Albiol et al. J Med Case Reports (2021) 15:326 https://doi.org/10.1186/s13256-021-02939-7 CASE REPORT Open Access Venetoclax in relapsed/refractory blastic plasmacytoid dendritic cell neoplasm with central nervous system involvement: a case report and review of the literature Nil Albiol1* , Silvana Novelli1,2, Anna Mozos3, Marta Pratcorona1,2, Rodrigo Martino1,2 and Jorge Sierra1,2 Abstract Background: We describe a patient with blastic plasmacytoid dendritic cell neoplasm with central nervous system involvement and the outcome of venetoclax use in this setting. Case presentation: A 54-year-old Caucasian male was referred to the Haematology Unit with an enlarged inguinal lymph node which was diagnostic of a blastic plasmacytoid dendritic cell neoplasm. The staging revealed dissemi- nated disease (skin, visceral, lymph nodes, and bone marrow). He received chemotherapy with an acute myeloid leukaemia-like regime. Afterwards, he underwent allogeneic haematopoietic stem cell transplantation, though it was not successful, showing a relapse 14 months later with hepatic and central nervous system dissemination. Intrathe- cal chemotherapy was administered, and venetoclax (anti-bcl2 agent) was started in an off-label indication based on most recent literature. The disease halted its course for 3 months. In the end, the patient’s disease progressed and so he succumbed due to infectious complications. Conclusions: Venetoclax monotherapy seems not enough to control the disease progression under CNS involve- ment and other treatments should be investigated. Keywords: Blastic plasmacytoid dendritic cell neoplasm, Bcl-2, Venetoclax, BPDCN Background to chemotherapy, autologous or preferably allogeneic Blastic plasmacytoid dendritic cell neoplasm (BPDCN) haematopoietic stem cell transplant (allo-HSCT) may is an aggressive haematological malignancy which fre- prolong survival [3]. However, the median survival is quently presents with skin, bone marrow (BM), lymph approximately 1 year or even shorter for patients with node, and splenic infiltration at a median age of 67 years. disseminated disease. Age >60 years, abnormal karyotype Central nervous system (CNS) involvement and circu- and TdT negativity are some prognostic factors which lating leukaemia cells might be present (10%) [1]. There have recently been associated with a lower overall sur- is no standard therapy, and patients frequently receive vival [4]. acute myeloid leukaemia (AML)-like regimens or are A gene expression analysis suggested that BPDCN enrolled in clinical trials [2]. For patients who respond was similar to AML on a molecular expression basis, and identified that the anti-apoptotic B-cell lymphoma 2 (BCL2) gene is highly expressed in BPDCN compared *Correspondence: nilalbiol@gmail.com 1 Haematology Department. Hospital de la Santa Creu i Sant Pau, Mas to normal plasmacytoid dendritic cells. BCL2 is also Casanovas 90, Barcelona, Spain expressed in AML, and recently it has been reported that Full list of author information is available at the end of the article © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. The Creative Commons Public Domain Dedication waiver (http://​creat​iveco​ mmons.​org/​publi​cdoma​in/​zero/1.​0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Albiol et al. J Med Case Reports (2021) 15:326 Page 2 of 7 some cases of AML are sensitive to the Bcl-2 inhibitor 2016, after which persisted a blast count of 11% in the venetoclax [5]. bone marrow (partial response –PR-). The main com- We present the case of a patient diagnosed with plication was pulmonary oedema due to ventricular BPDCN that relapsed after allo-HSCT; venetoclax was dysfunction secondary acute myocardial infarction considered the best therapeutic option based on recently which required implantation of a drug-coated stent on published data. the circumflex artery. He continued with an AML-like scheme with high doses of ara-C (3 g/m2 days 1, 3 and Case presentation 5) in December 2016, achieving a complete response A 54-year-old Caucasian male with a history non-ST (CR) assessed by BM biopsy and PET/CT. elevation myocardial infarction in 2015 was diagnosed Therefore, given the high risk of recurrence and the with blastic plasmacytoid dendritic cell neoplasm in availability of an identical human leucocyte antigen July 2016 due to an inguinal tumor. At the time of diag- (HLA) sibling, on March 2017 he underwent a reduced- nosis a positron emission tomography (PET/CT) scan intensity allo-HSCT (due to the history of two myocar- had revealed subcentimeter mildly hypermetabolic ade- dial infarctions), conditioned with fludarabine 