Major Molecular Response Rates Research Articles

Evaluating Effectiveness and Safety of Flumatinib for Chronic Phase Chronic Myeloid Leukemia in (CML-CP) without Optimal Response (Warning, Failure) to Imatinib or/and Dasatinib

Introduction Flumatinib is a novel second-generation BCR-ABL1 targeted kinase inhibitors (TKI) with better efficacy and safety than first generation TKIs in first-line treatment of chronic myeloid leukemia in chronic phase (CML-CP). In the previous phase III study, newly diagnosed CML-CP patients receiving flumatinib achieved higher treatment responses and safety than imatinib. When it comes to the patients not achieving the optimal response to TKIs, flumatinib is potentially a better option, nonetheless the robust evidence is unavailable. This study reports the effectiveness and safety of switching to flumatinib in patients who have not achieved the optimal molecular response to imatinib or/and dasatinib. Methods This prospective, multicentre study enrolled Philadelphia Chromosome-Positive (Ph+) CML-CP patients aged ≥18 years and who failed to achieve the optimal response with imatinib or/and dasatinib between March 2021 to October 2022. All patients were treated with flumatinib 600 mg once a day and followed up to 24 months. The primary endpoint of the study was rate of major molecular response (MMR) at 12 months as defined by European LeukemiaNet 2020 recommendations (BCR-ABL1 transcript level ≤0.1% in peripheral blood on RT-PCR assay on International Scale [IS]) and safety was the secondary endpoint assessed with CTCAE 4.03 version. In addition, the optimal molecular response in either the warning or failure patients was evaluated at 3, 6 and 12 months respectively, after switching to flumatinib, and the difference in effectiveness was also analyzed from the available mutation subtypes. Results Overall, 94 patients with Ph+ CML-CP were included in the study. The median (range) age of the patients were 53 (19.0-84.0) years old and 61.7% of the patients were males. A total of 38 (40.4%) patients reported warning response from the previous TKIs whereas 56 (59.6%) of patients reported treatment failure to the previous TKIs. Seventy-seven (81.9%) patients have been treated with one TKI, either imatinib or dasatinib, and 17 (18.1%) have been treated with both prior to the study. Overall, 25 (54%) patients achieved MMR at 12-months follow-up compared to the baseline (Figure 1). The rates of optimal molecular response at 3- and 6-months were also improved compared to the baseline. The optimal molecular response was 76(88%) at 3 months, and 52(73%) at 6 months. Subgroup analysis with previous response to TKIs revealed that flumatinib improved the rates of optimal molecular response in both warning and failure groups. Switching to flumatinib from imatinib or/and dasatinib have been reported with an enhanced optimal molecular response in patients who experienced warning compared with those who had treatment failure after the TKIs with 38 (100%) vs 38 (79%), 29 (91%) vs 23 (59%) and 15 (68%) vs 10 (42%) at 3-, 6- and 12-months respectively (Figure 2). Similarly, the rates of optimal molecular response were improved in patients without mutations compared to those having mutations, 65 (90%) vs 9 (75%) at 3 months, 46 (77%) vs 5 (56%) at 6 months and 23 (59%) vs 1 (20%) at 12 months respectively. The most common adverse events (AEs) were diarrhea in 17 (18%), rash in 11 (12%), bloating in 11 (12%), and thrombocytopenia in 11 (12%) patients. Common hematological AEs of grade 3/4 were thrombocytopenia in 7 (7%), anemia in 3 (3%) and leucopenia in 1 (1%) patients. Conclusion For Ph+ CML-CP patients without the optimal molecular response in previous imatinib or/and dasatinib, flumatinib is a better alternative to the existing treatments. In addition, if the patients were switched to flumatinib earlier, the optimal response was achieved faster. The grade 3/4 AEs were mainly hematologically related, whereas the gastrointestinal events were mostly of grade 1-2.

Efficacy of Frontline Treatment with Initial Low-Dose Tyrosine-Kinase Inhibitors in Elderly Patients with Chronic Myeloid Leukemia: A “Campus CML” Study

Introduction Three TKIs, imatinib (IM), dasatinib (DAS) and nilotinib (NIL), are approved for frontline therapy in Italy. Choice of frontline TKI is based mainly on evaluation of patient's characteristics and clinical expectations. To avoid long term adverse events or potential drug interactions, elderly patients may start CML treatment with a frontline reduced dose of TKI (RD-TKI). Aim To analyse outcome of CP-CML patients aged over 65 years in a large and unselected cohort treated with RD-TKI. Methods We retrospectively evaluated 747 patients from 1/2012 to 12/2019 at 36 Hematology Centres participating at the “Campus CML” project. Results Clinical features for the whole cohort according to frontline TKI initial dose are reported in Table 1. Among all patients, 605 (81%) were treated with standard dose (SD) while the remaining 142 (19%) with reduced dose (RD). As to frontline TKI, 579 patients (77%) received IM and 158 (23%) a 2G-TKI (DAS n=78, 49%; NIL n=80, 51%). Of the 142 RD-TKI, 122 (85.9%) started with IM, 14 (9.9%) with DAS and 6 (4.2%) with NIL. Median RD was 100 mg for IM (range 100-300), 20 mg for DAS (range 20-50) and 250 mg for NIL (range 150-300). RD-TKI was mainly reported in IM treated patients (p=0.018), in elderly (p<0.001) and in patients with comorbidities, in particular diabetes (p=0.005) and ischemic heart disease (p=0.039). Number of concomitant drugs was also significantly associated with RD-TKI (p<0.001) probably to avoid drug interactions and subsequent toxicity. In detail, among RD-TKI, 41.1% of patients was treated with more than five concomitant drugs. Sokal score did not impact on TKI starting dose. No differences emerged between SD-TKI and RD-TKI in terms of haematological or extra-haematological toxicity. TKI frontline dose was not associated with difference in resistance, nor primary neither secondary resistance. Progression to blastic phase was reported in 1.2% of the whole population, none of which in RD-TKI. At 12 months no differences were noted in terms of achievement of major molecular response (MMR), obtained in 22.4% of SD-TKI treated patients and in 19% of RD-TKI treated patients. RD-TKI had inferior probability of deep molecular response (DMR) achievement (p=0.003), reported in 12.6% of patients. No differences were reported in 12-months cumulative rate of permanent discontinuation for any cause and for primary resistance between SD-TKI and RD-TKI as reported in Figure 1. Conclusions RD-TKI was a frontline treatment strategy used mainly in frail elderly patients, with more comorbidities and concomitant therapies. RD-TKI did not impact on primary resistance leading to TKI switch. While no differences were reported in the rate of MMR, the rate of 12-months DMR achievement was inferior in RD-TKI, but this result need to be confirmed with longer follow-up.

