Will tyrosine kinase inhibitors be part of the treatment armamentarium for CML in the future?

KEYWORDS:

• CML
• therapy
• quality of life
• tyrosine kinase inhibitors

1. Introduction

The history of chronic myeloid leukemia (CML) therapy over the last 6 decades is one of the rapid changes and is fascinating. It started with supportive care, hydrea, busulfan, and radiation back in the 1960s [1]. These therapies mainly controlled the manifestations of the disease with little, if any, effect on the disease itself. With those therapies, the median survival was 3 years, and almost all patients died by 7 years. Following that, interferon therapy was introduced in the 1980s. With interferon, a small percentage of patients achieved cytogenetic and molecular remission, but with significant toxicity and a short duration of response [2,3]. Allogeneic hematopoietic stem cell transplantation (HCT) for CML also was introduced in the 1980s [4]. HCT demonstrated a survival benefit when compared to supportive care only and became the standard of care for eligible patients with CML. However, HCT is associated with significant morbidity, mortality, and reduced quality of life. Fast forward to 2001, when the first tyrosine kinase inhibitor (TKI), imatinib (STI571), was introduced in the clinic [5]. Imatinib not only led to high response rates, but also markedly improved survival and quality of life when compared to historical controls. Since then, several TKIs, including dasatinib [6], nilotinib [7], bosutinib [8], and ponatinib [9], have been developed and approved by the FDA for the therapy of patients with CML. With TKIs, a recent study demonstrated that the survival of patients with CML is almost similar to the general population [10–12]; however, treatment with these drugs is associated with significant impact on quality of life when compared to the general population [13]. In a study by Efficace et al., patients consistently reported increased fatigue and depression, difficulties with sleep, and high symptom burden particularly nausea, diarrhea, pain, fluid retention (puffy face), and skin problems [13], especially as compared to peers without cancer [14]. With this marked improvement in survival, research has now shifted to mainly improving patients’ quality of life. The best way to improve quality of life is by discontinuing TKI therapy. This led several groups to investigate stopping TKIs in patients with a sustained deep molecular response (SDMR). Of all newly diagnosed patients with CML, 30–50% will achieve an SDMR after 5 years of therapy with nilotinib [15], dasatinib [16], or imatinib [15,16], thereby becoming eligible for a treatment-free remission (TFR) trial [15,16]. Of those patients, only 50% will successfully achieve TFR. These data suggest that only 20% of newly diagnosed CML patients will be able to achieve a TFR with current therapies and 70–80% will need to continue lifelong TKI therapy [17].

For those patients who need to continue on lifelong therapy, the cost of TKIs cannot be overstated. Currently, the cost of TKIs in the USA ranges from $90,000 to $250,000 annually [18]. The cost of lifelong TKI therapy is so prohibitive in some developing countries that HCT remains the standard of care [19]. However, the cost should be decreasing soon with the availability of generic TKIs.

2. Expert opinion

Since the development of TKIs, little research has been ongoing in CML outside of TKI therapy. Some researchers and physicians think that no further research is needed in CML, given that survival is similar to the general population. However, most patients would disagree with that. Having to take a medication for the rest of their life with even low-grade side effects and possible long-term toxicities places significant psychological, physical, and financial burden on them. In recent years, most research has focused on optimizing TKI therapy by comparing the TKIs, reducing the dose of TKIs [20], or attempting to stop TKIs and achieving a TFR. Three large randomized trials have demonstrated that second-generation TKIs (dasatinib [6], nilotinib [7], and bosutinib [21]) lead to faster and deeper responses, but with no difference in overall survival. Now that the concept of TFR is finally catching on (and included in the National Comprehensive Cancer Network [NCCN] guidelines) more patients and physicians will consider TFR as the ultimate goal. To achieve that, current TKI therapy alone will not suffice. Several other therapies, either alone or in combination with TKIs, have demonstrated efficacy in the therapy of CML (e.g. proteosome inhibition, bcl-2 inhibition, immunotherapy, JAK2 inhibition, inecalcitol, interferon, arsenic trioxide, ABL001, and pioglitazone) [22]. Incorporating other therapies in combination with TKIs will be necessary for more patients to achieve a TFR. The biggest challenge in further CML research is the toxicity of those potential combinations. Many patients and physicians will be hesitant to enroll on studies given the excellent overall survival with TKIs alone. In addition, the bar will be set very high for adverse events, and there will be a low tolerance for side effects in this patient population. The goal of those studies would be to eradicate the leukemia stem cell or maintain residual disease in a quiescent stage without therapy [23].

Research in the coming years will focus on several areas. The first is better identification of patients who can achieve TFR. TKI discontinuation studies have demonstrated that certain criteria such as age, duration of TKI therapy, duration of deep molecular response, Sokal risk, proportion of mature Natural Killer (NK) cells, and digital PCR can predict successful achievement of TFR [24–27]. However, these have not been consistent across studies. Recently, studies have demonstrated that patients with higher percentage of NK cells in the peripheral blood are more likely to achieve TFR. These new data suggest that a particular patients’ immune profile may predict relapse [28]. Second, with the introduction of NCCN guidelines on discontinuation [29], the importance of proper education of patients and providers on eligibility for TFR, of appropriate monitoring after stopping TKIs, and of the minimal triggers to restart therapy is prudent. The worst thing that could happen is that patients’ survival would be affected because of improper selection for TFR or improper monitoring. Another focus of research will be the addition of new therapies to improve the likelihood of TKI-treated patients to achieve a deep molecular response in order to attempt drug discontinuation. Ongoing studies include adding ruxolitinib or interferon [30] to TKIs and attempting TFR for patients who achieve an SDMR with the addition of those therapies. Another ongoing study by Rousselot et al. will randomize patients to either TKI alone or TKI + pioglitazone. The study is designed to add experimental arms in the future in order to find the best combination for patients to achieve a TFR. Planned experimental arms include interferon, arsenic trioxide, anti-PDL1, and omacetaxine [30]. In the USA, several CML experts are currently collaborating in a CML consortium named after the late Jean Khoury, MD (Jean Khoury Cure CML consortium), with the goal of developing trials to cure CML. Cure defined as off-therapy with no evidence of disease.

In conclusion, there has been rapid progression through the last century of effective treatment for CML with TKIs. While TKI therapy has been a major advance, for most patients it is a lifelong treatment with accompanied long-term side effects and financial toxicity. In our opinion, with the ongoing reignited interest in CML research, TKIs will remain part of the treatment armamentarium for CML therapy in the future, but will not be the only therapy and will not be lifelong.

Declaration of interest

A Atallah has participated in a consulting or advisory role for Novartis, Bristol-Myers Squibb and Pfizer. E Ritchie participated in a consulting or advisory role for Incyte, Pfizer and Novartis, received speakers' Bureau from Novartis and has received research funding via his institute from Bristol-Myers Squibb, Novartis and Pfizer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. A reviewer on this manuscript has disclosed advisory board for Novartis, Pfizer, and Ariad/Incyte as well as consultant for Bristol–Myers Squibb.

Additional information

Funding

The authors are supported by National Cancer Institute grant 1R01CA184798-01A1.