Publications by authors named "Emmanuel Bachy"

86 Publications

The upper ECHELON against T-cell lymphoma.

Ann Oncol 2022 Jan 8. Epub 2022 Jan 8.

Lymphoma service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA.

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http://dx.doi.org/10.1016/j.annonc.2021.12.011DOI Listing
January 2022

Obinutuzumab plus lenalidomide (GALEN) in advanced, previously untreated follicular lymphoma in need of systemic therapy.

Blood 2021 Dec 22. Epub 2021 Dec 22.

CHU Lille, ULR 7365 - GRITA - Groupe de Recherche sur les formes Injectables et les Technologies Associées, Lille, France.

Obinutuzumab and lenalidomide (GALEN) is an active immunomodulatory combination with a manageable safety profile in multiple types of lymphoma. We report efficacy and safety results for the phase 2 GALEN study in previously-untreated patients with advanced follicular lymphoma (FL). Eligible patients aged ≥ 18 years had ECOG PS ≤ 2, high-tumor burden, grade 1-3a FL. Induction treatment was obinutuzumab (1000 mg IV, days 8/15/22, cycle 1; day 1, cycles 2-6) plus lenalidomide (20 mg/day, days 1-21, cycle 1; days 2-22, cycles 2-6) for 6 cycles. Maintenance included obinutuzumab (1000 mg every 2 cycles) plus lenalidomide (10 mg, days 2-22) for ≤ 12 cycles (year 1) followed by obinutuzumab (1000 mg every 56 days) for 6 cycles (year 2). The primary endpoint was complete response rate (CRR) after induction per IWG 1999 criteria. From October 2015 to February 2017, 100 patients were enrolled. CRR after induction was 47% and overall response rate (ORR) 92%. Post-hoc analyses per 2014 Lugano classification including patients with missing bone marrow assessments identified an additional 13 patients fulfilling CRR criteria, resulting in a complete metabolic response of 80% and ORR of 94%. At a median follow-up of 3.7 years, 3-year progression-free and overall survival were 82% and 94%, respectively. The most common adverse event was neutropenia (48% any-grade; 47% grade ≥ 3) but only 2% of patients presented febrile neutropenia; others were mainly grade ≤ 2. No other specific grade ≥3 toxicity occurred at a frequency higher than 3%. Overall, these results demonstrated promising clinical efficacy for the chemo-free backbone obinutuzumab and lenalidomide in previously untreated, high tumor burden FL patients. Except for neutropenia, the safety profile of the combination is remarkable. The study was registered with ClinicalTrials.gov, number NCT01582776.
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http://dx.doi.org/10.1182/blood.2021013526DOI Listing
December 2021

Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: the phase 2 ELARA trial.

Nat Med 2021 Dec 17. Epub 2021 Dec 17.

Novartis Pharma AG, Basel, Switzerland.

Tisagenlecleucel is an autologous anti-CD19 chimeric antigen receptor-T cell therapy with clinically meaningful outcomes demonstrated in patients with relapsed/refractory (r/r) B-cell lymphoma. In a previous pilot study of tisagenlecleucel in r/r follicular lymphoma (FL), 71% of patients achieved a complete response (CR). Here we report the primary, prespecified interim analysis of the ELARA phase 2 multinational trial of tisagenlecleucel in adults with r/r FL after two or more treatment lines or who relapsed after autologous stem cell transplant (no. NCT03568461). The primary endpoint was CR rate (CRR). Secondary endpoints included overall response rate (ORR), duration of response, progression-free survival, overall survival, pharmacokinetics and safety. As of 29 March 2021, 97/98 enrolled patients received tisagenlecleucel (median follow-up, 16.59 months; interquartile range, 13.8-20.21). The primary endpoint was met. In the efficacy set (n = 94), CRR was 69.1% (95% confidence interval, 58.8-78.3) and ORR 86.2% (95% confidence interval, 77.5-92.4). Within 8 weeks of infusion, rates of cytokine release syndrome were 48.5% (grade ≥3, 0%), neurological events 37.1% (grade ≥3, 3%) and immune effector cell-associated neurotoxicity syndrome (ICANS) 4.1% (grade ≥3, 1%) in the safety set (n = 97), with no treatment-related deaths. Tisagenlecleucel is safe and effective in extensively pretreated r/r FL, including in high-risk patients.
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http://dx.doi.org/10.1038/s41591-021-01622-0DOI Listing
December 2021

CAR-T cells, from principle to clinical applications.

Bull Cancer 2021 Oct;108(10S):S4-S17

Hospices civils de Lyon, centre hospitalier Lyon Sud, service d'hématologie, 69495 Pierre Bénite cedex, France; Université Claude-Bernard Lyon 1, 69100 Villeurbanne, France.

Chimeric antigen receptors (CAR)-T cells are genetically engineered T-lymphocytes redirected with a predefined specificity to any target antigen, in a non-HLA restricted manner, therefore combining antibody-type specificity with effector T-cell function. This strategy was developed some thirty years ago, after extensive work established the key role of the immune system against cancer. The first-engineered T-cell with chimeric molecule was designed in 1993 by Israeli immunologist Zelig Eshhar. Since then, several modifications took place, including the addition of co-stimulatory domain, to further improve CAR-T cell anti-tumor potency. The first clinical application of CAR-T cell was done in Rotterdam in 2005 for metastatic renal cell carcinoma and simultaneously at the National Cancer Institute (NCI) for metastatic ovarian cancer. These pioneered studies failed to demonstrate a therapeutic benefit, but warning emerged concerning their safety of use. The real clinical success came with anti-CD19 CAR-T cells, used since 2009 by Steven Rosenberg at the NCI in a patient with refractory follicular lymphoma and in 2011 by Carl June and David Porter from the University of Pennsylvania in patients with chronic lymphocytic leukemia and B-cell acute lymphoblastic leukemia. From that time, large centers in North America have embarked in several early phase and pivotal trials that have demonstrated unprecedent response rate in heavily pretreated chemo refractory patient with B-cell malignancies. Theses clinical success have led to the approval of three anti-CD19 CAR-T cells products for the management of B-cell malignancies in the United States and in Europe as of December 2020.
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http://dx.doi.org/10.1016/j.bulcan.2021.02.017DOI Listing
October 2021

CAR-T cell: Toxicities issues: Mechanisms and clinical management.

