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Stem-Cell Transplantation in Children With Acute Lymphoblastic Leukemia: A Prospective International Multicenter Trial Comparing Sibling Donors With Matched Unrelated Donors—The ALL-SCT-BFM-2003 Trial
Abstract
Although hematopoietic stem-cell transplantation is widely performed in children with high-risk acute lymphoblastic leukemia (ALL), the influence of donor types is poorly understood. Thus, transplantation outcomes were compared in the prospective multinational Berlin-Frankfurt-Muenster (BFM) study group trial: ALL-SCT-BFM 2003 (Allogeneic Stem Cell Transplantation in Children and Adolescents with Acute Lymphoblastic Leukemia).
After conditioning with total-body irradiation and etoposide, 411 children with high-risk ALL received highly standardized stem-cell transplantations during the first or later remissions. Depending on donor availability, grafts originated from HLA-genoidentical siblings or from HLA-matched unrelated donors who were identified and matched by high-resolution allelic typing and were compatible in at least 9 of 10 HLA loci.
Four-year event-free survival (± standard deviation [SD]) did not differ between patients with transplantations from unrelated or sibling donors (0.67 ± 0.03 v 0.71 ± 0.05; P = .405), with cumulative incidences of nonrelapse mortality (± SD) of 0.10 ± 0.02 and 0.03 ± 0.02 (P = .017) and relapse rates (± SD) of 0.22 ± 0.02 and 0.24 ± 0.04 (P = .732), respectively. Among recipients of transplantations from unrelated donors, no significant differences in event-free survival, overall survival, or nonrelapse mortality were observed between 9/10 and 10/10 matched grafts or between peripheral blood stem cells and bone marrow. The absence of chronic graft-versus-host disease had no effect on event-free survival. Engraftment was faster after bone marrow transplantation from siblings and was associated with fewer severe infections and pulmonary complications.
Although the majority of children and adolescents with acute lymphoblastic leukemia (ALL) are curable with current chemotherapy regimens, poor outcomes persist in some individuals.1,2 These high-risk patients require additional therapeutic approaches after achieving remission. Allogeneic hematopoietic stem-cell transplantation (HSCT) can effectively induce immunologic antileukemic control in children with ALL by means of the graft-versus-leukemia effect.3 HSCT from allogeneic donors has become the standard of care for such high-risk patients. Only 20% to 25% of children with indications for allogeneic HSCT have HLA-matched sibling donors (MSDs), but the availability of volunteer HLA-matched unrelated donors (MUDs) has increased transplantation rates over recent decades.4,5
Previous retrospective analyses demonstrated that some high-risk patients with ALL benefitted from unrelated donor HSCT, but they had nonrelapse mortality (NRM) rates of 25%.6,7 In addition, heterogeneity of available data regarding patient selection, quality of HLA typing, degree of matching, transplantation procedures, and study end points have hampered comparisons of different HSCT approaches. 8,9 Thus, in 2003, the Berlin-Frankfurt-Muenster (BFM) study group initiated the prospective international multicenter ALL-SCT-BFM 2003 (Allogeneic Stem Cell Transplantation in Children and Adolescents with Acute Lymphoblastic Leukemia) trial of allogeneic HSCT for children with ALL and indications for HSCT according to first-line and relapse chemotherapy protocols during first, second, or subsequent complete remissions (CRs). In these studies, all patients received pretransplantation treatments according to the ALL-BFM 2000 (Combination Chemotherapy Based on Risk of Relapse in Treating Young Patients With Acute Lymphoblastic Leukemia), the COALL (Multicenter Therapy Study of the Co-Operative Study Group for Childhood ALL), or the ALL-REZ BFM 2002 (ALL-REZ BFM 2002: Multi-Center Study for Children With Relapsed Acute Lymphoblastic Leukemia) protocols.10,11 Patients were allocated to receive HSCT from MSDs when they were available or allogeneic HSCT from 9/10 or 10/10 MUDs when no MSDs were available. Hence treatment assignments were biologically randomized according to the availability of donors.
Outcomes after HSCT are influenced by patient's remission status, age, conditioning regimens, graft-versus-host disease (GVHD) prophylaxis, and supportive care and are also influenced by donor selections and stem-cell sources.12–16 Therefore, this trial aimed to stratify patients according to their remission status and age to harmonize the transplantation procedures (which were clearly defined according to standardized protocols) and to include patients from 29 centers in Austria, Germany, and Switzerland (Data Supplement).
