Danazol in Combination with Busulfan Induces Long-Term Remission in Myeloproliferative Disorders (MPD).
Authors: Fontana Vincenzo , Ahn Eugene R. , Jimenez Joaquin , Dudkiewicz Pamela , Jy Wenchy , Ahn Yeon S. 
Published: April 2020

Abstract
MPD is a clonal stem cell disorder encompassing essential thrombocythemia (ET), polycythemia vera (PV), myelofibrosis (MF), chronic myelogenous leukemia (CML). Chemotherapy has been a mainstay of therapy for the treatment of MPD but new agents including anegrelide, interferon, imatinib mesylate and thalidomide have been recently introduced. In most cases, continuous therapy is required to maintain remission and relapses are the rule when the treatment is discontinued. We report long-term remission of MPD with combined therapy of danazol and busulfan and an unusually long remission following discontinuation of therapy. Nine patients (4 women, 5 men) with MPD (7 MF, 1 PV, 1 ET) were studied. Danazol (200–800mg/day) was given with dosage adjustment for liver function abnormalities. Busulfan (2–4mg/day) was administered intermittently for 3 months to 2 yrs depending on blood counts and status of remission. Spleen size was evaluated with physical exam and CAT scans. The responses were classified as “excellent” [E] or complete remission (CR) when blood counts were normal with absence of splenomegaly, “good” [G] when spleen size was reduced &gt; 50% with normal blood counts, “poor” [P] for no improvement in blood counts and splenomegaly and “fair” [F] for responses between P and G. Erythropoietin was administered when anemia developed.
RESULT. Overall response of E and G was 77% (7/9). There were 2 E, 5 G, 1F and 1P responses. Table 1 summarizes data on 2 E responders.
Table 1
Age/Sex Duration of MPD *Rx No (Rx yrs) ** Spleen Remission (Rm) Rm after D/C Rx * Rx=Danazol + Busulfan; No=Numbers of RX; (Yrs)=Duration of Rx. ** Size of spleen before and after each RX 72/F 2.5 yrs Rx1 (2.5 yrs) 6cm → 0 6.5 yrs 4yrs Rx2 (0.5 yrs) 2.5 yrs 2 yrs Rx3 (1 yr) 4cm → 0 6 yrs 5 yrs 72/F 3 yrs Rx1 (1.5 yrs) 25cm → 0 4 yrs 2.5 yrs Rx2 (0.5 yr) 20cm → 0 5/6 yrs 1/3 yrs
The duration of CR in 2 E responders (1 PV, 1 MF) was 15 years in the first and approximately 5 years in the second. The remissions lasted over 2 –4 years even after therapy was discontinued. CAT scans confirmed reduced or normal sized spleen. All 5 “good” responders showed a remarkable clinical improvement initially but when the treatment was withheld, disease recurred. Re-treatment induced remissions but responses were seldom complete and required more uninterrupted therapy. In all responders, re-treatment was as effective as initial therapy, indicating that the benefit was due to therapy, not a coincidence. Compared to E responders, G and F responders had more advanced disease and longer duration of MPD, ranging from 2–15 yrs (average 9.2 years). Therapy was tolerated well but bone marrow suppression was seen in 3 cases, all of which recovered without serious complications. Danazol was withheld or reduced in 4 patients due to liver function abnormalities but was safely resumed in lower doses.
SUMMARY. Danazol therapy with busulfan is very effective in MPD and offers a good alternative with potential clinical cure in some patients with MPD. Although clinical remissions were observed in most patients with MPD, those with shorter duration (&lt;3 years) of disease seemed to respond better than those with more advanced and longer duration of disease. Danazol together with busulfan may induce apoptosis of clonal stem cells leading to lasting remission over a decade. Randomized prospective study is required to validate this potentially curative therapy in MPD