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First-line allogeneic hematopoietic stem cell transplantation of HLA-matched sibling donors compared with first-line ciclosporin and/or antithymocyte or antilymphocyte globulin for acquired severe aplastic anemia

  1. Frank Peinemann1,*,
  2. Carmen Bartel2,
  3. Ulrich Grouven3

Editorial Group: Cochrane Haematological Malignancies Group

Published Online: 23 JUL 2013

Assessed as up-to-date: 22 APR 2013

DOI: 10.1002/14651858.CD006407.pub2


How to Cite

Peinemann F, Bartel C, Grouven U. First-line allogeneic hematopoietic stem cell transplantation of HLA-matched sibling donors compared with first-line ciclosporin and/or antithymocyte or antilymphocyte globulin for acquired severe aplastic anemia. Cochrane Database of Systematic Reviews 2013, Issue 7. Art. No.: CD006407. DOI: 10.1002/14651858.CD006407.pub2.

Author Information

  1. 1

    Children's Hospital, University of Cologne, Cologne, NW, Germany

  2. 2

    Cologne, Germany

  3. 3

    Hannover Medical School, Hannover, Germany

*Frank Peinemann, Children's Hospital, University of Cologne, Kerpener Str. 62, Cologne, NW, 50937, Germany. pubmedprjournal@gmail.com.

Publication History

  1. Publication Status: New
  2. Published Online: 23 JUL 2013

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Characteristics of included studies [ordered by study ID]
Bayever 1984

MethodsDuration

  • From 1977 to 1982


Randomization

  • Allocation compatible with 'Mendelian randomization'


Treatment

  • Number of arms: 2
  • Type of intervention
    • Test arm: MSD-HSCT
    • Control arm: IST


Median follow-up time

  • Not reported


ParticipantsSetting

  • Single-center study
  • United States


Eligibility criteria

  • Less than 25 years of age
  • All 35 patients who had an HLA-identical donor underwent bone marrow transplantation
  • The 22 patients without an HLA-identical donor received ATG therapy


Number of patients

  • MSD-HSCT arm: N = 35
  • IST arm: N = 27


Age

  • MSD-HSCT arm: median 17 (range 2 to 24) years
  • IST arm: median 15 (range 1 to 23) years


Gender

  • MSD-HSCT arm: males 67% (23 of 35) patients
  • IST arm: males 68% (15 of 22) patients


Further inclusion criteria to define SAA

  • Criteria for the diagnosis of SAA: bone marrow cellularity < 25% (with < 30% myeloid cells) and peripheral counts, taken on 3 occasions 24 hours apart, including at least 2 of the following: granulocytes < 0.5 X 109/L, platelets < 20 x 109/L, reticulocytes < 20 X 109/L


InterventionsMSD-HSCT arm

  • Patients received MSD-HSCT from 1977 to 1982
  • Interval from diagnosis to treatment median 60 (range 9 to 2520) days
  • Previous therapy: none reported
  • Discontinuation of treatment not reported, no criteria defined
  • Bone marrow was the stem cell source for all recipients


IST arm

  • Patients received IST from 1977 to 1982
  • Interval from diagnosis to treatment median 58 (range 8 to 2669) days
  • Previous therapy: none reported; quote from the introduction section: "(...)whether treatment with ATG should be the primary therapeutic approach(..)"
  • Discontinuation of treatment not reported, no criteria defined
  • ATG: treatment consisted of 1 dose of equine anti-human thymocyte globulin per day (20 mg/kg/day) for 8 days
  • Ciclosporin: no treatment


OutcomesPrimary outcome

  • Overall survival such as 2-year actuarial survival


Secondary outcomes

  • Treatment-related mortality denoted as causes of death after treatment such as graft rejection, acute GVHD, chronic GVHD, interstitial pneumonia, veno-occlusive disease, hemorrhage, infection
  • Adverse events denoted as complications after treatment such as acute GVHD, chronic GVHD, interstitial pneumonia, serum sickness, hypertension
  • Karnofsky performance scores of surviving patients
  • Response to treatment denoted as hematologic recovery with normal peripheral blood counts within 6 months of treatment (both treatment arms)


Notes
  • No competing interest reported, funding, grants, and awards received from non-for profit organizations
  • Supported in part by the National Cancer Institute, National Institutes of Health, and by the US Public Health Service


Risk of bias

BiasAuthors' judgementSupport for judgement

Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome

Incomplete outcome data (attrition bias)
All outcomes
Low riskThe data for all 57 included patients have been analyzed and it is conceivable that the outcome data were complete (Table 3 of the article)

Selective reporting (reporting bias)Unclear riskRelapse was reported for the IST group but not for the MSD-HSCT group. "All eight patients with severe aplastic anemia who responded after ATG therapy are alive. One of the responders has relapsed but still survives(..)"

