Rami Komrokji, MD: Let’s talk about myelofibrosis [MF]. Of those diseases, this is probably the most symptomatic disease, with a high burden on patients and worse outcome in general. Jamile, can you walk us through myelofibrosis? How do we diagnose, differentiate, and approach it? How do you risk stratify those patients?

Jamile Shammo, MD, FACP, FASCP: Myelofibrosis is the MPN [myeloproliferative neoplasm] associated with the worst outcome. It’s so critical to identify it right away. The most challenging piece about myelofibrosis is getting the doctors to do a bone marrow biopsy, because the only way to make a diagnosis of myelofibrosis is by demonstrating that you have 2- or 3-plus reticulin fibrosis. That becomes more critical in patients who have prior PV [polycythemia vera] or ET [essential thrombocythemia].

Because the progression can be insidious unless you’re totally on top of it, it’s important to look at the whole leukoerythroblastic picture if you’re familiar with the diagnosis of post-ET or post-PV MF, the development of anemia, leukoerythroblastosis, new splenomegaly, etc. You look at the constitutional symptoms and whether your patient with PV isn’t requiring phlebotomy and developing anemia when they shouldn’t, then perhaps you do a bone marrow biopsy. In someone who may have thrombocytosis without an explanation, you’d need to do bone marrow biopsy to make that diagnosis.

Essentially, that’s what should be done to make this diagnosis. Then it’s important to obtain all additional genetic testing that’s included in the cytogenetics when the diagnosis is made. But there’s a problem with that, because sometimes those patients can be a dry tap and you might not be able to obtain genetic tests or genetics. I typically get them from the peripheral blood, but I’m curious to see what you do. Next-generation sequencing has become so important for risk stratification and to determine what to do in terms of stem cell transplant, which continues to be the only curative treatment for this subset of patients. Granted, assessment of symptoms is so important in this patient population. It should be done at baseline and as we move forward with various treatments we employ.

Rami Komrokji, MD: I agree. We now know more about the phenotypes of myelofibrosis: cytopenic vs proliferative. The patient presentation with myelofibrosis is either those who have cytopenia predominantly up front or proliferative with splenomegaly constitutional symptoms. I always like to point out that not every fibrosis you see in the bone marrow is myelofibrosis. That can be seen with diseases that mimic myelofibrosis, like myelodysplastic syndrome. I’ve had several cases where it was marginal zone lymphoma or hairy cell leukemia. Not every fibrosis in the bone marrow is myelofibrosis.

On the other hand, you don’t always need to see fibrosis to establish the diagnosis of myelofibrosis, because now we talk about this prefibrotic myelofibrosis entity, where the classical megakaryocytic clustering that we see in MPN is enough to make the diagnosis. They don’t have to have the +2, +3, but it’s key. A lot of those patients will have evidence of a clonal marker. Almost 90% will have either JAK2, MPL, or calreticulin. I always go extensively more than if they were triple negative to make sure we’re labeling this the right way. To your point, we do most of the next-generation sequencing on peripheral blood in those patients. The concordance is pretty good and high. As you mentioned, many times with the bone marrow, it’s a dry tap.

Transcript edited for clarity.

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By Andrea S. Blevins Primeau, PhD, MBA
Hematology Advisor

Vaccination for SARS-CoV-2 infection reduced the risk of COVID-19 mortality and hospitalization in patients with myeloproliferative neoplasms (MPNs), according to the results of a study that was presented at the EHA 2022 Hybrid Congress.

Prior to this study, there were “no robust data on characterizing the clinical outcomes of patients with MPN and COVID-19 in the United States,” the authors reported.

The single-center, retrospective, observational cohort study evaluated data from 388 patients with MPN and COVID-19 between April 2020 and December 2021. Of these patients, 53 had positive SARS-CoV-2 test results by RT-PCR.

“To date, this is the largest cohort of MPN patients with COVID-19 infection in the US, which accounts for 14% of the MPN patients in our center,” the authors reported.

