Bone Marrow Clonal Hematopoiesis Prevalent in Elderly Patients with BPDCN

Take-aways:

• A high prevalence of BM CH was found in patients with BPDCN.
• BM CH was significantly associated with older males and frequently shared a clonal origin with BPDCN in elderly patients.
• Karyotypic abnormalities were detected in 66% of BPDCN but only 2% of BM hematopoietic cells, providing additional evidence of clonal evolution.

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Researchers have identified a high incidence of bone marrow (BM) clonal hematopoiesis (CH) in patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), according to a study published in Leukemia.

The study, led by Mahsa Khanlari, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, determined that BM CH was present in nearly two-thirds of BPDCN patients and was particularly prevalent in elderly patients.

Dr. Khanlari and colleagues also elucidated the clonal relationship between BM CH and BPDCN by identifying the respective mutations in BM hematopoietic cells and BPDCN cells in a large cohort of patients with a confirmed diagnosis of BPDCN.

“Our study is the first to show how BPDCN is related to BM CH beyond individual case studies,” the authors noted. “In summary, we show for the first time that BM CH is very prevalent in elderly patients with BPDCN.”

Study Cohort

Targeted next-generation sequencing (NGS) was performed on multiple BM, skin lesion, or sorted BPDCN cell samples from 51 patients with known BPDCN, of which 39 (77%) were men, and the median age was 68.7 years.

To enable a cytogenetic analysis of BPDCN versus BM hematopoietic cells, conventional karyotypic analysis was performed on G-banded metaphase cells prepared from unstimulated BM aspirate cultures.

At the time of BPDCN diagnosis, skin lesions with biopsy-proven BPDCN were present in 90% of patients, and BM involvement by BPDCN was present in 73% of patients, showing ≥10% BPDCN cells in 55%. “We, for the first time, show that substantial (≥10%) BM involvement at initial diagnosis by BPDCN is an independent risk factor,” Sa A. Wang, MD, a coauthor of the study, told Blood Cancers Today.

Of the cohort, 27 patients had BPDCN mutations, with TET2 being the most frequent (n=14), followed by ASXL1, NRAS, ZRSR2, ETV6, SRSF2, KRAS, and TP53. The remaining cohort could not be tested due to inadequate samples (16 patients) or the inability to verify whether the mutations came from BM hematopoietic cells or BPDCN cells (8 patients).

In terms of the BM CH mutations, 30 patients had confirmed BM hemato­poietic cell mutations; mutations were not present in 16 patients, and for five of the patient samples, researchers could not determine whether the mutation occurred in BM hematopoietic cells. TET2 was again the most frequently detected mutation (n=25), followed by ASXL1, SRSF2, ZRSR2, JAK2, DNMT3A, NRAS, BRINP3, and HRNPK.

Of 30 patients with confirmed mutations in BM hematopoietic cells, 11 (37%) had myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), or myeloproliferative neoplasms (MPNs), whereas none of the patients without BM CH had such a diagnosis (P=.008).

In terms of cytogenetics, an abnormal karyotype was detected in 15 patients (29%), including nine with a complex karyotype (CK).

BPDCN, BM Clonal Relationship

Researchers investigated the clonal relationship between BPDCN and BM hematopoietic cells in 24 patients by comparing mutation profiles of the paired samples. A clonal relationship was demonstrated in 13 patients (54%), with TET2 (n=10), ASXL1 (n=4), and ZRSR2 (n=2) being the most commonly shared mutations. In 10 patients (42%), mutations or karyotypic abnormalities were detected in BPDCN cells but not in the corresponding BM hematopoietic cells.

Overall, a higher number of mutations were found in BPDCN (median, 2 mutations; range, 0-7 mutations) than BM hematopoietic cells (median, 1 mutation; range, 0-4 mutations; P=.017), with NRAS (n=9) being the most common additional mutation in BPDCN.

Karyotypes of BPDCN were assessable in 29 patients, of which 19 (66%) had an abnormal karyotype, including 17 with a CK, and two with single abnormalities. In the 49 assessable BM hematopoietic cell samples, in contrast, only one karyotypic abnormality was detected, providing additional evidence of clonal evolution.

The patients with confirmed mutations in BM hematopoietic cells were significantly older (median age, 75.8 vs 36.8 years; P<.001) and more often male (90% vs 63%; P=.047).

“Our findings indicate that in a substantial subset of BPDCN patients, BM hematopoietic cells are not genetically altered, especially in young patients,” the authors wrote. “These data suggest that, in some cases of BPDCN, tumorigenesis may occur later in the process of progressive lineage commitment to myeloid-origin resting [plasmacytoid dendritic cells], which may be particularly true in pediatric or young adult patients.”

“These findings suggest that the origin of BPDCN may be diverse, especially between pediatric/young adults and elderly patients, which should be further explored,” said Dr. Wang.

The authors acknowledged that their method of determining mutations in BPDCN versus BM hematopoietic cells by comparing mutations in BM heavily involved by BPDCN could have been confounded by other genetic events, tumor heterogeneity, and imprecision of measurements. In addition, they noted that the frequency of CH in BPDCN patients could have been higher if a larger NGS panel or whole exome sequencing had been performed.

Another limitation was that of the 30 patients with confirmed mutations in BM hematopoietic cells, 11 (37%) had MDS, CMML, or MPNs, diagnosed either prior to BPDCN or at the same time the patient underwent BM staging for BPDCN involvement. Some of the remaining BM patients, although they did not meet the World Health Organization criteria for MDS or CMML, may have been biologically close to clonal cytopenia of unknown significance or low-grade MDS.

Reference

Khanlari M, Yin CC, Takahashi K, et al. Bone marrow clonal hematopoiesis is highly prevalent in blastic plasmacytoid dendritic cell neoplasm and frequently sharing a clonal origin in elderly patients. Leukemia. 2022;36(5):1343-1350.