Treatment of Newly Diagnosed Childhood MLDS

Chemotherapy.

In a Children's Oncology Group (COG) trial for newly diagnosed children with MLDS (AAML0431 [NCT00369317]), 204 children received a regimen that substituted high-dose cytarabine for the second of four induction cycles (thereby reducing cumulative anthracycline exposure from 320 mg to 240 mg), moving this cycle from intensification where it was used in the previous COG A2971 (NCT00003593) trial.[10,11] Intrathecal doses were reduced from seven to two total injections, and intensification included two cycles of cytarabine/etoposide.

In a Children's Oncology Group (COG) trial for newly diagnosed children with MLDS (AAML0431 [NCT00369317]), 204 children received a regimen that substituted high-dose cytarabine for the second of four induction cycles (thereby reducing cumulative anthracycline exposure from 320 mg to 240 mg), moving this cycle from intensification where it was used in the previous COG A2971 (NCT00003593) trial.[10,11] Intrathecal doses were reduced from seven to two total injections, and intensification included two cycles of cytarabine/etoposide.

When compared with the previous trial, these changes resulted in an overall improvement of approximately 10%.

In a Children's Oncology Group (COG) trial for newly diagnosed children with MLDS (AAML0431 [NCT00369317]), 204 children received a regimen that substituted high-dose cytarabine for the second of four induction cycles (thereby reducing cumulative anthracycline exposure from 320 mg to 240 mg), moving this cycle from intensification where it was used in the previous COG A2971 (NCT00003593) trial.[10,11] Intrathecal doses were reduced from seven to two total injections, and intensification included two cycles of cytarabine/etoposide.

The EFS rate was 89.9%, and the OS rate was 93%.

In a Children's Oncology Group (COG) trial for newly diagnosed children with MLDS (AAML0431 [NCT00369317]), 204 children received a regimen that substituted high-dose cytarabine for the second of four induction cycles (thereby reducing cumulative anthracycline exposure from 320 mg to 240 mg), moving this cycle from intensification where it was used in the previous COG A2971 (NCT00003593) trial.[10,11] Intrathecal doses were reduced from seven to two total injections, and intensification included two cycles of cytarabine/etoposide.

Relapse occurred in 14 patients and there were two treatment-related deaths, both related to pneumonia, neither of which occurred during induction 2.

In a Children's Oncology Group (COG) trial for newly diagnosed children with MLDS (AAML0431 [NCT00369317]), 204 children received a regimen that substituted high-dose cytarabine for the second of four induction cycles (thereby reducing cumulative anthracycline exposure from 320 mg to 240 mg), moving this cycle from intensification where it was used in the previous COG A2971 (NCT00003593) trial.[10,11] Intrathecal doses were reduced from seven to two total injections, and intensification included two cycles of cytarabine/etoposide.

No patient had central nervous system (CNS) involvement in this trial or the preceding COG A2971 trial.[10]

In a Children's Oncology Group (COG) trial for newly diagnosed children with MLDS (AAML0431 [NCT00369317]), 204 children received a regimen that substituted high-dose cytarabine for the second of four induction cycles (thereby reducing cumulative anthracycline exposure from 320 mg to 240 mg), moving this cycle from intensification where it was used in the previous COG A2971 (NCT00003593) trial.[10,11] Intrathecal doses were reduced from seven to two total injections, and intensification included two cycles of cytarabine/etoposide.

The only prognostic factor identified was MRD using flow cytometry on day 28 of induction 1. Among those who were MRD negative (≤0.01%), the disease-free survival (DFS) rate was 92.7%. In the 14.4% of patients who were MRD positive, the DFS rate was 76.2% (P = .011).

In the COG AAML1531 (NCT00369317) trial for children with newly diagnosed MLDS, removing the high-dose cytarabine cycle in those with standard-risk MLDS was unsuccessful.[16]

In the COG AAML1531 (NCT00369317) trial for children with newly diagnosed MLDS, removing the high-dose cytarabine cycle in those with standard-risk MLDS was unsuccessful.[16]

The interim analysis found that patients who did not receive high-dose cytarabine had a lower 2-year EFS rate of 85.6%, compared with the 2-year EFS rate of 93.5% for patients in the AAML0431 trial (P = .0002).

