Long-term Follow-up of Lower Dose Dasatinib 50mg Daily as Frontline Therapy in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia

Abstract

Background:

Dasatinib, a potent Bcr-Abl tyrosine kinase inhibitor (TKI), is approved for the treatment of chronic phase CML (CML-CP) in the frontline and salvage settings. Notable side-effects include pleural effusions and myelosuppression. We previously reported dasatinib 50mg daily to be active and better tolerated than the approved 100mg daily dose.

Study aims:

Update the long-term follow-up results of dasatinib 50mg daily as frontline therapy for CML-CP.

Methods:

Eighty-three patients with newly diagnosed CML-CP received dasatinib 50 mg daily. Eligibility and response criteria were standards as used in previous protocols.

Results:

After a minimum follow-up of 12 months, 81 patients were evaluable. Two patients came off study in <3 months. The rates of 3-month BCR-ABL1 transcript levels by International Standard (IS) ≤10% and ≤1% at 3 months were 96% and 77%, respectively. Cumulative rates for complete cytogenetic response (CCyR) by 6 and 12 months were 77% and 95% respectively. Cumulative rates for major molecular response (MMR) and molecular responses with 4.0 (MR4.0) and 4.5 (MR4.5) log reduction by 12 months were 81%, 55% and 49% respectively. Twenty-one (25%) patients had treatment interruptions for a median of 13 days [range 4–64]. Five (6%) patients developed pleural effusion; 4 (80%) patients required dose reduction. Two patients (2%) failed to achieve any cytogenetic and molecular response and were taken off study. At a median follow-up of 24 months, none of the patients transformed to accelerated or blastic phase. The 2-year event-free and overall survival rates were 100%.

Conclusion:

These updated results continue to support dasatinib 50mg daily as an effective and safe dose for early CML-CP. (ClinicalTrials.gov number, NCT02689440).

Precis:

Update the long-term follow-up results of dasatinib 50mg daily as frontline therapy for CML-CP.

Introduction

Chronic myeloid leukemia in chronic phase (CML-CP) is a clonal myeloproliferative disorder caused by constitutive activation of BCR-ABL1 tyrosine kinase resulting from translocation (9;22)(q34;q11.2) that produces the Philadelphia chromosome [1, 2]. The therapeutic landscape of chronic myeloid leukemia (CML) has changed dramatically with the development of small molecule tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1. The 10-year survival rate in CML in chronic phase has improved from approximately 20% to 80–90% [3]. To date, four TKIs including imatinib, nilotinib, dasatinib and bosutinib are approved for frontline therapy of patients with newly diagnosed CML-CP [3–6]. Therapy with second generation TKIs has demonstrated significantly deeper and faster responses with no impact on long-term survival [7].

Dasatinib, an oral second generation TKI is 325 times more potent than imatinib in inhibiting unmutated BCR-ABL1 kinase in vitro [8–10]. It also inhibits the Src family of kinases, which may be important in blunting critical cell signaling pathways [11]. Dasatinib was initially evaluated in patients in the salvage setting, and later compared to imatinib and approved for frontline CML therapy [5]. The final, five-year follow-up of the DASISION (Dasatinib versus Imatinib study in treatment-naïve chronic myeloid leukemia) trial showed that dasatinib induced more rapid and deeper responses at early time points compared with imatinib [7]. A higher percentage of patients treated with dasatinib achieved BCR-ABL1 transcripts (IS) ≤10% at 3 months compared to imatinib treated patients (84% vs 64%, P < 0.0001) [12]. Patients who achieved a BCR-ABL1 transcript (IS) ≤10% at 3 months had a higher rate of achieving complete cytogenetic response (CCyR), major molecular response (MMR) and molecular response with 4.5 log reduction (MR4.5) by 5 years. Dasatinib also induced higher rates of 12-month confirmed CCyR (77% vs 66%, p = 0.007), and higher 5-year cumulative MMR rates (76% vs 64%, p < 0.0022) and MR4.5 (42% vs 33%, P = 0.025). Drug-related pleural effusions occurred more frequently with dasatinib therapy than with imatinib (28% vs <1%) [7]. Additional side-effects encountered with dasatinib included myelosuppression (20%), and, occasionally, pulmonary hypertension (5%) [7, 12].

