1. Pemmaraju, Naveen MD

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In this column, I have tried to highlight rare subsets of hematologic cancers and patient populations with unique characteristics and specific considerations. This month, I would like to continue my focus by writing about a growing area in one of my group's own main research fields: blastic plasmacytoid dendritic cell neoplasm (BPDCN). I will highlight some of the new areas we are currently working on in BPDCN clinical research, as well as the work of several other groups from around the world. This article is meant to generate discussion and discourse, and is by no means meant to be a comprehensive listing of all active areas of research in our emerging field. My hope is to present here a few of the working ideas that my colleagues and I have been actively researching to help bring BPDCN research more to the forefront.

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BPDCN, a historically rare hematologic malignancy, is a challenging disease entity to recognize, diagnose, and treat. In 2008, the WHO reclassified the disease under AML and related family of neoplasms, and solidified the currently used term of "BPDCN" (Blood 2009;114(5):937-951). In the latest re-classification, in recognizing BPDCN's unique disease course and patho-biology, the WHO 2016 grouping now lists BPDCN as its own separate category under myeloid neoplasms (Blood 2016;127(20):2391-2405). The diagnosis is greatly aided by use of flow cytometry/immunohistochemical findings, including CD4+, CD56+, CD123+, (and TCL1+ in most cases), and generally requires expert hematopathology consultation (Am J Hematol 2016;91(3):283-286). Patients classically present with skin, bone marrow, and/or lymph node involvement, with a significant subset of patients having cerebrospinal fluid involvement at diagnosis or relapse (Oncotarget 2016;7(9):10174-10181). The median age in most adult series is reported to be 68-72 years and there is a striking male predominance (Blood 2013;122(21):741). Outcomes remain poor, with most groups reporting median overall survival of 8-14 months (Clin Adv Hematol Oncol 2016;14(4):220-222).


There has been no standard therapy or worldwide consensus on how to treat patients with BPDCN. Historically, treatment for BPDCN has included multi-agent intensive chemotherapy (ALL-based, AML-based, or lymphoma-based), but outcomes remain poor, with some improvements noted in a subset of patients able to undergo stem cell transplantation (Haematologica 2013;98(2):239-246, Blood 2013;121(3):440-446, Biol Blood Marrow Transplant 2013;19(7):1006-1012, Blood 2015;125(23):3559-3562). Currently, no worldwide standard of therapy exists for patients with BPDCN in either the frontline or relapsed settings, and, therefore, targeted/novel therapeutic approaches are urgently needed.


Search for Novel Targets & Targeted Therapy


CD123, also known as IL3-receptor alpha, has been found to be overexpressed in patients with myeloid leukemias (Leukemia 2000;14(10):1777-1784). CD123 is over-expressed on leukemia stem cells, as compared to normal hematopoietic precursor cells (Cytometry Part A 2015;87(4):346-356), making it a potentially attractive target for novel therapy (Blood 2014;124(3):310-312). Pre-clinical and clinical data demonstrate that CD123 is overexpressed in almost all patients with BPDCN (J Clin Oncol 2014; doi:10.1200/jco.2014.32.15_suppl.7118).


SL-401 in Patients With BPDCN or AML

This is a phase I/II multicenter study with two arms: one for patients with BPDCN (frontline or relapsed after prior therapy) and one for patients with AML. A pilot trial was completed with administration of SL-401 in patients with BPDCN that showed major responses in 7/9 (78%) evaluable patients, including five complete responses (Blood 2014;124(3):385-392).


SL-401 consists of human IL-3 (recombinant) that is genetically fused to a shortened diphtheria toxin (DT), which features the DT binding domain replaced with IL-3. One hypothesis for the mechanism of action includes the IL-3 of SL-401 targeting IL3R (CD123) over-expressing blasts, which in turn leads to receptor-mediated endocytosis, irreversible protein synthesis, and apoptotic cell death in CD123 over-expressing blasts (Blood 2014;124(3):310-312). One cycle of therapy consists of SL-401 administered intravenously for 5 consecutive days, every 21 days for 6 or more cycles. The trial is ongoing, and updated results for BPDCN were presented at ASH 2016 (Abstract 342). In the updated study group, with median age of 72 years, among 32 patients with BPDCN, we reported an 84 percent overall response rate in all lines of therapy. The ASH 2016 presentation highlighted the details of toxicities/side effects, including capillary leak syndrome (CLS), which can be fatal, and the protocol-wide measures undertaken to address, prevent, and treat CLS. The clinical trial is ongoing with continued enrollment of patients in the expansion phase.


