Category Archives: Essential Thrombocythemia

An Update on Current and Emergent Therapies for Essential Thrombocytosis

Posted on by

Daniel H. Foley, MD
Kristen Pettit, MD

The therapeutic landscape for myeloproliferative neoplasms is shifting toward a goal of meaningful disease modification.

Our understanding of pathophysiology driving Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs) has evolved considerably over the past decade. As a result, the therapeutic landscape is shifting toward a goal of meaningful disease modification. For patients with essential thrombocytosis (ET), the immediate goals remain thrombosis risk reduction and symptom control, but newer therapies on the horizon are likely to change our treatment paradigms considerably for this disease.

How do you approach a new patient with ET?
When it comes to the treatment of patients with ET, the main goal of current approved therapy is to mitigate the risk of thrombotic events, as the treatments have minimal impact on disease progression. The choice of treatment is determined by an individual’s specific risk factors for these events. The International Prognostic Score for Thrombosis in ET revised score is used to stratify patients into 4 risk groups: very low risk, low risk, intermediate risk, and high risk. For the majority of low-risk patients, low-dose aspirin is recommended, as it aids in preventing clotting, but patients classified as intermediate or high risk are generally advised to undergo cytoreductive therapy.

What are the standard options for cytoreductive therapy?

The selection of the most suitable cytoreductive agent depends on factors such as the patient’s comorbidities, tolerability of the treatment, future family planning, and individual preferences. Hydroxyurea (HU) and pegylated interferon alfa (peg-IFN) are the primary options for frontline cytoreductive treatment. In the phase 3 study MPD-RC 112 [NCT01259856], which included patients with both ET and polycythemia vera (PV), HU and peg-IFN demonstrated comparable rates of complete response and thrombotic events after 12 months.1 However, over time peg-IFN has shown improved molecular responses in both ET and PV.1-4 Although the clinical implications of these molecular responses aren’t yet entirely clear, these findings are quite exciting to see in this disease that has been so difficult to target. A longer-acting interferon (ropeginterferon alfa-2b-njft; Besremi) is currently in evaluation for patients with ET and has been approved in the United States for patients with PV. In cases where initial treatment approaches do not yield satisfactory results, anagrelide is another option, though its use is often limited by toxicities (eg, headaches, dizziness, palpitations, and fluid retention).

What is on the horizon for treatment of ET?

As we delve deeper into understanding the biologic drivers of ET, promising new therapeutic directions are emerging, including JAK inhibitors, epigenetic agents, and mutation-specific biologic/immunologic therapies.Ruxolitinib (Jakafi), a JAK1/2 inhibitor already widely used for other MPNs, continues to be evaluated in ET. In a randomized study, MAJIC [NCT05057494], ruxolitinib was compared with best available therapy (BAT) for patients with ET who had resistance or intolerance to HU. Both treatments showed similar rates of hematologic response, thrombosis, and hemorrhage. However, ruxolitinib outperformed BAT in improving disease-related symptoms.5 Another ongoing trial called Ruxo-BEAT [NCT02577926] is further exploring the use of ruxolitinib in ET.

When it comes to epigenetic regulators, BET inhibitors and LSD1 inhibitors are emerging as potential therapeutic targets. Both BET inhibitors and LSD1 inhibitors have shown the ability to reduce cytokine production via different mechanisms and impair self-renewal of malignant hematopoietic stem cells, so they may have more significant disease-modifying activity compared with other agents.6,7 The BET inhibitor pelabresib (CPI-0610) is currently being evaluated for ET as well as myelofibrosis. The LSD1 inhibitor bomedemstat is also being studied for both ET and MF, and preliminary reports from the ET study show encouraging ability to control platelets and improve symptoms for many patients.8

Biologic and immunologic approaches are emerging as promising strategies as well. Recently, at the American Society of Hematology annual meeting in 2022, preclinical data were presented on a monoclonal antibody that targets mutant CALR, a key diver for approximately 25% of patients with ET.9 This antibody showed impressive potency in selectively targeting mutant CALR-driven oncogenic mechanisms. There are also other antibody-based therapies showing significant efficacy in preclinical studies, and these strategies are now moving toward the development phases.10 Furthermore, the discovery of T-cell responses against mutant CALR has sparked the development of vaccine-based treatment strategies.11,12 

What are your final thoughts regarding the future of ET?

The development of more targeted agents with the potential to meaningfully disrupt the mechanisms driving MPNs provides a lot of optimism for the future in these diseases. As these therapies move toward “prime time,” we will need to reassess our treatment goals for our patients. Hopefully we will be able to raise the bar for response from simply hematologic control and thrombosis prevention toward the more lofty aims of lengthening survival, improving quality of life, and lowering risk of disease progression.

REFERENCES:

1. Mascarenhas J, Kosiorek HE, Prchal JT, et al. A randomized phase 3 trial of interferon-alpha vs hydroxyurea in polycythemia vera and essential thrombocythemia. Blood. 2022;139(19):2931-2941. doi:10.1182/blood.2021012743

2. Masarova L, Patel KP, Newberry KJ, et al. Pegylated interferon alfa-2a in patients with essential thrombocythaemia or polycythaemia vera: a post-hoc, median 83 month follow-up of an open-label, phase 2 trial. Lancet Haematol. 2017;4(4):e165-e175. doi:10.1016/S2352-3026(17)30030-3

3.Quintás-Cardama A, Abdel-Wahab O, Manshouri T, et al. Molecular analysis of patients with polycythemia vera or essential thrombocythemia receiving pegylated interferon α-2a. Blood. 2013;122(6):893-901. doi:10.1182/blood-2012-07-442012

