Hematol. Rev., Volume 1, Issue 1 (March 2009) – 10 articles

In 2005, an activating mutation in the Janus kinase 2 (JAK2) was identified in a significant proportion of patients with myeloproliferative neoplasms, mainly polycythemia vera, essential thrombocythemia and primary myelofibrosis. Many types of mutations in the JAK-STAT pathway have been identified, the majority are related to JAK2. Currently JAK2 mutations are important in the area of diagnosis of myeloid neoplasms, but its role beyond the confirmation of clonality is growing and widening our knowledge about these disorders. In addition to that, clinical trials to target JAK2-STAT pathway will widen our knowledge and hopefully will offer more therapeutic options. In this review, we will discuss the role of JAK2 abnormalities in the pathogenesis, diagnosis, classification, severity and management of hematologic neoplasms. Full article

Novel drugs such as bortezomib and high dose chemotherapy combined with stem cell transplantation improved the outcome of multiple myeloma patients in the past decade. However, multiple myeloma often remains incurable due to the development of drug resistance governed by the bone marrow micro-environment. Therefore targeting new pathways to overcome this resistance is needed. Histone deacetylase (HDAC) inhibitors represent a new class of anti-myeloma agents. Inhibiting HDACs results in histone hyperacetylation and alterations in chromatine structure, which, in turn, cause growth arrest differentiation and/or apoptosis in several tumor cells. Here we summarize the molecular actions of HDACi as a single agent or in combination with other drugs in different in vitro and in vivo myeloma models and in (pre)clinical trials. Full article

MicroRNAs (miRNAs) are small non-coding RNAs (ncRNAs) with important regulatory functions. After an initial phase, aimed at identifying whether a deregulation in miRNA expression occurred between hematologic malignancies and their normal counterparts, currently an increasing number of studies are focusing on the functional significance of these aberrancies. The identification of miRNA targeted genes has cast a new light on the role of these tiny ncRNAs in human cancerogenesis, providing a new rationale to the observed diagnostic, prognostic and therapeutic implications of miRNA aberrant expression in human hematologic malignancies. Full article

Splenectomy and splenic irradiation (SI) are the sole treatment modalities to control drug resistant splenomegaly in patients with myelofibrosis (MF). SI has been used in poor surgical candidates but optimal total dose and fractionation are unclear. We retrospectively reviewed 14 MF patients with symptomatic splenomegaly. Patients received a median of 10 fractions in two weeks. Fraction size ranged from 0.2–1.4 Gy, and total dose varied from 2–10.8 Gy per RT course. Overall results indicate that 81.8% of radiation courses achieved a significant spleen reduction. Splenic pain relief and gastrointestinal symptoms reduction were obtained in 94% and 91% of courses, respectively. Severe cytopenias occurred in 13% of radiation courses. Furthermore patients were divided in three groups according to the radiation dose they received: 6 patients in the low-dose group (LDG) received a normalized dose of 1.67 Gy; 4 patients in the intermediate-dose group (IDG) received a normalized dose 4.37 Gy; the remaining 4 patients in the high-dose group (HDG) received a normalized dose of 9.2 Gy. Subgroup analysis showed that if no differences in terms of treatment’s efficacy were seen among dose groups, hematologic toxicity rates distributed differently. Severe cytopenias occurred in 50% of courses in the HDG, and in the 14.3% and in 0% of the IDG and LDG, respectively. Spleen reduction and pain relief lasted for a median of 5.5 months in all groups. Due to the efficacy and tolerability of the low-dose irradiation 4 patients from the LDG and IDG were retreated and received on the whole 12 RT courses. Multiple retreatments did not show decremental trends in terms of rates of response to radiation nor in terms of duration of clinical response. Moreover, retreatment courses did not cause an increased rate of adverse effects and none of the retreated patients experienced severe hematologic toxicities. The average time of clinical benefit in retreated patients was much longer (21 months, range 44–10) than patients who were not retreated (5.75 months, range 3–6). Full article

