Ponatinib -- Review of Historical Development, Current Status, and Future Research

Abstract

Ponatinib is a third-generation BCR::ABL1 tyrosine kinase inhibitor (TKI) with high potency against Philadelphia chromosome (Ph)-positive leukemias, including T315I-mutated disease, which is resistant to first- and second-generation TKIs. Ponatinib was approved for T315I-mutated chronic myeloid leukemia (CML), CML resistant/intolerant to ≥2 prior TKIs, advanced phase CML and Ph-positive acute lymphoblastic leukemia (ALL) where no other TKIs are indicated, and T315I- mutated CML and Ph-positive ALL. The response-based dosing of ponatinib in chronic phase CML (CP-CML) improved treatment tolerance and reduced the risk of toxicities, including cardiovascular risks. Ponatinib-based therapy also resulted in significantly better outcomes in frontline Ph-positive ALL compared with prior TKIs and is becoming a new standard of care in this setting. As the clinical development of third-generation TKIs and their rational combinations progresses, we envision further transformative changes in the treatment of CML and Ph-positive ALL.

Introduction

Ponatinib is a third-generation oral BCR::ABL1 tyrosine kinase inhibitor (TKI) that exhibits high potency against the native and mutant breakpoint cluster region::Abelson (BCR::ABL1) murine leukemia1 fusion oncoprotein, including the ABL1-T315I-mutated oncoprotein, which is highly resistant to first- (imatinib) and second- (dasatinib, bosutinib, nilotinib) generation TKIs.¹ Ponatinib is one of the TKI therapies that dramatically improved the treatment landscape of Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML)^2-5 and Ph-positive acute lymphoblastic leukemia (ALL). The advent of the BCR::ABL1 TKIs (starting with imatinib in the late 1990s) increased the 10-year overall survival (OS) rate in CML from 20% to 80-90%.^2,6 The BCR::ABL1 TKIs also significantly increased the early (2- to 4-year) OS rates in Ph-positive ALL from 10-20% to 80-90% with chemotherapy-free regimens and substantially reduced the need for allogeneic hematopoietic stem cell transplantation (HSCT).^7-12

The Food and Drug Administration (FDA) first granted approval for ponatinib as a treatment for CML and Ph-positive ALL following intolerance or resistance to prior TKI therapies on December 14, 2012. Ponatinib showed high rates of cytogenetic and molecular responses in CML with resistance to multiple TKIs and/or in T315I-mutated disease. However, at the approved dose-schedule of 45 mg daily, ponatinib was associated with serious adverse events (SAEs), including arterio-occlusive events (AOEs), other cardiovascular problems, pancreatitis, liver dysfunction, hypertension, and skin rashes. Herein, we review the chemical structure of ponatinib and its importance in the drug’s biological activity, the history of the drug development in CML and Ph-positive ALL, its efficacy in real-world settings, the comparative data of ponatinib with other TKIs, and the prospects of ponatinib and other third-generation TKIs (e.g., asciminib, olverembatinib) in the treatment of CML and Ph-positive ALL.

Importance of the Ponatinib Structure in its Biological Activity

The chemical name of ponatinib is N-(3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide (Figure 1A). In 2009, ARIAD Pharmaceuticals (Cambridge, MA, USA) designed ponatinib based on a computational and structure-guided strategy.^1,13 The goal was to target the sterically hindered hydrophobic adenosine triphosphate (ATP) pocket of mutant BCR::ABL1 imposed by the threonine-to-isoleucine substitution at codon 315 (T315I). In the mutant ABL1 kinase, this substitution prevents the formation of a key hydrogen bond between the first- or second-generation TKIs and the side hydroxyl group of threonine. This blocks access of the TKIs to the hydrophobic ATP pocket, resulting in resistance.¹⁴ The structure of ponatinib is characterized by a key linear carbon-carbon triple bond (ethynyl linker) linked to a fused imidazo[1,2b]pyridazine scaffold (Figure 1A-B). This structural arrangement induces minimal steric hindrance in the hydrophobic ATP binding pocket of BCR::ABL1, even in the presence of the “gatekeeper” mutation T315I. A hydrophobic interaction is established between the triple bond and the side chain of the isoleucine residue at position 315 in the T315I mutant oncoprotein, which, together with other key structural features of ponatinib, form a network of optimized interactions with ABL1^T315I.^1,13 The ethynyl linker promotes an extended conformation of ponatinib, favoring binding to the inactive conformation that ABL1^T315I adopts.^1,15,16 These interactions lead to the potent inhibitory activity of ponatinib.

Figure 1:

(A) Chemical structure of ponatinib and (B) Triple bond (yellow) of ponatinib (blue) depicted in the hydrophobic cavity of ABL1T315I (residue I315: red space-filling spheres).

From [Ponatinib in refractory Philadelphia chromosome–positive leukemias. Cortes JE, Kantarjian H, Shah NP, et al. Ponatinib in refractory Philadelphia chromosome–positive leukemias. N. Engl. J. Med. 2012;367: 2075-2088. Copyright^©(2024). Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.]

