Dasatinib (Sprycel®) Update
Updated: Monday, November 16, 2020
Commentary by Gabriela S. Hobbs, MD, CML Co–Site Editor for JNCCN 360
Clinical Director, Leukemia Service at Massachusetts General Hospital
Treatment options for patients with chronic myeloid leukemia (CML) offer excellent disease control and the promise of normal or near-normal life expectancy.1 Dasatinib is a second-generation tyrosine kinase (TKI) inhibitor that is given once a day at a starting dose of 100 mg for patients with CML.
One of the challenges of TKI therapy in general, and dasatinib therapy in particular, is helping patients live with chronic toxicity. In the case of dasatinib, patients may experience mild but difficult-to-live-with myalgias/arthralgias, gastrointestinal issues, and fatigue, as well as more serious adverse effects, such as pleural effusions, which may result in treatment discontinuation. To address these concerns, clinicians can now consider dose reduction or TKI discontinuation in appropriately selected patients.
One of the challenges of TKI therapy in general, and dasatinib therapy in particular, is helping patients live with chronic toxicity.
In one small study, dasatinib at 50 mg daily was associated with a more favorable toxicity profile as well as excellent disease control.2,3 TKI discontinuation is now standard practice and has been included in the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for CML.4 Patients on first-line TKI therapy, including dasatinib, may be eligible for discontinuation.5 In addition, there are data to suggest that patients who are on second-line dasatinib therapy may also safely discontinue their TKI as long as they meet criteria.6 For all patients who discontinue therapy, it is critical to adhere to the monitoring guidelines and to restart therapy if major molecular remission (BCR-ABL1 transcript levels > 0.1% by polymerase chain reaction) is lost.
Dr. Hobbs has served on a scientific advisory board or as a consultant or expert witness for, Celgene Corporation, Incyte Corporation, BMS, Novartis, Constellation.
With the overwhelming success of TKIs in the management of CML, there is evidence that comorbidities or drug adverse events from long-term TKI therapy could have a greater impact on a patient’s quality of life than the disease itself.7 Although dasatinib is generally well tolerated, long-term use has revealed adverse events of clinical significance, including pleural effusion and myelosuppression.
Accordingly, there is an interest in preserving long-term patient quality of life either by deviating from standard dosing or by discontinuing TKI therapy in appropriately selected patients—while still providing adequate disease control. Since the original Dasatinib Spotlight was posted on JNCCN 360 in August 2018, studies have explored these two treatment strategies with the goal of maintaining disease control while minimizing the impact to quality of life.
There is an interest in preserving long-term patient quality of life either by deviating from standard dosing or by discontinuing TKI therapy in appropriately selected patients—while still providing adequate disease control.
A pilot study published in Cancer reported that giving dasatinib at 50 mg daily as first-line therapy to patients with CML in chronic phase was better tolerated, while still effective, compared with the standard 100-mg daily dose.2,3 In this study, 81 patients with newly diagnosed CML in chronic phase received dasatinib at 50 mg daily. The rates of BCR‐ABL1 transcript levels at ≤ 10% and ≤ 1% at 3 months were 96% and 77%, respectively, and the cumulative rate for a complete cytogenetic response by 12 months was 95%.
The cumulative rates for a major molecular response (MMR) and a deep molecular response with a 4.5‐log reduction of BCR‐ABL1 transcript levels (MR4.5) by 12 months were 81% and 49%, respectively. These rates were significantly higher than those observed with standard-dose dasatinib in the DASISION trial (46% and 5%, respectively),8 leading study authors to speculate that the efficacy of this strategy may be due to the minimal treatment interruptions and constant drug exposure associated with low-dose dasatinib.2 At a median follow‐up of 24 months, none of the patients had disease transformation to an accelerated or blastic phase, and the 2‐year event‐free and overall survival rates were 100%.
As for safety, 21 patients (25%) had treatment interruptions for a median of 13 days. Pleural effusions developed in five patients and four of them required a dose reduction. By comparison, pleural effusion was seen in up to 28% of patients in the DASISION trial with standard-dose dasatinib.
Of note, the NCCN Guidelines for CML state that although 50 mg daily can be considered for patients with “clinically significant intolerance” to 100 mg, “the minimum effective dasatinib dose has not been established in randomized clinical trials.”4 Moreover, the NCCN Guidelines indicate that prevention of serious adverse events such as pleural effusion and myelosuppression, for example, may require discontinuation of dasatinib.
