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Mutations of the isocitrate dehydrogenase-1 (IDH1) and IDH2 genes are among the most frequent alterations in acute myeloid leukemia (AML) and can be found in ∼20% of patients at diagnosis. Among 4930 patients (median age, 56 years; interquartile range, 45-66) with newly diagnosed, intensively treated AML, we identified IDH1 mutations in 423 (8.6%) and IDH2 mutations in 575 (11.7%). Overall, there were no differences in response rates or survival for patients with mutations in IDH1 or IDH2 compared with patients without mutated IDH1/2. However, distinct clinical and comutational phenotypes of the most common subtypes of IDH1/2 mutations could be associated with differences in outcome. IDH1-R132C was associated with increased age, lower white blood cell (WBC) count, less frequent comutation of NPM1 and FLT3 internal tandem mutation (ITD) as well as with lower rate of complete remission and a trend toward reduced overall survival (OS) compared with other IDH1 mutation variants and wild-type (WT) IDH1/2. In our analysis, IDH2-R172K was associated with significantly lower WBC count, more karyotype abnormalities, and less frequent comutations of NPM1 and/or FLT3-ITD. Among patients within the European LeukemiaNet 2017 intermediate- and adverse-risk groups, relapse-free survival and OS were significantly better for those with IDH2-R172K compared with WT IDH, providing evidence that AML with IDH2-R172K could be a distinct entity with a specific comutation pattern and favorable outcome. In summary, the presented data from a large cohort of patients with IDH1/2 mutated AML indicate novel and clinically relevant findings for the most common IDH mutation subtypes.
Clonal hematopoiesis of indeterminate potential (CHIP) is caused by recurrent somatic mutations leading to clonal blood cell expansion. However, direct evidence of the fitness of CHIP-mutated human hematopoietic stem cells (HSCs) in blood reconstitution is lacking. Because myeloablative treatment and transplantation enforce stress on HSCs, we followed 81 patients with solid tumors or lymphoid diseases undergoing autologous stem cell transplantation (ASCT) for the development of CHIP. We found a high incidence of CHIP (22%) after ASCT with a high mean variant allele frequency (VAF) of 10.7%. Most mutations were already present in the graft, albeit at lower VAFs, demonstrating a selective reconstitution advantage of mutated HSCs after ASCT. However, patients with CHIP mutations in DNA-damage response genes showed delayed neutrophil reconstitution. Thus, CHIP-mutated stem and progenitor cells largely gain on clone size upon ASCT-related blood reconstitution, leading to an increased future risk of CHIP-associated complications.
Bloodstream infections (BSI) are a frequent complication in patients with hematological and oncological diseases. However, the impact of different bacterial species causing BSI and of multiple BSI remains incompletely understood. We performed a retrospective study profiling 637 bacterial BSI episodes in hematological and oncological patients. Based on the 30-day (30d) overall survival (OS), we analyzed different types of multiple BSI and grouped BSI-associated bacteria into clusters followed by further assessment of clinical and infection-related characteristics. We discovered that polymicrobial BSI (different organisms on the first day of a BSI episode) and sequential BSI (another BSI before the respective BSI episode) were associated with a worse 30d OS. Different bacterial groups could be classified into three BSI outcome clusters based on 30d OS: favorable (FAV) including mainly common skin contaminants, Escherichia spp. and Streptococcus spp.; intermediate (INT) including mainly Enterococcus spp., vancomycin-resistant Enterococcus spp., and multidrug-resistant gram-negative bacteria (MDRGN); and adverse (ADV) including MDRGN with an additional carbapenem-resistance (MDRGN+CR). A polymicrobial or sequential BSI especially influenced the outcome in the combination of two INT cluster BSI. The presence of a polymicrobial BSI and the assignment into the BSI outcome clusters were identified as independent risk factors for 30d mortality in a Cox multivariate regression analysis. The assignment to a BSI outcome cluster and the differentiated perspective of multiple BSI open new insights into the prognosis of patients with BSI and should be further validated in other patient cohorts.