Validation of myeloproliferative neoplasms associated risk factor RDW as predictor of thromboembolic complications in healthy individuals: analysis on 6849 participants of the SHIP-study

Posted on June 27, 2023June 27, 2023 by mpn_admin

June 23, 2023

Kirsi Manz, Jeanette Bahr, Till Ittermann, Konstanze Döhner, Steffen Koschmieder, Tim H. Brümmendorf, Martin Griesshammer, Matthias Nauck, Henry Völzke & Florian H. Heidel

Chronic myeloproliferative neoplasms (MPN) are characterized by hyperproliferation of myeloid cells leading to erythrocytosis, thrombocytosis, leukocytosis and splenomegaly. Thromboembolic events (TE) are among the most prevalent complications in patients with different subtypes of MPN such as polycythemia vera (PV) [1, 2], with arterial and venous thromboses being among the major causes of morbidity and mortality. Pathophysiologic mechanisms that contribute to TE complications, besides increased cell counts, include functional alterations of leucocytes, red blood cells, platelets and endothelial cells [3]. The rate of thromboembolic complications in MPN patients ranges from 1.1 to 4.4% per year, while this rate is significantly lower in the normal population (0.6 and 0.9% per year in the absence or presence of cardiovascular risk factors, respectively) [4, 5]. Therefore, prediction of occurrence of thromboembolic events for risk estimation is of great importance. While the risk of these patients to experience thromboembolic complications is clearly high, prognostic parameters beyond age and past history of thrombosis are currently lacking. This leads to challenges in clinical decision making regarding the indication of cytoreductive drugs and the prophylaxis and use of anticoagulants. Therefore, in our previous work, we used a machine learning algorithm to identify risk factors for this high-risk population of patients with PV for clinical use that can predict thromboembolic events [6]. Using the publicly available OPTUM database that consists of patient data provided by US insurance companies, we could define red cell distribution width (RDW), lymphocyte and platelet counts as independent prognostic parameters for thromboembolic events: Lymphocyte ratio (LYP) and RDW predicted the risk of occurrence of TEs of patients without a history of TEs within the next 12 months. In addition, predictive factors for patients with a history of TE complications included lymphocyte ratio and platelet count. Recently, neutrophil-lymphocyte ratio (NLR) was confirmed as predictive risk factor for venous thrombosis in an independent retrospective cohort of PV patients [7]. While these analyses require prospective validation in clinical trials, the predictive value of these parameters in a normal control population without myeloproliferation or hematopoietic cancers remains to be investigated.

In order to validate these findings in a control cohort of non-MPN patients, we retrieved data of the SHIP study conducted at Greifswald University Medicine. The Study of Health in Pomerania (SHIP) is a population-based epidemiological study consisting of currently 5 independent cohorts [8]. The SHIP investigates common risk factors, subclinical disorders and manifest diseases with highly innovative non-invasive methods in the population of northeast Germany. As this study is not focused on one specific disease it aims to investigate health in all aspects and complexity involving the collection and assessment of data relevant to the prevalence and incidence of common, population-relevant diseases and their risk factors.

We utilized data from different independent cohorts of the SHIP study: the baseline examination of SHIP-START (SHIP-START-0) between 1997 and 2001 (n = 4308), and the baseline examination of SHIP-TREND (SHIP-TREND-0) between 2008 and 2011 (n = 4420). After excluding missing datapoints, a total of 2491 datasets (derived from individual participants) from the SHIP-START-0 and 4358 from the SHIP-TREND-0 were included in the analyses. Data on all probands with baseline data on RDW, lymphocyte percentage, platelet count, body mass index (BMI), prior TE, neutrophil percentage, leukocytes and hematocrit was used for the study. Also, all documented medication was recorded and included for analysis. Of note, SHIP-START-0 data does not include differential blood counts, including lymphocyte and neutrophil percentage. Occurrence of TE in SHIP-START was defined as thrombosis, stroke or myocardial infarction or use of an antithrombotic agent while SHIP-TREND also included evidence of thrombophlebitis. Antithrombotic agents were defined as agents belonging to the Anatomical Therapeutic Chemical (ATC) classification system section B01 “antithrombotic agents”. This section includes oral anticoagulants such as vitamin K antagonists, platelet inhibitors (ASA and P2Y-antagonists) and direct oral anticoagulants (DOACs) among others. Single use of antithrombotic agents e.g. for in-flight prophylaxis was not considered. Cardiovascular risk factors included were elevated blood lipids, hypertension, diabetes mellitus, current smoking, BMI, and subjects’ age. Subjects with missing diabetes mellitus status and HbA1c > = 6.5% were counted as diabetic. In the absence of elevated blood lipid status, subjects with cholesterol > = 6 mmol/l and/or triglyceride > 1.9 mmol/l were assigned to elevated blood lipids. Descriptive statistics are provided as median and minimum – maximum, or as frequency and percentage, as appropriate. The non-parametric Mann Whitney U test was used to assess differences of continuous variables between two groups. Categorical variables were compared using the Fisher’s exact test. First, all candidate variables were adjusted for age and sex. Then, all significant age- and sex-adjusted variables were included in the backward variable selection procedure. Variable selection was performed 1000 times using bootstrapping methods. To report the most relevant variables, the final model consists of those selected in at least 80% of the bootstrapping runs. In both cohorts, 70% of the data were used to build and 30% were used to validate the model. To assess the predictive value of both models, accuracy and receiver operating characteristic (ROC) curve were calculated. Statistical significance was claimed at 5% (p < 0.05) and no correction for multiple testing was performed. The data was prepared using SAS 9.4 (SAS Institute Inc., Cary, NC, USA) and analyzed using R Version 4.2.2 [9].

Regarding baseline characteristics, TE events had occurred in 321 (12.9%) of the 2491 individuals of the SHIP-START cohort while the prevalence of TE events was 21.4% (932 events in 4358 individuals) in the SHIP-TREND cohort. Overall, established risk factors for TE such as male sex, higher age, higher body-mass-index (BMI), arterial hypertension, hypercholesterolemia, and diabetes mellitus were associated with significantly higher rate of TE events (Table 1). Of note, TE events were more frequently reported in non-smokers compared to smokers in both cohorts. In regard to laboratory parameters, higher RDW and lower platelet counts showed significant association with TE complications. In contrast, higher leukocyte counts, lower hematocrit and lower lymphocyte ratio showed exclusively significance in the SHIP-TREND cohort analysis.

Table 1 Baseline characteristics of both cohorts.

To assess for effects of the above risk factors on TE events, we used multivariable logistic regression models. When investigating the SHIP-START cohort of 2491 individuals, male sex (p < 0.0001), presence of hypertension (p = 0.0042), hypercholesterolemia (p < 0.0001) or diabetes mellitus (p = 0.0008), and higher age (p < 0.0001) were validated as TE risk factors. Regarding laboratory parameters, higher RDW (p = 0.0006) was the only predictor for TE complications.

Analysis of the SHIP-TREND cohort of 4358 individuals confirmed independent predictive value of higher age (p < 0.0001) and hypercholesterolemia (p < 0.0001) while elevated body mass index (BMI; p = 0.0003) scored as an additional predictive factor due to availability of the respective data points in this cohort. In contrast, male sex and hypertension were not confirmed as independent risk factors. Consistent with the SHIP-START cohort, higher RDW (p < 0.0001) was identified as predictive for TE events, along with lower platelet counts (p < 0.0028). Taken together, alterations of laboratory parameters such as red cell distribution width and platelet count at study entry were associated with occurrence of thromboembolic events in this retrospective assessment of individuals without evidence for hematologic malignancies.

