Publications by authors named "Rene-Olivier Casasnovas"

56 Publications

Comparison of the Effectiveness and Safety of the Oral Selective Inhibitor of Nuclear Export, Selinexor, in Diffuse Large B Cell Lymphoma Subtypes.

Clin Lymphoma Myeloma Leuk 2021 Jul 22. Epub 2021 Jul 22.

Institute Jules Bordet, Brussels, Belgium.

Background: The SADAL study evaluated oral selinexor in patients with relapsed and/or refractory diffuse large B-cell lymphoma (DLBCL) after at least 2 prior lines of systemic therapy. In this post-hoc analysis, we analyzed the outcomes of the SADAL study by DLBCL subtype to determine the effects of DLBCL subtypes on efficacy and tolerability of selinexor.

Patients And Methods: Data from 134 patients in SADAL were analyzed by DLBCL subtypes for overall response rate (ORR), overall survival (OS), duration of treatment response, progression-free survival, and adverse events rate.

Results: ORR in the entire cohort was 29.1%, and similar in patients with germinal center (GCB) versus non-GCB DLBCL (31.7% vs. 24.2%, P = 0.45); transformed DLBCL showed a trend towards higher ORR than de novo DLBCL: 38.7% vs. 26.2% (P = 0.23). Despite similar prior treatment regimens and baseline characteristics, patients with DLBCL and normal C-MYC/BCL-2 protein expression levels had a significantly higher ORR (46.2% vs.14.8%, P = 0.012) and significantly longer OS (medians 13.7 vs. 5.1 months, hazard ratio 0.43 [95% CI, 0.23-0.77], P = 0.004) as compared with those whose DLBCL had C-MYC and BCL-2 overexpression. Among patients who had normal expression levels of either C-MYC or BCL-2 and baseline hemoglobin levels ≥ 10g/dL, ORR was 51.5% (n = 47), with median OS of 15.5 months and median PFS of 4.6 months. Similar rates of adverse events were noted in all subgroups.

Conclusions: Overall, single agent oral selinexor showed strong responses in patients with limited treatment alternatives regardless of germinal center B-cell type or disease origin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clml.2021.07.017DOI Listing
July 2021

PD-1 inhibitors in patients with Hodgkin lymphoma.

Eur J Cancer 2021 Aug 26. Epub 2021 Aug 26.

Department of Hematology, CHU Dijon-Bourgogne, Hôpital François Mitterrand, Dijon, France; INSERM, 1231 Unit, UFR Bourgogne Franche-Comté, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2021.06.059DOI Listing
August 2021

Enhanced detection of minimal residual disease by targeted sequencing of phased variants in circulating tumor DNA.

Nat Biotechnol 2021 Jul 22. Epub 2021 Jul 22.

Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, USA.

Circulating tumor-derived DNA (ctDNA) is an emerging biomarker for many cancers, but the limited sensitivity of current detection methods reduces its utility for diagnosing minimal residual disease. Here we describe phased variant enrichment and detection sequencing (PhasED-seq), a method that uses multiple somatic mutations in individual DNA fragments to improve the sensitivity of ctDNA detection. Leveraging whole-genome sequences from 2,538 tumors, we identify phased variants and their associations with mutational signatures. We show that even without molecular barcodes, the limits of detection of PhasED-seq outperform prior methods, including duplex barcoding, allowing ctDNA detection in the ppm range in participant samples. We profiled 678 specimens from 213 participants with B cell lymphomas, including serial cell-free DNA samples before and during therapy for diffuse large B cell lymphoma. In participants with undetectable ctDNA after two cycles of therapy using a next-generation sequencing-based approach termed cancer personalized profiling by deep sequencing, an additional 25% have ctDNA detectable by PhasED-seq and have worse outcomes. Finally, we demonstrate the application of PhasED-seq to solid tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41587-021-00981-wDOI Listing
July 2021

Survival among patients with relapsed/refractory diffuse large B cell lymphoma treated with single-agent selinexor in the SADAL study.

J Hematol Oncol 2021 07 16;14(1):111. Epub 2021 Jul 16.

Karyopharm Therapeutics, Newton, USA.

Patients with RR DLBCL who have received ≥ 2 lines of therapy have limited treatment options and an expected overall survival (OS) of < 6 months. The SADAL study evaluated single-agent oral selinexor in patients with RR DLBCL and demonstrated an overall response rate (ORR) of 29.1% with median duration of response (DOR) of 9.3 months. The analyses described here evaluated a number of subpopulations in order to understand how response correlates with survival outcomes in order to identify patients who could most optimally benefit from selinexor treatment. Median age was 67 years; 44.8% of patients were ≥ 70 years of age. The median OS was 9.0 months (95% CI 6.2, 13.7) at a median follow-up of 14.8 months. The median OS was not reached in patients with a CR or PR, while patients who did not respond have a median OS of 4.9 months (p < 0.0001). Patients < 70 years had an OS of 11.1 months compared with 7.8 months in patients ≥ 70 years. Among patients with or without prior ASCT, the median OS was 10.9 and 7.8 months, respectively. Among patients with disease refractory to the most recent DLBCL treatment regimen, the median OS was 7.0 months compared with 11.1 months for disease not refractory to the most recent treatment. In a patient population in which survival is expected to be < 6 months, treatment with single-agent oral selinexor was associated with a median survival of 9 months. Increased median OS observed in patients responding to selinexor was consistent across subgroups regardless of age, prior ASCT therapy, or refractory status. Randomized studies of selinexor in combination with a variety of other anti-DLBCL agents are planned. This trial was registered at ClinicalTrials.gov (NCT02227251) on August 28, 2014. https://clinicaltrials.gov/ct2/show/NCT02227251 .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13045-021-01122-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283921PMC
July 2021

