A phase III comparison of high dose ARA-C (HIDAC) versus HIDAC plus mitoxantrone in the treatment of first relapsed or refractory acute myeloid leukemia

Karanes, Chatchada; Kopecky, Kenneth J.; Head, David R.; Grever, Michael R.; Hynes, Harry E.; Kraut, Eric H.; Vial, R; Lichtin, Alan E.; Nand, Sucha; Samlowski, Wolfram E.; Appelbaum, Frederick R.

doi:10.1016/s0145-2126(99)00087-9

Cited by 81 publications

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“…Trials in AML have failed to date to show a survival benefit in the salvage setting 3, 16, 17. We report here the first results of different doses and schedules of guadecitabine, a next‐generation HMA, in a multicenter study of 103 patients.…”

Section: Discussionmentioning

confidence: 96%

Dose, schedule, safety, and efficacy of guadecitabine in relapsed or refractory acute myeloid leukemia

Roboz

Kantarjian

Yee

et al. 2017

Cancer

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BACKGROUNDOutcomes for patients with relapsed or refractory acute myeloid leukemia (AML) are poor. Guadecitabine, a next‐generation hypomethylating agent, could be useful in treating such patients.METHODSIn this multicenter, open‐label, phase 2 dose‐expansion study, AML patients from 10 North American medical centers were first randomized (1:1) to receive subcutaneous guadecitabine at 60 or 90 mg/m2 on 5 consecutive days in each 28‐day cycle (5‐day regimen). Subsequently, another cohort was treated for 10 days with 60 mg/m2 (10‐day regimen).RESULTSBetween June 15, 2012, and August 19, 2013, 108 patients with previously treated AML consented to enroll in the study, and 103 of these patients were treated; 5 patients did not receive the study treatment. A total of 103 patients were included in the safety and efficacy analyses (24 and 26 patients who were randomly assigned to 60 and 90 mg/m2/d, respectively [5‐day regimen] and 53 patients who were assigned to 60 mg/m2/d [10‐day regimen]). The 90 mg/m2 dose showed no benefit in clinical outcomes in comparison with 60 mg/m2 in the randomized cohort. Composite complete response (CRc) and complete response (CR) rates were higher with the 10‐day regimen versus the 5‐day regimen (CRc, 30.2% vs 16.0%; P = .1061; CR, 18.9% vs 8%; P = .15). Adverse events (grade ≥ 3) were mainly hematologic, with a higher incidence on the 10‐day regimen. Early all‐cause mortality was low and similar between regimens. Twenty patients (8 on the 5‐day regimen and 12 on the 10‐day regimen) were bridged to hematopoietic cell transplantation.CONCLUSIONSGuadecitabine has promising clinical activity and an acceptable safety profile and thus warrants further development in this population. Cancer 2018;124:325‐34. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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Section: Discussionmentioning

confidence: 96%

Dose, schedule, safety, and efficacy of guadecitabine in relapsed or refractory acute myeloid leukemia

Roboz

Kantarjian

Yee

et al. 2017

Cancer

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“…74 High-dose cytarabine has been an effective reinduction regimen. 75 However, the addition of other agents to HiDAC does not improve outcome. 75 Allogeneic HSCT may provide the highest likelihood of cure, presumably related to the generation of an immunologically mediated graft-versus leukemia reaction not present with salvage chemotherapy, preferably after induction of a second CR.…”

Section: Treatment Of Patients With Relapsed or Refractory Amlmentioning

confidence: 99%

Drug therapy for acute myeloid leukemia

Tallman

Gilliland

Rowe

2005

Blood

596

459

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Although improvement in outcomes has IntroductionAcute myeloid leukemia (AML) is a heterogeneous group of diseases characterized by uncontrolled proliferation of clonal neoplastic hematopoietic precursor cells and impaired production of normal hematopoiesis leading to neutropenia, anemia, and thrombocytopenia. 1 If untreated, patients die of infection or bleeding usually in a matter of weeks. Some older adults may have a slower progressive clinical course. An estimated 10 600 new cases occurred in the United States in 2002 and 7400 patients died of the disease. 2 The overall incidence is 3.4 cases per 100 000 population; 1.2 cases per 100 000 population at age 30 and more than 20 cases per 100 000 population at age 80 years. 2 The median age is 20 years and has been increasing over the past decade.Historically, the diagnosis and response to therapy were established from morphology and cytochemistry. Although morphology remains the initial diagnostic tool for any patient with acute leukemia, the past decade has witnessed increased reliance on cell-surface antigen expression by immunophenotyping, usually carried out by flow cytometry, as well as cytogenetic and molecular markers.During the past 4 decades, many studies have investigated a wide variety of cytotoxic antileukemic agents. Most recently, insights into the molecular pathogenesis of AML have led to the development of the more specific targeted therapy. This review focuses on current and evolving drug therapy in the treatment of adults with AML. Current treatment resultsApproximately 50% to 75% of adults with AML achieve complete remission (CR) with the deoxycytidine analog cytarabine and an anthracycline antibiotic, such as daunorubicin or idarubicin, or the anthracenedione mitoxantrone, which inhibit the enzyme topoisomerase IIa. However, only 20% to 30% of patients enjoy long-term disease-free survival (DFS). The majority of patients die of their disease, primarily because of persistent or relapsed AML. In an Eastern Cooperative Oncology Group (ECOG) analysis of the outcome of approximately 3000 patients with previously untreated AML entered on 5 successive clinical trials with cytarabine and daunorubicin for induction and with increasingly more intensive postremission therapy, 62% achieved CR, but 76% relapsed or died. 3,4 The 5-year overall survival (OS) rate among 2000 patients younger than 55 years has improved from 11% in the 1970s to 37% in the 1990s. (Figure 1A-C). In contrast, among 1000 patients age 55 years and older, progress over the past 3 decades has been very modest. 5 Prognostic factorsThe outcome for adults with AML depends on a variety of factors, including age of the patient, intensity of postremission therapy, and biologic characteristics of the disease, the most important of which are the cytogenetics at presentation. 4,[6][7][8] (Figure 2). Other factors include the presence of transmembrane transporter proteins, which extrude certain chemotherapy agents from the cell and confer multidrug resistance, 9 and mutations in or overex...

