Introduction
Castleman disease (CD) is uncommon non-clonal lymphoproliferative disorder with unknown etiology; also known as angiofollicular lymph node hyperplasia, this condition was first described in 1954 by Dr. Benjamin Castleman [
]. Histologically, CD may be classified as either hyaline-vascular or plasma-cell subtype with occasional cases demonstrating mixed features. This disease was also classified into two entities in terms of their clinical presentations, that is, unicentric CD (UCD) and multicentric CD (MCD). UCD is typically localized with minimal symptoms and treated with local therapy. However, MCD manifests with extensive lymphadenopathy, non-specific constitutional symptoms, and laboratory abnormalities and is associated with increased risk of developing certain malignancies and other diseases. Accordingly, systemic therapy is required for MCD [
].
Although surgical resection remains standard therapy for UCD, management of MCD is still challenging. Novel approaches should be developed given the malignant potential and lack of standard therapy recommendations for relapsed/refractory MCD. Here, we reported three relapsed/refractory MCD patients with lenalidomide as salvage treatment.
Presentation of cases
As experimental treatment, lenalidomide was used in three cases of relapsed/refractory MCD with negative screening for human immunodeficiency virus (HIV) and human herpes virus-8 in October 2014. A total of 10–25 mg agent was administered perorally on days 1–21 in a 28-day cycle; dosing scheme was based on that used in multiple myeloma. All three patients provided written informed consent to participate in the study. This study was approved by the Institutional Review Board of the First Affiliated Hospital, College of Medicine, Zhejiang University.
Case 1
A 21-year-old man was presented to our department; his symptoms were fatigue and petechia for two years in October 2014. Patient was diagnosed with MCD in April 2012 and initially received prednisone for therapy because of generalized lymphadenopathy and rash on chest and back. One year later, patient developed high fever with severe pancytopenia (white blood cell: 10 × 109/L; hemoglobin: 73 g/L; platelets: 18 × 109/L). Laboratory data revealed increased erythrocyte sedimentation rate (75 mm/h) and C-reactive protein level (335.40 mg/L). Chemotherapy of cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) regimen was initiated in April 2013. However, during treatment (4/2013–7/2013), clinical progression of disease was evident (aggravated thrombocytopenia and recurrent fever refractory to antibiotics), and radiological response was not observed in computed tomography. In September 2013, patient received conditioning chemotherapy of melphalan, cyclophosphamide, etoposide, and cytarabine (MEAC) followed by autologous hematopoietic stem cell transplantation (auto-HSCT), causing short-term remission for no longer than seven months. Another four cycles of chemotherapy were administered since May 2014. Results showed unsatisfactory efficacy. Positron emission tomography/computed tomography (PET/CT) revealed lymph node enlargement all over the body with maximum standardized uptake value (SUVmax) of 4.28. In September 2014, repeat biopsy of axillary lymph node demonstrated remarkable infiltration of plasma cells with immunohistochemistry (IHC) of cluster of differentiation 3 (+), cluster of differentiation 2 (+), cluster of differentiation 21 (+ in follicular dendritic cell), cluster of differentiation 20 (+), cluster of differentiation 79a (+), cluster of differentiation 138 (+ in plasma cell), IgG4 (+ in a small number of cells), kappa (k) (+), lambda (l) (+), Ki-67 (+); findings were consistent with primary diagnosis. We then turned to lenalidomide monotherapy (25 mg lenalidomide administered perorally on days 1–21 in 28-day cycle) since October 2014. With decrease in platelet count 10 days after lenalidomide initiation (lowest platelet value: 9 × 109/L), treatment was discontinued. Considering that thrombocytopenia did not improve despite lenalidomide withdrawal, patient commenced receiving methylprednisolone tablets since November 2014. Afterward, platelet count increased. Methylprednisolone tablets were then tapered off, and lenalidomide treatment was restarted. Regimen stabilized the disease for one month until platelets acutely decreased in February 2015, demonstrating relapse and making patient eligible for further treatment. Rituximab was combined in one cycle (375 mg/m2 rituximab administered intravenously on days 1, 8, and 15) and vindesine in three cycles (4 mg vindesine introduced intravenously on day 1) along with lenalidomide and methylprednisolone (25 mg lenalidomide administered perorally on days 1–21; 8 mg methylprednisolone dispensed perorally on days 1–28 in 28-day cycle). After treatment with lenalidomide-based regimen, patient exhibited evident clinical improvement in health status with reduction in lymph nodes size, platelet count and C-reactive protein level remaining within normal range. His treatment was then switched to lenalidomide monotherapy for maintenance, and nine cycles of lenalidomide were administered until March 2016.
