A total of 389 Pediatric acute leukemia samples were analyzed in this study, from which high quality gene expression data were obtained on 360 (93%). The successfully analyzed samples included: 332 diagnostic bone marrows (BM), 3 diagnostic peripheral bloods (PB), and 25 relapse ALL samples from BM or PB. 264 (79%) of the diagnostic ALL BM samples and all relapse samples were from patients treated on St. Jude Children's Research Hospital Total Therapy Studies XIIIA or XIIIB and correspond to 64% of the patients treated on these protocols. The details of these protocols have been previously published. 1,2 XIIIA ran from 12-20-91 to 8-23-94 and enrolled 165 patients, whereas XIIIB ran from 8-24-94 to 7-27-98 and enrolled 247 patients. No patients were lost to follow-up during treatment. When the databases were frozen for analysis, 100% and 93% of event-free survivors in studies XIIIA and XIIIB, respectively, had been seen within 12 months. The median (minimum, maximum) follow-up of the event-free survivors was 8.09 (6.59, 9.94) and 4.52 (2.37, 7.06) years for XIIIA and XIIIB, respectively. All other samples were obtained from patients treated on St. Jude Total Therapy Studies XI, XII, XIV, XV, or by best clinical management.
For the identification of gene expression profiles that predict specific genetic subtypes of ALL, 327 diagnostic BM samples were used. Inclusion in this dataset required availability of a cryopreserved diagnostic BM sample containing >75% blasts, and complete data from each of the following diagnostic studies: morphology, immunophenotype, cytogenetics, DNA ploidy, Southern blot for MLL gene rearrangements, and RT-PCR analysis for MLL-AF4, MLL-AF9, E2A-PBX1, TEL-AML1, and BCR-ABL. This final dataset includes diagnostic BM samples from XV (38), XIV (4), XIIIA (100), XIIIB (161), or from patients treated on one of our older protocols or by best clinical management (24).
The data sets used to identify expression profiles predicative of hematologic relapse and the development of therapy-induced AML are described below.
Table 10. Patient database [Diagnostic samples used for subtype classification (n=327)]
| BCR-ABL subgroup (n=15) | |||||||
|---|---|---|---|---|---|---|---|
| Label@ | Protocol# | Outcome% | Label@ | Protocol# | Outcome% | ||
| BCR-ABL-C1 | T13B | CCR | BCR-ABL-#4 | T11 | NA | ||
| BCR-ABL-R1 | T13A | Heme Relapse | BCR-ABL-#5 | T12 | NA | ||
| BCR-ABL-R2 | T13A | Heme Relapse | BCR-ABL-#6 | T12 | NA | ||
| BCR-ABL-R3 | T13B | Heme Relapse | BCR-ABL-#7 | T12 | NA | ||
| BCR-ABL-Hyperdip-R5 | T13B | Heme Relapse | BCR-ABL-#8 | T14 | NA | ||
