Anti-programmed cell death 1 (PD-1) and anti-programmed cell death ligand 1 (PD-L1) antibodies are novel immunotherapies for cancer that can induce immune-related adverse events (irAEs). These ...adverse events can involve all organs, including the haemopoietic system. Thus far, haematological irAEs (haem-irAEs) have not been extensively characterised. This study aims to provide a comprehensive report of the haem-irAEs induced by anti-PD-1 or anti-PD-L1.
In this descriptive observational study, we included consecutive patients aged at least 18 years with grade 2 or worse haem-irAEs induced by anti-PD-1 or anti-PD-L1 immunotherapy registered in three French pharmacovigilance databases: the Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie (REISAMIC; a prospective registry of patients treated with anti-PD-1 or anti-PD-L1 at a single centre), the ImmunoTOX committee of Gustave Roussy (a national referral database of suspected irAEs in patients treated with immunotherapy), and the registry of the Centre de Référence des Cytopénies Auto-Immunes de l'Adulte (CeReCAI; a national database of autoimmune cytopenias). Cases were reviewed by a central committee; adverse events had to be classed as certainly or probably related to anti-PD-1 or anti-PD-L1 therapy, and their severity was assessed according to the Common Terminology Criteria for Adverse Events (version 4.03). The primary endpoint was clinical description of haem-irAEs, as reported in all databases, and their frequency, as reported in the prospective REISAMIC registry.
We screened 948 patients registered in the three databases from June 27, 2014, to June 29, 2018 (745 from REISAMIC, 190 from the ImmunoTOX committee, and 13 from CeReCAI). 35 patients (21 men and 14 women) with haem-irAEs related to anti-PD-1 or anti-PD-L1 were included in the study. Of 745 patients in the REISAMIC registry treated with anti-PD-1 or anti-PD-L1, four had haem-irAEs, giving a frequency of 0·5%. Median age in the 35 patients was 65 years (IQR 51-75), and the most common tumour types were melanoma (15 43% patients), non-small-cell lung cancer (12 34% patients), and lymphoma (four 11% patients). 20 (57%) patients received nivolumab, 14 (40%) received pembrolizumab, and one (3%) received atezolizumab. Among the 35 patients, neutropenia, autoimmune haemolytic anaemia, and immune thrombocytopenia were the most common types of haem-irAE (each in nine patients 26%), followed by pancytopenia or aplastic anaemia (five patients 14%), bicytopenia (one patients with thrombocytopenia plus anaemia and one patient with neutropenia plus anaemia 6%), and pure red cell aplasia (one patient 3%). The maximum grade of severity was grade 2 in three (9%) patients, grade 3 in five (14%) patients, and grade 4 in 25 (71%) patients; two (6%) patients died from febrile neutropenia during haem-irAE related to anti-PD-1. Haem-irAEs resolved in 21 (60%) of the 35 patients.
Haem-irAEs induced by PD-1 or PD-L1 inhibitors are rare but potentially life-threatening events. The most common clinical presentations are neutropenia, autoimmune haemolytic anaemia, immune thrombocytopenia, and aplastic anaemia. Investigations into earlier detection and better management are warranted.
Gustave Roussy and Gustave Roussy Immunotherapy Program.
Hodgkin lymphoma (HL) was one of the first few cancers to be cured first with radiotherapy alone and then with a combination of chemotherapy and radiotherapy. Around 80% of the patients with HL will ...be cured by first-line therapy. However, the ionising radiation not only produces cytotoxicity but also induces alterations in the microenvironment, and patients often struggle with the long-term consequences of these treatments, such as cardiovascular disorders, lung diseases and secondary malignancies. Hence, it is essential to improve treatments while avoiding delayed side-effects. Immunotherapy is a promising new treatment option for Hodgkin lymphoma, and anti- programmed death-1 (PD1) agents have produced striking results in patients with relapsed or refractory disease. The microenvironment of Hodgkin lymphoma appears to be unique in the field of human disease: the malignant Reed-Sternberg cells only constitute 1% of the cells in the lymphoma, but they are surrounded by an extensive immune infiltrate. Reed-Sternberg cells exhibit 9p24.1/PD-L1/PD-L2 copy number alterations and genetic rearrangements associated with programmed cell death ligand 1/ ligand 2 (PD-L1/2) overexpression, together with major histocompatibility complex-I (MHC-I) and major histocompatibility complex-II (MHC-II) downregulation (which may facilitate the tumour's immune evasion). Although HL may be a situation in which defective immune surveillance is restored by anti-PD1 therapy, it challenges our current explanation of how anti-PD1 agents work because MHC-I expression is required for CD8-T-cell-mediated tumour antigen recognition. Here, we review recent attempts to understand the defects in immune recognition in HL and to design an optimal evidence-based treatment for combination with anti-PD1.
