Intolerant Chronic Myeloid Leukemia Research Articles

Developing therapeutic approaches for chronic myeloid leukemia: a review.

Modern clinical therapy of chronic myeloid leukemia (CML) with TKIs is highly efficacious in most CML patients, while it is not remedial and generally confined due to intolerance or resistance. CML is currently considered a severe disease. Interestingly, stem cell transplantation in the past decade was an attractive clinical therapeutic option in CML patients, but it is not successful due to independently more death rates in older patients. So, the targeting of BCR::ABL oncoprotein is extensively used to enhance the reduction in a higher percentage of CML patients by tyrosine kinase inhibitors (TKIs). However, resistance or intolerance responses to these inhibitors are responsible for future deterioration and further development of disease. At this point, the clinical treatment of CML is a major challenge, and the lack of molecular responses to TKIs are not succeeded with chemotherapy alone. So, the considerable efficacious clinical necessities remain unmet. Therefore, continuous efforts are needed to explore new potential treatment strategies with an increasing understanding of CML biology. Therefore, this review deals with the investigation of TKI treatment with interferon, chemotherapy (Hydroxyurea, Homoharringtonine, Omacetaxine, Cytarabine), and several other new TKIs under beneficial clinical trials. Additionally, the approaches towards TKIs-resistant or intolerant CML cells where the respective signaling pathway gets up-regulated are also targeted with its inhibitor. This review presents evidence that new TKIs under clinical and pre-clinical trials may improve the chemotherapy of CML.

PB1895: ANALYSIS REVEALS CANCER-ASSOCIATED GENE MUTATIONS IN CHRONIC MYELOID LEUKEMIA PATIENTS ：A CHINESE MONOCENTRIC RETROSPECTIVE STUDY

Background: Recent genetic studies have shown that tyrosine kinase inhibitors (TKI) resistant or intolerant Chronic myeloid leukemia (CML) patients often carry one or more genetic changes related to myeloid malignancies, suggesting that additional mutations other than ABL1 mutation may lead to TKI treatment failure or disease progression. Aims: We performed sequencing of 22 CML patients using next-generation sequencing (NGS). 23 CML patients tested WT1 expression detection. Methods: The second cohort (No. 1) tested by second-generation sequencing included 22 CML patients. The second cohort (No. 2) tested by WT1 expression detection included 23 CML patients. The study has been approved by the institutional ethics committee and patients provided written informed consent in accordance with the Fourth Affiliated Hospital of Zhejiang University School of Medicine.Definitions Response was defined as BCR-ABL1 transcript levels according to the International Scale (IS) ≤10%, ≤1% and ≤0.1% at 3, 6 and 12 months after initiating TKI-therapy. Molecular response with 4.0 log reduction (MR4.0) was defined as 0.01%. Molecular response with 4.5 log reduction (MR4.5) was defined as 0.0032% or less BCR-ABLtranscript level. The comparison between groups of measurement data showed that the data with normal distribution were analyzed by one-way ANOVA or t-test. Results: Overall, a total of 51 mutations involving 25 genes were detected most frequently in the ASXL1 (40.9%), KMT2C (27.3%), DIS3 (18.2%), ATM (13.6%), DNMT3A (13.6%) and NOTCH3 (13.6%) genes. NOTCH3 and RELN mutations were only 3/20 (10%) in those who did not reach 12M-MMR group. Although the difference was not statistically significant (P = 0.214, P = 0.476). The number of median mutant genes in reaching MR4.5 group was 1 (0-3). The number of median mutant genes in not reaching MR4.5 group was 4 (0-6), and the difference was statistically significant (P = 0.033). ASXL1 mutation in reaching MR4.0 group and non reaching MR4.0 group was statistically significant (P = 0.023). With KMT2C mutation group had lower PFS (P = 0.079). There was a potential statistical difference between low WT1 expression group and high WT1 expression group in early EMR after a 3-month treatment (P = 0.089).The research 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 2019–2024 Academician Workstation of the Fourth Affiliated Hospi-tal of the Zhejiang University School of Medicine; the 2019–2022 Key Medical Dis-cipline (Hematology) Fund of Jinhua, China. *Correspondence to: Dr Jian Huang, Department of Hematology, The Fourth Affiliated Hospital of Zhejiang University School of Medicine. N1 Shangcheng Road. Yiwu, Zhejiang, Peoples R China.E-mail: [email protected] Image:Summary/Conclusion: Genomic risk assessment can improve the risk stratification of clinical diagnosis, and can more accurately identify patients with poor effect of TKI treatment in the era of TKI treatment. The treatment effect of CML patients with NOTCH3, RELN and ASXL1 mutations and more than two gene mutations is poor. CML patients with high expression of WT1 at diagnosis have poor therapeutic effect in the early stage.

