Role of Cytotoxic Therapy with Hematopoietic Stem Cell Transplantation in the Treatment of Pediatric Acute Lymphoblastic Leukemia: Update of the 2005 Evidence-Based Review

Open ArchivePublished:January 03, 2012DOI:https://doi.org/10.1016/j.bbmt.2011.12.585
      Clinical research published since the first evidence-based review on the role of hematopoietic stem cell transplantation (SCT) in the treatment of pediatric acute lymphoblastic leukemia (ALL) is presented and critically evaluated in this update. Treatment recommendations are provided by an expert panel. Allogeneic SCT is recommended for children who: are in second complete remission (CR2) after experiencing an early marrow relapse for precursor-B ALL; experienced primary induction failure, but subsequently achieved a CR1; have T-lineage ALL in CR2; or have ALL in third or greater remission. Although the 2005 pediatric ALL evidence-based review (EBR) recommended allogeneic SCT for children with Philadelphia chromosome positive (Ph+) ALL in CR1, preliminary tyrosine kinase inhibitor (TKI) data demonstrate that early outcomes are comparable for allogeneic SCT and chemotherapy + imatinib. Based on the evidence, autologous SCT is not recommended for ALL in CR1. Allogeneic SCT is not recommended for: T-lineage ALL in CR1; mixed-lineage leukemia (MLL)+ ALL when it is the sole adverse risk factor; isolated central nervous system (CNS) relapse in precursor-B ALL. Based on expert opinion, allogeneic SCT may be considered for hypodiploid ALL and persistent matched related donor (MRD) positivity in ALL in CR1 or greater, although these are areas that need further study. Treatment recommendations pertaining to various transplantation techniques are also provided, as are areas of needed future research.

      Key Words

      Introduction

      In 1999, the American Society for Blood and Marrow Transplantation (ASBMT) began the development of systematic evidence-based reviews (EBRs) and position statements on the effectiveness of autologous and allogeneic hematopoietic stem cell transplantation (SCT) for specific diseases. In 2009, the ASBMT EBR Steering Committee determined that previously published reviews should be updated regularly at approximately 5-year intervals. This constitutes the update of the pediatric acute lymphoblastic leukemia (ALL) EBR originally published in 2005.

      Update of the Pediatric ALL EBR

      This pediatric ALL EBR update adheres to the methodology and grading systems presented in Appendix A (online only). In the original pediatric ALL EBR [
      • Hahn T.
      • Wall D.
      • Camitta B.
      • et al.
      The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute lymphoblastic leukemia in children: an evidence-based review.
      ], each article was summarized in detail in the text, accompanied by summary tables comparing study designs and patient outcomes. To streamline this update, a concise summary of outcomes is provided in each section of text, whereas descriptions of the study design, patient population, and clinical outcomes of each article are presented in summary tables. Therefore, the reader is urged to refer to the primary studies for additional details.
      Evidence in each section is presented with the highest quality studies first and the studies of equal quality are presented in descending order by study population size. New evidence is provided first in each table, followed by the highest quality studies (ratings from 1++ to 2++) used to make treatment recommendations in the original pediatric ALL EBR. Level 1 and level 2 evidence is presented in the tables for each study that provided biologic assignment (donor versus no donor) and randomized (autologous SCT versus chemotherapy) results.

      Treatment Recommendations

      Table 1 contains the summary of consensus treatment recommendations made by the expert panel based on the summarized evidence on the use of SCT to treat pediatric ALL. The consensus process is detailed in Appendix A (online only) and involves a teleconference during which panelists critically discuss the evidence for each section of the review and develop treatment recommendations rated according to the categories in Appendix A, Table 2.
      Table 1Summary of Updated Treatment Recommendations for Pediatric ALL
      Indication for SCTOriginal vs New RecTx Rec Grade
      Definitions for Grade of Recommendation: A = At least one meta-analysis, systematic review, or randomized controlled trial (RCT) rated as 1++, and directly applicable to the target population; or a systematic review of RCTs or a body of evidence consisting principally of studies rated as 1+, directly applicable to the target population, and demonstrating overall consistency of results; B = A body of evidence including studies rated as 2++, directly applicable to the target population, and demonstrating overall consistency of results; or extrapolated evidence from studies rated as 1++ or 1+; C = A body of evidence including studies rated as 2+, directly applicable to the target population and demonstrating overall consistency of results; or extrapolated evidence from studies rated as 2++; D = Evidence level 3 or 4; or extrapolated evidence from studies rated as 2+.
      Highest Level of Evidence
      Definitions for Levels of Evidence: 1++ High quality meta-analyses, systematic reviews of randomized controlled trials (RCTs), or RCTs with a very low risk of bias; 1+ Well conducted meta analyses, systematic reviews of RCTs, or RCTs with a low risk of bias; 1- Meta-analyses, systematic reviews of RCTs, or RCTs with a high risk of bias; 2++ High quality systematic reviews of case-control or cohort studies; or high quality case-control or cohort studies with a very low risk of confounding, bias, or chance and a high probability that the relationship is causal; 2+ Well conducted case control or cohort studies with a low risk of confounding, bias, or chance, and a moderate probability that the relationship is causal; 2- Case control or cohort studies with a high risk of confounding, bias, or chance, and a significant risk that the relationship is not causal; 3 Non-analytic studies (eg, case reports, case series); 4 Expert opinion.
      Ref. No.
      The references listed represent the highest level of evidence used to make the treatment recommendation and are not inclusive of all evidence described in each section of the review.
      Treatment Recommendation Comments
      TRANSPLANTATION VS CHEMOTHERAPY FOR PEDIATRIC ALL
      Autologous SCT vs chemotherapy in first morphologic complete remissionNew treatment recommendation based on new evidenceB1+2Autologous SCT is not recommended in CR1, nor is it a usual practice in children.
      Allogeneic SCT vs Chemotherapy in First Morphologic Complete Remission
       Ph+ ALLNew evidence changed the original recommendationB2+7In the 2005 EBR, there was a clear advantage for allogeneic SCT for Ph+ ALL in CR1 before the availability of TKI therapy. New, but preliminary, TKI data presented in one small study in this update demonstrate that early outcomes are comparable between allogeneic SCT and intensive chemotherapy with imatinib. Further study is needed to determine whether imatinib and intensive chemotherapy should replace SCT for some or all patients with Ph+ ALL. Moreover, the role of long-term TKI use is not known. This is an evolving field in need of further study.
       T-ALLNew treatment recommendation based on new evidenceC2+6While there are limited data to make a recommendation, based on expert opinion allogeneic SCT may be considered. One study showed a benefit for SCT in a subset of T-lineage ALL patients in CR1; however, this did not consider modern chemotherapy results with better EFS. There are subsets of T-ALL that seem to have a worse prognosis with chemotherapy, but it is not yet known if SCT would benefit these patients. This area requires further study.
       MLL+ ALLNew treatment recommendation based on new evidenceC2+5, 11Current data do not support allogeneic SCT when MLL+ ALL is the sole adverse risk factor. The presence of MLL+ along with other risk factors (age, WBC, prednisone response, other cytogenetic abnormalities) has been used to define very high risk groups for which allogeneic SCT may be recommended.
       Hypodiploid ALL (<44 chromosomes)New treatment recommendation based on expert opinionD4Outcomes remain dismal for hypodiploid ALL treated with modern chemotherapy only. While there are no published data to make a recommendation, based on expert opinion, allogeneic SCT may be considered. This area requires further study.
      Allogeneic SCT vs chemotherapy for ALL after primary induction failure
      § Primary induction failure defined as patients who failed to achieve first remission after the first 4-6 weeks of initial induction therapy, but who subsequently achieve a complete remission.
      New evidence changed the original recommendationC2+4Allogeneic SCT is recommended for ALL patients with primary induction failure who subsequently achieve complete remission.
      Allogeneic SCT vs chemotherapy for persistent MRD positivity (in CR1 or CR2)New treatment recommendation based on expert opinionD4Based on expert opinion allogeneic SCT may be considered for patients who have been identified by a validated assay as very high risk due to detection of persistent MRD; however, this is an evolving field in need of further study.
      Allogeneic SCT vs Chemotherapy for ALL in Second Morphologic Complete Remission
       Early marrow relapse (during or within 6 months of therapy completion or <36 months from diagnosis) in precursor-B ALLNew evidence changed the original recommendationB2++11Due to a significant benefit in survival outcomes, allogeneic SCT is recommended for patients in CR2 who have experienced an early marrow relapse.
       Later marrow relapse in precursor-B ALLNew evidence changed the original recommendationB2++11There may be a small EFS advantage for patients with allogeneic SCT, but taking into account salvage therapy, the outcomes with chemotherapy and SCT are equivalent for late marrow relapse. The decision to utilize SCT in these patients should be made by the patient, family, and transplant team with consideration of the risks and benefits involved.
       T-ALLNew treatment recommendation based on evidence from the original EBRC2+22Based on one small study and expert opinion, allogeneic SCT is recommended for T-lineage ALL in CR2 after a marrow relapse; however, further study is needed.
       Isolated CNS relapseNew treatment recommendation based on new evidenceB2++12Allogeneic SCT is not recommended for isolated CNS relapse in precursor-B ALL because survival of these patients with chemo/radiotherapy is equivalent. There are insufficient data to make a recommendation regarding allogeneic SCT for treatment of an isolated CNS relapse in T-lineage ALL.
       Isolated testicular relapseNo recommendationD4No data are available to make a recommendation regarding allogeneic SCT for treatment of an isolated testicular relapse.
      Allogeneic SCT vs chemotherapy for ALL in third or greater morphologic complete remissionNew treatment recommendation based on new evidenceC2+15Although patients with ALL in third or greater remission have a poor prognosis regardless of treatment, allogeneic SCT is recommended because it improves survival outcomes.
      Allogeneic SCT vs chemotherapy for ALL not in morphologic complete remissionNew treatment recommendation based on expert opinionD4There are no data to recommend allogeneic SCT for patients in active relapse with measurable disease. SCT for patients with ALL with measurable disease produces long-term disease-free survivals <10%. The decision to use SCT in these patients should be made by the patient, family, and transplant team with consideration of the risks and benefits involved.
      TRANSPLANTATION TECHNIQUES
      Related vs unrelated donor allogeneic SCTNew treatment recommendation based on new evidenceB2++23-24Survival outcomes after HLA-matched related or unrelated donor allogeneic SCT are similar. Based on studies in acute lymphoblastic and myeloid leukemia, in the absence of an HLA-matched related donor, an HLA-matched unrelated donor allogeneic SCT (using marrow, peripheral or cord blood) is an acceptable alternative.
      Autologous vs allogeneic SCTNew treatment recommendation based on new evidenceC2++29There are no data to support a benefit for autologous SCT in children. It is not a recommended treatment, nor is it standard practice.
      Maternal vs paternal donor allogeneic SCTNo recommendation based on new evidence2+30There are insufficient data to make a treatment recommendation regarding use of a maternal vs paternal donor for allogeneic SCT.
      HLA-matched vs mismatched unrelated donor allogeneic SCTNew treatment recommendation based on new evidenceC2−31Allogeneic SCT using the best possible HLA-match is recommended. Although HLA-mismatched unrelated donor allogeneic SCT may result in higher morbidity and mortality than HLA-matched unrelated donor allogeneic SCT, this does not preclude performing an HLA-mismatched unrelated donor allogeneic SCT.
      Imatinib versus no imatinib therapy pre and/or post-allogeneic SCT for Ph+ ALLNo recommendation based on new evidence2+32There are insufficient data to make a treatment recommendation regarding the use of imatinib therapy with allogeneic SCT in children with Ph+ ALL.
      Comparison of conditioning regimensNew evidence strengthens the original recommendationB2+33-34Myeloablative TBI-containing regimens have better survival outcomes than non-TBI-containing regimens.
      ALL indicates acute lymphoblastic leukemia; Rec., recommendation Tx, treatment; Ref., reference; SCT, stem cell transplantation; CR1, first complete remission; Ph+, Philadelphia chromosome positive; EBR, evidence-based review; TKI, tyrosine kinase inhibitor; EFS, event-free survival; MLL, mixed-lineage leukemia; CR2, second complete remission; MRD, matched related donor; CNS, central nervous system; MUD, matched unrelated donor; TBI, total body irradiation.
      Definitions for Grade of Recommendation: A = At least one meta-analysis, systematic review, or randomized controlled trial (RCT) rated as 1++, and directly applicable to the target population; or a systematic review of RCTs or a body of evidence consisting principally of studies rated as 1+, directly applicable to the target population, and demonstrating overall consistency of results; B = A body of evidence including studies rated as 2++, directly applicable to the target population, and demonstrating overall consistency of results; or extrapolated evidence from studies rated as 1++ or 1+; C = A body of evidence including studies rated as 2+, directly applicable to the target population and demonstrating overall consistency of results; or extrapolated evidence from studies rated as 2++; D = Evidence level 3 or 4; or extrapolated evidence from studies rated as 2+.
      Definitions for Levels of Evidence: 1++ High quality meta-analyses, systematic reviews of randomized controlled trials (RCTs), or RCTs with a very low risk of bias; 1+ Well conducted meta analyses, systematic reviews of RCTs, or RCTs with a low risk of bias; 1- Meta-analyses, systematic reviews of RCTs, or RCTs with a high risk of bias; 2++ High quality systematic reviews of case-control or cohort studies; or high quality case-control or cohort studies with a very low risk of confounding, bias, or chance and a high probability that the relationship is causal; 2+ Well conducted case control or cohort studies with a low risk of confounding, bias, or chance, and a moderate probability that the relationship is causal; 2- Case control or cohort studies with a high risk of confounding, bias, or chance, and a significant risk that the relationship is not causal; 3 Non-analytic studies (eg, case reports, case series); 4 Expert opinion.
      The references listed represent the highest level of evidence used to make the treatment recommendation and are not inclusive of all evidence described in each section of the review.
      § Primary induction failure defined as patients who failed to achieve first remission after the first 4-6 weeks of initial induction therapy, but who subsequently achieve a complete remission.
      The new treatment recommendations are based on the pediatric ALL evidence published from January 2005 through October 15, 2010. In addition, the treatment recommendations from the original pediatric ALL EBR are incorporated into the respective tables when applicable. It is indicated whether new evidence strengthens, modifies, or does not change the original recommendation.

