Myelofibrosis and moderate to severe anaemia

Myelofibrosis is a rare, chronic myeloproliferative neoplasm characterised by the abnormal proliferation of hematopoietic stem cells, resulting in bone marrow fibrosis and impaired blood cell production.

This condition leads to a range of complications, including splenomegaly, extramedullary haematopoiesis, and a range of systemic symptoms such as fever, night sweats, and weight loss. One of the most challenging aspects of managing myelofibrosis is its association with moderate to severe anaemia, a complication that significantly impacts patients’ quality of life and overall prognosis.1, 2

The pathophysiology of myelofibrosis involves mutations in genes such as JAK2, CALR, and MPL, which drive abnormal cellular proliferation. These mutations stimulate an overproduction of inflammatory cytokines, creating an environment that disrupts normal haematopoiesis. As a result, fibrosis develops in the bone marrow, leading to reduced space and capacity for blood cell production, ultimately causing cytopenia’s, including anaemia.

Anaemia in myelofibrosis is often progressive and may be worsened by additional factors, such as splenic sequestration, increased red blood cell turnover, or treatment-related cytotoxicity.1, 2

Anaemia in myelofibrosis is typically characterised by a low haemoglobin level often below 10 g/dL and is often refractory to conventional therapies. The degree of anaemia is an important determinant in the prognosis of patients with myelofibrosis, as lower haemoglobin levels correlate with poorer survival outcomes. Management of anaemia in these patients is challenging, as available treatments are limited, and response rates vary. Transfusions are frequently required, especially in cases of moderate to severe anaemia, but they provide only temporary relief and can lead to complications such as iron overload.1, 2, 3

Several therapeutic strategies aim to address anaemia in myelofibrosis, although each has limitations. Erythropoiesis-stimulating agents (ESAs) are often used in an attempt to stimulate red blood cell production, but are generally effective only in patients with lower levels of endogenous erythropoietin and limited to those with less severe anaemia. ESAs may not be appropriate for patients with significant splenomegaly, as they may exacerbate splenic enlargements and related symptoms.1, 2, 3, 4

Another treatment option is the use of androgens such as danazol, which has shown modest efficacy in some patients with myelofibrosis-related anaemia. Danazol may stimulate erythropoiesis and improve haemoglobin levels, but its use is often limited by potential side effects, including hepatotoxicity and masculinising effects in women. The response to danazol is variable, and long-term benefits are still under investigation.1, 2, 3, 4

Immunomodulatory drugs, such as thalidomide and lenalidomide, have also been explored for their potential to improve anaemia in myelofibrosis. These agents can stimulate erythropoiesis and reduce splenomegaly, but they are frequently associated with significant side effects, including neuropathy and myelosuppression. Combination therapy with corticosteroids may enhance their effectiveness, although this approach can lead to additional adverse effects, particularly with prolonged use.1, 2, 3, 4

The emergence of JAK inhibitors (JAKi), such as ruxolitinib and fedratinib, has transformed the treatment landscape for myelofibrosis, especially for symptomatic splenomegaly and constitutional symptoms. However, their effects on anaemia are complex. While JAK inhibitors can improve anaemia in some patients by reducing splenic sequestration and cytokine burden, they can also exacerbate anaemia, especially during the initial phases of treatment. Dose adjustments and supportive care are often necessary to manage this side effect, but the long-term impact on anaemia remains variable.2, 3, 5

Omjjara, an antineoplastic agent containing the active substance momelotinibis is a medication used to treat splenomegaly or other disease-related symptoms in adults with myelofibrosis who also have moderate to severe anaemia. It is prescribed for patients who are either new to Janus kinase inhibitors or have previously been treated with the JAKi ruxolitinib.

