Publications by authors named "Sarah Bertoli"

45 Publications

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

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

Life-threatening complications after high-dose methotrexate and the benefits of glucarpidase as salvage therapy: a cohort study of 468 patients.

Leuk Lymphoma 2020 Nov 12:1-8. Epub 2020 Nov 12.

Département de Néphrologie et Transplantation d'organes - Unité de Réanimation, Centre Hospitalier Universitaire de Toulouse, French Intensive Care Renal Network, Toulouse, France.

The aims of this study were to characterize the incidence and outcomes of severe toxicities following the administration of high-dose methotrexate (HD-MTX; ≥1 g/m). Among the 468 patients included in the study, 69 (14.9%) developed at least one episode of acute kidney injury (AKI; 138/1264 HD-MTX administrations), including 34 (7.2%) who developed KDIGO stage 2-3 AKI. The three baseline factors independently associated with the risk of developing AKI were age, body mass index and a diagnosis of acute lymphoblastic leukemia. Higher plasma MTX concentration was associated with AKI and extra-renal toxicities. Notwithstanding potentially confounding factors, most patients with AKI who received glucarpidase ( = 41) developed extra-renal toxicity (leading to the death of two patients) despite early administration. Thus, severe toxicity and death can occur whether or not glucarpidase is administered, which confirms the need for further interventional studies to provide greater precision on its role in the management of HD-MTX toxicity.
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http://dx.doi.org/10.1080/10428194.2020.1846733DOI Listing
November 2020

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

PLoS One 2020 1;15(10):e0238795. Epub 2020 Oct 1.

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

Hypomethylating agents are a classical frontline low-intensity therapy for older patients with acute myeloid leukemia. Recently, TP53 gene mutations have been described as a potential predictive biomarker of better outcome in patients treated with a ten-day decitabine regimen., However, functional characteristics of TP53 mutant are heterogeneous, as reflected in multiple functional TP53 classifications and their impact in patients treated with azacitidine is less clear. We analyzed the therapeutic course and outcome of 279 patients treated with azacitidine between 2007 and 2016, prospectively enrolled in our regional healthcare network. By screening 224 of them, we detected TP53 mutations in 55 patients (24.6%), including 53 patients (96.4%) harboring high-risk cytogenetics. The identification of any TP53 mutation was associated with worse overall survival but not with response to azacitidine in the whole cohort and in the subgroup of patients with adverse karyotype. Stratification of patients according to three recent validated functional classifications did not allow the identification of TP53 mutated patients who could benefit from azacitidine. Systematic TP53 mutant classification will deserve further exploration in the setting of patients treated with conventional therapy and in the emerging field of therapies targeting TP53 pathway.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238795PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529302PMC
November 2020

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

Leukemia 2020 Sep 18. Epub 2020 Sep 18.

Hematology Biology, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopôle, Université Toulouse III Paul Sabatier, Toulouse, 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.
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http://dx.doi.org/10.1038/s41375-020-01031-1DOI Listing
September 2020

Autophagy regulates fatty acid availability for oxidative phosphorylation through mitochondria-endoplasmic reticulum contact sites.

Nat Commun 2020 08 13;11(1):4056. Epub 2020 Aug 13.

Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse, Toulouse, France.

Autophagy has been associated with oncogenesis with one of its emerging key functions being its contribution to the metabolism of tumors. Therefore, deciphering the mechanisms of how autophagy supports tumor cell metabolism is essential. Here, we demonstrate that the inhibition of autophagy induces an accumulation of lipid droplets (LD) due to a decrease in fatty acid β-oxidation, that leads to a reduction of oxidative phosphorylation (OxPHOS) in acute myeloid leukemia (AML), but not in normal cells. Thus, the autophagic process participates in lipid catabolism that supports OxPHOS in AML cells. Interestingly, the inhibition of OxPHOS leads to LD accumulation with the concomitant inhibition of autophagy. Mechanistically, we show that the disruption of mitochondria-endoplasmic reticulum (ER) contact sites (MERCs) phenocopies OxPHOS inhibition. Altogether, our data establish that mitochondria, through the regulation of MERCs, controls autophagy that, in turn finely tunes lipid degradation to fuel OxPHOS supporting proliferation and growth in leukemia.
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http://dx.doi.org/10.1038/s41467-020-17882-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426880PMC
August 2020

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

Dactinomycin in acute myeloid leukemia with NPM1 mutations.

