Third-generation Tyrosine Kinase Inhibitors Ponatinib Research Articles

Ph+ ALL in 2022: is there an optimal approach?

Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) carried a very poor prognosis prior to the advent of tyrosine kinase inhibitors (TKIs) that block the activity of the BCR-ABL1 oncoprotein. With improvements in TKI efficacy and allogeneic hematopoietic cell transplantation (HCT), survival has improved over the past 3 decades, and the role of chemotherapy and allogeneic HCT is now changing. Better risk stratification, the application of the third-generation TKI ponatinib, and the use of immunotherapy with the CD19-CD3 bifunctional T-cell engaging antibody blinatumomab in place of chemotherapy has made therapy for Ph+ ALL more tolerable and arguably more efficacious, especially for older patients who comprise most patients with Ph+ ALL.

Towards chemotherapy-free treatment of Philadelphia chromosome-positive acute lymphoblastic leukaemia

The addition of tyrosine kinase inhibitors (TKIs) to conventional chemotherapy backbones for adults with newly diagnosed Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukaemia has substantially improved treatment outcomes.1,2 However, the long-term outcomes are still unsatisfactory, with treatment-related resistance and toxicity. Over the past 10 years, several clinical trials have incrementally shown improved outcomes and reduced toxicity for these patients. These steps include the upfront use of the third-generation TKI ponatinib, which is active against the gatekeeper mutation, Thr315Ile, in the ABL1 tyrosine kinase domain.

Olverembatinib (HQP1351) Overcomes Ponatinib Resistance in Patients with Heavily Pretreated/Refractory Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL)

Background Olverembatinib is a novel third-generation BCR-ABL1 tyrosine kinase inhibitor (TKI) with antitumor activity against CML and Ph+ ALL regardless of genotype and a preliminarily favorable human safety profile. This study is the first to report on the safety, efficacy, and pharmacokinetic (PK) profiles of olverembatinib in patients with CML (all phases) and Ph+ ALL outside China, whose disease failed ponatinib treatment and at least 2 prior TKI treatments. Methods In this multicenter, open-label, randomized trial, olverembatinib is administered orally on alternate days (QOD) in adults with chronic-phase (CP-CML), accelerated-phase (AP-CML), or blast-phase CML (BP-CML) or Ph+ ALL. Enrolled patients have had no fewer than 2 prior TKI failures, except for those whose disease harbors T315I mutation, for whom the number of previous TKIs is not limited. Study participants are randomized 3:3:2 to olverembatinib 30, 40, or 50 mg QOD in 28-day cycles. Results A total of 30 patients have been enrolled, including 23 with CP-CML, 4 with AP-CML, 2 with BP-CML, and 1 with Ph+ ALL. The median (range) treatment duration is 4.8 (0.03-21.29) months and the median (range) interval from CML/Ph+ ALL diagnosis to olverembatinib treatment onset, 7.0 (1.5-24.0) years. Half (15/30) of patients are men, and the median (range) age is 47.0 (21.0-74.0) years. In all, 1 (3.3%), 7 (23.3%), 8 (26.7%), and 9 (30.0%) patients received 2, 3, 4, and ≥ 5 prior TKIs, respectively. A total of 21 (70.0%) patients were pretreated with third-generation TKI ponatinib, including 17 (81.0%) with resistance and 4 (19.0%) with intolerance; a total of 5 (16.7%) were pretreated with asciminib; 12 (40.0%) had T315I mutations; and 13 (43.3%), hypertension. At baseline, all patient BCR-ABL1IS levels were > 1%. Olverembatinib was well tolerated. Twenty-two (73.3%) patients experienced any-grade treatment-related AEs (TRAEs; Table 1), incidences of which tended to be dose-dependent. Most nonhematologic TRAEs were grade 1/2. Common grade 3/4 hematologic TRAEs included thrombocytopenia (7/30; 23.3%), neutropenia (5/30; 16.7%), and decreased leukocyte counts (4/30; 13.3%). In all, 11 (36.7%) of 30 patients experienced serious AEs, of which 6 (20.0%) were considered olverembatinib-related and 1 (3.3%) led to treatment discontinuation. One patient with AP-CML from the 50-mg dose cohort died of progressive disease. Olverembatinib conferred potent antileukemic activity in patients with CML and Ph+ ALL (Table 2). Of 21 efficacy-evaluable patients, 17 were evaluable for cytogenetic response, of whom 10 (58.8%) had complete cytogenetic response (CCyR); 9/21 (42.9%) patients had major molecular responses (MMR). Olverembatinib was effective in patients with either T315I-mutant (62.5%, CCyR; 50%, MMR) or T315IWT (55.6%, CCyR; 38.5%, MMR), and its effectiveness was not compromised by prior use of ponatinib or asciminib. Among patients pretreated with ponatinib with available responses, 5 (55.6%) of 9 patients with ponatinib-resistant disease experienced CCyR and 6 (54.5%) of 11, MMR. Four of 5 patients pretreated with asciminib showed response. PK analyses indicated an approximately dose-proportional increase in olverembatinib plasma exposure from 30 to 50 mg QOD and comparable plasma exposure between Chinese and US CML populations. Conclusions Olverembatinib monotherapy is efficacious and well tolerated in patients with TKI-refractory CML and Ph+ ALL. Even in patients with CML who were ponatinib or asciminib resistant, or who had T315I mutations, olverembatinib showed strong efficacy. This analysis confirms that olverembatinib is a potentially viable treatment option for patients with CML and Ph+ ALL, including those with ponatinib failure or T315I mutation. Internal study identifier: HQP1351-CU101. Clinicaltrials.gov identifier: NCT04260022. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract 14372: Case Series: Non-Lipid Plaque Formation as the Mechanism for Ponatinib-Induced Vascular Toxicity Using Operator-Assisted Virtual Histology Optical Coherence Tomography

