t315i mutation
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2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Shohei Kawakami ◽  
Mitsuyo Tsuma-Kaneko ◽  
Masakazu Sawanobori ◽  
Tomoko Uno ◽  
Yoshihiko Nakamura ◽  
...  

AbstractIn this study, we examined the antileukemic effects of pterostilbene, a natural methylated polyphenol analog of resveratrol that is predominantly found in berries and nuts, using various human and murine leukemic cells, as well as bone marrow samples obtained from patients with leukemia. Pterostilbene administration significantly induced apoptosis of leukemic cells, but not of non-malignant hematopoietic stem/progenitor cells. Interestingly, pterostilbene was highly effective in inducing apoptosis of leukemic cells harboring the BCR/ABL fusion gene, including ABL tyrosine kinase inhibitor (TKI)-resistant cells with the T315I mutation. In BCR/ABL+ leukemic cells, pterostilbene decreased the BCR/ABL fusion protein levels and suppressed AKT and NF-κB activation. We further demonstrated that pterostilbene along with U0126, an inhibitor of the MEK/ERK signaling pathway, synergistically induced apoptosis of BCR/ABL+ cells. Our results further suggest that pterostilbene-promoted downregulation of BCR/ABL involves caspase activation triggered by proteasome inhibition-induced endoplasmic reticulum stress. Moreover, oral administration of pterostilbene significantly suppressed tumor growth in mice transplanted with BCR/ABL+ leukemic cells. Taken together, these results suggest that pterostilbene may hold potential for the treatment of BCR/ABL+ leukemia, in particular for those showing ABL-dependent TKI resistance.


2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Zhongzheng Lu ◽  
Yanli Jin ◽  
Chun Chen ◽  
Juan Li ◽  
Qi Cao ◽  
...  

An amendment to this paper has been published and can be accessed via the original article.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3599-3599
Author(s):  
David Andorsky ◽  
Sarah Tomassetti ◽  
Yehuda E. Deutsch ◽  
E Randolph Broun ◽  
Ghayas C. Issa ◽  
...  