When adjusting for age and sex (Fig. 1A, B), BMI, hypercholesterolemia, hypertension, diabetes mellitus and RDW consistently showed elevated odds ratios in both cohorts, using the basic model. Assessment for TE risk factors in the final model confirmed age, hypercholesterolemia and RDW as predictors of thromboembolic events in both cohorts. Here, RDW showed an OR of 1.28 (95% CI: 1.11–1.47) for SHIP-START and 1.25 (95% CI 1.12–1.38) for SHIP TREND (Fig. 1C, D). Of note, the SHIP-TREND model could also be validated using SHIP-START data. In order to select an optimal model, receiver operating characteristic (ROC) analysis was performed showing an AUC of 0.846 (95% CI: 0.805–0.886) for SHIP-START and an AUC of 0.847 (95% CI: 0.827–0.866) for SHIP-TREND (Fig. 1E, F). Accuracy of the SHIP-START model was 89.2% and of the SHIP-Trend model 86.8%.

**Fig. 1: Effects of risk factors on TE events.**

Red cell distribution width is a marker for the variation of erythrocyte size (anisocytosis) and used in combination with other laboratory markers for differential diagnosis of hematological diseases such as anemia and bone marrow dysfunction. Changes in RDW have been reported for a variety of chronic inflammatory conditions such as diabetes, cardiovascular disease, infections and cancer and its predictive and prognostic value has been reported for cardiovascular disease as well as for overall mortality of the general population [10]. Likewise, differential blood counts have been described as biomarkers of inflammatory processes and cancers. Identification of RDW, platelet counts and lymphocyte ratio as biomarkers for thromboembolic events in PV patients is therefore not surprising, as JAK2-mutated cancers are associated with broad activation of cell signaling [11] and increase of pro-inflammatory cytokines [3, 12]. Recently, exome-analysis studies have shown age-related clonal hematopoiesis (CH) in healthy individuals, driven by mutations of genes recurrently mutated in myeloid neoplasms and associated with an increased risk of hematologic cancer and cardiovascular disease. Critically, both SHIP-cohorts reported in this analysis have not been investigated for the presence of clonal hematopoiesis. Therefore, we cannot exclude the influence of CH on the predictive value of RDW and occurrence of TE events. Moreover, cutoffs for RDW may vary and have not been generally defined in previous analyses. Critical limit values of these potential biomarkers may depend on the underlying condition, comorbidities (e.g. previous TE complications) or concomitant medication. Finally, in SHIP-TREND, we used a broad definition of TE events (including peripheral thrombosis and thrombophlebitis) and predictive biomarker values may vary with a definition restricted to deep vein thrombosis, pulmonary embolism, myocardial infarction and stroke. Of note, the allocation of individuals into the “TE-event” cohort based on the use of anticoagulants may result in inclusion of individual participants using ASA and P2Y-antagonists as primary rather than secondary prophylaxis.

Taken together, we could confirm RDW as an independent predictive parameter for thromboembolic events in the general population. Development and prospective validation of predictive scoring systems combining predictive laboratory parameters are clearly warranted but are beyond the scope of this report.

New and Anticipated Advances Across Hematologic Malignancies Necessitate Improved Navigation of Current Options

Posted on June 27, 2023June 27, 2023 by mpn_admin

June 23, 2023

Courtney Flaherty

Recent approvals of BTK inhibitors, antibody-drug conjugates, and other targeted therapies for B-cell malignancies have rapidly expanded the treatment armamentarium and improved the standard of care. With several more potentially paradigm-shifting approvals on the horizon, a nuanced understanding of current decision-making in the absence of optimal sequencing, as well as a renewed focus on incorporating these agents into clinical practice, is still required to improve patient outcomes in this space, according to John M. Burke, MD.

“A lot of promising drugs are in development or have been approved in B-cell malignancies, myelofibrosis, and polycythemia vera,” Burke said following an OncLive^® State of the Science Summit^™ on leukemia and lymphoma, which he chaired. “Treating physicians, oncologists, and hematologists should be aware of these new developments and [use this knowledge to] help their patients make informed decisions about what’s best for them in a particular situation.”

Burke expanded on key topics discussed by himself and his colleagues at the meeting in an interview with OncLive, including the use of novel BTK inhibitor regimens in mantle cell lymphoma (MCL), treatment sequencing challenges and other unmet needs indiffuse-large B-cell lymphoma (DLBCL), the evolution of management strategies for myeloproliferative neoplasms, and the potential influence of new and emerging therapeutics in chronic lymphocytic leukemia (CLL).

Burke is the associate chair of the Hematology Research Program for US Oncology, and a medical oncologist and hematologist at Rocky Mountain Cancer Centers in Aurora, Colorado.

OncLive: What BTK inhibitor studies have had the most influence on the treatment landscape in treatment-naïve and relapsed/refractory MCL?

Burke: In the treatment-naive space, the two recent trials that made a splash were [the phase 3] SHINE [NCT01776840] and TRIANGLE [NCT02858258] studies. Both [SHINE and TRIANGLE] showed that adding the BTK inhibitor ibrutinib [Imbruvica] to conventional therapy for transplant-eligible and -ineligible patients improved progression-free survival [PFS] and failure-free survival [in each respective trial]. Adding the BTK inhibitor to initial therapy [kept] patients in remission for a longer period. Those are important findings, and experts [in the] community are debating exactly how to incorporate them into practice. [This is] made more complex by the recent withdrawal of ibrutinib from the market for MCL. That’s added a little bit of complexity to decision-making when we treat these patients.

As for combination studies [in the] relapsed/refractory [setting], there’s studies of BTK inhibitors with venetoclax [Venclexta], [as well as] some with CD20[-directed] antibodies. There’s a lot of novel combinations being looked at in the relapsed space. None of them have recently led to new approvals, but we’re seeing exciting, chemotherapy-free regimens being used. There’s quite a lot of exciting [things] going on in MCL.

Could you highlight some of the factors that influence the selection of current BTK inhibitor regimens in MCL?

It depends on where the patient is in their disease course. For those who are treatment-naive, [you’d ask]: Is this someone where the potential benefits of adding a drug into the treatment program may outweigh any added risks? [Are they] transplant-eligible? What chemotherapy and immunotherapy partner [would] you administer along with the BTK inhibitor? In the patients [who are] relapsed/refractory, you’re thinking about what treatment they received before, and weighing the pros and cons. What are the benefits? What are the risks? Is this the best treatment for the patient at that time? What are their comorbidities? Those are all factors that [contribute to] the decision when you’re picking a regimen for a patient with relapsed MCL.

What ongoing or upcoming trials in MCL are you interested to see conducted?

One of the trials I’m excited about looks at the recently approved pirtobrutinib [Jayprica] and compares that with conventional BTK inhibitors in MCL. That’s the ongoing [phase 3 BRUIN-MCL-321] trial [(NCT04662255) assessing] how the new non-covalent BTK inhibitor pirtobrutinib compares [with] covalent BTK inhibitors.

At the 2022 ASH Annual Meeting, we saw a presentation [of findings from a single-arm, phase 2 study (NCT03863184)] on acalabrutinib [Calquence] in combination with lenalidomide [Revlimid] and rituximab [Rituxan] as an exciting, novel chemotherapy-free regimen. We’re [also] seeing trials of venetoclax in combination with BTK inhibitors with or without CD20 antibodies that look promising.

One wonders whether, and how much, chemotherapy is going to be used in the future with these promising novel agents emerging. Right now, chemotherapy is part of standard practice, but we’ll see how the field moves. It is moving towards an increasing use of novel targeted therapies.