      Transplantation versus Chemotherapy for Pediatric ALL

      Published since the original pediatric ALL EBR, and briefly summarized in the text, are 13 studies comparing transplantation versus chemotherapy as treatment for pediatric patients (<18 years) with ALL in first morphologic complete remission (CR1; n = 6 studies) or in ≥ second complete remission (CR2) or relapsed disease (n = 7 studies).

       Transplantation versus Chemotherapy for Pediatric ALL in CR1

      Table 2 presents a detailed summary of the study designs, patient populations, and outcomes from the 6 new studies of patients in CR1, as well as four high quality (2++) studies comparing transplantation versus chemotherapy in CR1 that were used to make treatment recommendations in the original pediatric ALL EBR. The quality rating (Appendix A; Table 1) of these studies ranged from 1+ to 2+.
      Table 2Transplantation versus Chemotherapy for Pediatric ALL in Morphologic CR1
      Reference & Patient PopulationsQuality/Strength of Evidence
      Quality and strength of evidence definitions are listed in Appendix A, Table 1.
      Treatment RegimenSample SizeAge, Yrs, Median (Range)% WBC >100,000% Ph+% T LineageFollow-up (in Months) Median (Range)% TRM% EFS/DFS/LFS (95% CI)Signif. EFS/DFS/LFS
      NS: Not significant P > .05.
      % OS (95% CI)Signif. OS
      NS: Not significant P > .05.
      Update data published since January, 2005
      • Ribera J.M.
      • Ortega J.J.
      • Oriol A.
      • et al.
      Comparison of intensive chemotherapy, allogeneic, or autologous stem-cell transplantation as postremission treatment for children with very high risk acute lymphoblastic leukemia: PETHEMA ALL-93 trial.
      Ribera 2007
      1+Total76NR (<1-17)78 (15.6-149)ITT 5-yr DFSP =.365-year OSP = .23
      1993-2002Autologous SCT3853%7%47%5%44% (29-60%)45% (31-62%)
      Prospective, MulticenterChemotherapy3839%14%37%0%46% (32-62%)57% (43-73%)
      PETHEMA ALL-93
      Very HR ALL in CR12+Total100
      Donor (Allo SCT)2446%7%58%NR45% (37-55%)P = .9648% (30-67%)P = .83
      No donor (auto or chemo)7645% (27-65%)51% (43-61%)
      • Aricò M.
      • Schrappe M.
      • Hunger S.P.
      • et al.
      Clinical outcome of children with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia treated between 1995 and 2005.
      Aricò 2010
      2++Total5427.8 (.7-18)NR100%NR75.6 (1.2-138)3%5-year DFSP < .0015-year OSP = .003
      1995-2005Any SCT (MRD, MUD, or MMRD allo, or auto)32543.5% ± 2.9%Any SCT vs Chemo54% ± 2.8%Any SCT vs Chemo
      Retrospective, Multicenter
      Ph+ ALL in CR1Chemotherapy21734.2% ± 3.7%48.3% ± 3.5%
      No TKI therapy
      • Balduzzi A.
      • De Lorenzo P.
      • Schrauder A.
      • et al.
      Eligibility for allogeneic transplantation in very high risk childhood acute lymphoblastic leukemia: the impact of the waiting time.
      Balduzzi 2008
      2+Total357NR60 (NR)NR5-yr DFSP = .025-year OSP = .12
      1995-2000Donor (MSD allo)777 (4-12)9%39%56.7% ± 5.7%Donor vs No donor50.1% ± 3.1%
      Prospective, MulticenterNo donor2807 (3-11)24%45%40.6% ± 3.1%56.4% ± 5.9%
      Collaborative (5 groups)(ITT)
      Very HR
      Very high risk = at least one of the following: induction failure; Ph+ or t(4;11); poor response to prednisone.
      ALL in CR1
      Donor2556% ± 9.9%P = .03NRNR
      No donor (Induction failures only)5826.5% ± 5.9%Donor vs No donor
      MRD Allo SCT5563.1% ± 6.6%P = .017NRNR
      MUD Allo SCT4341.6% ± 7.6%MRD vs MUD or Chemo
      Chemotherapy (By actual treatment)25942.5% ± 3.2%
      • Mann G.
      • Attarbaschi A.
      • Schrappe M.
      • et al.
      Improved outcome with hematopoietic stem cell transplantation in a poor prognostic subgroup of infants with mixed-lineage-leukemia (MLL)-rearranged acute lymphoblastic leukemia: results from the Interfant-99 Study.
      Mann 2010
      2+Total277NR (≤1)63%NR1%60 (0-108)NR5-year DFSP =.095-year OSP =.32
      1999-2006Allo SCT (MSD, MUD or MMUD)Medium risk
      § High risk = MLL+, age <6 months, and either WBC ≥300 g/L or poor prednisolone response; Low risk = no MLL rearrangement; Medium risk = all others.
      Medium risk
      § High risk = MLL+, age <6 months, and either WBC ≥300 g/L or poor prednisolone response; Low risk = no MLL rearrangement; Medium risk = all others.
      Retrospective, Collaborative3760.9% ± 11.4%65.2% ± 10.6%
      Interfant-99 trialChemotherapy24053.8% ± 4.4%60.8% ± 4.1%
      MLL+ ALL in CR1
      High riskP = .01High riskP = .001
      Allo SCT59% ± 12.8%66% ± 12.4%
      Chemotherapy22.2% ± 7.8%19.3% ± 6.1%
      • Schrauder A.
      • Reiter A.
      • Gadner H.
      • et al.
      Superiority of allogeneic hematopoietic stem-cell transplantation compared with chemotherapy alone in high-risk childhood T-cell acute lymphoblastic leukemia: results from ALL-BFM 90 and 95.
      Schrauder 2006
      2+Total179<18 (NR)NR100%78 (NR)ITT 5-yr DFSP = .015-year OSP = .01
      1990-2000Allo BMT3667% ± 8%Allo BMT vs Chemo67% ± 8%Allo BMT vs Chemo
      Retrospective, MulticenterChemotherapy14362.5%5%42% ± 5%47% ± 5%
      ALL-BFM-90 and 95MSD Allo2360.9%0%65% ± 10%P = NS
      Very HR
      Very high risk = Poor prednisone response; nonresponse on day 33; Ph+ or t(4;11); BCR/ABL or MLL/AF4 rearrangement, plus one of the following: T-ALL, pro-B-cell ALL, coexpression of myeloid markers, or BRM-RF of 1.7 or higher.
      T ALL CR1
      MUD or MMRD Allo1353.8%31%69% ± 13%
      • Schultz K.R.
      • Bowman W.P.
      • Aledo A.
      • et al.
      Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a Children’s Oncology Group study.
      Schultz 2009
      2+Total57NR (1-21)NR100%NRNRNR3-year EFSP =.14NRNR
      2002-2006MSD Allo BMT2156.6% ± 21.5%
      Prospective, MulticenterAlternative donor BMT1171.6% ± 19%
      COG AALL0031

