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International audience; Essentials Risk factors of bleeding in adult immune thrombocytopenia are not known. This multicenter study assessed risk factors of bleeding at immune thrombocytopenia onset. Platelet count thresholds associated with bleeding were < 20 × 109 L-1 and < 10 × 109 L-1 . Exposure to anticoagulants was a major risk factor of severe bleeding.Summary: Background The aim of this cross-sectional study was to assess risk factors for bleeding in immune thrombocytopenia (ITP) adults, including the determination of platelet count thresholds. Methods We selected all newly diagnosed ITP adults included in the Cytopénies Auto-immunes Registre Midi-PyrénéEN (CARMEN) register and at the French referral center for autoimmune cytopenias. The frequencies of any bleeding, mucosal bleeding and severe bleeding (gastrointestinal, intracranial, or macroscopic hematuria) at ITP onset were assessed. Platelet count thresholds were assessed by the use of receiver operating characteristic curves. All potential risk factors were included in logistic regression models. Results Among the 302 patients, the frequencies of any, mucosal and severe bleeding were 57.9%, 30.1%, and 6.6%, respectively. The best discriminant threshold of platelet count for any bleeding was 20 × 109 L-1 . In multivariate analysis, factors associated with any bleeding were platelet count (< 10 × 109 L-1 versus ≥ 20 × 109 L-1 , odds ratio [OR] 48.2, 95% confidence interval [CI] 20.0-116.3; between 10 × 109 L-1 and 19 × 109 L-1 versus ≥ 20 × 109 L-1 , OR 5.2, 95% CI 2.3-11.6), female sex (OR 2.6, 95% CI 1.3-5.0), and exposure to non-steroidal anti-inflammatory drugs (NSAIDs) (OR 4.8, 95% CI 1.1-20.7). A low platelet count was also the main risk factor for mucosal bleeding. Exposure to anticoagulant drugs was associated with severe bleeding (OR 4.3, 95% CI 1.3-14.1). Conclusions Platelet counts of < 20 × 109 L-1 and < 10 × 109 L-1 were thresholds for major increased risks of any and mucosal bleeding. Platelet count, female sex and exposure to NSAIDs should be considered for assessment of the risk of any bleeding. Exposure to anticoagulant drugs was a major risk factor for severe bleeding.

ML18147 evaluated continued bevacizumab with second-line chemotherapy for patients with metastatic colorectal cancer (mCRC) progressing after the standard first-line bevacizumab-containing therapy.Evaluating outcomes according to tumor Kirsten rat sarcoma virus oncogene (KRAS) status was an exploratory analysis. KRAS data were collected from local laboratories (using their established methods) and/or from a central laboratory (mutation-specific Scorpion amplification-refractory mutation system). No adjustment was made for multiplicity; analyses were not powered to detect statistically significant differences.Of 820 patients, 616 (75%) had unambiguous KRAS data; 316 (51%) had KRAS wild-type tumors and 300 (49%) had mutant KRAS tumors. The median progression-free survival (PFS) was 6.4 months for bevacizumab plus chemotherapy and 4.5 months for chemotherapy [P0.0001; HR = 0.61; 95% confidence interval (CI): 0.49-0.77] for wild-type KRAS and 5.5 and 4.1 months, respectively (P = 0.0027; HR = 0.70; 95% CI: 0.56-0.89) for mutant KRAS. The median overall survival (OS) was 15.4 and 11.1 months, respectively (P = 0.0052; HR = 0.69; 95% CI: 0.53-0.90) for wild-type KRAS and 10.4 versus 10.0 months, respectively (P = 0.4969; HR = 0.92; 95% CI: 0.71-1.18) for mutant KRAS. In both analyses, no treatment interaction by KRAS status was observed (PFS, P = 0.4436; OS, P = 0.1266).Bevacizumab beyond first progression represents an option for patients with mCRC treated with bevacizumab plus standard first-line chemotherapy, independent of KRAS status.