Regarding your second presentation, what major changes have occurred for the management of relapsed/refractory DLBCL?

One huge paradigm shift that occurred about a year ago was the demonstration that [some] CAR T-cell products are superior to conventional salvage chemotherapy and stem-cell transplant in patients whose DLBCL relapsed within a year of initial therapy. The other thing we’re seeing is an increasing utilization of novel targeted agents in the relapsed setting. Examples of that are polatuzumab vedotin-piiq [Polivy] along with chemotherapy, tafasitamab-cxix [Monjuvi] along with lenalidomide, and loncastuximab tesirine-lpyl [Zylonta].

[Overall], a number of novel therapies have demonstrated benefit [in this space]. Recently [we had] the approval of the bispecific antibody epcoritamab-bysp (Epkinly) for patients with relapsed DLBCL. [This approval signals the start of] a new era where we’re hopefully going to see a few [more] bispecific antibodies being approved for relapsed DLBCL. Moving forward [we’ll also see attempts to] incorporate those effective agents into earlier lines of therapy to hopefully cure more people with DLBCL.

The other huge paradigm shift in DLBCL in the frontline [setting] is a demonstration of benefit [with] polatuzumab vedotin in combination with [rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP)]. [This was] compared with [cyclophosphamide, doxorubicin, prednisone, rituximab, and vincristine (R-CHOP), which] has been the standard therapy for several decades. The paradigm shifts in DLBCL [occurred in the] frontline, early relapse, and salvage [settings], with novel agents becoming available and taking the place of chemoimmunotherapy in relatively heavily pretreated patients.

Despite these advances, what unanswered questions remain in DLBCL?

[One] unanswered question will be: how do we sequence all these novel agents? That’s what everyone has been asking recently. In the past couple of years since we’ve seen approvals of [tafasitamab plus lenalidomide], [polatuzumab vedotin, bendamustine and rituximab (Pola-BR)], loncastuximab, selinexor [Xpovio], and now bispecific antibodies, [but we still don’t know if] there is a best sequence [of treatment options].

Another [unanswered question] is how can we utilize these [approved agents] more effectively? There are very few patients with relapsed DLBCL who benefit from all these drugs, because they don’t live long enough to receive all of them if they relapse. We need to do a better job of getting patients [earlier] exposure to these drugs to cure more people earlier.

How can these agents be incorporated [into clinical practice]? Ongoing studies have been [attempting to answer] that question for a couple of years and will continue to do so. For example, there’s been [the phase 3 frontMIND] trial [NCT04824092] of R-CHOP with or without tafasitamab and lenalidomide as a frontline therapy for DLBCL. [This study asks whether] we can and should incorporate that novel combination into the frontline setting to try to cure more people. [There is also] the use of pola-R-CHP in the frontline [setting], [which] bested R-CHOP in terms of PFS and changed the paradigm for frontline therapy in DLBCL. [Other unanswered] questions [include whether] we can incorporate bispecific [antibodies] into earlier lines, [whether] CAR T-cell therapy should be utilized earlier for patients with high-risk DLBCL or those who [don’t respond] well to initial R-CHOP, and [if] we can use novel therapies for elderly patients who can’t tolerate conventional R-CHOP chemotherapy. [There are] ongoing studies of loncastuximab and other [agents] in that space [to address this question.]

The key question here is: can we use some of these agents earlier in the treatment algorithm? Can we move these [approved agents] earlier [in the treatment course] and expose more patients to them to [help them] derive [more] benefit and hopefully [lead to more] cures.

Shifting to the presentation given by Christopher Benton, of Rocky Mountain Cancer Centers, how has the management of myelofibrosis changed in recent years?

Myelofibrosis is an interesting and changing disease. The JAK-2 inhibitor ruxolitinib [Jakafi] is the key drug approved for that disease, but there are a lot of promising new agents emerging. Examples include pacritinib (Vonjo) for those with low platelet counts, and we hope to see an approval soon for momelotinib, which might help patients with anemia. We saw a number of agents demonstrating benefit for patients with myelofibrosis in clinical trials, including improvement in anemia. One was called pelabresib [CPI-0610], and selinexor [also] looks promising.

[Overall, there are] a lot of promising agents that could help practitioners and patients overcome some of the problems that we [have in myelofibrosis]. Right now, we don’t have a great drug to treat anemia in patients with myelofibrosis and it’s a common [toxicity]. In fact, ruxolitinib can make anemia worse in patients with myelofibrosis. It would be great to have options [that] add to the benefit of ruxolitinib [but also] help people with anemia. Dr Benton reviewed several [agents] on the horizon [that] may be able to help folks with myelofibrosis.

How does the approval of zanubrutinib in CLL illustrate the importance of next-generation BTK inhibitors in that setting per the presentation given by Luke Mountjoy, of Colorado Blood Cancer Institute?

Zanubrutinib [Brukinsa] demonstrated benefit compared with chemoimmunotherapy, specifically BR, in treatment-naive CLL. [It also] led to improvements in PFS, [higher] response rates, and a more favorable toxicity profile compared with ibrutinib in the [phase 3] ALPINE study [NCT03734016] in patients with relapsed CLL. The next-generation BTK inhibitors including acalabrutinib [Calquence] and zanubrutinib have demonstrated enough favorable comparative results compared with ibrutinib, and most of us have transitioned from recommending ibrutinib to new patients to using one of the newer second-generation BTK inhibitors in that space.

As to whether patients who are on ibrutinib and doing fine should switch, [that] is a tougher question. My practice is not to do that, and most doctors I know are doing the same. But clearly the new, second-generation BTKs are here to stay and have some real advantages over ibrutinib for patients. They are probably the preferred BTK inhibitors for most people with CLL.

Dr Mountjoy also briefly touched on the phase 3 TRANSFORM study (NCT0357535) of lisocabtagene maraleucel (liso-cel; Breyanzi) in B-cell lymphoma. What data have been seen with the use of liso-cel so far, and what unmet needs could be addressed by the continued investigation of liso-cel in this space?

It’s an interesting backstory. Some of the first patients treated with CAR T-cell therapy had CLL and case reports [from a pilot, phase 1 study (NCT01029366) that] were published in the New England Journal of Medicine more than a decade ago. Ten-year follow up [data for] those patients were published about a year ago and showed that 2 individuals have no evidence of CLL in their bodies 10 years later, with evidence of CAR T cells still circulating. The presumption is that those patients are cured. With these initial extremely promising results, there was a hope and expectation that [CAR T-cell therapy was] going to be a homerun, and [that we’d] get the trials done and get it approved [quickly]. More than a decade later, the trials are still rolling along and nothing’s approved. [CAR T-cell therapy] is not available commercially for use for CLL.

In the session Q&A, we talked informally about why that is and [discussed] some of the challenges faced when treating [patients with] CLL and delivering these therapies in CAR T-cell trials. Liso-cel is demonstrating great promise and good results in CLL. [There are] still relatively small numbers of patients [being] reported in the trials, but [it is] showing good enough results where there’s still optimism and hope that CAR T-cell therapy will become available and utilized in CLL.* Perhaps [it will not be used] for most patients but certainly [could be an option] for those whose disease is very aggressive, continues to relapse, and is threatening their lives. CAR T-cell therapies, like liso-cel, offer promise for these patients.

Would you like to highlight any trials in the field of hematologic malignancies that are being conducted at your institution?

It’s a complex field, and it’s tough to stay up on everything, but [these advances are] exciting.

