Physicians Review Diagnosis and Management of BPDCN

Daniel Pollyea, MD, MS (MODERATOR)

Professor, Medicine-Hematology

Clinical Director of Leukemia Services

University of Colorado School of Medicine

Aurora, CO

CASE SUMMARY

A man aged 67 years was referred from a dermatologist. He was referred initially to the dermatologist by his primary care physician for progressive, persistent, cutaneous nodules that the patient had noticed 3 weeks prior.
The patient had fatigue and 5-kg weight loss over 3 months, and a medical history of sinusitis but no major comorbidities. Upon physical examination, there were multiple purpuric nodules (measuring up to 5 cm on arms, legs, torso). No palpable adenopathy or hepatosplenomegaly was observed. His ECOG performance status was 1.

• Laboratory results:
• White blood count: 14.1 × 103/µL
• Hemoglobin: 8.9 g/dL
• Platelets: 54 × 103/µL

Differential revealed 12% blasts, 32% neutrophils, 16% monocytes, 40% lymphocytes.

The patient’s skin had a purpuric nodule. On a peripheral blood smear,
there were blastic cells with large and round or slightly irregular nuclei;
blast cytoplasm stained grayish blue without granules or Auer rods.

Event region: Colorado, Utah

DISCUSSION QUESTION

• What should be included in the differential diagnosis, and what diagnostic assessments would you perform or order?

POLLYEA: I know that all our differentials of BPDCN [blastic plasmacytoid dendritic cell neoplasm] are quite limited. I could say with blasts, cytopenia, [and] skin involvement [that] we’re looking at acute leukemia.

We must confirm [whether] it is a myeloid or lymphoid process. The fastest way to get at that would be peripheral blood flow, and a pathologist can quickly tell you [whether] this is something in the myeloid or lymphoid family. My experience with adult acute lymphocytic leukemia is it’s unusual to have skin manifestations, at least at diagnosis, but it could happen.

If you have had a BPDCN case, how has it landed in your lap? I’d be interested in knowing that because, oftentimes, by the time we see them they’ve been circulating among other specialties like dermatologists, primary care doctors, etc, and still without a diagnosis. That’s been my experience.
Is it shared by others?

CALL: Not specifically for BPDCN, but I think it’s a challenge when there is initial cutaneous manifestation of any malignancy because a lot of times the first point of specialty contact is dermatologists who, I think appropriately, biopsy it.

But then, at least in our community, it goes to dermatopathologists, who I’m not sure where they are or what their experience is. Sometimes there can be a delay unless it’s clearly melanoma or something else. But we’ve seen patients who had delayed or incorrect diagnosis of solid tumors with skin metastases—for example, breast cancer.

In fact, I had a case where an elderly woman presented with cutaneous nodules, which weren’t purpuric, that had developed over several weeks. The initial dermatopathology interpretation was metastatic breast cancer, and then a few days later the diagnosis was changed to AML [acute myelocytic leukemia].

I think who’s getting the initial pathology specimens and their experience is part of the challenge. Most of the time skin biopsies aren’t sent to a hematopathologist. That’s a disconnect in general, especially for solid or hematologic tumors presenting with skin metastasis.

That does complicate and oftentimes delay and confuse the diagnosis. Sometimes when you try to get that specimen from the dermatopathologist and ask where it is, they say it’s been used up. Then you end up repeating the whole thing from the start. I think that’s a challenge.

POLLYEA: I have had that same experience. I couldn’t have said that any better.

SHARMA: I’ve seen 2 cases [over the past] 4 years. One of them presented exactly like this. They were from out of state, in their 80s, and diagnosed with AML, but it was leukemia cutis. They decided to pursue hospice and didn’t want treatment because they were in their 80s. The other patient presented with skin lesions too. So both patients had skin lesions, cytopenia, and blasts. We have a hematopathology department and they figured out that it looked like something funny, and so further work-up was done. The patient had some family in Houston, [Texas], so he went there.

POLLYEA: That’s interesting. There are similar patterns emerging here—delayed time to diagnosis and lack of awareness from dermatopathologists. I think hematopathologists, like Dr Call said, could quickly make this diagnosis because they’re thinking of it. Dermatopathologists take a while to consider this. Another challenge is [for] older patients; often they are not very fit for any treatment, so they have bad outcomes.

CASE UPDATE

A bone marrow biopsy showed 40% blasts and 80% cellular marrow with interstitial infiltrate. Immunohistochemistry of neoplastic cells showed positive CD123, CD4, CD56, and TCL1. Flow cytometry showed negative CD4, CD56, CD123, CD34, and T- and B-cell lineage-specific markers. The patient had 46,XY cytogenetics. A lumbar puncture did not indicate central nervous system involvement. The patient received a diagnosis of BPDCN based on clinical and histopathological findings.

DISCUSSION QUESTION

• Do you typically use CD123 expression in hematologic diagnostic panels?

SHARMA: We’ve had some suspicion when there’s cutaneous involvement and we don’t know the diagnosis. So we use our own flow cytometry as well as ARUP Laboratories’ flow cytometry. The ARUP flow includes it in miscellaneous tests. If you tell them the patient presented with skin lesion or something like that, they’ll do it. It’s not routinely done as far as I know.

POLLYEA: I think that’s a good policy. I would not be one to comment on what the pathologist’s algorithms and work-up are. But, as they always say, the more information we give them, the better. It does seem logical to me that they should amend their algorithms in the setting of skin involvement or something like that.

