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High-dose chemotherapy followed by autologous stem cell transplantation for patients with relapsed/refractory Hodgkin lymphoma

  1. Michaela Rancea1,*,
  2. Ina Monsef1,
  3. Bastian von Tresckow2,
  4. Andreas Engert1,
  5. Nicole Skoetz1

Editorial Group: Cochrane Haematological Malignancies Group

Published Online: 20 JUN 2013

Assessed as up-to-date: 1 MAR 2013

DOI: 10.1002/14651858.CD009411.pub2


How to Cite

Rancea M, Monsef I, von Tresckow B, Engert A, Skoetz N. High-dose chemotherapy followed by autologous stem cell transplantation for patients with relapsed/refractory Hodgkin lymphoma. Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD009411. DOI: 10.1002/14651858.CD009411.pub2.

Author Information

  1. 1

    University Hospital of Cologne, Cochrane Haematological Malignancies Group, Department I of Internal Medicine, Cologne, Germany

  2. 2

    University Hospital of Cologne, Department I of Internal Medicine, Cologne, Germany

*Michaela Rancea, Cochrane Haematological Malignancies Group, Department I of Internal Medicine, University Hospital of Cologne, Kerpener Str. 62, Cologne, 50924, Germany. michaela.rancea@uk-koeln.de.

Publication History

  1. Publication Status: New
  2. Published Online: 20 JUN 2013

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Characteristics of included studies [ordered by study ID]
BNLI

MethodsRandomisation

  • 2 arms: 1 week BEAM plus ABMT on day 7 versus mini-BEAM up to 3 cycles (after full haematological recovery)


Recruitment period

  • Not reported


Median follow-up time:

  • 34 months (range not reported)


ParticipantsPatients randomised (N = 40)

  • BEAM plus ABMT (N = 20); (N = 1 withdrew before informed consent was given, and was included in analyses of overall survival and event-free survival as a non-responder, but was excluded from the progression-free survival analysis)
  • Mini-BEAM (N = 20)


Eligibility criteria

  • Histologically confirmed HL
  • Patients with active resistant or relapsed disease at trial entry
  • Patients with high-risk HL: who did not achieve a CR with MOPP or a similar regimen; who had high-grade histology or an erythrocyte sedimentation rate above 59 mm/h at presentation; who did not attain a CR or who relapsed within 1 year of an initial alternating or hybrid regimen
  • Patients for whom 2 or more chemotherapy regimens had failed


Mean age

  • BEAM plus ABMT: 26 years (range 18 to 40); mini-BEAM: 32 years (range 17 to 49)


Gender (male)

  • BEAM plus ABMT: 14 (70%); mini-BEAM: 10 (50%)


Stage of disease (by BNLI)

  • Grade I (nodular sclerosis type I or lymphocyte predominant)
  • Grade II (nodular sclerosis type II, mixed cellularity or lymphocyte depleted)


Country

  • Not reported


InterventionsPrevious treatment:

  • 1 regimen of previous chemotherapy was administered to 6 patients from BEAM plus ASCT arm and 5 patients from the mini-BEAM arm
  • 2 regimens of previous chemotherapy (including alternating regimens as MOPP and ABVD) was administered to 11 patients in the BEAM plus ASCT arm and 13 patients in the mini-BEAM arm
  • 3 regimens of pervious chemotherapy was administered to 3 patients in the BEAM plus ASCT arm and 4 patients in the mini-BEAM arm
  • Previous RT was conducted in 11 patients in the BEAM-ASCT arm and four patients from the mini-BEAM arm


BEAM plus ASCT

  • Patients received carmustine (300 mg/m2), etoposide (800 mg/m2), cytarabine (1600 mg/m2) and melphalan (140 mg/m2) for 1 week. On day 7, at least 10 cryopreserved autologous nucleated bone marrow cells per kilogram were re-infused. When a residual mass persisted after chemotherapy, RT was permitted.


