{"doi":"10.1002/ajh.26417","title":"Venetoclax and hypomethylating agents in older/unfit patients with blastic plasmacytoid dendritic cell neoplasm","abstract":"Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive hematological neoplasm predominantly afflicting older males (median age; 66–70 years), frequently characterized by a cutaneous, lymph node, bone marrow, and/or central nervous system (CNS) involvement with dismal outcomes.1, 2 Tagraxofusp, a CD123 directed antibody conjugate composed of human interleukin-3 (IL-3) and truncated diphtheria toxin, is an approved therapy for BPDCN, with high response rates of 90% and 67% among untreated patients and those with relapsed disease, respectively.3 Nonetheless, survival continues to be compromised with 24-month overall survival of 52% and median overall survival of 8.5 months in treatment naïve and relapsed patients, respectively.3 Moreover, treatment-induced toxicities are not uncommon with potential for fatality; hepatotoxicity (64%), hypoalbuminemia (55%), thrombocytopenia (49%), and capillary leak syndrome (19%).3 Notably, not all patients with BPDCN will be eligible for CD123-targeted therapy as in the setting of baseline severe hypoalbuminemia, cardiac co-morbidities, or renal insufficiency. Furthermore, the widespread availability of CD123-targeted agents beyond the US and EU is not common. Allogeneic stem cell transplantation (SCT) can result in long-term remissions for selected younger/fit patients with BPDCN but given the older median age and significant co-morbidities in many real-world patients with BPDCN, SCT is often not an option.4 Interestingly, in pre-clinical investigations, BPDCN cells depicted BCL-2 dependence,5 and epigenetic dysregulation6-9 and treatment with venetoclax have been administered as monotherapy or in combination with chemotherapy in small series of patients.10 Venetoclax (Ven), an oral BCL-2 inhibitor in combination with hypomethylating agents (HMA) is approved for elderly and/or unfit acute myeloid leukemia (AML).11-13 Accordingly, we share our experience with Ven and HMA in 10 patients (median age; 70 years [range; 22–82 years]) with BPDCN treated at the Mayo Clinic (Rochester, MN [n = 3], Arizona [n = 1], Florida [n = 1]), and MD Anderson Cancer Center (n = 5). Study patients were retrospectively recruited after respective institutional review board approval. Diagnosis was established by skin, lymph node, or bone marrow biopsy. In addition, all patients underwent positron emission tomography (PET) imaging and cerebrospinal fluid sampling to evaluate for nodal and CNS disease. Table 1 summarizes clinical characteristics including treatment details for all 10 BPDCN patients treated with Ven + HMA. Notably, the majority of patients had baseline co-morbidities, including renal failure, cardiac disease, hypoalbuminemia, hepato-biliary disease that limited upfront CD123-targeted and clinical trial-based therapy. It is, therefore, an urgent unmet medical need to investigate non-CD123-based and noncytotoxic chemotherapy regimens that can be safely delivered in the setting of extensive co-morbidities in older/unfit patients with BPDCN.14, 15 All patients in this case series that were offered treatment with HMA + VEN in the front-line or for relapsed disease responded to therapy, although responses were short-lived, two patients proceeded to allogeneic SCT, and transplant is forthcoming for another patient. A detailed overview of five patients treated at the Mayo Clinic is provided below. ASXL1 TET2 ZRSR2 Azacitidine 75 mg/m2 day 1–7 Ven 400 mg × 28 days 2 cycles Complete response after 2 cycles (14 months ongoing) Haploidentical transplant 4 months post-diagnosis Alive 17 months Post-diagnosis 13 months post-transplant ASXL1 VUS SH2B3 TERT TET2 Azacitidine 75 mg/m2 day 1–7 + Ven 400 mg × 28 days (cycle 1–2), Azacitidine 75 mg/m2 day 1–5 + Ven 100 mg × 14 days (cycle 3–5) Treatment interruption 3 months Azacitidine 75 mg/m2 day 1–7 + Ven 100 mg × 28 days (cycle 6) Complete response after 2 cycles (6 months) Cutaneous Relapse 6 months after achieving CR Prolonged Cytopenias Reactivation of ","journal":"American Journal of Hematology","year":2021,"id":165128,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":37,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9679,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":18373,"name":"Marina Konopleva","orcid":"0000-0002-9347-2212","position":1,"is_corresponding":false},{"id":284241,"name":"Mrinal M. Patnaik","orcid":"0000-0001-6998-662X","position":2,"is_corresponding":false},{"id":230404,"name":"Elias Jabbour","orcid":"0000-0003-4465-6119","position":3,"is_corresponding":false},{"id":109577,"name":"Courtney D. DiNardo","orcid":"0000-0001-9003-0390","position":4,"is_corresponding":false},{"id":284256,"name":"Aref Al‐Kali","orcid":"0000-0002-0824-3715","position":5,"is_corresponding":false},{"id":339782,"name":"James M. Foran","orcid":"0000-0003-1673-1708","position":6,"is_corresponding":false},{"id":688691,"name":"Ginna L. Granroth","orcid":null,"position":7,"is_corresponding":false},{"id":688030,"name":"Horatiu Olteanu","orcid":"0000-0001-5783-4485","position":8,"is_corresponding":false},{"id":232841,"name":"Tapan M. Kadia","orcid":"0000-0002-9892-9832","position":9,"is_corresponding":false},{"id":431828,"name":"Ayalew Tefferi","orcid":"0000-0003-4605-3821","position":10,"is_corresponding":false},{"id":232838,"name":"Naveen Pemmaraju","orcid":"0000-0002-1670-6513","position":11,"is_corresponding":false},{"id":431829,"name":"Naseema Gangat","orcid":"0000-0002-9104-6172","position":0,"is_corresponding":true}],"reference_count":21,"raw_metadata":null,"created_at":"2026-07-18T23:45:36.425208Z","pmid":"34807470","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}