      Very HR Ph+ ALL
      Chemo + imatinib maintenance2587.7% ± 10.9%
      TKI – with chemo only
      Original Pediatric ALL EBR data
      • Wheeler K.A.
      • Richards S.M.
      • Bailey C.C.
      • et al.
      Bone marrow transplantation versus chemotherapy in the treatment of very high-risk childhood acute lymphoblastic leukemia in first remission: results from Medical Research Council UKALL X and XI.
      Wheeler 2000
      2++Total45296 Overall10-yr EFSP = NS10-yr OSP = NS
      1985-1997 MulticenterAllo BMT (MRD/ MUD)101NR73%14%41%60 (NR)17.8%50.4%61.2%
      Retrospective analysisChemotherapy351NR73%3%36%NR3.1%39.7%54%
      MRC UKALL X & XI
      ALL in CR1
      • Aricò M.
      • Valsecchi M.G.
      • Camitta B.
      • et al.
      Outcome of treatment in children with Philadelphia chromosome positive childhood acute lymphoblastic leukemia.
      Aricò 2000
      2++Total267100%87.6 Overall5-yr DFSP < .0015-yr OSP = .002
      1986-1996Any BMT1206.9 (.4-20)30%2%65% ± 8%Any BMT72% ± 8%Any BMT vs Chemo
      Retrospective, multicenterChemotherapy1477.5 (.4-20)50%3%5%25% ± 4%vs Chemo42% ± 4%
      Ph+ ALL in CR1
      Allo BMT95
      MRD388%
      MUD2143%
      MMRD1644%
      Other undefined Allo2025%
      Autologous BMT2512%
      • Pui C.H.
      • Gaynon P.S.
      • Boyett J.M.
      • et al.
      Outcome of treatment in childhood acute lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region.
      Pui 2002
      2++Total2300.65NR0%<1%84 OverallHazard DFSP = .014Hazard OSP = .004
      1983-1995Any BMT56(0.01-20.9)(18-200)20%1.61 (1.1-2.34)1.76 (1.08-2.45)
      Retrospective, multicenter 11 coop groups or single centers, US+ EuropeChemotherapy174At Dx4%1.01.0
      MRD1520%1.3 (0.67-2.52)P = .441.48 (0.47-2.48)P = .26
      MUD1421%1.47 (0.74-2.93)P = .271.9 (0.11-3.92)P = .078
      ALL with t(4;11)Other allo1729%2.22 (1.27-3.91)P = .00552.54 (1.15-3.92)P = .0008
      In CR1Autologous BMT90%1.29 (0.51-3.25)P = .590.83 (0-1.67)P = .71
      • Uderzo C.
      • Valsecchi M.G.
      • Balduzzi A.
      • et al.
      Allogeneic bone marrow transplantation versus chemotherapy in high-risk childhood acute lymphoblastic leukaemia in first remission. Associazione Italiana di Ematologia ed Oncologia Pediatrica (AIEOP) and the Gruppo Italiano Trapianto di Midollo Osseo (GITMO).
      Uderzo 1997
      2++Total16048 Overall4-yr DFSP = NSNRNR
      1986-1994Allo BMT308.3 (.1-15)60%20%60%10%58.5% ± 9.3%
      Prospective, multicenterChemotherapy1305.7 (.7-15)69%1%48%4%47.7% ± 4.8%
      AIEOP & GITMO
      HR
      ∗∗ HR = Ph+ t(4;11), BFM risk index >1.7, T-immunophenotype with WBC >100 x 109/L or with day 7 steroid resistance, and failure to obtain CR at day 42 of induction therapy.
      ALL in CR1
      ALL indicates acute lymphoblastic leukemia; CR1, first complete remission; Ph+, Philadelphia chromosome positive; TRM, treatment-related mortality; EFS, event-free survival; DFS, disease-free survival; LFS, leukemia-free survival; CI, confidence interval; Signif., significance; OS, overall survival; PETHEMA, Programa para el Estudio de la Terapéutica en Hemopatía Maligna; HR, high risk; Allo, allogeneic; SCT, stem cell transplantation; NR, not reported; Auto, autologous; MRD, matched related donor; MUD, matched unrelated donor; MMRD, mismatched related donor; TKI, tyrosine kinase inhibitor; MSD, matched sibling donor; ITT, intention-to-treat analysis; MLL, mixed-lineage leukemia; BMT, bone marrow transplantation; COG, Children’s Oncology Group; EBR, evidence-based review; Dx, diagnosis; AIEOP, Associazione Italiana di Ematologia ed Oncologia Pediatricia; GITMO, Gruppo Italiano Trapianto di Midollo Osseo; WBC, white blood cell count; MRC, Medical Research Council; BFM, Berlin-Frankfurt-Munster.
      Quality and strength of evidence definitions are listed in Appendix A, Table 1.
      NS: Not significant P > .05.
      Very high risk = at least one of the following: induction failure; Ph+ or t(4;11); poor response to prednisone.
      § High risk = MLL+, age <6 months, and either WBC ≥300 g/L or poor prednisolone response; Low risk = no MLL rearrangement; Medium risk = all others.
      Very high risk = Poor prednisone response; nonresponse on day 33; Ph+ or t(4;11); BCR/ABL or MLL/AF4 rearrangement, plus one of the following: T-ALL, pro-B-cell ALL, coexpression of myeloid markers, or BRM-RF of 1.7 or higher.
      ∗∗ HR = Ph+ t(4;11), BFM risk index >1.7, T-immunophenotype with WBC >100 x 109/L or with day 7 steroid resistance, and failure to obtain CR at day 42 of induction therapy.
      The prospective, multicenter, Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA) ALL-93 trial by Ribera et al. [
      • Ribera J.M.
      • Ortega J.J.
      • Oriol A.
      • et al.
      Comparison of intensive chemotherapy, allogeneic, or autologous stem-cell transplantation as postremission treatment for children with very high risk acute lymphoblastic leukemia: PETHEMA ALL-93 trial.
      ] reported no significant differences in 5-year disease-free survival (DFS) or overall survival (OS) between patients with very high-risk ALL in CR1 who were randomized to autologous SCT versus chemotherapy or for patients who had a donor (allogeneic SCT) versus those who did not (chemotherapy or autologous SCT).
      A retrospective analysis by Aricò et al. [
      • Aricò M.
      • Schrappe M.
      • Hunger S.P.
      • et al.
      Clinical outcome of children with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia treated between 1995 and 2005.
      ] reported a significant improvement in 5-year DFS and OS for patients with Philadelphia chromosome positive (Ph+) ALL in CR1 who underwent any SCT (matched related donor [MRD], matched unrelated donor [MUD], or mismatched related donor [MMRD] allogeneic SCT or autologous SCT) versus those who received only chemotherapy with no tyrosine kinase inhibitor (TKI) therapy.
      A prospective, collaborative group study by Balduzzi et al. [
      • Balduzzi A.
      • De Lorenzo P.
      • Schrauder A.
      • et al.
      Eligibility for allogeneic transplantation in very high risk childhood acute lymphoblastic leukemia: the impact of the waiting time.
      ], reported a significant improvement in 5-year DFS, but not OS, for very high-risk pediatric patients with ALL in CR1 who had a donor versus those who did not, including those who had primary induction failure, and also for those who underwent a MRD or MUD allogeneic SCT versus those who received chemotherapy only.
      Mann et al. [
      • Mann G.
      • Attarbaschi A.
      • Schrappe M.
      • et al.
      Improved outcome with hematopoietic stem cell transplantation in a poor prognostic subgroup of infants with mixed-lineage-leukemia (MLL)-rearranged acute lymphoblastic leukemia: results from the Interfant-99 Study.
      ] provided a retrospective analysis of infants (≤1 year) with mixed-lineage leukemia (MLL)+ ALL from the collaborative group study Interfant-99 trial, who underwent an HLA-MRD or HLA-mismatched unrelated donor (MMUD) allogeneic SCT versus chemotherapy alone. A significant benefit in 5-year DFS and OS for allogeneic SCT was reported, but only for patients with high-risk MLL+ with additional poor prognostic characteristics versus those with MLL positivity alone.
      In a retrospective analysis of the ALL-Berlin-Frankfurt-Münster (BFM)-90 and 95 trials, Schrauder et al. [
      • Schrauder A.
      • Reiter A.
      • Gadner H.
      • et al.
      Superiority of allogeneic hematopoietic stem-cell transplantation compared with chemotherapy alone in high-risk childhood T-cell acute lymphoblastic leukemia: results from ALL-BFM 90 and 95.
      ] reported a significant improvement in 5-year DFS and OS with allogeneic bone marrow transplantation (BMT) versus chemotherapy in pediatric patients with very high-risk T ALL in CR1.
      The prospective, multicenter, Children’s Oncology Group (COG) AALL0031 trial by Schultz et al. [
      • Schultz K.R.
      • Bowman W.P.
      • Aledo A.
      • et al.
      Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a Children’s Oncology Group study.
      ] reported no significant difference in 3-year event-free survival (EFS) among very high-risk pediatric patients with Ph+ ALL in CR1 who received imatinib therapy with an intensive chemotherapy regimen followed by a matched sibling allogeneic BMT, alternative donor allogeneic SCT, or chemotherapy plus imatinib maintenance without SCT.
      There were 4 high-quality (2++) studies in the original pediatric ALL EBR used to make a treatment recommendation about the use of transplantation versus chemotherapy to treat pediatric ALL in CR1. Aricò et al. [
      • Aricò M.
      • Valsecchi M.G.
      • Camitta B.
      • et al.
      Outcome of treatment in children with Philadelphia chromosome positive childhood acute lymphoblastic leukemia.
      ] reported significantly better 5-year EFS and OS for high-risk pediatric patients with Ph+ ALL receiving allogeneic or autologous BMT versus chemotherapy without TKI therapy. Wheeler et al. [
      • Wheeler K.A.
      • Richards S.M.
      • Bailey C.C.
      • et al.
      Bone marrow transplantation versus chemotherapy in the treatment of very high-risk childhood acute lymphoblastic leukemia in first remission: results from Medical Research Council UKALL X and XI.
      ] found no significant difference in 10-year EFS or 10-year OS, and Uderzo et al. [
      • Uderzo C.
      • Valsecchi M.G.
      • Balduzzi A.
      • et al.
      Allogeneic bone marrow transplantation versus chemotherapy in high-risk childhood acute lymphoblastic leukaemia in first remission. Associazione Italiana di Ematologia ed Oncologia Pediatrica (AIEOP) and the Gruppo Italiano Trapianto di Midollo Osseo (GITMO).
      ] found no significant difference in 4-year DFS between very high-risk pediatric patients with ALL who underwent allogeneic SCT vs chemotherapy. Pui et al. [
      • Pui C.H.
      • Gaynon P.S.
      • Boyett J.M.
      • et al.
      Outcome of treatment in childhood acute lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region.
      ] reported a significantly worse DFS and OS in pediatric patients with ALL with t(4;11) treated with autologous or allogeneic BMT versus chemotherapy.