Future Directions

Targeting CD123 via CAR T-Cell Therapy

In terms of treatment of myeloid malignancies, CD123 as a target is a rapidly emerging field and represents a novel immuno-oncologic approach to treatment for patients with CD123-overexpressing tumors, particularly AML and BPDCN (Curr Opin Hematol 2015;22(6):484-488). There are many therapeutic approaches being developed against CD123, including but not limited to monoclonal antibiodies, bi-specific/dual targeting agents, and CAR T-cell therapies. One of these approaches to highlight is a novel type of CAR T-cell therapy just opened up at our center, which specifically targets CD123 and is specific for patients with BPDCN. This phase I, open-label dose-escalation study will evaluate the safety, expansion, persistence, and clinical activity of a single dose of UCART123, administered in patients with BPDCN.


This new protocol utilizes UCART123, an allogeneic (or so-called "off the shelf") gene edited CAR T-cell product. As presented at ASH 2016 (Abstract 4039), we found in preclinical models that UCART123 leads to specific killing of BPDCN cells, and this was associated with cytokine production and T-cell degranulation of CAR T-cells (antigen-specific).


Additionally, this work demonstrated persistence of UCART123 cells in vivo in an NSGS model for primary BPDCN, and significant extension of survival or cures of mice injected with a single dose of CD123 CAR T (ASH 2016, Abstract 4039). This clinical trial is now open for enrollment as a dose-escalation phase I clinical trial here at our center.



In collaboration with our colleagues at Dana-Farber Cancer Institute, Boston, (Andrew Lane and colleagues), we have had long-standing interest in investigating the role of BCL-2 in BPDCN and AML. BCL-2 over-expression has been associated with the survival of AML cells and with resistance to standard chemotherapy agents. In gene expression profile comparing BPDCN to normal plasmacytoid dendritic cells (pDCs), the anti-apoptotic BCL-2 gene was upregulated in BPDCN (Blood 2013;122(21):2502). We hypothesized that this might lead to sensitivity to venetoclax. We generated primary patient-derived BPDCN xenografts (PDX models) and performed BH3 profiling" assays that show which anti-apoptotic pathways are most active in BPDCN (Cancer Cell 2007;12(2):171-185).


Using PDX models, we found that human BPDCN is specifically reliant on BCL-2 for survival and is highly-sensitive to the BCL-2 inhibitor at sub-nanomolar IC50. This work, from our groups, is now published and forms the basis for preclinical and clinical hypothesis for investigation of BCL-2 inhibition with venetoclax in patients with BPDCN (Cancer Discovery 2017;7(2):156-164).


Bromodomain Inhibition in BPDCN

Two different groups published papers on this topic over the past year. In one paper, by Emadali, et al, the investigators screened 47 patients with BPDCN and found that 36 percent had alterations in chromosome 5q. Upon deeper analysis, they discovered that the majority of these cases had deletion of NR3C1, which is the glucocorticoid receptor, and that haplo-insufficiency for NR3C1 was associated with poor outcomes. Furthermore, there was an association with nuclear lincRNA-3q activity, which was shown to have bromodomain (BET) pathway dependence; in preclinical models, BPDCN cells appeared to be suppressed by BET protein inhibition (Blood 2016;127(24):3040-3053).


In another study, by Ceribelli, et al, researchers demonstrated via RNAi screening that TCF4, a transcription factor important for normal pDC maintenance, was instrumental in BPDCN transcription. Moreover, they showed that TCF4 was a prominent downstream target of BETi in BPDCN, with preclinical demonstration of tumor burden reduction with BETi therapy (Cancer Cell 2016;30(5):764-778, Cancer Cell 2016;30(5):659-660). Taken together, these novel studies point towards rationale for further investigation of bromodomain inhibitors as potential therapy for BPDCN.


NAVEEN PEMMARAJU, MD, is Assistant Professor, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston.

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