NHL (diffuse large B cell lymphoma)

Mark Hill; Fiona Kyle

. 2008 Jan 18;2008:2401.

NHL (diffuse large B cell lymphoma)

Mark Hill ^1,^#, Fiona Kyle ^2,^#

PMCID: PMC2907930 PMID: 19450335

Abstract

Introduction

Non-Hodgkin’s lymphoma (NHL) is the sixth most common cancer in the UK; 9443 new cases were diagnosed in the UK in 2002, and it caused 4418 UK deaths in 2003. Incidence rates show distinct geographical variation, with age-standardised incidence rates ranging from 17 per 100,000 in Northern America to 4 per 100,000 in south-central Asia. NHL occurs more commonly in males than in females, and the age-standardized UK incidence increased by 10.3% between 1993 and 2002.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of first-line treatments for aggressive, or for relapsed aggressive, non-Hodgkin's lymphoma (diffuse large B cell lymphoma)? We searched: Medline, Embase, The Cochrane Library and other important databases up to April 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 33 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: allogeneic stem cell support, chemotherapy (conventional dose salvage, high-dose plus autologous transplant stem cell support, conventional dose in people with chemosensitive disease), CHOP 14, CHOP 21, CHOP 21 with radiotherapy, CHOP 21 with rituximab, MACOP-B, m-BACOD, PACEBOM, and ProMACE-CytaBOM.

Key Points

NHL is the sixth most common cancer in the UK, with a 10% increase in incidence between 1993 and 2002.

Risk factors include immunosuppression, certain viral and bacterial infections, and exposure to drugs and other chemicals.
Overall 5-year survival is around 55%. The main risk factors for a poor prognosis are older age, elevated serum lactate dehydrogenase levels, and severity of disease.

CHOP 21 has been shown to be superior or equivalent to all other combination chemotherapy regimens in terms of overall survival or toxicity in adults older or younger than 60 years.

Adding radiotherapy to a short CHOP 21 schedule (3 cycles) increases 5-year survival, while reducing the risks of congestive heart failure, compared with longer schedules of CHOP 21 alone.
Adding rituximab to CHOP 21 increases response rates and 5-year survival compared with CHOP 21 alone.
CHOP 14 may increase 5-year survival compared with CHOP 21 in people aged over 60, but remains unproven in younger adults. Toxicity is similar for the two regimens.

Consensus is that conventional-dose salvage chemotherapy should be used in people with relapsed NHL. Phase II studies report similar response rates with a number of different chemotherapy regimens.

Adding rituximab to salvage chemotherapy may improve initial response rates, but no more than 10% of people remain disease-free after 3-5 years.

High-dose salvage chemotherapy plus autologous bone-marrow transplantation may increase 5-year event-free survival compared with conventional-dose chemotherapy in people with relapsed chemotherapy-sensitive disease, but it increases the risk of severe adverse effects.

We don't know whether allogenic bone-marrow transplantation improves survival. Retrospective studies suggest that it increases the risk of graft versus host disease, and complications of immunosuppression.

About this condition

Definition

NHL consists of a complex group of cancers arising mainly from B lymphocytes (85% of cases), and occasionally from T lymphocytes. NHL usually develops in lymph nodes (nodal lymphoma), but can arise in other tissues almost anywhere in the body (extranodal lymphoma). NHL is categorised according to its appearance under the microscope (histology) and the extent of the disease (stage). Histology: Since 1966, four major different methods of classifying NHLs according to their histological appearance have been published (see tables 1 , 2 , 3 , and 4 ). At present, the WHO system is accepted as the gold standard of classification. The WHO system is based on the underlying principles of the REAL classification system. Historically, NHLs have been divided into slow-growing "low-grade" lymphomas and fast-growing "aggressive" lymphomas. This review deals only with the most common aggressive NHL — diffuse B cell lymphoma (WHO classification [see table 1 ]). Interpretation of older studies is complicated by the fact that histological methods have changed and there is no direct correlation between lymphoma types in the WHO and other classification systems. Attempts to generalise results must therefore be treated with caution. We have, however, included some older studies referring to alternative classification methods, if they included people with the following types of aggressive lymphomas, which overlap substantially with the WHO classification of interest: Working Formulation classification — primarily intermediate grades (grades E-H [see table 2 ]); Kiel classification — centroblastic, immunoblastic, and anaplastic (see table 3 ); and Rappaport classification — diffuse histiocytic, diffuse lymphocytic, poorly differentiated, and diffuse mixed (lymphocytic and histiocytic [see table 4 ]). Stage: NHL has traditionally been staged according to extent of disease spread using the Ann Arbor system (see table 5 ). The term "early disease" is used to describe disease that falls within Ann Arbor stage I or II, whereas "advanced disease" refers to Ann Arbor stage III or IV. However, all people with bulky disease, usually defined as having a disease site larger than 10 cm in diameter, are treated as having advanced disease, regardless of their Ann Arbor staging. Relapsed disease: Relapsed disease refers to the recurrence of active disease in a person who has previously achieved a complete response to initial treatment for NHL. Most studies of treatments in relapsed disease require a minimum duration of complete response of 1 month before relapse.

Table 1.

WHO Classification 2001 (see text).

Precursor B cell neoplasm
Precursor B-lymphoblastic leukemia/lymphoma (precursor B cell acute lymphoblastic leukemia)
Mature (peripheral) B-cell neoplasms
B-cell chronic lymphocytic leukemia/small cell lymphocytic lymphoma
Lymphoplasmacytic lymphoma
Splenic marginal zone B cell lymphoma (± villous lymphocytes)
Hairy cell leukemia
Plasma cell myeloma/plasmacytoma
Extranodal marginal zone B cell lymphoma of MALT type
Nodal marginal zone B cell lymphoma (± monocytoid B cells)
Follicular lymphoma
Mantle cell lymphoma
Diffuse large B cell lymphoma
- Mediastinal large B cell lymphoma
- Primary effusion lymphoma
Burkitt's lymphoma/Burkitt's cell leukemia
MALT, mucosa-associated lymphoid tissue; WHO, World Health Organization. Reproduced with permission of the copyright holder. Harris N, Jaffe E, Diebold J, et al. The World Health Organization Classification of Neoplastic Diseases of the Hematopoietic and Lymphoid Tissues. Ann Oncol 1999;10:1419–1432.

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Table 2.

International Working Formulation Classification (see text).

Grade	Working formulation	Classification
Low grade
A	Small lymphocytic, consistent with chronic lymphocytic leukaemia	SL
B	Follicular, predominantly small-cleaved cell	FSC
C	Follicular, mixed small-cleaved and large cell	FM
Intermediate grade
D	Follicular, predominately large cell	FL
E	Diffuse, small-cleaved cell	DSC
F	Diffuse mixed, small and large cell	DM
G	Diffuse, large cell-cleaved or non-cleaved cell	DL
High grade
H	Immunoblastic, large cell	BL
I	Lymphoblastic, convoluted or non-convoluted cell	LL
J	Small non-cleaved cell, Burkitt's or non-Burkitt's	SNC

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Table 3.

Updated Kiel classification (see text).

B cell lymphoma	T cell lymphoma
Low grade
Lymphocytic, chronic lymphocytic, and prolymphocytic leukaemia; hairy cell leukaemia	Lymphocytic, chronic lymphocytic, and prolymphocytic leukaemia
Lymphoplasmacytic/cytoid	Small, cerebriform cell mycosis fungoides, Sezary's syndrome
Plasmacytic	Lymphoepithedloid (Lennert's syndrome)
Centroblastic/centrocytic, follicular,	Angioimmunoblastic
and diffuse	T zone
High grade
Centrocytic	Pleomorphic, small cell
Immunoblastic	Immunoblastic
Large cell anaplastic	Large cell anaplastic
Burkitt's lymphoma
Lymphoblastic	Lymphoblastic

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Table 4.

Rappaport classification (see text).

Description	Classification
Diffuse lymphocytic, well differentiated	DLWD
Nodular lymphocytic poorly differentiated	NLPD
Nodular mixed, lympocytic and histiocytic	NM
Nodular histiocytic	NH
Diffuse lymphocytic poorly differentiated	DLDP
Diffuse mixed, lymphocytic and histiocytic	DM
Diffuse histiocytic	DH
Diffuse lymphoblastic	DL
Diffuse undifferentiated, Burkitt's or non-Burkitt's	DU

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Table 5.

Ann Arbor classification (see text).

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 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 extralymphatic organ or site or by involvement of the spleen of both.
IV	Diffuse or disseminated involvement of one or more extralymphatic organs of tissues, with or without associated lymph-node involvement.

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Reproduced with permission of American Association of Cancer Research (Cancer Research, 31: 1860–1861, 1971).

Incidence/ Prevalence

NHL is the sixth most common cancer in the UK; 9443 new cases were diagnosed in the UK in 2002 and it caused 4418 UK deaths in 2003. Incidence rates show distinct geographical variation, with age-standardised incidence rates ranging from 17 per 100,000 in Northern America to 4 per 100,000 in south-central Asia. NHL occurs more commonly in males than in females, and the age standardised UK incidence increased by 10.3% between 1993 and 2002.

