ORCID Profile
0000-0002-0081-1255
Current Organisation
Institut Paoli-Calmettes
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Publisher: American Society of Hematology
Date: 05-11-2020
DOI: 10.1182/BLOOD-2020-139971
Abstract: Introduction Clonal selection is one of the mechanisms leading to therapy-related myeloid neoplasms (TRMN). A preexisting somatic mutation in hematopoietic stem cell (defined as clonal hematopoiesis [CH]) emerges under pressure of chemotherapy or radiotherapy, leading to TRMN development. Most of these mutations belong to the DNA damage response (DDR) pathway as TP53 or PPM1D mutations and are known to confer a dismal prognosis. Recently authorized for the treatment of ovarian cancers (OC), the poly (ADP-ribose) polymerase inhibitors (PARPi) represent a promising targeted therapy. However, by inducing DNA damage and altering DNA repair process, PARP inhibition could represent a challenge for the genetic stability of the healthy tissues. Thus, we assessed the effect of PARP inhibition on the development of CH and TRMN after PARPi treatment for OC (TRMN-PARPi) in combination with chemotherapies. Methods Firstly, we performed a targeted 77 genes mutational analysis using Next Generation Sequencing (NGS) in 13 patients exposed to PARPi without TRMN. Secondly, we retrospectively identified, with the help of the UNIHEM group of Unicancer, 17 patients who experienced TRMN-PARPi. Clinical, biological and survival data were collected and compared to 23 OC patients with TRMN not treated with PARPi (Gustave Roussy institutional database). Lastly, NGS was performed for 3 patients with TRMN-PARPi with sequential s ling. Patient's s les were obtained with informed consent. Results Thirteen OC patients during maintenance treatment with PARPi without TRMN were explored by NGS. Median age at NGS was 64.5 years old (yo) (40.5-75.3). 4/13 (31%) patients harbored BRCA1/2 germline mutation. Time between OC diagnosis and NGS was 4.3 y (1-11.6). The median number of chemotherapy line at PARPi initiation was 2 (1-3). 7 received Olaparib, 5 Niraparib and 1 Rucaparib. The median duration of PARPi treatment before NGS was 4.7 months (1.1-25.1). 12/13 patients experienced hematological toxicities during the PARPi treatment. CH was found in 10/13 (77%) patients (Figure 1a), including mutations of DDR genes in 8/10 (80%). 6/8 (75%) patients had 2 or more gene mutations. Next we identified 17 cases of TRMN occurring during or after PARPi administration for OC (6/17 [35%] t-AML and 11/17 [65%] t-MDS). 12/17 (71%) patients had BRCA germline mutations (7 BRCA1 and 5 BRCA2). All received Olaparib with a median dose of 600mg/d (400-1200). Median duration of Olaparib treatment was 1.7 years (0.2-4.6). TRMN-PARPi were described 1.4 months (0-10.9) after the end of PARPi administration. We compared these patients to a cohort of TRMN post OC not treated by PARPi. Number of therapy lines for OC, time between TRMN and OC diagnosis, median age at TRMN, were, for TRMN-PARPi, 2 (1-8), 5.9 y (0.9-20.8), 64.4 yo (46-74) respectively, compared to 3 (1-8), 4.9 y (1.7-36.9), 59.3 yo (35.7-85.7) (p=ns). TRMN-PARPi cytogenetic was unfavorable for 16/17 (94%) (including 11/17 [65%] complex karyotype) compared to 16/23 (70%) (11/23 [48%] complex karyotype). C Median survival was significantly lower in the TRMN-PARPi group 3.9 months 95%CI [2.0-9.7] and 6.1 months 95%CI [4.1-15.8] respectively, p=0.046, Fig 1b). However, median survival from OC diagnosis was not different between the two groups 6.2 y 95%CI [5.6-NA] for TRMN-PARPi vs 5.6 y 95%CI [5.0-11.6]. NGS was available for 8/17 TRMN-PARPi and revealed mutations in DDR genes in 7/8 patients (6 patients with TP53 mutation, 2 with PPM1D mutation). For 3 patients, we had s les from OC stage, before PARPi administration. We found that mutations from TRMN stage were present at lower frequency, confirming clonal selection by PARPi treatment (Figure 1c). Conclusions Here we described, for the first time, a cohort of TRMN patients previously treated with PARPi for an OC. Intriguingly, most of these TRMN occurred with a short latency at the end of PARPi treatment, with unfavorable cytogenetic and very short OS. Moreover, we found a very high percentage of CH involved in the DDR pathway (62%) in patients under PARPi treatment without TRMN suggesting a potential clonal selection which could lead ultimately to TRMN. PARPi are now indicated in 1rst line high grade OC regardless of BRCA status, which should expand indications. Benefit for OC patients is not questionable however, caution will be warranted for patients with CH before PARPi treatment, especially implicating DDR mutations. Etienne: Incyte: Consultancy, Speakers Bureau Pfizer: Consultancy, Speakers Bureau Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau Novartis: Consultancy, Research Funding, Speakers Bureau.
Publisher: American Society of Hematology
Date: 15-11-2013
DOI: 10.1182/BLOOD.V122.21.3221.3221
Abstract: Several studies have demonstrated the impact of VTd on response rates and PFS either as induction or consolidation regimen. However, studies have also showed that VGPR and greater was associated with a better survival prognostic at completion of intensification regimen, and that these patients benefited most from consolidation. Questions remain as to the benefit of consolidation using VTd in patients that reached solely PR at completion of VTd induction, patients that display features of resistance to VTd partially. We aimed to assess the efficacy and safety of VTd as consolidation therapy in the context of VTd as induction regimen followed by a single auto (VTd-auto-VTd regimen) in patients that reached PR at completion of Induction with VTd. This study has included a group of 121 newly diagnosed MM patients that underwent auto from 2009 to 2011 across 9 IFM centers. Patients were to be eligible for auto in first-line of treatment, aged less than 65 years old and treated with VTd-auto-VTd regimen. We then studied the 54 patients that reached PR (n=54) at completion of VTd induction. The median age was 57 years, the sex ratio was 1,25, 58% had ISS 2 and 3, 25% had adverse FISH, including t(4 ) and/or del17p (similar in the 2 groups). Overall, 37 (68%) responded (at least VGPR) at completion of consolidation, including 33% and 35% that reached VGPR and CR, respectively. 55% and 37.5% of patients improved response rate after auto and consolidation, respectively. We then studied the role of consolidation whether or not patients responded to auto. Out of the 15 patients that remained on PR after auto (no benefit from auto), 35% responded at completion of consolidation. Out of the 31 patients that improved response rate to auto (at least VGPR), 32% further improved to CR at completion of consolidation. The median duration of response was prolonged from 10 (CI95% 10-14) months to 16 (13-20) months for patients in PR at completion of induction with VTd that further responded to consolidation VTd (p=0.24). With a median follow-up of 36 months, 30% and 11% had relapsed and died, respectively. The incidence rate of relapse was greater in patients that did not benefit from consolidation, 86% versus 14%, (p=0.27). The median TTP was 26 (95%CI 13-38) months in patients that did not benefit from consolidation versus not reached yet for the second group (p=0.012) the 3-year TTP was 18% and 87%. The 3-year PFS was 18% and 58%, respectively (p=0.03). The median OS was not reached in either group, and the 2-years OS was 75%. In univariate analysis, the variables that shortened TTP were high serum beta2m greater than 5mg/L (p=0.014), adverse FISH (p=0.05), elevated serum LDH (p .0001), absence of response following auto (p=0.022) and absence of response following consolidation (p=0.012). We have then sought for independent variables that impacted TTP in multivariate analysis after exclusion of LDH, beta2m and FISH known to be the most powerful predicators of short TTP and OS. The response to consolidation was then the most important marker to predict shorten median TTP [OR = 4.4, 95%CI = 1-21 p = 0.039]. The safety profile of VTd consolidation in this population was similar to reports in patients that reached VGPR and greater at completion of induction with no excess toxicity. The incidence rate of hematological EIs of grade 3 and 4 was 2% with no excess and non hematological EIs related to consolidation. The incidence rate of neuropathy all grades was 7%, but only 2% occurred during the consolidation. We have also observed 9 (9%) thromboembolic events (TE), with none occurring during the consolidation phase. This study showed an improved response rate in relation to the VTd consolidation phase in two-third of patients that only partially responded to the induction VTd regimen. This improved quality of responses translated into a lower relapse rate with a prolonged PFS. This study demonstrates that VTd consolidation in the context of a the VTd-auto-VTd regimen upfront should be recommended to all responders to the induction phase, including patients in PR characterized with a lower sensitivity to the VTd regimen. Leleu: Amgen: Honoraria Millennium : Honoraria Leopharma: Consultancy, Honoraria Onyx: Consultancy, Honoraria Celgene: Consultancy, Honoraria Janssen: Consultancy, Honoraria Novartis: Honoraria. Roussel:CELGENE: Honoraria JANSSEN: Honoraria. Facon:JANSSEN: Honoraria, Speakers Bureau CELGENE: Honoraria, Speakers Bureau. Attal:JANSSEN: Honoraria, Speakers Bureau CELGENE: Honoraria, Speakers Bureau. Moreau:JANSSEN: Honoraria, Speakers Bureau CELGENE: Honoraria, Speakers Bureau.
