Fludarabine and cytosine are less effective than standard ADE chemotherapy in high-risk acute myeloid leukemia, and addition of G-CSF and ATRA are not beneficial: results of the MRC AML-HR randomized trial

Blood ◽  
2006 ◽  
Vol 107 (12) ◽  
pp. 4614-4622 ◽  
Author(s):  
Donald W. Milligan ◽  
Keith Wheatley ◽  
Timothy Littlewood ◽  
Jenny I. O. Craig ◽  
Alan K. Burnett ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Relapse Rate ◽  
Myeloid Leukemia ◽  
Remission Rate ◽  
Disease Free Survival ◽  
High Dose ◽  
Standard Chemotherapy ◽  
All Trans Retinoic Acid ◽  
Acute Myeloid

AbstractThe optimum chemotherapy schedule for reinduction of patients with high-risk acute myeloid leukemia (relapsed, resistant/refractory, or adverse genetic disease) is uncertain. The MRC AML (Medical Research Council Acute Myeloid Leukemia) Working Group designed a trial comparing fludarabine and high-dose cytosine (FLA) with standard chemotherapy comprising cytosine arabinoside, daunorubicin, and etoposide (ADE). Patients were also randomly assigned to receive filgrastim (G-CSF) from day 0 until neutrophil count was greater than 0.5 × 109/L (or for a maximum of 28 days) and all-trans retinoic acid (ATRA) for 90 days. Between 1998 and 2003, 405 patients were entered: 250 were randomly assigned between FLA and ADE; 356 to G-CSF versus no G-CSF; 362 to ATRA versus no ATRA. The complete remission rate was 61% with 4-year disease-free survival of 29%. There were no significant differences in the CR rate, deaths in CR, relapse rate, or DFS between ADE and FLA, although survival at 4 years was worse with FLA (16% versus 27%, P = .05). Neither the addition of ATRA nor G-CSF demonstrated any differences in the CR rate, relapse rate, DFS, or overall survival between the groups. In conclusion these findings indicate that FLA may be inferior to standard chemotherapy in high-risk AML and that the outcome is not improved with the addition of either G-CSF or ATRA.

Analysis of Efficacy and Prognostic Factors of CLAG Treatment in Chinese Patients with Refractory or Relapsed Acute Myeloid Leukemia

2018 ◽  
Vol 141 (1) ◽  
pp. 43-53 ◽  
Author(s):  
Li Wang ◽  
Jun Xu ◽  
Xiaolong Tian ◽  
Tingting Lv ◽  
Guolin Yuan
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Risk Stratification ◽  
Salvage Therapy ◽  
Myeloid Leukemia ◽  
Median Overall Survival ◽  
Remission Rate ◽  
Chinese Patients ◽  
Acute Myeloid

Background/Aims: The aim of this work was to investigate the efficacy and predictive factors of CLAG treatment in refractory or relapsed (R/R) acute myeloid leukemia (AML) patients. Methods: Sixty-seven R/R AML patients were enrolled in this prospective cohort study and treated by a CLAG regimen: 5 mg/m2/day cladribine (days 1–5), 2 g/m2/day cytarabine (days 1–5), and 300 μg/day filgrastim (days 0–5). The median follow-up duration was 10 months. Results: A total of 57 out of 67 patients were evaluable for remission after CLAG therapy, of whom 57.9% achieved a complete remission (CR) and the overall remission rate was 77.2%. The median overall survival (OS) was 10.0 months, with a 1-year OS of 40.3 ± 6.0% and 3-year OS of 16.7 ± 5.7%. CR at first induction after the initial diagnosis was associated with a favorable CR. Age above 60 years, high risk stratification, second or higher salvage therapy, and bone marrow (BM) blasts ≥42.1% were correlated with an unfavorable CR. Secondary disease, age ≥60 years, high risk stratification, and second or higher salvage therapy were associated with worse OS. Patients developed thrombocytopenia (41, 61%), febrile neutropenia (37, 55%), leukopenia (33, 49%), neutropenia (18, 27%), and anemia (9, 13%). Conclusion: CLAG was effective and well tolerated for R/R AML. BM blasts ≥42.1%, age ≥60 years, high risk stratification, and second or higher salvage therapy were independent factors for a poor prognosis.

scholarly journals Distinct clinical and biological characteristics of acute myeloid leukemia with higher expression of long noncoding RNA KIAA0125

