ABSTRACT
Patients with mantle cell lymphoma (MCL) who experience first relapse/refractoriness can be categorized into early or late progression-of-disease (POD) groups, with a threshold of 24 months from the initial MCL diagnosis. Bruton tyrosine kinase inhibitors (BTKi) are established standard treatment at first relapse, but their effectiveness as compared to chemoimmunotherapy (CIT) in late-POD patients remains unknown. In this international, observational cohort study, we evaluated outcomes amongst patients at first, late-POD beyond 24 months. Patients treated upfront with BTKi were excluded. The primary objective was progression-free survival from time of second-line therapy (PFS-2) of BTKi versus CIT. After accrual, all patients were prospectively followed-up. Overall, 385 late-POD patients were included from 10 countries. Their median age was 59 (range:19-70) years and 77% were males. Median follow-up from time of first relapse was 53 months (range:12-144). Overall, 114 patients had second-line BTKi, while 271 had CIT, consisting of rituximab-bendamustine (R-B, n=101), R-B and cytarabine (R-BAC, n=70), or other regimens (mostly cyclophosphamide-hydroxydaunorubicin-vincristine-prednisone-CHOP- or platinum-based, n=100). The two groups were balanced for clinicopathological features, and median time to first relapse (48 months for both). Overall, BTKi was associated with significantly prolonged median PFS-2 than CIT [not reached-NR vs 26 months, respectively, P=.0003], and overall survival [NR and 56 months, respectively, P=.03]. Multivariate analyses showed that BTKi was associated with lower risk of death than R-B and other regimens (hazard ratio-HR, 0.41 for R-B, 0.46 for others), but similar to R-BAC. These results may establish BTKi as the preferable second-line approach in BTKi-naïve MCL patients.
ABSTRACT
Hepatitis C virus (HCV)-associated diffuse large B-cell lymphoma (DLBCL) displays peculiar clinicopathological characteristics, but its molecular landscape is not fully elucidated. In this study, we investigated the clinicopathological and molecular features of 54 patients with HCV-associated DLBCL. The median age was 71 years. An underlying marginal zone lymphoma component was detected in 14.8% of cases. FISH analysis showed rearrangements involving BCL6 in 50.9% of cases, MYC in 11.3% and BCL2 in 3.7%. Lymph2Cx-based assay was successful in 38 cases, recognizing 16 cases (42.1%) as ABC and 16 cases as GCB subtypes, while six resulted unclassified. ABC cases exhibited a higher lymphoma-related mortality (LRM). Next-generation sequencing analysis showed mutations in 158/184 evaluated genes. The most frequently mutated genes were KMT2D (42.6%), SETD1B (33.3%), RERE (29.4%), FAS and PIM1 (27.8%) and TBL1XR1 (25.9%). A mutation in the NOTCH pathway was detected in 25.9% of cases and was associated with worst LRM. Cluster analysis by LymphGen classified 29/54 cases within definite groups, including BN2 in 14 (48.2%), ST2 in seven (24.2%) and MCD and EZB in four each (13.8%). Overall, these results indicate a preferential marginal zone origin for a consistent subgroup of HCV-associated DLBCL cases and suggest potential implications for molecularly targeted therapies.
Subject(s)
Hepatitis C , Lymphoma, Large B-Cell, Diffuse , Mutation , Humans , Lymphoma, Large B-Cell, Diffuse/genetics , Lymphoma, Large B-Cell, Diffuse/virology , Male , Aged , Female , Middle Aged , Hepatitis C/complications , Hepatitis C/genetics , Aged, 80 and over , Hepacivirus/genetics , Adult , High-Throughput Nucleotide SequencingABSTRACT
The gastrointestinal (GI) tract is the most common extranodal site of occurrence of non-Hodgkin lymphomas. Most GI lymphomas are of B-cell lineage, while T-cell lymphomas are less frequent. The aim of our retrospective study was to depict the clinical-pathological profile of a series of patients affected by intestinal T-cell lymphomas (ITCL) and possibly define hallmarks of these neoplasms. A total of 28 patients were included: 17 enteropathy-associated T-cell lymphomas (EATL), 5 monomorphic epitheliotropic T-cell lymphomas (MEITL), 3 indolent T-cell lymphoproliferative disorders of the gastrointestinal tract (ITCLDGT), and 3 intestinal T-cell lymphomas not otherwise specified (ITCL-NOS). Celiac disease (CD) was diagnosed in around 70% of cases. Diagnosis of EATL showed a significant correlation with CD30 expression, whereas MEITL with angiotropism and CD56 positivity. ITCLDGT cases showed plasma cells infiltration. Peripheral lymphocytosis, the absence of a previous diagnosis of CD, an advanced Lugano clinical stage, and the histological subtype ITCL-NOS were significantly associated with worse survival at multivariate analysis. Our findings about the epidemiological, clinical, and histopathological features of ITCL were in line with the current knowledge. Reliable prognostic tools for these neoplasms are still lacking but according to our results lymphocytosis, diagnosis of CD, Lugano clinical stage, and histological subtype should be considered for patient stratification.