Publisher: American Association for Cancer Research (AACR)
Date: 09-09-2019
DOI: 10.1158/1078-0432.22488773
Abstract: Patient characteristics of the national cohort according to the type of PARPi received (olaparib vs. other PARP inhibitors).
Publisher: MDPI AG
Date: 09-11-2021
Abstract: Venetoclax is a BH3-mimetics agent specifically interacting with the antiapoptotic protein BCL-2, facilitating cytochrome c release from mitochondria, subsequent caspases activation, and cell death. Utilization of venetoclax has profoundly changed the landscape of treatment for the poor-prognosis category of AML patients unfit for intensive chemotherapy. In the phase III VIALE-A study, Venetoclax, in combination with the hypomethylating agent azacitidine, showed a 65% overall response rate and 14.7-month overall survival, in comparison with 22% and 8 months in the control arm. These results led to the widespread use of venetoclax in this indication. Other combination regimens, consisting of low-intensity, intensive, or targeted therapies are currently under evaluation. Despite promising results, preventing relapses or resistance to venetoclax is still an unmet clinical need. Numerous studies have been conducted to identify and overcome venetoclax resistance in preclinical models or in clinical trials, including the inhibition of other antiapoptotic proteins, the induction of proapoptotic BH3-only proteins, and/or the targeting of the mitochondrial metabolism and machinery.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488776
Abstract: Univariate analysis for overall survival from t-MN diagnosis of patients from the national cohort.
Publisher: Springer Science and Business Media LLC
Date: 02-11-2015
DOI: 10.1038/BMT.2015.257
Publisher: Walter de Gruyter GmbH
Date: 04-09-2014
Publisher: American Society of Hematology
Date: 15-11-2022
Publisher: Informa UK Limited
Date: 2023
DOI: 10.2147/OTT.S236740
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 08-11-2013
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488797.V1
Abstract: Flow chart of the study displaying the three cohorts.
Publisher: Informa UK Limited
Date: 22-07-2016
DOI: 10.1080/13543784.2016.1208170
Abstract: Although the combination of an anti-CD20 monoclonal antibody and chemotherapy has widely improved survival of patients with B-cell lymphoma, the disease still relapses. A better understanding of the biology of lymphomas has highlighted the role of the cell of origin in response to treatment and outcome. Lenalidomide represents an attractive therapeutic option due to its original mechanism of action. In this review, the authors describe the pharmacological properties of lenalidomide, and the rational for its use in B-cell lymphomas focusing on diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL). They discuss the mechanism of action of the drug and its current and future clinical development. They also review the current data in relapsed/refractory situations as well as in first-line treatment. Lenalidomide is an oral non-chemotherapy immunomodulatory agent with an acceptable toxicity profile and manageable side-effects. Efficacy has widely been demonstrated, especially in MCL, FL and non-Germinal Center DLBCL patients. Further studies are now warranted to better define the strategy for the use of lenalidomide in B-NHL patients, and clarify which subgroup of patients will really benefit of lenalidomide as part of first-line treatment or in a relapsed/refractory setting.
Publisher: Oxford University Press (OUP)
Date: 07-02-2018
DOI: 10.1093/NAR/GKY080
Publisher: Elsevier BV
Date: 03-2014
Abstract: This study investigated a possible link between the occupational or domestic exposure to animals and a histological subgroup of non-Hodgkin lymphomas (LNH) (diffuse large B-cell lymphomas [LDGCB], follicular lymphomas [LF], indolent non-follicular LNH [LNHINF] and T-cell LNH). This retrospective, descriptive study was carried out over one year in a regional cancer research center. Data on occupational and domestic exposures to animals, from patients treated for a LNH, was collected via a questionnaire. Among the 261 participants, 73.9% reported they had been exposed to animals, 5% were exposed at work, whereas 72.4% were exposed in a domestic setting. The occupational exposure tended to be more frequent in the subgroup of patients with a LF (P = 0.06). The domestic exposure was less frequent (P = 0.04) in patients with LDGCB (63.0%) than in patients with a small cell LNH B (LF and LNHINF) (76.0%). Although there was no obvious link between occupational or domestic exposure to animals and one of the four histological subgroups of LNH, domestic exposure seemed less common among LDGCB patients. These results need to be confirmed by further studies.
Publisher: American Society of Hematology
Date: 05-11-2021
DOI: 10.1182/BLOOD-2021-145424
Abstract: Although the BCL2 inhibitor venetoclax have been transformative in the management of AML, therapeutic resistance and relapse are frequently observed. In light of the urgent need to uncover novel therapeutic options in AML, we sought to study the potential role of ironomycin (AM5), a recently described small molecule that induces cell death through the sequestration of lysosomal iron. To evaluate the effects of ironomycin in AML, we chose a erse panel of AML cell lines. These data showed a potent and dose-dependent effect, on proliferation, cell cycle progression and survival at a nanomolar range. In contrast to venetoclax, the cell death induced by ironomycin did not result in potent caspase activation or PARP1 cleavage. Neither the caspase inhibitor Z-VAD-fmk nor the necroptosis inhibitor necrostatin-1 did prevent cell death. Consistent with previous observations, we found that ironomycin accumulates in the lysosomes of AML cells leading to a sequestration of iron in this organelle but inhibitors of canonical ferroptosis, including ferrostatin-1 and liproxstatin-1 failed to prevent the activity of ironomycin. To gain greater insight into the molecular mechanism of ironomycin in AML cells, we performed a genome-wide positive-selection resistance screen under ironomycin selection pressure and collected several s les for sequencing. We found nine genes whose knock out conferred resistance to the drug. Interestingly, these data implicated key components of mitochondrial metabolic pathways, including phosphoglycolate phosphatase (PGP), a central phosphatase involved in glycolysis and pentose phosphate pathway (PPP) regulation and Hexokinase 2 (HK2), the first enzyme of glycolysis. Mass-spectrometry metabolomics analyses highlighted that ironomycin treatment significantly reduced key components of the TCA cycle and consequently the reducing agent nicotinamide adenine dinucleotide (NADH) and increased the intracellular concentration of amino acids. These data were corroborated with RNAseq showing a mitochondrial stress response mediated through the Activating Transcription Factor 4 (ATF4) and its paralog Activating Transcription Factor 5 (ATF5). As mitochondria are major hubs of iron utilization for oxidative respiration, we used Mass-spectrometry to measure mitochondrial iron load. We observed a rapid and dose-dependent decrease in mitochondrial iron after treatment mirroring the iron sequestration into the lysosomes and inducing the mitochondrial dysfunction. We next examined the ultrastructural appearance of mitochondria after ironomycin using transmission electron microscopy and observed a dramatic alteration of the structural integrity of mitochondria resulting in abnormal cristae, matrix density changes and mitochondrial membrane blebbing. In cells lacking BAX and BAK, the two main effectors of mitochondrial membrane permeabilization, structural changes and cell death were almost completely rescued but cell proliferation was still markedly affected, consistent with a BAX/BAK dependent cell death following mitochondrial iron deprivation. In vivo imaging confirmed that BAX activation occurred after 30 hours of treatment and preceded cell death, but we observed some major differences with canonical apoptosis induced by venetoclax. First, the structural alterations were clearly distinct. Next, delay between MOMP and cell death was significantly longer and caspase inhibitors weakly delayed cell death. Finally, BCL2 overexpression and P53 deletion did not rescue ironomycin cell death. These non-canonical features prompted us to assess the efficacy of the combination between ironomycin and venetoclax. In vitro experiment on AML cell lines found a high synergy between the two drugs. In vivo experiments on xenotransplanted mice confirmed the efficacy of the combination, which was associated with a significant increase in mice survival in comparison with the controls (Figure). Finally, primary AML s les from patients clinically resistant or refractory to venetoclax were sensitive to ironomycin in monotherapy and even more in combination with venetoclax. These results demonstrate that the novel mechanism of ironomycin action can be leveraged to resensitize AML cells to venetoclax and substitute for cytotoxic drugs as a more effective therapeutic combination in the salvage setting. Figure 1 Figure 1. Huang: The Walter and Eliza Hall Institute of Medical Research: Patents & Royalties: Employee of the Walter and Eliza Hall Institute and eligilble for payments in relation to venetoclax. Wei: Novartis, Celgene, AbbVie, Servier, AstraZeneca, and Amgen: Research Funding Novartis, Janssen, Amgen, Roche, Pfizer, Abbvie, Servier, BMS, Macrogenics, Agios, Gilead: Membership on an entity's Board of Directors or advisory committees Astellas: Honoraria.
