Publications by authors named "Pierre-Yves Dumas"

33 Publications

Molecular classification and prognosis in younger adults with acute myeloid leukemia and intermediate-risk cytogenetics treated or not by gemtuzumab ozogamycin: Final results of the GOELAMS/FILO acute myeloid leukemia 2006-intermediate-risk trial.

Eur J Haematol 2021 Mar 25. Epub 2021 Mar 25.

Hématologie Clinique, Hôpital Cochin, AP-HP, Paris, France.

In this randomized phase 3 study, the FILO group tested whether the addition of 6 mg/m of gemtuzumab ozogamycin (GO) to standard chemotherapy could improve outcome of younger patients with de novo acute myeloid leukemia (AML) and intermediate-risk cytogenetics. GO arm was prematurely closed after 254 inclusions because of toxicity. A similar complete remission rate was observed in both arms. Neither event-free survival nor overall survival were improved by GO in younger AML patients (<60 years) ineligible for allogeneic stem-cell transplantation. (P = .086; P = .149, respectively). Using unsupervised hierarchical clustering based on mutational analysis of seven genes (NPM1, FLT3-ITD, CEBPA, DNMT3A, IDH1, IDH2, and ASXL1), six clusters of patients with significant different outcome were identified. Five clusters were based on FLT3-ITD, NPM1, and CEBPA mutations as well as epigenetic modifiers (DNMT3A, IDH1/2, ASXL1), whereas the last cluster, representing 25% of patients, had no mutation and intermediate risk. One cluster isolated FLT3-ITD mutations with higher allelic ratio and a very poor outcome. The addition of GO had no impact in these molecular clusters. Although not conclusive for GO impact in AML patients <60 years, this study provides a molecular classification that distinguishes six AML clusters influencing prognosis in younger AML patients with intermediate-risk cytogenetic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ejh.13626DOI Listing
March 2021

Conventional chemotherapy for acute myeloid leukemia in older adults: Impact on nutritional, cognitive, and functional status.

Eur J Haematol 2021 Jun 27;106(6):859-867. Epub 2021 Mar 27.

Clinical Hematology, Grenoble University Hospital, Grenoble, France.

Objectives: The impact of conventional treatment for acute myeloid leukemia (AML) on the nutritional, cognitive, and functional status of elderly patients is seldom studied. This assessment was performed in the context of the LAMSA 2007 trial.

Methods: The trial enrolled 424 patients with de novo AML. Among them, 316 benefited from geriatric assessment (GA) including nutritional, cognitive, and functional status and were scored according to Eastern Cooperative Oncology Group (ECOG) and sorror for the prediction of treatment toxicity, morbidity, and mortality. Patients were investigated at diagnosis for three times during follow-up.

Results: This study showed that AML and its treatment have no impact on cognitive (P = .554) nor functional status (P = .842 for Activity of Daily Living and P = .087 for Instrumental Activities of Daily Living). The nutritional status improved over time (P = .041). None of these three parameters at baseline, associated or not with ECOG and sorror scores, impacted survivals or toxicities.

Conclusions: The cognitive, functional, and nutritional status had no impact in this cohort of fit elderly AML patients without unfavorable cytogenetics. The GA tools used provided no additional information compared with ECOG and sorror scores, to predict toxicity, morbidity, or mortality due to intensive chemotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ejh.13624DOI Listing
June 2021

Real-life experience with CPX-351 and impact on the outcome of high-risk AML patients: a multicentric French cohort.

Blood Adv 2021 01;5(1):176-184

Cote d'Azur University, Hematology Department, Centre Hospitalier Universitaire de Nice, Nice, France.

CPX-351 is a liposomal formulation of cytarabine and daunorubicin approved for the treatment of adults with newly diagnosed, therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (MRC-AML). We retrospectively analyzed the efficacy and safety of CPX-351 in a real-world setting in 103 patients from 12 French centers, including the evaluation of molecular abnormalities at baseline and minimal residual disease (MRD) in responding patients, compared with a historical data set from Bordeaux-Toulouse DATAML registry. A favorable safety profile was observed, with a low frequency of alopecia (11%) and gastrointestinal toxicity (50%). The overall response rate after induction was 59%, and MRD <10-3 was achieved in 57% of complete response (CR)/CR with incomplete hematological recovery (CRi) patients. Only the presence of mutated TP53 (P = .02) or PTPN11 (P = .004) predicted lower response in multivariate analysis. Interestingly, high-risk molecular prognosis subgroups defined by 2017 European LeukemiaNet risk stratification, including ASXL1 and RUNX1 mutations, were not associated with a significantly lower response rate using CPX-351. With a median follow-up of 8.6 months, median overall survival (OS) was 16.1 months. Thirty-six patients underwent allogeneic stem cell transplantation with a significantly longer median OS compared with nontransplanted patients (P < .001). In multivariate analyses, only spliceosome mutations were associated with better OS (P = .04). In comparison with intensive chemotherapy, there was no difference in OS for patients <60 years. These data confirm the efficacy and safety of CPX-351 in high-risk AML (t-AML and MRC-AML) in a real-life setting. CPX-351 is a treatment of choice for patients aged ≥60 years.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2020003159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805314PMC
January 2021

Unsupervised Flow Cytometry Analysis Allows for an Accurate Identification of Minimal Residual Disease Assessment in Acute Myeloid Leukemia.

Cancers (Basel) 2021 Feb 5;13(4). Epub 2021 Feb 5.

Hematology Biology, Nantes University Hospital, 44000 Nantes, France.

