Advances in the Polycythemia Vera Paradigm Signal Hope for Providers in Pennsylvania Cluster Area

LUZERNE COUNTY, PENN. – Above-average rates of polycythemia vera (PV) have been reported for over a decade due to causes unknown to experts. Intriguing new developments in the ongoing research of the genetic, toxicological, and environmental factors related to these cases have created reason to believe that this issue is not a thing of the past.

The report of an abnormal number of PV diagnoses by a community physician in Hazelton, Pennsylvania drew the attention of the Pennsylvania Department of Public Health leading to what now marks 15 years of research.

Ronald Hoffman, MD, the Albert A. and Vera G. List professor of Medicine, professor of Medicine (Hematology and Medical Oncology), and director of the Myeloproliferative Disorders Research Program at the Icahn School of Medicine at Mount Sinai in New York, was a participant in the study that confirmed that high cases of PV in the area as a cancer cluster, Hoffman stated in an interview with Targeted Oncology™.

Hoffman became involved in the research through a professional connection with Vince Seaman who was then an epidemiologist and the principal investigator within the United States Center for Disease Control and Prevention (CDC).

“Vince’s team had been contacted by the Pennsylvania Department of Public Health about this potential cluster of patients with polycythemia vera that had been identified as occurring in these 3 counties: Luzerne, Carbon, and Schuylkill,” Hoffman stated.

The study ultimately identified patients with PV who were entered into a cancer registry between 2001 and 2005 and unregistered persons living within the cluster area. It was what these investigators found in the molecular tests that led to ongoing research into this public health issue.¹

Molecular Testing and Misdiagnosis

Hoffman explained that “the CDC looked at the cancer registries, and there was a fantastic medical oncologist who practiced in in Hazleton, his name was Paul Rhoda, who unfortunately passed away. He had become part of the Geisinger Health System. And in addition to those cases that were from cancer registries, they essentially also had a number from the community who had this diagnosis. So, they were able to approve about 97 individuals from this tri-county area.”

Of the 97 identified individuals who were previously diagnosed with PV, but 13 were deceased, 16 declined to participate, 30 could not be found, and 10 did not meet the criteria for the analysis. The remaining 36 patients from the registry along with 24 non registry participants were evaluated. The population assessed had a median age of 65 ± 13 years, 60% of them were male and the majority identified as White.¹

“There was a Tamaqua, Pennsylvania cluster area which was called area T, and area T was identified as a statistically significant cluster area in the geographic center of these 3 counties with Hazleton and Tamaqua to the north and south borders, respectively,” Hoffman shared.

Blood samples were available for evaluation from 52 patients previously diagnosed with PV. Utilizing a JAK2 617V>F assay, the marker was verified in only 53% of the tested population, hinting that molecular testing in the community setting was not in line with standard molecular testing practices during the time.

Advances in Molecular Testing Paint a New Picture

Since the first study of the PV cluster, 2 more studies conducted by the Agency for Toxic Substances and Disease Registry in Pennsylvania have looked at the rate of PV in tri-county cluster area and nearby areas to investigate diagnosis patterns in the community setting.

The first study revealed issues in how physicians diagnose myeloproliferative neoplasms (MPNs) and how they are entered into tumor registries², confirming the disease on only 44% of cases. The second study had a similar result, showing a 47% positive predictive value that the patients had PV.³

Looking at these studies in retrospect, they collectively show where molecular diagnostics were just 7 years ago, compared with today.

“Our ability to diagnose this disease has really been totally transformed by the use of molecular diagnostics,” Hoffman stated.

James Rossetti, DO, a medical oncologist and hematologist at UPMC Hillman Cancer Center, explained to Targeted Oncology™ in an interview, that molecular testing has made great strides since the first identification of the tri-county PV cluster.

“Molecular testing not only goes a long way, in identifying the disease more accurately but also is very important as it relates to risk stratification models that helped to guide therapy for a given patient on an individual level, Rossetti said. “Prior to the identification of the JAK2 mutation, and its various subtypes, patients, oftentimes, were essentially thought to have the disease, but oftentimes, there was no definitive diagnosis made. That was very frustrating for patients, especially those who have these symptoms that can crossover with a variety of other illnesses. It slowed down the identification of the disease and the proper treatment thereof. So, molecular modeling whether it be by PCR, next-generation sequencing becomes one of the most vital tools that we have in diagnosing these patients accurately, and risk stratifying their disease as it relates to the risk of transformation to more concerning blood cancers.”

In understanding the molecular makeup of a patient’s disease, patients in the cluster area today have a sleuth of options that weren’t available for the first patients diagnosed.

A Place for Targeted Therapy in the Crisis

Rossetti noted “the advent of JAK inhibitors was crucial for these patients as it relates to symptom management, reduction in risk of thrombosis, improving spleen sizes, and a variety and substantial improvement in a variety of other disease-related symptoms. There are also multiple agents between those that are available and those that are in clinical trials, and some awaiting approval.”

