Optimizing the treatment of liver metastases from uveal melanomas with transarterial chemoembolization using melphalan and calibrated microspheres.

INTRODUCTION: Patients with liver metastasis from uveal melanoma have a poor prognosis. Efficacy and safety of hepatic transarterial chemoembolization (TACE) using melphalan and microspheres was evaluated. MATERIALS AND METHODS: Monocentric retrospective study of all consecutive patients treated by TACE using melphalan and 250µm calibrated microspheres between 2004 and 2016. Radiological response was assessed according to RECIST 1.1, modified (m)-RECIST and EASL on contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI). The primary endpoint was overall survival (OS). Liver metastasis response, hepatic, extrahepatic and global progression free survival (PFS) complications were evaluated with the common terminology criteria for adverse events version 4.0 (CTCAE 4.0) and survival factors were secondary endpoints. RESULTS: Thirty-four patients underwent 138 TACE (4; 4.1 sessions; range 1-9). Median OS was 16.5 months (mean 21.6 months). Liver metastasis response combining partial and complete response was 42.4%, 97%, 97% with RECIST 1.1, mRECIST, EASL, respectively. There were 58 severe (CTCAE≥3) but manageable complications in 28 patients, except for 1 toxic death. CONCLUSION: For patients with liver metastases from uveal melanoma ineligible for local treatments, TACE using melphalan may be performed as first line therapy in metastatic miliary disease from uveal melanomas with careful supportive care.

Myoma Hot Spot: Tumor-to-Tumor Metastasis of Thyroid Origin into Uterine Leiomyoma.

INTRODUCTION: Distant metastases of papillary thyroid cancers are rare. Most common metastatic sites include bone and lung, whereas metastases to brain, eye, breast, liver, kidney, muscle, and skin are infrequent and almost always appear in advanced-stage tumor disease. Metastases to ovary and/or uterus are even scarcer. We report herein a very exceptional case of asymptomatic malignant-to-benign tumor-to-tumor metastasis of thyroid origin into a uterine leiomyoma. CASE PRESENTATION: We present the case of a 53-year-old female patient who had a previous history of pT1b N0 M0 R0 papillary carcinoma of the lower left thyroid lobe, treated by total thyroidectomy and central lymph node dissection and two successive administrations of radioactive treatment with iodine-131. Six years later, follow-up imaging disclosed an asymptomatic slow-growing 40-mm-long pedicled subserous heterogeneous uterine myoma including a 12-mm hypervascular nodule, which was suspicious for thyroid malignancy on MRI. DISCUSSION: Histopathology of a hysterectomy specimen disclosed a hypervascular well-limited poorly differentiated trabecular carcinomatous infiltration within the uterine leiomyoma. The immunohistochemical profile of the suspicious nodule was compatible with a thyroid origin. CONCLUSION: A hypervascular "hot spot" intramyoma nodule was the diagnostic clue in a clinical context of hematogenous tumor spread of thyroid origin (increased thyroglobulin level).

Dual-point FDG-PET/CT for treatment response assessment in Hodgkin lymphoma, when an FDG-avid lesion persists after treatment.

FDG-PET/CT (PET) is now considered the standard imaging tool for Hodgkin Lymphoma (HL) staging and restaging. However a CT-detected residual mass at the end of therapy (EoT) is still a challenge for PET interpretation. The aim of our study was to improve the overall accuracy of EoT PET/CT by using a dynamic dual-point scanning at 60 and 120 after FDG injection (2P-PET/CT). Fifty-one HL patients showing a single residual FDG-avid mass (SFAM) at EoT PET/CT were included in the study in Italy and Poland. Treatment was ABVD, ABVD followed by BEACOPP or ABVD plus radiotherapy. Only patients with a SFAM and a Deauville score (DS) > 2 in EoT PET/CT were included in the study. Two independent nuclear medicine reviewed images with a semi-quantitative analysis (SUVMax and retention index, RI) and a visual scoring according to DS. Compared to standard PET, 2P-PET/CT showed only a modest increase in NPV and PPV, from 0.87 to 0.89 and of the PPV from 0.67 to 0.71, respectively. Increase of the overall accuracy became substantial upon including in the analysis only patients whose images were acquired in strict adhesion to original protocol of 2P-PET/CT scanning: (t 120'-6040 min): the sensitivity increased from 0.60 to 1.00, PPV from 0.75 to 0.83 and NPV from 0.89 to 1. This study, with caution for the small number of patients included, seems to suggest that 2P-PET/CT could increase the overall accuracy of EoT PET/CT in correctly classifying treatment response in HL with a persisting SFAM at EoT.