Targeting UPR signaling pathway by dasatinib as a promising therapeutic approach in chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a myeloproliferative disease that mediated by BCR/ABL oncogenic signaling. CML can be targeted with the imatinib, dasatinib, and nilotinib TKI inhibitors, the latter two of them have been approved for imatinib-resistant or -intolerant CML patients. The TKIs resistance occurs by different molecular mechanisms, including overexpression of BCR-ABL, mutations in the TKI binding site of BCR/ABL, and ER-stress. Unfolded protein responses (UPR) is a cytoprotective mechanism which is activated by ER-stress. The IRE1, PERK, and ATF6 are three main arms of the UPR mechanism and are activated by a common mechanism involving the dissociation of the ER-chaperone BiP/GP78. There is a correlation between ER-stress, CML progression, and response to TKI treatment. In the present study, we aimed to determine alterations of the expression levels of genes related to UPR pathway signaling after treatment with dasatinib in K562 chronic myeloid leukemia cell line by quantitative RT-PCR relatively. The array-data revealed that treatment with dasatinib significantly decreased the UPR mechanism-related genes (including HSPA1B, HSPA2, HSPA4L, ATF6, ATF6B, CEBPB, PERK, TRIB3, DNAJB, ERN1, and UHRF1) in K562 cells. In conclusion, the results showed that dasatinib regulates the UPR mechanism that plays a significant role in cancer progression and therapy resistance in CML. Thus, dasatinib-induced dysfunction of the UPR mechanism may promise encouraging therapy for CML.

Four-year follow-up of patients with imatinib-resistant or intolerant chronic myeloid leukemia receiving dasatinib: efficacy and safety.

Dasatinib is a highly effective second-generation tyrosine kinase inhibitor used to treat chronic myeloid leukemia (CML). In 2007, a pivotal phase-2 study of dasatinib as second-line treatment was initiated in 140 Chinese CML patients. This report from the 4-year follow-up revealed that 73% of 59 patients in chronic phase (CML-CP) and 32% of 25 patients in accelerated phase (CML-AP) remained under treatment. The initial dosage of dasatinib for CML-CP and CML-AP patients were 100 mg once daily and 70 mg twice daily (total = 140 mg/ day), respectively. The cumulative major cytogenetic response (MCyR) rate among patients with CML-CP was 66.1% (versus 50.8% at 18 months), and the median time to MCyR was 12.7 weeks. All CML-CP patients who achieved MCyR after a 4-year follow-up also achieved a complete cytogenetic response. The cumulative complete hematological response (CHR) rate among patients with CML-AP was 64% (16/25), with three CML-AP patients achieving CHR between 18 months and 4 years of follow-up; the median time to CHR was 16.4 weeks. The adverse event (AE) profile of dasatinib at 4 years was similar to that at 6 and 18 months. The most frequently reported AEs (any grade) included pleural effusion, headache, and myelosuppression. These long-term follow-up data continue to support dasatinib as a second-line treatment for Chinese patients with CML.

One Size Does Not Fit to All: Intolerant or Resistant CML Patients Could Benefit from Different Ponatinib Starting Dose Strategies. Multicenter Italian Experience

Background: Ponatinib is effective as salvage treatment for chronic phase (CP) Ph+ chronic myeloid leukemia (CML) patients resistant or intolerant to prior TKIs. Based on the concern for an unfavourable cardiovascular toxicity profile, a dose reduction to 15 mg daily is currently recommended in CP patients after the achievement of treatment milestones. As more flexible approaches with TKIs dosage are increasingly adopted in clinical practice, identifying specific profiles of patients eligible for different treatment strategies, in order to improve the benefit/risk ratio, would be of particular interest.Aims: To update previous observations in an extended cohort of CML patients, resistant or intolerant to prior TKIs, describing the efficacy and toxicity of two different ponatinib schedules (de-escalated vs 15 mg starting dose). Secondly, to investigate whether specific subsets of CML patients were managed more successfully with one strategy.Methods: A retrospective analysis of CML-CP patients treated with ponatinib 15 mg, as starting or de-escalated dose has been performed. No pre-specified criteria to switch to ponatinib, to reduce or to start therapy with a lower dose were indicated. Cytogenetic and molecular responses were evaluated according to the ELN2013 recommendations. Toxicities under ponatinib treatment leading to transient or definitive discontinuation were recorded.Results: 68 patients were included in this analysis. Median age at ponatinib start was 57 years (range: 28-87). The median time from CML diagnosis to ponatinib treatment was 4.6 years (range: 0.4-19). Most patients (70.6%) were treated with imatinib as frontline treatment. 30/68 patients (44%) received ponatinib as 4th or subsequent line of therapy. ABL1 mutations were detected in 18 (26.5%) patients (being 44% of them positive for the T315I mutation). 50/68 (73.5%) of cases had less than MR2 at the time of ponatinib initiation, with one third exhibiting primary refractoriness to all prior treatments. Resistance to prior TKIs was the reason for switch in 85% of patients treated with higher doses of ponatinib, while 13/26 patients starting with 15 mg were purely intolerant or intolerant and resistant (p= 0.001). No other significant differences between the two groups were identified.MR2, MR3 and MR4/MR4.5 rates were 78.6%, 59.6% and 28.6% in 42 patients treated with the “de-escalated” approach, respectively. First step of dose reduction was decided after a median time of 3.1 months, with a subsequent decrease to 15 mg after a median of 10 months. Dose modifications were guided mostly by adverse events (73%) and, less frequently, to prevent toxicity and/or following response attainment (27%). Median duration of treatment was 27 months (range: 2-81), with 5/42 patients discontinuing ponatinib (1 cerebrovascular accident, 2 severe hematologic toxicities, two cases of resistance/progression). 4 deaths were registered, three after blast crisis and one for a fatal cardiovascular event.26 patients started ponatinib 15 mg daily, with a median duration of treatment was 15 months (range: 2-58). MR2 was obtained in 77%, MR3 in 69.3% and MR4 in 46.2% of cases, respectively. MR3 or deeper responses were maintained in 80% of patients; 7/26 lost their best acquired response, with subsequent dose escalation to higher than 15 mg in 5/26 patients. Treatment discontinuation was necessary in 3 cases (1 coronary vasospasm-induced acute coronary syndrome, 2 muscle skeletal pain).Of note, patients with ABL mutations gained benefit only from the “de-escalated” approach, with response improvements in 10/14 of cases vs 0/4 in the “low dose” group. Similarly, a higher rate of at least a MR2 was obtained in primary refractory patients treated ab initio with higher doses of ponatinib (57.1 % vs 14.3 %). However, focusing only on pure intolerant patients, 15 mg starting dose was very effective, with all patients achieving at least a MR3 or deeper response.Summary/Conclusion: With the limits of the retrospective nature and small sample size, these data suggest that different dose strategies could be applied to specific subsets of CP-CML patients. While mutations or refractoriness to previous treatments should address towards a “debulking approach” with 45 or 30 mg ponatinib dose, intolerant or “low level resistance” cases could benefit from lower starting dose. Further investigation in larger prospective trials is warranted. DisclosuresCastagnetti:Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Gugliotta:Bristol-Myers Squibb: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Abruzzese:Ariad: Consultancy; BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Breccia:Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria; Incyte: Honoraria. Levato:Novartis: Other: Advisory board. Pane:AMGEN: Speakers Bureau; BMS: Speakers Bureau; Novartis: Research Funding, Speakers Bureau.

