Tag Archives: mpn

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!

 

Fedratinib and Ruxolitinib: Advice for Deciding Which Agent to Give and When

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The introduction of fedratinib (Inrebic) to the treatment landscape of myelofibrosis (MF) and the challenges that have arisen over deciding between administering fedratinib or ruxolitinib (Jakafi) means more community oncologists should consult specialists when treating these patients, said Andrew Kuykendall, MD.

Research shows that fedratinib and the earlier JAK inhibitor, ruxolitinib have similar efficacy in patients with MF. However, their toxicity profiles differ, and the potential for encephalopathy with fedratinib is an ongoing concern, resulting in a black box warning on the label. Now that the agent is FDA approved for the treatment of MF, oncologists are left with a decision of which JAK inhibitor to give to which patients and when to prescribe them.

How to continue using ruxolitinib now that fedratinib is available remains an unanswered question, said Kuykendall, assistant member, Moffitt Cancer Center; however, experts in treating myeloproliferative neoplasms (MPNs) can be a helpful resource for other oncologists.

Another resource for treatment decision-making is clinical data from the JAKARTA-2 trial, which studied fedratinib in patients with MF who were previously treated with ruxolitinib. Findings from a re-analysis of the study were presented at the 2019 ASCO Annual Meeting and showed that 46 of the 83 assessable patients achieved a spleen response (55%; 95% CI, 44%-66%), meeting the primary endpoint of the study.

The most common adverse events included diarrhea (n = 60), nausea (n = 54), vomiting (n = 40), constipation (n = 20), and others. Additionally, hematologic abnormalities including, grade 3/4 anemia (n = 96), thrombocytopenia (n = 68), and neutropenia (n = 23) were seen. Eighteen patients (19%) discontinued treatment due to adverse events.

These data suggest that fedratinib may be a second-line option for patients who are resistant or sensitive to ruxolitinib. The management of the gastrointestinal (GI)-related toxicities and checking of thymine levels to prevent encephalopathy, however, are newer management concerns that physicians must be aware of when administering fedratinib to patients with MF and is another point when consulting an MPN specialist may come in handy.

Read Targeted Oncology’s interview with Dr. Kuykendall.

Examples of Approved VA Benefits for Vietnam Veterans

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The Department of Veterans Affairs has a search site to look up specific benefit claim cases.  Below are of few examples of MPN-related claims granted (on appeal).

To search the entire VA claims database click here. -for best results be sure to fill in specific illness and search all possible years.

Myelofibrosis

Citation 18101521-Read full report here

FINDINGS OF FACT –

1. An unappealed claim for service connection for myelomonocytic leukemia was denied by the RO in an October 2011 rating decision. The Veteran was notified of the rating decision, but did not appeal.

2. Evidence received since the last final October 2011 rating decision is new and material, and relates to an unestablished fact necessary to substantiate the claim for service connection for myelofibrosis.

3. The Veteran has a current diagnosis of myelofibrosis.

4. The Veteran is presumed to have been exposed to herbicide agents, to include Agent Orange, in service based on his service in the Republic of Vietnam during the Vietnam Era.

5. The medical evidence of record establishes that the Veteran’s myelofibrosis is related to presumed herbicide agent exposure during service.

CONCLUSION OF LAW -New and material evidence has been received to reopen service connection for myelomonocytic leukemia, now claimed as myelofibrosis. The criteria to establish service connection for myelofibrosis are met.

REASONS AND BASES FOR FINDING AND CONCLUSION-(View full report by clicking on citation number above)… This language was included in the Finding…

A letter dated August 2014 from T.A., MD notes that the doctor provided care for the Veteran beginning in 2005 after he was diagnosed with leukemia. Doctor T.A. stated that he reviewed the Veteran’s military records and considered his exposure in Vietnam to Agent Orange. Citing reports by the Institute of Medicine and the Myeloproliferative Neoplasm Research Foundation, Doctor T.A. stated that Agent Orange is a known causative agent of the type of leukemia with which the Veteran was diagnosed. Considering the Veteran’s diagnosis, military and medical records, and the absence of a family history of bone marrow disease, Doctor T.A. opined that it is more likely than not that the Veteran’s leukemia is a direct result of his exposure to Agent Orange during service. 

Citation=0309503-Read full report here

FINDING OF FACT –  There is competent evidence attributing the diagnosis of primary myelofibrosis to the veteran’s service.

CONCLUSION OF LAW –  Primary myelofibrosis was incurred in service.

REASONS AND BASES FOR FINDING AND CONCLUSION-  Although the Veterans Claims Assistance Act of 2000, Pub. L. No. 106-475, 114 Stat. 2096, is applicable to the veteran’s claim, the Board finds that it is unnecessary to address its applicability in this case in view of the disposition reached herein. The veteran’s service records show that his occupational specialty was that of an aircraft engine mechanic during his military career. In 2000, the veteran was diagnosed with primary myelofibrosis. The veteran asserts that he developed this disease due to Agent Orange exposure while in Vietnam.

