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Preventing thrombosis with ruxolitinib in polycythemia vera

Feb 21, 2020
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Myeloproliferative neoplasms (MPNs) are clonal disorders of hematopoietic stem cells that cause increased proliferation of cells from the myeloid lineage. Polycythemia vera (PV) is an MPN that is characterized by the overproduction of erythrocytes and may also be associated with an increase in leukocytes and thrombocytes. In most patients, PV arises due to a dysregulated JAK-STAT signaling pathway, resulting from an activating JAK2 mutation. In PV, the specific JAK2V617F mutation occurs at a frequency of 95%.1

The clinical features of PV include1:

  • headache, tiredness, dizziness, and sweating
  • pruritus, due to high levels of histamine released by mast cells in the skin (~40% of patients)
  • thrombotic events, e.g. strokes and pulmonary embolism (~33% of patients)
  • bleeding (~25% of patients)

The main aim of therapeutic management of PV is to alleviate the symptom burden, prevent or reduce the recurrence of thromboembolic events, and prevent disease transformation.2 The first-line treatment of patients with high-risk PV is hydroxyurea (HU), and studies suggest HU may have an anti-thrombotic effect.3,4 The current recommendation from the European LeukemiaNet (ELN) to prevent thrombosis in patients who become resistant or intolerant to HU is to administer the JAK1/JAK2 inhibitor ruxolitinib or recombinant interferon α therapy (rINFα). Since there is no comparison between these agents, the decision is usually made based on patient age and drug availability.4

Data supporting the use of ruxolitinib in this setting predominantly comes from the RESPONSE trials (RESPONSE and RESPONSE-2). Based on the results of these studies, the United States Food & Drug Administration (FDA) and European Medicines Agency (EMA) approved ruxolitinib for the treatment of patients who have an inadequate response to, or who cannot tolerate, HU.5,6 In the ELN recommendations, due to performance bias and a lack of comparator arm, the overall quality of evidence for the critical outcomes of the RESPONSE trials was downgraded, however, the hematocrit response and primary response were deemed to have a high level of evidence.4  So far, there is limited data evaluating the efficacy of ruxolitinib with regards to the reduction of thrombosis. For this reason, Arianna Masciulli, Papa Giovanni XXIII Hospital, Bergamo, IT, and colleagues conducted a systemic review and meta-analysis of randomized controlled trials (RCTs) comparing ruxolitinib to best available therapy (BAT), specifically for the purpose of reducing the incidence of thrombosis.3

Methods3

  • RCTs that evaluated the incidence of thrombosis in patients with PV receiving ruxolitinib vs. BAT were identified from medical databases and abstracts presented at congresses from 2014
  • Data were extracted: number of patients treated per arm, median and/or total follow-up time, number of patients with thromboembolic events, median/mean age of patients, and number of patients with history of thrombosis
  • The final selection for meta-analysis (quantitative data) included 15 records
  • Data came from four main RCTs, as shown in Table 1, with data specifically used for the meta-analysis coming from the publications indicated in bold

Table 1. RCTs used for systematic review3

*Data used for the meta-analysis comes from the publications indicated in bold

BAT, best available therapy; ET, essential thrombocythemia; HU, hydroxyurea; PV, polycythemia vera; RCT, randomized controlled trial

Trial name

PV population

Evaluation

Records identified

RESPONSE — open label phase III RCT

Resistant or intolerant to HU, with splenomegaly

Ruxolitinib vs. BAT.

Cross-over from ruxolitinib to BAT was allowed after 32-week cut-off

Verstovsek et al., 2014

Vannucchi et al., 2014 Vannucchi et al., 2015

Verstovsek et al., 2015

Verstovsek et al., 2016

Kiladjian et al., 2017

Alvarez-Larràn et al., 2018

Kiladjian et al., 2018

Kiladjian et al., 2018

RESPONSE-2 — open label phase IIIb RCT

Resistant or intolerant to HU, without splenomegaly

Ruxolitinib vs. BAT.

