Hyperleukocytosis in acute myeloid leukemia (AML) is associated with inferior outcomes. There is limited high quality evidence to support the benefits of leukapheresis. We retrospectively collected ...data from patients with newly-diagnosed AML who presented with a white cell count (WBC) >50 × 10
/L to 12 centers in the United States and Europe from 2006 to 2017 and received intensive chemotherapy. Logistic regression models estimated odds ratios for 30-day mortality and achievement of composite complete remission (CRc). Cox proportional hazard models estimated hazard ratios for overall survival (OS). Among 779 patients, clinical leukostasis was reported in 27%, and leukapheresis was used in 113 patients (15%). Thirty-day mortality was 16.7% (95% CI: 13.9-19.3%). Median OS was 12.6 months (95% CI: 11.5-14.9) among all patients, and 4.5 months (95% CI: 2.7-7.1) among those ≥65 years. Use of leukapheresis did not significantly impact 30-day mortality, achievement of CRc, or OS in multivariate analysis based on available data or in analysis based on multiple imputation. Among patients with investigator-adjudicated clinical leukostasis, there were statistically significant improvements in 30-day mortality and OS with leukapheresis in unadjusted analysis, but not in multivariate analysis. Given the significant resource use, cost, and potential complications of leukapheresis, randomized studies are needed to evaluate its value.
There are no studies analyzing how therapeutic changes impact on outcomes of older AML patients. This study analyzes patient´s and disease characteristics, treatment patterns, and outcomes of 3637 ...AML patients aged ≥60 years reported to the PETHEMA registry. Study periods were 1999-2006 (before hypomethylating agents-HMAs availability) vs 2007-2013, and treatments were intensive chemotherapy (IC), non-intensive, clinical trial (CT), and supportive care only (SC). Median age was 72 (range, 60-99), 57% male, median ECOG 1 (range, 0-4), secondary AML 914 (30%), with adverse-risk genetic in 720 (32%). Treatment differed between study periods (1999-2006 vs 2007-2013): IC 58% vs 32%, non-intensive 1 vs 23%, CT 0 vs 2%, SC 27 vs 28% (p < 0.001). Median OS was 4.7 months (1-year OS 29% and 5-years 7%, without differences between periods), 1.2 for SC, 7.8 for non-intensive, 8.6 for IC, and 10.4 for CT (p < 0.001). OS improved in the 2007-2013 period for IC patients (10.3 vs 7.5 months, p = 0.004), but worsened for SC patients (1.2 vs 1.6 months, p = 0.03). Our real-life study shows that, despite evolving treatment for elderly patients during the last decade, OS has remained unchanged. Epidemiologic registries will critically assess whether novel therapies lead to noteworthy advances in the near future (#NCT02606825).
Treatment options for patients with secondary acute myeloid leukemia (sAML) and AML with myeloid-related changes (AMLMRC) aged 60 to 75 years are scarce and unsuitable. A pivotal trial showed that ...CPX-351 improved complete remission with/without incomplete recovery (CR/CRi) and overall survival (OS) as compared with standard "3+7" regimens. We retrospectively analyze outcomes of 765 patients with sAML and AML-MRC aged 60 to 75 years treated with intensive chemotherapy, reported to the PETHEMA registry before CPX-351 became available. The CR/CRi rate was 48%, median OS was 7.6 months (95% confidence interval CI: 6.7-8.5) and event-free survival (EFS) 2.7 months (95% CI: 2-3.3), without differences between intensive chemotherapy regimens and AML type. Multivariate analyses identified age ≥70 years, Eastern Cooperative Oncology Group performance status ≥1 as independent adverse prognostic factors for CR/CRi and OS, while favorable/intermediate cytogenetic risk and NPM1 were favorable prognostic factors. Patients receiving allogeneic stem cell transplant (HSCT), autologous HSCT, and those who completed more consolidation cycles showed improved OS. This large study suggests that classical intensive chemotherapy could lead to similar CR/CRi rates with slightly shorter median OS than CPX-351.
Next-Generation Sequencing (NGS) implementation to perform accurate diagnosis in acute myeloid leukemia (AML) represents a major challenge for molecular laboratories in terms of specialization, ...standardization, costs and logistical support. In this context, the PETHEMA cooperative group has established the first nationwide diagnostic network of seven reference laboratories to provide standardized NGS studies for AML patients. Cross-validation (CV) rounds are regularly performed to ensure the quality of NGS studies and to keep updated clinically relevant genes recommended for NGS study. The molecular characterization of 2856 samples (1631 derived from the NGS-AML project; NCT03311815) with standardized NGS of consensus genes (
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) showed 97% of patients having at least one mutation. The mutational profile was highly variable according to moment of disease, age and sex, and several co-occurring and exclusion relations were detected. Molecular testing based on NGS allowed accurate diagnosis and reliable prognosis stratification of 954 AML patients according to new genomic classification proposed by Tazi et al. Novel molecular subgroups, such as mutated
and mutations in at least two myelodysplasia-related genes, have been associated with an adverse prognosis in our cohort. In this way, the PETHEMA cooperative group efficiently provides an extensive molecular characterization for AML diagnosis and risk stratification, ensuring technical quality and equity in access to NGS studies.
