Polycythemia Vera: Barriers to and Strategies for Optimal Management

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Andrea Duminuco,1,2 Patrick Harrington,1 Claire Harrison,1 Natalia Curto-Garcia1

1Department of Haematology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 2Haematology with BMT Unit, A.O.U. Policlinico “G.Rodolico-San Marco”, Catania, Italy

Correspondence: Claire Harrison, Guys’ and St Thomas’ Hospital, London, SE1 9RT, UK, Tel +207 188 2742, Email Claire.harrison@gstt.nhs.uk

Abstract: Polycythemia vera (PV) is a subtype of myeloproliferative neoplasms characterized by impaired quality of life and severe complications. Despite the increasingly in-depth knowledge of this condition, it necessitates a multifaceted management approach to mitigate symptoms and prevent thrombotic and hemorrhagic events, ensuring prolonged survival. The therapeutic landscape has been revolutionized in recent years, where venesection and hydroxycarbamide associated with antiplatelet therapy have a central role and are now accompanied by other drugs, such as interferon and Janus kinase inhibitors. Ongoing research and advancements in targeted therapies hold promise for further enhancing the therapeutic choice for PV management.

Keywords: polycythemia vera, barriers to treatment, current approach, future perspectives

Introduction

Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by the presence of erythrocytosis in peripheral blood due to an acquired mutation on the JAK2 gene (~95% with JAK2V617F in exon 14). Consequently, the JAK-STAT pathway is activated, promoting blood cell proliferation and inhibiting apoptosis. PV incidence is estimated at 22 per 100,000 population,1 and the average age of presentation is 65–74 years, although it has been described in younger patients.2,3

Excess erythrocytosis and panmyelosis characteristic of PV can lead to thrombotic events (TE – both arterial and venous), which may be the first presentation of PV or precede the diagnosis.4 Common symptoms in these patients are aquagenic pruritus, erythromelalgia (burning pain in the extremities), or hyperviscosity symptoms (headaches, blurry vision), and fatigue, among others.

Beyond the JAK2V617F mutation, other mutations have been associated with PV, such as those in exon 12 of JAK2, and other mutations involving epigenetic (ie, TET2, ASXL1) or splicing (ie, SRSF2, U2AF1); furthermore, abnormal cytogenetics such as del(20q), +8, and +9 are well described.5,6 The risk of disease progression to myelofibrosis (MF) and acute myeloid leukemia (AML) is estimated at 10 years at 4.9–6% and 2–5%, respectively, and at 20 years at 26% for MF and remains below 10% in the case of AML.7 The Mutation-Enhanced International Prognostic Scoring System for PV (MIPSS-PV) integrates genetic and clinical/demographic information to predict OS and risk of transformation to MF or AML, underlying the negative role of adverse mutations (among which spliceosome), age >67 years, leukocytosis ≥15 × 109/L, and thrombotic history.8

The current management of PV is based on risk stratification; hence, high-risk patients are defined as those aged ≥60–65 years old and/or the presence of PV-related TE. Other factors that have been considered are the presence of cardiovascular risk factors (CVRF – hypertension, hypercholesterolemia, diabetes); excess platelet levels ≥1500×109/L; need for venesection (VS) to keep hematocrit (Hct) <0.45, among others; increasingly genomic factors such as JAK2 VAF and additional mutations are also considered. Cytoreductive therapy with VS and antiplatelets is recommended for this high-risk population, while low-risk patients are managed with just venesection and antiplatelets.9,10

Here, we will focus on reviewing the classical and new therapies used in PV patients and the challenges in delivering care to this patient group, often not allowing optimal management.

Management of PV

At present, limited therapies are available to completely eradicate the neoplastic clone from which the MPN phenotype originates. Though recent studies have shown treatments are able to reduce the mutated allelic fraction, its disappearance is almost unprecedented, and the relevance of this reduction is not fully substantiated. The main goals of managing PV patients are to control hematocrit (Hct) and disease-related symptoms and reduce the risk of TE and disease progression. In this aspect, patients without a history of thrombosis and age ≤60/65 are stratified as low-risk disease, while, in case of a previous PV-related TE or age ≥60/65 years as high-risk.9,11 According to this stratification, the management approach ranges from a watch-and-wait to active treatment. Overall, VS and antiplatelet therapies are recommended for all PV patients to reduce the risk of thrombosis and would constitute watch and wait. Recent guidelines suggest cytoreductive treatment for low-risk patients with CVRF, uncontrolled Hct levels, elevated white blood cells (WBC), and extreme thrombocytosis,9 but these considerations can be challenging to implement, and, for example, guidelines are unclear as to what constitutes “elevation or extreme or uncontrolled”.

Prevention of Thrombotic Risk: General ApproachManagement of Cardiovascular Risk Factors and Lifestyle

It is well known that cardiovascular risk factors such as hypertension, hyperlipidemia, diabetes, or smoking habits can increase the risk of TE in the general population. In the PV patients, Cerquozzi et al described the correlation between the presence of hyperlipidemia (p = 0.03) and hypertension (p = 0.02) and arterial events.12 Equally, the survival of PV patients can be affected by the presence of cardiovascular risk factors.13 Therefore, it is highly recommended to manage these factors and promote a healthy lifestyle with an adequate diet, reduced smoking and alcohol consumption, and regular exercise. Moreover, some medications, such as ruxolitinib, can increase cholesterol levels; hence, a routine check of cholesterol levels is suggested in patients with this JAK inhibitor. Implementing routine cardiovascular risk factor screening for all patients and enhanced screening in some patients taking agents such as ruxolitinib is challenging, and which tools and thresholds for realization are unclear.

Few studies have focused on the role of diet in MPN in recent years. The Mediterranean diet has anti-inflammatory properties and could reduce the incidence of cardiovascular risk factors.14,15 The Nutrient Trial has explored the role of the Mediterranean diet in MPN patients, looking at reduction in inflammatory biomarkers and symptom burden, among others. Although no significant differences in the inflammatory markers were found, the adherence to this diet was good.16 Overall, a healthy and varied diet, together with regular exercise, should be encouraged for MPN patients, but, for the large part, these are not implemented in routine care.

Venesection

Venesection (VS) remains the cornerstone treatment for PV. Removing red blood cells from the peripheral blood is primarily aimed at reducing blood viscosity, thus preventing TE with associated complications and helping to alleviate symptoms common to PV, such as pruritus, headache, and fatigue.

In 1986, the PVSG-01 randomized trial (N = 431) prospectively evaluated the use of VS compared to other treatments. It demonstrated remarkable overall survival (OS) in the arm treated with VS (median 13.9 years) compared to patients treated with chlorambucil (8.9 years) or phosphorus-32 (11.8 years). Moreover, the study confirmed the hypothesis of a higher risk of transformation to AML in patients treated with alkylating or radioactive agents.17 Later, the randomized trial CYTO-PV defined the indications for VS and the Hct target to be achieved. The primary endpoint was the incidence of cerebral TE (stroke, transient ischemic attack), myocardial infarction, peripheral arterial occlusions, and venous thromboembolism were studied in two groups (target Hct <45% in one arm and between 45% and 50% in the other). The results reported a lower incidence of events (2.7%) in the group with a Hct target <45% (compared to 9.8% of the other group, p = 0.007). Moreover, considering the occurrence of superficial-vein thrombosis, the same differences were maintained (4.4% versus 10.9%, p = 0.02). No significant distinctions between the groups were reported for adverse bleeding events and/or myelofibrosis (MF)/AML/myelodysplasia progression.18

Thus, beyond the risk stratification, VS is indicated in PV patients with elevated Hct levels (>45%). In case of persistent symptomatic burden (erythromelalgia, amaurosis, persistent headache) or particular circumstances (pregnancy due to hemostatic changes, the greater thrombotic risk), the therapeutic target could also be lower (30–39%).19 Approximately 350/450 mL of blood is generally removed from the circulation during a procedure. The frequency of VS is individualized to maintain the Htc on target.

VS is generally well tolerated, but certain precautions and contraindications should be considered, and patients should be carefully evaluated before addressing the procedure in view of age and/or medical comorbidities such as hypertension or cardiac diseases.20 VS is also time-consuming and resource-intensive; it also results in a “see-saw” effect for patients, while some newer therapies (see below) aim to eradicate the need for this therapy.

Adverse effects of VS are generally mild and transient, including fatigue, light-headedness, and iron deficiency. Rarely serious events are syncope, nerve injury, vasovagal reaction, and infections.21 Typically, one VS reduces the body’s iron amount by about 250 milligrams, and questions often arise about iron supplementation to restore deposits and minimize iron deficiency-associated side effects. However, iron replacement in PV patients should be carefully and individually assessed, and overall, it is not recommended as it can increase the Hct and hemoglobin levels.22

A different procedure to reduce Hct levels may be erythrocyte-apheresis (ECP), although its usage in PV is limited. This apheresis technique is an extracorporeal blood separation whereby blood is extracted from a patient, and through an external machine, the red blood cells are discarded, and the remaining blood is returned to circulation. The risks associated, in this case, are related to the use of a larger venous catheter (with risk of bleeding and infections) or to the citrate used as an anticoagulant, which can reduce serum ionized calcium levels causing dizziness, paresthesia, twitching, muscle cramps, and tetany.23

In summary, guidelines suggest VS should begin as soon as possible after diagnosis to keep Hct <45%. Fluid replacement with VS is based on local practice and the patient’s medical history. The use of cytoreductive therapy can be considered in case of a high number of VS requirements (>6–7 procedures per year) and/or if patients develop resistance/intolerance to the procedure24 or persistent symptoms related to iron deficiency.

Antiplatelet Therapy

The use of aspirin in PV has historically been debated. Initially, in a study conducted by the Polycythemia Vera Study Group (PVSG), the use of high doses of aspirin (900 mg daily) was associated with an elevated risk of gastrointestinal bleeding.25 In 2004, the European Collaborative Low-dose Aspirin (ECLAP) randomized, double-blind trial evaluated the efficacy of aspirin (100 mg daily) versus placebo in preventing TE in PV patients. The study demonstrated that this dosage was associated with a significant reduction in deaths from cardiovascular events and nonfatal thrombosis (eg, stroke, myocardial infarction, venous thrombosis and/or pulmonary embolisms) [hazard ratio (HR) 0.4; 95% confidence interval (CI) 0.18–0.91; p = 0.02] without a significant increase of major bleeding in the aspirin group [relative risk (RR), 1.62; 95% CI, 0.27 to 9.71].26 In the case of intolerance to aspirin, such as mild indigestion, gastric ulcers or bleeding events, among others, clopidogrel (an ADP-receptor antagonist) should be used, although limited data are available about its role in preventing TE in the PV population. Furthermore, it raises an important question in those patients with acute coronary syndrome where clopidogrel is recommended as prevention in the general population, as well as the combined usage with aspirin in indicated cases.27

