Tag Archives: mpn

Navigating Cytoreduction in MPNs: Benefits, Risks, and Considerations

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Jordyn Sava

In an interview with Targeted Oncology, Douglas Tremblay, MD, discussed the significance of cytoreductive therapy in mitigating thrombotic risk in myeloproliferative neoplasms.

According to Douglas Tremblay, MD, cytoreductive therapy has emerged with a pivotal role in mitigating thrombotic risk in the treatment landscape of myeloproliferative neoplasms (MPNs), specifically essential thrombocytopenia (ET) and polycythemia vera (PV).

Despite the evident benefits, each therapy carries unique adverse effects, requiring the careful consideration of patient-specific factors in treatment administration. Deciding when to initiate cytoreductive therapy in patients with chronic MPNs relies on accurate risk assessment, with parameters such as age and prior thrombotic events often guiding treatment decisions.

Frontline therapies, such as hydroxyurea and interferon, manage blood counts for patients with ET and PV, and newer options are emerging, according to Tremblay, assistant professor of medicine at the Icahn School of Medicine at Mount Sinai. However, the long-term implications focus on thrombosis prevention and disease progression.

Ongoing research endeavors aim to delve deeper into surrogate end points and novel therapeutic avenues, promising to further refine and revolutionize the management of MPNs.

In an interview with Targeted OncologyTM, Tremblay discussed the significance of cytoreductive therapy in mitigating thrombotic risk in MPNs, specifically ET and PV.

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Identification of Novel Risk Variants of Inflammatory Factors Related to Myeloproliferative Neoplasm: A Bidirectional Mendelian Randomization Study

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Yang Li, Ting Sun, Jia Chen, Lei Zhang

Abstract

Epidemiological and experimental evidence has linked chronic inflammation to the etiology of myeloproliferative neoplasm (MPN). However, it remains unclear whether genetic associations with specific inflammatory biomarkers are causal or due to bias. This study aimed to assess the effect of C-reactive protein (CRP) and systemic inflammatory regulators on MPN within a bidirectional Mendelian randomization design. Genetic associations with MPN were derived from a publicly available genome-wide association study (GWAS) comprising 1,086 cases and 407,155 controls of European ancestry. Additionally, data on inflammation were extracted from two GWASs focusing on CRP and cytokines. The causal relationships between exposure and outcome were explored using the inverse variance weighted (IVW) method. To confirm the final results, multiple sensitivity analyses, including MR-Egger, weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO), were simultaneously employed. Our results suggest that lower levels of macrophage-migration inhibitory factor (IVW estimate odds ratio [OR IVW] per SD genetic cytokines change: 0.641; 95% confidence interval [CI]: 0.427–0.964; p = 0.032) and higher levels of interleukin-2 receptor α (lL2Rα, 1.377, 95% CI: 1.006–1.883; p = 0.046) are associated with an increased risk of MPN. Genetically predicted MPN is related to increased levels of RANTES (IVW estimate β: 0.043, 95% CI: 0.002–0.084; p = 0.039) and interleukin-10 (IVW estimate β: 0.030, 95% CI: 0.001–0.060; p = 0.041). This study provides evidence for a causal relationship between CRP, systemic inflammatory regulators, and MPN, and new insights into the etiology, prevention, and prognosis of MPN.

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Depression in patients with hematologic malignancies: The current landscape and future directions

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Thomas M. Kuczmarski, Lizabeth Roemer, Oreofe O. Odejide

February 13, 2024

Abstract

Patients with hematologic malignancies experience high rates of depression. These patients are vulnerable to depression throughout the disease trajectory, from diagnosis to survivorship, and at the end of life. In addition to the distressing nature of depression, it has substantial downstream effects including poor quality of life, increased risk of treatment complications, and worse survival. Therefore, systematic screening for depression and integration of robust psychological interventions for affected patients is crucial. Although depression has been historically studied mostly in patients with solid malignancies, research focusing on patients with hematologic malignancies is growing. In this article, we describe what is known about depression in patients with hematologic malignancies, including its assessment, prevalence, risk factors, and implications. We also describe interventions to ameliorate depression in this population. Future research is needed to test effective and scalable interventions to reduce the burden of depression among patients with blood cancers.