In early clinical trials evaluating dasatinib, the drug was noted to be active at doses lower than those with better safety profile [13]. In a randomized trial of four dose schedules of dasatinib (100mg vs 140mg daily; single dose vs twice daily schedule), dasatinib 100 mg single daily dose was found as effective as 140 mg daily with a better safety profile [14]. Furthermore investigators from the DASISION trial have reported the ability to maintain the efficacy of dasatinib among patients who had their dose reduced, while improving its safety profile [15]. The benefit of dasatinib was demonstrated in additional randomized clinical trials, further confirming the overall benefit of dasatinib in treating patients with CML [16, 17].

The aim of the study presented herein was to evaluate lower dose of dasatinib, 50 mg daily, in patients with newly diagnosed CML. Lower doses may improve efficacy by improving drug exposure and minimizing drug interruptions due to adverse events. Additionally, this strategy may prove to be more cost-effective. The first report of this study showed dasatinib 50mg daily to be effective and safe as initial therapy for CML-CP [18]. High rates of responses and rapid achievement of CCyR were observed in nearly all patients after 6 months from the start of therapy [18]. The 12-month MMR and MR4.5 rates of 79% and 46%, respectively, were encouraging [18]. The results were achieved with very favorable toxicity profiles. Here, we present additional data and longer follow-up on the efficacy and toxicity profile of lower dose dasatinib 50 mg orally daily in patients with early CML-CP with a minimum follow-up of 12 months.

Patients and Methods

Patients with a new diagnosis of Philadelphia chromosome (Ph)-positive CML-CP (diagnosis within 12 months from the start of study treatment) were eligible. Patients should have received no prior CML therapy other than hydroxyurea or 1 to 2 doses of cytarabine for debulking, or a maximum of 1 month of therapy with a TKI. Other eligibility criteria included age ≥ 18 years, performance status of 0 to 2, and adequate organ function. Patients with additional chromosomal abnormalities (ACA) were eligible provided they met all other criteria for chronic phase disease (blasts < 15%, blasts plus promyelocytes < 30%, basophils < 20%, and platelets > 100 × 10⁹/L unless related to therapy). Patients with uncontrolled angina within 3 months, diagnosed or suspected with congenital long QT syndrome, with any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or torsade de pointe) with prolonged QTc interval on pre-entry electrocardiogram (> 460 msec), or with a history of a significant bleeding disorder unrelated to CML were not eligible. The study was approved by the institutional review board (IRB); all patients signed an IRB–approved informed consent.

Patients received dasatinib 50 mg once daily. Treatment was continued until disease progression or unacceptable toxicity. Patients with grade 3 to 4 non-hematologic toxicity had treatment transiently interrupted, and dasatinib was restarted (after resolution to grade ≤1) at one dose level reduction to 40 mg once daily. For hematologic toxicity, treatment was interrupted for grade 4 neutropenia (neutrophils <0.5 × 10⁹/L) or thrombocytopenia (platelets <40 × 10⁹/L). Treatment was restarted at the same dose if recovery to above these levels occurred within 2 weeks. Treatment was restarted with a reduction of one dose level if recovery time was >2 weeks.

Patients who did not achieve BCR-ABL1 transcripts (IS) ≤10% by 3 months, a complete cytogenetic response after 6 months (Ph FISH positivity ≤2%; BCR-ABL1 transcripts (IS) ≤1%) or MMR after 12 months of therapy (BCR-ABL1 transcripts (IS) ≤0.1%) and who have experienced no grade ≥3 toxicity may have the dasatinib dose escalated to 100 mg daily.

