Published Ahead of Print on May 17, 2018, as doi:10.3324/haematol.2017.171249. Copyright 2018 Ferrata Storti Foundation. Safety and efficacy of second-line bosutinib for chronic phase chronic myeloid leukemia over a five-year period: final results of a phase 1/2 study by Carlo Gambacorti-Passerini, Jorge E. Cortes, Jeff H. Lipton, Hagop M. Kantarjian, Dong-Wook Kim, Philippe Schafhausen, Rocco Crescenzo, Nathalie Bardy-Bouxin, Mark Shapiro, Kay Noonan, Eric Leip, Liza DeAnnuntis, Tim H. Brümmendorf, and H. Jean Khoury Haematologica 2018 [Epub ahead of print] Citation: Carlo Gambacorti-Passerini, Jorge E. Cortes, Jeff H. Lipton, Hagop M. Kantarjian, Dong-Wook Kim, Philippe Schafhausen, Rocco Crescenzo, Nathalie Bardy-Bouxin, Mark Shapiro, Kay Noonan, Eric Leip, Liza DeAnnuntis, Tim H. Brümmendorf, and H. Jean Khoury. Safety and efficacy of second-line bosutinib for chronic phase chronic myeloid leukemia over a five-year period: final results of a phase 1/2 study. Haematologica. 2018; 103:xxx doi:10.3324/haematol.2017.171249 Publisher's Disclaimer. E-publishing ahead of print is increasingly important for the rapid dissemination of science. Haematologica is, therefore, E-publishing PDF files of an early version of manuscripts that have completed a regular peer review and have been accepted for publication. E-publishing of this PDF file has been approved by the authors. After having E-published Ahead of Print, manuscripts will then undergo technical and English editing, typesetting, proof correction and be presented for the authors' final approval; the final version of the manuscript will then appear in print on a regular issue of the journal. All legal disclaimers that apply to the journal also pertain to this production process.
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Supplementary Materials Methods Eligibility criteria Eligible patients were aged 18 years with a confirmed diagnosis of Philadelphia chromosome positive (Ph+) chronic phase (CP) chronic myeloid leukemia that was either resistant to full-dose imatinib or intolerant to any dose of imatinib. Primary imatinib resistance was defined as failure to achieve or maintain either hematologic improvement within 4 weeks, a complete hematologic response after 12 weeks, any cytogenetic response by 24 weeks, or a major cytogenetic response (MCyR) by 12 months with imatinib 600 mg/day. Acquired resistance was defined as loss of MCyR or hematologic response. Imatinib intolerance was defined as an inability to receive imatinib because of imatinib-related grade 4 hematologic adverse events (AEs) lasting >7 days, imatinib-related grade 3 nonhematologic AEs, grade 2 AEs that persist despite dose reductions and concomitant medications, or loss of response on lower-dose imatinib among patients with previous toxicity. In addition to prior imatinib therapy, patients were required to have an Eastern Cooperative Oncology Group Performance Status of 0 or 1, no antiproliferative or antileukemia treatment (with the exception of hydroxyurea or anagrelide) within 7 days of initiating bosutinib therapy, and adequate bone marrow function (imatinib-resistant patients), hepatic function, and renal function. Patients were excluded if they had a history of clinically significant or uncontrolled cardiac disease, had prolonged QTc 1