ABSTRACT
The combination of rituximab, bendamustine, and low-dose cytarabine (R-BAC) has been studied in a phase 2 prospective multicenter study from Fondazione Italiana Linfomi (RBAC500). In 57 previously untreated elderly patients with mantle cell lymphoma (MCL), R-BAC was associated with a complete remission rate of 91% and 2-year progression-free survival (PFS) of 81% (95% confidence interval [CI], 68-89). Here, we report the long-term survival outcomes, late toxicities, and results of minimal residual disease (MRD) evaluation. After a median follow-up of 86 months (range, 57-107 months), the median overall survival (OS) and PFS were not reached. The 7-year PFS and OS rates were 55% (95% CI, 41-67), and 63% (95% CI, 49-74), respectively. Patients who responded (n = 53) had a 7-year PFS of 59% (95% CI, 44-71), with no relapse or progression registered after the sixth year. In the multivariate analysis, blastoid/pleomorphic morphology was the strongest adverse predictive factor for PFS (P = .04). Patients with an end of treatment negative MRD had better, but not significant, outcomes for both PFS and OS than patients with MRD-positive (P = 0.148 and P = 0.162, respectively). There was no signal of late toxicity or an increase in secondary malignancies during the prolonged follow-up. In conclusion, R-BAC, which was not followed by maintenance therapy, showed sustained efficacy over time in older patients with MCL. Survival outcomes compare favorably with those of other immunochemotherapy regimens (with or without maintenance), including combinations of BTK inhibitors upfront. This study was registered with EudraCT as 2011-005739-23 and at www.clinicaltrials.gov as #NCT01662050.
Subject(s)
Lymphoma, Mantle-Cell , Humans , Adult , Aged , Rituximab/adverse effects , Lymphoma, Mantle-Cell/drug therapy , Bendamustine Hydrochloride/adverse effects , Follow-Up Studies , Cytarabine/adverse effects , Prospective Studies , Neoplasm Recurrence, Local/drug therapyABSTRACT
Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare entity whose neoplastic cells retain a B-cell phenotype with expression of CD20. Radiotherapy is recommended for favorable stage IA disease while for other stages guidelines suggest therapeutic strategies similar to those used for classic HL. The role of rituximab, although quite widespread, is not completely elucidated. We retrospectively analyzed baseline characteristics of 308 consecutive patients with NLPHL diagnosed in 19 Italian centers from 2000 to 2018. With a median follow-up of 8.4 years (interquartile range: 4.5-12.4) for treated patients, median overall survival (OS) was not reached and estimated 5-year OS was 97.8% and 5-year progression-free survival (PFS) was 84.5%. Five-year cumulative incidence of histological transformation was 1.4%, 95% confidence interval (CI), 0.5%-3.8%. After adjusting for lymphocyte count, splenic involvement, bulky disease and B symptoms (fever, drenching night sweats, unintentional loss >10% of body weight within the preceding 6 months), patients with stage II or more showed superior PFS with immunochemotherapy in comparison to chemotherapy alone (hazard ratio = 0.4, 95% CI, 0.2-0.8; P = 0.015). Our data suggest an advantage of the use of rituximab combined with chemotherapy ± radiotherapy in the treatment of stage II-III-IV NLPHL.