Patients were monitored by routine blood counts with differential and blood chemistry every 1 to 2 weeks for the first month, then every 4 to 8 weeks thereafter. Bone marrow evaluation with cytogenetic analysis and peripheral-blood quantitative reverse transcription polymerase chain reaction (RT-PCR) for BCR-ABL1 transcripts were performed at baseline, then peripheral blood FISH and PCR for BCR-ABL1 every 3 months for 1 year, and every 6 months thereafter. From patient 19 and onwards, a confirmatory conventional cytogenetic analysis was performed at 6 months. For FISH testing, 200 cells were routinely counted. Response criteria were as previously defined [19]. Complete cytogenetic response was defined by 0% Ph-positive metaphases based on G-banding with at least 20 metaphases counted, or by FISH ≤2%, or by BCR-ABL1/ABL1 (IS) ≤1%. Molecular responses were categorized as major molecular response (MMR) defined as BCR-ABL1/ABL1 (IS) ≤0.1%, MR4.0 defined as BCR-ABL1/ABL1 (IS) ≤0.01% and MR4.5 defined as BCR-ABL1/ABL1 (IS) ≤0.0032%.¹³

This was a pilot study (NCT02689440), with a total of 83 patients enrolled to assess and confirm the efficacy and safety of dasatinib 50mg daily in newly diagnosed CML-CP. The primary objective was to meet a target of MMR rate of 50% at 12 months. This was based on historical experience with dasatinib [20]. Two endpoints were monitored, the MMR probability at 12 months and the toxicity rate. The secondary endpoint was to meet a target of 75% rate of CCyR at 6 months. The goal was to determine whether lower dose of dasatinib would at least maintain the same efficacy as standard-dose dasatinib 100mg daily with a better safety profile. The cumulative response rates were calculated using the cumulative incidence approach and Kaplan-Meier method. The study would stop if, at any time during the study, it was determined that there is more than 5% chance that the MMR probability at 12 months is less than 50%, and more than 5% chance that the CCyR probability at 6 months is less than 75%. For toxicity monitoring, the study would stop if, at any time during the study, it was determined that there is more than 95% chance that the toxicity of grade 3 or higher, is more than 20%. This evaluation would be done at 6 months. These stopping rules for responses and toxicity would be applied starting from the first patient enrolled and in cohorts of 10.

Results

Patient and treatment characteristics

Between March 2016 and April 2018, 83 patients with CML-CP were treated. Baseline characteristics are summarized in Table 1. The median age was 47 years (range, 19–84 years). The median time from diagnosis to treatment was 6 days (range, 0–40); 18 (21%) patients had received TKI for ≤1 month prior to enrollment: 11 with dasatinib, 5 with imatinib, and 2 with nilotinib, with median time on prior TKI therapy of 19 days (range, 1–29). By Sokal risk score, 55 (66%) patients had low-risk, 21 (25%) had intermediate-risk, and 7 (9%) had high-risk. Six patients had ACA; 2 with Y-chromosome, 1 each with t(8;11), t(12;19), del 6, and t(1;11) and t(3;10) respectively. As of the data cutoff on April 2019, the median follow-up time for all patients is 24 months (range, 12–37).

Table 1.

Baseline patient characteristics, N=83

Parameter	No (%); or median [range]
Median age, yr	47 [19–84]
Male gender	40 (48)
Median WBC, × 109/L	37.4 [2–508]
Median hemoglobin, g/dl	12.3 [8–17]
Median platelets, × 109/L	331 [42–2103]
Median peripheral-blood basophils, %	3 [0–17]
Median peripheral-blood blasts, %	0 [0–7]
Median bone marrow blasts, %	1 [0–9]
Sokal risk
Low	55 (66)
Intermediate	21 (25)
High	7 (8)
Previous CML therapy (≤30 days)	18
Dasatinib	11 (61)
Imatinib	5 (27)
Nilotinib	2 (11)
BCR-ABL transcript type
b2a2 and b3a2	14 (17)
b2a2 / b3a2	32 (38) / 37(45)

Response and Outcome

Of the 83 patients enrolled on the study, 81 are evaluable for cytogenetic and molecular response. Two patients are not evaluable as they discontinued therapy early (<3 months); one patient after 5 days of treatment initiation due to a traumatic brain bleed and the second patient due to insurance issues. All remaining patients have been followed for a minimum of 12 months.

