Publications by authors named "Bertrand Joly"

18 Publications

  • Page 1 of 1

Prolonged in-hospital stay and higher mortality after Covid-19 among patients with non-Hodgkin lymphoma treated with B-cell depleting immunotherapy.

Am J Hematol 2021 08 12;96(8):934-944. Epub 2021 May 12.

Service d'Hématologie Oncologie, Centre Hospitalier de Versailles, Le Chesnay, France.

Prolonged Covid-19 is an emerging issue for patients with lymphoma or immune deficiency. We aimed to examine prolonged length of in-hospital stay (LOS) due to Covid-19 among patients with lymphoma and assess its determinants and outcomes. Adult patients with lymphoma admitted for Covid-19 to 16 French hospitals in March and April, 2020 were included. Length of in-hospital stay was analyzed as a competitor vs death. The study included 111 patients. The median age was 65 years (range, 19-92). Ninety-four patients (85%) had B-cell non-Hodgkin lymphoma. Within the 12 months prior to hospitalization for Covid-19, 79 patients (71%) were treated for their lymphoma. Among them, 63 (57%) received an anti-CD20 therapy. Fourteen patients (12%) had relapsed/refractory disease. The median LOS was 14 days (range, 1-235). After a median follow-up of 191 days (3-260), the 6-month overall survival was 69%. In multivariable analyses, recent administration of anti-CD20 therapy was associated with prolonged LOS (subdistribution hazard ratio 2.26, 95% confidence interval 1.42-3.6, p < 0.001) and higher risk of death (hazard ratio 2.17, 95% confidence interval 1.04-4.52, p = 0.039). An age ≥ 70 years and relapsed/refractory lymphoma were also associated with prolonged LOS and decreased overall survival. In conclusion, an age ≥ 70 years, a relapsed/refractory lymphoma and recent administration of anti-CD20 therapy are risk factors for prolonged LOS and death for lymphoma patients hospitalized for Covid-19. These findings may contribute to guide the management of lymphoma during the pandemic, support evaluating specific therapeutic approaches, and raise questions on the efficacy and timing of vaccination of this particular population.
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http://dx.doi.org/10.1002/ajh.26209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212109PMC
August 2021

Long-term outcome of imatinib 400 mg compared to imatinib 600 mg or imatinib 400 mg daily in combination with cytarabine or pegylated interferon alpha 2a for chronic myeloid leukaemia: results from the French SPIRIT phase III randomised trial.

Leukemia 2021 08 22;35(8):2332-2345. Epub 2021 Jan 22.

Inserm CIC 1427, Université de Paris, Paris, France.

The STI571 prospective randomised trial (SPIRIT) French trial is a four-arm study comparing imatinib (IM) 400 mg versus IM 600 mg, IM 400 mg + cytarabine (AraC), and IM 400 mg + pegylated interferon alpha2a (PegIFN-α2a) for the front-line treatment of chronic-phase chronic myeloid leukaemia (CML). Long-term analyses included overall and progression-free survival, molecular responses to treatment, and severe adverse events. Starting in 2003, the trial included 787 evaluable patients. The median overall follow-up of the patients was 13.5 years (range 3 months to 16.7 years). Based on intention-to-treat analyses, at 15 years, overall and progression-free survival were similar across arms: 85%, 83%, 80%, and 82% and 84%, 87%, 79%, and 79% for the IM 400 mg (N = 223), IM 600 mg (N = 171), IM 400 mg + AraC (N = 172), and IM 400 mg + PegIFN-α2a (N = 221) arms, respectively. The rate of major molecular response at 12 months and deep molecular response (MR4) over time were significantly higher with the combination IM 400 mg + PegIFN-α2a than with IM 400 mg: p = 0.0001 and p = 0.0035, respectively. Progression to advanced phases and secondary malignancies were the most frequent causes of death. Toxicity was the main reason for stopping AraC or PegIFN-α2a treatment.
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http://dx.doi.org/10.1038/s41375-020-01117-wDOI Listing
August 2021

Determinants of outcome in Covid-19 hospitalized patients with lymphoma: A retrospective multicentric cohort study.

EClinicalMedicine 2020 Oct 13;27:100549. Epub 2020 Oct 13.

Service d'Hématologie Oncologie, Centre Hospitalier de Versailles, 177, rue de Versailles, 78157 Le Chesnay Cedex, France.

Background: Patients with lymphoma are immunocompromised because of the disease and its treatments. We aimed to describe the characteristics of patients with lymphoma hospitalized for Coronavirus Disease 2019 (Covid-19) and to analyze pre-Covid-19 determinants of mortality.