Sarcomas in patients over 90: Natural history and treatment-A nationwide study over 6 years.

Soft tissue sarcomas (STS) are rare tumors accounting for less than 1% of human cancers. While the highest incidence of sarcomas is observed in elderly, this population is often excluded or poorly represented in clinical trials. The present study reports on clinicopathological presentation, and outcome of sarcoma patients over 90 recorded in the Netsarc.org French national database. NETSARC (netsarc.org) is a network of 26 reference sarcoma centers with specialized multidisciplinary tumor board (MDTB), funded by the French National Cancer Institute to improve the outcome of sarcoma patients. Since 2010, presentation to an MDTB, second pathological review, and collection of sarcoma patient characteristics and follow-up are collected in a database Information of patients registered from January 1, 2010, to December 31, 2016, in NETSARC were collected, analyzed and compared to the younger population. Patients with sarcomas aged >90 have almost exclusively sarcomas with complex genomics (92.0% vs. 66.3%), are less frequently metastatic (5.3% vs. 14·7%) at diagnosis, have more often superficial tumors (39.8% vs. 14.7%), as well as limbs and head and neck sites (75.2% vs. 38.7%) (all p < 0.001). Optimal diagnostic procedures and surgery were less frequently performed in patients over 90 (p < 0.001). These patients were less frequently operated in NETSARC centers, as compared to those of younger age groups including aged 80-90. However, local relapse-free survival, metastatic relapse-free survival and relapse-free survival were not significantly different from those of younger patients, in the whole cohort, as well as in the subgroup of operated patients. As expected overall survival was worse in patients over 90 (p < 0.001). Patients over 90 who were not operated had worse overall survival than younger patients (9.9 vs. 27.3 months, p < 0.001). Patients with STS diagnosed after 90 have distinct clinicopathological features, but comparable relapse-free survival, unless clinical practice guidelines recommendations are not applied. Standard management should be proposed to these patients if oncogeriatric status allows.

Radiotherapy or Autologous Stem-Cell Transplantation for Primary CNS Lymphoma in Patients 60 Years of Age and Younger: Results of the Intergroup ANOCEF-GOELAMS Randomized Phase II PRECIS Study.

PURPOSE: To determine the efficacy and toxicity of chemoimmunotherapy followed by either whole-brain radiotherapy (WBRT) or intensive chemotherapy and autologous stem-cell transplantation (ASCT) as a first-line treatment of primary CNS lymphoma (PCNSL). PATIENTS AND METHODS: Immunocompetent patients (18 to 60 years of age) with untreated PCNSL were randomly assigned to receive WBRT or ASCT as consolidation treatment after induction chemotherapy consisting of two cycles of R-MBVP (rituximab 375 mg/m2 day (D) 1, methotrexate 3 g/m2 D1; D15, VP16 100 mg/m2 D2, BCNU 100 mg/m2 D3, prednisone 60 mg/kg/d D1-D5) followed by two cycles of R-AraC (rituximab 375 mg/m2 D1, cytarabine 3 g/m2 D1 to D2). Intensive chemotherapy consisted of thiotepa (250 mg/m2/d D9; D8; D7), busulfan (8 mg/kg D6 through D4), and cyclophosphamide (60 mg/kg/d D3; D2). WBRT delivered 40 Gy (2 Gy/fraction). The primary end point was 2-year progression-free survival. Cognitive outcome was the main secondary end point. Analysis was intention to treat in a noncomparative phase II trial. RESULTS: Between October 2008 and February 2014, 140 patients were recruited from 23 French centers. Both WBRT and ASCT met the predetermined threshold (among the first 38 patients in each group, at least 24 patients were alive and disease free at 2 years). The 2-year progression-free survival rates were 63% (95% CI, 49% to 81%) and 87% (95% CI, 77% to 98%) in the WBRT and ASCT arms, respectively. Toxicity deaths were recorded in one and five patients after WBRT and ASCT, respectively. Cognitive impairment was observed after WBRT, whereas cognitive functions were preserved or improved after ASCT. CONCLUSION: WBRT and ASCT are effective consolidation treatments for patients with PCNSL who are 60 years of age and younger. The efficacy end points tended to favor the ASCT arm. The specific risk of each procedure should be considered.