ABSTRACT
Central nervous system (CNS) relapse of mantle cell lymphoma (MCL) is a rare phenomenon with dismal prognosis, where no standard therapy exists. Since the covalent Bruton tyrosine kinase (BTK) inhibitor ibrutinib is effective in relapsed/refractory MCL and penetrates the blood-brain barrier (BBB), on behalf of Fondazione Italiana Linfomi and European Mantle Cell Lymphoma Network we performed a multicenter retrospective international study to investigate the outcomes of patients treated with ibrutinib or chemoimmunotherapy. In this observational study, we recruited patients with MCL with CNS involvement at relapse who received CNS-directed therapy between 2000 and 2019. The primary objective was to compare the overall survival (OS) of patients treated with ibrutinib or BBB crossing chemotherapy. A propensity score based on a multivariable binary regression model was applied to balance treatment cohorts. Eighty-eight patients were included. The median age at study entry was 65 years (range, 39-87), 76% were males, and the median time from lymphoma diagnosis to CNS relapse was 16 months (range, 1-122). Patients were treated with ibrutinib (n = 29, ibrutinib cohort), BBB crossing chemotherapy (ie, high-dose methotrexate ± cytarabine; n = 29, BBB cohort), or miscellaneous treatments (n = 30, other therapy cohort). Both median OS (16.8 vs 4.4 months; P = .007) and median progression-free survival (PFS) (13.1 vs 3.0 months; P = .009) were superior in the ibrutinib cohort compared with the BBB cohort. Multivariable Cox regression model revealed that ibrutinib therapeutic choice was the strongest independent favorable predictive factor for both OS (hazard ratio [HR], 6.8; 95% confidence interval [CI], 2.2-21.3; P < .001) and PFS (HR, 4.6; 95% CI, 1.7-12.5; P = .002), followed by CNS progression of disease (POD) >24 months from first MCL diagnosis (HR for death, 2.4; 95% CI, 1.1-5.3; P = .026; HR for death or progression, 2.3; 95% CI, 1.1-4.6; P = .023). The addition of intrathecal (IT) chemotherapy to systemic CNS-directed therapy was not associated with superior OS (P = .502) as the morphological variant (classical vs others, P = .118). Ibrutinib was associated with superior survival compared with BBB-penetrating chemotherapy in patients with CNS relapse of MCL and should be considered as a therapeutic option.
Subject(s)
Lymphoma, Mantle-Cell , Male , Adult , Humans , Middle Aged , Aged , Aged, 80 and over , Female , Lymphoma, Mantle-Cell/pathology , Pyrimidines , Retrospective Studies , Pyrazoles/adverse effects , Neoplasm Recurrence, Local/drug therapy , Treatment Outcome , Central Nervous System/pathologyABSTRACT
Letermovir (LTV), recently approved for the prophylaxis of human cytomegalovirus (HCMV) reactivation after hematopoietic stem cell transplantation (HSCT), has been shown to decrease the rate of infection in the first months post-transplantation. The aim of this study was to evaluate the impact of LTV prophylaxis on immune reconstitution and late-onset infection. We studied HCMV infection and HCMV-specific T cell reconstitution in 2 matched groups of HSCT recipients, those treated with LTV prophylaxis (n = 30; LTV group) and those receiving preemptive therapy (n = 31; PET group). We analyzed the rates of graft-versus-host disease (GVHD), neutropenia, baseline disease recurrence, and overall survival in the 2 groups. Clinically significant infections necessitating preemptive therapy showed a similar rate in the 2 groups (PET: 21 of 31 [68%]; LTV: 17 of 30 [57%]; P = .434) but occurred significantly later (after prophylaxis discontinuation) in the LTV group. There was no between-group difference in peak HCMV DNAemia level (P = .232). HCMV-specific T cell recovery was delayed by approximately 100 days in the LTV group. HCMV-specific CD4 and CD8 T cell counts were significantly lower in the LTV group at days 120 to 360 and days 90 to 120, respectively. A lower rate of chronic GVHD (P = .024) was seen in the LTV group. Time to engraftment, rate of disease relapse, and 1-year survival were not different between the 2 groups, whereas trends toward a lower rate of neutropenia (P = .124) and a higher rate of acute GVHD grade III-IV (P = .103) were observed in the LTV group. Because LTV prophylaxis delays HCMV infection and HCMV-specific immune reconstitution, immunologic and virologic monitoring should be implemented after discontinuation of prophylaxis. The potential effect of LTV prophylaxis in reducing chronic GVHD should be evaluated in prospective studies.