Outcomes of HSCTs from MSDs and MUDs in children with ALL who had poor prognoses after treatment with a consistent remission induction protocol were prospectively compared.17,18
Patients were allocated to receive HSCT from MSDs when they were available or from 9/10 or 10/10 HLA-matched MUDs. Conditioning was performed with total-body irradiation (TBI) and etoposide in patients older than age 2 years and in the absence of contraindications for TBI. Patients will be observed indefinitely, and the median follow-up time at the time of this analysis was 4.2 years (see the Data Supplement for protocol outlines). This study was performed in accordance with the Declaration of Helsinki and Good Clinical Practice and was approved by the local institutional review board at each participating site. Patients and/or their legal guardians provided written informed consent before enrollment.
Eligible patients were treated with remission induction therapy according to the BFM or COALL trial protocol; were identified as high-risk by using the risk-adapted stratification criteria defined by BFM, including leukemia phenotype, response to induction chemotherapy, and time and site of relapse19; had morphologic remission (< 5% bone marrow blasts) at the time of HSCT; were age 18 years or younger at the time of initial diagnosis or relapse; and had no pregnancy, no secondary malignancy, and no previous HSCT.
HLA typing was performed by using allelic typing, with a resolution of four digits per allele at HLA-A, -B, -C, -DRB1, and -DQB1 loci. Matched sibling donors were defined as genotypically or phenotypically identical siblings. No 9/10 or 10/10 HLA-matched nonsibling donors were identified. Thus, in the absence of MSDs, 9/10 or 10/10 MUDs were recruited from national and international donor registries. The assignment to a donor group determined the transplantation regimen (ie, stem-cell source, stem-cell manipulation, conditioning protocol, and GVHD prophylaxis; details are provided in the Protocol [online only]).
In the absence of matched donors, patients continued with conventional chemotherapy, or other transplantation approaches were performed by using mismatched cord blood (CB) or haploidentical HSCTs. These patients will be described in a separate report.
For children, the preferred stem-cell source was bone marrow (BM) from either MSDs or MUDs, as indicated by a large retrospective analysis that showed a higher incidence of chronic GVHD (cGVHD) and lower overall survival (OS) after peripheral blood stem cell (PBSC) transplantation.20 Recipients of unrelated grafts received BM or PBSCs according to donor choices. CB from MSDs or MUDs was used when sufficient cell numbers were available (> 2.5 × 107 cells per kilogram of recipient body weight).21
The conditioning regimen for patients older than age 2 years comprised fractionated TBI (12 Gy in six fractions over 3 days with lung shielding at 10 Gy) and intravenous etoposide 60 mg/kg (upper total dose, 3,600 mg). Children younger than age 2 years and older children with contraindications for TBI (eg, CNS irradiation before HSCT, history of CNS toxicities, signs of leukoencephalopathy) were treated with chemotherapy consisting of intravenous busulfan without therapeutic drug monitoring according to the manufacturer's brochure and as described elsewhere,22 in combination with cyclophosphamide (120 mg/kg total dose) and etoposide (40 mg/kg total dose). Details of conditioning regimens are provided in the Protocol.
GVHD prophylaxis for MSD bone marrow transplantation consisted of initial intravenous cyclosporine 1.5 mg/kg twice per day followed by oral cyclosporine when appropriate. MUD-HSCT patients were administered cyclosporine at the same dosage with methotrexate 10 mg/m2 on days +1, +3, and +6 after HSCT, followed by folinic acid 15 mg/m2 24 hours after each dose. Antithymocyte globulin (ATG) was administered on days −3, −2, and −1 (ATG Fresenius 60 mg/kg total dose).
