CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: March 21, 2023
Expiration: March 20, 2024
Eunice Wang, MD:
Two trials presented at ASH 2022 represent the changes occurring in the treatment of CML. The first trial is ASC4MORE, which investigated asciminib, the most recently approved treatment for chronic-phase CML. Asciminib represents a different approach for treatment of CML—the first (and so far only) STAMP inhibitor that binds the ABL myristoyl pocket, a distinct site of the kinase domain of BCR::ABL.20
At ASH 2022, Cortes and colleagues21 presented results from the ongoing ASC4MORE study, a multicohort, open-label, randomized phase II trial in adults with chronic-phase CML who had not achieved DMR (BCR::ABL1 >0.01% to ≤1.0%) after ≥1 year of first-line imatinib therapy (N = 84). Patients were randomized to 5 arms: asciminib 40 mg daily plus imatinib, asciminib 60 mg daily plus imatinib, continued imatinib, switch from imatinib to nilotinib 300 mg twice daily, and switch from imatinib to asciminib 80 mg. Imatinib was dosed at 400 mg daily across arms. The primary endpoint was the rate of MR4.5 (ie, BCR::ABL1 ≤0.0032%) at 48 weeks.
Eunice Wang, MD:
At both Weeks 24 and 48, MR4.5 was achieved by a higher rate of patients who received the combination of asciminib at any dose plus imatinib. At Week 48, MR4.5 had been achieved by 19% receiving asciminib 40 mg plus imatinib and 29% receiving asciminib 60 mg plus imatinib vs no patients who continued imatinib and only 5% of those who switched to nilotinib.
The median time to MR4.5 was 12 weeks in patients receiving dual asciminib/imatinib therapy, 24 weeks in patients who switched to nilotinib, and >60 weeks in patients continuing imatinib.
Eunice Wang, MD:
At both Weeks 24 and 48, MR4.5 was achieved by a higher rate of patients who received the combination of asciminib at any dose plus imatinib. At Week 48, MR4.5 had been achieved by 19% receiving asciminib 40 mg plus imatinib and 29% receiving asciminib 60 mg plus imatinib vs no patients who continued imatinib and only 5% of those who switched to nilotinib.
The median time to MR4.5 was 12 weeks in patients receiving dual asciminib/imatinib therapy, 24 weeks in patients who switched to nilotinib, and >60 weeks in patients continuing imatinib.
Eunice Wang, MD:
The cumulative incidence of MR4.5 at 48 weeks was 29% with asciminib 60 mg plus imatinib, 19% with asciminib 40 mg plus imatinib, and 14% in those who switched to nilotinib. The rates of maintaining MR4.5 beyond 48 weeks were 60%, 80%, and 67%, respectively. No patient who remained on imatinib achieved MR4.5
Eunice Wang, MD:
Compared with those who switched to nilotinib, more patients in the asciminib add-on arms achieved deeper responses (42.9% and 28.6%) vs nilotinib (23.8%). As shown here, continuing imatinib in this setting is ineffective.
Eunice Wang, MD:
As expected, the risk of AEs increases when adding a second agent. However, the incidence of serious AEs was similar between the asciminib add-on arms and nilotinib alone (14.3% vs 23.8%, respectively). Likewise, rates of AEs leading to dose adjustment or discontinuation were not markedly worse in the asciminib arms vs nilotinib.
Looking at notable AEs, more liver function abnormalities (24% with increased ALT), rash (38%), and hypertension (19%) occurred in the nilotinib arm vs the dual regimens (<5%, <10%, and <5%, respectively). However, more gastrointestinal (GI) toxicity was seen with the combination therapy arms.
Eunice Wang, MD:
As expected, the risk of AEs increases when adding a second agent. However, the incidence of serious AEs was similar between the asciminib add-on arms and nilotinib alone (14.3% vs 23.8%, respectively). Likewise, rates of AEs leading to dose adjustment or discontinuation were not markedly worse in the asciminib arms vs nilotinib.
Looking at notable AEs, more liver function abnormalities (24% with increased ALT), rash (38%), and hypertension (19%) occurred in the nilotinib arm vs the dual regimens (<5%, <10%, and <5%, respectively). However, more gastrointestinal (GI) toxicity was seen with the combination therapy arms.
Eunice Wang, MD:
AEs of special interest were not markedly different between all of the treatment groups. These events included cardiac failure and other cardiovascular toxicities, edema, GI toxicity, hepatotoxicity, myelosuppression, pancreatic toxicity, and reproductive toxicity.
