Phthalate contamination in marine mammals off the Norwegian coast.

Phthalates are used in plastics, found throughout the marine environment and have the potential to cause adverse health effects. In the present study, we quantified blubber concentrations of 11 phthalates in 16 samples from stranded and/or free-living marine mammals from the Norwegian coast: the killer whale (Orcinus orca), sperm whale (Physeter macrocephalus), long-finned pilot whale (Globicephala melas), white-beaked dolphin (Lagenorhynchus albirostris), harbour porpoise (Phocoena phocoena), and harbour seal (Phoca vitulina). Five compounds were detected across all samples: benzyl butyl phthalate (BBP; in 50 % of samples), bis(2-ethylhexyl) phthalate (DEHP; 33 %), diisononyl phthalate (DiNP; 33 %), diisobutyl phthalate (DiBP; 19 %), and dioctyl phthalate (DOP; 13 %). Overall, the most contaminated individual was the white-beaked dolphin, whilst the lowest concentrations were measured in the killer whale, sperm whale and long-finned pilot whale. We found no phthalates in the neonate killer whale. The present study is important for future monitoring and management of these toxic compounds.

Nonrelapse mortality after CAR T-cell therapy for large B-cell lymphoma: a LYSA study from the DESCAR-T registry.

CD19 chimeric antigen receptor (CAR) T cells can induce prolonged remissions and potentially cure a significant proportion of patients with relapsed/refractory large B-cell lymphomas. However, some patients may die of causes unrelated to lymphoma after CAR T-cell therapy. To date, little is known about the nonrelapse mortality (NRM) after CAR T-cell therapy. Using the French DESCAR-T registry, we analyzed the incidence and causes of NRM and identified risk factors of NRM. We report on 957 patients who received standard-of-care axicabtagene ciloleucel (n = 598) or tisagenlecleucel (n = 359) between July 2018 and April 2022, in 27 French centers. With a median follow-up of 12.4 months, overall NRM occurred in 48 patients (5.0% of all patients): early (before day 28 after infusion) in 9 patients (0.9% of all patients and 19% of overall NRM), and late (on/after day 28 after infusion) in 39 patients (4.1% of all patients and 81% of overall NRM). Causes of overall NRM were distributed as follows: 56% infections (29% with non-COVID-19 and 27% with COVID-19), 10% cytokine release syndromes, 6% stroke, 6% cerebral hemorrhage, 6% second malignancies, 4% immune effector cell associated neurotoxicities, and 10% deaths from other causes. We report risk factors of early NRM and overall NRM. In multivariate analysis, both diabetes and elevated ferritin level at lymphodepletion were associated with an increased risk of overall NRM. Our results may help physicians in patient selection and management in order to reduce the NRM after CAR T-cell therapy.

Efficacy and safety of crizotinib in ALK-positive systemic anaplastic large-cell lymphoma in children, adolescents, and adult patients: results of the French AcSé-crizotinib trial.

BACKGROUND: The French phase II AcSé-crizotinib trial aimed to evaluate the safety and efficacy of crizotinib in patients with ALK, ROS1, and MET-driven malignancies, including ALK-positive anaplastic large-cell lymphoma (ALK+ ALCL). METHODS: ALK+ ALCL patients 12 months or older with measurable disease and no standard care options available received crizotinib twice daily at 165 mg/m2 in children and adolescents and 250 mg in adults. The primary end-point was the response rate at 8 weeks. RESULTS: Twenty-eight patients were enroled between February 2014 and March 2018. Three patients who were not treated were excluded from the analysis. The median age was 19 years. The median previous line of chemotherapy was two. In the 24 patients with an evaluable response, the response rate at 8 weeks was 67% (95% CI: 47-82%). All patients discontinued crizotinib after a median treatment duration of 3.7 months: eight for progression, two for adverse events (AEs) related to prior treatments, and 15 by choice, including six for allogeneic stem-cell transplantation. The median follow-up was 45 months. Nine patients experienced an event: eight relapses (seven after crizotinib discontinuation and one after dose reduction), and one died in complete remission. The median duration of response was 43.3 months (95% CI: 8.3-not reached). The 3-year progression-free and overall survival rates were 40% (95% CI: 23-59%) and 63% (95% CI: 43-79%). Grade 3 or 4 treatment-related AEs occurred in 32% of patients. CONCLUSION: Crizotinib shows efficacy and an acceptable safety profile in ALK+ ALCL relapsed/refractory patients. However, a large proportion of patients experience a relapse after crizotinib discontinuation. Future studies will assess if prolonged ALK inhibitor exposure has curative potential without consolidation.

