Intensive timed sequential remission induction chemotherapy with high-dose cytarabine for childhood acute myeloid leukemia

2001 ◽  
Vol 37 (4) ◽  
pp. 365-371 ◽  
Author(s):  
David M. Loeb ◽  
Daniel C. Bowers ◽  
Curt I. Civin ◽  
Alan D. Friedman
Keyword(s):  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Remission Induction ◽  
High Dose ◽  
High Dose Cytarabine ◽  
Childhood Acute Myeloid Leukemia ◽  
Acute Myeloid

Impact of high-dose cytarabine and asparaginase intensification on childhood acute myeloid leukemia: a report from the Childrens Cancer Group.

1993 ◽  
Vol 11 (3) ◽  
pp. 538-545 ◽  
Author(s):  
R J Wells ◽  
W G Woods ◽  
B C Lampkin ◽  
M E Nesbit ◽  
J W Lee ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Maintenance Therapy ◽  
Myeloid Leukemia ◽  
Survival Rates ◽  
Remission Induction ◽  
High Dose ◽  
Cancer Group ◽  
High Dose Cytarabine ◽  
Childhood Acute Myeloid Leukemia ◽  
Acute Myeloid

PURPOSE The purpose of this review was to determine the impact of high-dose cytarabine and asparaginase intensification, administered shortly after remission induction, on the outcome of childhood acute myeloid leukemia (AML). MATERIALS AND METHODS Three consecutive Childrens Cancer Group (CCG) trials of acute myeloid leukemia, CCG 251 (1979 to 1983), CCG 213P (1983 to 1985), and CCG 213 (1985 to 1989) with a total of 1,294 patients, were reviewed and provide the basis of this report. RESULTS CCG 213P demonstrated the importance of dose interval, in that two courses of cytarabine and asparaginase administered at 7-day intervals gave superior 5-year survival rates (58% v 41% from the end of induction, P < .04) to the same therapy administered at 28-day intervals. CCG 213 showed that there was no advantage to the maintenance therapy used for patients who received two courses of cytarabine and asparaginase at 7-day intervals (5-year survival, 68% [no maintenance] v 44% [maintenance] from the end of consolidation, P < .01). Inclusion of the 7-day interval cytarabine/asparaginase intensification was accompanied by an overall improvement in 5-year survival rates from diagnosis when compared with historical controls (CCG 213, 36% v CCG 251, 29%, P < .02) although other differences between these studies could also be responsible for the improvement seen. CONCLUSION High-dose cytarabine and asparaginase intensification eliminated the benefit of prolonged maintenance therapy in childhood AML and was accompanied by an overall improvement in survival.

Optimizing Cardiovascular Care in Children With Acute Myeloid Leukemia to Improve Cancer-Related Outcomes

2019 ◽  
Vol 37 (1) ◽  
pp. 1-6 ◽  
Author(s):  
Saro H. Armenian ◽  
Matthew J. Ehrhardt
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Systolic Function ◽  
Left Ventricular ◽  
Laboratory Evaluation ◽  
Remission Induction ◽  
High Dose ◽  
High Dose Cytarabine ◽  
Lv Systolic Function ◽  
Acute Myeloid

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 14-year-old African American female presented with fatigue, easy bruising, and fever. On examination, she had scattered bruising, lymphadenopathy, and hepatosplenomegaly. Laboratory evaluation revealed pancytopenia with peripheral blasts, and acute myeloid leukemia (AML; French-American-British M2, t[8;21][q22;q22.1]) was diagnosed on bone marrow biopsy. A baseline echocardiogram revealed normal left ventricular (LV) systolic function (ejection fraction [EF], 60%; shortening fraction [SF], 32%), and conventional chemotherapy was initiated that consisted of two cycles of remission induction (cytarabine, etoposide, and daunorubicin [50 mg/m2 × 3 days per cycle]) followed by intensification 1 (high-dose cytarabine and etoposide), intensification 2 (high-dose cytarabine and mitoxantrone [12 mg/m2/dose daily; four total doses]), and intensification 3 (high-dose cytarabine and l-asparaginase). Of note, an echocardiogram was not repeated before the start of intensification 1. During intensification 1, the patient developed Streptococcus viridans sepsis, which required 4 days in the intensive care unit with antimicrobial and inotropic support. Repeat echocardiogram after recovery from the sepsis episode demonstrated low-normal LV systolic function (EF, 53%; SF, 27%), and she subsequently began intensification 2. On day 3 of intensification 2, the patient developed afebrile tachypnea, tachycardia, and an increasing oxygen requirement. Chest x-ray revealed cardiomegaly and pulmonary vascular congestion. Cardiac troponins were normal, whereas N-terminal pro B-type natriuretic peptide was 10 times the upper limit of normal. Repeat echocardiogram showed an enlarged LV with moderate to severely depressed LV function (EF, 28%; SF, 14%). Day 4 mitoxantrone was omitted and a cardiology consult obtained.

