Abstract

Background: Nilotinib is a novel orally active aminopyrimidine. It is a highly specific Bcr-Abl tyrosine kinase inhibitor (TKI) 30-fold more potent than imatinib. Based on the efficacy and favorable tolerability demonstrated by nilotinib in the phase I study, this phase II open-label study was designed to evaluate the safety and efficacy of nilotinib in adult pts with Ph+ chronic myeloid leukemia in blast crisis (CML-BC) resistant to or intolerant of imatinib. The prognosis for these pts remains poor.

Methods: The primary endpoint was confirmed hematologic response (HR). Imatinib resistance was defined as either treatment with imatinib >600 mg/day with disease progression, no HR in bone marrow after 4 weeks, or pts receiving <600 mg/day with mutations in any of the following amino acids: L248, G250, Q252, Y253, E255, T315, F317, or H396. Imatinib intolerance was defined as grade 3/4 adverse events, or grade 2 events persisting for >1 month while on imatinib. Nilotinib therapy was commenced at 400 mg twice daily (BID) with escalation to 600 mg BID for pts who had inadequate responses and no safety concerns.

Results: Safety and efficacy data are reported for 135 BC (myeloid, n=103; lymphoid, n=29; unknown, n=3). The median age was 55 (18–79) years, the median time since CML diagnosis was 1.6 (<1–73) months, and 61.5% were men. 82% of the patients were imatinib-resistant and 18% were intolerant. Treatment with nilotinib is ongoing for 16 (12%) pts. The median treatment duration was 84 (3–485) days and the median average dose intensity was 800 mg/day. 119 (88%) pts discontinued treatment, of which 71 (53%) discontinued due to disease progression; 13 (10%) discontinued due to AEs. 38% of pts had >/=95% Ph+ metaphases at study entry. Chromosomal abnormalities other than Ph+ were also noted in 54% of pts at study entry. Extramedullary involvement was present in 39% of the pts. The most common Grade 3/4 hematologic laboratory abnormalities were neutropenia (67%), thrombocytopenia (62%), anemia (42%). The most common Grade 3/4 non- hematologic AEs were as follows: pneumonia (11%), pyrexia (7%), nausea (4%), diarrhea (4%), and asthenia (4%).

Conclusions: Based on the CHR rates achieved in this very advanced patient population, nilotinib monotherapy appears to have clinical activity in pts with imatinib-resistant CML BC. Overall nilotinib is well tolerated in this patient population with advanced disease and with non-heme toxicity comparable to that observed for pts with CML-CP. The hematological responses were similar between myeloid and lymphoid Ph+ CML blast crises.

Response for Patients With CML-BC With at Least 6 Months of Follow-up

Myeloid (N = 103) n (%)Lymphoid (N = 29) n (%)
Hematologic response 40 (39) 11 (38) 
CHR 25 (24) 8 (28) 
Marrow response 5 (5) 1 (3) 
Return to chronic phase 10 (10) 2 (7) 
SD 31 (30) 7 (24) 
PD 18 (17) 6 (21) 
Not evaluable 5 (5) 1 (3) 
Missing 9 (9) 4 (14) 
Myeloid (N = 103) n (%)Lymphoid (N = 29) n (%)
Hematologic response 40 (39) 11 (38) 
CHR 25 (24) 8 (28) 
Marrow response 5 (5) 1 (3) 
Return to chronic phase 10 (10) 2 (7) 
SD 31 (30) 7 (24) 
PD 18 (17) 6 (21) 
Not evaluable 5 (5) 1 (3) 
Missing 9 (9) 4 (14) 

Author notes

Disclosure:Employment: Haque, Gallagher--Novartis. Consultancy: Larson - Novartis; Baccarani - Novartis, BMS, Merck, Pfizer. Research Funding: Giles, Larson, Kantarjian, le Coutre - Novartis. Honoraria Information: Larson, le Coutre - Novartis. Paid Export Testimony Information: Larson - Novartis; Baccarani - Novartis, BMS, Schering AG, Pfizer. Membership Information: le Coutre - Novartis advisory board. Off Label Use: At the time of submission, nilotinib is not FDA approved for use in the United States.