CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: April 06, 2022
Expiration: April 05, 2023
B. Douglas Smith, MD:
Several interesting CML abstracts were presented at ASH 2021. The first is the ongoing ASCEMBL study evaluating asciminib, an allosteric inhibitor of BCR‑ABL1 that targets a myristoyl site.34,35 Asciminib has particularly good clinical efficacy in later‑line treatment of patients with CML who are resistant and refractory to prior TKIs.
Analysis of the ASCEMBL study reported at ASH 2020 for 24-week outcomes showed superior efficacy and favorable safety of asciminib vs bosutinib.35,36 Mauro and colleagues37 reported 48-week outcomes from the trial at ASH 2021.
B. Douglas Smith, MD:
ASCEMBL is an ongoing, multicenter, randomized phase III trial of 233 patients with chronic‑phase CML previously treated with ≥2 TKIs with failure or intolerance of the most recent TKI.37 Patients who were intolerant had to have BCR‑ABL1IS >0.1% to be eligible, and patients with T315I or V229L mutations were ineligible.
Patients were stratified by presence or absence of a major cytogenetic response and randomized 2:1 to receive 40 mg asciminib twice per day (n = 157) or 500 mg bosutinib once daily (n = 76). Treatment continued for up to 96 weeks after the initial dose.
The primary endpoint is the major molecular response (MMR) rate at 24 weeks. Secondary endpoints are the MMR at Week 96, but—again—these are the 48‑week data.
B. Douglas Smith, MD:
At 48 weeks, 56.7% of patients receiving asciminib remained on treatment vs 22.4% of patients receiving bosutinib.37 The primary reason for treatment discontinuation with both therapies was lack of efficacy, at 35.5% for bosutinib vs 23.6% for asciminib. There also was a notable difference in discontinuation due to AEs, with 23.7% of patients in the bosutinib arm vs 5.7% in the asciminib arm.
B. Douglas Smith, MD:
MMR was achieved by 29.3% of patients in the asciminib arm vs 13.2% in the bosutinib arm at 48 weeks.37 Of note, when asciminib was used in the fourth line or fifth line or greater, MMR was higher than with bosutinib (fourth line: 31.8% vs 6.9%; fifth line or greater: 22.6% vs 0%). The cumulative incidence of MMR at 48 weeks was 33.2% with asciminib and 18.6% with bosutinib.
B. Douglas Smith, MD:
Although few patients achieved molecular response (MR)4 or MR4.5, both slightly favored asciminib (MR4: 10.8% vs 3.9%; MR4.5: 7.6% vs 1.3%).37 The rate of treatment failure was significantly reduced in patients receiving asciminib vs bosutinib at 48.4% vs 80.3% (HR: 0.4; 95% CI: 0.3-0.6; P <.0001).
B. Douglas Smith, MD:
Grade ≥3 AEs were more common in the bosutinib‑treated arm (67.1% vs 54.5%), as were grade ≥3 AEs leading to discontinuation (18.4% vs 6.4%).37 The rates of dose reduction and interruption were also higher with bosutinib vs asciminib.
The most common AE in the asciminib arm was thrombocytopenia, affecting 29.5% of patients vs 19.7% of patients in the bosutinib arm. Otherwise, the incidence of AEs was comparable between arms or reduced with asciminib vs bosutinib.
Because many patients could not continue treatment with bosutinib, it is important to note that it is difficult to compare these efficacy data with long-term AE data.
B. Douglas Smith, MD:
Early-onset cytopenias affected 21% to 29% of patients receiving asciminib, but the rates of late‑onset cytopenias were lower.37 So, if a patient is receiving asciminib for >1 year and there is a sudden change in bone marrow function and stability, it is probably related to the disease and not the TKI.
B. Douglas Smith, MD:
As noted in other studies, third-generation TKIs such as asciminib cause arterial occlusive events in some patients.37 Any type of arterial occlusive event occurred in 4.5% (n = 7) of patients receiving asciminib vs 1.3% (n = 1) of patients receiving bosutinib.
Some of the arterial occlusive events may be related in part to prior TKI exposure, as all 7 patients with arterial occlusive events receiving asciminib had previously received nilotinib, and 5 of them also had previously received dasatinib.
