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International audience; Background During the 2005-2014 period, the GRAALL conducted the GRAALL-2005 trial in patients (pts) with Philadelphia chromosome (Ph)-negative ALL aged 18-59y. In this trial, all pts received a pediatric-inspired chemotherapy, whatever their age. Post-hoc analysis revealed an unacceptable TRM in pts aged 45-59y (Huguet et al. J Clin Oncol 2018; 36:2514-23). Allogeneic hematopoietic stem cell transplantation (HSCT) was offered in first complete remission (CR) to most CR pts, defined at high-risk (HR) by at least one baseline clinical or biological HR factor (CNS involvement, complex karyotype [≥5 abns.], low hypodiploidy/near triploidy, poor early blast clearance, late CR, as well as WBC ≥ 30x109/L, lack of CD10 expression, KMT2A rearrangement or TCF3::PBX1 fusion for B-cell precursor [BCP] ALL). Minimal residual disease (MRD) response was not considered for HSCT indication at that time.In the next GRAALL-2014 trial conducted in a similar population, we introduced two major changes in the treatment strategy. First, chemotherapy intensity (steroids, anthracycline and L-asparaginase) was reduced in pts aged 45-59y to decrease excessive TRM. Secondly, the indication for HSCT was modified, relying on IG/TR MRD response only (post-induction MRD ≥10-3 and/or post-consolidation MRD ≥10-4) while not on any former baseline HR criterion. Here, we compare the outcomes of the two trials, focusing on the impact of these two major evolutions.Patients & Methods A total of 743 pts treated in the GRAALL-2014 trial between 2015 and 2020 were compared to the 787 pts from the historical GRAALL-2005 trial, in terms of CR and induction death rates, rate of HSCT in CR1, cumulative incidence of TRM (CITRM) and relapse (CIR), relapse-free (RFS) and overall (OS) survival. It should be noted that two nested Phase 2 trials were introduced by amendment during the GRAALL-2014 course (in 2017 and 2018, respectively), aiming to evaluate post-remission addition of nelarabine and blinatumomab in 87 T-ALL and 94 BCP-ALL selected pts, respectively.Results Main patient characteristics, including age, gender, BCP/T-ALL, WBC, and historical baseline HR features, did not significantly differ between the two trial cohorts, even if CNS disease at diagnosis was more frequent in the 2014 cohort (12 vs 7%, p= 0.001).Outcome comparisons are shown in Table 1. Overall, the induction death rate was significantly reduced in the GRAALL-2014 (3 vs 6%, p= 0.005). As expected, this was only observed in pts aged 44-59y (3 vs 11%, p= 0.001), in whom dose-intensity reduction also translated into a higher need for second induction course (9 vs 5%, p= 0.05) eventually resulting in a higher CR rate (92 vs 86%, p= 0.05). Due to the newly introduced MRD-based stratification, the rate of pts with HSCT indication was markedly reduced (30 vs 65%, p

Isavuconazole (ISA), a triazole antifungal agent, is licensed for the treatment of invasive aspergillosis and mucormycosis. Therapeutic drug monitoring (TDM) is a cornerstone of treatment efficacy for triazole antifungals due to their pharmacokinetic variability, except for ISA, for which the utility of TDM is still uncertain. We performed a retrospective study that aimed to assess the inter- and intra-individual variability of ISA trough concentrations (Cmin) and to identify the determinants involved in such variability. ISA Cmin measured in adult patients at the Grenoble Alpes University Hospital between January 2018 and August 2020 were retrospectively analyzed. In total, 304 ISA Cmin for 33 patients were analyzed. The median ISA Cmin was 2.8 [25th–75th percentiles: 2.0–3.7] mg/L. The inter- and intra-individual variability was 41.5% and 30.7%, respectively. Multivariate analysis showed independent covariate effects of dose (β = 0.004 ± 3.56 × 10−4, p < 0.001), Aspartate aminotransférase (ASAT) (β = 0.002 ± 5.41 × 10−4, p = 0.002), and protein levels (β = 0.022 ± 0.004, p < 0.001) on ISA Cmin, whereas C reactive protein levels did not show any association. This study, conducted on a large number of ISA Cmin, shows that ISA exposure exhibits variability, explained in part by the ISA dose, and ASAT and protein levels.