Induction of apoptosis in imatinib sensitive and resistant chronic myeloid leukemia cells by efficient disruption of bcr-abl oncogene with zinc finger nucleases

BackgroundThe bcr-abl fusion gene is the pathological origin of chronic myeloid leukemia (CML) and plays a critical role in the resistance of imatinib. Thus, bcr-abl disruption-based novel therapeutic strategy may warrant exploration. In our study, we were surprised to find that the characteristics of bcr-abl sequences met the design requirements of zinc finger nucleases (ZFNs).MethodsWe constructed the ZFNs targeting bcr-abl with high specificity through simple modular assembly approach. Western blotting was conducted to detect the expression of BCR-ABL and phosphorylation of its downstream STAT5, ERK and CRKL in CML cells. CCK8 assay, colony-forming assay and flow cytometry (FCM) were used to evaluate the effect of the ZFNs on the viablity and apoptosis of CML cells and CML CD34+ cells. Moreover, mice model was used to determine the ability of ZFNs in disrupting the leukemogenesis of bcr-abl in vivo.ResultsThe ZFNs skillfully mediated 8-base NotI enzyme cutting site addition in bcr-abl gene of imatinib sensitive and resistant CML cells by homology-directed repair (HDR), which led to a stop codon and terminated the translation of BCR-ABL protein. As expected, the disruption of bcr-abl gene induced cell apoptosis and inhibited cell proliferation. Notably, we obtained similar result in CD34+ cells from CML patients. Moreover, the ZFNs significantly reduced the oncogenicity of CML cells in mice.ConclusionThese results reveal that the bcr-abl gene disruption based on ZFNs may provide a treatment choice for imatinib resistant or intolerant CML patients.

What Happens to Refractory or Intolerant Chronic Myeloid Leukemia Patients without Access to Clinical Trials?

What Happens to Refractory or Intolerant Chronic Myeloid Leukemia Patients without Access to Clinical Trials?

Intracranial stenting for nilotinib treatment-associated cerebrovascular stenosis in chronic myeloid leukemia

One of the second-generation tyrosine kinase inhibitors (TKIs), nilotinib, is increasingly used for imatinib-resistant or intolerant chronic myeloid leukemia (CML). Nilotinib is considered well tolerated with few side effects including hyperglycemia, hyperbilirubinemia and elevated levels of pancreatic enzymes. However, there is growing evidence that nilotinib accelerates atherosclerosis and causes peripheral arterial occlusive disease such as stroke, transient ischemic attack (TIA) and cardiovascular diseases. Herein, we report a case of a 74-year-old male CML patient with intracranial stenosis of the internal carotid artery developed during treatment with nilotinib successfully cured by the intracranial stent, Wingspan.