2020 ◽  
Author(s):  
Yu-Hung Wang ◽  
Chien-Chin Lin ◽  
Chia-Lang Hsu ◽  
Sheng-Yu Hung ◽  
Chi-Yuan Yao ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Noncoding Rna ◽  
De Novo ◽  
Remission Rate ◽  
Prognostic Significance ◽  
Multivariable Analysis ◽  
Disease Free Survival ◽  
Biological Characteristics ◽  
Acute Myeloid

AbstractExpression of long non-coding RNA KIAA0125 has been incorporated in various gene expression signatures for prognostic prediction in acute myeloid leukemia (AML) patients, yet its functions and clinical significance remain unclear. This study aimed to investigate the clinical and biological characteristics of AML bearing different levels of KIAA0125. We profiled KIAA0125 expression levels in bone marrow cells from 347 de novo AML patients and found higher KIAA0125 expression was closely associated with RUNX1 mutation, but inversely correlated with t(8;21) and t(15;17) karyotypes. Among the 227 patients who received standard chemotherapy, those with higher KIAA0125 expression had a lower complete remission rate, shorter overall survival (OS) and disease-free survival (DFS) than those with lower expression. The prognostic significance was validated in both TCGA and GSE12417 cohorts. Subgroup analyses showed that higher KIAA0125 expression also predicted shorter DFS and OS in patients with normal karyotype or non-M3 AML. In multivariable analysis, higher KIAA0125 expression remained an adverse risk factor independent of age, WBC counts, karyotypes, and mutation patterns. Bioinformatics analyses revealed that higher KIAA0125 expression was associated with hematopoietic and leukemic stem cell signatures and ATP-binding cassette transporters, two predisposing factors for chemoresistance.

scholarly journals A randomized study of high-dose cytarabine in induction in acute myeloid leukemia [see comments]

Blood ◽  
1996 ◽  
Vol 87 (5) ◽  
pp. 1710-1717 ◽  
Author(s):  
JF Bishop ◽  
JP Matthews ◽  
GA Young ◽  
J Szer ◽  
A Gillett ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Univariate Analysis ◽  
Disease Free Survival ◽  
Dose Effect ◽  
Induction Treatment ◽  
High Dose ◽  
Remission Duration ◽  
High Dose Cytarabine ◽  
Acute Myeloid

Abstract High-dose cytarabine (ara-c) may overcome cytarabine resistance in leukemic blasts. It has been used as a successful salvage and in postremission therapy but not as initial induction treatment. Patients aged 15 to 60 years, presenting with newly diagnosed acute myeloid leukemia (AML) were randomized to receive either high-dose cytarabine, 3 g/m2 12 hourly on days 1, 3, 5, and 7 for 8 doses, daunorubicin 50 mg/m2 days 1 to 3, etoposide 75 mg/m2 days 1 to 7, (HIDAC-3–7) or standard dose cytarabine 100 mg/m2 continuous intravenous infusion for 7 days with daunorubicin and etoposide at the same dose and schedule as above (7–3–7). Patients could receive a second or third induction course if complete remission (CR) was not achieved. All patients received the same postinduction consolidation therapy (5–2–5) for 2 courses. Eligible patients had no prior chemotherapy or myelodysplastic disease. Patients have been followed for a median of 4.5 years. Of 301 patients treated, complete response (CR) was achieved in 71% with HIDAC- 3–7 and 74% with 7–3–7. For patients in CR, the estimated median remission duration was 45 months with HIDAC-3–7 and 12 months with 7–3– 7 (P = .0005 univariate analysis, P = .0004 multivariate analysis). The estimated percentage of patients relapse free 5 years after achieving a CR was 49% on HIDAC-3–7 and 24% on 7–3–7. Patients in CR tended to survive longer with HIDAC-3–7 but there were no overall survival differences between the two arms. HIDAC-3–7 was associated with significantly more toxicity in induction with more leukopenia, thrombocytopenia, nausea, and vomiting and eye toxicity (all P < .001) but a similar incidence of severe central nervous system and cerebellar toxicity compared to 7–3–7. The consolidation treatment was the same in both arms but caused significantly more leukopenia and thrombocytopenia in patients previously treated with HIDAC-3–7 induction (P < .0001). We conclude that a dose-effect exists for cytarabine in AML and that HIDAC- 3–7 prolongs remission duration and disease-free survival and is tolerable when used as initial induction therapy in patients with de novo AML.

scholarly journals A phase 1 study of azacitidine with high-dose cytarabine and mitoxantrone in high-risk acute myeloid leukemia