Methods: This retrospective multicentric cohort study used the database to identify all adult patients with lymphoma, hospitalized for Covid-19 in March and April 2020, in 12 hospitals of three French regions with pandemic outbreaks. The characteristics of lymphoma and Covid-19 were collected from medical charts.

Findings: Eighty-nine patients were included. The median age was 67 years (range, 19-92), 66% were male and 72% had a comorbidity. Most patients had B-cell non-Hodgkin lymphoma (86%) and had received a lymphoma treatment within one year (70%). With a median follow-up of 33 days from admission, 30-day overall survival was 71%, (95% confidence interval, 62-81%). In multivariable analysis, having an age ≥ 70 years (hazard ratio 2·87, 1·20-6·85,  = 0·02) and relapsed/refractory lymphoma (hazard ratio 2·54, 1·14-5·66,  = 0·02) were associated with mortality. Recent bendamustine treatment ( = 9) was also pejorative (hazard ratio 3·20, 1·33-7·72,  = 0·01), but was strongly associated with relapsed/refractory lymphoma. Remarkably, 30-day overall survival for patients < 70 years of age without relapsed/refractory lymphoma was 88% (78% - 99%).

Interpretation: Thirty-day mortality was associated with being older and relapsed/refractory lymphoma. Survival of patients younger than 70 years without relapsed/refractory lymphoma was comparable to that of the general population.

Funding: There have been no specific funds to run this study.
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http://dx.doi.org/10.1016/j.eclinm.2020.100549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550257PMC
October 2020

Randomized Trial Comparing Double Versus Triple Bortezomib-Based Regimen in Patients With Multiple Myeloma and Acute Kidney Injury Due to Cast Nephropathy.

J Clin Oncol 2020 08 23;38(23):2647-2657. Epub 2020 Jun 23.

Department of Hematology and Immunology, Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris, INSERM UMR 1126, Paris, France.

Purpose: We report a multicenter controlled trial comparing renal recovery and tolerance profile of doublet versus triplet bortezomib-based regimens in patients with initial myeloma cast nephropathy (CN) and acute kidney injury (AKI) without need for dialysis.

Methods: After symptomatic measures and high-dose dexamethasone, patients were randomly assigned to receive bortezomib plus dexamethasone (BD), or BD plus cyclophosphamide (C-BD). In patients with < 50% reduction of serum free light chains (sFLCs) after 3 cycles, chemotherapy was reinforced with either cyclophosphamide (BD group) or thalidomide (C-BD group).

Results: Ninety-two patients were enrolled in each group. At random assignment, characteristics of the 2 groups were similar, including median age (68 years) and serum creatinine level (305.5 and 273.5 µmol/L in BD and C-BD group, respectively). At 3 months, renal response rate (primary end point) was not different (41 47 responders in the BD and C-BD groups, respectively; relative risk [RR], 0.87; = .46). Very good partial response (free light chain reduction ≥ 90%) or more was achieved in 36 and 47 patients, respectively (RR, 0.76; = .10). After 1 cycle of chemotherapy, 69 in the BD group and 67 patients in the C-BD group had achieved sFLC level ≤ 500 mg/L. Serious adverse events were recorded in 30 and 40 patients, respectively. At 12 months, 19 patients had died (9 in the BD group 10 in the C-BD group), including 10 (6 in the BD group and 4 in the C-BD group) from myeloma progression and 3 (0 in the BD group and 3 in the C-BD group) from infection. Within median follow-up of 27 months, 43 and 42 patients switched to new therapy, respectively. Overall, 50 patients (24 in the BD group and 26 in the C-BD group) had died.

Conclusion: This randomized study did not show any benefit of C-BD compared with BD on renal recovery of patients with initial CN not requiring dialysis. Adding cyclophosphamide did not sufficiently improve the efficacy-toxicity balance. Patients with myeloma with AKI are fragile, and indication for doublet or triplet regimen should be adapted to frailty.
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http://dx.doi.org/10.1200/JCO.20.00298DOI Listing
August 2020

Analysis of a cohort of 279 patients with hairy-cell leukemia (HCL): 10 years of follow-up.

Blood Cancer J 2020 05 27;10(5):62. Epub 2020 May 27.

Unite de Recherche Clinique, Hopital Avicenne, Assistance Publique des Hopitaux de Paris, Bobigny, France.

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.
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http://dx.doi.org/10.1038/s41408-020-0328-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253459PMC
May 2020

Evaluation of Residual Disease and TKI Duration Are Critical Predictive Factors for Molecular Recurrence after Stopping Imatinib First-line in Chronic Phase CML Patients.

