Abstract

Abstract 3629

Background:

High dose cytarabine containing regimens are still considered standard options for patients (pts) with AML relapsing after a first CR lasting more than 12 months. In a phase I study, 65 patients received fludarabine 15 mg/m2 every 12 hours and cytarabine 0.5 g/m2. Five days of administration were found to be safe and effective with a CR rate of 28%. Aim: This phase II study was conducted to evaluate the efficacy and safety of the combination of twice daily fludarabine and cytarabine (BIDFA) in patients with refractory/relapsed (R/R) acute myeloid leukemia (AML), high-risk myelodysplastic syndromes (MDS), and chronic myeloid leukemia in myeloid blast phase (CML-BP). Methods: Pts with R/R AML, intermediate-2 and high-risk MDS, and CML-BP, whose disease relapsed or was refractory to frontline and/or salvage therapy were eligible. Pts with performance status 0–3 and adequate organ function, received fludarabine 15 mg/m2 intravenously (IV) q12 hours on Days 1 to 5 and cytarabine 0.5 g/m2 IV over 2 hours q12 hours on Days 1 to 5. Gentuzumab ozogamycin (GO) was administered at 3 mg/m2 IV on day 1 in the first 59 pts. Pts with CML-BP were allowed to receive concomitant tyrosine kinase inhibitors. Results: 107 pts were enrolled. The median age was 62 years (range, 19 to 85). 93 pts had AML, 5 had high-risk MDS, and 9 had CML-BP. All pts had received prior therapy. 65 (61%) pts had failed previous intensive chemotherapy, while 42 (39%) had failed targeted and hypomethylating agents. Cytogenetics analysis showed diploid karyotype in 36 (33%) and unfavorable chromosomal abnormalities involving chromosome 5 and 7 in 22 (21%). Of the 107 pts, 52 were in first salvage: first CR duration of less than 12 months in 43 (40%) pts, and more than 12 months in 9 (9%). Overall, 22 pts (21%) achieved complete remission (CR) and 5 (5%) achieved a complete remission without platelet recovery (CRp), for an overall response rate (ORR) of 26% (Table 1). The CR rates for patients with relapsed AML with first CR duration (CRD1) ≥12 months, relapsed AML with CRD1< 12 months, and R/R AML beyond first salvage were 56%, 26%, and 11%, respectively. These compare favorably with the expected response rates in matched cohorts treated at our institution where the ORR were 50%, 11%, and 7%, respectively. A multivariate analysis identified the following 3 factors to be independent adverse prognostic factors for response: abnormal karyotype (versus diploid), second salvage (versus first salvage regardless of the duration of the first CR), and older age (Table 2). With a median follow-up of 7 months, the 6-month event-free survival, overall survival, and complete remission duration (CRD) rates were 18%, 35%, and 70%, respectively. Abnormal karyotype, older age, an increasing in the peripheral blood blasts percentage, and low platelets count (<30 × 109/L) were independently associated with a significant worse overall survival. The most common side effects observed were gastro-intestinal toxicities, including nausea, vomiting, diarrhea, and mucositis. The overall 4-week mortality rate was 9%. Conclusion: BIDFA is active with an ORR of 26% in a heavily pre- treated population. This combination is safe with a low rate of 4-week-mortality of 9%.

Table 1:

Response by disease and subset groups

StatusNPercentage
ORCRCRP
Overall 107 26 21 
S1, CRD1≥ 12 months 56 56 
S1, CRD1< 12 months 43 30 25 
≥S2 55 16 11 
Disease     
    AML 93 27 23 
    MDS 
    CML-BP 22 11 11 
GO     
    Yes 59 30 27 
    No 48 19 13 
StatusNPercentage
ORCRCRP
Overall 107 26 21 
S1, CRD1≥ 12 months 56 56 
S1, CRD1< 12 months 43 30 25 
≥S2 55 16 11 
Disease     
    AML 93 27 23 
    MDS 
    CML-BP 22 11 11 
GO     
    Yes 59 30 27 
    No 48 19 13 
Table 2:

Multivariate analysis of prognostic factors for response and survival

CharacteristicResponse
EFS
OS
ORp-valueHRp-valueHRp-value
Abnormal cytogenetic 0.31 0.006 2.43 <0.001 3.997 <0.001 
≥S2 0.29 0.008 2.31 <0.001 NS  
Older age 0.97 0.02 1.02 0.002 1.02 0.009 
Increasing PB blasts percentage NS  1.01 0.008 1.01 0.001 
Platelets <30 × 109/L NS  NS  1.01 0.04 
CharacteristicResponse
EFS
OS
ORp-valueHRp-valueHRp-value
Abnormal cytogenetic 0.31 0.006 2.43 <0.001 3.997 <0.001 
≥S2 0.29 0.008 2.31 <0.001 NS  
Older age 0.97 0.02 1.02 0.002 1.02 0.009 
Increasing PB blasts percentage NS  1.01 0.008 1.01 0.001 
Platelets <30 × 109/L NS  NS  1.01 0.04 

OR=objective response; EFS=event-free survival; OS=overall survival; OR=odds ration; HR=hazard ratio; S2=salvage 2; PB=peripheral blood; NS=not significant

Disclosures:

No relevant conflicts of interest to declare.

Author notes

*

Asterisk with author names denotes non-ASH members.