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In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 30-31

Abstract: BACKGROUND: In 2014 we identified a new subset of DLBCL, defined as "IgM-secreting" (Cox MC & Di Napoli A , PLOS One 2014). This was characterised by poor prognostic features and outcome as well as frequent central nervous (CNS) system localizations. Furthermore, IgM-secretion, was an independent prognostic factor in multivariate analysis. Here we report on the largest series of IgM-secreting-DLBCL, from a multicentre Italian study. METHODS: The observational and biological study was approved by the Ethical Committee of the AUO Sant'Andrea, Italy. Enrolment criteria were: DLBCL with an associated IgM paraprotein diagnosed between 1st January 2010 and 31st December 2018 (IgM-secreting). Data were collected both prospectively and retrospectively from 17 Centres participating in the study. In addition, histopathology samples were centrally revised for immunohistochemistry (IHC) and FISH analyses. The control group (CTRL) consisted in a series of consecutive DLBCL, without an associated IgM-paraprotein (diagnosed between 01/01/2013 and 30/06/2016, enrolled in the Lymphoma Registry of the Lazio region (ReLLi Network). Last follow-up was carried out on 31st December 2019. RESULTS: 569 DLBCL cases were enrolled: 102 (17.9%) were IgM-secreting; 48 (8.4%) had a non-IgM paraprotein (IgA, IgG, or other), and 414 (72.7%) had no associated paraprotein (CTRL). IgM-secreting cases within the consecutive DLBCL patients enrolled in the ReLLi Registry were 41/466 (8.8%, 95CI 6.4-11.7%) while non IgM-paraprotein DLBCL cases were 11/466 (2.4%, 95CI 1.2-4.2%). The median level of IgM paraprotein was 17gr/L (range: & lt;1-84gr/L); 83/102 (81.3%) were IgMk and 23/102 (22.5%) IgML respectively. The IgM-secreting group differed from the CTRL because the following characteristics were significantly more frequent: 1] age & gt;60 (p=.001); 2] advanced stage (p & lt;.001); 3] PS≥2 (p=.001); 4] LDH & gt;UNL (p=.008) ; 5] ≥2 Extra-nodal sites involved (p & lt;.001) ; 6] IPI 3-5 (p & lt;.001); 7] central nervous system (CNS) involvement at diagnosis or relapse (p & lt;.001); 8] lower rate of complete remission(CR) at the end of induction immunochemotherapy (p & lt;.001). Conversely, no differences were observed for: sex, B-symptoms, HCV and HBV status, bulky disease, age≥80 years, and for transformation from low-grade lymphoma. PATHOLOGICAL AND MOLECULAR FEATURES: Paraffin tissue from 74 CTRL and 69 IgM-secreting was suitable for immunohistochemistry (IHC). The non-GCB subtype, based on Hans algorithm, was prevalent in the IgM-secreting (p=.005). No difference in BCL2 expression alone or in MYC and BCL2 double expression was observed within groups. In 48/63(76%; 95CI: 64-86%) IgM-secreting cases, both the IgM heavy and the corresponding kappa or lambda light chain protein expression were detected in the cytoplasm of the neoplastic clone. FISH analyses for MYC, BCL2 and BCL6 genes rearrangements performed in 25 IgM-secreting cases with either expression of MYC protein or a GC-phenotype showed no evidence of double or triple hits (DH/TH). TREATMENT: in the IgM-secreting group more patients were treated with RCOMP and with less intensive approach than the CTRL (p & lt;.001). SURVIVAL: The median follow-up time was 46 months (95CI= 44-49; range 18-101) with 130 events and an incidence rate x100 person/year of 7.22 (95%CI 6.08-8.58) and a 5-yr OS of 76% (95CI 72-79%). The 5-PFS was 61% (95CI 57-65%). In univariable analysis age & gt;60, B-symptoms, bulky disease, IPI & gt;low risk and IgM-secreting IgM showed a worse survival (all with p & lt;0.001). Also, the IgM-secreting group, showed a worse survival compared to the DLBCL with an associated IgG/IgA paraprotein (p & lt;0.001). Adjusting in multiple Cox regression, IgM-secreting with IPI, gender, bulky and B-symptoms, maintain a higher risk of death either in the all cohort (HR 1.93, 95CI 1.34-2.78, p & lt;0.001) or in patients with age & lt;80 (HR 1.71, 95CI 1.16-2.54, p=0.007). Noteworthy, a survival sub-analysis showed that the 12/69 (17.4%) IgM-secreting with a GC-type had a better OS (9=0.008) and PFS (p=0.002) compared to the 57/69 (82.6%) IgM-secreting with a non-GC-type. CONCLUSION: Our data confirm that IgM-secreting DLBCL: 1) represents a sizable proportion of non-DH DLBCL; 2) have poor prognostic features and 3) have mostly a non-GC phenotype. Furthermore, IgM secretion appears to be an independent prognostic factor for both PFS and OS. Studies to define the biological features of this new subset are ongoing. Disclosures Cantonetti: Mundipharma: Consultancy; Takeda: Consultancy; Vifor: Consultancy; Roche: Consultancy. Re:BerGenBio ASA: Research Funding. Abruzzese:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bms: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-135909