•Hodgkin lymphoma (HL) is characterised by an ineffective immune infiltrate which seems addict to the PD1–PD-L1 axis.•Anti-PD1 therapy recently yielded high response rates in heavily pre-treated patients with classical HL.•New challenges are emerging with immunotherapy – notably about how to convert a partial response into a complete response.•Understanding the mechanisms of primary and secondary resistance will be decisive to design future treatment combinations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Background: Programmed cell death protein 1 (PD-1) blockade is commonly used to treat relapsed/refractory (RR) classical Hodgkin lymphoma (cHL) but the overall response rates (ORR) and complete ...response rates (CRR) of approved anti-PD1 antibodies remain suboptimal. Tislelizumab blocks PD-1 with a high specificity and affinity and minimized FcγR binding on macrophages leads to reduced clearance. Results of the initial phase 2 study of tislelizumab in Chinese patients with RR cHL were impressive, with ORR and CRR of 87% and 63%, respectively, and 3-year progression free survival (PFS) of 40%, warranting further evaluation in a Western population with different standard of care, including more frequent use of autologous stem cell transplantation (ASCT) and targeted agents. Methods: TIRHOL (NCT04318080) is an international, prospective phase 2 study for patients with RR cHL conducted in France, Belgium, USA and Australia. Cohort 1 includes patients who previously underwent ASCT; cohort 2 includes patients who were ineligible for ASCT. Prior therapy with brentuximab vedotin (BV) was required in initial design; the protocol was amended to remove this criterion for both cohorts in October 2021. Tislelizumab 200 mg is given intravenously every 3 weeks until progressive disease (PD), unacceptable toxicity, or study withdrawal; tumor assessments are performed every 12 weeks. The primary endpoint is the ORR (best overall response of CR or partial response PR), as assessed by investigator, according to PET-CT International Lugano 2014 criteria. Null hypothesis is ORR = 45 % based on previous clinical trials and alternative hypothesis is ORR > 45%. Assuming the observed ORR = 65%, a sample size of 42 patients provides ≥ 80% power of at the one-sided 5% significance level. Secondary endpoints are CRR, time to response (TTR), duration of response (DOR), safety and tolerability of tislelizumab. Main exploratory endpoints are PFS and overall survival (OS). Results: Patients who received at least 1 dose of tislelizumab were included in the analysis. Between August 2020 and September 2022, 45 patients (14 in cohort 1 and 31 in cohort 2) were enrolled and dosed. At inclusion, the median age was 64 years (range 18-87), 67% were male and all had ECOG performance status 0-1; most patients had advanced stage disease (38% III, 42% IV), 11% had bulky disease, 18% had B symptoms and 29% had disease refractory to last therapy. The median prior lines of therapy received was 2 (1 - 4); 12 patients (27%) received ≥3 prior lines of therapy and 33 (73%) received prior BV. At last follow-up, the median number of tislelizumab doses (cycles) was 8 (1 - 33), corresponding to a median duration of treatment 24 weeks (range 3-105). The ORR was 64.4% (90% CI, 51% - 76%) with 14 (31%) patients achieving CR and 15 (33%) patients achieving PR (Figure 1). Remaining patients had stable disease (n=2, 4%), PD (n=13, 29%), or were not evaluated (n=1, 2%). The ORR was similar in cohort 1 (n=9/14, 64.3%) and cohort 2 (20/31, 64.5%). The median TTR was 2.69 months (range 0.3-5.6). The median DOR was 12.3 months (95% CI, 3 - NR) and was not reached for patients achieving CR. Three patients with objective response underwent subsequent ASCT (1) or allogeneic SCT (2). With a median follow-up of 11.4 months (95% CI, 