Table 2 lists the rates of responses at 3, 6, 12, 18, 24 and 30 months respectively. All 81 evaluable patients have been followed for a minimum of 12 months. Sixty-five patients have reached the 18-month follow-up, 47 patients have reached the 24-month follow-up, and 18 patients have reached the 30-month follow-up. Responses occurred early on the study. At 3 months, 78/81 (96%) patients achieved BCR-ABL1/ABL1 (IS) ≤10%, and 62/81 (77%) patients achieved BCR-ABL1/ABL1 (IS) ≤1%.

Table 2.

Response rates – at 3, 6, 12, 18, 24 and 30 months of dasatinib at 50mg daily^*

No. Response/Total (%)	3 months	6 months	12 months	18 months	24 months	30 months
BCR-ABL1 transcripts (IS) ≤10%	78/81 (96)	79/81 (98)	---	---	---	---
PCR ≤1%	62/81 (77)	73/81 (88)	---	---	---	---
CCyR	40/81 (49)	70/81 (86)	76/81 (94)	61/65 (94)	44/47 (94)	18/18 (100)
MMR	27/81 (33)	53/81 (65)	65/81 (80)	57/65 (88)	41/47 (87)	18/18 (100)
MR4.0	5/81 (6)	28/81 (35)	48/81 (59)	48/65 (74)	31/47 (66)	15/18 (83)
MR4.5	3/81 (4)	21/81 (26)	40/81 (49)	44/65 (68)	27/47 (57)	14/18 (78)

CCyR=complete cytogenetic response; MMR=major molecular response (BCR-ABL1 transcripts [IS] ≤0.1%); MR4.0 = BCR-ABL transcripts (IS) ≤0.01%; MR4.5 = BCR-ABL transcripts (IS) ≤0.0032%

^*As the data matured showing discrepancy between PCR and FISH testing at 3 months, BCR-ABL1 transcripts (IS) ≤1% was used to define CCyR. In addition cytogenetic assessment by conventional cytogenetics was mandated at 6 months, starting patient 19 and onwards.

The cumulative rates of CCyR by 6 and 12 months after the initiation of dasatinib treatment were 77% and 95% respectively, with an estimated CCyR rate of 98% beyond 12 months (Figure 1). The cumulative rates of MMR by 6 and 12 months after the initiation of dasatinib were 53% and 81% respectively, with estimated 18-, 24-, and 30-month MMR rates of 86%, 88% and 89%, respectively (Figure 1). By 12 months, 55% patients and 49% patients achieved MR4.0 and MR4.5 respectively. Similarly, 27% patients had undetectable BCL/ABL1 transcripts (with a minimum 100,000 ABL copies detected) by 12 months. At any given point in time, 96% of the patients achieved CCyR as their best response to low dose dasatinib therapy, 86% patients achieved MMR as their best response, 68% patients achieved MR4.0 and 63% patients achieved MR4.5 as their best response to dasatinib therapy. There was a rapid reduction in transcript levels, with median BCR-ABL1/ABL1 (IS) of 0.24% (range, 0–20.1) at 3 months, 0.02% (range, 0–11.2) at 6 months, and 0.0035% (range, 0–9.5) at 12 months. The median time to CCyR was 4 months (range, 3–15), the median time to MMR was 7 months (range, 3–24), and the median time to MR4.0 and MR4.5 was 6 months (range, 3–24) and 9 months (range, 3–25) respectively.

