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Novel Targeted Therapies for Blastic Plasmacytoid Dendritic Cell Neoplasm

Pemmaraju, Naveen MD

doi: 10.1097/01.COT.0000652260.84492.25
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hematology research
hematology research:
hematology research

Now, one full year after the approval of the first targeted agent for patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), it is a good time to reflect on some of the developments in this emerging field.

BPDCN is a unique, clinically aggressive, and often confounding, shape-shifting hematologic malignancy (Haematologica 2013;98(2):239-246). Historically, BPDCN has been noted to be an older (median age closer to age 70 in most studies) and largely male predominance (Blood 2013;122(21):741) (3:1 to 5:1 male predominance in most studies). However, our modern era experience with BPDCN, as it is becoming more understood and recognized, is that we have observed more patients diagnosed in pediatric, adolescent, and young adult age groups and among female patients (Leuk Res 2018;73:21-23).

One of the major breakthroughs for diagnosis has been with developments in hemato- and dermatopathology with emerging uniformity of markers such as CD4, CD56, and CD123, along with other important markers to add to specificity including TCL-1, TCF4, and CD303, among others, which help clinicians differentiate BPDCN from other mimicking conditions such as acute myeloid leukemia with leukemia cutis, cutaneous T-cell lymphoma, or other disease states (Am J Hematol 2013;88(12);1055-1061; Cancers (Basel), 2019;11(5); Am J Surg Pathol 2019;43(10):1429-1437).

It is important for clinicians to recognize BPDCN in 2020 and beyond as a distinct entity given its unique pathobiology, clinical course, predilection for transformation to AML, and now, dedicated therapies and novel clinical trials specific to this patient population (Blood 2019;134(8):678-687; Ther Adv Hematol 2019; doi: 10.1177/2040620719874733). In this setting, let us briefly review a selection of targeted clinical trial approaches of interest to the author and other working groups in the field, in order to highlight some of these programs as we enter into 2020, recognizing this is by no means a complete or comprehensive list.


Tagraxofusp (formerly DT-IL3, SL-401) for patients with BPDCN

Historically, cytotoxic chemotherapy, including regimens borrowed from acute myeloid leukemia, acute lymphocytic leukemia (ALL), and lymphoma have been used widely in the treatment of patients with BPDCN. Some of the most durable results in our experience have been observed with ALL-based regimens including HCVAD in younger/fit qualified patients (Blood 2017;130(Suppl 1)).


It has been approximately 20 years since Jordan et al demonstrated the presence of CD123 (or IL3R alpha) overexpression in leukemia stem cells (Leukemia 2000;14(10):1777-1784). Angelot-Delettre et al showed that a novel drug, DT-388IL3 (later SL-401, later tagraxofusp), had both in vitro and in vivo effectiveness at femtomolar levels against BPDCN specifically in pre-clinical investigation (Blood 2013;122(21):3942). A pilot clinical trial involving 11 total patients with BPDCN was therefore conducted (Blood 2014;124(3):385-392). In this study, with only one cycle of drug available for the majority of patients, with median age of 70 and all male population, among nine patients evaluable, we reported a 78 major response rate (7/9 evaluable patients). One notable toxicity included capillary leak syndrome, or vascular leak syndrome (Blood 2014;124(3):385-392).

Based on these results, we set out to conduct a multi-center, multi-cycle prospective phase I/II clinical trial dedicated to patients with BPDCN. In this pivotal effort, 47 patients with BPDCN were treated with tagraxofusp. Among 29 patients treated in the upfront setting with target dose 12 μg/kg/day dosing, 90 percent achieved an overall response with 72 percent complete remission (including CR, CRi, CRc). Among the upfront treated patients, 45 percent were able to be successfully bridged to stem cell transplantation (SCT). Among patients with relapsed/refractory (R/R) BPDCN, an overall response rate of 67 percent was seen, with one patient in this group being bridged to SCT. This dataset helped to establish tagraxofusp as the first targeted drug approved for BPDCN (ages 2 and up) and also established this agent as the first CD123-directed targeted agent ever approved, granted FDA approval in December 2018 (N Engl J Med 2019;380(17):1628-1637).

Naveen Pemmaraju, MD
Naveen Pemmaraju, MD:
NAVEEN PEMMARAJU, MD, is Associate Professor in the Department of Leukemia at MD Anderson Cancer Center.

