Selected ASH Abstracts on Novel Treatments of Polycythemia Vera

Get Permission

Syed Ali Abutalib, MD

Syed Ali Abutalib, MD

Ruben A. Mesa, MD, FACP

Ruben A. Mesa, MD, FACP

To complement The ASCO Post’s continued comprehensive coverage of the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition, here are three abstracts selected from the meeting proceedings focusing on novel therapies for polycythemia vera. For full details of these study abstracts, visit

ABSTRACT 479: Safety and efficacy of single-agent oral idasanutlin (RG7388) in patients (n = 27) with hydroxyurea-resistant/intolerant polycythemia vera: Results of an international phase II study ( identifier NCT03287245)1

Mechanism of Action: MDM2, a negative regulator of the p53 protein, is overexpressed in CD34-positive myeloproliferative neoplasm cells harboring wild-type p53. It is the target of idasanutlin, an MDM2 antagonist that results in upregulation of p53 and downstream activators of apoptosis. Baseline MDM2 levels were higher in study participants than in normal controls (P = .01).

Methods: Idasanutlin was given orally once daily on days 1 to 5 of 28-day cycles for up to 24 months. The starting dose was 150 mg; an increase to 200 mg was allowed for nonresponders at cycle 3, day 28, and reduction to 100 mg was permitted for toxicity and for patients treated beyond cycle 12.

Key Findings: The population for primary endpoint evaluation consisted of patients with response assessed at week 32 (n = 16). Of 16 patients, 9 (56.3%) among all evaluable patients achieved hematocrit control: 6 of 11 ruxolitinib-naive patients and 3 of 5 ruxolitinib-exposed patients. Of 13 patients, 8 had hematocrit control duration of at least 12 weeks. At week 32, 8 of 16 patients achieved a complete hematologic remission (defined as hematocrit control and normalization of platelets/leukocytes), with 6 of 13 patients having a complete hematologic remission duration of at least 12 weeks beyond week 32.

Gastrointestinal toxicities (eg, taste disturbances, anorexia, nausea, vomiting, diarrhea, constipation, and abdominal pain) and fatigue were the most common adverse events occurring in at least 15% of patients. A total of three serious adverse events occurred: atrial flutter, atrial fibrillation, and nausea/vomiting. The serious cardiac adverse events occurred in patients with preexisting hypertension and a past incident of heart failure not symptomatic upon enrollment.

“PTG-300 looks promising in eliminating therapeutic phlebotomies in both low- and high-risk patients with polycythemia vera.”
— Syed Ali Abutalib, MD, and Ruben A. Mesa, MD, FACP

Tweet this quote

Clinical Implications: Idasanutlin showed relevant clinical activity in patients with hydroxyurea-resistant/intolerant polycythemia vera and also in a subset of patients with prior ruxolitinib treatment. However, the low-grade gastrointestinal toxicity profile of idasanutlin was not effectively mitigated with antiemetic prophylaxis and led to frequent discontinuations; this profile may be a barrier to its widespread use in a chronic disease such as polycythemia vera, where tolerability would be important. Antiemetic prophylaxis was mandatory in cycle 1 throughout the study and later became mandatory in all cycles.

ABSTRACT 481: Long-term use of ropeginterferon α-2b in polycythemia vera: 5-Year results from a randomized controlled study (PROUD-PV; NCT01949805) and its extension (CONTINUATION-PV; NCT02218047)2-4

Background: In both studies, long-term treatment with ropeginterferon α-2b (n = 95) was compared with standard cytoreductive therapy (n = 76; majority of patients on the control arm continued with hydroxyurea therapy) regarding thromboembolic and other adverse events as well as evolution of hematologic and molecular parameters over 5 years. At the time of this 5-year analysis, 70 patients in the ropeginterferon α-2b arm and 57 patients in the control arm remained on study; discontinuation rates were balanced between the treatment arms (ropeginterferon α-2b: 26.3%; control: 25.0%).

