Fan Zhou

Continuous Administration of Low-Dose Cyclophosphamide and Prednisone as a Salvage Treatment for Multiple Myeloma

PURPOSE The purpose of this study was to evaluate the efficacy and tolerability of continuous low-dose cyclophosphamide and prednisone (CP) as a salvage therapy for multiple myeloma (MM). PATIENTS AND METHODS A total of 27 consecutive patients with MM received a treatment regimen that consisted of oral cyclophosphamide 50 mg and prednisone 15 mg daily. Nineteen patients had severe comorbid conditions; 8 were unwilling to continue conventional chemotherapy as a result of severe infection associated with the conventional chemotherapy. Patients had received 1 to 4 chemotherapeutic regimens before the enrollment. RESULTS The overall response rate (complete remission, very good partial response, and partial response) was 66.7%. The median time to response was 2 months. In the patients who responded to the treatment, the median progression-free survival (PFS) has not been reached. In the nonresponding patients, the median PFS was 4 months. CONCLUSION Continuous low-dose CP is an effective and well-tolerated salvage therapy for MM.

A combination of thalidomide and arsenic trioxide is effective and well tolerated in patients with myelodysplastic syndromes

Twenty-two patients with myelodysplastic syndromes (MDS) were treated with thalidomide plus arsenic trioxide (ATO). Twenty-two MDS patients receiving supportive care were used as controls. The remission was achieved in 4 patients (18.2%) receiving thalidomide/ATO, and none in the control group (p<0.05). Fifteen of 22 patients in the treatment group achieved hematologic improvement (68.2% vs. 27.3% in the control, p<0.05). The progression-free survival was longer in the treatment group than that in the control (26 vs. 10 months, p<0.05). The overall survival was also longer in the treatment group than that in the control (36 vs. 16 months, p<0.05). No severe adverse reactions were observed. These preliminary findings suggest that thalidomide/ATO combination treatment is effective and safe for MDS.

Unfolded protein response inducers tunicamycin and dithiothreitol promote myeloma cell differentiation mediated by XBP-1

The unfolded protein response (UPR) is an essential pathway for both normal and malignant plasma cells to maintain endoplasmic reticulum (ER) homeostasis in response to the large amount of immunoglobulin (Ig) output. The inositol-requiring enzyme 1-X-box binding protein-1 (IRE1-XBP-1) arm of the UPR pathway has been shown to play crucial roles not only in relieving the ER stress by up-regulating a series of genes favoring ER-associated protein degradation and protein folding, but in mediating terminal plasmacytic differentiation and maturation. Myeloma cells comprise various subsets arrested in diverse differentiated phases, and the immaturity of myeloma cells has been taken as a marker for poor prognosis, suggesting that differentiation induction would be a promising therapeutic strategy for myeloma. Herein, we used low-dose pharmacological UPR inducers such as tunicamycin (TM) and dithiothreitol (DTT) to efficiently activate the IRE1-XBP-1 pathway in myeloma cells characterized by transcriptional expression increase in spliced XBP-1 and molecular chaperons, accompanied by significant differentiation and maturation of these myeloma cells, without concomitant cytotoxicity. These differentiated myeloma cells exhibited a more mature appearance with well-developed cytoplasm and a reduced nucleocytoplasmic ratio, and a further differentiated phenotype with markedly increased expression of CD49e together with significantly elevated cellular secretion of Ig light chain as shown by flow cytometry and ELISA, in contrast to the control myeloma cells without exposed to TM or DTT. Moreover, siRNA knockdown of XBP-1 disrupted TM- or DTT-induced myeloma cell differentiation and maturation. Our study, for the first time, validated that the modest activation of the UPR pathway enables myeloma cells to further differentiate, and identified that XBP-1 plays an indispensable role in UPR-mediated myeloma cell differentiation and maturation. Thus, we provided the rationale and feasibility for the exploration of the novel therapeutic strategy of differentiation induction for plasmacytic malignancies.

Clinicopathological implications of nuclear factor κB signal pathway activation in diffuse large B-cell lymphoma.

Although abnormal activation of the nuclear factor κB (NF-κB) signaling pathway plays an important role in the pathogenesis of diffuse large B-cell lymphoma (DLBCL), only a few studies have dealt with the relation of NF-κB activation to clinical outcomes in this disease. We analyzed the clinical characteristics of 147 consecutive DLBCL patients, examined paraffin-embedded tissues from 120 of them to identify the activation of the NF-κB pathway by using immunohistochemical staining, and performed an overall survival (OS) analysis. Expression of P-p65 and p52 was found in 30.0% (n = 36) and 35.8% (n = 43) of the patients, respectively. Coexpression of these factors was found in 16.7% (n = 14) of the cases. Patients were divided into 4 groups according to P-p65 and/or p52 expression: P-p65(+) only, p52(+) only, both P-p65(+) and p52(+), and both P-p65(-) and p52(-). The 3-year OS rates in the 4 groups were 51.3%, 68.3%, 34.6%, and 85.8%, respectively (P = .006). Univariate analysis showed that early stage (P = .032), low International Prognostic Index score (P = .001), less than 2 extranodal metastases (P = .014), complete remission with chemotherapy (P < .0001), germinal-center B-cell-like subtype (P = .049), Ki-67 < 75% (P = .017), and P-p65(-) (P = .002) or p52(-) (P = .031) were associated with longer 3-year OS. Multivariate analysis indicated that P-p65 expression was an independent prognostic factor for shorter OS (P = .032). In conclusion, NF-κB pathway activation markers P-p65 and p52 predict poor survival in DLBCL patients.

Thyroid function and its clinical significance in POEMS syndrome

POEMS syndrome, also known as Crow-Fukase syndrome, represents a rare multisystem syndrome characterized by polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes. Hypothyroidism is one of the common endocrine abnormalities which are central features of POEMS syndrome. The clinical data associated with the measurement of thyroid function and its clinical significance in POEMS syndrome is still rare. Herein, we report 24 cases with POEMS syndrome which were studied thyroid function and clinical manifestations and performed an associated analysis between hypothyroidism and edema/effusions. Of the 24 patients with POEMS syndrome, 17(70.8%) had a recognized hypothyroidism (including 11 clinical hypothyroidism and 6 subclinical hypothyroidism). Fourteen patients (58.3%) had some form of extravascular volume overload. In 14 patients with edema/effusions, 12 were diagnosed as having hypothyroidism. Hypothyroidism may be one of causes of edema/effusions. After thyroid hormone treatment and chemotherapy, symptoms of hypothyroidism and edema /effusions were improved greatly.

Continuous low-dose cyclophosphamide and prednisone in the treatment of relapsed/refractory multiple myeloma with severe heart failure.

Abstract Patients with relapsed/refractory (R/R) multiple myeloma (MM) complicated by severe heart failure typically do not tolerate conventional chemotherapy. Our previous study indicated that R/R MM patients with severe comorbidities could benefit from continuous low-dose oral cyclophosphamide and prednisone (CP regimen). We hereby performed a study of 56 R/R MM patients with severe heart failure (New York Heart Association class ≥ III) receiving the treatment of CP regimen. Among the 54 evaluable patients, clinical benefit was noted in 63.0% (complete response, 3.7%; very good partial response, 7.4%; partial response, 48.1%; stable disease, 3.7%). The median overall survival (OS) and progression-free survival (PFS) were 8 and 6 months. The left ventricular ejection fraction (LVEF) and the serum levels of B-type natriuretic peptide (BNP) were improved significantly. Slight adverse events were observed. In summary, the CP regimen is effective in R/R MM patients complicated with severe heart failure.