Moving toward disease modification in polycythemia vera

Polycythemia vera (PV) belongs to the BCR-ABL1–negative myeloproliferative neoplasms (MPNs) and is characterized by activating mutations in JAK2 (97% exon 14; 3% exon 12) leading to the proliferation of malignant hematopoietic stem and progenitor cells (HSPCs).^1-3 Clinically, patients with PV present with erythrocytosis, variable degrees of disease-related symptoms (eg, pruritus, night sweats, and fatigue), and an increased risk of both thromboembolic events and progression to myelofibrosis and acute myeloid leukemia (AML).^1,4 The recently published fifth edition of the World Health Organization Classification has reaffirmed the previously established major diagnostic criteria for PV, combining clinical (hemoglobin or hematocrit level >16.5 g/dL or 49%, respectively, in men; and 16 g/dL or 48%, respectively, in women), histopathological (bone marrow findings of trilineage hyperplasia [panmyelosis] and pleomorphic, mature megakaryocytes), and molecular features (presence of JAK2^V617 or exon 12 mutations).^5-7 A low serum erythropoietin level constitutes a minor criterion for PV diagnosis in the World Health Organization and the recently published International Consensus Classification.⁸ 

Treatment of patients with PV is individualized based on a patient’s age and a history of thrombosis, leading to the dichotomization of patients into those who are at low (no history of thrombosis and age ≤60 years) or high risk of thrombosis (history of thrombosis or age >60 years).⁶ Several other disease and patient characteristics have been associated with the risk of thrombosis (Table 1).

All patients with PV independent of risk should receive low-dose aspirin based on randomized, placebo-controlled clinical trial data showing a reduction in the composite risk of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes (relative risk, 0.40; 95% confidence interval [CI], 0.18-0.91; P = .03).^1,7,24 Additionally, the optimal management of cardiovascular risk factors in collaboration with primary care providers and other medical subspecialists is essential to reduce the risk of thrombotic complications among patients with PV.

In addition to low-dose aspirin, maintaining a hematocrit level <45% is recommended by both US and European management guidelines.^1,7 This recommendation is based on the CYTO-PV study, which demonstrated a reduced risk of major or fatal cardiovascular events in patients with PV, with the hematocrit level maintained strictly below a target of 45% compared with a more liberal target of 45% to 50% (hazard ratio [HR], 3.91; 95% CI, 1.45-10.53; P = .007).²⁷ 

Although US and European guidelines recommend the addition of cytoreductive therapy for patients with high-risk PV, patients with low-risk PV continue to be primarily managed with therapeutic phlebotomy and aspirin alone.^1,7 Of note, frequent phlebotomy or intolerance of phlebotomy, splenomegaly, progressive thrombocytosis, or leukocytosis, and significant disease-related symptoms can constitute an indication for the initiation of cytoreductive therapy for patients with otherwise low-risk PV.⁶ However, despite optimal hematocrit control, some patients with low-risk PV continue to experience a reduced quality of life and adverse events related to chronic phlebotomy (eg, iatrogenic iron deficiency) as well as a burden on patients and caregivers because of regular clinic visits.^30,31 Compared with matched controls, the risk of cardiovascular events remains increased among patients with low-risk PV, and almost half of the patients with PV included in a recent health care claims database study had insufficient hematocrit control, with values intermittently reaching >50%.^28,32 Because stable hematocrit control is essential to reduce the risk of thrombotic complications, the intermittent nature of phlebotomy limits its efficacy if hematocrit increases to >45% between treatments.^27,33 Therapeutic phlebotomy also does not address other blood count abnormalities such as leukocytosis, which potentially confers an increased risk of thrombosis, although studies have yielded conflicting results.^20,21 For example, in a recent multicenter, retrospective analysis of patients with PV with persistently elevated leukocyte trajectories had a similar risk of thrombotic events but higher rates of progression to myelofibrosis, myelodysplastic syndrome, or AML.²¹ Nonetheless, current guidelines use a leukocyte threshold of >15 × 10⁹/L as an indication for cytoreductive therapy.⁶ 

Additionally, phlebotomy alone does not address the underlying disease process and, as such, does not reduce the risk of long-term events such as progression to myelofibrosis or AML, which are driven by evolution and expansion of the malignant hematopoietic stem cell clone.³⁴ Thus a new approach to this disease is required.