Other biasHigh riskThe authors reported the study results at an early time point before all planned data had been gathered. "We present this interim report(...)". No other bias such as competing interest or cross-over.

Comparable baseline characteristicsLow riskThere were no differences of baseline characteristics between the 2 treatment groups, in particular with reference to age (Table 1 of the article)

Concurrent controlLow riskData for the control group were collected during the same time period as the data for the test group. "Fifty-seven consecutive patients younger than 25 years with severe aplastic anemia underwent treatment at
UCLA between November 1977 and October 1982."

Führer 1998

MethodsDuration

  • From 1993 to 1997 (update 1993 to 2001)


Randomization

  • Allocation compatible with 'Mendelian randomization'


Treatment

  • Number of arms: 2
  • Type of intervention
    • Test arm: MSD-HSCT
    • Control arm: IST


Median follow-up time

  • Not reported


ParticipantsSetting

  • Multi-center study
  • Germany and Austria


Eligibility criteria

  • Less than 17 years of age ("Two hundred and thirteen patients newly diagnosed with SAA younger than the age of 17 years").
  • "By biologic selection depending on the availability of an MSD, patients were assigned to either the BMT or the IST group."
  • "The diagnosis of SAA was based on morphology and blood counts."
  • "Fanconi anemia was excluded by chromosomal fragility test."


Number of patients

  • Total participants: N = 116 (update N = 213)
  • HSCT arm: N = 28; 25 patients received HSCT from MSD, 3 patients received HSCT from other donors (update N = 67; 62 patients received MSD-HSCT, in the remaining 5 patients, parents refused HSCT)
  • IST arm: N = 86; 86 patients received ciclosporin and antilymphocyte globulin (update N = 146; 151 patients were treated with horse antithymocyte globulin and ciclosporin including 5 patients with an MSD who were assigned to the HSCT arm in the first place but changed treatment arm after the parents refused HSCT


Age

  • MSD-HSCT arm: 10.1 (range 2.3 to 15.8) years
  • IST arm: 9.1 (range 0.9 to 15.2) years


Gender

  • MSD-HSCT arm: males 43% (12 of 28) patients
  • IST arm: males 62% (53 of 86) patients


Further inclusion criteria to define SAA

  • Criteria for the diagnosis of SAA: "They all met the internationally accepted diagnostic criteria. Patients were stratified into 3 groups according to severity of disease. Severity depends on PMN counts (VSAA: PMN <200/μI; SAA: PMN <500/μI; not severe aplastic anemia: >500/μI)."


InterventionsInterval from diagnosis to treatment

  • MSD-HSCT arm: median 49 (range 18 to 272) days
  • IST arm: median 23 (range 3 to 168) days


MSD-HSCT arm

  • Patients received MSD-HSCT from 1993 to 1997 (update 1993 to 2001)
  • Interval from diagnosis to treatment: not reported
  • Previous therapy: none reported
  • Discontinuation of treatment not reported, no criteria defined
  • Bone marrow was the stem cell source for all recipients


IST arm

  • Patients received IST from 1993 to 1997 (update 1993 to 2001)
  • Interval from diagnosis to treatment: not reported
  • Previous therapy: none reported
  • Discontinuation of treatment not reported, no criteria defined
  • ATG: treatment consisted of 1 dose of equine anti-human thymocyte globulin per day (0.75 ml/kg/day) for 8 days
  • Ciclosporin: treatment consisted of 2 doses per day (5 mg/kg/day) for at least 6 months


OutcomesPrimary outcome

  • Overall survival


Secondary outcomes

  • Event-free survival
  • Treatment response
  • New clonal disease after treatment


Notes
  • Financial support was provided by 2 pharmaceutical companies ("The SAA 94 study was supported by AMGEN andJMTIX"). Amgen Inc. is headquartered in Thousand Oaks, California, USA and a manufacturer of filgrastim, a human granulocyte colony-stimulating factor (G-CSF). The authors stated that G-CSF was given in addition to IST but did not mention the manufacturer in the methods chapter. The type of support, such as providing G-CSF or financial support, was not specified.


