Evaluation of the use, effectiveness and safety of tyrosine kinase inhibitors in chronic myelogenous leukaemia in a general university hospital

Abstract

Objectives

To evaluate the use, effectiveness and safety of tyrosine kinase inhibitors (TKIs) for chronic myelogenous leukaemia (CML) in clinical practice.

Methods

A retrospective longitudinal study of patients with CML who received TKIs for at least 6 months was performed. Endpoints to evaluate effectiveness were haematological, cytogenetic and molecular responses. Safety was assessed according to the occurrence of adverse events.

Results

Sixty-two patients were included. All received imatinib as the initial TKI; 8% switched to nilotinib due to lack of major molecular response (MMR) to imatinib and 3% switched to dasatinib because of progression to blast crisis or lack of MMR. At the end of the study all patients had achieved at least a complete cytogenetic response. With regard to safety, in 11 patients the dose of imatinib was decreased and four patients switched to a second-generation TKI due to imatinib toxicity.

Conclusions

Considering the good responses of most patients and its better known safety profile, imatinib should remain a good option for first-line treatment of CML.

Introduction

Imatinib, the first approved BCR-ABL tyrosine kinase inhibitor (TKI), has dramatically improved the outcome for patients with chronic myelogenous leukaemia (CML) and is the established standard of care BCR-ABL-targeted therapy for this disease. However, two new second-generation TKIs have been approved as first-line therapy for CML: dasatinib and nilotinib. Several studies have compared these treatment options and have confirmed that second-generation TKIs have more potent activity and responses were achieved sooner than with imatinib.^{1 2} Because of this, some authors regard them as the new standard in newly diagnosed CML. However, a high proportion of patients still achieve good responses with imatinib and the overall survival is similar for imatinib and second-generation TKIs,^{3 4} although small differences favourable to nilotinib have been found regarding progression-free survival.³

Taking into account that the safety profile of second-generation TKIs is not as well known as that of first-generation TKIs and that guidelines do not identify any of the three as the preferred option for first-line therapy in newly diagnosed CML,^{5 6} there is variability in their use in daily practice.

The aim of this study is to evaluate the use, effectiveness and safety of these TKIs for CML in real clinical practice of a tertiary hospital.

Methods

A longitudinal, retrospective, observational study was performed. The inclusion criteria were adult patients diagnosed with CML who were receiving TKIs at the time of inclusion and had been treated for at least 6 months. The exclusion criteria were patients who were participating in a clinical trial during the study period.

Patients’ medical records were reviewed and the following data were collected:

• demographic: date of birth, gender

• clinical: date of CML diagnosis, phase of the disease, risk scores

• pharmacotherapeutic: previous CML treatments if any, date of start of treatment with TKI, TKI and dose at the time of the study, treatment modifications and their reasons.

The endpoints for the evaluation of the effectiveness of treatment were haematological, cytogenetic and molecular responses (see online supplementary table 1).⁶

Safety was assessed on the basis of the occurrence of adverse events documented on the patients’ medical records. Also, whether or not these adverse events led to any change in treatment was evaluated.

Statistical analysis

Categorical variables were expressed as a percentage and quantitative variables were expressed as mean (range). Categorical variables were compared using the non-corrected χ² test or Fisher’s exact test, as necessary. Continuous variables were evaluated by the Student’s t-test if distribution was normal or by the Mann–Whitney test if distribution was not normal. SPSS 21.0 for Windows was used for the statistical analysis. Statistical significance was defined as P<0.05.

Results

Sixty-two patients (61.3% male, median age 47 years (range 24–88)) were included. Median age at diagnosis of CML was 39.8 years (range 21–83) and median time from diagnosis to the beginning of treatment with a TKI was 4.9 years (range 0.2–17.0). Seven patients had been treated with interferon prior to receiving a TKI. One of them had also received haematopoietic stem cell transplantation. All patients were in the chronic phase when they were diagnosed. During the study, all remained in the chronic phase except for one patient who progressed to blast crisis.

All patients started treatment with imatinib; 89% received the standard dose of 400 mg/day recommended in the summary of product characteristics, 8% started with a higher dose (600–800 mg/day as they were considered high risk) and 3% started with a reduced dose of 300 mg/day (patients with a previous history of cardiac failure due to concern of a potential deleterious effect of imatinib-induced fluid retention). Median treatment duration with imatinib was 4.0 years (range 0.6–11.1).

Eighty-nine percent of patients maintained treatment with imatinib, although 25% required dose reduction (11 patients because of toxicity (haematological toxicity in 7 and in 4 the reason was not recorded)) and 13% required dose increase (because of loss of major molecular response (MMR)).

