ライフサイエンスコーパス: ruxolitinib

1 reatment with the janus kinase 1/2 inhibitor ruxolitinib.

2 t that was abrogated by the JAK1/2 inhibitor ruxolitinib.

3 dependency and sensitizes leukemic cells to ruxolitinib.

4 6 patients with steroid-refractory GVHD with ruxolitinib.

5 d was impaired by the Janus kinase inhibitor ruxolitinib.

6 lar subsets of patients with MF treated with ruxolitinib.

7 r the administration of the JAK1/2 inhibitor ruxolitinib.

8 AT1 GOF mutations were treated in vitro with ruxolitinib.

9 ibrosis is the dual JAK1 and JAK2 inhibitor, ruxolitinib.

10 sponses or haematological toxic effects with ruxolitinib.

11 >/=3 mutations are less likely to respond to ruxolitinib.

12 t drugs, either alone or in combination with ruxolitinib.

13 introduction of the JAK1 and JAK2 inhibitor ruxolitinib.

14 e treated with a clinically relevant dose of ruxolitinib.

15 Herein the core features of ruxolitinib (1), a marketed JAK1/2 inhibitor, have been

16 ng a validated system to receive either oral ruxolitinib 10 mg twice daily or investigator-selected b

17 ith splenomegaly, in a 1:1 ratio, to receive ruxolitinib (110 patients) or standard therapy (112 pati

18 35%) acquired a new mutation while receiving ruxolitinib (14 [61%] in ASXL1).

19 omly assigned 1:1 to the JAK1/JAK2 inhibitor ruxolitinib (15 mg twice daily) plus capecitabine (1,000

20 e 3 or greater anemia was more frequent with ruxolitinib (15.3%; placebo, 1.7%).

21 high-risk myelofibrosis to twice-daily oral ruxolitinib (155 patients) or placebo (154 patients).

22 function, and no active infection, received ruxolitinib 25 mg orally twice a day for 4 weeks (1 cycl

23 p of 79 months, 86 patients had discontinued ruxolitinib (30 of whom died while on therapy).

24 lume was maintained in patients who received ruxolitinib; 67.0% of the patients with a response had t

25 were observed with similar frequency in the ruxolitinib (74.6%) and placebo (81.7%) groups.

26 1, the Food and Drug Administration approved ruxolitinib (a JAK1 and JAK2 inhibitor) for use in the t

27 on assay, we compared the effects of INC424 (ruxolitinib), a dual Jak1/Jak2 inhibitor, and hydroxyure

28 ranscription (JAK-STAT) signaling pathway by ruxolitinib, a JAK-STAT-specific inhibitor.

29 Importantly, Ruxolitinib, a JAK1 inhibitor, could rescue the phenotyp

30 Of note, ruxolitinib, a JAK1/2 inhibitor approved for the treatme

31 Finally, ruxolitinib, a JAK1/2 inhibitor, was effective in vivo i

32 Ruxolitinib, a Janus kinase (JAK) 1 and 2 inhibitor, was

33 In the pivotal RESPONSE study, ruxolitinib, a Janus kinase (JAK)1 and JAK2 inhibitor, w

34 nt with C188-9, a STAT3/5 inhibitor, or with ruxolitinib, a Janus kinase 1/2 (JAK1/2) inhibitor.

35 We evaluated the efficacy and safety of ruxolitinib, a potent and selective Janus kinase (JAK) 1

36 We show in this paper that, Ruxolitinib, a recently described selective inhibitor of

37 Ruxolitinib, a selective inhibitor of Janus kinase (JAK)

38 Here we investigated whether ruxolitinib affects dendritic cell (DC) biology.

39 As predicted, ruxolitinib alone had no significant antileukemic effect

40 d reduced bone marrow fibrosis compared with ruxolitinib alone.

41 Ruxolitinib also impaired both in vitro and in vivo DC m

42 Eight weeks-treatment with ruxolitinib, an FDA-approved JAK1/2 inhibitor, reduced c

43 Notably, three patients treated with oral ruxolitinib, an inhibitor of JAK1 and JAK2, achieved nea

44 ol was achieved in 60% of patients receiving ruxolitinib and 20% of those receiving standard therapy;

45 4 patients were randomly assigned to receive ruxolitinib and 75 to receive best available therapy.

