Challenges in Converting Acute Myeloid Leukemia (AML) Genomics Into AML Clinical Trials

In the article accompanying this editorial, Klein et al analyze results from 19 study groups assessing pediatric patients with acute myeloid leukemia (AML) during more than two decades in the largest pediatric t(8;21) AML cohort to date. Included are an analysis of the elements of intensive therapy that positively affect survival, as well as a description and characterization of the additional genomic changes in t(8;21) AML that may confer inferior survival rates. Patients with core binding factor (CBF) leukemia, including t(8;21) and inversion 16, have a better overall prognosis than that of other patients with nonCBF genomic alterations or normal cytogenetics. Nonetheless, eventfree survival and relapse rates remain poor. In the International Berlin-Frankfurt-Munster (iBFM) data set, 27% of the patients with t(8;21) AML and a good prognosis died, mostly from progressive disease and despite aggressive therapy. Since 1998, outcomes have improved largely because of both aggressive therapy and aggressive supportive care measures. It is validating to see that intensification of traditional induction chemotherapy, including high-dose cytarabine, etoposide, and high-dose anthracycline, did improve survival and lower the incidence of relapse. However, we are reaching a point of diminishing returns in that further intensification will no longer be possible and supportive care measures can no longer keep pace with the shortand long-term effects of therapy. For example, the current Children’s Oncology Group (COG) de novo AML study used a cumulative dose of anthracycline 444 mg/m for patients with t(8;21) disease. Such high cumulative doses of anthracycline increase the lifelong risk of life-altering cardiotoxicity and increase the risk of premature death in survivors. Further dose escalation will be difficult. Among the treatments identified to improve survival in the iBFM t(8;21) AML data set, only dose intensification of anthracyclines is routinely used by many of the cooperative groups. High-dose cytarabine is reserved for later courses, and etoposide at doses greater than 500 mg/m is used with mixed enthusiasm. Given this retrospective data set, one could argue that we should re-explore induction regimens for t(8;21) AML, but the prioritization of such studies should be weighed against the need to find effective targeted therapies that can improve survival while reducing long-term morbidity and mortality. When considering future studies for t(8;21) AML, we should not assume that target expression will equal a response to matched targeted therapy. In pediatric AML defined by t(8;21), the AML-ETO fusion protein impairs hematopoietic stem cell differentiation; however, this protein alone may not be sufficient for leukemogenesis. Cooperating mutations that impair differentiation or that dysregulate proliferation have long been hypothesized to be vital in the development of AML. Klein et al demonstrate that 68% of patients with t(8;21) AML have additional karyotype abnormalities, most commonly loss of sex chromosome, deletion of the long arm of chromosome 9, trisomy 8, trisomy 4, or abnormalities of the long arm of chromosome 7. In contrast, 24% and 15% have cKIT and Raspathway mutations, respectively. Of interest, only gain of chromosome 4 significantly affected survival. The sequence and contribution of second or subsequent mutations in the pathogenesis of t(8;21) AML are not well defined. The presence of multiple mutations makes it difficult to decipher those events necessary for the maintenance of the leukemic phenotype. Targeted therapies will have a role in t(8;21) AML only if they are matched to disease-defining genomic events. It is not clear which of the multiple genetic events in t(8;21) AML are necessary for maintenance of the malignant phenotype. It is also not clear if cKIT and Ras-pathway mutations are critical oncogenes in t(8;21) AML such that targeted inhibition will affect cell growth. Dissection of the contributions of individual and cooperative genomic events is needed to establish the biologic rationale for use of targeted therapies. To borrow an example from colorectal cancer, targeting the epidermal growth factor receptor is effective only in KRAS wild-type tumors. In the presence of KRAS mutations, targeting overexpressed epidermal growth factor receptor does not affect survival. In childhood AML, Bachas et al demonstrate that mutational shifts occur with loss and gain of Ras-pathway mutations at the time of diagnosis and relapse. It is likely that, although present, some mutations are neither necessary nor sufficient for leukemic cell survival and, therefore, will not prove to be clinically relevant targets for drug therapies. Although it is tempting to assume that the leukemic cell is exclusively dependent on the oncogenic signal initiated by identified mutant genes, especially if those mutant genes can be targeted with a known drug, we may find that multiple genomic events can maintain survival of leukemia cells. It may not be possible to apply a single targeted therapy to all patients with t(8;21) AML; however, as cooperative groups struggle to identify effective treatment strategies that combine single targeted agents with conventional chemotherapy, the study of multiple targeted therapies in combination seems to be a distant possibility. To date, the COG has used broadly targeted novel agents, such as gemtuzumab ozogamicin and bortezomib, in recent phase III trials. The COG and iBFM will face substantial challenges as we plan future JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 36 DECEMBER 2