Alan S. Gamis

Residual disease detected by multidimensional flow cytometry signifies high relapse risk in patients with de novo acute myeloid leukemia: a report from Children's Oncology Group

Early response to induction chemotherapy is a predictor of outcome in acute myeloid leukemia (AML). We determined the prevalence and significance of postinduction residual disease (RD) by multidimensional flow cytometry (MDF) in children treated on Childrens Oncology Group AML protocol AAML03P1. Postinduction marrow specimens at the end of induction (EOI) 1 or 2 or at the end of therapy from 249 patients were prospectively evaluated by MDF for RD, and presence of RD was correlated with disease characteristics and clinical outcome. Of the 188 patients in morphologic complete remission at EOI1, 46 (24%) had MDF-detectable disease. Those with and without RD at the EOI1 had a 3-year relapse risk of 60% and 29%, respectively (P < .001); the corresponding relapse-free survival was 30% and 65% (P < .001). Presence of RD at the EOI2 and end of therapy was similarly predictive of poor outcome. RD was detected in 28% of standard-risk patients in complete remission and was highly associated with poor relapse-free survival (P = .008). In a multivariate analysis, including cytogenetic and molecular risk factors, RD was an independent predictor of relapse (P < .001). MDF identifies patients at risk of relapse and poor outcome and can be incorporated into clinical trials for risk-based therapy allocation. This study was registered at www.clinicaltrials.gov as NCT00070174.

Increased Age at Diagnosis Has a Significantly Negative Effect on Outcome in Children With Down Syndrome and Acute Myeloid Leukemia: A Report From the Children’s Cancer Group Study 2891

PURPOSE To determine the outcome of children with Down syndrome (DS) and acute myeloid leukemia (AML) receiving standard timing chemotherapy without bone marrow transplantation (BMT), with determination of prognostic factors. PATIENTS AND METHODS Children with DS and newly diagnosed AML or myelodysplasia were prospectively enrolled on Childrens Cancer Group study 2891 (N = 161) and treated uniformly with four standard timing induction courses of dexamethasone, cytarabine arabinoside, 6-thioguanine, etoposide, daunorubicin (DCTER) followed by intensively timed high-dose cytarabine. RESULTS Children with DS were significantly younger at diagnosis than those without (median age, 1.8 v 7.5 years, respectively; P <.001), with more megakaryocytic leukemia (70% v 6%; P <.001). Higher complete remission rates (91%) were achieved in children with DS than among those without DS (75%; P <.001). Equivalent grade 3 to 4 toxicity (29% v 30%; P =.84) was seen, though children with DS had greater pulmonary toxicity (P <.01) during induction and mucositis during intensification (P =.12). Children with DS had significantly better 8-year event-free survival (EFS; 77% v 21% standard and 40% intensive induction; P <.0001). Multivariate analysis in children with DS revealed that only age at diagnosis of 2 years or older was a risk factor for greater relapse risk (odds ratio, 4.9; P =.006) and worse survival. Children between ages 0 to 2 years (n = 94) had a 6-year EFS of 86%; those from 2 to 4 years (n = 58), 70%; and those older than 4 years (n = 9), 28%. Remission failures were the primary reason for worse 6-year EFSs (1% in those 0 to 2 years v 14% if >2 years; P =.002). CONCLUSION Outcome for children with DS and AML is excellent with standard induction therapy, but declines with increasing age.

Gemtuzumab Ozogamicin in Children and Adolescents With De Novo Acute Myeloid Leukemia Improves Event-Free Survival by Reducing Relapse Risk: Results From the Randomized Phase III Children's Oncology Group Trial AAML0531

