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The prognosis of patients with relapsed diffuse large B-cell lymphoma (DLBCL) remains poor with current options. Here we prospectively evaluated the combination of pixantrone with obinutuzumab for up to six cycles for patients with relapsed or refractory DLBCL. Overall response rate (ORR) was the primary end-point. Sixty-eight patients were evaluated, median age was 75 years, median number of prior lines was three (range 1-10), 52 patients (76.5%) were diagnosed with DLBCL and 16 (23.5%) patients had transformed indolent lymphoma or follicular lymphoma (FL) IIIB. ORR was 35.3% for all and 40% for evaluable patients (16.6% complete response), median progression-free survival (PFS) and overall survival (OS) were 2.8 months and 8 months, respectively. Analysis of the cell of origin revealed a superior course for patients with non-GCB (germinal centre B-cell-like) phenotype [median OS not reached (n.r.) vs 5.2 months]. Patients with one prior line had an improved outcome over patients treated in later lines (PFS n.r. vs 2.5 months). Disease progression was the main reason for premature termination. Adverse events were mainly haematologic. The combination treatment revealed no unexpected adverse events. Most relevant non-haematologic toxicity was infection in 28% of patients. In summary, pixantrone-obinutuzumab showed clinical activity with sometimes long-term remission; however, the trial failed to meet its primary end-point., (© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Six cycles of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) are the standard treatment for aggressive B-cell non-Hodgkin lymphoma. In the FLYER trial, we assessed whether four cycles of CHOP plus six applications of rituximab are non-inferior to six cycles of R-CHOP in a population of patients with B-cell non-Hodgkin lymphoma with favourable prognosis., Methods: This two-arm, open-label, international, multicentre, prospective, randomised phase 3 non-inferiority trial was done at 138 clinical sites in Denmark, Israel, Italy, Norway, and Germany. We enrolled patients aged 18-60 years, with stage I-II disease, normal serum lactate dehydrogenase concentration, ECOG performance status 0-1, and without bulky disease (maximal tumour diameter <7·5 cm). Randomisation was computer-based and done centrally in a 1:1 ratio using the Pocock minimisation algorithm after stratification for centres, stage (I vs II), and extralymphatic sites (no vs yes). Patients were assigned to receive either six cycles of R-CHOP or four cycles of R-CHOP plus two doses of rituximab. CHOP comprised cyclophosphamide (750 mg/m 2 ), doxorubicin (50 mg/m 2 ), and vincristine (1·4 mg/m 2 , with a maximum total dose of 2 mg), all administered intravenously on day 1, plus oral prednisone or prednisolone at the discretion of the investigator (100 mg) administered on days 1-5. Rituximab was given at a dose of 375 mg/m 2 of body surface area. Cycles were repeated every 21 days. No radiotherapy was planned except for testicular lymphoma treatment. The primary endpoint was progression-free survival after 3 years. The primary analysis was done in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of assigned treatment. A non-inferiority margin of -5·5% was chosen. The trial, which is completed, was prospectively registered at ClinicalTrials.gov, NCT00278421., Findings: Between Dec 2, 2005, and Oct 7, 2016, 592 patients were enrolled, of whom 295 patients were randomly assigned to receive six cycles of R-CHOP and 297 were assigned to receive four cycles of R-CHOP plus two doses of rituximab. Four patients in the four-cycles group withdrew informed consent before the start of treatment, so 588 patients were included in the intention-to-treat analysis. After a median follow-up of 66 months (IQR 42-100), 3-year progression-free survival of patients who had four cycles of R-CHOP plus two doses of rituximab was 96% (95% CI 94-99), which was 3% better (lower limit of the one-sided 95% CI for the difference was 0%) than six cycles of R-CHOP, demonstrating the non-inferiority of the four-cycles regimen. 294 haematological and 1036 non-haematological adverse events were documented in the four-cycles group compared with 426 haematological and 1280 non-haematological adverse events in the six-cycles group. Two patients, both in the six-cycles group, died during study therapy., Interpretation: In young patients with aggressive B-cell non-Hodgkin lymphoma and favourable prognosis, four cycles of R-CHOP is non-inferior to six cycles of R-CHOP, with relevant reduction of toxic effects. Thus, chemotherapy can be reduced without compromising outcomes in this population., Funding: Deutsche Krebshilfe., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Malignant lymphoma is still the leading cause of death among AIDS-related diseases., Patients