Treatment-Free Remission Era: BCR-ABL1 mRNA Transcript Level

Background: Early acquisition of a deeper molecular response (DMR) and maintenance of a sustained DMR are prerequisites for implementing treatment-free remission (TFR) in CML patients. Earlier identification of patients who have not reached 24-month DMR and timely intervention is particularly important for patients with a strong desire for TFR. Early molecular response (EMR) of BCR-ABL1 mRNA <10% at 3 months after the initiation of TKI therapy is strongly predictive of a 12-month major molecular response (MMR). Whether the EMR <10% is also a good predictor of the 24-month DMR is unknown. Exploring early predictors of 24-month DMR could help guide clinical treatment decisions and advance the implementation of the TFR plan. Aim: Exploring early predictors of 24-month DMR. Methods: We performed a retrospective analysis of all adult patients with newly diagnosed CML-CP in the Department of Hematology at Guangdong Provincial People's Hospital (Guangzhou, China) between Mar 2009 and May 2019. Patients were monitored with BCR-ABL1 mRNA quantitative RT-PCR monthly for the first 3 months of TKI treatment, then every 3 months for a minimum of 2 years, and then every 3 to 6 months. Results: A total of 314 patients with complete medical recorders and routinely monitoring BCR-ABL1 mRNA transcript data of each molecular response milestone were enrolled. Patients' characteristics are summarized in Table 1. The median follow-up time was 54 months (14 to 146 months). The 5-year cumulative rate of MMR, MR 4 and MR 4.5 with TKI treatment were 80%, 48.1%, and 38.4%, respectively. The results of the ROC analysis showed that a 3-month BCR-ABL1 mRNA transcript level of 4.94% correlated well with the 24-month DMR. The sensitivity and specificity of its predictive function were 82.8% (95% CI, 73.6-89.8) and 66.97% (95% CI, 60.3-73.1), respectively. So, we adopted BCR-ABL1 mRNA transcript level ≤4.94% at 3 months as the optimal threshold for predicting 24-month DMR. To reveal the cumulative incidence (CI) of 12-month MMR, 24-month MR 4 and MR 4.5 at different thresholds of BCR-ABL1 mRNA transcript levels at 3 months. Patients were divided into 3 groups according to the BCR-ABL1 mRNA transcript levels, group I <5% (n=150, 47.7%), group II 5% to 10% (n=36, 11.5%), group III >10% (n=128, 40.8%). Patients with BCR-ABL1 mRNA transcript levels <5% at 3 months after TKI initiation are more likely to achieve DMR than the other two groups and take less time to achieve DMR. Patients of Group I with 12-month MMR and 24-month MR 4 were significantly higher than the other two groups, with 66.7% vs 30.6% or 8.6% and 50% vs 16.1% or 7% (P<0.001), respectively. And group II was compared with group III. The cumulative incidence of MMR, MR 4 and MR 4.5 was also significantly higher in Group I than in the other two groups (Fig.1). The survival outcome of patients with BCR-ABL1 transcript levels <5% at 3 months had significantly superior compared with those with BCR-ABL1 transcript levels ≥5%: the 5-year EFS， PFS and OS were 88.6% vs 86.4% (P=0.037), 100% vs 95.7% (P=0.011) and 100% vs 95% (P=0.014)， respectively (Fig. 1). Conclusion: BCR-ABL1 mRNA transcript levels <5% at 3 months is a new landmark EMR (EMR <5%) which can predict 24-month DMR for patients with TKI treatment. EMR <5% may be used to guide the clinical timely switching of TKI or treatment and facilitate the implementation of TFR.

Sustained Efficacy and Safety with Asciminib (ASC) after Almost 4 Years of Median Follow-up from Ascembl, a Phase 3 Study of ASC Vs Bosutinib (BOS) in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) after ≥2 Prior Tyrosine Kinase Inhibitors (TKIs): An End of Study Treatment (EOS Tx) Update, Including Results from Switch Population

