Sarah Bertoli

Core-binding factor acute myeloid leukemia in first relapse: a retrospective study from the French AML Intergroup.

Although core-binding factor-acute myeloid leukemia (CBF-AML) (t[8;21] or inv[16]/t[16;16]) represents a favorable cytogenetic AML subgroup, 30% to 40% of these patients relapse after standard intensive chemotherapy. The encouraging results of gemtuzumab ozogamicin (GO) in newly diagnosed AML, and particularly in CBF-AML, incited us to retrospectively investigate the impact of GO-based salvage in these patients. We retrospectively analyzed the outcome of 145 patients with CBF-AML (59 t[8;21], 86 inv[16]/t[16;16]) in first relapse. As salvage, 48 patients received GO-based chemotherapy and 97 patients received conventional chemotherapy. Median age was 43 years (range, 16-76). Median first complete remission duration was 12.1 months (range, 2.1-93.6). Overall, second complete remission (CR2) rate was 88%. With a median follow-up from relapse of 3.5 years, the estimated 5-year disease-free survival (DFS) was 50% and 5-year overall survival (OS) was 51%. Older age and shorter first complete remission duration was associated with a shorter OS. Patients treated with GO had similar CR2 rate but significantly higher 5-year DFS (68% vs 42%; P = .05) and OS (65% vs 44%; P = .02). In multivariate analysis, GO salvage was still associated with a significant benefit in DFS and OS. In the 78 patients who received allogeneic hematopoietic stem cell transplantation in CR2, GO before transplant significantly improved posttransplant DFS and OS without excess of treatment-related mortality.

Hemophagocytic syndrome in patients with acute myeloid leukemia undergoing intensive chemotherapy

Hemophagocytic lymphohistiocytosis is a condition of immune dysregulation characterized by severe organ damage induced by a hyperinflammatory response and uncontrolled T-cell and macrophage activation. Secondary hemophagocytic lymphohistiocytosis typically occurs in association with severe infections or malignancies. Patients with acute myeloid leukemia may be prone to develop hemophagocytic lymphohistiocytosis because of an impaired immune response and a high susceptibility to severe infections. In a series of 343 patients treated by intensive chemotherapy over a 5-year period in our center, we identified 32 patients (9.3%) with fever, very high ferritin levels, and marrow hemophagocytosis (i.e. patients with hemophagocytic lymphohistiocytosis). Compared to patients without hemophagocytic lymphohistiocytosis, these 32 patients had hepatomegaly, pulmonary or neurological symptoms, liver abnormalities, lower platelet count and higher levels of C-reactive protein as well as prolonged pancytopenia. A microbial etiology for the hemophagocytosis was documented in 24 patients: 14 bacterial infections, 9 Herpesviridae infections and 11 fungal infections. The treatment of hemophagocytic lymphohistiocytosis consisted of corticosteroids and/or intravenous immunoglobulins along with adapted antimicrobial therapy. Patients with hemophagocytic lymphohistiocytosis had a median overall survival of 14.9 months, which was significantly shorter than that of patients without hemophagocytic lymphohistiocytosis (22.1 months) (P=0.0016). Hemophagocytic lymphohistiocytosis was significantly associated with a higher rate of induction failure, mainly due to deaths in aplasia. Hemophagocytic lymphohistiocytosis can be diagnosed in up to 10% of patients with acute myeloid leukemia undergoing intensive chemotherapy and is associated with early mortality. Fever, very high ferritin levels and marrow hemophagocytosis represent the cornerstone of the diagnosis. Further biological studies are needed to better characterize and recognize this syndrome in patients with acute myeloid leukemia.

