Hodgkin's lymphoma (relapsed or refractory): autologous stem cell therapy Search date September 2014 Evangelos Terpos and Amin Rahemtulla ABSTRACT INTRODUCTION: People with Hodgkin's lymphoma usually present with a lump in the neck or upper chest, but a quarter of people also have fever, sweating, weight loss, fatigue, and itch. Almost all people with localised disease can be cured and, even among people with relapsed advanced disease, almost 50% to 60% survive event-free for 4 years or more. However, a proportion of patients with early Hodgkin’s lymphoma with poor prognostic factors (up to 15%) or with advanced disease (40%–50%) still relapses or has refractory disease. METHODS AND OUTCOMES: We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of high-dose chemotherapy plus autologous stem cell therapy for relapsed or refractory Hodgkin's lymphoma? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2014 (BMJ Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview). RESULTS: Searching of electronic databases retrieved 298 studies. Appraisal of titles and abstracts led to the exclusion of 245 studies and the further review of 53 full publications. Of the 53 full articles evaluated, one systematic review was added. We performed a GRADE evaluation for three PICO combinations. CONCLUSIONS: In this systematic overview, we categorised the efficacy for one intervention, based on information relating to the effectiveness and safety of high-dose chemotherapy plus autologous stem cell therapy (versus conventional chemotherapy).
QUESTIONS What are the effects of high-dose chemotherapy plus autologous stem cell therapy for relapsed or refractory Hodgkin's lymphoma?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 INTERVENTIONS HIGH-DOSE CHEMOTHERAPY PLUS AUTOLOGOUS STEM CELL THERAPY FOR RELAPSED OR REFRACTORY HODGKIN'S LYMPHOMA Likely to be beneficial High-dose chemotherapy plus autologous stem cell therapy New . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Key points • People with Hodgkin's lymphoma usually present with a lump in the neck or upper chest, but a quarter of people also have fever, sweating, weight loss, fatigue, and itch. Almost all people with localised disease can be cured and, even among people with relapsed advanced disease, almost 50% to 60% of them survive event-free for 4 years or more. • There are different treatment regimens available for the different stages of Hodgkin's lymphoma. This overview focuses on high-dose chemotherapy plus autologous stem cell therapy for people with refractory or relapsed disease. We examined evidence from RCTs and systematic reviews of RCTs only. • High-dose chemotherapy plus autologous stem cell therapy may be more effective than chemotherapy alone at improving progression-free survival in people with refractory or relapsed Hodgkin's lymphoma, but we don't know whether it is more effective at improving overall survival. This is based on evidence from two small RCTs. • High-dose chemotherapy plus autologous stem cell therapy may be more effective than chemotherapy alone at improving complete response rate in people with refractory or relapsed Hodgkin's lymphoma. This is based on evidence from two small RCTs. Clinical context
GENERAL BACKGROUND Hodgkin's lymphoma, also known as Hodgkin's disease, is a malignancy of the lymph nodes and lymphatic system. There are different treatment regimens available for the different stages of Hodgkin's lymphoma.
FOCUS OF THE REVIEW High-dose chemotherapy and autologous stem cell transplant is the current standard of care for patients with refractory or relapsed Hodgkin's lymphoma. We have focused this overview on the evidence base for this intervention. Please see the previous overview on Hodgkin's lymphoma for information on the evidence for other interventions at different stages of the condition.
COMMENTS ON EVIDENCE In this systematic overview, we have examined the evidence from RCTs and systematic reviews of RCTs only. The RCT evidence for autologous stem cell transplants in Hodgkin's lymphoma is limited to just two studies, both open© BMJ Publishing Group Ltd 2015. All rights reserved.
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label and neither of which were completed. It is very likely that there is an improvement in outcome as a result of this practice, but there are very few studies that provide the evidence base to back it. There are other publications, outside the inclusion criteria of this overview, which have studied the outcome of autologous stem cell transplant either in single institution or in stem cell transplant registry studies.
SEARCH AND APPRAISAL SUMMARY The literature search was carried out in September 2014. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the overview, please see the Methods section. Searching of electronic databases retrieved 298 studies. Appraisal of titles and abstracts led to the exclusion of 245 studies and the further review of 53 full publications. Of the 53 full articles evaluated, one systematic review was included. DEFINITION
Hodgkin's lymphoma, also known as Hodgkin's disease, is a malignancy of the lymph nodes and lymphatic system. Most people present with an enlarged but otherwise asymptomatic lump, most often in the lower neck or supraclavicular region. Mediastinal masses are frequent and are revealed after routine chest X-rays. About a quarter of people present with systemic symptoms at diagnosis, such as unexplained fever, profuse sweating, fatigue, itchy skin, and unexplained weight loss. Hepatosplenomegaly, anaemia, lymphocytopenia, and eosinophilia are also non-specific manifestations of the disease. Hodgkin's lymphoma is categorised according to appearance under the microscope (histology) and extent of disease (stage). Relapsed Hodgkin's lymphoma is the disease that relapses after one or more prior therapies but is not refractory to the most recent treatment. Refractory Hodgkin's lymphoma includes patients who have either responded to previous therapies and they are refractory to their last treatment or they have never responded to any given therapy (primary refractory). Histology Diagnosis is based on the recognition of Reed-Sternberg cells and/or Hodgkin's cells in an appropriate cellular background in tissue sections from a lymph node or another organ, such as the bone marrow, lung, or bone. Fine needle aspiration biopsy is not [1] adequate for diagnosis of Hodgkin's lymphoma; an open biopsy is always required. ReedSternberg cells are typically multinucleated giant cells, which (in 98% of cases) are thought to be [2] [3] derived from the germinal centre of peripheral B cells. The WHO classification is based on histological subtype (see Table 1, p 9 ). The distribution of histological subtypes varies between age groups, with young adults reportedly showing a greater proportion of nodular sclerosis compared [4] with older adults. Nodular lymphocyte-predominant (LP) Hodgkin's lymphoma is a rare subtype [5] that usually has a more indolent natural history, and is often treated differently. This subtype is not covered by this overview. Stage There are several different staging classification systems for Hodgkin's lymphoma. Fluorodeoxyglucose positron emission tomography/computerised tomography (FDG-PET/CT) is the major method of staging, while bone marrow trephine biopsy may be also used for the detection of marrow infiltration by malignant cells. Due to high accuracy of PET, staging laparotomy is no longer needed. Classification systems include the Ann Arbor classification [6] (see Table 2, p 9 ) and the Cotswolds (see Table 3, p 9 ). Staging methods have changed substantially over the past 20 years. Staging laparotomy with splenectomy is no longer routine practice due to a number of possible complications (including post-splenectomy sepsis, smallbowel obstruction, and even mortality), delay to the start of treatment, similar survival rates between people with or without a staging laparotomy, and the introduction of combined modality treatment [7] [8] [9] for all stages. Population For the purposes of this overview, we considered people with primary refractory or first-relapse histologically confirmed Hodgkin's lymphoma. We excluded those with comorbid HIV-associated Hodgkin's lymphoma, but included other comorbidities.