       Transplantation versus Chemotherapy for Pediatric ALL in ≥ CR2

      Table 3 presents a summary of the 7 new studies and 5 original ALL EBR studies comparing transplantation vs chemotherapy for patients with ALL in ≥ morphologic CR2 or relapsed disease. The quality ratings of these studies range from 2++ to 2+.
      Table 3Transplantation vs Chemotherapy for Pediatric ALL in ≥ Morphologic CR2
      Reference & Patient PopulationsQuality/Strength of Evidence
      Quality and strength of evidence definitions are listed in Appendix A, Table 1.
      Treatment RegimenSample SizeAge, Yrs, Median (range)% WBC >100,000% Ph+% T LineageFollow-up (in months) Median (range)% TRM% EFS/DFS/LFS (95% CI)Signif. EFS/DFS/LFS
      Not significant: P > .05.
      % OS (95% CI)Signif. OS
      Not significant: P > .05.
      Update data published since January, 2005
      • Eapen M.
      • Raetz E.
      • Zhang M.J.
      • et al.
      Outcomes after HLA-matched sibling transplantation or chemotherapy in children with B-precursor acute lymphoblastic leukemia in a second remission: a collaborative study of the Children’s Oncology Group and the Center for International Blood and Marrow Transplant Research.
      Eapen 2006
      2++Total374NRITT 8-yr LFSP < .0018-yr OSP < .003
      1991-1997MSD Allo BMT1868 (1-18)9%0%101 (16-160)13%In early relapse: TBI + Allo vs ChemoIn early relapse: TBI + Allo vs Chemo
      Retrospective, MulticenterEarly relapse
      Early relapse <36 months; late relapse ≥36 months.
      ; no TBI
      198% (1-24%)18% (5-37%)
      POG 9110, 9310, &Early relapse; TBI9241% (31-52%)44% (33-55%)
      9411 chemo trials vs CIBMTRLate relapse; no TBI1430% (10-54%)32% (23-40%)
      Late relapse; TBI6160% (46-71%)63% (49-74%)
      Pre-B ALL in CR2Chemotherapy1885 (1-18)8%0%103 (34-159)10%
      Early relapse11023% (15-31%)32% (23-40%)
      Late relapse7859% (47-69%)66% (54-76%)
      • Eapen M.
      • Zhang M.J.
      • Devidas M.
      • et al.
      Outcomes after HLA-matched sibling transplantation or chemotherapy in children with acute lymphoblastic leukemia in a second remission after an isolated central nervous system relapse: a collaborative study of the Children’s Oncology Group and the Center for International Blood and Marrow Transplant Research.
      Eapen 2008
      2++Total209NR (<18)NR8-yrITT 8-yr LFSP = .808-yr OSP = .14
      1990-2000MSD Allo SCT6022%23%108 (NR)22%58%62%
      Retrospective, MulticenterChemo/radiotherapy14913%7%96 (NR)9%66%67%
      POG 9061 & 9412
      Chemo trials vs CIBMTR
      ALL in CR2 after isolated CNS relapse
      • Tallen G.
      • Ratei R.
      • Mann G.
      • et al.
      Long-term outcome in children with relapsed acute lymphoblastic leukemia after time-point and site-of-relapse stratification and intensified short-course multidrug chemotherapy: results of trial ALL-REZ BFM 90.
      Tallen 2010
      2+Total440NR (<19)NRNRNR120 (NR)NR10-yr EFSP = .59NRNR
      1990-1995Any SCT11737% ± 5%
      Prospective, MulticenterChemotherapy32335% ± 3%
      ALL-REZ BFM 90
      ALL in CR2MRD Allo SCT6143% ± 6%P = .02
      MUD Allo SCT1942% ± 11%MRD/MUD
      MMRD/URD Allo SCT714% ± 13%vs
      Autologous SCT3027% ± 8%MMRD/URD
      • Saarinen-Pihkala U.M.
      • Heilmann C.
      • Winiarski J.
      • et al.
      Pathways through relapses and deaths of children with acute lymphoblastic leukemia: role of allogeneic stem-cell transplantation in Nordic data.
      Saarinen-Pihkala 2006
      2+Total202NRNRNR10-yr EFSP < .01NRNR
      1981-2001MRD or MUD Allo SCT625.5 (1-14)6%19%37%
      Retrospective, MulticenterChemotherapy1404.8 (1-14)6%8%15%
      NOPHO trials
      • Einsiedel H.G.
      • von Stackelberg A.
      • Hartmann R.
      • et al.
      Long-term outcome in children with relapsed ALL by risk-stratified salvage therapy: results of trial acute lymphoblastic leukemia-relapse study of the Berlin-Frankfurt-Münster Group 87.
      Einsiedel 2005
      2+Total172NR (≤18)NRNRNR188 (NR)15-yr EFSP = .026NRNR
      1987-1990MRD Allo SCT2715%59% ± 7%
      Prospective, MulticenterChemo/radiotherapy1454%30% ± 4%
      ALL-REZ BFM 87
      ALL in CR2
      • Gaynon P.S.
      • Harris R.E.
      • Altman A.J.
      • et al.
      Bone marrow transplantation versus prolonged intensive chemotherapy for children with acute lymphoblastic leukemia and an initial bone marrow relapse within 12 months of the completion of primary therapy: Children’s Oncology Group study CCG-1941.
      Gaynon 2006
      2+Total122NRNRNRNRITT 5-yr DFSP = NSNRNR
      1995-1998MRD Allo BMT504.7 (.6-17)4%29% ± 7%(for all comparisons)
      Prospective, MulticenterAlternative BMT
      § Randomized to alt. BMT or chemo; 41 of 113 refused randomization.
      376.2 (.7-17)19%21% ± 7%
      COG CCG-1941Chemotherapy
      § Randomized to alt. BMT or chemo; 41 of 113 refused randomization.
      353.1 (.4-18)9%20% ± 7%
      ALL in CR2
      • Malempati S.
      • Gaynon P.S.
      • Sather H.
      • La M.K.
      • Stork L.C.
      for the Children’s Oncology Group
      Outcome after relapse among children with standard-risk acute lymphoblastic leukemia: Children’s Oncology Group study CCG-1952.
      Malempati 2007
      2−Total158(Mean)NRNRNR28.8 (NR)NR2-yr EFSP = .39NRNR
      1996-2000Any SCT (Allo or Auto)774.7 (1-9)49.5% ± 6.1%
      Retrospective, MulticenterChemotherapy814.7 (1-9)49.1% ± 6.4%
      COG CCG-1952 trial(By actual salvage Tx)
      SR ALL in CR2
      Original Pediatric ALL EBR data
      • Barrett A.J.
      • Horowitz M.M.
      • Pollock B.H.
      • et al.
      Bone marrow transplants from HLA-identical siblings as compared with chemotherapy for children with acute lymphoblastic leukemia in a second remission.
      Barrett 1994
      2++Total510NRNR5-yr LFSP < .001NRNR
      1983-1991MSD Allo BMT2557 (.5-18.4)7%8%27%40% ± 3%Allo BMT vs Chemo
      Matched-pair, MulticenterChemotherapy2556 (.4-18.1)7%8%14%17% ± 3%
      POG 8303, 8304, 8710,& 8862 vs CIBMTR
      ALL in CR2
      • Wheeler K.
      • Richards S.
      • Bailey C.
      • Chessells J.
      Comparison of bone marrow transplant and chemotherapy for relapsed childhood acute lymphoblastic leukaemia: the MRC UKALL X experience. Medical Research Council Working Party on Childhood Leukaemia.
      Wheeler 1998
      2++Total432NR (1-14)NRNR24 Minimum4-yr EFSP = .05NRNR
      1985-1990Allo BMT11017%42.6%Allo BMT vs Chemo
      Retrospective, MulticenterAutologous BMT617%5%35.4%
      MRC UKALL XChemotherapy26110%5%28.2%
      ALL in CR2
      MRD Allo BMT836%
      MUD Allo BMT275%
      • Uderzo C.
      • Valsecchi M.G.
      • Bacigalupo A.
      • et al.
      Treatment of childhood acute lymphoblastic leukemia in second remission with allogeneic bone marrow transplantation and chemotherapy: ten-year experience of the Italian Bone Marrow Transplantation Group and the Italian Pediatric Hematology Oncology Association.
      Uderzo 1995
      2++Total287NR (0-18)NRNR74 Overall5-yr DFSP = .006NRNR
      1980-1989MRD Allo BMT5714%19.3%41.1%Allo BMT vs Chemo
      Retrospective, MulticenterChemotherapy23014%2.6%21.7%
      AIEOP & GITMO
      ALL in CR2
      • Harrison G.
      • Richards S.
      • Lawson S.
      • et al.
      Comparison of allogeneic transplant versus chemotherapy for relapsed childhood acute lymphoblastic leukaemia in the MRC UKALL R1 trial. MRC Childhood Leukaemia Working Party.
      Harrison 2000
      2++Total206NR (0-14)NRNR72 (48-108)NR8-yr EFSP = .60NRNR
      1991-1995Donor (MRD or MUD)6736%45%
      Retrospective, MulticenterNo donor (Chemo or Auto)13955%37%
      MRC UKALL R1
      ALL in CR2
      • Borgmann A.
      • von Stackelberg A.
      • Hartmann R.
      • et al.
      Unrelated donor stem cell transplantation compared with chemotherapy for children with acute lymphoblastic leukemia in a second remission: a matched-pair analysis.
      Borgmann 2003
      2+Total162NR (≤18)NRNR5-yr EFSP < .001NRNR
      1983-1994MUD BMT8111%49 (NR)30%42%
      Retrospective, MulticenterChemotherapy8111%95 (NR)4%17%
      Matched-pair analysis
      ALL-REZ BFM
      ALL in CR2
      ALL indicates acute lymphoblastic leukemia; CR, complete remission; Ph+, Philadelphia chromosome positive; TRM, treatment-related mortality; EFS, event-free survival; DFS, disease-free survival; LFS, leukemia-free survival; CI, confidence interval; NR, not reported; OS, overall survival; MSD, matched sibling donor; Allo, allogeneic; BMT, bone marrow transplantation; TBI, total body irradiation; POG, Pediatric Oncology Group; CIBMTR, Center for International Blood and Marrow Transplant Research; CNS, central nervous system; EFS, event-free survival; SCT, stem cell transplantation; ALL-REZ BFM, Relapsed Acute Lymphoblastic Leukemia Berlin-Frankfurt-Munster Study Group; MRD, matched related donor; MUD, matched unrelated donor; MMRD, mismatched related donor; URD, unrelated donor; NOPHO, Nordic Society for Pediatric Hematology and Oncology; NS, not significant; COG, Children’s Oncology Group; Auto, autologous; Tx, treatment; EBR, evidence-based review; AIEOP, Associazione Italiana di Ematologia ed Oncologia Pediatricia; GITMO, Gruppo Italiano Trapianto di Midollo Osseo; MRC, Medical Research Council; SR, standard risk.
      Quality and strength of evidence definitions are listed in Appendix A, Table 1.
      Not significant: P > .05.
      Early relapse <36 months; late relapse ≥36 months.
      § Randomized to alt. BMT or chemo; 41 of 113 refused randomization.
      A retrospective, multicenter study by Eapen et al. [
      • Eapen M.
      • Raetz E.
      • Zhang M.J.
      • et al.
      Outcomes after HLA-matched sibling transplantation or chemotherapy in children with B-precursor acute lymphoblastic leukemia in a second remission: a collaborative study of the Children’s Oncology Group and the Center for International Blood and Marrow Transplant Research.
      ] compared the outcomes in patients with precursor B-ALL in CR2 from 3 Pediatric Oncology Group (POG 9110, 9310, and 9411) chemotherapy trials to patients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) registry who underwent HLA-matched sibling allogeneic SCT. A significant benefit in leukemia-free survival (LFS) and OS was reported specifically for patients in early relapse who underwent an HLA-matched allogeneic SCT with a total body irradiation (TBI)-containing conditioning regimen versus those who received chemotherapy only.
      Another retrospective, multicenter study by Eapen et al. [
      • Eapen M.
      • Zhang M.J.
      • Devidas M.
      • et al.
      Outcomes after HLA-matched sibling transplantation or chemotherapy in children with acute lymphoblastic leukemia in a second remission after an isolated central nervous system relapse: a collaborative study of the Children’s Oncology Group and the Center for International Blood and Marrow Transplant Research.
      ] reported no significant difference in LFS or OS between pediatric patients with ALL in CR2 after central nervous system (CNS) relapse who underwent an HLA-matched sibling allogeneic SCT versus those who received chemo/radiotherapy only.
      Malempati et al. [
      • Malempati S.
      • Gaynon P.S.
      • Sather H.
      • La M.K.
      • Stork L.C.
      for the Children’s Oncology Group
      Outcome after relapse among children with standard-risk acute lymphoblastic leukemia: Children’s Oncology Group study CCG-1952.
      ] reported no significant difference in 2-year EFS between pediatric patients with ALL in CR2 in the COG CCG-1952 trial whose salvage therapy was any SCT (MRD, MUD, or unrelated cord blood allogeneic SCT, or autologous SCT) versus chemotherapy only in a comparison that combined all types of relapse risk (early, late, isolated extramedullary relapse).
      Tallen et al. [
      • Tallen G.
      • Ratei R.
      • Mann G.
      • et al.
      Long-term outcome in children with relapsed acute lymphoblastic leukemia after time-point and site-of-relapse stratification and intensified short-course multidrug chemotherapy: results of trial ALL-REZ BFM 90.
      ] found no significant difference in 10-year EFS between pediatric patients with ALL in CR2 who underwent any SCT (MRD, MUD, MMRD, mismatched unrelated donor [MMUD], or autologous SCT) vs those who received chemotherapy alone. However, there was a significant improvement in 10-year EFS for those patients who underwent an MRD or MUD allogeneic SCT vs those who underwent an MMRD or MMUD allogeneic SCT or autologous SCT.
      Saarinen-Pihkala et al. [
      • Saarinen-Pihkala U.M.
      • Heilmann C.
      • Winiarski J.
      • et al.
      Pathways through relapses and deaths of children with acute lymphoblastic leukemia: role of allogeneic stem-cell transplantation in Nordic data.
      ] reported a significant improvement in 10-year EFS for pediatric patients with ALL in ≥CR3 who underwent an HLA-MRD or MUD allogeneic SCT vs those who received chemotherapy alone in Nordic Society for Pediatric Hematology and Oncology (NOPHO) trials.
      Einsiedel et al. [
      • Einsiedel H.G.
      • von Stackelberg A.
      • Hartmann R.
      • et al.
      Long-term outcome in children with relapsed ALL by risk-stratified salvage therapy: results of trial acute lymphoblastic leukemia-relapse study of the Berlin-Frankfurt-Münster Group 87.
      ] reported a significant improvement in 15-year EFS in pediatric patients with ALL who experienced a bone marrow relapse after treatment in the ALL-REZ BFM 87 trial and who subsequently underwent an MRD allogeneic SCT vs chemotherapy/radiotherapy in CR2.
      Gaynon et al. [
      • Gaynon P.S.
      • Harris R.E.
      • Altman A.J.
      • et al.
      Bone marrow transplantation versus prolonged intensive chemotherapy for children with acute lymphoblastic leukemia and an initial bone marrow relapse within 12 months of the completion of primary therapy: Children’s Oncology Group study CCG-1941.
      ] reported no significant difference in 5-year DFS among pediatric patients with ALL in CR2 in the COG CCG-1941 trial who underwent an MRD allogeneic BMT or were randomized to receive either an alternative (MUD allogeneic or autologous) BMT or chemotherapy.
      Table 3 also presents 4 high-quality (2++) studies used to make a treatment recommendation in the 2005 pediatric ALL EBR on the use of transplantation vs chemotherapy to treat pediatric patients with ALL in CR2. Barrett et al. [
      • Barrett A.J.
      • Horowitz M.M.
      • Pollock B.H.
      • et al.
      Bone marrow transplants from HLA-identical siblings as compared with chemotherapy for children with acute lymphoblastic leukemia in a second remission.
      ], Wheeler et al. [
      • Wheeler K.
      • Richards S.
      • Bailey C.
      • Chessells J.
      Comparison of bone marrow transplant and chemotherapy for relapsed childhood acute lymphoblastic leukaemia: the MRC UKALL X experience. Medical Research Council Working Party on Childhood Leukaemia.
      ], and Uderzo et al. [
      • Uderzo C.
      • Valsecchi M.G.
      • Bacigalupo A.
      • et al.
      Treatment of childhood acute lymphoblastic leukemia in second remission with allogeneic bone marrow transplantation and chemotherapy: ten-year experience of the Italian Bone Marrow Transplantation Group and the Italian Pediatric Hematology Oncology Association.
      ] reported a significant improvement in 5-year LFS, 4-year EFS, or 5-year DFS, respectively, for patients who underwent allogeneic BMT versus chemotherapy only, whereas Harrison et al. [
      • Harrison G.
      • Richards S.
      • Lawson S.
      • et al.
      Comparison of allogeneic transplant versus chemotherapy for relapsed childhood acute lymphoblastic leukaemia in the MRC UKALL R1 trial. MRC Childhood Leukaemia Working Party.
      ] found no significant difference in 8-year EFS. In addition, a study by Borgmann et al. [
      • Borgmann A.
      • von Stackelberg A.
      • Hartmann R.
      • et al.
      Unrelated donor stem cell transplantation compared with chemotherapy for children with acute lymphoblastic leukemia in a second remission: a matched-pair analysis.
      ], which was not used to make a treatment recommendation in the original EBR, is provided in this update as level 2+ evidence for a treatment recommendation specifically regarding allogeneic SCT versus chemotherapy for T-lineage ALL in CR2. The study reported significantly better 5-year EFS for patients with T-lineage or high-risk precursor-B ALL who underwent an MUD allogeneic BMT compared to those who received chemotherapy only.