Risk of bias

BiasAuthors' judgementSupport for judgement

Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome

Incomplete outcome data (attrition bias)
All outcomes
High riskIn the 2005 update, 7.5% (5 of 67) patients assigned to the MSD-HSCT group dropped out because the parents refused the treatment. "Sixty-two patients received BMT after a conditioning treatment with ATG (...) and cyclophosphamide (...). In the remaining 5 patients, 3 with SAA and 2 with vSAA, parents refused BMT."

Selective reporting (reporting bias)High riskIn the 2005 update, overall survival, secondary clonal disease or malignancies, and also relapse were not reported separately for the 2 distinct treatment groups. Rather, the results were presented for 2 subgroups according to disease severity. This was different from the earlier report of the same study published in 1998 covering the study period from 1993 to 1997. See Fig. 1 and Tab. 1 of the article. "In 137 (64%) of 213 patients very SAA was diagnosed. Within the BMT group, patients with very SAA (N = 40) and with SAA (N = 27) reached comparable survival rates (5-year survival rate: very SAA 89% (95% CI 80% to 99%); SAA 96% (95% CI 89% to 100%)."

Other biasHigh riskFinancial support was provided by 2 pharmaceutical companies. "The SAA 94 study was supported by AMGEN and JMTIX".

Comparable baseline characteristicsLow riskThere were no differences in baseline characteristics between the 2 treatment groups, in particular with reference to age. See Table 1 and Table 2 of the 1998 article.

Concurrent controlLow riskData for the control group were collected during the same time period as the data for the test group. "Two hundred and thirteen patients newly diagnosed with SAA younger than the age of 17 years in 53 centers in Germany and Austria were included in the study between November 1993 and December 2001."

Gratwohl 1981

MethodsDuration

  • From 1976 to 1980


Randomization

  • Allocation compatible with 'Mendelian randomization'


Treatment

  • Number of arms: 3
  • Type of intervention
    • Test arm: MSD-HSCT ("HLA-A-, -B-, -Dr-identisches, MLC-identisches Geschwister")
    • Control arm: IST ("kein Spender")
    • Haploidentical family donor arm not relevant for the present review: HSCT from HLA-matched related family members ("HLA-haploidentisches, ABO-kompatibles, cross match-negatives Familienmitglied")


Median follow-up time

  • Not reported


ParticipantsSetting

  • Single-center study
  • Switzerland


Eligibility criteria

  • All 19 patients who had an HLA-identical donor underwent bone marrow transplantation ("19 Patienten mit einem HLA-identischen Geschwister erhielten eine KMT(...)")
  • The 13 patients without an HLA-identical donor received ALG therapy ("13 Patienten halten keinen Spender und erhielten ALG allein.")
  • The 26 patients with a haploidentical family donor were treated with ALG and bone marrow transplantation ("26 Patienten mit einem haploidentischen, ABO-kompatibIen, crossmatch-negativen Familienmitglied wurden mit Antilymphozytenglobulin und KMT behandelt")


Number of patients

  • MSD-HSCT arm: N = 19
  • IST arm: N = 13
  • Haploidentical family donor arm: N = 26


Age

  • MSD-HSCT arm: median 18 (range 4 to 29) years
  • IST arm: median 23 (range 7 to 37) years
  • Haploidentical family donor arm: median 16.5 (range 8 to 49) years


Gender

  • MSD-HSCT arm: males 53% (10 of 19) patients
  • IST arm: males 54% (7 of 13) patients
  • Haploidentical family donor arm: males 81% (21 of 26) patients


Further inclusion criteria to define SAA

  • Criteria for the diagnosis of SAA fulfilled according to reference 2 of the article. ("Alle hatten SAA, erfüllten zumindest zwei der drei Blutkriterien und hatten einen mit einer SAA kompatiblen histologischen Knochenmarkbefund")


InterventionsMSD-HSCT arm

  • Patients received MSD-HSCT from 1977 to 1982
  • Interval from diagnosis to treatment median 3.5 months (range not reported)
  • Previous therapy: it is conceivable that the patients received blood cells and antibiotics but no specific treatment such as IST ("Von den 61 überwiesenen Patienten sind 3 trotz intensivem Zellersatz und Antibiotika gestorben, bevor die spezifische Behandlung fUr die SAA begonnen werden konnte.")
  • Discontinuation of treatment not reported, no criteria defined
  • Bone marrow was the stem cell source for all recipients