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MPN Symptoms Mimic Other Conditions, Open Communication Is Key

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Brielle Benyon

Myeloproliferative neoplasm (MPN) symptoms can often appear as another condition, making it essential that patients find a cancer care team that they trust and can have open communication with, according to Patrick Buxton.

Buxton, who is a clinical nurse manager at Fred Hutchinson Cancer Center in Seattle and a 2023 MPN Hero, explained that certain side effects like constant fatigue could mimic conditions such as depression. That is why it is important for patients to work with their oncology team to establish a baseline of lab results and symptoms and keep them up to date on how they are feeling.

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Study Supports Further Exploration of Tamoxifen in MPNs

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Sabrina Serani

Findings from a phase 2 study support the further investigation of tamoxifen (Soltamox), a selective estrogen receptor modulator (SERM), as a treatment option in patients with myeloproliferative neoplasms (MPNs), with extra consideration for thrombotic risk.1

A total of 38 patients with MPNs with mutated JAK2V617F, CALRins5, or CALRdel52 peripheral blood allele burden greater than 20% were recruited, and 32 patients completed 24 weeks of treatment. A greater than 50% reduction in mutant allele burden at 24 weeks was observed in 3 patients, and a 25% or greater reduction in mutant allele burden at 24 weeks was observed in 5 patients.

An exploratory analysis of hematopoietic stem/progenitor cell (HSPC) transcriptome identified a difference between responders and non-responders. Investigators observed that in responder HSPCs, there was a high baseline expression of Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling and oxidative phosphorylation genes, which tamoxifen appeared to downregulate.

“The perfect segregation of the HSPC transcriptome from responders and non-responders at baseline could serve in the future as a platform for the stratification of patients based on their likelihood to respond to tamoxifen and for the identification of predictive biomarkers of response, if prospectively validated,” study authors wrote in findings published in Nature Communications.

“These results suggest that the metabolic effects of SERMs in cancer might be underappreciated and propose ways to modulate pathogenic JAK-STAT signaling through metabolic rewiring. These results warrant further investigation of tamoxifen as potential therapeutic for MPN in larger studies, after careful consideration of the risk of thrombosis,” study authors wrote.

Patients with essential thrombocythemia (ET), polycythemia vera (PV), primary myelofibrosis (MF), post-PV MF, and post-ET MF were included in the study. The primary end point was a mutant allele burden reduction of greater than 50% at 24 weeks. The secondary end points included mutant allele burden reduction between 25% and 50% at 24 weeks, a greater than 50% reduction at 12 weeks, thrombotic events, toxicities, and hematological response.

Thrombotic adverse events (AEs) potentially related to tamoxifen were reported in 2 patients, and 1 patient discontinued treatment due to this AE. Investigators identified that the thrombotic events only occurred in non-responders, so identifying responders before initiating treatment should help reduce risks to patients.

Regarding safety, 11 additional patients discontinued study treatment due to toxicity. A grade 1 intracranial hemorrhage unrelated to tamoxifen was reported. No patient deaths were reported. Complete symptoms response was observed in 19% of patients, while 71.4% of patients had a partial symptom response, and 9.5% of patients had no response.

The results of this study warrant further exploration into tamoxifen as a treatment option for MPNs and further investigation of SERMs with lower thrombotic risks.

REFERENCES:
1. Fang Z, Corbizi Fattori G, McKerrell T, et al. Tamoxifen for the treatment of myeloproliferative neoplasms: A phase II clinical trial and exploratory analysis. Nat Commun. 2023;14(1):7725. Published 2023 Nov 25. doi:10.1038/s41467-023-43175-5

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Dr Vincelette on MYC Expression in Myelofibrosis

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Nicole D. Vincelette, PhD

Nicole D. Vincelette, PhD, postdoctoral fellow, Moffitt Cancer Center, discusses findings from a study investigating the role of MYC expression and S100A9-mediated inflammation in a subgroup of triple-negative myeloproliferative neoplasms (MPNs).