| BCR-ABL-#1 | T13A | Censored | BCR-ABL-#9 | T15 | NA | ||
| BCR-ABL-#2 | T13B | Censored | BCR-ABL-Hyperdip-#10 | T12 | NA | ||
| BCR-ABL-#3 | T13B | Censored | |||||
| E2A-PBX1 subgroup (n=27) | |||||||
| Label@ | Protocol# | Outcome% | Label@ | Protocol# | Outcome% | ||
| E2A-PBX1-C1 | T13A | CCR | E2A-PBX1-#1 | Others | NA | ||
| E2A-PBX1-C2 | T13A | CCR | E2A-PBX1-#2 | Others | NA | ||
| E2A-PBX1-C3 | T13A | CCR | E2A-PBX1-#3 | Others | NA | ||
| E2A-PBX1-C4 | T13A | CCR | E2A-PBX1-#4 | Others | NA | ||
| E2A-PBX1-C5 | T13A | CCR | E2A-PBX1-#5 | Others | NA | ||
| E2A-PBX1-C6 | T13B | CCR | E2A-PBX1-#6 | Others | NA | ||
| E2A-PBX1-C7 | T13B | CCR | E2A-PBX1-#7 | T11 | NA | ||
| E2A-PBX1-C8 | T13B | CCR | E2A-PBX1-#8 | T11 | NA | ||
| E2A-PBX1-C9 | T13B | CCR | E2A-PBX1-#9 | T12 | NA | ||
| E2A-PBX1-C10 | T13B | CCR | E2A-PBX1-#10 | T12 | NA | ||
| E2A-PBX1-C11 | T13B | CCR | E2A-PBX1-#11 | T14 | NA | ||
| E2A-PBX1-C12 | T13B | CCR | E2A-PBX1-#12 | T15 | NA | ||
| E2A-PBX1-R1 | T13B | Heme Relapse | E2A-PBX1-#13 | T15 | NA | ||
| E2A-PBX1-2M#1 | T13B | 2nd AML | |||||
| Hyperdip>50 subgroup (n=64) | |||||||
| Label@ | Protocol# | Outcome% | Label@ | Protocol# | Outcome% | ||
| Hyperdip>50-C1 | T13A | CCR | Hyperdip>50-C33 | T13B | CCR | ||
| Hyperdip>50-C2 | T13A | CCR | Hyperdip>50-C34 | T13B | CCR | ||
| Hyperdip>50-C3 | T13A | CCR | Hyperdip>50-C35 | T13B | CCR | ||
| Hyperdip>50-C4 | T13A | CCR | Hyperdip>50-C36 | T13B | CCR | ||
| Hyperdip>50-C5 | T13A | CCR | Hyperdip>50-C37 | T13B | CCR | ||
| Hyperdip>50-C6 | T13A | CCR | Hyperdip>50-C38 | T13B | CCR | ||
| Hyperdip>50-C7 | T13A | CCR | Hyperdip>50-C39 | T13B | CCR | ||
| Hyperdip>50-C8 | T13A | CCR | Hyperdip>50-C40 | T13B | CCR | ||
| Hyperdip>50-C9 | T13A | CCR | Hyperdip>50-C41 | T13B | CCR | ||
| Hyperdip>50-C10 | T13A | CCR | Hyperdip>50-C42 | T13B | CCR | ||
| Hyperdip>50-C11 | T13A | CCR | Hyperdip>50-C43 | T13B | CCR | ||
| Hyperdip>50-C12 | T13A | CCR | Hyperdip>50-R1 | T13A | Heme Relapse | ||
| Hyperdip>50-C13 | T13A | CCR | Hyperdip>50-R2 | T13A | Heme Relapse | ||
| Hyperdip>50-C14 | T13A | CCR | Hyperdip>50-R3 | T13A | Heme Relapse | ||
| Hyperdip>50-C15 | T13B | CCR | Hyperdip>50-R4 | T13B | Heme Relapse | ||
| Hyperdip>50-C16 | T13B | CCR | Hyperdip>50-R5 | T13B | Heme Relapse | ||
| Hyperdip>50-C17 | T13B | CCR | Hyperdip>50-2M#1 | T13A | 2nd AML | ||
| Hyperdip>50-C18 | T13B | CCR | Hyperdip>50-2M#2 | T13B | 2nd AML | ||
| Hyperdip>50-C19 | T13B | CCR | Hyperdip>50-#1 | T13A | Censored | ||
| Hyperdip>50-C20 | T13B | CCR | Hyperdip>50-#2 | T13B | Censored | ||
| Hyperdip>50-C21 | T13B | CCR | Hyperdip>50-#3 | Others | NA | ||
