Abstract
the natural history of Chronic Myeloid Leukemia (CML) has changed after the introduction of first generation tyrosine kinase inhibitors (TKIs). Data from clinical trials suggest that about 30% of patients fails imatinib treatment and 18% never achieves complete cytogenetic remission (CCyR). However, CCyR and major molecular response (MMR) can be achieved with second generation TKIs in many patients.
We have analized 119 CML patients that have received at least one course of TKI and their outcomes. We have calculated how many patient are alive and continuing to receive first TKI therapy or patients who are alive but had to switch to alternative TKI therapy.
From May 1987 and May 2013 among chronic phase CML patients diagnosed, we have analized 119 patients who received at least one course of first, second or third generation TKIs. At diagnosis patients characteristic were: mean age 52 years (range 17-80); comorbidities unrelated to CML were found in 55 patients (i.e. arterial hypertension, ischemic heart disease, atrial fibrillation and chronic obstructive pulmonary disease (grading 1-2). Nine patients had a past history of epythelial cancer. Additional karyotype abnormalities were present in 7 patients (5%). Subjects were stratified according to Sokal score: 32 high risk, 39 intermediate risk and 48 low risk. Thirty five patients were diagnosed in pre-TKI era. Thus, they received second line imatinib, after conventional chemotherapy. Sixty-nine patients were treated with frontline imatinib, 14 subjects received frontline nilotinib and 1 frontline ponatinib in. The median follow up is 102,5 months (range 3-312).
Response to treatment was defined in according to 2009 European LeukemiaNet guidelines In our series 20 patient died (17%) because of: disease progression in imatinib (= 2; 1.7%), acute myocardial ischemia during imatinib therapy (= 2), respiratory failure in 1 case and second tumor in 9 subjects. Of nine additional patients, three were lost at follow up and 6 subjects died.
Overall 96/119 patients are alive (80,7%). Patients receiving frontline TKI are 55 ( 42in imatinib; 12 in nilotinib and 1 in ponatinib). Patients treated with second-line TKI are 30 (19in imatinib post chemoterapy, 6 in Nilotinib and 5 in dasatinib). Subjects receiving third-line TKI are 10 (9 in dasatinib and 1 in imatinib post allograft transplant). Only 1 patient receives ponatinib as fourth-line TKI. Responses are: CCyR in 96% of alive patients of whom 81% have a molecular response (MMR or better).
Switch to TKI other than imatinib (24 patients) was due to failure to achieve optimal response or loss of response according to LeukemiaNet guidelines. Moreover, three patients did not tolerate first line TKI. Nilotinib was generally well tolerated: we did not observe any cardiovascular adverse event. However we found that previous failure to imatinib predicted subsequent failure to nilotinib (=11). As previously reported, dasatinib induced three pleural effusions, resolved with medical therapy without requiring switch of therapy, except for one patient.
We noticed that Sokal score does not correlate with response to TKI therapy. Imatinib is well tolerated, only few patients discontinued because of side effects.However 24% of patients switched to second-line TKI due to loss of response especially among those patients previously treated with chemotherapy. Frontline nilotinib induced a sustained optimal response in 85,7%(=12) without adverse event. Our results about percentage of patient who switched therapy are slightly lower than those of clinical trials. This result support the notion that CML patients enrolled in clinical trials are not always fully representative of a general population referred to outpatient clinic.
No relevant conflicts of interest to declare.
Author notes
Asterisk with author names denotes non-ASH members.
