical and aggressive surgical therapies. The performance of echocardiography early during the course of invasive pulmonary aspergillosis, together with intensive combined therapies, might lower the high mortality associated with aspergillus pericarditis.

BACKGROUND Hypercalcemia has rarely been reported in patients with Richter's syndrome (RS). In this article, the authors report four cases with complementary pathophysiologic examinations. METHODS Four patients with hypercalcemia that indicated RS were admitted to the study unit between 1980 and 1994 with the following diagnoses: transformation of mixed follicular lymphoma, Waldenstrom's macroglobulinemia, and chronic lymphocytic leukemia, respectively, in 3 men ages 60 to 73 years, and chronic lymphocytic leukemia in a woman 73 years of age. Radiologic and histologic features were reported. Circulating levels of parathormone-related peptide (PTHrP), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) were measured. RESULTS Radiologic skeletal abnormalities were found in three of three cases: osteopenia twice and multifocal osteolysis once. All four patients had large cell lymphoma (LCL). Bone resorption assessed histomorphometrically was elevated in two of two cases. Serum TNF-α and IL-6 levels were high in three of three and one of three cases, respectively. Elevated values were also found in four patients with LCL but without hypercalcemia. The serum PTHrP level was increased in the only hypercalcemic patient tested and values were normal in the three control patients. CONCLUSIONS Hypercalcemia arising in a patient with a low grade lymphoproliferative disorder may indicate RS. Hypercalcemia is due to increased bone resorption, which may be caused by the secretion of osteoclast-stimulating factors by the LCL invading the bone marrow. Independently, TNF-α and/or IL-6 were unlikely causative factors of hypercalcemia in the patients in this study; however, synergism with PTHrP was suspected in one case. Cancer 1997; 79:1211-5. © 1997 American Cancer Society.

From November 1987 to April 1994, 522 adult (15-50 years) patients with de novo acute myeloblastic leukemia (AML) were included in the GOELAM 1 protocol comparing allogeneic bone marrow transplantation (BMT), intensive consolidation chemotherapy (ICC) and autologous BMT (ABMT). For induction treatment, patients were randomized to receive a combination of cytosine-arabinoside (ara-C) (200 mg/m2 per day continuous infusion on days 1-7) and either idarubicin (IDR) (8 mg/m2 per day on days 1-5) or rubidazone (RBA) (200 mg/m2 per day on days 1-4). After achievement, of complete remission (CR) an allogeneic BMT was proposed to patients up to the age of 40 with an HLA-identical sibling. Other patients in CR had to receive a first course of ICC (ICC1) with highdose ara-C (3 g/m2 every 12 by 3-h infusion on days 1-4, eight doses) and either IDR (10 mg/m2 per day on days 5-6) or RBZ (200 mg/m2 per day on days 5-6). Bone marrow was collected after ICC1 and cryopreserved without any in vitro manipulation. If the hematopoietic quality of the collected marrow was adequate, patients were then randomly assigned to receive a second course of ICC (ICC2) with m amsacrine (AMSA); (150 mg/m2 per day on days 1-5) and etoposide (VP-16) (100 mg/m2 per day on days 1-5) or an ABMT after a preparative regimen with busulfan (4 mg/kg per day for 4 days) and cyclophosphamide (50 mg/kg per day for 4 days). As of July 1, 1994 490 patients were evaluable and 361 (74%) achieved CR with no significant difference between IDR and RBZ. An allogeneic BMT was planned in 83 cases and was actually performed in 67. Out of the 278 other patients 227 did receive ICC1. The median duration of neutropenia after ICC1 was 19 days and there were nine toxic deaths (4%). A total of 171 patients were randomized between ICC2 (84) and ABMT (87), and 128 have currently been analyzed (61 ICC2, 67 ABMT). The main reasons for exclusion were toxicity, refusal, poor hematologic reconstituion post ICC1, and relapse. With a median follow up of 44 months, the overall survival of the entire cohort of patients is 37% at 6 years (median 22 months) with no difference between the two induction treatment arms. The 4-year disease-free survival (DFS) of the patients in CR who actually received the assigned treatment was 45% for allogeneic BMT, 53% for ICC2, and 47% for ABMT. When considering intention to treat there was no significant difference in DFS between allogeneic BMT and other forms of post-remission therapy or between ICC2 and ABMT. We conclude that (a) a significant improvement of survival can be obtained for patients with de novo AML up 50 years of age with three different modalities of intensive consolidation; (b) the three approaches give comparable results—after ICC1, ICC2 appears to be as effective as unpurged ABMT and is easier to perform; (c) new strategies are needed to reduce the exclusion rate.

