Mar 9, 2023

Ashling Wahner

Treatment with ruxolitinib impaired antibody responses to complete vaccination with the BNT162b2 SARS-CoV-2 vaccine in patients with myelofibrosis or polycythemia vera.

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

Read more

Tania Jain, MBBS, director, Adult Chimeric Antigen Receptor T-cell Therapy Program for Hematological Malignancies, Sidney Kimmel Comprehensive Cancer Center, Assistant Professor of Oncology, Johns Hopkins Medicine, discusses the unmet needs for patients with myelofibrosis who receive an allogeneic stem cell transplant (allo-SCT).

At the 2023 Transplantation and Cellular Therapy Meetings, Jain presented data from a retrospective study evaluating outcomes for patients with myelofibrosis who had haploidentical donors (HD) and posttransplant cyclophosphamide vs other common donor types.

Findings from the study reflected that investigators still have considerable work to do in order to optimize allo-SCTs for patients with myelofibrosis, Jain begins. One area of need is relapse prevention, Jain says, adding that investigators are working to set up studies evaluating maintenance strategies post–allo-SCT to improve relapse rates.

Moreover, in the retrospective study, investigators showed that relapse rates were higher for patients with a larger spleen size going into transplant, Jain says. Novel agents currently under investigation in myelofibrosis could improve spleen response in patients, Jain continues. These could be beneficial for patients who will undergo allo-SCT, and it will be helpful to observe what a improved spleen responses with advanced therapies could mean for patients achieve in terms of transplant outcomes, Jain explains.

If patients with myelofibrosis are going to be referred for transplant, it should be done early before they have the chance to get worse or progress, Jain continues. The longer the patient is not referred, the quicker the window for transplant closes, and sicker patients do not do as well on clinical trials, Jain says. Moreover, it is important not to delay transplant looking for a perfectly matched donor when there are options with different donor types that can also help patients, which is important to consider, Jain concludes.

Read more

Read more

At a live virtual event, Andrew Kuykendall, MD, discussed the rationale and data for the use of pacritinib in patients with high-risk primary myelofibrosis.

[There has been] a recent change in our understanding, like all things, that comes with having emerging medications that might be able to contribute to [treatment of] these more cytopenic patients. In the past, it wasn’t helpful to differentiate, because we didn’t have too many options, but it’s something that’s certainly growing in awareness. We often see that this proliferative phenotype is more consistent and almost resembles something like polycythemia vera or essential thrombocythemia.

On the other hand, we have the cytopenic phenotype, which is considered more aggressive from prognostic modeling and just overall outcomes, and perhaps that’s because we’re dealing with more mutations.¹ It’s a more complex picture and a less effective treatment, so it’s something I think we will hear more about as we go forward in the next few years as we try to get a better understanding of these patients.

I also think they can be 2 different diseases, but they’re 2 different kinds of phenotypes of a disease, and I think you can switch from one to another. Certainly you can have patients [who] present as cytopenic enough [with] typically just splicing mutations—more myelodysplastic syndrome-like mutations in conjunction with a JAK2 mutation—[who] tend to [also] present with lower platelet counts.²

[However], you can also have a patient [who] has more proliferative disease and then acquires new mutations, [which] contribute to this more cytopenic disease. Either way, you’re dealing with a more complex disease, with more mutations and bigger challenges to deal with as far as treatment goes. [In higher-risk patients], we have this decision point based on the platelets. [For a patient with] platelets greater than 50 × 10⁹ /L [who is] a transplant candidate, we certainly recommend going forward with that.³

The Role of Pacritinib

When patients have [a platelet count] less than 50,000, we used to say transplant was the only option, but now we have this emerging evidence for pacritinib, which is becoming more utilized. Pacritinib was added with a more recent update for patients with less than 50,000 platelets, but it also was added as a potential second-line option.⁴

When we talk about JAK inhibition, we have 3 approved therapies: ruxolitinib, fedratinib, and pacritinib.^5-7 All [these] have similarities in the sense that they inhibit JAK2, but they have some unique aspects. Ruxolitinib is a JAK1 and JAK2 inhibitor, fedratinib is mostly a JAK2 inhibitor but has some FLT3 inhibition, and pacritinib [also] has JAK2 and FLT3 inhibition, so these are more selective JAK2 inhibitors.

