Statin plus chemo yields encouraging results in poor-risk AML

Patients with poor-risk acute myelogenous leukemia (AML) had promising rates of response and survival following treatment with a statin added to standard chemotherapy, researchers reported.

Pravastatin in combination with idarubicin and cytarabine had a 30% response rate in poor-risk AML patients, according to Anjali S. Advani, MD, of the Taussig Cancer Institute at the Cleveland Clinic, and her coauthors.

Although that response rate did not meet a prespecified threshold for statistical significance, results of the phase 2 study were nevertheless “encouraging” for a group of patients with unfavorable cytogenetics and poor-risk molecular mutations, the researchers wrote. The study was published in Leukemia Research.

The estimated median overall survival was 4.1 months in the phase 2 trial, known as SWOG S0919. About one-quarter of the patients were able to proceed to allogeneic hematopoietic stem cell transplant, and for that group, median overall survival was 27.1 months.

These findings appear to provide further support for the hypothesis that targeting the cholesterol pathway may be a promising approach in patients with AML.

Some previous investigations suggested that AML blasts overexpress genes for lipoprotein receptors and regulatory enzymes, while others showed that these cells import and synthesize cholesterol at levels higher than what is seen in normal progenitor cells. In addition, some AML patients have hypocholesterolemia that usually resolves when they achieve a complete remission.

“These observations suggest that AML cells may require high levels of cholesterol for their survival and that abnormalities in cholesterol homeostasis are necessary for AML cell survival,” the researchers wrote.

This led to a phase 1 trial of pravastatin plus idarubicin/cytarabine, followed by the phase 2 SWOG S0919 trial, which demonstrated a 75% rate of complete response (CR) or complete response with incomplete count recovery (CRi) for the regimen.

The SWOG S0919 study was amended to include the poor-risk AML patients described in the present study. That cohort of 46 patients had a CR/CRi of less than 6 months after their last induction regimen or refractory disease. Many had poor-risk cytogenetics (43%) or one of a number of poor-risk mutations, according to the study report.

Pravastatin, in addition to working on the cholesterol pathway in AML, may also have a therapeutic advantage in patients with FLT3 mutations. Three out of six patients with FLT3 mutations achieved CR/CRi, corroborating earlier preclinical studies and suggesting further study of this specific patient population would be worthwhile, the researchers noted.

The study was supported in part by the National Institutes of Health and Bristol-Myers Squibb. Dr. Advani reported having no financial disclosures but other study authors reported relationships with various pharmaceutical companies.

SOURCE: Advani AS et al. Leuk Res. 2018 Apr;67:17-20.

Patients with poor-risk acute myelogenous leukemia (AML) had promising rates of response and survival following treatment with a statin added to standard chemotherapy, researchers reported.

Pravastatin in combination with idarubicin and cytarabine had a 30% response rate in poor-risk AML patients, according to Anjali S. Advani, MD, of the Taussig Cancer Institute at the Cleveland Clinic, and her coauthors.

Although that response rate did not meet a prespecified threshold for statistical significance, results of the phase 2 study were nevertheless “encouraging” for a group of patients with unfavorable cytogenetics and poor-risk molecular mutations, the researchers wrote. The study was published in Leukemia Research.

The estimated median overall survival was 4.1 months in the phase 2 trial, known as SWOG S0919. About one-quarter of the patients were able to proceed to allogeneic hematopoietic stem cell transplant, and for that group, median overall survival was 27.1 months.

These findings appear to provide further support for the hypothesis that targeting the cholesterol pathway may be a promising approach in patients with AML.

Some previous investigations suggested that AML blasts overexpress genes for lipoprotein receptors and regulatory enzymes, while others showed that these cells import and synthesize cholesterol at levels higher than what is seen in normal progenitor cells. In addition, some AML patients have hypocholesterolemia that usually resolves when they achieve a complete remission.

“These observations suggest that AML cells may require high levels of cholesterol for their survival and that abnormalities in cholesterol homeostasis are necessary for AML cell survival,” the researchers wrote.

This led to a phase 1 trial of pravastatin plus idarubicin/cytarabine, followed by the phase 2 SWOG S0919 trial, which demonstrated a 75% rate of complete response (CR) or complete response with incomplete count recovery (CRi) for the regimen.

The SWOG S0919 study was amended to include the poor-risk AML patients described in the present study. That cohort of 46 patients had a CR/CRi of less than 6 months after their last induction regimen or refractory disease. Many had poor-risk cytogenetics (43%) or one of a number of poor-risk mutations, according to the study report.

Pravastatin, in addition to working on the cholesterol pathway in AML, may also have a therapeutic advantage in patients with FLT3 mutations. Three out of six patients with FLT3 mutations achieved CR/CRi, corroborating earlier preclinical studies and suggesting further study of this specific patient population would be worthwhile, the researchers noted.

The study was supported in part by the National Institutes of Health and Bristol-Myers Squibb. Dr. Advani reported having no financial disclosures but other study authors reported relationships with various pharmaceutical companies.

SOURCE: Advani AS et al. Leuk Res. 2018 Apr;67:17-20.

Patients with poor-risk acute myelogenous leukemia (AML) had promising rates of response and survival following treatment with a statin added to standard chemotherapy, researchers reported.

Pravastatin in combination with idarubicin and cytarabine had a 30% response rate in poor-risk AML patients, according to Anjali S. Advani, MD, of the Taussig Cancer Institute at the Cleveland Clinic, and her coauthors.

Although that response rate did not meet a prespecified threshold for statistical significance, results of the phase 2 study were nevertheless “encouraging” for a group of patients with unfavorable cytogenetics and poor-risk molecular mutations, the researchers wrote. The study was published in Leukemia Research.

The estimated median overall survival was 4.1 months in the phase 2 trial, known as SWOG S0919. About one-quarter of the patients were able to proceed to allogeneic hematopoietic stem cell transplant, and for that group, median overall survival was 27.1 months.

These findings appear to provide further support for the hypothesis that targeting the cholesterol pathway may be a promising approach in patients with AML.

Some previous investigations suggested that AML blasts overexpress genes for lipoprotein receptors and regulatory enzymes, while others showed that these cells import and synthesize cholesterol at levels higher than what is seen in normal progenitor cells. In addition, some AML patients have hypocholesterolemia that usually resolves when they achieve a complete remission.

“These observations suggest that AML cells may require high levels of cholesterol for their survival and that abnormalities in cholesterol homeostasis are necessary for AML cell survival,” the researchers wrote.

This led to a phase 1 trial of pravastatin plus idarubicin/cytarabine, followed by the phase 2 SWOG S0919 trial, which demonstrated a 75% rate of complete response (CR) or complete response with incomplete count recovery (CRi) for the regimen.

The SWOG S0919 study was amended to include the poor-risk AML patients described in the present study. That cohort of 46 patients had a CR/CRi of less than 6 months after their last induction regimen or refractory disease. Many had poor-risk cytogenetics (43%) or one of a number of poor-risk mutations, according to the study report.

Pravastatin, in addition to working on the cholesterol pathway in AML, may also have a therapeutic advantage in patients with FLT3 mutations. Three out of six patients with FLT3 mutations achieved CR/CRi, corroborating earlier preclinical studies and suggesting further study of this specific patient population would be worthwhile, the researchers noted.

The study was supported in part by the National Institutes of Health and Bristol-Myers Squibb. Dr. Advani reported having no financial disclosures but other study authors reported relationships with various pharmaceutical companies.

SOURCE: Advani AS et al. Leuk Res. 2018 Apr;67:17-20.