Background Prognosis of relapses is severe in elderly multiple myeloma (MM). In recent studies, median survival at progression after 1st line therapy was between 9 and 13 months (T. Facon, Lancet 2007; C. Hulin, J Clin Oncol 2009). Bortezomib (V) plus dexamethasone (D) is a major regimen in the treatment of relapses. Bendamustine (B) demonstrated to be highly active in advanced MM. The IFM 2009-01 trial evaluates the combination of B, V and D in elderly patients with progressive MM on or after 1stline treatment. Methods Phase 2 IFM 2009-01 trial was dedicated to patients older than 65 years in 1st relapse or refractory to 1st line therapy. Inclusion criteria were measurable disease, PS ECOG 0-2, ANC > 1.5x109/l, platelets > 100x109/l, serum creatinine level < 250 mcmol/l, AST and ALT < 3xULN. Pts with prior exposure to bortezomib were excluded. Treatment regimen was B 70 mg/m2 day 1-8, V 1.3 mg/m2 day 1-8-15-22 and D 20 mg day 1-8-15-22 every 28 days. 6 cycles were administered. Responders were assigned to receive maintenance treatment with 6 additional cycles administered 1 month out of 2. Response was evaluated according to IMWG criteria. Response rate was the primary objective. Progression-free survival (PFS), overall survival (OS) and toxicity were secondary end-points. Results From 03/2010 to 07/2011, 73 pts were included. Median age was 75.8 years (range 66-86). Median time from diagnosis to inclusion was 29 months. All pts received only 1 prior line of therapy: Melphalan-Prednisone (MP) in 12, MP-Thalidomide in 42, Lenalidomide-Dexamethasone (LD) in 14, other IMiD-based regimen in 5. Median treatment cycles administered was 7 (1-12). 51 pts (69.8%) achieved at least partial response [best response CR: 10 pts (13.6%), VGPR: 12 pts (16.5%), PR: 29 pts (39.7%), MR: 4 pts (5.5%), SD: 5 pts (6.8%), progression: 12 pts (16.5%), unrelated early death: 1 pt (1.3%)]. Median PFS was 10.8 months (95%CI: 7-18.2 months) and median OS 23 months (15.4-27.5). Adverse prognostic factors for PFS were PS ECOG 2 (p=0.0002), beta 2 microglobulin level > 3.5 mg/l (p=0.0006) and del17p (p=0.01). 26 pts (35.6%) completed the planned 12 cycles of treatment. Cause of treatment discontinuation was progressive MM in 30 pts (41.1%), failure to achieve PR in 5 pts (6.8%), adverse event in 10 pts (13.6%), patient refusal and unknown 1 pt (1.3%) each. 37 pts (50.6%) had died at time of final analysis. Cause of death was MM in 30 pts, sepsis in 5 pts, renal failure in 1 pt and unrelated in 1 pt. Grade 3-4 adverse events were neutropenia: 14 pts (19.1%), thrombocytopenia: 8 pts (10.9%), sepsis: 14 pts (19.1%), gastro-intestinal: 6 pts (8.2%), anaphylaxis: 2 pt (2.7%). Grade 2 peripheral neuropathy occurred in 8 pts (10.%) and grade 3 in 3 pts (4.1%). Conclusions In this elderly population with poor prognosis MM, BVD combination provides a high overall response rate and manageable toxicity. These results compare favourably with those achieved with VD or LD. Disclosures: Roussel: CELGENE: Honoraria; JANSSEN: Honoraria. Leleu:CELGENE: Honoraria; JANSSEN: Honoraria. Cony-Makhoul:BMS: Honoraria. Avet-Loiseau:CELGENE: Honoraria, Speakers Bureau; JANSSEN: Honoraria, Speakers Bureau. Moreau:Janssen: Honoraria; Janssen and Millennium: Membership on an entity’s Board of Directors or advisory committees.