Gonadal Function Recovery in Patients With Advanced Hodgkin Lymphoma Treated With a PET-Adapted Regimen: Prospective Analysis of a Randomized Phase III Trial (AHL2011).

J Clin Oncol 2021 Jun 22:JCO2100068. Epub 2021 Jun 22.

Department of Haematology, University Hospital F Mitterrand and Inserm UMR1231, Dijon, France.

Purpose: The prospective, randomized AHL2011 trial demonstrated that the use of the doxorubicin, bleomycin, vinblastine, and dacarbazine regimen (ABVD) after two cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) in early responders on the basis of a positron emission tomography (PET)-driven strategy was safe and minimized toxicity compared with standard 6 BEACOPP cycles. This substudy investigated the benefit of this strategy in gonadal function and fertility in patients under 45 years old.

Methods: Ovarian function was assessed by serum measurement of follicle-stimulating hormone (FSH), estradiol, and anti-müllerian hormone in women, and semen analysis, FSH, and testosterone levels were used to evaluate testicular function in men at baseline, end of treatment, and during 5 years of follow-up.

Results: A total of 145 women and 424 men, enrolled between May 19, 2011, and April 29, 2014, were included. The risk of premature ovarian insufficiency (FSH > 24 IU/L) and of having a low ovarian reserve (anti-müllerian hormone < 0.5 ng/mL) was reduced after treatment in the PET-driven group (odds ratio [OR], 0.20; 95% CI, 0.08 to 0.50; = .001 and OR, 0.15; 95% CI, 0.04 to 0.56, = .005, respectively). Both parameters were correlated with age and dose of alkylating agents. However, no significant differences were observed in terms of pregnancy rates. Men in the PET-driven group had a higher recovery rate of sperm parameters after treatment compared with the standard BEACOPP group, as well as a lower risk of severe testicular damage (OR, 0.26; 95% CI, 0.13 to 0.5; < .0001) and a higher likelihood of achieving pregnancy (OR, 3.7; 95% CI, 1.4 to 9.3; = .004).

Conclusion: Although both treatments affected ovarian reserve and spermatogenesis, the PET-driven strategy decreased the risk of gonadal dysfunction and infertility in advanced Hodgkin lymphoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.21.00068DOI Listing
June 2021

The landscape of copy number variations in classical Hodgkin lymphoma: a joint KU Leuven and LYSA study on cell-free DNA.

Blood Adv 2021 04;5(7):1991-2002

Department of Human Genetics and.

The low abundance of Hodgkin/Reed-Sternberg (HRS) cells in lymph node biopsies in classical Hodgkin lymphoma (cHL) complicates the analysis of somatic genetic alterations in HRS cells. As circulating cell-free DNA (cfDNA) contains circulating tumor DNA (ctDNA) from HRS cells, we prospectively collected cfDNA from 177 patients with newly diagnosed, mostly early-stage cHL in a monocentric study at Leuven, Belgium (n = 59) and the multicentric BREACH study by Lymphoma Study Association (n = 118). To catalog the patterns and frequencies of genomic copy number aberrations (CNAs), cfDNA was sequenced at low coverage (0.26×), and data were analyzed with ichorCNA to yield read depth-based copy number profiles and estimated clonal fractions in cfDNA. At diagnosis, the cfDNA concentration, estimated clonal fraction, and ctDNA concentration were significantly higher in cHL cases than controls. More than 90% of patients exhibited CNAs in cfDNA. The most frequent gains encompassed 2p16 (69%), 5p14 (50%), 12q13 (50%), 9p24 (50%), 5q (44%), 17q (43%), 2q (41%). Losses mostly affected 13q (57%), 6q25-q27 (55%), 4q35 (50%), 11q23 (44%), 8p21 (43%). In addition, we identified loss of 3p13-p26 and of 12q21-q24 and gain of 15q21-q26 as novel recurrent CNAs in cHL. At diagnosis, ctDNA concentration was associated with advanced disease, male sex, extensive nodal disease, elevated erythrocyte sedimentation rate, metabolic tumor volume, and HRS cell burden. CNAs and ctDNA rapidly diminished upon treatment initiation, and persistence of CNAs was associated with increased probability of relapse. This study endorses the development of ctDNA as gateway to the HRS genome and substrate for early disease response evaluation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2020003039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045498PMC
April 2021

Upfront eBEACOPP chemotherapy without consolidation radiotherapy in early-stage unfavourable Hodgkin lymphoma.