6.7-13.5), the median PFS was 5.6 (95% CI, 5 - 14), 8, and 5 months for both cohorts combined, cohort 1, and 2, respectively. Thirteen patients with SUV increase meeting PD criteria but continued clinical benefit continued tislelizumab for a median of 3.6 months (range Q1:1.8 - Q3: 9.5) after PD. At last follow-up, 19 patients remain on tislelizumab and 11 (24%) have continued treatment for >1 year. The median OS was not reached with a 1-year OS rate of 93.5% (4 deaths; 95%CI, 75.0-98.5) and no treatment-related deaths. Grade ≥ 3 treatment emergent adverse events (TEAE) occurred in 15 (33%) patients, leading to discontinuation or interruption of tislelizumab in 9 and 2 patients, respectively. Immune-related (ir) AEs were observed in 15 (33%) patients and 3 patients had grade ≥ 3 irAEs (maculo-papular rash, hepatitis, hemolytic anemia). Conclusions: TIRHOL met its primary endpoint with an ORR of 64% and a CRR of 31% with an acceptable safety profile. This study confirmed that tislelizumab is a promising treatment option in cHL. Study follow-up is ongoing, but durable responses have been observed, especially in patients achieving CR.
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GEOZS, KILJ, NLZOH, NUK, OILJ, PNG, SAZU, UILJ, UL, UM, UPUK
Patient's selection in early phase clinical trials is guided by stringent clinical criteria and can be supported or improved by precise tumor characterization and/or molecular stratification. Most of ...the precision medicine data are generated using historical tumor biopsies often collected before anticancer drugs treatment, which may thus only partially reflect the tumor's molecular landscape at inclusion in early phase clinical trials. The gold standard fresh tumor biopsy is not always feasible without risk for the patient. For this reason, ctDNA could be a simple, safe and attractive technique for obtaining critical information on the tumor genomic landscape.
This study was designed to explore if whether NGS results obtained with from ctDNA could replace fresh tumor biopsies in patients (pts) at inclusion in early phase clinical trials. Data generated on both tissue samples collected in a short period of time in 52 pts treated for a B-cell aggressive lymphoma in the DITEP department at Gustave Roussy prior to inclusion were compared (18/52 pts had one course of chemotherapy between the 2 tissue samples). Characteristics at sampling were: mean age = 66 y.o., male/female: 32/20, Ann Arbor staging: 1/2/3/4 = 4 (7.7%), 5 (9.6%), 8 (15.4%) and 35 (67.3%) pts. The median number of prior chemotherapy was 2 (Min=1; Max=7). NGS tests were done using a panel of 39 genes and more recently 44 genes. 34 genes were found mutated in at least one pt. 150 mutations of pathologic significance were identified and 105 mutations out of 150 (70.0%) were concordant between the fresh biopsy and the blood (95%CI=62.0%; 77.2%). No patient had a mutation detected in the ctDNA analysis that was not found in the fresh tumor biopsy. In 8/52(15%) patients, no mutation was detected in both tumor biopsy and blood. Of the 44-remaining pts, 10 had no mutation detected in the blood and 34 pts (77.3%) carried at least one mutation detectable in both the tumor and blood. In 25/44patients (56.8%) all mutations identified in the tumor could be also detected in the blood (95%CI=41.0%; 71.7%), which are “informative ctDNA patients” if we consider that tumor biopsy is the “gold standard” as it is in clinical trials. Among the 44 pts that have at least one mutation detected in the tumor, the median VAF detection in the tumor biopsy was 41% (range 2-98%) and in the blood it was 7% (range 0-83%), but if we focus on the 105 mutations detected in both the biopsy and in the blood, the median VAF observed is 43% in the tumor (range 2-98%) and 14% in the blood (range 1-83%).
