Clinical Leukemia最新文献

Ineffective hematopoiesis, with premature death of marrow myeloid precursors, is a hallmark of myelodysplastic syndromes (MDS), with the apparent paradox of peripheral cytopenia associated with hypercellular bone marrow (BM). Excessive apoptosis appears relevant especially in low-risk MDS. Apoptosis, triggered by the BM microenvironment and/or intrinsic cellular defects, is regulated at different levels by numerous factors, such as oncogenes and their protein products, hematopoietic growth factors, immunologic factors, cell-cell or cellstromal interactions, critical adhesion receptors, and various cytokines. Deregulation of both the intrinsic and the extrinsic pathways have been reported in MDS cells. Many studies provide evidence that the activation of the Fas/Fas-ligand system might represent an important pathogenetic mechanism. Recently, it has been demonstrated that the erythroid apoptosis of low-risk MDS is initiated at a very early stage of stem cells and associated with mitochondrial dysfunction. There is a constitutive triggering to apoptosis via cytochrome C release from the mitochondrial intermembrane space, with subsequent activation of effector caspases and increased sensitivity to death ligands triggering the extrinsic apoptotic pathway. The role of the mitochondrial pathway might be relevant especially in refractory anemia with ring sideroblasts, where abnormalities in mitochondrial ferritin expression might directly influence iron homeostasis and contribute to alter the balance between cell growth and death. The pathogenesis of refractory anemia without ring sideroblasts seems to be more heterogeneous, with the involvement of alternative mechanisms, including T-cell–mediated BM failure. Elucidation of these pathogenetic mechanisms might lead to the development of novel therapeutic strategies.

Background

In an attempt to improve the cytogenetic and molecular response rate in Philadelphia chromosome–positive early chronic-phase CML, we compared the combination of imatinib plus low-dose cytarabine (Ara-C) versus imatinib alone.

Patients and Methods

After a follow-up of 4 years, we included 112 patients in a randomized allocation to receive imatinib 400 mg alone orally every day (group A, 81 patients) versus imatinib in the same schedule plus Ara-C 10 mg/m² per day by subcutaneous injection daily every 10 days each month (group B, 31 patients). Both treatment groups were comparable according to hematologic basal parameters, age, sex, and previous treatment.

Results

Complete hematologic response was achieved in > 90% of patients in both groups; however, a shorter time and a higher complete cytogenetic response rate was documented in patients in group B compared with patients treated with imatinib alone (48.5% vs. 34%). Although a higher relapse-free survival (RFS) was documented in group B, no difference was observed in overall survival (OS) in both groups.

Conclusion

Our results show that the addition of Ara-C in the treatment of patients with chronic-phase CML clearly improved the cytogenetic response rate and the RFS, but new modalities of treatment need to be evaluated after relapse because the OS rate was similar in both groups. Of interest is that there was more progression in group A than in group B (16 cases vs. 1 case). This modality of therapy needs to be compared with new emerging options of first-line treatment in this disease.

Arsenic trioxide is an older drug that has recently been introduced into new medicine. It is very potent against a specific type of leukemic cell harboring a translocation between chromosomes 15 and 17. It has been demonstrated that this drug is effective against all stages of acute promyelocytic leukemia (APL), including for remission induction of relapsed cases or as first-line treatment. It is also useful in the consolidation/maintenance phase of treatment. Many trials are ongoing to determine the best and optimum schedule for this drug as a single agent or in combination with other drugs. In the future, its indications might extend to other malignancies. In this review, we study the biologic effects of arsenic trioxide on APL cells and the results of clinical trials on the treatment of patients with APL. We will also discuss the toxicity and minimal residual detection during patient follow-up.

