Histomorphological responses after therapy with pegylated interferon α-2a in patients with essential thrombocythemia (ET) and polycythemia vera (PV)

Abstract

Background: Pegylated interferon alfa-2a (PEG-IFN-α-2a) is a potent immunomodulating agent capable of inducing high rate of hematologic and even complete molecular remission in patients with essential thrombocythemia (ET) and polycythemia vera (PV). We recently reported results of a phase 2 trial of PEG-IFN-α-2a in 83 patients with ET and PV after a median follow-up of 83 months. Here we report an analysis of bone marrow (BM) responses in these patients.

Methods: Among 83 patients, 58 (70%, PV 25, ET 31) had evaluable BM samples. BM responses and fibrosis grading were defined according to the International Working Group for Myeloproliferative Neoplasms Research and Treatment, and the European Consensus on grading of BM fibrosis, respectively. BM was assessed prior to enrollment, and every 6-24 months while on therapy in all patients, and after therapy discontinuation in some patients.

Results: The median age of analyzed 58 patients was 52 years, and 29% were males. After a median follow-up of 84 months, 32 patients are still on study. Hematologic (HR) and molecular responses (MR) were seen in 93 and 69% patients, respectively. Twenty-nine patients (50%) had a BM response, including 13 (22%) with a complete BM response (BM-CR). Moreover, 13 patients (22%) have experienced complete resolution of bone marrow reticulin fibrosis. Patients with BM response had higher duration of HR and MR, and lower discontinuation rate. Furthermore, patients with BM-CR had a higher probability of complete MR. The median duration of BM-CR was 30 months, and 9 patients have maintained their BM-CR (69%), including five who have maintained their response after discontinuation of therapy. Despite this observation, the pattern of HR, MR and BM response, their durability and interrelation was heterogeneous.

Conclusions: Our results show the ability of PEG-IFN-α-2a to induce complete BM responses in a subset of ET and PV patients, but its correlation with durable clinically relevant treatment benefit warrants further investigation. Trial registration This study is registered with ClinicalTrials.gov (NCT00452023), and is ongoing but not enrolling new patients.

Keywords: Essential thrombocythemia; Histomorphological response; Pegylated interferon alfa-2a; Polycythemia vera.

Figures

Fig. 1

BM Response patterns observed in patients treated with PEG-INF-α-2a. a BM biopsy sections from a patient with ET who is still on therapy after 84 + months with BM-CR and CMR that was achieved after 60 months on treatment (Pt 8, Fig. 3a). A, B Hematoxylin and eosin staining at (A) the start of therapy and (B) at BM-CR after 60 months on therapy. C, D reticulin staining showing BM fibrosis at (C) the start of therapy (MF-1/2) and D at the time of BM-CR (MF-0). b Patient with PV who is still on therapy after 96 + months who achieved a CHR, CMR and BM-CR but has only sustained a CMR (Pt 4, Fig. 3b). Loss of BM-CR occurred after 84 months and loss of CHR after 96 months. Hematoxylin and eosin staining showing osteosclerosis at (A) the start of therapy, B at the time of best response (60 months), and C at relapse after 84 months. D–F Hematoxylin and eosin staining showing BM cellularity and megakaryocyte morphology at (D) the start of therapy, E at the time of best response (60 months), and F at relapse (84 months). G, I, J Reticulin staining showing BM fibrosis at (G) the start of therapy (MF-2), I at the time of best response (MF-0), and J at relapse (MF-1). All images shown are magnified ×200

Fig. 2

a–i Kaplan–Meier curves with estimation of time to BM response, its durability and probability of maintenance over time. a–c Time to BM-CR, BM-PR and overall BM-response; d–f median duration of BM-CR, BM-PR and overall BM-response; g–i probability of maintaining achieved BM-CR, BM-PR and overall BM-response over time

Fig. 3

Probability of achieving a BM-response in patients treated with PEG-IFN-α-2a estimated by Kaplan–Meier curve. a Probability of achieving BM-CR; b Probability of achieving overall BM-response (BM-CR and BM-PR)

Fig. 4

Correlation of molecular and morphological responses over time in selected patients. Patients with a sustained BM-CR (MF-0). Blue arrows indicate time on active therapy. The number in the top left upper corner represents the patient # from Table 2. The red line indicates the JAK2 allele burden over time (missing in TN patients). The box in the bottom right corner shows the change in BM and response, NEG MPN = no signs of ET or PV, normal BM. The gray square represents the time of loss of HR (shown only in patients who lost their HR)

Fig. 5

Correlation of molecular and morphological responses over time in selected patients. Patients with a sustained BM-CR with mild reticulin fibrosis (MF 0/1). The number in the top left upper corner represents the patient # from Table 2. The red line indicates the JAK2 allele burden over time. The box in the bottom right corner shows the change in BM and response, NEG MPN = no signs of ET or PV, normal BM. The gray square represents the time of loss of HR (shown only in patients who lost their HR)

Fig. 6

Correlation of molecular and morphological responses over time in selected patients. Patients with BM-CR (MF-0/1, MF-1) and subsequent relapse. Blue arrows indicate time on active therapy. The number in the top left upper corner represents the patient # from Table 2. The red line indicates the JAK2 allele burden over time. The box in the bottom right corner shows the change in BM and response, NEG MPN = no signs of ET or PV, normal BM. The gray square represents the time of loss of HR (shown only in patients who lost their HR)