4.Kiladjian JJ, Cassinat B, Chevret S, et al. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood. 2008;112(8):3065-3072. doi:10.1182/blood-2008-03-143537

5.Harrison CN, Mead AJ, Panchal A, et al. Ruxolitinib vs best available therapy for ET intolerant or resistant to hydroxycarbamide. Blood. 2017;130(17):1889-1897. doi:10.1182/blood-2017-05-785790

6.Kleppe M, Koche R, Zou L, et al. Dual targeting of oncogenic activation and inflammatory signaling increases therapeutic efficacy in myeloproliferative neoplasms. Cancer Cell. 2018;33(1):29-43.e27. doi:10.1016/j.ccell.2017.11.009

7.Jutzi JS, Kleppe M, Dias J, et al. LSD1 inhibition prolongs survival in mouse models of MPN by selectively targeting the disease clone. Hemasphere. 2018;2(3):e54. doi:10.1097/HS9.0000000000000054

8.Gill H, Palandri F, Ross DM, et al. A phase 2 study of the LSD1 inhibitor bomedemstat (IMG-7289) for the treatment of essential thrombocythemia (ET). Blood. 2022;140(suppl 1):1784-1787. doi:10.1182/blood-2021-148210

9.Reis E, Buonpane R, Celik H, et al. Discovery of INCA033989, a monoclonal antibody that selectively antagonizes mutant calreticulin oncogenic function in myeloproliferative neoplasms (MPNs). Blood. 2022;140(suppl 1):14-15. doi:10.1182/blood-2022-159435

10.Tvorogov D, Thompson-Peach CAL, Foßelteder J, et al. Targeting human CALR-mutated MPN progenitors with a neoepitope-directed monoclonal antibody. EMBO Rep. 2022;23(4):e52904. doi:10.15252/embr.202152904

11.Holmström MO, Martinenaite E, Ahmad SM, et al. The calreticulin (CALR) exon 9 mutations are promising targets for cancer immune therapy. Leukemia. 2018;32(2):429-437. doi:10.1038/leu.2017.214

12.Holmström MO, Riley CH, Svane IM, Hasselbalch HC, Andersen MH. The CALR exon 9 mutations are shared neoantigens in patients with CALR mutant chronic myeloproliferative neoplasms. Leukemia. 2016;30(12):2413-2416. doi:10.1038/leu.2016.233

Read more

Survival Expectation After Thrombosis and Overt-Myelofibrosis in Essential Thrombocythemia and Prefibrotic Myelofibrosis: A Multistate Model Approach

Posted on by

July 28, 2023

Alessandra Carabbio, Alessandro Maria Vannucchi, Elisa Rumi, Valerio De Stefano, Alessandro Rambaldi, Giuseppe Carli, Heinz Gisslinger, Francesco Passamonti, Juergen Thiele, Naseema Gangat, and Tiziano Barbui

Ample evidence has been provided that accurate discrimination between essential thrombocythemia (ET) and early prefibrotic primary myelofibrosis (pre-PMF) has an impact not only on presenting laboratory data but also on complications, like thrombosis, progression to overt myelofibrosis (MF), transformation to blast phase (BP), and overall survival [1,2,3,4,5,6,7,8]. However, studies estimating the epidemiology of these critical events in the two entities have mainly focused on one isolated outcome at a time, without considering the entire spectrum of multiple intermediate disease states, possibly affecting probabilities and risk factors of the outcome of interest. This situation calls for a multistate model approach, a technique that allows a more in-depth insight into intermediate factors likely influencing the progressive transitioning from one status to another.

The aim of the present investigation was to estimate the probabilities that intermediate-state passages, including thrombosis, overt MF, and BP, impact the final absorbing state (death) in ET versus pre-PMF. To this purpose, retrospective data from two multicenter and well-documented studies [1, 9] were used: (i) ET patients (n = 791) from a multicenter international study of 891 cases, selected for the availability of complete disease history [1] and (ii) pre-PMF patients (n = 382) from four different Italian centers [9]. Both studies were approved by all institutional review boards or ethical committees of participating centers.

At the time of diagnosis, treatment-naïve ET and pre-PMF patients revealed different hematologic and clinical characteristics (Table S1). A parametric Markov multistate model [10] was applied to analyze data on survival considering intermediate states that are part of the natural history of ET and pre-PMF. The model included five states with ten possible transitions (Fig. S1): all patients begin in the initial state of diagnosis (ET, panel A, n = 791 or pre-PMF, panel B, n = 382) and then they could transit through the occurrence of an incident thrombotic event (Table S2) and/or the evolution to overt MF and/or BP (transient states) before death (absorbing state).

In ET, transition-1 from diagnosis to thrombosis included 101/791 patients (12.7%), but this status was transient in 21/101 patients that moved to death (21%) after a median time of 4.0 years (IQR: 1.6–6.4), 3/101 (6%) and in 1/101 (2%) to MF and BP, after a median time of 4.7 and 5.2 years, respectively. Remarkable was that in pre-PMF, the direct transition to thrombosis was found in 13.9%, a figure not different from ET (i.e., 12.7%). Conversely, pre-PMF substantially differed from ET for a higher rate of direct transition to overt MF or BP, that was 13 and 4% vs. 4 and 0.6%, respectively.

After 10 years, the state occupation probability of being event-free was 70 and 50% in ET and pre-PMF, respectively, and progressively decreased, particularly in pre-PMF (Fig. S2), due to earlier mortality, particularly for a greater probability of hematological evolutions. This trend was even more evident for death; regardless of the pathways through hematological evolutions, deaths were double in pre-PMF than ET, reaching 30, 60, and 80% vs. 15, 30, and 60% at 5, 10, and 20 years, respectively.