(average of >0.45 sec at screening), or had uncorrected hypomagnesemia or hypokalemia. Full eligibility criteria have been previously described. 10 Patients with documented history of T315I mutation could enroll in the study until a protocol amendment (May 28, 2008) made these patients ineligible. Patients already being treated could remain on study if enrollment had occurred before the amendment or if a baseline sample had subsequently tested positive for the T315I mutation. Statistical methods Time-to-event distributions and probabilities were estimated using the Kaplan- Meier method or cumulative incidence adjusting for the competing risk of treatment discontinuation without an event of PD/death or transformation. Two-sided 95% confidence intervals (CIs) for response rates and Kaplan-Meier quartiles were determined using the exact binomial and Brookmeyer-Crowley linear transformation methods, respectively. For Kaplan-Meier and cumulative incidence yearly probability estimates, two-sided 95% CIs were based on Greenwood s formula and Gray s method, respectively. Baseline and on-treatment (time-dependent) patient characteristics were evaluated as potential prognostic factors using backward-elimination, multivariate, cause-specific Cox regression models for duration of response and progression-free survival and a multivariate Cox regression model for overall survival. P values <0.05 were statistically significant and no adjustments for multiple comparisons were made. 2
Backward elimination criteria was 0.20 for all models. Results are presented as hazard ratios (95% confidence intervals). Covariates for multivariate Cox regression analysis Prior response to imatinib was defined as achievement of at least a minimal cytogenetic response (standard cytogenetic criteria: 66% 95% Ph+ cells from bone marrow or BCR-ABL1 from fluorescence in situ hybridization [FISH]). Determination of Ph+ ratio occurred during the screening visit within 14 days before registration of the patient in the study and required 20 metaphases for standard cytogenetics or 200 cells for FISH. Disease duration is defined as the time between the primary diagnosis and date of administration of first dose of study drug. Patients initiating imatinib treatment 6 months after diagnosis or after prior interferon therapy were considered to be in late CP. Bosutinib-sensitive mutations are those resulting in half maximal inhibitory concentration (IC 50 ) 3-fold higher than wild type (M244V, Q252H, Y253H, Y253F, D276G, E279K, E292L, F317L, M343T, M351T, F359I, F359V, L384M, H396P, H396R, G398R, F486S); moderately bosutinib-resistant mutations are those with IC 50 values 3 to 10-fold higher than wild type (L248V, G250E, E255V, and T315A); highly bosutinib-resistant mutations are those with IC 50 values >10-fold higher than wild type (L248R, L248R+F359I, E255K, V299L, T315I, T315V, F317R, F317V); the sensitivity of all other mutations is unknown. 15,21 Patients with multiple mutations of different sensitivities were categorized based on the following hierarchy: highly bosutinibinsensitive, bosutinib-insensitive, unknown sensitivity, and bosutinib-sensitive. 3
