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Sequential Azacitidine and Lenalidomide for Patients with Relapsed and Refractory Acute Myeloid Leukemia: Clinical Results and Predictive Modeling Using Computational Analysis

82 Pages Posted: 4 Jan 2019

See all articles by Brett Stevens

Brett Stevens

University of Colorado at Denver - Division of Hematology

Amanda Winters

University of Colorado at Denver - Children’s Hospital Colorado

Jonathan A. Gutman

University of Colorado at Denver - Division of Hematology

Aaron Fullerton

University of Colorado at Denver - Division of Hematology

Gregory Hemenway

University of Colorado at Denver - Division of Hematology

Derek Schatz

University of Colorado at Denver - Children’s Hospital Colorado

Nicholas Miltgen

University of Colorado at Denver - Children’s Hospital Colorado

Qi Wei

University of Colorado at Denver - Children’s Hospital Colorado

Taher Abbasi

Cellworks Group Inc.

Shireen Vali

Cellworks Group Inc.

Neeraj K Singh

Cellworks Group Inc.

Leylah Drusbosky

University of Florida

Christopher R. Cogle

University of Florida

Andrew Hammes

University of Colorado at Denver

Diana Abbott

University of Colorado at Denver - Department of Emergency Medicine; Denver Health - Rocky Mountain Poison & Drug Center

Craig T. Jordan

University of Colorado at Denver - Division of Hematology

Clayton Smith

University of Colorado at Denver - Division of Hematology

Daniel Pollyea

University of Colorado at Denver - Division of Hematology

More...

Abstract

Background: Patients with relapsed and refractory (R/R) acute myeloid leukemia (AML) have limited treatment options. Genomically-defined personalized therapies are only applicable for a minority of patients. Therapies without identifiable targets can be effective but patient selection is challenging. The sequential combination of azacitidine with high-dose lenalidomide has shown activity; we aimed to determine the efficacy of this genomically-agnostic regimen in R/R AML, with the intention of applying sophisticated methods to predict responders.

Methods: Thirty-seven R/R AML/myelodysplastic syndrome patients were enrolled in a phase 2 study of azacitidine with lenalidomide. The primary endpoint was complete remission (CR) and CR with incomplete blood count recovery (CRi) rate. A computational biological modeling (CBM) approach was applied retrospectively to predict outcomes based on understood mechanisms of azacitidine and lenalidomide in the setting of each patients' disease.

Findings: Four of 37 patients (11%) had a CR/CRi; the study failed to meet the alternative hypothesis. Significant toxicity was observed in some cases, with three treatment-related deaths and a 30-day mortality rate of 14%. However, the CBM method predicted responses in 83% of evaluable patients, with a positive and negative predictive value of 80% and 89%, respectively.

Interpretation: Sequential azacitidine and high-dose lenalidomide is effective in a minority of R/R AML patients; it may be possible to predict responders at the time of diagnosis using a CBM approach. More efforts to predict responses in non-targeted therapies should be made, to spare toxicity in patients unlikely to respond and maximize treatments for those with limited options.

Funding Statement: Celgene

Declaration of Interests: DAP is a consultant for Celgene and has received research funding from Celgene. TA, SV, NKS, LD and CRC are or have been employed by or received research funding from Cellworks.

Ethics Approval Statement: The study was approved by the institutional review board; all patients provided written informed consent prior to any procedures, and the study was performed in accordance with the Declaration of Helsinki.

Keywords: acute myeloid leukemia, myelodysplastic syndrome, relapsed, azacitidine, lenalidomide, phase 2

Suggested Citation

Stevens, Brett and Winters, Amanda and Gutman, Jonathan A. and Fullerton, Aaron and Hemenway, Gregory and Schatz, Derek and Miltgen, Nicholas and Wei, Qi and Abbasi, Taher and Vali, Shireen and Singh, Neeraj K and Drusbosky, Leylah and Cogle, Christopher R. and Hammes, Andrew and Abbott, Diana and Jordan, Craig T. and Smith, Clayton and Pollyea, Daniel, Sequential Azacitidine and Lenalidomide for Patients with Relapsed and Refractory Acute Myeloid Leukemia: Clinical Results and Predictive Modeling Using Computational Analysis (December 24, 2018). Available at SSRN: https://ssrn.com/abstract=3307702

Brett Stevens

University of Colorado at Denver - Division of Hematology

13001 E 17th Pl
Aurora, CO 80045
United States

Amanda Winters

University of Colorado at Denver - Children’s Hospital Colorado

13123 East 16th Avenue
Aurora, CO 80045
United States

Jonathan A. Gutman

University of Colorado at Denver - Division of Hematology

13001 E 17th Pl
Aurora, CO 80045
United States

Aaron Fullerton

University of Colorado at Denver - Division of Hematology

13001 E 17th Pl
Aurora, CO 80045
United States

Gregory Hemenway

University of Colorado at Denver - Division of Hematology

13001 E 17th Pl
Aurora, CO 80045
United States

Derek Schatz

University of Colorado at Denver - Children’s Hospital Colorado

13123 East 16th Avenue
Aurora, CO 80045
United States

Nicholas Miltgen

University of Colorado at Denver - Children’s Hospital Colorado

13123 East 16th Avenue
Aurora, CO 80045
United States

Qi Wei

University of Colorado at Denver - Children’s Hospital Colorado

13123 East 16th Avenue
Aurora, CO 80045
United States

Taher Abbasi

Cellworks Group Inc.

CA
United States

Shireen Vali

Cellworks Group Inc.

CA
United States

Neeraj K Singh

Cellworks Group Inc.

CA
United States

Leylah Drusbosky

University of Florida

PO Box 117165, 201 Stuzin Hall
Gainesville, FL 32610-0496
United States

Christopher R. Cogle

University of Florida

PO Box 117165, 201 Stuzin Hall
Gainesville, FL 32610-0496
United States

Andrew Hammes

University of Colorado at Denver

Box 173364
1250 14th Street
Denver, CO 80217
United States

Diana Abbott

University of Colorado at Denver - Department of Emergency Medicine

Aurora, CO
United States

Denver Health - Rocky Mountain Poison & Drug Center

1391 Speer Boulevard, Suite 600
Denver, CO 80204
United States

Craig T. Jordan

University of Colorado at Denver - Division of Hematology

13001 E 17th Pl
Aurora, CO 80045
United States

Clayton Smith

University of Colorado at Denver - Division of Hematology

13001 E 17th Pl
Aurora, CO 80045
United States

Daniel Pollyea (Contact Author)

University of Colorado at Denver - Division of Hematology ( email )

13001 E 17th Pl
Aurora, CO 80045
United States

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