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We report a randomized prospective phase 3 study (CLL7), designed to evaluate the efficacy of fludarabine, cyclophosphamide, and rituximab (FCR) in patients with an early-stage high-risk chronic lymphocytic leukemia (CLL). Eight hundred patients with untreated-stage Binet A disease were enrolled as intent-to-treat population and assessed for four prognostic markers: lymphocyte doubling time 10 U/L, unmutated IGHV genes, and unfavorable cytogenetics (del(11q)/del(17p)/trisomy 12). Two hundred and one patients with ≥2 risk features were classified as high-risk CLL and 1:1 randomized to receive either immediate therapy with 6xFCR (Hi-FCR, 100 patients), or to be observed according to standard of care (Hi-W&W, 101 patients). The overall response rate after early FCR was 92.7%. Common adverse events were hematological toxicities and infections (61.0%/41.5% of patients, respectively). After median observation time of 55.6 (0–99.2) months, event-free survival was significantly prolonged in Hi-FCR compared with Hi-W&W patients (median not reached vs. 18.5 months, p p = 0.864). In conclusion, although FCR is efficient to induce remissions in the Binet A high-risk CLL, our data do not provide evidence that alters the current standard of care “watch and wait” for these patients.

International audience; No abstract available

In total, 279 patients with hairy-cell leukemia (HCL) were analyzed, with a median follow-up of 10 years. Data were collected up to June 2018. We analyzed responses to treatment, relapses, survival, and the occurrence of second malignancies during follow-up. The median age was 59 years. In total, 208 patients (75%) were treated with purine analogs (PNAs), either cladribine (159) or pentosatin (49), as the first-line therapy. After a median follow-up of 127 months, the median overall survival was 27 years, and the median relapse-free survival (RFS) was 11 years. The cumulative 10-year relapse incidence was 39%. In patients receiving second-line therapy, the median RFS was 7 years. For the second-line therapy, using the same or another PNA was equivalent. We identified 68 second malignancies in 59 patients: 49 solid cancers and 19 hematological malignancies. The 10-year cumulative incidences of cancers, solid tumors, and hematological malignancies were 15%, 11%, and 5.0%, respectively, and the standardized incidence ratios were 2.22, 1.81, and 6.67, respectively. In multivariate analysis, PNA was not a risk factor for second malignancies. HCL patients have a good long-term prognosis. PNAs are the first-line treatment. HCL patients require long-term follow-up because of their relatively increased risk of second malignancies.

With the emergence of targeted therapies, defining the best strategy for the treatment of previously untreated CLL patients remains challenging. The aim of this phase 2 study was to compare the efficacy of an association with ibrutinib and venetoclax (IV) to the standard FCR regimen in fit patients with intermediate risk CLL defined by either unmutated IGHV status, 11q deletion or complex karyotype in the absence of TP53 abnormality. Patients were randomized 1:1 between two treatment arms, ie FCR 6 cycles or IV. After a lead-in phase of ibrutinib as a single agent from month (M)1 to M3, the total duration of treatment with IV was based on the response achieved at M9; if bone marrow (BM) MRD was < 0.01% using flow cytometry, the treatment was continued for 6 additional months until M15 and then stopped; if BM MRD at M9 was ≥ 0.01%, the treatment with IV was continued for 18 additional months until M27. The primary endpoint was the percentage of patients with BM MRD < 0.01% at M27 in both arms. We present here the preliminary results on the first evaluation done at M9 including CT-scan, BM biopsy and MRD assessment in PB and BM after the inclusion of all the 120 patients as initially planned. One hundred and twenty patients were enrolled from September 2019 to February 2021. The median age was 59 [34-72] and 61 [34-74] years in the FCR and IV arms, respectively. The characteristics of the patients were well balanced between the 2 arms in terms of gender (male 72% FCR, 74% IV), PS ECOG 0-1 (59% FCR, 68% IV) and Binet stage (A, B and C 15%, 64%, 21% for FCR ; 8.5%, 59% and 32% for IV). No major difference in terms of cytogenetic features was noted, all patients but one had unmutated IGHV. At the time of data cut-off for this interim analysis, the median follow-up for the all cohort was 11 [2.9 - 19.8] months. The frequency of all grades adverse events (AE) observed so far was 53% (grade 3-4, 24%) in the FCR arm and 47% (grade 3-4, 17%) in the IV arm. The rate of infusion-related reactions (IRR) in the FCR arm was 35% on cycle 1-day 1 (14% grade 3-4) ; for the IV arm, 6% of patients experienced tumor lysis syndrome (TLS) (grade 4 for 4 patients). ibrutinib doses were reduced for 7 patients (4 permanently stopped and 3 resumed at a lower dose because of toxicities (digestive, hepatic or haematological)). Venetoclax was permanently discontinued before M9 in 4 patients (digestive toxicities and grade 4 neutropenia). Forty serious adverse events were reported of which 15 in the IV arm (1 sudden death, 1 ischemic stroke, 2 atrial fibrillations, 2 clinical TLS, 1 hepatitis, 1 neutropenia, 4 COVID pneumonitis and one osteoporotic fracture) and 25 in the FCR arm (2 neutropenias, 1 anemia, 1 thrombocytopenia, 1 autoimmune haemolytic anemia, 3 IRR, 4 TLS, 2 COVID pneumonitis, 4 fever episodes of undetermined origin, 1 community-acquired pneumonia, 1 gastrointestinal toxicity, 1 confusion, 2 chest pains, 1 acute myeloid leukemia, 1 myelodysplasic syndrome). The patients with COVID pneumonitis had a favorable evolution with the need for intensive care and convalescent plasma for 3 of them. The first 60 patients included in the study have reached M9 and among them, 6 prematurely discontinued the study, 3 in each arm (active hemolysis, ischemic stroke and sudden death in the IV arm; 2 grade 4 hematologic toxicities and 1 early progression in the FCR arm). In the evaluated patients (n=54), 71% of patients in the FCR arm and 48% of patients in the IV arm achieved bone BM MRD < 0.01%. The complete (CR, CRi) and partial response rates were 54% and 46% in the FCR arm and 76% and 24% in the IV arm respectively. In conclusion, the preliminary results show a lower BM MRD rate in the IV arm compared to the FCR arm at M9, with a toxicity that remains significant and relatively similar between the two arms. However, BM MRD rate should improve after longer exposure to the IV combination and the analysis of the primary endpoint at M27 will be decisive in determining the best therapeutic strategy. Disclosures Quinquenel: Abbvie: Honoraria; Janssen: Honoraria; AstraZeneca: Honoraria. Laribi: Le Mans Hospital: Research Funding; Novartis: Other: Personal Fees, Research Funding; Takeda: Other: Personal Fees, Research Funding; BeiGene: Other: Personal Fees; IQONE: Other: Personal Fees; AbbVie: Other: Personal Fees, Research Funding; Astellas Phama, Inc.: Other: Personal Fees; AstraZeneca: Other: Personal Fees; Jansen: Research Funding. Cymbalista: Lilly-LOXO: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; ASTRA ZENECA: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Leblond: AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Lilly: Consultancy; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Roche: Honoraria; Amgen: Honoraria; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dartigeas: Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress. Ferrant: Janssen: Other: Travel, Accommodations, Expenses; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses; AstraZeneca: Honoraria. de Guibert: Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Feugier: Astrazeneca: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Honoraria; Janssen: Consultancy, Honoraria. Cartron: Roche, Celgene-BMS: Consultancy; Danofi, Gilead, Novartis, Jansen, Roche, Celgene-BMS, Abbvie, Takeda: Honoraria. Ysebaert: Abbvie, AstraZeneca, Janssen, Roche: Other: Advisory Board, Research Funding.

Fertility preservation embraces different techniques developed to improve young women chances of becoming mothers after healing. Among them, in vitro maturation (IVM) procedure is based on oocyte retrieval without any gonadotropin treatment, feasible under locoregional or local anesthesia, with very low operative complications. The present retrospective analysis of a preliminary case series of 25 women diagnosed with Hodgkin or non-Hodgkin lymphoma aims to evaluate the feasibility of IVM for urgent fertility preservation purposes in hematological context. A median of five mature oocytes was cryopreserved after one cycle of IVM, performed without delaying the start of the chemotherapy (median delay from histological diagnosis to start of the chemotherapy 17.5 days). No association was found between lymphomas' characteristics and the number of recovered or frozen oocytes. Although experimental, this technique could be relevant when fertility preservation has to be performed within a short time frame and without additional surgery nor any risk of malignant cells reintroduction.