In a joint trial (ML-DS 2006) from the BFM, Dutch Childhood Oncology Group (DCOG), and Nordic Society of Pediatric Hematology and Oncology (NOPHO), 170 children with Down syndrome were enrolled. This trial focused on reducing therapy by eliminating etoposide during consolidation, reducing the number of intrathecal doses from 11 to 4, and the elimination of maintenance from the reduced-therapy Down syndrome arm of AML-BFM 98.[13] As in the COG trials, no patient had CNS disease at diagnosis. The following two prognostic factors were identified:[13]

In a joint trial (ML-DS 2006) from the BFM, Dutch Childhood Oncology Group (DCOG), and Nordic Society of Pediatric Hematology and Oncology (NOPHO), 170 children with Down syndrome were enrolled. This trial focused on reducing therapy by eliminating etoposide during consolidation, reducing the number of intrathecal doses from 11 to 4, and the elimination of maintenance from the reduced-therapy Down syndrome arm of AML-BFM 98.[13] As in the COG trials, no patient had CNS disease at diagnosis. The following two prognostic factors were identified:[13]

Outcomes were no worse despite reduction in chemotherapy. The OS rate was 89% (± 3%), and the EFS rate was 87% (± 3%), similar to that observed in AML-BFM 98 (OS rate, 90% ± 4% [P = NS]; EFS rate, 89% ± 4% [P = NS]). The CIR rate was 6% in both trials.

In a joint trial (ML-DS 2006) from the BFM, Dutch Childhood Oncology Group (DCOG), and Nordic Society of Pediatric Hematology and Oncology (NOPHO), 170 children with Down syndrome were enrolled. This trial focused on reducing therapy by eliminating etoposide during consolidation, reducing the number of intrathecal doses from 11 to 4, and the elimination of maintenance from the reduced-therapy Down syndrome arm of AML-BFM 98.[13] As in the COG trials, no patient had CNS disease at diagnosis. The following two prognostic factors were identified:[13]

Nine patients relapsed, and seven of those patients died.

In a joint trial (ML-DS 2006) from the BFM, Dutch Childhood Oncology Group (DCOG), and Nordic Society of Pediatric Hematology and Oncology (NOPHO), 170 children with Down syndrome were enrolled. This trial focused on reducing therapy by eliminating etoposide during consolidation, reducing the number of intrathecal doses from 11 to 4, and the elimination of maintenance from the reduced-therapy Down syndrome arm of AML-BFM 98.[13] As in the COG trials, no patient had CNS disease at diagnosis. The following two prognostic factors were identified:[13]

Patients with a good early response (<5% blasts by morphology before induction cycle 2, n = 123 [72%]) had better outcomes (OS rate, 92% ± 3% vs. 57% ± 16%, P < .0001; EFS rate, 88% ± 3% vs. 58% ± 16%, P = .0008; and CIR rate, 3% ± 2% vs. 27% ± 18%, P = .003).

In a joint trial (ML-DS 2006) from the BFM, Dutch Childhood Oncology Group (DCOG), and Nordic Society of Pediatric Hematology and Oncology (NOPHO), 170 children with Down syndrome were enrolled. This trial focused on reducing therapy by eliminating etoposide during consolidation, reducing the number of intrathecal doses from 11 to 4, and the elimination of maintenance from the reduced-therapy Down syndrome arm of AML-BFM 98.[13] As in the COG trials, no patient had CNS disease at diagnosis. The following two prognostic factors were identified:[13]

Less toxicity was seen in this trial, and treatment-related mortality remained low (2.9% vs. 5%, P = .276).

In a joint trial (ML-DS 2006) from the BFM, Dutch Childhood Oncology Group (DCOG), and Nordic Society of Pediatric Hematology and Oncology (NOPHO), 170 children with Down syndrome were enrolled. This trial focused on reducing therapy by eliminating etoposide during consolidation, reducing the number of intrathecal doses from 11 to 4, and the elimination of maintenance from the reduced-therapy Down syndrome arm of AML-BFM 98.[13] As in the COG trials, no patient had CNS disease at diagnosis. The following two prognostic factors were identified:[13]

Trisomy 8 was an adverse factor (n = 37; OS rate, 77% vs. 95%, P = .07; EFS rate, 73% ± 8% vs. 91% ± 4%, P = .018; CIR rate, 16% ± 7% vs. 3% ± 2%, P = .02).

