Publications by authors named "Roch Houot"

94 Publications

Intravenous high-dose methotrexate based systemic therapy in the treatment of isolated primary vitreoretinal lymphoma: an LOC network study.

Am J Hematol 2021 Apr 17. Epub 2021 Apr 17.

Neurology, APHP, Sorbonne Université, Paris, France.

The treatment of primary vitreoretinal lymphoma (PVRL) remains controversial regarding the use of local, systemic, or combined treatments. The aim of this study was to analyze the efficacy and toxicity of intravenous high-dose methotrexate (IV HD-MTX) based systemic therapy in a uniformly treated population of PVRL patients. From a nationwide French database, we retrospectively selected 59 patients (median age: 70 years, median Karnofsky Performance Status: 90%) with isolated PVRL at diagnosis who received first-line treatment with HD-MTX between 2011-2018. 8/59 patients also received a local treatment. No deaths or premature discontinuations of MTX due to toxicity were reported. A complete response was obtained in 40/57 patients after chemotherapy. Before treatment, IL-10 was elevated in the aqueous humor (AH) or in the vitreous in 89% of patients. After treatment, AH IL-10 was undetectable in 87% of patients with a CR/uCR/PR and detectable in 92% of patients with PD/SD. After a median follow-up of 61 months, 41/59 (69%) patients had relapsed, including 29 isolated ocular relapses as the first relapse and a total of 22 brain relapses. The median overall survival, progression-free survival, ocular-free survival and brain-free survival were 75, 18, 29 and 73 months, respectively. IV HD-MTX based systemic therapy as a first-line treatment for isolated PVRL is feasible, with acceptable toxicity, even in an elderly population. This strategy seems efficient to prevent brain relapse with prolonged overall survival. However, the ocular relapse rate remains high. New approaches are needed to improve local control of this disease, and ocular assessment could be completed by monitoring AH IL-10. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/ajh.26199DOI Listing
April 2021

Correction to: Risk of relapse after anti-PD1 discontinuation in patients with Hodgkin lymphoma.

Eur J Nucl Med Mol Imaging 2021 Mar 20. Epub 2021 Mar 20.

Department of Hematology, University Hospital of Rennes, 2 rue Henri Le Guilloux, 35033, Rennes Cedex 9, France.

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http://dx.doi.org/10.1007/s00259-021-05321-3DOI Listing
March 2021

Allogeneic transplantation after PD-1 blockade for classic Hodgkin lymphoma.

Leukemia 2021 Mar 3. Epub 2021 Mar 3.

Department of Oncology and Hematology, Humanitas Clinical and Research Center-IRCCS, Rozzano-Milano, Italy.

Anti-PD-1 monoclonal antibodies yield high response rates in patients with relapsed/refractory classic Hodgkin lymphoma (cHL), but most patients will eventually progress. Allogeneic hematopoietic cell transplantation (alloHCT) after PD-1 blockade may be associated with increased toxicity, raising challenging questions about the role, timing, and optimal method of transplantation in this setting. To address these questions, we assembled a retrospective cohort of 209 cHL patients who underwent alloHCT after PD-1 blockade. With a median follow-up among survivors of 24 months, the 2-year cumulative incidences (CIs) of non-relapse mortality and relapse were 14 and 18%, respectively; the 2-year graft-versus-host disease (GVHD) and relapse-free survival (GRFS), progression-free survival (PFS), and overall survival were 47%, 69%, and 82%, respectively. The 180-day CI of grade 3-4 acute GVHD was 15%, while the 2-year CI of chronic GVHD was 34%. In multivariable analyses, a longer interval from PD-1 to alloHCT was associated with less frequent severe acute GVHD, while additional treatment between PD-1 and alloHCT was associated with a higher risk of relapse. Notably, post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis was associated with significant improvements in PFS and GRFS. While awaiting prospective clinical trials, PTCy-based GVHD prophylaxis may be considered the optimal transplantation strategy for this patient population.
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http://dx.doi.org/10.1038/s41375-021-01193-6DOI Listing
March 2021

Ovarian response to stimulation for fertility preservation in women with hematologic cancer.

J Gynecol Obstet Hum Reprod 2021 May 30;50(5):101925. Epub 2020 Sep 30.

CHU Rennes, Département de Gynécologie Obstétrique et Reproduction Humaine, F-35033, Rennes, France.

Purpose: To compare the ovarian response to controlled ovarian hyperstimulation (COH) in patients with hematologic malignancies treated for fertility preservation (FP) and healthy subjects (oocyte donors (OD)).

Patients And Methods: Retrospective cohort study comparing 41 women (18-37 years) who underwent COH for oocyte vitrification prior to gonadotoxic treatment for hematologic cancer (FP group) from January 2014 to February 2019 and with 117 women undergoing COH as part of an OD protocol (OD group) during the same period. The number of frozen mature oocytes, number of oocytes retrieved, total dose of rFSH, maximal estradiol levels, percentage of maturity, number of dominant follicles >14 mm, days of stimulation were evaluated. Results were adjusted for age, body mass index (BMI), anti-Mullerian hormone (AMH) and rFSH starting dose.

Results: Patients in the FP group were younger and had a lower BMI than those in the OD group. rFSH starting dose was higher in the FP group (median 225UI (125;450) vs 150UI (87.5;337.5), p < 0.0001). After adjusting for age, BMI and starting rFSH dose according to ANCOVA, more frozen mature oocytes (median 10 (0;45) vs 8 (0;22] p = 0.0055) and retrieved oocytes (median 12 (0;49) vs 11 (0;29) p = 0.0468) were found in the FP group. Other outcome measures did not differ between the groups.

