AbstractThere have been few reports of a response to dasatinib or nilotinib after failure of two prior sequential tyrosine kinase inhibitors. We report the outcome of 82 chronic phase patients who received nilotinib or dasatinib as third-line alternative tyrosine kinase inhibitor therapy. Thirty-four patients failed to respond to nilotinib and were started on dasatinib as third-line tyrosine kinase inhibitor therapy while 48 patients were switched to nilotinib after dasatinib failure. Overall, we obtained a cytogenetic response in 32 of 82 patients and major molecular response in 13 patients; disease progression occurred in 12 patients. At last follow up, 70 patients (85.4%) were alive with a median overall survival of 46 months. Our results show that third-line tyrosine kinase inhibitor therapy in chronic myeloid leukemia patients after failure of two prior sequential tyrosine kinase inhibitors may induce a response that, in some instances, could prolong overall survival and affect event-free survival.
The advent of tyrosine kinase inhibitors (TKIs) has dramatically changed the outcome of chronic myeloid leukemia (CML). Imatinib has induced rates of over 80% complete cytogenetic response (CCyR) and 70% major molecular response (MMR).21 Despite this success, about 20% of patients demonstrate primary or acquired resistance to this drug.43 Several mechanisms may contribute to this phenomenon,75 but the onset of mutations has been reported as a major determinant of resistance.108 With 2 generation TKIs (2 TKIs), dasatinib or nilotinib, it has been demonstrated that approximately 50% of patients failing to respond to previous treatments can be rescued.1511 Few reports have described the outcome of patients who, after failing to respond to 2 TKIs, were treated with third-line TKI.118 We report the long-term outcome of a large series of CML patients who received dasatinib or nilotinib as third-line TKI therapy.
Design and Methods
Patients being sequentially treated with 3 TKIs were recruited by 18 Italian centers. Patients were strictly monitored according to European Leukemia Net (ELN) recommendations5 at different time points. In cases of resistance, mutational analysis was performed with direct sequencing and DHPLC, before starting 2 TKIs. Patients were switched to dasatinib or nilotinib in cases of failure or severe intolerance and responses were monitored according to 2009 ELN provisional criteria for 2 TKI after imatinib resistance. Intolerance was defined as grade 34 hematologic or non-hematologic toxicity or persistent grade 2, despite best supportive therapies. Response criteria were defined according to ELN recommendations5 (Table 1). Univariate and multivariate logistical models were used to evaluate the effects of variables (gender, age, CyR to imatinib, etc.) on CyR to third-line TKI therapy (Table 2). Covariates in the multivariate logistical regression models were chosen by stepwise-with-backward elimination variable selection procedures. P values less than 0.05 were considered statistically significant. The analyses were performed using SPSS software for Windows, version 13.0. Survival probabilities were estimated by the Kaplan-Meier method, and compared by the log rank test.
This study was approved by the Ethical Committee at the Policlinico of Bari, Italy.
Results and Discussion
A total of 82 patients were recruited and treated sequentially with TKIs: median age was 62 years (range 33–85); 29 were male and 53 female. Sixty-two patients (75.6%) had received prior interferon-alpha before starting on imatinib; 20 patients (24.4%) received imatinib as first-line therapy. Sokal’s risk evaluation at baseline showed that 27% of patients were low, 25% intermediate and 48% high risk. No patient had undergone allogeneic transplant (HSCT) before receiving TKIs. At the start of imatinib, all patients were in chronic phase (CP). Median time on imatinib therapy was 45 months (range 4–101), and median imatinib dose was 400 mg/day. Ten patients received high-dose imatinib for resistance to standard dosage. Best overall response to imatinib was MMR in 6 patients (7.3%), CCyR in 19 patients (23.2%), partial CyR (PCyR) in 21 patients (25.6%), minor CyR (mCyR) in 10 patients (12.2%), only complete hematologic response (CHR) without any CyR in 21 patients (25.6%). No response (NR) was observed in 5 patients (6.1%). Imatinib was discontinued in 74 patients (90.2%) due to resistance and in 8 (9.8%) due to intolerance.