Eleven percent of the patients went through changes in their TKI. Statistically significant differences were not found (P>0.05) regarding patients’ basal characteristics between the group that maintained treatment with imatinib and those who had to change to a second-generation TKI. Five patients (8%) switched from imatinib to nilotinib (three patients changed due to imatinib intolerance and two because they did not achieve MMR at 12 and 18 months, respectively). Two patients (3%) switched from imatinib to dasatinib (one patient changed due to progression to blast crisis and another patient because of lack of MMR but, due to pleural effusion and to the presence of the F317L mutation treatment, was later switched to nilotinib). The reasons for change in treatment are shown in table 1.

Table 1.

Reasons for change in treatment

Reason	No of  patients	Adverse event	No of patients
Intolerance	16 (57.1%)	Haematological	5 (17.8%)
		Gastrointestinal	2 (7.1%)
		Cardiovascular	2 (7.1%)
		Neurological	1 (3.6%)
		Hepatic	3 (10.7%)
		Conjunctivitis	1 (3.6%)
		Pleural effusion	1 (3.6%)
		Muscular	1 (3.6%)
Not achieving adequate response	11 (39.3%)	11 (39.3%)
Progression	1 (3.6%)	1 (3.6%)

At the end of the study, 56 of the 62 patients (90.3%) were on treatment with imatinib, 4 (6.5%) with nilotinib and 2 (3.2%) with dasatinib. All patients achieved at least a complete cytogenetic response (CCyR) by the end of the study; 94.5% also achieved at least MMR. Median time to achievement of at least CCyR was 6 months (range 3–18 months). Of the 56 patients treated with imatinib by the end of the study, 51 (91%) achieved MMR (the remaining patients achieved CCyR). The two patients (100%) treated with dasatinib and three of the four patients (75%) treated with nilotinib achieved MMR.

Regarding safety, 17.7% of patients had to decrease the dose of imatinib to 300 mg/day because of toxicity. Of the seven patients who changed to a second-generation TKI, three of the changes to nilotinib and one to dasatinib were caused by imatinib intolerance (see online supplementary table 2).

Discussion

In this study, which evaluated all patients who were undergoing treatment with a TKI for CML in clinical practice, the starting TKI was imatinib in every case. These results indicate that imatinib was still the preferred option among our physicians. Also, 56 of the 62 patients treated with TKIs were still receiving imatinib treatment at the end of the study period. Of these, 91% presented MMR, with median treatment duration since TKI start of 4.0 years. This duration is comparable to the follow-up time of other retrospective studies, with treatment durations ranging from 2.5 to 4.8 years.^{7 8}

Our results show that most patients who were on TKI treatment during the time period considered had very good responses. Most of them remained on imatinib, even though second-generation TKIs had been available in our institution for some years. Although some studies indicate that cytogenetic and molecular responses are more intense and faster with second-generation TKIs,^{2 3} taking into account that a high proportion of patients achieved very good responses with imatinib and that so far there are no clear differences in overall survival and only minor differences in progression-free survival with nilotinib,³ this drug should still be considered as a very good option for first-line treatment, as reflected in the main guidelines of CML management.^{5 6}

Two patients were taking dasatinib by the end of our study, one of whom switched to this TKI due to an inadequate response to imatinib. Of the four patients treated with nilotinib by the end of the study, only one switched due to an inadequate response. The reason for the other switches of TKI was intolerance to imatinib. This also indicates that, even in patients who had to change treatment, in most cases it was not due to lack of treatment effectiveness with imatinib but to tolerance issues, supporting the idea that imatinib is effective in a high proportion of patients.

Since imatinib has been used all over the world for more than 15 years, its long-term safety profile is well known. On the other hand, dasatinib and nilotinib have been used for a much shorter time and some recent reports question their long-term safety profile. Several studies suggest that nilotinib increases the risk of vascular diseases and other observations have shown an increased risk of pleural and pericardial effusion as well as of pulmonary arterial hypertension with dasatinib.^{9 10}

Another aspect regarding the choice of first-line TKI would be the higher cost of second-generation TKIs compared with imatinib, which is an important issue in the current economic context in which budgets dedicated to healthcare are being reduced. Currently, the cost difference between first- and second-generation TKIs is more than 1000 euros per patient monthly because of new generic brands of imatinib.

Conclusion

This study provides a real-world example of the effectiveness and safety of TKIs in the treatment of CML. Taking into account the good responses achieved by most patients and its better known safety profile, imatinib should still be considered as a good option in first-line treatment for newly diagnosed CML.