Aetiology/ Risk factors

The aetiology of most NHLs is unknown. Incidence is higher in individuals who are immunosuppressed (congenital or acquired). Other risk factors include viral infection (human T cell leukaemia virus type-1, Epstein-Barr virus, HIV), bacterial infection (e.g. Helicobacter pylori), previous treatment with phenytoin or antineoplastic drugs, and exposure to pesticides or organic solvents.

Prognosis

Overall survival: Untreated aggressive NHLs would generally result in death in a matter of months. High-grade lymphomas, particularly diffuse large B cell lymphomas and Burkitt's lymphomas, have a high cure rate with both initial and salvage chemotherapy. The 5-year relative age-standardised survival for people diagnosed with and treated for NHL between 2000 and 2001 was 55% for men and 56% for women. Relapse: About 50% of people with NHL will be cured by initial treatment. Of the rest, about 30% will fail to respond to initial treatment (so called "chemotherapy refractory disease"), and about 20-30% will relapse. Most relapses occur within 2 years of completion of initial treatment. Up to 50% of these have chemotherapy-sensitive disease; the remainder tend to have chemotherapy-resistant disease. Prognostic indicators: Prognosis depends on histological type, stage, age, performance status, and lactate dehydrogenase levels. Prognosis varies substantially within each Ann Arbor stage, and further information regarding prognosis can be obtained from applying the International Prognostic Index (IPI). The IPI model stratifies prognosis according to the presence or absence of five risk factors: age (under 60 years v over 60 years), serum lactate dehydrogenase (normal v elevated), performance status (0 or 1 v 2-4), Ann Arbor stage (I or II v III or IV), and number of extranodal sites involved (0 or 1 v 2-4). People with two or more high-risk factors have a less than 50% chance of relapse-free and overall survival at 5 years. IPI staging is currently the most important system used to define disease stage and treatment options. However, most studies identified by our search predate the IPI staging system.

Aims of intervention

To increase disease-free survival, achieving cure if possible. Additionally, to palliate by achieving remission and prolonging survival, to minimise harmful effects of treatment, and to maximise quality of life.

Outcomes

Benefits: Overall survival (median and 5-year survival), disease-free survival, chemotherapy response rates (complete response and partial response; variously defined in different studies but usually measured at 1-2 months), quality of life. Harms: Treatment-related deaths, other adverse effects of treatment.

Methods

BMJ Clinical Evidence search and appraisal April 2007. The following databases were used to identify studies for this systematic review: Medline 1966 to April 2007, Embase 1980 to April 2007, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2007, Issue 1. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and National Institute for Health and Clinical Excellence (NICE). We also searched for retractions of studies included in the Review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for evaluation in this review were: published systematic reviews and RCTs in any language, including unblinded studies, and containing more than 50 people of whom more than 80% were followed up and a minimum follow-up period of 2 years. In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. This review applies to all stages of diffuse large B cell lymphomas (and other similar aggressive NHLs, see definition). This review includes all stages (early and advanced) unless otherwise specified at the option level. This review looks at all adults, but excludes people with HIV. CHOP 21 chemotherapy is the standard treatment for aggressive NHL (not including Burkitt's lymphoma), and placebo-controlled trials would be considered unethical. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).

Table.

GRADE evaluation of interventions for NHL (diffuse large B cell lymphoma)

Important outcomes	Response rates, relapse rates, mortality, quality of life, adverse effects
Number of studies (participants)	Outcome	Comparison	Type of evidence	Quality	Consistency	Directness	Effect size	GRADE	Comment
What are the effects of first-line treatments for aggressive NHL (diffuse large B cell lymphoma)?
8 (3241)	Mortality	CHOP 21 v other regimens	4	–1	–1	0	0	Low	Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting result
8 (3241)	Response rates	CHOP 21 v other regimens	4	–1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
2 (1399)	Mortality	CHOP 21 v CHOEP	4	–1	–1	0	0	Low	Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results
2 (1399)	Response rates	CHOP 21 v CHOEP	4	0	0	0	0	High
2 (1282)	Mortality	CHOP 21 v ACVBP	4	0	0	–1	0	Moderate	Directness point deducted for inclusion of interventions in one group
2 (1282)	Response rates	CHOP 21 v ACVBP	4	–1	0	–1	0	Low	Quality point deducted for incomplete reporting of results. Directness point deducted for inclusion of interventions in one group
1 (645)	Adverse effects	CHOP 21 v ACVBP	4	0	0	0	0	High
1 (401)	Mortality	Short-schedule CHOP 21 plus radiotherapy v long-schedule CHOP 21	4	0	0	0	0	High
1 (172)	Mortality	Low-dose radiotherapy v longer-schedule CHOP 21	4	–1	0	0	0	Moderate	Quality point deducted for sparse data
1 (341)	Mortality	Radiotherapy v chemotherapy	4	0	0	–1	0	Moderate	Directness point deducted for different regimen
1 (166)	Mortality	Radiotherapy v observation	4	–1	0	0	0	Moderate	Quality point deducted for sparse data
1 (576)	Mortality	Radiotherapy plus CHOP 21 v CHOP 21	4	–2	0	–1	0	Very low	Quality points deducted for short follow-up, and interim analysis of results. Directness point deducted for inclusion of people with different disease severities
1 (402)	Adverse effects	Short-schedule CHOP 21 plus radiotherapy v long-schedule CHOP 21	4	0	0	0	0	High
3 (1853)	Mortality	CHOP-R v CHOP 21	4	0	–1	–1	0	Low	Consistency point deducted for conflicting results. Directness point deducted for differences in regimens
3 (1853)	Response rates	CHOP-R v CHOP 21	4	0	0	–1	0	Moderate	Directness point deducted for differences in regimens
2 (1399)	Mortality	CHOP 14 v CHOP 21	4	0	–1	0	0	Moderate	Consistency point deducted for conflicting results
2 (1399)	Remission	CHOP 14 v CHOP 21	4	0	–1	0	0	Moderate	Consistency point deducted for conflicting results
What are the effects of treatments for relapsed aggressive NHL (diffuse large B cell lymphoma)?
1 (109)	Mortality	High-dose chemotherapy plus autologous stem-cell support v conventional chemotherapy	4	–1	0	–1	0	Low	Quality point deducted for sparse data. Directness point deducted for differences in inclusion of other interventions between groups
1 (109)	Response rates	High-dose chemotherapy plus autologous stem-cell support v conventional chemotherapy	4	–2	0	–1	0	Very low	Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for differences in inclusion of other interventions between groups

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CHOP-R, CHOP 21 plus rituximabType of evidence: 4 = RCT; 2 = Observational; 1 = Non-analytical/expert opinion. Consistency: similarity of results across studies Directness: generalisability of population or outcomes Effect size: based on relative risk or odds ratio

Glossary

ACVBP: Doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone.
Aggressive disease: Diffuse large B cell lymphoma has been classified variously as diffuse histiocytic lymphoma and occasionally as grades E–H; Kiel classification: centroblastic, immunoblastic, and anaplastic; Rappaport classification: diffuse histiocytic, diffuse lymphocytic, poorly differentiated, and diffuse mixed (lymphocytic and histiocytic).
BEAC: Carmustine, etoposide, cytarabine, and cyclophosphamide.
CHOP 14: Cyclophosphamide, doxorubicin, vincristine, and prednisolone given at 14-day intervals.
CHOP 21: Cyclophosphamide, doxorubicin, vincristine, and prednisolone given at 21-day intervals (standard CHOP cycle).
CHOP-R: Cyclophosphamide, doxorubicin, vincristine, prednisolone, and rituximab given at 21-day intervals.
Complete response/remission: Complete disappearance of all lymph-node masses to less than 1.5 cm in transverse diameter, as well as the normalisation of any biochemical abnormalities and a negative bone-marrow result (if the bone marrow had previously been shown to have been involved). These criteria were recommended by the International Workshop on NHL in 1999; before 1999 there were no consensus criteria for defining response to treatment in NHL.
Conventional-dose chemotherapy: Chemotherapy delivered at a dose that does not suppress bone marrow to such an extent that stem-cell support is required.
DHAP: Dexamethasone, cisplatin, cytarabine.
Early and Advanced Disease: Staging is historically done by the Ann Arbor system. We have considered people with stage I or stage II non-bulky disease as having early disease, whereas stage III or IV, or bulky disease are included as advanced disease. It is recognised that there will be substantial variation even within these groups and that for more recent trial participants, their stage of disease will be assessed by use of the International Prognostic Index.
HOP: Doxorubicin, vincristine, and prednisolone.
High-quality evidence: Further research is very unlikely to change our confidence in the estimate of effect.
IVAC: Ifosfamide, etoposide, and cytarabine.
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.
Moderate-quality evidence: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
PACEBOM: Prednisolone, doxorubicin, cyclophosphamide, etoposide, bleomycin, vincristine, and methotrexate.
Partial response: A minimum decrease of 50% in the sum of the products of the greatest diameters of the six largest nodes or nodal masses. This criterion was recommended by the International Workshop on NHL in 1999; before 1999 there were no consensus criteria for defining response to treatment in NHL.
Performance status: Scale grading the level of normal activity a person with aggressive NHL is capable of, where a minimum score of 0 represents normal activity and a maximum score of 4 represents being constantly bedridden.
REAL: A precursor to the present WHO classification system.
Very low-quality evidence: Any estimate of effect is very uncertain.
m-BACOD: Low-dose methotrexate, leucoverin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin.