Our results suggest that 85% of the pts included in phase I trials have at least one detectable mutation in the tumor biopsy, but approximately 50% of the pts have concordant mutations found in both ctDNA and fresh tumor samples. These results also suggest that ctDNA could be a useful tool in those “informative ctDNA” pts for residual disease assessment without sequential biopsies.
Ribrag:MSD: Membership on an entity's Board of Directors or advisory committees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel, accommodations, and expenses ; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses ; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; AZ: Membership on an entity's Board of Directors or advisory committees; ArgenX: Research Funding; Epizyme: Consultancy, Research Funding.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background: The AHL2011 study demonstrated that a PET-driven strategy allows to deescalate treatment to 4 x ABVD in PET negative patients after 2 cycles of escalated BEACOPP (BEACOPPesc) without loss ...of tumor control in patients with advanced Hodgkin lymphoma (HL) compared to a non PET-monitored treatment delivering 6 x BEACOPPesc (Casasnovas RO et al, Lancet Oncol 2019). The interim PET results after 2 (PET2) and 4 (PET4) cycles of chemotherapy were found to influence patients PFS and OS independently of IPS. To further refine the patients outcome prediction we evaluate the prognostic value of baseline Total Metabolic Tumor Volume (TMTV) and tumor dissemination (SDmax) in Ann Arbor stage III-IV patients included in the AHL2011 trial.
Patients and methods: 634 patients enrolled in the AHL2011 trial with stage Ann Arbor III or IV were included in the study. According to the AHL2011 trial, patients were randomized in a standard arm (6 x BEACOPPesc) or a PET-driven arm (2 x BEACOPPesc and 4 x ABVD in negative PET2 patients or 4 x BEACOPPesc in positive PET2 patients). For each patient, a semi automatic tumor segmentation was retrospectively performed in baseline PET to calculate TMTV using the 41% of SUVmax threshold and compute the maximum distance between the delineated lesions normalized by body surface area (SDmax). Optimal thresholds for TMTV and SDmax were calculated using X-Tile and ROC curve approaches in a randomly assigned training (n=317) and validation sets (n=317). The per protocol PET2 and PET4 responses were analyzed using the modified Deauville criteria (positive if residual uptake >140% background liver). Multivariate analysis included treatment arm, TMTV, SDmax, international prognosis score (IPS), PET2, and PET4 as covariates. The median follow-up was 5.6y.
Results : Median TMTV and SDmax were 215 ml and 0.221 m-1 in the whole population and similar in both randomized arms and in the training and validation sets. Optimal cutoffs were 220ml for TMTV (312 patients 49% had High TMTV) and 0.330 m-1 for SDmax (149 patients 24% had High SDmax) and similar in the training and validation sets. 5-year PFS for patients with TMTV>220ml was 84.1% vs 90.2% in low TMTV patients (p=0.02) in the whole population (in the training set: 83% vs 89%, p=0.088 ; in the validation set : 86% vs 92% p=0.11). 5-year PFS was significantly lower in patients with SDmax>0.333 m-1 (78.8% vs 89.7%; HR=2.15 95%CI: 1.38-3.35, p=0.0005) in the whole population (in the training set: 77% vs 89%; p=0.0037); in the validation set: 81% vs 91; p=0.046). The combination of TMTV and SDmax allows to identify two subgroups of patients, those having both low TMTV and low SDmax (n= 281; 44%) and those having high TMTV and/or SDmax (5-year PFS: 92% vs 83.4%; HR=2.24 95%CI: 1.39-3.62, p=0.0007) (figure 1). In multivariate analysis, high TMTV (p=0.034), high SDmax (p=0.0002), PET2 (p=0.02) and PET4 (p<0.001) positivity retained independent prognostic value for predicting PFS.
Conclusion: Tumor burden (TMTV) and dissemination (SDmax) assessed on baseline 18FDG PET allow to predict, independently of early reponse to treatment, the outcome of patients with advanced HL. These two parameters overcome the prognosis value of IPS and could be included into new prognostic scores to tailor personalized therapy in advanced Hodgkin Lymphoma.
