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Intro
Looking Deeper Into Myelofibrosis
The urgent need for answers in cytopenic MF
Introduction
his paradigm shift started about 10 years ago, when the first JAK1/2 inhibitor was in phase 3 studies. Since then, physicians have relied on this drug class to help many patients, says Dr Mascarenhas. But more needs to be done.
“We don’t see bone marrow fibrosis resolution; we don’t see molecular responses. There are still patients with low platelets and transfusion dependence who are not being served optimally.”
These cases—patients with cytopenias who are challenged by the myelosuppressive nature of current management options—are what motivate Dr Mascarenhas and his research. He and others have devoted their efforts to address this disparity in MF management.
Chapter 1
Peeling back the layers
of a heterogeneous disease
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Chapter 1
Peeling back the layers
of a heterogeneous disease
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Chapter 1
ematologists intrinsically know there are differences in biology and clinical presentation among patients with MF, says Dr Mascarenhas.
– John Mascarenhas, MD
For the better part of the last two decades, Dr Mascarenhas has interrogated the heterogeneity of MF and the inherent differences in pathophysiology between the two types—primary MF (PMF) and secondary MF (SMF). He and other researchers suggest that biological differences between the two may explain why patients respond differently to current management options.
One of the key biological distinctions between PMF and SMF is antecedent disease—SMF is associated with presence of polycythemia vera or essential thrombocythemia while PMF is de novo.
Emerging data show two critical variations between the two phenotypes are mutation profile and the frequency of JAK2V617F allele burden. PMF has a lower JAK2V617F allele burden but more somatic mutations; whereas SMF has a high JAK2V617F allele burden and is associated with just the single mutation.
In the clinic, patients with PMF are more likely to have low blood counts, be transfusion dependent, and have more aggressive disease, while those with SMF are more likely to have myeloproliferation and smoldering disease. Prevalence is different, too.
PMF represents 70% of all MF cases compared with SMF at about 30%.
“Of course, all of these factors appear on a spectrum. Not every patient fits perfectly into one or the other, but generally speaking, there does seem to be this dichotomy between primary and secondary MF,” says Dr Mascarenhas.
Unfortunately for patients with MF, physicians have not had a reason to discriminate between the two phenotypes. “Disease management has been pretty uniform for the past decade,” Dr Mascarenhas explains, adding that current options can exacerbate cytopenias, forcing dose reductions and limiting clinical benefit. “There's really an unmet need among patients with cytopenias, namely, to improve their low blood counts.”
Patient Story | Part 1
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Chapter 2
Mutations & pathways
suggest different biologies
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Chapter 2
Mutations & pathways
suggest different biologies
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Chapter 2
hen Dr Mascarenhas first started studying MF, little was known about mutations. That changed in 2005, he says, when the JAK2 mutation was discovered. “That revolutionized the way we look at MF and how we classify patients based on the presence or absence of the mutation.” Soon thereafter, mutations on the MPL gene and then the CALR gene were discovered. With three mutations in play, that also meant some patients would be triple negative.
Along with driver mutations, researchers believe variations in allele burden and multiple inflammation-mediated pathways likely drive disease. The latest data show that lower JAK2V617F allele burden portends a worse prognosis and indicates there may be other pathways, outside JAK-STAT, involved in pathogenesis.
“The take-home message is there is not going to be one way to manage MF, especially given multiple mutations, variations in JAK2V617F allele frequencies, and multiple potential pathways,” explains Dr Mascarenhas. “Each is relevant in different ways to different subgroups of patients.”
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Chapter 3
Myelofibrosis
a challenging condition to diagnose
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Chapter 3
Myelofibrosis
a challenging condition to diagnose
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Chapter 3
s researchers accumulate more knowledge about mutations, allele burden, and pathways that contribute to the heterogeneity of MF, it is also critical to consider the myriad clinical presentations that can play a role in a delayed diagnosis or misdiagnosis, says Dr Mascarenhas.
Referring physicians and community hematologists may not be as familiar with MF because of the rarity of the disease. And given how many symptoms mimic other conditions (fatigue, early satiety, weight loss, and night sweats), patients with MF inevitably visit several specialists before a hematologist.
“It is not uncommon that I meet patients who have seen cardiologists or pulmonologists for issues related to shortness of breath,” says Dr Mascarenhas. “I've met patients through gastroenterologists because of bowel irregularity or left upper quadrant pain, which turned out to be splenomegaly. And a common phenomenon is seeing patients after innumerable neurologist consults for headaches or other neurologic symptoms.”
– John Mascarenhas, MD
“I’d like to get that referral earlier,” says Dr Mascarenhas, “to ensure patients get the care they need.”
By reclassifying and reorganizing the potential mechanistic differences between PMF and SMF, he believes the implications from his research will translate to quicker diagnoses in the clinic.
Patient Story | Part 3
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Chapter 4
Moving Beyond
to meet the diverse needs of patients with MF
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Chapter 4
Moving Beyond
to meet the diverse needs of patients with MF
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Chapter 4
eing able to manage patients with PMF is a huge unmet need, but what’s encouraging is that some of the infrastructure is in place to rethink the disease, says Dr Mascarenhas. For example, clinical guidelines already incorporate some of the factors that differentiate PMF from SMF.
“Tucked into the prognostic risk stratification are clinical variables, platelet counts, cytogenetics, and molecular barriers for PMF,” notes Dr Mascarenhas. “From early on, every prognostic tool included anemia and transfusion-dependent anemia as core prognostic markers.”
For Dr Mascarenhas, the story of MF having different biologies and different phenotypes has always been there—the community might just need to look at it differently or call it by a different name.
– John Mascarenhas, MD
While the current clinical focus of reducing spleens is important, researchers are taking a holistic view of MF and its many facets, with an eye to modifying the disease process and the disease course. “As we learn more about the biology, we can better understand the differences in MF heterogeneity—which pathways are more relevant in which areas and which should be targeted.”
Dr Mascarenhas anticipates that the research will bring to bear a shift in how hematologists manage patients with PMF—there will no longer be a one-size-fits-all approach.
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Chapter 5
What’s next for patients
with primary myelofibrosis
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Chapter 5
What's next for patients
with primary myelofibrosis
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Chapter 5
r. Mascarenhas has hope for the future. “What drives me to work every day is the fact that we're just on the cusp of taking MF management to the next level.” Soon, Dr Mascarenhas believes the whole concept of PMF—how it is managed and how it is worked-up—will change drastically; he also foresees dramatic shifts in referral patterns and the clinical approach to this segment of hematology.
“Collectively, I don't think any of us researchers are happy with where we are. We’re happy with where we've come from, but we're really looking to improve upon that.”
– John Mascarenhas, MD