The assessment of minimal residual disease (MRD) is increasingly considered to monitor response to therapy in hematological malignancies. In acute myeloblastic leukemia (AML), molecular MRD (mMRD) is possible for about half the patients while multiparameter flow cytometry (MFC) is more broadly available. However, MFC analysis strategies are highly operator-dependent. Recently, new tools have been designed for unsupervised MFC analysis, segregating cell-clusters with the same immunophenotypic characteristics. Here, the Flow-Self-Organizing-Maps (FlowSOM) tool was applied to assess MFC-MRD in 96 bone marrow (BM) follow-up (FU) time-points from 40 AML patients with available mMRD. A reference FlowSOM display was built from 19 healthy/normal BM samples (NBM), then simultaneously compared to the patient's diagnosis and FU samples at each time-point. MRD clusters were characterized individually in terms of cell numbers and immunophenotype. This strategy disclosed subclones with varying immunophenotype within single diagnosis and FU samples including populations absent from NBM. Detectable MRD was as low as 0.09% in MFC and 0.051% for mMRD. The concordance between mMRD and MFC-MRD was 80.2%. MFC yielded 85% specificity and 69% sensitivity compared to mMRD. Unsupervised MFC is shown here to allow for an easy and robust assessment of MRD, applicable also to AML patients without molecular markers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13040629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914957PMC
February 2021

Single-cell profiling reveals the trajectories of natural killer cell differentiation in bone marrow and a stress signature induced by acute myeloid leukemia.

Cell Mol Immunol 2021 May 25;18(5):1290-1304. Epub 2020 Nov 25.

Aix Marseille University, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy, Marseille, France.

Natural killer (NK) cells are innate cytotoxic lymphoid cells (ILCs) involved in the killing of infected and tumor cells. Among human and mouse NK cells from the spleen and blood, we previously identified by single-cell RNA sequencing (scRNAseq) two similar major subsets, NK1 and NK2. Using the same technology, we report here the identification, by single-cell RNA sequencing (scRNAseq), of three NK cell subpopulations in human bone marrow. Pseudotime analysis identified a subset of resident CD56 NK cells, NK0 cells, as the precursor of both circulating CD56 NK1-like NK cells and CD56 NK2-like NK cells in human bone marrow and spleen under physiological conditions. Transcriptomic profiles of bone marrow NK cells from patients with acute myeloid leukemia (AML) exhibited stress-induced repression of NK cell effector functions, highlighting the profound impact of this disease on NK cell heterogeneity. Bone marrow NK cells from AML patients exhibited reduced levels of CD160, but the CD160 group had a significantly higher survival rate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41423-020-00574-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093261PMC
May 2021

Reduce Mortality and Morbidity in Acute Myeloid Leukemia With Hyperleukocytosis With Early Admission in Intensive Care Unit: A Retrospective Analysis.

J Hematol 2020 Dec 1;9(4):109-115. Epub 2020 Oct 1.

CHU de Bordeaux, Hopital Haut Leveque, Service d'Hematologie Clinique et Therapie Cellulaire, 1 Avenue de Magellan, 33600 Pessac, France.

Background: Patients presenting with acute myeloid leukemia (AML) at diagnosis are at high risk of severe complications and death, particularly with high white blood cell (WBC) count. In this retrospective study, we evaluate interest of early and systematic support in the intensive care unit (ICU) for AML with hyperleukocytosis (AML-HL) at diagnosis.

Methods: Patients with AML-HL, defined by WBC > 50 × 10/L, primary referred in ICU ("Early ICU") without organ failure and before initiating chemotherapy induction were compared to patients first admitted in the Hematology Department who required a secondary transfer in ICU ("Late ICU") or not ("No ICU"). Primary end point was mortality during the first month, and secondary end points were the use of life-sustaining therapies in ICU and risk factors for ICU transfer and mortality.

Results: One hundred fifty-four patients were included: 77 (50%) to the group "No ICU", 18 (12%) to "Late ICU" and 59 (38%) to "Early ICU". Mortality at day 30 was higher in "Late ICU" than in "Early ICU" and "No ICU", with 27.8%; 16.9% and 2.6% respectively (P < 0.001). "Late ICU" patients had an increased use of life-sustaining therapy comparing to "Early ICU" patients (56% vs. 29%, P = 0.04).

Conclusions: Early referral to ICU reduces morbidity and seems an effective strategy to reduce short-term mortality in AML-HL at diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.14740/jh691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665861PMC
December 2020

Lomustine is beneficial to older AML with ELN2017 adverse risk profile and intermediate karyotype: a FILO study.

Leukemia 2021 May 18;35(5):1291-1300. Epub 2020 Sep 18.

Clinical Hematology, Bordeaux University Hospital, Bordeaux University, Inserm 1035, Bordeaux, France.

We previously reported the benefit of lomustine addition to conventional chemotherapy in older acute myeloid leukemias with nonadverse chromosomal aberrations in the LAM-SA 2007 randomized clinical trial (NCT00590837). A molecular analysis of 52 genes performed in 330 patients included in this trial, 163 patients being treated with lomustine in combination with idarubicin and cytarabine and 167 without lomustine, identified 1088 mutations with an average of 3.3 mutations per patient. NPM1, FLT3, and DNMT3A were the most frequently mutated genes. A putative therapeutic target was identified in 178 patients (54%). Among five molecular classifications analyzed, the ELN2017 risk classification has the stronger association with the clinical evolution. Patients not treated with lomustine have an expected survival prognosis in agreement with this classification regarding the overall and event-free survivals. In strong contrast, lomustine erased the ELN2017 classification prognosis. The benefit of lomustine in nonadverse chromosomal aberrations was restricted to patients with RUNX1, ASXL1, TP53, and FLT3-ITD/NPM1 mutations in contrast to the intermediate and favorable ELN2017 patients. This post-hoc analysis identified a subgroup of fit elderly AML patients with intermediate cytogenetics and molecular markers who may benefit from lomustine addition to intensive chemotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41375-020-01031-1DOI Listing
May 2021

A personalized approach to guide allogeneic stem cell transplantation in younger adults with acute myeloid leukemia.

Blood 2021 01;137(4):524-532

Service d'Hématologie Clinique, Hôpital Henri Mondor, AP-HP, Créteil, France.

