Predicting severe toxicities with intensive induction chemotherapy for adult acute myeloid leukemia: analysis of SWOG Cancer Research Network trials S0106 and S1203.
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ABSTRACT:
SUBMITTER: Moseley A
PROVIDER: S-EPMC8282671 | biostudies-literature | 2021 Jul
REPOSITORIES: biostudies-literature
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Predicting severe toxicities with intensive induction chemotherapy for adult acute myeloid leukemia: analysis of SWOG Cancer Research Network trials S0106 and S1203.
Moseley Anna A Othus Megan M Garcia-Manero Guillermo G Appelbaum Frederick R FR Erba Harry P HP Walter Roland B RB
Leukemia & lymphoma 20210209 7
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Project description:To improve patient quality of life and reduce health care costs, many conditions formerly thought to require inpatient care are now treated in the outpatient setting. Outpatient induction chemotherapy for acute myeloid leukemia (AML) may confer similar benefits. This possibility prompted a pilot study to explore the safety and feasibility of intensive outpatient initial or salvage induction chemotherapy administration for adults with AML and high-risk myelodysplastic syndrome (MDS). Patients with no significant organ dysfunction and a treatment-related mortality (TRM) score corresponding to a day 28 mortality rate of <5% to 10% were eligible for study. Patients were treated as outpatients with daily evaluation by providers and only admitted to the hospital if mandated by complications. Twenty patients were consented, and 17 were treated. Eight patients received initial induction chemotherapy and 9 received salvage induction chemotherapy. Fourteen patients completed induction chemotherapy administration in the outpatient setting (82.4%; exact 95% confidence interval [CI], 55.8-95.3). Three patients were admitted during the course of chemotherapy administration, 2 for neutropenic fever and 1 for grade 3 mucositis. No patients died within 14 days of the initiation of induction chemotherapy (exact 95% CI, 0-22.9). Results of this pilot study suggest it is feasible to complete outpatient induction chemotherapy in select patients with AML and high-risk MDS. A team including nurses, social workers, medical providers, and pharmacists was key to the successful implementation of outpatient induction.
| S-EPMC7042997 | biostudies-literature
Project description:Due to infectious and bleeding risks, adults with acute myeloid leukemia or high-risk myelodysplastic syndromes typically remain hospitalized after remission induction chemotherapy until blood count recovery. Here, we explored the medical and financial effects of discharge immediately after chemotherapy completion with close outpatient follow up. Within 12 months, 15 patients fulfilling both medical and logistical criteria were discharged early, whereas 5 patients meeting medical criteria only served as inpatient controls. No patient died. Patients discharged early spent a median of 8 days (range 3-36 days), or 54% of their study time, as outpatients. These patients required less time on intravenous antibiotics (6 vs. 16 days; P=0.11), received fewer red blood cell transfusions (0.25 vs. 0.48 units/day; P=0.08), and incurred lower median daily charges ($3,270 vs. $5,467; P=0.01) than controls. Thus, early discharge of selected patients appears, safe and may reduce cost and resource utilization. (ClinicalTrials.gov Identifier: NCT00844441).
| S-EPMC3105654 | biostudies-literature
Project description:Acute myeloid leukemia (AML) is a rare yet deadly cancer of the blood and bone marrow. Presently, induction chemotherapy with the DNA damaging drugs cytarabine (ARA-C) and idarubicin (IDA), known as 7 + 3, is the standard of care for most AML patients. However, 7 + 3 is a relatively ineffective therapy, particularly in older patients, and has serious therapy-related toxicities. Therefore, a diagnostic test to predict which patients will respond to 7 + 3 is a critical unmet medical need. We hypothesize that a threshold level of therapy-induced 7 + 3 drug-DNA adducts determines cytotoxicity and clinical response. We further hypothesize that in vitro exposure of AML cells to nontoxic diagnostic microdoses enables prediction of the ability of AML cells to achieve that threshold during treatment. Our test involves dosing cells with very low levels of 14C-labeled drug followed by DNA isolation and quantification of drug-DNA adducts via accelerator mass spectrometry. Here, we have shown proof of principle by correlating ARA-C- and DOX-DNA adduct levels with cellular IC50 values of paired sensitive and resistant cancer cell lines and AML cell lines. Moreover, we have completed a pilot retrospective trial of diagnostic microdosing for 10 viably cryopreserved primary AML samples and observed higher ARA-C- and DOX-DNA adducts in the 7 + 3 responders than nonresponders. These initial results suggest that diagnostic microdosing may be a feasible and useful test for predicting patient response to 7 + 3 induction chemotherapy, leading to improved outcomes for AML patients and reduced treatment-related morbidity and mortality.
