The role of bosutinib as rescue treatment of Philadelphia chromosome‐positive chronic myeloid leukemia (CML) patients after failing three previous tyrosine kinase inhibitors (TKIs) is currently unknown. We report here the largest series (to our knowledge) of patients treated with bosutinib in fourth‐line, after retrospectively reviewing 30 patients in chronic phase, and pretreated with imatinib, nilotinib, and dasatinib. With a median follow up of 11.1 months, the probability to either maintain or improve their CCyR response was 56.6% (17/30) and 11 patients (36.7%) achieved or maintained their baseline MMR. In patients not having baseline CCyR, the probabilities of obtaining CCyR, MMR, and MR4.5 were 13, 11, and 14%, respectively. The probabilities of obtaining MMR and deep molecular response MR4.5 in patients with baseline CCyR were 40.0% (6/15) and 20.0% (3/15). At 20 months, progression‐free survival was 73%. Grade 3–4 hematological toxicities were more frequent in resistant than intolerant patients (45.4 vs. 0.0%). Nonhematological toxicities were also more frequent in resistant patients, being diarrhea the most conspicuous one. Bosutinib seems to be an appropriate treatment option for patients resistant or intolerant to three prior TKI's.Am. J. Hematol. 90:429–433, 2015. © 2015 Wiley Periodicals, Inc.

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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.

BACKGROUND: Despite the excellent prognostic of chronic myeloid leukemia (CML) patients since the introduction of tyrosine kinase inhibitors (TKIs), approximately 50% of patients that are treated with TKIs will discontinue first line treatment due to lack of efficacy or intolerance. Once patients need a second line treatment, a considerable proportion of patients will need third or even fourth line therapy during further evolution. At this moment, there is a lack of data about real benefit of this group of patients. We have recently published our experience of 30 CML patients treated with bosutinib in 4th line. We present an update of the study where we have increased the number of patients, and the follow-up. The aim of this study is to present safety and efficacy data CML chronic phase patients treated with bosutinib in 4th line. METHODS: We have collected data from 59 CML patients treated with bosutinib in 4th line after resistance or intolerance to IM, NI and DA. 51 patients have been treated under the Spanish compassionate use program (36 centers) and 10 patients were treated in a single institution from United Kingdom. Median age of patients at diagnosis was 53 years. The percentage of low, intermediate and high risk Sokal groups were 47%, 37% and 16%. Median time TKIs exposure before bosutinib was 9 years. The most common indication (30/59) was intolerant to DA and NI. Patients' dispositions and main line characteristics are shown in table 1. RESULTS: Median follow-up was 14.3 months. All patients started bosutinib at 500mg/d, median dose of was 450mg/d. Overall probabilities to either achieve or maintain previous response were 96% (57/59), 62% (37/59), 40% (24/59) and 17% (10/59) for complete hematological response (CHR), complete cytogenetic response (CCyR), major molecular response (MMR) and MR4.5 respectively. However, probabilities to obtain responses (in patients without response evaluated at baseline) were 27% (7/26), 26% (12/45) and 12% (7/55) for CCyR, MMR and MR4.5. As expected, probabilities to obtain CCyR were lower for patients resistant to DA and NI patients than for patients intolerant to DA and NI (8% VS 44%). Event free survival (EFS) and progression free survival (PFS) probabilities were 50% and 83% by 27 month. Treatment was discontinued in 20/58 (34%), most frequent reasons being adverse events 9/59(15%), lack of efficacy 5/59 (8.5%), disease progression 2/59 (3.4%) and death 1/59 (1.7%). Two patients discontinued due to stem cell transplantation. The adverse events that led to treatment discontinuation were pleural effusion (3), diarrhea (2), rash, renal impairment, auricular fibrillation and liver enzyme elevation one patient each. Overall, bosutinib was well tolerated. Grade 3-4 hematological toxicities were 3%, 6% and 6% for anemia, thromboctytopenia and neutropenia. Most common non hematological side effects were diarrhea (39%, nauseas 13% and liver alterations 14% and pleural effusion 14%. CONCLUSIONS: Little is known about the therapeutic role of Bosutinib in 4th line. The series presented here is, to our knowledge, the largest being presented. Bosutinib seems to be an appropriate treatment option for patients resistant or intolerant to three prior TKIs. Table 1. IM+NI-I+DA-R (N=4) IM+NI-R+DA-R (N=18) IM+NI-I+DA-I (N=30) IM+NI-R+DA-I (N=7) Total (N=59) Sex, N (%) Male 2 (50) 11 (61.1) 16 (53.3) 2 (28.6) 31 (52.5) Median age of diagnosis, yr (range) 57.32 (50-64) 49.19 (23-73) 54.95 (21-89) 48.87 (26-68) 53.15 (21-89) Median age of Bosutinib initiation, yr (range) 69.13 (61-70) 62.27 (39-79) 64.85 (25-90) 64.79(35-74) 63.7 (25-9) Median follow up, months (range) 18.5(7.8-34.1) 8.4(1.22-36.1) 16.3(0.5-34.7) 23.4(3.3-28.9) 14.3(0.7-36.1) SOKAL Index at diagnosis, N (%) High 2(50.0) 4 (23.5) 1 (4.3) 1 (20) 8 (16.3) Intermediate 1 (25.0) 5 (29.4) 10(43.5) 2 (40) 18 (36.7) Low 1 (25.0) 8 (47.1) 12 (52.2) 2 (40) 23 (46.9) Median Time from first TKI to BOS, (yr, range) 10.3 (4.8-11.9) 9.3 (2.0-11.4) 8.8 (0.7-13.6) 8.2 (5.1-12.3) 8.8 (0.7-13.6) Median duration of prior therapy, months (range) Imatinib 38.8 (11.8-69.8) 32.6 (6.3-96.8) 26.2 (1.6-102.6) 23.1 (8.3-66.8) 28.8 (1.6-102.6) Dasatinib 21.5 (12.6-75) 21.8 (7.7-69) 31.4 (0.4-87.1) 23.7 (10.3-53.6) 23.44 (0.4-87.1) Nilotinib 19.1 (2.1-46.2) 16.7 (5-65.6) 8.9 (0.2-58.5) 30.9 (6.9-49.3) 14.3 (0.2-65.6) BOS: bosutinib, IM, imatinib; DA, dasatinib; NI, nilotinib, I: Intolerance, R: Resistant, Yr: year Disclosures García-Gutiérrez: Ariad: Consultancy; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Milojkovic:Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Boque:Novartis: Honoraria; BMS: Honoraria; Celgene: Honoraria. Casado:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Jiménez:Pfizer: Consultancy, Honoraria. Giraldo:Pfizer: Consultancy. Steegmann:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Ariad: Consultancy, Honoraria, Research Funding, Speakers Bureau.