Eur J Haematol 2020 Sep 25;105(3):302-307. Epub 2020 May 25.

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

Objectives: Complete responses have been observed in NPM1-mutated AML patients with dactinomycin, a nucleolar stress-inducing drug. Here, we report a single-center experience of compassionate use of dactinomycin in untreated or relapsed/ refractory NPM1-mutated AML.

Methods: From September 2015 to February 2019, 26 adult patients with NPM1-mutated AML received dactinomycin in different situations: front-line treatment in 4 unfit patients (16%); morphologic (n = 16, 62%), molecular relapses (n = 4, 16%), refractory disease (n = 1, 13%), or postremission therapy in second complete response (n = 1, 13%).

Results: Median age was 62.5 years. Median number of dactinomycin cycle was 1 (1-8), and 7 patients (27%) received more than 3 cycles. Three out of 17 patients (18%) in morphologic relapse or refractory to chemotherapy achieved complete remission after the first cycle of dactinomycin. None of the 4 patients unfit for intensive chemotherapy responded to dactinomycin as front-line therapy. Grade 3-4 adverse events were thrombocytopenia (n = 11, 42%), neutropenia (n = 11, 42%), GI toxicity (n = 6, 23%), mucositis (n = 5, 19%), lung infection (n = 5, 19%), and skin rash (n = 2, 7.6%).

Conclusions: Dactinomycin is an inexpensive and easily available drug that may induce significant responses in few AML patients with NPM1 mutations with an acceptable safety profile.
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http://dx.doi.org/10.1111/ejh.13438DOI Listing
September 2020

Inhibition of ubiquitin-specific protease 7 sensitizes acute myeloid leukemia to chemotherapy.

Leukemia 2021 02 23;35(2):417-432. Epub 2020 May 23.

Cancer Research Center of Toulouse, INSERM U1037, CNRS ERL 5294, Université de Toulouse, Toulouse, France.

Resistance of acute myeloid leukemia (AML) to therapeutic agents is frequent. Consequently, the mechanisms leading to this resistance must be understood and addressed. In this paper, we demonstrate that inhibition of deubiquitinylase USP7 significantly reduces cell proliferation in vitro and in vivo, blocks DNA replication progression and increases cell death in AML. Transcriptomic dataset analyses reveal that a USP7 gene signature is highly enriched in cells from AML patients at relapse, as well as in residual blasts from patient-derived xenograft (PDX) models treated with clinically relevant doses of cytarabine, which indicates a relationship between USP7 expression and resistance to therapy. Accordingly, single-cell analysis of AML patient samples at relapse versus at diagnosis showed that a gene signature of the pre-existing subpopulation responsible for relapse is enriched in transcriptomes of patients with a high USP7 level. Furthermore, we found that USP7 interacts and modulates CHK1 protein levels and functions in AML. Finally, we demonstrated that USP7 inhibition acts in synergy with cytarabine to kill AML cell lines and primary cells of patients with high USP7 levels. Altogether, these data demonstrate that USP7 is both a marker of resistance to chemotherapy and a potential therapeutic target in overcoming resistance to treatment.
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http://dx.doi.org/10.1038/s41375-020-0878-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245510PMC
February 2021

CD34CD38CD123 Leukemic Stem Cell Frequency Predicts Outcome in Older Acute Myeloid Leukemia Patients Treated by Intensive Chemotherapy but Not Hypomethylating Agents.

