Myelofibrosis is a rare disorder characterized by anemia, bone marrow fibrosis, splenomegaly, constitutional symptoms, and high mortality rates. Nevertheless, the spectrum of clinical phenotype in myelofibrosis is highly heterogeneous, meaning that a number of treatment options can be justifiable applied, depending on individual cases.
In order to better assess long-term outcomes, researchers have developed the International Prognostic Scoring System, which uses 5 independent predictors of prognosis to determine risk in primary myelofibrosis. These are: patients presenting at an age above 65, hemoglobin levels less than 10 g/dL, a leucocyte count above 25×109/L, circulating blasts ≥ 1%, and the presence of constitutional symptoms.
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Based on these parameters, physicians can stratify their patients into 3 risk categories from low to high; furthermore, this scoring system can be used to assess prognosis at any point during the course of the disease.
There are a number of medical options available to treat myelofibrosis. Among the most commonly prescribed medications are JAK inhibitors, with ruxolitinib being the drug of choice due to its efficacy in alleviating constitutional symptoms and splenomegaly.
“The availability of JAK inhibitors has changed the treatment paradigm of [myelofibrosis] patients,” Polverelli and colleagues wrote in Cells.
Large-scale studies on the efficacy of JAK inhibitors (mainly ruxolitinib) in patients with myelofibrosis undergoing allogeneic hematopoietic stem cell transplantation (HCT) demonstrated that they had significantly better post-surgical outcomes compared to patients who were not prescribed JAK inhibitors. In addition, patients who were on JAK inhibitors had a lower risk of relapse and experienced a greater reduction in splenomegaly compared to those who were not.
What happens if a patient with myelofibrosis experiences ruxolitinib failure? This is a pressing challenge in myelofibrosis care today, given that there is still no consensus as to what constitutes “ruxolitinib failure.” Generally, ruxolitinib failure is said to have occurred if a patient cannot tolerate the drug or experiences relapses while on ruxolitinib therapy. Studies have suggested that patients who have experienced ruxolitinib failure tend to suffer from poorer transplantation outcomes.
Another primary area of clinical focus with regards to myelofibrosis care is the management of splenomegaly. Splenectomy has always been an option to deal with persistent splenomegaly, although this approach remains controversial. Some studies suggest that splenectomy increases the risk of relapses post-transplant, while others suggest that it has a positive disease-modifying effect. Studies within the last decade suggest that a splenectomy is associated with a higher probability of transplant eligibility within 4 months of surgery.
“The current evidence, therefore, suggests the use of splenectomy in all suitable patients with progressive splenomegaly, while on any medical treatment, palpable over 15 cm below left costal margin,” Polverelli et al wrote.
Issues Surrounding Allogeneic HCT
The only curative option for myelofibrosis is allogeneic HCT. However, this is not necessarily the best course of action for some patients, particularly those who are older and more frail. This is because it is a major surgery with a high rate of transplant-related morbidity and mortality.
Clinicians have developed various tools to assess a patient’s eligibility for an allogeneic HCT. One such tool is to evaluate eligibility based on 1’s Karnofsky performance status (KPS), which has a scale from 0 (death) to 100 (normality) based on a subject’s well-being. Higher KPS scores have been associated with better transplant outcomes; generally, patients with a score lower than 90 are projected to have a poor transplant result, owing to a rise in nonrelapse mortality.
When determining transplant eligibility, clinicians perform a thorough review of a patient’s past medical history. Generally, a patient who has a high number of comorbidities is not considered to be a good transplant candidate. The hematopoietic cell transplantation-specific comorbidity index (HCT-CI) is a scoring system that stratifies transplant risk according to comorbidities, although it has not been extensively used in clinical practice.
If allogeneic HCT is contraindicated, can clinicians offer an alternative therapy with similar potency? The short answer is no. According to Harrison and colleagues in the Annals of Hematology, “for those who do not undergo transplant, treatment remains palliative.” Attention then shift towards relieving various aspects of the disorder, such as cytopenia and constitutional symptoms.
Even if allogeneic HCT was to be given the green light, a few factors must still come together, aside from the relative health of the patient in question. For example, surgeons must identify a suitable donor, preferably a human leukocyte antigen-matched donor from a relative, which is associated with better outcomes.
Read more about myelofibrosis treatment
More innovative forms of transplants involve using stem cells from cord blood. However, this form of transplant remains something of a novelty, and some studies suggest that it increases graft failure and nonrelapse mortality. Some scientists support using the bone marrow as a source of stem cells; others advocate for the use of peripheral blood stem cells, which have been associated with faster recovery periods. Nevertheless, a significant portion of clinicians remain uncomfortable with the relatively experimental nature of these types of transplants.
“In summary, when considering allogeneic HCT in [myelofibrosis], sibling donors and high stem cells doses should be considered as the best options,” Polverelli and colleagues wrote.
Although myelofibrosis carries a poor prognosis, patients eligible for allogeneic HCT often describe having a new lease on life post-surgery. As for patients who are ineligible for surgery just yet, a number of medical therapies (and growing) are available to alleviate symptoms, improve quality of life, and extend survival.
References
Polverelli N, Farina M, D’Adda M, et al. How we manage myelofibrosis candidates for allogeneic stem cell transplantation. Cells. Published online February 5, 2022. doi:10.3390/cells11030553
Harrison CN, Schaap N, Mesa RA. Management of myelofibrosis after ruxolitinib failure. Ann Hematol. Published online March 20, 2020. doi:10.1007/s00277-020-04002-9
