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Real-world study identifying unmet needs in adolescents and young adults with MPN

Sep 6, 2022
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Learning objective: After reading this article, learners will be able to recall real-world data from children and young adults with myeloproliferative neoplasms.

Treatments for myeloproliferative neoplasms (MPN) are currently adapted to risk classification based on age and history of thrombosis.1 Most data around current therapeutics are gained from patients aged >60; the rarity of MPN in patients aged <25 years means there is a lack of knowledge around disease management, vascular complications, and disease transformation in this age group.1

To address this unmet need, Sobas, et al.1 performed a retrospective study in collaboration with members of the European Hematology Association Scientific Working Group (EHA-SWG) on MPN, with the aim of understanding the risks in contemporary young patients with MPN. We are pleased to provide a summary of their findings here.

Study design

Sequential patients diagnosed with MPN before the age of 25 years were included; suspected or confirmed hereditary cases were excluded. Treatment type and rationale, venesection, antithrombotic, and the use of cytoreductive drugs were assessed. Outcomes including hemorrhage-free survival, overall survival, and thrombosis-free survival were analyzed using established international prognostic scores.

Results

A total of 444 patients from 15 countries were included, with the majority diagnosed between 1990 and 2019 (Table 1). The median follow-up was 9.7 years. A total of 149 patients were asymptomatic. The most common MPN in this age group was essential thrombocythemia (ET).

Table 1. Patient characteristics at diagnosis*

Characteristic, % (unless otherwise stated)

Overall
(n = 444)

ET
(n = 318)

PV
(n = 81)

“Other” MPN
(n = 45)

Female

72.3

78

48.1

75.6

Median age (range), years

20.4
(2–25)

20.6
(2–25)

19.7
(2.3–25)

20.1
(5.3–24.4)

Symptoms

              Plethoric face

3.9

0.7

21.3

0

              Aquagenic pruritus

5.6

3.2

19.7

0

              Hyperviscosity

34.5

34.2

42.2

23.7

              Microvascular

10.8

11.6

5.8

14

              Constitutional

6.2

3.9

9.2

16.7

              Palpable splenomegaly

20.3

13.6

39.1

37.2

              Fatigue

19.8

16.5

34.5

20.9

              Cardiovascular risk
              factors

12.9

12.2

15.4

13.6

Blood parameters, median (range)

              Leucocytes (× 109/L)

9
(2.8–28.1)

8.9
(3–28.1)

9.8
(2.8–25)

10.3
(3–20.9)

              Hemoglobin (g/L)

140
(65–246)

139
(99–171)

174.5
(134–246)

132
(65–168)

              Platelets (× 109/L)

863
(99–3,290)

915
(182–3,290)

601
(160–1,170)

775
(99–2,036)

Mutations

              JAK2V617F

56

48.5

86.4

55.6

              JAK2 ex12

1.13

0

6.2

0

              JAK2 allele burden,
              median (range)

22
(1.75–86)

15.5
(1.75–86)

29
(3.7–77)

31.8
(11.8–49)

              CALR

13.3

14.5

0

28.9

              MPL

0.7

0.9

0

0

              Triple-negative

20

27

0

6.7

              Incomplete or unknown

8.8

9.1

7.4

0

ET, essential thrombocythemia; MF, myelofibrosis; MPN, myeloproliferative neoplasms; PV, polycythemia vera.
*Adapted from Sobas, et al.1
The 45 patients with “other” MPN comprised patients with primary MF (5%), pre-MF (2%), and “other” MPN (3%).

Mutation status

The driver mutation status was available for 405 patients and showed that JAK2V617F was the predominant mutation in all MPN subtypes (Figure 1). Triple-negative (i.e., the absence of driver mutations in JAK2, CALR, and MPL) disease was more common in children, whereas mutated JAK2 was more common in adolescents/young adults (diagnosed before the age of 25 years). The median mutant allele burden was 22% for the whole cohort.

Notably, logistic regression analysis revealed that JAK2V617F mutation and hyperviscosity symptoms were risk factors for thrombosis risk.

