Lucia Masarova

Pegylated interferon alfa-2a in patients with essential thrombocythaemia or polycythaemia vera: a post-hoc, median 83 month follow-up of an open-label, phase 2 trial

Background The durability of responses and long-term safety of pegylated interferon alpha-2a (PEG-IFN-a-2a) in patients with polycythemia vera and essential thrombocythemia have not been reported. Here, we present long-term efficacy and safety data from a single-center, prospective, phase 2 study, after 7 years of follow-up. Methods Patients older than 18 years who were diagnosed with essential thrombocythemia or polycythemia vera per 2001 World Health Organization criteria were eligble to enroll. Responses were assessed every 3–6 months: Data were analyzed using descriptive statistics. The rate of leukemia transformation was compared with age- and gender-matched patients who were not treated with PEG-IFN-α-2a. Findings PEG-IFN-α-2a induced hematologic (80%) and molecular responses (63%) in 83 patients with essential thrombocythemia (n=40) and polycythemia vera (n=43), with median durations of 66 and 53 months, respectively. Thirty-nine percent of hematologic responders and 71% of molecular responders (JAK2V617F+) have maintained some response during follow-up: 48% maintained their best molecular response, including 9 of 10 patients with a complete molecular response. The incidence of major venous-thrombotic events during the study was 1.22/person-year. Overall, 22% of patients discontinued therapy due to treatment-related toxicity. While toxicity rates decreased over time, 5 patients experienced treatment-limiting G3/4 toxicities after 60 months on therapy. Rates of transformation to MF/AML were similar between patients treated with PEG-IFN-a-2a and those from a historical control series. Interpretation PEG-IFN-α-2a can induce durable hematologic and molecular remissions in patients with essential thrombocythemia and polycythemia vera. We suggest a starting dose of 45 mcg/week, and its combination with other drugs should be explored further in clinical trials.BACKGROUND Pegylated interferon alfa-2a is an immunomodulatory agent used to treat polycythemia vera. The durability of responses and long-term safety of this drug in patients with polycythaemia vera and essential thrombocythaemia have not been reported. Here, we present long-term efficacy and safety data from a single-centre, open-label, phase 2 trial, after a median of 83 months follow up. METHODS Patients older than 18 years who were diagnosed with essential thrombocythaemia or polycythaemia vera according to 2001 WHO criteria were eligible to enrol in our study. The initial starting dose of pegylated interferon alfa-2a was 450 μg subcutaneously once per week, but was decreased in a stepwise manner due to toxic effects to a final starting dose of 90 mg per week: three patients were started at a dose of 450 mg per week, three at 360 mg per week, 19 at 270 mg per week, 26 at 180 mg per week, and 32 at 90 mg per week. Treatment was continued for as long as the patients derived clinical benefit with reductions in dose and frequency of administration allowed at the discretion of the treating physician. Haematological responses were assessed every 3-6 months on the basis of blood counts as defined by the European LeukemiaNet critieria. The primary endpoint of the initial study was the proportion of patients with a haematological response. Complete haematological response was defined as normalisation of blood counts (for patients with essential thrombocythaemia, platelets ≤440 × 109 per L; for patients with polycythaemia vera, haemoglobin <15·0 g/L without phlebotomy) with complete resolution of palpable splenomegaly or symptoms in the absence of a thrombotic event. Data were analysed with descriptive statistics and in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00452023 and is ongoing but not enrolling new patients. FINDINGS Between May 21, 2005, and Dec 1, 2015, patients were followed up for a median of 83 months (IQR 69-94 months). Pegylated interferon alfa-2a induced haematological (66 [80%] of 83 patients) and molecular responses (35 [63%] of 55 patients) in 40 patients with essential thrombocythaemia and 43 patients with polycythaemia vera, with median durations of 66 months (IQR 35-83) and 53 months (24-70), respectively. 26 (39%) of 66 haematological responders and 25 (71%) of 35 molecular responders (with the JAK2 Val617Phe mutation) have maintained some response during follow-up: 49% maintained their best molecular response (nine of ten patients who had a complete response, five of 20 who had a partial response, and three of five who had a minor response). The incidence of major venous-thrombotic events during the study was 1·22 per 100 person-years. Overall, 18 (22%) of 83 patients discontinued therapy due to treatment-related toxicity. Although toxicity rates decreased over time, five patients had treatment-limiting grade 3 or 4 toxicities after 60 months on therapy. 32 patients are still enrolled on the study. INTERPRETATION Pegylated interferon alfa-2a can induce durable haematological and molecular responses in patients with essential thrombocythaemia and polycythaemia vera. This drug alone and in combination with other drugs could be explored further in clinical trials. FUNDING US National Cancer Institute.

