This is the final ≥10-year report of a phase I/II study and its extension study of second-line bosutinib for chronic phase chronic myeloid leukemia (CP-CML), representing the longest follow-up to date of any tyrosine kinase inhibitor after imatinib failure (n=284). Median (range) follow-up and treatment duration were 53.7 (0.5–171.6) and 25.6 (0.2–170.5) months, respectively. At the start of year 11, 19.4% of patients were receiving bosutinib; 13.4% were receiving bosutinib at study completion. The most common reasons for treatment discontinuation were lack of efficacy (disease progression/unsatisfactory response; 26.8%) and adverse events (26.1%). Cumulative rates of complete cytogenetic response, major molecular response, and MR4 were 49.6%, 42.1%, and 37.1%, respectively. Kaplan–Meier probabilities of maintaining response at year 11 were 58.3%, 56.1%, and 55.7%, respectively. At year 11, cumulative incidence of on-treatment disease progression/death was 24.6%; 15 (5.3%) patients had ontreatment transformations to accelerated/blast phase (one after year 5). The Kaplan–Meier overall survival rate was 70.5%; 55 (19.4%) patients died on study (15 after year 5). At the start of year 11, 29/55 (52.7%) patients still on bosutinib were receiving ≥500 mg once daily. Thirteen patients had adverse events leading to discontinuation in year 6 or later. No new safety signals emerged. After ≥10 years, bosutinib demonstrated durable efficacy and acceptable safety as second-line treatment for CP-CML.

AIMS:This study aimed to describe first-line venetoclax in the Medicare population and its impacts on treatment patterns, utilization, and costs. MATERIALS AND METHODS:This retrospective cohort study used Medicare Fee-For-Service data from 1 September 2016, to 31 December 2022. Patients were continuously-enrolled, had incident acute myeloid leukemia (AML) and no confounding diagnoses, and were treated with first-line venetoclax-based regimens. Initiation of second line of therapy was modeled using cumulative incidence functions. RESULTS:Among 2,765 included patients, median age was 76 years. Median venetoclax dosage was 140.4 mg/day - lower than the 400-600 mg/day recommended by clinical guidelines. Patients were less likely to initiate second-line therapy if they were older or had more comorbidities.Patients had a per-month median of 5.3 outpatient visits, 0.3 emergency department visits, and 0.2 hospitalizations; length of stay was 10 days. Mean monthly healthcare costs were $18,092 (SD=$14,289) per patient, with $12,042 (SD=$12,147) and $6,050 (SD=$7,841) attributable to medical services and drug costs, respectively. CONCLUSIONS:A growing number of patients enrolled in Medicare Fee-For-Service with AML use first-line venetoclax. Older patients and those with comorbidities are less likely to initiate second-line therapy. Costs were lower and length of stay was shorter than described in previous research.

Abstract Introduction: Standard of care (SOC) first line (1L) therapy for diffuse large B-cell lymphoma (DLBCL) includes rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and polatuzumab vedotin plus R-CHP (Pola-R-CHP), among other regimens. For eligible patients who experience relapsed/refractory (R/R) disease, chimeric antigen receptor T-cell (CAR-T) therapies or high-dose chemotherapy with hematopoietic stem cell transplant (HSCT) are standard treatment options. For patients ineligible for CAR-T or HSCT or those who progress to 3L therapy, many therapeutic options exist; however, there is no single SOC. Given the rapidly evolving treatment landscape, including options like CAR-T, challenges exist in estimating real-world overall survival (rwOS) for patients receiving standard care in recent years. Our study contributes the latest data on rwOS for patients receiving 3L+ therapy for R/R DLBCL who are not eligible for HSCT or CAR-T at index line of therapy (LOT). Methods: Using the COTA electronic health record-based database and inclusion and exclusion criteria of the ECHELON-3 trial, eligible adult patients were identified who had received at least 2 prior LOTs. Qualifying patient-LOTs were identified based on the following criteria: initiation of 3L+ between OCT/18/2017 and DEC/31/2023, no documentation of an Eastern Cooperative Oncology Group (ECOG) performance status score of 3 or greater within the baseline period, no evidence of solid tumor malignancy within two years of index LOT, no exclusionary treatment history, and sufficiently precise (i.e., at least month and year precision) key study dates. Multiple index date qualification methodology was used to identify all qualifying LOTs (multiple per patient), first qualifying LOT (one per patient), and last qualifying LOT (one per patient), and characteristics and outcomes were assessed by each cohort. The baseline period was defined as the earlier of: 30 days prior to index or the end of prior LOT not exceeding 90 days until 7 days post-index. rwOS was evaluated using the Kaplan-Meier method. COTA's mortality variable includes dates of death abstracted from the health record and is supplemented with dates from third-party obituary data. The