52 mg/ nopathies in various territories (multiple lymph nodes day and busulfan 66 mg q6h plus graft-vs-host disease involvement, hepatic, and splenic infiltration). He also (GvHD) prophylaxis with sirolimus and tacrolimus. The had small skin plaques in lower extremities. The gan- number of haematopoietic stem cells infused was 5.02 glion biopsy had shown an infiltration of 56% of atypical ­x106 CD34/Kg. One month after transplant, April 2017, lymphocytes and peripheral blastosis, with a paracorti- a BM biopsy was performed showing CR. He developed cal infiltration by ­Tdt+ cells, without expression of B or mild skin chronic GvHD, which did not avoid immuno- T markers while CD123 and CD56 had resulted posi- suppressant suspension until 6 months after allo-HSCT. tive, and a Ki-67 index of 60%, with negativity for CD34, Nevertheless, 1 year later, March 2018, on a control CD3, CD20, myeloperoxidase, lysozyme. BM aspiration PET/CT nonspecific hepatic lesions were evidenced resulted dry and immunophenotype showed an abnormal (Fig. 1A), later confirmed by magnetic resonance imag- ­CD4+, ­CD45weak, ­CD56+, ­CD123+ and HLA-DR+ cells ing -MRI- (Fig. 2A) and tru-cut biopsy (Fig. 3); he then (dendritic cells). BPDCN is characterized by high levels received intermediate dose ara-C (1.5 g/m2 days 1–5) of CD123 and weak expression of CD45, while also being and first infusion of donor lymphocytes on May 2018. positive for CD4, CD36, CD56, as well as absence of line- One month after treatment start, a PET/CT and hepatic age-associated antigens; this is considered a unique phe- MRI (Fig. 2B) showed progression of one of the hepatic notype virtually pathognomonic of BPDCN [6]. lesions and later on that same week he consulted with a He received 2 cycles of hyper-CVAD without intrath- short history of oppressive headache, photophobia, and ecal therapy (cyclophosphamide 300 mg/m2 BID days tinnitus, without additional neurological symptoms. He 1–4, vincristine 2 mg days 4 and 11, doxorubicin 25 also referred blurred vision lasting a few minutes and mg/m2 q24h days 4–5, dexamethasone 40 mg QD days an episode of amaurosis fugax. The headache worsened 1–4 and 8–11, methotrexate 1 g/m2 day 1, and cytara- with decubitus and improved with sitting. Analgesic bine 3 g/m2 BID days 2–3) from July 2016 to November Fig. 1 A PET/CT scan with non-specific hepatic lesions (March 2018). B PET/CT scan showing progression and liver enlargement under venetoclax treatment (September 2018) Albiol et al. J Med Case Reports (2021) 15:326 Page 3 of 7 treatment was optimised without improvement, so he consulted again the day after. With suspicion of CNS dissemination, a cerebral CT scan was performed, which showed signs of leptome- ningeal spread. A lumbar puncture was executed with a high-pressure fluid outlet, so the procedure was sus- pended due to the risk of intracranial hypertension. Following the presumptive diagnosis of intracranial hypertension due to CNS dissemination of his leu- kaemia, dexamethasone (8 mg TID) was started and a new lumbar puncture was performed three days later administering triple intrathecal chemotherapy (meth- otrexate 12 mg, ara-C 30 mg, hydrocortisone 20 mg) thrice in July 2018. In cerebrospinal fluid (CSF), 1025 atypical cells were shown, compatible with dissemina- tion of dendritic cell leukaemia (Fig. 4). A week after, the 2nd dose was administered and a total of 165 cells were obtained. Three days after the 3rd dose was given obtaining 15 cells. No more CSF analysis was performed. All in all, 6 doses were given. After extensive review of literature and based on other cases previously reported [5, 7–10], taking into account that malignant cells had a high expression of bcl-2 (Fig. 3C), venetoclax off-label was begun in an ascending scheme. The patient agreed to this off-label use. He started at a dose of 50 mg QD (July 2018) and gradually increased it up to 800 mg QD. After two months under treatment, on August 2018 an hepatic MRI was performed showing stability (Fig. 2C). How- ever, on September 2018 a routine blood test suggested progression as liver enzymes and lactate dehydrogenase (LDH) increased while platelet levels went down. It was followed by a new BM aspirate and PET/CT, which confirmed progression under venetoclax treatment (Fig. 1B). A palliative strategy was adopted, stopping venetoclax and starting hydroxyurea, azacytidine and dexametha- sone. The patient eventually died one month and a half after stopping the treatment with venetoclax, on October 2018. A post-mortem next generation sequencing (NGS) TruSight®Tumor 15 (Illumina) kit, which analyses the study was performed on the liver biopsy using the following 15 genes: AKT1, BRAF, EGFR, ERBB2, FOXL2, GNA11, GNAQ, KIT, KRAS, MET, NRAS, PDGFRA, PIK3CA, RET, and TP53. The bioinformatics analysis was performed through the software Variant Studio, focus- ing on these regions: KRAS (exons 2, 3, and 4), NRAS (exons 2, 3, and 4), BRAF (exon 15), EGFR (exons 18, 19, Fig. 2 A Initial MRI showing liver spread of the disease (March 2018). 