CONCLUSIONS CML requires chronic therapy, emphasizing the need for Txs that are characterized by high, durable efficacy and a low adverse event (AE) burden. ASC, the first BCR::ABL1 inhibitor Specifically Targeting the ABL Myristoyl Pocket (STAMP), demonstrated significantly superior efficacy and better safety/tolerability compared with BOS in pts with CML-CP who received ≥2 prior TKIs in the phase 3 ASCEMBL study. Major molecular response (MMR) rate was 25.5% with ASC vs 13.2% with BOS at wk 24, meeting the primary objective, and 37.6% vs 15.8% at wk 96, meeting the key secondary objective. Despite the longer duration of exposure to ASC, safety/tolerability remained consistently better with ASC vs BOS, with fewer all-grade and grade ≥3 AEs and AEs leading to Tx discontinuation observed. After a median follow-up of 3.7 y, we report EOS Tx results from ASCEMBL (cutoff: March 22, 2023). We also report the first available data from pts who experienced Tx failure on BOS and switched to ASC. Adults (aged ≥18 y) with CML-CP after ≥2 prior TKIs, with intolerance or lack of efficacy per 2013 ELN recommendations were randomized 2:1 to receive either ASC 40 mg twice daily or BOS 500 mg once daily. Pts who met Tx failure criteria per 2013 ELN while on BOS could switch to ASC and were analyzed separately. Pts who discontinued BOS due to intolerance could not switch. EOS will occur 5 y from when the last enrolled pt received first Tx dose. A total of 233 pts were randomized to ASC (n=157) or BOS (n=76). The most common reason for discontinuation was lack of efficacy in 40 (25.5%) pts on ASC and 28 (36.8%) on BOS. At the time of EOS Tx cutoff, Tx with ASC and BOS was ongoing in 77 (49.4%) and 8 (10.5%) pts, respectively; pts deriving benefit from study Tx at EOS TX, per investigator assessment, continued receiving posttrial access. MMR rate at wk 156 continued to be higher with ASC (33.8%) than with BOS (10.5%) (Figure 1). The difference after adjusting for baseline (BL) major cytogenetic response was 23.2%(95% CI, 13.1%-33.2%; 2-sided P<.001). The BCR::ABL1IS ≤1% rate at wk 156 in pts without this level of response at BL also continued to be higher with ASC (43.0%) than with BOS (11.1%). Despite the longer median duration (range) of exposure to ASC (156.0 [0.1-256.3] wk) vs BOS (30.5 [1.0-239.3] wk), safety/tolerability of ASC continued to be better compared with BOS and were consistent with previous analyses. Two new pts had AEs leading to Tx discontinuation since the wk 96 cutoff (1 pt on ASC reported pregnancy; 1 pt on BOS reported diarrhea), and rates remained lower with ASC vs BOS (8.3% vs 27.6%). The most frequent (≥10%) grade ≥3 AEs with ASC vs BOS were thrombocytopenia (22.4% vs 9.2%), neutropenia (18.6% vs 14.5%), diarrhea (0% vs 10.5%), and increased alanine aminotransferase (0.6% vs 14.5%). Most AEs occurred within the first 6 months (Figure 2). Exposure-adjusted incidence rates of arterial occlusive events (AOEs) with ASC decreased since the wk 96 cutoff, from 3.0 to 2.2 per 100 pt-y, and no new AOEs occurred with ASC, indicating that the risk of AOEs did not increase over time. Among pts who discontinued Tx due to lack of efficacy or disease progression, no new mutations occurred since the wk 96 cutoff. Of 28 pts who discontinued BOS for lack of efficacy, 25 switched to ASC. Almost all switch pts (96%) had BL BCR::ABL1IS >10% prior to switch. No switch pts achieved MMR at or by wk 48 post switch. However, at wk 48, 24% achieved BCR::ABL1IS ≤10% and 8% achieved BCR::ABL1IS ≤1%. The safety profile of ASC in switch pts was consistent with that in pts receiving ASC in the randomized period. Most frequent (≥10%) grade ≥3 AEs were neutropenia (32.0%) and thrombocytopenia (24.0%). AEs leading to Tx discontinuation occurred in 8.0% of switch pts. With almost 4 y of follow-up in ASCEMBL, ASC continued to show greater efficacy and better safety/tolerability than BOS in pts with CML-CP after ≥2 prior TKIs. The robust safety profile of ASC was sustained through each analysis in ASCEMBL (wk 24, wk 96, and EOS Tx), confirming that pts receiving ASC can maintain a high level of response and continue Tx without experiencing late-emerging AEs. Results in the switch population support the use of ASC early in the Tx paradigm. ASCEMBL EOS Tx results continue to strongly support ASC as the therapy of choice for pts with suboptimal responses and/or intolerance to ≥2 prior TKIs, allowing more pts to remain on Tx and achieve their Tx goals without needing to switch.

ASC4START and ASC4FIRST: Two Ongoing Phase 3 Trials Investigating Asciminib Monotherapy As First-Line Therapy Versus Tyrosine Kinase Inhibitors in Patients with Newly Diagnosed Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic Phase