Publisher: American Society of Hematology
Date: 15-11-2022
Publisher: Springer Science and Business Media LLC
Date: 06-2015
DOI: 10.1038/BMT.2015.79
Publisher: American Society of Hematology
Date: 16-11-2012
DOI: 10.1182/BLOOD.V120.21.3096.3096
Abstract: Abstract 3096 Several studies have demonstrated the impact of VTd on response rates and PFS either as induction or consolidation regimen. However there are limitations to these studies, especially that no data is available regarding the role of VTd consolidation in the context of bortezomib-triple based VTd induction regimen followed by a single auto. At completion of therapy, the response rate (ORR, PR and better) was 89%, VGPR+CR rate 74%, CR rate 29%, relapse rate and median PFS was 53% and 26 months (median F-up 32 months) in the VTd arm of the phase 3 IFM2007-02 trial conducted for newly diagnosed MM (Moreau et al, Blood 2012). In this study, only a minority of patients had received a consolidation or maintenance. On the other hand, Cavo et al. (Blood 2012) reported 97.5%, 92%, 61%, 39% 3-year progression and 62% estimated 5-year PFS (F-up 43 months) respectively in the VTd arm. VTd was given as induction before and consolidation after double auto in this upfront GIMEMA phase 3 trial (Cavo et al, Lancet 2010). We aimed to assess the efficacy and safety of VTd as consolidation therapy in the context of VTd as induction regimen followed by a single auto (VTd-auto-VTd regimen). This study has included a first group of 121 newly diagnosed MM from 2009 to 2011 across 9 IFM centers. Patients were to be eligible for auto upfront, aged less than 65 and treated with VTd-auto-VTd regimen. The second cohort included MM treated with VTd-auto without consolidation from the IFM2007-02 trial (n=76). A third cohort comprised MM that received upfront a triplet Vd-based combination induction (VCd, VRd) -auto without consolidation (n = 40). In the whole study, the median age was 56 years, the sex ratio was 1,49, 50% had ISS 2 and 3, 22% had adverse FISH [t(4 ) del17p] (similar in the 3 groups). Overall, the ORR was identical in the 3 cohorts at completion of therapy, 104 (86%), 72 (94%) and 32 (80%) for the cohort 1 to 3, respectively. Nevertheless, the CR rate was significantly greater in patients that received a consolidation (cohort 1), as compared to the cohorts 2 and 3 that did not receive any consolidation, 59 (53%) vs. 26 (34%) and 13 (32.5%), respectively (p=0.0001). Interestingly, the CR rates were identical at the end of the induction in the 3 cohorts, 13%, 15% and 22.5%, respectively. With a median follow-up of 25 months, the incidence rate of relapse was significantly greater in the cohort 2 and 3 versus 1, further demonstrating the importance of the consolidation, 25 (21%), 42 (55%) and 13 (32.5%) patients (p=0.0001), respectively and 9 (8%), 6 (8%) and 8 (20%) had died in cohorts 1 to 3 (p=0.07). The median (95%CI) PFS was not reached in cohort 1, and was 32 (28 ) months and 30 (26 ) months in cohort 2 and 3, respectively. Importantly, 54.5%, 32% and 32% of patients were free of relapse at 32 months in the 3 cohorts, respectively. Similar data were obtained for TTP. The median (95%CI) OS was not significantly different in cohorts 1 to 3, although not reached for the first 2 cohorts and 38 (33 ) months for the 3rdcohort. The 3-year survival was 84%, 91% and 76%, respectively (p=ns). A longer follow up will certainly demonstrate greater survival end points benefit in favor for consolidation. The safety profile of the cohort that contained a consolidation was superimposable to that of the remaining 2 cohorts without consolidation. The incidence rate of hematological EIs of grade 3 and 4 was 4%, 6% and 8% in the 3 cohorts (p=ns), respectively. The incidence rate of neuropathy grade 1–2 and 3–4 was 5% and 2% in the cohort 1 with consolidation, but only 1% occurred during the consolidation. This data compares favorably to the 3% reported in the cohort 2 (Moreau et al. Blood 2012). We have also observed 9 (9%) thromboembolic events (TE), 8 of venous type and 1 arterial. None of them happened during the consolidation, and again, this incidence rate if superimposable to that reported in the IFM2007-02 vTd cohort. This study showed an impressive increase in CR rate in relation to the consolidation that translated into a lower relapse rate. This study also demonstrated that the VTd regimen, used both as induction and consolidation, in the context of a single auto upfront in MM, significantly contributed to improve clinical outcomes with an acceptable toxicity profile. VTd-auto-VTd compared very favorably to the other upfront protocols, and may become in the near future a standard of care in newly diagnosed patients with Myeloma. Leleu: Celgene: Honoraria, Research Funding, Speakers Bureau Janssen: Honoraria, Research Funding, Speakers Bureau Novartis: Honoraria, Research Funding Amgen: Honoraria, Research Funding Sanofi: Honoraria Onyx: Honoraria, Speakers Bureau LeoPharma: Honoraria, Speakers Bureau. Off Label Use: Pomalidomide. Roussel:celgene: Honoraria janssen: Honoraria. Facon:onyx: Membership on an entity's Board of Directors or advisory committees celgene: Membership on an entity's Board of Directors or advisory committees janssen: Membership on an entity's Board of Directors or advisory committees millenium: Membership on an entity's Board of Directors or advisory committees. Attal:celgene: Membership on an entity's Board of Directors or advisory committees janssen: Membership on an entity's Board of Directors or advisory committees.
Publisher: Wiley
Date: 14-03-2018
DOI: 10.1002/AJH.25077
Abstract: 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
Publisher: Wiley
Date: 08-2018
DOI: 10.1002/AJH.25154
Abstract: 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 pretreated 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 pretreated HL patients suggest that anti‐PD‐1 therapy might re‐sensitize tumor cells to CT.
Publisher: Cold Spring Harbor Laboratory
Date: 24-08-2023
DOI: 10.1101/2023.08.22.553791
Abstract: Caspase-2, one of the most evolutionarily conserved member of the caspase family, is an important regulator of the cellular response to oxidative stress. Given that ferroptosis is suppressed by antioxidant defense pathways, such as that involving selenoenzyme glutathione peroxidase 4 (GPX4), we hypothesised that caspase-2 may play a role in regulating ferroptosis. This study provides the first demonstration of an important and unprecedented function of caspase-2 in protecting cancer cells from undergoing ferroptotic cell death. Specifically, we show that depletion of caspase-2 leads to downregulation of stress response genes including SESN2, HMOX1, SLC7A11 and sensitises mutant-p53 cancer cells to cell death induced by various ferroptosis inducing compounds. Importantly, the canonical catalytic activity of caspase-2 is not required for its role and suggests that caspase-2 regulates ferroptosis via non-proteolytic interaction with other proteins. Using an unbiased BioID proteomics screen, we identified novel caspase-2 interacting proteins (including heat shock proteins and co-chaperones) that regulate cellular responses to stress. Finally, we demonstrate that caspase-2 limits chaperone mediated autophagic degradation of GPX4 to promote survival of mutant-p53 cancer cells. In conclusion, we document a novel role for caspase-2 as a negative regulator of ferroptosis in cells with mutant-p53. Our results provide evidence for a novel function of caspase-2 functions in cell death regulation and open potential new avenues to exploit ferroptosis in cancer therapy.
Publisher: John Libbey Eurotext
Date: 03-2015
Publisher: Ivyspring International Publisher
Date: 2014
DOI: 10.7150/JCA.8541
Publisher: Wiley
Date: 18-12-2015
DOI: 10.1111/BJH.13879
Publisher: John Libbey Eurotext
Date: 2013
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488779.V1
Abstract: TP53 mutations characteristics among t-MN PARPi national cohort.