A multistage model instructed by a large dataset (knowledge bank [KB] algorithm) has recently been developed to improve outcome predictions and tailor therapeutic decisions, including hematopoietic stem cell transplantation (HSCT) in acute myeloid leukemia (AML). We assessed the performance of the KB in guiding HSCT decisions in first complete remission (CR1) in 656 AML patients younger than 60 years from the ALFA-0702 trial (NCT00932412). KB predictions of overall survival (OS) were superior to those of European LeukemiaNet (ELN) 2017 risk stratification (C-index, 68.9 vs 63.0). Among patients reaching CR1, HSCT in CR1, as a time-dependent covariate, was detrimental in those with favorable ELN 2017 risk and those with negative NPM1 minimal residual disease (MRD; interaction tests, P = .01 and P = .02, respectively). Using KB simulations of survival at 5 years in a scenario without HSCT in CR1 (KB score), we identified, in a similar time-dependent analysis, a significant interaction between KB score and HSCT, with HSCT in CR1 being detrimental only in patients with a good prognosis based on KB simulations (KB score ≥40; interaction test, P = .01). We could finally integrate ELN 2017, NPM1 MRD, and KB scores to sort 545 CR1 patients into 278 (51.0%) HSCT candidates and 267 (49.0%) chemotherapy-only candidates. In both time-dependent and 6-month landmark analyses, HSCT significantly improved OS in HSCT candidates, whereas it significantly shortened OS in chemotherapy-only candidates. Integrating KB predictions with ELN 2017 and MRD may thus represent a promising approach to optimize HSCT timing in younger AML patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2020005524DOI Listing
January 2021

Delivering HDAC over 3 or 5 days as consolidation in AML impacts health care resource consumption but not outcome.

Blood Adv 2020 08;4(16):3840-3849

Service d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France.

Postremission treatment is crucial to prevent relapse in acute myeloid leukemia (AML). High-dose cytarabine delivered every 12 hours on days 1, 3, and 5 (HDAC-135) is the standard of care for younger adult patients with AML. Although this standard has been unsuccessfully challenged by other treatment regimens, including multiagent chemotherapy, the timing of HDAC administration has attracted little attention. Here, we retrospectively compared the safety, efficacy, and health care resource consumption associated with HDAC-135 and another standard, condensed HDAC-123 regimen, as consolidation treatment in younger AML patients in first complete response. This study included 221 patients (median age, 46.6 years; range, 18-60 years). HDAC-123 and HDAC-135 were used in 92 and 129 patients, respectively. Both regimens were associated with similar rates of relapse-free survival, cumulative incidence of relapse, nonrelapse mortality, and overall survival, including in core binding factor AML subgroup in which levels of minimal residual disease reduction were similar in both schedules. Hematological recovery times regarding neutrophils and platelets were significantly shorter in patients receiving HDAC-123, with an average difference of 3 to 4 days for each consolidation cycle. The total duration of hospitalization for the whole postremission program was shorter with HDAC-123 (32 days; interquartile ratio [IQR], 22.0,36.5) compared with HDAC-135 (41 days; IQR, 30.5, 50.0) (P < .0001). In conclusion, the condensed HDAC-123 regimen induced faster hematological recovery and therefore significantly reduced the length of hospital stay without affecting treatment response or outcome in younger AML patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2020002511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448603PMC
August 2020

Real-World Outcomes of Patients with Refractory or Relapsed -ITD Acute Myeloid Leukemia: A Toulouse-Bordeaux DATAML Registry Study.

Cancers (Basel) 2020 Jul 24;12(8). Epub 2020 Jul 24.

Service d'Hématologie, Institut Universitaire du Cancer de Toulouse Oncopole, Centre Hospitalier Universitaire de Toulouse, 31000 Toulouse, France.

Two recent phase 3 trials showed that outcomes for relapsed/refractory (R/R) -mutated acute myeloid leukemia (AML) patients may be improved by a single-agent tyrosine kinase inhibitor (TKI) (i.e., quizartinib or gilteritinib). In the current study, we retrospectively investigated the characteristics and real-world outcomes of R/R -internal tandem duplication (ITD) acute myeloid leukemia (AML) patients in the Toulouse-Bordeaux DATAML registry. In the study, we included 316 patients with -ITD AML that received intensive chemotherapy as a first-line treatment. The rate of complete remission (CR) or CR without hematological recovery (CRi) was 75.2%, and 160 patients were R/R after a first-line TKI-free treatment ( = 294). Within the subgroup of R/R patients that fulfilled the main criteria of the QUANTUM-R study, 48.9% received an intensive salvage regimen; none received hypomethylating agents or low-dose cytarabine. Among the R/R -ITD AML patients with CR1 durations < 6 months who received intensive TKI-free treatment, the rate of CR or CRi after salvage chemotherapy was 52.8%, and these results allowed a bridge to be transplanted in 39.6% of cases. Finally, in this QUANTUM-R standard arm-matched cohort, the median overall survival (OS) was 7.0 months and 1-, 3- and 5-year OS were 30.2%, 23.7% and 21.4%, respectively. To conclude, these real-world data show that the intensity of the second-line treatment likely affects response and transplantation rates. Furthermore, the results indicate that including patients with low-intensity regimens, such as low-dose cytarabine or hypomethylating agents, in the control arm of a phase 3 trial may be counterproductive and could compromise the results of the study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12082044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465142PMC
July 2020

Outcome of Relapsed or Refractory -Mutated Acute Myeloid Leukemia Before Second-Generation FLT3 Tyrosine Kinase Inhibitors: A Toulouse-Bordeaux DATAML Registry Study.

Cancers (Basel) 2020 Mar 25;12(4). Epub 2020 Mar 25.

CHU Bordeaux, Service d'Hématologie Clinique et de Thérapie Cellulaire, F-33000, Bordeaux, France.