The median age at baseline was 59 years, 51% of patients were men, and 46% had a body mass index (BMI) of 30 kg/m² or higher. The cohort comprised 55% of patients with myelofibrosis (MF), 28% with polycythemia vera (PV), and 17% with essential thrombocythemia (ET). The most common comorbidities were hypertension, present in 60% of patients, and diabetes, which was present in 19%.

Hospitalization was required for 47% of patients; of these patients, 68% required supplemental oxygen. Patients with MF had the highest rates of hospitalization, at 68%, compared with patients with PV or ET. The median length of stay was 8 days.

There were 49% of patients who had been vaccinated. Infection after the first dose of the vaccine occurred in 23% of patients.

Vaccination against SARS-CoV-2 was associated with better outcomes. Hospitalization rates were lower among patients who were immunized, at 28%, compared with 72% for patients who were not immunized.

Of the 9 patients who died, all but 1 were unvaccinated. The median overall survival of vaccinated patients was not reached, compared with 19.9 months among patients who were unvaccinated.

Overall, the case fatality rate of SARS-CoV-2 infection was 17%. The median overall survival was not reached during a median follow-up of 14.8 months.

The authors concluded that SARS-CoV-2 vaccination significantly decreases the risk of mortality and hospitalization in patients with MPN. In addition, they added that BMI 30 kg/m² or higher appears to be an important risk factor.

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Authors: Paulina Galka-Marciniak, Zuzanna Kanduła, Adrian Tire, Wladyslaw Wegorek, Kinga Gwozdz-Bak, Luiza Handschuh, Maciej Giefing, Krzysztof Lewandowski & Piotr Kozlowski

Abstract

Aaron T. Gerds, MD, MS, spoke with Healio about the REVEAL study, results of which were presented at this year’s European Hematology Association Congress.

REVEAL is the largest prospective, observational study of patients with polycythemia vera ever completed.

Researchers aimed to collect data on disease burden, clinical management and patient-reported outcomes of more than 2,500 adults with polycythemia vera.

The analysis presented at EHA showed elevated hematocrit levels, white blood cell counts and platelet counts influenced thromboembolism risk in this patient population.

In this video, Gerds — associate professor of medicine at Cleveland Clinic Taussig Cancer institute — provides an overview of the study findings and their potential implications.

“This represents a very ripe database that will most certainly pay off for years in the future as we go through several iterations of analysis,” Gerds told Healio.

Read more and watch the video

Reference:

Gerds AT, et al. Abstract P1062. Presented at: European Hematology Association Congress; June 9-12, 2022; Vienna.

Abstract

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The PAN Foundation today announced an expansion of its transportation fund, providing up to $500 per year to help eligible patients access affordable and reliable transportation to services and activities that improve their overall health outcomes.

PAN’s transportation program, which first launched in 2020, addresses socioeconomic barriers to medical care and medication adherence. A survey of PAN patients in 2021 showed that after receiving a transportation grant, medication adherence increased by 52 percent and adherence to physician visits increased by 29 percent.

Under the expanded program, patients will be able to use their grants to pay for transportation to access healthcare services, get social support, and even travel to the grocery store.

Expanding the program and covered services will better serve the holistic needs of each patient. Improving access to transportation removes barriers to medical care, reduces social isolation, and decreases risks for food insecurity, particularly for older adults and people living with serious illnesses.

“Since its inception, PAN’s transportation fund has led to better health outcomes for thousands of patients who needed help getting to their medical care,” said PAN President Kevin L. Hagan. “We know this expansion will help even more patients, who will now be able to use funding to better access social support and healthy food. We are grateful for the continued support of our generous donors, who enabled the expansion of this program that will reduce health barriers and improve lives.”

Patients who qualify are eligible to receive $500 per year in financial assistance in the form of a prepaid debit card, which is authorized for eligible expenses.

Eligibility requirements

To get financial assistance for transportation, patients must:

• Be currently enrolled in a co-pay or premium disease fund at the PAN Foundation and receiving treatment for that disease.
• Reside and receive treatment in the United States or U.S. territories. (U.S. citizenship is not a requirement.)

• Have health insurance that covers the qualifying medication or product.
• Have an income that falls at or below 500 percent of the federal poverty level.