The 9th web-based European Conference on Infections in Leukemia (ECIL-9), held September 16-17, 2021, reviewed the risk of infections and febrile neutropenia associated with more recently approved immunotherapeutic agents and molecular targeted drugs for the treatment of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Novel antibody based treatment approaches (inotuzumab ozogamicin, gemtuzumab ozogamicin, flotetuzumab), isocitrate dehydrogenases inhibitors (ivosidenib, enasidenib, olutasidenib), FLT3 kinase inhibitors (gilteritinib, midostaurin, quizartinib), a hedgehog inhibitor (glasdegib) as well as a BCL2 inhibitor (venetoclax) were reviewed with respect to their mode of action, their immunosuppressive potential, their current approval and the infectious complications and febrile neutropenia reported from clinical studies. Evidence-based recommendations for prevention and management of infectious complications and specific alerts regarding the potential for drug-drug interactions were developed and discussed in a plenary session with the panel of experts until consensus was reached. The set of recommendations was posted on the ECIL website for a month for comments from members of EBMT, EORTC, ICHS and ELN before final approval by the panelists. While a majority of these agents are not associated with a significantly increased risk when used as monotherapy, caution is required with combination therapy such as venetoclax plus hypomethylating agents, gemtuzumab ozogamicin plus cytotoxic drugs or midostaurin added to conventional AML chemotherapy.

AIMS Cytochrome 2C19 genotype-directed dosing of voriconazole (VRC) reduces the incidence of insufficient VRC trough concentrations (Cmin ) but does not account for CYP3A polymorphisms, also involved in VRC metabolism. This prospective observational study aimed to evaluate the utility of a genetic score combining CYP2C19 and CYP3A genotypes to predict insufficient initial VRC Cmin (

The 9th web-based European Conference on Infections in Leukemia (ECIL-9), held September 16-17, 2021, reviewed the risk of infections and febrile neutropenia associated with more recently approved immunotherapeutic agents and molecular targeted drugs for the treatment of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Novel antibody based treatment approaches (inotuzumab ozogamicin, gemtuzumab ozogamicin, flotetuzumab), isocitrate dehydrogenases inhibitors (ivosidenib, enasidenib, olutasidenib), FLT3 kinase inhibitors (gilteritinib, midostaurin, quizartinib), a hedgehog inhibitor (glasdegib) as well as a BCL2 inhibitor (venetoclax) were reviewed with respect to their mode of action, their immunosuppressive potential, their current approval and the infectious complications and febrile neutropenia reported from clinical studies. Evidence-based recommendations for prevention and management of infectious complications and specific alerts regarding the potential for drug-drug interactions were developed and discussed in a plenary session with the panel of experts until consensus was reached. The set of recommendations was posted on the ECIL website for a month for comments from members of EBMT, EORTC, ICHS and ELN before final approval by the panelists. While a majority of these agents are not associated with a significantly increased risk when used as monotherapy, caution is required with combination therapy such as venetoclax plus hypomethylating agents, gemtuzumab ozogamicin plus cytotoxic drugs or midostaurin added to conventional AML chemotherapy. ispartof: LEUKEMIA vol:36 issue:5 pages:1215-1226 ispartof: location:England status: published

Introduction: Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) with high-risk genetics and/or measurable residual disease (MRD) are at high-risk of disease recurrence. In the previous GRAALL-2005 study, we identified KMT2A rearrangements (KMT2A-r), IKZF1 intragenic deletion (IKZF1del) and post-induction (TP1, week 6) MRD ≥ 0.01% as independent factors to predict relapse in Ph-negative B-cell precursor (BCP) ALL (Beldjord K, Blood 2014). In the GRAALL-2014 trial, high-risk (HR) patients were thus defined by the presence of at least one of these three factors. Among them, only those with higher MRD levels defined as TP1-MRD ≥ 0.1% and/or week 12 (TP2) MRD ≥ 0.01% were considered at very high risk (VHR) and proposed allogeneic hematopoietic stem cell transplant (alloSCT) in first remission (Dhedin et al., Blood 2015). Since October 2018, all these patients were eligible to be included in the GRAALL-2014-QUEST phase 2 study to receive blinatumomab as part of consolidation and maintenance phases or as a bridge to transplant. Methods: From October 2018 to December 2020, 95 patients with high-risk Ph-negative BCP-ALL without central nervous system involvement at diagnosis and in continuous complete remission after induction and consolidation 1, were prospectively included to start blinatumomab at week 12. One patient was excluded because of T-ALL phenotype (with CD19 aberrant expression). Patients with alloSCT indication and a stem cell source received blinatumomab 28 microg/d administered by continuous intravenous infusion (cIV) until transplant. A minimum of 4 weeks blinatumomab was recommended before proceeding to transplantation. All other patients received 5 cycles of blinatumomab 28 microg/day cIV (for 28 days), during consolidation 2 and 3 and at months 1/3/5 of the maintenance phase respectively. The primary objective was disease-free survival (DFS). Secondary objectives included post-blinatumomab MRD response at TP3 (after consolidation 2 or before alloSCT), overall survival (OS), and safety. Early results are reported here. Results: Median age was 35 years old (range, 18-60). Median white blood cell count (WBC) at diagnosis was 12 G/L (range, 1-449). Oncogenetic analyses allowed classifying ALL as Ph-like (18%), KMT2A-r (17%), DUX4/ERGdel (13%), ZNF384-r (11%), low hypodiploidy/near triploidy (7%), B-other (26%) or unknown (9%). An IKZF1del was found in 37/93 (40%). A TP1-MRD ≥ 0.01% was found in 46/94 patients (49%). Final risk group was HR for 45 patients and VHR for 49 patients. Last pre-blinatumomab MRD was Conclusion. In patients wih high-risk BCP-ALL, blinatumomab added to consolidation is safe and gives promising results. A comparison to similar patients treated in the same GRAALL-2014 study before October 2018 is planned with a longer follow-up. Figure 1 Figure 1. Disclosures Boissel: Novartis: Consultancy, Honoraria, Research Funding; Incyte: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; SANOFI: Honoraria; Servier: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; CELGENE: Honoraria; JAZZ Pharma: Honoraria, Research Funding; PFIZER: Consultancy, Honoraria. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Chalandon: Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Amgen: Other: Advisory Board; Incyte: Speakers Bureau; Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Gilead, Amgen, Jazz, Astra Zenec: Other: Travel EXpenses, Accomodation. Delabesse: Astellas: Consultancy; Novartis: Consultancy. Dombret: Abbvie: Honoraria; Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; NOVARTIS: Research Funding; pfizer: Honoraria, Research Funding; servier: Research Funding; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. OffLabel Disclosure: Blinatumomab in frontline high-risk acute lymphoblastic leukemia