Although current US and European guidelines recommend cytoreductive therapy with hydroxyurea, interferon alfa (IFN-α), or ruxolitinib (second line only for patients with intolerance or inadequate response to hydroxyurea) only for patients at high-risk and selected patients at low-risk, data from a prospective cohort study showed that 66.4% of patients with low-risk PV receive cytoreductive therapy.^1,6,7,30 

Although cytoreductive therapy with hydroxyurea reduces cardiovascular events and remains the most commonly used cytoreductive agent used in PV, it does not reduce the risk of progression to myelofibrosis and AML.^30,35-37 In a propensity-matched cohort study from Italy that compared outcomes in patients with PV treated with phlebotomy alone or hydroxyurea, arterial but not venous thrombosis was significantly reduced among patients treated with hydroxyurea.³⁸ Especially for younger patients, cytoreduction with hydroxyurea necessitates long-term therapy, which has implications on family planning, an increased risk of cutaneous malignancies (eg, nonmelanoma skin cancer), and concerns related to clonal evolution.^39,40 The specific risk of nonmelanoma skin cancer among patients treated with hydroxyurea is variable, ranging from 0.3% to 27% of patients across studies, but close dermatologic surveillance is needed.^35,41 Additionally, the leukemogenic potential of hydroxyurea remains controversial with most, but not all, studies showing no increased incidence of AML among patients treated with hydroxyurea.^42-44 Nonetheless, alternative agents are needed, especially for younger patients and patients intolerant or refractory to treatment with hydroxyurea.

Various formulations of IFN-α have been developed and studied in clinical trials for patients with PV since the 1990s, with a growing body of evidence showing at least noninferiority to hydroxyurea.^36,45-48 Additionally, a subset of patients can achieve a complete molecular remission.^49,50 Table 2 provides an overview of recent phase 2/3 clinical trials of IFN-α in PV. A comprehensive systematic review and meta-analysis was published recently.⁴⁷ 

Compared with hydroxyurea and phlebotomy, this disease-modifying potential of IFN-α has also been shown to prolong myelofibrosis-free survival in a large retrospective analysis of patients with low-risk PV, whereas patients with high-risk PV also experienced an overall survival (OS) benefit with IFN-α.⁵⁰ However, it is important to note that this was a retrospective study and that there was a significantly higher proportion of patients with high-risk disease in the hydroxyurea group (24% vs 56%; P < .001).⁵⁰ 

Randomized clinical trials demonstrated that both ropegylated IFN-α2b (ropeg-IFN) and pegylated IFN-α2a (peg-IFN-α) are not inferior to hydroxyurea in terms of hematologic response at 12 months.^36,45,57 In the case of the Myeloproliferative Disorders Research Consortium (MPD-RC)-112 study (NCT01259856), this also included bone marrow responses.⁴⁵ Importantly, the depth of response to IFN-α deepens over time, with ropeg-IFN having been shown to be superior to hydroxyurea at 36 months in the CONTINUATION-PV study in terms of hematologic control (complete hematologic remission [CHR; defined as a hematocrit level <45% with no phlebotomy for ≥3 months, platelet count <400 × 10⁹/L, and leucocyte count <10 × 10⁹/L] 53% vs 38%; P = .044) and molecular responses (19.6% of patients treated with ropeg-IFN having achieved a JAK2^V617F variant allele fraction [VAF] of <1% at 60 months compared with only 1.4% in the control group [P = .0002]).^36,49 Additionally, the adverse event profile of IFN is distinct from that of hydroxyurea, with liver function test abnormalities, injection site reactions, influenza-like symptoms, and psychiatric symptoms (especially depression) being more common with IFN.^36,45 Limited data support the safety of IFN in pediatric and pregnant patients.^58,59 