Event-free survival (EFS) was the primary end point, taking the date of HSCT as the starting point, and the date of first event or of the last follow-up as the end of the interval. An event was defined as relapse, secondary malignancy, or death as a result of any cause. The null hypothesis is that MUD-HSCT is inferior to MSD-HSCT. To determine whether there was any difference in EFS between MSD-HSCT and MUD-HSCT, the cumulative incidence approach was used, with a one-sided CI for the difference of the Kaplan-Meier estimate of the 4-year EFS. With the initially planned sample size of 84 MSD patients and 228 MUD patients, 80% power can be achieved to show that MUD-HSCT is noninferior if a lower limit of the CI of 16% is used as the margin.23
Secondary end points were OS, relapse incidence (RI), NRM, engraftment, incidence and severity of acute GVHD (aGVHD) and cGVHD, and toxicity. For OS, death as a result of any cause was used as an event, and survivors were censored at the date of the last follow-up information. For RI, NRM, engraftment, and cGVHD, cumulative incidences were estimated by using the approach of Kalbfleisch and Prentice.24 Competing events were defined as follows: for RI, deaths from any cause and secondary malignancies; for engraftment and cGVHD, deaths from any cause; and for NRM, relapses and secondary malignancies.25 For the evaluation of risk factors and donor type, the comparison of cumulative incidences was done with Gray's test and an approach based on pseudovalues,26 respectively. The pseudovalue approach was also used to assess the impact of donor type on the 4-year probability of EFS and probability of OS in subgroups of patients because the proportional hazard assumption was violated. The incidences of aGVHD and grade 3 or 4 toxicity were compared by using the χ2 test.
The impact of prognostic factors on EFS and OS was evaluated by using Cox regression analyses, and pseudovalue regression analyses were used to separately evaluate the impact of donor type and of remission status on long-term event rates and survival times.
Between September 2003 and September 2011, 411 patients received HSCT according to the protocol (105 MSDs and 306 MUDs). Patient characteristics are provided in Table 1. In addition to these patients, 81 patients were given transplantations by using approaches that are beyond the scope of this article (Fig 1) and were excluded from analyses.
|
| Characteristic | Total | MSD | MUD | |||
|---|---|---|---|---|---|---|
| No. of Patients | % | No. | % | No. | % | |
| Patients | 411 | 105 | 306 | |||
| Age at SCT, years | ||||||
| Median | 10.1 | 10 | 10.1 | |||
| Range | 0.5-18.5 | 1.8-18.3 | 0.5-18.5 | |||
| 0-2 | 12 | 3 | 1 | 1 | 11 | 4 |
| > 2-12 | 249 | 61 | 68 | 65 | 181 | 59 |
| > 12-18 | 140 | 34 | 31 | 30 | 109 | 36 |
| > 18 | 10 | 2 | 5 | 5 | 5 | 2 |
| Sex | ||||||
| Male | 256 | 62 | 61 | 58 | 195 | 64 |
| Female | 155 | 38 | 44 | 42 | 111 | 36 |
| Remission | ||||||
| CR1 | 209 | 52 | 56 | 58 | 153 | 54 |
| CR2 | 173 | 42 | 41 | 42 | 132 | 46 |
| > CR2 | 29 | 8 | 8 | 8 | 21 | 7 |
| Immunophenotype | ||||||
| B | 309 | 75 | 79 | 75 | 230 | 75 |
| T | 87 | 21 | 21 | 20 | 66 | 22 |
| Other | 15 | 4 | 5 | 5 | 10 | 3 |
| BCR-ABL | ||||||
| Negative | 311 | 85 | 83 | 86 | 228 | 84 |
| Positive | 56 | 15 | 14 | 14 | 42 | 16 |
| No data | 44 | 8 | 36 | |||
| MLL/AF4 | ||||||
| Negative | 336 | 95 | 87 | 95 | 249 | 95 |
| Positive | 17 | 5 | 5 | 5 | 12 | 5 |
