High-dose cytosine arabinoside and etoposide: an effective regimen without anthracyclines for refractory childhood acute non-lymphocytic leukemia

Whitlock, James A.; Wells, RJ; Hord, JD; Janco, RL; Jp, Greer; Edwards, Jeffrey D.; McCurley, TL; Lukens, JN

doi:10.1038/sj.leu.2400572

Cited by 19 publications

(11 citation statements)

References 8 publications

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“…However, intensive regimens with or without anthracyclines appeared similarly effective, and this has important implications for the avoidance of cardiotoxicity in children with high cumulative exposure to anthracyclinescardiotoxicity was a cause of morbidity and mortality in AML 10 where children received 300 mg/m 2 of daunorubicin and 50 mg/m 2 of mitoxantrone, 3 and avoidance of further anthracyclines and/or strategies for cardioprotection should be employed wherever possible. Survival rates of 20-40% have been reported in selected patients receiving consolidation with intensive chemotherapy, ABMT or BMT in second remission, [17][18][19][22][23][24][25][26][27][28] and similar outcomes were observed both in this study, and by the BFM group. 7 Children who received chemotherapy alone in our study had significantly shorter first remissions than those treated by BMT, and 11/18 of this group relapsed again or died of toxicity prior to the median time to transplant indicating selection bias between treatment groups.…”

Section: Figuresupporting

confidence: 75%

Outcome for children with relapsed acute myeloid leukaemia following initial therapy in the Medical Research Council (MRC) AML 10 trial

et al. 1999

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children with acute myeloid leukaemia (AML) were treated in the MRC AML 10 trial. Three risk groups were identified based on cytogenetics and response to treatment. One hundred and twenty-five children relapsed -103 in the bone marrow only, 12 in the bone marrow combined with other sites, and six had isolated extramedullary relapses (site was not known in four cases). Eighty-seven children received further combination chemotherapy, one all-trans retinoic acid for acute promyelocytic leukaemia, and one a matched unrelated donor allograft in relapse, and 61 achieved a second remission. One patient with no details on reinduction therapy also achieved second remission. Treatment in second remission varied -44 children received a BMT (22 autografts, 12 matched unrelated donor allografts, 10 family donor allografts), and 17 were treated with chemotherapy alone. The overall survival rate for all children (treated and untreated) was 24% at 3 years, with a disease-free survival of 44% for those achieving a second remission. Length of first remission was the most important factor affecting response rates -children with a first remission of less than 1 year fared poorly (second remission rate 36%, 3 year survival 11%), whereas those with longer first remissions had a higher response rate (second remission rate 75%, 3 year survival 49%, P Ͻ 0.0001).

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Section: Figuresupporting

confidence: 75%

Outcome for children with relapsed acute myeloid leukaemia following initial therapy in the Medical Research Council (MRC) AML 10 trial

et al. 1999

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“…Etoposide and AraC Lesions Stimulate DNA Cleavage Mediated by Human Topoisomerase II␣ in an Additive or Synergistic Fashion-Chemotherapeutic regimens that combine araC with etoposide display synergistic effects in murine leukemia models and are used routinely for the treatment of patients with relapsed or refractory acute leukemias (1,57,58). Although abasic lesions dominate over etoposide and negate the enhancement of topoisomerase II-mediated DNA cleavage by the drug (not shown) (27), DNA distortions induced by the inclusion of an arabinose ring differ from those that accompany base loss (41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53).…”

Section: Resultsmentioning

confidence: 99%

Cytosine Arabinoside Lesions Are Position-specific Topoisomerase II Poisons and Stimulate DNA Cleavage Mediated by the Human Type II Enzymes