Publisher: American Association for Cancer Research (AACR)
Date: 03-2022
DOI: 10.1158/2159-8290.CD-21-0522
Abstract: Ironomycin couples targeting of cellular metabolism with cell death by reducing mitochondrial iron, resulting in the alteration of mitochondrial metabolism and the activation of BAX/BAK. Ironomycin induces MOMP through a different mechanism to BH3 mimetics, and consequently combination therapy has marked synergy in cancers such as acute myeloid leukemia. This article is highlighted in the In This Issue feature, p. 587
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488782.V1
Abstract: Univariate analysis for overall survival from t-MN diagnosis of patients diagnosed with t-MN after OC according to PARPi exposure.
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 23-07-2015
Publisher: American Association for Cancer Research (AACR)
Date: 24-12-2030
DOI: 10.1158/1078-0432.C.6532808
Abstract: AbstractPurpose: To provide insights into the diagnosis and management of therapy-related myeloid neoplasms (t-MN) following PARP inhibitors (PARPi). Experimental Design: In a French cancer center, we identified and described the profiles of 13 t-MN diagnosed among 37 patients with ovarian cancer referred to hematology consultation for cytopenia under PARPi. Next, we described these 13 t-MN post-PARPi among 37 t-MN post ovarian cancer according to PARPi exposure. Finally, we described 69 t-MN post-PARPi in a national cohort. Results: From 2016 to 2021, cumulative incidence of t-MN was 3.5% (13/373) among patients with ovarian cancer treated with PARPi. At time of hematologic consultation, patients with t-MN had a longer PARPi exposure (9 vs. 3 months, i P /i = 0.01), lower platelet count (74 vs. 173 G/L, i P /i = 0.0005), and more cytopenias (2 vs. 1, i P /i = 0.0005). Compared with t-MN not exposed to PARPi, patients with t-MN-PARPi had more i BRCA1/2 /i germline mutation (61.5% vs. 0%, i P /i = 0.03) but similar overall survival (OS). In the national cohort, most t-MN post-PARPi had a complex karyotype (61%) associated with a high rate of i TP53 /i mutation (71%). Median OS was 9.6 months (interquartile range, 4–14.6). In multivariate analysis, a longer time between end of PARPi and t-MN (HR, 1.046 i P /i = 0.02), olaparib compared with other PARPi (HR, 5.82 i P /i = 0.003) and acute myeloid leukemia (HR, 2.485 i P /i = 0.01) were associated with shorter OS. Conclusions: In a large series, we described a high incidence of t-MN post-PARPi associated with unfavorable cytogenetic and molecular abnormalities leading to poor OS. Early detection is crucial, particularly in cases of delayed cytopenia. /
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 19-12-2014
Publisher: American Society of Hematology
Date: 07-12-2017
DOI: 10.1182/BLOOD.V130.SUPPL_1.652.652
Abstract: Introduction: Hodgkin lymphoma (HL) pts who relapse after high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) and brentuximab vedotin (BV) therapy have a poor outcome. For these relapsed and refractory (R/R) HL pts, anti-PD-1 therapy gives a high rate of objective responses. However, the rate of complete response (CR) remains modest and in the updated results of anti-PD-1 therapy clinical trials, about 50% of pts are still without progressive disease after one year of treatment. As anti-PD-1 therapy modifies the anticancer immune response, we hypothesize that anti-PD-1 therapy may increase sensitivity to chemotherapy (CT) given after anti-PD-1 therapy (sequential strategy) or in combination with anti-PD-1 therapy after an unsatisfactory response to immunotherapy (concomitant strategy). We retrospectively analyzed these two clinical situations in 30 R/R HL pts from LYSA centers treated with anti-PD-1 therapy. Methods: We included R/R HL pts from 14 LYSA centers who received anti-PD-1 therapy in the context of clinical trials (N=4) or an authorization for temporary use (ATU) from the French medical drug agency (N=26). Before the anti-PD-1 therapy, pts had received a median of six (range, 2-14) lines of therapy, 69% had HDT+ASCT, 14% had allograft and 93% had been treated with BV. We considered two groups of pts: i. 19 pts (63%) in whom the anti-PD-1 therapy was stopped at the introduction of CT (Group 1) ii. 11 pts (37%) with an unsatisfactory response to anti-PD-1 therapy in whom a combination of CT with immunotherapy was initiated to optimize the response (Group 2). The quality of the response after the introduction of CT was evaluated retrospectively by each treating physicians according to Cheson 2007 or 2014 criteria. We also determined whether new CT treatments after and in combination with anti-PD-1 therapy led to unexpected toxicities and whether new treatment schedules made pts eligible for allograft. Results: At the start of anti-PD-1, the median age of pts was 37 years old (range, 20-75), 24% had Ann Arbor III/IV stages, 34% had B symptoms and 21% had a performance status (PS) of 2-3. Patients received a median of 10 infusions (range, 2-52) of anti-PD-1 therapy with nivolumab (N=26, 87%) or pembrolizumab (N=4, 13%). The best responses achieved during anti-PD-1 therapy were a complete response (CR) for 5 patients, a partial response (PR) for 17 pts, stable disease (SD) for 2 pts and progression for 6 pts. In group 1, 17 pts were in progression, one pt in PR, and another pt in SD at the end of anti-PD-1 therapy alone. In group 1, after anti-PD-1 therapy, the pts were treated with vinblastine (N=3), gemcitabine (N=2) or bendamustine alone (N=3) or in combination with BV (N=4), GVD (N=1), ICE (N=1), DHAP (N=1), escalated BEACOPP (N=1), vinorelbine (N=1), vepeside (N=1) and caelyx (N=1). In group 2, before the combination, the response status was progression for 7 pts and PR for 4 pts. In group 2, to optimize the response to anti-PD-1, pts received vinblastine (N=7), gemcitabine (N=2) and BV (N=2). In the 28 evaluable pts, 11/18 (61%) in group 1 and 9/10 (90%) in group 2 showed an improved response after chemotherapy alone or combination with anti-PD-1 therapy respectively. In group 1, there were 6 CR (32%), 5 PR (26%), 1 SD (5%) and 6 PD (32%) (Figure 1B). In group 2, there were 5 CR (45%), 5 PR (45%) and 1 SD (10%) (Figure 1A). Of note, among the ten pts treated with vinblastine, 4 were in CR, 3 in RP, 1 in SD and 2 in progression. No unexpected toxicity was observed during the CT. Four pts had an allograft after the sequential CT (N=3) and concomitant CT strategy (N=1). Three pts were in CR 274, 279 and 480 days after the allograft and the fourth has not yet been evaluated. Allografts are now scheduled for 6 pts. With a median follow-up of 9.1 months (95%CI, 6.1-14) following the initiation of chemotherapy (alone or combined) the median PFS and OS were 8.4 and 14.6 months, respectively. Conclusions: Our retrospective study showed that pts with an unsatisfactory response or PD with anti-PD-1 therapy had a new objective response with CT alone (61%) or CT in combination with anti-PD-1 therapy (90%). This response could make some pts eligible for allograft. Prospective clinical trials are needed to confirm the synergistic effect of CT with anti-PD-1 therapy and to determine which CT provides the best results in combination with these checkpoint inhibitors. Figure 1 Figure 1. Ysebaert: Janssen: Consultancy, Research Funding, Speakers Bureau. Ghesquières: Celgene and Mundipharma: Consultancy, Honoraria Roche: Research Funding.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488785.V1
Abstract: Commutation plot visualizing the mutated genes in t-MN after OC according to PARPi treatment.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488791
Abstract: Waffle chart (%) of patients addressed for cytopenia exploration after OC exposed to a PARPi treatment from cytopenia diagnosis (A) and cytopenia diagnosis based on NGS results (B). Dot plots (C) showing the median WBC, hemoglobin, and platelet counts from patients referred for cytopenia exploration after OC exposed to a PARPi treatment according to t-MN diagnosis (“t-MN”) or not (“Cytopenia”).
