Harned and Gaynon within 3 years of diagnosis (Gaynon et al 1998; Nguyen et al 2006). Second remissions are common. Four-drug therapy with vincristine, prednisone, asparaginase, and doxorubicin induces complete remissions in 38%, 80%, and 95% of children with initial remissions 18 months, 18–36 months, and 36 months, respectively. Of patients achieving CR2, 80% remain MRD positive at 10–4 by ﬂow cytometry after CR1 36 months compared to 50% positive for CR1 36 months (Raetz et al 2006). Therapeutic options after second remission (CR2) include further chemotherapy and/or hema- topoietic stem cell transplantation (HSCT) (Eapen et al 2006; Gaynon et al 2006). However, the majority of relapse patients still succumb to leukemia. For patients enrolled on Children’s Cancer Group (CCG) 1900 series studies between 1997 and 2002, the 3-year survival after marrow, CNS, and testes relapse was 28%, 60%, and 60%, respectively (Nguyen et al 2006). Adverse prognostic factors after relapse include early ver- sus late timing, marrow versus extramedullary relapse, and T-cell versus B-precursor immunophenotype (Chessells 1998; Eckert et al 2001; Chessells et al 2003; Einsiedel et al 2005). MRD after re-induction chemotherapy, as measured by PCR or ﬂow cytometry, may be predictive of outcome in CR2 after marrow relapse (Eckert et al 2001; Coustan-Smith et al 2004). Higher levels of pre-transplant MRD may predict relapse after hematopoietic stem cell transplant (HSCT) (Knechtli et al 1998; Bader et al 2002; Goulden et al 2003). Better pre-transplant chemotherapy is needed that allows more patients to proceed to transplant with lower MRD and less deep seated infection or organ damage. Although third remissions are attained with some fre- quency, outcomes for patients with second or subsequent relapse remain poor (Chessells 1998; Chessells et al 2003). Several drug combinations have signiﬁcant CR rates in refractory ﬁrst relapse, or second or subsequent relapse (Table 1). These CR rates cluster around 40%, despite the Table 1 Complete response rates in second and subsequent relapse ALL Regimen CR rate (%) Reference POG 8866 vincristine, 30/74 (41) Kurtzberg et al1993 Prednisone, L-asparaginase POG 9160 idarubicin,cytarabine 30/82 (37) Bernstein et al 1997 High-dose cytarabine, 22/52 (42) Harris et al 1998 L-asparaginase Ifosfamide, etoposide 8/20 (40) Crooks and Sato 1995 Topotecan, vinorelbine, thiotepa, 6/17 (35) Kolb and Steinherz Dexamethasone and gemcitabine 2003 Derived from Gaynon 2005. Abbreviations: ALL, acute lymphoblastic leukemia. 328 use of a variety of drugs with different putative mechanisms of action (Gaynon 2005). An overall 8% survival rate was reported among patients who achieved third remission after a second marrow relapse (Chessells et al 2003). We have proposed that candidate drug combinations with CR rates 40% are unlikely to be useful for improving cure rates. Alternatively, novel regimens with CR rates 60% would be of compelling interest (Gaynon 2005). Although data are lacking for CR3 and subsequent remissions, mea- surement of minimal residual disease (MRD) may be useful to assess response. Acute myelogenous leukemia (AML) comprises 15%–20% of childhood leukemia, but accounts for more than 30% of deaths from leukemia. In the US, approximately 1000 children per year are diagnosed with AML, with an incidence of between 5 and 7 cases per million per year (Grovas et al 1997; Jemal et al 2004). Better supportive care and better use of conventional agents have improved outcomes in childhood AML. Current therapy for patients with newly diagnosed AML involves induction therapy with myelosuppressive cytotoxic agents, including cytarabine and an anthracycline or anthracin- edione, and post-remission intensiﬁcation with chemotherapy or HSCT. Three recent large multi-center pediatric studies yielded remission induction rates of approximately 90%. Five-year event-free survival is nearing or surpassing 50% (Aladjidi et al 2003; Creutzig et al 2005, 2006; Gibson et al 2005). Risk-group stratiﬁcation based on cytogenetic features, FLT-3 expression (Pollard et al 2006), and response to therapy is becoming increasingly important. One-third to one-half of patients with AML relapse. Most relapses are isolated to the bone marrow, and are more likely to occur in the ﬁrst year after diagnosis. No standard therapy is recognized for patients with relapsed and/or refractory AML. Regimens that contain high-dose cytarabine, often in combination with other agents such as mitoxantrone, etoposide, fludarabine, or 2-chlorodeoxyadenosine, have significant activity (Golub et al 2006). Gemtuzamab ozogamicin, a monoclonal antibody directed against the CD33 differentiation antigen and coupled to genotoxic calicheamicin, has shown activity in relapsed and refractory AML in both children and adults (Sievers et al 2001; Zwaan et al 2003; Reinhardt et al 2004; Arceci et al 2005). Gemtuzamab is currently being studied in newly diagnosed children and adults in combination with multiagent chemotherapy (Burnett et al 2006). Perhaps 50% of patients with primary induction failure will achieve CR with subsequent therapy (Wells et al 2003) and 70% of patients with CR1 achieve a second remission employing similar drugs to those used initially (Webb 1999; Therapeutics and Clinical Risk Management 2008:4(2)