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: British Journal of Haematology, Wiley, Vol. 154, No. 5 ( 2011-09), p. 590-599

Type of Medium: Online Resource

ISSN: 0007-1048

URL: Article

DOI: 10.1111/j.1365-2141.2011.08789.x

Language: English

Publisher: Wiley

Publication Date: 2011

detail.hit.zdb_id: 1475751-5

In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 672-672

Abstract: Abstract 672 BACKGROUND: CLL is the most common adult-onset leukemia in the Western world. The most common known genetic lesion is the 13q14.3 deletion targeting MIR15/MIR16. We applied a very high resolution array to identify new genetic lesions in CLL. METHODS: 266 CLL samples were analyzed with Affymetrix Human Mapping 6.0 arrays, comprising over 1,8 million probes with a median distance of less than 1 Kb. Copy number was inferred using the circulary binary segmentation (CBS) algorithm. Minimal common regions (MCR) were defined using a modified version of the algorithm by Lenz et al. (PNAS 2008), specifically altered to identify very small genomic losses covered by only 2-9 probes and occurring in at least 5% of the cases (mMCRs). mMCRs having 100% overlap with known copy number variations were discarded. RESULTS: mMCRs occurred in 75 known genes. The most commonly affected genes were CDC73 (cell division 73; 63% of the cases, 3 probes), RREB1 (ras responsive element binding protein 1; 60%, 5 probes), JAK2 (47%, 8 probes), CCDC88A (AKT-phosphorylation enhancer,; 47%, 3 probes), AKT3 (43%, 4 probes). Other affected genes at a lower frequency were PIK3CA (26%), EGFR (25%), XRCC4 (18%), JAK1 (18%), PTPRK (15%), RB1 (14%), ERBB2 (10%), PDGFRA (8%), FHIT (7%). A functional analysis performed with DAVID 2008 (http://david.abcc.ncifcrf.gov/) identified the terms “anti-oncogene” and “tyrosine-protein kinase” and five KEGG (http://www.genome.jp/kegg/) pathways (“prostate cancer”, “non-small cell lung cancer”, “pancreatic cancer”, “endometrial” cancer”) as enriched among the 75 genes with a statistically significant p-value 〈 0.05 after Benjamini multiple test correction. Besides tumor suppressor genes such as RB1 and FHIT, very interestingly, many of the genes appeared to code for kinases and for oncogenes. The mMCRs occurred in intronic regions, and apparently targeted highly conserved regions. These regions might represent regulatory loci and their loss may cause gene activation. Validation of selected genes is on-going. CONCLUSIONS: The application of high resolution arrays on a large series of CLL samples has shown frequent small interstitial deletions targeting a discrete number of genes, highly enriched for transcripts coding for kinases. A potential mechanism of action might be the loss of regulatory regions determining gene activation. Once validated, the current data would provide the basis to explore the rationale for the use of kinase inhibitors in the treatment of CLL. Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.672.672

