Leukemia represents the most common pediatric malignancy, accounting for approximately 30% of all cancers in children less than 20 years of age. Most children diagnosed with leukemia are cured without hematopoietic stem cell transplantation (HSCT), but for some high-risk subgroups, allogeneic HSCT plays an important role in their therapeutic approach. The characteristics of these high-risk subgroups and the role of HSCT in childhood leukemias are discussed.
Leukemia represents the most common pediatric malignancy, accounting for approximately 30% of all cancers in children less than 20 years of age. Acute lymphoblastic leukemia (ALL) is the most frequent, accounting for approximately 23% of childhood cancers. Acute myeloid leukemia (AML) accounts for approximately 4% of pediatric cancer diagnoses and 20% of childhood leukemia. Chronic myelogenous leukemia (CML) is rare and accounts for approximately 1% of all pediatric cancer, although it accounts for 10% of leukemias in older adolescents. Juvenile myelomonocytic leukemia (JMML) is infrequent, accounting for about 2% of leukemias and 25% of myelodysplastic syndrome in childhood. Most children diagnosed with leukemia are cured without hematopoietic stem cell transplantation (HSCT), but for some high-risk subgroups, allogeneic HSCT plays an important role in their therapeutic approach.
ALL
Prognostic Variables and Risk Stratification at Diagnosis
Clinical and biologic features are used to subtype, risk stratify, and assign therapy at diagnosis. Initial risk group assignment is made based on age, peripheral white blood cell count (WBC), central nervous system (CNS) involvement, and phenotype. Phenotypic classification is determined by flow cytometry of lineage-associated cell surface markers. Most cases of ALL are of precursor B cell (pre-B) phenotype (CD10, CD19, HLA-DR, TDT+), 10% to 20% are T cell (CD2, CD3, CD5, and/or CD7+), and <5% are mature B cell or Burkitt type (CD20, surface-IgM+).
Cytogenetic studies are subsequently used to further define the risk of relapse. The t(12;21) translocation, the most frequent recurrent chromosomal translocation associated with childhood ALL, is identified in approximately 25% of cases and this is associated with a favorable prognosis. Gene rearrangements of the mixed-lineage leukemia (MLL) gene located at 11q23 is the most common cytogenetic finding in infants with ALL, and has an extremely poor prognosis. The so-called Philadelphia chromosome (Ph + ), which results from a translocation between chromosomes 9 and 22, t(9;22), also confers adverse risk. The t(1;19) translocation is also associated with an increased risk of relapse, but this can be offset by therapy intensification. Hyperdiploidy, which most often includes trisomies of chromosomes 4, 7, and/or 10, carries a favorable prognosis. Hypodiploid cases are at higher risk of relapse. Recently, gene expression analysis has been shown to allow further discrimination in risk classification and prediction of treatment response.
The initial response to therapy has important prognostic usefulness. A rapid early response (RER), defined as a marrow blast count less than 5% within 7 to 14 days, or clearance of peripheral blasts within 7 to 10 days, has a better outcome than when the response is slower (SER). Response to therapy can be further quantified by flow cytometric or molecular analysis of minimal residual disease (MRD), which has been shown to correlate with outcome.
Nontransplant Therapy
Approximately 80% of children with ALL are cured with chemotherapy, the intensity of which is determined by risk group assignment and treatment stratification. Most patients fall into the standard risk category characterized by age between 1 and 9 years, WBC <50,000/μL, B-precursor phenotype, and absence of high-risk chromosomal abnormalities. Therapy for B-precursor and T cell ALL consists of induction, consolidation/intensification/re-induction, CNS sterilization, and maintenance for 2 to 3 years. Individuals with mature B cell phenotype are treated using Burkitt lymphoma regimens, which most commonly include dose- and sequence-intensive, short-course combination chemotherapy.
The prognosis after relapse of ALL depends on the duration of the first remission (CR1) and the site of relapse. Outcome after short CR1 duration (<12–18 months) is very poor, as is the prognosis for individuals who are unable to achieve a second remission. Those with isolated extramedullary relapse fair better than those with marrow relapse.
