About 20% of patients with myelofibrosis initially have no symptoms, allowing many cases to exist under the clinical suspicion of primary care clinicians. The need to treat asymptomatic or minimally symptomatic disease has remained controversial in diagnosed disease. Even less consensus has existed about the need to treat pre-fibrotic myelofibrosis, which did not gain recognition as a distinct pathologic entity until 2016.
“It’s definitely an evolving paradigm,” said John Mascarenhas, MD, of the Icahn School of Medicine at Mount Sinai in New York City. “Historically, we would risk-stratify patients, and if they fell in the low-risk category, most people were observed, sort of anticipating progressive spleen symptoms as a reason to treat. But what you sometimes find is that there are low-risk patients who already have reason to treat. They have an enlarged spleen. They may even have some degree of symptom burden that’s worthy of intervening.”
“We don’t actually have prospective clinical trial data treating specifically low-risk patients. That was attempted years ago but never completed, so we can’t refer to prospective, randomized studies asking the question to treat or not to treat low-risk patients. I can say, anecdotally, there are definitely a subset of patients in this low-risk category that I think deserve, specifically, JAK [Janus kinase] inhibitor therapy, and there is some reason to believe that earlier intervention with a JAK inhibitor is more likely to have a more durable and potentially disease-modifying effect.”
An accumulation of evidence from a variety of sources has begun to nudge clinical opinion toward earlier intervention.
“Clinically early patients, who have relatively good blood counts, don’t have a very large spleen, and probably don’t have any blasts in the blood, I think a lot of the evidence is now mounting in favor of considering treatment,” said Prithviraj Bose, MD, of the University of Texas MD Anderson Cancer Center in Houston.
The same could — emphasis on could — also apply to patients with pre-fibrotic myelofibrosis.
“We’re not trying to say that every pre-fibrotic patient needs to start on treatment,” Bose told MedPage Today. “We’re saying that whether it’s pre-fibrotic or overt, forget the pathology for a moment and look at the patient. If the patient has some splenomegaly, some anemia, leukocytosis — in other words, clinical issues, and certainly if there are symptoms — then I think the field is going in favor of earlier initiation of ruxolitinib [Jakafi]. I say ruxolitinib only because that’s the best established drug and has the longest follow-up and most data.”
“If you wait, the spleen becomes bigger, the hemoglobin falls, the platelet count falls, and then you are in this sort of vicious cycle where you cannot give the dose of ruxolitinib that you would have liked to give, because it’s platelet count-dependent dosing. And then you compromise on efficacy,” he added.
Weighing the Evidence
Examples of the evidence pointing to potential benefits of earlier treatment include three studies reported from 2015-2018 — one each from England and Italy and one multinational — collectively showing a pattern of higher efficacy and lower toxicity in the setting of low-risk disease.
Earlier this year, Italian investigators reported a retrospective study of 1,055 patients who participated in a ruxolitinib expanded-access program outside of clinical trials. The cohort included 595 patients with low-risk myelofibrosis (intermediate-1 risk, as defined by Dynamic International Prognostic Scoring System or the prognostic model for secondary myelofibrosis, or MYSEC-PM). The results showed that low-risk patients had more frequent and durable responses to ruxolitinib with less toxicity as compared with intermediate/high-risk patients.
In an accompanying editorial, Bose and Pankit Vachhani, MD, of the University of Alabama at Birmingham, said the findings “add to a growing set of observations that suggest that ruxolitinib may be best used earlier in the disease course of MF [myelofibrosis]. That treatment of ‘early MF’ delivers higher efficacy and better durability is unsurprising, in line with the fundamental principle of the benefits of intervening early in oncology.”
Though most discussions about early intervention center on ruxolitinib, other emerging options could enter the discussion. Ropeginterferon alfa-2b (ropeg, Besremi) already has FDA approval for untreated or treated polycythemia vera (PV), a red-cell disorder that can evolve into secondary myelofibrosis.
Ropeg was evaluated in a phase II trial of Asian patients with pre-fibrotic or low/intermediate-risk myelofibrosis. Among 46 patients who had serial bone marrow biopsies, 42 had stable or improved fibrosis, including eight patients who had resolution bone marrow fibrosis after 48 weeks. A phase III trial is underway.