Conclusion: Ovarian response after COH in women with a hematologic cancer is similar to that in the general population. A higher number of mature oocytes were collected in the FP group after strong COH.
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http://dx.doi.org/10.1016/j.jogoh.2020.101925DOI Listing
May 2021

Molecular response after obinutuzumab plus high-dose cytarabine induction for transplant-eligible patients with untreated mantle cell lymphoma (LyMa-101): a phase 2 trial of the LYSA group.

Lancet Haematol 2020 Nov 21;7(11):e798-e807. Epub 2020 Sep 21.

Onco-Haematology, Université de Paris, Hôpital and Institut Necker-Enfants Malades, Assistance-Publique-Hôpitaux de Paris, INSERM U1151, Paris, France.

Background: Obinutuzumab monotherapy has shown promising efficacy in mantle cell lymphoma. We aimed to investigate the activity of obinutuzumab plus DHAP (dexamethasone, high-dose cytarabine, and cisplatin), measured by minimal residual disease quantitative (q)PCR status in the bone marrow after four cycles.

Methods: LyMa-101 was a prospective, open-label, single-arm, phase 2 trial. Participants were enrolled from 28 hospitals in France. Newly diagnosed patients with mantle cell lymphoma (aged 18 to <66 years) who were eligible for autologous stem-cell transplantation received four cycles of obinutuzumab plus DHAP (obinutuzumab 1000 mg/m intravenously on days 1, 8, and 15 at cycle 1 and day 1 at cycles 2, 3, and 4; dexamethasone 40 mg intravenously on days 1-4, cytarabine 2 g/m intravenously every 12 h on day 1, and according to local investigator, cisplatin 100 mg/m by continuous infusion over 24 h on day 1 or carboplatin area under the curve 5 or oxaliplatin 130 mg/m) every 21 days before transplantation, and 3 years of obinutuzumab (1000 mg/m every 2 months) maintenance followed by minimal residual disease-based obinutuzumab on-demand maintenance. The primary outcome was minimal residual disease negativity in the bone marrow after four cycles of obinutuzumab plus DHAP at the end of induction, measured in the efficacy set (all minimal residual disease-informative [bone marrow or peripheral blood] patients who received at least one dose of obinutuzumab). Obinutuzumab plus DHAP was considered effective if bone marrow minimal residual disease negativity was 70% or more by intention to treat. The trial is closed to recruitment and registered with ClinicalTrials.gov, NCT02896582.

Findings: 86 patients were enrolled between Nov 29, 2016, and May 2, 2018. 81 patients completed induction, 73 underwent autologous stem-cell transplantation, and 69 started maintenance therapy. 55 (75%) of 73 patients in the efficacy set reached minimal residual disease negativity in bone marrow at end of induction. According to the protocol definition, 18 (25%) of 73 patients in the efficacy set were minimal residual disease-positive: 12 patients who were minimal residual disease-positive in the bone marrow, plus two patients who progressed during induction, and four patients who did not have minimal residual disease assessment. The most common grade 3-4 treatment-emergent adverse events were anaemia (grade 3, 26 [31%] of 85 patients; grade 4, three [4%] of 85 patients) and neutropenia (grade 3, 13 [15%] of 85 patients; grade 4, 32 [38%] of 85 patients). 58 serious adverse events occurred during the induction phase. There were no treatment-related deaths.

Interpretation: Obinutuzumab plus DHAP is a well tolerated regimen and has good activity for inducing minimal residual disease negativity in the bone marrow of transplant-eligible patients with mantle cell lymphoma. Obinutuzumab plus DHAP has potential activity as induction chemotherapy, with bone marrow minimal residual disease negativity potentially predicting long-term disease control.

Funding: Roche SAS.
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http://dx.doi.org/10.1016/S2352-3026(20)30291-XDOI Listing
November 2020

Risk of relapse after anti-PD1 discontinuation in patients with Hodgkin lymphoma.

Eur J Nucl Med Mol Imaging 2021 Apr 28;48(4):1144-1153. Epub 2020 Aug 28.

Department of Hematology, University Hospital of Rennes, 2 rue Henri Le Guilloux, 35033, Rennes Cedex 9, France.

Introduction: Patients with relapsed/refractory Hodgkin lymphoma (R/R HL) experience high response rates upon anti-PD1 therapy. In these patients, the optimal duration of treatment and the risk of relapse after anti-PD1 discontinuation are unknown.

Methods: We retrospectively analyzed patients with R/R HL who responded to anti-PD1 monotherapy and discontinued the treatment either because of unacceptable toxicity or prolonged remission. A machine learning algorithm based on 17 candidate variables was trained and validated to predict progression-free survival (PFS) landmarked at the time of discontinuation of anti-PD1 therapy.

Results: Forty patients from 14 centers were randomly assigned to training (n = 25) and validation (n = 15) sets. At the time of anti-PD1 discontinuation, patients had received treatment for a median duration of 11.2 (range, 0-time to best response was not statistically significant in discriminating patients with PFS lesser or greater than 12 months). Considering PFS status as a binary variable (alive or dead) at a specific time point (12 months) is convenient, intuitive and allows for comparing the value of potential predicting variables in these two groups of patients. Nonetheless, this approach has two drawbacks: first, it binarizes outcome; second, it excludes patients alive with a time to last follow up lesser 12 months. Therefore, it is less powerful to demonstrate statistically significant association with PFS even if it exists 5 months. Patients discontinued anti-PD1 treatment either because of prolonged remission (N = 27, 67.5%) or unacceptable toxicity (N = 13, 32.5%). Most patients were in CR (N = 35, 87.5%) at the time of anti-PD1 discontinuation. In the training set, the machine learning algorithm identified that the most important variables to predict PFS were patients' age, time to best response, and presence or absence of CR. The performance observed in the training set was validated in the validation set.