| Hyperdip>50-C22 | T13B | CCR | Hyperdip>50-#4 | Others | NA | ||
| Hyperdip>50-C23 | T13B | CCR | Hyperdip>50-#5 | T12 | NA | ||
| Hyperdip>50-C24 | T13B | CCR | Hyperdip>50-#6 | T15 | NA | ||
| Hyperdip>50-C25 | T13B | CCR | Hyperdip>50-#7 | T15 | NA | ||
| Hyperdip>50-C26 | T13B | CCR | Hyperdip>50-#8 | T15 | NA | ||
| Hyperdip>50-C27-N | T13B | CCR | Hyperdip>50-#9 | T15 | NA | ||
| Hyperdip>50-C28 | T13B | CCR | Hyperdip>50-#10 | T15 | NA | ||
| Hyperdip>50-C29 | T13B | CCR | Hyperdip>50-#11 | T15 | NA | ||
| Hyperdip>50-C30 | T13B | CCR | Hyperdip>50-#12 | T15 | NA | ||
| Hyperdip>50-C31 | T13B | CCR | Hyperdip>50-#13 | T15 | NA | ||
| Hyperdip>50-C32 | T13B | CCR | Hyperdip>50-#14 | T15 | NA | ||
| Hyperdip47-50 subgroup (n=23) | |||||||
| Label@ | Protocol# | Outcome% | Label@ | Protocol# | Outcome% | ||
| Hyperdip47-50-C1 | T13A | CCR | Hyperdip47-50-C13 | T13B | CCR | ||
| Hyperdip47-50-C2 | T13A | CCR | Hyperdip47-50-C14-N | T13B | CCR | ||
| Hyperdip47-50-C3-N | T13A | CCR | Hyperdip47-50-C15 | T13B | CCR | ||
| Hyperdip47-50-C4 | T13A | CCR | Hyperdip47-50-C16 | T13B | CCR | ||
| Hyperdip47-50-C5 | T13A | CCR | Hyperdip47-50-C17 | T13B | CCR | ||
| Hyperdip47-50-C6 | T13B | CCR | Hyperdip47-50-C18 | T13B | CCR | ||
| Hyperdip47-50-C7 | T13B | CCR | Hyperdip47-50-C19 | T13B | CCR | ||
| Hyperdip47-50-C8 | T13B | CCR | Hyperdip47-50-2M#1 | T13A | 2nd AML | ||
| Hyperdip47-50-C9 | T13B | CCR | Hyperdip47-50-#1 | T15 | NA | ||
| Hyperdip47-50-C10 | T13B | CCR | Hyperdip47-50-#2 | T15 | NA | ||
| Hyperdip47-50-C11 | T13B | CCR | Hyperdip47-50-#3 | T15 | NA | ||
| Hyperdip47-50-C12 | T13B | CCR | |||||
| Hypodip subgroup (n=9) | |||||||
| Label@ | Protocol# | Outcome% | Label@ | Protocol# | Outcome% | ||
| Hypodip-C1 | T13A | CCR | Hypodip-C6 | T13B | CCR | ||
| Hypodip-C2 | T13A | CCR | Hypodip-2M#1 | T13A | 2nd AML | ||
| Hypodip-C3 | T13B | CCR | Hypodip-#1 | T15 | NA | ||
| Hypodip-C4 | T13B | CCR | Hypodip-#2 | T15 | NA | ||
| Hypodip-C5 | T13B | CCR | |||||
| MLL subgroup (n=20) | |||||||
| Label@ | Protocol# | Outcome% | Label@ | Protocol# | Outcome% | ||
| MLL-C1 | T13A | CCR | MLL-2M#1 | T13A | 2nd AML | ||
| MLL-C2 | T13B | CCR | MLL-2M#2 | T13A | 2nd AML | ||
| MLL-C3 | T13B | CCR | MLL-#1 | T13B | Censored | ||
| MLL-C4 | T13B | CCR | MLL-#2 | T13B | Censored | ||
| MLL-C5 | T13B | CCR | MLL-#3 | Others | NA | ||
| MLL-C6 | T13B | CCR | MLL-#4 | Others | NA | ||
| MLL-R1 | T13A | Heme Relapse | MLL-#5 | Others | NA | ||
| MLL-R2 | T13A | Heme Relapse | MLL-#6 | T12 | NA | ||
| MLL-R3 | T13B | Heme Relapse | MLL-#7 | T14 | NA | ||
| MLL-R4 | T13B | Heme Relapse | MLL-#8 | T14 | NA | ||