Cancers (Basel) 2020 May 6;12(5). Epub 2020 May 6.

Université Toulouse III Paul Sabatier, 31330 Toulouse, France.

The prognostic impact of immunophenotypic CD34CD38CD123 leukemic stem cell (iLSC) frequency at diagnosis has been demonstrated in younger patients treated by intensive chemotherapy, however, this is less clear in older patients. Furthermore, the impact of iLSC in patients treated by hypomethylating agents is unknown. In this single-center study, we prospectively assessed the CD34CD38CD123 iLSC frequency at diagnosis in acute myeloid leukemia (AML) patients aged 60 years or older. In a cohort of 444 patients, the median percentage of iLSC at diagnosis was 4.3%. Significant differences were found between treatment groups with a lower median in the intensive chemotherapy group (0.6%) compared to hypomethylating agents (8.0%) or supportive care (11.1%) ( <0.0001). In the intensive chemotherapy group, the median overall survival was 34.5 months in patients with iLSC ≤0.10% and 14.6 months in patients with >0.10% ( = 0.031). In the multivariate analyses of this group, iLSC frequency was significantly and independently associated with the incidence of relapse, event-free, relapse-free, and overall survival. However, iLSC frequency had no prognostic impact on patients treated by hypomethylating agents. Thus, the iLSC frequency at diagnosis is an independent prognostic factor in older acute myeloid patients treated by intensive chemotherapy but not hypomethylating agents.
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http://dx.doi.org/10.3390/cancers12051174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281486PMC
May 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.
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http://dx.doi.org/10.3390/cancers12040773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226007PMC
March 2020

Large granular lymphocytosis during quizartinib therapy.

Br J Haematol 2020 04 12;189(1). Epub 2020 Mar 12.

Université Toulouse III Paul Sabatier, Toulouse, France.

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http://dx.doi.org/10.1111/bjh.16373DOI Listing
April 2020

STAT5-dependent regulation of CDC25A by miR-16 controls proliferation and differentiation in FLT3-ITD acute myeloid leukemia.

Sci Rep 2020 02 5;10(1):1906. Epub 2020 Feb 5.

Cancer Research Center of Toulouse (CRCT), INSERM U1037, CNRS ERL5294, University of Toulouse, Toulouse, France.

We recently identified the CDC25A phosphatase as a key actor in proliferation and differentiation in acute myeloid leukemia expressing the FLT3-ITD mutation. In this paper we demonstrate that CDC25A level is controlled by a complex STAT5/miR-16 transcription and translation pathway working downstream of this receptor. First, we established by CHIP analysis that STAT5 is directly involved in FLT3-ITD-dependent CDC25A gene transcription. In addition, we determined that miR-16 expression is repressed by FLT3-ITD activity, and that STAT5 participates in this repression. In accordance with these results, miR-16 expression was significantly reduced in a panel of AML primary samples carrying the FLT3-ITD mutation when compared with FLT3wt cells. The expression of a miR-16 mimic reduced CDC25A protein and mRNA levels, and RNA interference-mediated down modulation of miR-16 restored CDC25A expression in response to FLT3-ITD inhibition. Finally, decreasing miR-16 expression partially restored the proliferation of cells treated with the FLT3 inhibitor AC220, while the expression of miR-16 mimic stopped this proliferation and induced monocytic differentiation of AML cells. In summary, we identified a FLT3-ITD/STAT5/miR-16/CDC25A axis essential for AML cell proliferation and differentiation.
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http://dx.doi.org/10.1038/s41598-020-58651-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002454PMC
February 2020

More than ten percent of relapses occur after five years in AML patients with mutation.

Leuk Lymphoma 2020 05 5;61(5):1226-1229. Epub 2020 Feb 5.

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

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http://dx.doi.org/10.1080/10428194.2019.1706733DOI Listing
May 2020

Are social inequalities in acute myeloid leukemia survival explained by differences in treatment utilization? Results from a French longitudinal observational study among older patients.