Introduction Primary plasma cell leukemia (pPCL) is a rare form of plasma cell malignancy with poor prognosis (usually less than 12 months survival with conventional chemotherapy). Only one prospective study with Lenalidomide-Dex before high dose therapy has been recently reported1. Bortezomib-based regimens and high dose Melphalan/ autologous stem cell transplantation (HDM/ASCT) have shown promising results in small retrospective studies. We report here the first prospective multicenter phase II trial for pPCL patients (pts) treated with Bortezomib-Doxorubicine-Dexamethasone (PAD) / Bortezomib-Cyclosphosphamide-Dexamethasone (VCD) as induction before HDM/ASCT. With the aim to improve response and survival, allograft or second ASCT plus consolidation/maintenance with Lenalidomide-Bortezomib-Dex (VRD) were proposed. Patients and method Non-previously treated pts with a diagnosis of pPCL were enrolled in this phase II study of the IFM group from April 2010 to July 2013. PAD (dexa 40 mg + bortezomib 1,3 mg/m2 on day 1, 4, 8, 11 + doxorubicine 30 mg/m2 day 4) and VCD (dexa + bortezomib + cyclophosphamide 300 mg/m2 day 1, 8) were administrated alternatively each 21 days for 4 cycles. For responding patients with circulating plasma cell < 1%, peripheral stem cells were collected after Cyclophosphamide + G-CSF. Either (i) double HDM/ASCT was performed followed by consolidation/maintenance íVDR (dexa 40mg + bortezomib 1,3 mg/m2 on day 1, 4, 8, 11 + lenalidomide 15 mg day 1-15) each 3 months and Lenalidomide 15 mg 21/28 days on others months, for 1 yearý or (ii) tandem HDM/ASCT-reduced intensity conditioning-allograft if there were < 66 years-old. Primary end-point was progression free survival (PFS); secondary end-points were responses rates, overall survival (OS), feasibility, and toxicity. We evaluated the disease response to therapy with the IMWG criteria and the percentage of circulating plasma cells; minimal residual disease (MRD) was evaluated during follow-up. Peripheral circulating plasma cells and bone marrow plasmocytes were collected at diagnosis for centralized FISH and SNP array analysis. Results 40 pts were enrolled with a median age of 55y (27-71). Median follow-up was 12.6 months (7.6-24.8). At diagnosis, the median number of circulating plasma cell was 5.2 G/L (1.3-66). Twenty-two percent had creatinine clearance < 50 ml/min, and 11% < 30 ml/min, 44% had an ISS score of 2 and 37% ISS 3. After induction 35 pts are evaluable. In the intent to treat analysis, 25 (72%) responded (VGPR+CR 37%, PR 28%, SD 5%) and 10/35 (28%) were refractory (pts having circulating plasma cell ≥ 1%) and did not continue the study. Twenty-three of the 25 responding pts underwent HDM/auto and 20 pts are evaluable at 3 months: CR+VGPR 14/20 (70%), PR 4/20 (20%), 1/20 (5%) and PD 1/20 (5%). Second HDM/auto was performed in 6 pts and allograft in 12. Ten of the 14 (72%) evaluable pts achieved VGPR or better and 4/14 (28%) PR. Six pts are currently on consolidation/maintenance phase with VRD. Median PFS was 17.8 months. Median OS was not reached. Genomic data are shown in Table I. MDR evaluation will be presented later. Major toxicities were hematological and infections. Eight pts died: 5 during induction, 1 at HDM/ASCT and 2 post allograft while in relapse. Of note, 2 pts had meningeal involvement at relapse. Conclusion This first large study for pPCL patients with PAD/VCD as induction and HDM/ASCT is effective and induce high responses rates. Consolidation with Allograft or bortezomib-lenalidomide-dex is currently investigated. 1Musto P et al. Blood (ASH Annual Meeting Abstracts) 2011; 118 Abstract2925Table I: genomic Disclosures: Leleu: CELGENE: Honoraria; JANSSEN: Honoraria. Moreau:Celgene: Honoraria, Speakers Bureau. Avet-Loiseau:CELGENE: Honoraria, Speakers Bureau; JANSSEN: Honoraria, Speakers Bureau.

From December 1987 to June 1992, 251 patients aged 50–65 with de novo acute myelogenous leukaemia (AML) were recruited to a multi-institutional randomized clinical trial. Induction therapy consisted of Ara-C (200 mg/m2, continuous infusion, days 1–7) with either zorubicin (ZRB) (200 mg/m2, i.v., days 1–4) or idarubicin (IDR) (8 mg/m2, i.v., days 1–5). Consolidation therapy consisted of a single course of intensive chemotherapy with high-dose Ara-C (3 g/m2, 3 h infusion, q 12 h, days 1–4) and m-Amsa (100 mg/m2/d, i.v., days 5–7). The complete remission (CR) rate was (73%) with Ara-C/IDR versus (60%) with Ara-C/ZRB (P = 0.033). In multivariate analysis, factors found to be significant in predicting CR were normal karyotype and treatment with IDR. With a median follow-up of 73 months, the median disease-free survival (DFS) duration of all CR patients and the probability of CR at 6 years were 17 months and 29%. In multivariate analysis the only factor associated with an increased DFS duration was a normal karyotype. The median event-free survival (EFS) duration for all evaluable patients and the median overall survival duration for all eligible patients were respectively 7 and 12 months without any difference between induction arms. The study shows that in patients aged 50–65 idarabicin is more effective than zorubicin for remission induction. However, the type of anthracycline did not influence overall survival duration. Using a unique consolidation course, we observed a prolonged DFS which compares favourably with results obtained with more prolonged consolidation therapy or maintenance treatment.

Hodgkin's disease (HD) confined below the diaphragm accounts for less than 5% of all patients with HD. Although the major characteristics of this presentation appear established, optimal modalities of treatment still remain difficult to define. From April 1972 to October 1988, 28 patients with newly diagnosed infra-diaphragmatic HD, clinical stages I or II have been treated with 3 successive prospective protocols combining initial chemotherapy and radiotherapy (40 gy). This series of patients accounted for 4,3% of patients with HD limited to clinical stages (CS) I and II. Overall survival and freedom from relapse at 15 years were 74,4% and 73% respectively, without significant differences between clinical stages I and II, presence or absence of B symptoms or histologic subtype. There is only a trend (p0,10) in favour of patients younger than 40 years. In all 7 clinically staged IA patients no relapses were seen and combined treatment does not appear to be better than inverted Y irradiation alone. On the other hand initial chemotherapy seems necessary in patients with CS II A and B since 15 of our 21 patients are alive in first CR whereas the crude rate of transdiaphragmatic nodal relapses may reach up to 53% following radiotherapy alone.