Introduction: The third-generation tyrosine kinase inhibitor ponatinib approved for treating chronic myeloid leukemia (CML) rendered drug resistant with a threonine-315-isoleucine (T315I) mutation is associated with increased incidence of vascular adverse events (VAEs). This case series sought to elucidate the mechanism of these VAEs. Methods: Two patients with CML and two patients with Philadelphia chromosome positive acute lymphocytic leukemia (Ph+ ALL) on at least one year of ponatinib therapy were imaged with optical coherence tomography (OCT) after presenting with angina. An additional four patients from an institutional OCT database were matched across clinical parameters (age, sex, diabetes, prior coronary artery disease (CAD) history, prior congestive heart failure (CHF) history, hypertension, and family history of CAD) to serve as controls. Plaque composition was assessed using operator-assisted virtual histology OCT (vOCT). Results: Clinical presentations included 2 cases of NSTEMI, 1 case of unstable angina, and 1 case of stable angina pectoris among the 4 ponatinib patients. Atherosclerosis was composed primarily of calcium and fibrous tissue with minimal lipid presence (0 ± 0°) compared to the matched controls. The matched controls had a mean non-zero lipid content of 48.43 ± 18.36°, ( P < 0.05) (Table 1). Three of the four patients had cardiovascular risk factors. Conclusions: Ponatinib causes VAEs through non-lipid plaque formation driving a symptomatology consistent with an oxygen supply-demand mismatch. This mechanism is distinct from traditional pathways of excess lipid and plaque instability causing coronary artery disease and merits further investigation.

STAT5 inhibitor Pimozide as a probable therapeutic option in overcoming Ponatinib resistance in K562 leukemic cells

Signal Transducer and Activator of Transcription 5 (STAT5) is a transcription factor that plays a key role in neoplasia, triggered by the fusion oncogene BCR-ABL1; it is not only an essential protein for the pathogenesis of chronic myeloid leukemia (CML), but also its overexpression is associated with drug resistance developed toward various generations of Tyrosine Kinase Inhibitors (TKIs); these are still accepted as gold standard therapeutics for the treatment of CML. In this study, it was investigated whether suppression of STAT5 via a “STAT5 inhibitor” Pimozide resulted in any regain of chemosensitivity to third-generation TKI Ponatinib. Accordingly, the experimental work was designed on both parental CML cell line K562WT and its 1 nM Ponatinib-resistant counterpart, indicated as K562-Pon1. Based on the experimental results, Pimozide was more effective in resistant cells compared to wild-type cells for inducing apoptosis and block cell arrest. Combination therapy of Pimozide and Ponatinib demonstrated that STAT5 was a significant protein for regaining chemosensitivity to Ponatinib when its expression was suppressed both at mRNA and protein level. In conclusion, we consider that STAT5 inhibitor Pimozide can be a good alternative or combination therapy with TKIs for patients suffering from chemotherapeutic drug resistance. Communicated by Ramaswamy H. Sarma

