Is 50 mg/day the new standard dose of dasatinib in newly diagnosed patients with chronic myeloid leukemia in chronic phase?

KEYWORDS:

• Chronic myeloid leukemia
• CML
• dasatinib
• low dose
• 50 mg

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1. Introduction

Dasatinib is a potent second-generation tyrosine kinase inhibitor (2G-TKI), which is licensed in the first-line management of patients with chronic myeloid leukemia in chronic phase (CML-CP) with a daily dose of 100 mg once a day (QD), as well as in the salvage setting. DASISION (DASatinib versus Imatinib Study In treatment-Naive CML patients) study is a randomized Phase III trial, which tested dasatinib 100 mg QD against imatinib 400 mg QD in patients with newly diagnosed CML-CP [1]. In this study, patients receiving first-line dasatinib achieved faster and deeper molecular responses, a result that was also supported by other trials. Following DASISION trial, dasatinib 100 mg/day was approved for the upfront treatment of CML-CP [2].

Besides being an efficacious 2G-TKI, dasatinib therapy can be associated with sometimes significant, treatment-related toxicities which may cause major morbidities (recurrent pleural effusions [PE], pulmonary arterial hypertension etc.), and thus, interfere with the quality of life (QoL) of the patients [3]. Five-year follow-up data of the DASISION showed that 28% of patients experienced all grades of PE attributed to dasatinib therapy [4]. The rates of grade 3/4 hematologic adverse events (AEs) associated with dasatinib; neutropenia, anemia and thrombocytopenia were 29%, 13% and 22%, consecutively [4]. These hematologic and non-hematologic toxicities may result in temporary or sometimes permanent cessation of dasatinib and/or dose modification of the TKI. Consequently, there have been inquiries to determine a lower optimal dosage that not only maintains therapeutic effectiveness compared to the standard daily dose of 100 mg, but also enhances the safety profile of the drug.

2. Low-dose dasatinib in newly diagnosed CML-CP patients

A comprehensive pilot study [5] was conducted at the MD Anderson Cancer Center (MDACC) in 2018, aiming to assess the efficacy of a reduced dosage of dasatinib, specifically 50 mg administered daily, and investigated its therapeutic benefits in patients with CML-CP with a median age 47 (range, 18 – 84 years). Median age of the dasatinib arm of the DASISION trial was also 46 years. The MDACC cohort mainly consisted of patients with low-risk according to the Sokal score (49% of total patients), on the other hand, only 33% of patients of the dasatinib arm of the DASISION study were in low-risk according to the Hasford risk stratification.

In the short-term analysis, a cohort of 75 patients receiving the reduced dose of 50 mg of dasatinib demonstrated favorable response rates [5]. After a median follow-up of 9 months, a significant proportion of patients achieved desirable outcomes, including BCR:ABL1 transcript levels of ≤10% and ≤1% at 3 months 93% and 72%, respectively. Furthermore, complete cytogenetic response (CCyR) rates at 6 and 12 months were observed to be 86% and 88%, respectively. Importantly, substantial proportions of patients achieved major molecular response (MMR), deep molecular responses (DMRs) (both MR^4.0 and MR^4.5), at 12 months, with rates of 79%, 71% and 46%, respectively, which were higher than those observed in dasatinib 100 mg arm of the DASISION trial (CCyR and MMR rates at 12 months were 83% and 46%, respectively) [1]. Following these results, the authors concluded that a lower daily dose of dasatinib (i.e., 50 mg) exhibited favorable tolerability with minimal instances of dose interruptions or AEs, including only 9 patients (12%) requiring treatment interruption, typically for a median duration of 14 days (ranging from 7 to 14 days). There have been no dose interruptions due to PE; strikingly PE was observed in only one patient (1%), leading to a dose reduction to 20 mg.

Following these encouraging initial results, long-term and five-year follow-up updates were also published [6,7]. In the long-term follow-up analysis of the same study with 81 patients, again mainly with Sokal low-risk (66% of total patients), and a median follow-up time of 24 months (range, 12 – 37 months) [6], 96% of patients achieved BCR:ABL1 transcript levels of ≤10%, and 77% achieved levels of ≤1% within 3 months, proving a rapid and effective a reduction of disease burden with the lower doses. The rates of CCyR at 6 and 12 months were 86% and 94%, respectively. Notably, at 12 months, the rates of MMR, MR^4.0, and MR^4.5 were high, with rates of 80%, 59%, and 49%, respectively [6], indicating sustained DMR rates. Dose interruptions were observed in 25% of cases, with a median duration of 13 days. PE occurred in a small proportion of patients (6%) and necessitated dose reduction in a limited number of cases (3 out of 5 patients). Importantly, none of the patients experienced disease progression to advanced phases, providing reassurance for their long-term prognosis and maintaining their optimism for improved outcomes. These findings highlight the favorable safety profile of the reduced dose dasatinib strategy, supporting its potential as an effective treatment option for patients with CML. The study’s outcomes were further supported by the 2-year event-free (EFS) and overall survival (OS) rates, both reaching 100%.

At the five-year follow-up [7], OS rate was 96% and the 5-year CML-specific OS rate was 100%. Among patients who reached the 5-year follow-up timepoint, CCyR, MMR, MR^4.0, and MR^4.5 rates were 100%, 100%, 90%, and 90%, respectively. Among 5 patients (6%) who had high-risk Sokal score at diagnosis, 3 patients (60%) achieved complete MR, and 2 (40%) switched to ponatinib because of lack of response.