IST arm

  • Patients received IST from 1977 to 1982
  • Interval from diagnosis to treatment median 6 months (range not reported)
  • Previous therapy: it is conceivable that the patients received blood cells and antibiotics but no specific treatment such as IST ("Von den 61 überwiesenen Patienten sind 3 trotz intensivem Zellersatz und Antibiotika gestorben, bevor die spezifische Behandlung fUr die SAA begonnen werden konnte.")
  • Discontinuation of treatment not reported, no criteria defined
  • 2 of the 13 included patients received a second-line HSCT after lack of response to IST
  • ATG: treatment details not reported
  • Ciclosporin: no treatment


Haploidentical family donor arm

  • Patients received ALG and bone marrow transplantation from 1977 to 1982
  • Interval from diagnosis to treatment median 6 months (range not reported)
  • Previous therapy: it is conceivable that the patients received blood cells and antibiotics but no specific treatment such as IST ("Von den 61 überwiesenen Patienten sind 3 trotz intensivem Zellersatz und Antibiotika gestorben, bevor die spezifische Behandlung fUr die SAA begonnen werden konnte.")
  • Discontinuation of treatment not reported, no criteria defined


OutcomesPrimary outcome

  • Overall survival


Secondary outcomes

  • Causes of death such as GVHD, graft failure, sepsis, hemorrhage


Notes
  • No competing interest reported, funding, received from non-for profit organizations
  • Supported in part by "Schweizerischer Nationalfond zur Förderung der wissenschaftlichen Forschung, die Schweizerische Krebsliga und das Bundesamt für Gesundheitswesen"


Risk of bias

BiasAuthors' judgementSupport for judgement

Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding of outcome assessor was not reported for any outcome

Incomplete outcome data (attrition bias)
All outcomes
High riskThe data for 58 of 61 consecutively recruited patients that fulfilled the eligibility criteria have been analyzed. Therefore 3 patients have dropped out. "Von den 61 überwiesenen Patienten sind 3 trotz intensivem Zellersatz und Antibiotika gestorben, bevor die spezifische Behandlung fUr die SAA begonnen werden konnte."

Selective reporting (reporting bias)Unclear riskBesides overall survival, no other outcome was reported systematically

Other biasUnclear risk15% (2 of 13) patients assigned to the IST group had an HLA-identical sibling donor and were actually eligible to be allocated to the MSD-HSCT group. "13 Patienten hatten keinen Spender und erhielten ALG allein. Von diesen 13 Patienten in Gruppe C hatten 2 einen HLA-identischen Spender". No other bias such as competing interest or cross-over. The study was supported by non-for-profit institutions such as a Swiss National Research Foundation, a Swiss Cancer Association, and the Swiss Department for Health.

Comparable baseline characteristicsLow riskThere were no differences of baseline characteristics between the 2 treatment groups, in particular with reference to age. "Diese drei Gruppen sind vergleichbar bezüglich Alter, Ätiologie, vorhergehender Behandlung und Schwere der SAA bei Einweisung (Tab. 2)."

Concurrent controlLow riskData for the MSD-HSCT arm were collected during the same time period as the data for the IST arm. "Dieser Bericht beschreibt alle Patienten, die dem Kantonsspital Basel zwischen Januur 1976 und Dezember 1980 wegen SAA überwiesen wurden."

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

ACS/NIH 1976Study design: not prospective: registry report

Ahn 2003Allocation: not consistent with 'Mendelian randomization': age unequally distributed
HSCT versus IST: 83 versus 61 patients in age category 14 to 40 years, 73 versus 3 patients in age category >= 41 years, P < 0.001

Arranz 1994Allocation: not consistent with 'Mendelian randomization': assignment by age, cut-off 40 years

Bacigalupo 1988Study design: not prospective: registry report

Bacigalupo 1996Study design: not prospective: registry report

Bacigalupo 2000aStudy design: not prospective: registry report

Bacigalupo 2000bStudy design: not prospective: registry report

Camitta 1976Control: fewer than 80% of patients with first-line IST

Camitta 1978Control: fewer than 80% of patients with first-line IST

Camitta 1979Control: fewer than 80% of patients with first-line IST

Cesaro 2010Study design: not prospective: registry report

Champlin 1984Allocation: not consistent with 'Mendelian randomization': assignment by age, cut-off 45 years

Chen 1992Fewer than 5 patients in one arm: 3 patients in MSD-HSCT group

Crump 1992Intervention: fewer than 80% of patients with first-line MSD-HSCT: 100% second-line HSCT

de Planque 1990Intervention: fewer than 80% of patients with first-line MSD-HSCT: 42% second-line HSCT