      Related versus Unrelated Donor Allogeneic SCT for Pediatric ALL

      Insufficient data resulted in no recommendation regarding the efficacy of related versus unrelated donor allogeneic SCT in the original pediatric ALL EBR. Published since the original pediatric ALL EBR, and briefly summarized below, are 5 studies comparing related versus unrelated donor allogeneic SCT as treatment for pediatric patients with ALL in morphologic CR1 (n = 1 study) or with a majority of patients in ≥ morphologic CR2 or with relapsed disease (n = 4 studies). Table 4 presents a detailed summary of the study designs, patient populations, and outcomes from this new evidence, ranging in quality from 2++ to 2+.
      Table 4Related Versus Unrelated Donor Allogeneic SCT for Pediatric ALL
      Reference and Patient PopulationsQuality/Strength of Evidence
      Quality and strength of evidence definitions are listed in Appendix A, Table 1.
      Treatment RegimenSample SizeAge, Yrs Median (range)Median Duration CR1 (mo)% Ph+% T LineageFollow Up (in months) Median (range)% TRM% EFS/DFS/LFS (95% CI)Signif. EFS/DFS/LFS
      Not significant: P > .05.
      % OS (95% CI)Signif. OS
      Not significant: P > .05.
      Update data published since January 2005
      • Tomblyn M.B.
      • Arora M.
      • Baker K.S.
      • et al.
      Myeloablative hematopoietic cell transplantation for acute lymphoblastic leukemia: analysis of graft sources and long-term outcome.
      Tomblyn 2009
      2++Total24213 (.5-55)NR18%10%69.6 (12-174)2-yr5-yr LFSP = .095-yr OSP = .12
      1990-2005MRD Allo SCT11326%40% (31-49%)42% (33-51%)
      Retrospective, Single CenterMUD Allo SCT1233%42% (14-70%)42% (14-70%)
      ALL in CR1 or CR2PMUD Allo SCT2138%NR38% (18-58%)
      (58% CR2)MMUD Allo SCT4562%27% (14-40%)31% (17-45%)
      62% <18 yrsCord Blood Allo SCT5124%49 (34-64%)51% (46-66%)
      • Smith A.R.
      • Baker K.S.
      • DeFor T.E.
      • Verneris M.R.
      • Wagner J.E.
      • Macmillan M.L.
      Hematopoietic cell transplantation for children with acute lymphoblastic leukemia in second complete remission: similar outcomes in recipients of unrelated marrow and umbilical cord blood versus marrow from HLA-matched sibling donors.
      Smith 2009
      2++Total87(<18)NR1-yr5-yr LFSP = .05NRNR
      1990-2007MSD Allo SCT324.6 (NR)25.213%79 (34-132)9%41% (24-68%)All others vs MMUD
      Prospective, Single CenterMUD/PMUD Allo SCT183.4 (NR)240%112 (41-174)22%57% (35-80%)
      ALL in CR2MMUD Allo SCT165.4 (NR)13.219%94 (84-162)69%19% (5-40%)
      Cord Blood Allo SCT214.2 (NR)26.410%49 (12-94)24%43% (23-63%)
      • Kennedy-Nasser A.A.
      • Bollard C.M.
      • Myers G.D.
      • et al.
      Comparable outcome of alternative donor and matched sibling donor hematopoietic stem cell transplant for children with acute lymphoblastic leukemia in first or second remission using alemtuzumab in a myeloablative conditioning regimen.
      Kennedy-Nasser 2008
      2+Total83NRNR3-yr DFSP = .84NRNR
      1998-2007MSD Allo SCT419.1 (2-20)17%78 (11-127)4.9%72% (55-84%)
      Retrospective, Single CenterAlternative Allo SCT427.8 (.8-19)12%34 (11-79)19.5%62% (45-75%)
      ALL in CR1 or CR2(MUD or MMUD)
      (77% CR2)
      • Muñoz A.
      • Diaz-Heredia C.
      • Diaz M.A.
      • et al.
      Allogeneic hemopoietic stem cell transplantation for childhood acute lymphoblastic leukemia in second complete remission-similar outcomes after matched related and unrelated donor transplant: a study of the Spanish Working Party for Blood and Marrow Transplantation in Children (Getmon).
      Muñoz 2008
      2+Total58NR0%NR5-yr EFSP = .25NRNR
      1999-2004Related donor Allo SCT318 (1-17)54 (24-80)16%43% ± 9%
      Prospective, MulticenterURD Allo SCT279 (3-14)52 (22-85)37%36% ± 9%
      GETMON
      ALL in CR2
      • Sanders J.E.
      • Im H.J.
      • Hoffmeister P.A.
      • et al.
      Allogeneic hematopoietic cell transplantation for infants with acute lymphoblastic leukemia.
      Sanders 2005
      2+Total40.55 (0-.98)NRNRNR84 (12-204)18%DFSP = .03OSP = .02
      1982-2003MSD Allo SCT8Estimates not reportedMSD vs MMRDEstimates not reportedMSD vs MMRD
      Retrospective, Single CenterMMRD Allo SCT16
      ALL in CR1 (43%) orURD Allo SCT16P = .06P = .49
      CR2/3 or relapse (58%)MSD vs URDMSD vs URD
      • Roy A.
      • Bradburn M.
      • Moorman A.V.
      • et al.
      Early response to induction is predictive of survival in childhood Philadelphia chromosome positive acute lymphoblastic leukaemia: results of the Medical Research Council ALL 97 trial.
      Roy 2005
      2+Total27NR100%0%42 (21-84)19%3-yr EFSP = .103-yr OSP = .10
      1997-2002MRD Allo BMT115.1 (1-18)45% (17-71%)45% (17-71%)
      Prospective, MulticenterMUD Allo BMT165.2 (1-18)68% (39-85%)74% (45-89%)
      MRC ALL-97(By actual treatment)
      Ph+ ALL in CR1
      SCT indicates stem cell transplantation; ALL, acute lymphoblastic leukemia; CR, complete remission; Ph+, Philadelphia chromosome positive; TRM, treatment-related mortality; EFS, event-free survival; DFS, disease-free survival; LFS, leukemia-free survival; CI, confidence interval; Signif., significance; OS, overall survival; PMUD, partially mismatched unrelated donor; NR, not reported; MMUD, mismatched unrelated donor; MSD, matched sibling donor; Allo, allogeneic; MUD, matched unrelated donor; GETMON, Spanish Working Party for BMT in Children; URD, unrelated donor; MMRD, mismatched related donor; MRD, matched related donor; BMT, bone marrow transplantation; MRC, Medical Research Council.
      Quality and strength of evidence definitions are listed in Appendix A, Table 1.
      Not significant: P > .05.
      In a single-center retrospective study, Tomblyn et al. [
      • Tomblyn M.B.
      • Arora M.
      • Baker K.S.
      • et al.
      Myeloablative hematopoietic cell transplantation for acute lymphoblastic leukemia: analysis of graft sources and long-term outcome.
      ] reported inferior 5-year DFS and OS for pediatric patients (62% were <18 years) with ALL in CR1 or CR2 who underwent MMUD allogeneic SCT compared to all other donor sources (MRD, MUD, partial mismatched unrelated donor [PMUD] or cord blood), but the differences were not significant.
      Smith et al. [
      • Smith A.R.
      • Baker K.S.
      • DeFor T.E.
      • Verneris M.R.
      • Wagner J.E.
      • Macmillan M.L.
      Hematopoietic cell transplantation for children with acute lymphoblastic leukemia in second complete remission: similar outcomes in recipients of unrelated marrow and umbilical cord blood versus marrow from HLA-matched sibling donors.
      ] reported the results of a single-center study of pediatric patients with ALL in CR2, which compared outcomes after HLA-matched sibling donor allogeneic BMT, HLA-well/PMUD or MMUD allogeneic BMT, and unrelated umbilical cord blood. Five-year LFS was significantly lower in recipients of MMUD allogeneic BMT, but comparable in all other groups.
      Kennedy-Nasser et al. [
      • Kennedy-Nasser A.A.
      • Bollard C.M.
      • Myers G.D.
      • et al.
      Comparable outcome of alternative donor and matched sibling donor hematopoietic stem cell transplant for children with acute lymphoblastic leukemia in first or second remission using alemtuzumab in a myeloablative conditioning regimen.
      ] reported no significant difference in 3-year DFS in pediatric patients with ALL in CR1 (23%) or CR2 (77%) who underwent allogeneic SCT from an HLA-matched sibling donor versus an MUD or MMUD.
      Muñoz et al. [
      • Muñoz A.
      • Diaz-Heredia C.
      • Diaz M.A.
      • et al.
      Allogeneic hemopoietic stem cell transplantation for childhood acute lymphoblastic leukemia in second complete remission-similar outcomes after matched related and unrelated donor transplant: a study of the Spanish Working Party for Blood and Marrow Transplantation in Children (Getmon).
      ] reported comparable 5-year EFS in pediatric patients with ALL in CR2, from the Spanish SHOP-94 and 99 and PETHEMA trials, who underwent an HLA-identical sibling or syngeneic donor allogeneic SCT versus an unrelated donor allogeneic SCT.
      Sanders et al. [
      • Sanders J.E.
      • Im H.J.
      • Hoffmeister P.A.
      • et al.
      Allogeneic hematopoietic cell transplantation for infants with acute lymphoblastic leukemia.
      ] reported a significantly lower DFS and OS among infants (diagnosed at age <1 year) with ALL in CR1, CR2/3, or relapse who underwent a nonsibling related donor allogeneic SCT vs an HLA-matched sibling donor allogeneic SCT at a single center. DFS and OS were also lower in infants who received an unrelated donor allogeneic SCT compared to those who underwent an HLA-matched sibling donor allogeneic SCT, but the difference was not statistically significant.
      Roy et al. [
      • Roy A.
      • Bradburn M.
      • Moorman A.V.
      • et al.
      Early response to induction is predictive of survival in childhood Philadelphia chromosome positive acute lymphoblastic leukaemia: results of the Medical Research Council ALL 97 trial.
      ] reported no significant difference in 3-year EFS or OS between pediatric patients with ALL in CR1 who underwent an MRD versus MUD allogeneic BMT.