One trial I would choose to highlight would be the pirtobrutinib vs other BTK inhibitor trial in MCL that I mentioned earlier. It’s not the most common disease or situation, but if I had relapsed MCL [that study] is one that I would choose to go on.

I also [want to] highlight some ongoing trials in other lymphomas. We have [the phase 2 LOTIS-9 trial (NCT05144009)] in DLBCL with loncastuximab plus rituximab [in] elderly [patients]. I find that one to be particularly exciting because elderly patients with DLBCL are not well served by current standards of care, if there is such a thing. We need better treatments for [this population].

Everyone is excited about bispecific antibodies, and we have some very exciting bispecific antibody trials of both mosunetuzumab [Lunsumio] and epcoritamab in various lymphomas in various stages. Some [involve] treatment-naive patients, and some [are enrolling those with] relapsed/refractory disease. [Ultimately, there are] a lot of fun [trials] going on.

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

Posted on June 27, 2023June 27, 2023 by mpn_admin

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

One Step Closer to an MPN Cure

Posted on June 14, 2023June 14, 2023 by mpn_admin

Published on: June 8, 2023

Andy Polhamus

CURE, MPN Special Issue 2023, Volume 22, Issue 03

“I was marathon trained,” recalls Alexander, a lawyer for the Environmental Protection Agency in Washington, D.C., and a native of Queens, New York. “I was in good shape. I knew what I could do, but then I couldn’t do it.”

In addition to having trouble running, Alexander found himself experiencing “horrible brain fog.” He once caught himself looking for his keys as he got ready for work in the morning, searching all over the house before he realized they were in his hand. Other times he’d come home and find that he’d put the shredded wheat cereal in the refrigerator and the milk in the cupboard. Once, in trying to find his way through an unfamiliar area of New York, he realized he couldn’t read a map.

“In retrospect, I knew something was wrong with me,” says Alexander. So he went to see his doctor, who seemed unconcerned. Alexander recalls his physician asking: “What do you want me to diagnose you with? Not being able to run a marathon anymore?”

“He later apologized,” Alexander adds.

The answer came in 2005, when Alexander was participating in a medical trial run by the National Institutes of Health as a healthy volunteer. He was part of the study’s control group. Investigators left him a message asking him to call for the results of a blood test, but he put it off. When he got in touch, he learned that his hematocrit levels were “sky-high,” meaning that red blood cells constituted too large a proportion of his blood. He was told to get to a doctor soon. On his way out the door, a receptionist wished him good luck.

“I knew it was not the kind of ‘good luck’ I wanted to hear,” says Alexander. “But I was damn lucky.”

Alexander followed up on the advice and was diagnosed with polycythemia vera (PV), a rare blood cancer characterized by an excess of red blood cells that belongs to a group of diseases called myeloproliferative neoplasms, or MPNs.

In patients with MPNs, the bone marrow produces inappropriate amounts of different types of blood cells. Other examples of MPNs include essential thrombocythemia (ET), in which the blood contains too many platelets, and primary myelofibrosis (MF), in which a person’s bone marrow develops scar tissue, causing low red blood cell and platelet counts.

Symptoms of MPNs are varied and can include anemia, splenomegaly (an enlargement of the spleen that may cause abdominal pain, weight loss and loss of appetite), fever, night sweats, fatigue, cognitive difficulties and itchy skin. Patients with MPNs often experience a decline in their quality of life, and as many as half of myelofibrosis patients can become dependent on blood transfusions within a year of diagnosis. Worse than that is the possibility that an MPN can progress to life-threatening acute leukemia.

Twenty years ago, few registered treatment options existed for patients with MPNs. There were medications to help with symptoms, but nothing to address the diseases themselves. In recent years, however, a fairly new class of drugs called Janus kinase (JAK) inhibitors has offered relief, though not a cure, to the hundreds of thousands of people estimated to be living with MPNs, according to the MPN Research Foundation.

Meeting an Unmet Need

Although the famous hematologist William Dameshek posited the idea that MF, ET and PV were all related in 1951, it wasn’t until 2005 that several groups of researchers independently identified a mutation in the JAK2 gene as one genetic driver of these diseases. In the several years that followed, researchers also identified the roles of the MPL and CALR genes.

The first JAK inhibitor, Jakafi (ruxolitinib), was approved by the Food and Drug Administration (FDA) for treating MF in 2011.

“It really has not been around that long, when you consider other drugs that we’ve had forever,” adds Dr. Aaron Gerds, an assistant professor of medicine and deputy director for clinical research at Cleveland Clinic Taussig Cancer Institute in Ohio, who has worked as a principal investigator on several JAK inhibitor clinical trials. For example, compared with certain chemotherapy options, JAK inhibitors are practically brand new.

“The unmet need that JAK inhibitors fill is the ability to have an agent that significantly improves quality of life for the majority of patients, particularly in regard to constitutional symptoms and bothersome spleen-related symptoms,”
says Dr. Olatoyosi Odenike, a professor of medicine and the director of the leukemia program at University of Chicago Medicine who has also worked on studies of JAK inhibitors. “There is also a modest survival benefit,” she adds.

Like all cancers, MPNs are rooted in a problem with the mechanisms that control cell growth.

“The JAK2 protein is central to a number of processes in the body, but particularly blood cell production,” says Odenike. She adds that not all diseases that can be described as MPNs are suitable for treatment with JAK inhibitors. This class of drugs works specifically on what are called the “classical” MPNs: PV, MF and ET.

JAK inhibitors are oral drugs that block the JAK-STAT pathway, a signaling system in the body’s cells that regulates how the bone marrow produces blood cells.

“Patients with myeloproliferative neoplasms all have one unified theme of hyperactivity of the JAK-STAT signaling pathway that seems to be occurring in their bone marrow cells, and this is irrespective of the driver mutation present in these cells,” explains Dr. John Mascarenhas, a professor of medicine at Icahn School of Medicine at Mount Sinai in New York who has also worked on multiple JAK inhibitor trials. “We realized that this common theme of hyperactivity of the JAK-STAT signaling pathway could be interrupted by these small-molecule inhibitors, whereas previously, the treatments we gave were really nonspecific chemotherapies like hydroxyurea. This was a targeted therapy that depresses the activity of the signaling pathway, and in doing so, it quiets down the proliferation of cells that leads to problems in the disease.”

These corrections in cellular activity reduce many of the signs and symptoms associated with MPNs, such as an enlarged spleen and its related problems, making JAK inhibitors an ideal example of targeted cancer therapy, notes Mascarenhas. JAK inhibitors are also used in other hematological, rheumatologic and dermatological diseases, as well as in graft-versus-host disease, which occurs as a complication following transplants.

One of the most striking effects of JAK inhibitors is how quickly they can reduce a patient’s symptom burden.

“Folks who practiced before 2011 will often talk about patients with huge spleens, (who were) emaciated with loss of weight, fevers and night sweats, and incredibly short lifespans,” says Gerds. “And you would put them on these JAK inhibitors, and overnight, almost, it seemed like these people would have miraculous turnarounds.”

Not only were patients living better lives with major reductions in symptoms, but they were also living longer.

Alexander, who is president of the MPN Education Foundation, managed his PV without medication for 12 years. To lower his hematocrit counts, he underwent regular phlebotomy, or blood drawing. He began taking Jakafi after he developed pruritus, a severe, painful itching of the skin and a common symptom in MPNs.

“They call it itching,” he says. “I’m here to tell you, when it gets bad, it ain’t itching. It was life-stopping.”

