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In recent years, the outcome of mantle cell lymphoma (MCL) has improved, especially in younger patients, receiving cytarabine-containing chemoimmunotherapy and autologous stem cell transplantation. Nevertheless, a proportion of MCL patients still experience early failure. To identify biomarkers anticipating failure of intensive chemotherapy in MCL, we performed target resequencing and DNA profiling of purified tumor samples collected from patients enrolled in the prospective FIL-MCL0208 phase 3 trial (high-dose chemoimmunotherapy followed by autologous transplantation and randomized lenalidomide maintenance). Mutations of KMT2D and disruption of TP53 by deletion or mutation associated with an increased risk of progression and death, both in univariate and multivariate analysis. By adding KMT2D mutations and TP53 disruption to the MIPI-c backbone, we derived a new prognostic index, the “MIPI-genetic” (“MIPI- g”). The “MIPI-g” improved the model discrimination ability compared to the MIPI-c alone, defining three risk groups: i) low-risk patients (4-year progression free survival and overall survival of 72.0% and 94.5%); ii) inter-mediate-risk patients (4-year progression free survival and overall survival of 42.2% and 65.8%) and iii) high-risk patients (4-year progression free survival and overall survival of 11.5% and 44.9%). Our results: i) confirm that TP53 disruption identifies a high-risk population characterized by poor sensitivity to conventional or intensified chemotherapy; ii) provide the pivotal evidence that patients harboring KMT2D mutations share the same poor outcome as patients harboring TP53 disruption; and iii) allow to develop a tool for the identification of high-risk MCL patients for whom novel therapeutic strategies need to be investigated. (Trial registered at clinicaltrials.gov identifier: NCT02354313).

A prospective trial conducted in the period 2000-2005 showed no survival advantage for high-dose chemotherapy with rituximab and autograft (R-HDS) versus conventional chemotherapy with rituximab (CHOP-R) as first-line therapy in 134 high-risk follicular lymphoma patients aged

We here describe a novel method for MYD88L265P mutation detection and minimal residual disease monitoring in Waldenström macroglobulinemia, by droplet digital polymerase chain reaction, in bone marrow and peripheral blood cells, as well as in circulating cell-free DNA. Our method shows a sensitivity of 5.00×10−5, which is far superior to the widely used allele-specific polymerase chain reaction (1.00×10−3). Overall, 291 unsorted samples from 148 patients (133 with Waldenström macroglobulinemia, 11 with IgG lymphoplasmacytic lymphoma and 4 with IgM monoclonal gammopathy of undetermined significance) were analyzed: 194 were baseline samples and 97 were followup samples. One hundred and twenty-two of 128 (95.3%) bone marrow and 47/66 (71.2%) baseline peripheral blood samples scored positive for MYD88L265P. To investigate whether MYD88L265P detection by droplet digital polymerase chain reaction could be used for minimal residual disease monitoring, mutation levels were compared with IGH-based minimal residual disease analysis in 10 patients, and was found to be as informative as the classical, standardized, but not yet validated in Waldenström macroglobulinemia, IGH-based minimal residual disease assay (r2=0.64). Finally, MYD88L265P detection by droplet digital polymerase chain reaction on plasma circulating tumor DNA from 60 patients showed a good correlation with bone marrow findings (bone marrow median mutational value 1.92×10−2, plasma circulating tumor DNA value: 1.4×10−2, peripheral blood value: 1.03×10−3). This study indicates that droplet digital polymerase chain reaction assay of MYD88L265P is a feasible and sensitive tool for mutation screening and minimal residual disease monitoring in Waldenström macroglobulinemia. Both unsorted bone marrow and peripheral blood samples can be reliably tested, as can circulating tumor DNA, which represents an attractive, less invasive alternative to bone marrow for MYD88L265P detection.

