Risk-tailored treatment of splenic marginal zone lymphoma.

Splenic marginal zone lymphoma (SMZL) is a rare lymphoproliferative disease involving B-cells and affecting elderly patients. SMZL plague peripheral blood and bone marrow, spleen. Lymph nodes are generally spared. SMZL is due to a protracted antigen stimulation of B lymphocytes and of microenvironment leading B-cell to polyclonal and then oligoclonal/monoclonal growth, promoting lymphoproliferation. Integration of the NOTCH2 and NFk-B signaling has been recently identified as the primary mechanism of neoplastic proliferation in SMZL. In total 20% of cases carry mutations in NOTCH2. Although SMZL has an indolent course, progression to diffuse large B-cell lymphoma occurs in about 10-15% of patients. Establishing the prognosis is a key step in disease management, depending on both individual risk and patients' health status. This review discusses tailored treatment of SMZL patients. Progression risk factors include nodal and extra-nodal involvement, peripheral lymphocytosis, anemia and thrombocytopenia. Patients with two or more score points have a median survival of <5 years. Watch and wait strategy is appropriate in low-risk and asymptomatic patients, whereas treatment of symptomatic patients ranges from splenectomy to rituximab monotherapy or associated with chemotherapy.

Biosimilar epoetin alfa increases haemoglobin levels and brings cognitive and socio-relational benefits to elderly transfusion-dependent multiple myeloma patients: results from a pilot study.

Anaemia is a complication reported in up to 70% of the multiple myeloma patients (MM), with remarkable clinical, cognitive and socio-relational consequences. Anaemia relates to the course of MM, normalizing in patients during remission and reappearing in relapsing/non-responding patients. In a pilot study with 31 patients with MM and transfusion-dependent anaemia, we evaluated the effects of Binocrit (biosimilar epoetin alfa) on transfusions, haemoglobin levels, mental status (mini-mental state evaluation) and the patients' social-relational functioning and quality of life (QoL). Within a 12-week interval, patients received 40.000 U Binocrit once a week. Binocrit significantly decreased the incidence of transfusion, regardless of the patients' transfusion history, and significantly increased haemoglobin levels (before-and-after-treatment median haemoglobin values = 8.20 vs. 9.40 g/dl, respectively; Wilcoxon Z test, p < .001). A comparatively greater increment in haemoglobin levels among patients who responded to first vs. additional lines of chemotherapy was also observed. Importantly, we additionally found moderate-to-strong positive associations between increments in haemoglobin levels and corresponding increments both in psychological well-being and QoL (FACT-An scores) and the patients' cognitive status (mini-mental state evaluation scores). After statistically controlling for possible concurrent benefits of anti-myeloma therapy, increments in haemoglobin levels clearly predicted both increments in socio-relational FACT-An scores (Spearman's rho = 0.60, p < .001) and in cognitive functioning scores (Spearman's rho = 0.49, p < .006). Binocrit thus appears as an effective, well-tolerated agent for the management of myeloma anaemia, whose documented benefits include amelioration of anaemia, reduction in transfusion, and improvements in the patients' social-relational functioning and cognitive well-being.

Salvage therapy with bortezomib and dexamethasone in elderly patients with relapsed/refractory multiple myeloma.

Bortezomib-dexamethasone (bort-dex) is effective for relapsed/refractory (R/R) multiple myeloma, but few data are available for elderly patients. The aim of this study was to evaluate efficacy and toxicity of bort-dex in elderly R/R MM patients. We evaluated 81 R/R MM patients treated with bort-dex. Eight of them had light-chain disease. The median age of the patients was 73 years (range 65-89 years). All patients were R/R MM patients and had been treated with melphalan and prednisone with or without thalidomide or bortezomib in the first line or with lenalidomide and dexamethasone in the second line. The median number of previous lines was 2. Thirty-nine (48%) patients received bortezomib intravenously and 42 (52%) patients received bortezomib subcutaneously. The median number of bort-dex cycles was 6 (range 1-11). Fifty-three (65.4%) patients achieved at least a partial response, including eight (11%) patients with complete response and nine (12.5%) patients with very good partial responses. The median duration of response, time to next therapy and treatment-free intervals were 8, 11 and 5 months. Duration of response was significantly longer for patients achieving complete response/very good partial response than for those achieving partial response (7.3 vs. 3.8 months, P=0.03). After a median follow-up of 24 months, 78 patients showed disease progression and 70 died. The median time to progression, progression-free survival and overall survival were 8.9, 8.7 and 22 months, respectively. Peripheral neuropathy occurred in 38 (47%) patients. Our data highlight that bort-dex is effective and tolerable in fit elderly patients, thus justifying the efforts for deeper responses. However, awareness of short-lived responses to bort-dex should lead to a thorough evaluation of the need for maintenance.

