Chronic myeloproliferative disorders: is quality-of-life the new goal?

Chronic myeloproliferative neoplasms (MPN) are a group of hematologic malignancies that include a variety of different illnesses¹. Chronic myeloid leukemia (CML) has been the primary illness for targeted therapy since the advent of tyrosine kinase inhibitors (TKI), and plays a separate role among MPN. Other MPN include polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF), all of which share common features and a common pathogenetic pathway. Disease presentation and complaints, such as abdominal pain/discomfort and microvascular-related symptoms (e.g. headache, fatigue, insomnia, concentration difficulties, and dizziness) can overlap across MPN, making presentation a mix between the three statuses¹.

Different studies have showed increased plasma levels of inflammatory cytokines, such as IL-1, IL-2, IL-6, IL-8, IL-12, TNFa, interferon (IFN)g, and growth factors, including granulocyte-macrophage colony-stimulating factor (GM-CSF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF) in MPNs that can be responsible, in total or in part, of pathogenesis and/or symptoms of the disease².

The symptom burden of MPN, its impact on quality-of-life (QoL), and ability to work, as well as disease management strategies, have been recently addressed by the online survey of almost 700 patients and over 200 physicians conducted in Australia, Canada, Germany, Japan, Italy, and the United Kingdom. That study confirmed that the majority of patients experience severe debilitating symptoms, reduced QoL, and impaired productivity, requiring the need of therapies that reduce systemic complaints and improve everyday life³. The results of that study also showed that 64% of patients with MPN suffer from some degree of sexual dysfunction, with 43% experiencing severe symptoms. Sexual problems were more severe in the elderly, and were associated with depression, microvascular-related symptoms, and a reduced QoL⁴. The contributing role of gender to the phenotypic profile and symptom expression has also been claimed, with females more affected than males, although the QoL scores in both sexes are similar⁵. Fatigue, fever, night sweats, bone and muscle pain, abdominal discomfort/pain, anorexia, and incoercible pruritus attributable to progressive cytopenias represent a formidable symptom profile in either primary or secondary MF⁶. The mix of those manifestations (systemic symptoms can be found also in less severe PV and ET) dramatically affects daily activities and is not relieved by conventional therapy. Although the prognosis of MF may be variable⁶, it is generally considered a chronic disorder, with a relatively long disease trajectory. Ninety per cent of MF patients, including those with low symptom burden or low risk score, have difficulty controlling systemic symptoms, especially fatigue, resulting in a reduced QoL³. Therefore, improving QoL should be considered a crucial issue in the MF management.

The recent discovery of the first Janus kinase inhibitor (Ruxolitinib) approved for the treatment of MF with splenomegaly has changed the treatment scenario of this disease^7,8. As reported by two phase III, multi-center, randomized controlled trials (COMFORT-I and COMFORT-II), patients reported an immediate and significant relief of systemic manifestations^9,10. These studies demonstrated that Ruxolitinib triggered a significant reduction of spleen size, as well as an improvement in myelofibrosis-associated symptoms and QoL, compared with the best available treatment or placebo^9–11. Two anecdotes support the findings of these studies. The first involves a 70-year-old patient who, the day after taking the drug for the first time, reported that he had carried two heavy grocery bags up two flights of stairs without fatigue, muscular pain, or dyspnoea for the first time in years. The second anecdote concerned a young woman who could finally take a bath, a simple enjoyable event for most people, but which she had avoided for years for fear of pruritus!