Focused ultrasound for the treatment of bone metastases: effectiveness and feasibility.

BACKGROUND: To evaluate the effectiveness and feasibility of high-intensity focused ultrasound (HIFU) for the treatment of bone metastases. METHODS: A single-center prospective study was made involving 17 consecutive patients with symptomatic bone metastases. Patients were treated by Focused Ultrasound (FUs) performed with magnetic resonance (MR) guidance. Surgical treatment or radiotherapy treatment was not indicated for patients who underwent FUs. Lesions were located in the appendicular and axial skeleton and consisted of secondary symptomatic lesions. The clinical course of pain was evaluated using the Visual Analog Scale (VAS) before treatment, at 1 week, and at 1 month after treatment and the Oral Morphine Equivalent Daily Dose (OMEDD) was also recorded. We used Wilcoxon signed rank test to assess change in patient pain (R CRAN software V 3.1.1). RESULTS: We observed a significant decrease in the pain felt by patients between pre- procedure and 1 week post-procedure (p = 2.9.10-4), and pre-procedure and 1 month post-procedure (p = 3.10-4). The proportion of responders according to the International Bone Metastases Consensus Working Party was: Partial Response 50% (8/16) and Complete Response 37.5% (6/16). CONCLUSIONS: HIFU under MR-guidance seems to be an effective and safe procedure in the treatment of symptomatic bone lesions for patients suffering from metastatic disease. A significant decrease of patient pain was observed. TRIAL REGISTRATION: NCT01091883. Registered 24 March 2010. Level of evidence: Level 3.

ABVD or BEACOPPbaseline along with involved-field radiotherapy in early-stage Hodgkin Lymphoma with risk factors: Results of the European Organisation for Research and Treatment of Cancer (EORTC)-Groupe d'Étude des Lymphomes de l'Adulte (GELA) H9-U intergroup randomised trial.

PURPOSE: For early-stage Hodgkin lymphoma (HL), optimal chemotherapy regimen and the number of cycles to be delivered remain to settle down. The H9-U trial compared three modalities of chemotherapy followed by involved-field radiotherapy (IFRT) in patients with stage I-II HL and risk factors (NCT00005584). PATIENTS AND METHODS: Patients aged 15-70 years with untreated supradiaphragmatic HL with at least one risk factor (age ≥ 50, involvement of 4-5 nodal areas, mediastinum/thoracic ratio ≥ 0.35, erythrocyte sedimentation rate (ESR) ≥ 50 without B-symptoms or ESR ≥ 30 and B-symptoms) were eligible for the randomised, open label, multicentre, non-inferiority H9-U trial. The limit of non-inferiority was set at 10% for the difference between 5-year event-free survival (EFS) estimates. From October 1998 to September 2002, 808 patients were randomised to receive either the control arm 6-ABVD-IFRT (n = 276), or one of the two experimental arms: 4-ABVD-IFRT (n = 277) or 4-BEACOPPbaseline-IFRT (n = 255). RESULTS: Results in the 4-ABVD-IFRT (5-year EFS, 85.9%) and the 4-BEACOPPbaseline-IFRT (5-year EFS, 88.8%) were not inferior to 6-ABVD-IFRT (5-year EFS, 89.9%): difference of 4.0% (90%CI, -0.7%-8.8%) and of 1.1% (90%CI,-3.5%-5.6%) respectively. The 5-year overall survival estimates were 94%, 93%, and 93%, respectively. Patients treated with combined modality treatment chemotherapeutic regimen comprising doxorubicin (Adriamycin), bleomycin, vincristine (Oncovin), cyclophosphamide, procarbazine, etoposide and prednisone (BEACOPP)baseline more often developed serious adverse events requiring supportive measures and hospitalisation compared with patients receiving the chemotherapeutic regimen comprising doxorubicin (Adriamycin), bleomycin, vinblastine and dacarbazine (ABVD). CONCLUSIONS: The trial demonstrates that 4-ABVD followed by IFRT yields high disease control in patients with early-stage HL and risk factors responding to chemotherapy. Although non-inferior in terms of efficacy, four cycles of BEACOPPbaseline were more toxic than four or six cycles of ABVD.