CHK1 as a therapeutic target to bypass chemoresistance in AML

AML patients have new hope for overcoming resistance to therapy by inhibiting the DNA checkpoint kinase CHK1. New hope for AML patients A pair of papers provides new hope for patients with acute myeloid leukemia (AML) by showing that the DNA replication checkpoint pathway is a viable target for therapeutic intervention. By integrating survival data from 198 treated AML patients with gene expression data for genes encoding proteins involved in the regulation of DNA replication, David et al. identified the CHEK1 gene and its product, the DNA replication checkpoint kinase CHK1, as both a prognostic indicator of survival and a therapeutic target to overcome resistance to the current standard of chemotherapy. The patients had all received standard-of-care chemotherapy. Patients with high expression of CHEK1 in their AML cells had reduced survival, and AML patient cells with high CHK1 abundance were resistant to the toxic effects of the DNA replication inhibitor cytarabine. CHK1 is activated by the kinase ATR in response to DNA replication stress arising from DNA damage. The identification of CHEK1 expression as high in lymphomas and leukemias, including AML, prompted Morgado-Palacin et al. to investigate targeting ATR and ATM, the most upstream kinases in the DNA damage response, as possible AML therapies. AML cells with oncogenic rearrangements in MLL are particularly resistant to genotoxic therapies that form the backbone of AML treatment. Inhibiting ATR resulted in death of AMLMLL cells in culture and exhibited antitumoral activity in AMLMLL mouse models. Inhibiting ATM also prolonged survival of the allograft mouse model, indicating that targeting the DNA damage response pathways alone or in combination with other chemotherapeutic agents may be beneficial in patients with AML. The nucleoside analog cytarabine, an inhibitor of DNA replication fork progression that results in DNA damage, is currently used in the treatment of acute myeloid leukemia (AML). We explored the prognostic value of the expression of 72 genes involved in various aspects of DNA replication in a set of 198 AML patients treated by cytarabine-based chemotherapy. We unveiled that high expression of the DNA replication checkpoint gene CHEK1 is a prognostic marker associated with shorter overall, event-free, and relapse-free survivals and determined that the expression of CHEK1 can predict more frequent and earlier postremission relapse. CHEK1 encodes checkpoint kinase 1 (CHK1), which is activated by the kinase ATR when DNA replication is impaired by DNA damage. High abundance of CHK1 in AML patient cells correlated with higher clonogenic ability and more efficient DNA replication fork progression upon cytarabine treatment. Exposing the patient cells with the high abundance of CHK1 to SCH900776, an inhibitor of the kinase activity of CHK1, reduced clonogenic ability and progression of DNA replication in the presence of cytarabine. These results indicated that some AML cells rely on an efficient CHK1-mediated replication stress response for viability and that therapeutic strategies that inhibit CHK1 could extend current cytarabine-based treatments and overcome drug resistance. Furthermore, monitoring CHEK1 expression could be used both as a predictor of outcome and as a marker to select AML patients for CHK1 inhibitor treatments.

Anthracycline dose intensification improves molecular response and outcome of patients treated for core binding factor acute myeloid leukemia.

Two prospective trials have demonstrated that daunorubicin used at a daily dose of 90 mg/m2 over three days improved overall survival as compared to 45 mg/m2 in patients with newly diagnosed acute myeloid leukemia (AML).[1][1],[2][2] Benefit of intensification seems limited to the patients without

Impact of obesity in favorable‐risk AML patients receiving intensive chemotherapy

We assessed the influence of obesity on the characteristics and prognosis of acute myeloid leukemia (AML). Indeed, safety of intensive chemotherapy and outcome of obese AML patients in a real‐life setting are poorly described, and chemotherapy dosing remains challenging. We included 619 consecutive genetically‐defined cases of AML treated with intensive chemotherapy between 2004 and 2012. In this cohort, 93 patients (15%) were classified in the obese category according to WHO classification; 59% of them received capped doses of chemotherapy because of a body surface area above 2 m2. Obese patients were older and presented more often with cardiovascular comorbidities. Although obese patients had more frequently de novo AML, main characteristics of AML including white blood cell count, karyotype and mutations were well‐balanced between obese and non‐obese patients. After induction chemotherapy, early death and complete remission rates were similar. Overall (OS), event‐free (EFS) and disease‐free (DFS) survival were not significantly different compared to non‐obese patients. However, in the European LeukemiaNet (ELN) favorable subgroup, obese patients had lower median OS, EFS and DFS than non‐obese patients (18.4, 16.8 and 17.2 vs. 43.6, 31.8 and 29.7 months, respectively) and obesity showed a significant impact on OS (OR 2.54; P = 0.02) in multivariate models. Although we did not find any significant impact of obesity on outcome in the whole series, this study suggests that special efforts for chemotherapy dose optimization are needed in the ELN favorable subgroup since dose capping may be deleterious. Am. J. Hematol. 91:193–198, 2016.

