Discontinuing tyrosine kinase inhibitors in chronic myeloid leukemia

Disclosures

The case for discontinuing tyrosine kinase inhibitors

It is fascinating to look back at the history of chronic myeloid leukemia (CML) treatment over the last 6 decades. Starting in the 1960s, the treatment was mainly supportive care with hydrea or busulfan [1]. Following that, with interferon therapy a small number of patients achieved a cytogenetic response [2, 3]. Around the same time, allogenic hematopoetic stem cell transplantation (alloHCT) was shown to cure approximately 50% of patients [4]. However, alloHCT is associated with significant morbidity and mortality. In 2001, imatinib, the first tyrosine kinase inhibitor (TKI), demonstrated significant activity in patients with CML [5]. This was soon followed by a large randomized trial which confirmed the superiority of imatinib over interferon [6]. With longer follow up, it became evident that patients response continues to improve the longer they are on TKI therapy, with very few relapses occurring after the fourth year of therapy [7]. Several other TKIs are currently FDA-approved for the therapy of patients with CML: nilotinib [8], dasatinib [9], bosutinib [10] and ponatinib [11]. More recently, several studies have demonstrated that patients with CML now have similar life expectancy to the general population [12]. However, to achieve this, patients need to stay on therapy indefinitely, which has drawbacks. First, patients with CML on TKI therapy have reduced quality of life compared to the general population. In one study, 25–30% of patients with CML receiving imatinib therapy had significant fatigue, musculoskeletal pain, muscle cramps and edema [13]. Second, there is a significant cost to patients and society. The current average cost of TKIs is about $100,000 per patient. With 40,000 patients alive with CML, the annual cost in the US for the TKI only (excluding all other health costs) in this rare disease would be close to $4 billion [14]. In addition, medication co-pay is a concern for most families. Hence, based on the excellent survival with TKIs, the logical next step is to focus on improving patients’ quality of life by discontinuing TKIs.

Which patients to select?

In a study by Mahon et al, 100 patients who had been on TKI therapy for at least 3 years and had undetectable BCR-ABL by PCR for at least 2 years, discontinued therapy with close monitoring. Of those patients, 40% remained in remission without needing to restart their TKI, ie, treatment-free remission (TFR). All patients who restarted TKIs achieved a second remission with no obvious harm to those patients [15]. However, many questions remained regarding the optimal TFR approach. In an attempt to answer some of those questions, several studies were conducted both nationally and internationally, enrolling more than 2,000 patients in total [16]. The first question was: which patients are candidates for stopping TKIs? A minimum of 3 years of TKI therapy is currently recommended prior to attempting discontinuation. In addition, a deep molecular response (DMR) for at least 2 years is also a prerequisite. However, the definition of DMR has varied across studies. In the initial studies, undetectable BCR-ABL by PCR was required. However, further studies enrolled patients with <0.01% (molecular response 4; MR4). The largest study was the Euro-SKI study, which demonstrated that the chances of TFR were similar for patients with MR4 vs. MR 4.5 vs MR5 [17]. Therefore, the current recommendation is a level < MR4f BCR-ABL/ABL^IS <0.01% for at least a period of 2 years. Patients with prior resistance to a TKI have a high failure rate and attempting TFR is not recommended in those patients. Finally, compliance is a must for TFR attempts. Regular PCR monitoring is required after TKI discontinuation. Most molecular recurrences occur in the first 6 months. Therefore, recommendations are for monthly PCRs in the first 6 months, and then every 2 months for a total of 2 years, with PCR monitoring every 3 months thereafter [18]. The duration of monitoring after 3 years is unclear at this point. Given the lack of evidence, PCR monitoring should continue every 3 months indefinitely. In the earlier studies, patients restarted when BCR-ABL became detectable. Several other studies have shown the safety of restarting only when patients lose major molecular response (MMR, BCR-ABL/ABL^IS >0.1%, MR³) [19].

Interestingly, in a patient-decision study conducted by Flynn and colleagues regarding drug discontinuation, only 50% who were eligible to discontinue drug would consider doing so. Patients cited several reasons for this, with uncertainty regarding chances of successful discontinuation being one of them [20].

Predicting treatment-free remission

Results have been inconsistent regarding various criteria that may predict successful TFR. Factors such as age, sex, and Sokal risk have been inconsistent across studies. The only prognostic clinical factor that has shown consistent significant association with TFR success has been duration on TKI therapy [21–32]. The longer patients are on TKI therapy, the more likely they are to achieve a TFR. A more recent study by Ilander et al demonstrated that patients with a higher percentage of NK cells in the peripheral blood are more likely to achieve TFR, suggesting that patients’ immune profile may predict relapse [33]. At the end of the day, only 20% of patients will successfully discontinue therapy (50% of patients achieve a DMR and of those only 50% achieve TFR). Several areas of research are needed at this time. First, a better predictive model is required for successful TFR. Second, there is potential to add other therapies to a TKI to either attempt a second TFR, or to improve patients’ response to attempt TFR. Several compounds, such as ruxolitinib, PD-1 inhibitors, arsenic, and inocalcitol, will be in clinical studies soon [34].  Third, understanding why some patients have disease detectable by PCR, but do not progress to clinical disease is very important. Lastly, we need to address the long-term side effects of TKIs for patients who need to continue on therapy indefinitely.

As TFR is currently in the NCCN guidelines, more patients and their physicians will attempt TFR [35, 36]. An involved team that includes the patient, pharmacy, physician and a standardized lab is required for successful and safe discontinuation. A key concern of discussing TFR is that some patients may decide to stop without close observation, or to stop before achieving a sustained DMR. This would lead to worse outcomes in patients with CML, a concern that needs to be addressed with patients and providers alike in order to select the right patients for a TFR trial.

Conclusion

In conclusion, CML therapy has evolved over the last few decades, from symptomatic therapy, to toxic therapy that cures some patients, to less toxic therapy that leads to a functional cure. Our next goal in CML therapy should be developing a true cure, ie, no evidence of disease with no therapy. This could be achieved by better identifying patients who could successfully achieve TFR and by adding other active therapies to TKIs, with the aim of either eradicating the leukemia stem cell or achieving a quiescent disease.