Supplementary Table S1. Demographics and Baseline Disease Characteristics IM-R (n=195) IM-I (n=89) Total (n=284) Median (range) age, y 51 (18 86) 55 (23 91) 53 (18 91) <65 y, n (%) 159 (82) 62 (70) 221 (78) 65 y, n (%) 36 (18) 27 (30) 63 (22) Men, n (%) 113 (58) 36 (40) 149 (52) Race, n (%) White Asian Black Other ECOG Performance Status, n (%) 0 1 2 131 (67) 41 (21) 11 (6) 12 (6) 151 (77) 44 (23) 0 55 (62) 21 (24) 5 (6) 8 (9) 66 (74) 21 (24) 1 (1) 186 (65) 62 (22) 16 (6) 20 (7) 217 (76) 65 (23) 1 (<1) Median time since CML diagnosis (range), y 4.1 (0.6 15.1) 2.7 (0.1 13.6) 3.7 (0.1 15.1) Number of prior therapies, n (%) 1 118 (61) 66 (74) 184 (65) 2 77 (39) 23 (26) 100 (35) Prior non-tki therapies, n (%) Interferon Stem cell transplant 77 (39) 23 (26) 6 (3) 2 (2) CML=chronic myeloid leukemia; ECOG=Eastern Cooperative Oncology Group; IM-I=imatinib intolerant; IM-R=imatinib-resistant; TKI=tyrosine kinase inhibitor. 100 (35) 8 (3) 4
Supplementary Table S2. Treatment Discontinuations by Year of Treatment* Reasons for Discontinuation Year 1 (n=284) Year 2 (n=197) Year 3 (n=153) Year 4 (n=136) Year 5 (n=123) Total (n=284) Discontinued treatment, n (%) 87 (31) 44 (22) 17 (11) 13 (10) 8 (7) 284 (100) AE 47 (17) 10 (5) 2 (1) 4 (3) 1 (1) 67 (24) PD 21 (7) 15 (8) 7 (5) 3 (2) 1 (1) 51 (18) Patient request 9 (3) 5 (3) 2 (1) 2 (1) 1 (1) 24 (8) Unsatisfactory response (efficacy) 5 (2) 9 (5) 4 (3) 1 (1) 2 (2) 23 (8) Death 0 2 (1) 1 (1) 0 2 (2) 8 (3) Investigator request 1 (<1) 0 1 (1) 1 (1) 0 8 (3) Lost to follow-up 1 (<1) 1 (<1) 0 2 (1) 0 4 (1) Symptomatic deterioration 1 (<1) 1 (<1) 0 0 0 2 (1) Other 2 (1) 1 (<1) 0 0 1 (1) 96 # (34) Discontinuation due to any AE,,ǁ n Thrombocytopenia 14 2 0 0 1 17 Neutropenia 6 0 0 0 0 6 ALT increased 6 0 0 0 0 6 Diarrhea 3 1 0 0 0 4 Rash 3 0 0 0 0 3 AST increased 3 0 0 0 0 3 Anemia 3 0 0 0 0 3 Pneumonia 0 1 0 0 0 1 Intestinal obstruction 0 1 0 0 0 1 Abdominal adhesions 0 1 0 0 0 1 Cardiac failure 0 1 0 0 0 1 Lipase increased 0 1 0 0 0 1 White blood cell count increased 0 1 0 0 0 1 CAD 0 0 1 0 0 1 Scleroderma 0 0 1 0 0 1 Renal failure 0 0 1 0 0 1 5
Ascites 0 0 0 1 0 1 Serositis 0 0 0 1 0 1 Increased blood creatinine 0 0 0 1 0 1 Pulmonary hypertension 0 0 0 1 0 1 AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CAD=coronary artery disease; PD=progressive disease. *In both Parts 1 and 2, patients received treatment until PD, death, unacceptable toxicity, or withdrawal of consent; denominators for years 1 5 are the number of patients on treatment during those time periods. Includes data after year 5 until the cutoff date. One year=48 weeks. AEs presented include those resulting in treatment discontinuation in years 2 5 or in 1% of patients overall. ǁ Totals are not necessarily the sum of those for individual AEs as patients may report multiple AEs leading to discontinuation. The same patient discontinued due to ascites and serositis. # Includes patients who enrolled in an extension study and those for whom discontinuation of study by the sponsor was the primary reason for treatment discontinuation. 6