INCIDENCE/ PREVALENCE
The annual incidence of Hodgkin's lymphoma is about 3/100,000 in the UK, without any large [10] [11] variations in incidence or in nature between countries or population groups. However, the age distribution of Hodgkin's lymphoma differs across geographical areas, as well as ethnic groups. In resource-rich countries, there is a bimodal age distribution with peaks at 15 to 34 years and over [12] 60 years, with nodular sclerosis being the most common subtype. Early-stage nodular sclerosis Hodgkin's lymphoma is the most common form in children living in resource-rich countries, but advanced mixed cellularity and lymphocyte-rich subtypes are seen most commonly in resource[13] [14] poor countries. In children in Europe and the US, incidence in males is double that of inci[15] dence in females, but in adolescents there is an equal distribution between sexes. The incidence [16] of Hodgkin's lymphoma generally correlates with the level of economic development.
AETIOLOGY/ The exact cause of Hodgkin's lymphoma remains unclear. However, it is accepted that Hodgkin's RISK FACTORS lymphoma is a heterogeneous condition that most probably consists of more than one aetiological entity. The Epstein-Barr virus has been implicated in the development of Hodgkin's lymphoma, but this association varies with age, with positivity being most prominent in children and older people. Epstein-Barr virus positivity is high in childhood Hodgkin's lymphoma worldwide, but low in adolescents in resource-poor countries with nodular sclerosis Hodgkin's lymphoma. Histological subtype, age, sex, socioeconomic status, and ethnic background have all been shown to influence the as© BMJ Publishing Group Ltd 2015. All rights reserved.
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[17]
sociation between the Epstein-Barr virus and Hodgkin's lymphoma. Although the pathogenesis of Hodgkin's disease is not yet fully understood, the nature of the Hodgkin/Reed-Sternberg (H/RS) cell has been recognised.The H/RS cell is derived from a B lymphocyte with clonal rearrangements in the V, D, and J segments of the IgH chain locus. Regulation of Fas-mediated apoptosis, and the nuclear factor-kappa B pathway seem to be strongly implicated in the pathogenesis of Hodgkin's [2] lymphoma. PROGNOSIS
Overall survival The outcome in both localised and advanced Hodgkin's lymphoma has improved greatly over the past 20 years. The disease is now considered curable in the majority of cases. Even if first-line treatment fails, the person may be cured later. Therefore, doctors confront the dilemma of whether it is preferable to use more-intensive treatment initially to cure the maximum number of people possible, or use less-aggressive treatment initially and rely on more-intensive salvage treatment in a greater proportion of people. The overall survival differs in terms of disease extent. People with localised disease (stage I/II) have a 10-year overall survival of more than 90% even in poor-risk groups. People with advanced disease (stage III/IV) have a 5-year overall survival [18] of almost 85%. Relapse The event-free survival at 4 years is up to 90% for people with localised [18] disease and almost 50% to 60% in people with relapsed advanced disease. Even with the use of combined chemotherapy (i.e., ABVD) and radiotherapy, 5% of patients with unfavourable stage I–II disease (with risk factors) progress during therapy and 15% relapse early, many of whom are resistant to salvage therapy. Prognostic indicators Despite an enormous effort to define clinically relevant and generally acceptable prognostic factors, stage and systemic B-cell symptoms are still the two key determinants for stratifying people with Hodgkin's lymphoma. Bulky disease (>10 cm nodal mass) has emerged as a third prognostic factor that meets general acceptance. In the US, most centres treat people according to the traditional classifications of early stages (I–IIA or B) and advanced stages (III–IVA or B; I–IIB with bulky disease). Additional prognostic factors often used in adults are shown in Table 4, p 10 . The International Prognostic Score (IPS) has been used by several study groups that are currently tailoring treatment strategies at first diagnosis depending on the risk for treatment failure (IPS 0–2 and 3–7), but stratifying people on the basis of the IPS is [19] still an experimental approach (see Table 4, p 10 ). Another group looked at prognostic factors specifically for children and young adults with Hodgkin's disease treated with combined modality treatment. They analysed 328 people aged 2 to 20 years old (48% were aged >14 years) and multivariate analysis identified five pre-treatment factors that correlated with inferior disease-free survival (male sex; stage IIB, IIIB, or IV disease; bulky mediastinal disease; white blood count of 9 >13.5 x 10 /L; and haemoglobin 14 years old). Using this prognostic score, people with Hodgkin's lymphoma could be stratified into four groups with significantly different 5-year disease[20] free survivals. Response to initial chemotherapy was also shown to be a predictor of outcome. Other paediatric studies found nodular sclerosis histology and B symptoms also correlated with [21] [22] inferior outcome.
AIMS OF To increase disease-free survival, achieving cure if possible; to palliate by achieving remission; to INTERVENTION prolong survival; to minimise harmful effects of treatment; and to maximise quality of life. OUTCOMES
Mortality (overall survival); disease progression/recurrence (progression-free survival); response rate (overall response rate, complete response rate, partial response rate); quality of life; adverse effects (e.g., treatment-related mortality).
METHODS
Search strategy BMJ Clinical Evidence search and appraisal date September 2014. Databases used to identify studies for this systematic overview include: Medline 1966 to September 2014, Embase 1980 to September 2014, The Cochrane Database of Systematic Reviews 2014, issue 9 (1966 to date of issue), the Database of Abstracts of Reviews of Effects (DARE), and the Health Technology Assessment (HTA) database. Inclusion criteria Study design criteria for inclusion in this review were systematic reviews and RCTs published in English, at least single-blinded, and containing 20 or more individuals (10 in each arm), of whom more than 80% were followed up. A minimum length of follow-up of 18 months was required. We excluded all studies described as 'open', 'open label', or not blinded unless blinding was impossible. BMJ Clinical Evidence does not necessarily report every study found (e.g., every systematic review). Rather, we report the most recent, relevant, and comprehensive studies identified through an agreed process involving our evidence team, editorial team, and expert contributors. Evidence evaluation A systematic literature search was conducted by our evidence team, who then assessed titles and abstracts, and finally selected articles for full text appraisal against inclusion and exclusion criteria agreed a priori with our expert contributors. In consultation with the expert contributors, studies were selected for inclusion and all data relevant to this overview extracted into the benefits and harms section of the review. In addition, information that did not meet our pre-defined criteria for inclusion in the benefits and harms section may have been reported in the 'Further information on studies' or 'Comment' section.