Long-Term Safety of Dasatinib in Chinese Chronic Phase Chronic Myeloid Leukemia Patients with Imatinib-Resistance or -Intolerance: Results from a 6-Year Follow-up of a Multicenter Phase II Study

Background:The development of BCR/ABL1 tyrosine kinase inhibitors (TKIs) has turned chronic myeloid leukemia (CML) from a fatal disease into a controllable chronic condition. Most CML patients, especially those who were in chronic phase (CP), now may require life-long TKIs therapy. Thus, the long-term safety of TKIs is of great importance. Dasatinib is a second-generation TKI that has been approved in China in 2011 as a treatment for imatinib-resistant or -intolerant CML. Previously we have reported safety findings from the Chinese dasatinib registration study after 4 years of follow-up. The results showed that dasatinib was well tolerated, with a low rate of discontinuation and a safety profile that supported previous data from large Phase 3 clinical trials (CA180-034)[1]. Here we present the safety results from the 6-year follow-up of 59 CML-CP patients in this pivotal Chinese studyAims:To evaluate the long-term safety of dasatinib in Chinese CML-CP patients who were resistant to or intolerant of imatinib after 6 years of follow-up. Important endpoints included the incidence and severity of adverse events (AEs) and treatment discontinuation due to drug-related AEs.Methods:This was an open-label, single-arm phase 2 clinical study conducted at 10 centers in China. Adult, Chinese CML patients with imatinib-resistant or -intolerant were recruited. CML-CP patients received oral dasatinib of 100mg/d, until disease progression or intolerable toxicity. Follow-up visits were scheduled at least every 4 weeks until all study-related toxicities returned to baseline or ≤ National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0 Grade 1, stabilized or were irreversible.Results:A total of 140 patients were enrolled, 59 of whom had CML-CP. After 6 years of follow-up, 61% (36/59) of patients with CML-CP remained on treatment. Between the 4- and 6-year follow-up, there were no further deaths on the study and no more patients with CML-CP discontinued treatment due to drug-related AEs.Overall, drug-related AEs of any grade were experienced by 74.6% (44/59) of patients with CML-CP, of which 3 patients experienced drug-related AEs after 4-year follow-up (Table). 20.3% (12/59) of patients with CML-CP experienced drug-related, Grade 3-4 AEs and 16.9% (10/59) experienced drug-related serious AEs (Table). 16.9% (10/59) of patients experienced haematological AEs (Grade 3-4, 11.9%, 7/59) and none of the 10 cases happened after 4-year follow-up. The most frequently reported drug-related AEs for CML-CP patients remained pleural effusion (25.4%, 15/59; Grade 3-4, 3.4%, 2/59) and 1.7% (1/59) of the patients discontinued dasatinib treatment due to pleural effusion. Only 1 new case of pleural effusion occurred between 4-year and 6-year follow-up and no more Grade 3-4 pleural effusion has been observed after 4-year follow-up. Pulmonary hypertension were experienced by 8.5% (5/59) patients. Only 1 new case of pulmonary hypertension happened between 4-year and 6-year follow-up and no more Grade 3-4 pulmonary hypertension occurred after 4-year follow-up. Between 4-year and 6-year follow-up, 1 patient (1.7%) experienced Grade 1-2 pulmonary arterial hypertension and this was the only case of pulmonary arterial hypertension observed in the study. Deep vein thrombosis (1.7%, 1/59) occurred to 1 patient in 4-year follow-up and no more cases of deep vein thrombosis occurred between 4-year and 6-year follow-up.Conclusion:The safety profile of dasatinib after 6-year follow-up was consistent with the results from 4-year follow-up, which confirmed the long-term safety of dasatinib in the treatment for Chinese CML-CP patients with imatinib-resistance or -intolerance. Pleural effusion remained the most common adverse event during long-term follow up. As TKI-associated vascular AEs (VAEs) is drawing more and more attention in recent years, we have evaluated their incidence in our study and the results showed that the risk of VAEs remained low with long-term dasatinib treatment.Acknowledgment: BMS funded this research and medical writing support.Reference[1] Huang XJ, Hu JD, Li JY, et al. Four-year follow-up of patients with imatinib-resistant or -intolerant chronic-phase chronic myeloid leukaemia receiving dasatinib: efficacy and safety. Poster (#54229) presented at the 19th European Haematology Association Annual Congress; 12-15 June 2014; Milan, Italy DisclosuresNo relevant conflicts of interest to declare.

Clinical Pharmacokinetics and Pharmacodynamics of Bosutinib.

Chronic myeloid leukemia (CML) is a clonal myeloproliferative stem cell disorder. Bosutinib is an oral, once-daily SRC/ABL tyrosine kinase inhibitor with very potent inhibitory activity. Bosutinib is effective against all phases of intolerant or resistant Philadelphia chromosome-positive CML that do not harbor the T315I or V299LABL kinase domain mutations. Peak plasma concentrations of bosutinib occur at 4-6 h following oral administration, and dose-proportional increases in exposure are observed at doses ranging from 200 to 800mg. Absorption of bosutinib increases with food. Bosutinib is distributed extensively into the tissues. It is highly plasma protein bound (94%) and is primarily metabolized in the liver by cytochrome P450 3A4. Bosutinib is well tolerated overall and has a unique but manageable toxicity profile. This article provides a review of the available clinical pharmacokinetic, pharmacodynamic, and drug-drug interaction data on bosutinib in healthy subjects, patients with CML, and special populations.

