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The prognostic effect of hypogammaglobulinemia (HGG), clinical and biologic characteristics on the infection risk and outcome has been retrospectively analyzed in 899 patients with stage A chronic lymphocytic leukemia (CLL). Low levels of IgG were recorded in 19.9% of patients at presentation, low levels of IgM and/or IgA in 10.4% and an additional 20% of patients developed HGG during the course of the disease. Before the start of any treatment, 160 (12.9%) patients experienced at least one grade ≥3 infection requiring a systemic anti-infective treatment and/or hospitalization. While IgG levels at diagnosis were not associated with an increased risk of grade ≥3 infection or with an adverse outcome, a significantly increased rate of grade ≥3 infections was recorded in patients with unmutated IGHV (p=0.011) and unfavorable FISH aberrations (p=0.009). Late onset HGG, more frequently recorded in patients with Rai stage I-II (p=0.001) and unmutated IGHV (p=0.001), was also associated with a higher rate of severe infections (p=0.002). These data indicate that, stage A patients with clinical and biologic characteristics of a more aggressive disease develop more frequently late onset HGG, grade ≥3 infections and require a closer clinical monitoring., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

ZAP-70 is a marker of clinical outcome in chronic lymphocytic leukemia (CLL), however its assessment suffers from a lack of standardization consensus. To identify novel markers able to surrogate IGHV mutational status, CD19(+)CD5(+)-B-lymphocytes from 216 patients enrolled in a prospective study (ClinicalTrial.gov Identifier:NCT00917540), underwent gene expression profiling. Samples were split into CLL-Training (n=102) and CLL-Validation (n=114) sets, and an independent supervised analysis for IGHV mutational status was performed considering all genes with gene expression equal or above that of ZAP-70. Thirty-one genes (23 up- and 8 down-regulated) and 23 genes (18 up- and 5 down-regulated) satisfied these criteria in the CLL-Training and CLL-Validation sets, respectively, and 20 common genes (15 up and 5 down) were found to be differentially regulated in both sets. Two (SNORA70F, NRIP1) of the down-regulated and 6 (SEPT10, ZNF667, TGFBR3, MBOAT1, LPL, CRY1) of the up-regulated genes were significantly associated with a reduced risk of disease progression in both sets. Forcing the afore-mentioned genes in a Cox multivariate model together with IGHV mutational status, only CRY1 (HR=2.3, 95% CI: 1.1-4.9, P=.027) and MBOAT1 (HR=2.1, 95% CI: 1.1-3.7, P=.018) retained their independent prognostic impact, supporting the hypothesis that these genes may potentially act as surrogates for predicting IGHV mutational status., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The use of both traditional and novel prognostic parameters combined in a statistical model for predicting patient clinical outcome has been recently proposed by both MD Anderson Cancer Center (MDACC) and German chronic lymphocytic leukemia (CLL) group. Using time to first treatment (TTFT) as end-point, we performed a comparative external validation of MDACC score versus a modified version of German score, which excluded thymidine kinase measurement, in a prospective, multicenter, community-based cohort consisting of 328 patients who had asymptomatic, early stage CLL. With both models a significant correlation between higher score and shorter TTFT could be found. As a matter of fact, patients with total point score ≥25 according to MDACC model (HR, 3.27; 95% CI, 2.07-5.18; P<0.0001) or ≥2 according to modified German model (HR, 2.02; 95% CI, 1.29-3.16; P=0.002) were more likely to receive therapy. Both models provided similar results in terms of sensitivity (MDACC score, 61.5%; modified German score, 57.7%; P=0.79), whereas specificity was significantly higher for MDACC score (72.1% versus 63%; P=0.02). The prognostic utility of either MDACC or modified German score was assessed by time-dependent Receiver Operating Characteristic (ROC) analysis. Results of this comparative analysis showed that after the 2nd year area under curve (AUC) for TTFT was higher than 0.60 for both models and kept unmodified this trend over the time. Results of this study suggest that in CLL both MDACC and modified German score group should be considered the benchmarking of comparison for any novel prognostic proposal having as endpoint TTFT in CLL and including both traditional and newer prognostic parameters., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Although vitamin D insufficiency is related to inferior prognosis in some cancers, limited data exist in hematologic malignancies. We evaluated the relationship between 25(OH)D serum levels and time to first treatment (TFT), a disease-specific end point, in 130 previously untreated Binet stage A chronic lymphocytic leukemia (CLL) patients. Measurement of 25(OH)D was performed by means of a direct, competitive chemiluminescence immunoassay using the DiaSorin LIAISON 25(OH)D TOTAL assay (DiaSorin, Inc., Stillwater, Minnesota). Overall, 41 patients (31.5%) had severe vitamin D insufficiency (<10 ng/mL), 66 (50.7%) had mild to moderate insufficiency (10-24 ng/mL), and 23 (17.6%) had 25(OH)D levels within the optimal range (25-80 ng/mL), with no relationship with between the season of sample collection and 25(OH)D level (P=0.188). A patient stratification according to these 3 groups led to significant difference in terms of TFT, with vitamin D insufficient patients having the shortest TFT (P=0.02). With respect to continuous 25(OH)D levels and clinical outcome, TFT was shorter as 25(OH)D decreased until a value of 13.5 ng/mL at which point the association of 25(OH)D and TFT remained constant. As a matter of fact, the 25(OH)D value of 13.5 ng/mL identified two patients subsets with different TFT risk (HR=1.91; 95% CI=1.06-3.44; P=0.03). In multivariate analysis the variable entering the model at a significant level were mutational status of IgVH (P<0.0001), serum thymidine kinase (P=0.02) and absolute lymphocyte count (P=0.03). Thus confirming the Mayo clinic experience, our data provide further evidence that 25(OH)D levels may be an important host factor influencing TFT of Binet stage A patients. Whether normalizing vitamin D levels may delay disease-progression of patients with early disease will require testing in future trials., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

