Publications by authors named "Gilles A Salles"

23 Publications

  • Page 1 of 1

Prephase rituximab/prednisone therapy and aging-related, pro-inflammatory cytokine milieu in older, vulnerable patients with newly diagnosed diffuse large B-cell lymphoma

Haematologica 2021 07 22. Epub 2021 Jul 22.

Department of Medicine, Division of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Medicine, Weill Cornell Medical College, New York.

Diffuse large B-cell lymphoma (DLBCL) predominantly affects older adults with suboptimal therapeutic outcomes due to increased treatment-related mortality and toxicities in vulnerable patients, clinically defined by geriatric impairments such as functional limitation, multimorbidity, or cognitive deficits. In this prospective pilot study, we evaluated a rituximab/prednisone prephase treatment strategy in 33 older, vulnerable patients with newly diagnosed DLBCL, defined by either age ≥70 years or age 60-70 years with Karnofsky performance scale (KPS).
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http://dx.doi.org/10.3324/haematol.2021.278719DOI Listing
July 2021

Outcomes of older patients with follicular lymphoma using individual data from 5922 patients in 18 randomized controlled trials.

Blood Adv 2021 03;5(6):1737-1745

University of Texas MD Anderson Cancer Center, Houston, TX.

Limited data exist to describe the clinical features and outcomes for elderly patients with follicular lymphoma (FL). The Follicular Lymphoma Analysis of Surrogacy Hypothesis (FLASH) group performed a prospectively planned pooled analysis of individual patient data from first-line randomized controlled trials (RCTs) and examined associations between age (≤70 vs >70 years), clinical characteristics, and FL outcomes. We identified 18 multicenter clinical RCTs in the FLASH database that enrolled elderly patients (>70 years). Primary end points were early disease outcomes, CR24 and CR30, and progression-free survival (PFS) at 24 months (PFS24). Secondary end points were PFS and overall survival (OS). We identified 5922 previously untreated FL patients from 18 RCTs. Patients age >70 years (vs ≤70 years) more commonly had elevated lactate dehydrogenase, hemoglobin <12 g/dL, ECOG PS ≥2, and elevated β2-microglobulin. Median follow-up was 5.6 years. Patients >70 years did not differ from patients ≤70 years in rates of CR24, CR30, or PFS24. With a median OS of 14.6 years for all patients, median OS was 7.4 and 15.7 years for patients >70 and ≤70 years of age, respectively (hazard ratio = 2.35; 95% confidence interval = 2.03-2.73; P < .001). Age >70 years was a significant predictor of OS and PFS due to higher rates of death without progression, but not PFS24, CR24, or CR30. FL patients >70 years treated on trials have similar early disease outcomes to younger patients. There is no disease-specific outcome difference between age groups. Age alone should not disqualify patients from standard treatments or RCTs.
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http://dx.doi.org/10.1182/bloodadvances.2020002724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993094PMC
March 2021

A phase 2 study of venetoclax plus R-CHOP as first-line treatment for patients with diffuse large B-cell lymphoma.

Blood 2021 02;137(5):600-609

Memorial Sloan Kettering Cancer Center, New York, NY.

The phase 2 CAVALLI (NCT02055820) study assessed efficacy and safety of venetoclax, a selective B-cell lymphoma-2 (Bcl-2) inhibitor, with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in first-line (1L) diffuse large B-cell lymphoma (DLBCL), including patients demonstrating Bcl-2 protein overexpression by immunohistochemistry (Bcl-2 IHC+). Eligible patients were ≥18 years of age and had previously untreated DLBCL, Eastern Cooperative Oncology Group performance status ≤2, and International Prognostic Index 2 to 5. Venetoclax 800 mg (days 4-10, cycle 1; days 1-10, cycles 2-8) was administered with rituximab (8 cycles) and cyclophosphamide, doxorubicin, vincristine, and prednisone (6-8 cycles) in 21-day cycles. Primary end points were safety, tolerability, and research_plete response (CR) at end of treatment (EOT). Secondary end points were progression-free survival (PFS) and overall survival. Comparative analyses used covariate-adjusted R-CHOP controls from the GOYA/BO21005 study, an appropriate contemporary benchmark for safety and efficacy. Safety and efficacy analyses included 206 patients. CR rate at EOT was 69% in the overall population and was maintained across Bcl-2 IHC+ subgroups. With a median follow-up of 32.2 months, trends were observed for improved investigator-assessed PFS for venetoclax plus R-CHOP in the overall population (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.43-0.87) and Bcl-2 IHC+ subgroups (HR, 0.55; 95% CI, 0.34-0.89) vs R-CHOP. Despite a higher incidence of grade 3/4 hematologic adverse events (86%), related mortality was not increased (2%). Chemotherapy dose intensity was similar in CAVALLI vs GOYA. The addition of venetoclax to R-CHOP in 1L DLBCL demonstrates increased, but manageable, myelosuppression and the potential of improved efficacy, particularly in high-risk Bcl-2 IHC+ patient subgroups.
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http://dx.doi.org/10.1182/blood.2020006578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869186PMC
February 2021

BCL2 Expression in First-Line Diffuse Large B-Cell Lymphoma Identifies a Patient Population With Poor Prognosis.

Clin Lymphoma Myeloma Leuk 2021 04 10;21(4):267-278.e10. Epub 2020 Nov 10.

Multidisciplinary Oncology Outpatient Clinic, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Turin, Italy.