resulting composite variable has been validated in prior publications. Results: In the COTA database, 476 unique patients qualified for the study with a total of 716 qualifying patient-LOTs. The median age at diagnosis and first qualifying index was 64 (IQR: 55, 73) and 67 years (IQR: 57, 76), respectively, and the patients were majority male (59%), White (69%), and treated in the community setting (66%). Of 357 patients with known cell of origin, 176 (49%) had GCB and 181 (51%) had non-GCB DLBCL at first qualifying index LOT. Median follow-up time (reverse KM) among all qualifying LOTs (N=716) was 26.7 months (mos) (95% CI: 23.7, 31.9), with 480 death events (299 unique patient death events). Median rwOS across all qualifying LOTs was 8.0 mos (95% CI: 7.1, 10.1). Median rwOS among unique patients from first qualifying LOT and last qualifying LOT was 11.4 (95% CI: 9.7, 13.6) and 6.3 mos (95% CI: 5.3, 8.0), respectively. For patients with documented ECOG score 0-2 (n=408 qualifying-LOTs, n=308 with missing/unknown ECOG score), the median rwOS was 6.9 mos (95% CI: 6.0, 8.5). Among those who had received CAR-T therapy (n=72 qualifying-LOTs) or SCT (n=98 qualifying-LOTs) prior to index (which was used as a proxy for ineligibility at index), median rwOS was 7.2 (95% CI: 5.5, 13.3) and 8.0 mos (95% CI: 5.9, 13.6), respectively. Among all qualifying-LOTs with GCB (n=252) and non-GCB (n=278) DLBCL, median rwOS was 8.1 (95% CI:7.0-10.8,) and 7.3 mos (95% CI: 6.4, 10.6), respectively. Conclusions: Patients in this analysis with 3L+ DLBCL had a median age of 67 years at first index and experienced a median rwOS of 8 mos from all qualifying index dates. This study demonstrates the feasibility of using real-world data to contextualize the results reported from a clinical trial and highlights the need for novel treatment options for patients with R/R DLBCL receiving 3L+ therapy who may be ineligible for HSCT and CAR-T therapy. Results of the study also suggest that considering only the first qualifying index date may result in overestimation of outcomes, while considering only the last qualifying index date may underestimate study outcomes.

Topic: 8. Chronic myeloid leukemia - Clinical Background: Bosutinib is approved for the treatment of Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia (CML) resistant/intolerant to prior therapy and newly diagnosed Ph+ chronic phase (CP) CML1. Body mass index (BMI) has been shown to influence treatment response with frontline dasatinib vs imatinib2 and bosutinib vs imatinib3, as well as AE profiles3. Aims: To evaluate the effect of BMI on the safety of bosutinib in patients (pts) with previously treated or newly diagnosed CML. Methods: Safety data from seven trials with bosutinib were pooled for this post hoc analysis. Three studies included pts ≥18 years with previously treated CML: B1871006 (NCT00261846; phase 1/2), B1871007 (NCT00811070; phase 1/2 in Japanese pts), B1871039 (NCT02228382, BYOND; phase 4). Three studies included pts ≥18 years with newly diagnosed CML: B1871048 (NCT03128411, phase 2 in Japanese pts), B1871008 (NCT00574873, BELA; phase 3), B1871053 (NCT02130557, BFORE; phase 3). An extension study (B1871040, NCT01903733) included pts from B1871006 or B1871008. Bosutinib dose across the studies ranged from 100 mg to 600 mg once daily and study follow-up ranged from 28 days to 5 years. Safety outcomes were assessed according to baseline BMI <18.5, 18.5–<25, 25–<30, and ≥30 kg/m2. Results: A total of 1,333 pts were included in this safety analysis; 45 (3.4%), 582 (43.7%), 439 (32.9%) and 267 (20%) pts had BMI <18.5, 18.5–<25, 25–<30, and ≥30 kg/m2, respectively. The number of pts who reported treatment-emergent adverse events (TEAEs) was 44 (97.8%), 572 (98.3%), 437 (99.5%) and 266 (99.6%) for BMI <18.5, 18.5–<25, 25–<30, and ≥30 kg/m2, respectively. Dose interruptions due to TEAEs occurred in 30 (66.7%), 402 (69.1%), 315 (71.8%) and 195 (73%) pts with BMI <18.5, 18.5–<25, 25–<30, and ≥30 kg/m2, respectively. Dose reductions due to TEAEs occurred in 27 (60%), 301 (51.7%), 224 (51%) and 141 (52.8%) pts with BMI <18.5, 18.5–<25, 25–<30, and ≥30 kg/m2, respectively. The number of pts who discontinued treatment due to any AE was 10 (22.2%), 151 (25.9%), 128 (29.2%) and 82 (30.7%) for BMI groups <18.5, 18.5–<25, 25–<30, and ≥30 kg/m2, respectively. The most common AEs leading to treatment discontinuation were increased ALT for pts with BMI 18.5–<25 (3.3%), 25–<30 (4.6%), and ≥30 kg/m2 (4.1%), and thrombocytopenia for pts with BMI <18.5 (6.7%) and 18.5–<25 (3.3%). Grade 3/4 TEAEs that occurred in ≥5% of pts of any BMI group is shown in the Table. The most common grade 3/4 AEs occurring after 12 months of treatment were anemia (6.7%) and neutropenia (6.7%) in pts with BMI <18.5; lipase increased in pts with BMI 18.5–<25 (5.3%) and 25–<30 (5.9%), and lipase increased (5.2%) and hypertension (5.2%) in pts with BMI ≥30 kg/m2. Summary/Conclusion: The incidence of certain high grade TEAEs appeared to differ between BMI groups, with hematologic TEAEs appearing to be most common in patients with BMI <18.5 kg/m2.References 1.Brümmendorf, TH, et al. Leukemia 2022; 36(7):1825–1833 2.Breccia M, et al. Blood 2019;134(suppl 1):4155.2 3.Brümmendorf, TH, et al. Journal of Clinical Oncology 2021; 39(suppl 15):7037 Keywords: Safety, Chronic myeloid leukemia, Clinical trial

