Twice Daily Fludarabine and Cytarabine Combination (BID-FA) Is Effective in Pts with De Novo Acute Myeloid Leukemia (AML), Relapsed/Refractory (R/R) AML, High-Risk Myelodysplastic Syndromes (MDS), and Blast Phase Chronic Myeloid Leukemia (CML-BP)

Abstract 4939 Background: High dose cytarabine containing regimens are still considered standard options for pts (pts) with AML relapsing after a first complete remission (CR1) lasting more than 12 months. No standard options exist for pts relapsing after shorter remission duration or with primary refractory disease. We conducted a phase II study assessing the efficacy and safety of twice daily fludarabine and cytarabine (BID FA) in pts with R/R AML, high-risk MDS and CML-BP. Pts and Methods: 147 pts with de Novo AML, R/R AML, intermediate-2 and high-risk MDS, and CML-BP, with a performance status of 3 or less, as well as normal organ functions were eligible. Pts were scheduled to receive fludarabine 15 mg/m2 intravenously (IV) q12 hrs on days 1 to 5 as well as cytarabine at the dose of 0. 5 g/m2IV over 2 hrs q12 hrs on days 1 to 5. GO was administered at the dose of 3 mg/m2 IV on day 1 for the first 70 pts enrolled. Courses were repeated every 4 to 6 weeks for a maximum of 7 courses. Pts with CML-BP were allowed to receive concomitant tyrosine kinase inhibitors. Four pts with AML who had FLT3 mutation were allowed to receive BID FA and sorafenib. Results: A total of 147 pts were treated. The median age was 63 years (range, 20 to 85 years). 131 (89%) had AML, 7 (5%) had high-risk MDS, and 9 (6%) had CML-BP. Of the 131 AML pts, 17 (12%) were de novo AML, 50 (38%) were in first salvage: first CR duration (CRD1) of less than 12 months in 39 pts (29%), and more than 12 months in 11 (9%) pts. Cytogenetic studies showed diploid karyotype in 52 pts (35%) and unfavorable chromosomal abnormalities involving chromosomes 5 and 7 in 30 pts (20%). 128 pts (87%) had a PS ≥1. Sixty-four pts (44%) had failed previous intensive chemotherapy, while 21 (14%) had failed targeted and hypomethylating agents. Forty-three (29%) pts had failed both. Overall, 34 pts (23%) achieved a complete remission (CR) and 8 (6%) achieved a CR without platelet recovery (CRp), for an overall response rate (ORR) of 29%. 6 pts received reinduction therapy, of which 3 achieved a CR. The CR rates for AML pts with frontline therapy, with relapsed AML with CRD1 ≥12 months, relapsed AML with CRD1< 12 months, and R/R AML beyond first salvage were 47%, 64%, 21%, and 14%, respectively. In CML-BP, 2 (22%) of 9 pts had objective responses (1 CR, 1 CRp). 1 of the 7 pts with MDS responded ([Table 1][1]). The treatment was well tolerated with only 7 of the pts experiencing grade 3 and 4 toxicities including mainly skin rash and increased liver enzymes. The overall 4-week mortality rate was 13%. With a median follow-up of 24 months (range, 10 to 33), 20 patients (14%) remained alive. The overall 6-month survival rate was 44%. The median overall survival (OS) and event free survival (EFS) were 5 months (range, 0. 1 to 33) and 1 month (range, 0. 1 to 33), respectively. The median CR/CRp duration was 12 months. Median OS for pts with de novo AML, a CRD1≥12 months, pts with CRD1<12 months and pts receiving second salvage and beyond were 8, 12, 5, and 4 months respectively. Median EFS for pts with de novo AML, a CRD1≥12 months, pts with CRD1<12 months and pts receiving second salvage and beyond were 3, 7, 1 and 1 month respectively. Conclusion: BID FA appears to be active with an ORR of 29% in a heavily pre-treated population. This combination is safe with a low rate of 4-week-mortality of 13%. | | | Percentage | |:------------------- | --- | ---------- | -- | | Status | N | OR | CR | CRP | | De novo AML | 17 | 59 | 47 | 12 | | S1, CRD1≥ 12 months | 11 | 64 | 64 | | | S1, CRD1< 12 months | 39 | 26 | 21 | 5 | | ≥S2 | 64 | 19 | 14 | 5 | | Disease | 147 | 29 | 23 | 6 | | AML | 131 | 30 | 25 | 5 | | MDS | 7 | 14 | 14 | | | CML-BP | 9 | 22 | 11 | 11 | | GO | | | | | | Yes | 70 | 30 | 26 | 4 | | No | 77 | 27 | 21 | 6 | * OR=objective response; CR=complete remission; CRp=complete remission without platelet recovery; S1=salvage 1; S2=salvage 2; CRD1=first complete remission duration; AML=acute myeloid leukemia; MDS=myelodysplastic syndrome; CML-BP=chronic myeloid leukemia in myeloid blast phase; GO=gemtuzumab ozogamicin. Table 1: Overall response by disease and subset groups | | % ORR | |:-------------------- | ----- | -------- | | Parameter | BIDFA | Expected | | S1, CRD1 ≥ 12 months | 64 | 50 | | S1, CRD1 < 12 months | 26 | 11 | | ≥ S2 | 19 | 7 | * S1=salvage 1; S2=salvage 2; CRD1=first complete remission duration. Table 2: Comparison to historical data Disclosures: No relevant conflicts of interest to declare. [1]: #T1