Conclusion: In this pilot, proof of concept study using a machine learning algorithm, we identified biomarkers capable of predicting the risk of relapse after anti-PD1 discontinuation (age, time to best response, quality of response). Once confirmed, these simple biomarkers will represent useful tools to guide the management of these patients.
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http://dx.doi.org/10.1007/s00259-020-05015-2DOI Listing
April 2021

Total immunotherapy for Hodgkin lymphoma.

Lancet Haematol 2020 09;7(9):e629-e630

Department of Hematology, Hôpital Claude Huriez, Centre Hospitalier Regional Universitaire, Lille, France; Lille University Hospital, University of Lille, Lille F-59000, France. Electronic address:

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http://dx.doi.org/10.1016/S2352-3026(20)30220-9DOI Listing
September 2020

Screening Strategies for COVID-19 in Patients With Hematologic Malignancies.

Front Oncol 2020 3;10:1267. Epub 2020 Jul 3.

Radiology Department, Gustave Roussy Cancer Campus, Villejuif, France.

COVID-19 has been declared a pandemic by the world health organization. Patients with cancer, and particularly hematologic malignancies may be at higher risk for severe complications due to their malignancy, immune dysregulation, therapy, and associated comorbidities. The oncology community has been proactive in issuing practice guidelines to help optimize management, and limit infection risk and complications from SARS-COV-2. Although hematologic malignancies account for only 10% of all cancers, their management is particularly complex, especially in the time of COVID-19. Screening or early detection of COVID-19 are central for preventative/mitigation strategy, which is the best current strategy in our battle against COVID-19. Herein, we provide an overview of COVID-19 screening strategies and highlight the unique aspects of treating patients with hematologic malignancies.
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http://dx.doi.org/10.3389/fonc.2020.01267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348065PMC
July 2020

Lenalidomide/rituximab induces high molecular response in untreated follicular lymphoma: LYSA ancillary RELEVANCE study.

Blood Adv 2020 08;4(14):3217-3223

Département d'Hématologie, Equipe d'Accueil 7365, CHU Lille, Lille, France.

Complete molecular response (CMR) after first-line immunochemotherapy reflects treatment efficacy and may predict prognosis in patients with follicular lymphoma (FL). RELEVANCE is the first phase 3 trial comparing the chemotherapy-free regimen lenalidomide/rituximab (R2) vs rituximab/chemotherapy (R-Chemo) in previously untreated FL patients (ClinicalTrials.gov identifier: NCT01650701). The objective of the minimal residual disease (MRD) analysis was to determine the ability of a chemotherapy-free regimen to induce CMR. Of 440 French patients participating in the Lymphoma Study Association (LYSA) RELEVANCE MRD study, all 222 patients with a BIOMED-2-detectable BCL2-JH translocation at diagnosis were analyzed. MRD was quantified by droplet digital polymerase chain reaction with a sensitivity ≤10-4. At week 24 (end of induction treatment), 98% and 78% of patients achieved CMR in peripheral blood (PB) and bone marrow (BM), respectively. Achievement of CMR (in PB and/or BM) had a significant impact on progression-free survival (PFS), with 3-year PFS of 84% and 55% for patients with CMR and detectable MRD, respectively (P = .015). CMR at week 24 was reached more frequently in the R2 arm (105/117; 90%) than in the R-Chemo arm (70/90; 77%) (P = .022). The poor prognostic value in terms of PFS for the persistence of molecular disease was observed irrespective of treatment arm (interaction test, P = .31). In agreement with the clinical results of the RELEVANCE trial, our results show that R2 immunomodulatory treatment in first-line FL can achieve high rates of CMR.
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http://dx.doi.org/10.1182/bloodadvances.2020001955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391139PMC
August 2020

Could anti-CD20 therapy jeopardise the efficacy of a SARS-CoV-2 vaccine?

Eur J Cancer 2020 09 25;136:4-6. Epub 2020 Jun 25.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

A vaccine against SARS-CoV-2 might represent the most promising approach to halt durably the current COVID-19 pandemic. We believe that anti-CD20 therapy may jeopardise the efficacy of such a vaccine. This is regrettable because patients receiving anti-CD20 therapy (i.e. those with haematologic malignancies or autoimmune disorders) are particularly at risk of severe COVID-19 and, as such, are the most in need of a vaccine. Here, we review the reasons why anti-CD20 therapy may abrogate or diminish the efficacy of a vaccine against SARS-CoV-2 and we draw physicians' attention towards this potential risk so that it can be considered when evaluating the risk/benefit ratio of anti-CD20 therapy during the current pandemic.
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http://dx.doi.org/10.1016/j.ejca.2020.06.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315961PMC
September 2020

Immune and Cell Therapy in Non-Hodgkin Lymphoma.

Cancer J 2020 May/Jun;26(3):269-277

From the Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.

The promise of immunotherapy has shone brightly for decades in hematologic malignancies and specifically in non-Hodgkin lymphoma. The last decade has witnessed the emergence of completely novel forms of immunotherapy, including immune checkpoint blockade, bispecific antibodies, and chimeric antigen receptor T cells. These treatments have shown phenomenal, and in some cases possibly curative, successes in various relapsed/refractory lymphomas. This review summarizes the most notable successes and promising findings as well as some of the attendant failures. These treatments will doubtlessly transform the treatment paradigms across many lymphoma subtypes. Yet, only if we can better understand their mechanisms of action, toxicity, and resistance will be able to maximize their therapeutic benefit.
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http://dx.doi.org/10.1097/PPO.0000000000000445DOI Listing
June 2020

Performance of CT Compared with F-FDG PET in Predicting the Efficacy of Nivolumab in Relapsed or Refractory Hodgkin Lymphoma.

