The issue of financial toxicity in the management of chronic myeloid leukemia with blast crisis

In the era of BCR-ABL1 tyrosine kinase inhibitors (TKIs), the outcome of patients with chronic myeloid leukemia in chronic phase (CML-CP) improved dramatically, and patients with CML-CP started to live near-normal life spans¹. Since the management of this disease is a long journey and TKIs are the mainstay of treatment in CML, these resulted in a substantial increase of the therapeutic expenses². The percentage of patients progressing to advanced disease (AD), especially to blast crisis (BC), is smaller when compared to the era prior to the introduction of imatinib. In CML-CP patients receiving upfront second-generation TKIs, this rate is even lower when compared to that of imatinib. Patients with BC usually have dismal outcomes³, and the management of BC is challenging for both physicians and patients. All TKIs (imatinib, second-generation TKIs (dasatinib, nilotinib, bosutinib), and third-generation TKI-ponatinib) were utilized alone in the setting of BC⁴; however, some TKIs should be chosen over others, e.g. dasatinib can be administered in patients with a central nervous system involvement, since it can penetrate the brain–blood barrier, and ponatinib should be the choice of treatment in cases with T315I mutation. Although these drugs may induce some responses, the results of TKIs alone in CML-BC are quite unsatisfactory, and the combination of TKIs with standard cytotoxic chemotherapy are generally preferred in the management of BC⁴. In eligible patients, allogeneic hematopoietic stem cell transplantation (AHSCT) should be utilized following these treatments, since it is the only curative option for patients with CML-BC.

These treatment modalities may place a significant strain on healthcare resource utilization (HCRU) and, with respect to this, Jabbour et al.⁵ published a company-sponsored study in JME evaluating HCRU and the economic burden of patients with CML with progression to BC using real-world data in an US population. In an ∼8-years time frame, among a cohort consisting of 8,091 patients with CML-CP, 587 (7%) experienced progression to BC. The authors showed that patients with progression had a significantly greater mean number of hospitalizations, longer mean length of hospital stay, more outpatient medical service claims, and more prescription claims than those without progression⁵. In addition to that, higher mean total healthcare costs per patient year, costs for hospitalizations and costs for outpatient medical services for patients with progression than those without progression were observed.

In a previously published study, the cost-utility analysis of imatinib for the treatment of AD was established, and it was shown that the costs per additional quality-adjusted life-year gained from imatinib compared with conventional therapies were £29,344 (accelerated phase) and £42,239 (BC)⁶. The conventional therapies were combination chemotherapy or palliative care, where combination chemotherapy was one course of daunorubicin, cytarabine arabinoside, and 6-tioguanine, given in hospital as an in-patient. Palliative care was either provided at hospital or in the patient’s home. Although the authors did not perform a cost-effective analysis for patients receiving AHSCT, which is the main therapeutic option in BC, they concluded that imatinib therapy resulted in considerably greater survival and quality-of-life than conventional treatments, but at greater costs in patients with CML⁶.

In the study by Knopf et al.⁷, the authors performed an analysis in order to understand the economic burden of TKI failure in CML, and they clearly showed that patients with treatment failure had significantly higher HCRU and costs. To give more details, total mean costs were higher among cases with TKI failure than non-failures ($103,857 vs $90,630, p < .037)⁷. Similar to the findings of Jabbour et al.⁵, Knopf et al.⁷ demonstrated that, as a consequence of higher utilization of medical services, patients with TKI failure had significantly higher mean medical costs ($52,619 vs $18,180, p < .001), primarily due to inpatient services ($31,305 vs $5,287, p < .001).

Similarly, in a recent pharmaceutical company-sponsored study, the authors evaluated the economic burden of TKI treatment failure in CML, by assessing all-cause HCRU and costs in the year after treatment failure by using real-world data⁸. They showed that there was an important economic burden, in terms of HCRU and costs, associated with TKI treatment failure in CML patients over the first year after TKI initiation. This economic burden increased by line(s) of therapy, and mainly due to the higher utilization of medical services and associated costs. The authors concluded that costs are driven by the increased need for medical management of CML, comorbidities, and adverse events (AEs) of the therapies⁸. As several TKIs are licensed in the management of CML, and since some patients may remain refractory to the initial TKI treatment and need sequential lines of TKI therapy, cost-effective sequential treatment strategies should be developed in order to cope with the economic burden of TKI treatment in CML^9,10.

Experiencing treatment failure and switching to a second- and third-line TKI was found to be associated with substantial HCRU and economic burden for patients with CML in the study of Kropf et al.¹¹. These findings were especially true for cases with treatment failure under second-line TKI therapy, as multiple TKI switches were associated with the greatest number of hospital and outpatient visits as well as the highest healthcare costs¹¹.

In the study by Perry et al.¹², it was shown that CML patients under the age of 65 years who are uninsured or have Medicaid have significantly worse survival than patients with other insurance coverage. Also it was speculated that, since most patients with CML are in CP at diagnosis, it is possible that delays in the diagnostic process or diminished access to TKI treatment may lead more uninsured patients to present with AD¹². In addition to that, the authors concluded that expenses associated with disease monitoring and follow-up can limit adherence to TKI therapy that might cause progression in patients with CML-CP. Supporting these findings, Dusetzina et al.¹³ clearly demonstrated that patients with higher copayments were more likely to discontinue or be non-adherent to TKI therapy. Similarly, in a very recent study, it was shown that higher out-of-pocket costs were associated with increased rates of delayed initiation and abandonment of insurer-approved prescriptions in patients receiving novel oral anti-cancer agents for various types of tumors including CML¹⁴.

Therefore, financial problems experienced in disease monitoring and TKI adherence might play a role in progression, and these expenses, in addition to many others, are expected to be greater in patients with BC, as shown by Jabbour et al.⁵.

On the other hand, in a company-sponsored study¹⁵, it was shown that frequent molecular monitoring and better adherence to TKIs were associated with lower HCRU and medical service costs. To be more precise, each additional molecular monitoring test (with a cost of ∼ $223) was associated with fewer inpatient admissions, inpatient days, and emergency room visits and an increase in days with outpatient services, generating a positive economic effect of $2,918 per patient per year¹⁵.

One should remember that TKI therapy is not without toxicities and TKIs are associated with some AEs that might be observed during treatment¹⁶. These AEs might result in temporary and/or permanent discontinuation of TKIs, and, what’s more, AEs were shown to be associated with financial toxicity, in addition to negative clinical outcomes¹⁷.

Although the study has some limitations, as stated by the authors⁵, they demonstrated that patients with BC had substantially higher HCRU and economic burden than those without disease progression. So prompt management of the disease with proper molecular monitoring and patient compliance with TKI therapy would reduce the percentage of patients progressing to AD, which would decrease the HCRU and economic burden. Also, as imatinib goes generic^18,19, this would decrease the therapy-related expenses, and, thus, increase the accessibility of TKI therapy, which might further minimize the rate of CML progression. However, with a proper and immediate treatment with imatinib, 20–30% of patients would develop resistance to the drug, which could result in progression to BC, and some high-risk patients would probably need to start with a more potent TKI in order to overwhelm the risk of disease progression.

Transparency

Declaration of funding

No funding is reported for this manuscript.

Declaration of financial/other relationships

AEE has received honoraria for advisory board membership from Novartis, and has received lecture fees from Novartis and Bristol-Myers Squibb. JME peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgements

AEE would like to thank retired Prof. Birsen Ulku for influencing him in choosing a career in hematology.