Neutropenic fever and severe sepsis in adult acute myeloid leukemia (AML) patients receiving intensive chemotherapy: Causes and consequences

Hämäläinen, Sari; Kuittinen, Taru; Matinlauri, Irma; Nousiainen, Tapio; Koivula, Irma; Jantunen, Esa

doi:10.1080/10428190701809172

Cited by 65 publications

(53 citation statements)

References 27 publications

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“…Rates of enasidenib-related grade 3-4 hematologic TEAEs (10%) and infections (1%) were low compared with other AML treatments, for which rates can range from 20-90%. [26][27][28][29] IDH-DS was reported for 10% of patients, which is less frequent than rates of differentiation syndrome reported for patients with acute promyelocytic leukemia treated with all-trans retinoic acid (ATRA) (~25% 30 ). 31,32 IDH-DS has also been reported in patients receiving ivosidenib.…”

Section: Discussionmentioning

confidence: 83%

“…A multicenter, randomized phase 1 5 AML classification, a n (%) N=213 (89) Myelodysplasia-related changes 27 (25) 45 (26) 57 (27) Recurrent genetic abnormalities 7 (6) 15 (9) 17 (8) Therapy-related myeloid neoplasms 1 (<1) 2 (1) Antecedent history of MDS, n (%) 17 (16) 30 (17) 30 (13) Prior stem cell transplantation, n (%) 12 (11) 24 (14) 28 (12) ECOG performance status, e n (%) 0 25 (23) 39 (22) 55 (23 A treatment-related TEAE was defined as any event that began or worsened on or after the start of enasidenib use until 28 days after the last dose, and was considered by the treating physician to be possibly or probably related to enasidenib. TEAEs were coded using the MedDRA dictionary version 16.0 a Includes the preferred terms: hyperbilirubinemia, blood bilirubin increased b Preferred term, "retinoic acid syndrome" c Includes the preferred terms: thrombocytopenia, platelet count decreased 1 For personal use only.…”

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confidence: 99%

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Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia

Stein

DiNardo

Pollyea

et al. 2017

Blood

1,231

954

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Key Points• Enasidenib, a selective inhibitor of mutant-IDH2 enzymes, was safe and welltolerated in patients with IDH2-mutated myeloid malignancies.• Enasidenib induced hematologic responses in patients with relapsed/refractory AML in this dose-escalation and expansion study. ABSTRACTRecurrent mutations in isocitrate dehydrogenase 2 (IDH2) occur in ~12% of patients with acute myeloid leukemia (AML). Mutated IDH2 proteins neomorphically synthesize 2-hydroxyglutarate resulting in DNA and histone hypermethylation, leading to blocked cellular differentiation. Enasidenib (AG-221/CC-90007) is a first-in-class, oral, selective inhibitor of mutant-IDH2 enzymes. This first-in-human, phase 1/2 study assessed the maximum tolerated dose (MTD), pharmacokinetic and pharmacodynamic profiles, safety, and clinical activity of enasidenib in patients with mutant-IDH2 advanced myeloid malignancies. We assessed safety outcomes for all patients (N=239) and clinical efficacy in the largest patient subgroup, those with relapsed or refractory AML (n=176), from the phase 1 dose-escalation and expansion phases of the study. In the doseescalation phase, an MTD was not reached at doses ranging from 50-650 mg daily.Enasidenib 100 mg daily was selected for the expansion phase based on pharmacokinetic and pharmacodynamic profiles and demonstrated efficacy. Grade 3-4 enasidenib-related adverse events included indirect hyperbilirubinemia (12%) and IDHinhibitor-associated differentiation syndrome (IDH-DS; 7%). Among patients with relapsed or refractory AML, overall response rate was 40.3%, with median response duration of 5.8 months. Responses were associated with cellular differentiation and maturation, typically without evidence of aplasia. Median overall survival among relapsed/refractory patients was 9.3 months, and for the 34 patients (19.3%) who attained complete remission was 19.7 months. Continuous daily enasidenib treatment was generally well-tolerated and induced hematologic responses in patients who had failed prior AML therapy. Inducing differentiation of myeloblasts, not cytotoxicity, appears to drive the clinical efficacy of enasidenib.

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Section: Discussionmentioning

confidence: 83%

mentioning

confidence: 99%

Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia

Stein

DiNardo

Pollyea

et al. 2017

Blood

1,231

954

View full text Add to dashboard Cite

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“…Indeed, more than half of our patients were admitted to the ICU due to infectious complications, such as septicemia, and respiratory failure known to be mostly of infectious origin. 28,[29][30][31] Interestingly, other disease-and patient-related factors including age, FAB subtype, and the karyotype, all known to be correlated with long-term survival, were not associated with ICU admission. Our findings underline the importance of tight adherence to guidelines concerning the prevention and treatment of infectious complications in patients with hematologic malignancies.…”

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confidence: 98%

Prognostic factors for intensive care unit admission, intensive care outcome, and post-intensive care survival in patients with de novo acute myeloid leukemia: a single center experience