      Other Comparative Studies of Allogeneic SCT for Pediatric ALL

      Published since the original pediatric ALL EBR, and briefly summarized below, were 7 comparative studies that investigated the impact of transplantation-related factors, such as allogeneic versus autologous SCT (n = 1 study), donor source (n = 1 study), donor match (n = 2 studies), pre- and/or post-allogeneic SCT imatinib therapy (n = 1 study), and conditioning regimen (n = 2 studies) on survival outcomes in pediatric patients with ALL. Table 5 presents a detailed summary of the study designs, patient populations, and outcomes from this new evidence. The quality ratings of the 5 studies ranged from 2++ to 2−.
      Table 5Other Comparative Studies of Allogeneic SCT for Pediatric ALL
      Reference & Patient PopulationsQuality/Strength of Evidence
      Quality and strength of evidence definitions are listed in Appendix A, Table 1.
      Treatment RegimenSample SizeAge, Yrs Median (range)Median Duration CR1 (mo)% Ph+% T LineageFollow Up (in months) Median (range)% TRM% EFS/DFS/LFS (95% CI)Signif. EFS/DFS/LFS
      Not significant: P > .05.
      % OS (95% CI)Signif. OS
      Not significant: P > .05.
      Update data published since January 2005
      Autologous vs Allogeneic SCT for Pediatric ALL
      • Badell I.
      • Muñoz A.
      • Ortega J.J.
      • et al.
      Long-term outcome of allogeneic or autologous haemopoietic cell transplantation for acute lymphoblastic leukaemia in second remission in children. GETMON experience 1983-1998.
      Badell 2005
      2++Total2198.7 (1-16)NRNR75 (NR)14-yr EFSP =.43NRNR
      1983-1998Donor (Allo SCT)9012%24%39% ± 5%
      Retrospective, MulticenterNo Donor (Auto SCT)12917%7%32% ± 4%
      GETMON
      ALL in CR2
      Maternal vs Paternal Donor in T–Cell-Depleted Haploidentical Allogeneic SCT
      • Stern M.
      • Ruggeri L.
      • Mancusi A.
      • et al.
      Survival after T cell-depleted haploidentical stem cell transplantation is improved using the mother as donor.
      Stern 2008
      2+Total ALL67Overall at SCTNRNRNR40.8 (6-166)5-yr EFSP = .10NRNR
      1993-2006Maternal Donor Allo SCT2419 (2-52)Overall45.8% ± 10%
      Retrospective, 2 CentersPaternal Donor Allo SCT4317 (2-41)13.1% ± 6%
      Total n=118 (ALL/AML)(ALL)
      57% ALL
      Overall, 57% in CR
      Bone Marrow vs Cord Blood Unrelated Donor Transplantation
      • Eapen M.
      • Rubinstein P.
      • Zhang M.J.
      • et al.
      Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukaemia: a comparison study.
      Eapen 2007
      2+Total785NR (<1-15)NRNRNRNR5-yr LFSPNRNR
      1995-2003MUD Allo BMT11660 (8-123)36%Not
      Retrospective, RegistryMMUD Allo BMT16659 (11-121)37%provided;
      CIBMTR, NCBPMUD Allo CBT3545 (3-124)60%results
      Total n = 785 (ALL/AML)1-antigen MMUD CBT LD4456 (12-120)36%reported
      63% ALL – Outcomes1-antigen MMUD CBT HD15740 (3-121)45%as “similar” and “possibly higher for MUD CBT”
      not stratified by disease2-antigen MMUD CBT26744 (3-119)33%
      CR1, ≥ CR2, or relapse
      HLA-Matched vs Mismatch Unrelated Donor Transplantation
      • Afify Z.
      • Hunt L.
      • Green A.
      • Guttridge M.
      • Cornish J.
      • Oakhill A.
      Factors affecting the outcome of stem cell transplantation from unrelated donors for childhood acute lymphoblastic leukemia in third remission.
      Afify 2005
      2−Total35NR (<18)NRNR3%45.6 (3-112)23%3-yr EFSP = .54NRNR
      35% ± 8%
      1990-2002MUD Allo BMT23(Comparison data NR)
      Retrospective, Single enterMMUD Allo BMT12
      ALL in CR3
      Imatinib vs No Imatinib Therapy Pre and/or Post-Allogeneic SCT
      • Burke M.J.
      • Cao Q.
      • Trotz B.
      • et al.
      Allogeneic hematopoietic cell transplantation (allogeneic HCT) for treatment of pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL).
      Burke 2009
      2+Total37MeanNR100%NR23 (1.3-153)3-yr DFSP = .993-yr OSP = .80
      1990-2006Imatinib Group138.3 (2-16)23%62%59%
      Retrospective, Single CenterNo Imatinib Group246.6 (1-14)21%53%58%
      Ph+ ALL in CR1 or CR2
      Comparison of Conditioning Regimens for Allogeneic SCT
      Update data published since January 2005
      • Marks D.I.
      • Forman S.J.
      • Blume K.G.
      • et al.
      A comparison of cyclophosphamide and total body irradiation with etoposide and total body irradiation as conditioning regimens for patients undergoing sibling allografting for acute lymphoblastic leukemia in first or second complete remission.
      Marks 2006
      2+Total502>24 mosNRCR15-yr LFS CR1P = NS5-yr OS CR1P = NS
      1989-1998Cy + TBI <13 Gy21718 (1-56)55%19%67 (8-156)13%54% (45-63%)54% (46-64%)
      Retrospective, MulticenterCy + TBI ≥13 Gy8116 (2-46)68%20%59 (17-149)19%51% (35-68%)60% (44-75%)
      CIBMTR and COH Cancer CenterVP16 + TBI <13 Gy5312 (2-41)46%19%52 (7-144)27%57% (36-77%)61% (41-80%)
      VP16 + TBI ≥13 Gy15125 (4-54)56%20%65 (3-156)12%61% (51-70%)62% (52-71%)
      ALL in CR1 or CR2
      CR25-yr LFS CR2P = .0075-yr OS CR2P = .02
      Cy + TBI <13 Gy20%33% (24-43%)VP16 + TBI vs40% (30-51%)VP16 + TBI vs
      Cy + TBI ≥13 Gy20%62% (46-76%)Cy + <13 Gy72% (58-84%)
      VP16 + TBI <13 Gy10%54% (35-73%)P = .00156% (36-75%)Cy + <13 Gy
      VP16 + TBI ≥13 Gy12%50% (35-65%)Cy + ≥13 Gy vs50% (35-65%)P = .001
      Cy + ≥13 Gy vs
      Cy + <13 Gy
      Cy + <13 Gy
      • Gassas A.
      • Sung L.
      • Saunders E.F.
      • Doyle J.J.
      Comparative outcome of hematopoietic stem cell transplantation for pediatric acute lymphoblastic leukemia following cyclophosphamide and total body irradiation or VP16 and total body irradiation conditioning regimens.
      Gassas 2006
      2+Total107NRNRNR3-yr EFSP = NS3-yr OSP = NS
      1990-2003Cy + fTBI (1200 cGy)458.7 (1-18)16%16%51% ± 8%53% ± 8%
      Retrospective, Single CenterVP16 + fTBI (1200 cGy)629.4 (.8-18)15%21%47% ± 7%55% ± 7%
      ALL any disease status
      Original Pediatric ALL EBR data
      • Bunin N.
      • Aplenc R.
      • Kamani N.
      • Shaw K.
      • Cnaan A.
      • Simms S.
      Randomized trial of busulfan vs total body irradiation containing conditioning regimens for children with acute lymphoblastic leukemia: a Pediatric Blood and Marrow Transplant Consortium study.
      Bunin 2003
      1+Total438.7 (.7-20)NR16%9%43.3 (13-64)3-yr EFSP = .033-yr OSP = .09
      1997-2000Cy + VP16 + TBI229%58%67%
      Prospective, MulticenterCy + VP16 + Oral Bu2129%29%47%
      PBMTC, Randomized
      ALL any disease status
      • Davies S.M.
      • Ramsay N.K.
      • Klein J.P.
      • et al.
      Comparison of preparative regimens in transplants for children with acute lymphoblastic leukemia.
      Davies 2000
      2++Total62737 (NR)3-yr LFSP = .0053-yr OSP = .003
      1988-1995Cy + TBI45112.9 (.7-20)194%21%15%50% (45-55%)55% (50-60%)
      Retrospective, MulticenterCy + Bu17611.3 (.7-20)233%13%23%35% (28-43%)40% (32-48%)
      IBMTR
      ALL any disease status
      • Weisdorf D.J.
      • Woods W.G.
      • Nesbit Jr., M.E.
      • et al.
      Allogeneic bone marrow transplantation for acute lymphoblastic leukaemia: risk factors and clinical outcome.
      Weisdorf 1994
      2++Total12314 (1-61)NRNRNR93.6 (NR)5-yr DFSP = NSOverall OS 34%NR
      1979-1991Cy + TBI8017%29%
      Retrospective, Single CenterCy + fTBI2817%32%
      Majority in CR2 (87)Cytarabine + TBI1563%27%
      75% <20 yrs
      SCT indicates stem cell transplantation; ALL, acute lymphoblastic leukemia; CR, complete remission; Ph+, Philadelphia chromosome positive; TRM, treatment-related mortality; EFS, event-free survival; DFS, disease-free survival; LFS, leukemia-free survival; CI, confidence interval; Signif., significance; OS, overall survival; NR, not reported; Allo, allogeneic; Auto, autologous; GETMON, Spanish Working Party for BMT in Children; AML, acute myeloid leukemia; MUD, matched unrelated donor; BMT, bone marrow transplantation; MMUD, mismatched unrelated donor; CIBMTR, Center for International Blood and Marrow Transplant Research; NCBP, National Cord Blood Program; CBT, cord blood transplantation; LD, low cell dose; HD, high cell dose; Cy, cyclophosphamide; TBI, total body irradiation; COH, City of Hope; EBR, evidence-based review; Bu, busulfan; PBMTC, Pediatric Blood and Marrow Transplant Consortium; IBMTR, International Bone Marrow Transplant Research; NS, not significant; fTBI, fractionated total body irradiation.
      Quality and strength of evidence definitions are listed in Appendix A, Table 1.
      Not significant: P > .05.