Pacritinib also has potential relevance in the sense that it inhibits CSF1R and IRQ1, and maybe this has some relevance as to how this is less myelosuppressive.⁸ Indications are similar for ruxolitinib and fedratinib, but pacritinib requires moderate thrombocytopenia, then the dosing is a stable flat dose for fedratinib and pacritinib. So 400 mg once daily for fedratinib, recommended to take with food to decrease some of this GI [gastrointestinal] toxicity.

Pacritinib [has the] same [recommendation regarding] being taken with food, but it’s given at 200 mg twice daily. Ruxolitinib is based on the platelet count, where there’s this dynamic dosing strategy to avoid causing severe thrombocytopenia. For patients with a platelet count of 50,000 to 100,000, [use] 50 mg twice a day. [If they have more than] 200,000 platelets, [use] 20 mg twice a day. Ruxolitinib has an inhibition of JAK1 and JAK2, but pacritinib [has] quite a difference between JAK1 and JAK2, and fedratinib is somewhere in between.

When you look at the impact of what not hitting JAK1 might be, JAK1 has a role in megakaryocytes releasing platelets, so if you inhibit that you tend to inhibit [not only] megakaryocyte maturation but also the release of platelets. If you don’t hit that, then maybe you’re just inhibiting megakaryopoiesis, but you’re not necessarily inhibiting the platelet production or the thrombopoiesis. Perhaps that’s why pacritinib is a little bit better tolerated in terms of platelet counts.

Highlights of the PERSIST Trials

PERSIST-1 [NCT01773187] was a frontline trial that looked at pacritinib in patients with any platelet count, but they couldn’t have had prior JAK inhibitors. [Patients were randomly assigned] 2:1 to pacritinib at 400 mg daily, which is not the recommended dose, vs the best available therapy [BAT], but the BAT could not be ruxolitinib.⁹ [The study then] looked at a primary end point of 35% [spleen volume reduction (SVR) at week 24].

For various reasons, we don’t look too much at PERSIST-1 now, because it’s kind of an obsolete dosing strategy. It doesn’t compare directly with ruxolitinib and doesn’t include prior ruxolitinib. [However], the PERSIST-2 study [NCT02055781] certainly has some relevance; it enrolled patients with thrombocytopenia [and] less than 100,000 platelets, and they were allowed to have had prior JAK inhibitor therapy.¹⁰

Patients were [randomly assigned] 1:1:1 to 2 different doses of pacritinib vs BAT, which could include ruxolitinib, then they looked at coprimary end points of spleen volume response and symptom response. When you look at the baseline demographics of this study, the important thing everyone wants to know is how much of BAT was ruxolitinib, and [approximately] 44% of patients received ruxolitinib as BAT.

Then when you look at the risk scores [of patients on this trial], it was more of an intermediate- to high-risk group, [with just over 50% in both groups being categorized as intermediate-2 risk scores]. The overall patient population was quite similar, but [approximately] 42% [in the pacritinib group] had platelets that were less than 50 × 10⁹ /L, and this is certainly the indication that it has now.

When you look at SVR at week 24 [for patients on the now] recommended dose of 200 mg twice daily, patients on pacritinib compared [with] BAT were more likely to achieve SVR at 29%, especially in those patients with less than 50×10⁹ /L platelets, compared [with] 3.1% in those patients [who] had BAT. It had quite a striking absolute difference between the 2 groups, at 25.9% [95% CI, 4.3%-44.5%].

When assessing the patients’ total symptom score [TSS], 32% of patients in the pacritinib arm compared [with] 14% in the BAT arm were able to achieve a TSS response of at least a 50% decrease in the symptoms.

[When looking specifically at the patients who had prior ruxolitinib as BAT], it seems like most of [them] were getting improvement in symptoms, albeit not to that 50% threshold, which may go along with the fact that they were getting suboptimal dosing. Furthermore, when we look at individual symptom scores in pacritinib vs BAT, across the board it seems to be that [those] in the thrombocytopenic patient population were getting better symptom improvement with pacritinib compared [with] BAT as well.

Reactions to Pacritinib

When considering red blood cell transfusions over time, we often think about pacritinib being used in this low-platelet population. You can compare pacritinib at 400 mg with 200 mg [with] BAT at baseline, and it looks like the BAT arm was getting [some] more transfusions on median number of transfusions for a month. [However], after week 12, the number of transfusions in the 200-mg twice daily arm decreases, whereas the number of infusions increases in the BAT arm.

Then at week 24, it decreases again in the pacritinib arm. Over time, [patients] on pacritinib—even those thrombocytopenic patient populations—are experiencing [fewer] red blood cell transfusions. When you look at the platelet counts and the trend over time, it appears that patients on pacritinib have a stable platelet count over these 24 to 36 weeks.

