Experience with pegylated interferon α-2a in advanced myeloproliferative neoplasms in an international cohort of 118 patients

Abstract

The Philadelphia negative myeloproliferative neoplasms, including polycythemia vera, essential thrombocythemia, and myelofibrosis, are associated with substantial vascular and transformative complications. Standard therapy for high-risk disease, particularly in patients that have failed initial therapy, remains controversial. Non-pegylated interferon has previously been shown to be effective in controlling erythrocytosis, thrombocytosis and thrombotic complications, but was found to have poor tolerability and excessive adverse effects. Recently, pegylated interferon alpha-2a was introduced and found to be better tolerated and less toxic than standard interferon. In addition, in recent phase II trials, pegylated interferon alpha-2a therapy was found to induce both hematologic and molecular remissions. We retrospectively analyzed 118 myeloproliferative patients who underwent pegylated interferon alpha-2a treatment. Responses were evaluated by ELN, IWG-MET and EUMNET standardized criteria sets and adverse effects were analyzed.

Introduction

Design and Methods

This study included 118 MPN patients treated with PegIFN2a at hematology clinics from eight academic centers in the US and European Union. The patients were retrospectively analyzed as a consecutive cohort of MPN patients treated with PegIFN2a therapy outside clinical trials at each participating center after receiving Institutional Review Board approval. There were no exclusion criteria. Each site recorded starting, maximum and final treatment dosages, as well as dosage adjustments. Adverse effects were graded according to Common Terminology Criteria for Adverse Events (CTCAE 3.0). European Leukemia Net (ELN) criteria were used to measure response in PV and ET. The International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) and European Myelofibrosis Network (EUMNET) criteria were used to evaluate response in MF.8-10 Raw data and response assessment was adjudicated by each of the sites, and were reviewed and confirmed by the first and senior authors.

Results and Discussion

The results of these cases and analysis have not been previously reported. In the overall MPN cohort (Table 1), the median age of diagnosis was 49 years and the female to male ratio was 1.5 to 1. A large proportion were Jak-2 mutation positive (76 patients, 64%), with the largest contribution from the PV subgroup (50 patients, 91%). Splenomegaly was present in 28 patients (23%) of the total MPN cohort, with 47% of MF patients presenting this clinical characteristic. Using the International Prognostic Scoring System (IPSS) Risk Group for MF patients, 5 patients (29%) were low risk, 9 patients (53%) were intermediate risk, and 2 patients (12%) were high risk. Eight patients (47%) developed MF post PV/ET. The mean baseline hemoglobin, leukocyte and platelet counts were similar amongst the MPN subgroups, likely representing the patients prior exposure to first-line therapies. Mean hemoglobin was 13.1 gm/dL, mean leukocyte count was 7.6×10/L, and the mean platelet count was 552×10/L. The most common prior therapies before initiation of PegIFN2a include hydroxyurea (63%), anagrelide (32%), non-pegylated interferon alpha (19%), and phlebotomy (10%).

Table 1.Clinical characteristics in 118 myeloproliferative neoplasm Myelofibrosis patients treated with pegylated interferon alpha 2a.

Patients received subcutaneous PegIFN2a weekly with a median starting dose of 80 micrograms/week (mcg/wk) (range 22.5-180 mcg/wk). Median maximum dose was 90 mcg/wk (range 30-300 mcg/wk). After adjustments for adverse effects and response, median weekly dosage at last follow up was 90 mcg/wk (range 15-180 mcg/wk). Dosage reductions occurred in 7 patients (6%). A total of 87 patients (74%) remain on PegINF2a with a median duration of treatment of 17 months (1.0-92). Twenty patients (17%) discontinued therapy secondary to adverse effects.

Both hematologic and non-hematologic adverse effects (AE) were grade (Gr) 3 or lower (Table 2), with only 4 patients (3%) experiencing Gr 3 AEs. In the composite hematologic AE profile of all MPN patients analyzed (118), there were 7 patients who developed anemia (6%), 10 with thrombocytopenia (8%) and 7 with leukopenia (6%). Most common non-hematologic toxicities were Grade 1-3 fatigue in 24 patients (20%), Grade 1 liver function test (LFT) elevation in 7 (6%), and Grade 1-2 skin/allergic reaction in 6 (5%). Adverse effects leading to discontinuation were primarily non-hematologic, although one patient (<1%) discontinued PegIFN2a therapy due to Grade 2 anemia. Other reasons for discontinuation include participation in clinical trials, progression of disease and pregnancy. The percentage of discontinuation due to adverse effects in this study is consistent with the recently published French study in MF and a US study in PV and ET. 3,4

Table 2.Adverse effects in 118 MPN patients treated with PegIFN2a.