Probabilities to direct transition to thrombosis (n = 101 in ET and n = 53 in pre-PMF) and overt MF (n = 29 in ET and n = 51 in pre-PMF) are compared in Fig. 1. The trend of experiencing thrombosis directly after ET diagnosis showed to increase in the first 10 years (10%) and to decline subsequently (less than 5% at 30 years). On the contrary, in the first decade after diagnosis (<5%), the same probability grew slowly in pre-PMF while subsequently rose up to crossing the ET trend (8% after 30 years). Instead, the direct transitions from pre-PMF to overt-MF had an opposite trend: in the first 10 years, it reached a peak of 11%, while in ET, the trend was less pronounced, reaching a probability not exceeding 2.3% in the same period post-diagnosis.

Fig. 1: Direct transition probabilities to thrombosis and evolution in overt MF.
figure 1

Direct transition probabilities over time from diagnosis of ET or pre-PMF to thrombosis (A) and overt MF (B). Transition probabilities are defined as the probability of going from a given state to the next state in a Markov process. Direct transitions refer to all the 791 and 382 ET and pre-PMF patients, respectively, initially at risk; thus, they represent the probability that a patient can first experience thrombosis or evolve into overt MF.

The performance of the IPSET-thrombosis score [11] was tested in both ET and pre-PMF for the direct transition to thrombosis. In ET, considering the low-risk group as a reference, the intermediate and high-risk groups determined by IPSET-thrombosis were confirmed to predict the thrombotic risk (HR = 2.08, 95% CI = 1.28–3.37, p = 0.003 and HR = 3.13, 95% CI = 1.82–5.40, p < 0.001, respectively). In pre-PMF, the same model was unpowered to reach statistical significance in the intermediate-risk group (HR = 2.50, 95% CI = 0.87–7.21, p = 0.089), while it was in the high-risk category (HR = 3.93, 95% CI = 1.52–10.11, p = 0.005).

Concerning survival, most of the deaths in ET and pre-PMF occurred directly from diagnosis (Fig. 2). The intermediate events that most influenced death were thrombosis (25.3%) in ET and BP (23.8%) in pre-PMF. In comparison with ET, the probability of direct transition from diagnosis to death in patients with pre-PMF increased linearly over time (Fig. 2) and was twofold higher, reaching values of 15, 30, and 60% at 5, 10, and 20 years, respectively. Of note, the probability of death in ET patients with an intermediate thrombosis state maintained a fourfold higher value over time than the ones without thrombosis. As expected, the probabilities of death in MF or BP status were higher and occurred faster, and not substantially different in ET or pre-PMF.

Fig. 2: Transition probabilities to death in ET and pre-PMF.
figure 2

Comparison of the direct and indirect (via thrombosis, evolution in MF or BP) transition probabilities to death (absorbing state) over time from diagnosis of ET (dash lines) or pre-PMF (solid lines).

We confirmed the good performance of the IPSET-survival score [12] to differentiate the risk of direct mortality in ET (intermediate: HR = 4.38, 95% CI = 1.63–11.73, p = 0.003 and high-risk: HR = 20.17, 95% CI = 7.71–52.78, p < 0.001, compared to low-risk). The IPSET-survival score was equally well performing in pre-PMF (HR = 3.52, 95% CI = 1.22–10.12, p = 0.019 and HR = 13.37, 95% CI = 4.63–38.57, p < 0.001, for intermediate and high-risk groups, respectively, compared to low-risk). However, the discriminatory power of the IPSET-survival in ET was lower when the multistate model evaluated the mortality mediated by the thrombosis state; only high-risk patients were discriminated (HR = 19.27, 95% CI = 2.46–51.01, p = 0.005), whereas the intermediate-risk group was not significantly different from the low-risk one (HR = 3.84, 95% CI = 0.55–26.12, p = 0.194). Thus, in addition to the IPSET-survival risk factors (i.e., age ≥60 years, previous thrombosis, and white blood cells count ≥11 × 109/L) we found that platelets count ≥1000 × 109/L (HR = 5.74, 95% CI = 1.79–18.40, p = 0.003) and arterial vs. venous thrombosis in the follow-up (HR = 4.43, 95% CI = 1.04–18.91, p = 0.044) were independent predictors. The low number of deaths after thrombosis (12/105, 11%) in pre-PMF did not allow us to analyze the IPSET-survival performance in this transition.

The present multistate analysis, provides new insights for a better understanding of ET and pre-PMF disease processes. For example, in pre-PMF, the probability of thrombosis in the first decade was lower (<5%) due to a strong competitor represented by the evolution in MF (up to 11%). Consequently, occupation of thrombosis state in the first decade was lower in pre-PMF than in ET patients but became comparable in the last decades of observation (13 and 14% in ET and pre-PMF, respectively), supporting our previous cumulative estimates obtained with conventional methodology [1]. This notion might have practical implications to differentiate treatments during the course of the two entities by preferring antithrombotic prophylaxis according to IPSET thrombosis in ET that kept its discriminatory power also in this multiple competing adjustment analysis. In pre-PMF, therapy of first choice might be directed to prevent myelofibrosis evolution, provided agents able to do that are positively evaluated in appropriate clinical trials.

Regarding BP evolution, we highlight that the direct transition from the diagnosis was predominant in ET (n = 6/7, 86%), and it was modestly influenced by the pathway through thrombosis (n = 1/7, 14%). Unfortunately, we could not provide sufficient information on the role of cytoreductive therapy in these transitions due to the unreliable timing of drug administration.