PURPOSE To evaluate first-line pembrolizumab monotherapy efficacy and safety in patients with unresectable cutaneous squamous cell carcinomas (CSCCs). PATIENTS AND METHODS Patients, predominantly men, with their CSSCs’ immunohistochemically determined programmed cell death-ligand 1 (PD-L1) status determined (tumor proportion score threshold, 1%), received pembrolizumab (200 mg every 3 weeks). The primary endpoint was the 39-patient primary cohort’s objective response rate at week 15 (ORRW15). Secondary objectives were best ORR, overall survival (OS), progression-free survival (PFS), duration of response (DOR), safety, ORR according to PD-L1 status and health-related quality of life using Functional Assessment of Cancer Therapy–General (FACT-G) score. An 18-patient expansion cohort, recruited to power the study to evaluate the ORRW15 difference between PD-L1+ and PD-L1– patients, was assessed for ORR, disease control rate, and safety, but not survival. RESULTS Median age of all patients was 79 years. The primary cohort’s ORRW15 was 41% (95% CI, 26% to 58%), including 13 partial and 3 complete responses. Best responses were 8 partial and 8 complete responses. At a median follow-up of 22.4 months, respective median PFS, DOR, and OS were 6.7 months, not reached, and 25.3 months, respectively. Pembrolizumab-related adverse events affected 71% of the patients, and 4 (7%) were grade ≥ 3. One death was related to rapid CSCC progression; another resulted from a fatal second aggressive head and neck squamous cell carcinoma diagnosed 15 weeks postinclusion. ORRW15 for the entire population was 42%; it was significantly higher for PD-L1+ patients (55%) versus PD-L1– patients (17%; P = .02). Responders’ W15 total FACT-G score had improved ( P = .025) compared with nonresponders. CONCLUSION First-line pembrolizumab monotherapy exhibited promising anti-CSCC activity, with durable responses and manageable safety. PD-L1 positivity appears to be predictive of pembrolizumab efficacy.

Introduction In previously untreated, medically fit patients with chronic lymphocytic leukaemia (CLL) and no 17p deletion, there is current research interest in improving survival outcomes and potentially sparing some patients from the standard 6 cycles of fludarabine, cyclophosphamide and rituximab (FCR). The phase II ICLL-07 (NCT02666898) trial, conducted by the French Innovative Leukemia Organization (FILO), aimed to explore the efficacy of obinutuzumab and ibrutinib treatment induction for 9 months, followed by a minimal residual disease (MRD)-driven strategy. Methods Following assessment at Month 9, patients in complete response (CR) with bone marrow (BM) MRD ResultsBetween 10/2015 and 05/2017, 135 patients were enrolled. At Month 9, only 8% of patients reached CR with BM MRD Conclusion These findings from the ICLL-07 trial demonstrated that, in previously untreated, medically fit patients with CLL and no 17p deletion, treatment induction with obinutuzumab and ibrutinib followed by an MRD-driven strategy yielded a high rate of CR with BM and PB MRD Disclosures Salles: Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Amgen: Honoraria, Other: Educational events. Leblond:Gilead: Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cartron:Roche, Celgene: Consultancy; Sanofi, Gilead, Janssen, Roche, Celgene: Honoraria. Cymbalista:Sunesis: Research Funding; Roche: Research Funding; Janssen: Honoraria; Abbvie: Honoraria; AstraZeneca: Honoraria; Gilead: Honoraria. Le Garff-Tavernier:Alexion: Consultancy, Honoraria. Letestu:Alexion: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts; Roche: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts. Feugier:janssen: Honoraria, Research Funding, Speakers Bureau; gilead: Honoraria, Research Funding, Speakers Bureau; abbvie: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau.

Mutational analyses performed following acquired ibrutinib resistance have suggested that chronic lymphocytic leukemia (CLL) progression on ibrutinib is linked to mutations in Bruton tyrosine kinase (BTK) and/or phospholipase Cγ2 (PLCG2) genes. Mutational information for patients still on ibrutinib is limited. We report a study aimed to provide a “snapshot” of the prevalence of mutations in a real-life CLL cohort still on ibrutinib after at least 3 years of treatment. Of 204 patients who initiated ibrutinib via an early-access program at 29 French Innovative Leukemia Organization (FILO) centers, 63 (31%) were still on ibrutinib after 3 years and 57 provided a fresh blood sample. Thirty patients had a CLL clone ≥0.5 × 109/L, enabling next-generation sequencing (NGS); BTK and PLCG2 mutations were detected in 57% and 13% of the NGS samples, respectively. After median follow-up of 8.5 months from sample collection, the presence of a BTK mutation was significantly associated with subsequent CLL progression (P = .0005 vs no BTK mutation). Our findings support that mutational analysis should be considered in patients receiving ibrutinib who have residual clonal lymphocytosis, and that clinical trials are needed to evaluate whether patients with a BTK mutation may benefit from an early switch to another treatment.

// Stephane Saint-Georges 1,2 , Maude Quettier 1,2 , Marouane Bouyaba 3 , Stephanie Le Coquil 1,2 , Vanessa Lauriente 1,2 , Lionel Guittat 1,2 , Vincent Levy 3 , Florence Ajchenbaum-Cymbalista 1,2,4 , Nadine Varin-Blank 1,2 , Christine Le Roy 1,2,* and Dominique Ledoux 1,2,* 1 INSERM U978, Bobigny, France 2 Universite Paris 13, Sorbonne Paris Cite, Labex “Inflamex”, Bobigny, France 3 Assistance Publique-Hopitaux de Paris, Hopital Avicenne, Unite de Recherche Clinique, Bobigny, France 4 Assistance Publique-Hopitaux de Paris, Hopital Avicenne, Service d’Hematologie Biologique, Bobigny, France * These authors are co-senior authors Correspondence to: Christine Le Roy, email: // Nadine Varin-Blank, email: // Keywords : CLL, lymphadenopathy, B-cell receptor, CXCR4/CXCR5, protein kinase D Received : December 23, 2015 Accepted : April 16, 2016 Published : April 26, 2016 Abstract In Chronic Lymphocytic Leukemia (CLL), infiltration of lymph nodes by leukemic cells is observed in patients with progressive disease and adverse outcome. We have previously demonstrated that B-cell receptor (BCR) engagement resulted in CXCR4 down-regulation in CLL cells, correlating with a shorter progression-free survival in patients. In this study, we show a simultaneous down-regulation of CXCR4, CXCR5 and CD62L upon BCR triggering. While concomitant CXCR4 and CXCR5 down-regulation involves PKDs, CD62L release relies on PKC activation. BCR engagement induces PI3K-δ-dependent phosphorylation of PKD2 and 3, which in turn phosphorylate CXCR4 Ser 324/325 . Moreover, upon BCR triggering, PKD phosphorylation levels correlate with the extent of membrane CXCR4 decrease. Inhibition of PKD activity restores membrane expression of CXCR4 and migration towards CXCL12 in BCR-responsive cells in vitro . In terms of pathophysiology, BCR-dependent CXCR4 down-regulation is observed in leukemic cells from patients with enlarged lymph nodes, irrespective of their IGHV mutational status. Taken together, our results demonstrate that PKD-mediated CXCR4 internalization induced by BCR engagement in B-CLL is associated with lymph node enlargement and suggest PKD as a potential druggable target for CLL therapeutics.