Anticoagulation Therapy

Direct oral anticoagulation (DOAC) therapy usage has been raised in the last year to prevent and treat TE in cardiovascular diseases.28 DOACs are studied and evaluated in solid cancers, while data in hematological neoplasms are less explored.29 The SELECT-D study, including lymphoma (n = 23) and myeloma (n = 5) patients with deep vein thrombosis (DVT) and pulmonary embolism (PE) compared the efficacy of rivaroxaban versus LMWH (dalteparin). The cumulative incidence of recurrent TE rate at 6 months was lower (4%, [95% CI 2–9]) in rivaroxaban arm versus dalteparin arm (11%, [95% CI 7–16]), with HR 0.43, 95% CI 0.19–0.99, associated with a lower rate of major bleedings events in DOAC arm compared to LMWH [4%, 95% CI; 2–8; vs 6%, 95% CI 3–11; respectively, HR 1.83, 95% CI 0.68–4.96].30 Despite the small number of hematological patients included in these studies, the use of DOAC has been extending in recent years. Ianotto et al presented a study with 25 patients (8 PV and 17 ET) treated with DOAC for atrial fibrillation (AF) and TE, with only one case of TE with treatment and 3 major bleeding (1 due to traumatic injury and 2 post-surgery).31 In a recent small review with MPN patient and disease-associated TE (n = 102), DOAC were given in 32 with only 1 case of mesenteric ischemia without other cases of recurrent TE after 84.7 patients’ years cumulatively. Equally, no major bleeding events were described and only 3 cases of minor bleeding.32 Recently, two retrospective studies led by How et al and Barbui et al have demonstrated the efficacy and safety of DOAC. How et al studied 133 MPN patients who received DOAC for TE and AF, finding a recurrent thrombosis of 5.5% (1.5–9.5%) and bleeding of 12.3% (6.4–18.2%) after 1 year. Moreover, the multivariate analysis described a high-risk of thrombosis in patients with dabigatran and edoxaban, younger age and history of thrombosis, while high WBC was associated with an increased risk of bleeding.33 Barbui et al revised 442 MPN patients with DOAC indication for AF or VTE and described rates of recurrent thrombosis in 10 cases (2.1% patients’ year) and 22 cases (9.2% patients’ year), respectively.34 Based on these, a multicenter Phase 3 prospective, randomized, and open-label trial (AVAJAK, NCT05198960) has been designed to compare the efficacy of apixaban (2.5mg bd)/rivaroxaban (10mg od) versus aspirin 100mg daily in preventing the occurrence of TE. Within the second endpoints are the bleeding events, therapeutic adherence, overall survival, and/or quality of life, among others. This study’s results would help define the role of DOAC in the MPN population.

A brief summary of the described studies is reported in Table 1.

Despite the current limited knowledge, overall, the use of DOAC has been extended and appears safe and efficacious for preventing and treating TE in PV.

Cytoreductive Treatment

Hydroxycarbamide (HC) has been the gold standard treatment in PV patients for years. It is a DNA synthesis inhibitor due to the activity of the hydroxylamine group (-NHOH) that interferes with essential enzymes for DNA synthesis, such as ribonucleotide-diphosphate reductase.35

The PVSG and the French Polycythemia Study Group reported the first evidence of HC’s role in PV in the 1970s. PSVG compared 51 patients treated with HC and 194 only with VS, evidencing an inferior thrombotic risk in the HC arm (9.8% vs 32.8% in the VS group; p = 0.009).36 Conversely, in a randomized trial, the French Polycythemia Study Group compared HC treatment to pipobroman in 292 patients <65 years. During a median follow-up of 9 years, no differences in terms of TE were reported; however, an increased risk of leukemic transformation was observed.37 Furthermore, the extended follow-up (16 years) confirmed a higher risk of AML/myelodysplastic syndrome transformation during pipobroman therapy (cumulative incidence of 52% at 20 years vs 24% with HC)38 that was suggested in previous studies.

A subgroup analysis of the ECLAP cohort compared 1042 patients with PV who received only VS or HC to maintain the Hct level <45%. The occurrence of TE was statistically higher in the VS group than in the HC arm (5.8 vs 3.0 per 100 person-years, p = 0.002) during a comparable observation period (29.9 months for VS and 34.7 for HC). MF progression was reported only in patients not treated with HC (n = 8, 2.3%) and AML transformation in 3 cases (n = 2 in the VS arm and n = 1 in the HC arm). Furthermore, the study demonstrated that the rate of TE and excess mortality was significantly higher in VS-cohort patients with high-risk disease and those who did not achieve target Hct <45% (p = 0.000).39

Recent trials have also reviewed the efficacy of HC compared to interferon-α as described by the randomized Myeloproliferative Disorders Research Consortium (MPD-RC 112) study.40 This trial demonstrated no difference between the overall response rates at 12 months between arms (69.8% for HC and 78% for IFN, p = 0.22). The PROUD-PV phase 3 clinical trial has recently published the results of monopegylated-IFN-α-2b (ropeg-IFN) use in both naïve and previously HC-treated high-risk PV patients. PROUD-PV was designed as a non-inferiority study with HC, and the study reached its primary objective of achieving complete hematological and spleen volume response by 12 months. The CONTI-PV study compared ropeg-IFN with the best available therapy as a continuation of the PROUD-PV study. Surprisingly, in the PROUD-PV study, at 12 months, the complete hematological response (CHR) favored the HC-treated cohort [75% vs 62.1%, p = 0.12],41 although in the CONTI-PV study, as ailed below, these results reverted in favor of IFN arm.42

Despite the good efficacy of HC, various side effects have been reported, as well as the onset of resistance/intolerance leading to treatment suspension. Hematological/oncological toxicities are manifested by myelosuppression, with anemia, leukopenia (the more common side effect), and thrombocytopenia, which leads to increasing infection and bleeding risk. Due to drug interactions, several gastrointestinal side effects (ie, gastritis, mucositis, and oral mucosa ulcers), such as liver toxicity and fatal and nonfatal pancreatitis, have been described. As a chemotherapy drug, it has toxicity on the reproductive system by reducing the count and motility of spermatozoa, with related effects responsible for malformations or fetal-neonatal toxicity, so it is contraindicated in pregnancy and while breastfeeding.43

On the other hand, HC has been associated with increased skin toxicities such as skin ulcers, which is a common cause of treatment interruption, as demonstrated by Antonioli et al among others. The authors showed that between 5% and 10% of MPN patients on HC stopped treatment due to these side effects.44 The development of non-melanoma skin cancers in HC-treated patients has been described in several different studies,45 even if the study MPN-K showed that patients exposed to HC had a risk of skin cancer similar to unexposed patients during a median period of 3 years.46 Patient education and skin monitoring for this toxicity are recommended.

Thus, the central challenge in managing PV patients with HC is the development of intolerance and resistance to the medication, which could lead to the interruption of therapy.47

The 2017 European Leukaemia Network (ELN) guidelines defined resistance as those who required VS to attain the established target of Hct <0.45, with platelets >400 × 109/L, and with failure to reduce splenomegaly by 50%, or to relieve symptoms, despite the use of HC dose of 2 g/day for 3 consecutive months (maximum dosage). Larran et al evaluated in a retrospective study 261 PV patients who received HC for a median of 4.4 years and found that 11.5% (30 patients) were/became refractory, as defined by ELN criteria, while complete response was achieved by 24% of patients. HC resistance was associated with a higher risk of death (HR 5.6, p < 0.001) and progression to AML or MF (HR 6.8, p < 0.001), with a median survival of 1.2 years after resistance was identified.48

Aiming to provide clear and standardized indications, the 2021 ELN guidelines respecified the refractory/intolerance to HC and subsequent treatment change recommendations (detailed in Box 1). While these criteria exist, operationalizing them in practice is challenging and delayed, or lack of recognition of resistance/intolerance has been well described. A further problem in current practice is a lack of definitive data regarding the long-term toxicity of HC, even if the studies available in sickle cell disease confirm its safety in patients treated for many years.49

Interferon

In younger patients, in whom HC use could lead to critical long-term toxicities, or in those refractories to previous therapy, interferon-α (IFN) represents the treatment of choice and, more recently, is considered perhaps the optimum treatment. Several trials aimed to establish the role of IFN and have demonstrated high rates of both hematological and molecular responses through the stimulation of an immune response directed towards neoplastic cells and the antiproliferative effect on hematopoietic precursor cells.19,50 Recently, the new formulation ropeg-IFN has been tested in the PROUD-PV trial (1:1 randomized phase 3 open-label), as introduced above. The study assessed the efficacy and safety of ropeg-IFN versus HC in 254 PV patients, stratified by prior HC exposure, age at enrolment (≤60 or >60 years), and the occurrence of previous thromboembolic events. The CHR (defined as Hct <45% at least 3 months after the last VS, accompanied by platelets <400 × 109/L and white blood cells <10 × 109/L at the 12-month treatment timepoint) was achieved by 43.1% (53 of 123 patients) in the ropeg-IFN arm, confirming thus a non-inferiority versus HC. Normalization of spleen size was not demonstrated. On the other side, the ongoing CONTINUATION-PV study (extension of PROUD-PV trial) evaluated the CHR, normalization of spleen size and improvement in disease burden (such as splenomegaly, microvascular disturbances, pruritus, and headache) in subsets of patients continuing from PROUD-PV. An interim analysis at 36 months reported CHR associated with improved disease burden (including spleen reduction) in 50 (53%) of 95 patients in the ropeg-IFN group, higher than 28 (38%) of 74 patients in the HC group [1.42 (1.01 to 2.00), p = 0.044], thus demonstrating a treatment alternative for patients diagnosed with PV showing advantages compared with HC therapy beyond the second year of treatment.42

In a new recent re-evaluation after overall 5 years of treatment, 53/95 patients (55.8%) in the ropeg-IFN arm and 33/75 (44.0%) in the HC arm confirmed CHR. The occurrence of PV progression among ropeg-IFN-treated patients was 0.2%-patient-years (MF = 1), while this was 1%-patient-years in the control treatment arm (n = 4 cases, MF = 2 and AML = 2). Regarding TE, no clear differences were reported with 5 events (1%-patient-year, n = 2 in the same patient) in the ropeg-IFN arm and 5 events (1.2%-patient-year).51 The ongoing ECLIPSE PV, phase 3b, open-label, multicenter study, aims to evaluate the efficacy (in terms of hematologic response at 24 weeks), safety, and tolerability of ropeg-IFN utilizing higher dose (from 250 to 500mcg) compared to the currently labeled dosing (Q2W starting at 100 up to 500, with 50mcg increases) (NCT05481151). Finally, peginterferon importantly reduced the JAK2 V617F allelic burden or VAF significantly by 35% (starting from a median of 41%) by week 18 of treatment (p = 0.479), and to 25% by week 50 (p < 0.001).52

Concerning side effects, the use of interferon-α (IFN) is limited by the wide range of side effects. Commonly, there are flu-like symptoms, fatigue and neuropsychiatric manifestations, such as depression and anxiety, that generally lead to treatment discontinuation in approximately 24–40% of patients within 1–2 years. Neutropenia is a frequent hematological toxicity, noted in 20% of patients in some studies, as well as autoimmune disease (mainly thyroid disorders), hepatotoxicity and retinopathies.53,54 Hence, we recommend completing a baseline liver, thyroid and autoimmune profile and retinal screening before starting IFN. During the treatment period, it is essential to closely monitor for these toxicities and adjust the dose of pegylated interferon (peg-IFN) to reduce the possible side effects. Problematically, no standardized criteria exist for IFN intolerance or resistance, and the role of JAK2 VAF monitoring requires guidance, as discussed later.