Efficacy and safety of isatuximab plus bortezomib, lenalidomide, and dexamethasone in patients with newly diagnosed multiple myeloma ineligible/with no immediate intent for autologous stem cell transplantation.

Patients with newly diagnosed multiple myeloma (NDMM) ineligible for autologous stem cell transplantation (ASCT) have lower survival rates and may benefit from frontline regimens that include novel agents. This Phase 1b study (NCT02513186) evaluated preliminary efficacy, safety, and pharmacokinetics (PK) of isatuximab, an anti-CD38 monoclonal antibody, combined with bortezomib-lenalidomide-dexamethasone (Isa-VRd) in patients with NDMM ineligible for/with no intent for immediate ASCT. Overall, 73 patients received four 6-week induction cycles of Isa-VRd, then maintenance with Isa-Rd in 4-week cycles. In the efficacy population (n = 71), the overall response rate was 98.6%, with 56.3% achieving a complete response or better (sCR/CR), and 36/71 (50.7%) patients reaching minimal residual disease negativity (10-5 sensitivity). Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 79.5% (58/73) of patients but TEAEs leading to permanent study treatment discontinuation were reported in 14 (19.2%) patients. Isatuximab PK parameters were within the previously reported range, suggesting that VRd does not alter the PK of isatuximab. These data support additional studies of isatuximab in NDMM, such as the Phase 3 IMROZ study (Isa-VRd vs VRd).

Prognostic Impact of Unsupervised Early Assessment of Bulk and Leukemic Stem Cell Measurable Residual Disease in Acute Myeloid Leukemia.

PURPOSE: Acute myeloid leukemias (AML) are clonal diseases that develop from leukemic stem cells (LSC) that carry an independent prognostic impact on the initial response to induction chemotherapy, demonstrating the clinical relevance of LSC abundance in AML. In 2018, the European LeukemiaNet published recommendations for the detection of measurable residual disease (Bulk MRD) and suggested the exploration of LSC MRD and the use of multiparametric displays. EXPERIMENTAL DESIGN: We evaluated the performance of unsupervised clustering for the post-induction assessment of bulk and LSC MRD in 155 patients with AML who received intensive conventional chemotherapy treatment. RESULTS: The median overall survival (OS) for Bulk+ MRD patients was 16.7 months and was not reached for negative patients (HR, 3.82; P < 0.0001). The median OS of LSC+ MRD patients was 25.0 months and not reached for negative patients (HR, 2.84; P = 0.001). Interestingly, 1-year (y) and 3-y OS were 60% and 39% in Bulk+, 91% and 52% in Bulk-LSC+ and 92% and 88% in Bulk-LSC-. CONCLUSIONS: In this study, we confirm the prognostic impact of post-induction multiparametric flow cytometry Bulk MRD in patients with AML. Focusing on LSCs, we identified a group of patients with negative Bulk MRD but positive LSC MRD (25.8% of our cohort) with an intermediate prognosis, demonstrating the interest of MRD analysis focusing on leukemic chemoresistant subpopulations.

A real-world comparison of tisagenlecleucel and axicabtagene ciloleucel CAR T cells in relapsed or refractory diffuse large B cell lymphoma.

Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) have both demonstrated impressive clinical activity in relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL). In this study, we analyzed the outcome of 809 patients with R/R DLBCL after two or more previous lines of treatment who had a commercial chimeric antigen receptor (CAR) T cells order for axi-cel or tisa-cel and were registered in the retrospective French DESCAR-T registry study ( NCT04328298 ). After 1:1 propensity score matching (n = 418), the best overall response rate/complete response rate (ORR/CRR) was 80%/60% versus 66%/42% for patients treated with axi-cel compared to tisa-cel, respectively (P < 0.001 for both ORR and CRR comparisons). After a median follow-up of 11.7 months, the 1-year progression-free survival was 46.6% for axi-cel and 33.2% for tisa-cel (hazard ratio (HR) = 0.61; 95% confidence interval (CI), 0.46-0.79; P = 0.0003). Overall survival (OS) was also significantly improved after axi-cel infusion compared to after tisa-cel infusion (1-year OS 63.5% versus 48.8%; HR = 0.63; 95% CI, 0.45-0.88; P = 0.0072). Similar findings were observed using the inverse probability of treatment weighting statistical approach. Grade 1-2 cytokine release syndrome was significantly more frequent with axi-cel than with tisa-cel, but no significant difference was observed for grade ≥3. Regarding immune effector cell-associated neurotoxicity syndrome (ICANS), both grade 1-2 and grade ≥3 ICANS were significantly more frequent with axi-cel than with tisa-cel. In conclusion, our matched comparison study supports a higher efficacy and also a higher toxicity of axi-cel compared to tisa-cel in the third or more treatment line for R/R DLBCL.