A few years after the PV cluster was identified in Pennsylvania’s Luzerne, Carbon, and Schuylkill counties, the JAK inhibitor ruxolitinib (Jakafi), was granted FDA approval for the treatment of PV. It was the first drug approved to treat the disease based on results from the RESPONSE trial (NCT01243944), which included 222 patients with PV who were randomized 1:1 to receive either ruxolitinib or standard therapy. During that time, standard therapy was managing hematocrit values of less than 45% through low-dose aspirin and cytoreductive therapy in patients with a high risk of thrombosis.⁴

The RESPONSE population was made up of patients who had been diagnosed with PV for 8 years or longer (range, 0.5-36 years), and 955 of the population had a JAK2 V617F mutation. The median age of the population was 61 years (range, 33-90), with the majority being younger than 65 years of age. The cohort was also 66% male, and these patients had a median spleen volume of 1272cm³ (range, 254 cm³-5147 cm³) at baseline. The median palpable spleen length at baseline in the RESPONSE population was 7 cm.

At week 32, responses were observed in 215 of the ruxolitinib population compared with less than 1% of the best available therapy (BAT) arm. Responses appeared durable at week 48 in 19% of the ruxolitinib compared with less than 1% of the BAT arm.

Notably, 24% of patients in the ruxolitinib arm achieved a complete hematologic remission at wees 32 compared with only 9% of the BAT arm. Sixty percent of the ruxolitinib also achieved hematocrit control at the 32-week mark versus only 20% of the control arm. Finally, spleen volume reduction was observed in 38% of the ruxolitinib arm compared with less than 1% of the BAT arm.

The most common nonhematologic treatment-emergent adverse events (TEAEs) observed up to week 32 in the RESPONSE trial were headaches, abdominal pain, and diarrhea. Based on pooled data of clinical trials involving ruxolitinib, oncologists are told to watch for thrombocytopenia, anemia neutropenia, risk of infection, symptom exacerbation after ruxolitinib discontinuation, and the development of nonmelanoma skin cancer.

Ruxolitinib is just one FDA-approved drug of many that are in the pipeline.

“There is a variety out there that can really help patients again, be treated on an individual basis. Treatment can be decided based on comorbidity, or their blood counts. One agent might be better for 1 patient for 1 particular patient than another,” Rosetti explained. “These drugs may also have some impact on the natural history of the disease. So, again, we previously looked primarily at phlebotomy and hydroxyurea, which improves blood counts, and reduces the risk of thrombosis and to some degree splenic improvement, but these strategies failed as it relates to altering the biology of the disease itself. As JAK inhibitors became available, things started to change.”

Other JAK inhibitors like pacritinib and mobocertinib are being explored as a treatment option for patients with post-PV myelofibrosis. New research is also looking at interferon agents for the treatment of PV.

“The interferons are our older agents, but they're being studied in new ways. As we have molecular data available to us and as we have better tools to look at the marrow more closely, to assess what's happening, what we're finding is that some of these agents including the interferons, ma be altering the natural progression of the disease. This is a tremendous gain in this field for patients with PV. Looking at different types of interferons, of course, is very exciting as well. Not only are some more effective and better tolerated, but even the frequency of treatment becomes much easier for the patient. There are a variety of these agents being studied,” Rosetti stated.

Most recently, a biologics license application was resubmitted to the FDA for the interferon agent, ropeginterferon alfa-2b-njft. The application is supported by findings from the phase 3 PROUD-PV/CONTINUATION-PV clinical trial (NCT01949805; NCT02218047).⁵

Roughly 306 patients were enrolled study, and 257 patients were randomly assigned to either the PROUD-PV cohort or the CONTINUATION-PV cohort. The 2 treatment arms explored in PROUD-PV were BAT by investigator choice and ropeginterferon alfa-2b. In CONTINUATION-PV patients received either hydroxyurea or ropeginterferon alfa-2b.⁶

Results from the study show that 21% of the patients in the ropeginterferon alfa-2b arm of PROUD-PV met the study end point of complete hematological response with normal spleen size, compared with only 28% of the patients on standard therapy met this end point. But, in CONTINUATION-PV, 53% of patients on ropeginterferon alfa-2b-njft met complete hematological response with improved disease burden markers, while only 38% of patients in the hydroxyurea group met this standard (P = 0.044).

Interferon treatment also appeared well-tolerated in the study subjects. The most common grade 3 and 4 treatment-related adverse events (TRAEs) were increased γ-glutamyl transferase (6%) and increased alanine aminotransferase (3%) in the ropeginterferon alfa-2b group. Leucopenia (5%) and thrombocytopenia (4%) were the most common TRAEs in the standard therapy group. Treatment-related serious AEs occurred in 2% of patients on ropeginterferon alfa-2b and 4% in the hydroxyurea group. Only 1 treatment related-death, acute leukemia, was reported in the hydroxyurea group.

