scholarly journals Extramedullary acute myeloid leukemia presenting in young adults demonstrates sensitivity to high-dose anthracycline: a subset analysis from ECOG-ACRIN 1900

Haematologica ◽  
2018 ◽  
Vol 104 (4) ◽  
pp. e147-e150 ◽  
Author(s):  
Hugo F. Fernandez ◽  
Zhuoxin Sun ◽  
Mark R. Litzow ◽  
Selina M. Luger ◽  
Elisabeth Paietta ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Young Adults ◽  
Myeloid Leukemia ◽  
High Dose ◽  
Subset Analysis ◽  
Acute Myeloid

A randomized trial comparing standard versus high-dose daunorubicin induction in patients with acute myeloid leukemia

Blood ◽  
2011 ◽  
Vol 118 (14) ◽  
pp. 3832-3841 ◽  
Author(s):  
Je-Hwan Lee ◽  
Young-Don Joo ◽  
Hawk Kim ◽  
Sung Hwa Bae ◽  
Min Kyoung Kim ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Young Adults ◽  
Randomized Trial ◽  
Myeloid Leukemia ◽  
Standard Dose ◽  
Survival Duration ◽  
High Dose ◽  
Different Doses ◽  
Acute Myeloid

Abstract We conducted a phase 3 randomized trial comparing 2 different doses of daunorubicin as induction chemotherapy in young adults (60 years of age or younger) with acute myeloid leukemia (AML). Of 383 patients who were analyzed, 189 received standard-dose daunorubicin (SD-DN, 45 mg/m2 per day times 3 days) and 194 received high-dose daunorubicin (HD-DN, 90 mg/m2 per day times 3 days) in addition to cytarabine (200 mg/m2 per day times 7 days) to induce complete remission (CR). The CR rates were 72.0% in the SD-DN arm and 82.5% in the HD-DN arm (P = .014). At a median follow-up of 52.6 months, overall (OS) and event-free (EFS) survival were higher in the HD-DN arm than in the SD-DN arm (OS, 46.8% vs 34.6%, P = .030; EFS, 40.8% vs 28.4%, P = .030). Differences in CR rate and both OS and EFS remained significant after adjusting for other variables (CR, hazard ratio [HR], 1.802, P = .024; OS, HR, 0.739, P = .032; EFS, HR, 0.774, P = .048). The survival benefits of HD-DN therapy were evident principally in patients with intermediate-risk cytogenetic features. The toxicity profiles were similar in the 2 arms. In conclusion, HD-DN improved both the CR rate and survival duration compared with SD-DN in young adults with AML. This study is registered at www.clinicaltrials.gov as #NCT00474006.

Cytarabine Dose of 36 g/m2 Compared With 12 g/m2 Within First Consolidation in Acute Myeloid Leukemia: Results of Patients Enrolled Onto the Prospective Randomized AML96 Study

2011 ◽  
Vol 29 (19) ◽  
pp. 2696-2702 ◽  
Author(s):  
Markus Schaich ◽  
Christoph Röllig ◽  
Silke Soucek ◽  
Michael Kramer ◽  
Christian Thiede ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Young Adults ◽  
Myeloid Leukemia ◽  
Disease Free Survival ◽  
Allogeneic Transplantation ◽  
High Dose ◽  
Serious Adverse Events ◽  
Hematopoietic Stem ◽  
Acute Myeloid ◽  
Intermediate Dose

Purpose To assess the optimal cumulative dose of cytarabine for treatment of young adults with acute myeloid leukemia (AML) within a prospective multicenter treatment trial. Patients and Methods Between 1996 and 2003, 933 patients (median age, 47 years; range 15 to 60 years) with untreated AML were randomly assigned at diagnosis to receive cytarabine within the first consolidation therapy at either a intermediate-dose of 12 g/m2 (I-MAC) or a high-dose of 36 g/m2 (H-MAC) combined with mitoxantrone. Autologous hematopoietic stem-cell transplantation or intermediate-dose cytarabine (10 g/m2) were offered as second consolidation. Patients with a matched donor could receive an allogeneic transplantation in a risk-adapted manner. Results After double induction therapy including intermediate-dose cytarabine (10 g/m2), mitoxantrone, etoposide, and amsacrine, complete remission was achieved in 66% of patients. In the primary efficacy analysis population, a consolidation with either I-MAC or H-MAC did not result in significant differences in the 5-year overall (30% v 33%; P = .77) or disease-free survival (37% v 38%; P = .86) according to the intention-to-treat analysis. Besides a prolongation of neutropenia and higher transfusion demands in the H-MAC arm, rates of serious adverse events were comparable in the two groups. Conclusion In young adults with AML receiving intermediate-dose cytarabine induction, intensification of the cytarabine dose beyond 12 g/m2 within first consolidation did not improve treatment outcome.