ADAMTS13, von Willebrand Factor, Platelet Microparticles, Factor VIII, and Impact of Somatic Mutations in the Pathogenesis of Splanchnic Vein Thrombosis Associated with BCR-ABL-Negative Myeloproliferative Neoplasms.

BACKGROUND: Myeloproliferative neoplasms (MPNs) are often associated with splanchnic vein thrombosis (SVT). Not all the factors involved in the thrombotic tendency are currently known. OBJECTIVES: This study aims to evaluate a possible association between ADAMTS13, von Willebrand factor (VWF), platelet microvesicles (MV), and factor VIII activity (FVIII:C) with thrombotic events in MPN patients. MATERIALS AND METHODS: In total, 36 consecutive MPN patients with SVT were enrolled. The MPNs were diagnosed based on clinical characteristics and one or more gene mutations among JAK-2, CALR, and MPL. As controls, 50 randomly selected patients with MPN without thrombosis, 50 patients with deep vein thrombosis without MPNs, and 50 healthy blood donors were evaluated. Complete blood count, ADAMTS13, VWF, MV, and FVIII:C in plasma were measured in all the subjects. RESULTS: The JAK-2 mutation was found in 94% of the patients with SVT, but none were triple-negative for genetic mutations (JAK2 V617F, CALR, MPL, and exon 12). Compared to the normal subjects, in all the MPN patients (with or without SVT), the levels of ADAMTS13 were found to be significantly lower (p < 0.001) and the MV concentrations were significantly higher (p < 0.001). Among the MPN patients, the VWF and FVIII:C levels were significantly higher in the patients with SVT than those without thrombosis (p = 0.007 and p = 0.04, respectively). Splenomegaly was present in 78% of MPN patients with SVT and in 30% of those without SVT (p < 0.001). The ADAMTS13/VWF ratio was reduced in all the patients, but not in the healthy blood donors (p < 0.001). CONCLUSIONS: The significant increase in circulating MV, VWF, and FVIII:C in the MPN patients and in the patients with thrombosis supports the role of endothelium damage in promoting thrombotic events. In particular, a significant increase in VWF and FVIII:C levels was found in the MPN patients with SVT.

Platelet Microvesicles, Inflammation, and Coagulation Markers: A Pilot Study.

BACKGROUND: Platelet "Microvesicles" (MVs) are studied for their role in blood coagulation and inflammation. The study aimed to establish if MVs are related to age, plasma levels of inflammation, coagulation, and fibrinolysis markers in healthy individuals. METHODS: We prospectively enrolled volunteers aged over 18 years. MVs, plasma levels of C-reactive protein (CRP), Interleukin 6 (IL-6), Interleukin 10 (IL-10), Interleukin 17 (IL-17), and transforming growth factor ß (TGF-ß), fibrinogen, plasminogen activator inhibitor-1 (PAI-1), von Willebrand factor (VWF), homocysteine, factor VII (FVII), thrombin activatable fibrinolysis inhibitor (TAFI), and Protein S were tested. RESULTS: A total of 246 individuals (median age 65 years ("IQR"54-72)) were evaluated. Both univariate analysis and logistic regression models showed that MVs positively correlate with age, CRP, IL-6, IL-10, IL-17, TGF-ß, fibrinogen, PAI-1, VWF, FVII, and homocysteine, while inversely correlating with TAFI and Protein S. The ROC curve analysis performed to identify a cut off for MV values (700 kMP) showed a good accuracy with over-range cytokines fibrinolysis factor and coagulation markers. CONCLUSIONS: To the best of our knowledge, this study is the first to correlate MVs with an entire panel of cardiovascular risk factors in healthy individuals. A future possible role of MVs in screening exams is suggested.