Background: The current standard of care (SoC) for newly diagnosed patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) is treatment with 1 of the 4 tyrosine kinase inhibitors (TKIs) approved for this use (first generation [1G] imatinib [IMA] and second generation [2G] bosutinib [BOS], dasatinib [DAS], and nilotinib [NIL]). Although TKIs have vastly improved treatment outcomes, pts with newly diagnosed CML-CP experience lack of efficacy and intolerance to available treatments. A large number of pts treated with IMA do not achieve major molecular response (MMR) and even fewer pts achieve deep molecular response, a key requirement to attempt treatment-free remission. Treatment with 2G TKIs results in larger proportions of pts achieving deep responses albeit still with a sizeable minority not reaching this goal. Also, many pts are intolerant to 2G TKIs, resulting in therapy switching, frequently multiple times. For pts who remain on treatment, even low-grade adverse events (AEs) may significantly impact quality of life (QoL) given the long-term nature of treatment. Improved treatments with high efficacy and improved tolerability are needed to limit therapy switching, reduce treatment discontinuation, maintain, or improve pt QoL, and allow pts to remain on treatment at an optimal dose for longer duration to achieve deep responses. Asciminib is the first and only approved BCR::ABL1 inhibitor that works by specifically targeting the ABL myristoyl pocket (STAMP). This unique mechanism of action (MoA) has no confirmed overlapping mutation-driven resistance profile with ATP-competitive TKIs. Asciminib shows better selectivity compared to other TKIs, with no known off-target kinase-mediated effects due to its MoA; this translates into improved tolerability. In clinical trials (Hughes et al. N Engl J Med. 2019; Rea et al. Blood 2021), asciminib has demonstrated sustained efficacy and a favorable safety profile over time in pts with Philadelphia chromosome positive (Ph+) CML-CP previously treated with ≥2 TKIs as well as in pts with T315I mutation. Asciminib as monotherapy and in combination with ATP-competitive TKIs is being studied as first-line (1L) treatment in CML. The ongoing ASC4FIRST (NCT04971226) study is investigating the efficacy and safety of asciminib 80 mg once daily (QD) monotherapy vs investigator-selected 1G or 2G TKI in adults with newly diagnosed Ph+ CML-CP ( Table 1). The primary endpoint of ASC4FIRST is MMR rate at 48 weeks. The ongoing ASC4START (NCT05456191) study is focused on pt-centric objectives, assessing the tolerability and efficacy of asciminib vs 2G TKI NIL in adults with newly diagnosed Ph+ CML-CP. The primary endpoint of ASC4START is time to treatment discontinuation due to an AE ( Table 1). Current Status: As of December 20, 2022, the ASC4FIRST study completed recruitment, with 405 pts enrolled worldwide. The end of study (EOS) will occur 5 years from the last pt first treatment in the study. Pts will continue to receive the assigned treatment until the EOS, or until premature discontinuation due to treatment failure, disease progression or intolerance, or due to investigator or participant decision. Between 21 November 2022 and 25 July 2023, 180 pts have been screened for the ASC4START study, with 147 pts randomized to treatment (n=52 France, n=40 Germany, n=9 Bulgaria, n=7 Czechia, n=7 Hungary, n=6 Korea, n=6 Singapore, n=2 Slovakia, n=5 Argentina, n=3 Greece, n=2 each from Slovakia, Malaysia, and Oman, and n=1 each from the USA, Italy, Romania, UK, Jordan, and Canada). Recruitment is ongoing. Patients will be treated until approximately 64 discontinuations of either study treatment due to an AE have been recorded. Conclusions: With demonstrated efficacy and improved tolerability compared to ATP-binding TKIs, asciminib has the potential to become the therapy of choice for CML in 1L, enabling newly diagnosed patients to remain on therapy with improved QoL and overall survival, and reducing the need for therapy switching, ultimately allowing patients to achieve optimal milestone responses and reach treatment goals. Findings from these two trials will provide comprehensive evidenceon the use of asciminib as 1L therapy for newly diagnosed pts with Ph+ CML-CP.

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.

Asciminib (ASC) Once-Daily (QD) Dosing Demonstrates Comparable Tolerability and Efficacy to Twice-Daily (BID) Dosing: Results from the ASC in Monotherapy 4 CML (AIM4CML) Study in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

CONCLUSIONS ASC is the only approved BCR::ABL1 inhibitor that Specifically Targets the ABL1 Myristoyl Pocket, distinguishing it from other approved treatments that target the ATP binding site. In the phase III ASCEMBL trial (NCT03106779) ASC 40 mg BID was well tolerated and demonstrated superior efficacy vs bosutinib 500 mg QD in pts previously treated with ≥2 TKIs, with major molecular response (MMR; BCR::ABL1IS ≤0.1%) rates of 25.5% vs 13.2% at wk 24 and 37.6% vs 15.8% at wk 96. We present an interim analysis of the primary endpoint of the AIM4CML trial (NCT04666259), which was initiated to assess the safety, efficacy, and QD dosing of ASC in a similar population of pts with CML-CP. This is a multicenter, phase IIIb, open-label study of ASC in pts with CML-CP without the T315I mutation after ≥2 prior TKIs and pts with the T315I mutation after ≥1 prior TKI. Adults aged ≥18 years with CML-CP who had treatment failure with or intolerance of the most recent TKI were eligible. Pts without the T315I mutation were randomized to receive ASC 40 mg BID (cohort A) or 80 mg QD (cohort B). Results for pts with the T315I mutation who received ASC 200 mg BID (cohort C) will not be presented for this analysis. The primary endpoints include adverse events (AEs) and serious AEs by wk 24 in cohorts A and B, with additional safety and efficacy secondary endpoints. This study was not powered to detect statistical differences between cohorts. End of study is when the last pt completes 72 wks of treatment or discontinues prematurely. The numbers of enrolled pts in cohorts A, B, and C were 26, 27, and 3, respectively. This interim analysis included 42 pts randomized to cohort A (n=22) or cohort B (n=20), who reached 24 wks after cycle 1 day 1 of treatment by February 17, 2023. Most baseline characteristics in cohorts A and B were comparable, but median time since initial diagnosis and median baseline BCR::ABL1IS levels were longer and higher, respectively in cohort B (Table). Median duration of exposure was 23.1 (range, 2.7-72.3) wks in cohort A and 24.1 (range, 1.3-71.0) wks in cohort B. Prior to wk 24, treatment was discontinued in 7 and 4 pts in cohorts A and B, respectively. Reasons for discontinuation included physician decision (cohort A, n=4; cohort B, n=2), AEs (cohort A, n=2; cohort B, n=1), or pt decision (cohort A, n=1; cohort B, n=1). At the time of this interim analysis, discontinuation due to treatment failure was reported only in cohort B in 2 pts that discontinued due to physician decision. Cohorts A and B had comparable all-grade, grade 3, and grade 4 AEs. Treatment-emergent all-grade AEs occurring in ≥20% in cohorts A and B were fatigue (32% and 25%), headache (27% and 20%), abdominal pain (27% and 15%), rash (23% and 5%), dyspnea (23% and 10%), nausea (14% and 30%), hypertension (14% and 20%), cough (18% and 20%), and arthralgia (9% and 20%). While many pts had AEs requiring additional therapy, few had serious AEs, and similar numbers of pts in cohorts A and B had AEs leading to dose adjustments/interruptions and treatment discontinuation (Figure). One pt in cohort B had a fatal AE due to sepsis that was not attributed to study treatment. This trial is ongoing; data for the wk 24 primary endpoint for all enrolled pts will be available at the time of presentation. Pts with ≥1 molecular response assessment by wks 4, 12, and 24 were 18, 19, and 20 in cohort A, respectively, and 17, 17, and 18 in cohort B, respectively. The proportions of pts who maintained or achieved BCR::ABL1IS ≤1% by wks 4, 12, and 24 were higher in cohort B with 52.9%, 76.5%, and 88.9%, respectively than in cohort A with 50.0%, 63.2%, and 65.0%, respectively, likely due to higher baseline BCR::ABL1IS levels in cohort B (Table). MMR rates by wks 4, 12, and 24 were 33.3%, 42.1%, and 45.0% in cohort A and 23.5%, 47.1%, and 61.1% in cohort B, respectively. Deep molecular response (MR 4; BCR::ABL1IS ≤0.01%) rates by wks 4, 12, and 24 were 27.8%, 31.6%, and 30.0% in cohort A and 5.9%, 11.8%, and 27.8% in cohort B, respectively. This interim analysis of the AIM4CML trial further demonstrates the tolerability and efficacy of ASC and is among the first clinical reports on QD dosing of ASC in pts with CML-CP. Safety was comparable between the 80-mg QD and 40-mg BID doses, with both demonstrating safety profiles consistent with prior reports. Pts receiving ASC at both doses achieved and maintained molecular responses, which deepened over time. These results support the flexibility of QD dosing with ASC.