Radiology 2020 06 14;295(3):651-661. Epub 2020 Apr 14.

From the Dept of Radiology, New York Presbyterian Hosp, Columbia Univ Medical Ctr, New York, NY (F.Z.M., L.D., A.C., L.H.S.); Dept of Radiology, Rangueil Univ Hosp, Toulouse, France (F.Z.M.); Dept of Radiology, First Affiliated Hosp of Nanjing Medical Univ, Nanjing, China (A.C.); Univ Lille, CHU Lille, EA 7365-GRITA-Groupe de Recherche sur les Formes Injectables et les Technologies Associées, Lille, France (F.M.); Dept of Hematology, Centre Henri Becquerel, Rouen, France (A.S.); Dept of Hematology, Paoli-Calmette Inst, Marseille, France (J.M.S.d.C.); Dept of Nuclear Medicine, Saint-Louis Hosp, AP-HP, Paris, France (L.V.); Dept of Hematology, Univ Hosp of Dijon, Dijon, France (O.C.); Dept of Hematology, Univ Hosp of Besançon, Besançon, France (A.C.); Dept of Hematology, Univ Hosp of Reims, Reims, France (A.D.); Dept of Hematology, Leon Berard Ctr, Lyon, France (E.N.V.); Dept of Hematology, Univ Hosp of Lyon, Lyon, France (H.G.); Dept of Hematology, Univ Hosp of Angers, Angers, France (M.P.M.M.); Dept of Hematology, Bergonie Inst, Bordeaux, France (A.S.); Dept of Hematology, Saint-Antoine Hosp, AP-HP, Paris, France (R.D.); Dept of Hematology, Univ Hosp of Bordeaux, Bordeaux, France (K.B.); Dept of Hematology, Institut Universitaire du Cancer Toulouse-Oncopole, Toulouse, France (C.B.); Dept of Hematology, Univ Hosp of Limoges, Limoges, France (M.T.); Dept of Hematology, Cochin Hosp, AP-HP, Paris, France (B.D.F.); Centre Antoine Lacassagne, Nice, France (F.P.); Dept of Nuclear Medicine, Institut Curie, Paris, France (R.D.S.); Dept of Hematology, Univ Hosp of Rennes, Rennes, France (G.M., R.H.); INSERM, U1236, Rennes, France (G.M., R.H.); and UMR1015, Institut Gustave Roussy, Université Paris Saclay, Villejuif 94800, France (L.D.).

Background CT and fluorine 18 (F) fluorodeoxyglucose (FDG) PET/CT performances following immune therapy are not well known in patients with relapsed or refractory Hodgkin lymphoma (RRHL). Purpose To compare CT and PET/CT for prognostic value of early response evaluation following nivolumab therapy. Materials and Methods This retrospective study included patients from 34 institutions who underwent early imaging response evaluation from July 2013 to April 2017. Three experienced readers classified imaging response by using Cheson et al and 2016 Lymphoma Response to Immunomodulatory Therapy Criteria as follows: complete (metabolic) response, partial (metabolic) response, stable disease or no metabolic response, or progressive (metabolic) disease. Primary CT and PET assessments were performed at a median of 2.0 months (interquartile range, 1.7-3.7 months) after nivolumab initiation. Kaplan-Meier analysis was used to determine the relationship of primary CT and PET assessment response categories to overall survival (OS). Agreements between primary and secondary imaging assessments were assessed by using κ analysis. Results A total of 45 patients (median age, 37 years; range, 18-77 years; 25 men) underwent a primary assessment using CT and PET/CT; 36 patients also underwent a subsequent assessment. Eleven patients (24%) died after a median follow-up of 21.2 months. CT and PET response categories were associated with OS ( = .03 for primary CT assessment; = .02 for primary PET assessment). There was no pseudoprogression at primary CT and PET assessments. At the primary assessment, response categories by using CT were reclassified by using PET in 44% (20 of 45) of patients. Among these, 55% (11 of 20) were reclassified to complete metabolic response (complete metabolic response rate: 29% [13 of 45 patients] vs complete response rate: 4% [two of 45 patients]), with a 2-year OS probability of 100%. At the secondary assessment, complete response rate using CT increased to 17% (six of 36 patients), hence a better agreement with PET (κ = 0.78; < .001). Conclusion Early CT and PET/CT at a median of 2 months after initiation of nivolumab predicted overall survival in relapsed or refractory Hodgkin lymphoma. Early PET detected additional patients with complete metabolic response. © RSNA, 2020 See also the editorial by Scott and Wang in this issue.
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http://dx.doi.org/10.1148/radiol.2020192056DOI Listing
June 2020

Chimeric antigen receptor (CAR) T-cells on the march: from diffuse large B-cell lymphoma to mantle cell lymphoma.

Eur J Cancer 2020 05 10;131:51-52. Epub 2020 Apr 10.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

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http://dx.doi.org/10.1016/j.ejca.2020.03.001DOI Listing
May 2020

KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma.

