A Phase II Trial of Imatinib Mesylate (Gleevec®) in Myeloproliferative Disorders Other Than CML.

Myeloproliferative disorders are a heterogeneous group of disorders characterized by increased cell numbers and variable degrees of organomegaly and myelofibrosis. To date, the standard of care has been phlebotomy followed by Hydroxyurea or anagrelide to control thrombocytosis. Anagrelide has gained popularity in recent years due to its theoretical non leukemogenic potential. Gleevec® is a small molecule inhibitor of several tyrosine kinases including c-kit and platelet derived growth factor receptor (PDGFR). The latter is expressed on platelets and megakaryocytes and may offer an explanation for the megakaryocytic hyperplasia and clustering via an autocrine loop action. In vitro, Gleevec® inhibits spontaneous burst formation in polycythemia vera (PV) probably by inhibiting c-kit. By inhibiting PDGFR, it could inhibit megakaryocytic proliferation by blocking an autocrine effect which may be responsible for megakaryocytic hyperplasia and clustering in essential thrombocytosis (ET) and PV. In 2003 we initiated a study to explore the effectiveness of Gleevec® in these two entities. 11 patients have been enrolled, 5 with PV, and 6 with ET. The starting dose in each case was 400mg, with escalation to 800 mg based on response. Complete response (CR) was defined as therapeutic range hematocrit without phlebotomy, a normal platelet count and discontinuation of Hydrea or Anagrelide. There were two CR’s and one PR in PV. All three patients discontinued treatment because of toxicity at 2, 6, and 10 months, respectively. There was one CR and one PR in ET, but both discontinued treatment due to toxicity at 7 months and non-compliance at 2 months, respectively. The toxicities observed that led to discontinuation of therapy were grade 2–3 diarrhea (3/11), grade 2–3 periorbital and ankle edema (5/11), grade 2 skin rash (1/11), grade 1 blurred vision (1/11). One major post operative bleeding was observed and was probably related to platelet dysfunction. Two patients (one each of PV & ET) had to discontinue therapy for lack of response at maximum tolerated dose. The ending dose was 400 mg (3), 600 mg (5), and 800 mg (3), with two at the 800 mg dose level being non-responders, and all others having discontinued therapy on account of toxicity. This study suggests that Gleevec® has activity in PV and ET, but toxicity at the studied dose escalation schedule could lead to discontinuation of therapy. However, this does not preclude its use in a new clinical trial with a more tolerable dosing schedule over a longer period of time.