Supplementary Table S3. Treatment Outcomes for Patients Aged 65 and 65 Years 65 y Parameter (n=221) Response,* n/n evaluable (%) [95% CI] Attained/maintained MCyR 123/201 (61) [54.1 68.0] Attained MCyR 115/192 (60) [52.6 66.9] Attained/maintained CCyR 101/201 (50) [43.1 57.4] Attained CCyR 93/192 (48) 65 y (n=63) Total (n=284) 33/61 (54) [40.9 66.9] 156/262 (60) [53.3 65.5] 26/54 (48) 141/246 (57) [34.3 62.2] [50.9 63.6] 29/61 (48) 130/262 (50) [34.6 60.7] [43.4 55.8] 23/54 (43) 116/246 (47) [41.2 55.7] [29.2 56.8] [40.8 53.6] Probability of maintaining MCyR at 5 y, % [95% CI] 73 [64 81] 63 [42 78] 71 [63 78] Probability of maintaining CCyR at 5 y, % [95% CI] 73 [62 81] 58 [35 75] 69 [60 77] 1 dose interruption due to AEs, n (%) 159 (72) 50 (79) 209 (74) 1 dose reduction due to AEs, n (%) 105 (48) 36 (57) 141 (50) On-treatment death due to an AE, n (%) 3 (1) 2 (3) 5 (2) Discontinued treatment, n (%) 221 (100) 63 (100) 284 (100) Enrolled in extension study 71 (32) 12 (19) 83 (29) AE 47 (21) 20 (32) 67 (24) PD 41 (19) 10 (16) 51 (18) Patient request 15 (7) 9 (14) 24 (8) Efficacy 18 (8) 5 (8) 23 (8) Other 12 (5) 1 (2) 13 (5) Death 3 (1) 5 (8) 8 (3) Investigator request 7 (3) 1 (2) 8 (3) Lost to follow-up 4 (2) 0 4 (1) Symptomatic deterioration 2 (1) 0 2 (1) 7
Study discontinued by sponsor 1 (<1) 0 1 (<1) Transformation to AP/BP CML at 5 y, ǁ % [95% CI] 5 [3 9] 3 [1 12] 5 [3 8] PD/death at 5 y, % [95% CI] 19 [15 25] 19 [11 32] 19 [15 24] OS at 5 y,,** % [95% CI] 85 [79 90] 77 [61 86] 84 [78 88] AE=adverse event; AP=accelerated phase; BP=blast phase; CCyR=complete cytogenetic response; CI=confidence interval; CML=chronic myeloid leukemia; MCyR=major cytogenetic response; OS=overall survival; PD=progressive disease. *Response among evaluable patients. Response could be newly achieved during the study or maintained from baseline for 4 weeks and was determined using standard cytogenetics with 20 metaphases counted for postbaseline assessments (fluorescence in situ hybridization analysis of bone marrow aspirate or peripheral blood with 200 cells to detect BCR- ABL1 was used if 20 metaphases were available postbaseline). 22 Evaluable patients received 1 bosutinib dose and had a valid baseline assessment of cytogenetic response with 20 metaphases or 1 Ph+ metaphase from bone marrow cytogenetics. Patients with a CCyR at baseline were excluded from the attained-only analyses. Based on Kaplan-Meier estimates. AEs resulting in death were acute cardiac decompensation, heart failure and chronic obstructive pulmonary disease (same patient), congestive heart failure, suicide, and pneumonia. ǁ Based on cumulative incidence adjusting for competing risk of treatment discontinuation without transformation. Based on cumulative incidence adjusting for competing risk of treatment discontinuation without PD or death; PD defined as transformation to AP or BP CML, increasing white blood cell count (doubling over 1 mo with second count >20 10 9 /L and confirmed 1 week later), or loss of confirmed complete hematologic response or unconfirmed MCyR). ** Analysis includes data from the long-term extension study. 8
