Publications by authors named "Stephane Leprêtre"

84 Publications

Outcomes after intensive care unit admission in newly diagnosed diffuse large B-cell lymphoma patients: A real-life study.

Eur J Haematol 2021 Feb 23. Epub 2021 Feb 23.

Department of Hematology, Centre Henri Becquerel, Rouen, France.

We conducted a retrospective study to analyze the prognostic factors impacting the overall survival (OS) and progression-free survival (PFS) of diffuse large B-cell lymphoma (DLBCL) patients undergoing first-line therapy and admitted to intensive care unit (ICU) compared to a control cohort who did not required ICU admission. Between January 1, 2008, and December 31, 2018, 828 patients were diagnosed with DLBCL at our institution, including 72 patients who were required ICU admission during disease course. Among them, forty-five patients undergoing homogeneous first-line therapy with /R-CHOP-like regimen and ICU-admitted were selected for the present analysis. Control "non-ICU" DLBCL patients were matched by age, IPI score and treatment received. The median age at ICU admission was 65 years, 97.8% of patients displayed advanced-stage disease (III/IV), and 84.4% had a high IPI score (3-5). The main reasons for ICU admission were acute respiratory failure (40.0%) and septic shock (33.3%). The ICU mortality rate was 33.3%. The 2-year PFS was lower in ICU survivors patients than in non-ICU patients: 31.7% (95% CI 18.5-54.1) vs 60.8% (95% CI 51.2-72.1, P = .00049). Admission to the ICU is an event that clearly impacts the outcomes of patients with DLBCL, until 2 years after the event. ICU prognosis seems mainly related to critical patient severity at admission rather than lymphoma-related prognostic factors (IPIs), suggesting that ICU admission criteria should not be based only on the lymphoma prognosis.
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http://dx.doi.org/10.1111/ejh.13606DOI Listing
February 2021

A prognostic index predicting survival in transformed Waldenström macroglobulinemia.

Haematologica 2020 Nov 12;Online ahead of print. Epub 2020 Nov 12.

Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

Histological transformation into diffuse large B-cell lymphoma is a rare complication in patients with Waldenström macroglobulinemia (WM) usually associated with a poor prognosis. The objective of this study was to develop and validate a prognostic index for survival in transformed WM patients. Through this multicenter, international collaborative effort, we developed a scoring system based on data from 133 patients with transformed WM who were evaluated between 1995 and 2016 (training cohort). Univariate and multivariate analyses were used to propose a prognostic index with 2-year survival after transformation as an end-point. For external validation, a data set of 67 patients was used to evaluate the performance of the model (validation cohort). By multivariate analysis, three adverse covariates were identified as independent predictors of 2-year survival after transformation: elevated serum LDH (2 points), platelet count < 100 x 109/L (1 point) and any previous treatment for WM (1 point). Three risk groups were defined: low-risk (0-1 point, 24% of patients), intermediate-risk (2-3 points, 59%, hazard ratio (HR) = 3.4) and high-risk (4 points, 17%, HR = 7.5). Two-year survival rates were 81%, 47%, and 21%, respectively (P < 0.0001). This model appeared to be a better discriminant than the International Prognostic Index (IPI) and the revised IPI (R-IPI). We validated this model in an independent cohort. This easy-to-compute scoring index is a robust tool that may allow identification of groups of transformed WM patients with different outcomes and could be used for improving the development of risk-adapted treatment strategies.
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http://dx.doi.org/10.3324/haematol.2020.262899DOI Listing
November 2020

A fixed-duration, measurable residual disease-guided approach in CLL: follow-up data from the phase 2 ICLL-07 FILO trial.

Blood 2021 Feb;137(8):1019-1023

Department of Hematology, Centre Hospitalier Régional Universitaire (CHRU) Nancy, Unité 1256, INSERM Lorraine University, Nancy, France.

Trials assessing first-line, fixed-duration approaches in chronic lymphocytic leukemia (CLL) are yielding promising activity, but few long-term data are available. We report follow-up data from a phase 2 trial (ICLL07 FILO) in previously untreated, medically fit patients (N = 135). Patients underwent obinutuzumab-ibrutinib induction for 9 months; then, following evaluation (N = 130 evaluable), those in complete remission and with bone marrow measurable residual disease (BM MRD) <0.01% (n = 10) received ibrutinib for 6 additional months; those in partial remission and/or with BM MRD ≥0.01%, the majority (n = 120), also received 4 cycles of immunochemotherapy (fludarabine/cyclophosphamide-obinutuzumab). Beyond end of treatment, responses were assessed every 3 month and peripheral blood MRD every 6 months. At median follow-up 36.7 months from treatment start, progression-free and overall survival rates (95% confidence interval) at 3 years were 95.7% (92.0% to 99.5%) and 98% (95.1% to 100%), respectively. Peripheral blood MRD <0.01% rates were 97%, 96%, 90%, 84%, and 89% at months 16, 22, 28, 34, and 40, respectively. No new treatment-related or serious adverse event occurred beyond end of treatment. Thus, in previously untreated, medically fit patients with CLL, a fixed-duration (15 months), MRD-guided approach achieved high survival rates, a persistent MRD benefit beyond the end of treatment, and low long-term toxicity. This trial was registered at www.clinicaltrials.gov as #NCT02666898.
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http://dx.doi.org/10.1182/blood.2020008164DOI Listing
February 2021

Diagnosis and Treatment of Chronic Lymphocytic Leukemia: Recommendations of the French CLL Study Group (FILO).

Hemasphere 2020 Oct 23;4(5):e473. Epub 2020 Sep 23.

CHU de Caen Normandie, Caen, France.