The combination of vindesine and cisplatin is considered a reference regimen in advanced NSCLC which has yielded a significant improvement in the duration of survival. A phase II study of a new semi-synthetic vinca alkaloid, Navelbine, reported an unusually high 29% response rate in stage III-IV NSCLC and a phase I-II study established the feasibility of the combination of Navelbine and cisplatin. We, therefore, designed a prospective randomized trial to compare Navelbine and cisplatin (NVB-P) to vindesine and cisplatin (VDS-P) and to evaluate whether the best of these regimens affords a survival benefit compared to Navelbine alone (NVB), an outpatient regimen. Forty-five centers included 612 patients in this study: 206 in NVB-P, 200 in VDS-P and 206 in NVB. Navelbine was given at a dose of 30 mg/m2 weekly, cisplatin at 120 mg/m2 on day 1, day 29 and then every 6 weeks and vindesine at 3 mg/m2 weekly for 6 weeks and then every other week. Treatment was continued until progression or toxicity. Patients' characteristics were similar in the three groups with 59% of patients presenting with metastatic disease. An objective response rate was observed in 30% of patients in NVB-P versus 19% in VDS-P (P = .02) and 14% in NVB (P.001). The median duration of survival was 40 weeks in NVB-P compared to 32 weeks in VDS-P and 31 weeks in NVB. The comparison of survival between the three groups demonstrated an advantage for NVB-P compared to VDS-P (P = .04) and NVB (P = .02). Neutropenia was significantly higher in the NVB-P group (P.001) and neurotoxicity more frequent with VDS-P (P.004). Since our results have demonstrated that NVB-P yields a longer survival duration and a higher response rate than VDS-P or NVB alone, with acceptable toxicity, this combination should be considered a reference regimen in advanced NSCLC.

PURPOSE Assessment of cisplatin (CDDP) tolerance in patients more than 80 years old in good general condition who may benefit from CDDP-based treatment. PATIENTS AND METHODS Data on 35 patients older than 80 years who received one to six chemotherapy cycles (median, three cycles; total number of cycles, 98) including CDDP (60 to 100 mg/m2) were analyzed retrospectively. Before treatment, all patients had normal renal function as defined by serum creatinine (SC) levels below 132 mumol/L. Renal function was evaluated by measurement of SC and creatinine clearance (CC) before and after each course of chemotherapy. CC was calculated according to the Cockroft and Gault formula, where CC = (140 - age) x weight kg/0.814 x SC mumol/L. Renal toxicity was evaluated by the difference between prechemotherapy SC and the maximum SC level observed (delta SC) and by the difference between prechemotherapy CC and the minimal CC observed after treatment with CDDP (delta CC). The evolution of SC and CC during repeated courses of CDDP was analyzed, as were any extrarenal toxicities. RESULTS Renal function remained stable in 19 patients (54%) with delta SC less than 18 mumol/L and 18 of 35 patients (51%) with delta CC less than 9 mL/min. A slight deterioration in renal function was observed in 13 patients (37%) with delta SC greater than 18 mumol/L and less than 60 mumol/L, and with a delta CC greater than 11 mL/min and less than 21 mL/min. In three patients (9%), delta SC was greater than 60 mumol/L (71, 73, 115 mumol/L) and delta CC was greater than 21 mL/min (25, 26, 36 mL/min). There were no cases of severe renal insufficiency, clinical ototoxicity, or neurotoxicity > or = grade 2. Treatment was terminated after one or two courses in three patients because of grade 2 or 3 hematologic toxicity and in two patients for grade 3 nausea or vomiting. CONCLUSION CDDP at moderate doses can reasonably be administered to patients older than 80 years who may benefit from antineoplastic chemotherapy.

Dihydropyrimidine dehydrogenase (DPD) is the major catabolic enzyme of pyrimidines and fluoropyrimidines. The clinical course of 2 patients with suspected DPD deficiency is described. Both patients had significantly delayed clearance of fluorouracil (5-FU), elevated plasma uracil concentrations, and subsequent lethal toxicity. The prevalence of DPD deficiency in the general population is unknown, but given the large number of cancer patients treated with 5-FU, it may be of great clinical significance. Lymphocytes have been previously shown to be a useful marker of systemic DPD activity. Because DPD activity has not been previously reported in a large population of cancer patients using 5-FU as the substrate, we determined DPD activity in lymphocytes from 66 patients with cancer. DPD activity was determined by a sensitive high performance liquid chromatography method. The mean DPD activity (S.D.) in 66 patients with head and neck cancer was 0.189 (0.071) nmol/min/mg protein with wide interpatient variability (range 0.058–0.357). DPD activity was not correlated to age ( r = −0.164, P = 0.188). The mean DPD activity in men [0.192 (0.074)] was not significantly different from that in women [0.172 (0.057); t -test P = 0.418]. Likewise, there was no statistical difference in DPD activity in patients who had not received prior chemotherapy [0.195 (0.066)] to patients receiving one or more cycles of chemotherapy [0.186 (0.074); t -test P = 0.638].

Two cases occurred of granulocytic sarcoma with cerebrospinal fluid involvement but no associated leukemia on presentation. Both cases were difficult to identify by histology and were initially misdiagnosed as malignant lymphoma. The characteristic cerebrospinal fluid cytologic picture allowed the diagnosis. These cases underscore the value of cytologic examination of tumor imprints and the use of myeloid markers in panels for immunophenotyping lymphomas.

