Ruxolitinib Approved Indications and Usage Guidelines
Ruxolitinib was the first drug approved (2011) to specifically treat patients with the intermediate- or high-risk myelofibrosis, including primary myelofibrosis, postpolycythemia vera myelofibrosis, and postessential thrombocythemia myelofibrosis.
This approval was based on the results of 2 large randomized phase III trials that enrolled patients with intermediate-2 or high-risk myelofibrosis and compared ruxolitinib with placebo (COMFORT-I)1 or best available therapy (COMFORT-II)2 in JAK inhibitor-naïve patients with myelofibrosis.
The primary efficacy endpoint was the proportion of patients who experienced a reduction in spleen volume of ≥ 35% at 24 weeks (COMFORT-I) or 48 weeks (COMFORT-II). The key secondary endpoint in COMFORT-I was the proportion of patients who experienced a ≥ 50% improvement from baseline in myelofibrosis total symptom score at 24 weeks.
The results of these studies showed that a greater proportion of patients treated with ruxolitinib experienced a ≥ 35% reduction in spleen volume as compared with those treated with placebo (42% vs. 1%, P < 0.0001) or best available therapy (29% vs. 0%, P < 0.0001). A greater proportion of patients in study 1 experienced a ≥ 50% reduction in the myelofibrosis total symptom score during treatment with ruxolitinib than with placebo (46% vs. 5%, P < 0.0001).
Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses 3 showed OS advantage also in ruxolitinib treated patient. This was an exploratory analysis of 5-year data pooled from the phase 3 COMFORT-I and -II trials. In both trials, patients could cross over to ruxolitinib from the control group (COMFORT-I, placebo; COMFORT-II, best available therapy). All continuing patients in the control groups crossed over to ruxolitinib by the 3-year follow-up. The risk of death was reduced by 30% among patients randomized to ruxolitinib compared with patients in the control group (median OS, 5.3 vs 3.8 years, respectively; hazard ratio [HR], 0.70 [95% CI, 0.54-0.91]; P = 0.0065).OS advantage was more pronounced for patients who were originally randomized to ruxolitinib compared with patients who crossed over from control to ruxolitinib.
This approval was based on the results of 2 large randomized phase III trials that enrolled patients with intermediate-2 or high-risk myelofibrosis and compared ruxolitinib with placebo (COMFORT-I)1 or best available therapy (COMFORT-II)2 in JAK inhibitor-naïve patients with myelofibrosis.
The primary efficacy endpoint was the proportion of patients who experienced a reduction in spleen volume of ≥ 35% at 24 weeks (COMFORT-I) or 48 weeks (COMFORT-II). The key secondary endpoint in COMFORT-I was the proportion of patients who experienced a ≥ 50% improvement from baseline in myelofibrosis total symptom score at 24 weeks.
The results of these studies showed that a greater proportion of patients treated with ruxolitinib experienced a ≥ 35% reduction in spleen volume as compared with those treated with placebo (42% vs. 1%, P < 0.0001) or best available therapy (29% vs. 0%, P < 0.0001). A greater proportion of patients in study 1 experienced a ≥ 50% reduction in the myelofibrosis total symptom score during treatment with ruxolitinib than with placebo (46% vs. 5%, P < 0.0001).
Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses 3 showed OS advantage also in ruxolitinib treated patient. This was an exploratory analysis of 5-year data pooled from the phase 3 COMFORT-I and -II trials. In both trials, patients could cross over to ruxolitinib from the control group (COMFORT-I, placebo; COMFORT-II, best available therapy). All continuing patients in the control groups crossed over to ruxolitinib by the 3-year follow-up. The risk of death was reduced by 30% among patients randomized to ruxolitinib compared with patients in the control group (median OS, 5.3 vs 3.8 years, respectively; hazard ratio [HR], 0.70 [95% CI, 0.54-0.91]; P = 0.0065).OS advantage was more pronounced for patients who were originally randomized to ruxolitinib compared with patients who crossed over from control to ruxolitinib.
Ruxolitinib was approved by FDA (2014) to treat polycythemia vera patients who have an inadequate response to or cannot tolerate hydroxyurea. Approval was based on the phase III RESPONSE trial4, which demonstrated efficacy in a highly selected patient population.