Incidence and Prognostic Factors for Infectious and Hemorrhagic Death in Patients with Acute Myeloid Leukemia: A Single-Centre Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4300-4300 ◽  
Author(s):  
Pau Montesinos ◽  
Guillermo Martin ◽  
Ninotchka Mendoza ◽  
Jesus Martinez ◽  
Federico Moscardo ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Multivariate Analysis ◽  
Prognostic Factors ◽  
Induction Chemotherapy ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Remission Induction ◽  
High Dose ◽  
Induction Failure ◽  
Acute Myeloid

Abstract INTRODUCTION: Death is as a common cause of remission induction failure in patients with acute myeloid leukemia (AML), mainly due to hemorrhage and infection. The relative incidence and chronology of each of these categories of induction failure, as well as their prognostic factors, have been investigated critically and in detail in rare studies only. OBJECTIVES: We report the incidence, chronology, and prognostic factors for induction death, analyzing separately hemorrhagic and infectious death, in a large series of 946 patients with AML who received induction therapy in a single institution over the last 30 years. PATIENTS AND METHODS: Adult patients were consecutively diagnosed of AML and started first induction chemotherapy in our institution. AML was classified according to the FAB criteria. Induction therapy consisted of the classic combination of cytarabine and anthracyclines (with or without a third agent) in 50% of patients, cytarabine plus adriamicine and thioguanine or vincristine in 17%, ATRA with chemotherapy in 9%, monochemotherapy with anthracycline in 7%, high dose cytarabine in 7%, and other regimens in 10%. Causes of induction death include the following categories: Infection, when death was due to a clinical, radiological or microbiologically documented infection, Hemorrhage, when a major bleeding occured in a vital organ (central nervous system, lungs). Gastrointestinal hemorrhage required massive melena or hematemesis accompanied by fall in blood pressure, and Other, i.e., any other cause not classified as infection or hemorrhage. RESULTS: From 1977 to 2007, 946 consecutive patients with diagnosis of AML received induction chemotherapy, 24% in the period 1 (1977–1986), 28% in the period 2 (1987–1993), 28% in the period 3 (1994–2000), and 20% in the period 4 (2001–2007). Median age was 55 years (range 13–83 years). One hundred and sixty-seven patients (18%) had antecedents of myelodysplastic/myeloprolipherative disease (10%) or other neoplasia (8%). Two hundred and thirty-seven patients (25%) died during induction therapy, 13% due to infection, 7% due to hemorrhage, 2% due to hemorrhage and infection, and 3% due to other causes. The induction mortality rates decreased gradually over the 4 periods (31% vs 24% vs 18% vs 18%), due to reduction of both hemorrhagic and non-hemorrhagic deaths. Overall, 42% of hemorrhagic deaths occurred within the first 10 days of induction therapy, whereas 86% of infectious deaths occurred after 10 days. In multivariate analysis, the following characteristics had an unfavorable impact on overall induction mortality: age >60 years, WBC >50x109/L, Quick index <65%, ECOG >1, and albumin serum levels <3.5mg/dL. Multivariate analysis identified the following factors predicting for infectious mortality: albumin <3.5mg/dL, age >50 years, AML secondary to neoplasia, ECOG >1, and fever at presentation. The following factors were associated with hemorrhagic mortality: WBC >50x109/L, FAB-M3, age >60 years, de novo AML, and ECOG >1. CONCLUSIONS: The main causes of induction death in AML patients, infection and hemorrhage, shows a different chronologic pattern and can be separately predicted by their own specific prognostic factors.

Optimization of Chemotherapy for Younger Patients With Acute Myeloid Leukemia: Results of the Medical Research Council AML15 Trial

2013 ◽  
Vol 31 (27) ◽  
pp. 3360-3368 ◽  
Author(s):  
Alan K. Burnett ◽  
Nigel H. Russell ◽  
Robert K. Hills ◽  
Ann E. Hunter ◽  
Lars Kjeldsen ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Remission Induction ◽  
High Dose ◽  
Younger Patients ◽  
High Risk Patients ◽  
High Dose Cytarabine ◽  
Risk Patients ◽  
Acute Myeloid