The European Consensus on grading of bone marrow fibrosis allows a better prognostication of patients with primary myelofibrosis.

We investigated the relationship between the International Prognostic Scoring System of the International Working Group for Myelofibrosis Research and Treatment and the European Consensus on grading of bone marrow fibrosis (MF) in patients with primary myelofibrosis. We compared them in 196 consecutive primary myelofibrosis patients (median follow-up 45.7 months; range 7.4-159). International Prognostic Scoring System classified 42 cases as low risk, 73 as intermediate risk-1, 69 as intermediate risk-2, and 12 as high risk; European Consensus on grading of bone marrow fibrosis classified 83 cases as MF-0, 58 as MF-1, 41 as MF-2, and 14 as MF-3. By the time of the analysis, 30 patients (15.3%) had died. Overall median survival was 3.8 years (95% confidence interval: 3.3-4.3). Multivariate analysis confirmed that both scoring systems independently predicted survival, with hazard ratios similar to those provided by univariate analysis (respectively, 2.40 (95% confidence interval: 1.47-3.91) and 2.58 (95% confidence interval: 1.72-3.89) but the likelihood ratio increased from 19.6 of the International Prognostic Scoring System or 29.0 of the European Consensus on grading of bone MF to 42.3 when both measures were considered together. Analysis of the overall survival curves documented that patients classified as having the most favourable rate with both prognostic scores (ie low risk and MF-0) survive longer than those with only one favourable score (ie low risk but MF >0 or MF-0, but International Prognostic Scoring System >low risk). In contrast, those patients classified as having the most unfavourable rate for both scores (high risk and MF-3) have a shorter survival than those with only one unfavourable score (ie high risk but MF<3 or MF-3, but International Prognostic Scoring System

Incidence of Venous Thromboembolism in Multiple Myeloma Patients across Different Regimens: Role of Procoagulant Microparticles and Cytokine Release.

Introduction: Multiple myeloma (MM) is characterized by a high prevalence of thrombotic complications. Microvesicles (MVs) are small membrane vesicles released from activated cells, and they may potentially contribute to thrombosis. Methods: We have evaluated the plasma levels of MVs and cytokines (IL-10, IL-17, and TGF-ß in MM and Watch and Wait Smoldering MM (WWSMM) from patients and related them to thrombotic complications. The secondary aim was to assess the impact of ongoing therapy on MV and on cytokine levels. Result: 92 MM and 31 WWSMM were enrolled, and 14 (12%) experienced a thrombotic episode. Using univariate analysis, TGF-ß and MV were significantly higher in patients with thrombotic events (p = 0.012; p = 0.008, respectively). Utilizing a Cox proportional hazard model, we confirmed this difference (TGF-ß p = 0.003; Odds ratio 0.001, 95% CI 0−0.003 and MV p = 0.001; Odds ratio 0.003, 95% CI 0.001−0.005). Active treatment management displayed higher levels of MV (p < 0.001) and lower levels of glomerular filtration-rate (p < 0.001), IL-17 (p < 0.001) as compared to the WWSMM group. The TGF-ß values of immunomodulatory derivatives patients were lower in the WWSMM (p < 0.001) and Dexamethasone/Bortezomib subgroup (p < 0.001). Conclusion: The increased levels of MVs in active regimens add insight into the mechanisms of hypercoagulation in MM. In addition, a role for cytokine-related thrombosis is also suggested.

Ferric Carboxymaltose and Erythropoiesis-Stimulating Agent Treatment Reduces the Rate of Blood Transfusion in Refractory Anemia.