Janus Kinase Inhibitor

The Janus kinase inhibitors (JAKi) widely impacted the treatment of MF, above all in the patients with worse prognosis according to the standard prognostic models,55 where over the years, several JAKi were tested and are currently used with significant results in terms of symptoms control, improvement in quality of life, and aiming to modify the disease outcome, alone or combined to other molecules with a different mechanism of action.56,57 In PV, ruxolitinib is the only JAKi licensed and widely used in intolerance or resistance to HC cases. A multicenter phase 3 (RESPONSE) trial compared ruxolitinib to other physician choices in a second-line therapy setting following HC in PV patients with splenomegaly, stratifying patients according to inadequate response or unacceptable side effects. The primary endpoints were Hct control (less than 45% in the absence of VS) and a 35% reduction of spleen size, evaluating as secondary aims the duration of response, the symptoms control and the safety. After 81 weeks in the ruxolitinib and 34 in the control arms (the median exposure to therapy assumed as data cut-off), 84.5% and 3.6% continued treatment, respectively, in the two groups, and the composite primary efficacy endpoints (Hct and spleen reduction taken together) were significantly more achieved by patients treated with JAKi (20.9% vs 0.9% in control arm, p < 0.001), without any difference according to whether patients were refractory or intolerant to HC. Moreover, at week 32, 36 of 74 patients in the ruxolitinib group (49%) reported at least a 50% reduction in the MPN-SAF total symptom score, higher than the standard-therapy group (4 of 81 patients, 5%) and a CHR in 24%.58 The RESPONSE-2 trial (enrolling HC-resistant or intolerant PV patients without splenomegaly) confirmed the efficacy of ruxolitinib compared to the best available treatment (HC, IFN, pipobroman, lenalidomide, or no therapy). Hct control (as primary endpoint) was achieved in 46 (62%) of ruxolitinib-treated patients, significantly higher than 14 (19%) of those who received the best available therapy (OR 7.28 [95% CI 3.43–15.45]; p < 0.0001).59 These results have allowed authorization of the use of ruxolitinib by different regulatory agencies such as FSA and EMA. Recently, the results of the Phase 2 trial MAJIC-PV confirmed the extended safety of ruxolitinib as a second-line treatment versus BAT in a UK cohort, assessing the complete response within 1 year, duration of response, event-free survival (EFS), control of symptoms, and the molecular response. CHR was achieved in 43% of patients on ruxolitinib compared to 26% on BAT, associated with improved thromboembolic-event-free survival (HR 0.56, 95% CI 0.32, 1.00, p = 0.05). The molecular response, evaluated as >50% reduction in JAK2 VAF, was more frequent with ruxolitinib and was correlated with reduced progression-free-survival, EFS and overall survival (all p < 0.01).60

Despite the well-assessed efficacy of ruxolitinib in controlling Hct levels, reducing spleen size, and improving symptom burden, several occurrences and/or adverse effects may limit ruxolitinib use, and its efficiency in reducing thrombosis and later events was unclear. Hematological toxicity is mainly represented by anemia and thrombocytopenia.61 Furthermore, not being a specific inhibitor of mutated JAK2, it may be related to impaired immune function with an increased risk of new infections or reactivation of latent infections,62,63 or impaired response to immunological stimulation (eg, in cases of vaccines both in MF and PV-treated patients).64,65

A further important and severe effect is the appearance of non-melanoma skin cancers, for which patients should be routinely screened for suspicious skin lesions.66 Also, in this case, MPN-K study, demonstrated how ruxolitinib shows a high risk (OR = 3.87, 95% CI 1.18–12.75), without excess risk of carcinoma and hematological second cancer compared with unexposed patients.46 Focusing on the cohort of MF patients in the COMFORT-1 trial, ruxolitinib-treated patients reported different metabolic side effects, such as weight gain and increased total cholesterol.67

Regardless of the potential adverse effects widely reported, the long-term data from the MAJIC-PV study demonstrated an acceptable safety with significative benefits, without any death related to infections, and not confirming metabolic side effects.60

The routine use of ruxolitinib as a second-line therapy is limited by cost, recognition of resistance or intolerance to HC and a lack of guidance for IFN failure. In addition, identifying early predictive parameters for an acceptable response to ruxolitinib represents a research target, such as the RR6 score for myelofibrosis.68,69 Currently, ruxolitinib is tested as a first-line PV therapy in the MITHRIDATE trial, compared to HC or IFN (any formulation) to evaluate the event-free survival (in terms of first major thrombosis/hemorrhage, death, progression/transformation), and, as second endpoints, the impact in quality-of-life, JAK2 V617 VAF reduction, and the adverse events (NCT04116502) during a follow-up of 3 years.

Pipobroman, Busulfan and Phosphorus-32

As mentioned above, pipobroman, busulfan and radioactive phosphorus were in the past widely used in the management of these conditions. They are currently recommended by the ELN only in subsequent lines of treatment after intolerance/loss of response to therapies such as either HC or IFN.70 In a Swedish cohort study, two or more lines of cytoreductive treatment (including an alkylating agent) were correlated with a 2.9-fold increase in transformation in AML/myelodysplastic syndrome rate.71 Because of the potential leukemogenicity, these agents should be reserved for elderly patients (>80 years) with a low risk of progression or those with a disease where the risk of thrombosis is superior to the risk of transformation.

A brief explanation of the available strategies to control PV clinical manifestations and reduce thrombotic risk, with their common side effects, is reported in Table 2.

Management of Symptoms

Symptomatic management of PV can be problematic. As already described, among the symptoms commonly present in patients with PV, pruritus is the most frequent (up to 70–85% of cases), with a spontaneous occurrence or evoked by water or changes in temperature (pruritus aquagenic) and causes a significant negative impact on quality of life.72 It is usually treated simultaneously with cytoreductive therapy/Hct control but can persist even in patients with well-controlled blood counts.73 Other purely symptomatic approaches are antihistamines (both H1 and H2 receptor antagonists),74,75 selective serotonin reuptake inhibitors (SSRIs),76 or anticonvulsant drugs. The referral to a dermatologist could be considered for refractory patients trying to treat with narrow-band-ultraviolet (UVB) or ultraviolet A (UVA), associated or not with oral psoralen to UV light (PUVA).77 These options are preferred in patients with only the presence of these symptoms but not with a thrombotic risk that requires cytoreductive therapy. In any case, persistent pruritus resistant to the above options can be an indication to start an active treatment just to control the symptom burden.

Regarding fatigue, no specific medicine can effectively treat this condition secondary to MPN or to side effects of treatment. Anxiety and depression related to cancer can increase it. Lifestyle modifications are central in the management, with adequate sleep with scheduled breaks, abstention from smoking and alcohol, hydration, and a balanced diet, associated with a referral to a psychologist to discuss one’s condition and receive support. The management of fatigue is a significant challenge in the modern management of PV.

Management of Thrombotic Events

The occurrence of a thrombotic event (TE) represents, as previously described, the factor that fixes patients as being at high risk of further thrombosis. Acute events should be managed according to current guidelines. TEs are divided into arterial (such as stroke or transient ischemic attack, acute myocardial infarction, and peripheral arterial thrombosis) and venous (deep vein thrombosis, superficial thrombophlebitis, and pulmonary embolism). Splanchnic venous thrombosis deserves special mention as, when necessary, it presents behind an MPN in a variable number of cases between 10% and 50%,78 where the specific cytoreductive therapy does not show effectiveness in reducing the risk of recurrence.79 For acute events involving the venous system, the first choice is low molecular weight heparin (LMWH), followed by indefinite secondary prophylaxis with vitamin K antagonists (VKA), as per guidelines.80 Novel direct oral anticoagulants (DOACs) are increasingly used as secondary prophylaxis with efficacy, although data on MPNs are still limited,31 as discussed earlier. In any case, every patient should be screened for CVRF, such as hypertension, hyperlipidemia, diabetes mellitus, and smoking history, as well as for prothrombotic-associated conditions (ie, antiphospholipid antibody syndrome, coagulation factor V and II mutations).

Conversely, in the case of an arterial event, the acute aim is the reperfusion of the affected extremity through thrombolysis or recanalization of the occluded vessel. It could be via catheter-directed thrombolysis (CDT, as interventional radiology treatment), surgical treatment (open bypass surgery, or the more common endovascular therapy, such as stenting, balloon angioplasty, or atherectomy) or use of thrombolytic drugs (serine proteases that cleave plasminogen into active plasmin such as streptokinase, alteplase, reteplase).81

Special conditions may require a particular approach. In the case of cerebral venous thrombosis, patients are stratified based on risk factors for poor outcome (malignancy, coma, deep venous thrombosis, mental status disturbance, male sex, intracranial hemorrhage) and treated with LMWH in case of lower risk, or endovascular procedures (endovascular thrombolysis or thrombectomy) or neurosurgery (decompressive craniotomy) in case of risk of high risk, followed by oral anticoagulation lifelong in case of the simultaneous severe prothrombotic condition, such as PV.82

Management of Hemorrhagic Events

Hemorrhagic events have been documented in individuals with PV, primarily affecting the integumentary system, mucous membranes, and gastrointestinal tract (particularly notable in cases with existing oesophageal varices). These occurrences are commonly attributed to persistent anticoagulation usage or platelet counts exceeding 1500 × 109/L, which increase the risk for acquired von Willebrand syndrome.83 The bleeding episodes are generally less frequent and severe events than the thrombotic counterpart and require management with tranexamic acid and/or platelet transfusion, associated with a subsequent cease/reduce aspirin shifting to DOACs (as mentioned above), and optimizing of cytoreductive treatment.80

Future Directions

In addition to the classic and established therapies currently available, there are several molecules (newly or used for different conditions) that are being tested in phase 2/3 trials and which, in the years to come, could represent one more possibility in the management of patients with PV in need of further treatment.

Concerning already available drugs, the efficacy and safety of peg-IFNα-2b in combination with ruxolitinib versus peg-IFNα-2b alone for treating HC-resistant/intolerant PV are currently being tested in a multicenter phase 2 study. The results, expected in 2028, could open a new window in the combination therapy between two already widely used molecules (NCT05870475).

Among the new molecules, rusfertide is a hepcidin-mimetic that binds ferroportin, causing a reduced availability of iron in the bone marrow, a fundamental element for erythrocytosis.84 It was tested in two different phase 2 trials. REVIVE trial (NCT04057040) enrolled patients with uncontrolled Hct despite VS (≥3 in the 6 months before study entry) associated with a cytoreductive therapy. This trial was divided into a 28-week open-label dose-finding phase (starting from rusfertide 20 mg subcutaneously, with subsequent dose titration, and associated with any prior cytoreductive treatment), followed by a 3-month double-blind randomization (compared to placebo), and a 3-year open-label extension, with rusfertide for all the patients enrolled. The results showed that the average clinically effective dose is approximately 40 mg weekly, without an increase in toxicity, whether rusfertide was administered with concurrent VS or cytoreductive therapy.85 The second trial (PACIFIC) enrolled patients with high Hct (>48%) for an induction period with 40mg twice weekly until the control of Hct value (<45%) and maintenance, with a schedule that may be adjusted every 2 to 4 weeks to maintain Hct, with a target of <43% (NCT04767802).

Based on these results, the phase 3 VERIFY trial is ongoing, recruiting PV patients who required ≥3 VS in the previous 6 months or ≥5 in the last 12 months due to inadequate Hct control. Patients with a stable cytoreductive regimen must be in a well-controlled scheme, with no need for dose modification, while patients managed only with VS must have interrupted cytoreductive therapy 2–6 months before screening. Patients are double-blinding randomized to 32 weeks of rusfertide or placebo added to each subject’s ongoing treatment.86 The results will definitively indicate the role of rusfertide in the PV setting.