Case 2
In second case, a male born in 1974 was diagnosed with hyaline-vascular CD at age 30 years. Initial manifestation was cervical lymphadenopathy without constitutional symptoms. Cervical lymph node biopsy revealed lymphoid hyperplasia with predominantly follicular pattern, showing focal vascular proliferation and hyalinization of germinal centers with onion-skin like mantle zone. IHC showed cluster of differentiation 3 (+), cluster of differentiation 20 (+), cluster of differentiation 138 (+ in plasma cell),k (+), l (+), cluster of differentiation 21 (+ in follicular dendritic cell), IgG4 (+ in a small number of cells), Ki-67 (+ in a few cells in germinal center). After 10 years of close observation, patient experienced progressive general lymphadenopathy and was then provided with prednisone treatment since September 2013. Two months later, cervical lymph nodes shrunk, and this process lasted for six months. Patient presented rapid enlargement of lymph nodes and progressive numbness of his lower limbs and intermittent sharp pains in feet in December 2014. Electromyogram revealed impaired sensory and motor nerves in lower limbs, suggesting polyneuropathy. Laboratory signs observed included monoclonal plasma proliferative disorder (serum IgG of 1930 mg/dl,lchain of 994 mg/dl; IgG, lchain positive in serum and urine immunofixation electrophoresis) and increased serum markers of inflammation (C-reactive protein 347.9 mg/L, interleukin-6 (IL-6) 5.25 pg/ml).
Patient was then admitted to hospital in January 2015 with diagnosis of polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome with CD. After failure of first-line treatment, patient was treated with lenalidomide in combination with dexamethasone (10 mg lenalidomide provided perorally on days 1–21 combined with intravenous administration of dexamethasone on days 1, 8, 15, and 22 in 28-day cycle). Shrinkage of lymph nodes was documented in computed tomography after one cycle of lenalidomide-based regimen. Then, patient was treated with three cycles of regimen, which was subsequently enhanced in combination with rituximab for another four cycles. Afterward, patient reverted to lenalidomide regimen in combination with dexamethasone for four cycles. Clinical condition improved with gradual remission of numbness in lower limbs and pains in his feet; C-reactive protein decreased to 4.1 mg/L, and urine immunofixation electrophoresis was negative by end of March 2016.
Case 3
Male patient born in 1962 manifested symptoms, such as recurrent fever, fatigue, night sweats, and muscle soreness. Laboratory data revealed abnormal full blood count (white blood cell: 7.3×109/L; hemoglobin: 89 g/L; platelets: 23×109/L) and increased serum markers of inflammation (C-reactive protein: 335.4 mg/L; IL-6: 6.58 pg/ml). Radiological examination showed that cervical, axillary, and inguinal regions were affected by pleural effusions, ascites, hepatomegaly, and generalized lymphadenopathy. PET/CT revealed no increased value of SUVmax. Bone marrow biopsy was unremarkable. Patient was initially suspected of tuberculosis, and empirical antituberculous therapy was administered. However, patient failed to respond after four weeks of antituberculous therapy. Lymph node biopsy was performed in May 2015 and revealed lymphoid hyperplasia with numerous plasma cells in interfollicular region. IHC demonstrated cluster of differentiation 20 (+), cluster of differentiation 79a (+), cluster of differentiation 23 (+ in follicular dendritic cells), cluster of differentiation 21 (+ in follicular dendritic cells), cluster of differentiation 138 (+ in plasma cells), Ki-67 (+),k (+), l (+), multiple myeloma oncogene 1 (+), IgG4 (+), terminal deoxynucleotidyl transferase (–), cyclin D1 (–), cluster of differentiation 56 (–). Plasma-cell CD was diagnosed. Patient was then treated with rituximab (intravenous administration of 375 mg/m2 rituximab once a week) combined with glucocorticoids. However, combined treatments failed to inhibit disease progression. Four weeks later, pleura effusions and ascites increased, and platelet count decreased to 8×109/L. Patient commenced receiving lenalidomide (10 mg peroral administration on days 1–21 in 28-day cycle) combined with rituximab, cyclophosphamide, vindesine, dexamethasone (R-COP) regimen for one cycle and then dexamethasone (20 mg once a week) for another cycle. Abdominal distention gradually subsided, and laboratory investigation revealed normalized platelet count (123 × 109/L) and significantly decreased C-reactive protein (13.4 mg/L) after one cycle of lenalidomide-based therapy. Moreover, computed tomography confirmed complete disappearance of pleural effusion and ascites and resolution of lymphadenopathy and hepatomegaly after approximately two months of lenalidomide-based therapy. Then, dosage of lenalidomide was increased to 25 mg perorally combined with dexamethasone 20 mg once a week on days 1–21 in 28-day cycle. Until March 2016, achieved complete remission was maintained per laboratory and radiological investigations.
