Imatinib Arm Research Articles

In-depth analysis of responders in the phase 3 PhALLCON trial of ponatinib vs imatinib in newly diagnosed Ph+ ALL.

6533 Background: Ponatinib, a third-generation BCR::ABL TKI, has potent activity against all clinically relevant BCR::ABL1 variants, including T315I. PhALLCON (NCT03589326), a phase 3 trial comparing frontline TKIs in adults with Ph+ ALL, met its primary endpoint with a higher rate of minimum residual disease–negative (MRD-neg) complete remission (CR) at end of induction (EOI) with ponatinib vs imatinib (34.4%/16.7%; P=0.002). Here, we report response rates of MRD-neg at any time and PFS by age and BCR::ABL1 variant subgroups. Methods: Adults with newly diagnosed Ph+ ALL were randomized 2:1 to ponatinib (30 mg QD reduced to 15 mg QD upon MRD-neg CR at or after EOI) or imatinib (600 mg QD) plus 20 cycles of reduced-intensity chemotherapy (induction: 3 cycles; consolidation: 6 cycles; maintenance: 11 cycles), followed by single-agent ponatinib or imatinib until disease progression or unacceptable toxicity. Hematopoietic stem cell transplant (HSCT) was per investigator’s discretion. Post hoc analyses compared MRD-neg ( BCR:: ABL1IS ≤0.01%; MR4) at any time and PFS (any-cause death, failure to achieve CR by EOI, relapse from CR, or failure to achieve/loss of MRD-neg) by age (</≥65 y) and BCR:: ABL1 variant (p190/p210). Data cutoff: Aug 12, 2022. Results: In the population of randomized patients (pts) with p190/p210 confirmed by central lab (n=232; 154/78 ponatinib/imatinib; median follow-up 20.1 mo), 68% vs 50% in the ponatinib vs imatinib arms were MRD-neg at any time, with similar benefit of ponatinib across age and variant subgroups (Table). Median PFS was more than twice as long with ponatinib vs imatinib across subgroups (Table). Pts achieving MRD-neg at any time were less likely to have HSCT with ponatinib vs imatinib (32%/56%). Among 107/42 pts without HSCT, exposure was >2-fold longer in the ponatinib vs imatinib arms (median 12.8/5.1 mo) with comparable rates of arterial occlusive (3%/2%) and venous thromboembolic events (11%/12%), and discontinuations due to TEAEs (13%/14%). Conclusions: Ponatinib was superior to imatinib in combination with reduced-intensity chemotherapy for frontline treatment of Ph+ ALL, with higher rates of MRD-neg at any time, substantially longer PFS across age and BCR::ABL1 variant subgroups, and a safety profile comparable to imatinib. Clinical trial information: NCT03589326 . [Table: see text]

Oral arsenic plus imatinib versus imatinib solely for newly diagnosed chronic myeloid leukemia: a randomized phase 3 trial with 5-year outcomes

PurposeThe synergistic effects of combining arsenic compounds with imatinib against chronic myeloid leukemia (CML) have been established using in vitro data. We conducted a clinical trial to compare the efficacy of the arsenic realgar–indigo naturalis formula (RIF) plus imatinib with that of imatinib monotherapy in patients with newly diagnosed chronic phase CML (CP-CML).MethodsIn this multicenter, randomized, double-blind, phase 3 trial, 191 outpatients with newly diagnosed CP-CML were randomly assigned to receive oral RIF plus imatinib (n = 96) or placebo plus imatinib (n = 95). The primary end point was the major molecular response (MMR) at 6 months. Secondary end points include molecular response 4 (MR4), molecular response 4.5 (MR4.5), progression-free survival (PFS), overall survival (OS), and adverse events.ResultsThe median follow-up duration was 51 months. Due to the COVID-19 pandemic, the recruitment to this study had to be terminated early, on May 28, 2020. The rates of MMR had no significant statistical difference between combination and imatinib arms at 6 months and any other time during the trial. MR4 rates were similar in both arms. However, the 12-month cumulative rates of MR4.5 in the combination and imatinib arms were 20.8% and 10.5%, respectively (p = 0.043). In core treatment since the 2-year analysis, the frequency of MR4.5 was 55.6% in the combination arm and 38.6% in the imatinib arm (p = 0.063). PFS and OS were similar at five years. The safety profiles were similar and serious adverse events were uncommon in both groups.ConclusionThe results of imatinib plus RIF as a first-line treatment of CP-CML compared with imatinib might be more effective for achieving a deeper molecular response (Chinadrugtrials number, CTR20170221).

International, Prospective Study Comparing Nilotinib Versus Imatinib with Early Switch to Nilotinib to Obtain Sustained Treatment-Free Remission in Patients with Chronic Myeloid Leukemia (SUSTRENIM trial): Analysis of the Eligibility to Treatment Discontinuation