Cline

Osheroff

1999

Journal of Biological Chemistry

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Cytosine arabinoside (araC) is an important drug used for the treatment of human leukemias. In order to exert its cytotoxic effects, araC must be incorporated into chromosomal DNA. Although specific DNA lesions that involve base loss or modification stimulate nucleic acid cleavage mediated by type II topoisomerases, the effects of deoxyribose sugar ring modification on enzyme activity have not been examined. Therefore, the effects of incorporated araC residues on the DNA cleavage/religation equilibrium of human topoisomerase II␣ and ␤ were characterized. AraC lesions were positionspecific topoisomerase II poisons and stimulated DNA scission mediated by both human type II enzymes. However, the positional specificity of araC residues differed from that previously reported for other cleavage-enhancing DNA lesions. Finally, additive or synergistic increases in DNA cleavage were observed in the presence of araC lesions and etoposide. These findings broaden the range of DNA lesions known to alter topoisomerase II function and raise the possibility that this enzyme may mediate some of the cellular effects of araC.Cytosine arabinoside (1-␤-D-arabinofuranosylcytosine, araC) 1 is one of the most important chemotherapeutic drugs used for the treatment of adult and pediatric leukemias (1, 2). The cytotoxicity of araC correlates with its incorporation into newly replicated DNA (1-7). As a prelude to this incorporation, the drug is converted to its "active" nucleoside triphosphate form by pyrimidine salvage pathways (1,2,8). Once integrated into chromosomes, the arabinoside inhibits chain elongation and bypass synthesis and in some cases can induce DNA chain termination or duplication of DNA sequences (1, 2, 7, 9 -19). Although the precise mechanism of araC-induced cell death has not been established, drug treatment leads to reduced rates of DNA replication, DNA strand breaks, and chromosome fragmentation (1, 2, 6, 16, 20 -23).Beyond their established mutagenic or cytotoxic effects, physiologically relevant DNA lesions such as apurinic/apyrimidinic sites and deaminated cytosine residues profoundly influence the activity of eukaryotic type II topoisomerases (24). These lesions act as position-specific topoisomerase II "poisons" and stimulate enzyme-mediated DNA scission when they are located within the 4-base stagger that separates the two phosphodiester bonds cleaved by the enzyme (24 -28). Some nucleoside alterations, such as abasic sites, enhance doublestranded DNA scission with a potency that is 1,000-fold greater than that of etoposide (24 -26, 28).Although DNA lesions that result from base loss or modification have been shown to alter the function of topoisomerase II (24 -28), the effects of sugar ring modification on enzyme activity have not been established. Therefore, the effects of incorporated araC residues on the DNA cleavage activity of human topoisomerase II␣ and -␤ were characterized. Substitution of a ␤-hydroxyl for a hydrogen at the 2Ј-position of deoxycytosine (converting the deoxyribose ring to an arabinose...

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“…These patients also tend to have higher incidences of fungal infections and mucositis. 25,26 A very recent study has suggested that delays in securing a matched donor may be circumvented if enhanced GVHD prophylaxis (albeit, without ex vivo T cell depletion) is offered and a haplo-identical-related donor is used without increasing the outcomes of acute or chronic GVHD. 27 Satisfactory antileukemic effects have long been described for TBI, in combination with piperazinedione, in adults with primary refractory acute leukemia in a series of reports.…”

Section: Discussionmentioning

confidence: 99%

Allogeneic stem-cell transplantation in patients with refractory acute leukemia: a long-term follow-up

Oyekunle

Kröger

Zabelina

et al. 2005

Bone Marrow Transplant

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We examined retrospectively 44 patients with refractory acute leukemia (acute myeloid leukemia (AML)/acute lymphoblastic leukemia ¼ 25/19) who underwent allogeneic transplantation at our center between 11/1990 and 04/2004. The median leukemic blasts was 25% and age 28 years (range, 3-56). Twenty-one patients had untreated relapse, 13 failed reinduction, eight in partial remission and two aplastic. Conditioning was myeloablative using cyclophosphamide, busulfan, total-body irradiation and etoposide (Bu/Cy/VP, n ¼ 22; TBI/Cy/VP, n ¼ 17; others, n ¼ 5) followed by marrow or peripheral blood transplant (n ¼ 23/21) from unrelated or related donors (n ¼ 28/16). All patients had graft-versus-host disease (GVHD) prophylaxis with cyclosporin and methotrexate. One patient experienced late graft failure. Severe acute-GVHD and chronic-GVHD appeared in eight and 14 patients, respectively. Thirteen patients (30%) remain alive after a median of 25.3 months (range, 2.4-134.1); with 31 deaths, mostly from relapse (n ¼ 15) and infections (n ¼ 12). Overall survival (OS) and progression-free survival (PFS) at 5 years was 28 and 26%, respectively. OS and PFS were significantly better with blasts p20% and time to transplant p1 year while transplant-related mortality was less with the use of TBI. We conclude that patients with refractory leukemia can benefit from allogeneic BMT, especially with p20% marrow blast.

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High-dose cytosine arabinoside and etoposide: an effective regimen without anthracyclines for refractory childhood acute non-lymphocytic leukemia

Abstract: The purpose of this report is to describe the tolerability and poside at 1200 mg/m 2 , in children with relapsed and refracactivity of the combination of high-dose cytosine arabinoside tory acute leukemias. Ara-C, daunorubicin, etoposide, thioguanine and dexame-

Cited by 19 publications

References 8 publications

Outcome for children with relapsed acute myeloid leukaemia following initial therapy in the Medical Research Council (MRC) AML 10 trial

Outcome for children with relapsed acute myeloid leukaemia following initial therapy in the Medical Research Council (MRC) AML 10 trial

Cytosine Arabinoside Lesions Are Position-specific Topoisomerase II Poisons and Stimulate DNA Cleavage Mediated by the Human Type II Enzymes

Allogeneic stem-cell transplantation in patients with refractory acute leukemia: a long-term follow-up

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