Subject(s)
Cytomegalovirus Infections , Hematopoietic Stem Cell Transplantation , Acetates , Cytomegalovirus , Cytomegalovirus Infections/prevention & control , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Neoplasm Recurrence, Local , Prospective Studies , QuinazolinesABSTRACT
The role of allogeneic stem cell transplantation (allo-SCT) in mantle cell lymphoma (MCL) is uncertain, even more in the era of bruton's tyrosine kinase inhibitors (BTKi) and chimeric antigen receptor T-cells. We retrospectively analyzed 55 patients who underwent allo-SCT for MCL relapsed or refractory (r/r) after rituximab and high-dose cytarabine within the MANTLE-FIRST project. With a median follow-up of 3.7 years, non-relapse mortality (NRM), progression-free survival, and overall survival were 23%, 53%, and 56%, respectively. NRM was significantly higher in the case of acute graft-versus-host disease, > 2 prior lines of therapy, age > 60 years. The outcome was similar for patients with early (≤24 months) and late progression of disease. The use of BTKi as a bridge to allo-SCT did not increase the toxicity and allowed a good control of disease. Our real-life experience confirms that allo-SCT still represents an option in MCL patients, especially if young and early-relapsed.
Subject(s)
Hematopoietic Stem Cell Transplantation , Lymphoma, Mantle-Cell , Adult , Hematopoietic Stem Cell Transplantation/adverse effects , Hematopoietic Stem Cell Transplantation/methods , Humans , Middle Aged , Neoplasm Recurrence, Local/therapy , Retrospective Studies , Stem Cell Transplantation/methods , Transplantation Conditioning/methods , Transplantation, Homologous/adverse effectsABSTRACT
Patients with mantle cell lymphoma (MCL) that fail induction treatment represent a difficult-to-treat population, where no standard therapy exists. We evaluated outcomes in patients with first relapsed-refractory (r/r) MCL after upfront high dose cytarabine including standard regimens. Overall survival (OS-2) and progression-free survival (PFS-2) were estimated from the time of salvage therapy. The previously described threshold of 24 months was used to define patients as early- or late-progressors (POD). Overall, 261 r/r MCL patients were included. Second-line regimens consisted of rituximab-bendamustine (R-B, 21%), R-B and cytarabine (R-BAC, 29%), ibrutinib (19%), and others (31%). The four groups were balanced in terms of clinicopathological features. Adjusting for age and early/late-POD, patients treated with R-BAC had significantly higher complete remission (63%) than comparators. Overall, Ibrutinib and R-BAC were associated with improved median PFS-2 [24 and 25 months, respectively], compared to R-B (13) or others (7). In patients with early-POD (n = 127), ibrutinib was associated with inferior risk of death than comparators (HR 2.41 for R-B, 2.17 for others, 2.78 for R-BAC). In patients with late-POD (n = 134), no significant differences were observed between ibrutinib and bendamustine-based treatments. Ibrutinib was associated with improved outcome in early-POD patients.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lymphoma, Mantle-Cell/mortality , Neoplasm Recurrence, Local/mortality , Salvage Therapy , Adult , Aged , Drug Resistance, Neoplasm , Female , Follow-Up Studies , Humans , International Agencies , Lymphoma, Mantle-Cell/drug therapy , Lymphoma, Mantle-Cell/pathology , Male , Middle Aged , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/pathology , Prognosis , Retrospective Studies , Survival Rate , Young AdultSubject(s)
Antiviral Agents/therapeutic use , Hepacivirus/drug effects , Hepatitis C/complications , Lymphoma, Mantle-Cell/drug therapy , Aged , Aged, 80 and over , Female , Follow-Up Studies , Hepatitis C/drug therapy , Hepatitis C/virology , Humans , Italy/epidemiology , Lymphoma, Mantle-Cell/epidemiology , Lymphoma, Mantle-Cell/virology , Male , Middle Aged , Prognosis , Retrospective StudiesABSTRACT
Chronic hepatitis C virus (HCV) infection is related with an increased risk of non-Hodgkin lymphomas (NHL). In indolent subtypes, regression of NHL was reported after HCV eradication with antiviral therapy (AT). In 2008 in Lombardy, a region of Northern Italy, the "Rete Ematologica Lombarda" (REL, Hematology Network of Lombardy-Lymphoma Workgroup) started a prospective multicenter observational cohort study on NHL associated with HCV infection, named "Registro Lombardo dei Linfomi HCV-positivi" ("Lombardy Registry of HCV-associated non-Hodgkin lymphomas"). Two hundred fifty patients with a first diagnosis of NHL associated with HCV infection were enrolled; also in our cohort, diffuse large B cell lymphoma (DLBCL) and marginal zone lymphoma (MZL) are the two most frequent HCV-associated lymphomas. Two thirds of patients had HCV-positivity detection before NHL; overall, NHL was diagnosed after a median time of 11 years since HCV survey. Our data on eradication of HCV infection were collected prior the recent introduction of the direct-acting antivirals (DAAs) therapy. Sixteen patients with indolent NHL treated with interferon-based AT as first line anti-lymphoma therapy, because of the absence of criteria for an immediate conventional treatment for lymphoma, had an overall response rate of 90%. After a median follow-up of 7 years, the overall survival (OS) was significantly longer in indolent NHL treated with AT as first line (P = 0.048); this confirms a favorable outcome in this subset. Liver toxicity was an important adverse event after a conventional treatment in 20% of all patients, in particular among DLBCL, in which it is more frequent the coexistence of a more advanced liver disease. Overall, HCV infection should be consider as an important co-pathology in the treatment of lymphomas and an interdisciplinary approach should be always considered, in particular to evaluate the presence of fibrosis or necroinflammatory liver disease.