Another class of targeted agents is histone deacetylase (HDAC) inhibitors. Givinostat, an HDAC inhibitor specific for JAK2 V617F-mutated cells, was tested in a phase 2 trial. Givinostat was administered in MPNs patients (including 12 with PV) at a starting dose of 50 mg twice daily. Apart from 2 patients who discontinued treatment, 7 out of 10 PV patients (70%) reached VS independence, and splenomegaly and pruritus were resolved in 70% and 90% of patients, respectively, with a reported reduction of JAK2 V617F allele burden. It was well tolerated, with no grade 4 toxicities.87

Subsequently, in a multicenter clinical trial, givinostat long-term efficacy and safety were tested. Of 45 patients enrolled and receiving treatment for a median of 4 years, complete/partial hematological remissions were described in 11% and 89%, respectively, with a Hct control (<45%) without VS and standard spleen size both observed in 56% of patients. The incidence of thrombosis was 2.3% of patients per year. Only three grade 3 and no grade 4 toxicities were observed.88 During an extended follow-up, the excellent safety profile was confirmed, with an overall response rate always more significant than 80%,89 laying the foundations for future phase 3 trials.

Vorinostat, another HDAC inhibitor, was tested in a phase 2 trial. Most patients who completed 24 weeks of treatment (24/33; 72%) reported a response, although 44% of patients discontinued the therapy due to adverse events, of which 25% of cases were severe (deep vein thrombosis, diarrhea, headache, progression to AML, palpitations, neuropathy, fatigue, and renal impairment).90 Using lower dosages of vorinostat combined with other drugs (eg, JAKi) will probably represent the therapy capable of conferring good responses without excessive toxicities.

In addition, several other molecules are currently being studied in phase 2 studies, which may represent potential mechanisms in the future. Summaries of these trials are shown in Table 3.

Conclusion

In the last decade, considerable advancements have transpired within the therapeutic landscape of PV, predominantly inspired by the revelation of the disease’s fundamental molecular driver mutations. However, in order to deliver effective care for patients, attention to details such as vascular risk, optimum control, defining how to utilize molecular assays, and recognizing when patients fail to continue to be a challenge. Notably, optimal management of debilitating symptoms, particularly fatigue, and cases with an associated complex clinical background necessitate the provision of an enhanced approach.

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Komrokji Analyzes Strategies to Address Anemia With Ruxolitinib in Myelofibrosis

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Targeted Oncology Staff

During a Targeted Oncology™ Case-Based Roundtable™ event, Rami Komrokji, MD, discussed issues related to dosing and management of patients receiving ruxolitinib for myelofibrosis.

CASE SUMMARY

  • A 68-year-old woman presented to her physician with symptoms of mild fatigue, moderate night sweats, and abdominal pain/fullness lasting 4 months; she also reported increased bruising and an unexplained 12-lb weight loss.
  • Her spleen was palpable 8 cm below the left costal margin.
  • Karyotype: 46,XX
  • Bone marrow biopsy results: megakaryocyte proliferation and atypia with evidence of reticulin fibrosis
  • Genetic testing results: JAK2 V617F mutation; CALR mutation negative
  • A blood smear result revealed leukoerythroblastosis.
  • Laboratory values
    • Red blood cell count: 3.40 × 1012/L
    • Hemoglobin level: 13.2 g/dL
    • Hematocrit: 36%
    • Mean corpuscular volume: 94 fL
    • White blood cell count: 23.0 × 109/L
    • Platelet count: 450 × 109/L
    • Peripheral blood blasts: 1%
  • Diagnosis: primary myelofibrosis
  • Risk
    • International Prognostic Scoring System: intermediate-2
    • Mutation and Karyotype-Enhanced International Prognostic Scoring System for Primary Myelofibrosis in adults 70 years or younger: intermediate
  • The patient refused stem cell transplant and received ruxolitinib (Jakafi).

Targeted Oncology: What effect did the titrated dose of ruxolitinib have on spleen volume and total symptom score in the COMFORT-I trial (NCT00952289)?

KOMROKJI: The spleen volume [reduction] is dose dependent [Figure 11]. You will rarely see a meaningful spleen reduction at below 10 mg twice a day, and it takes 3 to 4 months. That becomes the challenge. For the patients who [have] borderline [cytopenia], the more you’re going to push those [patients] to get the spleen response, the more they are going to [develop cytopenia]. The symptom improvement can be seen daily at 5 mg or 10 mg twice a day and [comes] faster. You could achieve that with a lower [dosage] than the spleen response [Figure 21]. Ruxolitinib is typically given twice a day because it has a short half-life. Sometimes in real-life practice, especially if the patients [were prescribed] a certain [dosage] of the pill, until we get the other [dosage of the] pill, we sometimes do it once a day or we tell them to cut the pill and do it twice a day. But ideally, it should be done twice daily.

What hematologic toxicities were observed with ruxolitinib in the COMFORT-I and COMFORT-II (NCT00934544) trials?

This drug, in general, is safe. The major issues with ruxolitinib are anemia, thrombocytopenia, and less often neutropenia, and those are very predictable, particularly the anemia. It’s almost a 2 g/dL hemoglobin [level] drop by week 8. If you started somebody with hemoglobin [level] of 13 g/dL…[by] month 2, it will be 11 g/dL. But for many of those patients, their symptoms are better and their spleen [enlargement] is gone, so they don’t mind the 11-g/dL [hemoglobin level]. If somebody started with hemoglobin [level] of 9 g/dL or 8 g/dL and [it is] dropping to 7 g/dL, then they will probably need transfusions.

The only way to mitigate the cytopenia most of the time is dose reductions. Sometimes for anemia, we add ESAs [erythropoiesis-stimulating agents]. The COMFORT-I trial did not allow adding any ESAs. The COMFORT-II trial from Europe had a small subset who had ESA addition.2 Technically, ruxolitinib inhibits the JAK/STAT pathway where erythropoietin signals through, but because it has a short half-life, it’s a reversible inhibition. There is a window of time where the ESA can work. Sometimes we do that in practice to mitigate anemia.

There is no difference in the response based on [grade 3 or 4] anemia, so whether the patients [had anemia] or not, in terms of their spleen and symptoms, they improved.3 Sometimes we used to push the dose before having the newer JAK2 [Janus kinase 2] inhibitors, and I used to struggle with this. The University of Texas MD Anderson Cancer Center [in Houston] had a philosophy of starting the patients on the higher dose even if they [have] transfusion [dependence]; then you back off. We escalated the dosing a little more, but at least the spleen and symptom improvement, even in the setting of anemia, can be achievable. I struggle with rendering somebody [with] transfusion [dependence] especially now that we have other choices.

What else should physicians keep in mind when using ruxolitinib?

If someone gets admitted for pneumonia or surgery, especially if they are on higher dosing and [are] responding, those drugs cannot be stopped cold turkey, particularly ruxolitinib and probably fedratinib [Inrebic] as well, because patients will have rebound cytokines. And if they are sick with pneumonia, they will [risk experiencing] SIRS [systemic inflammatory response syndrome] or septic shock. Even if they are going to surgery, we try not to interrupt if they can take [medication] orally. If your patients are not able to take oral medications, sometimes we bridge them with steroids as they are admitted.

If the case patient’s baseline hemoglobin level of 13 g/dL reduced to below 8 g/dL, is that a sign of ruxolitinib failure or progression?

That’s not typical, but I’ve seen some patients who will get profound cytopenia [later], so whether it’s a red flag or just sensitivity, I don’t know. Sometimes it depends on the timing. If somebody was on ruxolitinib for…a couple of years and I see this anemia, that’s…a red flag [ for] if there is anything changing the disease. If it was the first few months of ruxolitinib, I would assume it’s more likely to be ruxolitinib related. I would try to back off the dosing, [do] the classical things in medicine, make sure that the patient does not bleed [in case] something else was going on. But it will probably be somebody who is more sensitive. With that degree of drop, if I cannot get a spleen response or constitution symptoms relieved with a lower dose than nowadays, sometimes we would consider shifting to other JAK2 inhibitors if it was ruxolitinib related and I could not manage the symptoms with a lower dose.

How do you address the increased risk of skin cancer with ruxolitinib?

There are not very conclusive data, but there are data all over the place that any patients [with myelofibrosis] are at higher risk of skin cancer. For both hydroxyurea [Hydrea] and ruxolitinib, [it’s] a little higher than in patients who were not on treatment.4,5 Practicing in Florida adds another risk factor [for our patients developing skin cancer]. We tell them to get a baseline [dermatology exam] when we are starting and then get surveillance every 6 months. We don’t have many alternatives for treatment because both hydroxyurea and ruxolitinib increase the risk. There is no literature to say it’s dose dependent. I’ve rarely stopped the treatment because most of the time, if you’re doing surveillance, you can detect those early, but I’ve had patients who had bad…squamous cell carcinoma that [required] resection…. I held the treatment and tapered down, not knowing what else to do, because it…was extensive. There is literature, but there is no guidance.

What is the lowest dose of ruxolitinib you would use before making a switch?

The dosing of ruxolitinib is dependent on what I’m trying to achieve. If I’m going for a spleen response, I want them at least to be on 10-mg dosing because I rarely see a spleen response below 10 mg twice daily. [With] symptom improvement and [if] they’re feeling better [with] 5 mg to 10 mg, I settle and may not push the dosing more.

How do you safely switch from ruxolitinib to pacritinib (Vonjo)?

In terms of shifting, there is not much guidance, but we always taper down the ruxolitinib. We don’t stop it. If we’re shifting to pacritinib, [physicians] do different things. We taper down the ruxolitinib and sometimes put them on a bridge of steroids. I’ve had some colleagues who overlapped them in the first couple of weeks. Pacritinib has a much longer half-life, so it takes longer to kick in.6 With ruxolitinib, you see symptom control in a week or 2; with pacritinib, it takes 3 to 4 weeks. The approach is not to stop immediately…. Tapering ruxolitinib is 100% agreed on, particularly if you are stopping because of cytopenias, [but if] the patients were responding, that rebound will be even worse than [for] somebody who’s [experiencing progression]. The alternative strategies are to put them on a steroid bridge or overlap them…for a week or two and then stop the ruxolitinib completely. There is not much guidance if somebody was on pacritinib if you’re bridging them to something else, [and the same applies] with fedratinib. Pacritinib has less or no JAK1 effect, so in my experience, stopping it immediately is more tolerable. You don’t have to taper it. But we do with fedratinib. There are not many data yet with momelotinib [Ojjaara].

For patients who do not respond to management of anemia and require transfusions every 2 weeks, would you be concerned about iron overload?

There is not much literature about iron overloading in myelofibrosis, but it’s [a] very similar story to MDS [myelodysplastic syndrome]. Myelofibrosis is an inflammatory condition, so patients could have a high baseline [level] of ferritin. To [identify] somebody [having] iron overload, you have to get to the threshold of 15 to 20 units of blood transfusions.