Preclinical Studies of Ponatinib

O’Hare and colleagues conducted the first preclinical studies of ponatinib, demonstrating its inhibitory activity on native and mutant BCR::ABL1 harboring cells.¹ In vitro kinase assays demonstrated the potent inhibitory activity of ponatinib against native BCR::ABL1 and ABL1^T315I; the half-maximal inhibitory concentration (IC₅₀) of ponatinib was 0.37 nM and 2.0 nM, respectively. Ponatinib inhibited the growth of parental Ba/F3 cells and Ba/F3 cells expressing native BCR::ABL1 (IC₅₀ = 0.5 nM) and mutated BCR::ABL1 with point mutations in the kinase domain (IC₅₀ ranged between 0.5 and 36 nM), including the gatekeeper T315I mutation. The IC₅₀ of ponatinib in cells expressing mutated ABL^T315I was 11 nM.¹ The IC₅₀ values of imatinib, nilotinib, dasatinib, and bosutinib for ABL^T315I were more than 100- to 1,000-fold higher than the IC₅₀ of ponatinib, thereby demonstrating the high in vitro potency of ponatinib in cell proliferation assays.¹⁶ Ponatinib completely suppressed CML resistance from all mutations in vitro at a concentration of 40 nM.¹⁶ Thus, in line with these findings, ponatinib was considered to be a pan-BCR::ABL1 inhibitor given that it had the lowest IC₅₀ concentrations for nearly every mutant form of BCR::ABL1, including those with mutations in the ATP binding region, compared to the other TKIs.¹⁶ In preclinical studies, ponatinib was 500 times more potent in inhibiting BCR::ABL1 compared to imatinib.¹⁵ In vivo studies showed that oral ponatinib administered to a Ba/F3 BCR::ABL1 harboring xenograft mouse model increased the median survival to 27.5-30 days (depending on the dose, 2.5-5 mg ponatinib/kg) compared with 19 days in vehicle-treated mice (p<0.01 for both doses).¹ The median survival of mice injected with Ba/F3 BCR::ABL1^T315I cells increased in a dose-dependent manner with the oral administration of ponatinib.¹ Additionally, ponatinib significantly suppressed the tumor growth in a dose-dependent manner in a xenograft mouse model in which Ba/F3 BCR::ABL1^T315I cells had been subcutaneously injected.¹ In another preclinical study, ponatinib 30 mg/kg/day increased the survival of an aggressive CML mouse model driven by the T315I mutation more than twofold.¹³ Incubation with ponatinib for 72 hours induced apoptosis of primary CML cells from patients harboring native fusion proteins BCR::ABL1 and BCR::ABL1^T315I at 500-fold lower IC₅₀ concentrations compared with mononuclear blood or bone marrow cells from normal individuals.¹

Clinical Trials of Ponatinib in Chronic Myeloid Leukemia

Phase 1 Clinical Trial

The first dose-escalation phase 1 clinical trial (NCT00660920) included 81 patients with Ph-positive leukemias and resistance to TKIs. The maximum tolerated dose was determined to be 45 mg daily.¹⁷ Among all patients with chronic phase CML (CP-CML), the complete hematologic response (CHR) rate was 98%, the major cytogenetic response (MCyR; BCR::ABL1 transcript levels ≤10% on the International Scale [IS]) rate 72%, and the major molecular response (MMR or MR3; BCR::ABL1 [IS] ≤0.1%, or 3-log reduction in BCR::ABL1 transcript levels) rate 44%. Among patients with CP-CML and T315I mutation, the CHR rate was 100%, the MCyR rate 92%, and the MMR rate 67%.¹⁷ In patients without any mutation, the CHR rate was 100%, the MCyR rate 62%, and the MMR rate 15%.¹⁷ Responses were durable: the 1-year rate of durable MCyR was 89% and of durable MMR 82%.¹⁷ Among patients with accelerated phase CML (AP-CML) and blast phase CML (BP-CML) or Ph-positive ALL, the CHR rate was 36%, and the MCyR rate 32%.¹⁷

Pivotal Phase 2 Clinical Trials of Ponatinib

The efficacy and safety of ponatinib were assessed in two phase 2 clinical trials, PACE (Ponatinib Ph-positive Acute lymphoblastic leukemia and CML Evaluation; NCT01207440) and OPTIC (Optimizing Ponatinib Treatment In CP-CML; NCT02467270).

Phase 2 clinical trial PACE

The pivotal, single-arm phase 2 clinical trial PACE evaluated ponatinib (45 mg daily) in 267 patients with CP-CML. Patients were required to have T315I-mutated CML after treatment with TKIs or to have intolerance/disease resistance to dasatinib or nilotinib.¹⁸ Overall, the 12-month MCyR (primary endpoint of the study) was 55%. The MCyR rate in T315I-mutated CML was 70%.¹⁸ The complete cytogenetic remission (CCyR or MR2; BCR::ABL1 [IS] ≤1%, or 2-log reduction in BCR::ABL1 transcript levels) was 46%, and the MMR rate was 34%.¹⁸ Among 83 patients with AP-CML, 55% had a major hematologic response (MHR), and 39% had a MCyR. Among 62 patients with BP-CML, 31% had a MHR, and 23% had a MCyR. Among 32 patients with Ph-positive ALL, 41% had a MHR, and 47% had a MCyR.