Language: English

Publisher: American Society of Hematology

Publication Date: 2009

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 2339-2339

Abstract: Abstract 2339 Poster Board II-316 BACKGROUND: CLL, the most common adult-onset leukemia in the Western world, has a heterogeneous clinical course. Many advances have led to a better understanding of its pathogenesis and to improvements in treatment strategies, but striking solutions are still missing. We conducted a study to evaluate the impact of genomic aberrations on the clinical course. METHODS: From January 1980 to May 2008, 395 frozen samples of CLL patients, were prospectively collected in four centers. Extracted DNA was analyzed with Affymetrix Human Mapping 6.0 arrays. Normal matched DNA was analyzed for one fourth of the cases. Correlations between minimal common regions (MCR) and clinical parameters were evaluated with the Fisherôs-exact test and their impact on OS with the log-rank test. A p-value after Bonferroni multiple test correction (MTC) (p-adj.) 〈 0.05 was considered as statistically significant. Up to now 266 samples have been analyzed. RESULTS: Analysis of the clinical parameters (CPs) and known risk factors (Rai/Binet, age, doubling time, LDH, beta2, IGVH status, p53 mutations, telomere length, CD38, 11q, 17p) was consistent to previous published series. ZAP70 did not affect the clinical course, likely due inter-laboratories variability. After a median follow up of 53 months, 143/239 (60%) of the patients have started therapy and 63/261 (24%) died. 5-yr OS was 82%. Fisher test between the MCRs and CPs revealed an inverse relation between the presence of trisomy 12 by FISH and del13q14.3, an association between del17p and losses of 8p regions and between CD38 and 12q gain. Before MTC, 46 MCRs had a significant impact on OS and 67. After MTC, 3 regions maintained their role: 8p22 loss (38/248, 15%, p-adj.=0.002, median OS: 26 months vs. 48), 17p13.3-11.2 loss (20/248, 8%, p-adj.=0.001; median OS: 10 months vs. 48). In univariate analysis, the log-rank test among pts with 8p-/17p- (8/248, 3%), 8p- (30/248, 12%), 17p- (12/248, 5%), wild type (198/248, 80%) was statistically significant (p 〈 0.001; see figure). Importantly, none of the analyzed clinical and biological parameters was associated with this aberration. CONCLUSIONS: Loss of 8p22 designated a CLL subgroup with a worse outcome among all patients and in the subset with 17p loss. Our data suggested that this aberration might constitute an independent prognostic factor to be evaluated in independent studies. Results, including a Cox regression model, will be presented on all 395 cases. Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.2339.2339