A recent phase 3 trial showed that the outcome of patients with relapsed/refractory (R/R) -mutated acute myeloid leukemia (AML) improved with gilteritinib, a single-agent second-generation FLT3 tyrosine kinase inhibitor (TKI), compared with standard of care. In this trial, the response rate with standard therapy was particularly low. We retrospectively assessed the characteristics and outcome of patients with R/R -mutated AML included in the Toulouse-Bordeaux DATAML registry. Among 347 patients who received FLT3 TKI-free intensive chemotherapy as first-line treatment, 174 patients were refractory ( = 48, 27.6%) or relapsed ( = 126, 72.4%). Salvage treatments consisted of intensive chemotherapy ( = 99, 56.9%), azacitidine or low-dose cytarabine ( = 9, 5.1%), other low-intensity treatments ( = 17, 9.8%), immediate allogeneic stem cell transplantation ( = 4, 2.3%) or best supportive care only ( = 45, 25.9%). Among the 114 patients who previously received FLT3 TKI-free intensive chemotherapy as first-line treatment (refractory, = 32, 28.1%; relapsed, = 82, 71.9%), the rate of CR (complete remission) or CRi (complete remission with incomplete hematologic recovery) after high- or low-intensity salvage treatment was 50.0%, with a bridge to transplant in 34.2% ( = 39) of cases. The median overall survival (OS) was 8.2 months (interquartile range, 3.0-32); 1-, 3- and 5-year OS rates were 36.0% (95%CI: 27-45), 24.7% (95%CI: 1-33) and 19.7% (95%CI: 1-28), respectively. In this real-word study, although response rate appeared higher than the controlled arm of the ADMIRAL trial, the outcome of patients with R/R -mutated AML remains very poor with standard salvage therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12040773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226007PMC
March 2020

The Expression of Myeloproliferative Neoplasm-Associated Calreticulin Variants Depends on the Functionality of ER-Associated Degradation.

Cancers (Basel) 2019 Dec 2;11(12). Epub 2019 Dec 2.

CHRU Brest, Laboratoire d'Hématologie, 29200 Brest, France.

Background: Mutations in observed in myeloproliferative neoplasms (MPN) were recently shown to be pathogenic via their interaction with MPL and the subsequent activation of the Janus Kinase - Signal Transducer and Activator of Transcription (JAK-STAT) pathway. However, little is known on the impact of those variant CALR proteins on endoplasmic reticulum (ER) homeostasis.

Methods: The impact of the expression of Wild Type (WT) or mutant CALR on ER homeostasis was assessed by quantifying the expression level of Unfolded Protein Response (UPR) target genes, splicing of X-box Binding Protein 1 (XBP1), and the expression level of endogenous lectins. Pharmacological and molecular (siRNA) screens were used to identify mechanisms involved in CALR mutant proteins degradation. Coimmunoprecipitations were performed to define more precisely actors involved in CALR proteins disposal.

Results: We showed that the expression of CALR mutants alters neither ER homeostasis nor the sensitivity of hematopoietic cells towards ER stress-induced apoptosis. In contrast, the expression of CALR variants is generally low because of a combination of secretion and protein degradation mechanisms mostly mediated through the ER-Associated Degradation (ERAD)-proteasome pathway. Moreover, we identified a specific ERAD network involved in the degradation of CALR variants.

Conclusions: We propose that this ERAD network could be considered as a potential therapeutic target for selectively inhibiting CALR mutant-dependent proliferation associated with MPN, and therefore attenuate the associated pathogenic outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers11121921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966542PMC
December 2019

Chromosomal Abnormalities and Prognosis in -Mutated Acute Myeloid Leukemia: A Pooled Analysis of Individual Patient Data From Nine International Cohorts.

J Clin Oncol 2019 10 20;37(29):2632-2642. Epub 2019 Aug 20.

St Vincent's Hospital, Melbourne, Australia.

Purpose: Nucleophosmin 1 () mutations are associated with a favorable prognosis in acute myeloid leukemia (AML) when an internal tandem duplication (ITD) in the fms-related tyrosine kinase 3 gene () is absent (-ITD) or present with a low allelic ratio (-ITD). The 2017 European LeukemiaNet guidelines assume this is true regardless of accompanying cytogenetic abnormalities. We investigated the validity of this assumption.

Methods: We analyzed associations between karyotype and outcome in intensively treated patients with /-ITD AML who were prospectively enrolled in registry databases from nine international study groups or treatment centers.

Results: Among 2,426 patients with /-ITD AML, 2,000 (82.4%) had a normal and 426 (17.6%) had an abnormal karyotype, including 329 patients (13.6%) with intermediate and 83 patients (3.4%) with adverse-risk chromosomal abnormalities. In patients with /-ITD AML, adverse cytogenetics were associated with lower complete remission rates (87.7%, 86.0%, and 66.3% for normal, aberrant intermediate, and adverse karyotype, respectively; < .001), inferior 5-year overall (52.4%, 44.8%, 19.5%, respectively; < .001) and event-free survival (40.6%, 36.0%, 18.1%, respectively; < .001), and a higher 5-year cumulative incidence of relapse (43.6%, 44.2%, 51.9%, respectively; = .0012). These associations remained in multivariable mixed-effects regression analyses adjusted for known clinicopathologic risk factors ( < .001 for all end points). In patients with adverse-risk chromosomal aberrations, we found no significant influence of the mutational status on outcome.

Conclusion: Karyotype abnormalities are significantly associated with outcome in /-ITD AML. When adverse-risk cytogenetics are present, patients with share the same unfavorable prognosis as patients with wild type and should be classified and treated accordingly. Thus, cytogenetic risk predominates over molecular risk in /-ITD AML.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.19.00416DOI Listing
October 2019

Targeting Tyrosine Kinases in Acute Myeloid Leukemia: Why, Who and How?

Int J Mol Sci 2019 Jul 12;20(14). Epub 2019 Jul 12.

Institut National de la Santé et de la Recherche Médicale, U1035 Bordeaux, France.