In the final analysis of the PACE trial at 5 years (median 56.8 months) in patients with CP-CML, the MCyR rate was 60%, the CCyR rate 54%, the MMR rate 40%, and the MR4.5 (BCR::ABL1 [IS] ≤0.0032%; 4.5-log reduction in BCR::ABL1 transcript levels) rate 24%.¹⁹ Of 267 patients with CP-CML, 145 (54%) were still on ponatinib therapy at 5 years. Among patients in major cytogenetic response or MMR, 90-96% were on a dose reduction of ponatinib. The estimated 5-year progression-free survival (PFS) rate was 53%, and the 5-year OS rate was 73%.¹⁹ Patients who achieved MMR at 3 months had an improved 4-year PFS rate (80% versus 54%) and 4-year OS rate (89% versus 80%) compared with patients who did not achieve this landmark.²⁰

Overview of the Regulatory Approval of Ponatinib in CML

The high MCyR rates observed in the PACE trial (MCyR rate 60% overall; 72% in T315I-mutated disease) supported the US accelerated regulatory approval (December 2012) of ponatinib 45 mg daily as a treatment for CML after resistance or intolerance to other TKIs. In October 2013, the FDA and the sponsor mandated a reduction of the initial ponatinib dose to 30 mg or 15 mg daily, in response to concerns about the cumulative occurrence of AOEs.²¹ At the 5-year follow-up, the incidences of AOEs/SAEs, overall and by subset (cardiovascular, cerebrovascular, and peripheral vascular events) were: overall, 31%/26%; cardiovascular, 16%/12%; cerebrovascular, 13%/10%; peripheral vascular 14%/11%.¹⁹ There were 14.1/10.9 exposure-adjusted AOEs/SAEs per 100 patient-years (number of patients with events per 100 patient-years).¹⁹ A subsequent retrospective analysis of the AOEs by an independent adjudication committee reported lower rates of AOEs (21%; serious in 20%).²² The incidence of AOEs was highest in patients with ≥2 cardiovascular risk factors.^19,23 Another post hoc study of the adverse events (AEs) from 3 clinical trials demonstrated a significant association between the dose of ponatinib and the risk of AOEs (P <0.001) by multivariate analysis. The analysis also reported that each decrease of the average ponatinib dose by 15 mg daily resulted in an approximate 33% decrease in the risk of AOEs.²⁴ It is important to note that ponatinib therapy was also associated with other AEs/Grade 3-4 SAEs, including skin rashes (47%/4%), abdominal pain (46%/10%), thrombocytopenia (46%/35%), headache (43%/3%), constipation (41%/3%), hypertension (37%/14%), elevation of lipase (27%/13%), and pancreatitis (severe 6%).¹⁹

Following the initial approval of ponatinib in December 2012 in the US, ponatinib was withdrawn from the market in December 2013 due to concerns about serious adverse thrombotic vascular events at the initial dose of 45 mg daily. In January 2014, ponatinib was reinstated after re-evaluation of the data. In early 2014, the indications for ponatinib were limited to patients with T315I-mutated disease and patients for whom no other TKI therapy was indicated. The revised warning on the label included the risk of thrombotic events (13% annually), vascular occlusions, heart failure, and hepatotoxicity. In December 2020, the FDA approved a new supplemental drug application for ponatinib based on the results of the pivotal phase 2 OPTIC trial (discussed later). The indications for ponatinib treatment were expanded to include CP-CML with resistance or intolerance to at least 2 prior TKIs; AP-CML, BP-CML, or Ph-positive ALL for which no other TKIs are indicated; and T315I-mutated CML (CP, AP, BP) and T315I-mutated Ph-positive ALL. The frontline use of ponatinib is precluded due to the cardiotoxicity noted in the phase 3 clinical trial EPIC (NCT01650805) that compared ponatinib (45 mg daily) to imatinib in newly diagnosed CP-CML patients.²⁵

Phase 2 Clinical Trial OPTIC

Due to the high incidence of AOEs reported in the PACE trial, a global, multicenter, phase 2 clinical trial (OPTIC; NCT02467270) was conducted to optimize the dose-schedule of ponatinib. The study novelty was a mandatory response-based dose-reduction strategy, aiming to minimize the risk of cardiovascular events. The study enrolled patients with CP-CML who had been previously treated with at least 2 TKIs or had a T315I mutation. Patients were randomized (ratio 1:1:1) to 3 starting doses of ponatinib (45, 30, or 15 mg daily).²⁶ Once in CCyR, patients were continued on ponatinib 15 mg daily. The primary endpoint of 12-month CCyR was achieved in 44%, 29%, and 23% with ponatinib 45, 30, and 15 mg daily, respectively.²⁶ By 4 years into therapy, the incidence of CCyR was 60% with daily ponatinib 45 mg, 41% with 30 mg, and 40% with 15 mg. The 4-year PFS rates were 72%, 63%, and 64%, respectively. However, the 4-year OS rates were similar: 88%, 86%, and 88%, respectively. This suggests that, at least in non-T315I-mutated CML, a starting dose of ponatinib 30 mg daily may be as effective and safer than 45 mg daily. Better response rates were observed in T315I-mutated CML. The overall median dose-intensity (mg/day) was 27.7 in the 45-mg cohort, 23.0 in the 30-mg cohort, and 14.7 in the 15 mg cohort.²⁸

