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.

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.

High-Dose Mercaptopurine and Intermediate-Dose Cytarabine During First Remission of Acute Myeloid Leukemia

1997 ◽  
Vol 15 (2) ◽  
pp. 121-126
Author(s):  
Cengiz Canpolat ◽  
Sima Jeha ◽  
Sharon Lockhart ◽  
Irma Ramirez ◽  
Theodore Zipf ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
High Dose ◽  
First Remission ◽  
Acute Myeloid ◽  
Intermediate Dose

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.

Results of High Dose Chemotherapy and Autologous Stem Cell Transplantation in Patients with Acute Myeloid Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5196-5196
Author(s):  
Kenneth A. Ault ◽  
Delvyn C. Case ◽  
Marjorie A. Boyd ◽  
Thomas J. Ervin ◽  
Frederick R. Aronson ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Progression Free Survival ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Hematopoietic Stem ◽  
First Remission ◽  
Patient Selection Criteria ◽  
Acute Myeloid

Abstract 35 patients with acute myeloid leukemia have undergone transplantation at our institution over the past 12 years. Patient selection criteria included age less than 70 years, creatinine less than 2mg/ml, no active infection, cardiac ejection fraction >40%, DLCO > 50% of predicted and no other co-morbid conditions that would jeopardize survival. 31 patients were in first remission, 4 were in second or higher remission. 3 patients had favorable cytogenetics, 25 had intermediate or unfavorable cytogenetics. After achieving remission for at least 30 days, patients were consolidated with Etoposide and AraC, followed by G-CSF. Hematopoietic stem cells were collected when the WBC rebounded to at least 10,000/ml. The target dose of CD34 positive cells was 5x106/kg. The minimum dose given was 2.3 x 106/kg). The average age at transplantation was 41 years (range 22 to 61). Days of neutropenia (AGC<500/ml) ranged from 2 to 10 (average 5.1). The median length of follow up is 2.6 years. Currently 26 patients are alive, and 25 are free from progression. Overall survival is 63%, and progression-free survival is 47% at both 5 and ten years. Figure Figure

scholarly journals Acute toxicity and first clinical results of intensive postinduction therapy using a modified busulfan and cyclophosphamide regimen with autologous bone marrow rescue in first remission of acute myeloid leukemia [see comments]

Blood ◽  
1989 ◽  
Vol 74 (5) ◽  
pp. 1507-1516 ◽  
Author(s):  
DW Beelen ◽  
K Quabeck ◽  
U Graeven ◽  
HG Sayer ◽  
HK Mahmoud ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Marrow Transplantation ◽  
Myeloid Leukemia ◽  
Allogeneic Transplantation ◽  
Cytotoxic Agents ◽  
High Dose ◽  
Skin Reactions ◽  
Preparative Regimen ◽  
First Remission ◽  
Acute Myeloid

Abstract The combination of high-dose busulfan (16 mg/kg) and 200 mg/kg cyclophosphamide is gaining increasing significance as a preparative regimen prior to autologous, syngeneic, or allogeneic marrow transplantation. A new regimen of high-dose busulfan in conjunction with a reduced dose of 120 mg/kg cyclophosphamide has recently been described as a preparative regimen prior to allogeneic transplantation. To determine the drug-related nonhematologic toxic effects of this new regimen without confounding factors associated with allogeneic transplantation, we conducted a pilot study using this new regimen in 20 patients with acute myeloid leukemia (AML) in first remission prior to autologous unpurged marrow transplantation. All patients experienced transient non-life-threatening acute drug-related toxicity with skin reactions in 20 (100%), nausea and vomiting in 20 (100%), oral mucositis in 18 (90%), hepatic functional impairment in 17 (85%), hemorrhagic cystitis in three (15%), and generalized seizures in two (10%) of these patients, respectively. Two procedural, fatal complications resulted from infectious causes that were not directly related to the speed of hematopoietic reconstitution or the toxicity of the preparative regimen. The 3-year event-free survival estimate (55% +/- 11%) and probability of leukemic recurrence (38% +/- 11%) attained with this new regimen in recipients of autografts in first remission of AML are promising and challenge comparisons with preparative regimens employing combinations of cytotoxic agents or total body irradiation (TBI).

scholarly journals Defining the Optimal Total Number of Chemotherapy Courses in Younger Patients With Acute Myeloid Leukemia: A Comparison of Three Versus Four Courses