Figure 1 : PFS according to TMTV and SDmax in stage III-IV HL patients enrolled in the AHL2011 study
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Brice: Takeda: Consultancy, Honoraria, Research Funding; BMS: Honoraria; MSD: Honoraria. Ghesquieres: Janssen: Honoraria; Mundipharma: Consultancy, Honoraria; Roche: Consultancy; Celgene: Consultancy, Honoraria; Gilead Science: Consultancy, Honoraria. Stamatoullas-Bastard: Takeda: Consultancy. André: AbbVie: Other: Travel/accomodation/expenses; Roche: Other: Travel/accomodation/expenses, Research Funding; Johnson & Johnson: Research Funding; Incyte: Consultancy; Gilead: Consultancy, Other: Travel/Accommodations/Expenses; Karyopharm: Consultancy; Bristol-Myers-Squibb: Consultancy, Other: Travel/Accommodations/Expenses; Celgene: Other: Travel/accomodation/expenses; Takeda: Consultancy, Research Funding. Rossi: ROCHE: Honoraria, Research Funding; Takeda: Honoraria; JANSSEN: Honoraria; ABBVIE: Honoraria. Casasnovas: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background: Early drug development is associated with a high rate of failure in patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBLC), partly due to genomic heterogeneity. ...Precision medicine aims at identifying patients with cancer who are likely to respond to targeted therapies. Here we assessed the clinical impact of characterizing actionable and molecular targets and matching targeted therapy in pts with R/R DLBCL prior enrollment in early phase clinical trials (epCT).
Methods: Pts with R/R DLBCL enrolled in epCT, provided paired samples including germline and fresh tumor tissue sample. Paired samples were analyzed by targeted next generation sequencing (NGS) using a customized panel of 44 genes (Ion Torrent). Clinical actionability of genomic alterations and orientation to targeted therapy were prospectively assessed at the Hematological Tumor Board from our Institution according to the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) tiers (ESCAT scale; J. Mateo, Annals of Oncology, 20181). Pts were classified as molecularly matched (MM) i.e. treated based on the presence of an ESCAT actionable molecular abnormality, or non-molecularly matched (no-MM). Tumor and clinical characteristics and outcome of pts were collected.
Results: From 2013 to 2020, 90 pts with R/R DLBCL screened for early clinical trial had tumor & germline samples sequenced by NGS. The mean age was 62 years old (range, 23-83) and median prior lines of systemic therapy was 2 (range 1-9). Sixteen (18%) pts were enrolled in epCT and treated with MO drugs, 43 pts (48%) were enrolled in epCT and treated with no-MM drugs, and 31 (34%) pts were not enrolled in epCT. The main clinical characteristics of the pts were similar in both MM and no-MM groups (table 1). Based on ESCAT scale, targeted therapies of the 16 pts MM were distributed as “investigational-level” tier II in 6 pts (3 pts EZH2 mutant m treated with EZH2 inhibitors; 3 patients with a CD79Bm treated with BTK inhibitors); “hypothetical-level” tier III in 1 pt BRAFm treated with a BRAF inhibitor; and “hypothetical-level” tier IV in 9 pts (6 pts MYD88m treated with cereblon modulator drugs; 2 pts with BCL7Am/ARID1Am treated with investigational epigenetic modifier drugs; 1 pt with MYCm treated with a PI3K inhibitor). Median progression-free survival in MM and no-MM pts, were 3.3 and 1.7 months, respectively (p=0.0092; HR=0.47 CI95:0.27-0.83). Median overall survival in MM and no-MM pts were 20.0 and 6.7 months, respectively (p=0.0238; HR=0.49 CI95: 0.26-0.91) (figure 1).
Conclusions: Molecular orientation before inclusion in early phase clinical trials was associated with better outcomes in patients with R/R DLBCL. A molecular tumor profile could be useful to manage patients with R/R DLBCL with precision medicine helping to identify patients likely to respond to targeted therapies.
Reference.
1- Mateo J, Chakravarty D, Dienstmann R et al. A framework to rank genomic alterations as targets for cancer precision medicine: the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT). Annals of Oncology 2018; 29(9):1895-1902.
