Clinical Lymphoma and Myeloma最新文献

Stem cell transplantation in chronic lymphocytic leukemia (CLL) is an evolving field. Younger patients with high-risk disease might derive the greatest benefit from this approach and the availability of reduced-intensity conditioning regimens has made allogeneic stem cell transplantation more relevant to patients with CLL. Patient selection, timing of transplantation, and method of conditioning, stem cell delivery and immunosuppression appear to influence outcomes. We collect and review the available data to assist clinical decision-making in this field.

Kefir is produced by adding kefir grains (a mass of proteins, polysaccharides, bacteria, and yeast) to pasteurized milk; it has been shown to control several cellular types of cancer, such as Sarcoma 180 in mice, Lewis lung carcinoma, and human mammary cancer. Human T-cell lymphotropic virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia, which is a fatal disease with no effective treatment. The current study aims at investigating the effect of a cell-free fraction of kefir on HuT-102 cells, which are HTLV-1–positive malignant T-lymphocytes. Cells were incubated with different kefir concentrations: the cytotoxicity of the compound was evaluated by determining the percentage viability of cells. The effect of all the noncytotoxic concentrations of kefir cell-free fraction on the proliferation of HuT-102 cells was then assessed. The levels of transforming growth factor (TGF)-α mRNA upon kefir treatment were then analyzed using reverse transcriptase polymerase chain reaction. Finally, the growth inhibitory effects of kefir on cell cycle progression and/or apoptosis were assessed by flow cytometry. The maximum cytotoxicity recorded at 80 μg/μL for 48 hours was only 43%. The percent reduction in proliferation was very significant, dose and time dependent, and reached 98% upon 60-μg/μL treatment for 24 hours. Kefir cell-free fraction caused the downregulation of TGF-α, which is a cytokine that induces the proliferation and replication of cells. Finally, a marked increase in cell cycle distribution was noted in the pre-G₁ phase. In conclusion, kefir is effective in inhibiting proliferation and inducing apoptosis of HTLV-1–positive malignant T-lymphocytes. Therefore, further in vivo investigation is highly recommended.

The recent identification of activating mutations in NOTCH1 in the majority of T-cell acute lymphoblastic leukemias (T-ALLs) has brought major interest toward targeting the NOTCH signaling pathway in this disease. Small-molecule γ-secretase inhibitors (GSIs), which block a critical proteolytic step required for NOTCH1 activation, can effectively block the activity of NOTCH1 mutant alleles. However, the clinical development of GSIs has been hampered by their low cytotoxicity against human T-ALL and the development of significant gastrointestinal toxicity derived from the inhibition of NOTCH signaling in the gut. Improved understanding of the oncogenic mechanisms of NOTCH1 and the effects of NOTCH inhibition in leukemic cells and the intestinal epithelium are required for the design of effective anti-NOTCH1 therapies in T-ALL.

The outlook for newly diagnosed patients with chronic myeloid leukemia (CML) in the imatinib era is excellent for most patients. However, imatinib failure is observed in around 25%–30% of patients. With the availability of second-line tyrosine kinase inhibitor therapy and/or allogeneic transplantation, many of these patients with imatinib failure can still achieve durable cytogenetic and molecular responses. Early evidence of imatinib resistance, when the biology of the emerging leukemia might still be relatively favorable, is the best time to switch to second-line therapy. Close cytogenetic and molecular monitoring will facilitate early intervention in appropriate cases. However, caution should be used when interpreting minimal residual disease data, and the danger of inappropriate changes in therapy based on assay fluctuations should be recognized. A significant increase in the level of BCR-ABL to a level > 0.1% on the international scale (major molecular response) should prompt a repeat BCR-ABL assay, a mutation screen, and possibly marrow cytogenetics. What constitutes a significant increase depends on the laboratory-specific measurement reliability. The possibilities of poor compliance or drug interactions should be considered. If the repeat BCR-ABL assay, fluorescence in situ hybridization assay, or cytogenetics confirms loss of complete cytogenetic response or if a mutation is identified, a dose increase or a switch in therapy to a second-line kinase inhibitor might be indicated. At least until complete molecular response is achieved, regular real-time polymerase chain reaction monitoring reinforces the fact that leukemia is still present and that compliance is a challenge that requires ongoing vigilance from the patient and the clinician.