Subject(s)
Hepacivirus , Hepatitis C, Chronic , Interferons/administration & dosage , Lymphoma, Non-Hodgkin , Adult , Aged , Aged, 80 and over , Disease-Free Survival , Female , Follow-Up Studies , Hepatitis C, Chronic/diagnosis , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/mortality , Humans , Italy/epidemiology , Lymphoma, Non-Hodgkin/diagnosis , Lymphoma, Non-Hodgkin/drug therapy , Lymphoma, Non-Hodgkin/mortality , Male , Middle Aged , Prospective Studies , Survival RateABSTRACT
BACKGROUND: International guidelines suggest hepatitis C virus (HCV) eradication by direct-acting antivirals (DAAs) after first-line immunochemotherapy (I-CT) in patients with HCV-positive diffuse large B-cell lymphoma (DLBCL), although limited experiences substantiate this recommendation. Moreover, only a few data concerning concurrent administration of DAAs with I-CT have been reported. SUBJECTS, MATERIALS, AND METHODS: We analyzed hematological and virological outcome and survival of 47 consecutive patients with HCV-positive DLBCL treated at 23 Italian and French centers with DAAs either concurrently (concurrent cohort [ConC]: n = 9) or subsequently (sequential cohort [SeqC]: n = 38) to first-line I-CT (mainly rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone [R-CHOP]-like). RESULTS: Median age was 61 years, 89% of patients had stage III/IV, and 25% presented evidence of cirrhosis. Genotype was 1 in 56% and 2 in 34% of cases. Overall, 46 of 47 patients obtained complete response to I-CT. All patients received appropriate DAAs according to genotype, mainly sofosbuvir-based regimens (n = 45). Overall, 45 patients (96%) achieved sustained virological response, 8 of 9 in ConC and 37 of 38 in SeqC. DAAs were well tolerated, with only 11 patients experiencing grade 1-2 adverse events. Twenty-three patients experienced hepatic toxicity (grade 3-4 in seven) following I-CT in SeqC, compared to only one patient in ConC. At a median follow-up of 2.8 years, two patients died (2-year overall survival, 97.4%) and three progressed (2-year progression-free survival, 93.1%). CONCLUSION: Excellent outcome of this cohort of HCV-positive DLBCL suggests benefit of HCV eradication by DAAs either after or during I-CT. Moreover, concurrent DAAs and R-CHOP administration appeared feasible, effective, and ideally preferable to deferred administration of DAAs for the prevention of hepatic toxicity. IMPLICATIONS FOR PRACTICE: Hepatitis C virus (HCV)-associated diffuse large B-cell lymphomas (DLBCLs) represent a great therapeutic challenge, especially in terms of hepatic toxicity during immune-chemotherapy (I-CT) and long-term hepatic complications. The advent of highly effective and toxicity-free direct-acting antivirals (DAAs) created an exciting opportunity to easily eradicate HCV shortly after or in concomitance with first-line immunochemotherapy (usually R-CHOP). This retrospective international study reports the real-life use of the combination of these two therapeutic modalities either in the concurrent or sequential approach (DAAs after I-CT) in 47 patients. The favorable reported results on long-term outcome seem to support the eradication of HCV with DAAs in all patients with HCV-positive DLBCL. Moreover, the results from the concurrent approach were effective and safe and displayed an advantage in preventing hepatic toxicity during I-CT.