Introduction: The prognostic value of B-cell lymphoma 2 (BCL2) expression in de novo diffuse large B-cell lymphoma (DLBCL) treated with immunochemotherapy is of interest to define a target patient population for clinical development of BCL2 inhibitors. We aimed to develop a reproducible immunohistochemistry algorithm and assay to determine BCL2 protein expression and assess the prognostic value of BCL2 in newly diagnosed DLBCL cohorts.

Patients And Methods: The prospectively defined algorithm incorporated BCL2 staining intensity and percentage of BCL2-positive cells. Functionally relevant cutoffs were based on the sensitivity of lymphoma cell lines to venetoclax. This assay was highly reproducible across laboratories. The prognostic impact of BCL2 expression was assessed in DLBCL patients from the phase 3 MAIN (n = 230) and GOYA (n = 366) trials, and a population-based registry (n = 310).

Results: Approximately 50% of tumors were BCL2 positive, with a higher frequency in high International Prognostic Index (IPI) and activated B-cell-like DLBCL subgroups. BCL2 expression was associated with poorer progression-free survival in the MAIN study (hazard ratio [HR], 1.66; 95% confidence interval [CI], 0.81-3.40; multivariate Cox regression adjusted for IPI and cell of origin). This trend was confirmed in the GOYA and registry cohorts in adjusted multivariate analyses (GOYA: HR, 1.72; 95% CI, 1.05-2.82; registry: HR, 1.89; 95% CI, 1.29-2.78). Patients with BCL2 immunohistochemistry-positive and IPI-high disease had the poorest prognosis: 3-year progression-free survival rates were 51% (GOYA) and 37% (registry).

Conclusion: Findings support use of our BCL2 immunohistochemistry scoring system and assay to select patients with BCL2-positive tumors for future studies.
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http://dx.doi.org/10.1016/j.clml.2020.11.004DOI Listing
April 2021

Mutational landscape of gray zone lymphoma.

Blood 2021 04;137(13):1765-1776

Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada.

The mutational landscape of gray zone lymphoma (GZL) has not yet been established, and differences from related entities are largely unknown. Here, we studied coding sequence mutations of 50 Epstein-Barr virus (EBV)-negative GZLs and 20 polymorphic EBV+ diffuse large B-cell lymphoma (DLBCL) not otherwise specified (poly-EBV-L) in comparison with classical Hodgkin lymphoma (cHL), primary mediastinal large B-cell lymphoma (PMBCL), and DLBCL. Exomes of 21 GZL and 7 poly-EBV-L cases, along with paired constitutional DNA, were analyzed as a discovery cohort, followed by targeted sequencing of 217 genes in an extension cohort of 29 GZL and 13 poly-EBV-L cases. GZL cases with thymic niche involvement (anterior mediastinal mass) exhibited a mutation profile closely resembling cHL and PMBCL, with SOCS1 (45%), B2M (45%), TNFAIP3 (35%), GNA13 (35%), LRRN3 (32%), and NFKBIA (29%) being the most recurrently mutated genes. In contrast, GZL cases without thymic niche involvement (n = 18) had a significantly distinct pattern that was enriched in mutations related to apoptosis defects (TP53 [39%], BCL2 [28%], BIRC6 [22%]) and depleted in GNA13, XPO1, or NF-κB signaling pathway mutations (TNFAIP3, NFKBIE, IKBKB, NFKBIA). They also exhibited more BCL2/BCL6 rearrangements compared with thymic GZL. Poly-EBV-L cases presented a distinct mutational profile, including STAT3 mutations and a significantly lower coding mutation load in comparison with EBV- GZL. Our study highlights characteristic mutational patterns in GZL associated with presentation in the thymic niche, suggesting a common cell of origin and disease evolution overlapping with related anterior mediastinal lymphomas.
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http://dx.doi.org/10.1182/blood.2020007507DOI Listing
April 2021

Gene expression profiling of gray zone lymphoma.

Blood Adv 2020 06;4(11):2523-2535

Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada.

Gray zone lymphoma (GZL), a B-cell lymphoma with features intermediate between large B-cell lymphoma (LBCL) and classic Hodgkin lymphoma (cHL), is a rare and poorly defined entity. Alongside GZL, a subset of Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) has been described with polymorphic/GZL-like morphology (polymorphic-EBV-L). To fill the important gap in our understanding of the pathogenic process underlying these entities, we performed a gene expression study of a large international cohort of GZL and polymorphic-EBV-L, combined with cHL and primary mediastinal large B-cell lymphoma (PMBCL) cases. In an unsupervised principal component analysis, GZL cases presented with intermediate scores in a spectrum between cHL and PMBCL, whereas polymorphic-EBV-L clustered distinctly. The main biological pathways underlying the GZL spectrum were related to cell cycle, reflecting tumor cell content, and extracellular matrix signatures related to the cellular tumor microenvironment. Differential expression analysis and phenotypic characterization of the tumor microenvironment highlighted the predominance of regulatory macrophages in GZL compared with cHL and PMBCL. Two distinct subtypes of GZL were distinguishable that were phenotypically reminiscent of PMBCL and DLBCL, and we observed an association of PMBCL-type GZL with clinical presentation in the "thymic" anatomic niche. In summary, gene expression profiling (GEP) enabled us to add precision to the GZL spectrum, describe the biological distinction compared with polymorphic-EBV-L, and distinguish cases with and without thymic involvement as 2 subgroups of GZL, namely PMBCL-like and DLBCL-like GZL.
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http://dx.doi.org/10.1182/bloodadvances.2020001923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284085PMC
June 2020

Patient-reported long-term quality of life after tisagenlecleucel in relapsed/refractory diffuse large B-cell lymphoma.