As a result of significant recent developments, the management of patients with chronic lymphocytic leukemia (CLL) is changing, and new therapeutic options will continue to emerge in the near future. The recommendations of the French Innovative Leukemia Organization (FILO-CLL) group presented here are intended to provide practical recommendations for physicians taking care of CLL patients, taking into account the availability of both biological tests and therapies in daily practice in France at the time of publication. This text details the documented information and guidelines on diagnosis, indications for treatment, infectious complications and therapeutic strategies in frontline and relapsed CLL as well as in particular conditions such as autoimmune cytopenia or Richter syndrome.
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http://dx.doi.org/10.1097/HS9.0000000000000473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523785PMC
October 2020

Idelalisib treatment prior to allogeneic stem cell transplantation for patients with chronic lymphocytic leukemia: a report from the EBMT chronic malignancies working party.

Bone Marrow Transplant 2020 Oct 2. Epub 2020 Oct 2.

University of Heidelberg, Heidelberg, Germany.

No studies have been reported so far on bridging treatment with idelalisib for patients with chronic lymphocytic leukemia (CLL) prior to allogeneic hematopoietic cell transplantation (alloHCT). To study potential carry-over effects of idelalisib and to assess the impact of pathway-inhibitor (PI) failure we performed a retrospective EBMT registry-based study. Patients with CLL who had a history of idelalisib treatment and received a first alloHCT between 2015 and 2017 were eligible. Data on 72 patients (median age 58 years) were analyzed. Forty percent of patients had TP53 CLL and 64% had failed on at least one PI. No primary graft failure occurred. Cumulative incidences of acute GVHD °II-IV and chronic GVHD were 51% and 39%, respectively. Estimates for 2-year overall survival (OS), progression-free survival (PFS), and cumulative incidences of relapse/progression (CIR) and non-relapse mortality NRM were 59%, 44%, 25%, and 31%. In univariate analysis, drug sensitivity was a strong risk factor. For patients who had failed neither PI treatment nor chemoimmunotherapy (CIT) the corresponding 2-year estimates were 73%, 65%, 15%, and 20%, respectively. In conclusion, idelalisib may be considered as an option for bridging therapy prior to alloHCT. Owing to the high risk for acute GVHD intensified clinical monitoring is warranted.
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http://dx.doi.org/10.1038/s41409-020-01069-wDOI Listing
October 2020

Prognostic value of high-sensitivity measurable residual disease assessment after front-line chemoimmunotherapy in chronic lymphocytic leukemia.

Leukemia 2020 Sep 15. Epub 2020 Sep 15.

Laboratoire d'Hématologie, APHP CHU Avicenne, Bobigny, France.

Measurable residual disease (MRD) status is widely adopted in clinical trials in patients with chronic lymphocytic leukemia (CLL). Findings from FILO group trials (CLL2007FMP, CLL2007SA, CLL2010FMP) enabled investigation of the prognostic value of high-sensitivity (0.7 × 10) MRD assessment using flow cytometry, in blood (N = 401) and bone marrow (N = 339), after fludarabine, cyclophosphamide, and rituximab (FCR)-based chemoimmunotherapy in a homogeneous population with long follow-up (median 49.5 months). Addition of low-level positive MRD < 0.01% to MRD ≥ 0.01% increased the proportion of cases with positive MRD in blood by 39% and in bone marrow by 27%. Compared to low-level positive MRD < 0.01%, undetectable MRD was associated with significantly longer progression-free survival (PFS) when using blood (72.2 versus 42.7 months; hazard ratio 0.40, p = 0.0003), but not when using bone marrow. Upon further stratification, positive blood MRD at any level, compared to undetectable blood MRD, was associated with shorter PFS irrespective of clinical complete or partial remission, and a lower 5-year PFS rate irrespective of IGHV-mutated or -unmutated status (all p < 0.05). In conclusion, high-sensitivity (0.0007%) MRD assessment in blood yielded additional prognostic information beyond the current standard sensitivity (0.01%). Our approach provides a model for future determination of the optimal MRD investigative strategy for any regimen.
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http://dx.doi.org/10.1038/s41375-020-01009-zDOI Listing
September 2020

Ponatinib-based therapy in adults with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia: results of the real-life OPAL study.

Leuk Lymphoma 2020 09 8;61(9):2161-2167. Epub 2020 Jun 8.

Department of Hematology, Institut Universitaire du Cancer Toulouse-Oncopole, CHU de Toulouse, Toulouse, France.

The OPAL study is a French multicenter observational retrospective analysis of adults with relapsed/refractory Philadelphia chromosome-positive acute lymphoblastic leukemia treated in a real-life setting by ponatinib. Twenty-nine patients were included since 2012. Median age was 55  years. The initial dose of ponatinib, combined to chemotherapy in half of the patients, was 45 mg/day in most instances. The remission rate was 90% and seven patients received allogeneic stem cell transplantation. Median disease-free and overall survival were only 3.5 and 9.9 months respectively. The outcome of patients with ABL mutation was similar to that of unmutated patients. With a median duration of exposure to ponatinib of 4 months, only 3 cardio-vascular events were recorded despite a high incidence of risk factors, and overall safety was acceptable. These results underline the place of ponatinib to induce early response in advanced disease and the need of new combinations to improve long-term outcome.
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http://dx.doi.org/10.1080/10428194.2020.1762876DOI Listing
September 2020

Analysis of a cohort of 279 patients with hairy-cell leukemia (HCL): 10 years of follow-up.

Blood Cancer J 2020 05 27;10(5):62. Epub 2020 May 27.

Laboratoire d'Hematologie Biologique, CHU de Caen, Caen, France.

