Bosutinib Apears to be Safe, with Low Cross Intolerance, in Patients Treated in 4th Line. Results of the Spanish Compassionate Use Program

Abstract

Second-generation TKIs have demonstrated efficacy and an acceptable tolerability in patients (pts) with chronic myeloid leukemia (CML); however, new data from so called “off target” side effects have been published. For example, serious concerns have been raised about cardiovascular (CV) events with ponatinib, and, in lesser degree with nilotinib (NI), impeding or difficulting the treatment in patients with previous CV risk factors. Besides, patients with previous history of pleural effusion or pulmonary hypertension should avoid dasatinib (DA) if possible. Bosutinib could be a good candidate for situations which preclude the use of other TKI’s. We have previously presented efficacy data of 29 patients treated with bosutinib in forth line. The aim of this study is to report safety data of heavily CML patients treated with bosutinib in 4th line. We have studied 30 pts previously treated with imatinib (IM), dasatinib and nilotinib and 5 pts previously treated with IM-DA or NI since 2012 under the Spanish Compassionate Use Program. Patient’s baseline characteristics and previous treatments are shown in table 1. We have classified patients in 2 groups regarding to investigator-driven cause of discontinuation: intolerant (INT) or resistant (RES). At the data cutoff on June 16, 2014, the median follow up was 11.47 months (range, 2.03-45.97 months). Median duration of BOS treatment across all cohorts was 9.23 months (range, 0.63-23.40 months). We observed no significant differences in terms of Index prognostic factors (Sokal, Hasford or Eutos), sex, median duration of TKIs treatment or comorbidities. However, patients with resistance where significantly older observed: 56 years vs. 67 years (p<0.05). Toxicity spectrum pre-BOS: Main reason for treatment discontinuation for each TKI was: treatment failure in the case of IM (14/35) and intolerance for both DA 16/34 and NI 13/31. Hematological (HEM) toxicities grade 3-4 with all TKIs were more common in RES pts, being dasatinib the one that showed the highest rate of grade 3-4 HEM toxicities. Non-HEM toxicities to all TKIs were significantly more frequent in INT than in RES pts (p<0.05). Most common grade 3-4 non-HEM toxicities were rash for IM (3/35), pleural effusion for DA (7/34) and vascular events for NI (3/31 Peripheral arterial disease (PAOD), 3/31 Ischemic heart disease (IHD)). Toxicity spectrum with BOS treatment: treatment interruptions were more frequent in INT than in RES pts 52% vs 25%, as well as dose reductions 78% vs 66% respectively. Grade 3-4 HEM toxicities were more common in RES than INT pts (41.6% vs 4.3% respectively). Non-HEM toxicities were also more frequent in RES pts than INT: diarrhea (50% vs 43%), rash (16% vs 8%), ALT or AST increase (25% vs 13%) abdominal pain (16% vs 4%), grade 3-4 non HEM toxicities were more frequent in RES than INT pts (41% vs 17%) (Diarrhea 16.7% vs 4.3%, AST/ALT increase: 16.7% vs 0%). None (0/12) vs 4/23 (17%) pts discontinued treatment due to toxicity in the RES vs. INT group respectively. Cross intolerance was extremely rare, of the 7 pts who had rash with IM, only 1 suffered rash with BOS. None pts had pleural effusion with BOS out of 15 who previously suffered with DA neither vascular events out of the 10 pts that previously suffered with NI. EFS by 20 months was 75% vs 50% for INT and RES patients. We have shown how in previously heavily pretreated CML patients, most of them in 4th line bosutinib has an excellent safety profile with no patients interrupting treatment due to side effects in previously intolerant patients. Importantly, rates of cross intolerance (namely CV, pleural and skin ) have also been very low. We conclude that Bosutinib is an excellent alternative also in patients who are left without a suitable treatment option. Table IM+NI-I +DA-R IMA+NI-R +DA-R IM+NI-I +DA-I IM+NI-R +DA-I IM+NI/DA TOTAL Pts, N(%) 2 (5.7) 7 (20) 15 (43) 6 (17) 5 (14) 35 (100) Age of diagnosis, med yr 61.0 46.7 54.7 53.8 58.7 54.2 Age of BOS initiation, med yr 74.7 61.5 64.6 64.8 65.5 63.8 Sokal index at diagnosis, N (High/intermidiate/low) 1/0/1 1/2/4 0/5/7 1/2/2 0/2/2 3/11/16 Time from first TKI to BOS, med yr 11.7 10.0 9.9 7.4 10.7 10.0 Duration of IM treatment, med, mo 63.3 33.1 26.6 21.4 78.2 27.2 Duration of DA treatment, med, mo 48.7 16.0 41.9 19.2 18.7 23.6 Duration of NI treatment, med ,mo 29.1 14.2 9.0 21.0 24.2 11.6 I:iIntolerance, R: resistant, med: median, yr: year, mo: months Disclosures García-Gutiérrez: Novartis: Consultancy; BMS: Consultancy; Pfizer: Consultancy; Ariad: Consultancy. Steegmann:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Ariad: Consultancy.

Drug Therapy in the Progressed CML Patient With Multi-Tki Failure

“…Bosutinib could be an option for the CML situations which preclude the use of other TKIs. 14 In a Spanish study, cross intolerance with bosutinib was extremely rare, of the 7 patients who had rash with imatinib, only 1 suffered rash with bosutinib. None of the patients had pleural effusion with bosutinib out of 15 who previously experience it with dasatinib neither vascular events out of the ten patients that already had this side effect with nilotinib.…”

“…Importantly, the rates of cross intolerance (namely cardiovascular, pleural and skin) were also very low in the Spanish study. 14 …”

A case of worsening pulmonary arterial hypertension and pleural effusions by bosutinib after prior treatment with dasatinib

“…As previously reported, bosutinib is an excellent alternative in patients who are left without a suitable treatment option. 10 The non-hematologic toxicity is typically transient, with a low incidence of cardiovascular adverse effects reported. 1 However, of great concern is that bosutinib has been noted to cause marked worsening of pre-existing TKI-associated PAH.…”

“…Due to these adverse effects, dasatinib and bosutinib should be avoided in those patients with a history of pleural effusion or PH. 10 It has been advised that patients be evaluated for signs and symptoms of cardiopulmonary disease before and during dasatinib treatment. 14 Furthermore, due to the persistence of PAH in patients after dasatinib use, ongoing surveillance of their hemodynamics is important.…”

“…Despite these advances in efficacy, the use of these agents has come with its own set of consequences. Major AEs include PH, pleural effusions, and peripheral arterial and venous events 3 , 9 , 10 . Other cardiovascular adverse effects related to these agents include fluid retention, pleural‐pericardial effusion, heart failure, QT prolongation, and coronary artery disease 4 …”