Higher stakes in systemic mastocytosis​

Karen Titus

June 2021—Mastocytosis is not for quitters.

Not at any point, from considering the possible diagnosis, to doing a complement of stains, to looking for mutations beyond KIT D816V, to being curious about the presence of mast cells even after making a diagnosis of another myeloid disease.

Patients have already learned this grueling lesson. They can easily spend years seeking answers before their disease is properly identified. Pathologists can speed up that process—and the time to do so is now, says Tracy George, MD, chief medical officer and incoming president of ARUP Laboratories, and medical director of hematopathology.

Notes Dr. George: “There’s some exciting stuff going on with systemic mastocytosis.” New targeted KIT inhibitors appear to be quite effective, including at least one agent for advanced systemic mastocytosis that has been submitted to the Food and Drug Administration. “We anticipate there’s going to be approval by the FDA this summer,” says Dr. George, who’s been involved in the clinical trials for avapritinib (Blueprint Medicines).

This could build on the success of midostaurin, a breakthrough multikinase inhibitor that has been highly successful in treating patients with advanced SM. The newer therapies appear to be successful in patients with indolent disease as well as those with advanced disease, with fewer side effects than earlier medications, says Dr. George, who is also professor, University of Utah School of Medicine.

“Before, the refrain was, This is a rare disease, and we can’t help you,” Dr. George says. “But now we have an oral drug [avapritinib].” Just as imatinib helped change the way physicians approach chronic myeloid leukemia, says Dr. George, targeted KIT inhibitors are helping to move the needle on mastocytosis. “Instead of being a deadly disease, or one with incredible, terrible symptoms, this is a disease that people can be treated for and live with.”

Eric Duncavage, MD, of Washington University in St. Louis, compares current progress in mast cell disease to what occurred with lung cancer, when targeted therapies spurred awareness and testing. “We have far more requests for ALK fusion detection now than in the past. Before there were targeted therapies for ALK fusions, there wasn’t a huge clinical demand,” says Dr. Duncavage, professor, Department of Pathology and Immunology, and director of the section of clinical cancer genomics, Division of Anatomic and Molecular Pathology. “Targeted therapies definitely drive interest in doing these molecular assays.”

All this assumes physicians are considering the disease to begin with. But with mastocytosis, that’s never been a given.

It’s easy to not think about mastocytosis, which is why many physicians typically don’t. The abundance of nonspecific symptoms—fatigue, allergies, skin rashes, autoimmune indicators—doesn’t necessarily arouse clinical suspicion. “It could be anything,” says Dr. George.

For some patients symptoms are more dramatic. Adult patients may present with anaphylaxis, says Jason Gotlib, MD, MS, professor of medicine (hematology), Stanford Cancer Institute, Stanford University School of Medicine, “which would be one of the more telltale signs of an underlying mast cell disorder,” often triggered by Hymenoptera stings. And unlike for children (who rarely have systemic disease and whose skin lesions almost always spontaneously remit during puberty), for adults who present with skin lesions, 80 to 90 percent will be shown on bone marrow examination to have systemic mastocytosis.

Apart from anaphylaxis and skin lesions, the symptoms can be so vague that Dr. Gotlib calls these mast cell diseases “the great mimickers.” Flushing, weight loss, diarrhea, brain fog, bone pain, and other mast cell mediator symptoms are fairly nonspecific, and therefore it is necessary to connect the dots to arrive at a diagnosis of mast cell disease.

With new treatments likely nearing, those thoughts might start showing up quicker. Publicity around new drugs has its place, say those who’ve often been frustrated by the desultory diagnostic pace. “Having FDA-approved drugs is so important,” says Celalettin Ustun, MD, professor of medicine and the Coleman Foundation chair of hematology/BMT and director of the section of BMT/cell therapy, Division of Hematology, Oncology and Cell Therapy, Rush University Medical Center, Chicago. He recalls seeing oncologist colleagues home in on SM much more often when midostaurin became available.

Such nudges are nothing to sneeze at. Dr. George says it can take patients seven years to receive the right diagnosis, in part because “symptoms are all over the place. Obviously most of those patients have the indolent form of the disease.” Those with more advanced forms will present sicker and receive health care sooner. “But it just shows these patients go through this odyssey of seeing all sorts of different doctors, depending on their symptoms.”

“It needs to be diagnosed earlier,” Dr. Ustun agrees, noting that the range of physicians who might see a patient with mast cell disease is wide: primarily oncologists and hematologists, but with other stops along the way, including GI, cardiologists, dermatologists, and endocrinologists, not to mention family and internal medicine physicians. “Patients keep seeing other doctors for years before someone thinks, Oh, you might have mastocytosis.” And that whole time, he says, patients are suffering.

Weighing the possibility should be merely the first in a long line of thoughts. Mastocytosis workups could easily benefit from a simple disclaimer at the outset: Much assembly required.