Clin Cancer Res 2019 11 10;25(22):6606-6613. Epub 2019 Jul 10.

Groupe Fi-LMC, Bergonié Institut, Bordeaux, France.

Purpose: Tyrosine kinase inhibitor (TKI) discontinuation is an emerging goal in chronic myelogenous leukemia (CML) management and several studies have demonstrated the feasibility of safely stopping imatinib. A sustained deep molecular response on long-term TKI is critical prior to attempting treatment-free remission. Reproducible results from several studies reported recently, failed to identify robust and reproducible predictive factors for the selection of the best candidates for successful TKI cessation.

Patients And Methods: We conducted a prospective national phase II study evaluating the cessation of imatinib after at least 2 years of MR4.5 obtained on imatinib first-line in patients with chronic phase CML.

Results: A total of 218 patients with chronic phase CML were involved in the study. The median follow-up after imatinib cessation was 23.5 (1-64) months, 2 patients died from unrelated causes, and 107 experienced a confirmed increase in levels defined as molecular recurrence. The molecular recurrence-free survival was 52% [95% confidence interval (CI), 45%-59%] at 6 months, and 50% (95% CI, 43%-57%) at 24 months. Droplet digital PCR (ddPCR) was used to evaluate more accurately low levels of in 175 of 218 patients at imatinib cessation. To apply positive ratios on the international scale (IS), a conversion factor was calculated for ddPCR and the significant cut-off point was established at 0.0023%. In a multivariate analysis, the duration of TKI (≥74.8 months) and ddPCR (≥0.0023%) were the two identified predictive factors of molecular recurrence, with = 0.0366 (HR, 0.635; 95% CI, 0.415-0.972] and = 0.008 (HR, 0.556; 95% CI, 0.360-0.858), respectively.

Conclusions: We conclude that the duration of TKI and residual leukemic cell load as determined by ddPCR are key factors for predicting successful treatment-free remission for patients with chronic phase CML..
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3373DOI Listing
November 2019

PET-adapted treatment for newly diagnosed advanced Hodgkin lymphoma (AHL2011): a randomised, multicentre, non-inferiority, phase 3 study.

Lancet Oncol 2019 02 15;20(2):202-215. Epub 2019 Jan 15.

LYSA Imaging, Hôpital H Mondor, Creteil, France.

Background: Increased-dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) improves progression-free survival in patients with advanced Hodgkin lymphoma compared with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), but is associated with increased risks of haematological toxicity, secondary myelodysplasia or leukaemia, and infertility. We investigated whether PET monitoring during treatment could allow dose de-escalation by switching regimen (BEACOPP to ABVD) in early responders without loss of disease control compared with standard treatment without PET monitoring.

Methods: AHL2011 is a randomised, non-inferiority, phase 3 study done in 90 centres across Belgium and France. Eligible patients were aged 16-60 years and had newly diagnosed Hodgkin lymphoma, excluding nodular lymphocyte predominant subtype, an Eastern Cooperative Oncology Group performance status score less than 3, a life expectancy of at least 3 months, an Ann Arbor disease stage III, IV, or IIB with mediastinum-to-thorax ratio of 0·33 or greater than or extranodal localisation, and had received no previous treatment for Hodgkin lymphoma. Randomisation was unmasked and done centrally by the permuted block method. Patients were randomly assigned to standard treatment (BEACOPP given every 21 days for six cycles) or PET-driven treatment. All patients received two cycles of upfront BEACOPP, after which PET assessment was done (PET2). In the standard treatment group, PET2 patients completed two additional cycles of BEACOPP induction therapy irrespective of PET2 findings. In the PET-driven treatment group, patients with positive PET2 scans received the further two cycles of BEACOPP and those with a negative PET2 scan switched to two cycles of ABVD for the remaining induction therapy. In both treatment groups, PET at the end of induction therapy was used to decide whether to continue with consolidation therapy in those with negative scans or start salvage therapy in patients with positive scans (either two cycles of ABVD in PET2-negative patients in the PET-driven arm or two cycles of BEACOPP). BEACOPP consisted of bleomycin 10 mg/m and vincristine 1·4 mg/m intravenously on day 8, etoposide 200 mg/m intravenously on days 1-3, doxorubicin 35 mg/m and cyclophosphamide 1250 mg/m intravenously on day 1, 100 mg/m oral procarbazine on days 1-7, and 40 mg/m oral prednisone on days 1-14. ABVD was given every 28 days (doxorubicin 25 mg/m, bleomycin 10 mg/m, vinblastine 6 mg/m, and dacarbazine 375 mg/m intravenously on days 1 and 15). The primary endpoint was investigator-assessed progression-free survival. Non-inferiority analyses were done by intention to treat and per protocol. The study had a non-inferiority margin of 10%, to show non-inferiority of PET-guided treatment versus standard care with 80% power and an alpha of 2·5% (one-sided). This study is registered with ClinicalTrials.gov, number NCT01358747.