Acute myeloid leukemia (AML) is a myeloid malignancy carrying a heterogeneous molecular panel of mutations participating in the blockade of differentiation and the increased proliferation of myeloid hematopoietic stem and progenitor cells. The historical "3 + 7" treatment (cytarabine and daunorubicin) is currently challenged by new therapeutic strategies, including drugs depending on the molecular landscape of AML. This panel of mutations makes it possible to combine some of these new treatments with conventional chemotherapy. For example, the FLT3 receptor is overexpressed or mutated in 80% or 30% of AML, respectively. Such anomalies have led to the development of targeted therapies using tyrosine kinase inhibitors (TKIs). In this review, we document the history of TKI targeting, FLT3 and several other tyrosine kinases involved in dysregulated signaling pathways.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms20143429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679203PMC
July 2019

Killer immunoglobulin-like receptor genotypes and chronic myeloid leukemia outcomes after imatinib cessation for treatment-free remission.

Cancer Med 2019 Sep 9;8(11):4976-4985. Epub 2019 Jul 9.

Institut National de la Santé et de la Recherche Médicale INSERM U1218, Bordeaux, France.

Background: Natural Killer (NK) cells are innate lymphoid cells that can be cytotoxic toward a large panel of solid tumors and hematological malignancies including chronic myeloid leukemia (CML). Such a cytotoxicity depends on various receptors. Killer immunoglobulin-like receptors (KIR) belong to these receptors and are involved in maturation process, then in the activation abilities of NK cells.

Methods: We investigated the prognostic impact of the KIR2DL5B genotype in 240 CML patients included in two clinical trials investigating tyrosine kinase inhibitors (TKI) discontinuation: STIM and STIM2.

Results: After adjustment for standard risk factors in CML, we found that the inhibitory receptor KIR2DL5B-positive genotype was independently related to a delayed second deep molecular remission (HR 0.54, 95% CI [0.32-0.91], P = 0.02) after TKI rechallenge but not to time to first deep molecular remission or treatment-free remission rates.

Conclusion: These results suggest that KIR2DL5B could carry a role in lymphocyte-mediated control of leukemic residual disease control in patient with CML relapse.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cam4.2371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718597PMC
September 2019

Hematopoietic niche drives FLT3-ITD acute myeloid leukemia resistance to quizartinib STAT5-and hypoxia-dependent upregulation of AXL.

Haematologica 2019 10 28;104(10):2017-2027. Epub 2019 Mar 28.

Université de Bordeaux, Institut National de la Santé et de la Recherche Médicale INSERM U1035, F-33000 Bordeaux

Internal tandem duplication in Fms-like tyrosine kinase 3 (FLT3-ITD) is the most frequent mutation observed in acute myeloid leukemia (AML) and correlates with poor prognosis. FLT3 tyrosine kinase inhibitors are promising for targeted therapy. Here, we investigated mechanisms dampening the response to the FLT3 inhibitor quizartinib, which is specific to the hematopoietic niche. Using AML primary samples and cell lines, we demonstrate that convergent signals from the hematopoietic microenvironment drive FLT3-ITD cell resistance to quizartinib through the expression and activation of the tyrosine kinase receptor AXL. Indeed, cytokines sustained phosphorylation of the transcription factor STAT5 in quizartinib-treated cells, which enhanced AXL expression by direct binding of a conserved motif in its genomic sequence. Likewise, hypoxia, another well-known hematopoietic niche hallmark, also enhanced AXL expression. Finally, in a xenograft mouse model, inhibition of AXL significantly increased the response of FLT3-ITD cells to quizartinib exclusively within a bone marrow environment. These data highlight a new bypass mechanism specific to the hematopoietic niche that hampers the response to quizartinib through combined upregulation of AXL activity. Targeting this signaling offers the prospect of a new therapy to eradicate resistant FLT3-ITD leukemic cells hidden within their specific microenvironment, thereby preventing relapses from FLT3-ITD clones.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2018.205385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886433PMC
October 2019

MiR-10a and HOXB4 are overexpressed in atypical myeloproliferative neoplasms.

BMC Cancer 2018 Nov 12;18(1):1098. Epub 2018 Nov 12.

INSERM U1035, Université de Bordeaux, Bordeaux, France.

Background: Atypical Myeloproliferative Neoplasms (aMPN) share characteristics of MPN and Myelodysplastic Syndromes. Although abnormalities in cytokine signaling are common in MPN, the pathophysiology of atypical MPN still remains elusive. Since deregulation of microRNAs is involved in the biology of various cancers, we studied the miRNome of aMPN patients.

Methods: MiRNome and mutations in epigenetic regulator genes ASXL1, TET2, DNMT3A, EZH2 and IDH1/2 were explored in aMPN patients. Epigenetic regulation of miR-10a and HOXB4 expression was investigated by treating hematopoietic cell lines with 5-aza-2'deoxycytidine, valproic acid and retinoic acid. Functional effects of miR-10a overexpression on cell proliferation, differentiation and self-renewal were studied by transducing CD34 cells with lentiviral vectors encoding the pri-miR-10a precursor.

Results: MiR-10a was identified as the most significantly up-regulated microRNA in aMPN. MiR-10a expression correlated with that of HOXB4, sitting in the same genomic locus. The transcription of these two genes was increased by DNA demethylation and histone acetylation, both necessary for optimal expression induction by retinoic acid. Moreover, miR-10a and HOXB4 overexpression seemed associated with DNMT3A mutation in hematological malignancies. However, overexpression of miR-10a had no effect on proliferation, differentiation or self-renewal of normal hematopoietic progenitors.

Conclusions: MiR-10a and HOXB4 are overexpressed in aMPN. This overexpression seems to be the result of abnormalities in epigenetic regulation mechanisms. Our data suggest that miR-10a could represent a simple marker of transcription at this genomic locus including HOXB4, widely recognized as involved in stem cell expansion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-018-4993-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233495PMC
November 2018

Author Correction: Natural killer cells and other innate lymphoid cells in cancer.

Nat Rev Immunol 2018 Nov;18(11):726

Innate Pharma Research Labs, Innate Pharma, Marseille, France.

In Box 1 in the originally published version of this article, three key references referring to mouse and human killer inhibitory receptors were mistakenly deleted during revision of the article. These references have now been added to the corrected version of the article.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41577-018-0077-4DOI Listing
November 2018

Improved Survival by Adding Lomustine to Conventional Chemotherapy for Elderly Patients With AML Without Unfavorable Cytogenetics: Results of the LAM-SA 2007 FILO Trial.

