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Risk factors for thrombotic events in patients with PV and ET

Dec 29, 2021
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Polycythemia vera (PV) and essential thrombocytopenia (ET) present increased risk of thrombosis, which is associated with poor survival.1 The stratification of thrombotic risk is vital, given that targeted therapy for PV and ET primarily focus on reducing the risk of thrombosis rather than leukemic or fibrotic progression.1 You can read a summary of how thrombotic risk may guide treatment decisions here.

At the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition, three collaborative studies were presented on clinical parameters used to predict thrombosis. These include the individual impact of absolute neutrophil, lymphocyte, and monocyte counts (ANC, ALC, and AMC, respectively), JAK2V617F variant allele frequency (VAF), and the potential to use the neutrophil to lymphocyte ratio (NLR) as a predictor of thrombosis onset. We summarize these findings below.

Farrukh et al.2

This study focused on the individual prognostic impact of ANC, ALC, and AMC for arterial thrombosis (AT) and venous thrombosis (VT) in patients with ET and PV.

Two cohorts were analyzed. The first was a study cohort comprising 487 patients recruited from the Mayo Clinic: 349 with ET and 138 with PV. The second cohort was a validation set of patients with PV (N = 576).

Patient characteristics

Patient characteristics for patients with ET and PV are summarized in Table 1.

Table 1. Patient characteristics*

Characteristic

ET
(n
 = 349)

PV
(n
 = 138)

Median age, years (range)

57 (18–89)

62 (20–94)

Female, %

61

50

Hemoglobin levels, g/dL, median (range)

13.8 (11.1–16.4)

17.9 (16.1–24)

Leukocyte count ×109/L, median (range)

8.2 (3.2–52)

11.8 (2.7–65.8)

Platelet count ×109/L, median, (range)

859 (451–3,460)

434 (44–1,679)

Venous events at diagnosis, %

11

16

Venous events after diagnosis, %

9

16

Arterial events at diagnosis, %

12

20

Arterial events after diagnosis, %

18

11

ET, essential thrombocytopenia; PV, polycythemia vera.
*Adapted from Farrukh, et al.2

ANC and AMC are associated with VTE in patients with ET and PV

  • ANC, ALC, and AMC did not correlate with AT prior to or at diagnosis for either ET or PV (p > 0.1 for both).
  • Higher ANC and AMC, however, were associated with VT prior to or at diagnosis in both ET (p = 0.05 and p = 0.005, respectively) and PV (p = 0.04 and p = 0.07, respectively).
  • AT-free survival was not affected by AMC and ANC in either ET or PV (p > 0.1 for both).
  • A higher ANC was associated with reduced VT-free survival in patients with ET (p = 0.05) and PV (p = 0.003), while AMC and ALC did not have significant impact.
  • A multivariate analysis confirmed higher ANC as a negative independent prognostic factor of VT-free survival in ET (p = 0.01) and PV (p = 0.007). The only other significant factor for VT-free survival was older age, reported in patients with ET (p < 0.001).

External validation cohort3

  • Higher ANC was associated with compromised VT-free survival (p = 0.003), however the association of AMC was not significant (p = 0.7).
  • Higher ANC significantly impacted VT-free survival in patients with low-risk disease (p = 0.02) while producing a borderline significant association in patients with high-risk disease (p = 0.07).

In summary, this study provided evidence for the predictive impact of neutrophils, and possibly monocytes, toward VT in patients with PV and ET, but not AT.

Loscocco et al.4

The second presentation on risk factors for thrombotic events focused on the elucidation of JAK driver mutations in patients with PV, which are not currently used as a prognostic factor in this population. The aim of this study was to evaluate JAK2V617F VAF on the rate of AT and VT. Results from this abstract were recently published in Blood Cancer Journal.5

A total of 576 patients diagnosed with PV were included from the University of Florence. Again, a validation cohort was used, comprising 289 patients with PV.

Patient characteristics

Characteristics and incidence of risk factors for the training cohort are summarized in Table 2.

Table 2. Patient characteristics*

Characteristic

(N = 576)

Median age, years (range)

61.4 (16.2–91.8)

Male, %

58

High-risk for thrombosis, %

60.4

Median JAK2V617F VAF, % (range)

41.5 (0.3–100)

Leukocytosis ≥11 × 109/L, %

37.9

Cardiovascular risk factors, %

              Hypertension

56

              Diabetes

10.3

              Hyperlipidemia

15.9

              Active smoking

16

Arterial thrombosis

              Before/at diagnosis, n

76

              Follow-up, n

49

Venous thrombosis

              Before/at diagnosis, n

52

              Follow-up, n

39

VAF, variant allele frequency.

