Second-generation Tyrosine Kinase Inhibitors Research Articles

The Prognostic Impact of HMGCLL1 Gene Variant on Treatment Outcomes in Chronic Myeloid Leukemia (CML) Patients: Adverse Impact on the Response, Failure, and Progression with Imatinib Which Can be Abrogated By the Use of 2nd Generation Tyrosine Kinase Inhibitor (TKI) Upfront Therapy

BackgroundHMGCLL1 is characterized as a lyase activity enzyme located in the extramitochondrial region. Its biological and physiological role is not fully elucidated. Our previous study (Leukemia 2019) demonstrated that: 1) The HMGCLL1 gene variant, ACGTAATG haplotype (A-haplotype) is associated with increased expression of overall levels and isoform 3 (IS3) of the HMGCLL1 gene and predicts a decreased likelihood of deep molecular response after Imatinib (IM) therapy, 2) blockade of HMGCLL1 IS3 results in G0/G1 cell cycle arrest, leading to increased eradication of CML cell lines and CML leukemic stem cells, 3) blockade of HMGCLL1 isoform 3 significantly suppressed CD34+ fractions in CML patients (pts). It was unclear whether a second-generation tyrosine kinase inhibitor (2G-TKI) can reverse the adverse impact of the HMGCLL1 gene variant in CML pts. The present study assessed the prognostic impact of the HMGCLL1 gene variant in CML pts treated with IM or 2G-TKI, and its impact on treatment-free remission (TFR) after TKI discontinuation. Patients and methods Samples from 387 pts were sequenced. Group 1 included 252 pts from 2 centers whose samples were archived retrospectively. These pts were treated with IM (n=190, 75.3%) or second-generation TKIs (n=62) including Dasatinib (n=15, 6.0%), Nilotinib (n=37, 14, 7%), and Bosutinib (n=10; 4.0%). Group 2 included 135 patient samples from 4 countries that attempted to discontinue TKI for TFR. We applied our internal CML-specific smMIP panel with 332 amplicon probes including 8 HMGCLL1 SNPs (rs10948926, rs10948927, rs9370435, rs4546489, rs4275061, rs9475323, rs9475327, rs9296791). Linkage disequilibrium (LD) was assessed using Haploview software (Bioinformatics 2005). For Group 1, treatment outcomes were evaluated concerning major molecular response (MMR), molecular response (MR) with 2 log/deeper (MR2) or 4 log/deeper (MR4), failure-free survival (FFS), progression, and overall survival (OS). Disease characteristics and treatment outcomes were evaluated and compared according to the HMGCLL1 variants using a dominant model. For Group 2, molecular relapse-free survival (RFS) was calculated from the date of TKI discontinuation to the date of confirmed loss of molecular response (either loss of major MMR or two consecutive episodes of MR loss). Kaplan-Meier survival estimate was used to evaluate RFS and Cox's proportional hazard regression model was applied using the dominant model. Results HMGCLL1genotype and haplotype As shown in Fig A, the LD plot showed no recombination among the 8 SNPs, leading to one block for the 8 SNPs to construct a haplotype. Two haplotypes were constructed as CTCAGGCA (C-) or ACGTAATG (A-haplotype) with MAF of 0.674:0.279 in Group 1, and 0.703:0.216 in Group 2, respectively. Summary of outcomes in table 1. Treatment outcomes following TKI therapy according to the HMGCLL1 haplotype Homozygous A-haplotype (A/A) was associated with worse outcomes, showing a lower MR2 (65.9% vs 78.9% at 12 months, p=0.012), lower MMR (64.4% vs 86.8% at 3 years, p=0.00029), lower MR4 (34.7% vs 62.3% at 5 years, p=0.0001; worse FFS (62.8% vs 77.3% at 3 years, p=0.0014), higher risk of progression (16.2% vs 3.4% at 5 years, p=0.000678), and worse OS (56.1% vs 77.7% at 10 years, p=0.0021). The adverse impact of A/A-haplotype was more prominent in the pts treated with Imatinib: A/A-haplotype pts showed a 30-50% lower chance of MR2, MMR, and MR4 achievement, and 2-3 times higher risk of TFR and progression in comparison to those having C-haplotype when treated with Imatinib. However, the use of 2G-TKIs could abrogate the adverse impact of the A/A-haplotype. Impact of HMGCLL1 variant on treatment-free remission following TKI discontinuation While the 12-month RFS rate was 59.9% in overall pts (n=135), an inferior 12-month RFS rate was noted in A/A haplotype (43.8% vs 62.3%) but with borderline significance (p=0.116). Conclusion: The present study demonstrated that the HMGCLL1 gene variant is confirmed as predictive of CML outcomes. Moreover, our result suggests that the adverse impact of the HMGCLL1 genotype can be abrogated by using 2G-TKIs as upfront therapy. We aim to validate this data in a larger cohort of pts treated with 2G-TKI therapy to reach a clearer conclusion on this result. HMGCLL1 genotype information would be helpful to guide CML therapy given that pts with adverse HMGCLL1 genotypes could benefit from 2G-TKI therapy as front-line therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Five-Year Overall Survival Analysis Using First- and Second-Generation Tyrosine Kinase Inhibitors in Patients with Chronic Myeloid Leukemia in the Chronic Phase in a Prospective Observational Study (SIMPLICITY)

Five-Year Overall Survival Analysis Using First- and Second-Generation Tyrosine Kinase Inhibitors in Patients with Chronic Myeloid Leukemia in the Chronic Phase in a Prospective Observational Study (SIMPLICITY)

Subjects with Chronic Myeloid Leukemia Identified As Intermediate- or High-Risk Subjects Using the Imatinib Therapy Failure (IMTF) Model Benefit from Initial Therapy with a Second-Generation Tyrosine Kinase Inhibitor

Objective Validate the imatinib therapy failure (IMTF) model in 3,752 subjects with chronic phase chronic myeloid leukemia (CML) receiving initial imatinib therapy, and further test prediction accuracy in 1,353 persons receiving initial a second-generation tyrosine kinase inhibitor (2G-TKI). Compare the cumulative incidences of therapy failure in each IMTF risk cohort between initial imatinib and a 2G-TKI therapy. Methods Data from 1,356 consecutive subjects with chronic phase CML receiving initial imatinib therapy at one centre (Beijing, China) were interrogated as an internal dataset and compared with results in 2,396 similar subjects from 65 other centers in China, an external dataset to validate the IMTF model (https://www.nature.com/articles/s41375-022-01527-y.) The IMTF model divided subjects into the very low-, low-, intermediate-, high- and very high-risk cohorts. Data from 1,353 subjects receiving initial 2G-TKI therapy were also interrogated using the IMTF model to extensionally test predictive performance. Propensity score matching (PSM) was used to adjust the differences in baseline co-variates between subjects receiving initial imatinib or a 2G-TKI. Results In the imatinib internal validation dataset, 467 (34%), 263 (19%), 302 (22%), 219 (16%) and 105 (9%) subjects were classified as the very low-, low-, intermediate-, high- and very high-risk cohorts. 5-year cumulative incidences of therapy-failure were 7% (95% Confidence Interval [CI] 4, 9%), 19% (15, 23%), 33% (29, 37%), 52% (46, 58%) and 78% (67, 89%; p < 0.001; Figure 1A). Hazard ratios (HRs) (very low-risk cohort as reference) were 2.6 (1.7, 4.0; p < 0.001), 4.3 (2.9, 6.3; p < 0.001), 6.4 (4.3, 9.5; p < 0.001) and 11.3 (7.5, 17.2; p < 0.001; p for trend < 0.001; Figure 1B). In the imatinib external validation dataset, 575 (24%), 589 (24%), 696 (29%), 420 (18%) and 116 (5%) were classified as the very low-, low-, intermediate-, high- and very high-risk cohorts. 5-year cumulative incidences of therapy-failure were 9% (7, 11%), 21% (16, 26%), 36% (25, 47%), 41% (33, 50%) and 58% (46, 70%; p < 0.001; Figure 2A). HRs (very low-risk cohort as reference) were 2.0 (1.5, 2.8; p < 0.001), 4.0 (3.0, 5.3; p < 0.001), 4.9 (3.6, 6.6; p < 0.001) and 6.9 (4.8, 9.9; p < 0.001; p for trend < 0.001; Figure 2B). In the internal 2G-TKI dataset, 74 (24%), 55 (18%), 67 (21%), 69 (22%) and 44 (15%) subjects were classified as the very low-, low-, intermediate-, high- and very high-risk cohorts. 5-year cumulative incidences of therapy-failure were 10% (4, 15%), 15% (3, 27%), 19% (5, 33%), 36% (13, 59%) and 63% (44, 82%) (p < 0.001; Figure 3A). There were no significant differences in therapy failure among the cohorts except those in the high- and very-high risk. In the external 2G-TKI dataset, 287 (27%), 227 (22%), 284 (27%), 179 (17%) and 67 (7%) subjects were classified very low-, low-, intermediate-, high- or very high-risk cohorts. 5-year cumulative incidences of therapy-failure were 3% (0, 6%), 10% (4, 16%), 18% (6, 31%), 24% (12, 36%) and 52% (25, 79%; < 0.001; Figure 3B). In PSM analyses, subjects in the intermediate- and high-risk cohorts in the 2G-TKI internal dataset receiving initial 2G-TKI therapy had significantly lower cumulative incidences of therapy-failure compared with those receiving initial imatinib therapy (p = 0.038 and 0.018) whereas therapy-failure was similar in the very low-, low- and the very high-risk cohorts (p = 0.42 - 0.47, Figure4A-4E). Similar results were obtained in the 2G-TKI external dataset (Figure4F-4J). Conclusions The IMTF model accurately predicts therapy failure in persons receiving initial imatinib therapy and in those receiving initial 2G-TKI therapy. Subjects identified as intermediate- and high-risk using the using the IMTF model might benefit from initial 2G-TKI therapy whereas those in lower risk cohorts might not. If further validated by randomized controlled trial (in process), our data on preferred initial therapy should help physicians optimize TKI-therapy strategy in persons with chronic phase CML. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Outcome of Third-Line Tyrosine Kinase Inhibitors in Patients with Chronic Myeloid Leukemia in Chronic Phase: A Propensity Score Analysis

