Page 198 - Haematologica May 2022

Letters to the Editor
leukemia, or who had received prior anti-leukemic thera- py (with the exception of limited corticosteroids or intrathecal chemotherapy) were ineligible. All patients had karyotypes and fluorescence in situ hybridization (FISH) to determine KMT2A status performed in COG- approved laboratories, with central review of results (AJC and NAH). Informative KMT2A FISH data were required to continue on AALL0631 post-induction therapy.
AALL0631 opened to accrual in January 2008 and the original COG P9407-based induction regimen (cohort 1) resulted in excessive toxic mortality due to infections (4 of 26 patients, 15.4%).9 The study was temporarily closed to accrual in November 2008 and amended to sub- stitute an Interfant-99 based induction3 with additional supportive care guidelines (cohort 2). This led to signifi- cantly less induction mortality and maintained complete remission rates.9 Post-induction, infants with KMT2A-g were non-randomly assigned to the Standard Risk (SR) arm (Online Supplementary Table S1). The study met accrual goals and closed to enrollment in June 2014.
Data as of March 31, 2019, are included in this report. Median follow-up was 6.3 years. EFS was defined as the time from study entry to first event (treatment failure, relapse, second malignant neoplasm [SMN], or death) or censored at date of last contact. OS was defined as the time from study entry to death or censored at last con- tact. Estimates of EFS and OS were calculated using the Kaplan-Meier method with standard errors (SE) using Peto’s formula.10,11 Two-sided log-rank tests were used to compare survival between curves. Fisher’s exact tests were used to compare proportions and Wilcoxon rank- sum tests were used to compare distributions of continu- ous measures. Statistical significance was defined as P- value less than 0.05.
AALL0631 enrolled 210 eligible patients, including 64 (30.5%) with KMT2A-g (4 in cohort 1 and 60 in cohort 2). Patient characteristics were compared to infants with KMT2A-r in AALL0631, infants with KMT2A-g in P9407, and children age 1-9 years with KMT2A-g ALL and with- out Down Syndrome or Philadelphia chromosome-posi- tive ALL, enrolled on the COG ALL classification studies AALL03B1 and AALL08B1 from March 1, 2004 to July 20, 2018, using frozen data from December 31, 2020 (Table 1). Notable differences in comparison to infants with KMT2A-r include older age and lower WBC count at diagnosis. Among infants with KMT2A-g, the propor- tion of females was higher in AALL0631 than in P9407. Central nervous system (CNS) leukemia was more com- mon in infants than in children age 1-9 years with KMT2A-g, but less frequent than in infants with KMT2A- r (Table 2). The cytogenetic findings for infants with KMT2A-g are listed in the Online Supplementary Table S2.
Among 64 infants with KMT2A-g, 62 were evaluable for morphologic remission at the end of induction (week 6). One patient was removed from protocol prior to post- induction evaluation of remission due to withdrawal of consent and one did not have bone marrow morphology evaluated due to an administrative error. Of the 62 patients with marrow assessed, 55 (89%) achieved remis- sion and seven (11%) did not achieve remission (all had ≥5% marrow blasts). Four patients went off protocol prior to post-induction therapy, one each for: withdrawal of consent, physician preference, family preference, and severe adverse event (cerebral edema). All remaining 60 patients (100%) achieved remission by the end of induc- tion intensification (week 10). There were no treatment failure events.
The 5-year EFS (±SE) was 87.3 ± 4.7% and 5-year OS (±SE) was 93.6 ± 3.5% for infants with KMT2A-g. There
Table 2. Univariate analysis of prognostic factors in infants with KMT2A-g leukemia.
Sex Female
Male
Age at diagnosis <6 months
≥6 months
WBC count (cells per L) <50x109
≥50x109
WBC count (cells per L) <300x109
≥300x109
Diagnosis
B-lymphoblastic leukemia T-lymphoblastic leukemia
N 5-year Estimated P EFS (SE) hazard ratio
33 96.9% (3.3%) ref 0.045 31 77.4% (8.9%) 4.39
12 81.8% (13.2%) ref 0.68 52 88.5% (4.9%) 0.72
37 91.7% (5.1%) ref 0.32 27 81.5% (8.5%) 1.95
57 85.7% (5.3%) 0.29 7 100%
58 86.0% (5.2%) 0.31 6 100%
Cytogenetics
Normal diploid
Abnormal
Unknown 11
17 87.5% (9.8%) ref 0.36 36 91.7% (5.1%) 0.48
CNS status
CNS 1
CNS 2
CNS 3
Unknown 1
41 92.5% (4.6%) ref 0.10 16 75.0% (11.3%) 4.23
6
83.3% (19.6%) 2.13
KMT2A-g: KMT2A-germline; EFS: event-free survival; SE: standard error; WBC: white blood cell; L: liter; CNS: central nervous system; MRD: minimal residual disease.
were no deaths as first events. Eight infants relapsed (5 bone marrow and 3 isolated CNS). All relapses occurred within the first 3 years after diagnosis; five during contin- uation chemotherapy and three within 12 months after completion of continuation therapy. One infant devel- oped a SMN (mucoepidermoid carcinoma) during the 5- year follow-up period after the completion of chemother- apy. The relapse pattern was similar to that of P9407, which recorded five relapses, two marrow and three iso- lated extramedullary (1 subcutaneous, 1 CNS, 1 testicu- lar), in 35 infants with KMT2A-g.
The Kaplan-Meier survival curves for OS and EFS for the overall cohort and EFS curves for subgroups by sex, age < or ≥6 months at diagnosis, and WBC count < or ≥50,000 cells/μL at diagnosis are shown in Figure 1. The 5-year EFS among girls was superior to that of boys (96.9 ± 3.3% vs. 77.4 ± 8.9%, P=0.045; estimated hazard ratio: 4.4). In univariate analyses, age <6 months, WBC count ≥50,000 cells/μL, WBC count ≥300,000 cells/μL, B-cell vs. T-cell phenotype, normal diploid vs. abnormal cytogenet- ics, and CNS classification were not prognostic of 5-year EFS (Table 2).
In cases with karyotypic data (n=53), the most frequent recurrent cytogenetic abnormalities involved chromo- some 9p (10 patients, 19%) and t(1;19)(q23;p13.3) or 19p13.3 variant (5 patients, 9%). The recurrent chromo- some abnormality dic(9;20)(p13.2;q11) was identified in five of 53 cases (9%). Translocation of chromosome 5p15 with chromosome 15 was observed in two cases. Abnormalities of chromosome bands 15q11-15 have pre- viously been identified in cases of infant ALL, occur in 1% of pediatric ALL overall, and may indicate a favorable prognosis, if NUTM1 fusion is involved.12-14 Molecular studies for PAX5 and NUTM1 rearrangements were not performed in AALL0631, and the prognostic significance
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