Effectiveness of Second Generation Tyrosine Kinase Inhibitor

Study

Intervention

Dosage

MMR

MMR4.5^x

5-year OS

(HR 1.01; 95%CI 0.58-1.73)

Adverse Events*

: Drug-related Pleural Effusion

DASISION

5-year Follow-up

Dasatinib

100mg daily

76 (P-value= 0.0022)

42(P-value= 0.0022)

91%

28%

Imatinib

400mg daily

64 (P-value= 0.0251)

33(P-value= 0.0251)

90%

0.8%

Table 10 DASISION 5-year Follow-up Study (*No new adverse events were reported;

^x See Appendix B: Parameters for measuring TKI effectiveness)

Study

Intervention

Dosage

MMR4.5

OS

Overall Adverse Events

ENESTnd

5-year Follow-up

Nilotinib

300mg twice daily

54%

93.7% (95%CI 90.8-90.6)

32.9%

Pleural Effusion: 1.8%

Nilotinib

400mg twice daily

52%

96.2% (95%CI 93.9-98.5)

41.4%

Pleural Effusion: 0.7%

Imatinib

400mg daily

31%

91.7% (95%CI 88.3-95.0)

32.7%

Pleural Effusion: 1.1%

Table 11 ENESTnd 5-year Follow-up Study

Discussion

The pooled data from 2692 patients show that the second-generation TKIs were more effective than the first-generation TKI imatinib. The results from the three RCTs which compare dasatinib with imatinib give an average absolute risk reduction (ARR) of 26.0%; for nilotinib, average ARR is 24.6% (Table 12). Together, second-generation TKIs produce a very promising complete cytogenic response in 253 per 1000 patients per year. As a comparison, a Cochrane systematic review conducted by Aguilar MI et al., 2005 to understand the efficacy of oral anticoagulants in preventing ischemic heart attacks, collected data from five RCTs with a pool of 2313 patients. This showed that warfarin gives an ARR of 4.05% and so the use of warfarin as a common anticoagulant was continued to be supported (33). Hence, a very high combined ARR of 25.3% shown in this review emphasises the potency of second-generation TKIs in treating CML-CP. With continuous treatment using these TKIs, remission can be attained.

RCT

Intervention

Odds Ratio

Absolute Risk Reduction (ARR %)

ARR per 1000 population (per year)

DASISION

Dasatinib

0.5242 (95%CI 0.3437 to 0.7997 P=0.0027)

0.11089 (11.1%)

110.9

S0325

Dasatinib

0.0803 (95%CI 0.0434 to 0.1489 P<0.0001)

0.55409 (55.45%)

554.1

SPIRIT 2

Dasatinib

0.6217 (95%CI 0.4713 to 0.8203 P= 0.0008)

0.11825 (11.8%)

118.3

ENESTchina

Nilotinib

1.1871 (95%CI 0.6578 to 2.1426 P=0.5691)

-0.04282 (-4.28%)

-42.82

ENESTnd

Nilotinib (300mg)

0.1772 (95%CI 0.1217 to 0.2581 P<0.0001)

0.40358 (40.4%)

403.6

Nilotinib (400mg)

0.2025 (95%CI 0.141 to 0.2925 P<0.0001)

0.37672 (37.7%)

376.7

Table 12 Data processed by the review author

Dasatinib Trials

The DASISION trial was industry-sponsored and as such, the results are to be approached with caution due to a possible risk of bias. However, the largest dasatinib trial, SPIRIT 2 also shows a very similar ARR of 11.8%. Moreover, the European LeukemiaNet Panel used the results from the DASISION and other similar studies to set the 2013 guidelines in the management of CML-CP (34). Hence, the results are widely acknowledged by the scientific community.

However, due importance must be given to toxicity data generated from these studies whilst interpreting the results. Whilst DASISION stated that adverse events (AEs) for both arms were similar, toxicity data were not explicitly reported in DASISION and SPIRIT 2 studies. The S0325 trial addressed this issue (See Results). The team suggested that the choice of TKI should only be made based on a patient’s individualised ‘risk of progression, pre-existing comorbidity and compliance‘ (24). With reference to this, the 5-year follow-up of DASISION emphasised that there were no new events reported outside of the initial 12 month period (23).

Nonetheless, both teams reiterated the quick response of dasatinib in treating CML-CP as an indication of its greater efficacy. However, this increased effectiveness becomes equalised in the long-term, with both dasatinib and imatinib producing similar overall survival rates five years post-treatment (23).

Nilotinib Trials

Compared to dasatinib, the risk of AEs was only slightly increased in nilotinib patients. Unlike the other RCTs, ENESTnd trial observed imatinib-treated patients to have a high risk of AEs. Nausea and diarrhoea were reported in a very high percentage of patients- 41.1% and 46.1% respectively. The molecular mechanisms of AEs are not currently understood and no studies have been trialled in patients to quantify and assess TKI-related AEs. Hence, a clinically-relevant conclusion was not drawn from these results.

Limitations

One main factor limiting this review is the absence of direct comparative studies between dasatinib and nilotinib. The S0325 trials observed that the standard dose of dasatinib produced more AEs than imatinib and the ENESTnd trial showed that the higher dose of nilotinib produced more AEs than imatinib. However, these observations alone cannot be used to highlight nilotinib over dasatinib.

Another limitation is the possibility of selection bias. Currently, numerous on-going clinical trials worldwide aim to compare the various TKIs. However, much data is yet unpublished. These could not be included in this review due to the lack of an appropriate critical appraisal tool, other than the CASP tool used in this review, with more rigorous criteria. Despite these, conclusions drawn from a large pooled study population of 2692 patients remain reliable.

Nonetheless, inconsistencies on both efficacy and AEs data were present when comparing the five trials. The ENESTchina trial observed a better result with imatinib at twelve months than nilotinib (OR= 1.1871; 95%CI 0.6578 to 2.1426 P=0.5691). Additionally, the ENESTnd trial reported imatinib to be associated with higher AEs than dasatinib. However, the pooled data show a greater efficacy of dasatinib and nilotinib than imatinib. Dasatinib is also associated with more AEs than standard dose nilotinib and imatinib.

The comparability of ENESTchina to other trials could be questioned. ‘Patients from all ethnicities’ was a definite inclusion criterion and hence this study could not be excluded. The primary aim was to “evaluate the efficacy and safety of nilotinibaˆ¦vs imatinibaˆ¦ (in) patients with newly diagnosed P

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