Lancet Oncol 2021 02;22(2):161-162

Department of Haematology, University Hospital F Mitterrand and INSERM 1231, Dijon 21000, France. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(20)30640-9DOI Listing
February 2021

Health-related quality of life and utility outcomes with selinexor in relapsed/refractory diffuse large B-cell lymphoma.

Future Oncol 2021 Apr 2;17(11):1295-1310. Epub 2021 Feb 2.

Department of Haematology, Somogy County Kaposi Mór Hospital, Kaposvár, 7400, Hungary.

Evaluate health-related quality of life (HRQoL) and health utility impact of single-agent selinexor in heavily pretreated patients with relapsed/refractory diffuse large B-cell lymphoma. Functional Assessment of Cancer Therapy (FACT) - Lymphoma and EuroQoL five-dimensions five-levels data collected in the single-arm Phase IIb trial SADAL (NCT02227251) were analyzed with mixed-effects models. Treatment responders maintained higher FACT - Lymphoma (p ≤ 0.05), FACT - General (p < 0.05) and EuroQoL five-dimensions five-levels index scores (p < 0.001) beginning in cycle 3. The estimated difference in health state utilities for treatment response and progressive disease was both statistically significant and clinically meaningful (mean difference: 0.07; p = 0.001). In patients with relapsed/refractory diffuse large B-cell lymphoma, objective response to selinexor was associated with HRQoL maintenance, reduction in disease-related HRQoL decrements and higher health utilities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/fon-2020-0946DOI Listing
April 2021

Subcutaneous Rituximab-MiniCHOP Compared With Subcutaneous Rituximab-MiniCHOP Plus Lenalidomide in Diffuse Large B-Cell Lymphoma for Patients Age 80 Years or Older.

J Clin Oncol 2021 Apr 14;39(11):1203-1213. Epub 2021 Jan 14.

Department of Hematology, Centre Henri Becquerel, UNIROUEN, University of Normandy, INSERM U1245, Rouen, France.

Purpose: The prognosis of elderly patients with diffuse large B-cell lymphoma (DLBCL) is worse than that of young patients. An attenuated dose of chemotherapy-cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab (R-miniCHOP)-is a good compromise between efficacy and safety in very elderly patients. In combination with R-CHOP (R2-CHOP), lenalidomide has an acceptable level of toxicity and may mitigate the negative prognosis of the non-germinal center B-cell-like phenotype. The Lymphoma Study association conducted a multicentric, phase III, open-label, randomized trial to compare R-miniCHOP and R2-miniCHOP.

Patients And Methods: Patients of age 80 years or older with untreated DLBCL were randomly assigned into the R-miniCHOP21 group or the R2-miniCHOP21 group for six cycles and stratified according to CD10 expression and age. The first cycle of rituximab was delivered by IV on D1 after a prephase and then delivered subcutaneously on D1 of cycles 2-6. Lenalidomide was delivered at a dose of 10 mg once daily on D1-D14 of each cycle. The primary end point was overall survival (OS).

Results: A total of 249 patients with new DLBCL were randomly assigned (127 R-miniCHOP and 122 R2-miniCHOP). The median age was 83 years (range, 80-96), and 55% of the patients were classified as non-GCB. The delivered dose for each R-miniCHOP compound was similar in both arms. Over a median follow-up of 25.1 months, the intention-to-treat analysis revealed that R2-miniCHOP did not improve OS (2-year OS 66% in R-miniCHOP and 65.7% in R2-miniCHOP arm, = .98) in the overall population or in the non-GCB population. Grade 3-4 adverse events occurred in 53% of patients with R-miniCHOP and in 81% of patients with R2-miniCHOP.

Conclusion: The addition of lenalidomide to R-miniCHOP does not improve OS. Rituximab delivered subcutaneously was safe in this population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.20.02666DOI Listing
April 2021

Baseline SUVmax is related to tumor cell proliferation and patient outcome in follicular lymphoma.

Haematologica 2020 12 17;Online ahead of print. Epub 2020 Dec 17.

Centre de Recherches en Cancérologie de Toulouse (CRCT), UMR1037 INSERM, Université Toulouse III: Paul-Sabatier, ERL5294 CNRS, Université de Toulouse, Toulouse, France; Laboratoire d'Excellence TOUCAN, Toulouse, France; Programme Hospitalo-Universitaire en Cancérologie CAPTOR, Toulouse, France; CALYM Carnot Institute, Pierre-Bénite, France; Département de pathologie, Institut Universitaire du Cancer de Toulouse, Toulouse.