Outcomes of patients with aggressive B-cell lymphoma after failure of anti-CD19 CAR T-cell therapy: a DESCAR-T analysis.

Anti-CD19 chimeric antigen receptor (CAR) T-cells represent a major advance in the treatment of relapsed/refractory aggressive B-cell lymphomas. However, a significant number of patients experience failure. Among 550 patients registered in the French registry DESCAR-T, 238 (43.3%) experienced progression/relapse, with a median follow-up of 7.9 months. At registration, 57.0% of patients presented an age-adjusted International Prognostic Index of 2 to 3, 18.9% had Eastern Cooperative Oncology Group performance status ≥2, 57.1% received >3 lines of treatment prior to receiving CAR T-cells, and 87.8% received bridging therapy. At infusion, 66% of patients presented progressive disease, and 38.9% had high lactate dehydrogenase (LDH). Failure after CAR T-cell treatment occurred after a median of 2.7 months (range: 0.2-21.5). Fifty-four patients (22.7%) presented very early failure (day [D] 0-D30); 102 (42.9%) had early failure (D31-D90), and 82 (34.5%) had late (>D90) failure. After failure, 154 patients (64%) received salvage treatment: 38.3% received lenalidomide, 7.1% bispecific antibodies, 21.4% targeted treatment, 11% radiotherapy, and 20% immunochemotherapy with various regimens. Median progression-free survival was 2.8 months, and median overall survival (OS) was 5.2 months. Median OS for patients failing during D0-D30 vs after D30 was 1.7 vs 3.0 months, respectively (P = .0001). Overall, 47.9% of patients were alive at 6 months, but only 18.9% were alive after very early failure. In multivariate analysis, predictors of OS were high LDH at infusion, time to CAR-T failure

The impact of physician's characteristics on decision-making inhead and neck oncology: Results of a national survey.

OBJECTIVES: The aim of this study was to identify the socio-professional and behavioral factors influencing decision-making between surgical and non-surgical treatment in Upper AeroDigestive Tract (UADT) oncology among surgeons and oncologists. MATERIALS AND METHODS: We conducted a nationwide online survey among surgeons and medical or radiation oncologists treating head and neck cancer patients in France. The questionnaire collected physicians' demographics, type of practice, individual behavioral characteristics (attitudes toward risk and uncertainty) and data on decision-making via clinical case scenarios. RESULTS: In total, 197 questionnaires were usable. Clinical case scenarios were grouped into three categories according to the prognostic and functional impact of the choice between surgical or non-surgical treatment. For clinical case scenarios where evidence-based medicine considered surgery as the best option, surgeons were significantly more likely to offer surgery in multivariable analysis. When surgery and non-surgical treatment were equivalent, multivariable analysis showed that the tendency to offer surgery increased with the physician's age, and decreased as the number of patients treated per year increased. When non-surgical treatment was the best option because of very high surgical morbidity, multivariable analysis showed a higher propensity to opt for surgery for the age group 40 - 59 versus 25 - 39, and a lower likelihood of choosing surgery among oncologists. CONCLUSION: This study sheds light on the physicians' socio-professional and behavioral factors influencing decision-making in UADT oncology. These mechanisms, poorly studied and probably underestimated, partly explain the variability of the decisions taken when confronted with clinical situations that are subject to debate. CLINICALTRIALS: gov ID: NCT03663985.

Azacitidine, intensive chemotherapy or best supportive care in relapsed or refractory acute myeloid leukemia, a DATAML registry study.