DISCUSSION QUESTION

• What are your impressions of the data from the phase 1/2 study (NCT02113982) of tagraxofusp (Elzonris) for BPDCN?1

SHARMA: In a rare disease with horrible outcomes, this is a targeted CD123 agent, which is pan expressed in BPDCN, that I would be excited about. It’s a niche population.

POLLYEA: Have you used it?

SHARMA: I have not because we couldn’t use it. We were all excited, but then we couldn’t use it because the patient was too old, and he decided to do hospice.

POLLYEA: So, if you would have been able to, what would it have involved? Did you get as far as to talk to your hospital and staff? Would this have been done inpatient or intensive care unit [ICU]? Would this have been a pharmacy issue?

SHARMA: We started talking about it, but it never panned out. For us, it would probably be on the floor, but I’m not sure. I don’t have experience doing this. We do CAR [chimeric antigen receptor] T-cell therapies and stem cell transplants on the floor. Even the label [states that] you admit the patient for the first cycle, so I would admit. ICU is not too far, if they need ICU. That would probably be my approach. We were starting to talk about it, but I’m not entirely sure what would happen because this was a patient in his 80s who didn’t necessarily want treatment.

POLLYEA: Looking at some of the guidelines, would you have considered tagraxofuspfor a patient in that age group with that level of comorbidities [if they were interested]?

SHARMA: Having not used it, and the adverse events can be severe, this is something you need to discuss [with the patient]. If they are fit, I would probably consider but I’m not entirely sure. I probably want to hear from others who have experience. It’s challenging to treat an 80-year-old patient.

PATEL: Could you comment on giving tagraxofusp,inpatient and reimbursement issues with this drug, and what diagnoses-related group it might be bundled into?

POLLYEA: I’m curious about that too. What other expensive infusions are [individuals] doing inpatient and asking the administrators to look the other way? Are they doing it outpatient and immediately admitting after when the course is over? How are [individuals] handling that one?

SHARMA: That’s a concern. It happens almost every couple of weeks with AML treatment, trying to get Vyxeos [daunorubicin/cytarabine].

MIKHAEEL: I would use [tagraxofusp]. I am impressed by the data, especially by the fact that patients are having immediate response within 1 cycle. When it’s a visible [reaction], it’s very annoying to the patient and physician. If a rash or big lesion goes away very quickly, I would be more than willing to consider it because that by itself is an important issue for the patient and physician.

[The data are impressive] and the median overall survival of 15.8 months is pretty good. The duration of response seems to be very good, too.¹ As far as toxicity and all that, when rituximab [Rituxan] came out, it was scary to us until we got used to it and it’s not a problem at all right now. It’s more of getting used to it. The first cycle must be given inpatient or maybe all cycles must be given inpatient, but I think you can get used to it. As far as [insurance] coverage in the hospital, it’s usually a struggle but then most of the time we get some help from the company to figure out how to get that coverage. Most of the time we’re able to get it, though. This happens with too many other drugs, not just this. The thrombotic thrombocytopenic purpura drug caplacizumab [Cablivi], is a big trouble but we can get it most of the time.

MUSHTAQ: About the community practice, getting a drug probably is not the biggest challenge, but diagnosing these skin involvements is challenging. I have a patient with T-cell lymphoma, which has been biopsied at least 5 or 6 times in [the past] 4 years. The patient had a biopsy done by a dermatologist and then by plastic surgeon, and then they sent the specimen to a send-out laboratory, most of the time in Texas, [to be seen] by a dermatopathologist. Every time the diagnosis was very different [until] we got one of the biopsies done at the National Institutes of Health and the diagnosis was very different.

So, especially with this skin involvement, it is very challenging. Even I’m not sure about the hematopathology on the bone marrow if they do the CD123, CD4, and CD56 [testing], which they do on almost everyone. We have a lot of patients who have pancytopenia, and some of them have skin lesions, but we still don’t know what’s going on with these patients.

POLLYEA: That’s a good comment because all the advanced treatments in the world won’t help us if we’re not able to effectively diagnose these rare diseases. It’s hard and very frustrating for us, the patients, and families when we can’t nail down what this is. Without that, we can’t treat.

In my experience, BPDCN is not tough to diagnose; it’s just tough to think of because it has this very characteristic gain-and-flow pattern. There aren’t many other things that it can be if you’re thinking of it, and you go after it. I think there doesn’t need to be a lot of the same frustration with this disease if pathology colleagues are thinking of it, but your point is very well taken. In community practice, and in any practice, we clinicians can’t do anything without our pathologists working these cases up and doing their best, too.

MUSHTAQ: Do you do any commercially available myeloid panel on the peripheral blood that could be helpful in diagnostics? Labcorp has the IntelliGEN myeloid panel, which tests 50 genes.

POLLYEA: On the mutation front, we do. I think any comprehensive panel by any company is fine—NeoGenomics, ARUP, etc. Whomever you contract with is fine; I think they’re all equivalent. Some commercial laboratories will do flow [cytometry] work-ups. In my experience, the best one would be from Hematologics, which has CD123 on it.

_REFERENCE

_{Pemmaraju N, Sweet KL, Stein AS, et al. Long-term benefits of tagraxofusp for patients with blastic plasmacytoid dendritic cell neoplasm. J Clin Oncol. 2022;40(26):3032-3036. doi:10.1200/JCO.22.00034}