In patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase, a 400-mg dose of bosutinib (Bosulif) was associated with higher rates of major molecular response (MMR) and complete cytogenetic response (CCyR) than imatinib (Gleevec).
Jorge Cortes, MD
In patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase, a 400-mg dose of bosutinib (Bosulif) was associated with higher rates of major molecular response (MMR) and complete cytogenetic response (CCyR) than imatinib (Gleevec).1The responses with bosutinib occurred earlier and were deeper, but dose interruptions and dose reductions were more frequent with bosutinib. In addition, higher rates of gastrointestinal events and transaminase elevations were recorded in patients randomized to bosutinib, but rarely lead to discontinuation, said Jorge Cortes, MD, in a presentation at the 2017 ASCO Annual Meeting.
In the open-label, randomized phase BFORE III study, which examined bousutinib in the first-line setting, the MMR rate at 12 months in the modified intent-to-treat (ITT) population was 47.2% in bosutinib recipients compared with 36.9% in patients randomized to imatinib (OR, 1.55;P= .02). The rate of CCyR by 12 months was also significantly higher with bosutinib (77.2% vs 66.4%; HR, 1.74;P<.01), and the time to CCyR was shorter with bosutinib (HR, 1.34;P<.02).
“With these results, I believe that bosutinib could become a very welcome new treatment option for frontline therapy of chronic-phase CML,” said Cortes, deputy department chair and D. B. Lane Cancer Research Distinguished Professor for Leukemia Research, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston.
Bosutinib is a dual SCR/ABL tyrosine kinase inhibitor (TKI) approved at 500 mg for the treatment of adults with Philadelphia chromosome (Ph+) CML who are resistant or intolerant to prior TKI therapy. Previous studies have shown efficacy in this setting as well as in newly diagnosed chronic-phase CML (in the phase III BELA study).
In BELA, the rate of CCyR at 12 months was numerically higher with 500 mg/day of bosutinib compared with imatinib, but the difference was not statistically significant, and the study therefore did not meet its primary endpoint.2BELA also demonstrated an improved rate of MMR at 12 months and a shorter time to response with bosutinib.
In the multinational BFORE trial, 536 patients with newly diagnosed Ph+ chronic-phase CML were randomized 1:1 to bosutinib, 400 mg/day, or imatinib, 400 mg/day. Per the study protocol, efficacy was assessed in a modified ITT population of 487 Ph+ patients with e13a2 and/or e14a2 transcripts. The 400-mg dose of bosutinib was chosen in an attempt to reduce the toxicity observed with bosutinib in BELA, said Cortes.
Eighty-two percent of patients in each arm completed 12 months of treatment. In the bosutinib arm, 22% discontinued treatment, including 12.7% who discontinued due to an adverse event (AE) related to bosutinib. In the imatinib arm, 27% discontinued treatment, including 8.7% who discontinued due to an AE related to imatinib. More patients in the imatinib arm discontinued due to a suboptimal response or treatment failure compared with the bosutinib arm (6% vs 2%).
In addition to the superior MMR rate with bosutinib observed in the modified ITT population, the MMR rate was also higher with bosutinib than with imatinib in the ITT population (47.2% vs 36.9%; OR, 1.57;P= .02). The MMR rates at 12 months were higher with bosutinib across all Sokal risk groups: high (34% vs 17%), intermediate (45% vs 39%), and low (58% vs 46%). The rates of achievingBCR-ABLtranscripts ≤10% at 3 months were 75.2% in the bosutinib group and 57.3% in the imatinib group. A deep MR (MR4.5) was achieved by 8.1% of the bosutinib patients at 12 months, compared with 3.3% of the imatinib group.
A higher percentage of patients in the bosutinib group required dose interruption (56% vs 36%) as well dose reduction (35% vs 17%) “but these tend to be brief, lasting a median of 23 days with bosutinib and 15 days with imatinib, and the median dose intensity was pretty close to what we expected: 392 mg/day with bosutinib, 400 mg with imatinib,” said Cortes.
The superior rate of MMR in the bosutinib group was apparent by 6 months (P<.0001) and remained significant at 9 months (P<.01) and 12 months (P= .02).
Ten patients (3.7%) randomized to bosutinib and 15 randomized to imatinib (6.4%) had event-free survival (EFS) events, defined as death, transformation to accelerated phase (AP)/blast phase (BP), a doubling of white blood cell count without complete hematologic response (CHR), loss of CCyR or loss, of CHR, by the cutoff date. Cortes emphasized that longer follow-up is needed to assess for difference in EFS events. The overall survival rates were 99.6% in the bosutinib arm and 97.9% in the imatinib arm. Four bosutinib-treated patients and 6 in the imatinib group progressed to AP/BP during treatment.
Safety data were consistent with known safety profiles of the 2 agents. Grade ≥3 diarrhea occurred in 7.8% and 0.8% of bosutinib and imatinib recipients, respectively. Increased levels of alanine (19% vs 1.5%) and aspartate (9.7% vs 1.9%) aminotransferase levels were more common with bosutinib compared with imatinib. Musculoskeletal AEs (all grades) were more common with imatinib than with bosutinib (59% vs 30%). There were few cardiovascular, cerebrovascular, or peripheral vascular AEs with either treatment.
Selection of a TKI in newly diagnosed patients with chronic-phase CML should consider not only the possibility of earlier and deeper responses but patient comorbidities as well, said Cortes.