and Methods: We performed a retrospective analysis of 50 HIV-positive lymphoma patients. The median interval between HIV and malignant lymphoma diagnosis was 4 years. Eight patients (16%) had Hodgkin lymphoma and 42 (84%) non-Hodgkin lymphoma. Among non-Hodgkin lymphoma patients, diffuse large B-cell lymphoma (n = 18, 42%), Burkitt lymphoma (n = 11, 26%), and plasmoblastic lymphoma (n = 5, 12%) were the most frequent entities., Results: Lymphoma was treated according to standard protocols. Forty-four patients (88%) received combination antiretroviral therapy, 2 (4%) were not treated, and in 4 (8%) the HIV treatment status was not clarified. Response to first-line therapy was complete response (CR) in 24 (56%), partial response (PR) in 15 (35%), and stable disease in 1 (2%). Three patients (7%) developed progressive disease, and 9 (18%) experienced relapse after CR or PR. At a median observation period of 31 (range, 0.4-192) months, the 1-, 2-, and 5-year overall survival was 87%, 79%, and 76%, respectively. At univariate analysis, remission status after first-line treatment was predictive of outcome, as the 2-year overall survival was 95%, 66%, and 0 for patients with CR, with PR, and with progressive disease (P < .001). Results of the multivariate analysis revealed lactate dehydrogenase concentration at lymphoma diagnosis (P = .046) and relapse (P = .050) to be independent factors for overall survival., Conclusion: First-line treatment of lymphoma in HIV positive patients is crucial. Patients who experienced and maintained a first CR had a favorable prognosis., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: For more than two decades, high-dose chemotherapy (HDT) and autologous blood stem cell transplantation (ABSCT) were treatment options for patients with aggressive B-cell non-Hodgkin's lymphoma (B-NHL). However, the ideal timing and the collective patient benefits are still being debated., Method: We retrospectively analyzed the data of 163 patients with B-NHL who received an HDT protocol followed by ABSCT between 2001 and 2007. Patients were analyzed according to the time point of HDT/ABSCT to compare upfront (directly after induction, n = 72, 44%) versus secondary transplantation (at first relapse, n = 91, 56%)., Results: The overall response rate was 100% and 94% after upfront and secondary HDT/ABSCT, respectively. No significant differences were found for hematopoietic recovery and toxicity profile. The progression-free survival (PFS) and overall survival (OS) probability were found to be significantly higher in the upfront HDT/ABSCT treatment group (P = .018 and P = .004). In multivariate analysis, upfront HDT/ABSCT and low IPI risk score had a significant beneficial effect on OS (P = .031 and P = .019)., Conclusion: HDT and ABSCT directly after induction chemotherapy were confirmed to be feasible with high PFS and OS rates. In addition, for patients with relapse after first-line therapy and consecutively poor prognosis, HDT/ABSCT also offers an effective treatment strategy., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Mantle cell lymphoma (MCL) is a rare, aggressive, incurable B-cell malignancy. Ibrutinib has been shown to be highly active for patients with relapsed/refractory (R/R) MCL. The RAY trial (MCL3001) was a phase 3, randomized, open-label, multicenter study that compared ibrutinib with temsirolimus in patients with R/R MCL. Active disease is frequently associated with impaired functional status and reduced well-being. Therefore, the current study employed two patient-reported outcome instruments, the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) and the EQ-5D-5L, to assess symptoms, well-being, health status, and health-related quality of life of patients on treatment within the RAY trial. We found that patients on ibrutinib had substantial improvement in FACT-Lym subscale and total scores, and had improvement in EQ-5D-5L utility and VAS scores compared with temsirolimus patients, indicating a superior well-being. These improvements in well-being correlated with clinical response, indicating that better health-related quality of life was associated with decreased disease burden.

This analysis reports on 72 patients with relapsed or refractory non-Hodgkin lymphoma who were treated with R-DHAP salvage chemotherapy regimen followed by high-dose chemotherapy and stem cell transplantation. The overall remission rate was 58.3%. Median time of follow-up was 28.7 months. Median progression-free survival was 29 months, estimated median overall survival was 37 months. Within a matched pair analysis these results were compared to a group that received DHAP salvage therapy without rituximab showing similar overall response rates and better estimated five-year overall survival of 59.2% versus 43.5%. R-DHAP therapy was shown to be effective and feasible with acceptable toxicity.

In patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL), R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin) is a commonly used regimen for salvage therapy and for mobilization of peripheral blood stem cells (PBSCs). At our center, a modified R-DHAP regimen with administration of 25 mg/m(2) cisplatin as a 3-hour infusion over 4 consecutive days, instead of a single infusion of 100 mg/m(2) over 24 hours, has been established. The aim of this study was to analyze the efficiency of this modified R-DHAP regimen plus G-CSF as a mobilization strategy. We retrospectively analyzed clinical characteristics, PBSC collection and autologous stem cell transplantation parameters, and hematologic reconstitution data for 65 patients with relapsed or refractory DLBCL who underwent PBSC collection after mobilization with the modified R-DHAP protocol at our institution between 2002 and 2013. Data were evaluated for the overall cohort and with regard to the number of R-DHAP cycles received before PBSC collection. PBSC collection was performed after the first R-DHAP course in 32 patients (49%), after the second course in 30 patients (46%), and after the third course in 3 patients (5%). Sixty-three patients (97%) achieved the collection goal of ≥2.0 × 10(6) CD34(+) cells/kg body weight. A significantly higher median CD34(+) cell collection yield was achieved when cells were collected after the first R-DHAP course compared with after the second course (P < .01). A peripheral blood leukocyte increase of ≥1.0 × 10(9)/L and a platelet increase of ≥20 × 10(9)/L were observed by 11 days after ASCT. In our cohort, the modified R-DHAP regimen proved safe and feasible, showed an overall response rate (complete response, complete response unconfirmed, and partial response) of 66%, and allowed efficient mobilization of CD34(+) cells for PBSC collection., (Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Introduction: The aim of this retrospective analysis was to investigate the efficacy and safety of nonpegylated liposomal doxorubicin (NPLD) as part of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) in patients with diffuse large B-cell lymphoma (DLBCL) and preexisting cardiac diseases., Patients and Methods: Twenty-five patients were evaluated, median age was 73 (range 24-85) years, 23 patients received NPLD as part of their first-line therapy. Most patients suffered from more than 1 cardiac disease and in 14 patients left ventricular ejection fraction (LVEF) was reduced. One hundred nineteen cycles of NPLD were applied with a median of 5 (range 2-8) cycles per patient. Median dose per cycle was 95 mg (50 mg/m(2))., Results: The overall response rate was 96% (44% complete remission, 52% partial remission). After a median follow-up of 23 months, 4 patients had disease relapse. Seven patients died, translating to an estimated 3-year progression-free and overall survival of 66% and 73%, respectively. Reasons for death were progressive disease or infection in 2 patients each and cardiovascular disease in 3 patients. After chemotherapy, LVEF decreased significantly in 28% and improved in 12% of patients, whereas median LVEF did not change (51% vs. 50%). No higher frequencies of decreased LVEF was observed in the group of patients with preexisting reduced LVEF. Five adverse events induced therapy termination: 2 myocardial infarctions, 2 pneumonias, and 1 reduced condition. No hand-foot-syndrome was observed., Conclusion: NPLD as a component of R-CHOP is an effective treatment in patients with DLBCL and preexisting cardiac diseases, whereas cardiac events were observed in 36% of patients in this cardiac high-risk group. However, these results need to be confirmed in a prospective randomized trial., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Waldenström's macroglobulinemia (WM) is an indolent lym phomaand is responsive to therapy regimens containing alkylating agents, purine analogs and rituximab if treatment becomes necessary. We initiated a multicenter phase II trial to determine the safety and efficacy of a regimen containing pentostatin, cyclophosphamide and rituximab (PER) in patients with WM. Between May 2005 and December 2010, 25 patients with WM were included in the study. Twenty-one patients received PER as first-line therapy. In these patients, 2-year progression-free survival was 83.6% and 2-year overall survival was 100%. Thirteen patients (52%) received R maintenance therapy. In these patients, the 2-year progression-free survival was 91.67% and 2-year overall survival was 100%. We have provided evidence that PER is a safe and effective regimen for WM. Although R maintenance therapy after PER seemed to induce a better long-term outcome, this study was not powered to address this issue.