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Adverse effects All serious adverse effects, or those adverse effects reported as statistically significant, were included in the harms section of the overview. Pre-specified adverse effects identified as being clinically important were also reported, even if the results were not statistically significant. Although BMJ Clinical Evidence presents data on selected adverse effects reported in included studies, it is not meant to be, and cannot be, a comprehensive list of all adverse effects, contraindications, or interactions of included drugs or interventions. A reliable national or local drug database must be consulted for this information. Comment and Clinical guide sections In the Comment section of each intervention, our expert contributors may have provided additional comment and analysis of the evidence, which may include additional studies (over and above those identified via our systematic search) by way of background data or supporting information. As BMJ Clinical Evidence does not systematically search for studies reported in the Comment section, we cannot guarantee the completeness of the studies listed there or the robustness of methods. Our expert contributors add clinical context and interpretation to the Clinical guide sections where appropriate. Data and quality To aid readability of the numerical data in our overviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). BMJ Clinical Evidence does not report all methodological details of included studies. Rather, it reports by exception any methodological issue or more general issue that may affect the weight a reader may put on an individual study, or the generalisability of the result. These issues may be reflected in the overall GRADE analysis. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table, p 11 ). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com). QUESTION
What are the effects of high-dose chemotherapy plus autologous stem cell therapy for relapsed or refractory Hodgkin's lymphoma?
OPTION
HIGH-DOSE CHEMOTHERAPY PLUS AUTOLOGOUS STEM CELL THERAPY. . . . . . . . New
•
For GRADE evaluation of interventions for Hodgkin's lymphoma (relapsed or refractory): autologous stem cell therapy, see table, p 11 .
•
High-dose chemotherapy plus autologous stem cell therapy may be more effective than chemotherapy alone at improving progression-free survival in people with refractory or relapsed Hodgkin's lymphoma, but we don't know whether it is more effective at improving overall survival. This is based on evidence from two small RCTs.
•
High-dose chemotherapy plus autologous stem cell therapy may be more effective than chemotherapy alone at improving complete response rate in people with refractory or relapsed Hodgkin's lymphoma. This is based on evidence from two small RCTs. Benefits and harms
High-dose chemotherapy plus autologous stem cell therapy versus chemotherapy alone: [23] We found one systematic review (search date 2013), which identified three open-label RCTs. Comparators assessed in the systematic review were conventional chemotherapy alone, and additional sequential high-dose chemotherapy followed by autologous stem cell therapy. Here, based on BMJ Clinical Evidence reporting criteria, results are presented for two RCTs, which evaluated high-dose chemotherapy plus autologous stem cell therapy versus chemotherapy alone. Mortality High-dose chemotherapy plus autologous stem cell therapy compared with conventional chemotherapy alone We don't know whether high-dose chemotherapy plus autologous stem cell transplantation is more effective than conventional chemotherapy at improving overall survival in people with primary refractory or first-relapse Hodgkin's lymphoma (low-quality evidence).
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Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Overall survival [23]
Systematic review
People with primary refractory or first-relapse Hodgkin's lymphoma 2 RCTs in this analysis
Overall survival , length of fol- HR 0.67 low-up unclear 95% CI 0.41 to 1.07 with high-dose chemotherapy P = 0.10 plus autologous stem cell transplantation See Further information on studies with conventional chemotherapy Not significant
Absolute results not reported 157 people (2 open-label RCTs) in this analysis Overall survival was the time interval from randomisation or study entry to death from any cause, or to last follow-up
Disease progression/recurrence High-dose chemotherapy plus autologous stem cell therapy compared with conventional chemotherapy alone Highdose chemotherapy plus autologous stem cell therapy may be more effective than conventional chemotherapy at improving progression-free survival in people with primary refractory or first-relapse Hodgkin's lymphoma (lowquality evidence). Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Progression-free survival [23]
Systematic review
People with primary refractory or first-relapse Hodgkin's lymphoma 2 RCTs in this analysis
Progression-free survival , length of follow-up unclear with high-dose chemotherapy plus autologous stem cell transplantation with conventional chemotherapy
HR 0.55 95% CI 0.35 to 0.86 P = 0.009 See Further information on studies
high-dose chemotherapy plus autologous stem cell therapy
Absolute results not reported 157 people (2 open-label RCTs) in this analysis Progression-free survival was the time interval from randomisation or study entry to first progression or relapse, death from any cause, or the last follow-up
Response rate High-dose chemotherapy plus autologous stem cell therapy compared with conventional chemotherapy alone Highdose chemotherapy plus autologous stem cell therapy may be more effective than conventional chemotherapy at improving complete response rate in people with primary refractory or first-relapse Hodgkin's lymphoma (low-quality evidence). Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Overall response rate [23]
Systematic review
People with primary refractory or first-relapse Hodgkin's lymphoma 2 RCTs in this analysis
Overall response rate , length of follow-up unclear 70/81 (86%) with high-dose chemotherapy plus autologous stem-cell transplantation 57/76 (75%) with conventional chemotherapy
RR 1.15 95% CI 0.99 to 1.34 P = 0.08 See Further information on studies
Not significant
157 people (2 open-label RCTs) in this analysis © BMJ Publishing Group Ltd 2015. All rights reserved.
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Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Overall response rate is a composite of complete and partial response rate
Complete response rate [23]
Systematic review
People with primary refractory or first-relapse Hodgkin's lymphoma 2 RCTs in this analysis
Complete response rate , length of follow-up unclear
RR 1.32 95% CI 1.07 to 1.64
60/81 (74%) with high-dose chemotherapy plus autologous stem-cell transplantation 42/76 (55%) with conventional chemotherapy
P = 0.01
high-dose chemotherapy plus autologous stem cell therapy
See Further information on studies
157 people (2 open-label RCTs) in this analysis
Quality of life No data from the following reference on this outcome.
