Dose-related efficacy and toxicity of gemtuzumab ozogamicin in pediatric acute myeloid leukemia

Figures & data

Table 1. Overview of ongoing clinical trials of gemtuzumab ozogamicin in AML, also enrolling children.

Title	Status	Number of patients	Dose of GO (mg/m^2)	Combination/single agent therapy	Trial number
Phase II Study of Treatment of Acute Promyelocytic Leukemia (APL) With ATRA, Arsenic Trioxide and Gemtuzumab Ozogamicin (GO)	Recruiting	100	9	Combination	NCT01409161
Allogeneic Stem Cell Transplantation Following by Targeted Immune Therapy (Gemtuzumab Ozogamicin) in Average Risk Acute Myelogenous Leukemia and Myelodysplastic Syndrome (AML/MDS)(IND 111024)	Recruiting	26 (up to 30 years)	9	Single agent	NCT02117297
Allogeneic Stem Cell Transplantation Followed by Targeted Immune Therapy In Average Risk Acute Myelogenous Leukemia/Myelodysplastic Syndrome/Juvenile Myelomonocytic Leukemia (AML/MDS/JMML)	Ongoing, not recruiting	18 (1 month till 64 years	Dose-escalation regimen	Combination	NCT01020539
Gemtuzumab Ozogamicin (Mylotarg [Registered]) Expanded Access Protocol for Treatment of Patients in the United States with Relapsed/Refractory Acute Myelogenous Leukemia Who May Benefit from Treatment and Have No Access to Other Comparable/Alternative Therapy	Expanded access	Unknown (3 months and older)	9 mg/m^2 as a single agent	Single agent and combination	NCT02312037
A Pilot Study of Gemtuzumab Ozogamicin in Combination with Busulfan and Cyclophosphamide (Bu/Cy) (Immunochemotherapy) and Allogeneic Stem Cell Transplantation (AlloSCT) in Patients with High Risk Acute Myelogenous Leukemia and Myelodysplastic Syndrome (AML/MDS)	Recruiting	25 (up to 30 years old	7.5	Combination	NCT02221310

AML: acute myeloid leukemia; GO: gemtuzumab ozogamicin.

Table 2. Search terms electronic databases.

Database 30 February 2015	Search terms
PubMed	‘Child’[Mesh] OR ‘Infant’[Mesh] OR child*[tw] OR schoolchild*[tw] OR infan*[tw] OR adolescen*[tw] OR pediatri*[tw] OR paediatr*[tw] OR neonat*[tw] OR boy[tw] OR boys[tw] OR boyhood[tw] OR girl[tw] OR girls[tw] OR girlhood[tw] OR youth[tw] OR youths[tw] OR baby[tw] OR babies[tw] OR toddler*[tw] OR teen[tw] OR teens[tw] OR teenager*[tw] OR newborn*[tw] OR postneonat*[tw] OR postnat*[tw] OR puberty[tw] OR preschool*[tw] OR suckling*[tw] OR picu[tw] OR nicu[tw] OR ‘Leukemia, Myelomonocytic, Juvenile’[Mesh] AND ‘gemtuzumab’ [Supplementary Concept] OR gemtuzumab[tiab] OR Mylotarg[tiab]
Embase	[embryo]/lim OR [fetus]/lim OR [newborn]/lim OR [infant]/lim OR [preschool]/lim OR [school]/lim OR [child]/lim OR [adolescent]/lim OR child*:ab,ti OR schoolchild*:ab,ti OR infan*:ab,ti OR adolescen*:ab,ti OR pediatri*:ab,ti OR paediatr*:ab,ti OR neonat*:ab,ti OR boy:ab,ti OR boys:ab,ti OR boyhood:ab,ti OR girl:ab,ti OR girls:ab,ti OR girlhood:ab,ti OR youth:ab,ti OR youths:ab,ti OR baby:ab,ti OR babies:ab,ti OR toddler*:ab,ti OR teen:ab,ti OR teens:ab,ti OR teenager*:ab,ti OR newborn*:ab,ti OR postneonat*:ab,ti OR postnat*:ab,ti OR puberty:ab,ti OR preschool*:ab,ti OR suckling*:ab,ti OR picu:ab,ti OR nicu:ab,ti OR ‘childhood leukemia’/exp AND ‘gemtuzumab ozogamicin’/exp OR gemtuzumab:ab,ti OR mylotarg:ab,ti

Figure 1. Overview selection criteria for study inclusion.