| Not done | 2 | 0 | 2 | |||
| No data | 56 | 13 | 43 | |||
| CMV (donor-patient) | ||||||
| Negative-negative | 84 | 22 | 32 | 33 | 52 | 18 |
| Negative-positive | 56 | 14 | 8 | 8 | 48 | 17 |
| Positive-negative | 61 | 16 | 13 | 13 | 48 | 17 |
| Positive-positive | 186 | 48 | 45 | 46 | 141 | 49 |
| Incomplete data | 24 | 7 | 17 | |||
| Stem-cell source | ||||||
| Bone marrow | 309 | 75 | 99 | 94 | 210 | 69 |
| PBSC | 88 | 21 | 0 | 88 | 29 | |
| CB SC | 4 | 1 | 4 | 4 | 0 | |
| Other | 10 | 2 | 2 | 2 | 8 | 3 |
| Time from indication to HSCT, months | ||||||
| No. of patients | 408 | 104 | 304 | |||
| Median | 4.3 | 4.1 | 4.4 | |||
| Range | 0.3-16.6 | 1.1-9.9 | 0.3-16.6 | |||
| CR1: time from initial diagnosis to HSCT, months | ||||||
| No. of patients | 208 | 56 | 152 | |||
| Median | 6.6 | 6.3 | 6.7 | |||
| Range | 4.1-39.3 | 4.3-11.4 | 4.1-39.3 | |||
| CR2, > CR2: time from last relapse to HSCT, months | ||||||
| Median | 5.2 | 5.3 | 5.1 | |||
| Range | 2.4-9 | 3.4-6.6 | 2.4-9 | |||
| Type of relapse | ||||||
| Isolated BM | 162 | 80 | 34 | 69 | 128 | 84 |
| Isolated extramedullary | 9 | 4 | 5 | 10 | 4 | 3 |
| Combined | 31 | 15 | 10 | 20 | 21 | 14 |
| CR2, > CR2: time from initial diagnosis to diagnosis of last relapse, months | ||||||
| No. of patients | 173 | 41 | 128 | |||
| Median | 29.9 | 31.8 | 29.3 | |||
| Range | 3-128 | 8.9-86.4 | 3-128 | |||
| < 18 | 35 | 20 | 7 | 17 | 28 | 21 |
| 18-30 | 52 | 30 | 11 | 27 | 41 | 31 |
| > 30 | 86 | 50 | 23 | 56 | 63 | 48 |
| Conditioning regimen | ||||||
| TBI and etoposide | 370 | 90 | 96 | 90 | 274 | 90 |
| Chemotherapy conditioning | 41 | 10 | 9 | 10 | 32 | 10 |
Abbreviations: BM, bone marrow; CB, cord blood; CMV, cytomegalovirus; CR1, first complete remission; CR2, second complete remission; HSCT, hematopoietic stem-cell transplantation; MSD, matched sibling donor; MUD, matched unrelated donor; PBSC, peripheral blood stem cell; SC, stem cell; SCT, stem-cell transplantation; TBI, total-body irradiation.
Fig 1. Patient recruitment. CB, cord blood; HSCT, hematopoietic stem-cell transplantation; MMD, HLA-mismatched donor; MSD, HLA-matched sibling donor; MUD, HLA-matched unrelated donor; PBSC, peripheral blood stem cell.
Patient groups had comparable proportions of patients in first or later remissions and had similar times from initial diagnosis or relapse to HSCT (median, 4.3 months) and phenotypical risk factors. In all, 90% of patients in both groups received conditioning regimens containing TBI and etoposide.
Among 105 patients who received MSD-HSCT, 99 received BM alone, four received CB, and two received BM and CB. The majority of patients with MUD transplantations (210 patients; 69%) received BM, whereas 88 patients (29%) received PBSCs and the remaining eight patients received CB or a combination of CB and BM or PBSCs after delayed engraftment. At the time of analysis in November 2013, the median follow-up from time of diagnosis until last follow-up evaluation was 4.2 years (range, 0.27 to 9.1 years).
Engraftment was significantly faster after MSD-HSCT (Table 2). The median time to neutrophil engraftment (ie, absolute neutrophil count ≥ 500/μL) was 17 days after MSD-HSCT and 22 days after MUD-HSCT with a 30-day cumulative incidence of 76% versus 44% (P < .001). Lymphocyte count ≥ 100/μL was observed in the MSD group on day 14 compared with day 23 after MUD-HSCT with 30-day cumulative incidences of 92% versus 76% (P < .001).
