Interferon
BACKGROUND ON MPNs:
Healthy hematopoietic stem cells are essential for maintaining a robust immune system and overall well-being. These stem cells give rise to various blood cells, including red blood cells, white blood cells, and platelets, which contribute to efficient oxygen transport, protection against infections and malignancies, and proper blood clotting and tissue repair (2020).
In myeloproliferative neoplasms (MPNs), JAK2-pathway overactivation results in the proliferation of an abnormal clone that dominates the bone marrow, outcompeting healthy hematopoietic stem cells.
The hyperactivation of JAK2 and excessive production of inflammatory cytokines by MPN cells contribute to chronic inflammation (2021).
As the cancerous mass increases, the likelihood of acquiring additional mutations also rises, further promoting the disease's progression and exacerbating the decline in healthy stem cell function (2010).
MPNs can be recognized as a disease of accelerated aging through the loss of stem cell function (2013) and chronic inflammation that causes damage to tissues, promote cellular senescence, and impair the function of other organ systems (2022).
HOW TO DEAL WITH MPNs?
These strategies emerge from our understanding of basic biology of MPNs:
Minimize the tumor mass to minimize the chances of progression and the chronic inflammation that comes with a large tumor mass.
Maintain a healthy stem cell function for as long as possible to minimize the effects of accelerated aging.
Interferon-alpha (INF-alpha) is an immunomodulatory and antiviral drug with both anti-tumor and anti-inflammatory properties (2013):
Enhances the immune response: INF-alpha activates the immune system and boosts the body's natural defenses, enabling it to better recognize and eliminate cancer cells or viral infections.
Inhibits viral replication: INF-alpha has antiviral properties, effectively reducing viral replication in infected cells, and helping to control and clear viral infections.
Modulates cell growth and differentiation: INF-alpha can influence the growth and differentiation of various cell types, including MPN cells, potentially inhibiting their proliferation and promoting apoptosis (programmed cell death).
Interferon-alpha is effective in patients with Polycythemia Vera (PV) and other MPNs with deep and durable responses (2011, 2015, 2010):
INF-alpha maintains a healthy stem cell function as long as possible by minimizing the MPN cancer clone in hematopoietic niche.
By normalizing elevated leukocyte and platelet counts, INF-alpha helps minimize the sustained release of inflammatory cytokines and chemokines and concurrently improves immune cell function which is important for intact tumor immune surveillance (2021).
Hydroxyurea is typically used as first-line cytoreduction in MPN patients. Although no difference has been found in secondary cancer rates between interferon and hydroxyurea [66], there are still concerns for hydroxyurea’s long-term effects [44, 67, 68]. Interferon’s potential for durable responses and disease modification makes it a more appealing choice for younger patients given that treatment can last for decades (2020).
INTERFERON-ALPHA for PV:
The 5-year CONT-PV study showed the effectiveness of ropeginterferon alfa-2b in reducing symptoms in patients with high-risk polycythemia vera (PV), showing that only 15.7% of patients reported symptoms by the sixth year compared to 20.7% in the control group, and only 18.6% required phlebotomy compared to 40% in the control group; it also demonstrated significantly lower disease progression or thromboembolic events (5.3% versus 16.2%) and a higher reduction in JAK2V617F allele burden (20.7% achieved less than 1% compared to 1.4% in the control group), suggesting improved quality of life and potential to reduce myelofibrosis risk.
Interferon-alfa treatment significantly improved myelofibrosis-free survival (27 years) and overall survival (28 years) compared to hydroxyurea (18 and 26 years) and phlebotomy-only (14 and 25 years) in patients with polycythemia vera, supporting its earlier use in treatment plans, even for younger, low-risk patients, according to a retrospective study presented in 2019.
A 2021 Weill Cornell retrospective study of 470 polycythemia vera (PV) patients found that treatment with Interferon-alpha (rIFNα) improved myelofibrosis-free survival (MFS) and overall survival (OS) rates in both low and high-risk patients compared to hydroxyurea (HU) and phlebotomy-only (PHL-O).
Normal life expectancy for polycythemia vera (PV) patients is possible with interferon-alpha treatment (2021); the study found a 65% lower mortality rate in the Weill Cornell Medicine (WCM) cohort compared to a national-database population, and PV-WCM patients treated with rIFNα had similar overall survival to the matched healthy US population.
A 2017 prospective clinical trial involving 58 patients with ET and PV found that long-term therapy with peg-interferon α-2a could normalize bone marrow morphology and reverse bone marrow fibrosis after a median of 7 yrs of therapy. 50% of patients experienced a bone marrow response with 22% achieving Complete Bone Marrow Response (BM-CR) and 28% achieving partial bone marrow response (BM-PR). BM response took on average 4 yrs with BM improvement continuing all the way to 6 yrs of therapy in some patients.
A 2020 study analyzed the kinetics of JAK2V617F allele burden in 66 interferon-alpha2 (IFN) treated patients and 6 untreated patients with essential thrombocythemia and polycythemia vera, finding that without IFN treatment, the JAK2V617F allele burden doubled every 1.4 years, while IFN treatment reduced the burden with half-lives of 1.6 years indicating the importance of early intervention.
Pegylated interferon has improved tolerability compared to standard interferon but still has a significant side effect profile, with discontinuation rates of 15-20% in clinical trials.
Combination therapy of interferon with JAK2 inhibitors, such as ruxolitinib, may improve tolerability and enhance interferon signaling, with Phase II COMBI and RUXOPEG trials showing rapid decreases in spleen size, JAK2 V617F allele burden, and improvement in hematologic parameters.
Interferon-alpha for treating polycythemia vera yields improved myelofibrosis-free and overall survival, 2021
Interferon-alpha (rIFNα) is the only disease-modifying treatment for polycythemia vera (PV), but whether or not it prolongs survival is unknown. This large single center retrospective study of 470 PV patients compares the myelofibrosis-free survival (MFS) and overall survival (OS) with rIFNα to two other primary treatments, hydroxyurea (HU) and phlebotomy-only (PHL-O). The median age at diagnosis was 54 years (range 20–94) and the median follow-up was 10 years (range 0–45). Two hundred and twenty-nine patients were women (49%) and 208 were high-risk (44%). The primary treatment was rIFNα in 93 (20%), HU in 189 (40%), PHL-O in 133 (28%) and other cytoreductive drugs in 55 (12%). The treatment groups differed by ELN risk score (p < 0.001). In low-risk patients, 20-year MFS for rIFNα, HU, and PHL-O was 84%, 65% and 55% respectively (p < 0.001) and 20-year OS was 100%, 85% and 80% respectively (p = 0.44). In high-risk patients, 20-year MFS for rIFNα, HU, and PHL-O was 89%, 41% and 36% respectively (p = 0.19) and 20-year OS was 66%, 40%, 14% respectively (p = 0.016). In multivariable analysis, longer time on rIFNα was associated with a lower risk of myelofibrosis (HR: 0.91, p < 0.001) and lower mortality (HR: 0.94, p = 0.012). In conclusion, this study supports treatment of PV with rIFNα to prevent myelofibrosis and potentially prolong survival.