In total, 279 patients with hairy-cell leukemia (HCL) were analyzed, with a median follow-up of 10 years. Data were collected up to June 2018. We analyzed responses to treatment, relapses, survival, and the occurrence of second malignancies during follow-up. The median age was 59 years. In total, 208 patients (75%) were treated with purine analogs (PNAs), either cladribine (159) or pentosatin (49), as the first-line therapy. After a median follow-up of 127 months, the median overall survival was 27 years, and the median relapse-free survival (RFS) was 11 years. The cumulative 10-year relapse incidence was 39%. In patients receiving second-line therapy, the median RFS was 7 years. For the second-line therapy, using the same or another PNA was equivalent. We identified 68 second malignancies in 59 patients: 49 solid cancers and 19 hematological malignancies. The 10-year cumulative incidences of cancers, solid tumors, and hematological malignancies were 15%, 11%, and 5.0%, respectively, and the standardized incidence ratios were 2.22, 1.81, and 6.67, respectively. In multivariate analysis, PNA was not a risk factor for second malignancies. HCL patients have a good long-term prognosis. PNAs are the first-line treatment. HCL patients require long-term follow-up because of their relatively increased risk of second malignancies.
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http://dx.doi.org/10.1038/s41408-020-0328-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253459PMC
May 2020

Targeted genotyping of circulating tumor DNA for classical Hodgkin lymphoma monitoring: a prospective study.

Haematologica 2021 01 1;106(1):154-162. Epub 2021 Jan 1.

Department of Hematology, Centre Henri Becquerel, University of Rouen, Rouen, France.

The relevance of circulating tumor DNA (ctDNA) analysis as a liquid biopsy and minimal residual disease tool in the management of classical Hodgkin Lymphoma (cHL) patients was demonstrated in retrospective settings and remains to be confirmed in a prospective setting. We developed a targeted Next-Generation sequencing (NGS) panel for fast analysis (AmpliSeq technology) of nine commonly mutated genes in biopies and ctDNA of cHL patients. We then conducted a prospective trial to assess ctDNA follow up at diagnosis and after 2 cycles of chemotherapy (C2). Sixty cHL patients treated by first line conventional chemotherapy (BEACOPPescalated [21.3%], ABVD/ABVD-like [73.5%] and other regimens [5.2%, for elderly patients] were assessed in this non-interventional study. Median age of the patients was 33.5 years (range 20-86). Variants were identified in 42 (70%) patients. Mutations of NFKBIE, TNFAIP3, STAT6, PTPN1, B2M, XPO1, ITPKB, GNA13 and SOCS1 were found in 13.3%, 31.7%, 23.3%, 5%, 33.3%, 10%, 23.3%, 13.3% and 50% of patients, respectively. ctDNA concentration and genotype are correlated with clinical characteristics and presentation. Regarding early therapeutic response, 45 patients (83%, NA=6) had a negative positron emission tomography (PET) after C2 (Deauville Score 1-3). Mean of DeltaSUVmax after C2 was -78.8%. We analyzed ctDNA after C2 for 54 patients (90%). ctDNA became rapidly undetectable in all cases after C2. Variant detection in ctDNA is suitable to depict the genetic features of cHL at diagnosis and may help to assess early treatment response, in association with PET. Clinical Trial reference: NCT02815137.
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http://dx.doi.org/10.3324/haematol.2019.237719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7776248PMC
January 2021

Early treatment with FCR versus watch and wait in patients with stage Binet A high-risk chronic lymphocytic leukemia (CLL): a randomized phase 3 trial.

Leukemia 2020 08 18;34(8):2038-2050. Epub 2020 Feb 18.

Unite de Recherche Clinique, Hopital Avicenne, Bobigny, France.

We report a randomized prospective phase 3 study (CLL7), designed to evaluate the efficacy of fludarabine, cyclophosphamide, and rituximab (FCR) in patients with an early-stage high-risk chronic lymphocytic leukemia (CLL). Eight hundred patients with untreated-stage Binet A disease were enrolled as intent-to-treat population and assessed for four prognostic markers: lymphocyte doubling time <12 months, serum thymidine kinase >10 U/L, unmutated IGHV genes, and unfavorable cytogenetics (del(11q)/del(17p)/trisomy 12). Two hundred and one patients with ≥2 risk features were classified as high-risk CLL and 1:1 randomized to receive either immediate therapy with 6xFCR (Hi-FCR, 100 patients), or to be observed according to standard of care (Hi-W&W, 101 patients). The overall response rate after early FCR was 92.7%. Common adverse events were hematological toxicities and infections (61.0%/41.5% of patients, respectively). After median observation time of 55.6 (0-99.2) months, event-free survival was significantly prolonged in Hi-FCR compared with Hi-W&W patients (median not reached vs. 18.5 months, p < 0.001). There was no significant overall survival benefit for high-risk patients receiving early FCR therapy (5-year OS 82.9% in Hi-FCR vs. 79.9% in Hi-W&W, p = 0.864). In conclusion, although FCR is efficient to induce remissions in the Binet A high-risk CLL, our data do not provide evidence that alters the current standard of care "watch and wait" for these patients.
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http://dx.doi.org/10.1038/s41375-020-0747-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387319PMC
August 2020

Adult T-cell acute lymphoblastic leukemias with IL7R pathway mutations are slow-responders who do not benefit from allogeneic stem-cell transplantation.

Leukemia 2020 07 28;34(7):1730-1740. Epub 2020 Jan 28.

Université de Paris, Institut Necker-Enfants Malades, Institut National de Recherche Médicale U1151, Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants-Malades, Paris, France.

