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O. Moser et al.
Table 4. Second malignant neoplasms after non-Hodgkin lymphoma in children in patients with known cancer predisposition condition.
Sex Age (years) at NHL-Dx
M 1.9
M 3.4
M 9.3
M 9.6
F 1.3
F 9.5 NBS PB
F 5.6 NBS DLBCL F 9.6 CMMRD DLBCL
Predisposing condition
Fanconi Anemia
1. NHL
BL
Therapy RT* SMN type
B-NHL No Medulloblastoma
ALL-type No AML B-NHL No DLBCL B-NHL No c-ALL B-NHL No Leiomyosarcoma B-NHL No BL B-NHL No ALCL B-NHL No c-ALL
ALL-type No B-NHL
ALL-type No Colon-CA
ALL-type Yes NPC
Latency time to SMN (years)
3. malignant 4. malignant Outcome neoplasm neoplasm
MDS-RAEB/AML - Death of SMN 1.8 - - DeathofSMN 4.8 Osteosarcoma T-ALL Death of SMN 4.4 - - DeathofSMN
2.1
Neurofibromatosis 1 ID n.f.c.
ID (organ transplant) ID (organ transplant)
T-LBL ALCL DLBCL NHL n.f.c.
1.9 3.4 3.8 2.4
11.1
9.8
8.8
-
- alive
- Death of SMN - Death (other) - alive
Anaplastic alive astrocytoma
Death of SMN
Death
(therapy related)
T-ALL
-
F 1.2
F 6.5
F 6.9
(compound heterozygote
PMS2-mutation)** CMMRD (mutation in the MSH2 gene)** CMMRD (mutation in PMS2 gene) Gorlin-Goltz syndrome
T-LBL
T-LBL
T-LBL
Phylloides- tumor;
Colon-CA
Urothel-CA - - -
*Six of the 57 patients with known cancer predisposition condition in the study cohort received radiotherapy; **CMMRD diagnosis was first made after the occurrence of SMN. ALCL: anaplastic large-cell lymphoma; BL: Burkitt lymphoma; B-NHL: mature B-cell lymphoma (other than BL/B-AL); CA: carcinoma; DLBCL: diffuse large B-cell lymphoma; CMMRD: constitutive mismatch repair deficiency syndrome, caused by mutations in DNA mismatch repair genes PMS2, MSH6, MSH2 or MLH1; CPC: cancer predisposing condi- tion; Dx: diagnosis; F: female; ID: immune deficiency; M: male; NBS: Nijmegen breakage syndrome; n.f.c.: not further classified; NHL: non-Hodgkin lymphoma; NPC: nasopharyn- geal carcinoma; PB: plasmoblastic lymphoma; RT: radiotherapy; T-LBL: T-cell lymphoblastic lymphoma.
compared to patients with other NHL-entities (3.9% at 20 years, SE=0.8%, P<0.0001) (Figure 2B). In patients with LBL, both carcinomas and AML/MDS were the most com- mon SMN (14 cases each), accounting for 72% of all SMN after LBL. The cumulative incidence of AML/MDS was 1.8%, SE=0.5% after LBL compared to 0.1%, SE=0.1% after mature B-NHL (P<0.0001). Carcinomas had a higher cumulative incidence in LBL compared to mature B-NHL as well (4.6%, SE=1.5% vs. 2.5%, SE=0.7%, P=0.04). Second lymphoid malignancy represented the largest SMN-group (34%) after mature B-NHL. Female sex was a risk factor for SMN (20-year cumulative incidence 8.4% vs. 4.0% in males, P=0.0008) (Table 1). Patients with known cancer predisposing condition (CPC) were at sig- nificantly higher risk for development of SMN (cumula- tive incidence 19.9% vs. 4.9%, P<0.0001) (Figure 2C). The majority of patients with CPC were female (66.7%). The most frequent SMN in patients with CPC was another lymphoid malignancy (Table 3; Online Supplementary Table S3). With a median age of 6.4 years (range, 1.3-9.6 years) at primary NHL diagnosis, patients with CPC were younger than other patients with SMN. Neither disease stage nor bone marrow involvement at primary diagnosis were significant risk factors (Table 1).
Only patients with LBL received ALL-type therapy. Only ALL-type therapy contains >200 mg/m2 doxorubicin equivalent. Accordingly, the cumulative incidence of SMN at 20 years was significantly higher after ALL-type thera- py (8.7%, SE=1.7) compared to B-NHL-type therapy (3.7%, SE=0.7; P=0.0002) and among patients who had received >200 mg/m2 doxorubicin equivalent (8.7, SE=1.8) compared to patients receiving less (4.3, SE=0.8, P<0.0001). Exposure to etoposide was not a risk factor for AML/MDS (results not shown). 76% of patients who
developed AML/MDS did not receive any epipodophyllo- toxins. The use of high cumulative doses of alkylating agents was not associated with higher incidence of SMN (Table 1).
Patients who received cranial radiotherapy were at sig- nificantly higher risk for developing a second CNS malig- nancy (P=0.01), (Table 1).
Stem cell transplantation correlated with SMN-develop- ment among patients who received B-NHL-type therapy (cumulative incidence 10.4%, SE=3.9 vs. 2.8, SE=0.6; P=0.005).
Because the previous reports of SMN after childhood cancer did not include non-melanoma skin cancer, for comparison purpose we performed cumulative incidence analyses excluding basal-cell carcinoma. Cumulative inci- dence of all SMN excluding basal-cell carcinoma at 20 years was 4.8% (SE=0.7). Cumulative incidence of SMN remained significantly higher among patients with LBL (8.6% at 20 years, SE=1.7%) compared to patients with other NHL-entities (3.4% at 20 years, SE=0.7%, P<0.0001), and in patients with known CPC (19.6% at 20 years, SE=7.1) compared to patients without known CPC (4.4% at 20 years, SE=0.7, P<0.0001) after exclusion of basal-cell carcinoma from the analysis.
Multivariate analysis of risk factors
In a stepwise Cox regression analysis taking into account risk factors significant in univariate analysis, which are listed in Table 1, only female sex (HR 1.9, 95% CI: 1.2-2.9, P=0.004), CNS-involvement (HR 2.2, 95% CI: 1.0-4.9, P=0.04), diagnosis of LBL (HR 2.6, 95% CI: 1.7-4.0, P<0.001), and a known CPC (HR 11.2, 95% CI: 5.5-22.8, P<0.001) represented independent risk factors for the development of SMN (Table 2). Looking for the
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