Darbepoetin Alfa for the Treatment of Anemia in Patients with Myelofibrosis with Myeloid Metaplasia (MMM). Results from a Danish Multicenter Study.
Authors: Hannestad Kathrine , Larsen Thomas Stauffer , Andersen Torben Mourits , Clausen Niels Aage Toeffner , Hansen Per Boye , Jensen Bjarne Anker , Birgens Henrik Sverre , Hasselbalch Hans Carl 
Published: November 2019

Background: Treatment with recombinant human erythropoietin (rHuEPO) may increase the hemoglobin (Hb) concentration in patients with myelofibrosis with myeloid metaplasia (MMM). Only one study in this setting has used darbepoetin alfa (Aranesp®) (DA), an erythropoiesis-stimulating protein with a long half-life allowing less frequent administration.We report the largest series of patients with MMM being treated with DA so far.

Methods: Twenty-eight patients were enrolled in a prospective Danish multicenter study. Median age was 71 years (range 50 – 86 years). Inclusion criteria were symptoms of anemia or a Hb concentration ≤ 10 g/dL. Response criteria: A major response (MAR) was defined as either a complete response (CR = no need for blood transfusions and a increase in the Hb-level > 11.5 g/dl), or a partial response (PR = a 50% reduction in the need of blood transfusions, compared to the average monthly need during the 6 months before the start of DA in combination with a stable Hb level > 10 g/dl. A minor response (MIR) was defined as a 50% reduction in the need for blood transfusions compared to the average monthly need the last 6 months preceding start of DA treatment. Non-responders (NRS) were defined as patients with no change or an increased need for blood transfusions.

Treatment: All patients were scheduled to receive DA 300 μg sc. once-weekly for at least 12 weeks. In patients who achieved a normal Hb concentration at this dose, the DA dose was decreased to 300 μg every second week or even third week if possible. If the Hb concentration subsequently declined and the patient developed anemia in the subsequent weeks, the dose of DA was increased to a level that maintained a normal Hb concentration. Patients achieving a CR or a PR continued DA beyond 12 weeks. In NRS, the treatment was discontinued after 12 weeks of treatment.

Results: The response rate was 65% (17 out of 26 evaluable patients), 6 patients achieving a CR (23%), 3 PR (12%) and 8 MIR (30%). Six of the patients received antibiotic treatment during the study period. Two of these were non-responders. One non-responder developed AML in week 9 and died one week later. Three patients discontinued DA due to possible side-effects (gastrointestinal complaints in 2 patients and in one, bone- and muscle pains, the latter symptoms also being related to disease activity). Four of 17 responders had a serum erythropoietin (s-EPO) > 125 IU/L (median 53 IU/L; range 4,9 – 520 IU/L, while 4 of 9 non-responders had a s-EPO >125 IU/L (median 103 IU/L ; range 11,9 – 730 IU/L. The median serum EPO level was significantly higher in NRS (103 IE/l; range 11, 9 – 730 IU/L) as compared to responding patients (57 IE/l; range 4, 9 – 520 IU/L).

Conclusion: Darbepoetin alfa is a well tolerated drug with few side effects and a high response rate in patients with MMM, implying an increase in the Hb concentration and a decrease in the need for blood transfusions in about 50% of the patients. A serum EPO < 125 IU/L is a predictor of a favorable EPO-response, although responses may also be seen in patients with higher serum EPO levels.