Supplementary Table S4. Cytogenetic Response Before and After Bosutinib Dose Reduction IM-R (n=195) IM-I (n=89) Total (n=284) Patients reducing dose to 400 mg, n 81 51 132 Attained/maintained MCyR,* n (%) 51 (63) 30 (59) 81 (61) MCyR after reduction 39 (48) 18 (35) 57 (43) Median (range) duration of MCyR (non-k-m), wk 134 (0 338) 185 (0 290) 167 (0 338) MCyR before and after reduction 9 (11) 10 (20) 19 (14) Median (range) duration of MCyR (non-k-m), wk 299 (11 324) 281 (44 342) 283 (11 342) MCyR before but not after reduction 3 (4) 2 (4) 5 (4) Newly-attained MCyR,* n (%) 44 (63) 23 (58) 67 (61) Attained MCyR after reduction 32 (46) 16 (40) 48 (44) Median (range) duration of MCyR (non-k-m), wk 122 (0 338) 185 (0 290) 150 (0 338) Attained MCyR before and after reduction 9 (13) 6 (15) 15 (14) Median (range) duration of MCyR (non-k-m), wk 299 (11 324) 281 (44 342) 283 (11 342) Attained MCyR before but not after reduction 3 (4) 1 (3) 4 (4) Patients reducing dose to 300 mg, n 32 18 50 Attained/maintained MCyR, n (%) 22 (69) 7 (39) 29 (58) MCyR after reduction 6 (19) 2 (11) 8 (16) Median (range) duration of MCyR (non-k-m), wk 17 (0 251) 116 (0 233) 17 (0 251) MCyR before and after reduction 15 (47) 5 (28) 20 (40) Median (range) duration of MCyR (non-k-m), wk 252 (11 323) 276 (97 331) 260 (11 331) MCyR before but not after reduction 1 (3) 0 1 (2) Newly-attained MCyR, n (%) 20 (69) 5 (36) 25 (58) 9
Attained MCyR after reduction 7 (24) 2 (14) 9 (21) Median (range) duration of MCyR (non-k-m), wk 22 (0 251) 116 (0 233) 22 (0 251) Attained MCyR before and after reduction 12 (41) 3 (21) 15 (35) Median (range) duration of MCyR (non-k-m), wk 254 (11 323) 276 (97 283) 267 (11 323) Attained MCyR before but not after reduction 1 (3) 0 1 (2) IM-I=imatinib intolerant; IM-R=imatinib-resistant; K-M=Kaplan-Meier; MCyR=major cytogenetic response. *Denominators are the number of patients who dose reduced to bosutinib 400 mg daily for the respective cohort. Denominators for newly-attained response rates also exclude patients with CCyR at baseline. Denominators are the number of patients who dose reduced to bosutinib 300 mg daily for the respective cohort. Denominators for newly-attained response rates also exclude patients with CCyR at baseline. 10
Supplementary Table S5. Incidence of and Response by Mutation Status Incidence* Response to BOS, n/n Evaluable IM-R IM-I Total CHR MCyR Baseline Patients assessed for mutations at baseline, n 156 68 224 194/223 121/208 No mutation at baseline 83 (53) 62 (91) 145 (65) 128/145 75/130 1 mutation 60 (38) 6 (9) 66 (29) 56/65 40/66 1 mutations 73 (47) 6 (9) 79 (35) 66/78 46/78 2 mutations 13 (8) 0 13 (6) 10/13 6/12 Individual mutations L248V 5 (3) 0 5 (2) 5/5 3/5 G250E 6 (4) 0 6 (3) 5/6 3/5 Y253F 1 (1) 0 1 (<1) 1/1 0 Y253H 4 (3) 0 4 (2) 4/4 4/4 E255K 3 (2) 0 3 (1) 0 2/3 E255V 2 (1) 0 2 (1) 2/2 1/2 M244V 6 (4) 0 6 (3) 6/6 4/6 D276G 1 (1) 0 1 (<1) 1/1 0 E286G 1 (1) 0 1 (<1) 1/1 1/1 L298V 1 (1) 0 1 (<1) 0 0 F311I 2 (1) 0 2 (1) 2/2 1/2 F311L 2 (1) 0 2 (1) 2/2 2/2 T315I 9 (6) 0 9 (4) 2/9 2/9 F317L 4 (3) 0 4 (2) 4/4 3/4 N331S 1 (1) 0 1 (<1) 1/1 1/1 V338A 1 (1) 0 1 (<1) 1/1 1/1 11
M351T 8 (5) 0 8 (4) 8/8 7/8 E355A 1 (1) 0 1 (<1) 1/1 1/1 E355G 1 (1) 0 1 (<1) 1/1 1/1 F359I 1 (1) 0 1 (<1) 1/1 1/1 F359S 0 1 (1) 1 (<1) 1/1 1/1 F359V 8 (5) 1 (1) 9 (4) 8/9 4/9 L364P 1 (1) 0 1 (<1) 1/1 1/1 N368S 1 (1) 0 1 (<1) 1/1 0 L387F 0 1 (1) 1 (<1) 1/1 0 L387M 1 (1) 0 1 (<1) 1/1 1/1 M388L 1 (1) 0 1 (<1) 1/1 1/1 H396P 1 (1) 1 (1) 2 (1) 2/2 2/2 H396R 2 (1) 0 2 (1) 1/2 0 T406A 1 (1) 0 1 (<1) 1/1 0 S417F 1 (1) 0 1 (<1) 1/1 1/1 D421G 1 (1) 0 1 (<1) 1/1 0 I432T 1 (1) 0 1 (<1) 1/1 0 E450G 1 (1) 0 1 (<1) 1/1 0 E450V 1 (1) 0 1 (<1) 1/1 1/1 E453G 1 (1) 0 1 (<1) 0 0 E453K 0 1 (1) 1 (<1) 1/1 1/1 E453Q 1 (1) 0 1 (<1) 1/1 1/1 E453R 1 (1) 0 1 (<1) 0 0 E459K 0 1 (1) 1 (<1) 1/1 0 K459G 1 (1) 0 1 (<1) 1/1 0 K459R 1 (1) 0 1 (<1) 1/1 0 P480A 1 (1) 0 1 (<1) 1/1 1/1 12