Figure 1. Mutational landscape for each MPN subtype* .

ET, essential thrombocythemia; MPN, myeloproliferative neoplasms; PV, polycythemia vera.
*Adapted from Sobas, et al.1

Treatment

During follow-up, 301 patients received ≥1 cytoreductive treatment, 333 patients received antiplatelet and anticoagulant therapy, and 47 did not receive any treatment. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) was performed in seven patients. The distribution of therapies across disease subgroups is shown in Figure 2.

Figure 2. Distribution of treatments across disease subtypes*

ET, essential thrombocythemia; MPN, myeloproliferative neoplasms; PV, polycythemia vera.
*Data from Sobas, et al.1

Thrombosis

A total of 49 patients had a history of thrombosis. Of these, 27 were patients with ET, 17 with polycythemia vera (PV), and five with “other” MPN. The 5-year incidence rate was 5.67% across the cohort, with a median time from diagnosis to first thrombotic event of 5 years. In comparison, the median time from first to second event was 4.4 years. One-third of patients experienced recurrent events, with venous events being more frequent than arterial. Perihepatic vein thrombosis was the most common, accounting for 47.6% of all venous events. Moreover, across the cohort, the presence of JAK2 mutation, along with hyperviscosity and thrombosis history, was a significant predictive factor of thrombosis-free survival.

Hemorrhage

A total of 25 patients had a prior history of hemorrhage; 19 of these patients had a diagnosis of ET. Overall, 44 patients experienced hemorrhagic events (1 event in each patient), which were more common in patients with PV and “other” MPN compared with ET (Figure 3). The overall thrombosis incidence rate was 1.04% patients/year, with a 5-year incidence rate of 4.37% across the whole cohort. The median time from diagnosis to first event was 4.7 years.

Univariate analysis identified several factors associated with a significant increase in risk of bleeding, including:

  • Hyperviscosity (odds ratio [OR], 2.17; 1.07–4.37; p = 0.039)
  • Splenomegaly (OR, 3.05; 1.50–6.20; p = 0.004)
  • History of bleeding (OR, 11.05; 4.66–26.20; p = 0.000)
  • Platelet count >1,500 g/L (OR, 2.61; 1.14–5.98; p = 0.031)

    Figure 3. Frequency of new hemorrhage events by MPN subtype* 

    ET, essential thrombocythemia; MPN, myeloproliferative neoplasms; PV, polycythemia vera.
    *Data from Sobas, et al.1

    Phenotypic evolution

    There were 48 phenotypic evolutions (10.9%) across the cohort, with 10% occurring in patients with ET and PV, and 15.6% in patients with “other” MPN. The global incidence rate was 1.13% patients/year. The most common transformation was evolution to secondary myelofibrosis, which had a 5-year incidence of 2.49% across the cohort. Transformation to PV occurred in 12 patients, all of whom harbored the JAK2V617F mutation. Palpable splenomegaly was noted to be the only significant risk factor for evolution.

    Mortality

    Eight deaths occurred throughout the study, with three of these occurring after allo-HSCT. Some causes of death included bleeding, leukemia, and solid cancer.

    Conclusion

    Sobas, et al. performed the largest real-world analysis of young patients with MPN to date, which highlighted a high disease burden, including high rates of thrombotic events and transformations. Limitations include the retrospective format and an underrepresentation of the total number of cases per country due to the EHA-SWG patient centers not being the exclusive care centers for MPN. There were also challenges in detecting splenomegaly and confirming mutational status. Despite this, the authors concluded that this is a reliable representation of MPN in young patients due to the rarity of young adults or adolescents presenting with MPN; however, further analysis should be performed in order to better manage risks and identify further unmet needs.

  1. Sobas M, Kiladjian JJ, Beauverd Y, et al. Real-world study of children and young adults with myeloproliferative neoplasms identifying risks and unmet needs. Blood Adv. 2022. Online ahead of print. DOI: 1182/bloodadvances.2022007201