Blood Adv 2020 02;4(4):629-637

Peter MacCallum Cancer Centre, St Vincent's Hospital and University of Melbourne, Melbourne, VIC, Australia.

The JULIET phase 2 trial evaluated a single infusion of tisagenlecleucel in adult patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL). The objective of the current analysis was to evaluate patient-reported health-related quality of life (HRQoL) with a median follow-up of 19.3 months among patients infused with a single dose of tisagenlecleucel. Patients enrolled were ≥18 years of age with r/r DLBCL after ≥2 lines of therapy and had either undergone a failed autologous stem cell transplant or were ineligible for the procedure. Two validated HRQoL instruments, Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) and Short Form-36 (SF-36) Health Survey, were used to measure HRQoL at baseline and months 3, 6, 12, and 18. At data cutoff (21 May 2018), 115 patients had received tisagenlecleucel infusion. Among the 99 patients evaluated, overall response rate was 54%, and 40% of patients achieved complete response (CR). Initially, 108 patients completed the HRQoL assessments at baseline, including 57 patients who eventually achieved CR or partial response (PR). Further, 30 and 21 patients in clinical response who completed assessments at baseline also completed assessments at months 12 and 18, respectively. Patients who achieved CR or PR sustained HRQoL improvement in all FACT scores at all time points. SF-36 instruments showed improvement above the minimal clinically important differences on 5 of 8 subscales. Long-term follow-up in the phase 2 JULIET study demonstrated that patients with r/r DLBCL who respond to tisagenlecleucel therapy had sustained, clinically meaningful improvements in HRQoL. This trial was registered at www.clinicaltrials.gov as #NCT02445248.
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http://dx.doi.org/10.1182/bloodadvances.2019001026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042998PMC
February 2020

Obinutuzumab combined with lenalidomide for relapsed or refractory follicular B-cell lymphoma (GALEN): a multicentre, single-arm, phase 2 study.

Lancet Haematol 2019 Aug 8;6(8):e429-e437. Epub 2019 Jul 8.

Haematology Department, Centre Hospitalier Universitaire de Rennes, Rennes, France.

Background: Lenalidomide plus rituximab is approved to treat patients with relapsed or refractory follicular lymphoma. Obinutuzumab has been shown to enhance antibody-dependent cellular cytotoxicity, phagocytosis, and direct B-cell killing better than rituximab. Our aim was to determine the activity and safety of lenalidomide plus obinutuzumab in previously treated patients with relapsed or refractory follicular lymphoma.

Methods: In this multicentre, single-arm, phase 2 study, patients were enrolled from 24 Lymphoma Academic Research Organisation centres in France. Eligible patients (age ≥18 years) had histologically confirmed CD20-positive relapsed or refractory follicular lymphoma of WHO grade 1, 2, or 3a; an ECOG performance status of 0-2; and received at least one previous rituximab-containing therapy. Patients received oral lenalidomide (20 mg) plus intravenously infused obinutuzumab as induction therapy (1000 mg; six 28-day cycles), 1-year maintenance with lenalidomide (10 mg; 12 28-day cycles; days 2-22) plus obinutuzumab (1000 mg; alternate cycles), and 1-year maintenance with obinutuzumab (1000 mg; six 56-day cycles; day 1). The primary endpoint was the proportion of patients who achieved an overall response at induction end as per investigator assessment using the 1999 international working group criteria. The secondary endpoints were event-free survival, progression-free survival, overall survival, and safety. Analyses were per-protocol; the efficacy population included all patients who received at least one dose of both obinutuzumab and lenalidomide, and the safety population included all patients who received one dose of either investigational drug. The study is registered with ClinicalTrials.gov, number NCT01582776, and is ongoing but closed to accrual.

Findings: Between June 11, 2014, and Dec 18, 2015, 89 patients were recruited and 86 patients were evaluable for efficacy and 88 for safety. Median follow-up was 2·6 years (IQR 2·2-2·8). 68 (79%) of 86 evaluable patients (95% CI 69-87) achieved an overall response at induction end, meeting the prespecified primary endpoint. At 2 years, event-free survival was 62% (95% CI 51-72), progression-free survival 65% (95% CI 54-74), duration of response 70% (95% CI 57-79), and overall survival 87% (95% CI 78-93). Complete response was achieved by 33 (38%, 95% CI 28-50) of 86 patients at induction end, and the proportion of patients achieving a best overall response was 70 (81%, 95% CI 72-89) and 72 (84%, 74-91) of 86 patients during induction and treatment, respectively. The most common adverse events were asthenia (n=54, 61%), neutropenia (n=38, 43%), bronchitis (n=36, 41%), diarrhoea (n=35, 40%), and muscle spasms (n=34, 39%). Neutropenia was the most common toxicity of grade 3 or more; four (5%) patients had febrile neutropenia. 57 serious adverse events were reported in 30 (34%) of 88 patients. The most common serious adverse events were basal cell carcinoma (n=5, 6%), febrile neutropenia (n=4, 5%), and infusion-related reaction (n=3, 3%). One patient died due to treatment-related febrile neutropenia.

Interpretation: Our data shows that lenalidomide plus obinutuzumab is active in previously treated patients with relapsed or refractory follicular lymphoma, including those with early relapse, and has a manageable safety profile. Randomised trials of new immunomodulatory regimens, such as GALEN or using GALEN as a backbone, versus lenalidomide plus rituximab, are warranted.

