CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: August 15, 2024
Expiration: February 14, 2025
Case 5: A Patient Receiving Imatinib for Two Years Presenting With Loss of Response
A 62-year-old woman with a history of hypertension, hyperlipidemia, type 2 diabetes mellitus, and chronic constipation has been on imatinib for chronic phase CML for the last 2 years. She has been in CCyR. A recent assessment revealed BCR::ABL1 transcript of 2.1% which was confirmed 1 month later to be 6%. A BCR:ABL mutation analysis revealed a F359V mutation.
For this patient, I would recommend that treatment be changed to a newer-generation TKI. The F359V mutation confers resistance to imatinib but not to the second-generation TKIs. Bosutinib has a favorable cardiovascular profile and is a good choice for this patient with cardiovascular comorbidities, and chronic constipation, since bosutinib could possibly cause diarrhea.
BCR::ABL1 Mutations Which Eliminate Certain Treatment Options
If a patient has clearly identified treatment failure with TKI resistance, it is important to do a full assessment which includes a bone marrow examination to look at the full karyotype and a BCR::ABL1 mutation analysis to help direct what subsequent TKI to use.2,19 Different TKIs target different mutations, but only 30% to 50% of patients will have a mutation and only a handful of mutations are informative for selecting a TKI. Still, it is important to do a mutation analysis since the presence of BCR::ABL1 mutations makes some agents ineffective, such as with the last case example, of the patient with a E255V mutation and resistance to nilotinib.
Response, PFS With Second-Generation TKIs in Imatinib-Resistant Chronic-Phase CML
This table shows data from key studies of 3 second-generation TKIs—dasatinib, nilotinib, and bosutinib—after imatinib failure.5,37-40 Of importance, the CCyR rate after switching to a second-generation TKI was only 40% to 50% while MCyRs were seen in 56% to 63% and the 2-year PFS rates ranged from 64% to 85%.
Patients should be evaluated for BCR::ABL1 mutations in order to guide the choice of second-line TKI. If a patient has already received a second-generation TKI as frontline therapy, another second-generation TKI may or may not be the best second-line approach (depending on the mutational profile and the patient comorbidities), and a third-generation TKI or a STAMP inhibitor should be considered.
Treatment of TKI Resistant CML
If it is determined based on BCR::ABL1 kinase domain mutation status that a patient has disease resistant to imatinib at 400 mg daily, changing to a second-generation TKI, such as bosutinib, dasatinib, or nilotinib would be an appropriate course.25 The choice of TKI would depend on patient-specific factors, such as comorbidities, or other medications which may potentially interact with the chosen TKI.
For patients with resistance to a second-generation TKI, an alternate TKI (other than imatinib) can be considered based on the mutation profile.
Case 6: A Patient Receiving Dasatinb for 18 Months Presenting With Loss of Response
Let’s consider another case of a 57-year-old woman with a history of hyperlipidemia and chronic phase CML that has been receiving dasatinib for 18 months and was in MMR. She was found to have increasing BCR::ABL1 transcript levels to 3%, and then to 8% a month later. A bone marrow biopsy revealed that the patient remains in chronic phase but has developed a T315I mutation.
For this patient with chronic phase CML and the loss of a response due to a T315I mutation, I would recommend ponatinib based on data from the OPTIC trial, starting at a dose of 45 mg daily for T315I-mutated disease, and with a subsequent dose reduction to 15 mg daily once BCR::ABL1 transcripts are ≤1%. T315I confers resistance to imatinib and all second-generation TKIs. Ponatinib and asciminib are both FDA-approved for patients with T315I mutation. In this case, the patient has no major cardiovascular disease noted, therefore ponatinib can be used in a dose-adapted fashion as reported in the OPTIC trial. This strategy was shown to improve safety while maintaining efficacy. Asciminib is also a safe alternative to ponatinib, however the recommended dose of 200 mg twice daily is considerably more expensive than the dose of ponatinib in this setting.