Bull Cancer 2021 Oct;108(10S):S117-S127

Hospices Civils de Lyon, Service d'hématologie clinique, CHU Lyon sud, 415, chemin du grand revoyet, 69310 Pierre-Bénite, France; Université Claude bernard Lyon 1, 43, boulevard du 11 Novembre 1918, 69622 Villeurbanne cedex, France. Electronic address:

CAR-T cells are modified T cells expressing a chimeric antigen receptor targeting a specific antigen. They have revolutionized the treatment of B cell malignancies (aggressive lymphomas, B-ALL), and this has raised hopes for application in many other pathologies (myeloma, AML, solid tumors, etc.). However, these therapies are associated with novel and specific toxicities (cytokine release syndrome and neurotoxicity). These complications, although mostly managed in a conventional hospitalization unit, can sometimes be life threatening, leading to admission of patients to the intensive care unit. Management relies mainly on anti-IL6R (tocilizumab) and corticosteroids. However, the optimal treatment regimen is still a matter of debate, and the management of the most severe forms is even less well codified. In addition to CRS and ICANS, infections, cytopenia and hypogammaglobulinemia are other frequent complications. This article reviews the mechanisms, risk factors, clinical presentation, and management of these toxicities.
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http://dx.doi.org/10.1016/j.bulcan.2021.05.003DOI Listing
October 2021

Second-Line Tisagenlecleucel or Standard Care in Aggressive B-Cell Lymphoma.

N Engl J Med 2021 Dec 14. Epub 2021 Dec 14.

From the David and Etta Jonas Center for Cellular Therapy, University of Chicago, Chicago (M.R.B.); Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC (M. Dickinson), Fiona Stanley Hospital, Murdoch, WA (D.P.), and the Department of Haematology, St. Vincent's Hospital Sydney, and St. Vincent's Clinical School, University of New South Wales, Sydney (N.H.) - all in Australia; Hospital Universitari Vall d'Hebron and Universitat Autònoma de Barcelona (P. Barba) and the Clinical Hematology Department, Institut Català d'Oncologia-Hospitalet de Llobregat (A. Sureda), Barcelona, and the Hematology Department, Hospital 12 de Octubre, Complutense University, Instituto de Investigación Hospital 12 de Octubre, Centro Nacional de Investigaciones Oncológicas, Madrid (J.M.-L.) - all in Spain; the Department of Biomedical Sciences, Humanitas University and IRCCS Humanitas Research Hospital-Humanitas Cancer Center, Milan (A. Santoro); the Department of Hematology, Oncology, and Cardiovascular Medicine, Kyushu University Hospital, Fukuoka (K.K.), and Tohoku University Hospital, Sendai (H. Harigae) - both in Japan; the Third Medical Department, Paracelsus Medical University, Salzburg Cancer Research Institute-Center for Clinical Cancer and Immunology Trials and Cancer Cluster Salzburg, Salzburg (R.G.), and Internal Medicine I, Bone Marrow Transplant Unit (W.R.), and the Clinical Division of Hematology and Hemostaseology, Department of Medicine I (U.J.), Vienna General Hospital-Medical University of Vienna, Vienna - both in Austria; Assistance Publique-Hôpitaux de Paris, Hemato-Oncology, Hôpital Saint-Louis, Paris (C.T.), Centre Hospitalier Régional Universitaire de Lille, Lille (F.M.), Hospices Civils de Lyon and Université Claude Bernard Lyon 1, Lyon (E.B.), and Centre de Recherche en Cancérologie et Immunologie Nantes-Angers, INSERM, and Nantes Medical University, Nantes (S.L.G.) - all in France; the Department of Hematology, Oncology, and Tumorimmunology, Charité-University Hospital Berlin, Campus Benjamin Franklin, and the Experimental and Clinical Research Center of the Max Delbrück Center for Molecular Medicine and Charité Berlin, Berlin (M.J.), Medizinische Klinik III, LMU Klinikum, Munich (M. Dreyling), and Clinic I for Internal Medicine, University Hospital Cologne, Cologne (P. Borchmann) - all in Germany; Sarah Cannon Research Institute-Tennessee Oncology, Nashville (I.F., P.M.); the Department of Medicine, Queen Mary Hospital, Hong Kong (Y.-L.K.); the Department of Hematology, Amsterdam UMC, University of Amsterdam, Amsterdam (M.J.K.), and Universitair Medisch Centrum Utrecht, Department of Medical Oncology, Utrecht (M.C.M.) - both in the Netherlands; the Department of Oncology, Oslo University Hospital, and K.G. Jebsen Center for B-Cell Malignancies - both in Oslo (H. Holte); the National University Cancer Institute Singapore, Singapore (E.H.L.C.); the Department of Medical Oncology and Hematology, University Hospital, Zurich (A.M.S.M.), and Novartis Pharma, Basel (S.N., E.D., G.A.) - both in Switzerland; the Center for Hematologic Malignancies, Knight Cancer Institute, Oregon Health and Science University, Portland (R.T.M.); the Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Cancer Center, Westwood (J.P.M.); Ohio State University, Columbus (D.B.); Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco (C.A.); the Division of Hematology-Oncology and Blood and Marrow Transplantation and Cellular Therapy Program, Mayo Clinic, Jacksonville, FL (M.K.-D.); Novartis Pharmaceuticals, East Hanover, NJ (R.A., C.C., A.M.); the Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia (S.J.S.); and the Department of Lymphoma and Myeloma, M.D. Anderson Cancer Center, Houston (J.R.W.).

Background: Patient outcomes are poor for aggressive B-cell non-Hodgkin's lymphomas not responding to or progressing within 12 months after first-line therapy. Tisagenlecleucel is an anti-CD19 chimeric antigen receptor T-cell therapy approved for diffuse large B-cell lymphoma after at least two treatment lines.

Methods: We conducted an international phase 3 trial involving patients with aggressive lymphoma that was refractory to or progressing within 12 months after first-line therapy. Patients were randomly assigned to receive tisagenlecleucel with optional bridging therapy (tisagenlecleucel group) or salvage chemotherapy and autologous hematopoietic stem-cell transplantation (HSCT) (standard-care group). The primary end point was event-free survival, defined as the time from randomization to stable or progressive disease at or after the week 12 assessment or death. Crossover to receive tisagenlecleucel was allowed if a defined event occurred at or after the week 12 assessment. Other end points included response and safety.

Results: A total of 322 patients underwent randomization. At baseline, the percentage of patients with high-grade lymphomas was higher in the tisagenlecleucel group than in the standard-care group (24.1% vs. 16.9%), as was the percentage with an International Prognostic Index score (range, 0 to 5, with higher scores indicating a worse prognosis) of 2 or higher (65.4% vs. 57.5%). A total of 95.7% of the patients in the tisagenlecleucel group received tisagenlecleucel; 32.5% of the patients in the standard-care group received autologous HSCT. The median time from leukapheresis to tisagenlecleucel infusion was 52 days. A total of 25.9% of the patients in the tisagenlecleucel group had lymphoma progression at week 6, as compared with 13.8% of those in the standard-care group. The median event-free survival in both groups was 3.0 months (hazard ratio for event or death in the tisagenlecleucel group, 1.07; 95% confidence interval, 0.82 to 1.40; P = 0.61). A response occurred in 46.3% of the patients in the tisagenlecleucel group and in 42.5% in the standard-care group. Ten patients in the tisagenlecleucel group and 13 in the standard-care group died from adverse events.