This was a phase 3 open-label study to evaluate the efficacy and safety of ruxolitinib versus standard therapy in patients with polycythemia vera who had an inadequate response to or had unacceptable side effects from hydroxyurea. The primary end point was both hematocrit control through week 32 and at least a 35% reduction in spleen volume at week 32, as assessed by means of imaging. The primary end point was achieved in 21% of the patients in the ruxolitinib group versus 1% of those in the standard-therapy group (P<0.001). Hematocrit control was achieved in 60% of patients receiving ruxolitinib and 20% of those receiving standard therapy. A complete hematologic remission was achieved in 24% of patients in the ruxolitinib group and 9% of those in the standard-therapy group (P=0.003) (CHR meant normal hemoglobin, normal platelets, hematocrit under 45%, controlled platelets, and controlled white count.)
In this RESPONSE trial it was shown that ruxolitinib was superior to standard therapy in controlling the hematocrit, reducing the spleen volume, and improving symptoms associated with polycythemia vera and hence it was approved for this indication.
From the 5-year follow-up data of RESPONSE trial5, the study the probability of maintaining hematocrit control and spleen volume reduction was good, at 73% and 72%, respectively. The probability of maintaining the complete hematologic response [CHR] at 5 years was 55% with ruxolitinib.
The RESPONSE-2 trial6was identical to RESPONSE, except that splenomegaly was not a requirement in RESPONSE -2 trial (Note that all patients in RESPONSE trial had splenic volume > 450 cm3 at enrollment). RESPONSE-2 assessed the efficacy and safety of ruxolitinib in controlling disease in patients with polycythaemia vera without splenomegaly (no palpable spleen at enrollment) who need second-line therapy. Haematocrit control was achieved in 62% of ruxolitinib-treated patients versus 19% of patients who received best available therapy (odds ratio 7·28 [95% CI 3·43–15·45]; p<0·0001). It proved that benefit in PV is not only because of splenic volume reduction.
Note: In PV goal of ruxolitinib in 2nd line is to get the hematocrit under 45% and keep it under 45%, control the white cells, and control the symptoms. In PV starting dose is at 10 mg twice daily and then titrate.
This was a phase 3 open-label study to evaluate the efficacy and safety of ruxolitinib versus standard therapy in patients with polycythemia vera who had an inadequate response to or had unacceptable side effects from hydroxyurea. The primary end point was both hematocrit control through week 32 and at least a 35% reduction in spleen volume at week 32, as assessed by means of imaging. The primary end point was achieved in 21% of the patients in the ruxolitinib group versus 1% of those in the standard-therapy group (P<0.001). Hematocrit control was achieved in 60% of patients receiving ruxolitinib and 20% of those receiving standard therapy. A complete hematologic remission was achieved in 24% of patients in the ruxolitinib group and 9% of those in the standard-therapy group (P=0.003) (CHR meant normal hemoglobin, normal platelets, hematocrit under 45%, controlled platelets, and controlled white count.)
In this RESPONSE trial it was shown that ruxolitinib was superior to standard therapy in controlling the hematocrit, reducing the spleen volume, and improving symptoms associated with polycythemia vera and hence it was approved for this indication.
From the 5-year follow-up data of RESPONSE trial5, the study the probability of maintaining hematocrit control and spleen volume reduction was good, at 73% and 72%, respectively. The probability of maintaining the complete hematologic response [CHR] at 5 years was 55% with ruxolitinib.
The RESPONSE-2 trial6was identical to RESPONSE, except that splenomegaly was not a requirement in RESPONSE -2 trial (Note that all patients in RESPONSE trial had splenic volume > 450 cm3 at enrollment). RESPONSE-2 assessed the efficacy and safety of ruxolitinib in controlling disease in patients with polycythaemia vera without splenomegaly (no palpable spleen at enrollment) who need second-line therapy. Haematocrit control was achieved in 62% of ruxolitinib-treated patients versus 19% of patients who received best available therapy (odds ratio 7·28 [95% CI 3·43–15·45]; p<0·0001). It proved that benefit in PV is not only because of splenic volume reduction.
Note: In PV goal of ruxolitinib in 2nd line is to get the hematocrit under 45% and keep it under 45%, control the white cells, and control the symptoms. In PV starting dose is at 10 mg twice daily and then titrate.
