Change in Chronic Low-Grade Nonhematologic Adverse Events (AEs) and Quality of Life (QoL) in Adult Patients (pts) with Philadelphia Chromosome–Positive (Ph+) Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Switched From Imatinib (IM) to Nilotinib (NIL)

A large number of Ph+ CML pts treated with IM experience mild to moderate AEs that can negatively impact QoL. A recent study (Efficace F et al. Ann Hematol. 2012) reported that pts and healthcare professionals ranked several AEs induced by BCR-ABL tyrosine kinase inhibitors (fatigue ranked first) in the top 10 issues that adversely impact QoL in pts. The primary objective of the ongoing ENRICH study is to evaluate improvement of IM-related chronic low-grade nonhematologic AEs at the end of cycle (EOC) 3 (ie, after 12 weeks) in CML-CP pts when switched from IM to NIL because of chronic low-grade AEs. This is a report on 45 evaluable pts who completed EOC 3 as of the data cut-off (6/1/2012).

Pts were eligible if they were treated with IM 400 mg/d for ≥3 mo and had IM-related grade (G) 1/2 nonhematologic AEs persisting '2 mo or recurring ≥3 times and recurring despite best supportive care. The study planned to enroll 50 pts in the US and Canada. Pts received NIL 300 mg twice daily for 1 y (or longer if NIL was not yet commercially available for frontline treatment). Nonhematologic AEs were graded using the Common Terminology Criteria for Adverse Events (version 4.03; 6/14/2010) grading scale. Molecular response was monitored by a central PCR lab monthly for the first 3 mo and then every 3 mo on study. Pt-reported outcomes, measured by 2 QoL questions and the MD Anderson Symptom Inventory (MDASI)-CML, were administered at baseline, EOC 1, EOC 3, and then every 3 mo thereafter.

52 pts were enrolled into the study; enrollment closed in January 2012. The median duration (range) of previous IM treatment (tx) was 24.7 mo (2.3–123.0 mo); median duration (range) of NIL tx was 11.9 mo (0.2–23.7 mo). At baseline 199 IM-related nonhematologic AEs were reported (141 G1; 58 G2). Data for 49 pts were available and included in the safety and molecular response analyses; 45 pts were included in the primary end point analysis since 4 withdrew consent prior to EOC 3. These 45 pts accounted for 183/199 of the baseline IM-related AEs (130 G1; 53 G2); 1 AE evaluation is missing at EOC 3. 130/182 AEs (71.4%) improved by EOC 3 (primary end point): 117 resolved (90, 19, 8 by mo 1, 2, 3, respectively) and 13 improved from G2 to G1 (Table).

By EOC 3, 64.1% and 53.8% of pts (n = 39) reported an improvement in global QoL from baseline over the last 24 h and last 7 d, respectively. Mean reductions from baseline in MDASI-CML severity score and interference score, and therefore improvement in symptoms, were 1.1 (n = 40) and 1.4 (n = 39) at EOC 1, and 1.2 (n = 39) and 1.7 (n = 38) at EOC 3, respectively.

At baseline, 31/49 (63.3%) pts had major molecular response (MMR, 3-log reduction of BCR-ABL1; ≤0.1% IS); 18 and 10 pts had 4-log (MR⁴; BCR-ABL1 ≤0.01% IS) and 4.5-log reductions (MR^4.5; BCR-ABL1 ≤0.0032% IS) in BCR-ABL1, respectively. After switch to NIL, all pts with a baseline MMR maintained MMR and 14/17 remaining pts without baseline MMR achieved MMR. Deeper responses were reported for 16 pts who reached MR⁴ after the switch, and 14 reached MR^4.5.

20 pts were dose-reduced for NIL-related AEs, 2 of whom did not restart study drug. The other 18 pts were dose-reescalated to the original dose when the AEs improved to G1 or resolved. 40 G3 AEs occurred in 19 pts; of these, 24 AEs were investigator-reported as suspected to be NIL-related (hypophosphatemia, hyperglycemia, hypokalemia, increased bilirubin, increased lipase, arthralgia, pleural effusion, acute pancreatitis, dehydration, bronchitis, pruritus, rash, erythematous rash, exfoliative rash, papular rash, abdominal pain, gastroenteritis, and joint pain). 1 G4 AE (cardiac arrest, NIL-suspected) was reported; the pt recovered from the event but was discontinued from the study. Most AEs were managed by brief dose interruption. 9 pts discontinued study (5 due to AEs; 4 withdrew consent). No QTcF prolongation >500 msec occurred.

The majority of IM-related nonhematologic AEs improved within 3 mo after switching to NIL; nearly half of the AEs resolved by EOC 1. More than half of pts experienced improvement in QoL and symptom burden on NIL. In general, pts achieved deeper molecular responses on study and approximately a quarter of pts reached MR^4.5 after the switch to nilotinib.

Cortes:Bristol-Myers Squibb: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Research Funding; Ariad Pharmaceuticals: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; ChemGenex Pharmaceuticals: Consultancy, Research Funding; Deciphera Pharmaceuticals: Research Funding. Lipton:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding. Miller:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding. Ailawadhi:Millennium Pharmaceuticals: Consultancy, Honoraria. Akard:Cellerant: Research Funding; ChemGenex: Research Funding; Millennium: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria; Bristol Myers-Squibb: Honoraria; Pfizer: Research Funding. Pinilla-Ibarz:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Research Funding. Lin:Novartis Pharmaceuticals: Employment, Equity Ownership. Ericson:Novartis Pharmaceuticals Corp: Employment, Equity Ownership. Mauro:Novartis Pharmaceuticals: Consultancy, Honoraria.