Blastic plasmacytoid dendritic cell neoplasm: the first report of two cases treated by 5‐Azacytidine

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy which was first included as an independent cutaneous lymphoma in the 2008 World Health Organisation (WHO) classification (1). BPDCN usually has an extremely poor prognosis, with quick relapses after chemotherapy (2; 3). Here, we report two cases of patients diagnosed in 2011 with BPDCN and myelodysplasia, and who were treated for the first time with 5‐azacytidine (5‐Aza); a drug approved by the Food and Drug Administration (FDA) and mainly used in the treatment of myelodysplastic syndrome (Kaminskas E, et al. 2005 Clin Cancer Res, 11, 3604–8). The first case was an 81‐year‐old man who presented with unusual CD10+, CD56‐ immunohistochemistry and 45X, ‐Y abnormality using fluorescent in situ hybridization (FISH) analysis. The second case was a 78‐year‐old woman who manifested monosomy 13 and chromosome instability due to D13S319 locus deletion in 13q14 as determined by FISH. Both patients showed excellent responses of their skin lesions after one cycle of chemotherapy, and their hematological disease was stabilized; however, pulmonary sepsis set in, followed by neutropenia after the fourth and the fifth cycle of treatment, that is, eight and 9 months postdiagnosis, respectively, leading to patient death.     

母细胞性浆细胞样树突细胞肿瘤1例及文献复习

目的:通过病例报道及文献复习提高对母细胞性浆细胞样树突细胞肿瘤的临床及病理特征的认识。方法:报道1例母细胞性浆细胞样树突细胞肿瘤患者的临床表现、实验室检查及病理特点,观察CHOP方案疗效,并进行文献复习。结果:CHOP方案化疗对该患者疗效不佳。结论:母细胞性浆细胞样树突细胞肿瘤具有高度侵袭性,预后差,治疗方案尚未统一,尤其高龄患者的有效治疗还有待进一步的研究。     

Blastic plasmacytoid dendritic cell neoplasm: diagnostic criteria and therapeutical approaches

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare haematological malignancy derived from the precursors of plamacytoid dendritic cells, with an aggressive clinical course and high frequency of cutaneous and bone marrow involvement. Neoplastic cells express CD4, CD43 (also termed SPN), CD45RA and CD56 (also termed NCAM1), as well as the plasmacytoid dendritic cell‐associated antigens CD123 (also termed IL3RA), BDCA‐2 (also termed CD303, CLEC4E) TCL1 and CTLA1 (also termed GZMB). The median survival is only a few months as the tumour exhibits a progressive course despite initial response to chemotherapy. The best modality of treatment remains to be defined. Generally, patients receive acute leukaemia‐like induction, according to acute myeloid leukaemia (AML)‐type or acute lymphoid leukaemia (ALL)‐type regimens. The frequent neuromeningeal involvement indicates systematic pre‐emptive intrathecal chemotherapy in addition to intensive chemotherapy. Allogeneic haematopoietic stem cell transplantation (HSCT), particularly when performed in first remission, may improve the survival. Preliminary data suggest a potential role for immunomodulatory agents and novel targeted drugs. Herein epidemiology, clinical manifestations, diagnosis and management of BPDCN will be presented. In detail, this review focuses on the therapeutic aspects of BPDCN, proposing a treatment algorithm for the management of the disease, including induction chemotherapy, allogeneic HSCT and intrathecal prophylaxis at different steps of treatment, according to compliance, biological and clinical characteristics of patients.     

