CHAPTER 1

Myeloid diseases, including Primary Myelofibrosis, are connected at their roots — LIKE DIFFERENT TYPES OF MUSIC.

Michael Savona, MD on stage at the Ryman Auditorium in Nashville, TN.

Michael Savona, MD

Head of Hematology, Cellular Therapy, and Stem Cell Transplant, Vanderbilt University

While Nashville’s roots are fixed in country music, concert-goers flock to Music City for more than the Grand Ole Opry. Walk along Broadway, through Printer’s Alley, or around the SoBro studios and bars, and music of all genres swaggers through the air. The manic strings of bluegrass curl into the folk timbre of a singer-songwriter, while heavy metal guitars melt into the moods of lo-fi hip hop. As these varied musical styles emanate from venue to venue, one thing they all share is the source of their sound: all this music comes from the same 12 notes. Myeloid diseases follow a similar pattern, says Michael Savona, director of Hematologic Malignancies Research and Early Therapy Program at Vanderbilt University Medical Center in downtown Nashville. They’re all variations on a theme. “We’ve found there are a lot more connections between different myeloid diseases and the stories we hear from patients and the clinical aspects that inform our science,” says Dr Savona.

90% of the mutations occur in the same 50 genes.

Michael Savona, MD at the Ryman Auditorium (above). Poster for Emmylou Harris made by Hatch Show Print, displayed at the Ryman Auditorium (left).

In myeloid disease, 90% of the mutations occur in the same 50 genes, says Dr Savona. This contrasts with cancers like colon, lung, or melanoma that have mutations within 200 to 300 different genes. For Dr Savona, classification to some degree just comes down to naming, and he’s more interested in the rhythm of the disease than its label.
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“Sometimes, patients are referred for, say, primary myelofibrosis, but I introduce myself to patients as a doctor who takes care of chronic myeloid disease. Rather than classify their disease, I try to learn more about the phenotypic and genotypic features. To me, it’s less important what I call it than what’s happening mechanistically.” Dr Savona says research in these dynamic shifts in genotype, driving changes in the clinical phenotypic, are pushing the field forward.

Nashville is more than just country music. Like MF is more than MF. Like most myeloid diseases, It is driven by clonal hematopoiesis and chronic inflammation.

CHAPTER 2

DR SAVONA AND TEAM DISCOVER HOW DIFFERENT MUTATIONS UPSET HEMATOPOIESIS

Staff members and students of the Savona Lab.

The Savona Lab

Dr Savona’s lab at Vanderbilt focuses on the study of clonal hematopoiesis to accelerate treatments for myeloid diseases, like MF.

Just two decades ago, customized therapy for patients with myelofibrosis seemed like science fiction, says Dr Savona. But gains in research and technology, as well as the canonical discovery of the JAK mutation, have pulled back the curtain on a new set of discoveries in precision medicine. This milieu is where Dr Savona and his team dedicate their work—sifting through the stacks of various genetic code, searching for different mutations and their frequency in the bloodstream, and identifying which subtle signs are most important in contributing to the patients’ condition.

Mutations in myelofibrosis can change as often as acts on open mic night.

Alex Silver, MD/PhD student working under Dr Savona (left).

The lab team is working to answer fundamental questions about the biology of myeloid disease, how hematopoietic cells evolve under different pressures, which biomarkers are critical to pathogenesis and disease progression, and how all this information translates from bench to bedside.
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“We’re getting better at understanding an individual patient’s prognosis, and how their trajectory is going to look, much of which comes from recognizing specific mutations and other ways in which their cells are unique,” says Alex Silver, an MD/PhD student working under Dr Savona’s tutelage at the Savona Lab at Vanderbilt. “We are now entering into an age of genetic medicine, where we’ll be able to target specific genetic changes that are harming the patient to try to mitigate those deleterious effects.”

Some key genetic players have already been identified.

The ASXL1 mutation in myelofibrosis signifies a higher risk of transformation to acute leukemia. When Dr Savona sees this on the results of a patient’s next generation sequencing (NGS) panel, he says he might speak more to the benefits of pursuing a stem cell transplant with his patient because the benefits might outweigh the risks in this setting.
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Other genetic players in MF include splicing mutations (SRSF2, U2AF1, SF3B1, and ZRSR2), which are present in ~50% of MF patients and are associated with cytopenias. When these appear, says Dr Savona, he may be less worried about acute leukemia and more focused on the likelihood of transfusion dependence and how that informs treatment selection.
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Activating mutations have also been explored. Well named, these mutations make myelofibrosis more active—hematopoietic cells become more apt to acquire new mutations and spin into more proliferative disease. Also in the mix, of course, are driver mutations, such as the familiar JAK2V617F, as well as epigenetic mutations, like ASXL1 mentioned above. In other words, mutations in myelofibrosis can change as much as acts on open mic night.

Donovan, a research assistant working in the Savona Lab (above).

Dr Savona’s CHIVE project brings together biologists, geneticists, and AI data scientists.

At Vanderbilt, Dr Savona and team have access to a biobank of samples and anonymized medical health records from patient volunteers. With these materials, Dr Savona’s lab assesses patients’ DNA to see how their phenotypes match their genotypes. What makes Vanderbilt’s database unique is they have been collecting DNA for a couple of decades, says Dr Savona. “In some cases, we have DNA that is 20 years old, and if we’re lucky, we have that same patient’s DNA from 10 years ago, 5 years ago, and 2 years ago, and we can see changes in their blood.”
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In 2020, Dr Savona started another collaborative project known as CHIVE (Clonal Hematopoiesis and Inflammation in the VasculaturE). Through CHIVE, experts across disciplines at Vanderbilt, including molecular biology, genetics, and data science, work together to better understand age-related clonal hematopoiesis and its contribution to myeloid disease. “What we are doing at CHIVE is prospectively studying specific genetic changes over time and trying to pinpoint which ones are the most risky,” says Dr Savona.