In vivo use of rIL-2 autologous BMT may be the means of reproducing a kind of "adoptive immunotherapy" from grafted cells after allogeneic BMT. This approach may enhance the spontaneous generation of cytotoxic T-cells and NK cells which are presumably involved in this immunotherapy. Potential risks of such an approach would be to increase the usual toxicity of rIL-2 and to jeopardize the hemopoietic reconstitution. To determine the feasibility of this approach we have treated 19 poor prognosis patients with a succession of autologous BMT followed 78 +/- 12 days later by a continuous infusion of rIL-2. Eighteen million international units (IU) per m2 per day of Proleukine (CETUS, Amsterdam, The Netherlands) were administrated over 6 or 12 days. No patient died of the procedure. Clinical toxicity related to rIL-2 was not increased. Hemopoietic toxicity, significant both for platelets and granulocytes, was transient. Immune stimulation was dramatic for lymphocytes and subpopulations (CD3+ and NK cells) and for cytolytic functions (NK and LAK activity). This trial establishes the feasibility of administration of high doses of rIL-2, 2 months after autologous BMT. In this setting a 6 day period of continuous infusion of 18 million per m2 per day of Proleukine appears to be a regularly tolerable dosage conducting to a major immune activation and invites further studies to determine the clinical impact of such an approach.

Forty-seven patients with high risk acute lymphoblastic leukemia (ALL) received an allogeneic (allo) or autologous (auto) bone marrow transplant (BMT). Patients in both groups were comparable in terms of age, initial presentation of ALL and induction chemotherapy. Allo patients were transplanted earlier (median 3 months after CR) than auto patients (median 6.5 months after CR). Auto patients received more consolidation chemotherapy before BMT. All patients received total body irradiation 2.2 Gy/day x 5 days after cyclophosphamide 60 mg/kg x 2 (18 allo and five auto) or melphalan 140 mg/m2 (seven allo and 17 auto). Prevention of graft-versus-host disease (GVHD) was by conventional immunosuppression in 17 patients and T cell depletion in eight. Seven patients (28%) developed moderate to severe acute GVHD. Auto marrow was treated in vitro in each case. Seven patients died in CR from BMT complications (five allo and two auto). The probability of relapse was 9% for patients receiving allo BMT and 52% for patients receiving auto BMT (p less than 0.01). The disease-free survival was 71% for allo BMT and 40% for auto BMT (p = NS). Early BMT is an effective form of consolidation for high risk patients with ALL in first CR. An allogeneic anti-leukemia effect was demonstrated in this study.

Twenty-six patients (median age 33 years) with poor-risk malignancies were treated with high-dose combination chemotherapy associating BCNU-etoposide-cytosine arabinoside and melphalan (BEAM) followed by autologous bone marrow transplantation (ABMT). Twenty-one patients had malignant lymphomas, three, acute lymphoblastic leukemia (ALL), and two, malignant thymomas. Eleven patients (group 1) were not in complete remission (CR) at the time of BEAM, and fifteen patients (group 2) were in CR. Hematological recovery occurred in all patients. The duration of aplasia and the non-hematological toxicities were similar in both groups. Ten of the eleven patients (group 1) evaluable for response achieved CR and one achieved partial remission (PR). Five patients relapsed, and five are in continuous CR with a short follow-up (median 8 months). Among the fifteen patients in CR at the time of BEAM (group 2), four patients relapsed and ten patients are in unmaintained continuous CR with a median follow-up of 15 months (one patient died in CR). The disease-free survival is 53%, with 29% for patients receiving BEAM while in relapse (group 1) and 65% for patients receiving BEAM while in CR (group 2). These data indicate that BEAM followed by ABMT can produce a high antitumor response with an acceptable toxicity in patients with poor-risk malignancies.

A mouse IgG monoclonal antibody (MoAb) directed against the human LFA1 molecule (25.3 MoAb) was used in nine adult leukemic patients to prevent graft rejection after T cell-depleted HLA matched bone marrow transplantation. Based on the results of a previous study in children 0.1 mg/kg of 25.3 was given on days -3, -1, +1, +3, +5 in addition to a standard conditioning regimen with cyclophosphamide (120 mg/kg) and fractionated total body irradiation. The marrow transplant was T cell-depleted using T101 Fab immunotoxin ricin A chain. Seven patients received post-graft immunosuppression with methotrexate and cyclosporine A; two patients received no immunosuppression post-graft. A mean T cell depletion of 98.3% (80-100%) was achieved. Tolerance to the infusions of 25.3 MoAb was excellent. No patient developed any form of graft-versus-host disease. However two patients failed to engraft and three patients had delayed graft failures. These results show that this regimen of anti LFA1 MoAb, which was extremely good at permitting engraftment of HLA mismatched T cell-depleted transplant in children with constitutional diseases, is not able to prevent graft failure and rejection of T cell-depleted HLA matched transplants in adults with leukemia. Further efforts are needed to overcome graft failures in this clinical situation.