Figure 1:

Cumulative response rates over time – by 3, 6, 12, 18, 24 and 30 months of dasatinib at 50mg daily*

*CCyR=complete cytogenetic response; MMR=major molecular response (BCR-ABL1 transcripts [IS] ≤0.1%); MR4.0 = BCR-ABL transcripts (IS) ≤0.01%; MR4.5 = BCR-ABL transcripts (IS) ≤0.0032%; CMR= complete molecular remission (BCR-ABL transcripts (IS) undetectable)

Only 4 patients that failed to achieve a CCyR at 6 months had the dasatinib dose increased to 100 mg daily per treating physician discretion. None of these 4 patients tested positive for ABL kinase domain mutations at the time of dose increase to 100mg. Two of these 4 patients subsequently came off dasatinib therapy and were deemed as failures. The first patient was noted to have a decline in hemoglobin to 6 g/dl and platelets of 60×10⁹/L 8 weeks into treatment with dasatinib 100mg daily dose. Work-up for anemia was negative. Dasatinib was held for 3 weeks and resumed with the recovery of blood counts, at a dose reduction to 70mg daily dose. At the 12 month follow-up, repeat bone marrow exam showed persistent disease without evidence of cytogenetic or molecular response. No ABL kinase domain mutations were detected. The patient was taken off study due to lack response to dasatinib therapy. He was subsequently started on ponatinib 15mg daily and achieved a CCyR at 9 months into therapy. The second patient failed to achieve a cytogenetic response at 6 months. Dasatinib was increased to 100mg daily. However repeated ABL kinase domain testing a month into 100mg dose of dasatinib showed gatekeeper mutation T315I. Patient was therefore taken off study and started on ponatinib 30mg daily. Patient was noted to have rising BCR-ABL1 transcript levels 6 months into ponatinib therapy and was switched to axitinib + bosutinib combination study. He had no to response to therapy. He underwent matched related donor stem cell transplant. The remaining 2 patients who had the dose increased to 100mg due to lack of CCyR remain on study at the time of this analysis. One patient with dose increase at 12 months achieved a CCyR and MMR at 18 months and continues to maintain the response. The second patient had the dose increased to 100mg at 6 months and achieved a CCyR at 12 months and MMR at 18 months respectively.

Responses have been durable: only one patient who achieved a CCyR by 9 months, lost cytogenetic response at 12 months. This occurred in the context of ongoing abdominal pain with work-up revealing a gastric mass. The patient subsequently had partial gastrectomy with pathology showing ectopic pancreatic tissue. Patient currently remains on the study and with low level positivity for BCR/ABL1 at 4.5% by FISH. All patients are alive, and none had disease transformation to accelerated or blast phase.

Safety

Treatment was well-tolerated overall. Twenty-one (25%) patients had dose interruption at any time during therapy for a median of 13 days (range, 4–64): 2 for gastrointestinal bleed, 2 for grade 2 elevation in creatinine, 2 for transaminitis, 3 for thrombocytopenia, 2 for unintended pregnancy, and 1 each for traumatic subdural hemorrhage, interstitial lung disease, asthma exacerbation, pseudoseizures, lower extremity edema and neuropathy. Five (6%) patients developed pleural effusions (1 patient had prior dose interruption for renal dysfunction and later developed pleural effusion). All events were grade 2 (80%) or 3 (20%). Median duration of dasatinib interruption for pleural effusion was 19 days (range, 14–55). Six patients required dose reduction; 1 patient with pseudoseizure and 1 patient with neuropathy had dose reduction to dasatinib 40mg daily, while 3/5 patients with pleural effusion had dose reduction to dasatinib 20mg, 1 patient with pleural effusion had dose reduction to 40mg. One patient with pleural effusion had no dose reduction since the pleural effusion occurred with underlying pneumonia. None of the patients with pleural effusion had recurrence after resuming dasatinib. Patient with interstitial lung disease was taken off study. One patient, 75-year-old, had traumatic subdural bleeding on day 4 from the start of therapy. This was unlikely related to dasatinib, but the patient was taken off study on day 5 of dasatinib and was not evaluable for response.

At the time of this analysis, 77 patients remain on study. Five patients had treatment failure (Figure 4). Two patients failed to achieve any cytogenetic and molecular response despite increasing dose of dasatinib to 100mg daily and were therefore taken off study. One patient was taken off study due to developing interstitial lung disease possibly related to dasatinib; 1 patient lost CCyR at 12 months into therapy; while 1 one patient failed to achieve CCyR or MMR at 12 months into dasatinib therapy. The latter 2 patients remain on the study. One patient who achieved a CCyR and undetectable BCR-ABL1 level came off study due to insurance issues and was not counted as failure. The 2-year event-free and overall survival rates are 100% (Figure 4).