Progressive cardiotoxicity following treatment with doxorubicin-based chemotherapy in patients with non-Hodgkin’s lymphoma (NHL) may lead to late onset cardiomyopathy. So, early prediction of toxicity can lead to prevention of heart failure in these patients. The aim of this work was to investigate the role of H-FABP as an early diagnostic marker of anthracycline-induced cardiac toxicity together with brain natriuretic peptide (BNP) as an indication of ventricular dysfunction in such patients. Our study was conducted on 40 NHL patients who received 6 cycles of a doxorubicin containing chemotherapy protocol (CHOP), not exceeding the total allowed dose of doxorubicin (500 mg/m²). Ten healthy controls were included in our study. Human heart-type fatty acid-binding protein (H-FABP) was assessed 24 h after the first cycle of CHOP. Plasma levels of BNP were estimated both before starting chemotherapy and after the last cycle of CHOP. Resting echocardiography was also performed before and at the end of chemotherapy cycles. The ejection fraction (EF) of 8 of our patients decreased below 50% at the end of the sixth cycle. Elevated levels of both H-FABP and BNP were found in all patients wth EF below 50% and both markers showed a positive correlation with each other. We concluded that H-FABP may serve as a reliable early marker for prediction of cardiomyopathy induced by doxorubicin. Thus, in patients with elevated H-FABP, alternative treatment modalities with no cardiac toxicity may be considered in order to prevent subsequent heart failure in these patients. Full article

Whereas the reduction of transfusion related viral transmission has been a priority during the last decade, bacterial infection transmitted by transfusion still remains associated to a high morbidity and mortality, and constitutes the most frequent infectious risk of transfusion. This problem especially concerns platelet concentrates because of their favorable bacterial growth conditions. This review gives an overview of platelet transfusion-related bacterial contamination as well as on the different strategies to reduce this problem by using either bacterial detection or inactivation methods. Full article

Emerging evidence suggests that the three tyrosine kinase inhibitors currently approved for the treatment of patients with chronic myelogenous leukemia (CML)—imatinib, dasatinib, and nilotinib—have potential cardiotoxic effects. The mechanisms behind these events, and the relations between them, are largely unclear. For example, relative to dasatinib and nilotinib, severe congestive heart failure and left ventricular dysfunction are rare but prominent with imatinib treatment, particularly in patients receiving higher doses (>600 mg/day). In comparison with imatinib, prolongation of the QT interval is relatively common in patients treated with either dasatinib or nilotinib. In contrast to nilotinib, pericardial effusions are observed with both imatinib and dasatinib. It is suggested that these data, an evaluation of cardiac status, use of concomitant medications, and potential risk factors should be considered in the management of CML. Full article

Autologous stem cell transplantation is still considered the standard of care in young patients with multiple myeloma (MM). This disease is the most common indication for high-dose therapy (HDT) supported by hematopoietic stem cell transplantation and much data support the benefit of this procedure. Results of randomized studies are in favor of tandem autologous transplantation although the effect on overall survival is unclear. Based on sequential registration trials in the Nordic area, we aimed to evaluate the outcome of conventional single or double HDT. During 1994–2000 we registered a total of 484 previously untreated patients under the age of 60 years at diagnosis who on a regional basis initially were treated with single [Trial NMSG #5/94 and #7/98 (N = 383)] or double [Trial Huddinge Karolinska Turku Herlev (N = 101)] high-dose melphalan (200 mg/m²) therapy supported by autologous stem cell transplantation. A complete or very good partial response was achieved by 40% of patients in the single transplant group and 60% of patients in the double transplant group (p = 0.0006). The probability of surviving progression free for five years after the diagnosis was 25% (95% CL 18–32%) in the singletransplant group and 46% (95% CL 33–55%) in the double transplant group (p = 0.0014). The estimated overall five-year survival rate was 60% in the single transplant group and 64% in the double transplant (p = 0.9). In a multivariate analysis of variables, including single versus double transplantation, β2 microglobulin level, age, sex and disease stage, only β2 microglobulin level was predictive for overall survival (p > 0.0001) and progression free survival (p = 0.001). In accordance with these results, a 1:1 case-control matched comparison between double and single transplantation did not identify significant differences in overall and progression free survival. In this retrospective analysis up front double transplantation with melphalan (200 mg/m²) as compared to single transplantation did not seem to improve the final outcome among patients in the Nordic area. These data are in accordance with recent publications from the Bologna 96 trial indicating that a second transplant should not be recommended up front as standard care. Full article

At present, there are no compounds in clinical development in the field of chronic myeloid leukemia (CML) or Philadelphia-positive (Ph⁺) acute lymphoblastic leukemia (ALL) that have been documented to harbor significant activity against the imatinib-resistant T315I mutation. Recent reports on the pre-clinical activity of some emerging tyrosine kinase inhibitors such as ON012380, VX-680 and PHA-739358 promise possible clinical efficacy against this specific Bcr-Abl mutant form. Here, we focus on the role of aurora kinase inhibitor VX-680 and PHA-739358 in blocking the leukemogenic pathways driven by wild-type and T315I-Bcr-Abl in CML or Ph⁺ ALL by reviewing recent research evidence. We also discuss the possibility of employing aurora kinase inhibitors as a promising new therapeutic approach in the treatment of CML and Ph⁺ ALL patients resistant to first and second generation TK inhibitors. Full article