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In patients with relapse of classical Hodgkin lymphoma (cHL) after autologous stem cell transplant, brentuximab vedotin and anti-PD1 treatment, the outcome is poor. To assess the efficacy of the bispecific anti-CD30/CD16A, NK-cell engaging antibody AFM13 and to select the optimal treatment schedule (arm A-C), we initiated a randomized two-stage phase II trial (NCT02321592). Due to slow recruitment, the trial was terminated after treatment of 25 patients. Treatment with AFM13 was well tolerated: only two treatment-associated serious adverse events (SAEs) were reported; all SAEs resolved completely. With an objective response rate (ORR) of 16.7% (1/5 in arm A, 1/11 in arm B, and 2/8 in arm C) and a 12-month progression-free survival (PFS) of 12.6% (95% CI 3.2-28.9), treatment efficacy of AFM13 monotherapy in all evaluable patients was modest. The continuous application schedule (arm C) might be more effective, but the visit schedule should be better aligned with patients' daily life.

Background: Hodgkin's lymphoma (HL) is a cancer of the lymphatic system, and involves the lymph nodes, spleen and other organs such as the liver, lung, bone or bone marrow, depending on the tumour stage. With cure rates of up to 90%, HL is one of the most curable cancers worldwide. Approximately 10% of people with HL will be refractory to initial treatment or will relapse; this is more common in people with advanced stage or bulky disease. Standard of care for these people is high-dose chemotherapy and autologous stem cell transplantation (ASCT), but only 55% of participants treated with high-dose chemotherapy and ASCT are free from treatment failure at three years, with an overall survival (OS) of about 80% at three years.Checkpoint inhibitors that target the interaction of the programmed death (PD)-1 immune checkpoint receptor, and its ligands PD-L1 and PD-L2, have shown remarkable activity in a wide range of malignancies. Nivolumab is an anti-(PD)-1 monoclonal antibody and currently approved by the US Food and Drug Administration (FDA) for the treatment of melanoma, non-small cell lung cancer, renal cell carcinoma and, since 2016, for classical Hodgkin's lymphoma (cHL) after treatment with ASCT and brentuximab vedotin., Objectives: To assess the benefits and harms of nivolumab in adults with HL (irrespective of stage of disease)., Search Methods: We searched CENTRAL, MEDLINE, Embase, International Pharmaceutical Abstracts, conference proceedings and six study registries from January 2000 to May 2018 for prospectively planned trials evaluating nivolumab., Selection Criteria: We included prospectively planned trials evaluating nivolumab in adults with HL. We excluded trials in which less than 80% of participants had HL, unless the trial authors provided the subgroup data for these participants in the publication or after we contacted the trial authors., Data Collection and Analysis: Two review authors independently extracted data and assessed potential risk of bias. We used the software RobotReviewer to extract data and compared results with our findings. As we did not identify any randomised controlled trials (RCTs) or non-RCTs, we did not meta-analyse data., Main Results: Our search found 782 potentially relevant references. From these, we included three trials without a control group, with 283 participants. In addition, we identified 14 ongoing trials evaluating nivolumab, of which two are randomised. Risk of bias of the three included studies was moderate to high. All of the participants were in relapsed stage, most of them were heavily pretreated and had received at least two previous treatments, most of them had also undergone ASCT. As we did not identify any RCTs, we could not use the software RobotReviewer to assess risk of bias. The software identified correctly that one study was not an RCT and did not extract any trial data, but extracted characteristics of the other two studies (although also not RCTs) in a sufficient way.Two studies with 260 participants evaluated OS. After six months, OS was 100% in one study and median OS (the timepoint when only 50% of participants were alive) was not reached in the other trial after a median follow-up of 18 months (interquartile range (IQR) 15 to 22 months) (very low certainty evidence, due to observational trial design, heterogenous patient population in terms of pretreatments and various follow-up times (downgrading by 1 point)). In one study, one out of three cohorts reported quality of life. It was unclear whether there was an effect on quality of life as only a subset of participants filled out the follow-up questionnaire (very low certainty evidence). Three trials (283 participants) evaluated progression-free survival (PFS) (very low certainty evidence). Six-month PFS ranged between 60% and 86%, and median PFS ranged between 12 and 18 months. All three trials (283 participants) reported complete response rates, ranging from 12% to 29%, depending on inclusion criteria and participants' previous treatments (very low certainty evidence).One trial (243 participants) reported drug-related grade 3 or 4 adverse events (AEs) only after a median follow-up of 18 months (IQR 15 to 22 months); these were fatigue (23%), diarrhoea (15%), infusion reactions (14%) and rash (12%). The other two trials (40 participants) reported 23% to 52% grade 3 or 4 AEs after six months' follow-up (very low certainty evidence). Only one trial (243 participants) reported drug-related serious AEs; 2% of participants developed infusion reactions and 1% pneumonitis (very low certainty evidence).None of the studies reported treatment-related mortality., Authors' Conclusions: To date, data on OS, quality of life, PFS, response rate, or short- and long-term AEs are available from small uncontrolled trials only. The three trials included heavily pretreated participants, which had previously undergone regimens of BV or ASCT. For these participants, median OS was not reached after follow-up times of at least 16 months (more than 50% of participants with a limited life expectancy were alive at this timepoint). Only one cohort out of three only reported quality of life, with limited follow-up data so that meaningful conclusions were not possible. Serious adverse events occurred rarely. Currently, data are too sparse to make a clear statement on nivolumab for people with relapsed or refractory HL except for heavily pretreated people, which had previously undergone regimens of BV or ASCT. When interpreting these results, it is important to consider that proper RCTs should confirm these findings.As there are 14 ongoing trials evaluating nivolumab, of which two are RCTs, it is possible that an update of this review will be published in the near future and that this update will show different results to those reported here.

Introduction: Hodgkin lymphoma (HL) is a B-cell-derived malignancy mostly affecting young adults. More than 80% of patients are cured after stage-adapted first-line treatment with chemotherapy and/or radiotherapy. About 50% of patients with disease recurrence achieve long-term remission with second-line treatment consisting of high-dose chemotherapy and autologous stem cell transplantation. However, HL treatment is often associated with acute toxicity and in part life-threatening late effects. Implementing targeted drugs may reduce toxicity and potentially further optimize efficacy. In recent years, the CD30-directed antibody-drug conjugate brentuximab vedotin (BV) and anti-PD-1 antibodies, nivolumab and pembrolizumab, underwent extensive evaluation in HL. They have exhibited encouraging single agent activity and a favorable toxicity profile in patients with multiple relapses. Therefore, they are currently under investigation in different additional indications. Areas covered: This article gives an overview over clinical trials evaluating targeted drugs either as single agent or as part of combination therapies in HL patients. Expert commentary: A multitude of targeted drugs are investigated in HL. Promising data have particularly emerged from studies with BV and anti-PD-1 antibodies. However, mature data needed for final conclusions are still pending.

Radiotherapy is an established local treatment in patients with various malignancies. Systemic responses following local irradiation have been described as abscopal effects. Modern cancer immunotherapy with immune checkpoint inhibitors has shown impressive response rates and prolongation of survival even in heavily pretreated patients with advanced solid malignancies and lymphomas. Radiotherapy has been shown to modulate immune response, and its application in the context of immune checkpoint inhibition has recently evolved into an active field of research. Prospective studies investigating combination treatment are currently ongoing and will answer questions as to the optimal schedule and radiation dosing. This short review focuses on the immunomodulatory role of radiotherapy and the use of immune checkpoint inhibition with a special focus on Hodgkin lymphoma.

