Surgical therapy
Splenectomy has a long history of providing palliative relief for select patients with symptomatic splenomegaly. Although surgical technique and the availability of specific surgical expertise have improved, the procedure remains prone to significant rates of peri- and post-operative morbidity and mortality. Results of a retrospective study of 314 patients with MF-related splenomegaly who underwent splenectomy at the Mayo Clinic-Rochester between 1976 and 2004 show a perioperative complication rate of 27.7 % and a mortality rate due to surgical complications of 6.7 % [
5]. The median OS after splenectomy was 19 months with 48 %, 50 %, and 40 % of patients experiencing an improvement in splenomegaly-related symptoms, anemia, and portal hypertension, respectively. No difference in post-splenectomy OS was noted when analyzed against leukemic transformation, MF risk score, decade during which splenectomy was performed, or type of MF.
Patient selection is critical to limiting peri- and post-operative morbidity. Preoperative thrombocytopenia with platelets < 50x10
9/L appears to be associated with significantly worse OS. Patients with a history or suspicion of splenic infarct may be prone to a higher incidence of postoperative bleeding [
5]. Splenectomy is appropriate only for patients with substantial splenic symptoms unresponsive to at least 1 prior medical therapy and those with an adequate performance status and a life expectancy of more than 1 year. Patients should be in otherwise good health without decompensated coagulopathy or significant comorbidities.
Radiotherapy
Splenic irradiation is used in select patients to control various debilitating MF-associated symptoms. In general, the most appropriate candidates are those with significant symptoms and an adequate platelet count who, because of age or comorbidities, are not candidates for splenectomy [
7]. Response rates ranging from 63 % to 95 % have been reported [
8,
9]. The results are transient, however, lasting for a median of only 6 months in one study [
8] and 3.5 months in another [
9]. The complications, which include myelosuppression, can be severe or even life-threatening. Significant side effects include potentially critical cytopenias, hemorrhage, complicated post-irradiation splenectomy [
8] and delayed hemorrhage [
7].
Recently, 2 cases were reported in which a regimen of induction-maintenance radiation therapy was used to treat MF with a marked improvement of the underlying accelerated phase of the disease [
10]. At induction doses of 100 cGy (in 4 fractions of 25 cGy/fraction) with maintenance at the same or higher level, there was complete resolution of peripheral leukoerythroblastosis and eradication of peripheral blasts in one patient, and significant reduction in leukoerythroblastosis in the other. Both patients had marked improvement in functional status and a reduction in spleen size from >30 cm below the left costal margin (LCM) to 22 cm and 15 cm. The authors of this report concluded that this regimen was well tolerated and should be considered in specific clinical situations (e.g., rapid growth of spleen).
JAK2 inhibitors
JAKs are cytoplasmic kinases that play important roles in normal hematopoiesis and proper immune function [
32]. Dysregulation of the JAK-STAT pathway is a highly prevalent aberration in patients with MPNs, including MF [
33]. A number of alterations, such as excess cytokines and increased JAK1 signaling, as well mutations in JAK2 and mutations involving the thrombopoietin receptor (TPO-r or myeloproliferative leukemia,
MPL, oncogene) have also been implicated in the etiology and symptomatology of MF, PV, and ET [
33‐
36]. Although JAK2V617F is the most common mutation associated with these MPNs [
3,
35], it is not necessary for their development [
37‐
39]. Several JAK2 (or JAK1/JAK2) inhibitors are currently in clinical trials for MF. Ruxolitinib (formerly INCB018424; Incyte Corporation, Wilmington, DE, USA) recently became the first FDA-approved drug for the treatment of MF [
40] and SAR302503 (formerly TG101348; Sanofi, Paris, France) is in the phase 3 trial for possible approval as therapy for MF. These 2 medications are described here in more detail.
Ruxolitinib is a potent and selective JAK1- and JAK2-inhibitor (IC
50 of 3.3 and 2.8 nmol/L, respectively, in “naked” kinase assays in cell-free in vitro systems). It demonstrates modest selectivity against Tyk2 (~ 6-fold) and ≥ 130-fold selectivity against JAK3. Treatment with ruxolitinib is associated with a dramatic decrease in circulating levels of proinflammatory cytokines, IL-6, and tumor necrosis factor (TNF)-α, which have been implicated in the pathogenesis of MPNs [
41].