Background: Tyrosine Kinase Inhibitors (TKI) dramatically improve survival in patients with chronic myeloid leukemia in chronic phase (CML-CP). However, patients may develop intolerance of or resistance to TKI therapy over years. Given multiple effective therapies available, the optimal selection of third-line therapy is not clear. The aim of this study is to evaluate the outcomes of third-line TKI therapy in patients with CML-CP. Methods: We retrospectively combined patient-level data of third-line TKI therapy in the clinical trials of PACE and OPTIC studies with patients who received third-line TKI therapy at our institution. Given equivalent outcomes between second-generation TKIs (2G-TKI), we compared the outcomes of patients between 2G-TKI and ponatinib as third-line TKI therapy. Patients with T315I mutations were excluded in our study given the known resistance to all the 2G-TKI therapies. Multiple imputations was performed for missing covariates to reduce bias. Univariate and multivariate Cox regression analysis was performed for survival to identify prognostic factors with a p-value cutoff of 0.05 from univariate to multivariate analysis. One-to-one propensity score matching was performed with a caliper of 0.200, using matching covariates with age at the time of third-line therapy, gender, race, comorbidity, prior TKI therapy, the duration of prior TKI therapy, best prior response during the front-line and second-line TKI therapy, body mass index, white blood cell count, platelet count, percentages of basophils and blasts in peripheral blood, and BCR::ABL1 levels on the international scale. Progression-free survival (PFS) was defined from the start of third-line TKI therapy to the time of loss of major cytogenetic response during the study, progression to accelerated phase or blast phase at any time, death from any cause at any time, or the date of last follow-up; overall survival (OS) was defined as the start of third-line TKI therapy to death from any cause or the date of last follow-up. The Kaplan-Meier method was used for survival with the log-rank test and a significance p-value level of 0.05. Results: We identified 354 patients who received third-line TKI therapy [204 patients (58%) from our institution; 63 patients (18%) from the PACE study; 87 (25%) patients from the OPTIC study] with a median follow-up of 46 months (Table 1). Among them as third-line TKI therapy, 173 patients received 2G-TKI [69 patients (19%), dasatinib; 64 patients (18%), nilotinib; 40 patients (11%), bosutinib], and 181 patients received ponatinib (51%). Overall, the median age at the time of third-line TKI therapy was 54 years (range, 18-87). Prior to third-line TKI therapy, 313 patients (88%) received imatinib; 156 patients (44%), dasatinib; 161 patients (45%), nilotinib; 35 patients (10%), bosutinib. The overall median BCR::ABL1 level was 16.3% on the international scale at the time of third-line TKI therapy. Patients who received ponatinib had higher rates of non-ischemic cardiovascular comorbidity, shorter total duration of prior TKI therapies, higher percentage of basophiles in peripheral blood, and higher levels of BCR::ABL1 on the international scale. Propensity score matching minimized the baseline covariates and identified 96 patients at each group with a median follow-up of 46 months after propensity score matching. There is a tendency of deeper response with ponatinib at baseline BCR::ABL1 levels of >1-10% and >0.1-1% before and after propensity score matching. Using pre-matched data, multivariate Cox regression showed older age at the time of third-line TKI therapy and higher BCR::ABL1 levels as adverse prognostic factors for survival ; the third-line ponatinib therapy was associated with favorable survival [P=0.003; hazard ratio (HR), 0.435; 95% confidence internal (CI), 0.253-0.748]. The 4-year PFS rates were 58% and 75% in the 2G-TKI and ponatinib group, respectively, before matching (P<0.001); the 4-year PFS rates were 78% and 89%, respectively, after matching (P=0.0099). The 4-year OS rates were 57% and 80% in the 2G-TKI and ponatinib group, respectively, before matching; the 4-year OS rates were 78% and 87%, respectively, after matching (Figure 1). Conclusion: Third-line ponatinib therapy is optimal selection for patients with CML-CP who failed prior 2 TKI therapies in the absence of T315I mutation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Choice of Tyrosine Kinase Inhibitor and Early Events during the First Year of Therapy in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia (CML) Patients with Concomitant Diabetes: A "Campus CML" Study

Background Tyrosine kinase inhibitors (TKIs) have dramatically changed the treatment of chronic myeloid leukemia (CML). Most of data on the TKIs safety derive from sponsored controlled trials, where patients with multiple comorbidities had fewer opportunities to be included. Many questions about the management of newly diagnosed CML can only be answered by analysing large cohorts in real world practice. Methods To evaluate the choice of TKI and the incidence of early events during the 1st year of therapy in newly diagnosed chronic phase CML patients with concomitant diabetes, we retrospectively studied 1732 CP-CML patients diagnosed from 1/2012 to 12/2019 at 33 Italian Hematology Centres and treated with frontline imatinib (IM) or second-generation TKIs (2G). Among these, 197 patients (11.4%) had concomitant diabetes. Results The main clinical features at diagnosis of the entire cohort and in patients with diabetes are reported in the Table. Compared with non-diabetic patients, subjects with diabetes were older, had higher Sokal and ELTS scores (Sokal intermediate + high 74.5% vs 59.2%, ELTS intermediate + high 62.6% vs 41.1%) and were more likely affected by other comorbidities as arterial hypertension, COPD, ischemic heart disease/cerebrovascular events and previous neoplasms: as a consequence, diabetic patients reported a higher number of concomitant drugs (> 5 in 38.6% vs 10.1%, p<0.001). The number of white blood cells at diagnosis was lower in diabetic patients (44.9x109/l vs 59.3 x109/l, p=0.008)). Significant differences were observed in the choice of frontline TKI: comparing diabetic with non-diabetic patients, IM was prescribed in 72% vs 54%, dasatinib in 23.4% vs 15.3% and nilotinib in 4.6% vs 30.7% of cases (p<0.001). There were 51 early events (25.9%) in the 1st year of treatment leading to permanent frontline TKI discontinuation in the diabetic patients, compared to 285 (18.7%) in non-diabetic patients (p=0.037). One-year cumulative incidence of TKI permanent discontinuation was 25.9% (95%CI 19.8 - 32.0) in diabetic patients compared to 18.5% (95%CI 16.6 - 20.4) in non-diabetic patients (p=0.015). Conclusions This real-world study on over 1700 CML patients shows that concomitant diabetes is an important factor in newly diagnosed CML patients, affecting both the clinical presentation and the frontline treatment choice: in addition, concomitant diabetes is linked to a high incidence of early events and frontline TKI permanent discontinuation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The First Report of Third-Generation TKI Olverembatinib in Adult Ph/BCR-ABL1-Positive Acute Lymphoblastic Leukemia with T315I Mutation and Relapsed Disease