Autoimmune hemolytic anemia after nivolumab treatment in Hodgkin lymphoma responsive to immunosuppressive treatment. A case report.

The patients with refractory Hodgkin lymphoma have a poor prognosis. The nivolumab, an IgG4 monoclonal antibody inhibiting the program death 1 pathway has recently demonstrated its efficacy and its safety in patients with heavily pretreated refractory Hodgkin lymphoma. The side effects of this immunotherapy include autoimmune-like syndromes. A 75-year-old woman with no significant comorbidities was treated by nivolumab (3 mg/kg every 2 wk) as a third-line treatment for refractory Hodgkin lymphoma. A clinical response was observed with the first injection of nivolumab, with a reduction in superficial lymph nodes. After the second injection, the patient presented an authentic autoimmune hemolytic anemia with a profound anemia at 64 g/L and biologic characteristics of hemolysis (elevated unconjugated bilirubin, lactate dehydrogenase, and reticulocytes). The direct antiglobulin test was strongly positive for IgG antibodies, and the indirect antiglobulin test became positive with a very high level of autoantibodies. After 2 injections of nivolumab, the patient underwent a fluodeoxyglucose F 18 positron emission tomography-computed tomography, showing a partial response according to modified Cheson criteria. A treatment with prednisone (2 mg/kg), initiated after transfusion of 2 units of red blood cells, permitted the complete resolution of this autoimmune reaction after 3 months of corticotherapy. The fluodeoxyglucose F 18 positron emission tomography-computed tomography performed at the end of the corticotherapy showed a clear disease progression. Considering the very good response achieved after only 2 injections of nivolumab, the limited therapeutic resources for this old woman, and the complete resolution of the autoimmune hemolytic anemia, nivolumab was reintroduced at the same dose, with close clinical and biological monitoring. She received 6 more injections of nivolumab without recurrence of hemolysis.

[Is FDG TEP CT practice changing in the management of sarcomas in adults?]. / Évaluation de l'utilisation de la TEP au FDG pour le bilan des sarcomes de l'adulte en pratique quotidienne.

BACKGROUND: FDG PET (PET)±computed tomography (CT) has increasingly been used in some areas of oncology imaging. It is sometimes performed outside recommendations, at diagnosis or monitoring of sarcomas. We assessed the value of PET-CT in routine practice in sarcomas. MATERIAL AND METHODS: All consecutive sarcoma adult patient charts presented at the multidisciplinary sarcoma meeting in a tertiary care center over a period of 10months were examined in order to analyze the performances of PET-CT when available. RESULTS: Of 232 patients, 50 (21 %) underwent a PET-CT. Sensitivity and specificity of PET-CT were 94.7 %, 57.1 %, respectively. SUV values were highly variable, including for a given histology or grade. PET-CT resulted in practice changing in 14 % of cases. When extrapulmonary metastases are suspected and for some subtypes of sarcomas, PET-CT could provide additional information because in view of its good sensitivity. CONCLUSION: Given the most frequent pulmonary tropism, first hand chest CT may be sufficient at first diagnostic work-up for the detection of pulmonary metastases. However, the relatively poor specificity suggests that further analyses should be performed to identify clinical situations where PET-CT may be of added value compared to current standards.