Physiological immune checkpoint pathways are important to regulate self-tolerance, limit immune reactions, and moderate autoimmunity. Various cancers are commonly exploiting these mechanisms to evade the host immune system by restraining a durable, efficient anti-tumor immune response. Immune checkpoints include, but are not limited to, the programmed death 1 (PD1) and the cytotoxic T-lymphocyte-associated protein-4 (CTLA4) axis, which are both druggable by monoclonal antibodies referred to as checkpoint inhibitors (CIs). To date, the anti-PD1 antibodies nivolumab and pembrolizumab are approved for relapsed or refractory classical Hodgkin lymphoma (cHL) due to high response rates with a favorable yet distinct safety profile, and other agents are under investigation. This review summarizes the available preclinical and clinical data including the toxicity and efficacy of different CIs in cHL. It also provides future perspectives based on ongoing clinical trials, potentially synergistic combinatory approaches, and their fit in the therapeutic landscape in cHL., (© 2017 S. Karger GmbH, Freiburg.)

To evade elimination by the host immune system, tumor cells commonly exploit physiological immune checkpoint pathways, restraining efficient anti-tumor immune cell function. Growing understanding of the complex dialog between tumor cells and their microenvironment contributed to the development of immune checkpoint inhibitors. This innovative strategy has demonstrated paradigm-shifting clinical activity in various malignancies. Antibodies targeting programmed death 1 and cytotoxic T-lymphocyte-associated protein-4 are also being investigated in lymphoid malignancies with varying levels of activity and a favorable toxicity profile. To date, evaluated only in the setting of relapsed or refractory disease, anti-programmed death 1 antibodies such as nivolumab and pembrolizumab show encouraging response rates particularly in classical Hodgkin lymphoma but also in follicular lymphoma and diffuse-large B-cell lymphoma. As the first immune checkpoint inhibitor in lymphoma, nivolumab was approved for the treatment of relapsed or refractory classical Hodgkin lymphoma by the Food and Drug Administration in May 2016. In this review, we assess the role of the pathways involved and potential rationale of checkpoint inhibition in various lymphoid malignancies. In addition to data from current clinical trials, immune-related side effects, potential limitations and future perspectives including promising combinatory approaches with immune checkpoint inhibition are discussed., (Copyright© Ferrata Storti Foundation.)

Background: Independent central review of clinical imaging remains the standard for oncology clinical trials with registration potential. A limited independent central review strategy has been proposed for solid tumor trials based on concordance between central and local evaluation of response. Concordance between independent central review and local evaluation of response in hematological malignancies is not known., Methods: We retrospectively evaluated concordance between prospectively performed central and local assessments of response using the Revised Response Criteria for Malignant Lymphoma across two international, open-label, single-arm, registration studies of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma (N = 102) or systemic anaplastic large-cell lymphoma (N = 58)., Results: Overall objective response rates were similar between assessors for both the trial in Hodgkin lymphoma (75% independent central review, 72% local evaluation) and the trial in anaplastic large-cell lymphoma (86% independent central review, 83% local evaluation). Patient-specific objective response concordance was also substantial (Hodgkin lymphoma: kappa = 0.68; anaplastic large-cell lymphoma: kappa = 0.74). Median progression-free survival was similar between assessors for patients with anaplastic large-cell lymphoma (14.3 months by independent central review (95% confidence interval: 6.9, -); 14.5 months by local evaluation (95% confidence interval: 9.4, -)), but longer by local evaluation in patients with Hodgkin lymphoma (5.8 months by independent central review (95% confidence interval: 5.0, 9.0); 9.0 months by local evaluation (95% confidence interval: 7.1, 12.0)). Median duration of response was longer by local evaluation in both malignancies, which was primarily attributable to earlier computed tomography and positron emission tomography-based scoring of progression by independent central review., Conclusion: A limited independent review audit strategy for clinical trials of some lymphomas appears feasible and practical based on substantial concordance in assessments of overall objective response by central and local evaluation in two international, prospective, registration trials in lymphoma. Some variability between assessors in the time-to-event endpoints was observed, which appeared attributable to earlier assignments of progression by independent central review compared with local evaluation., (© The Author(s) 2016.)

Background: Malignant cells of classical Hodgkin's lymphoma are characterised by genetic alterations at the 9p24.1 locus, leading to overexpression of PD-1 ligands and evasion of immune surveillance. In a phase 1b study, nivolumab, a PD-1-blocking antibody, produced a high response in patients with relapsed and refractory classical Hodgkin's lymphoma, with an acceptable safety profile. We aimed to assess the clinical benefit and safety of nivolumab monotherapy in patients with classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin., Methods: In this ongoing, single-arm phase 2 study, adult patients (aged ≥18 years) with recurrent classical Hodgkin's lymphoma who had failed to respond to autologous stem-cell transplantation and had either relapsed after or failed to respond to brentuximab vedotin, and with an Eastern Cooperative Oncology Group performance status score of 0 or 1, were enrolled from 34 hospitals and academic centres across Europe and North America. Patients were given nivolumab intravenously over 60 min at 3 mg/kg every 2 weeks until progression, death, unacceptable toxicity, or withdrawal from study. The primary endpoint was objective response following a prespecified minimum follow-up period of 6 months, assessed by an independent radiological review committee (IRRC). All patients who received at least one dose of nivolumab were included in the primary and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT02181738., Findings: Among 80 treated patients recruited between Aug 26, 2014, and Feb 20, 2015, the median number of previous therapies was four (IQR 4-7). At a median follow-up of 8·9 months (IQR 7·8-9·9), 53 (66·3%, 95% CI 54·8-76·4) of 80 patients achieved an IRRC-assessed objective response. The most common drug-related adverse events (those that occurred in ≥15% of patients) included fatigue (20 [25%] patients), infusion-related reaction (16 [20%]), and rash (13 [16%]). The most common drug-related grade 3 or 4 adverse events were neutropenia (four [5%] patients) and increased lipase concentrations (four [5%]). The most common serious adverse event (any grade) was pyrexia (three [4%] patients). Three patients died during the study; none of these deaths were judged to be treatment related., Interpretation: Nivolumab resulted in frequent responses with an acceptable safety profile in patients with classical Hodgkin's lymphoma who progressed after autologous stem-cell transplantation and brentuximab vedotin. Therefore, nivolumab might be a new treatment option for a patient population with a high unmet need. Ongoing follow-up will help to assess the durability of response., Funding: Bristol-Myers Squibb., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: This phase I/II study investigated JNJ-40346527, a selective inhibitor of the colony-stimulating factor-1 receptor (CSF-1R) tyrosine kinase as treatment for relapsed or refractory classical Hodgkin lymphoma (cHL)., Experimental Design: Patients ≥18 years with histopathologically confirmed initial diagnosis of cHL that had relapsed or was refractory after ≥1 appropriate therapies were assigned to sequential cohorts of oral daily doses of JNJ-40346527 (150, 300, 450, 600 mg every day, and 150 mg twice a day). For the dose-escalation phase, the primary endpoint was to establish the recommended phase II dose. Secondary endpoints included safety, pharmacokinetics, and pharmacodynamics., Results: Twenty-one patients [(150 mg: 3; 300 mg: 5; 450 mg: 3, 600 mg: 3) every day, and 150 mg twice a day: 7] were enrolled, 10 men, median age 40 (range, 19-75) years, median number of prior systemic therapies 6 (range, 3-14). No dose-limiting toxicities were observed; maximum-tolerated dose was not established. Best overall response was complete remission in 1 patient (duration, +352 days) and stable disease in 11 patients: (duration, 1.5-8 months). Median number of cycles: 4 (range, 1-16). Most common (≥20% patients) possibly drug-related adverse events (per investigator assessment) were nausea (n = 6), headache, and pyrexia (n = 5 each). JNJ-40346527 exposure increased in near dose-proportional manner over a dose range of 150 to 450 mg every day, but plateaued at 600 mg every day. Target engagement was confirmed (>80% inhibition of CSF-1R phosphorylation, 4 hours after dosing)., Conclusions: JNJ-40346527, a selective inhibitor of CSF-1R was well tolerated, and preliminary antitumor results suggested limited activity in monotherapy for the treatment of cHL., (©2015 American Association for Cancer Research.)