Efficacy and safety of ponatinib in the PACE and OPTIC clinical trials

Based on the findings from the OPTIC trial, the optimal benefit-to-risk ratio was achieved with a starting ponatinib dose of 45 mg daily, which was reduced to 15 mg daily upon achievement of CCyR.^26,27 This dose-schedule was most beneficial in T315I-mutated CML. In non-T315I mutated CML, a starting dose of 30 mg daily may be as effective and less toxic.^26,27 This dose-adjusted approach to ponatinib therapy was also supported by a recent assessment of the dose-response relationship and the safety of ponatinib, showing that the outcomes of the patients were superior in the OPTIC study (at an initial dose of 45 mg daily lowered to 15 mg daily upon achieving response) compared with the PACE study.²⁸ In the PACE and OPTIC studies, the 2-year CCyR rates were 46% and 56%, respectively.^28,29 The 2-year OS rates were 86% and 91%, and the 2-year PFS rates were 68% and 80%, respectively.²⁸ The attenuation of the ponatinib dosing in OPTIC reduced the risk of AOEs.²⁸ A propensity score analysis of the AOEs in both trials (accounting for baseline risk factors) showed that the overall risk decreased by about 60% in OPTIC compared to PACE.²⁸ The incidences of exposure-adjusted treatment-emergent AOEs (TE-AOEs) and serious TE-AOEs were also lower in OPTIC. There were 7.6 exposure-adjusted TE-AOEs per 100 patient-years in OPTIC and 12.5 in PACE at 0 to <1 year.²⁸ From 1 to <2 years, the exposure-adjusted TE-AOEs were 5.9 in OPTIC and 15.7 in PACE. In the PACE and OPTIC trials, 12% and 5% of the patients experienced Grade ≥3 TE-AOEs, respectively, and the incidence of serious TE-AOEs was 15% in PACE and 4% in OPTIC.²⁸ Further analysis of the OPTIC data showed that patients treated with ≤2 TKIs had fewer TE-AOEs (7%) compared to patients treated with ≥3 TKIs (12%).²⁷

Current status of ponatinib in CML

Ponatinib efficacy by BCR::ABL1 mutation status

In the PACE trial, the rate of CCyR at 5 years was 69% in T315I-mutated disease, compared with 43% and 46% in CML without the mutation or with other ABL1 kinase mutations, respectively (Table 1).²⁹ Similarly, in the OPTIC trial, patients with the T315I mutation, treated in the 45-mg cohort, showed a higher CCyR rate compared to those without the mutation, at 3 years (Table 2).^26,29,30. Additional analysis from the PACE and OPTIC trials suggested that ponatinib therapy led to favorable response rates and survival outcomes in CML resistant to second-generation TKIs, regardless of the BCR::ABL1 mutation status at baseline.^29,30 These findings suggest that using ponatinib 45 mg daily may be preferred in patients harboring the T315I mutation, while 30 mg daily is as effective when used in patients without the mutation.

Table 1.

Efficacy of ponatinib based on baseline mutation status of CP-CML patients in the PACE trial.²⁹

BCR::ABL1IS ≤1% by 60 months (%)
No mutations	43
T315I mutation	69
Mutation other than T315I	46
PFS at 60 months (%)
No mutations	58
T315I mutation	47
Mutation other than T315I	46
OS at 60 months (%)
No mutations	80
T315I mutation	62
Mutation other than T315I	67

Abbreviations: CP-CML, chronic phase chronic myeloid leukemia; PFS: progression-free survival; OS, overall survival.

Table 2.

Efficacy of ponatinib based on baseline mutation status in the OPTIC trial.³⁰

Ponatinib dose	45 mg−>15 mg daily	30 mg−>15 mg daily	15 mg daily
BCR::ABL1IS ≤1% by 36 months (%)
No T315I mutation	54.5	41	44
T315I mutation	60	25	10.5
PFS at 36 months (%)
No T315I mutations	71	75	74
T315I	75	49	61
OS at 36 months (%)
No T315I mutations	90	93	94
T315I mutation	86	79	85

Abbreviations: CP-CML, chronic phase chronic myeloid leukemia; NR, not reported; PFS, progression-free survival; OS, overall survival.