This is important because clonal hematopoiesis, an age-related phenomenon, does not guarantee evolution to myeloid disease, he says. “The key is understanding why 10% of 70-year-olds have clonal hematopoiesis, but not all 10% get MDS or myelofibrosis. How does it go from point A to point B? That’s the challenge.” Dr Savona adds, “We are starting to formulate some ideas about that.”
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In addition, Dr Savona’s research is helping to elucidate the molecular epidemiology of myeloid disease, how often different genes appear, and how they function and interact with each other. “That’s a whole new ball of wax,” says Dr Savona. “I think the generation after me is going to be dealing with patients and molecular biology and a manipulation of genetic abnormalities in a way that we can barely fathom right now.”

CHAPTER 3

Myelofibrosis never stands still. Which means, as doctors and researchers, we can’t either.

Dr Savona (left), and Cindy, a patient with myelofibrosis (right)

If the disease state starts to change. It’s evolving genetically. And that’s a trigger.

Like the evolution of music, science is an incremental business, says Dr Savona. “While we want our work to be meaningful, it doesn’t have to necessarily be a big breakthrough,” he says. “But it does need to contribute to moving the science forward and, ultimately, that next thing for patients.”
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What’s hot in myelofibrosis right now is knowing what to do when a patient’s disease trajectory pivots, says Dr Savona. A pivot might look like a drop in blood counts, a growing spleen, a reprise of night sweats, or more marrow fibrosis or failure. If the disease state starts to change, it’s likely evolving genetically, and that’s a trigger, warns Dr Savona.

What this means for community hematologist-oncologists is ordering another NGS panel and consulting with an MPN specialist. This should happen more often for patients with more progressive disease. “NGS is part of standard of care now,” says Dr Savona. But reading and reading and interpreting the panels can be tricky because each disease has its own genetic hidden tracks. “I don’t fault a community oncologist for not wanting to overturn a stone and then have to deal with results that may be difficult to interpret.”
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That’s why the most ideal route for community hematologist-oncologists working with patients who have myelofibrosis is to get NGS panels interpreted by a subspecialist at a major medical center, says Dr Savona. “Especially in these rare diseases, a subspecialist can provide an initial consult and see a patient at a given interval to set the patient off in the right direction and support the community oncologist. And if there’s a pivot and a new mutation, they might suggest a change in therapeutic approach.”

Cindy compares managing symptoms in MF to a mixing board in a music studio.

Changing therapy in myelofibrosis is “a whole new world,” says Dr Savona. What was once driven by a one-hit-wonder in myelofibrosis has now expanded. “There were two JAK inhibitors, now there are three, soon to be four,” says Dr Savona of the available treatments for MF. “This really changes how we treat this disease.”
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When it comes to precision medicine across all myeloid disease, experts like Dr Savona are making steady strides in moving the clinical perspective from the upper deck to the front row. They are learning how hematopoietic clones evolve over time and how to parse out their importance. The good news is the treatments on offer are becoming as diverse as the talent on stage at the historic Ryman Theater in Nashville. And nothing is better than giving the audience what it wants.

References:

1. Franco Castillo Tokumori, Chetasi Talati, Najla E. Al Ali, David A. Sallman, Seongseok Yun, Kendra L. Sweet, Eric Padron, Jeffrey E. Lancet, Rami Komrokji, Andrew T. Kuykendall; Characteristics of Different Splicing Factor Mutation Hotspots in Myelofibrosis. Blood 2020; 136 (Supplement 1): 37. doi: https://doi.org/10.1182/blood-2020-140145

Myeloid diseases, including Primary Myelofibrosis, are connected at their roots — LIKE DIFFERENT TYPES OF MUSIC.

Michael Savona, MD

90% of the mutations occur in the same 50 genes.

Nashville is more than just country music. Like MF is more than MF. Like most myeloid diseases, It is driven by clonal hematopoiesis and chronic inflammation.

DR SAVONA AND TEAM DISCOVER HOW DIFFERENT MUTATIONS UPSET HEMATOPOIESIS

The Savona Lab

Mutations in myelofibrosis can change as often as acts on open mic night.

Some key genetic players have already been identified.

Myelofibrosis never stands still. Which means, as doctors and researchers, we can’t either.

If the disease state starts to change. It’s evolving genetically. And that’s a trigger.

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Myeloid diseases, including Primary Myelofibrosis, are connected at their roots — LIKE DIFFERENT TYPES OF MUSIC.

Michael Savona, MD

90% of the mutations occur in the same 50 genes.

Nashville is more than just country music. Like MF is more than MF. Like most myeloid diseases, It is driven by clonal hematopoiesis and chronic inflammation.

DR SAVONA AND TEAM DISCOVER HOW DIFFERENT MUTATIONS UPSET HEMATOPOIESIS

The Savona Lab

Mutations in myelofibrosis can change as often as acts on open mic night.

Some key genetic players have already been identified.

Myelofibrosis never stands still. Which means, as doctors and researchers, we can’t either.

If the disease state starts to change. It’s evolving genetically. And that’s a trigger.

More Like This

More Like This