Language: English

Publisher: American Society of Hematology

Publication Date: 2009

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 1434-1434

Abstract: Background: Hepatitis C virus (HCV) chronic infection has been associated with increased risk of non-Hodgkin lymphoma (NHL) in people living with human immunodeficiency virus (HIV) as well as with a trend of inferior overall survival (OS) in HIV-associated NHL in the modern antiretroviral therapy (ART) era (Besson 2020). The recent introduction of interferon (IFN)-free direct-acting antivirals (DAAs) led to the achievement of sustained virologic response (SVR) in nearly all treated patients (pts) with negligible toxicity in all settings, including HIV/HCV coinfected pts, in which, however, careful attention to interactions with ART is required. We recently showed that DAAs' administration after immuno-chemotherapy (I-CT) may improve long-term outcome in HIV-negative HCV-associated diffuse large B-cell lymphomas (DLBCL) pts (Merli 2019), however, only scant data have been reported so far about the use of DAAs in HIV/HCV coinfected NHL pts. METHODS: We retrospectively collected clinical and virological features, treatments and outcome data of all consecutive pts with NHL and HIV/HCV co-infection, diagnosed and treated at 13 Italian centers between 2005 and 2021, with a special focus on pts affected by DLBCL and treated with DAAs. Only pts who received ART were included. The primary endpoints were SVR rate after DAAs and 2-year OS in HIV/HCV-positive NHL pts. RESULTS: Overall, we collected data of 74 HIV/HCV coinfected pts with NHL (69 males, 93%), including 52 DLBCL, 13 Burkitt lymphoma (BL), 5 plasmablastic lymphoma (PL), 1 anaplastic large-cell ALK negative, 1 T lymphoblastic, 1 gastric MALT and 1 lymphoplasmacytic lymphoma (Table 1). Median age was 51 years (22-57). Previous AIDS defining event was recorded in 16 cases (22%). The main HIV transmission group was represented by intravenous drug users (69%). Stage was III-IV in 63 pts (85%) and aaIPI was ≥2 in 57 pts (77%). At NHL diagnosis 38% of pts had CD4+ & lt;200/mmc and 31% ≥400 HIV-RNA copies/ml. ARL-IPI score was intermediate or high in 49 pts (64%). HCV genotype was 1 in 26 pts (58%), 3 in 12 (27%) and 4 in 7 (15%). Cirrhosis was present in 39% of pts (Child-Pugh B or C in 25%). Overall, 70 pts underwent curative first line therapy alongside ART, including (R-)CHOP-like in 50 (71%), (R-)EPOCH in 9 (13%), (R-)CODOX-M/IVAC in 8 (11%). Rituximab was used in 53% of cases (60% in DLBCL). 46 pts (66%) achieved a complete response (CR), 7 (10%) a partial response (PR), while 17 (24%) did not respond or progressed. At a median follow-up of 1.8 years (95%CI 0.1-12.3), 33 pts (45%) progressed, with a 2-year PFS of 53.5% (95%CI 40.7-64.8), and 38 (51%) died (30 due to NHL, 7 to infections and 1 to hepatocellular carcinoma), with a 2-year OS of 58.2% (95%CI 45.7-78.9). Two-year OS for DLBCL was 61.4% (95%CI 46.3-73.4), significantly higher than BL (39%, 95%CI 14.1-62.8; p=.0.47, Fig. 1). Considering anti-HCV therapy, 13 pts received IFN-based regimens, 5 of whom achieved SVR (38%). After 2016, 21 pts (14 DLBCL, 3 BL, 2 indolent and 2 T-cell lymphoma), including 4 who previously failed IFN, received various DAAs regimens after I-CT (sofosbuvir-based in 20). Toxicity of DAAs was minimal, with only 2 grade (G) ≥2 adverse events (1 G2 peripheral neuropathy and 1 G2 insomnia). SVR was achieved in 20/21 pts (95%): notably, the only non-responder had discontinued DAAs autonomously. DAAs use was associated with improved OS in all pts (p=0.01) and in DLBCL (p=0.04) and with better PFS (p=0.01) in all pts. Similarly, the achievement of SVR after either DAAs or IFN predicted a better OS (Fig.2) and PFS in all pts (p=0.005 and p=0.008, respectively) and in DLBCL (p=0.018 and p=0.047, respectively). The impact of DAAs and SVR on OS remained significant also if considering only pts who achieved CR or PR after I-CT (p & lt;0.05). At univariate analysis, age & gt;60 years (p=0.02), ARL-IPI (p=0.013), PS ECOG ≥2 (p=0.018) were associated with inferior OS. By applying multivariate Cox regression analysis, age & gt;60 years (HR 67.9, 95% CI 7.2- 643.3, p & lt;0.001), ARL-IPI (HR 2.87, 95%CI 1.03-8.06, p=0.044) and SVR after IFN or DAAs (HR 0.30, 95%CI 0.12-0.75, p=0.01) retained independent prognostic influence on OS. CONCLUSIONS: In this very high risk series of HIV/HCV coinfected pts with NHL, mainly represented by DLBCL, the administration of DAAs after I-CT resulted feasible and effective (SVR 95%), and displayed an independent favourable influence on OS. These results strongly support DAAs' use in this hard to treat population. Figure 1 Figure 1. Disclosures Tisi: Incyte: Membership on an entity's Board of Directors or advisory committees; BWS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zilioli: Roche, Italfarmaco: Consultancy, Honoraria; MSD, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations; Takeda: Other: travel expenses, accommodation; Gentili, Takeda, Gilead, Servier: Consultancy, Speakers Bureau. Passamonti: AbbVie: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Arcaini: Celgene, Roche, Janssen-Cilag, Gilead: Other: Travel expenses; Bayer, Celgene, Gilead Sciences, Roche, Sandoz, Janssen-Cilag, VERASTEM: Consultancy; Gilead Sciences: Research Funding; Celgene: Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-151174

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: European Journal of Haematology, Wiley, Vol. 94, No. 2 ( 2015-02), p. 186-186

Type of Medium: Online Resource

ISSN: 0902-4441 , 1600-0609

URL: Issue

URL: Article

DOI: 10.1111/ejh.2015.94.issue-2

DOI: 10.1111/ejh.12312

Language: English

Publisher: Wiley

Publication Date: 2015

detail.hit.zdb_id: 2027114-1

In: European Journal of Haematology, Wiley, Vol. 96, No. 6 ( 2016-06), p. 650-654

