The microenvironment of follicular lymphoma (FL) is composed of tumor-infiltrating CD8+ T cells, follicular regulatory T cells, lymphoma-associated macrophages and mast cells, follicular helper T cells, follicular dendritic cells, and follicular reticular cells, all of which have been reported to have relevance in the prognosis of FL patients. In addition, some of these cells play a role in the histologic transformation of FL. Macrophages contribute to a poor prognosis in FL patients treated in the pre-rituximab era, but are associated with good prognosis in those treated in the rituximab era. T-cell immunoglobulin and mucin domain protein (TIM) 3 are markers of T-cell exhaustion, and T cells co-expressing programed death 1 (PD1) in peripheral blood and lymph nodes secrete interleukin (IL)-12 in the serum. Serum CXCL9, IL-2 receptor, and IL-1 receptor agonist are associated with shorter survival of FL patients. Agents for manipulation of the microenvironment surrounding FL cells include the immunomodulatory drug lenalidomide, immune check-point inhibitors, and cyclophosphamide prior to rituximab. To battle FL and to improve the outcomes of FL patients, understanding the relationship between neoplastic cells and the various microenvironmental cellular components is crucial for developing therapeutics against the microenvironment.
The introduction of novel agents, such as bortezomib, thalidomide, and lenalidomide, into daily practice has dramatically improved clinical outcomes and prolonged survival of patients with multiple myeloma (MM). However, despite these advanced clinical benefits, MM remains an incurable hematological malignancy. Therefore, development of new agents and novel therapeutic strategies is urgently needed. Recent advances toward understanding the mechanism of myeloma cell growth and drug resistance in the bone marrow milieu have provided clues for the development of next-generation agents aimed at improving patient outcomes. In this review article, we discuss new possible agents for the treatment of MM based on recent advances in the understanding of signaling pathways in myeloma cells.
Lymphoblastic lymphoma (LBL) is a rare subtype of non-Hodgkin lymphoma. There are limited reports on allogeneic stem cell transplantation (allo-SCT) in patients with LBL. We retrospectively analyzed the clinical outcomes of 15 adult patients with LBL who received allo-SCT at our institution. The median age at allo-SCT was 29 years (range, 18-42). Disease status at the time of transplantation was complete remission (CR), partial remission (PR), and advanced disease in 4, 4, and 7 patients, respectively. The median follow-up duration of survivors was 25 months (range, 6-106). The probabilities of overall survival (OS) and progression-free survival (PFS) at 2 years after allo-SCT were 37% and 24%, respectively. The respective 2-year OS and PFS rates of the 8 patients with CR or PR at the time of transplantation were 57% and 45%, while those with advanced disease were 14% and 0%. In conclusion, the treatment outcomes of allo-SCT in patients with LBL were unsatisfactory. Although outcomes were promising in patients with CR or PR at the time of transplantation, they were dismal in patients with progressive disease. Further advances in chemotherapy, both induction and salvage therapies, are needed to improve the clinical outcomes of patients with LBL.
Although clinical trials of first- and second-generation tyrosine kinase inhibitors (TKIs) have been shown to improve the prognosis of chronic myeloid leukemia (CML), there is still uncertainty about the clinical features, treatment outcomes, adverse effects, and other possible problems of their use in the clinical setting. We retrospectively analyzed 51 CML patients treated with TKIs at a single institution between 2002 and 2014. The patients (median age: 53.8 years) were classified as having chronic (n = 48), accelerated (n = 2), or blastic phase (n = 1) CML. Our treatments included both 1st generation TKIs (60.8%) and 2nd generation TKIs (39.2%). We found that the overall response rates of complete cytogenetic response (CCyR), major molecular response (MMR), and MR4 (molecular response 4) were 90.2%, 78.4%, and 64.7%, respectively. Second line 2nd generation TKIs had response rates equivalent to those of 1st line 1st generation TKIs. Moreover, 1st line 2nd generation TKIs tended to achieve an early response rate. Overall survival (OS) at 5 years was 93.2%. Sudden blastic crisis (BC) occurred in 2 CML patients receiving TKI with CCyR status. Hematopoietic stem cell transplantation was performed for BC (n = 1) and sudden BC (n = 2). Side effects of all grades (1-3) and grade 3 alone were 64.7% and 11.8%, respectively. Dose reduction, replacement with another TKI, or low dose TKI treatment may be useful methods to control side effects. Further reasons of TKI discontinuation were economic problems (n = 3) and pregnancy (n = 1). Consequently, our treatment strategy for CML demonstrated good response rate and OS. Currently, treatment discontinuation due to intolerance, resistance, economic problems, pregnancy, and sudden BC remains a concern in clinical practice.
