Abstract 2913

Background:

Limited data suggest that survival of patients with Myelodysplastic syndromes (MDS) after the failure of treatment with the hypomethylating agent decitabine is poor (Jabbour et. Al. Cancer. 2010 May 17). However, there is no published data pertaining to azacitidine failure addressing survival and response expectations with salvage treatments. We report the outcome of patients with MDS after azacitidine failure managed at our institution.

Materials and Methods:

This was a retrospective database review with chart verification of MDS patients treated with azacitidine at our institution. This analysis focused on patients with azacitidine failure defined as loss of response, no response or progression on azacitidine treatment. Patients in whom azacitidine treatment was discontinued due to adverse events or death on treatment or who proceeded to stem cell transplant were excluded. Disease status was defined by both the French American British (FAB) and the World Health Organization (WHO) classification systems, and risk was scored by the International Prognostic Scoring System (IPSS), World Health Prognostic Scoring System (WPSS), and MD Anderson Scoring System (MDAS) at start of therapy and at time of failure. Response to azacitidine and subsequent therapies was defined per the International Working Group (IWG 2006) criteria. Descriptive statistics were used for baseline characteristics and responses. Kaplan-Meier estimates were used to calculate overall survival (OS).

Results:

Out of 151 patients treated at Moffitt Cancer Canter with azacitidine, a total of 59 patients with de novo MDS (n= 28), therapy related MDS (t-MDS) (n=14), myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) (n= 11), and unknown (n=6) who failed azacitidine regimens from Jan 2004 to December 2009 were included. The median age was 68 years (46-85 years) with a Caucasian predominance 88% (n=52), and 66% (n=39) were male. Table-1 summarizes classification and risk stratification of the cases before azacitidine and at time of failure.

Best response to azacitidine was complete response (CR) in 8 (13.6%) patients, bone marrow CR in 2 (3.4%). Hematologic improvement included erythroid in 16 (27%) patients (HI-E), 14 (23.7%) platelet response (HI-P), and 10 (16.9%) patients had neutrophil response (HI-N).The median number of cycles administered was 5, ranging (2-26). Median length of treatment was 157 days. The median OS post azacitidine failure was 252 days (95% confidence interval (CI) 192–311 days), and estimated 12-month survival was 20%. At failure, 12 patients (20.3%) had transformation to AML. The IPSS, WPSS, and MDAS scores post azacitidine failure were each predictive of OS.

Subsequent treatment following azacitidine failure included induction chemotherapy (IC) (n=13), Decitabine (n=6), lenalidomide (n=3), hematopoietic stem cell transplant (HSCT) (n=2), clinical trial (n=5), supportive care (n=5), other (n=2) and unknown (n=22). The response rate for patients who received IC was CR 23.1%, CRi 7.7%, and PR 15.4%. No patient responded to decitabine after azacitidine failure.

Conclusion:

Outcome of MDS patients having failed treatment with azacitidine is poor. CR rate to IC is disappointing emphasizing the unmet therapeutic need in this group of patients, for whom clinical trials should be prioritized.

Table-1

Classification and Risk stratification upon start of azacitidine and at time of failure

Before azacitidine therapy startAfter azacitidine therapy failure
WHO 1 (1.7%) 
RA 1 (1.7%) 1 (1.7%) 
RARS 17 (28.8%) 5 (8.5%) 
RCMD 8 (13.6%) 8 (13.6%) 
RAEB I 17 (28.8%) 12 (20.3%) 
RAEB II 8 (13.6%) 3 (5.1%) 
CMML 4 (6.8%) 
MDS/MPN-U 2 (3.4%) 12 (20.3%) 
AML 1 (1.7%) 18 (30.5%) 
Unknown   
FAB 16 (27.1%) 5 (8.5%) 
RA 3 (5.1%) 1 (1.7%) 
RARS 23 (39%) 14 (23.7%) 
RAEB 4 (6.8%) 16 (27.1%) 
RAEB-t 8 (13.6%) 3 (5.1%) 
CMML 5 (8.5%) 18 (30.5%) 
Unknown   
IPSS 1 (1.7%) 1 (1.7%) 
Low 20 (33.9%) 13 (22%) 
Int-1 23 (39%) 9 (15.3%) 
Int-2 11 (18.6%) 15 (25.4%) 
High 4 (6.8%) 21 (35.6%) 
Unknown   
WPSS 1 (1.7%) 1 (1.7%) 
Low 9 (15.3%) 4 (6.8%) 
Int 17 (28.8%) 10 (16.9%) 
High 15 (25.4%) 13 (22%) 
Very high 17 (28.8%) 31 (52.5%) 
Unknown   
MDAS 1 (1.7%) 1 (1.7%) 
Low 12 (20.3%) 2 (3.4%) 
Int-1 14 (23.7%) 11 (18.6%) 
Int-2 29 (49.2%) 24 (40.7%) 
High 3 (5.1%) 21 (35.6%) 
unknown   
Before azacitidine therapy startAfter azacitidine therapy failure
WHO 1 (1.7%) 
RA 1 (1.7%) 1 (1.7%) 
RARS 17 (28.8%) 5 (8.5%) 
RCMD 8 (13.6%) 8 (13.6%) 
RAEB I 17 (28.8%) 12 (20.3%) 
RAEB II 8 (13.6%) 3 (5.1%) 
CMML 4 (6.8%) 
MDS/MPN-U 2 (3.4%) 12 (20.3%) 
AML 1 (1.7%) 18 (30.5%) 
Unknown   
FAB 16 (27.1%) 5 (8.5%) 
RA 3 (5.1%) 1 (1.7%) 
RARS 23 (39%) 14 (23.7%) 
RAEB 4 (6.8%) 16 (27.1%) 
RAEB-t 8 (13.6%) 3 (5.1%) 
CMML 5 (8.5%) 18 (30.5%) 
Unknown   
IPSS 1 (1.7%) 1 (1.7%) 
Low 20 (33.9%) 13 (22%) 
Int-1 23 (39%) 9 (15.3%) 
Int-2 11 (18.6%) 15 (25.4%) 
High 4 (6.8%) 21 (35.6%) 
Unknown   
WPSS 1 (1.7%) 1 (1.7%) 
Low 9 (15.3%) 4 (6.8%) 
Int 17 (28.8%) 10 (16.9%) 
High 15 (25.4%) 13 (22%) 
Very high 17 (28.8%) 31 (52.5%) 
Unknown   
MDAS 1 (1.7%) 1 (1.7%) 
Low 12 (20.3%) 2 (3.4%) 
Int-1 14 (23.7%) 11 (18.6%) 
Int-2 29 (49.2%) 24 (40.7%) 
High 3 (5.1%) 21 (35.6%) 
unknown   
Disclosures:

Lancet:Celgene: Research Funding. List:Celgene: Research Funding. Komrokji:Celgene: Research Funding, Speakers Bureau.

Author notes

*

Asterisk with author names denotes non-ASH members.