Abstract

Abstract 43

Background

Clofarabine is a second generation nucleoside analogue with activity in adults with AML. A recent randomized phase III study in relapsed AML showed higher response rates and better event-free survival (EFS) with the combination of clofarabine and cytarabine (CA) compared to cytarabine alone. A phase I/II trial of CIA in patients with relapsed/refractory AML had shown an overall response rate (ORR) of 38% (21% CR; 11% CRp). To explore this combination further, we conducted a phase II study of CIA in patients </= 60 years with previously untreated AML.

Patients and Methods

Eligible were patients >18–60 years with newly diagnosed AML and adequate renal and hepatic function. Patients were excluded for ECOG PS > 2, cardiac ejection fraction < 45%, or active and uncontrolled infection. For the first 30 patients, induction therapy consisted of Clofarabine (C) 22.5 mg/m2 iv daily (days 1–5), Idarubicin (I) 6 mg/m2 daily (days 1–3), and Cytarabine (A) 0.75 g/m2 daily (days 1–5). From patients 31 onward, induction doses were amended to C 20 mg/m2 × 5, I 10 mg/m2 × 3, and A 1 g/m2 × 5. Patients who did not achieve CR following induction could receive one re-induction course. Patients in CR/CRp/CRi continued with up to 6 consolidation cycles (C 22.5 mg/m2 × 3, I 6 mg/m2 × 2, and A 0.75 g/m2 × 3, subsequently amended to C 15 mg/m2 × 3, I 8 mg/m2 × 2, and A 0.75 g/m2 × 3).

Results

From April 2010 until February 2012, 59 patients were enrolled (Table 1). Fifty-seven patients were evaluable. Forty-two patients (74%) achieved CR and 3 (5%) CRp for an overall response rate of 79%. Ten patients required a re-induction {4/10 (40%) patients achieved CR, 2/10 (20%) achieved CRp). All patients received a median of 2 cycles (1–8 cycles), 24 (42 %) patients proceeded with an allogeneic stem cell transplant in first remission. With a median follow up of 10.9 months (1.6 - 23.1), the median OS was not reached, the median EFS was 13.5 months, and the median relapse free survival was not reached.

Most toxicities were < grade 2. Toxicities > grade 2 included nausea (47%), rash (39 %), diarrhea (25%), elevated transaminases (23%), and elevated bilirubin (12%). Myelosuppression was ubiquitous but prolonged myelosuppression > 42 days was infrequent. Four week mortality was 2%. The response rate and toxicity were similar in both dose schedules. In subgroup analysis, patients < 40 years had better OS (HR 0.12, 95%CI, 0.02–0.90, P = 0.04) and EFS (HR 0.12, 95%CI, 0.02–0.93, P = 0.04) compared to patients > 40 years old. Compared to a historical group of patients who were treated with IA combination (I 12 mg/m2 IV daily × 3 plus A 1.5 g/m2 IV daily × 4) and after controlling for age, cytogenetics and other important clinical factors, the OS and EFS were significantly higher (P = 0.005, 0.0001, respectively) for CIA treated patients. Furthermore, in multivariate analysis, CIA retained its superior impact on OS (HR 0.53, 95% CI, 0.29 to 0.97, P =0.03) and EFS (HR 0.40, 95% CI, 0.22 to 0.73, P =0.003) compared to IA.

Conclusion

CIA is an active combination for patients </= 60 years with newly diagnosed AML. Patients < 40 years had significantly better OS and EFS. Compared to IA alone, CIA achieved significantly longer OS and EFS. A randomized comparison with standard induction therapy will be needed to further assess the role of CIA in frontline AML therapy of younger patients.

Table 1.

Patient's characteristics

Parameter  
Patients No. 59 
Median age, years, (range) 48 (17–60) 
Median WBC X 109/L, (range) 3.2 (6–100.2) 
Median hemoglobin g/dl, (range) 9.3 (7.3–14.6) 
Median platelets 103/mL, (range) 49 (6–270) 
Median peripheral blood blast %, (range) 12 (0–94) 
Median bone marrow blast %, (range) 42 (3–92) 
ECOG performance status > 2, No. (%) 4 (7) 
AML history, No. (%)  
de novo 40 (68) 
MDS-related 10 (17) 
Therapy-related 8 (13) 
Mixed phenotype 1 (2) 
Cytogenetic abnormalities*, No. (%)  
Diploid 21 (36) 
Intermediate 14 (25) 
Unfavorable 20 (34) 
Insufficient metaphases 3 (5) 
Molecular abnormalities, No. (%)  
FLT3-ITD 6 (10) 
NPM1 8 (14) 
RAS 4 (7) 
CEBPa 4 (7) 
Parameter  
Patients No. 59 
Median age, years, (range) 48 (17–60) 
Median WBC X 109/L, (range) 3.2 (6–100.2) 
Median hemoglobin g/dl, (range) 9.3 (7.3–14.6) 
Median platelets 103/mL, (range) 49 (6–270) 
Median peripheral blood blast %, (range) 12 (0–94) 
Median bone marrow blast %, (range) 42 (3–92) 
ECOG performance status > 2, No. (%) 4 (7) 
AML history, No. (%)  
de novo 40 (68) 
MDS-related 10 (17) 
Therapy-related 8 (13) 
Mixed phenotype 1 (2) 
Cytogenetic abnormalities*, No. (%)  
Diploid 21 (36) 
Intermediate 14 (25) 
Unfavorable 20 (34) 
Insufficient metaphases 3 (5) 
Molecular abnormalities, No. (%)  
FLT3-ITD 6 (10) 
NPM1 8 (14) 
RAS 4 (7) 
CEBPa 4 (7) 
*

Defined as per the MRC criteria

Abbreviations: AML: acute myeloid leukemia, MDS: myelodysplastic syndrome, FLT3-ITD: FMS-like tyrosine kinase-3 internal tandem duplication, NPM1: nucleophosmin 1, CEBPa: CCAAT/enhancer-binding protein alpha.

Disclosures:

Off Label Use: Clofarabine in AML. Ravandi:Genzyme: Research Funding. Kantarjian:Genzyme: Research Funding. Faderl:Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Author notes

*

Asterisk with author names denotes non-ASH members.