Biology and prognostic impact of clonal plasmacytoid dendritic cells in chronic myelomonocytic leukemia

Lucas, Nolwenn; Duchmann, Matthieu; Rameau, Philippe; Noël, Floriane; Michea, Paula; Saada, Véronique; Kosmider, Olivier; Pierron, Gérard; Fernández-Zapico, Martín E.; Howard, Matthew T.; King, Rebecca; Niyongere, Sandrine; Diop, M’Boyba; Fenaux, Pierre; Itzykson, Raphaël; Willekens, Christophe; Ribrag, Vincent; Fontenay, Michaëla; Padron, Eric; Soumelis, Vassili; Droin, Nathalie; Patnaik, Mrinal M.; Solary, Éric

doi:10.1038/s41375-019-0447-3

Cited by 74 publications

(96 citation statements)

References 56 publications

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“…The presence of pDC in AML patients raises important diagnostic challenges. Very few patients in our cohort had a history of CMML and the mutational profiles are largely different from that of CMML (including the ones with pDC expansion) (25,52), arguing against a progression from CMML in the majority of patients. On the other hand, a few patients had greater than 20% pDCs in the marrow with immature pDC morphology, suggesting a potential diagnosis of BPDCN.…”

Section: Discussionmentioning

confidence: 89%

“…pDCs were markedly depleted in the bone marrow of the majority of AML patients with a median pDC proportion of 0.03% (IQR 0.006-0.14%), a 10-fold reduction compared to normal controls (p<0.001). While none of the normal controls had greater than 1% pDCs, there have been reports of as high as 1.6% pDCs in other normal control cohorts (25). Therefore, 2% was chosen to delineate a stringent cut-off for pDC expansion, which is equivalent to 10 standard deviations (SD) from the mean PDC level of normal controls.…”

Section: A Subset Of Aml Is Characterized By Increased Levels Of Pdcsmentioning

confidence: 99%

“…In sum, pDCs may have anti-tumor or pro-tumor effects dependent upon the malignancy and inflammatory context. Normally, pDCs account for <1% of total nucleated cells in both bone marrow and peripheral blood (24)(25)(26). Neoplastic expansion of pDCs or PDC precursors leads to blastic plasmacytoid dendritic cell neoplasm (BPDCN) (27,28) and clonal expansion of mature pDCs has been reported in chronic myelomonocytic leukemia (CMML) (29).…”

Section: Introductionmentioning

confidence: 99%

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Plasmacytoid dendritic cell expansion defines a distinct subset of RUNX1 mutated acute myeloid leukemia

Xiao

Chan

Waarts

et al. 2020

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194, no more than 200 words)Plasmacytoid dendritic cells (pDC) are the principal natural type I interferon producing dendritic cells. Neoplastic expansion of pDCs and pDC precursors leads to blastic plasmacytoid dendritic cell neoplasm (BPDCN) and clonal expansion of mature pDCs has been described in chronic myelomonocytic leukemia (CMML). The role of pDC expansion in acute myeloid leukemia (AML) is poorly studied. Here we characterize AML patients with pDC expansion (pDC-AML), which we observe in approximately 5% of AML. pDC-AML often possess crosslineage antigen expression and have adverse risk stratification with poor outcome. RUNX1 mutations are the most common somatic alterations in pDC-AML (>70%) and are much more common than in AML without PDC expansion. We demonstrate that pDCs are clonally related to, and originate from, leukemic blasts in pDC-AML. We further demonstrate that leukemic blasts from RUNX1-mutated AML upregulate a pDC transcriptional program, poising the cells towards pDC differentiation and expansion. Finally, tagraxofusp, a targeted therapy directed to CD123, reduces leukemic burden and eliminates pDCs in a patient-derived xenograft model. In conclusion, pDC-AML is characterized by a high frequency of RUNX1 mutations and increased expression of a pDC transcriptional program. CD123 targeting represents a potential treatment approach for pDC-AML.

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Section: Discussionmentioning

confidence: 89%

Section: A Subset Of Aml Is Characterized By Increased Levels Of Pdcsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Plasmacytoid dendritic cell expansion defines a distinct subset of RUNX1 mutated acute myeloid leukemia

Xiao

Chan

Waarts

et al. 2020

Preprint

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“…These include targeted agents such as tagraxofusp, a CD123-directed cytotoxin (IL-3 conjugated diphtheria toxin; NCT 02268253) and tipifarnib, a farnesyl transferase inhibitor with activity in RAS wild type CMML (NCT 02807272). 20 We hope that these efforts translate into biomarker driven therapies that can truly alter disease biology. However, for now, with the exception of allogenic HCT, there really are limited curative options for these patients.…”

Section: Discussionmentioning

confidence: 99%

Suboptimal response rates to hypomethylating agent therapy in chronic myelomonocytic leukemia; a single institutional study of 121 patients

et al. 2019

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Hypomethylating agents (HMA) are currently the only FDA approved therapy for patients with chronic myelomonocytic leukemia (CMML). In the current retrospective study, we assessed response rates as adjudicated by the IWG (International Working Group) MDS (myelodysplastic syndrome) and MDS/MPN myeloproliferative neoplasm overlap syndrome response criteria, in 121 CMML patients treated with Azacitidine (AZA, n = 56) and Decitabine (DAC, n = 65). The overall response rates were 41% by the IWG MDS (AZA-45%, DAC-39%), and 56% by the IWG MDS/MPN (AZA-56%, DAC-58%) response criteria, with CR (complete remission) rates of <20% for both agents, by both criteria. There were no significant differences in response rates between proliferative and dysplastic CMML. Moreover, 29% of CMML patients in a CR with HMA progressed to AML (blast transformation), underscoring the limited impact of these agents on disease biology. Progression after HMA response was associated with a median overall-survival (OS) of 8 months, while median OS in patients with primary HMA failure was 4 months. Lower serum LDH levels (<250 Units/L) were associated with HMA responses by both criteria; while ASXL1 and TET2 mutational status had no impact. HMA treated patients had a longer median OS (31 vs 18 months; P = .01), in comparison to those treated with conventional care regimens (excluding observation only patients), without any differences between AZA vs DAC (P = .37). In conclusion, this study highlights the inadequacies of HMA therapy in CMML, retrospectively validates the IWG MDS/MPN response criteria and underscores the need for newer, rationally derived therapies.

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“…A recent study also reported a high frequency of myeloid neoplasms in adults with ECD (10%), with the most common neoplasm being chronic myelomonocytic leukaemia (CMML) (Papo et al , ). It is well known that occasional CMML cases have skin infiltration with monocytes, and are frequently characterized by clonal plasmacytoid dendritic cell (DC) nodules in bone marrow biopsies (Lucas et al , ). In a recent case series, next generation sequencing of xathelesmas from three CMML patients showed identical mutations in both the marrow and skin specimen (Bonnet et al , ).…”

mentioning

confidence: 99%

Concomitant Erdheim‐Chester disease and chronic myelomonocytic leukaemia: genomic insights into a common clonal origin

et al. 2019

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Biology and prognostic impact of clonal plasmacytoid dendritic cells in chronic myelomonocytic leukemia

Cited by 74 publications

References 56 publications

Plasmacytoid dendritic cell expansion defines a distinct subset of RUNX1 mutated acute myeloid leukemia

Plasmacytoid dendritic cell expansion defines a distinct subset of RUNX1 mutated acute myeloid leukemia

Suboptimal response rates to hypomethylating agent therapy in chronic myelomonocytic leukemia; a single institutional study of 121 patients

Concomitant Erdheim‐Chester disease and chronic myelomonocytic leukaemia: genomic insights into a common clonal origin

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