Outcomes of Second-Line Treatment By Dasatinib in Imatinib-Resistant or -Intolerant Chronic Myeloid Leukemia Patients with and without Comorbidities

▪Patients in chronic phase chronic myeloid leukemia (CML-CP) with comorbidities may have reduced overall survival and worse safety of TKI treatment as compared in those without comorbidities. Dasatinib is a promising treatment option for CML-CP patients resistant or -intolerant to imatinib. Benefits and risks of this treatment regimen might be dependent on the presence of comorbidity. We aimed to study clinical outcomes, safety and QoL in CML-CP patients with and without comorbidities receiving dasatinib as second-line treatment in a "real-world" setting.30 CML-CP patients resistant or -intolerant to imatinib were enrolled in multicenter prospective observational real-world study (mean age 48 years old, SD 13.1; range 22-60 years; male/female - 14/16). All the patients received dasatinib as the second-line therapy (100 mg daily) during 18 months. Ten patients exhibited comorbidities: Charlson Comorbidity Index varied from 1 to 5. Treatment outcomes were evaluated at 18 months of dasatinib therapy. For QoL assessment patients filled out SF-36 questionnaire before and 18 months after dasatinib treatment start. Group comparisons were made using t-test. Clinically significant differences were analyzed by computing Effect Size (ES).At 18 months of dasatinib treatment there were no statistically significant differences in clinical response between the groups with and without comorbidities: complete hematologic response was observed in 90 and 95% patients, respectively; complete cytogenetic response - in 80 and 55% patients, respectively; molecular response - in 60% patients in both groups (complete molecular response - in 50 and 25% patients, respectively; major molecular response - in 10 and 35% patients, respectively). In the group with comorbidities 2 patients had severe adverse effects (SAE) at 18 months of treatment: headache, hyperglycemia, pleural effusion, visual problems, neuropathy, memory loss, diarrhea, visual problems. In the group without comorbidities 5 patients exhibited SAE at 18 months of treatment: fatigue, memory loss, headache, neutropenia, sleepless.QoL before dasatinib treatment was more impaired in the group with comorbidities than in patients without comorbidities: physical functioning - 57.8 vs 80.4 (p=0.01, ES=0.89), Integral QoL index - 0.29 vs 0.44 (ES=0.75). After 18 months of dasatinib treatment QoL improvement or stabilization was registered in both groups as compared with base-line. Patients without comorbidities had significant improvement of role physical functioning (55 vs 82.5, p=0.01), vitality (59 vs 73, p<0.01), role emotional functioning (70 vs 86.7, p=0.02), mental health (62.0 vs 76.8, p=0.01); Integral QoL index significantly increased during treatment as compared with base-line (0.44 vs 0.6, p<0.01). Patients with comorbidities exhibited pronounced improvement of physical functioning during treatment (57.8 vs 69, ES=0.57); no changes in other QoL domains and Integral QoL index were observed.Thus, outcomes of second-line treatment by dasatinib in CML-CP patients with and without comorbidities were studied a "real world"setting. Clinical outcomes and safety profile were similar in patients with and without comorbidities. After 18 months of dasatinib treatment definite QoL improvement was registered in patients without comorbidities and QoL stabilization - in patients with comorbidities. Assessment of the outcomes of second-line therapy by dasatinib in CML-CP both from physician's and patient's perspective allows provide to comprehensive evaluation of benefits and risks of treatment in this heterogeneous patient population. DisclosuresNo relevant conflicts of interest to declare.

Anti-Leukemic Activity of Axitinib Against Cells Harboring the BCR-ABL Point Mutation

Introduction: The BCR-ABL1 fusion gene is a causative oncogene in chronic myeloid leukemia (CML) and 30-50% of acute lymphoblastic leukemia cases. Although ABL tyrosine kinase inhibitors (ABL TKI) such as imatinib have improved CML treatment, such therapies cannot cure patients with Philadelphia chromosome (Ph)-positive leukemia because of leukemia stem cells. Moreover, some patients develop BCR-ABL point mutations and become resistant to ABL TKI therapy. In particular, the ABL kinase domain mutation T315I is resistant to imatinib and second-generation ABL TKIs (e.g., nilotinib, dasatinib, and bostinib). Accordingly, this mutation is often found in patients with TKI-resistant disease. A third-generation ABL TKI, ponatinib, was recently developed. Ponatinib is a potent oral tyrosine kinase inhibitor that affects both unmutated and mutated BCR-ABL; it is effective against T315I mutant cells and has been approved for TKI-resistant or intolerant CML and Ph-positive ALL patients.Recently, the vascular endothelial growth factor receptor (VEGFR) inhibitor axitinib was found to exhibit anti-leukemic activity against T315I-mutant disease. Axitinib is an orally active and potent TKI of VEGFRs 1, 2, and 3 and inhibits BCR-ABL1, especially the T315I variant, via a distinct binding conformation.Materials and methods: In this study, we investigated whether axitinib could suppress ponatinib-resistant compound mutant cells harboring the T315I mutation and primary samples.Results: A 72 h axitinib treatment inhibited the growth of Ba/F3 T315I cells (Figure 1A). Immunoblot analysis of axitinib-treated cells revealed dose-dependent decreases in BCR-ABL, the downstream molecule CrkL, and ribosomal S6 protein phosphorylation and increases in caspase 3 and Poly (ADP-ribose) polymerase (PARP) activity. Ponatinib and axitinib also induced apoptosis, significantly increased caspase activity, and reduced Akt activity. In contrast, clinically available concentrations of axitinib did not inhibit the growth of ponatinib-resistant Ba/F3 cells. Immunoblot analysis revealed that BCR-ABL, Crk-L, and S6 kinase phosphorylation were not inhibited by axitinib or ponatinib. Similarly, no increase in caspase activity or decrease in Akt activity was observed following axitinib treatment, and neither ponatinib nor axitinib affected apoptosis in these cells. We next evaluated primary T315I-mutant and ponatinib-resistant compound mutant samples. Axitinib potently inhibited the growth of T315I mutant primary cells in a dose-dependent manner. Immunoblot analysis further revealed reduced Crk-L and S6 kinase phosphorylation after axitinib or ponatinib treatment. In contrast, the growth of ponatinib-resistant primary cells was not affected by ponatinib or axitinib. Immunoblotting revealed that neither ponatinib nor axitinib affected the phosphorylation of Crk-L and S6 kinase in ponatinib-resistant cells.Conclusion: In CML, ABL TKI resistance is frequently caused by ABL kinase domain mutations. The T315I mutation is resistant to all ABL TKIs except ponatinib. Although axitinib, which is currently being investigated for efficacy in patients with Ph-positive T315I-mutant leukemia, induced apoptosis in T315I-mutant cells, it was ineffective against cells with a compound mutation including T315I. Current evidence to direct the management of ABL TKI-resistant disease, particularly those harboring T315I and compound mutations, is limited. New molecular-targeted drugs and an understanding of ABL TKI resistance mechanisms are required to apply an appropriate therapeutic approach. DisclosuresNo relevant conflicts of interest to declare.