Conclusions: Tisagenlecleucel was not superior to standard salvage therapy in this trial. Additional studies are needed to assess which patients may obtain the most benefit from each approach. (Funded by Novartis; BELINDA ClinicalTrials.gov number, NCT03570892.).
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http://dx.doi.org/10.1056/NEJMoa2116596DOI Listing
December 2021

Romidepsin Plus CHOP Versus CHOP in Patients With Previously Untreated Peripheral T-Cell Lymphoma: Results of the Ro-CHOP Phase III Study (Conducted by LYSA).

J Clin Oncol 2022 Jan 29;40(3):242-251. Epub 2021 Nov 29.

Service d'Hématologie adultes, Hopital Universitaire Necker Enfants Malades, AP-HP, Paris, France.

Purpose: Romidepsin, a histone deacetylase inhibitor, has demonstrated activity in relapsed or refractory peripheral T-cell lymphoma (PTCL) as a single agent. Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy is widely used as first-line treatment of PTCL; however, it has limited efficacy. Results from a phase Ib and II study showed the feasibility of combining romidepsin with CHOP (Ro-CHOP).

Methods: This study is a randomized phase III study of Ro-CHOP versus CHOP in adult patients with previously untreated PTCL. All patients received CHOP in 3-week cycles for six cycles. Romidepsin, 12 mg/m, was administered intravenously over a 4-hour period on days 1 and 8 of each 3-week cycle for six cycles. The primary end point was progression-free survival (PFS) according to International Working Group 1999 criteria.

Results: Between January 2013 and December 2017, 421 patients were enrolled (Ro-CHOP, n = 211; CHOP, n = 210). The median PFS for Ro-CHOP versus CHOP was 12.0 months (95% CI, 9.0 to 25.8) versus 10.2 months (95% CI, 7.4 to 13.2) with a hazard ratio of 0.81 ( = .096). In the Ro-CHOP versus CHOP arms, the median overall survival was 51.8 versus 42.9 months and the objective response rate was 63% versus 60% with complete response plus unconfirmed complete response rates of 41% versus 37% ( > .1 in all comparisons), respectively. Grade 3 or 4 treatment-emergent adverse events occurring in ≥ 30% of patients in the Ro-CHOP arm included thrombocytopenia (50% 10% in the Ro-CHOP CHOP arms, respectively), neutropenia (49% 33%), anemia (47% 17%), and leukopenia (32% 20%).

Conclusion: The addition of romidepsin to CHOP did not improve PFS, response rates, nor overall survival and increased the frequency for grade ≥ 3 treatment-emergent adverse events. Ro-CHOP does not represent a significant advance in the standard of care for patients with previously untreated PTCL.
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http://dx.doi.org/10.1200/JCO.21.01815DOI Listing
January 2022

Genome-wide CRISPR screen identifies CDK6 as a therapeutic target in Adult T-cell leukemia/lymphoma.

Blood 2021 Nov 24. Epub 2021 Nov 24.

Hokkaido University Faculty of Medicine, Sapporo, Japan.

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive T-cell malignancy with a poor prognosis with current therapy. Here we report genome-wide CRISPR-Cas9 screening of ATLL models, which identified CDK6, CCND2, BATF3, JUNB, STAT3, and IL10RB as genes that are essential for the proliferation and/or survival of ATLL cells. As a single agent, the CDK6 inhibitor palbociclib induced cell cycle arrest and apoptosis in ATLL models with wild type TP53. ATLL models that had inactivated TP53 genetically were relatively resistant to palbociclib owing to compensatory CDK2 activity, and this resistance could be reversed by APR-246, a small molecule activator of mutant TP53. The CRISPR-Cas9 screen further highlighted the dependence of ATLL cells on mTORC1 signaling. Treatment of ATLL cells with palbociclib in combination with mTORC1 inhibitors was synergistically toxic irrespective of the TP53 status. This work defines CDK6 as a novel therapeutic target for ATLL and supports the clinical evaluation of palbociclib in combination with mTORC1 inhibitors in this recalcitrant malignancy.
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http://dx.doi.org/10.1182/blood.2021012734DOI Listing
November 2021

Rituximab in combination with adapted-dose of ifosfamide and etoposide as salvage treatment in elderly refractory/relapsed diffuse large B-cell lymphoma patients non-candidate for high dose therapy: a retrospective study.

Leuk Lymphoma 2021 Oct 31:1-9. Epub 2021 Oct 31.

Department of Hematology, Hôpital Lyon-Sud, Hospices Civils de Lyon, Université Claude Bernard Lyon 1, Lyon, France.

We retrospectively reviewed for 72 relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) patients ineligible for autologous stem-cell transplantation (ASCT) treated between 2004 and 2017, efficacy and safety profile of rituximab (375 mg/m) in combination with etoposide (300 mg/m) and ifosfamide (1500 mg/m) at 2, 3, or 4-week intervals. Median age was 79 years (range, 64-92). The median number of previous line was 1 (range 1-8). Patients received a median of six cycles (1-12). Fourteen patients (19%) presented partial and 14 complete responses (19%). Among the 369 cycles, nine patients developed febrile neutropenia (13%), 14 a grade 3-4 neutropenia (19%), 7 a grade 3-4 thrombocytopenia (10%) without grade 3-4 non-hematological toxicity. With a median follow up of 7.8 months, the median progression-free survival, overall survival, and duration of response were 4.4 months, 9.4 months, and 12 months, respectively. This regimen represents a therapeutic option in R/R DLBCL patients ineligible to ASCT.
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http://dx.doi.org/10.1080/10428194.2021.1998483DOI Listing
October 2021

New Insights into the Biology and Diagnosis of Splenic Marginal Zone Lymphomas.

Curr Oncol 2021 09 6;28(5):3430-3447. Epub 2021 Sep 6.

Institut de pathologie multi-sites, Hôpital Lyon Sud, Hospices Civils de Lyon, 69310 Pierre Bénite, France.