5-year results from the PROUD-PV and CONTINUATION-PV studies (link)
This analysis included all patients enrolled in the CONTINUATION-PV (NCT02218047) study:
89.6% of patients (n = 95) treated with ropeginterferon alfa-2b in the PROUD-PV study entered in the CONTINUATION-PV extension study, and 73.7% of these patients (n = 70) continued their treatment until Month 60
Similarly, 68.5% of patients (n = 76) treated with hydroxyurea in the PROUD-PV study enrolled in the CONTINUATION-PV extension study to receive best available treatment, where 88% of these were treated with hydroxyurea and 75% (n = 57) were treated up to Month 60
Complete hematologic response (CHR, defined as hematocrit [HCT] < 45% and no phlebotomy for at least 3 months, platelets < 400 × 109/L, and white blood cells < 10 × 109/L) is reported in Table 3 (LOCF).
Normal life expectancy for polycythemia vera (PV) patients is possible, 2021
We obtained demographics and survival data of adult PV pts from our Weill Cornell Medicine (WCM) Research Database Repository (PV-WCM) diagnosed from 1974-2020 as previously described (Abu-Zeinah et al. Leukemia 2021); and from the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) Program, 2001-2017. PV-WCM thrombosis and MF progression data were available.
Results: We identified 470 PV-WCM and 16,492 PV pts from SEER. The median OS of the PV-WCM cohort and the SEER population was 26.6 and 12.8 years, respectively, but the groups differed by age and sex (Fig 1A). PV-WCM and matched PV-SEER, however, were well balanced by age, sex, and race (standardized mean difference <0.1). The median OS of PV-WCM was 10.8 years longer than PV-SEER (p<0.001, Fig 1B). MVA confirmed 65% lower mortality in the PV-WCM group relative to the PV-SEER population (p<0.001, Fig 1C). PV-SEER OS was shorter than actuarial OS of the US population (mortality HR 2.47, p<0.001), whereas PV-WCM OS was not significantly different than expected (mortality HR 1.15, p=0.136). Excess late mortality was observed in PV-WCM after 17 years, potentially due to increased incidence of MF progression, affecting almost 50% of PV pts after 25 years (Fig 1D).
PV-WCM pts treated with rIFNα (n=137), previously shown to have improved MF-free survival and OS (Abu-Zeinah et al. Leukemia 2021), had an OS similar to the matched US population (p=0.33, Fig 1F); whereas pts not treated with rIFNα had modestly shortened OS (HR 1.26, p=0.03). Because PV progression is among the leading causes of late morbidity and mortality, and available therapy can mitigate this, it may be time to reconsider and improve upon PV risk stratification and treatment.
Managing Polycythemia Vera in 2021 - Dr. Richard T. Silver
https://www.youtube.com/watch?v=Qi1MSJjTxgk
Histomorphological responses after therapy with pegylated interferon α-2a in patients with essential thrombocythemia (ET) and polycythemia vera (PV), 2017
ASH 2019: Interferon-Alfa Treatment Offers Best Outcomes in Polycythemia Vera
Study findings provide evidence for earlier use, even in younger, healthier patients, 2019
Significant improvements in outcomes were seen when recombinant interferon-alfa was used for treatment of patients with polycythemia vera in a study with a follow-up period that lasted up to 45 years. The findings were presented here at the 61st American Hematology Society Annual Meeting & Exposition, which took place from December 7 to 10.
The improvements, which were independent of age, support the view that the early use of interferon-alpha should be a routine aspect of polycythemia vera treatment, “especially in younger patients, who should not be deprived of a disease-modifying therapy for being ‘low-risk’ by consensus criteria,” lead author Richard T. Silver, MD, of New York-Presbyterian Weill Cornell Medical Center in New York, told Elsevier’s PracticeUpdate. “For years, there has been argument whether patients should be treated with phlebotomy only or, if cytoreduction therapy is needed, should it be [hydroxyurea] or interferon?” said Dr. Silver. “We believe the latter, as do many others, since interferon has biologic reasons for its use in polycythemia vera. It is not a nonspecific cell poison like [hydroxyurea].”
The retrospective study focused on 306 polycythemia vera patients whose median age was 54 years (range 20–91 years), and 49% of whom were women. Most patients (82%) were white, 42% were judged high-risk, 28% had cardiovascular risk factors, and 13% had a history of thrombosis.
First-line treatment was interferon-alpha in 75 patients (25%), hydroxyurea in 134 (44%), or other cytoreductive regimens in 37 (12%). Treatment by phlebotomy only was conducted in 60 patients (20%). Alternate second-line treatment was subsequently used in 82 patients (27%). This involved a shift from hydroxyurea to other therapy in 34% or to interferon-alpha in 24%; a shift from interferon-alpha to hydroxyurea in 6% or to a therapy other than hydroxyurea in 15%; or a shift from a cytoreductive regimen to interferon-alpha in 2%, hydroxyurea in 5%, or other therapy in 13%. Treatment arms differed by age at diagnosis with a median of 50, 59 and 52 years for interferon-alpha, hydroxyurea, and phlebotomy only groups, respectively (P < .01).
The findings were presented by Ghaith Abu-Zeinah, MD, a fellow at Weill Cornell.
After a median follow-up period of 11 years (range 1–45 years), the overall median myelofibrosis-free survival (MFS) was 19.5 years. Median overall survival (OS) was 26.3. When evaluating outcomes based on treatment type, median MFS and OS were, respectively, 27 and 28 years for the interferon-alpha arm, 18 and 26 years for the hydroxyurea arm, and 14 and 25 years for the phlebotomy only arm (log-rank P < .01 for MFS and P = .01 for OS).