[23]
Adverse effects Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Adverse effects [23]
Systematic review
People with primary refractory or first-relapse Hodgkin's lymphoma
Treatment-related mortality , length of follow-up unclear 3/81 (4%) with high-dose chemotherapy plus autologous stem-cell transplantation
RR 0.61 95% CI 0.16 to 2.22 P = 0.45 Not significant
5/76 (7%) with conventional chemotherapy 157 people (2 open-label RCTs) in this analysis [23]
Systematic review
117 people with primary refractory or first-relapse Hodgkin's lymphoma Data from 1 RCT
Serious adverse effects
Significance not assessed
51/61 (84%) with high-dose chemotherapy plus autologous stem-cell transplantation 49/56 (88%) with conventional chemotherapy Open-label RCT Serious adverse effects (WHO grade 3 and 4 toxicity) included infection, oral (mucositis), gastrointestinal, pulmonary or respiratory tract, cardiac, neurological, hepatic, and renal
-
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Further information on studies [23]
The systematic review identified and meta-analysed two open-label RCTs evaluating high-dose chemotherapy (BEAM) plus autologous stem cell transplantation compared with conventional chemotherapy (mini-BEAM in one RCT, and Dexa-BEAM in the other RCT) in people with primary refractory or first-relapse Hodgkin's lymphoma. The median follow-up was 34 months in one RCT, and 83 months in the other RCT (ranges were not reported). Both studies were stopped before reaching final trial size. In one RCT, participants refused randomisation and demanded treatment with autologous stem cell transplantation. In the other RCT, the scientific committee stopped the study early due to "low accrual of patients". Blinding in both RCTs was unclear. However, the authors of the review stated that "trials evaluating stem cell transplantation are usually not blinded".
Comment:
Clinical guide High-dose therapy and autologous stem cell transplant is the standard of care for patients with refractory or relapsed Hodgkin's lymphoma. Approximately 50% of these patients are cured after autologous stem cell transplantation; however, most patients with unfavourable risk factors progress after transplantation. For these patients, novel agents have been entered into clinical practice. Brentuximab vedotin induces durable objective responses and results in tumour regression for most patients with relapsed or refractory Hodgkin's lymphoma post autologous stem cell transplan[24] tation. Furthermore, a recent phase 3 study showed that early consolidation with brentuximab vedotin after autologous stem cell transplantation improved progression-free survival in patients [25] with Hodgkin's lymphoma with risk factors for relapse or with progression after transplantation. Allogeneic stem cell transplantation, especially with reduced intensity conditioning regimens, is another option after failure of autologous stem cell transplantation in eligible patients with relapsed [26] or refractory Hodgkin's lymphoma, offering a 25% probability of 5-year overall survival.
GLOSSARY B symptoms Fever, night sweats, or weight loss of more than 10% of baseline weight. BEAM Carmustine, etoposide, cytarabine, and melphalan. Dexa-BEAM Dexamethasone, carmustine, etoposide, cytarabine, and melphalan. Low-quality evidence Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Mini-BEAM Low-dose carmustine, etoposide, cytarabine, and melphalan.
SUBSTANTIVE CHANGES High-dose chemotherapy plus autologous stem cell therapy New option. One systematic review added. Categorised as 'likely to be beneficial'.
[23]
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Sureda A, Robinson S, Canals C, et al. Reduced-intensity conditioning compared with conventional allogeneic stem-cell transplantation in relapsed or refractory Hodgkin's lymphoma: an analysis from the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol 2008;26:455–462.[PubMed]
Amin Rahemtulla Consultant Haematologist & Senior Lecturer Faculty of Medicine Imperial College London UK Evangelos Terpos Associate Professor of Haematology University of Athens School of Medicine Athens Greece Competing interests: AR and ET declare that they have no competing interests.
Disclaimer The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
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TABLE 1
WHO classification (see text).
Classical Hodgkin's lymphoma Nodular sclerosis Hodgkin's lymphoma Mixed cellularity Hodgkin's lymphoma Lymphocyte depletion Hodgkin's lymphoma Lymphocyte-rich classical Hodgkin's lymphoma Nodular lymphocyte-predominant Hodgkin's lymphoma
TABLE 2
Ann Arbor classification (see text).
[6]
Stage
Description
I
Involvement of a single lymph node region or of a single extralymphatic organ or site
II
Involvement of two or more lymph node regions on the same side of the diaphragm or localised involvement of extralymphatic organ or site of one or more lymph node regions on the same side of the diaphragm
III
Involvement of lymph node regions on both sides of the diaphragm, which may also be accompanied by localised involvement of extralymphatic organ or site or by involvement of the spleen or both
IV
Diffuse or disseminated involvement of one or more extralymphatic organs or tissues with or without associated lymph node involvement
Reproduced with permission of American Association of Cancer Research (Cancer Research, 31:1860–1861, 1971).
TABLE 3
Ann Arbor Staging System with Cotswolds modification (see text).
Stage
Description
I
Involvement of a single lymph node region or lymphoid structure (e.g., spleen, thymus, Waldeyer's ring)
II
2 or more lymph node regions on the same side of the diaphragm
III
Lymph nodes on both sides of the diaphragm
III1
With splenic hilar, coeliac, or portal nodes
III2
With para-aortic, iliac, or mesenteric nodes
IV
Involvement of extranodal site beyond that designated “E”
Modifying features A
No symptoms
B
Fever, drenching night sweats, weight loss >10% in 6 months
X
Bulky disease: greater than one third widening of mediastinum or >10 cm maximum diameter of nodal mass
E
Involvement of single, contiguous, or proximal extranodal site
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TABLE 4
Factors prognostic of unfavourable outcome (see text).