Background. Treatment free remission (TFR) is one of the most important aims of CML treatment but, so far, the best treatment strategy to obtain a durable deep molecular response (DMR) and the overall rate of patients able to achieve a successful TKI discontinuation based on intention-to-treat principle from CML diagnosis are still debated. In November 2016 we launched an international, prospective, randomized, two arms study to evaluate both the depth of the molecular response and the rate of TFR in newly diagnosed CP-CML patients treated with a second generation TKI (Nilotinib, NIL) or with imatinib (IM) followed by switching to NIL in absence of optimal response (Clinical Trial number 02602314). Patients were randomized 1:1 between NIL and IM, stratifying on the Sokal score. All the patients achieving a MR4.0 or better by three years and maintaining this level of response up to the end of the fourth year of therapy were qualified for the discontinuation phase. We recently reported that patients enrolled in the NIL arm had a rate of MR4.5 at two years (primary co-endpoint of the study), significantly higher than those in the IM arm (32 vs 22%, p = 0.023 Pane F. et al, EHA 2022). The aim of the present analysis is to assess, in both arms of the trial, the percentage of patients achieving the eligibility to treatment discontinuation, defined as a MR4 maintained in 4 consecutive MRD analysis within the fourth year of therapy. Methods. In this pilot analysis, we first examined the rate of patients eligible to discontinuation and their baseline features (i.e. age, gender, ELTS and Sokal risk, BCR::ABL1 isoform) compared to patients without sustained MR4, using Fisher's exact test or Wilcoxon according to variable type. In patients discontinuing TKIs at 48 months, the successful TFR probability at 12 months after TKI withdrawal was computed with the Kaplan Meier method. Molecular relapse, defined as the loss of MMR or confirmed loss of MR3.0, progression, or death were considering as event in the event-free survival curve. Results. Of the 448 randomized patients, 289 had at least 48-month observation at the time of the present analysis and were evaluated for TFR eligibility, 141 in the IM arm and 148 in the NIL arm, respectively. Ninety-three patients (32%) showed a sustained MR4 in the fourth year and were deemed eligible for treatment discontinuation, 45 in the IM arm (32%) and 48 in the NIL arm (32%). Of the remaining 196 patients, 59 did not have the criteria to discontinue treatment and 137 previously went off study for failure, progression, toxicity, death, or other causes (66 in the IM arm and 71 in the NIL arm, respectively). We found that sustained MR4 achievement was significantly associated with low disease risk, according to both ELTS (81.7% vs 47.2% p<0.0001) and Sokal scores (50.5% vs 34.2%, p=0.008). There is a weak correlation to the age, being those eligible younger (median 52.5 vs 55 years, p=0.037), while no differences in gender and BCR::ABL1 isoform distributions were observed. Within the IM arm, patients who switched to NIL were 60/141 (43%), 44 within the first 12 months and 16 after the first year; those patients had a lower probability of starting the TFR phase compared to patients continuing IM (22% vs 40%, p=0.025). The median follow-up of the 93 patients who attempted treatment discontinuation at 48 months is 9.9 months (IQR: 5.3-12.1). The percentages of those patients in TFR were 82.9% (95% CI:74.8-91.8) at 6 months and 74.3% (95% CI:63.9-86.4) at 12 months. The analysis per random was considered premature given the short follow-up and the proportion of patients not yet evaluable for the discontinuation. Conclusions Although the results are still preliminary to draw definitive conclusions on the rate of sustained DMR and stable TFR , our data indicates that despite higher 24-month rates of MR4.5 in the NIL arm, the probability of reaching criteria for TFR attempt may be not different in the two study arms: one third of patients attempted discontinuation and the majority of them appear to be free of relapse after a median of 10 months from the therapy discontinuation. Among patients of the IM arm, patients switching to NIL due to absence of optimal response had a lower probability to attempt discontinuation. Noteworthy, as for the MR4.5 rate at 24 mo. of therapy, patients at low ELTS risk score are those with the highest probability to achieve sustained MR4 and being eligible for the treatment discontinuation.

Ponatinib Versus Imatinib in Patients with Newly Diagnosed Ph+ ALL: Subgroup Analysis of the Phase 3 Phallcon Study

Background: BCR::ABL1 tyrosine kinase inhibitors (TKIs) in combination with chemotherapy or steroids remain the standard of care in patients with newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Most patients treated with first- or second-generation TKIs eventually experience disease progression due to treatment resistance. Ponatinib is the only currently approved pan-BCR::ABL1 inhibitory TKI that potently inhibits wild-type and single resistance mutation variants of BCR::ABL1, including T315I. Multiple studies have shown promising minimal residual disease (MRD) negativity (neg) rates and survival outcomes with ponatinib in combination with chemotherapy or chemotherapy-free regimens. PhALLCON (NCT03589326) is the first randomized study comparing frontline TKIs in adults with Ph+ ALL. The primary endpoint for PhALLCON was met, with a clinically significantly higher MRD-neg complete remission (CR) rate at end of induction (EOI) with ponatinib vs imatinib (34.4% vs 16.7%; risk difference: 0.18 [95% confidence interval (CI): 0.06‒0.29]; P=0.0021) and a manageable safety profile comparable with imatinib. Here we report subgroup efficacy analyses from PhALLCON. Methods: This global, registrational, phase 3, open-label study randomized newly diagnosed adult patients with Ph+ ALL 2:1 to receive ponatinib (30 mg once daily [QD]) or imatinib (600 mg QD) plus reduced-intensity chemotherapy through EOI (Cycles 1-3), consolidation (Cycles 4-9), and post-consolidation (Cycles 10-20). Following post-consolidation, patients continued to receive single-agent ponatinib or imatinib until disease progression or unacceptable toxicity. The composite primary endpoint was MRD-neg ( BCR:: ABL1 ≤0.01% [MR4])CR for 4 weeks at EOI. Event-free survival (EFS; any-cause death, failure to achieve CR by EOI, relapse from CR) was a key secondary endpoint. A post-hoc analysis of progression-free survival (PFS; EFS-defined events, failure to achieve MRD-neg by the end of treatment, and loss of MRD-neg) was conducted. Subgroup analyses were performed relative to baseline demographic and disease characteristics. Results: Of 245 randomized patients, 232 (ponatinib, n=154; imatinib, n=78) had baseline BCR::ABL1 p190/p210 variants verified by central lab (efficacy-evaluable population); median age was 54 years (37.1% ≥60 years). As of Aug 2022, 78 patients (ponatinib/imatinib: 68 [41.5%]/10 [12.3%]) remained on study treatment; the top 3 reasons for discontinuation were hematopoietic stem cell transplantation (HSCT; 30.5%/37.0%), adverse events (12.2%/12.3%), and lack of efficacy (7.3%/25.9%). Median follow-up in the ponatinib and imatinib arms was 20 months and 18 months, respectively. Benefit for ponatinib was observed across all subgroups analyzed ( Table). All age subgroups had higher rates of MRD-neg CR with ponatinib vs imatinib, with the greatest benefit observed in patients ≥60 years (40.0% ponatinib vs 10.3% imatinib; P=0.0005). MRD-neg CR rate was higher for ponatinib vs imatinib among those with the BCR::ABL1 p190 variant (38.6%/17.0%; P=0.0017); it was higher for the p210 variant as well, but not significantly (22.5% vs 16.0%; P=0.51). Median PFS was longer with ponatinib vs imatinib regardless of age, with the greatest difference observed in the subgroup of patients ≥60 years (22.5 months for ponatinib vs 8.3 months for imatinib; hazard ratio: 0.594 [95% CI: 0.332-1.063]). Conclusions: Ponatinib was superior to imatinib in combination with reduced-intensity chemotherapy in the front-line setting for patients with Ph+ ALL, with a clinically significantly higher MRD-neg CR rate at EOI. Benefit was observed across all subgroups, particularly for patients ≥60 years and for those with the BCR::ABL1 p190 variant.