Abstract: Plasmablastic lymphoma ( PBL ) is a rare subtype of non‐Hodgkin lymphomas ( NHL ) strongly associated with HIV infection, even if cases in other immunosuppressed patients such as solid organ transplant recipients and in immunocompetent individuals have been increasingly reported. Current treatment strategy for HIV ‐negative patients is similar to DLBCL as first‐line treatment, but durable remissions are seldom observed. Anthracycline‐containing regimens could be too toxic for elderly patients and/or with cardiac failure, because a non‐pegylated liposomal doxorubicin ( NLD ) could be used in this field. Bortezomib, a proteasome inhibitor currently approved for patients with multiple myeloma and relapsed mantle‐cell lymphoma, has recently showed clinical activity in PBL patients. Herein, we report a rapid and long‐term remission of a PBL patient with cardiac failure and that had previously received a double kidney transplant, treated front‐line with COMP (with a NLD substituted for doxorubicin) followed by subcutaneous bortezomib consolidation. We suggest first‐line treatment outcome is determinant for PBL patients. Bortezomib has a promising role and should be incorporated in future clinical trials and NLD could represent a suitable option for patients with cardiac failure or high cardiovascular risk.

Type of Medium: Online Resource

ISSN: 0902-4441 , 1600-0609

URL: Issue

URL: Article

DOI: 10.1111/ejh.2016.96.issue-6

DOI: 10.1111/ejh.12732

Language: English

Publisher: Wiley

Publication Date: 2016

detail.hit.zdb_id: 2027114-1

In: The Journal of Pathology, Wiley, Vol. 242, No. 4 ( 2017-08), p. 511-512

Type of Medium: Online Resource

ISSN: 0022-3417

URL: Issue

URL: Article

DOI: 10.1002/path.2017.242.issue-4

DOI: 10.1002/path.4914

Language: English

Publisher: Wiley

Publication Date: 2017

detail.hit.zdb_id: 1475280-3

In: American Journal of Hematology, Wiley, Vol. 89, No. 5 ( 2014-05), p. 480-486

Abstract: In a phase II trial, we evaluated chlorambucil and rituximab (CLB‐R) as first‐line induction treatment with or without R as maintenance for elderly chronic lymphocytic leukemia (CLL) patients. Treatment consisted of eight 28‐day cycles of CLB (8 mg/m 2 /day, days 1–7) and R (day 1 of cycle 3, 375 mg/m 2 ; cycles 4–8, 500 mg/m 2 ). Responders were randomized to 12 8‐week doses of R (375 mg/m 2 ) or observation. As per intention‐to‐treat analysis, 82.4% (95% CI, 74.25–90.46%) of 85 patients achieved an overall response (OR), 16.5% a complete response (CR), 2.4% a CR with incomplete bone marrow recovery. The OR was similar across Binet stages (A 86.4%, B 81.6%, and C 78.6%) and age categories (60–64 years, 92.3%; 65–69, 85.2%; 70–74, 75.0%; ≥75, 81.0%). CLB‐R was well tolerated. After a median follow‐up of 34.2 months, the median progression‐free survival (PFS) was 34.7 months (95% CI, 33.1–39.5). TP53 abnormalities, complex karyotype, and low CD20 gene expression predicted lack of response; SF3B1 mutation and BIRC3 disruption low CR rates. IGHV mutations significantly predicted PFS. R maintenance tended towards a better PFS than observation and was safe and most beneficial for patients in partial response and for unmutated IGHV cases. CLB‐R represents a promising option for elderly CLL patients. Am. J. Hematol. 89:480–486, 2014. © 2014 Wiley Periodicals, Inc.

Type of Medium: Online Resource

ISSN: 0361-8609 , 1096-8652

URL: Issue

URL: Article

DOI: 10.1002/ajh.v89.5

DOI: 10.1002/ajh.23668

Language: English

Publisher: Wiley

Publication Date: 2014

detail.hit.zdb_id: 1492749-4

In: Cancer, Wiley, Vol. 121, No. 20 ( 2015-10-15), p. 3746-3747

Type of Medium: Online Resource

ISSN: 0008-543X , 1097-0142

URL: Issue

URL: Article

DOI: 10.1002/cncr.v121.20

DOI: 10.1002/cncr.29509

Language: English

Publisher: Wiley

Publication Date: 2015

detail.hit.zdb_id: 1479932-7

detail.hit.zdb_id: 2599218-1

detail.hit.zdb_id: 2594979-2

detail.hit.zdb_id: 1429-1