We reviewed 70 consecutive children with AML who received hematopoietic stem cell transplantation (HSCT) in our institution between 1994 and 2005. Forty-seven children were transplanted in CR1 and 23 were transplanted in CR2. BU/CY was the most common pretransplant conditioning regimen for CR1 patients and a TBI-based conditioning regimen was the most common regimen for CR2 patients. Most patients transplanted in CR1 (81%) received related donor HSCT, whereas most of the CR2 patients (74%) received unrelated donor HSCT. Expectedly, there was a significant increase in acute GVHD incidence in CR2 patients (40 vs 25% for grades I–II and 30 vs 10% for grades III–IV; P=0.02) and a significant increase in transplant-related mortality (38 vs 11%; P=0.01). Although the difference between 3-year EFS for CR1 and CR2 was not statistically significant, there was a significantly superior 3-year overall survival for CR1 patients (74 vs 51%; P=0.05). Children with relapsed AML who achieve and maintain remission until HSCT, have a reasonable survival, but the outcome of children receiving HSCT in CR1 remains superior.
Significant advances have been made in the treatment of pediatric AML and CR can now be achieved in >90% of children. However, 40–50% of patients relapse after achieving a CR1 with chemotherapy alone, and EFS remains at approximately 50% in most large series.1, 2, 3 Although CR2 may be achieved in the majority of these children with chemotherapy alone, long-term survival is limited to 8–33%.4, 5, 6 While most would recommend allogeneic hematopoietic stem cell transplant (HSCT) as therapy for relapsed AML, the role of HSCT is less certain for children with AML in CR1.1, 2, 7 With the excellent results of chemotherapy and the known risks and long-term side effects of HSCT, the decision to proceed with HSCT in CR1 remains controversial. HSCT provides the ability to administer high doses of chemo- or radiotherapy to eradicate the leukemia and the potential benefit of a GVL effect.8 Survival rates as high as 72% have been reported for children transplanted in CR1.9 For children with AML beyond CR1, HSCT may be the only curative option. However, the clinical outcome for children transplanted in CR2 is not well defined, as studies published to date report data of these patients combined with other childhood diseases or with adult patients.10, 11 The objective of this study was to determine the outcome of consecutive children with AML who received an allogeneic HSCT in CR2, to compare it with those who received HSCT in CR1 and to analyze the effectiveness of HSCT for this group of patients.
Patients, materials and methods
We retrospectively reviewed 70 consecutive pediatric patients with AML who underwent first allogeneic HSCT between 1994 and 2005. Patients with mixed-lineage/biphenotypic acute leukemia and children with Down's syndrome were excluded. AML subtypes were classified using the FAB system. Risk definition and cytogenetic abnormalities were classified according to the United Kingdom Medical Research Council (UK-MRC) criteria, favorable if t(8;21), t(15;17) or inversion 16 was present, unfavorable if −5, −7, del (5q), abn (3q) and complex cytogenetics and standard group for the remaining.
Patient characteristics are described in Table 1. The indications for HSCT in CR1 have changed over the years and as our understanding of childhood AML has progressed. In the early years of the study (1994–1998), HSCT was offered to all AML patients who had a matched sibling donor. More recently (1999–to date), the UK-MRC risk stratification criteria were utilized and HSCT was offered to the standard-risk group if there was a matched related donor and for the poor-risk group HSCT using related or unrelated donors was offered. Good-risk patients in CR1 were treated with chemotherapy only. Upfront AML chemotherapy has also changed during the study period. Children were treated according to the Pediatric Oncology Group 9421 protocol for the first half of the study period, and according to the UK-MRC 10 protocol for the second half of the study period. Salvage chemotherapy after relapse to achieve CR2 was mainly based on the treating oncologist's discretion for the first half of the study period, and the FLAG chemotherapy protocol was instituted for the second half of the study period. Patients were defined as being in CR2 if they had less than 5% blasts in a normocellular BM and normal peripheral blood counts after chemotherapy.