Recently, standardized definitions were established to foster more objective assessment of treatment response. This analysis used all the standardized response definitions available, including the European Leukemia Net (ELN) criteria to measure response in PV and ET patients, the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) and European Myelofibrosis Network (EUMNET) criteria sets to evaluate response in MF patients (Table 3). According to ELN criteria, a complete response (CR) or partial response (PR) was observed in 30 (54%) and 18 (33%) PV patients treated with PegINF2a, respectively. In ET, 29 patients (63%) had CR while 7 (15%) experienced PR. Modest but useful rates of response were seen in MF patients. According to IWG-MRT criteria there were no complete remissions (CR); however, 2 patients (12%) had partial remission (PR), 3 had clinical improvement (CI) (18%), and 7 patients (41%) had stable disease (SD). According to EUMNET criteria, one MF patient had complete response (CR) (6%), 4 patients (24%) had major response (MaR), and 3 patients (18%) had minor response (MiR). In the overall cohort with splenomegaly (28 patients), 19 patients (68%) experienced a reduction in spleen size (cm) as measured below costal margin on clinical examination, with a mean 82% reduction in spleen size.

Table 3.Response assessment in 118 myeloproliferative neoplasm patients treated with pegylated interferon alpha-2a.

The Philadelphia negative MPNs are associated with substantial vascular and transformative sequelae. Unlike their BCR-ABL positive counterparts, medications that are both cytoreductive and possess the ability to induce molecular remissions have been elusive in the treatment of MPNs. The enhanced tolerability of the pegylated formulation of IFN2a in conjunction with significant hematologic and molecular remission rates makes it an attractive second-line agent. Whether it is preferable to HU as first-line therapy deserves consideration. Furthermore, Jak-2 inhibitors are now approved for advanced MF. The role of Jak-2 inhibition in early MF, PV and ET is the subject of ongoing study and may play a role complementary to that of PegIFN2a.

This study is limited by its retrospective nature, possible selection bias, and lack of standardized assessment of adverse events; however, use of PegIFN2a in these MPNs was associated with similar response rates, discontinuation rates, and adverse event profile, as previously reported in clinical trials. Although not quantitated in this analysis, additional benefit from PegIFN2a may be related to its ability to induce molecular remissions, as shown in previous phase II studies. Recent data support Jak-2 allelic burden as being associated with more aggressive and symptomatic manifestations amongst MPNs, as reflected by higher hematocrits, leukocyte counts, LDH and alkaline phosphatase values in those with elevated levels Jak-2V6l7F RNA.11-12 Jak-2 mutational status is also a known factor associated with risk of vascular events.13 The relationship of allele burden to thrombotic events, which were not recorded in this study, deserves further investigation.

In conclusion, PegIFN2a is a non-leukemogenic therapy that possesses the ability to induce both hematologic and molecular remissions in MPNs and may be an agent of particular interest in the treatment of real world patients who have failed prior therapies or in those with early MF with the intent to hinder progression to overt MF.

From the experience of the collaborative investigators in this study, a starting dose of PegIFN2a at 45 mcg weekly titrated to a goal dosage of 90 mcg weekly is suggested as the optimal dosing strategy to limit AEs and maximize response. Upcoming randomized clinical trials through the Myeloproliferative Disorders Research Consortium will help further define the role of Peg IFN2a in MPNs.

Footnotes

• Authorship and Disclosures: The information provided by the authors about contributions from persons listed as authors and in acknowledgments is available with the full text of this paper at www.haematologica.org. Financial and other disclosures provided by the authors using the ICMJE (www.icmje.org) Uniform Format for Disclosure of Competing Interests are also available at www.haematologica.org.

• Received January 3, 2012.
• Revision received February 20, 2012.
• Accepted March 6, 2012.