| S-EPMC6387632 | biostudies-literature
Project description:Intensive chemotherapy for newly diagnosed acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) is associated with significant treatment-related morbidity and mortality. Herein, we investigate how pretreatment characteristics relate to early adverse outcomes in such patients, studying 205 consecutive individuals receiving curative-intent induction chemotherapy with cytarabine and an anthracycline ("7 + 3"; n?= 175) or a "7 + 3"-like regimen (n?=?30). Among the entire cohort, baseline grade 4 neutropenia (i.e., absolute neutrophil count <500 cells/µL) was associated with development of fever (P?=?0.04), documented infection (P < 0.0001), and bacteremia (P = 0.002) but not requirement for intensive care unit-level care; after exclusion of the 30 patients who received "7?+?3"-like induction, baseline grade 4 neutropenia remained associated with documented infection (P < 0.0001) and bacteremia (P = 0.0005). Among patients achieving a complete remission with the initial treatment cycle, grade 4 neutropenia was associated with delayed neutrophil count recovery (P < 0.0001). Low monocyte and lymphocyte counts at baseline were similarly associated with increased risk of documented infection or bacteremia. After adjustment for age, gender, disease type, cytogenetic/molecular risk, and performance status, the risk of fever, documented infection, or bacteremia was 1.87 (95% confidence interval: 1.04-3.34; P=0.04)-fold, 4.95 (2.20-11.16; P<0.001)-fold, and 3.14 (0.99-9.98; P=0.05)-fold higher in patients with initial grade 4 neutropenia. Together, our studies identify severe baseline neutropenia as a risk factor for infection-associated adverse events after induction chemotherapy and may provide the rationale for the risk-adapted testing of myeloid growth factor support in this high-risk AML/MDS patient subset.
| S-EPMC4391649 | biostudies-other
Project description: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.
| S-EPMC3943310 | biostudies-other
Project description:IntroductionBlood product transfusion retains a critical role in the supportive care of patients with acute myeloid leukemia (AML). Whereas previous studies have shown increased transfusion dependency to portend inferior outcome, predictive factors of an increased transfusion burden and the prognostic impact of transfusion support have not been assessed recently.Methods/patientsWe performed a retrospective analysis on a recent cohort of patients given intensive induction chemotherapy in 2014-2022.ResultsThe analysis comprised 180 patients with a median age of 57 years with 80% designated as de novo AML. Fifty-four patients (31%) were FLT3-ITD mutated, and 73 patients (42%) harbored NPM1. Favorable risk and intermediate risk ELN 2017 patients accounted for 43% and 34% of patients, respectively. The median number of red blood cell (RBC) and platelet units given during induction were 9 and 7 units, respectively. Seventeen patients (9%) received cryoprecipitate, and fresh frozen plasma (FFP) was given to 12 patients (7%). Lower initial hemoglobin and platelet levels were predictive of increased use of RBC (p < 0.0001) and platelet transfusions (p < 0.0001). FFP was significantly associated with induction related mortality (42% vs. 5%; p < 0.0001) and with FLT3-ITD (72% vs. 28%; p = 0.004). Blood group AB experienced improved mean overall survival compared to blood group O patients (4.1 years vs. 2.8 years; p = 0.025). In multivariate analysis, increased number of FFP (hazard ratio [HR], 4.23; 95% confidence interval [CI], 2.1-8.6; p < 0.001) and RBC units (HR, 1.8; 95% CI, 1.2-2.8; p = 0.008) given was associated with inferior survival.ConclusionTransfusion needs during induction crucially impact the clinical trajectory of AML patients.
| S-EPMC10601600 | biostudies-literature
Project description:Progress with intensive chemotherapy and supportive care measures has improved survival in newly diagnosed acute myeloid leukemia (AML). Predicting outcome helps in treatment decision making. We analyzed survival as the treatment endpoint in 3728 patients with newly diagnosed AML treated with intensive chemotherapy from 1980 to 2021. We divided the total study group (3:1 basis) into a training (n = 2790) and a validation group (n = 938). The associations between survival and 27 characteristics were investigated. In the training cohort, the multivariate analysis identified 12 consistent adverse prognostic variables independently associated with worse survival: older age, therapy-related myeloid neoplasm, worse performance status, cardiac comorbidity, leukocytosis, anemia, thrombocytopenia, elevated creatinine and lactate dehydrogenase, cytogenetic abnormalities, and the presence of infection at diagnosis except fever of unknown origin. We categorized patients into four prognostic groups, favorable (7%), intermediate (43%), poor (39%), and very poor (11%) with estimated 5-year survival rates of 69%, 36%, 13%, and 3% respectively (p < .001). The predictive model was validated in an independent cohort. In a subset of patients with molecular mutation profiles, adding the mutation profiles after accounting for the effects of previous factors identified NPM1 (favorable), PTPN11, and TP53 (both unfavorable) mutations as molecular prognostic factors. The new proposed predictive model for survival with intensive chemotherapy in patients with AML is robust and can be used to advise patients regarding their prognosis, to modify therapy in remission (e.g., proposing allogeneic stem cell transplantation in first remission), and to compare outcome and benefits on future investigational therapies.
