A Phase II Study of CC-5013 Treatment for Myelofibrosis with Myeloid Metaplasia: A Preliminary Report.
Authors: Tefferi Ayalew , Hogan William J. , Wolanskyj Alexandra P. , Shaw Trudy A. , Reyes Gayle E. , Hoering Antje , McClure Rebecca F. , Mesa Ruben A. 
Published: October 2019

Abstract
Background : CC-5013 (Revlimid™) is an immunomodulatory analog of thalidomide that is substantially more potent than the parent drug in terms of both anti-angiogenic and anti-TNF-α activity. CC-5013 has shown therapeutic activity in thalidomide-responsive hematological malignancies including relapsed multiple myeloma (Blood2002;100:3063) and myelodysplastic syndrome (Blood2002;100:96a). Myelofibrosis with myeloid metaplasia (MMM) has also been shown to respond to thalidomide (BJH2002;117:288). Furthermore, both angiogenesis and altered TNF-α activity have been pathogenetically implicated in MMM.
Methods : The current report considers the first 15 patients in an ongoing phase II treatment trial of single agent CC-5013 in MMM based on a minimum of 3 month follow-up from day 1 of protocol treatment. Study eligibility criteria included no concomitant MMM-directed therapy, a hemoglobin (Hgb) level of < 10 g/dL, an absolute neutrophil count (ANC) of ≥ 1 x 109/L, and a platelet count of ≥ 100 x 109/L. Previous thalidomide therapy in the absence of high-grade skin toxicity was allowed. All patients were started with daily oral CC-5013 (10 mg/day) to be taken for three 28-day treatment cycles. Three additional treament cycles were planned in case of anemia response.
Results : Median age was 64 years (range, 40–75) and 10 pts were males. Twelve of the 15 study pts (80%) were red cell transfusion-dependent, 14 (93%) were previously treated including 12 with cytoreductive and 4 with thalidomide therapy. The spleen was palpably enlarged in 13 pts (median 18 cm, range 7–23). Eight of the 15 pts (53%) successfully completed 3 months of protocol treatment. Treatment was discontinued in the remaining 7 pts because of drug toxicity (2 pts), disease progression (1 pt), other co-morbid condition (3 pts), or patient discretion (1 pt).
Treatment response data : Clinically relevant responses were documented in 4 patients (27%) and consisted of measurable improvements in anemia (2 pts), splenomegaly (2 pts), and/or constitutional symptoms (3 pts). One pt experienced an increase in Hgb level from 8.3 to 13.4 g/dL, a decrease in leukocyte count from 66.2 to 7.7 x 109/L, and complete resolution of myelophthisis including disapperance of circulating blasts that measured 9% before treatment. Another pt became transfusion-independent (Hgb level increased to > 10 g/dL) as well as enjoyed a profound improvement in constitutional symptoms. Interestingly, serum lactate dehydrogenase (LDH) level decreased in 11 pts (73%) to either within the normal ramge (5 pts) or by more than 30 % (6 pts).
Treatment toxicity data : Grade 3 or 4 adverse events that were possibly, probably, or definitely attributed to CC-5013 included rash (2 pts), neutropenia (5 pts), thrombocytopenia (3 pts), and fatigue (2 pts). In addition, 3 patients experienced drug-associated extreme thrombocytosis while a histologically-proven disseminated extramedullary hematopoiesis was documented in one patient after one month of CC-5013 treatment.
Conclusion : The current preliminary report suggests a substantial biological activity of CC-5013 in MMM with a therapeutic potential for a subset of patients. Additional studies with a longer duration of therapy, different dose schedules, and combinations of CC-5013 and corticosteroids are warranted.