Abstract BACKGROUND: Chronic myeloid leukemia (CML) is driven by the constitutively active BCR-ABL1 tyrosine kinase. Several adenosine triphosphate (ATP)-competitive tyrosine kinase inhibitors (TKIs) are approved that inhibit BCR-ABL1 activity, and these have transformed CML from a fatal disease to a chronic one with near-normal life expectancy. However, many patients (pts) experience resistance to or intolerance of successive lines of TKI therapy. These pts have poor outcomes and few remaining treatment options. Moreover, pts with CML harboring the T315I mutation have limited treatment options as they are resistant to all approved TKIs except for ponatinib. Hence, there is a need for new CML therapies that are effective and well tolerated. Asciminib is an investigational agent with a novel mechanism of action. It is the first BCR-ABL1 inhibitor that inhibits BCR-ABL1 kinase activity by Specifically Targeting the ABL Myristoyl Pocket (STAMP). This contrasts with approved TKIs that target the ATP site of BCR-ABL1 to inhibit its kinase activity but are not entirely BCR-ABL1-specific and may target other kinases. In the phase III ASCEMBL trial in pts with CML in chronic phase (CP) after prior treatment with ≥2 ATP-competitive TKIs, asciminib showed superior efficacy vs bosutinib: major molecular response (MMR; BCR-ABL1 on the International Scale ≤0.1%) rate at week 24 was 25.5% vs 13.2%, respectively. In a large phase I trial, asciminib demonstrated promising efficacy and safety in pts with CML-CP without the T315I mutation previously treated with ≥2 TKIs and in those with the T315I mutation previously treated with ≥1 TKI: by 6 months, 37% and 25% of pts, respectively, achieved or maintained an MMR. Here, we describe the AIM4CML trial that was initiated to further assess the efficacy and safety of asciminib and explore a once-daily (QD) dosing regimen in pts with CML-CP (ClinicalTrials.gov, NCT04666259). DESIGN: This is a multicenter, phase IIIb, open-label, 3-cohort study of asciminib in pts with CML-CP without T315I after ≥2 prior TKIs and pts with T315I after ≥1 prior TKI (Figure 1). Adults aged ≥18 years with a diagnosis of CML-CP are eligible. Pts must have treatment failure with (as per 2020 European LeukemiaNet recommendations) or intolerance of the most recent TKI at screening. Key eligibility criteria are described in Table 1. Pts without the T315I mutation will undergo random selection to receive either asciminib 40 mg twice daily (BID; cohort A) or 80 mg QD (cohort B); those with the T315I mutation will receive asciminib 200 mg BID (cohort C). OBJECTIVES AND ENDPOINTS: The primary objective is to evaluate the safety profile of asciminib 40 mg BID and 80 mg QD in pts with CML-CP without T315I after ≥2 prior TKIs and of asciminib 200 mg BID in pts with T315I after ≥1 prior TKI. Primary endpoint analyses include incidence and severity of adverse events (AEs), serious AEs, changes in laboratory values and vital signs, and incidence of notable electrocardiogram abnormalities for 24 weeks. Primary and secondary study objectives/endpoints are summarized in Table 2. CONCLUSIONS: The AIM4CML study is currently enrolling pts across multiple sites in the United States, with an anticipated enrollment of approximately 115 heavily pretreated pts with CML-CP. Asciminib has the potential to transform the standard of care in this pt population through its novel mechanism of action as a BCR-ABL1 inhibitor that works by Specifically Targeting the ABL Myristoyl Pocket (STAMP). This study is sponsored by Novartis. Figure 1 Figure 1. Disclosures Andorsky: AbbVie: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; AbbVie: Research Funding; AstraZeneca: Other: served on steering committees; Celgene/Bristol Myers Squibb: Research Funding; Epizyme: Research Funding. Tomassetti: Seagene: Research Funding; Rigel: Research Funding; Beigene: Research Funding; Natera: Research Funding; Novartis: Research Funding; Parexel: Research Funding. Deutsch: Astellas: Membership on an entity's Board of Directors or advisory committees. Issa: Syndax Pharmaceuticals: Research Funding; Novartis: Consultancy, Research Funding; Kura Oncology: Consultancy, Research Funding. Levy: Dova: Consultancy, Other: Promotional speaker; Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Novartis: Consultancy, Other: Promotional speaker; Epizyme: Consultancy, Other: Promotional speaker; AbbVie: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Beigene: Consultancy, Honoraria, Speakers Bureau; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Other: Promotional speaker; Amgen Inc.: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Morphosys: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau. Deininger: Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees; SPARC, DisperSol, Leukemia & Lymphoma Society: Research Funding; Blueprint Medicines Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Fusion Pharma, Medscape, DisperSol: Consultancy. Maegawa: Novartis Pharmaceuticals Corporation: Current Employment, Current equity holder in publicly-traded company. Shrestha: Novartis: Current Employment. Mauro: Bristol Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Sun Pharma / SPARC: Research Funding.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1230-1230
Author(s):  
Josep-Maria Ribera ◽  
Olga Garcia ◽  
Jordi Ribera ◽  
Pau Montesinos ◽  
Isabel Cano ◽  
...  

