Successful treatment with low-dose gemtuzumab ozogamicin in combination chemotherapy followed by stem cell transplantation for children with refractory acute myeloid leukaemia

Authors


The prognosis of children with acute myeloid leukaemia (AML) who are refractory after relapse is dismal, even with allogeneic stem cell transplantation (SCT). To improve the clinical outcomes of these patients, novel approaches should be applied to overcome the intrinsic resistance of leukaemia cells against chemotherapy. Gemtuzumab ozogamicin (GO), a monoclonal anti-CD33 antibody conjugated with calicheamicin, is a promising agent for patients with AML that is resistant to conventional chemotherapy. Regrettably, in July 2010, GO was voluntarily withdrawn from the United States market based in part on the results of a trial conducted by the Southwest Oncology Group (SWOG trial S0106), which examined GO as an addition to induction chemotherapy in newly diagnosed adult cases (Petersdorf et al, 2009). Given this, GO has been recommended for use as a mono-agent, but not as part of combination chemotherapy in Japan. In contrast to the result of the SWOG S0106 trial, several subsequent studies, such as AAML03P1 conducted by the Children's Oncology Group (Cooper et al, 2012) and the Medical Research Council (MRC) AML 15 trial (Burnett et al, 2011), determined that it is feasible to include GO in combination with intensive chemotherapy. However, little is known about its usefulness for cytoreductive therapy prior to SCT in children with refractory AML.

Here, we report two cases of refractory AML successfully treated with low-dose GO in combination chemotherapy followed by unrelated SCT with full intensity conditioning at the Children's Medical Centre, Japanese Red Cross Nagoya First Hospital (Table 1). These cases comprise a 7-year-old girl with RUNX1/RUNX1T1, who relapsed 13 months from the initial diagnosis (Case 1) and an 11-year-old girl with MLL/MLLT3, who relapsed 18 months from the initial diagnosis (Case 2). Because they were refractory to two courses of re-induction therapy, they received GO in combination with fludarabine, cytarabine, granulocyte colony-stimulating factor (G-CSF), and idarubicin (FLAG-IDA) as cytoreductive therapy prior to preconditioning for SCT; the protocol was 15 mg/m2 of fludarabine and 1 g/m2 of cytarabine (days 1–4), 6 mg/m2 of idarubicin (days 2–4), and 400 μg/m2 of G-CSF (days 1–4). Gemtuzumab ozogamicin was administered at a dose of 3 mg/m2 on day 5 of the treatment. To prevent veno-occlusive disease (VOD), danaparoid-based prophylaxis consisting of 60 iu/kg per day of danaparoid sodium, ursodeoxycholic acid, ethyl icosapentate, and tocopherol nicotinate was initiated from the first day of the regimen. Written informed consent was obtained from the parents of each patient. Both patients achieved complete remission after the GO infusion (Case 1 on day 27 and Case 2 on day 17) and they promptly received unrelated bone marrow or cord blood transplantation with preconditioning, which consisted of 180 mg/m2 of melphalan and 12 Gy of total body irradiation. The interval between GO and SCT was 40 d for Case 1 and 27 d for Case 2. In these patients, engraftment with full donor chimerism was obtained and no major transplant-related complications, including VOD, were seen. Despite their high-risk status, both girls are alive and in remission (Case 1 at 28 months and Case 2 at 29 months) following SCT.

Table 1. Summary of patient and treatment characteristics
 Case 1Case 2
  1. GO, Gemtuzumab ozogamicin; FAB, French-British-American classification; SCT, stem cell transplantation; UR, unrelated; CB, cord blood; BM, bone marrow; HLA, human leucocyte antigen; L-PAM, melphalan; TBI, total body irradiation; sMTX, short-term methotrexate; FK506, tacrolimus; ANC, absolute neutrophil count; PLT, platelet count; Ret, reticulocytes; GVHD, graft-versus-host disease; VOD, veno-occlusive disease; HHV6, human herpes virus 6; CR complete remission.

Characteristics before GO therapy
Age/sex7 years/female11 years/female
Diagnosis (FAB type)M2M4
Cytogenetics46,XX,t(8;21)(q22;q22)46,XX,t(9;11)(p22;q23), del(11)(q?)
Genetic abnormalitiesRUNX1/RUNX1T1MLL/MLLT3
Disease status2nd relapse1st relapse
CD33 expression (%)86·799·7
SCT characteristics
Interval between GO and SCT4027
DonorUR-BMUR-CB
Infused nucleated cells (/kg)4·04 × 1082·30 × 107
Infused CD34(+) cells (/kg)4·67 × 1062·49 × 105
HLA match (DNA typing)8/8 match7/8 match (DR mismatch)
ConditioningL-PAM + TBIL-PAM + TBI
GVHD prophylaxissMTX + FK506sMTX + FK506
Outcome
Engraftment
ANC > 0·5 × 109/lDay 15Day 21
PLT > 20 × 109/lDay 26Day 49
Ret > 10 ‰Day 26Day 29
Regimen-related toxicity
Bilirubin elevationGrade 1Grade 1
Transaminase elevationGrade 2Grade 2
VODNoneNone
InfectionSepsism (E. faecium)HHV6 reactivation
Acute GVHD/chronic GVHDNone/NoneNone/None
Survival> 28 months (CR)> 29 months (CR)

This report describes the use of GO in cytoreductive combination therapy just prior to SCT in children with refractory AML. Gemtuzumab ozogamicin is classically known to have several side effects, including significant liver toxicity that might increase the risk of VOD after allogeneic SCT. Prior studies have shown the greatest risk of VOD in patients who received SCT within a short interval from GO exposure (<3·5 months) (Wadleigh et al, 2003; Arceci et al, 2005). In contrast to previous reports with concerns about GO-related complications, no transplant-related complications, including VOD, were seen in the current study. This might be attributed to the use of low-dose GO (3 mg/m2) and danaparoid-based VOD prophylaxis, which has been reported to prevent the development of VOD (Sakaguchi et al, 2010). On the other hand, regimens of GO combined with reduced intensity conditioning have been proposed to reduce the risk of VOD after allogeneic SCT in adult studies (Bornhauser et al, 2008; de Lima et al, 2008). These studies indicated that GO may be safely combined with reduced intensity conditioning. However, the overall clinical outcomes were poor in these studies and relapse of leukaemia was the major reason for treatment failure, suggesting that these approaches cannot overcome resistance to therapy. Discouraging results of cytoreductive therapy with GO as a mono-agent prior to SCT were also reported for 12 paediatric patients with refractory AML; none of these children survived long-term (Sibson et al, 2009). In contrast, both of our patients are alive and in remission more than 2 years following SCT in spite of their high-risk status, suggesting that GO in combination chemotherapy with full intensity conditioning is required to overcome the resistance against chemotherapy in high-risk cases. Given these findings, at least in children, we believe that this could be a novel approach to improve clinical outcomes of patients with refractory AML. In conclusion, low-dose GO in a combination regimen with FLAG-IDA followed by unrelated SCT with full intensity conditioning could be a safe and effective salvage therapy for children with refractory AML, if adequate VOD prophylaxis is applied. Further research is necessary to establish the optimal use of GO in children with refractory AML.

Author contributions

N.Y. and K.K. designed and performed the research and wrote the paper; N.Y., H.S., K.M., and K.K. collected and managed clinical data.

Disclosure of conflicts of interest

The authors declare no conflicts of interest.

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