The responses to ESA are [fewer] than in MDS because those patients have a higher endogenous serum erythropoietin level; you rarely see responses. There have been studies looking at…combination ruxolitinib/danazol and ruxolitinib/thalidomide…with modest activity.7,8 There is an ongoing phase 3 trial [INDEPENDENCE; NCT04717414] looking at ruxolitinib vs ruxolitinib/luspatercept-aamt [Reblozyl] because in the phase 2 trial [ACE-536-MF-001; NCT03194542], it seemed…that luspatercept can work in myelofibrosis to help with ruxolitinib-induced anemia.9 If patients have lower-risk myelofibrosis or I estimate their survival to be in years and they [have] high transfusion burden, I may consider some iron chelation. The problem [is] that the decision has to be individualized because even in MDS, we do the same because those iron chelations come with their own adverse events and toxicities. The subcutaneous pump is not easy for patients, and the oral ones have renal insufficiency, etc. But in selected cases, you could consider it.

If a patient with baseline hemoglobin level of 8 g/dL receives ruxolitinib and develops transfusion dependence, at what point do you consider it to be ruxolitinib failure?

[With] momelotinib approved, it will probably start taking that area of patients who [have anemia] at baseline because momelotinib does have anemia response in almost 25% of patients.10 I would say [to wait] 3 to 4 months for the main thing you are [managing]. If you’re [managing] the spleen and constitutional symptoms [and] you don’t see the spleen response by 3 to 4 months, then that’s failure. The [time to consider it] intolerance to treatment if they develop profound cytopenias is 2 to 3 months as well. I look at…am I achieving the primary end point? Did I at least reduce the spleen [size] by 25%? Is the patient feeling better at 4 months? If yes, I would continue. The other part I look at is if I make the patient [have] transfusion [dependence], are they having severe cytopenias? Sometimes you can start making the call on that at 2 months.

What approaches to controlling anemia related to myelofibrosis are most promising?

Whatever you use for anemia, [approximately] 30% response is the best [we’ve achieved]. In my experience of patients who [have cytopenia] without any spleen or constitutional symptoms, the most success had been with thalidomide plus prednisone, [where] 1 of 4 patients would respond. But if there was a response, some of the responses were very durable. You do the steroids the first 3 months, you take them off, [and] then you continue to thalidomide. I’ve had patients on [JAK inhibition] for 7 or 8 years. With the newer JAK2 inhibitors, pacritinib and momelotinib, the story is changing a little bit, particularly if they have spleen and constitutional symptoms. Then you are [managing] both. We still have to see data on somebody who [has cytopenia] without any spleen or constitutional symptoms [and] how much they will benefit from something like momelotinib or pacritinib for anemia.

REFERENCES

1. Verstovsek S, Gotlib J, Gupta V, et al. Management of cytopenias in patients with myelofibrosis treated with ruxolitinib and effect of dose modifications on efficacy outcomes. Onco Targets Ther. 2013;7:13-21. doi:10.2147/OTT.S53348

2. McMullin MF, Harrison CN, Niederwieser D, et al. The use of erythropoiesis-stimulating agents with ruxolitinib in patients with myelofibrosis in COMFORT-II: an open-label, phase 3 study assessing efficacy and safety of ruxolitinib versus best available therapy in the treatment of myelofibrosis. Exp Hematol Oncol. 2015;4:26. doi:10.1186/s40164-015-0021-2

3. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807. doi:10.1056/NEJMoa1110557

4. Lin JQ, Li SQ, Li S, et al. A 10-year retrospective cohort study of ruxolitinib and association with nonmelanoma skin cancer in patients with polycythemia vera and myelofibrosis. J Am Acad Dermatol. 2022;86(2):339-344. doi:10.1016/j.jaad.2021.10.004

5. Hydrea. Prescribing information. Bristol Myers Squibb; 2021. Accessed November 20, 2023. https://tinyurl.com/dt9v7jft

6. Mascarenhas J, Hoffman R, Talpaz M, et al. Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis: a randomized clinical trial. JAMA Oncol. 2018;4(5):652-659. doi:10.1001/jamaoncol.2017.5818

7. Gowin K, Kosiorek H, Dueck A, et al. Multicenter phase 2 study of combination therapy with ruxolitinib and danazol in patients with myelofibrosis. Leuk Res. 2017;60:31-35. doi:10.1016/j.leukres.2017.06.005

8. Duan M, Zhou D. Improvement of the hematologic toxicities of ruxolitinib in patients with MPN-associated myelofibrosis using a combination of thalidomide, stanozolol and prednisone. Hematology. 2019;24(1):516-520. doi:10.1080/16078454.2019.1631509

9. Gerds AT, Harrison C, Kiladjian JJ, et al. Safety and efficacy of luspatercept for the treatment of anemia in patients with myelofibrosis: results from the ACE-536-MF-001 study. J Clin Oncol. 2023;41(suppl 16):7016. doi:10.1200/JCO.2023.41.16_suppl.7016

10. Gerds AT, Verstovsek S, Vannucchi AM, et al. Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis previously treated with a JAK inhibitor (MOMENTUM): an updated analysis of an international, double-blind, randomised phase 3 study. Lancet Haematol. 2023;10(9):e735-e746. doi:10.1016/S2352-3026(23)00174-6

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Preliminary data shows lowered cytokine levels in myelofibrosis with PIM1 kinase inhibitor

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December 19, 2023

SAN DIEGO — Treatment with a selective PIM1 kinase inhibitor showed positive clinical reactions in a sample of 23 patients with relapsed/refractory myelofibrosis, according to preliminary data presented at ASH Annual Meeting.

TP-3654, an oral investigational highly selective PIM1 kinase inhibitor, is the subject of the phase 1/phase 2 study evaluating monotherapy in relapsed/refractory myelofibrosis, according to results published by a team led by Lindsay A.M. Rein, MD, a hematologic oncologist at Duke Cancer Center.

Elevated circulating cytokines have previously been noted as having a strong association with myelofibrosis, and preclinical studies evaluating TP-3654 as both a monotherapy and in tandem with ruxolitinib (Jakafi, Incyte) displayed lowered cytokine response and other responses, such as spleen reduction and bone marrow fibrosis reduction.

As such, the phase 1/phase 2 study further examined TP-3654 monotherapy in a cohort of patients with intermediate or high-risk myelofibrosis, and who had been previously treated with or were ineligible for JAK inhibitor treatment.

The 23 patients — who had a median age of 73 years and all but one of whom had previously received JAK inhibitor treatment — were monitored for cytokine changes over 12 weeks of TP-3654 monotherapy. “Broad reductions” in cytokine levels were observed in as little as 24 hours, and over the course of 12 weeks, patients with higher cytokine reduction levels were found to have greater reduction in symptoms.

Twelve of 13 eligible patients saw a reduction in their total symptom score, with seven having their score reduced by 50% or more. Treatment-related adverse events, such as nausea and vomiting, were observed in over 20% of patients.

Rein noted that enrollment is still ongoing.

Reference:

Rein LAM, et al. Phase 1/2 study of TP-3654, a selective PIM1 kinase inhibitor: Preliminary data showed clinical activity and cytokine reductions in relapsed/refractory myelofibrosis patients. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2023; San Diego.

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Get Patients to Open Up About MPN Symptoms

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Patrick Buxton, RN, BSN

Myeloproliferative neoplasm (MPN) symptoms can often seem to be other conditions, so it is essential that nurses develop a good rapport with their patients to ensure that they always communicate any changes in how they feel, explained Patrick Buxton, RN, BSN.

“A big part of my nurse style is to find out what their baseline is, and to make sure that they communicate, even if it’s a very subtle change,” Buxton, who is a clinical nurse coordinator with the hematology department at the Fred Hutchinson Cancer Center, said.

To establish that kind of patient-provider communication, Buxton said that he is very persistent, and ensures that his patients know that they can call him any time and he will always call them back. He lets patients know that symptom management, unfortunately, is not an exact science, since every patient is different, but he makes sure that they feel they are going through the process together.

Then, once it is apparent that there are MPN-related side effects that need to be addressed, Buxton said that certain individuals may have their medications titrated, while others have their dose lowered.

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Allogeneic HSCT Improves Overall Survival in MDS/MPN With Neutrophilia

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Lauren Dembeck, PhD
A large, nationwide, population-based study of patients with myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) with neutrophilia found that, to date, only allogeneic hematopoietic stem cell transplantation (alloHSCT) significantly improves overall survival (OS), according to research published in Blood Advances.

“MDS/MPN with neutrophilia is a very rare disease. It carries a poor median overall survival of 15 months (with a reported range of 12.4 to 37 months),” the study authors explained in their report. “Without treatment, 30-40% of patients progress to acute myeloid leukemia.”

Researchers retrospectively analyzed a cohort of 347 adult patients diagnosed with MDS/MPN with neutrophilia, previously known as atypical chronic myeloid leukemia, who were registered in the Netherlands Cancer Registry between 2001 and 2019. The aim of the study was to validate known prognostic markers, identify novel prognostic markers, and provide evidence-based treatment recommendations.

The demographic baseline data of the cohort was consistent with those of cohorts from other studies. Most patients were male (65%) and >65 years old (71%). The median age at diagnosis was 72 years (range, 22-95 years). Only 5 patients (1.4%) were known to have a prior hematological malignancy (MDS, n=2; lymphoma, n=3). The median OS for the overall cohort was 15.8 months (95% CI, 13.8-17.2 months), and no significant difference in OS was observed between the sexes.

Among 110 patients diagnosed between 2014-2019, cytogenetic testing data was available for 89% of patients. Of those, 15% had cytogenetic abnormalities, which were all in patients aged >65 years. The most common cytogenetic abnormality was trisomy 8 (6/15 patients).

Within the same subgroup, molecular analysis was available for 92% of patients. Of those, 49 patient harbored a total of 16 distinct molecular mutations, with some patients (16/101) having up to 3 different mutations. The most frequent mutations were in ASXL1 (22%), SETBP1 (18%), SRSF2 (12%), and CSFR3 (12%).

In the overall cohort, a multivariable Cox regression analysis adjusted for primary therapy revealed that age (>65 years of age hazard ratio [HR], 1.85; 95% CI, 1.34-2.55; P =.001) and alloHSCT (HR, 0.51; 95% CI, 0.26-0.97; P =.039) were associated with OS.

“As no other treatment modality, seemed to impact survival and might cause toxicity, we propose that all patients eligible for alloHSCT should whenever possible receive an allogeneic transplant. It is imperative that we strive to improve outcomes for patients not eligible for alloHSCT,” the study authors concluded in their report.

Reference

Klein SK, Huls GA, Visser O, Kluin-Nelemans HC, Dinmohamed AG. Characteristics, primary treatment, and survival of MDS/MPN with neutrophilia: a population-based study. Blood Adv. Published online November 7, 2023. doi:10.1182/bloodadvances.2023011181

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SRSF2 Mutations Lead to Lessened Frequency of Polycythemia in Preclinical MPN Models

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Kyle Doherty

The presence of mutated SRSF2 in knock-in mouse models of JAK2 V617F–driven myeloproliferative neoplasms (MPNs) reduced the rate of polycythemia and hampered hematopoietic progenitor functions, according to findings from a preclinical study published in Blood Cancer Journal.

Findings from the study demonstrated that coexpression of mutant SRSF2 P95H decreased red blood cell (RBC), neutrophil, and platelet counts, as well as attenuated splenomegaly in JAK2 V617F-positive mice. Notably, bone marrow fibrosis was not induced in JAK2 V617F-positive mice. Coexpression of SRSF2 P95H was also found to reduce the competitiveness of JAK2 V617F–mutated hematopoietic stem/progenitor cells.

