PF550 AZACITIDINE (VIDAZA<sup>®</sup>) IN PEDIATRIC PATIENTS WITH RELAPSED ADVANCED MDS: RESULTS OF A PHASE I/II STUDY BY THE ITCC CONSORTIUM AND THE EWOG‐MDS GROUP: STUDY ITCC‐015
Authors: N.K. van Eijkelenburg, M.M. van den Heuvel‐Eibrink, H. Hasle, C.M. Niemeyer, M.N. Dworzak, M. Zecca, M.I. Lopez, R. Hoogendijk, J. Janssen, A. Huitema, C.M. Zwaan
Journal: HemaSphere (2019)

Background: Pediatric myelodysplastic syndromes (MDS) are a rare heterogenous group of clonal malignant diseases, characterized by ineffective hematopoiesis and subsequent development of AML. So far, stem cell transplantation (SCT) is the only curative treatment option which results in approximately 60% survival (Strahm et al, 2011). The demethylating agent azacitidine improves survival in adult MDS patients not fit for SCT and is approved for this indication. The safety and efficacy of azacitidine in pediatric MDS has not yet been established. Aims: To establish a recommended dose and preliminary efficacy of azacitidine in children with advanced primary relapsed MDS or juvenile myelomonocytic leukemia (JMML) in a pre‐transplantation window. Methods: An international, collaborative, prospective phase I/II trial (Dutch Trial registry 2578) was initiated and sponsored by Erasmus MC, Rotterdam, the Netherlands. Azacitidine was provided by Celgene. Key inclusion criteria were: age 1 month to 18 yrs; advanced primary relapsed MDS or JMML; life expectancy 3 months; and resolved toxicities from prior therapy. Both Azacitidine intravenous (iv) and subcutaneous (sc) were allowed, with a starting dose level (DL1) of 75 mg/m 2 x 7 days in cycles of 28 days. It was aimed to prescribe at least 3 cycles prior to HSCT. Tumor response was evaluated after the 1 st and subsequent courses with bilateral bone marrow aspirates and trephines, using central morphology review. The overall morphologic response rate (ORR) was defined as the number of patients with either complete response (CR) or partial response (PR). Adverse events were graded using CTCAE version 4.0. DLTs were limited to the 1 st course. The two independent study‐arms followed a 2‐stage design taking treatment tolerability and response data into account. For the MDS arm the dose would be increased only if &lt;2/6 evaluable patients achieved a response (CR or PR), and/or there were £ 2 dose‐limiting toxicities (DLTs). Pharmacokinetic (PK) parameters of the 1 st course were calculated from plasma concentration‐time profiles using non‐compartmental methods. The enrollment in the MDS arm of the study was closed on 28‐nov‐2018, the enrollment in the JMML arm is ongoing. Results: From 2013 to 2018, 9 pediatric patients were recruited: 6 MDS and 3 JMML. Three boys and 3 girls with MDS were recruited with a median age of 14.3 yrs. In total 17 cycles were administered, 14 iv and 3 sc. Median duration of treatment was three cycles (range 2–4). One patient experienced several DLTs: pulmonary hemosiderosis, splenomegaly, erytrocytosis and erythema nodosum, reported as SUSARs. Other grade 3 and 4 events consisted of febrile neutropenia, anemia, thrombocytopenia, elevation of ALT or bilirubin, anorexia and headache. After a median follow‐up of 14.2 months, the ORR was 0/6 patients: 4 stable disease and 2 progression. No patients were dose‐escalated to DL2. In 2 of 4 patients who received SCT graft‐versus‐host disease was reported. The 3‐year overall survival of transplanted patients was 75% (95% CI 42,6 – 100). Both non‐transplanted patients deceased. PK analyses (n = 9) showed drug exposure in line with results in adults. Median AUC0‐inf was 631 h ∗ ng/mL and Cmax was 2285 ng/mL (n = 6) after iv administration and 913 h ∗ ng/mL and 1430 ng/mL (n = 3) after s.c. administration. High interindividual variability was observed mainly caused by a single outlier. Summary/Conclusion: Despite the fact that azacitidine was in general well tolerated, the ORR in the MDS patients was not satisfactory. Recruitment in JMML is ongoing. The PK behavior of azacitidine was similar to adult PK.