Human basophils activated through high-affinity immunoglobulin E (IgE) receptors (FcRI) are involved in the late phase of the allergic reaction. To investigate the possible involvement of protein-tyrosine kinases in this activation we used human acute basophilic leukemia (ABL) cells in culture as well as a pure population of normal basophils in vitro-derived from human bone marrow precursor cells (HBMB). ABL cells were 50–80% basophils at various stages of maturation as assessed by staining, morphology, ultrastructure, and flow cytometry analysis, and only basophils in ABL cells expressed FcRI. Aggregation of FcRI by IgE and anti-IgE, IgE and antigen, or anti-FcRI monoclonal antibodies on ABL cells or on HBMB, led to increased tyrosine phosphorylation of 120-, 100-, 80-, 72-, 50- to 65-, and 38-kDa substrates. Tyrosine phosphorylations in ABL cells were in basophils because 1) they were detected after a 5-s stimulation, 2) they were observed under conditions where mediator release is minimal, i.e., in the absence of extracellular calcium, 3) hapten addition during antigen stimulation resulted in almost total disappearance of tyrosine phosphorylations within 30 s. There was correlation between histamine release and tyrosine phosphorylation in anti-IgE dose-responses and in dose-responses of the tyrosine kinase inhibitor genistein. The tyrosine kinase p72syk was detected in the cells. Stimulation of ABL cells for 1 min resulted in extracellular calcium-independent tyrosine phosphorylation and activation of p72syk Therefore, tyrosine kinases are involved in the early steps of human FcRI signaling in basophils. Tyrosine kinases and their substrates could represent new potential therapeutic targets to prevent the development of the allergic reaction. 1996.

We demonstrated previously that sera from quinine-treated patients reversed the MDR phenotype in vitro. Then, the combination of quinine with mitoxantrone (MTX) and cytarabine (Ara-C) was shown to be well-tolerated in patients with acute leukemias. To answer the question whether the response rate could be improved by quinine, we designed a phase III multicentric study. During the first year, the trial involved 112 adult patients (age 18–65y) with either relapsed or refractory acute myeloblastic or lymphoblastic leukemia or secondary leukemia or blastic transformation of myelodysplastic or myeloproliferative syndrome. All patients were treated with a combination of MTX (12 mg/m2/day — 4 days) and Ara-C (1 g/m2/12h — 5 days — 3 hrs iv infusion). After randomisation, 55 patients also received quinine (30 mg/kg/d — 5 days — beginning 24 hrs before MTX infusion). A 20% dose decrease was necessary in 14 patients due to vertigo or tinnitus and quinine was discontinued in 1 patient, due to excessive QT extension The remaining 57 patients received the chemotherapy alone. Toxic death was observed in 2 patients (one in each group) and ten patients (7 in quinine-treated group) died in aplasia before day 30. Response was assessable in 106 patients. As compared with the patients treated with MTX-Ara-C only, the patients treated with MTX-Ara-C plus quinine had a higher overall rate of response [29 / 52 (56%) versus 26 / 54 (48%)]. However, this difference is not significant. Quinine increased the duration of neutropenia (28,3 vs 23,9 days; p < 0.05) and thrombopenia (35 vs 28,3; p = 0.02). The incidence of nausea, vomiting and mucositis was also significantly higher in the quinine-treated group. This partial analysis confirmed the feasibility of using quinine in combination with MTX and Ara-C and suggested a trends for quinine to improve the response rate although these results have to be confirmed by the extended study.

Philadelphia positive (Ph) Acute Lymphoblastic Leukemia (ALL) constitutes 20 to 25% of adult ALL. The management of Ph + ALL is difficult and even if complete remissions (CR) can be achieved with conventional chemotherapy, they are usually short and the long-term disease free survival is less than 10%. Following the initial report by Ohyashiki et al. (Leukemia 1991, 5: 611,) showing encouraging results in 3 patients, we have tried to maintain CR induced by conventional chemotherapy with a Interferon. Eight patients (5 male, 3 female) aged 38–66 years (med 57) who had achieved CR with various induction regimen received a Interferon (α IFN) after consolidation chemotherapy. Six patients were in first CR of de novo Ph positive ALL, one patient was in second CR after a relapse post allogenic bone marrow transplantation, one was in CR after lymphoid blast cusis of chronic myeloid leukemia (CML). The dose of α IFN varied from 3 M IU/m2 3 times weekly (4 patients) to 5 M IU/m2 daily. Of the 8 patients 6 relapsed 1 to 11 months (median 3) after initiation of a IFN therapy. In 2 cases hematological relapse was preceded by cytogenetic relapse (4 and 3 months before). Two patients remain in continous CR at 8 and 14 months. These preliminary results do not appear to confirm the initial positive results. However, more patients are needed to assess the exact place of a IFN in Ph + ALL.