The potency of ponatinib compared to second-generation TKIs in CML

No head-to-head randomized clinical trials compared ponatinib to second- and third-generation TKIs. However, several studies have demonstrated the higher potency of ponatinib compared with second-generation TKIs in CML. A systematic review that compiled data from 12 clinical trials demonstrated that the probability of achieving CCyR in patients with CP-CML resistant/intolerant to 2 prior TKIs, including a second-generation TKI, was more than twofold higher with ponatinib (60%) compared to second-generation TKIs (22-26%).³¹

A study of 354 patients with CP-CML (204 patients from the MD Anderson Cancer Center, 63 patients from the PACE trial, and 87 patients from the OPTIC trial) treated with third-line TKIs showed that ponatinib is the optimal treatment for patients who failed 2 prior TKIs.³² In a multivariate analysis, ponatinib therapy in the third-line setting was the sole independent factor associated with prolonged survival in CP-CML (HR=0.45; P =0.003). After propensity score matching, the 3-year OS rate was 87% with ponatinib versus 83% with second-generation TKIs (P =0.03); the 3-year PFS rate was 83% with ponatinib versus 59% with second-generation TKIs (P <0.001).³²

CML treatment with ponatinib in real-life settings

Breccia and colleagues analyzed the real-world data in 666 patients with CML (515 CP-CML, 50 AP-CML, 101 BP-CML) treated with ponatinib after ≥2 prior TKIs. Thirty-nine percent had received 2 prior TKIs, 39% had 3 prior TKIs, and 22% had 4+ prior TKIs.³³ Among the 515 patients with CP-CML, the CCyR rate was 78%, the MMR rate 65.6%, and the MR4 rate 43%. In AP/BP-CML, the CCyR rate was 50%, the MMR rate 37%, and the MR4 rate was 29%.³³ Surprisingly, these results are in fact superior to those reported in the controlled/sponsored trials, which is even more reassuring with regard to the efficacy of ponatinib.

A prospective study from Belgium assessed the outcomes of 33 patients with CML and 17 patients with Ph-positive ALL enrolled in the Belgian Registry over 3 years (2016-2019) in a real-life setting; 55% of the CML patients had been treated with ≥3 TKIs.³⁴ The estimated 3-year OS and PFS rates in CML were 85.3% and 81.6%, respectively. In CML, the MMR rate was 58%. The dose of ponatinib was reduced in 61% of the patients, primarily due to AEs; and 45% discontinued ponatinib (53% due to AEs).³⁴

In the PEARL observational study, among 48 patients with CP-CML treated with ponatinib after failing ≥2 TKIs, the 3-year OS rate was 81% and the MMR rate 82%; 47% of patients experienced cardiovascular AEs.³⁵

In another 2-year post-marketing surveillance study of 189 patients from Japan with CP-CML resistant/intolerant to TKIs and treated with ponatinib (without previous MMR), the 2-year MMR rate was 67% overall and 75% among 19 patients with T315I mutation. Overall, the incidence of AOEs was 6.2%, and the incidence of AOEs per 100 patient-years was 4.5 events.³⁶

Comparison of ponatinib with other third-generation TKIs

Unlike the ATP-competitive BCR::ABL1 TKIs, asciminib is a potent, orally bioavailable first-in-class TKI that binds to the myristoyl binding pocket of BCR::ABL1, inducing allosteric inhibition of the kinase (Specifically Targeting the ABL1 Myristoyl Pocket; or STAMP inhibitor).³⁷ Asciminib received regulatory approval in October 2021 as a third-line therapy in Ph-positive CP-CML post ≥2 TKI or with a T315I mutation. The approval was based on the randomized phase 3 trial ASCEMBL (NCT03106779), which compared asciminib (40 mg twice daily) with bosutinib (500 mg daily) in the third-line setting of CP-CML (and additional separate data in T315I-mutated CML).³⁸ The study showed a higher 6-month MMR rate (primary endpoint of the study) with asciminib versus bosutinib: 25.5% versus 12.2% (P=0.029). The 6-month CCyR rate was 49.0% versus 23.7%. The incidence of AOEs was 3.2% with asciminib versus 1.3% with bosutinib.³⁸ A longer follow-up of the ASCEMBL trial confirmed the sustained higher MMR rates with asciminib: 2-year MMR rate 37.6% with asciminib versus 15.8% with bosutinib (secondary endpoint of the study). Fewer Grade ≥3 AEs were noted with asciminib compared to bosutinib (56.4% versus 68.4%); the incidence of AOEs was 5.1% with asciminib. However, the 2-year OS rates were similar, 97% with asciminib and 99% with bosutinib.³⁹ No head-to-head studies comparing ponatinib and asciminib are available, and the real-world experiences with asciminib are too preliminary to allow comparisons with the ponatinib real-world experiences.^3-5,33

The outcomes of patients with CP-CML, AP-CML, and BP-CML treated with third-generation TKIs after acquiring a T315I mutation were recently analyzed. The 5-year OS of patients in CP-CML treated with ponatinib and/or asciminib (90% treated with ponatinib and 10% with asciminib) was 77% compared to 50% with other therapies, including second-generation TKIs and chemotherapy. A multivariate analysis showed that ponatinib and/or asciminib treatment (HR= 0.46; P = 0.03) and allogeneic HSCT (HR= 0.06; P <0.001) were independently associated with better OS.⁴⁰ Of note, in T315I-mutated CML, the asciminib dose-schedule is 200 mg twice daily, which costs about $1.45 million/year in the United States compared with $275,000/year for ponatinib. The cost of allogeneic HSCT, a one-time curative but toxic procedure, varies from $40,000 to $700,000, depending on the geography and HSCT-associated variations in therapy.^3,5,41