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.C.6532808.V1
Abstract: AbstractPurpose: To provide insights into the diagnosis and management of therapy-related myeloid neoplasms (t-MN) following PARP inhibitors (PARPi). Experimental Design: In a French cancer center, we identified and described the profiles of 13 t-MN diagnosed among 37 patients with ovarian cancer referred to hematology consultation for cytopenia under PARPi. Next, we described these 13 t-MN post-PARPi among 37 t-MN post ovarian cancer according to PARPi exposure. Finally, we described 69 t-MN post-PARPi in a national cohort. Results: From 2016 to 2021, cumulative incidence of t-MN was 3.5% (13/373) among patients with ovarian cancer treated with PARPi. At time of hematologic consultation, patients with t-MN had a longer PARPi exposure (9 vs. 3 months, i P /i = 0.01), lower platelet count (74 vs. 173 G/L, i P /i = 0.0005), and more cytopenias (2 vs. 1, i P /i = 0.0005). Compared with t-MN not exposed to PARPi, patients with t-MN-PARPi had more i BRCA1/2 /i germline mutation (61.5% vs. 0%, i P /i = 0.03) but similar overall survival (OS). In the national cohort, most t-MN post-PARPi had a complex karyotype (61%) associated with a high rate of i TP53 /i mutation (71%). Median OS was 9.6 months (interquartile range, 4–14.6). In multivariate analysis, a longer time between end of PARPi and t-MN (HR, 1.046 i P /i = 0.02), olaparib compared with other PARPi (HR, 5.82 i P /i = 0.003) and acute myeloid leukemia (HR, 2.485 i P /i = 0.01) were associated with shorter OS. Conclusions: In a large series, we described a high incidence of t-MN post-PARPi associated with unfavorable cytogenetic and molecular abnormalities leading to poor OS. Early detection is crucial, particularly in cases of delayed cytopenia. /
Publisher: Impact Journals, LLC
Date: 19-07-2017
Publisher: John Libbey Eurotext
Date: 07-2015
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488794
Abstract: Blood smear and bone marrow aspiration of patient referred for cytopenia post PARPi.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488791.V1
Abstract: Waffle chart (%) of patients addressed for cytopenia exploration after OC exposed to a PARPi treatment from cytopenia diagnosis (A) and cytopenia diagnosis based on NGS results (B). Dot plots (C) showing the median WBC, hemoglobin, and platelet counts from patients referred for cytopenia exploration after OC exposed to a PARPi treatment according to t-MN diagnosis (“t-MN”) or not (“Cytopenia”).
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488797
Abstract: Flow chart of the study displaying the three cohorts.
Publisher: Springer Science and Business Media LLC
Date: 02-03-2015
DOI: 10.1038/BMT.2015.22
Publisher: Springer Science and Business Media LLC
Date: 29-07-2012
Publisher: EMBO
Date: 11-10-2023
Publisher: Springer Science and Business Media LLC
Date: 11-02-2022
DOI: 10.1038/S41409-022-01596-8
Abstract: Cytarabine-based immuno-chemotherapy followed by autologous stem cell transplantation (ASCT) consolidation is standard of care for fit patients with Mantle Cell Lymphoma (MCL). BEAM (Carmustine, Etoposide, Aracytine, Melphalan) is among the most frequently used conditioning regimen. Studies comparing BEAM with Bendamustine-EAM (BeEAM) have suggested that patients treated with BeEAM have a better progression-free survival (PFS). We performed a cross-study analysis to better evaluate BeEAM. Thirty-five patients from a retrospective study who received R-DHAP/BeEAM were compared to 245 patients from the LyMa trial (NCT00921414) who all received R-DHAP followed by R-BEAM. PFS and Overall Survival (OS) were estimated using Kaplan-Meier methods. At 2 years there was no difference between R-BEAM and BeEAM in either PFS (84.9% versus 87.9% p = 0.95) or OS (91.8% versus 94.2% p = 0.30). Analyses were repeated on a propensity score to reduce biases. Each patient from the BeEAM cohort (n = 30) was matched to three patients from the R-BEAM cohort (n = 90) for age, sex, MIPI score, pre-transplant status disease and rituximab maintenance (RM). PFS and OS at 2 years remained similar between R-BEAM and BeEAM with more renal toxicity in BeEAM group. MCL patients who received R-DHAP induction before ASCT have similar outcome after R-BEAM or BeEAM conditioning regimen.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2014
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488776.V1
Abstract: Univariate analysis for overall survival from t-MN diagnosis of patients from the national cohort.
Publisher: American Association for Cancer Research (AACR)
Date: 06-10-2022
DOI: 10.1158/1078-0432.CCR-22-1622
Abstract: To provide insights into the diagnosis and management of therapy-related myeloid neoplasms (t-MN) following PARP inhibitors (PARPi). In a French cancer center, we identified and described the profiles of 13 t-MN diagnosed among 37 patients with ovarian cancer referred to hematology consultation for cytopenia under PARPi. Next, we described these 13 t-MN post-PARPi among 37 t-MN post ovarian cancer according to PARPi exposure. Finally, we described 69 t-MN post-PARPi in a national cohort. From 2016 to 2021, cumulative incidence of t-MN was 3.5% (13/373) among patients with ovarian cancer treated with PARPi. At time of hematologic consultation, patients with t-MN had a longer PARPi exposure (9 vs. 3 months, P = 0.01), lower platelet count (74 vs. 173 G/L, P = 0.0005), and more cytopenias (2 vs. 1, P = 0.0005). Compared with t-MN not exposed to PARPi, patients with t-MN-PARPi had more BRCA1/2 germline mutation (61.5% vs. 0%, P = 0.03) but similar overall survival (OS). In the national cohort, most t-MN post-PARPi had a complex karyotype (61%) associated with a high rate of TP53 mutation (71%). Median OS was 9.6 months (interquartile range, 4–14.6). In multivariate analysis, a longer time between end of PARPi and t-MN (HR, 1.046 P = 0.02), olaparib compared with other PARPi (HR, 5.82 P = 0.003) and acute myeloid leukemia (HR, 2.485 P = 0.01) were associated with shorter OS. In a large series, we described a high incidence of t-MN post-PARPi associated with unfavorable cytogenetic and molecular abnormalities leading to poor OS. Early detection is crucial, particularly in cases of delayed cytopenia.
Publisher: American Society of Hematology
Date: 02-12-2016
DOI: 10.1182/BLOOD.V128.22.1825.1825
Abstract: Although progression free survival and overall survival of patients with Hodgkin lymphoma (HL) has improved with modern treatment in the past 10 years, 10 % of patients will fail to conventional therapy and die of their lymphoma. The search of new prognostic factors for identifying these high risk patients at diagnosis of HL remains challenging in daily practice. The evaluation of the tumor microenvironnement was shown to help identifying a subset of patients treated with ABVD having a high risk of treatment failure (Tan KL et al, Blood 2012). PET positivity after 2 cycles of chemotherapy allows also identifying a subset of patients with poor outcome (Gallamini, JCO 2007) and PET-guided strategy were developed to improve the management of HL patients in order to either intensify treatment for high risk patients or deescalate treatment for sparing the others from toxicities. The aim of this study was therefore to evaluate the impact of baseline tumor microenvironnement in a large cohort of HL patients prospectively treated with upfront escalated BEACOPP in a randomized phase III clinical trial evaluating a PET-driven strategy (AHL 2011, NCT01358747) and to compare its prognostic value with other clinicopathological markers. Material and Methods Tumoral material was collected from May 2011 to May 2014 from HL patients prospectively enrolled in the AHL 2011 study. The AHL 2011 trial was designed to evaluate in 16-60 years old HL patients with Ann Arbor stage III, IV or high risk IIB, a de-escalade PET-driven strategy after 2 cycles of BEACOPPesc randomly compared to a standard treatment not driven by PET and delivering 6 cycles of BEACOPPesc. PET were centrally reviewed and interpreted according to Deauville criteria. As recently reported (Casasnovas, ASH 2015 Abs 577), the 2y-PFS was similar in the PET-driven (88%) and the standard arm (91% p =0.79). The tumor microenvironnement was analyzed on formalin fixed paraffin embedded lymph node biopsy obtained for the diagnosis before treatment by morphological evaluation on standard staining (% polynuclear eosinophils, % lymphocytes, % plasmocytes, % histiocytes), and immunohistochemistry (IHC) scoring (score 0-1-2-3) for CD20, CD3, CD68-TAMs (tumor-associated macrophages) and CD163 and were centrally reviewed. Percentage of tumoral cells and EBV status were also analysed. In this analysis, the prognosis value of tissue markers expressions were compared to those of clinical and biological patient's characteristics, and PET results after 2 cycles of escalated BEACOPP. Results Six hundred fifty eight patients with available IHC data out of 823 enrolled in AHL2011 study were included in the analysis. With a median follow-up of 16.1 months, 2-year PFS was 89.4% (95% CI [86.2% 91.9%]) and 2-year OS 98.7% (95% CI [96.4% 99.5%]). In univariate analysis male gender, at least one extra-nodal involvement, B symptoms, Hemoglobin .5g/dL, Albumin g/L, IPS score≥ 3, positive PET2, immunophenotyping CD20 (2-3vs0-1) and CD163 (2-3 vs 1) were significantly associated with shorter PFS. In multivariate analysis positive PET2 was the only factor retaining an independent prognosis value and associated to a shorter PFS (p=.04, HR=2.5, CI95% (1.03-5.8)). Among baseline patients characteristics, male gender, hemoglobin .5g/dL, IPS score ≥3, low % of lymphocytes, immunophenotyping CD3 (score ≥1), high CD20 (score ≥2), CD68 and CD163 expression were significantly associated with a higher risk of PET2 positivity. In multivariate analysis high CD68 expression (score 2-3 vs 1) was the only independent prognostic factor predicting PET2 positivity (p=.03, HR=2.4, CI95% (1.1-5.2)). 79% of PET2 positive patients have high CD68 expression and the combination of high CD68 expression and PET2 positivity identifies a subset of 50 patients (%) with a shorter 2y-PFS (72%) than PET2+/CD68low patients (2y-PFS=100%, p 0.066). In conclusion, CD68 expression was confirmed to be an important prognostic marker in this large prospective cohort of patients treated with upfront escalated BEACOPP in a modern PET-guided strategy. Baseline high CD68 expression is associated to a higher risk of PET2 positivity and the combination of this microenvironment marker and PET2 results allowed identifying a population of patients with high risk of treatment failure. Figure 1 Figure 1. Figure 2 Figure 2. Brice: Takeda Pharmaceuticals International Co.: Honoraria, Research Funding Bristol Myers-Squibb: Honoraria Seattle Genetics: Research Funding Gilead: Honoraria Roche: Honoraria. Casasnovas:BMS: Consultancy, Honoraria Sanofi: Consultancy, Honoraria Takeda: Consultancy, Honoraria Abbvie: Consultancy, Honoraria Gilead: Consultancy, Honoraria, Research Funding ROCHE: Consultancy, Honoraria, Research Funding.