Findings: From May 19, 2011, to April 29, 2014, 823 patients were enrolled-413 in the standard care group and 410 in the PET-driven group. 346 (84%) of 410 patients in the PET-driven treatment group were assigned to receive ABVD and 51 (12%) to continue receiving BEACOPP after PET2. With a median follow-up of 50·4 months (IQR 42·9-59·3), 5-year progression-free survival by intention to treat was 86·2%, 95% CI 81·6-89·8 in the standard treatment group versus 85·7%, 81·4-89·1 in the PET-driven treatment group (hazard ratio [HR] 1·084, 95% CI 0·737-1·596; p=0·65) and per protocol the values were 86·7%, 95% CI 81·9-90·3 and 85·4%, 80·7-89·0, respectively (HR 1·144, 0·758-1·726; p=0·74). The most common grade 3-4 adverse events were leucopenia (381 [92%] in the standard treatment group and 387 [95%] in the PET-driven treatment group), neutropenia (359 [87%] and 366 [90%]), anaemia (286 [69%] vs 114 [28%]), thrombocytopenia (271 [66%] and 163 [40%]), febrile neutropenia (145 [35%] and 93 [23%]), infections (88 [22%] and 47 [11%]), and gastrointestinal disorders (49 [11%] and 48 [11%]). Serious adverse events related to treatment were reported in 192 (47%) patients in the standard treatment group and 114 (28%) in the PET-driven treatment group, including infections (84 [20%] of 412 vs 50 [12%] of 407) and febrile neutropenia (21 [5%] vs 23 [6%]). Six (1%) patients in the standard care group died from treatment-related causes (two from septic shock, two from pneumopathy, one from heart failure, and one from acute myeloblastic leukaemia), as did two (<1%) in the PET-driven treatment group (one from septic shock and one from acute myeloblastic leukaemia).

Interpretation: PET after two cycles of induction BEACOPP chemotherapy safely guided treatment in patients with advanced Hodgkin lymphoma and allowed the use of ABVD in early responders without impairing disease control and reduced toxicities. PET staging allowed accurate monitoring of treatment in this trial and could be considered as a strategy for the routine management of patients with advanced Hodgkin lymphoma.

Funding: Programme Hospitalier de Recherche Clinique.
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http://dx.doi.org/10.1016/S1470-2045(18)30784-8DOI Listing
February 2019

A phase 2 study of rituximab, bendamustine, bortezomib and dexamethasone for first-line treatment of older patients with mantle cell lymphoma.

Haematologica 2019 01 31;104(1):138-146. Epub 2018 Aug 31.

Hematology Department, Catherine de Sienne Clinic, Nantes.

We present results of a prospective, multicenter, phase II study evaluating rituximab, bendamustine, bortezomib and dexamethasone as first-line treatment for patients with mantle cell lymphoma aged 65 years or older. A total of 74 patients were enrolled (median age, 73 years). Patients received a maximum of six cycles of treatment at 28-day intervals. The primary objective was to achieve an 18-month progression-free survival rate of 65% or higher. Secondary objectives were to evaluate toxicity and the prognostic impact of mantle cell lymphoma prognostic index, Ki67 expression, [F]fluorodeoxyglucose-positron emission tomography and molecular minimal residual disease, in peripheral blood or bone marrow. With a median follow-up of 52 months, the 24-month progression-free survival rate was 70%, hence the primary objective was reached. After six cycles of treatment, 91% (54/59) of responding patients were analyzed for peripheral blood residual disease and 87% of these (47/54) were negative. Four-year overall survival rates of the patients who did not have or had detectable molecular residual disease in the blood at completion of treatment were 86.6% and 28.6%, respectively (<0.0001). Neither the mantle cell lymphoma index, nor fluorodeoxyglucose-positron emission tomography nor Ki67 positivity (cut off of ≥30%) showed a prognostic impact for survival. Hematologic grade 3-4 toxicities were mainly neutropenia (51%), thrombocytopenia (35%) and lymphopenia (65%). Grade 3-4 non-hematologic toxicities were mainly fatigue (18.5%), neuropathy (15%) and infections. In conclusion, the tested treatment regimen is active as frontline therapy in older patients with mantle cell lymphoma, with manageable toxicity. Minimal residual disease status after induction could serve as an early predictor of survival in mantle cell lymphoma. .
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http://dx.doi.org/10.3324/haematol.2018.191429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312036PMC
January 2019

Effect of High-Cutoff Hemodialysis vs Conventional Hemodialysis on Hemodialysis Independence Among Patients With Myeloma Cast Nephropathy: A Randomized Clinical Trial.