Discontinuing TKI therapy with any agent in this class, including dasatinib, has the potential to reduce side effects associated with lifelong TKI therapy as well as costs. However, not all patients are eligible to stop therapy. The NCCN Guidelines for CML outline the following criteria for TKI discontinuation:4
- At least 18 years of age
- Chronic-phase CML with no history of accelerated- or blast-phase CML
- On approved TKI therapy for at least 3 years
- Prior evidence of quantifiable BCR-ABL1 transcript
- Stable molecular response (MR4.0) for at least 2 years
- Access to a reliable quantitative polymerase chain reaction test with a sensitivity of detection of at least MR4.5
- Monthly molecular monitoring for the first 6 months following discontinuation, then bimonthly for 6 months, then quarterly.
In the event that a patient loses MMR, resumption of TKI therapy within 4 weeks together with monthly molecular monitoring is necessary until MMR is re-established. The NCCN Guidelines recommend consultation with a CML specialist to review the appropriateness of TKI discontinuation and a thorough discussion of the risks and benefits. They also specify that if the patient is not enrolled in a clinical trial, discontinuation of a TKI should be considered only if all NCCN Guidelines criteria are met, with regular monitoring thereafter.
Discontinuing First-Line Dasatinib
The results of the phase II first-line dasatinib discontinuation (DADI) trial hinted that front-line use of dasatinib may move patients into deep molecular remission more rapidly, thus shortening the total time on treatment before treatment-free remission (TFR) is attempted.5 The single-arm, multicenter Japanese study included 68 patients with newly diagnosed CML in chronic phase who had received at least 24 months of dasatinib treatment with a sustained deep molecular response—a BCR-ABL1/ABL1 international scale ≤ .0069% in at least four successive samples spanning a 12-month period. Of the 58 patients who met criteria for discontinuation based on MR4 for a 12-month period, 32 (55%) had TFR after 6 months. This is consistent with prior discontinuation studies.
Likewise, the 6-month TFR in the preceding DADI trial, a study that explored the discontinuation of second-line or subsequent dasatinib in patients with CML in chronic phase, was 49% after 6 months. The final analysis of this study, released in 2018, revealed that 44% of patients had maintained TFR after 3 treatment-free years, suggesting that discontinuation in the second-line setting is safe and feasible.6 Imatinib resistance was identified to be a significant risk factor for molecular relapse.
The findings of the first-line DADI trial suggest that dasatinib may be safely discontinued after first-line treatment in patients with CML who had received at least 36 months of therapy and sustained deep molecular response. Larger prospective studies are necessary to investigate the long-term effectiveness of the lower-dose dasatinib and TFR approaches before they can be widely recommended, but may be a reasonable option for some patients with CML.
- Bower H, Björkholm M, Dickman PW, et al. Life expectancy of patients with chronic myeloid leukemia approaches the life expectancy of the general population. J Clin Oncol 2016;34:2851–2857.
- Naqvi K, Jabbour E, Skinner J, et al. Long-term follow-up of lower dose dasatinib (50 mg daily) as frontline therapy in newly diagnosed chronic-phase chronic myeloid leukemia. Cancer 2020;126:67–75.
- Naqvi K, Jabbour E, Skinner J, et al. Early results of lower dose dasatinib (50 mg daily) as frontline therapy for newly diagnosed chronic-phase chronic myeloid leukemia. Cancer 2018;124:2740–2747.
- Deininger MW, Shah NP, Altman JK, et al. NCCN Clinical Practice Guidelines in Oncology: Chronic Myeloid Leukemia. Version 2.2021. Accessed October 27, 2020. To view the most recent version of these guidelines, visit NCCN.org.
- Kimura S, Imagawa J, Murai K, et al. Treatment-free remission after first-line dasatinib discontinuation in patients with chronic myeloid leukaemia (first-line DADI trial): a single-arm, multicentre, phase 2 trial. Lancet Haematol 2020;7:E218–E225.
- Okada M, Imagawa J, Tanaka H, et al. Final 3-year results of the dasatinib discontinuation trial in patients with chronic myeloid leukemia who received dasatinib as a second-line treatment. Clin Lymphoma Myeloma Leuk 2018;18:353–360.e1.
- Pinilla-Ibarz J, Sweet K, Emole J, et al. Long-term BCR-ABL1 tyrosine kinase inhibitor therapy in chronic myeloid leukemia. Anticancer Res 2015;35:6355–6364.
- Cortes JE, Saglio G, Kantarjian HM, et al. Final 5-year study results of DASISION: the dasatinib versus imatinib study in treatment-naive chronic myeloid leukemia patients trial. J Clin Oncol 2016;34:2333–2340.