Flumatinib Versus Imatinib As a Frontline Therapy for Patients with Chronic Myeloid Leukemia in Chronic Phase: A Propensity Score Matching Study from Real-World Data

Background: Flumatinib mesylate, as a novel oral BCR-ABL1 tyrosine kinase inhibitor, is approved as a frontline therapy for chronic myeloid leukemia in chronic phase (CML-CP) in China since 2019. Mechanistically, with its structure of trifluoromethyl and pyridine flumatinib blocked BCR-ABL1 kinase autophosphorylation with much more potent activity than did imatinib and even showed higher efficacy than nilotinib against wild-type BCR-ABL1 kinase. Currently, there is still lacking the real-world effectiveness and safety of flumatinib in patients with CML. Methods: We retrospectively analyzed efficacy and safety of CML-CP patients (≥16 years) used flumatinib (600mg daily) or imatinib (400mg daily) as first-line treatment from 2020 to 2023, presenting a real-world comparison study. A propensity score (PS) matching was performed to adjust for Sokal risk score to compare the treatment efficacy, survival outcomes and safety of flumatinib and imatinib in a clinically well matched cohort. Results: PS matching resulted in 20 patients from each cohort being matched for Sokal risk scores. The median follow-up of the flumatinib-treated and imatinib-treated cohorts was 441 days and 487 days, respectively. In the intention-to-treat (ITT) population analysis, there is no differences between flumatinib and imatinib groups in 3-month early molecular response rate (85% vs. 80%, p = 0.677), 6-month major molecular response rate (MMR) (50% vs. 40%, p = 0.525) and 12-month MMR (55% vs. 50%, p = 0.752). In term of deep molecular response, more patients receiving flumatinib achieved molecular remission 4.5 (MR4.5) and molecular remission 4 (MR4.0) at 6 months (35% vs.0%, p = 0.004; and 45% vs. 5.0%, p = 0.003, respectively) and appeared to have higher 12-month MR4.5 and 12-month MR4.0 (45% vs.10%, p = 0.013; and 45% vs. 20%, p = 0.091, respectively; Table). During the follow-up period, treatment discontinuation occurred in 6 and 9 patients in flumatinib-treated and imatinib-treated cohorts respectively, including 2 and 3 patients due to drug resistance and 3 and 4 patients due to toxicity. The 2-year probability of event-free survival was 70% among the patients who received flumatinib and 47% among those who received imatinib ( p = 0.85), and the corresponding 2-year failure-free survival probabilities were 85% and 76%, respectively ( p = 0.77). Adverse events of edema, rash were more frequent in imatinib arm (any grade; 0% vs. 25%, p = 0.017; and 0% vs. 25%, p = 0.035, respectively), whereas alanine transaminase elevation appeared to be more frequent in flumatinib arm (any grade, 15% vs. 0%, p = 0.072). Of note, one patient receiving flumatinib had grade 3 QT prolongation and ventricular premature beat and was discontinued. Conclusions: The real-world data demonstrated that as a first-line treatment setting, flumatinib can bring patients with chronic phase CML higher rates of responses, and faster and deeper responses, indicating that flumatinib could be an alternative effective first-line treatment for CML-CP. The adverse events of flumatinib, such as cardiovascular events, abnormal liver function, and diarrhea, need to be given continuous concern in future studies.

Attenuated Dose Dasatinib in Newly Diagnosed Chronic Myeloid Leukemia Chronic Phase Patients in India.

BCR-ABL Tyrosine kinase inhibitors (TKI's) are most successful of targeted therapies and are currently considered the cornerstone in the management of patients with chronic myeloid leukemia (CML). A recent study reported excellent outcomes of Dasatinib 50mg with better sustained response. Therefore, we aim to evaluate the molecular responses and safety of upfront Dasatinib 50mg in Indian CML-Chronic Phase patients. It was an observational single-centre study. CML-CP patients started on Dasatinib 50mg daily were offered to participate in this study. Data of imatinib was collected retrospectively as a comparator group. Between June 2020 to Feb 2022, fifty patients were included in the dasatinib 50mg once daily group. Median age was 40 yrs. ranging from (19 to73) years. At a median follow up of 9.2 months, 49 patients completed three months treatment, out of which 48 patients were evaluated as one patient stopped medication after a month due to financial constraints. The response rate at three months for dasatinib 50mg daily and Imatinib were 68.75% and 69.7% respectively. At 12 months, 68% and 66.6% patients achieved major molecular response [MMR] in dasatinib 50mg and imatinib groups respectively. In conclusion, low dose dasatinib is safe and effective as an upfront therapy in CML-CP. Early molecular response [EMR] rates were comparable in low dose dasatinib and imatinib arm but deep molecular responses were significantly higher in low dose dasatinib arm. Dasatinib, taken daily at a dose of 50mg, may offer a new, alternative choice as generic versions are available now for frontline therapy in CML-CP.

Efficacy and Safety Results from ASC4MORE, a Randomized Study of Asciminib (ASC) Add-on to Imatinib (IMA), Continued IMA, or Switch to Nilotinib (NIL) in Patients (Pts) with Chronic-Phase Chronic Myeloid Leukemia (CML-CP) Not Achieving Deep Molecular Responses (DMRs) with ≥1 Year of IMA