*Adapted from Loscocco, et al.4

JAK2V617F VAF is associated VT but not AT

  • In the follow-up period, JAK2V617F VAF as a continuous variable was significantly associated with the risk of VT (p = 0.003) but not AT (p = 0.8).
    • The rate of VT in follow-up was greater in patients with VAF >50% (>50%: 14.5% vs 2.4%; p < 0.0001).
  • VT-free survival was also significantly shorter in patients with JAK2V617F VAF >50% (hazard ratio [HR], 4; 95% confidence interval [CI], 1.9–8.6, p < 0.0001); no difference was found for AT.
  • Multivariate analysis of VT-free survival confirmed JAK2V617F VAF >50% as an independent negative prognostic factor for future VT (HR, 3.8; p = 0.001) alongside previous VT (HR, 2.2; p = 0.04).
    • JAK2V617F VAF >50% was significantly associated with risk of VT both in patients with low- and high-risk disease (HR, 10.6; p = 0.005, and HR, 3.5; p = 0.002, respectively).
  • JAK2V617F VAF >50% was not associated with risk of AT events or AT-free survival.
    • A multivariate analysis revealed diabetes (HR, 2.4; p = 0.02), hyperlipidemia (HR, 2.3; p = 0.01), and previous AT (HR, 2.1; p = 0.04) as independent prognostic factors for future AT events.

Validation cohort

  • JAK2V617F VAF >50% was associated with higher rates of VT at follow-up (HR, 2.9; 95% CI, 1.2–4.2; p = 0.007).
  • Multivariate analysis again confirmed JAK2V617F VAF >50% (HR 2.4; 95% CI 1.2–4.8, p = 0.01) and previous VT (HR 2.8; 95% CI, 1.4–5.7; p = 0.005) as independent risk factors for future VT.

In summary, this retrospective study revealed unique risk factors for VT and AT. This includes confirmation of JAK2V617F VAF as independent prognostic factor for future VT and VT-free survival. The appropriate cut-off for JAK2V617F VAF was >50%.

Carobbio et al.6

This was a retrospective study analysing 1,508 patients with PV from the ECLAP database over a median follow-up of 2.51 years. The aim was to observe whether NLR can predict AT and VT in PV.

Univariate analysis

  • NLR was not associated with AT.
    • Factors identified as having significant associations included age (p = 0.003), previous thrombosis, especially if arterial (p < 0.001), and the presence of at least one cardiovascular risk factor (p = 0.009).
  • For VT, increasing values of NLR (p = 0.002) defined as increased neutrophil counts (p = 0.002) simultaneously occurring with decreased lymphocyte counts (p = 0.002), was associated with VT.
    • Additionally, age (p = 0.039), history of VT (p < 0.001), and low hemoglobin (p = 0.039) were reported as a risk factors for subsequent VT.

Multivariate analysis

  • A multivariate analysis adjusted for age, gender, and treatment at baseline revealed NLR values ≥5 as an independent risk factor for VT (HR, 2.13; p = 0.001)
    • In addition, previous VT (HR, 5.48; p  0.001) presented as a risk factor for future VT.
  • For AT, older age (≥65 years; HR, 1.88; p = 0.005) and previous AT (HR, 1.92; p = 0.003) retained the prognostic statistical significance.

Validation cohorts

  • An NLR value ≥5 was identified as a prognostic factor in two external validation cohorts from Florence (n = 282; p = 0.0012) and Rome (n = 175; p = 0.0035).

In summary, this study demonstrated NLR as an independent predictor of VT for patients with PV and could potentially be used in a new scoring system for the diagnosis of PV.

Conclusion

Data from these abstracts presented at ASH 2021 have distinguished unique and shared risk factors for AT and VT. Previous thrombotic events were confirmed to predict both future AT and VT. Leukocytosis was previously promoted as a prognostic factor for future VT, and novel data from Farrukh et al.2 have provided evidence for a strong association of ANC, and perhaps AMC, in the risk of subsequent VT, and VT-free survival. Furthermore, Carobbio’s presentation encourages further research into utilizing NLR as a prognostic tool of VT in patients with PV. Finally, identification of JAK2VF VAF >50% was a confirmed molecular risk factor for VT in patients with PV, in line with published data.

  1. Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2021 update on diagnosis, risk-stratification and management. Am J Hematol. 2020;95(12)1599-1613. DOI: 1002/ajh.26008
  2. Farrukh F, Guglielmelli P, Loscocco GG, et al. Deciphering the individual contribution of absolute neutrophil and monocyte counts to thrombosis risk in polycythemia vera and essential thrombocythemia. Poster #3651. 63rd American Society of Hematology Annual Meeting and Exposition;Dec 13, 2021; Atlanta, US.
  3. Farrukh F, Guglielmelli P, Loscocco GG, et al. Deciphering the individual contribution of absolute neutrophil and monocyte counts to thrombosis risk in polycythemia vera and essential thrombocythemia. Am J Hematol. 2021. Online ahead of print. DOI: 10.1002/ajh.26423
  4. Loscocco GG, Guglielmelli P, Mannarelli C, et al. A JAK2V617F variant allele frequency greater than 50% identifies patients with polycythemia vera at high risk for venous thrombosis. Oral abstract #237. 63rd American Society of Hematology Annual Meeting and Exposition; Dec 11, 2021; Atlanta, US.
  5. Guglielmelli P, Loscocco GG, Mannarelli C. JAK2V617F variant allele frequency> 50% identifies patients with polycythemia vera at high risk for venous thrombosis. Blood Cancer J. 2021;11(12):1-9. DOI. 1038/s41408-021-00581-6
  6. Carobbio A, Vannucchi A, Guglielmelli P, et al. Neutrophil-to-lymphocyte ratio (NLR) is a risk factor for venous thrombosis in polycythemia vera. Poster #1499. 63rd American Society of Hematology (ASH) Annual Meeting and Exposition; Dec 11, 2021; Atlanta, US.

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