Follicular lymphoma (FL) is the most common indolent lymphoma. Despite the clear benefit of CD20-based therapy, a subset of FL patients still progress to aggressive lymphoma. Thus, identifying early biomarkers that incorporate PET metrics could be helpful to identify patients with a high risk of treatment failure with Rituximab. We retrospectively included a total of 132 untreated FL patients separated into training and validation cohorts. Optimal threshold of baseline SUVmax was first determined in the training cohort (n=48) to predict progression-free survival (PFS). The PET results were investigated along with the tumor and immune microenvironment, which were determined by immunochemistry and transcriptome studies involving gene set enrichment analyses and immune cell deconvolution, together with the tumor mutation profile. We report that baseline SUVmax >14.5 was associated with poorer PFS than baseline SUVmax ≤14.5 (HR=0.28; p=0.00046). Neither immune T-cell infiltration nor immune checkpoint expression were associated with baseline PET metrics. By contrast, FL samples with Ki-67 staining ≥10% showed enrichment of cell cycle/DNA genes (p=0.013) and significantly higher SUVmax values (p=0.007). Despite similar oncogenic pathway alterations in both SUVmax groups of FL samples, 4 out of 5 cases harboring the infrequent FOXO1 transcription factor mutation were seen in FL patients with SUVmax >14.5. Thus, high baseline SUVmax reflects FL tumor proliferation and, together with Ki-67 proliferative index, can be used to identify patients at risk of early relapse with R-chemotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2020.263194DOI Listing
December 2020

Obinutuzumab vs rituximab for advanced DLBCL: a PET-guided and randomized phase 3 study by LYSA.

Blood 2021 Apr;137(17):2307-2320

Department of Hematology, University Hospital F. Mitterrand, Dijon, France; and.

Rituximab plus polychemotherapy is the standard of care in diffuse large B-cell lymphoma (DLBCL). GAINED, a randomized phase 3 trial, compared obinutuzumab to rituximab. Transplant-eligible patients (18-60 years) with an untreated age-adjusted International Prognostic Index (aaIPI) score ≥1 DLBCL were randomized (1:1) between obinutuzumab or rituximab and stratified by aaIPI (1; 2-3) and chemotherapy regimen (doxorubicin, cyclophosphamide, prednisone plus vindesine, bleomycin [ACVBP] or vincristine [CHOP]). Consolidation treatment was determined according to response to interim positron emission tomography (PET). Responders after cycle 2 and 4 (PET2-/PET4-) received immunochemotherapy. Responders after only cycle 4 (PET2+/4-) received transplantation. The primary objective was an 8% improvement (hazard ratio [HR] = 0.73; 80% power; α risk, 2.5%; 1-sided) in 2-year event-free survival (EFS) in the obinutuzumab arm. From September 2012, 670 patients were enrolled (obinutuzumab, n = 336; rituximab, n = 334). A total of 383 (57.2%) were aaIPI 2-3, 339 (50.6%) received CHOP. Median follow-up was 38.7 months. The 2-year EFS was similar in both groups (59.8% vs 56.6%; P = .123; HR = 0.88). The 2-year PFS in the whole cohort was 83.1% (95% confidence interval, 80% to 85.8%). PET2-/4- and PET2+/4- had similar 2-year progression-free survival (PFS) and overall survival (OS): 89.9% vs 83.9% and 94.8% vs 92.8%. The 2-year PFS and OS for PET4+ patients were 62% and 83.1%. Grade 3-5 infections were more frequent in the obinutuzumab arm (21% vs 12%). Obinutuzumab is not superior to rituximab in aaIPI ≥1 DLBCL transplant-eligible patients. This trial was registered at www.clinicaltrials.gov as #NCT01659099.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2020008750DOI Listing
April 2021

Phase 2 study of parsaclisib (INCB050465), a highly selective, next-generation PI3Kδ inhibitor, in relapsed or refractory diffuse large B-cell lymphoma (CITADEL-202).

Leuk Lymphoma 2021 02 3;62(2):368-376. Epub 2020 Nov 3.

Department of Haematology, St Vincent's Hospital, Darlinghurst, NSW, Australia.

Parsaclisib, a potent, highly selective, next-generation PI3Kδ inhibitor, was evaluated as monotherapy in CITADEL-202 (NCT02998476), an open-label, multicenter, phase 2 study in patients with relapsed or refractory diffuse large B-cell lymphoma. Patients enrolled into 2 groups (A, Bruton tyrosine kinase [BTK] inhibitor naïve,  = 55; B, BTK inhibitor experienced,  = 5) received oral parsaclisib 20 mg once daily for 8 weeks, then 20 mg once weekly while deriving benefit. The futility boundary was crossed at the interim analysis of Group A, resulting in a negative study. Parsaclisib monotherapy demonstrated an objective response rate (ORR) of 25.5% (8 complete metabolic responses/6 partial metabolic responses) and a median duration of response of 6.2 months. ORR in Group B was 20.0% (1 complete metabolic response). Parsaclisib monotherapy demonstrated manageable toxicities with no new safety signals reported. Further evaluation of parsaclisib in combination with standard therapies and active investigational agents is underway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10428194.2020.1832660DOI Listing
February 2021

Fully automatic segmentation of diffuse large B cell lymphoma lesions on 3D FDG-PET/CT for total metabolic tumour volume prediction using a convolutional neural network.

Eur J Nucl Med Mol Imaging 2021 05 24;48(5):1362-1370. Epub 2020 Oct 24.

Department of Nuclear Medicine, CHU H. Mondor, AP-HP, F-94010, Créteil, France.

Purpose: Lymphoma lesion detection and segmentation on whole-body FDG-PET/CT are a challenging task because of the diversity of involved nodes, organs or physiological uptakes. We sought to investigate the performances of a three-dimensional (3D) convolutional neural network (CNN) to automatically segment total metabolic tumour volume (TMTV) in large datasets of patients with diffuse large B cell lymphoma (DLBCL).