Our patient responded to treatment and the BCR::ABL1 transcript dropped to 0.5% after 3 months of ponatinib therapy. At that time, the dose of ponatinib was reduced to 15 mg daily. It was further recommended that the patient maintain physical activity to improve cardiovascular health. Use of prophylactic aspirin and statin was also advised to reduce the risk of cardiovascular events with ponatinib.
PACE Final (5-Year) Results: Response to Ponatinib in Patients With CML Resistant to ≥1 TKI
The T315I mutation occurs in up to 16% of patients with TKI-resistant CML and causes resistance to the first- and second-generation TKIs approved in the United States, but not ponatinib.19,41 Ponatinib was the first of the third-generation BCR::ABL1 kinase inhibitors to be studied in clinical trials. PACE was a phase II trial of ponatinib in Ph chromosome–positive leukemias resistant or intolerant to dasatinib or nilotinib.
Five-year results in the cohort of patients with chronic-phase CML (n = 267) and resistance to at least 1 previous TKI showed a MCyR rate of approximately 60%, most of which are actually CCyRs.42 As shown here, these are DMRs, with nearly 25% of patients achieving MR4.5. In addition, these responses are very durable: At 5 years, 82% of patients maintained their MCyR and 59% maintained their MMR.
The OPTIC Approach: Efficacy and Safety of Ponatinib
Arterial occlusive events are a concern in patients with CML treated with ponatinib, with a cumulative incidence correlated with higher doses and longer treatment duration. Because of this risk, trials like OPTIC have implemented response-directed dose adjustment to determine whether lower starting doses would preserve efficacy and decrease the risk of toxicity with ponatinib.43
In this study, ponatinib was evaluated at different starting doses in 94 patients per cohort with chronic-phase CML and either resistance to at least 2 TKIs or with the T315I mutation. Results showed clearly that 45 mg as the starting dose is the most effective, with an overall response rate of 44% compared with only 29% with 30 mg. Starting with 45 mg and reducing the dose to 15 mg after achieving a BCR::ABL1 ≤1% has decreased the incidence of arterial occlusive events to only 9.6%, compared with, historically, approximately 25% to 35% of patients. Five patients had grade ≥3 treatment-emergent arterial occlusive events, and 4 patients had to discontinue treatment.
OPTIC: Overall Safety and Efficacy by Starting Dose
Improved management of patients by changing the dose of ponatinib can optimize the risk–benefit ratio. As shown here, efficacy is significantly improved by starting with 45 mg and reducing the dose to 15 mg after achieving a response: 51.6% of patients achieved <1% BCR::ABL1 transcripts by 1 year vs 35.5% with 30 mg.43 Of note, the risk of arterial occlusive events decreased with lower starting doses.
OPTIC 4-Yr Update: Ponatinib Dose-Reduction Study
At the 4-year update of the OPTIC study, it was shown that using a dose-reduction strategy of ponatinib in patients with highly resistant chronic-phase CML who attained ≤1% BCR::ABL1IS resulted in longer-term efficacy outcomes.44 A post-hoc analysis of the data in patients with a T315I mutation showed that median PFS and median OS were not reached in the 45 mg group.45
Phase I Study of Asciminib in CML With T315I Mutation
Asciminib, a first-in-class STAMP inhibitor, has a different mechanism of action than other BCR::ABL1 TKIs. Asciminib targets the myristoyl pocket rather than the ATP-binding pocket of the BCR::ABL1 kinase. Asciminib as monotherapy was evaluated in 48 patients with previous exposure to TKI and the T315I mutation, with 31.3%, 35.4%, and 16% having received 2, 3, and 4 or more TKIs, respectively.41 Of all patients evaluated, 62.2% achieved BCR::ABL1IS ≤1% at 96 weeks. When separating these patients based on previous ponatinib exposure, ponatinib-naive patients were seen to be more likely to experience deeper responses.
