Unique Diagnostic Profile for BPDCN Warrants Focus on Hematopathology

Gary Schiller, MD

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a hematologic malignancy with poor outcomes, which can be challenging to diagnose due to its rarity and indistinct skin manifestations. In a recent virtual Case-Based Roundtable meeting that brought together oncologists in California, Gary J. Schiller, MD, professor of hematology/oncology and director of the hematological malignancies/stem cell transplantation unit at UCLA Health Jonsson Comprehensive Cancer Center, explained the challenges surrounding the diagnosis of BPDCN and the hope gained from the development CD123-targeted therapy by dramatically improving outcomes in a patient population with no prior approved treatments.

Targeted Oncology^TM: Can you describe the diagnostic evaluation approach for BPDCN?

Gary J. Schiller, MD: You could do a skin biopsy and make the diagnosis, but the best way to make the diagnosis is flow cytometry of the blasts from the bone marrow or peripheral blood , and they have a characteristic expression pattern that's very easy to remember…. They have CD123 which is present on the normal dendritic cells as well and sometimes present in acute myeloid leukemia [AML]. But there's this odd expression of CD4 and CD56.¹ It's easy to remember: CD123, 4, 56.

The question is, does your hematopathologist run a CD123 [test]? I'm sure they run CD4 and CD56, but they may not run CD123, so it's pretty important. For maybe 10 years, I've been going around and giving talks to pathologists to be sure to have CD123 in their panel. It's also useful for AML, because some cases of AML have expressed this, so it is not an obscure test, but it's not always run, and it depends on the skill of the hematopathologist. If you don't have a hematopathologist, I'm sure you refer to one of the commercial laboratories, because you probably don't send your bone marrow to a general pathologist. I do not typically do a leptomeningeal spinal fluid assessment immediately, but I do it during the induction, and as adjunct, we would do cytogenetics and molecular pathology. But the molecular pathology is not stereotypical. Patients have different mutational events and different cytogenetics. The diagnosis is made on this flow cytometric pattern of expression: CD123, CD4, CD56. CD123 is [expressed on] myeloid cells, CD4 on T cell, and CD56 on natural killer cells. [BPDCN] is none of the above. It's in the plasmacytoid dendritic cell.

Cutaneous lesions are helpful to make a diagnosis. I can remember a patient who did not have skin lesions, but the vast majority of patients have skin lesions that have not been diagnosed or have been written off in some other way. [Skin lesions include those] that could be interpreted as ecchymosis. They're not ecchymosis, because if you took a biopsy, it would be full of these cells, but I think that they could be confused in a patient who is thrombocytopenic. [Presentation can be] very distinct, because there is some nodularity to all of these hemorrhagic papules. But there are patients who don't have papules, who have macules and thin plaques that people mistake for ecchymoses. A patient can have 1 or 1000. They typically are more disseminated and typically spare the dermis. When you do a biopsy, it has to be to the deep dermis or subcutaneous fat.² Again, these patients should have circulating blasts that will make the diagnosis instead of having to do a deep skin biopsy. But if the dermatologist sees the patient, they will need to do more than a superficial biopsy.

How do you approach the workup and differential diagnoses of cutaneous T-cell lymphomas?

I have had several patient cases in the last 2 years where I made the diagnosis of a cutaneous T-cell lymphoma. [For one], I ran peripheral flow cytometry, and sure enough, she not only had mycosis fungoides, she had Sézary syndrome, because she had so many of the cells in the peripheral blood. We are hematologist-oncologists. We typically look at the blood, and a dermatologist would take a biopsy. A skin biopsy is not a very big deal, but flow cytometry from the peripheral blood would identify cutaneous T-cell lymphoma many times, and will diagnose BPDCN, rather than relying on the skin biopsy. But they have a very large differential diagnosis: purpuric disorders, angiosarcoma, Kaposi sarcoma, extramedullary hematopoiesis, neuroblastoma, and nonneoplastic [etiologies].^2,3 The only thing it could be would be trauma and multiple ecchymoses, and if there's nodules, then multiple ecchymoses are not likely to be the reason.

How does the morphology of BPDCN blood or bone marrow cells appear?

In the bone marrow, if you look at the morphology, it looks like the morphology in the blood [of] large mononuclear cells with nucleoli. That's why they're blasts, but there's nothing about the morphology that will make it a distinct impression on you. These could be monocytes, that could be lymphocytes. There is no group that would make a diagnosis without flow cytometry, because we know that this morphology is not very specific in hematologic malignancies.⁴

Do these patients always have pancytopenia or severe leukocytosis? Have you seen patients with BPDCN relatively normal blood counts?

No, because they're never picked up that early. It doesn't take them that many months to go from skin to pancytopenia. They may not be experiencing severe pancytopenia. They may have a platelet count of 50,000/µL. They may or may not have leukocytosis. The white blood cell count could be high, normal, or low. They're typically anemic. I have not seen somebody who had skin-only disease and normal blood counts. It should make it a little easier.

What molecular and cytogenetic features are common with BPDCN?

In terms of the cytogenetics and the molecular, there is nothing absolutely distinct here. The common cytogenetic abnormalities are a little unusual and wouldn't be typically seen in AML, although some of them you do see in myeloid disorders, like 5q abnormality, [and like in] myeloma and lymphoma, 13q and 15q [anomalies]. MYC gene rearrangements have been reported; it's associated with worse prognosis. The other molecular abnormalities are very common, like the ones that we see in myelodysplasia or AML. but there's not one particular set that you would expect to see in this disease.⁵

What therapeutic approaches are available for BPDCN?

BPDCN first-line therapy years ago was either therapy directed at AML, acute lymphoblastic leukemia [ALL], or lymphoma. It didn't work, was toxic, and had fast relapse with early death. So tagraxofusp [Elzonris] was a fundamental intervention that changed this disease. It’s the first of what will very soon be at least a couple of CD123-directed therapies, but this is the only one that's FDA approved. This drug is a fusion protein. It's a CD123-targeted therapy consisting of human interleukin-3 fused to a truncated diphtheria toxin payload.⁶ The fusion protein binds to CD123, and its toxin is delivered; the diphtheria toxin blocks protein synthesis, and the cell dies. Right now, it’s the only FDA- and EMA-approved treatment for BPDCN. The AML, ALL, and lymphoma therapies have not been approved by any regulatory agency for management of BPDCN.

DISCLOSURES: Schiller previously reported commercial interests in BMS, Amgen, and Johnson & Johnson; and receiving fees from AbbVie, Agios, Amgen, Astellas, BMS, Incyte, Janssen, Jazz, Karyopharm, Kite, Pharmacyclics, Sanofi/Genzyme, and Stemline Therapeutics.

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