Rossetti mentioned during the interview with Targeted Oncology™ that clinical trials are also exploring LSD inhibitors, HDAC inhibitors, and combination regimens for PV. This shows, according to Rossetti, that clinical trials are important for the future of disease management.

“Clinical trials: this is where we need to interface at the larger academic centers with the community oncologist. The community oncologists are finding the patients, and awareness has increased the number of patients we're seeing. This is because patients know not only do the physicians in the community recognize the disease and are more able to make the diagnosis of PV more accurately, but they now know that there are things that can be done outside of phlebotomy and hydroxyurea. So, they can get the patients here for clinical trials.”

As more people in the Pennsylvania cluster area are diagnosed, there are now multiple clinical trials that community oncologists can refer their patients to. Research from this year shows environmental factors that may contribute to more diagnoses of PV in the affected area.

Pinpointing the Environmental Impact of the PV Cluster

With such a rare form of cancer found in a significant number in the area T study, investigators believed that environmental factors may have played a role in the PV cluster. Hoffman stated that “the total number of confirmed cases that is both with clinical and molecular characteristics of PV showed a probability of this being a random event was less than 1 in 2000. We thought it was due to some sort of environmental toxin that was present in that area, because of the concerns about the contamination from the coal industry, and the dumping of wastes in many of these abandoned coal sites.”

In February 2021, investigators identified 18 chemical contaminants that may be harmful to individuals in the tri-county cluster area. The scientists investigated how likely each toxin was to cause DNA damage.⁷

According to the researchers led by EA Irvin-Barnwell of the CDC’s ATSDR division, “most of the toxins evaluated using the comet assay showed potential to induce DNA damage in hematopoietic cells, and the genotoxic effects were dose-dependent.”

The chemicals found in the cluster area include arsenic trioxide, benzo(a)pyrene, potassium chloride, ethylbenzene, benzo[k]fluoranthene, styrene, cadmium chloride, hydroquinone, 1-1,1-trichloroethane, TCDD, TCE, methylene chloride, sodium cyanide, and manganese chloride. The scientists also noted that some of the toxins, namely benzene, cadmium chloride, chromium oxide, potassium chloride, lead oxide, and sodium cyanide lead to increased cell death and 100% of the cells had DNA damage after exposure to the toxins.

It was also noted in the paper that historical levels of these toxins in the cluster area would have been higher. Still, Hoffman expresses that despite the release of this information so long after the cluster began, it is important to understand the environmental factors that may have impacted patients in the area.

“I feel good about this research. There was a lot of doubt that this PV cluster was just by happenstance. A lot of uncertainty and a lot of resentment for people within the community was created from the lack of environmental knowledge. Patients’ family members were being affected by the disease and an inordinate number of cases were being observed, and as government administrations changed, the CDC straddled the fence between denial and interest. It's very reassuring to me that they researched this over time.”

_References:

_{1. Seaman V, Jumaan A, Yanni E, et al. Use of molecular testing to identify a cluster of patients with polycythemia vera in Eastern Pennsylvania. Cancer Epidemiol Biomarkers Prev. 2009;18(2):534-40. doi: 10.1158/1055-9965.EPI-08-0922.}

_{2. Roda P, Ferrari A, Tang X, et al. Determination of accuracy of polycythemia vera diagnoses. Ann Hematol. 2014;93: 1467–1472. doi: 10.1007/s00277-014-2068-2}

_{3. Buchanich JM, Mertz KJ, Washington TL, et al. Updated and expanded study of polycythemia vera and other myeloproliferative neoplasms in the tri-county area. J Registry Manag. 2014;41(4):175-81. doi: https://bit.ly/3xwGwXH}

_{4. Reader LA. Jakafi (Ruxolitinib): First FDA-approved medication for the treatment of patients with polycythemia vera. Am Health Drug Benefits. 2015; 8(Spec Feature):75-79.}

_{5. Pharmaessentia Resubmits Application to the US FDA for Ropeginterferon alfa-2b-njft to Treat Polycythemia Vera (PV). News release. PharmaEssentia Corporation. May 14, 2021. Accessed August 10, 2021. https://bit.ly/2SkrTI8}

_{6. Gisslinger H, Klade C, Georgiev P, et al. Ropeginterferon alfa-2b versus standard therapy for polycythaemia vera (PROUD-PV and CONTINUATION-PV): a randomised, non-inferiority, phase 3 trial and its extension study. Lancet Haematol. 2020;7(3):e196-e208. doi: 10.1016/S2352-3026(19)30236-4}

_{7. Irvin-Barnwell EA, Benson KM, Lu M et al. Environmental toxins found historically in the polycythemia vera cluster area and their potential for inducing DNA damage. J Environ Anal Toxicol. 2021; 8(1): 10.4172/2161-0525.1000551. doi: 10.4172/2161-0525.1000551}