Publisher: American Society of Hematology
Date: 15-11-2022
Publisher: American Society of Hematology
Date: 15-11-2013
DOI: 10.1182/BLOOD.V122.21.2144.2144
Abstract: haploidentical stem cell transplantation (SCT) represents an alternative option for those patients lacking a HLA-identical donor. Patients with relapsed or refractory Hodgkin's lymphoma may benefit from allogeneic SCT and, in particular, patients without a HLA-identical donor may receive SCT from a haploidentical one. The aim of this retrospective analysis is to compare outcome of HL patients undergoing allogeneic SCT from haploidentical vs. HLA-id. Donor. patients with diagnosis of HL who received allogeneic SCT at Istituto Clinico Humanitas (Milan, Italy) and Institut Paoli-Calmettes (Marseille, France) were included in the analysis. Outcome was estimated according to SC source (HLA-id. vs. haplo) and disease status at transplant: CR, PR or SP/PD. a total of 58 and 36 patients received SCT from a HLA-id. and haploidentical donor, respectively. SCT were performed from February 1999 to December 2012. Ninety-two patients received reduced-intensity conditioning all but one patient in haplo group received post-transplant cyclophosphamide as GVHD prophylaxis. Median follow-up was 63 months (range: 6-160) in HLA-id. group and 20 months (range: 6-50) in haplo group. In HLA-id. group, 2-year PFS was 62%, 33% and 17% among patients in CR, PR or SD/PD before allogeneic SCT, respectively 2-year PFS in haplo patients was 86%, 53% and 0% among CR, PR and SD/PD patients. Results are shown in Table 1. Notably, a lower number of relapse events were observed in chemosensitive patients in haplo group compared with HLA-id.: 1/21 vs. 7/28 among CR patients and 2/9 vs. 10/18 among those in PR (see Table 1) this translates into better PFS after haplo-SCT. Conversely, outcome of refractory patients confirmed to be poor in both groups. At last follow-up, among the 30 chemosensitive patients receiving haplo-SCT, last relapse occurred at day +392 post-SCT. present analysis showed better PFS in haplo group among high-risk, chemosensitive (CR + PR) patients compared with HLA-id. and better OS among patients who were in PR before SCT this was due to lower relapse rate among chemosensitive patients after haplo-SCT vs. HLA-id. In conclusion, haplo-SCT showed high antitumor activity, leading to promising outcome of chemosensitive patients compared with HLA-id transplants. Present data may challenge donor choice in this subset of patients, who may benefit from graft-versus-lymphoma effect, potentially enhanced by haplo disparity. No relevant conflicts of interest to declare.
Publisher: MDPI AG
Date: 16-04-2022
Abstract: Venetoclax (VEN) belongs the BH3-mimetic class that selectively targets BCL-2, activating apoptosis. The combination of VEN and azacitidine (AZA) has changed the paradigm of treatment of newly diagnosed (ND) acute myeloid leukemia (AML) patients ineligible for intensive chemotherapy. There is scarce evidence for the use of VEN–AZA for relapsed or refractory (R/R) AML. We compared the outcome of 39 R/R AML and 38 ND AML patients treated between 01/20 and 12/21. The median age was 69 (22–86) and 73 (61–81) in the R/R and ND groups, respectively. Adverse cytogenetics were found in 36% of patients in the R/R group and 59% of patients in the ND group. Overall response rate was 37% in R/R AML, including 13% CR, 8% CRi, 3% PR and 13% MLFS, and 58% in the ND AML, including 32% CR, 13% CRi and 13% MLFS. Adverse cytogenetics was associated with treatment failure in the R/R group (Relative Risk = 0.13, p = 0.005). Median overall survival (OS) was 5.9 months in the R/R group and 9.4 months in the ND group. Median OS was 2.2 months in the adverse cytogenetics group versus 8.7 months in the intermediate cytogenetics group in the R/R group (p = 0.02). Median leukemia-free survival was not different between the two groups (9.4 months and 10.3 months), indicating that VEN–AZA can be an efficient salvage treatment for selected R/R AML patients. In conclusion, VEN–AZA is a promising treatment for ND AML and for selected R/R AML patients.
Publisher: Informa UK Limited
Date: 11-2015
DOI: 10.2147/COAYA.S70365
Publisher: Elsevier BV
Date: 09-2015
Publisher: Wiley
Date: 03-12-2013
DOI: 10.1002/HON.2119
Abstract: Patients with relapsed or refractory Hodgkin lymphoma (RR-HL) have poor outcomes. Brentuximab vedotin (BV), an antibody-drug conjugate comprising an anti-CD30 antibody conjugated to the potent anti-microtubule agent, monomethyl auristatin E, induces high tumour responses with moderate adverse effects. In a retrospective study, we describe objective response rates and subsequent allogeneic stem cell transplantation (allo-SCT) in patients with RR-HL treated by BV in a named patient program in two French institutions. Twenty-four adult patients with histologically proven CD30(+) RR-HL treated with BV were included from July 2009 to November 2012. Response to BV treatment was evaluated after four cycles. Eleven patients were in complete response (45.8%), while five patients were in partial response (20.8%), with an overall response rate of 66.6%. Eight patients failed to respond to BV (33.3%). All of the responding patients could receive consolidation treatment after BV: three patients underwent autologous stem cell transplantation (auto-SCT), three patients received a tandem auto-SCT/allo-SCT, nine patients received allo-SCT and one patient was treated with donor lymphocyte infusion. We found no treatment-related mortality at day 100 among the 12 patients who underwent BV following by allogeneic transplantation. With a median follow-up of 20 months (range 10.5-43.2), none of them relapsed or died. BV followed by allo-SCT represents an effective salvage regimen in patients with RR-HL.