20, and 21), PIK3CA (exons 10 and 21). None of them Hepatic lesions were identified in segments VII and VIII of the liver. B was mutated. However, a mutation in the exon 7 of TP53 Progression of the hepatic lesions. C Stability of the hepatic lesions under venetoclax treatment (August 2018) (p.Gly245Ser, g. 7577548, c.733G>A) was found in 57,4% of the samples. Albiol et al. J Med Case Reports (2021) 15:326 Page 4 of 7 Fig. 3 Histological sections of the liver biopsy showed a nodular infiltrate of blast cells, with ample cytoplasm, irregular nuclei and small nucleoli. There were occasional small lymphocytes intermingled with neoplastic cells. Tumour cells were diffusely positive for TdT, CD43 and CD56, as well as CD123. Only heterogeneous expression of CD4 was observed. A Nodular infiltration of the liver by blast cells. B Neoplastic cells show diffuse immunoreactivity for CD123. C Positive immunoreactivity for bcl-2. D Occasional intense positivity for p53 (less than 3%) Fig. 4 Cerebrospinal fluid smear (May-Grünwald-Giemsa staining) showing massive blast cell infiltration of the central nervous system. Lower right quadrant detail: zoom-in of blasts morphology in CNS. Upper right quadrant detail: blast morphology in peripheral blood. Blast cells are of large size and show a monocytic appearance, with irregular nuclei shape and some of them with nucleoli Albiol et al. J Med Case Reports (2021) 15:326 Page 5 of 7 The tru-cut biopsy had already showed intense expres- symptoms. Albeit venetoclax’s role in CNS has not been sion of p53 in few cells that should be related to that specifically studied, mainly because CLL rarely involves mutation found in the NGS analysis, presumably corre- CNS, and there are no tests available in our centre to lating to a malfunctioning p53 protein, and thus leading measure its concentration in CSF, there is evidence that to a poorer prognosis. suggests it can get to the CNS, though this has only been proved in mice [9]. Discussion and conclusions Although disease progression stopped for two months, Currently, the pathogenesis underlying the transforma- better results have been achieved in the previously tion of haematopoietic progenitors to BPDCN remains described case reports. This may be due to the addi- unclear. Using targeted sequencing techniques, some tion of a hypomethylating agent in some of them or due genes (e.g. ASXL1, TP53, TET2) have been found to be to the clinical features of the patients. We did not add a mutated in BPDCN as well as in other myeloid malignan- hypomethylating agent because at that time there was cies [7]. However, none was specific of BPDCN. little evidence of its efficacy in combination therapy in Venetoclax is a bcl-2 inhibitor currently authorised to BPDCN. Thus, the fact that neither of them presented treat chronic lymphocytic leukaemia (CLL). BPDCN also CNS disease suggests a less aggressive subset of BPDCN. shows BCL2 gene overexpression and TP53 mutation [7]. Moreover, as they were not treated with allo-HSCT, the Following this reasoning, it has been tested on BPDCN disease might be more chemo-sensitive, considering they with favourable outcomes [5, 7, 8]. Montero et al. first received less intense chemotherapy regimens. In fact, the described promising results with venetoclax both in vitro patient who showed a CR of 10 months had only been and in vivo (through xenografts) [7]. They also proved in treated with CHOP and auto-HSCT, whereas our patient mice an overall survival of 21 days. received hyper-CVAD, AML-like scheme and reduced At the time of giving venetoclax to our patient, there intensity conditioning regime for allo-HSCT plus intrath- were 6 cases reported: one by Agha et al. [10] two also ecal therapy. There is also the possibility that our patient’s by Montero et al. [7] two by DiNardo et al. [5] and one disease was not fully sensitive to venetoclax, as we did by Grushchak et al. [8]. The first one responded very not perform a bcl-2 overexpression test at relapse. fast and maintained complete response for at least 9 At the time of writing this paper, more results of vene- months reported [10]. The two reported by Montero et toclax use are available. In another case report by