Purpose: To study pharmacokinetics, toxicity, and efficacy of prolonged rituximab exposure in elderly patients with diffuse large B-cell lymphoma (DLBCL)., Patients and Methods: In the SMARTE-R-CHOP-14 trial, rituximab 375 mg/m(2) was administered, together with six cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone on a 14-day schedule (6×R-CHOP-14), on days -4, 0, 10, 29, 57, 99, 155, and 239. Pharmacokinetics and outcome were to be compared with those of patients who had received 6×R-CHOP-14 in combination with eight 2-week applications of rituximab in the RICOVER-60 (Rituximab With CHOP Over Age 60 Years) trial., Results: The complete response (CR)/unconfirmed CR rate was 85% in 189 evaluable patients, 90% for 90 good-prognosis patients (International Prognostic Index [IPI], 1 or 2), and 81% for 99 poor-prognosis patients (IPI, 3 to 5); 3-year event-free survival (EFS) was 71%, 75%, and 67%, respectively; and 3-year overall survival (OS) was 84%, 88%, and 80%, respectively, with no differences between men and women. The preplanned historical comparison with 306 RICOVER-60 patients (good prognosis, n = 183; poor prognosis, n = 123) revealed no outcome differences for all and good-prognosis patients; however, the longer exposure time in SMARTE-R-CHOP-14 compared with RICOVER-60 was associated with better 3-year EFS (67% v 54%) and OS (80% v 67%) in poor-prognosis patients., Conclusion: Extended rituximab exposure compared with eight 2-week applications in combination with 6×R-CHOP-14 significantly improved outcome of elderly poor-prognosis patients without increasing toxicity. To our knowledge, results obtained with the SMARTE-R-CHOP-14 rituximab schedule are the best reported for elderly patients with DLBCL to date. In the subgroup of poor-prognosis patients treated with extended rituximab exposure, the outcome seemed superior to that of a similar historical cohort of patients treated with 6×R-CHOP-14 plus 2-week rituximab, with similar toxicity. A randomized comparison of the two schedules is warranted., (© 2014 by American Society of Clinical Oncology.)

To define the role of radiotherapy and intrathecal prophylaxis in extralymphatic craniofacial involvement (ECFI) of aggressive B-cell lymphoma, we analyzed 11 consecutive German High-Grade Non-Hodgkin Lymphoma Study Group trials. ECFI occurred in 290/4155 (7.0%) patients (orbita, 31; paranasal sinuses, 93; main nasal cavity, 38; tongue, 27; remaining oral cavity, 99; salivary glands, 54). In a multivariable analysis adjusted for International Prognostic Index rituximab improved event-free and overall survival both in patients with and without ECFI. Three-year event-free (79% vs 79%; P = .842) and overall survival (86% vs 88%; P = .351) rates were similar in 145 patients receiving and 57 not receiving radiotherapy. Without rituximab, the 2-year cumulative rate of central nervous system (CNS) disease was increased in 205 ECFI patients compared with 2586 non-ECFI patients (4.2% vs 2.8%; P = .038), whereas this was not observed with rituximab (1.6% in 83 ECFI vs 3.4% in 1252 non-ECFI patients; P = .682). In 88 ECFI patients who received intrathecal prophylaxis with methotrexate, the 2-year rate of CNS disease was 4.2% compared with 2.3% in 191 patients who did not (P = .981). In conclusion, rituximab eliminates the increased risk for CNS disease in patients with ECFI. This retrospective analysis does not support intrathecal prophylaxis or radiotherapy to ECFI patients in complete remission/unconfirmed complete remission. These findings should be confirmed in a prospective study., (© 2014 by The American Society of Hematology.)

Background: The current standard treatment of patients with relapsed or refractory diffuse large cell B-Cell lymphoma (DLBCL) primarily consists of intensified salvage therapy and, if the disease is chemo-sensitive, high dose therapy followed with autologous stem cell transplantation. In the rituximab era however, this treatment approach has shown only limited benefit. In particular, patients relapsing after rituximab-containing primary treatment have an adverse prognosis, especially if this occurs within the first year after therapy or if the disease is primarily refractory. Therefore there is an ultimate need for improved salvage treatment approaches., Methods/design: The STORM study is a prospective, multicentre phase I/II study to evaluate the safety, feasibility and activity of salvage therapy consisting of the mTOR inhibitor temsirolimus added to the standard therapy rituximab and DHAP for the treatment of patients with relapsed or refractory DLBCL. The primary objective of the phase I of the trial is to establish the maximum tolerated dose (MTD) of temsirolimus in combination with rituximab and DHAP. The secondary objective is to demonstrate that stem cells can be mobilized during this regimen in patients scheduled to proceed to high dose therapy. In phase II, the previously established maximum tolerated dose of temsirolimus will be used. The primary objective is to evaluate the overall response rate (ORR) in patients with relapsed DLBCL. The secondary objective is to evaluate progression free survival (PFS), overall survival (OS) and toxicity. The study will be accompanied by an analysis of lymphoma subtypes determined by gene expression analysis (GEP)., Discussion: The STORM trial evaluates the safety, feasibility and activity of salvage therapy consisting of the mTOR inhibitor temsirolimus added to standard therapy of rituximab and DHAP for the treatment of patients with relapsed or refractory DLBCL. It also might identify predictive markers for this treatment modality., Trial Registration: ClinicalTrials.gov NCT01653067.