Patients with post-essential thrombocythemia and post-polycythemia vera differ from patients with primary myelofibrosis

Prognostic scoring systems for primary myelofibrosis (PMF) are not accurate in patients with post-essential thrombocythemia and post-polycythemia vera myelofibrosis (PET-MF; PPV-MF). Given the paucity of data describing the clinical characteristics, disease course and outcomes of these patients, we sought to describe and compare the clinical characteristics and outcomes of 755 patients with PMF, 181 with PPV-MF, and 163 with PET-MF referred to our institution between 1984 and 2013. The median follow-up was 31 months, and 56% (n=616) patients had died. Over an observation period of 3502 person-years, 11% of patients had progression to AML, with similar rates among groups. The proportion of patients with transfusion dependency (higher in PMF), leukocytosis and systemic symptoms (higher in PPV-MF), and thrombocytopenia (higher in PMF, PPV-MF) differed among groups. Median overall survival (OS) was longest in PET-MF patients (73 mo vs 45 mo (PMF) vs 48 mo (PPV-MF), p <0.001). Stratification of OS by DIPSS was only discriminatory in patients with PMF, and it failed to distinguish higher risk patients with PPV/PET-MF. In multivariate analysis, predictors of inferior OS were higher age, anemia, systemic symptoms, thrombocytopenia, and high peripheral blasts in PMF; age, anemia, and systemic symptoms for PPV-MF; and anemia, peripheral blasts and thrombocytopenia in PET-MF. Although the clinical characteristics of PPV/PET-MF patients are not substantially different from those with PMF, their outcomes differ and prognostic scoring systems for PET/PPV-MF should be improved.

Secondary solid tumors and lymphoma in patients with essential thrombocythemia and polycythemia vera – single center experience

Essential thrombocythemia (ET) and polycythemia vera (PV) are chronic myeloproliferative neoplasms (MPNs) with increased risk of thrombosis, and evolution to myelofibrosis or acute myeloid leukemia...

Long-term results of a phase II trial of lenalidomide plus prednisone therapy for patients with myelofibrosis

Lenalidomide, with or without prednisone, is an active therapy for patients with myelofibrosis (MF). We provide an update of a phase II study of lenalidomide plus prednisone in patients with MF, after median follow up of 9 years. Forty patients were enrolled in the study and all patients were evaluable for response. Response to the treatment was reevaluated using IWG response criteria published in 2013: quality of response improved over time and overall response rate was 35%. Response in splenomegaly was seen in 39% of patients and anemia response in 32%. The median time to treatment failure (TTF) in all patients was 8.2 months and the median duration of response was 34.6 months. Response was highly durable in some patients: six patients (15%) had TTF for more than 60 months (5 years) and three patients are still on the treatment beyond 109 months (9 years). Complete and partial responses were seen in one and five patients, respectively, but achieving deeper response was not necessary for the response to be durable. New clinical studies are needed to explore safe and well tolerated lenalidomide-based combination strategies for patients with MF.

Association of lymphoid malignancies and Philadelphia-chromosome negative myeloproliferative neoplasms: Clinical characteristics, therapy and outcome

The co-occurrence of myeloproliferative and lymphoproliferative neoplasms (MPN/LPN) has been reported, mostly in case reports. The aim of this study was to assess the characteristics and clinical course of the coexistent diseases. Among 9866 patients who presented to our institution from 1960 to 2014, 34 (0.3%) were diagnosed with MPN/LPN. LPN was diagnosed first in 16 patients, second in 15, and at the same time in 3. The time to secondary malignancy was longer when LPN was diagnosed first (119 vs 98 months). Myelofibrosis (41%), polycythemia vera (24%), and essential thrombocythemia (18%) were the most common MPNs, and non-Hodgkin lymphoma (50%) and chronic lymphocytic leukemia (32%) were the most common LPNs. Seventy-three percent of patients treated for MPN and 72% of those treated for LPN achieved a complete response. After a median follow-up from MPN diagnosis of 84 months, 16 patients are alive and 18 died (4 related to MPN and 2 LPN). Coexistent MPN/LPN is a rare event that does not appear to predict worse outcomes. Treatment choice is generally oriented towards controlling the prevalent disease; the other malignancy may influence treatment strategies in selected cases.