Updated Safety and Efficacy Results of Phase 1 Study of Olverembatinib (HQP1351), a Novel Third-Generation BCR-ABL Tyrosine Kinase Inhibitor (TKI), in Patients with TKI-Resistant Chronic Myeloid Leukemia (CML)

▪Background: Management of CML using TKIs is often constrained by treatment resistance, which portends a poor prognosis. Treatment failure may be due to therapeutic resistance (BCR-ABL1 mutation-dependent or independent), intolerance, and/or suboptimal adherence. The BCR-ABL1 T315I (“gatekeeper”) genotype is insensitive to first- and second-generation TKIs, while compound mutations complicate management with all TKIs (including third-generation TKI ponatinib). HQP1351 (olverembatinib) is a novel, third-generation, orally active BCR-ABL1 TKI with evidence of antitumor activity against CML regardless of genotype (Ren X et al. Med Chem 2013;56:879-94) and a preliminary favorable safety profile in clinical trials (Jiang Q et al. Blood 2020;136:50-1).Methods: This Chinese, open label, multicenter, phase 1 trial evaluated the safety and efficacy of olverembatinib in adults with CML in chronic phase (CML-CP) or accelerated phase (CML-AP). Eligible patients have CML-CP or CML-AP that is resistant or intolerant to first- or second-generation TKIs. Patients with severe cardiovascular diseases, hypertension, and pulmonary arterial hypertension were excluded. Olverembatinib is orally administered once every other day in 28-day cycles at 11 dose cohorts ranging from 1 to 60 mg. This study reports data on patients with long-term follow-up.Results: From October 26, 2016, through February 2, 2021 (data cutoff date), 101 patients with CP-CML (n = 86) and AP-CML (n = 15) were enrolled and treated with olverembatinib. Seventy-one (70.3%) patients were male, the median age was 40 (range, 20-64) years, and median (range) interval from diagnosis to initial olverembatinib treatment was 6.0 (0.3-15.2) years. Eighty-four (83.2%) patients received ≥ 2 prior lines of TKI-therapy, and 63 (62.4%) harbored T315I mutation. At baseline, compound mutations were detected in 11 (10.9%) patients, of whom 7 (63.6%) had the BCR-ABL1 T315Igenotype. A total of 20 (19.8%) patients had 2 (n = 13) or ≥ 3 (n = 7) mutations. The median follow-up was 30.8 (1.2-51.8) months. As of the data cutoff date, 81 (80.2%) of 101 patients continued on treatment and 20 (14 CP-CML and 6 AP-CML) discontinued because of disease progression, intolerance, or occurrence of a secondary cancer. The cumulative median (range) drug exposure was 13,635 (1,650-20,975) mg. Of 101 patients, 18 (17.8%) were treated for > 3 years and 5 (5%) for > 4 years. Of evaluable patients without baseline responses, 97.0% had complete hematologic responses (CHR), 62.1% complete cytogenetic responses (CCyR), and 51.0% major molecular responses (MMR). Most evaluable patients with T315I mutations experienced 100% for CHR, 83.7% for MCyR, and 71.2% for MMR among patients in CP-CML, as well as 80.0% for CHR and 54.5% each for MCyR and MMR in AP-CML. At 36 months, the PFS rate (95% CI) was 96.3% (89.1%-98.8%) in patients with CP-CML and 71.4% (40.6%‒88.2%) in those with AP-CML. Treatment responses were durable and unaffected by baseline BCR-ABL1 mutational status. Corresponding values in patients with > 4 years of treatment were 100% (CHR), 80% (CCyR), and 60% (MMR). The mean (95% confidence interval) PFS rate was 100% (100%-100%) at 36 months, 100% at 48 months, and not reached (NR-NR) at 60 months. Most treatment-related adverse events were grade 1 or 2. The most frequent nonhematologic adverse event was (mostly grade 1 or 2) skin hyperpigmentation (86.1%). Grade ≥ 3 nonhematologic AEs included hypertriglyceridemia (10.9%), pyrexia (6.9%), and proteinuria (5.0%). The most common hematologic treatment-related adverse event was thrombocytopenia in 78 (77.2%) patients, including 52 (51.5% of total population) with grade ≥ 3 and 6 (5.9%) with serious adverse events. Leukopenia was grade ≥ 3 in 21 (20.8%) patients but not serious, while anemia was grade 3 or higher in 16 (15.8%) patients and serious in 4 (4.0%).Conclusions: In patients with TKI-resistant CML-CP or CML-AP and long-term treatment, olverembatinib was efficacious and well tolerated. Internal study identifier HQP1351-SJ002. [Display omitted] DisclosuresChen: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Niu: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Men: Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company. Wang: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Yang: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding. Zhai: Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding; Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding.