In May 2019 FDA approved Ruxolitinib for the treatment of steroid-refractory acute GVHD in adult and pediatric patients 12 years and older. Ruxolitinib is the first and only FDA-approved treatment for this indication. The approval was based on data from REACH1 trail7, phase 2, an open-label, single-arm, multicenter study of Ruxolitinib in combination with corticosteroids in patients with steroid-refractory grade II-IV acute GVHD.
In this study, patients aged at least 12 years with grades II to IV steroid-refractory aGVHD were eligible to receive ruxolitinib orally, starting at 5 mg twice daily plus corticosteroids, until treatment failure, unacceptable toxicity, or death. The primary end point was overall response rate (ORR) at day 28; the key secondary end point was duration of response (DOR) at 6 months.
At day 28, 39 patients (54.9%; 95% confidence interval, 42.7%-66.8%) had an overall response, including 19 (26.8%) with complete responses. Best ORR at any time was 73.2% (complete response, 56.3%). Responses were observed across skin (61.1%), upper (45.5%) and lower (46.0%) gastrointestinal tract, and liver (26.7%). Overall survival estimate at 6 months was 51.0%. Ruxolitinib produced durable responses and encouraging survival compared with historical data in patients with steroid-refractory aGVHD who otherwise have dismal outcomes and based on this data it was approved for this indication.
Info: The REACH clinical program also includes the collaborative Novartis-sponsored randomized pivotal Phase 3 trials in patients with steroid-refractory acute GVHD (REACH2) and steroid-refractory chronic GVHD (REACH3).
Phase 3 trial (REACH2)8 that was conducted to compare the efficacy and safety of ruxolitinib with the investigator’s choice of therapy from a list of nine commonly used options (“best available care”) in patients 12 years of age or older who had glucocorticoid-refractory acute GVHD after allogeneic stem-cell transplantation. Overall response at day 28 was higher in the ruxolitinib group than in the control group (62% vs. 39%; odds ratio, 2.64; 95% confidence interval [CI], 1.65 to 4.22; P<0.001). Durable overall response at day 56 was higher in the ruxolitinib group than in the control group (40% vs. 22%; odds ratio, 2.38; 95% CI, 1.43 to 3.94; P<0.001). The estimated cumulative incidence of loss of response at 6 months was 10% in the ruxolitinib group and 39% in the control group. The median overall survival was 11.1 months in the ruxolitinib group and 6.5 months in the control group (hazard ratio for death, 0.83; 95% CI, 0.60 to 1.15).
This trial (REACH2) showed that, among patients with grade II to IV glucocorticoid-refractory acute GVHD, ruxolitinib therapy led a significantly higher overall response than control therapy at day 28 and a higher durable overall response at day 56. Patients receiving ruxolitinib had a higher incidence of thrombocytopenia and modestly higher incidence of anemia, infection, and cytomegalovirus infection than those who received control therapy.
In this study, patients aged at least 12 years with grades II to IV steroid-refractory aGVHD were eligible to receive ruxolitinib orally, starting at 5 mg twice daily plus corticosteroids, until treatment failure, unacceptable toxicity, or death. The primary end point was overall response rate (ORR) at day 28; the key secondary end point was duration of response (DOR) at 6 months.
At day 28, 39 patients (54.9%; 95% confidence interval, 42.7%-66.8%) had an overall response, including 19 (26.8%) with complete responses. Best ORR at any time was 73.2% (complete response, 56.3%). Responses were observed across skin (61.1%), upper (45.5%) and lower (46.0%) gastrointestinal tract, and liver (26.7%). Overall survival estimate at 6 months was 51.0%. Ruxolitinib produced durable responses and encouraging survival compared with historical data in patients with steroid-refractory aGVHD who otherwise have dismal outcomes and based on this data it was approved for this indication.
Info: The REACH clinical program also includes the collaborative Novartis-sponsored randomized pivotal Phase 3 trials in patients with steroid-refractory acute GVHD (REACH2) and steroid-refractory chronic GVHD (REACH3).