Transplantation
There have been no large, prospective, controlled clinical trials to evaluate the relative efficacy of allogeneic HSCT in comparison with chemotherapy for childhood ALL. However, multiple comparative studies suggest that relapse rates are lower after HSCT. Some of the benefits of relapse-free survival are offset by transplant-associated morbidity and mortality. Consequently, HSCT is usually reserved for the management of relapse and it is rarely used for children in CR1 except for those with extremely high-risk features ( Fig. 1 ; Table 1 ). Results of recent trials of HSCT for children and adolescents with ALL in second remission (CR2) are presented in Table 2 . For those with HLA-matched sibling donors, allogeneic HSCT in second remission is considered standard. Unrelated donor HSCT is usually reserved for those at high risk of relapse with chemotherapy ( Figs. 1 and 2 ). The approach in individual cases varies based on risk/benefit analysis, donor options, and access to transplantation. The American Society for Blood and Marrow Transplantation (ASBMT) has published consensus guidelines for the use of HSCT in childhood ALL ( Table 3 ). Suggested algorithms for HSCT in pediatric ALL are presented in Figs. 1 and 2 .
| Study Group | Dates of Study | High Risk Indicator | Patients (n) | Outcome (Years) | References |
|---|---|---|---|---|---|
| Toronto | 1985–2001 | t(9;22) | 11 MRD, MUD 10 chemo | 53% EFS (4) | Sharathkumar, 2004 |
| UKALL-X UKALL-XI | 1985–1990 1990–1997 | WBC >100,000/μL ± t(9;22), near-haploid, induction failure | 76 MRD, 25 MUD 351 chemo | 45% EFS (10) 39% EFS (10) | Wheeler, 2000 |
| AIEOP/GITMO | 1986–1994 | WBC >100,000/μL, BFM risk index >1.7, t(9;22), t(8;11), steroid resistance, T-cell disease, induction failure | 30 MRD 130 chemo | 58% DFS (4) 48% DFS (4) | Uderzo, 1997 |
| NOPHO | 1981–1991 | WBC >100,000/μL | 22 MRD 44 chemo a 405 chemo b | 73% DFS (10) 50% DFS (10) 59% DFS (10) | Saarinen, 1996 |
| IBMTR | 1978–1990 | t(9;22) | 33 MRD | 38% DFS (2) | Barrett, 1992 |
| Groupe d’Etude de la Greffe de Moelle Osseuse | 1980–1987 | t(9;22) WBC >100,000/μL, induction failure | 32 MRD | 84% DFS (2.5) | Bordigoni, 1989 |
| Study Group | Dates of Study | Patients (n) | Outcome (Years) | References |
|---|---|---|---|---|
| BFM | 1985–1991 | 51 MRD | 52% EFS (5) | Dopfer, 1991 |
| IBMTR/POG | 1983–1991 | 255 MRD 255 chemo | 40% DFS (5) 17% DFS (5) | Barrett, 1994 |
| Leiden | 1982–1991 | 25 MRD 97 chemo | 44% DFS (4) 24% DFS (4) | Hoogerbrugge, 1995 |
| AIEOP/GITMO | 1980–1990 | 57 MRD 230 chemo | 41% DFS (5) 21% DFS (5) | Uderzo, 1995 |
| Paris | 1983–1993 | 42 MRD | 53% (4) | Moussalem, 1995 |
| UKALL-X | 1985–1990 | 83 MRD, 27 MUD 61 ABMT 261 chemo | 40% EFS (5) 34% EFS (5) 26% EFS (5) | Wheeler, 1998 |
| UKALL-R1 | 1991–1995 | 63 MRD 41 MUD 15 ABMT, 89 chemo | 46% EFS (5) 54% EFS (5) 43% EFS (5) | Harrison, 2000 |
| IBMTR/COG | 1991–1997 | CR1 <36 months 92 MRD + TBI 19 MRD no TBI 110 chemo CR1 ≥36 months 61 MRD + TBI 14 MRD no TBI 78 chemo | 32% OS (8) 44% OS (8) 18% OS (8) 66% OS (8) 63% OS (8) 32% OS (8) | Eapen, 2006 |
| COG | 1995–1998 | 32 MRD 19 MUD 23 chemo | 42% DFS (3) 29% DFS (3) 30% DFS (3) | Gaynon, 2006 |
| Recommendation | Indication | References |
|---|---|---|
| HSCT in CR1 | Benefit demonstrated for matched related donor HSCT for Philadelphia chromosome+ only Not recommended for other high-risk patients, except in the setting of a clinical trial | Wheeler, 2000 Chessells, 1992 Arico, 2000 Uderzo, 1997 |
| HSCT in CR2 with prior bone marrow relapse | Recommended for those with matched related donors Evidence insufficient to recommend unrelated donor HSCT | Barrett, 1994 Wheeler, 1998 Uderzo, 1995 Harrison, 2000 |
A retrospective matched cohort analysis performed by the Children’s Oncology Group (COG) and International Bone Marrow Transplant Registry (IBMTR) compared matched related HSCT with chemotherapy for children with ALL in CR2. Leukemia-free survival and relapse rates were better after HSCT in all patient groups regardless of the CR1 duration. In a more recent study from the COG and IBMTR, overall survival, leukemia-free survival, and treatment-related mortality were superior for patients with a short CR1 duration (<36 months) who underwent HSCT with total body irradiation (TBI)-based conditioning regimens (vs chemotherapy and non-TBI transplant regimens). For those with a late relapse (≥36 months CR1 duration), outcomes were equivalent in the chemotherapy and TBI transplant groups. Those treated with HSCT without TBI had higher risk of relapse and inferior disease-free survival (DFS) rates regardless of CR1 duration.