In our institution, pretransplant conditioning regimens for childhood AML included a nonradiation-based regimen, mainly BU/CY (BU q6h × 16 doses (adjusted as per PK measurements to obtain concentration–time curve of 900–1500 μM min) followed by CY 50 mg/kg/day × 4 days) when utilizing related donors and a TBI- (1200 cGy in six fractions over 3 days) based conditioning regimen (CY/TBI=CY 50 mg/kg/day × 4 days followed by TBI, VP-16/TBI=VP-16 60 mg/kg as a single dose followed by TBI) for unrelated donors or those with central nervous system involvement. All patients were nursed in protective isolation rooms with high-efficiency particulate air filters. All patients received fluconazole for fungal prophylaxis, ganciclovir for CMV prophylaxis, Pneumocystis jiroveci pneumonia prophylaxis for 6 months to 1 year and pneumococcal prophylaxis with penicillin for at least 1 year or until vaccination with pneumococcal vaccine. BM was the preferred stem cell source and the day of stem cell infusion was defined as day 0. The desired minimum cell dose was 2 × 108 nucleated cells per kg of recipient body weight.
GVHD prophylaxis consisted of MTX and CsA. Acute GVHD was graded as 0–1V according to the criteria of Glucksberg et al.12 Chronic GVHD was defined as none, limited or extensive according to previously reported criteria.13 Tissue biopsy samples were obtained to confirm GVHD diagnosis whenever clinically indicated and feasible. Relapse was diagnosed by either morphological evidence of disease in the peripheral blood, marrow and extramedullary sites, or by the recurrence and sustained presence of pretransplant chromosomal abnormalities based on cytogenetic analysis of BM cell. Neutrophil engraftment was defined as the first of three consecutive days of ANC >0.5 × 109/l, following the neutrophil nadir. Primary graft failure was defined in patients surviving beyond day +28 as failure to attain an ANC >0.5 × 109/l before death or upon receipt of a second graft.
Differences in continuous outcomes between the CR1 and CR2 groups were compared using the Wilcoxon's rank-sum test. Categorical variables were compared using the χ2 test or Fisher's exact test as appropriate. EFS, overall survival (OS), cumulative incidence of transplant-related mortality (TRM) and cumulative incidence of relapse were described according to the Kaplan–Meier method and groups were compared using the log-rank test. In the determination of EFS, death, relapse, graft rejection and graft failure were considered as events. TRM was defined as any death in remission.
Seventy consecutive children with AML were included in the analysis. All patients received HSCT in remission except one patient in the CR1 group whose BM aspirate just before HSCT contained 8% blast cells. Using the UK-MRC risk stratification criteria, the majority of CR1 patients were found to be in the standard (intermediate) group and most received matched related donor HSCT (81%) using BU/CY, whereas the majority of the CR2 patients were in the good-risk group and received unrelated donor HSCT (74%) using TBI-containing regimens. Four patients relapsed following first transplant and were treated with second HSCT; however, for purposes of analysis they were considered only in their original group. Age, gender, donor source, conditioning regimens and risk group stratification are summarized in Table 1.
Clinical outcomes are summarized in Table 2. Primary graft failure was encountered in two CR2 patients; one patient was re-transplanted successfully and remains alive in remission and the other patient died of sepsis and respiratory failure. The remaining 21 patients engrafted at a median of 19 days (range 11–29 days). Two patients in CR1 died before day +28 and were not evaluable for engraftment or GVHD. The remaining CR1 patients engrafted at a median of 21 days (range 12–32 days). GVHD incidence (acute and extensive chronic) occurred more frequently among CR2 patients compared with CR1 patients. This is explained by the increased number of unrelated donor transplants among CR2 patients. Nine patients died while in remission in the CR2 group compared with only five patients in the CR1 group (TRM 38 vs 11%; P-value=0.01). Causes of death were the following: infection and severe sepsis in six patients, pulmonary complications in three patients, acute severe GVHD with multi-organ failure in three patients, severe veno-occlusive disease with multi-organ failure in one patient and cardiac failure in one patient. Among CR2 patients, there were 12 who had an early relapse post-CR1 (defined as relapse less than or equal to 1 year from diagnosis), of whom five died from non-relapse causes. Eleven of the CR2 patients had a late relapse post-CR1 (defined as relapse more than 1 year from diagnosis), and 4 out of 11 died from non-relapse causes.