A Prospective Randomized Comparison of Idarubicin and High-Dose Daunorubicin in the Induction Chemotherapy for Acute Myeloid Leukemia: An Interim Analysis

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3628-3628 ◽  
Author(s):  
Je-Hwan Lee ◽  
Young-Don Joo ◽  
Jung-Hee Lee ◽  
Hawk Kim ◽  
Sung Hwa Bae ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Young Adults ◽  
Randomized Trial ◽  
Induction Chemotherapy ◽  
Interim Analysis ◽  
Myeloid Leukemia ◽  
Survival Duration ◽  
High Dose ◽  
Free Survival ◽  
Acute Myeloid

Abstract Abstract 3628 Introduction: We conducted a randomized trial comparing two different doses of daunorubicin as induction chemotherapy in young adults with acute myeloid leukemia (AML) and showed intensification of induction therapy using a high daily dose of daunorubicin (90 mg/m2/d × 3d) improved both complete remission (CR) rate and survival duration compared to standard daunorubicin dose (45 mg/m2/d × 3d) (Lee JH et al. Blood 2011;118:3832). Our results confirmed the ECOG work (Fernandez HF et al. N Engl J Med 2009;361:1249). Thus, high-dose daunorubicin (90 mg/m2/d) for 3 days should be the future standard of care for induction of patients with AML. However, it is not known whether a dose of 90 mg/m2/d is superior to a dose of 45–90 mg/m2/d. It is also necessary to compare the effects of high-dose daunorubicin with that of other agents, especially idarubicin. For these reasons, we began another randomized trial comparing two induction regimens in young adults with AML: idarubicin vs. high-dose daunorubicin. This study is now recruiting patients (ClinicalTrials.gov #NCT01145846). Here, we present the results of interim analysis of the study. Methods: This study began on May 2010 and target number of patient's accrual is 300. A total of 161 patients (65 years or younger) with newly diagnosed AML except acute promyelocytic leukemia were registered in this study as of March 22, 2012. Four patients were removed from the study (patient's refusal to be randomized in 2 and change of diagnosis in 2) and the remaining 157 patients were analyzed. After random assignments, 81 patients received idarubicin (AI, 12 mg/m2/d × 3d) and 76 patients received high-dose daunorubicin (AD, 90 mg/m2/d × 3d) in addition to cytarabine (200 mg/m2/d × 7d) for induction of CR. Patients with persistent leukemia received the second attempt of induction chemotherapy, consisting of idarubicin (AI, 12 mg/m2/d × 2d) or daunorubicin (AD, 45 mg/m2/d × 2d) plus cytarabine (5d). Patients who attained CR received 4 cycles of high-dose cytarabine (3 g/m2 × 6 doses) in patients with good- or intermediate-risk cytogenetics and 4 cycles of cytarabine (1 g/m2 × 6d) plus etoposide (150 mg/m2 × 3d) in those with high-risk cytogenetics. Hematopoietic cell transplantation (HCT) was performed according to attending physician's discretion. Results: CR was induced in 123 (78.3%) of 157 patients. Reasons for induction failure were resistant disease in 26, hypoplastic death in 2, and indeterminate cause in 6. As postremission therapy, 3 patients received no further treatment, 35 received consolidation chemotherapy without HCT, 73 underwent allogeneic HCT, and 12 underwent autologous HCT. The CR rates were not significantly different between two arms: 77.8% (63 of 81, AI) vs. 78.9% (60 of 76, AD) (P=0.859). With a median follow-up of 285 days, overall survival probabilities at 18 months were 65.6% in AI vs. 72.6% in AD (P=0.278). The probabilities at 18 months for relapse-free survival were 78.5% in AI vs. 86.2% in AD (P=0.563) and those for event-free survival were 61.5% in AI vs. 67.7% in AD (P=0.078). Toxicity profiles were similar between two arms. Conclusions: The results of interim analysis of this ongoing phase 3 trial, which compares idarubicin (12 mg/m2/d × 3d) with high-dose daunorubicin (90 mg/m2/d × 3d), did not show significant differences in the outcomes of patients. It appears that the effects of two drugs with the doses in current study are equivalent as an induction chemotherapeutic agent in regards to CR rates and overall, relapse-free or event-free survivals. Disclosures: No relevant conflicts of interest to declare.