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.

Contributor Information

Mark Hill, Kent Oncology Centre, Kent, UK.

Fiona Kyle, St George's Hospital, London, UK.

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BMJ Clin Evid. 2008 Jan 18;2008:2401.

CHOP 21

Summary

MORTALITY Compared with other regimens: CHOP 21 may be as effective at 5 years as other regimens (MACOP-B, m-BACOD, ProMACE-CytaBOM, and PACEBOM) at increasing overall estimated survival rates in people with high-grade NHL lymphomas, and has similar toxicity profiles ( low-quality evidence ). Compared with CHOEP: We don’t know whether CHOP 21 may increase overall survival, and 5-year event-free survival rates, in people with high-grade NHL lymphomas compared with CHOEP (low-quality evidence). Compared with ACVBP: CHOP 21 does not increase overall survival, and 5-year estimated event-free survival rates, in people with low-risk, localised lymphomas, or in people with poor-prognosis, aggressive lymphomas compared with ACVBP ( moderate-quality evidence ). Compared with CHOP 21 plus radiotherapy: CHOP 21 may not increase disease-free survival or overall survival rates at 5 years in people with low-risk, localised aggressive NHL compared with CHOP 21 plus radiotherapy ( very low-quality evidence ). Longer-schedule CHOP 21 (8 cycles) compared with shorter-schedule CHOP 21 (3 cycles) plus radiotherapy: Longer-schedule CHOP 21 is less effective at increasing 5-year progression-free survival and overall survival rates in people with early-stage disease compared with shorter-schedule CHOP 21 plus radiotherapy ( high-quality evidence ). Longer-schedule CHOP 21 compared with longer-schedule CHOP 21 plus radiotherapy: Longer-schedule CHOP 21 is less effective at 6 years than longer-schedule CHOP 21 followed by low-dose radiotherapy at improving disease-free survival rates, but not overall survival rates, in people with early-stage disease ( moderate-quality evidence ). Compared with CHOP 21 plus rituximab: CHOP 21 may be less effective at 3–5 years than CHOP 21 plus rituximab at increasing event-free survival and overall survival rates in people with diffuse large B cell lymphoma (low-quality evidence). Compared with CHOP 14: CHOP 21 is less effective than CHOP 14 at increasing estimated overall 5-year survival rates, but we we don’t know whether it is more effective at increasing estimated 5-year event-free survival rates in people with previously untreated, aggressive NHL and with good prognosis (moderate-quality evidence). RESPONSE RATES Compared with other regimens: CHOP 21 is as effective as other regimens (MACOP-B, m-BACOD, ProMACE-CytaBOM, and PACEBOM) at increasing complete response rates in people with high-grade NHL lymphomas (moderate-quality evidence). Compared with CHOEP: CHOP 21 is less effective than CHEOP at increasing complete response rates in people with previously untreated, aggressive NHL but is associated with fewer toxic effects ( high-quality evidence ). Compared with ACVBP: CHOP 21 may be as effective as ACVBP at increasing complete response rates in people with low-risk, localised lymphomas, or in people with poor prognosis, aggressive lymphomas (low-quality evidence). Compared with CHOP 21 plus rituximab: CHOP 21 is less effective at 155 days to 2 years than CHOP 21 plus rituximab at increasing response rates in people with stage II–IV diffuse large B cell lymphoma (moderate-quality evidence). REMISSION RATES Compared with CHOP 14: We don’t know whether CHOP 21 improves remission rates in people with previously untreated, aggressive NHL and with good prognosis compared with CHOP 14 (moderate-quality evidence). ADVERSE EFFECTS Compared with ACVBP: CHOP 21 is associated with fewer treatment-related deaths, severe infections, and grade 4 haematological toxicities compared with ACVBP (high-quality evidence). Longer-schedule CHOP 21 compared with shorter-schedule CHOP 21 plus radiotherapy: Longer-schedule CHOP 21 is associated with an increased risk of myelosuppression and congestive heart failure compared with shorter-schedule CHOP 21 plus radiotherapy (high-quality evidence). NOTE CHOP 21 is the standard treatment for aggressive NHL (not including Burkitt's lymphoma).

Benefits

CHOP 21 versus other regimens (MACOP-B, m-BACOD, ProMACE-CytaBOM, PACEBOM, BCOP, HOP, CHOEP, ACVBP):

We found three systematic reviews (search date not reported, 2000, and 2003) which, between them, identified eight RCTs (reported in 9 publications; 3241 people) comparing CHOP 21 versus MACOP-B, m-BACOD, ProMACE-CytaBOM, and PACEBOM. None of these alternative regimens were consistently shown to be significantly superior to CHOP 21 in terms of overall survival (see table 6 ). The most recent systematic review identified 2 RCTs comparing CHOP 21 versus CHOEP , and two RCTs comparing CHOP 21 versus ACVBP. The first RCT included in the review (710 people aged 18–60 years with previously untreated aggressive NHL according to the REAL classification, with good prognosis [defined as normal lactate dehydrogenase level]; 15-year event-free survival was estimated after a median observation time of 58 months) compared four six-cycle treatments in a 2 × 2 factorial design: CHOP 14 (172 people), CHOP 21 (176 people), CHOP 14 plus etoposide (177 people), and CHOP 21 plus etoposide (185 people). Participants in the CHOP 14 regimens also received granulocyte colony-stimulating factor (filgrastim) support between days 4 and 13 (inclusive). Radiotherapy (36 Gy) was given to sites of initial bulky disease and extranodal disease at completion of chemotherapy. Patients treated with CHOEP had a superior complete response (CR) rate (84.9%, 95% CI 78.9% to 89.7%) and 5-year event-free survival (69.2%, 95% CI 62.2% to 76.1%) compared with patients receiving CHOP-21 (CR rate: 80.1%, 95% CI 73.4% to 85.7%; 5-year event-free survival: 54.7%, 95% CI 46.7% to 62.6%). The second RCT included in the review (689 people aged 61–75 years with previously untreated, aggressive NHL according to the REAL classification; 5-year event-free survival was estimated after a median observation time of 58 months) compared four six-cycle treatments in a 2 × 2 factorial design: CHOP 14 (172 people), CHOP 21 (178 people), CHOP 14 plus etoposide (169 people), and CHOP 21 plus etoposide (170 people). Granulocyte colony-stimulating factor (filgrastim) and radiotherapy were given as in the first RCT. Patients treated with CHOEP 21 had a higher CR rate than did the CHOP 21 group (70%, 95% CI 62.5% to 76.8% for CHOEP 21 v 60.1%, 95% CI 52.5% to 67.4% for CHOP 21) but event-free survival and overall survival were not significantly improved by the addition of etoposide (event-free survival: RR 0.82, 95% CI 0.63 to 1.07; P = 0.145; death: RR 0.79, 95% CI 0.59 to 1.05; P = 0.79). The third RCT included in the review compared three cycles of CHOP 21 plus involved field radiotherapy (40 Gy in 22 fractions, 329 people) versus ACVBP (3 induction courses given at 2 weekly intervals plus sequential consolidation, 318 people; see comment below). It found no difference between treatments in CR rates (647 people aged inder 61 years with localised stage I or II aggressive lymphoma and no adverse prognostic features; AR for CR: 93% with ACVBP v 92% with CHOP 21 + radiotherapy; P value not reported). It found that ACVBP significantly increased 5-year estimated event-free survival and overall survival compared with CHOP 21 (event-free survival: 82% with ACVBP v 74% with CHOP + radiotherapy; P less than 0.001; overall survival: 90% with ACVBP v 81% with CHOP + radiotherapy; P = 0.001). The fourth RCT included in the review compared eight cycles of standard CHOP 21 (312 people) versus ACVBP (4 induction courses at 3-weekly intervals plus sequential consolidation therapy, 323 people; see comment below). It found no significant difference between treatments in CR rates but found that ACVBP significantly increased 5-year event-free survival and overall survival compared with CHOP 21 (635 people aged 61–69 years with poor risk, aggressive NHL defined as stage III or IV disease, with raised serum lactate dehydrogenase or an Eastern Cooperative Oncology Group performance status of 2–4; AR for CR: 58% with ACVBP v 56% with CHOP 21; P less than 0.5; 5-year estimated event-free survival: 39% with ACVBP v 29% with CHOP 21; P less than 0.007; overall survival: 46% with ACVBP v 38% for CHOP 21; P 0.03). In this RCT growth factor support and prophylactic intrathecal methotrexate to prevent meningeal relapse were given routinely to all patients receiving ACVBP during the induction cycles, whereas no growth factor support or central nervous system prophylaxis were given to CHOP 21 recipients. The RCT included some people with lymphoblastic and Burkitts lymphoma. The reviews did not find any RCTs comparing CHOP 21 versus BCOP or HOP that met inclusion criteria for this review.

