Diagnosing and Treating Blastic Plasmacytoid Dendritic Cell Neoplasm in a Resource-Limited Setting

ABSTRACT

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematological malignancy with limited treatment options and poor prognosis. This case report presents the clinical course and management of a 62-year-old man with BPDCN in a resource-limited setting. The patient presented with constitutional symptoms and abnormal complete blood count findings. Initial treatment was performed with an acute lymphoblastic leukemia–based chemotherapy regimen, and the patient achieved complete remission, but the disease recurred 7 months after the initial diagnosis was confirmed in April 2022. The subsequent therapy was not effective, and the patient died during treatment. This case highlights the challenges in managing BPDCN and the need for further research to improve outcomes.

Case Presentation

A 62-year-old man was admitted to Yeolyan Hematology and Oncology Center in Yerevan, Armenia, with worsening fatigue, generalized weakness, loss of appetite, shortness of breath on exertion, and hematochezia. The patient had a history of alcohol use disorder over the past decade. Although he previously had been treated for pneumonia in another hospital, abnormal complete blood count (CBC) results prompted a referral to this hospital, the main referral center in Armenia, for further evaluation and management.

Physical examination showed that the patient had an ECOG performance status of 2. A singular bruiselike cutaneous lesion was identified on his chest, with no other skin or mucosal abnormalities. The patient had swollen eyelids, although fever and scleral icterus were absent. The patient had bloody stools and constipation. Examination disclosed a nontender, distended abdomen with palpable peripheral lymph nodes of the left axillary region.

Initial laboratory and imaging findings were significant for the following:

• CBC results showed anemia
• Hemoglobin: 9.5 g/dL
• Platelets: 64 × 109/L
• White blood cells: 18.6 × 109/L

Abdominal ultrasound revealed an enlarged liver (18.5 × 7.5 cm) and spleen (21 × 8.5 cm). Enlarged lymph nodes were also identified, with the largest in the right inguinal region (2.6 × 2.0 cm), followed by nodes in the left axillary and cervical regions. Bone marrow immunophenotyping with flow cytometry showed 73% of blast cells expressing CD4, CD7, CD56, CD38, CD43, HLA-DR, and CD123, indicating blastic plasmacytoid dendritic cell neoplasm (BPDCN). A lack of expression for specific negative markers (MPO, lysozyme, CD3, CD14, CD19, CD34) excluded T- or B-lymphoblastic leukemia and acute myeloid leukemia (AML).

Chemotherapy with the German Multicenter Acute Lymphoblastic Leukemia (GMALL) regimen for patients aged 55 to 75 years was initiated (dexamethasone, vincristine, daunorubicin, cytarabine, cyclophosphamide, methotrexate, PEG-asparaginase plus colony-stimulating factor). Induction chemotherapy led to complete remission (CR). Bone marrow aspiration showed no blasts with cell recovery. The patient had no central nervous system involvement and had received intrathecal chemotherapy according to protocol. The patient was in CR for 7 months but relapsed and continued maintenance therapy with methotrexate and 6-mercaptopurine.

Recurrent symptoms included fatigue and swollen masses in the axillary and neck regions. Blast cells were identified in CBC and bone marrow testing. Second-line induction therapy, incorporating azacitidine and venetoclax, was initiated. After the second cycle, a partial response was observed. After 2 months, because of loss of response, the patient received venetoclax plus bendamustine, which was not effective. The patient died at home 1 year after receiving the diagnosis.

Discussion

BPDCN is a rare and aggressive hematological malignancy derived from plasmacytoid dendritic cells. Due to its elusive origin, its nomenclature was not standardized in the past. In 2008, the World Health Organization (WHO) initially categorized BPDCN as a subtype of AML, but it was later recognized as a distinct entity in the 2016 revision.^1,2 In the 2022 WHO Classification of Hematolymphoid Tumors, 5th edition, the disease is recognized under myeloid/histiocytic/dendritic neoplasms.³ Although BPDCN can affect individuals of all ages and sexes, it most commonly affects older patients, with a median age of diagnosis in the sixth decade of life and a male-to-female ratio of 3:1.^3,4

Diagnosis of BPDCN is based on a combination of clinical presentation, immunophenotyping, and histopathological findings. BPDCN cells express CD4, CD56, and specific plasmacytoid dendritic cell antigens, including CD123, TCL-1, and CD303.

Notably, CD123 overexpression is a consistent feature of BPDCN.5 According to the WHO 2022 guidelines, the diagnosis of BPDCN requires the presence of CD123 and at least 1 other pDC marker (CD123, TCL1, TCF4, CD304, or CD303), along with either CD4 or CD56 expression.⁶ In the cases described above, immunophenotyping using flow cytometry demonstrated the characteristic expression of CD4, CD7, CD56, CD38, CD43, HLA-DR, and CD123. Additionally, for a confirmed diagnosis, a lack of expression for specific negative markers (MPO, lysozyme, CD3, CD14, CD19, and CD34) should be present. That condition was met in this particular case, which excluded T-lymphocyte, B-lymphocyte, and myeloid leukemias.⁷ The disease often involves multiple organs, including the skin, bone marrow, blood, and lymph nodes, with clinical manifestations varying based on the site of involvement.⁸ The patient in this case presented with constitutional symptoms, cytopenia, hepatosplenomegaly, lymph node, and skin involvement, which are commonly observed in BPDCN.