e18504 Background: Gemtuzumab ozogamicin (GO) is approved in the US for the treatment of newly diagnosed and relapsed/refractory (R/R) CD33-positive acute myeloid leukemia (AML) in adults and pediatric patients of 1 month and older and 2 years and older, respectively. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for most adult patients with AML in first complete remission (CR1). Clinical studies have linked GO with hepatotoxicity and hepatic veno-occlusive disease (VOD); the risk of these events may be further elevated in patients receiving HSCT. This study aimed to characterize the toxicity after HSCT in adult patients with AML who were treated with GO prior to HSCT. These analyses look at outcomes in patients who were in CR1 at the time of HSCT. Methods: This non-interventional post-authorization safety study used de-identified healthcare data from the Center for International Blood and Marrow Transplant Research (CIBMTR) database. Data were collected from adult patients in the US with newly diagnosed AML treated with GO prior to proceeding with HSCT. Data collection began on 01 September 2017, data cutoff was 04 July 2023. Results: We present data of 84 patients receiving HSCT for AML in CR1 from 19 centers with a median follow-up of 23.9 months (range, 3.0-49.7). Median age was 54.2 y (range, 18.7-74.5); 55% male. Total cumulative GO dose was 1-3 mg/m2 in 15 (18%), 4-6 mg/m2 in 15 (18%), 7-9 mg/m2 in 28 (33%) and ≥10 mg/m2 in 8 (12%) patients. Measurable residual disease (MRD) was undetectable in 50% (n=42) of patients after GO and 51% (n=43) of patients at the time of HSCT. Most patients (58%; n=49) received myeloablative conditioning and 57% (n=48) received HLA matched unrelated donor HSCT. Non-fatal VOD was reported in 6 (7%) patients, most cases were mild (n=5; 83%). Cumulative incidences of transplant-related mortality (TRM) were: 6 months, 7% (95% CI, 3-14); 2 years, 15% (95% CI, 7-25). The 2-year relapse rate was 26% (95% CI, 16-36%). Kaplan-Meier probabilities of leukemia-free survival (LFS) outcomes at 1 and 2 years were, 68% (95% CI, 57-78) and 59% (95% CI, 47-71), respectively. There were 22 deaths during the study, 10 (46%) from relapse of AML, no VOD-related deaths were observed. Conclusions: The use of GO prior to allogeneic HSCT appears to be safe with low rates of posttransplant VOD observed in patients with AML in CR1. TRM and survival outcomes are similar to historically reported rates. Clinical trial information: B1767034.

6516 Background: Gemtuzumab ozogamicin (GO) is a CD33-directed antibody-drug conjugate approved by the FDA in 2017 for the treatment of newly diagnosed and relapsed/refractory (R/R) CD33-positive acute myeloid leukemia (AML) in adults and pediatric patients of 1 month and older and 2 years and older, respectively. Previous data have associated GO with adverse events (AEs) including hepatotoxicity and hepatic veno-occlusive disease (VOD). Patients receiving allogeneic hematopoietic stem cell transplantation (HSCT) may be at greater risk of VOD with GO. This study aimed to characterize AEs after HSCT in adult patients with AML who were treated with GO. Methods: This non-interventional post-authorization safety study used de-identified healthcare data from the Center for International Blood and Marrow Transplant Research (CIBMTR) database. Data were collected from 01 September 2017. Safety outcomes post-HSCT were evaluated in adult patients with newly diagnosed or R/R AML who received GO prior to first HSCT. Data cutoff was 04 July 2023. Results: We present the interim data of 157 patients from 24 centers with a median follow-up of 12.9 months (range, 3.0-49.7). At the time of HSCT, 84 patients were in first complete remission (CR1), 48 patients were in second CR (CR2) and 25 patients were in third or greater CR, relapse or primary induction failure (CR3, n=5; Rel, n=12; PIF, n=8). Most patients (n=105; 67%) received GO as first line therapy. Median lines of therapy prior to HSCT were 2, 3.5 and 5 in CR1, CR2 and CR3/Rel/PIF groups, respectively. Median age was 52.5 y (range, 18.7-74.9); 53% male. Time from diagnosis to first GO dose was <3 months for most patients (n=120; 76%). Total cumulative GO dose was 1-3 mg/m2 in 25 (16%), 4-6 mg/m2 in 28 (18%), 7-9 mg/m2 in 45 (29%) and ≥10 mg/m2 in 14 (9%) patients. The most common HSCT donor type was unrelated (n=93; 59%), and 55% of patients received myeloablative conditioning regimens. Non-fatal VOD was reported in 7 (4%) patients. Median time from HSCT to VOD was 0.9 months (range, 0.4-2.2). No VOD-related deaths occurred. Outcome probabilities for 6-month transplant-related mortality (TRM) were 8% (95% CI, 4-13) and 5% (95% CI, 2-8) for 100-day VOD. Conclusions: The use of GO appears to be safe prior to HSCT in adults with AML. Rates for 100-day VOD and TRM were comparable to those previously reported for patients with AML who received HSCT with or without prior GO. Clinical trial information: B1767034.