Trial in Progress: Phase 1b Bridging Study of the Pharmacokinetics (PK), Safety, and Efficacy of Orally Administered Olverembatinib (HQP1351) in Patients with Refractory Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph⁺ ALL)

Background: Management of CML using tyrosine kinase inhibitors (TKIs) is often constrained by treatment failure, which portends a poor prognosis, particularly among patients who fail second-generation TKIs because of resistance. Treatment failure may be due to therapeutic resistance (whether BCR-ABL1 mutation-dependent or independent), intolerance, and/or suboptimal adherence. The BCR-ABL1 T315I (“gatekeeper”) genotype is insensitive to first- and second-generation TKIs, and compound mutations complicate management with all members of the class (including third-generation TKI ponatinib). Olverembatinib (HQP1351) is a novel, potent, orally active BCR-ABL1 TKI with promising activity against CML, including antitumor activity regardless of genotype, and a preliminarily favorable safety profile.Methods: This open-label bridging trial is evaluating the PK, efficacy, and safety of olverembatinib administered orally every other day (QOD) in adults who have chronic-phase, accelerated-phase, or blast-phase CML (CP-CML, AP-CML, or BP-CML) and Ph⁺ ALL, with or without the T315I mutation, and have experienced resistance to or intolerance (including NCI CTCAE v5.0 grade ≥ 2 adverse events) of at least 3 TKIs. Eligible patients have no residual grade ≥ 2 adverse events (other than alopecia or skin pigmentation change) due to prior treatments, a maximum ECOG performance status of 2, and a minimum life expectancy of 3 months. Study participants are being randomly allocated in a 1:1:1 ratio to 3 dose cohorts: 30, 40, or 50 mg of oral olverembatinib QOD over a cycle length of 28 days, with 10 patients per cohort and randomization stratified according to CML phase (CP-CML, AP-CML, or BP-CML) or Ph⁺ ALL and T315I mutational status. Study endpoints comprise the PK profile of olverembatinib at Cycle 1 Day 1 and Day 27; efficacy endpoints of major cytogenetic and hematologic responses; and safety. The recommended phase 2 dose of olverembatinib will be determined based on a comprehensive assessment of PK, safety, and efficacy data in US and Chinese patients. As of July 14, 2021, 14 of 30 patients have been enrolled. Internal study identifier HQP1351-CU-101. Clinicaltrial.gov identifier: NCT04260022. DisclosuresJabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Kantarjian: Aptitude Health: Honoraria; Daiichi-Sankyo: Research Funding; Ascentage: Research Funding; Astra Zeneca: Honoraria; Ipsen Pharmaceuticals: Honoraria; Immunogen: Research Funding; Pfizer: Honoraria, Research Funding; KAHR Medical Ltd: Honoraria; BMS: Research Funding; NOVA Research: Honoraria; Astellas Health: Honoraria; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Jazz: Research Funding; AbbVie: Honoraria, Research Funding; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Issa: Kura Oncology: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Syndax Pharmaceuticals: Research Funding. Mukherjee: Genentech: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees; Acceleron: Membership on an entity's Board of Directors or advisory committees; Partnership for Health Analytic Research: Honoraria; AbbVie: Membership on an entity's Board of Directors or advisory committees; BioPharm: Consultancy; AAMDS in Joint Partnership with Cleveland Clinic Taussig Cancer Institute: Honoraria; Eusa Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Teaching and Speaking; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research/Independent Contractor, Research Funding; McGraw Hill: Honoraria, Other: Editor of Hematology Oncology Board Review (ongoing); Bristol-Myers Squibb Co.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Research/Independent Contractor, Research Funding; Jazz Pharmaceuticals: Research Funding. Oehler: OncLive: Honoraria; Pfizer: Research Funding; Takeda: Consultancy; BMS: Consultancy. Chen: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Lu: Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. Fu: Ascentage Pharma Group Inc: Current Employment, Current equity holder in publicly-traded company. Zhai: Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding; Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding. Yang: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding.