46 lic events occurred in one patient receiving ruxolitinib and in six patients receiving standard thera

47 JAK1/2 inhibitors (such as ruxolitinib and JAK inhibitor I) strongly stimulate VSV

48 val, some have disease that is refractory to ruxolitinib and many lose their response over time.

49 Ruxolitinib and most other JAK inhibitors exert a saluta

50 Moreover, combining VSV with ruxolitinib and Polybrene or DEAE-dextran successfully b

51 demonstrate preclinical in vivo efficacy of ruxolitinib and rapamycin in this high-risk B-ALL subtyp

52 ithm is uncertain, given the availability of ruxolitinib and renewed interest in interferons.

53 vestigated the efficacy of the JAK inhibitor ruxolitinib and the mTOR inhibitor rapamycin in xenograf

54 inhibition of JAK2/STAT3 and MEK/ERK/1/2 by ruxolitinib and trametinib potentiated tumor response to

55 tumor-bearing mice, whereas BV combined with ruxolitinib and/or with Navitoclax resulted in a sustain

56 fety and efficacy of JAK inhibitors, such as ruxolitinib, and evaluate their role in the context of o

57 Moreover, the combination of BMN673, ruxolitinib, and hydroxyurea was highly effective in viv

58 The combination of dasatinib, ruxolitinib, and the corticosteroid dexamethasone yielde

59 OR and JAK2 rearrangements were sensitive to ruxolitinib, and the ETV6-NTRK3 fusion was sensitive to

60 Among patients who received ruxolitinib, anemia and thrombocytopenia were the most c

61 In the ruxolitinib arm, with continued therapy, spleen volume r

62 t 24 weeks in 45.9% of patients who received ruxolitinib as compared with 5.3% of patients who receiv

63 Ruxolitinib, as compared with placebo, provided signific

64 symptoms, as well as the risk of developing ruxolitinib-associated anemia and thrombocytopenia, occu

65 ith intermediate-2 or high-risk MF receiving ruxolitinib at MD Anderson Cancer Center (MDACC) on phas

66 I study, suggest that continued therapy with ruxolitinib at optimal doses contributes to the benefits

67 d efficacy of ruxolitinib, it is likely that ruxolitinib-based combinations will be a major way forwa

68 tion by hydroxyurea and JAK1/2 inhibition by ruxolitinib, both of which are not curative.

69 able spleen length had decreased by 56% with ruxolitinib but had increased by 4% with the best availa

70 00 mg once a day or BAT (which could include ruxolitinib, chemotherapy, steroids, no treatment, or ot

71 Either ruxolitinib combined with Navitoclax or BV alone prolong

72 Ruxolitinib continues to be well tolerated.

73 The degree of spleen volume reduction with ruxolitinib correlated with improvements in TSS, PGIC, P

74 The findings of this study indicate that ruxolitinib could be considered a standard of care for s

75 The Janus kinase (JAK)-inhibitor ruxolitinib decreases constitutional symptoms and spleen

76 The median follow-up after ruxolitinib discontinuation for the remaining 56 patient

77 Here we describe outcomes after ruxolitinib discontinuation in MF patients enrolled in a

78 nhematologic adverse event led to definitive ruxolitinib discontinuation in more than 1 patient.

79 In vivo, ruxolitinib displayed activity in 6 of 6 patient-derived

80 od cell transfusions while on ruxolitinib or ruxolitinib dose reduction to less than 20 mg twice a da

81 LKB1-defcient mice with the JAK1/2 inhibitor ruxolitinib dramatically decreased polyposis.

82 singly, both JAK/STAT pathway activation and ruxolitinib efficacy were independent of the presence of

83 Patients receiving ruxolitinib experienced improvements in individual myelo

84 Dysfunction of ruxolitinib-exposed DCs was further underlined by their

85 an adenoviral infection model, we show that ruxolitinib-exposed mice exhibit delayed adenoviral clea

86 After ruxolitinib failure, however, there are few therapeutic

87 nduced murine model of CP, administration of ruxolitinib for one week significantly reduced biomarker

88 the dual Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib for the treatment of myeloproliferative neop

89 esulting in first approved JAK1/2 inhibitor, ruxolitinib, for the treatment of patients with myelofib

90 ection was reported in 6% of patients in the ruxolitinib group and 0% of those in the standard-therap

91 g because of adverse events was 11.0% in the ruxolitinib group and 10.6% in the placebo group.

