CML: live long and prosper

Chronic myeloid leukemia provides one of the outstanding success stories in hematologic oncology. Thousands of patients have been able to continue their lives because of a remarkably effective, genetically targeted therapy.

Within the lifespan of most hematologists practicing today, CML has gone from a uniformly fatal disease to a chronic, subclinical disorder that can be managed with a once- or twice-per-day oral medication. CML is the poster child for targeted therapy in oncology. Indeed, this year the American Society of Hematology is honoring Dr Janet Rowley and Dr Brian Druker with the Beutler Lecture and Prize for their pioneering work in translating basic science into a highly effective treatment. In addition, the success of tyrosine kinase inhibitors (TKIs) in CML has prompted the pharmaceutical industry to pursue new drug development in other orphan diseases that are genetically defined, because the financial returns are high when a disease-suppressive agent requires on-going therapy over a long time.

It has now been 12 years since the first human subjects with refractory CML volunteered to receive imatinib on clinical trials. Since then, we have learned that responses occur rapidly and in many cases are quite durable.¹  In contrast to the initial concern that malignant cells would rapidly become resistant to inhibition of Bcr/Abl, many patients in fact experience deeper and deeper molecular remissions after several years on therapy.²  Some no longer have detectable mRNA for BCR/ABL, even using highly sensitive RT-PCR methods. Prospective, carefully monitored clinical studies suggest that perhaps one-half of such patients may be able to safely discontinue imatinib therapy, at least for a period of time, without suffering recurrent disease.³ 

Imatinib, and the second-generation analogues nilotinib and dasatinib, are remarkably effective and remarkably well tolerated. Serious side effects have been quite uncommon in large multicenter clinical trials evaluating these agents in newly diagnosed patients with CML in chronic phase. Additional TKIs bosutinib and ponatinib are making their way through clinical development and the regulatory approval process. In general, these agents have nonoverlapping toxicities, and it is usually possible to switch to an equally effective treatment for patients who have intolerance to the initial medication.

The current consensus recommendation is that imatinib, or one of the second-generation Bcr/Abl inhibitors, should be continued life-long as long as the CML clone remains suppressed. Thus, there is no respite from chronic low-grade adverse events. What is the impact of this therapy on a patient's quality of life? In clinical trials, investigators typically focus on severe or life-threatening toxicities and develop management strategies for minimizing them or avoiding them altogether. Particularly in oncology, low-grade, treatment-related toxicities are generally considered to be the price that patients must pay to prolong their survival.⁴  But what about CML patients who now expect to live out their normal lifespan? Are there chronic, cumulative, or late effects from these TKIs that impact on patients' activities of daily life and feelings of well-being, and thus might also interfere with their adherence to daily dosing?

In this issue of Blood, Efficace and colleagues report on a survey measuring the health-related quality of life (QOL) reported by > 400 CML patients in Italy.⁵  These patients had been taking imatinib for 3-9 years. Although patients older than 60 years had QOL profiles very similar to those reported by the general population, younger patients, and women in particular, reported marked impairments due in part to physical and emotional problems. Fatigue was the most frequently reported symptom, followed by muscle cramps, pain, and edema (see figure). Remarkably, over one-quarter of all respondents stated that these 4 symptoms bothered them “quite a bit or very much,” despite a median of 5 years on imatinib treatment. Because lack of adherence to daily dosing appears to be one of the major causes of imatinib treatment failure, it is important for hematologists to appreciate the frequency and severity of these on-going adverse effects in their patients.⁶  Effective management to reduce or eliminate these “low grade” symptoms is a necessary adjunct to prolonged, life-saving antileukemia therapy.