Abstract Background and objective. The combination of HyperCVAD and ponatinib resulted in a high molecular response rate and survival in adults with Ph+ ALL, suggesting improved outcome compared with combinations of chemotherapy with first- or second-generation tyrosine kinase inhibitors (TKI) (Jabbour E, et al, Lancet Haematol. 2018;5:e618-e627). The Spanish PETHEMA group conducted the phase 2 PONALFIL trial, which incorporates ponatinib to the same chemotherapy as that of the ALL Ph08 trial that used imatinib as TKI (Ribera JM et al. Cancer 2019;125:2810-17). Final results of this trial are reported. Patients and method. PONALFIL trial (NCT02776605) combined ponatinib (30 mg/d) and induction chemotherapy (vincristine, daunorubicin, prednisone) followed by consolidation (high-dose methotrexate, high-dose ARA-C, mercaptopurine, etoposide) and allogeneic hematopoietic stem cell transplantation (alloHSCT). Ponatinib was scheduled after alloHSCT only for patients (pts) with persistence/reappearance of MRD. Response to therapy (complete morphological [CR], molecular [complete -CMR- or major -MMR-] after induction and before alloHSCT) (assessed by centralized BCR-ABL1/ABL1 ratio), disease-free survival (DFS), overall survival [OS]) and toxicity were analyzed. The following genetic studies were performed: 1. Additional gene abnormalities (Copy Number Alteration [CNA] analysis by SNP array Affymetrix 750K), 2. ABL1 mutation status at diagnosis (Sanger sequencing), 3. T315I mutation at diagnosis (allele-specific PCR). A propensity score comparison with the results of the ALL Ph08 trial was performed. Results. Median age was 49 (19-59) years (y), and 13/30 pts were female. One pt showed CNS involvement at diagnosis. ECOG score was <2 in 90% of pts. Median WBC count was 6.4 x10 9/L (0.6-359.3), Hb 90 g/L (63-145), platelets 38 x10 9/L (11-206). Immunologic phenotype was common in 26 cases, with p190 isoform in 20 pts (67%), p210 in 9 (30%) and p230 in 1 (3%). CR was attained in 30/30 pts, CMR in 14/30 (47%), MMR in 5/30 (17%) and no molecular response in 11/30 (37%). Two pts withdrew the trial during induction (thrombosis of central retina artery and severe intestinal infection, one case each). Consolidation was given to 28 pts, 2 pts withdrew the trial (physician's decision and lack of molecular response, one case each) and 26 pts received alloHSCT (20 in CMR, 6 in MMR). No relapses before HSCT were detected. One pt died by severe GVHD and two withdrew the trial (grade IV hepatic toxicity:1, protocol deviation after molecular relapse:1). One pt relapsed in BM after HSCT. Ponatinib was given after HSCT in 4/26 pts and dasatinib in 1/26 due to MRD reappearance, and 1/26 received dasatinib in CMR because of refusal to receive CNS prophylaxis, whereas 20/26 pts did not receive any TKI therapy after HSCT. Twenty-nine pts are alive (median follow-up 2.3y, range 1.3-4). 2y DFS and OS probabilities were 97% (91%-100%) and 97% (91%-100%) (Figure 1). Among 7/16 pts without CMR after consolidation and genetic material available, 4 showed IKZF1 deletion (IKZF1 plus in 2), 1 showed CDKN2A/B and PAX5 deletion and 2 did not show any CNA. Among 5/19 pts with molecular relapse, 3 showed IKZF1 deletion (1 being IKZF1 plus), and 2 pts did not show any CNA. No ABL1 mutations or T315I mutation at diagnosis were found. Propensity score with 1:1 matching identified 30 pts in each cohort (variables: age, gender, ECOG, WBC, CNS involvement, cytogenetic risk and BCR/ABL isoform). 2y DFS rates for PONALFIL and ALL Ph08 trials were 97% and 62%, (p=0.005), and 2y OS rates were 97% and 66% (p=0.001) (Figure 2). 107 adverse events (AE) were registered in 20 pts (21 severe in 11 pts), prompting to withdrawn of the trial in 3 (thrombosis of central retina artery, severe bowel infection, grade IV hepatic toxicity). The most frequent AE were hematologic (28%), gastrointestinal (14%), hepatic (11%), infections (7%), and cutaneous (5%). Cardiovascular events occurred in 2 patients (angor pectoris and thrombosis of central artery of the retina). Conclusions. The results of the PONALFIL trial show a high antileukemic efficacy with acceptable toxicity profile and compare favorably with the same chemotherapy schedule and imatinib. Supported in part by grant 2017 SGR288 (GRC) Generalitat de Catalunya and "La Caixa" Foundation. Figure 1. OS (A) and DFS (B). PONALFIL. Figure 2. OS (A) and DFS (B). PONALFIL vs. ALL Ph08. Figure 1 Figure 1. Disclosures Ribera: AMGEN: Consultancy, Research Funding, Speakers Bureau; NOVARTIS: Consultancy, Speakers Bureau; TAKEDA: Consultancy, Research Funding, Speakers Bureau; ARIAD: Consultancy, Research Funding, Speakers Bureau; SHIRE: Consultancy, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau. Esteve: Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Abbvie: Consultancy; Bristol Myers Squibb/Celgene: Consultancy; Novartis: Research Funding; Jazz: Consultancy; Astellas: Consultancy. Mercadal: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences, Inc.: Honoraria, Speakers Bureau. Martínez-López: Roche, Novartis, Incyte, Astellas, BMS: Research Funding; Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy. OffLabel Disclosure: This trial includes Ponatinib in off-label indication.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3603-3603
Author(s):  
Massimo Breccia ◽  
Luigia Luciano ◽  
Mario Annunziata ◽  
Imma Attolico ◽  
Alessandra Malato ◽  
...  