Publisher: American Society of Hematology
Date: 15-11-2022
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2014
Publisher: Informa UK Limited
Date: 24-04-2019
Publisher: American Society of Hematology
Date: 05-11-2020
DOI: 10.1182/BLOOD-2020-141229
Abstract: IDH mutations are strongly enriched in cytogenetically normal AML harboring NPM1 mutation (CN-NPM1mut-AML). The impact of these mutations on response to treatment is still a matter of debate. In the ELN 2017 classification, NPM1mut/FLT3-ITD allelic ratio & .5 (FLT3-high) are considered intermediate-risk AML, whereas NPM1mut/ FLT3-ITD neg or & .5 (FLT3-low) are low-risk. We aimed to evaluate the impact of IDH mutation in CN-NPM1mut-AML patients (pts) treated intensively. For this purpose, we retrospectively analyzed 177 CN-NPM1-AML pts from the Paoli-Calmettes Institute and from the French Innovative leukemia organization (FILO) databases who had received conventional intensive chemotherapy according to the FILO protocols (anthracycline-cytarabine based regimen for induction and High-intermediate dose cytarabine (HIDAC) for consolidation. Forty-seven (26%) AML pts had an IDH mutation -18 IDH1-R132 (10%), 27 IDH2-R140 (15%) and 2 IDH2-R172 (1%) - while 130 AML pts were IDHwt. Pts characteristics are presented in the Table.The complete response rate after one or two courses of chemotherapy (CR1) was 100% and 90% (p-value=.03) in the IDHmut and IDHwt groups, respectively. For pts in CR1, NPM1 molecular residual disease after the first consolidation (MRD2) was negative (& Log reduction) in 86% vs 53% of pts (p-value=.04). Nine (19%) and 24 (18%) pts received an allogeneic transplantation in CR1. The median time between CR1 and relapse was 11 months and 8 months, in IDHmut and IDHwt pts, respectively (p-value=.008). Day-100 non-relapse mortality was 8% and 12% respectively (p-value=ns). Median follow-up is 45 months (range, 2.4-115). Median EFS and OS are 21 months vs 12 months (p-value=.01) and 112 vs 23 months (p-value=.02), in the IDHmut vs IDHwt groups respectively (Figure). No survival differences were observed between IDH1mut and IDH2mut AML patients. Multivariate analyses with age& , FLT3-high and IDHmut as covariates showed that IDHmut was independently associated with a higher EFS (HR=1.7, ranges 1.1-2.6) and OS (HR=1.7, ranges 1.1-2.7). Our results suggest that IDHmut is associated with a better response and a good disease control with high-dose chemotherapy. Nevertheless, some relapses still occur justifying the use of an IDH inhibitor combined with first-line chemotherapy or in a post-remission maintenance setting. Figure No relevant conflicts of interest to declare.
Publisher: Springer Science and Business Media LLC
Date: 17-01-2020
DOI: 10.1038/S41409-020-0783-Y
Abstract: 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.
Publisher: SAGE Publications
Date: 2014
DOI: 10.1177/1430.15831
Publisher: Elsevier BV
Date: 08-2021
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488782
Abstract: Univariate analysis for overall survival from t-MN diagnosis of patients diagnosed with t-MN after OC according to PARPi exposure.
Publisher: Public Library of Science (PLoS)
Date: 05-03-2020
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488794.V1
Abstract: Blood smear and bone marrow aspiration of patient referred for cytopenia post PARPi.
Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.BULCAN.2016.10.011
Abstract: Lymphoma is one of the most frequent cancers in adolescent and young adults. Hodgkin Lymphoma is curable in more than 90% of cases. Recent pediatric and adults protocols aimed to decrease long term toxicities (mostly gonadic and cardiovascular) and secondary malignancies, reducing the use of alkylating agents and limiting radiation fields. Risk-adapted strategies, using positron emission tomography staging, are about to become a standard, both in adult and pediatric protocols. These approaches allow obtaining excellent results in adolescents with Hodgkin lymphoma. On the other hand, treatment of adolescents with diffuse large B-cell lymphoma raises some questions. Even through children have good outcomes when treated with risk-adapted strategies, adolescents who are between 15 and 18 years old seem to experience poorer survivals, whereas patients older than 18 years old have globally the same outcome than older adults. This category of patient needs a particular care, based on a tight coordination between adults and pediatric oncologists. Primary mediastinal lymphomas, a subtype of BLDCL frequent in young adult population, exhibits poorer outcomes in children or young adolescent population than in older ones. Taking together, B-cell lymphoma benefited from recent advances in immunotherapy (in particular with the extended utilization of rituximab) and metabolic response-adapted strategies. In conclusion, adolescent and young adult's lymphomas are very curable diseases but require a personalized management in onco-hematological units.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488785
Abstract: Commutation plot visualizing the mutated genes in t-MN after OC according to PARPi treatment.
Publisher: Public Library of Science (PLoS)
Date: 11-05-2016
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488779
Abstract: TP53 mutations characteristics among t-MN PARPi national cohort.
Publisher: Springer Science and Business Media LLC
Date: 05-04-2013
DOI: 10.1038/LEU.2013.101
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488773.V1
Abstract: Patient characteristics of the national cohort according to the type of PARPi received (olaparib vs. other PARP inhibitors).
Publisher: American Society of Hematology
Date: 06-12-2014
DOI: 10.1182/BLOOD.V124.21.3863.3863
Abstract: Introduction: although high-dose chemotherapy (HDC) is the golden standard for the treatment of many relapsed or refractory lymphomas, the outcome is still unsatisfactory especially in some subsets of patients with adverse prognostic features. To improve these results, we treated high-risk patients with a tandem strategy associating debulking with HDC followed by autologous stem cell transplantation (ASCT) and subsequent adoptive immunotherapy consisting in allogeneic SCT (tandem auto-allo). We report here the outcome of 111 lymphoma patients undergoing this procedure in addition, the role of two ASCT conditioning regimens is discussed. Patients and Methods: adult patients consecutively treated at two centers (Milan, Italy and Marseille, France) were included. Criteria for receiving tandem auto-allo were: refractory disease after first-line therapy, less than CR after first salvage treatment, histology of transformed follicular, mantle-, T- and NK-cell lymphoma, relapse after prior ASCT, multiple relapses. Disease evaluation was performed by using PET scan starting from 2003. Results: 111 consecutive patients with HL or NHL were transplanted from June 2002 to September 2013. Main characteristics are shown in Table 1. Median interval between ASCT and allogeneic SCT was 85 days (range: 36-235). Sixty-two patients (56%) received BEAM (8 of them without BCNU) and 46 (41%) high-dose Melphalan (HD-Mel, 100-200 mg/m2) 3 patients received other regimens. Main characteristics were not significantly different between BEAM and HD-Mel groups with the exception of the use of more alternative donor (i.e. non HLA-identical) in the HD-Mel group: 33% vs. 13%, p=0.01. Disease status before ASCT was: CR (n=47), PR (n=38), SD (n=10), PD (n=16). Grade 3-4 mucositis occurred in 49 patients (44%) and documented infections during hospital stay in 30 (27%), without differences between BEAM and HD-Mel groups, p=0.57 and p=0.14. Disease status before allogeneic SCT was: CR (n=79), PR (n=22), SD (n=5), PD (n=5). Among the 64 patients with active disease before ASCT, the overall response rate was 87% (n=56 responders) and the rate of CR was 53% (n=34), these latter adding to the 45 (out of the 47) patients in CR before ASCT nine patients (8%) progressed between ASCT and allogeneic SCT. Again, no differences were observed in terms of response among BEAM and HD-Mel group (p=0.28). Allogeneic SCT was performed after NMA (n=43), RIC (n=66) or MA (n=2) conditioning donor was either HLA-identical (n=86), MUD 9/10 (n=2), haploidentical (n=20) or cord blood (n=3). After a median follow-up of 38 months after allogeneic SCT, 3-y OS of entire cohort was 68% (95% CI: 59-77), 3-y PFS was 61% (52-70), rates of acute GvHD grade 2-4 and chronic GvHD were 28% and 38% respectively. TRM rate was 18% (n=20). Last relapse event occurred at day +853. No difference between BEAM and HD-Mel group was observed for OS (73% and 64% respectively, p=0.40) or TRM (19% and 13%, p=0.44). CR before allogeneic SCT confirms to a major prognostic factors for OS (Figure 1), whereas donor type did not significantly impact on survival (p=0.68). No survival difference was observed between HL and NHL (p=0.53). Conclusions: tandem auto-allo confirms to be a feasible and effective therapeutic strategy in those lymphoma patients whose prognosis is expected to be unsatisfactory with ASCT alone. BEAM vs. HD-Mel appeared to be similar in terms of extrahematological toxicity, disease response and survival. Disease status before allogeneic SCT confirms to be a significant prognostic factor, underlying the importance of high-dose chemotherapy followed by ASCT as further tumor shrinking before allogeneic immunotherapy in this setting of high-risk patients. Table 1. Main patients’ and transplant characteristics Variable Value % N 111 100% Pt's age (median) 44 range:16-69 Gender M 66 59% F 45 41% Disease HL 44 40% DLBCL 12 11% FL 21 19% Transf FL 9 8% MCL 9 8% MZL 1 1% T lymph 13 12% Grey zone 1 1% NK lymphoma 1 1% Indication for tandem auto-allo 1ary refractory 28 25% no CR after salvage 43 39% histology 10 9% relapse after prior ASCT 6 5% multiple relapse 24 22% Prior therapy lines (median) 2 range: 0-7 Prior radiotherapy 26 23% ASCT conditioning BEAM 54 49% EAM 8 7% HD-Mel 100 1 1% HD-Mel 140 12 11% HD-Mel 200 33 30% other 3 3% Allogeneic stem cell donor HLA-id sibling 62 56% MUD 10/10 24 22% MUD 9/10 2 2% haplo 20 18% cord blood 3 3% Figure 1. OS according to disease status after ASCT. Figure 1. OS according to disease status after ASCT. No relevant conflicts of interest to declare.