JAMA 2017 12;318(21):2099-2110

Department of Hematology and Immunology, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1126, Hôpital Saint-Louis, Assistance Publique Hôpitaux de Paris, Paris, France.

Importance: Cast nephropathy is the main cause of acute kidney injury in multiple myeloma and persistent reduction in kidney function strongly affects prognosis. Strategies to rapidly remove nephrotoxic serum-free light chains combined with novel antimyeloma agents have not been evaluated prospectively.

Objective: To compare the hemodialysis independence rate among patients newly diagnosed with myeloma cast nephropathy treated with hemodialysis using a high-cutoff dialyzer (with very large membrane pores and high permeability to immunoglobulin light chains) or a conventional high-flux dialyzer (with small pores and lower permeability).

Design, Setting, And Participants: Randomized clinical trial involving 98 patients with biopsy-proven myeloma cast nephropathy requiring hemodialysis treated at 48 French centers between July 2011 and June 2016; the final date of follow-up was June 29, 2016.

Interventions: Intensive hemodialysis (eight 5-hour sessions over 10 days) with either a high-cutoff dialyzer (46 patients) or a conventional high-flux dialyzer (48 patients). All patients received the same chemotherapy regimen of bortezomib and dexamethasone.

Main Outcomes And Measures: Primary end point was hemodialysis independence at 3 months; secondary end points: hemodialysis independence rates at 6 and 12 months, hemodialysis- and chemotherapy-related adverse events, and death.

Results: Among 98 randomized patients, 94 (96%) (median age, 68.8 years [interquartile range, 61.2-75.3 years]; 45% women) were included in the modified intent-to-treat analysis. The hemodialysis independence rate at 3 months was 41.3% (n = 19) in the high-cutoff hemodialysis group vs 33.3% (n = 16) in the conventional hemodialysis group (between-group difference, 8.0% [95% CI, -12.0% to 27.9%], P = .42); at 6 months, the rate was 56.5% (n = 26) vs 35.4% (n = 17), respectively (between-group difference, 21.1% [95% CI, 0.9% to 41.3%], P = .04); and at 12 months, the rate was 60.9% (n = 28) vs 37.5% (n = 18) (between-group difference, 23.4% [95% CI, 3.2% to 43.5%], P = .02). The incidence of hemodialysis-related adverse events was 43% in the high-cutoff hemodialysis group vs 39% in the conventional hemodialysis group; chemotherapy-related serious adverse events, 39% vs 37%, respectively; and at 12 months, 9 patients vs 10 patients died.

Conclusions And Relevance: Among patients with myeloma cast nephropathy treated with a bortezomib-based chemotherapy regimen, the use of high-cutoff hemodialysis compared with conventional hemodialysis did not result in a statistically significant difference in hemodialysis independence at 3 months. However, the study may have been underpowered to identify an early clinically important difference.

Trial Registration: clinicaltrials.gov Identifier: NCT01208818.
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http://dx.doi.org/10.1001/jama.2017.17924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5820717PMC
December 2017

Success rates in smoking cessation: Psychological preparation plays a critical role and interacts with other factors such as psychoactive substances.

PLoS One 2017 11;12(10):e0184800. Epub 2017 Oct 11.

Biostatistics and Bioinformatics (DIM), University Hospital, Dijon, France; Bourgogne Franche-Comté University, Dijon, France.

Introduction: The aim of this study was to identify factors associated with the results of smoking cessation attempts.

Methods: Data were collected in Clermont-Ferrand from a smoking cessation clinic between 1999 and 2009 (1,361 patients). Smoking cessation was considered a success when patients were abstinent 6 months after the beginning of cessation. Multivariate logistic regression was used to investigate the association between abstinence and different factors.

Results: The significant factors were a history of depression (ORadjusted = 0.57, p = 0.003), state of depression at the initial consultation (ORa = 0.64, p = 0.005), other psychoactive substances (ORa = 0.52, p<0.0001), heart, lung and Ear-Nose-Throat diseases (ORa = 0.65, p = 0.005), age (ORa = 1.04, p<0.0001), the Richmond test (p<0.0001; when the patient's motivation went from insufficient to moderate, the frequency of abstinence was twice as high) and the Prochaska algorithm (p<0.0001; when the patient went from the 'pre-contemplation' to the 'contemplation' level, the frequency of success was four times higher). A high score in the Richmond test had a greater impact on success with increasing age (significant interaction: p = 0.01). In exclusive smokers, the contemplation level in the Prochaska algorithm was enough to obtain a satisfactory abstinence rate (65.5%) whereas among consumers of other psychoactive substances, it was necessary to reach the preparation level in the Prochaska algorithm to achieve a success rate greater than 50% (significant interaction: p = 0.02).