Table 1.Patient's characteristics at time of R/R DLBCL relapse and tumor sample in molecularly matched patients (MM group) and non-molecularly matched patients (no-MM group). Data presented are n (%) unless otherwise stated.
MM= Molecularly matched. no-MM= Non-molecularly matched. R/R DLBCL= relapsed or refractory diffuse large B-cell lymphoma. y.o. = years old. mo.= months. ECOG PS= Eastern Cooperative Oncology Group performance status. NHL=non-Hodgkin lymphoma. ASCT= Autostem cell transplantation. IHC= Immunohistochemistry. COO= Cell of origin. GC= Germinal center. ABC= Activated B-cell. NA= Not available. LDH= Lactate deshydrogenase.
*the p-value indicates the comparison between the proportions of the groups from a contingency table, and was calculated by the exact Fisher test. All tests were non-parametric. The p values were calculated by two-tailed and a 95% confidence interval was used, with values less than 0.005 considered being significantly different.
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Michot:Argen-x: Research Funding; Eos: Research Funding; Exelixis: Research Funding; Amgen: Research Funding; Astex: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Eisai: Research Funding; Daiichi Sankyo: Research Funding; AstraZeneca: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Lysarc: Research Funding; Lilly: Research Funding; Kyowa: Research Funding; Genentech: Research Funding; Forma: Research Funding; Agios: Research Funding; AZD: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Mundi Pharma: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Celgene: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Bristol-Myers Squibb: Membership on an entity’s Board of Directors or advisory committees, Other; Xencor: Research Funding; Sanofi: Research Funding; Roche: Research Funding; Medimmune: Research Funding; Lytix Biopharma: Research Funding; Janssen: Other, Research Funding; Debiopharm: Research Funding; Gustave Roussy: Honoraria, Other: Abbvie, Aduro, Agios, Amgen, Argen-x, Astex, AstraZeneca, Aveo pharmaceuticals, Bayer, Beigene, Blueprint, BMS, Boeringer Ingelheim, Celgene, Chugai, Clovis, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Gamamabs, Genentech, Gortec, GSK, H3 bio, Research Funding; Abbvie: Research Funding. Varga:Astra Zeneca: Current Employment. Ribrag:argenX: Current equity holder in publicly-traded company, Research Funding; Roche/Genentech: Consultancy, Membership on an entity’s Board of Directors or advisory committees; arGEN-X-BVBA: Research Funding; BAY1000394 studies on MCL: Patents & Royalties; Institut Gustave Roussy: Current Employment; Epizyme: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; AZD: Honoraria, Other; Pharmamar: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Eisai: Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; MSD: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Servier: Consultancy, Honoraria; AstraZeneca: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Nanostring: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; F. Hoffmann-La Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: Travel Expenses; Immune Design: Consultancy, Membership on an entity’s Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: Travel Expenses; Infinity: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees.
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GEOZS, KILJ, NLZOH, NUK, OILJ, PNG, SAZU, UILJ, UL, UM, UPUK
Background. Diffuse large B cell lymphoma (DLBCL) is the most common adult non-Hodgkin lymphoma. Despite therapeutic advances, 40% of the patients (pts) and especially pts older than 65 years old ...(y/o), will experience a relapsed or refractory (R/R) disease. Novel therapies as well as predictive biomarkers are required for these patients with a poor prognosis after standard salvage regimens. We aimed at establishing whether tumor molecular characterization by a customized target panel in pts with R/R DLBLC prior to enrollment in a phase I clinical trials might impact therapeutic decision making and outcome prediction.
Methods. Paired targeted next generation sequencing for all consecutive pts with R/R DLBCL from germline sample and fresh tumor biopsy were performed at the time of enrollment in phase I clinical trials within the early phase clinical department. Tumor and germline samples of enrolled patients were sequenced using Ion Torrent technology on an in-house customized panel of 44 genes. Molecular and cluster mapping of recurrent molecular abnormalities was determined by integrated completed likelihood (ICL) in patients with relapsed diffuse large B-cell lymphoma. Predictive and prognostic impact of molecular profile was assessed on overall survival (OS).