INTRODUCTION: In chronic myeloid leukemia (CML) patients in chronic phase (CML-CP), BCR-ABL levels ≤10% at 3 months measured by RT-qPCR (IS) has been consistently correlated with probabilities to obtain an optimal response at 12 months. Monitoring molecular response with automated cartridge-based detection system GeneXpert BCR-ABL (Cepheid®) method has shown an optimal correlation with standardized BCR-ABL (IS) EUTOS method in patients with complete cytogenetic response (CCyR). However, is not known if both methods are also equivalent when measuring BCR-ABL levels above 1%, and therefore, the utility of GeneXpert in order to evaluate response at 3 months must be confirmed. AIMS: To validate the predictive value of molecular response at 3 months with GeneXpert method METHODS: We have studied 125 new consecutive CML-CP patients treated with tyrosine kinase inhibitors (TKIs) followed in 13 centers. Median age at diagnosed was 55 years. The percentage of low, intermediate and high risk Sokal groups were 42%, 40% and 18% . First line treatment was imatinib (IM), nilotinib (NI), dasatinib (DA) or bosutinib (BO) in 58%, 28%, 13% and 1% of the patients, respectively. BCR-ABL level was measured by GeneXpert platform, where all necessary steps to measure BCR-ABL levels are automatically performed. ABL was used as gene control. The study was approved by the Ethics Committee. RESULTS: Median follow up was 43 months. The proportion of patients that achieved CCyR by 12 months, analyzed by intention to treat, was 84% (108/123). Probabilities for each specific TKI were 78%, 93%, 100% and 100% for IM, NI, DA and BO respectively. 23% (96/125) of patients required treatment changed due to resistance or intolerance. Treatment discontinuation probabilities were 32%, 11%, 5% and 0% for IM, NI, DA and BO respectively. Only 4% (5/125) did not achieve an optimal response at 3 months (BCR-ABL ≤10%), which is significant lower compare to results obtain with historical series when using EUTOS IS method. 10% cut-off at 3 month was unable to identify patients that achieved an optimal response in further evaluations. By 12 months, this cutoff did not correlate with probabilities to obtain CCyR (50% vs 86% (p=0.1) or major molecular response (MMR) (60% vs 79% (p=0.21)). In order to find a cutoff that could correlate with optimal response at 12 months, we used a receiver operating characteristic curve to identify the optimal cutoff in transcript level that would allow us to classify the patients as high risk or low risk with maximal sensitivity and specificity for each individual outcome. At 3 months, patients with transcript levels ≤ 1.6% had significantly better probabilities to obtain an optimal response by 12 months, with 81% and 94% sensitivity and specificity for CCyR. With this new cutoff, probabilities for CCyR and MMR at 12 months were 98% vs 54% (p<0.001) and 88% vs 56% (p<0.001) respectively (OR:. Finally, this cutoff has also been correlated with probability for treatment changed at any time (46% vs 16% (p=0.005)) CONCLUSIONS: The results of our study seem to show that the 10% threshold, commonly used to evaluate response at 3 months when using BCR-ABL (IS) EUTOS method, is not associated with probabilities to achieve further optimal responses when using the GeneXpert platform. We have shown how a new cutoff of 1,6% % at 3 months when using GeneXpert could better identify patients with lower risk to achieve an optimal response at 12 months. Disclosures García-Gutierrez: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Steegmann:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Ariad: Consultancy, Honoraria, Research Funding, Speakers Bureau.