Fourteen patients relapsed from the CR1 group. Two of them relapsed late, after 1 year post-HSCT, and were salvaged with a repeat HSCT, and in one of them a single dose of donor leukocyte infusion was given after the second HSCT. Both patients are long-term survivors. One patient suffered a very late relapse, 8 years after HSCT. This patient is presently being treated and followed elsewhere. Four patients relapsed from the CR2 group; one patient was salvaged with donor leukocyte infusions and is a long-term survivor.
Overall, there was no significant difference in EFS or relapse rate between the two groups. Non-relapse or TRM was significantly higher in the CR2 group, leading to a significantly superior 3-year OS for CR1 patients (74 vs 51%; P=0.05). OS and EFS are shown in Figures 1, 2, respectively.
In this large study of pediatric AML receiving HSCT, we found that the outcome of children receiving HSCT in CR1 is superior to those receiving HSCT in CR2. Patient characteristics for the CR1 and CR2 groups (in particular original risk group stratification, stem cell source and conditioning regimens) were different, making comparisons between the two groups difficult. Nonetheless, our data suggest that children with AML receiving HSCT in CR1 have a better survival compared with children receiving HSCT in CR2.
Most data suggest that children with relapsed AML cannot be cured with chemotherapy alone.4, 5, 6 To improve the treatment outcome of these patients; high-dose chemo/radiotherapy combined with allogeneic HSCT has been undertaken. Data from series of children transplanted for AML in CR2 are limited.10, 11 Patient numbers are usually small and long-term follow-up is rarely reported. Our CR2 HSCT results are to be compared with those from another single-centre study from Seattle reporting 5-year EFS of 58% for children with AML transplanted in CR2; however, the number of patients was only 12.14 A previous study of allogeneic HSCT has reported an EFS of 22% and OS of 33% for nine children transplanted in CR2 for AML.10 A recent study has observed a 5-year OS of 35.9±8.0% for children with AML transplanted in CR2.5 A French multicentre study has reported the outcome of children who received transplantation in CR2 with EFS of 60% for matched sibling donor and 44% for alternative donor HSCT with 12 and 16 patients in each group, respectively.6 In another trial in Germany, EFS of 2.5 years was observed in 7 of 16 (43%) children transplanted from a matched sibling donor, and only 1 of 4 (25%) survived after a matched unrelated donor transplant.15 Our encouraging results may have been influenced by the unusually large percentage of children with favorable risk cytogenetics in our CR2 sample. The reported incidence of TRM for CR2 AML patients receiving HSCT has been in the range of 10–50%.6, 10, 11, 16, 17 In our study, we observed significantly more TRM in CR2 HSCT recipients compared with CR1 HSCT recipients. This is to be expected due to the CR2 patients being heavily treated before HSCT, with an increased incidence of opportunistic infections and organ damage. Relapse is a major risk post-HSCT and occurs in 30–60% of children with AML.2, 6, 10 The majority of relapses occur in the first year after HSCT and in our study, for CR1 and CR2 HSCT recipients, we observed that patients who relapse later than 1-year post-HSCT are amenable to further therapy, donor leukocyte infusions and a second HSCT, with long-term survivors.
