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Interferon therapy in the management of myeloproliferative neoplasms

Jan 28, 2021
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Treatment with interferon (IFN) therapy is considered successful for patients with myeloproliferative neoplasms (MPN), such as polycythemia vera (PV) and essential thrombocythemia (ET), since it has shown to deliver disease-modifying changes with durable responses and reversal of bone marrow fibrosis. However, only few data are available on IFN’s ability to prevent progression to myelofibrosis (MF) and improve overall survival (OS) compared with other treatment options in patients with PV. Also, as chronic treatment with IFN can itself cause treatment-related morbidity for many patients, this needs to be weighed when assessing long-term outcomes. Strategies to shorten exposure to IFN need to be explored to improve quality of life for patients.

The results of two clinical trials exploring the use of IFN in the treatment of MPN, were presented during the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, and here, we summarize their findings. Ghaith Abu-Zeinah and colleagues1 presented their research on OS benefit and risk of progression to MF, comparing IFN with hydroxyurea (HU) and phlebotomy (PHL) in patients with PV, while Rafael De Oliveira and colleagues,2 analysed factors that would allow discontinuation of IFN therapy without impacting on outcomes of patients with MPN.

Long-term outcomes of IFN treatment in patients with PV compares favourably with other options1

Study design

Single-center, retrospective cohort study performed at Weill Cornell Medicine, New York, US, and based on a MPN research data repository spanning from 1966 to 2019. A total of 470 patients were identified who had received the following treatments for at least 1 year: IFN (n = 93), HU (n = 189), or PHL (n = 133). Outcome measures were myelofibrosis-free survival (MFS) and OS at 20 years.

Patient characteristics

Overall patient demographics were matched between treatment groups in terms of sex (49% females) and history of thrombosis (14%). It should be noted that patients treated with IFN where significantly younger (50 versus 54 years; p < 0.001) and were less frequently ELN high-risk (24% vs 44%; p < 0.001), compared with the overall patient population. Also, less patients treated with PHL had cardiovascular risk factors (10% vs 21%; p = 0.002).   

Results

  • The intention-to-treat (ITT) analysis showed that OS at 20 years was significantly better for IFN compared with HU or PHL, while MFS showed only a trend in improvement with IFN (see Table 1)
  • When looking at the ELN low-risk patients only, MFS at 20 years was significantly better for IFN, while there was no significant difference in OS between treatments 

Table 1. ITT analysis: Outcomes at 20 years1

ELN, European LeukemiaNet; HU, hydroxyurea; IFN, interferon; ITT, intention-to-treat; MFS, myelofibrosis-free survival; OS, overall survival; PHL, phlebotomy.

Outcome

Treatment

p value

IFN

HU

PHL

ELN high-risk, %

MFS

OS

 

89

66

 

41

40

 

36

14

 

p = 0.19

p = 0.016

ELN low-risk patients, %

MFS

OS

 

84

100

 

65

85

 

55

80

 

p = 0.0011

p = 0.44

  • Time on treatment analysis demonstrated that every year on IFN reduced the risk of progression to MF by 9% (HR 0.91 [95% CI, 0.87–0.95]; p < 0.001), and was associated with a mortality risk reduction by 6% per year (HR 0.94 [95% CI, 0.90–0.99]; p < 0.012). Discontinuation rates were similar between IFN (2.2/100 patient-years) and HU (2.8/100 patient-years)
  • Furthermore, IFN was also shown to reduce the risk of MF compared with HU and PHL (Table 2)

 In a multivariate analysis the following factors impacted positively on survival:

  • Age (HR 1.1 [95% CI, 1.07–1.12]; p < 0.001)
  • Female sex (HR 0.54 [95% CI, 0.36–0.83]; p = 0.005)
  • Time on IFN (HR 0.94 [95% CI, 0.90–0.99]; p < 0.012) 

Table 2. Percentage of patients with Grade 2–3 bone marrow fibrosis1

IFN, interferon; HU, hydroxyurea; PHL, phlebotomy.

Time from diagnosis

% patients with Grade 2–3 bone marrow fibrosis

p value

IFN

HU

PHL

0–2 years

4

15

0

 

2–8 years

24

35

36

 

8–14 years

16

49

62

p < 0.01

> 14 years

38

55

74

p < 0.01

Summary

For patients with PV, IFN presents a superior treatment option in terms of long-term outcomes, both for patients with ELN low-risk (when compared with PHL) and for patients with ELN high-risk (when compared with HU), which should, according to the authors, be reflected in current treatment guidelines.