Cross-over from ruxolitinib to BAT was allowed after 28-week cut-off

Passamonti et al., 2016

Passamonti et al., 2017

Passamonti et al., 2018

Greisshammer et al., 2018

 

 

RELIEF — double blind RCT

Condition generally well controlled with HU but presented with symptoms of PV

Randomized switch study from HU to ruxolitinib

Mesa et al., 2017

MAJIC — randomized phase II trial

Resistant or intolerant to HU. Also included patients with ET

Second-line administration of ruxolitinib vs. BAT

Harrison et al., 2018

Curto-Garcia et al., 2019

The risk of bias was assessed and deemed low. However, to avoid bias from the possibility of cross-over, data were only included up to the cut-off period for cross-over (where applicable).

Results3

Qualitative synthesis of results

All four studies (RESPONSE, RESPONSE-2, RELIEF, and MAJIC) used surrogate efficacy endpoints. Specifically, these included complete hematologic response (CHR) and molecular response (MR), with the incidence of thromboembolic events reported in the safety analyses. All four studies found ruxolitinib had a significant effect on CHR. The MAJIC substudy (of patients with PV only) found ruxolitinib was more efficient than BAT in obtaining MR, which is important because MR may correlate with a lower risk of thrombosis.

Follow-up analyses of the RESPONSE trial considered thrombosis incidence after long-term treatment with ruxolitinib. These analyses compared:

  • Ruxolitinib vs. propensity-score matched patients: advantage of ruxolitinib in overall survival and thrombosis
  • BAT (32-week follow-up) vs. ruxolitinib (from the beginning of treatment with 5-year follow-up): thrombosis incidence was lower in patients receiving ruxolitinib (1.2% vs. 8.2%) but significance was not reported

Patients treated with BAT on the RESPONSE trials who crossed over to ruxolitinib had a thrombosis rate approximately in the middle of the two main patient populations analyzed.

Meta-analysis of thrombosis incidence: ruxolitinib vs. BAT3

For all studies, and for both arms, the investigators calculated the thrombosis incidence and relative risk (RR) of thrombosis. Of the 663 patients included in the analysis, patient characteristics were overall balanced (median age, years [BAT vs ruxolitinib]: 63.9 vs. 63.3). However, follow-up duration varied between studies and from arm to arm, ranging from 0.3 to 2.6 years. Overall, the data do not show a clear advantage of ruxolitinib over BAT in preventing thrombosis in the follow-up period examined.

Table 2. Annual incidence of thrombosis per study arm3

BAT, best available therapy; RR, relative risk

Trial name

Events/total (n)
BAT

Events/total (n)
ruxolitinib

Median follow-up
(years)

RR

RESPONSE

6/112

1/110

0.6

0.2

RESPONSE-2

4/75

3/74

1.3 (BAT)

2.6 (ruxolitinib)

0.4

RELIEF

2/56

2/54

0.3

1.0

MAJIC

10/89

10/93

2.6

1.0

Total

22/332

16/331

0.6

Based on a meta-regression of ruxolitinib treatment effect (n = 663), thrombosis incidence rates are shown below:

  • Overall: 4.30% (95% CI, 3.00–5.60)
  • BAT: 5.51% (95% CI, 3.72–7.30)
  • Ruxolitinib: 3.09% (95% CI, 1.22–4.96)
  • The RR of thrombosis for ruxolitinib vs. BAT was 0.56, however this was not statistically significant (p = 0.098)

Conclusion3

  • The overall thrombosis rate was numerically lower with ruxolitinib, but the hazard ratio was not statistically significant
  • Limitations of this study include:
    • Limited number of events
    • Annual thrombosis rate estimates are limited to a short follow-up duration in some treatment arms
  • Evidence that ruxolitinib prevents thrombotic events is lacking and a prospective clinical trial in a selected patient population is warranted. However, the authors question whether such a trial would be feasible as it would require thousands of patients to be enrolled
  • Alternatively, preliminary evidence seems to suggest that maintaining a target hematocrit does correlate with lower incidence of cardiovascular events. The authors therefore suggest using combined or surrogate endpoints (such as hematocrit) may better assess impact of treatment on thrombosis rates

Expert Opinion

The short-term objective of therapy in polycythemia vera (PV) is to reduce the risk of major venous and arterial thrombosis, while the long-term aim is to limit the risk of evolution into myelofibrosis or acute leukemia.