INTRODUCTION: With the evolving CML treatment landscape, improvement in quality of life and treatment-free remission have become important therapy goals in CML-CP. In the 1st line (1L), more pts are able to achieve DMRs with 2nd-generation (2G) tyrosine kinase inhibitors (TKIs) than IMA. However, 30% to 60% of pts treated with 2G TKIs do not achieve DMR after 5 y of therapy, and 2G TKIs are associated with increased toxicity. Safe and effective treatment options are needed in early lines to help more pts achieve durable DMR. ASC is the 1st BCR::ABL1 inhibitor to Specifically Target the ABL Myristoyl Pocket (STAMP). ASC was 1st approved in the US for the treatment of adult pts with Philadelphia chromosome-positive CML-CP after ≥2 prior TKIs and pts with the T315I mutation. In the phase 3 ASCEMBL study, ASC led to superior major molecular response vs bosutinib (BOS) at wk 24 and 96. More pts on ASC vs BOS achieved MR4 (wk 24: 10.8% vs 5.3%; wk 48: 10.8% vs 3.9%; wk 96: 17.2% vs 10.5%) and MR4.5 (wk 24: 8.9% vs 1.3%; wk 48: 7.6% vs 1.3%; wk 96: 10.8% vs 5.3%). ASC demonstrated a favorable safety profile. Here, we present results from the ASC4MORE study (NCT03578367) of ASC add-on to IMA vs continued IMA vs switch to NIL in pts not achieving DMR with ≥1 y of 1L IMA (cutoff: Jan 10, 2022). METHODS: In this open-label, multicenter, qualitative trial, eligible adults with CML-CP were randomized 1:1:1:1 to receive ASC (40 or 60 mg once daily [QD]) add-on to IMA 400 mg QD, continue IMA 400 mg QD, or switch to NIL 300 mg twice daily. The primary endpoint was MR4.5 rate at wk 48. Pts in the IMA arm could switch to the ASC 60-mg QD add-on arm if they had not achieved MR4.5 at wk 48; data from these pts will be analyzed separately and are not part of the current analysis. Pts must have received 1L IMA 400 mg QD for ≥1 y with BCR::ABL1IS >0.01% to ≤1% at randomization. Pts were excluded if they met failure criteria (per European LeukemiaNet 2013), had previous treatment with any TKIs other than IMA, or had achieved DMR at any time with IMA. RESULTS: Eighty-four pts were randomized to receive ASC 40- or 60-mg QD add-on to IMA, continue IMA, or switch to NIL (n=21 each); baseline characteristics were mostly well-balanced between arms. At cutoff, 85.7%, 76.2%, 23.8%, and 61.9% of pts, respectively, remained on treatment, with median (range) durations of exposure of 104.7 (27-160), 94.0 (1-148), 78.9 (1-146), and 53.4 (50-142) wk, respectively. Top reasons for discontinuation were pt decision in the ASC 40-mg add-on arm (9.5%), AEs in the ASC 60-mg add-on and NIL arms (14.3% and 23.8%, respectively), and physician decision in the IMA arm (57.1%) (pts who crossed over to the ASC 60-mg add-on arm were considered discontinued for IMA arm). In the 40-mg ASC add-on, 60-mg ASC add-on, IMA, and NIL arms, respectively, 19.0%, 28.6%, 0%, and 4.8% of pts were in MR4.5 at wk 48, with 42.9%, 28.6%, 0%, and 23.8% in MR4 at wk 48. DMRs were achieved earlier in pts receiving ASC 40- and 60-mg add-on vs NIL; median time to MR4.5 was 12.1, 12.4, and 24.6 wk, respectively (Figure). The Kaplan-Meier-estimated rate of maintaining MR4.5 for ≥48 wk was 60.0%, 80.0%, and 66.7% in the 40- and 60-mg ASC add-on and NIL arms, respectively. As expected in these pts tolerating IMA for ≥1 y, ASC add-on was associated with higher rates of adverse events (AEs), serious AEs, and discontinuations than continued IMA, but less than switching to NIL. AEs leading to discontinuation in the 40-mg add-on, 60-mg ASC add-on, IMA, and NIL arms were reported in 4.8%, 14.3%, 0%, and 23.8% of pts, respectively, with dose adjustments/interruptions occurring in 28.6%, 33.3%, 5.0%, and 23.8%, respectively. There were no new or worsening safety findings with ASC (Table). CONCLUSIONS: More pts achieved DMR at wk 48 with ASC add-on to IMA vs continued IMA or switch to NIL in pts not achieving DMR with IMA alone for ≥1 y. In this population of pts tolerating IMA for ≥1 y, ASC add-on was generally well tolerated. While not powered to identify the best arm for achievement of DMR in this setting, the high rate of DMR in the ASC add-on arms is promising. Further studies are needed to assess if ASC alone can provide equivalent efficacy and better tolerability vs add-on to IMA. Ongoing studies are assessing ASC monotherapy in 1L, including ASC4FIRST (NCT04971226) and ASC4START. ASC may provide an important early-line treatment option to help more pts safely achieve rapid and deep responses and reduce therapy switching. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and Safety of Bosutinib Vs Imatinib By Charlson Comorbidity Index in Newly Diagnosed Patients with Chronic Myeloid Leukemia

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

Comparison of Generic Dasatinib Versus Imatinib in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia with Reference to Early Molecular Response: Results from a Single-Center, Randomized Controlled Study from India

Background: Chronic myeloid leukemia (CML) is the commonest leukemia in adult population in India. The advent of tyrosine kinase inhibitors (TKI) targeting BCR-ABL1 fusion transcript in CML has dramatically improved survival of CML patients. Generic formulations of imatinib mesylate have been the mainstay of TKI therapy in Indian CML patients for more than a decade, due to prohibitive costs of 2nd generation TKIs and poor socio-economic status of majority of patients. However, with the availability of generic dasatinib in India since March 2021, the cost of dasatinib therapy has become comparable to that of generic imatinib treatment, thereby enabling more extensive use of dasatinib as first-line TKI therapy in CML patients in India. Achievement of early molecular response (EMR) after 3 months of first-line TKI therapy, defined as blood BCR-ABL1 transcript level ≤ 10% [international scale (IS)], has emerged as an important predictor of favorable long-term outcome in CML-CP. There is scarcity of data on efficacy & safety of generic formulations of dasatinib vis-à-vis generic imatinib in CML-CP patients in India, which the present study has attempted to explore at a tertiary care hospital in India. Objectives: The objectives of the study were to compare early molecular response (EMR) [defined as BCR-ABL1 transcript level ≤ 10%, I.S.] at 3 months of therapy with generic dasatinib versus generic imatinib in newly diagnosed CML-CP patients and to compare treatment-related adverse effects in the two groups. Methods: This randomized controlled study enrolled newly diagnosed CML-CP patients after obtaining institutional ethics committee approval & informed consent. Inclusion Criteria:Newly diagnosed patients with chronic phase CML.Age ≥ 12 years. Exclusion Criteria:Patients with de novo accelerated phase or blast phase CML.Pregnancy & lactation.Patients with pre-existing pleural effusion, grade ≥ 3 lung disease, or pulmonary arterial hypertension.Patients with angina, or grade ≥ 3 cardiac disease [as defined by the New York Heart Association (NYHA) criteria] at diagnosis.Patients with prolonged QTc interval (> 480 msec) at baseline. The EUTOS long-term survival (ELTS) risk score was calculated at diagnosis. Patients were randomized to one of the two following treatment groups: Group A: Dasatinib 100 mg p.o. once daily (60 mg/m2/day for age <18 years). Group B: Imatinib 400 mg p.o. once daily (340 mg/m2/day for age < 18 years). Follow up & monitoring of patients was done every 2 weekly till completion of 3 months of TKI therapy, followed by assessment of hematological response & molecular response as per standard criteria. Results: A total of 61 consecutive CML patients were screened between June 2021 and March 2022, out of which 54 patients with confirmed diagnosis of CML-CP were enrolled in the study and were randomized to receive generic dasatinib or generic imatinib as first-line therapy and were followed up for 3 months for EMR and complete hematological response (CHR). Four patients were lost to follow up and data was analyzed for 50 patients for whom EMR results at 3 months was available. Out of these 50 patients, 24 patients received dasatinib & 26 patients received imatinib. The median age of patients was 33 years (range 18-64 years), with male: female ratio of 1.3: 1. Achievement of CHR was documented in 96% of patients in both dasatinib & imatinib treatment arms. EMR at 3 months was achieved in overall 72% patients in study [19/24 patients (79%) in dasatinib arm & 17/26 patients (65%) in imatinib arm]. However, the difference was not statistically significant (p = 0.27). Notably, EMR rates in ELTS intermediate-risk group was 86% in dasatinib arm versus 42% in imatinib arm, and EMR rates in ELTS high-risk group was 82% in dasatinib arm versus 57% in imatinib arm (p = 0.33). The incidence of grade 3-4 adverse events was not significantly different in the two treatment groups. The patient characteristics & treatment results are summarized in Table 1 & Figure 1. Conclusion: The results of the present study suggested that generic formulations of dasatinib were well-tolerated and were associated with improved early molecular response rates compared to generic imatinib in CML-CP patients in India. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and Safety of Bosutinib Versus Imatinib in US Patients with Newly Diagnosed Chronic Myeloid Leukemia after 5-Years Follow-up in the Bfore Trial

