Unmet Need in Essential Thrombocythemia and Polycythemia Vera

Ashwin Kishtagari, MD, Aaron T. Gerds, MD, MS

BCR-ABL1–negative myeloproliferative neoplasms (MPNs) comprise a group of clonal hematopoietic stem cell disorders characterized by aberrant proliferation of mature myeloid elements manifesting as erythrocytosis (polycythemia vera [PV]), thrombocy- tosis (essential thrombocytosis [ET]), leukocytosis and/or bone marrow fibrosis. Dys- regulated JAK-STAT signaling resulting from the acquired mutations involving janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia virus (MPL) with in the hematopoietic stem and progenitor cells is at the heart of MPN pathophys- iology.1 This leads to elevated inflammatory cytokines, which contribute to the wide spectrum of symptomatology experienced by patients with PV and patients with ET, including pruritis, fatigue, and splenomegaly. Patients with PV/ET have lifelong pro- pensity for thrombohemorrhagic complications, and in some cases progression to myelofibrosis, and evolution to acute myeloid leukemia.

Despite the tremendous advances in understanding the pathophysiology of these diseases, there are currently no curative treatments for these diseases outside of allogeneic hematopoietic stem cell transplantation. Given the lifelong propensity for thrombohemorrhagic complications, most currently approved treatments focus on mitigation of these risks. Current therapeutic options for PV/ET include aspirin (ASA), therapeutic phlebotomy for controlling hematocrit, and cytoreductive drugs such as hy- droxyurea. Therapeutic options for ET and PV are expanding, with many new agents in various stages of clinical trial evaluation. Large-scale genomic studies have identified the molecular underpinnings (JAK2, MPL, CALR) of the BCR-ABL1–negative MPNs, leading to the development of molecularly targeted therapies, which are currently in clinical trials. Ruxolitinib, a JAK1/2 inhibitor, is approved for the treatment of hydroxyurea-resistant PV. Despite its benefit in management of symptoms and blood counts, it does not appear to change the natural history of the disease.2 The quest for disease-modifying treatments in PV/ET has propelled the exploration of several agents in various stages of drug development, such as murine double minute 2 (MDM2) inhibitors, histone-deacetylase (HDAC) inhibitors, and lysine-specific histone demethylase 1 (LSD1) inhibitors (Fig. 1). Even with these exciting advances occurring, there are still several outstanding issues in considering the care of patients with PV and ET, which we discuss.

The ECLAP study has long been held up as the standard for antiplatelet therapy in MPNs. This study was conducted in 518 patients with PV with randomization in a double-blinded fashion to low-dose ASA (100 mg daily) or placebo.3 The use of aspirin resulted in a relative reduction (60%) of combined risk of nonfatal myocardial infarc- tion, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes (P 5 .03). The incidence of major bleeding was not significantly increased in the aspirin group as compared with placebo (P 5 .08). However, this study was conducted before the CYTO-PV study,4 and hematocrit was not as tightly controlled as it is today. In fact, the median hematocrit was 48% and 47% for the ASA and placebo groups, respectively. It is unclear if better hematocrit control would affect the results of this study. Nonetheless, given the risk-to-benefit ratio demonstrated in the ECLAP study, low-dose ASA is still recommended in PV.5,6
Randomized, prospective studies evaluating ASA in ET have not been conducted, as noted in a Cochrane Review,7 and the recommendation for the use of ASA in ET is largely extrapolated from the ECLAP study and retrospective analyses. In one retro- spective analysis of patients with ET given either low-dose ASA as monotherapy versus observation alone, JAK2 V617F-positive disease was associated with an increased risk of venous thrombosis in patients not receiving antiplatelet medication (incidence rate ratio [IRR] 4.0; 95% confidence interval [CI] 1.2–12.9; P 5 .02).8 An additional retrospective analysis suggests that there is an increased risk of bleeding in patients with CALR-mutated disease who receive low-dose ASA as compared with those who did not (12.9 vs 1.8 episodes per 1000 patient-years, P 5 .03) and no reduction in thrombosis risk.9 Based on this, low-dose ASA is recommended only for patients with high risk for thrombosis.5,6

