Clofarabine or cladribine with LDAC in elderly patients with newly diagnosed AML

The treatment of elderly patients with acute myeloid leukemia (AML) remains suboptimal, with patient fatality rates ranging from 24% to 45% at 4 weeks for patients ≥60 years and >44% for patients ≥70. Intensive chemotherapy regimens can be harder for older patients to tolerate, which has led to increased interest in low intensity treatment regimens for this subgroup. Newer agents and combination treatments hold much promise in this respect. To investigate this further, Kadia, et al. analyzed two low intensity treatment regimens in patients with newly diagnosed AML: clofarabine with low dose-cytarabine (LDAC) (NCT00778375) and cladribine with LDAC (NCT01515527).¹

Study design

This analysis evaluated results from two clinical trials with a total of 248 elderly patients with newly diagnosed AML, the baseline patient characteristics are shown in Table 1. For the entire cohort, the median age was 69 years, with 41% of patients >70 years of age. With respect to cytogenetic features, 44% had an adverse karyotype and 35% had a diploid karyotype.

Table 1. Baseline patient characteristics*

AML, acute myeloid leukemia; CMML, chronic myelomonocytic leukemia; LDAC, low dose cytarabine; LDH, lactate dehydrogenase; MPN, myeloproliferative neoplasm; WBC, white blood cell. *Adapted from Kadia, et al.1
Characteristic, % (unless otherwise stated)	N = 248	Clofarabine/ LDAC (n = 119)	Cladribine/ LDAC (n = 129)
Median age (range), years	69 (49–85)	68 (60–81)	69 (49–85)
Age ≥70 years	41	39	44
Secondary AML	15	16	15
Treated-secondary AML	12	13	12
Prior MPN	6	3	8
Prior CMML	3	3	2
Bone marrow blast (range)	35 (3–95)	36 (4–95)	32 (3–95)
WBC (range), x109/L	2.7 (0.3–187)	2.5 (0.4–187)	2.9 (0.3–72)
Platelets (range), x109/L	43 (4–772)	47 (6–416)	38 (4–772)
Peripheral blood blast (range)	9 (0–98)	9 (0–98)	9 (0–95)
LDH (range), U/L	663 (111–8,887)	641 (226–8,887)	739 (111–8,425)
Bilirubin (range), mg/dL	0.6 (0.2–2)	0.5 (0.2–1.5)	0.6 (0.2–2)
Creatinine (range), mg/dL	0.88 (0.36–19.4)	0.9 (0.5–1.4)	0.88 (0.36–1.94)
Cytogenetics
Diploid	35	39	31
Intermediate	16	14	17
Adverse	44	42	45

Results

Complete response and overall survival data

Overall, 59% of patients achieved a complete response (CR) and this value was similar between the two trials. The median number of cycles given was three in the clofarabine trial and four in the cladribine trial and both had a median of one cycle until response. For the whole group, 4-week mortality was 2% which rose to 11% at 8 weeks (Table 2). The median overall survival (OS) was 12.5 months during a median follow-up of 60 months. The 1-year OS was 51% and the 2-year OS was 29%.

There was no statistically significant difference in OS between the clofarabine and cladribine trials.

• Clofarabine/LDAC: median OS 10.4 months; 1-year OS rate 44%, 2-year OS rate 29%.
• Cladribine/LDAC: median OS 13.8 months; 1-year OS rate 59%, 2-year OS rate 28% (p = 0.54).

Table 2. Survival outcomes between the two trials*

CR, complete response; CRc, composite CR; CRi, complete response with incomplete hematologic recovery; LDAC, low dose cytarabine. *Adapted from Kadia, et al.1
Outcome, % (unless otherwise stated)	N = 248	Clofarabine/ LDAC (n = 119)	Cladribine/ LDAC (n = 129)
CR	59	60	59
CRi	7	8	6
CRc (CR + CRi)	66	67	66
No response	20	16	23
Died	9	13	6
Died ≤4 weeks	2	3	2
Died ≤8 weeks	11	13	9
Median number of cycles given (range), n	3 (1–19)	3 (1–19)	4 (1–18)
Median number of cycles to response (range), n	1 (1–6)	1 (1–6)	1 (1–4)

Median relapse free survival in the clofarabine/LDAC group was 10.5 months and for the cladribine/LDAC trial it was 11.3 months.

For patients with secondary AML, the median CR duration was 10.8 months and for those with non-secondary AML, the median CR duration was 14.9 months; the median relapse free survival for the overall group was 14.1 months.

The duration of remission for patients achieving CR was 14.7 months vs 10.8 months for those who achieved CR with incomplete hematologic recovery.

Regarding patients with known prior myeloid neoplasms:

• The median OS was 11.4 months for patients with secondary AML and 7.6 months for those with treated secondary AML.
• The median OS was 7.8 months for those with prior MPN and 23.9 months for those with prior CMML.

The cohort was divided into three age groups to ascertain the impact of age on OS. For the group of patients aged ≥60 years, the median OS was 12.3 months, and the 1-year and 2-year OS rates were 51% and 28%, respectively. For those ≥70 years, the median OS was 11.7 months, and the 1-year and 2-year OS rates were 49% and 27%, respectively. Finally, for those ≥75 years, the median OS was 10.5 months, with 1-year and 2-year OS rates of 42% and 26%, respectively.

Of the entire cohort, 15% (22% of responding patients) went on to have stem cell transplant (SCT). Transplant was associated with a significant improvement in OS, with a median OS of 18.1 months compared with 16.4 months for non-transplanted patients. The 2-year OS rate for SCT patients was 46% vs 38% for non-SCT patients.

Cytogenetic analysis

Cytogenetic factors were also investigated, and subgroups are shown in Table 3. Patients with a diploid karyotype had a composite CR (CRc) rate of 83% compared with patients with an adverse-risk karyotype, who had a CRc rate of 56%. The median OS for the group of patients with a diploid karyotype was 19.9 months, whereas for the adverse risk group it was 8.2 months. This led to a 2-year OS of 9% for the adverse risk group compared with 45% for the diploid patients.

Table 3. Genomic subgroups and associated survival outcomes*

CRc, composite complete response; OS, overall survival. Data from Kadia, et al.1
Genetic abnormality	N	CRc, %	Median OS, months	1-year OS, %	2-year OS, %
RAS	36	69	11.4	50	21
NPM1	30	97	28.7	75	50
TP53	25	44	5.4	44	16
FLT3-ITD	19	95	15.2	68	41
ASXL1	17	65	12.7	50	42
RUNX1	16	63	17.6	80	44
IDH1	12	58	11	50	25
IDH2	12	92	16.9	92	56
FLT3-D835	6	83	17	67	50
Diploid karyotype	86	83	19.9	72	45
Intermediate-risk karyotype	39	77	20.2	56	44
Adverse-risk karyotype	108	56	8.2	33	9

The highest CRc rates were recorded in patients with NPM1 (97%), FLT3-ITD (95%) and IDH2 (92%) mutations. Patients with NPM1 mutations had a median OS of 28.7 months, while patients with TP53 mutations had a median survival of 5.4 months.

Conclusion

Both clofarabine/LDAC and cladribine/LDAC were associated with high CRc rates and low mortality rates in elderly patients with newly diagnosed AML in this analysis. Further analysis by age group showed longer OS rates in younger patients (≥60) compared with older patients (≥65 and ≥70). While cytogenetic analysis was not available for every patient, for those in whom the information was available, a diploid karyotype was associated with increased OS compared with an adverse karyotype. This uncontrolled comparison of two trials shows that these two low intensity regimens warrant further investigation for older patients with AML.