Table 6.

Comparison of CHOP 21 versus alternative chemotherapy regimens (MACOP-B, MBACOD, ProMACE-CytaBOM, PACEBOM) for first-line treatment.

Comparison	Population	Benefits	Harms
CHOP 21 v MACOP-B	304 people aged 16–72 years (67% under 60 years) with Working Formulation intermediate (D–G; 6% grade D) or high (H) grade lymphoma; stage I (bulky) to stage IV disease (64% stage III or IV); median follow-up 6.5 years (65 people excluded on histological or other grounds)	Complete response rate:65/111 [59%] with CHOP v 64/125 [51%] with MACOP-B; P = 0.3 Overall survival estimated at: 4 years: 51% with CHOP v 56% with MACOP-B; P = 0.7 5 years: 41% with CHOP v 54% with MACOP-B; P = 0.035 8 years: 36% with CHOP v 45% with MACOP-B; P = 0.16 Disease-free survival estimated at: 4 years: 32% with CHOP v 44% with MACOP-B; P = 0.47 5 years: 30% with CHOP v 42% with MACOP-B; P = 0.045 8 years: 25% with CHOP v 37% with MACOP-B; P = 0.057	Stomatitis:9% with CHOP v 45% with MACOP-B; P less than 0.0001 Cutaneous toxicity:0% with CHOP v 11% with MACOP-B; P = 0.0001 Gastrointestinal ulceration:4% with CHOP v 12% with MACOP-B; P = 0.0001 Grade 3–4 haematological toxicity:Significantly lower with CHOP; P = 0.04 (no further data reported) Alopecia:71% with CHOP v 48% with MACOP-B; P = 0.0006 Tolerance:MACOP-B was poorly tolerated in older people (over 60 years) with 43% completing treatment compared with 83% of younger people

CHOP 21 v MACOP-B	405 people aged 18–67 years with aggressive lymphomas according to the Kiel classification (centroblastic, immunoblastic, anaplastic large cell and peripheral T cell), stage I–IV disease (51.6% stage III or IV); median follow-up 57 months (31 people excluded on histological or other grounds)	Complete response rate:37% with CHOP v 41% with MACOP-B; P = NS Overall survival estimated at 5 years:59% with CHOP v 60% with MACOP-B; P = NS Disease-free survival estimated at 5 years:44% with CHOP v 47% with MACOP-B; P = NS QoL:QoL was assessed by 1 centre in 92/106 (87%) people. It found significantly lower QoL with MACOP-B at 12 weeks (P = 0.04; European Organisation for Research into Treatment of Cancer 30, modified QoL score) and worse physical function. However, at 56 weeks the difference was no longer significant	Treatment-related mortality:1.9% with CHOP v 1.7% with MACOP-B; P = NS Less appetite loss with MACOP-B but more fatigue After 12 weeks (MACOP-B course completed, CHOP still ongoing): constipation, diarrhoea, fatigue, dry mouth, nausea/vomiting dizziness, hair loss, and mucositis were higher in the CHOP arm At 56 weeks: neuropathic symptoms and mucositis more common in the MACOP-B arm. (Absolute figures not reported; results presented graphically)

CHOP 21 v MACOP-B v m-BACOD v Pro-MACE-Cyta-BOM	1138 people aged 15–81 years (75% under 65 years), with Working Formulation intermediate or high grade lymphomas D–H, and J (15% grade D or E; 4% grade J); stage II (bulky) to stage IV disease; median follow- up 49 months (239 people excluded after histology revealed low-grade lymphoma)	Complete response rate:44% with CHOP v 51% with MACOP-B v 48% with m-BACOD v 56% with ProMACE-CytaBOM; P = NS for overall between group comparison. Overall survival estimated at 3 years:55% with CHOP v 49% with MACOP-B v 51% with m-BACOD v 53% with ProMACE-CytaBOM; overall P = 0.68 for overall between group comparison. Disease-free survival estimated at 3 years:43% with CHOP v 40% with MACOP-B v 43% with m-BACOD v 44% with ProMACE-CytaBOM; overall P = 0.40 for overall between group comparison.	Fatal toxicity:1% with CHOP v 6% with MACOP-B v 5% with m-BACOD v 3% with ProMACE-CytaBOM Life threatening toxicity:31% with CHOP v 43% with MACOP-B v 29% with m-BACOD v 54% with ProMACE-CytaBOM Overall toxicity: significantly lower with CHOP and ProMACE-CytaBOM than m-BACOD and MACOP-B (P = 0.001)

CHOP 21 v m-BACOD	392 people (51% aged 60 years or over) with Working Formulation lymphoma grades F–H; stage III or IV; median follow-up 4 years (67 people excluded because of incorrect pathological assessment)	Complete response rate:51% with CHOP v 56% with m-BACOD; P = 0.32 Overall survival estimated at 5 years:48% with CHOP v 49% with m-BACOD; P = 0.54 Disease-free survival:Results shown graphically; P = NS	Grades 2–4 pulmonary toxicity:3% with CHOP v 23% with m-BACOD; P less than 0.001 Grades 3 and 4 infection:13% with CHOP v 35% with m-BACOD; P less than 0.001 Grades 3 and 4 thrombocytopaenia:2% with CHOP v 13% with m-BACOD; P = 0.003 Grades 3 and 4 stomatitis:2% with CHOP v 37% with m-BACOD; P = 0.001 Treatment-related mortality:8/174 [5%] with CHOP v 9/151 [6%] with m-BACOD; P = NS

CHOP 21 v Pro-MACE-CytaBOM	175 people aged 21–82 years (47% under 60 years) with Working Formulation intermediate or high grades D–H (7% with grade D); stages II–IV disease (75% stages III and IV); median follow-up 52 months (27 people excluded from study; further 14 people excluded from analysis because of early death or treatment refusal)	Complete response rate: 57.5% with CHOP v 62.3% with ProMACE-CytaBOM; P = NS Overall survival estimated at 5 years:42% for both CHOP and ProMACE-CytaBOM; P = NS Median survival:45 months with CHOP v 27 months with ProMACE-CytaBOM; significance not reported	Grade 3 and 4 toxicity:P = NS (absolute figures not reported) Treatment-related mortality:1/72 [1.4%] with CHOP v 6/76 [7.9%] with ProMACE-CytaBOM; P = 0.126

CHOP 21 v PACEBOM	459 people aged 16–69 years, with Working Formulation lymphoma grades F and G, stages II–IV disease (67% stage III or IV)	Complete response rate:57% with CHOP v 64% with PACEBOM; P = 0.14 (Criteria for complete response stricter than for most RCTs, required normal results 3 months after treatment) Overall survival estimated at: 5 years: 50% with CHOP v 60% with PACEBOM; P = 0.18 8 years: 41% with CHOP v 51% with PACEBOM; P = 0.11 Disease-free survival estimated at: 5 years: 59% CHOP v 67% PACEBOM; P = 0.9 8 years: 60% with CHOP v 65% with PACEBOM; P = 0.65	Treatment-related mortality:3/226 [1.3%] with CHOP v 4/233 [1.7%] with PACEBOM; significance not reported WHO grade 3 or 4 haematological toxicity:34% with CHOP v 50% with PACEBOM; P = 0.02

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CHOP – cyclophosphamide, doxorubicin, vincristine, prednisolone; m-BACOD – low-dose methotrexate, leucoverin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin; MACOP-B – methotrexate, leucoverin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin; NS, not significant; PACEBOM – prednisolone, doxorubicin, cyclophosphamide, etoposide, bleomycin, vincristine, methotrexate; ProMACE-CytaBOM – prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine, methotrexate, with leucoverin rescue; QoL – quality of life.

CHOP 21 alone versus CHOP 21 plus radiotherapy:

See benefits of CHOP 21 plus radiotherapy.

CHOP 21 versus CHOP 21 plus rituximab:

See benefits of CHOP 21 plus rituximab.

CHOP 21 versus CHOP 14:

See benefits of CHOP 14.

Harms

CHOP 21 versus other regimens (MACOP-B, m-BACOD, ProMACE-CytaBOM, PACEBOM, BCOP, HOP):

No alternative regimen was shown to be superior to CHOP 21 in terms of adverse effects (see table 6 ).