2020 ◽  
pp. JCO.20.01170
Author(s):  
Alan K. Burnett ◽  
Nigel H. Russell ◽  
Robert K. Hills ◽  
Stephen Knapper ◽  
Sylvie Freeman ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Gemtuzumab Ozogamicin ◽  
High Dose ◽  
Optimum Number ◽  
Younger Patients ◽  
National Cancer Research Institute ◽  
The Impact ◽  
Acute Myeloid

PURPOSE The optimum number of treatment courses for younger patients with acute myeloid leukemia (AML) is uncertain. The United Kingdom National Cancer Research Institute AML17 trial randomly assigned patients who were not high risk to a total of three versus four courses. PATIENTS AND METHODS Patients received two induction courses based on daunorubicin and cytarabine (Ara-C), usually with gemtuzumab ozogamicin. Following remission, 1,017 patients were randomly assigned to a third course, MACE (amsacrine, etoposide, and Ara-C), plus a fourth course of MidAc (mitoxantrone and Ara-C) and following an amendment to one or two courses of high-dose Ara-C. Primary end points were cumulative incidence of relapse (CIR), relapse-free survival (RFS), and overall survival (OS). Outcomes were correlated with patient characteristics, mutations, cytogenetics, induction treatments, and measurable residual disease (MRD) postinduction. RESULTS In logrank analyses, CIR and RFS at 5 years were improved in recipients of four courses (50% v 58%: hazard ratio [HR] 0.81 [0.69-0.97], P = .02 and 43% v 36%: HR 0.83 [0.71-0.98], P = .03, respectively). While OS was not significantly better (63% v 57%: HR 0.84 [0.69-1.03], P = .09), the noninferiority of three courses to four courses was not established. The impact on relapse was only significant when the fourth course was Ara-C. In exploratory analyses, although MRD impacted survival, a fourth course had no effect in either MRD-positive or MRD-negative patients. A fourth course was beneficial in patients who lacked a mutation of FLT3 or NPM1, had < 3 mutations in other genes, or had a presenting WBC of < 10 × 109 L−1 CONCLUSION Although a fourth course of high-dose Ara-C reduced CIR and improved RFS, it did not result in a significant OS benefit. Subsets including those with favorable cytogenetics, those lacking a mutation of FLT3 or NPM1, or those with < 3 other mutations may derive survival benefit.

scholarly journals Acute toxicity and first clinical results of intensive postinduction therapy using a modified busulfan and cyclophosphamide regimen with autologous bone marrow rescue in first remission of acute myeloid leukemia [see comments]

Blood ◽  
1989 ◽  
Vol 74 (5) ◽  
pp. 1507-1516
Author(s):  
DW Beelen ◽  
K Quabeck ◽  
U Graeven ◽  
HG Sayer ◽  
HK Mahmoud ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Marrow Transplantation ◽  
Myeloid Leukemia ◽  
Allogeneic Transplantation ◽  
Cytotoxic Agents ◽  
High Dose ◽  
Skin Reactions ◽  
Preparative Regimen ◽  
First Remission ◽  
Acute Myeloid

The combination of high-dose busulfan (16 mg/kg) and 200 mg/kg cyclophosphamide is gaining increasing significance as a preparative regimen prior to autologous, syngeneic, or allogeneic marrow transplantation. A new regimen of high-dose busulfan in conjunction with a reduced dose of 120 mg/kg cyclophosphamide has recently been described as a preparative regimen prior to allogeneic transplantation. To determine the drug-related nonhematologic toxic effects of this new regimen without confounding factors associated with allogeneic transplantation, we conducted a pilot study using this new regimen in 20 patients with acute myeloid leukemia (AML) in first remission prior to autologous unpurged marrow transplantation. All patients experienced transient non-life-threatening acute drug-related toxicity with skin reactions in 20 (100%), nausea and vomiting in 20 (100%), oral mucositis in 18 (90%), hepatic functional impairment in 17 (85%), hemorrhagic cystitis in three (15%), and generalized seizures in two (10%) of these patients, respectively. Two procedural, fatal complications resulted from infectious causes that were not directly related to the speed of hematopoietic reconstitution or the toxicity of the preparative regimen. The 3-year event-free survival estimate (55% +/- 11%) and probability of leukemic recurrence (38% +/- 11%) attained with this new regimen in recipients of autografts in first remission of AML are promising and challenge comparisons with preparative regimens employing combinations of cytotoxic agents or total body irradiation (TBI).

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