The rarity and aggressiveness of BPDCN have posed challenges in establishing a standard of care. The typical approach involves chemotherapy in conjunction with allogeneic stem cell transplantation (allo-SCT), which can extend survival.^9,10 Recent research conducted by Brüggen et al substantiated the benefits of allo-SCT compared with any form of chemotherapy regimen.¹¹ Despite the substantial supporting evidence, we couldn’t proceed with this treatment method because adult patients in Armenia did not have access to allo-SCT at that time, and the patient couldn’t afford to travel to another country for the procedure due to financial constraints.

According to results of recent studies, tagraxofusp monotherapy has shown excellent clinical results in patients with relapsed/refractory BPDCN.^12,13 During the course of this patient’s treatment, tagraxofusp, a targeted therapy specifically approved for BPDCN, was not mentioned as part of the treatment plan. Tagraxofusp is a targeted therapy that was granted accelerated approval by the FDA in 2018 for the treatment of BPDCN in patients 2 years and older.¹⁴ Tagraxofusp is a CD123-directed cytotoxin and has shown promising results in clinical trials, with response rates and CR rates of 100% and 70%, respectively, in patients who are treatment naive, and 70% and 10%, respectively, in patients who were previously treated.¹⁵ In a recent study by Pemmaraju et al, survival rates at 18 and 24 months were 59% and 52%, respectively.¹⁶ Because this drug is expensive and not readily available in Armenia, we did not treat the patient with this medication.

The patient received induction therapy following the GMALL regimen, which is commonly used in the management of BPDCN.¹⁷ Despite this multiagent chemotherapeutic regimen, the overall survival (OS) rate remains low, with relapse occurring mostly within 2 years after initial complete remission.^18-20 In a study by Huang et al, the survival rates at 1, 3, 5, and 10 years were 68.7%, 49.8%, 43.9%, and 39.2%, respectively.¹⁶ Laribi et al demonstrated that patients receiving lymphoid-type treatment regimens followed by hematopoietic stem cell transplantation (HSCT) consolidation exhibited higher CRs and lower relapse rates. Specifically in their study, the ALL-based regimen achieved a 94% CR rate with a 13% relapse rate, whereas the non-Hodgkin lymphoma–type regimens achieved a 100% CR rate with a 33% relapse rate. In contrast, patients treated with an AML-based regimen followed by HSCT consolidation had an 88% CR rate, but a higher relapse rate of 58%.²¹

In our case, due to financial constraints, we could only implement the ALL-based regimen without HSCT. Taylor et al, in a study comparing the use of these different regimens as a first-line treatment for BPDCN, analyzed 59 patients from 3 cancer centers in the United States. Patients treated with initial lymphoid-type regimens exhibited improved progression-free survival (PFS) compared with those treated with myeloid regimens (2-year PFS, 40% vs 11%, respectively; P = .075).¹⁸ In our case, we opted for the ALL-based regimen, specifically the GMALL group for patients aged 55 to 75 years, which we believe is the optimal choice in this case, even though the patient experienced a relapse after 7 months of remission.

Recognizing the aggressive nature of and frequent relapses associated with BPDCN, the patient was subsequently treated with second-line induction therapy, which included subcutaneous azacitidine and oral venetoclax. Venetoclax, a BCL2 inhibitor, is being investigated as a potential therapeutic approach. Patients’ partial and full responses to venetoclax monotherapy have shown promising results in case reports.²² Venetoclax and hypomethylating drugs such as azacitidine are also being explored in combination. ^23-25 This treatment approach had shown some response in this case, with a decrease in blast cell count and a reduction in lymph node size. However, the disease continued to progress, and the patient experienced further complications due to disease progression.

Unfortunately, despite the use of various treatment modalities and supportive care, the patient’s health continued to deteriorate, and he eventually died at home. The dismal outcomes seen in this case highlight the challenges in managing this aggressive and refractory disease.

Conclusion

In this case report, we detailed the diagnostic journey, treatment approaches, and disease progression of a 62-year-old man with BPDCN, a rare and aggressive hematological malignancy. Despite the implementation of multiple treatment strategies, including the GMALL regimen for patients aged 55 to 75 years, the patient achieved only temporary complete remission before experiencing disease relapse. The unavailability of targeted therapies such as tagraxofusp, coupled with financial constraints, limited our treatment options. Furthermore, at that time the unavailability of allo-SCT was another major challenge, despite its proven superiority in clinical studies. This case highlights the urgent need for more accessible and effective treatment modalities for BPDCN, as well as the importance of additional research to improve outcomes for this challenging malignancy. The outcome of this case serves as a reminder of the aggressive and refractory nature of BPDCN, emphasizing the pressing need for novel therapeutic approaches and resources to better manage this disease and make the best available care accessible to a wider group
of patients.

Author Affiliations

¹Yerevan State Medical University, Yerevan, Armenia

²Yeolyan Hematology and Oncology Center,
Yerevan, Armenia

³Immune Oncology Research Institute, Yerevan, Armenia

⁴Montefiore Einstein Comprehensive Cancer Center, New York, NY, USA

⁵The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Corresponding author:

Gevorg Tamamyan, MD, MSc, DSc

7 Nersisyan St, 0014, Yerevan, Armenia

Tel: +374 10 283800,
Email: gevorgtamamyan@gmail.com

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