In recent years, the Comprehensive Geriatric Assessment (CGA), which is used in gerontology to assess functioning in elderly individuals, has been said to be useful in geriatric oncology. Therefore, we examined whether items in the CGA were associated with survival time in elderly patients with non-Hodgkin lymphoma (NHL). We conducted the CGA for 93 patients aged ≥ 65 years who had undergone treatment for NHL retrospectively. The CGA includes activities of daily living, instrumental activities of daily living, mood, cognition, nutrition, and the Charlson comorbidity index. For each category, we divided subjects into a “good” group and a “poor” group. In regard to the Charlson comorbidity index, patients were divided into two groups using different cutoffs to divide the groups; the two groups were established according to the division with the largest significant difference in survival time. Multivariate analysis was then performed with the following prognostic factors affecting survival: all CGA items, NHL classification, stage, performance status, and doxorubicin use/non-use. We also performed similar analysis for 43 diffuse large B-cell lymphoma (DLBCL) patients who had undergone anthracycline treatment. Results are factors affecting survival in NHL cases included comorbidity score ≥ 6 (P < 0.0001), doxorubicin non-use (P = 0.005), and cognitive impairment (P = 0.0488). In cases of DLBCL, survival was affected by comorbidity score ≥ 5 (P = 0.0016). High comorbidity score was strongly associated with survival in both NHL and DLBCL.
A dose modified ifosfamide, epirubicin, and etoposide (IVE) regimen was prospectively assessed for its efficacy in mobilizing peripheral blood stem cells for autologous transplantation. Two patients with Hodgkin’s lymphoma and two with non-Hodgkin’s lymphoma who were undergoing stem cell therapy were studied. All patients had a history of multiple treatments with insufficient stem cell mobilization. The dose modified IVE regimen consisted of ifosfamide 3 g/m2 intravenously (IV) administered on days 1-2 in combination with epirubicin 50 mg/m2 IV on day 1 and etoposide 200 mg/m2 (100 mg/m2 in two patients with complete remission) IV on days 1-3. The ifosfamide dosage was reduced to two-thirds of the original protocol. A substantial high yield of CD34+ cells was achieved when patients were treated with a dose-modified IVE regimen, compared with that during the previous regimen (two with the ifosfamide, carboplatin, and etoposide [ICE] regimen, one with high-dose cyclophosphamide and one with the original IVE regimen). Two patients who had refractory and residual disease received a 200 mg/m2 dose of etoposide, which resulted in tumor reduction (one patient with complete remission and one with further reduction in tumor size). After the IVE regimen, all four patients had a sufficient yield of CD34+ cells in total, which was available for stem cell transplantation. Hematological and non-hematological toxicities were comparable in all regimens. This single-center prospective study demonstrated that the dose-modified IVE regimen can be used as a safe treatment with high mobilizing efficacy in heavily pretreated lymphoma patients.
Composite CD10-positive low-grade B-cell and CD5-positive low-grade B-cell lymphoma is extremely rare. We report a case of a composite follicular lymphoma (FL) and CD5-positive nodal marginal zone lymphoma (NMZL) in a resected inguinal lymph node of a 72-year-old Japanese male. Histologically, multiple follicles had reactive-germinal centers with tingible body macrophages, a thin mantle zone and a wide marginal zone. The wide marginal zone consisted of medium-sized cells having slightly indented nuclei and clear cytoplasm, indicating monocytoid cells with CD5-positive B-cells. Several follicles had germinal centers filled with many centrocytes, with CD10-positive B-cells. Polymerase chain reaction/sequence analysis of the immunoglobulin heavy chain gene obtained from microdissected regions of CD5-positive NMZL and FL showed different sequences within the CDR3 region. To our knowledge, this is the first report of FL and CD5-positive NMZL.
We report an incidental case of intravascular large B-cell lymphoma (IVLBCL) coexisting with an ovarian carcinoma in a 76-year-old woman. She visited our hospital with difficulty in defecation. Magnetic resonance imaging and computerized tomography scan revealed a solid and cystic mass probably arising from the left ovary. Gross examination of the tumor obtained by an exploratory surgery showed a solid area in a simple cyst. The ovarian tumor was diagnosed as a high-grade serous carcinoma (HGSC). Early in the post-operative course, this patient developed fever of unknown origin with central nervous system manifestations. Magnetic resonance imaging of the brain showed multiple space-occupying lesions. When we reviewed the histological sections, atypical lymphocytes were found in the lumina of small vessels of almost the entire ovary. These cells were positive for CD20 and CD79a by immunohistochemistry. A diagnosis of IVLBCL coexisting with HGSC was finally made. Although radiation therapy for brain lesions was performed and rituximab was administered, she died two months after the operation. To the best of our knowledge, this is the first case of IVLBCL incidentally identified in HGSC through microscopic examination. This case serves to create awareness of the rare event where IVLBCL may involve the ovary of patients who also have carcinoma in the organ.
We hereby report a case of acute myeloid leukemia with translocation t(2;3) and involvement of the ectopic virus integration site-1 (EVI1) gene. Like most other 3q26-related disorders reported thus far, we describe a phenotype with elevated platelet counts and dysmegakaryopoesis. The clinical course of our patient was complicated by symptomatic thrombophilia and chemoresistance. In addition, our case exhibited FLT3 (Fms-related tyrosine kinase 3) internal tandem duplication. Although anagrelide was successful in controlling elevated platelet counts, allogeneic stem cell transplantation failed to overcome chemoresistance due to simultaneous graft-versus-host-disease and relapse of acute myeloid leukemia. Given the dismal outcome of our case and previously reported cases, we propagate the implementation of targeted therapies to newly diagnosed patients with acute myeloid leukemia t(2;3). Preclinical models indicate drugs that plausibly target the EVI1-related molecular vulnerability as candidates for basket trials. Anagrelide exhibited a hopeful signal of activity in 3q26-related thrombocytosis and should be evaluated for implementation as supportive care.
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