[Looking at adverse reactions to the therapy, there is still] the signal for GI toxicity. This often happens when [therapies] hit FLT3, as pacritinib does, like fedratinib. There is only 4% of patients in the pacritinib arm with grade 3 or greater diarrhea, but there is still a significant amount of diarrhea in [approximately] 50% of patients, [which is] much more than those on BAT.

We’re seeing a little more of other adverse reactions in pacritinib vs BAT: thrombocytopenia [34% vs 23%, respectively], nausea [32% vs 11%], anemia [24% vs 15%], edema [20% vs 15%], and vomiting [19% vs 5%]. The take-home message here is that there is more GI toxicity in some patients’ myelosuppression, although to a much milder extent than what we saw previously with ruxolitinib and fedratinib.

Read more

Thu, March 2, 2023 at 8:35am EST

World-Renowned Physician-Scientist and Global Expert in Myeloproliferative Neoplasms

Will Be Instrumental in Advancing the Development of Navtemadlin and Other Innovative Therapies to Improve the Lives of Cancer Patients

REDWOOD CITY, Calif., March 02, 2023–(BUSINESS WIRE)–Kartos Therapeutics, Inc. (“Kartos” or the “Company”), a clinical stage biopharmaceutical company dedicated to the development of novel, targeted therapeutics that meaningfully improve the lives of patients with cancer, today announced that Dr. Srdan (Serge) Verstovsek, MD, PhD, has been named Chief Medical Officer (CMO).

Dr. Verstovsek is a world-renowned physician-scientist and a leading global authority on the treatment of myeloproliferative neoplasms (MPN), including myelofibrosis (MF). Since 1998, Dr. Verstovsek has been affiliated with the University of Texas MD Anderson Cancer Center where he served as hematologist-oncologist and more recently as the United Energy Resources, Inc. Professor of Medicine. He was also Director of the world’s largest MPN clinical research center, the Hanns A. Pielenz Clinical Research Center for MPNs, and Chief of the Section for MPNs.

Dr. Verstovsek has achieved international acclaim for pioneering practice-changing therapeutic advances for the treatment of MPNs. He has led more than 80 early/advanced phase clinical trials of novel MPN drugs, including ruxolitinib, which until 2019 was the only FDA-approved medication for myelofibrosis. He has published 24 book chapters, more than 600 peer-reviewed original articles/reviews in leading medical journals and has received numerous clinical research awards.

“We are humbled that Dr. Serge Verstovsek has decided to continue his extraordinary career as part of the Kartos team,” said Jesse McGreivy, MD, Chief Executive Officer of Kartos Therapeutics. “Serge’s deep understanding of MPNs and his accomplishments as a clinician and drug developer are unparalleled. Having Serge onboard will be tremendously impactful in our quest to bring navtemadlin and other innovative medicines to patients across the globe.”

“I am thrilled to join a Company so dedicated to developing novel, targeted therapeutics that meaningfully improve the lives of patients with cancer,” said Dr. Verstovsek. “Having worked closely with Kartos’ outstanding executive team and been deeply involved in designing several of the company’s studies, I know firsthand about the incredible talent and science driving the development of navtemadlin. I am very enthusiastic about the clinical potential of this groundbreaking drug and look forward to devoting the next stage of my career to help ensure its complete success.”

Dr. Verstovsek is a member of the American Society for Clinical Investigation and is co-founder and an Executive Committee Member of the International Working Group for MF Treatment and Research. Dr. Verstovsek received his MD and PhD from the University of Zagreb, Croatia.

Read more

Feb 20, 2023

Medical Source: Dr. Muneeb Niazi

Updated February 17th, 2023

Myelofibrosis (MF) belongs to a group of blood cancers called myeloproliferative neoplasms (MPNs). These cancers originate in the myeloid tissue, commonly known as the bone marrow, which lines the inside of large bones, such as the vertebral column or the hip bones.

“The [abnormal] cell of origin [for these cancers] is in the bone marrow… There are three classical MPNs, essential thrombocytosis, which is too many platelets, polycythemia vera, which is too many red cells, and MF, which is a condition in which there is a proliferation of cells in the bone marrow. But there’s also a significant amount of scarring or fibrosis in the bone marrow,” explains Dr. James Mangan, Hematologist/Medical Oncologist at the University of California San Diego.