In a joint trial (ML-DS 2006) from the BFM, Dutch Childhood Oncology Group (DCOG), and Nordic Society of Pediatric Hematology and Oncology (NOPHO), 170 children with Down syndrome were enrolled. This trial focused on reducing therapy by eliminating etoposide during consolidation, reducing the number of intrathecal doses from 11 to 4, and the elimination of maintenance from the reduced-therapy Down syndrome arm of AML-BFM 98.[13] As in the COG trials, no patient had CNS disease at diagnosis. The following two prognostic factors were identified:[13]

This was confirmed in multivariate analysis, where lack of good early response and trisomy 8 maintained their adverse impact on relapse, with relative risks of 8.55 (95% confidence interval [CI], 1.96–37.29; P = .004) and 4.36 (95% CI, 1.24–15.39; P = .022), respectively.

A 2024 analysis included a cohort of Japanese patients with MLDS (n = 204) who were treated with uniform chemotherapy. Patients underwent extensive somatic testing to further define variants most commonly seen with this diagnosis. Somatic variants in 26 genes known to be driver genes in MLDS were identified again. These included variants in cohesin and cohesin-related proteins (43.6%), epigenetic regulators (39.2%), tyrosine kinases (25.5%), and genes important in the RAS pathway (11.8%). An additional 16 novel genes were also described. Of these, variants in two transcription factors (IRX1: 16.2%; ZBTB7A: 13.2%) were found, and functional studies confirmed their role as tumor suppressor genes that impacted signaling through MYC/E2F pathways. Structural variants were also observed. RUNX1 partial tandem duplications were seen in 13.7% of patients, which may result in partial loss of function of the gene. This causes upregulation expression through the addition of an extra promoter, which results in isoform disequilibrium, with RUNX1A bias versus RUNX1. Recent studies have shown that this disequilibrium contributes to MLDS pathogenesis. Variants of RUNX1, IRX1, and ZBTB7A also activate MYC/E2F genes, suggesting that targeting this pathway may provide therapeutic benefit.[20]

A 2024 analysis included a cohort of Japanese patients with MLDS (n = 204) who were treated with uniform chemotherapy. Patients underwent extensive somatic testing to further define variants most commonly seen with this diagnosis. Somatic variants in 26 genes known to be driver genes in MLDS were identified again. These included variants in cohesin and cohesin-related proteins (43.6%), epigenetic regulators (39.2%), tyrosine kinases (25.5%), and genes important in the RAS pathway (11.8%). An additional 16 novel genes were also described. Of these, variants in two transcription factors (IRX1: 16.2%; ZBTB7A: 13.2%) were found, and functional studies confirmed their role as tumor suppressor genes that impacted signaling through MYC/E2F pathways. Structural variants were also observed. RUNX1 partial tandem duplications were seen in 13.7% of patients, which may result in partial loss of function of the gene. This causes upregulation expression through the addition of an extra promoter, which results in isoform disequilibrium, with RUNX1A bias versus RUNX1. Recent studies have shown that this disequilibrium contributes to MLDS pathogenesis. Variants of RUNX1, IRX1, and ZBTB7A also activate MYC/E2F genes, suggesting that targeting this pathway may provide therapeutic benefit.[20]

Four somatic alterations were associated with inferior outcomes in this study cohort.

A 2024 analysis included a cohort of Japanese patients with MLDS (n = 204) who were treated with uniform chemotherapy. Patients underwent extensive somatic testing to further define variants most commonly seen with this diagnosis. Somatic variants in 26 genes known to be driver genes in MLDS were identified again. These included variants in cohesin and cohesin-related proteins (43.6%), epigenetic regulators (39.2%), tyrosine kinases (25.5%), and genes important in the RAS pathway (11.8%). An additional 16 novel genes were also described. Of these, variants in two transcription factors (IRX1: 16.2%; ZBTB7A: 13.2%) were found, and functional studies confirmed their role as tumor suppressor genes that impacted signaling through MYC/E2F pathways. Structural variants were also observed. RUNX1 partial tandem duplications were seen in 13.7% of patients, which may result in partial loss of function of the gene. This causes upregulation expression through the addition of an extra promoter, which results in isoform disequilibrium, with RUNX1A bias versus RUNX1. Recent studies have shown that this disequilibrium contributes to MLDS pathogenesis. Variants of RUNX1, IRX1, and ZBTB7A also activate MYC/E2F genes, suggesting that targeting this pathway may provide therapeutic benefit.[20] › Four somatic alterations were associated with inferior outcomes in this study cohort.