BMC Cancer 2019 Sep 5;19(1):883. Epub 2019 Sep 5.

LEASP, UMR 1027, Equipe labellisée Ligue Nationale Contre le Cancer, Faculté de médecine de Purpan, Inserm-Université Toulouse III Paul Sabatier, 37 allées Jules Guesde, 31000, Toulouse, France.

Background: Evidences support social inequalities in cancer survival. Studies on hematological malignancies, and more specifically Acute Myeloid Leukemia (AML), are sparser. Our study assessed: 1/ the influence of patients' socioeconomic position on survival, 2/ the role of treatment in this relationship, and 3/ the influence of patients' socioeconomic position on treatment utilization.

Methods: This prospective multicenter study includes all patients aged 60 and older, newly diagnosed with AML, excluding promyelocytic subtypes, between 1st January 2009 to 31st December 2014 in the South-West of France. Data came from medical files. Patients' socioeconomic position was measured by an ecological deprivation index, the European Deprivation Index. We studied first, patients' socioeconomic position influence on overall survival (n = 592), second, on the use of intensive chemotherapy (n = 592), and third, on the use of low intensive treatment versus best supportive care among patients judged unfit for intensive chemotherapy (n = 405).

Results: We found an influence of patients' socioeconomic position on survival (highest versus lowest position HR: 1.39 [1.05;1.87] that was downsized to become no more significant after adjustment for AML ontogeny (HR: 1.31[0.97;1.76] and cytogenetic prognosis HR: 1.30[0.97;1.75]). The treatment was strongly associated with survival. A lower proportion of intensive chemotherapy was observed among patients with lowest socioeconomic position (OR: 0.41[0.19;0.90]) which did not persist after adjustment for AML ontogeny (OR: 0.59[0.25;1.40]). No such influence of patients' socioeconomic position was found on the treatment allocation among patients judged unfit for intensive chemotherapy.

Conclusions: Finally, these results suggest an indirect influence of patients' socioeconomic position on survival through AML initial presentation.
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http://dx.doi.org/10.1186/s12885-019-6093-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6729078PMC
September 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.

University Hospital Münster, Münster, Germany.

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

Outcome of patients aged 60-75 years with newly diagnosed secondary acute myeloid leukemia: A single-institution experience.

Cancer Med 2019 07 7;8(8):3846-3854. Epub 2019 Jun 7.

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

A recent phase 3 trial showed that outcome of older patients with secondary acute myeloid leukemia (AML) may be improved by a liposomal encapsulation of cytarabine and daunorubicin (CPX-351). This phase 3 study represents a unique example of prospective data in this rare subgroup providing basis for comparison with real life data. Here, we retrospectively assessed characteristics and outcome of patients aged 60-75 years with secondary or therapy-related AML in real life. Out of 218 patients that fulfilled CPX-351 study criteria, 181 patients (83.0%) received antileukemic treatment either intensive chemotherapy (n = 121) or hypomethylating agents (HMA, n = 60). As compared with patients treated by chemotherapy, HMA-treated patients were older, had lower WBC, more often AML with antecedent myelodysplastic syndrome and adverse cytogenetic risk. In chemotherapy-treated patients, the complete response rate was 69%, median overall survival (OS) was 11 months whereas 3-year and 5-year OS was 21% and 17%, respectively. In HMA-treated patients, the complete response rate was 15%, median OS was 11 months whereas 3-year and 5-year OS was 15% and 2%, respectively. In conclusion, although outcome of older patients with high-risk AML is very poor, a significant proportion of patients treated by standard intensive chemotherapy but not HMA are long-term survivors.
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http://dx.doi.org/10.1002/cam4.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639188PMC
July 2019

Outcome of AML patients with IDH2 mutations in real world before the era of IDH2 inhibitors.

Leuk Res 2019 06 27;81:82-87. Epub 2019 Apr 27.