Additionally, RBC, hemoglobin, and hematocrit levels were significantly reduced in the bone marrow of JAK2 V617F–positive mice that displayed enforced expression of S100A9. Mutated SRSF2 P95H decreased TGF-β levels and increased S100A8 and S100A9 expression in JAK2 V617F–positive mice.

“We demonstrated that SRSF2 P95H mutant reduces polycythemia and impairs competitiveness of JAK2 V617F–mutant hematopoietic stem/progenitor cells but does not promote the development of bone marrow fibrosis inJAK2 V617F-induced MPN,” lead study author Yue Yang, MD, of the Department of Biochemistry and Molecular Genetics at the University of Virginia School of Medicine in Charlottesville, and coinvestigators wrote.

To conduct their study, investigators created JAK2 V617F knock-in, SRSF2 P95H knock-in, and Mx1Cre transgenic mouse models, all on a C57BL/6 background. Intraperitoneal injection of 3 doses of polyinosine-polycytosine 300 μg were given at 4 weeks after birth in order to induce Mx1Cre expression. Wild-type C57BL/6 and UBC-GFP mice were acquired from an outside laboratory.

To create non-competitive bone marrow transplantation assays, 1 x 106 bone marrow cells were taken from the mice in each of the 4 groups (control of wild-type or Mx1Cre; SRSF2 P95H-positive; JAK2 V617F-positive; and SRSF2 P95H/JAK2 V617F-positive) and transplanted into lethally irradiated C57BL/6 mice. Polyinosine-polycytosine was administered to the recipient mice at a dose of 300 μg 3 times at 4 weeks following transplantation.

Competitive transplantation assays were created by mixing bone marrow cells from uninduced JAK2 V617F-positive/GFP-positive or SRSF2 P95H/JAK2 V617F-positive/GFP-positive were mixed with wild-type competitor bone marrow cells at a 1:1 ratio and transplanted into wild-type C57BL/6. Recipient mice received 3 doses of polyinosine-polycytosine 300 μg at 4 weeks post transplantation.

To create colony-forming assays, investigators plated 2 X 104 mouse bone marrow cells in cytokine-containing complete methylcellulose medium. After 1 week, burst forming units-erythroid and granulocyte-macrophage colony-forming units were tallied. Spleen cells at a quantity of 1 x 105 were plated in MethoCult M3234 medium without cytokine to detect epo-independent colony-forming units-erythroid.

Epo-independent colony-forming units-erythroid were stained with benzidine solution and counted 2 days afterwards. Colony-forming units-megakaryocytes were determined by plating 1 x 105 bone marrow cells in collagen-based MegaCult medium with Tpo, IL-3, IL-6, and IL-11. Colony-forming units-megakaryocytes were scored at day 8.

S100A8 or S100A9 overexpression’s effect on granulocyte-macrophage colony-forming units and burst forming units-erythroid formation of JAK2 V617F-positive bone marrow, cells lineage-negative cells were isolated from the bone marrow. Puromycin 2.5 μg/mL administered for 48 hours was used to select infected cells and 2.5 × 103 lineage-negative cells were plated in duplicates in cytokine-supplemented complete methylcellulose medium.

Study authors analyzed the mice models using flow cytometry and real-time quantitative PCR. Additionally, the TGF-β1 ELISA kit was used to determine TGF-β1 serum levels.

Further findings revealed that mice with heterozygous JAK2 V617F displayed polycythemia vera with increased white blood cell, neutrophil, platelet, RBC, hemoglobin, and hematocrit counts in peripheral blood compared with control mice. Those with heterozygous SRSF2 P95H experienced decreased hemoglobin with increased mean corpuscular volume vs the control group. SRSF2 P95H/JAK2 V617F-positive mice had significantly decreased white blood cell, neutrophil, platelet, RBC, hemoglobin, and hematocrit levels vs JAK2 V617F–positive mice. Concurrent expression of JAK2 V617F and SRSF2 P95H mutations resulted in higher mean corpuscular volume values and reduced spleen size and weight vs JAK2 V617F–positive mice, which displayed splenomegaly.

JAK2 V617F–positve mice bone marrow sections had hypercellularity with significant increase in erythroid precursors and megakaryocyte clusters compared with JAK2 V617F/SRSF2 P95H–positive mice, which had normal bone marrow cellularity and a reduction of erythroid precursors and megakaryocyte clusters. At 24 weeks, reticulin staining of bone marrow of SRSF2 P95H/JAK2 V617F–positive mice did not reveal fibrosis; bone marrow fibrosis was also not observed at 1 year following induction.

Together, JAK2 V617F and SRSF2 P95H mutations significantly reduced LSK, short- and long-term hematopoietic stem cell, and multipotent progenitor counts in the bone marrow of mice with both alterations. In comparison, mice with only JAK2 V617F mutations had increased frequencies and totals in terms of LSK, short- and long-term hematopoietic stem cells, and multipotent progenitors. The presence of both mutations also resulted in decreased frequency and total numbers of myeloid progenitors, common myeloid progenitors, granulocyte-macrophage progenitors, and megakaryocyte-erythroid progenitors in the bone marrow compared with mice with JAK2 V617F mutations alone.

Expression of an SRSF2 P95H mutation was also found to reduce the competitiveness of JAK2 V617F hematopoietic stem/progenitor cells. Mice that received of JAK2 V617F–positive bone marrow displayed significantly higher percentages of GFP-positive granulocyte, erythroid, megakaryocyte, B-lymphocyte, and T-lymphocyte cells in the peripheral blood compared with those that received SRSF2 P95H/ JAK2 V617F–positive bone marrow. Reduced percentages of the same hematopoietic stem/progenitor cells were observed in the bone marrow of mice that received SRSF2 P95H/ JAK2 V617F–positive bone marrow vs JAK2 V617F–positive bone marrow.

“Similar observations [to ours] have been made in a recent study by Willekens et al. Additional mutations or genetic abnormalities are required in association with SRSF2 P95H and JAK2 V617F mutations in the development of full-blown myelofibrosis,” the study investigators concluded.

Reference

Yang Y, Abbas S, Sayem MA, et al. SRSF2 mutation reduces polycythemia and impairs hematopoietic progenitor functions in JAK2V617F-driven myeloproliferative neoplasm. Blood Cancer J. 2023;13(1):171. doi:10.1038/s41408-023-00947-y

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AI Model May Help Distinguish Between Two Rare Hematologic Malignancies

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By The ASCO Post Staff

Posted: 12/13/2023

A novel artificial intelligence (AI) model may help physicians distinguish and identify prefibrotic primary myelofibrosis from essential thrombocythemia, according to new findings presented by Srisuwananukorn et al at the 2023 American Society of Hematology (ASH) Annual Meeting and Exposition (Abstract 901).

Background

Myeloproliferative neoplasms are a type of cancer in which the bone marrow overproduces certain types of blood cells. Prefibrotic primary myelofibrosis is rarer and has a much worse prognosis than essential thrombocythemia—with a median survival of 12 years vs 22 years, respectively. As a result, prefibrotic primary myelofibrosis may require more aggressive treatment; however, experts may not always agree on a definitive diagnosis when interpreting laboratory and biopsy results.

Despite being integral to informing treatment approaches and enrolling patients in clinical trials, distinguishing the two hematologic malignancies is often challenging with current diagnostic methods.

Study Methods and Results

In the new study, researchers used a novel AI model—which had previously been trained with 32,000 pan-cancer biopsy images and was familiar with general pathologic features—to analyze images from U.S. and Italian patients in order to differentiate between prefibrotic primary myelofibrosis and essential thrombocythemia.

To aid diagnosis, the researchers trained an AI model to distinguish features indicating the two conditions in bone marrow biopsy images from 200 patients. They then tested the model’s ability to differentiate the two types of myeloproliferative neoplasms in biopsies from 26 additional patients.

The researchers found that the AI model was able to return results in an average of just over 6 seconds for a new patient and performed well, demonstrating a 92.3% rate of agreement with human experts. The sensitivity and specificity for prefibrotic primary myelofibrosis diagnosis was 66.6% and 100%, respectively.

Conclusions

“With the combined accuracy, sensitivity, and specificity we saw, it would allow the physician to be confident in one diagnosis vs another and help rule in or rule out the rarer [prefibrotic primary myelofibrosis] diagnosis, particularly for clinical trials,” emphasized lead study author Andrew Srisuwananukorn, MD, Assistant Professor at The Ohio State University Comprehensive Cancer Center. “[Our] hope is that it would maintain this accuracy when tested in larger cohorts,” he added.

The researchers hope that with further testing, the novel AI model could potentially be used as a companion tool for clinical diagnoses and may help physicians match patients with the most appropriate clinical trials—which could result in more effective treatments. However, the researchers cautioned that the model was intended to complement, not replace, human experts.

“What we’re trying to develop is a clinical decision support tool, with an emphasis on support. Physicians with no computer science backgrounds are increasingly recognizing the value of AI [models] and closer to being able to use them for their clinical practice. [M]ore investigations would be needed for this [model] to be used in clinical practice, including testing in cohorts with different racial backgrounds,” underscored Dr. Srisuwananukorn.

The researchers plan to continue refining the AI model and hope to test it with larger data sets. The researchers concluded that AI models could potentially be utilized in the advancement of basic research on myeloproliferative neoplasms to link biologic processes with particular morphological features visible on biopsy slides and develop strategies to predict prognoses or response to treatment.

Disclosure: For full disclosures of the study authors, visit ash.confex.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.

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Managing blood cancer: Claire Harrison on ruxolitinib for polycythemia vera

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Rod Tucker
13 December 2023
The recent UK approval of ruxolitinib for the blood cancer polycythaemia vera marks a significant milestone in tackling unmet need for an under-represented patient population. Here, consultant haematologist Professor Claire Harrison speaks to Rod Tucker about ongoing challenges for the condition’s management, how this latest approval will benefit patients and clinicians, and other key research in the pipeline.

Ruxolitinib is a Janus kinase 2 (JAK2) inhibitor with diverse indications covering conditions such as eczema, psoriasis, vitiligo and myelofibrosis.

Most recently, in the UK at least, it has been added to the treatment arsenal for the rare blood cancer polycythaemia vera (PV) after its recommendation in October 2023 by the National Institute for Health and Care Excellence (NICE).

Professor Claire Harrison, consultant haematologist, professor of myeloproliferative neoplasms at Guy’s and St. Thomas’ NHS Foundation Trust in London, UK, has dedicated much of the last decade to researching ruxolitinib for use in PV and was instrumental in securing NICE’s endorsement.

‘It’s [a good] example of following a scientific story from discovery of the mutation, development of the drug, testing it in a more severe but related condition (myelofibrosis) then putting it into second line for PV,’ she says.

Despite the approval, there’s still work to be done to achieve the next ambition of ruxolitinib being approved for first-line use in PV. And Professor Harrison is on hand to get the ball rolling.

Diagnosing and managing polycythaemia vera

Today, diagnosing PV is much easier than when Professor Harrison first started as a consultant in 2001.

Previously, the diagnosis was arrived at following a series of tests to exclude all other possible causes of a patient’s symptoms and abnormal blood count. But after the description of a JAK2 mutation which is present in 97–98% of patients with PV, the diagnosis can be arrived at much more quickly.

‘This particular mutation for which it’s very easy to test for. It’s a cheap test and, for the most part, if it’s present, the patient has either got PV or one of the family of conditions, or it has very low levels of mutations but is likely to change into that,’ Professor Harrison says.