For patients who are refractory to or intolerant of hydroxyurea, peg-IFN-α can be an attractive option, with an overall response rate of 60% (22% complete remission [CR]) reported in the MPD-RC–111 phase 2 study (NCT01259856).⁵⁴ Interestingly, clinical responses appeared to be independent of a reduction in JAK2^V617F allele burden.⁵⁴ Symptom burden was also significantly improved among responders compared with that among nonresponders in a combined analysis of the MPD-RC–111 and MPD-RC–112 trials.⁶⁰ Similar response rates have been reported by several other clinical trials using various IFN formulations.^47,51,52,61

Among patients with low-risk PV, the addition of ropeg-IFN led to higher response rates (hematocrit level <45%) compared with phlebotomy alone in a randomized phase 2 trial (84% vs 60%; P = .0075; NCT03003325).⁵⁶ Additionally, the total number of phlebotomies per year was lower in the experimental arm (2.8 [95% CI, 2.1-3.5] vs 3.8 [95% CI, 3.1-4.5]; P = .029), with 16% of treated patients attaining phlebotomy freedom throughout the 12-month study period.⁵⁶ However, rates of treatment-emergent adverse events were higher with ropeg-IFN (78% vs 42%; P < .0001).⁵⁶ The final results of the trial were recently published, with 81% of patients treated with ropeg-IFN achieving the primary end point of maintaining a median hematocrit level <45% over 12 months in the absence of progressive disease, compared with 51% in the standard group.⁶² Additionally, the rate of moderate/severe symptoms was lower in the ropeg-IFN arm compared with in the standard arm after 24 months (33% vs 67%). Patients treated with ropeg-IFN also demonstrated a decrease in the JAK2^V617F VAF from baseline to 12 and 24 months (−11.9% and −23.1%, respectively), with no changes in the control group. Extended follow-up is necessary to evaluate whether treatment of low-risk PV leads to a reduction in cardiovascular events, progression to myelofibrosis or AML, and ultimately prolongation of OS. Furthermore, it is noteworthy that ropeg-IFN was given at a fixed, low dose of 100 μg every 2 weeks with phlebotomy to maintain a median hematocrit level ≤45% in the Low-PV study, which is different from the PROUD-PV and CONTINUATION-PV studies that used response-adapted doses of ropeg-IFN of up to 500 μg every 2 weeks.^36,62 Whether the fixed, low-dose strategy used in the Low-PV study contributed to the 19% nonresponse rate among patients treated with ropeg-IFN is uncertain, especially because no biomarkers of response were identified in this study. Thus, the best dosing strategy of ropeg-IFN in patients with PV and parameters that should be used for dose titration remain unclear. The latter aspect is currently being explored in the ECLIPSE study (NCT05481151) that randomizes patients with PV to conventional slow titration of ropeg-IFN as per the US Food and Drug Administration label vs an accelerated titration approach. The rationale is to explore whether faster attainment of CHR can induce molecular responses more effectively. A comparison of toxicity profiles will also be informative in determining the balance of clinical effect and tolerability in terms of optimal dosing strategy for ropeg-IFN.

Retrospective data suggest that responses in a subset of patients who discontinue IFN-α are durable, suggesting an elimination (or at least prolonged suppression) of the malignant stem cell clone.⁶³ This observation would be in line with preclinical studies showing that IFN-α is able to eradicate the disease-initiating JAK2^V617F-mutant hematopoietic stem cell clone in a murine model.⁶⁴ The effect of IFN-α on the HSPC compartment is further supported by data showing that IFN-α targets the human JAK2^V617F-mutant HSPCs more effectively than mature cells.⁶⁵ Furthermore, homozygous JAK2^V617F clones responded more rapidly than heterozygous clones.⁶⁵ Although additional follow-up and prospective validation is needed, this suggests that time-limited therapy in PV might be possible, which is especially attractive for younger patients.