Funding: Lymphoma Academic Research Organisation, and Celgene and Roche.
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http://dx.doi.org/10.1016/S2352-3026(19)30089-4DOI Listing
August 2019

Treatment of aggressive B-cell non-Hodgkin lymphoma beyond frontline therapy in patients not eligible for stem cell transplantation: a structured review.

Leuk Lymphoma 2019 07 31;60(7):1610-1625. Epub 2019 Jan 31.

e Department of Haematology , Université de Rouen , Rouen , France.

Aggressive B-cell non-Hodgkin lymphoma (aNHL) accounts for ∼50% of all NHL cases. The only potentially curative, broadly available treatment for patients with relapse, failing frontline treatment, is high-dose therapy followed by autologous stem cell transplantation (ASCT); patients ineligible for/who have failed ASCT have limited standard-of-care options. We conducted a structured review of treatments for relapsed/refractory patients with aNHL based on literature published between 2006 and 2017. Of the 22 publications identified for inclusion, most described phase II, single-arm trials ( = 25-217), and only three were randomized studies (phase II [ = 96], phase II/III [ = 111] and phase III [ = 338]). The majority of treatments evaluated resulted in only modest efficacy (median progression-free survival, 2.1-20.0 months) and ultimately poor health outcomes (median overall survival, 25 weeks-15.5 months). In conclusion, there is an unmet need for novel, effective, and tolerable treatments for patients with relapsed/refractory aNHL who are ineligible for/have failed ASCT.
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http://dx.doi.org/10.1080/10428194.2018.1564828DOI Listing
July 2019

Rituximab plus Lenalidomide in Advanced Untreated Follicular Lymphoma.

N Engl J Med 2018 09;379(10):934-947

From Université Lille, Centre Hospitalier Universitaire (CHU), Groupe de Recherche sur les formes Injectables et les Technologies Associées, Lille (F.M.), CHU Régional de Nancy, Service d'Hématologie, Vandoeuvre lès Nancy (P.F.), Institut Paoli-Calmettes (R.B.) and Department of Pathology, Institut Paoli-Calmettes, Centre de Recherche en Cancerologie de Marseille, INSERM, Centre National de la Recherche Scientifique, Aix-Marseille Université (L.X.), Marseille, Centre Henri Becquerel, Unité 1245 and Département d'Hématologie, Université de Rouen, Rouen (H.T.), Institut d'Hématologie de Basse Normandie, Caen (C.F.), CHU Le Bocage Service d'Hématologie Clinique, Dijon (R.-O.C.), Hôpital Henri Mondor Unité Hémopathies Lymphoïdes, Créteil (C.H.), Centre Hospitalier Départemental Vendée Service d'Onco-Hématologie, La Roche sur Yon (H.M.), Institut Universitaire du Cancer de Toulouse Oncopole Service d'Hématologie, Toulouse (L.Y.), CHU Bordeaux, Service d'Hématologie, Bordeaux (K.B.), Hôpital Saint Louis Service d'Onco-Hématologie, Paris (P.B.), Gustave Roussy Cancer, Villejuif (V.R.), Centre Hospitalier Annecy Genevois Service, Annecy (N.D.), CHU de Nantes-Hôtel Dieu Service d'Hématologie Clinique, Centre de Recherche en Cancerologie et Immunologie, INSERM, Centre National de la Recherche Scientifique, Université de Nantes, Nantes (S.L.G.), Centre Hospitalier Métropole Savoie Service Hématologie, Chambery (G.M.P.), Department of Hematology, CHU Montpellier, University of Montpellier, Montpellier (G.C.), and Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, University of Lyon, Pierre-Benite (G.A.S.) - all in France; the Department of Lymphoma and Myeloma, University of Texas M.D. Anderson Cancer Center, Houston (N.H.F.); the Department of Medicine, Memorial Sloan Kettering Cancer Center, New York (M.L.P.); the Department of Medicine, Division of Medical Oncology, University of Washington, Seattle (E.N.L.); Sarah Cannon Research Institute-Tennessee Oncology, Nashville (I.W.F.); Washington University School of Medicine, Siteman Cancer Center, St. Louis (N.L.B.); the Department of Hematology, Hospital Universitario de Salamanca and Instituto de Investigación Biomédica de Salamanca, Centro de Investigación Biomédica en Red de Cáncer, Salamanca (A.M.G.-S.), and the Department of Hematology, Hospital Clinic de Barcelona, Barcelona (A.L.-G.) - both in Spain; CHU de Québec, Hôpital de l'Enfant-Jésus, Quebec (J.-F.L.), and British Columbia Cancer Centre for Lymphoid Cancer, University of British Columbia, Vancouver (L.H.S.) - both in Canada; the Department of Hematology and Oncology, Tokai University Hospital, Kanagawa, Japan (K.A.); Instituto Português de Oncologia Lisboa Francisco Gentil Departamento de Hematologia, Lisbon (M.G.S.); the Department of Hematology, CHU Université Catholique de Louvain Namur, Yvoir (M.A.), and the Department of Hematology, Ziekenhuis Netwerk Antwerpen Stuivenberg, Antwerp (P.Z.) - both in Belgium; the Department of Hematology, National Cancer Center Hospital, Tokyo, Japan (K.T.); and Celgene, Summit, NJ (D.L., J.W.).

Background: Rituximab plus chemotherapy has been shown to be effective in patients with advanced-stage, previously untreated follicular lymphoma; nevertheless, most patients will have a relapse. Combination immunotherapy with lenalidomide and rituximab is an immunomodulatory regimen that has shown promising activity in patients with indolent B-cell non-Hodgkin's lymphoma.