Conclusion: The psychological preparation of the smoker plays a critical role. The management of smoking cessation must be personalized, especially for consumers of other psychoactive substances and/or smokers with a history of depression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0184800PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5636087PMC
October 2017

Bendamustine for the treatment of relapsed or refractory peripheral T cell lymphomas: A French retrospective multicenter study.

Oncotarget 2016 Dec;7(51):85573-85583

Department of Hematology, University Hospital of Nancy, Vandoeuvre Les Nancy, France.

Peripheral T-cell lymphoma (PTCL) is a group of diseases with poor outcome and few therapeutic options. We aimed to assess the efficacy of bendamustine in real life cohort of patients.Between November 2009 and March 2015, 138 PTCL patients were treated with bendamustine in 27 centers. Population median age was 64 (28-89) years with male/female ratio of 1.4. There were mainly angio-immunoblastic (AITL = 71), PTCL-not otherwise specified (PTCL-NOS = 40) and anaplastic large cell lymphoma (ALCL = 8). The majority of patients (96%) had disseminated disease and extranodal localizations (77%). Median number of chemotherapy lines prior to bendamustine was 2 (1-8). Median duration of response (DoR) after the last chemotherapy prior to bendamustine was 4.3 months (1-70) and 50% of patients had refractory disease.Median number of administered bendamustine cycles was 2 (1-8) and 72 patients (52%) received less than 3 mostly because of disease progression. Median dose was 90 (50-150) mg/m². Overall response rate (ORR) was 32.6% with complete response (CR) rate of 24.6% and median DoR was 3.3 months (1-39). AITL patients were more sensitive than PTCL-NOS patients (ORR: 45.1 versus 20%, p = 0.01). Median PFS and OS were 3.1 (0.2-46.3) and 4.4 (0.2-55.4) months. On multivariate analysis, refractory disease (p = 0.001) and extranodal localization (p = 0.028) adversely influenced ORR. Grade 3-4 thrombocytopenia, neutropenia and infections were reported in 22, 17 and 23% of cases respectively.Bendamustine as single agent could be considered as a therapeutic option for relapsed or refractory PTCL, particularly in chemosensitive or AITL patients. Combinations of bendamustine with other drugs warrant further evaluation.
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http://dx.doi.org/10.18632/oncotarget.10764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356759PMC
December 2016

Characteristics of B-cell lymphomas in HIV/HCV-coinfected patients during the combined antiretroviral therapy era: an ANRS CO16 LYMPHOVIR cohort study.

J Acquir Immune Defic Syndr 2013 Jun;63(2):249-53

Department of Internal Medicine II, Université Paris 6 Pierre et Marie Curie UMR S 943, Paris, France.

Hepatitis C virus (HCV) infection is frequent among HIV-infected patients. We describe, the characteristics of 6 HIV/HCV-coinfected patients with B-cell non-Hodgkin lymphoma (NHL) included in a prospective cohort study of HIV-related lymphomas. Five of the 6 cases had features of marginal zone/lymphoplasmacytic NHL versus 1 of 33 HIV only-infected patients. Remarkably, anti-HCV treatment led to a hematological response in a patient with splenic marginal zone lymphoma. This supports the role of chronic antigenic stimulation by HCV on lymphomagenesis and further evaluation of HCV antiviral therapy in coinfected patients with NHL.
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http://dx.doi.org/10.1097/QAI.0b013e31828a77f0DOI Listing
June 2013

Results from a prospective, open-label, phase II trial of bendamustine in refractory or relapsed T-cell lymphomas: the BENTLY trial.

J Clin Oncol 2013 Jan 29;31(1):104-10. Epub 2012 Oct 29.

Centre Hospitalier Universitaire, Amiens, France.

Purpose: To determine the efficacy and safety of bendamustine as a single agent in refractory or relapsed T-cell lymphomas.

