Treating Blastic Plasmacytoid Dendritic Cell Neoplasm

A 22-year-old man with no significant prior medical history presented to his local clinic with a two-month history of maculopapular skin lesions. An initial lesion noted on the face adjacent to his nose was non-pruritic and had a purplish discoloration. Several other lesions appeared in subsequent weeks, and the patient was seen by his local primary care team. He had no fevers, night sweats, or weight loss. Results from both standard complete blood count and chemistry panel were within normal ranges (no circulating blasts, no liver/kidney abnormalities, adequate albumin level). He was given a working diagnosis of a nonspecific skin infection, was prescribed antibiotics, and was asked to return. Upon return three weeks later, the skin lesions had not resolved, with several more appearing in the trunk and lower extremities. The clinic performed a biopsy of one of the target lesions, with the differential diagnosis in this previously young, healthy patient including various common skin infections and common dermal/cutaneous tumors. To the surprise of the local team and the patient, the final diagnosis was BPDCN. With an ECOG performance status of zero, the patient inquired about frontline therapy options and was referred to our clinic for discussion of clinical trial approaches.

Patient Management

With its history of confusing nomenclature and diverse clinical manifestations, BPDCN has been a truly protean disease for pathologists and clinicians alike. While not the only hematologic malignancy to involve the skin, BPDCN is now recognized as one of the most common and most deadly blood-skin connecting cancers in this limited differential diagnosis space. Frequently, patients can present with skin-only disease, which can precedes blood/marrow involvement, but this is still associated with a poor prognosis and rapid evolution to an acute leukemia state in many patients, despite no marrow involvement at baseline.⁵  We stage all patients with BPDCN to reflect the three most common compartments of involvement — skin, bone marrow, lymph nodes. In fact, this patient had involvement of all three; bone marrow was ultimately positive for involvement (with flow and IHC demonstrating CD4⁺CD56⁺CD123⁺), and computed tomography imaging revealed lymph node enlargement.

Groups worldwide have borrowed from the experience of acute leukemia and lymphoma for delivery of therapeutic regimens to patients with BPDCN.^18,19  In our own experience with the ALL-based regimen (HCVAD alternating with methotrexate and ARA-C), we observed a greater than 80 percent overall response rate (ORR) in the frontline setting; however, relapses occur at a high rate, and the median OS still remains at two years or less, and the most common causes of death remain relapse and multiorgan failure.⁵  On the basis of the finding of almost universal positivity for CD123, we performed a small pilot study for patients with BPDCN with a CD123-targeting agent known as diphtheria toxin–interleukin-3(DT-IL3), later known as SL-401 (tagraxofusp; Stemline Inc). In this study, seven of nine evaluable patients achieved a major response with one cycle of available drug, five of which were CRs.¹³  On this basis, we set out to conduct a larger multicenter clinical trial with multiple cycles of SL-401.²⁰  As updated recently at the 2018 European Hematology Association Annual Congress, 45 patients treated in stages 1-3 (median age 70 years, range 22-84) achieved an ORR of 90 percent in the frontline setting at the target dose identified (12 μg/kg/day IV, days 1-5 on a 21-day cycle [n=29]), with 45 percent of patients in the frontline setting being bridged to SCT and a 69 percent ORR in the relapsed/refractory setting. Among 114 patients treated across all clinical trials with SL-401 as a single agent at 12 μg/kg/day dosing, the most notable safety signal was the occurrence of capillary leak syndrome (CLS), which constituted 20 percent of all adverse events at all grades. CLS has been found to be expected and generally manageable with safety parameters in place; these consist of assessment of baseline heart and organ function and careful daily assessments of clinical parameters prior to each dose, including albumin levels, patient weight, renal function, and liver function. Now, with median follow-up of 13.8 months (range 0.2-37.4 months+), the median OS has not yet been reached among frontline treated patients at 12 μg/kg/day dosing.²¹ 

Patient Disposition and Long-Term Follow-Up

Historically, we have treated younger patients with ALL-based chemotherapy such as hyper-CVAD. We reviewed cytotoxic chemotherapy options versus clinical trial options. After discussion about the natural history of BPDCN and limited therapy options, the patient opted for clinical trial with frontline SL-401. He received a total of five cycles, achieved a CR, maintained fit performance status throughout, and saw resolution of his skin lesions, normalization of marrow studies, and resolution of enlarged lymph nodes. He had no major complications during therapy and was able to proceed to an allogeneic SCT in CR1. Post-SCT, he was monitored closely and experienced no graft-versus-host disease. At the one-year mark, the patient was noted to remain in CR1 and thriving. Indeed, based on an ORR of 90 percent and a 45 percent rate of proceeding to SCT in the frontline setting, if/when available, the SL-401 clinical trial has now become our de facto frontline standard of care for patients with BPDCN.

Future Directions and Therapy Strategies

In terms of targeting CD123, an emerging area of research is yielding novel therapeutic approaches with monoclonal antibodies, bi-specific antibodies, immunotherapy, and CAR-T therapies.¹⁷  Moving beyond single-agent CD123, therapies other than CD123 or combinations with CD123 will represent the next era of research in BPDCN. Other therapy approaches based on newer gene signature studies or novel biological rationale include bortezomib,²²  BCL-2 inhibitors,²³  hypomethylator therapies,²⁴  and bromodomain inhibitors.^10,25  For those patients who are able to, SCT still seems to be the best overall curative option as part of any therapy program (cytotoxic chemotherapy, hypomethylator, or targeted therapy) given the poor durability in many patients treated with cytotoxic chemotherapy alone and still unknown long-term durability of targeted agents in BPDCN. Approaches in the SCT field besides allogeneic SCT in CR1 will include further investigation of timing, intensity, and types of allogeneic SCT, particularly in older patients, investigation of maintenance therapies post-SCT, as well as more focus on autologous SCT for some patients (perhaps skin-only, or older patients unfit for allogeneic SCT), as some studies have suggested long-term benefit in select patients.²⁶