Abstract 598 Background: Several biological parameters have been described, which define patients with multiple myeloma with a high-risk of progression. Nevertheless, apart from the International Staging System (ISS), no clear, simple and reliable prognostic index has yet been identified, especially for the classification of patients with very high-risk disease. We aimed to characterize the group of patients who have a high risk of early death from progression in the context of frontline therapy using novel agents-based induction therapy and autologous stem cell transplantation. Methods: We investigated prognostic parameters of patients enrolled in the IFM2005-01 trial, which compared bortezomib-dexamethasone versus VAD induction followed by ASCT (Harousseau et al, J Clin Oncol 2010;28:4621–4629). Results: In a multivariate logistic regression analysis, the risk of death from progressive disease (and not toxicity) (42 cases out of 482 patients) within the first 2 years from the start of therapy was related to 3 independent adverse baseline characteristics: high LDH > normal value (p = 0.0014), ISS 3 (p = 0.0097) and cytogenetic abnormalities defined by the presence of either t(4;14) or 17p deletion (p = 0.0002). These 3 variables enabled the definition of a simple scoring system consisting of 4 categories (scores 0–3) that predicts for overall survival (OS). Score 0 was defined by the absence of adverse factors (neither high LDH, nor ISS 3, nor t(4;14) and/or del(17p)); in this group of patients, representing 57% of the overall population, the 4-year OS rate was 84%. A score of 1 was defined by the presence of only 1 adverse factor (either high LDH or ISS 3 or t(4;14) and/or del(17p)). The 4-year OS rate in this group of patients (32% of the overall population) was 73%. A score of 2 defined by the presence of high LDH plus ISS 3 in the absence of t(4;14) and/or del(17p), was found in 6% of the overall population. The 4-year OS rate in this group was 68%. Score 3 was defined by the presence of t(4;14) and/or del(17p) in addition to either ISS 3 or high LDH. In this group of patients, representing 5% of the overall population, the median OS was only 19 months (Figure). Conclusion: We have defined a new and simple scoring system that allows the identification of a small group of patients with very high-risk disease and a shortened survival despite the use of intensive novel agents-based therapy. These preliminary findings require confirmation using data from a large number of patients enrolled in the most recent prospective clinical trials investigating triplet induction regimens prior to ASCT. The subgroup of patients with a score of 3, which is associated with a detrimental outcome, might benefit from innovative therapeutic approaches. Disclosures: Moreau: janssen: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees. Attal:janssen: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees. Hulin:janssen: Membership on an entity's Board of Directors or advisory committees; celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Facon:millenium: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; onyx: Membership on an entity's Board of Directors or advisory committees. Kolb:celgene: Honoraria; janssen: Honoraria. Roussel:janssen: Honoraria; celgene: Honoraria. Leleu:celgene: Honoraria; janssen: Honoraria. Avet-Loiseau:janssen: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees.

Abstract 4044 Background: Prognosis of relapse is severe in elderly multiple myeloma (MM). In recent studies, median survival at progression after 1st line therapy was between 9 and 13 months (T. Facon, Lancet 2007; C. Hulin, J Clin Oncol 2009). Bortezomib (V) plus dexamethasone (D) is a major regimen in the treatment of relapses. Bendamustine (B) demonstrated to be highly active in advanced MM. The IFM 2009-01 trial evaluates the combination of B, V and D in elderly patients with progressive MM on or after 1st line treatment. Methods: Phase 2 IFM 2009-01 trial was dedicated to patients older than 65 years in 1st relapse or refractory to 1st line therapy. Inclusion criteria were measurable disease, PS ECOG 0–2, ANC > 1.5×109/l, platelets > 100×109/l, serum creatinine level < 250 mcmol/l, AST and ALT < 3xULN. Pts with prior exposure to bortezomib were excluded. Treatment regimen was B 70 mg/m2 D1–8, V 1.3 mg/m2 D1–8-15–22 and D 20 mg D1–8-15–22 every 28 days. 6 cycles were administered. Responders were assigned to receive maintenance treatment with 6 additional cycles administered 1 month out of 2. Response was evaluated according to IMWG criteria. Response rate was the primary objective. Progression-free survival (PFS), overall survival (OS) and toxicity were secondary end-points. Results: The present analysis is restricted to the 6 monthly cycles. From 03/2010 to 07/2011, 73 pts were included. Median age was 75.8 years (range 66–86). Median time from diagnosis to inclusion was 29 months. All pts received only 1 prior line of therapy: melphalan-prednisone (MP) in 12, MP-Thalidomide in 44, Lenalidomide-Dexamethasone (LD) in 14, other IMiD-based regimen in 3. 49 pts (67.1%) achieved at least partial response [best response CR: 9 pts (12.3%), VGPR: 12 pts (16.5%), PR: 28 pts (38.3%), MR: 6 pts (8.2%), SD: 4 pts (5.5%), progression: 13 pts (17.8%), early discontinuation: 1 pt (1.3%)]. Adverse prognostic factors for response were 1st line regimen with IMiD (p=0.006) and del17p (p=0.036). At 6 months, PFS was 67.1% and OS 80.8%. Cause of death was MM in 9 pts, sepsis in 4 pts and renal failure in 1 pt. Grade 3–4 adverse events were neutropenia: 16 pts (21.9%), thrombocytopenia: 7 pts (9.6%), sepsis: 14 pts (19.2%), gastro-intestinal: 9 pts (12.3%), anaphylaxis: 1 pt (1.3%). Grade 2 peripheral neuropathy occurred in 10 pts (13.6%) and grade 3 in 2 pts (2.7%). At 6 months, treatment was discontinued in 33 pts (45.2%). Cause of discontinuation was progressive MM in 18 pts (24.6%), failure to achieve PR in 5 pts (6.8%), adverse event in 8 pts (10.9%), patient refusal or lost to follow-up 1 pt (1.3%) each. Conclusion: In this elderly population with poor prognosis MM, BVD combination provides a high overall response rate and manageable toxicity. These results compare favorably with those achieved with VD or LD. Disclosures: Hulin: celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees. Kolb:janssen: Honoraria; celgene: Honoraria. Roussel:celgene: Honoraria; janssen: Honoraria.