With up to 8 Years of Therapy, Asciminib (ASC) Monotherapy Demonstrated Continued Favorable Efficacy, Safety, and Tolerability in Patients (Pts) with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic Phase (Ph+ CML-CP) without the T315I Mutation: Final Results from the Phase 1 X2101 Study

CONCLUSIONS Tyrosine kinase inhibitors (TKIs) have extended the life expectancy for pts with CML, approximating that of the general population, and established BCR::ABL1-targeted therapies as the standard of care for CML. However, multi-TKI resistance and intolerance remain challenges that may lead to treatment (Tx) discontinuation. ASC is the first and only approved BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP) with higher selectivity for ABL, reducing off-target effects seen with TKIs. A follow-up analysis (median exposure: 4.2 y) of the phase 1 ASC study in pts with CML-CP without T315I after receiving ≥2 TKIs demonstrated durable efficacy and favorable tolerability, with nearly one-third of pts achieving deep molecular response by cutoff (Jan 6, 2021). Here we present final end-of-study (EOS) efficacy and safety results from the phase 1 ASC study in pts with CML-CP without the T315I mutation (cutoff: Mar 14, 2023). This analysis included adults with Ph+ CML-CP without the T315I mutation and an ECOG performance status of 0-2 who had relapsed disease or were refractory to or intolerant of ≥2 prior TKIs. Pts received ASC monotherapy at starting doses of 10-200 mg twice daily (BID) or 80-200 mg once daily (QD). The study started with dose escalation to estimate the maximum tolerated dose (MTD), followed by expansion to establish safety and tolerability of ASC. Dose adjustments were allowed if pts did not tolerate the dosing schedule. The EOS was declared when all pts completed ≥64 wks within the study or discontinued Tx; pts continuing to receive ASC at the EOS were provided continued access to ASC. A total of 115 pts were enrolled between Apr 2014 and Mar 2023. Across all starting doses, the median exposure duration was 5.9 y, with a maximum exposure of 8.4 y; 112 pts (97.4%) had received ≥2 prior TKIs and 82 (71.3%) had received ≥3 prior TKIs. By data cutoff, 70 pts (60.9%) who completed the study on ASC were provided continued access to ASC. Among 45 pts who ended Tx early, 15 (13.0%) and 8 (7.0%) ended due to adverse events (AEs) and disease progression, respectively. Efficacy of ASC at EOS was sustained and consistent with previous reports, with the majority of pts (65.1%) achieving major molecular response (MMR) by the cutoff. While most responses were observed by wk 48, cumulative MMR rates continued to increase up to wk 144 (Figure 1). The median time to MMR (range) was 58.3 (2-360) wks among pts who achieved MMR but were not in MMR at screening. Among the 56 pts who achieved MMR, 50 maintained or improved the response up to data cutoff. At wks 24, 48, and 96, respectively, 18.9%, 17.9%, and 23.6% of pts achieved MR 4 and 13.2%, 15.1%, and 18.9% achieved MR 4.5. Safety and tolerability of ASC improved with longer durations of exposure. The most frequent all-grade AEs included arthralgia (40.9%), increased lipase (39.1%), fatigue (38.3%), and headache (38.3%), and only 13.0% of pts experienced AEs leading to Tx discontinuation. Even with longer durations of Tx, AEs were less likely to occur after the first year on ASC (Figure 2). The safety and tolerability of ASC remained consistent with prior analyses; there were no new or worsening safety issues compared with those already known for ASC and no new on-Tx deaths. The MTD of ASC was not reached. Based on safety, tolerability, efficacy, and pharmacokinetic data, ASC 40 mg BID was selected as the recommended dose for expansion in adults with CML-CP without the T315I mutation. In this final analysis of the phase 1 ASC trial in pts with CML-CP without the T315I mutation, ASC continued to show favorable efficacy and sustained safety and tolerability over a median exposure duration of 5.9 y, with a maximum exposure of 8.4 y. Pts achieved high rates of MMR with nearly one-fourth of pts achieving deep molecular responses at wk 96, demonstrating durable efficacy of ASC over time. Even with longer exposures, the risk of AEs did not increase and there were no new or worsening safety issues. With ASC, most AEs occurred early, and no new late-emerging safety issues were seen, supporting ASC as a safe and tolerable long-term Tx, highly clinically relevant in the management of resistant/intolerant CML-CP. Based on results from this and the ASCEMBL study, 40 mg BID and 80 mg QD have since been approved for use in this pt population.