We analyzed 526 consecutive acute myeloid leukemia patients refractory to or relapsing after chemotherapy. 270 patients received intensive salvage chemotherapy (IC), 97 azacitidine (AZA) and 159 best supportive care (BSC). Complete response was obtained in 37/19/0% (p = .0008). Allogeneic stem-cell transplantation (alloSCT) was performed in 39.3/10.3/0%. Median overall survival (OS) and 5-year OS were 8.2/9.6/2.2 months and 16/6/2% (p < .0001). Predictive factors of worse OS were post-myelodysplastic/chronic myelomonocytic leukemia, bone marrow blasts ≥20%, adverse cytogenetics, AZA cycle ≥2 and no alloSCT at R/R for AZA and age, performance status, white blood cell count and myelodysplasia-related changes for IC. The impact of treatment was time-dependent: adjusted hazard ratio for OS was in favor of AZA up to 1 month, was not different between 1 and 7 months, then was in favor of IC after 7 months. While AZA represents a therapeutic option for the oldest patients, it does not lead to long-term survivors.

The CADM1 tumor suppressor gene is a major candidate gene in MDS with deletion of the long arm of chromosome 11.

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis leading to peripheral cytopenias and in a substantial proportion of cases to acute myeloid leukemia. The deletion of the long arm of chromosome 11, del(11q), is a rare but recurrent clonal event in MDS. Here, we detail the largest series of 113 cases of MDS and myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) harboring a del(11q) analyzed at clinical, cytological, cytogenetic, and molecular levels. Female predominance, a survival prognosis similar to other MDS, a low monocyte count, and dysmegakaryopoiesis were the specific clinical and cytological features of del(11q) MDS. In most cases, del(11q) was isolated, primary and interstitial encompassing the 11q22-23 region containing ATM, KMT2A, and CBL genes. The common deleted region at 11q23.2 is centered on an intergenic region between CADM1 (also known as Tumor Suppressor in Lung Cancer 1) and NXPE2. CADM1 was expressed in all myeloid cells analyzed in contrast to NXPE2. At the functional level, the deletion of Cadm1 in murine Lineage-Sca1+Kit+ cells modifies the lymphoid-to-myeloid ratio in bone marrow, although not altering their multilineage hematopoietic reconstitution potential after syngenic transplantation. Together with the frequent simultaneous deletions of KMT2A, ATM, and CBL and mutations of ASXL1, SF3B1, and CBL, we show that CADM1 may be important in the physiopathology of the del(11q) MDS, extending its role as tumor-suppressor gene from solid tumors to hematopoietic malignancies.

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

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

[Chimeric antigen receptor T cells]. / Lymphoproliférations B de bas grade et cellules CAR-T.

Chimeric antigen receptor T-cell (CAR T-cells) therapies which are genetically modified T lymphocyte targeting tumor antigens have modified therapeutic landscape in hematology. Aggressive B cells lymphoma are currently treated in daily practice with anti-CD19 CAR T. In indolent B cell lymphomas, their efficacy has been established by recent clinical trials. Longer follow-up evaluation is needed to determine their added value in a field where approved strategies already provide high long-term survival rates. They will also be challenged by another immunotherapy with bispecific antibodies. In chronic lymphoid leukemia, early phase trials have identified several limitations related to the immune context of this disease, but associations with targeted therapy like ibrutinib are very promising. In this moving therapeutic landscape, molecular and cellular engineering progress will increase the capacities of these new cellular-based therapies.

Activation of Vitamin D Receptor Pathway Enhances Differentiating Capacity in Acute Myeloid Leukemia with Isocitrate Dehydrogenase Mutations.

Relapses and resistance to therapeutic agents are major barriers in the treatment of acute myeloid leukemia (AML) patients. These unfavorable outcomes emphasize the need for new strategies targeting drug-resistant cells. As IDH mutations are present in the preleukemic stem cells and systematically conserved at relapse, targeting IDH mutant cells could be essential to achieve a long-term remission in the IDH mutant AML subgroup. Here, using a panel of human AML cell lines and primary AML patient specimens harboring IDH mutations, we showed that the production of an oncometabolite (R)-2-HG by IDH mutant enzymes induces vitamin D receptor-related transcriptional changes, priming these AML cells to differentiate with pharmacological doses of ATRA and/or VD. This activation occurs in a CEBPα-dependent manner. Accordingly, our findings illuminate potent and cooperative effects of IDH mutations and the vitamin D receptor pathway on differentiation in AML, revealing a novel therapeutic approach easily transferable/immediately applicable to this subgroup of AML patients.

A deep dive into fat: Investigating blubber lipidomic fingerprint of killer whales and humpback whales in northern Norway.