Mini-BEAM

  • Patients received carmustine (60 mg/m2), etoposide (300 mg/m2), cytarabine (800 mg/m2) and melphalan (30 mg/m2) for 3 weeks. Patients who responded to a cycle, were given a second cycle after full haematological recovery. A third cycle could be given, if there was a further, but incomplete, response. When a residual mass persisted after chemotherapy, RT was permitted
  • Patients who did not respond were taken off protocol and received further therapy at their physician's direction


OutcomesReported

  • Primary outcome
    • Overall survival
  • Secondary outcome
    • Progression-free survival
    • Event-free survival
    • Response rate


Not reported (relevant for this review)

  • Adverse events


NotesThere were no conflicts of interest stated. The trial was closed early, before the target accrual was achieved (40 patients instead of 66 patients), because patients refused randomisation and demanded ABMT. No information about the funding of this trial is provided


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComment: the authors describe the sequence generation process by "central sealed card system"

Allocation concealment (selection bias)Unclear riskNo information provided

Blinding of participants and personnel (performance bias)
All outcomes
High riskNo information provided. Trials evaluating stem cell transplantation are usually not blinded

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information provided. Trials evaluating stem cell transplantation are usually not blinded

Incomplete outcome data (attrition bias)
All outcomes
Low riskITT analysis.

Quote: "1 of the 20 patients assigned BEAM treatment withdrew before it was given. This patient was included in analysis of overall survival and event-free survival as a non-responder, but was excluded from the progression-free analysis since no response assessment was possible"

Selective reporting (reporting bias)Unclear riskNo protocol available

Other biasUnclear riskEarly closing of the trial, before accrual was met

Quote: "Recruitment to the trial became increasingly difficult because patients refused randomisation and requested ABMT. It was therefore closed early (40 patients rather than 66 intended)"

HDR1

MethodsRandomisation

  • 2 arms: all patients received 2 cycles of Dexa-BEAM; BEAM plus ASCT (autologous haemopoietic stem cell transplantation) versus additional 2 cycles of Dexa-BEAM


Recruitment period

  • February 1993 to September 1997


Median follow-up time

  • 83 months (range not reported)


ParticipantsPatients enrolled and randomised to pretreatment (N = 161)

  • BEAM plus ASCT (N = 88); (27 were excluded after randomisation and pretreatment: 6 did not qualify, 1 incomplete data, 6 died, 4 severe infection, 2 protocol violation, 1 patient refused, 7 did not achieve PR)
  • Dexa-BEAM (N = 73); (17 were excluded after randomisation and pretreatment: 7 did not qualify, 3 incomplete data, 2 died, 1 severe infection, 1 protocol violation, 2 patients refused, 1 did not achieve PR)


Chemosensitive patients randomised (N = 117)

  • BEAM plus ASCT (N = 61)
  • Dexa-BEAM (N =56)


Eligibility criteria

  • Patients with advanced HL aged 16-60 years with a biopsy-confirmed relapse
  • Patients who had received primary multiple drug chemotherapy with or without RT
  • Patients with stage I or II at relapse with additional risk factors (bulky mediastinum, involvement of 3 or more lymph-node regions, extranodal disease, or erythrocyte sedimentation rate > 30 mm) or stage III or IV early in the course of disease
  • Karnofsky performance score > 70% and stable cardiac, pulmonary, renal and liver function
  • Only chemosensitive patients (in CR or PR) after 2 courses of Dexa-BEAM were randomised to further therapy


Mean age (117 chemosensitive patients reported)

  • BEAM plus ASCT: 30 years (range 21-57 years); Dexa-BEAM: 34 years (range 16-55 years)


Gender (male) (117 chemosensitive patients reported)

  • BEAM plus ASCT: 39 (64%); Dexa-BEAM 36 (64%)


Stage of disease

  • Stage IA to IIB: BEAM plus ASCT: 18 (30%); Dexa-BEAM: 23 (41%)
  • Stage IIIA to IVB: BEAM plus ASCT: 39 (64%); Dexa-BEAM: 30 (54%)
  • Missing: BEAM plus ASCT: 4 (7%); Dexa-BEAM: 3 (5%)


Stratum

  • Early first relapse: BEAM plus ASCT: 21 (34%); Dexa-BEAM 17 (30%)
  • Late first relapse: BEAM plus ASCT: 29 (48%); Dexa-BEAM 26 (46%)
  • Multiple relapses: BEAM plus ASCT: 11 (18%); Dexa-BEAM 13 (23%)


Countries

  • 58 participating centres from: Czech Republic, Norway, Sweden, Finland, Germany, Switzerland, Italy, and the UK


InterventionsPrevious treatment:

  • All patients randomised to BEAM plus ASCT or Dexa-BEAM received prior treatment consisting of 2 cycles of Dexa-BEAM (8 mg/m2 dexamethasone, 60 mg/m2 carmustine, 250 mg/m2 etoposide, 100 mg/m2 cytarabine, and 20 mg/m2 melphalan)
  • All patients received G-CSF on day 8 of Dexa-BEAM, which was continued until leukocyte recovery or until last day of stem-cell harvesting if blood-progenitor cells were gathered
  • Chemosensitive patients in CR or PR after 2 cycles of Dexa-BEAM were randomised further


BEAM plus ASCT

  • BEAM started 4 weeks after WBC count returned to normal after Dexa-BEAM, and consisted of carmustine (300 mg/m2 intravenously on day -7), etoposide (150 mg/m2 intravenously, every 12 h from day -7 to day -4), cytarabine (200 mg/m2, every 12 h from day -7 to day -4), and melphalan (140 mg/m2, on day -3)
  • Bone marrow or progenitor cells were harvested after the second cycle of Dexa-BEAM and chemosensitive patients received transplantation of either autologous bone marrow or peripheral-blood-progenitor cells after high-dose chemotherapy
  • Cryopreserved bone-marrow or peripheral-blood-progenitor cells were infused on day 0 followed by G-CSF until leukocyte recovery


Dexa-BEAM

  • Chemosensitive patients, after the first 2 cycles of Dexa-BEAM, received the third cycle as soon as restaging showed at least partial remission and haemological recovery
  • The fourth cycle Dexa-BEAM was given after haemological recovery from cycle 3


OutcomesReported

  • Primary outcome
    • Freedom from treatment failure


  • Secondary outcomes
    • Response rate
    • Complete remission
    • Overall survival


NotesThe scientific committee decided to stop the study because of low accrual of patients after 117 chemosensitive patients had been recruited

There were no conflicts of interest declared

Funding: Deutsche Krebshilfe e.V. and Mildreed Scheel Stiftung


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomised controlled trial

Quote: "Data managers randomly assigned eligible patients..."

Allocation concealment (selection bias)Low riskInformation about allocation concealment provided

Quote: "Data managers randomly assigned eligible patients at the GHSG trial office by computer before any therapeutic intervention"

Blinding of participants and personnel (performance bias)
All outcomes
High riskNo information provided. Trials evaluating stem cell transplantation are usually not blinded

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information provided. No information provided.Trials evaluating stem cell transplantation are usually not blinded

Incomplete outcome data (attrition bias)
All outcomes
High riskAnalysis was conducted per protocol; 23% mission data in Dexa-BEAM group and 31% missing data in BEAM plus ASCT group

Selective reporting (reporting bias)Unclear riskNo protocol available

Other biasUnclear riskEarly closure of study because of low accrual of patients after 117 chemosensitive patients had been recruited

HDR2

MethodsRandomisation

  • 2 arms: pre-phase with 2 cycles DHAP for all patients, then random assignment to BEAM and ASCT (autologous transplantation with peripheral blood stem cells) versus SHDCT followed by BEAM plus ASCT (autologous transplantation with peripheral blood stem cells)


Recruitment period

  • December 2000 to December 2006


Median follow-up time

  • 42 months (range not reported)


ParticipantsPatients randomised (N = 241)

  • 2 cycles of DHAP for all recruited patients (N = 284)
  • BEAM plus ASCT (N = 119); (7 were excluded from study after randomisation: 3 disease progression, 1 patient's wish, 1 toxicity and 2 other reasons)
  • SHDCT plus BEAM plus ASCT (N = 122); (11 were excluded from study after randomisation: 7 patient's wish and 4 other reasons)


Eligibility criteria

  • Patients with histologically confirmed early or late relapsed HL or multiple relapses and no prior ASCT
  • Patients aged 16-60 years
  • Eastern Cooperative Oncology Group performance status ≤ 2
  • Patients who had received primary multiple drug chemotherapy with or without RT


Mean age

  • BEAM plus ASCT: 35.3 years (range not reported); SHDCT plus BEAM plus PBSCT: 35.4 years (range not reported)


Gender (male)

  • BEAM plus PBSCT: 74 (62%); SHDCT plus BEAM plus PBSCT: 83 (68%)


Stage of disease (Ann Arbor stage)