This final analysis from the phase 4 BYOND trial reports outcomes with bosutinib in patients with previously treated chronic myeloid leukemia (CML); 163 patients with CML resistant/intolerant to previous tyrosine kinase inhibitors received bosutinib (starting dose: 500 mg QD). At study completion (median follow-up, 47.8 months), 48.1% (n = 75/156) of patients with Philadelphia chromosome-positive chronic phase CML were still receiving treatment. Among evaluable patients, 71.8% (95% CI, 63.9-78.9) and 59.7% (95% CI, 51.4-67.7) attained or maintained major molecular response (MMR) and molecular response (MR)4, respectively, at any time on treatment. The majority of patients achieved a deeper molecular response relative to baseline while on bosutinib. Kaplan-Meier probabilities (95% CI) of maintaining MMR and MR4 at 36 months were 87.2% (78.0-92.7) and 80.7% (69.4-88.1), respectively. At 48 months, the Kaplan-Meier overall survival rate was 88.3% (95% CI, 81.8-92.6); there were 17 deaths, including 2 that were considered CML related. Long-term adverse events (AEs) were consistent with the known safety profile of bosutinib, and no new safety issues were identified. The management of AEs through dose reduction maintained efficacy while improving tolerability. These results support the use of bosutinib in patients with previously treated CML.ClinicalTrials.gov, NCT02228382.

The BYOND study evaluated the efficacy and safety of bosutinib 500 mg once daily in patients with chronic myeloid leukemia (CML) resistant/intolerant to prior tyrosine kinase inhibitors (TKIs). These post-hoc analyses assessed the efficacy and safety of bosutinib by resistance or intolerance to prior TKIs (imatinib-resistant vs dasatinib/nilotinib-resistant vs TKI-intolerant), and cross-intolerance between bosutinib and prior TKIs (imatinib, dasatinib, nilotinib), in patients with Philadelphia chromosome-positive chronic phase CML. Data are reported after ≥3 years' follow-up. Of 156 patients with Philadelphia chromosome-positive chronic phase CML, 53 were imatinib-resistant, 29 dasatinib/nilotinib-resistant, and 74 intolerant to all prior TKIs; cumulative complete cytogenetic response rates at any time were 83.7%, 61.5%, and 86.8%, and cumulative major molecular response rates at any time were 72.9%, 40.7%, and 82.4%, respectively. Of 141, 95, and 79 patients who received prior imatinib, dasatinib, and nilotinib, 64 (45.4%), 71 (74.7%), and 60 (75.9%) discontinued the respective TKI due to intolerance; of these, 2 (3.1%), 5 (7.0%), and 0 had cross-intolerance with bosutinib. The response rates observed in TKI-resistant and TKI-intolerant patients, and low cross-intolerance between bosutinib and prior TKIs, further support bosutinib use for patients with Philadelphia chromosome-positive chronic phase CML resistant/intolerant to prior TKIs. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02228382.

Background: Previous research has demonstrated substantial healthcare resource utilization (HCRU) and poor survival outcomes in older patients diagnosed with acute myeloid leukemia (AML). Venetoclax-based regimens are a standard of care for patients not eligible for intensive chemotherapy (NIC). This study describes characteristics, treatment, and outcomes among US Medicare beneficiaries newly diagnosed with AML and receiving a first line (1L) venetoclax-based regimen. Methods: This retrospective cohort study used Medicare Fee-For-Service (FFS) Parts A/B/D claims and enrollment data to identify patients diagnosed with AML not yet in remission between September 1, 2016, and September 30, 2022, who initiated a 1L venetoclax-based regimen. Outcomes included duration of therapy and follow-up, time to next treatment (TTNT), per-beneficiary per-month (PBPM) costs (adjusted to 2022 USD), and HCRU, including hospitalizations, emergency department (ED) visits, outpatient services, blood transfusions, and pharmacy. Outcomes were measured from 1L initiation to first occurrence of AML relapse, second-line initiation, stem cell transplant, death, disenrollment, or end of study. Time to transfusion independence was defined as time from 1L start until beginning of first 2-month period without transfusion. TTNT was modeled using cumulative incidence functions (CIF) with death as a competing event and was reported overall and across age groups and Deyo-Charlson Comorbidity Index scores of 0-2, 3-4, and ≥5. Results: Of 55,033 beneficiaries diagnosed with AML not yet in remission, 3,184 received 1L treatment, met minimum continuous enrollment, and had no confounding diagnoses. Among these, 2,765 (86.8%) received a 1L venetoclax-based regimen (study population). Study patients were followed for a median of 6.9 months (interquartile range [IQR]=8.0). Median age at diagnosis was 76 years (IQR=8), and majority were male (n=1,528, 55.3%) and white (n=2,439, 88.2%). The most common 1L venetoclax regimen included administration of unspecified antineoplastics (n=702, 25.4%) followed