Best Response to BOS, n/n With Mutation CHR PCyR CCyR Newly-emerging Patients assessed for new mutations, n 73 31 104 Patients with new mutations 20 (27) 6 (19) 26 (25) Individual mutations T315I,, 7 (35) 2 (33) 9 (35) 5/9 2/9 1/9 V299L 3 (15) 2 (33) 5 (19) 3/5 1/5 1/5 M244V 1 (5) 1 (17) 2 (8) 0 0 1/2 E255V 1 (5) 0 1 (4) 1/1 0 0 E450A 1 (5) 0 1 (4) 1/1 0 0 E450G 0 1 (17) 1 (4) 1/1 0 0 F359V 1 (5) 0 1 (4) 0 0 1/1 G250E, 1 (5) 0 1 (4) 1/1 0 0 H295L 1 (5) 0 1 (4) 0 0 1/1 K378E 1 (5) 0 1 (4) 0 1/1 0 L273M 1 (5) 0 1 (4) 0 0 1/1 S348L 1 (5) 0 1 (4) 0 0 1/1 S410G 1 (5) 0 1 (4) 0 0 1/1 BOS=bosutinib; CHR=complete hematologic response; CCyR=complete cytogenetic response; IM-I=imatinib-intolerant; IM-R=imatinib-resistant; MCyR=major cytogenetic response; PCyR=partial cytogenetic response. Values are expressed as n (%) unless otherwise noted. Shaded rows indicate mutations that are resistant (light gray) or highly resistant (dark gray) to BOS. 15 *Denominators are number of patients assessed for mutations at baseline or newly-emerging during the study. Newly-emerging mutations are those not present at baseline. Mutations that are resistant or highly resistant to dasatinib. Mutations that are resistant or highly resistant to nilotinib. One patient had no detectable response. 13
Supplementary Table S6. TEAEs Occurring in 10% of Patients and Laboratory Abnormalities Occurring in 30% of Patients Overall IM-R (n=195) IM-I (n=89) Total (n=284) TEAE, n (%) All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 Any TEAE 194 (99.5) 145 (74.4) 89 (100) 75 (84.3) 283 (99.6) 220 (77.5) Hematologic* Thrombocytopenia 77 (39.5) 45 (23.1) 41 (46.1) 27 (30.3) 118 (41.5) 72 (25.4) Anemia 51 (26.2) 23 (11.8) 32 (36.0) 15 (16.9) 83 (29.2) 38 (13.4) Neutropenia 29 (14.9) 16 (8.2) 17 (19.1) 12 (13.5) 46 (16.2) 28 (9.9) Leukopenia 22 (11.3) 8 (4.1) 15 (16.9) 7 (7.9) 37 (13.0) 15 (5.3) Gastrointestinal Diarrhea 167 (85.6) 18 (9.2) 76 (85.4) 9 (10.1) 243 (85.6) 27 (9.5) Nausea 85 (43.6) 1 (0.5) 46 (51.7) 4 (4.5) 131 (46.1) 5 (1.8) Vomiting 73 (37.4) 3 (1.5) 33 (37.1) 8 (9.0) 106 (37.3) 11 (3.9) Abdominal pain 52 (26.7) 4 (2.1) 25 (28.1) 2 (2.2) 77 (27.1) 6 (2.1) Upper abdominal pain 42 (21.5) 1 (0.5) 17 (19.1) 0 59 (20.8) 1 (0.4) Constipation 22 (11.3) 0 17 (19.1) 1 (1.1) 39 (13.7) 1 (0.4) Infections and infestations Nasopharyngitis 25 (12.8) 0 13 (14.6) 0 38 (13.4) 0 Urinary tract infection 22 (11.3) 2 (1.0) 8 (9.0) 0 30 (10.6) 2 (0.7) Influenza 22 (11.3) 0 7 (7.9) 2 (2.2) 29 (10.2) 2 (0.7) Upper respiratory tract infection 19 (9.7) 0 10 (11.2) 1 (1.1) 29 (10.2) 1 (0.4) Investigations ALT increased 42 (21.5) 15 (7.7) 21 (23.6) 9 (10.1) 63 (22.2) 24 (8.5) AST increased 38 (19.5) 7 (3.6) 18 (20.2) 4 (4.5) 56 (19.7) 11 (3.9) Weight decreased 28 (14.4) 1 (0.5) 8 (9.0) 2 (2.2) 36 (12.7) 3 (1.1) Other Rash 64 (32.8) 15 (7.7) 39 (43.8) 11 (12.4) 103 (36.3) 26 (9.2) Pyrexia 58 (29.7) 1 (0.5) 18 (20.2) 2 (2.2) 76 (26.8) 3 (1.1) 14