Despite the lower relapse rates after HSCT, this approach carries the risk of transplant-associated mortality and morbidity (eg, graft-versus-host disease [GVHD]). Further, chemotherapy alone can be effective. Approximately 30% to 40% of children who sustain a late relapse (≥36 months CR1 duration) may achieve long-term DFS with aggressive chemotherapy alone.
Decisions about the role for and timing of HSCT for children with relapsed ALL are commonly individualized based on biologic, clinical, treatment, and donor factors (see Fig. 2 ). Transplant is usually recommended for children with relapse who have HLA-matched sibling donors irrespective of other prognostic factors. An alternative approach for those with a long CR1 duration is to reserve HSCT in the event of another relapse. For individuals who sustain bone marrow relapse during front-line therapy or within 6 months of completion of therapy the prognosis is poor with chemotherapy alone, and HSCT with an alternative (ie, unrelated or HLA-mismatched related) donor should be considered. HSCT is also often considered for T-cell ALL with marrow relapse. Additional factors that place an individual at high risk of subsequent relapse or that limit the ability to administer chemotherapy (eg, allergy, organ toxicity) also warrant consideration of HSCT.
HSCT in first remission has no proven benefits for patients defined as high risk by WBC count, gender, and age. However, transplantation is commonly considered for those at very high risk of relapse with standard therapy (eg, hypodiploidy, induction failure) (see Fig. 1 , Table 1 ). Although historically HSCT has been considered for children with Ph + ALL, the addition of imatinib mesylate, a tyrosine kinase inhibitor, to chemotherapy seems to have improved nontransplant outcome, diminishing the role of HSCT as upfront therapy. The role of HSCT for other very high-risk groups should be considered in the setting of a clinical trial. HSCT in infants <18 months old, especially those with MLL rearrangements remains controversial because of the high risk of adverse effects of transplant conditioning in such young patients. Some series report outcomes following HSCT in CR1 that may be superior to chemotherapy. However, others show no definitive benefit compared with intensive chemotherapy. A IBMTR database review report 3-year probabilities of DFS of approximately 50% after HLA-matched sibling and unrelated donor transplantation in CR1 for infants with ALL.
Conditioning Regimens
Multiple studies indicate that TBI-based transplant conditioning regimens are associated with lower risk of relapse compared with chemotherapy-only regimens for children with ALL. Second HSCT using TBI has been successful for children who have relapsed after a busulfan-based preparative regimen.
Disease Status
Individuals with ALL should be transplanted in complete remission (CR) and there is little to no role for HSCT in patients with ALL who are not in CR. Recent data indicate that the MRD level at the time of HSCT correlates with outcome. Children with no detectable MRD (<1 leukemia cell in 10,000 bone marrow cells) have excellent posttransplant outcomes. In addition, many series report that patients transplanted in earlier remissions fare better than those with a history of multiple relapses, although such studies are subject to significant selection bias.
Donor Selection
Outcomes of alternative donor transplantation have improved in recent years and several groups report equivalent outcomes to HLA-identical sibling donors using matched unrelated, partially matched related, partially mismatched unrelated cord blood, and haploidentical donors. Donor T cell depletion and improvements in supportive care of infection and GVHD have improved the outcomes of such alternative donor transplants. However, T cell depletion is associated with increased risk of graft rejection, mixed chimerism, delayed immune reconstitution, and infectious complications. Treatment-associated mortality remains high, exceeding 20% in published series of alternative donor transplants for ALL, due in part to the high-risk nature of patients treated with that approach. Rates of extensive chronic GVHD also remain high after alternative donor transplants.