Introduction: Bosutinib is approved for the treatment of patients with Philadelphia chromosome positive, chronic phase (CP) chronic myeloid leukemia (CML). First-line bosutinib was approved based on the results from the phase 3 BFORE trial, which showed the superior efficacy of bosutinib versus imatinib after ≥12 months of follow-up (Cortes et al., J Clin Oncol 2018). The final efficacy and safety results from BFORE after 5-years of follow-up were recently published (Brümmendorf et al., Leukemia 2022). This analysis investigated the efficacy and safety of bosutinib versus imatinib after 5-years follow-up in a subpopulation of US patients enrolled in the BFORE trial. Methods: BFORE (NCT02130557) was a global, multicenter, open-label, randomized, phase 3 study of bosutinib versus imatinib. 536 patients with newly diagnosed BCR-ABL1-positive CP-CML were randomized 1:1 to a starting dose of bosutinib or imatinib 400 mg once daily. Study treatment was continued for 5-years or until treatment failure, unacceptable toxicity, death, or withdrawal of consent. Efficacy was assessed by major molecular response (MMR) rate in the intent-to-treat population (all randomized patients). Safety was assessed by the incidence of treatment-emergent adverse events (TEAEs) and permanent treatment discontinuation in the safety population (patients who received ≥1 dose of study treatment). This analysis is based on the final database lock: June 12, 2020, after 5-years (240 weeks). Results: The US subpopulation in BFORE comprised 88 patients (16% of randomized patients); 39 received bosutinib and 49 received imatinib. Baseline disease characteristics were well balanced between treatment arms. The median (range) duration of treatment with bosutinib and imatinib was 54.8 (0.9-58.9) months and 54.8 (1.2-56.4) months, respectively. The median (range) dose intensity with bosutinib and imatinib was 383.5 (162-562) mg/day and 400.0 (189-754) mg/day, respectively. MMR rate at 12 months was 41.0% for bosutinib versus 32.7% for imatinib (Table 1). Cumulative MMR rate by 60 months was 74.4% for bosutinib versus 63.3% for imatinib (Table 1). All patients in both treatment arms experienced at least one TEAE. In the bosutinib arm, the most common TEAEs (≥30% of patients) were diarrhea (84.6%), nausea (61.5%), fatigue (53.8%), thrombocytopenia (41.0%), headache (35.9%), rash (33.3%), increased alanine aminotransferase (ALT; 30.8%), and constipation (30.8%). In the imatinib arm, the most common TEAEs were nausea (63.3%), diarrhea (55.1%), fatigue (36.7%), periorbital edema (34.7%), and muscle spasm (30.6%). 13 (33.3%) patients in the bosutinib arm permanently discontinued treatment due to AEs, versus 7 (14.3%) in the imatinib arm. The most common causes of permanent treatment discontinuation were increased ALT (7.7%) with bosutinib and increased lipase (4.1%) with imatinib. Additional analyses of the US subpopulation are ongoing and will be presented. Conclusions: The efficacy and safety outcomes in this US subpopulation from BFORE were generally consistent with the overall study population at 5 years (Brümmendorf et al., Leukemia 2022). These results confirm the use of bosutinib as a standard of care in patients with newly diagnosed CP-CML. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Outcomes in Patients with Chronic Myeloid Leukemia in the Chronic Phase Randomized to Dasatinib or Imatinib after Suboptimal Responses to 3 Months of Imatinib Therapy: Final 5-Year Results from DASCERN

Introduction: Dasatinib has demonstrated superior responses versus imatinib in patients (pts) with newly diagnosed chronic myeloid leukemia in the chronic phase (CML-CP) (Cortes JCO 2016). Achievement of early molecular response (EMR; BCR::ABL1 ≤ 10% International Scale [IS]) at 3 months increases the probability of subsequent deep molecular response (DMR) and improves survival (Cortes JCO 2016, Hochhaus Leukemia 2016). However, ⅓ of pts treated with imatinib did not reach an EMR (Hughes Blood 2014); there are no standard treatment strategies for these pts. DASCERN (NCT01593254) is the first prospective, randomized, phase 2b trial to demonstrate the potential benefit of switching early to dasatinib in pts with no EMR after 3 months of initiating imatinib. At 12 months, pts randomized to dasatinib had significantly higher major molecular response (MMR) rates versus imatinib (29% vs 13%, primary endpoint) (Cortes Leukemia 2020). At 3 years, cumulative MMR rates were 67% and 40% with dasatinib and imatinib, respectively (Cortes EHA 2020 EP756). Switching to dasatinib did not increase the incidence of treatment-emergent adverse events (AEs). Here we report the results from the final 5-year analysis. Methods: Pts with complete hematologic response but no EMR at 3 months after initiating imatinib 400 mg were randomized 2:1 to an early switch to dasatinib (100 mg) or continue imatinib (≥ 400 mg). Pts who experienced subsequent failure with imatinib (per European LeukemiaNet 2013 recommendations at the time of the study) crossed over to dasatinib. The intent-to-treat (ITT) population included all pts randomized to each arm, irrespective of crossover status. Study endpoints included time to MMR and molecular response 4.5 (MR4.5; 4.5-log reduction in BCR::ABL1 levels; ≤ 0.0032% IS), progression-free survival (PFS), overall survival (OS), and safety. Results: At a median follow-up of 80 months (data cutoff, April 24, 2022), 174 and 86 pts with no EMR after imatinib were randomized to dasatinib and imatinib, respectively; 46 (53%) imatinib-randomized pts experienced subsequent imatinib failure and crossed over to dasatinib in a median of 9.5 months. Detailed baseline characteristics have been previously reported (Cortes EHA 2020 EP756). The median age was 37 years, and 73% of patients were Asian. All pts discontinued treatment, mainly due to study drug toxicity (26 [10%]), and other reasons (176 [68%], mostly study completion); 6 (2%) discontinued due to death. The MMR rate by 5 years in the ITT population was 77% and 44%, respectively, for pts in the dasatinib and imatinib arms. After accounting for crossover, cumulative MMR rates were 74% with dasatinib and 44% with imatinib; 65% of pts who crossed over from imatinib to dasatinib achieved MMR (Figure). Across the 5-year study period, more pts randomized to dasatinib than imatinib achieved MR4 and MR4.5 (MR4, 52% vs 31%; MR4.5, 36% vs 26%). Only 1/46 pts who later crossed over to dasatinib after imatinib failure achieved MR4.5. PFS in the ITT population was 94% in both treatment arms. PFS was numerically lower in pts who later crossed over to dasatinib after imatinib failure (90%). OS in the ITT population was similar between both arms (96% vs 95%). OS in pts who crossed over to dasatinib was 94%. Six additional deaths were reported since the 3-year follow-up. Any grade treatment-related AEs were experienced by 149 pts (87%) randomized to dasatinib, 69 (80%) randomized to imatinib, and 37 patients (80%) who crossed over to dasatinib. Treatment-related pleural effusion occurred in 31 pts (18%) randomized to dasatinib (n = 6 grade 3/4), 9 pts (20%) who crossed over to dasatinib after imatinib failure (n = 2 grade 3/4), and 0 pts who remained on imatinib (no crossover). Conclusions: At the final 5-year follow-up, sustained clinical benefit was observed from an early switch to dasatinib after suboptimal responses to 3 months of imatinib. MMR and DMR rates were higher in pts randomized to dasatinib versus imatinib. Overall, the safety profile was consistent with previous reports. These results complement the previous findings that switching to dasatinib promptly after a lack of EMR with imatinib increases the chance of achieving DMR, which may improve outcomes in pts with CML-CP. Therefore, this study further highlights the significance of achieving optimal responses early during treatment. Study support: Funded by Bristol Myers Squibb. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Nilotinib vs. imatinib in Japanese patients with newly diagnosed chronic myeloid leukemia in chronic phase: 10-year follow‑up of the Japanese subgroup of the randomized ENESTnd trial.

