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Allogeneic, but not autologous, hematopoietic cell transplantation improves survival only among younger adults with acute lymphoblastic leukemia in first remission: an individual patient data meta-analysis

Vikas Gupta, Sue Richards and Jacob Rowe on behalf of the Acute Leukemia Stem Cell Transplantation Trialists' Collaborative Group

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Tables

  • Table 1

    Trial descriptions

    Trial ID; paper (P) or abstract (A)Start yearEligibilityStem cell sourceNo of courses pre-HCTPost-HCT maintenance
    Trials comparing autograft versus chemotherapy
        Trials with data
            P EORTC ALL-3/06861111986Age 15-50 y ALL or lymphoblastic NHLBM2No
            P UKALLXII/E2993141993Age 15-65 y (initially 60); not t(9;22); in CR after 2 inductionsBM or PB3No
            P PETHEMA ALL-93151993Age 30-50 y; one of: WBC > 25, t(9;22), t(4;11), 11q23, t(1;19)BM or PB4No
            P LALA-94161994Age 15-60 y; one of: WBC > 30, t(9;22), t(4;11), t(1;19), 11q23, CNS disease, no CR after 1 induction, myeloid markersPB3-4Yes
            A EORTC ALL-4/06951171996Not t(9;22); age 20-60 y or 15-19 y with one of: WBC > 30, CNS disease, no CR after 1 induction; ALL or lymphoblastic NHLPB3-4Yes
        Trials with no data available
            P LALA-85101985Age 15-50 yBM2No
            P LALA-87121987Age 15-50 yBM2No
            P Italian 1987 (n = 29)131989Age 12-60 yBM2No
    Trial ID; paper (P) or abstract (A)Start year/median follow-upEligibility for HCTConditioningGVHD prophylaxisNo of courses pre-HCTChemo arm
    Trials comparing donor versus no donor receiving chemotherapy
        Trials with data
            A UKALLXA211985WBC ≥ 50; CNS disease; late remission; t(9;22),t(1;19), or t(4;11)Center choiceCenter choice2induction + 2 intensification + maintenance to 108w
            P PMH 92231992Age 16-54 yTBI + cyclophosphamidemethotrexate + cyclosporin + prednisolone3-5induction + consolidation + intensification + maintenance to 2y
            P JALSG-ALL93241993Age < 40 yNSNS2induction + 3 consolidation + 4 intensification + maintenance to 57w
            P GRAALL 2003252003Age ≤ 55 y; B cells and WBC ≥ 30; CNS disease; t(4;11), t(1;19), MLL-AF4, or E2A-PBX1 fusion transcript; low hypodiploidy, near triploidy, or poor response.TBI + cyclophosphamidemethotrexate + cyclosporin4 or 7induction + 9 consolidation + intensification + maintenance for 2y.
        Trials with no data available
            P MD Anderson (n = 66)191980High riskTBI + piperazinedionemethotrexate/T-cell depletion/cyclosporin2induction + consolidation + intensification + maintenance for 18m
            Zagreb 83-88201983Age 15-44 yTBI + cyclophosphamide/busulfan + cyclophosphamidecyclosporin + methotrexate2induction + consolidation + (4 consolidation or 1 intense) + maintenance to 4y