Beziat al. had relapsed disease after CD123-targeting therapy et al., the patient did not exhibit a very good response, and achieved a partial response at 4 weeks of venetoclax as some cutaneous lesions remained stable while others treatment: one of them progressed after 12 weeks and the responded [11]. Then, two other papers in combination other one died from intracranial haemorrhage probably therapy with hypometilating agents report pretty good secondary to severe venetoclax-induced thrombocyto- results, with rapid and durable responses [12, 13]. A sum- paenia; the two included in DiNardo’s trial had received mary of cases in which venetoclax was used, including more than 2 prior lines of therapy and achieved cutane- ours, is available in Table 1. ous response with venetoclax; the remaining one relapsed Taking everything into account, there is limited bibli- after CHOP and auto-HSCT, after which received vene- ography available involving blastic plasmacytoid den- toclax achieving a CR during 10 months. Only in one of dritic cell neoplasms, and the treatment regimens are not them a PET/CT response and >50% of blast reduction in based on the strongest level of evidence [1, 2]. Moreover, bone marrow were reported. few cases are diagnosed each year and the survival rate of When comparing these patients to ours, the median them is little to nothing. age was older (73,4), neither of them had CNS involve- The best therapeutic option for a newly diagnosed ment nor were treated with allo-HSCT. Furthermore, in case of BPDCN is to be enrolled in a clinical trial or, if all the 5 cases specific techniques were used to predict not available, to receive acute lymphoblastic leukaemia bcl-2 inhibition response. Although we could not per- (ALL)-like regimens, AML-like regimens or a combina- form any of these techniques at the relapse, we decided tion of both followed by an allo-HSCT if eligible. No sta- to try it out in our patient, as the malignant cells overex- tistical differences have been observed between using an pressed bcl-2 in the previous hepatic biopsy. The disease ALL-like regime against an AML-like one [2]. However, a halted its course for two months. After that, it was reac- recent analysis by the MSKCC and two other US centres tivated reactivated. For that reason, venetoclax therapy found statistically significant differences between ALL was stopped. and AML-like regimens, suggesting a better overall sur- Even though the patient had CNS disease, during vene- vival (OS) if an ALL-like regime was used [4]. toclax treatment period no neuroimaging techniques As of clinical trials, there are different approaches were performed. However, he did not show neurologic being tested right now. The most innovative seem to Albiol et al. J Med Case Reports (2021) 15:326 Page 6 of 7 Table 1. Summary of cases available in the literature that used venetoclax in BPDCN Study N Median age Median previous lines Added treatments Type of response Max. Follow-up duration of response Grushchak et al. Medicine (2017) 1 65 2 No CR >10 months 10 months [8] Montero et al. Cancer Discov. 2 76,5 3 No PR 4 weeks Until death (2017)[7] DiNardo et al. Am J Hematol. 2 74,5 3 Yes, NR but prob- CR/PR NR NR (2018)[5] ably HMA or LDAC Agha et al. N Engl J Med. (2018) 1 62 4 No CR >9 months 9 months [10] Beziat et al. Leuk Res. (2019)[11] 1 77 1 No PR 1 month NR Piccini et al. Ann Hematol. (2020) 1 64 2 Azacitidine CR >11 months 11 months [12] Samhouri et al. J Oncol Pharm 1 79 1 Azacitidine PR >6 months 6 months Pract. (2020)[13] Albiol et al. J Med Case Rep. (2021) 1 54 4 plus intrathecal therapy No PR 3 months Until death CR complete response, PR partial response, NR not reported, HMA hypomethylating agent, LDAC low-dose ara-C be those targeting CD123 (interleukin-3 receptor), as it Moreover, considering the infrequency of this disease it is quite specific of blastic plasmacytoid dendritic cells. is unlikely that in the nearly following years we can get and IL-3 fusion protein -Tagraxofusp (Tagrax®)- also One of the most promising trials is a diphtheria toxin any strong evidence about it. known as SL-401 [14, 15]. It is a CD-123 directed cyto- Abbreviations toxin which has shown high response rates at the cost BPDCN: Blastic plasmacytoid dendritic cell neoplasm; BM: Bone marrow; CNS: of little toxicity, so it enlightens the future of BPDCN Central nervous system; AML: Acute myeloid leukaemia; allo-HSCT: Allogeneic management. It was approved by the Food and Drug haematopoietic stem cell transplant; DNA: Deoxyribonucleic acid; PET/CT: Positron emission tomography/computerised tomography scan; PR: Partial