Abstract Background. Ponatinib is a third-generation tyrosine kinase inhibitor indicated for adults with resistant or intolerant chronic phase (CP), accelerated phase (AP), or blast phase (BP) chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia, or those carrying the T315I mutation. Ponatinib has been commercially available since January 2015, yet there is a paucity of data on its use in the real-world setting. The goal of the Observational study of Iclusig ® (ponatinib) Treatment in patients with CML in Italy (OITI) was to evaluate treatment patterns and outcomes, including safety and efficacy, in patients with CML treated in Italy since the approval of ponatinib. Methods. This noninterventional study included patients aged ≥18 years with CP, AP, or BP CML who initiated ponatinib treatment in routine clinical practice across 26 Italian centers (academic and hospital settings). The study population comprised a prospective cohort, including patients who started treatment with ponatinib after site activation during the 12-month enrollment period; a retrospective cohort, including patients who started treatment with ponatinib but died or were lost to follow-up prior to site activation; and a retrospective/prospective cohort, including patients who started treatment with ponatinib prior to site activation and were still on treatment or in follow-up at the end of the study. Demographic, efficacy, and safety data were collected from patient medical charts at study entry and routine visits. The primary endpoint was the complete cytogenetic response (CCyR) rate in CP CML patients 6 months after starting ponatinib. In the absence of cytogenetic evaluation, molecular assessment was used, considering patients in MR2 or better to be in CCyR. Here, the primary analysis of all evaluable patients for the primary endpoint (median follow-up, 23.7 months [range, 1.3-70.8]) is presented. Results. A total of 119 patients (110 CP, 6 AP, and 3 BP CML) were analyzed. Fifty-nine (49.6%) received ponatinib in second-line (2L), 41 (34.4%) in 3L, and 19 (16.0%) in ≥4L. Prior cardiovascular disease/hypertension was recorded in 56 (47.1%) patients. Median age at ponatinib start was 60 years (range, 19-93). Of 68 evaluated patients, 24 (35.3%) had a confirmed ABL1 mutation, including 7 (10.3%) with the T315I mutation. Starting doses of ponatinib were 45 mg (37.0%), 30 mg (41.2%), or 15 mg (21.8%). Median treatment duration was 22.8 months (range, 1.4-73.6). At baseline, 56 patients with CP CML had less than CCyR and 53 were in CCyR. For 1 patient, assessment was not available. At 6 months, 80/107 evaluable patients with CP CML were in CCyR; 29/56 (51.8%) achieved and 50/50 (100%) maintained CCyR compared to baseline, respectively. For 1 patient, baseline data were unavailable. Additionally, 37 (34.6%) and 19 (17.8%) patients with CP CML achieved a major molecular response (MMR; MR3) and a deep molecular response (MR4-MR5), respectively (Table 1). Progression-free survival rates estimated for patients with CP CML at 12 and 24 months were 92.6% (95% CI, 87.8-97.7%) and 84.6% (95% CI, 77.2-92.6%), respectively. Corresponding overall survival rates were 95.4% (95% CI, 91.6-99.4%), and 88.4% (95% CI, 81.7-95.7%). Seventy-one (59.7%) patients had treatment-related adverse events (AEs), most commonly rash, hypertension (Grade 1-2), and thrombocytopenia (Grade 3). Treatment-related arterial occlusive events occurred in 2 (1.7%) patients. Dose modifications occurred in 77 patients: 37.1% were due to AEs, 13.5% were reductions after at least major cytogenetic response, 10.6% were increases due to lack of efficacy, 1.7% were medical decisions, and 37.1% were for other reasons. Thirty-three patients discontinued ponatinib due to AEs (33.3%), medical decisions (24.2%), and other reasons (42.4%), such as death, progression, and hematopoietic stem cell transplantation. Conclusions. This observational study demonstrates that ponatinib has a favorable efficacy and safety profile in patients with CML treated in standard clinical practice. By 6 months, 74.8% of evaluable patients were in CCyR and 52.3% achieved at least MMR. Further, the probability of survival at 2 years was >88%. No new safety signals emerged with ponatinib treatment compared to prior studies. The early use of ponatinib and careful dose selection appear key to the safety and efficacy outcomes observed in this real-world study. Figure 1 Figure 1. Disclosures Breccia: Abbvie: Honoraria; Bristol Myers Squibb/Celgene: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Abruzzese: Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Bonifacio: Pfizer: Honoraria; Amgen: Honoraria; Bristol Myers Squibb: Honoraria; Novartis: Honoraria. Castagnetti: Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Galimberti: Inctye Bioscience Italy Srl: Current Employment. Iurlo: Incyte: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4346-4346
Author(s):  
Afsar Ali Mian ◽  
Hadiqa Raees ◽  
Sujjawal Ahmad ◽  
Oliver Ottmann ◽  
El-Nasir M A Lalani