            A City of Hope (n = 105)221989Age < 50 yTBI + VP16 + cyclophosphamidemethotrexate + prednisolone + cyclosporin1-2induction + 9 consolidation + intensification + maintenance to 30m
    Trials comparing donor versus no donor receiving autograft
        Trials with dataPre-allo or autoPost automaintenance?
            P HOVON 18 ALL271992Age 15-50 yTBI + cyclophosphamideT-cell depletion of graft and cyclosporin3No
            P GOELAL02281994Age 15-50 y; one of: age > 35 y, B-ALL, WBC > 30, t(9;22), t(4;11), t(1;19), no CR after 1 inductionTBI + VP16 + cyclophosphamideNS3No
            P NILG ALL08/96291996B-lineage; one of:t(9;22), t(4;11), CD10 blasts ≥ 10 × 109/LNS melphalan + TBI for autoNS≥ 1 (4 for auto, which was purged)No
            P HOVON 37 ALL271999Age 16-55 yTBI + cyclophosphamideT-cell depletion of graft and cyclosporin3Yes (daily 6 MP and weekly methotrexate for a maximum of 1 y vs no maintenance)
        Trials with no data available
            P BGMT 1990 (n = 120)261990Age 15-55 yTBI + cyclophosphamidemethotrexate + cyclosporin3IL2 (randomized)
    Trials comparing donor versus no donor receiving chemotherapy or autograft
        Trials with dataPre-alloChemo arm
            P EORTC ALL-3 /06861111986Age 15-50 y; ALL or lymphoblastic NHLTBI + cyclophosphamidemethotrexate + cyclosporin/T-cell depletion2-3induction + consolidation + 6 intensification + maintenance to 3 y
            P UKALLXII/ECOG E2993141993Age 15-55 y (initially 50 y); not t(9;22); in CR after 2 inductionsTBI + VP16methotrexate + cyclosporin/T-cell depletion32 induction + Intensification + 4 consolidation + maintenance to 98 wk
            P PETHEMA ALL-93151993Age 30-50 y; one of: WBC > 25, t(9;22), t(4;11), 11q23, t(1;19)TBI + cyclophosphamidemethotrexate + cyclosporin4induction + 6 intensification + maintenance to 2 y
            P LALA-9416*1994Age 15-50 y; one of: WBC > 30, t(9;22), t(4;11), t(1;19), 11q23, CNS disease, no CR after 1 induction, myeloid markersTBI + cyclophosphamidemethotrexate + cyclosporin/cyclosporin alone2induction + consolidation + maintenance with intensive blocks for 2 y
            A EORTC ALL-4171995Age 15-50 y; one of: WBC > 30, t(9;22), t(4;11), t(1;19), 11q23, CNS disease, no CR after 1 induction, myeloid markersTBI + cyclophosphamidemethotrexate + cyclosporin/cyclosporin alone2induction + consolidation + maintenance with intensive blocks for 2 y
        Trials with no data available
            P LALA-85101985Age 15-40 y (50 y for auto)TBI + cyclophosphamidemethotrexate + cyclosporin/cyclosporin alone1induction + 3 consolidation + maintenance for 80 wk
            P LALA-87181987Age 15-40 yTBI + cyclophosphamidemethotrexate + cyclosporin/cyclosporin alone1induction + 3 consolidation + maintenance for 80 wk
            P Italian 1987 (n = 45)131987Age 12-60 yNSNS2induction + 2 intensification
    • NS indicates nonspecified; and TBI, total body irradiation.