by combination with azacitidine (n=695, 25.1%); while 445 received venetoclax monotherapy (16.1%). Median venetoclax dosage per day was 140.4 mg (IQR=182.8). Median duration of treatment was 5.2 months (IQR=7.2) and 30.9% of patients had a documented diagnosis of AML relapse as the reason for 1LOT termination. During 1L treatment, patients had a per-month median of 5.3 (IQR=4.3) office visits, 1 transfusion day (IQR=2.2), 0.3 (IQR=0.6) ED visits, and 0.2 (IQR=0.4) hospitalizations [with median hospital length of stay of 10 days (IQR=23.0)]. The median time to transfusion independence was 5.6 weeks (IQR=6.4). Mean total healthcare costs were $18,092 (SD=$14,289) PBPM, with $12,042 (SD=$12,147) PBPM attributable to medical services and $6,050 (SD=$7,841) PBPM attributable to Part D prescription drugs. AML-specific care constituted 78.1% of total healthcare costs. Across patients receiving 1L venetoclax-based regimens, there was a 46.4% (95% confidence interval=44.4-48.3%) probability of progressing to next treatment within one year of initiating treatment; a further 22.0% of patients died within the year without receiving a next treatment. Patients under 65 years of age had a 66.8% probability of progressing to next treatment within one year, versus 63.5% for ages 65-69, 55.9% for ages 70-74, 42.2% for ages 75-79, and 33.7% for ages 80+ (p<0.0001). The probability of progressing to the next treatment within one year was 50.3% for patients with CCI 0-2, 47.1% with CCI 3-4, and 43.7% with CCI≥5 (p=0.0028). Discussion: Within this Medicare study population, relapse was the most common reason for discontinuation of 1L venetoclax, aligning with high rates of relapse seen in older populations. Older patients and those with complex comorbidities were less likely to receive subsequent treatment. As clinicians shift towards evaluating both age and overall fitness when making AML therapy decisions, these treatment patterns are likely to evolve. Our findings provide initial insights into outcomes for an increasingly common AML therapy and can inform future hypothesis-driven research on clinical and economic outcomes.

INTRODUCTION:Tyrosine kinase inhibitors (TKIs) have become the mainstay of treatment for chronic myeloid leukaemia (CML), but cardiovascular (CV) risk and exacerbation of underlying risk factors associated with TKIs have become widely debated. Real-world evidence reveals little application of CV risk factor screening or continued monitoring within UK CML management. This consensus paper presents practical recommendations to assist healthcare professionals in conducting CV screening/comorbidity management for patients receiving TKIs. METHODS:We conducted a multidisciplinary panel meeting and two iterative surveys involving 10 CML specialists: five haematologists, two cardio-oncologists, one vascular surgeon, one haemato-oncology pharmacist and one specialist nurse practitioner. RESULTS:The panel recommended that patients commencing second-/third-generation TKIs undergo formal CV risk assessment at baseline, with additional investigations and involvement of cardiologists/vascular surgeons for those with high CV risk. During treatment, patients should undergo CV monitoring, with the nature and frequency of testing dependent on TKI and baseline CV risk. For patients who develop CV adverse events, decision-making around TKI interruption, cessation or change should be multidisciplinary and balance CV and haematological risk. CONCLUSION:The panel anticipates these recommendations will support healthcare professionals in implementing CV risk screening and monitoring, broadly and consistently, and thereby help optimise TKI treatment for CML.

In the phase 4 BYOND trial, patients with pretreated chronic myeloid leukemia (CML) received bosutinib (starting dose: 500 mg/day). Efficacy and safety after ≥3 years of follow-up in 156 patients with Philadelphia chromosome–positive chronic phase CML by age and Charlson Comorbidity Index scores (without the age component; mCCI) is reported. Cumulative major molecular response rates at any time on treatment were 73.6%, 64.5%, and 74.1% in patients <65, 65–74, and ≥75 years of age, and 77.9%, 63.0%, and 59.3% in patients with mCCI scores 2, 3, and ≥4, respectively. Patients <65, 65–74, and ≥75 years of age experienced grade 3/4 treatment-emergent adverse events (TEAEs) at rates of 74.7%, 78.8%, and 96.4% and permanent discontinuations due to AEs at rates of 22.1%, 39.4%, and 46.4%, respectively. In patients with mCCI 2, 3, and ≥4, respective rates of grade 3/4 TEAEs were 77.8%, 77.8%, and 86.7%, and permanent discontinuations due to AEs were 25.3%, 33.3%, and 43.3%. In conclusion, a substantial proportion of patients maintained/achieved cytogenetic and molecular responses across age groups and mCCI scores. Older patients (≥75 years) and those with high comorbidity burden (mCCI ≥4) may require more careful monitoring due to the increased risk of TEAEs. Clinicaltrials.gov: NCT02228382.