Omjjara is effective for three types of myelofibrosis: primary myelofibrosis, where the cause is unknown; post-polycythaemia vera myelofibrosis, related to an excess of red blood cells; and post-essential thrombocythaemia myelofibrosis, linked to an overproduction of platelets. Since these conditions are rare, Omjjara has been designated as an ‘orphan medicine,’ a status given to treatments for rare diseases.6, 7, 8

New therapeutic approaches have been under investigation to specifically target anaemia in myelofibrosis. Luspatercept, an erythroid maturation agent, has shown promise in clinical trials for myelofibrosis-associated anaemia by promoting red blood cell maturation and improving haemoglobin levels. Its mechanism differs from traditional erythropoiesis-stimulating agents, as it directly addresses ineffective erythropoiesis rather than simply stimulating erythropoietin signalling. Early studies suggest that luspatercept may reduce transfusion requirements in a subset of patients, although further research is needed to establish its efficacy and safety profile in this population.1, 2

Stem cell transplantation remains the only curative option for myelofibrosis, but it is associated with high morbidity and mortality and is generally reserved for younger patients with high-risk disease. For patients who undergo transplantation, anaemia may initially worsen due to myeloablative conditioning, but successful engraftment can lead to normalisation of blood counts, including haemoglobin. However, transplantation is not a viable option for many patients due to age, comorbidities, and other risk factors.1, 2, 3, 4

Management of anaemia in myelofibrosis requires a tailored approach, considering each patient’s disease characteristics, symptoms, and treatment goals.

Supportive care with red blood cell transfusions remains a cornerstone of management for patients with moderate to severe anaemia, but the risks associated with chronic transfusions, such as iron overload and alloimmunisation, complicate long-term management.

Iron chelation therapy may be required in transfusion-dependent patients to prevent complications related to iron overload.1, 2

Anaemia in myelofibrosis is a multifaceted challenge with a significant impact on patient outcomes. While several therapeutic options are available, including ESAs, androgens, immunomodulatory drugs, and JAK inhibitors, none are uniformly effective, and each has limitations. Emerging therapies offer hope for improved anaemia management, but further studies are needed to confirm their efficacy and define their role within current treatment paradigms.9 A multidisciplinary approach, involving haematologists, transplant specialists, and supportive care teams, is essential to optimise the management of anaemia in myelofibrosis and improve patients’ quality of life.

Author
Theresa Lowry-Lehnen, RGN, PG. Dip Coronary Care, RNP, BSc, MSc, PG. Dip. Ed (QTS), M. Ed, PhD, Clinical Nurse Specialist and Associate Lecturer South East Technological University.

References:

1. Mayo Clinic (2024) Myelofibrosis. Available here.
2. Passamonti, F., Harrison, C., Mesa, R., Kiladjian, J., Vannucchi, A., Verstovsek, S. (2022). Anaemia in myelofibrosis: Current and emerging treatment options, Critical Reviews in Oncology/Haematology. Volume 180, 2022. Available at: https://www.sciencedirect.com/science/article/pii/S1040842822002864
3. Naymagon, L., Mascarenhas, J. (2017). Myelofibrosis-Related Anaemia: Current and Emerging Therapeutic Strategies. Hemasphere. 2017 Dec 20;1(1): e1. doi: 10.1097/HS9.0000000000000001. PMID: 31723730; PMCID: PMC6745971.
4. Palumbo, G., Stella, S., Pennisi, M., Pirosa, C., Fermo, E., Fabris, S., Cattaneo, D., Iurlo, A. The role of new technologies in myeloproliferative neoplasms. Front. Oncol. 2019, 9, 321.
5. Bose, P., Verstovsek, S. (2020). JAK inhibition for the treatment of myelofibrosis: Limitations and future perspectives. Hemasphere 2020, 4, e424.
6. European Medicines Agency. Omjjara. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/omjjara
7. Medicines and Healthcare products Regulatory Agency (MHRA). (2024). Omjjara licensed for anaemic myelofibrosis patients to treat the symptoms of their disease. Available at: https://www.gov.uk/government/news/omjjara-licensed-for-anaemic-myelofibrosis-patients-to-treat-the-symptoms-of-their-disease
8. Chifotides, H., Bose, P., Verstovsek, S. Momelotinib: an emerging treatment for myelofibrosis patients with anaemia. J Hematol Oncol 15, 7 (2022). Available at: https://doi.org/10.1186/s13045-021-01157-4
9. Duminuco, A., Nardo. A., Giuffrida, G., Leotta, S., Markovic, U., Giallongo, C., Tibullo, D., Romano, A., Di Raimondo, F., Palumbo, G. Myelofibrosis and Survival Prognostic Models: A Journey between Past and Future. Journal of Clinical Medicine. 2023; 12(6):2188. https://doi.org/10.3390/jcm12062188