The pain, he continues, was comparable to the worst sunburn imaginable topped off with being bitten by horseflies.

After Alexander began Jakafi treatment, his symptoms reduced in a matter of days. It particularly helped with the pruritus, but he says it did not help with episodes of transient global amnesia, a sudden, passing memory loss.

“Within a day or two, and I am not exaggerating, of taking the first pills, I just felt 20 years younger,“ he says. “My legs didn’t ache when I bounded up the steps at work. Within two days, according to my stopwatch, I could get up the steps faster.”

The Current Landscape of JAK Inhibitors

In 2014, three years after approving Jakafi for the treatment of patients with MF, the FDA approved the drug for the treatment of PV, making it the first drug specifically approved for that disease. The agency based its initial approval of Jakafi on two phase 3 clinical trials in which Jakafi outperformed both placebo and the best previously available therapy in reducing patients’ spleen sizes and overall symptom burdens. The 2014 expansion to use the drug for PV came on the heels of a study demonstrating that Jakafi reduced the need for phlebotomy among patients with PV and significantly reduced splenomegaly.

In 2019, a second JAK inhibitor, Inrebic (fedratinib), received FDA approval, also for MF related to MPNs, after study results showed that it significantly reduced spleen volume. Further, the clinical trial that served as the basis for Inrebic’s approval found that the drug reduced symptom burdens by more than half in about 40% of patients. Inrebic, Mascarenhas notes, can even be useful for patients whose treatment with Jakafi fails.

More recently, the FDA has approved Vonjo (pacritinib) for treating patients with myelofibrosis. And another JAK inhibitor, momelotinib, also shows promise for patients with MPNs and is the subject of a phase 3 trial.

One of Mascarenhas’ patients, Joseph Cusati, of Long Island, New York, received a diagnosis of MF in October 2019 and opted to participate in a trial of Vonjo rather than undergo a bone marrow transplant.

When he first began treatment, Cusati was told his red blood cell count was less than half of what it should be.

“I’d had nothing — absolutely nothing,” Cusati says when asked about his symptoms at the time of diagnosis. “I got a call from my primary physician who told me I had an issue with my blood. I went, and then they told me to go to the hospital. And I’ve been on this program ever since.”

He had heard of JAK inhibitors in passing as part of his job at HealthCare Partners. And when he looked up his diagnosis on the internet, he learned there was no cure.

“That was in the back of my mind, that I needed to make a decision one way or the other,” he says.

Although Cusati briefly considered a bone marrow transplant, he turned it down, in part because he wanted to avoid graft-versus-host disease.

“When you get a transplant, it’s not you that’s the problem,” he says. “It’s the bone marrow. Does it accept your body?”

Cusati received regular transfusions, usually about every week or two, early on in his treatment. But as the months on the study drug went by, he found he no longer needed transfusions.

“Whatever started to work is working,” he says. “It’s like a miracle. My energy level is astronomical. So, something is working.”

Although Cusati needed a wheelchair to move around the hospital during his early visits to see Mascarenhas at Mount Sinai, at his most recent visit, Cusati was able to walk everywhere he went. He can now spend two hours on an exercise bike at the gym.

Gerds notes that whereas many cancer drugs are approved based upon their effects on tumor size, the approval of JAK inhibitors for MPNs is based on reductions in symptoms and improvements in patients’ quality of life. He expects further innovations in the field of MPN treatment to include combining the drugs with other medicines.

Drawbacks and Limitations

JAK inhibitors also have their downsides. One major drawback is that because the drugs lower counts of certain blood cells, they can cause these counts to drop too low.

“If we are blocking JAK1 and JAK2 too much, we can cause worsening of anemia and thrombocytopenia: low red blood cells and low platelets,” says Gerds. “In someone with PV, that’s a wanted side effect. We’d want to control the red blood cell count. Same with ET: We’d want to control that platelet count. But for someone who’s already starting out with anemia and thrombocytopenia, it can certainly make that worse.”

For this reason, experts and patient advocates say that among the current options available, no JAK inhibitor is necessarily superior to another. Jakafi or Inrebic may not be safe for use in patients who have low platelet counts because they could reduce those low counts even further, so pacritinib will offer another option for those with thrombocytopenia. Momelotinib, says Mascarenhas, may be particularly useful for patients with transfusion-dependent anemia.

“It all depends,” says Alexander. “What is an undesired effect in one context (lowering counts) can be treatment in another context (PV).”

In Alexander’s case, Jakafi’s effect on his immune system meant he had to stop using the drug after two years and four months. He developed a dry cough and found himself struggling to bicycle up a small hill that was part of his usual morning commute. Eventually, doctors identified spots on his lungs and determined that he had an infection from Cryptococcus neoformans, a common fungus that occurs virtually everywhere in the world, which can be fatal in people who are immunocompromised.

To beat the infection and avoid similar ones in the future, Alexander had to stop taking Jakafi, which he describes as “very sad.” Treatment with the drug had been a positive experience, largely controlling his symptoms and shrinking his spleen.

“Would I take (Jakafi) again if I could? Sure enough,” says Alexander. “Would I suggest a fellow patient take it, based on my experience? Of course I would, with qualifications.”

Those qualifications, he adds, include being on the lookout for the risk of severe infections.

Beyond side effects, doctors say, one of the biggest caveats is that JAK inhibitors do not cause remission from MPNs.

“For all the good they do, they don’t, unfortunately, cure patients,” says Mascarenhas. “So the disease can continue and progress, despite (the patient) even enjoying some benefits of the drug.”

Odenike points out that the classical MPNs tend to progress to acute myeloid leukemia, which is much more aggressive. “(Researchers) shared the enthusiasm that (JAK inhibitors) would be tantamount to attacking these diseases at their root cause, which would lead to transformational effects,” she adds.

She and other researchers hoped that the medications could stop fibrosis, or scarring of the bone marrow, and perhaps even make the JAK2 mutation undetectable, possibly halting the progression to leukemia. None of this, she continues, has turned out to be true so far.

“It seems now, after 10 years of experience with JAK inhibi- tors, that this is not a realistic goal with this class of drugs in their current form,” Odenike explains.

In addition, although JAK inhibitors demonstrate some improvement in survival for patients who take them, Odenike has been somewhat disappointed by the results.

“We wanted so much more,” she says.

‘Better Things Are Coming’

Alexander encourages anyone with PV or another MPN to consult with an expert because “your hometown internist isn’t likely” to have much experience with these diseases.

“For most people, you’re going to be managing a chronic disease and its symptoms, which can be annoying or more than annoying for a long time,” he says.

Alexander also emphasizes that although receiving a diagnosis of PV is an initiation into a club nobody wants to join, it is possible to live a long and fulfilling life with the disease.

“You’re going to have years and years in front of you,” says Alexander, who remains an active runner and cyclist. “We’ve all gone through the adjustment of having a disease (that) is indeed likely to be life-shortening. The way I think of it, I don’t think (about) my prognosis. According to what I read in the literature, at 17 years, I think I’m at my median prognostic lifespan. Which is ridiculous. I’m not done. I’m not close to done.“

Alexander adds, “Be glad you’re diagnosed in this modern era. Better things are here, and better things are coming for you.”

Gerds agrees. “The combinations that are forthcoming are really exciting,” he says.

A nonprofit group, the MPN Research Foundation, is dedicated to ongoing efforts to treat, and perhaps someday cure, these diseases.

In the MANIFEST trial, pairing Jakafi with another drug appears to significantly improve response rates and the durability of benefit. Another combination is showing responses even with relapsed or refractory disease, and still more combinations attack disease from multiple pathways at once.

