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Clinical and molecular predictors of fibrotic progression in patients with essential thrombocythemia

Sep 17, 2021
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Essential thrombocythemia (ET), a Ph-negative myeloproliferative neoplasm (MPN) is prone to higher risk of thrombohemorrhagic complications including progression to myelofibrosis (MF), which is associated with poorer prognosis. Most patients with ET harbor one of the three MPN-specific clonal markers, including JAK2V617F, calreticulin (CALR), and thrombopoietin receptor gene (MPL) mutations that are drivers of JAK-STAT signaling pathway. Previously a few studies have identified driver CALR and MPL mutations and additional SF3B1 and U2AF1 mutations as risk factors for progression to MF; however, data are limited on the risk of progression to MF.

Loscocco et al,1 recently published a retrospective cohort study in the American Journal of Hematology, identifying clinical and molecular variables predictive of inferior myelofibrosis-free survival (MFS) in patients with ET, defined by World Health Organization (WHO). The key findings are summarized here.

Study design

A retrospective, multicenter, cohort study utilizing three independent cohorts: University of Florence, Italy (n = 718) as the experimental cohort; Mayo Clinic, USA (n = 479), and Catholic University, Rome, Italy (n = 410) as two independent validation cohorts.

Results

Baseline characteristics of the experimental cohort

Median age at diagnosis was 57.9 years (range, 12.9−92.9) (Table 1) with a median follow-up of 106 months (range, 6−422) in the experimental Florence cohort. Palpable splenomegaly, constitutional symptoms, major thrombosis at diagnosis, major bleeding, and acute myeloid leukemia (AML) progression were not statistically significant variables at baseline.

Table 1. Clinical and laboratory variables of patients, stratified by their driver mutational status*

Variable

All patients
(n = 718)

JAK2
(n = 471, 65.6%)

CALR type 1/1-like
(n = 92, 12.8%)

CALR type 2/2-like
(n = 51, 7.1%)

MPL
(n = 26, 3.6%)

TN
(n = 78, 10.9%)

p value

Age in year,
median (range)

57.9
(12.9−92.9)

62.0
(14.9−92.9)

52.6
(12.9−85.1)

48.9
(20.5−84.4)

54.8
(37.3−89.2)

49.2
(15.2−81.3)

<0.001

Age ≥60 years, %

46.4

53.7

32.6

25.5

42.3

33.3

<0.001

Sex, females, %

64.8

67.5

42.6

49.0

76.9

80.8

<0.001

WBC × 109/,
median (range) (n = 695)

8.3
(3.7−18.2)

8.7
(3.7−18.2)

8.2
(3.9−18.2)

7.2
(3.8−14.7)

6.8
(4.0−16.7)

7.6
(6.4−13.3)

<0.001

WBC ≥11 × 109/L
(n = 695), %

16.4

19.6

12.8

4.2

20.0

7.7

0.01

Hb, g/dl,
median (range)

14.1
(11.5−16.5)

14.4
(11.8−16.5)

13.8
(11.8−15.9)

13.7
(11.9−16.3)

13.6
(11.9−16.1)

13.5
(11.5−16.4)

<0.001

Hematocrit, median (range)

42.9
(35.1−51.0)

43.9
(36.0−50.0)

41.6
(36.7−47.9)

41.2
(35.6−49.4)

41.3
(38.0−47.0)

40.9
(35.1−51.0)

<0.001

Platelets × 109/L,
median (range)

739
(455−2,348)

698
(455−1,881)

823
(504−2,000)

886
(495−2,348)

852
(467−1,742)

794
(460−1,700)

<0.001

Platelets ≥ 1,000 × 109/L, %

17.5

12.9

26.1

31.4

26.9

23.1

0.001

Major thrombosis before diagnosis
(n = 633), %

6.2

8.6

1.2

0.0

0.0

3.8

0.01

Overall thrombosis at follow-up
(n = 715), %

13.8

14.7

15.4

14.0

26.9

2.6

0.01

Cardiovascular risk factors
(n = 618), %

52.9

59.5

44.7

34.1

48.0

39.7

<0.001

Microcirculatory symptoms
(n = 709), %

33.1

32.0

28.1

36.0

61.5

34.6

0.03

MF progression, %

7.4

4.9

21.7

7.9

19.2

1.3

<0.001

Death, %

14.8

16.3

16.3

5.9

23.1

6.4

0.04

CALR, calreticulin; Hb, hemoglobin; JAK2, Janus kinase 2; MPL, myeloproliferative leukemia; MF, myelofibrosis; TN, triple negative; WBC, white blood cell.
*Adapted from Loscocco et al.1
Evaluable patients.
Statistically significant values.