Mantle cell lymphoma patients have variable clinical courses, ranging from indolent cases that do not require immediate treatment to aggressive, rapidly progressing diseases. Thus, diagnostic tools capable of stratifying patients according to their risk of relapse and death are needed. This study included 83 samples from the Fondazione Italiana Linfomi MCL-0208 clinical trial. Through gene expression profiling and quantitative real-time PCR we analyzed 46 peripheral blood and 43 formalin-fixed paraffin-embedded lymph node samples. A prediction model to classify patients was developed. By analyzing the transcriptome of 27 peripheral blood samples, two subgroups characterized by a differential expression of genes from the B-cell receptor pathway (B-cell receptorlow and B-cell receptorhigh) were identified. The prediction model based on the quantitative real-time PCR values of six representative genes (AKT3, BCL2, BTK, CD79B, PIK3CD, and SYK), was used to classify the 83 cases (43 B-cell receptorlow and 40 B-cell receptorhigh). The B-cell receptorhigh signature associated with shorter progression-free survival (P=0.0074), selected the mantle cell lymphoma subgroup with the shortest progression-free survival and overall survival (P=0.0014 and P=0.029, respectively) in combination with high (>30%) Ki-67 staining, and was an independent predictor of short progression- free survival along with the Mantle Cell Lymphoma International Prognostic Index-combined score. Moreover, the clinical impact of the 6- gene signature related to the B-cell receptor pathway identified a mantle cell lymphoma subset with shorter progression-free survival intervals also in an external independent mantle cell lymphoma cohort homogenously treated with different schedules. In conclusion, this 6-gene signature associates with a poor clinical response in the context of the MCL- 0208 clinical trial. (clinicaltrials.gov identifier: 02354313).

Despite improvements in standard therapy with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone for patients with untreated, diffuse large B-cell lymphoma, up to 40% of these patients relapse. Lenalidomide alone or in combination with rituximab has been shown to be active in relapsed/refractory aggressive lymphomas. In this phase I study we determined the maximum tolerated dose of lenalidomide plus rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone in untreated, elderly (median age 68 years) patients with diffuse large B-cell lymphoma. Four lenalidomide doses (5, 10, 15, and 20 mg/day on days 1–14) allocated using the continual reassessment method were planned to be administered for 14 days in combination with each course of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone for a total of six courses. Seven cohorts of patients (n=3 in each cohort) were treated (total n=21) at 10, 20, 15, 15, 15, 10, and 10 mg of lenalidomide. Dose-limiting toxicities occurred in seven patients during the first three courses of treatment. The third dose-level of lenalidomide (15 mg/day) was selected as the maximum tolerated dose, with an estimated probability of dose-limiting toxicities of 0.345 (95% credibility interval 0.164–0.553). Grade 3–4 hematologic adverse events were: neutropenia in 28% of the courses, thrombocytopenia in 9%, and anemia in 3%. Non-hematologic toxicities were moderate: grade 4 increase of creatinine phosphokinase (n=1), grade 3 cardiac (n=2), grade 3 neurological (n=3), and grade 3 gastrointestinal (n=1). In this phase I study, the overall response rate was 90%, with 81% achieving complete remission. This combination regimen appears safe in elderly patients with diffuse large B-cell lymphoma and its efficacy will be assessed in the ongoing phase II trial. This trial was registered at www.clinicaltrials.gov as NCT00907348.

Background Characterization of the immunoglobulin gene repertoire has improved our understanding of the immunopathogenesis of lymphoid tumors. Early B-lymphocyte precursors of multiple myeloma are known to exist and might be susceptible to antigenic drive.Design and Methods To verify this hypothesis, we collected a database of 345 fully readable multiple myeloma immunoglobulin sequences. We characterized the immunoglobulin repertoire, analyzed the somatic hypermutation load, and investigated for stereotyped receptor clusters.Results Compared to the normal immunoglobulin repertoire, multiple myeloma displayed only modest differences involving only a few genes, showing that the myeloma immunoglobulin repertoire is the least skewed among mature B-cell tumors. Median somatic hypermutation load was 7.8%; median length of complementarity determining-region 3 was 15.5 amino acids. Clustering analysis showed the absence of myeloma specific clusters and no similarity with published chronic lymphocytic leukemia or lymphoma subsets.Conclusions Analysis of multiple myeloma immunoglobulin repertoire does not support a pathogenetic role for antigen selection in this tumor.

Identification of prognosticators for Binet A chronic lymphocytic leukemia is important for selecting patients with dismal prognosis. We analyzed CD49d expression in 140 consecutive Binet A chronic lymphocytic leukemia. At diagnosis, CD49d ≥30% (54/140, 38.6%) associated with proliferation markers, namely CD38 ≥30% (p=3.9×10−6), LDH (p=0.007) and β2-microglobulin (p=0.020). Univariate log-rank analysis identified CD49d ≥30% as a risk factor of treatment free survival (p=8.3x10−5), time to progression to a more advanced stage (p=4.7×10−4), and time to lymphocyte doubling (p=0.009). Multivariate analysis selected CD49d ≥30% as an independent treatment free survival predictor after adjustment for biological (HR 2.28; 95% CI 1.71–4.45, p=0.015) and both biological and clinical variables analyzed together (HR 3.33, 95% CI 1.61–6.90, p=0.001). Within Binet A subgroups harboring favorable biological variables (IGHV homology