The exact biologic mechanisms by which IFN-α leads to the elimination of the malignant clone remains unknown.^64-66 MPNs, including PV, are characterized by a chronic inflammatory state, which is sustained by the malignant clone itself.⁶⁷ IFN-α has been associated with various immunomodulatory functions, enhancing antitumor responses via the activation of B and T cells and natural killer cells and enhanced expression of major histocompatibility complex class I molecules by tumor cells.^46,68,69 Furthermore, IFN-α has antiproliferative and proapoptotic effects including inhibition of telomerase activity and downregulation of telomerase reverse transcriptase.^70,71 Finally, gene expression profiles of patients with MPN revealed the deregulation of oxidative stress pathways, which was reversible by treatment with recombinant IFN-α.⁷² 

The pattern of concurrent mutations could serve as a predictive biomarker and provide additional insights into resistance mechanisms. For example, TET2 mutations have been associated with lower response rates to IFN-α.^73,74 The impact of other mutations as well as clonal complexity on response likelihood to IFN-α requires additional studies.⁷³ Additionally, in the DALIAH trial, the emergence of DNMT3A mutations was more common among patients treated with IFN-α than that among patients treated with hydroxyurea and was associated with lower rates of CHR.⁶⁶ IFN-λ4 diplotype status has been suggested as a potential biomarker but requires additional validation.⁷⁵ Of note, changes in the immune cell repertoire among patients treated with IFN-α did not correlate with hematologic or molecular responses.⁶⁸ 

Although limited by small numbers, Quintas-Cardama et al showed that patients who failed to achieve a complete molecular remission (defined as undetectable JAK2^V617F mutation using a polymerase chain reaction assay with 5% sensitivity) had higher rates of clonal evolution than patients who achieved a complete molecular remission (9 of 14 patients vs 0 of 9 patients).⁷³ However, whether reducing clonal evolution is associated with delaying progression to myelofibrosis or AML requires longer duration of follow-up, and current evidence is insufficient to justify a general recommendation to initiate cytoreductive therapy early for patients with low-risk PV based on preventing clonal evolution alone.

