Transplantation for myelofibrosis: yes! But for whom?

Myelofibrosis is a rare disease characterized by progressive obliteration of the marrow space by fibrosis, extramedullary hematopoiesis, splenomegaly, and presence of immature hematopoietic cells in the blood. It is a clonal disorder of pluripotent hematopoietic stem cells that release fibrogenic cytokines and colonize extramedullary sites. Hence it is potentially curable if the abnormal clone can be eradicated and replaced by donor cells. Patients with myelofibrosis were long thought to be poor candidates for transplantation because of a perceived risk of graft failure related to the lack of marrow space. Several previous smaller studies and retrospective surveys confirmed that transplantation could induce durable remissions in at least some patients with myelofibrosis. The study by Deeg and colleagues (page 3912), a single-institution series of 56 patients accrued over a 22-year period, firmly establishes transplantation as a curative procedure.

But the report generates as many questions as it answers. The most important ones are for whom to recommend this treatment and when to recommend it. Myelofibrosis is a pleomorphic disorder with a highly variable clinical course. Deeg et al find that patients with lower Dupriez scores (a prognostic score based on white blood cell count and hemoglobin level), higher platelet counts, a lesser degree of marrow fibrosis, and a normal karyotype fared better than patients with more advanced disease. Younger age was also associated with a better outcome. But, as discussed by Barosi,¹  normal karyotype, low Dupriez score, and younger age also predict an indolent natural history. Younger patients in particular often do remarkably well. Cervantes et al²  found a median survival of 128 months in a group of 121 patients younger than 55 years old. It is difficult to escape the conclusion that transplantation for myelofibrosis has the best results in the subgroup of patients with the most favorable presentation. The dilemma for such patients and their physicians will be whether to choose transplantation with a definite likelihood of cure, but also a considerable risk of treatment-related mortality, or to take a conservative approach with a considerable longterm risk of death from the disease. This dilemma is quite familiar to hematologists when discussing treatment recommendations for a more common disease, chronic myeloid leukemia. Ultimately, it can only be resolved by the patient who is well-in-formed about risks and benefits of all treatment options. One can only hope that more accurate risk classification schemes will make future decisions more straightforward.

In this regard, the recently reported association between peripheral blood CD34 number and prognosis of myelofibrosis may be of interest.³ 

For the older patient and the patient with unfavorable prognostic features, the dilemma is different but no less difficult. At least 50% of such patients died, usually from transplantation-related complications. Transplantation as currently performed is at best marginally effective in such patients and there is a need for better-tolerated yet effective conditioning regimens. Whether the new generation of nonmyeloablative regimens will fulfill that promise can only be established through continued accrual and additional follow-up.⁴