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Second malignancy after childhood NHL
dred and fifty-two patients received consolidation by stem cell transplantation. Patients developing any kind of SMN did not significantly differ from those who did not with respect to the age at diagnosis, stage of NHL, or bone-marrow involvement.
With a median follow-up of 9.4 years (quartile [Q] range, Q1 6.7 and Q3 12.1), the probability of survival at 20 years was 83%, standard error (SE)=0.01 for the total group of 3,590 patients.
Second malignant neoplasms
Ninety-five SMN were documented: 26 carcinomas (including nine basal-cell carcinomas), 21 acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS), 20 second lymphoid malignancies (12 NHL, four ALL, four Hodgkin disease), 12 malignant CNS-tumors, five sarco- mas, five malignant melanomas, and seven other SMN (Figure 1, Table 3).
Second lymphoid malignancy was considered to be proven when (i) in lymphoid malignancy there was a lin- eage change, i.e., B lineage to T lineage and vice versa, (ii) in lymphoid malignancy there was a change with respect to the differentiation compartment, i.e., from a precursor B (or T) neoplasm to mature B (or T) neoplasm or vice versa, (iii) in Burkitt lymphoma/Burkitt leukemia there was a MYC rearrangement at different break points between the first and the second cancer or (iiii) in mature B-NHL there was a different immunoglobulin light-chain restriction between the first and second malignancy i.e., l to κ or vice versa. Not included as SMN were eight late- recurring lymphoid malignancies with different clonal rearrangements of immunoglobulin H- and T-cell-recep- tor-genes, but no differences with respect to discrimina- tors listed above (i-iiii), since clonal evolution in these
cases could not be excluded. Evaluation of clonal origin via multiplex-polymerase chain reaction (BIOMED-2 method26) was performed for all available tumor samples in cases of second lymphoid malignancy.
We also observed 20 benign neoplasms (eight low-grade meningeomas, five adenomas, four osteochondromas, one pilomatrixoma, chondroblastoma, neurinoma each).
The SIR for all SMN without basal cell carcinoma was 19.8 (95% CI: 14.5-26.5).
Cumulative incidence of all SMN at 20 years was 5.3% (SE=0.7) (Figure 2A). Cumulative incidences of distinct SMN-groups are depicted in Figure 3. The median age at diagnosis of NHL within the population of <15 years was
Table 2. Stepwise Cox regression analysis of risk factors for the devel- opment of second malignant neoplasms after non-Hodgkin lymphoma in children < 15 years of age at diagnosis, treated according to one of the consecutive NHL-BFM studies NHL-BFM-81, through EURO-LB- 02/B-NHL-04.
Sex
female vs. male
NHL entity
LBL vs. other
CNS involvement positive vs. negative
Known CPC
yes vs. no
HR (95% CI)
1.87 (1.23-2.86)
2.6 (1.69-3.97)
2.24 (1.03-4.88)
11.2 (5.52-22.75)
P
0.004
<0.001
0.042
<0.001
CI: Confidence Interval; CNS: central nervous system; CPC: cancer-predisposing con- dition; HR: hazard ratio; LBL: lymphoblastic lymphoma; NHL: non-Hodgkin lym- phoma.
Figure 1. Consort diagram: numbers of analyzed patients and second malignant neoplasms. ALCL: anaplastic large-cell lymphoma; AML/MDS: acute myeloid leukemia/myelodysplastic syndrome; LBL: lymphoblastic lymphoma; NHL: non-Hodgkin lymphoma, No.: number; SLM: second lymphoid malignancy, SMN: second malignant neoplasm.
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