The JAK1/2 inhibitor ruxolitinib has demonstrated superior rates of hematocrit control (60% vs 20%) and CHR (24% vs 9%; P = .003) compared with standard of care in a randomized trial of patients with PV and splenomegaly who were phlebotomy dependent and received prior treatment with hydroxyurea.⁷⁶ With extended follow-up, responses to ruxolitinib appear sustained, with numerically lower rates of exposure-adjusted thromboembolic events (1.2 per 100 patient-years with ruxolitinib vs 8.2 with best available therapy [BAT]), although OS and progression to myelofibrosis and AML were not improved by treatment with ruxolitinib.⁷⁷ A similar open-label phase 3 trial compared ruxolitinib with BAT (hydroxyurea [n = 50%], IFN or peg-IFN [12%], pipobroman [7%], lenalidomide [1%], or no treatment [29%]) among 149 patients with PV without splenomegaly who were intolerant of or resistant to hydroxyurea.^78,79 Hematocrit control by week 28 was achieved in 62% vs 19% of patients treated with ruxolitinib and BAT, respectively (odds ratio, 7.28; 95% CI, 3.43-15.45; P < .0001).⁷⁹ After 260 weeks of follow-up, 22% of the patients in the ruxolitinib group achieved durable hematocrit control, with a 5-year OS rate of 96% (95% CI, 87-99) vs 91% (95% CI, 80-96) in the BAT group.⁷⁸ The role of ruxolitinib in the frontline setting is being explored in the Ruxo-BEAT trial (NCT02577926), with early data showing a significant decrease in both mean hematocrit (45.9%-41.0%; P = .0003) and annual number of phlebotomies (4.2-0.96; P = .0009).⁸⁰ However, a formal comparison with the control arm of BAT is not available. Finally, the phase 2 MAJIC-PV trial randomized 180 patients with PV who were resistant to or intolerant of hydroxyurea to ruxolitinib or BAT and showed a higher CR rate (defined per 2013 European LeukemiaNet criteria) with ruxolitinib than with BAT (43% vs 26%; odds ratio, 2.12; 90% CI, 1.25-3.60; P = .02).^25,81 Importantly, event-free survival (EFS; defined as a composite of major thrombosis, hemorrhage, transformation, and death) was superior for patients receiving ruxolitinib (hazard ratio, 0.58; 95% CI, 0.35-0.94; P = .03) as was thromboembolic-free survival. EFS was also improved for patients who obtained a CR and/or molecular responses.²⁵ Interestingly, correlative studies showed a reduction in the clonal burden of JAK2^V617F in the HSPC compartment of ruxolitinib-treated patients suggesting a direct impact on the malignant stem cell clone, which also correlated with improved EFS.²⁵ These findings argue for the relevance of molecular responses (defined as a ≥50% reduction in VAF) to the improvement of other clinical outcomes in PV. No trials of ruxolitinib for patients with low-risk PV or as an alternative to phlebotomy have been conducted. However, prior data have shown that JAK2^V617F allele burden in isolation is an insufficient predictor of thrombosis risk because other disease, patient, and treatment characteristics that interact with JAK2^V617F allele burden also define the risk of thrombosis.^82,83 Additionally, ruxolitinib was associated with an increased risk of certain adverse events compared with BAT in the MAJIC-PV study, including infections (20 grade 3 or 4 events vs 8 with BAT), squamous cell carcinoma of the skin (11 vs 0 events), metabolic disorders (9 vs 7 grade 3 or 4 events), and herpes zoster infection (27 vs 12 grade 3 or 4 events).²⁵ 

For patients who are unable to tolerate or are resistant to second-line treatment with ruxolitinib, enrollment in a clinical trial is preferred. Outside of a clinical trial, treatment with busulfan can be effective, with a CHR rate of 83% reported in a study of 15 patients with advanced PV refractory or intolerant to hydroxyurea.⁸⁴ Comparable results have been reported from a multicenter, retrospective study that included 51 patients with MPNs treated with busulfan after hydroxyurea failure, with a rate of complete or partial hematologic remission of 75%.⁸⁵ However, treatment with busulfan has been associated with an increased risk of progression to AML in some (but not all) studies; therefore, this agent is best used for older patients in need of better blood count control.^84,86,87 Other treatment options such as pipobroman or radioactive phosphorus should not be used based on limited efficacy and leukemogenic potential.^6,88 

Because inflammation is an important contributor to the pathogenesis of PV, combination treatment with ruxolitinib and IFN-α could have synergistic effects, given the immunomodulatory properties of both agents.⁴⁶ Additionally, the antiinflammatory effects of ruxolitinib could increase the tolerability to IFN-α and reduce rates of early discontinuation. Early-stage clinical trials evaluating the safety and efficacy of combination therapy with ruxolitinib and peg-IFN-α have recently been reported. In a single-arm phase 2 trial (EudraCT2013-003295-12) of ruxolitinib and peg-IFN-α that enrolled 32 patients with PV (94% with prior peg-IFN-α exposure), 31% achieved either a complete (9%) or partial (22%) hematologic remission.⁸⁹ The mean reduction in JAK2^V617F VAF was numerically greater among patients who were previously intolerant to peg-IFN-α or were IFN-α naive compared with patients who were previously refractory (61%, 65%, and 34%, respectively).⁸⁹ It remains to be seen whether early combination therapy for patients with newly diagnosed PV can be more effective at eliminating the malignant clone and reducing the risk of thrombosis or disease progression. Preliminary data from 25 patients with newly diagnosed PV (19 at high risk and 6 at low risk) enrolled in an ongoing single-arm trial of ruxolitinib + peg-IFN-α showed attainment of CHR in all 25 patients, with significant reductions in JAK2^V617F VAF (median of 47% [95% CI, 35-59] at baseline to 6% [95% CI, 3-12] after 24 months; 4 patients achieved a JAK2^V617F VAF < 1%).⁹⁰ There was 1 case of acute myocardial infarction but no other thromboembolic events. Additionally, 1 patient progressed to myelofibrosis 10 months after starting treatment.⁹⁰ 