Deyell 2009Study design: not prospective

Doney 1981Intervention: fewer than 80% of patients with first-line HSCT: haploidentical marrow

Doney 1997Allocation: not consistent with 'Mendelian randomization': assignment by age, cut-off 55 years

Fouladi 2000Study design: not prospective, no clues to prospective design

Ganapiev 2010Study design: not prospective, no clues to prospective design [Russian]

Garanito 2009Study design: not prospective

George 2010Study design: not prospective

Ghavamzadeh 2004Allocation: not consistent with 'Mendelian randomization': assignment by age, cut-off 45 years

Gillio 1997Study design: not prospective, reporting of retrospective design

Gluckman 1979Study design: not prospective, no clues to prospective design; a randomized allocation was reported for the last year of investigation, however, the number of patients randomized and the years of transplantation were not reported

Gluckman 1981Study design: not prospective: registry report

Gluckman 1987Study design: not prospective: registry report

Golubovskaya 2010Unclear information: conference abstract without required information, authors did not clearly report whether allocation was based on availability of MSD and not on patient age

Halperin 1989Study design: not prospective, no clues to prospective design

Hirabayashi 1995Study design: not prospective: registry report

Horowitz 1989Study design: not prospective: registry report

Horowitz 1997Study design: not prospective: registry report

Howard 2004Outcome: not a predefined outcome

Höcker 1987Allocation: not consistent with 'Mendelian randomization': by age [German]

Ilhan 2001Patients: fewer than 80% of patients with SAA

Kahn 2002Allocation: not consistent with 'Mendelian randomization': assignment by age, cut-off 40 years

Kim 1994Allocation: not consistent with 'Mendelian randomization'

Kim 2003Allocation: not consistent with 'Mendelian randomization': assignment by age, cut-off 50 years

Kodera 1999Study design: not prospective: registry report

Kojima 1988Study design: not prospective, no clues to prospective design

Kojima 2000Study design: not prospective, reporting of retrospective design

Kosaka 2004Intervention: fewer than 80% of patients with first-line MSD-HSCT: 100% second-line

Kulagin 2006Fewer than 5 patients in one arm

Lawlor 1997Study design: not prospective, reporting of retrospective design

Ljungman 1991Study design: not prospective, no clues to prospective design [Swedish]

Locasciulli 1990Study design: not prospective: registry report

Locasciulli 2007Study design: not prospective: registry report

McCann 1994Study design: not prospective: registry report

Milosevic 1998Intervention: fewer than 80% of patients with first-line MSD-HSCT [Serbian]

Mollee 2001Allocation: not consistent with 'Mendelian randomization': by age

Montante 2009Fewer than 5 patients in one arm

Mrsic 2009Allocation: not consistent with 'Mendelian randomization' [Croatian]

Nagler 2001Patients: fewer than 80% of patients with SAA

Paquette 1995Allocation: not consistent with 'Mendelian randomization': age unequally distributed
HSCT versus IST, 36% versus 15% in age category 16 to 19 years, 42% versus 40% in age category 19 to 29 years, 22% versus 45% in age category >= 30 years, P = 0.02

Pitcher 1999Patients: not at least 80% SAA: 23% of patients with non-severe aplastic anemia

Podesta 1998Outcome: not a predefined outcome

Pokorski 1998Study design: not prospective: registry report

Shaw 1999Patients: fewer than 80% of patients with SAA

Socié 1993Patients: fewer than 80% of patients with SAA

Sovinz 2010Unclear information: conference abstract without required information, authors did not clearly report whether allocation was based on availability of MSD and not on patient age

Stalder 2009Study design: not prospective

Starý 1998Study design: not prospective [Czech]

Tichelli 1994Allocation: not consistent with 'Mendelian randomization': by age

Tschiedel 2010Fewer than 5 patients in one arm [German]

Tsukimoto 1989Outcome: not a predefined outcome

Tukic 2009Unclear information: conference abstract without required information, authors did not clearly report whether allocation was based on availability of MSD and not on patient age

Tzeng 1989Study design: not prospective, no clues to prospective design

UCLA 1976Control: fewer than 80% of patients with first-line IST: androgens only

Uss 1999Study design: not prospective [Russian]

Viollier 2005Allocation: not consistent with 'Mendelian randomization': assignment by age, cut-off 40 years

