The parallel CCG 1953 and POG 9407 studies were designed to test the hypothesis that intensification of early therapy would improve the outcome of infants with ALL. This was achieved by two approaches, dose intensification of chemotherapy and HSCT for infants with MLL-positive ALL early in CR1.
Dosing of chemotherapy for infants in previous protocols was determined by weight, not BSA, resulting in significantly lower doses of drugs for infants. To intensify the protocol therapy, BSA was used to calculate doses of all agents except vincristine and, after protocol amendment, daunorubicin. Dexamethasone was chosen as the corticosteroid based on reports of improved outcome with dexamethasone.17
At the time these protocols were developed, there were no reported large prospective trials of HSCT in infants with ALL. The promising results from the Fred Hutchinson Cancer Research Center (FHCRC) of 11 infants (seven of 11 infants were MLL
positive) who received transplantation in first or second remission were the basis for evaluating this treatment modality. On the basis of this experience, a major objective of the CCG 1953 and POG 9407 studies was to prospectively evaluate the role of HSCT in the highest risk infants with MLL
The decision to include TBI in the pretransplantation preparative regimen was based on the favorable outcome of the infants treated at the FHCRC. Two reports of acceptable neurocognitive outcomes for infants treated with TBI-containing transplantation regimens were available at the time, although more recent reports do cite neurocognitive and hormonal disturbances as late effects associated with TBI.20–22
Cytarabine was incorporated based on superior results with regimens incorporating either hyperfractionated TBI (1.2 Gy three times daily for 4 days)23
or high-dose cytarabine.24
The combination of cytarabine with cyclophosphamide and TBI had been demonstrated to be tolerable in older children.25
A major impediment to successful transplantation in these patients was the lack of suitable family donors. To increase the number of patients with suitable donors, acceptable stem-cell sources included family or unrelated donors with up to a one antigen mismatch including unrelated cord blood units. Single-agent cyclosporine was the protocol-specified GVHD prophylactic regimen with the hope of an enhanced graft-versus-leukemia effect.
To our knowledge, this experience represents the largest evaluation of infants with MLL-rearranged ALL who received transplantation in CR1 compared with a concomitantly treated control group who received intensive chemotherapy. The results suggest that HSCT offered no advantage compared with intensive chemotherapy regardless of the choice of preparative regimen. The 5-year EFS rates for the 53 infants who received transplantation in CR1 and for the 47 infants treated with intensive chemotherapy were not dissimilar. Potential reasons for the lack of a difference in outcome between patients who did and did not received transplantation were the improved outcome of patients treated with the chemotherapy regimens and the suboptimal transplantation regimen.
The overall 3-year EFS rates for CCG 1953 (33.6%)13
and POG 9407 (40%)26
are comparable to those reported in the multi-institution Japan Infant Leukemia Study Group trial in which the 3-year EFS rate for infants with MLL
-positive ALL was 44% (95% CI, 28.5% to 58.7%). However, for the 29 infants who underwent HSCT, the EFS rate was 64%.27
The CCG 1953/POG 9407 results contrast somewhat with the results of selected single-center experiences of HSCT in infants. The FHCRC reported a 3-year disease-free survival rate of 76% among 17 infants (three without documented MLL
rearrangement) who received transplantation in CR1.22
The Children's Memorial Hospital experience included 16 infants who received transplantation (age, 1 to 15 months at diagnosis; five infants without MLL
rearrangement) and demonstrated a 1-year EFS rate of 64% (95% CI, 40% to 88%) and a 3-year overall survival rate of 75% (95% CI, 47% to 92%).28
Differences in patient characteristics, such as older age, lower WBC count, and inclusion of infants without the MLL
rearrangement, preclude strict comparison with our data.
The recently published international study Interfant-99 demonstrated a disease-free survival advantage for HSCT (n = 16) over chemotherapy alone (n = 71) in patients with MLL
-positive ALL identified as high risk based on age less than 6 months and either poor response to corticosteroid at day 8 or WBC greater than 300 × 103
/μL. This advantage was more evident with each successive year.3
However, an earlier review of 497 children, including infants and noninfants, with ALL and 11q23 rearrangements failed to prove an advantage for HSCT over intensified chemotherapy.4
More than half the infants included in this report did not receive transplantation according to the protocol specifications. When comparing HSCT with chemotherapy, bias is introduced when patients receive transplantation after prolonged periods in remission, resulting in unbalanced allocation of patients who experience relapse early to the chemotherapy arm. To address this problem, the protocol specified that infants with MLL-positive ALL and suitable donors were eligible for transplantation, which was to be scheduled within 4 months of enrollment. However, 60% of patients treated with the protocol-specified preparative regimen and only 29% of the patients treated with non–protocol-specified preparative regimens received transplantation within 4 months of enrollment ( and ).
Additionally, more than half of the patients were not treated with the protocol-specified preparative regimen. Five-year EFS rate was 56.9% (95% CI, 35.8% to 78.1%) for HSCT-OFF patients compared with 40.0% (95% CI, 19.8% to 60.2%) for HSCT-ON patients (P = .17). The median time to transplantation was 6 months for the HSCT-OFF group compared with 4 months for the HSCT-ON group. This difference in time to transplantation may partially explain the nonsignificantly better outcome of the off-protocol transplantation cohort.
Decreased transplantation-related morbidity also may have contributed to the better outcome of the off-protocol cohort. Grade 3 or 4 GVHD occurred more often in the HSCT-ON group. A more intensive GVHD prophylactic regimen may have improved EFS for this group. The preparative regimen, which incorporated high-dose cytarabine and corticosteroids, may have contributed to the higher transplantation-related morbidity and mortality of the protocol-specified transplantation regimen. TBI does not seem to have affected EFS (C). The transplantation-related morbidity was quite high in this study compared with the chemotherapy-only control group and compared with other studies of HSCT in infants. With a less morbid transplantation preparative regimen, the EFS in the patients who received transplantation may have been more favorable compared with the control group.
Additional limitations to this study include the broad heterogeneity of preparative regimens and GVHD prophylaxis in patients who received transplantation with non–protocol-specified therapy. In addition, because the decision for HSCT was investigator option on POG 9407, investigator bias must be included as a potential limitation.
The conclusions of our study and the recent report of Interfant-99 establish several important points regarding the treatment of infant ALL. First, there is no role for the routine use of HSCT in infant ALL, and most infants clearly do not benefit from this approach. Interfant-99 demonstrated a modest advantage for a small subgroup of particularly high-risk infants. We did not see an advantage for HSCT in a similar population in our trial, but numbers were limited, making subgroup analyses difficult. Second, in both studies, there is a high early failure rate for the highest risk group, particularly those younger than 3 months of age. A primary goal of future trials must be to improve complete remission rates, decrease early relapse, and lessen the toxic death rate for this patient population.
Additional studies, such as gene expression profiles or minimum residual disease, might be useful for identification of subgroups most likely to benefit from HSCT (or, conversely, who would have a high cure rate with chemotherapy alone). As chemotherapy and transplantation regimens change, the comparison of HSCT and chemotherapy in infants with MLL-rearranged ALL will require re-evaluation.