Lenalidomide versus investigator's choice in relapsed or refractory mantle cell lymphoma (MCL-002; SPRINT): a phase 2, randomised, multicentre trial.

BACKGROUND: Lenalidomide, an immunomodulatory drug with antineoplastic and antiproliferative effects, showed activity in many single-group studies in relapsed or refractory mantle cell lymphoma. The aim of this randomised study was to examine the efficacy and safety of lenalidomide versus best investigator's choice of single-agent therapy in relapsed or refractory mantle cell lymphoma. METHODS: The MCL-002 (SPRINT) study was a randomised, phase 2 study of patients with mantle cell lymphoma aged 18 years or older at 67 clinics and academic centres in 12 countries who relapsed one to three times, had Eastern Cooperative Oncology Group performance status of 0-2, at least one measurable lesion to be eligible, and who were ineligible for intensive chemotherpy or stem-cell transplantation. Using a centralised interactive voice response system, we randomly assigned (2:1) patients in a permuted block size of six to receive lenalidomide (25 mg orally on days 1-21 every 28 days) until progressive disease or intolerability, or single-agent investigator's choice of either rituximab, gemcitabine, fludarabine, chlorambucil, or cytarabine. Randomisation was stratified by time from diagnosis, time from last anti-lymphoma therapy, and previous stem-cell transplantation. Individual treatment assignment between lenalidomide and investigator's choice was open label, but investigators had to register their choice of comparator drug before randomly assigning a patient. Patients who progressed on investigator's choice could cross over to lenalidomide treatment. We present the prespecified primary analysis results in the intention-to-treat population for the primary endpoint of progression-free survival, defined as the time from randomisation to progressive disease or death, whichever occurred first. Patient enrolment is complete, although treatment and collection of additional time-to-event data are ongoing. This study is registered with ClinicalTrials.gov, number NCT00875667. FINDINGS: Between April 30, 2009, and March 7, 2013, we enrolled 254 patients in the intention-to-treat population (170 [67%] were randomly assigned to receive lenalidomide, 84 [33%] to receive investigator's choice monotherapy). Patients had a median age of 68·5 years and received a median of two previous regimens. With a median follow-up of 15·9 months (IQR 7·6-31·7), lenalidomide significantly improved progression-free survival compared with investigator's choice (median 8·7 months [95% CI 5·5-12·1] vs 5·2 months [95% CI 3·7-6·9]) with a hazard ratio of 0·61 (95% CI 0·44-0·84; p=0·004). In the 167 patients in the lenalidomide group and 83 patients in the investigator's choice group who received at least one dose of treatment the most common grade 3-4 adverse events included neutropenia (73 [44%] of 167 vs 28 [34%] of 83) without increased risk of infection, thrombocytopenia (30 [18%] vs 23 [28%]), leucopenia (13 [8%] vs nine [11%]), and anaemia (14 [8%] vs six [7%]). INTERPRETATION: Patients with relapsed or refractory mantle cell lymphoma ineligible for intensive chemotherapy or stem-cell transplantation have longer progression-free survival, with a manageable safety profile when treated with lenalidomide compared with monotherapy investigator's choice options. FUNDING: Celgene Corporation.

A multicenter phase II study of sepantronium bromide (YM155) plus rituximab in patients with relapsed aggressive B-cell Non-Hodgkin lymphoma.

This phase II study evaluated YM155, a novel small-molecule survivin suppressant, in combination with rituximab in patients with relapsed aggressive B-cell non-Hodgkin lymphoma (NHL) who failed or were not candidates for autologous stem cell transplant (ASCT). During 14-day cycles, 41 patients received YM155 (5mg/m(2)/d) by continuous intravenous (IV) infusion for 168 hours (day 1-7), and rituximab (375mg/m(2)) IV on days 1 and 8 during cycles 1-4 and repeated for 4 cycles every 10 cycles. Forty patients (97.6%) had prior rituximab and 15 patients (36.6%) prior ASCT. Most frequent grade 3-4 adverse events were neutropenia (19.5%) and thrombocytopenia (12.2%). In the per-protocol set (n = 34), objective response rate was 50% and median progression-free survival 17.9 months. Median overall survival was not reached at study termination (median follow-up, 23 months). YM155 in combination with rituximab was tolerable with encouraging antitumor activity and durable responses in relapsed aggressive B-cell NHL patients.