Methods: Ropeginterferon α-2b is a structurally novel monopegylated proline interferon designed for administration once every 2 weeks. Patients enrolled were either cytoreduction-naive or hydroxyurea-pretreated for up to 3 years. A total of 257 patients were randomly assigned 1:1 (stratified by age > 60 years, prior thromboembolic events, and hydroxyurea pretreatment) to receive ropeginterferon α-2b (subcutaneously every 2 weeks, starting at 100 μg) or hydroxyurea (orally starting at 500 mg/d) at individualized doses for 12 months in the initial study (PROUD-PV). In the extension study (CONTINUATION-PV), patients in the hydroxyurea arm were permitted to switch to the best available treatment.

Key Findings: At the 5-year visit, 58.5% of patients receiving ropeginterferon α-2b had well-controlled hematocrit (< 45%) without requiring phlebotomy; they also achieved a molecular response, compared with 17.3% on standard treatment (relative ratio = 3.52 [2.13–5.81]; P < .0001).

Few patients in the ropeginterferon α-2b arm experienced a major thromboembolic adverse event (4.2% [1.2% per patient year], and 6.6% [1.2% per patient-year] of patients in the control arm did so during the entire treatment period. The rate of molecular response at 5 years was also significantly with ropeginterferon α-2b than with the control (69.1% vs 21.6%; relative ratio = 3.2 [95% confidence interval 2.1–4.9; P < .0001]).

Regarding safety and tolerability, no new signals were detected in the fifth year. In the ropeginterferon α-2b group, the most frequently reported grade 3 or 4 treatment-related adverse events included increased gamma-glutamyltransferase (6%) and increased alanine aminotransferase (3%).4

Clinical Implications: In a randomized controlled setting, ropeginterferon α-2b treatment effectively controlled hematocrit and minimized the occurrence of thromboembolic events in patients with polycythemia vera and leads to more durable responses than hydroxyurea therapy. Disease progression was rare during long-term treatment with ropeginterferon α-2b, and this possible change in the disease natural history appears to be related to deep and durable molecular responses selectively achieved with ropeginterferon α-2b. The current National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for polycythemia vera suggest consideration of an interferon as an option for front- and/or second-line therapy. Considering the high and durable hematologic and molecular responses and its tolerability, ropeginterferon α-2b offers a valuable and safe long-term treatment option, with features distinctly improved from hydroxyurea.

ABSTRACT 482: Subcutaneous PTG-300 eliminates the need for therapeutic phlebotomy in both low- and high-risk polycythemia vera (seven and six patients, respectively; NCT04057040)5

Background: Investigators of the study previously demonstrated that PTG300, a hepcidin-mimetic, caused dose-related anemia in preclinical studies by blocking in vivo iron availability for erythropoiesis. In a phase II trial in β-thalassemia, PTG-300 led to a sustained (3–7 days) decrease in serum iron and transferrin saturation due to reduced ferroportin expression on cells that store or recycle iron without off-target effects.5,6 The current study aims to compare the iron status and phlebotomy requirements in patients with polycythemia vera who have a high need for therapeutic phlebotomy before and during treatment with PTG-300. Patients were on therapeutic phlebotomy alone (n = 6), plus either concurrent hydroxyurea (n = 6) or concurrent interferon (n = 1).

Key Findings: Eight patients have been treated for at least 3 months with PTG-300. Three patients have been randomly assigned.

During the open-label dose-finding portion of the study, all patients were phlebotomy-free with the exception of one. Three patients completed part 1 (28 weeks) with no therapeutic phlebotomy as compared with three to five therapeutic phlebotomies required in a similar period prior to study initiation. During the 28-week dose-finding period, the hematocrit was continuously controlled below 45% in all but two patients. Two patients had hematocrits transiently higher than 45% but remained below 45% after phlebotomy in one patient and dose increase in both patients. Furthermore, erythrocyte numbers decreased, and mean corpuscular volume increased in all but two patients. These findings suggest a redistribution of iron within erythropoiesis. Lastly, prior to treatment, mean iron--related parameters were consistent with systemic iron deficiency, whereas serum ferritin increased progressively toward the normal range.