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antiviral Agents/therapeutic use , Hepacivirus/drug effects , Hepatitis C, Chronic/drug therapy , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/virology , Adult , Aged , Aged, 80 and over , Cyclophosphamide/administration & dosage , Disease-Free Survival , Doxorubicin/administration & dosage , Female , Hepatitis C, Chronic/epidemiology , Hepatitis C, Chronic/pathology , Hepatitis C, Chronic/virology , Humans , Incidence , Italy/epidemiology , Lymphoma, Large B-Cell, Diffuse/epidemiology , Lymphoma, Large B-Cell, Diffuse/pathology , Male , Middle Aged , Prednisone/administration & dosage , Retrospective Studies , Rituximab/administration & dosage , Vincristine/administration & dosageSubject(s)
Antimetabolites, Antineoplastic/therapeutic use , Cytarabine/therapeutic use , Lymphoma, Mantle-Cell/drug therapy , Adult , Aged , Antimetabolites, Antineoplastic/pharmacology , Cytarabine/pharmacology , Disease Progression , Female , Humans , Lymphoma, Mantle-Cell/mortality , Male , Middle Aged , Risk Factors , Survival RateABSTRACT
Although patients with early-stage Hodgkin's lymphoma have a high rate of cure, a portion of these are resistant to or relapse after standard treatment. Current prognostic criteria based on clinical and laboratory parameters at diagnosis do not allow to accurately identify the subset of patients with less favourable clinical outcome. An increased number of tumour-infiltrating macrophages was found to be associated with shortened survival in patients with classic Hodgkin's Lymphoma. The aim of this study was to assess the clinical significance of the proportion of CD68-positive infiltrating macrophages in patients with early-stage classic Hodgkin's lymphoma. By using immunohistochemistry technique, we evaluated for CD68 expression diagnostic biopsies of 106 patients affected by supradiaphragmatic early-stage classic Hodgkin's lymphoma treated at our institution since 2000 to 2010. All patients were treated with adriamycin, bleomycin, vinblastine, and dacarbazine chemotherapy followed by radiotherapy in the majority. The 2-year overall survival and progression-free survival (PFS) in the entire cohort were 97% and 83% respectively. The 2-year PFS was statistically different between patients with favourable and those with unfavourable prognosis according to the European Organisation for Research and Treatment of Cancer (EORTC) risk criteria (96% vs 79%, p = 0.039) and between patients having less than 25% of CD68-positive infiltrating macrophages and those with more than 25% (85% vs 67%, p = 0.012). All patients with favourable EORTC criteria had CD68 expression lower than 25%. Within those with unfavourable EORTC criteria, patients with a CD68+ count greater than 25% had a worse 2-year PFS than patients having values lower than 25% (64% vs 82%, p = 0.03). Moreover, in multivariate analysis, after adjusting for CD68+ macrophages count and EORTC score, only CD68+ macrophages count higher than 25% retained a prognostic effect on PFS (hazard ratio = 2.8, 95%CI: 1.1-7.6, p = 0.038). Our data show that a proportion of tumour-infiltrating macrophages greater than 25% is associated with unfavourable clinical outcome in patients with early-stage Hodgkin's lymphoma Copyright © 2016 John Wiley & Sons, Ltd.