Background: Erythropoiesis-stimulating agents (ESAs) are used to treat refractory anemia (RA). Guidelines suggest iron supplementation for unresponsive patients, regardless of iron deficiency. The primary aim of this study was to evaluate the effect of iron supplementation with ferric carboxymaltose (FCM) on the reduction of red blood cell transfusion (RBCT) rate in transfusion-dependent RA patients. Methods: This was a prospective quasi-randomized study, wherein patients were randomly assigned into three groups: (A) ESAs alone, (B) ferric gluconate (FG) and ESAs, and (C) FCM and ESAs. Hemoglobin and ferritin levels, as well as the number of RBCTs at 4 and 28 weeks were compared. Economic evaluation was also performed. Results: A total of 113 RA patients were enrolled. In total, 43 were treated with intravenous FG and ESAs, 38 with FCM and ESAs, and 32 with ESAs alone. At both follow-ups, erythropoietic response was increased in those receiving iron as compared with those with ESAs alone (p = 0.001), regardless of the type of iron. At one month, ferritin levels were higher in the FCM and ESA groups (p = 0.001). RBCTs were lower in both iron groups. The less costly treatment strategy was FCM, followed by FG, and lastly ESAs. Conclusions: Addition of iron to ESAs in RA reduced RBCT requirement and improved hemoglobin values.

A randomized comparison of caspofungin versus antifungal prophylaxis according to investigator policy in acute leukaemia patients undergoing induction chemotherapy (PROFIL-C study).

BACKGROUND: Invasive fungal infections (IFIs) are considered a major problem among patients undergoing acute leukaemia (AL) induction treatment. PROphylaxis of Fungal invasive Infections in Leukaemia-Caspofungin (PROFIL-C) is a multicentre study aiming to assess the comparative yield of using caspofungin versus standard policy (SP) regimens and the overall impact of IFI in routine clinical care conditions. METHODS: All AL patients receiving IFI prophylaxis according to local SP were prospectively included in the study by Northern Italy Leukaemia Group (NILG) centres. To allow the comparison of caspofungin versus SP regimens as prophylaxis strategies, caspofungin treatment was assigned via a centralized randomized procedure. The study was registered at http://www.clinicaltrial.gov (NCT00501098). RESULTS: Over a 2 year period, 175 patients were included. The overall incidence of IFI was 32/175 (18.3%) [10/175 (5.7%) probable/proven and 22/175 (12.6%) possible], with no statistically significant differences between caspofungin-based versus SP-based regimens [overall: 15/93 (16.1%) versus 17/82 (20.7%), relative risk (RR) 0.78, 95% confidence interval (CI) 0.42-1.46; probable/proven: 7/93 (7.5%) versus 3/82 (3.7%), RR 2.06, 95% CI 0.55-7.7; possible: 8/93 (8.6%) versus 14/82 (17.1%), RR 0.5, 95% CI 0.22-1.14]. Only one IFI-related death was recorded (10%). CONCLUSIONS: The incidence and mortality of IFI were lower than expected in this strictly sequential cohort representative of the routine care in the NILG network. The efficacy and safety of caspofungin were similar to other prophylactic regimens.

Improved risk classification for risk-specific therapy based on the molecular study of minimal residual disease (MRD) in adult acute lymphoblastic leukemia (ALL).

Clinical risk classification is inaccurate in predicting relapse in adult patients with acute lymphoblastic leukemia, sometimes resulting in patients receiving inappropriate chemotherapy or stem cell transplantation (SCT). We studied minimal residual disease (MRD) as a predictive factor for recurrence and as a decisional tool for postconsolidation maintenance (in MRD(neg)) or SCT (in MRD(pos)). MRD was tested at weeks 10, 16, and 22 using real-time quantitative polymerase chain reaction with 1 or more sensitive probes. Only patients with t(9;22) or t(4;11) were immediately eligible for allogeneic SCT. Of 280 registered patients (236 in remission), 34 underwent an early SCT, 60 suffered from relapse or severe toxicity, and 142 were evaluable for MRD at the end of consolidation. Of these, 58 were MRD(neg), 54 MRD(pos), and 30 were not assessable. Five-year overall survival/disease-free survival rates were 0.75/0.72 in the MRD(neg) group compared with 0.33/0.14 in MRD(pos) (P = .001), regardless of the clinical risk class. MRD was the most significant risk factor for relapse (hazard ratio, 5.22). MRD results at weeks 16 to 22 correlated strongly with the earlier time point (P = .001) using a level of 10(-4) or higher to define persistent disease. MRD analysis during early postremission therapy improves risk definitions and bolsters risk-oriented strategies. ClinicalTrials.gov identifier: NCT00358072.

Novel second mitochondria-derived activator of caspases (Smac) mimetic compounds sensitize human leukemic cell lines to conventional chemotherapeutic drug-induced and death receptor-mediated apoptosis.