ASC4KIDS: A Multicenter, Open-Label, Phase Ib/II Study to Determine the Dose and Safety of Asciminib in Pediatric Patients with Chronic Myeloid Leukemia in the Chronic Phase

Background Tyrosine kinase inhibitors (TKIs) are the standard of care for adult and pediatric patients with chronic myeloid leukemia in the chronic phase (CML-CP). More treatment options with improved efficacy and safety profiles are needed for pediatric patients. Asciminib is a first-in-class allosteric inhibitor of ABL (non-receptor tyrosine) kinases, specifically targeting the ABL myristoyl pocket (STAMP), and does not inhibit other protein kinases. Asciminib was approved by the US Food and Drug Administration (FDA) with subsequent approvals worldwide for patients aged ≥18 years with Philadelphia chromosome-positive (Ph+) CML-CP treated with ≥2 prior TKIs in October 2021. Asciminib 40 mg twice daily (bid) has demonstrated improved major molecular response rates (25.5% vs 13.2% at week 24) and a favorable safety profile compared with bosutinib 500 mg once daily (qd) in adult patients with Ph+ CML-CP in the phase 3 ASCEMBL study (NCT03106779). This study aims to characterize the pharmacokinetics (PK), long-term safety profile, and antileukemic effects of asciminib in pediatric patients and identify a pediatric formulation dose that will lead to asciminib exposure comparable to 80 mg qd or 40 mg bid in adult patients. Methods This multicenter, open-label study (NCT04925479) includes patients aged 1 to <18 years with Ph+ CML-CP, without a BCR::ABL1 T315I mutation, treated with ≥1 prior TKI. For the pediatric formulation group, at least 15 patients will be included in each of the two age groups (1 to <12 years and 12 to <18 years), consisting of Part 1, 2 and 3. The study started with an exploratory adult formulation group of Adolescent patients (aged 14 to <18 years, body weight ≥40 kg) treated with the adult formulation dose (40 mg bid or 80 mg qd tablet) under fasting conditions. The primary endpoint includes PK parameters; secondary endpoints include: hematologic and molecular responses, safety, and acceptability/palatability of the pediatric formulations. Part 1 (dose-determining cohort): 4 to 6 patients will receive the asciminib pediatric formulation bid (a mini-tablet of 1.3 mg/kg with food) to assess safety, and to assess if the exposure in pediatric patients is comparable to exposure with the adult formulation over the first 28 days (patients either from pediatric or adult categories). After the interim analysis, if a dose adjustment is required, an additional 4 to 6 patients will be assessed at an adjusted dose. Part 2 (expansion cohort, 40 mg bid regimen): 14 to 16 patients will receive the dose determined in part 1. The second interim PK and safety analysis will be conducted after all patients from parts 1 and 2 complete 28 days of treatment. Part 3 (expansion cohort, 80 mg qd regimen): 10 patients (5 from each age group) will receive the same total daily dose of asciminib qd. The PK, safety profile, and pharmacodynamic endpoints will be assessed for the bid regimen after all patients in parts 1 and 2 complete 52 weeks of treatment. The primary analysis for the combined bid and qd regimen will be performed after all patients complete 52 weeks of treatment (total treatment period: 5 years [ Figure]). A final analysis will be performed after all patients complete treatment. Patients who discontinue treatment early will be followed up for survival until the end of the study. There are 32 study sites open out of planned 35 study sites in 14 countries worldwide. The exploratory and the pediatric formulation groups recruited 4 patients and 9 patients, respectively, as of June 07, 2023, with a total of 13 patients in the study. The study is still recruiting. This study will determine a pediatric dose for asciminib and support a strategy of full extrapolation from adult data to use in the pediatric patients with CML-CP.

Real-World Effectiveness of Dasatinib Versus Imatinib in Newly Diagnosed Patients With Chronic Myeloid Leukemia

IntroductionLimited data exist comparing dasatinib with imatinib in clinical practice. This study assessed real-world outcomes associated with first-line (1L) dasatinib or imatinib treatment of chronic myeloid leukemia (CML). Patients and MethodsThis retrospective, observational, United States multisite cohort study analyzed electronic medical record data from adults with Philadelphia chromosome-positive (Ph+) CML in the chronic phase (CML-CP) after 1L dasatinib or imatinib between January 2014 and September 2018. Rates of and times to major molecular response (MMR) and deep molecular response (DMR) were assessed overall and in subgroups (low vs. intermediate/high risk, aged <65 vs. ≥65 years, low/normal vs. high body mass index [BMI]). ResultsThe dasatinib cohort (n = 309) experienced higher rates of MMR (n = 304, 79% vs. 65%, P < .001) and DMR (44% vs. 25%, P < .001) vs. the imatinib cohort with shorter median times to MMR (11.9 vs. 14.7 months, P < .001) and DMR (30.3 vs. 66.1 months, P < .001). Patients with intermediate-/high-risk disease and those aged <65 years had higher MMR and DMR rates and achieved response earlier with dasatinib (P < .01). Patients with low-risk disease treated with dasatinib had higher rates of DMR (60% vs. 32%, P = .01). Across BMI strata, rates of MMR and DMR were higher with dasatinib (P < .05). ConclusionsPatients with CML-CP treated with 1L dasatinib achieved higher rates of, with shorter times to, MMR and DMR versus 1L imatinib. These clinically meaningful improvements were observed across subgroups.