       Allogeneic versus Autologous SCT for Pediatric Patients with ALL

      There was one study published since the original pediatric ALL EBR, which specifically compared the use of allogeneic versus autologous SCT for pediatric patients with ALL. A retrospective analysis by Badell et al. [
      • Badell I.
      • Muñoz A.
      • Ortega J.J.
      • et al.
      Long-term outcome of allogeneic or autologous haemopoietic cell transplantation for acute lymphoblastic leukaemia in second remission in children. GETMON experience 1983-1998.
      ] found no significant difference in 14-year EFS in pediatric patients with ALL in CR2 who underwent an allogeneic or autologous SCT depending on the availability of an HLA-matched sibling donor.
      The quality ratings for the 8 studies comparing autologous versus allogeneic SCT in the original pediatric ALL EBR ranged from 2+ to 2−, and no recommendation was made based on a lack of evidence. There-fore, the original EBR studies of autologous versus allogeneic SCT are not presented in detail in this update.

       Maternal versus Paternal Donor in T Cell-Depleted Allogeneic SCT

      In a retrospective analysis, Stern et al. [
      • Stern M.
      • Ruggeri L.
      • Mancusi A.
      • et al.
      Survival after T cell-depleted haploidentical stem cell transplantation is improved using the mother as donor.
      ] reported better 5-year EFS in pediatric/young adult patients with ALL from 2 centers who underwent a T cell-depleted, haploidentical allogeneic SCT from the mother versus the father, but the difference was not statistically significant. There were no data in the original EBR on this topic.

       Bone Marrow versus Cord Blood Unrelated Donor Transplantation

      There was one study published since the original pediatric ALL EBR, which compared the impact of bone marrow versus cord blood unrelated donor transplantation for pediatric ALL. A retrospective CIBMTR and National Cord Blood Program registry study by Eapen et al. [
      • Eapen M.
      • Rubinstein P.
      • Zhang M.J.
      • et al.
      Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukaemia: a comparison study.
      ] reported similar outcomes in 5-year LFS among pediatric patients with ALL (63%) or acute myelogenous leukemia (AML) who underwent an MUD or MMUD allogeneic BMT versus an HLA-matched or 1 or 2-antigen mismatched unrelated cord blood transplant.

       Matched versus Mismatched Unrelated Donor Transplantation

      There was one study published since the original pediatric ALL EBR, which compared the impact of MUD versus MMUD allogeneic SCT for pediatric ALL. A retrospective analysis by Afify et al. [
      • Afify Z.
      • Hunt L.
      • Green A.
      • Guttridge M.
      • Cornish J.
      • Oakhill A.
      Factors affecting the outcome of stem cell transplantation from unrelated donors for childhood acute lymphoblastic leukemia in third remission.
      ] reported no significant difference in 3-year EFS between pediatric patients with ALL in CR3 who underwent an MUD versus MMUD allogeneic SCT at a single center in the United Kingdom. There were no data in the original EBR on this topic.

       Imatinib versus No Imatinib Therapy Pre- and/or Post-Allogeneic SCT

      Burke et al. [
      • Burke M.J.
      • Cao Q.
      • Trotz B.
      • et al.
      Allogeneic hematopoietic cell transplantation (allogeneic HCT) for treatment of pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL).
      ] reported a single-center study showing no significant difference in the 3-year DFS or OS between pediatric patients with Ph+ ALL in CR1 or CR2 who received imatinib pre and/or post-myeloablative allogeneic SCT versus those who did not receive any imatinib therapy. There were no data in the original EBR on this topic.

       Comparison of Conditioning Regimens for Allogeneic SCT

      Marks et al. [
      • Marks D.I.
      • Forman S.J.
      • Blume K.G.
      • et al.
      A comparison of cyclophosphamide and total body irradiation with etoposide and total body irradiation as conditioning regimens for patients undergoing sibling allografting for acute lymphoblastic leukemia in first or second complete remission.
      ] compared the outcomes of patients (1-56 years) who underwent HLA-identical sibling donor allogeneic peripheral blood stem cell transplantation (PBSCT) or BMT for ALL in CR1 or CR2 after conditioning with cyclophosphamide (Cy) + TBI (<13 Gy or ≥13 Gy) versus etoposide (VP16) + TBI (<13 Gy or ≥13 Gy). Although not all patients were pediatric, the median age for 3 of the 4 treatment groups was ≤18 years. For patients in CR1, there were no significant differences in 5-year LFS or OS by conditioning regimen. For patients in CR2, 5-year LFS and OS were significantly improved with the etoposide-based regimen or with TBI doses ≥13 Gy. Transplant-related mortality (TRM) did not differ by conditioning regimen for either disease status.
      Gassas et al. [
      • Gassas A.
      • Sung L.
      • Saunders E.F.
      • Doyle J.J.
      Comparative outcome of hematopoietic stem cell transplantation for pediatric acute lymphoblastic leukemia following cyclophosphamide and total body irradiation or VP16 and total body irradiation conditioning regimens.
      ] reported no significant differences by conditioning regimen in 3-year EFS, OS, or TRM for pediatric patients with ALL (majority in CR2/3) from a single center who underwent either MRD or MUD allogeneic SCT after conditioning with Cy + TBI (1200 cGy in 6 fractions) versus VP16 + TBI (1200 cGy in 6 fractions).
      There were 3 high-quality studies (1+ to 2++) that were used to make a treatment recommendation regarding conditioning regimens in the original pediatric ALL EBR. A randomized trial by Bunin et al. [
      • Bunin N.
      • Aplenc R.
      • Kamani N.
      • Shaw K.
      • Cnaan A.
      • Simms S.
      Randomized trial of busulfan vs total body irradiation containing conditioning regimens for children with acute lymphoblastic leukemia: a Pediatric Blood and Marrow Transplant Consortium study.
      ] reported a significant improvement in 3-year EFS and TRM, but not OS, in pediatric patients with ALL who received Cy + VP16 + TBI versus those who received Cy + VP16 + busulfan (Bu) as conditioning before allogeneic SCT. Davies et al. [
      • Davies S.M.
      • Ramsay N.K.
      • Klein J.P.
      • et al.
      Comparison of preparative regimens in transplants for children with acute lymphoblastic leukemia.
      ] reported significantly better 3-year LFS and OS in pediatric patients with ALL who received Cy + TBI versus Cy + Bu as conditioning before allogeneic BMT. In a single-center study by Weisdorf et al. [
      • Weisdorf D.J.
      • Woods W.G.
      • Nesbit Jr., M.E.
      • et al.
      Allogeneic bone marrow transplantation for acute lymphoblastic leukaemia: risk factors and clinical outcome.
      ], no significant difference was reported in 5-year DFS among pediatric patients with ALL who received Cy + TBI, Cy + fractionated TBI, or cytarabine + TBI as conditioning before allogeneic BMT.

      Noncomparative Studies of Transplant for Pediatric ALL

      There were 14 noncomparative cohort studies [
      • Balduzzi A.
      • Bonanomi S.
      • Valsecchi M.G.
      • et al.
      Autologous purified peripheral blood SCT in childhood low-risk relapsed ALL.
      ,
      • Diaz M.A.
      • Gonzalez-Vicent M.
      • Gonzalez M.E.
      • et al.
      Long-term outcome of allogeneic PBSC transplantation in pediatric patients with hematological malignancies: a report of the Spanish Working Party for Blood and Marrow Transplantation in Children (GETMON) and the Spanish Group for Allogeneic Peripheral Blood Transplantation (GETH).
      ,
      • Diaz M.A.
      • Gonzalez-Vicent M.
      • Ramirez M.
      • et al.
      Allogeneic cord blood transplantation in children with hematological malignancies: a long-term follow-up single-center study.
      ,
      • Elorza I.
      • Palacio C.
      • Dapena J.L.
      • Gallur L.
      • Sánchez de Toledo J.
      • Díaz de Heredia C.
      Relationship between minimal residual disease measured by multiparametric flow cytometry prior to allogeneic hematopoietic stem cell transplantation and outcome in children with acute lymphoblastic leukemia.
      ,
      • Iori A.P.
      • Arcese W.
      • Milano F.
      • et al.
      Unrelated cord blood transplant in children with high-risk acute lymphoblastic leukemia: a long-term follow-up.
      ,
      • Klingebiel T.
      • Cornish J.
      • Labopin M.
      • et al.
      Results and factors influencing outcome after fully haploidentical hematopoietic stem cell transplantation in children with very high-risk acute lymphoblastic leukemia: impact of center size: an analysis on behalf of the Acute Leukemia and Pediatric Disease Working Parties of the European Blood and Marrow Transplant group.
      ,
      • Petterson T.E.
      • Gabriel M.
      • Tiedemann K.
      • et al.
      Outcome following unrelated cord blood transplant in 136 patients with malignant and non-malignant diseases: a report from the Australian and New Zealand children’s haematology and oncology group.
      ,
      • Satwani P.
      • Sather H.
      • Ozkaynak F.
      • et al.
      Allogeneic bone marrow transplantation in first remission for children with ultra-high-risk features of acute lymphoblasticleukemia: a Children’s Oncology Group Study report.
      ,
      • Sawczyn K.K.
      • Quinones R.
      • Malcolm J.
      • et al.
      Cord blood transplant in childhood ALL.
      ,
      • Schechter T.
      • Ishaqi K.M.
      • Rojas M.
      • Irina Z.
      • Doyle J.J.
      • Gassas A.
      Outcome of hematopoietic stem cell transplantation of children with very high risk acute lymphoblastic leukemia in first complete remission.
      ,
      • Talano J.M.
      • Casper J.T.
      • Camitta B.M.
      • et al.
      Alternative donor bone marrow transplant for children with Philadelphia chromosome ALL.
      ,
      • Teuffel O.
      • Schrauder A.
      • Sykora K.W.
      • et al.
      The impact of cyclosporin A on acute graft-versus-host disease after allogeneic bone marrow transplantation in children and adolescents with acute lymphoblastic leukemia.
      ,
      • Verneris M.R.
      • Eapen M.
      • Duerst R.
      • et al.
      Reduced-intensity conditioning regimens for allogeneic transplantation in children with acute lymphoblastic leukemia.
      ,
      • Watanabe N.
      • Matsumoto K.
      • Yoshimi A.
      • et al.
      Outcome of bone marrow transplantation from HLA-identical sibling donor in children with hematological malignancies using methotrexate alone as prophylaxis for graft-versus-host disease.
      ] published since the original EBR, which examined the use of SCT as therapy for pediatric ALL. The design, methodology, and outcomes data from these noncomparative studies are summarized in Appendix B (online only). The studies represent nonrandomized single or multi-institutional experiences with various transplantation techniques or retrospective analyses of transplantation registry data. The quality of the noncomparative allogeneic SCT studies ranged from 2++ to 2+; the quality of the autologous SCT study was 2+. Collectively, the outcomes data from these studies contribute to the overall understanding of the effectiveness of various transplantation techniques for the treatment of pediatric ALL.