Responses to second-line TKIs
Thirty-four patients received nilotinib as second-line TKI therapy at a starting dose of 400 mg BID (Group A): 30 of 34 (88.2%) patients were in CP, 2 (5.9%) in accelerated phase, and 2 (5.9%) in blastic phase (BP). Thirty-two patients were switched to nilotinib due to resistance, and 2 to intolerance to imatinib. Median time of imatinib treatment before the switch was 47 months (range 6–67). Mutational screening at baseline, performed in 19 patients, revealed that 10 patients had developed mutations before starting treatment, probably due to the long duration of the disease (Online Supplementary Table S1). The most frequent mutations detected were F317L(2), A269S, H295P+F311L+Y320H, M244V, M351T+F359C, E255K(2), Y253H, S417F. Twenty-four patients (70.6%) received no other treatment before starting nilotinib, whereas 7 patients (20.6%) received hydroxyurea (HU), 2 patients (5.9%) high-dose imatinib, one patient (2.9%) HSCT. Best response to nilotinib was CCyR in 7 patients (20.6%), PCyR in 5 patients (14.8%), mCyR in 6 patients (17.6%), CHR in 8 patients (23.5%), and NR in 8 patients (23.5%). None of the treated patients obtained MMR. Median time on second-line nilotinib was 30 months (range 1–36).
Forty-eight patients were treated with dasatinib as second-line TKI therapy (Group B): 42 of 48 (87.5%) patients were in CP, 5 (10.4%) in accelerated phase, one (2.1%) in BP. Twenty patients (41.7%) received a starting dose of 70 mg BID, the remaining patients received doses of 50 mg BID or 100 mg QD. In 35 patients (73%), no interval treatment was given between the discontinuation of imatinib and the start of dasatinib, whereas one patient received IFNα, one chemotherapy (cytosine-arabinoside), 3 patients high-dose imatinib, 6 patients HU, and 2 patients underwent HSCT. Ten patients (29.4%) were found to have mutations before starting dasatinib: the most common mutations were M244V(3), F359V(2)+E450G, N322D+K400E+E409G+K467R, T315A+P309R, M351K, M351V, D276G. Forty-two patients were considered resistant and 6 intolerant to imatinib. Best response to dasatinib included MMR in 11 patients (22.9%), CCyR in 9 patients (18.7%), PCyR in 4 patients (8.3%), mCyR in 3 patients (6.3%), only CHR in 13 patients (27.1%), and no response in 8 patients (16.7%). Median time on second-line dasatinib was 13 months (range 4-59) (Table 1).
Efficacy and safety of third-line TKIs
Group A was made up of 34 patients: 30 patients were in CP (88.2%), one patient in accelerated phase (2.9%) and 3 patients in BP (8.8%). These patients were started on dasatinib as third-line TKI therapy. Fourteen patients (41%) were switched to dasatinib for intolerance; 17 (50%) patients were considered resistant to nilotinib: 8 patients were screened for mutations and these were found in 4 of them (T315I, F317L, F359C, E255V). Three patients were considered both intolerant and resistant: none of these patients presented mutations. Eighteen patients were evaluated for mutational screening at the time of the switch and mutations were identified in 8: 5 new mutations (F359V, T315I, F359V, Y253H (2)+F359V) and 3 confirmed mutations (A269S, F317L, F359C).
Group B was made up 48 patients: 38 patients in CP (79%), 8 patients in accelerated phase (16.6%) and 2 patients in BP (4%). These patients were started on nilotinib as third-line TKI therapy. Twenty-four patients (50%) were considered intolerant to dasatinib: among these, mutations were found in 6 of 18 patients tested (F317L(2), M244V(2), L387M, M351T). Twenty-four patients were considered resistant to dasatinib and switched to nilotinib: 8 of 18 patients tested presented a mutation at the time of the switch (F317L(3), M244V(2), M318T, T315I, G250E). Twenty-four patients were taken off because of intolerance (most common side effects were pleural effusion and thrombocytopenia). Overall, best response to third-line TKI treatment was MMR in 13 patients (15.9%), CCyR in 14 patients (17.1%), PCyR in 12 patients (14.6%), mCyR in 6 patients (7.3%), only CHR in 26 patients (31.7%). Twelve patients (14.6%) did not achieve any response. In Group A, treatment was discontinued in 14 of 34 (41.2%) patients because of toxicity. In Group B, 24 patients of 48 (50%) experienced severe toxicity requiring treatment discontinuation. Two new mutations (F317L, E255V) emerged with dasatinib and 2 new mutations (Y253H, G250E) with nilotinib as third-line TKI therapy; 9 patients (26%) in group A and 3 patients (21%) in group B had disease transformation. After a median follow up of 14 months (range 2–37), 50 patients (48 CP and 2 accelerated phase) are still in treatment (33 patients with nilotinib and 17 with dasatinib). At last follow up, 70 patients (85.4%) were still alive with a median overall survival of 46 months (range 15–300). Twelve patients died (14.6%) of disease progression associated with T315I development.