Patients And Methods: Patients with histologically confirmed peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma who progressed after one or more lines of prior chemotherapy received bendamustine at 120 mg/m(2) per day on days 1 through 2 every 3 weeks for six cycles. The primary end point was overall response rate (ORR). Secondary end points were duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

Results: Of the 60 patients included, 27 (45%) were refractory to their last prior chemotherapy, and the median duration of the best previous response was 6.6 months. Histology was predominantly angioimmunoblastic lymphadenopathy and PTCL not otherwise specified. The disease was disseminated in the majority of patients (87%). The median number of previous lines of chemotherapy was one (range, one to three). Twenty patients (33%) received fewer than three cycles of bendamustine, mostly because of disease progression. In the intent-to-treat population, the ORR was 50%, including complete response in 17 patients (28%) and partial response in 13 patients (22%). Bendamustine showed consistent efficacy independent of major disease characteristics. The median values for DoR, PFS, and OS were 3.5, 3.6, and 6.2 months, respectively. The most frequent grade 3 to 4 adverse events were neutropenia (30%), thrombocytopenia (24%), and infections (20%).

Conclusion: Bendamustine showed an encouraging high response rate across the two major PTCL subtypes, independent of age and prior treatment, with acceptable toxicity in refractory or relapsed T-cell lymphoma.
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http://dx.doi.org/10.1200/JCO.2012.43.7285DOI Listing
January 2013

Targeting intratumoral B cells with rituximab in addition to CHOP in angioimmunoblastic T-cell lymphoma. A clinicobiological study of the GELA.

Haematologica 2012 Oct 27;97(10):1594-602. Epub 2012 Feb 27.

Faculté de Médecine, Université Paris Est Creteil, UPEC, Créteil, France.

Background: In angioimmunoblastic T-cell lymphoma, symptoms linked to B-lymphocyte activation are common, and variable numbers of CD20(+) large B-blasts, often infected by Epstein-Barr virus, are found in tumor tissues. We postulated that the disruption of putative B-T interactions and/or depletion of the Epstein-Barr virus reservoir by an anti-CD20 monoclonal antibody (rituximab) could improve the clinical outcome produced by conventional chemotherapy.

Design And Methods: Twenty-five newly diagnosed patients were treated, in a phase II study, with eight cycles of rituximab + chemotherapy (R-CHOP21). Tumor infiltration, B-blasts and Epstein-Barr virus status in tumor tissue and peripheral blood were fully characterized at diagnosis and were correlated with clinical outcome.

Results: A complete response rate of 44% (95% CI, 24% to 65%) was observed. With a median follow-up of 24 months, the 2-year progression-free survival rate was 42% (95% CI, 22% to 61%) and overall survival rate was 62% (95% CI, 40% to 78%). The presence of Epstein-Barr virus DNA in peripheral blood mononuclear cells (14/21 patients) correlated with Epstein-Barr virus score in lymph nodes (P<0.004) and the detection of circulating tumor cells (P=0.0019). Despite peripheral Epstein-Barr virus clearance after treatment, the viral load at diagnosis (>100 copy/μg DNA) was associated with shorter progression-free survival (P=0.06).

Conclusions: We report here the results of the first clinical trial targeting both the neoplastic T cells and the microenvironment-associated CD20(+) B lymphocytes in angioimmunoblastic T-cell lymphoma, showing no clear benefit of adding rituximab to conventional chemotherapy. A strong relationship, not previously described, between circulating Epstein-Barr virus and circulating tumor cells is highlighted.
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http://dx.doi.org/10.3324/haematol.2011.061507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3487562PMC
October 2012

Molecular predictors of response to decitabine in advanced chronic myelomonocytic leukemia: a phase 2 trial.

Blood 2011 Oct 9;118(14):3824-31. Epub 2011 Aug 9.

Hôpital Avicenne, Assistance Publique-Hôpitaux de Paris (AP-HP), Hématologie Clinique, University Paris XIII, Bobigny, France.

Hydroxyurea is the standard therapy of chronic myelomonocytic leukemia (CMML) presenting with advanced myeloproliferative and/or myelodysplastic features. Response to hypomethylating agents has been reported in heterogeneous series of CMML. We conducted a phase 2 trial of decitabine (DAC) in 39 patients with advanced CMML defined according to a previous trial. Median number of DAC cycles was 10 (range, 1-24). Overall response rate was 38% with 4 complete responses (10%), 8 marrow responses (21%), and 3 stable diseases with hematologic improvement (8%). Eighteen patients (46%) demonstrated stable disease without hematologic improvement, and 6 (15%) progressed to acute leukemia. With a median follow-up of 23 months, overall survival was 48% at 2 years. Mutations in ASXL1, TET2, AML1, NRAS, KRAS, CBL, FLT3, and janus kinase 2 (JAK2) genes, and hypermethylation of the promoter of the tumor suppressor gene TIF1γ, did not predict response or survival on DAC therapy. Lower CJUN and CMYB gene expression levels independently predicted improved overall survival. This trial confirmed DAC efficacy in approximately 40% of CMML patients with advanced myeloproliferative or myelodysplastic features and suggested that CJUN and CMYB expression could be potential biomarkers in this setting. This trial is registered at EudraCT (eudract.ema.europa.eu) as #2008-000470-21 and www.clinicaltrials.gov as #NCT01098084.
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http://dx.doi.org/10.1182/blood-2011-05-352039DOI Listing
October 2011

