Exceptional Responses to Epigenetic Based Therapy in Pediatric and Young Adult Monosomy 7 MDS/AML Patients with and without TP53 Mutations

Background: Children and young adults with relapsed/refractory or secondary acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) may not be candidates for conventional cytotoxic chemotherapy salvage regimens due to chemotherapy refractory disease or comorbidities. Hypomethylating agents including decitabine and azacitidine have favorable toxicities profiles and have demonstrated activity in adult AML/MDS. Favorable responses to decitabine have been associated with TP53 mutations in adult patients with AML/MDS (Welch et al., New England Journal of Medicine 2016) as well as elderly patients with high risk MDS and multiple autosomal monosomies (Lübbert et al., Annals of Hematology 2016). Pediatric data with hypomethylating agents are scarce due to lack of large prospective clinical trials. Previously, in a cohort of eight patients, we reported that decitabine therapy resulted in a complete response (CR) or complete response with incomplete count recovery (CRi) in 38% of patients, and at least a partial response in 75% of patients(Phillips et al., British Journal of Hematology 2013). However, prognostic factors for response are lacking in children and young adults.

Methods: Data was collected using an IRB-approved retrospective chart review of any patient with MDS or AML who received epigenetic therapy with azacitidine or decitabine between 2012 and 2017 at a single center. Patients included received at least one course of hypomethylating agent and had response assessed by bone marrow evaluation.

Patients received either decitabine at 20 mg/m² IV for 10 days or azacitidine at 75mg/m2 IV for 7 days. Courses in which a hypomethylating agent was given in combination with vorinostat or sorafenib were also included.

Results: 14 patients were treated with hypomethylating agents, with a median age of 8.5 years [range 2-34]; 10 of whom received concurrent vorinostat therapy. Previous therapy included an average of two prior regimens [range 1-3], with 46% having undergone hematopoietic stem cell transplant (HSCT). Genetic alterations included monosomy 7 (5/14 patients), as well as mutations in TP53 (2/14 germline, 1/14 somatic) and PTPN11 (1 somatic).

CR/CRi was achieved in 4/14 patients, with partial response (PR) in 2/14 and stable disease (SD) in 3/14. In CR/CRi and PR patients, the best response was observed after a median of 1.5 cycles [range 1-4]. CR/CRi was achieved in 3/5 patients with monosomy 7 (2 CR/1 CRi); 2 of these patients had a germline TP53 mutation and secondary MDS/AML with monosomy 7. The third responding monosomy 7 AML patient had a somatic PTPN11 mutation, and was refractory to cytarabine and anthracyclines. This patient achieved CRi with azacitidine and sorafenib and remains alive 4 years following HSCT. The remaining 2 patients with monosomy 7 had stable disease over an average of three cycles of hypomethylating therapy. In contrast, of the 9 patients without monosomy 7, one patient achieved CR (11%), 2 others had a partial response, and one had stable disease. The single patient without monosomy 7 who achieved a CR had a normal karyotype but FISH detected loss of one copy of 16q22 (CBFB) and trisomy of 9q22. In the 3/14 patients with TP53 mutations, there were 2 CR/CRi and 1 SD. Overall, 3/14 patients (1 with monosomy 7) remain in CR two to four years post HSCT, after receiving hypomethylating therapy.

Conclusions: Hypomethylating agent therapy demonstrates activity in a subset of children and young adults with relapsed/refractory MDS/AML with responses noted in 3 of 5 patients with monosomy 7, consistent with the published experience in adults.However, a clear conclusion on response pattern in pediatric patients with somatic TP53 mutations cannot be drawn, given this small sample size. This data warrants further investigation of response and resistance patterns in pediatric patients with relapsed/refractory AML/MDS.