Fatigue 49 (25.1) 1 (0.5) 24 (27.0) 2 (2.2) 73 (25.7) 3 (1.1) Cough 46 (23.6) 0 19 (21.3) 0 65 (22.9) 0 Headache 35 (17.9) 0 18 (20.2) 0 53 (18.7) 0 Arthralgia 31 (15.9) 2 (1.0) 17 (19.1) 1 (1.1) 48 (16.9) 3 (1.1) Decreased appetite 30 (15.4) 2 (1.) 12 (13.5) 0 42 (14.8) 2 (0.7) Asthenia 26 (13.3) 7 (3.6) 16 (18.0) 0 42 (14.8) 7 (2.5) Back pain 22 (11.3) 1 (0.5) 16 (18.0) 0 38 (13.4) 1 (0.4) Oropharyngeal pain 25 (12.8) 0 10 (11.2) 0 35 (12.3) 0 Dyspnea 24 (12.3) 5 (2.6) 10 (11.2) 0 34 (12.0) 5 (1.8) Pain in extremity 28 (14.4) 2 (1.0) 4 (4.5) 0 32 (11.3) 2 (0.7) Pleural effusion 21 (10.8) 5 (2.6) 9 (10.1) 4 (4.5) 30 (10.6) 9 (3.2) Cardiac AEs 25 (12.8) 11 (5.6) 12 (13.5) 5 (5.6) 37 (13.0) 16 (5.6) Vascular AEs 13 (6.7) 9 (4.6) 9 (10.1) 2 (2.2) 22 (7.7) 11 (3.9) Hypertension-related AEs ǁ 19 (9.7) 7 (3.6) 7 (7.9) 1 (1.1) 26 (9.2) 8 (2.8) Renal AEs 27 (13.8) # 5 (2.6) 10 (11.2) 1 (1.1) 37 (13.0) # 6 (2.1) Laboratory Abnormalities, n (%) All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 Any laboratory abnormality 194 (99.5) 136 (69.7) 89 (100) 68 (76.4) 283 (99.6) 204 (71.8) Hematologic Low hemoglobin 180 (92.3) 24 (12.3) 76 (85.4) 17 (19.1) 256 (90.1) 41 (14.4) Low lymphocytes 149 (76.4) 25 (12.8) 71 (79.8) 16 (18.0) 220 (77.5) 41 (14.4) Low platelet count 131 (67.2) 47 (24.1) 64 (71.9) 27 (30.3) 195 (68.7) 74 (26.1) Low WBC count 102 (52.3) 13 (6.7) 47 (52.8) 10 (11.2) 149 (52.5) 23 (8.1) Low ANC 98 (50.3) 25 (12.8) 47 (52.8) 19 (21.3) 145 (51.1) 44 (15.5) Nonhematologic High ALT 109 (55.9) 20 (10.3) 61 (68.5) 13 (14.6) 170 (59.9) 33 (11.6) High AST 97 (49.7) 8 (4.1) 50 (56.2) 7 (7.9) 147 (51.8) 15 (5.3) Low phosphorous 91 (46.7) 20 (10.3) 35 (39.3) 6 (6.7) 126 (44.4) 26 (9.2) Low calcium 85 (43.6) 6 (3.1) 40 (44.9) 4 (4.5) 125 (44.0) 10 (3.5) 15
High glucose 87 (44.6) 4 (2.1) 29 (32.6) 5 (5.6) 116 (40.8) 9 (3.2) High creatinine 78 (40.0) 5 (2.6) 38 (42.7) 2 (2.2) 116 (40.8) 7 (2.5) High alkaline phosphatase 73 (37.4) 0 34 (38.2) 0 107 (37.7) 0 Low bicarbonate 62 (31.8) 0 28 (31.5) 1 (1.1) 90 (31.7) 1 (0.4) High lipase 57 (29.2) 24 (12.3) 32 (36.0) 9 (10.1) 89 (31.3) 33 (11.6) AE=adverse event; ALT=alanine aminotransferase; ANC=absolute neutrophil count; AST=aspartate aminotransferase; IM-I=imatinibintolerant; IM-R=imatinib-resistant; TEAE=treatment-emergent adverse event; WBC=white blood cell. *Hematologic TEAEs (thrombocytopenia, anemia, neutropenia, leukopenia) were clustered separately with the corresponding terms from the Medical Dictionary for Regulatory Activities system order class (SOC) Investigations (Platelet count decreased, Hemoglobin decreased, Neutrophil count decreased, WBC count decreased). Includes the high-level group terms (HLGTs) Cardiac arrhythmias, Pericardial disorders, and Heart failures under the Cardiac disorders SOC; the preferred terms (PTs) Cardiac death, Sudden cardiac death, and Sudden death under the General disorders and administration site conditions SOC; the PTs Decreased ejection fraction, Abnormal electrocardiogram QT interval, Prolonged electrocardiogram QT, Torsade de pointes, Ventricular tachycardia, Congenital long QT syndrome under the Investigations SOC. Includes 2 patients who had grade 5 events. Includes the HLGTs Coronary artery disorders, Arteriosclerosis, stenosis, vascular insufficiency and necrosis, and Embolism and