In a series of 84 chronic lymphocytic leukemia (CLL) patients we sought to establish whether BAFF (B-cell activating factor of the TNF family) circulating levels correlated with clinical characteristics of disease. BAFF serum levels were significantly higher in 20 healthy controls (i.e., median 695 ng/mL, range 389-1040) in comparison to the whole population of CLL patients (median 376, range 93-8914; P<0.0001). After setting a cut-off at the median value observed in healthy controls (i.e., 695 ng/mL) we found that 6 out of 15 (40%) patients with familial CLL had increased BAFF levels while the same occurred only in 5 out of 64 (7.2%) patients with sporadic CLL (P=0.0007). No significant difference in age (P=0.82), sex (P=0.97), Binet clinical stage (P=0.20), incidence of autoimmune hemolytic anemia (AIHA) or immune thrombocytopenia (ITP) (P=0.47), mutational status of IgVH (P=1.00), CD38 (P=0.34) and ZAP-70 expression (P=0.16) could be detected between patients with sporadic and familial CLL, respectively. The only feature characterizing familial CLL patients was a higher serum BAFF level (sporadic CLL 336 ng/mL, range 93-925; familial CLL 601 ng/mL, range 138-8914; P=0.002). Our data suggest that BAFF levels are elevated in patients with familial CLL. The small cohort of patients used implies that a larger study is needed to reinforce the observation.

Individual differences in xenobiotica metabolising capacity can influence susceptibility to multiple myeloma. NQO1 and GSTT1 polymorphisms were recently reported as risk factors for multiple myeloma and GSTP1 genotype was found to be a prognostic marker for therapy outcome in multiple myeloma. The aim of this study was to determine whether specific defective alleles of NQO1 (P187S) and GSTP1 (I105V) genes are associated with increased risk of multiple myeloma. Individual genotypes of 128 patients affected by multiple myeloma and 245 healthy controls were determined and our results do not support any major role of NQO1 or GSTP1 polymorphisms in multiple myeloma pathogenesis.

