Topotecan and Cytarabine Is an Active Combination Regimen in Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia

Beran, Miloslav; Estey, Elihu H.; O’Brien, Susan; Cortes, Jorge; Koller, Charles; Giles, Francis J.; Kornblau, Steven M.; Andreeff, Michael; Vey, Norbert; Pierce, Sherry; Hayes, Kimberly; Wong, Gee Chuan; Keating, Michael J.; Kantarjian, Hagop M.

doi:10.1200/jco.1999.17.9.2819

Cited by 122 publications

(76 citation statements)

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“…13,14 These results, observed in CMML, RAEB and RAEB-T seem to be better than those we observed with CPT-11, but with greater hematological toxicity. Indeed, when topotecan was given alone, median time to recovery of granulocytes and platelets was 26 and 30 days, respectively, whereas with CPT-11, at the dose we tested (median duration of neutropenia was 7 days and only 25% of courses required patient hospitalization.…”

Section: Figurecontrasting

confidence: 53%

“…[8][9][10][11][12] Topotecan, a DNA topoisomerase-I inhibitor has recently shown activity in high-risk MDS, alone or in combination with cytarabine. 13,14 In the present study, we used CPT-11, another DNA topoisomerase-I inhibitor with a different spectrum of activity and toxicity, in 26 patients with MDS with an excess of marrow blasts who could not receive anthracycline/cytarabine intensive chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

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Phase II trial of CPT-11 in myelodysplastic syndromes with excess of marrow blasts

et al. 2003

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7 ULB, BelgiumCPT-11 is an antineoplastic agent which acts as a specific inhibitor of DNA topisomerase 1 and has a broad spectrum of activity in solid tumors. Very few studies have evaluated the activity of CPT-11 in hematological malignancies. We conducted a phase II trial of CPT-11 in 26 patients with high-risk MDS (RAEB 1: n = 4; RAEB 2: n = 9; MDS having progressed to AML: n = 10; CMML: n = 3) who could not receive anthracycline/cytarabine intensive chemotherapy. Induction therapy consisted of four courses of CPT-11 given intravenously at 200 mg/m 2 every 2 weeks. Patient characteristics were: median age, 71 (range 51-77); sex, (M/F), 21/5, median % marrow blasts cells, 13.5 (range 7-52). Cytogenetics according to IPSS were: low-risk n = 13, intermediate-risk n = 6, high-risk n = 3, failure or not done n = 4. Six patients stopped treatment after only one or two courses of CPT-11 due to severe infection (n = 2), progressive disease (n = 3), acute lysis syndrome with renal failure (n = 1). In the 20 patients who received at least three cycles of CPT-11, complete remission was achieved in one case, partial remission in four cases, and hematological improvement in three cases with an overall response rate of 33% in the 26 patients. Duration of response was short (median 4 months, range 1-6 months) and median survival was 8 months (range 1-23 months). Digestive toxicity (diarrhea) occurred in 26/89 (29%) courses, but was mild (grade 1, 20% courses; grade 2 or 3, 9% courses). Hematological toxicity was difficult to assess in non-responders because of initial pancytopenia, but all the patients who responded had grade 3/4 hematological toxicity associated with grade у2 infection requiring hospitalization in 18% of the courses. No other major toxicity was observed. Thus CPT-11 has an interesting activity in MDS with excess of blasts; toxicity is easily managed and most patients can be treated in the out-clinic setting. These results suggest that further evaluation of CPT-11 in MDS is warranted.

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Section: Figurecontrasting

confidence: 53%

Section: Introductionmentioning

confidence: 99%

Phase II trial of CPT-11 in myelodysplastic syndromes with excess of marrow blasts

et al. 2003

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“…1,2 Recently, topoisomerase inhibitors, cytokines, and multidrug resistant (MDR)-1 blockers have been evaluated, but they failed to have major impact on patient survival. [3][4][5][6][7] Most chemotherapy agents used in the treatment of hematologic malignancies eliminate cells by inducing apoptosis, and many factors that inhibit chemotherapy-induced apoptosis have been identified. The initiation of a cascade of cysteine proteases of the ICE/ced3 family (caspases) plays a pivotal role in apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Novel triterpenoid CDDO-Me is a potent inducer of apoptosis and differentiation in acute myelogenous leukemia