Université Toulouse III Paul Sabatier, Toulouse, France; Cancer Research Center of Toulouse, UMR1037-INSERM, ERL5294 CNRS, Toulouse, France; Service d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France. Electronic address:

Describing the prognosis of sub-groups of acute myeloid leukemia (AML) patients treated in real world with current therapies is becoming increasingly relevant to estimate the benefit that new targeted drugs will bring in the field. This is particularly the case when novel drugs are registered on the basis of non-randomized studies. IDH2 inhibitors have recently emerged as promising drugs in patients with IDH2 or IDH2 mutations. Enasidenib, a first-in-class IDH2 inhibitor, has been approved following promising results of a phase 1-2 clinical trial in relapsed or refractory AML patients with IDH2 mutations. In this study, we described the characteristics, treatments and outcome of 75 IDH2 mutated patients both at diagnosis and relapse or refractory disease. Among the 33 relapsed/refractory AML patients with either IDH2 or IDH2, 28 (84.8%) patients received salvage therapy and 14 achieved a complete response (50%). Median duration of response was 15.2 months. Median, 1-y, 3-y and 5-y OS were 15.1 months (IQR, 4.6-37.7), 53.1% (95% CI, 33.2-69.5), 29.2% (95% CI, 12.6-48.1) and 24.4% (95% CI, 9.3-43.1), respectively. In responding patients, median OS was 37.7 months and 1-y, 3-y and 5-y OS was 85.7%, 57.1% and 47.6%, respectively. In non-responding patients, median OS was 5.0 months (IQR, 4.5-8.6) and 1-y and 3-y OS was 17.9% and 0%, respectively. Thus, a substantial number of R/R AML patients with IDH2 mutations can be salvaged by current treatments and benefit from prolonged survival. It is expected that novel targeted agents such as enasidenib will further improve efficacy and safety in the next future.
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http://dx.doi.org/10.1016/j.leukres.2019.04.010DOI Listing
June 2019

Hydroxyurea prior to intensive chemotherapy in AML with moderate leukocytosis.

Leuk Res 2018 12 31;75:7-10. Epub 2018 Oct 31.

Service d'Hématologie, CHU de Toulouse, Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France; Université Toulouse III Paul Sabatier, Toulouse, France; Cancer Research Center of Toulouse, UMR1037-INSERM, ERL5294 CNRS, Toulouse, France.

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http://dx.doi.org/10.1016/j.leukres.2018.10.015DOI Listing
December 2018

Ferritin heavy/light chain (FTH1/FTL) expression, serum ferritin levels, and their functional as well as prognostic roles in acute myeloid leukemia.

Eur J Haematol 2019 Feb 28;102(2):131-142. Epub 2018 Nov 28.

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

Objectives: We previously reported the prognostic value of serum ferritin in younger patients with intermediate-risk acute myeloid leukemia (AML). The aims of this study were to confirm this finding in a larger cohort regardless of age and prognostic subgroups, to explore the expression and functional role of ferritin in AML cells as well as the regulation of serum ferritin levels in AML patients.

Patients/materials/methods: Serum ferritin levels at diagnosis were collected in a cohort of 525 patients treated by intensive chemotherapy. In silico, in vitro, and in vivo analyses were conducted to assess the pattern of expression and functional role of FTH1 and FTL in AML.

Results: We confirmed the independent prognostic value of serum ferritin. In transcriptomic databases, FTH1 and FTL were overexpressed in AML and leukemic stem cells compared to normal hematopoietic stem cells. The gene signature designed from AML patients overexpressing FTH1 revealed a significant enrichment in genes of the immune and inflammatory response including Nf-KB pathway, oxidative stress, or iron pathways. This gene signature was enriched in cytarabine-resistant AML cells in a patient-derived xenograft model. FTH1 protein was also overexpressed in patient's samples and correlated with the in vitro cytotoxic activity of cytarabine. Lastly, we demonstrated that chemotherapy induced an inflammatory response including a significant increase in serum ferritin levels between day 1 and 8 of induction chemotherapy that was blocked by dexamethasone.

