Impact of Age on Efficacy and Toxicity of Nilotinib in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP): ENEST1st Sub-Analysis

Background: The incidence of CML increases with age and also the disease characteristics vary with age. However, whether age has any impact on molecular response (MR) with TKIs or not has not been clearly established.

Objective: To assess the effect of age on MR and adverse events (AEs) with nilotinib (NIL) in patients (pts) with CML in the ENEST1st (NCT01061177) phase 3b trial.

Patients and Methods: ENEST1st is an open-label study of NIL 300 mg BID in adults with newly diagnosed CML-CP. Treated pts with typical transcripts and ≤ 3 months of prior imatinib (IM) therapy were included in the sub-analysis and were stratified according to age (> 65 years and ≤ 65 years). Primary endpoint was rate of MR⁴ (defined as BCR-ABL ≤ 0.01% on the International Scale [BCR-ABL^IS] or undetectable BCR-ABL in cDNA with ≥ 10,000 ABL transcripts) at 18 months.

Results: Of the 1089 pts (median age, 53 years; range, 18 - 91 years) enrolled into the study, 1052 had b2a2 and/or b3a2 BCR-ABL transcripts and were treated with IM for ≤ 3 months. Sokal risk scores were low, intermediate, and high in 34.9%, 37.5%, and 18.1% of pts, respectively (9.5% missing).

The rate of MR⁴ at 18 months in all treated pts with typical transcripts and ≤ 3 months of prior IM (n = 1052) was 38.4% (95% CI, 35.5% - 41.3%). The cumulative rates of MR at 24 months are shown in the figure.

At 12 months the rates of MR⁴ and MR^4.5 were 30.8% and 15.3% respectively. Among pts who were in MR⁴ and MR^4.5 at 12 months, 60.8% and 33.9% pts were able to maintain continuous MR⁴ and MR^4.5 until Month 24, with no documented loss of MR⁴ and MR^4.5 between 12 and 24 months, respectively.

Among all pts treated (n=1089), six pts (0.6%) progressed to accelerated phase/blast crisis (AP/BC) on study; 13 pts (1.2%) died by 24 months, including one due to CML progression (16 month after study drug discontinuation). The most common AEs of any cause were rash (21.4%), pruritus (16.5%), and headache (15.2%).

Subgroup-analysis by age: As per the WHO guidelines, pts > 65 years are defined as older. Accordingly, for this sub-analysis, pts with typical transcripts and treated with IM for ≤ 3 months (n = 1052) were stratified into two subgroups: 851 pts (80.9%) were ≤ 65 years of age and 201 pts (19.1%) were > 65 years old at the time of enrollment. The median age at enrollment was 71 (range 66 - 91) and 48 (range 18 - 65) years in the old and young group, respectively. Among old pts, Sokal risk scores were low, intermediate, and high in 4.5%, 61.2%, and 23.4% of pts, respectively (10.9% missing). Among young pts, Sokal risk scores were low, intermediate, and high in 42.1%, 32.0%, and 16.9% of pts, respectively (9.0% missing).

Cumulative incidence of MR⁴ by 18 months was 48.8% (95% CI, 45.4% - 52.1%) among younger pts and 48.3% (95% CI, 41.4% - 55.2%) in older pts. Rate of MR⁴ by 18 months among younger pts with low, intermediate, and high Sokal score was 53.6%, 45.2%, and 35.4%, respectively. Rate of MR⁴ by 18 months among older pts with low, intermediate, and high Sokal score was 44.4%, 49.6%, and 44.7%, respectively.

The incidence rate of MR^4.5 by 18 months in younger pts and older pts was 32.5% and 28.4%, respectively.

Most common AEs experienced by younger patients were rash (23%), headache (17%), pruritus (16%), and fatigue (14%). In older population, the list of most common AEs includes pruritus (19%), nausea (18%), and rash (14%) (Table).

Conclusions: In this study, frontline NIL yielded equivalent rates of molecular responses in older and younger pts with a similar safety profile.

Adverse Event	Patients ≤65 years (n = 851) %	Patients >65 years (n = 201) %
Rash	23.2	13.8
Headache	17.1	7.6
Pruritus	16.0	18.6
Fatigue	14.0	13.3
Thrombocytopenia	11.0	7.6
Nasopharyngitis	10.8	8.6
Alopecia	10.8	9.5
Nausea	9.8	17.6
Diarrhea	8.0	11.4
Asthenia	8.4	11.0
Anemia	5.1	10.5
Abdominal pain	6.9	10.5
Dry skin	8.2	10.0

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