Assessment Of Early Cytogenetic Response By 3 Months Versus >3-6 Months Or No Response By 6 Months As a Predictor Of Long-Term Clinical Outcomes In a Phase 1/2 Study Of Bosutinib In Chronic Phase CML
Authors: Cortes Jorge E. , Khoury H. Jean , Hochhaus Andreas , Apperley Jane F , O'Brien Stephen G. , Leip Eric , Turnbull Kathleen , Conlan Maureen G. , Kantarjian Hagop M. , Brümmendorf Tim H. 
Published: October 2019

Abstract
Bosutinib (BOS), an oral dual Src/Abl tyrosine kinase inhibitor (TKI), showed clinical activity and manageable toxicity in an open-label, phase 1/2 trial in patients (pts) with chronic phase (CP) chronic myeloid leukemia (CML) following resistance (R)/intolerance (I) to imatinib (IM) only (2nd line; CP2L) or to IM plus dasatinib (D) and/or nilotinib (N) (3rd/4th line; CP3L). In this retrospective analysis, a major cytogenetic response (MCyR) by 3 or by 6 mo (but not by 3 mo) was assessed as a predictor of long-term outcomes in CP2L or CP3L pts receiving BOS.
CP-CML pts aged ≥18 y received BOS starting at 500 mg/d. MCyR and complete cytogenetic response (CCyR) rates and maintenance of MCyR were assessed in CP2L pts at 4 y and CP3L pts at 3 y. Pts with MCyR newly attained or maintained from baseline by 3 mo, by >3 to ≤6 mo (but not by 3 mo), or no MCyR by 6 mo were assessed for overall survival (OS) at 2 y (all pts) and cumulative incidence of progression (including lack of efficacy)/death at 4 y (CP2L) or 3 y (CP3L), adjusted for competing risks (see Table). OS rates were limited to 2 y (pts were followed for only 2 y from BOS discontinuation). P values were based on Gray's test for comparison of cumulative incidence distributions and log-rank test for OS distributions (no adjustment for multiple comparisons).Table.MCyR by 3 moMCyR by >3 to ≤6 moNo MCyRby ≤6 moCP2L ptsOSEvaluable pts,* n9628151KM rate at 2 y (95% CI), %98 (91.8–99.5)†96 (77.2–99.5)89 (82.1–92.7)Cumulative incidence of progression (including lack of efficacy)/death,‡ %Evaluable pts,µ n9026100Rate at 4 y (95% CI), %13 (7.9–22.7)†23 (11.4–46.6)40 (31.5–50.9)CP3L ptsOSEvaluable pts,* n281271KM rate at 2 y (95% CI), %89 (68.9–96.2)100 (Not estimable–100)84 (73.1–90.9)Cumulative incidence of progression (including lack of efficacy)/death,‡ %Evaluable pts,µ n241237Rate at 3 y (95% CI), %33 (18.9–58.7)25 (9.4–66.6)51 (37.5–70.3)*Pts known to be alive as of the 6-mo response landmark.†P≤0.0004 vs no MCyR by ≤6 mo (comparison of OS and cumulative incidence distributions, unadjusted [P≤0.0002] and adjusted [P≤0.0004] for pre-existing neutropenia and/or thrombocytopenia and presence of a baseline mutation).‡Adjusted for the competing risk of treatment discontinuation without progression/death.µPts known to be alive with no disease progression as of the 6-mo response landmark.
CP2L pts (n=286 [IM-R, n=196; IM-I, n=90]) had a median (range) age of 53 (18–91) y. CP3L pts (n=118 with prior IM failure [D-R, n=38; D-I, n=50; N-R, n=26; N-I or D-R/I + N-R/I, n=4]) had a median (range) age of 56 (20–79) y. Median time from CML diagnosis was 3.7 (0.1–15.1) and 6.6 (0.6–18.3) y for CP2L and CP3L pts, respectively; BOS treatment duration was 24.8 (0.2–83.4) and 8.5 (0.2–78.1) mo; follow-up duration was 47.3 (0.6–90.6) and 33.1 (0.3–84.8) mo. Time from last enrolled pt's first dose to database snapshot was ≥48 mo for CP2L and ≥36 mo for CP3L.
Of 264 CP2L pts with a valid baseline assessment, 107/183 (58%) IM-R and 49/81 (60%) IM-I pts attained/maintained a MCyR; 88/183 (48%) and 42/81 (52%) pts had CCyR. The Kaplan-Meier (KM) probability of maintaining MCyR at 4 y was 69% for IM-R and 86% for IM-I pts. Of 110 CP3L pts with valid assessment, overall MCyR and CCyR rates were 40% and 32%; the KM probability of maintaining MCyR at 3 y was 65%.
There was no significant difference in OS or cumulative incidence of progression/death distribution between CP2L pts with MCyR by 3 mo vs by >3 to ≤6 mo; however, OS (P=0.0004) and cumulative incidence of progression/death (P=0.0002) distributions were significantly better for CP2L pts with MCyR by 3 mo vs no MCyR by 6 mo (Table). For CP3L pts, there was no significant difference in long-term outcomes between early response groups.
In conclusion, in CP-CML pts receiving BOS as 2nd-line therapy following IM failure (CP2L), pts who attained/maintained a MCyR by 3 mo had better OS and a lower progression/death distribution vs pts without MCyR by 6 mo; no significant differences were observed between pts achieving MCyR by 3 mo vs by >3 to ≤6 mo, although pt number was low for late responders. There were no significant differences in outcomes for CP-CML pts receiving BOS as 3rd/4th-line therapy, regardless of when or if MCyR was achieved, although the number of pts with MCyR was low. These results suggest that pts not achieving a MCyR by 6 mo, particularly in the 2nd-line setting, may require alternative therapies if options with better likelihood of response are available.

Disclosures:
Cortes: Pfizer, Ariad, Teva: Consultancy; Novartis, Bristol Myers Squibb, Pfizer, Ariad, Teva: Research Funding. Hochhaus:Pfizer: Research Funding. Apperley:Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Pfizer, Ariad: Honoraria (not direct from company), Honoraria (not direct from company) Other. O'Brien:BMS: Consultancy, Honoraria, Research Funding; Ariad, Novartis, Pfizer: Research Funding. Leip:Pfizer Inc: Employment. Turnbull:Pfizer Inc: Employment. Conlan:Pfizer Inc: Employment. Kantarjian:Pfizer Inc: Research Funding. Brümmendorf:Patent on the use of imatinib and hypusination inhibitors: Patents & Royalties; Ariad: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb, Pfizer: Consultancy, Honoraria.