Of 177 patients with comprehensive somatic testing, CDKN2A deletions and variants in ZBTB7A, TP53, and JAK2 were all associated with inferior outcomes.

A 2024 analysis included a cohort of Japanese patients with MLDS (n = 204) who were treated with uniform chemotherapy. Patients underwent extensive somatic testing to further define variants most commonly seen with this diagnosis. Somatic variants in 26 genes known to be driver genes in MLDS were identified again. These included variants in cohesin and cohesin-related proteins (43.6%), epigenetic regulators (39.2%), tyrosine kinases (25.5%), and genes important in the RAS pathway (11.8%). An additional 16 novel genes were also described. Of these, variants in two transcription factors (IRX1: 16.2%; ZBTB7A: 13.2%) were found, and functional studies confirmed their role as tumor suppressor genes that impacted signaling through MYC/E2F pathways. Structural variants were also observed. RUNX1 partial tandem duplications were seen in 13.7% of patients, which may result in partial loss of function of the gene. This causes upregulation expression through the addition of an extra promoter, which results in isoform disequilibrium, with RUNX1A bias versus RUNX1. Recent studies have shown that this disequilibrium contributes to MLDS pathogenesis. Variants of RUNX1, IRX1, and ZBTB7A also activate MYC/E2F genes, suggesting that targeting this pathway may provide therapeutic benefit.[20] › Four somatic alterations were associated with inferior outcomes in this study cohort.

If patients had at least one of these variants, EFS and OS rates were significantly lower than those of patients who lacked any four of these abnormalities (3-year EFS rates, 66.6% vs. 94.2%; P for unadjusted Cox regression < .001; 3-year OS rates, 69.0% vs. 95.6%; P for unadjusted Cox regression < .001).

A 2024 analysis included a cohort of Japanese patients with MLDS (n = 204) who were treated with uniform chemotherapy. Patients underwent extensive somatic testing to further define variants most commonly seen with this diagnosis. Somatic variants in 26 genes known to be driver genes in MLDS were identified again. These included variants in cohesin and cohesin-related proteins (43.6%), epigenetic regulators (39.2%), tyrosine kinases (25.5%), and genes important in the RAS pathway (11.8%). An additional 16 novel genes were also described. Of these, variants in two transcription factors (IRX1: 16.2%; ZBTB7A: 13.2%) were found, and functional studies confirmed their role as tumor suppressor genes that impacted signaling through MYC/E2F pathways. Structural variants were also observed. RUNX1 partial tandem duplications were seen in 13.7% of patients, which may result in partial loss of function of the gene. This causes upregulation expression through the addition of an extra promoter, which results in isoform disequilibrium, with RUNX1A bias versus RUNX1. Recent studies have shown that this disequilibrium contributes to MLDS pathogenesis. Variants of RUNX1, IRX1, and ZBTB7A also activate MYC/E2F genes, suggesting that targeting this pathway may provide therapeutic benefit.[20] › Four somatic alterations were associated with inferior outcomes in this study cohort.

In multivariable analysis, all of these abnormalities were associated with inferior outcomes.

A 2024 analysis included a cohort of Japanese patients with MLDS (n = 204) who were treated with uniform chemotherapy. Patients underwent extensive somatic testing to further define variants most commonly seen with this diagnosis. Somatic variants in 26 genes known to be driver genes in MLDS were identified again. These included variants in cohesin and cohesin-related proteins (43.6%), epigenetic regulators (39.2%), tyrosine kinases (25.5%), and genes important in the RAS pathway (11.8%). An additional 16 novel genes were also described. Of these, variants in two transcription factors (IRX1: 16.2%; ZBTB7A: 13.2%) were found, and functional studies confirmed their role as tumor suppressor genes that impacted signaling through MYC/E2F pathways. Structural variants were also observed. RUNX1 partial tandem duplications were seen in 13.7% of patients, which may result in partial loss of function of the gene. This causes upregulation expression through the addition of an extra promoter, which results in isoform disequilibrium, with RUNX1A bias versus RUNX1. Recent studies have shown that this disequilibrium contributes to MLDS pathogenesis. Variants of RUNX1, IRX1, and ZBTB7A also activate MYC/E2F genes, suggesting that targeting this pathway may provide therapeutic benefit.[20] › Four somatic alterations were associated with inferior outcomes in this study cohort.

Validation of these findings in additional cohorts is needed. However, these findings may help identify patients with higher-risk MLDS in the future.