Abstract
Background
Multidrug-resistant Gram-negative bacterial (MRGNB) infections represent a major public health threat. Cancer patients and, among them, hematological patients are most vulnerable ...to these infections. Gut colonization by MRGNB is a common phenomenon occurring during hospitalization and chemotherapy exposure. In the neutropenic phase that occurs after chemotherapy, MRGNB translocation occurs increasing patient’s mortality. Fluoroquinolone prophylaxis with ciprofloxacin or levofloxacin efficacy is now being questioned due to the increase of incidence in MRGNB.
Methods
A phase III randomized, controlled, clinical trial, open-label parallel-group with a 1:1 ratio, aimed to demonstrate the non-inferiority of oral fosfomycin versus oral ciprofloxacin for febrile neutropenia prevention in patients with acute leukemia (AL) or hematopoietic cell transplant (HSC) receptors. Weekly surveillance cultures are planned to detect gut colonization. Changes in fecal microbiome at the beginning and end of prophylaxis will also be analyzed.
Discussion
This trial will provide evidence of the efficacy of an alternative drug to ciprofloxacin for febrile neutropenia prevention in high-risk hematological patients. The battery of planned microbiological studies will allow us to evaluate prospectively the microbiological safety of both pharmacological strategies in terms of the selection of MRGNB occurring in each arm. In addition, valuable information on the way in which each drug changes the fecal microbiome of the patients throughout the treatment will be generated.
Trial registration
Clinical trials NCT05311254, Registered on 5 April 2022,
https://clinicaltrials.gov/ct2/show/NCT05311254?term=FOVOCIP&cntry=ES&draw=2&rank=1
. Protocol version: 3.0, dated 20 May 2022.
FLT3−ITD results in a poor prognosis in terms of overall survival (OS) and relapse-free survival (RFS) in acute myeloid leukemia (AML). However, the prognostic usefulness of the allelic ratio (AR) to ...select post-remission therapy remains controversial. Our study focuses on the prognostic impact of FLT3−ITD and its ratio in a series of 2901 adult patients treated intensively in the pre-FLT3 inhibitor era and reported in the PETHEMA registry. A total of 579 of these patients (20%) harbored FLT3−ITD mutations. In multivariate analyses, patients with an FLT3−ITD allele ratio (AR) of >0.5 showed a lower complete remission (CR rate) and OS (HR 1.47, p = 0.009), while AR > 0.8 was associated with poorer RFS (HR 2.1; p < 0.001). Among NPM1/FLT3−ITD-mutated patients, median OS gradually decreased according to FLT3−ITD status and ratio (34.3 months FLT3−ITD-negative, 25.3 months up to 0.25, 14.5 months up to 0.5, and 10 months ≥ 0.5, p < 0.001). Post-remission allogeneic transplant (allo-HSCT) resulted in better OS and RFS as compared to auto-HSCT in NPM1/FLT3−ITD-mutated AML regardless of pre-established AR cutoff (≤0.5 vs. >0.5). Using the maximally selected log-rank statistics, we established an optimal cutoff of FLT3−ITD AR of 0.44 for OS, and 0.8 for RFS. We analyzed the OS and RFS according to FLT3−ITD status in all patients, and we found that the group of FLT3−ITD-positive patients with AR < 0.44 had similar 5-year OS after allo-HSCT or auto-HSCT (52% and 41%, respectively, p = 0.86), but worse RFS after auto-HSCT (p = 0.01). Among patients with FLT3−ITD AR > 0.44, allo-HSCT was superior to auto-HSCT in terms of OS and RFS. This study provides more evidence for a better characterization of patients with AML harboring FLT3−ITD mutations.