8014 Background: Bortezomib (V) plus dexamethasone (D) is a treatment of choice of RRMM. In small series, the addition of an alkylator was beneficial. Bendamustine (B) showed a high activity in advanced MM. The IFM 2009-01 trial evaluates the combination of B, V and D in elderly pts with MM progressive on or after 1st line therapy. Methods: We conducted a phase 2 trial combining B 70 mg/m2 D1-8, V 1.3 mg/m2 D1-8-15-22 and D 20 mg D1-8-15-22 every 28 days. 4 cycles were administered. In responders (PR or better), 2 additional cycles were provided followed by a maintenance phase with 6 cycles given every 2 months. Inclusion criteria were progression on or after 1 prior line of therapy, measurable disease, PS ECOG 1.5x109/l, platelets > 100x109/l, creatinine < 250 mcmol/l, AST and ALT < 3xULN. Pts with prior exposure to bortezomib were excluded. Response was evaluated according to IMWG criteria. Primary end point was response at end of cycle 4, secondary objectives overall response rate (ORR), progression-free survival (PFS), overall survival (OS) and toxicity. Results: The present analysis was restricted to the first 4 cycles. From 03/2010 to 07/2011, 73 pts were included, median age 75.8 years (range 66-86). Median time from diagnosis to inclusion was 29 months. All pts received only 1 prior therapy: MP in 12, MP-thalidomide in 44, lenalidomide-dexamethasone (LD) in 14, other in 3. 42 pts (57.5%) were responders at end of cycle 4 [CR: 8 (10.9%), VGPR: 9 (12.3%), PR: 25 (34.2%), SD: 10 (13.6%), progression: 11 (15%), early discontinuation: 10 (13.6%)]. 6pts/10 were in PR and 1pt/10 in VGPR at time of discontinuation. ORR was 67.1% (49/73 pts). 11 pts died (MM: 6, sepsis: 4, renal failure: 1). Adverse events grade 3-4 were neutropenia: 16 pts, thrombocytopenia: 7 pts, sepsis: 12 pts, gastro-intestinal: 8 pts, anaphylaxis: 1 pt. 2 pts had DVT. Peripheral neuropathy grade>1 occurred in 9 pts, all grade 2. Treatment was stopped in 20 pts (lack of efficacy: 11, toxicity: 9). Conclusions: These results compare favorably with those achieved with VD or LD. The triplet BVD combination is very effective and tolerable in elderly pts with MM in 1st progression.

Background High dose melphalan is used widely in the treatment of multiple myeloma (MM) and in the conditioning regimen of autologous stem cell transplantation (ABST). Double courses of high dose melphalan and double autologous bone marrow transplantation (ABMT) programs also have been widely reported. However, there are no data about the feasibility and efficacy of three courses of high dose therapy, such as high dose melphalan or powerful therapies in the treatment of malignant disease. Methods In 1991, a retrospective study in France was initiated to evaluate how many patients with MM had received three courses of high dose therapy with or without hematopoietic stem cell rescue. Results This small study of six patients with multiple myeloma showed that three courses of high dose therapy with or without stem cell rescue can be performed with relative safety. Stem cell rescue appears to shorten the duration of aplasia. In terms of antitumor response, long term response could be obtained in patients with MM that responded to the first course of high dose melphalan. Conclusions High dose therapy with or without ABMT can be an effective treatment for relapse in a subgroup of patients with MM who respond to high dose melphalan as initial treatment.

