Gemtuzumab Ozogamicin In Refractory Childhood Acute Myeloid Leukemia.

Gemtuzumab ozogamicin, a CD33 linked calicheamicin, has been used in children with refractory AML since some years. In a phase I/II study, the treatment feasibility and moderate toxicity of the compound have been demonstrated (Zwaan et al. British Journal of Haematology, 2010).

Here we report the treatment results of 62 children and adolescents with refractory AML after at least two intensive regimens (n=62; male n=40; female n=22) and/or allogeneic stem cell transplant (n=9). Twenty-eight children received GO-monotherapy (7.5mg/m² day 1 and day 15; group A)*, in 34 children GO 3mg/m² was combined with cytarabine (500mg/m²/d 96h continuous infusion; group B).

The median age at initial diagnosis was 10 years (range 0.2 to 21 years). Nine children had secondary AML following a previous malignant disease and in 4 cases an acute leukemia of ambigious lineage (ALAL) had been diagnosed.

The morphological subtypes were AML FAB M0 n=4; M1/M2 n=17 M3 n =1; M4/M5 n=25; M4Eo n=1; M6/M7 n=9, undifferentiated (AUL)/acute leukemia of ambiguous lineage (ALAL) n=5.

In cytogenetics, most patients had a normal karyotype (n=16; including 7 with FLT3-ITD) followed by MLL-rearrangements (n=14), numerical aberrations (n=7; including FLT3-ITD n=2), others aberrations (n=10; FLT3-ITD n=1), complex karyotype (n=3) and BCR/ABL positive AML (n=1). Favorable translocations [t(8;21), inv 16, t(15;17)] were diagnosed in 4 patients. In 7 patients no cytogenetic results were available.

Five children suffered acute anaphylactic reaction during or short after infusion (CTC grade III n=3, grade IV n=2). Severe, long lasting myelosuppression has been observed in almost all patients. While the frequency of severe infection during myelosuppression was moderate, side effects such as mucositis have rarely been reported. A vena occlusive-disease (VOD)-like syndrome was observed in 5 children after alloSCT, in two cases with fatal outcome.

An overall response (CR, CRp, PR) has been documented in 32 children (group A n=10/28, 36%; group B n=22/34, 65%). A higher response rate has been observed in children with AML FAB M1/2 with auer rods (n=18 response n=12, 67%) and AML with favorable aberrations (n=3/4). Six out of 10 children with FLT3-ITD positive AML responded to GO whereas patients with AUL/ALAL (n=9; response n=1, 11%) and AML FAB M6/7 (n=10; response n=3, 30%) showed a poorer response.

Thirty-five patients received allogeneic SCT following GO treatment, 30 of the responders and 5 patients without GO response. In total 13 children are alive. Out of the responders 11 children or adolescents are still in complete remission (follow-up 2.7 years, 0.5 to 8.2 yrs.). Again children with AML FAB M1/2 and/or favorable cytogenetics had the best prognosis (7 /19 children alive, 37%). By contrast, none of the children with AML FAB M6/7, AUL or ALAL survived.

Out of the 30 patients who did not respond to GO, following alloSCT 2 children are alive, however, the follow-up of 0.5 years (0.3 to 0.9 yrs) is very short.

in this particular poor group of heavily pretreated children and adolescents with multiple relapsed, refractory AML, GO seems to improve the prognosis in some children and enables further treatment e.g. alloSCT. Based on the specific needs of children it is of importance that clinical trials continue in childhood AML to identify the appropriate patient group and schedule of GO combined with chemotherapy.

* Seven patients out of this group were eligible for the International AML 2001/02 study “Salvage of refractory childhood AML with Mylotarg, Zwaan et al. BJH, 2010.

No relevant conflicts of interest to declare.