Leukemia (2005) 19, 965–970 & 2005 Nature Publishing Group All rights reserved 0887-6924/05 $30.00 www.nature.com/leu
Postremission therapy for children with acute myeloid leukemia: the children’s cancer group experience in the transplant era TA Alonzo1,2, RJ Wells3, WG Woods4, B Lange5, RB Gerbing2, AB Buxton2, S Neudorf6, J Sanders7, FO Smith8 and SA Feig9 1 University of Southern California Keck School of Medicine, Los Angeles, CA, USA; 2Children’s Oncology Group, Arcadia, CA, USA; 3University of Texas MD Anderson Cancer Center, Houston, TX, USA; 4AFLAC Cancer Center, Emory University/Children’s Healthcare, Atlanta, GA, USA; 5Children’s Hospital of Philadelphia, Philadelphia, PA, USA; 6Children’s Hospital of Orange County, Orange, CA, USA; 7Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 8Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; and 9Mattel Children’s Hospital, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
We reviewed consolidation therapy results and analyzed postremission outcomes for 1464 children less than 21 years old at diagnosis in five consecutive Children’s Cancer Group acute myeloid leukemia trials between 1979 and 1996. Children in remission were allocated to allogeneic bone marrow transplantation (BMT) (N ¼ 373) in first remission, if a matched family donor was available. Remaining children were assigned consolidation chemotherapy (N ¼ 688) or autologous purged BMT (N ¼ 217), or withdrew from study before assignment, or with unknown data (N ¼ 186). Overall and disease-free survival were superior for children assigned allogeneic transplants. High (450 000/ll) diagnostic white blood cell (WBC) count was prognostic for inferior outcome, but French–American–British (FAB) subtypes were not. Inv(16) is a favorable karyotypic feature for children in first remission and t(8;21) is not. Allogeneic transplantation benefit was evident in most children, including those with high or low diagnostic WBC count, each FAB subtype, and t(8;21), but was not seen in children with inv(16). Therefore, these data suggest reserving matched related donor allogeneic transplantation for children with inv(16) for second remission, but not those with t(8;21). Leukemia (2005) 19, 965–970. doi:10.1038/sj.leu.2403763 Published online 14 April 2005 Keywords: acute myeloid leukemia; children; chemotherapy; bone marrow transplantation; karyotype
Introduction In the last 25 years, we have seen marked improved survival of children and adolescents with acute myeloid leukemia (AML) when the ability to deliver extremely intensive chemotherapy is critical to eradication of leukemia cells.1,2 Although escalation of therapeutic intensity has been associated with more prolonged myelosuppression and immunosuppression, improvements in supportive care may have diminished morbidity and mortality of these complications, and contributed to better outcomes. Since 1979, the Children’s Cancer Group (CCG, now part of the Children’s Oncology Group (COG)) has completed five prospective therapeutic trials for children with newly diagnosed AML (CCG-251, -213, -2861, -2891, and -2941 in chronological order). In each of these studies, remission was induced with intensive chemotherapy in 74–80% of children; those children who entered remission received consolidation consisting of chemotherapy, autologous bone marrow transplant (BMT) (in Correspondence: Dr TA Alonzo, University of Southern California Keck School of Medicine, Los Angeles, CA, and Children’s Oncology Group, 440 E Huntington Dr, Suite 300, PO Box 60012, Arcadia, CA 91066-0064, USA; Fax: þ 1 626 445 4334; E-mail:
[email protected] or
[email protected] Received 16 November 2004; accepted 4 March 2005; Published online 14 April 2005
CCG-2861 and CCG-2891), or allogeneic hematopoietic stem cell transplantation. This report summarizes cumulative results of remission consolidation in these five CCG trials. Specifically, we compared outcomes of various postinduction treatments, investigated prognostic significance of karyotypes, diagnostic white blood cell (WBC) count, and French–American–British (FAB) subtypes, and we present data that bear upon the discussion of whether to transplant children in first remission who have cytogenetic abnormalities determined in other studies to be relatively favorable.