Arterial Hypertension and Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia: A Systematic Review and Meta-Analysis.

Background: Off-target effects in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs) are associated with cardiovascular toxicity. Hypertension represents an important cardiovascular complication and, if not appropriately managed, can contribute to developing thrombotic events. Third-generation TKI ponatinib is associated with hypertension development, and its use is more restricted than in the past. Few data are reported for second-generation TKI, nilotinib, dasatinib, and bosutinib. The aim of this article was to evaluate with a systematic review and meta-analysis the real incidence of hypertension in CML patients treated with second- or third-generation TKI.Methods: The PubMed database, Web of Science, Scopus, and ClinicalTrials.gov were systematically searched for studies published between January 1, 2000, and January 30, 2021; the following terms were entered in the database queries: Cardiovascular, Chronic Myeloid Leukemia, CML, Tyrosine kinases inhibitor, TKI, and Hypertension. The study was carried out according to the Preferred Reporting Items for Systematic and Meta-Analyses (PRISMA) statement.Results: A pooled analysis of hypertension incidence was 10% for all new-generation TKI, with an even higher prevalence with ponatinib (17%). The comparison with the first-generation imatinib confirmed that nilotinib was associated with a significantly increased risk of hypertension (RR 2; 95% CI; 1.39-2.88, I2=0%, z=3.73, p=0.0002). The greatest risk was found with ponatinib (RR 9.21; 95% CI; 2.86-29.66, z=3.72, p=0.0002).Conclusion: Hypertension is a common cardiovascular complication in CML patients treated with second- or third-generation TKI.

TKI-BiTE Combo Produces CMRs in Most with ALL.

Early results from a phase II clinical trial show that the third-generation tyrosine kinase inhibitor ponatinib plus the bispecific T-cell engager blinatumomab can produce complete molecular remissions in most patients with Philadelphia chromosome-positive acute lymphoblastic leukemia.

The role of ponatinib in adult BCR-ABL1 positive acute lymphoblastic leukemia after allogeneic transplantation: a real-life retrospective multicenter study.

The experience of third-generation tyrosine kinase inhibitor ponatinib treatment in Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph'+ ALL) patients post-allogeneic transplantation is limited. We retrospectively collected data on 25 Ph'+ ALL patients who were started on ponatinib after allogeneic transplantation between July 2015 and July 2019 from nine transplantation centers in Italy. Ponatinib was given in prophylaxis in five (20%), as pre-emptive treatment in seven (28%), and as salvage therapy in thirteen (52%) patients. It was combined with donor leukocyte infusions in ten patients. Half of the patients (12/25) harbored T315I mutation of BCR/ABL1, while in the remaining mutational analysis was negative or not performed. Among the 20 patients who received ponatinib as pre-emptive/salvage treatment, complete molecular response was achieved in 15 (75%) patients. Estimated overall survival at 2-year post-initiation of treatment in the whole cohort was 65% (respectively 60%, 60%, and 78% for the prophylaxis, pre-emptive, and salvage therapy groups). In patients with T315I-positive mutational status, the estimated 2-year survival was 40%. Fourteen patients (56%) experienced toxicity, requiring temporary or definitive suspension of treatment. In conclusion, treatment of Ph'+ ALL patients with ponatinib after transplantation is effective, although the question of adequate drug dose and treatment duration remains unanswered.

PF190 PLASMA LEVELS AND OUTCOMES OF PROPHYLACTIC POST-TRANSPLANT PONATINIB ADMINISTRATION IN PATIENTS WITH PHILADELPHIA CHROMOSOME-POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA (PH+ALL)

