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Background: When treating indolent B-cell lymphoma, combining continuously administered oral phosphatidylinositol 3-kinase (PI3K) inhibitors with immunochemotherapy has been associated with toxicity. CHRONOS-4 (Phase III; NCT02626455) investigates the intravenous, intermittently administered pan-class I PI3K inhibitor copanlisib in combination with rituximab plus bendamustine (R-B) or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with relapsed indolent B-cell lymphoma. We report safety run-in results., Patients and Methods: Patients aged ≥18 years with relapsed CD20-positive indolent B-cell lymphoma received copanlisib (45 mg, increasing to 60 mg if no dose-limiting toxicities) weekly on an intermittent schedule with R-B or R-CHOP. Primary objective was to identify a recommended Phase III dose (RP3D). We also assessed objective response, safety, and tolerability., Results: Ten patients received copanlisib plus R-B and 11 received copanlisib plus R-CHOP. No dose-limiting toxicities were reported; RP3D was 60 mg. All patients had ≥1 treatment-emergent adverse event (TEAE), most commonly (all grade/grade 3/4) for copanlisib plus R-B: decreased neutrophil count (80%/50%), nausea (70%/0%), decreased platelet count (60%/10%), hyperglycemia (60%/50%); for copanlisib plus R-CHOP: hyperglycemia (82%/64%), hypertension (73%/64%), decreased neutrophil count (64%/64%). Two and 8 patients had serious TEAEs with copanlisib plus R-B and R-CHOP, respectively. Among evaluable patients, objective response rates were 90% (5 complete, 4 partial) and 100% (3 complete, 7 partial) with copanlisib plus R-B and R-CHOP, respectively., Conclusion: Copanlisib is the first PI3K inhibitor to demonstrate safe, tolerable, and effective combinability with immunochemotherapy in patients with relapsed indolent B-cell lymphoma at full dose (60 mg). Further evaluation is ongoing., Competing Interests: Disclosure MJM: consultancy: Bayer, Daiichi Sankyo, Roche, Genentech, Juno Therapeutics, Merck, Rocket Medical, Seattle Genetics, Takeda, Teva; honoraria: Bayer, Roche, Genentech, GlaxoSmithKline, ImmunoVaccine Technologies, Janssen, Pharmacyclics, Seattle Genetics, Takeda; research funding: Bayer, Roche, Genentech, GlaxoSmithKline, ImmunoVaccine Technologies, Janssen, Pharmacyclics, Rocket Medical, Seattle Genetics. MD: scientific advisory boards: Amgen, AstraZeneca, Bayer, Beigene, BMS/Celgene, Genmab, Gilead/Kite, Janssen, Novartis, Roche; speaker honoraria: Amgen, AstraZeneca, Bayer, BMS/Celgene, Gilead/Kite, Janssen, Roche; institutional research support: AbbVie, Bayer, Celgene, Janssen, Roche. SL: consultancy: Celgene, CHO Pharma USA, Incyte, Gilead, Janssen, Merck, Novartis, Roche, Takeda; honoraria: Merck, Roche, Takeda; research funding: Bayer, Celgene, Genmab, Janssen, Nanovector, Novartis, Roche, Takeda. AS: speaker bureau: AbbVie, Amgen, ArQule, AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, Eisai, Gilead, Lilly, MSD, Novartis, Pfizer, Roche, Sandoz, Servier, Takeda; advisory boards: Bayer, Bristol Myers Squibb, Eisai, Gilead, MSD, Pfizer, Servier; consultancy: ArQule. VB, BHC: employees of Bayer HealthCare Pharmaceuticals, Inc. MF: employee of Bayer AG. PLZ: honoraria: AbbVie, ADC Therapeutics, Bristol Myers Squibb, EUSA Pharma, Gilead, Incyte, Janssen, Kyowa Kirin, Merck, MSD, Roche, Servier, Takeda, TG Therapeutics, Verastem; board of directors or advisory committee memberships: AbbVie, ADC Therapeutics, Bristol Myers Squibb, Celgene, Celltrion, EUSA Pharma, Gilead, Immune Design, Incyte, Janssen-Cilag, Kyowa Kirin, Merck, MSD, Portola, Roche, Sandoz, Servier, Takeda, Verastem; speaker bureau: AbbVie, ADC Therapeutics, Bristol Myers Squibb, Celgene, Celltrion, EUSA Pharma, Gilead, Immune Design, Incyte, Janssen, Janssen-Cilag, Kyowa Kirin, Merck, MSD, Portola, Roche, Servier, Takeda, TG Therapeutics, Verastem; consultancy: EUSA Pharma, Janssen, MSD, Sanofi, Verastem; research funding: Portola. MP: none., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Copanlisib is a phosphoinositol 3-kinase (PI3K) inhibitor approved for the third-line treatment of follicular non-Hodgkin lymphoma. Although the drug is generally well-tolerated, it can be associated with several unique and potentially serious adverse effects (AEs). Two of the most common toxicities not seen with other PI3K inhibitors include hyperglycemia and hypertension, which primarily occur during infusion and resolve shortly thereafter, and likely relate to targeting the PI3K alpha isoform. Other toxicities less commonly observed with copanlisib than with other approved drugs in this class include non-infectious pneumonitis, infections, diarrhea and colitis, and hepatobiliary toxicity., Materials and Methods: A panel composed of experts in lymphoma, diabetes, and hypertension convened to develop guidance pertaining to the administration of copanlisib and the management of the AEs associated with copanlisib treatment., Results: Recommendations were formulated pertaining to the management of AEs associated with copanlisib treatment, particularly infusion-related hyperglycemia and hypertension, noninfectious pneumonitis, infections, diarrhea, and colitis. The recommendations herein reflect the consensus of the members of this panel, all of whom contributed to these suggested approaches to patient supportive care., Conclusion: There are a number of challenges associated with the use of copanlisib. Infusion-related hypertension