The long-term efficacy and safety of nilotinib in pediatric patients with CML: a 5-year update of the DIALOG study

AbstractThe efficacy and safety of nilotinib in pediatric patients with imatinib/dasatinib resistant/intolerant (R/I) or newly diagnosed (ND) Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) was demonstrated in the phase 2, open-label DIALOG study. In this final analysis, long-term efficacy and safety are presented for patients who completed 66 cycles (of 28 days) of treatment with nilotinib (230 mg/m2 twice daily) or discontinued early. Overall, 59 patients were enrolled and 58 were treated (R/I, n = 33; ND, n = 25; median time on treatment: 60.5 and 51.9 months, respectively). In the R/I cohort, the cumulative major molecular response (MMR; BCR::ABL1 international scale [IS] ≤ 0.1%) rate was 60.6%, and no patients had a confirmed loss of MMR. Among ND patients, the best overall MMR rate was 76.0%; 3 patients had a confirmed loss of MMR. The cumulative molecular response MR4 (BCR::ABL1IS ≤ 0.01%) and MR4.5 (BCR::ABL1IS ≤ 0.0032%) rates by 66 cycles were 27.3% and 12.1% in the R/I cohort, and 56.0% and 44.0% in the ND cohort, respectively. The safety profile of nilotinib was consistent with those of earlier reports. No on-treatment deaths occurred. These long-term (up to ∼5 years) data support the efficacy and safety of nilotinib in pediatric patients with Ph+ CML-CP. This trial was registered at www.clinicaltrials.gov.uk as #NCT01844765.

Adverse outcomes for chronic myeloid leukemia patients with splenomegaly and low in vivo kinase inhibition on imatinib

Variability in the molecular response to frontline tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia may be partially driven by differences in the level of kinase inhibition induced. We measured in vivo BCR::ABL1 kinase inhibition (IVKI) in circulating mononuclear cells after 7 days of therapy. In 173 patients on imatinib 600 mg/day, 23% had low IVKI (<11% reduction in kinase activity from baseline); this was associated with higher rates of early molecular response (EMR) failure; lower rates of major molecular response (MMR), and MR4.5 by 36 months, compared to high IVKI patients. Low IVKI was more common (39%) in patients with large spleens (≥10 cm by palpation). Notably 55% of patients with large spleens and low IVKI experienced EMR failure whereas the EMR failure rate in patients with large spleens and high IVKI was only 12% (p = 0.014). Furthermore, patients with large spleen and low IVKI had a higher incidence of blast crisis, inferior MMR, MR4.5, and event-free survival compared to patients with large spleen and high IVKI and remaining patients. In nilotinib-treated patients (n = 73), only 4% had low IVKI. The combination of low IVKI and large spleen is associated with markedly inferior outcomes and interventions in this setting warrant further studies.

Adherence to tyrosine kinase inhibitor and clinical outcomes in patients with chronic myeloid leukemia

PurposeTo ensure optimal care for patients with chronic myeloid leukemia (CML), adherence to tyrosine kinase inhibitors (TKIs) has emerged as a critical component. The objective of this study was to assess the impact of TKIs adherence on clinical outcomes in a cohort of Chinese CML patients who received treatment with TKIs. MethodsThis retrospective study employed a cross-sectional design utilizing questionnaires to assess adherence to TKIs in a sample of 398 patients diagnosed with CML. Adherence was measured using the Morisky Medication Adherence Scale (MMAS-8), which dichotomizes patients into low, medium, and high adherence groups. ResultsOf the patients included in this study, 34.2% were classified as highly adherent, with 43.2% and 22.6% of patients categorized as having medium and low adherence, respectively. Compared to the low-adherence group, patients in the medium- and high-adherence groups exhibited significantly higher rates of achieving major molecular response (MMR) and lower rates of switching TKIs. Moreover, patients who failed to adhere to TKIs treatment demonstrated significantly lower event-free survival and failure-free survival compared to those in the high-adherence group. Notably, regular molecular monitoring and utilization of the “CML Academy” mobile application were positively associated with increased TKI adherence. On the other hand, patients receiving third-generation or above first-line TKIs treatment displayed reduced adherence. ConclusionThe findings suggest that high adherence to TKIs treatment confers clinical benefits to patients with CML. Accordingly, the implementation of effective guidance and intervention measures aimed at promoting adherence to TKIs therapy in real-world settings is imperative.

Canadian real-world experience of asciminib treatment in heavily pre-treated chronic myeloid leukemia (CML) patients who failed multiple lines of tyrosine kinase inhibitor (TKI) therapy

BackgroundAsciminib is a novel drug specifically targeting ABL myristoyl pocket in the ABL1 protein. MethodsForty one patients with chronic myeloid leukemia treated with asciminib from 2018 to 2022 were reviewed and analyzed for the efficacy and tolerability of asciminib using real-world experience data. ResultsThe median age was 60 years (range 17–90) with a past history of a cardiovascular event in 21 patients (51%). Patients were pretreated with a median of 3 previous tyrosine kinase inhibitors (range 1–5). After a median of 12 months of asciminib (range 3–41), major molecular response (MMR) rate was 39% (n = 11/28) and 42% (n = 5/12) at 6 and 12 months, respectively. Molecular response with 2 log reduction (MR2) was noted in 54% (n = 15/28) and 50% (n = 6/12) at 6 and 12 months. The cumulative incidence of MMR and MR2 was 46.3% and 66% at 12 months.Five patients discontinued asciminib due to treatment failure (n = 3) or thrombocytopenia (n = 2). There were no cardiovascular events. Out of 7 patients treated with high dose asciminib for T315I mutation, 5 patients achieved MMR or deeper response. The event-free survival was 63% at 12 months. ConclusionThis study confirmed clinical efficacy and tolerability of asciminib with real-world experience.

The EMA Assessment of Asciminib for the Treatment of Adult Patients With Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic Phase Who Were Previously Treated With At Least 2 Tyrosine Kinase Inhibitors.