Purpose Treatment outcomes in younger patients with acute myeloid leukemia (AML) have improved, but optimization and new combinations are needed. We assess three combinations in induction and consolidation. Patients and Methods Younger untreated patients with AML (median age, 49 years; range, 0 to 73 years) were randomly allocated to two induction courses of daunorubicin and cytarabine (DA) with or without etoposide (ADE; n = 1983) or ADE versus fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-Ida; n = 1268), and to amsacrine, cytarabine, etoposide, and then mitoxantrone/cytarabine (MACE-MidAC) or high-dose cytarabine (n = 1,445) 3 g/m2 or 1.5 g/m2 (n = 657) in consolidation, and finally to a fifth course (cytarabine) or not (n = 227). Results Overall remission rates were similar for DA versus ADE (84% v 86%; P = .14) and ADE versus FLAG-Ida (86% v 85%; P = .7), with more course 1 remissions after FLAG-Ida (77%) reducing relapse (38% v 55%; P < .001) and improving relapse-free survival (45% v 34%; P = .01), overall and in subgroups, but with increased myelosuppression, reducing participation in the consolidation randomization. Overall outcomes were similar between MACE/MidAc and high-dose cytarabine (1.5/3.0 g/m2), but cytarabine required less supportive care. MACE/MidAc was superior for high-risk patients. A fifth course provided no benefit. The outcome for recipients of only two FLAG-Ida courses were not different from that with DA/ADE with consolidation. Conclusion FLAG-Ida is an effective remission induction treatment, with a high complete remission rate after course 1 and reduced relapse. Consolidation with MACE/MidAc is similar overall to high-dose cytarabine, but superior in high-risk patients. Cytarabine at 1.5 g/m2 is equivalent to a 3 g/m2 dose. A fifth course is unnecessary. In patients receiving FLAG-Ida (two courses) and cytarabine (two courses), 8-year survival was 63% for patients with intermediate-risk and 95% for those with favorable-risk disease.

scholarly journals Clofarabine Can Replace Anthracyclines and Etoposide in Remission Induction Therapy for Childhood Acute Myeloid Leukemia: The AML08 Multicenter, Randomized Phase III Trial

2019 ◽  
Vol 37 (23) ◽  
pp. 2072-2081 ◽  
Author(s):  
Jeffrey E. Rubnitz ◽  
Norman J. Lacayo ◽  
Hiroto Inaba ◽  
Kenneth Heym ◽  
Raul C. Ribeiro ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Survival Rate ◽  
Myeloid Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Residual Disease ◽  
Phase Iii ◽  
Remission Induction ◽  
High Dose ◽  
Childhood Acute Myeloid Leukemia ◽  
Acute Myeloid

PURPOSE To identify effective and less toxic therapy for children with acute myeloid leukemia, we introduced clofarabine into the first course of remission induction to reduce exposure to daunorubicin and etoposide. PATIENTS AND METHODS From 2008 through 2017, 285 patients were enrolled at eight centers; 262 were randomly assigned to receive clofarabine and cytarabine (Clo+AraC, n = 129) or high-dose cytarabine, daunorubicin, and etoposide (HD-ADE, n = 133) as induction I. Induction II consisted of low-dose ADE given alone or combined with sorafenib or vorinostat. Consolidation therapy comprised two or three additional courses of chemotherapy or hematopoietic cell transplantation. Genetic abnormalities and the level of minimal residual disease (MRD) at day 22 of initial remission induction determined final risk classification. The primary end point was MRD at day 22. RESULTS Complete remission was induced after two courses of therapy in 263 (92.3%) of the 285 patients; induction failures included four early deaths and 15 cases of resistant leukemia. Day 22 MRD was positive in 57 of 121 randomly assigned evaluable patients (47%) who received Clo+AraC and 42 of 121 patients (35%) who received HD-ADE (odds ratio, 1.86; 95% CI, 1.03 to 3.41; P = .04). Despite this result, the 3-year event-free survival rate (52.9% [44.6% to 62.8%] for Clo+AraC v 52.4% [44.0% to 62.4%] for HD-ADE, P = .94) and overall survival rate (74.8% [67.1% to 83.3%] for Clo+AraC v 64.6% [56.2% to 74.2%] for HD-ADE, P = .1) did not differ significantly across the two arms. CONCLUSION Our findings suggest that the use of clofarabine with cytarabine during remission induction might reduce the need for anthracycline and etoposide in pediatric patients with acute myeloid leukemia and may reduce rates of cardiomyopathy and treatment-related cancer.

scholarly journals Clinical Impact of an Accurate Genetic Characterization of Older Acute Myeloid Leukemia Patients: A Report from the Northern Italy Leukemia Group (NILG) Randomized Trial 02/06