and hyperglycemia occur frequently, although they are transient, reversible, and rarely of clinical significance; this report provides guidance as to their management., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Brentuximab vedotin (BV) is approved for the treatment of patients with relapsed or refractory CD30-positive Hodgkin lymphoma, and relapsed or refractory systemic anaplastic large-cell lymphoma. Several uncertainties remain regarding the optimal use of the drug in its approved indications as well as outside them. This article reports recommendations on the use of BV issued during a consensus project, sponsored by the Italian Society of Hematology (SIE) and its affiliate societies, Società Italiana di Ematologia Sperimentale (SIES) and Gruppo Italiano Trapianto di Midollo Osseo (GITMO). Scientific evidence on BV was evaluated by a panel of experts, and consensus was developed by group discussion for key questions selected according to the clinical relevance. The following key issues were addressed: testing CD30 positivity to assess eligibility to BV; assessing practice indications of BV in Hodgkin lymphoma and systemic anaplastic large-cell lymphoma; providing pretreatment evaluation of patients candidates to BV; monitoring the response to BV; managing patients treated with BV; and assessing the role of BV in other CD30-positive lymphomas., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: The optimal treatment of patients with heavily pretreated Hodgkin's lymphoma is controversial. Brentuximab vedotin is an active single agent in this context. Also, bendamustine can be regarded as a safe and effective alternative for patients with relapse after autologous transplantation and as an interesting cytoreductive strategy before allogeneic transplantation., Patients and Methods: An observational, multicenter, retrospective study is reported of single-agent bendamustine in 27 heavily pretreated patients with relapsed or refractory Hodgkin's lymphoma, who had all received brentuximab vedotin as their last treatment and who showed disease progression, refractory disease, or early relapse. The primary study endpoint was the objective response rate, and the secondary endpoint was the safety of the bendamustine regimen., Results: The overall response rate was 55.5%, with 10 of 27 patients (37.0%) obtaining a complete response. In comparison, the overall response rate previously observed with brentuximab vedotin in the same subset of patients was much lower (18.5%). Among the 10 patients with a complete response after bendamustine, only 1 had had a complete response to brentuximab, with 2 having a partial response and 7 stable or progressive disease. With a median duration of response of 8 months, all these patients had maintained a continuous response at the last follow-up examination. The treatment was well tolerated, with rather infrequent adverse events and transient and manageable toxicities., Conclusion: Albeit with the limits of an observational retrospective study, these data indicate that bendamustine shows its efficacy in patients already treated with brentuximab vedotin, regardless of their previously obtained response and without any significant toxicity., (Copyright © 2015 Elsevier Inc. All rights reserved.)

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)., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Lymphomas with involvement of soft tissues as a primary event are very rare. The published studies have a small sample size, most of them being reported as case reports., Patients and Methods: In this article we describe our experience with soft tissue non-Hodgkin lymphomas (NHL) diagnosed and treated in our institution over a 15-year period. Moreover, we systematically review the available data from the literature in the past 2 decades, considering all the published series and case reports available from 1990 to 2011 using a PubMed access., Results: In the monocentric analysis, 16 consecutive patients treated at our Institution from 1996 to 2011 were considered. In the literature search, we selected 16 case reports (18 patients) and 5 case series (49 patients), including a total of 67 patients. Eighty-three patients were finally considered in the combined analysis. The most common histologic subtype was diffuse large B cell lymphoma (DLBCL) (>50% of cases in both groups). In both analyses we observed an inferior outcome for DLBCL compared with indolent B-cell NHL (5-year progression free survival: 34% vs. 64%, respectively, in the combined analysis; P = .01). Furthermore, the prognosis in the DLBCL group appears to be worse compared with the historical data of DLBCL patients treated with chemoimmunotherapy., Conclusions: Though indolent soft tissue B-cell NHLs appear to have a good outcome, soft tissue DLBCLs represent an anatomic-clinical entity with aggressive features, and dismal prognosis. Strategies of first-line therapy intensification could be considered. Studies aiming to a better biologic characterization of this peculiar entity are warranted., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of aggressive non-Hodgkin lymphoma and despite recent chemotherapeutic advances up to half of all patients relapse. Here we report the results from a phase 2, single-arm, single-center trial evaluating the safety and efficacy of lenalidomide plus rituximab in elderly patients with relapsed or refractory DLBCL., Patients and Methods: Between March and June 2009, elderly patients (65 years