BACKGROUND: We decided to evaluate the evolution of vulnerability in breast cancer survivors receiving an individualized survivorship care plan and living in an area (Seine-Saint-Denis, SSD), which is among the poorest in France with a median household income is 68% lower than in Paris. In SSD, cancer is the leading cause of premature mortality. Whereas it is widely admitted in France that 25% of patients are faced with financial difficulties after breast cancer, this proportion reaches 40% in SSD. PATIENTS AND METHODS: Ac'Santé93 is a non-profit organization whose aim is to provide supportive care, health education and individualized assistance to patients and families, and to facilitate timely access to quality medical and psychosocial care. Vulnerability was evaluated using a 11-item standardized score (EPICES) previously investigated by French Health Examination Centers. Strictly speaking this score was aimed at measuring precarity, a concept referring to a social condition assumed to face worsening. This score is more strongly related to health status than the administrative classification of poverty (Sass, Sante Publique 2006). Vulnerability was defined by a score ≥30 and considered as severe when ≥40. In SSD two thirds of the population are affected by vulnerability. Patients included in the study were scored after cancer diagnosis (E1) and 6 mos. after the first evaluation (E2). Patients were divided into tertiles according to E1: 30-40, 40-67 and 67-100. Psychosocial comorbidities, demographic data, and supportive care received were also recorded. Actions undertaken were divided in three categories: social/advocacy (e.g. help with filling out administrative forms), individual (e.g. dietician consultation) and group (e.g. group sessions led by a sport instructor). RESULTS: Over the year 2014, 120 breast cancer survivors were included and had E1 and E2 scores. Median E1 and E2 were 52.1 and 47.3 and the mean difference was 7.2 (p CONCLUSION: Survivorship care plans can improve vulnerability in most pts. Paradoxically, it seems easier to improve vulnerability in pts with highest initial scores. Furthermore these patients are those who benefit the most from support groups. We hypothesize that desocialization is frequently underestimated in this population, and that support groups, besides their primary goal, act through developing social links. Finally, the finding that younger patients are at higher risk for worsening vulnerability underscores the burden of unmet needs in youngest breast cancer survivors. Citation Format: Jaouen A, Festa A, Boubaya M, Levy V, Zelek L. How can we improve vulnerability score in breast cancer survivors? A pilot experience in an underprivileged community. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-12-12.

Immunoglobulin replacement therapy (IgRT) is increasingly used in secondary immunodeficiency (SID) related to hematological malignancies (HM) to prevent infections. Study's objective was to document prospectively the efficacy and safety of IgRT in patients with HM-associated SID.Non-interventional, prospective French longitudinal study.One-hundred and sixty patients starting IgRT for HM-associated SID (myeloma: 54 cases, chronic lymphoid leukemia: 54, aggressive non-Hodgkin B-cell lymphoma: 19, indolent non-Hodgkin B-cell lymphoma: 29, and Hodgkin disease: 4. entered an observational, prospective, longitudinal study and were followed-up for 8.7 ± 4.0 months. Seventeen patients died (five within the context of sepsis). Compared to baseline, IgRT increased serum immunoglobulin levels by 3.4 ± 2.4 g/L and decreased frequency and severity of infections. Treatment was discontinued in 9% of patients, stopped for futility in 31%, temporally interrupted in 8%, suspended during summertime in 14% and pursued without interruption in 38% of patients.Our data confirm the efficacy of IgRT in reducing the risk of infections in HM-associated SID therefore fulfilling physicians' main expectations. They also illustrate the heterogeneity of management policies within the community setting.

International audience; Peripheral T-cell lymphoma carries a poor prognosis. To document a possible graft-versus-lymphoma effect in this setting, we evaluated the impact of immunomodulation in 63 patients with peripheral T-cell lymphoma who relapsed after allogeneic transplant in 27 SFGM-TC centers. Relapse occurred after a median of 2.8 months. Patients were then treated with non-immunologic strategies (chemotherapy, radiotherapy) and/or immune modulation (donor lymphocyte infusions (DLI) and/or discontinuation of immunosuppressive therapy). Median overall survival (OS) after relapse was 6.1 months (DLI group: 23.6 months, non-DLI group: 3.6 months). Among the 14 patients who received DLI, 9 responded and 2 had stable disease. Among the remaining 49 patients, a complete response accompanied by extensive chronic GvHD was achieved in two patients after tapering of immunosuppressive drugs. Thirty patients received radio-chemotherapy, with an overall response rate of 50%. In multivariate analysis, chronic GvHD (odds ratio: 11.25 (2.68–48.21), P=0.0009) and skin relapse (odds ratio: 4.15 (1.04–16.50), P=0.043) were associated with a better response to treatment at relapse. In a time-dependent analysis, the only factor predictive of OS was the time from transplantation to relapse (hazards ratio: 0.33 (0.17–0.640), P=0.0009). This large series provides encouraging evidence of a true GvL effect in this disease

We report our experience on bendamustine and rituximab (BR) combination in 26 patients with chronic lymphocytic leukemia (CLL) complicated by autoimmune hemolytic anemia (AIHA). At the time of BR initiation, 88% of the patients had already been treated for AIHA and CLL was progressive regardless of AIHA in all patients but one. Overall response rates were 81% for AIHA and 77% for CLL. Median time to next treatment was 28.3 months and 26.2 months for AIHA and CLL, respectively. BR therapy may represent a good and safe therapeutic option in this setting where adequate control of CLL seems important for long-term AIHA response.

Only a minority of chronic lymphocytic leukemia (CLL) patients harboring a positive direct antiglobulin test (DAT) will develop autoimmune hemolytic anemia (AIHA). In a single institution cohort of 378 CLL patients, 56 patients (14.8%) had at least one positive DAT during the course of the disease, either at diagnosis or later. We found no relationship between the time of the first positive DAT and overall survival (OS). However, patients with a positive DAT who did not develop AIHA had the same adverse outcome as patients who developed AIHA. Of the patients who were in Binet stage A at diagnosis, those with a positive DAT had a significantly shorter OS, regardless of their IGHV mutational status, however, there was a strong association with VH1-69. By multivariate analysis, a positive DAT was found to be an independent adverse prognostic factor for OS. Thus, DAT represents a strong adverse prognostic factor and its determination should be repeated during follow-up.

9547 Background: Cemiplimab, a PD-1-axis blocking agent, has recently been approved for unresectable cSCCs. We report results of the CARSKIN study evaluating pembrolizumab in the first-line setting. Methods: Chemotherapy naive patients (pts) with unresectable cSCCs, either locally or regionally advanced or metastatic, and ECOG PS ≤1 were accrued to this multi-institutional phase II trial to assess tumor response rate (RR) and safety of pembrolizumab administered IV (200 mg Q3W) for a period up to 24 months (mo). Baseline PD-L1 expression was centrally assessed on tumor. The primary endpoint was the RR at 15 weeks (wks) per RECIST v1.1 (independent review). A Simon two-stage design was used. Results: From 03/2017 to 01/2018, 39 pts (79% males, median age 79 years) were enrolled. Disease was local (18%), regional (62%) or metastatic (21%); 38% of pts were PS 0. The median number of infusions was 8. The median follow-up was 10.2 mo; 15 pts are still on pembrolizumab. Thirty-four pts were evaluable for tumor response, and 39 for toxicity. The RR at 15 wks was 38.5 % (95% CI: 24–55%) in the ITT population corresponding to 2 CR and 13 PR. The best responses were 3 CR and 12 PR. The DCR was 51% (20/39 including 5 SD) at 15 wks. The median PFS was 8.4 mo and the median OS was not reached. No responder has progressed to date including 2 pts who discontinued pembrolizumab for 6 to 12 mo. Treatment-related AEs (TRAEs) occurred in 67% of pts, including 8% with severe TRAEs (1 gr 3 cholestasis, 1 gr 3 colitis and 1 death due to recurrence of a non-related head and neck cancer) and 10% who discontinued because of a TRAE. Centrally assessed baseline PD-L1 expression was positive in 77% of patients (1% tumor staining threshold), but it failed to predict response at 15 wks with a median PD-L1 expression of 10% in responders and non-responders at 15 wks (P = .55). Conclusions: In this series of 39 elderly pts with unresectable cSCCs, the safety profile was consistent with previous pembrolizumab studies. First-line pembrolizumab provided robust antitumor activity regardless of PD-L1 expression levels. Clinical trial information: NCT02883556.