“If you don’t think about it, you won’t do the right testing,” Dr. Gotlib says. He gives the following example: In patients with systemic mastocytosis, the most frequently detected associated hematologic neoplasm is chronic myelomonocytic leukemia, or CMML. Knowing that, it makes sense to order tryptase or CD25 stains. “But sometimes that logical extension isn’t undertaken.” The hardest part isn’t doing these common tests, he says—it’s thinking to do them.

Dr. Duncavage agrees. It’s not unusual, he says, to receive cases where the oncologist or hematologist suspects mast cell disease. “So we’re already clued in that we’re heading down this path. And we’ll do all the requisite stains and testing.

“But it’s always hard to make a diagnosis when you’re not thinking of the diagnosis,” he continues. “That happens a lot with these hematologic disorders that occur with mast cell disease.”

Systemic mastocytosis is simultaneously uncommon and common enough, says Dr. Duncavage. “I think most pathologists are going to bump into it in their practice,” he says.

But what happens beyond that bump quickly grows complicated. Easier, perhaps, to pick the true heir to the throne in 15th-century Britain. Good luck sorting through all those Richards, Henrys, Margarets, and Elizabeths (not to mention a passel of Woodvilles). Do you follow York? Lancaster? Or turn to the Tudors?

What has raised the stakes at Washington University, Dr. Duncavage says, is the widespread use of sequencing-based panels. Next-generation sequencing has both created awareness that mastocytosis is a clonal process and brought it to clinical attention.

Five years ago, when clinical sequencing was relatively new and more expensive, “We didn’t do a lot of bone marrow sequencing for our patients,” he says. Today, “basically every new patient bone marrow biopsy we do now, we sequence,” which will from time to time turn up a KIT mutation. “We’ve picked up a couple of cases like that, where we weren’t totally expecting it.” In addition to such unexpected cases, NGS can point Dr. Duncavage and his colleagues to cases where mastocytosis co-occurs with another disease and where more follow-up is needed.

The uncommon-common motif ripples through gene sequencing as well. Physicians tend to associate KIT D816V with mastocytosis—not surprisingly, since it is the most common mutation, present in more than 90 to 95 percent of cases—but other, less common mutations can also occur. Ten years ago, says Dr. Duncavage, the search focused solely on KIT D816V, mostly because that’s what the technology allowed for. NGS can target a more diverse set of mutations, “and that allows us to diagnose more cases.”

The other big advance on the molecular side, he says, is that NGS can turn up mutations in other myeloid-associated disorders, such as TET2, ASXL1, and EZH2. “Most centers are now doing these sequencing panels, so we can start putting together the clues from some of these other gene mutations.”

Dr. George notes advanced systemic mastocytosis is similar to acute myeloid leukemia in that both are multimutated diseases. Patients with advanced SM have not only the KIT D816V mutation but often also other myeloid gene mutations. Certain ones—she cites the combination of SRSF2, ASXL1, and RUNX1, the so-called S/A/R panel—carry a worse prognosis and, not surprisingly, appear to respond less well to midostaurin. Responses to avapritinib have been shown in clinical trials regardless of S/A/R genotype.

For these patients, ddPCR for KIT would be insufficient. “You also need to do NGS on bone marrow,” Dr. George says.

NGS sensitivity is around five percent, she notes; droplet digital is 0.01 percent (“depending on who’s running it,” Dr. George says). “That’s why we recommend both,” she says. For patients with indolent disease and very little bone marrow involvement, NGS will miss the KIT mutation.

The latest NCCN guidelines, released in April, incorporate these updates. “The importance of pathology in this disease has been recognized, so they’ve added more pathologist authors to the NCCN guidelines for myeloproliferative neoplasms and mastocytosis,” says Dr. George, who along with Dr. Gotlib is one of the document’s coauthors.

NGS has become more accessible, but payers haven’t always kept pace. “It’s been kind of a roller coaster in terms of reimbursement and coverage,” Dr. Duncavage says. “It was good in the 2012–2014 era, and then it went way down. But I think payers have finally realized the value,” although he says large comprehensive panels seem to be less well covered. “So in-house, we’ve switched to a smaller, less expensive panel.” The coverage rate is high, he reports, matching that of IHC or any other pathology assay. “The coverage indications for smaller panels are pretty broad, so basically most symptomatic patients that you would consider a diagnosis of mast cell disease in would meet a covered indication.”

The key at his lab, he says, was to retool the lab’s molecular offerings around the more focused panels billed under the lower-value (CPT 81450) code. The larger comprehensive panels (billed under CPT 81455) are reimbursed at a higher rate and can identify more gene mutations, but payer coverage is challenging. “The thinking several years ago was that bigger is better, and you’d potentially miss something if you weren’t sequencing hundreds of genes. But for most myeloid malignancies, you don’t need a large comprehensive panel of 500 or 700 genes,” Dr. Duncavage says. “We just need a handful.” Larger panels might pick up a few edge cases, he acknowledges, but that occurs in only a tiny fraction of cases (in a disease that is already relatively rare). And if the mutation occurs in a gene bereft of clinical data, “then it’s hard to make informed clinical decisions.” While it’s good to think about mastocytosis, best not to overthink the molecular testing and jump to a larger panel out of the gate, he suggests. “For most patients, these smaller panels are the better way to go.”