Resume L’infection par le virus d’Epstein-Barr (EBV) est une infection ubiquitaire, le plus souvent asymptomatique, et touchant plus de 95 % de la population mondiale ; c’est egalement une infection virale persistante associee a des cancers chez des individus immunocompetents ou immunodeprimes. Chez le patient greffe de cellules souches hematopoietiques (CSH) ou transplante d’organe solide, le deficit de controle de l’infection a EBV par le systeme immunitaire peut conduire a une lymphoproliferation ou syndrome lymphoproliferatif post-transplantation (SLPT). Le diagnostic du SLPT repose sur un faisceau d’arguments cliniques, biologiques et d’imagerie. La charge virale EBV (CVEBV) dans le sang est un marqueur sensible mais peu specifique de la survenue d’un SLPT. Elle est utilisee dans tous les centres dans le suivi des patients transplantes, mais aucun consensus n’existe a ce jour sur le seuil de CVEBV a partir duquel un traitement preemptif doit etre conduit. Chaque centre doit faire sa propre experience de suivi de la CVEBV : le laboratoire de virologie (matrice, unite de mesure ou seuil de CVEBV) et les services cliniques (interpretation des resultats dans le contexte clinique). Chez un patient dont la CVEBV augmente rapidement, le traitement preemptif EBV peut comprendre la levee de l’immunodepression et/ou l’instauration d’un traitement par le rituximab, un anticorps monoclonal anti-CD20 ciblant les lymphocytes B. Download : Download high-res image (187KB) Download : Download full-size image © SPL/PHANIE

Reactivation of BK virus (BKV) can occur during intensive immunosuppression such as in allogenic hematopoietic stem cell transplant (AHSCT) recipients for whom a systematic PCR urine test for BKV will be positive in 50 to 100% of patients. Only 5 to 40% will develop BKV hemorrhagic cystitis (HC). Thus, BKV PCR testing is useful to confirm a diagnosis of BKV-HC but not to predict its occurrence. The aim of this retrospective study was to ascertain the risk factors of developing BKV HC, mostly in patients receiving post-transplant cyclophosphamide. The study looked at data from Grenoble Alpes University Hospital included in the national retrospective register ProMISe, administered by the "Societe Francophone de Greffe de Moelle et de Therapie Cellulaire". Urine BKV PCR was performed when patients presented grade ≥2 hematuria with clinical symptoms of cystitis. BKV-HC was defined as an association of clinical symptoms of cystitis, grade ≥2 hematuria and BKV viruria >7 log10 copies/mL. From January 2014 to January 2018, 168 AHSCTs were considered for analysis, of which 43 (25.6%) developed BKV-HC and 44.9% of the sub-group that received post-transplant cyclophosphamide. After logistic regression, the risk factors associated with BKV-HC were reduced to: post-transplantation exposure to cyclophosphamide (OR 4.25, [1.66; 10.87], p=0.02), age