Hydroxyurea (HU), in addition to phlebotomy and low-dose aspirin, has been a long-standing first-line cytoreductive treatment for patients at high risk of thrombosis (age > 60 years and/or previous major thrombosis). Unfortunately, 25% of these patients exhibit resistance or intolerance to this drug. The recent European LeukemiaNet (ELN) and National Comprehensive Cancer Network (NCCN) guidelines recommend the use of ruxolitinib in this selected population, even though evidence regarding its efficacy in terms of thrombosis reduction is still uncertain. By analyzing four randomized controlled trials, including 663 patients (1057 patients per year), a systematic review and meta-analysis documented a rate of major thrombosis consistently lower in patients on ruxolitinib ( 3.09% patients per year) as compared with those treated with the best available therapy (BAT; 5.51% patients per year), but the difference did not reach statistical significance (p = 0.098). These rates appear less impressive than those recently reported in the 5-year follow-up of RESPONSE trial, in which exposure-adjusted rate (per 100 patient years) of thromboembolic events in patients administered with ruxolitinib was 1.2, and 8.2 in patients given BAT, accordingly. The main reason for this difference lies in the fact that in RESPONSE trial, the ruxolitinib arm had a follow-up as long as 5 years, compared with 1 year available for BAT, whereas in our meta-analysis, we chose to exclude data from the later follow-ups from the RESPONSE trial.

Although the estimates are not formally in favor of ruxolitinib, a trend towards a reduction in thromboembolic events in patients resistant or intolerant to HU included in this meta-analysis cannot be understated. We admit that the body of evidence had a high risk of bias and varied broadly in quality. Nevertheless, this result could have an important practical implication for those patients who, being strictly defined at high vascular risk according to the guidelines (age and/or prior thrombosis), could limit their risk of stroke, myocardial infarction, venous thrombosis, and pulmonary embolism. However, to validate these findings, well-designed additional clinical trials, in which the primary hard endpoint should be reduction of vascular events, are needed. To our knowledge, the only clinical prospective study that aims to address this medical need is the MITHRIDATE study (NCT04116502). The primary end point of this phase III, randomized trial is event-free survival; the combined events are the first major thrombosis/hemorrhage, death, transformation to myelodysplastic syndromes, acute myeloid leukemia, or post-PV myelofibrosis within the 3-year trial period. It could be that even this study does not have the power to convincingly resolve the question of the antithrombotic efficacy of ruxolitinib, due to the number of incident thromboembolic events in a population not conventionally defined as high-risk. In fact, in the MITHRIDATE trial, patients with leukocytosis and thrombocytosis, independent of age and prior thrombosis, are also included, even though it is still uncertain whether these two factors can identify high-risk cases and to what extent their normalization can reduce the vascular events.

  1. Greisshammer M. et al. Ruxolitinib for the treatment of inadequately controlled polycythemia vera without splenomegaly: 80-week follow-up from the RESPONSE-2 trial. Ann Hematol. 2018 May 27; 97:591–1600. DOI: 1007/s00277-018-3365-y
  2. Greisshammer M. et al. Ruxolitinib for the treatment of inadequately controlled polycythemia vera without splenomegaly: 80-week follow-up from the RESPONSE-2 trial. Ann Hematol. 2018 May 27; 97:591–1600. DOI: 1007/s00277-018-3365-y
  3. Masciulli A. et al. Ruxolitinib for the prevention of thrombosis in polycythemia vera: a systematic review and meta-analysis. Blood Adv. 2020 Jan 27; 4(2):380–386. DOI: 1182/bloodadvances.2019001158.
  4. Barbui T. et al. Philadelphia chromosome-negative classical myeloproliferative neoplasms: revised management recommendations from European LeukemiaNet. Leukemia. 2018 Feb 27; 32:1057–1069. DOI: 1038/s41375-018-0077-1
  5. FDA Approves ruxolitinib to treat patients with polycythemia vera. Available at: https://www.esmo.org/oncology-news/FDA-Approves-Ruxolitinib-to-Treat-Patients-With-Polycythemia-Vera Published 2014 Dec 05. [Accessed 2020 Feb 13]
  6. European Medicines Agency (EMA). Assessment Report; Jakavi. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/jakavi [Accessed 2020 Feb 13]

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