This analysis from the multicenter, open-label, phase 3 BFORE trial reports efficacy and safety of bosutinib in patients with newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML) after five years’ follow-up. Patients were randomized to 400-mg once-daily bosutinib ( n = 268) or imatinib ( n = 268; three untreated). At study completion, 59.7% of bosutinib- and 58.1% of imatinib-treated patients remained on study treatment. Median duration of treatment and time on study was 55 months in both groups. Cumulative major molecular response (MMR) rate by 5 years was higher with bosutinib versus imatinib (73.9% vs. 64.6%; odds ratio, 1.57 [95% CI, 1.08–2.28]), as were cumulative MR 4 (58.2% vs. 48.1%; 1.50 [1.07–2.12]) and MR 4.5 (47.4% vs. 36.6%; 1.57 [1.11–2.22]) rates. Superior MR with bosutinib versus imatinib was consistent across Sokal risk groups, with greatest benefit seen in patients with high risk. Treatment-emergent adverse events (TEAEs) were consistent with 12-month data. After 5 years of follow-up there was an increase in the incidence of cardiac, effusion, renal, and vascular TEAEs in bosutinib- and imatinib-treated patients, but overall, no new safety signals were identified. These final results support 400-mg once-daily bosutinib as standard-of-care in patients with newly diagnosed CP CML. This trial was registered at www.clinicaltrials.gov as #NCT02130557.

Introduction: The efficacy and safety of bosutinib (BOS) vs imatinib (IMA) in patients with newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML) was assessed in the phase 3 BFORE trial (NCT02130557) after 5 years of follow-up (Brümmendorfet al., J Clin Oncol, 2022). Here we analyze the impact of comorbidities on efficacy and safety, reporting the results by Charlson Comorbidity Index (CCI) score. Methods: Patients with newly diagnosed CP CML were randomized 1:1 to receive BOS or IMA (starting dose: 400 mg QD). Outcomes were assessed after 5 years (240 weeks) of follow-up (database lock: June 12, 2020) according to the CCI score without the age component (mCCI). Patients were grouped by mCCI scores of 2 (BOS, n=195; IMA, n=196 [2 untreated]) and >2 (BOS, n=73; IMA, n=72 [1 untreated]). Efficacy was assessed in all randomized patients (intent-to-treat population) and safety in patients who received >1 dose of study medication (safety population). Results: In patients with mCCI 2 and >2, the median treatment duration was 55.1 and 53.4 months with BOS vs 55.0 and 55.1 months with IMA; respective median (range) dose intensity was 396.4 (39−583) and 367.2 (74−573) mg/day with BOS vs 400.0 (240−765) and 400.0 (189−754) mg/day with IMA. Permanent treatment discontinuations in patients with mCCI 2 and >2, respectively, were reported in 36.4% and 50.7% of patients with BOS vs 45.4% and 32.4% of patients with IMA. The most common primary reasons for permanent discontinuation were adverse events (AEs) in the BOS arm (BOS: mCCI 2, 21.0%; mCCI >2, 35.6%; IMA: mCCI 2, 13.9%; mCCI >2, 8.5%) and lack of efficacy (suboptimal response, treatment failure, or disease progression) in the IMA arm (BOS: mCCI 2, 6.7%; mCCI >2, 2.7%; IMA: mCCI 2, 20.6%; mCCI >2, 9.9%). In both treatment arms, the majority of permanent discontinuations due to AEs occurred in year 1 (BOS: mCCI 2, 11.3%; mCCI >2, 20.5%; IMA: mCCI 2, 7.7%; mCCI >2, 5.6%). Among patients with mCCI 2 and >2, respectively, the proportion who achieved an early molecular response (BCR::ABL1 ≤10% at 3 months) was 79.4% and 83.8% with BOS vs 56.5% and 71.0% with IMA (Table 1). Cumulative response rates according to mCCI score and treatment arm are shown in the Table 1. There were 14 deaths during the study period in both the BOS- (mCCI 2, n=7; mCCI >2, n=7) and IMA (mCCI 2, n=9; mCCI >2, n=5) arms; 3 and 4 deaths, respectively, were assessed by investigators as CML-related (all in patients with mCCI 2). Treatment-emergent AEs (TEAEs) occurred in ≥98.5% of patients in each treatment arm and across CCI subgroups. In patient with CCI 2 and >2, respectively, the most common (≥30% in either subgroup) TEAEs with BOS were diarrhea (79.5% and 63.0%), thrombocytopenia (37.4% and 31.5%), nausea (35.9% and 41.1%), increased alanine aminotransferase ([ALT] 34.4% and 31.5%), and fatigue (17.9% and 30.1%). Most common TEAEs with IMA were diarrhea (37.1% and 49.3%), nausea (41.2% and 45.1%), muscle spasms (33.0% and 