Methods
Patients and treatments All children less than 21 years of age with AML who achieved remission on the five CCG studies were analyzed (N ¼ 1464), excluding children with acute promyelocytic leukemia (APL) (M3), myelodysplastic syndrome (MDS), or Down’s syndrome (DS). The details of treatment have been reported and are summarized briefly in Table 1. In all studies, children with related donors, matched at five or six of the six HLA-A, -B, and DR antigens, were allocated to allogeneic BMT. Histocompatibility was assessed by serological HLA typing and early on by mixed leukocyte culture. The remaining children were assigned to chemotherapy, except for those on CCG-2891, on which children who did not have matched family donors (MFD) were randomly allocated to receive consolidation chemotherapy or a 4-hydroperoxycyclophosphamide purged autologous BMT, or on CCG-2861, on which all children received allogeneic or autologous BMT. Clinical characteristics of children who achieved remission are presented in Table 2. Some data were not available for children on CCG-251, which accounts for the number of children in remission exceeding the total of the three regimens. Acute graft-versus-host disease (GVHD) was graded according to standard criteria.3 Reporting of chronic GVHD was inconsistent in early studies and could not be evaluated. AML was classified according to FAB criteria.4 Morphology, histochemistry, and karyotypes were centrally reviewed as reported.5 All studies were reviewed and approved by the institutional review boards of participating CCG member institutions. Appropriate written informed consent/assent was obtained before children were entered, in accordance with the Declaration of Helsinki.
Statistical methods Data were analyzed from CCG-251, -213, -2861, -2941, and -2891 through December 2002, August 2001, September 2001, March 2002, and January 2004, respectively. These analyses
Postremission therapy for pediatric AML TA Alonzo et al
966 only included children with AML (excluded children with APL, DS, or MDS) who were in first remission at the end of induction on their respective studies. The significance of observed differences in proportions was tested using the w2 test and Fisher’s exact test when data were
Table 1
sparse. The Mann–Whitney test was used to determine the significance between differences in medians.6 The Kaplan– Meier method7 was used to calculate estimates of overall survival (OS), defined as the time from achievement of remission at the end of induction therapy to death from any cause, and
Sequential CCG studies of AML
Study
251
213
2861
2891
2941
Years N Induction therapy
1979–1983 355 ‘7+3’ (C+R)
1985–1989 355 ‘7+3’ (C+R) vs DCTER (‘Denver’)
1988–1989 84 DCTER (IT)
1989–1995 617 DCTER IT vs ST N ¼ 398a N ¼ 209a
1995–1996 53 Ida-DCTER (IT) vs Ida-CTER (IT)
8 – drug cyclic (Aza, C, Car, MP, MTX, P, V, T) vs 5 – drug cylic (Aza, C, CTX, V, T) Allo CTX SD TBI MTX
HDC 75 – drug cylic (Aza, C, CTX, V, T) Allo CTX FTBI CSA, SCMTX
HDC
HDCb
Allo or auto BU/CTX
Allo or auto BU/CTX
Allo BU/CTX
MTX
MTX
MTX
Consolidation/maintenance Chemotherapy Stem cell transplant GVHD prophylaxis
Aza ¼ 5 Azacytidine; BU ¼ busulfan; C ¼ cytarabine; CAR ¼ carmustine; CSA ¼ cyclosporin A; CTX ¼ cyclophosphamide; D ¼ dexamethasone; E ¼ etoposide; FTBI ¼ fractionated total body irradiation; GVHD ¼ graft-versus-host disease; HDC ¼ high-dose cytarabine; IDA ¼ idarubicin; IL2 ¼ interleukin-2; IT ¼ intensive timing; MP ¼ 6-mercaptopurine; MTX ¼ long-course methotrexate; P ¼ prednisone; R ¼ rubidamycin; SC MTX ¼ short-course methotrexate; ST ¼standard timing; SDTBI ¼ single dose total body irradiation; T ¼ 6-thioguanine; V ¼ vincristine. a In all, 10 patients received both ST and IT timing when ST was closed. b Some patients were entered on a pilot study of IL-2 after completion of chemotherapy on CCG-2941.
