Myelofibrosis (MF)

Myelofibrosis (MF) is a rare bone marrow disease that can be primary or secondary to other blood diseases, such as polycythemia vera and essential thrombocythemia.^1,2 Symptoms in MF derive from defects affecting the production of blood cells. Patients report fatigue, fever, night sweats, and frequent infections, and typically present with splenomegaly.¹

Treatment of MF is targeted toward specific symptom relief. In addition to the Janus-associated Kinase (JAK) inhibitors that can reduce spleen volume and alleviate MF-related symptoms, other strategies are used to manage the disease and treat symptoms. Patients may experience severe cytopenia with disease progression, which often requires blood transfusions and possibly the surgical removal of the spleen.^1,2,3 The only curative treatment available for MF patients remains allogeneic hematopoietic stem cell transplantation (SCT).²

Splenectomy Surgery in Myelofibrosis

The splenomegaly observed in MF patients results from the extramedullary hematopoiesis which can affect not only the spleen but other organs such as the liver, lungs, or kidneys.³ 

The surgical removal of the spleen — splenectomy — is an effective approach for managing symptomatic splenomegaly that is refractory to pharmacological treatment.³ Indications for undergoing surgery include abdominal pain and discomfort, severe thrombocytopenia, portal hypertension, and frequent blood transfusions.^3,4 

Prior to surgery, a complete blood cell count (CBC) should be obtained and patients may require either receive cytoreductive therapy or transfusions to normalize blood cell levels and reach adequate platelet levels before surgery.⁴ Patients will need also to receive anti-infective prophylaxis.⁵

Several complications may develop in the post-operative period of the surgery, including reactive thrombocytosis and thrombohemorrhagic events. These complications are fatal in about 8% of the patients.³

Read more about MF complications

There is also associated mortality and morbidity with this surgery, as well as risk of disease transformation.³ In a 2000 study by Tefferi et al, 9% operative mortality and 31% operative morbidity rates were reported in 223 patients who underwent surgical splenectomy. A 2020 study by Malato et al revealed that 26.4% of patients undergoing splenectomy experienced progression to acute myeloid leukemia.^3,6 

Factors affecting the outcome of a splenectomy include:⁷

• Older age (>65 years),
• Transfusion need,
• Presence of circulating blasts ≥ 5%, and
• Leukocyte count >25 x 10⁹/L.

Any decision to perform the surgery before or after a stem cell transplantation should be considered case by case. Although SCT is often the first choice of treatment before splenectomy, massive splenomegaly may require immediate surgical action, as long as the benefit outweighs the higher risk of graft rejection post-surgery.^3,8

Read more about MF guidelines

Allogeneic Stem Cell Transplantation

Indications for an allogeneic SCT are currently based on prognostic scores, such as the

International Prognostic Scoring System (IPSS), the Dynamic IPSS (DIPSS), and the DIPSS-plus.^2,5 The European LeukemiaNet/ European Group for Blood and Marrow Transplantation (EBMT) expert consensus has proposed that patients younger than 70 years with intermediate-2 or high-risk disease according to the IPSS, DIPSS, or DIPSS-plus should be considered potential candidates for transplant. Intermediate-1 or low-risk patients with high-risk mutations may also be candidates.^8,9 A recent study by the EBMT has shown that the yearly number of patients undergoing an allogeneic SCT has increased between 2014 and 2018.² 

For each allogeneic SCT procedure, a suitable donor must be identified. Transplant candidates will then undergo an assessment to ensure proper organ function reserve for handling the medical procedure. Tests include evaluation of the cardiac, pulmonary, hepatic, and renal function.² 

Read more about MF treatment

Before the transplant, patients will also undergo a conditioning regimen (myeloablative conditioning (MAC), reduced intensity conditioning (RIC), or non-myeloablative (NMA)) to achieve immunosuppression and reduce graft rejection.² Anemia should be controlled, as frequent transfusions may lead to iron overload. This state can induce short- and long-term complications due to its impact on the bone marrow environment which may become not permissive for the hematopoietic cells.⁵

In recent years, the prognosis of allogeneic SCT in MF patients has been evaluated using the scoring systems DIPSS and DIPPS-plus. A 2010 study by Bacigalupo et al found spleen size, donor type, and transfusion history to be predictive of outcome. Their study showed 79% survival for low-risk disease and 8% survival for high-risk disease.¹⁰  

In 2019, the Myelofibrosis Transplant Scoring System (MTSS) was developed as a prognostic tool specific to allogeneic SCT. This index, which is predictive of non-relapse mortality, considers donor-recipient HLA matching, mutational analysis, and clinical data available at the time of the transplant.¹⁰

Read more about MF prognosis

References

1. Primary myelofibrosis. National Organization for Rare Disorders (NORD). Accessed December 28, 2022
2. Ali H, Bacigalupo A. 2021 update on allogeneic hematopoietic stem cell transplant for myelofibrosis: a review of current data and applications on risk stratification and management. Am J Hematol. 2021;96(11):1532-1538. doi:10.1002/ajh.26349
3. Malato A, Rossi E, Tiribelli M, Mendicino F, Pugliese N. Splenectomy in myelofibrosis: indications, efficacy, and complications. Clin Lymphoma Myeloma Leuk. 2020;20(9):588-595. doi:10.1016/j.clml.2020.04.015
4. Lal A. Primary myelofibrosis treatment and management. Medscape. Updated September 21, 2022. Accessed December 28, 2022. 
5. Polverelli N, Farina M, D’Adda M, et al. How we manage myelofibrosis candidates for allogeneic stem cell transplantation. Cells. 2022;11(3):553. doi:10.3390/cells11030553
6. Tefferi A, Mesa RA, Nagorney DM, Schroeder G, Silverstein MN. Splenectomy in myelofibrosis with myeloid metaplasia: a single-institution experience with 223 patients. Blood. 2000;95(7):2226-33.
7. Tefferi A, Mudireddy M, Gangat N, et al. Risk factors and a prognostic model for postsplenectomy survival in myelofibrosis. Am J Hematol. 2017;92(11):1187-1192. doi:10.1002/ajh.24881
8. Kröger NM, Deeg JH, Olavarria E, et al. Indication and management of allogeneic stem cell transplantation in primary myelofibrosis: a consensus process by an EBMT/ELN international working group. Leukemia. 2015;29(11):2126-2133. doi:10.1038/leu.2015.233
9. Lal A. Primary myelofibrosis treatment and management. Medscape. Updated September 21, 2022. Accessed December 28, 2022.
10. Bacigalupo A, Innocenti I, Rossi E, et al. Allogeneic hemopoietic stem cell transplantation for myelofibrosis: 2021. Front Immunol. 2021;12:637512. doi:10.3389/fimmu.2021.637512

Reviewed by Harshi Dhingra, MD, on 12/30/2022.

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Diana Diez Gaspar, PharmD, PhD

Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.