Mortality prediction in ET was the topic addressed in a previous study [12]. On the basis of the hazard ratio estimates from Cox regression models, the IPSET-survival model was constructed, and 867 ET patients were allocated into three risk categories with significantly different survival [12]. In the present analysis, in a selected group of patients (n = 791) from the same database, we re-evaluated the risk factors of death considering the possible influence of the intermediate states that occurred before death, and confirmed the performance of the IPSET-survival scoring system for the prediction of direct mortality. However, we also found that the effect on mortality exerted by the intermediate thrombosis state was not negligible (accounting for 25% of deaths) and fourfold higher than in patients without incident thrombosis. Whether the reduction of vascular complications may impact survival remains to be demonstrated in appropriate prospective studies. Furthermore, we found two additional independent predictors of mortality in thrombosis-mediated transition, namely platelet count >1000 × 109/L (HR = 5.74, 95% CI = 1.79–18.40, p = 0.003), in line with a previous observation [13], and the incident arterial vs. venous thrombosis (HR = 4.43, 95% CI = 1.04–18.91, p = 0.044).

Limitations of this study concern its retrospective design and a possible bias related to the reporting accuracy of events, in terms of completeness and timing. In addition, since in these databases, the administration times of the cytoreductive drugs (hydroxyurea in absolute prevalence) were not well specified, we could not reliably evaluate the influence of the pharmacological cytoreduction on the post-diagnosis events. Furthermore, given that current results were obtained in the same ET database used for IPSET scores, a possible “self” confirmation bias could not be excluded. However, our aim was not to confirm the overall performance of the two scores, but to evaluate whether the transition from one state to another could have affected the overall survival or the cumulative incidence of thrombosis in a different way.

Strengths of the study are the relatively large number of patients for rare diseases such as ET and pre-PMF and the clinical and hematological diagnostic accuracy of the two entities and outcomes.

In conclusion, this multistate analysis provides novel information on the temporal probability of intermediate critical events occurring in ET and pre-PMF, and their impact on mortality. This knowledge might inform clinical practice and could also make more feasible the design of clinical trials.

Read more

EXCEED-ET Investigates an Alternative Option for Disease Modification in Essential Thrombocytopenia

Posted on by

July 16, 2023

Nichole Tucker

An overperforming JAK-STAT pathway, including the presence of JAK2, CALR, and MPL gene mutations leads to high platelet count in patients with essential thrombocytopenia (ET).1 Safe and potent therapies are needed for these populations, especially for those requiring cytoreduction, regardless of their prior exposure to hydroxyurea and/or anagrelide, according to Lucia Masarova, MD, et al.

There is also an unmet need for treatments that can reduce the risk of thrombohemorrhagic events, ultimately stopping or preventing the development of post-ET myelofibrosis.1

Ropeginterferon alfa-2b-njf (Besremi) is a next-generation interferon alfa agent. It is FDA-approved to treat another myeloproliferative neoplasm (MPN), polycythemia vera (PV). In ET, ropeginterferon alfa-2b-njf is being investigated for the treatment of adult patients in a single-arm, multicenter trial (EXCEED-ET; NCT05482971).

At the American Society of Clinical Oncology (ASCO) 2023 Annual Meeting, Masarova, assistant professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, presented the EXCEED-ET study design, noting its potential to fill an unmet need for new therapies to treat adults with ET.

“Eventually, we can hopefully add it to something and maybe keep on some agents that have been around to help control the counts. At the same time, maybe we can do a low-dose interferon for a longer time as a disease modification agent, and hopefully you will wake up in an era where there’s going to be no ET or PV,” Masarova told Targeted OncologyTM, in an interview.

In the interview, Masarova, discussed EXCEED-ET in detail and provided insights into the treatment options for ET and PV.

Targeted Oncology: In terms of disease modification, what is the current state of treatment in MPNs?

Masarova: We hope there will be a goal of therapy in the coming decades. Currently, the therapy goals are kind of focused more in controlling the accounts displaying the symptoms and getting deeper responses. Right now, with some therapies that showed us that we could decrease the allele burden, or we could alter the bone marrow fibrosis, or the bone marrow morphology is going to be the disease modification. As of now, there is no agent that would do it, except for the interferon, which showed quite promisingly that we can bring it into the landscape of the disease.

What does the treatment landscape currently look like for ET?

ET is considered a benign disease. People live with it for a very long time. Currently, treatment is for only those we call high-risk disease patients. Patients that had thrombosis in the past, and then patients that are over the age of 60 years and have a dAkt mutation, and that’s according to the revised International Prognostic Score of Thrombosis for Essential Thrombocytopenia score. Those patients are treated to decrease the risk of thrombosis, but not to do anything else. This is modified just to simply increase the thrombosis risk. That is hydroxyurea, it’s a standard frontline agent, which is an easy to take oral drug. However, it could lead to some resistance or about 30% patients can become.

Because ET also affects younger people, plenty of younger females, they don’t really want to take chemotherapy forever, which I don’t blame them for. They are interested in taking something else. The standard interferon, recombinant or pegylated, which is called the peginterferon alfa-2a [Pegasys]. We’ve recently used this for the couple years has been around for MPNs, particularly for ET and the PV. That is about 40 years almost. This treatment has a lot of data, and a lot of implications. This may be a disease modifying agent, which is an agent that could decrease the allele burden, eradicate the malignant clone, and ultimately change the disease behavior. We were excited. We had novel interferon called ropeginterferon-alpha-2b-njft approved in patients with progressive disease back in 2021. That has been preceded by approval in European Union in 2019. That’s an excellent option in terms of interferons. The normal alternative with the ropeginterferon, which is the novel mono-pegylated form, is kind of more convenient because it’s used every other week. Once we reached complete hematologic control, it’s used once a month. That’s a significant improvement in inconvenience for patients and in tolerability as well as compliance issues. We were excited to get it in PV, and we have it in some studies in PV to expand the access and maybe try a different schedule, and you move it to ET patients. That’s something that we’re going to be looking at.