|
| End Point | MSD (n = 105) | MUD (n = 306) | P | ||||||
|---|---|---|---|---|---|---|---|---|---|
| No. of Events | % | No. of Patients | 30-Day Cumulative Incidence (± SD) | No. of Events | % | No. of Patients | 30-Day Cumulative Incidence (± SD) | ||
| Engraftment achieved (per microliter) | |||||||||
| > 1,000 leucocytes | 105 | 0.96 ± 0.02 | 299 | 0.91 ± 0.02 | .008 | ||||
| > 100 lymphocytes | 93 | 0.92 ± 0.03 | 268 | 0.76 ± 0.03 | .002 | ||||
| > 500 neutrophils | 97 | 0.76 ± 0.04 | 251 | 0.44 ± 0.03 | < .001 | ||||
| > 20,000 platelets | 93 | 0.64 ± 0.05 | 225 | 0.33 ± 0.03 | < .001 | ||||
| > 50,000 platelets | 104 | 0.92 ± 0.03 | 296 | 0.89 ± 0.02 | < .001 | ||||
| Graft failure | 2 | 2 | 105 | 15 | 5 | 301 | .259 | ||
| aGVHD | |||||||||
| 0 | 25 | 24 | 78 | 26 | |||||
| 1 | 47 | 45 | 121 | 40 | |||||
| 2 | 21 | 20 | 71 | 23 | |||||
| 3 or 4 | 11 | 11 | 29 | 10 | .751* | ||||
| Death without aGVHD | 0 | 0 | 6 | 2 | |||||
| Death before day 100 | 1 | 18 | |||||||
| cGVHD | |||||||||
| Patients at risk | 104 | 288 | |||||||
| 2-year cumulative incidence | 30 | 0.29 ± 0.05 | 51 | 0.18 ± 0.02 | .026† | ||||
| Limited | 15 | 0.15 ± 0.04 | 31 | 0.11 ± 0.02 | .307† | ||||
| Extensive | 14 | 0.14 ± 0.03 | 16 | 0.06 ± 0.01 | .012† | ||||
| Unknown extent | 1 | 5 | |||||||
| Death without cGVHD | 17 | 0.15 ± 0.04 | 57 | 0.19 ± 0.02 | .377† | ||||
| Grade 3 or 4 toxicity | |||||||||
| Nausea and vomiting | 7 | 7 | 104 | 42 | 14 | 291 | .055 | ||
| Hypoxia | 9 | 9 | 102 | 52 | 18 | 283 | .026 | ||
| Tachypnea | 4 | 4 | 93 | 30 | 11 | 264 | .062 | ||
| Infection | 16 | 16 | 103 | 111 | 39 | 287 | < .001 | ||
| Central neurotoxicity | 0 | 0 | 101 | 16 | 6 | 285 | .016 | ||
Abbreviations: aGVHD, acute graft-versus-host disease; cGVHD, chronic GVHD; MSD, matched sibling donor; MUD, matched unrelated donor; SD, standard deviation.
*χ2 test.
†Gray test.
Transfusion-independent platelet count ≥ 20,000/μL was reached on day 22 after MSD-HSCT and on day 32 after MUD-HSCT with 30-day cumulative incidences of 64% versus 33% (P < .001). Although graft failure was generally rare, it was more frequent among patients who received MUD-HSCT (n = 2 v n = 15; P = .259).
No differences in incidence or severity of aGVHD were observed between MSD-HSCT and MUD-HSCT patients; in contrast, extensive cGVHD occurred more frequently after MSD-HSCT (Table 2). For the MUD group, in which more intensive immunosuppression was used, the 2-year cumulative incidence of extensive cGVHD was only 0.06 ± 0.01 and did not vary between BM and PBSCs or with HLA disparities (9/10 or 10/10 matches; Fig 2). Fourteen patients (14%) developed extensive cGVHD after MSD-HSCT; 16 patients (6%) developed extensive cGVHD after MUD-HSCT. Five of those patients had a Karnovsky/Lansky performance status below 80% 2 years after MSD-HSCT and only six of 16 MUD-HSCT patients reached a performance status of 80% to 100%, reflecting the reduced quality of life with such complications.
Fig 2. Influence of (A, C, E) HLA-matched unrelated donor (MUD) and (B, D, F) stem-cell source on incidence and severity of chronic graft-versus-host disease (cGVHD v extensive cGVHD v limited cGVHD, according to Glucksberg criteria). 9/10 and 10/10, nine of 10 and 10 of 10 HLA matches defined by allelic typing on HLA-A, -B, -C, -DRB1, and -DQB1 loci.
After MSD-HSCT, patients older than age 12 years had a higher incidence of extensive cGVHD compared with younger patients (25% v 48%). Sex match of donor and recipient, year of HSCT, phenotype, and cytomegalovirus status did not influence the incidence and severity of cGVHD after MSD-HSCT.