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“…In the case of multisystem organ dysfunction, the subject had a history of prior allogeneic stem cell transplant and multiple prior anthracycline-based regimens. This subject's extensive prior therapy likely contributed to her impaired ability to withstand infectious complications of induction, despite her young age (31) and adequate baseline organ studies at enrollment. In summary, it was not clear that sirolimus increased the hematologic or nonhematologic toxicity of the MEC regimen.…”

Section: Discussionmentioning

confidence: 99%

“…MEC has primarily been tested in patients with relapsed and refractory AML (28)(29)(30), and shows activity and toxicity comparable to other high-dose cytarabine-containing regimens (31)(32)(33). Reversible mucositis, transaminase elevation, diarrhea, and neutropenic infection are the most commonly reported toxicities of this treatment.…”

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confidence: 99%

A Phase I Study of the Mammalian Target of Rapamycin Inhibitor Sirolimus and MEC Chemotherapy in Relapsed and Refractory Acute Myelogenous Leukemia

Perl

Kasner

Tsai

et al. 2009

Clinical Cancer Research

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Purpose: Inhibiting mammalian target of rapamycin (mTOR) signaling in acute myelogenous leukemia (AML) blasts and leukemic stem cells may enhance their sensitivity to cytotoxic agents. We sought to determine the safety and describe the toxicity of this approach by adding the mTOR inhibitor, sirolimus (rapamycin), to intensive AML induction chemotherapy. Experimental Design: We performed a phase I dose escalation study of sirolimus with the chemotherapy regimen MEC (mitoxantrone, etoposide, and cytarabine) in patients with relapsed, refractory, or untreated secondary AML. Results: Twenty-nine subjects received sirolimus and MEC across five dose levels. Dose-limiting toxicities were irreversible marrow aplasia and multiorgan failure. The maximum tolerated dose (MTD) of sirolimus was determined to be a 12 mg loading dose on day 1 followed by 4 mg/d on days 2 to 7, concurrent with MEC chemotherapy. Complete or partial remissions occurred in 6 (22%) of the 27 subjects who completed chemotherapy, including 3 (25%) of the 12 subjects treated at the MTD. At the MTD, measured rapamycin trough levels were within the therapeutic range for solid organ transplantation. However, direct measurement of the mTOR target p70 S6 kinase phosphorylation in marrow blasts from these subjects only showed definite target inhibition in one of five evaluable samples. Conclusions: Sirolimus and MEC is an active and feasible regimen. However, as administered in this study, the synergy between MEC and sirolimus was not confirmed. Future studies are planned with different schedules to clarify the clinical and biochemical effects of sirolimus in AML and to determine whether target inhibition predicts chemotherapy response. (Clin Cancer Res 2009;15(21):6732-9) Although intensive combination chemotherapy is effective in temporizing acute myelogenous leukemia (AML) in most treated patients, the majority of those who achieve complete remission (CR) subsequently relapse and ultimately die of their disease (1-3). More than 30 years of combination chemotherapy clinical trials have failed to substantially improve survival in AML, leading to efforts to develop targeted therapeutics for this disease. We and others have concentrated on identifying agents or signaling inhibitors that target AML cells and AML stem cells without additional toxicity to normal hematopoietic cells. Some of these agents seem to be cytotoxic by themselves (4-9), whereas others alter the response of AML cells to chemotherapy (10, 11). The most extensively studied drugs in this class are the FLT3 inhibitors, for which clinical trials are ongoing (12-16). Use of FLT3 inhibitors has been studied primarily in patients with FLT3 mutations, which are known to confer a (12,15,17,18).Phosphatidylinositol-3′-kinase (PI3K) is a potential novel therapeutic target in AML. The role of PI3K signaling in leukemia has been studied in both murine models and primary human cells. Yilmaz et al. studied a murine leukemia model that conditionally induces activated PI3K signaling in hematop...

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A phase III comparison of high dose ARA-C (HIDAC) versus HIDAC plus mitoxantrone in the treatment of first relapsed or refractory acute myeloid leukemia

Cited by 81 publications

References 10 publications

Dose, schedule, safety, and efficacy of guadecitabine in relapsed or refractory acute myeloid leukemia

Dose, schedule, safety, and efficacy of guadecitabine in relapsed or refractory acute myeloid leukemia

Drug therapy for acute myeloid leukemia

A Phase I Study of the Mammalian Target of Rapamycin Inhibitor Sirolimus and MEC Chemotherapy in Relapsed and Refractory Acute Myelogenous Leukemia

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