Splenic marginal zone lymphoma (SMZL) is a small B-cell lymphoma, which has been recognized as a distinct pathological entity since the WHO 2008 classification. It classically presents an indolent evolution, but a third of patients progress rapidly and require aggressive treatments, such as immuno-chemotherapy or splenectomy, with all associated side effects. In recent years, advances in the comprehension of SMZL physiopathology have multiplied, thanks to the arrival of new devices in the panel of available molecular biology techniques, allowing the discovery of new molecular findings. In the era of targeted therapies, an update of current knowledge is needed to guide future researches, such as those on epigenetic modifications or the microenvironment of these lymphomas.
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http://dx.doi.org/10.3390/curroncol28050297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8482189PMC
September 2021

Clinicopathological features and survival in EBV-positive diffuse large B-cell lymphoma not otherwise specified.

Blood Adv 2021 08;5(16):3227-3239

Département d'Innovation thérapeutique, Institut Gustave Roussy, Villejuif, France.

In this retrospective study, we report 70 cases of Epstein-Barr virus (EBV)+ diffuse large B-cell lymphoma not otherwise specified (DLBCL-NOS) among 1696 DLBCL-NOS cases diagnosed between 2006 and 2019 (prevalence of 4.1%). At diagnosis, median age was 68.5 years; 79% of the cases presented with an advanced-stage disease (III-IV), 48% with extranodal lesions, and 14% with an hemophagocytic lymphohistiocytosis (HLH) (8 at diagnosis and 1 on therapy). A total of 46 cases presented a polymorphic pattern, and 21 were monomorphic. All had a non-germinal center B phenotype, with the majority of tumor cells expressing CD30 and programmed death ligand 1 (98% and 95%, respectively). Type II and III EBV latency was seen in 88% and 12% of the cases, respectively. Patients were treated with immunochemotherapy (59%) or chemotherapy (22%), and 19% received palliative care due to advanced age and altered performance status. After a median follow-up of 48 months, progression-free survival (PFS) and overall survival (OS) at 5 years were 52.7% and 54.8%, respectively. Older age (>50 years) and HLH were associated with shorter PFS and OS in multivariate analysis (PFS: hazard ratio [HR], 14.01; 95% confidence interval [CI], 2.34-83.97; and HR, 5.78; 95% CI, 2.35-14.23; OS: HR, 12.41; 95% CI, 1.65-93.53; and HR, 6.09; 95% CI, 2.42-15.30, respectively). Finally, using a control cohort of 425 EBV- DLBCL-NOS, EBV positivity was associated with a shorter OS outcome within patients >50 years (5-year OS, 53% [95% CI, 38.2-74] vs 60.8% [95% CI, 55.4-69.3], P = .038), but not in younger patients.
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http://dx.doi.org/10.1182/bloodadvances.2021004515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405194PMC
August 2021

Autologous EBV-specific T cell treatment results in sustained responses in patients with advanced extranodal NK/T lymphoma: results of a multicenter study.

Ann Hematol 2021 Oct 24;100(10):2529-2539. Epub 2021 Jul 24.

Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital, Houston, TX, USA.

We conducted a phase II clinical trial to develop an autologous EBV-specific T cell product (baltaleucel T) for advanced, relapsed ENKTL. Among 47 patients who provided whole blood starting material for manufacturing the product, 15 patients received a median of 4 doses of baltaleucel T. Thirty-two (68%) patients did not receive baltaleucel-T due to manufacturing failure, rapid disease progression, and death. Of the 15 patients, 10 patients had measurable disease at baseline (salvage cohort), and 5 patients had no disease at baseline assessment (adjuvant cohort). In the 15 patients, the median follow-up duration was 10.2 months (range 2.0-23.5 months), median progression-free survival (PFS) was 3.9 months, and the median overall survival (OS) was not reached. Patients in the salvage cohort achieved a 30% complete response (CR) and a 50% overall response rate (ORR). In the adjuvant cohort, disease progression was reported in three patients and two patients did not relapse during study follow-up. When we compared survival outcomes of seven responders and eight non-responders, the PFS (P = 0.001) and OS (P = 0.014) of responders proved statistically superior to that of non-responders. Baltaleucel-T was well tolerated. We have performed a phase II clinical trial of autologous EBV-specific T cell treatment (baltaleucel-T) in R/R ENKTL. Autologous EBV-specific T cells were well tolerated and demonstrated single-agent activity in R/R ENTKL.
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http://dx.doi.org/10.1007/s00277-021-04558-0DOI Listing
October 2021

Plasticity of Mature B Cells Between Follicular and Classic Hodgkin Lymphomas: A Series of 22 Cases Expanding the Spectrum of Transdifferentiation.

Am J Surg Pathol 2022 Jan;46(1):58-70

Hematology Department, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre Bénite.

Follicular lymphoma and classic Hodgkin lymphoma can be associated in composite and/or sequential lymphomas. Common IGH and BCL2 rearrangements have already been identified between both contingents of these entities, but mutation profiles have not yet been investigated. The main objective of this study was to analyze the transdifferentiation process that may occur between Hodgkin and follicular contingents in sequential and composite lymphomas to better characterize these entities. From 2004 to 2020, a retrospective multicentric study was performed, including 9 composite and 13 sequential lymphomas. Clinical data were retrospectively collected. Fluorescent in situ hybridization of BCL2 and BCL6 rearrangements, polymerase chain reaction of IGH and IGK rearrangements, next-generation sequencing of IGK rearrangement, and targeted next-generation sequencing (TNGS) on a panel of genes frequently mutated in lymphomas were performed on each contingent of composite and sequential lymphomas. For TNGS, each contingent was isolated by laser capture microdissection. Clinical presentation and evolution were more aggressive in sequential than composite lymphomas. By fluorescent in situ hybridization, common rearrangements of BCL6 and BCL2 were identified between both contingents. Similarly, a common clonal relationship was established by evaluating IGH and IGK rearrangement by polymerase chain reaction or next-generation sequencing. By TNGS, the same pathogenic variants were identified in both contingents in the following genes: CREBBP, KMT2D, BCL2, EP300, SF3B1, SOCS1, ARID1A, and BCOR. Specific pathogenic variants for each contingent were also identified: XPO1 for Hodgkin lymphoma contingent and FOXO1, TNFRSF14 for follicular lymphoma contingent. This study reinforces the hypothesis of a transdifferentiation process between Hodgkin and follicular contingent of sequential/composite lymphomas.
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http://dx.doi.org/10.1097/PAS.0000000000001780DOI Listing
January 2022

CAR-HEMATOTOX: a model for CAR T-cell-related hematologic toxicity in relapsed/refractory large B-cell lymphoma.

Blood 2021 12;138(24):2499-2513

Department of Medicine III, University Hospital, Ludwig Maximilian University (LMU) Munich, Munich, Germany.