Background Tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of patients(pts) with Ph/BCR-ABL1-positive (Ph/BCR-ABL1+) acute lymphoblastic leukemia (ALL). However, mutations in the ABL1 kinase domain, especially T315I, are the main mechanism of resistance to the first- or second-generation TKIs. Olverembatinib is a novel third-generation TKI developed in China and approved in Dec. 2021, which has been demonstrated great efficacy and safety in clinical trials of CML with T315I mutation. Our study is the first application of Olverembatinib in adult Ph/BCR-ABL1+ ALL with T315I mutation. Herein, we report the preliminary results. Methods In this exploratory study, adult Ph/BCR-ABL1+ ALL pts with T315I mutation or disease progression were treated with olverembatinib monotherapy (40 mg, every 2 days) or in combination with VP based low intensive chemotherapy (Vincristine/Prednisone) in our institution. Efficacy was assessed by complete remission (CR) rate, MRDneg (<0.01%) rate by multiparameter flow cytometry (MFC) and CMR (BCR-ABL1 transcript<10-5) rate by real-time quantitative polymerase chain reaction (RT-qPCR). Safety profiles were also monitored in this study. Results From December 2021 to June 2022, 10 Ph/BCR-ABL1+ ALL pts were treated with olverembatinib due to T315I mutation or disease recurrence, after prior TKIs combined with chemotherapy. Median age was 60.5 years (range, 37-65), and 6/10 were males. 5 pts had received 2 types of TKIs previously, of which 2 pts relapsed after ponatinib (Table 1). Among 10 pts, 6 were still in CR1 (pt 1-6), their T315I mutations were detected during regular follow-up. 4/6 pts were persistently molecular positive, while the other 2 had molecular relapse. Median time from diagnosis to the administration of olverembatinib was 5 months (range, 3-17). Among the 4 pts with hematologic relapse (pt 7-10), 2 (pt 7, 8) had T315I mutation. Because of the successive occurrence of G250E, Y253H, L248V mutations and L248 K274del, the 3rd one (pt 9) relapsed twice and failed to response to two kinds of TKIs and chemotherapy. As for the last pt (pt 10), although no ABL1 mutations were found, she was in 3rd relapse with CNS and BM involvement. Median time from diagnosis to the start of olverembatinib for these 4 relapsed pts was 28 months (range, 5-41). Among 6 pts with T315I mutation and persistent molecular diseases or molecular relapse, the CMR rate was 66.7%, with a median time of 3 months (range, 1-4) to achieve CMR. Then 2 pts underwent allo-HSCT (pt3, 4), who were still in CR. Among 4 hematological relapsed pts, the CR rate was 75%. 1 pt (pt8) with T315I was unresponsive, while another T315I positive patient achieved MRDneg by MFC after 1 month of treatment, with a complete disappearance of T315I mutation (pt7), though the BCR-ABL1 transcript was still positive. The remaining 2 relapsed pts without T315I mutation achieved hematologic CR after 1 month of olverembatinib monotherapy (pt9,10). Totally, overall response rate (ORR) was 70% and MRDneg rate by MFC was 71.4% (5/7), while the CMR rate by PCR was 57.1% (4/7). Notably, olverembatinib was ineffective in neither of the 2 pts who have been previously treated by ponatinib. Meanwhile, the olverembatinib-based therapy was well-tolerated, and the main adverse events of the third-generation TKIs, such as cytopenia, elevated transaminases, hypertension, and cardiovascular events, were less frequent than those reported relating to ponatinib. In addition, 4 patients developed grade 1 skin pigmentation (pt2,3,6,9). There were no drug-related death or permanent discontinuation due to toxicity. Conclusion This work suggests that Olverembatinib is a very promising 3rd-generation TKI. It is effective and safe in Chinese adult Ph/BCR-ABL1+ ALL with extremely poor prognosis, especially in T315I mutated or relapsed pts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Discontinuation of Tyrosine Kinase Inhibitor Therapy and Treatment-Free Remission in Chronic-Phase Chronic Myeloid Leukemia: An Observational Retrospective Multi-Center Study

Introduction: Discontinuation of tyrosine kinase inhibitor (TKI) therapy and achievement of treatment-free remission (TFR) in chronic-phase chronic myeloid leukemia (CP-CML) patients is feasible and can be implemented in clinical practice. We conducted a retrospective study at 3 tertiary care centers in Riyadh, Saudi Arabia of all CP-CML patients who discontinued TKI therapy. Methods: All CP-CML patients being followed at participating centers who discontinued TKI, were eligible. TKI discontinuation was carried out as per clinical practice guidelines. Criterion to restart TKI therapy in relapsed patients was loss of major molecular response (MMR; BCR-ABL > 0.1). We collected data on gender, age, prognostic risk-score, type(s) of TKI therapy, type and duration of last TKI before discontinuation, total duration of TKI therapy and response, time to achieve MMR, relapse data including time to relapse and response to re-initiation of TKI therapy, and analyzed the risk factors for relapse. Study was approved by the institutional review boards of all participating centers. Results: Fifty-five patients (35 females) with a median age of 40 years (range 16-74) were included in the study. Median age at TKI stop was 48 years (range 21-80). Majority of the patients (48; 87.27%) received imatinib as first line therapy; 29 (53.74) patients were receiving imatinib at TKI-stop, and 26 (47.27) a second-generation TKI (dasatinib or nilotinib). Fifty-two (94.5%) patients discontinued TKI as per clinical practice (shared decision between treating physician and the patient), and 3 (5.5%) stopped because of pregnancy; 2 patients fulfilled the criteria to stop post-delivery as they remained in deep MR, they were offered to continue stopping. One patient refused to restart TKI (dasatinib) after delivery although she had only 24 months of deep response but continues to have deep remission after 91 months of follow up. Median time to achieve MMR after diagnosis was 12 (range 2-164) months. All the patients had achieved MR4.5 or better (complete molecular response) before stop. Median time from diagnosis to TKI stop was 86 months (IQR 60;132) and median time of last TKI before stop was 66 months (IQR 47;114). After a median follow up of 42 months (IQR 12.5;69) post TKI-discontinuation, 15 (28%) patients relapsed. Median time to relapse was 5 months (range 3-38). Most of the relapses occurred during the first 6 months, except 3 patients who relapsed after 10, 11, and 38 months. Most of the relapsed patients had intermediate or high risk Sokal score. All the relapsed patients achieved MMR after a median of 3 months (range 2-6) after restarting TKI. None of the patients progressed to advanced phase. Conclusion: In real-life practice, TKI discontinuation was possible without relapse for CP-CML patients in deep molecular response, with over two-third of patients continuing in TFR. Majority of the relapsed patients belonged to the intermediate/high-risk score Sokal category at diagnosis. Although this study has the limitation of a retrospective study, our experience in this population confirms that discontinuation of TKI therapy in CP-CML patients is feasible and safe in clinical practice.

Frontline Combination of Hyper-CVAD with Ponatinib for Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia-6-Year Follow-up Results

Background: The combination of cytotoxic chemotherapy with a BCR::ABL1 tyrosine kinase inhibitor (TKI) has historically been standard of care for patients (pts) with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Ponatinib is 3rd generation TKI with more potent BCR::ABL1 inhibition than earlier-generation TKIs. Ponatinib also suppresses T315I clones, which are responsible for most relapses with other TKIs. Here we present the 6-year follow-up results of hyper-CVAD plus ponatinib for patients with newly diagnosed Ph+ ALL. Methods: This was a phase 2, single-arm study to evaluate the efficacy and safety of hyper-CVAD with ponatinib in adults with newly diagnosed Ph+ ALL. Pts age 18 years or older with previously untreated Ph+ ALL were eligible; pts who had received 1 to 2 courses of prior chemotherapy, with or without a TKI, were also eligible. Pts were required to have an ECOG performance status of 2 or less, bilirubin <3mg/dl, creatinine <3mg/dl, and normal cardiac function. Pts received hyper-CVAD alternating with high-dose methotrexate and cytarabine for 8 cycles. Initially, ponatinib was given at a dose of 45 mg daily. Due to 2 deaths due to cardiovascular events related to ponatinib, beginning with pt #37, the protocol was amended. After the amendment, ponatinib was administered at a dose of 45 mg for 14 days in cycle 1, then 30mg daily once patients achieved CR and 15mg daily once a complete molecular response (CMR) was achieved. Maintenance therapy was given for 2 years, vincristine, prednisone and ponatinib. Pts received 12 doses of intrathecal chemotherapy with alternating doses of cytarabine and methotrexate. Results: 86 pts were treated. Pts characteristics are summarized in Table 1. The median age was 46 years (range 21-80). Sixty-six pts (77%) had received no prior ALL-directed therapy, and 20 pts (23%) had received 1-2 courses of therapy prior to enrollment. Among these 20 pts, 18 were in CR and 2 had persistent disease at the time of enrollment. Sixty three pts (73%) had a p190 transcript, and 21 (24%) had a p210 transcript. Among 68 pts with active disease at enrollment, all pts achieved CR. Among 54 pts evaluable for cytogenetic response, all pts achieved complete cytogenetic response, including 50 pts (93%) after 1 cycle. Among 85 pts evaluable for molecular response, 83 pts (98%) achieved at least a major molecular response and 73 pts (86%) achieved a CMR. No pts died in the first 4 weeks of therapy. After a median follow up of 75 months (range, 16-123+ months), the 5-year overall survival (OS) and relapse-free survival rates were 75% and 68%, respectively (Figure 1). Twenty pts (23%) underwent stem cell transplantation (SCT) in first remission (5 of whom relapsed post SCT and 1 of whom died from post-SCT complications), 10 pts (12%) died in CR, 13 pts (19%) relapsed without SCT, and 43 pts (50%) are in ongoing remission without SCT. Of the relapsed pts, 5 were on ponatinib at the time of relapse, 2 of whom acquired an E255K kinase domain mutation at relapse; and 5 were on imatinib or dasatinib at the time of relapse, 3 of whom acquired a T315I kinase domain mutation. Among the 10 deaths in CR, 2 were treatment-related (both due to myocardial infarction before the amendment to implement lower doses of ponatinib). In a 8-month landmark analysis, the 5-year OS for pts without ASCT and with ASCT were 87% and 70%, respectively (p =0.09). Among the pts who are in ongoing remission without ASCT, 3 received subsequent therapy for MRD-positive disease. The most common grade ≥3 AE was infections and/or febrile neutropenia, seen in 82 pts (95%). Other grade ≥3 AEs including elevated transaminases in 25 pts (29%), increased amylase and/or lipase in 15 (17%), hyperbilirubinemia in 13 pts (15%), and clinical pancreatitis in 13 pts (15%). Five pts (6%) had a grade ≥3 venous thrombotic event, and 5 pts (6%) had a grade ≥3 arterial cardiovascular event. Two patients died from ponatinib-related cardiovascular complications, both from MI during cycle 2. Conclusion: The combination of hyper-CVAD and ponatinib results deep and durable remissions in pts with newly diagnosed Ph+ ALL. The overall CMR rate was 86% and the 5-year OS was 75%, which compares favorably with regimens using first- or second-generation TKIs in this population. The combination was safe; the use of lower doses of ponatinib maintained efficacy and mitigated the risk of ponatinib-related toxicity. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