Olverembatinib is a novel, potent, third-generation BCR::ABL1 TKI that binds tightly to the ATP binding sites of native BCR::ABL1 and a large number of BCR::ABL1 mutants, including the T315I gatekeeper mutation.⁴² Olverembatinib received regulatory approval as a treatment for TKI-resistant CP-CML and AP-CML with T315I mutations in China in November 2021. Olverembatinib was also approved for CP-CML resistant or intolerant to first- and second-generation TKIs in China in November 2023. In the 5-year follow-up of the first-in-human phase 1 study of olverembatinib (HQP1351-SJ0002) in patients with TKI-resistant CP-CML, the 4-year MCyR rate was 80%, the CCyR rate 71%, and the MMR rate 55%. The 4-year PFS rate was 85.6%. Among evaluable patients with CP-CML and T315I mutation, the MCyR rate was 83.7%, and the MMR rate was 73.1%.⁴³ The incidences of notable AEs/Grade 3-4 AEs were: skin pigmentation, 84%/0%; hypertriglyceridemia 57%/7%; proteinuria 51%/4%; elevated liver enzymes, 36%/2%; hypertension, 13%/5%; elevated lipase, 13%/3%; thrombocytopenia 76%/51%; anemia 54%/23%.^43,44 Other cardiovascular events included pericardial effusion (8.5%), retinal vein occlusion (2%) as well as angina, arrythmias, tachycardia, cardiomegaly, and cerebral ischemia/infarction <1% each.⁴³ The overall incidence of serious cardiovascular events (including hypertension) was 11.5%.⁴³

The safety and efficacy of olverembatinib were further evaluated in 1) a single-arm phase 2 trial (NCT03883087) in China in patients with TKI-resistant CP-CML; 2) in a registrational randomized (2:1) phase 2 trial in China (NCT04126681) that compared olverembatinib to best available therapy; and 3) in a study outside China, evaluating the pharmacokinetics, efficacy, and safety of olverembatinib (3 doses; 30, 40, 50 mg every other day) in pretreated/refractory CP-CML and Ph-positive ALL, previously treated with ponatinib and/or asciminib (NCT04260022). All 3 studies, in abstract forms, reported similarly favorable efficacy results, the third one showing olverembatinib efficacy in CML with resistance to ponatinib or asciminib.^44-46

Ponatinib in Ph-positive Acute Lymphoblastic Leukemia

Combination of ponatinib with chemotherapy

Ponatinib received full regulatory approval in 2016 as a treatment for T315I-mutated Ph-positive ALL and Ph-positive ALL for which no other TKIs are indicated. Adult Ph-positive ALL was historically associated with a dismal prognosis in the pre-TKI era.^7,8 Since 2000, the addition of TKIs to intensive chemotherapy significantly improved the outcomes in Ph-positive ALL. More recently, the simultaneous chemotherapy-free combination of ponatinib and blinatumomab dramatically increased the 2-year OS rate to 90% (compared to 13% in the pre-TKI era). This regimen decreased the need for allogeneic HSCT in the frontline setting.⁹

The frontline combination of the hyper-CVAD regimen (fractionated courses of cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine; developed in 1992) with the newer and more potent TKIs in Ph-positive ALL significantly increased the rates of complete response (CR), complete molecular response (CMR; undetectable BCR::ABL1 transcripts by PCR), and OS.^7,8 The combination of hyper-CVAD and imatinib or dasatinib resulted in 5-year OS rates of 43-46%.^49,50 However, the outcomes were still suboptimal because the CMR rates were modest. Up to 75% of relapses with these first- or second-generation TKIs were associated with the emergence of T315I-mutated clones.⁵¹

In the PACE trial, among patients with relapsed or refractory Ph-positive ALL treated with ponatinib monotherapy, the CCyR rate was 38%, and the 3-year OS rate was 12%.^18,19 In a 2-year post-marketing surveillance study of 390 patients with relapsed/refractory Ph-positive ALL treated with ponatinib in Japan, the 2-year CCyR rate was 80%.³⁶

Based on the previous findings, ponatinib was combined with hyper-CVAD as frontline therapy in Ph-positive ALL.¹² Intrathecal (IT) chemotherapy prophylaxis with alternating methotrexate and cytarabine was increased from 8 to 12 ITs, because central nervous system (CNS) relapses (15%) were observed as patients lived longer. After a median follow-up time of 80 months, among 86 patients treated, the cumulative CMR rate was 86%, the 6-year EFS rate was 65%, and the 6-year OS rate 75%.¹² Twenty-three percent of the patients underwent allogeneic HSCT; the 6-year OS rate was 70% with allogeneic HSCT and 87% without HSCT (P=0.13). In this study, the initial dose of ponatinib was 45 mg daily; however, after 2 Grade 5 AOEs occurred, the protocol was amended to use a response-adapted dosing schedule (45 mg daily during the first 14 days of induction; reduction to 30 mg and 15 mg daily after achievement of CR and CMR, respectively), which eliminated further ponatinib-related deaths.¹²

