Genetic Landscape of BPDCN Arising in CML Remission

Background

BPDCN (blastic plasmacytoid dendritic cell neoplasm) is a rare and highly aggressive hematologic malignancy which often affects skin lesion. BPDCN initially responds to traditional chemotherapy, but has a high relapse rate and a poor prognosis even after autologous or allogeneic stem cell transplantation (SCT). Almost all patients have CD123 positive tumor, and CD123 targeting therapies are being developed.

BPDCN mainly develops de novo, however, up to 20% of BPDCN patients have prior history of other hematologic malignancies (CMML, AML, MDS). Some groups propose to classify BPDCN with PCHM (preexisting or concurrent hematologic malignancies) into a unique subtype based on the clinical course (Blood (2019) 134 (Supp.1): 2723). On the other hand, there are attempts to classify BPDCN according to molecular profile, and they defined two subclasses based on somatic mutations (Blood Cancer Journal (2022) 12:101). Thus substantial efforts are being made to classify BPDCN from various aspects, the classification is still under development due to insufficient number of cases.

Herein we experienced a rare case of BPDCN arising in the course of CML as a history of PCHM. Unexpectedly, there have been no reports of BPDCN with preexisting CML, therefore, we report the clinical course and genetic background in our case.

Case: 70 year old male

Clinical course of CML:

He was referred to our hospital at age 60 with elevated white blood cell count (93,550/ul, blast 1.0%). Diagnosis of CML (chronic phase) was made; Sokal score was 0.31 (low risk). With initial therapy of dasatinib 100 mg, his disease status achieved complete molecular response (CMR) at 24 months of treatment; achieved CMR (MR 4.5) at 43 months. Due to side effects (pleural effusion and cytopenia), dasatinib was discontinued at month 74 of treatment, and however, CMR has been maintained.

Clinical course of BPDCN:

At 48 months after completion of dasatinib treatment, multiple bruise-like skin lesions appeared on the head and abdomen. Skin biopsy revealed diffuse proliferation of blastic cells. Immunohistochemistry and flow cytometry were positive for CD4, CD56, and CD123, and a diagnosis of BPDCN was made. Bone marrow involvement (13%) was also observed. HyperCVAD/MA (cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate and arabinocytocine) was selected as induction therapy. The skin and bone marrow lesions rapidly improved and the patient achieved hematological remission, but a few CD123-positive tumor cells remained in the bone marrow. Considering autologous SCT, peripheral blood stem cell collection was performed. Unfortunately, the graft was contaminated with CD123-positive cells, and it was determined that autologous SCT was not expected. Allogeneic SCT was not planned due to age and regimen related toxicity. We are currently preparing to conduct a clinical trial of CD123-targeting agent.

Molecular Analysis

WES of peripheral blood and bone marrow samples was performed. At the hematological remission after 2 cycles of HyperCVAD/MA, high VAF mutations in the splicing factor ZRSR2 gene (p.Y292X (84.6-85.2% VAF)) as well as the histone modifiers ASXL1 (p.L743fs (40.6-43.1% VAF)) and TET2 (c.3955-2A>G (36.2-38.3% VAF), p.T1959fs (42.1-47.0% VAF)) were observed. ZRSR2 nonsense mutation site in our case was located 3 residues upstream of the previously reported site, which has not been reported in previous BPDCN cases (Cancer Discovery (2022) 12: 522-541). Although the tumor cell rate in each sample was less than 10%, the VAF of ZRSR2 mutation was high (84.6-85.2%), indicating that clonal hematopoiesis with ZRSR2 mutations underlies the development of BPDCN.

Conclusion

This is the first report of BPDCN with a history of CML as a preceding hematologic malignancy. Based on WES data at the remission of BPDCN, we confirmed that the patient had clonal hematopoiesis with not only ASXL1 and TET2 mutations, but also ZRSR2 mutation, a driver mutation characteristic of BPDCN. Despite the fact that clonal hematopoiesis with ASXL1 and TET2 mutations is occasionally observed after CML treatment with TKIs (Blood (2017) 129: 38-47), there were no case reports of BPDCN in patients with preexisting CML. These facts suggest that the presence of mechanism is essential for the development of BPDCN other than driver mutation in ZRSR2. Further investigation of BPDCN with PCHM would provide useful information on the pathogenesis of BPDCN.

Ogawa:Esai Pharmatheutical: Consultancy; ASAHI Genomics: Current equity holder in publicly-traded company; Chordia Threapeutics: Consultancy, Current equity holder in publicly-traded company, Research Funding; Otsuka Pharmatheutical: Research Funding; Sysmex: Honoraria; Nanpu Hospital: Research Funding; Astellas: Speakers Bureau; Novartis: Honoraria, Speakers Bureau; The Mitsubishi foundation: Honoraria; MSD: Speakers Bureau; Clinical Research Support Center Kyushu: Research Funding; Kirin/Chugai: Speakers Bureau; The Chemo-Sero-Therapeutic Research Institute: Speakers Bureau; Astrazeneca: Speakers Bureau; DaiichiSankyo: Speakers Bureau; Pfaizer: Speakers Bureau; 2013-526957 (JP02): Patents & Royalties; 2013-096582 (JP01): Patents & Royalties; 2015-239547: Patents & Royalties; PCT/JP2014/062112 (WO01): Patents & Royalties; 15/353395 (US03): Patents & Royalties; 62/187386 (US01): Patents & Royalties; 2014-191287: Patents & Royalties. Nannya:Bristol Myers Squibb: Speakers Bureau; Otsuka Pharmaceutical: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo RD Novare: Research Funding; Daiichi Sankyo Co., Ltd: Research Funding; Filgen: Speakers Bureau; Janssen Pharmaceutical: Speakers Bureau; Nippon Shinyaku: Speakers Bureau; Asahi Kasei Pharma: Speakers Bureau; Kyowa-Kirin: Speakers Bureau; Fuji Pharma: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Speakers Bureau; Sumitomo Pharma: Speakers Bureau; Chugai Pharmaceutical: Speakers Bureau; Pfizer: Speakers Bureau; Takeda Pharmaceutical Company: Speakers Bureau.