Administration (FDA) in December 2018 and it is now response; CR: Complete response; FDA: Food and Drug Administration; GVHD: recommended as a first line induction regime (evidence Magnetic resonance imaging (MRI); HLA: Human leucocyte antigen; TID: Ter grade 2C) [16]. in die; CSF: Cerebrospinal fluid; QD: Quaque die; BID: Bis in die; NGS: Next Generation Sequencing; CLL: Chronic Lymphocytic Leukaemia; ALL: Acute There are also antibodies against CD-123 (e.g. lymphoblastic leukaemia; MSKCC: Memorial Sloan Kettering Cancer Center; IMGN632, a CD123-Targeting Antibody-Drug Con- OS: Overall survival; ADC: Antibody-Drug Conjugate; CAR-T cells: Chimeric jugate (ADC) with a deoxyribonucleic acid (DNA)- Antigen Receptor T cells. Alkylating Payload) and CAR-T cells [17], which are Acknowledgements showing promising results but are still on preclinical Not applicable. phase due to safety profile issues [18]. Authors’ contributions Other promising agents include pralatrexate, an anti- NA gathered the data and wrote the main text of the report. SN reviewed folate drug used in 8 patients with BPDCN achieving and corrected the manuscript, and she also was the main physician in charge an overall response rate of 75% and 4 of them reach- of the treatment decisions. AM performed the histological analysis of the biopsies’ samples. MP performed and interpreted the molecular analysis of ing complete response, and enasidenib, an IDH2 inhibi- the sample. RM performed the research involving this patient’s clinical deci- tor which halted disease progression for 8 months in a sions. JS reviewed and corrected the manuscript. Consent for publication patient with IDH2 mutation [4]. was obtained from all of the authors. All authors read and approved the final manuscript. All in all, evidence suggests that venetoclax in com- bination with hypomethylating agents could be use- Funding ful in some BPDCN patients, but in advanced stages it No funding was granted for this research. shows little efficacy, especially if it is used alone. Nev- Availability of data and materials ertheless, further studies are needed to demonstrate its Data sharing is not applicable to this article as no datasets were generated or real role. Currently, there is an on-going clinical trial analysed during the current study. (NCT03485547) which is trying to give more answers. Albiol et al. J Med Case Reports (2021) 15:326 Page 7 of 7 Declarations 7. Montero J, Stephansky J, Cai T, Griffin GK, Cabal-Hierro L, Togami K, et al. Blastic plasmacytoid dendritic cell neoplasm is dependent on BCL-2 and Ethics approval and consent to participate sensitive to venetoclax. Cancer Discov. 2017;7(2):156. This report has been approved by the Ethics Committee of Hospital de la 8. Grushchak S, Joy C, Gray A, Opel D, Speiser J, Reserva J, et al. Novel Santa Creu i Sant Pau and all of the research has been performed in accord- treatment of blastic plasmacytoid dendritic cell neoplasm: a case report. ance with the Declaration of Helsinki. Medicine (Baltimore). 2017;96(51):e9452. 9. Reda G, Cassin R, Dovrtelova G, Matteo C, Giannotta J, D’Incalci M, et Consent for publication al. Venetoclax penetrates in cerebrospinal fluid and may be effec- Written informed consent was obtained from the patients for publication of tive in CLL with central nervous system involvement. Haematologica. this case report and any accompanying images. A copy of the written consent 2019;104(5):e222. is available for review by the Editor-in-Chief of this journal. 10. Agha ME, Monaghan SA, Swerdlow SH. Venetoclax in a Patient with a Blastic Plasmacytoid Dendritic-Cell Neoplasm. N Engl J Med. Competing interests 2018;379(15):1479–81. https://​doi.​org/​10.​1056/​NEJMc​18083​54. The authors declare no conflicts of interests. 11. Beziat G, Ysebaert L, Gaudin C, Steinmeyer Z, Balardy L. Venetoclax to treat relapsed blastic plasmacytoid dendritic cell neoplasm: a case-report Author details and review of literature. Leukemia Research. 2019;85:106199. 1 Haematology Department. Hospital de la Santa Creu i Sant Pau, Mas Casano- 12. Piccini M, Loscocco GG, Gianfaldoni G, Grieco P, Palmieri G, Pilerci S, et al. vas 90, Barcelona, Spain. 2 Josep Carreras Leukaemia Research Institute (Hospi- Quick complete response achievement with venetoclax and azacitidine tal Sant Pau Campus), Barcelona, Spain. 3 Pathology Department. Hospital de la in a case of relapsed disseminated blastic plasmacytoid dendritic cell Santa Creu i Sant Pau, Barcelona, Spain. neoplasm. Ann Hematol. 2020;99:907–9. 13. Samhouri Y, Ursu S, Dutton N, Tanvi V, Fazal S. 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