Page 26 - Haematologica June

PERSPECTIVES
Present results and future perspectives in optimizing chronic myeloid leukemia therapy
Angelo M. Carella,1 Giuseppe Saglio,2 Xavier F. Mahon3 and Michael J. Mauro4
1Hematology and BMT Unit, Ospedale Policlinico San Martino, Genova,Italy; 2Dipartimento di Scienze Cliniche e Biologiche Università di Torino and Ospedale Mauriziano di Torino, Italy; 3Bergonié Cancer Institute, University of Bordeaux, France and 4Myeloproliferative Neoplasms Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
E-mail: angelomcarella@gmail.com doi:10.3324/haematol.2017.182022
The presence of the Philadelphia chromosome and BCR/ABL1 fusion, combined with an elevated leuko- cyte count and other less specific clinical and hemato- logical features, defines chronic myeloid leukemia (CML). In the last two decades, tyrosine kinase inhibitors (TKIs) have revolutionized CML treatment.1 The challenge now is to erad- icate the disease. Three main crucial questions remain: first, which TKI should be used as first-line therapy, given the ‘embarrassment of riches’ with regard to the choices; second, who should discontinue TKI, and when; and last, what about the future?
Which TKI should be chosen as first–line therapy?
Being the first TKI to receive approval for the treatment of CML, imatinib has definitely changed the natural history of this disease. The recently published update of the IRIS trial shows that patients assigned to receive imatinib 400 mg per day have an estimated overall survival (OS) rate of 83.3% at 10 years, almost matching that of a control population with- out CML.2 However only approximately half of the original- ly enrolled patients (48.3%) completed study treatment with imatinib with such a long follow-up; discontinuation occurred in 15.9% of patients because of insufficient thera- peutic effect and in 6.9% of cases because of adverse events; in addition, during study treatment 6.9% of the patients pro- gressed to accelerated or blast crisis. Most of the patients who discontinued imatinib and who were not transplanted were subsequently moved to alternate treatment.
As it is well known that the final outcome in terms of OS and progression free survival (PFS) of CML patients corre- lates to the depth and rapidity of the cytogenetic and molec- ular responses achieved, the European LeukemiaNet (ELN) recommendations have established molecular and cytoge- netic parameters to be achieved by patients at specific time- points after the start of TKI therapy. If these parameters are not achieved, a switch of TKI, if possible, is recommended.3
The second-generation TKI dasatinib, initially approved in 2006 as second-line treatment for patients resistant or intol- erant to imatinib,4 was finally approved as a first-line thera- py in 2010 following the results of the phase 3 DASISION study.5 In this study the cumulative one-year major molecu- lar response (MMR; 0.1% BCR-ABL) rate was 46% for dasa- tinib and 28% for imatinib. At five years, the cumulative MMR rate remained higher with dasatinib (76%) than with imatinib (64%). Whereas only 16% of the patients treated with dasatinib failed to achieve, at three months, early molecular response (EMR; a threshold of BCR-ABL is seen to correlate with OS and PFS) this percentage was 36% with imatinib.6 Finally, very deep molecular responses (DMR;
MR4, MR4.5), which were of greater interest due to the understandable desire of many patients to achieve treatment free remission (TFR), were definitely higher with dasatinib than with imatinib (MR4.5 42% vs. 32%). However, the five-year OS and PFS rates for dasatinib were 91% and 85%, respectively, and did not differ from that observed with ima- tinib; in addition, dasatinib therapy was associated with risk of developing pleural effusion.6
Nilotinib is a second-generation TKI which was accepted in 2007 for the treatment of CML resistant or intolerant to imatinib.7 It was approved for first-line treatment of chronic phase CML in 2010, following the positive results from the phase 3 ENESTnd study.8 In the aforementioned trial, after a minimum follow-up of five years, the rates of MMR and MR4.5 continue to be significantly higher in both nilotinib arms versus the imatinib arm (MMR: 77 and 77.2% versus 60%; MR4.5: 53.5 and 52.3% versus 31.4%), with more than half of the nilotinib-treated patients achieving MR4.5 by five years. Comparing nilotinib 300 mg twice daily (BID) with imatinib 400 mg daily, several differences emerge at the three month landmark on therapy: 91% of nilotinib-treated versus 67% of imatinib-treated patients achieved BCR-ABL transcript levels ≤10% EMR; 56% of nilotinib versus only 16% of imatinib patients achieved BCR-ABL transcript levels ≤1%. Although rates of freedom from progression to accel- erated phase and blastic phase (AP/BC) remain statistically higher in the nilotinib-treated patients (96.3% and 97.8% for nilotinib versus 92.1% for imatinib), the estimated rate of OS is statistically superior only for nilotinib 400 mg BID arm patients compared to imatinib. Importantly, the occurrence of metabolic changes such as worsening glycemic control and lipid increase as well as cardiovascular events (CVEs) increasing over time with follow-up has been more fre- quently observed in both nilotinib arms. Although mainly observed in patients with an increased Framingham risk score, predictive of CVEs,9 increased attention to cardiovas- cular risk assessment and comorbidities for all CML patients is warranted.
Frontline use of bosutinib was initially investigated in the phase 3 BELA trial, but this study failed to meet its primary endpoint of complete cytogenetic response (CCyR) at 12 months.10 Bosutinib has been subsequently re-investigated versus imatinib for chronic phase CML patients at a dosage of 400mg per day in the phase 3 BFORE trial. In this study, the proportion of patients who achieved MMR at 12 months (primary endpoint) was greater with regard to statistical sig- nificance in the bosutinib group, compared with the ima- tinib group: 47.2 versus 36.9 percent, respectively.10 Deeper molecular responses were also higher in the bosutinib group
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haematologica | 2018; 103(6)