“We’re expecting readouts from at least four or five randomized trials in the next year and a half,” Gerds says. “It’s an exciting time.”

Novel Approaches Create a Bridge to Transplant in MPNs

Posted on June 14, 2023June 14, 2023 by mpn_admin

Published on: June 7, 2023

Katie Kosko

CURE, MPN Special Issue 2023, Volume 22, Issue 03

Researchers may have uncovered new ways to help patients with accelerated-phase and blast-phase MPNs live longer by borrowing therapies from other blood cancers.

In 1999, Meg Lowry learned that her platelet count ran high after having routine bloodwork done during an annual physical exam. Her primary care physician told her not to worry.

Eight years later, after her annual physical, she received a life-changing phone call from her doctor’s office.

“The nurse said, ‘We need to see you at 8 a.m. tomorrow.’ When I went in, I was told that my platelet count was 890,000 and that I needed to start taking Hydrea (hydroxyurea),” Lowry recalls.

Normally, platelet counts range from 150,000 to 400,000 platelets per microliter. Although Lowry was hesitant at first, she followed the instruction to take the chemotherapy medication. At the same time, she developed painful lesions on her skin.

“They almost looked like mosquito bites. They were raised and itchy, then would scab over and stay on my skin for weeks,” she says.

Lowry saw a dermatologist who biopsied the lesions and was told she had Sweet syndrome, a rare skin condition characterized by infiltration of neutrophils (a type of white blood cell) that can be triggered by an infection, an illness such as cancer, medication and sometimes even pregnancy. She was given cortisone and told she would need to see an oncologist. Trying to wrap her head around those words, Lowry called her friend who works at The University of Texas MD Anderson Cancer Center in Houston to share what she was told. Within five days, Lowry had an appointment with the head of the leukemia department. In January 2008, Lowry, who was 56 years old at the time, received a diagnosis of essential thrombocythemia (ET), which is a rare blood cancer and one of three main types of myeloproliferative neoplasms (MPNs). She was told to continue the Hydrea and see an oncologist every six months.

Road to Progression

The three main types of MPNs are ET, polycythemia vera (PV) and myelofibrosis (MF). ET is caused by the bone marrow producing too many platelets, the part of the blood needed for clotting; PV occurs when the bone marrow produces too many red blood cells; and MF is characterized by the buildup of scar tissue in the bone marrow. It is often found during routine bloodwork, usually in its early phases. Symptoms of the group of incurable diseases include anemia, fatigue, pain or fullness in the belly from an enlarged spleen, prolonged bleeding from minor cuts, shortness of breath and weakness. It can also less commonly cause blood clots. It wasn’t until 2014, however, that Lowry felt her condition was more dire. She began to run a low-grade fever daily, had brain fog, fatigue, joint and muscle aches, nausea and night sweats.

“I got to the point where I carried a thermometer in my purse. I was always pushing through,” she says. In May 2015, Lowry left her home in Austin, Texas, and headed for MD Anderson Cancer Center yet again, where her labs showed that her platelets were 3.1 million and that her hemoglobin level had dropped.

“The doctor told me, ‘I think you have leukemia or myelofibrosis,’” Lowry recalls. Ten days later, she learned that her ET diagnosis had progressed to accelerated MPN and that she was positive for an IDH1 mutation. MPN in the accelerated phase is not as common as the chronic phase and is defined by 10% to 19% myeloid blasts (a type of immature white blood cell) in the peripheral blood or bone marrow, according to Dr. Aaron Gerds, an assistant professor of medicine and deputy director for clinical research at Cleveland Clinic Taussig Cancer Institute in Ohio. Accelerated-phase MPN is often a precursor to blast-phase MPN, also referred to as acute myeloid leukemia (AML). Blast-phase MPN is associated with 20% or more myeloid blasts.

“Depending on the analysis, the lifetime risk for ET to turn into blast-phase disease is less than 5%,” Gerds says. “(For) MF, (it) is much higher — 10% to 20%.”

Progression can only be confirmed through blood or bone marrow biopsy analysis. Typically, patients will have significant blood changes — decreased hemoglobin, a rapid platelet drop and a rapid rise in white blood cells, explains Dr. Abdulraheem Yacoub, an associate professor of medicine in the Division of Hematologic Malignancies and Cellular Therapeutics and clinical director of the Ambulatory Hematology Clinics at University of Kansas Medical Center in Kansas City. Patient symptoms may also worsen, or new symptoms will develop, such as drenching night sweats, weight loss and an enlarged spleen.

“Usually transformation is gradual, not sudden,” Yacoub says. “Patients considered high risk will be watched closely with labs every one to three months. So even at this rate, you can still catch it early as it happens.”

Although there is no specific predictor of which patients with MPNs might progress over time, certain patients are at higher risk based on specific disease features, i.e., having a primary diagnosis of MF and testing positive for genetic mutations such as IDH1/IDH2, RAS and TP53.

“You can test for mutations at any time,” Gerds says. “Generally, it’s advised to test, if you can, a large panel of genes not only for driver mutations, but also others that can be important in prognosis.”

Evolution of Treatment

The only way to potentially cure MPNs in accelerated phase or blast phase is through an allogeneic stem cell transplant, which uses healthy blood stem cells from a donor to replace diseased or damaged bone marrow. Without a transplant, other therapies are short-lived — effective for just a few months — according to Dr. Naseema Gangat, an associate professor of medicine at Mayo Clinic in Rochester, Minnesota. However, based on age, functioning and comorbidities, not every patient is a good candidate for stem cell transplant.

“The majority of patients are about 65 years of age and not in the position to tolerate aggressive treatment,” Gangat says. “If they are fit and (younger than) 70 years old, I would go with intensive AML chemotherapy, followed by transplant.”

Even with transplant, two-year overall survival rates (the time from treatment that a patient with cancer is still alive) range from 29% to 75% for advanced MPNs. With limited treatment options, researchers have begun to borrow therapies from other blood cancers, particularly molecularly targeted therapies, to see how well they work for these patients. Clinical trials, although small because of the available patient population, are being conducted for efficacy and safety. In one study, Venclexta (venetoclax), an inhibitor of the BCL2 protein, was combined with a hypomethylating agent (which can trigger the reprogramming of tumor cells), such as Vidaza (azacitidine) or decitabine, in patients with blastphase MPNs.

The study included 32 patients with a median age of 69, and two-thirds of them had a mutation or three or more chromosomal aberrations. Twenty patients had not received prior therapy. A complete response (defined as a disappearance of all signs of cancer) was achieved by 14 patients and was more likely in those who did not have preleukemic PV/post-PV myelofibrosis. Six of these patients were able to go on to receive an allogeneic stem cell transplant.

“Even though these new approaches are available, they are being used more as a bridge to allogeneic stem cell transplant. And if you’re an unfit patient, they improve your quality of life,” says Gangat, who was an author on the study. Another study, presented at the 2021 annual meeting of the American Society of Hematology, included 39 patients with blast-phase MPNs and found that they responded best to the combination of Venclexta and a hypomethylating agent compared with intensive chemotherapy or a hypomethylating agent alone. Patients were divided into four groups to receive one of the following: Venclexta/hypomethylating agent; fludarabine, high-dose cytarabine and granulocyte-colony stimulating factor; a hypomethylating agent only; or daunorubicin and cytarabine.

“What’s more important is understanding accelerated- and blast-phase disease and targeting it in innovative ways,” Gerds says. “There are patients who can have ET for decades, and then all of a sudden, it turns into blast-phase disease. The pattern of mutations is very different. Mutations in genes like TP53 and NRAS seem to be key with late disease progression, whereas mutations in EZH2 and RUNX1 are key players in those who progressed more (quickly) after diagnosis.”