Conclusion: Ferritin is deregulated in most AML patients likely through inflammation, associated with chemoresistance, and could represent a new therapeutic target.
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http://dx.doi.org/10.1111/ejh.13183DOI Listing
February 2019

FLT3-TKD Mutations Associated With NPM1 Mutations Define a Favorable-risk Group in Patients With Acute Myeloid Leukemia.

Clin Lymphoma Myeloma Leuk 2018 12 13;18(12):e545-e550. Epub 2018 Jun 13.

Department of Hematology, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite, France; Faculté de Médecine Lyon-Sud Charles Mérieux, Université Claude Bernard Lyon I, Pierre Bénite, France; LBMC, ENS, CNRS UMR5239, Faculté de Médecine Lyon-Sud, Pierre Bénite, France. Electronic address:

Background: Outcome of patients with mutation of the FLT3 tyrosine kinase domain (FLT3-TKD) in acute myeloid leukemia (AML) remains controversial.

Patients And Methods: Herein, we present a retrospective study of 126 newly diagnosed patients with AML performed in 2 French centers.

Results: FLT3-TKD mutations represented 12.7% of patients, whereas FLT3-internal tandem duplication (ITD) mutation was observed in 20.6% of AML cases and 1.6% of patients harbored both anomalies. At diagnosis, FLT3-TKD and FLT3-ITD were associated with higher peripheral leukocytes count and a higher blast count in bone marrow (P < 10). Mutations of the NPM1 gene were frequently associated to FLT3-TKD (68.7%) and FLT3-ITD (61.5%) mutations compared with FLT3 wild type (WT) patients (P < 10). Patients with both FLT3-TKD and NPM1 mutations (n = 12; 9.5%) showed a favorable outcome. Interestingly, mutations in NPM1 gene lost their favorable prognostic when not associated with FLT3-TKD both in univariate and multivariate analyses.

Conclusion: Our data suggest that FLT3-TKD mutations should be routinely determined at the time of diagnosis. In association with NPM1 mutations, patients should follow the therapeutic schedule of favorable-risk patients with AML.
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http://dx.doi.org/10.1016/j.clml.2018.06.006DOI Listing
December 2018

Physician uncertainty aversion impacts medical decision making for older patients with acute myeloid leukemia: results of a national survey.

Haematologica 2018 12 13;103(12):2040-2048. Epub 2018 Jul 13.

INRA, UR 1303 ALISS, Ivry-sur-Seine, France.

Elderly patients with acute myeloid leukemia can be treated with intensive chemotherapy, low-intensity therapy such as low-dose aracytine or hypomethylating agents, or best supportive care. The choice between these treatments is a function of many patient-related and disease-related factors. We investigated how physicians' behavioral characteristics affect medical decision-making between intensive and non-intensive therapy in this setting. A nationwide cross-sectional online survey of hematologists collected data on medical decision-making for 6 clinical vignettes involving older acute myeloid leukemia patients that were representative of routine practice. Questionnaires elicited physicians' demographic and occupational characteristics along with their individual behavioral characteristics according to a decision theory framework. From the pattern of responses to the vignettes, a K-means clustering algorithm was used to distinguish those who were likely to prescribe more intensive therapy and those who were likely to prescribe less intensive or no therapy. Multivariate analyses were used to identify physician's characteristics predictive of medical decision-making. We obtained 230 assessable answers, which represented an adjusted response rate of 45.4%. A multivariate model (n=210) revealed that physicians averse to uncertainty recommend significantly more intensive chemotherapy: Odds Ratio (OR) [95% Confidence Interval (CI)]: 1.15 [1.01;1.30]; =0.039. Male physicians who do not conform to the expected utility model (assumed as economically irrational) recommend more intensive chemotherapy [OR (95% CI) = 3.45 (1.34; 8.85); =0.01]. Patient volume per physician also correlated with therapy intensity [OR (95% CI)=0.98 (0.96; 0.99); =0.032]. The physicians' medical decision-making was not affected by their age, years of experience, or hospital facility. The significant association between medical decision and individual behavioral characteristics of the physician identifies a novel non-biological factor that may affect acute myeloid leukemia patients' outcomes and explain variations in clinical practice. It should also encourage the use of validated predictive models and the description of novel bio-markers to best select patients for intensive chemotherapy or low-intensity therapy.
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http://dx.doi.org/10.3324/haematol.2018.192468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269286PMC
December 2018