  • Stage IA: BEAM plus ASCT: 17 (14%); SHDCT plus BEAM plus PBSCT: 17 (14%)
  • Stage IB: BEAM plus ASCT: 3 (3%); SHDCT plus BEAM plus PBSCT: 2 (2%)
  • Stage IIA: BEAM plus ASCT: 29 (24%); SHDCT plus BEAM plus PBSCT: 38 (31%)
  • Stage IIB: BEAM plus ASCT: 8 (7%); SHDCT plus BEAM plus PBSCT: 5 (4%)
  • Stage IIIA: BEAM plus ASCT: 21 (18%); SHDCT plus BEAM plus PBSCT: 15 (12%)
  • Stage IIIB: BEAM plus ASCT: 11 (9%); SHDCT plus BEAM plus PBSCT: 14 (11%)
  • Stage IVA: BEAM plus ASCT: 17 (14%); SHDCT plus BEAM plus PBSCT: 17 (14%)
  • Stage IVB: BEAM plus ASCT: 13 (11%); SHDCT plus BEAM plus PBSCT: 13 (11%)


Stratum

  • Early relapse: BEAM plus ASCT: 27 (23%); SHDCT plus BEAM plus PBSCT: 34 (28%)
  • Late relapse: BEAM plus ASCT: 74 (62%); SHDCT plus BEAM plus PBSCT: 68 (56%)
  • Multiple relapses: BEAM plus ASCT: 18 (15%); SHDCT plus BEAM plus PBSCT: 19 (16%)


Countries

  • Multicentre study from: Belgium, Croatia, Denmark, Germany, the Netherlands, Poland, Portugal and Switzerland


InterventionsPrevious treatment:

  • All patients received 2 cycles of DHAP (dexamethasone (40 mg intravenously, days 1-4), cytarabine (2 x 2000 mg/m2 intravenously over 3 hours, day 3), cisplatin (100 mg/m2 continuous intravenously over 24 hours, day 1) followed by 10 µg/kg of daily G-CSF until the end of peripheral blood stem cell apheresis)


BEAM plus ASCT:

  • BEAM: carmustine (300 mg/m2 intravenously, over 2 hours, day 37), etoposide (2 x 150 mg/m2 intravenously over 30 minutes, days 37-40), cytarabine (2 x 200 mg/m2 intravenously over 30 minutes, days 37-40), melphalan (140 mg/m2 intravenously over 30 minutes, day 37) followed by ASCT with at least 2 x 106 of CD 34+ peripheral blood stem cells per kilogram body weight on day 42 and G-CSF 5 µg/kg subcutaneously twice a day from day 41 until WBC count was ≥ 3000/µL for 3 days


SHDCT plus BEAM plus PBSCT:

  • SHDCT: cyclophosphamide (4000 mg/m2 intravenously over 8 hours, day 37), prophylactic uromitexane (4000 mg/m2 continuously intravenously days 37-39) followed by G-CSF 5 µg/kg subcutaneously by day 38 until WBC count > 3000/µL for 3 days, followed by high-dose methotrexate (8000 mg/m2 intravenously for 6 hours, day 51) and vincristine (1.4 mg/m2, maximum 2 mg, intravenously, day 51) followed by high-dose etoposide (500 mg/m2 intravenously for 8 hours, days 58-61 with G-CSF 5 µg/kg subcutaneously from day 62 until WBC > 3000/µL for 3 days) followed by BEAM (at same dosages as the other treatment arm) plus ASCT (peripheral blood stem cells were re-infused and G-CSF were administered until haematological recovery)
  • Patients with residual lymphoma (> 1.5 cm on computed tomography scan), received additionally 30 Gy involved-field RT


Outcomes
  • Primary outcome
    • Freedom from treatment failure
  • Secondary outcomes
    • CR rate 100 days after PBSCT
    • Progression-free survival
    • Overall survival
    • WHO grade 3/4 toxicity
    • Secondary neoplasia


NotesNo conflicts of interest were reported

Funding: German Cancer Aid


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomised controlled trial

Quote: "...patients were centrally randomly assigned..."

Allocation concealment (selection bias)Unclear riskNo information about allocation concealment provided

Quote: "...patients were randomly assigned in the GHSG central trial office..."

Blinding of participants and personnel (performance bias)
All outcomes
High riskNo information provided. Trials evaluating stem cell transplantation are usually not blinded

Blinding of outcome assessment (detection bias)
All outcomes
High riskQuote: "...participating centres were informed without masking..."