The European Organisation for Research and Treatment of Cancer (EORTC) and the German Hodgkin's Lymphoma Study Group (GHSG) have defined people with stage I–II disease as unfavourable or interme[18] diate if any of the adverse factors listed below are present:
EORTC system Large mediastinal mass Age 50 years or above Elevated ESR (50 mm/hour or more without B symptoms or 30 mm/hour or more with B symptoms) 4 or more involved regions
GHSG system Large mediastinal mass Extranodal disease Elevated ESR (50 mm/hour or more without B symptoms or 30 mm/hour or more with B symptoms) 3 or more involved regions
Many investigators and many new clinical trials employ a clinical staging system that divides people into 3 major groups that are also useful for the practising physician:
[15]
Early favourable: clinical stage I or II without any risk factors Early unfavourable: clinical stage I or II with one or more of the following risk factors: Large mediastinal mass (>33% of the thoracic width on the CXR, 10 cm or more on CT scan) Extranodal involvement Elevated ESR (>30 mm/hour for B stage, >50 mm/hour for A stage) 3 or more lymph node areas involvement B symptoms Advanced: clinical stage III or IV For people with advanced-stage Hodgkin's lymphoma, the International Prognostic Factors Project has developed an International Prognostic Index with a prognostic score that is based on 7 adverse factors. [19] These factors were found to predict 5-year rates of freedom from progression in 4695 people with advanced stage disease (28% were 15–24 years old):
[16]
Albumin level of
QUESTIONS What are the effects of high-dose chemotherapy plus autologous stem cell therapy for relapsed or refractory Hodgkin's lymphoma?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 INTERVENTIONS HIGH-DOSE CHEMOTHERAPY PLUS AUTOLOGOUS STEM CELL THERAPY FOR RELAPSED OR REFRACTORY HODGKIN'S LYMPHOMA Likely to be beneficial High-dose chemotherapy plus autologous stem cell therapy New . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Key points • People with Hodgkin's lymphoma usually present with a lump in the neck or upper chest, but a quarter of people also have fever, sweating, weight loss, fatigue, and itch. Almost all people with localised disease can be cured and, even among people with relapsed advanced disease, almost 50% to 60% of them survive event-free for 4 years or more. • There are different treatment regimens available for the different stages of Hodgkin's lymphoma. This overview focuses on high-dose chemotherapy plus autologous stem cell therapy for people with refractory or relapsed disease. We examined evidence from RCTs and systematic reviews of RCTs only. • High-dose chemotherapy plus autologous stem cell therapy may be more effective than chemotherapy alone at improving progression-free survival in people with refractory or relapsed Hodgkin's lymphoma, but we don't know whether it is more effective at improving overall survival. This is based on evidence from two small RCTs. • High-dose chemotherapy plus autologous stem cell therapy may be more effective than chemotherapy alone at improving complete response rate in people with refractory or relapsed Hodgkin's lymphoma. This is based on evidence from two small RCTs. Clinical context
GENERAL BACKGROUND Hodgkin's lymphoma, also known as Hodgkin's disease, is a malignancy of the lymph nodes and lymphatic system. There are different treatment regimens available for the different stages of Hodgkin's lymphoma.
FOCUS OF THE REVIEW High-dose chemotherapy and autologous stem cell transplant is the current standard of care for patients with refractory or relapsed Hodgkin's lymphoma. We have focused this overview on the evidence base for this intervention. Please see the previous overview on Hodgkin's lymphoma for information on the evidence for other interventions at different stages of the condition.
COMMENTS ON EVIDENCE In this systematic overview, we have examined the evidence from RCTs and systematic reviews of RCTs only. The RCT evidence for autologous stem cell transplants in Hodgkin's lymphoma is limited to just two studies, both open© BMJ Publishing Group Ltd 2015. All rights reserved.
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label and neither of which were completed. It is very likely that there is an improvement in outcome as a result of this practice, but there are very few studies that provide the evidence base to back it. There are other publications, outside the inclusion criteria of this overview, which have studied the outcome of autologous stem cell transplant either in single institution or in stem cell transplant registry studies.
SEARCH AND APPRAISAL SUMMARY The literature search was carried out in September 2014. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the overview, please see the Methods section. Searching of electronic databases retrieved 298 studies. Appraisal of titles and abstracts led to the exclusion of 245 studies and the further review of 53 full publications. Of the 53 full articles evaluated, one systematic review was included. DEFINITION
Hodgkin's lymphoma, also known as Hodgkin's disease, is a malignancy of the lymph nodes and lymphatic system. Most people present with an enlarged but otherwise asymptomatic lump, most often in the lower neck or supraclavicular region. Mediastinal masses are frequent and are revealed after routine chest X-rays. About a quarter of people present with systemic symptoms at diagnosis, such as unexplained fever, profuse sweating, fatigue, itchy skin, and unexplained weight loss. Hepatosplenomegaly, anaemia, lymphocytopenia, and eosinophilia are also non-specific manifestations of the disease. Hodgkin's lymphoma is categorised according to appearance under the microscope (histology) and extent of disease (stage). Relapsed Hodgkin's lymphoma is the disease that relapses after one or more prior therapies but is not refractory to the most recent treatment. Refractory Hodgkin's lymphoma includes patients who have either responded to previous therapies and they are refractory to their last treatment or they have never responded to any given therapy (primary refractory). Histology Diagnosis is based on the recognition of Reed-Sternberg cells and/or Hodgkin's cells in an appropriate cellular background in tissue sections from a lymph node or another organ, such as the bone marrow, lung, or bone. Fine needle aspiration biopsy is not [1] adequate for diagnosis of Hodgkin's lymphoma; an open biopsy is always required. ReedSternberg cells are typically multinucleated giant cells, which (in 98% of cases) are thought to be [2] [3] derived from the germinal centre of peripheral B cells. The WHO classification is based on histological subtype (see Table 1, p 9 ). The distribution of histological subtypes varies between age groups, with young adults reportedly showing a greater proportion of nodular sclerosis compared [4] with older adults. Nodular lymphocyte-predominant (LP) Hodgkin's lymphoma is a rare subtype [5] that usually has a more indolent natural history, and is often treated differently. This subtype is not covered by this overview. Stage There are several different staging classification systems for Hodgkin's lymphoma. Fluorodeoxyglucose positron emission tomography/computerised tomography (FDG-PET/CT) is the major method of staging, while bone marrow trephine biopsy may be also used for the detection of marrow infiltration by malignant cells. Due to high accuracy of PET, staging laparotomy is no longer needed. Classification systems include the Ann Arbor classification [6] (see Table 2, p 9 ) and the Cotswolds (see Table 3, p 9 ). Staging methods have changed substantially over the past 20 years. Staging laparotomy with splenectomy is no longer routine practice due to a number of possible complications (including post-splenectomy sepsis, smallbowel obstruction, and even mortality), delay to the start of treatment, similar survival rates between people with or without a staging laparotomy, and the introduction of combined modality treatment [7] [8] [9] for all stages. Population For the purposes of this overview, we considered people with primary refractory or first-relapse histologically confirmed Hodgkin's lymphoma. We excluded those with comorbid HIV-associated Hodgkin's lymphoma, but included other comorbidities.
INCIDENCE/ PREVALENCE
The annual incidence of Hodgkin's lymphoma is about 3/100,000 in the UK, without any large [10] [11] variations in incidence or in nature between countries or population groups. However, the age distribution of Hodgkin's lymphoma differs across geographical areas, as well as ethnic groups. In resource-rich countries, there is a bimodal age distribution with peaks at 15 to 34 years and over [12] 60 years, with nodular sclerosis being the most common subtype. Early-stage nodular sclerosis Hodgkin's lymphoma is the most common form in children living in resource-rich countries, but advanced mixed cellularity and lymphocyte-rich subtypes are seen most commonly in resource[13] [14] poor countries. In children in Europe and the US, incidence in males is double that of inci[15] dence in females, but in adolescents there is an equal distribution between sexes. The incidence [16] of Hodgkin's lymphoma generally correlates with the level of economic development.