Analysis of risk factors for myelodysplasias, leukemias and death from infection among patients with congenital neutropenia. Experience of the French Severe Chronic Neutropenia Study Group.

Haematologica 2005 Jan;90(1):45-53

Service d'Hémato-Oncologie Pédiatrique, Hôpital Trousseau, Paris, France.

Background And Objectives: The two main complications of severe chronic neutropenia are fatal sepsis and myelodysplasia/acute leukemia (MDS/AL). Granulocyte colony-stimulating factor (G-CSF) therapy has significantly reduced the frequency and severity of infections, but its possible influence on the risk of malignancy is not known.

Design And Methods: The French Severe Chronic Neutropenia (SCN) Registry has prospectively collected data since 1994 on 231 patients with various forms of SCN, namely severe congenital neutropenia (n=101), cyclic neutropenia (n=60), glycogen storage disease type Ib (GSDIb) (n=15) and Shwachman-Diamond syndrome (SDS)(n=55). The median overall follow-up is 11.1 years. Parameters of exposure to G-CSF therapy, such as the time averaged dose, follow up after first use of G-CSF, and the cumulative dose, have been recorded.

Results: Eight septic deaths occurred, of which 6 among patients with severe congenital neutropenia and 2 in patients with cyclic neutropenia; none of these 8 patients was receiving G-CSF therapy. No septic deaths occurred during G-CSF therapy. Thirteen cases of MDS/AL were recorded. The cumulative incidence of MDS/AL was 2.7% (SD 1.3%) at 10 years and 8.1% (SD 2.7%) at 20 years.

Interpretation And Conclusions: Risk factors for MDS/AL were the diagnostic category, the severity of neutropenia, younger age at diagnosis, and strong exposure to G-CSF. MDS/AL only occurred in patients with severe congenital neutropenia and SDS. Owing to their particular susceptibility to infections, patients with severe congenital neutropenia had the strongest exposure to G-CSF; the risk of leukemia increased with the degree of G-CSF exposure in this subgroup.
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January 2005

Pyothorax-associated lymphoma: a peculiar clinicopathologic entity derived from B cells at late stage of differentiation and with occasional aberrant dual B- and T-cell phenotype.

Am J Surg Pathol 2002 Jun;26(6):724-32

Département de Pathologie and EA2348, Hôpital Henri Mondor, AP-HP, Créteil, France.

We report 12 European cases of pyothorax-associated lymphomas occurring 30-67 years following artificial pneumothorax for pleuropulmonar tuberculosis. Eleven patients presented with a localized pleural tumor mass, whereas one patient also had liver involvement. Histologic examination showed a diffuse proliferation of large lymphoid cells with frequent plasmacytoid differentiation (n = 8), expressing CD20 (n = 10), CD79a (n = 11), and/or CD138 (n = 5) B-cell antigens. Aberrant expression of T-cell markers (CD2, CD3, CD4) was noted in five cases. The B-cell origin of lymphoma cells was confirmed by the demonstration of immunoglobulin light chain restriction or clonal B cell population in six cases. In 11 of 12 cases in situ hybridization disclosed Epstein-Barr virus genome in most tumor cells and immunohistochemistry a type III LMP-1+/ EBNA-2+ latency profile. HHV-8/ORF73 antigen was not detected in all tested cases (n = 11). All investigated cases (10 of 10) disclosed a uniform CD10-/BCL-6-/MUM1+/CD138+/- phenotype, consistent with a derivation from late germinal center (GC)/post-GC B cells. Clinical outcome was poor with a median survival time of 5 months. Only one patient was in complete remission after 34 months. This study further confirms that pyothorax-associated lymphoma represents a distinct clinicopathologic entity among diffuse large B-cell lymphoma, which is characterized by a peculiar clinical presentation, frequent plasmacytoid features, and a strong association with EBV. Moreover, we show that this lymphoma entity likely originates from B cells at a late stage of differentiation and occasionally shares an aberrant dual B/T phenotype.
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http://dx.doi.org/10.1097/00000478-200206000-00005DOI Listing
June 2002
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