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers potential cure to acute myeloid leukemia (AML) patients. However, infections with commensal bacteria are an important cause for non-relapse mortality (NRM). We have previously described the impact of multidrug-resistant organism (MDRO) colonization on the survival of allo-HSCT patients. In the aforementioned publication, according to consensus, we there did not consider the opportunistic gram-negative bacterium Stenotrophomonas maltophilia (S. maltophilia) to be an MDRO. Since rate of S. maltophilia colonization is increasing, and it is not known whether this poses a risk for allo-HSCT patients, we here analyzed here its effect on the previously described and now extended patient cohort. We report on 291 AML patients undergoing allo-HSCT. Twenty of 291 patients (6.9%) were colonized with S. maltophilia. Colonized patients did not differ from non-colonized patients with respect to their age, remission status before allo-HSCT, donor type and HSCT-comorbidity index. S. maltophilia colonized patients had a worse overall survival (OS) from 6 months up to 60 months (85% vs. 88.1% and 24.7% vs. 59.7%; p = 0.007) due to a higher NRM after allo-HSCT (6 months: 15% vs. 4.8% and 60 months: 40.1% vs. 16.2% p = 0.003). The main cause of mortality in colonized patients was infection (46.2% of all deaths) and in non-colonized patients relapse (58.8% of all deaths). 5/20 colonized patients developed an invasive infection with S. maltophilia. The worse OS after allo-HSCT due to higher infection related mortality might implicate the screening of allo-HSCT patients for S. maltophilia and a closer observation of colonized patients as outpatients.
Treatment with inhibitors of the receptor tyrosine kinase FLT3 are currently studied as promising therapies in acute myeloid leukemia (AML). However, only a subset of patients benefit from these treatments and the presence of activating mutations within FLT3 can predict response to a certain extent only. ...
Autologous hematopoietic stem cell transplantation (auto-HSCT) provides a potentially curative treatment option for relapsed and refractory lymphomas. Obesity displays an emerging epidemic risk factor for global mortality and is associated with an increased mortality in cancer patients. To date, the impact of obesity on the outcome of lymphoma patients undergoing auto-HSCT is understudied. We conducted a retrospective single-center study assessing 119 lymphoma patients who underwent auto-HSCT. Overall survival (OS) served as the primary endpoint whereas progression free survival (PFS), cumulative incidence of non-relapse related mortality (NRM) and cumulative incidence of relapse were analyzed as secondary endpoints. Obese patients (Body mass index, BMI≥30) had significantly lower OS (45.3% vs. 77.9%; p = 0.005) and PFS (29.8% vs. 67.2%; p<0.001) compared to non-obese patients at 48 months post-transplantation. The cumulative incidence of NRM displayed no significant differences while the cumulative incidence of relapse was significantly increased in patients with BMI≥30 (66.2% vs. 21.5%; p<0.001). Patients with a BMI<25 and overweight patients (BMI 25–30; 76.1% vs. 80.9%; p = 0.585), showed no significant difference in OS, whereas patients with BMI≥30 exhibited significant lower OS when compared to either of both groups (76.1% vs. 45.3%; p = .0.021 and 80.9% vs. 45.3%; p = 0.010). Furthermore, in a multivariate analysis, obesity was identified as an independent risk factor for death (Hazard ratio 2.231; 95% CI 1.024 to 4.860; p = 0.043). Further studies are needed to evaluate the reasons for the higher relapse rate causing higher mortality in obese patients.
Acute kidney injury (AKI) complicates the clinical course of hospitalized patients by increasing need for intensive care treatment and mortality. There is only little data about its impact on AML patients undergoing intensive induction chemotherapy. In this study, we analyzed the incidence as well as risk factors for AKI development and its impact on the clinical course of AML patients undergoing induction chemotherapy. We retrospectively analyzed data from 401 AML patients undergoing induction chemotherapy between 2007 and 2019. AKI was defined and stratified according to KIDGO criteria by referring to a defined baseline serum creatinine measured on day 1 of induction chemotherapy. Seventy-two of 401 (18%) AML patients suffered from AKI during induction chemotherapy. AML patients with AKI had more days with fever (7 vs. 5, p = 0.028) and were more often treated on intensive care unit (45.8% vs. 10.6%, p < 0.001). AML patients with AKI had a significantly lower complete remission rate after induction chemotherapy and, with 402 days, a significantly shorter median overall survival (OS) (median OS for AML patients without AKI not reached). In this study, we demonstrate that the KIDGO classification allows mortality risk stratification for AML patients undergoing induction chemotherapy. Relatively mild AKI episodes have impact on the clinical course of these patients and can lead to chronic impairment of kidney function. Therefore, we recommend incorporating risk factors for AKI in decision-making considering nutrition, fluid management, as well as the choice of potentially nephrotoxic medication in order to decrease the incidence of AKI.