AETIOLOGY/ The exact cause of Hodgkin's lymphoma remains unclear. However, it is accepted that Hodgkin's RISK FACTORS lymphoma is a heterogeneous condition that most probably consists of more than one aetiological entity. The Epstein-Barr virus has been implicated in the development of Hodgkin's lymphoma, but this association varies with age, with positivity being most prominent in children and older people. Epstein-Barr virus positivity is high in childhood Hodgkin's lymphoma worldwide, but low in adolescents in resource-poor countries with nodular sclerosis Hodgkin's lymphoma. Histological subtype, age, sex, socioeconomic status, and ethnic background have all been shown to influence the as© BMJ Publishing Group Ltd 2015. All rights reserved.
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[17]
sociation between the Epstein-Barr virus and Hodgkin's lymphoma. Although the pathogenesis of Hodgkin's disease is not yet fully understood, the nature of the Hodgkin/Reed-Sternberg (H/RS) cell has been recognised.The H/RS cell is derived from a B lymphocyte with clonal rearrangements in the V, D, and J segments of the IgH chain locus. Regulation of Fas-mediated apoptosis, and the nuclear factor-kappa B pathway seem to be strongly implicated in the pathogenesis of Hodgkin's [2] lymphoma. PROGNOSIS
Overall survival The outcome in both localised and advanced Hodgkin's lymphoma has improved greatly over the past 20 years. The disease is now considered curable in the majority of cases. Even if first-line treatment fails, the person may be cured later. Therefore, doctors confront the dilemma of whether it is preferable to use more-intensive treatment initially to cure the maximum number of people possible, or use less-aggressive treatment initially and rely on more-intensive salvage treatment in a greater proportion of people. The overall survival differs in terms of disease extent. People with localised disease (stage I/II) have a 10-year overall survival of more than 90% even in poor-risk groups. People with advanced disease (stage III/IV) have a 5-year overall survival [18] of almost 85%. Relapse The event-free survival at 4 years is up to 90% for people with localised [18] disease and almost 50% to 60% in people with relapsed advanced disease. Even with the use of combined chemotherapy (i.e., ABVD) and radiotherapy, 5% of patients with unfavourable stage I–II disease (with risk factors) progress during therapy and 15% relapse early, many of whom are resistant to salvage therapy. Prognostic indicators Despite an enormous effort to define clinically relevant and generally acceptable prognostic factors, stage and systemic B-cell symptoms are still the two key determinants for stratifying people with Hodgkin's lymphoma. Bulky disease (>10 cm nodal mass) has emerged as a third prognostic factor that meets general acceptance. In the US, most centres treat people according to the traditional classifications of early stages (I–IIA or B) and advanced stages (III–IVA or B; I–IIB with bulky disease). Additional prognostic factors often used in adults are shown in Table 4, p 10 . The International Prognostic Score (IPS) has been used by several study groups that are currently tailoring treatment strategies at first diagnosis depending on the risk for treatment failure (IPS 0–2 and 3–7), but stratifying people on the basis of the IPS is [19] still an experimental approach (see Table 4, p 10 ). Another group looked at prognostic factors specifically for children and young adults with Hodgkin's disease treated with combined modality treatment. They analysed 328 people aged 2 to 20 years old (48% were aged >14 years) and multivariate analysis identified five pre-treatment factors that correlated with inferior disease-free survival (male sex; stage IIB, IIIB, or IV disease; bulky mediastinal disease; white blood count of 9 >13.5 x 10 /L; and haemoglobin 14 years old). Using this prognostic score, people with Hodgkin's lymphoma could be stratified into four groups with significantly different 5-year disease[20] free survivals. Response to initial chemotherapy was also shown to be a predictor of outcome. Other paediatric studies found nodular sclerosis histology and B symptoms also correlated with [21] [22] inferior outcome.
AIMS OF To increase disease-free survival, achieving cure if possible; to palliate by achieving remission; to INTERVENTION prolong survival; to minimise harmful effects of treatment; and to maximise quality of life. OUTCOMES
Mortality (overall survival); disease progression/recurrence (progression-free survival); response rate (overall response rate, complete response rate, partial response rate); quality of life; adverse effects (e.g., treatment-related mortality).
METHODS
Search strategy BMJ Clinical Evidence search and appraisal date September 2014. Databases used to identify studies for this systematic overview include: Medline 1966 to September 2014, Embase 1980 to September 2014, The Cochrane Database of Systematic Reviews 2014, issue 9 (1966 to date of issue), the Database of Abstracts of Reviews of Effects (DARE), and the Health Technology Assessment (HTA) database. Inclusion criteria Study design criteria for inclusion in this review were systematic reviews and RCTs published in English, at least single-blinded, and containing 20 or more individuals (10 in each arm), of whom more than 80% were followed up. A minimum length of follow-up of 18 months was required. We excluded all studies described as 'open', 'open label', or not blinded unless blinding was impossible. BMJ Clinical Evidence does not necessarily report every study found (e.g., every systematic review). Rather, we report the most recent, relevant, and comprehensive studies identified through an agreed process involving our evidence team, editorial team, and expert contributors. Evidence evaluation A systematic literature search was conducted by our evidence team, who then assessed titles and abstracts, and finally selected articles for full text appraisal against inclusion and exclusion criteria agreed a priori with our expert contributors. In consultation with the expert contributors, studies were selected for inclusion and all data relevant to this overview extracted into the benefits and harms section of the review. In addition, information that did not meet our pre-defined criteria for inclusion in the benefits and harms section may have been reported in the 'Further information on studies' or 'Comment' section.
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Adverse effects All serious adverse effects, or those adverse effects reported as statistically significant, were included in the harms section of the overview. Pre-specified adverse effects identified as being clinically important were also reported, even if the results were not statistically significant. Although BMJ Clinical Evidence presents data on selected adverse effects reported in included studies, it is not meant to be, and cannot be, a comprehensive list of all adverse effects, contraindications, or interactions of included drugs or interventions. A reliable national or local drug database must be consulted for this information. Comment and Clinical guide sections In the Comment section of each intervention, our expert contributors may have provided additional comment and analysis of the evidence, which may include additional studies (over and above those identified via our systematic search) by way of background data or supporting information. As BMJ Clinical Evidence does not systematically search for studies reported in the Comment section, we cannot guarantee the completeness of the studies listed there or the robustness of methods. Our expert contributors add clinical context and interpretation to the Clinical guide sections where appropriate. Data and quality To aid readability of the numerical data in our overviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). BMJ Clinical Evidence does not report all methodological details of included studies. Rather, it reports by exception any methodological issue or more general issue that may affect the weight a reader may put on an individual study, or the generalisability of the result. These issues may be reflected in the overall GRADE analysis. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table, p 11 ). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com). QUESTION
What are the effects of high-dose chemotherapy plus autologous stem cell therapy for relapsed or refractory Hodgkin's lymphoma?