The incidence of grade 3 to 4 infection was significantly higher in the MUD group and was associated with a tendency toward pulmonary complications (Table 2). Other extramedullary toxicities of grade > 2 were rare and were predominantly associated with oral mucositis. Thirty-three patients died as a result of nonrelapse complications, including three of 105 from the MSD-HSCT group and 30 of 306 from the MUD-HSCT group (P = .017). The main causes of death were bacterial (n = 6) and viral (n = 6) infections, Epstein-Barr virus–lymphoproliferative disease (n = 3), multiorgan failure (n = 6), toxicity (n = 4), and aGVHD (n = 2) or cGVHD (n = 6). A total of nine patients developed secondary malignancies at a median of 5 years (range, 26 to 84 months) after HSCT: five thyroid cancers, one myelodysplastic syndrome, one osteosarcoma, one rhabdomyosarcoma, and one colon carcinoma. Among these patients, three were in the MSD-HSCT group and six were in the MUD-HSCT group. All patients received TBI.
The 4-year EFS rate after MUD-HSCT was similar to that after MSD-HSCT (0.67 ± 0.03 v 0.71 ± 0.05; P = .405). The upper limit of the 95% CI for the difference in 4-year EFS was 13% (Fig 3A). No significant differences in OS or RI were observed (4-year cumulative incidence, 0.22 ± 0.02 after MUD-HSCT and 0.24 ± 0.02 after MSD-HSCT).
Fig 3. Four-year (A) event-free survival (EFS), (B) overall survival (OS), (C) relapse incidence (RI), and (D) nonrelapse mortality (NRM). MSD, HLA-matched sibling donor; MUD, HLA-matched unrelated donor. (*) Based on pseudovalues at 4 years.
However, NRM at 4 years was 0.10 ± 0.02 with transplantations from MUDs and was 0.03 ± 0.02 with transplantations from MSDs (P = .017). Patients receiving transplantations during the first CR (CR1) had better outcomes than those with subsequent remissions (Fig 4 and Fig 5). No differences in patient outcomes were found between MUD-HSCT with 9/10 and 10/10 HLA matches or between patients receiving BM and PBSCs (Fig 2). No differences in EFS, RI, or OS were identified between patients with and without limited or extensive cGVHD (Data Supplement). Moreover, no significant influences of other prognostic factors, including immunophenotype and cytogenetic abnormalities, were identified in univariable or multivariable analyses (Data Supplement).
Fig 4. Outcomes for patients who received a transplantation in first complete remission. (A) Event-free survival (EFS), (B) overall survival (OS), (C) relapse incidence (RI), and (D) nonrelapse mortality (NRM). MSD, HLA-matched sibling donor; MUD, HLA-matched unrelated donor. (*) Based on pseudovalues at 4 years.
Fig 5. Outcomes for patients transplanted in second or third complete remissions. (A) Event-free survival (EFS), (B) overall survival (OS), (C) relapse incidence (RI), and (D) nonrelapse mortality (NRM). MSD, HLA-matched sibling donor; MUD, HLA-matched unrelated donor. (*) Based on pseudovalues at 4 years.
This is the first prospective study to compare HSCT from different donor types in well-defined cohorts of children with high-risk ALL by using a standardized transplantation and prophylaxis protocol. All patients received comparable risk-stratified chemotherapy before HSCT and were selected for HSCT according to prognostically relevant leukemia phenotypes and response to induction chemotherapy or according to time and site of relapse. Donor selections were determined according to the availability of suitable siblings, which produced biologically randomized treatment groups. The close cooperation and compliance of study centers, the prospective evaluation, and quality assurance from regular patient conferences about complications led to noticeable treatment improvements compared with those of some previous retrospective studies.27–29 Moreover, multicenter cooperation allowed stringent alignment of selection criteria for allogeneic HSCT according to predictions of contemporary chemotherapy outcomes. Patients with a long-term survival prognosis of less than 50% after validated chemotherapy were selected for HSCT. In contrast with previous trials, these criteria were defined in first-line protocols and did not differ for MSD or MUD indications. Specifically, known risk factors, such as phenotype, response to prednisone, age at diagnosis, relapse, duration of first remission, and site of relapse, were defined in the indication for allogeneic HSCT. For patients with CR1 and second CR (CR2) HSCT indications, the minimal residual disease level at 4 and 12 weeks after initial treatment became a major selection criteria.10,12,30
EFS and OS of patients in the MUD group were superior to those in previously published data from children with high-risk ALL who were treated with MUD transplantations,31,32 and the quality of HLA typing and the degree of matching may have played an important role.