ASC2ESCALATE: A Phase 2, Single-Arm, Dose-Escalation Study of Asciminib Monotherapy in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Previously Treated with 1 Prior Tyrosine Kinase Inhibitor (TKI)

BACKGROUND: The discovery of adenosine triphosphate (ATP)-competitive TKIs has extended life expectancy in CML; despite these advances, 28% to 40% of newly diagnosed pts with CML-CP discontinue treatment by 5 years, prompting a switch to second-line (2L) therapy. Discontinuation rates increase in 2L; up to 86% of pts discontinue therapy, with 20% to 30% discontinuing 2L therapy due to disease progression. Dose-escalation studies show that some pts experiencing resistance to therapy can achieve responses with higher doses of their TKI, while use of another second-generation (2G) TKI has shown limited clinical benefit in pts experiencing resistance to a 2G TKI. Asciminib is the 1st BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP), allowing asciminib to have activity against most BCR::ABL1 mutations that impart resistance to ATP-competitive TKIs. Asciminib was 1st approved in the United States for pts with CML-CP after ≥2 TKIs at 80 mg once daily (QD) and 40 mg twice daily (BID) and CML-CP with the T315I mutation at 200 mg BID. In the phase 3 ASCEMBL study, asciminib 40 mg BID showed superior efficacy vs bosutinib 500 mg QD in pts with CML-CP after ≥2 prior TKIs at weeks 24 (major molecular response [MMR], 25.5% vs 13.2%) and 96 (MMR, 37.6% vs 15.8%) and favorable tolerability with >2 years’ follow-up. In a large phase 1 dose-finding trial, asciminib demonstrated safety across doses of 80 to 200 mg QD and 10 to 200 mg BID in pts with CML-CP/accelerated phase without and with the T315I mutation previously treated with ≥2 and ≥1 TKIs, respectively (maximum tolerated dose was not reached in this study). Here, we describe the phase 2 ASC2ESCALATE trial investigating the efficacy and safety of 2L asciminib with dose escalation in pts with CML-CP (NCT05384587). STUDY DESIGN AND METHODS: This is a phase 2, open-label, multicenter, single-arm, dose-escalation study in the United States (Figure). Adult pts (aged ≥18 years) with CML-CP without the T315I mutation who experienced resistance (BCR::ABL1IS >1% with 6-12 months of first-line [1L] treatment or >10% with >12 months of 1L treatment) or intolerance (BCR::ABL1IS >0.1%) with ≥6 months of treatment with 1 prior ATP-competitive TKI are eligible (Table). All pts will initiate treatment with asciminib 80 mg QD. For pts not achieving BCR::ABL1IS <1% at 6 months, dose will be escalated to 200 mg QD if pts do not have grade ≥3 toxicity or persistent grade 2 toxicity refractory to optimal management. In pts not achieving MMR at 12 months, either dose escalation from 80 to 200 mg QD or from 200 mg QD to 200 mg BID will occur or the pts will discontinue study treatment. Pts who achieve MMR at 12 months will continue asciminib at their current dose. Pts deriving clinical benefit from asciminib per investigator assessment may receive post-trial access. Pts may discontinue at any time due to unacceptable toxicity or progression or at investigator/pt discretion. The primary endpoint is the proportion of pts achieving MMR at 12 months. Secondary endpoints include MMR rates by 3, 6, 18, and 24 months; MR4.5 (BCR::ABL1IS ≤0.0032%) at 24 months; time to and duration of MMR; time to treatment failure; and safety/tolerability. To investigate progression-free and overall survival, time from the first dose to progression or death due to any cause during the study, respectively, will be measured. CONCLUSIONS: ASC2ESCALATE is the 1st clinical trial designed to assess asciminib in pts with CML-CP requiring 2L therapy and seeks to provide information on the efficacy and safety of dose escalation for pts not meeting certain response milestones. Treatment using a dose escalation strategy with asciminib in 2L could enable a greater proportion of pts with CML-CP not meeting milestones to achieve molecular responses and provide another option for those experiencing intolerance of or resistance to ATP-competitive TKIs. Recruitment for this study is planned to begin August 2022 with an approximate enrollment of 92 pts with CML-CP across ≈40 sites. This study is sponsored by Novartis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Permanent Discontinuation of Tyrosine Kinase Inhibitor Frontline Therapy in Patients with Chronic Phase Chronic Myeloid Leukemia Patients during the First 36 Months of Treatment: A "Campus CML" Study

Background Tyrosine kinase inhibitors (TKIs) have changed prognosis and treatment results of chronic myeloid leukemia (CML). However, the first years of therapy are crucial to achieve optimal response, defined as the achievement of deep molecular response: in this early phase, however, different toxicities or suboptimal response/resistance may occur, leading to permanent frontline TKI discontinuation and need for a second-line switch. Methods To evaluate in a large real-life cohort of CML patients the incidence and the different pattern of events leading to a permanent frontline TKI discontinuation during the first 3 years of therapy, 1168 CP-CML patients diagnosed from 1/2012 and 12/2019 at 21 Hematology Centres and treated with frontline imatinib (IM) or second-generation (2G) TKIs dasatinib or nilotinib were retrospectively analysed. Results Frontline TKI was IM in 737 (63.1%) and 2G-TKIs in 431 (36.9%) cases: the main clinical features at diagnosis of the entire cohort and according to frontline treatment are reported in the Table 1. Commonest comorbidities were arterial hypertension (37.4%), previous neoplasm (14.1%), diabetes (10.9%), peripheral vascular diseases (8.4%), ischemic heart disease (6.9%) and COPD (6.7%). IM-treated patients were older (p<0.001) and had more comorbidities (p=0.002 for COPD and p<0.001 for all other diseases). Total number of patients who had discontinued frontline TKI at the 36th month of observation was 391/1168 (33.5%), being higher with IM (294/737, 39.8%) than with 2G-TKIs (96/431, 22.3%) (p<0.001). Cumulative incidence of permanent TKI discontinuation was 19.6% [95% confidence interval (CI) 17.3-21.9] at 12 months, 29.7% (95%CI 27.0-32.4) at 24 months and 34.2% (95%CI 31.5-36.9) at 36 months, respectively: cumulative incidence of discontinuation according to frontline TKI is shown in the Figure (p<0.001 at any time-point). Among the 391 patients who discontinued frontline TKI, the main causes were hematologic toxicity in 27 (6.9%), extra-hematologic toxicity in 106 (27.1%), primary resistance in 166 (42.4%), secondary resistance in 18 (4.6%), evolution in blastic phase in 17 (4.3%), unrelated deaths in 36 (9.2%) and other causes in 21 (5.4%). At univariate analysis, in addition to IM as frontline TKI, baseline factors predictive for an higher rate of TKI discontinuation were age > 65 years (p=0.001), WBC ≥ 100 x 109/l (p<0.001), Hb < 10 g/dl (p<0.001), spleen enlargement ≥ 5 cm below costal margin (p<0.001) and high Sokal score (p<0.001). At multivariate regression logistic analysis, frontline IM (HR 3.22; 95%CI 2.34 - 4.42, p<0.001), WBC ≥ 100 x 109/l (HR 2.18; 95%CI 1.57 - 3.02, p<0.001), spleen enlargement ≥ 5 cm (HR 1.91; 95%CI 1.22 - 3.00, p=0.005) and Sokal high risk (HR 1.78; 95%CI 1.16 - 2.72, p=0.007) retained an independent predictive role on TKI discontinuation. Conclusions This real-world study on over 1100 CML patients reveals that about one third of newly diagnosed CML patients discontinued frontline TKI during the first 3 years of therapy, mostly for primary resistance or toxicity. Discontinuation rates were higher with IM compared to 2G-TKIs at any time-point: however, the impact of older age, higher risks and heavier burden of comorbidities in IM patients should be considered. Other factors seemed to affect the risk of frontline TKI discontinuation but their role needs further refined investigations. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

ASC4START: A Phase IIIb, Open-Label, Randomized Study of Tolerability and Efficacy of Asciminib Versus Nilotinib in Patients with Newly Diagnosed Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia in Chronic Phase