The prognostic value of IL7-receptor pathway (IL7Rp) mutations in T-cell acute lymphoblastic leukemia (T-ALL) remains unclear. We performed a comprehensive study of 200 adult patients with T-ALL included in the GRAALL2003/2005 protocols to address the clinical significance of IL7Rp mutations. Next-generation sequencing of the IL7Rp (IL7R/JAK1/JAK3/STAT5B) revealed that IL7Rp mutations were frequent in adult T-ALL (28%) particularly in immature/early T-cell progenitor (ETP)-ALL. They were associated with mutations of NOTCH-pathway, PHF6, and PRC2 components but not with K/NRAS. IL7Rp mutated (IL7Rp) T-ALL were slow-responders, with a high rate of M2/M3 day-8 marrow compared with IL7Rp non-mutated (IL7Rp) T-ALL (p = 0.002) and minimal residual disease positivity at 6-weeks (MRD1) (p = 0.008) but no difference in MRD2 positivity at 12-weeks. Despite this, no adverse prognosis was evidenced when censored for allogeneic hematopoietic stem cell transplantation (HSCT). In time-dependent analysis, HSCT did not benefit IL7Rp patients whereas it was of marked benefit to IL7Rp cases. IL7Rp-mutations identify a subgroup of slow-responder T-ALLs which benefit from post-induction chemotherapy regimens but not from HSCT. Our data suggest that prior knowledge of the mutation status of IL7Rp may influence HSCT decision and help to guide therapy reduction.
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http://dx.doi.org/10.1038/s41375-019-0685-4DOI Listing
July 2020

[Low-grade dural extranodal marginal zone lymphoma].

Ann Pathol 2020 Jun 13;40(3):243-247. Epub 2020 Jan 13.

Inserm U1245, service d'anatomie pathologique, UNIROUEN, Normandie Université, CHU de Rouen, 76000 Rouen, France.

Primary low-grade dural marginal zone lymphoma is an indolent low grade lymphoma occurring especially among middle-aged immunocompetent women, and is not associated to an infectious process, contrary to gastric or intestinal marginal zone lymphomas. Dural location is rare since only 105 cases have been reported so far. We report herein on two additional cases, a 72-year-old woman and a 36-year-old man whose lymphoma was revealed by partial seizures and headaches. Morphological analysis of surgical specimens displayed a tumoral proliferation made of small lymphocytes arranged in sheets or in nodules with CD20, CD79a and BCL2-immunopositivity, but CD5 and CD10 negativity. Molecular analysis using a panel of 34 genes involved in lymphomagenesis disclosed a deletion of SOCS1 and TNFAIP3 genes, implicated in the JAK/STAT and NFκB pathways respectively in the first patient that could explain unfavourable prognosis despite complementary radiotherapy. No anomaly was identified in the second patient who is alive with no recurrence or progression seven years after the diagnosis. Currently, there are no standardized treatment schedules, but the vast majority of patients are treated by surgery, then radiotherapy followed by adjuvant chemotherapy using methotrexate alone or in combination with rituximab. Literature review indicates that five-year survival has been estimated at 96.7%, suggesting a better prognosis compared to other locations.
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http://dx.doi.org/10.1016/j.annpat.2019.12.006DOI Listing
June 2020

Successful treatment of fungemia with isavuconazole in a patient with hematologic malignancies.

Infect Drug Resist 2019 9;12:2015-2018. Epub 2019 Jul 9.

Department of Parasitology/Mycology, Rouen University Hospital, Rouen, France.

spp. are yeast-like microorganisms responsible for skin, urinary, pulmonary, or bloodstream infections. Due to intrinsic resistance to echinocandins, poor susceptibility to polyenes, and preferred occurrence in immunocompromised patients, such infections are often of poor prognosis. Yet no consensual therapeutic guidelines are presently available. Several clinical cases of infections have been successfully treated with azole therapy, including voriconazole which appeared frequently effective against both in vitro and in vivo. However, the low efficacy associated with some genotypes, complex pharmacokinetics, and the side effects of voriconazole represent limitations for its use and has prompted a search for other therapeutic options. Here, we report a case of fungemia in a patient with B-cell acute lymphoblastic leukemia which was successfully treated with isavuconazole consecutive to stopping voriconazole therapy due to severe side effects. This observation suggests that isavuconazole with a similar spectrum to voriconazole, fewer pharmacology interactions, and side effects may be considered as a valuable therapeutic option against infections.
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http://dx.doi.org/10.2147/IDR.S211148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628197PMC
July 2019

Obinutuzumab and ibrutinib induction therapy followed by a minimal residual disease-driven strategy in patients with chronic lymphocytic leukaemia (ICLL07 FILO): a single-arm, multicentre, phase 2 trial.

Lancet Haematol 2019 Sep 16;6(9):e470-e479. Epub 2019 Jul 16.

Department of Hematology, CHRU Nancy, Nancy, France.

Background: In patients with chronic lymphocytic leukaemia, achievement of a complete response with minimal residual disease of less than 0·01% (ie, <1 chronic lymphocytic leukaemia cell per 10 000 leukocytes) in bone marrow has been associated with improved progression-free survival. We aimed to explore the activity of induction therapy for 9 months with obinutuzumab and ibrutinib, followed up with a minimal residual disease-driven therapeutic strategy for 6 additional months, in previously untreated patients.