“Interferon is an interesting and rational approach in the early-MF disease state because we use it typically, and it is FDA approved for PV, which could be looked at as an early [myeloproliferative neoplasm],” said Mascarenhas. “It has potential to modify disease aspects and potentially, the course of those diseases. There is some early data that came out of Asia in early MF suggesting the ability to induce responses, both spleen and symptoms, and potentially disease modification.”
Since FDA approval of ruxolitinib in 2011, three other JAK inhibitors have emerged from FDA review with myelofibrosis indications: fedratinib (Inrebic) in 2019, pacritinib (Vonjo) in 2022, and momelotinib (Ojjaara) in 2023. The availability of multiple drugs in the same class creates a potential for sequencing. Though typically used after progression or intolerance with ruxolitinib, the three newer drugs could find a role in first-line therapy.
Diagnostic Challenges
Discussions about early intervention obviously cannot occur without early recognition (or suspicion) and diagnosis, which can pose a challenge, particularly in the primary care setting. Signs and symptoms often are vague and nonspecific: fatigue, weakness, shortness of breath, abdominal discomfort, and decreased appetite. Anemia is the hallmark finding that should prompt further investigation, despite being associated with a number of conditions.
“I think anemia is probably the biggest clue, for a primary care physician, in an early stage of MF,” said Bose. “I would expect symptoms and splenomegaly to come later. If a patient is complaining of itching and bone pain and night sweats, which are also fairly classic symptoms, that could certainly be a clue as well.”
“Now there is also a need to be aware that PV and ET [essential thrombocythemia] will have higher blood counts,” he added. “They will have high red cells, high white cells, high platelets. So, I would say that any sort of unexplained abnormality in blood count, whether it’s high or low, probably should cause some concern for a myeloproliferative neoplasm.”
Definitive diagnosis requires a bone marrow biopsy and molecular/genetic testing. The classic finding that is diagnostic for myelofibrosis is reticulin/collagen fibrosis with megakaryocytes and atypia. Pre-fibrotic myelofibrosis is characterized by hypercellularity, granulocyte proliferation, and megakaryocyte proliferation with atypia in the absence of fibrosis. Most patients with myelofibrosis or pre-fibrotic disease have driver mutations in JAK2, CALR, or MPL.
The differential diagnosis should distinguish between myelofibrosis, PV, and ET. Both PV and ET can transform into secondary myelofibrosis. The hallmark feature of ET is unexplained elevation in platelet count, and the major differentiating factors from myelofibrosis are the extent of hypercellularity and presence of fibrosis.
Primary findings diagnostic for PV are elevated red blood cells, arterial oxygen saturation ≥92%, and splenomegaly. Diagnosis also can occur with the first two primary factors in combination with at least two of the following: specific elevation cutoffs for platelets, white cells, leukocyte alkaline phosphatase, or serum vitamin B12 or B12 binding capacity.
Primary myelofibrosis is a more aggressive disease, although the overall approach to treatment does not differ between primary and secondary myelofibrosis. Investigators in clinical trials of myelofibrosis often stratify patients according to type (primary or secondary) to determine whether response to a specific treatment differs according to the classification, said Mascarenhas.
“Otherwise, I would say that we don’t really treat them differently,” he added.
Bose said the distinction can be important to patient management in some situations.
“As far as pharmacologic treatment is concerned, there is no difference between primary and secondary myelofibrosis,” he said. “But I would argue that there is still value to separating them out, because the prognosis is much better for secondary, when you try to prognosticate them using different scoring systems. Most importantly, the distinction is important when trying to decide whether they need a stem-cell transplant.”
Disclosures
Mascarenhas has disclosed relationships with Celgene, Jubilant, E.R. Squibb & Sons, PharmaEssentia, Karyopharm, Blue print, AbbVie, GlaxoSmithKline, Incyte, and CTI BioPharma.
Bose has disclosed relationships with Karyopharm, PharmaEssentia, AbbVie, Jubilant, Blueprint, MorphoSys, Sumitomo, CTI BioPharma, GSK, and Incyte.
Vachhani disclosed relationships with Abbvie, Amgen, Blueprint Medicines, Cogent Biosciences, Incyte, CTI BioPharma Corp (now Sobi), Genentech, GSK, Karyopharm, Merck, MorphoSys, Novartis, Pfizer, Stemline, and Takeda.
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Source link : https://www.medpagetoday.com/spotlight/myelofibrosis/112746
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Publish date : 2024-11-04 21:38:17
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