Despite recent advances in cytogenetics and molecular research, universal biomarkers for the diagnosis of the myelodysplastic syndromes (MDS) are still lacking. It is not easy to diagnose MDS by morphology alone, particularly in patients with < 5% blasts in the bone marrow (BM) and normal karyotype. Therefore, the possibility of misdiagnosis and discordance among observers can occur. In order to resolve these problems, we propose a grading system for diagnostic accuracy of MDS. The diagnostic accuracy of MDS is graded into “definite,” “probable,” or “possible” in addition to “idiopathic cytopenia(s) of uncertain significance (ICUS).” The criteria of grading for diagnostic accuracy are a combination of (1) the frequency of blasts in BM, (2) grade of dysplasia (high, intermediate, or low), and (3) division of cytogenetics (abnormal, normal, or unknown). For quantitative morphologic evaluation of dysplasias, we classified morphologic dysplastic changes into highly specific category A (pseudo–Pelger-Huet anomaly, degranulation of neutrophils, micromegakaryocytes, and ringed sideroblasts) and less specific category B (dysplasias other than those in category A). We believe that diagnostic problems would be reduced by using our grading system and repeating BM examination at suitable intervals for patients who are allocated into the “possible” or “ICUS” categories, and this will make the vague margin of MDS category clearer.

Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries, with recent evidence suggesting that the disease should be divided into high- and low-risk categories. First-line treatment strategies vary, but combination chemotherapy or chemoimmunotherapy has been an acceptable initial approach. It remains unclear whether patients at high risk should be treated similarly to patients at low risk, but clinical trials are attempting to resolve this issue. This review discusses the commonly used prognostic factors in CLL; reviews data on first-line therapy, with special focus on large prospective randomized studies; and provides insight as to how we might approach this disease using a risk-stratified approach.

Immune thrombocytopenic purpura (ITP) is observed in 2% of patients with chronic lymphocytic leukemia (CLL). Steroids, intravenous immunoglobulins, anti-Rh(D) immunoglobulins, and splenectomy remain the mainstays of treatment in ITP. Rituximab is a chimeric monoclonal antibody against CD20 antigen expressed on B-lymphocytes and, therefore, has B-cell–depleting and immunomodulatory capabilities. Many case reports, series, and retrospective studies have reported its efficacy in the treatment of patients with refractory ITP. However, its efficacy in CLL-associated ITP is not well described. Herein, a patient with refractory CLL-associated ITP who achieved a durable complete response for 8 months after treatment with rituximab is described.

MicroRNAs (miRNAs) are small noncoding RNAs with important regulatory functions, including hematopoietic differentiation. The advent of high-throughput methods to detect miRNA expression has allowed the study of miRNA levels during normal hematopoiesis and have revealed a widespread aberrant miRNA expression in leukemic cells with respect to the normal hematopoietic cells, suggesting a role for miRNAs in human leukemogenesis. Studies have demonstrated that miRNAs are indeed involved in the initiation and progression of human leukemias. Mutations in miRNA genes and in their target sites could predispose to cancer by altering miRNA expression or by affecting its regulatory function on the target messenger RNA. Furthermore, miRNA expression profiling could also distinguish patients with leukemia with poor outcome independent from other biomarkers. Herein, we review the main studies investigating the role of miRNAs in normal human hematopoiesis as well as in acute and chronic leukemias. In addition, we will discuss the emerging role of other noncoding RNAs (namely the ultraconserved regions) in leukemia.

Background

The introduction of imatinib, the first of a family of abl kinase inhibitors, opened a new era in the therapy of chronic myeloid leukemia (CML). The majority of treated patients achieve complete cytogenetic response, although the disease is often detectable by molecular techniques.

Materials and Methods

Using a mathematical model for the architecture of hematopoiesis and progression of disease as well as clinical data, we develop a unified framework that models the origin and clonal expansion of CML, the response to abl kinase inhibitors, and relapse upon cessation of therapy.

Results

The model predicts that a small pool of mutated stem cells is enough to drive CML. Inhibition of the abl kinase decreases the self-renewal capability of CML progenitors, altering their fitness compared with normal progenitors. Persistence of CML progenitors, however, is responsible for the rapid relapses observed upon cessation of therapy. We demonstrate how the architecture of hematopoiesis plays an instrumental role in growth of the CML clone and its response to treatment.

Conclusion

A small pool of stem cells is enough to drive the chronic phase of CML. Imatinib reverses the fitness advantage of CML cells, allowing return of normal hematopoiesis in most patients. Persistence of CML progenitor cells seems to be responsible for the observed relapse kinetics.