Initial absolute lymphocyte count as a prognostic factor for outcome in acute myeloid leukemia

Abstract The absolute lymphocyte count (ALC) at presentation has been associated with survival in various malignancies. However, its prognostic value in acute myeloid leukemia (AML) has not been established. In a series of 1702 newly diagnosed patients with AML, we evaluated the prognostic value of ALC at diagnosis with regard to induction chemotherapy response, disease-free survival (DFS) and overall survival (OS). Low initial ALC (< 1 × 109/L) appeared as a poor prognostic factor for DFS (p = 0.01) and OS (p = 0.02), while higher ALC (> 4.5 × 109/L) showed a lower response rate after one (p = 0.004) or two induction chemotherapy courses (p = 0.01). However, ALC did not appear as an independent predictor of outcome in a multivariate analysis model also including age, cytogenetics and white blood cell count. Examination of lymphocyte subsets is warranted to specify the relationship between ALC at diagnosis and clinical outcome in AML.

Intensive chemotherapy, azacitidine, or supportive care in older acute myeloid leukemia patients: An analysis from a regional healthcare network

We assessed in a French regional healthcare network the distribution of treatments, prognostic factors, and outcome of 334 newly diagnosed acute myeloid leukemia patients aged 60 years or older over a 4‐year period of time (2007–2010). Patients were selected in daily practice for intensive chemotherapy (n = 115), azacitidine (n = 95), or best supportive care (n = 124). In these three groups, median overall survival was 18.9, 11.3, and 1.8 months, respectively. In the azacitidine group, multivariate analysis showed that overall survival was negatively impacted by higher age (P = 0.010 for one unit increase), unfavorable cytogenetics (P = 0.001), lymphocyte count <0.5 G/L (P = 0.015), and higher lactate dehydrogenase level (P = 0.005 for one unit increase). We compared the survival of patients treated by azacitidine versus intensive chemotherapy and best supportive care using time‐dependent analysis and propensity score matching. Patients treated by intensive chemotherapy had a better overall survival compared with those treated by azacitidine from 6 months after diagnosis, whereas patients treated by azacitidine had a better overall survival compared with those treated by best supportive care from 1 day after diagnosis. This study of “real life” practice shows that there is a room for low intensive therapies such as azacitidine in selected elderly acute myeloid leukemia patients. Am. J. Hematol. 89:E244–E252, 2014.

CDC25A governs proliferation and differentiation of FLT3-ITD acute myeloid leukemia

We investigated cell cycle regulation in acute myeloid leukemia cells expressing the FLT3-ITD mutated tyrosine kinase receptor, an underexplored field in this disease. Upon FLT3 inhibition, CDC25A mRNA and protein were rapidly down-regulated, while levels of other cell cycle proteins remained unchanged. This regulation was dependent on STAT5, arguing for FLT3-ITD-dependent transcriptional regulation of CDC25A. CDC25 inhibitors triggered proliferation arrest and cell death of FLT3-ITD as well as FLT3-ITD/TKD AC-220 resistant cells, but not of FLT3-wt cells. Consistently, RNA interference-mediated knock-down of CDC25A reduced the proliferation of FLT3-ITD cell lines. Finally, the clonogenic capacity of primary FLT3-ITD AML cells was reduced by the CDC25 inhibitor IRC-083864, while FLT3-wt AML and normal CD34+ myeloid cells were unaffected. In good agreement, in a cohort of 100 samples from AML patients with intermediate-risk cytogenetics, high levels of CDC25A mRNA were predictive of higher clonogenic potential in FLT3-ITD+ samples, not in FLT3-wt ones. Importantly, pharmacological inhibition as well as RNA interference-mediated knock-down of CDC25A also induced monocytic differentiation of FLT3-ITD positive cells, as judged by cell surface markers expression, morphological modifications, and C/EBPα phosphorylation. CDC25 inhibition also re-induced monocytic differentiation in primary AML blasts carrying the FLT3-ITD mutation, but not in blasts expressing wild type FLT3. Altogether, these data identify CDC25A as an early cell cycle transducer of FLT3-ITD oncogenic signaling, and as a promising target to inhibit proliferation and re-induce differentiation of FLT3-ITD AML cells.