Eunice Wang, MD:
In conclusion, results from ASC4MORE show that using 2 BCR::ABL1 therapies with different mechanisms of action in patients who did not achieve DMR to a single tyrosine kinase inhibitor (TKI) may be a very effective approach to achieve molecular endpoints. In this trial, the addition of asciminib to imatinib led to a higher rate of DMR at 48 weeks vs continuing imatinib or switching to nilotinib in patients with chronic-phase CML and a suboptimal response to 1 year of imatinib therapy. However, it was not powered to identify the best therapy for DMRs.
Achieving deeper molecular endpoints in patients with CML previously has been demonstrated to lengthen the disease-free interval and may help with earlier achievement of treatment-free remission status. In my practice, younger patients diagnosed with CML in the current era are interested in reaching treatment-free remission as soon as possible so they can discontinue their TKI. Therefore, this combinatorial approach makes sense both mechanistically and clinically.
Amir Fathi, MD:
These data are exciting. I do think combination regimens seem to be more effective in CML. It is reassuring that severe AEs are not worse with the combination. That said, there does seem to be a greater propensity for AEs in general with the combination. Long-term treatment with 2 medications with a propensity for causing GI AEs can be challenging in patients who otherwise feel well. Some patients are reluctant to consider long-term therapy with a single TKI, much less two of them.
Eunice Wang, MD:
Dasatinib is a second-generation BCR::ABL1 TKI approved for the treatment of newly diagnosed Ph-positive chronic-phase CML at a dose of 100 mg/day.22 In a pilot study, a lower dose of 50 mg/day appeared effective and safe, with 12-month cumulative rates of CCyR and MMR of 95% and 81%, respectively.23 This raises the question of whether we are overtreating patients with dasatinib, and many patients would prefer lower-dose treatment because of AEs.
At ASH 2022, Gener-Ricos and colleagues24 presented 5-year follow-up results from the pilot study of dasatinib 50 mg/day in newly diagnosed chronic-phase CML (N = 83). Those who did not achieve a sufficient response could be increased to 100 mg/day.
Endpoints included responses (CCyR, complete molecular response, MMR, MR4, MR4.5) and survival (failure-free survival, EFS, treatment-free survival, OS).
The patients in this study were relatively young, with a median age of 47 years (range: 20-84). Of note, only 5 of these patients (6%) were considered high risk by Sokal scoring; 30% were intermediate risk, and 64% were low risk.
Eunice Wang, MD:
The CCyR rate at 12 months was 94%, with a 79% rate of MMR and a 43% rate of MR4.5. However, by 60 months, 95% of patients had achieved MMR and 82% had achieved MR4.5. Of importance, the MMR and MR4.5 rates at 1, 2, and 5 years of dasatinib 50 mg compare favorably with historical data for dasatinib 100 mg and imatinib 400 mg.
Eunice Wang, MD:
The 5-year OS was outstanding, with 98% of patients remaining alive and 92% event free.
Eunice Wang, MD:
At 5 years, the most common AEs were hematologic, but most were mild and affected <50% of patients; few grade 3/4 events were reported. For example, anemia was reported in 67% of patients but was grade 3/4 in only 5%. Of importance, grade 3/4 cardiovascular/pulmonary issues and grade 3/4 edema were seen in only 1 patient each and grade 3/4 pleural effusion in only 2 patients.
Eunice Wang, MD:
Approximately 20% of patients did require a dose reduction to 20 mg/day, but the responses were not lost in the majority of patients, and a few patients even deepened their response. In total, 10 patients had to switch TKIs, one half due to resistance or suboptimal response.
Eunice Wang, MD:
In this trial, patients with low-risk and intermediate-risk Sokal scores were started on one half of the approved dose for dasatinib and achieved meaningful clinical responses over 5 years, with excellent OS and the potential for decreased AEs. Presumably, this also translates into better compliance and adherence to their prescribed regimen.
Amir Fathi, MD:
These are such interesting—and reassuring—data. In my clinic, I already start TKIs at a lower dose for selected patients with CML, for example, those with previous compliance issues or organ dysfunction. I had a patient who was exposed to many TKIs, and tolerability became an issue. I ended up, after several dose reductions, placing her on dasatinib 3 times a week at 50 mg, and she was able to achieve a DMR. The data reassure me that lower-dose TKIs may be appropriate for a subset of patients.
Eunice Wang, MD:
In our practice, we have adopted this lower-dose dasatinib approach and have seen no difference in terms of response rates to the TKI. Anecdotally, there seems to be a decreased incidence of pleural effusions, which can plague patients for months or even years after therapy. Low-dose dasatinib may be the preferred approach, particularly for older patients who may have comorbidities including asthma, chronic obstructive pulmonary disease, or cardiac issues.
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