In general, the lay perception of a cancer diagnosis is that it represents a death sentence, and it becomes difficult to assuage patients of this fear.

While PV is incurable and lowers life-expectancy, it is not usually life-threatening, although Professor Harrison says some patients do present with life-threatening blood clots.

‘It’s a cancer but some low-risk patients we just treat with aspirin and phlebotomy, so removing blood,’ she says. ‘So that’s quite tricky saying “you’ve got cancer, but all we’re going to give you is an aspirin and take a pint of blood off you”, and other patients we do give treatments to, but we have limited options.’

Moreover, while these treatments do provide a clinical benefit in some patients, they frequently fail to alleviate symptoms.

This has become abundantly clear from the findings of the ongoing prospective REVEAL study. This showed that patients with PV experience symptoms that affect their quality of life and lead to work productivity impairments with an overall negative impact on their lives.

‘So, 80% of patients will complain of fatigue,’ Professor Harrison says. ‘It’s PV, it’s not a nothing condition: 20% of patients have to give up work or reduce their working time, others do die of the condition and the average life-expectancy is probably 15 to 20 years.’

Professor Harrison also highlights poor awareness of PV. ‘What patients would say, probably, is that people don’t understand the condition, GPs don’t understand the condition and their employers don’t understand the condition. It takes up a lot of their time and it has a big burden on their quality of life.’

She hopes that greater awareness of the condition will make it easier for people to support and make adaptations for this patient group.

Addressing unmet needs in PV

There haven’t been any new treatments for PV in around 20 years, with hydroxyurea and interferon alpha having long been the two options.

But that all changed with the description of the mutation. Professor Harrison says that after first helping with diagnosis, these learnings aided the development of drugs that could target the downstream effects of that mutation, principally JAK inhibitors.

‘These were first tested and used in more aggressive conditions in the family such as myelofibrosis. But with the advent of these drugs and their use in PV, we have been able to show that we can address some of the other unmet needs for patients,’ she says.

‘I could comment on how disappointing it is that the UK is five years behind the rest of Europe in the approval of ruxolitinib for PV, but I would prefer to celebrate that it’s a really important milestone for patients that they have an alternative therapy.’

This is particularly important as resistance or intolerance to treatments can develop in some patients, and there are other side effects and contraindications that mean traditional treatments may not be suitable.

‘An important side effect of hydroxyurea, which is also a side effect of ruxolitinib, is skin cancer,’ says Professor Harrison. ‘That’s something that we need to manage very carefully. If a patient has a skin cancer on hydroxyurea, we will sometimes change the therapy.

‘Interferon does cause quite serious mood disturbance – sometimes suicidal ideation – so it can’t really be used in patients who’ve got a significant history of anxiety or depression.

‘Similarly, [hydroxyurea] can’t be used for the 20% of patients below the age of 40 who might want to conceive a child. But we have the option to alternate between the first-line therapies.’

Emerging benefits of ruxolitinib

One of the key studies that led to the approval of ruxolitinib for PV in the UK was MAJIC-PV. This phase II trial, for which Professor Harrison was the lead author, randomised patients to either ruxolitinib or best available care in those intolerant or resistant to hydroxyurea, which is the current standard care therapy.

What was clear from MAJIC-PV was the superiority of ruxolitinib, with 43% of patients achieving a complete response based on several haematological criteria compared with only 26% of those receiving current best practice care.

While ruxolitinib does not cure PV, the MAJIC-PV trial provided reassurance that over five years no new longer-term safety issues emerged, Professor Harrison notes.

The trial also uncovered several additional biological actions of the drug. During the study, researchers measured the amount of abnormal JAK2 present in patients. This enabled clinicians to determine whether treatments had any effect on the aberrant mutations that were present.

Surprisingly, in those assigned ruxolitinib, there was a reduction in the level of this mutation.

As such, the MAJIC-PV study hinted at a mutation-specific effect of the drug which hadn’t previously been observed. Furthermore, this reduction in the level of abnormal JAK was associated with an increased life expectancy and a reduction in PV-related complications for patients.

‘Interestingly, when we were using the drug to treat patients with myelofibrosis, colleagues in Italy were reporting that their patients who had myelofibrosis but had the autoimmune condition alopecia, the hair was coming back,’ Professor Harrison adds. This hints at the wider benefits of ruxolitinib as an anti-inflammatory drug which is being harnessed in for example the treatment of eczema.

Delving deeper, Professor Harrison also describes how in research by colleague Adam Mead ruxolitinib appeared to modify PV at the stem cell level using research tools enaling the analysis of mutations at a single cell level.

Ruxolitinib as a first-line option?

Despite MAJIC-PV showing that ruxolitinib reduced levels of the abnormal JAK mutations, the current NICE approval recommends that the drug is used second-line for patients who either become resistant to or intolerant of hydroxyurea.

Notwithstanding this restriction, Professor Harrison still feels that it is important for patients to have access to ruxolitinib as another treatment option, either because of contra-indications or adverse effects from the currently available drugs.

Another consideration is the issue of drug resistance. ‘All of the available drugs are generally effective for the majority of patients, but over time, around 20–25% of patients will become resistant to that drug,’ she explains.

As a result, relying on a single drug isn’t the most effective way of controlling a patient’s blood count over time.

Encouraged by the findings from MAJIC-PV, a further phase III open-label trial, MITHRIDATE, for which Professor Harrison is the chief investigator, is starting to enrol patients.

It is designed to compare ruxolitinib with either hydroxyurea or interferon alpha as first-line therapy for high-risk PV patients.

Ruxolitinib also has a powerful effect on disease related symptoms for example patients with PV experience pruritus (itching) which can be extremely disabling, and the drug has a big impact on this troublesome symptom.

Although it is too early to draw any conclusions, Professor Harrison is hopeful that the MITHRIDATE trial will demonstrate the advantages of using ruxolitinib as a first-line treatment option and perhaps offer further insight into the drug’s disease-modifying properties.

Future treatment developments

While the introduction of JAK inhibitors such as ruxolitinib are a welcome addition to a clinician’s arsenal in the treatment of PV, Professor Harrison believes that future treatments need to focus on the off-target effects of these drugs such as immune suppression.

Although the development of JAK mutation-specific therapies in PV would be an advantage, Professor Harrison is of the opinion that it is just as important to improve understanding of how and when to use ruxolitinib in patients with PV.

Alongside the potential development of mutation-specific drugs, there is increasing interest in immune-mediated therapy.

‘I think we’ve had this massive step forward with description of molecular markers and therapies targeting JAK. We’ll probably go to treating PV earlier, and treating with a disease-modifying therapy,’ she concludes.

But focusing on the latest developments, Professor Harrison believes the introduction of innovations such as ruxolitinib would not have been possible without the support of various charities such as MPN Voice and Blood Cancer UK, as well as various academic centres and companies such as Novartis.

Working collaboratively, it has been possible to clearly demonstrate that ruxolitinib can go a long way towards helping to relieve the symptom burden of patients living with polycythaemia vera and improve quality of life for this under-represented patient population.

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New therapies against myelofibrosis, a blood cancer that risks evolving into acute leukemia – breaking latest news

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Myelofibrosis is a chronic myeloproliferative neoplasm which every year is diagnosed in approximately one thousand Italians, mostly in their sixties, but many cases occur in young people. There are therapies capable of keeping the disease under control even for years, but two important problems remain open: preventing the disease from evolving into acute myeloid leukemia (this happens in approximately 10% of patients) and preventing excessive enlargement of the spleen, very frequent, which entails serious consequences for patients. A step forward comes from one study presented at the annual meeting of the American Society of Hematology, underway in San Diego (California), whose main author is Francesco Passamonti, director of Hematology at the IRCCS Polyclinic Foundation of Milan: Obtaining a response on the spleen in a high percentage of patients and managing to maintain it for a long time implies well-being for the patient and a greater share of control over the disease – comments the expert -. This is why this result is important.

What is myelofibrosis

Myelofibrosis is a bone marrow disease characterized by the presence of alterations in the blood count (anaemia, thrombocytopenia, leukopenia or leukocytosis), accompanied by an increase in the spleen (splenomegaly) and the presence of symptoms such as fever, night sweats and a drop in weight. a rare pathology that determines the gradual appearance in the bone marrow of a fibrous tissue that no longer allows it to function correctly, with a consequent alteration in the production of blood cells – explains Passamonti – The disease is due to the presence of acquired genetic mutations in the JAK2 genes , MPL and CALR. These mutations determine the clinical manifestations of the disease, also releasing pro-inflammatory substances and a survival advantage for the diseased cells which then populate the marrow and spleen. In the early stages, myelofibrosis remains asymptomatic and the diagnosis may be made incidentally after a blood test performed for other reasons. Most patients are diagnosed in more advanced stages and manifest themselves with even serious symptoms such as anemia, enlargement of the spleen (splenomegaly) and thrombosis. It is therefore important to have new drugs available that can combat more advanced disease.

Enlarged spleen and other symptoms

The enlargement of the spleen affects approximately 8 out of 10 patients and causes symptoms such as digestive difficulties, sensations of heaviness, discomfort in the abdomen, early satiety and alterations in normal intestinal functions. In some cases the spleen is so enlarged that it occupies a large part of the abdomen and compresses the lungs (causing a dry cough). In some cases, its surgical removal is necessary. Other extremely debilitating symptoms, which can prevent you from carrying out normal daily and work activities and having a normal social and relational life, are fatigue or asthenia, a chronic sense of tiredness, to which fever, night sweats, itching can be added. widespread throughout the body (which worsens with contact with water, also known as aquagenic itching) and weight loss due to lack of appetite and digestive difficulties adds Passamonti.

The therapies

The therapies available today make it possible to extend the survival of patients and reduce debilitating symptoms, allowing, in most cases, a return to daily and work activities and a normal social life, but the only treatment that allows for definitive recovery is bone marrow transplant from a healthy donor, reserved for certain phases of the disease, for those in good general condition and under 70-75 years of age. The disease is progressive with an increase in the size of the spleen, a progressive decline in hemoglobin and platelets and increasingly disabling symptoms – says Passamonti -. It can also progress to acute leukemia. Based on the clinical characteristics of the pathology and the age of the patient, the risk of worsening of myelofibrosis is calculated: depending on the level of risk, a decision can be made for simple observation without therapy up to an allogeneic bone marrow transplant. Today, effective drugs such as JAK inhibitors (ruxolitinib and fedratinib) are available in Italy, aimed at those genetic alterations that we know are responsible for the neoplasm, allowing patients to extend their survival and reduce debilitating symptoms, allowing, in most cases, the return to daily and work activities and a normal social life. However, they have limitations: The response of the drugs on the spleen is limited and, even when they work, the validity of the treatment decreases over time – continues the expert -. And the transplant is a complex procedure, which cannot be offered to the majority of patients.

The new TRANSFORM-1 study

In short, we need new treatments that have a greater effect on the spleen and control symptoms in the long term. And they fit into this context data from the TRANSFORM-1 study, presented at the American Hematology Conference. This is a phase three trial (the last before the final approval and entry onto the market of a medicine) which enrolled over 250 patients with myelofibrosis who had not yet received any therapy, but who needed to start one . One half received the current standard treatment (ruxolitinib) and the other half ruxolitinib plus the new drug navitoclax. Navitoclax is an oral therapy which, by hitting a precise target (the BCL-2/BCL-XL proteins which promote tumor activity), causes the death of diseased cells which would otherwise live too long – clarifies Passamonti -. was administered as first line treatment with the goal of shrinking the spleen by more than 35% (measured by nuclear magnetic resonance imaging). The milestone, after six months of treatment, was reached in 63% of patients with the combination navitoclax and ruxolitinib and in 31% of those receiving standard care alone. The response was obtained in 76% and 41% in the two populations respectively. Furthermore, loss of response was recorded in 18% of patients with the combination and in 26% with ruxolitinib alone.