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 434-434
Author(s):  
Chiara Caprioli ◽  
Tamara Intermesoli ◽  
Orietta Spinelli ◽  
Silvia Salmoiraghi ◽  
Pamela Zanghì ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Risk Stratification ◽  
Myeloid Leukemia ◽  
Genetic Characterization ◽  
Remission Induction ◽  
High Dose ◽  
Cell Transplant ◽  
High Dose Cytarabine ◽  
Acute Myeloid

Abstract Introduction In acute myeloid leukemia (AML) older age is independently associated with poor outcome, due to patient- and disease-related factors. Different genetic profiles characterize AML patients and their frequency varies according to age. Their identification can improve early risk stratification to select the most appropriate therapy, including alternative, not chemotherapy based, treatment modalities, such as hypomethylating and targeted agents (Döhner H et al., Blood 2017). We analyzed the clinical outcome of AML patients aged ≥60 years who were enrolled in the randomized multicentric trial NILG 02/06, and were deeply genetically characterized (Clinical Trials.gov Identifier: NCT00495287). Patients and Methods Five hundred seventy-four newly diagnosed AML patients were enrolled into the study and 168 were aged ≥60 years; all patients were randomized to receive conventional induction chemotherapy with idarubicin, cytarabine and etoposide (ICE) or sequential high-dose cytarabine and idarubicin (sHD), followed by consolidation courses with high dose cytarabine (Bassan R et al., annual congress EHA. Jun 9, 2016, abstr S485). Genetic characterization at diagnosis was obtained by conventional cytogenetics and RT-PCR for 145 and 168 patients, respectively, while Next Generation Sequencing was performed for 51 patients with normal karyotype. Patients were re-classified as per the 2017 European Leukemia Net (ELN) guidelines (Döhner H et al., Blood 2017). A myelodysplastic/myeloproliferative (MDS/MPN) related genetic signature was defined according to cytogenetic WHO criteria and/or molecular abnormalities known to be associated with MDS/MPN (Bullinger L et al., J Clin Oncol 2017) and used for outcome correlation. Results The characteristics of patients are summarized in Table 1. According to the ELN risk stratification, patients were classified as favorable, intermediate or adverse risk (23%, 38% and 39% of patients, respectively). A genetic MDS/MPN signature was demonstrated in 42% of patients (63/149), which was a higher proportion compared to that of patients with a clinical diagnosis of an antecedent MDS/MPN (19% of patients, 32/168). No significant difference was observed between the induction regimens regarding the achievement of complete remission (CR) (71% for sHD and 61% for ICE, P=0.23) and early death rate (12% and 10.6%, P=0.96). After achieving CR, a median of 2 consolidation courses was administered (range 1-5) within both treatment arms. A limited proportion of patients with high-risk genetic or clinical features (14%) had the opportunity to undergo an allogeneic hematopoietic stem cell transplant (alloHSCT), the majority of them (63%) receiving a reduced intensity conditioning. By intention to treat, 5-years overall survival (OS) and disease- free survival (DFS) on the whole study population were 29% and 32% respectively, without significant differences between the remission induction treatment (for sHD and ICE, OS: 29% and 28%, P=0.88; DFS: 34% and 29%, P=0.90). According to the ELN risk stratification, 5-years OS was 68%, 25% and 7% for favorable, intermediate and adverse groups (P<0.0001), while 3-years DFS was 73%, 28% and 13% (P<0.0001) (Figure 1A). According to the presence or absence of a MDS/MPN signature at diagnosis, 5-years OS was 11% vs 41% (P=0.0001) while 3-years DFS was 12% vs 49% (P<0.0001) (Figure 1B). AlloHSCT was associated with a significant benefit in terms of 5-years OS (57% vs 25%, P=0.0162) and DFS (53% vs 26%, P=0.0363) (Figure 1C). As expected, age had also an impact, with patients aged 60-64 years performing better than patients aged ≥65 years (5-years OS 38% vs 13%, P=0.003; 5-years DFS 43% vs 10%, P=0.002). Conclusions Older AML patients with favorable risk features according to ELN benefit from standard chemotherapy. The definition of an adverse genetic risk profile and particularly of a MDS/MPN signature is crucial to identify patients who have a very dismal outcome. These patients should be considered for alternative, innovative treatment options. In high-risk, ≥60 years old AML patients with a good performance status, alloHSCT significantly improves both OS and DFS and should always be considered as the most effective post consolidation treatment. Disclosures Cattaneo: GILEAD: Other: Advisory Board. Cortelezzi:janssen: Consultancy; novartis: Consultancy; abbvie: Consultancy; roche: Consultancy. Rambaldi:Italfarmaco: Consultancy; Omeros: Consultancy; Roche: Consultancy; Amgen Inc.: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Celgene: Consultancy.

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