Table 2
Clinical characteristics of children with AML in first remission Total
Allo-BMT
Chemo
Auto-BMT
Other
(N ¼ 1464)
(N ¼ 373)
(N ¼ 688)
(N ¼ 217)
(N ¼ 186)
Allo vs chemo
Chemo vs auto
Allo vs auto
7.5 18.6 70
8.9 16.6 70
7.0 18.5 70
6.2 21.7 69
6.0 19.9 73.5
o0.001 0.059 0.734
0.873 0.226 0.487
0.007 0.010 0.711
Gender – N (%) Male Female
749 (51%) 715 (49%)
205 (55%) 168 (45%)
332 (48%) 356 (52%)
112 (52%) 105 (48%)
100 (54%) 86 (46%)
0.043
0.433
0.484
FAB – N (%) M0 M1/M2 M4 M5 M6 M7
21 708 374 211 37 45
(2%) (51%) (27%) (15%) (3%) (3%)
8 177 113 42 8 13
(2%) (49%) (31%) (12%) (2%) (4%)
5 360 172 108 22 16
(1%) (53%) (25%) (16%) (3%) (2%)
3 92 49 29 4 12
(2%) (49%) (26%) (15%) (2%) (6%)
5 79 40 32 3 4
(3%) (49%) (25%) (20%) (2%) (3%)
0.073 0.286 0.042 0.082 0.466 0.328
0.381 0.368 0.910 0.965 0.583 0.011
0.756 0.991 0.224 0.272 1.000 0.210
Karyotype – N (%) Normal Inv(16) t(8;21) t(9;11) 11q23 t(6;9) 7/7q 5/5q +8 +21 Pseudodiploid Hyperdiploid Hypodiploid Other
243 54 93 49 61 8 28 7 42 13 80 31 12 32
(32%) (7%) (12%) (7%) (8%) (1%) (4%) (1%) (6%) (2%) (11%) (4%) (2%) (4%)
62 19 31 17 9 1 7 1 7 1 20 9 3 4
(33%) (10%) (16%) (9%) (5%) (1%) (4%) (1%) (4%) (1%) (11%) (5%) (2%) (2%)
131 20 35 14 33 5 13 3 23 8 33 14 6 27
(36%) (6%) (10%) (4%) (9%) (1%) (4%) (1%) (6%) (2%) (9%) (4%) (2%) (7%)
27 10 17 10 13 1 6 2 5 2 18 5 1 0
(23%) (9%) (15%) (9%) (11%) (1%) (5%) (2%) (4%) (2%) (15%) (4%) (1%) (0%)
23 5 10 8 6 1 2 1 7 2 9 3 2 1
(29%) (6%) (13%) (10%) (8%) (1%) (3%) (1%) (9%) (3%) (11%) (4%) (3%) (1%)
0.476 0.074 0.031 0.023 0.096 0.669 0.859 1.000 0.267 0.175 0.694 0.788 1.000 0.017
0.014 0.329 0.184 0.073 0.630 1.000 0.423 0.599 0.556 1.000 0.077 0.789 1.000 0.005
0.102 0.836 0.812 0.919 0.059 1.000 0.568 0.560 0.771 0.560 0.274 0.918 1.000 0.301
Age (years) – median WBC – median BM blast (%) – median
Leukemia
P-values
Postremission therapy for pediatric AML TA Alonzo et al
967 disease-free survival (DFS), defined as the time from achievement of remission at the end of induction therapy to relapse or death from any cause. Cumulative incidence estimates were used to estimate the relapse risk (RR) and treatment-related mortality (TRM).8 RR was defined as the cumulative incidence of relapse or death from progressive disease after remission, when nonprogressive disease-related death was a competing event. TRM was defined as the cumulative incidence of nonprogressive disease-related death after remission, when relapses and deaths from progressive disease were competing events. Children lost to follow-up were censored at their date of last known contact or at a cutoff 6 months before the date the data were frozen. Since the primary interest was in long-term outcome and not, for example, the shape of the survival and cumulative incidence curves, comparisons of outcomes at 8 years were used. Differences in 8-year estimates were tested for significance using Wald statistics of differences in Kaplan–Meier estimates (for OS and DFS) and cumulative incidence estimates (for RR and TRM) that employed standard errors of Greenwood9 and Gaynor et al,10 respectively. Seven children who died without relapse and without information on the main cause of death were excluded from the analyses of RR and TRM. Differences in the cure fractions (ie long-term survival) for children with and without MFD, after adjusting for the study each child was enrolled on were tested for significance using multivariate nonmixture parametric cure regression models. Approximately 15% of children did not receive the regimen to which they were allocated. This was true for all studies and all regimens. However, all comparisons of regimens are reported as intent to treat.
