Consistent Findings Validate Viability of TKI Discontinuation in CML

Article

First- and second-generation TKIs confer a significant survival benefit for patients with chronic-phase chronic myeloid leukemia (CP-CML)—so much so, that treatment discontinuation has become a viable option for select patients.

Frank T. Slovick, MD

Frank T. Slovick, MD

Frank T. Slovick, MD

First- and second-generation TKIs confer a significant survival benefit for patients with chronic-phase chronic myeloid leukemia (CP-CML)—so much so, that treatment discontinuation has become a viable option for select patients.

Although the safety of TKI treatment discontinuation has been questioned in the past, long-term follow-up data indicate that specific patients, in accordance with NCCN guidelines, are able to come off treatment without sacrificing outcomes.

“If you stop the TKI, it’s important that you’re prepared to monitor the patient monthly for the first 12 months, every 6 to 8 weeks for the next 12 months, and pretty much every 3 months indefinitely,” said Frank T. Slovick, MD, a medical oncologist at Sarah Cannon Research Institute, HCA Midwest Health, in a presentation during the 2019 OncLive® State of the Science Summit™ on Hematologic Malignancies.

In the presentation, Slovick discussed the trials that have examined TKI discontinuation in patients with CP-CML that were presented at the 2018 ASH Annual Meeting and 2018 ASCO Annual Meeting.

The criteria for TKI discontinuation are very stringent, explained Slovick. Patients have to be in CP, have received a TKI >3 years, and be in a deep molecular remission for more than 2 years—a benchmark that is commonly defined as MR4.5, and is also quantified by an undetectable BCR/ABL transcript of <.0032.

Patients who lose their major molecular response (MMR) are unlikely to qualify for discontinuation, as they often have a MR3, or BCR/ABL transcript >.1 on consecutive tests, added Slovick.

The first trials to examine TKI discontinuation were conducted in 2010 and 2013 in the STIM1 and TWISTER2 trials, respectively. Both trials examined discontinuation with the first-generation TKI imatinib (Gleevec), and showed treatment-free remissions (TFR; MR4.5) ranging from 40% to 47% at 24 months. The majority of relapses occurred in the first 4 to 6 months of therapy, said Slovick. Notably, there were no relapses after the first year of discontinuation. If MMR was lost, all patients regained sensitivity to imatinib upon retreatment.

In 2017, a second-generation TKI discontinuation trial was conducted, referred to as STOP 2G-TKI, explained Slovick. Sixty patients in their first-, second-, or third-line of therapy were enrolled and included in the interim analysis. Although 63.3% of patients experienced a 1-year TFR, 26 patients later relapsed.3 The median time to relapse was 4 months (range, 1-38 months), and cumulative incidences of molecular relapse by 12 months was 35%.

Investigators noted that patients who had a suboptimal response or resistance to initial treatment with imatinib had a higher relapse rate upon discontinuation. Although 26% of patients lost MR4.5, they remained in a major molecular response off-therapy, noted Slovick.

Similar findings were reported at the 2018 ASCO Annual Meeting with the updated data from the ENESTop trial,4 in which 126 patients discontinued second-line nilotinib (Tasigna). At 144 weeks, 61 patients (48.8%) remained treatment-free, said Slovick. However, 6 of the initial 67 patients who were treatment free at 96 weeks lost MMR at 144 weeks. Similarly, a trend toward regained sensitivity was noted in the trial, as 97% of patients who restarted nilotinib responded, and 91% regained MR4.5.

“Patients had no progression to accelerated phase or blast crisis, nor was there any death related to CML,” said Slovick.

These findings were echoed in the ENESTfreedom trial,5 in which 190 patients receiving first-line nilotinib were taken off treatment. At 144 weeks, (46.8%) patients remained in TFR; however, 4 patients lost MMR after 96 weeks. Of 91 patients who restarted nilotinib, 90 regained MMR and 84 regained MR4.5. Although 10 patient deaths were reported, none resulted from CML.

“As long as patients meet the criteria and are followed closely, it’s safe to stop the TKI, realizing that you’re going to have to restart it about 50% of the time” said Slovick.

In the community setting, several trials have reported on the feasibility of TKI discontinuation, including a Korean trial6 with imatinib and a Spanish trial7 that compiled data on patients receiving imatinib, nilotinib, and dasatinib (Sprycel). Both trials reported TFR rates >50% at 2 years, although 1 patient who achieved MMR in the first trial developed blast crisis and went on to receive transplant, reported Slovick. In the second trial, 64% of patients remained treatment-free at 4 years. Seventy-five percent of relapses occurred in the first 6 months off the drug, with the latest reported relapse occurring at 30 months. If patients had been on a TKI >5 years or had a MR4.5 >4 years, they were less likely to relapse, said Slovick.

“In community practice, the longer the patient is on the TKI and the longer they’re in a deep molecular remission, the safer it may be to stop the drug,” explained Slovick.

The importance of time on therapy was reiterated in the Treatment-Free Remission Accomplished by Dasatinib trial, in which patients who had failed a first discontinuation attempt with imatinib showed a higher discontinuation failure rate with dasatinib if they were taken off the drug after only 1 year of retreatment.8

In terms of the efficacy between the first- and second-generation TKIs, 5-year follow-up data from the UK National Cancer Research Institute trial indicated no statistically significant differences in overall survival (OS) or event-free survival in patients with newly diagnosed CP-CML treated with either imatinib or dasatinib,9 said Slovick.