Abstract Introduction: Chronic myeloid leukemia (CML) and 30% of adult acute lymphatic leukemia (ALL) are characterized by the Philadelphia chromosome (Ph +), having a (9;22) chromosomal translocation. The BCR-ABL1 fusion protein is the hallmark of Ph + leukemia. BCR-ABL1 is characterized by constitutively activated ABL1 tyrosine kinase activity that determines its transformation potential. Tyrosine kinase inhibitors (TKI) have greatly improved the overall prognosis of these diseases. However, unsatisfactory responses in advanced disease stages, resistance and long-term tolerability of BCR-ABL1 inhibitors represent major clinical problems. The most important resistance mechanism against TKIs is the acquisition of point mutations within the BCR-ABL1 kinase domain that impair drug binding, restoring the oncoprotein's constitutively active tyrosine kinase activity. The selection of leukemic clones driven by BCR-ABL1 harboring point mutations, such as the E255K, Y253F/H (P-loop), H396R (activation loop) or the T315I (gatekeeper). Second- and third generation TKIs such as nilotinib, dasatinib, and ponatinib effectively overcome point mutation-mediated resistance. Ponatinib is the only U.S. Food and Drug Administration approved TKI with activity against all known BCR-ABL1 point mutations, including BCR-ABL1-T315I. However, the emergence of compound mutations (two mutations within the same BCR-ABL1 allele) has been linked to resistance to all approved TKIs, including ponatinib, posing a clinical challenge with limited treatment options. The anti-cancer agent arsenic trioxide (ATO) has been used to treat patients with acute promyelocytic leukemia (APL). APL patients respond very well to ATO therapy and achieve complete remission, possibly through induction of apoptosis and differentiation. In addition, it has been demonstrated that combined treatment of ATO with interferon or nilotinib significantly suppressed cell proliferation. However, the potential effects of ATO on BCR-ABL1 mutations and especially on compound mutation is not apparent. This study aimed to investigate the role of ATO in BCR-ABL1 resistant mutations, including compound mutation in Ph + leukemias. Methods: We undertook preclinical evaluation of ATO and compared it with approved TKIs e.g. imatinib, nilotinib, dasatinib, ponatinib and ABL inhibitor asciminib, in vitro models of CML and primary patient-derived long term cultures (PD-LTC) of Ph + ALL patients with or without mutation. The effects on mutational resistance were investigated in Ba/F3 cells expressing BCR-ABL1 with T315I mutation and T315I-E255K mutation. For non-mutational resistance, we used PD-LTCs from Ph + ALL patients with different levels of non-mutational drug resistance. Cell proliferation was assessed by XTT. Results: ATO efficiently inhibited the growth of all PD-LTCs in cellular assays at dosages of 200-500nM. It also suppressed the growth of Ph + PD-LTC with non- mutational resistance (BV) and the BCR-ABL1-T315I positive PD-LTC (KO) in this dosage range. In all modelsWe treated Ba/F3 cells expressing native BCR-ABL1, BCR-ABL1-T315I mutation and BCR-ABL1-T315I-E255K (compound mutation) with increasing concentrations of imatinib (250, 500 and 1000nM), nilotinib (100, 200 and 400nM), dasatinib (10, 25 and 50nM), ponatinib (10, 50 and 100nM), asciminib) (ABL allosteric inhibitor) (5, 10 and 20nM) and ATO (0.5, 1.0 and 2.0 µM). We found that all the inhibitors significantly inhibited the proliferation of Ba/F3 cells expressing wild type BCR-ABL1 in a dose-dependent manner. In contrast, the growth of Ba/F3 cells expressing BCR-ABL1-T315I was inhibited by increasing concentration of ponatinib, asciminib and ATO. ATO potently inhibited the most challenging mutation (T315I-E255K) with a clinically relevant concentration (IC50 250nM). All approved ABL kinase inhibitors (AKIs) and allosteric inhibitors like asciminib could not inhibit the growth of Ba/F3 cells expressing BCR-ABL1 compound mutation. Conclusions: Our findings indicate that ATO significantly suppressed the proliferation of cells expressing non-mutated BCR-ABL1, single and compound mutated BCR-ABL1. These results support including ATO in treating patients with Ph + leukemias having BCR-ABL1 resistant single or compound mutati Disclosures Ottmann: Novartis: Honoraria; Amgen: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Fusion: Honoraria; Incyte: Honoraria, Research Funding.