A multivariate analysis that included age revealed lower risks of post-polycythemia vera myelofibrosis (hazard ratio 0.43, P = .003) and death (hazard ratio 0.44 P = .004) in patients treated with interferon-alpha arm, compared with hydroxyurea. A similar pattern was seen when comparing interferon-alpha treatment with phlebotomy only, with a hazard ratio of 0.22 (P < .01) for myelofibrosis and a hazard ratio of 0.35 (P = .03) for death.
Accounting for crossover, 138 patients received interferon-alpha at any time. This treatment was associated with an 8% relative risk reduction in post-polycythemia vera myelofibrosis, with an age-adjusted hazard ratio of 0.92 (P < .01) as well as a 7% risk reduction in all-cause mortality, with an age-adjusted hazard ratio of 0.93 (P = .01).
“This is the first time that interferon has been shown to improve survival in patients with polycythemia vera, compared with phlebotomy only or [hydroxyurea], as well as significantly increasing the time to develop myelofibrosis,” said Dr. Silver “The limitations to the study are that it is a single institution and retrospective. Nevertheless, this is a new observation of significance.”
Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera (2008)
Polycythemia vera (PV) is a myeloproliferative disorder with risks of blood clots, bleeding, and progression to other blood cancers. The JAK2V617F mutation is involved in PV pathophysiology and disease monitoring. We completed a phase 2 multicenter study of pegylated interferon-alfa-2a (peg-IFN-α-2a) in 40 PV patients. Objectives included assessing efficacy, safety, and monitoring residual disease using JAK2V617F quantification (%V617F). Median follow-up was 31.4 months.
At 12 months, all 37 evaluable patients had hematologic response, including 94.6% complete responses (CRs). Only 3 patients (8%) had stopped treatment. Hematologic responses were sustained long-term; at final analysis all patients remained in response. The 29 patients treated with peg-IFN-α-2a alone were in CR, still on treatment (n=24) or off therapy (n=5) but in maintained CR.
Peg-IFN-α-2a was overall well tolerated. 33 patients (89%) had adverse events (AEs) during the first 12 months (total 239 AEs); all were grade 1-2 except one grade 3 skin toxicity. 13 patients (35%) stopped treatment during entire study, including 9 (24.3%) for AEs.
Sequential samples for %V617F monitoring were available in 29 mutated patients. Median %V617F decreased from 45% before peg-IFN-α-2a to 22.5%, 17.5%, 5%, and 3% after 12, 18, 24, and 36 months, respectively. Complete (undetectable %V617F) or partial (≥50% decrease) molecular response was achieved in 72.4% patients.
Complete molecular response was achieved in 7 patients (24.1%), lasting 6-18+ months. In 5 patients achieving complete response who stopped peg-IFN-α-2a, JAK2V617F remained undetectable for 6-18 months after drug discontinuation.
In conclusion, peg-IFN-α-2a yields high hematologic and molecular response rates in PV with acceptable toxicity. It reduces %V617F in a substantial proportion of patients and may eliminate the JAK2 mutated clone in selected cases. Comparison with standard therapy is warranted to precisely determine if peg-IFN-α-2a could change treatment paradigms in PV.
Final Results of Prospective Treatment with Pegylated Interferon Alfa-2a for Patients with Polycythemia Vera and Essential Thrombocythemia in First and Second-Line Settings (2019)
Yacoub et al. (2019) conducted a controlled analysis comparing the efficacy and safety of pegylated interferon alfa-2a (PEG) treatment in patients with polycythemia vera (PV) and essential thrombocythemia (ET) who were either treatment-naïve (TN) or refractory/intolerant (R/I) to prior hydroxyurea (HU) therapy. The study included 39 TN ET patients, 65 R/I ET patients, 43 TN PV patients, and 50 R/I PV patients from two concurrent prospective trials using the same PEG dosing regimen.
Key conclusions:
PEG was equally effective as a first-line or second-line therapy for high-risk ET, with equivalent overall response rates (ORR) of 69.2% in both the TN and R/I ET groups at 12 months.
For PV, PEG was more effective as a first-line therapy than second-line, with ORRs of 86% in TN PV versus only 60% in R/I PV patients (p=0.005).
Key points:
Baseline characteristics were well balanced between TN and R/I patients, except R/I ET patients had slightly lower hemoglobin and R/I PV patients had lower phlebotomy rates.
Complete response rates in ET were 43.1% for R/I and 43.6% TN. Partial response rates were 26.2% for R/I and 25.6% for TN ET.
In PV, complete response was 22% for R/I versus 27.9% for TN. Partial responses were 38% for R/I versus 58.1% for TN.
PEG was equally well tolerated in both groups, with similar discontinuation rates due to adverse events (13.9% R/I versus 14.6% TN).
Mean PEG doses were lower in TN patients (85.7 mcg R/I ET versus 128.7 mcg R/I PV). Distribution of adverse events was similar between groups.
In summary, this well-designed analysis of prospectively treated ET and PV patients demonstrated that PEG is an effective and safe therapeutic option for high-risk TN disease as well as for those intolerant/refractory to prior HU therapy. However, PEG was notably more effective when used as a first-line versus second-line agent for PV patients. The authors conclude that PEG should be considered for both treatment scenarios in PV and ET. Additional studies are still needed to optimize PEG therapy and further investigate predictors of response.
Update on Long-acting Interferons for MPN, 2016
Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera (2008)
Ropeginterferon effective for treating PV (link)
Data-driven analysis of JAK2V617F kinetics during interferon-alpha2 treatment of patients with polycythemia vera and related neoplasms, 2020
Treatment with PEGylated interferon-alpha2 (IFN) of patients with essential thrombocythemia and polycythemia vera induces major molecular remissions with a reduction in the JAK2V617F allele burden to undetectable levels in a subset of patients. A favorable response to IFN has been argued to depend upon the tumor burden, implying that institution of treatment with IFN should be as early as possible after the diagnosis. However, evidence for this statement is not available. We present a thorough analysis of unique serial JAK2V617F measurements in 66 IFN-treated patients and in 6 untreated patients. Without IFN treatment, the JAK2V617F allele burden increased exponentially with a period of doubling of 1.4 year. During monotherapy with IFN, the JAK2V617F allele burden decreased mono- or bi-exponentially for 33 responders of which 28 patients satisfied both descriptions. Bi-exponential description improved the fits in 19 cases being associated with late JAK2V617F responses. The decay of the JAK2V617F allele burden during IFN treatment was estimated to have half-lives of 1.6 year for the monoexponential response and 1.0 year in the long term for the bi-exponential response. In conclusion, through data-driven analysis of the JAK2V617F allele burden, we provide novel information regarding the JAK2V617F kinetics during IFN-treatment, arguing for early intervention.
