Vosaroxin and vosaroxin plus low-dose Ara-C (LDAC) vs low-dose Ara-C alone in older patients with acute myeloid leukemia

Dennis, Mike; Russell, Nigel H.; Hills, Robert Kerrin; Hemmaway, Claire; Panoskaltsis, Nicki; McMullin, M. F.; Kjeldsen, Lars; Dignum, Helen; Thomas, Ian; Clark, Richard E.; Milligan, Don; Burnett, Alan Kenneth

doi:10.1182/blood-2014-10-608117

Cited by 49 publications

(41 citation statements)

References 25 publications

(27 reference statements)

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“…17 In addition, toxicity in patients treated with vosaroxin mirrored that seen in the phase 3 study, with gastrointestinal toxicity significantly more common in the patients treated with vosaroxin. However, the 30-day and 60-day mortality were similar in the 2 arms of the study.…”

Section: Vosaroxinmentioning

confidence: 78%

Emerging therapeutic drugs for AML

Stein

Tallman

2016

Blood

166

152

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Multiple new drugs are being developed to treat acute myeloid leukemia (AML), including novel formulations of traditional chemotherapy-antibody drug conjugates and agents that target specific mutant enzymes. Next-generation sequencing has allowed us to discover the genetic mutations that lead to the development and clinical progression of AML. Studies of clonal hierarchy suggest which mutations occur early and dominate. This has led to targeted therapy against mutant driver proteins as well as the development of drugs such as CPX-351 and SGN-CD33A whose mechanisms of action and efficacy may not be dependent on mutational complexity. In this brief review, we discuss drugs that may emerge as important for the treatment of AML in the next 10 years.

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Section: Vosaroxinmentioning

confidence: 78%

Emerging therapeutic drugs for AML

Stein

Tallman

2016

Blood

166

152

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“…They may be further influenced by the microenvironment or epigenetic alterations. Presence of complex aberrant cytogenetic changes has been described to correlate with resistance to low-dose cytarabine treatment before (43). However, even patients without any cytogenetic aberrations do not uniformly respond to chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial BAX Determines the Predisposition to Apoptosis in Human AML

Reichenbach

Wiedenmann

Schalk

et al. 2017

Clinical Cancer Research

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Cell-to-cell variability in apoptosis signaling contributes to heterogenic responses to cytotoxic stress in clinically heterogeneous neoplasia, such as acute myeloid leukemia (AML). The BCL-2 proteins BAX and BAK can commit mammalian cells to apoptosis and are inhibited by retrotranslocation from the mitochondria into the cytosol. The subcellular localization of BAX and BAK could determine the cellular predisposition to apoptotic death. The relative localization of BAX and BAK was determined by fractionation of AML cell lines and patient samples of a test cohort and a validation cohort. This study shows that relative BAX localization determines the predisposition of different AML cell lines to apoptosis. Human AML displays a surprising variety of relative BAX localizations. In a test cohort of 48 patients with AML, mitochondria-shifted BAX correlated with improved patient survival, FLT3-ITD status, and leukocytosis. Analysis of a validation cohort of 80 elderly patients treated with myelosuppressive chemotherapy confirmed that relative BAX localization correlates with probability of disease progression, FLT3-ITD status, and leukocytosis. Relative BAX localization could therefore be helpful to identify elderly or frail patients who may benefit from cytotoxic therapy. In this retrospective analysis of two independent AML cohorts, our data suggest that Bax localization may predict prognosis of patients with AML and cellular predisposition to apoptosis, combining the actual contribution of known and unknown factors to a final "common path." .

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“…To date, negative results with tipifarnib, ATO, GO, and vosaroxin in combination with LDAC have been reported by the British group. [81][82][83][84] Singleagent sapacitabine or clofarabine also failed to improve outcomes over LDAC. 85,86 Addition of quizartinib, ganetespib, tosedostat, or selinexor to LDAC is currently under investigation.…”

Section: Treatment Of Older Aml Patientsmentioning

confidence: 99%

An update of current treatments for adult acute myeloid leukemia

Dombret

Gardin

2016

Blood

460

381

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Recent advances in acute myeloid leukemia (AML) biology and its genetic landscape should ultimately lead to more subset-specific AML therapies, ideally tailored to each patient's disease. Although a growing number of distinct AML subsets have been increasingly characterized, patient management has remained disappointingly uniform. If one excludes acute promyelocytic leukemia, current AML management still relies largely on intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT), at least in younger patients who can tolerate such intensive treatments. Nevertheless, progress has been made, notably in terms of standard drug dose intensification and safer allogeneic HSCT procedures, allowing a larger proportion of patients to achieve durable remission. In addition, improved identification of patients at relatively low risk of relapse should limit their undue exposure to the risks of HSCT in first remission. The role of new effective agents, such as purine analogs or gemtuzumab ozogamicin, is still under investigation, whereas promising new targeted agents are under clinical development. In contrast, minimal advances have been made for patients unable to tolerate intensive treatment, mostly representing older patients. The availability of hypomethylating agents likely represents an encouraging first step for this latter population, and it is hoped will allow for more efficient combinations with novel agents.

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Vosaroxin and vosaroxin plus low-dose Ara-C (LDAC) vs low-dose Ara-C alone in older patients with acute myeloid leukemia

Abstract: Key Points Vosaroxin alone or together with LDAC does not benefit older acute myeloid leukemia patients not considered fit for intensive therapy. In exploratory analyses, no demographic subgroup showed a survival benefit.

Cited by 49 publications

References 25 publications

Emerging therapeutic drugs for AML

Emerging therapeutic drugs for AML

Mitochondrial BAX Determines the Predisposition to Apoptosis in Human AML

An update of current treatments for adult acute myeloid leukemia

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