Then, for patients with PV refractory to hydroxyurea, we have approved sunitinib [Sutent] which is the JAK inhibitor that has solid data in the field after hydroxyurea based on results from the RESPONSE [NCT01243944] and RESPONSE-2 [NCT02038036] trials. It will be 10 years since we had refractory patients treated with ruxolitinib [Jakafi]. It’s an excellent drug for controlling the symptoms and spleen count.

Last year, we had a very excited study called MAGIC-PV [ISRCTN61925716], which was reported by our European colleagues that showed the advantage of ruxolitinib for decreasing the rate of thrombosis hemorrhage. It also actual improved event-free survival, death, and adverse events in terms of progression to myelofibrosis. So, it was exciting. If we consider disease modification is what’s going to be preventing the disease to go into myelofibrosis, I think that will be exciting to see how far we can get in that field.

Can you discuss the rationale of the EXCEED-ET study [NCT05482971]?

The EXCEED-ET study is getting the ropeginterferon, which is the novel interferon into the space of ET. It is phase 1/2 study that gets the ropeginterferon in patients in North America. The patients are hydroxyurea-refractory or hydroxyurea-naive. Patients that have ET platelets over 450,000 need the therapy with some symptoms, and do not have a contraindication for interferons, which also had to be mentioned that the drugs could not be used in patients that have previous autoimmune disease, psychiatric diseases, or neurological because it could aggravate their symptoms. But those patients, if they would be eligible, they could be getting the full access to the drug. Also, with patients with ET, the escalation is going to be a lot faster to 250 micrograms, every other week, 350, and then 500 is the maximum dose that has been explored. However, I have to say the approval of ropeginterferon for PV had even higher dose, and the maximum-tolerated dose was not reached. This is a perfectly safe dose that we have patients on. We’re going to see how it’s going to do in ET patients. There is a core treatment period, which continues after the 4 weeks of escalation of up to 56 weeks. The patients will be dosed every other week with a tolerable dose. We will be monitoring the primary end points of durability of control, hematologic control, platelets less than 450, white cells less than 10. That will basically sustain 80% of 36 consecutive weeks. Then, the key secondary end points are going to include all important end points in ET patients, such as complete hematologic response, composite hematologic response, that includes control of spleen, control of symptoms, absence of disease progression, and absence of thromboembolic events. Then, it’s going to also have this excited end point, which is basically a decline or allele burden. We’ll be checking the allo burden, what we call the molecular response, and then bone marrow morphology response.

Also, there are a couple other exploratory or pharmacokinetic studies that we’re going to be conducting. It’s a study that does not allow patients that were exposed to interferon. For example, patients and [peginterferon alfa-2a] would not be eligible. However, with a plan amendment, there is going to be measurement of neutralizing antibodies against ropeginterferon. If patients are not detected to carry those, they will be still eligible.

If positive, how do you see this study impacting the field?

I’m excited about it. I’ve used interferons in the off-label setting ever since I came to MD Anderson, and it’s been proven to be an effective therapy for young people. I have a lot of patients come in from everywhere and they don’t want to do chemotherapy, they seek the agent. So far, we’ve been only able to give them the [peginterferon alfa-2a], where we have to deal with insurance companies, because it was off-label setting.

Last year, we published 15 years follow-up on our phase 2 study. But this is going to open the use of the agent, I’m excited about the less frequent interactions, which my patients are excited about as well. I’m going to be really comparing and lucky for me, I’ve seen the tolerance of the [peginterferon alfa-2a] in these patients. I will really be comparing them to the ropeginterferon, seeing what this agent could offer, and seeing the results in PV. I’m quite excited about it. I don’t think we will have any data about what we call the disease modification or how we call it in the next 10 years, maybe because it’s a very low progressing disease, but I’m looking forward to seeing whether we’re going to see elimination or absence of disease progression to myelofibrosis. I also wonder if we will see minimization of the thromboembolic events. That will be the ultimate disease modification change.

Afterwards, hopefully we can add it to something and maybe keep patients on some agents that have been around and help control the counts. At the same time, maybe we can do a low dose interferon for a longer time as a disease modification agent, and hopefully you will wake up in an era where there’s going to be no ET or PV.

REFERENCE:

Masarova L, Mascarenhas J, Qin A, et al. EXCEED-ET: A single-arm multicenter study to assess the efficacy, safety, and tolerability of ropeginterferon alfa-2b-njft (P1101) in North American adults with essential thrombocythemia. J Clin Oncol. 2023;41(suppl 16): TPS7088- TPS7088. doi:10.1200/JCO.2023.41.16_suppl.TPS7088

Read more

 

Educated Patient® MPN Summit Essential Thrombocythemia Panel: May 20, 2023

Posted on by

Published on: June 14, 2023

Kristie L. Kahl

This panel was moderated by Brielle Benyon and included Dr. Lucia Masarova, from MD Anderson Cancer Center, Dr. Laura C. Michaelis, from the Medical College of Wisconsin, and Celia Miltz, from the MPN Research Foundation.

Benyon: So to start, Dr. Masarova, can you distinguish between (Essential thrombocythemia [ET])-related migraines and simply a continuation of migraines and a patient who has a history of them?

Masarova: That’s a very good point. So surely, we will have patients that had migraines preceding their diagnosis. We have to make sure that we gather all the information about the migraines from the past, especially making sure that there is no worsened, frequency type side control with the medications before, I’m pretty positive, that neurologists would like to have some scan done to make sure it could be lots of ocular migraines associated with the different events in life and stuff like that. So that is important to know.