BACKGROUND: We decided to evaluate the effect of patient navigation in an area (Seine-Saint-Denis, SSD) with an estimated population of 1.4 billion, which is among the poorest in France. Median household income is 68% lower than in Paris (+68%), a gap growing with time. In SSD, cancer is the leading cause of premature mortality. Whereas it is widely admitted in France that 25% of patients are faced with financial difficulties after breast cancer, this proportion reaches 40% in SSD. PATIENTS AND METHODS: Oncologie 93 is a non-profit organization whose aim is to provide supportive care, health education and individualized assistance to patients and families, and to facilitate timely access to quality medical and psychosocial care. Vulnerability was evaluated using a 11-item standardized score (EPICES) previously investigated by French Health Examination Centers. Strictly speaking this score was aimed at measuring precarity, a concept referring to a social condition assumed to face worsening. This score is more strongly related to health status than the administrative classification of poverty (Sass, Sante Publique 2006). Vulnerability was defined by a score >30 and considered as severe when >40. In SSD two thirds of the population are affected by vulnerability. Patients included in the navigation program were scored after cancer diagnosis (E1) and 1 year after the beginning of cancer therapy (E2). Psychosocial comorbidities, demographic data, and treatments received were also recorded. RESULTS: Over a 1-year period 74 breast cancer patients were included and had E1 and E2 scores, detail of therapy was available for 64 pts. The score significantly improved for the whole population (p = 0.04) but worsened in 23 pts (31%). Among all the variables studied, undergoing surgery was the only one to be significantly correlated with outcome. However, surprisingly, patients who did not undergo surgery had a significantly better evolution of the score than those who did (p = 0.04). E1 score was lower in patients eligible for surgery. Evolution of median vulnerability score before (E1) and after (E2) breast cancer therapy, first and third quartiles (Q1-Q3) and minimal-maximal values. n =E1Q1-Q3min-maxE2Q1-Q3min-maxwhole population7439.615.8-63.53.17-92.232.87.1-45.81.6-92.1no surgery2447.925.8-57.83.17-75.115.13.6-40.22.7-78.7surgery403714.5-63.93.17-92.233.48-47.31.6-92.9 CONCLUSION: We showed that patient navigation significantly improves vulnerability score during cancer therapy. It emphasizes the importance of evaluating deprivation with standardized tools in cancer patients in order to propose appropriate interventions. The only factor correlated with the evolution of the score is surgery. Patients that were not eligible for surgery had higher E1 score but significantly better evolution during the following year. We hypothesize that deprivation leads to more advanced tumors or is associated with comorbidities contraindicating breast surgery. For unclear reasons, the magnitude of the benefit seems greater in this population. About one third of patients experience worsening of the vulnerability after breast cancer therapy and the underlying mechanisms remain to be determined. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-09-20.

Objective To assess the prevalence of disability and the oncologic factors associated with disability in older outpatients with cancer. Materials and Methods The Physical Frailty in Elderly Cancer patients (PF-EC) study (France) is a prospective bicentric observational cohort study. Two hundred and ninety outpatients with cancer were included. A cross-sectional analysis of oncologic factors and geriatric variables associated with disability that were collected using a comprehensive geriatric assessment (CGA) was conducted. Disability was defined as impairment in activities of daily living (ADL) and/or instrumental activities of daily living (IADL), simplified to four items. Univariate and multivariate logistic models of disabled patients were performed. The three final multivariate models were compared using the area under the receiver operating characteristic curve (AUC/ROC) of the logistic model. Results The mean age was 80.6years, and 51% of the patients were women with various types of cancer. The prevalence of disability was 67.6%. No oncologic factors (cancer site, cancer extension) were associated with disability. Impaired mobility, poor functional status, depressive mood, cognitive impairment and polypharmacy were independently associated with disability ( P Conclusion Disability was highly prevalent in older cancer outpatients before cancer treatment but was not associated with oncologic factors. Impaired mobility, depressed mood, cognitive impairment and polypharmacy were the geriatric variables significantly and independently associated with disability. Identifying these factors prior to cancer treatment could enable the implementation of corrective actions to improve patient autonomy before treatment and during follow-up.

International audience; Elderly patients with chronic lymphocytic leukemia (CLL) are underrepresented in trials evaluating fludarabine, cyclophosphamide, and rituximab (FCR). We assessed four cycles of FCR with two additional rituximab doses on day 14 of cycles 1 and 2 in 194 untreated CLL patients \textgreater 65 years (median age 71.2) without del17p. Four FCR cycles were administered to 90.7% (176/194), with (n = 74) or without (n = 102) dose-delay and/or dose-reduction. A total of 50% grade 3/4 neutropenia occurred after each cycle. Only 6.2% cycles were associated with severe infection. Complete remission (CR) was achieved in 19.7%, and partial remission (PR) in 73.9% of patients. Minimal residual disease (MRD) was negative in 36.7%. Overall survival at 36 months was estimated at 87.4%. Oral FC and dose-dense rituximab is feasible and active in fit elderly CLL patients. However, myelosuppression is significant and frequent dose adaptations are required implying that these results cannot be generalized to unfit or frail elderly CLL

Background Autoimmune cytopenia (AIC) are well-known complications of chronic lymphocytic leukemia, occurring in approximately 4 to 10% of patients. The management of CLL-associated AIC is not consensual and patient with uncontrolled AIC are systematically excluded from clinical trials. Few data evaluating the efficacy of BCR inhibitors on CLL-related AIC are available. If some preliminary data focusing on patients included in clinical trials with controlled AIC suggested that ibrutinib was able to control AIC, the duration of responses were unknown. Moreover, no data regarding the ability of idelalisib to control AIC have been currently reported. The aim of this study was to retrospectively analyze the outcome of CLL patients suffering from autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), Evans syndrome or pure red cell anemia (PRCA) and treated with ibrutinib or idelalisib. Results Forty-four patients from 15 FILO centers were included in this study. First kinase inhibitor (KI) was ibrutinib for 25 patients and idelalisib for 19 patients. Among the ibrutinib treated patients, diagnosis of AIC was AIHA for 16 patients (64%), ITP for 5 patients (20%), Evans syndrome for 3 patients (12%) and PRCA for one patient (4%). In the idelalisib group, 12 patients were treated for AIHA (63%), 6 patients for ITP (32%) and one patient for an Evans syndrome (5%). Most patients presented with adverse prognostic factors such as 11q or 17p deletion by FISH and unmutated IgHV. Most patients had previously been treated either for CLL progression, autoimmune cytopenia or both and median number of prior therapies was 1 (0 to 6). Before starting ibrutinib or idelalisib, 34 patients (77%) had a history of AIC and had previously received corticosteroid monotherapy (N=15), rituximab monotherapy (N=15), a combination of rituximab, cyclophosphamide and dexamethasone (N=23) or rituximab and bendamustine (N=15). At the time of KI initiation, 66% of patients were receiving concomitant AIC therapy, consisting in corticosteroids in 26 patients (59%) or TPO (thrombopoietin) receptor agonists in 3 patients (7%). Overall response rates (ORRs) to ibrutinib and idelalisib on AIC were 92% and 95% respectively, and were not correlated to the AIC type. On ibrutinib therapy, 87.5% of patients with AIHA and 100% of patients with ITP or Evans syndrome achieved at least partial response (PR). In the idelalisib group, the ORR was 92% for AIHA patients and 100% for patients with ITP or PRCA. Considering CLL, Ibrutinib ORR and bone marrow unconfirmed complete response (CR) were 100% and 24% respectively. ORR and BM unconfirmed CR on CLL were 95% and 37% respectively the idelalisib group. KI therapy allowed discontinuing corticosteroids in 86% of ibrutinib patients and in 67% of idelalisib patients. Fifteen patients (34%) of the whole cohort experienced progression of CLL, CAI or both during the follow-up. Among them, nine (20%) experienced relapses of the CAI, and all of them were AIHA. In the ibrutinib arm, 1 patient withdrew ibrutinib shortly after initiation because of uncontrolled AIHA and 2 patients experienced relapse of AIHA while on therapy. In the idelalisib group, treatment failed to control AIHA in one case, but for responding patients, no AIHA relapse was described during idelalisib treatment. Five patients experienced relapse of AIHA after idelalisib discontinuation. With a median follow-up of the entire cohort of 26.8 months, the estimated two years overall survival (2y-OS) of the whole cohort was 88%, while the estimated two years progression free survival (2y-PFS) were 75.3% for CLL and 65.1% for AIC. In the ibrutinib cohort, 2y-OS was 95% and 2y-PFS were 81% for AIC and 94.4% for CLL. In the idelalisib arm, 2y-OS was 80%. Median PFS was 19 months for AIC and 25.7 months for CLL. Conclusion Our results demonstrate that kinase inhibitors are able to induce long-term control of both AIC and CLL and represent new therapeutics options for patients with AIC associated with CLL. Disclosures Quinquenel: Jansen Cilag: Honoraria, Research Funding; Abbvie: Honoraria. Ysebaert:Roche: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