Chronic myeloproliferative neoplasms

In hematology, great progress in the last 20 years has been achieved thanks to the discovery of genetic mutations underlying numerous diseases and often responsible for tumor proliferation, as well as its resistance to treatment – comments Paolo Corradini, president of the Italian Society of Hematology (Sie) -. Scientific research then began to create drugs that only affected DNA alterations, sparing healthy cells. This has also led to important results in chronic myeloproliferative neoplasms, such as myelofibrosis, polycythemia vera (characterized by the progressive increase in red blood cells) and essential thrombocythemia involving the excessive increase in the number of platelets. They are rare diseases, which together cause around a thousand new cases to be recorded in Italy every year. They can accompany the patient for years without worsening, requiring only periodic checks or therapies, more or less aggressive depending on the case. The important role of our country in the TRANSFORM-1 trial demonstrates, once again, the high quality of Italian hematology.

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MorphoSys’ Pelabresib Improves All Four Hallmarks of Myelofibrosis in Phase 3 MANIFEST-2 Study

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Pelabresib and ruxolitinib combination significantly reduced spleen size, with an SVR35 response rate nearly double that of placebo plus ruxolitinib

Showed a strong positive trend in reducing symptom burden and a twofold increase in patients achieving both SVR35 and TSS50 versus placebo plus ruxolitinib

Improved measures of anemia, including higher hemoglobin response rates, fewer patients requiring transfusions and fewer anemia adverse events versus placebo plus ruxolitinib

Improved bone marrow fibrosis by at least one grade in more patients versus placebo plus ruxolitinib

Demonstrated safety results consistent with prior clinical trials, with fewer grade ≥3 adverse events compared with placebo plus ruxolitinib

MorphoSys will host an investor event to review findings on Monday, December 11

MorphoSys AG (FSE: MOR; NASDAQ: MOR) today announced comprehensive results from the Phase 3 MANIFEST-2 study investigating pelabresib, an investigational BET inhibitor, in combination with the JAK inhibitor ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis. These findings were presented in an oral presentation at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, California.

Myelofibrosis is characterized by four hallmarks: an enlarged spleen, anemia, bone marrow fibrosis and disease-associated symptoms. In MANIFEST-2, all hallmarks were improved with the pelabresib and ruxolitinib combination versus placebo plus ruxolitinib, which is the standard of care in myelofibrosis. Ruxolitinib dosing was similar in both arms of the study and was determined based on its approved myelofibrosis indication.

“The MANIFEST-2 results demonstrated clear benefits across the four hallmarks of myelofibrosis, including a significant reduction in spleen size – a key finding given the known association between spleen volume reduction and patient survival,” said Raajit K. Rampal, M.D., Ph.D., Director, Center for Hematologic Malignancies, and Director, Myeloproliferative Neoplasms Program, Memorial Sloan Kettering Cancer Center. “The comprehensive results presented at ASH also show that the pelabresib combination improves anemia, disease-associated symptoms and bone marrow fibrosis, and that it is well-tolerated. These findings point to pelabresib and ruxolitinib as a potential paradigm-shifting first-line treatment of this debilitating disease.”

MANIFEST-2 Comprehensive Findings

MANIFEST-2 is a global, multicenter, double-blind, Phase 3 study of 430 JAK inhibitor-naïve adults with myelofibrosis, randomized 1:1 to receive the pelabresib and ruxolitinib combination or placebo plus ruxolitinib. MANIFEST-2 is one of the largest studies in this disease to date.

Strong Reductions in Spleen Size and Symptoms

In the MANIFEST-2 study, pelabresib and ruxolitinib demonstrated a near doubling in the proportion of patients achieving a ≥35% reduction in spleen volume (SVR35) at 24 weeks, the primary endpoint, versus placebo plus ruxolitinib (p<0.001).

For the first key secondary endpoint assessing symptom reduction, absolute change in total symptom score (TSS) at 24 weeks, there was a strong numerical improvement for patients receiving pelabresib and ruxolitinib versus placebo plus ruxolitinib. The response rate for the second key secondary endpoint, proportion of patients achieving ≥50% reduction in symptom score (TSS50) at 24 weeks, was also numerically greater for patients receiving pelabresib and ruxolitinib. Significant improvements in both key secondary endpoints were observed with the pelabresib combination for patients classified as intermediate-risk (Dynamic International Prognostic Scoring System [DIPSS] Int-1 and Int-2), who account for over 90% of the MANIFEST-2 population.

The proportion of patients achieving both SVR35 and TSS50 at 24 weeks was doubled with pelabresib and ruxolitinib versus placebo plus ruxolitinib (40.2% vs. 18.5%, respectively).

Details are included in the table below.

Endpoint Pelabresib + Ruxolitinib
(N=214)		 Placebo +
Ruxolitinib
(N=216)		 Difference
SVR35 65.9% 35.2% 30.4%*
P-value: p<0.001
Absolute Change in TSS -15.99
(Mean Baseline: 28.26)		 -14.05
(Mean Baseline: 27.36)		 -1.94**
P-value: 0.0545
TSS50 52.3% 46.3% 6.0%*
P-value: 0.216

*Difference calculated using Cochran–Mantel–Haenszel (CMH) common risk difference

**Least square mean estimate

Improvement in Anemia

Patients receiving pelabresib in combination with ruxolitinib reported fewer anemia adverse events (43.9%, grade ≥3: 23.1%) compared with placebo plus ruxolitinib (55.6%, grade ≥3: 36.4%). Additionally, by week 24, fewer patients in the pelabresib and ruxolitinib arm required red blood cell transfusions compared with the placebo arm (30.8% vs. 41.2%, respectively).

A greater proportion of patients achieved a hemoglobin response — defined as a ≥1.5 g/dL mean increase in hemoglobin levels over baseline in the absence of transfusions during the previous 12 weeks — with pelabresib and ruxolitinib versus placebo plus ruxolitinib (9.3% vs. 5.6%, respectively). Average hemoglobin levels were greater in patients receiving pelabresib and ruxolitinib than in those receiving placebo plus ruxolitinib, starting at week 9 and continuing to week 24. Anemia benefits were observed across all studied patient risk groups.

“Anemia can reduce patients’ quality of life by causing severe fatigue and necessitating blood transfusions,” said Professor Claire Harrison, Guy’s and St. Thomas’ NHS Foundation Trust, London, United Kingdom. “In MANIFEST-2, patients receiving the combination therapy showed clear benefits on anemia, including greater hemoglobin levels, fewer red blood cell transfusions and fewer anemia and fatigue adverse events. Given its strong efficacy, safety profile and signs of disease modification, the pelabresib and ruxolitinib combination has the potential to become the new standard of care in the first-line treatment of myelofibrosis.”

Improvement in Bone Marrow Fibrosis

Bone marrow fibrosis, or the replacement of bone marrow with fibrous scar tissue, is a central pathological feature of myelofibrosis. In MANIFEST-2, fibrosis was improved by at least one grade in a greater proportion of patients receiving pelabresib and ruxolitinib (38.5% vs. 24.2% with placebo plus ruxolitinib) and worsened by at least one grade in a smaller proportion of patients receiving pelabresib and ruxolitinib (16.3% vs. 28.3% with placebo plus ruxolitinib) at 24 weeks. Bone marrow fibrosis is graded on a scale from 0 (normal) to 3 (most severe) based on fiber density; studies suggest a correlation between the grade of bone marrow fibrosis and patient prognosis.

Biomarker Analysis Suggests Disease Modification

In a biomarker analysis, average plasma levels of inflammatory cytokines (IL-8, IL-6, TNF-α and NF-κB-regulated cytokines) were reduced in patients receiving pelabresib and ruxolitinib compared with placebo plus ruxolitinib at 24 weeks. Increased cytokine levels are associated with all four disease hallmarks; increased IL-8 levels are also associated with worse survival outcomes. These biomolecular improvements suggest early evidence of a disease-modifying effect.

Well-Tolerated Safety Profile

Overall, grade ≥3 treatment-emergent adverse events (TEAEs) were reported less frequently with pelabresib and ruxolitinib than with placebo plus ruxolitinib (49.1% vs. 57.5%, respectively).

In the pelabresib and ruxolitinib arm, the most common (≥10%) hematologic TEAEs were anemia (43.9%; grade ≥3: 23.1%), thrombocytopenia (32.1%; grade ≥3: 9.0%) and platelet count decrease (20.8%; grade ≥3: 4.2%). In the placebo plus ruxolitinib arm, the most common hematologic TEAEs were anemia (55.6%; grade ≥3: 36.4%), thrombocytopenia (23.4%; grade ≥3: 5.6%) and platelet count decrease (15.9%; grade ≥3: 0.9%).

The most common (≥10%) nonhematologic TEAEs in the pelabresib and ruxolitinib arm were diarrhea (23.1%; grade ≥3: 0.5%), dysgeusia (18.4%; grade ≥3: 0.5%), constipation (18.4%; grade ≥3: 0%), nausea (14.2%; grade ≥3: 0.5%), cough (12.7% grade ≥3: 0), asthenia (11.8% grade ≥3: 0.5%), fatigue (11.8%; grade ≥3: 0.5%), dizziness (11.3%; grade ≥3: 0%), headache (11.3% grade ≥3: 0.5%) and COVID-19 (11.3%; grade ≥3: 0%). The most common nonhematologic TEAEs in the placebo plus ruxolitinib arm were constipation (24.3%; grade ≥3: 0%), diarrhea (18.7%; grade ≥3: 1.4%), fatigue (16.8%; grade ≥3: 0.9%), COVID-19 (15.9%; grade ≥3: 1.9%), nausea (15.0%; grade ≥3: 0%), asthenia (13.6%; grade ≥3: 0%), dyspnea (13.1%; grade ≥3: 0.9%), cough (11.2%; grade ≥3: 0%) and headache (10.7%; grade ≥3: 0%). Discontinuation rates due to adverse events were 10.7% with pelabresib and ruxolitinib and 6.5% with placebo plus ruxolitinib.

The safety profile of the pelabresib and ruxolitinib combination therapy was consistent with previous clinical studies. No new safety signals were observed.

“The four hallmarks of myelofibrosis – enlarged spleen, anemia, bone marrow fibrosis and disease-associated symptoms – have a strong impact on a patient’s life. In MANIFEST-2, the combination of JAK and BET inhibition addressed all four of these hallmarks with the potential to modify the course of the disease,” said Tim Demuth, M.D., Ph.D., MorphoSys Chief Research and Development Officer. “We are confident that the comprehensive data package will provide impactful insights into the promising and well-tolerated combination of pelabresib and ruxolitinib. Our goal now is to bring this first-line therapy to patients with intermediate- and high-risk myelofibrosis as quickly as possible. We look forward to meeting with regulatory agencies regarding these data and are diligently preparing regulatory filings with the intention of submitting applications to the U.S. Food and Drug Administration and the European Medicines Agency in the middle of 2024.”

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