IMGN632 for patients with R/R CD123-positive hematologic malignancies (NCT03386513)

A multi-center, phase I clinical trial of a new agent, known as IMGN632, which is a conjugated CD123-directed therapy consisting of a novel DNA-alkylating payload, is now underway. This active clinical investigates its use in R/R hematologic malignancies that express CD123, including patients with BPDCN and AML (Ther Adv Hematol 2019; doi: 10.1177/2040620719874733). IMGN632 was shown to have a signal for activity and prolong survival in AML xenograft models (Adams et al Blood 2016: abstract 2832). Patients with AML and BPDCN have been enrolled, and preliminary results were presented at the 2018 American Society of Hematology meeting, which established preliminary safety and showed an early signal for efficacy (Daver et al, ASH 2018). This trial offers a potentially novel approach to CD123-targeted therapy in patients with BPDCN.

MB-102 in relapsed/refractory BPDCN: CAR-T directed against CD123 (NCT04109482)

A phase I multi-center clinical trial is currently being planned to assess the safety and efficacy of MB-102 in patients with R/R BPDCN, AML, and high-risk myelodysplastic syndrome. This new study features a novel, autologous chimeric antigen receptor T-cell (CAR-T) construct which is targeted against CD123. It will begin as a phase I dose-escalation study, including patients with R/R BPDCN.


Venetoclax in BPDCN

Pre-clinical work with regards to BCL-2 overexpression and possibility for inhibition specifically in BPDCN has been established (Cancer Discov 2017;7(2):156-164). Furthermore, in this report, two patients with R/R BPDCN were treated with oral venetoclax monotherapy. Further clinical experience from our group and others has demonstrated responses in patients treated with venetoclax in combination with other agents, including hypothmethylating agents (Am J Hematol 2018;93(3):401-407) and cytotoxic chemotherapy regimens (N Engl J Med 2018;379(15):1479-1481; N Engl J Med 2019;380(7):695-696).

A formal phase I clinical trial of venetoclax (NCT03485547) for patients with BPDCN has been launched and is being conducted with our colleagues at Dana-Farber Cancer Center and is specifically dedicated to patients with BPDCN. Notably, venetoclax is now FDA-approved for patients with chronic lymphocytic leukemia, and now for older patients unfit for chemotherapy with AML (in combination with low-dose cytarabine or hypomethylating agents (Cancer Discov 2016;6(10):1106-1117).

Post-SCT Maintenance in BPDCN

An evolving, emerging area of research in the field of BPDCN is understanding, optimizing, and implementing SCT and effective pre- and post-SCT therapy in the treatment of the patients with BPDCN. At the 2019 European Hematology Association (EHA) Congress, our group reported the outcomes of 24 patients with BPDCN who had SCT (n=14 allogeneic, n=10 autologous). Their median age was 52 years (range 18-79). Among patients transplanted before or after 2015, the 2-year progression-free survival (PFS) was 13 percent versus 54 percent (p=0.009), respectively, and 2-year OS was 13 percent and 68 percent (p=0.017) (Qazilbash/Pemmaraju et al, EHA 2019). We are working with our SCT colleagues to design and open post-SCT maintenance trials for patients with BPDCN.

Pathology & Specialized Molecular Markers

As I continue my work in our growing field of BPDCN, I want to share with all of you the sheer importance of expert pathology review and close collaboration, with both dermatopathology and hematopathology colleagues, in establishing a diagnosis of BPDCN in patients. The significance of assessing each patient case carefully with morphology, flow cytometry, cytogenetics, molecular analysis, and immunohistochemistry markers in making the diagnosis of BPDCN cannot be overstated.

The most basic triad, that of CD123, CD4 and CD56 (Think “CD123456”) (Pemmaraju and Konopleva, The Hematologist 2018), in combination with additional markers that add specificity: TCL-1 (Am J Clin Pathol 2012;137(3):367-376) and CD303 (J Clin Exp Hematop 2018;58(1):1-9) can aid in the diagnosis of BPDCN. There are exceptions, however, as in rare cases that are CD56 negative (Am J Surg Pathol 2010;34(1):75-87). The identification of TCF4 with CD123 as a novel dual marker has added even further specificity to make the diagnosis (Am J Surg Pathol 2019;43(10):1429-1437).

The Future & Other Targeted Therapies

There are several new leads in our growing BPDCN field. Highlighting the work of several of our colleagues from around the world, there has been pre-clinical and early clinical research in many areas, among others, including exploring inhibition of NFkB (Blood 2013;122(21):2502; Haematologica 2017:102(11):1861-1868), bromodomain (Cancer Cell 2016;30(5):764-778; Blood 2016;127(24):3040-3053), hypomethylators (Eur J Haematol 2014;93(1):81-85), and novel cytotoxic chemotherapy regimens (Clin Cancer Res 2011;17(19):6163-6173; Hematol Oncol 2019;37(4):487-489) that we will need to further investigate novel therapies and novel combination regimens together in clinical trials as our field progresses forward.

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