      Areas of Needed Research and Ongoing Studies

      After reviewing the updated evidence on the use of SCT for pediatric ALL, the expert panel identified the following important areas of needed research:
      • 1.
        Reevaluate allogeneic SCT versus intensive chemotherapy regimens in the current era, as both approaches have changed. Comparative studies should be performed using methodology that avoids bias.
      • 2.
        Investigate the role and potential benefit of maternal antigen microchimerism to reduce the risk of graft-versus-host disease and enhance the graft-versus-leukemia effect after allogeneic BMT.
      • 3.
        Identify and address the treatment of high-risk T-lineage ALL subsets.
      • 4.
        Reevaluate the promising early studies of imatinib in combination with chemotherapy or SCT for Ph+ ALL in larger studies.
      • 5.
        Investigate the optimal treatment for patients who are persistently positive for minimal residual disease.
      • 6.
        Improve the detection and monitoring of MRD during initial treatment to guide individual patient eligibility and timing of allogeneic SCT.
      • 7.
        Monitoring MRD after SCT to detect early post-SCT relapse in need of preemptive therapy.
      • 8.
        Investigate the indications for using reduced intensity versus myeloablative conditioning regimens for allogeneic SCT.
      • 9.
        Determine conditioning regimens that reduce or eliminate the need for TBI while maintaining effectiveness for ALL.
      • 10.
        Investigate the prognostic role of initial risk classification (NCI SR/HR assignment) on outcomes after relapse.
      • 11.
        Investigate whether allogeneic SCT performed in CR1 patients identified as very high risk for relapse by molecular methods (ie, specific gene mutations, gene expression profiles, etc.) improves outcome compared to chemotherapy.
      • 12.
        Investigate the impact of psychosocial support and shared decision-making models to assist families in weighing the risks versus benefits of SCT for their children with ALL.

       Ongoing Studies

      There are new trials and ongoing studies on the treatment of pediatric ALL that are accruing patients, maturing follow-up, or that have been published in abstract form. These studies were not used as evidence for the review or for making treatment recommendations. This section is provided for the reader’s information only.
      Rives et al. [
      • Rives S.
      • Estella J.
      • Camós M.
      • et al.
      Intermediate dose of imatinib in combination with chemotherapy followed by allogeneic stem cell transplantation (SCT) improves early outcome in childhood Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Results of the Spanish Cooperative Group SHOP/SEHOP studies SHOP 94, SHOP 99 and SHOP 05.
      ] described the results of the Spanish Cooperative Group SHOP/SEHOP studies, which investigated intermediate dose imatinib given in combination with intensive chemotherapy (SHOP 05) compared to no imatinib use (SHOP 94/99), followed by allogeneic SCT for patients with Ph+ ALL in CR1. This study addresses Area of Needed Research #4. Median follow-up for the SHOP 94/99 and SHOP 05 trials was 113 and 30 months, respectively. The clinical outcomes of interest were EFS and OS at 30 months.
      Although not intended to guide patient eligibility or timing of allogeneic SCT, a retrospective study by Ruggeri et al. [
      • Ruggeri A.
      • Michel G.
      • Dalle J.-H.
      • et al.
      Impact of minimal residual disease at unrelated cord blood transplantation in children with acute lymphoblastic leukemia in remission: a study on behalf of Eurocord-EBMT and EBMT-PDWP.
      ] on behalf of the Eurocord-EBMT and EBMT-PDWP investigated the prognostic significance of being MRD positive or negative before unrelated cord blood transplantation after a myeloablative conditioning regimen. This study addresses Area of Needed Research #6. Of 316 children and adolescents with ALL in ≥CR1, 170 had MRD assessments; 74 positive and 96 negative. The median follow-up was 46 months (4-104 months), and the clinical outcomes of interest were 4-year LFS, non-relapse mortality and relapse.
      Following are several ongoing pediatric ALL studies that do not relate specifically to any of the areas of needed research suggested by the expert panel.

       Myeloablative Related versus Unrelated SCT for Relapsed ALL

      Tracey et al. [
      • Tracey J.
      • Zhang M.-J.
      • Sobocinski K.A.
      • et al.
      Transplant conditioning regimens and outcomes after allogeneic hematopoietic cell transplantation (HCT) in children and adolescents with acute lymphoblastic leukemia (ALL).
      ] examined the impact of conditioning regimen and donor source on outcomes in children and adolescents with ALL in ≥CR2 (90%) or active relapse (10%). TBI dosing (<13 Gy versus ≥13 Gy) or the addition of etoposide to a TBI + Cy regimen was examined in 765 children who received either an HLA-matched sibling (n = 160) or unrelated donor (n = 605) SCT.

       Cord Blood Transplantation

      A clinical trial (NCT00861679) sponsored by the Hadassah Medical Organization is currently accruing patients ≤18 years with ALL to compare HLA-matched sibling or other matched donor versus HLA-mismatched family or unrelated donor cord blood transplantation versus a historical control of chemotherapy only. The estimated enrollment is 552 patients, and the primary outcomes of interest are EFS and OS.
      A phase III, randomized, prospective clinical trial (NCT00412360) sponsored by the National Heart, Lung, and Blood Institute, in collaboration with the Blood and Marrow Transplant Clinical Trials Network and National Cancer Institute, compares single versus double cord transplantation for patients 1 to 21 years of age with high-risk leukemia, including ALL, or myelodysplasia. The estimated enrollment is 220 patients, and the primary outcomes of interest are 1-year OS and TRM.

       Intensive Chemotherapy and Early SCT for MLL

      Koh et al. [
      • Koh K.
      • Tomizawa D.
      • Saito A.M.
      • et al.
      Early phase administration of hematopoietic stem cell transplantation to prevent early relapse for infants with acute lymphoblastic leukemia and MLL gene rearrangement; a report from the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) Trial MLL03.
      ] reported the results of a Japanese Pediatric Leukemia/Lymphoma Study Group multicenter, nonrandomized trial (MLL03) of infants <12 months with ALL + MLL gene rearrangement to test the efficacy of intensive chemotherapy followed by SCT ≤4 months after achieving CR1. Conditioning regimen was Bu and Cy. Of 63 registered patients, 49 achieved CR1, and 44 underwent SCT from unrelated cord blood (n = 32) or a related donor (n = 11; 1 unknown).

      Strengths/Limitations and Discussion

      The strengths of this updated systematic evidence-based review are the details about each study’s design and outcomes conveyed in the summary tables for each major section, and the treatment recommendations made by the pediatric ALL expert panel. The reader is directed to Appendix A, which describes the methodology of this systematic evidence-based review. Of note, the treatment recommendations are reached by consensus of the expert panel based on the evidence included in the tables of this review. A different panel constitution (as well as the reader) may yield a different treatment recommendation, especially in areas with little or no data. Hence, the data are presented in an objective, nonjudgmental format with enough detail so the reader can assess the value of the evidence and the treatment recommendations.
      A limitation of this review is the exclusion of non-peer-reviewed data. Many studies with negative findings go unpublished or are published as non-peer-reviewed abstracts, while those with positive findings are published as full research articles, which can lead to publication bias. However, the inclusion of high-quality, peer-reviewed, publicly available data was of paramount importance for this review. Except in the Ongoing Studies section, data published in abstract form were not included in this review due to the inadequate details of study design or patient characteristics, making a true assessment of the widespread applicability or impact of the treatment outside the scope of the trial difficult.
      The quality of this systematic EBR is affected by treatment modalities, which vary over time. Chemotherapy regimens, HLA typing techniques, novel pre and post-SCT biologic and TKI therapies, and post-SCT supportive care change considerably over the course of these reviews and updates. The clinical research process is lengthy, making data from many of these studies outmoded by the time of publication. Much of the newly presented data may not reflect current practice or represents preliminary results from small studies, stressing the need for faster conduct of well-designed studies, shorter accrual times, and swift analysis and publication of research. In addition, the lengthy process of conducting and reporting clinical research emphasizes the need to identify surrogate endpoints or molecular markers that are predictive of long-term survival in pediatric patients with ALL. Further delineation of clinical risk factors may facilitate appropriate selection of patients with ALL for SCT.
      Comparative studies of chemotherapy and SCT are very difficult to conduct and interpret. Many studies with randomized designs have failed to meet accrual objectives or failed to deliver therapy as intended, resulting in special issues that should be considered when comparing chemotherapy with SCT. These issues include the following:
      • Analyses should be either from attainment of CR or only include those who attain CR. Include only patients who received a transplantation who were in remission and chemotherapy patients who maintain remission until median time to SCT.
      • High-risk groups should be analyzed separately. If a risk factor (eg, MLL) means poor prognosis in one group (eg, infants <6 months with high WBC) and prognosis above 60% in other groups (eg, older infants and children with ALL), any beneficial effect of one treatment group over another is masked if high and low-risk patients are pooled. Meta-analysis of individual patient level data should be considered if specific studies are of insufficient size to answer the subgroup questions.
      • Appropriate statistical methods, explicit study definitions, and clear exclusion/inclusion criteria should be used and reported. It is essential that studies also report hematopoietic cell source, the approach, timing and eligibility for SCT, and the preparatory and conditioning regimens used.
      • Era-appropriate, high-quality chemotherapy should be used in the chemotherapy cohort.
      Despite, and due to these challenges, it is of utmost importance that children with ALL be enrolled in ongoing clinical studies to better understand the role of SCT in their therapy. The decision to utilize SCT in children with ALL should be made by the patient (when possible), the family/guardians, and an interdisciplinary team of providers with full consideration of both the clinical and psychosocial risks versus benefits involved, including possible late and long-term effects of treatment. Shared decision-making models (in which both the provider and the patient/family share their views of uncertainty, their own risk/benefit consideration, and their expectations of outcome), should be considered in clinical trial enrollment strategies and follow-up plans, along with short and long-term psychosocial assessment and support for the patient and family.

      Acknowledgments

      Financial disclosure: Major funding for this study was provided by the National Marrow Donor Program . The authors declare no financial conflicts of interest. The American Society for Blood and Marrow Transplantation and Drs. Hahn and McCarthy are indebted to the members of the pediatric ALL EBR Update Expert Panel and the ASBMT Evidence-Based Review Steering Committee, who voluntarily and enthusiastically participated in this endeavor. The authors of this pediatric ALL EBR Update and the American Society for Blood and Marrow Transplantation thank the National Marrow Donor Program, and especially Jeffrey Chell, MD, and Michael Boo for their support of this project. The authors acknowledge C. Fred LeMaistre, MD, for pioneering and supporting this effort and Thomas Joseph, MPS, CAE, for his invaluable administrative assistance. The authors are grateful to all the patients who participated in the clinical trials that led to the evidence upon which this EBR update is based.

      Supplementary Data

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      Linked Article

      • Erratum
        Biology of Blood and Marrow TransplantationVol. 18Issue 9
        • In Brief
          In “The Role of Cytotoxic Therapy with Hematopoietic Stem Cell Transplantation in the Treatment of Pediatric Acute Lymphoblastic Leukemia: Update of the 2005 Evidence-Based Review” [Hahn et al., Biol Blood Marrow Transplant 2012:18:505-522] in the abstract, the acronym “MRD” in the second to the last sentence should be expanded to “minimal residual disease” to read “Based on expert opinion, allogeneic SCT may be considered for hypodiploid ALL and persistent minimal residual disease (MRD) positivity in ALL in CR1 or greater, although these are areas that need further study.”
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