TY - JOUR
T1 - Azacitidine (Vidaza®) in Pediatric Patients with Relapsed Advanced MDS and JMML
T2 - Results of a Phase I/II Study by the ITCC Consortium and the EWOG-MDS Group (Study ITCC-015)
AU - Rubio-San-Simón, Alba
AU - van Eijkelenburg, Natasha K A
AU - Hoogendijk, Raoull
AU - Hasle, Henrik
AU - Niemeyer, Charlotte M
AU - Dworzak, Michael N
AU - Zecca, Marco
AU - Lopez-Yurda, Marta
AU - Janssen, Julie M
AU - Huitema, Alwin D R
AU - van den Heuvel-Eibrink, Marry M
AU - Laille, Eric J
AU - van Tinteren, Harm
AU - Zwaan, Christian M
N1 - © 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.
PY - 2023
Y1 - 2023
N2 - BACKGROUND: Advanced myelodysplastic syndrome (MDS) and juvenile myelomonocytic leukemia (JMML) are rare hematological malignancies in children. A second allograft is recommended if a relapse occurs after hematopoietic stem cell transplantation, but the outcome is poor.OBJECTIVE: We conducted a phase I/II multicenter study to evaluate the safety, pharmacokinetics, and activity of azacitidine in children with relapsed MDS/JMML prior to the second hematopoietic stem cell transplantation.METHODS: Patients enrolled from June 2013 to March 2019 received azacitidine intravenously/subcutaneously once daily on days 1-7 of a 28-day cycle. The MDS and JMML cohorts followed a two-stage design separately, with a safety run-in for JMML. Response and safety data were used to evaluate efficacy and establish the recommended dose. Pharmacokinetics was also analyzed. The study closed prematurely because of low recruitment.RESULTS: Six patients with MDS and four patients with JMML received a median of three and five cycles, respectively. Azacitidine 75 mg/m2 was well tolerated and plasma concentration-time profiles were similar to observed in adults. The most prevalent grade 3-4 adverse event was myelotoxicity. No responses were seen in patients with MDS, but 83% achieved stable disease; four patients underwent an allotransplant. Overall response rate in the JMML cohort was 75% (two complete responses; one partial response) and all responders underwent hematopoietic stem cell transplantation. One-year overall survival was 67% (95% confidence interval 38-100) in MDS and 50% (95% confidence interval 19-100) in JMML.CONCLUSIONS: Azacitidine 75 mg/m2 prior to a second hematopoietic stem cell transplantation is safe in children with relapsed MDS/JMML. Although the long-term advantage remains to be assessed, this study suggests that azacitidine is an efficacious option for relapsed JMML.CLINICAL TRIAL REGISTRATION: EudraCT 2010-022235-10.
AB - BACKGROUND: Advanced myelodysplastic syndrome (MDS) and juvenile myelomonocytic leukemia (JMML) are rare hematological malignancies in children. A second allograft is recommended if a relapse occurs after hematopoietic stem cell transplantation, but the outcome is poor.OBJECTIVE: We conducted a phase I/II multicenter study to evaluate the safety, pharmacokinetics, and activity of azacitidine in children with relapsed MDS/JMML prior to the second hematopoietic stem cell transplantation.METHODS: Patients enrolled from June 2013 to March 2019 received azacitidine intravenously/subcutaneously once daily on days 1-7 of a 28-day cycle. The MDS and JMML cohorts followed a two-stage design separately, with a safety run-in for JMML. Response and safety data were used to evaluate efficacy and establish the recommended dose. Pharmacokinetics was also analyzed. The study closed prematurely because of low recruitment.RESULTS: Six patients with MDS and four patients with JMML received a median of three and five cycles, respectively. Azacitidine 75 mg/m2 was well tolerated and plasma concentration-time profiles were similar to observed in adults. The most prevalent grade 3-4 adverse event was myelotoxicity. No responses were seen in patients with MDS, but 83% achieved stable disease; four patients underwent an allotransplant. Overall response rate in the JMML cohort was 75% (two complete responses; one partial response) and all responders underwent hematopoietic stem cell transplantation. One-year overall survival was 67% (95% confidence interval 38-100) in MDS and 50% (95% confidence interval 19-100) in JMML.CONCLUSIONS: Azacitidine 75 mg/m2 prior to a second hematopoietic stem cell transplantation is safe in children with relapsed MDS/JMML. Although the long-term advantage remains to be assessed, this study suggests that azacitidine is an efficacious option for relapsed JMML.CLINICAL TRIAL REGISTRATION: EudraCT 2010-022235-10.
KW - Adult
KW - Humans
KW - Child
KW - Azacitidine/adverse effects
KW - Leukemia, Myelomonocytic, Juvenile/drug therapy
KW - Myelodysplastic Syndromes/drug therapy
KW - Remission Induction
KW - Hematologic Neoplasms
KW - Leukemia, Myeloid, Acute/chemically induced
U2 - 10.1007/s40272-023-00588-5
DO - 10.1007/s40272-023-00588-5
M3 - Article
C2 - 37695474
SN - 1174-5878
VL - 25
SP - 719
EP - 728
JO - Paediatric drugs
JF - Paediatric drugs
IS - 6
ER -