Background: Some retrospective studies demonstrated that the administration of first- and second-generation tyrosine kinase inhibitors (TKIs) to patients with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ALL) after allogeneic hematopoietic cell transplantation (allo-HCT) led to better overall survival (OS) and progression-free survival (PFS). However, most patients become intolerant, making it difficult to continue treatment. Experimental data show that third-generation TKI ponatinib is effective against various BCR-ABL1 mutations, including T315I, at plasma levels of 21.3 ng/mL. In addition, a recent study demonstrated that a reduced dose of ponatinib might result in a lower incidence of cardiovascular adverse events (AEs). However, few studies have examined ponatinib maintenance after allo-HCT to prevent relapse. We herein investigate the efficacy and safety of maintenance with low-dose ponatinib after allo-HCT to prevent relapse and evaluated plasma concentration of ponatinib. Aims: The purpose of this study was to examine whether ponatinib maintenance after allo-HCT was tolerable and contributed to superior OS and PFS. Methods: We retrospectively analyzed data of consecutive patients with Ph+ALL who underwent allo-HCT at our institution between January 2008 and December 2018. The initial ponatinib dose was 15 mg daily; thereafter, it was at the physicians’ discretion. Plasma trough levels of ponatinib were measured using liquid chromatography tandem mass spectrometry on and after day 8 following the first administration. We compared outcomes between patients who did or did not receive ponatinib maintenance using 1:2 nearest neighbor propensity matching based on factors such as age, number of transplants, and minimal residual disease (MRD). Results: A total of 31 patients aged 19–65 years (median, 46) were included. Of them, 29 achieved complete remission and 24 had a negative MRD status before allo-HCT, while 10 had prior history of BCR-ABL1 mutations including T315I (n = 7). Seven patients received ponatinib maintenance for a median of 48 days (range, 36–124) after allo-HCT. The median follow-up times for all patients and for those on ponatinib maintenance were 553 (range, 34–3,836) days and 240 (69–405) days, respectively. Two-year OS and PFS in the ponatinib maintenance group tended to be better than those in the non-ponatinib group after propensity matching (n = 21) as shown in Figure 1 (100% vs. 62.5%, P = 0.206; 100% vs. 55.1%, P = 0.120, respectively). In the ponatinib group, median plasma concentration during 15 mg daily administration of ponatinib was 15.6 ng/mL (range, 4.8–23.3). The plasma level exceeded 21.3 ng/mL in only one patient and was below 10 ng/mL in two patients. The initial ponatinib dose was continued in six patients and changed to 30 mg in one patient. Although grades 3–4 non-hematologic AEs occurred in three patients, all were reversible. No cardiovascular AEs occurred during follow-up. One patient developed acute skin graft-versus-host disease shortly after ponatinib administration. In the ponatinib group, 93.5% of intended doses were administered. We found no relationship between plasma ponatinib concentrations and AEs or drug interruption.Summary/Conclusion: Our results suggest that prophylactic post-transplant ponatinib administration in patients with Ph+ALL is relatively safe and effective. It would be worthwhile to prospectively evaluate ponatinib maintenance efficacy after allo-HCT in a large patient cohort.

Thrombotic microangiopathy as a cause of cardiovascular toxicity from the BCR-ABL1 tyrosine kinase inhibitor ponatinib

AbstractThe third-generation tyrosine kinase inhibitor (TKI) ponatinib has been associated with high rates of acute ischemic events. The pathophysiology responsible for these events is unknown. We hypothesized that ponatinib produces an endothelial angiopathy involving excessive endothelial-associated von Willebrand factor (VWF) and secondary platelet adhesion. In wild-type mice and ApoE−/− mice on a Western diet, ultrasound molecular imaging of the thoracic aorta for VWF A1-domain and glycoprotein-Ibα was performed to quantify endothelial-associated VWF and platelet adhesion. After treatment of wild-type mice for 7 days, aortic molecular signal for endothelial-associated VWF and platelet adhesion were five- to sixfold higher in ponatinib vs sham therapy (P < .001), whereas dasatinib had no effect. In ApoE−/− mice, aortic VWF and platelet signals were two- to fourfold higher for ponatinib-treated compared with sham-treated mice (P < .05) and were significantly higher than in treated wild-type mice (P < .05). Platelet and VWF signals in ponatinib-treated mice were significantly reduced by N-acetylcysteine and completely eliminated by recombinant ADAMTS13. Ponatinib produced segmental left ventricular wall motion abnormalities in 33% of wild-type and 45% of ApoE−/− mice and corresponding patchy perfusion defects, yet coronary arteries were normal on angiography. Instead, a global microvascular angiopathy was detected by immunohistochemistry and by intravital microscopy observation of platelet aggregates and nets associated with endothelial cells and leukocytes. Our findings reveal a new form of vascular toxicity for the TKI ponatinib that involves VWF-mediated platelet adhesion and a secondary microvascular angiopathy that produces ischemic wall motion abnormalities. These processes can be mitigated by interventions known to reduce VWF multimer size.