The randomized CYTO-PV study set the standard for hematocrit control in PV.4 Keep- ing the hematocrit less than 45%, as compared with less stringent range between 45% and 50%, resulted in a reduction in time until death from cardiovascular cause or major thrombotic event (hazard ratio [HR] 3.91; 95% CI 1.45–10.53; P 5 .007). Although the lower limit of the confidence interval includes possibility of marginal benefit (0.45-fold greater risk in the high hematocrit group), consensus guidelines have widely adopted the practice of keeping the hematocrit to less than 45% owing to a favorable risk-to-benefit ratio.5,6 If you scour the guidelines, there is no equivalent evidence-based cytoreductive goal for platelet counts in ET.
At a minimum, it makes clinical sense to reduce the platelet count numbers in those who are at high risk for bleeding due to acquired von Willebrand syndrome as a result of extreme thrombocytosis. The paradox of an association between extreme throm- bocytosis (platelet counts more than 1000 109/L) and bleeding has been known for some time.10 In one retrospective analysis of 565 patients with ET, extreme throm- bocytosis was associated with a 2.3-fold increase (95% CI 1.3–3.7, P 5 .003) in the risk of bleeding events in a multivariate analysis.11 However, in low-risk young patients with ET, extreme thrombocytosis may not lead to an excess in bleeding events.12 Further complicating the matter, acquired von Willebrand syndrome has been described in patients with ET without extreme thrombocytosis. A carefully taken bleeding history can help identify patients who may have excess bleeding and warrant a workup for a concurrent bleeding diathesis.
Extreme thrombocytosis aside, in the absence of a randomized controlled trial or rigorous retrospective study, there is no consensus on a goal platelet count when beginning cytoreduction to lower the platelet counts of patients with ET. In a prospec- tive, randomized study of patients with high-risk ET (age >60 years and/or prior history of thrombosis), 56 patients received hydroxyurea and 58 were not given cytoreductive therapy.13 With a median follow-up of 27 months, the incidence of thrombotic epi- sodes was found to be significantly lower in patients treated with hydroxyurea

(3.6%) as compared with those who received no cytoreductive therapy (24%; differ- ence of 20.4%, 95% CI 8.5%–32%; P 5 .003). As of note, 69% of the patients in either arm of the study were receiving antiplatelet therapy. In the treatment arm, the hydroxy- urea dose was adjusted to a goal platelet count of 600 109/L or less based on a prior retrospective study.14 For many patients, it takes little cytoreduction, such as hydroxy- urea dosages of 500 to 1000 mg daily, to attain platelet counts in the normal range. However, for patients with counts more resistant to cytoreduction, the value of driving the counts into the normal range is unknown. This fact underscores both the need to approach platelet count goals on a case-by-case basis, and the need for new thera- peutics that enact a deeper disease modification.