    • * LALA-94 had 4 risk groups, in 3 of which HCT was recommended. Group 2 received sibling allograft or were randomized between autograft or chemotherapy; groups 3 and 4 received allograft or autograft, with matched unrelated allografts allowed.

  • Table 2

    Patient and disease characteristics and length of follow-up in randomized autograft versus chemotherapy trials

    TrialNSexAge, yWBCImmunophenotypePh+Median follow-up, yLost to follow-up < 5 y
    MF< 2525-3435-44≥ 45< 3030-99≥ 100BTOtherYesNo
    EORTC ALL-3/06861114532 (71%)13 (29%)16 (36%)13 (29%)10 (22%)6 (13%)26 (58%)10 (22%)9 (20%)26 (65%)9 (23%)5 (13%)2 (10%)18 (90%)9.42 (4%)
    UKALLXII/E299314457284 (62%)173 (38%)159 (35%)110 (24%)89 (19%)99 (22%)320 (70%)84 (19%)50 (11%)333 (76%)99 (23%)6 (1%)16 (4%)385 (96%)8.434 (7%)
    PETHEMA ALL-93159857 (58%)41 (42%)46 (47%)26 (27%)17 (17%)9 (9%)58 (59%)21 (21%)19 (19%)69 (70%)29 (30%)0 (0%)14 (15%)78 (85%)5.618 (18%)
    LALA-9416152101 (66%)51 (34%)56 (37%)25 (16%)35 (23%)36 (24%)89 (59%)34 (22%)29 (19%)103 (79%)26 (20%)1 (1%)0 (0%)107 (100%)6.216 (11%)
    EORTC ALL-4/06951177747 (61%)30 (39%)33 (43%)15 (19%)14 (18%)15 (19%)49 (64%)16 (21%)12 (16%)39 (51%)33 (43%)5 (6%)0 (0%)40 (100%)7.29 (12%)
    Autograft429269 (63%)160 (37%)159 (37%)108 (25%)80 (19%)82 (19%)277 (65%)87 (20%)64 (15%)282 (69%)115 (28%)10 (2%)17 (5%)329 (95%)7.737 (9%)
    Chemotherapy400252 (63%)148 (37%)151 (38%)81 (20%)85 (21%)83 (21%)265 (67%)78 (20%)55 (14%)288 (77%)81 (21%)7 (2%)15 (5%)299 (95%)7.642 (10%)
  • Table 3

    First remission treatment received by donor availability and randomized allocation

    TrialDonorNo donor
    Sibling donor HCTAutograftChemotherapyOtherAuto-graftChemotherapyOther
    Donor versus no donor (chemo)
        MRC UKALLXA2135 (74%)12 (26%)33 (38%)54 (62%)
        PMH 922324 (71%)10 (29%)36 (100%)
        JALSG-ALL932422 (69%)10 (31%)5 (5%)75 (77%)17 (18%)
        GRAALL 20032538 (86%)6 (14%)60 (68%)28 (32%)
    Donor v no donor (auto)
        HOVON 18 ALL2732 (89%)1 (3%)2 (6%)1 (3%)49 (84%)5 (9%)4 (7%)
        GOELAL022832 (97%)1 (3%)80 (84%)15 (16%)
        NILG ALL08/962911 (61%)7 (39%)17 (63%)10 (37%)
        HOVON 37 ALL2742 (78%)1 (2%)10 (19%)1 (2%)71 (67%)23 (22%)12 (11%)
    Donor versus no donor (chemo/auto)
        EORTC 068611143 (64%)23 (34%)1 (1%)28 (18%)121 (79%)4 (3%)
        UKALLXII/E299314327 (72%)5 (1%)120 (26%)1 (0%)149 (20%)533 (72%)58 (8%)
        PETHEMA ALL-931549 (70%)2 (3%)19 (27%)31 (37%)53 (63%)
        LALA-941686 (74%)6 (5%)24 (21%)63 (36%)105 (60%)6 (3%)
        EORTC ALL-4/069511764 (69%)2 (2%)23 (25%)4 (4%)29 (24%)85 (71%)6 (5%)
    Randomized armAutograft (all patients)Chemotherapy (all patients)
        EORTC 068611115 (63%)9 (38%)21 (100%)
        UKALLXII/E299314136 (59%)84 (37%)9 (4%)2 (0%)222 (97%)4 (2%)
        PETHEMA ALL-931531 (62%)19 (38%)1 (2%)46 (96%)1 (2%)
        LALA-941663 (73%)23 (27%)66 (100%)
        EORTC ALL-4/069511730 (75%)10 (25%)1 (3%)36 (97%)
    • Ph+ patients have been excluded.

  • Table 4

    Patient and disease characteristics and length of follow-up in donor versus no donor trials