The Inhibitor of Apoptosis Proteins (IAPs) are important regulators of programmed cell death. XIAP is the most potent among them and is over-expressed in several hematological malignancies. Its activity is endogenously antagonized by SMAC/DIABLO, and also by small molecules mimicking Smac that can induce apoptosis in tumor cells. Here we describe the activity of 56 newly synthesized Smac-mimetics in human leukemic cell lines and normal CD34(+) progenitor cells. Our compounds bind to XIAP with high affinity, reduce the levels of cIAP1 and are cytotoxic at nanomolar or low micromolar concentrations. Furthermore, the Smac-mimetics synergize with Cytarabine, Etoposide and especially with TRAIL in combination treatments. Apoptosis activation was clearly detectable by the occurrence of sub G(1) apoptotic peak and the accumulation of cleaved PARP, caspase 8 and caspase 3. Interestingly, the down-regulation of XIAP sensitized Jurkat cells to drugs too, confirming the role of this protein in drug-resistance. In conclusion, while being very active in leukemic cells, our Smac-mimetics have modest effects on normal hematopoietic progenitors, suggesting their promising therapeutic potential as a new class of anticancer drugs in onco-hematology, particularly when combined with TRAIL, to overcome the resistance of cancer cells.

The clinical and biological features of a series of immunophenotypic variant of B-CLL.

OBJECTIVES: To describe the clinical and biological features of a series of immunophenotypic variant of B-CLL (v-CLL) characterised by intermediate RMH score, in the absence of t(11;14)(q13;q32) in FISH analysis in comparison with a series of typical CLL. METHODS: We studied the clinical and biological features of 63 cases of v-CLL and 130 cases of CLL. RESULTS: We observed significant differences in terms of age <70 yr (P < 0.001), lymphocytosis <20 x 10(9)/L (P < 0.001), lymphocyte doubling time

Molecular and transcriptional characterization of 17p loss in B-cell chronic lymphocytic leukemia.

Distinct genetic abnormalities, such as TP53 deletion at 17p13.1, have been identified as having adverse prognostic relevance in B-cell chronic lymphocytic leukemia (B-CLL), and conventional cytogenetic studies have shown that TP53 deletion in B-CLL is mainly associated with the loss of 17p due to complex chromosomal rearrangements. We used an integrative genomic approach to investigate the significance of 17p loss in 18 B-CLLs in Binet stage A, carrying a TP53 monoallelic deletion detected by means of fluorescence in situ hybridization (FISH). Genome-wide DNA analysis using single nucleotide polymorphism (SNP) arrays of 12 of 18 samples showed 17p loss in 11 cases, with breakpoints scattered along the 17p11.2 region. FISH analysis confirmed these findings and revealed 17p loss in a small fraction of leukemic cells in the remaining TP53-deleted case, and it also indicated 17p loss in the six cases not investigated by means of SNP arrays. Mutations in exons 2-11 of the remaining TP53 allele were found in 9 of 12 deleted samples. Gene-expression profiling of 60 B-CLLs, including seven patients with 17p loss, identified 40 differentially expressed genes in 17p- versus 17p normal samples, 35 of which were downregulated in 17p-tumors. The majority (30 of 35) of these transcripts, including putative tumor suppressor genes, mapped to 17p, thus indicating a remarkable gene-dosage effect. Our data provide evidence that 17p loss may play an additional pathogenetic role in B-CLL and suggest that the concomitant loss of multiple tumor suppressor genes could be responsible for the highly adverse prognostic relevance associated with TP53 loss.

Bone marrow glycophorin-positive erythroid cells of myelodysplastic patients responding to high-dose rHuEPO therapy have a different gene expression pattern from those of nonresponders.