Vgamma9Vdelta2 (gammadelta) T lymphocytes, a critical peripheral blood lymphocyte subset, are directly cytotoxic against many solid and hematologic tumor types. Vgamma9Vdelta2 T lymphocytes can be selectively expanded in vivo with BrHPP (IPH1101) and IL-2. The present phase I trial was conducted with the aim of determining the maximum-tolerated dose (MTD) and safety of IPH1101 combined with a low dose of IL-2 in patients with solid tumors.A 1-h intravenous infusion of IPH11 was administered alone at cycle 1, combined with a low dose of SC IL-2 (1 MIU/M(2) d1 to d7) in the subsequent cycles (day 1 every 3 weeks). The dose of IPH1101 was escalated from 200 to 1,800 mg/m(2).As much as 28 patients with solid tumors underwent a total of 109 treatment cycles. Pharmacodynamics data demonstrate that gammadelta T lymphocyte amplification in humans requires the co-administration of IL-2 and is dependent on IPH 1101 dose. Dose-limiting toxicity occurred in two patients at a dose of 1,800 mg/m(2): one grade 3 fever (1 patient) and one grade 3 hypotension (1 patient) suggesting cytokine release syndrome immediately following the first infusion. At lower doses the treatment was well tolerated; the most frequent adverse events were mild fever, chills and abdominal pain, without exacerbation in the IL-2 combined cycles.IPH1101 in combination with SC low-dose IL-2 is safe, well tolerated and induces a potent gammadelta T lymphocyte expansion in patients. Its clinical activity will be evaluated in phase II clinical trials.

9534Background: Patients (pts) with advanced squamous cell carcinoma of the skin (SCCS) have a poor prognosis. Response rate (RR) of 46% with an anti PD-1 (REGN2810) was recently shown in 25 pre-tr...

Everolimus displays antiproliferative effects on cancer cells, yields antiangiogenic activity in established tumours, and shows synergistic activity with paclitaxel in preclinical models. This study assessed the safety and the pharmacokinetic interactions of everolimus and paclitaxel in patients with advanced malignancies. Everolimus was dose escalated from 15 to 30 mg and administered with paclitaxel 80 mg m(-2) on days 1, 8, and 15 every 28 days. Safety was assessed weekly, and dose-limiting toxicity (DLT) was evaluated in cycle 1. A total of 16 patients (median age 54.5 years, range 33-69) were entered; 11 had prior taxane therapy for breast (n=5), ovarian (n=3), and vaginal cancer (n=1) or angiosarcoma (n=2). Grade 3 neutropenia in six patients met the criteria for DLT in two patients receiving everolimus 30 mg weekly. Other drug-related grade 3 toxicities were leucopenia, anaemia, thrombocytopenia, stomatitis, asthenia, and increased liver enzymes. Tumour stabilisation reported in 11 patients exceeded 6 months in 2 patients with breast cancer. Everolimus showed an acceptable safety profile at the dose of 30 mg when combined with weekly paclitaxel 80 mg m(-2), warranting further clinical investigation.

Purpose To identify prognostic factors and to evaluate the outcome of children with acute lymphoblastic leukemia (ALL) failure after induction therapy. Patients and Methods Between June 1993 and December 1999, 1,395 leukemic children were included in the French Acute Lymphoblastic Leukemia 93 study. Results Fifty-three patients (3.8%) had a leukemic induction failure (LIF) after three- or four-drug induction therapy. In univariate analysis, high WBC count (P = .001), mediastinal mass (P = .017), T-cell phenotype (T-ALL; P = .001), t(9;22) translocation (P = .001), and a slow early response (at day 8 and/or on day 21, P = .001) were predictive of LIF. The following three prognostic groups for LIF were identified by multivariate analysis: a low-risk group with B-cell progenitor (BCP) ALL without t(9;22) (odds ratio [OR] = 1), an intermediate-risk group with T-ALL and a mediastinal mass (OR = 7.4, P < .0001), and a high-risk group with BCP-ALL and t(9;22) or T-ALL without a mediastinal mass (OR = 28.4, P < .0001). Complete remission (CR) was subsequently obtained in 43 patients (81%). The 5-year overall survival (OS) rate of the 53 patients was 30% ± 6%. The 5-year OS rate among allogeneic graft recipients, autologous graft recipients, and after chemotherapy were 30.4% ± 9.6% (50% ± 26% after genoidentical transplantation), 50% ± 17.7%, and 41.7% ± 14.2%, respectively (P = .18). Fourteen patients (26%) were still in first CR after a median of 83 months (range, 53 to 117 months). Conclusion Three risk categories for LIF in children with ALL were identified. Approximately one third of patients with LIF can be successfully treated with salvage therapy overall. Subsequent CR after LIF is mandatory for cure.

Participation in clinical trials remains low and is a central issue in oncology. The authors identified, through a systematic review, 75 papers published up to August 2004 that report barriers to recruitment of patients in clinical trials. These barriers range from patient preference and concern about information/consent to clinical problems with protocols. Strategies to overcome barriers on the part of patients and clinicians are needed and should be carefully evaluated. Thirty-three (44%) papers reported factors related to patients as influencing the inclusion of patients, 28 (37%) reported clinician's related factors, and 37 (49%) other factors from either specific groups of patients (30 papers, 40%) and/or other scopes (13 papers, 17%). No differences in prevalence were found between papers dedicated to hematologic malignancies and solid tumors. Factors related to clinicians as influential were more frequently reported before 1995 (70%) than thereafter (25%; P = 0.0009). Reporting specific groups of patients as influential was more frequent in North American articles (50%) than in others (14%, P = 0.008). Patients' barriers included mostly patient preference (12 papers), concern about information and/or consent (11 papers), worry about uncertainty (7 papers), and/or relationship with medical team (7 papers). Concerning clinicians, incompatibility of protocol with normal practice (nine papers), problems in complying with the protocol (eight papers), and/or consent procedure (eight papers) were the most reported factors. The remaining factors mostly relied on specific groups of patients (30 papers), notably age of patients (18 papers) and/or minority population (11 papers, all from the USA). Strategies to overcome these barriers are needed and should be carefully evaluated.

Diagnosis of leukemic B-cell chronic lymphoproliferative disorders (B-CLPD) is a frequent challenge in hematology. In this multicentric study, we prospectively studied 165 new consecutive leukemic patients with B-CLPD selected on the basis of Royal Marsden Hospital scoring system < or =3. The primary aim of the study was to try to decipher the atypical cases and identify homogenous subgroups. Overall, morphological examination contributed to diagnosis in only 20% cases, all of them CD5 negative. Thirty additional cases were CD5 negative suggestive of leukemic marginal zone lymphoma in most cases. The significantly poorer survival of the 26 cyclin D1 positive cases justifies recommending its systematic determination among atypical B-CLPD. CD20 expression segregated clearly two subgroups among CD5 positive cyclin D1 negative B-CLPD. The 17 patients with the CD20 dim profile represent a homogeneous subgroup very close to typical B-cell chronic lymphocytic leukemia (B-CLL) on morphological, phenotypical and cytogenetical criteria. In contrast, the subgroup of 51 patients with a CD20 bright profile is heterogeneous. Their significantly lower p27 expression level suggest the presence of a proliferative component, underlying a more aggressive disease. Further genomic studies are warranted to establish their precise nature. These cases should not be included in the same therapeutic trials as B-CLL.

Fludarabine (FDR) therapy gives a response rate of about 30% in previously treated patients with Waldenström's macroglobulinemia (WM). The combination of FDR and cyclophosphamide (Cy) has been shown to be effective in chronic lymphoproliferative disorders. We administered the combination of FDR (30 mg/m2 i.v. D1-D3) and Cy (300 mg/m2 i.v. D1-D3) to 49 patients. Median age was 64 years. The median hemoglobin, albumin, beta 2 microglobulin and immunoglobulin M (IgM) levels were 9.9 g/100 ml, 39.6 g/l, 3 mg/l and 24.7 g/l, respectively. In all, 14 patients (29%) had not previously been treated. FDR/Cy was administered every 4 weeks for a median of four cycles. In all, 38 patients (77.6%) had partial responses, nine had stable disease and two had progressive disease. After a median of follow-up of 25 months, six patients relapsed and two patients developed large-cell lymphoma. The median time to treatment failure was 27 months. The main toxicity was hematological. In all, 12 patients died, four from progression, one from large-cell lymphoma, three from infection and four from a second malignancy. Two factors negatively influenced overall and event-free survival, age65 years and IgM40 g/l. The FDR/Cy combination, therefore, gives a high response rate in WM, even in previously treated patients with factors of poor prognosis.