Phase 3 trial (REACH2)8 that was conducted to compare the efficacy and safety of ruxolitinib with the investigator’s choice of therapy from a list of nine commonly used options (“best available care”) in patients 12 years of age or older who had glucocorticoid-refractory acute GVHD after allogeneic stem-cell transplantation. Overall response at day 28 was higher in the ruxolitinib group than in the control group (62% vs. 39%; odds ratio, 2.64; 95% confidence interval [CI], 1.65 to 4.22; P<0.001). Durable overall response at day 56 was higher in the ruxolitinib group than in the control group (40% vs. 22%; odds ratio, 2.38; 95% CI, 1.43 to 3.94; P<0.001). The estimated cumulative incidence of loss of response at 6 months was 10% in the ruxolitinib group and 39% in the control group. The median overall survival was 11.1 months in the ruxolitinib group and 6.5 months in the control group (hazard ratio for death, 0.83; 95% CI, 0.60 to 1.15).
This trial (REACH2) showed that, among patients with grade II to IV glucocorticoid-refractory acute GVHD, ruxolitinib therapy led a significantly higher overall response than control therapy at day 28 and a higher durable overall response at day 56. Patients receiving ruxolitinib had a higher incidence of thrombocytopenia and modestly higher incidence of anemia, infection, and cytomegalovirus infection than those who received control therapy.
In September 2021 FDA approved Ruxolitinib for treatment of chronic graft-versus-host disease (GVHD) after failure of one or two lines of systemic therapy in adult and pediatric patients 12 years and older. The FDA approval was based on the REACH3 study9, a Phase 3, randomized, open-label, multicenter study of Ruxolitinib in comparison to best available therapy (BAT) for treatment of steroid-refractory chronic GVHD after allogeneic stem cell transplantation.
REACH3 study evaluated the efficacy and safety of ruxolitinib at a dose of 10 mg twice daily, as compared with the investigator’s choice of therapy from a list of 10 commonly used options considered best available care (control), in patients 12 years of age or older with moderate or severe glucocorticoid-refractory or -dependent chronic GVHD (n = 329). The primary end point was overall response (complete or partial response) at week 24. Overall response at week 24 was greater in the ruxolitinib group than in the control group (49.7% vs. 25.6%; odds ratio, 2.99; P<0.001). Ruxolitinib led to longer median failure-free survival than control (>18.6 months vs. 5.7 months; hazard ratio, 0.37; P<0.001) and higher symptom response (24.2% vs. 11.0%; odds ratio, 2.62; P=0.001).
Among patients with glucocorticoid-refractory or -dependent chronic GVHD, ruxolitinib led to significantly greater overall response, failure-free survival, and symptom response and based on these outcomes it was approved in cGVHD for above mentioned indication.
REACH3 study evaluated the efficacy and safety of ruxolitinib at a dose of 10 mg twice daily, as compared with the investigator’s choice of therapy from a list of 10 commonly used options considered best available care (control), in patients 12 years of age or older with moderate or severe glucocorticoid-refractory or -dependent chronic GVHD (n = 329). The primary end point was overall response (complete or partial response) at week 24. Overall response at week 24 was greater in the ruxolitinib group than in the control group (49.7% vs. 25.6%; odds ratio, 2.99; P<0.001). Ruxolitinib led to longer median failure-free survival than control (>18.6 months vs. 5.7 months; hazard ratio, 0.37; P<0.001) and higher symptom response (24.2% vs. 11.0%; odds ratio, 2.62; P=0.001).
Among patients with glucocorticoid-refractory or -dependent chronic GVHD, ruxolitinib led to significantly greater overall response, failure-free survival, and symptom response and based on these outcomes it was approved in cGVHD for above mentioned indication.
Ruxolitinib Dosing Guidelines
Initial dose depends on baseline PLT count
| PLT >200 x10^9/L: 20 mg PO BID |
| PLT 100-200 x10^9/L: 15 mg PO BID |
| PLT 50 to <100 x10^9/L: 5 mg PO BID |
- Do not increase dose during the first 4 weeks of therapy and no more frequently than q2Weeks.
- Hold therapy for PLT Less than 50 X 109/L (if baseline > 100) and PLT Less than 25 X 109/L (if baseline > 50-100) and or for bleeding requiring intervention.