Different outcome of T cell acute lymphoblastic leukemia with translocation t(11;14) treated in two consecutive children leukemia group EORTC trials.

Acute lymphoblastic leukemia of T cell lineage (T-ALL) is an aggressive malignant disease which accounts for 15 % of childhood ALL. T(11;14) is the more frequent chromosomal abnormality in childhood T-ALL, but its prognostic value remained controversial. Our aim was to analyze the outcome of childhood T-ALL with t(11;14) to know if the presence of this translocation is associated with a poor prognosis. We conducted a retrospective study from a series of 20 patients with t(11;14), treated in two consecutive trials from the European Organization for Research and Treatment of Cancer Children Leukemia Group over a 19-year period from 1989 to 2008. There were no significant differences between the 2 consecutive groups of patients with t(11;14) regarding the clinical and biological features at diagnosis. Among 19 patients who reached complete remission, 9 patients relapsed. We noticed 7 deaths all relapse- or failure-related. In the 58881 study, a presence of t(11;14) was associated with a poor outcome with an event-free survival at 5 years at 22.2 % versus 65.1 % for the non-t(11;14) T-ALL (p = 0.0004). In the more recent protocol, the outcome of T-ALL with t(11;14) reached that of non-t(11;14) T-ALL with an event-free survival at 5 years at 65.5 versus 74.9 % (p = 0.93). The presence of t(11;14) appeared as a poor prognostic feature in the 58881 trial whereas this abnormality no longer affected the outcome in the 58951 study. This difference is probably explained by the more intensive chemotherapy in the latest trial.

Off-label use of targeted therapies in osteosarcomas: data from the French registry OUTC'S (Observatoire de l'Utilisation des Thérapies Ciblées dans les Sarcomes).

BACKGROUND: The objective of this study is to explore the off-label use of targeted therapies (TTs) for patients with osteosarcoma registered within the French Sarcoma Group--Bone Tumor Study Group (GSF-GETO) national registry. METHODS: All patients with an osteosarcoma, registered between January 1, 2009 and July 15, 2013 were analyzed. RESULTS: Twenty-nine patients with refractory relapsed osteosarcomas received 33 treatment lines of TTs. The median age at the beginning of treatment was 19 years (range 9-72). The median number of previous lines of chemotherapy was 3 (range 1-8). Before inclusion, 3 patients were in second complete remission, 26 were in progression for metastatic relapse. Twenty-three patients received sirolimus (in combination with cyclophosphamide for 18); 5, sunitinib; 4, sorafenib; and one, pazopanib. Stable disease was observed for 45.5% of patients (95% Confidence Interval (CI) [20-52.8]). The median Progression-Free Survival (PFS) was 3 months (95% CI [2-5.4]) for patients treated by sirolimus and 1.8 months (95% CI [1.3-2.8]) for patients receiving multi-targeted tyrosine kinase inhibitors; 6-month PFS 15%. The median Overall Survival (OS) was 6.8 months (95% CI [4.7-12.1]), and one-year OS was 24%. In a multivariate analysis, PFS was superior for patients receiving sirolimus compared to other TTs (Hazard Ratio (HR) = 2.7, 95% CI [1.05-7.1]). No toxic death was reported. Grade 3 and 4 toxicities were observed in 27 and 6% of cases respectively. CONCLUSION: Off-label TTs, especially sirolimus, reported benefit in the treatment of refractory osteosarcomas with an acceptable toxicity profile, including in pediatric population.