Citation 0731552-Read full report here

FINDINGS OF FACT:

1. The veteran served on active duty in the Republic of Vietnam during the Vietnam era.

2. He currently has myeloproliferative disorder with myelofibrosis; this condition was initially diagnosed many years after service.

3. Medical evidence is in relative equipoise as to whether the veteran’s myeloproliferative disorder with myelofibrosis was caused by exposure to Agent Orange in service.

 

Background/Analysis:

The veteran has submitted evidence which suggests an association between myeloproliferative disorder with myelofibrosis and exposure to chemicals, such as benzene. He submitted articles which discuss the use of Agent Orange during the Vietnam War. The articles indicate that Agent Orange was a 50-50 mix of two chemicals and that the combined product was mixed with kerosene or diesel fuel and dispersed by aircraft. Other articles note that benzene is a volatile aromatic hydrocarbon which causes various types of leukemia, lymphoma and blood diseases, including myelofibrosis. The greatest risk was to workers who use various petroleum solvents containing benzene such as painters, gasoline distribution workers, refinery workers, chemical workers, rubber workers, printers, newspaper pressworkers and shoe and leather workers. The veteran submitted additional articles regarding herbicide exposure, benzene exposure, dioxins and the health risks associated with exposure to small amounts of chemical benzene.

CONCLUSION OF LAW -Resolving all reasonable doubt in favor of the veteran, myeloproliferative disorder with myelofibrosis was incurred as the result of exposure to Agent Orange in service.

 

Essential Thrombocythemia

Citation 19144431 -Read full report here

FINDINGS OF FACT

1. Resolving reasonable doubt in his favor, the Veteran was exposed to Agent Orange during active service.

2. The Veteran’s thrombocythemia is associated with in-service Agent Orange exposure.

3. The Veteran’s venous stasis ulceration of the bilateral lower extremities is proximately due to his service-connected thrombocythemia

…The Veteran submitted two letters from his treating physicians linking his thrombocythemia to his Agent Orange exposure. An October 2010 letter from the Veteran’s oncologist, Dr. D.B., indicated that the Veteran was diagnosed with thrombocythemia and has been under his care since June 2009. Dr. D.B. wrote that the Veteran was exposed to Dioxin while in Vietnam. He indicated that the Veteran’s diagnosis of essential thrombocytosis was as likely as not related to Dioxin (Agent Orange). A January 2011 letter from Dr. N.B., a hemotologist, indicated that the Veteran was also under her care. Dr. N.B. wrote that the Veteran was exposed to dioxin on different occasions while serving in Vietnam. At the time, she indicated that she was not aware of any studies linking dioxin to essential thrombocythemia but felt that the Veteran’s condition may be as likely as not related to his dioxin exposure.

CONCLUSION OF LAW – Essential thrombocythemia, a form of leukemia, was incurred in active service.

 

Polycythemia Vera

Citation 1414817- Read full report here

FINDINGS OF FACT

1. The Veteran served in the Republic of Vietnam during the Vietnam era, and therefore he is presumed to have been exposed to herbicides.

2. The most probative evidence of record demonstrates that the Veteran’s polycythemia vera is etiologically related to his in-service herbicide exposure.

CONCLUSION OF LAW The criteria for service connection for polycythemia vera are met.

Please see language below in this case the “nexus” is specifically explained as contributing to the decision to grant benefits.

“Concerning Shedden element (3), a nexus between the Veteran’s in-service herbicide exposure and his current polycythemia vera, the Board notes that there are positive nexus opinions of record. An October 2009 treatment record by Dr. Green, D.O., indicated that it was notable that the Veteran had served in Vietnam and that it was entirely possible that he had been exposed to chemicals during his tour of duty which may have contributed to his myeloproliferative disorder (polycythemia vera is categorized as a myeloproliferative disorder). Also of record are several letters from Dr. Webb, M.D., the Veteran’s primary care physician. In the most recent letter, dated August 2012, Dr. Webb noted that the Veteran was previously evaluated by a hematologist who believed that chemical exposure during the Veteran’s tour in Vietnam, specifically Agent Orange, had contributed to his current medical condition. Dr. Webb went on to reason that given the lack of other possible etiologies for his condition and the mounting evidence that Agent Orange has been implicated in other cases of polycythemia, the Veteran’s exposure would make the most sense for a cause and effect relationship. Dr. Webb opined that, based on his review of the Veteran’s records, he concurred that the Veteran’s Vietnam exposure was at least as likely as not to be contributory to his current medical condition. In the absence of any contrary nexus evidence, the Board finds the private physicians’ opinions to be the most probative evidence concerning the etiology of the Veteran’s polycythemia vera. Accordingly, the Board finds Shedden element (3) has been satisfied.”