- Continuation of treatment for >6 months should be limited to patients in whom the benefits outweigh the potential risks. Discontinue treatment if there is no spleen size reduction or symptom improvement after 6 months of therapy.
- Therapy discontinuation: Consider gradually tapering off (by 5 mg twice daily each week) if discontinuing for reasons other than thrombocytopenia. (Slow taper is advised to prevent Ruxolitinib discontinuation syndrome)
- 10 mg PO BID
- Interrupt dosing if Hemoglobin less than 8 g/dL OR platelet count less than 50 X 109/L
- 5 mg PO BID*/10 mg PO BID
- * may increase to 10 mg BID after at least 3 days if ANC and platelet counts have not decreased by ≥50% compared to baseline.
- 10 mg PO BID
Adverse Reactions
In myelofibrosis and polycythemia vera, the most common hematologic adverse reactions (incidence > 20%) are thrombocytopenia and anemia. The most common non hematologic adverse reactions (incidence >10%) are bruising, dizziness, and headache.
In acute graft versus host disease, the most common hematologic adverse reactions (incidence > 50%) are anemia, thrombocytopenia, and neutropenia. The most common non hematologic adverse reactions (incidence > 50%) are infections and edema.
Ruxolitinib Discontinuation Syndrome (RDS) : It is characterized by acute relapse of disease symptoms, accelerated splenomegaly, worsening of cytopenias, and occasional hemodynamic decompensation, including a septic shock like syndrome or ARDS like phenomena. RDS is mainly a diagnosis of exclusion. Indeed, there are no clinical features, laboratory or histopathology findings that are diagnostic; the syndrome can be suspected based on the temporal relationship between drug withdrawal and onset of clinical manifestations, that can appear from less than 24 hours up to 3 weeks after discontinuation. RDS might be mechanistically related to a sudden and dramatic rebound of previously downregulated cytokines’ release and/or signaling via JAK2. To prevent RDS, a slow tapering of ruxolitinib eventually associated to corticosteroids is suggested; it should be noted, however, that dose-tapering schedule of ruxolitinib is not guaranteed to universally prevent the development of cytokine-rebound phenomena. Fortunately this is quite uncommon phenomena.
References:
- Verstovsek S et al. A Double-Blind, Placebo-Controlled Trial of Ruxolitinib for Myelofibrosis (COMFORT I). N Engl J Med 2012; 366:799-807. DOI: 10.1056/NEJMoa1110557
- Harrison C, Kiladjian J-J, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis (COMFORT II). N Engl J Med. 2012;366(9):787-798. DOI: 10.1056/NEJMoa1110556
- Verstovsek S et al. Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses. J Hematol Oncol. 2017 Sep 29;10(1):156. doi: 10.1186/s13045-017-0527-7.
- Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med. 2015;372(5):426-435. doi:10.1056/NEJMoa1409002
- Kiladjian JJ, Zachee P, Hino M, et al. Long-term efficacy and safety of ruxolitinib versus best available therapy in polycythaemia vera (RESPONSE): 5-year follow up of a phase 3 study. Lancet Haematol. 2020;7(3):e226-e237. doi:10.1016/S2352-3026(19)30207-8
- Passamonti F, Griesshammer M, Palandri F, et al. Ruxolitinib for the treatment of inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): a randomised, open-label, phase 3b study. Lancet Oncol. 2017;18(1):88-99. doi:10.1016/S1470-2045(16)30558-7
- Madan Jagasia, Miguel-Angel Perales, Mark A. Schroeder, Haris Ali, Nirav N. Shah, Yi-Bin Chen, Salman Fazal, Fitzroy W. Dawkins, Michael C. Arbushites, Chuan Tian, Laura Connelly-Smith, Michael D. Howell, H. Jean Khoury,
Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label phase 2 trial,
Blood,Volume 135, Issue 20,2020, Pages 1739-1749,ISSN 0006-4971, doi:10.1182/blood.2020004823. - Robert Zeiser, M.D et al, Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease, N Engl J Med 2020; 382:1800-1810. DOI: 10.1056/NEJMoa1917635
- Robert Zeiser, M.D et al. Ruxolitinib for Glucocorticoid-Refractory Chronic Graft-versus-Host Disease, N Engl J Med 2021; 385:228-238, DOI: 10.1056/NEJMoa2033122.