Methods: We did a single-arm, phase 2 trial in 27 university hospitals, general hospitals, and specialist cancer centres in France. Eligible patients were at least 18 years old and previously untreated, and had immunophenotypically confirmed B-cell chronic lymphocytic leukaemia; an Eastern Cooperative Oncology Group (ECOG) performance status score of less than 2; a Binet stage C according to IWCLL 2008 criteria or Binet stage A and B with active disease; no 17p deletion or absence of p53 mutation; and were considered medically fit. In the first part of the study (induction phase), all participants received eight intravenous infusions of obinutuzumab 1000 mg over six 4-weekly cycles and oral ibrutinib 420 mg once per day for 9 months. In part 2, after assessment on day 1 of month 9, patients with a complete response and bone marrow minimal residual disease of less than 0·01% received only oral ibrutinib 420 mg once per day for 6 additional months. Patients with a partial response, or with a complete response and bone marrow minimal residual disease of 0·01% or more, received 6 months of four 4-weekly cycles of intravenous fludarabine, cyclophosphamide, and obinutuzumab 1000 mg, alongside continuing ibrutinib 420 mg once per day. The primary endpoint was the proportion of patients achieving a complete response with bone marrow minimal residual disease less than 0·01% on day 1 of month 16 assessed by intention to treat (ITT). This trial is registered with ClinicalTrials.gov (number NCT02666898) and is still open for follow-up.

Findings: Between Oct 27, 2015, and May 16, 2017, 135 patients were enrolled. After induction treatment (day 1 of month 9), 130 patients were evaluable, of which ten (8%) achieved a complete response with bone marrow minimal residual disease of less than 0·01% and were assigned to ibrutinib, and 120 (92%) were assigned to ibrutinib plus fludarabine, cyclophosphamide, and obinutuzumab. After minimal residual disease-guided treatment (day 1 of month 16), 84 (62%, 90% CI 55-69) of 135 patients (ITT population) achieved a complete response with bone marrow minimal residual disease of less than 0·01%. The most common haematological adverse event was thrombocytopenia (in 45 [34%] of 133 patients at grade 1-2 in months 1-9 and in 43 [33%] of 130 patients at grade 1-2 in months 9-15). The most common non-haematological adverse events were infusion-related reactions (in 83 [62%] patients at grade 1-2 in months 1-9) and gastrointestinal disorders (in 62 [48%] patients at grades 1 and 2 in months 9-15). 49 serious adverse events occurred, most frequently infections (ten), cardiac events (eight), and haematological events (eight). No treatment-related deaths occurred.

Interpretation: Obinutuzumab and ibrutinib induction therapy followed by a minimal residual disease driven strategy is safe and active in patients with previously untreated chronic lymphocytic leukaemia. With longer follow-up, including assessing the evolution of minimal residual disease, if response is maintained, this strategy could be an option in the first-line setting in patients with chronic lymphocytic leukaemia, although randomised evidence is needed.

Funding: Roche, Janssen.
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http://dx.doi.org/10.1016/S2352-3026(19)30113-9DOI Listing
September 2019

Light chain lambda myeloma with fatal AL cardiac amyloidosis in a 21-year-old patient: A case report and review.

Clin Case Rep 2019 Jun 7;7(6):1171-1177. Epub 2019 May 7.

Inserm U1245 and Department of Hematology Centre Henri Becquerel and Normandie Univ UNIROUEN Rouen France.

Multi-organ AL amyloidosis is a therapeutic challenge because of light chain deposits severely damaging the function of concerned organs. Cardiac involvement, which leads to concentric hypertrophy of both ventricles, is particularly severe and leads to poor prognosis regardless of combination chemotherapy. This case pinpoints the relevance of combining clinical, histological, and echocardiographic information in the management of this complex and life-threatening disease.
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http://dx.doi.org/10.1002/ccr3.2165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6552948PMC
June 2019

Epigenetic Silencing Affects l-Asparaginase Sensitivity and Predicts Outcome in T-ALL.

Clin Cancer Res 2019 04 18;25(8):2483-2493. Epub 2019 Jan 18.

Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM), Institut National de recherche Médicale (INSERM) U1151, and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, Paris, France.

Purpose: Biological explanation for discrepancies in patient-related response to chemotherapy depending on the underlying oncogenic events is a promising research area. TLX1- or TLX3-deregulated T-cell acute lymphoblastic leukemias (T-ALL; TLX1/3) share an immature cortical phenotype and similar transcriptional signatures. However, their prognostic impacts differ, and inconsistent clinical outcome has been reported for TLX3. We therefore hypothesized that the overlapping transcriptional profiles of TLX1 and TLX3 T-ALLs would allow identification of candidate genes, which might determine their distinct clinical outcomes.

Experimental Design: We compared TLX1 and TLX3 adult T-ALL outcome in the successive French national LALA-94 and GRAALL-2003/2005 multicentric trials and analyzed transcriptomic data to identify differentially expressed genes. Epigenetic regulation of asparagine synthetase () and l-asparaginase sensitivity were evaluated for T-ALL cell lines and primary samples.

Results: We show that TLX1 patients expressed low levels of when compared with TLX3 and TLX-negative patients, due to epigenetic silencing of by both DNA methylation and a decrease of active histone marks. Promoter methylation of the gene correlated with l-asparaginase sensitivity in both T-ALL cell lines and patient-derived xenografts. Finally, promoter methylation was an independent prognostic factor for both event-free survival [HR, 0.42; 95% confidence interval (CI), 0.24-0.71; = 0.001] and overall survival (HR, 0.40; 95% CI, 0.23-0.70; = 0.02) in 160 GRAALL-2003/2005 T-ALL patients and also in an independent series of 47 LL03-treated T lymphoblastic lymphomas ( = 0.012).

Conclusions: We conclude that methylation status at diagnosis may allow individual adaptation of l-asparaginase dose.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1844DOI Listing
April 2019

mutation is associated with increased age and adverse outcome in adult T-cell acute lymphoblastic leukemia.