Towards Comprehension of the ABCB1/P-Glycoprotein Role in Chronic Myeloid Leukemia.

The introduction of imatinib (IM), a BCR-ABL1 tyrosine kinase inhibitor (TKI), has represented a significant advance in the first-line treatment of chronic myeloid leukemia (CML). However, approximately 30% of patients need to discontinue IM due to resistance or intolerance to this drug. Both resistance and intolerance have also been observed in treatment with the second-generation TKIs—dasatinib, nilotinib, and bosutinib—and the third-generation TKI—ponatinib. The mechanisms of resistance to TKIs may be BCR-ABL1-dependent and/or BCR-ABL1-independent. Although the role of efflux pump P-glycoprotein (Pgp), codified by the ABCB1 gene, is unquestionable in drug resistance of many neoplasms, a longstanding question exists about whether Pgp has a firm implication in TKI resistance in the clinical scenario. The goal of this review is to offer an overview of ABCB1/Pgp expression/activity/polymorphisms in CML. Understanding how interactions, associations, or cooperation between Pgp and other molecules—such as inhibitor apoptosis proteins, microRNAs, or microvesicles—impact IM resistance risk may be critical in evaluating the response to TKIs in CML patients. In addition, new non-TKI compounds may be necessary in order to overcome the resistance mediated by Pgp in CML.

Cardiovascular Complications of Targeted Therapies for Chronic Myeloid Leukemia.

The development of tyrosine kinase inhibitors (TKIs) dramatically changed the treatment landscape for many different cancers including chronic myeloid leukemia (CML). With the introduction of imatinib, the first TKI developed and approved to effectively treat CML, patient survival has increased dramatically and, in some cases, this fatal cancer can be managed as a chronic disease. Since the approval of imatinib in 2002, four additional TKIs have been developed to treat this disease including the second-generation TKIs nilotinib, dasatinib, and bosutinib and the third-generation TKI ponatinib. Despite their significant impact on the progression of CML, there is increasing recognition of cardiovascular toxicities which can limit their long-term use and impact patient morbidity and mortality. The majority of the cardiotoxicities are associated with the second- and third-generation TKIs, the most concerning of which are vascular events including myocardial infarction, stroke and peripheral arterial disease. In addition, QT prolongation, pleural effusions, and both systemic and pulmonary hypertension are also observed. It is essential for both cardiologists and oncologists to possess knowledge of these issues in order to develop appropriate monitoring and risk mitigation strategies to prevent these toxicities and avoid premature cessation of the drug.

In Vitro Modeling of Ph-like ALL Fusions Identifies Novel Kinase-Domain Mutations As Mode of TKI-Resistance - Implications for Targeted Therapy