The incidence of cardiac morbimortality in acute myeloid leukemia (AML) is not well known. We aim to estimate the cumulative incidence (CI) of cardiac events in AML patients and to identify risk ...factors for their occurrence. Among 571 newly diagnosed AML patients, 26 (4.6%) developed fatal cardiac events, and among 525 treated patients, 19 (3.6%) experienced fatal cardiac events (CI: 2% at 6 months; 6.7% at 9 years). Prior heart disease was associated with the development of fatal cardiac events (hazard ratio (HR) = 6.9). The CI of non-fatal cardiac events was 43.7% at 6 months and 56.9% at 9 years. Age ≥ 65 (HR = 2.2), relevant cardiac antecedents (HR = 1.4), and non-intensive chemotherapy (HR = 1.8) were associated with non-fatal cardiac events. The 9-year CI of grade 1-2 QTcF prolongation was 11.2%, grade 3 was 2.7%, and no patient had grade 4-5 events. The 9-year CI of grade 1-2 cardiac failure was 1.3%, grade 3-4 was 15%, and grade 5 was 2.1%; of grade 1-2, arrhythmia was 1.9%, grade 3-4 was 9.1%, and grade 5 was 1%. Among 285 intensive therapy patients, median overall survival decreased in those experiencing grade 3-4 cardiac events (
< 0.001). We observed a high incidence of cardiac toxicity associated with significant mortality in AML.
Cytarabine is considered the most effective chemotherapeutic option in acute myeloid leukemia (AML). The impact of 10 polymorphisms in cytarabine metabolic pathway genes were evaluated in 225 adult ...de novo AML patients. Variant alleles of DCK rs2306744 and CDA rs602950 showed higher complete remission (p = .024, p = .045), with lower survival rates for variant alleles of CDA rs2072671 (p = .015, p = .045, p = .032), rs3215400 (p = .033) and wild-type genotype of rs602950 (p = .039, .014). Induction death (p = .033) and lower survival rates (p = .021, p = .047) were correlated to RRM1 rs9937 variant allele. In addition, variant alleles of CDA rs532545 and rs602950 were related to skin toxicity (p = .031, p = .049) and mucositis to DCK rs2306744 minor allele (p = .046). Other toxicities associated to variant alleles were hepatotoxicity to NT5C2 rs11598702 (p = .032), lung toxicity (p = .031) and thrombocytopenia to DCK rs4694362 (p = .046). This study supports the interest of cytarabine pathway polymorphisms regarding efficacy and toxicity of AML therapy in a coherent integrated manner.
Information regarding the impact on healthcare systems of secondary acute myeloid leukemia (sAML) is scarce.
A retrospective review of medical charts identified patients aged 60-75 years with sAML ...between 2010 and 2019. Patient information was collected from diagnosis to death or last follow-up. Outpatient resource use, reimbursement, frequency and duration of hospitalization, and transfusion burden were assessed. Forty-six patients with a median age of 64 years were included. Anthracycline plus cytarabine regimens were the most common induction treatment (39 patients, 85%). The ratio of the total days hospitalized between the total follow-up was 29%, with a sum of 204 hospitalizations (average four/patient; average duration 21 days). The total average reimbursement was EUR 90,008 per patient, with the majority (EUR 77,827) related to hospital admissions (EUR 17,403/hospitalization). Most hospitalizations (163, mean 22 days) occurred in the period before the first allogeneic hematopoietic stem cell transplant (alloHSCT), costing EUR 59,698 per patient and EUR 15,857 per hospitalization. The period after alloHSCT (in only 10 patients) had 41 hospitalizations (mean 21 days), and a mean reimbursement cost of EUR 99,542 per patient and EUR 24,278 per hospitalization. In conclusion, there is a high consumption of economic and healthcare resources in elderly patients with sAML receiving active treatments in Spain.
This retrospective study investigated outcomes of 404 patients with relapsed/refractory (R/R) FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) acute myeloid leukemia (AML) enrolled ...in the PETHEMA registry, pre-approval of tyrosine kinase inhibitors. Most patients (63%) had received first-line intensive therapy with 3 + 7. Subsequently, patients received salvage with intensive therapy (n = 261), non-intensive therapy (n = 63) or supportive care only (n = 80). Active salvage therapy (i.e., intensive or non-intensive therapy) resulted in a complete remission (CR) or CR without hematological recovery (CRi) rate of 42%. More patients achieved a CR/CRi with intensive (48%) compared with non-intensive (19%) salvage therapy (p < 0.001). In the overall population, median overall survival (OS) was 5.5 months; 1- and 5-year OS rates were 25% and 7%. OS was significantly (p < 0.001) prolonged with intensive or non-intensive salvage therapy compared with supportive therapy, and in those achieving CR/CRi versus no responders. Of 280 evaluable patients, 61 (22%) had an allogeneic stem-cell transplant after they had achieved CR/CRi. In conclusion, in this large cohort study, salvage treatment approaches for patients with FLT3-ITD mutated R/R AML were heterogeneous. Median OS was poor with both non-intensive and intensive salvage therapy, with best long-term outcomes obtained in patients who achieved CR/CRi and subsequently underwent allogeneic stem-cell transplant.
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