Thrombotic risk
In this interferon vs Hydrea trial. Thrombosis risk was only 1.2% per year for both interferon and hydrea arms. These folks are also on Aspirin. Link
Thrombosis rate of 2-3% was reported for those diagnosed after 2005.
Patterns of presentation and thrombosis outcome in patients with polycythemia vera strictly defined by WHO-criteria and stratified by calendar period of diagnosis (Link)
ECLAP study. Aspirin arm had 2.4% major or minor thrombosis per year (2.8yrs of study, 6.7% rate of thrombosis during this period).
Efficacy and Safety of Low-Dose Aspirin in Polycythemia Vera (Link)
Histomorphological responses after therapy with pegylated interferon α-2a in patients with essential thrombocythemia (ET) and polycythemia vera (PV) (2017)
We report on histomorphological BM responses in 58 patients with ET/PV treated with PEG-IFN-α-2a in a prospective, single-center, phase 2 clinical trial after a therapy for a median of 84 months (7 yrs).
Our current research substantiates existing data showing that long-term therapy with PEG-IFN-α-2a is not only able to induce CHR and CMR, but could also lead to complete normalization of BM morphology in a subset of patients. Moreover, PEG-IFN-α-2a was capable to completely reverse BM fibrosis in up to 22% of patients, which is higher than previously observed by other investigators [23, 26]. BM responses were achieved after median time on therapy of 48 months, confirming the observation that a long treatment duration is necessary to achieve such a response.
Our study also reports a few novel observations. In contrast to previously published results [21], we have noticed significant reduction in BM cellularity in patients with PV who achieved CMR. Patients with BM-CR seemed to derive the most benefits from the therapy with longest duration of initial responses (CHR and CMR), higher rates of CMR, and the fewest disease-related complications. Importantly, none of the patients who had achieved BM-CR progressed to overt MF, and majority of patients who had lost their initial BM-CR have maintained their hematologic and molecular responses. BM-CR was durable, as 69% of them were sustained at the time of last follow-up. Furthermore, 5 of 6 (83%) patients who continued to have BM evaluations after treatment discontinuation, have maintained their BM-CR after a median duration off therapy of 48 months. However, 2 of them have lost their best MR at the time of last follow-up, and one patients has lost his hematologic response.
Study population:
58 MPN patients (27 PV, 31 ET)
Median age of 52 yrs old
72% are JAK2 positive
median allele burden of 34%
Median WBC of 9
Median platelets of 721
62% previously treated with other drugs, 75% of them with hydroxyurea
60% had reticulin fibrosis of grade MF-1 or MF-2
Treatment:
Pegylated interferon α-2a
90mcg weekly or higher as the initial dose.
The dose was modified throughout the study based on toxicity or lack of efficacy.
Hematologic response
Initial HR was achieved in 54 (93%) patients, and it was sustained in 33% of them (n = 18) throughout the entire follow-up on a study with a median response duration of 92 months (range 58–101 +). The remaining 36 patients lost their HR after a median duration of 55 months (range 10.4–91). Sixteen patients who lost their HR, are still on study, 14 of them actively treated, as they continue to derive clinical benefit (no clinical symptoms and organomegaly) with good tolerance.
Molecular response
MR rate was 72% (n = 32) among 44 patients who were JAK2V617F-positive.
9 (20%) experienced Complete MR [undetectable JAK2V617F allele burden].
19 (43%) experienced Partial MR [ 50% reduction in JAK2V617F allele burden].
4 (9%) experienced Minor MR [mMR; 20–49% reduction in JAK2V617F allele burden].
Pre-treatment allele burden did not differ among patients with CMR, PMR and mMR.
The response duration was similar in patients with CMR (68 months; range 21–94), PMR (53 months; range 7–79) and mMR (50 months; range 12–60).
Bone marrow response
29 patients (50%) had BM response
13 patients (22%) with BM-CR (Table 3, Fig. 1)
16 patients (28%) with BM-PR [12]
Furthermore, 13 patients (22%) had complete resolution of bone marrow reticulin fibrosis (MF-0), including 3 patients with initial grade 2.
Table 3 (BM-Complete Response)
Vascular complications
Overall, 6 (10%) patients experienced unprovoked vascular complications (5 thrombotic and one bleeding event): one while having BM-CR, 2 BM-PR, and 3 BM-NR. The incidence rate of major unprovoked thromboembolic event in enrolled patients during the entire study follow-up was 1.37 per 100 person years.
Disease progression
Progression to overt MF and AML occurred in 5 patients (9%; 4 MF and 1 AML), and none of these patients had a BM response.
Patients after therapy discontinuation
Among patients with a BM response who discontinued therapy, 6 continued to have BM biopsies performed, with a median of 4 samples per patient (range 3–6). Four stopped therapy while in BM-CR and 2 while in BM-PR.
Two patients (#1 and #11, Figs. 4, 5), who had achieved a BM-PR at the time of treatment discontinuation, continued to show improvements in their BM despite being off therapy. Remarkably, both achieved a BM-CR after being off therapy for 32 and 36 months, and maintained their BM-CR for 30 and 24 months, still off therapy, respectively. One of these patients (#1, Fig. 5) has lost his CHR and best MR while still remaining in BM-CR; the other one continues to be in CHR (MR not evaluable for JAK2 negativity). Among those 4 patients who stopped therapy at the time of BM-CR (#9, #10, #12, and #13, Fig. 4), 3 remain in sustained BM-CR. One of them has lost his best MR (#10, Fig. 4), one remains in CMR (#9, Fig. 4) and one is JAK2 negative (#12, Fig. 4). All three patients maintain their initial CHR. Only one patient has lost his BM-CR after being off therapy for 24 months, he has also lost his CHR and best MR (#13, Fig. 6).
At present, therefore, 5 of 6 evaluable patients are in BM-CR after stopping therapy, and are maintaining their BM-CR for a median time of follow-up after therapy discontinuation of 48 months (range 32–68).
Real World Data on Safety and Efficacy of Pegylated Interferon (PEG-IFN) in Patients with Myeloproliferative Neoplasms (MPN) (2023)
The abstract by Garg et al (2023) presents real world data on the safety and efficacy of pegylated interferon (PEG-IFN) for treating myeloproliferative neoplasms (MPNs) from a single center in the UK. The study included 212 patients with MPNs (93 with polycythemia vera, 98 with essential thrombocythemia, 21 with myelofibrosis) treated with PEG-IFN from January 2014 to July 2022. Median follow up was 60 months (range 12-114).