Z-BeEAM (Ibritumomab tiuxetan, Bendamustine, Etoposide, Cytarabine, Melphalan) before autologous stem cell transplantation is safe and efficient for refractory large B-cell lymphoma.

BACKGROUND: Refractory or relapsed large B-cells lymphoma are usually treated with a high dose chemotherapy regimen followed by an autolougous stem cells transplantation. BEAM (carmustine, etoposide, cytarabine, melphalan) or more recently Z-BEAM (ibritumomab tiuxetan and BEAM) are commonly used regimens, but recently carmustine availability became difficult. The purpose of this study was to evaluate the feasibility and the safety of replacing carmustine by bendamustine in a new Z-BeEAM regimen (ibritumomab tiuxetan, bendamustine, etoposide, cytarabine, melphalan) prior to autologous stem cell transplantation. FINDINGS: This study was a retrospective analyze of six patients, with a median age of 60, treated by Z-BeEAM before autologous stem cell transplantation. We did not put in evidence any additional toxicities compared to conventional induction chemotherapy. The main toxicities were mucositis (3 grade III among 6 patients), gastrointestinal (2 grade III vomiting and 2 grade III diarrhea) and neutropenia (6 grade IV). Engraftment was successfully achieved for all patients. At the time of analysis of this study all patients were alive and in complete response based on the PET-CT evaluation. CONCLUSIONS: BeEAM plus ibritumomab tiuxetan combined regimen before autologous stem cell transplantation is feasible and safe in aggressive relapsing large B-cell lymphoma.

Successful re-treatment of a relapsed V600E mutated HCL patient with low-dose vemurafenib.

Hairy cell leukemia (HCL) is a chronic B-cell lymphoproliferative disorder that accounts for 2% of all leukemia. Recent identification of the recurrent V600E BRAF mutation in a majority of HCL patients has led some teams to evaluate the clinical potential of vemurafenib, a BRAF V600 specific inhibitor in a limited number of refractory HCL patients. Recently, we published the case of an HCL patient successfully treated with a low dose of vemurafenib. Eight months after the ending of treatment this patient relapsed. We present here the successful retreatment of this patient with a second line of vemurafenib. Our data suggest for the first time that vemurafenib at the dose of 240 mg once a day could be sufficient to maintain a complete hematological remission after an initial induction treatment with low-dose vemurafenib (2 × 240 mg) daily without inducing major toxicity.

Trabectedin in combination with doxorubicin for first-line treatment of advanced uterine or soft-tissue leiomyosarcoma (LMS-02): a non-randomised, multicentre, phase 2 trial.

BACKGROUND: Metastatic leiomyosarcomas of uterine or soft-tissue origin have poor prognosis and moderate chemosensitivity. Trabectedin has shown activity in pretreated leiomyosarcoma. We did a single-group, multicentre, phase 2 trial (LMS-02) to assess the effect of first-line doxorubicin and trabectedin combination on disease control and survival. METHODS: Adults (18 years to physiological age ≤70 years) with measurable metastatic or unresectable uterine leiomyosarcoma or soft-tissue leiomyosarcoma who had not received any previous chemotherapy were enrolled at 19 centres in France. Treatment consisted of 60 mg/m(2) intravenous doxorubicin followed by 1·1 mg/m(2) trabectedin in a 3 h intravenous infusion on day 1, both by the central venous route, and 6 mg subcutaneous pegfilgrastim on day 2, repeated every 3 weeks for up to six cycles. Surgery for residual disease was permitted. The primary endpoint was the proportion of patients achieving disease control, defined as complete or partial response or stable disease. Stratification was done by anatomical site and analyses were per protocol. This study is registered with ClinicalTrials.gov, number NCT02131480. FINDINGS: Between July 28, 2010, and May 10, 2013, 109 patients were enrolled and treated, of whom 108 were assessable for response: 47 in the uterine leiomyosarcoma group and 61 in the soft-tissue leiomyosarcoma group. 32 (68%) patients in the uterine leiomyosarcoma group and 45 (74%) in the soft-tissue leiomyosarcoma group received all six cycles of treatment. Of 47 patients with uterine leiomyosarcoma, 28 (59·6%, 95% CI 44·3-73·6) achieved a partial response and 13 (27·7%, 15·6-42·6) stable disease; 41 (87·2%, 74·3-95·2) patients achieved disease control. Of 61 patients with soft-tissue leiomyosarcoma, two (3·3%, 95% CI 0·4-11·7) achieved a complete response, 22 (36·1%, 25·0-50·8) had a partial response, and 32 (52·5%, 40·8-67·3) had stable disease; 56 (91·8%, 81·9-97·3) of patients achieved disease control. The most common grade 3-4 treatment-associated adverse events were neutropenia (84 [78%] of 108 patients), increased alanine aminotransferase concentration (42 [39%]), thrombocytopenia (40 [37%]), anaemia (29 [27%]), febrile neutropenia (26 [24%]), and fatigue (21 [19%]). INTERPRETATION: Despite expected but manageable toxic effects, these results support the activity of doxorubicin plus trabectedin as first-line treatment for uterine leiomyosarcoma and soft-tissue leiomyosarcoma. This combination should be developed further in a phase 3 trial against the present standard of care. FUNDING: Pharmamar and Amgen.