Hematotoxicity represents a frequent chimeric antigen receptor (CAR) T-cell-related adverse event and remains poorly understood. In this multicenter analysis, we studied patterns of hematopoietic reconstitution and evaluated potential predictive markers in 258 patients receiving axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) for relapsed/refractory large B-cell lymphoma. We observed profound (absolute neutrophil count [ANC] <100 cells per µL) neutropenia in 72% of patients and prolonged (21 days or longer) neutropenia in 64% of patients. The median duration of severe neutropenia (ANC < 500 cells per µL) was 9 days. We aimed to identify predictive biomarkers of hematotoxicity using the duration of severe neutropenia until day +60 as the primary end point. In the training cohort (n = 58), we observed a significant correlation with baseline thrombocytopenia (r = -0.43; P = .001) and hyperferritinemia (r = 0.54; P < .0001) on univariate and multivariate analysis. Incidence and severity of cytokine-release syndrome, immune effector cell-associated neurotoxicity syndrome, and peak cytokine levels were not associated with the primary end point. We created the CAR-HEMATOTOX model, which included markers associated with hematopoietic reserve (eg, platelet count, hemoglobin, and ANC) and baseline inflammation (eg, C-reactive protein and ferritin). This model was validated in independent cohorts, one from Europe (n = 91) and one from the United States (n = 109) and discriminated patients with severe neutropenia ≥14 days to <14 days (pooled validation: area under the curve, 0.89; sensitivity, 89%; specificity, 68%). A high CAR-HEMATOTOX score resulted in a longer duration of neutropenia (12 vs 5.5 days; P < .001) and a higher incidence of severe thrombocytopenia (87% vs 34%; P < .001) and anemia (96% vs 40%; P < .001). The score implicates bone marrow reserve and inflammation prior to CAR T-cell therapy as key features associated with delayed cytopenia and will be useful for risk-adapted management of hematotoxicity.
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http://dx.doi.org/10.1182/blood.2020010543DOI Listing
December 2021

Adverse outcome in follicular lymphoma is associated with MYC rearrangements but not MYC extra copies.

Br J Haematol 2021 07 21;194(2):382-392. Epub 2021 Jun 21.

Department of Hematology, Grenoble-Alpes University Hospital, Grenoble, France.

Follicular lymphomas (FLs) with MYC rearrangements (MYC-R) and extra copies of MYC (MYC-EC) are rare and the prognosis impact is uncertain. We conducted a retrospective study including 321 FL patients, among whom 259 (81%) had no 8q24 alterations and 62 (19%) were assigned to 8qAlt. Forty-five cases were classified as MYC-EC and six as MYC-R. MYC-R patients were significantly older (P = 0·008), had higher follicular lymphoma international prognostic index (FLIPI) stage (P = 0·05) and β2-microglobulin (β2m; P = 0·05). Among patients treated with immuno-chemotherapy, four presented a MYC-R and 25 a MYC-EC. Univariate analysis showed the absence of significant difference between MYC-EC and normal MYC (MYC-NL) regarding progression-free survival (PFS; HR1·3; 95% CI [0·4-1·6]) and specific overall survival (SOS; HR 1·6; 95% CI [0·4-5·7]). Those results were compared to data from the PRIMA trial. This confirmed that MYC-EC had no impact on PFS (P = 0·86) or SOS (P = 0·9). Conversely, MYC-R was associated with a trend to inferior outcome regarding PFS (HR : 6·1; 95% CI [2·2-17·1]; P = 0·00026), lymphoma-related death (SOS; HR 13·6; 95% CI [2·9-65]; P = 0·00014) and risk of transformation (transformation-free survival (TFS); HR 82·7; 95% CI [14·8-463·4]; P < 0·0001). In conclusion, MYC-EC has no prognostic impact in FL but MYC-R FL tended to be associated with an increased risk of transformation and poorer outcome.
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http://dx.doi.org/10.1111/bjh.17550DOI Listing
July 2021

Droplet digital PCR allows vector copy number assessment and monitoring of experimental CAR T cells in murine xenograft models or approved CD19 CAR T cell-treated patients.

J Transl Med 2021 06 21;19(1):265. Epub 2021 Jun 21.

INSERM UMR1098, Right, EFSBFC, UFC, Laboratoire de Thérapeutique Immuno-Moléculaire Et Cellulaire Des Cancers, 8 rue du Dr Jean François Xavier Girod, 25020, Besançon, France.

Background: Genetically engineered chimeric antigen receptor (CAR) T lymphocytes are promising therapeutic tools for cancer. Four CAR T cell drugs, including tisagenlecleucel (tisa-cel) and axicabtagene-ciloleucel (axi-cel), all targeting CD19, are currently approved for treating B cell malignancies. Flow cytometry (FC) remains the standard for monitoring CAR T cells using a recombinant biotinylated target protein. Nevertheless, there is a need for additional tools, and the challenge is to develop an easy, relevant, highly sensitive, reproducible, and inexpensive detection method. Molecular tools can meet this need to specifically monitor long-term persistent CAR T cells.

Methods: Based on 2 experimental CAR T cell constructs, IL-1RAP and CS1, we designed 2 quantitative digital droplet (ddPCR) PCR assays. By targeting the 4.1BB/CD3z (28BBz) or 28/CD3z (28z) junction area, we demonstrated that PCR assays can be applied to approved CD19 CAR T drugs. Both 28z and 28BBz ddPCR assays allow determination of the average vector copy number (VCN) per cell. We confirmed that the VCN is dependent on the multiplicity of infection and verified that the VCN of our experimental or GMP-like IL-1RAP CAR T cells met the requirement (< 5 VCN/cell) for delivery to the clinical department, similar to approved axi-cel or tisa-cel drugs.

Results: 28BBz and 28z ddPCR assays applied to 2 tumoral (acute myeloid leukemia (AML) or multiple myeloma (MM) xenograft humanized NSG mouse models allowed us to quantify the early expansion (up to day 30) of CAR T cells after injection. Interestingly, following initial expansion, when circulating CAR T cells were challenged with the tumor, we noted a second expansion phase. Investigation of the bone marrow, spleen and lung showed that CAR T cells disseminated more within these tissues in mice previously injected with leukemic cell lines. Finally, circulating CAR T cell ddPCR monitoring of R/R acute lymphoid leukemia or diffuse large B cell lymphoma (n = 10 for tisa-cel and n = 7 for axi-cel) patients treated with both approved CAR T cells allowed detection of early expansion, which was highly correlated with FC, as well as long-term persistence (up to 450 days), while FC failed to detect these events.