Asciminib is an allosteric high-affinity tyrosine kinase inhibitor (TKI) of the BCR-ABL1 protein kinase. This kinase is translated from the Philadelphia chromosome in chronic myeloid leukemia (CML). Marketing authorization for asciminib was granted on August 25, 2022 by the European Commission. The approved indication was for patients with Philadelphia chromosome-positive CML in the chronic phase which have previously been treated with at least 2 TKIs. Clinical efficacy and safety of asciminib were evaluated in the open-label, randomized, phase III ASCEMBL study. The primary endpoint of this trial was major molecular response (MMR) rate at 24 weeks. A significant difference in MRR rate was shown between the asciminib treated population and the bosutinib control group (25.5% vs. 13.2%, respectively, P = .029). In the asciminib cohort, adverse reactions of at least grade 3 with an incidence ≥ 5% were thrombocytopenia, neutropenia, increased pancreatic enzymes, hypertension, and anemia. The aim of this article is to summarize the scientific review of the application which led to the positive opinion by the European Medicines Agency's Committee for Medicinal Products for Human Use.

Asciminib: the first-in-class allosteric inhibitor of BCR::ABL1 kinase.

The prognosis of patients with chronic phase (CP) chronic myeloid leukemia (CML) has significantly improved due to the development of potent BCR::ABL1 tyrosine kinase inhibitors (TKIs). However, approximately 15‒20% of patients ultimately experience treatment failure due to resistance or intolerance to TKI therapy. As the prognosis of patients in whom multiple TKIs fail remains poor, an optimal therapeutic approach is required to treat the condition. Asciminib, an allosteric inhibitor that targets ABL1 myristoyl pocket, has been approved by the Food and Drug Administration for use in patients with CP-CML resistant or intolerant to ≥2 prior TKIs or those with T315I mutation. In a phase 1 trial, asciminib monotherapy showed a relatively favorable safety profile and potent efficacy in patients with and without the T315I mutation. In a subsequent phase 3 trial, asciminib treatment was associated with a significantly higher major molecular response rate and lower discontinuation rate than bosutinib in patients with CP-CML for whom two previous TKIs failed. Several clinical trials are being performed in various clinical settings to evaluate the role of asciminib as a frontline treatment for newly diagnosed CP-CML, either as a single agent or in combination with other TKIs as a second-line or additive treatment to improve treatment-free or deep remission. This review summarizes the incidence, available therapies, and outcomes of patients with CP-CML who experienced treatment failure, the mechanism of action, preclinical and clinical data, and ongoing trials for asciminib.

Asciminib vs bosutinib in chronic-phase chronic myeloid leukemia previously treated with at least two tyrosine kinase inhibitors: longer-term follow-up of ASCEMBL

Asciminib, the first BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP), is approved worldwide for the treatment of adults with Philadelphia chromosome–positive chronic myeloid leukemia in chronic phase (CML-CP) treated with ≥2 prior tyrosine kinase inhibitors (TKIs). In ASCEMBL, patients with CML-CP treated with ≥2 prior TKIs were randomized (stratified by baseline major cytogenetic response [MCyR]) 2:1 to asciminib 40 mg twice daily or bosutinib 500 mg once daily. Consistent with previously published primary analysis results, after a median follow-up of 2.3 years, asciminib continued to demonstrate superior efficacy and better safety and tolerability than bosutinib. The major molecular response (MMR) rate at week 96 (key secondary endpoint) was 37.6% with asciminib vs 15.8% with bosutinib; the MMR rate difference between the arms, after adjusting for baseline MCyR, was 21.7% (95% CI, 10.53–32.95; two-sided p = 0.001). Fewer grade ≥3 adverse events (AEs) (56.4% vs 68.4%) and AEs leading to treatment discontinuation (7.7% vs 26.3%) occurred with asciminib than with bosutinib. A higher proportion of patients on asciminib than bosutinib remained on treatment and continued to derive benefit over time, supporting asciminib as a standard of care for patients with CML-CP previously treated with ≥2 TKIs.

Therapy for patients with chronic phase-chronic myeloid leukemia previously treated with ⩾2 tyrosine kinase inhibitors: a systematic literature review.

ATP-competitive tyrosine kinase inhibitors (TKIs) are the current standard of care for patients with chronic phase-chronic myeloid leukemia (CP-CML) in the first-line and second-line (2 L) setting. Treatment after 2 L is not clearly established. The objective of this study was to summarize the available evidence to compare the efficacy and safety of interventions in the treatment of CP-CML patients who had received ⩾2 prior TKIs. A systematic literature review was performed. A systematic literature review (SLR) of studies published until May 2021, reporting clinical outcomes in adult patients with CP-CML who had received ⩾ 2 prior TKIs was performed. Studies were identified through the database searches via Ovid platform (Embase, MEDLINE Epub Ahead of Print, In-Process and Other Non-Indexed Citations, and Cochrane Central Register of Controlled Trials), the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), bibliographic search of relevant reviews, and proceedings from the previous 3 years of the key conferences in the field of oncology. Our search identified 38 relevant studies. Among the identified studies of the current third-line treatments, the major molecular response (MMR) rate for ponatinib was 19.0-66.7%, 23.3-25.5% for asciminib, 19.2% for omacetaxine, and 13.2% for bosutinib at 6 months. The complete cytogenetic response (CCyR) rate was 21.4-64.8% for ponatinib, 38.7-40.8% for asciminib, 18-24.2% for bosutinib, and 16.1% for omacetaxine at 6 months. The findings from current SLR demonstrated the lack of data for patients with CML treated with ⩾2 TKIs. TKIs such as asciminib, ponatinib, and bosutinib are valid options for those patients. Further research is needed to identify the best treatment option for patients with CML receiving later lines of therapy.

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

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