23.9%), and anemia (17.5% and 36.6%). Among patients with CCI 2 and >2, respectively, grade 3/4 TEAEs were observed in 69.2% and 84.9% with BOS vs 55.2% and 62.0% with IMA. The most frequently reported grade 3/4 TEAEs are shown in Table 2. TEAEs resulting in death in the BOS arm (n=3) were acute cardiac failure, myocardial ischemia, and renal failure (all in patients with CCI >2). TEAEs leading to death in the IMA arm (n=4) were sepsis and CML in patients with CCI 2, and pneumonia and cerebrovascular accident in patients with CCI >2. Conclusions: After 5 years of follow-up in the BFORE study, a substantial proportion of patients across mCCI scores achieved molecular responses with BOS or IMA. In the BOS arm, there was a trend toward a higher rate (>10% difference) of MR4 in patients with CCI 2 vs CCI >2, with a similar proportion of patients achieving MMR and MR4.5 in both subgroups. Molecular response rates by 60 months were higher with BOS vs IMA in patients with CCI 2 and similar in patients with CCI >2. Safety data were consistent with the known safety profiles of BOS and IMA. Discontinuations due to AEs were higher (>10% difference) in patients with CCI >2 in the bosutinib arm and similar across CCI groups in the imatinib arm. However, in both treatment arms, there were no relevant differences in the frequency of TEAEs across the most commonly occurring AEs between patients with CCI 2 and CCI >2. These results support the use of 400 mg once daily BOS in patients with newly diagnosed CP CML irrespective of baseline comorbidities. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Background: Bosutinib is approved for patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML) resistant or intolerant to prior therapy and newly diagnosed patients in chronic phase. The efficacy and safety of bosutinib in patients with CML resistant or intolerant to prior tyrosine kinase inhibitors (TKIs) was evaluated in the phase 4 BYOND trial (NCT02228382; Gambacorti-Passerini et al, Blood, 2021). Aims: The efficacy and safety of bosutinib in resistant and intolerant patients with CML treated with 2 (3L) and 3 (4L) prior TKIs was characterized. Methods: The BYOND trial included 163 patients with CML resistant or intolerant to prior TKIs. A sub-analysis of 48 patients treated with 2 (3L) and 3 (4L) prior TKIs, categorized by resistance or intolerance to the last received TKI, was performed. This sub-analysis is based on the final November 23, 2020 database lock. Results: There were 18 and 30 patients resistant or intolerant to the last received TKI who entered the study without complete cytogenetic response (CCyR) or major molecular response (MMR), respectively. Median (range) treatment duration was 10.6 months (1.6–48.5) vs 28.3 months (0.2–48.6) and median (range) dose intensity was 447.1 mg/d (131.3–520.4) vs 288.8 mg/d (79.7–500.0) for resistant vs intolerant patients. Prior TKIs included imatinib (88.9% vs 100.0%), dasatinib (88.9% vs 83.3%), and nilotinib (66.7% vs 63.3%) for resistant vs intolerant patients. Overall, 61.1% vs 66.7% of resistant vs intolerant patients discontinued bosutinib, mostly commonly due to adverse events (AEs) in 27.8% vs 16.7% patients; 16.7% vs 6.7% discontinued bosutinib due to insufficient clinical response. Rates of CCyR and MMR are shown in the Table. Among responders (resistant vs intolerant patients), median (range) time to CCyR was 5.1 months (2.8–8.8) vs 3.0 months (2.7–6.1); median (range) time to MMR was 5.8 months (2.8–9.4) vs 3.2 months (2.8–9.3). In resistant vs intolerant patients, any grade treatment-emergent AEs (TEAEs) were reported by 100.0% vs 96.7% patients; grade 3/4 TEAEs were reported by 72.2% vs 83.3% patients. Grade 3/4 TEAEs >10% in resistant patients were thrombocytopenia (22.2%) and neutropenia (11.1%), and in intolerant patients were increased alanine aminotransferase (26.7%), diarrhea (23.3%), pleural effusion (13.3%), and rash (13.3%). Image:Summary/Conclusion: This sub-analysis of resistant and intolerant patients without baseline CCyR or MMR shows bosutinib was active in heavily pretreated patients with resistance or intolerance to the last received TKI. Despite a difference between resistant and intolerant patients with CML, efficacy outcomes, though lower than the overall BYOND population, are encouraging, and safety was generally consistent with previous reports.