Haematologica 2019 08 17;104(8):1617-1625. Epub 2019 Jan 17.

Université Paris Diderot, Institut Universitaire d'Hématologie, EA-3518, AP-HP, University Hospital Saint-Louis, Paris, France

The prognostic implications of genotype in T-cell acute lymphoblastic leukemia are incompletely understood. We performed comprehensive genetic and clinico-biological analyses of T-cell acute lymphoblastic leukemia patients with mutations treated during the GRAALL-2003 and -2005 studies. Eighteen of 198 cases (9.1%) had alterations. Two patients also had mutations in non-leukemic cell DNA, providing the first potential evidence of age-related clonal hematopoiesis in T-cell acute lymphoblastic leukemia. mutation was associated with older age (median 43.9 years 29.4 years, <0.001), immature T-cell receptor genotype (53.3% 24.4%, =0.016) and lower remission rates (72.2% mutated 94.4% non-mutated, =0.006). alterations were significantly associated with worse clinical outcome, with higher cumulative incidence of relapse (HR 2.33, 95% CI: 1.05-5.16, =0.037) and markedly poorer event-free survival (HR 3.22, 95% CI: 1.81-5.72, <0.001) and overall survival (HR 2.91, 95% CI: 1.56-5.43, =0.001). Adjusting for age as a covariate, or restricting the analysis to patients over 40 years, who account for almost 90% of -mutated cases, did not modify these observations. In multivariate analysis using the risk factors that were used to stratify treatment during the GRAALL studies, mutation was significantly associated with shorter event-free survival (HR 2.33, 95% CI: 1.06 - 4.04, =0.02). Altogether, these results identify genotype as a predictor of aggressive T-cell acute lymphoblastic leukemia biology. The GRAALL-2003 and -2005 studies were registered at as and , respectively.
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http://dx.doi.org/10.3324/haematol.2018.197848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669163PMC
August 2019

(teleomorph ) candidaemia in a patient with aplastic anaemia: a case report.

JMM Case Rep 2018 Aug 10;5(8):e005160. Epub 2018 Jul 10.

INSERM U1245, Department of Hematology, Centre Henri Becquerel, Université of Rouen Normandie, Rouen, France.

Introduction: We present what is believed to be the first report of candidaemia caused by () (teleomorph of ) in a patient with an aplastic anaemia.

Case Presentation: The patient, a 21-year-old male, presented with hepatic cytolysis, cutaneous and pulmonary involvement, and septic shock. was identified by aerobic blood culture and MS. The patient initially received multiple and combined antifungal therapy, but continued to have persistent skin lesions and fever. He was successfully treated by emergency haploidentical haematopoietic stem cell transplantation, combined with triple antifungal therapy and supportive care.

Conclusion: , teleomorph of , which is not usually invasive, can lead to an opportunistic invasive infection in unhealthy adult patients. For treatment of the invasive candida infection, it is necessary to combine antifungal therapy and supportive care.
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http://dx.doi.org/10.1099/jmmcr.0.005160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6152400PMC
August 2018

Mutational and cytogenetic analyses of 188 CLL patients with trisomy 12: A retrospective study from the French Innovative Leukemia Organization (FILO) working group.

Genes Chromosomes Cancer 2018 11 11;57(11):533-540. Epub 2018 Sep 11.

Sorbonne Universités, UPMC Univ Paris 06, AP-HP, GRC-11, Groupe de recherche clinique sur les hémopathies lymphoïdes (GRECHY), Hôpital Pitié-Salpétrière, APHP, Paris, France.

Trisomy 12 (tri12) is the second most frequent chromosomal aberration (15%-20%) in chronic lymphocytic leukemia (CLL). Tri12 confers an intermediate prognosis but is a heterogeneous entity. We examined whether additional mutational or chromosomal alterations might impact tri12 patient outcomes. This retrospective study, carried out by the French Innovative Leukemia Organization, included 188 tri12 patients with comprehensive information on immunoglobulin heavy chain (IGHV) gene status, karyotypic/FISH abnormalities, and NOTCH1, TP53, SF3B1, and MYD88 mutations. The main cytogenetic abnormalities associated with tri12 were del(13q) (25%), additional trisomies (14%) (including tri19 (10%) and tri18 (4%)), 14q32 translocations (10%), del(17p) (6.5%), del(14q) (4%), and del(11q) (4%). Unmutated (UM) IGHV, NOTCH1, and TP53, mutations were identified in respectively 66%, 25%, and 8.5% of cases. Multivariate analyses showed that additional trisomies (HR = 0.43, 95% CI = 0.23-0.78, P = .01) were associated with a significantly longer time to first treatment in Binet stage A patients and with a lower risk of relapse (HR = 0.37, 95% CI = 0.15-0.9, P = .03) in the overall tri12 population. Binet stage B/C, TP53 disruption, and UM IGHV status were associated with a shorter time to next treatment, while Binet stage B/C (HR = 4, 95% CI = 1.6-4.9, P = .002) and TP53 disruption (HR = 5, 95% CI = 1.94-12.66, P = .001) conferred shorter overall survival in multivariate comparisons. These data indicate that additional cytogenetic and mutational abnormalities, and particularly additional trisomies, IGHV status, and TP53 disruption, influence tri12 patient outcomes and could improve risk stratification in this population.
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http://dx.doi.org/10.1002/gcc.22650DOI Listing
November 2018

Prolonged third complete remission after busulfan, thiotepa, and autologous stem cell transplant in a primary central nervous system lymphoma patient.