Conclusion: Overall, we designed and validated 2 ddPCR assays allowing routine or preclinical monitoring of early- and long-term circulating approved or experimental CAR T cells, including our own IL-1RAP CAR T cells, which will be evaluated in an upcoming phase I clinical trial.
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http://dx.doi.org/10.1186/s12967-021-02925-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215786PMC
June 2021

Prognostic Impact of 18F-FDG PET/CT in Patients With Aggressive B-Cell Lymphoma Treated With Anti-CD19 Chimeric Antigen Receptor T Cells.

Clin Nucl Med 2021 Aug;46(8):627-634

Departments of Nuclear Medicine.

Purpose Of The Report: We aimed to evaluate the role of 18F-FDG PET/CT in predicting patient outcome following chimeric antigen receptor T (CAR T) cells infusion in aggressive B-cell lymphoma.

Methods: 18F-FDG PET/CT data before leukapheresis, before CAR T-cell infusion and 1 month (M1) after CAR T-cell infusion, from 72 patients were retrospectively analyzed. SUVmax, total lesion glycolysis (TLG), metabolic tumor volume (MTV), and parameters describing tumor kinetics were calculated for each 18F-FDG PET/CT performed. The aim was to evaluate the prognostic value of 18F-FDG PET/CT metabolic parameters for predicting progression-free survival (PFS) and overall survival (OS) following CAR T-cell therapy.

Results: Regarding PFS, ∆MTVpre-CAR and ∆TLGpre-CAR were found to be more discriminating compared with metabolic parameters at preinfusion. Median PFS in patients with a ∆MTVpre-CAR of less than 300% was 6.8 months (95% confidence interval [CI], 2.8 months to not reached) compared with 2.8 months (95% CI, 0.9-3.0 months) for those with a value of 300% or greater (P = 0.004). Likewise, median PFS in patients with ∆TLGpre-CAR of less than 420% was 6.8 months (95% CI, 2.8 months to not reached) compared with 2.7 months (95% CI, 1.3-3.0 months) for those with a value of 420% or greater (P = 0.0148). Regarding OS, metabolic parameters at M1 were strongly associated with subsequent outcome. SUVmax at M1 with a cutoff value of 14 was the most predictive parameter in multivariate analysis, outweighing other clinicobiological variables (P < 0.0001).

Conclusions: Disease metabolic volume kinetics before infusion of CAR T cells seems to be superior to initial tumor bulk itself for predicting PFS. For OS, SUVmax at M1 might adequately segregate patients with different prognosis.
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http://dx.doi.org/10.1097/RLU.0000000000003756DOI Listing
August 2021

HMGA1 induces EZH2 overexpression in human B-cell lymphomas.

Am J Cancer Res 2021 15;11(5):2174-2187. Epub 2021 May 15.

Institute of Endocrinology and Experimental Oncology-CNR c/o Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II" Naples, Italy.

EZH2 is an enzymatic subunit of PRC2, an epigenetic regulator that triggers the methylation of the histone H3 lysine 27 silencing the transcription of several genes. EZH2 has a critical role in cancer progression, since its overexpression has been associated with increased cancer cell invasiveness, drug resistance and poor patient survival. However, the mechanisms accounting for EZH2 overexpression in cancer remain still unclear. Intriguingly, also HMGA protein overexpression is a feature of many human malignancies and correlates with the presence of metastases and a poor outcome. The HMGA proteins, including HMGA1 and HMGA2, belong to the architectural transcription factors that play a key role in the organization of chromatin structure. Here, we report a statistically significant correlation between HMGA1 and EZH2 expression in human lymphomas. We demonstrate that HMGA1 is able to bind promoter and induce its activity. Consistently, silencing of expression results in the downregulation of the levels leading to a decreased proliferation and migration rate of human lymphoma cell lines. Therefore, these data identify HMGA1 as an activator, suggesting a novel molecular mechanism contributing to EZH2 overexpression in human malignancies and a synergism of these proteins in cancer progression.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167683PMC
May 2021

Chronic T cell receptor stimulation unmasks NK receptor signaling in peripheral T cell lymphomas via epigenetic reprogramming.

J Clin Invest 2021 07;131(13)

INSERM U1111, CNRS UMR 5308, Centre International de Recherche en Infectiologie, Lyon, France.

Peripheral T cell lymphomas (PTCLs) represent a significant unmet medical need with dismal clinical outcomes. The T cell receptor (TCR) is emerging as a key driver of T lymphocyte transformation. However, the role of chronic TCR activation in lymphomagenesis and in lymphoma cell survival is still poorly understood. Using a mouse model, we report that chronic TCR stimulation drove T cell lymphomagenesis, whereas TCR signaling did not contribute to PTCL survival. The combination of kinome, transcriptome, and epigenome analyses of mouse PTCLs revealed a NK cell-like reprogramming of PTCL cells with expression of NK receptors (NKRs) and downstream signaling molecules such as Tyrobp and SYK. Activating NKRs were functional in PTCLs and dependent on SYK activity. In vivo blockade of NKR signaling prolonged mouse survival, demonstrating the addiction of PTCLs to NKRs and downstream SYK/mTOR activity for their survival. We studied a large collection of human primary samples and identified several PTCLs recapitulating the phenotype described in this model by their expression of SYK and the NKR, suggesting a similar mechanism of lymphomagenesis and establishing a rationale for clinical studies targeting such molecules.
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http://dx.doi.org/10.1172/JCI139675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245185PMC
July 2021

Phase III Clinical Trials in First-Line Follicular Lymphoma: A Review of Their Design and Interpretation.

Adv Ther 2021 07 26;38(7):3489-3505. Epub 2021 May 26.

University College London, London, UK.

Follicular lymphoma (FL) is one of the most common subtypes of non-Hodgkin lymphoma worldwide. Improved survival outcomes with rituximab-based therapy in clinical trials led to the establishment of rituximab-based immunochemotherapy as standard of care for first-line (1L) treatment of FL. In the GALLIUM trial, obinutuzumab-based immunochemotherapy demonstrated improved progression-free survival (PFS), prolonged time-to-next antilymphoma treatment (TTNT) and comparable overall survival (OS) compared with rituximab-based immunochemotherapy as 1L treatment for FL. Using GALLIUM as an example, this article aims to explain how improved outcomes in 1L treatment of FL have changed the landscape for the design and interpretation of future trials. As approved therapies for 1L FL already achieve good responses, it is becoming more difficult to design trials that demonstrate further treatment benefits with the currently accepted primary endpoints. New endpoints are needed to reflect the long remission times, low relapse rates, and impact of subsequent therapies in FL. PFS is used as a primary efficacy endpoint in registrational clinical trials for indolent malignancies like FL, where improvement in OS is not always observed due to the large number of patients and long study duration required to demonstrate a clear survival benefit. However, there are limitations to using PFS as the primary endpoint. Other potential endpoints, including TTNT, progression of disease within 2 years, response rate, and minimal residual disease status are explored.
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http://dx.doi.org/10.1007/s12325-021-01738-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280048PMC
July 2021

Outcome after hematopoietic stem cell transplantation in patients with extranodal natural killer/T-Cell lymphoma, nasal type: A French study from the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC).