Chronic myeloid leukemia (CML) is characterized at the molecular level by the presence of the Philadelphia chromosome (Ph) and the resultant oncogenic signaling by the BCR-ABL fusion protein. The treatment and outlook for CML were revolutionized by the introduction of imatinib, but resistance is a substantial barrier to successful treatment in many patients. Introduction of the second-generation tyrosine kinase inhibitors (TKI) dasatinib and nilotinib has provided effective therapeutic options for many patients with resistance to front-line imatinib. However, the T315I mutation remains a significant clinical issue because it is insensitive to all currently available agents. A number of new agents are in development and many hold the promise of activity in T315I-mutated disease. Successful treatment of patients with disease harboring T315I might lie in the effective combination or sequencing of these new agents with existing TKI therapies.

During the past 5 years, we have witnessed an explosion in our understanding, classification, and number of therapeutic opportunities for patients with myelodysplastic syndromes (MDS). These include the development of new histologic classifications, scoring systems, supportive care measures, and most importantly, effective treatments that are safe and can modify the natural history of this complex group of hematopoietic disorders. In this brief review, and as part of the Leukemia 2008, Fourth International Conference, held in Houston during September 2008, I summarize some of the most important recent developments in the field of MDS and try to identify new problems and opportunities for patients and researchers in this area.

Over the past few years, molecular oncology research has revealed that abnormalities in both protein-coding genes (PCGs) and noncoding RNAs (ncRNAs) can be identified in tumors and that the interplay between PCGs and ncRNAs is causally involved in the initiation, progression, and metastases of human cancers. MicroRNAs (miRNAs), which are among the most studied ncRNAs, are small 19- to 25-nucleotide genes involved in the regulation of PCGs and other ncRNAs. With the recent findings of miRNAs' involvement in cancer, RNA inhibition can be used to treat cancer patients in two ways: (1) by using RNA or DNA molecules as therapeutic drugs against messenger RNA of genes involved in the pathogenesis of cancers and (2) by directly targeting ncRNAs that participate in cancer pathogenesis. In this review, we focus on the possible use of miRNAs or compounds interacting with miRNAs as new therapeutic agents in cancer patients.

The discovery of the JAK2V617F mutation followed by the discovery of JAK2 exon 12 and MPLW515 mutations has completely modified the understanding, diagnosis, and management of the classic myeloproliferative disorders (MPDs), which include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Nonetheless, genetic defects have not yet been identified in about 40% of ET and PMF. There is now strong evidence that these mutations are the oncogenic events that drive these disorders and are responsible for most biologic and clinical abnormalities. In addition, there are convincing data indicating that the number of JAK2V617F copies (homozygosity vs. heterozygosity) is important in explaining how a single mutation can be associated with several disorders. However, it is still uncertain whether these mutations are sufficient to explain the full development, heterogeneity, and progression of MPD, or if other genetic or epigenetic events are also necessary. In this review, we discuss different hypothetical models of MPD pathogenesis supported by recent findings. Further characterization of the molecular events operating in these disorders will be essential in fully understanding their pathogenesis and in developing new therapeutic approaches.

T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) are considered the same disease, differing by the extent of bone marrow infiltration. According to recent gene expression profiling data, T-ALL and T-LBL can be separated by prediction analysis of microarrays showing an overexpression of MML1 in T-LBL and CD47 in T-ALL. Immunophenotypes of T-LBL and T-ALL are identical but differ in frequency, with a higher rate of cortical or mature immunophenotypes in T-LBL, which is probably related to the higher rate (> 90%) of mediastinal tumors. Treatment approaches in T-LBL changed from conventional non-Hodgkin lymphoma (NHL) protocols to intensive NHL protocols but recently to ALL-designed protocols. T-ALL remission rates are 90%, and overall survival (OS) has improved to 60%–70%. Mediastinal tumors resolve in most cases of T-ALL with chemotherapy only, whereas in T-LBL additional mediastinal irradiation seems to be beneficial. Strategies for stem cell transplantation (SCT) in T-LBL and T-ALL differ. Autologous SCT in complete remission (CR) in T-LBL gives a 70% survival rate, which is similar to chemotherapy alone. In T-ALL, the subtypes of early and mature T-ALL have a poor outcome with chemotherapy alone (< 30%) and might profit from an allogeneic transplantation in first CR (OS > 50%). There seems to be no need for transplantation in thymic T-ALL in first CR. Prognostic factors are published for T-ALL but not for T-LBL. MRD may guide further treatment strategies in T-ALL and probably also in T-LBL as indications for a SCT or for the evaluation of novel, particularly T-cell–specific, drugs.

Large granular lymphocyte (LGL) leukemia is a rare disorder of mature cytotoxic T or natural killer cells. Large granular lymphocyte leukemia is characterized by the accumulation of cytotoxic cells in blood and infiltration in the bone marrow, liver, and spleen. Herein, we review clinical features of LGL leukemia. We focus our discussion on known survival signals believed to play a role in the pathogenesis of LGL leukemia and their potential therapeutic implications.