To determine how MYC expression drives MPNs, such as polycythemia vera, essential thrombocythemia, and primary myelofibrosis, Vincelette and colleagues conducted a study in which they generated a mouse model that overexpresses MYC in the stem cell compartment. This analysis demonstrated that MYC overexpression was associated with the mice developing a myelofibrosis-like phenotype, which included anemia, atypical megakaryocytes, splenomegaly, bone marrow fibrosis, liver fibrosis, spleen fibrosis. The mice also experienced adverse clinical outcomes, such as reduced overall survival (OS), compared with wild-type mice, Vincelette says.

Since the MYC-overexpressed mice developed myelofibrosis, the next step of this research was to investigate how MYC drives myelofibrosis, Vincelette explains. Investigators performed single-cell RNA sequencing to compare the bone marrow cells from MYC-overexpressed and wild-type mice. MYC overexpression correlated with upregulation of the S100A9 protein, which contributes to inflammation and innate immunity, according to Vincelette. Therefore, MYC drives the development of myelofibrosis through S100A9-mediated chronic inflammation. To validate the role of S100A9 downstream of MYC in myelofibrosis, investigators created a mouse model with S100A9 knockout in the presence of MYC overexpression, Vincelette notes. The S100A9 knockout protected against the development of myelofibrosis phenotype in that mouse model, Vincelette emphasizes.

By generating a mouse model that overexpresses S100A9, investigators also determined that S100A9 overexpression alone contributes to the development of myelofibrosis phenotypes, Vincelette says. When investigators treated the MYC-overexpressing mice with the S100A9 inhibitor tasquinimod (ABR-215050), the agent only partially abrogated the myelofibrosis phenotype, meaning the mice had reduced atypical megakaryocytes and splenomegaly. Additionally, the mice developed anemia and no OS difference occurred between tasquinimod and vehicle treatment, potentially because of off-target drug effects, Vincelette concludes.

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The role of inherited genetic variants in rare blood cancer

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January 17, 2024

Researchers from the University of Cambridge, Wellcome Sanger Institute, and collaborators have shown how inherited genetic variants can influence the risk of developing a rare blood cancer.

Large-scale genetic analysis has helped researchers uncover the relationship between cancer-driving genetic mutations and inherited genetic variants in a rare type of blood cancer.

The team combined datasets to understand the impact of cancer-driving spontaneous mutations and inherited genetic variation on the risk of developing myeloproliferative neoplasms (MPN).

Published in Nature Genetics, the study describes how inherited genetic variants can influence whether a spontaneous mutation in a particular gene increases the risk of developing this rare blood cancer.

The analysis will have an impact on current clinical predictions of disease development in individuals.

More research is needed to understand the mechanisms behind how the inherited genetic variants influence the probability of developing rare blood cancer.

In the future, the work could aid drug development interventions that reduce the risk of disease.

Myeloproliferative neoplasms

MPNs are a group of rare and chronic blood cancers, with around 4,000 cases in the UK each year. These occur when the bone marrow overproduces blood cells, resulting in blood clots and bleeding.

MPNs can also progress into other forms of blood cancer.

Genetic risk score

There is a large amount of natural variation between individuals’ blood cells which can affect the amount of blood cells a person has and their traits. This is because different genes can influence blood cell features in an individual.

Researchers take known information about these genes during routine blood tests and analyse the variation to give a genetic risk score. This is how likely that individual is to develop a disease over their lifetime.

MPNs have been linked to random somatic mutations in a gene called JAK2; however, mutated JAK2 is commonly found in the global population. The vast majority of these individuals do not have or go on to develop MPN.

Previous studies identified over a dozen associated inherited genetic variants that increase the risk of MPN. However, these studies do not explain why most individuals do not go on to develop MPN.

Inherited genetic variants can influence risk

The new study combined information on the known somatic driver mutations in MPN inherited genetic variants, and genetic risk scores from individuals with MPN.

They found that the inherited genetic variants that cause natural blood cell variation in the population also impact whether a JAK2 somatic mutation will cause MPN. The team also discovered that individuals with an inherited risk of having a higher blood cell count could display MPN features in the absence of cancer-driving mutations, mimicking disease.