Second Transplants
For patients who relapse following allogeneic HSCT for ALL, a second transplant may be possible, although the outlook is very poor. This approach carries a high risk of mortality as a result of progressive disease and/or treatment-associated toxicity. Although remission can be obtained in as many as 50% to 70% of patients, the duration is typically short and only 10% to 30% achieve long-term event-free survival. The prognosis is better for those with longer remission duration after the first HSCT. Donor leukocyte infusion (DLI) has a limited role in the setting of ALL and posttransplant relapse, although successful remission induction with withdrawal of immunosuppression and/or DLI has been reported in a small percentage of cases (discussed elsewhere in this issue).
AML
Prognostic Variables and Risk Stratification at Diagnosis
The French-American-British (FAB) classification system categorizes AML into 7 distinct subtypes based on morphology and phenotype. AML subtype and other clinical and biologic features that influence outcome have recently been used to stratify treatment.
Nontransplant Therapy
In most cases AML treatment consists of intensive induction, consolidation, and CNS-directed chemotherapy. Approximately 75% to 90% of children with AML achieve a CR and increasing the treatment intensity of induction improves DFS rates. Postremission consolidation chemotherapy is essential and can be delivered in standard doses or as high-dose therapy with autologous stem cell rescue with similar DFS rates. Despite treatment intensification the outcome is guarded for most children with AML, and only about 50% are cured with chemotherapy alone. Individuals with acute promyelocytic leukemia (FAB M3) have a better prognosis, with 80% DFS rates observed when all- trans -retinoic acid is added during induction and a maintenance phase. Young children with trisomy 21 who develop AML also have excellent outcomes and require less intensive therapy.
Transplantation
Given the relatively poor outcome for pediatric patients with AML, allogeneic HSCT has commonly been used as consolidation in CR1. There have been multiple genetic randomization studies of matched related allogeneic HSCT in which individuals who have matched sibling donors are assigned to transplantation. Allogeneic HSCT confers a lower risk of relapse and improves DFS compared with chemotherapy with or without autologous rescue ( Table 4 ). However, clinical benefits can be offset by transplant-related morbidity and mortality, which may eliminate any overall survival advantage in low-risk groups. Consequently, there is some debate as to whether allogeneic HSCT should be used in CR1 or CR2 for AML in childhood. The ASBMT has published consensus guidelines for the use of HSCT in pediatric AML ( Table 5 ) and a suggested approach is presented in Fig. 3 .
| Study Group | DFS | Median Follow-up (Years) | References | ||
|---|---|---|---|---|---|
| Matched Related Donor HSCT (%) | Chemotherapy (%) | Autologous HSCT (%) | |||
| AML-80 | 43 | 31 | – | 6 | Dahl, 1990 |
| AIEOP LAM-87 | 51 a | 27 | 21 | 5 | Amadori, 1993 |
| CCG-213 | 54 a | 37 | – | 5 | Wells, 1994 |
| CCG-251 | 45 a | 32 | – | 8 | Nesbit, 1994 |
| POG-8821 | 52 a | 36 | 38 | 3 | Ravindranath, 1996 |
| MRC AML-10 | 61 a | 46 | 68 b | 7 | Stevens, 1998 |
| AML BFM-93 | 64 | 61 | – | 5 | Creutzig, 2001 |
| CCG-2891 | 55 a | 47 | 42 | 8 | Woods, 2001 |
| LAME-89/91 | 72 a | 48 | – | 6 | Perel, 2002 Aladjidi, 2003 |
a P ≤.05 allogeneic versus others.
| Recommendation | Indication | References |
|---|---|---|
| HSCT in CR1 | Benefit demonstrated for matched related donor HSCT | Alonzo, 2005 Woods, 2001 Ravindranath, 1996 Wells, 1994 Nesbit, 1994 Amadori, 1993 |
| HSCT in CR2 | Recommended for those with matched related donors Evidence insufficient to recommend unrelated donor HSCT, except in the setting of a clinical trial | Aladjidi, 2003 Pession, 2000 Gorin, 1996 |
In the United States, matched related sibling donor HSCT is the most common consolidation therapy used for children with AML in CR1 outside specific low-risk groups. This approach is based largely on clinical trials conducted by the Pediatric Oncology Group (POG) and the Children’s Cancer Group (CCG). Both groups reported superior outcomes for high- and intermediate-risk patients treated with HSCT in CR1. The 5-year overall survival rate for patients transplanted with a matched sibling donor in CR1 ranges from 52% to 72% (see Table 4 ).
Long-term DFS can be achieved in approximately 30% of children with AML who are transplanted in CR2 with either matched unrelated or mismatched related donors. Consequently, HSCT is sometimes reserved for management of patients who relapse after chemotherapy, especially for low-risk groups or those without sibling donors. ASBMT consensus guidelines recommend HSCT in CR2 only for patients with matched related donors, as evidence supporting unrelated donor HSCT is lacking.