Results
Comparison of outcomes for postinduction therapies Children assigned allogeneic BMT had significantly better OS and DFS compared with those without an available MFD, after Table 3
Effects of WBC, FAB, and karyotypes on outcomes Among 1462 who had data on diagnostic WBC count available, 379 (25.9%) had WBC of at least 50 000/ml. Children with a high diagnostic WBC (at least 50 000/ml) have inferior postremission outcome compared with those with lower diagnostic WBC (8-year OS: 4375 vs 4873%, P ¼ 0.065; DFS: 3075 vs 4373%, Po0.001; and RR: 6375 vs 4773%, Po0.001). The benefit of allogeneic transplantation relative to chemotherapy is evident for children with high WBC and for children with lower WBC (Table 4, Figure 1). FAB subtypes were available for 95.4% of the children (Table 2). The most common subtypes were M1/M2 (51%), M4 (27%), and M5 (15%). None of the FAB subtypes were prognostic for outcome. However, there was a trend for inferior OS for children with FAB M6 or M7 (37711 vs 4873%, P ¼ 0.059). For each FAB subtype, children assigned allogeneic transplantation had superior outcome compared to those without an MFD. For example, children with FAB M1/M2 who had an MFD had an 8-year OS of 5678% compared with 4374% (P ¼ 0.004) for children with FAB M1/M2 who did not have an MFD.
Comparison of postremission therapies. Outcomes at 8 years from the end of induction (2 s.e.) Allo-BMT
N OS DFS RR TRM
adjusting for the study each child was enrolled on (Table 3). The RR at 8 years for children assigned to allogeneic transplantation was significantly lower than that for children not having an MFD (3675 vs 5673%, Po0.001). There was no benefit of autologous transplantation compared with chemotherapy (Table 3). Among the 302 children with an MFD who had information on the donor source, 288 (95.4%) had a matched sibling donor and 14 (4.6%) had a matched parental donor. The 8-year TRM was significantly higher among children assigned allogeneic transplants than among children without an MFD available (1774 vs 772%, Po0.001) (Table 3). This may have been related in part to complications of acute GVHD (aGVHD). Grades 1, 2, and 3/4 aGVHD were reported in 18, 15, and 13% of allogeneic transplanted recipients, respectively.
373 54% (5%) 47% (5%) 36% (5%) 17% (4%)
No donor
1091 45% (3%) 37% (3%) 56% (3%) 7% (2%)
Chemo
688 42% (4%) 34% (4%) 60% (4%) 6% (3%)
Auto-BMT
217 49% (7%) 42% (7%) 52% (7%) 7% (4%)
Otherb
186 49% (8%) 41% (7%) 50% (8%) 9% (4%)
P-valuea Allo vs no donor
Allo vs chemo
Chemo vs auto
Allo vs auto
0.026 0.005 o0.001 o0.001
0.064 0.004 o0.001 o0.001
0.371 0.832 0.613 0.711
0.031 0.075 o0.001 0.279
a
Cure regression P-values that account for the study each child was enrolled on. Withdrew from study prior to regimen assignment or unknown data.
b
Table 4 (2 s.e.)
Comparison of those with and without an MFD stratified by diagnostic WBC count. Outcomes at 8 years from the end of induction
WBC o50 000
N OS DFS RR TRM
WBC X50 000
Donor vs no donor
Donor
No donor
Donor
No donor
P-valuea
301 54% (6%) 48% (6%) 33% (6%) 19% (5%)
782 46% (4%) 41% (4%) 52% (4%) 7% (2%)
71 56% (12%) 45% (12%) 43% (12%) 12% (8%)
308 40% (6%) 27% (5%) 67% (5%) 6% (3%)
0.028 0.008 o0.001 o0.001
a
Cure regression P-values that adjust for WBC and the study each child was enrolled on. Leukemia
Postremission therapy for pediatric AML TA Alonzo et al
968
Disease-free survival
1
0.75 Donor, WBC ≥ 50,000 (N=71) Donor, WBC < 50,000 (N=301)
0.5
No donor, WBC < 50,000 (N=782) 0.25
No donor, WBC > 50,000 (N=308) P