CHOP 21 versus CHOEP 21:

Incidence of WHO grade 3 and 4 myelosuppression was significantly higher in patients treated with CHOEP 21 than in those treated with CHOP 21 in both RCTs comparing these regimens. In young, low-risk patients, one therapy-associated death occurred with CHOEP 21 compared with none in the CHOP 21 group. In the RCT comparing CHOP 21 versus CHOEP 21 in patients aged 61–75 years, nine therapy-associated deaths occurred in the CHOEP 21 group compared with six in the CHOP 21 group. The third RCT, comparing ACVBP plus sequential consolidation versus CHOP 21 plus radiotherapy, found no treatment-related deaths with either treatment, but found that ACVBP increased grade 3 infection compared with CHOP 21 plus radiotherapy (11% with ACVBP v 1% with CHOP 21 + radiotherapy; P value not reported). The fourth RCT found that ACVBP significantly increased treatment-related deaths, grade 4 leukopenia, grade 4 thrombocytopenia, and severe infections compared with CHOP 21 (treatment-related death: 43/323 [13%] with ACVBP v 23/312 [7%] with CHOP; P less than 0.014; grade 4 leukopenia: 91.5% with ACVBP v 53.8% with CHOP; P less than 0.001; grade 4 thrombocytopenia: 48.3% with ACVPB v 10.6% with CHOP; P less than 0.001; severe infections: 36% with ACVBP v 15% with CHOP; P less than 0.001).

Drug safety alert

MHRA issues drug safety alert on the risk of progressive multifocal leukoencephalopathy (PML) associated with rituximab (07 November 2008).

A drug safety alert has been issued on the risk multifocal leukoencephalopathy (PML) associated with rituximab (http://www.mhra.gov).

Comment

Older people:

We found a third systematic review (search date 2000), which assessed different chemotherapy regimens in people at least 60 years old with previously untreated advanced-stage aggressive NHL. Twelve RCTs were reviewed, three of which compared CHOP 21 versus alternative regimens covered by our search (all of which were identified by the two reviews included above). The review confirmed that the use of anthracycline containing regimens such as CHOP 21 resulted in superior outcomes compared with other regimens in this age group. However, all trials except one excluded people with significant comorbidity.

Maintenance rituximab:

The effect of rituximab appears to be additive rather than synergistic, therefore challenging the time frame of administering rituximab. In a randomised trial of CHOP versus CHOP plus rituximab in 632 people, as a second stage, 415 people who responded to treatment were randomly allocated to maintenance rituximab versus observation (no maintenance rituximab).See benefits of CHOP 21 plus rituximab. From the second randomisation, the 2-year failure-free survival rate was 77% with CHOP plus rituximab, 79% with CHOP plus rituximab plus maintenance rituximab, 74% with CHOP plus maintenance rituximab, and 45% with CHOP alone. The response rates with maintenance rituximab for those not responding to initial therapy were not reported.

Substantive changes

CHOP 21 One RCT comparing CHOP 21 versus CHOP plus rituximab addedand one RCT comparing CHOP 21 versus CHOP plus radiotherapy added; benefits and harms data enhanced, categorisation of 'CHOP 21 (no alternative regimen [MACOP-B, m-BACOD, ProMACE-CytaBOM, PACEBOM] shown to be superior)' unchanged (Beneficial).

BMJ Clin Evid. 2008 Jan 18;2008:2401.

CHOP 21 plus radiotherapy

Summary

MORTALITY Shorter-schedule CHOP 21 (3 cycles) plus radiotherapy compared with longer-schedule CHOP 21 (8 cycles): Shorter-schedule CHOP 21 plus radiotherapy increases 5-year progression-free survival and overall survival rates in people with early-stage disease compared with longer-schedule CHOP 21 ( high-quality evidence ). Longer-schedule CHOP 21 plus radiotherapy compared with longer-schedule CHOP 21: Longer-schedule CHOP 21 followed by low-dose radiotherapy improves disease-free survival rates at 6 years, but not overall survival rates, in people with early-stage disease compared with longer-schedule CHOP 21 ( moderate-quality evidence ). Radiotherapy compared with chemotherapy: Adjuvant radiotherapy applied to sites of nodal bulky disease increases 5-year event-free survival and overall survival rates in people with advanced (stage IV) diffuse large B cell lymphoma who have achieved a complete response after initial treatment with a CHOP-like regimen compared with chemotherapy alone (moderate-quality evidence). Radiotherapy compared with observation: Field radiotherapy increases 10-year progression-free survival and overall survival rates in people with high- or intermediate-risk diffuse large B cell lymphoma with residual disease after chemotherapy compared with observation alone (moderate-quality evidence). Compared with CHOP 21: CHOP 21 plus radiotherapy may be no more effective at 5 years than CHOP 21 alone at increasing disease-free survival or overall survival rates in people with low-risk, localised aggressive non-Hodgkin’s lymphoma (very low-quality evidence) . ADVERSE EFFECTS Shorter-schedule CHOP 21 plus radiotherapy compared with longer-schedule CHOP 21: Longer-schedule CHOP 21 is associated with an increased risk of myelosuppression and congestive heart failure compared with shorter-schedule CHOP 21 plus radiotherapy (high-quality evidence).

Benefits

CHOP 21 plus radiotherapy versus CHOP 21 alone:

We found two systematic reviews (initial search date 1993, updated in 2001; and 2003), which identified two RCTs, and we found three subsequent RCTs. The first RCT identified by the reviews (401 people with stage I or II Working Formulation grades D–J lymphoma, excluding lymphoblastic lymphoma; 75% grades G and H; 49% aged 60 years or over) compared longer-schedule CHOP 21 alone (8 cycles) versus short-schedule CHOP 21 plus radiotherapy (3 cycles plus a total dose of radiotherapy of 40–55 Gy). It found that short-schedule CHOP 21 plus radiotherapy significantly improved progression-free survival and overall survival at 5 years compared with long-schedule CHOP 21 alone (estimated progression-free survival: 77% with CHOP 21 + radiotherapy v 64% with CHOP 21 alone; estimated HR 1.5, 95% CI 1.0 to 2.2; estimated overall survival: 82% with CHOP 21 + radiotherapy v 72% with CHOP 21 alone; estimated HR 1.7, 95% CI 1.1 to 2.7). This RCT included people with low-risk stage I disease, follicular large cell, and Burkitt's lymphoma, all of whom were excluded from the second RCT identified by second review. The second RCT identified by the second review randomised people who had achieved complete remission after eight cycles of CHOP 21 to adjuvant low-dose radiotherapy (30 Gy to initial disease sites) or observation. It found that CHOP 21 plus radiotherapy increased 6-year disease-free survival compared with CHOP alone (172 people with stage I [with risk factors] and stage II diffuse aggressive lymphoma [Working Formulation diffuse large cell, diffuse mixed large, and diffuse/small cleaved cell] before CHOP 21 treatment; disease-free survival: 73% with CHOP 21 + radiotherapy v 56% CHOP 21 alone; P = 0.05). CHOP 21 plus radiotherapy reduced treatment failure, but this reduction did not reach significance (AR for treatment failure: 17/58 [29%] with CHOP 21 + radiotherapy v 31/93 [33%] with CHOP 21 alone; P = 0.06). The RCT found no significant difference between treatments in overall 6-year survival (82% with CHOP 21 + radiotherapy v 71% with CHOP 21 alone; P = 0.24). The proportion of people with extranodal disease was higher in this RCT than in the first RCT (47% v 37%), as was the proportion of people with stage II disease. This RCT also assessed the efficacy of high-dose radiotherapy (40 Gy) in 71 people who achieved a partial response after eight cycles of CHOP 21. Twenty two people (31%) achieved a complete response after high-dose radiotherapy, but failure-free survival, relapse rate, time to progression, and overall survival did not differ significantly between people converting to complete response and those remaining in partial response.The first subsequent RCT (341 people with stage IV aggressive diffuse large B cell lymphoma and bulky nodal disease (diameter more than 10 cm) at presentation who had achieved a complete response following treatment with eight cycles of a CHOP-like regimen (cyclophosphamide, epirubicin, vincristine, prednisolone, and bleomycin) randomised to either 40 Gy radiotherapy to the site of bulky disease (168 people) or observation only (173 people). Both 5-year event-free survival and overall survival were statistically higher in the irradiated group (5-year event-free survival: 82%, 95% CI 70% to 89% with radiotherapy v 55%, 95% CI 41% to 64% with observation; P less than 0.001; overall survival: 87%, 95% CI 80% to 99% with radiotherapy v 66%, 95% CI 51% to 73% with observation; P less than 0.01). The second subsequent RCT (166 people with high- or intermediate-risk diffuse large B cell lymphoma, who had residual disease after chemotherapy [defined as a tumour mass of less than 5 cm in diameter]) randomised patients to 30 Gy radiotherapy delivered to the involved field or observation only. After a median follow-up of 135 months, 10-year progression-free survival and overall survival were statistically superior in the group treated with radiotherapy (progression-free survival: 86% with radiotherapy v 32% with observation; overall survival: 89% with radiotherapy v 58% with observation; P less than 0.001). All relapses in the group treated with radiotherapy occurred outside the radiation field. The third subsequent RCT (576 people) compared the addition of radiotherapy to the primary treatment of aggressive NHL with four cycles of CHOP 21 in older people. Participants had a median age of 68 years (range 60–85 years) with aggressive (diffuse large B cell lymphoma approximately 80% of people) stage 1 disease (65% of participants) or stage II disease (34% of participants) with no adverse prognostic factors of the International Prognostic Index. The RCT was started in 1993 and terminated early because of the advent of rituximab, and the results are based on a planned interim analysis. The RCT found no significant difference in event-free or overall survival between CHOP plus radiotherapy and CHOP alone in people with low-risk, localised aggressive NHL at 5 years (event-free survival: 63% with CHOP plus radiotherapy v 62% with CHOP alone, P = 0.8; overall survival: 68% v 71%, P = 0.6). A multivariate analysis suggested that overall survival was affected by stage II disease (P = 0.001) and male sex (P = 0.03) rather than by bulky disease (event-free survival: 70% with stage I v 49% with stage II; overall survival: 76% with stage I v 58% with stage II). Problems of interpretation with this RCT include the small number of people with bulky disease (49 people), and the advent of rituximab leading to the early termination of the study.