Discontinuation of IFN therapy is feasible in patients with MPN: Identification of risk factors for relapse2

Study design

  • Unicentric, retrospective study conducted at Hôpital Saint-Louis, Paris, FR, investigating 469 patients diagnosed with MPN who had received IFN for a minimum of 3 months (patient characteristics are depicted in Table 3)
  • Outcome measures were OS, event-free survival (EFS), cumulative incidence of relapse (CIR), and complete hematologic remission (CHR)

 Table 3. Patient characteristics2

ET, essential thrombocythemia; MPN, myeloproliferative neoplasm; PMF, primary myelofibrosis; PV, polycythemia vera.

Characteristic

n = 381

Median age, years (interquartile range)

44 (33–54)

Female patients, %

44

MPN subtypes, %

PV

ET

PMF

MPN unclassified

 

47

45

7

1

Genetic mutations, %

JAK2 V617F

CALR

MPL

Triple negative

 

74

 17

 3

6

Results

  • Of 469 patients treated with IFN, 293 discontinued IFN treatment for at least 3 months (reasons for discontinuation were achievement of CHR [n = 96], toxicity [n = 138], disease progression [n = 28], and other reasons [n = 31]). Of these 293 patients, 205 achieved a CHR, whereas 176 patients continued IFN treatment, with 148 achieving CHR
  • The following factors were investigated for their association with persistent CHR: age, sex, MPN subtype, driver mutations, cytoreductive treatment before IFN, number of treatment lines, and reasons for IFN discontinuation
  • Factors associated with persistent CHR after IFN discontinuation in univariate analysis were: diagnosis of PV, duration of CHR before IFN discontinuation, and driver mutation variant allele frequency (VAF)
  • In a multivariate analysis, two of these factors were confirmed as independently associated with long-term CHR after IFN discontinuation (see Table 4) 

Table 4. Factors independently associated with persistent CHR2

CHR, complete hematologic remission; CR, complete remission; IFN, interferon; VAF, variant allele frequency.

Variables

Univariate analysis

Multivariate analysis

OR (95% CI)

p value

OR (95% CI)

p value

Duration of CR/CHR before IFN discontinuation ≥ 24 months

2.969 (1.390–6.341)

0.005

14.612 (1.765–120.944)

0.013

VAF ≥ 10% at time of IFN discontinuation

0.087 (0.024–0.311)

< 0.001

0.128 (0.025–0.638)

0.012

  • In addition, discontinuation of IFN before 24 months and a VAF ≥ 10% were significantly associated with higher cumulative incidence of relapse, after IFN discontinuation
  • Furthermore, OS and EFS (both, in terms of thrombotic events and transformation) were not different between patients discontinuing IFN and those who did not
  • In patients who discontinued, 29% did not receive any other treatment, 35% were treated with other therapies, and 36% received IFN again; 80% of patients who were retreated with IFN achieved CHR, indicating that there was no development of IFN resistance 

Summary

The discontinuation of IFN is safe and feasible in MPN patients who achieved CHR, and who have a driver VAF lower than 10% at the time of IFN discontinuation. These patients show long-term CHR and no difference in OS and EFS compared with patients who continued treatment.

Conclusion

These studies demonstrate IFN is an effective treatment for MPN, able to achieve meaningful clinical benefits and able to improve outcomes, also in low-risk disease. However, in patients who achieve prolonged CHR on IFN treatment, and without a VAF ≥ 10%, IFN can be safely discontinued to reduce the impact on patients’ lives.

  1. Abu-Zeinah G, Krichevsky S, Cruz T, et al. Interferon in polycythemia vera (PV) yields improved myelofibrosis-free and overall survival. Oral Abstract #480. 62nd ASH Annual Meeting and Exposition; Dec 6, 2020; Virtual.
  2. De Oliveira RD, Soret-Dulphy J, Zhao L-P, et al. Interferon-alpha (IFN) therapy discontinuation is feasible in myeloproliferative neoplasm (MPN) patients with complete hematological remission. Oral Abstract #483. 62nd ASH Annual Meeting and Exposition; Dec 6, 2020; Virtual.

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