Thirty-eight patients with haematological malignancies were treated with bone marrow transplantation using histocompatible immunotoxin T cell-depleted marrow siblings. All patients received conventional postgraft immunosuppression (methotrexate and/or cyclosporin A). Donor bone marrow was treated ex vivo with T101 Fab fragment coupled to ricin A-chain (T101 Fab-RTA) at a concentration of 10(-8) M of A-chain in association with NH4Cl (2 x 10(-2) M) in pH adjusted (7.8) incubation medium. A median cytoreduction of 99.5% (91-99.5) was obtained. The median of follow-up was 300 days. Only three patients developed grade II acute graft-versus-host disease (GVHD) (actuarial rate of acute GVHD: 9.1%). No chronic GVHD occurred. All patients but one engrafted. Six out of the 37 patients developed a documented bone marrow rejection (actuarial rate of graft failure: 18%). Ten patients relapsed (actuarial rate of relapse: 36.9%). These findings demonstrate that treatment of donor marrow with T101 Fab-RTA in association with NH4Cl at critical pH value can achieve a high level of mature T cell depletion and greatly reduce the incidence of bone marrow rejection and relapse after T cell-depleted allogeneic bone marrow transplantation.

We evaluated retrospectively the incidence and prognosis of bacteremias after bone marrow transplantation treated in protected environment with intestinal decontamination. Bacteremias are more frequent during the extreme granulopenia (55% of the patients) than during recovery of granulocyte counts greater than 500/mm3 (35% of the patients). Gram + organisms are more frequently responsible of bacteremias (80%), mainly Staphylococcus epidermidis and Streptococci. Mortality is low (7%) and related to additional factors like GVH, resistant leukemia. These data invite to develop new approaches of prevention of bacterial infection, with measures possibly efficient on Gram + organisms.

From February 1986 to July 1987, 87 patients who underwent an autologous or allogeneic bone marrow transplantation were randomized to receive ticarpen tobramycin or ticarpen moxalactam for their first febrile episode. Forty received ticarpen tobramycin and 47 ticarpen moxalactam. The two groups were similar according to age, sex, conditioning regimen, underlaying pathology and duration of granulocytopenia. We observed 58.6% of fever unknown origin and 37% of bacteremia. A similar number of clinical and bacteriological successes occurred in the two groups. Hepatic and renal toxicities were similar in the two groups. Vancomycin was widely used in these patients without particular justification. We conclude that the use of two beta lactam is a possible antibiotherapy in marrow transplantation where renal function should be preserved from additional toxicity.

International audience; BACKGROUND: Metastatic colorectal cancer (mCRC) is increasingly treated using targeted therapies. Their real-life evaluation is insufficient, especially in elderly and frail patients. The aim was to describe use, safety, and effectiveness of targeted therapies in first-line mCRC treatment according to age. PATIENTS AND METHODS: Two field cohorts of patients initiating bevacizumab or cetuximab for first-line mCRC were pooled. Patients characteristics, use, and safety were compared between younger and elderly patients (/=75 years). Two-year overall survival (OS) and progression-free survival (PFS) were estimated in both age groups using the Kaplan-Meier method adjusted on factors associated with death or progression identified with Cox multivariate modeling. RESULTS: Eight hundred patients (n = 411, 51.4% bevacizumab) were included: 498 (62.3%) male, median age 64 years, 118 (14.8%) Eastern Cooperative Oncology Group performance status (ECOG-PS) >/=2. Elderly patients (n = 126, 15.8%) were more often treated with 5-fluorouracil alone than younger. Severe adverse events were equivalent across age groups. ECOG-PS >/=1, abnormal hemoglobin, and abnormal alkaline phosphatases were associated with a higher risk of death; OS adjusted on these factors was similar between elderly and younger patients. ECOG-PS >/=1, lung metastases, abnormal hemoglobin, and abnormal creatinine clearance were associated with a higher risk of progression or death; PFS adjusted on these factors was similar across groups. CONCLUSION: Despite treatment adaptations, elderly patients could benefit from targeted therapies as younger without safety warning.