Methods: The dataset contained pre-therapy FDG-PET/CT from 733 DLBCL patients of 2 prospective LYmphoma Study Association (LYSA) trials. The first cohort (n = 639) was used for training using a 5-fold cross validation scheme. The second cohort (n = 94) was used for external validation of TMTV predictions. Ground truth masks were manually obtained after a 41% SUVmax adaptive thresholding of lymphoma lesions. A 3D U-net architecture with 2 input channels for PET and CT was trained on patches randomly sampled within PET/CTs with a summed cross entropy and Dice similarity coefficient (DSC) loss. Segmentation performance was assessed by the DSC and Jaccard coefficients. Finally, TMTV predictions were validated on the second independent cohort.

Results: Mean DSC and Jaccard coefficients (± standard deviation) in the validations set were 0.73 ± 0.20 and 0.68 ± 0.21, respectively. An underestimation of mean TMTV by - 12 mL (2.8%) ± 263 was found in the validation sets of the first cohort (P = 0.27). In the second cohort, an underestimation of mean TMTV by - 116 mL (20.8%) ± 425 was statistically significant (P = 0.01).

Conclusion: Our CNN is a promising tool for automatic detection and segmentation of lymphoma lesions, despite slight underestimation of TMTV. The fully automatic and open-source features of this CNN will allow to increase both dissemination in routine practice and reproducibility of TMTV assessment in lymphoma patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00259-020-05080-7DOI Listing
May 2021

Mutational landscape of gray zone lymphoma.

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

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

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

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2020007507DOI Listing
April 2021

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2020001955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391139PMC
August 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-020-0783-yDOI Listing
June 2020

Lenalidomide maintenance for diffuse large B-cell lymphoma patients responding to R-CHOP: quality of life, dosing, and safety results from the randomised controlled REMARC study.

Br J Haematol 2020 04 8;189(1):84-96. Epub 2019 Nov 8.

Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute, Salzburg, Austria.

Lenalidomide maintenance therapy prolonged progression-free survival (PFS) versus placebo in elderly patients with diffuse large B-cell lymphoma (DLBCL) responding to induction chemotherapy in the phase 3 REMARC study. This subpopulation analysis assessed the impact of lenalidomide maintenance and treatment-emergent adverse events (TEAEs) on health-related quality of life (HRQOL). Global health status (GHS), and physical functioning and fatigue subscales were evaluated in patients who completed the European Organisation for Research and Treatment of Cancer quality-of-life questionnaire-C30 v3.0. The impact of TEAEs classified post hoc as subjective (patients can feel) or observable (only measurable by physicians) on dose reductions and discontinuations was assessed. Among 457 patients (lenalidomide, n = 229; placebo, n = 228), mean (standard deviation) GHS was similar between treatment arms [68·2 (20·7) Versus 72·0 (17·8)] at randomisation and remained similar during maintenance. Patients receiving lenalidomide experienced no meaningful changes in GHS, physical functioning, or fatigue. Observable TEAEs were more common (81·1% Versus 66·3%) and more likely to lead to dose reductions, than subjective TEAEs in both arms. PFS was superior in the lenalidomide arm regardless of dose reduction. Lenalidomide maintenance prolonged PFS and did not negatively impact HRQOL in patients with DLBCL despite TEAEs being more common, when compared with placebo.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.16300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154674PMC
April 2020

Fatigue level changes with time in long-term Hodgkin and non-Hodgkin lymphoma survivors: a joint EORTC-LYSA cross-sectional study.

Health Qual Life Outcomes 2019 Jul 2;17(1):115. Epub 2019 Jul 2.

Centre de Traitement des Données du Cancéropôle Nord-Ouest, Plateforme de Recherche Clinique Ligue Contre le Cancer, Centre François Baclesse, 3 Avenue Général Harris, 14076, Caen, Cedex 5, France.

Background: Long-term lymphoma survivors often complain of persistent fatigue that remains unexplained. While largely reported in Hodgkin lymphoma (HL), long-term fatigue is poorly documented in non-Hodgkin lymphomas (NHL). Data collected in two cohort studies were used to illustrate the fatigue level changes with time in the two populations.

Methods: Two cross-sectional studies were conducted in 2009-2010 (HL) and in 2015 (NHL) in survivors enrolled in European Organisation for Research and Treatment of Cancer (EORTC) Lymphoma Group and Lymphoma Study Association (LYSA) trials. The same protocol and questionnaires were used in both studies including the Multidimensional Fatigue Inventory (MFI) tool to assess fatigue and a checklist of health disorders. Multivariate linear regression models were used in the two populations separately to assess the influence of time since diagnosis and primary treatment, age, gender, education level, cohabitation status, obesity and health disorders on fatigue level changes. Fatigue level changes were compared to general population data.

