Dose Escalation of Azacitidine in Patients Failing Standard or Investigational Combinations of the Agent in the Myelodysplastiic Syndrome or Evolved AML
Authors: Silverman Lewis R. , Navada Shyamala C. , Odchimar-Reissig Rosalie , Michalak Maria , Demakos Erin P , Holland James F 
Published: October 2019

Abstract 4932

Background:

The hypomethylating agent azacitidine (azaC) which can reverse epigenetic silencing, is the first agent demonstrated to alter the natural history of MDS and improve survival in higher-risk patients (Silverman JCO 2002, Fenaux Lancet Oncology 2009). AzaC also produces comparable rates of response in patients with non-proliferative AML and appears to affect survival (Silverman JCO 2006). The response rate to single agent azaC is about 50% with median duration of response about 14 to 22 months. Patients who are refractory to or relapse following first line therapy with azaC have a median survival of 4 to 6 months (Jabbour 2010, Prebet 2011). Options for these patients failing first-line therapy with azaC are limited and there is no standard of care. Investigational therapies are being explored but not always widely available for these patients. Prior studies with azaC explored higher doses but were inconclusive to a dose response effect secondary to the slow time to response with a median of 2 to 3 cycles. In vitro, azaC has a wide range of concentrations that can induce differentiation up to 4 μm. In patients the standard clinical dose achieves a plasma level of 1. 25 μm thus suggesting that higher doses might have a clinical benefit (Marcucci 2005).

Methods:

Patients who were refractory to or relapsing following treatment with an azaC based regimen for MDS where alternative investigational options were not available and who were not rapidly progressing (i. e rapidly rising WBC or myeloblast %), were treated with higher doses of single agent azaC. The dose was increased by 33% from the baseline prior failing regimen (eg 55 to 75 or 75 to 100 mg/m2). The azaC was administered SC × 7 days q 28 days; response status was assessed after 2 cycles. Patients stable or responding were continued on 28 day cycles. Myeloid cytokine support was utilized for patients with ANC < 200 and ESA support for patients who were RBC dependent.

Results:

As of the data cut for this submission 13 patients are evaluable for toxicity and response. Among the 13 patients the median age was 68 and 11 were male. All had been treated with azaC based regimens before and 10 had responded: 4 CR; 1 PR; 5 HI; 2 NR; 1 unknown. The immediate therapy prior to increased dosing included: azaC + histone deacetylase inhibitor (HDACi) (6); single agent azaC (5); investigational treatment (2). 6 had MDS (int-1 (2); int-2 (3); high (1) and 7 AML (all transformed following MDS all smoldering). Responses among evaluable patients have occurred in 11 of 13 (85%); 1 PR, 7 HI (4 CRm), 1 CRm, (CR+CRi=53%) 2 PRm, 1 SD, 1 NR. Although responses occurred, the abnormal MDS/AML clone persisted, suggesting that the higher dose did not have a cytotoxic effect on the malignant clone. A total of 117 cycles have been administered, range 2 to 17 with a mean 8 cycles. Median time to treatment failure was 11. 6 months and median survival is 17. 5 months. Eight patients have come off treatment for progression (5); relapse (2); co-morbidities (1). No grade 3 or 4 non-hematologic toxicities were observed. Hematologic toxicity was similar to that seen with standard dose azaC.

Conclusion:

Modification of the dose of azaC in select patients, who lack alternative options including investigational agents or stem cell transplant, may improve blood counts and reduce the bone marrow blasts. The quality of the response to the increased dose after primary failure does not attain the level of the original response in most, however, this approach may increase therapeutic options in a poor risk population. Investigations into the potential mechanisms of action are being explored.

Disclosures:

Silverman: celgene: Speakers Bureau. Demakos:celgene: Speakers Bureau.