Publisher: Elsevier BV
Date: 10-2022
DOI: 10.1016/J.CCELL.2022.09.007
Abstract: There is increasing recognition of the prognostic significance of tumor cell major histocompatibility complex (MHC) class II expression in anti-cancer immunity. Relapse of acute myeloid leukemia (AML) following allogeneic stem cell transplantation (alloSCT) has recently been linked to MHC class II silencing in leukemic blasts however, the regulation of MHC class II expression remains incompletely understood. Utilizing unbiased CRISPR-Cas9 screens, we identify that the C-terminal binding protein (CtBP) complex transcriptionally represses MHC class II pathway genes, while the E3 ubiquitin ligase complex component FBXO11 mediates degradation of CIITA, the principal transcription factor regulating MHC class II expression. Targeting these repressive mechanisms selectively induces MHC class II upregulation across a range of AML cell lines. Functionally, MHC class II
Publisher: American Society of Hematology
Date: 05-11-2020
DOI: 10.1182/BLOOD-2020-139918
Abstract: Therapy related Acute Lymphoblastic Leukemia (t-ALL) refers to ALL developed in patients who have received prior cytotoxic therapies, including chemotherapies (CT) and/or radiotherapy (RT). Contrary to therapy-related myeloid neoplasms, t-ALL has not been fully recognized and its clinical and biological features remain poorly described. We reviewed all consecutive cases of adult t-ALL treated at our institution and described their clinical, phenotypic, and genetic characteristics. Between 1998 and 2019, 36 patients were admitted at Institut Paoli-Calmettes for t-ALL which represents 3.5% of all ALL admitted during the same period (n=1036). Median age was 67.5 years (ranges, 20-83). Twenty-eight (78%) patients were females. Thirty-eight (78%) patients of the t-ALL were secondary to a solid cancer. Among the most frequent solid tumors, we found 14 (39%) breast cancers, 5 (14%) pulmonary cancers and 4 (11%) thyroid cancers. Eight patients had a t-ALL secondary to a hematological malignancy (4 Non-Hodgkin lymphomas, 3 Hodgkin lymphomas and one myeloma). Three (8%) patients presented with more than one primary cancer. Primary malignancies were treated with CT in 7 cases (19%), RT in 11 cases (31%) and CT+RT in 16 cases (44%), in association or not with surgery of the primary tumor. Median time between the start of first malignancy treatment and t-ALL diagnosis was 5.4 years (ranges, 0.3-35). Median white blood cell count (WBC) was 15.9 (ranges, 0.6-386). Phenotypic characteristics at diagnosis were consistent with B-ALL for 31 patients (86%), and T-ALL or acute mixed-lineage leukemia for 2 (6%) and 3 (8%) patients, respectively. 9 (22%) cases were Philadelphia chromosome-positive by karyotype or Fluorescent in situ hybridization, 5 (14%) cases had MLL rearrangement, 5 (14%) cases had hypodiploidy, 3 (8%) cases had hyperdiploidy and 3 (8%) cases had normal karyotype. The 11 (30%) other cases had other genetic abnormalities. Thirty-one (86%) patients received intensive CT and 5 (14%) patients received a palliative treatment. For one patient, treatment modalities were missing. Twenty-eight (78%) were in complete remission (CR) after CT and 7 (19%) patients underwent an allogenic hematopoietic stem cell transplantation in first CR. Median follow-up was 52 months. Median overall survival calculated from the time of t-ALL diagnosis was 16 months and median leukemia-free survival was 14.3 months. Multivariate analyses taking age, WBC, MLL alteration, complex karyotype and BCR-ABL rearrangement into account, found that BCR-ABL alteration was associated with a higher OS (HR=4.9 ranges, 1.1-22.6). In conclusion, our results confirm that t-ALL is a rare event. Besides an older age at diagnosis, t-ALL does not display specific phenotypic or genetic characteristics. In our series, the patient outcome was poor. Further genetic studies are needed to better understand the pathogenesis of this ALL subgroup. No relevant conflicts of interest to declare.
Publisher: Informa UK Limited
Date: 14-02-2014
DOI: 10.3109/10428194.2013.858814
Abstract: The aim of our study was to assess whether large B-cell lymphoma (LBCL) in adolescents and young adults (AYA) should be considered as a clinocopathological entity, and to evaluate the prognostic value of age. Fifty-five patients aged > 15-30 years were fully matched to 365 adult patients aged 31-65 years. We found a high incidence of primary mediastinal thymic LBCL subtype (33% vs. 5%), while histological transformation was rare (2% vs. 14%). LBCL in AYA presented with a bulky mediastinal mass (51% vs. 21%), and the lactate dehydrogenase (LDH) value was significantly higher (73% vs. 54%). The complete response rate to chemotherapy was similar in the two groups. Five-year overall survival (OS) and event-free survival (EFS) of AYA were 73% and 68%, respectively. The matched-control analysis showed no difference for either OS or EFS. LBCL in AYA presents with some critical features which differ from those of older adults. However, the outcome is equivalent to that observed in older patients.
Publisher: Springer Science and Business Media LLC
Date: 12-10-2019
DOI: 10.1186/S13148-019-0738-6
Abstract: The epigenetic machinery is frequently altered in acute myeloid leukemia. Focusing on cytogenetically normal (CN) AML, we previously described an abnormal H3K27me3 enrichment covering 70 kb on the HIST1 cluster (6.p22) in CN-AML patient blasts. Here, we further investigate the molecular, functional, and prognosis significance of this epigenetic alteration named H3K27me3 HIST1 in NPM1 -mutated ( NPM1 mut) CN-AML. We found that three quarter of the NPM1 mut CN-AML patients were H3K27me3 HIST1 high . H3K27me3 HIST1 high group of patients was associated with a favorable outcome independently of known molecular risk factors. In gene expression profiling, the H3K27me3 HIST1 high mark was associated with lower expression of the histone genes HIST1H1D , HIST1H2BG , HIST1H2AE , and HIST1H3F and an upregulation of genes involved in myelomonocytic differentiation. Mass spectrometry analyses confirmed that the linker histone protein H1d, but not the other histone H1 subtypes, was downregulated in the H3K27me3 HIST1 high group of patients. H1d knockdown primed ATRA-mediated differentiation of OCI-AML3 and U937 AML cell lines, as assessed on CD11b/CD11c markers, morphological and gene expression analyses. Our data suggest that NPM1 mut AML prognosis depends on the epigenetic silencing of the HIST1 cluster and that, among the H3K27me3 silenced histone genes, HIST1H1D plays a role in AML blast differentiation.
Publisher: OAE Publishing Inc.
Date: 2023
Abstract: The use of the BCL2 inhibitor venetoclax has transformed the management of patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. By triggering intrinsic apoptosis, the drug is an excellent illustration of how our greater understanding of molecular cell death pathways can be translated into the clinic. Nevertheless, most venetoclax-treated patients will relapse, suggesting the need to target additional regulated cell death pathways. To highlight advances in this strategy, we review the recognized regulated cell death pathways, including apoptosis, necroptosis, ferroptosis and autophagy. Next, we detail the therapeutic opportunities to trigger regulated cell death in AML. Finally, we describe the main drug discovery challenges for regulated cell death inducers and their translation into clinical trials. A better knowledge of the molecular pathways regulating cell death represents a promising strategy to develop new drugs to cure resistant or refractory AML patients, particularly those resistant to intrinsic apoptosis.
No related grants have been discovered for Sylvain Garciaz.