Malignant hematolymphoid disorders arising from NK cells have become widely recognized over the past decade. The two forms of NK-cell malignancy, aggressive NK-cell leukemia (ANKL) and extranodal NK-cell lymphoma of nasal type (ENKL) are both characterized by the proliferation of tumor cells with an NK-cell like immunophenotype. ANKL usually presents with bone marrow tumor cells accompanied by circulating leukemic cells, and hepatosplenomegalay is a common clinical feature. ENKL most frequently affects the nasal or paranasal regions, with cutaneous involvement also being common. Approximately 70 percent of ENKL present with localized tumor cells, and follow an indolent clinical course, but, in advanced cases, tumors rapidly expand and are frequently fatal. Tumor cells from both ANKL and ENKL are surface CD3- and CD56+ but differ in their expression of CD16. Epstein-Barr virus (EBV) is found in most cases of NK-cell leukemia/lymphoma, suggesting an oncogenic role, but patients may have biclonal or polyclonal populations of malignant cells based on differential EBV genome incorporation. NK-cell neoplasms are frequently resistant to chemotherapy due to p-glycoprotein expression and associated multidrug resistance. The prognoses of both localized and advanced stages of NK-cell malignancies are worse than most other lymphoid malignancies, but studies are currently underway to assess the safety and efficacy of novel chemoradiotherapy regimens for the treatment of these neoplasms.
We examined effects of combination chemotherapy with dexamethasone, melphalan, vincristine, and MCNU (DMVM), plus IFN-α in patients with previously untreated and treated multiple myeloma (MM). In the study, 78 previously untreated and 47 treated MM patients were evaluated. The overall response rate was 76% [27% complete response (CR)] : 85% [37% CR] in previously untreated patients and 62% [11% CR] in previously treated patients. The 50% survival time was 45.3 months for untreated patients and 30.1 months for previously treated patients. This regimen is effective in producing a high CR rate and prolonging survival duration of MM patients.
Translocation of chromosome t (6 ; 14) (p21 ; q32) results in overexpression of the cyclin D3 gene (CCND3), and is a recurrent genetic alteration in multiple myeloma. To elucidate the biological role of the overexpression of the cyclin D3 protein (CCND3) in t (6 ; 14) (p21 ; q32), we transfected a CCND3-specific, small-interfering RNA (siRNA) into KMM-1 cells carrying t (6 ; 14) (p21 ; q32). Following transfection, CCND3 expression levels decreased with maximal effect after 24 hours. While CCND3 expression was down regulated the rate of proliferation in transfected KMM-1 cells was half that in control cells. Cell-cycle analysis revealed that transfection resulted in transition fron G1 to S being blocked, and the transfected cells underwent apoptosis. Immunoprecipitation experiments demonstrated that CCND3 formed a complex with the majority of p27kip1 in KMM-1 cells under steady-state conditions. When CCND3 expression was down regulated the P27kip1 shifted to cyclin E protein (CCNE) and formed a complex. Our results show that CCND3 is essential for the cellular growth of t (6 ; 14) (p21 ; q32)-positive myelomas and that CCND3 sequesters p27kip1 from CCNE, resulting in functional inactivation of its anti-proliferative role. Modification of CCND3 and p27kip1 interaction may be a novel therapeutic approach for t (6 ; 14) (p21 ; q32)-positive myeloma.
Monocytes from patients with chronic myelomonocytic leukemia (CMML-Mo) strongly expressed CD14 and CD2, but not CD16. Macrophages (MΦ) generated from CMML-Mo expressed CD32, but not CD16. The expression levels of CD64 were significantly reduced from normal MΦ. While CMML-Mo-derived MΦ phagocytosed sensitized SRBC, these cells exhibited a similar defect as CMML-Mo in the ability to produce O2-. CMML-Mo could generate dendritic cells (DC), but not multinucleated giant cells (MGC), suggesting that CMML-Mo are different from normal Mo in cell surface marker expression, O2- production, and the ability to differentiate into MΦ and MGC, but not DC.
Reduced-intensity unrelated cord blood transplantation was performed on two patients (a 55-year-old woman and a 52-year-old man) with multiple myeloma that had progressed after high-dose chemotherapy (melphalan : 200 mg/m2) with autologous stem cell transplantation support. The conditioning regimen consisted of fludarabine (180 mg/m2) and busulfan (8 mg/kg) without total body irradiation. Tacrolimus was administered as a graft-versus-host disease prophylaxis. The engraftments were rapid (day +17 in patient 1 and day +26 in patient 2). Regimen-related toxicity was tolerable and acute graft-versus-host disease (grade I) appeared only in patient 2. Complete donor chimerism continued following the treatment and no disease progression was observed in the succeeding 12 months. These results demonstrate the feasibility and effectiveness of reduced-intensity cord blood transplantation after autologous stem cell transplantation in older patients.