| Normal subgroup (n=18) | |||||||
| Label@ | Protocol# | Outcome% | Label@ | Protocol# | Outcome% | ||
| Normal-C1-N | T13A | CCR | Normal-C10 | T13B | CCR | ||
| Normal-C2-N | T13A | CCR | Normal-C11-N | T13B | CCR | ||
| Normal-C3-N | T13A | CCR | Normal-C12 | T13B | CCR | ||
| Normal-C4-N | T13B | CCR | Normal-R1 | T13A | Heme Relapse | ||
| Normal-C5 | T13B | CCR | Normal-R2-N | T13B | Heme Relapse | ||
| Normal-C6 | T13B | CCR | Normal-R3 | T13B | Heme Relapse | ||
| Normal-C7-N | T13B | CCR | Normal-#1 | T13A | Censored | ||
| Normal-C8 | T13B | CCR | Normal-#2 | T13B | Censored | ||
| Normal-C9 | T13B | CCR | Normal-#3 | T13B | Censored | ||
| Pseudodip subgroup (n=29) | |||||||
| Label@ | Protocol# | Outcome% | Label@ | Protocol# | Outcome% | ||
| Pseudodip-C1 | T13A | CCR | Pseudodip-C16-N | T13B | CCR | ||
| Pseudodip-C2-N | T13A | CCR | Pseudodip-C17 | T13B | CCR | ||
| Pseudodip-C3 | T13A | CCR | Pseudodip-C18 | T13B | CCR | ||
| Pseudodip-C4 | T13A | CCR | Pseudodip-C19 | T13B | CCR | ||
| Pseudodip-C5 | T13A | CCR | Pseudodip-R1-N | T13A | Heme Relapse | ||
| Pseudodip-C6 | T13A | CCR | Pseudodip-#1 | T13B | Other Relapse | ||
| Pseudodip-C7 | T13A | CCR | Pseudodip-#2 | T13B | Censored | ||
| Pseudodip-C8 | T13A | CCR | Pseudodip-#3 | Others | NA | ||
| Pseudodip-C9 | T13A | CCR | Pseudodip-#4 | Others | NA | ||
| Pseudodip-C10 | T13B | CCR | Pseudodip-#5 | T15 | NA | ||
| Pseudodip-C11 | T13B | CCR | Pseudodip-#6 | T15 | NA | ||
| Pseudodip-C12 | T13B | CCR | Pseudodip-#7 | T15 | NA | ||
| Pseudodip-C13 | T13B | CCR | Pseudodip-#8-N | T15 | NA | ||
| Pseudodip-C14 | T13B | CCR | Pseudodip-#9 | T15 | NA | ||
| Pseudodip-C15 | T13B | CCR | |||||
| T-ALL subgroup (n=43) | |||||||
| Label@ | Protocol# | Outcome% | Label@ | Protocol# | Outcome% | ||
| T-ALL-C1 | T13A | CCR | T-ALL-C23 | T13B | CCR | ||
| T-ALL-C2 | T13A | CCR | T-ALL-C24 | T13B | CCR | ||
| T-ALL-C3 | T13A | CCR | T-ALL-C25 | T13B | CCR | ||
| T-ALL-C4 | T13A | CCR | T-ALL-C26 | T13B | CCR | ||
| T-ALL-C5 | T13A | CCR | T-ALL-R1 | T13A | Heme Relapse | ||
| T-ALL-C6 | T13A | CCR | T-ALL-R2 | T13B | Heme Relapse | ||
| T-ALL-C7 | T13A | CCR | T-ALL-R3 | T13B | Heme Relapse | ||
| T-ALL-C8 | T13A | CCR | T-ALL-R4 | T13B | Heme Relapse | ||
| T-ALL-C9 | T13B | CCR | T-ALL-R5 | T13B | Heme Relapse | ||
| T-ALL-C10 | T13B | CCR | T-ALL-R6 | T13B | Heme Relapse | ||
| T-ALL-C11 | T13B | CCR | T-ALL-2M#1 | T13B | 2nd AML | ||
| T-ALL-C12 | T13B | CCR | T-ALL-#1 | T13B | Other Relapse | ||
| T-ALL-C13 | T13B | CCR | T-ALL-#2 | T13B | Other Relapse | ||
| T-ALL-C14 | T13B | CCR | T-ALL-#3 | T13B | Censored | ||