The combination of ruxolitinib with either hydroxyurea or IFN-α for patients with newly diagnosed high-risk PV is also being studied in a randomized, open-label phase 3 trial (NCT04116502).

Selected ongoing clinical trials of novel agents in PV are summarized in Table 3. In an ongoing phase 2 trial, rusfertide, a hepcidin mimetic, reduced the hematocrit level to <45% without the need for phlebotomy in all 16 patients who were phlebotomy naive and who received treatment.⁹¹ Among patients with insufficient hematocrit control despite phlebotomy with and without cytoreductive therapy, rusfertide substantially reduced the mean number of phlebotomies from 4.63 in the 28 weeks before enrollment to 0.43 with treatment.⁹² Although these results are highly encouraging and the sustained and constant hematocrit control with rusfertide might lead to a lower risk of thrombotic events than with intermittent phlebotomy, larger studies with longer duration of follow-up are needed. Additionally, it is important to note that rusfertide is unlikely to lead to a reduction in leukocyte count or to sustained molecular remissions based on its mechanism of action that appears to be primarily centered on iron metabolism.^21,22,92 The randomized, placebo-controlled phase 3 VERIFY trial (NCT05210790) is ongoing and should provide additional insights into the efficacy and safety profile of rusfertide in a broader patient population.⁹³ 

Murine double-minute 2 (MDM2) is a key negative regulator of the tumor suppressor protein p53 that inhibits p53 function and has been shown to be upregulated in PV stem and progenitor cells, making it a potential therapeutic target.^94,95 Preclinical data also suggest synergy of combination treatment with MDM2 inhibition and IFN.⁹⁴ In a recently completed phase 2 study (NCT03287245) of the MDM2 inhibitor idasanutlin that enrolled 27 patients with PV who were phlebotomy dependent and hydroxyurea resistant/intolerant, 56% and 50% achieved hematocrit control and CHR, respectively.⁹⁶ Response rates were comparable among patients who were ruxolitinib naive and those previously exposed to ruxolitinib (55% vs 60%).⁹⁶ Additionally, there was a median reduction in JAK2^V617F allele burden by 76%, which was associated with hematologic responses.⁹⁶ However, gastrointestinal adverse events were common (nausea [93%; 11% grade ≥3], diarrhea [78%], and vomiting [41%]) and 41% of enrolled patients discontinued treatment early.⁹⁶ Analysis of patient samples also revealed a transient expansion of TP53-mutant clones during treatment with idasanutlin, which was reversible with treatment discontinuation and not associated with disease progression.⁹⁷ Nonetheless, this phenomena will require attention in future studies.

We believe that increased awareness and a better understanding of disease modification across MPNs will be crucial for drug development and may ultimately change the treatment paradigm for patients. Such efforts are already underway to begin defining what constitutes disease modification in myelofibrosis.^98,99 Similar to myelofibrosis, disease modification in PV likely includes several aspects such as cytokine level modulations and hematologic, molecular, and histopathologic parameters and their relationship to objective and clinically relevant clinical outcomes (eg, thrombotic events, progression to myelofibrosis and AML, and OS). Ultimately, the goals of treatment should be refined and focused on allowing patients the best chance to live a normal lifespan free of the sequelae of the disease. With this premise in mind, we have summarized clinical trial end points and surrogate markers for disease-modifying effects of investigational therapies (Table 4).

