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Clinical Trial
, 90 (9), 755-68

Long-term Efficacy and Safety of Bosutinib in Patients With Advanced Leukemia Following Resistance/Intolerance to Imatinib and Other Tyrosine Kinase Inhibitors

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Clinical Trial

Long-term Efficacy and Safety of Bosutinib in Patients With Advanced Leukemia Following Resistance/Intolerance to Imatinib and Other Tyrosine Kinase Inhibitors

Carlo Gambacorti-Passerini et al. Am J Hematol.

Abstract

Long-term efficacy and safety of bosutinib (≥4 years follow-up from last enrolled patient) were evaluated in an ongoing phase 1/2 study in the advanced leukemia cohort with prior treatment failure (accelerated-phase [AP, n = 79] chronic myeloid leukemia [CML], blast-phase [BP, n = 64] CML, acute lymphoblastic leukemia [ALL, n = 24]). Fourteen AP, 2 BP, and 1 ALL patient remained on bosutinib at 4 years (vs. 38, 8, 1 at 1 year); median (range) treatment durations: 10.2 (0.1-88.6), 2.8 (0.03-55.9), 0.97 (0.3-89.2) months. Among AP and BP patients, 57% and 28% newly attained or maintained baseline overall hematologic response (OHR); 40% and 37% attained/maintained major cytogenetic response (MCyR) by 4 years (most by 12 months). In responders at 1 versus 4 years, Kaplan-Meier (KM) probabilities of maintaining OHR were 78% versus 49% (AP) and 28% versus 19% (BP); KM probabilities of maintaining MCyR were 65% versus 49% (AP) and 21% versus 21% (BP). Most common AEs (AP, BP) were gastrointestinal (96%; 83%), primarily diarrhea (85%; 64%), which was typically low grade (maximum grade 1/2: 81%; 59%) and transient; no patient discontinued due to diarrhea. Serious AEs occurred in 44 (56%) AP and 37 (58%) BP patients, most commonly pneumonia (n = 9) for AP and pyrexia (n = 6) for BP; 11 and 13 died within 30 days of last dose (2 considered bosutinib-related [AP] per investigator). Responses were durable in ∼50% AP responders at 4 years (∼25% BP patients responded at year 1, suggesting possible bridge-to-transplant role in BP patients); toxicity was manageable.

Figures

Figure 1
Figure 1
Duration of OHR (A) and MCyR (B). Duration of response was calculated from the first date of response to confirmed loss, treatment discontinuation due to progressive disease or death, or death within 30 days of the last dose of study drug; responders without events were censored at the last follow‐up visit. 2L, Second‐line (prior imatinib only); ≥3L, third‐/fourth‐line (imatinib followed by dasatinib and/or nilotinib); ALL, acute lymphoblastic leukemia; AP, accelerated phase; BP, blast phase; CI, confidence interval; CML, chronic myeloid leukemia; MCyR, major cytogenetic response; NR, not reached; NE, not evaluable; OHR, overall hematologic response.
Figure 2
Figure 2
OHR (A) and MCyR (B) by individual baseline Bcr‐Abl mutations in AP, BP, and ALL cohorts. Individual patients may have had more than one detected mutation. Bosutinib IC50 concentrations were based on data from 34. aIncludes one evaluable ALL patient with a F317L mutation who did not achieve a response; bincludes one evaluable ALL patient with a G250E mutation who did not achieve a response; cincludes one evaluable ALL patient with a E255V mutation who did not achieve a response; dincludes three evaluable ALL patients with a T315I mutation who did not achieve a response; eincludes one evaluable ALL patient with a F359C mutation who did not achieve a response. Eval, number of patients with each baseline mutation who had a valid baseline efficacy assessment for the respective endpoint; IC50, half‐maximal inhibitory concentration; MCyR, major cytogenetic response; OHR, overall hematologic response.
Figure 3
Figure 3
Cumulative incidence of PD/death adjusting for the competing risk of treatment discontinuation without PD/death (A) and overall survival (B). Criteria for PD included transformation to AP/BP CML, increasing white blood cell count (doubling over ≥1 month with second count >20 × 109/L and confirmed ≥1 week later, or loss of confirmed CHR or unconfirmed MCyR. OS was calculated from the date of first study dosing to the date of death, with patients without events censored at the last contact, and was evaluated throughout the 2‐year follow‐up period after treatment discontinuation. The median follow‐up was 28.4 (0.3–88.6), 10.4 (0.4–79.9), and 3.6 (0.4–89.2) months for AP, BP, and ALL patients, respectively. 2L, Second‐line (prior imatinib only); ≥3L, third‐/fourth‐line (imatinib followed by dasatinib and/or nilotinib); ALL, acute lymphoblastic leukemia; AP, accelerated phase; BP, blast phase; CI, confidence interval; CML, chronic myeloid leukemia; NR, not reached; OS, overall survival; Ph+, Philadelphia chromosome‐positive; PD, progressive disease.

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