Role of ruxolitinib in management of polycythaemia vera

Polycythaemia vera (PV) is associated with increased risk of thromboembolic and haemorrhagic complications that negatively impact patients’ quality of life (QoL) and disease prognosis. Unfortunately, PV patients may become intolerant of or resistant to current standard therapies, underscoring the need for effective alternative treatments. At the 2023 Asian Myeloid Malignancies Exchange Forum, Professor Claire Harrison of Guy’s and St Thomas’ NHS Foundation Trust, London, UK, discussed unmet needs in PV management and implications of the superior clinical and molecular responses associated with the Janus kinase (JAK) 1/2 inhibitor, ruxolitinib, in PV patients intolerant of or refractory to standard care.

Unmet needs in PV management
PV is the most common myeloproliferative neoplasm characterized by erythrocytosis and thromboembolic and haemorrhagic events that may progress to myelofibrosis and acute myeloid leukaemia, concomitantly resulting in poorer prognosis. [Haematologica 2017;102:18-29; Leukemia 2021;35:3339-3351]

“PV is associated with substantial burden on patients’ QoL as well as emotional and financial impacts due to the complexity of disease-associated symptoms [eg, fatigue, pruritus, effects of splenomegaly, constitutional symptoms] and the uncertainty of future disease changes,” shared Harrison. [Haematologica 2017;102:18-29]

“PV treatment primarily includes phlebotomy, low-dose aspirin, and/or cytoreductive strategies, with the goal of providing symptom relief, preventing thrombosis and haemorrhage, reducing transformation risk, and managing risk situations such as pregnancy and surgery,” she continued. “We also aim to minimize iatrogenic morbidity [eg, worsening of fatigue and other signs of iron deficiency due to phlebotomy, intolerance to hydroxycarbamide, interferon toxicities].” [Haematologica 2017;102:18-29; J Clin Oncol 2011;29:761-770]

Currently, risk-adopted criteria are used for therapy decision making. In addition to phlebotomy and low-dose aspirin, cytoreduction is recommended for conventionally defined high-risk PV patients (ie, with history of thrombosis and/or age >60/65 years). [J Clin Oncol 2005;23:2224-2232; Blood 2014;124:3021-3023; Haematologica 2017;102:18-29; J Clin Oncol 2011;29:761-770]

“Regardless of patients’ risk category, we should perform comprehensive assessment of additional risk factors for thromboembolism, including smoking, hypertension, diabetes, abnormal lipid levels and obesity, and encourage a healthy lifestyle,” advised Harrison. “Even in conventionally defined low-risk PV patients, the annual risk of thromboembolic complications is 2.23 percent, which is higher than that in the general population with cardiovascular risk factors [0.9 percent]. Thus, low risk in PV does not mean no thrombotic risk, and a personalized approach may be needed.” [J Cancer Res Clin Oncol 2022;148:2693-2706; Haematologica 2017;102:18-29]

The trend towards personalized PV management has also been propelled by patients requiring second-line therapy due to resistance or intolerance to current treatments, resulting in inadequately controlled disease, and the role of molecular response monitoring such as sequential assessment of JAK2^V617F allele burden for therapeutic interventions that may induce molecular responses. In these scenarios, targeted therapy with a JAK1/2 inhibitor, ruxolitinib, has become a valid option specifically for patients with PV who are resistant to or intolerant of hydroxycarbamide. [Haematologica 2017;102:18-29; J Clin Oncol 2011;29:761-770; J Clin Oncol 2023;41:3534-3544]

Ruxolitinib for hydroxycarbamide-resistant/intolerant PV
In high-risk PV patients, first-line cytoreductive treatment includes hydroxycarbamide or interferon. [Br J Haematol 2019;184:176-191] However, both treatments are associated with toxicities or resistance over time, and second-line options are limited to dose reductions, use of phlebotomies that may also be poorly tolerated and cause symptomatic iron deficiency, or switching between hydroxycarbamide to interferon and vice versa. [Haematologica 2017;102:18-29; Br J Haematol 2019;184:176-191]