J Clin Oncol 2018 Nov 27;36(32):3203-3210. Epub 2018 Sep 27.

Arnaud Pigneux and Pierre-Yves Dumas, Bordeaux University Hospital, Bordeaux University, INSERM 1035; Louis-Rachid Salmi, Ariane Mineur, and Julien Asselineau, Bordeaux University Hospital, Bordeaux; Marie C. Béné, and Jacques Delaunay, Nantes University Hospital, Nantes; Caroline Bonmati, Nancy University Hospital, Nancy; Romain Guièze, Clermont-Ferrand University Hospital, Clermont Ferrand; Isabelle Luquet, Eric Delabesse, and Christian Récher, Toulouse University Hospital, Toulouse; Pascale Cornillet-Lefebvre, Reims University Hospital, Reims; Jean-Christophe Ianotto, Brest University Hospital, Brest; Mario Ojeda-Uribe, Mulhouse Regional Hospital, Mulhouse; Mathilde Hunault and Norbert Ifrah, Angers University Hospital and INSERM U 892/CNRS 6299, Angers; Anne Banos, Cote Basque General Hospital, Bayonne; Luc Matthieu Fornecker, Strasbourg University Hospital, Strasbourg; Marc Bernard, Rennes University Hospital, Rennes; Eric Jourdan, Nîmes University Hospital, Nîmes; Norbert Vey, Institut Paoli Calmettes, Marseilles; Hacene Zerazhi, Avignon General Hospital, Avignon; Yosr Hishri, Montpellier University Hospital, Montpellier; Roselyne Delepine, Tours University Hospital, Tours; and Jean-Yves Cahn, Grenoble University Hospital, Grenoble, France.

Purpose: Acute myeloid leukemia (AML) in elderly patients has a poor prognosis. In an attempt to improve outcome for these patients, the prospective open-label phase III LAM-SA 2007 (Adding Lomustine to Chemotherapy in Older Patients With Acute Myelogenous Leukemia (AML), and Allogeneic Transplantation for Patients From 60 to 65 Years Old) trial randomly assigned patients to a standard induction regimen with lomustine added or to a consolidation regimen with cytarabine and idarubicin.

Patients And Methods: Adults age 60 years or older with previously untreated AML who were fit to receive intensive chemotherapy and who were without unfavorable cytogenetics received standard chemotherapy with lomustine (idarubicin, cytarabine, and lomustine [ICL]) or without (idarubicin and cytarabine [IC]). The primary objective of the study was overall survival (OS); secondary objectives were response rate, cumulative incidence of relapse (CIR), event-free survival (EFS), and safety.

Results: From February 2008 to December 2011, 459 patients were enrolled. Comparing patients in the IC and ICL arms, complete response or complete response with incomplete recovery was achieved in 74.9% versus 84.7% ( = .01). The proportional hazards assumption was rejected for OS ( = .02), which led us to consider two separate time intervals: during and after induction. There was no significant difference between the two arms during induction, although induction deaths were 3.7% versus 7.7%, respectively ( = .11). However, significantly better results were observed after induction with an improved 2-year OS of 56% in the ICL arm versus 48% in the IC arm ( = .02). At 2 years, EFS was improved at 41% in the ICL arm versus 26% in the IC arm ( = .01). The CIR at 2 years was 41.2% in the ICL arm versus 60.9% in the IC arm ( = .003). Grade 3 and 4 toxicities, mostly hematologic, were significantly higher in the ICL arm ( = .04), and fewer patients required a second treatment after ICL.

Conclusion: Adding lomustine to standard chemotherapy significantly improved the outcome of elderly patients with AML.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.2018.78.7366DOI Listing
November 2018

Natural killer cells and other innate lymphoid cells in cancer.

Nat Rev Immunol 2018 11;18(11):671-688

Innate Pharma Research Labs, Innate Pharma, Marseille, France.

Immuno-oncology is an emerging field that has revolutionized cancer treatment. Most immunomodulatory strategies focus on enhancing T cell responses, but there has been a recent surge of interest in harnessing the relatively underexplored natural killer (NK) cell compartment for therapeutic interventions. NK cells show cytotoxic activity against diverse tumour cell types, and some of the clinical approaches originally developed to increase T cell cytotoxicity may also activate NK cells. Moreover, increasing numbers of studies have identified novel methods for increasing NK cell antitumour immunity and expanding NK cell populations ex vivo, thereby paving the way for a new generation of anticancer immunotherapies. The role of other innate lymphoid cells (group 1 innate lymphoid cell (ILC1), ILC2 and ILC3 subsets) in tumours is also being actively explored. This Review provides an overview of the field and summarizes current immunotherapeutic approaches for solid tumours and haematological malignancies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41577-018-0061-zDOI Listing
November 2018

Breakthrough invasive aspergillosis and diagnostic accuracy of serum galactomannan enzyme immune assay during acute myeloid leukemia induction chemotherapy with posaconazole prophylaxis.

Oncotarget 2018 Jun 1;9(42):26724-26736. Epub 2018 Jun 1.

Department of Hematology and Cell Therapy, University Hospital, F-33000 Bordeaux, France.