Results:
Complete hematological response per ELN criteria was achieved in 141 patients (66%) at a median of 6 months. Partial response seen in 52 patients (24%).
Molecular response assessed in 153 JAK2 mutated patients. Complete molecular response achieved in 4 patients (2.6%) at median 58 months.
Deeper and more sustained responses seen with earlier PEG-IFN use and in younger patients as first line vs second/subsequent line (74% vs 63% response rate).
PEG-IFN discontinued in 36 patients - 7 for ineffectiveness, 18 for intolerance, 10 unrelated causes, 3 for disease progression.
Thrombotic events on PEG-IFN occurred in 14 patients - 11 arterial, 3 venous events. Mostly in JAK2+ MPN patients (12/14) and those with polycythemia vera (10/14).
Adverse events: hypothyroidism (3.7%), hepatitis grade 1-2 (21.6%), hepatitis grade 3 (1.8%), alopecia, rash, psoriasis exacerbation. Managed by dose reduction.
5 patients developed second malignancies on PEG-IFN.
PEG-IFN effective at reducing elevated counts and modifying disease course - seen in sustained responses, JAK2 allele burden reduction, and reduced thrombosis risk.
Conclusions:
PEG-IFN is a safe and effective cytoreductive agent for all MPN subtypes. Provides an alternative to hydroxyurea.
Second line option in older patients and first line in younger patients.
Corrects elevated counts and reduces thrombosis risk.
Modifies disease course as shown by sustained responses and JAK2 allele burden reduction.
Well tolerated - adverse events generally manageable.
Least restrictive on quality of life compared to other agents.
In summary, this real world data study by Garg et al (2023) demonstrates PEG-IFN is an efficacious and safe treatment option for MPNs, with cytoreductive and disease modifying effects, more sustained responses with earlier use, manageable adverse event profile, and minimal quality of life impact. PEG-IFN provides an alternative to hydroxyurea as first or second line therapy in MPN patients.
Final Analysis of the Daliah Trial: A Randomized Phase III Trial of Interferon-alpha Versus Hydroxyurea in Patients with MPN (2023)
The Daliah phase III randomized trial by Knudsen et al (2023) compared the efficacy and safety of hydroxyurea (HU) versus pegylated interferon-alpha (IFNα) for treatment of myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET), polycythemia vera (PV), prefibrotic myelofibrosis (PreMF) and primary myelofibrosis (PMF), over 5 years of follow-up.
A total of 203 patients were included in the modified intention-to-treat (ITT) analysis (ET: 73, PV: 89, PreMF: 16, PMF: 25). Patients were randomized 1:1:1 to HU, IFNα-2a or IFNα-2b if age >60, or to IFNα-2a or IFNα-2b if age ≤60. Median age was 68 years for HU and 59 years for IFNα (p<0.0001).
The primary outcome was JAK2V617F molecular response (MR) rate per 2009 ELN (ET/PV/PreMF) or 2005 EUMNET (PMF) criteria at 18, 36 and 60 months. By ITT analysis, the MR rate was similar between HU and IFNα groups at all timepoints (18 months: 19% vs 21%, p=1.00; 36 months: 19% vs 26%, p=0.64; 60 months: 23% vs 24%, p=1.00).
However, the median JAK2V617F allele burden was significantly lower with IFNα versus HU at 36 months and beyond. The median change in allele burden from baseline to 60 months was greater with IFNα (-20%) compared to HU (-7%), p=0.0053. Two IFNα patients achieved complete molecular remission at 60 months.
The complete clinicohematologic response (CHR) rate by ITT analysis was higher with HU at 18 months (58% vs 38%, p=0.03) but similar thereafter.
In subgroup analysis of HU versus IFNα in patients >60 years, efficacy results were comparable. In per-protocol analysis limited to patients remaining on treatment, MR and CHR rates were superior with IFNα from 36 months onward (e.g. MR at 60 months: 35% for HU vs 67% for IFNα, p=0.03).
Overall treatment discontinuation by 60 months was 60% (HU 37% vs IFNα 65%, p=0.0019), primarily due to adverse events (16% for HU vs 43% for IFNα). Grade ≥3 adverse events occurred in 46% overall (58% for HU vs 45% for IFNα, p=0.15).
19 major thrombotic events occurred in 16 patients (HU: 4 events in 4 patients; IFNα>60 years: 12 events in 10 patients; IFNα≤60 years: 3 events in 2 patients). This corresponds to an event rate of 2.6 per 100 person-years for HU versus 3.4 per 100 person-years for IFNα. No patients transformed to acute leukemia. 5 patients died during follow-up (HU: 2; IFNα: 3).
In summary, the ITT analysis found no significant difference in MR or CHR rates between HU and IFNα over 5 years of treatment for MPNs, likely reflecting the higher discontinuation rate with IFNα. However, MR and CHR were superior with IFNα versus HU from 36 months onward in the per-protocol analysis of patients remaining on treatment. IFNα was associated with deeper molecular responses over time, but more frequent adverse events and discontinuations compared to HU. The authors conclude that both HU and IFNα are viable long-term treatment options for MPNs.
New Perspectives of Interferon-alpha2 and Inflammation in Treating Philadelphia-negative Chronic Myeloproliferative Neoplasms, 2021
In recent years, the use of recombinant interferon-alpha (rIFNα) as the initial treatment of the myeloproliferative neoplasms (MPNs), essential thrombocythemia, polycythemia vera and myelofibrosis, has been increasing. In a subset of patients, treatment with rIFNα for approximately 5 years may result in minimal residual disease (MRD) characterized by hematologic remission, a low JAK2V617F allele burden, and normal bone marrow morphology. The important role of chronic inflammation as the driving force for clonal evolution and disease progression and the impact of chronic inflammation upon symptom burden have been substantiated. Here, we highlight timely research questions regarding the use of rIFNα in the future MPN landscape and underscore the importance of early diagnosis and treatment with it to achieve MRD. Based upon the highly encouraging results from combination therapy of stem cell-targeted therapy with rIFNα and the potent anti-inflammatory drug, ruxolitinib, we also place in perspective studies of combinations with older, inexpensive agents (eg, statins, N-acetylcysteine, and colchicine), which have well-established anti-inflammatory and antithrombotic capabilities. Mathematical modeling studies have substantiated the concept that chronic inflammation is a trigger and driver of MPN development, and stress the importance of initiating rIFNα treatment as early as possible. Studies of the impact of rIFNα in individuals carrying the JAK2V617F or the CALR mutation as clonal hematopoiesis of indeterminate potential (CHIP) are urgently needed to determine whether rIFNα treatment at this early CHIP stage may eradicate the malignant clone. We foresee a bright future for patients with an MPN, in whom early intervention with stem cell-targeted therapy, rIFNα, alone or in combination with drugs targeting the chronic inflammatory state, may allow many to achieve MRD, thus becoming candidates for clinical trials employing vaccines leading to the possibility of cure.