Purpose To evaluate the outcome of cancer patients considered for admission to the intensive care unit (ICU). Patients and Methods Prospective, one-year hospital-wide study of all cancer and hematology patients, including bone marrow transplantation patients, for whom admission to the ICU was requested. Results Of the 206 patients considered for ICU admission, 105 patients (51%) were admitted. Of the 101 patients who were not admitted, 54 patients (26.2%) were considered too sick to benefit, and 47 patients (22.8%) were considered to be too well to benefit from the ICU. Of these 47 patients, 13 patients were admitted later. Survival rates after 30 and 180 days were significantly associated with admission status (P < .0001). Remission of the malignancy (odds ratio [OR], 3.37; 95% CI, 1.25 to 9.07) was independently associated with ICU admission, whereas poor chronic health status (OR, 0.38; 95% CI, 0.16 to 0.74) and solid tumor (OR, 0.43; 95% CI, 0.24 to 0.78) were associated with ICU refusal. In admitted patients, 30-day and 6-month survival rates were 54.3% and 32.4%, respectively. Of the patients considered too sick to benefit from ICU admission, 26% were alive on day 30 and 16.7% on day 180. Among patients considered too well to benefit, the 30-day survival rate was a worrisome 78.7%. Calibration of the Mortality Probability Model (the only score available at triage) was of limited value for predicting 30-day survival (area under the curve, 0.62). Conclusion Both the excess mortality in too-well patients later admitted to the ICU and the relatively good survival in too-sick patients suggest the need for a broader admission policy.

Mantle cell lymphoma (MCL) is a distinct clinico-pathological entity with a poor prognosis. We have conducted a prospective study in patients with MCL to evaluate a therapeutic strategy in which CHOP polychemotherapy was followed by DHAP if CHOP failed to induce complete remission. Responding patients then proceeded to an intensification therapy with autologous peripheral blood stem cell transplantation (APBSCT). Twenty-eight consecutive patients with newly diagnosed aggressive MCL were included. After four cycles of CHOP regimen, two complete responses (CR) were obtained (7%) and 14 (50%), five (18%) and seven (25%) patients achieved partial (PR), minor (MR) and no response, respectively (one patient died from septic complications during CHOP induction). The two patients in CR after CHOP underwent intensification with TBI, high-dose cyclophosphamide-etoposide and APBSCT. The other twenty-five patients received DHAP and in this group a response rate of 92% (21 CR (84%), two PR (8%)) was observed. Two patients had progressive disease. The twenty-three responding patients received high-dose therapy (TAM8 regimen: TBI-cytarabine-melphalan) followed by APBSCT. One of the two partial responding patients achieved CR after TAM8. After a median follow-up of 47.6 months (range, 14-70), seven patients have relapsed. Our data confirm that: (1) CHOP regimen induces a low CR rate in MCL; (2) CHOP plus DHAP appears to be much more efficient and allows a large proportion of patients to proceed to high-dose therapy in CR; (3) consolidation therapy including TBI and high-dose Arac-C followed by APBSCT may improve event-free survival.

Purpose: To incorporate quality-of-life considerations in assessing high dose therapy (HDT) for patients with Multiple Myeloma (MM). Patients and methods: A quality-adjusted survival analysis, using the quality-adjusted time without symptoms or toxicity (Q-TWiST) method, was applied to two randomized clinical trials conducted in patients with MM which compared randomized assignment to HDT vs. conventional chemotherapy (CCT) alone (MAG91) or followed by HDT (MAG90). Treatment benefit in terms of mean Q-TWiST was assessed through threshold utility analyses, i.e., sensitivity analyses of the choice of the utility coefficients over all possible values of utility weights. Results: In both trials, results slightly favored the first-line HDT group over the first-line CCT group, with an average gain in TWiST of about 5.5 months over the 58 month-median follow-up period (27.8 vs. 22.3 months, respectively) in the MAG90 trial and 5.8 months over the 56 month-median follow-up period (19.1 vs. 13.3 months, respectively) in the MAG91 trial. The utility threshold analyses revealed that the first-line HDT group had a statistically increased mean quality-of-life adjusted time compared to the other group for a broad range of utility coefficient values. Conclusion: The development of such understandable and intuitive measures of expressing the relative benefit of complex treatment strategies is expected to be used in clinical decision making in the near future.

TPS9596 Background: Treatment options are limited for patients (pts) with locally advanced or metastatic cSCCs. Cisplatin-based combinations have some efficacy but their toxicity often prohibits their use, particularly for the elderly. New therapeutic options are needed. Tumors divert the programmed death receptor 1 (PD-1) pathway suppressing immune control. Pembrolizumab (MK-3475) is a high-affinity humanized monoclonal anti-PD-1 antibody. It leads to dual PD-1 ligand (PD-L1 and PD-L2) blockade that may reactivate the immune surveillance and elicit anti-tumor response. It has antitumor activity in several tumors including head and neck SCCs. Moreover, an efficacy of pembrolizumab in cSCCs has been reported recently in a series of 6 cases. Methods: CARSKIN (ClinicalTrials.gov, NCT02883556) is a French multicenter, open-label, nonrandomized phase 2 trial, designed to evaluate the efficacy and safety of pembrolizumab in 39 pts with unresectable and/or metastatic cSCCs, naive of chemotherapy and of EGFR inhibitors. Pembrolizumab is administered (200 mg IV Q3W) for up to 24 months or until disease progression or unacceptable toxicity. Eligible pts must undergo a baseline biopsy of the tumor prior to treatment for PD-L1 evaluation. Response is to be assessed at baseline, wk 9, 15 and 24, and thereafter Q12W by central radiology review per RECIST 1.1 and per modified RECIST v1.1. The primary objective is response rate (RR) at wk 15 per RECIST 1.1. Secondary efficacy objectives are to assess whether patients with PD-L1+ tumors have a better RR than the whole sample at wk 15 and to assess in the whole sample and in PD-L1+ pts, disease control rate (DCR) at wk15, RR at wk 24, best RR, overall survival (OS), progression free survival (PFS), duration of response / control and time to disease progression. A Simon optimal two-stage design will be used. Four responders among 19 pts will be needed in the 1st step to continue the trial. Overall 9 responses will be needed to conclude the effectiveness. Kaplan-Meier statistics will assess PFS and OS. Adverse events (AEs) will be assessed throughout the study and for 30 d thereafter (6 m for serious AEs) and graded per NCI CTCAE v4.0. Clinical trial information: NCT02883556.

PURPOSE: Prognostic studies of posttransplantation lymphoproliferative disorders (PTLDs) are hindered by the small number of cases at each transplant center. We analyzed prognostic factors and long-term outcome according to clinical manifestations, pathologic features, and treatment and investigated the prognostic value of the non-Hodgkin’s lymphoma International Prognostic Index (IPI) in 61 patients with PTLD. PATIENTS AND METHODS: We studied 61 patients in two institutions who developed PTLD and analyzed factors influencing the complete remission and survival rates. RESULTS: In univariate analysis, factors predictive of failure to achieve complete remission were performance status (PS) ≥ (P = .0001) and nondetection of Epstein-Barr virus (EBV) in the tumor (P = .01). Only a negative link with PS ≥ 2 was observed in multivariate analysis. In univariate analysis, factors predictive of lower survival were PS ≥ 2, the number of sites (one v > one), primary CNS localization, T-cell origin, monoclonality, nondetection of EBV, and treatment with chemotherapy. The IPI failed to identify a patient subgroup with better survival and was less predictive of the response rate than was a specific index using two risk factors (PS and number of involved sites), which defined three groups of patients: low-risk patients whose median survival time has not yet been reached, intermediate-risk patients with a median survival time of 34 months, and high-risk patients with a median survival time of 1 month. CONCLUSION: PS and the number of involved sites defined three risk groups in our population. The value of these prognostic factors needs to be confirmed in larger cohorts of patients treated in prospective multicenter studies.