Sensitivity of NGS has improved, but it still varies across platforms and labs. “We can definitely sequence with a much higher sensitivity now than we could a few years ago,” Dr. Duncavage says, adding that it’s possible to sequence for measurable residual disease, thanks to new error-corrected sequencing methods. While these are not quite to the level of ddPCR in terms of sensitivity, they offer the advantage of larger breadth. “But it is possible that you send out for a 40-gene panel to one lab, then realize it wasn’t sensitive enough,” he says. “And then you’d have to send out for a ddPCR or a higher-coverage panel.”

The need for assiduity persists past NGS.

Dr. Duncavage points to one specific diagnostic problem related to flow cytometry. Mast cells tend to aggregate in the marrow, in part because they are often surrounded by fibrosis. “So when you do an aspirate, they don’t like to come out. It’s challenging—they like to stick in the marrow, so we can’t always detect them by flow cytometry.”

Sequencing presents less of a challenge, but it can still be problematic, he says. “But from the blood,” Dr. Duncavage says, “doing digital droplet is a great way to detect very low-level involvement by mast cell disease,” though it remains, for the foreseeable future, more of a reference lab assay. His own lab sends out ddPCR as well as other, more esoteric testing that might be needed to make a diagnosis.

“If you see mast cells, and the patient meets some of the clinical criteria, know to send out for the flow and for the molecular. Those two things are probably the most critical,” Dr. Duncavage says. Keep digging, in other words. “The name of the game is to establish clonality.” That can either be flow cytometry, looking at CD2 or CD25 expression, or it could be molecular, looking for KIT or one of the associated mutations, for example, in genes that are part of the S/A/R panel.

It can be hard to follow up on early steps, Dr. Duncavage concedes. “You can imagine a situation where the report comes back, ‘KIT mutation is present’”—how do you follow up? Maybe mast cell disease wasn’t noticeable in the marrow, but there’s this low-level D816V mutation. How do you work it up? What other testing do you need to consider? “Those would be the perfect cases to send out and get experts’ advice,” he says.

That’s what Dr. George is trying to offer, not only at ARUP but beyond.

Dr. George has been a pioneering figure in systemic mastocytosis, developing a central pathology review as a new business model of sorts at ARUP, she says, “capitalizing on the notion that for really difficult types of diseases where pathology diagnoses are critical, it’s far better to have a single place or group of experts diagnosing them.”

Though the business tackles various types of disorders, hematological disorders are the focus, including mast cell disease. “It’s been really fun,” Dr. George says. “We’re finding that we can gain greater insight into the disease when it’s centralized and you have this rigorous review going on all at the same time.”

ARUP also recently launched a ddPCR test for the KIT D816V mutation. That doesn’t eliminate the need for bone marrows, but, as Dr. George puts it: “We’re trying to get the word out: Yes, patients may need a bone marrow for diagnosis. But like most rare diseases, most patients don’t have it,” she says. “So if the goal is to exclude the disease, far better to have a simple blood test than to have to get a bone marrow biopsy.”

In addition to training colleagues at ARUP, Dr. George has set her sights wider. She and others have formed the American Initiative in Mast Cell Diseases (http://www.aimcd.net), which held its second biennial meeting in late May. As part of this effort, the group has been soliciting applications from different sites to become Centers of Excellence or reference centers for mast cell disease. “There’s a real need for these patients,” says Dr. George. “They don’t know where to go. How do they get on these clinical trials? How do they get properly diagnosed?”

Even the non-ARUPs can up their game, however.

Dr. George sees more than her fair share of referrals, and she’s often startled by what she sees. The initial workup will note increased mast cells. “That’s a start. But that’s where it stops,” she says. “They don’t describe the shape of the mast cells.”

Moreover, Dr. George adds, initial reports will often neglect to note whether the mast cells are aggregating. Sometimes the initial workup will fail to cover proper stains to identify mast cells, or some but not all stains will be done to look for aberrant expression. “So the comment will then be, ‘This might be mast cell disease.’ And I’m thinking, Argh, this is so unhelpful!”

To subclassify the disease requires a bone marrow. But that’s often the least of Dr. George’s concerns. “Often what I see is an incomplete diagnosis,” she says. “It’s not just hematopathologists who need to be aware of this, but surgical pathologists and dermatopathologists as well.” Not only do they need to understand how to diagnose the disease, but also to know what the disease looks like in those being treated with a targeted therapy, she says.