Methods: We conducted this multicenter, international, phase 3 superiority trial to evaluate rituximab plus lenalidomide, as compared with rituximab plus chemotherapy, in patients with previously untreated follicular lymphoma. Patients were randomly assigned to receive one of the two regimens, followed by maintenance monotherapy with rituximab. Treatment with rituximab plus lenalidomide consisted of 18 cycles of the two drugs, followed by rituximab maintenance therapy every 8 weeks for 12 cycles (six additional doses). Treatment with rituximab plus chemotherapy consisted of the investigator's choice of one of three rituximab-based regimens, followed by maintenance monotherapy with rituximab every 8 weeks for 12 cycles. The primary end points were complete response (confirmed or unconfirmed) at 120 weeks and progression-free survival.

Results: A total of 1030 patients were randomly assigned to receive rituximab plus lenalidomide (513 patients) or rituximab plus chemotherapy (517 patients). The rate of confirmed or unconfirmed complete response at 120 weeks was similar in the two groups: 48% (95% confidence interval [CI], 44 to 53) in the rituximab-lenalidomide group and 53% (95% CI, 49 to 57) in the rituximab-chemotherapy group (P=0.13). The interim 3-year rate of progression-free survival was 77% (95% CI, 72 to 80) and 78% (95% CI, 74 to 82), respectively. A higher percentage of patients in the rituximab-chemotherapy group had grade 3 or 4 neutropenia (32% vs. 50%) and febrile neutropenia of any grade (2% vs. 7%), and a higher percentage of patients in the rituximab-lenalidomide group had grade 3 or 4 cutaneous reactions (7% vs. 1%).

Conclusions: Among patients with previously untreated follicular lymphoma, efficacy results were similar with rituximab plus lenalidomide and rituximab plus chemotherapy (with both regimens followed by rituximab maintenance therapy). The safety profile differed in the two groups. (Funded by Celgene; RELEVANCE ClinicalTrials.gov numbers, NCT01476787 and NCT01650701 , and EudraCT number, 2011-002792-42 .).
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http://dx.doi.org/10.1056/NEJMoa1805104DOI Listing
September 2018

Diagnosis-to-Treatment Interval Is an Important Clinical Factor in Newly Diagnosed Diffuse Large B-Cell Lymphoma and Has Implication for Bias in Clinical Trials.

J Clin Oncol 2018 06 19;36(16):1603-1610. Epub 2018 Apr 19.

Matthew J. Maurer, Thomas M. Habermann, Carrie A. Thompson, Cristine Allmer, Patrick B. Johnston, Ivana N. Micallef, David J. Inwards, William R. Macon, Andrew L. Feldman, Susan L. Slager, Stephen M. Ansell, James R. Cerhan, Thomas E. Witzig, and Grzegorz S. Nowakowski, Mayo Clinic, Rochester, MN; Hervé Ghesquières and Gilles A. Salles, Université Claude Bernard, Lyon; Jean-Philippe Jais, Richard Delarue, Thierry J. Molina, Hopital Necker, Paris; Corinne Haioun, Groupe Hospitalier Mondor, Créteil; Frederic Peyrade, Centre Antoine Lacassagne, Nice; Olivier Fitoussi, Polyclinique Bordeaux Nord-Aquitaine, Bordeaux; Hervé Tilly, Centre de lutte Contre le Cancer Henri Becquerel, Rouen, France; Brian K. Link, Umar Farooq, Sergei Syrbu, and George J. Weiner, University of Iowa, Iowa City, IA; and Nicolas Ketterer, Clinique Bois-Cerf, Lausanne, Switzerland.

Purpose Selection bias in clinical trials has consequences for scientific validity and applicability of study results to the general population. There is concern that patients with clinically aggressive disease may not have enrolled in recent diffuse large B-cell lymphoma (DLBCL) trials due to the consent process and the inability to delay therapy for eligibility evaluation. We have examined the diagnosis-to-treatment interval (DTI) and its association with clinical factors and outcome in a clinic-based observational cohort of patients with DLBCL from the United States. Validation of results was performed in an independent, clinical trial-based cohort from Europe. Patients and Methods Patients were prospectively enrolled in the University of Iowa and Mayo Clinic Specialized Programs of Research Excellence Molecular Epidemiology Resource (MER; N = 986) or the Lymphoma Study Association (LYSA) LNH-2003 clinical trials program (N = 1,444). All patients received anthracycline-based immunochemotherapy at initial diagnosis. Associations of DTI with clinical factors and outcome were examined. Outcome was assessed using event-free survival at 24 months from diagnosis (EFS24). Results Median (range) DTI was 15 days (0 to 155 days in the MER and 23 days (0 to 215 days) in LYSA. Shorter DTI was strongly associated with adverse clinical factors, including elevated lactate dehydrogenase levels, poor performance status, B symptoms, and higher International Prognostic Index in both cohorts (all P < .001). Longer DTI was associated with improved EFS24 in both the MER (per-week odds ratio, 0.80; 95% CI, 0.74 to .0.87) and LYSA (per-week odds ratio, 0.90; 95% CI, 0.86 to 0.94); association with EFS24 remained significant after adjustment for International Prognostic Index. Conclusion DTI is strongly associated with prognostic clinical factors and outcome in newly diagnosed DLBCL. DTI should be reported in all clinical trials of newly diagnosed DLBCL and future trials should take steps to avoid selection bias due to treatment delay.
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http://dx.doi.org/10.1200/JCO.2017.76.5198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5978469PMC
June 2018

New Agents to Treat Chronic Lymphocytic Leukemia.