Results: Overall, data of 2023 HL and 1619 NHL survivors with fatigue assessment available (99 and 97% of cases, respectively) were analyzed. Crude levels of fatigue were similar in the two populations. Individuals who reported health disorders (61% of HL and 64% of NHL) displayed higher levels of fatigue than those who did not (P <  0.001). HL survivors showed increasing fatigue level with age while in NHL survivors mean fatigue level remained constant until age 70 and increased beyond. HL survivors showed fatigue changes with age higher than those of the general population with health disorders while NHL survivors were in between those of the general population with and without health disorders.

Conclusions: Among lymphoma survivors progressive increase of fatigue level with time since treatment completion is a distinctive feature of HL. Our data suggest that changes in fatigue level are unlikely to only depend on treatment complications and health disorders. Investigations should be undertaken to identify which factors including biologic mechanisms could explain why a substantial proportion of survivors develop high level of fatigue.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12955-019-1186-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604328PMC
July 2019

Long-term fatigue in survivors of non-Hodgkin lymphoma: The Lymphoma Study Association SIMONAL cross-sectional study.

Cancer 2019 07 22;125(13):2291-2299. Epub 2019 Mar 22.

French Center on eHealth, North-West Region Data Processing Center and French National League Against Cancer Clinical Research Platform, Caen, France.

Background: Long-term survivors of non-Hodgkin lymphoma (NHL) must cope with treatment complications and late toxicities that affect their health-related quality of life. Little is known about the risk-to-benefit ratio of new agents like rituximab. The impact of treatment regimens and health disorders on long-term fatigue levels was investigated in a cross-sectional study.

Methods: Two self-administered questionnaires, the 20-item Multidimensional Fatigue Inventory (MFI-20) and a Life Situation Questionnaire, were mailed in 2015 to NHL survivors enrolled onto 12 successive clinical studies (1993-2010) conducted by the Lymphoma Study Association. Private addresses were obtained for 3317 survivors, of whom 1671 (50%) returned the questionnaires. Severe fatigue was defined as MFI-20 scores ≥60 on dimension scales scored from 0 to 100. Linear regression models were used to assess factors that were linked to increased fatigue levels.

Results: The study population included 906 men and 765 women, and the median age was 64 years (age range, 24-95 years). Overall, 811 survivors had received cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP)-like chemotherapy, 518 had received high-dose CHOP, and 342 had undergone upfront autologous stem cell transplantation; 829 survivors also had received rituximab. In total, 1100 survivors (66%) reported 1 or more late health disorders. Severe fatigue was reported by 602 survivors (37%). Increased fatigue levels were associated (P < .001) with increased age, obesity, and the presence of health disorders, but not with initial treatment or rituximab.

Conclusions: The survey confirms that high proportions long-term NHL survivors have severe fatigue. The results suggest that initial treatment and the receipt of rituximab have no influence on the development of long-term fatigue.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.32040DOI Listing
July 2019

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

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

LYSA Imaging, Hôpital H Mondor, Creteil, France.

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

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

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

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

Funding: Programme Hospitalier de Recherche Clinique.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(18)30784-8DOI Listing
February 2019

Rituximab plus Lenalidomide in Advanced Untreated Follicular Lymphoma.

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

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

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

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

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

Conclusions: Among patients with previously untreated follicular lymphoma, efficacy results were similar with rituximab plus lenalidomide and rituximab plus chemotherapy (with both regimens followed by rituximab maintenance therapy). The safety profile differed in the two groups. (Funded by Celgene; RELEVANCE ClinicalTrials.gov numbers, NCT01476787 and NCT01650701 , and EudraCT number, 2011-002792-42 .).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa1805104DOI Listing
September 2018

Circulating Tumor DNA Measurements As Early Outcome Predictors in Diffuse Large B-Cell Lymphoma.

J Clin Oncol 2018 10 20;36(28):2845-2853. Epub 2018 Aug 20.

David M. Kurtz, Florian Scherer, Michael C. Jin, Joanne Soo, Alexander F.M. Craig, Mohammad Shahrokh Esfahani, Jacob J. Chabon, Henning Stehr, Chih Long Liu, Robert Tibshirani, Lauren S. Maeda, Neel K. Gupta, Michael S. Khodadoust, Ranjana H. Advani, Ronald Levy, Aaron M. Newman, Maximilian Diehn, and Ash A. Alizadeh, Stanford University, Stanford, CA; Florian Scherer, University Medical Center Freiburg, Freiburg; Ulrich Dührsen and Andreas Hüttmann, University Hospital Essen, Essen, Germany; Michel Meignan, Hôpitaux Universitaires Henri Mondor, Creteil; René-Olivier Casasnovas, Hôpital Le Bocage, Centre Hospitalier Universitaire, Dijon, France; Jason R. Westin, University of Texas MD Anderson Cancer Center, Houston, TX; Mark Roschewski and Wyndham H. Wilson, National Cancer Institute, National Institutes of Health, Bethesda, MD; Gianluca Gaidano and Davide Rossi, University of Eastern Piedmont, Novara, Italy; and Davide Rossi, Oncology Institute of Southern Switzerland and Institute of Oncology Research, Bellinzona, Switzerland.

Purpose: Outcomes for patients with diffuse large B-cell lymphoma remain heterogeneous, with existing methods failing to consistently predict treatment failure. We examined the additional prognostic value of circulating tumor DNA (ctDNA) before and during therapy for predicting patient outcomes.