PURPOSE To improve survival rates in children with acute myeloid leukemia (AML), we evaluated gemtuzumab-ozogamicin (GO), a humanized immunoconjugate targeted against CD33, as an alternative to further chemotherapy dose escalation. Our primary objective was to determine whether adding GO to standard chemotherapy improved event-free survival (EFS) and overall survival (OS) in children with newly diagnosed AML. Our secondary objectives examined outcomes by risk group and method of intensification. PATIENTS AND METHODS Children, adolescents, and young adults ages 0 to 29 years with newly diagnosed AML were enrolled onto Children’s Oncology Group trial AAML0531 and then were randomly assigned to either standard five-course chemotherapy alone or to the same chemotherapy with two doses of GO (3 mg/m2/dose) administered once in induction course 1 and once in intensification course 2 (two of three). RESULTS There were 1,022 evaluable patients enrolled. GO significantly improved EFS (3 years: 53.1% v. 46.9%; hazard ratio [HzR], 0.83; 95% CI, 0.70 to 0.99; P.04) but not OS (3 years: 69.4% v. 65.4%; HzR, 0.91; 95% CI, 0.74 to 1.13; P = .39). Although remission was not improved (88% v. 85%; P = .15), posthoc analyses found relapse risk (RR) was significantly reduced among GO recipients overall (3 years: 32.8% v. 41.3%; HzR, 0.73; 95% CI, 0.58 to 0.91; P = .006). Despite an increased postremission toxic mortality (3 years: 6.6% v. 4.1%; HzR, 1.69; 95% CI, 0.93 to 3.08; P = .09), disease-free survival was better among GO recipients (3 years: 60.6% v. 54.7%; HzR, 0.82; 95% CI, 0.67 to 1.02; P = .07). CONCLUSION GO added to chemotherapy improved EFS through a reduction in RR for children and adolescents with AML.

AAML03P1, a pilot study of the safety of gemtuzumab ozogamicin in combination with chemotherapy for newly diagnosed childhood acute myeloid leukemia: a report from the Children's Oncology Group.

The development of antigen‐targeted therapies may provide additional options to improve outcomes in children with acute myeloid leukemia (AML). The Childrens Oncology Group AAML03P1 trial sought to determine the safety of adding 2 doses of gemtuzumab ozogamicin, a humanized anti‐CD33 antibody‐targeted agent, to intensive chemotherapy during remission induction and postremission intensification for children with de novo AML.

Molecular alterations of the IDH1 gene in AML: a Children's Oncology Group and Southwest Oncology Group study

Recent whole-genome sequencing efforts led to the identification of IDH1R132 mutations in acute myeloid leukemia (AML) patients. We studied the prevalence and clinical implications of IDH1 genomic alterations in pediatric and adult AML. Diagnostic DNA from 531 AML patients treated on Childrens Oncology Group trial COG-AAML03P1 (N=257), and Southwest Oncology Group trials SWOG-9031, SWOG-9333 and SWOG-9500 (N=274), were tested for IDH1 mutations. Codon R132 mutations were absent in the pediatric cohort, but were found in 12 of 274 adult patients (4.4%, 95% CI 2.3–7.5). IDH1R132 mutations occurred most commonly in patients with normal karyotype, and those with FLT3/ITD and NPMc mutations. Patients with IDH1R132 mutations trended toward higher median diagnostic white blood cell counts (59.2 × 109 vs 29.1 × 109 per liter, P=0.19) than those without mutations, but the two groups did not differ significantly in age, bone marrow blast percentage, overall survival or relapse-free survival. Eleven patients (2.1%) harbored a novel V71I sequence alteration, which was found to be a germ-line polymorphism. IDH1 mutations were not detected in pediatric AML, and are uncommon in adult AML.

Long-term follow-up care for pediatric cancer survivors

Progress in therapy has made survival into adulthood a reality for most children, adolescents, and young adults diagnosed with cancer today. Notably, this growing population remains vulnerable to a variety of long-term therapy-related sequelae. Systematic ongoing follow-up of these patients, therefore, is important for providing for early detection of and intervention for potentially serious late-onset complications. In addition, health counseling and promotion of healthy lifestyles are important aspects of long-term follow-up care to promote risk reduction for health problems that commonly present during adulthood. Both general and subspecialty pediatric health care providers are playing an increasingly important role in the ongoing care of childhood cancer survivors, beyond the routine preventive care, health supervision, and anticipatory guidance provided to all patients. This report is based on the guidelines that have been developed by the Childrens Oncology Group to facilitate comprehensive long-term follow-up of childhood cancer survivors (www.survivorshipguidelines.org).