92 ssion was achieved in 24% of patients in the ruxolitinib group and 9% of those in the standard-therap

93 oint was reached in 41.9% of patients in the ruxolitinib group as compared with 0.7% in the placebo g

94 Thirteen deaths occurred in the ruxolitinib group as compared with 24 deaths in the plac

95 Patients in the ruxolitinib group had an improvement in overall quality-

96 A total of 28% of the patients in the ruxolitinib group had at least a 35% reduction in spleen

97 t was achieved in 21% of the patients in the ruxolitinib group versus 1% of those in the standard-the

98 ) and angina pectoris (two [3%] of 74 in the ruxolitinib group vs none in the best available therapy

99 ause, included thrombocytopenia (none in the ruxolitinib group vs two [3%] of 75 in the best availabl

100 y grade were anaemia (ten [14%] of 74 in the ruxolitinib group vs two [3%] of 75 in the best availabl

101 In the ruxolitinib group, grade 3 or 4 anemia occurred in 2% of

102 to acute myeloid leukemia; both were in the ruxolitinib group.

103 Patients receiving ruxolitinib had longer survival (5 years, 95% confidence

104 Recently, ruxolitinib has been shown in 2 phase 3 studies to be ef

105 However, although ruxolitinib has changed the therapeutic scenario of MF,

106 011, the Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib has evolved to become the centerpiece of the

107 Ruxolitinib has modest antileukemic activity as a single

108 Ruxolitinib has shown success in alleviating the symptom

109 ological blockade of Jak-Stat signaling with ruxolitinib has significant antileukemic activity in thi

110 ors CP-690,550 (tofacitinib) and INCB018424 (ruxolitinib) have demonstrated clinical efficacy in rheu

111 anus kinase 1/2 (JAK1/2) inhibitors, such as ruxolitinib, have been developed as immunosuppressive ag

112 Mechanistically, we could show that ruxolitinib impaired differentiation of CD4(+) T cells i

113 our findings offer compelling evidence that ruxolitinib impairs NK cell function in MPN patients, of

114 Ruxolitinib improved survival independent of mutation pr

115 tes JAK2 in CLL cells and the JAK2 inhibitor ruxolitinib improves symptoms in patients with myelofibr

116 BAT was ruxolitinib in 46 (89%) of 52 patients.

117 rt of patients with MF who were treated with ruxolitinib in a phase 1/2 study.

118 58-71% of patients treated with ruxolitinib in clinical trials so far have not achieved

119 studies to test the therapeutic efficacy of ruxolitinib in CLL are warranted.

120 tudy, we assessed the efficacy and safety of ruxolitinib in controlling disease in patients with poly

121 ossibility that the therapeutic potential of ruxolitinib in ETP-ALL extends beyond those cases with J

122 stablish the preclinical in vivo efficacy of ruxolitinib in ETP-ALL, a biologically distinct subtype

123 e of the Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib in murine models of hemophagocytic lymphohis

124 ative neoplasms (MPNs) has led to studies of ruxolitinib in other clinical contexts, including JAK-mu

125 lacebo-controlled phase III study evaluating ruxolitinib in patients with intermediate-2 or high-risk

126 We conducted a phase 2 study of ruxolitinib in patients with relapsed/refractory leukemi

127 clinical trial to evaluate BV combined with ruxolitinib in select patients with HL.

128 to investigate the therapeutic potential of ruxolitinib in treating autoimmunity secondary to STAT1

129 he small-molecule Janus kinase 1/2 inhibitor ruxolitinib in vitro and in vivo restored perforin expre

130 ed sensitivity of JAK2-mutant progenitors to ruxolitinib in vitro.