How to apply

Patients or caregivers applying on their behalf can apply for assistance using the PAN Foundation’s online patient portal. A series of how-to guides are also available for the patient portal, including common tasks like creating an account and applying for assistance online.

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–          Navitoclax is being studied in myelofibrosis, a rare, difficult-to-treat blood cancer
–          Results are from an exploratory analysis of 34 myelofibrosis patients who received at least one dose of navitoclax in combination with ruxolitinib after suboptimal response or disease progression with ruxolitinib monotherapy
–          Median overall survival was not reached for patients who had a ≥ 1 grade improvement in bone marrow fibrosis or ≥ 20% variant  allele frequency reduction
–          At the time of analysis with > 2 year follow up the survival estimate was 100% in patients who had improvements in bone marrow fibrosis or variant allele frequency
–          Results were presented at the American Association for Cancer Research annual meeting

NORTH CHICAGO, Ill., April 12, 2022 /PRNewswire/ — AbbVie (NYSE: ABBV) today announced new data from a Phase 2 trial of navitoclax in combination with ruxolitinib in patients with myelofibrosis. The results were presented at the American Association for Cancer Research annual meeting (AACR 2022, abstract #LB108). Navitoclax is an investigational, first-in-class, oral BCL-X_L/BCL-2 inhibitor that is designed to activate programmed cell death (apoptosis) in cancer cells. Navitoclax and its safety and efficacy are under evaluation as part of ongoing Phase 2 and registrational Phase 3 studies.

“Myelofibrosis is a cancer that originates in the bone marrow, leading to fibrosis. Currently, available therapies do not address the underlying disease biology and have not shown a consistent effect on both biomarkers of disease modification and overall survival. Disease control with reversal of bone marrow fibrosis is a key objective for improving patient outcomes,” said Mohamed Zaki, M.D., Ph.D., vice president and global head of oncology clinical development at AbbVie. “That’s why we are especially pleased about these early results of navitoclax in combination with ruxolitinib that indicate its novel mechanism of action of inducing cell death may cause reversal of bone marrow fibrosis and extend survival for patients who respond to treatment.”

Myelofibrosis is a rare, difficult-to-treat blood cancer that results in excessive scar tissue formation (fibrosis) in the bone marrow. Anti-fibrosis activity, measured by reversal of bone marrow fibrosis (BMF) and reduction in driver gene variant allele frequency (VAF) have been suggested as potential biomarkers to measure disease modification in myelofibrosis, but their association with a survival benefit have not been widely described.¹ These data build on AbbVie’s history of transforming standards of care in blood cancers with significant unmet needs.

The results presented at AACR 2022 were from REFINE (NCT03222609) – a Phase 2 trial evaluating navitoclax in combination with ruxolitinib (a JAK1/2 inhibitor), which included patients with myelofibrosis who had progressed on or had a suboptimal response to at least 12 weeks of ruxolitinib monotherapy. Median exposure to prior ruxolitinib was 91 weeks (range: 19 weeks – 391 weeks) in the first 34 patients enrolled earlier in the trial.

In the exploratory analysis of 32 patients who were evaluable for improvements in BMF, 12 (38%) had a ≥1 grade improvement during any time point in the study. For driver gene VAF reduction, 26 patients were evaluable and 6 (23%) achieved a ≥20% reduction at week 24. Five patients achieved both BMF and VAF responses.

Median overall survival (OS) for all patients was not reached as presented previously by Harrison² et al. For patients who had a ≥1 grade improvement BMF median OS was not reached compared with 28.5 months for patients who did not experience an improvement. Similarly, median OS was also not reached for patients who achieved a ≥20% driver gene VAF reduction versus 28.5 months for patients who did not.

All 34 patients (100%) experienced at least one adverse event (AE), and 15 (44%) experienced a serious adverse event (SAE).² The most common AEs of any grade were thrombocytopenia  (n= 30, 88%), diarrhea (n= 24, 71%), fatigue (n= 21, 62%), and nausea (n= 13, 38%). The most common SAEs were pneumonia (n= 4, 12%) and splenic infarction (n= 2, 6%).² There were no SAEs of bleeding and thrombocytopenia was manageable and reversible with dose reduction/interruption of navitoclax and/or ruxolitinib.² REFINE was a dose-finding study and the target dose of navitoclax was reduced subsequent to these findings.

