Azacitidine (Vidaza®) in Pediatric Patients with Relapsed Advanced MDS and JMML: Results of a Phase I/II Study by the ITCC Consortium and the EWOG-MDS Group (Study ITCC-015)

Alba Rubio-San-Simón; Natasha K A van Eijkelenburg; Raoull Hoogendijk; Henrik Hasle; Charlotte M Niemeyer; Michael N Dworzak; Marco Zecca; Marta Lopez-Yurda; Julie M Janssen; Alwin D R Huitema; Marry M van den Heuvel-Eibrink; Eric J Laille; Harm van Tinteren; Christian M Zwaan

doi:10.1007/s40272-023-00588-5

Azacitidine (Vidaza®) in Pediatric Patients with Relapsed Advanced MDS and JMML: Results of a Phase I/II Study by the ITCC Consortium and the EWOG-MDS Group (Study ITCC-015)

Alba Rubio-San-Simón, Natasha K A van Eijkelenburg, Raoull Hoogendijk, Henrik Hasle, Charlotte M Niemeyer, Michael N Dworzak, Marco Zecca, Marta Lopez-Yurda, Julie M Janssen, Alwin D R Huitema, Marry M van den Heuvel-Eibrink, Eric J Laille, Harm van Tinteren, Christian M Zwaan

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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.

Originele taal-2	Engels
Pagina's (van-tot)	719-728
Aantal pagina's	10
Tijdschrift	Paediatric drugs
Volume	25
Nummer van het tijdschrift	6
DOI's	https://doi.org/10.1007/s40272-023-00588-5
Status	Gepubliceerd - 2023

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10.1007/s40272-023-00588-5

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Rubio-San-Simón, A., van Eijkelenburg, N. K. A., Hoogendijk, R., Hasle, H., Niemeyer, C. M., Dworzak, M. N., Zecca, M., Lopez-Yurda, M., Janssen, J. M., Huitema, A. D. R., van den Heuvel-Eibrink, M. M., Laille, E. J., van Tinteren, H., & Zwaan, C. M. (2023). Azacitidine (Vidaza®) in Pediatric Patients with Relapsed Advanced MDS and JMML: Results of a Phase I/II Study by the ITCC Consortium and the EWOG-MDS Group (Study ITCC-015). Paediatric drugs, 25(6), 719-728. https://doi.org/10.1007/s40272-023-00588-5

@article{238a9a0e62a845b390a42456466ae51f,

title = "Azacitidine (Vidaza{\textregistered}) in Pediatric Patients with Relapsed Advanced MDS and JMML: Results of a Phase I/II Study by the ITCC Consortium and the EWOG-MDS Group (Study ITCC-015)",

abstract = "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.",

keywords = "Adult, Humans, Child, Azacitidine/adverse effects, Leukemia, Myelomonocytic, Juvenile/drug therapy, Myelodysplastic Syndromes/drug therapy, Remission Induction, Hematologic Neoplasms, Leukemia, Myeloid, Acute/chemically induced",

author = "Alba Rubio-San-Sim{\'o}n and {van Eijkelenburg}, {Natasha K A} and Raoull Hoogendijk and Henrik Hasle and Niemeyer, {Charlotte M} and Dworzak, {Michael N} and Marco Zecca and Marta Lopez-Yurda and Janssen, {Julie M} and Huitema, {Alwin D R} and {van den Heuvel-Eibrink}, {Marry M} and Laille, {Eric J} and {van Tinteren}, Harm and Zwaan, {Christian M}",

note = "{\textcopyright} 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.",

year = "2023",

doi = "10.1007/s40272-023-00588-5",

language = "English",

volume = "25",

pages = "719--728",

journal = "Paediatric drugs",

issn = "1174-5878",

publisher = "Adis International Ltd",

number = "6",

}

Rubio-San-Simón, A, van Eijkelenburg, NKA , Hoogendijk, R, Hasle, H, Niemeyer, CM, Dworzak, MN, Zecca, M, Lopez-Yurda, M, Janssen, JM, Huitema, ADR , van den Heuvel-Eibrink, MM, Laille, EJ, van Tinteren, H & Zwaan, CM 2023, 'Azacitidine (Vidaza®) in Pediatric Patients with Relapsed Advanced MDS and JMML: Results of a Phase I/II Study by the ITCC Consortium and the EWOG-MDS Group (Study ITCC-015)', Paediatric drugs, vol. 25, nr. 6, blz. 719-728. https://doi.org/10.1007/s40272-023-00588-5

Azacitidine (Vidaza®) in Pediatric Patients with Relapsed Advanced MDS and JMML: Results of a Phase I/II Study by the ITCC Consortium and the EWOG-MDS Group (Study ITCC-015). / Rubio-San-Simón, Alba; van Eijkelenburg, Natasha K A ; Hoogendijk, Raoull et al.
In: Paediatric drugs, Vol. 25, Nr. 6, 2023, blz. 719-728.

Onderzoeksoutput: Bijdrage aan tijdschrift › Artikel › peer review

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

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 -

Azacitidine (Vidaza®) in Pediatric Patients with Relapsed Advanced MDS and JMML: Results of a Phase I/II Study by the ITCC Consortium and the EWOG-MDS Group (Study ITCC-015)

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