Recent developments in the management of chronic lymphocytic leukemia (CLL) patients have made necessary the availability of dependable prognostic factors. We have developed a prognostic index derived from the multivariate analysis of 339 stage A patients at diagnosis, exhaustively studied for classical and recent predictive markers. Only 4 biologic parameters were found to be independent predictors of progression-free survival (PFS): serum thymidine kinase (sTK), lymphocytosis, β2-microglobulin, and CD38 expression. Two groups were distinguishable: cases with no or 1 risk factor (among whom 85% did not progress after 7 years), and cases with 2 or more factors showing a median PFS of 20 months. Finally, we propose an easy, fast, cost-effective strategy for a trustworthy prognostication in stage A patients, who currently represent more than 80% of the CLL population, allowing physicians to adapt follow-up individually.

International audience; BACKGROUND:Although recent studies have demonstrated an improvement in the prognosis of critically ill cancer patients, little is known regarding the prognosis of patients with non-aggressive underlying malignancies. The aims of this study were to assess the prognosis of critically ill patients with chronic lymphocytic leukemia (CLL) and to evaluate risk factors for hospital mortality.METHODS:In retrospective mono-center cohort study, consecutive adult patients with CLL requiring ICU admission from 1997 to 2008 were included.RESULTS:Sixty-two patients of 67 years (62-75) were included. Median time interval between CLL diagnosis and ICU admission was 6.7 years (2.6-10.8). Nine patients (15 %) had stage C disease at the time of ICU admission, and seven patients (11 %) had Richter syndrome. Most ICU admissions were related to bacterial or fungal pulmonary infections (n = 47; 76 %). ICU, in-hospital, and 90-day mortality were 35 % (n = 22), 42 % (n = 26), and 58 % (n = 36), respectively. Only three factors were independently associated with in-hospital mortality: oxygen saturation lower than 95 % when breathing room air (odds ratio (OR) 5.80; 95 % confidence interval (CI) 1.23-27.33), need for vasopressors (OR 27.94; 95 % CI 5.37-145.4), and past history of infection (OR 6.62; 95 % CI 1.34-32.68). The final model did not change when disease-related variables (Binet classification, Richter syndrome, long-term steroids) or treatment-related variables (fludarabine, rituximab, or alemtuzumab) were included.CONCLUSION:Acute pulmonary infections remain the leading cause of ICU admission in patients with CLL. The severity at ICU admission and past history of infection were the only factors associated with hospital mortality. Neither disease characteristics nor previous cancer treatments were associated with outcome.

7505Background: A promising concept to improve outcome in CLL is maintenance with immunotherapy after induction with FCR to improve quality and duration of response. Methods: Treatment-naive, ≥ 65 ...

Purpose Acadesine has shown in vitro to selectively induce apoptosis in B cells from chronic lymphocytic leukemia (CLL) patients. We conducted a phase I/II open-label clinical study, to determine the safety and tolerability of acadesine given intravenously as a 4-h infusion to CLL patients. Methods Patient population included CLL patients with relapsed/refractory disease who had received one or more prior lines of treatment including either a fludarabine or an alkylator-based regimen. Twenty-four patients were included: eighteen in Part I treated at single doses of 50–315 mg/kg, and six in Part II, three with two doses at 210 mg/kg and three with five doses at 210 mg/kg. Results A manageable and predictable safety profile was demonstrated for acadesine at single doses between 50 and 210 mg/kg; 210 mg/kg was the maximum tolerated dose (MTD) and optimal biological dose (OBD). Grade ≥2 hyperuricemia occurred commonly but was not clinically significant and resolved with the administration of prophylactic allopurinol. Other adverse events included transient anemia and/or thrombocytopenia (not clinically significant), renal impairment, and transient infusion-related hypotension (clinically significant). Trends of efficacy such as a reduction of peripheral CLL cells and reduction in lymphadenopathy were observed; however, the results were variable due to the small population and the range of doses tested. Conclusions A MTD of 210 mg/kg was established with single acadesine dose. Multiple dose administrations at the OBD were tested with an acceptable safety profile, showing that acadesine might be a valuable agent for the treatment of relapsed/refractory CLL patients.

Objective About 15% of colorectal adenocarcinomas have a deficient DNA mismatch repair phenotype. The frequency of deficient DNA mismatch repair tumours increases with age due to the hypermethylation of hMLH1 promoter. The study aimed to determine the prognostic value of deficient DNA mismatch repair phenotype in elderly patients. Design Mismatch repair phenotype was retrospectively determined by molecular analysis in consecutive resected colorectal adenocarcinoma specimens from patients over 75 years of age from 4 Oncology centres. Results 231 patients (median age: 81, range: 75–100) were enrolled from 2005 to 2008. Mean prevalence of deficient DNA mismatch repair phenotype was 22.5%, and 36% for patients over 85 years. Deficient DNA mismatch repair status was significantly associated with older age, female sex, proximal colon primary and high grade tumour. For stage II tumours no deficient DNA mismatch repair tumours had a recurrence at end of follow-up compared to 17% for tumours with proficient phenotype. The proficient phenotype status was significantly associated with worse age-adjusted overall survival [HR 2.60; 95% CI 1.05–6.44; p = 0.039]. For stage III tumours a trend for less recurrence was observed for deficient DNA mismatch repair phenotype (16%) compared to proficient phenotype (36%). Conclusion deficient DNA mismatch repair phenotype is a prognostic factor in stage II colorectal tumour in elderly patients. Our results suggest that mismatch repair phenotype should be taken in consideration for adjuvant chemotherapy decision in elderly patients.

Background: To estimate the prevalence of adults and children with acute leukemia (AL) included in clinical trials and to determine factors associated with noninclusion. Patients and methods: All patients with AL admitted to the 17 departments managing AL in Paris area from 2005 to 2007 were prospectively included. Clinical data, therapeutic decisions, and enrollment in trials were recorded. Reasons that prevented accrual were identified. Results: A total of 1066 admissions with AL (85% of adults) were recorded, and 34 trials were open. In adults, the rate of inclusion in a trial was 25% [95% confidence interval (CI) 21% to 28%] for acute myeloid leukemia (AML) and 23% (95% CI 17% to 29%) for acute lymphoid leukemia (ALL). In children, the rate of inclusion was 58% (95% CI 41% to 73%) for AML and 64% (95% CI 55% to 72%) for ALL. The rate of inclusion varied across centers, with a significant increase when they were involved in clinical research. Patients included in trials differed significantly from those not included according to age, primary/secondary AL, leukemia type, results of cytogenetic analyses, and stage of disease. Conclusions: The rate of inclusion is higher than in oncology. This difference may be explained by management in specialized centers often involved in clinical research.

Interferon-α-2a (IFNa) has proven antitumor activity in a variety of neoplastic diseases, but no clear modality of administration has been validated. The aim of our study was to estimate the optimal dose of continuous subcutaneous administration of IFNa in stage IV metastatic melanoma patients. An innovative dose-finding approach, combining phase I and phase II trials, was planned to evaluate the toxicity and efficacy of four dose levels of IFNa (3, 6, 9, and 12 MIU/day). Sixteen patients were enrolled in this study. Three patients were treated according to the dose-allocation rule with IFNa at 3 MIU/day, nine patients at 6 MIU/day, and four patients at 9 MIU/day. Dose-limiting toxicities were grade 3 in five patients (three at a dose level of 6 MIU/day and two at a dose level of 9 MIU/day). Four clinically relevant responses were obtained, one at dose level 3 MIU/day, one at a dose level of 6 MIU/day, and two at a dose level of 9 MIU/day. The three final responses, at dose levels of 6 and 9 MIU/day, were associated with a dose-limiting toxicity. A dose level of 6 MIU/day was well tolerated but did not reach the desired efficacy target of 20%, and a dose level of 9 MIU/day was estimated to be too toxic. This original dose-finding methodology made it possible to estimate the rate of toxicity and efficacy in a small sample of patients without toxicity associated with each dose level.