When this study was designed, it was still common practice to use unrelated donors with 7/8 HLA matches, as determined by medium-resolution typing. However, the drawback of this procedure has been a high rate of transplantation-associated complications, especially aGVHD and cGVHD, which particularly affects the growing organs of children. Petersdorf et al33 and Flomenberg et al34 demonstrated striking prognostic efficacy of high-resolution typing and, consequently, only donors with 9/10 or 10/10 HLA matches (four digits per allele) were used in this study. MUDs were identified for more than 70% of patients who lacked MSDs, and the search for donors did not delay HSCT. Moreover, no differences in outcomes were identified between patients receiving transplantations from 9/10 or 10/10 matches.
Among patients with MUD transplantations, no differences in OS were observed between recipients of BM or PBSC, probably reflecting the protective effect of intensive GVHD prophylaxis with cyclosporine, methotrexate, and ATG Fresenius.35,36 Furthermore, no significant differences in outcomes were observed between patients with various degrees of aGVHD or cGVHD. These data demonstrate that long-term relapse-free survival after MUD-HSCT can be achieved without a high incidence of cGVHD, which is a devastating disease for children and adolescents.37,38
Despite excellent outcomes of MUD-HSCT, our data indicate that MSD BM transplantation remains superior, which is possibly a result of faster engraftment and more rapid immune reconstitution resulting in fewer severe infections. We speculate that this is influenced by the short and limited GVHD prophylaxis in this setting. This investigator-initiated, multicenter study has limitations. Because only 10% of children with ALL qualify for an allogeneic HSCT, the recruitment duration was more than 7 years. Although no striking differences in supportive care were observed, some new techniques developed over time and possibly influenced the treatment intensity of aGVHD and cGVHD; extracorporeal photopheresis and mesenchymal stem-cell infusion were increasingly used to reduce pharmacologic immunosuppression. One of the most important tools is the evaluation of minimal residual disease before and after HSCT. The results of this investigation in our study group were recently reported, and additional analyses are under way.39,39a
The risk of secondary malignancies is a major concern,40–42 and our data demonstrate this risk with nine secondary malignancies in patients who received TBI, with the expectation of more with longer follow-up. The long-term effects of TBI in children and adolescents also include organ dysfunction, growth retardation, and hormonal insufficiencies.43–45 Thus, future studies are required to develop effective alternatives to TBI.
In conclusion, our data demonstrate excellent EFS and OS, and low incidence of relapse in children with high-risk ALL after treatment with TBI and etoposide before allogeneic HSCT from HLA-matched siblings or well-matched unrelated donors. This large, prospective, multicenter trial suggests that MUD-HSCT could be a standard of care for patients with ALL who have a high risk of relapse and who lack MSDs.
See accompanying article on page 1275; listen to the podcast by Dr Bunin at www.jco.org/podcasts
Written on behalf of the Berlin-Frankfurt-Muenster (BFM) Study Group, the International BFM Study Group, the Children's Cancer Research Institute, and the European Society for Blood and Marrow Transplantation Paediatric Diseases Working Party.
Supported by the Children's Cancer Research Institute, Vienna, Austria; Deutsche Krebshilfe, Bonn, Germany; Deutsche Knochenmarkspenderdatei, Tübingen, Germany; Orphan Pharmaceuticals and Amomed Pharma, Vienna, Austria; Fresenius Biotech, Gräfelfing, Germany; Gilead Sciences, Vienna, Austria; and Medac, Wedel, Germany.
Authors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.
The supporting institutes and companies had no role in study design, data collection, data analysis, data interpretation, or writing of the report. All data were maintained by the Berlin-Frankfurt-Muenster statistics and data center and were reviewed by an independent data safety monitoring committee.
Clinical trial information: NC01423747.
Disclosures provided by the authors are available with this article at www.jco.org.