Cytoplasmic nucleophosmin is not detected in blastic plasmacytoid dendritic cell neoplasm

Acute myeloid leukemia carrying cytoplasmic mutated nucleophosmin (NPMc⁺ AML) and blastic plasmacytoid dendritic cell neoplasm have been included as new entities in the 4^th edition (2008) WHO classification of myeloid neoplasms. These conditions may show clinical and pathological overlapping features (leukemic and skin involvement, and expression of macrophage markers). In this study, we provide evidence that aberrant cytoplasmic dislocation of nucleophosmin – the immunohistochemical surrogate for NPM1 mutations – allows the two entities to be genetically separated. In fact, nucleophosmin is consistently cytoplasmic in NPMc⁺ AML (because of the presence of NPM1 mutations), whilst it is nucleus-restricted (predictive of a germline NPM1 gene) in blastic plasmacytoid dendritic cell neoplasm. Our results clearly point cytoplasmic nucleophosmin (a full predictor of NPM1 mutations) as a new marker for distinguishing NPMc⁺ AML and blastic plasmacytoid dendritic cell neoplasm, further clarify the cell of origin of NPMc⁺ AML, and justify the inclusion of these pathological conditions as separate entities in the new WHO classification.     

Blastic plasmacytoid dendritic cell neoplasm in children: diagnostic features and clinical implications

Background

Blastic plasmacytoid dendritic cell neoplasm is a rare malignancy that typically follows a highly aggressive clinical course in adults, whereas experience in children with this disease is very limited.

Design and Methods

This retrospective study analyzed the pathological and clinical findings of nine cases of blastic plasmactyoid dendritic cell neoplasm presenting in patients under the age of 18 years who were reviewed at our institution. We also identified 20 well-documented additional pediatric cases in the literature.

Results

In the combined analysis, the overall survival rate among the 25 patients with available follow-up, all having received chemotherapy, was 72% (follow-up ranging from 9 months to 13 years, with a median of 30 months). The event-free survival rate was 64%. Nine patients were alive 5 years after the original diagnosis, although only three of them had undergone hematopoietic stem cell transplantation – one in first complete remission and two in second remission. Of the seven patients who lacked cutaneous disease at presentation, 100% survived, including five who were alive more than 5 years after diagnosis, although only two had undergone stem cell transplantation. Among the 18 patients who presented with cutaneous disease and for whom follow-up data were available, only 11 survived (61%). Detailed immunophenotypic characterization and clinical features of all cases are presented. Unexpectedly, three of four cases of blastic plasmacytoid dendritic cell neoplasm tested showed focal positivity for S-100. S-100 was negative in 28 cases of acute myeloid leukemia evaluated for this marker.

Conclusions

In contrast to adult cases, in which long-term survival depends on stem cell transplantation in first complete remission, blastic plasmacytoid dendritic cell neoplasms in children are clinically less aggressive. Treatment with high-risk acute lymphoblastic leukemia-type chemotherapy appears to be effective, and stem cell transplantation may be reserved for children who relapse and achieve a second remission. Outcomes were more favorable in cases that lacked cutaneous disease at presentation, although a comparison of cutaneous and non-cutaneous cases might be confounded by differences in treatment regimens. Focal expression of S-100 may be seen in concert with other markers of plasmacytoid dendritic cells.     

Activity and safety of combination chemotherapy with methotrexate,ifosfamide, l‐asparaginase and dexamethasone (MILD) for refractory lymphoid malignancies: a pilot study

Optimal salvage chemotherapy has not been established for lymphoid malignancy, which is refractory to the conventional cyclophosphamide, doxorubicin, vincristine, and prednisone regimen. To explore an effective regimen, we conducted a phase I pilot study of combination chemotherapy with methotrexate, ifosfamide, l‐asparaginase and dexamethasone (MILD), which are unaffected by MDR1‐encoded P‐glycoprotein. A total of 18 patients with lethal lymphoid malignancy were enrolled over a 2‐yr period. The median age was 63 yr. Eleven patients had T/NK‐cell malignancies, six had B‐cell malignancies, and one was diagnosed with a blastic plasmacytoid dendritic cell neoplasm. Patients aged ≥60 and <60 yr were planned to receive a set of starting doses of methotrexate and ifosfamide, which should induce myelosuppression. Eleven patients completed two courses of MILD therapy. Treatment‐related death because of systemic mucormycosis was observed in one patient. Major treatment‐related adverse events were grade 3 or more hematologic toxicities, which included lymphopenia corresponding to dose‐limiting toxicity. The most common grade 3 non‐hematologic toxicity was febrile neutropenia. Of the 14 evaluated patients, three achieved a complete response, and four showed a partial response. The overall response rate was 57%. It was very interesting that all of seven responders had T/NK‐cell malignancies. MILD therapy was feasible and presented acceptable toxicity in patients with refractory or lethal lymphoid malignancies. The efficacy for T/NK‐cell malignancies should be further evaluated.     

