Final Analysis of a Multicenter Pilot Phase 2 Study of Ruxolitinib and Danazol in Patients with Myelofibrosis

Introduction:

Most myelofibrosis (MF) patients develop anemia during evolution of the disease process predicting decreased survival. Previous studies exploring the effect of danazol for the treatment of anemia in MF demonstrate responses in anemia. In prior randomized-controlled studies, ruxolitinib demonstrated improvements in splenomegaly, symptom burden, and even survival yet improvements in cytopenias were uncommon. We designed a phase II multicenter pilot study to evaluate the efficacy and tolerability of combination therapy with ruxolitinib and danazol in MF patients with anemia.

Methods:

This was a Simon optimum two-stage phase II trial. Eligible subjects received ruxolitinib, a JAK 1/ JAK2 inhibitor, at 10mg (plat >75 x10x9) BID or 5mg (plat <75 x10 x9) BID) representing initial dose reduction for JAK inhibitor na•ve patients to minimize cytopenias, in combination with tapered danazol up to 200mg orally TID. Dose escalation was allowed after completion of 28 days for lack of response or for disease progression. Pts without progression continued for 6 cycles at 56 days each. Treatment modifications were allowed for either medication based on emergent adverse events (AE). Treatment responses were evaluated every cycle by IWG-MRT criteria (Blood 2006). Patient reported outcome questionnaires (MPN-SAF, EORTC QLQ-C30) were administered at baseline, prior to treatment cycles, and at study discontinuation.

Results:

Patients: Fourteen pts enrolled (9 Mayo Arizona, 5 Mount Sinai). Median (Med) age 70.5 (range 43-78), M:F ratio 1.8:1. Ten primary MF, 2 post-essential thrombocythemia MF, and 2 post-polycythemia vera MF. JAK2 V617F positive in 42.9%. DIPSS Low in 1 pt, Int-1 in 1pt, Int-2 in 8 pts, High in 2 pts, and unknown in 2pts. Transfusion dependence in 35.7% at baseline. Med baseline hemoglobin (hgb) was 9.0 g/dL (R: 8.3 - 12.4), platelet (plt)157 x10⁹/L (R:143 - 520). Thirteen pts received prior therapy, with 9 pts (64.2%) on a JAK inhibitor within 3 months of study entry.

 Tolerability: Nine pts (64.2%) ended active treatment, due to progression of disease in 2 pts (22.2%), adverse event (AE) in 2, pt preference in 2, stem cell transplant in 1, unrelated death in 1, and comorbidity in 1. Med duration of therapy: 91 days (range 24-287). AEs regardless of attrition included: hematologic grade 3 or >: anemia in 7 pts (50%), neutropenia in 2 (14.3%), leukopenia in 1 (7.1%), and thrombocytopenia in 2 (14.3%). Non-hematologic grade 3 or >: electrolyte abnormalities in 3 pts (21.4%), infection in 2 (14.3%), edema in 1(7.1%), hypertension in 1 (7.1%), and intracranial hemorrhage in 1 (7.1%).

Efficacy:

Of the 5 JAK inhibitor na•ve pts, 4 had stable or increasing hgb levels with therapy despite new ruxolitinib therapy. Of the 9 pts on prior JAK inhibitor (5 ruxolitinib, 4 other), 5 (55.5%) and 7 (77.7%) patients had stable or increasing hgb or plt levels, respectively. See Table #1. Four pts (28.6%) had at least 50% improvement from baseline on MPN-SAF TSS (95% CI 8.4%-58.1%). Overall treatment response: (IWG-MRT) stable disease (SD) in 10 pts (71.4%), clinical improvement (CI) in 3 (21.4%) all of which were spleen responses, and progressive disease (PD) in 1 (7.1%). Trial was halted secondary to lack of anemia response.

Table #1: Patient Specific Response

Patient	IWG-MRT Response:	Study Cycles (N):	Prior therapy (within 3 mo)	Hemoglobin Response*: (initial, final g/dL)	Platelet Response*:  (initial, final 10(9)/L)
			Ruxolitinib
1	CI-Spleen	5		D (8.8, 7.6)	S (221,212)
2	SD	4		D (10.3,7.9)	S (54,46)
3	SD	2		S (8.8,8.9)	S (82,101)
4	SD	3		I (8.9,9.8)	S (441,458)
5	SD	3		S (9.6, 9.5)	I (161, 231)
			JAK Inhibitor:
6	SD	5	Momelotinib	S (9.0, 9.2)	S (132,113)
7	SD	1	NS-018	D (8.3, 7.1)	D (120,43)
8	SD	3	NS-018	D (10.1,9.0)	D (138,111)
9	SD	2	LY2784544	S (8.7,9.1)	S (56,21)
			Other:
10	CI-Spleen	9	Procrit	I (10.5,11.9)	S (153,198)
11	CI-Spleen	7	None	I (8.9,10.2)	D (338,133)
12	PD	1	Hydroxyurea	S (12.4, 12.2)	D (310, 82)
13	SD	1	Procrit	D (10.1, 8.6)	D (192, 71)
14	SD	1	Hydroxyurea	S (9.1,8.9)	D (346,119

*S=stable (Hgb +/- 0.5g/dL, Plt +/- 50x10⁹, D=decreasing, I=increasing.

Conclusions:

Although overall well tolerated, the addition of danazol to ruxolitinib therapy has modest incremental efficacy by IWG -MRT criteria. Clinical improvement was observed in 21.4% of treated patients, however responses were limited to spleen reduction. The degree to which danazol may stabilize expected cytopenias is interesting and may require further investigation.