In the PONALFIL trial, 30 patients (median age 50 years; range 19-59 years) received ponatinib 30 mg/day alongside induction chemotherapy consisting of vincristine, daunorubicin, and prednisone, followed by consolidation therapy involving high-dose methotrexate, cytarabine, mercaptopurine, and etoposide. Allogeneic HSCT was performed in 26 patients (87%). Post-induction, the CMR rate was 47% and improved to 71% during consolidation. The 3-year OS and EFS rates were 97% and 70%, respectively. These outcomes are superior to previous regimens combining chemotherapy with imatinib, which yielded a 3-year survival rate of 53%.⁵²

A phase 2 trial investigated the efficacy of combining ponatinib 45 mg with prednisone as a frontline treatment. Forty-four patients (median age 66 years; range 26-85 years) were treated, with 41% achieving CMR within 6 months. The EFS was 14.3 months; the median OS was not reached. Noteworthy is the occurrence of cardiovascular AEs in approximately 30% of the patients, likely attributed to the high dose of ponatinib.⁵³

The outcome of 204 patients with Ph-positive ALL treated with hyper-CVAD and imatinib, dasatinib, or ponatinib was analyzed.⁵⁴ By multivariate analysis, treatment with ponatinib was the only significant factor associated with PFS (HR = 0.388; P = 0.028) and OS (HR = 0.379; P = 0.042). Patients treated with ponatinib had a 5-year PFS rate of 81% compared to 64% with imatinib and 54% with dasatinib. The 5-year OS rate was 84% with ponatinib, 64% with imatinib, and 62% with dasatinib. Undergoing allogeneic HSCT was not a prognostic factor for PFS and OS when CMR was achieved within 3 months of treatment.⁵⁴

In a retrospective analysis of 230 patients with Ph-positive ALL (from 5 transplant centers in the US)– treated with a TKI-based regimen– who achieved CMR within 3 months and who underwent allogeneic HSCT (98 patients) or did not (132 patients), undergoing HSCT was not associated with a superior OS (adjusted HR= 1.05, P= 0.86) or relapse-free survival (RFS; adjusted HR= 0.86, P= 0.53) by multivariate analysis.⁵⁵ A propensity score matching analysis corroborated the results: the 5-year OS rates were 68% and 61% (P=0.63), and the RFS rates were 63% and 52% (P=0.42) with or without HSCT.⁵⁵ These data highlight the importance of achieving CMR and how this information can guide HSCT decisions in Ph-positive ALL. Patients achieving CMR (or, even better, next-generation sequencing (NGS)-clonoSEQ MRD negativity) may not need allogeneic HSCT in remission if they agree to continue on long-term TKI therapy. Given the higher CMR rates associated with frontline ponatinib-based therapy, these ponatinib-based combination therapies are less likely to necessitate consolidative HSCT.

The superiority of ponatinib compared to earlier generation TKIs (imatinib, dasatinib, nilotinib) was further confirmed in a meta-analysis of 26 studies in patients with newly diagnosed Ph-positive ALL treated with hyper-CVAD and TKIs. The CMR rate was 79% with ponatinib combined with chemotherapy compared to a pooled CMR rate of 34% with earlier-generation TKIs combined with chemotherapy. The 3-year OS rate was 79% with ponatinib versus 50% with earlier generation TKIs.⁵⁶

PhALLCON is the first head-to-head clinical trial comparing 2 TKIs in frontline Ph-positive ALL. This randomized phase 3 clinical trial (NCT03589326) evaluated the efficacy of ponatinib (30 mg once daily) versus imatinib (600 mg once daily) in combination with reduced-intensity chemotherapy through the end of induction (EOI; induction: 3 cycles), consolidation (6 cycles) and post-consolidation (11 cycles).⁵⁷ The composite primary endpoint was negative measurable residual disease (MRD) CR, defined as MR4 for 4 weeks at EOI. Ponatinib achieved a significantly higher MRD-negative CR rate at EOI compared to imatinib (34.4% versus 16.7%; P=0.002). The most significant benefit of ponatinib was noted in patients ≥60 years: the MRD-negative CR rate was 40.0% versus 10.3%, and the median PFS was 22.5 months versus 8.3 months.⁵⁷ The results from the PhALLCON trial resulted in the regulatory approval of ponatinib as frontline therapy in Ph-positive ALL in March 2024.

Combinations of blinatumomab with ponatinib and other TKIs

Blinatumomab is a bispecific T-cell engager (BiTE) that enables CD3-positive T-cells to engage with and eliminate CD19-positive B-ALL cells.⁵⁸ In the subset analysis of Ph-positive B-ALL from the pivotal multi-institutional phase 3 clinical trial comparing blinatumomab to standard-of-care chemotherapy in relapsed/refractory B-cell precursor ALL, blinatumomab was superior to intensive chemotherapy.⁵⁹

In a phase 2 clinical trial in Italy (GIMEMA LAL2116, D-ALBA; NCT02744768), the efficacy of the chemotherapy-free treatment of dasatinib and glucocorticoids (induction) followed by 2 courses of blinatumomab was evaluated in newly diagnosed Ph-positive ALL. The final long-term analysis (median follow-up of 53 months) reported the combination to result in a 4-year MRD-negativity rate of 86.7%, a 4-year PFS rate of 75.8%, and a 4-year OS rate of 80.7%. About 50% of the patients underwent allogeneic HSCT in first CR.⁶⁰ A similar study was conducted in the US evaluating dasatinib/prednisone induction, followed by dasatinib and blinatumomab in older adults ≥65 years of age. Twenty-four patients were treated (median age 73 years). The CR rate after dasatinib/prednisone was 92%, and the CMR was 50%. Seven relapses (3 with T315I mutations) were observed. The 3-year disease-free survival (DFS) rate was 77% and the 3-year OS rate 87%. The relapse rate of approximately 30% is higher than in the D-ALBA study and may be related to not performing allogeneic HSCT in first CR in this older population.⁶¹