Interferon alpha therapy in essential thrombocythemia and polycythemia vera—a systematic review and meta-analysis (2020)
This meta-analysis included 44 studies with a total of 1359 patients (730 with essential thrombocythemia (ET) and 629 with polycythemia vera (PV)) treated with interferon-alpha (IFN).
The overall response rate (ORR) was 80.6% (95% CI 76.6-84.1%) for ET patients. The complete hematologic response (CHR) rate was 59.0% (95% CI 51.5-66.1%).
For PV patients, the ORR was 76.7% (95% CI 67.4-84.0%) and the CHR rate was 48.5% (95% CI 37.8-59.4%).
Response rates were similar for pegylated IFN versus non-pegylated IFN, and between studies with follow-up <24 months versus ≥24 months.
The rate of thromboembolic events was low at 1.2% per patient-year for ET and 0.5% per patient-year for PV.
The rate of treatment discontinuation due to adverse events was 8.8% per patient-year for ET and 6.5% per patient-year for PV.
Flu-like symptoms were the most common adverse effects, but serious adverse events were rare.
Molecular responses, defined as ≥50% reduction in JAK2 V617F allele burden, occurred in up to 57% of PV patients.
The authors concluded that both pegylated and non-pegylated IFN are effective and safe long-term treatments for ET and PV, with durable molecular responses suggesting potential disease-modifying effects.
Limitations include heterogeneity in outcome definitions and reporting between studies, and limited data directly comparing IFN to standard treatments like hydroxyurea.
Overall, this meta-analysis provides strong evidence that IFN is an effective treatment option for ET and PV, with low rates of thromboembolic events, manageable side effect profiles, and potential disease-modifying benefits compared to other cytoreductive therapies.
Symptomatic Diffs between PEG and HU (2022)
What are the biggest symptomatic differences between Pegasys and Hydroxyurea? I downloaded the symptom (AE) data in this paper and ranked by the difference. Topmost elements = higher symptom burden with Pegasys. Bottommost elements = higher symptom burden with Hydroxurea. Rows marked with * are p<0.05 (statistically significant differences). The rest might be due to chance.
A word of caution: The timeframe for this study is 3-12 months after starting treatment. This makes the comparison somewhat unfair to Pegasys. We know that you get the best results with interferon after 3-5 years. Many users even reduce the frequency of injections, reducing the sides. Hydrea only becomes less effective over time. Pegasys becomes more effective over time, allowing dose reductions and providing symptom relief even at the same dose.
Impact of Cytoreductive Drugs upon Outcomes in a Contemporary Cohort of Adolescent and Young Adults with Essential Thrombocythemia and Polycythemia Vera (2023)
Overview
This was a large collaborative study analyzing outcomes in 348 adolescents and young adults (AYAs) diagnosed with essential thrombocythemia (ET) or polycythemia vera (PV) before age 25 (Beauverd et al., 2023).
The aim was to investigate the impact of different cytoreductive therapies on thrombosis-free survival (TFS) and myelofibrosis-free survival (MFS).
Study Cohort & Treatment Groups
Median age at diagnosis was 20-21 years.
Majority were females with ET (n=216).
237/348 (68%) received cytoreduction, most commonly hydroxyurea (HU) (n=126), interferon (IFN) (n=55) or anagrelide (ANA) (n=52).
111 (32%) received no cytoreductive therapy (NoCYTO).
39 high-risk and 197 low-risk patients received cytoreduction per ELN risk classification.
Thrombosis-Free Survival
10-year overall TFS was 87%. Similar 10-year TFS in ET (87%) and PV subgroups (86%).
Elevated white blood cell count (>11 x 10^9/L) associated with higher thrombosis risk (HR 2.8). Splenomegaly associated with lower thrombosis risk (HR 0.2).
In low-risk patients, no significant difference in 10-year TFS between HU (82%), IFN (84%), ANA (93%) and NoCYTO (94%) groups. Suggests no benefit for cytoreduction in low-risk patients.
In high-risk patients, no significant difference in 10-year TFS between groups - HU (78%), IFN (67%), ANA (86%).
Myelofibrosis-Free Survival
10-year overall MFS was 95%. Similar in ET (95%) and PV (93%).
CALR mutations (HR 6.0) and history of thrombosis at diagnosis (HR 3.8) associated with increased MF progression risk overall.
In ET, CALR mutations (HR 4.2) and baseline splenomegaly (HR 2.9) increased MF risk.
IFN group had significantly better MFS compared to other treatments - 10-year MFS 100% for IFN versus 92-94% for other groups. 20-year MFS 100% for IFN versus 73-74% for others.
Conclusions
Early cytoreductive treatment did not impact TFS in low-risk patients. No difference in TFS based on drug choice in high-risk patients.
IFN yielded superior long-term MFS compared to HU, ANA and no treatment. Supports IFN as disease-modifying therapy.
Study warrants consideration of earlier IFN treatment to improve long-term outcomes.
In summary, this large collaborative study provides valuable real-world evidence on long-term thrombosis and myelofibrosis outcomes in young patients with Ph-negative MPNs treated with different cytoreductive regimens. Key conclusions support the preferential use of IFN as a disease-modifying therapy to improve fibrosis-free survival.
Does Interferon work for MF?
Silver et al. demonstrated that early treatment with low-dose interferon (IrIFNα) provides clinical benefit in 73% of patients with low or intermediate-1 risk myelofibrosis (MF) who lack high molecular risk (HMR) mutations, with acceptable toxicity.
The study showed improvements in bone marrow histopathology (fibrosis) in 40% of patients with MF. Although the overall reduction in median JAK2 V617F variant allele frequency (VAF) was minimal (pretreatment: 46.2%; post-treatment: 42.4%), the 5 patients who had an improvement in their bone marrow histopathology experienced a more substantial median reduction of 23%.