Natural history of transient myeloproliferative disorder clinically diagnosed in Down syndrome neonates: a report from the Children's Oncology Group Study A2971

Transient myeloproliferative disorder (TMD), restricted to newborns with trisomy 21, is a megakaryocytic leukemia that although lethal in some is distinguished by its spontaneous resolution. Later development of acute myeloid leukemia (AML) occurs in some. Prospective enrollment (n = 135) elucidated the natural history in Down syndrome (DS) patients diagnosed with TMD via the use of uniform monitoring and intervention guidelines. Prevalent at diagnosis were leukocytosis, peripheral blast exceeding marrow blast percentage, and hepatomegaly. Among those with life-threatening symptoms, most (n = 29/38; 76%) received intervention therapy until symptoms abated and then were monitored similarly. Organomegaly with cardiopulmonary compromise most frequently led to intervention (43%). Death occurred in 21% but only 10% were attributable to TMD (intervention vs observation patients: 13/14 vs 1/15 because of TMD). Among those solely observed, peripheral blasts and all other TMD symptoms cleared at a median of 36 and 49 days from diagnosis, respectively. On the basis of the diagnostic clinical findings of hepatomegaly with or without life-threatening symptoms, 3 groups were identified with differing survival: low risk with neither finding (38%), intermediate risk with hepatomegaly alone (40%), and high risk with both (21%; overall survival: 92% ± 8%, 77% ± 12%, and 51% ± 19%, respectively; P ≤ .001). Among all, AML subsequently occurred in 16% at a median of 441 days (range, 118-1085 days). The trial is registered at http://www.clinicaltrials.gov as NCT00003593.

Leukemic mutations in the methylation-associated genes DNMT3A and IDH2 are rare events in pediatric AML: A report from the Children's Oncology Group†

Mutations in the DNMT3A, TET2, IDH1, and IDH2 genes carry prognostic significance and occur frequently in adult acute myeloid leukemia (AML). Leukemic mutations in all four genes have recently been implicated in aberrant DNA methylation, a hallmark of neoplasia. We previously reported that IDH1 mutations were absent, whereas TET2 mutations were present in 6%, of pediatric AML patients; in the present study, we determined the prevalence of DNMT3A and IDH2 mutations in pediatric AML.

Identification of Regulators of Polyploidization Presents Therapeutic Targets for Treatment of AMKL

The mechanism by which cells decide to skip mitosis to become polyploid is largely undefined. Here we used a high-content image-based screen to identify small-molecule probes that induce polyploidization of megakaryocytic leukemia cells and serve as perturbagens to help understand this process. Our study implicates five networks of kinases that regulate the switch to polyploidy. Moreover, we find that dimethylfasudil (diMF, H-1152P) selectively increased polyploidization, mature cell-surface marker expression, and apoptosis of malignant megakaryocytes. An integrated target identification approach employing proteomic and shRNA screening revealed that a major target of diMF is Aurora kinase A (AURKA). We further find that MLN8237 (Alisertib), a selective inhibitor of AURKA, induced polyploidization and expression of mature megakaryocyte markers in acute megakaryocytic leukemia (AMKL) blasts and displayed potent anti-AMKL activity in vivo. Our findings provide a rationale to support clinical trials of MLN8237 and other inducers of polyploidization and differentiation in AMKL.

Acute myeloid leukemia and Down syndrome evolution of modern therapy--state of the art review.

Over the past decade, a series of clinical reports have described the experience of Down syndrome (DS) children treated for acute myeloid leukemia (AML). Whereas prior to the first reports in the early 1980s it was felt that DS children with AML had poor outcomes, these clinical trials concluded that DS had a better outcome than non‐DS (NDS) children with AML. With these recent reports, it is clear that DS children have a better outcome utilizing less intensive chemotherapy regimens. They also tolerate the more intensive regimens less well than the NDS children. This review focuses upon the six multi‐institutional reports that described the DS and AML experience in order to better ascertain the chemotherapy combinations that may be useful in the future for these children. Regimens of varying intensity have all had similar outcomes. In general, the remission rates are approximately 90% with event‐free survival (EFS) approximating 70–80%. Most recently, the clinical trials have been large enough to explore prognostic factors specifically in the DS children. This has identified that the younger DS children fair significantly better than the older children. AML in DS is unique and these differences in comparison to NDS children are highlighted. The significantly better outcomes for DS children likely represents a combination of the unique AML seen in DS children and the heightened sensitivity to cytarabine that DS AML cells have. Future trials should focus on age‐stratified approaches that exploit the greater sensitivity of DS AML to cytarabine.