However, patients on imatinib had a lower 5-year therapy completion rate than dasatinib (47.8% vs 56.7%, respectively), higher rates of suboptimal response leading to discontinuation (17.4% vs 1.7%), and a higher need for transplant (7.6% vs 1.5%). Although the cumulative rate of MR3 (63.0% for imatinib vs 83.0% for dasatinib)/MR4 (57.2% vs 77.5%) seemed to favor dasatinib, there were also higher rates of toxicity leading to discontinuation in the dasatinib arm (30.3% vs 16.7%) and greater likelihood of treatment failure (52.9% vs 60.9%).

Although the incidence of pleural effusions with dasatinib remains a pain point for providers, Slovick explained that these findings parallel those of the DASISION trial, which showed that 100 mg of dasatinib once daily is a safe and effective first-line therapy for the long-term treatment of patients with CML-CP.

If patients are started on frontline imatinib, that is not to say that they can’t switch to dasatinib, explained Slovick. In the DASCERN trial, patients with CP-CML who had not received BCR/ABL <10% at 3 months were randomized 2:1 to dasatinib versus imatinib continuation.10 Those on imatinib were crossed over to receive dasatinib if they failed to meet the 2013 European LeukemiaNet guidelines for optimal response at the 3-month mark.

Results showed a higher median treatment duration, higher rate of MMR at 1 year, and longer time to MMR with dasatinib, regardless of whether or not patients had crossed over. Although the study met its primary endpoint of median time to MMR, Slovick explained that longer follow-up is required to fully gauge the impact of early switching on OS and progression-free survival.

Slovick also pointed out that although imatinib remains a feasible frontline therapy, data from an observational trial reported at the 2018 ASH Annual Meeting suggested that its generic counterpart may confer a lower survival benefit. However, mature survival data are pending.11

In the pipeline are next-generation TKIs, including the fourth-generation TKI PF-114 mesylate, which is being tested in a phase I trial for patients who have received ≥2 prior lines of therapy, said Slovick. Moreover, asciminib (ABL001), a specific BCR/ABL inhibitor has shown promise for patients who harbor T3151 mutations, irrespective of prior exposure to ponatinib, concluded Slovick.

References

  1. Mahon FX, Rèa D, Guilhot J, et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicenter Stop Imatinib (STIM) trial. Lancet Oncol. 2010;11(11):1029-1035. doi: 10.1016/S1470-2045(10)70233-3.
  2. Ross DM, Branford S, Seymour JF, et al. Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study. Blood. 2013;122(4):515-522. doi: 10.1182/blood-2013-02-483750.
  3. Rea D, Nicolini FE, Tulliez M, et al. Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia: interim analysis of the STOP 2G-TKI study. Blood. 2017;129(7):846-854. doi: 10.1182/blood-2016-09-742205.
  4. Mahon F-X, Boquimpani C, Takahashi N, et al. Long-term treatment-free remission (TFR) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) after stopping second-line (2L) nilotinib: ENESTop 144-wk results. J Clin Oncol. 2018;36 (suppl 15; abstr 7003). doi: 10.1200/JCO.2018.36.15_suppl.7003.
  5. Radich JP, Masszi T, Casares MTG, et al. Long-term treatment-free remission (TFR) following frontline (1L) nilotinib in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP): ENESTfreedom 144-wk results. J Clin Oncol. 2018;36 (suppl 15; abstr 7063). doi: 10.1200/JCO.2018.36.15_suppl.7063.
  6. Zang DY, Lee WS, Mun Y-C, et al. Long-term follow-up after treatment discontinuation in patients with chronic myeloid leukemia: the Korean imatinib discontinuation (KID) study. Presented at: 2018 ASH Annual Meeting; Dec. 1-4, 2018; San Diego, CA. Abstract 4252. ash.confex.com/ash/2018/webprogram/Paper118026.html.
  7. Boluda JCH, Pereira A, Pastor-Galan I, et al. Feasibility of treatment discontinuation in chronic myeloid leukemia in clinical practice in Spain: results from a nationwide series of 236 patients. Presented at: 2018 ASH Annual Meeting; Dec. 1-4, 2018; San Diego, CA. Abstract 47. ash.confex.com/ash/2018/webprogram/Paper109976.html.
  8. Kim DDH, Busque L, Forrest DL, et al. Second attempt of TKI discontinuation for treatment-free remission after failing first attempt with imatinib: treatment-free remission accomplished by dasatinib (TRAD trial). Presented at: 2018 ASH Annual Meeting; Dec. 1-4, 2018; San Diego, CA. Abstract 787. ash.confex.com/ash/2018/webprogram/Paper114656.html.
  9. O’Brien S, Cork L, Bandeira V, et al. Spirit 2: final 5-year analysis of the UK National Cancer Research Institute randomized study comparing imatinib with dasatinib in patients with newly diagnosed chronic phase CML. Presented at: 2018 ASH Annual Meeting; Dec. 1-4, 2018; San Diego, CA. Abstract 457. ash.confex.com/ash/2018/webprogram/Paper110128.html.
  10. Cortes J, Jiang Q, Wang J, et al. Dasatinib versus imatinib in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) who have not achieved an optimal response to 3 months of imatinib therapy: discern. Presented at: 2018 ASH Annual Meeting; Dec. 1-4, 2018; San Diego, CA. Abstract 788. ash.confex.com/ash/2018/webprogram/Paper111978.html.
  11. Pagnano KB, Fava C, Miranda EC, et al. Efficacy and safety of generic imatinib compared to glivec in chronic phase - chronic myeloid leukemia - a multicenter, observational study. Presented at: 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 46. ash.confex.com/ash/2018/webprogram/Paper113718.html.
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