N Engl J Med 2016 06;374(22):2185-6

Ernest and Helen Scott Haematological Research Institute, Leicester, United Kingdom

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http://dx.doi.org/10.1056/NEJMc1602674DOI Listing
June 2016

The 2016 revision of the World Health Organization classification of lymphoid neoplasms.

Blood 2016 05 15;127(20):2375-90. Epub 2016 Mar 15.

Hematopathology Section, Laboratory of Pathology, National Cancer Institute, Bethesda, MD.

A revision of the nearly 8-year-old World Health Organization classification of the lymphoid neoplasms and the accompanying monograph is being published. It reflects a consensus among hematopathologists, geneticists, and clinicians regarding both updates to current entities as well as the addition of a limited number of new provisional entities. The revision clarifies the diagnosis and management of lesions at the very early stages of lymphomagenesis, refines the diagnostic criteria for some entities, details the expanding genetic/molecular landscape of numerous lymphoid neoplasms and their clinical correlates, and refers to investigations leading to more targeted therapeutic strategies. The major changes are reviewed with an emphasis on the most important advances in our understanding that impact our diagnostic approach, clinical expectations, and therapeutic strategies for the lymphoid neoplasms.
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http://dx.doi.org/10.1182/blood-2016-01-643569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874220PMC
May 2016

Idelalisib: Targeting the PI3 Kinase Pathway in Non-Hodgkin Lymphoma.

Cancer J 2016 Jan-Feb;22(1):12-6

From the *Faculté de Médecine Lyon-Sud Charles Mérieux, Université Claude Bernard Lyon-1; †Laboratoire d'Hématologie Biologique, Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud; ‡INSERM U1052, Equipe "Clinical and Experimental Models of Lymphomagenesis," Cancer Research Center of Lyon; and §Unité de Pharmacie Clinique Oncologique, Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Lyon; ‖Université Claude Bernard Lyon-1, EMR 3738, Pierre-Bénite; and ¶Service d'Hématologie Clinique, Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Lyon, France.

Based on substantial preclinical rationale, the restricted hematopoietic expression of the δ isoform of the phosphatidylinositol 3-kinase represents an attractive therapeutic target in B-cell malignancies. Its inhibition results in a direct antiproliferative effect on tumor cells as well as several modifications of their cellular microenvironment, all accounting for the potential therapeutic interest. Idelalisib, the first-in-class phosphatidylinositol 3-kinase δ-specific inhibitor, was developed in patients with B-cell lymphomas and chronic lymphocytic leukemia. Early clinical results demonstrated a potent antitumor effect across different subtypes of indolent and mantle cell lymphomas (where response duration was short). Adverse events, including transaminitis, neutropenia, pneumonitis, and diarrhea, were observed. A pivotal phase II study in patients with double refractory disease showed a 57% response rate, with response lasting for about 1 year, leading to market approval of the drug in the United States and Europe. Further developments of idelalisib combinations will contribute to delineate the position of this drug in the therapeutic strategy of indolent lymphomas.
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http://dx.doi.org/10.1097/PPO.0000000000000167DOI Listing
November 2016

Genome-Wide Association Study of Event-Free Survival in Diffuse Large B-Cell Lymphoma Treated With Immunochemotherapy.

J Clin Oncol 2015 Nov 12;33(33):3930-7. Epub 2015 Oct 12.

Hervé Ghesquieres, Universite Claude Bernard Lyon 1, Centre Leon Berard; Amelie S. Veron and David G. Cox, L'Institut National de la Santé et de la Recherche Médicale (INSERM) U1052, Cancer Research Center of Lyon, Centre Leon Berard, Lyon; Hervé Ghesquieres and Gilles A. Salles, Faculté de Médecine Lyon-Sud; Gilles A. Salles, Universite Claude Bernard Lyon 1, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite; Fabrice Jardin, Sylvain Mareschal, and Herve Tilly, INSERM U918, Centre Henri Becquerel, Rouen; Thierry Fest, INSERM U917, Université de Rennes 1, Hopital Pontchaillou; Thierry Lamy, Université de Rennes 1, Hopital Pontchaillou, Rennes; Marie C. Bene, Centre Hospitalier Universitaire Nantes, Nantes; Corinne Haioun, Hospital Henri Mondor, Assistance Publique-Hôpitaux de Paris (AP-HP) and University Paris Est, Créteil; Thierry Jo Molina, Universite Paris Descartes, AP-HP, Hôpital Necker, Paris; Noel Milpied, University Hospital and University of Bordeaux, Bordeaux, France; Hervé Ghesquieres, Susan L. Slager, Matthew J. Maurer, Thomas M. Habermann, Anne J. Novak, Stephen M. Ansell, Thomas E. Witzig, Andrew L. Feldman, Ahmet Dogan, Julie M. Cunningham, Curtis L. Olswold, and James R. Cerhan, Mayo Clinic, Rochester, MN; Yan W. Asmann, Mayo Clinic, Jacksonville, FL; and George J. Weiner and Brian K. Link, University of Iowa, Iowa City, IA.

Purpose: We performed a multistage genome-wide association study to identify inherited genetic variants that predict outcome in diffuse large B-cell lymphoma patients treated with immunochemotherapy.