In the 10-year analysis of Japanese patients with newly diagnosed CML-CP in the ENESTnd trial, nilotinib yielded higher cumulative response rates. There were no new occurrences of disease progression or deaths since the 5-year analysis. Cumulative 10-year rates of MMR and MR4.5 were higher in the nilotinib arms [300mg twice daily (BID), 86.2% and 69.0%, respectively; 400mg BID, 78.3% and 69.6%, respectively] than the imatinib arm (400mg once daily, 60.0% and 48.0%, respectively). Nasopharyngitis (85.7%, 77.3%, 79.2%), rash (50.0%, 68.2%, 37.5%), headache (39.3%, 45.5%, 25.0%), and back pain (39.3%, 50.0%, 29.2%) were the most frequently reported all-grade adverse events (AEs) for nilotinib 300 and 400mg BID and imatinib, respectively. Cardiovascular AEs were more common with nilotinib than with imatinib. More patients on nilotinib had pre-diabetic and diabetic levels of HbA1c (300mg BID, 17.9% and 10.7%, respectively; 400mg BID, 22.7% and 18.2%, respectively) compared with imatinib (4.2% each). Overall, 10-year results from the Japanese cohort are consistent with prior results from the full ENESTnd cohort and the Japanese subgroup, and continue to support the long-term use of nilotinib in Japanese patients with newly diagnosed CML-CP, but with proper monitoring and management of comorbidities.

Imatinib (IM) in Combination with Hydroxyurea Showed Significantly Lower Major Molecular Response Rates at 6 Months but Similar MMR at 18 Months in Patients with CML1st CP Compared to IM Alone. Final Results of the CML2004 Study. NCT 02480608

Introduction: Imatinib (IM) monotherapy remains an important option to treat newly diagnosed patients with chronic myeloid leukemia (CML) in chronic phase (CP). Hydroxyurea (HU) is effective in controlling elevated white blood cell counts and was widely used to treat CML prior to the era of tyrosine kinase inhibitors (TKIs). After combinations of IM and HU showed additive effects on Ph+ cells in vitro the East German Study Group conducted a study in patients with CML first chronic phase.Methodes: Starting in 2002, 20 adult patients with newly diagnosed CP-CML were included in the phase I study to identify the dose of HU in combination with standard dose IM (400mg daily) that would result in mild myelosuppression (white blood cell count 3,000-4,000/mL). Starting dose of HU was 500mg daily increasing by 500mg every 3 weeks to a maximum of 3,000 mg daily. In line with the protocol, 500mg HU was chosen as the starting dose for the randomized phase II study which tested the combination vs. standard dose IM, with the rate of major molecular response (MMR) at 18 months as the primary endpoint.Additional 93 patients were enrolled in the phase II of the study, 5 of whom were excluded, leaving 88 patients to be randomized 2:1 to the IM/HU (n=59) and IM (n=29) arm, respectively. Three patients (2 IM/HU, 1IM) were lost to follow-up. As prospectively designed, IM/HU patients (n=77) from the phase I and II were analyzed in combination with patients from the CML study IV (n=49) selected by propensity score matching. The median age of the 154 patients was 55 years (range 18 - 82). The EUTOS long-term survival prognostic score was available for 141 patients and was high in 8 (5.7%), intermediate in 35 (24.8%) and low in 98 (69.5%), with no significant differences between treatment groups. The median HU dose was 500mg (range 152-3000); the median IM dose was 400 mg (range 145-617mg) in both arms.Results: The 5-year overall survival (OS) was 90.4% and 84,9% in the IM/HU and IM arm respectively (not significant). Similarly, progression-free survival (PFS) at 5 years amounted to 86.7% in the IM/HU and 84.9% in the IM arm.With IM/HU, the probabilities of complete cytogenetic response (CCR) at 6, 12, and 18 months were 54.3, 84.0, and 93.7%, respectively. In the IM arm, the corresponding numbers were 70.4, 84.9, and 83.3% (p=not significant).Molecular Response Rates (MMR) in the two arms were evaluated at 6 months with 21.6 (IM/HU) vs. 41.1% (IM) (p=0.0383) and at 12 months with 41.9 (IM/HU) vs. 58.9% (IM; not significant). The primary endpoint of the study (MMR rate at 18 months) did not significantly differ between the IM/HU (65.8%) and the IM (66.0%) arms.No significant differences were detected in time to event analyses of OS and PFS or in group comparisons between the probabilities of CCR and MMR.The gross numbers of adverse events in general or of adverse events of grade 4 were not different between the two arms. However, cumulative incidences showed an earlier occurrence in the IM/HU than in the IM arm (p= 0.0343, Gray test)Conclusion: Compared to Imatinib only, the combination of Imatinib and HU resulted in a lower MMR rate at 6 months but a similar MMR rate at 18 months. Furthermore, IM/HU was associated with more early adverse events. There was no indication of a beneficial effect in the treatment of CML patients in 1st chronic phase using the combination of IM with HU. DisclosuresLange:Novartis: Honoraria, Research Funding. Al-Ali:Gilead: Consultancy, Honoraria; Alexion: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Pfirrmann:Novartis: Honoraria; BMS: Honoraria. Hehlmann:Novartis: Research Funding; BMS: Consultancy. Deininger:Incyte: Consultancy; BMS: Consultancy, Research Funding; Ariad Pharmaceuticals, Bristol Myers Squibb, CTI BioPharma Corp, Gilead, Incyte, Novartis, Pfizer, Celgene, Blue Print, Galena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; ARIAD: Consultancy; Gilead: Research Funding; Celgene: Research Funding; Novartis: Consultancy, Research Funding.