Nilotinib therapy in an imatinib intolerant chronic myeloid leukemia patient with pulmonary severe hypertension

Imatinib mesylate is a tyrosine kinase inhibitor that has significant efficacy in the treatment of chronic myelogenous leukemia. In general, hematologic and extrahematologic side effects of imatinib therapy are mild to moderate, with the large majority of patients tolerating prolonged periods of therapy. However, a minority of patients are completely intolerant of therapy, while others are able to remain on therapy despite significant side effects. Here, we describe a chronic phase CML patient with pulmonary arterial hypertension, mechanical hearth valve, who experienced extrahematologic adverse event (persistent grade III cutaneous rash, despite two discontinuations of imatinib and using of steroid). Necessitating switch to one of new tyrosine kinase inhibitors, nilotinib, has resulted in complete cytogenetic response and major molecular response, after 3 and 6 months, respectively. No cross-intolerance with imatinib was observed during nilotinib therapy. Besides, this clinical case suggests that warfarin and nilotinib can be used concurrently without the risk of increased anticoagulant effect.

Quality of life, symptom profile and clinical efficacy of second-line treatment with dasatinib in patients with imatinib-resistant or -intolerant chronic myeloid leukemia: results of 2-year follow-up

The article is focused on the results of the multicenter observational study “Quality of life and symptom profile in patients with chronic myeloid leukemia in chronic phase in long-term follow-up of second-line treatment” (2012–2015). Thirty imatinib-resistant or-intolerant patients with chronic myeloid leukemia in chronic phase were observed in the real-world clinical setting during 24 months after start of second-line treatment with dasatinib. Mean age – 48 years old (SD = 13.1); males / females – 14 / 16; one third of patients were with comorbidity, Charlson Index – 0–5 scores. All the patients received dasatinib in the dosage of 100 mg daily. Study time points – 12, 18 and 24 months after second-line treatment start. Treatment outcomes were analyzed in terms of clinical efficacy and safety as well as in terms of patient-reported outcomes, including quality of life and symptom profile assessment. For quality of life and symptom assessment the SF-36 and CSP-CML questionnaires were used, respectively. Statisticallly significant changes in quality of life and symptom severity were analyzed by generalized estimated equation (GEE). Complete hematological response was observed in 96.3 % patients, complete cytogenetic response – in 66.6 % patients, complete or major molecular response – in 60 % patients. The acceptable tolerability of dasatinib treatment was shown during long-term follow-up: hematological and non-hematological serious adverse events were rare and didn’t lead to treatment discontinuation. Significant improvement of physical functioning, role physical functioning, role emotional functioning, vitality and mental health as compared to base-line parameters was observed (p < 0.05). The severity of a number pronounced symptoms decreased and the proportion of patients with severe symptoms reduced (p = 0.01) after 24 months of second-line treatment start. Quality of life treatment response in terms of stabilization or improvement was registered in 83 % of patients. The data of this real-world study in CML patients are in line with the results of clinical studies in terms of dasatinib treatment efficacy and safety. In addition, they demonstrate the value of patient-reported outcomes to evaluate benefits and risks of long-term dasatinib treatment from patient perspective.

The role of dasatinib in the management of chronic myeloid leukemia.