“Data obtained from this exploratory analysis holds promise for potential future clinical research,” said Jacqueline S. Garcia, M.D., Dana-Farber Cancer Institute, assistant professor of medicine at Harvard Medical School. “What is most notable in this analysis is the overall survival among patients who demonstrate VAF and BMF responses and all patients were alive at time of analysis. Patients in this Phase 2 trial had suboptimal response to ruxolitinib at time of study entry and then had navitoclax added to ruxolitinib on the trial. VAF and BMF responses occurred despite the presence of high molecular risk mutations, which suggests the potential efficacy of combination navitoclax and ruxolitinib could be independent of underlying risk factors.”

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Dr Jamile Shammo  is a Professor of Medicine and Pathology in the Department of Internal Medicine, Division of Hematology, Oncology and Cell Therapy, at Rush Medical College.

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

As a medical student ( a very very long time ago!)  , I was fascinated and intrigued by the complexity and highly specialized role of each component of  what makes our blood. I remember thinking, how can red cells shed their nucleus and continue to function? The more I learned about blood, the more interesting it got! Furthermore, The growing body of science surrounding the field of hematology has grown and continues to do so in an exponential manner which keeps me challenged and I find it very satisfying to my scientific curiosity and interests in general. Finally, I find the concepts in hematology to be more abstract and “less palpable” than in any other field.  It is for all those reasons that I collectively chose hematology as a field of study and practice. I have never looked back!

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

Being a clinician and a pathologist granted me a much deeper understanding of  MPN’s as a disease entity and helped sharpen my diagnostic skills. I have participated in trials and witnessed the emergence of various effective therapies that I could now offer my patients which is greatly satisfying. I know we need to do more, but seeing the science in that area explode with the discovery of multiple disease-associated mutations, and the plethora of available clinical trials aiming to improve the response rate and duration in this disease, I know that we are coming on better times for our patients. 

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

Know thyself! Identify an area of interest preferably early on in you academic career.  Identify a mentor who can support you through the process of establishing yourself as an investigator. Collaborate with your like-minded peers and never give up!

Dr. Linda Resar, is a Professor of Medicine at Johns Hopkins Medicine, where she studies molecular mechanisms leading to cancer, blood diseases, sickle cell anemia, hemophilia and other coagulopathies.

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

  I first became interested in hematology during my pediatrics training at Hopkins as our institution serves a large community of children and young adults with sickle cell anemia and many other blood diseases.  I found it rewarding to care for these patients who face many challenges and are in great need of excellent hematologic care.  I fell in love with hematology because blood is essential for every organ in the body to function, and physicians caring for these patients must consider the effects of blood diseases on the entire body, making hematology a challenging but particularly rewarding field.  Moreover, blood diseases such as MPN involve blood stem cells which are fascinating from a scientific perspective since these remarkable stem cells must generate 200 billion red cells each day for many decades.  The opportunity to modulate stem cell function to improve outcomes for our MPN patients is particularly exciting.

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

My laboratory focuses on a  gene, called HMGA1, which is important regulator for normal stem cell function and becomes abnormally activated in cancer.  We recently discovered that HMGA1 plays a critical role in blood stem cell function in MPN, particularly when patients progress to more advanced disease.  We are currently searching for approaches to modulate HMGA1 in blood stem cells as therapy to treat, or even better, to prevent, progression in MPN.

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

Please do not ever let anyone convince you that you are not suited for medicine, hematology, or research.  Unfortunately, women and others who are under-represented in medicine continue to confront unconscious bias, or even more blatant signals, that they do not belong since the field has been dominated by men.  However, it is clear that diversity in medicine, not only benefits our patients, but also scientific discovery.  Let any hurdles, failed experiments, and critiques serve to further ignite your passion for medicine, hematology, and research and work to foster the careers of other women in medicine, hematology, and MPN.