N Engl J Med 2020 04;382(14):1331-1342

From the University of Texas M.D. Anderson Cancer Center, Houston (M.W.), and Texas Oncology, Dallas (H.H.); Banner M.D. Anderson Cancer Center, Gilbert, AZ (J.M.); John Theurer Cancer Center, Hackensack, NJ (A.G.); Moffitt Cancer Center, Tampa (F.L.L.), and the University of Miami, Miami (A.B.) - both in Florida; Dana-Farber Cancer Institute, Boston (C.A.J.); Cleveland Clinic Foundation, Cleveland (B.T.H.), and the Ohio State University Comprehensive Cancer Center, Columbus (S.J.); David Geffen School of Medicine at UCLA, Los Angeles (J.M.T.), Stanford University School of Medicine, Stanford (D.B.M.), and Kite, a Gilead company, Santa Monica (W.P., L.Z., J.M.R., R.K.J., A.V.R.) - all in California; Sarah Cannon Research Institute-Tennessee Oncology, Nashville (I.W.F.); Colorado Blood Cancer Institute, Denver (P.A.M.); Swedish Cancer Institute, Seattle (J.M.P.); the Academic Medical Center, University of Amsterdam, Amsterdam, for the Lunenburg Lymphoma Phase I/II Consortium (M.-J.K.); Centre Hospitalier Universitaire (CHU) Bordeaux, Service d'Hematologie et Therapie Cellulaire, Bordeaux (N.M.), and CHU Rennes, INSERM French Blood Establishment, Rennes (R.H.) - both in France; Fox Chase Cancer Center, Philadelphia (H.F.); Universitätsklinikum Würzburg, Würzburg, Germany (M.S.T.); and the University of Rochester Medical Center, Rochester, NY (P.M.R.).

Background: Patients with relapsed or refractory mantle-cell lymphoma who have disease progression during or after the receipt of Bruton's tyrosine kinase (BTK) inhibitor therapy have a poor prognosis. KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, may have benefit in patients with relapsed or refractory mantle-cell lymphoma.

Methods: In a multicenter, phase 2 trial, we evaluated KTE-X19 in patients with relapsed or refractory mantle-cell lymphoma. Patients had disease that had relapsed or was refractory after the receipt of up to five previous therapies; all patients had to have received BTK inhibitor therapy previously. Patients underwent leukapheresis and optional bridging therapy, followed by conditioning chemotherapy and a single infusion of KTE-X19 at a dose of 2×10 CAR T cells per kilogram of body weight. The primary end point was the percentage of patients with an objective response (complete or partial response) as assessed by an independent radiologic review committee according to the Lugano classification. Per the protocol, the primary efficacy analysis was to be conducted after 60 patients had been treated and followed for 7 months.

Results: A total of 74 patients were enrolled. KTE-X19 was manufactured for 71 patients and administered to 68. The primary efficacy analysis showed that 93% (95% confidence interval [CI], 84 to 98) of the 60 patients in the primary efficacy analysis had an objective response; 67% (95% CI, 53 to 78) had a complete response. In an intention-to-treat analysis involving all 74 patients, 85% had an objective response; 59% had a complete response. At a median follow-up of 12.3 months (range, 7.0 to 32.3), 57% of the 60 patients in the primary efficacy analysis were in remission. At 12 months, the estimated progression-free survival and overall survival were 61% and 83%, respectively. Common adverse events of grade 3 or higher were cytopenias (in 94% of the patients) and infections (in 32%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 15% and 31% of patients, respectively; none were fatal. Two grade 5 infectious adverse events occurred.

Conclusions: KTE-X19 induced durable remissions in a majority of patients with relapsed or refractory mantle-cell lymphoma. The therapy led to serious and life-threatening toxic effects that were consistent with those reported with other CAR T-cell therapies. (Funded by Kite, a Gilead company; ZUMA-2 ClinicalTrials.gov number, NCT02601313.).
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http://dx.doi.org/10.1056/NEJMoa1914347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731441PMC
April 2020

First-in-Human Study of Utomilumab, a 4-1BB/CD137 Agonist, in Combination with Rituximab in Patients with Follicular and Other CD20 Non-Hodgkin Lymphomas.

Clin Cancer Res 2020 06 6;26(11):2524-2534. Epub 2020 Mar 6.

Washington University School of Medicine, Siteman Cancer Center, St Louis, Missouri.

Purpose: In this phase I study (NCT01307267), we evaluated safety, pharmacokinetics, clinical activity, and pharmacodynamics of treatment with utomilumab plus rituximab in patients with relapsed/refractory follicular lymphoma (FL) and other CD20 non-Hodgkin lymphomas (NHL).

Patients And Methods: Primary objectives were to assess treatment safety and tolerability for estimating the MTD, using a modified time-to-event continual reassessment method, and selecting the recommended phase II dose (RP2D).

Results: Sixty-seven patients received utomilumab (0.03-10.0 mg/kg every 4 weeks) and rituximab (375 mg/m weekly) in the dose-escalation groups or utomilumab (1.2 mg/kg every 4 weeks) plus rituximab in the dose-expansion cohort. No patient experienced dose-limiting toxicity. The MTD for utomilumab in combination with rituximab was not reached and estimated to be ≥10 mg/kg every 4 weeks. The majority of the utomilumab treatment-related adverse events (AE) were grade 1 to 2; the most common AE was fatigue (16.4%). The pharmacokinetics of utomilumab in combination with rituximab was linear in the 0.03 to 10 mg/kg dose range. A low incidence (1.5%) of treatment-induced antidrug antibodies against utomilumab was observed. The objective response rate was 21.2% (95% CI, 12.1%-33.0%) in all patients with NHL, including four complete and 10 partial responses. Analysis of paired biopsies from a relapsed/refractory FL patient with complete response showed increased T-cell infiltration and cytotoxic activity in tumors. Biomarker correlations with outcomes suggested that clinical benefit may be contingent on patient immune function.