In cetaceans, blubber is the primary and largest lipid body reservoir. Our current understanding about lipid stores and uses in cetaceans is still limited, and most studies only focused on a single narrow snapshot of the lipidome. We documented an extended lipidomic fingerprint in two cetacean species present in northern Norway during wintertime. We were able to detect 817 molecular lipid species in blubber of killer whales (Orcinus orca) and humpback whales (Megaptera novaeangliae). The profiles were largely dominated by triradylglycerols in both species and, to a lesser extent, by other constituents including glycerophosphocholines, phosphosphingolipids, glycerophosphoethanolamines, and diradylglycerols. Through a unique combination of traditional statistical approaches, together with a novel bioinformatic tool (LION/web), we showed contrasting fingerprint composition between species. The higher content of triradylglycerols in humpback whales is necessary to fuel their upcoming half a year fasting and energy-demanding migration between feeding and breeding grounds. In adipocytes, we assume that the intense feeding rate of humpback whales prior to migration translates into an important accumulation of triacylglycerol content in lipid droplets. Upstream, the endoplasmic reticulum is operating at full capacity to supply acute lipid storage, consistent with the reported enrichment of glycerophosphocholines in humpback whales, major components of the endoplasmic reticulum. There was also an enrichment of membrane components, which translates into higher sphingolipid content in the lipidome of killer whales, potentially as a structural adaptation for their higher hydrodynamic performance. Finally, the presence of both lipid-enriched and lipid-depleted individuals within the killer whale population in Norway suggests dietary specialization, consistent with significant differences in δ15N and δ13C isotopic ratios in skin between the two groups, with higher values and a wider niche for the lipid-enriched individuals. Results suggest the lipid-depleted killer whales were herring specialists, while the lipid-enriched individuals might feed on both herrings and seals.

Physician practice variation in head and neck cancer therapy: Results of a national survey.

OBJECTIVES: Choice between surgical or medical treatments in head and neck cancer depends of many patient-related and disease-related factors. We investigated how patients' socioeconomic status and practitioners' specialty could affect medical decision-making. MATERIALS AND METHODS: We conducted a cross-sectional online, nationwide survey, send to surgeons, oncologists and radiotherapists specialized in head and neck oncology. We collected data on medical decision-making for seven clinical scientific scenarios involving head and neck carcinoma and physicians' demographic data. Patients' gender and socioeconomic position were distributed across scientific scenarios using a Latin square design. The scientific scenarios were grouped into several categories according to the prognostic and functional impact of the therapeutic choice. RESULTS: We obtained 206 assessable answers. Surgeons seemed to propose surgery in 49% of cases, whereas oncologists and radiotherapists opted for it in 34% of cases only. This was particularly relevant when the oncological result of surgery and the medical approach were equivalent, and when the surgery appeared to be superior in terms of curative potential but was burdened by a large functional impact. Patient's socioeconomic position also influence therapeutic decision. Among surgeons, the "single male manager" had significantly more chance of being offered surgery than the "married male blue-collar worker". Among oncologists and radiotherapists, the "single male blue-collar worker" had the lowest probability of being proposed surgery. Regarding gender, surgeons tended to offer surgical management more to women regardless of their clinical profile. CONCLUSIONS: Patients' sex, marital status, socioeconomic status, practitioners' specialty affect therapeutic management decisions in head and neck oncology.

Mitochondrial metabolism supports resistance to IDH mutant inhibitors in acute myeloid leukemia.

Mutations in IDH induce epigenetic and transcriptional reprogramming, differentiation bias, and susceptibility to mitochondrial inhibitors in cancer cells. Here, we first show that cell lines, PDXs, and patients with acute myeloid leukemia (AML) harboring an IDH mutation displayed an enhanced mitochondrial oxidative metabolism. Along with an increase in TCA cycle intermediates, this AML-specific metabolic behavior mechanistically occurred through the increase in electron transport chain complex I activity, mitochondrial respiration, and methylation-driven CEBPα-induced fatty acid ß-oxidation of IDH1 mutant cells. While IDH1 mutant inhibitor reduced 2-HG oncometabolite and CEBPα methylation, it failed to reverse FAO and OxPHOS. These mitochondrial activities were maintained through the inhibition of Akt and enhanced activation of peroxisome proliferator-activated receptor-γ coactivator-1 PGC1α upon IDH1 mutant inhibitor. Accordingly, OxPHOS inhibitors improved anti-AML efficacy of IDH mutant inhibitors in vivo. This work provides a scientific rationale for combinatory mitochondrial-targeted therapies to treat IDH mutant AML patients, especially those unresponsive to or relapsing from IDH mutant inhibitors.

