Idarubicin and Cytarabine Combined with Clofarabine or Fludarabine for the Treatment of Newly Diagnosed Acute Myeloid Leukemia: Interim Result of a Phase II Clinical Trial

Background: The combination of 7+3 with a purine nucleoside analogue improved overall survival (OS) in patients with acute myeloid leukemia (AML). We randomized patients to receive either clofarabine (CIA) or fludarabine (FIA) combined with idarubicin and cytarabine.

Methods: Patients who were diagnosed with non-CBF AML or non-APL AML were eligible and were randomized using a Bayesian design to one of the following two induction chemotherapy regimens: CIA (clofarabine 15 mg/m² IV daily for 5 days, idarubicin 10 mg/m² IV daily for 3 days, cytarabine 1,000 mg/m² IV daily for 5 days) or FIA (fludarabine 30 mg/m² IV daily for 5 days, idarubicin 10 mg/m² IV daily for 3 days, cytarabine 1,000 mg/m² IV daily x 5 days). Patients could proceed to up to 6 cycles of consolidation with the same drugs according to an attenuated schedule.

Results: One-hundred-fifty-eight patients (97 patients, CIA; 61 patients, FIA) were treated so far. Patient characteristics and outcome are summarized in Table 1. Median age is 53 years (range, 20-66) in CIA and 49 years (range, 18-66) in FIA. All patients were evaluable for response. Responses are summarized in Table 1. MRD negativity was observed in 43 (74%) patients treated with CIA and in 19 (35%) patients treated with FIA (p=0.049). Median follow up is 21 months and 16 months for patients treated with CIA and FIA, respectively. Treatment was well tolerated with 8-week mortality rates of 1% and 2%, for patients treated with CIA and FIA respectively. The overall median EFS and OS for the whole population were 12 months and 25 months, respectively. Median EFS for patients treated with CIA and FIA was 14 months and 11 months, respectively (p=0.81). No difference in OS between CIA and FIA was observed: the 2-year OS rates were 48% and 53% (p=0.45), respectively. Furthermore, there was no difference in survival whether patients were censored or not at the time of transplantation. Compared to IA regimen in similar patients population, the triplet (FIA and CIA) showed an improvement in 2-year EFS (60% vs 34%; p=0.05) and a trend for better survival (40% vs 32%; p=0.5) in younger patients (40 years and younger).

Conclusions: The combination of clofarabine or fludarabine to idarubicin and cytarabine is safe and effective with high CR and negative MRD rates in patients with newly diagnosed AML. Particularly in younger patients, CIA or FIA can lead to a superior outcome compared to 3+7.

Table 1. Patient characteristic and outcome

	CIA N= 97 (61%)	FIA N= 61 (39%)	P
Median age, y	53 [20-66]	49 [18-66]	NS
PS ≥ 1	79 (81)	48 (79)	NS
Hemoglobin, g/dL	9.4 [7.3-13.1]	9.2 [7.8-11.4]	NS
Platelets x 109/L	37 [1-1069]	40 [5-399]	NS
WBC x 109/L	3.6 [0.6-103.0]	4.1 [0.5-59.4]	NS
blast (PB)	11 [0-92]	10 [0-94]	NS
blast (BM)	52 [1-96]	50 [11-96]	NS
Creatinine, mg/dL	0.79 [0.34-1.35]	0.79 [0.49-1.72]	NS
LDH, IU/L	819 [325-11952]	684 [231-12042]	NS
Bilirubin, mg/dL	0.6 [0.2-1.9]	0.5 [0.2-1.5]	0.03
Cytogenetic # evaluable	97	61	NS
Diploid	46 (47)	26 (43)
-5/-7 or complex	25 (26)	19 (31)
Misc	26 (27)	16 (26)
FLT3-ITD, # evaluable	94	61	NS
Mutated	20 (21)	11 (18)
NPM1, # evaluable	90	55	0.05
Mutated	28 (31)	9 (16)
Response # evaluable	97	61	0.347
ORR	82 (85)	48 (79)
CR	70 (72)	41 (67)
CRp	9 (10)	6 (10)
PR	1 (1)	1 (2)
MRD Negativity	43/58 (74)	19/35 (54)	0.049
Overall MRD Negativity	54/64 (84)	24/37 (65)	0.024
CR/CRp     > SCT	33/79 (42)	23/47 (49)	0.435
Death (on study)	2 (2)	1 (2)	NS
4-week mortality	0 (0)	1 (2)	NS
8-week mortality	1 (1)	1 (2)	NS
Median F/U (m)	21.3 [0.9-44.7]	16.3 [4.3-42.0]	NS
Events, # evaluable	97	61	NS
Events	51 (53)	31 (51)
Primary failure	15 (15)	13 (21)
Relapse	26/82 (32)	13/48 (27)
Death in CR	6 (9)	4 (7)