2020 ◽  
Vol 4 (4) ◽  
pp. 599-606 ◽  
Author(s):  
Kirk E. Cahill ◽  
Yasmin H. Karimi ◽  
Theodore G. Karrison ◽  
Nitin Jain ◽  
Margaret Green ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Phase 1 ◽  
High Dose ◽  
Phase 2 ◽  
Phase 1 Study ◽  
High Dose Cytarabine ◽  
Acute Myeloid

Abstract In this phase 1 study, azacitidine (AZA) was given before high-dose cytarabine (HiDAC) and mitoxantrone (mito) based on the hypothesis that epigenetic priming with a hypomethylating agent before cytotoxic chemotherapy would improve response rates in patients with high-risk acute myeloid leukemia (AML), including relapsed/refractory disease. The primary objective was to establish the recommended phase 2 dose of AZA given before standard HiDAC/mito. In a dose escalation scheme, 46 patients (median age, 66 years) received AZA at 37.5, 50, or 75 mg/m2 subcutaneously or IV once daily on days 1 to 5 followed by HiDAC (3000 mg/m2) and mitoxantrone (30 mg/m2) once each on days 6 and 10 (the HiDAC/mito dose was reduced 33% in elderly subjects). Two dose-limiting toxicities occurred (both in the same patient): acute liver failure and kidney injury at the 50 mg/m2 dose. The 30-day induction death rate was 2.2% (1 of 46). The overall response rate, including complete remission and complete remission with incomplete count recovery, was 61% (28 of 46). Previously untreated patients aged ≥60 years with therapy-related AML and de novo AML were more likely to respond than untreated patients with AML progressing from an antecedent hematologic disorder (myelodysplastic syndrome and chronic myelomonocytic leukemia). Patients with favorable European Leukemia Network risk (P = .008), NPM1 mutations (P = .007), or IDH2 mutations (P = .03) were more likely to respond, and those with TP53 mutations (P = .03) were less likely to respond. The recommended phase 2 dose of AZA is 75 mg/m2 per day on days 1 to 5 followed by HiDAC (3000 mg/m2) and mitoxantrone (30 mg/m2) once each on days 6 and 10. This trial was registered at www.clinicaltrials.gov as #NCT01839240.

Therapeutic Advances in Acute Myeloid Leukemia

2011 ◽  
Vol 29 (5) ◽  
pp. 487-494 ◽  
Author(s):  
Alan Burnett ◽  
Meir Wetzler ◽  
Bob Löwenberg
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Remission Rate ◽  
Nucleoside Analogs ◽  
Clinical Decision ◽  
High Dose ◽  
Younger Patients ◽  
Molecular Features ◽  
New Treatments ◽  
Acute Myeloid

The choice of treatment approach and outcome in acute myeloid leukemia (AML) depends on the age of the patient. In younger patients, arbitrarily defined as being younger than 60 years, 70% to 80% enter complete disease remission with several anthracycline-based chemotherapy combinations. Consolidation with high-dose cytarabine or stem-cell transplantation in high-risk patients will restrict overall relapse to approximately 50%. A number of demographic features can predict the outcome of treatment including cytogenetics and an increasing list of molecular features (ie, FLT3, NPM1, MLL, WT1, CEBPalpha, EVI1). These are increasingly being used to direct postinduction therapy, but they are also molecular targets for a new generation of small molecule inhibitors that are in early development; however, randomized data have yet to emerge. In older patients who comprise the majority, which will increase with demographic change, the initial clinical decision to be made is whether the patient should receive an intensive or nonintensive approach. If the same anthracycline/cytarabine–based approach is deployed, the remission rate will be around 50%, but the risk of subsequent relapse is approximately 85% at 3 years. This difference from younger patients is explained partly by the ability of patients to tolerate effective therapy, and also the aggregation of several poor risk factors compared with the young. There remains a substantial proportion of patients older than 60 years who do not receive intensive chemotherapy. Their survival is approximately 4 months, but there is considerable interest in developing new treatments for this patient group, including novel nucleoside analogs and several other agents.

scholarly journals CLAG-Based Induction Therapy in Previously Untreated High Risk AML Patients

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4892-4892
Author(s):  
Karen Seiter ◽  
Stephanie Germani ◽  
Julie Martin ◽  
Rosemarie Raffa ◽  
Michele Reilly ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Early Death ◽  
High Dose ◽  
Cell Transplant ◽  
Kaplan Meier ◽  
Duration Of Response ◽  
Acute Myeloid