Given the absence of a disease-modifying treatment effect, the associated burden on patients and caregivers, and the development of novel, alternative approaches, the role of phlebotomy as the primary and exclusive treatment for patients with low-risk PV is diminishing. Additionally, the use of hydroxyurea as the default choice for cytoreductive therapy is debatable, especially with the approval of novel IFN-α formulations that are better tolerated and could offer an attractive option for a broad range of patients with low- or high-risk disease. Increasing evidence suggests that IFN-α has the potential to change the natural history of PV with deep (and sometimes durable) molecular remissions in a subset of patients that may translate into an improved myelofibrosis-free survival and OS.⁵⁰ Whether this could enable time-limited therapy (ie, treatment for a finite period of time followed by treatment discontinuation and active surveillance after a predefined response threshold is met) and what patient and disease characteristics may predict response to IFN-α remain to be determined with the execution of prospective trials with sufficient follow-up. In the case of younger patients, the benefits of IFN-α could include improvement in the quality of life with a reduction in the time spent in the health care office for receiving therapeutic phlebotomies and the potential long-term toxicities associated with hydroxyurea.³¹ However, we would like to emphasize that the current evidence does not support the general implementation of such an early, IFN-α–based intervention strategy for all patients with low-risk PV. Longer follow-up is necessary to evaluate whether early intervention and the high rates of hematologic and molecular responses seen with IFN-α–based therapies lead to a reduction in clinically relevant long-term outcomes such as thrombotic events and progression to myelofibrosis and AML. Especially, because treatment with IFN-α can be associated with adverse events in patients who would otherwise not receive any medication, selecting patients at high risk of disease progression, for example based on molecular features, can lead to a more favorable risk-to-benefit ratio.¹⁰⁰ Finally, the health-economic implications of this paradigm shift are unclear and warrant further study.

With the increasing availability of molecular testing, a paradigm shift away from indefinite therapy to a time-limited treatment approach might become possible. Such time-limited treatment could be based on predefined clinical and molecular parameters similar to the milestones established for treatment discontinuation in chronic myeloid leukemia based on quantitative BCR-ABL1 transcript assessments.¹⁰⁵ For example, Kiladjian et al suggested potential criteria for treatment discontinuation (JAK2^V617F VAF < 10%; sustained CHR for ≥2 years; and no disease progression, thromboembolic events, or worsening of disease-related signs or symptoms over the entire treatment period).⁴⁹ However, prospective validation of these criteria is needed.

Furthermore, novel prospective studies with end points such as progression-free survival and OS are needed to advance the treatment of patients with PV. Such trials will likely require many years to complete, and a concerted and coordinated investment of time and resources on the part of investigators and the pharmaceutical industry will be required. In parallel, the search for surrogate markers of progression-free survival and OS using existing data sets should be pursued and integrated into prospective clinical investigations (Table 4).

Although normalization of complete blood count (CBC) parameters remains the cornerstone of PV management and should be considered an essential end point in clinical trials of PV,²⁷ we would argue that it is time to incorporate molecular responses more prominently in the response criteria; data from recent trials demonstrating improved EFS in patients treated with ruxolitinib achieving molecular responses as well as older data showing a lower rate of progression to myelofibrosis among patients with PV with low JAK2^V617F allele burden support such considerations.^25,83,106 Because hematologic and molecular responses are frequently correlated among patients treated with IFN but not those treated with hydroxyurea,^25,36,62,83 we would suggest reporting both hematologic and molecular end points in clinical trials, with an emphasis on standardization of assessment and reporting. Additional prospective data are needed to determine what the optimal depth of molecular response is, because JAK2^V617F is among the most common mutations encountered in individuals with clonal hematopoiesis.¹⁰⁷ With increasingly sophisticated techniques it will also be possible to disentangle the HSPC compartment from other cell types harboring JAK2^V617F. However, molecular responses require time to achieve and can deepen over time, as exemplified by the multiple studies with IFN, which is an important consideration for clinical trial design. Finally, it will be essential to standardize testing of JAK2^V617F in terms of which assay to use, timing of assessment, and whether peripheral blood or bone marrow should be analyzed. This harmonization effort across the research community in collaboration with regulatory agencies will be essential to establish JAK2^V617F allele burden as a molecular biomarker of response.