Independent risk factors in experimental Florence cohort

  • Age > 60 years, male sex, palpable splenomegaly, constitutional symptoms, CALR 1/1-like or MPL mutation and JAK2V617F variant allele frequency (VAF) were all identified as independent risk factors for fibrotic transformation in the experimental Florence cohort (Table 2).
  • JAK2V617F VAF was identified as a continuous variable correlated with MF progression (hazard ratio [HR] 1.0, 95% CI, 1−1.1; p = 0.002).
  • JAK2V617F-mutated patients with VAF >35% showed a significantly higher risk for MF progression (HR 5.9, 95% CI, 2.4−14.4; <0.001) vs VAF ≤35% in univariate analysis and remained significant (HR 4.3, 95% CI, 1.7−11.0; p = 0.003) in multivariate analysis.
  • JAK2V617F-mutated patients with VAF >35% were older (p = 0.02) more likely to be male (p = 0.008), displaying higher hemoglobin (p = 0.02), platelet counts (p = 0.03), palpable splenomegaly (p <0.001) and constitutional symptoms (p = 0.009).
  • Reduced overall survival (HR 1.5, 95% CI, 0.9−2.4; p = 0.08) without differences in thrombosis risk (HR 0.9, 95% CI, 0.5−1.6; p = 0.9) and leukemic progression (HR 2.0, 95% CI, 0.5−7.7; p = 0.3) was also observed in JAK2V617F-mutated patients with VAF >35%.

Table 2. Multivariate analysis of clinical and molecular risk factors for MFS*

Variables

Multivariable analysis
p value (HR; 95% CI)

Multivariable analysis
p value (HR; 95% CI)

Multivariable analysis§
p value (HR; 95% CI)

Age > 60 years

0.005
(2.5; 1.3−4.9)

0.02
(3.8; 1.3−11.4)

0.05
(1.9; 0.9−3.5)

Sex, male

0.02
(2.1; 1.2−3.9)

0.3
(1.7; 0.7−4.2)

0.01
(2; 1.2−3.5)

Constitutional symptoms

0.06
(2.1; 0.9−4.7)

0.3
(2.6; 0.5−12.1)

0.04
(2.2; 1−4.8)

Palpable splenomegaly

0.01
(2.1; 1.2−3.9)

0.003
(4.3; 1.7−11.0)

0.02
(2.1; 1.1−3.8)

CALR 1/1-like/MPL

< 0.001
(3.4; 1.9−6.1)

JAK2V617F VAF >35% vs ≤35%

0.003
(4.2; 1.6−10.8)

CALR 1/1-like + MPL + JAK2V617F > 35% vs all the others

< 0.0001
(5.2; 2.7−10.0)

CALR, Calreticulin; JAK2, Janus kinase 2; MPL, myeloproliferative leukemia; VAF, variant allele frequency.
*Adapted from Loscocco et al.1
All ET cohort (n = 718) with CALR type 1/1-like/MPL as molecular risk variable.
Only JAK2 patients (n = 471) with VAF >35% as molecular risk variable.
§All ET cohort (n = 718) with CALR type 1/1-like/MPL/ JAK2 VAF >35% as molecular risk variable.

  • In the validation Mayo Clinic cohort, JAK2V617F VAF >35% (HR 4.0, 95% CI, 1.9−8.2; p = < 0.01) and presence of CALR type 1/1-like and MPL mutations (HR 2.2, 95% CI, 1.3−3.8; p = 0.003) were independent factors in predicting MF progression.
  • In the validation Rome cohort, JAK2V617F VAF >35% (HR 2.9, 95% CI, 1.2−7.0; p = 0.01) was independently associated with predicting transformation to MF.

Molecular model for risk of MF progression in ET

  • The two-tiered, driver mutation-based model identifying high (JAK2V617F VAF >35%, CALR type 1/1-like and MPL) and low (JAK2V617F VAF ≤35%, CALR type 2/2-like and TN) molecular risk was developed for the experimental Florence cohort and validated using the validation cohorts.
  • The risk rates of fibrotic transformation were 8% vs 1.2% at 10 years and 33% vs 8% at 20 years (HR 6.1, 95% CI 3.2−11.7; p < 0.001), respectively, for the high-risk and low-risk category in the experimental Florence cohort.
  • The risk rates of fibrotic transformation in the validation cohorts:
  • Mayo Clinic Cohort: 16% vs 7% at 10 years and 44% vs 25% at 20 years (HR 2.5, 95% CI, 1.6−4.1; p < 0.001)
  • Rome cohort: 7.8% vs 4.6% at 10 years and 31.2% vs 7.1% at 20 years (HR 2.7, 95% CI, 1.3−5.8; p = 0.007)

Conclusion

The study showed useful risk signals for fibrotic transformation in patients with ET and enhanced the identification of patients who require close monitoring and appropriate counselling. However, the findings from the study should be interpreted with caution due to the certain caveats such as retrospective study leading to selection bias.

  1. Loscocco GG, Guglielmelli P, Gangat N, et al. Clinical and molecular predictors of fibrotic progression in essential thrombocythemia: A multicenter study involving 1607 patients. Am J Hematol. 2021. DOI: 1002/ajh.26332

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