Clin Case Rep 2018 Aug 4;6(8):1418-1421. Epub 2018 Jun 4.

Department of Hematology Centre Henri Becquerel Rouen France.

Primary central nervous system lymphoma (PCNSL) remains a therapeutic challenge due to impaired drugs diffusion as a result of the blood-brain barrier and high risk of relapse. Patients with good performance status, chemo-sensitive disease, and eligible for autologous stem cell transplant (ASCT) may benefit from salvage therapy and therapeutic intensification that may allow long-term remission.
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http://dx.doi.org/10.1002/ccr3.1630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099056PMC
August 2018

Non-invasive monitoring of diffuse large B-cell lymphoma by cell-free DNA high-throughput targeted sequencing: analysis of a prospective cohort.

Blood Cancer J 2018 08 1;8(8):74. Epub 2018 Aug 1.

INSERM U1245, Centre Henri Becquerel, University of Rouen, Rouen, France.

From a liquid biopsy, cell-free DNA (cfDNA) can provide information regarding basal tumoral genetic patterns and changes upon treatment. In a prospective cohort of 30 diffuse large B-cell lymphomas (DLBCL), we determined the clinical relevance of cfDNA using targeted next-generation sequencing and its correlation with PET scan imaging at the time of diagnosis and during treatment. Using a dedicated DLBCL panel, mutations were identified at baseline for 19 cfDNAs and profiles were consistent with expected DLBCL patterns. Tumor burden-related clinical and PET scan features (LDH, IPI, and metabolic tumor volume) were significantly correlated with the quantity of tumoral cfDNA. Among the four patients presenting additional mutations in their cfDNAs, three had high metabolic tumor volumes, suggesting that cfDNA more accurately reflects tumor heterogeneity than tissues biopsy itself. Mid-treatment, four patients still had basal mutations in their cfDNAs, including three in partial response according to their Deauville scores. Our study highlights the major interests in liquid biopsy, in particular in the context of bulky tumors where cfDNA allows capturing the entire tumoral mutation profile. Therefore, cfDNA analysis in DLBCL represents a complementary approach to PET scan imaging.
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http://dx.doi.org/10.1038/s41408-018-0111-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6070497PMC
August 2018

Moxetumomab pasudotox in relapsed/refractory hairy cell leukemia.

Leukemia 2018 08 20;32(8):1768-1777. Epub 2018 Jul 20.

Developmental Therapeutics Consortium, Chicago, IL, USA.

This is a pivotal, multicenter, open-label study of moxetumomab pasudotox, a recombinant CD22-targeting immunotoxin, in hairy cell leukemia (HCL), a rare B cell malignancy with high CD22 expression. The study enrolled patients with relapsed/refractory HCL who had ≥2 prior systemic therapies, including ≥1 purine nucleoside analog. Patients received moxetumomab pasudotox 40 µg/kg intravenously on days 1, 3, and 5 every 28 days for ≤6 cycles. Blinded independent central review determined disease response and minimal residual disease (MRD) status. Among 80 patients (79% males; median age, 60.0 years), durable complete response (CR) rate was 30%, CR rate was 41%, and objective response rate (CR and partial response) was 75%; 64 patients (80%) achieved hematologic remission. Among complete responders, 27 (85%) achieved MRD negativity by immunohistochemistry. The most frequent adverse events (AEs) were peripheral edema (39%), nausea (35%), fatigue (34%), and headache (33%). Treatment-related serious AEs of hemolytic uremic syndrome (7.5%) and capillary leak syndrome (5%) were reversible and generally manageable with supportive care and treatment discontinuation (6 patients; 7.5%). Moxetumomab pasudotox treatment achieved a high rate of independently assessed durable response and MRD eradication in heavily pretreated patients with HCL, with acceptable tolerability.
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http://dx.doi.org/10.1038/s41375-018-0210-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6087717PMC
August 2018

Intensified Therapy of Acute Lymphoblastic Leukemia in Adults: Report of the Randomized GRAALL-2005 Clinical Trial.

J Clin Oncol 2018 08 4;36(24):2514-2523. Epub 2018 Jun 4.

Françoise Huguet, Eric Delabesse, Institut Universitaire du Cancer, Toulouse; Sylvie Chevret, Nicolas Boissel, Hervé Dombret, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris (AP-HP); Université Paris Diderot; Agnès Buzyn, Vahid Asnafi, Elizabeth Macintyre, Hôpital Necker, AP-HP; Université Paris Descartes, Paris; Thibaut Leguay, Centre Hospitalier Universitaire, Pessac; Xavier Thomas, Véronique Lhéritier, Hôpital Lyon-Sud, Pierre Bénite; Martine Escoffre-Barbe, Centre Hospitalier Universitaire, Rennes; Patrice Chevallier, Marie C. Béné, Centre Hospitalier Universitaire, Nantes; Mathilde Hunault, Norbert Ifrah, Centre Hospitalier Universitaire, Angers; Norbert Vey, Institut Paoli-Calmettes, Marseille; Caroline Bonmati, Centre Hospitalier Universitaire, Nancy; Stéphane Lepretre, Centre Henri Becquerel, Rouen; Jean-Pierre Marolleau, Centre Hospitalier Universitaire, Amiens; Philippe Rousselot, Centre Hospitalier, Versailles; Jean-Yves Cahn, Centre Hospitalier Universitaire Grenoble-Alpes, La Tronche, France; Thomas Pabst, Inselspital; Swiss Group for Clinical Cancer Research, Bern; and Yves Chalandon, Swiss Group for Clinical Cancer Research, Bern; Hôpital Universitaire, Geneva, Switzerland.