Abstract 994 The outcome of patients with multiple myeloma (MM) is highly influenced by chromosomal abnormalities, and especially translocation t(4;14) and del(17p). However, these data have been mostly demonstrated in young patients, less than 65 years of age, treated with high-dose chemotherapy. Almost no data is available in elderly patients. In order to address this issue, we retrospectively analyzed patients over 66 years old, treated with various regimens in the Intergroupe Francophone du Myélome (IFM). Since chromosomal abnormalities are centrally analyzed in the IFM, we focused our analyses on 1890 patients (age=65–94, median=71 y). The patients were divided in two groups: 66–74 y (1239 patients) and over 75 y (651 patients). We first analyzed the incidence of the following abnormalities: del(13), del(17p) (defined by a deletion present in at least 60% of the plasma cells), and t(4;14). The incidence of del(13) was 43.6% in the first group, and 37% in the second one (p=.007). For del(17p), the incidences were 5.9% and 6.1%, respectively (p=NS). Finally, for t(4;14), the incidences were 10.9% and 8.3%, respectively (p=.09). When compared to patients < 65 y, we observed a highly significant lower incidence of t(4;14) in elderly patients (14% vs 10.9% vs 8.3%, p Disclosures: Hulin: Janssen-Cilag: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Facon:Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria.

Abstract 1944 Cytogenetic abnormalities have been associated with specific outcome in myeloma, as in many other hematologic malignancies. Among the large spectrum of chromosomal changes observed in myeloma, at least two of them are clearly associated with a specific poor outcome, both in terms of PFS and OS, i.e., t(4;14) and del(17p). Recent data suggested that bortezomib can at least partially overcome the prognostic value of t(4;14). However, t(4;14) remains a prognostic factor in the IFM series. Deletion 17p is rare (< 10%), but is associated with a very poor outcome, whatever the treatment proposed to these patients. In 2005, the IFM designed a clinical trial aiming to test the role of lenalidomide maintenance until relapse in patients under 65 years of age treated with a VAD or bortezomib/dexamethasone induction, followed by high-dose melphalan. Six hundred and fourteen patients have been enrolled, and the clinical results of this trial are presented in another abstract. Chromosomal data focused on t(4;14) and del(17p) were available for 488 of those patients, as analyzed at diagnosis by FISH on sorted plasma cells. The t(4;14) was observed in 13.3% of the patients and del(17p) (defined by presence in at least 60% of the plasma cells) was present in 6.6% of them, incidences that are in agreement with previous reports. The median PFS (calculated from the date of randomization) for patients with t(4;14) were 15 months and 27 months for patients in the placebo and lenalidomide arms, respectively. The median for patients with del(17p) were 14 months and 29 months for patients in the placebo and lenalidomide arms, respectively. The comparison of PFS in the lenalidomide arm for patients with t(4;14) or del(17p), as compared with those lacking the chromosomal abnormalities shows a significant difference, in favor of the “no abnormality” group. In conclusion, lenalidomide maintenance very significantly improves the PFS of patients with high-risk cytogenetics, albeit these chromosomal changes retain their prognostic value. Disclosures: Facon: celgene: Consultancy, Research Funding; johnson and johnson: Consultancy. Attal:celgene: Consultancy, Research Funding; johnson and johnson: Consultancy, Research Funding.

Abstract 1982 Background: Systemic mastocytosis (SM) is a myeloproliferative disabling disorder for which no consensual curative therapy is currently available. Preliminary experiences in small groups of patients using cladribine (2-CdA) were encouraging, but no long term follow-up to evaluate its efficacy and safety have been reported. Patients and Methods: We studied the efficacy and safety of 2-CdA in 44 patients with mastocytosis enrolled in a compassionate program in France. Characteristics of patients were as follows: 22 male, 22 female, mean age 54y (18-83y), mean duration of disease 13 y (6m-39y). Symptoms of the disease included pigmentosa urticaria (31), Fatigue (35), flushs (24), prurit (24), abdominal pain (21), Ascite (9), diarrhea (23), weight loss (16), Headache (14), Cough (10), splenomegaly (20), Lymph nodes (6), Bone fractures (6), pleural effusions (2), Neuropsychological symptoms (19). Blood cell count showed eosinophils >0.5g/l (10), Hb2N (1/44). Patients were classified as having cutaneous mastocytosis (CM) (n=3) indolent SM (n=19), smoldering (SSM) (n=3), aggressive SM (ASM) (n=12) or SM with an associated clonal hematologic non-MC-lineage (AHNMD) (n=6), mast cell leukemia (n=1). Mean tryptase level was 158 (2.7-1240). All failed previous symptomatic therapy and/or recombinant interferon-a(n=10) or kinase inhibitors (n=7). Treatment consisted in intravenous 2-CdA (1 to 6 cycles of 0.15 mg/kg/d administered in a 2-hour infusion or subcutaneously for 5 d, repeated at 4–12 weeks), the mean number of infusion was 4.1 (1-15) to treat severe SM-related infiltration or symptoms. Results: After a median follow up of 35m (0-96m) 28 pts were alive, 14 were dead (all with ASM/ASM-AHNMD/MCL of mastocytosis progression n=5, Solid neoplasia n=2, hematological malignancy n= 3, septic shok n=4) and 2 were lost of follow up. Safety anlalysis showed 18 acute (pneumonia n=3) but no opportunistic infections except two zoster infections, and one renal tubulopathy. Five solid neoplasia were reported and one AML. Responses were observed for most of the symptoms with improvement of pigmentosa urticaria (n=24/31), fatigue (n=17/35), flushs (14/24), prurit (9/24), abdominal pain (9/21), Ascite (1/9), diarrhea (11/23), weight loss (8/16), Headache (4/14), Cough (5/10), splenomegaly (7/20), Lymph nodes (2/6), pleural effusions (0/2), Neuropsychological symptoms (5/19). Eosinophils count was normalized in 7/10 cases, Hb Conclusion: As a single agent, cladribine is an effective and safe treatment in symptomatic and aggressive SM. Cladribine improves significantly symptoms associated with the disease and may induce regression of mast cell tumoral burden. Its tolerability and efficacy argues for the possibility to use it even in ISM and symptomatic CM. Cladribine is ineffective to improve AHNMD. Further work is warranted to define the optimal regimen with respect to dose and schedule, and the usefulness of maintenance cladribine therapy. Disclosures: Hermine: Lipomed: Research Funding. Off Label Use: Cladribine.