131 -acid substitutions conferring resistance to ruxolitinib (INCB018424) and cross-resistance to the JAK

132 In conclusion, we postulate that ruxolitinib-induced deficiencies in DSB repair pathways

133 Ruxolitinib inhibited 2 major DSB repair mechanisms, BRC

134 ation of CLL cells with the JAK1/2 inhibitor ruxolitinib inhibited IgM-induced STAT3 phosphorylation

135 ic studies revealed that in vivo exposure to ruxolitinib inhibited signal transducer and activation o

136 the incorporation of JAK inhibitors such as ruxolitinib into future clinical trials for patients wit

137 that patients with ruxolitinib-resistant or ruxolitinib-intolerant myelofibrosis might achieve signi

138 r, in patients with ruxolitinib-resistant or ruxolitinib-intolerant myelofibrosis.

139 Ruxolitinib is a potent Janus kinase (JAK)1/JAK2 inhibit

140 Ruxolitinib is a small-molecule inhibitor of the JAK kin

141 tion of increased STAT1 phosphorylation with ruxolitinib is an important option for therapeutic inter

142 Ruxolitinib is in late-phase clinical trials in essentia

143 Ruxolitinib is JAK1/JAK2 inhibitor with established clin

144 The MAJIC-ET trial suggests that ruxolitinib is not superior to current second-line treat

145 The Janus kinase (JAK) inhibitor ruxolitinib is the only approved therapy for patients wi

146 -positive and JAK2-negative MF; one of them, ruxolitinib, is the current best available therapy for M

147 Given the proven safety and efficacy of ruxolitinib, it is likely that ruxolitinib-based combina

148 MAJIC is a randomized phase 2 trial of ruxolitinib (JAK1/2 inhibitor) vs best available therapy

149 Treatment with the JAK1/2 inhibitor ruxolitinib lowered the white blood count and reduced sp

150 This observation suggests that ruxolitinib may modify the natural history of PMF.

151 eeded, even though pegylated IFN-alfa-2a and ruxolitinib might be useful in particular settings.

152 owed reduction of mutated allele burden, and ruxolitinib might extend survival of patients with highe

153 DM1 null tumours with the JAK/STAT inhibitor ruxolitinib mimics CADM1 gene restoration in preventing

154 s with myelofibrosis previously treated with ruxolitinib, momelotinib was not superior to BAT for the

155 tent inhibition of downstream signaling than ruxolitinib monotherapy.

156 In the intent-to-treat population (ruxolitinib, n = 64; placebo, n = 63), the hazard ratio

157 in these studies, we analyzed the cohort of ruxolitinib-naive patients used for developing the dynam

158 rate the dose-dependent inhibitory effect of ruxolitinib on the generation of dendritic cells (DCs) f

159 -4 anaemia or thrombocytopenia occurred with ruxolitinib; one patient (1%) reported grade 3-4 anaemia

160 ded 58 and 52 patients randomized to receive ruxolitinib or BAT, respectively.

161 fficiently blocked by JAK inhibitors such as ruxolitinib or CMP6 in short-term assays.

162 e use of the two-agent combination of either ruxolitinib or Navitoclax with BV or the three-agent com

163 Treatment with ruxolitinib or PU-H71 improved survival of mice engrafte

164 equired red blood cell transfusions while on ruxolitinib or ruxolitinib dose reduction to less than 2

165 hrombocythemia myelofibrosis to receive oral ruxolitinib or the best available therapy.

166 ensitive to decitabine, the JAK1/2 inhibitor ruxolitinib, or the heat shock protein 90 inhibitor 8-(6

167 Participants were given 10 mg ruxolitinib orally twice a day.

168 long-term impact, and why would they choose ruxolitinib over other JAK inhibitors that are freely av

169 IPSS risk have shown a survival advantage of ruxolitinib over placebo (COMFORT-1) or best available t

170 d PRO-related labeling (abiraterone acetate, ruxolitinib phosphate, and crizotinib).