In summary, our current treatment approaches are inadequate to help patients with PV live the longest and best lives possible. Available therapies such as IFN provide an opportunity for patients with PV to achieve deep molecular responses as a surrogate for disease burden reduction, and the integration of mutational testing into the management of PV should allow us to delineate minimal residual disease states. Cooperative group approaches with academia, community-based practitioners, industry partners, and regulatory agencies will need to focus resources and energy into efficiently developing the next generation of prospective clinical trials with end points such as EFS and OS and embedded molecular correlates that not only identify predictive biomarkers for response but also surrogate biomarkers for remission and functional cure.

Contribution: J.P.B. and R.K.R. conceptualized the study and wrote the initial draft of the manuscript; and all authors reviewed and contributed to subsequent drafts of the manuscript.

Conflict-of-interest disclosure: P.B. reports research funding from Incyte, Bristol Myers Squibb, Cell Therapeutics Inc (CTI) BioPharma, MorphoSys, Kartos, Telios, Sumitomo, Ionis, Disc, Blueprint, Cogent, Geron, and Janssen and honoraria/consulting fees from Incyte, Bristol Myers Squibb, CTI BioPharma, GlaxoSmithKline, AbbVie, MorphoSys, Jubilant, Morphic, Blueprint, Cogent, Karyopharm, Pharma Essentia, Sumitomo, and Novartis. N.P. is a member of the board of directors of Dan’s House of Hope; had a consultancy with, served on the scientific advisory board for, or received speaking fees from AbbVie, Aplastic Anemia and Myelodysplastic Syndrome International Foundation, Aptitude Health, Astellas, Blueprint, Bristol Myers Squibb, CancerNet, CareDx, Celgene, Cimeio Therapeutics, ClearView, CTI, Curio Science, Dava Oncology, EUSA Pharma, Harborside Press, Imedex, ImmunoGen, Intellisphere, Magdalen Medical Publishing, Medscape, Menarini Group, Neopharm, Novartis, OncLive, Pacylex, Patient Power, PeerView Institute for Medical Education, PharmaEssentia, and Physician Education Resource. J.M. receives research funding paid to the institution from CTI BioPharma, Incyte, Novartis, Bristol Myers Squibb, Geron, Kartos, Karyopharm, PharmaEssentia, and AbbVie and consulting fees from Celgene/Bristol Myers Squibb, Incyte, Novartis, AbbVie, CTI BioPharma, PharmaEssentia, Roche, Karyopharm, Kartos, MorphoSys, Imago, GlaxoSmithKline, Pfizer, Sierra Oncology, Disc Medicines, and Galecto. R.K.R. has received research funding from Zentalis, Incyte, Constellation, Stemline and has received consulting fees from Constellation, Zentalis, Incyte, Celgene/Bristol Myers Squibb, Novartis, Promedior, CTI, Jazz Pharmaceuticals, Servier, Blueprint, Stemline, Galecto, PharmaEssentia, AbbVie, Sierra Oncology/GlaxoSmithKline, Disc Medicines, Sunimoto Dainippon, Kartos, and Karyopharm. The remaining authors declare no competing financial interests.

Correspondence: Raajit K. Rampal, Leukemia Service, Memorial Sloan Kettering Cancer Center, 530 East 74th St, New York, NY 10065; e-mail: rampalr@mskcc.org.