Unfortunately, there are no specific medications to target many of these mutations, explains Yacoub. Yet other mutations seen in MPNs can be targeted. For example, researchers are exploring the use of Rydapt (midostaurin), which targets the FLT3 mutation. This mutation appears in approximately 3% of patients with MPNs in accelerated phase or blast phase. Rydapt is already approved by the Food and Drug Administration (FDA) for the frontline treatment of patients with AML.

IDH1 and IDH2 are also potential targets because up to 20% to 25% of patients with accelerated- or blast-phase MPNs have one of these mutations. Tibsovo (ivosidenib), an IDH1 inhibitor, and Idhifa (enasidenib), an IDH2 inhibitor, are being examined in combination with chemotherapy or a hypomethylating agent. Lowry was lucky enough to arrive back at MD Anderson Cancer Center when she did because she was one of the first patients to join a clinical trial in June 2015 that investigated Tibsovo and which ultimately led to the FDA approval of this agent.

“Before this, I was constantly nauseated,” Lowry says. “This was the best I’ve felt.” Within a year of starting the trial drug, her platelets were in normal range and all her symptoms disappeared. Lowry calls her response miraculous. “It gave me my life back, my energy back,” she says. “I try to live in gratitude.”

Living With a Chronic Disease

In addition to these approaches, research is being conducted using Janus kinase (JAK) inhibitors in combination with other medications because MPNs are caused in a large part by mutations that drive the JAK-STAT growth signaling pathway. For instance, clinical trials have examined Jakafi (ruxolitinib) plus decitabine. But patient responses have been modest, Gangat explains. The immunotherapy medication Keytruda (pembrolizumab) is also under investigation in an early clinical trial for patients with advanced MPNs, including accelerated phase and blast phase, who did not respond to therapy with a hypomethylating agent. Because so much research is evolving, Yacoub notes that it’s crucial for patients to be their own best advocates.

“Sometimes you might have to travel for a clinical trial that would be best suited for your diagnosis,” he says. “I strongly recommend that patients seek care under the care of experts in a center that can deliver a transplant.”

The ultimate goal, says Gerds, is to help patients with accelerated-phase and blast-phase MPNs live better and longer lives. “I think the key is finding treatments that can improve remissions but don’t cause a lot of toxicities,” he says. “We need to focus on treatments that can lead to response but not at the risk of a patient’s quality of life.”

Currently, Lowry’s platelets are in the low 400,000s, and she continues to receive Hydrea and Tibsovo. The married mother of two is back to enjoying time with her five grandchildren, traveling with high school girlfriends and doing yoga three days a week.

“If you know you have a blood disease, you need to see a hematologist,” Lowry says. “You need to be in a supportive community because if I had been going to someone who was more knowledgeable about blood, I wouldn’t have suffered so long.”

Ruxolitinib Improves Spleen Volume, TSS in Myelofibrosis Irrespective of Anemia, Transfusion Status

Posted on June 14, 2023June 14, 2023 by mpn_admin

Jun 10, 2023

Gina Mauro

Conference|European Hematology Association Congress

Ruxolitinib was found to improve spleen volume and tumor symptom score in patients with myelofibrosis, irrespective of their anemia and transfusion status, according to data from a post-hoc analysis of the phase 3 COMFORT-I and -II trials.

Ruxolitinib (Jakafi) was found to improve spleen volume and tumor symptom score (TSS) in patients with myelofibrosis, irrespective of their anemia and transfusion status, according to data from a post-hoc analysis of the phase 3 COMFORT-I (NCT00952289) and -II (NCT00934544) trials that were published during the 2023 EHA Congress.¹

Results showed that the reduction in spleen volume of 35% or greater from baseline (SVR35) rates at week 24 in patients with new or worsening anemia up to week 12 were 48.8%, 33.3%, and 41.4%, respectively, for those who were nonanemic, anemic/nontransfusion dependent, and anemic/transfusion dependent at baseline. These rates were 43.2%, 23.1%, and 28.2%, respectively, in patients who did not have new or worsening anemia at week 24.

SVR35 at week 48 was achieved in 42.1%, 44.1%, and 34.6% of patients who had new or worsening anemia and were nonanemic, anemic/nontransfusion dependent, and anemic/transfusion dependent at baseline compared with 42.4%, 22.2%, and 27.3% in those who did not have new or worsening anemia.

A 50% or greater reduction in TSS at week 24 was achieved by 51.1%, 42.1%, and 46.7% of those with new or worsening anemia up to week 12 and who were nonanemic, anemic/nontransfusion dependent, or anemic/transfusion dependent at baseline. In patients who did not have new or worsening anemia up to week 12, these rates were 42.9%, 40.0%, and 54.2%, respectively.

Ruxolitinib, a JAK1/2 inhibitor, is indicated for patients with intermediate- or high-risk myelofibrosis. The FDA approval for ruxolitinib in this setting was based off findings from the COMFORT-I² and COMFORT-II³ trials. Findings showed that ruxolitinib demonstrated a reduction in spleen volume, improved myelofibrosis-related symptoms, and prolonged overall survival. This was in comparison with placebo in COMFORT-I and with best available therapy (BAT) in COMFORT-II.

Transient dose-dependent anemia is a treatment-related adverse effect (TRAE) that has been observed with ruxolitinib. In COMFORT-I, grade 3/4 anemia occurred in 45.2% of patients on ruxolitinib vs 19.2% with placebo. In COMFORT-II, the most frequently reported serious adverse effect in both arms was anemia (5% with ruxolitinib vs 4% with BAT).

Therefore, in the post-hoc analysis presented during the congress, investigators sought to determine how new or worsening anemia from ruxolitinib treatment impacts SVR and TSS in this patient population.¹

Patients were treated with ruxolitinib twice daily with an initial dose based on platelet count. For those with a platelet count of 100 to 200 x 109/L, the dose was 15 mg vs 20 mg for those whose platelet count was above 200 x 109/L. Stratification factors included anemia status at baseline (yes vs no) and transfusion status at baseline (transfusion dependent vs nontransfusion dependent).

Anemia was defined as hemoglobin less than 100 g/L and patients were considered transfusion dependent if they received 2 or more units of red blood cells over 8 to 12 weeks before their first dose of ruxolitinib. Investigators stratified outcomes via presence or absence of new or worsening anemia postbaseline, which was defined as a decrease in hemoglobin of at least 15 g/L or new transfusion requirement at weeks 4, 8, or 12.

Specifically, investigators assessed patients with a reduction in spleen volume of at least 35% from baseline from the pooled COMFORT-I/-II data at weeks 24 and 48, and with at least a 50% reduction in modified Myelofibrosis Symptom Assessment Form TSS at week 24, from the COMFORT-I data.

A total of 277 patients were included in the analysis. Regarding baseline characteristics, the median age ranged from 65.0 to 71.0 years, and between 47% and 56% were male. More than half of patients were baseline nonanemic (n = 154; 55.6%) 19.9% (n = 55) were anemic/nontransfusion dependent, and 24.5% (n = 68) were anemia/transfusion dependent.

References

Al-Ali HK, Mesa R, Hamer-Maansson JE, Braunstein E, Harrison, C. Effect of new or worsening anemia on clinical outcomes in patients with myelofibrosis (MF) treated with ruxolitinib (RUX): a post hoc analysis of the COMFORT-I and -II trials. Presented at: 2023 European Hematology Association Congress; June 8-11, 2023; Frankfurt, Germany. Abstract PB2185.
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
Harrison C, Kiladjian J-J, Al-Ali HK, et al. JAK Inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366:787-798. doi:10.1056/NEJMoa1110556.