Treatment‐related complications contribute substantially to morbidity and mortality in acute myeloid leukemia (AML) patients undergoing induction chemotherapy. Although AML patients are susceptible to fluid overload (FO) (e.g., in the context of chemotherapy protocols, during sepsis treatment or to prevent tumor lysis syndrome), little attention has been paid to its role in AML patients undergoing induction chemotherapy. AML patients receiving induction chemotherapy between 2014 and 2019 were included in this study. FO was defined as ≥5% weight gain on day 7 of induction chemotherapy compared to baseline weight determined on the day of admission. We found FO in 23 (12%) of 187 AML patients undergoing induction chemotherapy. Application of >100 ml crystalloid fluids/kg body weight until day 7 of induction chemotherapy was identified as an independent risk factor for FO. AML patients with FO suffered from a significantly increased 90-day mortality rate and FO was demonstrated as an independent risk factor for 90-day mortality. Our data suggests an individualized, weight-adjusted calculation of crystalloid fluids in order to prevent FO-related morbidity and mortality in AML patients during induction chemotherapy. Prospective trials are required to determine the adequate fluid management in this patient population.
Introduction: Vacuolization is a frequently found morphological feature in acute myeloid leukemia (AML) blasts. Subcellular origin and biological function as well as prognostic impact are currently unknown. The aim of this study was to evaluate whether vacuolization correlates with clinically relevant AML features.
Materials & methods: Bone marrow smears of patients diagnosed with AML at the University Hospital Frankfurt between January 2011 and August 2013 were analyzed for blast vacuolization and correlated with clinically relevant AML features. Patients undergoing standard induction chemotherapy were further analyzed for molecular and cytogenetic features as well as treatment response and survival.
Results: 14 of 100 patients diagnosed with AML receiving standard induction chemotherapy had evidence of blast vacuolization. Positivity for vacuolization correlated with a CD15 positive immunophenotype and with a higher incidence of high-risk AML according to the European LeukemiaNet risk stratification. AML patients with blast vacuolization had a poor blast clearance after standard induction chemotherapy and poor survival.
Discussion: In conclusion, our findings demonstrate that vacuolization can easily be determined in myeloid leukemia blasts and may be a useful biomarker to predict AML risk groups as well as early treatment response rates and survival.
INTRODUCTION: Older patients with acute myeloid leukemia (AML) experience short survival despite intensive chemotherapy. Azacitidine has promising activity in patients with low proliferating AML. The aim of this dose-finding part of this trial was to evaluate feasibility and safety of azacitidine combined with a cytarabine- and daunorubicin-based chemotherapy in older patients with AML.
TRIAL DESIGN: Prospective, randomised, open, phase II trial with parallel group design and fixed sample size.
PATIENTS AND METHODS: Patients aged 61 years or older, with untreated acute myeloid leukemia with a leukocyte count of <20,000/µl at the time of study entry and adequate organ function were eligible. Patients were randomised to receive azacitidine either 37.5 (dose level 1) or 75 mg/sqm (dose level 2) for five days before each cycle of induction (7+3 cytarabine plus daunorubicine) and consolidation (intermediate-dose cytarabine) therapy. Dose-limiting toxicity was the primary endpoint.
RESULTS: Six patients each were randomised into each dose level and evaluable for analysis. No dose-limiting toxicity occurred in either dose level. Nine serious adverse events occurred in five patients (three in the 37.5 mg, two in the 75 mg arm) with two fatal outcomes. Two patients at the 37.5 mg/sqm dose level and four patients at the 75 mg/sqm level achieved a complete remission after induction therapy. Median overall survival was 266 days and median event-free survival 215 days after a median follow up of 616 days.
CONCLUSIONS: The combination of azacitidine 75 mg/sqm with standard induction therapy is feasible in older patients with AML and was selected as an investigational arm in the randomised controlled part of this phase-II study, which is currently halted due to an increased cardiac toxicity observed in the experimental arm.