Am J Hematol 2021 07 3;96(7):834-845. Epub 2021 May 3.

Department of Hematology, Inserm U1163, IMAGINE Institute, Paris University, Necker Hospital, Paris, France.

We evaluated the outcome of 65 French patients with Extranodal NK/T-cell lymphoma, nasal type (ENKTL) undergoing hematopoietic stem cell transplantation (HSCT) (19 allogeneic and 46 autologous). Fifty-four patients (83%), most of which receiving L-asparaginase (L-aspa) containing regimens (81%), achieved complete or partial response at time of HCST. After a median follow-up of 79.9 months, 4-years progression-free survival (PFS) and overall survival (OS) were similar in both autologous and allogeneic groups (PFS: 34% vs. 26%, p = .12 and OS: 52% vs. 53%, p = .74). Response status at HSCT was the major independent prognostic factor on survival (OS: HR: 4.013 [1.137; 14.16], p = .031 and PFS: HR: 5.231 [1.625; 16.838], p = .006). As compared to control patients receiving chemotherapy and/or radiotherapy containing regimens only, upfront HSCT did not improve the outcome of responder patients, including those treated by L-aspa. However, it tends to provide survival benefit for relapsed patients with initial high-risk clinical features who achieved second remission. Whereas the place of HSCT in upfront therapy has still to be clarified, these data confirm that HSCT should be considered for consolidation in selected patients with relapsed ENKTL. Based on a large non Asian ENKTL cohort since the L-aspa era, this study provides some insight into the survival patterns of ENKTL patients with HSCT in the Western hemisphere and may give future direction for the next clinical trial design.
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http://dx.doi.org/10.1002/ajh.26200DOI Listing
July 2021

Autologous stem cell transplantation for post-transplant lymphoproliferative disorders after solid organ transplantation: a retrospective analysis from the Lymphoma Working Party of the EBMT.

Bone Marrow Transplant 2021 09 16;56(9):2118-2124. Epub 2021 Apr 16.

Lymphoma Working Party EBMT, Paris, France.

Published data describing the efficacy and safety of autologous stem-cell transplantation (autoSCT) in post-transplant lymphoproliferative disorders (PTLD) is limited to case reports. This is a retrospective analysis of 21 patients reported to the EBMT registry who received an autoSCT for PTLD post solid organ transplant (SOT). Median age at autoSCT was 47 (range: 22-71) years. The commonest SOTs were kidney (48%) and liver (24%). Commonest histologies included DLBCL-type PTLD (14/21) and plasmacytoma-like PTLD (3/21). Patients received a median of two lines of therapy (range: 1-4) pre-autoSCT. ECOG performance status pre-autoSCT was 0 in 14% and 1 in 86%. Remission status pre-autoSCT was CR 47% and PR 38%. BEAM conditioning was used in 57% and high-dose melphalan in 10%. The median follow-up post-autoSCT was 64 months for alive patients. 3-year PFS was 62% [95% confidence interval (CI) 44-87%] and 3-year OS was 61% [95% CI:43-86]. There were 12 deaths, including four related to autoSCT. 100-day non-relapse-mortality (NRM) was 14% and 1-year NRM was 24%. This study suggests that autoSCT, although feasible and with potential therapeutic activity, is associated with a high NRM, primarily driven by infectious toxicity. A multi-disciplinary approach, expert microbiological input and stringent patient selection are required to optimise outcomes.
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http://dx.doi.org/10.1038/s41409-021-01270-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410594PMC
September 2021

Real-life targeted next-generation sequencing for lymphoma diagnosis over 1 year from the French Lymphoma Network.

Br J Haematol 2021 06 25;193(6):1110-1122. Epub 2021 Mar 25.

Pathology Department, Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France.

As the impact of targeted next-generation sequencing (TNGS) on daily diagnosis has not been evaluated, we performed TNGS (46 genes) on lymphomas of unclear subtype following expert haematopathological review. The potential impact on patient care and modifications of final diagnosis were divided into major and minor changes according to the European Society of Medical Oncology (ESMO) guidelines. Among 229 patients [19 primary central nervous system lymphomas (PCNSL), 48 large B-cell lymphomas (LBCLs), 89 small BCLs (SBCLs), seven Hodgkin lymphomas (HL), 66 T-cell lymphomas], the overall concordance rate of histological and TNGS diagnosis was 89·5%. TNGS confirmed the histological diagnosis in 144 cases (62·9%), changed the diagnosis in 24 cases (10·5%) and did not help to clarify diagnosis in 61 cases (26·7%). Modifications to the final diagnosis had a clinical impact on patient care in 8·3% of cases. Diagnostic modifications occurred in all types of lymphoma except in PCNSL and HL; the modification rate was 14·6% in SBCL and 12·5% in LBCL. While comparing informative and uninformative cases, no differences were found in terms of DNA amplification, quality or depth of sequencing and biopsy type. The present study highlights that TNGS may directly contribute to a more accurate diagnosis in difficult-to-diagnose lymphomas, thus improving the clinical management in routine practice.
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http://dx.doi.org/10.1111/bjh.17395DOI Listing
June 2021

Characteristics of T- and NK-cell Lymphomas After Renal Transplantation: A French National Multicentric Cohort Study.

Transplantation 2021 08;105(8):1858-1868

Department of Pathology, INSERM U955, APHP Hôpital Henri Mondor, Université Paris-Est, Créteil, France.

Background: Posttransplant lymphoproliferative disorders (PTLDs) encompass a spectrum of heterogeneous entities. Because the vast majority of cases PTLD arise from B cells, available data on PTLD of T or NK phenotype (T/NK-cell PTLD) are scarce, which limits the quality of the management of these patients.

Methods: All adult cases of PTLD diagnosed in France were prospectively recorded in the national registry between 1998 and 2007. Crosschecking the registry data with 2 other independent national databases identified 58 cases of T/NK-cell PTLD. This cohort was then compared with (i) the 395 cases of B-cell PTLD from the registry, and of (ii) a cohort of 148 T/NK-cell lymphomas diagnosed in nontransplanted patients.