Dr Jing Guo, from the University of Cambridge and the Wellcome Sanger Institute and first author of the study, said: “Our large-scale statistical study has helped fill the knowledge gaps in how variants in DNA, both inherited and somatic, interact to influence complex disease risk.

“By combining these three different types of datasets we were able to get a more complete picture of how these variants combine to cause blood disorders.”

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Women’s History Month – Claire Harrison, MD

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Claire Harrison, MD, DM, FRCP, FRCPath is a Professor of Hematology at the Guy’s and St. Thomas’ NHS Foundation Trust in London, UK. Prof. Harrison became a Consultant at the Guy’s and St. Thomas’ NHS Foundation Trust in 2001, where she is now a Clinical Director. 

1. How did you become interested in hematology versus other areas of medicine?

Haematology captivated me as a student at Oxford I had the privilege of being taught by Prof Sir David Weatherall I think it was the opportunity to both bring science direct to the bedside and to look after patients with a chronic illness.

2.  What have been the highlights in your career, specifically in the area of MPNs?

Working in an area you are passionate about with a fabulous team locally and many others.. the fantastic international community of clinicians and scientists and the strong partnership with patient communities and also colleagues in biotech and pharma who are pushing the boundaries to improve the lives of our patients.

3.  As a female in this area of medicine, what advice would you give women grappling with career choices in hematology and medical research? 

It’s the same advice regardless of gender….  Find something that you are passionate about, identify a mentor or two, don’t be afraid to admit if you don’t know always ask, balancing work and family life is a challenge but feasible keep looking for solutions.

Higher Symptom Burden More Likely to Improve With MPN Treatment

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Patient and doctor
Researchers analyzed data from 2 clinical trials to determine how 2 MPN therapies affect symptom burden. Source: Getty Images

By Vicki Moore, PhD

Higher Symptom Burden More Likely to Improve With MPN Treatment

Data from 2 clinical trials involving patients with myeloproliferative neoplasms (MPNs) revealed the importance of considering symptom burden in evaluating treatment efficacy and tolerability. The study results were published in The Lancet Haematology.

The analysis included data from the single-arm phase 2 MPN-RC 111 study (ClinicalTrials.gov Identifier: NCT01259817) and from the randomized, open-label phase 3 MPN-RC 112 study (ClinicalTrials.gov Identifier: NCT01258856). MPN-RC 111 evaluated clinical-hematologic response to pegylated interferon alfa-2a in patients who had hydroxyurea resistance or intolerance. MPN-RC 112 evaluated clinical-hematologic response to pegylated interferon alfa-2a in comparison with hydroxyurea in treatment-naïve patients who had high-risk essential thrombocythemia (ET) or polycythemia vera (PV).

This analysis made use of results from patient questionnaires including the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) and the European Organisation for the Research and Treatment of Cancer Core Quality of Life Questionnaire. The objective of the analysis was to analyze symptom burden with respect to both the clinical-hematologic response at 12-months and the baseline symptom burden.

Symptom burden was categorized as either high (total symptom score ≥20) or low (total symptom score <20). The researchers considered a clinically significant improvement in symptom burden to be an improvement of 50% or more in MPN-SAF total symptom score over 12 months for patients who had a nonzero total symptom score at baseline.

There were 114 patients analyzed from the MPN-RC 111 study (64 with ET, 50 with PV) and 166 patients (79 with ET, 87 with PV) from the MPN-RC 112 study. Among patients from the MPN-RC 111 study, 32% of complete responders and 20% of partial responders reported clinically significant improvements in symptom burden at 12 months.

For patients from the MPN-RC 112 study, among those treated with pegylated interferon alfa-2a, 19% of complete responders and 18% of partial responders reported a clinically significant improvement in symptom burden at 12 months. Of those treated with hydroxyurea, this outcome was reported in 27% of complete responders and 22% of partial responders.

Overall, responders — complete or partial — more often experienced a clinically significant improvement than did nonresponders (22% and 5%, respectively; P =.0003). However, the study investigators noted that most responders did not report a clinically significant improvement.