Wagner 1996Patients: fewer than 80% of patients with SAA

Webb 1991Study design: not prospective, reporting of retrospective design

Werner 1989Study design: not prospective, reporting of retrospective design

Windass 1987Patients: fewer than 80% of patients with SAA

Yan 2011Intervention: fewer than 80% of patients with first-line MSD-HSCT [Chinese]

Yoshida 2011Allocation: not consistent with 'Mendelian randomization': donors were family members and not siblings

 
Comparison 1. MSD-HSCT versus IST - all patients

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

 1 Mortality3229Hazard Ratio (Random, 95% CI)0.95 [0.43, 2.12]

 2 Secondary clonal disease or malignancies2170Peto Odds Ratio (Peto, Fixed, 95% CI)0.54 [0.07, 4.00]

 
Summary of findings for the main comparison. First-line allogeneic hematopoietic stem cell transplantation of HLA-matched sibling donors compared with first-line ciclosporin and/or antithymocyte or antilymphocyte globulin for acquired severe aplastic anemia

First-line allogeneic hematopoietic stem cell transplantation of HLA-matched sibling donors compared with first-line ciclosporin and/or antithymocyte or antilymphocyte globulin for acquired severe aplastic anemia

Patient or population: patients with acquired SAA
Settings: hospital
Intervention: first-line allogeneic hematopoietic stem cell transplantation of HLA-matched sibling donors (MSD-HSCT)
Comparison: first-line ciclosporin and/or antithymocyte or antilymphocyte globulin (IST)

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

Assumed riskCorresponding risk

First-line ciclosporin and/or antithymocyte or antilymphocyte globulin (IST)First-line allogeneic hematopoietic stem cell transplantation of HLA-matched sibling donors (MSD-HSCT)

Overall mortality
Follow-up: 2 years
Moderate1 HR 0.95
(0.45 to 1.91)
203
(3 studies)
⊕⊕⊝⊝
low2,3

31 per 10030 per 100
(15 to 51)

Treatment-related mortality

Follow-up: not reported
See commentSee commentNot estimable54
(2 studies4)
⊕⊝⊝⊝
very low4
Case series; 15 of 54 of the MSD-HSCT group affected

Health-related quality of lifeSee commentSee commentNot estimable0
(0)
See commentNo studies identified

Graft failure

Follow-up: not reported
See commentSee commentNot estimable54
(2 studies4)
⊕⊝⊝⊝
very low4
Case series; 4 of 54 of the MSD-HSCT group affected

No response to IST

Follow-up: not reported
See commentSee commentNot estimable35
(2 studies4)
⊕⊝⊝⊝
very low4
Case series; 16 of 35 of the IST group affected

Graft-versus-host disease

Follow-up: not reported
See commentSee commentNot estimable52
(2 studies4)
⊕⊝⊝⊝
very low4
Case series; 22 of 52 of the MSD-HSCT group affected

Secondary clonal disease or malignancies

Follow-up: not reported
Moderate1 Peto OR 0.54
(0.07 to 4)
170
(2 studies)
⊕⊕⊝⊝
low2,3

2 per 1001 per 100
(0 to 10)

*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; IST: immunosuppressive therapy; MSD-HSCT: first-line allogeneic hematopoietic stem cell transplantation from HLA-matched (identical) sibling donor; OR: odds 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.

 1Median control group risk across studies.
2'Mendelian randomization'.
3Wide confidence interval.
4Case series.
 
Table 1. Conditioning for transplantation

Medicinal productMSD-HSCT1 Bayever 1984Führer 2005

Dose and duration of therapy


Cyclophosphamide50 mg/kg/day for 4 days (-5, -4, -3, -2); BMT preparative regimenYes, as recommendedYes, as recommended

Antithymocyte globulin30 mg/kg/day for 3 days (-5, -4, -3); horse ATG; BMT preparative regimenNRFührer 1998 reports antilymphocyte globulin 0.75 ml/kg/day for 4 days

Führer 2005 reports horse ATG 0.75 ml/kg/day for 4 days

Methylprednisolone2 mg/kg/day for 3 days (-5, -4, -3); BMT preparative regimen; usually not used for childrenYes, 2 mg/kg/day prednisone in patients who developed acute GVHD of grade 2 or higherNR

Methotrexate15 mg/m2/day for 1 day (+1) and 10 mg/m2/day for 3 days (+3, +6, +11); BMT post-transplant immunosuppressionYes, as recommendedNR

Führer 1994 (protocol): methotrexate was planned

Ciclosporin5 mg/kg/day; BMT post-transplant immunosuppression; starting on day -1 continued for 12 months with tapering beginning at 9 months; Marsh 2009NRNR