This study examines the response to dexamethasone-doxorubicin-vincristine (DAV) therapy, followed by conditioning regimen and autologous stem cells transplantation (ASCT) in patients with multiple myeloma in relation with the presence of polymorphisms in genes involved in drug metabolism (GSTP1) and DNA synthesis (TYMS). GSTP1 G313G genotype (OR=5.49; 95% CI, 1.3-22.5, p=0.02) and TYMS A227A genotype (OR=3.41; 95% CI, 1.3-8.9, p=0.01) resulted significantly associated with a poor response following chemotherapy and the risk increased for the combined genotype (OR=13.54; 95% CI, 2.0-91.3, p=0.01). TYMS T157T genotype was significantly associated with a poor response after ASCT (OR=4.60; 95% CI, 1.2-16.9, p=0.02). Pre-therapeutic individual determination of the GSTP1 and TYMS polymorphisms could help in choosing the most appropriate protocol.

We investigated the effects of a single s.c. injection of peg-filgrastim in 32 patients with multiple myeloma who underwent autologous stem cell transplantation (AuSCT) as first line treatment. For comparison, 32 myeloma patients with similar characteristics and receiving standard daily administration of filgrastim were matched. Overall, there were no statistically significant differences between peg-filgrastim and filgrastim in terms of tolerability, marrow recovery, severity of neutropenia, incidence and duration of febrile neutropenia, documented infections and transfusions. However, some favourable trends or effects in favour of peg-filgrastim were observed. This was confirmed by a review of the published papers about this topic.

TCR gamma/delta profiles were analyzed in 13 multiple myeloma patients after allogeneic non-myeloablative transplantation. Results show that both aGVHD and minimal residual disease (MRD) eradication did significantly affect TCR gamma/delta profile. During follow-up, six patients developed an aGVHD episode; in five of them, this event fitted with a modification of the TCR profile. Eleven patients achieved PCR-negativity during follow-up. In the 90% of them, the appearance of a new predominant TCR peak was concomitant to the disappearance of the IgH clone. These results suggest that different T gamma/delta populations would sustain GVM and GVH effects after non-myeloablative allogeneic transplant.

This study evaluates the prognostic value of molecular monitoring of minimal residual disease (MRD) in 20 patients with multiple myeloma (MM) following autologous (peripheral blood stem cell transplantation, PBSCT) and non-myeloablative allogeneic (NMT) transplant. All patients completed their program, with a treatment-related mortality (TRM) of 20% and a 2-year progression-free survival (PFS) of 51%. After PBSCT, only 3 patients (15%) achieved PCR-negativity, versus 12 (60%) after NMT. The eradication of MRD had a favorable impact on 2-year OS. In fact, 76% of patients with no detectable MRD was still alive versus 34% of persistently IgH-positive cases (p=0.03). PCR status did not correlate with chimerism percentage: Seventy-five percent of patients achieved full donor chimerism, which was more frequently observed in cases presenting cGHVD (p=0.01). These data sustain the relevant role of molecular monitoring in MM patients undergoing NMT. MRD monitoring would assist physicians in making additional therapeutic decisions to better control this hematological malignancy.

Expression of two MDR genes, BCRP and MDR1, was evaluated by real-time PCR technique in 51 AML patients. Fifty-six percent expressed the BCRP gene, with the 48.2% showing intermediate levels. Eighty-eight percent expressed the MDR1, with 23.8% of cases at high expression. A significant correlation between BCRP and MDR1 values was found by regression analysis. Either levels of BCRP or MDR1 did not correlate with clinical characteristics of patients at diagnosis.

We report a case of Ph1-negative, bcr-negative CML-BC, in which the primary leukemic cells displayed T-related antigens (CD7, CD4) in addition to HLA-DR and CD25 determinants. No B-lymphoid, myeloid and megakaryoblastic surface antigens were detected. In spite of this phenotype, DNA analysis revealed a germ-line configuration of the T-cell receptor beta chain gene region. Moreover, in-vitro culture studies demonstrated a proliferative response of the blast cell population to natural and recombinant myeloid-related factors, while no proliferative signal was observed in the presence of IL-2. The myeloid lineage was further demonstrated by the expression of myeloid-associated antigens on cultured blast cells, which still retained the CD7 antigen. Finally, cytogenetic analysis revealed a monosomy 7 which is usually associated with a stem cell leukemia. These results support the hypothesis that Ph1-negative, bcr-negative CML is characterized by the involvement of a multipotent stem cell capable of multilineage expression and indicate that differentiative and proliferative assays provide a further tool towards a more precise recognition of hematological disorders of uncertain origin.