In this study, we investigated the quality of life (QoL) of long-term survivors with Hodgkin lymphoma who received high-dose chemotherapy (HDCT) followed by peripheral blood stem cell transplantation (PBSCT). QoL of this group was compared with QoL of patients who were treated with conventional chemotherapy and with QoL of the healthy German population. Two standardized questionnaires, the EORTC QLQ-C30 and the EQ-5D, including the visual analogue scale (VAS) were applied. A total of 98 patients were included in the study, all of them treated in our institution. Thirty-seven patients who received HDCT with PBSCT between 1986 and 2007 were compared with 61 patients treated with conventional chemotherapy and supplementary radiation between 1998 and 2009. The median follow-up for the HDCT group was 11 years. Statistical analysis with the one-sample t-test shows a reduced QoL of both groups of patients compared to the healthy population. Compared to the group of patients who received conventional chemotherapy, there is a tendency towards reduced QoL in patients with HDCT in all of the three main categories of the EORTC-QLQ-C30. However, these differences were not statistically significant, with the exception of the subcategory of dyspnoea, which was worse in the group that was treated with BCNU containing high-dose protocols. We conclude that the negative impact of both HDCT and conventional therapy on the QoL of long-term survivors with Hodgkin lymphoma should not be underestimated and should lead to the development of less toxic therapy strategies.

Background: The strategy to apply involved-field radiotherapy (IF-RT) after immunochemotherapy in patients with bulky follicular lymphoma (FL) remains controversial., Patients and Methods: To evaluate the benefit of consolidating IF-RT, we retrospectively analysed relapse patterns and survival of patients with bulky FL. All patients were treated within a multicenter prospective randomized trial on 126 patients with one, three or six cycles Rituximab and six cycles CHOP. According to the protocol, patients presenting with bulky disease were to undergo consolidating IF-RT after immunochemotherapy. Forty-two eligible patients with bulky disease were identified, of which 26 were irradiated and 16 were not, contrary to the demand of the protocol., Results: There was no significant difference between the irradiated and the non-irradiated group regarding presenting characteristics (P > 0.05). After a median follow-up of 60 months, 21 patients relapsed. In the irradiated group, relapse occurred in 12 of 26 patients. Fifty percent of relapses were located within the original bulk or within the bulk plus a new location. In the non-irradiated group, 9 of 16 patients relapsed. There was no statistically significant difference between exposure to IF-RT and the likelihood of a relapse per se (P = 0.751) or at a specific location (P = 0.66). Six-yr-PFS- (P = 1.0) and OS-rates (P = 0.68) were 52% and 80% after IF-RT and 48% and 73% without IF-RT., Conclusion: There was no difference in relapse rate, PFS and OS between patients treated with and without consolidating IF-RT. This is the first analysis of its kind conducted in the Rituximab era. However, these results are based on a relatively small cohort size and are derived from a retrospective analysis, with the limitations of such an analysis being well known.

Patients with diffuse large B-cell lymphoma (DLBCL) treated with the R-CHOP regime receive a high cumulative dose of prednisone. We used computer tomography-ascertained Hounsfield units (HU) as a surrogate parameter for bone mineral density (BMD) in three different locations of the L3 vertebral body at baseline and post-treatment. HU were measured in 50 patients with DLBCL of the previously published FLYER-trial which compared four cycles of R-CHOP + 2 × rituximab infusion to six cycles of R-CHOP in young, favorable DLBCL patients. In total, median loss was 26.8 HU in all patients over time. The median HU loss was significantly lower in the four cycles arm (21.3 HU vs. 41.3 HU, p = 0.023). In conclusion, young patients with DLBCL receiving R-CHOP have significant HU/BMD loss under treatment with R-CHOP. Patients receiving four cycles of R-CHOP had less HU/BMD loss than patients receiving six cycles. [ABSTRACT FROM AUTHOR]