A single-center, single-arm phase 2 clinical trial (NCT03263572) from MD Anderson evaluated the simultaneous combination of ponatinib with blinatumomab (administered together during induction) in patients with frontline Ph-positive ALL.⁹ The goal was to develop a chemotherapy-free regimen that could reduce toxicities and the need for allogeneic HSCT in first CR. The ponatinib dose was 30 mg daily until CMR was achieved, and then 15 mg daily for at least 5 years. Blinatumomab was given at the standard dose-schedule as a continuous infusion for 28 days every 6 weeks for 5 courses.⁹ The IT prophylaxis was 12 ITs, but was increased to 15 ITs, as 4 CNS relapses were noted (with the omission of high-dose methotrexate-cytarabine systemic chemotherapy). In a recent update of 62 patients with newly diagnosed Ph-positive ALL, the CMR rate was 84%. The MRD negativity rate was 94% by NGS (sensitivity of 1x10⁻⁶). The 2-year EFS and OS rates were 78% and 90%, respectively. Only 2 patients (3%) underwent allogeneic HSCT.

The non-chemotherapy regimens produce suboptimal results in CML with evolution to lymphoid BP, in refractory-relapsed ALL, and in de novo CML lymphoid BP. To address these subsets, a low-intensity chemotherapy regimen of mini-hyper-CVD (mini-HCVD) plus ponatinib, with sequential ponatinib-blinatumomab, was evaluated.⁶² Preliminary data showed a CMR rate of 83% in newly diagnosed disease. The 2-year continuous remission duration was 93%, the 2-year OS was 83%, 67% of the patients were in remission without HSCT, and only 1 patient underwent HSCT in CR.⁶²

Several ongoing trials are evaluating asciminib in combination with dasatinib and prednisone, as well as olverembatinib alone or with blinatumomab in Ph-positive ALL.^63-66 One study evaluated the efficacy of olverembatinib in 40 patients with relapsed/refractory Ph-positive ALL, and reported a 1-year DFS rate of 80.3% and a 1-year OS rate of 93.3%.⁶⁶

Conclusions and Future Prospects

The advent of TKIs transformed the treatment landscape in CML and improved the 10-year OS rate from < 20% before 2000 to approximately 80-90%. Ponatinib has added to the TKI benefits, particularly improving the outcomes in patients with CML resistant to second-generation TKIs and those with T315I-mutated CML. Newer third-generation TKIs (asciminib, olverembatinib) may add to such benefits in CML later-line therapies, and perhaps in frontline therapy if: 1) they improve the rates of durable deep molecular response, 2) demonstrate long term safety at 7-10 years, and 3) are cost-effective (less than $40,000/year of therapy).

Prior to the development of TKIs, adult Ph-positive ALL was historically associated with dismal outcomes (5-year OS rate <10% with intensive chemotherapy; improved to 30-40% in fit patients who could undergo HSCT in first CR). The BCR::ABL1 TKIs revolutionized the treatment paradigm, improving the 3-year OS rate to 80-90% with the chemotherapy-free TKI-blinatumomab regimens that mitigate toxicities and reduce the need for allogeneic HSCT.^7,8 Future studies will evaluate the combination of newer generation TKIs (asciminib, olverembatinib, others) with chemotherapy and blinatumomab in Ph-positive ALL. They will need to address several emerging questions: 1) the need for additional CNS-directed therapy if CNS relapse emerges as a serious issue with the elimination of high-dose cytarabine-methotrexate; 2) the role of allogeneic HSCT in first CR; and 3) the duration of TKI therapy (could be based on the duration of NGS MRD negativity).

A final comment about the role, benefit, and toxicities/costs of TKIs versus allogeneic HSCT in CML and Ph-positive ALL. To make a long story short…"it is complicated". Patented TKIs are too expensive at the current prices. Their cost-analysis versus allogeneic HSCT depends on the geography and the use of patented versus generic TKIs. For example, currently, generic imatinib costs $500/year (available anywhere) and generic dasatinib $5,000-$20,000/year (India versus other geographies). Allogeneic HSCT has a one-time cost range of $20,000 (India, Mexico) to > $500,000 (US). Today, ponatinib costs about $270,000/year, while asciminib 40 mg twice daily costs about $290,000/year, and 200 mg twice daily (for T315I-mutated CML) about $1.45 million/year. Thus, in contrast to Ph-positive ALL where the role of allogeneic HSCT is diminishing, its role may be having a “come-back” in CML post resistance to a second-generation TKI, in view of the cost and long-term toxicities of ponatinib, and the cost and lack of long-term toxicity data (7-10 years) for asciminib.