Objectives: Tyrosine kinase inhibitors (TKIs) have greatly improved treatment outcomes for patients with newly diagnosed chronic myelogenous leukemia in chronic phase (CML-CP), transforming it into a chronic disease requiring long-term treatment. This emphasizes the need for treatments that combine high efficacy with a favorable safety profile, improving over currently available options. Asciminib is a first-in-class BCR::ABL1 inhibitor specifically targeting the ABL myristoyl pocket (STAMP) which has been approved by the FDA with subsequent approvals worldwide for patients with Philadelphia chromosome-positive (Ph+) CML-CP, previously treated with ≥2 prior TKIs based on the results of the ASCEMBL (NCT03106779) trial. The ABL specificity of asciminib compared with the selectivity of second-generation (2G) TKIs can reduce off-target effects and improve tolerability while maintaining efficacy and reducing the probability of developing resistance. The ongoing ASC4FIRST (NCT04971226) study will evaluate the efficacy and safety of asciminib vs investigator-selected TKI in patients with newly diagnosed Ph+ CML-CP. Additional data on asciminib in newly diagnosed Ph+ CML-CP may help to address patient-centric objectives, in particular the ability of patients to remain on treatment without having to permanently discontinue due to adverse events (AEs). The ASC4START study (NCT05456191) will primarily evaluate the tolerability of asciminib vs the 2G TKI nilotinib in adult patients with newly diagnosed Ph+ CML-CP, as measured by the time to study treatment discontinuation due to adverse event (TTDAE). The study will also report on further safety, efficacy and quality of life (QoL) outcomes. Methods: This is a phase IIIb, multi-center, open-label, randomized study in patients ≥18 years of age with newly diagnosed Ph+ CML-CP. The trial will enroll approximately 541 patients with CML-CP diagnosed within 3 months of study entry and an Eastern Cooperative Oncology Group (ECOG) performance status ≤1. Patients cannot be included if they have received previous treatment for CML with any other anticancer agents (except hydroxyurea and/or anagrelide), have confirmed central nervous system infiltration, or present impaired cardiac function or abnormalities in cardiac repolarization. Patients will be randomized 1:1 to receive asciminib 80 mg once daily or nilotinib 300 mg twice daily, both administered orally under fasting conditions; randomization will be stratified based on European Treatment Outcome Study long-term survival (ELTS) score at diagnosis (high vs intermediate vs low) to help achieve balance between the treatment arms (Figure). The primary endpoint is TTDAE, defined as the time from the date of the first dose of study treatment to the date of discontinuation of study treatment due to an AE. Secondary endpoints include type, frequency and severity of AEs; dose modifications due to AE; changes in laboratory values that fall outside pre-determined ranges; clinically notable ECG changes; time to discontinuation due to selected reasons (lack of efficacy/treatment failure/disease progression/suboptimal response/death); major molecular response (MMR), MR4, MR4.5, complete hematological response (CHR), and BCR::ABL1 ≤1% at and by all scheduled data collection time points; duration of and time to first MMR, MR4 and MR4.5; time to treatment failure; event-free survival, progression-free survival and overall survival. Secondary endpoints related to QoL include change from baseline in overall scores and individual scales of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires QLQ-C30 and QLQ-CML24. Participants will be treated in the study until approximately 64 discontinuations due to AEs are met; treatment duration for an individual patient is expected to be 2‒4.5 years. Current status: The study is recruiting as of October 2022. This study was sponsored by Novartis Pharmaceuticals. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Predictive Scoring System for Therapy Failure in Persons with Chronic Myeloid Leukemia Receiving Initial a Second-Generation Tyrosine Kinase Inhibitor Therapy

Purposes Develop and validate a predictive scoring system for therapy failure in persons with chronic phase chronic myeloid leukemia (CML) receiving initial a second-generation tyrosine kinase inhibitor (2G-TKI). Methods Data from 329 consecutive subjects with CML receiving initial 2G-TKI therapy at one centre (Beijing, China) in a training dataset were interrogated to develop a predictive model which was then validated in 1,083 subjects from 65 other centers in China. Therapy-failure was defined using the 2020 ELN criteria including progression to accelerated or blast phases or CML-related death. Fine-Gray model was used for uni- and multi-variable analyses (UVA and MVA) to identify co-variates significantly-associated with therapy-failure. Akaike information criterion (AIC) was used to select prognostic co-variate and determine the best model. 1000 bootstrap re-samplings, Fine-Gray test, the minimal p-value approach, Bonferroni correction and kernel density estimator were used to determine optimal cut-offs to classify subjects into risk cohorts. Time-dependent receiver-operator characteristic curves (ROC) were used to estimate prediction accuracy and calibration plots used to determine concordance between predicted and observed cumulative incidences. Decision curve analysis (DCA) was used to calculate the net benefit using the model. Results In the training dataset, 279 subjects (85%) initially received nilotinib; and 50 (15%), dasatinib. Median 2G-TKI therapy-duration was 36 months (interquartile range [IQR], 24-68 months). 75 subjects (23%) had therapy-failure at a median of 9 months (IQR 3-12 months) after therapy start. In MVA, increasing splenomegaly and a higher percentage blood blasts were significantly-associated with the higher cumulative incidences of therapy-failure. We used these data to develop a predictive scoring system: "2G-TKI failure risk score= 0.6405×[(spleen size below the costal margin in cm + 0.2)/10] + 0.1348×(blood blasts + 0.2)" which divided subjects into low- (score ≤ 0.3021; n = 89; 31%), intermediate- (0.3021 < score < 1.4508; n = 155; 54%) and high-risk (score ≥ 1.4508; n = 43; 15%) cohorts with 5-year cumulative incidences of therapy-failure of 3% (95% Confidence Interval [CI], 0, 5%), 26% (20, 32%) and 72% (56, 88%; p-value for trend < 0.001; Figure 1A). Hazard ratios (HRs) for therapy-failure (low-risk cohort as reference) were 4.8 (1.7, 13.6; p = 0.002) and 16.5 (5.7, 47.6; p < 0.001; p for trend < 0.001) for the intermediate- and high-risk cohorts. In the external validation dataset, subjects were classified into the low- (n = 433; 40%), intermediate- (n = 583; 54%) and high-risk (n = 67; 6%) cohorts using our scoring system. 5-year cumulative incidences of therapy failure were 8% (3, 13%), 18% (12, 25%) and 44% (29, 60%; p for trend < 0.001; Figure 1B). HRs (low-risk cohort as reference) were 2.7 (1.9, 3.6; p < 0.001) and 10.6 (5.8, 15.4; p < 0.001; p for trend < 0.001) for the intermediate- and high-risk cohorts. In the training dataset cohort time-dependent AUROC curves for therapy-failure at 1-, 3-, and 5-years in the model were 0.73-0.82 and 0.68-0.75 in the validation dataset. Calibration plots for the 1-, 3- and 5-years cumulative incidences of therapy-failure indicated good concordance between predicted and observed outcomes. DCA curves indicated net benefit from using the predictive scoring system in clinical settings. Conclusions We developed and externally validated a therapy-failure scoring system in persons with chronic phase CML receiving initial 2G-TKI. The model had high AUROCs and performed well in calibration plots and DCAs. Our model may help physicians decide appropriateness of initial the 2G-TKI therapy including possible selection of appropriate haematopoietic cell transplant candidates. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Additional Mutational Events at Diagnosis of CML Confer Inferior Failure-Free Survival and Molecular Response for Patients Treated with Frontline Imatinib but Not for Patients Treated with Frontline Second-Generation Tyrosine Kinase Inhibitors

