[Show abstract][Hide abstract] ABSTRACT: Purpose:
The randomized HD2000 trial compared six cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), four escalated plus two standard cycles of BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone), and six cycles of COPP-EBV-CAD (cyclophosphamide, lomustine, vindesine, melphalan, prednisone, epidoxorubicin, vincristine, procarbazine, vinblastine, and bleomycin; CEC) in patients with advanced-stage Hodgkin lymphoma. After a median follow-up of 42 months, patients who received BEACOPP were reported to have experienced better progression-free survival (PFS) but not better overall survival (OS) results than those receiving ABVD. We here report a post hoc analysis of this trial after a median follow-up of 10 years.
Patients and methods:
Three hundred seven patients were enrolled, 295 of whom were evaluable. At the time of our analysis, the median follow-up for the entire group was 120 months (range, 4 to 169 months).
The 10-year PFS results for the ABVD, BEACOPP, and CEC arms were 69%, 75%, and 76%, respectively; corresponding OS results were 85%, 84%, and 86%. Overall, 13 second malignancies were reported: one in the ABVD arm and six each in the BEACOPP and CEC arms. The cumulative risk of developing second malignancies at 10 years was 0.9%, 6.6%, and 6% with ABVD, BEACOPP, and CEC, respectively; the risk with either BEACOPP or CEC was significantly higher than that reported with ABVD (P = .027 and .02, respectively).
With these mature results, we confirm that patients with advanced Hodgkin lymphoma have similar OS results when treated with ABVD, BEACOPP, or CEC. However, with longer follow-up, we were not able to confirm the superiority of BEACOPP over ABVD in terms of PFS, mainly because of higher mortality rates resulting from second malignancies observed after treatment with BEACOPP and CEC.
Preview · Article · Dec 2015 · Journal of Clinical Oncology
[Show abstract][Hide abstract] ABSTRACT: The purpose of this phase 2 study was to determine the activity and safety of 6 cycles of bendamustine and 8 rituximab (RB) as first-line treatment of adult patients with advanced stage non-follicular indolent non-Hodgkin lymphomas (INFL). The primary endpoint was the complete response rate (CRR) with expected CRR of 75%. Sixty-nine patients were enrolled; median age was 65 years (45-75), 65% were male, 93% of patients had stage IV disease. Complete and overall response rates were 48% (95% IC 35.6-60.2), and 86% (IC 75.0-92.8). The most common grade 3/4 adverse events were neutropenia (43%), thrombocytopenia (7%), anemia (4%); whereas the rate of febrile neutropenia was very low (3%). At a median follow up of 22 months (1-43 months), 2-year progression free survival was 89% (IC: 79-95), and 2-year overall survival was 96% (IC: 87-99). RB combination is active and well tolerated in patients with advanced stage previously untreated INFL.
[Show abstract][Hide abstract] ABSTRACT: DIS3 is a catalytic subunit of the human exosome complex, containing exonucleolytic (RNB) and endonucleolytic (PIN) domains, recently found mutated in multiple myeloma (MM), a clinically and genetically heterogeneous form of plasma cell (PC) dyscrasia. We analyzed by next-generation sequencing (NGS) the DIS3 PIN and RNB domains in purified bone marrow PCs from 164 representative patients, including 130 cases with MM, 24 with primary PC leukemia and 10 with secondary PC leukemia. DIS3 mutations were found respectively in 18.5%, 25% and 30% of cases. Identified variants were predominantly missense mutations localized in the RNB domain, and were often detected at low allele frequency. DIS3 mutations were preferentially carried by IGH-translocated/nonhyperdiploid patients. Sequential analysis at diagnosis and relapse in a subset of cases highlighted some instances of increasing DIS3 mutation burden during disease progression. NGS also revealed that the majority of DIS3 variants in mutated cases were comparably detectable at transcriptional level. Furthermore, gene expression profiling analysis in DIS3-mutated patients identified a transcriptional signature suggestive for impaired RNA exosome function. In conclusion, these data further support the pathological relevance of DIS3 mutations in plasma cell dyscrasias and suggest that DIS3 may represent a potential tumor suppressor gene in such disorders.