Predictive factors of early progression after CAR T-cell therapy in relapsed/refractory diffuse large B-cell lymphoma.

Chimeric antigen receptor (CAR) T-cell therapy has emerged as an option for relapsed/refractory aggressive B-cell lymphomas that have failed 2 lines of therapy. Failures usually occur early after infusion. The purpose of our study was to identify factors that may predict failure, particularly early progression (EP), within the first month after infusion. Characteristics of 116 patients were analyzed at the time of decision (TD) to use commercial CAR (axicabtagene ciloleucel, n = 49; tisagenlecleucel n = 67) and at the time of treatment (TT), together with total metabolic tumor volume (TMTV) at TT. With a median follow-up of 8.2 months, 55 patients failed treatment; 27 (49%) were early progressors. The estimated 12-month progression-free survival (PFS) and overall survival (OS) were 47.2% (95% confidence interval [CI], 38.0-58.6) and 67.0% (95% CI, 57-79), respectively. Univariate analyses for PFS and OS identified Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥2, stage III/IV disease, extranodal (EN) sites ≥2, elevated lactate dehydrogenase (LDH), increased C-reactive protein (CRP), high International Prognostic Index at TD and at TT, as well as increased CRP, bulky mass, and high TMTV at TT, as risk factors. Multivariate analyses for PFS, EP, and OS identified elevated LDH and EN sites ≥2 at TD and the same predictors at TT (ie, increased CRP, EN sites ≥2, and TMTV >80 mL). In summary, risk factors identified for early progression at TD and at TT were EN involvement (≥2 sites) and lymphoma burden (LDH, TMTV).

Impact of TP53 mutations in acute myeloid leukemia patients treated with azacitidine.

Hypomethylating agents are a classical frontline low-intensity therapy for older patients with acute myeloid leukemia. Recently, TP53 gene mutations have been described as a potential predictive biomarker of better outcome in patients treated with a ten-day decitabine regimen., However, functional characteristics of TP53 mutant are heterogeneous, as reflected in multiple functional TP53 classifications and their impact in patients treated with azacitidine is less clear. We analyzed the therapeutic course and outcome of 279 patients treated with azacitidine between 2007 and 2016, prospectively enrolled in our regional healthcare network. By screening 224 of them, we detected TP53 mutations in 55 patients (24.6%), including 53 patients (96.4%) harboring high-risk cytogenetics. The identification of any TP53 mutation was associated with worse overall survival but not with response to azacitidine in the whole cohort and in the subgroup of patients with adverse karyotype. Stratification of patients according to three recent validated functional classifications did not allow the identification of TP53 mutated patients who could benefit from azacitidine. Systematic TP53 mutant classification will deserve further exploration in the setting of patients treated with conventional therapy and in the emerging field of therapies targeting TP53 pathway.

CD34+CD38-CD123+ Leukemic Stem Cell Frequency Predicts Outcome in Older Acute Myeloid Leukemia Patients Treated by Intensive Chemotherapy but Not Hypomethylating Agents.

The prognostic impact of immunophenotypic CD34+CD38-CD123+ leukemic stem cell (iLSC) frequency at diagnosis has been demonstrated in younger patients treated by intensive chemotherapy, however, this is less clear in older patients. Furthermore, the impact of iLSC in patients treated by hypomethylating agents is unknown. In this single-center study, we prospectively assessed the CD34+CD38-CD123+ iLSC frequency at diagnosis in acute myeloid leukemia (AML) patients aged 60 years or older. In a cohort of 444 patients, the median percentage of iLSC at diagnosis was 4.3%. Significant differences were found between treatment groups with a lower median in the intensive chemotherapy group (0.6%) compared to hypomethylating agents (8.0%) or supportive care (11.1%) (p <0.0001). In the intensive chemotherapy group, the median overall survival was 34.5 months in patients with iLSC ≤0.10% and 14.6 months in patients with >0.10% (p = 0.031). In the multivariate analyses of this group, iLSC frequency was significantly and independently associated with the incidence of relapse, event-free, relapse-free, and overall survival. However, iLSC frequency had no prognostic impact on patients treated by hypomethylating agents. Thus, the iLSC frequency at diagnosis is an independent prognostic factor in older acute myeloid patients treated by intensive chemotherapy but not hypomethylating agents.