Dexamethasone in hyperleukocytic acute myeloid leukemia.

Haematologica 2018 06 8;103(6):988-998. Epub 2018 Mar 8.

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

Patients with acute myeloid leukemia and a high white blood cell count are at increased risk of early death and relapse. Because mediators of inflammation contribute to leukostasis and chemoresistance, dexamethasone added to chemotherapy could improve outcomes. This retrospective study evaluated the impact of adding or not adding dexamethasone to chemotherapy in a cohort of 160 patients with at least 50×10 white blood cells. studies, primary samples, leukemic cell lines, and xenograft mouse models were used to explore the antileukemic activity of dexamethasone. There was no difference with respect to induction death rate, response, and infections between the 60 patients in the dexamethasone group and the 100 patients in the no dexamethasone group. Multivariate analysis showed that dexamethasone was significantly associated with improved relapse incidence (adjusted sub-HR: 0.30; 95% CI: 0.14-0.62; =0.001), disease-free survival (adjusted HR: 0.50; 95% CI: 0.29-0.84; =0.010), event-free survival (adjusted HR: 0.35; 95% CI: 0.21-0.58; <0.001), and overall survival (adjusted HR: 0.41; 95% CI: 0.22-0.79; =0.007). In a co-culture system, dexamethasone reduced the frequency of leukemic long-term culture initiating cells by 38% and enhanced the cytotoxicity of doxorubicin and cytarabine. In a patient-derived xenograft model treated with cytarabine, chemoresistant cells were enriched in genes of the inflammatory response modulated by dexamethasone. Dexamethasone also demonstrated antileukemic activity in -mutated samples. Dexamethasone may improve the outcome of acute myeloid leukemia patients receiving intensive chemotherapy. This effect could be due to the modulation of inflammatory chemoresistance pathways and to a specific activity in acute myeloid leukemia with mutation.
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http://dx.doi.org/10.3324/haematol.2017.184267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058767PMC
June 2018

Improved outcome for AML patients over the years 2000-2014.

Blood Cancer J 2017 11 29;7(12):635. Epub 2017 Nov 29.

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

Few recent studies from registries have reported an improvement in overall survival of younger patients with acute myeloid leukemia (AML). However, reasons for this improvement are not defined. We analyzed the therapeutic course and outcome of 976 patients treated by intensive chemotherapy between 2000 and 2014. The number of patients receiving allogeneic stem cell transplantation in first or second response significantly increased over time whereas autologous transplantation was progressively abandoned. In the 513 younger patients, there were no differences in first complete response, induction failure, incidence of relapse, or non-relapse mortality over time. The period of time was significantly associated with a better overall survival especially in 2010-2014. The 2010-2014 period effect was still significant in multivariate analysis and was independent of allogeneic stem cell transplantation. In the 463 older patients, there was a significant interaction between the period and leukocytosis in multivariate analysis meaning that the 2010-2014 period had only an impact in patients with white blood cell count >50 giga/L for response and overall survival. Progresses have been made in each phase of the therapeutic course of younger AML patients resulting in survival improvement. In older patients, the outcome of hyperleukocytic patients has significantly improved in 2010-2014.
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http://dx.doi.org/10.1038/s41408-017-0011-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5802565PMC
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.
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http://dx.doi.org/10.18632/oncotarget.15988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5668025PMC
October 2017

Platelet transfusion refractoriness in patients with acute myeloid leukemia treated by intensive chemotherapy.

