Second Neoplasms After Treatment of Childhood Acute Lymphoblastic Leukemia
Authors: Schmiegelow Kjeld , Levinsen Mette , Attarbashi Andishe , Baruchel Andre , Devidas Meenakshi , Escherich Gabriele , Gibson Brenda , Heydrich Christiane , Horibe Keizo , Ishida Yasushi , Liang Der-Cherng , Locatelli Franco , Michel Gerard , Pieters Rob , Piette Caroline , Pui Ching-Hon , Raimondi Susana C. , Silverman Lewis B. , Stanulla Martin , Stark Batia , Winick Naomi , Valsecchi Maria Grazia 
Published: October 2019

Abstract
Abstract 661

Purpose:
The 10-year overall survival (OS) for childhood ALL is now 80% or higher with many contemporary treatment programs. Although, second neoplasms (SMN) after diagnosis of childhood acute lymphoblastic leukemia (ALL) are rare events, toxic death in remission and death due to a SMN may constitute up to one third of all deaths among children with ALL. Previously reported cumulative incidences of SMN have varied between treatment protocols from less than 1% to 10% or more due to differences in the antileukemic therapy and duration and structure of follow-up.

Method:
18 collaborative groups from Europe, Asia and the US analyzed risk factors and outcome of 642 SMNs occurring as first event after childhood ALL entered onto ALL trials between 1980 and 2007.

Result:
186 patients had acute myeloid leukemias (AML), 138 brain tumors, 78 carcinomas, 81 lymphomas, 69 myelodysplasias (MDS), and 90 others malignancies. The median time interval to SMN was 4.8 years, being shortest for hematological malignancies (2.9 years) and longest for patients with carcinomas (10.1 years), meningiomas (16.2 years) and melanomas (10.0 years). AML/MDS (t-MN) with monosomy 7 or 5q- was associated with high-hyperdiploid ALL karyotypes, whereas MLL-rearranged AML/MDS was associated with ALL translocations (p=0.03). The pattern of SMN was significantly influenced by the preceding ALL therapy. The vast majority of CNS tumors had received cranial irradiation. The 12 CNS tumor patients who had not received CNS-irradiation were diagnosed at significantly shorter intervals after ALL than the 97 CNS tumors that occurred after CNS irradiation (median, 6.6 versus 9.1 years, P=0.01). 38 of 50 (76.0%) cases of t-MN with an aberrant karyotype and previous exposure to epipodophyllotoxins had 11q23/MLL rearrangements, whereas only four (8.0%) had monosomy 7 and none had 5q-. Patients developing myeloid malignancies had received higher maintenance therapy 6-mercaptopurine starting doses than patients with other SMNs (p< 0.001). Transplantation during first remission of ALL had been performed in 29 of the 510 ALL patients (5.7%) with available information. One of 74 (1.4%) patients with CNS tumors and seven of 193 (3.6%) with t-MN had been transplanted as compared to 9 of 32 (28.1%) with carcinomas and 8 of 52 (15.4%) with other SMNs (P<0.001). The 5 year OS for all SMNs was 40.4±2.1. Acute myeloid leukemia, myelodysplastic syndrome, and non-meningioma brain tumors (n=116) had the poorest outcome (5-year survival rate, 18.1±2.9%, 31.1±6.2%, and 18.3±3.8%, respectively). Allogeneic stem-cell transplantation failed to improve outcome of secondary myeloid malignancies after adjusting for waiting time to transplantation. The OS was 30.3±4.4% for 119 transplanted AML/MDS patients vs 11.4±4.0% for 66 non-transplanted patients (p< 0.001), but this difference in survival was eliminated after adjustment for waiting time to transplant (4.1 months). Five year OS rates were above 90% for patients with meningiomas, Hodgkin disease, thyroid carcinoma, basal cell carcinomas, and glandula parotis tumors, and 68.5±6.4% for NHL.

Conclusion:
Disease- and treatment-related factors influence risk of SMN among childhood ALL patients, being most pronounced for central nervous system irradiation. Except for brain tumors, AML and MDS, survival after SMN was very similar to their primary counterparts.

Disclosures:
No relevant conflicts of interest to declare.