Case 7: A Patient With Chronic Phase CML and Progression Following 2 Previous Lines of TKI Therapy
For our last case, let’s consider a 65-year-old man with chronic-phase CML and no significant additional medical history who was initially treated with imatinib 400 mg daily for 1 year with suboptimal response. He was then switched to dasatinib for 2 years. His BCR::ABL1 transcript level has recently increased to 7%. Repeat bone marrow biopsy did not identify any ABL1 kinase mutation.
For this patient, I would recommend a change to ponatinib and evaluation/workup for an allogenic stem cell transplantation. Patients whose disease does not respond to 2 lines of therapy, including second-generation TKIs should be switched to a third-generation TKI (ponatinib or asciminib) rather than rotating second-generation TKIs. This strategy has been shown to improve the rates of CCyR.
For patients, such as this one, who are started on a third-generation TKI, a stem cell transplant consultation is recommended in case the patient does not respond to oral therapy. Our patient was started on ponatinib 30 mg daily and after 6 months of therapy, his BCR::ABL1 transcript level became 0.3% and the dose was reduced to 15 mg daily. This patient has a 10/10 matched unrelated donor, but the transplant remains on hold for now since the patient’s disease responded nicely to treatment.
In patients failing 2 prior TKIs, both ponatinib and asciminib are associated with a CCyR rate of more than 50% and are both effective against the T315I mutation. The decision to use ponatinib or asciminib depends on the patient’s comorbidities and the financial considerations. Asciminib may be preferred in patients with cardiovascular comorbidities such as coronary artery disease since ponatinib is associated with an increased risk of cardiovascular events. However, asciminib is significantly more expensive than ponatinib, particularly at the dose of 200 mg twice daily used for patients with the T315I mutation.
Patients failing ponatinib and/or asciminib could be considered for newer TKIs as part of clinical trials such as olverembatinib, ELVN-001, TERN-701, or others.46 They should be referred for allogeneic stem cell transplantation which is a one-time curative procedure. The benefits and risks of each of these approaches should be discussed with the patient before making an informed decision.
Comparative Efficacy of Third-line TKI Therapy for Achieving CCyR in CML
As shown here, for patients whose disease is no longer responding to imatinib and a second-generation TKI, the optimal third-line choice is a third-generation TKI. In this analysis, with the caveat of a limited number of patients, ponatinib was more strongly associated with CCyR than either bosutinib, dasatinib, or nilotinib in patients with CML and imatinib and a second-generation TKI failure.47
A propensity score matching analysis was performed to evaluate outcomes between ponatinib or other second-generation TKIs in 354 patients receiving a third-line TKI.48 The reported response rates of 51% having a 2-log reduction with ponatinib were consistent with the previous findings of approximately 60% achieving CCyR with ponatinib.47,48
ASCEMBL: Asciminib vs Bosutinib for Previously Treated Chronic-Phase CML
Following a phase I/II trial showing clinical benefit in patients with CML who had failed multiple TKIs or who had the T315I mutation, the phase III ASCEMBL trial was conducted to compare asciminib to bosutinib.49
In ASCEMBL, 233 patients with chronic-phase CML and at least 2 prior TKIs were randomized to receive asciminib 40 mg twice daily vs bosutinib 500 mg once daily. The primary endpoint was the MMR rate at 24 weeks. Secondary endpoints included an MMR rate at Week 96 (meeting no treatment failure criteria before
Week 96), safety and tolerability, CCyR/MMR rates, time to and duration of CCyR/MMR, time to treatment failure, PFS, OS, and pharmacology parameters.
ASCEMBL: Response Rates
At 96 weeks, the MMR rate with asciminib was more than double that with bosutinib, at 37.6% vs 15.8%, respectively. Likewise, the percentage of patients with BCR::ABL1 ≤1% was 45.1% vs 19.4%. Durability was good, with more than 95% of patients retaining their MMR for at least 72 weeks, and at least 40% retaining BCR::ABL1 ≤1%. Finally, the cumulative incidence of BCR::ABL1 ≤1% also showed superiority of asciminib, at 53.7% vs 33.7% with bosutinib.
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