Interestingly, baseline driver mutation status (JAK2/CALR/MPL) did not correlate with response or survival, contrasting with some prior reports. However, the presence of ASXL1, SRSF2, or ≥3 total mutations was associated with worse outcomes, suggesting that molecular profiling at diagnosis may predict prognosis and response to rIFNα. Furthermore, spleen size <4 cm at baseline was associated with better response and progression-free survival.
The study reported favorable overall and progression-free survival rates at 5 years (91.5% and 88%, respectively) compared to historical cohorts, although the small sample size is a limitation. Long-term rIFNα treatment can induce durable bone marrow responses, spleen size reduction, and disease stabilization in early MF, but those patients with a more advanced moleculer profile and spleen size may require additional therapies such as a Ruxolitinib.
[1] https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.30679
[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541411/#
Mechanism of Action of Interferon, 2020
Both Type I and II interferons exert their effects through human interferon alfa receptor chains, which activate signaling via the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway [21,22]. The anti-viral properties of interferon have led to its successful use in diseases such as hepatitis B and C and Kaposi sarcoma. Interferon’s mechanism of action in MPNs is less clear. Numerous studies have demonstrated an apoptotic effect on hematopoietic progenitors, with a preference for the mutated clone [23,24]. Colony unit megakaryocyte proliferation is also directly targeted, which likely accounts for interferon’s effects on thrombocytosis. In addition, there is evidence that interferon inhibits thrombopoietin (TPO) activation via suppression of JAK2 substrate phosphorylation [25]. Mouse models have shown that interferon can directly activate dormant hematopoietic stem cells in vivo [26], and specifically can induce differentiation in JAK2 V617F mutated quiescent stem cells [27]. This results in potential long-term depletion of the mutant clone via direct targeting of progenitor cells.
However, interferon also induces broader stimulatory effects on the immune system, enhancing surveillance and targeting of the mutant clone. Studies have demonstrated that interferon augments T-cell, macrophage, and natural killer cell activity, and increases expression of tumor-associated and major histocompatibility complex antigens [28,29,30].
Mechanisms of action of IFN-alpha2 (link)
Depletion of Jak2V617F myeloproliferative neoplasm-propagating stem cells by interferon-α in a murine model of polycythemia vera (2013)
Based on the information provided in the article, interferon-α (IFNα) appears to deplete JAK2V617F mutant hematopoietic stem cells (which drive myeloproliferative neoplasms like polycythemia vera) by promoting their differentiation and cell cycle activation, rather than directly killing them. Some key points that support this:
IFNα treatment preferentially depleted JAK2V617F mutant long-term hematopoietic stem cells (LT-HSCs) compared to wild-type LT-HSCs (Figure 3B).
IFNα caused JAK2V617F LT-HSCs to exit quiescence and enter the cell cycle more than wild-type LT-HSCs (Figure 4B-C).
IFNα promoted megakaryocyte-erythroid progenitor differentiation from JAK2V617F HSCs (Figure 3C-E).
The authors state: "IFNα achieves CMR in MPN patients through its effects on MPN stem cells" and "IFNα preferentially depletes Jak2VF MPN-propagating stem cells by activating cell cycle and promoting Jak2VF-driven erythroid-lineage differentiation."
They did not find evidence that IFNα directly induces apoptosis in JAK2V617F LT-HSCs.
So in summary, the article suggests IFNα depletes MPN stem cells by pushing them out of quiescence to differentiate, not by directly killing them.
Abstract
Interferon-α (IFNα) is an effective treatment of patients with myeloproliferative neoplasms (MPNs). In addition to inducing hematological responses in most MPN patients, IFNα reduces the JAK2V617F allelic burden and can render the JAK2V617F mutant clone undetectable in some patients. The precise mechanism underlying these responses is incompletely understood and whether the molecular responses that are seen occur due to the effects of IFNα on JAK2V617F mutant stem cells is debated. Using a murine model of Jak2V617F MPN, we investigated the effects of IFNα on Jak2V617F MPN-propagating stem cells in vivo. We report that IFNα treatment induces hematological responses in the model and causes depletion of Jak2V617F MPN-propagating cells over time, impairing disease transplantation. We demonstrate that IFNα treatment induces cell cycle activation of Jak2V617F mutant long-term hematopoietic stem cells and promotes a predetermined erythroid-lineage differentiation program. These findings provide insights into the differential effects of IFNα on Jak2V617F mutant and normal hematopoiesis and suggest that IFNα achieves molecular remissions in MPN patients through its effects on MPN stem cells. Furthermore, these results support combinatorial therapeutic approaches in MPN by concurrently depleting dormant JAK2V617F MPN-propagating stem cells with IFNα and targeting the proliferating downstream progeny with JAK2 inhibitors or cytotoxic chemotherapy.
How do Interferons work against MPNs? (2024)
Although the exact Mechanism of Action of interferons in MPNs is not fully understood, one potential mechanism is the induction of apoptosis in hematopoietic progenitors of MPN, with a preference for the mutated clone. Another proposed mechanism is through activation of the cell cycle and promotion of JAK2 V61F-driven erythroid-lineage differentiation by preferentially depleting JAK2 V61F MPN-propagating stem cells.
1. Targeting JAK2V617F-positive hematopoietic progenitor cells (Lu et al, 2010; Mullally et al, 2013):
IFN-α selectively suppresses the growth of JAK2V617F-positive hematopoietic progenitor cells (HPCs) in vitro, with a greater effect on JAK2V617F homozygous vs heterozygous HPCs (Lu et al, 2010).
In a murine model of polycythemia vera, IFN-α treatment depletes JAK2V617F MPN-propagating stem cells over time, impairing disease transplantation (Mullally et al, 2013).
2. Inducing cell cycle activation and differentiation of JAK2V617F stem cells (Mullally et al, 2013):
IFN-α treatment activates the cell cycle of quiescent JAK2V617F long-term hematopoietic stem cells (LT-HSCs) and promotes their differentiation down the erythroid lineage.
This leads to depletion of the JAK2V617F LT-HSC population over time.
3. Acting through the p38 MAPK pathway (Lu et al, 2010):
IFN-α treatment activates the p38 mitogen-activated protein kinase (MAPK) pathway in polycythemia vera CD34+ cells.
Pharmacologic inhibition of p38 MAPK reverses the growth inhibition and apoptosis induced by IFN-α, indicating the p38 MAPK pathway mediates IFN-α's effects.
4. Direct antiproliferative effects on hematopoietic progenitors (Raefsky et al, 1985):
IFN-α and IFN-γ potently suppress normal and malignant hematopoietic colony formation in vitro, with a direct inhibitory effect on isolated erythroid progenitor cells.