[Show abstract][Hide abstract] ABSTRACT: Multiple myeloma (MM) is a clinically and genetically heterogeneous plasma cell (PC) malignancy. Whole-exome sequencing has identified therapeutically targetable mutations such as those in the mitogen-activated protein kinase (MAPK) pathway, which are the most prevalent MM mutations. We used deep sequencing to screen 167 representative patients with PC dyscrasias [132 with MM, 24 with primary PC leukemia (pPCL) and 11 with secondary PC leukemia (sPCL)] for mutations in BRAF, NRAS and KRAS, which were respectively found in 12%, 23.9% and 29.3% of cases. Overall, the MAPK pathway was affected in 57.5% of the patients (63.6% of those with sPCL, 59.8% of those with MM, and 41.7% of those with pPCL). The majority of BRAF variants were comparably expressed at transcript level. Additionally, gene expression profiling indicated the MAPK pathway is activated in mutated patients. Finally, we found that vemurafenib inhibition of BRAF activation in mutated U266 cells affected the expression of genes known to be associated with MM. Our data confirm and extend previous published evidence that MAPK pathway activation is recurrent in myeloma; the finding that it is mediated by BRAF mutations in a significant fraction of patients has potentially immediate clinical implications.
[Show abstract][Hide abstract] ABSTRACT: Background and Aims: Hepatitis B surface antigen (HBsAg)- negative/anti-hepatitis B core antigen (anti-HBc)-positive patients undergoing Rituximab (RTX)-based chemotherapy (R-CT) for non-Hodgkin’s B cell lymphoma (NHL) face up to 27% risk of hepatitis B virus (HBV) reactivation. Aim of the study was to assess the efficacy and safety of lamivudine (LMV) prophylaxis in these patients.
Methods: Sixty-seven consecutive HBsAg-negative/anti-HBc- positive patients (median age 70yrs, 61% males, 13% HCV seropositive, 100% serum HBV DNA negative by sensitive PCR assay, 75% anti-HBs positive, 100% with ALT <ULN) undergoing different R-CT protocols (48% R-CHOP) in two hematological centres were retrospectively enrolled. LMV prophylaxis was started before the first R-CT dose and planned to last for 18 months after the end of R-CT. R-CT was administered for 6 cycles (range: 1–15) during 5 (range: 1–38) months, while LMV was administered for 20 (range: 3–54) months. Serum ALT, HBsAg and HBV DNA levels by PCR assay were assessed every 3–4 months.
Results: All patients remained HBV DNA and HBsAg negative during a median of 20 months (range: 2–60), including both the LMV prophylaxis and the subsequent off treatment follow-up. Anti-HBs titers declined in 18% of patients but none lost serum reactivity for anti-HBs. Overall, 2 patients had an increase of ALT (>ULN) but this event was unrelated to HBV reactivation and 7 patients died of liver unrelated causes. No safety issues related to LMV were recorded.
Conclusions: LMV monotherapy is an inexpensive, safe and effective prophylaxis regimen to prevent HBV reactivation in such a high-risk population as HBsAg-negative/anti-HBc-positive patients receiving RTX-based chemotherapy for non-Hodgkin’s B cell lymphoma.
No preview · Article · Apr 2015 · Journal of Hepatology
[Show abstract][Hide abstract] ABSTRACT: Hepatitis B surface antigen (HBsAg)-negative/anti-hepatitis B core antigen (anti-HBc)-positive patients undergoing Rituximab (RTX)-based chemotherapy (R-CT) for non–Hodgkin's B cell lymphoma (NHL) face up to 27% risk of hepatitis B virus (HBV) reactivation. Aim of the study was to assess the efficacy and safety of lamivudine (LMV) prophylaxis in these patients
No preview · Article · Feb 2015 · Digestive and Liver Disease
[Show abstract][Hide abstract] ABSTRACT: A subanalysis of the GIMEMA-MMY-3006 trial was performed to characterize treatment-emergent peripheral neuropathy (PN) in patients randomized to thalidomide-dexamethasone (TD) or bortezomib-TD (VTD) before and after double autologous transplantation (ASCT) for multiple myeloma (MM). 236 patients randomized to VTD and 238 to TD were stratified according to the emergence of grade ≥2 PN. Gene expression profiles (GEP) of CD138+ plasma cells were analyzed in 120 VTD-treated patients. The incidence of grade ≥2 PN was 35% in the VTD arm and 10% in the TD arm (p<0.001). PN resolved in 88% and 95% of patients in VTD and TD groups, respectively. Rates of complete/near complete response, progression-free and overall survival were not adversely affected by emergence of grade ≥2 PN. Baseline characteristics were not risk factors for PN, while GEP analysis revealed the deregulated expression of genes implicated in cytoskeleton rearrangement, neurogenesis and axonal guidance. In conclusion, in comparison with TD, incorporation of VTD into ASCT was associated with a higher incidence of PN which, however, was reversible in most of the patients and did not adversely affect their outcomes nor their ability to subsequently receive ASCT. GEP analysis suggests an interaction between myeloma genetic profiles and development of VTD-induced PN.