    TrialPh+ excludedTotal analyzedSexAge, yWBCImmunophenotypeMedian follow-up, yLost to follow-up < 5 y
    MF< 2525-3435-44≥ 45< 3030-99> 100BTOther
    MRC UKALLXA212213492 (69%)42 (31%)75 (56%)35 (6%)18 (13%)6 (4%)28 (21%)46 (34%)60 (45%)57 (50%)53 (47%)3 (3%)16.41 (1%)
    PMH 9223177050 (71%)20 (29%)28 (40%)17 (24%)19 (27%)6 (9%)46 (70%)14 (21%)6 (9%)44 (65%)24 (35%)0 (0%)8.43 (4%)
    JALSG-ALL93241412974 (7%)55 (43%)78 (60%)30 (23%)20 (16%)1 (1%)94 (73%)22 (7%)13 (10%)92 (74%)15 (12%)17 (14%)4.733 (26%)
    GRAALL 200325013287 (66%)45 (34%)55 (42%)27 (20%)27 (20%)23 (17%)76 (58%)30 (23%)25 (19%)90 (68%)42 (32%)0 (0%)4.077 (58%)
    HOVON 18 ALL27109455 (59%)39 (41%)48 (51%)21 (22%)15 (16%)10 (11%)66 (70%)14 (15%)14 (15%)65 (69%)27 (29%)2 (2%)9.51 (1%)
    GOELAL02281812886 (67%)42 (33%)56 (44%)37 (29%)24 (19%)11 (9%)77 (60%)35 (27%)16 (13%)94 (73%)34 (27%)0 (0%)4.738 (30%)
    HILG ALL08/9629184513 (29%)32 (71%)10 (22%)17 (38%)10 (22%)8 (18%)28 (62%)17 (38%)0 (0%)9.91 (2%)
    HOVON 37 ALL273016099 (62%)61 (38%)59 (37%)39 (24%)31 (19%)31 (19%)122 (76%)19 (12%)19 (12%)112 (70%)45 (28%)3 (2%)5.433 (21%)
    EORTC 068611111220148 (67%)72 (33%)101 (46%)54 (25%)45 (20%)20 (9%)141 (65%)43 (20%)34 (16%)113 (62%)51 (28%)19 (10%)10.98 (4%)
    UKALLXII/E2993141541193765 (64%)428 (36%)520 (44%)318 (27%)232 (19%)123 (10%)793 (67%)214 (18%)181 (15%)872 (75%)280 (24%)15 (1%)8.2135 (11%)
    PETHEMA ALL-93152615486 (56%)68 (44%)71 (46%)46 (30%)29 (19%)8 (5%)82 (53%)43 (28%)29 (19%)99 (64%)55 (36%)0 (0%)6.325 (16%)
    LALA-9416104290179 (62%)111 (38%)96 (33%)63 (22%)60 (21%)71 (24%)170 (59%)64 (22%)56 (19%)205 (81%)46 (18%)1 (0%)6.433 (11%)
    EORTC ALL-4/069511718213120 (56%)93 (44%)85 (40%)48 (23%)44 (21%)36 (17%)147 (69%)39 (18%)27 (13%)134 (63%)69 (32%)10 (5%)6.523 (11%)
  • Table 5

    Availability of a matched sibling donor in donor versus no donor trials

    TrialTotalSibling donorSibling no donorNo siblingsNot known if siblings, no donorAll no donor
    MRC UKALLXA2113447 (35%)68 (51%)19 (14%)87 (65%)
    PMH 92237034 (49%)23 (33%)13 (19%)36 (51%)
    JALSG-ALL932412932 (25%)97 (75%)97 (75%)
    GRAALL 20032513244 (33%)88 (67%)88 (67%)
    HOVON 18 ALL279436 (38%)52 (55%)6 (6%)58 (62%)
    GOELAL022812833 (26%)95 (74%)95 (74%)
    NILG ALL08/96294518 (40%)27 (60%)27 (60%)
    HOVON 37 ALL2716054 (34%)84 (53%)22 (14%)106 (66%)
    EORTC 068611122067 (30%)118 (54%)34 (15%)1 (0%)153 (70%)
    UKALLXII/E2993141193453 (38%)614 (51%)126 (11%)740 (62%)
    PETHEMA ALL-931515470 (45%)84 (55%)84 (55%)
    LALA-9416290116 (40%)118 (41%)43 (15%)13 (4%)174 (60%)
    EORTC ALL-4/069511721393 (44%)95 (45%)25 (12%)120 (56%)
    • Ph+ patients have been excluded.