Effect of haematological improvement on survival in patients given targeted therapy as initial treatment of acute myeloid leukaemia or high‐risk myelodysplastic syndrome

Yanada, Masamitsu; Huang, Xuelin; O’Brien, Susan; Ravandi, Farhad; Borthakur, Gautam; Issa, Jean–Pierre J.; Kantarjian, Hagop M.; Estey, Elihu H.

doi:10.1111/j.1365-2141.2007.06670.x

Cited by 4 publications

(2 citation statements)

References 10 publications

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“…Similar results have been reported in the AZA-001 trial, although, so far, only in abstract form, 7 and with decitabine. 11,26 Such findings suggest that improvement of survival by AZA is, in part, attributable to the correction of anemia, or, more probably, that AZA allows disease regression to an earlier stage, with less cytopenias and a lower risk of progression to AML.…”

Section: Discussionmentioning

confidence: 84%

Prognostic factors for response and overall survival in 282 patients with higher-risk myelodysplastic syndromes treated with azacitidine

Itzykson

Thépot

Quesnel

et al. 2011

Blood

346

287

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Prognostic factors for response and survival in higher-risk myelodysplastic syndrome patients treated with azacitidine (AZA) remain largely unknown. Two hundred eighty-two consecutive high or intermediate-2 risk myelodysplastic syndrome patients received AZA in a compassionate, patient-named program. Diagnosis was RA/RARS/RCMD in 4%, RAEB-1 in 20%, RAEB-2 in 54%, and RAEB-t (AML with 21%-30% marrow blasts) in 22%. Cytogenetic risk was good in 31%, intermediate in 17%, and poor in 47%. Patients received AZA for a median of 6 cycles (1-52). Previous low-dose cytosine arabinoside treatment (P ‫؍‬ .009), bone marrow blasts > 15% (P ‫؍‬ .004), and abnormal karyotype (P ‫؍‬ .03) independently predicted lower response rates. Complex karyotype predicted shorter responses (P ‫؍‬ .0003). Performance status > 2, intermediate-and poor-risk cytogenetics, presence of circulating blasts, and red blood cell transfusion dependency > 4 units/8 weeks (all P < 10 ؊4 ) independently predicted poorer overall survival (OS). A prognostic score based on those factors discriminated 3 risk groups with median OS not reached, 15.0 and 6.1 months, respectively (P < 10 ؊4 ). This prognostic score was validated in an independent set of patients receiving AZA in the AZA-001 trial (P ‫؍‬ .003). Achievement of hematological improvement in patients who did not obtain complete or partial remission was associated with improved OS (P < 10 ؊4 ). In conclusion, routine tests can identify subgroups of patients with distinct prognosis with AZA treatment. (Blood. 2011; 117(2):403-411)

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Section: Discussionmentioning

confidence: 84%

Prognostic factors for response and overall survival in 282 patients with higher-risk myelodysplastic syndromes treated with azacitidine

Itzykson

Thépot

Quesnel

et al. 2011

Blood

346

287

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“…The experience with 5-azacytidine and decitabine, however, has demonstrated that relief of cytopenia, even if technical criteria for CR are unmet, is also linked with longer survival: in an analysis of decitabine-treated patients (N ϭ 31), hematologic improvement sans CR was associated with significantly better OS 33 and, in a multicenter cohort study of high-risk MDS patients (N ϭ 282), achievement of any type of hematologic improvement was accompanied by a significant improvement in OS, in a multivariate analysis that incorporated cytogenetic status, myeloblast percentage, and other risk factors. 34 …”

Section: Clinical Observation #3 Hematologic Improvement Without Cr Imentioning

confidence: 99%

Key clinical observations after 5-azacytidine and decitabine treatment of myelodysplastic syndromes suggest practical solutions for better outcomes

Saunthararajah

2013

Hematology

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Clinical experience with 5-azacytidine and decitabine treatment of myelodysplastic syndromes (MDS), complemented by biological and pharmacological studies, has revealed compelling mechanism of action differences compared with traditional myeloid cancer treatment mainstays such as cytarabine. For example, 5-azacytidine and decitabine produce remissions and better overall survival in MDS with high-risk chromosome abnormalities at a surprisingly high rate, consistent with experimental observations that noncytotoxic DNA methyltransferase depletion by 5-azacytidine/decitabine can trigger cell cycle exit independently of p53, thus circumventing a basis for resistance to apoptosis-based DNAdamaging therapy. That responses cut across the chaotic genomic landscape of MDS highlights common threads in disease, such as high expression in myeloblasts of differentiation-driving transcription factors yet paradoxical epigenetic suppression of proliferation-terminating late-differentiation genes. Less toxic regimens (lower dosages but more frequent administration) of 5-azacytidine/decitabine have been more successful, underscoring the importance of preserving functionally normal stem cells, which are rendered more precious by attrition from age, previous cytotoxic treatments, and the disease process and are needed to relieve cytopenias, the cause of morbidity and mortality. Also emphasized is that there can be no therapeutic benefit, regardless of mutation or cytogenetic subtype, if DNA methyltransferase is not depleted by sufficient overlap between intracellular drug half-lives and S-phase entries of malignant cells. Improved understanding of mechanism-of-action differences demands new approaches, from historic (but not scientific) more-is-better and one-sizefits-all empiricism to pharmacodynamic-based designs and combinations directed not solely at suppressing malignant clones, but at improving therapeutic indices.

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Targeted Therapy in Acute Myelogenous Leukemia

Estey¹

Targeted Cancer Therapy

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Effect of haematological improvement on survival in patients given targeted therapy as initial treatment of acute myeloid leukaemia or high‐risk myelodysplastic syndrome

Cited by 4 publications

References 10 publications

Prognostic factors for response and overall survival in 282 patients with higher-risk myelodysplastic syndromes treated with azacitidine

Prognostic factors for response and overall survival in 282 patients with higher-risk myelodysplastic syndromes treated with azacitidine

Key clinical observations after 5-azacytidine and decitabine treatment of myelodysplastic syndromes suggest practical solutions for better outcomes

Targeted Therapy in Acute Myelogenous Leukemia

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