| T-ALL-C15 | T13B | CCR | T-ALL-#4 | T13B | Censored | ||
| T-ALL-C16 | T13B | CCR | T-ALL-#5 | T15 | NA | ||
| T-ALL-C17 | T13B | CCR | T-ALL-#6 | T15 | NA | ||
| T-ALL-C18 | T13B | CCR | T-ALL-#7 | T15 | NA | ||
| T-ALL-C19 | T13B | CCR | T-ALL-#8 | T15 | NA | ||
| T-ALL-C20 | T13B | CCR | T-ALL-#9 | T15 | NA | ||
| T-ALL-C21 | T13B | CCR | T-ALL-#10 | T15 | NA | ||
| T-ALL-C22 | T13B | CCR | |||||
| TEL-AML1 subgroup (n=79) | |||||||
| Label@ | Protocol# | Outcome% | Label@ | Protocol# | Outcome% | ||
| TEL-AML1-C1 | T13A | CCR | TEL-AML1-C41 | T13B | CCR | ||
| TEL-AML1-C2 | T13A | CCR | TEL-AML1-C42 | T13B | CCR | ||
| TEL-AML1-C3 | T13A | CCR | TEL-AML1-C43 | T13B | CCR | ||
| TEL-AML1-C4 | T13A | CCR | TEL-AML1-C44 | T13B | CCR | ||
| TEL-AML1-C5 | T13A | CCR | TEL-AML1-C45 | T13B | CCR | ||
| TEL-AML1-C6 | T13A | CCR | TEL-AML1-C46 | T13B | CCR | ||
| TEL-AML1-C7 | T13A | CCR | TEL-AML1-C47 | T13B | CCR | ||
| TEL-AML1-C8 | T13A | CCR | TEL-AML1-C48 | T13B | CCR | ||
| TEL-AML1-C9 | T13A | CCR | TEL-AML1-C49 | T13B | CCR | ||
| TEL-AML1-C10 | T13A | CCR | TEL-AML1-C50 | T13B | CCR | ||
| TEL-AML1-C11 | T13A | CCR | TEL-AML1-C51 | T13B | CCR | ||
| TEL-AML1-C12 | T13A | CCR | TEL-AML1-C52 | T13B | CCR | ||
| TEL-AML1-C13 | T13A | CCR | TEL-AML1-C53 | T13B | CCR | ||
| TEL-AML1-C14 | T13A | CCR | TEL-AML1-C54 | T13B | CCR | ||
| TEL-AML1-C15 | T13A | CCR | TEL-AML1-C55 | T13B | CCR | ||
| TEL-AML1-C16 | T13A | CCR | TEL-AML1-C56 | T13B | CCR | ||
| TEL-AML1-C17 | T13A | CCR | TEL-AML1-C57 | T13B | CCR | ||
| TEL-AML1-C18 | T13A | CCR | TEL-AML1-R1 | T13A | Heme Relapse | ||
| TEL-AML1-C19 | T13A | CCR | TEL-AML1-R2 | T13A | Heme Relapse | ||
| TEL-AML1-C20 | T13A | CCR | TEL-AML1-R3 | T13B | Heme Relapse | ||
| TEL-AML1-C21 | T13A | CCR | TEL-AML1-2M#1 | T13A | 2nd AML | ||
| TEL-AML1-C22 | T13A | CCR | TEL-AML1-2M#2 | T13A | 2nd AML | ||
| TEL-AML1-C23 | T13A | CCR | TEL-AML1-2M#3 | T13A | 2nd AML | ||
| TEL-AML1-C24 | T13A | CCR | TEL-AML1-2M#4 | T13B | 2nd AML | ||
| TEL-AML1-C25 | T13A | CCR | TEL-AML1-2M#5 | T13B | 2nd AML | ||
| TEL-AML1-C26 | T13A | CCR | TEL-AML1-#1 | T13B | Other Relapse | ||
| TEL-AML1-C27 | T13A | CCR | TEL-AML1-#2 | T13A | Censored | ||
| TEL-AML1-C28 | T13A | CCR | TEL-AML1-#3 | T13A | Censored | ||
| TEL-AML1-C29 | T13B | CCR | TEL-AML1-#4 | T13B | Censored | ||
| TEL-AML1-C30 | T13B | CCR | TEL-AML1-#5 | T15 | NA | ||
| TEL-AML1-C31 | T13B | CCR | TEL-AML1-#6 | T15 | NA | ||
| TEL-AML1-C32 | T13B | CCR | TEL-AML1-#7 | T15 | NA | ||
| TEL-AML1-C33 | T13B | CCR | TEL-AML1-#8 | T15 | NA | ||
| TEL-AML1-C34 | T13B | CCR | TEL-AML1-#9 | T15 | NA | ||
| TEL-AML1-C35 | T13B | CCR | TEL-AML1-#10 | T15 | NA | ||