Results. Between 2013 and 2020, 89 pts with R/R DLBCL were included in the study. At time of inclusion, mean age was 62 (range 23-83) y/o, 50 pts (56%) were male, median prior lines of systemic treatment was 2 (range 1-9). Age adjusted international prognostic index (aaIPI) score was 0-1 in 42 pts (47%) and 2-3 in 47 pts (53%). Among the 82 cases with a cell of origin (COO) status assessed by immunohistochemistry, 55 (67%) pts had a germinal center (GC) and 27 pts (33%) a non-GC. The sequencing panel was informative in 86 pts (97%) and 3 pts (3%) had no variants identified. The most recurrently altered genes by mutations (m) were TP53m (n=38; 43%), CREBBPm (n=29; 33%), KMT2Dm (n=24; 27%), PIM1m (n=23; 26%) and BCL2m (n=20; 22%). Mutual exclusivity and co-occurrence analysis underlined that KMT2Dm were fully exclusive from MEF2Bm (p<0.0001); and TNFRSF14m highly significantly co-occurred with BCL2m (p=0.0001). From an unsupervised ICL clustering (based on a distance matrix derived from the presence or absence of variants within the 44 genes), 67/86 pts (78%) with one or more somatic variant could be classified into four distinct genetic groups: group M/K (n=21 patients 24% enriched in MYCm, EZH2m and KMT2Dm; group S (n=18 patients 20%, enriched in SOCS1m, B2Mm, STAT6m and PIM1m), group B (n=17 patients 19%, enriched in BCL2m, GNA13m, TNFSRF14m and MEF2Bm) and group M/C (n=11 patients 12%, enriched in MYD88m and CD79Bm) (figure 1). Within B and M/K groups, the vast majority had a GCB COO status (n=17/17 100% in the B group and n=19/21 90% in the M/K group), whereas within M/C and S groups the COO status was evenly distributed (n=5 GC versus vs n=5 non-GC in M/C group; n=7 GC vs n=8 non-GC in S group). Based on their distinct patterns these four genetic groups could serve as a basis for molecular driven targeted therapeutic approaches; such as epigenetics modifiers for M/K group, JAK-STAT pathway inhibitors for S group, BCL2 and apoptosis inhibitors for B group and BTK downstream inhibitors for M/C group. As an exploratory analysis, univariate prognostic analysis for OS was performed. A shorter OS was associated with ECOG performance status ≥2 vs 0-1 (p<0.0001) and Ann Arbor stage III-IV vs I-II (p=0.0023); while the other clinical characteristics were not found significantly associated (including age ≥ 60 y/o vs <60 y/o p=0.2741 and LDH elevated vs non-elevated p=0.1883). Among the most recurrently altered genes, a shorter OS was associated with GNA13m (p=0.0009), CARD11m (p=0.0147), CDKN2Am (p=0.0192) and MYCm (p=0.0220); whereas no significant association was found between the four distinct genetic patient’s groups (p=0.7301).
Conclusion. A molecular tumor characterization of patients with R/R DLBCL emphasizes high incidence of TP53 and epigenetic modifying oncogenes CREBBP and KMT2D mutations. Four distinct genetic clusters were identified that could serve as the basis for a molecular-matched therapeutic approach.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The histone methyltransferase EZH2 has an essential role in the development of follicular lymphoma (FL). Recurrent gain-of-function mutations in EZH2 have been described in 25% of FL patients and ...induce aberrant methylation of histone H3 lysine 27 (H3K27). We evaluated the role of EZH2 genomic gains in FL biology. Using RNA sequencing, Sanger sequencing and SNP-arrays, the mutation status, copy-number and gene-expression profiles of EZH2 were assessed in a cohort of 159 FL patients from the PRIMA trial. Immunohistochemical (IHC) EZH2 expression (n=55) and H3K27 methylation (n=63) profiles were also evaluated. In total, 37% of patients (59/159) harbored an alteration in the EZH2 gene (mutation n=46, gain n=23). Both types of alterations were associated with highly similar transcriptional changes, with increased proliferation programs. An H3K27me3/me2 IHC score fully distinguished mutated from wild-type samples, showing its applicability as surrogate for EZH2 mutation analysis. However, this score did not predict the presence of gains at the EZH2 locus. The presence of an EZH2 genetic alteration was an independent factor associated with a longer progression-free survival (hazard ratio 0.58, 95% confidence interval 0.36-0.93, P=0.025). We propose that the copy-number status of EZH2 should also be considered when evaluating patient stratification and selecting patients for EZH2 inhibitor-targeted therapies.