Conception and design: Christina Peters, Martin Schrappe, Arend von Stackelberg, André Schrauder, Peter Bader, Wolfram Ebell, Peter Lang, Johanna Schrum, Bernhard Kremens, Michael H. Albert, Roland Meisel, Susanne Matthes-Martin, Tayfun Gungor, Wolfgang Holter, Brigitte Strahm, Bernd Gruhn, Ansgar Schulz, Wilhelm Woessmann, Ulrike Poetschger, Martin Zimmermann, Thomas Klingebiel
Provision of study materials or patients: Christina Peters, Martin Schrappe, Arend von Stackelberg, André Schrauder, Peter Bader, Wolfram Ebell, Peter Lang, Johanna Schrum, Bernhard Kremens, Michael H. Albert, Roland Meisel, Susanne Matthes-Martin, Tayfun Gungor, Wolfgang Holter, Brigitte Strahm, Bernd Gruhn, Ansgar Schulz, Wilhelm Woessmann, Ulrike Poetschger, Martin Zimmermann, Thomas Klingebiel
Collection and assembly of data: Christina Peters, Martin Schrappe, Arend von Stackelberg, André Schrauder, Peter Bader, Wolfram Ebell, Peter Lang, Johanna Schrum, Bernhard Kremens, Michael H. Albert, Roland Meisel, Susanne Matthes Martin, Tayfun Gungor, Wolfgang Holter, Brigitte Strahm, Bernd Gruhn, Ansgar Schulz, Wilhelm Woessmann, Ulrike Poetschger, Martin Zimmermann, Thomas Klingebiel
Data analysis and interpretation: Christina Peters, Martin Schrappe, Arend von Stackelberg, Peter Bader, Peter Lang, Karl-Walter Sykora, Johanna Schrum, Bernhard Kremens, Karoline Ehlert, Michael H. Albert, Roland Meisel, Susanne Matthes-Martin, Tayfun Gungor, Wolfgang Holter, Brigitte Strahm, Bernd Gruhn, Ansgar Schulz, Wilhelm Woessmann, Ulrike Poetschger, Martin Zimmermann, Thomas Klingebiel
Manuscript writing: All authors
Final approval of manuscript: All authors
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The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc.
Honoraria: EUSA Pharma, Medac Pharma
Consulting or Advisory Role: Medac Pharma, EUSA Pharma, Pfizer
Speakers' Bureau: Amgen, Novartis, Medac Pharma, Fresenius Biotech
Research Funding: Amgen (Inst), Fresenius Biotech (Inst), Genzyme (Inst), Medac (Inst), RIEMSER Pharma (Inst)
Travel, Accommodations, Expenses: Pierre Fabre
No relationship to disclose
Honoraria: Amgen
Consulting or Advisory Role: Amgen (Inst)
Research Funding: EUSA Pharma (Inst)
No relationship to disclose
Travel, Accommodations, Expenses: Medac Pharma, Novartis
No relationship to disclose
No relationship to disclose
Travel, Accommodations, Expenses: Medac Pharma
No relationship to disclose
No relationship to disclose
No relationship to disclose
Stock or Other Ownership: Amgen, Biogen Idec
Travel, Accommodations, Expenses: Neovii Biotech, Astellas Pharma
No relationship to disclose
No relationship to disclose
No relationship to disclose
No relationship to disclose
No relationship to disclose
Consulting or Advisory Role: Amgen, EUSA Pharma
Travel, Accommodations, Expenses: EUSA Pharma, Neovii Biotech
No relationship to disclose
No relationship to disclose
No relationship to disclose
No relationship to disclose
Expert Testimony: Novartis
Travel, Accommodations, Expenses: EUSA Pharma, Medac Pharma
Acknowledgment
We thank the children, their families, and the staff from the participating centers (physicians, nurses, and other health care professionals) whose outstanding work made this study possible. We thank the data coordinators Ingeborg Hirsch, Julia Dobke, Melanie Gerzmehle, Susanne Karlhuber, and Kirsten Mischke for their enthusiastic engagement throughout the whole study period. Furthermore, we thank the data safety monitors Ruth Ladenstein and Jakob Passweg, Karin Dieckman for her advice regarding total-body irradiation procedures, Gottfried Fischer for HLA typing recommendations, the laboratory staff for the microbiology, chimerism, and MRD analyses, and the Austrian, German, and Swiss Donor registries for their continuous collaboration. We also thank Diana Samson, Hartmut Ehlerding, and Heinz Brenner for assisting in the preparation of this manuscript. We express our deep gratitude to Helmut Gadner, who supported the study during the entire process.
Presented in part at the 52nd Annual Meeting of the American Society of Hematology, Orlando, FL, December 4-7, 2010; at the 7th Biannual Childhood Leukemia Symposium, Antalya, Turkey, October 4-6, 2010; and at the International European Society for Blood and Marrow Transplantation Annual Meeting, Geneva, Switzerland, April 1-4, 2012.