To me, what would be interesting at the diagnosis is, has anything changed? Have the migraines differed from what (they were) before? And how does it respond? Has it really changed with aspirin? Does it really respond to something else? Do we dare to change, to do aspirin more? So those kinds of questions are relevant and very important.

Other than that, I don’t really think we have actually a tool. So we can imagine or look and then say, “Hey, this is from our ET, we just take aspirin and we’re fine.” Versus we actually blame it on one or the other. It certainly could be that it is aggravated by the diagnosis. I had, unfortunately, lots of patients that have migraines at baseline. And they’ve kind of complained…But I have also viewed it that the symptoms got better and stabilized. But unfortunately, a few of my patients have just intractable migrants, and they have to take a lot of anti-migraine medication from neurologists, even though the disease with ET is perfectly controlled. However, there is not a direct correlation.

I can tell as we work from the past, if the disease is controlled, there is no symptoms. That’s not true. We have seen patients that have completely normal blood count and are healthy, and have still miserable symptoms. So I cannot really 100% tell you, I know how to distinguish them. But what I will be really, really looking at would be whether something’s changed in the character and behavior and the response, and whether we must establish treatment for the ET and how everything else it produces look like. For example, there’s only migraine that sustained, consistent and intractable and not controlled, but other symptoms disappeared. Well, it’s unlikely that the disease is the primary driver of the migraine. But at the same time, it is the driver that happens every time of the year, every time on some event. And we know the triggers as well. It could be triggered by something else, maybe by the underlying bathymetric changes in the disease. So we would maximize treatment for making sure everything else is controlled as much as we can, and then work together with a neurologist to support. But to really tell you which, I don’t think we (know) right now.

Benyon: Thank you so much. And my next question is for Celia. So we talked a bit on the importance of clinician communication. Can you speak to the importance of communication between patients and caregivers and their clinicians, especially when it comes to questions that they have side effects they’re experiencing and things like that?

Militz: I think patients should realize that the MPN Research Foundation website, mpnresearchfoundation.org, If you go on to that there are a couple of tabs that are really important for patients to look at. And one of the tabs is understanding MPNs and that has a list of ET, PV (polycythemia vera) and MF (myelofibrosis). And the second tab is called Living with Impedance. And then there is also a guideline that has been published, which is also on the website from the National Comprehensive Cancer Network that gives you guidelines for treatment strategies. So if the patient is aware of what the treatment strategies might be, and how it impacts their disease, then they can go to their doctors ask the right questions. In my case, I was the caregiver for my daughter who was diagnosed at the age of 16. Many years ago, I had to be her best advocate, so I had to learn. So the caregivers should also learn to ask the right questions and be their own best advocates for the patients. The patients should become their own best advocates. And there’s just a wealth of information on the MPN Research Foundation website for patients, caregivers and clinicians.

Benyon: Fantastic, thank you so much. My next question is for Dr. Michaelis. Is there a time of day that is best to take Hydrea (hydroxyurea) – maybe late in the afternoon or earlier in the day? Does this timing of the drug matter here?

Michaelis: No, the timing doesn’t matter. I can’t remember exactly if it’s required for food or non-food. But usually I tell people, especially initially, they might get a little bit of nausea when they take it. And so sometimes I start it in the evening time and tell them to because that way they could sleep through the symptoms. I do think it’s important for whenever you take a new medicine, whether or not it’s interferon, Hydrea, any new medication in the first week or so that you take it, just write down any symptoms that you might think are new or associated. Because then you can, first off, understand what’s related or not. And sometimes it’s good to write down those symptoms before you take it and then afterwards, so “Oh, yeah, I had headaches before I took this medicine, it’s not just related to it.” But also, then you can juggle the timing. I do have some people who take it in the morning, and most people, especially with hydroxyurea, a lot of (patients) don’t mention a lot of immediate side effects to it.

Benyon: Great, thank you. And this one, I guess I’ll throw it out to anybody. Is there any research yet on COVID and long-COVID In patients with ET, and if it increases any risk factors or symptoms?

Michaelis: Well, I can speak a little bit to that. So the the world of long-term COVID research, I think, is only just beginning, I think there is some role for understanding the sense of the inflammation that goes along with COVID and how that causes the body to release additional cytokines or become a little bit more sensitive to the cytokines that are released, meaning that their cytokine receptors, the things that tell you that you’re tired, the things that tell you that you’re worn out, the things that give you night sweats, you might be more likely to feel those if you went through COVID and had long-COVID, for example. But I think what (that we’re) learning from COVID. And that those features (from) COVID, that lasts a long time, we’ve only just begun to understand. Most of my patients who had long-COVID got better, did recover. After about six to eight months of feeling that persistent fatigue, almost like people that had a bad mononucleosis, might feel fatigued for a long period of time. But interesting, I think that the science that develops from studying long-COVID may, in the future, be applicable to our understanding of the symptoms related to MPNs. And then maybe some other diseases that are marked by fatigue and a sense of frustration and inability to do things.

Benyon: Thank you so much. Our next question is for Dr. Masarova. Is there an association between mutated allele burden and survival rates? And on that note, is there any benefit of having hematologists and clinicians measure allele burden periodically, say every few years?

Masarova: Very, very good point. I do not think we will be able to measure that around the clock because (they are) expensive tests. We do have some experiences, for example, as Dr. Michaelis said, from interferon and I published that from our own on data where we had few patients with EEG, where our burden completely disappeared. Well, then we were actually able to eradicate a disease. Well, we had a follow up on any coding, they’re very deep assessments of bone marrow biopsies and we did indeed have some patients that got cured, so everything’s improved. But we did have also patients that had the treatment (and then their disease) returned. So on that note, of course, we always would like to have lower allele burden and lower disease scores than have been shown. Also, as Dr. Michaelis said, in the major PV study where we have other forms of interferon and working up with the allele burden and I’m getting the lower-dose patient had the longest benefits, the best survival, the lower risk of progression of the disease. So definitely, that implies the consequences were the lower we get, the better we can expect.

