High-dose cytosine arabinoside and daunorubicin induction therapy for adult patients with de novo non M3 acute myelogenous leukemia: impact of cytogenetics on achieving a complete remission

Stein, AS; Mr, O'Donnell; Ml, Slovak; Nademanee, Auayporn; Dagis, Andrew; Schmidt, GM; Parker, Pablo; Snyder, DS; Ep, Smith; Margolin, Kim; Arber, Daniel A.; Niland, Joyce C.; Forman, Scott

doi:10.1038/sj.leu.2401839

Cited by 16 publications

(11 citation statements)

References 25 publications

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“…Although nonspecific in their effects, these regimens have significantly increased the survival of AML patients. [3][4][5] Recently, more targeted therapy has been developed. Treatment of acute promyelocytic leukemia (APL) patients with trans-retinoic acid (tRA) results in the differentiation of the leukemic cells, with 90% of the patients achieving a complete remission.…”

Section: Introductionmentioning

confidence: 99%

Induction of apoptosis in retinoid-refractory acute myelogenous leukemia by a novel AHPN analog

Zhang

Dawson²,

Ning³

et al. 2003

Blood

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IntroductionAcute myelogenous leukemia (AML) is a heterogeneous disease composed of numerous subclassifications displaying a wide spectrum of phenotypes. 1,2 The major therapeutic approach to this disease has been the use of chemotherapeutic agents with associated life-threatening toxicity. Although nonspecific in their effects, these regimens have significantly increased the survival of AML patients. [3][4][5] Recently, more targeted therapy has been developed. Treatment of acute promyelocytic leukemia (APL) patients with trans-retinoic acid (tRA) results in the differentiation of the leukemic cells, with 90% of the patients achieving a complete remission. [6][7][8] The tRA exerts its effect by modulating gene expression through its role as a ligand to the retinoic acid nuclear receptors, RARs, with the subsequent binding of this complex to the retinoic acid response element (RARE) consensus sequences located in the regulatory regions of retinoid-responsive genes. 9 The selective sensitivity of APL cells to tRA-mediated differentiation resides in their specific expression of a unique promyelocytic leukemia (PML)-RAR␣ fusion product that results in the subsequent maturation arrest of these cells at the promyelocyte stage [10][11][12] ; exposure of these cells to a micromolar concentration of tRA allows for the degradation of the PML-RAR␣ fusion product, with subsequent maturation of the APL cells. [13][14] Unfortunately, the other AML subtypes as classified by the French-American-British (FAB) classification demonstrate inherent resistance to tRA-mediated differentiation and induction of apoptosis. 15,16 We and others have recently described a novel retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN/CD437), which is a potent inducer of apoptosis in a variety of cell types and which displays resistance to tRA-mediated differentiation and apoptosis. [17][18][19][20][21] The mechanistic pathways by which AHPN induces apoptosis in malignant cells are not clearly defined. AHPN binds and transactivates both the RAR␤ and RAR␥ receptors. 22,23 The roles of these retinoid nuclear receptors in AHPN-mediated apoptosis are controversial. While some studies have suggested that binding and transactivation of RAR␥ are essential for AHPN/CD437-mediated apoptosis, 24,25 others have indicated that neither the RARs nor the retinoid X receptors (RXRs) to which AHPN does not bind or transactivate are involved. 20,21,26 bloodjournal.org FromIn the present study, we assessed the ability of the AHPN analog 4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC/MM002) to induce apoptosis in a number of human AML cell lines as well as in primary cultures of leukemic blasts obtained from patients. The 3-Cl-AHPC differs from AHPN in its inability to recruit RAR coactivators and transactivate the RARs (Zhang et al 27 and data not shown). We found that 3-Cl-AHPC is a potent inducer of apoptosis in these cells, which display resistance to the antiproliferative/differentiating effects of tRA. The 3-C...