Posaconazole prophylaxis has demonstrated efficacy in the prevention of invasive aspergillosis during prolonged neutropenia following acute myeloid leukemia induction chemotherapy. Antifungal treatment decreases serum galactomannan enzyme immunoassay diagnostic accuracy that could delay the diagnosis and treatment. We retrospectively studied patients with acute myeloid leukemia who underwent intensive chemotherapy and antifungal prophylaxis by posaconazole oral suspension. Clinical, radiological, microbiological features and treatment response of patients with invasive aspergillosis that occurred despite posaconazole prophylaxis were analyzed. Diagnostic accuracy of serum galactomannan assay according to posaconazole plasma concentrations has been performed. A total of 288 patients with acute myeloid leukemia, treated by induction chemotherapy, who received posaconazole prophylaxis for more than five days were included in the present study. The incidence of invasive aspergillosis was 8% with 12 (4.2%), 8 (2.8%) and 3 (1%), possible, probable and proven invasive aspergillosis, respectively. Posaconazole plasma concentration was available for 258 patients. Median duration of posaconazole treatment was 17 days, and median posaconazole plasma concentration was 0.5 mg/L. None of patients with invasive aspergillosis and posaconazole concentration ≥ 0.5 mg/L had a serum galactomannan positive test. Sensitivity of serum galactomannan assay to detect probable and proven invasive aspergillosis was 81.8%. Decreasing the cut-off value for serum galactomannan optical density index from 0.5 to 0.3 increased sensitivity to 90.9%. In a homogenous cohort of acute myeloid leukemia patients during induction chemotherapy, increasing the posaconazole concentration decreases the sensitivity of serum galactomannan assay.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.25477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003556PMC
June 2018

Optimizing the pretransplant regimen for autologous stem cell transplantation in acute myelogenous leukemia: Better outcomes with busulfan and melphalan compared with busulfan and cyclophosphamide in high risk patients autografted in first complete remission: A study from the acute leukemia working party of the EBMT.

Am J Hematol 2018 07 28;93(7):859-866. Epub 2018 Apr 28.

Chaim Sheba Medical Center, EBMT ALWP Chair, Hematology and Bone Marrow Transplantation, Tel Hashomer, Israel.

Autologous stem cell transplantation remains a clinical option to consolidate some adult patients with acute myelogenous leukemia (AML) in first complete remission (CR1). In a small cohort of patients, we have previously shown better outcomes following Busulfan and Melphalan (BUMEL) over Busulfan and Cyclophosphamide (BUCY). To identify the subpopulations that might get the highest benefit with BUMEL, we designed a larger study. All adult patients with primary AML and available cytogenetics, autografted from January 2000 to December 2016 in CR1, were included: 1137 patients received BUCY and 512 BUMEL. All factors differing in distribution between the 2 conditioning groups were introduced in multivariate analyzes. In a primary analysis, we found an interaction between conditioning and the poor risk group defined as poor cytogenetics and/or presence of the FLT3-ITD mutation. During analysis of the poor risk group, 176 patients received BUCY and 62 BUMEL. BUMEL was associated with a lower RI at 5 years (53% versus 69%, HR: 0.52, P = .002), a better Leukaemia-free survival (LFS) (42% versus 25%, HR: 0.54, P = .002) and a better OS (54% versus 36%, HR: 0.61, P = .02). During analysis of the non poor risk group, 961 patients received BUCY and 450 BUMEL. At 5 years, the RI was 50% and 47%, the LFS 45% and 48% and the OS 56% and 60% respectively, with no significant difference. We conclude that BUMEL is the preferable conditioning regimen for the poor risk leukemic patients, while in AML patients without poor risk cytogenetics or FLT3 both conditioning regimens are valid.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajh.25105DOI Listing
July 2018

Chronic myeloid leukemia progenitor cells require autophagy when leaving hypoxia-induced quiescence.

Oncotarget 2017 Nov 30;8(57):96984-96992. Epub 2017 Jun 30.

Cellules Souches Hématopoïétiques Normales et Leucémiques, INSERM U1035 BMGIC, Université de Bordeaux, 33076 Bordeaux Cedex, France.

Albeit tyrosine kinase inhibitors anti-Abl used in Chronic Myeloid Leukemia (CML) block the deregulated activity of the Bcr-Abl tyrosine kinase and induce remission in 90% of patients, they do not eradicate immature hematopoietic compartments of leukemic stem cells. To elucidate if autophagy is important for stem cell survival and/or proliferation, we used culture in low oxygen concentration (0.1% O for 7 days) followed back by non-restricted O supply (normoxic culture) to mimic stem cell proliferation and commitment. Knockdown of expression, a key player in autophagy, in K562 cell line inhibited autophagy compared to control cells. Upon 7 days at 0.1% O both K562 and K562 shATG7 cells stopped to proliferate and a similar amount of viable cells remained. Back to non-restricted O supply K562 cells proliferate whereas K562 shATG7 cells exhibited strong apoptosis. Using immunomagnetic sorted normal and CML CD34 cells, we inhibited the autophagic process by lentiviral infection expressing shATG7 or using a Vps34 inhibitor. Both, normal and CML CD34 cells either competent or deficient for autophagy stopped to proliferate in hypoxia. Surprisingly, while normal CD34 cells proliferate back to non restricted O supply, the CML CD34 cells deficient for autophagy failed to proliferate. All together, these results suggest that autophagy is required for CML CD34 commitment while it is dispensable for normal CD34 cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.18904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5722539PMC
November 2017

Azacitidine or intensive chemotherapy for older patients with secondary or therapy-related acute myeloid leukemia.

Oncotarget 2017 Oct 7;8(45):79126-79136. Epub 2017 Mar 7.

Service d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France.

The treatment of older patients with acute myeloid leukemia that is secondary to previous myelodysplastic syndrome, myeloproliferative neoplasm, or prior cytotoxic exposure remains unsatisfactory. We compared 92 and 107 patients treated, respectively, with intensive chemotherapy or azacitidine within two centres. Diagnoses were 37.5% post-myelodysplastic syndrome, 17.4% post-myeloproliferative neoplasia, and 45.1% therapy-related acute myeloid leukemia. Patients treated by chemotherapy had less adverse cytogenetics, higher white blood-cell counts, and were younger: the latter two being independent factors entered into the multivariate analyses. Median overall-survival times with chemotherapy and azacitidine were 9.6 (IQR: 3.6-22.8) and 10.8 months (IQR: 4.8-26.4), respectively ( = 0.899). Adjusted time-dependent analyses showed that, before 1.6 years post-treatment, there were no differences in survival times between chemotherapy and azacitidine treatments whereas, after this time-point, patients that received chemotherapy had a lower risk of death compared to those that received azacitidine (adjusted HR 0.61, 95%CI: 0.38-0.99 at 1.6 years). There were no interactions between treatment arms and secondary acute myeloid leukemia subtypes in all multivariate analyses, indicating that the treatments had similar effects in all three subtypes. Although a comparison between chemotherapy and azacitidine remains challenging, azacitidine represents a valuable alternative to chemotherapy in older patients that have secondary acute myeloid leukemia because it provides similar midterm outcomes with less toxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.15988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5668025PMC
October 2017

Autologous stem cell transplantation for adult acute myelocytic leukemia in first remission-Better outcomes after busulfan and melphalan compared with busulfan and cyclophosphamide: A retrospective study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT).