Purpose To evaluate randomly the role of hyperfractionated cyclophosphamide (hyper-C) dose intensification in adults with newly diagnosed Philadelphia chromosome-negative acute lymphoblastic leukemia treated with a pediatric-inspired protocol and to determine the upper age limit for treatment tolerability in this context. Patients and Methods A total of 787 evaluable patients (B/T lineage, 525 and 262, respectively; median age, 36.1 years) were randomly assigned to receive a standard dose of cyclophosphamide or hyper-C during first induction and late intensification. Compliance with chemotherapy was assessed by median doses actually received during each treatment phase by patients potentially exposed to the full planned doses. Results Overall complete remission (CR) rate was 91.9%. With a median follow-up of 5.2 years, the 5-year rate of event-free survival (EFS) and overall survival (OS) was 52.2% (95% CI, 48.5% to 55.7%) and 58.5% (95% CI, 54.8% to 61.9%), respectively. Randomization to the hyper-C arm did not increase the CR rate or prolong EFS or OS. As a result of worse treatment tolerance, advanced age continuously affected CR rate, EFS, and OS, with 55 years as the best age cutoff. At 5 years, EFS was 55.7% (95% CI, 51.8% to 59.4%) for patients younger than 55 years of age versus 25.8% (95% CI, 19.9% to 35.6%) in older patients (hazard ratio, 2.16; P < .001). Patients ≥ 55 years of age, in whom a lower compliance to the whole planned chemotherapy was observed, benefited significantly from hyper-C, whereas younger patients did not. Conclusion No significant benefit was associated with the introduction of a hyper-C sequence into a frontline pediatric-like adult acute lymphoblastic leukemia therapy. Overall, tolerability of an intensive pediatric-derived treatment was poor in patients ≥ 55 years of age.
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http://dx.doi.org/10.1200/JCO.2017.76.8192DOI Listing
August 2018

Rituximab maintenance versus observation following abbreviated induction with chemoimmunotherapy in elderly patients with previously untreated chronic lymphocytic leukaemia (CLL 2007 SA): an open-label, randomised phase 3 study.

Lancet Haematol 2018 Feb 20;5(2):e82-e94. Epub 2017 Dec 20.

UPMC GRC11-GRECHY, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France.

Background: Most patients with chronic lymphocytic leukaemia relapse after initial therapy combining chemotherapy with rituximab. We assessed the efficacy and safety of rituximab maintenance treatment versus observation for elderly patients in remission after front-line abbreviated induction by fludarabine, cyclophosphamide, and rituximab (FCR).

Methods: This randomised, open-label, multicentre phase 3 trial at 89 centres in France enrolled treatment-naive and fit patients aged 65 years or older with chronic lymphocytic leukaemia without del(17p). Eligible patients had an Eastern Cooperative Oncology Group performance status of 0-1 and adequate renal and hepatic function. Patients in response to complete induction treatment with four monthly courses of full-dose FCR with two interim rituximab doses on day 14 of cycles 1 and 2 (oral fludarabine [40 mg/m per day] and oral cyclophosphamide [250 mg/m per day] for the first 3 days of each cycle, rituximab at 375 mg/m intravenously on day 0 of cycle 1 and subsequently at 500 mg/m on day 14 of cycle 1, days 1 and 14 of cycle 2, and day 1 of cycles 3 and 4) were eligible for randomisation. Recovery from FCR toxicity and patient willingness to continue the trial were mandatory. We randomly assigned (1:1) patients to either receive intravenous rituximab (500 mg/m) every 8 weeks for up to 2 years or undergo observation, with a central computer-generated randomisation list using randomly permuted blocks of variable sizes. Randomisation was stratified by IGHV mutational status, the presence or absence of del(11q), and response level to induction treatment. The primary endpoint was progression-free survival, with the objective to assess the superiority of rituximab maintenance relative to observation. The final analysis was done in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug in the rituximab group and in all patients in the observation group. This trial is closed to accrual whilst continuing patient follow-up. The study is registered with ClinicalTrials.gov, number NCT00645606.

Findings: Between Dec 14, 2007, and Feb 18, 2014, 542 patients were enrolled, of whom 525 started FCR induction. Between June 10, 2008, and Aug 14, 2014, 409 (78%) patients were randomly assigned to rituximab maintenance (n=202) or observation (n=207). Four (2%) patients in the rituximab group did not receive the allocated treatment (progressive disease [n=1], adverse events [n=3]). After a median follow-up of 47·7 months (IQR 30·4-65·8), median progression-free survival in the rituximab group (59·3 months, 95% CI 49·6-not estimable) was improved compared with the observation group (49·0 months, 39·9-60·5; hazard ratio 0·55, 95% CI 0·40-0·75; p=0·0002). Neutropenia and grade 3-4 infections were more common with rituximab maintenance (105 [53%] of 198 patients vs 74 [36%] of 207 patients and 38 [19%] vs 21 [10%], respectively) during the study. The most common grade 3-4 infection was lower respiratory tract infection (24 [12%] vs eight [4%]). The incidence of second cancers, except basal cell carcinoma, was similar in both groups (29 [15%] vs 23 [11%]). Deaths were related to adverse events for 23 (11%) patients in the rituximab group and 16 (8%) in the observation group.

Interpretation: 2-year maintenance rituximab in selected elderly patients improves progression-free survival and shows an acceptable safety profile. Immunotherapy maintenance strategy is a relevant option in front-line treatment of chronic lymphocytic leukaemia, even in the age of targeted therapy.

Funding: French National Cancer Institute (INCa), Roche, Chugai.
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http://dx.doi.org/10.1016/S2352-3026(17)30235-1DOI Listing
February 2018