Conclusions: Utomilumab in combination with rituximab demonstrated clinical activity and a favorable safety profile in patients with CD20 NHLs.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2973DOI Listing
June 2020

Urelumab alone or in combination with rituximab in patients with relapsed or refractory B-cell lymphoma.

Am J Hematol 2020 05 29;95(5):510-520. Epub 2020 Feb 29.

Stanford University School of Medicine, Stanford, California.

Urelumab, a fully human, non-ligand binding, CD137 agonist IgG4 monoclonal antibody, enhances T-cell and natural killer-cell antitumor activity in preclinical models, and may enhance cytotoxic activity of rituximab. Here we report results in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and other B-cell lymphomas, in phase 1 studies evaluating urelumab alone (NCT01471210) or combined with rituximab (NCT01775631). Sixty patients received urelumab (0.3 mg/kg IV Q3W, 8 mg IV Q3W, or 8 mg IV Q6W); 46 received urelumab (0.1 mg/kg, 0.3 mg/kg, or 8 mg IV Q3W) plus rituximab 375 mg/m IV QW. The maximum tolerated dose (MTD) of urelumab was determined to be 0.1 mg/kg or 8 mg Q3W after a single event of potential drug-induced liver injury occurred with urelumab 0.3 mg/kg. Treatment-related AEs were reported in 52% (urelumab: grade 3/4, 15%) and 72% (urelumab + rituximab: grade 3/4, 28%); three led to discontinuation (grade 3 increased AST, grade 4 acute hepatitis [urelumab]; one death from sepsis syndrome [urelumab plus rituximab]). Objective response rates/disease control rates were 6%/19% (DLBCL, n = 31), 12%/35% (FL, n = 17), and 17%/42% (other B-cell lymphomas, n = 12) with urelumab and 10%/24% (DLBCL, n = 29) and 35%/71% (FL, n = 17) with urelumab plus rituximab. Durable remissions in heavily pretreated patients were achieved; however, many were observed at doses exceeding the MTD. These data show that urelumab alone or in combination with rituximab demonstrated manageable safety in B-cell lymphoma, but the combination did not enhance clinical activity relative to rituximab alone or other current standard of care.
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http://dx.doi.org/10.1002/ajh.25757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383599PMC
May 2020

Bendamustine-EAM versus BEAM regimen in patients with mantle cell lymphoma undergoing autologous stem cell transplantation in the frontline setting: a multicenter retrospective study from Lymphoma Study Association (LYSA) centers.

Bone Marrow Transplant 2020 06 17;55(6):1076-1084. Epub 2020 Jan 17.

Department of Clinical Hematology, Caen University Hospital, F-14000, Caen, France.

The combination of carmustine, etoposide, cytarabine, and melphalan (BEAM) as conditioning regimen prior to autologous stem-cell transplantation (ASCT) remains the standard of care for patients with mantle cell lymphoma (MCL) who are eligible for transplantation. The replacement of carmustine with bendamustine (BeEAM) was described as a promising alternative in non-Hodgkin lymphoma. The aim of this retrospective study was to compare the BeEAM with the BEAM regimen in MCL patients in the frontline setting. Sixty and 108 patients were included in the BeEAM and the BEAM groups, respectively. At 3 years, progression-free survival (PFS) was significantly higher in the BeEAM than in the BEAM group (84% [73-96] vs. 63% [51-79], p = 0.03). The overall survival was not statistically different between the two groups (p = 0.2). In multivariable analysis, BeEAM regimen remained associated with higher PFS (HR = 0.377, 95% CI, 0.146-0.970; p = 0.043). Subgroup analyses in patients treated with prior rituximab-aracytine induction alone showed that BeEAM improved the PFS compared with BEAM regimen (p = 0.04). Despite the high rate of acute renal failure KDIGO III (32%), treatment-related mortality was not increased with the BeEAM regimen. A prospective randomized trial will be necessary to confirm the beneficial effect of the BeEAM regimen in MCL patients undergoing ASCT.
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http://dx.doi.org/10.1038/s41409-020-0783-yDOI Listing
June 2020

Hyperprogression upon immunotherapy: A chance for (hyper-)progress.

Eur J Cancer 2020 02 13;126:139-140. Epub 2020 Jan 13.

Drug Development Department (DITEP), Gustave Roussy, Paris- Saclay University, Villejuif, France; Medical School, Paris-Saclay University, Paris-Sud University, Le Kremlin Bicêtre, France.

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http://dx.doi.org/10.1016/j.ejca.2019.12.011DOI Listing
February 2020

Management and outcome of primary CNS lymphoma in the modern era: An LOC network study.

Neurology 2020 03 6;94(10):e1027-e1039. Epub 2020 Jan 6.