Because the majority of patients receiving bosutinib discontinued early, there are not enough data for a meaningful comparison, which may explain why the incidence of arterial occlusive events was lower in that arm.
B. Douglas Smith, MD:
The updated results of this trial were not very surprising, but it was nice to see continued efficacy of asciminib at the 48‑week follow-up. The data from ASCEMBL suggest asciminib improves the rate of MMR at 24 and 48 weeks and may slightly improve the rates of MR4.0 or an MR4.5. However, we need more data to better understand the cardiovascular and arterial occlusive toxicities observed with asciminib and other third-generation TKIs.
Dr. Wang, what is your take on the longer‑term data with asciminib?
Eunice S. Wang, MD:
I was pleased to see these results because there have been questions about the tolerability of asciminib since its FDA approval. ASCEMBL provides assurance that asciminib is equivalent, if not superior, to bosutinib despite the fact that most patients who received bosutinib discontinued by 48 weeks. It also was reassuring that asciminib does not have the same incidence of cardiovascular and peripheral vascular AEs seen with ponatinib. So, I think asciminib is a step forward for CML therapy.
B. Douglas Smith, MD:
Many patients can be safely and effectively maintained on much lower doses of dasatinib than the FDA-approved dose, so I really found this next abstract interesting.38 This study compared low-dose dasatinib with the standard dose in patients with newly diagnosed CP-CML. The data were presented by Sasaki and colleagues39 at ASH 2021.
B. Douglas Smith, MD:
This study measured responses in patients with newly diagnosed CP-CML receiving low-dose dasatinib (50 mg/day; n = 83) or standard-dose dasatinib (100 mg/day; n = 150).39
Propensity score matching was used to identify 77 patients in each cohort with similar baseline characteristics for analysis, including age, white blood cell count, and hemoglobin. Patients were assessed for response, failure-free survival, EFS, treatment-free survival, OS, and safety.
B. Douglas Smith, MD:
It is not surprising that the 4‑year OS was 97% with 50 mg and 96% with 100 mg because it is rare for there to be a large OS difference when comparing different starting doses of the same drug.39 All the OS data tell us is that dasatinib is a highly effective therapy for patients with CML.
The 36‑month rates of complete cytogenetic remission, MMR, MR4.0, and MR4.5 slightly favored the 50-mg dose. To me, this immediately suggests that the lower dose may be better tolerated, allowing for treatment intensity to be maintained more successfully.
B. Douglas Smith, MD:
The incidence of cytopenia was slightly lower with the 50-mg dasatinib dose vs the standard 100-mg dose.39 The incidence of liver function abnormalities was similar with both doses.
The incidence of any-grade pleural effusions was significantly lower in patients receiving the 50-mg dose (5% vs 21%; P = .016), which is another important reason to consider treatment with a lower dose.
B. Douglas Smith, MD:
There was a slightly higher discontinuation rate with the 100-mg dasatinib dose (10% vs 3%).39 Although 94% of the patients who initially received 50 mg remained at that dose at 12 months of treatment, only 56% of the patients who initially received 100 mg were receiving 100 mg at 12 months.
B. Douglas Smith, MD:
This was a single institution study and not a randomized trial, so these data need to be carefully weighed, but I think they suggest that a lower starting dose of dasatinib is effective and safe. Dr Wang, what is your take on lower starting doses for TKIs, particularly dasatinib? Is this something we should consider for more of our patients?
Eunice S. Wang, MD:
I was encouraged by these data because they have very practical implications. It is a challenge to put older patients with comorbidities on full‑dose TKIs because of toxicities such as liver function abnormalities and pleural effusion.
I also think low-dose TKI therapy might be more consistent with the overall clinical cadence of CML, because the aggressiveness of the disease is not really the issue, but rather the long‑term ability of patients to stay on drug, particularly our older patients.
B. Douglas Smith, MD:
Yes, I really like their initiative here. I think it behooves us to do randomized studies in this space to better assess the need for intensive dosing and how best to escalate or de‑escalate to keep people on drugs longer.
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