Harms

The first RCT identified by the reviews found that two people died as a result of treatment. One person treated with longer-schedule CHOP 21 alone died from sepsis associated with neutropenia, and one person treated with short-schedule CHOP 21 plus radiotherapy died from liver failure, which is consistent with radiation-induced hepatitis. Life-threatening toxic events were more common in people treated with longer-schedule CHOP 21 alone but the difference did not reach statistical significance (61/200 [31%] with CHOP 21 + radiotherapy v 80/201 [40%] with longer CHOP 21 alone; P = 0.06). The most common life-threatening adverse event was myelosuppression, which caused grade 4 neutropenia (absolute neutrophil count less than 500 /mm³ : 71/201 [35%] with longer-schedule CHOP 21 v 54/200 [27%] with short-schedule CHOP 21 + radiotherapy; P = 0.09). The RCT also found that significantly more people with longer-schedule CHOP 21 alone experienced symptoms or signs of congestive heart failure, or more than a 20% decrease from baseline in left ventricular ejection fraction (0/201 [0%] with CHOP 21 + radiotherapy v 7/201 [3.5%] with longer CHOP 21; P = 0.02). The second RCT reported four treatment-related deaths associated with CHOP 21 treatment (2 from infection, 2 from congestive heart failure) among the 394 participants enrolled in the pre-randomisation induction phase. Grade 4 neutropenia occurred in 128/394 (32%) people receiving CHOP 21. This RCT did not report on harms associated with radiotherapy. The first subsequent RCT reported only mild acute toxicity associated with radiotherapy treatment. The most frequently observed adverse effects were abdominal pain, diarrhoea, nausea, and vomiting, all of which were grade I in severity and resolved 6–9 months after treatment. Three cases of asymptomatic late cardiac toxicity were reported. The second subsequent RCT reported mild acute radiotherapy-associated toxicity only with no late toxicity.The third subsequent RCT reported that, among the seven deaths that occurred during treatment, five resulted from toxicity secondary to chemotherapy and two resulted from lymphoma progression. Eight episodes (3%) of grade 3 infection were reported in the CHOP alone group compared with ten episodes (3%) of grade 3 and two episodes (less than 1%) of grade 4 infection with the chemoradiotherapy group (statistical analysis between groups not reported).

Comment

The second review recommends a lower radiotherapy dose of 30–36 Gy for consolidation-involved field radiotherapy than that used in the third RCT (45 Gy) to limit long-term occurrence of secondary cancers.

Substantive changes

CHOP 21 plus radiotherapy One RCT added;benefits and harms data enhanced, categorisation of 'CHOP 21 plus radiotherapy (increases disease-free survival compared with CHOP 21 alone)' unchanged (Beneficial).

BMJ Clin Evid. 2008 Jan 18;2008:2401.

CHOP 21 plus rituximab

Summary

MORTALITY Compared with CHOP 21: CHOP 21 plus rituximab may increase event-free survival and overall survival rates at 3–5 years in people with diffuse large B cell lymphoma compared with CHOP 21 ( low-quality evidence ). RESPONSE RATES Compared with CHOP 21: CHOP 21 plus rituximab is more effective at 155 days to 2 years than CHOP 21 at increasing response rates, and at reducing events (progression, relapse, or need for second-line treatment) at 5 years, in people with stage II–IV diffuse large B cell lymphoma ( moderate-quality evidence ).

Benefits

We found one systematic review (search date 2002), which identified one RCT with a 5-year follow-up comparing CHOP 21 alone versus CHOP 21 plus rituximab (CHOP-R), and we found two subsequent RCTs. The RCT identified by the review (399 people aged 60–80 years with previously untreated stage II–IV diffuse large B cell lymphoma) compared eight cycles of CHOP 21 alone (197 people) versus eight cycles of CHOP-R (375 mg/m²; 202 people) given on day 1 of each CHOP 21 cycle. The complete response rate at 2 years was significantly higher with CHOP-R than with CHOP 21 alone (76% with CHOP-R v 63% with CHOP 21 alone; P = 0.005). The RCT found that CHOP-R significantly reduced events (disease progression, relapse, need for second-line treatment) and death compared with CHOP 21 alone at 5 years (AR for event: 52.5% with CHOP-R v 72% with CHOP 21 alone; 5-year event-free survival: 47%, 95% CI 35.8% to 54.1% with CHOP-R v 29%, 95% CI 23.1% to 35.8% with CHOP 21; P = 0.00002; 5-year overall survival: 58%, 95% CI 50.8% to 64.5% with CHOP-R v 45%, 95% CI 39.1% to 53.3% with CHOP 21; P less than 0.073). The first subsequent RCT (822 patients with stage II–IV or bulky stage I, good prognosis diffuse large B cell lymphoma) randomised people to either six cycles of CHOP-like chemotherapy plus rituximab (411 people) or six cycles of CHOP-like chemotherapy alone (411 people). Radiotherapy (30–40 Gy) was delivered to sites of primary bulky disease. The RCT found that complete response and unconfirmed complete response rates 155 days after start of treatment were significantly higher with chemotherapy plus rituximab than with chemotherapy alone (86%, 95% CI 82% to 89% with chemotherapy + rituximab v 68%, 95% CI 63% to 73% with chemotherapy alone; P less than 0.0001). Three-year event-free survival and overall survival were also significantly higher with chemotherapy plus rituximab than with chemotherapy alone (event-free survival: 79%, 95% CI 75% to 83% with chemotherapy + rituximab v 59%, 95% CI 54% to 64% with chemotherapy alone; P less than 0.0001; overall survival: 93%, 95% CI 90% to 95% with chemotherapy + rituximab v 84%, 95% CI 80% to 88%; P = 0.0001). In this RCT, 48% of the patients received CHOP 21, 44% received CHOEP 21, and a small number received PMitCEBO (4%) or MACOP-B (4%). This trial was stopped early because of a significantly improved 15-month event-free survival in the group treated with chemotherapy plus rituximab compared with chemotherapy alone. The second subsequent RCT (632 people aged 60 years or over with untreated diffuse large B cell lymphoma, stage I-IV disease) found that CHOP plus rituximab significantly increased the primary end-point of failure-free survival rate (time to relapse, non-protocol treatment, or death) compared with CHOP 21 alone at 3 years (53% with CHOP-R v 46% with CHOP alone; HR 0.78, 95% CI 0.61 to 0.99; P = 0.04).It found no significant difference between CHOP plus rituximab and CHOP alone on overall survival (HR 0.83, 95% CI 0.63 to 1.09; P = 0.18).

Harms

The RCT identified by the review found that the incidence of grade 3 and 4 adverse events occurred with similar frequency in people taking CHOP 21 alone and CHOP-R (overall figures not reported). There was a higher incidence of cardiac events with CHOP-R, which was because of an increase in grade 1 events (AR for cardiac events: 47% with CHOP-R v 35% with CHOP 21 alone; AR for grade 1 cardiac events: 24% with CHOP-R v 13% with CHOP 21 alone; significance of either comparison not reported). This difference was thought to be caused by mild to moderate infusion reactions associated with rituximab, as predicted by phase II studies. Grade 3 or 4 infusion-related events were observed in 19 people (9%) treated with CHOP-R, the most frequent of these being respiratory symptoms, chills, fever, and hypotension. In all cases, the symptoms resolved on slowing of the infusion, and all participants were able to receive subsequent infusions of rituximab without recurrence of grade 3 or 4 infusion-related reaction. No participants died as a result of a rituximab infusion-related event. In total, 23 participants in both groups died during the treatment period (16 [4%] from infection, 4 [1%] from cachexia, and 3 [0.8%] from cardiovascular events). There was no significant difference in non-lymphoma mortality between treatment groups (absolute figures and P values not reported). At 5 years of follow-up the number of patients developing a second malignancy was similar in each treatment group (10 with CHOP 21 v 9 with CHOP-R). In the first subsequent RCT treatment groups did not differ in terms of the frequency of adverse events. A total of seven treatment-related deaths occurred, four of which were in the chemotherapy alone group (1 sepsis, 2 MIs, and 1 due to intrathecal vincristine application), and three were in the chemotherapy plus rituximab group (all septicaemias; P = 0.123). The second subsequent RCT reported that there were no significant differences between groups in adverse events (P greater than 0.18). Lethal toxicities included infection (8 people with CHOP plus rituximab v 7 people with CHOP alone), cardiac toxicity (5 people v 5 people), and pulmonary toxicity (1 person v 1 person).