From Service de Neurologie 2-Mazarin, Sorbonne Université, IHU, ICM (C. Houillier, A.A., D.D., H.D., D.G., B.A., K.H.-X.), Service d'Hématologie (S. Choquet), Service de Neuro-Radiologie (N.M.-D.), Service d'Ophtalmologie (V.T.), Service de Médecine Nucléaire (A.K.), Service de Neuro-Pathologie (K.M.), Service d'Anatomie et Cytologies Pathologiques (F.C.), Service de Radiothérapie (L.F.), Service d'Hémato-Biologie (M.L.G.-T., M.C.), and Service de Neurochirurgie (B.M., M.P.), APHP, Groupe Hospitalier Pitié-Salpêtrière, Paris; Service d'Hématologie (C. Soussain), Institut Curie, Site Saint-Cloud; Service d'Hématologie (H.G.), CHU Lyon Sud; Service d'Hématologie (P.S., A.S.), Institut Bergonié, Bordeaux; Service de Neuro-Oncologie (O. Chinot), Aix-Marseille Université, CNRS, INP, AP-HM, CHU de la Timone, Marseille; Service de Neurologie (L.T., M.B.), CHU de Nancy; Service d'Hématologie (R.H.), Inserm U1236 Université de Rennes 1 (T.L.), CHU de Rennes; Service de Neurologie (G.A.), Hôpitaux Civils, Colmar; Service d'Hématologie (G.D.), CHU de Caen; Service d'Oncologie Médical (P.A.), Institut de Cancérologie de l'Ouest, Saint Herblain; Service d'Hématologie (C.M.-C.), CHU de Clermont-Ferrand; Service de Neurologie (A.A.), CHU de Toulouse; Service d'Oncologie Hématologique et de Thérapie Cellulaire (V.D.), CHU de Poitiers, INSERM, CIC 1402, Centre d'Investigation Clinique, Université de Poitiers; Service d'Oncologie Médicale (M.F.), Institut du Cancer de Montpellier Val d'Aurelle; Service d'Hématologie (F.J.), Centre Henri Becquerel, Rouen; Service d'Hématologie (A.C.), CHU de Besançon; Service d'Hématologie (M.P.M.-M.), CHU d'Angers; Service d'Hématologie (F.M., E.B.), CHRU de Lille; Service d'Hématologie (O. Casasnovas), CHU de Dijon; Service d'Onco-Hématologie (R.G.), CHU de Grenoble; Service d'Hématologie (L.M.F.), CHU de Strasbourg; Service d'Hématologie (J.A.), CHU de Limoges; Service d'Hématologie (J.-P.M.), CHU d'Amiens; Service d'Hématologie (A.T.), CHU de Brest; Service de Neurologie (C.C.) and Service d'Hématologie (A.W.), CHU de Nîmes; Clinique Courlancy (P.C.), Reims; Service d'Hématologie (J.T.), Hôpital Cochin, APHP, Paris; Service d'Hématologie Clinique (K.L.), Centre Hospitalier, Le Mans; Service d'Hématologie (C. Serrier), Centre Hospitalier de Perpignan; Service d'Hématologie (C. Haioun), Hôpital Henri Mondor, Créteil, APHP; Service d'Hématologie Clinique (S. Chebrek), Centre Hospitalier d'Avignon; Service d'Hématologie (J.O.B.), CHU de Clermont-Ferrand; Service d'Hématologie (L.O.), Institut Universitaire du Cancer de Toulouse; Service de Neuro-Oncologie (E.T.), Aix-Marseille Univ, CNRS, INP, AP-HM, CHU de la Timone; Service d'Ophtalmologie (N.C.), Institut Curie, Université Paris V Descartes et PSL (Paris Science et Lettre), Paris; and Service d'Hématologie et Thérapie Cellulaire (E.G.), Centre d'Investigations Cliniques INSERM U1517, Centre Hospitalier Universitaire, Université de Tours, France.

Objective: Real-life studies on patients with primary CNS lymphoma (PCNSL) are scarce. Our objective was to analyze, in a nationwide population-based study, the current medical practice in the management of PCNSL.

Methods: The French oculo-cerebral lymphoma network (LOC) database prospectively records all newly diagnosed PCNSL cases from 32 French centers. Data of patients diagnosed between 2011 and 2016 were retrospectively analyzed.

Results: We identified 1,002 immunocompetent patients (43% aged >70 years, median Karnofsky Performance Status [KPS] 60). First-line treatment was high-dose methotrexate-based chemotherapy in 92% of cases, with an increasing use of rituximab over time (66%). Patients <60 years of age received consolidation treatment in 77% of cases, consisting of whole-brain radiotherapy (WBRT) (54%) or high-dose chemotherapy with autologous stem cell transplantation (HCT-ASCT) (23%). Among patients >60 years of age, WBRT and HCT-ASCT consolidation were administered in only 9% and 2%, respectively. The complete response rate to initial chemotherapy was 50%. Median progression-free survival was 10.5 months. For relapse, second-line chemotherapy, HCT-ASCT, WBRT, and palliative care were offered to 55%, 17%, 10%, and 18% of patients, respectively. The median, 2-year, and 5-year overall survival was 25.3 months, 51%, and 38%, respectively (<60 years: not reached [NR], 70%, and 61%; >60 years: 15.4 months, 44%, and 28%). Age, KPS, sex, and response to induction CT were independent prognostic factors in multivariate analysis.

Conclusions: Our study confirms the increasing proportion of elderly within the PCNSL population and shows comparable outcome in this population-based study with those reported by clinical trials, reflecting a notable application of recent PCNSL advances in treatment.
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http://dx.doi.org/10.1212/WNL.0000000000008900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238921PMC
March 2020

Early F-FDG PET/CT Response Predicts Survival in Relapsed or Refractory Hodgkin Lymphoma Treated with Nivolumab.

J Nucl Med 2020 05 18;61(5):649-654. Epub 2019 Oct 18.

