Safety and efficacy of low-dose dasatinib in elderly patients with newly diagnosed chronic myeloid leukemia in chronic phase

BCR-ABL1 tyrosine kinase inhibitor (TKI) can make the life expectancy of chronic myeloid leukemia (CML) patients approach that of the general population, and even enable some patients to stop taking the drug without relapse
.

More than 20% of CML patients are older than 70 years
.

Most elderly patients had other comorbidities and polypharmacy, and comorbidities at the time of diagnosis of CML were strongly associated with overall survival
.

Compared with the second-generation TKI, the first-generation TKI imatinib has fewer cardiovascular complications, so it is often used in elderly patients
.

The DASISION clinical trial showed that patients with newly diagnosed CML in the chronic phase treated with the second-generation TKI dasatinib (100 mg/day) had higher rates of major molecular remission and faster remission rates compared with patients treated with the first-generation TKI imatinib Fast; nearly half of patients had deep molecular remissions lasting at least 1 year without relapse after discontinuation of dasatinib
.

In a single-center phase II clinical trial, dasatinib reduced to 50 mg/day was effective in patients with chronic phase CML
.

Another single-center retrospective study showed that 20% of standard doses of dasatinib (≤20 mg/day) were effective and well tolerated in elderly patients with chronic phase CML
.

However, there is insufficient evidence from single-centre studies and the treatment regimens of these studies were determined by the attending physician on a case-by-case basis, so there is insufficient convincing to apply low-dose dasatinib in the clinical treatment of elderly patients with CML
.

Based on this, some researchers conducted a single-arm, multicenter phase II clinical study to evaluate the safety and efficacy of low-dose dasatinib in elderly patients with newly diagnosed CML in the chronic phase
.

Research Methods This study (DAVLEC; UMIN000024548) was a multicenter, single-arm, phase II clinical trial conducted in 25 hospitals in Japan
.

Inclusion criteria: age >70 years; newly diagnosed chronic phase CML; Eastern Cooperative Oncology Group performance status score 0-2; good organ function; no treatment within 4 weeks, excluding hydroxyurea ≤1 month
.

Exclusion criteria: history of TKI or interferon therapy; significant or uncontrolled cardiovascular disease or complications, including massive pleural effusion, myocardial infarction within 6 months, angina within 3 months, congestive heart failure within 3 months Failure, congenital QT interval prolongation syndrome or 12-lead QTc interval prolongation ≥500ms; combined with other cancers; allergy to dasatinib; the attending physician considered ineligible for the study
.

Dosage regimen: Dasatinib was administered orally, starting at 20% of the standard dose (20 mg/day)
.

If the patient had a best response and an adverse event ≤ Grade 2 at assessments at 3, 6, and 9 months of treatment, continue on the same dose of the drug
.

If the response is suboptimal and the adverse event is ≤ grade 2, the dose is increased by 20 mg/day
.

Once the patient's dose was reduced due to grade ≥3 adverse events, the dose was not increased
.

Treatment was discontinued if disease progressed to accelerated or blast phase
.

The primary endpoint was the primary molecular response rate (MRR; MR3.
0) at 12 months; secondary endpoints included the 12-month deep molecular response rate (MR4.
0 or MR4.
5), adverse events of all grades, and grade 3 vs.
The incidence of grade 4 adverse events, the rate of treatment termination due to adverse events, and the rate of treatment termination due to disease progression,
etc.

Results The baseline characteristics of patients were from October 1, 2016 to October 30, 2019.
The study finally included 52 elderly patients with chronic CML at the beginning of diagnosis for data analysis
.

The median follow-up time was 366 days (range: 353–372 days)
.

The median age at diagnosis was 77.
5 years (range: 73.
5-83.
0 years)
.

Thirty-five (67%) patients were male and 17 (33%) were female
.

Thirty-eight (73%) patients had other medical conditions before CML diagnosis, 33 (64%) patients had comorbidities at or after CML diagnosis, and 47 (90%) patients required regular medication
.

Forty-four (85%) patients received dasatinib for up to 12 months
.

The specific baseline characteristics are shown in the table below
.

Table 1 Efficacy Analysis For the primary endpoint, at 12 months, 31 (31/52, 60%) patients achieved a major molecular response (unilateral 95% CI 48-71), including 23 patients with dasatinib The dose remains at 20 mg/day
.

Thirty-nine (75%) patients achieved best response, 38 (73%) patients had BCR-ABL1 mRNA international standard (BCR-ABL1 IS) less than 10% at 3 months, 25 (48%) patients 3 BCR-ABL1 IS≤1.
0% at month
.

The specific mitigation is shown in the figure below
.

Figure 1 For secondary endpoints, at 12 months, 14 (27%) patients achieved MR4.
0 (one-sided 95% CI 16.
8-37.
0) and 7 (13.
5%) patients achieved MR4.
5 (5.
7-21.
3 )
.

Eight (15%) patients discontinued treatment due to treatment failure (n=3), withdrawal of consent (n=2), drug-related adverse events (n=1), or other reasons (n=2)
.

No patients discontinued treatment due to disease progression to accelerated or blast phase
.

Compared with patients who did not achieve a major molecular response, patients who achieved a major molecular response at 12 months had statistically lower BCR-ABL1 IS values ​​at diagnosis and at 3 months
.

Patients who continued to receive 20 mg/day of dasatinib and achieved a major molecular response at 12 months had statistically significant lower BCR-ABL1 IS values ​​throughout the study period
.

Safety analysis 50 (50/52, 96%) patients had treatment-related adverse events of any grade
.

Eosinophilia, basophilia, elevated lactate dehydrogenase, and elevated C-reactive protein were associated with CML disease itself, not dasatinib treatment
.

Four patients developed pleural effusion without pulmonary hypertension
.

Medication discontinuation occurred in 5 patients due to hematologic (n=3) and non-hematologic adverse events (n=2), with a median of 7 days (range: 5-36 days)
.

Three patients required dose reductions to 20 mg every other day, and one patient discontinued due to drug-related toxicity (QT interval prolongation)
.

There were no treatment-related deaths
.

Notably, only 1 patient developed lymphocytosis
.

There were no statistically significant differences in lymphocyte profiles between patients who achieved a major molecular response and those who did not
.

Adverse events are detailed in the table below
.

Table 2 Conclusions of the study This study showed that dasatinib at a starting dose of 20 mg/day was effective and well tolerated in elderly patients with newly diagnosed chronic phase CML
.

A rapid decrease in BCR-ABL1 IS regardless of TKI dose is an important indicator of molecular remission
.

However, the findings need to be supported by long-term follow-up data
.

Reference: Kazunori Murai, Hiroshi Ureshino, Takashi Kumagai, et al.
Low-dose dasatinib in older patients with chronic myeloid leukaemia in chronic phase (DAVLEC): a single-arm, multicentre, phase 2 trial.
Lancet Haematol.
2021 Dec; 8(12): e902-e911.
Reviewer: Quinta Typesetting: Quinta pokes "read the original text", let's make progress together