Bosutinib Vs Imatinib for Newly Diagnosed Chronic Myeloid Leukemia in the BFORE Trial: Results By 3-Month BCR-ABL1 Transcript Level

Introduction: Bosutinib is a potent SRC/ABL tyrosine kinase inhibitor approved for treatment of Philadelphia chromosome-positive CML in adults resistant or intolerant to prior therapy. This analysis evaluated the efficacy of first-line bosutinib versus imatinib in the BFORE study (NCT02130557) by 3-month BCR-ABL1 transcripts ≤10% versus >10% and examined baseline and on-treatment characteristics as predictors of time to major molecular response (MMR).Methods: In this ongoing, multinational, phase 3, open-label study, 536 patients were randomized 1:1 to bosutinib 400 mg or imatinib 400 mg once daily. The present analysis is based on ≥12 months of follow-up. Baseline and on-treatment time-dependent covariates were analyzed using a proportional subdistribution hazards model predicting time to initial MMR. No adjustment for multiple comparisons was made.Results: The intent-to-treat (ITT) population included 268 patients in the bosutinib arm and 268 patients (including 3 untreated patients) in the imatinib arm. Among evaluable patients (≥3000 ABL1 analyzed) at 3 months in the ITT population, more patients in the bosutinib arm than in the imatinib arm had BCR-ABL1 transcripts ≤10% (80.6% of 248 patients vs 60.5% of 253 patients; P <0.0001). The MMR rate at 12 months was higher in evaluable patients who had transcripts ≤10% versus >10% at 3 months with bosutinib (117 [58.5%] vs 7 [14.6%], P <0.0001) and with imatinib (83 [54.2%] vs 14 [14.0%], P <0.0001). The cumulative MMR rates were also higher in evaluable patients with transcripts ≤10% with bosutinib (138 [69.0%] vs 12 [25%]; P <0.0001) and with imatinib (100 [65.4%] vs 30 [30.0%]; P <0.0001). In the ITT population, transcripts ≤10% (vs >10% or not evaluable) at 3 months was a predictor of time to MMR in both arms (Table; bosutinib: hazard ratio [HR]=6.44, P <0.0001; imatinib: HR=3.69, P <0.0001). The only other predictor of time to MMR among the covariates examined was not having a bosutinib dose reduction to 300 mg due to an adverse event.Conclusion: BOS treatment was associated with a higher number of patients presenting transcripts ≤10% at 3 months than those treated with IMA. Patients with transcripts ≤10% at 3 months had higher rates of 12-month MMR and achieved response faster than those with transcripts >10%. These findings suggest that the transcript level at 3 months may be a predictor of response to first-line bosutinib and imatinib. [Display omitted] DisclosuresHochhaus:Novartis: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Ariad: Research Funding; MSD: Research Funding; BMS: Research Funding. Gambacorti-Passerini:Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy. Deininger:BMS: Consultancy, Research Funding; ARIAD: Consultancy; Ariad Pharmaceuticals, Bristol Myers Squibb, CTI BioPharma Corp, Gilead, Incyte, Novartis, Pfizer, Celgene, Blue Print, Galena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Gilead: Research Funding; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Celgene: Research Funding. Mauro:Bristol-Myers Squibb: Consultancy. Chuah:Chiltern: Honoraria; BMS: Honoraria, Other: Travel; Novartis: Honoraria; Avillion: Honoraria. Kim:Il-Yang: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Milojkovic:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Honoraria, Speakers Bureau; ARIAD: Consultancy, Honoraria. le Coutre:BMS: Honoraria; Pfizer: Honoraria; Novartis: Honoraria, Research Funding; Incyte: Honoraria; ARIAD: Honoraria. García Gutiérrez:Incyte: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Reilly:Avillion LLP: Employment. Jeynes-Ellis:Avillion LLP: Employment, Equity Ownership. Crescenzo:Pfizer: Employment, Equity Ownership. Leip:Pfizer: Employment, Equity Ownership. Bardy-Bouxin:Pfizer: Employment, Equity Ownership. Brümmendorf:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Cortes:ARIAD: Consultancy, Research Funding; Teva: Research Funding; Sun Pharma: Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding.

Bosutinib in Newly Diagnosed Chronic Myeloid Leukemia (CML): Gastrointestinal (GI), Liver, and Hematological Safety Characterization in the BFORE Trial

Bosutinib in Newly Diagnosed Chronic Myeloid Leukemia (CML): Gastrointestinal (GI), Liver, and Hematological Safety Characterization in the BFORE Trial

English

BACKGROUND Chronic myeloid leukemia (CML) accounts for 15 - 20 % of leukemia in adults worldwide. At present, the three tyrosine kinase inhibitors (TKI) imatinib, dasatinib, or nilotinib are accepted as the standard first-line treatment in chronic phase (CP). Nilotinib is a second generation TKI having faster and deeper response compared to imatinib. We wanted to see if the response achieved with nilotinib in the first three months could be translated into long term benefits when imatinib was given after 3 months. METHODS Newly diagnosed CML-CP patients were randomized into two arms. The patients on the first arm were given imatinib and in the second arm nilotinib was given for first 3 months. After three months nilotinib was switched over to imatinib. The molecular response was assessed in both arms at 3 months and 6 months. RESULTS Twenty-six patients in each arm were analysed. The optimal molecular response (QPCR &lt;10 %) after 3 months was significantly higher in patients receiving nilotinib than imatinib (96.1 % vs 65.38 %; P &lt; 0.0048). The optimal response after 6 months (QPCR &lt; 1 %) was found to be more in the initial nilotinib arm than the initial imatinib arm (76.9 % vs 65.3 %; P - value = 0.35). CONCLUSIONS Patients on nilotinib arm did well even after switching to imatinib. It gives us an important platform for an economically backward country like India where the therapy with more potent drug like nilotinib is given in the initial three months or even six months. KEYWORDS Chronic Myeloid Leukaemia, Imatinib, Nilotinib, Optimal Response, Major Molecular Response

Outcomes before and after dose reduction in patients with newly diagnosed chronic myeloid leukemia receiving bosutinib or imatinib.