Department of Radiology, New York Presbyterian Hospital, Columbia University Medical Center, New York, New York

Monoclonal antibodies (mAbs) against programmed cell death 1 (PD-1), such as nivolumab and pembrolizumab, are associated with high response rates in patients with relapsed or refractory classic Hodgkin lymphoma (HL). To date, no prognostic factor for overall survival (OS) has been established with these agents in HL. We examined whether the first early response assessment evaluated using F-FDG PET/CT may be associated with OS in this setting. This retrospective study included 45 patients from 34 institutions. In a masked, centralized review, 3 independent radiologists classified PET/CT scans obtained at a median of 2.0 mo (interquartile range, 1.7-3.7 mo) after nivolumab initiation using existing criteria (i.e., 2014 Lugano classification and 2016 LYRIC). Patients were classified according to 4 possible response categories: complete metabolic response (CMR), partial metabolic response (PMR), no metabolic response (NMR), or progressive metabolic disease (PMD). Because the OS of patients with NMR and PMR was similar, they were grouped together. OS was estimated using the Kaplan-Meier method and compared between groups using log-rank testing. Eleven patients (24%) died after a median follow-up of 21.2 mo. The classification was identical between Lugano and LYRIC because all 16 progression events classified as indeterminate response per LYRIC were confirmed on subsequent evaluations. Both Lugano and LYRIC classified patients as CMR in 13 cases (29%), PMD in 16 (36%), NMR in 4 (9%), and PMR in 12 (27%). The 2-y OS probability was significantly different in patients with PMD (0.53; 95% confidence interval [95%CI], 0.32-0.87), NMR or PMR (0.80; 95%CI, 0.63-1.00), and CMR (1.00; 95%CI, 1.00-1.00) in the overall population ( = 0.02, 45 patients), as well as according to a landmark analysis at 3 mo ( = 0.05, 32 patients). In relapsed or refractory HL patients treated with anti-PD-1 mAbs, the first early PET/CT assessment using either Lugano or LYRIC predicted OS and allowed early risk stratification, suggesting that PET/CT might be used to develop risk-adapted strategies.
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http://dx.doi.org/10.2967/jnumed.119.232827DOI Listing
May 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

Long-term efficacy of anti-PD1 therapy in Hodgkin lymphoma with and without allogenic stem cell transplantation.

Eur J Cancer 2019 07 10;115:47-56. Epub 2019 May 10.

Department of Hematology, University Hospital of Rennes, Rennes, France; INSERM, U1236, Rennes, France. Electronic address:

Introduction: Long-term efficacy of anti-PD1 therapy and the need for a consolidation with allogenic haematopoietic stem cell transplantation (allo-HSCT) remain unclear in patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL).

Methods: We retrospectively analysed 78 patients with R/R HL treated with nivolumab in the French Early Access Program and compared their outcomes according to subsequent allo-HSCT.

Results: After a median follow-up of 34.3 months, the best overall response rate was 65.8%, including 38.2% complete responses (CRs). The median progression-free survival (PFS) was 12.1 months. Patients reaching a CR upon nivolumab had a significantly longer PFS than those reaching a partial response (PR) (median = not reached vs 9.3 months, p < 0.001). In our cohort, 13 patients who responded (i.e. in CR or PR) to nivolumab monotherapy underwent consolidation with allo-HSCT. Among responding patients, none of those who underwent subsequent allo-HSCT (N = 13) relapsed, whereas 62.2% of those who were not consolidated with allo-HSCT (N = 37) relapsed (p < 0.001). There was no difference in overall survival (OS) between the two groups. Five of 6 patients who were not in CR at the time of transplantation (4 PRs and 1 progressive disease) converted into a CR after allo-HSCT.

Conclusion: Most patients with R/R HL treated with anti-PD1 monotherapy eventually progressed, notably those who did not achieve a CR. Patients undergoing consolidation with allo-HSCT after anti-PD1 therapy experienced prolonged disease-free survival compared with non-transplanted patients, but this difference did not translate into a benefit in OS. This information should be considered when evaluating the risk/benefit ratio of allo-HSCT after anti-PD1 therapy.
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http://dx.doi.org/10.1016/j.ejca.2019.04.006DOI Listing
July 2019

Renal Dysfunction in Patients With Direct Infiltration by B-Cell Lymphoma.

Kidney Int Rep 2019 May 12;4(5):688-697. Epub 2019 Feb 12.

CHU de Rennes, Service de Néphrologie, Rennes, France.

Background: B-cell lymphoproliferative disorders with renal involvement are relatively frequent, but remain poorly described. A kidney biopsy is usually required to detect the renal lesions that are often missed using other diagnostic tools.

Methods: We retrospectively identified 34 patients with renal lymphoma diagnosed by percutaneous kidney biopsy (PKB) at Rennes University Hospital and its affiliated hospital centers between January 1, 2004, and May 1, 2016. Clinical, biological, radiological, and histological characteristics were collected at biopsy time.

Results: The included patients had Waldenström macroglobulinemia ( = 12; 35.3%), chronic lymphocytic leukemia/lymphocytic lymphoma ( = 10; 29.5%), high-grade B-cell lymphoma ( = 6; 17.6%), and low-grade B-cell lymphoma ( = 6; 17.6%). The median follow-up was 29 months. Renal involvement led to renal function impairment in 29 patients (85.3%), among whom 20 had acute kidney injury (70%), and to nephrotic syndrome in 4 patients (11.8%). Only 13 patients (38.2%) presented morphological kidney anomalies among whom 5 showed bilateral infiltration. Histologically, interstitial infiltrate (97.1%) was the most common kidney lesion, and 9 patients (26.5%) had specific lymphomatous intraglomerular lesions. After hematological treatment ( = 29), a renal response was observed only in 8 patients (27.6%).

Conclusion: Renal involvement in the context of B-cell lymphoproliferative disorders is not uncommon. PKB is the best method to confirm this diagnosis. It should be performed early to rapidly initiate the hematological treatment to preserve kidney function.
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http://dx.doi.org/10.1016/j.ekir.2019.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506703PMC
May 2019