Comparison of 60 or 90 mg/m2 of daunorubicin in induction therapy for acute myeloid leukemia with intermediate or unfavorable cytogenetics

To the Editor: Induction therapy for acute myeloid leukemia (AML) based on 3 days of anthracycline and 7 days of cytarabine has been a standard of care since many years but the optimal regimen is still a matter of debate. Recently, the use of high dose 90 mg/ m daunorubicin (DNR) was reported in several phase III clinical trials to improve both complete remission (CR) rate and overall survival (OS) as compared with low dose DNR (45 mg/m) and is now considered as a standard of care [1,2]. However, the dose of 45 mg/m is not used worldwide and several groups use intermediate dose of 60 mg/m and reported OS of approximately 40%–45% at 5 years in younger AML patients [3,4]. A formal comparison between daunorubicin 60 and 90 mg/m has yet to be published. In 2010 following Fernandez reports and in the absence of active protocol, GOELAMS switched the DNR induction dose from 60 to 90 mg/m for all newly diagnosed patients. Both reports of Fernandez and L€owenberg suggest that patients with favorable cytogenetics benefit the most from high dose DNR while outcome of unfavorable cytogenetic patients was not improved using 90 versus 45 mg/m of DNR. To deal with this possible interaction between cytogenetics and DNR dose, we previously compared 60 with 90 mg/ m in the specific setting of core binding factor AML (CBF-AML) in a separate report and showed that 90 mg improved outcome compared with 60 mg [5]. However, it was not certain that the same comparison would be beneficial in patients with intermediate or unfavorable cytogenetic features. In this present study, we compared the outcome of AML patients with intermediate or unfavorable cytogenetics treated with 90 mg/m daunorubicin to historical controls treated with 60 mg/m. We retrospectively analyzed 300 consecutive patients with previously untreated AML who received induction therapy in Marseille and Toulouse. Selection criteria were: (1) adult patients younger than 61 years; (2) diagnosis of AML according to the WHO classification [6]; (3) induction therapy with DNR (60 or 90 mg/m/d, 3 days) and cytarabine (200 mg/m/d, 7 days); and (4) patients with favorable cytogenetics [t(8;21), inv(16), t(16;16), t(15;17)] were not included in this study and have been reported elsewhere [5]. This study was approved by our institutional review board and is in accordance with the Helsinki declaration. We performed univariate comparisons according to DNR dose in subgroups of age ( and >50 years), white blood cells (WBC) ( and >50 G/L), AML occurrence (de novo and secondary), cytogenetics (intermediate and unfavorable), and genotype (favorable [NPM1-mutated/FLT3-wild-type or CEBPA-mutated/FLT3-wild-type] and other [other combinations of these three genes]). The impact of DNR dose was adjusted using a multivariate Cox model including age ( vs. >50 years), WBC ( vs. >50 G/L), occurrence of AML (de novo vs. secondary), and cytogenetics (intermediate vs. unfavorable). Seventy-five patients treated from 2010 to 2012 received 90 mg/m daunorubicin (DNR90 group), and 225 patients treated from 2006 to 2010 received 60 mg/m daunorubicin (DNR60 group) (Table I). There was no difference between the two dose groups except a trend for higher median WBC at diagnosis in the DNR90 group (9 vs. 15 G/L, P5 0.056). As the treatment periods were different between the two groups, the median follow up was longer in the DNR60 group (58 vs. 31 months, P< 0.001). No differences in terms of CR, CR1CRi, or induction death rates