Full-text · Article · Dec 2014 · American Journal of Hematology
[Show abstract][Hide abstract] ABSTRACT: Multiple Myeloma is a plasma cell disorder, characterized by malignant plasma cell infiltration in the bone marrow, serum and/or urine monoclonal protein and organ damage. The aim of this study was to investigate the impact of chromosome 1 abnormalities in a group of elderly (>65 years) newly diagnosed Multiple Myeloma patients, enrolled in the GIMEMA-MM-03-05 trial and treated with bortezomib, melphalan and prednisone vs bortezomib, melphalan, prednisone and thalidomide followed by bortezomib and thalidomide maintenance. We also evaluated the link between chromosome 1 abnormalities and other clinical, genetic and immunophenotypic features by a multivariate logistic regression model. Interphase fluorescence in situ hybridization on immunomagnetically purified plasma cells and bone marrow multiparameter flow cytometry were employed. By a multivariate Cox model, chromosome 1 abnormalities, age >75 and CD19+/CD117- bone marrow plasma cells immunophenotype emerged as independent risk factors for Overall Survival in elderly, newly diagnosed multiple myeloma patients. Moreover, a detrimental effect of thalidomide, even when administered in association with bortezomib, was observed in abnormal chromosome 1 as well as (17p)deleted patients, while the benefit of thalidomide addiction to the bortezomib-melphalan-prednisone regimen was noted in patients carrying an aggressive CD19+/CD117- bone marrow plasma cells immunophenotype. This trial was registered at www.clinicaltrials.gov as #NCT01063179.
[Show abstract][Hide abstract] ABSTRACT: Indolent nonfollicular B-cell lymphoma (INFBCL) has been classified in the World Health Organization 2008 system among the mature B-cell neoplasms and includes nodal and extranodal marginal zone lymphoma (MZL), lymphoplasmacytic lymphoma (LPL), and small lymphocytic lymphoma (SLL). Recently, the array and sequencing technologies have provided new insights into their molecular pathogenesis; the molecular discoveries, however, have not yet translated into consistent changes in their management. Thus, the therapy for INFBCL remains challenging. To promote widespread adoption of appropriate clinical practice, the Italian Society of Hematology and affiliate societies (Italian Society of Experimental Hematology and Italian Group for Bone Marrow Transplantation) reviewed the evidence regarding the management of these lymphomas to produce evidence-based recommendations aimed at contributing to therapy optimization and standardization. We used the Grades of Recommendation, Assessment, Development, and Evaluation system, which is based on a sequential assessment of the quality of evidence, followed by an analysis of the benefit/risk balance and subsequent judgment about the strength of recommendations. For issues without consistent evidence, we used the consensus technique. We have provided separate recommendations for diagnostic and staging requirements, first-line therapy, and postinduction therapy for the most frequent INFBCLs (ie, LPL, SLL, and nodal, splenic, and gastric MZL).
No preview · Article · Jul 2014 · Clinical Lymphoma, Myeloma and Leukemia
[Show abstract][Hide abstract] ABSTRACT: Aims:
To identify molecular characteristics to hepatitis C virus (HCV)-associated diffuse large B-cell lymphoma (DLBCL) through a comprehensive miRNAs expression profiling.
In this study, miRNA profiles were obtained from 37 patients with DLBCLs and 60 patients with reactive lymph nodes, equally distributed according to HCV presence. Germinal centres, from reactive lymph nodes were used as controls. Clinical features at presentation were available for all patients.
A set of 52 miRNAs define a signature for HCV-associated DLBCL. Importantly, decreased expression of miR-138-5p and increased expression of miR-147a, miR-147b and miR-511-5p in HCV DLBCL was found to be a poor prognostic factor for HCV-positive DLBCL patients.
These data reveal molecular differences in diffuse DLBCL patients according to HCV presence, potentially useful as novel prognostic or therapeutic biomarkers.