Table 1 displays overview of applied regimens and their effects; Fig. 1 reviews histopathological findings.
Discussion
CD is uncommon lymphoproliferative disorder that continuously poses clinical challenges. Although surgical resection remains standard therapy for UCD, recommendations lack of management for MCD, particularly in relapsed or refractory cases. In recent years, anti-CD20 antibody rituximab and novel agents targeting IL-6 showed potency as new additions to basic treatment [
]. Rituximab is highly active against MCD. In HIV-associated MCD, role of this drug is supported by prospective and retrospective trials demonstrating sustained remissions [
–
]. Small case series also demonstrated activity in HIV negative MCD patients [
–
]. Novel agents targeting IL-6 showed interesting potency in HIV-negative MCD [
,
]. Two cases in literature demonstrated activity of IL-6 targeted therapy in HIV-associated MCD [
], focusing on need for prospective clinical trials in these patients. Thalidomide is immunomodulatory drug, which showed efficacy in MCD management. Several case reports documented excellent therapeutic effects of thalidomide [
–
] as monotherapy or part of combination therapy in MCD.
Lenalidomide is functional and structural analog of thalidomide with improved potency and reduced non-hematologic toxicity [
]. This drug was approved by FDA for treatments of multiple myeloma, myelodysplastic syndrome associated with del 5q and resistant mantle cell lymphoma, and research also described its potential in acute myelocytic leukemia lymphoma, non-Hodgkin lymphoma, chronic lymphocytic lymphoma, and Hodgkin lymphoma treatment [
]. Lenalidomide has immunomodulating and antiangiogenic properties, and it decreases production of IL-6, role of which is well established in pathogenesis and symptomatology of CD [
]. However, only few clinical reports provide information on lenalidomide as therapy for CD. Four case reports were obtained from MEDLINE literature search using keywords lenalidomide and Castleman disease/POEMS [
–
] (Table 2); those reports documented remissions achieved by highly pretreated patients with CD after administration of lenalidomide-based therapy.
Herein, we reported three adult patients with MCD and observed manifestation of aggressive multisystem symptoms. One patient (Case 2) was diagnosed with hyaline-vascular CD with POEMS syndrome, and the other two had plasma-cell CD. Partial remission was achieved in Cases 1 and 2, and complete remission was achieved in Case 3. All cases previously demonstrated refractory and were difficult to manage. In Case 1, enlarged lymph nodes shrank, and platelet count, and C-reactive protein level were normalized. In Case 3, we noted complete disappearance of pleural effusion and ascites and recovery of platelet to normal range. Second case was CD with POEMS syndrome. CD is present in about 11%–30% of POEMS patients. Elevation of angiogenic cytokines, such as vascular endothelial growth factor (VEGF) is assumed to represent pathogenic association of CD to POEMS syndrome. In contrast to POEMS, in which VEGF is the most consistently elevated cytokine, IL-6 in CD is dominant and aberrantly overexpressed cytokine [
]. IL-6 level was increased in these cases; however, confirmation of VEGF level was not performed. Lenalidomide showed potential; this result was in accordance with previously reported studies [
–
]. With regard to side effects, all three patients experienced myelotoxicity and infection but were provided with proper treatment.
In our cases, lenalidomide was used as monotherapy or combined with traditional chemotherapy. As is well known, bortezomib inhibits myeloma cell growth by blocking nuclear factor-kB and decreasing IL-6 level. Additionally, use of such drug in MCD treatment was effective in some case reports [
]. Similar with bortezomib, carfilzomib and ixazomib are novel proteasome inhibitors with high activity in multiple myeloma [
,
]. On the basis of proteasome inhibitors against B cell malignancies and results of bortezomib use in MCD reported in recent years [
,
,
], we assume that combination of lenalidomide and proteasome inhibitors may have great potential in treating MCD.
Conclusions
Lenalidomide showed encouraging efficacy in patients with CD, particularly in those with subtype plasma-cell CD, though long-term efficacy remains to be discovered. In addition, lenalidomide has favorable safety profile. Therefore, this drug represents an attractive alternative for MCD after rituximab and traditional chemotherapy failures. We propose further investigation of therapeutic potential of this drug in MCD.
Higher Education Press and Springer-Verlag Berlin Heidelberg
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