Subject(s)
Hodgkin Disease/mortality , Hodgkin Disease/pathology , Macrophages/pathology , Adult , Aged , Antigens, CD/metabolism , Antigens, Differentiation, Myelomonocytic/metabolism , Biomarkers , Biopsy , Cell Count , Female , Hodgkin Disease/therapy , Humans , Immunohistochemistry , Macrophages/metabolism , Male , Middle Aged , Neoplasm Staging , Prognosis , Proportional Hazards Models , Retrospective Studies , Survival AnalysisSubject(s)
Antibodies, Monoclonal, Murine-Derived/therapeutic use , Antineoplastic Agents/therapeutic use , Central Nervous System Neoplasms/drug therapy , Immunologic Factors/therapeutic use , Nitrogen Mustard Compounds/therapeutic use , Waldenstrom Macroglobulinemia/drug therapy , Bendamustine Hydrochloride , Bone Marrow/drug effects , Bone Marrow/metabolism , Bone Marrow/pathology , Central Nervous System Neoplasms/complications , Central Nervous System Neoplasms/metabolism , Central Nervous System Neoplasms/pathology , Humans , Male , Middle Aged , Remission Induction , Rituximab , Treatment Outcome , Waldenstrom Macroglobulinemia/complications , Waldenstrom Macroglobulinemia/metabolism , Waldenstrom Macroglobulinemia/pathologyABSTRACT
Hepatitis C virus has been found to be associated with B-cell non-Hodgkin lymphomas, mostly marginal zone lymphomas and diffuse large B-cell lymphoma. Deregulation of signaling pathways involved in normal marginal zone development (NOTCH pathway, NF-κB, and BCR signaling) has been demonstrated in splenic marginal zone lymphoma. We studied mutations of NOTCH pathway signaling in 46 patients with hepatitis C virus-positive diffuse large B-cell lymphoma and in 64 patients with diffuse large B-cell lymphoma unrelated to HCV. NOTCH2 mutations were detected in 9 of 46 (20%) hepatitis C virus-positive patients, and NOTCH1 mutations in 2 of 46 (4%). By contrast, only one of 64 HCV-negative patients had a NOTCH1 or NOTCH2 mutation. The frequency of the NOTCH pathway lesions was significantly higher in hepatitis C virus-positive patients (P=0.002). The 5-year overall survival was 27% (95%CI: 5%-56%) for hepatitis C virus-positive diffuse large B-cell lymphoma patients carrying a NOTCH pathway mutation versus 62% (95%CI: 42%-77%) for those without these genetic lesions. By univariate analysis, age over 60 years, NOTCH2 mutation, and any mutation of the NOTCH pathway (NOTCH2, NOTCH1, SPEN) were associated with shorter overall survival. Mutation of the NOTCH pathway retained an independent significance (P=0.029). In conclusion, a subset of patients with hepatitis C virus-positive diffuse large B-cell lymphoma displays a molecular signature of splenic marginal zone and has a worse clinical outcome.
Subject(s)
Hepatitis C/genetics , Homeodomain Proteins/genetics , Lymphoma, Large B-Cell, Diffuse/genetics , Mutation/genetics , Neoplasm Recurrence, Local/genetics , Nuclear Proteins/genetics , Receptor, Notch1/genetics , Receptor, Notch2/genetics , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/genetics , DNA-Binding Proteins , Female , Follow-Up Studies , Hepacivirus/isolation & purification , Hepatitis C/mortality , Hepatitis C/pathology , Hepatitis C/virology , Humans , Lymphoma, Large B-Cell, Diffuse/mortality , Lymphoma, Large B-Cell, Diffuse/pathology , Lymphoma, Large B-Cell, Diffuse/virology , Male , Middle Aged , Neoplasm Grading , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/virology , Polymerase Chain Reaction , Prognosis , RNA-Binding Proteins , Survival RateABSTRACT
High-dose chemotherapy with autologous stem cell transplantation (ASCT) has been shown effective in the control of relapsed/refractory follicular lymphoma. We evaluate the long-term outcome of patients with relapsed or refractory follicular lymphoma treated with ASCT with in vivo purged progenitors cells. We report the long-term results of a prospective multicenter phase 2 trial on 124 relapsed/refractory follicular lymphoma patients treated with a program of anthracycline-based debulking chemotherapy, immunochemotherapy, mobilization of in vivo purged PBSC followed by ASCT. Median age was 52 years; 14% of patients had grade 3A histology. Debulking chemotherapy produced CR in 16% and PR in 71%, while 13% of patients progressed. After rituximab, cyclophosphamide, vincristine, prednisone (R-COP), CR was obtained in 60% and PR in 35%; 118 patients successfully mobilized PBSC and 117 proceeded to ASCT. The harvest in all the 32 molecularly informative patients was bcl-2 negative. TRM was 0%. The 5-year PFS was 54% and the 5-year OS was 83%. After a median f-up of 6.7 years (range 1.5-13.6), 54% are still in CR. These data show that prolonged PFS is achievable in relapsed/refractory patients with high dose autologous transplantation of in vivo purged progenitor cells.