Full-text · Article · Jun 2014 · Journal of Clinical Pathology
[Show abstract][Hide abstract] ABSTRACT: Tumour regression after antiviral therapy (AT) is in favour of an etiological role of hepatitis C virus (HCV) in non-Hodgkin's B-cell lymphomas (NHL).
We performed a cohort study of 704 consecutive HIV-negative, HCV-positive patients with indolent NHL diagnosed and treated from 1993 to 2009 in 39 centers of the Fondazione Italiana Linfomi; 134 patients were managed with AT for lymphoma control.
For entire cohort, 5-yr overall survival (OS) was 78% (95%CI: 74-82%) and 5-yr progression-free survival (PFS) was 48% (95%CI: 44-53%). In multivariate analysis, use of AT during the patients' life had positive impact on OS. Fourty four of the 100 patients treated with first-line AT achieved a CR and 33 a partial response (PR). HCV-RNA clearance was achieved in 80 patients and was related to lymphoma response. At a median follow-up of 3.6 years, 5-yr PFS was 63% (95%CI: 50%-73%). CR+PR rate was 85% with AT as second-line treatment.
AT produces HCV-RNA clearance and consequent tumour regression in most patients with HCV-related indolent NHL. AT used at any time is associated with improved OS. Consequently, AT can be considered an option for patients with indolent lymphomas who do not need immediate cytoreductive treatment.
Full-text · Article · May 2014 · Annals of Oncology
[Show abstract][Hide abstract] ABSTRACT: We report updated results at a median follow-up of 12 years of a phase II trial assessing first-line MATILDE chemotherapy and response-tailored radiotherapy in patients with primary CNS lymphomas (PCNSL).
Forty-one HIV-negative patients (18-70 years; Eastern Cooperative Oncology Group performance status ≤3) with histologically confirmed PCNSL received 3 courses of MATILDE chemotherapy followed by whole-brain radiotherapy (WBRT). Chemotherapy activity was the primary endpoint.
Overall response rate was 76% (95% confidence interval [CI] 63%-89%) after chemotherapy and 83% (95% CI 71%-95%) after chemotherapy ± radiotherapy. At a median follow-up of 144 months (range 47-153), 31 patients experienced an event: relapse in 24, progressive disease in 3, and toxic death in 4, with a 5-year progression-free survival of 24% ± 8%. Two patients experienced a late relapse (100 and 101 months). Nine patients are alive and disease-free, 8 of whom are alive at >10 years, with a 5-year overall survival of 30% ± 7%. At 10 years from diagnosis, no patient showed chronic hematologic and nonhematologic toxicities, with a Mini-Mental State Examination score of ≥29 in all cases but one.
At a median follow-up of 12 years, MATILDE regimen followed by WBRT confirmed the previously reported survival plateau, which further proves its long-lasting efficacy with acceptable neurologic deficits.
This study provides Class IV evidence that in patients with PCNSL, MATILDE chemotherapy followed by response-tailored radiotherapy increases the probability of disease remission at 12 years.
[Show abstract][Hide abstract] ABSTRACT: Peripheral T-cell lymphomas (PTCLs) receiving conventional treatment have a poor clinical outcome. We conducted a phase II study to evaluate the feasibility and efficacy of chemo-immunotherapy in young (60 years old, Clin A study) and elderly (>60 and 75 years old, Clin B study) patients with newly diagnosed PTCL. Clin A patients (n=61) received two courses of CHOP (cyclophosphamide, adriamycin, vincristine, prednisone)-21 with alemtuzumab (AL, 30 mg) followed by two courses of high-dose chemotherapy. On the basis of donor availability, patients in response received allogeneic (allo) or autologous (auto) stem cell transplantation (SCT). Clin B patients (n=25) received six courses of CHOP-21 and AL (10 mg). Clin A responding patients were 38 of 61 (62%) and received alloSCT (n=23) or autoSCT (n=14); one complete remission (CR) patient was not transplanted. At a median follow-up of 40 months, the 4-year overall survival (OS), progression-free survival (PFS) and disease-free survival (DFS) rates were 49, 44 and 65%, respectively. In Clin B study, the response rate was 72%. At a median follow-up of 48 months, the 4-year OS, PFS and DFS rates were 31, 26 and 44%, respectively. In conclusion, front-line alloSCT or autoSCT is effective in prolonging DFS in young patients; AL in elderly improved response with no survival benefit.Leukemia advance online publication, 25 March 2014; doi:10.1038/leu.2014.79.
No preview · Article · Feb 2014 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K