Incomplete outcome data (attrition bias)
All outcomes
Low riskAnalyses were performed according to ITT principle

Selective reporting (reporting bias)Low riskProtocol available at clinicaltrials.gov/ct2/show/NCT00025636

Other biasLow riskThe trial seems free of other biases

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Avigdor 2000Not a randomised controlled trial

Bolanos-Meade 2007No differentiation between HL and NHL

Evens 2007Not a randomised controlled trial

Ferme 2002Not a randomised controlled trial

Gutierrez-Delgado 2003Not a randomised controlled trial

Kuruvilla 2004Not a randomised controlled trial

Morschhauser 2008Not a randomised controlled trial

Sweetenham 1997Not a randomised controlled trial

Van Agthoven 2001Cost analysis

Vellenga 2001No differentiation between HL and NHL

Weaver 1996No differentiation between HL and NHL in outcomes

 
Comparison 1. High-dose chemotherapy (HDCT) before autologous stem cell transplantation (ASCT)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Overall survival - overall analysis2157Hazard Ratio (Fixed, 95% CI)0.67 [0.41, 1.07]

 2 Overall response rate - overall analysis2157Risk Ratio (M-H, Fixed, 95% CI)1.15 [0.99, 1.34]

 3 Complete response rate - overall analysis2157Risk Ratio (M-H, Fixed, 95% CI)1.32 [1.07, 1.64]

 4 Treatment-related mortality - overall analysis2157Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.16, 2.22]

 5 Progression-free survival2157Hazard Ratio (Fixed, 95% CI)0.55 [0.35, 0.86]

 
Summary of findings for the main comparison. High-dose chemotherapy followed by autologous stem cell transplantation for patients with relapsed/refractory Hodgkin lymphoma

High-dose chemotherapy followed by autologous stem cell transplantation for patients with relapsed/relapsed Hodgkin lymphoma

Patient or population: Patients with refractory/relapsed Hodgkin lymphoma
Settings:
Intervention: High-dose chemotherapy followed by autologous stem cell transplantation

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlHigh-dose chemotherapy followed by ASCT

Mortality
(after 3 years)
Study populationHR 0.67
(0.41 to 1.07)
157
(2 studies)
⊕⊕⊕⊝
moderate1
-

18 per 100013 per 1000
(8 to 20)

Moderate


Relapse or death

(at 3 years)
Study populationHR 0.55
(0.35 to 0.86)
157
(2 studies)
⊕⊕⊕⊝
moderate1
-

14 per 10008 per 1000
(5 to 13)

Moderate


Treatment-related mortality - overall analysis

(at 3 years)
Study populationRR 0.61
(0.16 to 2.22)
157
(2 studies)
⊕⊕⊕⊝
moderate1
-

66 per 100040 per 1000
(11 to 146)

Moderate

45 per 100027 per 1000
(7 to 100)

Adverse events
not estimable
Study populationNot estimable100
(1 study)
See commentOnly 1 trial reported this outcome, therefore not assessable

See commentSee comment

Moderate


Quality of life
not reported
Study populationNot estimable0
(0 studies)
See commentNeither study provided data with regard to this outcome

See commentSee comment

Moderate


*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; HR: hazard ratio; RR: risk ratio.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: 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.
Very low quality: We are very uncertain about the estimate.

 1 Both trials were closed prematurely.
 
Table 1. Adverse events in HDR1

WHO grade 3 and 4 toxicityConventional chemotherapy

(N = 49)
HDCT plus ASCT

(N = 51)
P value

Infection24 (49%)24 (47%)0.848

Oral (mucositis)10 (24%)19 (37%)0.168

Gastrointestinal10 (20%)7 (14%)0.374

Pulmonary or respiratory tract6 (12%)2 (4%)0.125

Cardiac3 (6%)1 (2%)0.288

Neurological2 (4%)1 (2%)0.534

Hepatic2 (4%)00.145

Renal1 (2%)00.305

 ASCT: autologous stem cell transplantation; HDCT: high-dose chemotherapy; WHO: World Health Organization.
WHO grades 3 and 4 toxic effects per treatment group
 
Table 2. Adverse events in HDR2

WHO grade 3 and 4 toxicityHDCT

(N = 113)
SHDCT

(N = 110)
P value

Anaemia59 (52%)77 (70%)0.007

Thrombopenia100 (89%)102 (93%)0.28

Leukopenia98 (87%)98 (89%)0.59

Infection37 (33%)53 (48%)0.02

Nausea40 (35%)50 (46%)0.13

Mucositis64 (57%)74 (67%)0.10

Respiratory7 (6%)11 (10%)0.30

 WHO: World Health Organization; WHO grade 3/4 toxic effects per treatment group.