IntroductionTreatment-resistant acute lymphoblastic leukemia (ALL) remains a significant clinical issue. Recently, genomic profiling has identified a new subtype of high-risk ALL termed Philadelphia-chromosome-like (Ph-like) ALL, associated with a poor outcome1. Ph-like ALL has a gene expression profile similar to Ph+ (BCR-ABL1+) ALL, characterized by the presence of fusion genes converging on kinase and cytokine signaling pathways. These pathways have been shown to be targetable both in vitro and in case reports by tyrosine kinase inhibitors (TKIs). Despite well-documented efficacy profiles, it is known from TKI-use in chronic myeloid leukemia (CML) andPh+ ALL that resistance is likely, resulting in relapse. Our study aims to model and understand mechanisms of TKI-resistance inPh-like ALL, informing future therapeutic strategies that may avert or overcome resistance, potentially improving patient outcomes.MethodsThree Ph-like ALL lines were generated via retroviral-transduction from plasmids of fusion genes identified in patient cohorts (RANBP2-ABL1, SSBP2-CSF1R and PAX5-JAK2, a kind gift from C. Mullighan)2 into Ba/F3 pro-B cells. Transformation was confirmed via growth of cells in the absence of IL-3. Cells were tested for sensitivity to a panel of TKIs (imatinib, dasatinib, ponatinib, ruxolitinib and BMS-911543) via Annexin-V/7-AAD flow-cytometry and western blotting of downstream effector proteins. Drug resistance was generated through exposure of cells to incrementally increasing concentrations of TKIs over a period of 3-6 months, and cell death LD50 determined byAnnexin-V/7-AAD. Sanger sequencing of the 3-prime partner gene of each fusion was performed to identify the emergence of any kinase-domain mutations.ResultsBa/F3 Ph-like cells demonstrated sensitivity to TKIs at clinically relevant doses (RANBP2-ABL1: 1 μM imatinib, 5 nM dasatinib & 5 nM ponatinib; SSBP2-CSF1R: 1 μM imatinib, 6 nM dasatinib; PAX5-JAK2: 1 μM ruxolitinib & 2 μM BMS-911543). This correlated with decreased levels of relevant downstream signaling proteins including p-Stat5, p-Erk and p-CrkL. TKI-resistant Ph-like ALL lines were tolerant to a significantly higher concentration of TKIs compared to control (RANBP2-ABL1: 10 μM imatinib, 200 nM dasatinib & 200 nM ponatinib; SSBP2-CSF1R: 10 μM imatinib, 200 nM dasatinib; PAX5-JAK2: 10μMruxolitinib & 10μM BMS-911543; Table 1).Sequencing analysis revealed that Ba/F3 RANBP2-ABL1 imatinib and dasatinib resistant cells acquired the clinically significant ABL1 T315I (c.944C>T) kinase-domain mutation, which was ultimately targetable using the third-generation TKI ponatinib (LD50: 25 nM). An ABL1 E255K (c.763G>A) and c-terminus deletion was discovered in the ponatinib-resistant line. In Ba/F3 SSBP2-CSF1R cells, a novel CSF1R L785M (c.2566C>A) mutation was identified in imatinib-resistant cells whereas a deletion spanning the SSBP2-CSF1R breakpoint was acquired in the dasatinib-resistant line. A JAK2 Y931C (c.3286A>G) point mutation previously associated with resistance to ATP-competitive inhibitors was acquired in Ba/F3 PAX5-JAK2ruxolitinib and BMS-911543 resistant lines.ConclusionIn vitro modeling of Ph-like ALL resistance has identified novel kinase domain mutations and deletions that may arise as a result of targeted TKI therapy. In addition, previously identified mutations (T315I and E255K) were also identified. Detection of these mutations is important because alterations in drug-binding regions are known to result in significantly reduced TKI sensitivity, leading clinically to relapse3. This study describes an in vitro platform that can be utilized to inform future clinical approachesincluding the development of rational therapeutic approaches (and/or combination therapies) to avert resistance inPh-like ALL cases treated with rationally targeted therapies.Abbreviations:ABL1 - Abelson tyrosine protein kinase 1CSF1R - Colony stimulating factor 1 receptorJAK2 - Janus kinase 2PAX5 - Paired box 5RANBP2 - RAN-binding protein 2SSBP2 - Single-stranded DNA binding protein 2

Ponatinib—A Step Forward in Overcoming Resistance in Chronic Myeloid Leukemia

With the current therapy, the improvement in survival of patient with early chronic phase chronic myelogenous leukemia (CML) is unrivaled by that of any other leukemia. In fact, extrapolation of the survival curves may suggest that life expectancy of patients who achieve and maintain predetermined milestones may not differ from that of the age-matched healthy adults. The main reasons for such success are the presence of a well-defined molecular target, the BCR-ABL oncogene, necessary and sufficient for the initiation and propagation of CML, and the powerful and selective agents that inhibit it. Five U.S. Food and Drug Administration (FDA)-approved tyrosine kinase inhibitors (TKI), each with unique activities and toxicity profiles, allow for individualized patient care. Despite the remarkable responses of most patients, a small but significant fraction of patients develops clinical resistance to the TKIs, some of which is attributed to the BCR-ABL kinase domain mutations affecting TKI binding and activity. The recently approved third-generation TKI ponatinib showed remarkable activity in the patients with multi-TKI-resistant disease. Particularly impressive was its efficacy in patients with T315I mutation that is resistant to all other TKIs. In lieu of the current emphasis on achieving earlier and more profound responses and excellent activity of ponatinib in the refractory setting, its optimal position among the available armamentarium of agents is being established.