thrombosis; the high-level terms (HLTs) Arterial therapeutic procedures (excluding aortic), Central nervous system hemorrhages and cerebrovascular accidents, and Central nervous system vascular disorders not elsewhere classified (NEC); Non-site specific vascular disorders NEC, Peripheral vascular disorders NEC (excluding the PTs Flushing and Hot flash), Transient cerebrovascular events, Vascular imaging procedures NEC, and Vascular therapeutic procedures NEC. ǁ Includes HLGTs Vascular hypertensive disorders and Cardiac and vascular investigations (excluding enzyme tests), the HLT Vascular tests NEC (including blood pressure) and the PTs Abnormal blood pressure, Abnormal ambulatory blood pressure, Increased ambulatory blood pressure, Abnormal diastolic blood pressure, Increased diastolic blood pressure, Increased blood pressure, Abnormal systolic blood pressure, and Increased systolic blood pressure. Includes the HLT Renal failure and impairment; the PTs Blood creatinine abnormal, Blood creatinine increased, Creatinine renal clearance abnormal, Creatinine renal clearance decreased, Glomerular filtration rate abnormal, and Glomerular filtration rate decreased. # Includes 1 patient who had a grade 5 event. 16
Supplementary Table S7. Cross-Intolerance* in Patients Intolerant to Imatinib Outcome with BOS Due to Same AE Reason for Prior Intolerance Intolerant to Prior IM, n Same AE on BOS, n (%) Dose Delay, n (%) Dose Reduction, n (%) Discontinued, n (%) Any AE 85 52 (61) 25 (29) 14 (16) 14 (16) Hematologic disorders Anemia 11 5 (45) 1 (9) 0 0 Leukopenia 4 1 (25) 1 (25) 0 0 Neutropenia 13 5 (38) 3 (23) 2 (15) 2 (15) Thrombocytopenia 16 12 (75) 8 (50) 6 (38) 4 (25) Gastrointestinal disorders Diarrhea 7 6 (86) 2 (29) 2 (29) 1 (14) Nausea 5 4 (80) 1 (20) 0 0 Vomiting 4 2 (50) 2 (50) 0 1 (25) Other Fatigue 6 2 (33) 1 (17) 1 (17) 1 (17) Edema 10 4 (40) 0 0 0 Liver disorder 3 1 (33) 0 0 0 Fluid retention 3 0 0 0 0 Myalgia 4 1 (25) 0 1 (25) 0 Rash 12 8 (67) 4 (33) 0 1 (8) AE=adverse event; BOS=bosutinib; IM=imatinib. *Defined as discontinuing bosutinib and a prior tyrosine kinase inhibitor due to the same AE. Defined as permanent discontinuation due to this treatment-emergent AE; AEs leading to discontinuation in 3 prior imatinib-treated patients are presented. The specific AE reported as the reason for discontinuation of prior imatinib was unknown for 4 patients. 17
Figure S1. Patient Disposition. Enrollment (N=284) IM-R (n=195) IM-I (n=89) Discontinued (n=135) Enrolled in extension study n=61 Death n=37 Lost to follow-up n=12 Patient request n=9 Study discontinued by sponsor n=1 Other n=15 Discontinued (n=50) Enrolled in extension study n=27 Death n=7 Lost to follow-up n=4 Patient request n=8 Study discontinued by sponsor n=0 Other n=4 Completed study (n=60) Completed study (n=39) Evaluable Patients Safety* n=195 Molecular response n=127 Cytogenetic response n=182 Hematologic response n=194 Evaluable Patients Safety* n=89 Molecular response n=70 Cytogenetic response n=80 Hematologic response n=89 IM-I=imatinib-intolerant; IM-R=imatinib-resistant. *Includes all patients who received 1 dose. Not assessed using the international scale; data from patients at sites in China, India, Russia, and South Africa are not available. 18