Figure 4:

Failure-free (FFS), event-free (EFS) and overall survival (OS)

Discussion

In this update of dasatinib 50 mg daily in patients with early CML-CP, low dose of dasatinib remains effective and safe. At a minimum follow-up of 12 months, 77% patients achieved a CCyR by 6 months and 95% by 12 months from the start of therapy, respectively. The 12-month cumulative MMR rate was 81%; the 12-month MR4.0 and MR4.5 rates were 55% and 49%, respectively.

Treatment was overall well tolerated with 21 patients (25%) requiring treatment interruption. Thirteen patients resumed dasatinib without any dose modification. Pleural effusion was encountered in 5 patients (6%) and requiring dose reduction in 4 patients (3, 20mg and 1,40 mg). These results compare favorably with the historical experience at our institution in similar patients treated with standard-dose dasatinib as well as the DASISION study [7, 20, 21]. In the 5 year follow-up of the DASISION study, 28% patients developed dasatinib-related pleural effusion requiring drug interruption in 62%, and/or dose reduction in 41% of the cases [7].

When compared with historical data in patients treated with imatinib (n=260) and dasatinib 100mg daily (n=259), the results obtained with lower doses of dasatinib were more favorable [7]. Higher rates of CCyR and MMR were noted with dasatinib 50mg daily compared to dasatinib 100mg daily and imatinib (Figure 2) [5, 7]. For example, the 12-month cumulative MMR rate with dasatinib 50mg daily was 81%, which is higher than that reported with standard-dose dasatinib (46% by 12 months) and with imatinib (28% by 12 months). Similarly, the results with lower dose dasatinib were more favorable when compared to other 2^nd generation TKIs. In the ENESTnd trial, the 12-month cumulative MMR rate with nilotinib 300mg twice daily, nilotinib 400mg twice daily versus imatinib 400mg daily were 55%, 51% and 27% respectively [22]. In the BFORE trial, the MMR rates at 12-month with bosutinib versus imatinib were 47.2% versus 36.9% [4].

Figure 2:

CCyR and MMR rates compared to historical data (DASISION trial)^{[5, 7]}

Early response to therapy with BCR-ABL1 transcripts (IS) ≤10% and ≤1% at 3 months was also noted to be higher with lower dose dasatinib compared to historical data with dasatinib 100mg and imatinib (Figure 3) [12]. To date 5 (6%) patients failed therapy (4 due to treatment failure and 1 due to intolerance). This also compares favorably to the historical experience where 70 (27%) patients in the standard-dose dasatinib arm and 53 (21%) in the imatinib arm discontinued therapy due to treatment failure and intolerance to respective TKIs.

Figure 3.

Responses according to BCR-ABL1 transcript levels at 3 and 6 months – a comparison with historical data (DASISION trial)^[7]