| TEL-AML1-C36 | T13B | CCR | TEL-AML1-#11 | T15 | NA | ||
| TEL-AML1-C37 | T13B | CCR | TEL-AML1-#12 | T15 | NA | ||
| TEL-AML1-C38 | T13B | CCR | TEL-AML1-#13 | T15 | NA | ||
| TEL-AML1-C39 | T13B | CCR | TEL-AML1-#14 | T15 | NA | ||
| TEL-AML1-C40 | T13B | CCR | |||||
Label@ key:
Subtype Name-C# = Dx Sample of patient in CCR
Subtype Name-R# = Dx Sample of patient who developed a hematologic relapse
Subtype Name-# = Dx Sample used for subgroup classification only
Subtype Name-2M# = Dx Sample of patient who later developed 2nd AML
Subtype Name-N = Dx Sample in novel group
Protocol# key:
Protocol that patient was treated on
Outcome% key:
CCR = Continuous complete remission
Heme Relapse = Hematologic relapse
Other Relapse = Extramedullary relapse
2nd AML = Diagnostic samples of patients who later developed 2nd AML
Censored = Censored due to BM transplant, treated off protocol, or died in CR
NA = Not applicable, primarily because the patient was not treated on Total 13, and thus is excluded from the analysis used to identify gene expression profiles predictive of outcome
In addition to the 201 CCR and 27 Heme Relapse cases listed in Table 10, five additional relapse cases were also included in the prognostic analysis. This gives a total of 233 cases for this analysis. These additional cases were not included in the subgroup prediction dataset because they did not meet the established criteria for the reasons listed below.
| Label | Protocol | Comment | ||
|---|---|---|---|---|
| BCR-ABL-R4 | T13B | Did not meet QC criteria because contained 70% blasts | ||
| MLL-R5 | T13A | Peripheral Blood Sample (90% blasts) | ||
| Normal-R4 | T13B | Molecular studies not performed | ||
| T-ALL-R7 | T13A | Peripheral Blood Sample (90% blasts) | ||
| T-ALL-R8 | T13B | Peripheral Blood Sample (90% blasts) |
In addition to the 201 CCR and 13 secondary AML cases listed in Table 10, three additional diagnostic marrow samples from patients who developed secondary AML were also included in the prognostic analysis. This gives a total of 217 cases used for this analysis. These additional cases were not included in the diagnostic data set because they did not meet the established criteria for the reasons listed below.
| Label | Protocol | Comment | ||
|---|---|---|---|---|
| Hyperdip>50-2M#3 | T12 | Non Total 13 diagnostic sample | ||
| Hypodip-2M#2 | T13B | No molecular studies performed | ||
| Hypodip-2M#3 | T12 | Non Total 13 diagnostic sample |
Twenty-five relapse samples were analyzed, 17 samples which were paired to the diagnostic samples listed in Table 10 and 8 additional non-paired relapse samples.