The main clinical problems of low-risk patients with myelodysplastic syndromes (MDS), as defined by the International Prognostic Scoring System, are infections and the need for frequent transfusions due to ineffective myelopoiesis and peripheral blood cytopenia. Promising results in treating MDS-related anemia have been obtained using high-dose recombinant human erythropoietin (rhEPO). To evaluate the molecular basis of the response to rhEPO, we used commercially available macro-arrays to investigate gene expression profiles in the glycophorin-expressing (Gly+) bone marrow (BM) erythroid cells of five responders (ERs) and five non-responders (ENRs) to rhEPO treatment. The cells were separated by means of positive selection using an immunomagnetic procedure, after which flow cytometry showed that their purity was more than 97% in all cases. The array data were validated by means of real time RT-PCR. The results showed that the genes responsible for proliferation/differentiation and DNA repair/stability were repressed in the BM Gly+ erythroid cells of the ENRs, but almost normally expressed in the ERs. Furthermore, the expression of genes involved in signal transduction suggested that the activity of the MAPK signaling pathway is inhibited in ERs. The different gene expression profiles of ERs and ENRs may provide a basis for early gene testing as a means of predicting the response to rhEPO of MDS patients with low endogenous EPO levels.

A multicenter retrospective clinical study of CD5/CD10-negative chronic B cell leukemias.

CD5-negative chronic B cell lymphoproliferative disorders in leukemic phase (B-CLPD) are heterogeneous and relatively uncommon pathologies that often lack a histopathological definition because of the absence of accessible pathological tissue. We describe the clinical features and evolution-related variables of 156 patients with CD5/CD10-negative B-CLPD (median age 66 years, range 25-86). The median follow-up was 51 months (range 6-216), and overall 3- and 5-year survival was respectively 87 and 76%; 50 patients needed therapy at diagnosis, 56 during follow-up, and 50 remained untreated until the last control. A combined clinical, histological, cytomorphological, immunophenotypical, and cytogenetic diagnostic approach allowed the complete classification of only a minority of patients as being affected by splenic marginal zone or lymphoplasmacytic lymphoma; the majority of cases remained unclassifiable. Multivariate analysis showed that the clinicohematological variables adversely related to overall survival were serum LDH levels and age, whereas high serum LDH levels, hemoglobin levels of <11 g/dl, and splenomegaly related to treatment-free time (in "wait and see" cases); only splenomegaly related to time to progression (in treated patients). In conclusion, our retrospective study describes the clinical features and variables related to evolution in a large group of patients with CD5/CD10-negative chronic B-cell lymphoid leukemias and underlines the fact that a probable lymphoplasmacytic or marginal zone normal cell origin can be supposed in such leukemic forms, but never surely demonstrated.

Integrative genomic analysis reveals distinct transcriptional and genetic features associated with chromosome 13 deletion in multiple myeloma.

BACKGROUND AND OBJECTIVES: The chromosome 13 deletion (Delta13) is one of the most frequent chromosomal alterations in multiple myeloma (MM). Delta13 is associated with an unfavorable prognosis, although there is increasing agreement that its prognostic relevance must be related to the ploidy status and the presence of different chromosomal translocations. The aim of this study was to provide a comprehensive analysis of the transcriptional features of Delta13 in MM. DESIGN AND METHODS: Highly purified plasma cells from 80 newly diagnosed MM patients were characterized by means of fluorescence in situ hybridization (FISH) and high-density oligonucleotide microarray for gene expression profiling and chromosomal alterations. RESULTS: We identified 67 differentially expressed genes in the patients with and without the chromosome 13 deletion, all of which were downregulated in the cases with Delta13: 44 mapped along the whole chromosome 13, seven on chromosome 11 and three on chromosome 19. Functional analyses of the selected genes indicated their involvement in protein biosynthesis, ubiquitination and transcriptional regulation. An integrative genomic approach based on regional analyses of the gene expression data identified distinct chromosomal regions whose global expression modulation could differentiate Delta13-positive cases, in particular the upregulation of 1q21-1q42 and the downregulation of 19p and almost the entire chromosome 11. FISH analyses confirmed the close relationship between Delta13-positivity and the presence of extra copies of 1q21-1q42 (p=6 x 10(-4)) or the absence of chromosome 11 and 19 trisomy (p=5 x 10(-4)). INTERPRETATION AND CONCLUSIONS: Our results indicate that distinct types of chromosomal aberrations are closely related to the transcriptional profiles of Delta13-positive cases, suggesting that the contribution of Delta13 to the malignancy should be considered together with associated abnormalities.

Clearance of minimal residual disease after allogeneic stem cell transplantation and the prediction of the clinical outcome of adult patients with high-risk acute lymphoblastic leukemia.