Table 3. Overview of the most important variables of all eligible studies in pediatric AML, single-agent therapy.

Study	Number of patients	Mean age (range)	Single dose (mg/m^2)	Total dose of GO (mg/m^2)	Newly diagnosed, refractory of relapsed	Combination therapy or single-agent therapy	Grade III/IV bilirubin (%)	VOD (%)	CR + CRi (%)
Zwaan et al. 2003	15	8.9 (0.7–17.3)	9	18	4 refractory, 11 relapsed	Single agent	7	7	33
Arceci et al. 2005	29	12 (1–16)	9	18	10 refractory, 19 relapsed	Single agent	7	24	28
Roman et al. 2005	8	9 (0.5–15)	6	12	Relapsed	Single agent	0	0	63
Brethon et al. 2006	12	5.5 (1–17.2)	3	9	3 refractory, 9 relapsed	Single agent	8.3	0	25
Sibson et al. 2009	12	8 (1–13)	9	18	4 refractory, 8 relapsed	Single agent	NR	8.3	17
Zwaan et al. 2010	30	9.4 (1.4–16.6)	7.5	15	17 refractory, 13 relapsed	Single agent	3	0	37
Sayar et al. 2010	3	0.75 (0.2–1.2)	9	18	2 patients initial/1 relapse	Single agent	0	0	100
Reinhardt et al. 2010	28	10 (0.2–21)	7.5	15	Relapsed	Single agent	NR	3.6	36
Hasle et al. 2012	53	NR	5	10	Newly diagnosed	Single agent, post-consolidation	0	0	88

AML: acute myeloid leukemia; CR: complete remission; CRi: CR with incomplete blood count recovery; GO: gemtuzumab ozogamicin; NR: not reported; VOD: veno-occlusive disease.

Table 4. Overview of the most important variables of all eligible studies in pediatric AML, combination therapy.

Study	Number of patients	Mean age (range)	Single dose (mg/m^2)	Total dose of GO (mg/m^2)	Newly diagnosed, refractory of relapsed	Combination therapy or single-agent therapy	Grade III/IV bilirubin (%)	VOD (%)	CR + CRi (%)
Aplenc et al. 2008	20	12.8 (1.2–19.3)	3	3	1 refractory, 19 relapsed	Combination	5	10	55
	25	10.7 (0.8–19.8)	2	2	8 refractory, 17 relapsed	Combination	5	8	40
Brethon et al. 2008	17	10.8 (0.9–22.3)	3	9	1 newly diagnosed, 2 refractory, 14 relapsed	Combination	0	0	53
Reinhardt et al. 2010	34		3	3	Refractory	Combination	NR	11.8	65
Cooper et al. 2012	340	9.5 (0.07–21.6)	3	6	Initial	Combination	NR	5.6	86.9
Satwani et al. 2012	3	7.3 (1–17)	3	3	Relapsed	Combination	0	33	NR
	3	4.7 (2–10)	4.5	4.5	2 refractory, 1 relapsed	Combination	0	0	NR
	3	9.3 (2–15)	6	6	1 refractory, 2 relapsed	Combination	0	33	NR
	3	5 (1–12)	7.5	7.5	Relapsed	Combination	0	0	NR
Yoshida et al. 2012	2	9 (7–11)	3	3	Relapsed	Combination	0	0	100

AML: acute myeloid leukemia; CR: complete remission; CRi: CR with incomplete blood count recovery; GO: gemtuzumab ozogamicin; NR: not reported; VOD: veno-occlusive disease.

Figure 2. Scatterplot for the single dose of gemtuzumab ozogamicin in relation to incidence of VOD. Single-agent therapy.

Figure 3. Scatterplot for the cumulative dose of gemtuzumab ozogamicin in relation to incidence of VOD. Single-agent therapy.

Figure 4. Scatterplot for the single dose of gemtuzumab ozogamicin in relation to incidence of VOD. Combination therapy.

Figure 5. Scatterplot for the cumulative dose of gemtuzumab ozogamicin in relation to incidence of VOD. Combination therapy.