171 Ruxolitinib plus capecitabine was generally well tolerat

172 Emerging concepts include the use of ruxolitinib pretransplant, optimizing MAC to decrease to

173 The JAK1/JAK2 inhibitor ruxolitinib produced significant reductions in splenomeg

174 Although the Janus kinase inhibitor ruxolitinib provides symptomatic relief, it does not red

175 lipopolysaccharide-induced maturation step, ruxolitinib reduced DC activation as demonstrated by dec

176 reatment with the Janus kinase 1/2 inhibitor ruxolitinib reduced hyperresponsiveness to type I and II

177 In the present study the JAK1/2 inhibitor ruxolitinib reduced phosphorylation of STAT3 and STAT6 a

178 nt of cultured PSC with the Jak1/2 inhibitor ruxolitinib reduced STAT3 phosphorylation, cell prolifer

179 In vivo treatment with the Jak1/2 inhibitor ruxolitinib reduced the severity of experimental CP, sug

180 hock protein 90 (HSP90) inhibitor PU-H71 and ruxolitinib reduced total and phospho-JAK2 and achieved

181 ated symptoms improved in patients receiving ruxolitinib relative to BAT.

182 analysis, 45% of the patients randomized to ruxolitinib remained on treatment.

183 In summary, ruxolitinib represents a novel targeted approach in GVHD

184 thrombocythaemia myelofibrosis, found to be ruxolitinib resistant or intolerant after at least 14 da

185 mary endpoint, suggesting that patients with ruxolitinib-resistant or ruxolitinib-intolerant myelofib

186 a JAK2-selective inhibitor, in patients with ruxolitinib-resistant or ruxolitinib-intolerant myelofib

187 and Janus kinase 2 (JAK2) with dasatinib and ruxolitinib, respectively.

188 Moreover, the JAK1/2 inhibitor ruxolitinib restored sensitivity to the BCL2 inhibitor v

189 Unexpectedly, another JAK inhibitor, ruxolitinib (RUX), was ineffective in 8 of 10 FED-respon

190 le of this pathway using the JAK2 inhibitor, ruxolitinib (RUX).

191 cells were treated with the JAK1/2 inhibitor ruxolitinib (RUX).

192 Additionally, patients randomized to ruxolitinib showed longer overall survival than those ra

193 if some patients treated with interferon and ruxolitinib showed reduction of mutated allele burden, a

194 Our results demonstrate that ruxolitinib significantly affects DC differentiation and

195 models, treatment with the JAK1/2 inhibitor ruxolitinib significantly lessened the clinical and labo

196 with myelofibrosis (MF) derive benefit from ruxolitinib, some are refractory, have a suboptimal resp

197 cally relevant doses of the JAK1/2 inhibitor ruxolitinib suppresses the harmful consequences of macro

198 13 mg/L), OS was significantly greater with ruxolitinib than with placebo (hazard ratio, 0.47; 95% C

199 re much more sensitive to the JAK inhibitor, ruxolitinib, than JAK2V617F-expressers, suggesting that

200 analysis was performed to determine whether ruxolitinib therapy altered the JAK2p.V617F allele burde

201 tors, and deletion of Jak2 following chronic ruxolitinib therapy markedly reduced mutant allele burde

202 ution or decreasing platelet counts while on ruxolitinib therapy may be markers of poor prognosis.

203 Ruxolitinib therapy results in a dramatic reduction in c

204 y improved, a survival advantage in favor of ruxolitinib therapy was demonstrated.

205 Continuous ruxolitinib therapy, as compared with the best available

206 tem involvement was significantly reduced by ruxolitinib therapy.

207 the prolongation of survival associated with ruxolitinib therapy.