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 &gt; 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 &gt; 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 &gt; 6 mo assessment. In the IMA arm, 32/50 (64%) pts had MMR &gt; 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 &gt; 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 &gt; 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 &gt; 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.

The effect of body mass index on efficacy and safety of bosutinib or imatinib in patients with newly diagnosed chronic myeloid leukemia.

7037 Background: Bosutinib (BOS) is approved for the treatment (Tx) of Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia (CML) resistant/intolerant to prior therapy and newly diagnosed Ph+ chronic phase (CP) CML. Body mass index (BMI) was shown to influence Tx response with front-line dasatinib vs imatinib (IMA). We report the efficacy and safety of BOS and IMA by BMI in patients (pts) with newly diagnosed CP CML. Methods: In the open-label BFORE trial, pts were randomized to receive 400 mg once daily BOS or IMA. Outcomes were assessed according to baseline BMI ≥25 or = 25 kg/m2. This post hoc analysis was based on the final 5-y analysis (database lock: June 12, 2020). Results: In the BOS and IMA arms, respectively, 149 (56.4%) vs 115 (43.6%) pts and 145 (54.3%) vs 122 (45.7%) pts had BMI ≥25 vs = 25. In both the BOS and IMA arms, median Tx duration and time on study was 55 mo for pts with BMI ≥25 or = 25; respective median dose intensity was 394 vs 393 mg/d and 400 vs 400 mg/d. Molecular response (MR) rates are shown in the table. Cumulative incidence of major MR was similar in pts with ≥25 vs = 25 receiving BOS (HR 0.99; 95% CI 0.74−1.31) or IMA (HR 1.09; 95% CI 0.81−1.47). Event-free survival (EFS) and overall survival (OS) rates at 60 mo are shown in the table. Most common reasons for Tx discontinuation were adverse events (AEs) (BOS 28.2 vs 20.0%; IMA 13.3 vs 10.7%) and lack of efficacy (BOS 5.4 vs 5.2%; IMA 16.1 vs 19.8%). In pts with BMI ≥25 vs = 25, dose reductions and interruptions due to Tx-emergent AEs (TEAEs) occurred in 43.6 % vs 46.2% and 66.4% vs 69.7% of pts with BOS and 24.5% vs 24.6% and 40.6% vs 50.8% with IMA. Any grade TEAEs in ≥30% of pts with BMI ≥25 vs = 25 were diarrhea (73.8 vs 73.1%), nausea (40.9 vs 31.9%), thrombocytopenia (30.9 vs 41.2%), increased alanine (37.6 vs 28.6%) and aspartate aminotransferase (30.2 vs 20.2%) with BOS and diarrhea (49.0 vs 29.5%), nausea (46.2 vs 37.7%), muscle spasms (33.6 vs 26.2%), neutropenia (14.7 vs 32.0%) and thrombocytopenia (10.5% vs 30.3%) with IMA. Conclusions: Efficacy of BOS was consistent in pts with BMI ≥25 or = 25; however, with IMA a low (vs high) BMI appeared to be associated with worse survival outcomes. Differences in certain TEAEs were observed between BMI subgroups in both treatment arms. Clinical trial information: NCT02130557. [Table: see text]

Long-term outcomes with frontline nilotinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: ENESTnd 10-year analysis

In the ENESTnd study, with ≥10 years follow-up in patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase, nilotinib demonstrated higher cumulative molecular response rates, lower rates of disease progression and CML-related death, and increased eligibility for treatment-free remission (TFR). Cumulative 10-year rates of MMR and MR4.5 were higher with nilotinib (300 mg twice daily [BID], 77.7% and 61.0%, respectively; 400 mg BID, 79.7% and 61.2%, respectively) than with imatinib (400 mg once daily [QD], 62.5% and 39.2%, respectively). Cumulative rates of TFR eligibility at 10 years were higher with nilotinib (300 mg BID, 48.6%; 400 mg BID, 47.3%) vs imatinib (29.7%). Estimated 10-year overall survival rates in nilotinib and imatinib arms were 87.6%, 90.3%, and 88.3%, respectively. Overall frequency of adverse events was similar with nilotinib and imatinib. By 10 years, higher cumulative rates of cardiovascular events were reported with nilotinib (300 mg BID, 16.5%; 400 mg BID, 23.5%) vs imatinib (3.6%), including in Framingham low-risk patients. Overall efficacy and safety results support the use of nilotinib 300 mg BID as frontline therapy for optimal long-term outcomes, especially in patients aiming for TFR. The benefit-risk profile in context of individual treatment goals should be carefully assessed.

Flumatinib versus Imatinib for Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia: A Phase III, Randomized, Open-label, Multi-center FESTnd Study.

Flumatinib has been shown to be a more potent inhibitor of BCR-ABL1 tyrosine kinase than imatinib. We evaluated the efficacy and safety of flumatinib versus imatinib, for first-line treatment of chronic phase Philadelphia chromosome-positive chronic myeloid leukemia (CML-CP). In this study, 394 patients were randomized 1:1 to flumatinib 600 mg once daily (n = 196) or imatinib 400 mg once daily (n = 198) groups. The rate of major molecular response (MMR) at 6 months (primary endpoint) was significantly higher with flumatinib than with imatinib (33.7% vs. 18.3%; P = 0.0006), as was the rate of MMR at 12 months (52.6% vs. 39.6%; P = 0.0102). At 3 months, the rate of early molecular response (EMR) was significantly higher in patients receiving flumatinib than in those receiving imatinib (82.1% vs. 53.3%; P < 0.0001). Compared with patients receiving imatinib, more patients receiving flumatinib achieved molecular remission 4 (MR4) at 6, 9, and 12 months (8.7% vs. 3.6%, P = 0.0358; 16.8% vs. 5.1%, P = 0.0002; and 23.0% vs. 11.7%, P = 0.0034, respectively). No patients had progression to accelerated phase or blast crisis in the flumatinib arm versus 4 patients in the imatinib arm by 12 months. Adverse events of edema, pain in extremities, rash, neutropenia, anemia, and hypophosphatemia were more frequent in imatinib arm, whereas diarrhea and alanine transaminase elevation were more frequent in flumatinib arm. Patients receiving flumatinib achieved significantly higher rates of responses, and faster and deeper responses compared with those receiving imatinib, indicating that flumatinib can be an effective first-line treatment for CML-CP. This trial was registered at www.clinicaltrials.gov as NCT02204644.See related commentary by Müller, p. 3.