I think the major point would be easy, doable to achieve and stay. I think that would become a very interesting treatment point, to lead our future to really guide our decisions based on where we are, how the disease looks like, there are different aspects to it as well, in terms of other molecular backgrounds, where we know that we have drugs such as interferon that does target more than active mutated clones. However, it has been also tried in patients with (inaudible), but then we get some studies that suggested that it’s not so effective. Regardless, I have patients that are completely clear (after treatment with) interferon. So both are possible.

And the other side, we may have cortical and directed monoclonal antibody, which Dr. Michaelis nicely showed where we actually can be targeting and (more importantly) eliminating the clone. And (does) actually mean we cure completely the disease and (it) worked? That’s going to be the case, but I think it is relevant, and it’s going to be more and more relevant to us to shoot deeper and cleaner and then get rid of it. But I think we (are all going to learn what kind of implications for the future it is going to have in terms not only the one driver, but the whole conglomerates of the disease backgrounds. So if there are other comutations, other abnormalities that we want to clean? Are we going to have effective agents to do so? And then what is really the directionality to do the cleaning to do right, so we measure those, how often what does that tell us if we decrease it? Are we going to change our approach? Are we going to add on something? I’m hoping we’re going to be in the era where we have more effective therapies, very tolerable therapies, as we currently have much more movements in the myelofibrosis field where we add on, if we see it’s not ideal responding, and we’re going to be able to act on it based on if the algorithm doesn’t go the right direction. I hope so. But I’m really going to be looking forward to the future and to see what it stands for us and tells us, but based on other diseases that we had, for example, in CML, we’ve seen the Philadelphia chromosome, we eliminate that people can get cured, so-called cured, right? And (we) stop the medicines completely, where we eliminate what’s driving the disease, and it automatically dies off and people don’t need the medicine? Is it going to be that easy in this disease, which is more complex? And we don’t have one driver giving us the same disease, when you’re going to soon hear about PV and myelofibrosis? Well, JAK3, could lead to all three, why? Why one patient is acting, he didn’t have very simple ET, one has a very complicated model of a process. That’s something we have to really bebe more alert of and put all of those things into context to see. We kind of imply and hope that the longer the disease burden, the better. And that’s what we’ve seen. However, the long-term implications are still to be learned.

Benyon: Great, thank you. And my final question is for Celia. What is your advice for patients and their loved ones, their caregivers, who are newly diagnosed, and maybe they’re not sure where to go? They’re unfamiliar with the disease? What’s a good first step for these patients?

Militz: That’s a very good question. Back when my daughter was diagnosed, there wasn’t much on the internet, and a lot (of what) was on the internet was quite frightening. But once again, I suggest that patients and their caregivers try to educate themselves on the MPN Research Foundation, (it) is probably the best site in order to get a better understanding about what the disease is, what it means to have it, how it may be treated. And again, learn about it, educate yourself about it. And then you have the tools with which to talk to your doctor about your disease and whether or not you should be treated. And, if so, what treatment seems to be best. Again, being your own best advocate is my suggestion. And the best way to do that is to go to the MPN Research Foundation website and learn about it and then take your questions to your doctor being an educated patient. That’s the most important thing

Read more

Pelabresib Provides Clinical Benefit in Hydroxyurea-Refractory or Intolerant High-Risk Essential Thrombocythemia

Posted on by

Caroline Seymour
Conference|European Hematology Association Congress

Treatment with pelabresib monotherapy led to a 60% confirmed complete or partial hematologic response at any time without incurring grade 4 or 5 treatment-related adverse effects in patients with high-risk essential thrombocythemia refractory or intolerant to hydroxyurea.

Treatment with pelabresib monotherapy led to a 60% confirmed complete or partial hematologic response at any time without incurring grade 4 or 5 treatment-related adverse effects (AEs) in patients with high-risk essential thrombocythemia (ET) refractory or intolerant to hydroxyurea, according to preliminary findings from arm 4 of the phase 2 MANIFEST trial (NCT02158858) presented at the 2023 EHA Congress.

At data cutoff of July 29, 2022, 7 of 20 patients had been treated for at least 6 months, and 14 patients continued to receive treatment with pelabresib. The confirmed complete and partial hematologic response rates were 40% and 20%, respectively.

“Pelabresib monotherapy resulted in hematologic response and symptom improvement in patients with high-risk ET who are resistant/intolerant to hydroxyurea,” Francesco Passamonti, MD, lead study author, professor of hematology at the University of Insubria of Varese, and head of the Division of Hematology at the University Hospital of Varese in Italy, said.

ET is a myeloproliferative neoplasm (MPN) defined by progressive thrombocytosis, thrombohemorrhagic events, and systemic symptoms. Despite first-line cytoreductive therapy with hydroxyurea and interferon alfa-2a, resistance and intolerance remain issues for this population, creating an unmet medical need.

Pelabresib is an oral, small molecule inhibitor of BET, which has the potential to downregulate the expression of genes that reside within the pathogenic pathways that underly MPN progression.

MANIFEST in a 4-arm, ongoing, global, open-label, phase 2 study evaluating pelabresib in patients with myelofibrosis and ET. Arm 1 is evaluating pelabresib alone, and arms 2 and 3 are investigating pelabresib plus ruxolitinib (Jakafi), all in patients with myelofibrosis. Arm 1 is evaluating pelabresib monotherapy as second-line therapy in patients with ruxolitinib-refractory or intolerant disease. Arm 2 is evaluating pelabresib as an add-on to ruxolitinib in the second line following suboptimal response or progression. In arm 3, the combination is being evaluated in the frontline in patients with Dynamic International Prognostic Scoring System intermediate-2/high disease.