Hodgkin lymphoma (HL) is a B cell-derived lymphoid malignancy most often affecting young adults. More than 80% of HL patients achieve long-term remission after appropriate first-line treatment consisting of multiagent chemotherapy and/or radiotherapy (RT). In addition, approximately 50% of patients with disease recurrence remain relapse-free after salvage therapy with high-dose chemotherapy followed by autologous stem cell transplantation (ASCT). However, patients with multiple relapses are mostly in a palliative situation, and novel drugs for this patient group are needed. Furthermore, novel less toxic but equally effective first-line and second-line approaches are required as therapy-related late sequelae represent a relevant cause of morbidity and mortality in HL survivors. Several antibodies and antibody-drug conjugates (ADC) targeting CD30 and CD20 have recently been evaluated in HL. Excellent response rates in heavily pretreated patients were observed with the ADC brentuximab vedotin directed against CD30. Thus, ongoing trials investigate brentuximab vedotin in different additional indications. One example is the first-line treatment of advanced HL where the drug is currently being evaluated in combination with variants of the first-line protocols ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) and escalated BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone). Anti-CD20 antibodies given either as single agent or in combination with conventional chemotherapy have also been investigated and still undergo investigation in prospective studies including HL patients. This article reviews the available data on treatment approaches including antibodies and ADC in HL patients., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Despite advancements in the treatment of non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL), patients continue to relapse and thus a need for new targeted therapies remains. The CD40 receptor is highly expressed on neoplastic B cells and activation leads to enhanced proliferation and survival. Lucatumumab (HCD122) is a fully human antagonistic CD40 monoclonal antibody. A phase IA/II study was designed to determine the maximum tolerated dose (MTD) and activity of lucatumumab in patients with relapsed/refractory lymphoma. Determination of the MTD was the primary objective of the phase IA dose escalation portion and clinical response was the primary objective of the phase II dose expansion portion. Patients received escalating doses of lucatumumab administered intravenously once weekly for 4 weeks of an 8-week cycle. MTD was determined at 4 mg/kg of lucatumumab. A total of 111 patients with NHL (n = 74) and HL (n = 37) were enrolled. Responses were observed across various lymphoma subtypes. The overall response rate by computed tomography among patients with follicular lymphoma (FL) and marginal zone lymphoma of mucosa-associated lymphatic tissue (MZL/MALT) was 33·3% and 42·9%, respectively. Lucatumumab demonstrates modest activity in relapsed/refractory patients with advanced lymphoma, suggesting that targeting of CD40 warrants further investigation., (© 2013 John Wiley & Sons Ltd.)

Only limited data are available on the role of brentuximab vedotin (SGN-35) in transplant-naive relapsed or refractory patients with Hodgkin lymphoma (HL). We thus retrospectively analyzed 14 patients with primary refractory or relapsed HL who were treated with brentuximab vedotin as single agent in a named patient program, who had not received prior high-dose chemotherapy (HDCT) and autologous stem cell transplant (ASCT) due to refractory disease (n = 9), comorbidity (n = 4) and unknown reasons (n = 1). Brentuximab vedotin resulted in an overall response rate of 71% (10/14) with five complete responses (CRs). Five of those patients with refractory disease and four patients with relevant comorbidity responded. Consolidating ASCT (n = 4) or allogeneic SCT (n = 1) was performed in five patients. Median progression-free survival (PFS) was 9 months and the median overall survival (OS) was not reached. These data indicate the therapeutic efficacy of brentuximab vedotin in chemotherapy-refractory transplant-naive patients with HL.

Purpose of Review: Despite the advances in the treatment of Hodgkin Lymphoma, patients with refractory disease still have a poor prognosis. Hodgkin Lymphoma can be refractory at first diagnosis or might become refractory later in the course of treatment. Both situations represent a therapeutic challenge., Recent Findings: Intensified chemotherapy with BEACOPP escalated has been evaluated in early unfavourable and advanced Hodgkin Lymphoma and led to an improved tumour control and reduced rates of refractory disease. Furthermore, there is growing evidence for the role of tandem autologous transplant in breaking refractory disease. For patients relapsing after autologous transplant, more recent analyses have reported outcome and defined risk factors. The antibody drug conjugate brentuximab vedotin is a new, highly effective therapeutic option for these patients. Dose-reduced allogeneic transplant is a therapeutic alternative for patients relapsing after autologous transplant, but induction of a remission is the prerequisite for a successful allogeneic transplant. Brentuximab vedotin has been evaluated as a bridge to allogeneic transplant for patients refractory to conventional treatment., Summary: Recent therapeutic advances have improved the prognosis of Hodgkin Lymphoma by prevention or successful treatment of refractory disease. The use of new drugs such as brentuximab vedotin will hopefully further increase the cure rates.

Background: Hodgkin lymphoma (HL) is one of the most common malignancies in young adults and has become curable for the majority of patients, even in advanced stage. After first-line therapy, 15% to 20% do not respond to treatment and relapse. For those patients, high-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) is a frequently used therapy option., Objectives: To find the best available treatment with HDCT followed by ASCT for patients with relapsed or refractory HL after first-line treatment., Search Methods: We searched the Central Register of Controlled Trials (CENTRAL), MEDLINE, and relevant conference proceedings up to January 2013 for randomised controlled trials (RCTs). We also contacted experts for unpublished data., Selection Criteria: We included RCTs comparing HDCT followed by ASCT versus conventional chemotherapy without ASCT, or versus additional sequential HDCT (SHDCT) followed by ASCT. We also included RCTs with different HDCT regimens before ASCT in patients with relapsed or primary refractory HL after any first-line therapy., Data Collection and Analysis: Two review authors (MR, NS) independently selected relevant studies, extracted data and assessed trial quality. We used hazard ratios (HR) for overall survival (OS) and progression-free survival (PFS), and we calculated risk ratios (RR) for the other outcomes. We presented all measures with 95% confidence intervals (CI).We assessed the quality of evidence using GRADE methods., Main Results: Our search resulted in 1663 potentially relevant references, of which we included three trials with 14 publications, assessing 398 patients. Overall, we judged the quality of the trials as moderate. The trials were all reported as randomised controlled and open-label. We included two RCTs assessing the effect of HDCT followed by ASCT compared with conventional chemotherapy in a meta-analysis. The number of studies was very low, therefore, the quantification of heterogeneity was not reliable. We included one further RCT (one assessing additional SHDCT followed by ASCT versus HDCT followed by ASCT), which was not compatible with our meta-analysis. For this trial, we performed further analyses.Two trials showed a non-statistically significant trend that HDCT followed by ASCT compared to conventional chemotherapy increases OS (HR 0.67; 95% CI 0.41 to 1.07; P value = 0.10, 157 patients, moderate quality of evidence). However, the increase in PFS was statistically significant for people treated with HDCT followed by ASCT (HR 0.55; 95% CI 0.35 to 0.86; P value = 0.009, 157 patients, moderate quality of evidence). Adverse events were reported in one trial only and did not differ statistically significant between the treatment arms. We were not able to draw conclusions regarding treatment-related mortality (TRM) because of insufficient evidence (RR 0.61; 95% CI 0.16 to 2.22; P value = 0.45, 157 patients, moderate quality of evidence).For the second comparison, SHDCT plus HDCT followed by ASCT versus HDCT followed by ASCT there was no difference between the treatment arms regarding OS (HR 0.93; 95% CI 0.5 to 1.74; P value = 0.816, three-year OS: 80% SHDCT versus 87% HDCT, 241 patients), or PFS (HR 0.87; 95% CI 0.58 to 1.30; P value = 0.505, 241 patients). Seven patients died in the SHDCT arm and one in the HDCT arm due to increased toxicity of the treatment. Adverse events were increased with SHDCT plus HDCT followed by ASCT after two cycles of dexamethasone plus high-dose cytarabine plus cisplatin (DHAP) (88% SHDCT versus 45% HDCT, 223 patients, P value < 0.00001). Overall, more statistically significant World Health Organization (WHO) grade 3/4 infections occurred with SHDCT (48% SHDCT versus 33% HDCT; P value = 0.002, 223 patients)., Authors' Conclusions: The currently available evidence suggests a PFS benefit for patients with relapsed or refractory HL after first-line therapy, who are treated with HDCT followed by ASCT compared to patients treated with conventional chemotherapy. In addition, data showes a positive trend regarding OS, but more trials are needed to detect a significant effect.Intensifying the HDCT regime before HDCT followed by ASCT did not show a difference as compared to HDCT followed by ASCT, but was associated with increased adverse events.

Background: Chronic lymphocytic leukaemia (CLL) accounts for 25% of all leukaemias and is the most common lymphoid malignancy in western countries. Standard treatments include mono- or polychemotherapies, usually combined with monoclonal antibodies such as rituximab or alemtuzumab. However, the impact of these agents remains unclear, as there are hints for increased risk of severe infections., Objectives: The objectives of this review are to provide an evidence-based answer regarding the clinical benefits and harms of monoclonal anti-CD20 antibodies (such as rituximab, ofatumumab, GA101) compared to no further therapy or to other anti-leukaemic therapies in patients with CLL, irrespective of disease status., Search Methods: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 12, 2011), MEDLINE (from January 1990 to 4 January 2012), and EMBASE (from 1990 to 20 March 2009) as well as conference proceedings (American Society of Hematology, American Society of Clinical Oncology, European Hematology Association and European Society of Medical Oncology) for randomised controlled trials (RCTs)., Selection Criteria: We included RCTs examining monoclonal anti-CD20 antibodies compared to no further therapy or to anti-leukaemic therapy such as chemotherapy or monoclonal antibodies in patients with newly diagnosed or relapsed CLL., Data Collection and Analysis: We used hazard ratios (HR) as effect measures for overall survival (OS), progression-free survival (PFS) and time to next treatment, and risk ratios (RR) for response rates, treatment-related mortality (TRM) and adverse events (AEs). Two review authors independently extracted data and assessed quality of trials., Main Results: We screened a total of 1150 records. Seven RCTs involving 1763 patients were identified, but only five could be included in the two separate meta-analyses we performed. We judged the overall the quality of these trials as moderate to high. All trials were randomised and open-label studies. However, two trials were published as abstracts only, therefore we were unable to assess the potential risk of bias for these trials in detail.Three RCTs (N = 1421) assessed the efficacy of monoclonal anti-CD20 antibodies (i.e. rituximab) plus chemotherapy compared to chemotherapy alone. The meta-analyses showed a statistically significant OS (HR 0.78, 95% confidence interval (CI) 0.62 to 0.98, P = 0.03, the number needed to treat for an additional beneficial effect (NNTB) was 12) and PFS (HR 0.64, 95% CI 0.55 to 0.74, P < 0.00001) advantage for patients receiving rituximab. In the rituximab-arm occurred more AEs, World Health Organization (WHO) grade 3 or 4 (3 trials, N = 1398, RR 1.15, 95% CI 1.08 to 1.23, P < 0.0001; the number needed to harm for an additional harmful outcome (NNTH) was 9), but that did not lead to a statistically significant difference regarding TRM (3 trials, N = 1415, RR 1.19, 95% CI 0.70 to 2.01, P = 0.52).Two trials (N = 177) evaluated rituximab versus alemtuzumab. Neither study reported OS or PFS. There was no statistically significant difference between arms regarding complete response rate (CRR) (RR 1.21, 95% CI 0.94 to 1.58, P = 0.14) or TRM (RR 0.31, 95% CI 0.06 to 1.51, P = 0.15). However, the CLL2007FMP trial was stopped early owing to an increase in mortality in the alemtuzumab arm. More serious AEs occurred in this arm (43% with alemtuzumab versus 22% with rituximab; P = 0.006).Two trials assessed different dosages or time schedules of monoclonal anti-CD20 antibodies. One trial (N = 104) evaluated two different rituximab schedules (concurrent arm: fludarabine plus rituximab (Flu-R) plus rituximab consolidation versus sequential arm: fludarabine alone plus rituximab consolidation). The comparison of the concurrent versus sequential regimen of rituximab showed a statistically significant difference of the CRR with 33% in the concurrent-arm and 15% in the sequential-arm (P = 0.04), that did not lead to statistically significant differences regarding OS (HR 1.14, 95% CI 0.20 to 6.65, P = 0.30) or PFS (HR 0.96, 95% CI 0.43 to 2.15, P = 0.11). Furthermore results showed no differences in occurring AEs, except for neutropenia, which was more often observed in patients of the concurrent arm. The other trial (N = 61) investigated two different dosages (500 mg and 1000 mg) of ofatumumab in addition to FluC. The arm investigating ofatumumab did not assess OS and a median PFS had not been reached owing to the short median follow-up of eight months. It showed no statistically significant differences between arms regarding CRR (32% in the FCO500 arm versus 50% in the FCO1000 arm; P = 0.10) or AEs (anaemia, neutropenia, thrombocytopenia)., Authors' Conclusions: This meta-analysis showed that patients receiving chemotherapy plus rituximab benefit in terms of OS as well as PFS compared to those with chemotherapy alone. Therefore, it supports the recommendation of rituximab in combination with FluC as an option for the first-line treatment as well as for the people with relapsed or refractory CLL. The available evidence regarding the other assessed comparisons was not sufficient to deduct final conclusions.

Background: Several clinical studies have compared single with tandem (also called double) autologous stem cell transplantation (ASCT) as first-line treatment in patients with symptomatic multiple myeloma (MM), one of the leading indications for ASCT worldwide., Objectives: The present Cochrane Review compares tandem autologous stem cell transplantation (TASCT) with single autologous stem cell transplantation (SASCT) as first-line treatment in patients with symptomatic MM with respect to overall survival (OS), event-free survival (EFS), quality of life (QoL) and treatment- or transplantation-related mortality., Search Methods: We systematically identified controlled trials published between January 1995 and May 2011 in two bibliographic databases (MEDLINE and CENTRAL) and in clinical trial registries., Selection Criteria: One researcher screened references for controlled trials to determine eligibility for the systematic review (SR) according to pre-specified inclusion and exclusion criteria, reflecting characteristics of disease and the interventions. We required a minimal set of details to be reported for observational studies for the studies to be included., Data Collection and Analysis: We critically evaluated eligible trials with respect to quality of design and actual performance. One researcher extracted individual trial results, which were checked by another researcher. We recapitulated the results of the individual trials in a standardised way for the SR in order to allow a systematic assessment of potential sources of bias., Main Results: Overall, we identified 14 controlled studies. One registered randomised controlled trial (RCT) is still recruiting patients at the time of this review and no clinical results have been published. Two registered RCTs have remained unpublished despite their termination. Publications on one RCT had been retracted. We excluded five observational studies since neither patients nor treatment regimens were sufficiently characterised to allow an assessment of potential confounding by indication. We conducted a SR of study designs, definition of endpoints, treatment regimens and baseline characteristics of patients in the five included RCTs (two full-text publications, three conference presentations) enrolling1506 patients in total. Because we identified substantial clinical and methodological heterogeneity, we refrained from conducting a formal meta-analysis.While we included only previously untreated, symptomatic patients with MM the treatment regimens differed notably with respect to acute toxicity, between trials and also between study arms. Compared to state of the art treatment standards, the treatment regimens applied in all trials have to be considered as below standard from a contemporary perspective in at least one component.Three trials were likely to have the potential of being highly biased while two RCTs had a moderate potential for bias. The observed treatment effects in the set of included trials may have been influenced by a steep decrease in compliance with the second ASCT and the concomitant selection of patients. In addition, OS data were confounded by the treatment subsequent to first-line therapy.OS was statistically significantly improved in one trial only. While EFS was prolonged in four of the five trials, the median prolongation ranged between three to 12 months, with an uncertain direction of bias in the individual trials. QoL was not reported in any study. Results concerning treatment- or transplantation-related mortality could not be adequately assessed due to substantial differences in definitions between trials and low reporting quality., Authors' Conclusions: We did not consider any study to be sufficiently informative for contemporary treatment decisions concerning the question single versus tandem ASCT in view of inherent biases. In addition, none of the trials integrated the so-called "novel agents" which are now considered standard treatment for MM. To improve the quality of future studies, sample size calculations should consider the potentially steep decrease in compliance with the second ASCT. Reporting of results of treatment- or transplantation-related mortality should clearly specify the type and number of events (the numerator) in a well-defined population (the denominator).

The CD30-targeting Ab-drug conjugate brentuximab vedotin (SGN-35) was recently approved for the treatment of relapsed Hodgkin lymphoma and anaplastic large-cell lymphoma by the Food and Drug Administration. In the present study, we report the experience of the German Hodgkin Study Group with brentuximab vedotin as single agent in 45 patients with refractory or relapsed CD30(+) Hodgkin lymphoma who were treated either in a named patient program (n = 34) or in the context of a safety study associated with the registration program of this drug. In these very heavily pretreated patients, an objective response rate of 60%, including 22% complete remissions, could be documented. The median duration of response was 8 months. This retrospective analysis supports the previously reported excellent therapeutic efficacy of brentuximab vedotin in heavily pretreated CD30(+) malignancies.

Purpose: Hodgkin's lymphoma (HL) has no standard of care for patients who are relapsed or refractory to autologous stem-cell transplantation (ASCT). This phase II study examined safety and activity of panobinostat in this population., Patients and Methods: Panobinostat 40 mg was administered orally three times per week. The primary end point was objective response rate (ORR) based on investigator assessment of radiologic imaging. Secondary end points included ORR by independent central review, time to response (TTR), duration of response (DOR), progression-free survival (PFS), overall survival, and safety. Exploratory biomarker analyses were performed., Results: The 129 treated patients (median age, 32 years; range, 18 to 75 years) were heavily pretreated with a median of four (range, two to seven) prior systemic regimens, and 41% did not respond to the regimen immediately preceding panobinostat. Tumor reductions occurred in 96 patients (74%). Objective response was achieved by 35 patients (27%), including 30 (23%) partial responses and five (4%) complete responses. The median TTR was 2.3 months, median DOR was 6.9 months, and median PFS was 6.1 months. The estimated 1-year overall survival rate was 78%. Common nonhematologic adverse events (AEs)-diarrhea, nausea, vomiting, and fatigue-were generally grade 1 and 2. Most common grade 3 and 4 hematologic AEs-thrombocytopenia, anemia, and neutropenia-were manageable. Early reductions in thymus and activation-regulated chemokine were observed in patients achieving complete or partial response., Conclusion: In the largest, prospective, multicenter, international trial conducted in heavily pretreated patients with HL who relapsed or were refractory to ASCT, panobinostat monotherapy demonstrated antitumor activity, resulting in durable responses.

Purpose: Brentuximab vedotin is an antibody-drug conjugate (ADC) that selectively delivers monomethyl auristatin E, an antimicrotubule agent, into CD30-expressing cells. In phase I studies, brentuximab vedotin demonstrated significant activity with a favorable safety profile in patients with relapsed or refractory CD30-positive lymphomas., Patients and Methods: In this multinational, open-label, phase II study, the efficacy and safety of brentuximab vedotin were evaluated in patients with relapsed or refractory Hodgkin's lymphoma (HL) after autologous stem-cell transplantation (auto-SCT). Patients had histologically documented CD30-positive HL by central pathology review. A total of 102 patients were treated with brentuximab vedotin 1.8 mg/kg by intravenous infusion every 3 weeks. In the absence of disease progression or prohibitive toxicity, patients received a maximum of 16 cycles. The primary end point was the overall objective response rate (ORR) determined by an independent radiology review facility., Results: The ORR was 75% with complete remission (CR) in 34% of patients. The median progression-free survival time for all patients was 5.6 months, and the median duration of response for those in CR was 20.5 months. After a median observation time of more than 1.5 years, 31 patients were alive and free of documented progressive disease. The most common treatment-related adverse events were peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea., Conclusion: The ADC brentuximab vedotin was associated with manageable toxicity and induced objective responses in 75% of patients with relapsed or refractory HL after auto-SCT. Durable CRs approaching 2 years were observed, supporting study in earlier lines of therapy.

Hodgkin lymphoma (HL) has become one of the most easily curable malignancies in oncology. More than 80% of patients can be cured with risk-adapted treatment that includes chemotherapy and radiotherapy. This progress is mainly due to the development of multi-agent chemotherapy and improved radiation techniques; however, severe, life-threatening treatment-related side effects occur, which include organ toxicity and secondary malignancies. Thus, the treatment approaches must be carefully balanced between optimal disease control and the risk of long-term sequelae. Although this article is meant to provide an overview of the current treatment approaches for patients with HL, in many instances conflicting results from various clinical trials are available, and a personal judgment is inevitable. Here, we focus on evidence from large clinical trials with solid conclusions.

Background: Chronic lymphocytic leukaemia (CLL) accounts for 25% of all leukaemias and is the most common lymphoid malignancy in Western countries. Standard treatment  includes mono- or poly-chemotherapies. Nowadays, monoclonal antibodies are added, especially alemtuzumab and rituximab. However, the impact of these agents remains unclear, as there are hints of an increased risk of severe infections., Objectives: To assess alemtuzumab compared with no further therapy, or with other anti-leukaemic therapy in patients with CLL., Search Methods: We searched CENTRAL and MEDLINE (from January 1985 to November 2011), and EMBASE (from 1990 to 2009) as well as conference proceedings for randomised controlled trials (RCTs). Two review authors (KB, NS) independently screened search results., Selection Criteria: We included RCTs comparing alemtuzumab with no further therapy or comparing alemtuzumab with anti-leukaemic therapy such as chemotherapy or monoclonal antibodies in patients with histologically-confirmed B-cell CLL. Both pretreated and chemotherapy-naive patients were included., Data Collection and Analysis: We used hazard ratios (HR) as an effect measure for overall survival (OS) and progression-free survival (PFS) and risk ratios (RRs) for response rates, treatment-related mortality (TRM) and adverse events. Two review authors independently extracted data and assessed the quality of trials., Main Results: Our search strategies led to 1542 potentially relevant references. Of these, we included five RCTs involving 845 patients. Overall, we judged the quality of the five trials as moderate. All trials were reported as randomised and open-label studies. However, two trials were published as abstracts only, therefore, we were unable to assess the potential risk of bias for these trials in detail. Because of the small number of studies in each analysis (two), the quantification of heterogeneity was not reliable.Two trials (N = 356) assessed the efficacy of alemtuzumab compared with no further therapy. One trial (N = 335), reported a statistically significant OS advantage for all patients receiving alemtuzumab (HR 0.65 (95% confidence interval (CI) 0.45 to 0.94; P = 0.021). However, no improvement was seen for the subgroup of patients in Rai stage I or II (HR 1.07; 95% CI 0.62 to 1.84; P = 0.82). In both trials, the complete response rate (CRR) (RR 2.61; 95% CI 1.26 to 5.42; P = 0.01) and PFS (HR 0.58; 95% CI 0.44 to 0.76; P < 0.0001) were statistically significantly increased under therapy with alemtuzumab. The potential heterogeneity seen in the forest plot could be due to the different study designs: One trial evaluated alemtuzumab additional to fludarabine as relapse therapy; the other trial examined alemtuzumab compared with no further therapy for consolidation after first remission.There was no statistically significant difference for TRM between both arms (RR 0.57; 95% CI 0.17 to 1.90; P = 0.36). A statistically significant higher rate of CMV reactivation (RR 10.52; 95% CI 1.42 to 77.68; P = 0.02) and infections (RR 1.32; 95% CI 1.01 to 1.74; P = 0.04) occurred in patients receiving alemtuzumab. Seven severe infections (64%) in the alemtuzumab arm in the GCLLSG CLL4B study led to premature closure.Two trials (N = 177), evaluated alemtuzumab versus rituximab. Neither study reported OS or PFS. We could not detect a statistically significant difference for CRR (RR 0.85; 95% CI 0.67 to 1.08; P = 0.18) or TRM (RR 3.20; 95% CI 0.66 to 15.50; P = 0.15) between both arms. However, the CLL2007FMP trial was stopped early due to an increase in mortality in the alemtuzumab arm. More serious adverse events occurred in this arm (43% versus 22% (rituximab), P = 0.006).One trial (N = 297), assessed the efficacy of alemtuzumab compared with chemotherapy (chlorambucil). For this trial, no HR is reported for OS. Median survival has not yet been reached, 84% of patients were alive in each arm at the data cut-off or at the last follow-up date (24.6 months). The TRM between arms shows no statistical significant difference (0.6% versus 2.0%; P = 0.34). Alemtuzumab statistically significantly improves PFS (HR 0.58; 95% CI 0.43 to 0.77; P = 0.0001), time to next treatment (23.3 compared with 14.7 months; P = 0.0001), ORR (83.2% versus 55.4%; P < 0.0001), CRR (24.2% versus 2.0%; P < 0.0001), and minimal residual disease rate (7.4% versus 0%; P = 0.0008) compared with chlorambucil. Statistically, significantly more asymptomatic (51.7% versus 7.4%) and symptomatic cytomegalovirus (CMV) infections (15.4% versus 0%) occurred in the patients treated with alemtuzumab., Authors' Conclusions: In summary, the currently available evidence suggests an OS, CRR and PFS benefit for alemtuzumab compared with no further therapy, but an increased risk for infections in general, CMV infections and CMV reactivations. The role of alemtuzumab versus rituximab still remains unclear, further trials with longer follow-up and overall survival as primary endpoint are needed to evaluate the effects of both agents compared with each other. Alemtuzumab compared with chlorambucil seems to be favourable in terms of PFS, but a longer follow-up period and trials with overall survival as primary endpoint are needed to determine whether this effect will translate into a survival advantage.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) accounts for ∼ 5% of Hodgkin lymphoma cases. The disease is characterized by a strong CD20 expression on the malignant cells and a more indolent clinical course compared with classic HL. Anti-CD20 antibody treatment has shown clinical activity in relapsed NLPHL. In this phase 2 trial, we investigated rituximab in newly diagnosed stage IA NLPHL patients. Four weekly applications at 375 mg/m(2) were given. Among the 28 evaluable patients, overall response rate was 100%, 24 patients (85.7%) achieved complete remission, and 4 (14.3%) achieved partial remission. At a median follow-up of 43 months, overall survival was 100%; progression-free survival at 12, 24, and 36 months was 96.4%, 85.3%, and 81.4%, respectively. No grade 3 or 4 toxicity was observed. Although treatment results with rituximab appear inferior compared with radiotherapy and combined-modality approaches in early-stage patients, investigation of anti-CD20 antibody-based combinations in NLPHL is warranted. This study was registered at www.clinicaltrials.gov as #NCT00346684.

The individual risk of infection and requirements for medical treatment after high-dose chemotherapy have been unpredictable. In this prospective, multicenter, open-label study we investigated the potential of granulocyte colony-stimulating factor (G-CSF) responsiveness as a predictor. A total of 168 patients with multiple myeloma or lymphoma received a single dose of subcutaneous G-CSF (lenograstim, 263 μg) after high-dose chemotherapy. Highly variable leukocyte peaks were measured and grouped as low (quartile 1; leukocytes 100-10 100/μL), medium (quartile 2; leukocytes > 10 100-18 300/μL), and high (quartiles 3/4; leukocytes > 18 300-44 800/μL). G-CSF responsiveness (low vs medium vs high) was inversely correlated with febrile neutropenia (77% vs 60% vs 48%; P = .0037); the rate of infection, including fever of unknown origin (91% vs 67% vs 54%; P < .0001); days with intravenous antibiotics (9 vs 6 vs 5; P < .0001); and antifungal therapy (P = .042). In multivariate analysis, G-CSF responsiveness remained the only factor significantly associated with infection (P = .016). In addition, G-CSF responsiveness was inversely correlated with grade 3/4 oral mucositis (67% vs 33% vs 23%; P < .0001). G-CSF responsiveness appears as a signature of the myeloid marrow reserve predicting defense against neutropenic infection after intensive chemotherapy. This study is registered at http://www.clinicaltrials.gov as NCT01085058.

This 12th biannual report of the Cochrane Haematological Malignancies Group highlights recently published randomized controlled trials in the field of hemato-oncology, covering the publication period from September 1, 2009, through June 30, 2010. Implication for clinical practice and methodological aspects are the main principles used to select trials for this report. Studies on tyrosine kinase inhibitors for patients with chronic myeloid leukemia were identified through electronic search of MEDLINE with a broad search filter that covered all topics in hemato-oncology combined with a highly sensitive search filter for randomized studies as described in the Cochrane Handbook for Systematic Reviews of Interventions.

Background: A systemic and intraventricular polychemotherapy regimen (the Bonn protocol) without radiotherapy resulted in durable responses in 75% of patients <60 years with primary CNS lymphoma (PCNSL), but was complicated by a high rate of Ommaya reservoir infections. Here, the efficacy and toxicity of this regimen without intraventricular treatment was evaluated in PCNSL., Patients and Methods: From August 2003 to November 2005, 18 patients with PCNSL <60 years (median age, 53 years) were treated in a phase II trial with a high-dose methotrexate (MTX; cycles 1, 2, 4 and 5) and cytarabine (Ara-C; cycles 3 and 6) based systemic therapy including dexamethasone, vinca-alkaloids, ifosfamide and cyclophosphamide., Results: Study accrual was prematurely stopped in November 2005 due to a high rate of early relapses. Seventeen of 18 patients were assessable for response: nine (53%) achieved complete response (CR), two (12%) complete response/unconfirmed (CRu) and two (12%) partial response (PR); four (24%) showed progressive disease (PD). One treatment was stopped due to toxicity. Median follow-up was 23 months, median response duration was only 10 months in responding patients, and median time to treatment failure (TTF) was 8 months in the whole group. Median overall survival (OS) has not been reached. Systemic toxicity was mainly hematologic., Conclusions: In PCNSL patients <60 years, polychemotherapy without intraventricular treatment results in a high response rate, but is associated with early relapses in the majority of cases. This is in contrast to the results achieved with the same protocol but with intraventricular treatment.

Background: Granulopoiesis-stimulating factors, such as granulocyte-colony-stimulating factor (G-CSF) and granulocyte-macrophage-colony-stimulating factor (GM-CSF), are being used to prevent febrile neutropenia and infection in patients undergoing treatment for malignant lymphoma. The question of whether G-CSF and GM-CSF improve dose intensity, tumour response, and overall survival in this patient population has not been answered yet. Since the results from single studies are inconclusive, a systematic review was undertaken., Objectives: To determine the effectiveness of G-CSF and GM-CSF in patients with malignant lymphoma with respect to preventing neutropenia, febrile neutropenia and infection; improving quality of life, adherence to treatment protocol, tumour response, freedom from treatment failure (FFTF) and overall survival (OS); and adverse effects., Search Strategy: We searched The Cochrane Library, MEDLINE, EMBASE, CancerLit, and other relevant literature databases; Internet databases of ongoing trials; and conference proceedings of the American Society of Clinical Oncology and the American Society of Hematology (1980 - 2007). We included full-text and abstract publications as well as unpublished data., Selection Criteria: Randomised controlled trials comparing prophylaxis with G-CSF or GM-CSF versus placebo/no prophylaxis in adult patients with malignant lymphoma undergoing chemotherapy were included for review. Both study arms had to receive identical chemotherapy and supportive care., Data Collection and Analysis: Trial eligibility and quality assessment, data extraction and analysis were done by two reviewers independently. Authors were contacted to obtain missing data., Main Results: We included 13 eligible randomised controlled trials with 2607 randomised patients. Compared with no prophylaxis, both G-CSF and GM-CSF did not improve overall survival (hazard ratio 0.97; 95% CI 0.87 to 1.09) or FFTF (hazard ratio 1.11; 95% CI 0.91 to 1.35). Prophylaxis significantly reduced the relative risk (RR) for severe neutropenia (RR 0.67; 95% confidence interval (CI) 0.60 to 0.73), febrile neutropenia (RR 0.74; 95% CI 0.62 to 0.89) and infection (RR 0.74; 95% CI 0.64 to 0.85). There was no evidence that either G-CSF or GM-CSF reduced the number of patients requiring intravenous antibiotics (RR 0.82; 95%CI 0.57 to 1.18); lowered infection related mortality (RR 0.93; 95% CI 0.51 to 1.71); or improved complete tumour response (RR 1.03; 95% CI 0.95 to 1.10).One study evaluated quality of life parameters and found no differences between the treatment groups., Authors' Conclusions: G-CSF and GM-CSF, when used as a prophylaxis in patients with malignant lymphoma undergoing conventional chemotherapy, reduce the risk of neutropenia, febrile neutropenia and infection. However, based on the randomised trials currently available, there is no evidence that either G-CSF or GM-CSF provide a significant advantage in terms of complete tumour response, FFTF or OS.

With improved treatment strategies and prognosis for patients with Hodgkin lymphoma (HL), interest has increasingly focused on high-risk groups. These groups include a small proportion of patients who experience relapse or who have primary refractory disease despite state-of-the-art treatment. Although many research efforts have been made in this field, specific biological markers that reliably predict unfavorable outcome during first-line treatment are lacking. Recent analyses in HL and other malignancies, however, have demonstrated an important impact of patient-related factors, such as individual differences in hematologic toxicity and drug metabolism, on disease outcome. A different cytochrome enzyme status and slower drug clearance in female patients, resulting in higher systemic toxicity and effectiveness of treatment, indicate that sex-specific aspects are important. In this Review, we discuss the current data on hematotoxicity among male and female patients with HL and other malignancies. In addition, we highlight the potential causes of hematotoxicity and its impact on treatment outcome and the role of future strategies.

R-etodolac is a novel pro-apoptotic agent with potential antitumor activity against B-cell chronic lymphocytic leukemia (B-CLL). This phase I clinical trial was conducted to determine the tolerability, safety, and maximum tolerated dose (MTD) of R-etodolac, administered orally twice a day (BID), in patients with B-CLL. Secondary objectives included evaluating clinical response, pharmacodynamic activity (reduction of lymphocytes), and pharmacokinetic (PK) profile. Forty-three patients were enrolled in the study. The most frequently reported adverse events were diarrhea, rash, pruritus, and headache. Increases in alanine aminotransferase (ALT) were also observed. Adverse events were generally mild and self-limiting, although in an apparent dose-response relationship, grade 2 and 3 gastrointestinal toxicities and grade 3 skin toxicities were reported with the highest dose regimens (1,800 and 2,400 mg BID). Hematologic toxicity was rare. The MTD was determined to be 1,200 mg BID. PK results indicated that oral absorption of R-etodolac was rapid (time to maximum concentration ranged from 2 to 4 h), and the half-life ranged from 5 to 7 h. The increase in maximum concentration, however, was not proportional to the increase in dose. R-etodolac significantly reduced absolute lymphocyte count (ALC) in B-CLL patients in a dose-dependent manner up to 1,800 mg BID and caused partial responses in 2 patients. Further study of R-etodolac as a possible new maintenance therapy or as a part of combination therapy of B-CLL appears warranted.

Because nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) express CD20, rituximab may be used as a nonmutagenic treatment option to avoid late toxicities in this rather indolent entity. Between 1999 and 2004, the German Hodgkin Study Group (GHSG) investigated the activity of rituximab (375 mg/m(2) in 4 doses) in a phase 2 trial in 21 relapsed or refractory NLPHL patients. The initial diagnosis of NLPHL was confirmed in 15 of the 21 enrolled patients by reference pathology. The remaining cases were reclassified as Hodgkin lymphoma transformed to T-cell rich B-cell lymphoma (TCRBCL; n = 2) or CD20(+) classical Hodgkin lymphoma (cHL; n = 4). In NLPHL patients the overall response rate was 94%, including 8 complete remission (CR) and 6 partial remission (PR). With a median follow-up of 63 months (range, 3-84), the median time to progression was 33 months, with the median overall survival (OS) not reached. Thus, rituximab is highly effective in relapsed and refractory NLPHL. This study is registered at http://www.klinisches-studienzentrum.de/trial/285.

Background: Randomized controlled trials (RCTs) reported conflicting results on the impact of high-dose chemotherapy (HDCT) and autologous stem cell transplantation in the first-line treatment of patients with aggressive non-Hodgkin lymphoma (NHL)., Methods: We performed a systematic meta-analysis to assess the efficacy HDCT compared to conventional chemotherapy in aggressive NHL patients with regard to complete response (CR), overall survival (OS), event-free survival (EFS), toxicity, and impact of the age-adjusted International Prognostic Index (aaIPI) risk factors. We searched the Cochrane Library, MEDLINE and other databases (1/1990 to 1/2005). Hazard ratio (HR), relative risks (RR) and 95% confidence intervals (CIs) were calculated using the fixed effect model., Results: Fifteen RCTs including 2728 patients were identified. HDCT improved CR when compared to conventional chemotherapy (RR 1.11, CI 1.04-1.18). Overall, there was no evidence for HDCT to improve OS (HR 1.05, 95% CI 0.92-1.19) or EFS (HR 0.92, 95% CI 0.80-1.05) when compared with conventional chemotherapy. However, subgroup analysis indicated OS differences (p=0.032) between good (HR 1.46, 95% CI 1.02-2.09) and poor risk (HR 0.95, 95% CI 0.81-1.11) patients. Conflicting results were reported for poor risk patients, where some studies reported improved and others reduced OS and EFS after HDCT., Conclusion: There was no evidence that HDCT improved OS and EFS in good risk NHL patients. The evidence for poor risk patients is inconclusive. HDCT should not be further investigated in good risk patients with aggressive NHL but high quality studies in poor risk patients are warranted.

Background: Addition of the anti-CD20 monoclonal antibody rituximab to chemotherapy (R-chemo) has been shown to improve response rates and progression-free survival in patients with indolent or mantle cell lymphoma. However, the impact of R-chemo on overall survival is unclear. We performed a comprehensive systematic review and meta-analysis to examine the efficacy of combined immunochemotherapy using R-chemo compared with the identical chemotherapy alone with respect to overall survival in patients with advanced indolent lymphoma or mantle cell lymphoma., Methods: Medical databases and conference proceedings were searched for randomized controlled trials published from January 1990 through December 2005 that compared R-chemo with chemotherapy alone in patients with newly diagnosed or relapsed indolent lymphoma or mantle cell lymphoma. We included full-text and abstract publications. Endpoints were overall survival, disease control, overall response, and toxicity. A fixed-effects model was assumed in all meta-analyses. For binary data, the relative risk was used as an indicator of treatment effect, and the Mantel-Haenszel method was used to pool relative risks. Statistical tests for heterogeneity were one-sided; statistical tests for effect estimates were two-sided., Results: Seven randomized controlled trials involving 1943 patients with follicular lymphoma, mantle cell lymphoma, or other indolent lymphomas were included in the meta-analysis. Five studies were published as full-text articles, and two were in abstract form. Patients treated with R-chemo had better overall survival (hazard ratio [HR] for mortality = 0.65; 95% confidence interval [CI] = 0.54 to 0.78), overall response (relative risk of tumor response = 1.21; 95% CI = 1.16 to 1.27), and disease control (HR of disease event = 0.62; 95% CI = 0.55 to 0.71) than patients treated with chemotherapy alone. R-chemo improved overall survival in patients with follicular lymphoma (HR for mortality = 0.63; 95% CI = 0.51 to 0.79) and in patients with mantle cell lymphoma (HR for mortality = 0.60; 95% CI = 0.37 to 0.98). However, in the latter case, there was heterogeneity among the trials (P = .07), making the survival benefit less reliable., Conclusion: In patients with indolent or mantle cell lymphoma, R-chemo is superior to chemotherapy alone with respect to overall survival.

Statins are used to treat hypercholesterolemia and seem to have a preventive effect against cancer through pleiotropic effects including prenylation-inhibition. So far nothing is known about the activity of statins or more specific prenylation-inhibitors in Hodgkin's lymphoma (HL). We, therefore, evaluated the anti-HL activity of simvastatin and specific prenylation-inhibitors. 2 microM Simvastatin induced caspase-related apoptosis via depletion of prenylation-substrates in several HL-cell lines. Furthermore, it effectively impaired tumor growth in a mouse model for HL. Since the prenylation-inhibitors FTI-277 and GGTI-298 were also effective against HL-cells, we conclude that statins and specific prenylation-inhibitors should be evaluated in HL patients.

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in the Western world. Historically, CLL patients have received prednisone- or chlorambucil-containing regimens, resulting in modest responses and a slim chance of long-term survival. The addition of purine nucleoside analogues, specifically fludarabine, to the armamentarium has significantly improved efficacy in treatment-naive or heavily pretreated CLL patients. Since the 1980s, fludarabine monotherapy has demonstrated an improvement in response over historical chemotherapeutic agents. Single-agent fludarabine therapy has expanded into a combination regimen containing cyclophosphamide and has further evolved to incorporate monoclonal antibodies. A review of the fludarabine literature shows that these advancements in fludarabine-containing therapy have enhanced the overall patient response with a potential increase in survival time, thus representing progress towards a superior treatment for CLL.

This is an updated systematic review of 57 trials and 9353 cancer patients from articles, abstracts, and reports published between January 1, 1985, and April 30, 2005, on the effects of epoetin alfa and beta (i.e., epoetin) and darbepoetin alfa (i.e., darbepoetin). We included randomized controlled trials comparing epoetin or darbepoetin plus red blood cell transfusion with red blood cell transfusion alone for prophylaxis or treatment of anemia in cancer patients with or without concurrent antineoplastic therapy. The Cochrane Library, MEDLINE, EMBASE, and conference proceedings were searched. Effect estimates and 95% confidence intervals (CIs) were calculated with fixed-effects models. Treatment with epoetin or darbepoetin statistically significantly reduced the risk for red blood cell transfusions (relative risk [RR] = 0.64, 95% CI = 0.60 to 0.68; 42 trials and 6510 patients) and improved hematologic response (RR = 3.43, 95% CI = 3.07 to 3.84; 22 trials and 4307 patients). Treatment with epoetin or darbepoetin increased the risk of thrombo-embolic events (RR = 1.67, 95% CI = 1.35 to 2.06; 35 trials and 6769 patients). Uncertainties remain as to whether and how epoetin or darbepoetin affects overall survival (hazard ratio = 1.08, 95% CI = 0.99 to 1.18; 42 trials and 8167 patients). Caution is advised when using epoetin or darbepoetin in combination with thrombogenic chemotherapeutic agents or for cancer patients who are at high risk for thrombo-embolic events.

Background: Rituximab monotherapy can achieve remissions of up to 80% in follicular lymphoma. As the antibody has only been on the market since 1997, long-term observations are still rare., Case Report: We report about a patient with follicular lymphoma who received a single treatment of 4 x 375 mg/m(2) of the monoclonal antibody rituximab without chemotherapy and has been in complete remission (CR) for 8 years., Discussion: This remarkable response duration highlights the efficacy of rituximab monotherapy. A number of recently published studies have indicated that CR of more than 4 years after rituximab monotherapy may be a regularly occurring event., Conclusions: These patients are likely to represent a yet poorly characterized patient group that profits considerably from rituximab monotherapy.

Due to the dramatic improvements in cure and survival of young patients of reproductive age suffering from malignant or systemic disease, the preservation of fertility and ovarian function during cytostatic treatment has become of increased importance during the last decade. Pharmacological therapy with GnRH analogues and the cryopreservation of ovarian tissue are discussed in this context. The value of these treatment procedures and their potential clinical applications are critically reviewed in this article.

Due to its selective overexpression on the malignant cells of Hodgkin's lymphoma (HL) and large cell anaplastic lymphoma (ALCL), CD30 is an excellent target for immunotherapy of these diseases. The fully human monoclonal anti-CD30-antibody 5F11 has been shown to be effective against CD30-expressing cell lines both in vitro and in vivo. In addition, 5F11 shows promising antitumor activity in phase 1/2 clinical trials. To extend these promising results, the authors evaluated combinations of 5F11 with conventional cytostatic drugs against a variety of lymphoma cell lines in vitro. Most combinations tested showed at least additive cytotoxic effects on the HL-derived cell lines L428, L540, and L1236 and the ALCL-derived cell line Karpas 299 as measured by proliferation assays (XTT) and the induction of apoptosis (annexin-V FACS analysis). The most impressive results were detected with the combination of 5F11 and gemcitabine or etoposide. The data suggest that the combination of the human antibody 5F11 with conventional chemotherapy might be beneficial in the combined chemo-immunotherapy of CD30-positive lymphomas., (Copyright 2004 Lippincott Williams & Wilkins)