The most frequent adverse events were injection-site reactions reported by three patients. Most of the reactions were grade 1 or 2 and were transient in nature, and no patient discontinued the drug.

Clinical Implications: The current results indicate that PTG-300 is an effective agent for the treatment of polycythemia vera, eliminating the need for therapeutic phlebotomy in patients by mimicking hepcidin and hence limiting the use of iron in erythropoiesis (and thus substitutes for phlebotomy). Elimination of therapeutic phlebotomy requirements for 7 months in therapeutic phlebotomy–dependent patients with polycythemia vera is significant and allows iron deficiency to slowly resolve. The effect of PTG-300 on polycythemia vera–related symptoms is also being evaluated. Continued patient enrollment will enable more definitive conclusions regarding the efficacy and safety of PTG-300 in patients with polycythemia vera who have high therapeutic phlebotomy requirements. PTG-300 looks promising in eliminating therapeutic phlebotomies in both low- and high-risk patients with polycythemia vera and could alter the approach to use of medications to control lower-risk polycythemia vera. 

DISCLOSURE: Dr. Abutalib has served on the advisory board for AstraZeneca and Partner Therapeutics. Dr. Mesa has received honoraria from AOP Orphan Pharmaceuticals, Novartis, Shire, and Sierra Oncology; has served as a consultant or advisor to Baxalta, Galena Biopharma, Incyte, and Novartis; has received institutional research funding from AbbVie, Celgene, CTI, Genentech, Gilead Sciences, Imago Pharma, Incyte, NS Pharma, Pfizer, PharmaEssentia, and Promedior; has been reimbursed for travel, accommodations, or other expenses by AOP Orphan Pharmaceuticals, Incyte, Novartis, and PharmaEssentia.


1. Mascarenhas J, Higgins B, Anders D, et al: Safety and efficacy of idasanutlin in patients with hydroxyurea-resistant/intolerant polycythemia vera: Results of an international phase II study. 2020 ASH Annual Meeting & Exposition. Abstract 479. Presented December 6, 2020.

2. Gisslinger H, Klade C, Georgiev P, et al: Long-term use of ropeginterferon alpha-2b in polycythemia vera: 5-Year results from a randomized controlled study and its extension. 2020 ASH Annual Meeting & Exposition. Abstract 481. Presented December 6, 2020.

3. Verger E, Soret-Dulphy J, Maslah N, et al: Ropeginterferon alpha-2b targets JAK2V617F-positive polycythemia vera cells in vitro and in vivo. Blood Cancer J 8:94, 2018.

4. Gisslinger H, Klade C, Georgiev P, et al: Ropeginterferon alfa-2b versus standard therapy for polycythaemia vera (PROUD-PV and CONTINUATION-PV): A randomised, non-inferiority, phase 3 trial and its extension study. Lancet Haematol 7:e196-e208, 2020.

5. Kremyanskaya M, Ginzburg Y, Kuykendall AT, et al: PTG-300 eliminates the need for therapeutic phlebotomy in both low and high-risk polycythemia vera patients. 2020 ASH Annual Meeting & Exposition. Abstract 482. Presented December 6, 2020.

6. Taranath R, Bourne G, Zhao L, et al: Regulation of iron homeostasis by PTG-300 improves disease parameters in mouse models for beta-thalassemia and hereditary hemochromatosis. 2019 ASH Annual Meeting & Exposition. Abstract 3540.

Dr. Abutalib is Associate Director of the Hematology and BMT/Cellular Therapy Programs and Director of the Clinical Apheresis Program at the Cancer Treatment Centers of America, Zion, Illinois; Associate Professor at Rosalind Franklin University of Medicine and Science; and Founder and Co-Editor of Advances in Cell and Gene Therapy. Dr. Mesa is Professor of Medicine and Executive Director of the Mays Cancer Center at UT Health San Antonio MD Anderson and the Mays Family Foundation Distinguished University Presidential Chair.