Methods: We conducted a meta-analysis of two genome-wide association study data sets, one from the LNH2003B trial (N = 540), a prospective clinical trial from the Lymphoma Study Association, and the other from the Molecular Epidemiology Resource study (N = 312), a prospective observational study from the University of Iowa-Mayo Clinic Lymphoma Specialized Program of Research Excellence. Top single nucleotide polymorphisms were then genotyped in independent cohorts of patients from the Specialized Program of Research Excellence (N = 391) and the Groupe Ouest-Est des Leucémies Aiguës et Maladies du Sang (GOELAMS) -075 randomized trial (N = 294). We calculated the hazard ratios (HRs) and 95% CIs for event-free survival (EFS) and overall survival (OS) using a log-additive genetic model with adjustment for age, sex, and age-adjusted International Prognostic Index.

Results: In a meta-analysis of the four studies, the top loci for EFS were marked by rs7712513 at 5q23.2 (near SNX2 and SNCAIP; HR, 1.39; 95% CI, 1.23 to 1.57; P = 2.08 × 10(-7)), and rs7765004 at 6q21 (near MARCKS and HDAC2; HR, 1.38; 95% CI, 1.22 to 1.57; P = 7.09 × 10(-7)), although they did not reach conventional genome-wide significance (P = 5 × 10(-8)). Both rs7712513 (HR, 1.49; 95% CI, 1.29 to 1.72; P = 3.53 × 10(-8)) and rs7765004 (HR, 1.47; 95% CI, 1.27 to 1.71; P = 5.36 × 10(-7)) were also associated with OS. In exploratory analyses, a two-single nucleotide polymorphism risk score was highly predictive of EFS (P = 1.78 × 10(-12)) and was independent of treatment, IPI, and cell-of-origin classification.

Conclusion: Our study provides encouraging evidence for associations between loci at 5q23.2 and 6q21 with EFS and OS in patients with diffuse large B-cell lymphoma treated with immunochemotherapy, suggesting novel biology and the potential contribution of host genetics to the prognosis of this aggressive malignancy.
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http://dx.doi.org/10.1200/JCO.2014.60.2573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879713PMC
November 2015

Single nucleotide polymorphisms in ABCB1 and CBR1 can predict toxicity to R-CHOP type regimens in patients with diffuse non-Hodgkin lymphoma.

Haematologica 2015 May 30;100(5):e204-6. Epub 2015 Jan 30.

Anticancer Antibody Team, INSERM U1052, CNRS UMR 5286, Cancer Research Center of Lyon, France Hospices Civils de Lyon, France ProfileXpert, Lyon, France Laboratory of Hematology, Hospices Civils de Lyon, Pierre-Bénite, France.

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http://dx.doi.org/10.3324/haematol.2014.120113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4420233PMC
May 2015

PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma.

N Engl J Med 2014 Mar 22;370(11):1008-18. Epub 2014 Jan 22.

The authors' affiliations are listed in the Appendix.

Background: Phosphatidylinositol-3-kinase delta (PI3Kδ) mediates B-cell receptor signaling and microenvironmental support signals that promote the growth and survival of malignant B lymphocytes. In a phase 1 study, idelalisib, an orally active selective PI3Kδ inhibitor, showed antitumor activity in patients with previously treated indolent non-Hodgkin's lymphomas.

Methods: In this single-group, open-label, phase 2 study, 125 patients with indolent non-Hodgkin's lymphomas who had not had a response to rituximab and an alkylating agent or had had a relapse within 6 months after receipt of those therapies were administered idelalisib, 150 mg twice daily, until the disease progressed or the patient withdrew from the study. The primary end point was the overall rate of response; secondary end points included the duration of response, progression-free survival, and safety.

Results: The median age of the patients was 64 years (range, 33 to 87); patients had received a median of four prior therapies (range, 2 to 12). Subtypes of indolent non-Hodgkin's lymphoma included follicular lymphoma (72 patients), small lymphocytic lymphoma (28), marginal-zone lymphoma (15), and lymphoplasmacytic lymphoma with or without Waldenström's macroglobulinemia (10). The response rate was 57% (71 of 125 patients), with 6% meeting the criteria for a complete response. The median time to a response was 1.9 months, the median duration of response was 12.5 months, and the median progression-free survival was 11 months. Similar response rates were observed across all subtypes of indolent non-Hodgkin's lymphoma, though the numbers were small for some categories. The most common adverse events of grade 3 or higher were neutropenia (in 27% of the patients), elevations in aminotransferase levels (in 13%), diarrhea (in 13%), and pneumonia (in 7%).

Conclusions: In this single-group study, idelalisib showed antitumor activity with an acceptable safety profile in patients with indolent non-Hodgkin's lymphoma who had received extensive prior treatment. (Funded by Gilead Sciences and others; ClinicalTrials.gov number, NCT01282424.).
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http://dx.doi.org/10.1056/NEJMoa1314583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4039496PMC
March 2014

Obinutuzumab (GA101) in patients with relapsed/refractory indolent non-Hodgkin lymphoma: results from the phase II GAUGUIN study.

J Clin Oncol 2013 Aug 8;31(23):2920-6. Epub 2013 Jul 8.

Hospices Civils de Lyon-Université de Lyon, 165 Chemin du Grand Revoyet, 69495 Pierre-Bénite cedex, France.

Purpose: The phase II part of the phase I/II GAUGUIN study evaluated the efficacy and safety of two different doses of obinutuzumab (GA101), a type II, glycoengineered, humanized anti-CD20 monoclonal antibody, in patients with relapsed/refractory indolent non-Hodgkin lymphoma.