Background We previously performed an integrative genomic analysis for 47 chronic phase (CP)-CML patients at diagnosis who were specifically selected based on optimal or very poor outcome to tyrosine kinase inhibitors (TKIs). Patients who subsequently progressed to blast phase (BP) had a significantly higher frequency of cancer-related gene mutations at diagnosis compared with patients who achieved an optimal response (54% versus 16%). A novel mutational subtype associated with the formation of the Philadelphia (Ph) chromosome, termed Ph-associated rearrangements, were also described and included novel fusions, deletions and inversions adjacent to the BCR::ABL1 junction. These occurred at a higher frequency of patients who progressed to BP compared to those with an optimal response (33% versus 11%). Consequently, we sought to investigate the true incidence and effect of cancer-gene mutations and Ph-associated rearrangements (collectively termed additional mutational events, AMEs) detected at diagnosis and whether outcomes differ based on the TKI initiated. Aim To assess the impact on outcome and molecular response of AMEs detected at diagnosis for patients consecutively treated with imatinib compared to patients treated with second-generation TKIs (2G-TKI). Methods A recently validated hybridization capture sequencing method targeting genes involved in both myeloid and lymphoid malignancies was applied to available diagnostic RNA of consecutive clinical trial patients treated with either frontline imatinib or 2G-TKIs. The 200 imatinib-treated patients (TIDEL II; CML9) were commenced on 600mg daily of imatinib and managed with a highly proactive treatment intervention strategy for suboptimal response, which was either imatinib dose increase or switch to nilotinib. The 2G-TKI patients were enrolled in either DIRECT;CML12 (n=72), where patients commenced dasatinib 100mg daily before dose modification, or either ENESTxtnd or PINNACLE;CML11 (n=44) where patients commenced nilotinib 300mg twice daily. Variants in cancer genes with variant allele frequencies ≥5%, including single nucleotide variants, RNA splice altering variants, small insertions/deletions, gene fusions and focal gene deletions were assessed for pathogenicity using strict criteria. Ph-associated rearrangements were identified. Clinically relevant variants were confirmed as somatic and validated. Kaplan-Meier and cumulative incidence analyses were performed to assess the effect of AMEs on failure-free survival and key molecular outcomes by 36 months. Failure events were as defined by the European LeukemiaNet 2020. Results The incidence of AMEs for imatinib-treated patients was 31% (61/200): 33 (16%) cancer gene mutations and 36 (18%) Ph-associated rearrangements; 8 patients had both subtypes. In the 2G-TKI group, 41 AMEs were identified in 29% (34/116) of patients: 20 (17%) cancer gene mutations and 16 (14%) Ph-associated rearrangements; 2 patients had both subtypes. In total, 14 cancer genes were mutated. Consistent with other studies, ASXL1 mutations were most frequently detected: 18/200 imatinib patients (9%) and 9/116 2G-TKI patients (8%). Using 36-month outcomes as comparison, imatinib-treated patients with AMEs had inferior failure-free survival (84% versus 69%, P=.03), major molecular response (84% versus 72%, P=.02) and MR4 (62% versus 37%, P=.001). In contrast, outcomes in the 2G-TKI cohort were similar irrespective of the presence of AMEs, with regards to failure-free survival (94% versus 91%, P=.47) and achievement of major molecular response (88% versus 83%, P=.71). Interestingly, achievement of MR4 was delayed for patients with AMEs compared to those without AMEs at diagnosis: 51% versus 69%, P=.02 by 24 months; and 63% versus 70%, P=.40 by 36 months. No differences were observed for overall survival or transformation-free survival in either the frontline imatinib or 2G-TKI cohorts. Conclusion These results indicate that while the presence of AMEs do predict for inferior outcomes and molecular responses when patients are treated with frontline imatinib, the more potent 2G-TKIs may overcome the negative impact of the AMEs. The effect for imatinib treated patients was evident despite a starting dose of 600mg and more stringent treatment intervention than currently recommended. This supports a strategy of mutation analysis at diagnosis of CP-CML for optimal TKI selection. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Targeted Next-Generation Sequencing Identifies Additional Mutations Other Than BCR-ABL in Chronic Myeloid Leukemia Patients: A Chinese Monocentric Retrospective Study

The discovery of tyrosine kinase inhibitors (TKIs) has drastically changed the treatment of chronic myeloid leukemia (CML) patients. However, a proportion of patients still show resistance or intolerance to TKI therapy. These patients often carry somatic variants related to myeloid malignancies, indicating that additional mutations other than BCR-ABL1 may lead to TKI treatment failure or disease progression. We retrospectively evaluated 151 CML patients receiving TKI therapy and performed next-generation sequencing (NGS) analysis of 22 CML patients to explore the mutation spectrum other than BCR-ABL1 affecting the achievement of molecular responses. We also performed a comprehensive evaluation of clinical characteristics, distinct TKI options and scoring systems in the correlation with the molecular response of TKI. In total, 161 variants were detected by NGS, most of which were nonsynonymous SNVs (Figure A). The coexistence pattern among high-frequency variants was quite intricate(Figure B). Among 25 genes with allele mutation frequency (VAF) ≥5%, the most frequently mutated gene was ASXL1 (40.9%), followed by KMT2C (27.3%), DIS3 (18.2%), ATM (13.6%), DNMT3A (13.2%) and NOTCH3 (13.6%) (Figure C). NOTCH3 and RELN mutations were only carried by subjects failing to achieve a major molecular response (MMR) at 12 months, suggesting CML patients with NOTCH3 and RELN mutations might have poor long-term treatment effects (Figure D, Figure E). The distribution frequency of ASXL1 mutations was higher in the group that did not achieve MR4.0 at 36 months (P=0.023), indicating that ASXL1 mutation was an adverse factor for the achievement of MR4.0. Furthermore, subjects in this group possessed more mutations related to activation signaling pathway genes (P=0.003) and chromatin modification genes (P=0.029) (Figure F). In the group that failed to achieve MR4.5 at 12 months, there were more subjects carrying >2 gene mutations (9.1% vs. 63.6%, P=0.024), implying that it is less likely to achieve MR4.5 with the increase in the number of mutated genes and that the existence of more than two mutations is a poor prognostic factor for achieving deep molecular response (DMR) (Figure G, Figure H). However, no statistical significance was found in the effects of mutations in ASXL1 (P=0.371), KMT2C (P=0.079), DIS3 (P=0.467), ATM (P=0.280), DNMT3A (P=0.479) and NOTCH3 (P=0.479) on PFS. In the analysis of clinical characteristics, multivariate analysis identified hemoglobin concentration (HB) (relative risk, [RR], 1.023; P=0.08) and BCR-ABLIS level at 12 months (RR, 2.485; P＜0.001) as independent predictive covariates for MR4.5(Figure I). Subjects who received initial second-generation TKI (2GTKI) were more likely to achieve early molecular response (EMR) at 3 months (P=0.012), BCR-ABLIS ≤1% at 6 months (P=0.012) and MMR at 12 months (P=0.018) than initial first-generation TKI (1GTKI). And there did not show statistical significance in achieving BCR-ABLIS≤1% at 6 months, MMR at 12 months and MR4.5 between original 1GTKI (Group A1, Glevic, Novartis, Switzerland) and generic 1GTKI (Group A2, Genike, Chiatai Tianqing Pharmaceutical Group Co., Ltd.). As for scoring system, ELTS score was sensitive in differentiating whether patients could achieve EMR (P=0.001) and MMR (P=0.004). EUTOS scoring system had a significant difference in achieving MMR at 12 months (P=0.049). However, there was no significant difference in subjects stratified by the Hasford and Sokal scoring systems. In conclusion, ASXL1 mutation, activation signal pathway genes, chromatin modification genes and the presence of >2 mutations were adverse factors in achieving molecular response with TKI treatment. HB and MMR were independent factors for DMR, and initial 2GTKI therapy was better than 1GTKI in the achievement of molecular response. For the scoring system, we found that the ELTS score was the best in predicting the efficacy of TKI therapy. Acknowledgement: The work was supported by the Key R&D Program of Zhejiang (No. 2022C03137.), Public Technology Application Research Program of Zhejiang, China (No. LGF21H080003.), the Key Project of Jinhua Science and Technology Plan, China (No. 2020-3-011.), the 2019-2022 Key Medical Discipline (Haematology) Fund of Jinhua, China. Correspondence to: Dr Jian Huang, The First Affiliated Hospital of Zhejiang University School of Medicine. No. 79 Qingchun Road. Hangzhou, Zhejiang, PR China. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Real-World Usage of Asciminib in Patients with Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) in the United States (US) Using a Large Claims Database

BACKGROUND Since the early 2000s, the standard treatment for CML-CP has been tyrosine kinase inhibitors (TKIs). Approximately 20% of CML patients fail to respond to first- and second-generation TKIs due to intolerance or treatment resistance, with limited treatment options being available for later-line settings. Asciminib received FDA approval in October 2021 for the treatment of adult patients with Philadelphia chromosome-positive (Ph+) CML-CP who were previously treated with two or more TKIs, and in patients with Ph+ CML-CP with the T315I mutation. Considering recent approval, no real-world data on the use of asciminib in clinical practice are available. OBJECTIVE This study aims to describe patient demographic and clinical characteristics, and initial treatment patterns among patients with CML-CP treated with asciminib in the real-world. METHODS This was a retrospective cohort study using IQVIA open-source pharmacy and medical claims data. Eligible patients had ≥ 1 pharmacy claim for asciminib between 01 November 2021 - 30 April 2022 (first claim date = index date), were at least 18 years of age on the index date and had at least 6 months of continuous pre-index data available. Demographic characteristics were assessed on the index date. Among a subgroup of patients with available medical claims baseline clinical characteristics were assessed during the fixed 6-month pre-index period, not including the index date. A claims-based proxy, defined as having prior therapy with ponatinib and a Current Procedural Terminology (CPT) code indicating mutation testing prior to or within 1-month of ponatinib initiation, was used to identify T315I mutation status. RESULTS A total of 320 patients with asciminib pharmacy claims were identified; 277 (86.6%) had at least 6 months of pre-index data available. The mean (standard deviation, SD) age was 56 (15) years, 30.0% were ≥65 years old, 51.6% were female, and 32.5% were from the southern region of the US. Asciminib was mostly prescribed by hematologists and/or oncologists (83.8%). Most patients initiated therapy with a daily dose of 80 mg (86.1%) or 400 mg (8.9%) per the label-recommended dosing for patients in 3L+ and for patients with the T315I mutation, respectively. Overall, 67.2% of patients had at least one claim for another TKI during the 6 months prior to asciminib initiation, with the most commonly observed TKIs being ponatinib (23.1%), dasatinib (20.6%) and bosutinib (16.6%). The median time from discontinuation of the previous TKI and initiation of asciminib was 8 days. Evidence of non-TKI CML therapy (i.e., interferon, chemotherapy, or allogenic stem cell transplant) in the 6 months prior to asciminib initiation was observed in 11.9% of patients. A total of 236 (73.6%) asciminib-treated patients had data for medical claims available. Among these, 63.6% had a diagnosis of CML on a medical claim observed during the 6-months prior to asciminib initiation (including index date) and 3.4% had the T315I mutation, based on a proxy measure, likely underestimating the true prevalence of this mutation. During the 6 months prior to asciminib initiation common comorbidities observed include hypertension (28.8%), osteoarthritis (16.1%) and diabetes (14.0%). Common medication classes observed during the 6 months prior to asciminib initiation include diuretics (27.5%), beta blockers (24.6%) and proton pump inhibitors (20.8%). CONCLUSION To our knowledge, this is the first study that describes real-world demographic and clinical characteristics of patients who initiated asciminib therapy immediately after launch in October 2021. Results show steady utilization of asciminib in clinical practice in patients with great unmet need as observed by the high comorbidity burden and high rates of medication use prior to initiation of asciminib. Results from this analysis are limited by the timeframe after launch and may not be representative of the broader asciminib-eligible CML population as treatment patterns evolve over time. Additional research with more mature data is needed to understand the true usage of asciminib in clinical practice and to assess outcomes in these patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Long-Term Molecular Testing and Clinical Response of Tyrosine Kinase Inhibitors in Patients with Chronic Myeloid Leukemia in the Chronic Phase: 5-Year Follow-up from SIMPLICITY, a Prospective, Observational Study