Schellongowski¹,

Staudinger²,

Kundi³

et al. 2010

Haematologica

114

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BackgroundAcute myeloid leukemia is a life-threatening disease associated with high mortality rates. A substantial number of patients require intensive care. This investigation analyzes risk factors predicting admission to the intensive care unit in patients with acute myeloid leukemia eligible for induction chemotherapy, the outcome of these patients, and prognostic factors predicting their survival. Design and MethodsA total of 406 consecutive patients with de novo acute myeloid leukemia (15-89 years) were analyzed retrospectively. Markers recorded at the time of diagnosis included karyotype, fibrinogen, C-reactive protein, and Charlson comorbidity index. In patients requiring critical care, the value of the Simplified Acute Physiology Score II, the need for mechanical ventilation, and vasopressor support were recorded at the time of intensive care unit admission. The independent prognostic relevance of the parameters was tested by multivariate analysis. ResultsSixty-two patients (15.3%) required intensive care, primarily due to respiratory failure (50.0%) or life-threatening bleeding (22.6%). Independent risk factors predicting intensive care unit admission were lower fibrinogen concentration, the presence of an infection, and comorbidity. The survival rate was 45%, with the Simplified Acute Physiology Score II being the only independent prognostic parameter (P<0.05). Survival was inferior in intensive care patients compared to patients not admitted to an intensive care unit. However, no difference between intensive care and non-intensive care patients was found concerning continuous complete remission at 6 years or survival at 6 years in patients who survived the first 30 days after diagnosis (nonintensive care patients: 28%; intensive care patients: 20%, P>0.05). ConclusionsOngoing infections, low fibrinogen and comorbidity are predictive for intensive care unit admission in acute myeloid leukemia. Although admission was a risk factor for survival, continuous complete remission and survival of patients alive at day 30 were similar in patients who were admitted or not admitted to an intensive care unit.Key words: acute myeloid leukemia, intensive care unit, outcome, infection.Citation: Schellongowski P, Staudinger T, Kundi M, Laczika K, Locker GJ, Bojic A, Robak O, Fuhrmann V, Jäger U, Valent P, and Sperr WR. Prognostic IntroductionAcute myeloid leukemia (AML) is a life-threatening stem cell disorder characterized by rapid and uncontrolled proliferation and accumulation of myeloblasts.1,2 The prognosis and clinical course of AML differs among patients depending on specific molecular and cytogenetic properties of the clone.1-9 Moreover, apart from diseaseassociated features, patient-related factors including age and pre-or co-existing diseases (comorbidity) are of prognostic importance. 1,[10][11][12] Although the rate of complete remission in AML patients is relatively high (ranging between 60 and 75%), only a small percentage of patients are permanently cured. [12][13][14] Patients with AML usually pres...

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“…1,2 Among patients with febrile neutropenia, early identification of those developing severe sepsis or septic shock is difficult, even with using the biomarkers available. 3 New tools are needed to predict unfavorable outcome at an early stage of the course of febrile neutropenia.…”

Section: Introductionmentioning

confidence: 99%

High pentraxin 3 level predicts septic shock and bacteremia at the onset of febrile neutropenia after intensive chemotherapy of hematologic patients

Vänskä¹,

Koivula²,

Hämäläinen³

et al. 2011

Haematologica

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We evaluated pentraxin 3 as a marker for complications of neutropenic fever in 100 hematologic patients receiving intensive chemotherapy. Pentraxin 3 and C-reactive protein were measured at fever onset and then daily to day 3. Bacteremia was observed in 19 patients and septic shock in 5 patients (three deaths). In comparison to C-reactive protein, pentraxin 3 achieved its maximum more rapidly. Pentraxin 3 correlated not only with the same day C-reactive protein but also with the next day C-reactive protein.High pentraxin 3 on day 0 was associated with the development of septic shock (P=0.009) and bacteremia (P=0.046). The non-survivors had constantly high pentraxin 3 levels. To conclude, pentraxin 3 is an early predictor of complications in hematologic patients with neutropenic fever. High level of pentraxin 3 predicts septic shock and bacteremia already at the onset of febrile neutropenia. Haematologica 2011;96(9):1385-1389. doi:10.3324/haematol.2011 This is an open-access paper. ABSTRACTIn this 3-year prospective study, we compared the long PTX3 with C-reactive protein as a biomarker in predicting complications (bacteremia and septic shock) among 100 hematologic patients with febrile neutropenia after intensive chemotherapy.

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Neutropenic fever and severe sepsis in adult acute myeloid leukemia (AML) patients receiving intensive chemotherapy: Causes and consequences

Cited by 65 publications

References 27 publications

Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia

Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia

Prognostic factors for intensive care unit admission, intensive care outcome, and post-intensive care survival in patients with de novo acute myeloid leukemia: a single center experience

High pentraxin 3 level predicts septic shock and bacteremia at the onset of febrile neutropenia after intensive chemotherapy of hematologic patients

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