Drug safety alert

MHRA issues drug safety alert on the risk of progressive multifocal leukoencephalopathy (PML) associated with rituximab (07 November 2008).

A drug safety alert has been issued on the risk multifocal leukoencephalopathy (PML) associated with rituximab (http://www.mhra.gov).

Comment

Subgroup analysis showed superior event-free survival in patients with both high- and low-risk International Prognostic Index (IPI) scores. Significantly longer overall survival was found in patients with low-risk IPI scores. but not in high-risk IPI patients, mainly because of a higher mortality rate in high-risk patients from non-lymphoma-related medical conditions. See comment in CHOP 21 option.

Substantive changes

CHOP 21 plus rituximab One RCT comparing CHOP 21 plus rituximab versus CHOP 21 alone added;benefits and harms data enhanced, categorisation of 'CHOP 21 plus rituximab (increases survival compared with CHOP 21 alone)' unchanged (Beneficial).

BMJ Clin Evid. 2008 Jan 18;2008:2401.

CHOP 14

Summary

MORTALITY Compared with CHOP 21: CHOP 14 increases estimated overall 5-year survival rates in people with previously untreated, aggressive NHL and good prognosis, compared with CHOP 21, but we don’t know whether it increases estimated 5-year event-free survival rates ( moderate-quality evidence ). REMISSION RATES Compared with CHOP 21: We don’t know whether CHOP 14 improves remission rates in people with previously untreated, aggressive NHL and good prognosis, compared with CHOP 21 (moderate-quality evidence).

Benefits

We found one systemic review, which identified two RCTs comparing CHOP 21 versus CHOP 14. The first RCT (710 people aged 18–60 years with previously untreated aggressive NHL according to the REAL classification [see comment below] with good prognosis [defined as normal lactate dehydrogenase level]) compared four six-cycle treatments in a 2 x 2 factorial design: CHOP 14 (172 people), CHOP 21 (176 people), CHOP 14 plus etoposide (177 people), and CHOP 21 plus etoposide (185 people). Participants in the CHOP 14 regimens also received granulocyte colony stimulating factor (filgrastim) support between days 4 and 13 (inclusive). Radiotherapy (36 Gy) was given to sites of initial bulky disease and extranodal disease at completion of chemotherapy. The RCT found no significant difference between CHOP 14 and CHOP 21 in complete remission rates or estimated 5-year event-free survival (AR for no complete remission: 21.5% with CHOP 14 v 19.9% with CHOP 21; adjusted OR 1.10, 95% CI 0.66 to 1.86; AR for event: 39.2% with CHOP 14 v 45.3% with CHOP 21; adjusted RR 0.93, 95% CI 0.66 to 1.29). However, CHOP 14 significantly increased estimated overall 5-year survival compared with CHOP 21 (AR for death: 15.0% with CHOP 14 v 25.1% with CHOP 21; adjusted RR 0.61, 95% CI 0.37 to 0.96). This RCT included only people with “good prognosis”, defined as having a lactate dehydrogenase level within normal limits. The second RCT (689 people aged 61–75 years with previously untreated, aggressive NHL according to the REAL classification [see comment below]) compared four six-cycle treatments in a 2 x 2 factorial design: CHOP 14 (172 people), CHOP 21 (178 people), CHOP 14 plus etoposide (169 people), and CHOP 21 plus etoposide (170 people). Granulocyte colony stimulating factor (filgrastim) and radiotherapy were given as in the first RCT. CHOP 14 significantly improved complete remission rates (AR for no complete remission: 23.9% with CHOP 14 v 39.9% with CHOP 21; adjusted OR 0.45, 95% CI 0.28 to 0.73). CHOP 14 significantly improved estimated 5-year event-free survival and overall survival compared with CHOP 21 (AR for event: 56.2% with CHOP 14 v 67.5% with CHOP 21; adjusted RR 0.66, 95% CI 0.50 to 0.87; AR for death: 46.7% with CHOP 14 v 59.4% with CHOP 21; adjusted RR 0.58, 95% CI 0.43 to 0.79). In this RCT there was an imbalance in the frequency of diffuse large B cell lymphoma in the treatment arms (74.4% in CHOP 14 group v 63.5% in CHOP 21 group; significance not reported). Adjustment for diffuse large B cell lymphoma in the second RCT did not significantly affect the comparison of CHOP 14 and CHOP 21 (RR for an event remained at 0.66). Both RCTs included people with aggressive lymphomas, namely Burkitt's lymphomas (first RCT: 1.4% of people; second RCT: 3.7% of people) and lymphoblastic lymphomas.

Harms

In both RCTs, toxicity in the CHOP 21 and CHOP 14 arms was similar. Because of the use of granulocyte colony stimulation factor (filgrastim) in the bi-weekly regimen, grade 3 and 4 leucopenia occurred less frequently with CHOP 14 than with CHOP 21 (first RCT: 33.6% with CHOP 14 v 34.1% with CHOP 21; second RCT: 70.1% with CHOP 14 v 72.1% with CHOP 21; significance not reported). Grade 3 and 4 anaemia occurred more frequently with CHOP 14 than with CHOP 21 (first RCT: 5.6% with CHOP 14 v 3.6% with CHOP 21; second RCT: 19.5% with CHOP 14 v 4.7% with CHOP 21). Grade 3 and 4 thrombocytopenia was more frequent with CHOP 14 than with CHOP 21 in the second RCT, in older participants, but not in the first RCT (first RCT: 1.2% with CHOP 14 v 2.4% with CHOP 21; second RCT: 15.1% with CHOP 14 v 4.7% with CHOP 21). Infection occurred in 4.2% (first RCT) and 10.6% (second RCT) with CHOP 14 and 1.8% (first RCT) and 8.0% (second RCT) with CHOP 21. Other toxicities were alopecia (64.8% [first RCT] and 58.3% [second RCT] with CHOP 14 v 63.6% and 62.5% with CHOP 21), nausea and vomiting (6.5% and 13.5% with CHOP 14 v 11.7% and 8.0% with CHOP 21), and mucositis (3.0% and 7.1% with CHOP 14 v 2.9% and 0% with CHOP 21). There was no increase in the incidence of neurological toxicity with the bi-weekly regimen (0.6% [first RCT] and 3.6% [second RCT] with CHOP 14 v 3.5% and 3.4% with CHOP 21). There were no treatment-related deaths in either study.

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 Jan 18;2008:2401.

Conventional-dose salvage chemotherapy (PACEBOM, ESHAP, RICE, IVAC)

Summary

We found no clinically important results about different conventional-dose salvage chemotherapy regimens (PACEBOM, ESHAP, RICE, IVAC) in people with relapsed aggressive NHL. The consensus is that people with relapsed disease should be treated with salvage chemotherapy. All regimens reported similar response rates and no single superior regimen could be identified. The effect of rituximab in this setting is likely to be beneficial in rituximab-naive people, but requires further information in rituximab-experienced/refractory people.

Benefits

Salvage chemotherapy regimens versus each other:

We found two systematic reviews (search date not reported and initial search date 2003), which identified no RCTs (see comment below) comparing different conventional-dose salvage chemotherapy regimens (PACEBOM, ESHAP, RICE, IVAC) in people with relapsed aggressive NHL.

Harms

The systematic reviews gave no information on adverse effects.

Drug safety alert

MHRA issues drug safety alert on the risk of progressive multifocal leukoencephalopathy (PML) associated with rituximab (07 November 2008).

A drug safety alert has been issued on the risk multifocal leukoencephalopathy (PML) associated with rituximab (http://www.mhra.gov).

Comment

Clinical guide:

The consensus is that people with relapsed disease should be treated with salvage chemotherapy. The first systematic review identified 22 phase II studies (1210 people overall; individual trials from 20–208 people) using 15 different combinations of cytotoxic drugs for conventional-dose second-line (salvage) chemotherapy. The most common included drugs were etoposide (20 studies), ifosfamide (14 studies), and methotrexate (11 studies). Other drugs included cisplatin (6 studies), cytarabine (4 studies), mitoxantrone (3 studies), bleomycin (3 studies), and mitoguazone (3 studies). All 22 studies revealed similar results, with second-line combination chemotherapy frequently inducing remission in people with relapsed or refractory aggressive NHL. The second review also reported the use of rituximab in non-controlled trials (number of trials not reported). The reviews found that overall 60–70% of people with relapsed disease showed objective tumour responses. Complete remission was seen in 20–40% of people. However, these remissions were frequently short-lived, with a maximum of 10% of responders remaining disease-free after 3–5 years. The authors of the reviews were unable to conclude that any particular salvage chemotherapy regimen was superior to any of the others from the literature reviewed. The effect of rituximab on the long-term outcome after high-dose therapy for relapsed B cell NHL is likely to be beneficial, although rituximab is now standard treatment within the first-line setting. The effect of rituximab in this setting is likely to be beneficial in rituximab-naive people, but requires further information in rituximab experienced/refractory people.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 Jan 18;2008:2401.