We investigated the activities of an ImmunoTOX board, an academic, multidisciplinary group of oncologists and organ specialists that adopts a real-life, case-by-case approach in the management of ...patients with immune-related adverse events (irAEs).
The ImmunoTOX assessment board was set up in 2016 at Gustave Roussy in France. It meets every 2 weeks to discuss the case-by-case management of patients presenting with irAEs. Here, we describe the ImmunoTOX board's activities between 2016 and 2019.
Over study period, 398 requests (concerning 356 patients) were submitted to the ImmunoTOX board. Most of the requests concerned the putative causal link between immunotherapy and the irAE (n = 148, 37%), followed by possible retreatment after temporary withdrawal because of an adverse event (n = 109, 27%), the clinical management of complex situations (n = 100, 25%) and the initiation of immunotherapy in patients with pre-existing comorbidities (n = 41, 10%). The ImmunoTOX board discerned 273 irAEs. The five organ systems most frequently involved by irAEs were lung (n = 58, 21%), gastrointestinal tract (n = 36, 13%), liver or biliary tract (n = 33, 12%), musculoskeletal system (n = 27, 10%), and nervous system (n = 23, 8%). The time to occurrence was shorter for severe irAEs (grade III and VI) than for mild irAEs (grades I and II), with medians of 47 and 91 days, respectively (p = 0.0216).
The main medical needs in the management of irAEs involved the lung organ. Severe irAEs were expected to occur earlier than mild irAEs. This real-life study can help to better estimate medical needs and therefore help to assess the management of irAEs.
•Severe irAEs (grade III-IV) occurred earlier than mild irAEs (grade I-II) in this study.•The main medical needs in the management of immune-related adverse events (irAEs) involved the lung organ.•Rechallenge after previous irAE was assessed as feasible in 65% of cases.•Initiation of immunotherapy in patients with autoimmune comorbidity was assessed as feasible in 93% of cases.•A multidisciplinary approach could help to better appraise and manage irAEs in real life.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
We aimed to define the depth and time of maximal anti-tumour response to programmed death-1 blockade antibodies (anti-PD1) in heavily pre-treated patients with classical Hodgkin lymphoma (HL). To ...this end, we evaluated the kinetics of response for up to two years.
The 18F-FDG positron-emission tomography (PET) and contrast-enhanced computerised tomography (CECT) data of all relapsed or refractory HL treated at Gustave Roussy, Villejuif, France, from 2013 to 2015 were retrospectively reviewed according to the International Harmonisation Project Cheson 2014 criteria and the LYmphoma Response to Immunomodulatory therapy Criteria (LYRIC).
Sixteen patients were included. The median (range) treatment duration was 18.4 (2.8–23.7) months. Fifty-six percent of patients (9/16) achieved an objective response at 3 months, including 19% (3/16) of complete response. Seventeen percent (1/6) of partial responders at 3 months were converted in a complete response. 22% (2/9) of responders at 3 months relapsed before one year. The nadir was reached at 12.7 (3.0–23.0) months. The median (range) depth of response at nadir was −77% (−50% to 100%).
We concluded that complete metabolic responses occurred within 6 months, a minority of partial responses were converted in complete response, and the median nadir was observed one year after treatment initiation. These data could help to better define the optimal treatment strategy by PET or CECT-directed approaches.
•Anti-PD1 induced an early anti-tumour activity, as compared with the pre-treatment period in 6/6 patients.•62% (10/16) of patients experienced an objective response.•22% (2/9) of 3-month responders relapsed before one year.•17% (1/6) of 3-month partial responders were converted in a complete response.•The nadir was observed 12.7 months after anti-PD1 initiation with a depth of response at −77%.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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