The question of whether to transplant children with AML in CR1 or not is important. Although in the past all children with AML were considered for HSCT in CR1 particularly if there was a related donor, with the current state-of-the-art intensive chemotherapy, this decision remains controversial. Large studies conducted by the Children Cancer Group (CCG), CCG 251, CCG 213 and CCG 2891, have proven that outcome of children with AML receiving related donor HSCT in CR1 is superior, compared with chemotherapy only.18 Furthermore, a recently published study conducted by the same group, CCG 2961, again demonstrated significantly better disease-free survival for children with AML receiving related donor HSCT in CR1, vs chemotherapy only (60 vs 50%; P=0.02).19 In our study, the 3-year TRM was 11% in our CR1 HSCT recipients. This relatively low TRM could be explained by the fact that most of our CR1 patients received matched related donor cells and had better organ function and less infectious complications compared with CR2 patients. This low TRM in CR1 HSCT patients is similar to the upfront chemotherapy infection-related mortality incidence recently published for 492 children with AML in the CCG 2961.20 Nonetheless, with the current excellent results of chemotherapy only for pediatric AML, offering HSCT to CR1 AML children, apart from the poor-risk group, remains controversial. In our institution, we have adopted the UK-MRC recommendations and continue to offer HSCT to children with standard risk AML if there is a fully matched related donor, and continue to offer any donor HSCT for the poor-risk group. However, we no longer offer HSCT to the good-risk group. Hence, only two patients in the CR1 group were transplanted and fell in the good-risk group (Table 1). These two patients received HSCT early in the study period, when our knowledge and risk stratification about pediatric AML were not optimal.
The outcome of children receiving HSCT in CR1 was encouraging in our study and was significantly better compared with CR2 HSCT recipients despite having a generally good-risk group in CR2 HSCT recipients. One can speculate that if we compare the outcomes of children with standard risk AML receiving HSCT in CR1 vs CR2, this better outcome for CR1 HSCT recipients may be even more pronounced. We acknowledge the fact that more than 50% of our CR2 patients belonged to the favorable-risk group. This was completely coincidental and may be explained in two ways. First, we offer HSCT in CR1 to poor-risk patients and intermediate-risk patients with a family donor, and we do not offer HSCT to favorable-risk group in CR1. Relapse post-chemotherapy only is usually more common compared with that after HSCT, and about 35% of the good-risk group usually relapse post-chemotherapy.2 Second, it is known that the favorable group enters remission, in CR1 or CR2, much easily compared with other risk groups in pediatric AML. In the UK MRC 10 trial, survival from relapse at 5 years was significantly different: survival for good, standard and poor risk was 57, 14 and 8% (P=0.0003). Therefore, these good-risk patients could potentially enter and maintain their remissions and receive HSCT, and are expected to have better survivals after relapse compared with standard and poor-risk patients.2
Our objective in this study was to examine the effect of HSCT on children with AML who enter remission and receive HSCT in CR1 or CR2 and compare their outcome. Therefore, we have not examined pediatric AML based on an ‘intention-to-treat’ analysis. Furthermore, our institution is a tertiary referral centre for HSCT and we are unable to obtain exact figures of all children with AML from other referral centers who did not enter remission or did not survive to the time of HSCT.
In summary, curing children with relapsed AML is a realistic goal even after aggressive first-line therapy. Although direct comparisons with previous studies are not valid, we consider the current results to be encouraging and supportive of the role of allogeneic HSCT for children with recurrent AML. Furthermore, we found that outcomes of children with AML receiving HSCT in CR1 were very encouraging and superior compared with the outcomes of children receiving HSCT in CR2.
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We are indebted to the patients, families, nursing and medical staff of the 8B unit and the oncology units at our partner centers for the provision of excellent patient care, which has been crucial for the achievement of the results reported here.
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Gassas, A., Ishaqi, M., Afzal, S. et al. A comparison of the outcomes of children with acute myelogenous leukemia in either first or second complete remission (CR1 vs CR2) following allogeneic hematopoietic stem cell transplantation at a single transplant center. Bone Marrow Transplant 41, 941–945 (2008). https://doi.org/10.1038/bmt.2008.16
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