Results: T/NK-cell PTLD occurred significantly later after transplantation and had a worse overall survival than B-cell PTLD. Two subtypes of T/NK-cell PTLD were distinguished: (i) cutaneous (28%) and (ii) systemic (72%), the latter being associated with a worse prognosis. Compared with T/NK-cell lymphomas of nontransplanted patients, overall survival of systemic T/NK-cell PTLD was worse (hazard ratio: 2.64 [1.76-3.94]; P < 0.00001).

Conclusions: This difference, which persisted after adjustment on tumoral mass, histological subtype, and extension of the disease at diagnosis could be explained by the fact that transplanted patients were less intensively treated and responded less to chemotherapy.
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http://dx.doi.org/10.1097/TP.0000000000003568DOI Listing
August 2021

Integrative analysis of a phase 2 trial combining lenalidomide with CHOP in angioimmunoblastic T-cell lymphoma.

Blood Adv 2021 01;5(2):539-548

Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Henri Mondor, Unité Hémopathies Lymphoïdes, Créteil, France.

Angioimmunoblastic T-cell lymphoma (AITL) is a frequent T-cell lymphoma in the elderly population that has a poor prognosis when treated with cyclophosphamide, doxorubicin, vincristine, and prednisone  (CHOP) therapy. Lenalidomide, which has been safely combined with CHOP to treat B-cell lymphoma, has shown efficacy as a single agent in AITL treatment. We performed a multicentric phase 2 trial combining 25 mg lenalidomide daily for 14 days per cycle with 8 cycles of CHOP21 in previously untreated AITL patients aged 60 to 80 years. The primary objective was the complete metabolic response (CMR) rate at the end of treatment. Seventy-eight of the 80 patients enrolled were included in the efficacy and safety analysis. CMR was achieved in 32 (41%; 95% confidence interval [CI], 30%-52.7%) patients, which was below the prespecified CMR rate of 55% defined as success in the study. The 2-year progression-free survival (PFS) was 42.1% (95% CI, 30.9%-52.8%), and the 2-year overall survival was 59.2% (95% CI, 47.3%-69.3%). The most common toxicities were hematologic and led to treatment discontinuation in 15% of patients. This large prospective and uniform series of AITL treatment data was used to perform an integrative analysis of clinical, pathologic, biologic, and molecular data. TET2, RHOA, DNMT3A, and IDH2 mutations were present in 78%, 54%, 32%, and 22% of patients, respectively. IDH2 mutations were associated with distinct pathologic and clinical features and DNMT3A was associated with shorter PFS. In conclusion, the combination of lenalidomide and CHOP did not improve the CMR in AITL patients. This trial clarified the clinical impact of recurrent mutations in AITL. This trial was registered at www.clincialtrials.gov as #NCT01553786.
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http://dx.doi.org/10.1182/bloodadvances.2020003081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839364PMC
January 2021

[Eligibility of patients for CAR T-cell: Expert opinion-based collaborative work by the SFGM-TC].

Bull Cancer 2021 Jul-Aug;108(7-8):725-729. Epub 2021 Jan 7.

CHU de Lille, université Lille, Inserm U1286, Infinite, Lille, France.

The chimeric antigen receptor T-cells are a new class of anticancer treatment consisting in genetically modifying autologous or allogenic T-cells to make express a CAR directed against a membrane tumor antigen. In Europe, tisagenlecleucel (Kymriah) has a marketing authorization for the treatment of relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia in children and young adults and of R/R diffuse large B-cell lymphoma (DLBCL). The marketing authorization for axicabtagene ciloleucel (Yescarta) is the treatment of DLBCL and primary R/R mediastinal B-cell lymphoma. The two products are autologous T-cells directed against CD19. This collaborative work, part of a series of expert opinion-based work, aims to give practical advice to help centers in selection of patients for commercially available CAR T-cell treatment.
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http://dx.doi.org/10.1016/j.bulcan.2020.10.017DOI Listing
July 2021

Description of neurotoxicity in a series of patients treated with CAR T-cell therapy.

Sci Rep 2020 11 4;10(1):18997. Epub 2020 Nov 4.

Department of Neurology, Hôpital Saint-Louis, Assistance Publique - Hôpitaux de Paris, 1 Avenue Claude Vellefaux, 75010, Paris, France.

Chimeric antigen receptor-modified T (CAR T) cell therapy is a highly promising treatment for haematological malignancies but is frequently associated with cytokine release syndrome and neurotoxicity. Between July 2018 and July 2019, all patients treated with CD19-targeted CAR T-cell therapy for relapsing lymphoma were followed-up longitudinally to describe neurological symptoms and their evolution over time. Four different French centres participated and 84 patients (median age 59 years, 31% females) were included. Neurotoxicity, defined as the presence of at least one neurological symptom appearing after treatment infusion, was reported in 43% of the patients. The median time to onset was 7 days after infusion with a median duration of 6 days. More than half of the patients (64%) had grade 1-2 severity and 34% had grade 3-4. CRS was observed in 80% of all patients. The most frequent neurological symptoms were cognitive signs, being severe in 36%, and were equally distributed between language disorders and cognitive disorders without language impairment. Non-pyramidal motor disorders, severe in 11%, were reported in 42% of the patients. Elevation of C-reactive protein (CRP) within 4 days after treatment was significantly correlated with the occurrence of grade 3-4 neurotoxicity. Although sometimes severe, neurotoxicity was almost always reversible. The efficacy of steroids and antiepileptic drugs remains unproven in the management of neurotoxicity. Neurotoxicity associated with CAR T-cell therapies occurs in more than 40% of patients. The clinical pattern is heterogeneous but cognitive disorders (not limited to language disorders) and, to a minor degree, non-pyramidal motor disorders, appeared as a signature of severe neurotoxicity.
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http://dx.doi.org/10.1038/s41598-020-76055-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642402PMC
November 2020

Controversies in the Treatment of Peripheral T-cell Lymphoma.

Hemasphere 2020 Oct 1;4(5):e461. Epub 2020 Sep 1.

Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Bologna, Italy.

Peripheral T-cell lymphomas are a heterogeneous group of rare diseases with an aggressive behavior and dismal prognosis. Their classification is complex and still evolving, and several biomolecular markers now help refine the prognosis of specific disease entities, although still have limited impact in tailoring the treatment. First-line treatment strategies can cure only a minority of patients and relapsed-refractory disease still represents the major cause of failure. Frontline autologous transplantation may have an impact in the consolidation of response; however, its role is still questioned as far as complete responses obtained after induction chemotherapy are concerned. Newer drugs are now being evaluated in clinical trials, but effective salvage strategies for those who experience treatment failures are lacking. Here we review and discuss the most controversial aspects of diagnosis and treatment of peripheral T-cell lymphomas.
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http://dx.doi.org/10.1097/HS9.0000000000000461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469987PMC
October 2020
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