Diabetic ketoacidosis secondary to L‐asparaginase in acute lymphoblastic leukaemia

We describe a case of severe hyperglycaemia resulting in diabetic ketoacidosis secondary to L‐asparaginase. There are few reports of this potentially life‐threatening complication, particularly in the English literature. Awareness and recognition of this preventable and manageable problem will improve safe delivery of this anti‐leukaemic drug.     

Circulating plasmacytoid dendritic cells in patients with primary and Helicobacter pylori-associated immune thrombocytopenia

Objectives: Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by the production of autoreactive antibodies against platelet antigens. Although dysfunction of multiple aspects of cellular immunity is considered to be important in the pathogenesis of ITP, it has not been clarified which cell types play a principal role. Methods: We enrolled 46 untreated patients with chronic ITP and 47 healthy adult volunteers, and investigated by flow cytometry the percentage and absolute number of cells in their peripheral blood that participate in the regulation of cellular immunity. These included plasmacytoid dendritic cells (pDCs), myeloid dendritic cells (mDCs), natural killer (NK) cells, natural killer T (NKT) cells, regulatory T (Treg) cells, and Th17 cells. Results: We found a significant reduction in the absolute number of pDCs, but not of mDCs, in patients with ITP when compared with healthy controls (P < 0.001). Reduced numbers of circulating pDCs were observed in both Helicobacter pylori (H. pylori)‐positive and Helicobacter pylori (H. pylori)‐negative patients with ITP. In contrast, there were no significant differences in the numbers of circulating Treg cells, Th17 cells, NK cells, or NKT cells. Interestingly, we observed increases in the number of pDCs after H. pylori eradication by antibiotics in responders but not in non‐responders, while pDCs and mDCs decreased markedly after prednisolone therapy in both responders and non‐responders. In patients without treatment, low pDC numbers persisted during the observational period. Conclusions: We demonstrated that the number of circulating pDCs is low in patients with primary and H. pylori‐associated ITP and that it changes depending on treatment modality. Further investigation is warranted with regard to the role of pDCs in the immunopathogenesis of ITP.     

Viral suppression correlates with dendritic cell restoration in chronic hepatitis B patients with autologous cytokine‐induced killer cell transfusion

Background: Myeloid and plasmacytoid dendritic cells (mDCs, pDCs) are functionally impaired in patients with chronic hepatitis B (CHB). Adoptive immunotherapy can suppress hepatitis B virus (HBV) replication in CHB patients, but whether it can restore the functionality of mDCs and pDCs remains unknown. Methods: Autologous cytokine‐induced killer (CIK) cells obtained from 14 CHB patients were transfused back to patients, case by case, to observe the effect of CIK‐cell treatment on the frequency and functionality of mDCs and pDCs in CHB patients during a 24‐week follow‐up investigation. Results: Seven virological responders exhibited a sustained decrease in HBV load after CIK‐cell transfusion; another seven non‐virological responders showed only sustained high levels of HBV load during the 24‐week period following CIK‐cell transfusion. The rate of hepatitis B e antigen loss or seroconversion was also higher in virological responders than in non‐virological responders. Importantly, we found that the frequency and cytokine‐producing capacity of mDCs and pDCs increased significantly in virological responders, but not in non‐virological responders. In addition, these patients exhibited a close correlation between restoration DC subsets and a decrease in HBV DNA load, rather than a change in the alanine aminotransferase level. Conclusion: Cytokine‐induced killer‐cell treatment reduced HBV DNA load in some CHB patients; the efficiency at least partially correlates with the restoration of frequency and functionality of mDCs and pDCs.     

