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Allogeneic SCT for myelofibrosis
Table 1. Key characteristics of pivotal non-JAK2/CALR or MPL mutations in myelofibrosis.
Chromosome Characteristics Reference
Spliceosome mutations
SRSF2
U2AF1
SF3B1
Chromatin modifications
ASXL1
EZH2
Other
IDH1 IDH2
• Mutations reported in up to 17% of PMF
17q25.1 • Commonly monoallelic mutations affecting residue P95 70
• More common in older age, higher DIPSS-plus group, accompanying IDH mutations • Associated with worse outcome: OS and LFS
• Involved in pre-mRNA splicing
21q22.3 • Mutations reported in up to 16% of PMF
• Mutations associated with older age; normal karyotype; anemia and thrombocytopenia
71,72
• Incidence of around 6%
2q33.1 • More common with bulky splenomegaly 73
• Presence does not appear to influence survival
• Frequently frameshift mutations – majority associated with similar outcomes
20q11 • Associated with worse OS 74
7q36.1
• Poor risk category CALR [-]/ ASXL1 [+]
• Loss of function mutations associated with poor OS
• May have higher white cell counts and frequently co-exist with JAK2V617F
75
• Higher frequency of mutations in blast phase disease
2q33.3 • Clusters with older age 76
15q26.1 • ? more often associated with a normal karyotype
DIPSS: Dynamic International Prognostic Scoring System; PMF: primary myelofibrosis; OS: overall survival; LFS: leukemia-free survival.
symptom burden and objective quality of life assessment. Given the marked intra-category heterogeneity, refinement of prognostication should occur with cytogenetic and mutational data and the patient should be counseled appro- priately, particularly if high molecular risk features are pres- ent. Certainly, acquisition of high-risk karyotypes, transfu- sion dependence or steadily increasing peripheral blood blast counts would suggest a trigger to move towards allo- geneic SCT.
Recipient age: does this play a role in the transplant decision?
The majority of prognostic scoring systems incorporate age as a risk factor; however, multiple dynamic factors determine post-transplant outcome (Figure 1). One of the most common questions is how old is ‘too old’? Transplantation may be more challenging for elderly recip- ients and there is marked variation globally in the arbitrary age ‘cut-off’ for allogeneic SCT for myelofibrosis. Historically, many earlier studies suggested worse outcome with increasing age. For example, early myeloablative con- ditioning (MAC) studies involving total body irradiation demonstrated worse outcome for those patients >45 years old, and other small studies suggested worse outcomes for those >50 and >60 years old.25-27 In contrast, the Seattle group reported on a highly selected group of myelofibrosis patients undergoing allogeneic SCT with a median age of 65 years (range, 60-78 years), many of whom had multiple co-morbidities.28 Time to engraftment and graft-versus-host- disease (GvHD) rates did not differ significantly from those
in younger cohorts. Moreover, no significant outcome dif- ferences were identified when comparing patients <65 years old with those >65 years old. Focusing on chronolog- ical age alone may not be correct and well-selected elderly patients with minimal co-morbidities and good organ func- tion can benefit significantly from allogeneic SCT. However, real-life decisions can be more difficult in those >70 years old or in those individuals aged 65-70 years who have co-morbidities. In some cases, potential candidates may be frail because of disease symptom burden and have a worse Performance Status, a history of thrombosis or sig- nificant potential for hepatic dysfunction. These factors need careful consideration and optimization where possi- ble. As described above, an upper age limit of 70 years was cautiously suggested but this does not mean that ‘fit’ indi- viduals within a few years above this threshold should be excluded. In general, the transplant decision is heavily influ- enced by careful assessment of the patient and a multi-dis- ciplinary approach. Moreover, factors incorporated in the comprehensive geriatric assessment should be considered and this requires validation in the setting of patients with myelofibrosis undergoing allogeneic SCT.29
Is there a role for splenectomy before transplantation for myelofibrosis?
Evidence on the beneficial role of splenectomy prior to allogeneic SCT remains somewhat sparse although in the- ory splenectomy may be an attractive strategy as it could
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