Gemtuzumab ozogamicin in combination with vorinostat and azacitidine in older patients with relapsed or refractory acute myeloid leukemia: a phase I/II study

Walter, Roland B.; Medeiros, Bruno C.; Gardner, Kelda M.; Orlowski, Kaysey F.; Gallegos, Leonel; Scott, Bart L.; Hendrie, Paul C.; Estey, Elihu H.

doi:10.3324/haematol.2013.096545

Cited by 47 publications

(25 citation statements)

References 27 publications

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“…Azacitidine-based combinations have recently been investigated in early phase clinical trials in relapsing/refractory AML [76][77][78] and in retrospective cohorts of limited size [60,69,79,80]. Subgroups of relapsed/refractory patients likely to benefit from such azacitidine-based regimens have not been identified to date.…”

Section: Combinationmentioning

confidence: 98%

RETRACTED ARTICLE: 5-Azacitidine for treating acute myelogenous leukemia

Fakih

Champlin²,

Oran³

2015

Expert Opinion on Orphan Drugs

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Section: Combinationmentioning

confidence: 98%

RETRACTED ARTICLE: 5-Azacitidine for treating acute myelogenous leukemia

Fakih

Champlin²,

Oran³

2015

Expert Opinion on Orphan Drugs

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“…94 Although GO is not easily available outside clinical trials, we try to get this drug based on published evidence in elderly relapsed patients with CD33 expression of the blasts as a bridge to transplantation. 95 GO has also been used in combination with demethylating agents such as vorinostat 96 or AZA. 97 These preliminary studies are especially promising for patients not tolerating intense chemotherapy, and modifications of the antibody and its linker might lead to further improvement.…”

Section: Targeting Cd33mentioning

confidence: 99%

How I treat refractory and early relapsed acute myeloid leukemia

Thol

Schlenk

Heuser

et al. 2015

Blood

241

180

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Between 10% and 40% of newly diagnosed patients with acute myeloid leukemia (AML) do not achieve complete remission with intensive induction therapy and are therefore categorized as primary refractory or resistant. Few of these patients can be cured with conventional salvage therapy. They need to be evaluated regarding eligibility for allogeneic hematopoietic stem cell transplantation (HSCT) as this is currently the treatment with the highest probability of cure. To reduce the leukemia burden prior to transplantation, salvage chemotherapy regimens need to be employed. Whenever possible, refractory/relapsed patients should be enrolled in clinical trials as we do not have highly effective and standardized treatments for this situation. Novel therapies include tyrosine kinase inhibitors, small-molecule inhibitors (eg, for Polo-like kinase 1 and aminopeptidase), inhibitors of mutated isocitrate dehydrogenase (IDH) 1 and IDH2, antibody-based therapies, and cell-based therapies. Although the majority of these therapies are still under evaluation, they are likely to enter clinical practice rapidly as a bridge to transplant and/or in older, unfit patients who are not candidates for allogeneic HSCT. In this review, we describe our approach to refractory/early relapsed AML, and we discuss treatment options for patients with regard to different clinical conditions and molecular profiles.

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“…Gemtuzumab ozogamicin was granted accelerated approval by the FDA in 2000 for the treatment of patients over 60 years of age with relapsed CD33-positive AML (3), but was voluntarily withdrawn in 2010 when a postapproval commitment study failed to confirm clinical benefit and hepatic sinusoidal obstruction syndrome (SOS) became recognized as an adverse event (4)(5)(6). However, several recent clinical trials have clarified the optimal conditions for gemtuzumab ozogamicin use and demonstrated benefits to specific patient populations (7,8). Currently, gemtuzumab ozogamicin is still approved and available in Japan.…”

Section: Introductionmentioning

confidence: 99%

Liver Microvascular Injury and Thrombocytopenia of Antibody–Calicheamicin Conjugates in Cynomolgus Monkeys—Mechanism and Monitoring

Guffroy

Falahatpisheh

Biddle

et al. 2017

Clinical Cancer Research

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Purpose: Adverse reactions reported in patients treated with antibody-calicheamicin conjugates such as gemtuzumab ozogamicin (Mylotarg) and inotuzumab ozogamicin include thrombocytopenia and sinusoidal obstruction syndrome (SOS). The objective of this experimental work was to investigate the mechanism for thrombocytopenia, characterize the liver injury, and identify potential safety biomarkers.Experimental Design: Cynomolgus monkeys were dosed intravenously at 6 mg/m 2 /dose once every 3 weeks with a nonbinding antibody-calicheamicin conjugate (PF-0259) containing the same linker-payload as gemtuzumab ozogamicin and inotuzumab ozogamicin. Monkeys were necropsied 48 hours after the first administration (day 3) or 3 weeks after the third administration (day 63).Results: PF-0259 induced acute thrombocytopenia (up to 86% platelet reduction) with nadirs on days 3 to 4. There was no indication of effects on megakaryocytes in bone marrow or activation of platelets in peripheral blood. Microscopic evaluation of liver from animals necropsied on day 3 demonstrated midzonal degeneration and loss of sinusoidal endothelial cells (SECs) associated with marked platelet accumulation in sinusoids. Liver histopathology on day 63 showed variable endothelial recovery and progression to a combination of sinusoidal capillarization and sinusoidal dilation/hepatocellular atrophy, consistent with early SOS. Among biomarkers evaluated, there were early and sustained increases in serum hyaluronic acid (HA) that correlated well with serum aspartate aminotransferase and liver microscopic changes, suggesting that HA may be a sensitive diagnostic marker of the liver microvascular injury.Conclusions: These data support the conclusion that target-independent damage to liver SECs may be responsible for acute thrombocytopenia (through platelet sequestration in liver sinusoids) and development of SOS.

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Gemtuzumab ozogamicin in combination with vorinostat and azacitidine in older patients with relapsed or refractory acute myeloid leukemia: a phase I/II study

Abstract: The primary objective of this study was to determine the vorinostat dose with the most favorable efficacy and toxicity when combined with azacitidine and GO. Methods Study population

Cited by 47 publications

References 27 publications

RETRACTED ARTICLE: 5-Azacitidine for treating acute myelogenous leukemia

RETRACTED ARTICLE: 5-Azacitidine for treating acute myelogenous leukemia

How I treat refractory and early relapsed acute myeloid leukemia

Liver Microvascular Injury and Thrombocytopenia of Antibody–Calicheamicin Conjugates in Cynomolgus Monkeys—Mechanism and Monitoring

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