BACKGROUND: In patients with chronic-phase chronic myeloid leukemia (CP-CML), imatinib resistance is of increasing importance. Imatinib dose escalation was the main treatment option before dasatinib, which has 325-fold more potent inhibition than imatinib against unmutated Bcr-Abl in vitro. Data with a minimum of 2 years of follow-up were available for the current study of dasatinib and high-dose imatinib in CP-CML resistant to imatinib at daily doses from 400 mg to 600 mg. METHODS: A phase 2, open-label study was initiated of 150 patients with imatinib-resistant CP-CML who were randomized (2:1) to receive either dasatinib 70 mg twice daily (n = 101) or high-dose imatinib 800 mg (400 mg twice daily; n = 49). RESULTS: At a minimum follow-up of 2 years, dasatinib demonstrated higher rates of complete hematologic response (93% vs 82%; P = .034), major cytogenetic response (MCyR) (53% vs 33%; P = .017), and complete cytogenetic response (44% vs 18%; P = .0025). At 18 months, the MCyR was maintained in 90% of patients on the dasatinib arm and in 74% of patients on the high-dose imatinib arm. Major molecular response rates also were more frequent with dasatinib than with high-dose imatinib (29% vs 12%; P = .028). The estimated progression-free survival also favored dasatinib (unstratified log-rank test; P = .0012). CONCLUSIONS: After 2 years of follow-up, dasatinib demonstrated durable responses and improved response and progression-free survival rates relative to high-dose imatinib. Cancer 2009. © 2009 American Cancer Society.

Rationale Case vignettes have been validated as an efficient tool for assessing the quality of clinical practices, and have been used in a variety of medical settings. However, their use in the field of hematology has not been tested. Objectives We undertook a study to pre-test seven case vignettes, and thereby to assess practice patterns and, when possible, guideline adherence in the treatment of chronic lymphocytic leukemia (CLL) by French hematologists. Findings Of the 64 hematologists who agreed to participate, 26 (41%) completed the vignettes. We found significant differences in the physicians’ patterns of ordering further investigations among young and old patients in the same clinical context. This is not consistent with published guidelines. Moreover, the most striking differences concerned the physicians’ interpretations of prognostic factors and the use of radiological testing before treatment. Modalities of treatment were variable across clinical situations, especially with regard to second-line treatments. Clinicians understood the vignettes well, except for those that dealt with stem cell transplantation. Conclusions This pilot study showed the feasibility of the use of case vignettes to assess the quality of clinical practice in CLL. The initial results identified deviations from the published guidelines. A large-scale European survey will commence in a few months.

International audience; Initially described in 1982, the persistent polyclonal B-cell lymphocytosis (PPBL) is characterized by a chronic, stable, persistent and polyclonal lymphocytosis, the presence of binucleated lymphocytes in the peripheral blood and a polyclonal increase in serum immunoglobulin-M (IgM). In this apparently benign entity, we showed that PPBL was associated with recurrent chromosomal abnormalities and a typical cytogenetic profile including isochromosome 3q, +i(3q), premature chromosome condensation (PCC), both abnormalities in the same patient or chromosomal instability. Despite clinical and polyclonal lymphocytosis stability, the long-term follow-up is not yet well established.We analyse and report here the long-term follow-up of 111 patients with typical PPBL.

To determine the maximum-tolerated dose (MTD), dose-limiting toxicities and pharmacokinetic of semisynthetic homoharringtonine (ssHHT), given as a twice daily subcutaneous (s.c.) injections for 9 days, in patients with advanced acute leukaemia, 18 patients with advanced acute myeloid leukaemia were included in this sequential Bayesian phase I dose-finding trial. A starting dose of 0.5 mg m(-2) day(-1) was explored with subsequent dose escalations of 1, 3, 5 and 6 mg m(-2) day(-1). Myelosuppression was constant. The MTD was estimated as the dose level of 5 mg m(-2) day(-1) for 9 consecutive days by s.c. route. Dose-limiting toxicities were hyperglycaemia with hyperosmolar coma at 3 mg m(-2), and (i) one anasarque and haematemesis, (ii) one life-threatening pulmonary aspergillosis, (iii) one skin rash and (iv) one scalp pain at dose level of 5 mg m(-2) day(-1). The mean half-life of ssHHT was 11.01+/-3.4 h, the volume of distribution at steady state was 2+/-1.4 l kg(-1) and the plasma clearance was 11.6+/-10.4 l h(-1). Eleven of the 12 patients with circulating leukaemic cells had blood blast clearance, two achieved complete remission and one with blast crisis of CMML returned in chronic phase. The recommended daily dose of ssHHT on the 9-day schedule is 5 mg m(-2) day(-1).

In acute myeloid leukemia (AML), coexpression of death receptors and ligands of the tumor necrosis factor (TNF) receptor/TNF-α superfamily on leukemic cells after chemotherapy is not always accompanied by apoptosis, suggesting that the apoptotic death receptor signaling pathway is disrupted. Because Fas-associated protein with death domain (FADD) is the main adaptor for transmitting the Fas, TNF-related apoptosis-inducing ligand receptors, and TNF receptor 1 death signal, expression of FADD was analyzed by Western blot and immunocytochemistry in leukemic cells of 70 de novo AML patients treated with the European Organization of Research and Treatment of Cancer AML-10 randomized trial before initiation of induction chemotherapy. Thirty seven percent of patients (17 of 46) with FADD negative/low (FADD−/low) leukemic cells had a primary refractory disease compared with 12% of FADD+ patients (3 of 24; P = 0.05). FADD−/low expression was significantly associated with a worse event-free survival [EFS (P = 0.04)] and overall survival (P = 0.04). In multivariate analysis, FADD−/low protein expression was independently associated with a poor EFS and overall survival (P = 0.002 and P = 0.026, respectively). Importantly, FADD−/low protein expression predicted poor EFS even in patients with standard- or good-risk AML (P = 0.009). Thus, we identified low or absent expression of the FADD protein in leukemic cells at diagnosis as a poor independent prognostic factor that can predict worse clinical outcome even for patients with standard- or good-risk AML.

Nodal mantle cell lymphoma (MCL) is a well-defined entity, but non-nodal leukemic cyclin D1 positive lymphoproliferative disorders have been reported and their relationship with MCL remains controversial and their prognosis heterogeneous. We prospectively studied the expression of cyclin D1 in CD5 positive leukemic B lymphoproliferative disorders at diagnosis and identified 65 cases overexpressing cyclin D1. We did not distinguish any clinical or biological criteria allowing one to identify a non-MCL group. Multivariate analysis identified age, anemia and p27kip1 expression as independent prognostic factors of survival. By univariate analysis, p27kip1 high expression proved to be the strongest predictor of prolonged survival. The median survival of p27 low expressors was 30 months, while it was not reached for p27 high expressors. A high level of p27 expression was often found associated with the absence of nodal involvement and the presence of somatic mutations, but neither of them was restricted to the p27 high expression group. In conclusion, we hypothesize that MCL and these cyclin D1 positive leukemic lymphoproliferative disorders represent a continuous spectrum of diseases. Determination of p27 expression level appears as a routine applicable test allowing identification of a subset of patients who could be considered for different therapeutic approaches.

Purpose: Rai’s and Binet’s staging systems have contributed significantly to the identification of major prognostic groups in chronic lymphocytic leukemia (CLL), though they fail to accurately predict disease progression at the individual level. Biologic factors, such as the mutational status of the immunoglobulin heavy-chain variable genes (VH, cytogenetics, CD38 expression, and some serum markers, have recently improved prognostic assessment in CLL. In this study, we analyzed the prognostic value of VH mutational status within the different stages of Binet’s classification in 145 patients. Patients and Methods: Our series consisted of 83 VH mutated (MT) and 62 VH unmutated (UM) patients. MT cases predominated within Binet’s stage A (70%), whereas UM cases predominated among stages B and C (62%). Results: Median overall survival (OS) was 84 months for UM patients and was not achieved for the MT group (70% 12-year survival, P < .0001). Concerning Binet’s stage A, both median OS and progression-free survival were significantly shorter for UM patients when compared with those of MT patients (97 months v not achieved, P = .0017; and 42 v 156 months, P < .0001), which compared favorably with the classical A′ and A″ substaging. The VH mutational profile could also segregate stage B and C patients into two groups with different survival patterns (median OS, 78 v 120 months for UM and MT patients, respectively; P = .002). Conclusion: The significant survival differences observed between the VH mutational groups, among stage A and stage B and C patients, indicate that Binet’s classification and VH genes are independent prognostic variables and are most likely complementary.