Can Interferons Enact Disease Modification?
Interferon-alpha (IFN-a) and hydroxyurea are recommended cytoreductive treatments of symptomatic and high-risk patients with PV and ETs.4,5 Over the past 3 decades, various forms of IFN-a have been successfully used to treat patients with MPNs, including PV and ET. IFN-a can control erythrocytosis and thrombocytosis, as well as reduce the risk of thrombotic complications, splenomegaly, and pruritis in most pa- tients with PV or ET. IFN-a treatment has a disease-modifying potential by inducing complete hematologic-remissions, reversal of bone marrow fibrosis, and more recently evidenced by a reduction in mutation allele burden.15 It induces this response via antiproliferative, anti-angiogenic, pro-apoptotic, immunomodulatory, and differen- tiating properties on hematopoietic progenitors and may preferentially target the ma- lignant clone.16
Long-term efficacy and safety data show that IFN-a treatment accomplishes a high rate of complete hematologic response, minimized the occurrence of thromboembolic events, and remarkable rates of molecular responses.17,18 Most of these responses are also durable, an appealing aspect of IFN-a treatment.
The efficacy of ropeginterferon alpha-2b, a monopegylated recombinant IFN-a, was evaluated in the noninferiority randomized phase III PROUD-PV trial and its extension study CONTINUATION-PV compared with best available therapy (80% of which was hydroxyurea) in 257 patients with PV. Ropeginterferon alpha-2b treatment was asso- ciated with well-controlled hematocrit (<45%) levels without requiring therapeutic phlebotomy and minimized the occurrence of thromboembolic events. Most impor- tantly, disease progression was sporadic during 5-year results with ropeginterferon alpha-2b treatment. This indicates that the change in disease course may be related to deep and durable molecular responses achieved with this treatment.19,20 Ropegin- terferon alpha-2b is approved in the European Union as monotherapy for the treat- ment of patients with PV without symptomatic splenomegaly. Other critical evidence of the potential for IFN-a treatment to alter the natural history of MPNs is that it is the only treatment that can provide a long-term complete hema-tologic response after discontinuation of the treatment. This is particularly evident in patients with a driver mutation VAF lower than 10% at the time of discontinuation.21 This suggests that deeper driver mutation remission may be a biomarker surrogate for disease course modification. Recently published data show an association of germline genetic factors such as interferon lambda 4 (IFNL4) diplotype status and mo- lecular remission with IFN-a therapy in patients with PV reflecting the differential effect of IFN-a treatment on JAK2 V617 F mutational burden.22 There is now evidence that IFN-a treatment in patients with PV will improve overall survival and alter the disease course by reversing the bone marrow fibrosis.23 In this single-center retrospective study in 470 patients with PV, IFN-a (n 5 93) demonstrated superior myelofibrosis-free survival and overall survival advantage over hydroxyurea (n 5 189) or phlebotomy only (n 5 133) treatments with a median follow-up of 10 years.23 This constitutes other data supporting the disease-modifying potential of IFN-a. A Case for Murine Double Minute 2 Inhibitors The loss-of-function mutations in the TP53 gene, located on chromosome 17p13.1, is seen in most cancers. Its protein product, p53, functions as an essential tumor sup- pressor, and is tightly regulated by several mechanisms, including posttranslational modifications and interaction with the negative regulator E3 ligase MDM2. JAK2 V617 F increases MDM2 protein translation, resulting in upregulation of MDM2 levels in PV/ET CD341 stem/progenitor cells, and nutlins, a class of drugs that inhibit MDM2 activity and in turn lead to increased p53 activity, are capable of depleting mutated PV/ ET stem/progenitor cells.24,25 This is strong rationale to treat patients with ET/PV with an MDM2 inhibitor. The safety and efficacy of idasanutlin, a second-generation oral nutlin, was evalu- ated in a phase 1 trial, alone or in combination with IFN-a in patients with high-risk PV/ET for whom at least 1 prior line of therapy had failed.26 Twelve patients (PV, n 5 11; ET, n 5 1) with JAK2 V617 F-positive PV/ET were treated with idasanutlin at 100 and 150 mg daily, respectively, for 5 consecutive days of a 28-day cycle. The overall response rate after 6 cycles was 58% (7/12) with idasanutlin monotherapy. Median duration of response was 16.8 months (range, 3.5–26.7). Most importantly, the treatment was associated with a 43% mean reduction in the JAK2 V617 F variant allele frequency signifying the disease-modifying potential of the treatment. These encouraging results prompted the international multicenter phase 2 study evaluating idasanutlin in patients with PV who were hydroxyurea-resistant/intolerant and phlebotomy-dependent (>1 phlebotomy in the 16-week period before screening). Ida- sanutlin was given orally once daily for 5 consecutive days of a 28-day cycle for up to 24 months. The primary endpoint at 32 weeks was the composite response of hemat- ocrit control and spleen volume reduction greater than 35% by computed tomogra- phy/MRI in patients with splenomegaly and hematocrit alone in patients without splenomegaly; 27 patients were enrolled with median duration of treatment of 257 days (range, 5–677). The median number of treatment cycles was 8 (range, 1– 22). At week 32, 16 patients were assessed for primary endpoint. Nine (56.3%) of the 16 patients have achieved hematocrit control and 8 (50%) of 16 patients achieved complete hematologic response. Idasanutlin treatment resulted in reduction in JAK2 V617 F variant allele frequency, which was observed as early as after 3 cycles (median reduction, 39%; n 5 19) and was sustained in patients receiving treatment. Interest- ingly, the reduction in the clonal burden was significantly greater in patients with com- plete hematologic response and hematocrit control, indicating the disease-modifying potential of the drug.27,28 These enthusiastic results were dampened by the toxicities of the drug, a total of 3 serious adverse events were reported: atrial flutter, atrial fibril- lation, and nausea/vomiting. The recurrent gastrointestinal toxicity (nausea/vomiting) was common and was not alleviated with antiemetic prophylaxis throughout the treat- ment and led to frequent treatment discontinuations.
KRT-232, another oral small molecule MDM2 inhibitor, is currently being evaluated for the treatment of patients with phlebotomy-dependent PV. A randomized, open- label, multicenter, phase 2a/2b study to determine the efficacy and safety of KRT- 232 compared with ruxolitinib is currently accruing patients (NCT03669965).