Conditioning Regimens
Comparative clinical trials in adults reveal similar results with busulfan/cyclophosphamide compared with TBI/cyclophosphamide. Pediatric studies are limited, although no obvious differences are apparent. In general, busulfan/cyclophosphamide is the most commonly used pretransplant preparative regimen for pediatric AML.
Disease Status
In most of the published series of HSCT for pediatric AML, transplantation is performed for patients in remission. Although some individuals with AML who undergo HSCT in relapse can achieve long-term DFS, small pediatric studies suggest that the percentage of pretransplant blasts correlates with posttransplant relapse and that outcomes are improved when HSCT is performed in remission.
Donor Selection
Donors mismatched for natural killer cell (NK) killer immunoglobulin-like receptor may improve posttransplant outcome in AML as a result of allogeneic NK-cell mediated antileukemic effects, an approach that is currently under study in pediatric AML (see the article by Lankester and colleagues elsewhere in this issue).
Second Transplants
As in ALL, the outcome of second transplants for children with AML varies based on the interval since prior transplantation.
AML
Prognostic Variables and Risk Stratification at Diagnosis
The French-American-British (FAB) classification system categorizes AML into 7 distinct subtypes based on morphology and phenotype. AML subtype and other clinical and biologic features that influence outcome have recently been used to stratify treatment.
Nontransplant Therapy
In most cases AML treatment consists of intensive induction, consolidation, and CNS-directed chemotherapy. Approximately 75% to 90% of children with AML achieve a CR and increasing the treatment intensity of induction improves DFS rates. Postremission consolidation chemotherapy is essential and can be delivered in standard doses or as high-dose therapy with autologous stem cell rescue with similar DFS rates. Despite treatment intensification the outcome is guarded for most children with AML, and only about 50% are cured with chemotherapy alone. Individuals with acute promyelocytic leukemia (FAB M3) have a better prognosis, with 80% DFS rates observed when all- trans -retinoic acid is added during induction and a maintenance phase. Young children with trisomy 21 who develop AML also have excellent outcomes and require less intensive therapy.
Transplantation
Given the relatively poor outcome for pediatric patients with AML, allogeneic HSCT has commonly been used as consolidation in CR1. There have been multiple genetic randomization studies of matched related allogeneic HSCT in which individuals who have matched sibling donors are assigned to transplantation. Allogeneic HSCT confers a lower risk of relapse and improves DFS compared with chemotherapy with or without autologous rescue ( Table 4 ). However, clinical benefits can be offset by transplant-related morbidity and mortality, which may eliminate any overall survival advantage in low-risk groups. Consequently, there is some debate as to whether allogeneic HSCT should be used in CR1 or CR2 for AML in childhood. The ASBMT has published consensus guidelines for the use of HSCT in pediatric AML ( Table 5 ) and a suggested approach is presented in Fig. 3 .
| Study Group | DFS | Median Follow-up (Years) | References | ||
|---|---|---|---|---|---|
| Matched Related Donor HSCT (%) | Chemotherapy (%) | Autologous HSCT (%) | |||
| AML-80 | 43 | 31 | – | 6 | Dahl, 1990 |
| AIEOP LAM-87 | 51 a | 27 | 21 | 5 | Amadori, 1993 |
| CCG-213 | 54 a | 37 | – | 5 | Wells, 1994 |
| CCG-251 | 45 a | 32 | – | 8 | Nesbit, 1994 |
| POG-8821 | 52 a | 36 | 38 | 3 | Ravindranath, 1996 |
| MRC AML-10 | 61 a | 46 | 68 b | 7 | Stevens, 1998 |
| AML BFM-93 | 64 | 61 | – | 5 | Creutzig, 2001 |
| CCG-2891 | 55 a | 47 | 42 | 8 | Woods, 2001 |
| LAME-89/91 | 72 a | 48 | – | 6 | Perel, 2002 Aladjidi, 2003 |
a P ≤.05 allogeneic versus others.
| Recommendation | Indication | References |
|---|---|---|
| HSCT in CR1 | Benefit demonstrated for matched related donor HSCT | Alonzo, 2005 Woods, 2001 Ravindranath, 1996 Wells, 1994 Nesbit, 1994 Amadori, 1993 |
| HSCT in CR2 | Recommended for those with matched related donors Evidence insufficient to recommend unrelated donor HSCT, except in the setting of a clinical trial | Aladjidi, 2003 Pession, 2000 Gorin, 1996 |
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