Melatonin synergizes with low doses of L‐DOPA to improve dendritic spine density in the mouse striatum in experimental Parkinsonism

The dopamine precursor, L‐3,4‐dihydroxyphenylalanine (L‐DOPA), is the preferred drug for Parkinson's disease, but long‐term treatment results in the drug‐induced dyskinesias and other side effects. This study was undertaken to examine whether melatonin could potentiate low dose L‐DOPA effects in 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced experimental parkinsonism. Mice were treated with the parkinsonian neurotoxin, MPTP, and different doses of melatonin and low doses of L‐DOPA. Behavior, striatal histology, and dopamine metabolism were evaluated on the 7th day. MPTP‐induced striatal dopamine loss was not modified by melatonin administration (10–30 mg/kg; i.p. at 10‐hr intervals, 6 times; or at 2‐hr intervals, by day). However, low doses of L‐DOPA (5 mg/kg, by oral gavage) administered alone or along with melatonin (10 mg/kg, i.p.) twice everyday for 2 days, 10 hr apart, after two doses of MPTP significantly attenuated striatal dopamine loss and provided improvements in both catalepsy and akinesia. Additionally, Golgi‐impregnated striatal sections showed preservation of the medium spiny neurons, which have been damaged in MPTP‐treated mouse. The results demonstrated that melatonin, but not L‐DOPA, restored spine density and spine morphology of medium spiny neurons in the striatum and suggest that melatonin could be an ideal adjuvant to L‐DOPA therapy in Parkinson's disease, and by the use of this neurohormone, it is possible to bring down the therapeutic doses of L‐DOPA.     

Ten‐year follow‐up after intense chemoimmunotherapy with Rituximab‐HyperCVAD alternating with Rituximab‐high dose methotrexate/cytarabine (R‐MA) and without stem cell transplantation in patients with untreated aggressive mantle cell lymphoma

Mantle cell lymphoma (MCL) has a poor overall survival after treatment with conventional chemotherapy. Intense chemoimmunotherapy without consolidation stem cell transplantation is a potential therapeutic option. We report on a prospective Phase II study with rituximab in combination with fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone (R‐Hyper‐CVAD) alternating with rituximab in combination with high‐dose methotrexate‐cytarabine (R‐MA) in untreated patients with diffuse and nodular MCL and their blastoid variants. Ninety‐seven patients were treated, of whom 97% responded and 87% achieved a complete remission. At 10 years of follow up (median 8 years), the median overall survival (OS) for all patients had not been reached and the median time to failure (TTF) for all patients was 4.6 years, without a plateau in the curves. For the group of patients aged 65 years or younger, the median OS had not been reached and the median TTF was 5.9 years. Multivariate analysis revealed pre‐treatment serum levels of β₂ microglobulin, International Prognostic Index (IPI) score and mantle cell IPI (MIPI) score, as predictive of both OS and TTF. We conclude that intense chemoimmunotherapy without stem cell transplantation is effective for untreated aggressive MCL.     

Asparaginase‐related venous thrombosis in UKALL 2003‐ re‐exposure to asparaginase is feasible and safe

We report the incidence and outcome of venous thrombosis (VT) in the UK acute lymphoblastic leukaemia (ALL) 2003 trial. VT occurred in 59/1824 (3·2%) patients recruited over 5 years with 90% occurring during a period of Asparagine depletion. Pegylated Escherichia Coli Asparaginase (Peg‐ASP) 1000 units/m² was used throughout. Thirty‐four children received further Peg‐ASP, most with concurrent heparin prophylaxis. There were no episodes of bleeding or recurrent thrombosis. Optimal Asparagine depletion is central to success of modern regimes for treatment of ALL. This report confirms a significant risk of thrombosis with such therapy, but demonstrates that re‐exposure to Asparaginase is feasible and safe.