Randomized Phase II Study of Clofarabine-Based Consolidation for Younger Adults With Acute Myeloid Leukemia in First Remission

2017 ◽  
Vol 35 (11) ◽  
pp. 1223-1230 ◽  
Author(s):  
Xavier Thomas ◽  
Stéphane de Botton ◽  
Sylvie Chevret ◽  
Denis Caillot ◽  
Emmanuel Raffoux ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
High Dose ◽  
Younger Patients ◽  
Hazard Ratios ◽  
Randomized Phase Ii ◽  
Nonhematologic Toxicity ◽  
Donor Identification ◽  
First Remission ◽  
Acute Myeloid

Purpose To evaluate the efficacy and safety of a clofarabine-based combination (CLARA) versus conventional high-dose cytarabine (HDAC) as postremission chemotherapy in younger patients with acute myeloid leukemia (AML). Patients and Methods Patients age 18 to 59 years old with intermediate- or unfavorable-risk AML in first remission and no identified donor for allogeneic stem-cell transplantation (SCT) were eligible. Two hundred twenty-one patients were randomly assigned to receive three CLARA or three HDAC consolidation cycles. The primary end point was relapse-free survival (RFS). To handle the confounding effect of SCT that could occur in patients with late donor identification, hazard ratios (HRs) of events were adjusted on the time-dependent treatment × SCT interaction term. Results At 2 years, RFS was 58.5% (95% CI, 49% to 67%) in the CLARA arm and 46.5% (95% CI, 37% to 55%) in the HDAC arm. Overall, 110 patients (55 in each arm) received SCT in first remission. On the basis of a multivariable Cox-adjusted treatment × SCT interaction, the HR of CLARA over HDAC before or in absence of SCT was 0.65 (95% CI, 0.43 to 0.98; P = .041). In a sensitivity analysis, when patients who received SCT in first remission were censored at SCT time, 2-year RFS was 53.3% (95% CI, 39% to 66%) in the CLARA arm and 31.0% (95% CI, 19% to 43%) in the HDAC arm (HR, 0.63; 95% CI, 0.41 to 0.98; P = .043). Gain in RFS could be related to the lower cumulative incidence of relapse observed in the CLARA arm versus the HDAC arm (33.9% v 46.4% at 2 years, respectively; cause-specific HR, 0.61; 95% CI, 0.40 to 0.94; P = .025). CLARA cycles were associated with higher hematologic and nonhematologic toxicity than HDAC cycles. Conclusion These results suggest that CLARA might be considered as a new chemotherapy option in younger patients with AML in first remission.

New Strategies for the Treatment of Acute Myeloid Leukemia Including Antibodies and Other Novel Agents

Hematology ◽  
2005 ◽  
Vol 2005 (1) ◽  
pp. 143-150 ◽  
Author(s):  
Martin S. Tallman
Keyword(s):  
Older Adults ◽  
Acute Myeloid Leukemia ◽  
Multidrug Resistance ◽  
Myeloid Leukemia ◽  
Cytotoxic Agents ◽  
High Dose ◽  
Farnesyltransferase Inhibitors ◽  
Younger Adults ◽  
The Impact ◽  
Acute Myeloid

Abstract The prognosis for younger adults (≤ 55–60 years) with acute myeloid leukemia (AML) has improved during the last four decades. However, there has been little progress in the treatment of older adults. This disappointing observation is important because the median age of patients with AML is about 70 years. Approximately 60%–80% of younger adults with AML achieve complete remission (CR) with the cytotoxic agents cytarabine and an anthracycline such as daunorubicin or idarubicin or the anthracenedione mitoxantrone. However, only 30%–40% of such patients are alive and disease-free at 5 years. Among older adults, CR is achieved in 40%–55%, but there are very few long-term survivors. Many studies have evaluated the impact of alternative doses and schedules, as well as additional cytotoxic drugs, on the prognosis for this group of patients. The outcome has not improved substantially beyond that achieved with conventional doses of an anthracycline and cytarabine followed by high-dose cytarabine consolidation. Several factors identified at diagnosis can predict outcome. The most important of these is the karyotype of the leukemic cells. Another critical factor is the presence of transmembrane transporter proteins, which confer multidrug resistance and mutations in or overexpression of specific genes such as WT1, C/EBPα, BAX, and BCL-2/BAX ratio, BAALC, EVI1, KIT and FLT3. The development of specific agents directed at gene mutations, signal transduction pathways and unique cell surface antigens provide the foundation for new therapeutic strategies. Such agents include the immunoconjugate gemtuzumab ozogamicin, multidrug resistance inhibitors, farnesyltransferase inhibitors, histone deacetylase and proteosome inhibitors, antiangiogenesis agents, FLT3 inhibitors, apoptosis inhibitors, and nucleoside analogs. All of these agents can potentially address the heterogeneous abnormalities in AML and significantly improve the outcome for patients.

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