Patients And Methods: We studied the dynamics of ctDNA from 217 patients treated at six centers, using a training and validation framework. We densely characterized early ctDNA dynamics during therapy using cancer personalized profiling by deep sequencing to define response-associated thresholds within a discovery set. These thresholds were assessed in two independent validation sets. Finally, we assessed the prognostic value of ctDNA in the context of established risk factors, including the International Prognostic Index and interim positron emission tomography/computed tomography scans.

Results: Before therapy, ctDNA was detectable in 98% of patients; pretreatment levels were prognostic in both front-line and salvage settings. In the discovery set, ctDNA levels changed rapidly, with a 2-log decrease after one cycle (early molecular response [EMR]) and a 2.5-log decrease after two cycles (major molecular response [MMR]) stratifying outcomes. In the first validation set, patients receiving front-line therapy achieving EMR or MMR had superior outcomes at 24 months (EMR: EFS, 83% v 50%; P = .0015; MMR: EFS, 82% v 46%; P < .001). EMR also predicted superior 24-month outcomes in patients receiving salvage therapy in the first validation set (EFS, 100% v 13%; P = .011). The prognostic value of EMR and MMR was further confirmed in the second validation set. In multivariable analyses including International Prognostic Index and interim positron emission tomography/computed tomography scans across both cohorts, molecular response was independently prognostic of outcomes, including event-free and overall survival.

Conclusion: Pretreatment ctDNA levels and molecular responses are independently prognostic of outcomes in aggressive lymphomas. These risk factors could potentially guide future personalized risk-directed approaches.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.2018.78.5246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161832PMC
October 2018

Efficacy of chemotherapy or chemo-anti-PD-1 combination after failed anti-PD-1 therapy for relapsed and refractory Hodgkin lymphoma: A series from Lysa centers.

Am J Hematol 2018 Jun 8. Epub 2018 Jun 8.

Department of Hematology, Centre Hospitalier Lyon Sud, Pierre-Bénite, France.

Anti-PD-1 therapy provides high response rates in Hodgkin lymphoma (HL) patients who have relapsed or are refractory (R/R) to autologous stem cell transplantation (ASCT) and brentuximab vedotin (BV), but median progression free survival (PFS) is only one year. The efficacy of treatment following anti-PD-1 is not well known. We retrospectively investigated the efficacy of salvage therapies for unsatisfactory response to anti-PD-1 therapy, assessed by PET-CT according to the Lugano criteria, in 30 R/R HL patients. Patients were highly pre-treated before anti-PD-1 (70% received ASCT and 93% BV). Unsatisfactory responses to anti-PD1 therapy were progressive disease (PD) (n=24) and partial response (PR) (n=6). For the 24 PD patients, median anti-PD-1 related PFS was 7.5 months (95%CI, 5.7-11.6); 17 received subsequent CT alone (Group 1) and 7 received CT in addition to anti-PD-1 (Group 2). 16/24 patients (67%) obtained an objective response. In the 15 patients treated with the same CT, twelve obtained PR or complete response (CR). In Group 1, there were 7 CR (41%), 3 PR (18%), and 7 PD (41%). In Group 2, there were 4 CR (57%), 2 PR (29%), and 1 SD (14%). No unexpected toxicity was observed. Six patients who achieved response proceeded to allogeneic SCT. With a median follow-up of 12.1 months (7-14.7), the median PFS following the initiation of CT was 11 months (95%CI, 6.3; not reached) and the median of overall survival was not reached. These observations in highly pre-treated HL patients suggest that anti-PD-1 therapy might re-sensitize tumor cells to CT. This article is protected by copyright. All rights reserved.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajh.25154DOI Listing
June 2018

Total metabolic tumor volume, circulating tumor cells, cell-free DNA: distinct prognostic value in follicular lymphoma.

Blood Adv 2018 04;2(7):807-816

Paris-Est Créteil University, Créteil, France.

Outcomes for follicular lymphoma (FL) have greatly improved, but most patients will ultimately relapse. High total metabolic tumor volume (TMTV), computed from baseline F-fluorodeoxyglucose-positron emission tomography (PET), is associated with shorter progression-free survival (PFS), but circulating tumor cells (CTCs) and cell-free DNA (cfDNA) may also reflect tumor burden and be of prognostic value. The aim of our study was to correlate CTCs and cfDNA with TMTV in FL at diagnosis and to determine their prognostic values. We retrospectively analyzed 133 patients (with previously untreated FL and a baseline PET) from 2 cohorts with either a baseline plasma sample (n = 61) or a bcl2-JH-informative peripheral blood (PB) sample (n = 68). Quantification of circulating bcl2-JH cells and cfDNA was performed by droplet digital polymerase chain reaction. A significant correlation was found between TMTV and both CTCs ( < .0001) and cfDNA ( < .0001). With a median 48-month follow-up, 4-year PFS was lower in patients with TMTV > 510 cm ( = .0004), CTCs >0.0018 PB cells ( = .03), or cfDNA >2550 equivalent-genome/mL ( = .04). In comparison with TMTV alone, no additional prognostic information was obtained by measuring CTCs. In contrast, Cox multivariate analysis, including cfDNA and TMTV, showed that both cfDNA and TMTV remained predictive of outcome. In conclusion, CTCs and cfDNA correlate with TMTV in FL, and all 3 influence patient outcome. PFS was shorter for patients with high cfDNA and TMTV, suggesting that these parameters provide relevant information for tumor-tailored therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2017015164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5894260PMC
April 2018

Prognostic model for high-tumor-burden follicular lymphoma integrating baseline and end-induction PET: a LYSA/FIL study.