High-dose chemotherapy with carmustine, etoposide, cytarabine and melphalan followed by autologous stem cell transplant is an effective treatment for elderly patients with poor-prognosis lymphoma.

Autologous stem cell transplant (ASCT) after high-dose chemotherapy (HDT) increases overall survival when used in relapsed non-Hodgkin lymphoma (NHL) in patients under 65 years old. Limited experience is available for older patients. We present a retrospective analysis of 73 consecutive patients aged over 65 years treated for aggressive or relapsed lymphoma by HDT with carmustine, etoposide, cytarabine and melphalan (BEAM) at full dosage followed by ASCT. Patient data were obtained from medical charts from two institutions. Median age was 67 years (65-74). Significant comorbidities were present in 24.7% of patients. The median number of days for grade 4 neutropenia was 9 (5-18). The early treatment-related mortality rate (<100 days) was 2.7%. The estimated 2-year progression-free survival and overall survival rates were 67.2% and 78.5%, respectively. In conclusion, the full-dose HDT-ASCT regimen is feasible, safe and efficient in selected patients over 65 years old.

Are nilotinib-associated vascular adverse events an under-estimated problem?

Vascular adverse events have been reported with nilotinib, a tyrosine kinase inhibitor prescribed for chronic myeloid leukaemia. However, few data specify their incidence, or whether they occur in predisposed patients. Hence, we prospectively studied 30 consecutive patients to assess the frequency of such adverse reactions and determine whether the patients presenting with these adverse events bear predisposing factors. From 3 to 73 months after nilotinib initiation, 10 of the 30 patients experienced vascular events. Three patients of these 10 were devoid of any patent cardiovascular risk factor, except for age. This study points out an occurrence more frequent than expected of vascular adverse events associated with nilotinib (> 30% vs. < 1% in summary of product characteristics), and particularly of vascular events of late onset in patients with no pre-existing risk factors.

Treating metastatic sarcomas locally: a paradoxe, a rationale, an evidence?

PURPOSE: The mainstay of first line treatment in metastatic sarcomas is chemotherapy with response rates of ≈25% but the optimal management of further events is debated. We assessed the benefit of local metastatic treatment in metastatic sarcomas. RESULTS: Local control of local treatment strategies (≈85%) is excellent but highly institution-dependent and subject to selection biases. Formal evidence of an improvement of survival with local ablative treatments has been limited to retrospective studies. On the other hand, some chemotherapy trials are inconclusive because about 20% of patients receive local metastatic ablation as it is considered unethical to omit local treatment in these patients. Further, technology has made surgery, stereotactic irradiation and radiofrequency ablation highly effective on local control with limited morbidity. CONCLUSION: The benefit on survival of metastatic ablation deserves prospective studies integrating quality of life, cost effectiveness and patient-reported outcomes assessment.