Additionally, patients who had a high symptom burden at baseline showed improvements in symptom burden at both 3 and 12 months, whether treated with pegylated interferon alfa-2a or hydroxyurea, with mean symptom score changes of -10.2 for pegylated interferon alfa-2a and -6.8 for hydroxyurea. Patients with low baseline symptom burden, however, experienced worse symptom burden at these time points. Mean symptom score changes were 3.2 with pegylated interferon alfa-2a and 3.4 with hydroxyurea for these patients.

“In summary, clinicians, researchers, and regulatory agencies should consider symptom burden and quality of life when evaluating treatment efficacy in patients with essential thrombocythaemia and polycythaemia vera,” they concluded.

Disclosures: Some authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

A Patient Story: The decision to get a Stem Cell Transplant

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Parachuting from a Crippled Plane

 

By Dave D.

My daughter came to Ohio to provide support to me and my wife during my recent stem cell transplant (SCT). In explaining the process to her I used the analogy of parachuting from a crippled airplane and she found it very helpful. I hope that this analogy might also help others understand my experience. Like with parachuting, there are risks there are steps to take. Each step is a small victory, but the ultimate victory is landing safely.

When I was diagnosed with Primary Myelofibrosis in 2013, it became clear that my high-flying airplane (my body) had a problem. It was still possible that it could fly on for years with relatively few problems, but we needed to keep an eye on it. Medications like Jakafi and Inrebic made the flight a bit more pleasant, but blood counts and bone marrow biopsies indicated that we were losing altitude.

This December I realized through consultation with Dr. Aaron Gerds from the Cleveland Clinic that the plane’s problems were becoming unmanageable. I was now High Risk and I was headed for a fatal crash sooner rather than later. It was difficult to say just how long it would take – but our calculator (MIPPS70) predicted about 5 years – give or take.

At that point I needed to decide whether I would take the risks involved in jumping out of the plane or choose to die in the crash. In consultation with my dear wife and my medical team and with the prayers of my friends and family we considered my options. I decided to make the jump.

View Our Recent Stem Cell Transplant Webinar 

Some people cannot find a good donor match – or they have physical problems that would make SCT pointless. But in my case, everything appeared promising. The team at the Cleveland Clinic put me through tests that showed I was relatively fit. They found multiple 10/10 unrelated donor matches for me. We received necessary insurance approvals. We received logistical support from our family, church family and friends for help throughout the process.

Finally everything was in place. I was giving up on the old airplane that was certainly failing and entrusting myself to the parachute for a safe descent and landing.

  1. I got my final approval to go ahead (negative COVID test. 2/16)
  2. I got the notification that the parachute was in hand (the donor cells had been collected and received by Cleveland Clinic. 2/17)
  3. I prepared myself with the equipment make the jump (my Hickman port was installed through my chest up to my heart. 2/18)
  4. I jumped out the door of the plane (I received chemotherapy to kill my defective bone marrow. from 2/19-2/22)
  5. I put on my parachute and pulled the ripcord (The donor cells were infused into my body. Day Zero – 2/24.

The free fall is not very much fun. The chemo continued to kill off my bone marrow and other fast-growing cells and I didn’t feel well. I had some nausea. I felt very tired. My mouth got sore to the point that I could barely swallow and needed to get most meds through my port. Eventually I needed transfusions of whole blood almost every day and platelets every other day.

And there is always the nagging question of whether or not that parachute would actually open! I was very happy when my fall turned around on day +14. That day my WBC finally went up from 0.050 to 0.090. And it continued to gradually climb so that by day +19 I was able to leave the hospital. At that point I had not needed a transfusion in three days, and they canceled my first outpatient transfusion day.

I am now at day +69 and I have not needed any transfusions for 7 weeks! I feel well. I’m able to exercise. I’m down to one Cleveland Clinic visit each week. Every week they tweak my meds – add one, change the dose of another. We keep watch for any sign of infection or of Graft versus Host Disease. (I’m happy to report there’s nothing much to report so far.)

I am doing well and I am very grateful. I am grateful to God who is the source of my life and my salvation. I am grateful to my beloved friends and family for their prayers and their constant encouragement. I am grateful to the all the people at Cleveland Clinic for their expertise and good care for me. And I am very grateful to the donor who provided me with my parachute – I don’t know him but I do know that he is 25 years old, lives somewhere in the USA and goes out of his way to help strangers!