Folia Medica ◽  
2021 ◽  
Vol 63 (5) ◽  
pp. 670-675
Author(s):  
Veselina Goranova-Marinova ◽  
Alexander Linev ◽  
Hristo J. Ivanov ◽  
Ivan Zheljazkov ◽  
Vily Stoyanova ◽  
...  

Introduction: The T315I mutation in patients with chronic myeloid leukemia (CML) has been associated with therapeutic resistance and an unfavourable prognosis. Aim: To study the frequency of T315I mutation in patients with CML, BCR-ABL&nbsp;(+), their clinical characteristics, disease evolution, and median survival. Patients and methods: We studied 75 patients with CML and BCR-ABL1&nbsp;(+). T315I mutation was detected by digital droplet PCR and BCR-ABL1 was analyzed by RT-PCR. A comparative analysis was performed by sex, age, disease phase, risk group, treatment, molecular response (MR), and median survival in T315I&nbsp;(+) and T315I&nbsp;(&minus;) patients. Results: T315I mutation was detected in 11 patients (14.7%). No significant difference was found in the phase, risk group, and first-line therapy. A significantly higher proportion of T315I&nbsp;(+) did not achieve MR&nbsp;>3.5 log: 8 (72.7%) vs. 22 (34.4%) (p=0.023). The lowest mean BCR-ABL1 levels were significantly higher in the CML T315I&nbsp;(+) group compared to the CML T315I&nbsp;(&minus;) group: 12.1&plusmn;6.0 vs. 3.77&plusmn;1.28 (p=0.009). The median survival of T315I&nbsp;(+) patients was significantly shorter: 73 months vs. 175 months (p<0.0001, CI 95%). Conclusions: Our data confirm the world experience on the frequency of T315I mutation, including the unfavourable evolution, resistance to TKI treatment and short survival. ddPCR is a highly sensitive method for early detection of genetic mutations which gives the chance for effective treatment.


