Second Malignancy after Childhood AML Treatment - a Retrospective Analysis of the AML-BFM Stud

In the past decades the outcome in ped AML patients improved continuously. However, secondary malignancies seem to be a severe side-effect, affecting the quality of life in survivors. This retrospective data analysis in patients treated according to AML-BFM protocols, is focused the occurrence of secondary malignancies after AML treatment and evaluates the consequences thereof.

Between 1993 - 2019 (total n=2797) 51 patients were documented with a secondary malignancy (SM) after AML treatment. 5 pat (10%) were excluded due to a lack of data concerning the SMs exact diagnosis or a clear differentiation from AMLs relapse. Patients were included if the de novo AML occurred before <18yrs. 46 pat (f=20; m=26) remained in the analysis. All pat were treated acc to the current AML-BFM protocol version at the time of their AML diagnosis and for their SM acc. to local standard of care. For AML treatment the cumulative dose of i.v.-cytarabine ranged from 41,380 to 51,380 mg/m²(median 47,380 mg/m²), i.th. cytarabine from 140 to 370 mg age and weight-depended (median 330 mg), etoposide was given constantly with 950 mg/m² and from 2004 to 2017 anthracyclines with cumulative doses of 500 mg/m² were applied (idarubicin/mitoxantrone calculated with equivalence dosage of 1:5). Since 2004 the i.th. therapy was added with a max. dose of 70 mg prednisolone and 84 mg MTX, both depending on age and weight.

The median age on initial AML was 7.3 yrs, ranged from 0.1-17.5 yrs while the median age at date of SM diagnosis was 14.4 yrs, ranged from 0.86-30.2 yrs. The median percentage of BM blasts was 61% (0 - 100%), the median WBC of 7,200/ μl (670 - 214,000/μl) and hemoglobin was 8.7 g/dl (4.6-14.2 g/dl). Acc. to the FAB classification, FAB M4/M5 (43%) was the largest group, followed by FAB M0/M1/ M2 (35%), FAB M6/M7 (6%), M3 (6%) and others (6%). In 63% of the cohort a normal karyotype was detected. Beside a single patient (2%) all others received CR during AML treatment. The median time between AML and SM was 3.6 yrs (0.6 to 19.7 years). Interestingly the median time differs between AML followed by blood cancers with 3.2 yrs (0.8- 15.2 yrs) to 8.1 yrs (0.6-19.7 yrs) for AML followed by a solid tumor. Leukemia (n=13, 28%), such as ALL (n=10) or CML (n=3), was the most frequent SM, however also secondary myelodysplastic syndromes (n=8, 17%; including RAEB and RAEB in transformation), lymphoma (n=7, 15%), head and neck tumors (n=6, 13%), skin cancer (n=3, 7%), CNS tumors (n=3, 7%) and other diagnoses (n=6, 13%) were reported. None of the patients was reported with known genetic disorders explaining the SM, but in 9 cases (20%) pre-existing diseases (malignant and non-malignant) was documented, often as multi-morbidity (e.g., heart, lung, neurological diseases). According to a median follow-up-period of 11.7 yrs (0.6-22.3 yrs) after AML diagnosis, the 5-yr-overall survival (OS) rate of the cohort was 97±2% after AML and decreases to 78±6% from the date of SM. The OS of 97±2% resulted from a single patient, which was diagnosed with the SM and died at the same day. The 5-yr-event-free-survival (EFS), defined as death by any cause, relapse (independently of AML or SM) and third malignancy, was 87±5% vs. 71±7%. Patients suffering from blood cancers as SM (n=29, 63%) had a slightly poorer outcome in comparison to solid tumor patients (n=17, 37%) with a 5-yr-OS of 79±8% vs. 88±2% (p 0.223) and 5-yr-EFS of 65±9% vs. 82±9% (p 0.097).

With a cumulative incidence of 2%, SM are extremely rare after ped AML. In contrast, in the same period three times more t-AML cases were reported, therefor AML itself is the most frequent treatment-related malignancy in ped patients as previously published. The results showed a shorter period between AML followed by blood cancers than solid tumors, which suggesting either that AML and the SM are pathophysiologically related whereas solid tumors may be therapy-induced only or that hematopoiesis is more sensitive for toxic effects or shows a higher proliferation rate. Due to the very limited case numbers and lack of further genetic results to exclude e.g. predisposition syndromes, these hypotheses are speculative and cannot be proven. Based on the frequency of SM after ped AML and the outcome thereof, a further therapy intensification to improve especially the AMLs EFS is justifiable. Caused on the results and the revealed median intervals, a long-term follow up for ped AML patients into their adult life is highly recommendable to learn more about these rare events.

Reinhardt:BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cerus: Membership on an entity's Board of Directors or advisory committees; Medac: Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; BlueBird Bio: Research Funding.