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Section: Introductionmentioning

confidence: 99%

Induction of apoptosis in retinoid-refractory acute myelogenous leukemia by a novel AHPN analog

Zhang

Dawson²,

Ning³

et al. 2003

Blood

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“…More recently, two phase II trials have also used high dose cytarabine during induction in an effort to improve CR rates. Stein et al [20] at the City of Hope used cytarabine 3 g/m 2 bid for eight doses followed by daunorubicin 60 mg/m 2 on Days 5 and 6. In this single institution study, CR was seen in 80% of patients including 62% of patients with poor-risk cytogenetics [20].…”

Section: Discussionmentioning

confidence: 99%

“…Stein et al [20] at the City of Hope used cytarabine 3 g/m 2 bid for eight doses followed by daunorubicin 60 mg/m 2 on Days 5 and 6. In this single institution study, CR was seen in 80% of patients including 62% of patients with poor-risk cytogenetics [20]. Mitus et al [12] piloted the 3 1 7 1 3 regimen investigated in this SWOG study.…”

Section: Discussionmentioning

confidence: 99%

Phase II evaluation of an intensified induction therapy with standard daunomycin and cytarabine followed by high dose cytarabine for adults with previously untreated acute myeloid leukemia: A southwest oncology group study (SWOG‐9500)

et al. 2007

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Induction therapy for acute myeloid leukemia (AML) usually consists of 7 days of cytarabine at 100-200 mg/ m 2 /day and an anthracycline. Such combinations produce complete response (CR) rates of 60-80% in patients with de novo AML. On the basis of a previous report, suggesting a higher CR rate using a regimen of standard daunomycin and cytarabine followed by 3 days of high-dose cytarabine (HDAC), 101 eligible patients received this regimen in a phase II trial. Sixty patients [59%, 95% confidence interval (CI) 49-69%] achieved a CR, and 10 patients died of infection during induction. Although cytogenetic risk group affected overall survival (P 5 0.0016) and relapse-free survival (P 5 0.0043), it had no impact on CR rate (P 5 0.63). Patients received postremission therapy with repetitive courses of alternate day high-dose cytarabine; this was associated with considerable toxicity and the majority of patients could not receive all of the scheduled postremission therapy. The estimated median survival was 23 months (95% CI 15-34 months), and the estimated probability of surviving 5 years was 34% (95% CI 24-43%). The results of this intensive induction regimen were similar to that seen in previous trials and were not as promising as reported in the previous pilot study. Am. J. Hematol. 82:1056-1062, 2007

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“…41 Cytogenetic abnormalities are used to define prognostic subgroups of AML with respect to achieving CR and remaining disease free. The group with favorable cytogenetics benefits more from cytarabine dose escalation in induction therapy (Burnett AK et al Br J Haemtol 1996; 93(Suppl 2): 313; abstract) [59][60][61] and from HDAC in consolidation therapy. 62,63 Jahns et al 64 reported the findings of cell-cycle studies of the blast cells from different cytogenetic risk groups.…”

Section: Discussionmentioning

confidence: 99%

Timed-sequential chemotherapy with concomitant granulocyte colony-stimulating factor for newly diagnosed de novo acute myelogenous leukemia

Pohlman²,

Lichtin³

et al. 2003

Leukemia

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High-dose cytosine arabinoside and daunorubicin induction therapy for adult patients with de novo non M3 acute myelogenous leukemia: impact of cytogenetics on achieving a complete remission

Cited by 16 publications

References 25 publications

Induction of apoptosis in retinoid-refractory acute myelogenous leukemia by a novel AHPN analog

Induction of apoptosis in retinoid-refractory acute myelogenous leukemia by a novel AHPN analog

Phase II evaluation of an intensified induction therapy with standard daunomycin and cytarabine followed by high dose cytarabine for adults with previously untreated acute myeloid leukemia: A southwest oncology group study (SWOG‐9500)

Timed-sequential chemotherapy with concomitant granulocyte colony-stimulating factor for newly diagnosed de novo acute myelogenous leukemia

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