High-dose chemotherapy plus autologous stem-cell support

Summary

MORTALITY Compared with conventional chemotherapy: High-dose chemotherapy plus autologous stem-cell support may increase 5-year event-free survival and overall survival rates in people with a chemotherapy-sensitive relapse of aggressive NHL compared with conventional chemotherapy ( low-quality evidence ). RESPONSE RATES Compared with conventional chemotherapy: High-dose chemotherapy plus autologous stem-cell support may increase response rates in people with a chemotherapy-sensitive relapse of aggressive NHL compared with conventional chemotherapy (low-quality evidence). NOTE We found no clinically important results comparing high-dose chemotherapy plus autologous bone-marrow transplantation or peripheral blood stem-cell transplant compared with conventional chemotherapy in people with chemotherapy-resistant disease.

Benefits

In people with chemotherapy-sensitive disease:

We found two systematic reviews (search dates 2000 and 2003), which identified one RCT (see comment below). The multicentre RCT identified by the review enrolled 215 people aged 18–60 years, with a first or second relapse of intermediate-grade or high-grade NHL. Participants had achieved a complete response to previous treatment with a doxorubicin containing regimen, maintained for at least 4 weeks. All participants were initially treated with two cycles of DHAP chemotherapy. Participants who responded to DHAP (109 people) were considered to have chemotherapy-sensitive lymphoma, and were randomised to receive either conventional chemotherapy (a further 4 courses of DHAP plus involved field radiotherapy to bulky disease sites; 54 people) or high-dose BEAC chemotherapy with autologous bone-marrow transplantation plus involved field radiotherapy (55 people). Among the 109 randomised participants, five (5%) had International Working Formulation Classification grade I or J lymphoma, and six (6%) had grade D lymphoma. The RCT found that the response rate was higher with autologous transplantation than with conventional chemotherapy (84% with transplantation v 44% with conventional chemotherapy; significance not reported). Autologous transplantation significantly improved 5-year event-free survival and overall survival compared with conventional chemotherapy (median follow-up 63 months; 5-year event-free survival: 46% with transplantation v 12% with conventional chemotherapy; P = 0.001; 5-year overall survival: 53% with transplantation v 32% with conventional chemotherapy; P = 0.038).

In people with chemotherapy-resistant disease:

We found no RCTs comparing high-dose chemotherapy plus autologous bone-marrow transplantation or peripheral blood stem-cell transplant versus conventional chemotherapy in people with chemotherapy-resistant relapses.

Harms

In people with chemotherapy-sensitive disease:

The RCT found that toxicity was greater in the group receiving high-dose chemotherapy plus autologous bone-marrow transplantation than in the group receiving conventional chemotherapy. In the high-dose chemotherapy plus autologous bone-marrow transplantation group, four people (6%) died from treatment-related complications (2 from sepsis, 1 from cardiac toxicity, and 1 from a late pulmonary infection). There were no treatment-related deaths in the conventional chemotherapy group. Autologous transplant was associated with increased incidences of bacterial infection (30 episodes with autologous transplant v 6 episodes with conventional chemotherapy; 1 case of septic shock in each group), viral infection (8 v 2 episodes), fungal infection (6 v 1 episodes), hepatic toxicity (4 v 1 episode), mucositis (27 v 4 episodes), and diarrhoea (16 v 3 episodes; significance not reported for any comparison). Three people in each treatment arm had pneumonitis and one person in the autologous transplant group developed grade 4 cardiac toxicity compared with two people with grade 1 cardiac toxicity in the conventional chemotherapy group. Only renal toxicity was more common in the conventional chemotherapy group than in the autologous transplant group (14 cases with conventional chemotherapy v 5 with autologous transplantation; significance not reported).

Comment

The RCT identified by the review excluded 90 people who failed to respond to treatment with DHAP before randomisation. An additional 16 responders were also excluded from randomisation for unspecified protocol violations. Of the 55 people randomised to autologous transplant (and analysed with this group), six people were not treated according to the trial protocol. This was because of early-disease progression in four cases, the development of new cardiac problems in one case, and failure to harvest adequate stem cells from bone marrow in the final case. A total of 22 of 55 people (40%) in the autologous transplant group received radiotherapy compared with only 12/54 people (22%) in the conventional chemotherapy group (significance not reported). Overall, 18 of the 45 people (40%) in the conventional chemotherapy group who had further relapses were subsequently treated with high-dose chemotherapy plus autologous bone-marrow transplantation. Since publication of this RCT, the standard procedure for high-dose chemotherapy has changed from transplantation of stem cells harvested from bone marrow to peripheral blood stem-cell transplantation. This change is based on European Bone Marrow Transplant registry data, retrospective studies, and clinical experience, including experience in all subtypes of NHL. Although there have been no direct comparisons of peripheral blood stem-cell transplantation versus autologous bone-marrow transplantation in aggressive NHLs, peripheral blood stem-cell transplantation seems to be more effective than transplantation of autologous bone-marrow stem cells in several other diseases. One of the systematic reviews also identified seven retrospective studies involving 460 people treated for chemosensitive relapse of aggressive NHL with high-dose chemotherapy plus stem-cell support. No comparisons were made with conventional-dose salvage chemotherapy in these studies.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 Jan 18;2008:2401.

High-dose chemotherapy plus allogeneic stem-cell support

Summary

We found no direct information about allogeneic stem-cell support in the treatment of people with NHL (diffuse large B cell lymphoma).

Benefits

We found no systematic review or RCTs (see comment below).

Harms

We found no systematic review or RCTs.

Comment

Clinical guide:

We found RCTs assessing the use of allogeneic transplantation. Two large retrospective studies compared allogeneic transplantation versus control groups who received autologous transplants; groups were not matched for several important disease characteristics. Allogeneic transplantation carries a higher mortality than autologous transplantation, associated with graft versus host disease and prolonged immunosuppression. In the first study there was no significant difference in overall survival (RR 0.92, 95% CI 0.5 to 1.68 with autologous unpurged [P = 0.79] v RR 1.3, 95% CI 0.73 to 2.31 with allogenic T cell replete [P = 0.37]) or relapse rate (RR 1.68, 95% CI 0.78 to 3.61 with autologous unpurged [P = 0.19] v RR 0.99, 95% CI 0.46 to 2.12 with allogenic T cell replete [P = 0.98]) between autologous and allogeneic transplant for high-grade lymphoma. The second study used a matched analysis (matching was over 90% exact but was impaired significantly by missing data on bone-marrow involvement and presence of a mass at time of transplant). The study found that, for people with high-grade lymphoma, the survival rate and relapse rate were similar at 5 years for autologous and allogeneic transplantation (survival rate: 168/765 [22%] with autologous procedures v 53/255 [21%] with allogeneic transplant; relapse rate: 148/765 [19%] with autologous procedure v 49/255 [19%] with allogeneic transplant).

Substantive changes

No new evidence

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PERMALINK

NHL (diffuse large B cell lymphoma)

Mark Hill

Fiona Kyle

Roles

Abstract

Introduction

Methods and outcomes

Results

Conclusions

Key Points

About this condition

Definition

Table 1.

Table 2.

Table 3.

Table 4.

Table 5.

Incidence/ Prevalence

Aetiology/ Risk factors

Prognosis

Aims of intervention

Outcomes

Methods

Table.

Glossary

Disclaimer

Contributor Information

References

CHOP 21

Summary

Benefits

CHOP 21 versus other regimens (MACOP-B, m-BACOD, ProMACE-CytaBOM, PACEBOM, BCOP, HOP, CHOEP, ACVBP):

Table 6.

CHOP 21 alone versus CHOP 21 plus radiotherapy:

CHOP 21 versus CHOP 21 plus rituximab:

CHOP 21 versus CHOP 14:

Harms

CHOP 21 versus other regimens (MACOP-B, m-BACOD, ProMACE-CytaBOM, PACEBOM, BCOP, HOP):

CHOP 21 versus CHOEP 21:

Drug safety alert

Comment

Older people:

Maintenance rituximab:

Substantive changes

CHOP 21 plus radiotherapy

Summary

Benefits

CHOP 21 plus radiotherapy versus CHOP 21 alone:

Harms

Comment

Substantive changes

CHOP 21 plus rituximab

Summary

Benefits

Harms

Drug safety alert

Comment

Substantive changes

CHOP 14

Summary

Benefits

Harms

Comment

Substantive changes

Conventional-dose salvage chemotherapy (PACEBOM, ESHAP, RICE, IVAC)

Summary

Benefits

Salvage chemotherapy regimens versus each other:

Harms

Drug safety alert

Comment

Clinical guide:

Substantive changes

High-dose chemotherapy plus autologous stem-cell support

Summary

Benefits

In people with chemotherapy-sensitive disease:

In people with chemotherapy-resistant disease:

Harms