e19055 Background: Bosutinib (BOS) is approved for pts with Philadelphia chromosome-positive CML resistant/intolerant to prior therapy and newly diagnosed pts in chronic phase. Methods: The BYOND trial (NCT02228382) evaluated the efficacy and safety of BOS in 163 pts with CML resistant/intolerant to prior tyrosine kinase inhibitors (TKIs; Gambacorti-Passerini et al, Blood, 2021). We report a sub-analysis of 48 pts treated with 2 (3L) and 3 (4L) prior TKIs, categorized by resistance/intolerance to the last received TKI. This sub-analysis is based on the final Nov 23, 2020 database lock. Results: There were 18 and 30 pts resistant or intolerant to the last TKI who entered the study without complete cytogenetic response (CCyR) or major molecular response (MMR), respectively. Median (range) treatment duration was 10.6 mo (1.6–48.5) vs 28.3 mo (0.2–48.6) and median (range) dose intensity was 447.1 mg/d (131.3–520.4) vs 288.8 mg/d (79.7–500.0) for resistant vs intolerant pts. Prior TKIs included imatinib (88.9% vs 100.0%), dasatinib (88.9% vs 83.3%), and nilotinib (66.7% vs 63.3%) for resistant vs intolerant pts. Overall, 61.1% vs 66.7% of resistant vs intolerant pts discontinued BOS, mostly commonly due to adverse events (AEs) in 27.8% vs 16.7% pts; 16.7% vs 6.7% discontinued BOS due to insufficient clinical response. Rates of CCyR/MMR are shown in the table. Among responders (resistant vs intolerant pts), median (range) time to CCyR was 5.1 mo (2.8–8.8) vs 3.0 mo (2.7–6.1); median (range) time to MMR was 5.8 mo (2.8–9.4) vs 3.2 mo (2.8–9.3). In resistant vs intolerant pts, any grade treatment-emergent AEs (TEAEs) were reported by 100.0% vs 96.7% pts; grade 3/4 TEAEs were reported by 72.2% vs 83.3% pts. Grade 3/4 TEAEs > 10% in resistant pts were thrombocytopenia (22.2%) and neutropenia (11.1%), and in intolerant pts were increased alanine aminotransferase (26.7%), diarrhea (23.3%), pleural effusion (13.3%), and rash (13.3%). Conclusions: This sub-analysis of resistant/intolerant pts without baseline CCyR or MMR shows BOS was active in heavily pretreated pts with resistance/intolerance to the last TKI. Despite a difference between resistant/intolerant pts, efficacy outcomes, though lower than the overall BYOND population, are encouraging, and safety was generally consistent with previous reports. Clinical trial information: NCT02228382. [Table: see text]

7049 Background: Efficacy and safety of BOS vs imatinib (IMA) in patients (pts) with newly diagnosed chronic phase CML was assessed in the phase 3 BFORE trial. Here we characterize the safety profile of BOS after 5 yrs follow-up, with a focus on GI, liver, effusion and renal treatment-emergent adverse events (TEAEs). Methods: Pts who received ≥1 dose of BOS (n=268) or IMA (n=265) 400 mg/d in BFORE were included. Adverse events (AEs) of special interest were analyzed by selecting prespecified MedDRA terms to generate TEAE clusters. Final database lock: June 12, 2020. Results: Median duration of treatment (Tx) was 55 mo for pts receiving BOS or IMA; respective median (range) dose intensity was 393.6 (39–583) vs 400.0 (189–765) mg/d. Any grade TEAEs occurred in 98.9% and 98.9% of BOS- vs IMA-treated pts. Most common newly occurring TEAEs (any grade) after 12 mos were increased lipase (9.0%) with BOS, and diarrhea (8.3%) with IMA. In BOS- vs IMA-treated pts, 25.4% vs 14.3% had AEs leading to permanent Tx discontinuation; the majority discontinued in yr 1 (14.2% vs 10.6%). Most frequent AEs leading to discontinuation were increased ALT (overall, 4.9%; yr 1, 4.5%) with BOS vs thrombocytopenia (overall, 1.5%; yr 1, 1.5%) with IMA. GI, liver, effusion and renal TEAEs, respectively, occurred in 79.9%, 44.0%, 6.0% and 10.4% (maximum grade 3/4 [G3/4]: 9.0%, 26.9%, 1.1% and 2.2%) of BOS- vs 61.5%, 15.5%, 2.3% and 9.8% (G3/4: 1.1%, 4.2%, 0.4% and 0.8%) IMA-treated pts. One grade 5 renal TEAE occurred in the BOS arm and was not considered related to Tx. Cumulative rates per Tx yr are shown in the Table. Most common GI TEAEs were diarrhea (BOS vs IMA: 75.0% vs 40.4% [G3/4: 9.0% vs 1.1%]) with BOS, and nausea (37.3% vs 42.3% [G3/4: 0% vs 0%]) with IMA. In both arms, the most common liver, effusion and renal TEAEs, respectively, were increased ALT and/or AST (34.0% vs 8.3% [G3/4: 22.0% vs 2.3%]), pleural effusion (5.2% vs 1.9% [G3/4: 0.7% vs 0.4%]) and increased blood creatinine (6.7% vs 8.3% [G3/4: 0.4% vs 0.4%]). GI, liver, effusion and renal TEAEs infrequently led to Tx discontinuation (1.9%, 7.8%, 0.7% and 0.7% vs 1.1%, 0.8%, 0% and 0.4%). Conclusions: The safety profiles of BOS and IMA in BFORE were distinct, with no new safety signals identified after 5 yrs follow-up. Onset of TEAEs occurred primarily during yr 1 (eg, GI and liver), with an increased incidence of some TEAEs (eg, effusion and renal) in later yrs. Discontinuations due to AEs generally occurred early into Tx, with few due to GI, liver, effusion and renal AEs. These safety results support the use of first-line BOS as a standard of care in pts with CP CML. Clinical trial information: NCT02130557. [Table: see text]