5. Immunomodulatory effects (How and Hobbs, 2020):
IFNs stimulate immune surveillance and targeting of the malignant clone by augmenting T-cell, macrophage, and natural killer cell activity.
They increase expression of tumor-associated antigens and MHC antigens on malignant cells.
6. Pro-apoptotic effects (How and Hobbs, 2020):
IFNs induce known mediators of apoptosis such as caspases and TRAIL in malignant cells.
In summary, IFNs deplete the malignant JAK2V617F clone in MPNs through multiple direct and indirect mechanisms. They preferentially target JAK2V617F-mutated hematopoietic stem and progenitor cells, forcing them out of quiescence, increasing their differentiation, and making them more susceptible to apoptosis - effects mediated in part by activation of p38 MAPK signaling. Additionally, IFNs harness the immune system to better recognize and eliminate the malignant clone. The combination of these actions enables molecular remissions and potential long-term modification of disease course in MPN patients treated with IFN therapy.
Lu M, Zhang W, Li Y, et al. Interferon-alpha targets JAK2V617F-positive hematopoietic progenitor cells and acts through the p38 MAPK pathway. Exp Hematol 2010; 38: 472–480.
Mullally A, Bruedigam C, Poveromo L, et al. Depletion of Jak2V617F myeloproliferative neoplasm-propagating stem cells by interferon-α in a murine model of polycythemia vera. Blood 2013; 121: 3692–3702.
Raefsky EL, Platanias LC, Zoumbos NC, et al. Studies of interferon as a regulator of hematopoietic cell proliferation. J Immunol 1985; 135(4): 2507–2512.
How J, Hobbs G. Use of interferon alfa in the treatment of myeloproliferative neoplasms: perspectives and review of the literature. Cancers (Basel) 2020; 12: 1954.
How Interferons Work Against MPNs
The exact mechanism of action (MOA) of IFNs in MPNs is not fully understood, but several potential mechanisms have been proposed:
Induction of apoptosis: IFNs can induce apoptosis (programmed cell death) in hematopoietic progenitor cells, which are responsible for producing blood cells. This effect is more pronounced in cells with the JAK2V617F mutation, which is a common driver of MPNs.
Cell cycle activation and differentiation: IFNs can activate the cell cycle of dormant hematopoietic stem cells and promote their differentiation into mature blood cells. This can lead to the depletion of the mutated stem cells that drive MPN progression.
Activation of the p38 MAPK pathway: IFNs can activate the p38 mitogen-activated protein kinase (MAPK) pathway, which plays a role in cell growth, differentiation, and apoptosis. This pathway may mediate some of the anti-proliferative and pro-apoptotic effects of IFNs in MPNs.
Direct antiproliferative effects: IFNs can directly inhibit the proliferation of hematopoietic progenitor cells, both normal and malignant. This effect is more pronounced in malignant cells, suggesting that IFNs may selectively target cancer cells.
Immunomodulatory effects: IFNs can stimulate the immune system to recognize and eliminate cancer cells. They can enhance the activity of immune cells like T cells, macrophages, and natural killer cells, and increase the expression of tumor-associated antigens on malignant cells.
Key Studies on Interferon Mechanisms in MPNs
Several studies have investigated the mechanisms of IFN action in MPNs:
Lu et al. (2010): This study showed that interferon-alpha (IFNα) can selectively target and suppress the growth of JAK2V617F-positive hematopoietic progenitor cells (HPCs) in vitro. The inhibitory effects of IFNα were mediated through activation of the p38 MAPK pathway, leading to increased apoptosis of the mutated cells.
Mullally et al. (2013): This study used a mouse model of polycythemia vera (PV) to show that IFNα treatment can deplete JAK2V617F-positive stem cells and impair disease progression. IFNα also promoted cell cycle activation and differentiation of the mutated stem cells, leading to their depletion over time.
Raefsky et al. (1985): This study demonstrated that both IFN-gamma (IFNγ) and IFNα can suppress the formation of blood cell colonies from human bone marrow cells in vitro. This suggests that IFNs have a direct inhibitory effect on hematopoietic progenitor cells.
O'Neill et al. (2016): This case series reported on the use of Peg-IFNα-2a in patients with ET or PV who developed early signs of myelofibrosis (MF). The treatment improved anemia and reduced splenomegaly in most patients. Interestingly, the study also found that Peg-IFNα-2a treatment was associated with a transient increase in serum lactate dehydrogenase (LDH) and immature myeloid cells in the peripheral blood, followed by normalization of these findings in responders. The authors hypothesized that this may represent activation of malignant stem cells followed by their inhibition and re-establishment of normal hematopoiesis.
How J, Hobbs G. Use of interferon alfa in the treatment of myeloproliferative neoplasms: perspectives and review of the literature. Cancers (Basel) 2020; 12: 1954.
Mechanism of Action of Interferon
Both Type I and II interferons exert their effects through human interferon alfa receptor chains, which activate signaling via the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway [21,22]. The anti-viral properties of interferon have led to its successful use in diseases such as hepatitis B and C and Kaposi sarcoma. Interferon’s mechanism of action in MPNs is less clear. Numerous studies have demonstrated an apoptotic effect on hematopoietic progenitors, with a preference for the mutated clone [23,24]. Colony unit megakaryocyte proliferation is also directly targeted, which likely accounts for interferon’s effects on thrombocytosis. In addition, there is evidence that interferon inhibits thrombopoietin (TPO) activation via suppression of JAK2 substrate phosphorylation [25]. Mouse models have shown that interferon can directly activate dormant hematopoietic stem cells in vivo [26], and specifically can induce differentiation in JAK2 V617F mutated quiescent stem cells [27]. This results in potential long-term depletion of the mutant clone via direct targeting of progenitor cells.
However, interferon also induces broader stimulatory effects on the immune system, enhancing surveillance and targeting of the mutant clone. Studies have demonstrated that interferon augments T-cell, macrophage, and natural killer cell activity, and increases expression of tumor-associated and major histocompatibility complex antigens [28,29,30]. These immunologic changes implicate immunotherapy as a potential therapeutic modality of MPN. Additional putative mechanisms of interferon include its pro-apoptotic properties, with gene expression profiles demonstrating induction of known mediators of apoptosis such as caspase and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) [31]. It is unclear how interferon’s anti-angiogenic effects contribute to its efficacy in myeloid malignancies [32], although it is possible that angiogenesis plays a role in the tumor microenvironment.
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