Führer 1994 (protocol): ciclosporin was planned

Irradiation2Radiation-based regimens should be avoided3 Gy total body irradiation on day -1NR

Führer 1994 (protocol): irradiation was not planned

 1Recommended dose and duration of therapy according to Schrezenmeier 2000 unless indicated.
2Schrezenmeier 2000: "While irradiation-based programs have been effective in reducing rejection, they have accomplished their goal at the price of more transplant-related complications. A combination of cyclophosphamide and antithymocyte globulin was found as effective as irradiation in preventing rejection with better long-term outcome. In regards to conditioning regimens, radiation-based regimens should be avoided because of the higher associated likelihood of inducing secondary cancer, the deleterious effects on fertility, and the potential detrimental effects on growth and development, a policy that would be particularly important for pediatric patients."
Abbreviation: ATG: antithymocyte globulin; BMT: bone marrow transplantation; GVHD: graft-versus-host disease; Gy: Gray; MSD-HSCT: first-line allogeneic hematopoietic stem cell transplantation from HLA-matched sibling donor; NR: not reported
 
Table 2. Immunosuppressive treatment

Medicinal productIST1 Bayever 1984Führer 2005

Dose and duration of therapy


Antithymocyte globulin40 mg/kg/day horse ATG for 4 days (1, 2, 3, 4)

or

3.5 mg/kg/day; rabbit ATG for 5 days (1, 2, 3, 4, 5) Scheinberg 2011
20 mg/kg/day for 8 days (1, 2, 3, 4, 5, 6, 7, 8)Führer 1998 reported antilymphocyte globulin 0.75 ml/kg/day for 8 days

Führer 2005 reported horse ATG 0.75 ml/kg/day for 8 days

Methylprednisolone1 mg/kg/day for 14 days (1 to 14) and tapering off until day 2840 mg/m2/day prednisone for 5 days (8, 9, 10, 11, 12)Yes, as recommended

Ciclosporin5 mg/kg/day; starting on day 1 continued at least until day 112, further treatment depending upon responseNRYes, dose as recommended for at least 6 months

 1Recommended dose and duration of therapy according to Schrezenmeier 2000 unless indicated.
Abbreviation: ATG: antithymocyte globulin; IST: immunosuppressive therapy including ciclosporin and/or antithymocyte or antilymphocyte globulin; NR: not reported
 
Table 3. Overall survival

StudyMSD-HSCTISTTime1 P value





NOS (95% CI)NOS (95% CI)Year

Bayever 19843572% (64 to 80)2245% (29 to 61)20.18

Führer 19982884% (NR)8687% (NR)40.43

Gratwohl 19811947% (NR)1369%2 (NR)50.563

 1Time point of Kaplan-Meier estimate.
2Gratwohl 1981: Two of 13 patients were eligible for MSD-HSCT but donors were not available in the first place; the two patients died after they received a second-line HSCT from the then again available MSD that was offered after the patients showed no response to IST.
3 The P value was not reported and we calculated the P value using Fisher's exact test.
Abbreviations: CI: confidence interval; IST: immunosuppressive therapy including ciclosporin and/or antithymocyte or antilymphocyte globulin; MSD-HSCT: first-line allogeneic hematopoietic stem cell transplantation from HLA-matched sibling donor; N: number of analyzed patients; NR: not reported; OS: overall survival
 
Table 4. Mortality

StudyMSD-HSCTIST



NDied%NDied%

Bayever 198435925.722940.9

Führer 199828414.38689.3

Gratwohl 1981191052.613430.8

Total822328.01212117.4

 Note: This table is meant to support the information about overall mortality. The difference between the two treatment groups MSD-HSCT and IST is calculated by the hazard ratio shown in Figure 4. Therefore, we did not calculate P values.
Abbreviations: IST: immunosuppressive therapy including ciclosporin and/or antithymocyte or antilymphocyte globulin; MSD-HSCT: first-line allogeneic hematopoietic stem cell transplantation from HLA-matched sibling donor; N: number of analyzed patients
 
Table 5. Treatment-related mortality after MSD-HSCT

StudyMSD-HSCT

% (N affected of N evaluable)

Bayever 198420 (7 of 35)

Führer 1998NR

Gratwohl 1981142 (8 of 19)