Since PV is associated with JAK2 driver mutations, in particular the JAK2^V617F mutation, ruxolitinib became the first targeted therapy approved for adult PV patients with resistance or intolerance to hydroxycarbamide. [Blood 2017;129:1607-1616; Haematologica 2017;102:18-29; Jakavi Hong Kong Prescribing Information]

Randomized phase III/IIIb trials previously showed that ruxolitinib improved control of blood counts, splenomegaly and disease-associated symptoms vs best available therapy (BAT) in patients with PV. However, these trials allowed crossover to ruxolitinib, limiting longer-term assessment of vascular events, disease progression, and survival. [N Engl J Med 2015;372:426-435; Lancet Oncol 2017;18:88-99; Br J Haematol 2017;176:76-85; J Clin Oncol 2023;41:3534-3544]

MAJIC-PV trial
“The phase II randomized MAJIC-PV trial assessed ruxolitinib’s long-term benefits [ie, thrombosis, haemorrhage, disease transformation, and overall survival (OS)] vs BAT [including hydroxycarbomide monotherapy and hydroxycarbomide-based therapy] in patients aged ≥18 years with high-risk PV resistant or intolerant to hydroxycarbamide [n=180],” explained Harrison.“We also assessed specific clinical targets, including comprehensive blood count control and molecular response. No per-protocol crossover to ruxolitinib was allowed.” [J Clin Oncol 2023;41:3534-3544]

MAJIC-PV had a median follow-up period of 4.8 years. Primary outcome was complete response (CR) rate within 12 months by European LeukemiaNet criteria: haematocrit <45 percent without venesection for 3 months, platelet count ≤400 x 10⁹/L, white blood cell count ≤10 x 10⁹/L, and normal spleen size. This was achieved in 40 patients (43 percent) on ruxolitinib vs 23 patients (26 percent) on BAT (odds ratio, 2.12; 90 percent confidence interval [CI], 1.25–3.60; p=0.02).

Ruxolitinib was also associated with significantly improved event-free survival (EFS; ie, freedom from thrombosis, haemorrhage, transformation, or death) vs BAT (hazard ratio [HR], 0.58; 95 percent CI, 0.35–0.94; p=0.03). Significant improvements were also demonstrated in thromboembolic event–free survival (HR, 0.56; 95 percent CI, 0.32–1.00; p=0.05). (Figure)

Although there is no strict recommendation for routine monitoring of molecular response, serial analysis of JAK2^V617F variant allele fraction (VAF) showed that molecular response (ie, >50 percent reduction in VAF) was more frequent with ruxolitinib vs BAT (at final evaluable time point: 56 percent vs 25 percent) and, more importantly, associated with significantly improved progression-free survival (PFS; p=0.001), EFS (p=0.001) and OS (p=0.01). [J Clin Oncol 2011;29:761-770; J Clin Oncol 2023;41:3534-3544]

“The JAK2^V617F VAF burden reduction associated with ruxolitinib treatment supports consideration of routine molecular response monitoring during targeted therapy in PV patients,” commented Harrison. [J Clin Oncol 2023;41:3534-3544]

No new adverse events (AEs) emerged over the course of the trial. Infections as well as gastrointestinal and vascular disorders were the most frequently reported AEs. Infections were more common with ruxolitinib vs BAT, in particular, respiratory, genitourinary and cutaneous herpes zoster infections (27 vs 12 grade 3/4 events), but no infection-related deaths or atypical infections were reported. Squamous-cell skin cancer was also more common with ruxolitinib vs BAT (11 vs 0 events).

Summary
Results from MAJIC-PV demonstrated ruxolitinib’s longer-term efficacy, providing superior CR, EFS and molecular response vs BAT in patients with PV resistant/intolerant of hydroxycarbamide.

“We are also the first to demonstrate the link between molecular response and EFS, PFS and OS, which supports the benefit of molecular monitoring in PV patients,” concluded Harrison.