Introduction Tyrosine kinase inhibitors (TKIs) are commonly used as first-line therapy for the treatment of patients with chronic myeloid leukemia in the chronic phase (CML-CP). Molecular response is monitored regularly after initiating TKI therapy and less frequently after achieving BCR::ABL1 ≤ 0.1%. Although responses to TKIs have been extensively evaluated in clinical trials, utilization of molecular testing and clinical response associated with TKI therapy is not as well understood in real-world settings. SIMPLICITY (NCT01244750) is a prospective observational study assessing TKI use, molecular testing patterns, and clinical response in patients with CML-CP in routine clinical practice. Methods The SIMPLICITY study followed patients with CML-CP from routine clinical practice who received first-line treatment with the first-generation TKI imatinib (IM) or second-generation TKIs dasatinib (DAS) or nilotinib (NIL) in the USA and Europe. As this was an observational study, molecular testing was performed at the discretion of the treating team without directives from the study protocol. The cumulative proportion of US patients who underwent ≥ 1 molecular test as well as the rates of major molecular response (MMR; BCR::ABL1 ≤ 0.1%) and deep (4.5-log) molecular response (MR4.5; BCR::ABL1 < 0.0032%) were evaluated through 3 and 6 months, and yearly through 5 years, after starting TKI treatment. Patients were stratified by index TKI (IM or DAS/NIL). Descriptive statistics are presented. Results At data cutoff (January 28, 2020), a total of 810 prospective US patients were enrolled and included in this analysis, of whom 244 received IM and 566 received DAS/NIL. The median age (range) at diagnosis was 56 (18-91) years (IM, 58 [18-90] years; DAS/NIL, 55 [19-91] years). A total of 796 (98.3%) patients were followed through 3 months from the start of index TKI treatment, 792 (97.8%) through 6 months, 762 (94.1%) through 1 year, 704 (86.9%) through 2 years, 652 (80.5%) through 3 years, 590 (72.8%) through 4 years, and 538 (66.4%) through 5 years. Of those followed, the overall proportion of patients tested for molecular response ranged from 20.7% through 3 months to 92.2% through 5 years (Figure). The proportion of assessed patients who achieved MMR at least once increased over time; MMR was achieved in 15.8% of patients assessed through 3 months (IM, 11.1%; DAS/NIL, 17.1%), 35.0% through 6 months (IM, 28.7%; DAS/NIL, 36.8%), 58.2% through 1 year (IM, 51.6%; DAS/NIL, 60.5%), 77.4% through 2 years (IM, 72.9%; DAS/NIL, 79.2%), 86.6% through 3 years (IM, 84.8%; DAS/NIL, 87.3%), 92.5% through 4 years (IM, 90.6%; DAS/NIL, 93.4%), and 95.4% through 5 years (IM, 95.9%; DAS/NIL, 95.2%). The proportion of patients who achieved MR4.5 at least once also increased over time; MR4.5 was achieved in 6.1% of patients assessed through 3 months (IM, 2.8%; DAS/NIL, 7.0%), 15.9% through 6 months (IM, 9.2%; DAS/NIL, 17.9%), 32.5% through 1 year (IM, 23.4%; DAS/NIL, 35.6%), 50.2% through 2 years (IM, 41.3%; DAS/NIL, 53.6%), 63.8% through 3 years (IM, 54.9%; DAS/NIL, 67.4%), 73.8% through 4 years (IM, 67.9%; DAS/NIL, 76.3%), and 79.2% through 5 years (IM, 75.9%; DAS/NIL, 80.6%). Among all 810 enrolled patients, 473 (58.4%) and 393 (48.5%) achieved MMR and MR4.5, respectively, and remained in the study through 5 years. Mean (standard deviation) time from index TKI to best response in tested patients was 2.4 (0.5) months among patients assessed through 3 months and 24.4 (15.4) months among those assessed through 5 years. Conclusions At 5-year follow-up in US patients from the SIMPLICITY study, there was a consistent increase in the proportion of assessed patients who achieved MMR and MR4.5 over time for all patients treated with TKIs, with the caveat that patients who remained on treatment at each subsequent time point were more likely to respond. In general, a consistently higher proportion of patients treated with DAS/NIL achieved MR4.5 across the time points assessed compared with IM in this non-controlled study. Further studies evaluating molecular response to IM, DAS, NIL, and other TKIs beyond 5 years can help delineate further differences in outcomes and determine whether molecular testing frequency correlates with outcomes. Study support This study was funded by Bristol Myers Squibb. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

More Than Ten Years Follow-up of Frontline Tyrosine Kinase Inhibitor Therapy in Patients with Chronic Myeloid Leukemia

Background: Tyrosine kinase inhibitor (TKI) therapy improved survival in patients (pts) with chronic myeloid leukemia (CML). Treatment-free remission (TFR) can be considered for a minority of pts, particularly in those who achieved sustained deep molecular response (DMR). Given most pts needs TKI therapy over decades, the aim of this study is to evaluate the very long-term outcome of pts (pts) treated with frontline TKI. Methods: We analyzed 557 pts with newly diagnosed CML in chronic phase (CP) and accelerated phase (AP; based solely on the presence of clonal evolution) who were treated with frontline TKI therapy (standard-dose imatinib, 73 pts; higher-dose imatinib, 210 pts; dasatinib, 144 pts; and nilotinib, 130 pts) from July 2000 to September 2014. The presence of comorbidity was assessed by the Adult Comorbidity Evaluation-27. Responses criteria were previously defined (complete cytogenetic response, CCyR; major molecular response, MMR; molecular response with a 4-log reduction, MR4; molecular response with a 4.5-log reduction, MR4.5). Failure-free survival (FFS) was calculated from the start of therapy to the treatment discontinuation for any reason except of TFR; event-free survival (EFS), to the date of any of the events while on study as defined in the IRIS study; transformation-free survival (TFS), to the date of transformation to accelerated or blast phases during study; overall survival (OS), to the date of death from any cause at any time or date of last follow-up. We evaluated prognostic factors with univariate and multivariate Cox proportional hazard models with a p-value cutoff of 0.100 or less by univariate analysis for variable selections; cumulative incidence of response was assessed with a competing risk model. Multiple imputation was performed for missing variables to reduce bias. Time to complete cytogenetic response was analyzed as a time-dependent variable in the Cox regression Results: The median age at the start of TKI therapy was 49 years (range, 15.1-86.4). The overall median follow-up was 178 months (range, 5.3-253.9) (standard-dose imatinib, 231 months; higher-dose imatinib, 212 months; dasatinib 137 months; nilotinib 138 months) (Table 1). Overall, the 10-year cumulative incidence rates of CCyR, MMR, MR4, and MR4.5 were 91%, 87%, 76%, and 72%, respectively; among pts who responded, the median time to CCyR, MMR, MR4, and MR4.5 were 3.1 months, 5.9 months, 9.5 months, and 12.5 months, respectively. The cumulative incidence rates of CCyR, MMR, MR4, and MR4.5 were higher in the higher-dose imatinib, dasatinib, and nilotinib cohorts compared to standard-dose imatinib. The 10-year FFS rates were 48%, 52%, 67%, and 44% in the standard-dose imatinib, higher-dose imatinib, dasatinib, and nilotinib cohorts, respectively (P<0.001); the 10-year TFS rates were 84%, 98%, 98%, and 96%, respectively (P<0.001); the 10-year EFS rates were 67%, 80%, 89%, 86%, respectively (P=0.001); the 10-year OS rates were 67%, 80%, 89%, and 86%, respectively (P=0.206) (Figure 1). Backward multivariate Cox regression analysis identified older age at TKI therapy, the presence of smoking history, higher severity of comorbidity by the Adult Comorbidity Evaluation-27, higher percentage of blasts in peripheral blood, and longer time to achieve CCyR as adverse prognostic factors for survival. With the minimum median follow-up of more than 10 years in all the TKI groups, the 10-year relative survival rate was 91.4%; among pts who achieved CCyR within 1 year of frontline TKI therapy, the 10-year relative survival rate was 94.4%; MMR, 97.0%; MR4, 96.7%; MR4.5, 96.2%. Conclusion: TKI therapy has significantly improved outcomes of pts with CML-CP. Frontline second-generation TKIs achieve higher rates of DMR response than standard-dose imatinib. The assessment of comorbidity is essential assessment for the optimal selection of frontline TKI therapy. The survival of pts with CML-CP is similar to that of general population at 10 years. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Chronic Myeloid Leukemia Failed Second Generation Tyrosine Kinase Inhibitor Patients' Molecular Interrogation Using Next Generation Sequencing

