A randomized phase 3 study of tipifarnib compared with best supportive care, including hydroxyurea, in the treatment of newly diagnosed acute myeloid leukemia in patients 70 years or older

Harousseau, Jean‐Luc; Martinelli, Giovanni; Jędrzejczak, Wiesław Wiktor; Brandwein, Joseph; Bron, Dominique; Masszi, Tamás; Ossenkoppele, Gert J.; Alexeeva, Julia; Beutel, Gernot; Maertens, Johan; Vidriales, María‐Belén; Dombret, Hervé; Thomas, Xavier; Burnett, Alan Kenneth; Robak, Tadeusz; Khuageva, Nuriet K.; Голенков, А К; Tóthová, Elena; Möllgård, Lars; Park, Youn C.; Bessems, Annick; Porre, Peter De; Howes, Angela

doi:10.1182/blood-2009-01-198093

Cited by 130 publications

(78 citation statements)

References 26 publications

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“…Yet, 1-year survival estimates appear similar between the two trials. Likewise, the decitabine results compare favorably with other treatment approaches in unfit patients (11,17,(26)(27)(28). The current standard for this group is low-dose cytarabine, based on positive survival results from a randomized trial of cytarabine vs. hydroxyurea and best supportive care.…”

Section: Discussionmentioning

confidence: 99%

Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine

Blum¹,

Garzon²,

Klisovic³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

437

396

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A phase II clinical trial with single-agent decitabine was conducted in older patients (≥60 years) with previously untreated acute myeloid leukemia (AML) who were not candidates for or who refused intensive chemotherapy. Subjects received low-dose decitabine at 20 mg/m 2 i.v. over 1 h on days 1 to 10. Fifty-three subjects enrolled with a median age of 74 years (range, 60-85). Nineteen (36%) had antecedent hematologic disorder or therapy-related AML; 16 had complex karyotypes (≥3 abnormalities). The complete remission rate was 47% (n = 25), achieved after a median of three cycles of therapy. Nine additional subjects had no morphologic evidence of disease with incomplete count recovery, for an overall response rate of 64% (n = 34). Complete remission was achieved in 52% of subjects presenting with normal karyotype and in 50% of those with complex karyotypes. Median overall and disease-free survival durations were 55 and 46 weeks, respectively. Death within 30 days of initiation of treatment occurred in one subject (2%), death within 8 weeks in 15% of subjects. Given the DNA hypomethylating effect of decitabine, we examined the relationship of clinical response and pretreatment level of miR-29b, previously shown to target DNA methyltransferases. Higher levels of miR-29b were associated with clinical response (P = 0.02). In conclusion, this schedule of decitabine was highly active and well tolerated in this poor-risk cohort of older AML patients. Levels of miR-29b should be validated as a predictive factor for stratification of older AML patients to decitabine treatment.methylation | microRNA | azanucleoside

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Section: Discussionmentioning

confidence: 99%

Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine

Blum¹,

Garzon²,

Klisovic³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

437

396

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“…Studies using diverse combinations of drugs are currently underway. New agents, such as clofarabine, laromustine, tipifarnib [28], and gemtuzumab ozogamicin [29], are currently being assessed as potential prognosis improvers in the clinical trial setting on an elderly AML patient population. In our study, a novel regimen containing fludarabine was designed with the goal of overcoming drug resistance.…”

Section: Discussionmentioning

confidence: 99%

Fludarabine, cytarabine, and attenuated‐dose idarubicin (m‐FLAI) combination therapy for elderly acute myeloid leukemia patients

et al. 2012

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We performed a phase II trial to evaluate the efficacy and safety of the modified fludarabine, cytarabine, and attenuated-dose idarubicin (m-FLAI) regimen in elderly acute myeloid leukemia (AML) patients. Elderly (60 years) AML patients who had not previously received chemotherapy were enrolled in the study. Patients received two consecutive cycles of m-FLAI chemotherapy as an induction. The m-FLAI regimen comprised fludarabine (25 mg/m 2 , days 1-4), cytarabine (1,000 mg/m 2 , days 1-4), and attenuated-dose idarubicin (5 mg/ m 2 , days 1-3). The primary end point was complete remission (CR) rate. Secondary end points were overall survival (OS), event-free survival (EFS), and treatment-related mortality (TRM). There were 108 patients (median age 68.4 years, M:F 5 64:44) enrolled in the study. CR was achieved in 56.5% of patients, and the TRM rate was 21.3%. Median OS and median EFS were 10.2 and 6.6 months, respectively. The mortality at 30 and 60 days was 15 and 21%, respectively. Performance status and comorbidity did not have prognostic value in this patient cohort. Bone marrow expression of CD117 was associated with increased EFS and OS. m-FLAI is an effective induction regimen for previously untreated AML in elderly patients. In addition, bone-marrow CD117 expression is an independent favorable prognostic factor in elderly AML patients. (ClinicalTrials.gov number, NCT01247493). Am. J. Hematol. 88:10-15, 2013. V

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“…As a single agent, the overall response rate (ORR) is <20% (Harousseau et al, 2007;Lancet et al, 2007;Morgan & Sowa, 2007) with significant gastrointestinal, neurologic and infectious toxicities (Karp et al, 2001;Laubach & Rao, 2008). Compared to supportive care in older patients, tipifarnib alone did not result in an OS advantage (Harousseau et al, 2009), and may be best used as a maintenance therapy for patients in CR with high relapse risk .…”

Section: Farnesyl Transferase Inhibitorsmentioning

confidence: 99%

Acute myeloid leukaemia in the elderly: a review

Pollyea¹,

Kohrt²,

Medeiros³

2011

Br J Haematol

134

125

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SummaryThe majority of patients with acute myeloid leukaemia (AML) are elderly. Advancements in supportive care and regimen intensification have resulted in improvements in clinical outcomes for younger AML patients, but analogous improvements in older patients have not been realized. While outcomes are compromised by increased comorbidities and susceptibility to toxicity from therapy, it is now recognized that elderly AML represents a biologically distinct disease that is more aggressive and less responsive to therapy. Some patients tolerate and benefit from intensive remission‐induction approaches, while others are best managed with less aggressive strategies. The challenge is to differentiate these groups based on host‐related and biological features, in order to maximize the therapeutic benefit and minimize toxicity. As more is understood about the complicated pathogenesis and molecular basis of AML, there are more opportunities to develop and test targeted therapies. Elderly patients, with their narrow therapeutic window, are well positioned to derive a benefit from these novel agents, and therefore, despite a difficult past, there are reasons to be optimistic about the future of elderly AML.

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A randomized phase 3 study of tipifarnib compared with best supportive care, including hydroxyurea, in the treatment of newly diagnosed acute myeloid leukemia in patients 70 years or older

Cited by 130 publications

References 26 publications

Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine

Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine

Fludarabine, cytarabine, and attenuated‐dose idarubicin (m‐FLAI) combination therapy for elderly acute myeloid leukemia patients

Acute myeloid leukaemia in the elderly: a review

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