JAK2 gene: Function, conditions, and research

Posted on June 14, 2023June 14, 2023 by mpn_admin

By Oladimeji Ewumi

June 9, 2023

The JAK2 gene is a protein-coding gene of the Janus kinase family. It plays a role in cellular signaling. Evidence notes connections between this gene and some medical conditions.

The JAK2 geneTrusted Source is present on chromosome 9. It produces a protein that sends signals in cells to help control how many blood cells the bone marrow produces.

Variations in this gene may cause the body to produce too many blood cells. Evidence suggests a link between alterations in the JAK2 gene and some types of blood conditions.

This article will provide an overview of the JAK2 gene, including its functions and related medical conditions.

According to a 2014 article, the JAK2 gene instructs cells to make the JAK2 protein. This protein helps control cell growth and division. Specifically, JAK2 proteins help control the activation and production of hematopoietic stem cells.

Hematopoietic stem cellsTrusted Source are immature cells present in bone marrow. They can differentiate into all blood cell types, including red blood cells, white blood cells, and blood platelets.

A 2017 reviewTrusted Source suggests that the JAK2 gene regulates the JAK-STAT signaling pathway — a chain of enzymatic interactions that controls cell division, immunity, cell death, and tumor formation.

Dysregulation of the JAK-STAT pathway can result in immune disorders. The National Library of MedicineTrusted Source notes that the JAK2 gene and the JAK-STAT signaling pathway are therapeutic targets for treating excessive inflammatory responses and viral infections.

JAK2 function

The following are the most common functions of the JAK2 gene:

regulating the production of blood cells
promoting cellular processes, including cell growth, development, differentiation, and modifications
mediating essential signaling events in immunity
acting as a diagnostic biomarker for most myeloproliferative neoplasms (MPNs), which are rare disorders of the bone marrow

JAK2 and blood conditions

Evidence notes an association between the expression of the JAK2 gene and some blood conditions. For example, MPNs are a group of hematopoietic stem cell conditions that arise due to an overproduction of mature blood cells.

JAK2 V617F is the most common alteration of the JAK2 gene present in blood conditions. According to a 2019 study, this alteration has a prevalence rate of 0.2% in the general population.

Primary myelofibrosis

In primary myelofibrosis (PMF), JAK2 gene variations replace typical bone marrow cells with scar tissue. This alteration affects 50%Trusted Source of people with PMF.

These JAK2 variations lead to the overproduction of atypical megakaryocytes that stimulate other cells to release collagen in the bone marrow. This causes scar tissue to form in a process called fibrosis. Due to this fibrosis, the bone marrow cannot produce enough typical blood cells, leading to symptoms of PMF.

Polycythemia vera

Polycythemia vera (PV) occurs when JAK2 overstimulates the production of red blood cells, causing an excess in the circulatory system. About 96%Trusted Source of people with PV have the V617F variation of the JAK2 gene.

Having extra cells in the bloodstream increases the risk of atypical blood clots. In addition, the thicker blood flows more slowly through the vessels, reducing the amount of oxygen in body tissues.

Essential thrombocythemia

In around 50% of people with essential thrombocythemia (ET), the JAK2 V617F alteration results in the body replacing the amino acid valine with phenylalanine. Switching these amino acids results in the continual activation and production of the JAK2 protein, leading to an overproduction of megakaryocytes.

Since platelets form from megakaryocytes, an increased number of platelets may result in more blood clots.

JAK2 and inflammatory bowel disease

Inflammatory bowel disease (IBD)Trusted Source is a term for two conditions: Crohn’s disease and ulcerative colitis. Both occur due to inflammation of the gastrointestinal tract.

According to a 2016 studyTrusted Source, increased expression of the JAK2 gene may impact inflammatory responses, causing severe gut inflammation in people with IBD.

JAK2 and other conditions

Research suggests that JAK2 may play a role in other blood disorders, including leukemia and Budd-Chiari syndrome (BCS).

A 2018 studyTrusted Source indicates that JAK2 variation is rare in de novo acute myeloid leukemia, an aggressive cancer of the bone marrow.

Additional research from 2015 that analyzed JAK2 alteration in those with BCS suggests that 20% had latent MPNs. BCS occurs when a blood clot blocks the hepatic veins. This blockage can cause blood to flow back to the liver.

JAK2 research

Many clinical trials are focusing on trying to manipulate the JAK2 gene and enzyme to find a better treatment for many related conditions the protein causes.

These suggest that therapeutic approaches targeting the JAK2 signaling pathways may prove Trusted Source effective in inhibiting pathogenic variations, providing new insights for developing pharmacological interventions.

For example, ruxolitinibTrusted Source is part of a Janus kinase inhibitor class of medication doctors prescribe to treat several conditions, including PMF and PV. Some other examples of Janus kinase inhibitors include Trusted Source:

abrocitinib
baricitinib
filgotinib
delgocitinib

Summary

The JAK2 gene is a protein-coding gene of the Janus kinase family. It initiates several cellular signaling processes, including cell division, immunity, and tumor formation.

Evidence notes that problems with this gene can result in the body producing too many blood cells. Medical experts have found links between the JAK2 gene and some blood conditions, including myelofibrosis, polycythemia vera, and thrombocythemia.

Last medically reviewed on June 9, 2023

Study Unveils Family Risk for Certain Types of Blood Cancers

Posted on August 15, 2019August 15, 2019 by mpn_admin

Individuals with a parent, sibling or child with blood cancer appear to have a higher likelihood of also being diagnosed with the disease, according to study results published in Blood.

Moreover, age of diagnosis; whether the relative is a parent, sibling or child; and the number of affected first-degree relatives were substantially associated with familial risk for certain blood cancers.

“Although many hematological malignancies are individually rare, collectively they contribute significantly to the overall cancer burden in the population,” the researchers wrote, adding that the etiological basis of most blood cancers is poorly understood.

Therefore, they analyzed data from over 16 million individuals from the Swedish Family-Cancer Database to determine the familial risk of the different blood cancer and their possible inter-relationship.

Those with a familial link to the disease represented 4.1% of all blood cancer diagnoses – higher than patients with cancers of the nervous system, kidney and pancreas. However, this was lower than those with cancers of the breast, colon and prostate, which ranged from 8% to 15%.

In total, the researchers identified 153,115 patients who were diagnosed with a primary blood cancer, including myeloproliferative neoplasms (MPN; polycythemia vera, essential thrombocythemia, myelofibrosis and MPN not otherwise specified), chronic myeloid leukemia, myelodysplastic syndrome, acute myeloid leukemia, acute lymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, Burkitt lymphoma, small lymphocytic lymphoma, hairy cell leukemia, chronic lymphocytic leukemia and multiple myeloma.

The researchers found the highest relative risks for familial risk among patients with certain Hodgkin lymphoma subtypes (lymphoplasmacytic lymphoma and mantle cell lymphoma) and with polycythemia vera, myelodysplasia and essential thrombocythemia.

“This information improves our understanding of the causes of – and potential inherited predisposition to – blood cancers and should inform the identification and characterization of genetic risk factors for blood cancer, as well as how we best clinically manage patients and their relatives,” lead study author Dr. Amit Sud, from The Institute of Cancer Research in London, said in a press release. “The results should also encourage conversations among families, clinicians and patients about familial risk.” (Cure Magazine)