208 We did a phase 2 trial of ruxolitinib to test this hypothesis.

209 Ruxolitinib-treated mice immunized with ovalbumin (OVA)/

210 Ruxolitinib-treated patients achieved clinically meaning

211 The majority (91%) of ruxolitinib-treated patients designated as >/= 50% TSS r

212 51 patients in the phase 1/2 trial, and 155 ruxolitinib-treated patients in phase 3 COMFORT-I study,

213 We found a reduction in NK cell numbers in ruxolitinib-treated patients that was linked to the appe

214 ocrit control was achieved in 46 (62%) of 74 ruxolitinib-treated patients versus 14 (19%) of 75 patie

215 Ruxolitinib-treated patients who achieved a >/= 35% redu

216 Ruxolitinib-treated patients with a lesser degree of sym

217 reased infection rates have been reported in ruxolitinib-treated patients, and natural killer (NK) ce

218 n may result in increased infection rates in ruxolitinib-treated patients.

219 partial molecular response in CALR-positive ruxolitinib-treated patients.

220 rmore, more than 50% of patients discontinue ruxolitinib treatment after 3-5 years.

221 Importantly, ruxolitinib treatment also significantly improved the su

222 a cohort of 28 MPN patients with or without ruxolitinib treatment and 24 healthy individuals.

223 Ruxolitinib treatment decreased peripheral blast counts

224 Patients who had myelofibrosis and previous ruxolitinib treatment for at least 28 days who either re

225 Conversely, ruxolitinib treatment in allo-HCT recipients increased F

226 Combined gedatolisib and ruxolitinib treatment of CRLF2/JAK-mutant models more ef

227 In vivo, ruxolitinib treatment suppressed signal transducer and a

228 ductions in allele burden from baseline with ruxolitinib treatment that correlated with spleen volume

229 Whether ruxolitinib treatment would benefit patients with CLL re

230 Ruxolitinib treatment yielded significantly lower periph

231 During ruxolitinib treatment, liver tissue damage receded conco

232 sible long-term side effects associated with ruxolitinib treatment.

233 of NK cells in MPN was further aggravated by ruxolitinib treatment.

234 omised, open-label, phase 3b study assessing ruxolitinib versus best available therapy in patients wi

235 study to evaluate the efficacy and safety of ruxolitinib versus standard therapy in patients with pol

236 ade 3 and 4 anemia occurred in 19% and 0% of ruxolitinib vs 0% (both grades) in the BAT arm, and grad

237 3 and 4 thrombocytopenia in 5.2% and 1.7% of ruxolitinib vs 0% (both grades) of BAT-treated patients.

238 reported in 27 (46.6%) patients treated with ruxolitinib vs 23 (44.2%) with BAT (P = .40).

239 lenomegaly and improvements in symptoms with ruxolitinib vs placebo at week 24.

240 INTERPRETATION: In patients with CLL, ruxolitinib was associated with significant improvements

241 sis of a matrix screen of drug combinations, ruxolitinib was combined with the Bcl-2/Bcl-xL inhibitor

242 The median duration of response with ruxolitinib was not reached, with 80% of patients still

243 Although the JAK inhibitor ruxolitinib was recently approved for use in hydroxyurea

244 unacceptable side effects from hydroxyurea, ruxolitinib was superior to standard therapy in controll

245 Overall, ruxolitinib was very well tolerated with only 4 patients

246 identify genes that may predict response to ruxolitinib, we performed targeted next-generation seque

247 Enhanced responses to ruxolitinib were observed in samples harboring JAK-activ

248 omegaly and symptom reductions achieved with ruxolitinib were sustained with long-term therapy.

249 ree compounds, roflumilast, tofacitinib, and ruxolitinib, were topically administered to the mouse ea

250 Moreover, combining VSV with polycations and ruxolitinib (which inhibits antiviral signaling) success

251 Food and Drug Administration (dasatinib and ruxolitinib, which inhibit BCR-ABL and Janus kinases, re

252 Moreover, ruxolitinib, which preferentially blocks JAK1 and JAK2,

253 eatment-II (the COMFORT-II Trial), comparing ruxolitinib with the best available therapy (BAT) in 219

254 w-up, 58 patients (54%) were still receiving ruxolitinib, with overall survival (OS) of 69%.

255 from diagnosis of 100 PMF patients receiving ruxolitinib within COMFORT-2 with that of 350 patients o

256 ients with myelofibrosis, we postulated that ruxolitinib would improve disease-related symptoms in pa