2021 ◽  
Vol 12 ◽  
Author(s):  
Shan Cheng ◽  
Pan Jin ◽  
Heying Li ◽  
Duanqing Pei ◽  
Xiaodong Shu

Tyrosine kinase inhibitors (TKIs) to BCR-ABL1 have been successfully used to treat chronic myeloid leukemia (CML), however, multiple TKI-associated adverse events have been reported and become an emerging problem in patients. The mechanisms of TKI-induced toxicity are not fully understood and it remains challenging to predict potential cardiovascular toxicity of a compound. In this study, we established a zebrafish model to evaluate potential in vivo cardiovascular toxicity of TKIs. We treated the endothelium labeled Tg(kdrl:EGFP) transgenic zebrafish embryos with TKIs then performed confocal imaging to evaluate their vascular structure and function. We found that among FDA approved CML TKIs, ponatinib (the only approved TKI that is efficacious to T315I mutation) is the most toxic one. We then evaluated safety profiles of several clinical stage kinase inhibitors that can target T315I and found that HQP1351 treatment leads to vasculopathies similar to those induced by ponatinib while the allosteric ABL inhibitor asciminib does not induce noticeable cardiovascular defects, indicating it could be a promising therapeutic reagent for patients with T315I mutation. We then performed proof-of-principle study to rescue those TKI-induced cardiovascular toxicities and found that, among commonly used anti-hypertensive drugs, angiotensin receptor blockers such as azilsartan and valsartan are able to reduce ponatinib or HQP1351 induced cardiovascular toxicities. Together, this study establishes a zebrafish model that can be useful to evaluate cardiovascular toxicity of TKIs as well as to develop strategies to minimize TKI-induced adverse events.


Author(s):  
Isamu Sugiura ◽  
Noriko Doki ◽  
Tomoko Hata ◽  
Ryuko Cho ◽  
Toshiro Ito ◽  
...  

The standard treatment for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) in Japan is imatinib-based chemotherapy followed by allogeneic hematopoietic stem cell transplantation (HSCT). However, approximately 40% of patients cannot undergo HSCT in their first complete remission (CR1) because of chemotherapy-related toxicities and relapse before HSCT, and older age. We evaluated dasatinib-based two-step induction with the primary endpoint of 3-year event-free survival (EFS) in this study. The first induction (IND1) was dasatinib plus prednisolone to achieve CR and the second (IND2) was dasatinib plus intensive chemotherapy to achieve minimal residual disease (MRD)-negativity. Patients who achieved CR and had an appropriate donor were recommended to undergo HSCT during a consolidation phase later than the first consolidation, which included high-dose methotrexate. Prophylactic dasatinib after HSCT was assigned to patients with positive pre-transplant MRD. All 78 eligible patients achieved CR or incomplete CR after IND1, and 52.6% achieved MRD-negativity after IND2. Non-relapse mortality (NRM) was not reported. T315I mutation was detected in all 4 hematological relapses before HSCT. Fifty-eight (74.4%) patients underwent HSCT in CR1 and 44 (75.9%) were negative with pre-transplant MRD. At a median follow-up of 4.0 years, the 3-year EFS and overall survival were 66.2% (95% confidence interval [CI], 54.4-75.5) and 80.5% (95% CI, 69.7-87.7), respectively. The cumulative incidence of relapse and NRM at 3 years from enrollment were 26.1% and 7.8%, respectively. Dasatinib-based two-step induction was demonstrated to improve the 3-year EFS. This study was registered in the UMIN Clinical Trial Registry as #UMIN000012173.


Author(s):  
Nazanin Heidari ◽  
Fatemeh Noroozi ◽  
Najmaldin Saki

Background: Among the known ABL mutations in chronic myeloid leukemia (CML), T315I is of particular importance. The T315I mutation may develop resistant cells that increase disease progression. TWIST-1 expression is impaired in patients with increased drug resistance. Objectives: The current study aimed to measure the expression of TWIST-1 gene in CML patients to investigate its association with T315I mutation. Methods: Peripheral blood samples were taken from 40 CML patients. The expression of TWIST-1 and BCR-ABL1 genes was quantified by real-time polymerase chain reaction (PCR). The gene expression was evaluated by REST software. cDNA was used for amplification refractory mutation system (ARMS)-PCR reaction. Results: Of the 40 patients (age range: 19 - 72 years) participating in the study, 23 (57.7%) were female, and 17 (42.5%) were male. The expression of TWIST-1 gene was 43 ± 184.09-fold. The T315I mutation was detected in 3 (7.5%) patients. Conclusions: According to our results, the TWIST-1 gene expression in patients with T315I mutation was significantly higher than patients without that mutation.


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