The study population in arm 4 consisted of patients with high-risk ET refractory or intolerant to hydroxyurea with at least 2 symptoms of average score of 3 or more, or a total symptom score (TSS) of 15 or more per Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) in the past 7 days, and platelets above 600 x 109/L.

Patients were treated with 225 mg of oral pelabresib monotherapy once daily for 14 days in 21-day cycles (n = 21).

The primary end point of this arm of the study was confirmed complete hematologic response at any time. Secondary end points included confirmed partial hematologic response at any time and symptom improvement. Exploratory end points included translational evaluation of Interleukin-8 (IL-8) expression change, cytokines, and mutation status.

Regarding baseline characteristics (n = 20), the median patient age was 64 years (range, 42-83) and most were older than 60 years (60%) and female (60%). Median hemoglobin, platelet count, white blood cell count, and spleen volume was 13 g/dL (range, 10-16), 722 x 109/L (range, 418-1255), 7.9 x 109/L (range, 4-12.3), and 402 cc (range, 124-907), respectively. Spleen was not palpable in 90% of patients, and median TSS was 32.7 (range, 6.9-123). Median prior hydroxyurea duration was 103 months (range, 0.7-245). Most patients had received at least 2 prior lines of therapy (60%). Fifteen percent of patients had prior thrombosis. Twenty percent of patients had myelofibrosis high-molecular risk, with JAK2, CALR, ASXL1, and MPL mutations residing in 45%, 40%, 15%, and 5% of tumors, respectively.

With respect to blood counts over time, the median platelet, white blood cell, and hemoglobin (n = 13) counts at week 12 were 446 x 109/L, 8.2 x 109/L, and 13.0 g/dL, respectively. Sixty percent of patients had platelets no higher than 400 x 109/L over time. Similarly, most patients (95%) did not experience white blood cell counts above 10 x 109/L over time. The median percentage change in platelet and white blood cell counts at week 12 were –40% and 8.2 x 109/L, respectively. Additionally, by week 24 (n = 7), median hemoglobin remained stable at 13.4 g/dL.

TSS was evaluated in 14 patients, showing 50% reduction in TSS50 in MPN-SAF at any time. By week 12, median TSS had been reduced by 31%.

A NF-κB target cytokine panel linked to bone marrow pathogenesis and inflammation was assayed. Included cytokines were CD40, CD40-L, CRP, IL-6, IL-18, IP-10, MMP-2, TNF-α, thrombospondin-1, RANTES, VCAM-1, and VEGF.

“Pelabresib monotherapy demonstrated a durable reduction in NF-κB–driven cytokines associated with bone marrow abnormalities and inflammation,” Passamonti said, reaching close to 40%.

In addition, IL-8 gene expression was evaluated in whole blood prior to and 4 hours after pelabresib administration. Passamonti stated that “rapid reduction in IL-8 gene expression was observed,” with median expression changes of –67% (95% CI, –79% to –56.9%), –69% (95% CI, –76.5% to –12.2%), and –52% (95% CI, –85% to 106.6%) at cycle 1 day 1 (n = 16), cycle 1 day 14 (n = 11), and cycle 3 day 1 (n = 10), respectively.

Furthermore, investigators explained that although variant allele fraction (VAF) levels were maintained in most patients with 30% or fewer driver mutations, 2 of 6 patients with post baseline JAK2 V617F–mutation assessment showed meaningful reduction in VAF from 60% to 20% and 52% to 40%.

Regarding safety, serious AEs occurred in 3 patients, consisting of leukocytosis, thrombocytosis, and eyelid bleeding in 1 patient, infection in another, and dyspnea and pulmonary embolism in the third. Another 3 patients reported treatment-emergent AEs that led to pelabresib discontinuation. No grade 5 AEs occurred.

“Safety results [were] as expected in the underlying population and consistent with the known safety profile of pelabresib,” Passamonti said.

Leukopenia was the only reported hematologic AE (all-grade, 10%). Non-hematologic AEs included nausea (60%), diarrhea (35%), constipation (30%), vomiting (25%), dyspepsia (10%), dysgeusia (35%), ageusia (30%), abdominal pain (25%), rash (20%), respiratory tract infection (15%), weight decrease (15%), muscle spasms (15%), myalgia (10%), headache (10%), insomnia (10%), pruritus (10%), hypertension (10%), fatigue (10%), and arthralgia (10%).

Hemorrhagic and thromboembolic events included pulmonary embolism (grade 3, 5%), deep vein thrombosis (all-grade, 5%), acute myocardial infarction (all grade, 5%), hemorrhagic diarrhea (grade 3, 5%), eyelid bleeding (grade 3, 5%), hematoma (all grade, 5%), hematuria (all grade, 5%), and petechia (all grade, 5%). All cases of thromboembolic events and eyelid bleeding were unrelated to pelabresib.

“These preliminary safety and efficacy results in patients with high-risk essential thrombocythemia continue to provide evidence for the potential clinical benefit of pelabresib in myeloid diseases,” Passamonti concluded.

Reference

Passamonti F, Patriarca A, Knapper S, et al. Pelabresib (CPI-0610) monotherapy in patients with high-risk essential thrombocythemia refractory or intolerant to hydroxyurea: preliminary results from MANIFEST study. Presented at: 2023 EHA Congress; June 8-11, 2023; Frankfurt, Germany. Abstract S168.

Read more