Other Agents that May Lead to Disease Modification in Myeloproliferative Neoplasms
Givinostat is an orally bioavailable, potent inhibitor of class I and II histone-deacetylase (HDAC) that has demonstrated preclinical activity in selective targeting of the JAK2 V617 F clone by attenuating JAK2/STAT5 signaling and inducing apoptosis.29 Subse- quently, several studies have shown that givinostat is clinically active either as mono- therapy or in combination with hydroxyurea in patients with PV. The phase Ib/II proof- of-concept trial of givinostat in patients with PV was studied at the dosage of 100 mg twice daily. The objective response rate was 80.6% at the end of 3 cycles and 50% of patients reported symptomatic improvement (pruritus, headache) with givinostat treatment. Also, the givinostat treatment resulted in moderate reduction of JAK2 V617 F allele burden after 3 and 6 cycles of treatment. Almost all patients experienced a grade 1/2 treatment-related adverse event (diarrhea, 51%; thrombocytopenia, 45%; increased serum creatinine, 37%).30 Based on these results, a global registration phase III trial that will evaluate the efficacy of givinostat versus hydroxyurea in high- risk PV patients is under way.
Lysine-specific demethylase 1 (LSD1) is an epigenetic enzyme that can demethylate mono- and di-methylated lysine residues, specifically histone 3 and lysine 4 and 9 (H3K4 and H3K9), and plays a critical role in regulating gene transcription. LSD1 is essential for steady-state hematopoiesis as genetic knockdown or pharmacologic in- hibition of LSD1 abrogates erythropoiesis, granulopoiesis, and thrombopoiesis in a reversible fashion. In addition, LSD1 is found to be overexpressed in patients with MPN.31 Bomedemstat (IMG-7289), an irreversible LSD1 inhibitor, reduced spleno- megaly and bone marrow fibrosis, and normalized blood counts in the Jak2 V617 F murine model.32 Most importantly, this treatment resulted in reduction in mutant allele burden and improved survival of treated mice. This encouraging result has led to the ongoing clinical evaluation of bomedemstat as a second-line agent in PV and ET (NCT04262141, NCT04254978).
Hematocrit control through therapeutic phlebotomy in PV is achieved by reducing the iron stores in the body available for erythropoiesis. However, iron deficiency can also lead to symptoms including fatigue, brittle nails, and pica syndrome. Iron defi- ciency also suppresses hepcidin levels, which, in turn, increases absorption of iron and enhances red blood cell production. The hepcidin-mimetic PTG-300 is aiming to control red cell counts, by degradation of the ferroportin receptor in iron- absorptive enterocytes and iron-recycling macrophages, thus inducing iron- restricted erythropoiesis. In the case of PV, the hematocrit could be controlled in the absence of therapeutic phlebotomy and iron deficiency. It is currently being eval- uated in an ongoing phase II trial in patients requiring at least 3 phlebotomies in the preceding 24 weeks either with or without cytoreduction to maintain a hematocrit of less than 45% ( Identifier: NCT04057040). Of the first 13 patients enrolled (8 of whom have been treated for at least 3 months), all but 1 was phlebotomy-free on PTG-300.33 Moreover, iron-related parameters suggested a steady improvement in iron deficiency. This provides an exciting new way of control- ling red blood cell counts in PV, but it remains to be seen if there will be an associated reduction in symptom burden, thrombosis risk, or evidence of disease modification.

Most of the currently available treatment options for patients with PV/ET are mainly aimed at minimizing the risk of thrombosis and/or bleeding. So far, none of the approved treatments for PV/ET has shown clear evidence of disease-modifying potential. The ultimate goal of the novel treatments currently in various stages of drug development is disease modification; however, there is significant ambiguity in how to define this goal. Despite the tremendous success of JAK inhibitors in controlling the symptom burden, spleen size, and blood counts in patients with MPNs, as well as pro- longing survival in MF, these treatments are not considered disease-modifying.34 In the era of genomics, the standard approach is to measure disease modification with the reduction in the mutant allele burden of the driver mutation (JAK2, CALR, or MPL). Although it is intuitive, achieving molecular remission is not a validated endpoint in PV/ET, as its correlation with clinical outcomes, such has thrombotic events, disease progression, or overall survival, has not been established. Given that there are other pathways outside of JAK-STAT that are key in disease develop- ment, reduction of the driver mutant allele burden may prove not to be an effective sur- rogate endpoint for disease modification. Therefore, sustained exploration of the pathobiology and continued consensus on measurement of disease modification is needed for the future development of successful treatments.

MPNs are a group of clonal hematopoietic stem cell disorders characterized by abnormal myeloproliferation leading to elevated blood counts, splenomegaly, sys- temic inflammation, and propensity to thrombosis. To date, none of the available ther- apies for PV/ET have been shown to improve survival or prevent transformation to myelofibrosis or acute leukemia, instead, therapies are primarily targeted at prevent- ing thrombo-hemorrhagic complications and alleviating symptom burden. This is an urgent unmet clinical need in PV/ET. Although genetic driver mutation-specific tar- geted therapy is at the center of MPN drug development, recent evidence (eg, IFN-a, idasanutlin, givinostat, bomedemstat) highlights the importance of targeting other cellular pathways in MPN. There is now long-term evidence, albeit in a nonrandomized setting, that IFN-a treatment in patients with PV will improve overall survival and reverse bone marrow fibrosis in a fraction of treated patients, potentially altering the natural history of the disease. This emphasizes the importance of a broader approach to target novel pathways in MPN, with the goal of improving treatment outcomes.

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