Blood 2018 05 20;131(22):2449-2453. Epub 2018 Mar 20.

Lymphoma Study Association Imaging, Hôpitaux Universitaires Henri Mondor, Université Paris Est, Créteil, France.

Both total metabolic tumor volume (TMTV), computed on baseline positron emission tomography (PET), and end of induction (EOI) PET are imaging biomarkers showing promise for early risk stratification in patients with high-tumor-burden follicular lymphoma. A model was built incorporating these 2 factors in 159 patients from three prospective trials: 2 Lymphoma Study Association (LYSA) studies and 1 Fondazione Italiana Linfomi (FIL) trial. Median follow up was 64 months. High TMTV (>510 cm) and positive EOI PET were independent, significant risk factors for progression. Their combination stratified the population into 3 risk groups: patients with no risk factors (n = 102; 64%) had a 5-year progression-free survival (PFS) of 67% vs 33% (hazard ratio [HR], 2.9; 95% confidence interval [CI], 1.8-4.9) for patients with 1 risk factor (n = 44; 27%) and only 23% (HR, 4.6; 95% CI, 2.3-9.2) for patients with both risk factors (n = 13; 8%). 2-year PFS was respectively 90% vs 61% (HR, 4.8; 95% CI, 2.2-10.4) and 46% (HR, 8.1; 95%CI, 3.1-21.3). This model enhances the prognostic value of PET staging and response assessment, identifying a subset of patients with a very high risk of progression and early treatment failure at 2 years.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2017-11-816298DOI Listing
May 2018

Antibody-Drug Conjugates for the Treatment of Hematological Malignancies: A Comprehensive Review.

Target Oncol 2018 06;13(3):287-308

Hématologie Clinique, Hôpital Le Bocage-CHU Dijon, 14 rue Paul Gaffarel, 21079, Dijon Cedex, France.

Antibody-drug conjugates (ADCs) are an emerging class of therapeutic agents that bring new opportunities for the treatment of hematological malignancies by meeting unmet medical needs. These drugs consist of a cytotoxic agent connected by a linker to a human, humanized, or chimeric antibody targeting a surface antigen specifically expressed by tumor cells. These ADCs are being developed to specifically deliver the cytotoxic agent into tumor cells. The cytotoxic payload is released from the ADC after internalization and cleavage of the linker, ultimately triggering the death of the cancer cell. Second- and even third-generation ADCs are currently being developed and have more stable linkers and more potent payloads, which should improve ADC efficacy even further. In this review, we analyze the results for the main ADCs currently developed and discuss the advantages and drawbacks of this therapeutic option.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11523-018-0558-1DOI Listing
June 2018

Bendamustine-based conditioning prior to autologous stem cell transplantation (ASCT): Results of a French multicenter study of 474 patients from LYmphoma Study Association (LYSA) centers.

Am J Hematol 2018 Jun 14;93(6):729-735. Epub 2018 Mar 14.

Institut d'Hématologie de Basse-Normandie, CHU, Caen, France.

Carmustine shortage has led to an increase use of alternative conditioning regimens prior to autologous stem cell transplantation for the treatment of lymphoma, including Bendamustine-based (BeEAM). The aim of this study was to evaluate the safety of the BeEAM regimen in a large cohort of patients. A total of 474 patients with a median age of 56 years were analyzed. The majority of patients had diffuse large B-cell lymphoma (43.5%). Bendamustine was administered at a median dose of 197 mg/m /day (50-250) on days-7 and -6. The observed grade 1-4 toxicities included mucositis (83.5%), gastroenteritis (53%), skin toxicity (34%), colitis (29%), liver toxicity (19%), pneumonitis (5%), and cardiac rhythm disorders (4%). Nonrelapse mortality (NRM) was reported in 3.3% of patients. Acute renal failure (ARF) was reported in 132 cases (27.9%) (G ≥2; 12.3%). Organ toxicities and death were more frequent in patients with post conditioning renal failure. In a multivariate analysis, pretransplant chronic renal failure, bendamustine dose >160 mg/m and age were independent prognostic factors for ARF. Pretransplant chronic renal failure, hyperhydration volume, duration of hyperhydration, and etoposide dose were predictive factors of NRM. A simple, four-point scoring system can stratify patients by levels of risk for ARF and may allow for a reduction in the bendamustine dose to avoid toxicity. Drugs shortage may have dangerous consequences. Prospective, comparative studies are needed to confirm the toxicity/efficacy extents from this conditioning regimen compared to other types of high dose therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajh.25077DOI Listing
June 2018
-->