were seen (Table I). Once in CR or CRi (IWG2003 criteria[7]), 116/238 (49%) patients underwent allogeneic hematopoietic stem cell transplantation (Allo-HSCT), without significant difference between the two dose groups [DNR60: 88/177 (50%) vs. DNR90: 28/61 (46%), P5 0.891]. Two-year cumulative incidence of relapse was 36% and 33% in the DNR60 and DNR90, respectively, (P5 0.836), while the 2-year cumulative incidence of death in CR was 12% and 10% in the DNR60 and DNR90 groups, respectively (P5 0.645). Interestingly, in the specific setting of patients who underwent Allo-HSCT in CR1, the cumulative incidence of death in CR was not increased in the DNR90 group (14%) compared with the DNR60 group (16%) (P5 0.873). We found similar 2-year probability of RFS (52% vs. 57% in the DNR60 vs. DNR90 groups, respectively, P50.688) and 2-year probability of OS (54% vs. 59% in the DNR60 vs. DNR90 groups, respectively, P5 0.352; Table II). There was no difference according to DNR dose in all the subgroups of age, WBC, cytogenetics, and genotypes (Table II). After adjustment with multivariate Cox model, daunorubicin dose did not significantly influence either RFS [Hazard ratio, 95% confidence interval (HR, 95CI): 0.91, 0.58–1.43; P5 0.692] or OS (HR, 95CI: 0.84, 0.57– 1.26; P5 0.404) while age 50 years (RFS: HR, 95CI: 1.48, 1.01–2.15; P5 0.040; OS: HR, 95CI: 1.53, 1.11–2.10; P5 0.010), WBC 50 G/L (RFS: HR, 95CI: 1.68, 1.09–2.61; P5 0.020; OS: HR, 95CI: 1.48, 1.02–2.15, P5 0.040) and unfavorable cytogenetics (RFS: HR, 95CI: 1.48, 0.94–2.33; P5 0.090; OS: HR, 95CI: 1.52, 1.05–2.19; P5 0.026) were associated with poor outcome. Our results suggest that a dose of 90 mg/m of DNR did not confer further benefit as compared with an “intermediate” dose of 60 mg/m in the setting of patients without favorable cytogenetics. The 2-year OS of the DNR90 arm in the Fernandez study was 49% (59% in our study) although they included also patients with favorable cytogenetics [2]. The better results in our series that excluded favorable cytogenetics are likely due to the higher proportion of patients who underwent allogeneic transplantation in first CR (49%) compared with 10% in the Fernandez report. We could suggest that this major difference in transplantation rates in our study compared with the Fernandez study explains in part the different conclusions regarding DNR doses. We failed to identify subgroups which could benefit from high dose DNR. No difference was found according to DNR dose in all “conventional” subgroups as shown by ECOG and HOVON studies [1,2]. It stresses the need to identify new predictive markers of chemosensitive disease to select patients for intensified induction therapy. Molecular findings could be a promising approach to solve in part this issue. The dose issue in the specific setting of AML with favorable genotype is of particular interest when intensified chemotherapy appears as a promising way to improve outcome in this situation [8,9]. In this setting, we did not find any difference between the DNR90 and DNR60 groups. However, the low number of patients with favorable genotype does not allow us drawing clear conclusions. It was reported that patients with some somatic mutations such as DNMT3A mutant could specifically benefit from intensive anthracycline dose regimens [10,11]. Of note, we showed that DNR90 mg/m was not associated to an increased treatment-related mortality as compared with DNR60 and had no deleterious impact on post-transplant outcome.

Improved outcome for AML patients over the years 2000–2014

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.