The interesting paper by Oritani et al.¹² presents the same revolutionary situation: the improvement of QoL in patients with MF treated with Ruxolitinib in Japan. The authors reported a pooled analysis regarding QoL and symptoms burden over a 24-week period in 81 Japanese patients with intermediate or high-risk MF who had received Ruxolitinib after their enrolment in the Asian and Japanese clinical trials, which substantially confirmed the clinical results of the COMFORT-I and COMFORT-II studies^13,14. Their pooled analysis included the entire cohort of the Japanese study, adding the Japanese patients previously included in the Asian clinical trial. QoL was measured using the European Organization for Research and Treatment of Cancer QLQ-C30 (EORTC QLQ-C30, scoring from 0–100), and symptoms burden profile was determined using the 7-day MF Symptom Assessment form (MFSAF, 0–10 scale)^15,16. The majority of patients reported >50% reduction of the MFSAF at 24 weeks, and an increase in QoL. Notably, improvements in QoL and symptoms relief were associated with reduction of splenomegaly; in particular, patients who achieved a reduction in spleen size greater than one third compared to baseline experienced the largest improvements of QoL and symptoms relief. The greatest clinical benefits correlated with higher dosages of administered drug, such as 20 or 25 mg BID of Ruxolitinib, although favorable results were recorded in all groups receiving the drug. The authors concluded that Ruxolitinib allowed for substantial improvements in symptoms and QoL in Japanese MF patients, and that higher Ruxolitinib doses were associated with better responses, confirming the clinical benefits of this JAK-2 inhibitor in previous studies^9,10.

The reduction of symptoms burden that impacts QoL in patients chronically treated for hematological malignancies has become a critical issue, and one of the major goals of treatment¹⁷. In particular, the improvement in survival seen in CML after the use of targeted drugs, now approaching that of general population¹⁸, has brought up the need for investigators to explore QoL, because it directly affects patient compliance to lifelong treatment. In this context, even low-grade adverse effects can substantially impair daily life of CML patients and, therefore, negatively affect adherence to therapy and clinical response^19,20. From this perspective, the role of the patient is becoming increasingly relevant, and the patient’s reported outcome assessment (PRO) is rapidly changing clinical and research practice in the setting of hematologic neoplasms. For example, the use of self-reported QoL in patients with Myelodysplastic Syndromes (MDS) has improved prognostic accuracy and the development of new prognostic models²¹, with significant advances in the clinical daily MDS management²². The contribution of PRO in the treatment of MF has been critical in determining the most effective strategies for these patients, and this area of research now represents a focus of active investigations. By using disease-specific PRO measures such as MF-SAF, improvement in key symptoms, including fatigue, was demonstrated in patients treated with Ruxolitinib, compared to those who received a placebo. These improvements were also noted in patients who did not achieve the spleen size reduction of 35%, which represented the primary end-point of this controlled study. The placebo group, in contrast, reported worsening of MF-related symptoms and other PRO symptoms over time. These results significantly supported the FDA approval of Ruxolitinib for MF patients²³.

In conclusion, MF is a challenging disease for which clinical management until now consisted only of supportive care for the vast majority of MF patients not eligible for allogeneic stem cell transplantation (SCT), the only treatment able to modify the natural course of the disease^1,6. Given the historically limited therapeutic choices, Ruxolitinib, through its proven inhibition of the JAK-2/STAT pathway, has represented a breakthrough treatment, although its effects appear limited to symptoms palliation and reduction of the spleen size^7,8. Target treatments in the setting of MF and other Ph negative MPN are less effective compared to CML, because of the complex pathways and multiple molecular lesions that sustain neoplastic activity. The impressive clinical results observed in the setting of CML, including treatment discontinuation in some patients²⁴, have not been observed in MF by JAK-2 inhibitor therapy. It is hoped that newer effective treatments will be developed for MF patients, the majority of whom are not eligible for allogeneic SCT. Inhibitors such as Pacritinib and Momelotinib are potentially attractive in cytopenic patients; furthermore, there is interest in combining JAK inhibitors with traditional and/or experimental agents, with the aim of improving survival and QoL²⁵.

The relief of constitutional and debilitating symptoms and the maintenance of the best possible QoL are currently the key issues in MF management, as outlined by Oritani et al.¹². Meanwhile, new research on PRO assessment and QoL in the MF setting is strongly anticipated to improve disease management and QoL in these patients.

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Declaration of funding

This manuscript was not funded.

Declaration of financial/other interests

The authors have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article. CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgements

None reported.