COVID-19 Vaccine Efficacy Decreases With Ruxolitinib Use in MPNs

Giuseppe A. Palumbo, MD, PhD

Treatment with ruxolitinib (Jakafi) impaired antibody responses to complete vaccination with the BNT162b2 SARS-CoV-2 vaccine in patients with myelofibrosis or polycythemia vera (PV), according to findings from a prospective, single-center study.¹

After completing 2 doses of the vaccine, the average level of serum immunoglobulin G (IgG) neutralizing antibody levels against the receptor-binding domain portion of the spike protein of SARS-CoV-2 (anti-S) was 369.5 BAU/mL (range, 0-6901). Of the 43 patients who received 2 vaccine doses, 14 (32.6%) had anti-S antibody levels below the threshold for immunogenicity positivity, 27 had levels below 60 BAU/mL, and 28 had levels below 100 BAU/mL. Specifically, of the patients with myelofibrosis, 13 did not achieve an antibody response, and of those with PV, 1 did not achieve an antibody response.

Previously in 2020, results from the clinical trial investigating the efficacy of the BNT162b2 mRNA COVID-19 vaccine demonstrated that fully vaccinated patients gained 95% protection against the virus.² However, this trial did not include patients from certain fragile patient populations, such as immunocompromised patients, in whom the vaccine’s protection may be lower because of their ongoing treatments and diseases.

More recent studies have shown that the vaccine is less effective in patients with hemato-oncological diseases. Previous research with the vaccine in small cohorts of patients with myeloproliferative neoplasms (MPNs) treated with ruxolitinib has shown that these patients may exhibit lower responses to the first and second doses of the vaccine, and that responses differ across MPNs. For instance, a study investigating long-term responses to the vaccine in patients with essential thrombocythemia (ET), PV, and myelofibrosis receiving ruxolitinib showed that median antibody titers were 811 BAU/mL (range, 184->2500), 274 BAU/mL (range, 1.7->2500), and 51.4 BAU/mL (range, 0.6-529), respectively, over 1 month after the second vaccine dose.³

“As little data were available in [patients with MPNs] treated with ruxolitinib who had completed the vaccination cycle (2 doses) and a third booster dose, in this study, we investigated whether these patients could reach a protective antibody level against the SARS-CoV-2 virus,” lead study author, Giuseppe A. Palumbo, MD, PhD, of the University of Catania in Italy, and colleagues, wrote in a paper of the data published in Frontiers in Oncology.¹

This study evaluated 43 patients with primary myelofibrosis (n = 15), secondary myelofibrosis (n = 15), and PV (n = 13) who received ruxolitinib for their respective MPNs. All patients received both doses of the intramuscular BNT162b2 mRNA vaccine at 30 mcg per dose 3 weeks apart, per the Italian national guidelines. Patient sera samples were obtained at a median of 36 days (range, 14-53) after they received the second vaccine dose.

Of the 43 patients, 39 received the booster dose, 2 died before receiving the booster dose, and 2 refused the booster dose. Patients received their booster dose at a median of 153 days (range, 32-243) after their second dose. Sera samples were obtained from each patient before they received the booster dose, either on the same day or the day before, and at a median of 26 days (range, 11-49) following their booster dose.

All patients began ruxolitinib treatment at a median of 1236 days (range, 10-3370) before their first vaccine dose; 1414 days (range, 10-3288) for patients with myelofibrosis and 817 days (range, 53-3370) for those with PV. At the time of their first vaccine dose, patients were receiving ruxolitinib at a median of 14.7 mg twice daily (range, 2.5-25). The median ruxolitinib dose was 16.1 mg twice daily (range, 2.5-25) for patients with myelofibrosis and 11.5 mg twice daily (range, 5-15) for those with PV.

Of the patients with primary myelofibrosis, 2, 5, 7, and 1 had low-, intermediate-1–, intermediate-2–, and high-risk disease, respectively, when they received their first vaccine dose, per the Dynamic International Prognostic Scoring System (DIPSS). No patients had DIPSS score changes at the time of their booster dose. Of these patients, 13 had JAK2 V617F mutations, and 2 had CALR mutations.

Of the patients with secondary myelofibrosis, 1, 5, 5, and 4 had low-, intermediate-1–, intermediate-2–, and high-risk disease, respectively, when they received their first vaccine dose, per Myelofibrosis Secondary to PV and ET-Prognostic Model score. At the time of their booster dose, 1 patient each had progressed from low-risk to intermediate-1–risk disease and intermediate-2–risk to high-risk disease. Of these patients, 13 had JAK2V617F mutations, and 2 had CALR mutations.

Of the patients with PV, 12 had JAK2 V617F mutations and 1 had a JAK2 exon 12 mutation. All patients with PV had received hydroxyurea before switching to ruxolitinib. Seven patients switched because of hydroxyurea intolerance, and 6 patients switched because of hydroxyurea resistance per the European Leukemia Network consensus criteria.

At first vaccine dose, all patients had a median age of 69 years (range, 46-86); The median age was 72 years (range, 46-86) in patients with myelofibrosis and 64 years (range, 50-78) in those with PV. The overall median spleen size was 3 cm below the costal margin (range, 0-20), including a median of 4.6 cm (range, 0-20) in patients with myelofibrosis and 0 cm (range, 0-2) in those with PV.

This study evaluated vaccine immunogenicity by measuring the anti-S serum IgG neutralizing antibody levels. Per the World Health Organization, an anti-S value above 7 BAU was considered positive. The investigators also measured IgG against SARS-CoV-2 nucleocapsid proteins (anti-N) to determine whether patients had a prior or ongoing SARS-CoV-2 infection before or during vaccination.

Of all patients, 2 with primary myelofibrosis had anti-N IgG antibodies, indicating their exposure to SARS-CoV-2 prior to their first vaccine dose. These patients had a high post-vaccination antibody response, of 1333.9 BAU/mL and 6901.5 BAU/mL.

With 2 vaccine doses, patients achieved antibody levels at a median of 12.3 BAU/mL (range, 0-54.2). After the booster dose, patients reached a median antibody level of 272.3 BAU/mL (range, 0-1399). With the booster, 8/40 patients (20%), 7/27 with myelofibrosis and 1/12 with PV, did not achieve antibody levels above the positivity threshold. In total, 19 patients had antibody levels below 60 BAU/mL, and 24 had levels below 100 BAU/mL.

“Our study confirmed that [patients with] ruxolitinib-treated MPNs who have received 2 standard doses of BNT162b2 show a markedly impaired antibody production,” the study authors wrote. “Although the third booster dose was able to reduce the number of patients who remained fully negative, the median antibody value reached was not significantly better, and levels were far from those obtained with the same vaccine dose and schedule in normal subjects.”

The investigators recommend delaying ruxolitinib treatment in patients with myeloproliferative diseases until they have received at least 2 vaccine doses, and for patients and their caregivers to use COVID-19 risk mitigation strategies, including hygiene measures and social distancing.

References

1. Palumbo GA, Cambria D, La Spina E, et al. Ruxolitinib treatment in myelofibrosis and polycythemia vera causes suboptimal humoral immune response following standard and booster vaccination with BNT162b2 mRNA COVID-19 vaccine. Front Oncol. Published online February 14, 2023. doi:10.3389/fonc.2023.1117815
2. Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. 2020;383(27):2603-2615. doi:10.1056/NEJMoa2034577
3. Auteri G, Bartoletti D, Di Pietro C, et al. Longer-term response to SARS-CoV-2 vaccine in MPN patients: role of ruxolitinib and disease severity. Leuk Res. 2022;(5)116:106819. doi:10.1016/j.leukres.2022.106819