OPTION
HIGH-DOSE CHEMOTHERAPY PLUS AUTOLOGOUS STEM CELL THERAPY. . . . . . . . New
•
For GRADE evaluation of interventions for Hodgkin's lymphoma (relapsed or refractory): autologous stem cell therapy, see table, p 11 .
•
High-dose chemotherapy plus autologous stem cell therapy may be more effective than chemotherapy alone at improving progression-free survival in people with refractory or relapsed Hodgkin's lymphoma, but we don't know whether it is more effective at improving overall survival. This is based on evidence from two small RCTs.
•
High-dose chemotherapy plus autologous stem cell therapy may be more effective than chemotherapy alone at improving complete response rate in people with refractory or relapsed Hodgkin's lymphoma. This is based on evidence from two small RCTs. Benefits and harms
High-dose chemotherapy plus autologous stem cell therapy versus chemotherapy alone: [23] We found one systematic review (search date 2013), which identified three open-label RCTs. Comparators assessed in the systematic review were conventional chemotherapy alone, and additional sequential high-dose chemotherapy followed by autologous stem cell therapy. Here, based on BMJ Clinical Evidence reporting criteria, results are presented for two RCTs, which evaluated high-dose chemotherapy plus autologous stem cell therapy versus chemotherapy alone. Mortality High-dose chemotherapy plus autologous stem cell therapy compared with conventional chemotherapy alone We don't know whether high-dose chemotherapy plus autologous stem cell transplantation is more effective than conventional chemotherapy at improving overall survival in people with primary refractory or first-relapse Hodgkin's lymphoma (low-quality evidence).
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Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Overall survival [23]
Systematic review
People with primary refractory or first-relapse Hodgkin's lymphoma 2 RCTs in this analysis
Overall survival , length of fol- HR 0.67 low-up unclear 95% CI 0.41 to 1.07 with high-dose chemotherapy P = 0.10 plus autologous stem cell transplantation See Further information on studies with conventional chemotherapy Not significant
Absolute results not reported 157 people (2 open-label RCTs) in this analysis Overall survival was the time interval from randomisation or study entry to death from any cause, or to last follow-up
Disease progression/recurrence High-dose chemotherapy plus autologous stem cell therapy compared with conventional chemotherapy alone Highdose chemotherapy plus autologous stem cell therapy may be more effective than conventional chemotherapy at improving progression-free survival in people with primary refractory or first-relapse Hodgkin's lymphoma (lowquality evidence). Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Progression-free survival [23]
Systematic review
People with primary refractory or first-relapse Hodgkin's lymphoma 2 RCTs in this analysis
Progression-free survival , length of follow-up unclear with high-dose chemotherapy plus autologous stem cell transplantation with conventional chemotherapy
HR 0.55 95% CI 0.35 to 0.86 P = 0.009 See Further information on studies
high-dose chemotherapy plus autologous stem cell therapy
Absolute results not reported 157 people (2 open-label RCTs) in this analysis Progression-free survival was the time interval from randomisation or study entry to first progression or relapse, death from any cause, or the last follow-up
Response rate High-dose chemotherapy plus autologous stem cell therapy compared with conventional chemotherapy alone Highdose chemotherapy plus autologous stem cell therapy may be more effective than conventional chemotherapy at improving complete response rate in people with primary refractory or first-relapse Hodgkin's lymphoma (low-quality evidence). Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Overall response rate [23]
Systematic review
People with primary refractory or first-relapse Hodgkin's lymphoma 2 RCTs in this analysis
Overall response rate , length of follow-up unclear 70/81 (86%) with high-dose chemotherapy plus autologous stem-cell transplantation 57/76 (75%) with conventional chemotherapy
RR 1.15 95% CI 0.99 to 1.34 P = 0.08 See Further information on studies
Not significant
157 people (2 open-label RCTs) in this analysis © BMJ Publishing Group Ltd 2015. All rights reserved.
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Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Overall response rate is a composite of complete and partial response rate
Complete response rate [23]
Systematic review
People with primary refractory or first-relapse Hodgkin's lymphoma 2 RCTs in this analysis
Complete response rate , length of follow-up unclear
RR 1.32 95% CI 1.07 to 1.64
60/81 (74%) with high-dose chemotherapy plus autologous stem-cell transplantation 42/76 (55%) with conventional chemotherapy
P = 0.01
high-dose chemotherapy plus autologous stem cell therapy
See Further information on studies
157 people (2 open-label RCTs) in this analysis
Quality of life No data from the following reference on this outcome.
[23]
Adverse effects Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Adverse effects [23]
Systematic review
People with primary refractory or first-relapse Hodgkin's lymphoma
Treatment-related mortality , length of follow-up unclear 3/81 (4%) with high-dose chemotherapy plus autologous stem-cell transplantation
RR 0.61 95% CI 0.16 to 2.22 P = 0.45 Not significant
5/76 (7%) with conventional chemotherapy 157 people (2 open-label RCTs) in this analysis [23]
Systematic review
117 people with primary refractory or first-relapse Hodgkin's lymphoma Data from 1 RCT
Serious adverse effects
Significance not assessed
51/61 (84%) with high-dose chemotherapy plus autologous stem-cell transplantation 49/56 (88%) with conventional chemotherapy Open-label RCT Serious adverse effects (WHO grade 3 and 4 toxicity) included infection, oral (mucositis), gastrointestinal, pulmonary or respiratory tract, cardiac, neurological, hepatic, and renal
-
© BMJ Publishing Group Ltd 2015. All rights reserved.
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Hodgkin's lymphoma (relapsed or refractory): autologous stem cell therapy
Further information on studies [23]
The systematic review identified and meta-analysed two open-label RCTs evaluating high-dose chemotherapy (BEAM) plus autologous stem cell transplantation compared with conventional chemotherapy (mini-BEAM in one RCT, and Dexa-BEAM in the other RCT) in people with primary refractory or first-relapse Hodgkin's lymphoma. The median follow-up was 34 months in one RCT, and 83 months in the other RCT (ranges were not reported). Both studies were stopped before reaching final trial size. In one RCT, participants refused randomisation and demanded treatment with autologous stem cell transplantation. In the other RCT, the scientific committee stopped the study early due to "low accrual of patients". Blinding in both RCTs was unclear. However, the authors of the review stated that "trials evaluating stem cell transplantation are usually not blinded".