BACKGROUND AND OBJECTIVES: The molecular analysis of minimal residual disease (MRD) may provide information on the risk of recurrence in patients with acute lymphoblastic leukemia (ALL). The aim of this study was to correlate the kinetics of MRD clearance after allogeneic transplantation with the clinical outcome of adults with ALL. DESIGN AND METHODS: MRD was evaluated by real-time quantitative polymerase chain reaction (RQ-PCR) using probes derived from fusion chimeric genes (BCR/ABL and MLL/AF4) (n=22) or rearrangements of the T-cell receptor or immunoglobulin genes (n=21). Forty-three adult patients with ALL were studied to correlate the kinetics of MRD clearance before and after allogeneic hematopoietic stem cell transplantation. RESULTS: At 36 months, the overall survival of patients who underwent transplantation in hematologic remission (n= 37) was 80% for those who were PCR-negative before transplantation (n= 12) compared to 49% for PCR-positive patients (n= 25)(p=0.17). For the same patients the cumulative incidence of relapse was 0% and 46%, respectively (p=0.027). Moreover, the relapse rate of patients who were PCR-negative at day +100 after transplantation was remarkably low (7%) compared to that among patients who were PCR-positive (80%, p=0.0006). INTERPRETATION AND CONCLUSIONS: The kinetics of MRD clearance may help to identify patients at high risk of leukemia relapse after allogeneic stem cell transplantation. Patients not achieving an early molecular remission after transplantation require prompt and appropriate pre-emptive treatments such as infusions of donor lymphocytes or new experimental drugs.

Induction of neurotrophin expression via human adult mesenchymal stem cells: implication for cell therapy in neurodegenerative diseases.

In animal models of neurological disorders for cerebral ischemia, Parkinson's disease, and spinal cord lesions, transplantation of mesenchymal stem cells (MSCs) has been reported to improve functional outcome. Three mechanisms have been suggested for the effects of the MSCs: transdifferentiation of the grafted cells with replacement of degenerating neural cells, cell fusion, and neuroprotection of the dying cells. Here we demonstrate that a restricted number of cells with differentiated astroglial features can be obtained from human adult MSCs (hMSCs) both in vitro using different induction protocols and in vivo after transplantation into the developing mouse brain. We then examined the in vitro differentiation capacity of the hMSCs in coculture with slices of neonatal brain cortex. In this condition the hMSCs did not show any neuronal transdifferentiation but expressed neurotrophin low-affinity (NGFR(p75)) and high-affinity (trkC) receptors and released nerve growth factor (NGF) and neurotrophin-3 (NT-3). The same neurotrophin's expression was demonstrated 45 days after the intracerebral transplantation of hMSCs into nude mice with surviving astroglial cells. These data further confirm the limited capability of adult hMSC to differentiate into neurons whereas they differentiated in astroglial cells. Moreover, the secretion of neurotrophic factors combined with activation of the specific receptors of transplanted hMSCs demonstrated an alternative mechanism for neuroprotection of degenerating neurons. hMSCs are further defined in their transplantation potential for treating neurological disorders.

Personalized treatment strategies for elderly patients with myelodysplastic syndromes.

INTRODUCTION: Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic disorders characterized by ineffective hematopoiesis and peripheral cytopenia, and their possible transformation into acute myeloid leukemia (AML). They typically affect the elderly but, when making treatment decisions, considering chronological age may be insufficient because it poorly correlates with patient frailty: the challenge is to select the optimal treatment in these patients by balancing efficacy and toxicity. Areas covered: This review discusses the rationale for and methods of personalizing the treatment of elderly MDS patients. Expert commentary: Decisions concerning treatment strategies for elderly MDS patients should be made after assessing their frailty on the basis of a geriatric assessment and an estimate of age-adjusted life expectancy. We suggest that all elderly MDS patients should undergo a timed up and go test (TUGT) as a preliminary means of identifying frail patients, and that all non-frail patients should then undergo a comprehensive geriatric assessment (CGA) in order to distinguish fit and pre-frail patients. Fit patients should receive standard dose treatment; pre-frail patients should receive individualized therapy; and frail patients should receive symptom-related therapy. A repeated CGA may be useful to evaluate the hematological, cognitive and socio-relational effects of MDS treatment.