Abstract The CLAG regimen (G-CSF 300 mcg sc, cladribine 5 mg/m2 over 2 hours, and cytarabine 2 gm/m2 over 4 hours beginning 2 hours after cladribine, all daily times 5 days) was originally devised by Robak et al (Leuk Lymphoma 2000; 36:121-9) as induction therapy for patients with relapsed or refractory acute myeloid leukemia. Fifty percent of patients achieved a CR with a median duration of 22.5 weeks. This group subsequently added mitoxantrone to the regimen (Wrzesien-Kus A, et al. Ann Hematol 2005; 84:557-64). We treated 20 patients with previously untreated acute myeloid leukemia who were considered unsuitable for our intensive high-dose cytarabine, high-dose mitoxantrone frontline induction regimen either due to age or cardiac dysfunction with CLAG-based therapy. Patients with a cardiac ejection fraction above 50% additionally received either mitoxantrone (mito) or idarubicin (ida), 12 mg/m2 times 3 days, concurrently with CLAG. Of 20 patients treated, 5 received CLAG, 12 received CLAG-ida and 3 received CLAG-mito. The median age was 64 years (range 42-79 years). There were 13 men and 7 women. Six patients had received prior chemo and/or RT for a previous malignancy. In addition 3 patients had a prior MPD and 1 had prior MDS (total of 10 patients with secondary AML). Patients had a median of 3 comorbidities (range 0-7). Cytogenetic risk was good: 2 patients (however one was FLT3 ITD+), intermediate: 10 patients, poor: 8 patients. Only one patient was FLT3 ITD+. Responding patients (CR or PR) received 1 (5 pts), 2 (2 pts), 3 (8 pts) or 4 (2 pts) cycles of CLAG+/- ida or mito followed by allogeneic stem cell transplant (4 pts), hidac (2 pts) or decitabine maintenance (4 pts). Most patients responded to therapy. There were 13 formal CRs (65%), 1 CRp (5%), 3 PR (15%, defined as 6-10% blasts on marrow with complete hematologic recovery in the peripheral blood), 2 failures (10%) and one early death (5%). Other than the early death, treatment was well tolerated with few toxicities other than neutropenic fever and cytopenias. Estimated overall survival by Kaplan Meier analysis is 29.6 months (95% CI 20.1-39.2 months). Duration of response is 32.3 months (95% CI 21.6-43.1 months). CLAG-based therapy is a well-tolerated, efficacious induction strategy in previously-untreated patients with high risk AML. CLAG-based regimens should be studied in a broader group of newly diagnosed AML patients. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Off Label Use: Use of cladribine in AML.

scholarly journals Etoposide Combined with FLAG Salvage Therapy Is Effective in Multiple Relapsed/Refractory Acute Myeloid leukemia

2019 ◽  
Vol 143 (5) ◽  
pp. 438-445
Author(s):  
Jonas Westhus ◽  
Richard Noppeney ◽  
Christine Schmitz ◽  
Michael Flasshove ◽  
Ulrich Dührsen ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Remission Rate ◽  
Disease Free Survival ◽  
Heavily Pretreated ◽  
Refractory Acute Myeloid Leukemia ◽  
Pretreated Patients ◽  
Therapeutic Alternatives ◽  
Acute Myeloid

Managing acute myeloid leukemia (AML) is often hampered by repeated failure to achieve complete remission as well as recurrent relapse that causes an emergent need for alternative salvage therapies. The efficacy of most salvage therapies is based on anthracycline combinations. In highly pretreated patients who are not eligible for anthracycline-based protocols therapeutic alternatives are limited. For this particular group we evaluated the efficacy and safety of fludarabine, cytarabine, granulocyte colony-stimulating factor (FLAG) in combination with etoposide (FLAG-Eto) in 36 patients. The complete remission rate (CR) was 25.7% with a median overall survival of 6 months (95% CI 4.5–7.7). The median disease-free survival for CR/CRi/MLFS (CR/CR with incomplete he­matological recovery/morphologic leukemia-free state) patients was 8 months (95% CI 0.6–15.5). The mortality rate on day 30 was 8% and increased on day 60 to 17%. Our results show meaningful anti-leukemic activity of the FLAG-Eto regimen with a moderate toxicity profile in heavily pretreated relapsed/refractory AML patients enabling consolidating allogeneic stem cell transplantation.

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