Univariate and multivariate analyses were performed to identify predictive factors associated with the achievement of CyR to third-line TKI therapy (Table 2). Patients who did achieve a CyR on imatinib or with low and intermediate Sokal risk had a higher probability of achieving CyR with third-line TKI therapy (P<0.001). The presence of a mutation before starting a third-line TKI therapy did not affect the response. During follow up, 13 (15.9%) patients failed to respond to third-line TKI therapy and 12 (14.6%) died of disease progression. The 30-month probabilities of event-free survival (EFS) and overall survival (OS) were 76.4% in CP patients and 16.5% in AP (advanced phase: accelerated phase+BP) (P<0.001) and 98.5% in CP patients and 76.1% in AP (P<0.001), respectively (Figure 1A and B).
Although the use of imatinib has improved cytogenetic and molecular responses as compared to previously available therapies,1716 approximately 30–50% of patients did not achieve a CCyR within 12 months of therapy. Furthermore, IRIS results at 8-year follow up showed that 17% of patients had primary resistance and 15% lost a previously obtained CyR.1918 From sponsored trials, 40–50% of resistant patients can be rescued by 2 generation TKIs, but patients who failed to respond to first-line are at risk of losing the response also to second-line TKIs.1514 Tam et al. suggested that patients treated with 2 TKIs had a higher progression rate if they did not obtain an MCyR within 12 months or were completely Ph after 3 or 6 months.4 Limited data have been published on the use of nilotinib or dasatinib after failure of two prior TKIs. Garg et al. reported 48 CML patients, 25 in CP and 23 in accelerated phase/BP (34 treated with dasatinib after imatinib/nilotinib failure and 14 with nilotinib after imatinib/dasatinib failure):8 with third-line therapy, CP patients obtained MMR (5 patients) and CCyR (3 patients) as best response, the latter showing a median duration of 16 months. Even in advanced phases of disease, in terms of best response, 2 patients achieved MMR and 3 patients a CCyR. After a median follow up of 16 months, 13 patients were still continuing therapy and median EFS was 13 months. Quintas-Cardama and colleagues reported a single center experience of the use of dasatinib after failure of previous imatinib and nilotinib in 23 patients (19 patients in advanced phases), obtaining a CCyR rate of 30%.11 Nilotinib was reported to overcome imatinib and dasatinib failure in 67 patients (27 C P, 15 accelerated phase and 25 BP): in CP patients the MCyR rate was 32%, whereas 23% of the accelerated phase patients returned to C P. Of 20 evaluable BP patients, 15% had a CHR and 5% returned to CP.20 The results of the present study, confirm the impressive efficacy of both agents used as rescue therapy after failure of two prior TKIs, but highlighted some important issues. Firstly, the median duration of responses obtained with a third-line TKI therapy is not so long. Secondly, as shown also in our experience, the frequency of emerging mutations in patients treated sequentially with different TKIs is higher. In fact, two new mutations with an IC50 of more than 3 nM (F317L, E255V) emerged with dasatinib and two new mutations with an IC50 of more than 150 nM (Y253H, G250E) emerged with nilotinib as third-line TKI therapy, reflecting the use of sequential TKI therapy. In our experience, approximately 14% of patients died of progression associated with the onset of a T315I; as also reported elsewhere, sequential treatment with several TKIs could cause selection of this mutation.2321 We observed a similar toxicity rate in third-line TKI therapy with both agents (41.2% discontinuation of nilotinib and 50% of dasatinib). However, in spite of the presence of side effects, 70 of 82 patients are still alive with a median OS of 46 months. Among patients who failed to respond to dasatinib or nilotinib or with a T315I mutation, recent results showed that ponatinib, a 3 generation TKI, could have anti-leukemic activity and may also act as a bridge to HSCT.24 In conclusion, our results show that a third-line TKI therapy, after failure of two prior TKIs, might induce a response that, although transient in some instances, could prolong OS and, in particular, delay the onset of events. Third-line TKI therapy could be a valid therapeutic option for some categories of patients not eligible for HSCT, such as elderly patients with comorbidities.
The authors would like to thank Ms MVC Pragnell, B.A. for language revision of the manuscript.
- Funding This work was supported by the Associazione Italiana contro le Leucemie, Linfomi e Mieloma (AIL)-Bari, MIUR (Ministero dell’Istruzione, dell’Universita’ e della Ricerca).
- Authorship and Disclosures Information on authorship, contributions, and financial & other disclosures was provided by the authors and is available with the online version of this article at www.haematologica.org.
- Received February 16, 2012.
- Accepted July 12, 2012.
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