Cancer 2017 03 1;123(5):824-831. Epub 2016 Dec 1.

EBMT Office, INSERM Unit 938, St. Antoine Public Assistance Hospital, Pierre and Marie Curie University, Paris, France.

Background: Autologous stem cell transplantation (ASCT) for adult acute myelogenous leukemia (AML) is a valid therapeutic option for patients with good-risk and intermediate-risk disease. The authors used the registry of the European Society for Blood and Marrow Transplantation to compare combined busulfan and melphalan (BUMEL) with combined busulfan and cyclophosphamide (BUCY) before transplantation.

Methods: From 2005 to 2013, 853 patients with available cytogenetics underwent ASCT in first remission, including 257 after receiving BUMEL and 596 after receiving BUCY. The proportion of patients with good-risk AML was lower in those who received BUMEL (14% vs 20%; P = .02). More patients who received BUMEL underwent autograft in molecular remission (89% vs 78%; P = .02). Three years after transplantation, the relapse incidence (RI) was 48.7%, the leukemia-free survival (LFS) rate was 47.7%, the overall survival (OS) rate was 66.2%, and the nonrelapse mortality (NRM) rate was 3.6%.

Results: Patients who underwent an autograft after receiving BUMEL fared better than those who underwent an autograft after receiving BUCY with a lower RI (39.5% vs 52.2%; hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.49-0.87; P = .003) a better LFS (55.4% vs 44.6%; HR, 0.69; 95% CI, 0.53-0.89; P = .005), and a better OS (73.8% vs 63%; HR, 0.62; 95% CI, 0.47-0.82; P = .0007). There was no difference in the NRM rate (BUMEL vs BUCY, 4.5% vs 3.2%, respectively). Among 74 patients in the BUMEL group and 187 in the BUCY group who underwent autograft in molecular remission, the RI was 30% versus 51%, respectively (univariate analysis; P = .01), and the LFS rate was 66% versus 47%, respectively (univariate analysis; P = .03).

Conclusions: In patients with AML in first complete remission who undergo ASCT, the BUMEL combination is a better preparative regimen. Cancer 2017;123:824-31. © 2016 American Cancer Society.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.30400DOI Listing
March 2017

BCR-ABL-positive acute myeloid leukemia: About one case treated with ponatinib.

Ann Hematol 2017 Feb 20;96(2):335-336. Epub 2016 Oct 20.

CHU de Bordeaux, Hematology Department, Pessac, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00277-016-2855-zDOI Listing
February 2017

Impact of eculizumab treatment on paroxysmal nocturnal hemoglobinuria: a treatment versus no-treatment study.

Am J Hematol 2016 Jun;91(4):366-70

Hematology-Transplantation Department, AP-HP, Saint-Louis Hospital, Paris, France.

Intravascular hemolysis in Paroxysmal nocturnal hemoglobinuria (PNH) can effectively be controlled with eculizumab, a humanized monoclonal antibody that binds complement protein C5. We report here a retrospective comparison study between 123 patients treated with eculizumab in the recent period (>2005) and 191 historical controls (from the French registry). Overall survival (OS) at 6 years was 92% (95%CI, 87 to 98) in the eculizumab cohort versus 80% (95%CI 70 to 91) in historical controls diagnosed after 1985 (HR 0.38 [0.15 to 0.94], P = 0.037). There were significantly fewer thrombotic events (TEs) in the group of patients treated with eculizumab (4% [1-10]) as compared to the historical cohort (27% [20-34]). However, we found that TEs may still occur after the initiation of eculizumab treatment and that previous TEs still have a negative impact on survival. Evolutions to myelodysplastic syndrome or acute leukemia were similar in both cohorts. There was less evolution to aplastic anemia in the treatment group. In multivariate analysis, absence of a previous TE and treatment with eculizumab were associated with a better OS. Treatment with eculizumab improves overall survival in classic PNH patients without increasing the risk of clonal evolution.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajh.24278DOI Listing
June 2016

CBL controls a tyrosine kinase network involving AXL, SYK and LYN in nilotinib-resistant chronic myeloid leukaemia.

J Pathol 2015 Sep 4;237(1):14-24. Epub 2015 Jun 4.

Hématopoïèse Leucémique et Cibles Thérapeutiques, INSERM U1035, Université de Bordeaux, France.

A tyrosine kinase network composed of the TAM receptor AXL and the cytoplasmic kinases LYN and SYK is involved in nilotinib-resistance of chronic myeloid leukaemia (CML) cells. Here, we show that the E3-ubiquitin ligase CBL down-regulation occurring during prolonged drug treatment plays a critical role in this process. Depletion of CBL in K562 cells increases AXL and LYN protein levels, promoting cell resistance to nilotinib. Conversely, forced expression of CBL in nilotinib-resistant K562 cells (K562-rn) dramatically reduces AXL and LYN expression and resensitizes K562-rn cells to nilotinib. A similar mechanism was found to operate in primary CML CD34(+) cells. Mechanistically, the E3-ligase CBL counteracts AXL/SYK signalling, promoting LYN transcription by controlling AXL protein stability. Surprisingly, the role of AXL in resistance was independent of its ligand GAS6 binding and its TK activity, in accordance with a scaffold activity for this receptor being involved in this cellular process. Collectively, our results demonstrate a pivotal role for CBL in the control of a tyrosine kinase network mediating resistance to nilotinib treatment in CML cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/path.4561DOI Listing
September 2015