Leuk Res 2017 10 30;61:62-67. Epub 2017 Aug 30.

Université Toulouse III Paul Sabatier, Toulouse, France; Service d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France; Centre de Recherches en Cancérologie de Toulouse, UMR1037-INSERM, ERL5294 CNRS, Toulouse, France.

Platelet transfusion refractoriness (PTR) is a major adverse event in the management of acute myeloid leukemia (AML). In a series of 897 adult patients with AML receiving intensive chemotherapy, we identified 41 patients (4.8%) with PTR. PTR was more frequently observed in parous women, patients with extra-medullary disease, a low white blood cell count, an infection, or hemophagocytic syndrome. Among the 31 patients with anti-human leucocyte antigen (HLA) antibodies, an HLA-matched donor was identified for 18 patients (58.1%). Median time between diagnosis of PTR and the first HLA-matched transfusion was 12.5days. HLA-matched transfusions induced a significant increment in platelet counts in 37% of cases. Thrombopoietin receptor agonists were given to 10 patients but did not shorten the duration of thrombocytopenia, reduce severe bleeding, or early death. Grade 3-4 bleeding events during induction, early death caused by bleeding, and death caused by bleeding at any time were significantly greater in patients that had platelet transfusion refractoriness (22% vs. 4.1%, P<0.0001; 12.2% vs. 1.4%, P=0.0006; and 24.4% vs. 5.3%, P<0.0001; respectively). PTR during chemotherapy for AML significantly increased the risk of early and late deaths caused by a severe bleeding event. Improved understanding of platelet destruction is needed to design mechanism-based therapeutic strategies.
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http://dx.doi.org/10.1016/j.leukres.2017.08.015DOI Listing
October 2017

Prognostic impact of viral reactivations in acute myeloid leukemia patients undergoing allogeneic stem cell transplantation in first complete response.

Medicine (Baltimore) 2016 Nov;95(48):e5356

Service d'Hématologie, Institut Universitaire du Cancer de Toulouse Oncopole Université Toulouse III Paul Sabatier Service d'Epidémiologie, Centre Hospitalier Universitaire de Toulouse UMR 1027, INSERM-Université de Toulouse III Service d'Immunologie, Centre Hospitalier de Toulouse Rangueil Service de Virologie, Centre Hospitalier de Toulouse Purpan UMR 1037, Centre de Recherche en Cancérologie de Toulouse, INSERM-Université de Toulouse III, Toulouse, France.

Cytomegalovirus (CMV) serological status of donor and recipient as well as CMV reactivation have been associated with a lower risk of relapse in acute myeloid leukemia (AML) patients after allogeneic stem cell transplantation (alloSCT). Since immunosuppression following transplant allows resurgence of many other viruses, we retrospectively evaluated the impact of viral reactivations on relapse and survival in a cohort of 136 AML patients undergoing alloSCT in first remission from sibling (68%) or unrelated (32%) donors. Myeloablative and reduced-intensity conditioning regimen were given to 71 and 65 patients, respectively. Including CMV reactivations, at least 1 viral reactivation was recorded in 76 patients. Viral reactivations were associated with a lower risk of relapse (adjusted HR 0.14; 95% CI 0.07-0.30; P < 0.01), better disease-free survival (aHR 0.29; 95% CI 0.16-0.54; P < 0.01) but higher non relapse mortality. This translated into a better overall survival (aHR 0.44; 95%CI 0.25-0.77; P < 0.01) in patients who experienced viral reactivation. Thus, viral reactivations, including but not limited to CMV reactivation, are associated with a better outcome particularly with regard to the risk of relapse in AML patients undergoing alloSCT. New guidelines regarding the choice of donor according to the CMV serostatus are needed.
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http://dx.doi.org/10.1097/MD.0000000000005356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5134805PMC
November 2016