Konopleva

Tsao

Ruvolo

et al. 2002

Blood

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It has been shown that the novel synthetic triterpenoid CDDO inhibits proliferation and induces differentiation and apoptosis in myeloid leukemia cells. In the current study the effects of the C-28 methyl ester of CDDO, CDDO-Me, were analyzed on cell growth and apoptosis of leukemic cell lines and primary acute myelogenous leukemia (AML) . IntroductionAcute myelogenous leukemia (AML) remains incurable in most patients, largely because of its resistance to chemotherapy. The therapeutic regimens used have not changed in the past 3 decades and usually include cytosine arabinoside (ara-C) and anthracycline analogs. 1,2 Recently, topoisomerase inhibitors, cytokines, and multidrug resistant (MDR)-1 blockers have been evaluated, but they failed to have major impact on patient survival. [3][4][5][6][7] Most chemotherapy agents used in the treatment of hematologic malignancies eliminate cells by inducing apoptosis, and many factors that inhibit chemotherapy-induced apoptosis have been identified. The initiation of a cascade of cysteine proteases of the ICE/ced3 family (caspases) plays a pivotal role in apoptosis. 8 The extrinsic death receptor pathway, triggered by members of the tumor necrosis factor family, is activated when the proximal regulator caspase-8 is recruited into the death receptor complex. The Bcl-2 family of proteins, on the other hand, seems to play a central role in the regulation of the mitochondrial (intrinsic) apoptotic pathway. In particular, Bcl-2 and Bcl-X L overexpression prevent the mitochondrial release of cytochrome c, caspase activation, and apoptosis (for review, see [9][10][11] ). Bax is a pro-apoptotic member of the Bcl-2 family that dimerizes with itself or with Bcl-2/Bcl-X L , and an increase in the levels of free Bax, or Bax homodimers, promotes apoptosis. 12,13 Bcl-2 has been the subject of intense study as a mechanism of chemoresistance because of its ability to suppress chemotherapy-induced apoptosis. 12,14,15 Recent studies have demonstrated that phosphorylation of Bcl-2 at the serine 70 site is required to inhibit apoptosis. 16,17 Protein kinase (PKC)-␣ and the mitogen-activated protein (MAP) kinases ERK1 (p44) and ERK2 (p42) were identified as physiologic Bcl-2 kinases, 18,19 and PKC-␣ expression was observed to modulate the prognostic impact of Bcl-2 in AML. 20 These collective results strongly suggest that Bcl-2 phosphorylation plays a role in the resistance of cells to chemotherapy-induced apoptosis.Triterpenoids The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 U.S.C. section 1734. For personal use only. on April 27, 2019. by guest www.bloodjournal.org From are both derived from squalene and have definite, though weak, anti-inflammatory and anticarcinogenic properties. 22,23 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) is a novel synthetic triterpenoid that is more than 10 000-fold more potent than its parent compound, ole...

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“…43 Intensive chemotherapy with intermediate doses of Ara-C and topotecan was investigated in a phase II trial in CMML, obtaining a CR rate of 44%, with a median remission duration of 33 weeks and a median survival of 41 weeks. 56 Therapy with topotecan as single agent induced CR in 28% of CMML patients, with a median survival time of 10.5 months, and a median CR duration of 7.5 months. 57 In a more recent trial in 90 patients with MDS and CMML treated with oral topotecan following 2 different schedules, the response rate in CMML patients was…”

Section: Category Response Criteria (Responses Must Last At Least 4 Wmentioning

confidence: 99%

Management recommendations for chronic myelomonocytic leukemia: consensus statements from the SIE, SIES, GITMO groups

et al. 2013

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MethodsAn expert panel of 8 hematologists with a long experience and scientific interest in CMML was selected. During an initial meeting on December 2011, the areas of major concern in the management of CMML were identified. Clinical key-questions were generated and rank-ordered using the criterion of clinical relevance (Table 1).Each panelist drafted statements that addressed the key questions, and the remaining panelists scored their agreement with those statements providing suggestions for re-phrasing. To exploit this phase of the process, the Delphi questionnaire method was used. 4 Finally, the panel met three times in Bologna, Italy, for consensus conferences. The nominal group technique 5 was used according to which participants were first asked to comment in round-robin fashion on their preliminary votes and then to propose a new vote. Results Patient evaluation at diagnosisThe diagnosis of CMML relies largely on findings of bone With the aim of reviewing critical concepts and producing recommendations for the management of chronic myelomonocytic leukemia, key questions were selected according to the criterion of clinical relevance. Recommendations were produced using a Delphi process and four consensus conferences involving a panel of experts appointed by the Italian Society of Hematology and affiliated societies. This report presents the final statements and recommendations, covering patient evaluation at diagnosis, diagnostic criteria, risk classification, first-line therapy, monitoring, second-line therapy and allogeneic stem cell transplantation. For the first-line therapy, the panel recommended that patients with myelodysplastic-type chronic myelomonocytic leukemia and less than 10% blasts in bone marrow should be managed with supportive therapy aimed at correcting cytopenias. In patients with myelodysplastic-type chronic myelomonocytic leukemia with a high number of blasts in bone marrow (≥10%), supportive therapy should be integrated with the use of 5-azacytidine. Patients with myeloproliferative-type chronic myelomonocytic leukemia with a low number of blasts (<10%) should be treated with cytoreductive therapy. Hydroxyurea is the drug of choice to control cell proliferation and to reduce organomegaly. Patients with myeloproliferative-type chronic myelomonocytic leukemia, and a high number of blasts should receive polychemotherapy. Both in myelodysplastic-type and myeloproliferative-type chronic myelomonocytic leukemia, allogeneic stem cell transplantation should be offered within clinical trials in selected patients. Management recommendations for chronic myelomonocytic leukemia: consensus statements from the SIE, SIES, GITMO groups ABSTRACTmarrow (BM) morphological dysplasia or clonal genetic abnormalities in patients with persistent peripheral blood monocytosis. Conventional cytogenetic analysis can allow clonal abnormalities to be indentifed, even if most patients with CMML exhibit a normal karyotype. 6 The most frequent abnormalities involve chromosome 7, mostly consisting of monosomy, triso...

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Topotecan and Cytarabine Is an Active Combination Regimen in Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia

Cited by 122 publications

References 40 publications

Phase II trial of CPT-11 in myelodysplastic syndromes with excess of marrow blasts

Phase II trial of CPT-11 in myelodysplastic syndromes with excess of marrow blasts

Novel triterpenoid CDDO-Me is a potent inducer of apoptosis and differentiation in acute myelogenous leukemia

Management recommendations for chronic myelomonocytic leukemia: consensus statements from the SIE, SIES, GITMO groups

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