Background The practise of prescribing Chronic Myeloid Leukaemia (CML) patients with indefinite tyrosine kinase inhibitors (TKIs) has gone uncontested, and the capacity of TKIs to eliminate the CML clone is uncertain. Although the vast majority of CML patients do respond to TKIs, nonetheless, resistance may develop either de novo or during treatment. TKI resistant pathways are commonly classified as BCR-ABL1-dependent or BCR-ABL1-independent. The causal factors in molecular evolution for this group of patients is still unknown. In this study, our goal was to explore the molecular mechanisms involved in patients who failed second-generation TKIs where we hope to identify potential genetic signatures and pathways that lead to TKI resistance. Materials and Methods CML patients who failed second generation TKI were identified and labeled as non-responders. Eight RNA samples were analysed for purity and processed using the Illumina Stranded Total RNA Prep, Ligation with Ribo-Zero Plus kit (Illumina, CA, USA) and were sequenced on Illumina Novaseq 6000 system (Illumina, CA, USA) system with an average of approximately 133 million passed paired reads, 100 bp in length, per sample. The paired-end reads were aligned to the human reference genome (version hg38/GRch38) using the Illumina DRAGEN (Dynamic Read Analysis for GENomics) Bio-IT Platform. The same system was used for gene-expression quantification, fusion gene detection, and variants analysis. Genes that demonstrate Log2 fold-change ≥3 and P≤0.01 were identified as differentially expressed genes (DEGs). The significantly enriched pathways from several pathway databases were filtered at a false-discovery rate (FDR) of <0.01. ResultsVariant analysis As shown in Table 1, an average of 628,935 ± 190,0862 variants were identified in the non-responder compared to 545,496 ± 58,000 variants in the responder. Out of the variants detected in the non-responder, 90.39% ± 0.30% was SNPs, 4.83% ± 0.15% insertions, and 4.78% ± 0.17% deletions. A total of 21,782 variants were found to be exclusively present in non-responder only. Differentially Expressed Genes (DEGs) Whole transcriptomic analysis identified a total of 201 differentially regulated genes (DEGs; Log2 fold-change ≥ 3 and P ≤ 0.01, Student's t-test), of which 87 genes were up-regulated and 114 genes down-regulated in the non-responder group. Network and Gene Enrichment Analysis The identified DEGs were subjected to network and gene enrichment analysis using STRING database. A total of 3 distinct clustered were identified, corresponding to histone acetylation/deacetylation (HDACs/HATs), cellular senescence, and RNA polymerase regulation as shown in the Figure 1. Discussion & Conclusion Techniques with enhanced sensitivity such as next-generation sequencing and the use of artificial intelligence techniques coupled with the development of mathematical modelling and computational prediction methods may reveal the underlying mechanism of drug resistance and facilitate the design of more effective treatment strategies in CML patients. This preliminary analysis found that individuals who failed second-generation TKIs expressed a potentially unique genetic signature. However, a larger sample size is necessary to verify these findings. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Toxicity of Asciminib in Real Clinical Practice; Analysis of Side Effects and Cross-Intolerance with Tyrosine Kinase Inhibitors

Introduction: Although Tyrosine Kinase Inhibitors (TKIs) have changed the natural history of chronic myeloid leukemia (CML), still a significant percentage of patients fail the TKIs available to date. Asciminib is a first-in-class BCR:ABL1 inhibitor specifically targeting the myristoyl pocket of ABL. Since adverse events (AEs) are mostly related to inhibition of non-target kinases by ATP-binding TKIs, asciminib could provide improved tolerability. Asciminib has demonstrated a good safety profile in clinical trials and in some preliminary studies in real clinical practice recently reported by several groups. Our objective is to perform an analysis focused on the toxicities shown with asciminib, as well as to study the cross-intolerances with other TKIs, which may limit the expected success. Materials and methods: We retrospectively studied 77 CML patients from 36 centers, who had presented a therapeutic failure to second-generation TKI. All of them received asciminib through a compassionate use program between Oct-2018 and June-2022. Statistical analysis was performed by SPSS using Fisher's exact test. Results: the mean age at data collection was 66 years. 88% of patients had received ³3 TKIs previously. 34% had previously received ponatinib. Except for one patient who started in accelerated phase, the rest had chronic phase disease. Switching to asciminib was due to intolerance in 64% of patients. 25% had BCR-ABL mutations (4 patients T315I). Asciminib was initiated at a dose of 40mg BID, with the exception of patients with T315I mutation, who were initiated at 200mg BID. Frequency of AEs is shown in Figure 1. 55% of patients had some AE with asciminib, most of them mild (grades 1-2), with 18% being grade 3-4. Most frequent AE were fatigue (18%), thrombocytopenia (17%), anemia (12%) and arthralgias (12%). None of the patients with previous cardiovascular events presented a new event. There were no cases of de novo occlusive peripheral arterial disease (PAD), although one patient experienced worsening of preexisting PAD. In 20 patients a dose adjustment was required and in 19 of them a temporary suspension of treatment. The need for dose adjustment was more frequent in the intolerant group than in the group resistant to previous lines (33% vs 14%). Patients who required a dose reduction had an MMR rate at the end of follow-up of 55% (11/20) vs. 63% (34/54) in those who maintained standard doses. 8% (6/77) of patients had to stop treatment definitively due to side effects (pleural effusion, pneumonitis, renal failure, worsening of PAD, two due to pancreatitis). When comparing AEs of asciminib versus previous classical TKIs, a lower percentage of cytopenias was observed (Fig.1b). For non-hematologic toxicities (Fig.1c), the frequency of AEs was visibly lower for the percentage of headache, pleural/pericardial effusion, diarrhea, and edema. No significant differences were observed for the rate of arthralgias, fatigue, abdominal pain and nausea. Cross-intolerance with previous TKIs was analyzed for the most frequent AEs observed with asciminib (Table 1). Cross-toxicity risk was statistically significant for thrombopenia, anemia, neutropenia, fatigue, vomiting and pancreatitis. Cross-toxicity does not appear to affect the occurrence of cardiovascular events, edema, abdominal pain, diarrhea or rash. Cross intolerance led to treatment discontinuation in 5 patients (pleural effusion, pneumonitis, worsening of PAD, two cases of pancreatitis). In terms of efficacy, 73% of patients maintained or achieved a complete cytogenetic response (CCyR) and 60% a major molecular response (MMR). Of the patients who had no prior response, 50% achieved CCyR and 49% achieved MMR. Responses were much better in patients who started asciminib for intolerance versus those who started it for resistance (80% of intolerant patients maintained or achieved MMR vs 26% in the resistant group). With a median follow-up of 13,74 months a 71% of the patients continued treatment with asciminib. Of the total dropouts 7/22 (9% of total) were due to intolerance, 10/22 due to resistance and 5/22 due to death from any cause. Conclusion: Asciminib is a molecule with a good safety profile, with a lower rate of AEs compared to classical TKIs. However, this drug, despite its novel mechanism of action presents risk of cross-intolerance with classical TKIs for some toxicities, including hematologic toxicity, fatigue, vomiting and pancreatitis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Olverembatinib in chronic myeloid leukemia.

The introduction of tyrosine kinase inhibitors (TKIs) represents a new era in the management of chronic myeloid leukemia (CML). Despite their long clinical success, point mutations emerging before or during TKI treatment remain an obstacle for several cases. T315I is one of these point mutations in the tyrosine kinase domain of BCR::ABL1. It is a major cause of resistance against first- and second-generation TKIs and therefore lowers survival rates of a small group of patients. Olverembatinib (HQP-1351, formerly GZD-824) is a novel, orally active TKI, which acts through targeting the ATP-binding site of the BCR::ABL1 tyrosine kinase. In recent studies, olverembatinib appears to be an effective and safe treatment option for CML patients harboring T315I mutation. This article mainly focuses on the efficacy and safety data of olverembatinib along with other clinically available and potentially active drugs against T315I-mutated CML.