We and others have previously reported on the favorable impact of the achievement of 3-month BCR-ABL1/ABL1 (IS) ≤10%, and of 6-month CCyR on long-term event-free and progression-free survival in patients treated with second generation TKI in the frontline setting [8, 15]. In the current study, the 3-month rates of BCR-ABL1/ABL1 (IS) ≤10% were 96%, compared with 84% with dasatinib 100mg, and 64% with imatinib 400mg, respectively, in historical series (Figure 3) [12]. This is also true for other 2^nd generation TKIs. The 3-month rates of BCR-ABL1/ABL1 (IS) ≤10% were 91%, 89% and 67% with nilotinib 300mg twice daily, nilotinib 400mg twice daily and imatinib respectively [22]. With bosutinib, 3-month rates of BCR-ABL1/ABL1 (IS) ≤10% were 75.2% versus 57.3% with imatinib [4]. Furthermore, the 12-month cumulative MMR and MR4.5 rates (81% and 49%) were significantly higher than the rates obtained with standard-dose dasatinib (46% and 5%, respectively) [7]. Although, a higher percentage of patients in the current study were low risk by Sokal, the distribution was similar to what has been reported in our previous studies with dasatinib and nilotinib [20, 23]. The high efficacy of this strategy may therefore reside in the safety profile of low-dose dasatinib with minimal treatment interruptions and constant drug exposure. In the long-term follow-up of the DASISION study, drug related pleural effusion was more common with dasatinib, seen in up to 28% of the patients. This was managed with dose interruption in 62% and/or dose reduction in 41% of the cases. In the current study with low dose dasatinib, pleural effusion occurred in 6% of the patients resulting in a median duration of dose interruption of 19 days (range, 14–55). Previous studies have shown that treatment interruptions correlated with worse outcomes. Once again these extrapolations should be considered with caution because the comparisons refer to historical controls and with relatively short follow-up. The inclusion criteria for all these studies (imatinib and standard-dose dasatinib) were identical, and there were no obvious differences in the patient characteristics [20]. So far the results from low dose of dasatinib continue to appear encouraging when compared to those achieved with other second generation TKIs [7, 15, 22]. A confirmation of these findings is warranted. A randomized study comparing 50mg of dasatinib with the standard dose could be considered. Furthermore, lower treatment intensity may be required in the frontline setting compared to the relapsed setting across all TKIs. This is the case for nilotinib (300 mg twice daily versus 400 mg twice daily) and bosutinib (400 mg daily versus 500 mg daily) [4, 6, 24, 25]. Further dose de-escalation may be considered.

This brings us to the next important milestone in CML patients i.e. role of TKI discontinuation. The high rate of MR4.5 may play a crucial role in treatment discontinuation, but it is too early in our present study to assess the rate of sustained MR4.5, the most generally accepted criterion to be considered. Several studies have evaluated whether TKIs can be safely discontinued in patients who have achieved long-term deep molecular responses. In the largest treatment-free remission trial, the EURO-SKI trial, 821 CML patients treated with frontline imatinib, nilotinib or dasatinib, who had achieved at least MR4.0 and who subsequently stopped TKI therapy, the molecular recurrence-free survival at 2 years was 52% [26]. Higher treatment-free remission rates can be achieved with low-dose dasatinib due to the relatively faster, deeper, and more sustained molecular responses achieved with this strategy, when compared to imatinib and standard-dose second generation TKIs. This makes low dose dasatinib as the preferred initial therapy for patients in whom the eventual TKI discontinuation may be particularly valued (e.g. younger patients expected to live for 2+ decades and who may benefit from TKI discontinuation).

Today, most patients with CML-CP are functionally cured with long-term TKI therapy. However the need for indefinite TKI treatment remains unclear. Treatment-free remission rates vary between 40–60% with majority of the relapses occurring in the first 6 months of stopping therapy. Strategies should be explored in order to increase the proportion of patients who achieve treatment-free remissions. One possible cause of disease relapse are the leukemia stem cells resistant to TKI therapy that can persist despite undetectable BCR-ABL1 transcript levels and likely responsible for disease relapse. Carter and colleagues reported on emerging data suggesting that the combination of Bcl-2 inhibitors (venetoclax) with TKIs enhanced cytotoxicity, depleted the CML stem cells, and prolonged survival in a murine CML model [27, 28]. Such a strategy may lead to a potentially higher percent of patients who achieve long-term complete molecular remissions and a treatment-free remission status. A study combining dasatinib 50 mg daily with venetoclax in frontline CML-CP is ongoing at our institution.

In summary, dasatinib 50 mg daily continues to be effective and safe as initial therapy for CML-CP. In this update, low dose dasatinib continues to demonstrate faster and deeper molecular responses compared to standard-dose dasatinib and imatinib. Moreover the safety profile of low dose dasatinib remains consistent, with no new safety signals identified as yet. Dasatinib 50mg daily might constitute a new, cost-effective option for frontline therapy in CML-CP.