 1Gratwohl 1981: Treatment-related mortality not stated in article but implied by the authors of the present review as 3 patients died of graft failure and 5 patients died of GVHD in the MSD-HSCT group; in general graft failure and GVHD are complications of HSCT.
Abbreviations: MSD-HSCT: first-line allogeneic hematopoietic stem cell transplantation from HLA-matched sibling donor; N: number; NR: not reported
 
Table 6. Graft failure after MSD-HSCT

StudyAny graft failure

% (N affected of N evaluable)

Bayever 19843 (1 of 35)

Führer 1998NR

Gratwohl 198116 (3 of 19)

 Abbreviations: MSD-HSCT: first-line allogeneic hematopoietic stem cell transplantation from HLA-matched sibling donor; N: number; NR: not reported
 
Table 7. GVHD after MSD-HSCT

StudyGVHD

% (N affected of N evaluable)

Bayever 198451 (17 of 33)1

Führer 1998NR

Gratwohl 198126 (5 of 19)

 1Bayever 1984: 51 patients with GVHD, acute or chronic. Of 35 patients receiving MSD-HSCT, 2 were not able to develop GVHD because 1 patient died of sepsis 1 day after transplant and 1 patient experienced a graft rejection. Of 33 patients, 17 patients developed GVHD according to the results section of the article, without specifying the acute or chronic type. In the discussion section, the authors report moderate to severe GVHD in 10 patients. This could be the number of patients with acute GVHD. However, it is not clearly described how many patients had acute versus chronic GVHD.
Abbreviations: GVHD: graft-versus-host disease; MSD-HSCT: first-line allogeneic hematopoietic stem cell transplantation from HLA-matched sibling donor; N: number; NR: not reported
 
Table 8. No response to IST

StudyNo response

% (N affected of N evaluable)

Bayever 198464 (14 of 22)

Führer 1998NR

Gratwohl 198115 (2 of 13)

 Abbreviations: IST: immunosuppressive therapy including ciclosporin and/or antithymocyte or antilymphocyte globulin; MSD-HSCT: first-line allogeneic hematopoietic stem cell transplantation from HLA-matched sibling donor; N: number; NR: not reported
 
Table 9. Relapse

StudyMSD-HSCTIST

% (N affected of N evaluable)


Bayever 1984NR12.5 (1 of 8) at 5 years

Führer 1998NRNR

Gratwohl 1981NRNR

 Abbreviations: IST: immunosuppressive therapy including ciclosporin and/or antithymocyte or antilymphocyte globulin; MSD-HSCT: first-line allogeneic hematopoietic stem cell transplantation from HLA-matched sibling donor; N: number; NR: not reported
 
Table 10. Secondary clonal disease or malignancies

StudyMSD-HSCTISTP value1 Type of secondary clonal disease or malignancy

% (N affected of N evaluable)




Bayever 19843 (1 of 34)0 (0 of 22)1.00MSD-HSCT: 1 x T-cell lymphoma

Führer 19980 (0 of 28)5 (4 of 86)0.57IST: 4 x acute myelogenous leukemia

Gratwohl 1981NRNRNRNR

 1We calculated the P value using Fisher's exact test.
Abbreviations: IST: immunosuppressive therapy including ciclosporin and/or antithymocyte or antilymphocyte globulin; MSD-HSCT: first-line allogeneic hematopoietic stem cell transplantation from bone marrow of HLA-matched sibling donor; N: number; NR: not reported
 
Table 11. Karnofsky performance status

StudyScore 71% to 100%Score 41% to 70%Score 0% to 40%P value1





MSD-HSCTISTMSD-HSCTISTMSD-HSCTIST

% (N affected of N evaluable)



Bayever 198492 (24 of 26)46 (6 of 13)4 (1 of 26)54 (7 of 13)4 (1 of 26)0 (0 of 13)< 0.001

Führer 1998NRNRNRNRNRNRNR

Gratwohl 1981NRNRNRNRNRNRNR

 1We calculated the P value using Fisher's exact test.
Karnofsky performance status scale definitions according to NPCRC 2012: 71% to 100%: able to carry on normal activity and to work; no special care needed (100%: normal, no complaints); 41% to 70%: unable to work; able to live at home and care for most personal needs; varying amount of assistance needed; 0% to 40%: unable to care for self; requires equivalent of institutional or hospital care; disease may be progressing rapidly (0%: dead).
Abbreviations: IST: immunosuppressive therapy including ciclosporin and/or antithymocyte or antilymphocyte globulin; MSD-HSCT: first-line allogeneic hematopoietic stem cell transplantation from HLA-matched sibling donor; N: number; NR: not reported