A Phase I Dose Escalation Study Of Oral Bexarotene In Combination With Intravenous Decitabine In Patients With AML
Authors: Welch John , Niu Haixa , Uy Geoffrey L. , Westervelt Peter , Abboud Camille N. , Vij Ravi , Stockerl-Goldstein Keith E. , Jacoby Meagan , Pusic Iskra , Schroeder Mark A. , Dipersio John F. , Cashen Amanda F 
Published: October 2019

We sought to determine whether bexarotene can be combined with decitabine in elderly and relapsed AML patients. Both drugs have been shown to be well tolerated in acute myeloid leukemia (AML) patients as single agents, and these agents have non-overlapping mechanisms and side-effect profiles; bexarotene activates transcriptional effects of RXRA through hetero- and homodimers, while decitabine is thought to act through DNA hypomethylation. Furthermore, through Affymetrix expression array profiling of 111 AML patients and Nanostring analysis of 7 MDS and AML patients, we observed consistently elevated levels of RXRA relative to RARA, suggesting that a ligand specific for RXR may be more effective to induce AML differentiation than the RARA ligand ATRA. We treated 18 elderly (≥ 60 years old) or relapsed AML patients in 3+3 dose escalating bexarotene cohorts: 100 mg/m2/day, 200 mg/m2/day, 300 mg/m2/day. All patients were treated with decitabine 20 mg/m2IV on days 1-5 of 28 day cycles. All patients were monitored for hypertriglyceridemia and hypothyroidism, and treated accordingly. The average age was 73, the average performance status was 1, an adverse karyotype was observed in 9 patients, and 12 patients had relapsed after prior therapy. Only one patient experienced a dose limiting toxicity (grade 3 fatigue) and 8 patients were treated with the maximum dose (myelosuppression, infection, differentiation syndrome, hypertriglyceridemia, hyperlipidemia, hypothyroidism, nausea, weight loss and reversible electrolyte abnormalities were not considered dose limiting). The overall response rate was 22%: 1 patient achieved complete remission with incomplete count recovery (CRi) and 3 patients achieved blast reduction greater than 50% (partial response, PR). In addition, six patients achieved stable disease (SD). Patients with CRi, PR, or SD completed an average of 4.25 cycles, while other patients completed an average of 1.2 cycles. Of note, 3 patients successfully transitioned to allogeneic transplant following therapy (average age 68).

We correlated ex vivo bexarotene sensitivity with clinical response. Bone marrow cells were collected on day 0 and day 3 of bexarotene therapy (during cycle 1, decitabine was administered on day 3 after bone marrow collection) and co-cultured with irradiated MS5 murine stromal cells for 72hrs with or without further bexarotene treatment. We used flow cytometry to compare CD11b expression in cells treated with and without bexarotene ex vivo, and compared expression between samples collected on day 0 vs day 3 (in vivo treatment). Bexarotene increased CD11b expression greater in the 4 responding patients vs non-responders (fold increase in CD11b: ex vivo average 2.1 ± 0.3 vs 1.1 ± 0.1 fold, p < 0.003; and in vivo 1.6 ± 0.3 vs 0.7 ± 0.2 fold, p < 0.03; increase in absolute percentage of CD11b+ cells: ex vivo average 24% ± 2.6% vs 0.7% ± 1%, p < 0.001; and in vivo 13.6% ± 4% vs -3.6% ± 2.2%, p < 0.002). Furthermore, all 4 responding patients demonstrated an equivalent or increased induction of CD11b when treated ex vivo with ATRA compared with bexarotene.

These results show that bexarotene, a retinoid which selectively binds to and activates RXRs, but not RARs, can be safely combined with decitabine in relapsed and refractory AML patients. This combination leads to partial response in a subset of patients, is well tolerated, and can bridge elderly patients to allogeneic transplant. Because ex vivo bexarotene treatment identified all patients achieving a PR, further studies should focus on patients who display ex vivo sensitivity. Finally, the mechanism of RXRA-activated differentiation is likely to be through the RXRA/RARA heterodimer, as all 4 patients who responded to bexarotene also responded to ATRA when tested ex vivo.

Disclosures:

Welch: Eisai: Research Funding. Off Label Use: Bexarotene for the treatment of AML. Abboud:Ariad, Alexion, Novartis, Teva: Honoraria, Speakers Bureau. Stockerl-Goldstein:Celgene : Speakers Bureau; Millennium: Speakers Bureau.