of age or older) with relapsed/refractory DLBCL who had been heavily pretreated were recruited. Oral lenalidomide (20 mg/d for 21 days of each 28-day cycle) was initiated for four cycles and rituximab (375 mg/m(2)) was administered on day 1 and day 21 of each 28-day cycle for four cycles. After this induction phase, patients achieving a complete response (CR), partial response (PR), or stable disease (SD) were given lenalidomide maintenance therapy at the same schedule for another 8 months., Results: A total of 23 patients with a median of three prior treatments (range, 2 to 8) were included. The overall response rate (CR + PR) at the end of the induction phase was 35% (n = 8). Ten patients (7 CR, 1 PR, and 2 SD patients) were eligible for lenalidomide maintenance and 8 of these patients achieved a CR. Adverse events were manageable and the most common included neutropenia and thrombocytopenia., Conclusion: Oral lenalidomide in combination with rituximab is active in elderly patients with relapsed/refractory DLBCL with a high percentage of patients achieving a continuous CR after lenalidomide maintenance., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: We performed a retrospective investigation to assess the efficacy of chemotherapy and rituximab as front-line treatment for primary bone lymphoma (PBL)., Patients and Methods: Between 1999 and 2009, 21 previously untreated patients received a diagnosis of PBL. All the patients were treated with anthracycline-containing chemotherapeutic regimens, with the addition of rituximab; 11 patients received consolidative radiation therapy after induction treatment., Results: Patients' median age was 34 years (range, 18-82 years); all presented with diffuse large B-cell lymphoma. Complete responses were seen in 95.2% of the patients treated. No relapses were observed at a median follow-up of 43.9 months. Eight-year overall survival and disease-free survival were 95.2% and 100.0%, respectively., Conclusion: These data indicate that the combined chemotherapy plus rituximab treatment may represent a suitable front-line approach in PBL, with a high rate of responses and an excellent long-term survival., (Copyright © 2011. Published by Elsevier Inc.)

Introduction: Two hundred ten patients with newly diagnosed Hodgkin's lymphoma (HL) were consecutively enrolled in this prospective trial to evaluate the cost-effectiveness of fluorine-18 ((18)F)-fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) scan in initial staging of patients with HL., Methods: All 210 patients were staged with conventional clinical staging (CCS) methods, including computed tomography (CT), bone marrow biopsy (BMB), and laboratory tests. Patients were also submitted to metabolic staging (MS) with whole-body FDG-PET scan before the beginning of treatment. A standard of reference for staging was determined with all staging procedures, histologic examination, and follow-up examinations. The accuracy of the CCS was compared with the MS. Local unit costs of procedures and tests were evaluated. Incremental cost-effectiveness ratio (ICER) was calculated for both strategies., Results: In the 210 patients with HL, the sensitivity for initial staging of FDG-PET was higher than that of CT and BMB in initial staging (97.9% vs. 87.3%; P < .001 and 94.2% vs. 71.4%, P < 0.003, respectively). The incorporation of FDG-PET in the staging procedure upstaged disease in 50 (24%) patients and downstaged disease in 17 (8%) patients. Changes in treatment would be seen in 32 (15%) patients. Cumulative cost for staging procedures was $3751/patient for CCS compared to $5081 for CCS + PET and $4588 for PET/CT. The ICER of PET/CT strategy was $16,215 per patient with modified treatment. PET/CT costs at the beginning and end of treatment would increase total costs of HL staging and first-line treatment by only 2%., Conclusion: FDG-PET is more accurate than CT and BMB in HL staging. Given observed probabilities, FDG-PET is highly cost-effective in the public health care program in Brazil., (Copyright © 2011. Published by Elsevier Inc.)

Background: Based on historical data on the role of radioimmunotherapy (RIT) in pretreated non-Hodgkin lymphoma, we reviewed our hospital's clinical database., Patients and Methods: Between 2005 and 2008, 57 patients previously treated with at least 1 rituximab-containing chemotherapy were treated with Yttrium-90-labeled ibritumomab tiuxetan ((90)Y-IT). The median number of pretreatments was 3 (range, 1-9 pretreatments). A total of 46 patients had stage III/IV disease (31 with bone marrow involvement); 6 had bulky disease. According to histology, 53 were follicular lymphoma (FL), 2 were marginal zone lymphoma, and 2 were small lymphocytic lymphoma., Results: Overall response rate was 93% (53 of 57); complete response (CR) rate was 70% (40 of 57). Twenty-six of 40 patients (65%) who obtained a CR are in continuous CR (CCR) with a median follow-up of 20 months (range, 10-42 months); 4 of them still maintain their CCR after 36 months. All patients achieving a CCR had FL, and 21 of them with stage III/IV disease; 12 of 26 had been heavily pretreated (>or= 3 previous treatments), and 2 had had autologous stem cell transplantation. Toxicity was primarily hematologic and mostly transient; no grade 4 extrahematologic toxicity was observed., Conclusion: This study confirms the safety and high efficacy of (90)Y-IT RIT in heavily pretreated FL patients, with the possibility of having a subset of long-term responders.