Long-Term Results and Adverse Events Of Second Line Nilotinib Therapy After Imatinib Failure In Patients With Chronic Myeloid Leukemia In Chronic Phase In Clinical Practice

The experience of usage of second line tyrosine kinase inhibitors (TKI2) in chronic myeloid leukemia (CML) patients in routine clinical practice in Russian Federation is still limited. Therefore the information about long-term therapy results and adverse events (AEs) is very important.

To provide information about the results of TKI2 nilotinib treatment in patients with chronic phase (CP) CML. To evaluate the long-term hematological and non-hematological AEs.

Follow-up data of 37 CML CP patients treated by nilotinib 2^nd line after imatinib failure due to resistance (28 [76%]) or intolerance (9 [24%]) were obtained and analyzed. The patients formerly participated in clinical trial ENACT after which continued treatment in routine clinical practice. A median CML observation prior to the nilotinib treatment was 66 months (range 7.9 to 148.1). Hematological, cytogenetic and molecular responses and AEs were evaluated with a median follow-up of 40 months (range 1.2 to 76.7).

At the moment of evaluation 15 (41%) of 37 patients continue nilotinib treatment, 12 of 15 have been treated by nilotinib for more than 5 years. Nilotinib dose is 800 mg daily for all but one patient with 400 mg dose daily reduced due to constitutional hyperbilirubinemia. Nilotinib was discontinued in 22 (59%) of 37 patients: in 4 of 22 due to cytogenetic resistance, in 9 of 22 due to hematologic relapse, in 7 of 22 due to AEs. Two of 22 patients with concomitant atherosclerosis and diabetes diagnosed before nilotinib treatment died because of cardiovascular events.

Complete hematological remission (CHR), major cytogenetic response (MCyR) and complete cytogenetic response (CCyR) were obtained in 34 (92%), 26 (70%) and 18 (48%) consequently. Major molecular response (MMR) and complete molecular response (CMR) was achieved in 16 (43%) and 9 (24%) consequently. Currently 10 (27%) patients have stable CCyR, 5 of those 10 have stable CMR lasting more than 5 years in 2 of these 5.

No cases of progression to accelerated phase (AP) and blast crisis (BC) before treatment discontinuation were observed. Hematologic relapses were within CP. Deaths due to CML progression were not observed on nilotinib treatment.

Grade 3-4 thrombocytopenia was observed in 8 (22%) patients, grade 3-4 neutropenia was observed in 5 (14%) and grade 3 anemia was observed in 1 (3%) patient.

The most common AE was rash (12 [32%] patients), in some cases with pruritus and xerodermia. The hemorrhagic syndrome was observed in 4 (11%) patients, associated with grade 3-4 thrombocytopenia only in 2 patients. The other 2 patients had uterine bleeding with questionable connection to therapy. Neither QT prolongation nor other abnormalities were revealed by ECG. As to laboratory findings: hyperbilirubinemia occurred in 33 (89%) patients, mostly due to indirect fraction, 5 of those 33 had hyperbilirubinemia grade 3. ÀL” and AST elevation (all grades) was observed in 26 (70%) and in 20 (54%) patients respectively, grade 3-4 was observed in 3 (8%) patients. Grade 1 hyperglycemia occurred in 7 (19%) patients, grade 3 hyperglycemia was observed in 1 (3%) patient with concomitant type 2 diabetes. All AEs were manageable according to general rules. No life-threatening AEs were diagnosed.

The results of long-term nilotinib 2^nd line therapy are satisfactory for patients who achieved stable CCyR. Low level of high grade toxicity AEs was observed on nilotinib treatment, no new kinds of AEs appeared during long-term treatment.

Bykova: Federal State Budgetary Institution Hematology Research Center of Health Ministry of Russia, Moscow, Russian Federation : Employment. Gusarova:Novartis International AG : Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Federal State Budgetary Institution Hematology Research Center of Health Ministry of Russia, Moscow, Russian Federation : Employment. Chelysheva:Novartis International AG : Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Federal State Budgetary Institution Hematology Research Center of Health Ministry of Russia, Moscow, Russian Federation : Employment. Turkina: Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.