How should we diagnose and treat blastic plasmacytoid dendritic cell neoplasm patients?

Abstract

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive leukemia for which we developed a nationwide network to collect data from new cases diagnosed in France. In a retrospective, observational study of 86 patients (2000-2013), we described clinical and biological data focusing on morphologies and immunophenotype. We found expression of markers associated with plasmacytoid dendritic cell origin (HLA-DRhigh, CD303+, CD304+, and cTCL1+) plus CD4 and CD56 and frequent expression of isolated markers from the myeloid, B-, and T-lymphoid lineages, whereas specific markers (myeloperoxidase, CD14, cCD3, CD19, and cCD22) were not expressed. Fifty-one percent of cytogenetic abnormalities impact chromosomes 13, 12, 9, and 15. Myelemia was associated with an adverse prognosis. We categorized chemotherapeutic regimens into 5 groups: acute myeloid leukemia (AML)-like, acute lymphoid leukemia (ALL)-like, lymphoma (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP])-like, high-dose methotrexate with asparaginase (Aspa-MTX) chemotherapies, and not otherwise specified (NOS) treatments. Thirty patients received allogeneic hematopoietic cell transplantation (allo-HCT), and 4 patients received autologous hematopoietic cell transplantation. There was no difference in survival between patients receiving AML-like, ALL-like, or Aspa-MTX regimens; survival was longer in patients who received AML-like, ALL-like, or Aspa-MTX regimens than in those who received CHOP-like regimens or NOS. Eleven patients are in persistent complete remission after allo-HCT with a median survival of 49 months vs 8 for other patients. Our series confirms a high response rate with a lower toxicity profile with the Aspa-MTX regimen, offering the best chance of access to hematopoietic cell transplantation and a possible cure.

Graphical abstract

Figure 1.

Representative morphologies of BPDCN in blood or bone marrow aspirates. (A-D) Typical morphology with large pseudopodia, microvacuoles in some blasts, an eccentrically located nucleus, and heterogeneous coloration of the cytoplasm (lightly basophile with some gray areas). The nuclei are sometimes prominent (C). (E) Lymphoid-like morphology with small cells, very small cytoplasm, and mature chromatin of the nucleus. In this case, other cells (arrows) are bigger and present a more immature profile. (F-G) Monoblast-like blasts. Cells are bigger and more basophilic, with irregular nuclei and prominent nucleoli. Case G is BPDCN secondary to acute transformation of CMML. (H) A more immature morphology with a high nucleocytoplasmic ratio, diffuse chromatin, nucleoli, and basophilic cytoplasm. (I-J) Presence of granules in the cytoplasm (arrows). (K) Atypical big and round vacuoles in the cytoplasm. May-Grünwald-Giemsa, original magnification ×1000.

Figure 2.

Two representative examples of BPDCN patients. Live cells are gated on a first forward scatter (FCS)/side scatter (SSC) to exclude debris and a FCS area (A)/FSC height (H) gate to select singlets (not shown). The CD45^bright /SSC^low cells are lymphocytes (blue), and CD45^dim /CD123^bright cells are a BPDCN blastic population (pink). (A) Patient P165. Blasts are CD4⁺ (lower than T lymphocytes in blue) and CD56⁺ with a bimodal expression, CD303⁺, CD304⁺ HLA-DR⁺, cTCL1⁺, ILT7^low, CD36⁺, CD38⁺, and CD43⁺.There is no expression of classical dendritic cell markers (CD1c, CD141, and CD11c) or immature markers (CD34, CD133, and Tdt). (B) Patient P149. Blasts are CD4⁺ and CD56^{partial and low}, CD303⁺, CD304⁺ HLA-DR⁺, cTCL1⁺, ILT7⁻, CD36^−/partial, and CD38⁺. The blasts also expressed CD7 and CD33 without CD13. Classical dendritic cell markers (CD1c, CD141, and CD11c) and immature markers (CD34 and CD133) are negative. APC, allophycocyanin; FITC, fluorescein isothiocyanate; PE, phycoerythrin.

Figure 3.

Number of BPDCN cases that express nonspecific lineage markers and association of different expression combinations. The analysis presents 61 patients in whom a large myeloid and B-/T-lymphoid panel were analyzed (CD19, CD20, CD22, cCD22, and cCD79a; T: cCD3, CD3, CD2, CD5, and CD7; myeloid: CD13, CD33, CD15, CD65, CD117, MPO, CD11c, CD14, and CD64). Numbers indicate the number of cases in each group of associated markers. Of note, 4 cases simultaneously expressed B, T, and myeloid markers.

Figure 4.

Chromosomal abnormalities evidenced by conventional cytogenetic analysis in 62 cases. (A) Distribution of karyotype results. (B) Percentage and type of abnormality for each chromosome depicted on the left. Chromosomal abnormalities of particular interest are listed on the right, with loci concerned (green), candidate genes already described (blue), and number of patients (red) for each type of abnormality (gray) (ie, monosomies, trisomies, deletions, isochromosome, addition, and translocations). add, addition; chr, chromosome; del, deletion.

Figure 5.

Comparison of survival according to treatment type and response. OS according to response to first-line treatment (A) and initial treatment groups (AML-like, ALL-like, and Aspa-MTX vs CHOP-like and NOS) (B).

Figure 6.

OS according to performance of HCT as part of treatment.

Figure 7.

Flowchart illustrating the phenotypic diagnosis of BPDCN. In the absence of expression of specific lineage markers, high expression of CD123 and HLA-DR plus CD4 (which can be low) and CD56 (which can be low or negative) raises the possibility of BPDCN, even if isolated or associated less-specific lineage markers are expressed (such as CD7, C2, CD33, CD13, CD117, CD22, and cCD79a). Diagnosis should be confirmed using cTCL1, CD303, and CD304. c, intracytoplasmic; −, negative (expressed in <20%of the blastic population); +, positive (>20%); low, intensity of expression less than normal cells expressing this marker (eg, NK cells for CD56, normal pDCs for CD303 and CD304, T cells for CD4, and monocytes for CD11c and CD64).