Patients And Methods: Patients were randomly assigned to receive eight cycles of obinutuzumab (GA101) as a flat dose of 400 mg on days 1 and 8 of cycle 1 and also on day 1 of cycles 2 to 8 (400/400 mg) or 1,600 mg on days 1 and 8 of cycle 1 and 800 mg on day 1 of cycles 2 to 8 (1,600/800 mg).

Results: Forty patients were enrolled, including 34 with follicular lymphoma; 38 of 40 patients had previously received rituximab and 22 of 40 were rituximab refractory. The overall response rate at the end of treatment was 55% (95% CI, 32% to 76%) in the 1,600/800-mg group (9% complete responders) and 17% (95% CI, 4% to 41%) in the 400/400-mg group (no complete responders). Five of 10 rituximab-refractory patients had an end-of-treatment response in the 1,600/800-mg group versus one of 12 in the 400/400-mg group. Median progression-free survival was 11.9 months in the 1,600/800-mg group (range, 1.8 to 33.9+ months) and 6.0 months in the 400/400-mg group (range, 1.0 to 33.9+ months). The most common adverse events were infusion-related reactions (IRRs) seen in 73% of patients, but only two patients had grade 3 to 4 IRRs (both in the 1,600/800-mg group). No IRRs were considered serious, and no patients withdrew for IRRs.

Conclusion: The 1,600/800-mg dose schedule of obinutuzumab (GA101) has encouraging activity with an acceptable safety profile in relapsed/refractory indolent non-Hodgkin lymphoma.
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http://dx.doi.org/10.1200/JCO.2012.46.9718DOI Listing
August 2013

Immuno-fluorescence in situ hybridization index predicts survival in patients with diffuse large B-cell lymphoma treated with R-CHOP: a GELA study.

J Clin Oncol 2009 Nov 28;27(33):5573-9. Epub 2009 Sep 28.

Assistance Publique-Hôpitaux de Paris, Groupe Henri Mondor-Albert Chenevier, L'Institut National de la Santé et de la Recherche Médicale, Unité 955, Institut Mondor de Recherche Biomédicale; Université Paris 12, Faculté de médecine, Créteil.

Purpose: To evaluate the prognostic value of cell of origin immunohistochemical markers and BCL2, BCL6, and c-MYC translocations in a homogeneous cohort of patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).

Patients And Methods: Patients with CD20+ DLBCL were enrolled in the randomized LNH98-5 and 01-5B Groupe d'Etude des Lymphomes de l'Adulte trials. Paraffin-embedded tumor samples of 119 patients treated with R-CHOP were analyzed by immunohistochemistry for CD10, BCL6, MUM1/IRF4, LMO2, and forkhead box protein P1 (FOXP1) expression and for BCL2, BCL6, and c-MYC breakpoints by fluorescence in situ hybridization (FISH) on tissue microarray.

Results: LMO2 expression and BCL2 breakpoint were associated with the germinal center (GC) subtype defined by Hans' algorithm, respectively (P < .0001; P = .0002) whereas FOXP1 expression and BCL6 breakpoint were associated with the non-germinal center (non-GC) subtype (P = .008 and P = .0001, respectively). The immunohistochemical markers analyzed independently, GC/non-GC phenotype and BCL2 breakpoint did not predict overall survival (OS). BCL6 breakpoint was significantly associated with an unfavorable impact on OS (P = .04). Interestingly, an immunoFISH index, defined by positivity for at least two of three non-GC markers (FOXP1, MUM1/IRF4, BCL6 breakpoint) was significantly associated with a shorter 5-year OS rate (44%; 95% CI, 28 to 60 v 78%; 95% CI, 59 to 89; P = .01) which was independent (P = .04) of the age-adjusted International Prognostic Index (P = .04) in multivariate analysis.

Conclusion: Our study demonstrates that combining immunohistochemistry with FISH allows construction of an immunoFISH index that significantly predicts survival in elderly DLBCL patients treated with R-CHOP.
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http://dx.doi.org/10.1200/JCO.2009.22.7058DOI Listing
November 2009

Clinical features, prognosis and treatment of follicular lymphoma.

Authors:
Gilles A Salles

Hematology Am Soc Hematol Educ Program 2007 :216-25

Centre Hospitalier Lyon-Sud, 165, Ch du Grand Revoyet, 69495 Pierre-Benite, France.

Follicular lymphoma constitutes the most frequent indolent lymphoma, well characterized by its clinical presentation related to nodal involvement and its morphologic and biologic features. Some rare locations of extranodal involvement, such as the gastrointestinal tract or skin, were recently further refined. The description of the Follicular Lymphoma International Prognostic Index (FLIPI) represents an important step in identifying patient subgroups with predictable outcome and comparing the results of clinical trials, although its use in clinical practice remains to be established. Analyses of gene expression profiles or constitutive gene variations may also provide additional insights for prognostication in the near future. Furthermore, these data underline the complex interactions between the tumor cells and their microenvironment; recent attempts to translate these findings with immunohistochemical studies remain unable to robustly predict patient outcome. The therapeutic strategies in follicular lymphoma have been transformed by monoclonal antibodies, used alone or in combination with chemotherapy. Treatment options should be adapted to the clinical features at diagnosis and appear to be able to modify the overall survival of some subgroups of patients. Further efforts may focus on strategies that can alter the natural history of this disease.
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http://dx.doi.org/10.1182/asheducation-2007.1.216DOI Listing
July 2009
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