Abstract 3043 Introduction: The Thalidomide-Dexamethasone (TD) regimen has provided encouraging results in relapsed MM. To improve results, bortezomib (Velcade) has been added to the combination in previous phase II studies, the so called VTD regimen. In January 2006, the European Group for Blood and Marrow Transplantation (EBMT) and the Intergroupe Francophone du Myélome (IFM) initiated a prospective, randomized, parallel-group, open-label phase III, multicenter study, comparing VTD (arm A) with TD (arm B) for MM patients progressing or relapsing after autologous transplantation. Patients and Methods: Inclusion criteria: patients in first progression or relapse after at least one autologous transplantation, including those who had received bortezomib or thalidomide before transplant. Exclusion criteria: subjects with neuropathy above grade 1 or non secretory MM. Primary study end point was time to progression (TTP). Secondary end points included safety, response rate, progression-free survival (PFS) and overall survival (OS). Treatment was scheduled as follows: bortezomib 1.3 mg/m2 was given as an i.v bolus on Days 1, 4, 8 and 11 followed by a 10-Day rest period (days 12 to 21) for 8 cycles (6 months) and then on Days 1, 8, 15, 22 followed by a 20-Day rest period (days 23 to 42) for 4 cycles (6 months). In both arms, thalidomide was scheduled at 200 mg/Day orally for one year and dexamethasone 40 mg/Day orally four days every three weeks for one year. Patients reaching remission could proceed to a new stem cell harvest. However, transplantation, either autologous or allogeneic, could only be performed in patients who completed the planned one year treatment period. Response was assessed by EBMT criteria, with additional category of near complete remission (nCR). Adverse events were graded by the NCI-CTCAE, Version 3.0.The trial was based on a group sequential design, with 4 planned interim analyses and one final analysis that allowed stopping for efficacy as well as futility. The overall alpha and power were set equal to 0.025 and 0.90 respectively. The test for decision making was based on the comparison in terms of the ratio of the cause-specific hazards of relapse/progression, estimated in a Cox model stratified on the number of previous autologous transplantations. Relapse/progression cumulative incidence was estimated using the proper nonparametric estimator, the comparison was done by the Gray test. PFS and OS probabilities were estimated by the Kaplan-Meier curves, the comparison was performed by the Log-Rank test. An interim safety analysis was performed when the first hundred patients had been included. The safety committee recommended to continue the trial. Results: As of 1st July 2010, 269 patients had been enrolled in the study, 139 in France (IFM 2005-04 study), 21 in Italy, 38 in Germany, 19 in Switzerland (a SAKK study), 23 in Belgium, 8 in Austria, 8 in the Czech republic, 11 in Hungary, 1 in the UK and 1 in Israel. One hundred and sixty nine patients were males and 100 females; the median age was 61 yrs (range 29–76). One hundred and thirty six patients were randomized to receive VTD and 133 to receive TD. The current analysis is based on 246 patients (124 in arm A, 122 in arm B) included in the second interim analysis, carried out when 134 events were observed. Following this analysis, the trial was stopped because of significant superiority of VTD over TD. The remaining patients were too premature to contribute to the analysis. The number of previous autologous transplants was one in 63 vs 60 and two or more in 61 vs 62 patients in arm A vs B respectively. The median follow-up was 25 months. The median TTP was 20 months vs 15 months respectively in arm A and B, with cumulative incidence of relapse/progression at 2 years equal to 52% (95% CI: 42%-64%) vs 70% (95% CI: 61%-81%) (p=0.0004, Gray test). The same superiority of arm A was also observed when stratifying on the number of previous autologous transplantations. At 2 years, PFS was 39% (95% CI: 30%-51%) vs 23% (95% CI: 16%-34%) (A vs B, p=0.0006, Log-Rank test). OS in the first two years was comparable in the two groups. Conclusion: VTD resulted in significantly longer TTP and PFS in patients relapsing after ASCT. Analysis of response and safety data are on going and results will be presented at the meeting. Protocol EU-DRACT number: 2005-001628-35. Disclosures: Niederwieser: Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau.