Abstract
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.
Plain language summary
Nivolumab for adults with Hodgkin's lymphoma
Background
Hodgkin's lymphoma (HL) is a cancer of the lymphatic system. As part of the immune system, the lymphatic system comprises a network of lymphatic vessels, which transport lymph throughout the body. Lymph is a fluid which contains white blood cells, that tackle infection. HL occurs in children and adults, but it is more common in the third decade of life. It is one of the most curable forms of cancer and up to 90% of people will be cured; however, approximately 10% of people with HL will relapse (the cancer will return). Treatment options are chemotherapy, radiotherapy, or both, or newly developed agents, called checkpoint inhibitors that target the cancer cell directly. Nivolumab is one checkpoint inhibitor and currently approved by the US Food and Drug Administration for the treatment of various cancers and relapsed HL after treatment with stem cell transplantation and brentuximab vedotin, which is a medicine used to treat cancer. In stem cell transplantation patients receive blood building cells, so called stem cells, which replace their own when they have been destroyed along the disease or previous therapy regimens.
Review question
This systematic review evaluated the benefits and harms of nivolumab for adults with Hodgkin's lymphoma.
Study characteristics
We searched important medical databases for clinical trials assessing the benefits and harms of nivolumab in adults with HL. Two review authors independently screened, summarised and analysed the results. In addition, we tested the computer software RobotReviewer to extract data. Our search led to the inclusion of three studies involving 283 participants and 14 ongoing trials.
The evidence provided is current to May 2018.
Key results
Two studies with 260 participants evaluated survival. After six months, all participants were alive in one trial (17 participants). One trial reported quality of life for a subgroup of participants using a questionnaire but not all follow‐up data were available. Although it seemed that the participants answering the questionnaire might have had a benefit, it was unclear whether this applied to all the participants. The studies also reported tumour control and tumour response, but with different results, depending on the treatment and how many previous treatments participants had received before nivolumab was given.
As nivolumab is given until the disease progresses (gets worse) or until unacceptable side effects occur, people receive the drug for a long time. Therefore, reporting of side effects is related to the time the person received the medicine, with potentially more side effects with longer usage. The most commonly reported side effects were fatigue (tiredness), diarrhoea (loose stools), infusion reactions (during or shortly after giving the medicine by a vein) and rash. Only one study reported medicine‐related serious side effects. They occurred rarely (infusion reactions and lung disease). Deaths related to the medicine were not reported.
Reliability of the evidence
Due to the study design and varied type of participants with different numbers of previous treatments and various treatment options, the reliability of the evidence was low to very low.
Conclusion
This systematic review evaluated the benefits and harms of nivolumab in adults with HL.
Data on survival, quality of life, tumour response and side effects were available from small trials only. The three trials included only people different previous treatment options, very often also with a previous stem cell transplantation. In one trial, all participants were alive after six months. Quality of life data were not reported for all the included participants; moreover, data after a long period of treatment were not available for all evaluated participants, therefore meaningful conclusions were not possible. Serious side effects occurred rarely. Currently, data are too sparse to make a clear statement on nivolumab for people with relapsed or refractory HL except for those who had received several treatments before. As there are currently 14 ongoing trials evaluating nivolumab, of which two are well designed, 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.
Summary of findings
Summary of findings for the main comparison. Nivolumab compared to no other intervention for adults with Hodgkin's lymphomas.
| Nivolumab for adults with Hodgkin's lymphoma | |||
|
Patient or population: adults with Hodgkin's lymphoma Settings: inpatient or outpatient cancer care Intervention: nivolumab Comparison: none | |||
| Outcomes | Impacts | No of Participants (studies) | Quality of the evidence (GRADE) |
| OS follow‐up: range 6‐27 months |
CheckMate 205 reported that median OS has not been reached after a median follow‐up of 18 months. Hatake 2016 reported 100% OS after 6 months. A retrospective analysis of participants with third relapse of cHL not treated with nivolumab shows a 6‐month OS of 90% and a 12 month OS of 73%. |
260 (2 observational studies) | ⊕⊝⊝⊝ Very lowa,b |
| QoL follow‐up: mean 7 months | Both the EQ‐5D visual analogue scale (and the EORTC QLQ‐C30 indicated improved QoL for those participants who filled out the forms. (EQ‐5D: from 62 (standard deviation (SD) 30) at baseline (72 (90%) participants) to 80 (SD 18) at week 33 (44 (55%) participants); EORTC QLQ‐C30 suggested improvement from baseline across functional, symptom and global health scores) | 80 (1 observational study) | ⊕⊝⊝⊝ Very lowa,c |
| PFS follow‐up: range 6 months to 23 months | 2 trials reported 6‐month PFS of 60‐86%. In the other trial, median PFS was 12‐18 months. A retrospective analysis of third relapsed people with cHL not treated with nivolumab demonstrated a 6‐month PFS of 76% and a 12‐month PFS of 51%. | 283 (3 observational studies) | ⊕⊝⊝⊝ Very lowa,b |
| Response rate follow‐up: range 6‐23 months | Complete response rate was 12‐29% depending on inclusion criteria and participants' previous treatments | 283 (3 observational studies) | ⊕⊝⊝⊝ Very lowa,b |
| Treatment‐related mortality | Not reported | – | |
| Grade 3 or 4 AEs follow‐up: range 8‐23 months | 1 trial reported drug‐related AEs only (fatigue (23%), diarrhoea (15%), infusion reactions (14%) and rash (12%)). The other 2 trials reported 23% to 52% AEs. | 283 (3 observational studies) | ⊕⊝⊝⊝ Very lowa,b |
| SAEs follow‐up: range 16‐23 months | 2% of participants had infusion reactions and 1% pneumonitis (drug‐related SAEs). | 243 (1 observational study) | ⊕⊝⊝⊝ Very lowa,b,d |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). AE: adverse event; cHL: classical Hodgkin's lymphoma; CI: confidence interval; EORTC: European Organisation for Research and Treatment of Cancer; OS: overall survival; PFS: progression‐free survival; QoL: quality of life; SAE: serious adverse event. | |||
| GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | |||
aSince all included studies where uncontrolled studies, the certainty of the evidence for all outcomes started at "low" (2 points)
bDifferent study populations with different previous therapeutic regimen and various follow‐up times led to inconsistency (downgraded 1 point).
cOnly a subset of participants was evaluated (cohort B, 80 participants, but only 44 filled out follow‐up data) (downgraded by 1 point).
dSmall number of events leads to imprecision (downgraded 1 point).
Background
Description of the condition
Hodgkin's lymphoma (HL) is a cancer of the lymphatic system that involves the lymph nodes, spleen and other organs such as the liver, lung, bone or bone marrow, depending on the tumour stage (Lister 1989). The incidence of HL typically shows a bimodal age distribution with a first peak around the age of 30 years and a second peak after the age of 60 years. HL accounts for 10% to 15% of all lymphoma in industrialised countries, with an incidence of 2 to 3 per 100,000 inhabitants per year. It can therefore be regarded as a relatively rare disease, but is nevertheless one of the most common malignancies in young adults (Thomas 2002).
The disease usually develops in lymph nodes in the upper part of the body, mostly the latero‐cervical lymph nodes, and results in painless swelling of the lymphatic tissue involved. Normally HL appears within these parts of the body, with peripheral extranodal involvement being rare. As a sign of large tumour size or spreading, 25% of people present with so‐called B‐symptoms, such as fever, drenching night sweats and a loss of more than 10% bodyweight (Connors 2009; Pileri 2002).
The World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues distinguishes between two types of HL: classic HL (cHL), which represents about 95% of all HL, and lymphocyte‐predominant HL, which represents about 5% of all HL (Mathas 2016). The types differ in morphology, phenotype and molecular features, and therefore in clinical behaviour and presentation (Re 2005).
The Ann Arbor Classification is used for staging and distinguishes between four different tumour stages (Rosenberg 1971). Stages I to III indicate the degree of lymph node and localised extranodal organ involvement or both, and stage IV includes disseminated organ involvement, which can be found in 20% of cases. Factors associated with a poor prognosis include a large mediastinal mass, three or more involved lymph node areas, a high erythrocyte sedimentation rate, extranodal lesions, B‐symptoms (weight loss greater than 10%, fever, drenching night sweats) and advanced age, but the factors considered clinically significant vary slightly between different study groups (German Hodgkin Study Group (GHSG), European Organisation for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC)). HL is classified into early favourable, early unfavourable and advanced stage (Engert 2007). In Europe, the early favourable‐stage group usually comprises Ann Arbor stages I and II without risk factors. The early unfavourable‐stage group includes people with Ann Arbor stages I or II and one or more risk factors. Most people with stages IIB, III or IV disease are included in the advanced‐stage risk group (Engert 2003).
With cure rates of up to 90%, HL is one of the most curable cancers worldwide (Engert 2010; Engert 2012; von Tresckow 2012). A combination of adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) is widely accepted as the gold‐standard chemotherapy regimen in people with HL (Canellos 1992; Engert 2010). People with limited‐stage disease usually receive a combination of chemotherapy and involved‐field radiation therapy (IF‐RT) (Engert 2010; von Tresckow 2012), whereas those with advanced‐stage disease usually receive an intensified regimen, such as BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) (Borchmann 2011; Engert 2012; Skoetz 2013) or ABVD. One large randomised trial showed that two cycles of ABVD followed by 20 Gy of IF‐RT is sufficient for the treatment of early‐favourable HL (Engert 2010). Two cycles of escalated BEACOPP (BEACOPPesc) followed by two cycles of ABVD can improve progression‐free survival (PFS) in comparison to four cycles of ABVD in people with early‐unfavourable HL (von Tresckow 2012).
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 people treated with high‐dose chemotherapy and ASCT have been shown to be free from treatment failure at three years, with survival rated of about 80% at three years (Rancea 2013). For people progressing after ASCT, brentuximab vedotin can improve PFS and is the preferred treatment (Younes 2012). Chen and colleagues reported an OS rate of 41% and PFS rate of 22% at five years in 102 participants who had failed haematopoietic ASCT and received brentuximab vedotin (Chen 2016). However, most participants eventually become refractory to brentuximab vedotin, with limited treatment options.
Description of the intervention
The European Medicines Agency (EMA) approved nivolumab for the treatment of people with relapsed/refractory cHL after ASCT and treatment with brentuximab vedotin in October 2016. The approval was based on an objective response rate (ORR) of 66% in a combined analysis of 95 participants with relapsed or refractory cHL who received nivolumab either in the phase II CheckMate‐205 trial or the phase I CheckMate‐039 trial (Ansell 2015; Younes 2016). The 12‐month PFS was 54.6% and 12‐month overall survival (OS) was 94.9% (Timmermann 2016).
The most common drug‐related adverse events (AEs) include fatigue, infusion‐related reaction, arthralgia and rash. The most common drug‐related grade 3 or 4 AEs were neutropenia and increased lipase concentrations. The most common serious adverse events (SAEs) include fever and meningitis (4% or less each) (Timmermann 2016; Younes 2016).
Nivolumab is now also used in combination with other drugs to treat people with relapsed or refractory HL (Ansell 2016).
How the intervention might work
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. Development started in solid tumours and is most advanced in malignant melanoma and lung cancer (Brahmer 2015; Hamid 2013). In cHL, malignant Hodgkin Reed‐Sternberg (HRS) cells are dispersed within an extensive inflammatory/immune cell infiltrate (Küppers 2009; Mathas 2016). HRS cells frequently overexpress PD‐L1 and PD‐L2 due to alterations in chromosome 9p24.1 and HL tumours may thus be genetically susceptible to blockade of the PD‐1 pathway (Green 2012; Roemer 2016). 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 (Matsuki 2016), and, since 2016, cHL after treatment with ASCT and brentuximab vedotin.
Why it is important to do this review
To our knowledge, no systematic review on the effectiveness of nivolumab in people with HL has been performed. As nivolumab is now approved by the EMA and the FDA based on non‐randomised data, we critically appraised all published trials and conducted this rapid review on nivolumab. If we identify controlled clinical trials in a future update, we will meta‐analyse these data, which will lead to a more precise and reliable evaluation of the benefits and harms of nivolumab. In this way, we aim to overcome the limitations of individual studies, such as small sample sizes and a lack of statistical power.
For this review, we used the software RobotReviewer to extract study data (Marshall 2016; RobotReviewer 2015). For review updates including randomised controlled trials (RCT), we will use this software also to assess risk of bias. As this software has not been not validated, one review author will extract all these data manually and a second review author will compare the results from the software tool and the first review author. We will resolve any discrepancies between the software results and the manually extracted data by discussion between review authors.
Objectives
To assess the benefits and harms of nivolumab in adults with HL (irrespective of stage of disease).
Methods
Criteria for considering studies for this review
Types of studies
We searched for RCTs. As we did not identify any RCTs or quasi‐RCTs (e.g. assignment to treatment by alternation or by date of birth) or cross‐over trials, we included published reports of prospectively planned studies.
We included both full‐text and abstract publications if sufficient information was available on study design, characteristics of participants, interventions and outcomes.
Types of participants
We included studies that evaluated adults of 18 years or more with a confirmed diagnosis of HL, with no gender or ethnicity restrictions. We considered people with all subtypes and stages of HL, undergoing first‐line treatment, or having relapsed, or being refractory to previous treatment attempts. In trials that included mixed populations of participants with haematological malignancies, we would have included data from participants with HL; however, we did not identify such a trial. 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.
Types of interventions
The experimental intervention was nivolumab (with or without other drugs). If we identify RCTs in future updates of this review, the comparison of interest will be nivolumab (with or without other drugs) versus control treatment. We will conduct separate analyses for trials that evaluate nivolumab and nivolumab combined with other drugs.
Types of outcome measures
Primary outcomes
Overall survival (OS).
Quality of life (QoL), if measured using reliable and valid instruments.
Secondary outcomes
-
Progression‐free survival (PFS):
time interval from random treatment assignment onto the study to first confirmed progression, relapse or death from any cause, or to the last follow‐up.
-
Response rate:
measured as overall response, complete response and partial response according to Cheson and colleagues (Cheson 2014).
Treatment‐related mortality (TRM).
Overall rate of grade 3 and grade 4 adverse events (AEs), including potential relationship between intervention and adverse reactions.
Overall rate of serious adverse events (SAEs).
Search methods for identification of studies
We adapted search strategies from the Cochrane Handbook for Systematic Reviews of Interventions (Lefebvre 2011). We searched for studies in all languages to limit language bias.
Electronic searches
We searched the following databases and sources and started the search in 2000 as PD‐L1 blockade for tumour control, the underlying mechanism of nivolumab, was first mentioned in 2002 (Iwai 2002).
-
Databases of medical literature:
Cochrane Central Register of Controlled Trials (CENTRAL; 2018 Issue 5) (Appendix 1);
MEDLINE (Ovid) (2000 to 13 April 2018) (Appendix 2);
Embase (2000 to October 2017) (Appendix 3);
International Pharmaceutical Abstracts (2000 to October 2017) (Appendix 4).
-
Conference proceedings of the annual meetings of the following societies for abstracts (2000 to May 2018, if not included in CENTRAL):
American Society of Hematology;
American Society of Clinical Oncology;
European Hematology Association;
International Symposium on Hodgkin Lymphoma.
-
Databases of ongoing trials:
ISRCTN: www.isrctn.com;
EU clinical trials register: www.clinicaltrialsregister.eu/ctr‐search/search (Appendix 5);
ClinicalTrials.gov: clinicaltrials.gov/ (Appendix 6);
WHO International Clinical Trials Registry Platform (ICTRP): apps.who.int/trialsearch/AdvSearch.aspx (Appendix 7);
EORTC: www.eortc.be;
GHSG: www.ghsg.org.
Databases and websites of relevant institutions, such as pharmaceutical organisations, agencies and societies.
Searching other resources
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Handsearching:
we checked the reference lists of all identified trials, relevant review articles and current treatment guidelines for further literature.
-
Personal contacts:
we contacted experts in the field, drug manufacturers and regulatory agencies to retrieve information on unpublished trials.
Data collection and analysis
Selection of studies
Two review authors independently screened the results of the search strategies for eligibility for this review by reading the abstracts using Covidence software (Covidence 2016). We coded the abstracts as either 'retrieve' or 'do not retrieve.' In the case of disagreement or if it was unclear whether we should retrieve the abstract or not, we obtained the full‐text publication for further discussion. Two review authors assessed the full‐text articles of selected studies. If the two review authors were unable to reach a consensus, we consulted a third review author to reach final decision (Higgins 2011a).
We documented the study selection process in a flow chart, as recommended in the PRISMA statement (Moher 2009), and showed the total numbers of retrieved references and the numbers of included and excluded studies. We listed all articles we excluded after full‐text assessment and their reasons for exclusion in the Characteristics of excluded studies table.
Data extraction and management
We planned that one review author extracted data on the characteristics of included studies and a second review author compared them with the results from the software RobotReviewer (Marshall 2016; RobotReviewer 2015). However, as we identified no eligible RCTs and the software is currently designed to extract RCTs, two review authors (MG and NS) additionally extracted data independently. The two review authors resolved any discrepancies by discussion; had they not reached consensus, they planned to consult a third review author, but this was not necessary. If required, they would have contacted the authors of specific studies for supplementary information (Higgins 2011b).
We extracted the following information.
General information: author, title, source, publication date, country, language, duplicate publications.
Quality assessment (as specified in the Assessment of risk of bias in included studies section).
Study characteristics: trial design, aims, setting and dates, source of participants, inclusion/exclusion criteria, comparability of groups, subgroup analysis, statistical methods, power calculations, treatment cross‐overs, compliance with assigned treatment, length of follow‐up.
Participant characteristics: age, gender, ethnicity, number of participants recruited/allocated/evaluated, participants lost to follow‐up, additional diagnoses, stage of disease, previous treatment (type of (multi‐agent) chemotherapy (intensity of regimen, number of cycles), field and dose of radiotherapy, ASCT, brentuximab vedotin dosage and duration).
Interventions: nivolumab dosage, duration of treatment, duration of follow‐up, for RCTs: comparator (type, dosage).
Outcomes: OS, QoL, PFS, response rate, TRM, AEs (including assessment of causality, how it was determined, relation between intervention and adverse drug reaction, method of AEs ascertainment (passive or active methods), method of measurement, how severity or seriousness was measured).
Assessment of risk of bias in included studies
Randomised controlled trials
If we identify RCTs for future updates, we will assess risk of bias with the Cochrane 'Risk of bias' tool for each RCT. Thereafter, we will use the RobotReviewer software to assess risk of bias (RobotReviewer 2015), and a second review author will compare these results with the results from the first review author. See Differences between protocol and review for a more detailed description of the 'Risk of bias' assessment we will undertake if we identify eligible RCTs in future updates.
Non‐randomised prospectively planned trials (including control arm)
As reported in the Types of studies section, we would have included non‐randomised studies with a control arm only if we did not identify any RCTs. However, we did not identify any non‐randomised prospectively planned study with a control arm. If we identify non‐randomised studies with a control arm in review updates, we will independently assess eligible studies for methodological quality and risk of bias (using the Risk Of Bias in Non‐randomised Studies ‐ of Interventions (ROBIN‐I) tool) (Sterne 2016).
Uncontrolled studies
As reported in the Types of studies section, we included non‐randomised studies without a control arm only as we did not identify any RCTs.
Two review authors independently assessed eligible studies for methodological quality and risk of bias (using the "risk of bias assessment criteria for observational studies" tool provided by the Childhood Cancer Group (see Table 2). The quality assessment strongly depends upon information on the design, conduct and analysis of the trial. The two review authors resolved any disagreements regarding the quality assessments by discussion, in case they would not have reached a consensus they would have consulted a third review author until final consensus.
1. Risk of bias assessment criteria for observational studies.
| Heading | Internal validity | External validity |
| Study group |
Selection bias (representative: yes/no)
or
|
Reporting bias (well defined: yes/no)
and
|
| Follow‐up |
Attrition bias (adequate: yes/no)
or
|
Reporting bias (well defined: yes/no)
|
| Outcome |
Detection bias (blind: yes/no)
|
Reporting bias (well defined: yes/no)
|
| Risk estimation |
Confounding(adjustment for other factors: yes/no)
|
Analyses (well defined: yes/no)
|
We assessed the following domains of bias.
Internal validity.
Representative study group (selection bias).
Complete outcome assessment/follow‐up (attrition bias).
Outcome assessors blinded to investigated determinant (detection bias).
Important prognostic factors or follow‐up taken adequately into account (confounding).
External validity.
Well‐defined study group (reporting bias).
Well‐defined follow‐up (reporting bias).
Well‐defined outcome (reporting bias).
Well‐defined risk estimates (analyses).
For every criterion, we made a judgement using one of three response options.
High risk of bias.
Low risk of bias.
Unclear risk of bias.
Measures of treatment effect
We estimated the dichotomous outcomes of individual studies as rates by extracting the number of events and the total number of participants (overall and complete response rate, TRM, AEs).
We estimated survival data (OS, PFS) using Kaplan–Meier methods.
We measured continuous outcomes (e.g. QoL) as mean differences (MD).
In case we identify eligible RCTs in updates of this review, we will extract and report effect measures in accordance with the procedures outlines in the Differences between protocol and review section.
Unit of analysis issues
Studies with multiple treatment groups
We did not identify any eligible studies with multiple treatment groups. We described how we will proceed with such studies in review updates in the Differences between protocol and review section.
Dealing with missing data
Chapter 16 of the Cochrane Handbook for Systematic Reviews of Interventions suggests a number of potential sources for missing data (Higgins 2011a), which we needed to take into account at study level, at outcome level and at summary data level. In the first instance, it is of the utmost importance to differentiate between data 'missing at random' and 'not missing at random.'
If data have been missing, we would have requested these data from the original investigators. If, after this, data were still missing, we would have to make explicit assumptions of any methods the included studies used: for example, we would have assumed that the data were missing at random or we would have assumed that missing values had a particular value, such as a poor outcome.
Assessment of heterogeneity
If we find sufficient data for meta‐analysis in updates of this review, we will assess potential heterogeneity as described in Appendix 8.
Assessment of reporting biases
In updates of this review where a meta‐analysis is feasible, we will assess potential reporting biases in accordance with the methods described in Appendix 8.
Data synthesis
We did not meta‐analyse data from the included uncontrolled trials, as there might be no additional benefit in meta‐analysing data without a control group. We reported results of each included trial. As data did not allow quantitative assessment, we presented outcome data individually per study (see Characteristics of included studies table). In further updates of this review we will meta‐analyse data in accordance with the procedure described in Appendix 8.
'Summary of findings' table
We used the GRADE approach to assess the quality of the evidence. We used GRADEpro Guideline Development Tool (GDT) software to create a 'Summary of findings' table (GRADEpro GDT 2014), as suggested in the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2011). In addition, we provided an interactive 'Summary of findings' table for a better user‐experience and for improved dissemination of the findings of this Cochrane Review (Schünemann 2016). We avoided use of lengthy text in the results and discussion section.
We prioritised outcomes according to their relevance to people with HL.
OS.
QoL.
PFS.
Response rates.
TRM.
AEs.
SAEs.
Since all included studies were uncontrolled studies, the certainty of the evidence for all outcomes started at "low certainty" (2 points)
Subgroup analysis and investigation of heterogeneity
For future updates including meta‐analyses, we will perform subgroup analyses following the procedure described in Appendix 8.
Sensitivity analysis
For future updates including meta‐analyses, we will perform sensitivity analyses according to the methods described in Appendix 8.
Results
Description of studies
Results of the search
We identified 782 potentially relevant references. At the initial screening stage, we excluded 107 duplicates and 626 reference due to a lack of conformity with the inclusion criteria. We further evaluated the remaining 49 publications either as full‐text publications or, if not available, as abstract publications or study registry entry. This led to exclusion of five further trials. In addition, we identified 14 ongoing trials (18 references), which will be completed by 2021, two studies (five references) studies already reported interim results for some of the included participants (NCT01896999; NCT02572167). Only two of these ongoing trials are RCTs (NCT03004833; NCT03138499). We finally included three studies (26 references) in this systematic review.
We reported the overall numbers of references screened, identified, selected, excluded and included in a PRISMA flow diagram (see Figure 1).
1.
Study flow diagram.
Results of the application of RobotReviewer
Although our search did not identify any eligible RCTs, we uploaded available full‐texts of the three included studies into the software RobotReviewer. The software recognised correctly that one study was not an RCT and therefore did not extract any data of this study. However, the two remaining studies were falsely labelled to be RCTs. The extraction results on both studies could not be used in the further review process. Yet some characteristics of included trials were given sufficiently. This is especially concerning the data regarding included participants and study interventions. We did not consider the 'Risk of bias' function of the software, since it was based on the criteria of the Cochrane 'Risk of bias' tool for RCTs only.
Included studies
For detailed description of the studies see the Characteristics of included studies table. Here we provided a brief overview.
Three prospectively planned, uncontrolled trials evaluated the effect and safety of nivolumab in people with HL (283 participants) (CheckMate 039; CheckMate 205; Hatake 2016). All of these trials included heavily pretreated participants and were published as full‐texts.
Design
CheckMate 039 was a phase I trial, CheckMate 205 and Hatake 2016 were phase II trials. Follow‐up ranged between 12 months and 23 months.
Sample sizes
The smallest trial involved 17 people with HL (Hatake 2016), CheckMate 039 involved 23 participants and CheckMate 205 involved 243 participants.
Location
Hatake 2016 was conducted in Japan and the other two trials were in several countries in US, Europe and Canada.
Participants
All trials included adults with at least one prior chemotherapy regimen.
CheckMate 039 evaluated participants with relapsed or refractory HL with at least one prior chemotherapy regimen. The mean age was 35 years.
CheckMate 205 included adults after failure of ASCT. It had three cohorts: cohort A had 63 people with cHL after failure of ASCT, cohort B had 80 people with cHL after failure of ASCT who received subsequent brentuximab vedotin and cohort C had 100 people with cHL after failure of ASCT who had previous or subsequent brentuximab vedotin treatment (or both). The mean age was 34 years.
Hatake 2016 evaluated participants with history of treatment with ASCT, people to whom ASCT was not indicated or who refused to receive treatment with ASCT. The mean age was 63 years.
Interventions
CheckMate 039: consisted of a dose escalation cohort and an expansion cohort. The dose escalation cohort (phase I trial) received nivolumab 1 mg/kg bodyweight with escalation to 3 mg/kg. With 3 mg/kg as the final dose, the maximum tolerated dose leading to dose‐limiting toxicities was not reached in this phase I trial with a preset fixed‐dose escalation plan. The expansion cohort received nivolumab 3 mg/kg at week one, week four, and then every two weeks until disease progression or complete response for a maximum of two years.
CheckMate 205: participants received nivolumab 3 mg/kg intravenously over 60 minutes every two weeks until disease progression, death, unacceptable toxicity, withdrawal of consent or study end (five years or more of follow‐up).
Hatake 2016: participants received nivolumab 3 mg/kg on day one of the treatment phase; subsequent doses were administered on day one of each 14‐day cycle. Nivolumab was continued if treatment continuation criteria were met; trial was to continue until all participants discontinued treatment in the event of progressive disease, an unacceptable AE or other clinically relevant reasons, so trial participants are still under investigation.
Outcomes
The primary outcomes were:
proportion of participants achieving an objective response;
overall response rate;
safety.
The secondary outcomes were:
duration of response outcomes;
proportion of participants who achieved response;
PFS;
OS;
safety and tolerability;
QoL;
safety endpoints;
Conflicts of interest
Bristol‐Myers Squibb funded the CheckMate 039 and CheckMate 205 trials and Ono Pharmaceutical Co., Ltd. funded Hatake 2016, which are the pharmaceutical companies producing nivolumab.
Excluded studies
After screening of titles/abstracts we excluded 561 records that did not match our inclusion criteria. We evaluated five study reports in more detail, which were finally excluded: three trials were not prospectively planned, one study evaluated people with non‐HL only and one report was a case report (see Characteristics of excluded studies table).
Risk of bias in included studies
Overall, we considered potential risk of bias as high, due to the non‐randomised study design, the unblinded outcome assessment and the absence of a control group. For further information, see the 'Risk of bias' sections in the Characteristics of included studies table and Figure 2 ('Risk of bias' summary figure presenting all our judgements in a cross‐tabulation).
2.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Internal validity
Representative study group (selection bias)
All trials were non‐randomised with no control arm. As selection bias was not assessable in this type of trial, we judged risk of selection bias as unclear. However, recurrent cHL was an inclusion criterion in all included studies.
Complete outcome assessment/follow‐up (attrition bias)
We judged the risk of attrition bias to be low because the analyses reported results for all included participants.
For QoL, given for a subset of participants (cohort B) in CheckMate 205, follow‐up data for only 44/80 participants were available. Therefore, we judged the risk of bias for QoL to be high.
Outcome assessors blinded to investigated determinant (detection bias)
Two trials did not blind outcome assessors (CheckMate 205; Hatake 2016) (potential high risk of bias) and one study had unclear blinding (CheckMate 039). For OS, lack of blinding was not an issue, therefore we judged risk of bias for OS as low.
Important prognostic factors or follow‐up taken adequately into account (confounding)
All included trials reported previous treatments with ASCT and BV. CheckMate 039 and CheckMate 205 separately reported clinical activity results for participants in whom previous ASCT and BV failed, participants in whom BV failed who did not undergo ASCT and participants who did not receive ASCT. However, no multi‐variable analyses taking into account important prognostic factors like pretreatments, participant age or the length of follow‐up were reported. Therefore, we judged the risk of bias due to confounding to be high.
External validity
We considered the risk of reporting bias as high related to the criterion well‐defined study groups, as all trials included heterogenous participant populations and they did not report doses for the received pretreatments.
Follow‐up data, outcome reporting and the methods used for risk‐estimation were well‐defined, therefore we judged these criteria for all trials as low risk of bias.
Effects of interventions
See: Table 1
Primary outcome: overall survival
Two studies evaluated OS. CheckMate 205 reported that median OS was not reached after a median follow‐up of 18 months (interquartile range (IQR) 15 to 22 months) for the overall study population, meaning that more than 50% of participants are still alive. The one‐year OS was 92% (95% confidence interval (CI) 88% to 95%) for the overall study population; 93% (95% CI 82% to 98%) for cohort A (63 participants with cHL after failure of ASCT); 95% (95% CI 87% to 98%) for cohort B (80 participants with cHL after failure of ASCT and subsequent brentuximab vedotin treatment); and 90% (95% CI 82% to 94%) for cohort C (100 participants with cHL after failure of ASCT, and previous or subsequent (or both) brentuximab vedotin treatment). Hatake 2016 reported 100% OS after six months.
Overall survival in participants not treated with nivolumab
Broeckelmann 2017 was a retrospective analysis of people with third or higher relapsed/refractory cHL, CheckMate 205 had a median number of previous chemotherapy regimens of four and Hatake 2016 had a median number of previous chemotherapy regimens of three. OS was 73.2% (95% CI 62.6 to 83.8) at 12 months for all participants. In Broeckelmann 2017, participants with third relapse who underwent previous ASCT had an OS of 69.4% (95% CI 56.5% to 82.3%) at 12 months. The OS of participants who had a third relapse who did not receive ASCT was 62.5% (95% CI 29.0% to 96.0%) at 12 months. The OS at six months for both groups was 89.6% (95% CI 82.4% to 96.9%), in contrast to 100% in Hatake 2016.
Primary outcome: quality of life
Only one of the three cohorts of CheckMate 205 (cohort B, 80 participants with cHL after failure of ASCT and subsequent brentuximab vedotin treatment) reported QoL using the EQ‐5D visual analogue scale (developed by the EuroQol Group; Brooks 1996), and the EORTC QLQ‐C30 (developed by EORTC to measure QoL; Aaronson 1993). The scores increased over time with nivolumab treatment, indicating improved QoL (EQ‐5D: from 62 (standard deviation (SD) 30) at baseline (72 (90%) participants) to 80 (SD 18) at week 33 (44 (55%) participants); EORTC QLQ‐C30 suggested improvement from baseline across functional, symptom and global health scores). However, at week 33 only a subset of the included participants filled out the instruments.
Secondary outcome: progression‐free survival
All trials reported PFS. CheckMate 039 published an investigator‐assessed PFS at six months of 86% (95% CI 62% to 95%). The overall PFS in CheckMate 205 was 14.7 (95% CI 11.3 to 18.5). The study also reported data for the three cohorts (A: 63 participants with cHL after failure of ASCT, B: 80 participants with cHL after failure of ASCT and subsequent brentuximab vedotin treatment, C: 100 participants with cHL after failure of ASCT, and previous or subsequent (or both) brentuximab vedotin treatment). The median PFS was 18.3 months (95% CI 11.1 to 22.4) for cohort A, 14.7 months (95% CI 10.5 to 19.6) for cohort B and 11.9 months (95% CI 11.1 to 18.4) for cohort C.
Hatake 2016 presented a centrally assessed PFS at six months of 60% (95% CI 31.8% to 79.7%).
Progression‐free survival in participants not treated with nivolumab
The retrospective analysis of participants with third or higher relapse of cHL showed a six‐month PFS of 76.3% (95% CI 66.1% to 86.4%) for all included participants (Broeckelmann 2017). The PFS at 12 months' follow‐up was 50.8% (95% CI 38.9% to 62.8%). The 12‐month PFS for participants with a third relapse and previous ASCT was 44.9% (95% CI 31.0% to 58.8%) and for participants with third relapse and without ASCT was 50.0% (95% CI 15.4% to 84.6%).
Secondary outcome: response rate
CheckMate 039 reported a complete response rate of 17% and a partial response rate of 70% at median follow‐up of 86 weeks (range 32 to 107 weeks).
In CheckMate 205, the median duration of response overall was 16.6 months (95% CI 13.2 to 20.3). For cohorts A it was 20.3 months, for cohort B it was 15.9 months and for cohort C it was 14.5 months. Overall, the complete response rate was 16%, while 29% of participants received complete response in cohort A, 13% in cohort B and 12% in cohort C. There was a partial response in 53% of participants overall and 37% of participants in cohort A, 55% of participants in cohort B and 61% of participants in cohort C.
Hatake 2016 reported for a centrally assessed response (one participant ineligible) a complete response rate of 25% and a partial response of 56.3% at a median follow‐up of 9.8 months (range 6 to 11 months).
Secondary outcome: treatment‐related mortality
None of the trials reported TRM.
Secondary outcome: overall rate of grade 3 and grade 4 adverse events, including potential relationship between intervention and adverse reaction
CheckMate 039 reported at a median follow‐up of 86 weeks (range 32 to 107 weeks) 52% of grade 3 or 4 AEs.
CheckMate 205 reported drug‐related AEs only after a median follow‐up of 18 months (IQR 15 to 22 months). The most common drug‐related AEs were fatigue (23%), diarrhoea (15%), infusion reactions (14%) and rash (12%). The most common grade 3 to grade 4 drug‐related AEs for this follow‐up timeframe were lipase increases (5%), neutropenia (3%) and alanine transaminase increases (3%).
Hatake 2016 presented data at a median follow‐up of 9.8 months (range 6 to 11 months). Four of 17 (23.5%) participants developed grade 3 or 4 AEs.
Secondary outcome: overall rate of serious adverse events
CheckMate 205 reported only drug‐related SAEs. About 2% of participants had infusion reactions and 1% had pneumonitis.
Adverse events in participants not treated with nivolumab
Due to data deviations, the results of the studies included in this review could not be reasonably compared with those of the retrospective analysis (Broeckelmann 2017).
Discussion
Summary of main results
Although our search did not identify any eligible RCTs, we uploaded available full‐texts of the three included studies into the software RobotReviewer. The software recognised correctly that one study was not an RCT and, therefore, did not extract any data of this study. However, the two remaining studies were falsely labelled to be RCTs and characteristics of included study were extracted, in a sufficient way for types of participants and types of interventions.
The following clinical findings emerged from this Cochrane Review in participants with heavily pretreated HL, for whom currently only three non‐randomised, uncontrolled trials were published (283 individuals).
Median OS was not reached (the time point when only 50% of participants were alive) in one study after 12 months of follow‐up and was 100% in another trial after six months of follow‐up.
Based on the currently available research, we were unable to draw any conclusions with regard to QoL as there were insufficient data available.
PFS was between 60% and 86% at six months, median PFS between 11.9 and 18.3 months, depending on participant population and previous treatments.
Complete response rates ranged from 12% to 29%, depending on inclusion criteria and participant characteristics.
None of the trials reported TRM.
Only one trial reported SAEs, with a low number of participants experiencing SAEs. Depending on follow‐up time, between 23% and 52% of participants developed grade 3 or 4 AEs. Most common were fatigue, diarrhoea, infusion reactions and rash.
When interpreting these results, it is important to consider that RCTs are needed to confirm these findings.
Overall completeness and applicability of evidence
We found three published non‐randomised, uncontrolled trials evaluating nivolumab in adults with relapsed HL of whom most had received intensive therapies such as ASCT before. These trials included 283 participants who had received different therapeutic regimens before entering the trials. Therefore, the participant population might have been too small and heterogenous to generalise results. Currently, 14 trials are ongoing, of which two studies are designed as RCTs (one for participants receiving first‐line treatment, one for participants with relapsed HL) (NCT01822509; NCT01896999; NCT02408861; NCT02572167; NCT02758717; NCT02927769; NCT02940301; NCT02973113; NCT03004833; NCT03016871; NCT03033914; NCT03057795; NCT03138499; NCT03161613). The publication of the results of these studies will necessitate an update of this review. The conclusions of this updated review could differ from those of the present review, and may allow a better judgement about the efficacy and safety of nivolumab.
One of the primary outcomes of this review was OS, due to its clinical relevance and its importance for participants. Moreover, it is a commonly accepted measure of the benefit of cancer treatment, as well as an endpoint that is not subject to bias by the evaluator. Two studies reported that median survival was not reached after six months (100% of participants were alive) or 12 months of follow‐up. Two of the three cohorts of one study reported survival rates over 94%. However, data were not reported for the third cohort within this trial.
The other primary outcome of this review, QoL, is of utmost importance for patients, especially those with several pretreatments. One of three cohorts from one study reported QoL but follow‐up data were lacking, therefore an overall assessment was not possible. Detailed data for all three study cohorts might help to assess QoL sufficiently.
Quality of the evidence
All three trials were prospectively planned, non‐randomised and uncontrolled trials leading to potential high risk of bias. Currently, there is no standard instrument available to assess risk of bias for this type of trials. We used the form developed by the Cochrane Childhood Cancer Group.
As we included three small observational trials only (altogether fewer than 300 participants), the certainty of evidence was low to very low for most of the outcomes (see interactive Summary of Findings table and Summary of findings table 1).
Potential biases in the review process
We tried to avoid bias by dually carrying out all relevant processes (searching, data collection, analysis). We performed a sensitive search strategy and searched all relevant data of international HL conferences and study registries to detect potential publication bias. In addition, two authors of this review (AE, BvT) are very experienced in clinical studies on HL (AE is the head of the GHSG). Therefore, we are confident that we have identified all studies relevant to the review question. We are not aware of any obvious flaws in our review process.
Agreements and disagreements with other studies or reviews
To our knowledge this is the first comprehensive systematic review focusing on nivolumab for adults with HL.
Authors' conclusions
Implications for practice.
To date, data on overall survival, quality of life, progression‐free survival, response rate, or short‐ and long‐term adverse events are available from small non‐randomised, uncontrolled trials only. The three trials included heavily pretreated participants, which had previously undergone regimens of BV or ASCT. For these participants, median overall survival was not reached after follow‐up times of up to 16 to 23 months, depending on pretreatment, meaning that more than 50% of these heavily pretreated participants with a limited life expectancy were alive at 16 to 23 months. Complete response rates ranged between 12% and 29%. Quality of life data were reported for one cohort out of three only, with limited follow‐up data so that meaningful conclusions are 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 Hodgkin's lymphoma except for heavily pretreated people, which had previously undergone regimens of BV or ASCT. When interpreting these results, it is important to consider that well‐designed randomised controlled trials should confirm these findings.
Implications for research.
Randomised controlled trials or at least non‐randomised trials with a control group are needed to confirm findings of this review. As there are 14 ongoing trials evaluating nivolumab, of which two are randomised, it is possible that an update of this review will be published in the near future. It might well be that this update will show different results than those published in this systematic review.
Notes
Some passages in this protocol, especially in the Methods section, are from the standard template of the CHMG.
Acknowledgements
We thank the following members of Cochrane Haematological Malignancies Group (CHMG) for their comments, which improved the review: Nicola Köhler (Editorial Base), Professor Benjamin Djulbegovic and Professor Robert Killeen (Editors), and Celine Fournier (Consumer Editor). Also we thank Dr Karla Soares‐Weiser and Dr David Tovey of the Cochrane Editorial Unit.
Appendices
Appendix 1. CENTRAL search strategy
ID Search
#1 MeSH descriptor: [Lymphoma] this term only
#2 MeSH descriptor: [Hodgkin Disease] explode all trees
#3 Germinoblastom*
#4 Reticulolymphosarcom*
#5 Hodgkin*
#6 (malignan* near/2 lymphogranulom*) or (malignan* near/2 granulom*)
#7 #1 or #2 or #3 or #4 or #5 or #6
#8 nivolumab*
#9 opdivo*
#10 nivo*
#11 (BMS‐936558 or MDX‐1106 or ONO‐4538 or BMS936558 or MDX1106 or ONO4538)
#12 (Anti‐PD‐1 or Anti‐PD1)
#13 ("death 1 (PD‐1)" near/3 checkpoint‐inhibitor*)
#14 #8 or #9 or #10 or #11 or #12 or #13
#15 #7 and #14
Appendix 2. MEDLINE (via Ovid) search strategy
| # | Searches |
| 1 | *LYMPHOMA/ |
| 2 | exp HODGKIN DISEASE/ |
| 3 | Germinoblastom$.tw,kf,ot. |
| 4 | Reticulolymphosarcom$.tw,kf,ot. |
| 5 | Hodgkin$.tw,kf,ot. |
| 6 | (malignan$ adj2 (lymphogranulom$ or granulom$)).tw,kf,ot. |
| 7 | or/1‐6 |
| 8 | nivolumab*.tw,kf,ot,nm. |
| 9 | Opdivo*.tw,kf,ot. |
| 10 | nivo*.tw,kf,ot. |
| 11 | (BMS‐936558 or MDX‐1106 or ONO‐4538 or BMS936558 or MDX1106 or ONO4538).tw,kf,ot. |
| 12 | (Anti‐PD‐1 or Anti‐PD1).tw,kf,ot. |
| 13 | ("death 1 (PD‐1)" adj3 checkpoint‐inhibitor*).tw,kf,ot. |
| 14 | or/8‐13 |
| 15 | 7 and 14 |
Appendix 3. Embase (via EBSCO) search strategy
| No. | Query |
| #1 | 'lymphoma'/mj |
| #2 | 'hodgkin disease'/exp |
| #3 | germinoblastom* |
| #4 | reticulolymphosarcom* |
| #5 | hodgkin*:ti,ab,de |
| #6 | hodgkin*:tt |
| #7 | (malignan* NEAR/2 (lymphogranulom* OR granulom*)):ti,ab,de |
| #8 | (malignan* NEAR/2 (lymphogranulom* OR granulom*)):tt |
| #9 | #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 |
| #11 | nivolumab* |
| #12 | opdivo* |
| #13 | nivo* |
| #14 | 'bms 936558' OR 'mdx 1106' OR 'ono 4538' OR bms936558 OR mdx1106 OR ono4538 |
| #15 | 'anti pd 1' OR 'anti pd1' |
| #16 | 'death 1 (pd‐1)' NEAR/3 'checkpoint inhibitor*' |
| #17 | #11 OR #12 OR #13 OR #14 OR #15 OR #16 |
| #18 | #9 AND #17 |
Appendix 4. International Pharmaceutical Abstracts (via EBSCO) search strategy
| # | Query |
| S1 | Germinoblastom* |
| S2 | Reticulolymphosarcom* |
| S3 | Hodgkin* OR (SU Lymphoma) |
| S4 | (malignan* N2 (lymphogranulom* or granulom*)) |
| S5 | S1 OR S2 OR S3 OR S4 |
| S6 | nivolumab* |
| S7 | opdivo* |
| S8 | nivo* |
| S9 | BMS‐936558 OR MDX‐1106 OR ONO‐4538 OR BMS936558 OR MDX1106 OR ONO4538 |
| S10 | Anti‐PD‐1 OR Anti‐PD1 |
| S11 | "death 1 (PD‐1)" N3 checkpoint‐inhibitor* |
| S12 | S6 OR S7 OR S8 OR S9 OR S10 OR S11 |
| S13 | S5 AND S12 |
Appendix 5. EU Clinical Trials Register search strategy
hodgkin in the condition
AND nivolumab in the intervention
Appendix 6. ClinicalTrials.gov search strategy
Conditions: Hodgkin OR Lymphom
Interventions: nivolumab OR BMS‐936558 OR MDX‐1106 OR ONO‐4538 OR Opdivo
Appendix 7. WHO ICTRP search strategy
hodgkin in the condition
AND nivolumab in the intervention
Appendix 8. Assessment of heterogeneity and risk of bias
Assessment of risk of bias in included studies
Randomised controlled trials
As we identified neither randomised controlled trials (RCTs) nor non‐RCTs with a control group, we could not use the Cochrane 'Risk of bias' tool or Risk Of Bias in Non‐randomised Studies ‐ of Interventions (ROBIN‐I) for risk of bias assessment. We used the "risk of bias assessment criteria for observational studies" tool provided by the Childhood Cancer Group to assess risk of bias for prospectively planned studies without a control arm (see Table 2).
If we identify RCTs for future updates, we will assess risk of bias with the Cochrane 'Risk of bias' tool for each RCT. Thereafter, we will use the RobotReviewer software to assess risk of bias (RobotReviewer 2015), and a second review author will compare these results with the results from the first review author. Both review authors will resolve any discrepancies between the results from the first review author and the software by discussion. We will use the following criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b).
Sequence generation.
Allocation concealment.
Blinding (participants, personnel, outcome assessors).
Incomplete outcome data.
Selective outcome reporting.
Other sources of bias.
For every criterion, we will make a judgement using one of three categories.
'Low risk:' if the criterion was adequately fulfilled in the study (i.e. the study was at a low risk of bias for the given criterion).
'High risk:' if the criterion was not fulfilled in the study (i.e. the study was at high risk of bias for the given criterion).
'Unclear risk:' if the study report did not provide sufficient information to allow for a judgement of 'low risk' or 'high risk,' or if the risk of bias was unknown for one of the criteria listed above.
In case we identify non‐randomised studies with a control arm in review updates, we will independently assess eligible studies for methodological quality and risk of bias (using the ROBIN‐I tool) (Sterne 2016). The quality assessment strongly depends upon information on the design, conduct and analysis of the trial. The two review authors will resolve any disagreements regarding the quality assessments by consulting a third review author until they reach a consensus.
We will assess the following domains of bias.
Bias due to confounding.
Bias in selection of participants into the study.
Bias in classification of interventions.
Bias due to deviations from intended interventions.
Bias due to missing data.
Bias in measurement of outcomes.
Bias in selection of the reported result.
For every criterion, we will make a judgement using one of five response options.
Yes.
Probably yes.
Probably no.
No.
No information.
Non‐randomised prospectively planned trials (including control arm)
As reported in the Types of studies section, we would have included non‐randomised studies with a control arm only if we did not identify any RCTs. However, we did not identify any non‐randomised prospectively planned study with a control arm. In case we identify non‐randomised studies with a control arm for review updates, we will independently assess eligible studies for methodological quality and risk of bias (using the ROBIN‐I tool) (Sterne 2016).
Uncontrolled studies
As reported in the Types of studies section, we included non‐randomised studies without a control arm only as we did not identify any RCTs. We added the following criteria to assess potential risk of bias, as the ROBIN‐I tool works for controlled trials only.
Two review authors independently assessed eligible studies for methodological quality and risk of bias (using the "risk of bias assessment criteria for observational studies" tool provided by the Childhood Cancer Group (see Table 2). The quality assessment strongly depends upon information on the design, conduct and analysis of the trial. The two review authors resolved any disagreements regarding the quality assessments by discussion, in case they would not have reached a consensus they would have consulted a third review author until final consensus.
We assessed the following domains of bias.
Internal validity.
Representative study group (selection bias).
Complete outcome assessment/follow‐up (attrition bias).
Outcome assessors blinded to investigated determinant (detection bias).
Important prognostic factors or follow‐up taken adequately into account (confounding).
External validity.
Well‐defined study group (reporting bias).
Well‐defined follow‐up (reporting bias).
Well‐defined outcome (reporting bias).
Well‐defined risk estimates (analyses).
For every criterion, we made a judgement using one of three response options.
High risk of bias.
Low risk of bias.
Unclear risk of bias.
Measures of treatment effect
For RCTs, we would have extracted dichotomous outcomes from both study arms and reported them as risk ratios (RR) with 95% confidence intervals (CIs) (Deeks 2011).
For updates identifying RCTs, we will extract and report hazard ratios (HR). If HRs are unavailable, we will estimate the HR by using the available data as described by Parmar 1998 and Tierney 2007.
For review updates identifying RCTs, we will extract and report the mean or mean change from baseline, standard deviation and total number of participants in both the experimental and control arms. If the same scale is used to measure effect, we will perform analyses using the mean difference (MD) with 95% CIs. If the included studies used different scales to measure effect, we will use standardised mean differences with 95% CIs.
Unit of analysis
Studies with multiple treatment groups
As recommended in Section 16.5.4 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a), for review updates identifying studies with multiple treatment groups, we will combine arms as long as they can be regarded as subtypes of the same intervention. When arms cannot be pooled this way, we will compare each arm with the common comparator separately. For pair‐wise meta‐analysis, we will split the 'shared' group into two or more groups with smaller sample size, and include two or more (reasonably independent) comparisons. For this purpose, for dichotomous outcomes, both the number of events and the total number of participants will be divided up, and for continuous outcomes, the total number of participants will be divided up with unchanged means and standard deviations.
Assessment of heterogeneity
In case of meta‐analyses, we would have assessed heterogeneity of treatment effects between trials using a Chi2 test with a significance level at P value < 0.1. For future updates containing meta‐analyses we will use the I2 statistic to quantify possible heterogeneity (I2 statistic value > 30% to signify moderate heterogeneity, I2 statistic > 75% to signify considerable heterogeneity) (Deeks 2011). If heterogeneity is above 80%, and we identify a cause for the heterogeneity, we will explore potential causes through sensitivity and subgroup analyses. If we cannot find a reason for heterogeneity, we will not perform a meta‐analysis, but will comment on results from all studies and presented these in tables.
Assessment of reporting biases
In review updates including meta‐analyses involving at least 10 trials, we intend to explore potential publication bias by generating a funnel plot and statistically testing this by conducting a linear regression test (Sterne 2011). We will consider a P value of less than 0.1 as significant for this test.
Data synthesis
For review updates if the clinical and methodological characteristics of individual studies with a control group are sufficiently homogeneous, we will pool the data in a meta‐analysis. We will perform analyses according to the recommendations of theCochrane Handbook for Systematic Reviews of Interventions (Deeks 2011). We will use Review Manager 5 (RevMan 5) software for analyses (Review Manager 2014). One review author will enter the data into the software, and a second review author will check the data for accuracy. As we expect some heterogeneity in trial design, we will use a random‐effects model.
We will not conduct meta‐analyses by including both RCTs and non‐RCTs. In case meta‐analysis is feasible for non‐randomised but controlled trials, we will only analyse outcomes with adjusted effect estimates if these are adjusted for as recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Reeves 2011).
Subgroup analysis and investigation of heterogeneity
For future updates including meta‐analyses, we will perform subgroup analyses of the following characteristics.
Age.
Stage of disease (first‐line treatment versus relapsed and refractory disease, early versus advanced stage).
Type of previous therapy (autologous stem cell transplantation, brentuximab vedotin).
Duration of follow‐up.
We will use the tests for interaction to test for differences between subgroup results.
Sensitivity analysis
For future updates including meta‐analyses, we will perform sensitivity analyses for the following.
Quality components.
Preliminary results versus mature results.
Characteristics of studies
Characteristics of included studies [ordered by study ID]
CheckMate 039.
| Methods | Phase I study consisting of dose escalation and expansion cohorts | |
| Participants | Eligibility criteria
Nivolumab cohort: Participants recruited: 23 Mean age: 35 years (range 20 to 54) Gender: 12 (52%) men, 11 women Stage of disease:
Extent of pretreatment (number of previous systemic therapies):
|
|
| Interventions |
Dose escalation cohort: nivolumab 1mg/kg bodyweight with escalation to 3 mg/kg. Max tolerated dose not reached. Nivolumab cohort: Expansion cohort: nivolumab 3 mg/kg at week 1, week 4 and then every 2 weeks until disease progression or CR for a max of 2 years |
|
| Outcomes | Primary outcomes:
Secondary outcomes:
Assessment:
Results:
|
|
| Notes | Supported by: Bristol‐Myers Squibb Several authors declared financial conflicts of interest, including the first and the last author. The original study also included people with non‐Hodgkin's B‐ and T‐cell lymphoma, as well as multiple myeloma and follicular B‐cell lymphoma. The data and study results for participants with cHL were reported separately and could therefore be included in this review. Study also included a cohort evaluating nivolumab plus ipilimumab; this cohort included less than 80% of people with HL and no disease‐specific results were reported for this cohort. Therefore, we excluded this cohort. |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Representative study group (selection bias) | Unclear risk | Histologically confirmed evidence of relapsed or refractory HL as inclusion criterion |
| Complete outcome assessment/follow‐up (attrition bias) | Low risk | Quote: "All the patients who received at least one dose of nivolumab were included in the safety and efficacy analyses." |
| Outcome assessors blinded to investigated determinant (detection bias) | Unclear risk | Blinding NR |
| Important prognostic factors or follow‐up taken adequately into account (confounding) | High risk | Clinical activity results separately reported for:
Follow‐up not taken into account No multi‐variable analysis reported |
| Well‐defined study group (reporting bias) | High risk | Doses of prior treatments NR |
| Well‐defined follow‐up (reporting bias) | Low risk | Quote: "The median duration of follow‐up was 40 weeks (range, 0 to 75)" |
| Well‐defined outcome (reporting bias) | Low risk | All outcomes reported Outcomes well‐defined in appendix |
| Well‐defined risk estimates (analyses) | Low risk | Use of Kaplan‐Meier methods described for time‐to‐event outcomes |
CheckMate 205.
| Methods | Multi‐centre, non‐comparative multi‐cohort, single‐arm phase II study Cohorts:
|
|
| Participants | Eligibility criteria
In total:
Cohort A:
Cohort B:
Cohort C:
|
|
| Interventions | Participants received nivolumab 3 mg/kg IV over 60 minutes at every 2 weeks until disease progression, death, unacceptable toxicity, withdrawal of consent or study end (≥ 5 years of follow‐up) | |
| Outcomes | Primary outcomes
Secondary outcomes
Exploratory endpoints
Assessment:
Results: In total:
Cohort A: At median follow‐up: 14 months (range 1 to 20)
Cohort B: At median follow‐up: 8.9 months (range 1.9 to 11.7)
At median follow‐up: 15 months (range 2 to 19)
Cohort C: At median follow‐up: 8.8 months
|
|
| Notes | Other study cohorts included:
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Representative study group (selection bias) | Unclear risk | Recurrent cHL after failure of ASCT and subsequent BV as inclusion criterion |
| Complete outcome assessment/follow‐up (attrition bias) | Low risk | Quote: "All patients who received at least one dose of nivolumab were included in the clinical activity and safety analyses." "80 patients were recruited and enrolled into the trial, all of whom were given treatment and included in the analyses." |
| Outcome assessors blinded to investigated determinant (detection bias) | High risk | Blinding NR |
| Important prognostic factors or follow‐up taken adequately into account (confounding) | High risk | Clinical activity results separately reported for
Follow‐up not taken into account No multi‐variable analysis reported |
| Well‐defined study group (reporting bias) | High risk | Doses of prior treatments NR |
| Well‐defined follow‐up (reporting bias) | Low risk | Quote: "median follow‐up of 8.·9 months (IQR 7.8 – 9.9)" |
| Well‐defined outcome (reporting bias) | Low risk | All outcomes reported Statistical methods well‐defined |
| Well‐defined risk estimates (analyses) | Low risk | Use of Kaplan‐Meier methods including median values and 95% CIs for time‐to event outcomes well defined |
Hatake 2016.
| Methods | Non‐randomised, open‐label, multi‐centre phase II study
Median duration of follow‐up: 9.8 months (range 6.0 to 11.1) |
|
| Participants | Eligibility criteria
Participants enroled (17 in safety analysis set) Median age: 63 years (range: 29 to 83) Gender: 13 (76.5%) men Stage of disease
Extent of pretreatment
|
|
| Interventions | Participants received their first dose of nivolumab 3 mg/kg on day 1 of treatment phase; subsequent doses were to be administered on day 1 of each 14‐day cycle nivolumab was continued if treatment continuation criteria were met; trial was to continue until all participants discontinued treatment in the event of progressive disease, an unacceptable AE or other clinically relevant reasons. | |
| Outcomes | Primary endpoint:
Secondary endpoints:
Assessment
Results At median follow‐up of 5.1 months
At median follow‐up of 9.8 months (range 6 to 11)
|
|
| Notes | Funded by Ono Pharmaceutical Co., Ltd. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Representative study group (selection bias) | Unclear risk | Histopathological diagnosis of cHL as eligibility criterion |
| Complete outcome assessment/follow‐up (attrition bias) | Low risk | 17 participants enroled; 17 participants included in safety analysis and 16 participants included in efficacy analysis |
| Outcome assessors blinded to investigated determinant (detection bias) | High risk | Open‐label design |
| Important prognostic factors or follow‐up taken adequately into account (confounding) | High risk | Prior treatments assessed, including prior BV, prior ASCT and prior radiotherapy Length of follow‐up not taken into account No multi‐variable analysis described |
| Well‐defined study group (reporting bias) | High risk | Doses of prior treatments NR |
| Well‐defined follow‐up (reporting bias) | Low risk | Quote: "The median (range) duration of treatment and follow‐up were 7.0 (1.4–10.6) months and 9.8 (6.0–11.1) months, respectively." |
| Well‐defined outcome (reporting bias) | Low risk | All outcomes reported Statistical methods well‐defined |
| Well‐defined risk estimates (analyses) | Low risk | Using the Clopper‐Pearson methods for 95% CI for response rates and the Kaplan‐Meier method for time‐to‐event outcomes was well described. |
AE: adverse events; ASCT: autologous stem cell transplantation; BV: brentuximab vedotin; cHL: classical Hodgkin's lymphoma; CI: confidence interval; CR: complete response; CS: clinical stage; CT: computed tomography; DOR: duration of response; ECOG: Eastern Cooperative Oncology Group; esc: escalated; FDG: fluorodeoxy‐D‐glucose; HL: Hodgkin's lymphoma; IF‐RT: involved‐field radiotherapy; IN‐RT: involved‐node radiotherapy; IQR: interquartile range; IRRC: immune‐related response criteria; IV: intravenous; IGEV: ifosfamide, gemcitabine and vinorelbine; max: maximum; min: minimum; MRI: magnetic resonance imaging; MT: magnetisation transfer; NA: not applicable/available; NFT: no further treatment; NR: not reported; OR: overall response; ORR: objective response rate; OS: overall survival; PBSC: peripheral blood stem cell; PD: programmed death; PET: positron emission tomography; PFS: progression‐free survival; PR: partial response; QoL: quality of life; SAE: serious adverse events; SD: standard deviation; VEBEP: vinblastine, etoposide, bleomycin, epirubicin, prednisone; WHO: World Health Organization.
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Armand 2016 | Adults with non‐Hodgkin's lymphoma as study population |
| Falchi 2016 | Retrospective study |
| Herbaux 2015 | Retrospective study |
| Merryman 2017 | Retrospective study |
| Yared 2016 | Case report |
Characteristics of ongoing studies [ordered by study ID]
NCT01822509.
| Trial name or title | Ipilimumab or nivolumab in treating adults with relapsed hematologic malignancies after donor stem cell transplant |
| Methods | Phase I study
|
| Participants | Eligibility criteria
|
| Interventions | Arm A: ipilimumab Arm B: nivolumab |
| Outcomes | (Current) primary outcome:
(Current) secondary outcomes:
|
| Starting date | 9 April 2013; planned primary completion date: 31 December 2018 |
| Contact information | Principal Investigator: Matthew Davids, Dana‐Farber Cancer Institute |
| Notes | Study supported by: National Cancer Institute (NCI) (Study Sponsor) |
NCT01896999.
| Trial name or title | Brentuximab vedotin and nivolumab with or without ipilimumab in treating adults with relapsed or refractory Hodgkin's Lymphoma |
| Methods | Randomised phase I/II trial Phase I study consisting of dose escalation followed by a phase II study Recruitment period
"Patients will be randomised into 1 of 2 arms" |
| Participants | Eligibility criteria (phase I)
Interim results for 2 cohorts: 20 July 2016:
Mean age: 46 years (range 25 to 53) Gender: 6 men Stage of disease
Extent of pretreatment
3 October 2017
Mean age: 44 years (range 21 to 70) Gender: 9 men Extent of pretreatment
Brentuximab vedotin, ipilimumab, nivolumab‐cohort
|
| Interventions | Arm 1:
Arm 2:
|
| Outcomes | Primary outcome:
Secondary outcome:
|
| Starting date | 13 July 2013; estimated primary completion date: not reported; interim results for some of the cohorts already reported |
| Contact information | Principal Investigator: Catherine Diefenbach, ECOG‐ACRIN Cancer Research Group |
| Notes | Funding not reported; several authors declared financial conflicts of interest |
NCT02408861.
| Trial name or title | Nivolumab and ipilimumab in treating adults with HIV associated relapsed or refractory classical Hodgkin's lymphoma or solid tumours that are metastatic or cannot be removed by surgery |
| Methods | Phase I
|
| Participants | Inclusion criteria
|
| Interventions | Arm A: nivolumab Arm B: ipilimumab Participants receive nivolumab IV over 60 minutes on day 1. Participants in dose level 2 also receive ipilimumab IV over 90 minutes on day 1 of every third course of nivolumab, and participants in dose level ‐2 also receive ipilimumab IV over 90 minutes on day 1 of every sixth course of nivolumab. Courses repeat every 14 days for up to 46 courses of nivolumab (with ipilimumab if receiving dose level 2 or ‐2) in the absence of disease progression or unacceptable toxicity. |
| Outcomes | Current primary outcomes:
|
| Starting date | 27 August 2015; estimated primary completion date: 31 December 2020 |
| Contact information | Principal Investigator: Lakshmi Rajdev AIDS Malignancy Consortium |
| Notes | Study supported by (Study Sponsor): National Cancer Institute (NCI) |
NCT02572167.
| Trial name or title | A study of brentuximab vedotin combined with nivolumab for relapsed or refractory Hodgkin's lymphoma |
| Methods | Phase I/II study Study start date: October 2015; estimated completion date 2020 Study location: US |
| Participants | Eligibility criteria
Participants enroled: Interim analysis: Participants enroled to this date: 62 Median age: 36 years Gender: 52% women Stage of disease
|
| Interventions | Brentuximab vedotin 1.8 mg/kg by IV infusion for up to 4 cycles + nivolumab 3 mg/kg by IV infusion for up to 4 cycles |
| Outcomes | Primary outcomes:
Secondary outcomes
Assessment:
Interim results:
|
| Starting date | Study start date: October 2015; estimated study completion date: October 2020 |
| Contact information | Study director: Faith Galderisi, DO, Seattle Genetics, Inc. |
| Notes | Study sponsor: Seattle Genetics, Inc. Collaborator: Bristol‐Myers Squibb |
NCT02758717.
| Trial name or title | Phase II, multi‐center trial of nivolumab and brentuximab vedotin in individuals with untreated Hodgkin lymphoma over the age of 60 years or unable to receive standard adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy |
| Methods | Phase II
|
| Participants | Inclusion criteria
Exclusion criteria
|
| Interventions | Arm A: brentuximab vedotin, nivolumab Participants receive brentuximab vedotin IV over 30 minutes and nivolumab IV over 60 minutes on day 1. Treatment repeats every 21 days for 7 courses and 6‐8 weeks in course 8 in the absence of disease progression or unacceptable toxicity |
| Outcomes | Primary objective:
Secondary objective:
Tertiary objective:
|
| Starting date | 13 May 2016; estimated primary completion date: 13 November 2019 |
| Contact information | Principal investigator: Bruce Cheson, Academic and Community Cancer Research United |
| Notes | Study sponsor: Academic and Community Cancer Research United; Collaborator: National Cancer Institute (NCI) |
NCT02927769.
| Trial name or title | A phase I study of ipilimumab and nivolumab in advanced HIV‐associated solid tumours with expansion cohorts in HIV‐associated solid tumours and a cohort of HIV‐associated classical Hodgkin's lymphoma |
| Methods | Phase I study
|
| Participants | Inclusion criteria
Exclusion criteria
|
| Interventions | Arm A: nivolumab, ipilimumab Participants receive nivolumab IV over 60 minutes on day 1. Participants in dose level 2 also receive ipilimumab IV over 90 minutes on day 1 of every third course of nivolumab, and participants in dose level ‐2 also receive ipilimumab IV over 90 minutes on day 1 of every sixth course of nivolumab. Courses repeat every 14 days for up to 46 courses of nivolumab (with ipilimumab if receiving dose level 2 or ‐2) in the absence of disease progression or unacceptable toxicity. |
| Outcomes | Primary objective:
Secondary objectives:
|
| Starting date | 27 August 2015; estimated primary completion date: 31 December 2020 |
| Contact information | Principal investigator: Lakshmi Rajdev, AIDS Malignancy Consortium |
| Notes | Study sponsor: National Cancer Institute (NCI) |
NCT02940301.
| Trial name or title | Ibrutinib and nivolumab in treating adults with relapsed or refractory classical Hodgkin's lymphoma |
| Methods | Phase II study, single group assignment, open label, treatment |
| Participants | Eligibility criteria
Exclusion criteria
|
| Interventions | Arm A: experimental: treatment (ibrutinib, nivolumab) Participants receive ibrutinib orally once daily on days 1‐21 and nivolumab IV continuously over 60 minutes on day 1 Treatment with nivolumab repeats every 21 days for up to 16 courses and treatment with ibrutinib continues in the absence of disease progression or unacceptable toxicity |
| Outcomes | Current primary outcomes
Current secondary outcomes
|
| Starting date | 20 December 2016; estimated primary completion date: 31 May 2019 (final data collection date for primary outcome) |
| Contact information | Principal investigator: Lapo Alinari Ohio State University Comprehensive Cancer Center |
| Notes | Study Sponsor: Ohio State University Comprehensive Cancer Center |
NCT02973113.
| Trial name or title | Nivolumab with Epstein Barr virus specific T cells (EB‐VSTS), relapsed/refractory EBV positive lymphoma (PREVALE) |
| Methods | Phase I, single‐group assignment, open label, treatment |
| Participants | Eligibility criteria Procurement inclusion
Treatment inclusion
And
Exclusion criteria Procurement exclusion
Treatment exclusion
|
| Interventions | EB‐VST cells + PD1 inhibitor nivolumab 3 mg/kg (maximum dose: 240 mg) every 2 weeks for total 4 doses and repeat 1 day prior to each EB‐VST infusion EB‐VST‐ 1 × 108/m2 at days +1 and +15. PD1 inhibitor nivolumab 3 mg/kg (maximum dose: 240 mg) every 2 weeks for total 4 doses and repeat a day prior to each EB‐VST infusion Can receive up to 3 additional infusions of EB‐VSTs with a single dose of nivolumab at 6‐12 week intervals starting ≥ 6 weeks after the second infusion if stable disease or a partial response at week 8 evaluation |
| Outcomes | Current primary outcome
For the purpose of this study, dose‐limiting‐toxicity will be defined as any of the below listed items considered to be primarily related to the EB‐VST infusion or nivolumab
Current secondary outcomes
|
| Starting date | 16 February 12016; estimated primary completion date: 16 April 2019 (final data collection date for primary outcome) |
| Contact information | Principal investigator: Ravi Pingali, MD, Baylor College of Medicine |
| Notes | Study sponsor: Baylor College of Medicine |
NCT03004833.
| Trial name or title | Nivolumab and AVD in early‐stage unfavourable classical Hodgkin lymphoma (NIVAHL) |
| Methods | Phase II, randomised, parallel assignment, open label, treatment |
| Participants | Eligibility criteria
Exclusion criteria
|
| Interventions | Arm A:
Arm B:
|
| Outcomes | Current primary outcome:
Current secondary outcomes:
|
| Starting date | 21 February 2017; estimated primary completion date: December 2018 (final data collection date for primary outcome) |
| Contact information | Principal investigator: Professor Andreas Engert |
| Notes | Study sponsor: University of Cologne |
NCT03016871.
| Trial name or title | Nivolumab, ifosfamide, carboplatin, and etoposide as second‐line therapy in treating adults with refractory or relapsed Hodgkin lymphoma |
| Methods | Phase II, single‐group assignment, open label, treatment |
| Participants | Eligibility criteria
Exclusion criteria
|
| Interventions | Participants receive nivolumab IV over 30 minutes on day 1. Courses repeat every 14 days for up to 6 weeks in the absence of disease progression or unacceptable toxicity Participants with CR or PR receive nivolumab for an additional 6 weeks Participants with SD or PD after 6‐week nivolumab treatment or participants with PR, SD or PD after 12‐week nivolumab treatment receive nivolumab IV over 30 minutes on day 1, etoposide IV on days 1‐3, ifosfamide IV continuously over 24 hours on day 2, and carboplatin IV on day 2. Treatment repeats every 21 days for up to 2 courses in the absence of disease progression or unacceptable toxicity |
| Outcomes | Current primary outcomes:
Current secondary outcomes:
Current other outcome:
|
| Starting date | 8 May 2017; estimated primary completion date: 24 April 2019 (final data collection date for primary outcome) |
| Contact information | Principal investigator: Robert Chen, MD, City of Hope Medical Center |
| Notes | Study sponsor: City of Hope Medical Center |
NCT03033914.
| Trial name or title | (B)VD followed by nivolumab as frontline therapy for higher risk patients with classical Hodgkin lymphoma |
| Methods | Phase I, non‐randomised, parallel assignment, open label, treatment Cohort A will include adults < 60 years of age with advanced stage (Stage III or IV) cHL who are at higher risk for relapse due to baseline IPS of 3‐7 or positive PET scan after 2 cycles of ABVD ("PET‐2 positive"). Cohort B will include adults ≥ 60 years of age with HL (any stage) and receive AVD |
| Participants | Eligibility criteria
The following eligibility criteria apply to both cohort A and B except when stated otherwise.
Exclusion criteria
|
| Interventions | High‐risk advanced‐stage HL
Older people with HL
|
| Outcomes | Current primary outcome
|
| Starting date | 25 January 2017; estimated primary completion date: January 2020 (final data collection date for primary outcome) |
| Contact information | Principal investigator: Alison Moskowitz, MD, Memorial Sloan Kettering Cancer Center |
| Notes | Study sponsor: Memorial Sloan Kettering Cancer Center |
NCT03057795.
| Trial name or title | Nivolumab and brentuximab vedotin after stem cell transplant in treating patients with relapsed or refractory high‐risk classical Hodgkin lymphoma |
| Methods | Phase II, single group assignment, open label, treatment |
| Participants | Eligibility criteria
Exclusion criteria
|
| Interventions | Beginning 30‐60 days post‐ASCT, participants receive brentuximab vedotin IV over 30 minutes and nivolumab IV over 60 minutes on day 1. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. |
| Outcomes | Current primary outcomes:
Current secondary outcomes:
|
| Starting date | 3 May 2017; estimated primary completion date: April 2019 (final data collection date for primary outcome) |
| Contact information | Principal investigator: Alex Herrera, MD, City of Hope Medical Center |
| Notes | Study sponsor: City of Hope Medical Center |
NCT03138499.
| Trial name or title | A study of nivolumab plus brentuximab vedotin versus brentuximab vedotin alone in patients with advanced stage classical Hodgkin lymphoma, who are relapsed/ refractory or who are not eligible for autologous stem cell transplant (CheckMate 812) |
| Methods | Phase III, randomised, parallel assignment, open label, treatment |
| Participants | Inclusion criteria
Exclusion criteria
|
| Interventions | Arm A
Arm B
|
| Outcomes | Current primary outcome
Current secondary outcomes
|
| Starting date | 16 May 2017; estimated primary completion date: 29 November 2020 (final data collection date for primary outcome) |
| Contact information | Study director: Bristol‐Myers Squibb |
| Notes | Study sponsor: Bristol‐Myers Squibb |
NCT03161613.
| Trial name or title | Study to assess the safety of nivolumab in the treatment of metastatic melanoma, lung cancer, renal cancer, squamous cell carcinoma of the head and neck, and chronic Hodgkin's lymphoma in adults in Mexico |
| Methods | Observational study, prospective |
| Participants | Eligibility criteria
Exclusion criteria
|
| Interventions | Other: non‐interventional |
| Outcomes | Current primary outcomes:
Current secondary outcomes:
|
| Starting date | 17 July 2017; estimated primary completion date: 1 April 2019 (final data collection date for primary outcome) |
| Contact information | Study director: Bristol‐Myers Squibb |
| Notes | Study sponsor: Bristol‐Myers Squibb |
ABVD: adriamycin, bleomycin, vinblastine, dacarbazine; AE: adverse event; ALL: acute lymphoblastic leukaemia; ALT: alanine aminotransferase; AML: acute myeloid leukaemia; ANC: absolute neutrophil count; ASCT: autologous stem cell transplantation; AST: aspartate aminotransferase; AVD: adriamycin, vinblastine, dacarbazine; BCNU: bis‐chloroethylnitrosourea; cHL: classical Hodgkin's lymphoma; CLL: chronic lymphocytic leukaemia; CML: chronic myeloid leukaemia; CMR: complete metabolic remission; CNS: central nervous system; CR: compete response; CRR: complete response rate; CS: clinical staging; CT: computed tomography; CTCAE: Common Terminology Criteria for Adverse Events; DLT: dose‐limiting toxicity; DOR: duration of response; EB‐VST: Epstein Barr virus specific T cells; EBV: Epstein Barr virus; ECOG: Eastern Cooperative Oncology Group; FDA: Food and Drug Administration; FDG: fluorodeoxy‐D‐glucose; HAART: highly active antiretroviral therapy; HBc: hepatitis B core; HBsAg: hepatitis B surface antigen; HBV: hepatitis B virus; hCG: human chorionic gonadotropin; HCV: hepatitis C virus; HL: Hodgkin's lymphoma; HSCT: haematopoietic stem cell transplantation; HTLV: human T‐lymphotropic virus; IF‐RT: involved‐field radiotherapy; IPS: international prognostic score; IV: intravenous; LVEF: left ventricular ejection fraction; MDS: myelodysplastic syndrome; MM: multiple myeloma; MPN: myeloproliferative neoplasms; MRI: magnetic resonance imaging; MSS: microsatellite stable; MTD: maximum tolerated dose; N/A: not available; NCI CTCAE v 3.0: National Cancer Institute, Common Terminology Criteria for Adverse Events Version 3.0; NHL: non‐Hodgkin's lymphoma; OR: overall response; ORR: objective response rate; OS: overall survival; PD: programmed death; PET: positron emission tomography; PFS: progression‐free survival; PRR: partial response rate; RCC: renal cell carcinoma; RNA: ribonucleic acid; SAE: serious adverse event; SC: subcutaneous; SCCHN: squamous cell carcinoma of the head and neck; SCT: stem cell transplantation; SqNSCLC: squamous non‐small‐cell lung carcinoma; TPN: total parenteral nutrition; ULN: upper limit of normal; WHO: World Health Organization; WOCBP: women of childbearing potential.
Differences between protocol and review
In the protocol we specified the full methods for the assessment and analyses of randomised controlled trials (RCTs) and non‐RCTs. Further we gave a detailed description of the methods we would have applied to meta‐analyse data. However, as we identified neither RCTs nor non‐RCTs we were not able to assess such studies nor to undertake a meta‐analysis.Therefore we moved respective methods to the appendix.
Contributions of authors
MG: developed and wrote the review.
MD: trial selection and data extraction.
GG: provided methodological expertise.
IM: designed the search strategy.
PD: provided methodological expertise.
JPG: provided content expertise.
AE: provided clinical expertise and content input.
BvT: provided clinical expertise.
NS: developed and wrote the review and provided methodological expertise.
Sources of support
Internal sources
Cochrane Haematological Malignancies, Department of Internal Medicine, University Hospital of Cologne, Germany.
External sources
No sources of support supplied
Declarations of interest
MG: none known.
MD: none known.
GG: none known.
IM: none known.
PD: none known.
JPG: none known.
AE: none known.
BvT: received travel grants, scientific grants, personal fees and non‐financial support from Novartis; travel grants, scientific grants, personal fees and non‐financial support from Takeda; personal fees from Amgen; personal fees from Celgene; scientific grants and personal fees from MSD; and a travel grant from Bristol‐Myers Squibb.
NS: none known.
New
References
References to studies included in this review
CheckMate 039 {published data only}
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CheckMate 205 {published data only}
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- Engert A, Santoro A, Shipp M, Zinzani PL, Timmerman J, Ansell S, et al. CheckMate 205: a phase 2 study of nivolumab in patients with classical Hodgkin lymphoma following autologous stem cell transplantation and brentuximab vedotin. Haematologica 2016;101:319. [Google Scholar]
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- Engert A, Taylor F, Bennett B, Hirji I, Cocks K, McDonald J, et al. Patient subgroup analysis of quality‐of‐life outcomes in CheckMate 205, a phase 2 study of nivolumab in patients with classical Hodgkin lymphoma. Blood. 2016; Vol. 128, issue 22:1831.
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NCT02927769 {published data only}
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NCT02973113 {published data only}
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NCT03004833 {published data only}
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NCT03016871 {published data only}
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NCT03033914 {published data only}
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NCT03138499 {published data only}
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NCT03161613 {published data only}
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