The dosing regimen for ruxolitinib was established during a phase I/II trial in 153 patients with primary MF, post-PV MF, or post-ET MF [
42]. Sixty-one of 140 patients (44 %) with splenomegaly at baseline had a reduction in spleen size ≥ 50 % by palpation within the first 3 months of therapy. Response was highest among patients receiving 15 mg twice daily (bid; 52 %) and was similar in patients with or without JAK2 mutation. Ruxolitinib-treated patients also demonstrated reductions in spleen volume by MRI. The majority of patients reported a > 50 % improvement in MF-related symptoms. Thrombocytopenia was the dose-limiting adverse event. [
42].
Results from 2 randomized phase III trials of ruxolitinib in patients with intermediate-2 or high-risk MF have recently been published. In the
Co ntrolled
M yelo
f ibrosis Study with
Or al JAK Inhibitor
T reatment [COMFORT]-I trial MF patients received oral ruxolitinib (n = 155) 15 or 20 mg bid (depending on baseline platelet count) or placebo (n = 154). The primary endpoint, a ≥ 35 % reduction in spleen volume (by MRI or CT) at week 24, was achieved in 41.9 % of ruxolitinib-treated patients vs. 0.7 % of placebo-treated patients (P < 0.001). At week 24, significantly (P < 0.001) more patients in the ruxolitinib group achieved a ≥ 50 % improvement in the Myelofibrosis Symptom Assessment Form (MFSAF) Total Symptom Score (45.9 % vs. 5.3 % for placebo). At the time of a planned safety update with 4 additional months of follow-up, there was a significant survival advantage for ruxolitinib over placebo (hazard ratio = 0.50; P = 0.04). The most common nonhematologic adverse events that occurred more often in the ruxolitinib group were ecchymosis, dizziness, and headache; these were mostly grade 1 or 2. The most common adverse events were hematologic. The rates of grade 3 and 4 anemia and thrombocytopenia in the ruxolitinib group were 45 % and 13 %, respectively, compared to 19 % and 1 %, respectively in the placebo group [
43].
In the COMFORT II study patients received ruxolitinib (n = 146) or best available therapy (BAT; n = 73). At week 48, 28.5 % of ruxolitinib-treated patients met the primary endpoint of a ≥ 35 % reduction in spleen volume vs. 0 % in BAT group (P < 0.001). The most common nonhematologic adverse events (all grades) were (ruxolitinib vs. BAT) diarrhea (23 % vs. 12 %) and peripheral edema (22 % vs. 26 %). In the ruxolitinib group, grade 3/4 anemia and thrombocytopenia were reported in 42 % and 8 % of patients, respectively, versus 31 % and 7 % respectively in the BAT group [
44]. In both studies, anemia and thrombocytopenia were manageable and rarely led to discontinuation.
SAR302503 is a selective and potent JAK2 inhibitor profiled in 223 kinases and found to have an IC
50 < 50 nM in 3 kinases— JAK2, FLT3, Ret [
45]. It inhibits growth of erythroid colonies in the presence of JAK2V617F, MPL W515K, and JAK2 exon 12 mutations [
46] and is 35 and 334 times more selective for JAK2 compared with JAK1 and JAK3, respectively [
45]. Pardanani
et al. recently reported the results of a phase I dose escalation study in which TG101348 was administered in 28-day cycles [
47]. The study comprised 59 patients with MF, post-PV MF, or post-ET MF with high/intermediate risk disease and symptomatic splenomegaly unresponsive to available therapy. Many patients with early satiety, night sweats, fatigue, pruritus, and cough at baseline reported rapid and durable improvement in these symptoms. Spleen response was seen within the first 2 cycles of therapy. By 6 and 12 cycles 39 % and 47 % of patients, respectively, had achieved a spleen response (IWG-MRT criteria). No consistent change in plasma cytokine levels was seen, indicating that this agent’s effect on the spleen and the constitutional symptoms may be cytokine-independent. The most common nonhematologic grade 3 or 4 adverse events included nausea (3.4 %), vomiting (3.4 %), and diarrhea (10.2 %). Grade 3 or 4 anemia, neutropenia, and thrombocytopenia was seen in 35.1 %, 10.2 %, and 23.7 % of patients, respectively.
Table
1 summarizes the clinical study findings for these and several other agents currently in clinical trials for MF (some published only in the abstract form).