Comment:
Clinical guide High-dose therapy and autologous stem cell transplant is the standard of care for patients with refractory or relapsed Hodgkin's lymphoma. Approximately 50% of these patients are cured after autologous stem cell transplantation; however, most patients with unfavourable risk factors progress after transplantation. For these patients, novel agents have been entered into clinical practice. Brentuximab vedotin induces durable objective responses and results in tumour regression for most patients with relapsed or refractory Hodgkin's lymphoma post autologous stem cell transplan[24] tation. Furthermore, a recent phase 3 study showed that early consolidation with brentuximab vedotin after autologous stem cell transplantation improved progression-free survival in patients [25] with Hodgkin's lymphoma with risk factors for relapse or with progression after transplantation. Allogeneic stem cell transplantation, especially with reduced intensity conditioning regimens, is another option after failure of autologous stem cell transplantation in eligible patients with relapsed [26] or refractory Hodgkin's lymphoma, offering a 25% probability of 5-year overall survival.
GLOSSARY B symptoms Fever, night sweats, or weight loss of more than 10% of baseline weight. BEAM Carmustine, etoposide, cytarabine, and melphalan. Dexa-BEAM Dexamethasone, carmustine, etoposide, cytarabine, and melphalan. Low-quality evidence Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Mini-BEAM Low-dose carmustine, etoposide, cytarabine, and melphalan.
SUBSTANTIVE CHANGES High-dose chemotherapy plus autologous stem cell therapy New option. One systematic review added. Categorised as 'likely to be beneficial'.
[23]
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Rancea M, Monsef I, von Tresckow B, et al. High-dose chemotherapy followed by autologous stem cell transplantation for patients with relapsed/refractory Hodgkin lymphoma. In: The Cochrane Library, Issue 9, 2014. Chichester, UK: John Wiley & Sons, Ltd. Search date 2013.
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Younes A, Bartlett NL, Leonard JP, et al. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med 2010;363:1812–1821.[PubMed]
25.
Moskowitz CH, Nademanee A, Masszi T, et al. Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin's lymphoma at risk of relapse or progression (AETHERA): a randomised, doubleblind, placebo-controlled, phase 3 trial. Lancet 2015;385:1853–1862.[PubMed]
26.
Sureda A, Robinson S, Canals C, et al. Reduced-intensity conditioning compared with conventional allogeneic stem-cell transplantation in relapsed or refractory Hodgkin's lymphoma: an analysis from the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol 2008;26:455–462.[PubMed]
Amin Rahemtulla Consultant Haematologist & Senior Lecturer Faculty of Medicine Imperial College London UK Evangelos Terpos Associate Professor of Haematology University of Athens School of Medicine Athens Greece Competing interests: AR and ET declare that they have no competing interests.
Disclaimer The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
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8
Blood and lymph disorders
Hodgkin's lymphoma (relapsed or refractory): autologous stem cell therapy
TABLE 1
WHO classification (see text).
Classical Hodgkin's lymphoma Nodular sclerosis Hodgkin's lymphoma Mixed cellularity Hodgkin's lymphoma Lymphocyte depletion Hodgkin's lymphoma Lymphocyte-rich classical Hodgkin's lymphoma Nodular lymphocyte-predominant Hodgkin's lymphoma
TABLE 2
Ann Arbor classification (see text).
[6]
Stage
Description
I
Involvement of a single lymph node region or of a single extralymphatic organ or site
II
Involvement of two or more lymph node regions on the same side of the diaphragm or localised involvement of extralymphatic organ or site of one or more lymph node regions on the same side of the diaphragm
III
Involvement of lymph node regions on both sides of the diaphragm, which may also be accompanied by localised involvement of extralymphatic organ or site or by involvement of the spleen or both
IV
Diffuse or disseminated involvement of one or more extralymphatic organs or tissues with or without associated lymph node involvement
Reproduced with permission of American Association of Cancer Research (Cancer Research, 31:1860–1861, 1971).
TABLE 3
Ann Arbor Staging System with Cotswolds modification (see text).
Stage
Description
I
Involvement of a single lymph node region or lymphoid structure (e.g., spleen, thymus, Waldeyer's ring)
II
2 or more lymph node regions on the same side of the diaphragm
III
Lymph nodes on both sides of the diaphragm
III1
With splenic hilar, coeliac, or portal nodes
III2
With para-aortic, iliac, or mesenteric nodes
IV
Involvement of extranodal site beyond that designated “E”
Modifying features A
No symptoms
B
Fever, drenching night sweats, weight loss >10% in 6 months
X
Bulky disease: greater than one third widening of mediastinum or >10 cm maximum diameter of nodal mass
E
Involvement of single, contiguous, or proximal extranodal site
© BMJ Publishing Group Ltd 2015. All rights reserved.
............................................................................................................. 9
Blood and lymph disorders
Hodgkin's lymphoma (relapsed or refractory): autologous stem cell therapy
TABLE 4
Factors prognostic of unfavourable outcome (see text).
The European Organisation for Research and Treatment of Cancer (EORTC) and the German Hodgkin's Lymphoma Study Group (GHSG) have defined people with stage I–II disease as unfavourable or interme[18] diate if any of the adverse factors listed below are present:
EORTC system Large mediastinal mass Age 50 years or above Elevated ESR (50 mm/hour or more without B symptoms or 30 mm/hour or more with B symptoms) 4 or more involved regions
GHSG system Large mediastinal mass Extranodal disease Elevated ESR (50 mm/hour or more without B symptoms or 30 mm/hour or more with B symptoms) 3 or more involved regions
Many investigators and many new clinical trials employ a clinical staging system that divides people into 3 major groups that are also useful for the practising physician:
[15]
Early favourable: clinical stage I or II without any risk factors Early unfavourable: clinical stage I or II with one or more of the following risk factors: Large mediastinal mass (>33% of the thoracic width on the CXR, 10 cm or more on CT scan) Extranodal involvement Elevated ESR (>30 mm/hour for B stage, >50 mm/hour for A stage) 3 or more lymph node areas involvement B symptoms Advanced: clinical stage III or IV For people with advanced-stage Hodgkin's lymphoma, the International Prognostic Factors Project has developed an International Prognostic Index with a prognostic score that is based on 7 adverse factors. [19] These factors were found to predict 5-year rates of freedom from progression in 4695 people with advanced stage disease (28% were 15–24 years old):
[16]
Albumin level of
