Outcomes before and after dose reduction in patients with newly diagnosed chronic myeloid leukemia receiving bosutinib or imatinib.
Authors: Deininger Michael W , Brümmendorf Tim H. , Milojkovic Dragana , Cervantes Francisco , Huguet Françoise , Viqueira Andrea , Leip Eric , Purcell Simon , Cortes Jorge E. 
Published: June 2021

7039 Background: Bosutinib (BOS) is approved for patients (pts) with Philadelphia chromosome-positive chronic myeloid leukemia (CML), at a starting dose of 400 mg QD in newly diagnosed pts in chronic phase (CP). This analysis evaluated the impact dose reduction has on the outcomes of BOS and imatinib (IMA) in pts with CP CML. Methods: In the open-label BFORE trial, 536 pts with newly diagnosed CP CML were randomized to receive 400 mg QD BOS (N = 268) or IMA (N = 268; 3 untreated). Dose could be reduced to 300 mg QD for toxicity. Following sponsor approval, dose reduction to BOS 200 mg QD was permitted for 4 wks maximum; after this time, dose escalation or treatment discontinuation was required. Maintenance of response after dose reduction was defined as having a response > 6 mo after the first reduction. Database lock: June 12, 2020, 5 y after the last pt enrolled. Results: In the BOS arm, dose reduction to 300 (without further reduction) or 200 mg QD was seen in 82 (31%) and 33 (12%) pts, and median time to dose reduction was 85 and 205 d. In the IMA arm, 50 (19%) pts had a dose reduction to 300 mg QD, and median time to dose reduction was 92 d. Most common (≥2% of pts) treatment-emergent adverse events (TEAEs) leading to dose reduction were increased alanine aminotransferase (8%), thrombocytopenia (7%), diarrhea (7%), increased lipase (6%), increased aspartate aminotransferase (4%), nausea (4%), neutropenia (3%), rash (3%) and abdominal pain (2%) with BOS, and neutropenia (4%) with IMA. Of the pts who remained on 400 mg QD BOS (n = 153) or IMA (n = 214), respectively, 120 (78%) and 139 (65%) achieved major molecular response (MMR). Among pts who had a BOS dose reduction to 300 mg QD, 51/82 (62%) had MMR > 6 mo after dose reduction: 14 (17%) maintained MMR before and after dose reduction and 37 (45%) achieved MMR for the first time after dose reduction. Seven (9%) pts had MMR before dose reduction but discontinued treatment before the next > 6 mo assessment. In the IMA arm, 32/50 (64%) pts had MMR > 6 mo after dose reduction: 9 (18%) maintained MMR before and after dose reduction and 23 (46%) achieved MMR for the first time after dose reduction. One (2%) pt had MMR before dose reduction but discontinued treatment before the next > 6 mo assessment and 1 (2%) pt lost a previously attained MMR after dose reduction. Among pts who had a BOS dose reduction to 200 mg QD, 12/33 (36%) had MMR > 6 mo after dose reduction: 7 (21%) maintained MMR before and after dose reduction and 5 (15%) achieved MMR for the first time after dose reduction. Six (18%) pts had MMR before dose reduction but discontinued treatment before the next > 6 mo assessment. Similar trends were seen for complete cytogenetic response. Conclusions: Management of TEAEs through BOS or IMA dose reduction enabled pts to continue treatment, with a substantial number of pts achieving MMR for the first time after dose reduction. Clinical trial information: NCT02130557.