Dasatinib is a second-generation tyrosine kinase inhibitor (TKI) for chronic, blastic, or accelerated phase chronic myeloid leukemia (CML) patients who are resistant or intolerant to previous treatment. It potently inhibits BCR/ABL and SRC-family kinases (SRC, LCK, HCK, YES, FYN, FGR, BLK, LYN, FRK), as well as c-KIT, PDGFR-a and -b, and ephrin receptor kinase. Various clinical trials have provided evidence that it has more durable complete hematologic and cytogenetic responses, as well as more potency in imatinib-resistant or -intolerant CML, and it has also shown its advantages in newly diagnosed CML compared to imatinib. In this review, we mainly focus on the structure, mechanisms, pharmacokinetics, and pharmacogenetics of dasatinib. We also summarize clinical trials with dasatinib on CML and provide our recommendations for dasatinib in the treatment of CML.

Nilotinib treatment for patients with imatinib-resistant or intolerant chronic myeloid leukemia

This study was purposed to evaluate the efficacy and safety of nilotinib for treating patients with imatinib-resistant or intolerant chronic myeloid leukemia (CML). A total of 23 patients with imatinib-resistant or intolerant CML were enrolled in this study. These patients received nilotinib orally 600-800 mg every day, their curative efficacy, tolerance and overal survival were evaluated. The results showed that all the patients treated with nilotinib obtained complete hematologic remission (CHR), out of them 82.6% patients achieved complete cytogenetic remission (CCyR) and 56.5% patients achieved complete molecular remission (CMR), their adverse events mostly were mild to moderate, generally were transient and easily cured; the median treatment time with nilotinib was 13.5 (1-44) months, and the median follow-up time was 40 (12-102) months. It is concluded that nilotinib has been confirmed to be effective for patients with imatinib-resistant or intolerant CML, and may be selected as a second generation of tyrosine kinase inhibitor (TKI).

Resistant mutations in CML and Ph(+)ALL - role of ponatinib.

In 2012, ponatinib (Iclusig®), an orally available pan-BCR-ABL tyrosine kinase inhibitor (TKI) developed by ARIAD Pharmaceuticals, Inc., was approved by the US Food and Drug Administration for use in resistant or intolerant chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). Ponatinib is the only approved TKI capable of inhibiting BCR-ABL with the gatekeeper T315I kinase domain mutation, known to be the cause for 20% of resistant or relapsed CML cases. In 2013, ponatinib sales were temporarily suspended due to serious side effects seen in nearly 12% of the patient population. These side effects are thought to stem from the potent nature and pan-activity of this TKI. ARIAD Pharmaceuticals, Inc. has since been permitted to resume sales and marketing of ponatinib to a limited patient population with an expanded black box warning. In the following review, the use of ponatinib in CML and Ph+ALL will be discussed. Mechanisms of resistance in CML are discussed, which provide insight and background into the need for this third generation TKI, followed by the molecular design and pharmacology of ponatinib, which lead to its success as a therapeutic. Finally, the efficacy, safety, and tolerability of ponatinib will be highlighted, including summaries of the important clinical trials involving ponatinib as well as its current place in therapy.

Long-term outcome with dasatinib after imatinib failure in chronic-phase chronic myeloid leukemia: follow-up of a phase 3 study

AbstractWe present long-term follow-up of a dasatinib phase 3 study of patients with imatinib-resistant/-intolerant chronic myeloid leukemia (CML). In the CA180-034 study, 670 patients with imatinib-resistant/-intolerant CML in chronic phase (CML-CP) received dasatinib 100 mg once daily, 50 mg twice daily, 140 mg once daily, or 70 mg twice daily. At 6 years, 188 (28%) of 670 patients remained on study treatment. Estimated 6-year protocol-defined progression-free survival (PFS) rates were 49%, 51%, 40%, and 47%, respectively, and estimated 6-year overall survival (OS) rates were 71%, 74%, 77%, and 70%, respectively (intent-to-treat population, including protocol-defined progression or death after discontinuation). Estimated 6-year rates of survival without transformation on study treatment were 76%, 80%, 83%, and 74%, respectively. Major molecular response was achieved in 43% (100 mg once daily) and 40% (all other arms) of patients by 6 years. Molecular and cytogenetic responses at 3 and 6 months were highly predictive of PFS and OS. Notably, estimated 6-year PFS rates based on ≤1%, >1% to 10%, and >10% BCR-ABL transcripts at 3 months were 68%, 58%, and 26%, respectively. Most adverse events occurred by 2 years. Imatinib-resistant/-intolerant patients with CML-CP can experience long-term benefit with dasatinib therapy, particularly if achieving BCR-ABL ≤10% at 3 months. This study was registered at ClinicalTrials.gov: NCT00123474.

Multicenter phase II clinical trial of nilotinib for patients with imatinib-resistant or -intolerant chronic myeloid leukemia from the East Japan CML study group evaluation of molecular response and the efficacy and safety of nilotinib