On behalf of the GRAALL group. Introduction. Tyrosine kinase inhibitors (TKIs) have dramatically improved the outcome of patients diagnosed with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). In a previous randomized trial (GRAAPH-2005; Chalandon Y., Blood 2015), our group demonstrated that anthracycline and cyclophosphamide could be safely omitted during the first Hyper-CVAD chemotherapy cycle when combined to imatinib. In the present GRAAPH-2014 trial, we investigated whether the use of nilotinib, a 2 nd generation TKI, would allow further decreasing chemotherapy intensity through the omission of high-dose cytarabine (HD-AraC) during consolidation cycles 2 and 4. Methods. From March 2016, patients aged 18-60 years old were randomized frontline to receive 4 cycles (1=3, 2=4) of chemotherapy combined with continuous nilotinib 400 mg bid. Cycle 1 and 3 were similar in both arms, identical to the less-intensive first cycle of the previous GRAAPH-2005 trial with weekly vincristine and dexamethasone and nilotinib instead of imatinib. Cycle 2 and 4 differed between control arm A (MTX 1 g/sqm over 24h, HD-AraC 3 g/sqm/12h for 2 days) and experimental arm B (MTX 1 g/sqm over 24h only). Marrow minimal residual disease (MRD) was assessed by both BCR-ABL1 and IG-TCR qPCR after each cycle (MRD1-4). Patients in complete remission (CR) after cycle 4 were eligible to receive allogeneic stem cell transplant (alloSCT). Non allografted patients had the option to receive autologous SCT (autoSCT) if a major molecular response (MMolR) (MRD4 BCR-ABL1 40y) and BCR-ABL1 breakpoint region (M/m-bcr). MMolR rate at MRD4 was the primary endpoint of this non-inferiority study, with a margin set at 0.15. In February 2019, the study DSMB decided to stop the randomizations after an unplanned analysis demonstrating a significant excess of relapse in arm B (without HD-AraC). An intention-to-treat analysis is provided. All patients gave informed consent. The study is registered at EudraCT under the number: 2014-002146-44. Results. A total of 156 patients were randomized (77 in arm A, and 79 in arm B). Median age was 47.1 years old (range 18.1-59.9). One-hundred and ten patients had the m-bcr (70.5%) and 46 (29.5%) the M-bcr. An IKZF1 intragenic deletion was found in 87/153 (56.9%). Median follow-up was 2.8 years (95%CI 2.6-3.1). All evaluable patients reached CR after a maximum of two cycles. Three patients died during cycle 1 (2 in arm A, 1 in arm B), and 2 during cycle 2 (1 per arm). Most patients received the 4 scheduled cycles (n=143, 91,7%). AlloSCT was performed in 91 patients (58.3%), whereas 41 patients received an autoSCT (26.3%) with no difference in allo/autoSCT rates between arms. A non-inferiority in late MRD response (MRD4) between the two arms was observed (primary endpoint). MMolR was reached in 55/75 (73.3%) and 61/78 (78.2%) of CR patients in arm A and B, respectively, with an estimated 95% CI of difference of -11% to +16% (-9.2% to +20.8% in the ITT analysis treating missing data as failures). At 3 years, overall survival (OS) was 86.0% in arm A versus 74.2% in arm B (p=.08, Figure A). Progression-free survival (PFS) was 79.6% in arm A versus 57.2% in arm B (p=.008, Figure B). Thirty-one patients experienced hematological relapse (8 in arm A and 23 in arm B). Twenty-height out of 31 relapsed patients were tested for the acquisition of BCR-ABL1 mutations, 20/28 (71%) had at least one mutation and 10/28 (36%) had a T315I mutation. At 3 years, the cumulative incidence of relapse (CIR) was 21.3%, significantly higher in arm B than in arm A (30.8% vs 10.6%, p=.007). When analyzing the CIR considering alloSCT as a competing event for relapse, a significant higher CIR was still observed in arm B as compared to arm A (Figure C). Conclusion. Four cycles of the combined administration of nilotinib and chemotherapy is very efficient for bridging younger adults with Ph-positive ALL to SCT. However, omitting HD-AraC is associated with a higher relapse incidence despite non-inferior levels of BCR-ABL1 MRD4. Figure 1 Figure 1. Disclosures Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Chalandon: Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Gilead, Amgen, Jazz, Astra Zenec: Other: Travel EXpenses, Accomodation; Incyte: Speakers Bureau; Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Amgen: Other: Advisory Board. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Vincent: Takeda: 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. Vey: Amgen: Honoraria; BMS: Honoraria; BIOKINESIS: Consultancy, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding; SERVIER: Consultancy; JAZZ PHARMACEUTICALS: Honoraria; JANSSEN: Consultancy. Raffoux: PFIZER: Consultancy; CELGENE/BMS: Consultancy; ASTELLAS: Consultancy; ABBVIE: Consultancy. Boissel: Amgen: Consultancy, Honoraria, Research Funding; CELGENE: Honoraria; Servier: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Incyte: Honoraria; SANOFI: Honoraria; PFIZER: Consultancy, Honoraria; JAZZ Pharma: Honoraria, Research Funding. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. OffLabel Disclosure: Nilotinib as a therapy for PH-positive acute lymphoblastic leukemia