A propensity score analysis, based on the same cohort, to compare dose limiting toxicities (DLTs) and therapeutic efficacy between low-dose dasatinib (50 mg) and standard dose dasatinib (100 mg) was published later in 2022 [8]. Seventy-seven patients on each group, equally matched according to age (47 vs. 49) and Sokal risk scores (low-risk patients, 65% vs. 69%), were followed with a median of 60 months. At the 12-month timepoint, MMR rate was 82% for patients receiving low-dose dasatinib, while it was 75% among those on standard-dose dasatinib (p=0.229). Notably, within the first year of therapy, the rates of MR^4.0, MR^4.5, and CCyR were higher in the low-dose group compared to the patients receiving standard-dose dasatinib (63% vs. 43%, p=0.009; 53% vs. 36%, p=0.031; 46% vs. 33%, p=0.060, respectively). Additionally, patients treated with dasatinib at 50 mg/day experienced a significantly lower incidence of grade 3-4 PE compared to those on the standard dose (3% vs. 10%, p=0.016), which was 3% in the dasatinib arm at the 5-year update of DASISION trial [4]. Regarding survival data, dasatinib 50 mg daily treatment resulted in significantly higher failure-free survival (FFS), with a 4-year FFS rate of 89% compared with 77% with standard-dose dasatinib (p=0.04). However, EFS, OS, and transformation-free survival (TFS) rates were comparable between the two dosing strategies [8].

In the DAVLEC phase II study [9], dasatinib at a daily dose of 20 mg was evaluated as a frontline therapy for CML-CP in older Japanese patients (≥70 years). The study demonstrated encouraging results, with 73% of patients achieving a BCR:ABL1^IS transcript level less than 10% at 3 months. Additionally, the rates of MMR, MR^4.0, and MR^4.5 at 12 months were reported as 60%, 27%, and 14%, respectively [9]. Moreover, when comparing the clinical activity and safety of dasatinib in the DAVLEC study to the standard dose of 100 mg used in the DASISION trial, notable differences were observed. The DAVLEC study showed a higher rate of MMR at 12 months (60% vs. 46% in the DASISION trial) and a lower incidence of PE (8% vs. 19% in the DASISION trial) [1, 9]. Same group recently published their successful examples of newly diagnosed elderly CML-CP patients treated with intermittent low-dose therapy (twice-weekly, thrice-weekly, or four-times-weekly administration of 20 mg/day dasatinib) with a quite long follow-up period (e.g. 11 years) and DMRs [10].

Another study from Korea [11], showed supporting findings, a beneficial effect of lower starting dose of dasatinib in an Asian population cohort with a median age of 48.9 years. The study focused on optimizing the initial dose of dasatinib for CML patients. The findings revealed that patients with a higher dasatinib dose per body weight (Dose/BW) had a greater incidence of dose-limiting toxicities (DLTs), although they did not affect the rate of MMR. Therefore, a starting dose of 80 mg once daily was suggested as more appropriate, particularly for Asian patients with lower BW. Even though these findings suggest that using a lower dose of dasatinib may provide favorable outcomes with reduced side effects in elderly patients with CML, both studies highlight the need for further research involving more comprehensive and ethnically diverse patient populations emphasized to confirm these results and establish the broader applicability of this treatment approach [9, 11].

3. Combination of low-dose dasatinib and venetoclax in CML-CP patients in the frontline setting

A recently published study by the MDACC group comparing 50 mg/day dasatinib and venetoclax combination with low-dose dasatinib showed that this combination did not induce superior MMR and DMR response rates at 12 months with more hematologic toxicities [12]. Another aim of this study was to assess the rate of durable DMRs and their impact on treatment-free remission (TFR), where longer follow-up is needed to evaluate the impact of this dual inhibition on these parameters. TFR option in CML-CP patients receiving low-dose dasatinib is not a well addressed topic in the literature. In a retrospective study evaluating TFR in CML patients receiving any low-dose TKI, 18% received dasatinib with a lower daily dose than 100 mg (the percentages of patients receiving 20 mg, 50 mg, and 80 mg dasatinib were 11.1%, 55.6%, and 33.3%, respectively) and among patients who had DMR under any low-dose TKI (irrespective of the treatment line), 71.1% achieved and maintained TFR after a median follow-up of 29.2 months and patients with a longer DMR duration showed a trend towards prolonged TFR [13].

4. Conclusion

In conclusion, main caveat of the MDACC low-dose dasatinib studies are the relatively high percent of Sokal low-risk patients which raises question about the efficacy of this dosing strategy in intermediate- or high-risk patients [14]. Furthermore, age is a major risk factor in determining CML-related survival estimates and low-risk might generally mean a relatively younger patient, especially when compared to real-life data [15]. Nevertheless, especially based on the findings of the DAVLEC study, it is reasonable to say that a firm ground of evidence is accumulating towards using lower than standard dose dasatinib in newly diagnosed CML-CP patients, especially in the older age groups and with co-morbidities, in whom PE occurs more frequently. Also, the impact of higher dasatinib dose/BW should be taken into account while evaluating the effectiveness of low-dose dasatinib in Japanese and Korean patients [1, 4, 15]. Studies have not shown an OS advantage of standard dose dasatinib over lower dose schedules, and therefore, better EFS indicates that lower doses may be associated with less AEs, therefore, better treatment adherence and response rates and consequently, with an improved QoL, where “less can be more”. As the follow-up of patients on low-dose dasatinib extends, more data especially on DMR and the possibility of TFR attempt will accumulate. Having said that, obviously more data is still needed before suggesting lowering the standard 100 mg daily dose of dasatinib in every newly diagnosed patient with CML-CP in clinical practice.

Declaration of interest

AE Eşkazan has received advisory board and speaker bureau honoraria from Novartis, Bristol-Myers Squibb, and Pfizer, outside the present study. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

B Saydan and D Özmen contributed equally to this paper.

Additional information

Funding

This paper was not funded.