BackgroundNilotinib is a second-generation tyrosine kinase inhibitor that exhibits significant efficacy as first- or second-line treatment in patients with chronic myeloid leukemia (CML). We conducted a multicenter Phase II Clinical Trial to evaluate the safety and efficacy of nilotinib among Japanese patients with imatinib-resistant or -intolerant CML-chronic phase (CP) or accelerated phase (AP).ResultsWe analyzed 49 patients (33 imatinib-resistant and 16 imatinib-intolerant) treated with nilotinib 400 mg twice daily. The major molecular response (MMR) rate was 47.8% at 12 months among 35 patients who did not demonstrate an MMR at study entry. Somatic BCR-ABL1 mutations (Y253H, I418V, and exon 8/9 35-bp insertion [35INS]) were detected in 3 patients at 12 months or upon discontinuation of nilotinib. Although 75.5% of patients were still being treated at 12 months, nilotinib treatment was discontinued because of progressing disease in 1 patient, insufficient effect in 2, and adverse events in 9. There was no statistically significant correlation between MMR and trough concentrations of nilotinib. Similarly, no correlation was observed between trough concentrations and adverse events, except for pruritus and hypokalemia. Hyperbilirubinemia was frequently observed (all grades, 51.0%; grades 2–4, 29%; grades 3–4, 4.1%). Hyperbilirubinemia higher than grade 2 was significantly associated with the uridine diphosphate glucuronosyltransferase (UGT)1A9 I399C/C genotype (P = 0.0086; Odds Ratio, 21.2; 95% Confidence Interval 2.2–208.0).ConclusionsNilotinib was efficacious and well tolerated by patients with imatinib-resistant or -intolerant CML-CP/AP. Hyperbilirubinemia may be predicted before nilotinib treatment, and may be controlled by reducing the daily dose of nilotinib in patients with UGT1A9 polymorphisms.Trial registrationclinicaltrials.gov: UMIN000002201

Efficacy Of Dasatinib Therapy In Patients With Imatinib-Resistant Or -Intolerant Chronic Myeloid Leukemia From Physician's and Patient's Perspective: “Real World” Data

There is limited published data about the efficacy and safety of the second-line therapy with dasatinib in patients in chronic phase chronic myeloid leukemia (CML-CP) in a “real world” patients setting outside clinical trials. In addition, comprehensive evaluation of benefits and risks of the treatment is worthwhile to better define treatment outcomes in this patients' population. We aimed to study clinical and patient-reported outcomes as well as safety of dasatinib treatment in a “real world” setting within the context of its approved indication through the analysis of prospectively collected data in patients with imatinib resistance or intolerance receiving dasatinib as the second-line therapy.75 CML-CP patients resistant or -intolerant to imatinib were enrolled in the prospective, multicenter, non-interventional study (mean age 51.3 years old, SD 15.4; range 22–83 years; male/female – 37/38). The median of disease duration was 5.0 years (0.75–17 years). 63 patients had resistance to imatinib; 12 patients were intolerant to imatinib; the median duration of imatinib treatment 40 months (3–121 months). All the patients received dasatinib as the second-line therapy (100 mg daily). Median follow-up was 12 months. For quality of life (QoL) and symptom assessment patients filled out the SF-36 and Comprehensive Symptom Profile in Chronic Myeloid Leukemia Patients (CSP Leuk-CML), respectively, at base-line, in 1, 3, 6 months after treatment start and every 6 months thereafter. Comparison of QoL and symptom scores was conducted using t-test. QoL scores were analyzed using t-test, adjusting for sociodemographic and disease status. Mean symptom severity and percentage of patients with moderate-to-severe (ratings ³ 5) symptoms was evaluated.After 12 months of treatment 83% patients achieved or maintained complete hematologic response and 35 % – complete cytogenetic response. The twenty four-month progression free survival rate was 93% (95% CI; 84–97%). Four cases of pleural effusion events were registered: they were easily managed in 3 cases; one patient died at 1 month after treatment start due to accompanied infection complication. No severe hematological adverse effects were observed except two cases of grade III-IV neutropenia. Two patients were resistant to dasatinib. Two patients died of disease progression at 6 months of follow-up. At 12 months of dasatinib treatment QoL parameters were stable for 5 out of 8 scales; vitality, social functioning and mental health significantly improved as compared with base-line (p< 0.01). At 24 months of dasatinib treatment improvement of physical functioning, vitality, social functioning and mental health as compared with base-line was registered (p< 0.01); no worsening was observed for other QoL scales. Before treatment 75% of patients experienced at least one moderate-to-severe symptom; more than 40% had more than 7 moderate-to-severe symptoms. The majority of patients (96%) experienced fatigue; half of them suffered from moderate-to-severe fatigue. While treatment the number of patients with moderate-to-severe symptoms decreased. After 12 months of therapy only 25% of patients experienced moderate-to-severe fatigue. Before treatment 36% of patients exhibited critical or severe QoL impairment. Remarkably, in the subgroup of patients (44%) with critical or severe QoL impairment at base-line dramatic QoL improvement was observed: QoL index increased 3.4 fold (p<0.01).Thus, our study on “real world” patient data confirms that dasatinib as second-line therapy in CML-CP patients is effective both in terms of clinical outcomes and patient-reported outcomes, as well as exhibits good tolerability. Comprehensive evaluation of the outcomes of the second-line treatment of CML-CP allows to assess the benefits and risks of therapy both from physician's and patient's perspective. Disclosures:Ionova:BMS: Research Funding. Nikitina:BMS: Research Funding. Gritsenko:BMS: Research Funding. Ivanova:BMS: Research Funding. Kuchma:BMS: Research Funding. Shnaider:BMS: Research Funding. Sannikova:BMS: Research Funding. Fedorenko:BMS: Research Funding. Kurbatova:BMS: Research Funding.