| S-EPMC11915495 | biostudies-literature
Project description:IntroductionThe global spread of multidrug-resistant organisms (MDRO) complicates treatment and isolation measures in hospitals and has shown to increase mortality. Patients with disease- or therapy-related immunodeficiency are especially at risk for fatal infections caused by MDRO. The impact of MDRO colonization on the clinical course of AML patients undergoing intensive induction chemotherapy-a potentially curative but highly toxic treatment option-has not been systematically studied.Materials & methods312 AML patients undergoing intensive induction chemotherapy between 2007 and 2015 were examined for MDRO colonization. Patients with evidence for MDRO before or during the hospital stay of induction chemotherapy were defined as colonized, patients who never had a positive swab for MDRO were defined as noncolonized.ResultsOf 312 AML patients 90 were colonized and 130 were noncolonized. Colonized patients suffered from significantly more days with fever, spent more days on the intensive care unit and had a higher median C-reactive protein value during the hospital stay. These findings did not result in a prolonged length of hospital stay or an increased mortality rate for colonized patients. However, in a subgroup analysis, patients colonized with carbapenem-resistant enterobacteriaceae (CRE) had a significantly reduced 60- and 90-day, as well as 1- and 2-year survival rates when compared to noncolonized patients.ConclusionOur analysis highlights the importance of intensive MDRO screening especially in patients with febrile neutropenia since persisting fever can be a sign of MDRO-colonization. CRE-colonized patients require special surveillance, since they seem to be at risk for death.
| S-EPMC6343922 | biostudies-literature
Project description:BackgroundAberrant DNA methylation is known to occur in patients with acute myeloid leukemia (AML), whereas methylation signatures and prognostic markers have been proposed. The objective of the current study was to evaluate all CpG sites of the genome and identify prognostic methylation markers for overall survival in patients with AML with normal karyotype (AML-NK).MethodsAML-NK samples from 7 SWOG trials were analyzed using a novel genome-wide approach called "CHARMcox" (comprehensive high-throughput array-based relative methylation analysis combined with the Cox proportional hazards model) controlling for known clinical covariates. CHARMcox was applied to a phase 1 discovery cohort (72 patients) to identify survival-associated methylation regions (SAMRs). Subsequently, using bisulfite pyrosequencing, SAMRs were studied in phase 2 model-building (65 patients) and phase 3 validation (65 patients) cohorts. An independent external cohort from The Cancer Genome Atlas (TCGA) AML study (LAML) was used for further validation (93 patients).ResultsTwo SAMRs, located at the CpG island shores of leucine zipper tumor suppressor 2 (LZTS2) and nuclear receptor subfamily 6 group a member 1 (NR6A1), respectively, were identified. Multivariable analyses demonstrated that hypomethylation of either LZTS2 or NR6A1 was associated with worse overall survival in the SWOG cohort (P<.001). The prognosis was validated in patients with AML-NK from the TCGA-LAML cohort. Methylation values below the median at both markers predicted worse overall survival (SWOG: hazard ratio, 1.89 [P<.001]; and TCGA-LAML: hazard ratio, 2.08 [P=.006]). The C-statistic was 0.71 for both cohorts, and the impact was independent of the Fms-related tyrosine kinase 3 internal tandem duplication (FLT3-ITD) status.ConclusionsThe 2 methylation markers, measurable by clinically applicable assays such as bisulfite pyrosequencing, are promising for risk stratification among patients with AML-NK. Cancer 2017;123:2472-81. © 2017 American Cancer Society.
| S-EPMC5705230 | biostudies-literature
Project description:The progress with intensive chemotherapy and supportive care measures has improved survival in patients with newly diagnosed acute myeloid leukemia (AML). Given the recent development of effective low intensity therapies, an optimal decision on the therapy intensity may improve survival through the avoidance of early mortality. We reviewed the outcome of 3728 patients with newly diagnosed AML who received intensive chemotherapy between August 1980 and May 2020. Intensive chemotherapy was defined as a cumulative cytarabine dose ≥ 700 mg/m2 during induction therapy. We divided the whole cohort into a training and validation group at a 3:1 ratio. The population was divided into a training (2790 patients) and a validation cohort (938 patients). The median age was 55 years (range, 15-99). Among them, 442 patients (12%) had core-binding factor AML. Binary logistic regression identified older age, worse performance status, hyperbilirubinemia, elevated creatinine, hyperuricemia, cytogenetic abnormalities other than CBF and -Y, and pneumonia as adverse prognostic factors for an early 4-week mortality. This risk classification for early mortality was verified in the validation cohort of patients. In the validation cohort of more recently treated patients from 2000 to 2017, the 4-week mortality rates with intensive chemotherapy were 2%, 14%, and 50% in the low-, high-, and very high-risk group, respectively. The mortality rates with low intensity therapies were 3%, 9%, and 20%, respectively. The risk classification guides treatment intensity by the assessment of age, frailty, organ dysfunction, cytogenetic abnormality, and infection to avoid early mortality.
| S-EPMC11809073 | biostudies-literature