Chronic lymphocytic leukemia and myeloproliferative neoplasms concurrently diagnosed: clinical and biological characteristics

Abstract Chronic lymphocytic leukemia (CLL) and myeloproliferative neoplasms (MPN) may occur concomitantly. However, little is known about the pathobiological characteristics and interaction between the neoplastic clones in these rare cases of coinciding malignancies. We retrospectively examined the clinical and biological characteristics of 13 patients with concomitant CLL and MPN – eight primary myelofibrosis (PMF), three essential thrombocytosis (ET), and two polycythemia vera (PV) – who presented to our institution between 1998 and 2014, and tested all patients for MPN-specific aberrations, such as JAK2, MPL and CALR mutations. Along with epidemiological and molecular characterization of this rare condition, we found that JAK2 mutation can be detected 9 years prior to PMF diagnosis, suggesting that PMF clinical phenotype may require several years to develop and CLL/MPN clinical co-occurrence might be sustained by common molecular events. Some features of these patients suggest that pathobiologies of these diseases might be intertwined.

Complete remission in a patient with JAK2- and IDH2-positive myelofibrosis

To the editor: Here we present a case of a patient with JAK2V617F- and IDH2-mutation–positive myelofibrosis (MF) with elevated blasts on ruxolitinib therapy for 8 years with a complete hematologic, histomorphologic, cytogenetic, and molecular remission. MF is a rare Philadelphia chromosome–

The co-occurrence of driver mutations in chronic myeloproliferative neoplasms

Myeloproliferative neoplasms (MPNs) are clonal disorders characterized by proliferation of one or more elements of the myeloid lineage. Key genetic aberrations include the BCR-ABL1 gene rearrangement in Philadelphia chromosome-positive chronic myelogenous leukemia (CML) and JAK2/MPL/CALR aberrations in Philadelphia chromosome-negative MPNs. While thought to be mutually exclusive, occasional isolated reports of coexistence of BCR-ABL1 and JAK2, and JAK2 with MPL or CALR aberrations have been described. Given the paucity of data, clinical characteristics and outcome of patients harboring concurrent Philadelphia-positive and Philadelphia-negative mutations or dual Philadelphia-negative driver mutations have not been systematically evaluated, and their clinical relevance is largely unknown. It is difficult to determine the true relevance of co-existing driver mutations on outcomes given the rarity of its occurrence. In this case series, we describe those patients who had dual driver mutations detected at any point during the course of their disease and characterized their clinical and laboratory features, bone marrow pathology, and overall disease course.

Therapy-related myelofibrosis does not appear to exist

There is no evidence to support the existence of therapy-related myelofibrosis.Therapy for previous malignancy has no impact on myelofibrosis prognosis.

Significance of thrombocytopenia in patients with primary and postessential thrombocythemia/polycythemia vera myelofibrosis

Severe thrombocytopenia (platelets <50 × 109/L) is associated with very poor outcome of patients with myelofibrosis (MF). As patients with primary myelofibrosis (PMF) differ from patients with postessential thrombocythemia (PET‐MF) and postpolycythemia vera myelofibrosis (PPV‐MF), we aimed to evaluate the significance of low platelets among these patients. We present clinical characteristics and outcome of patients with either PMF, PPV‐MF, or PET‐MF, and thrombocytopenia who presented to our institution between 1984 and 2015. Of 1269 patients (877 PMF, 212 PPV‐MF, 180 PET‐MF), 11% and 14% had platelets either <50 × 109/L or between 50‐100 × 109/L, respectively. Patients with platelets <50 × 109/L were most anemic and transfusion dependent, had highest blast count and unfavorable karyotype. In general, their overall and leukemia‐free survival was the shortest with median time of 15 and 13 months, respectively; with incidence of acute leukemia almost twice as high as in the remaining patients (6.9 vs 3.6 cases per 100 person‐years). Nevertheless, this observation remains mostly significant for patients with PMF, as those with PEV/PVT‐MF have already significantly inferior prognosis with platelets <100 × 109/L.