Phase I/II Study of CPX-351 Followed by Fludarabine, Cytarabine, and Granulocyte-Colony Stimulating Factor for Children With Relapsed Acute Myeloid Leukemia: A Report From the Children's Oncology Group.

2020

JCO1903306

2020 May 13

1527-7755

<p><strong>PURPOSE: </strong>Effective regimens are needed for children with relapsed acute myeloid leukemia (AML). AAML1421 is a phase I/II study of CPX-351, a liposomal preparation of daunorubicin and cytarabine. AAML1421 sought to determine the recommended phase II dose (RP2D) of CPX-351 and the response rate after up to 2 cycles of therapy.</p>

<p><strong>PATIENTS AND METHODS: </strong>Children &gt; 1 and ≤ 21 years of age with relapsed/refractory AML were eligible for dose finding; those in first relapse were eligible for the efficacy phase. Dose-limiting toxicity (DLT) assessment occurred during cycle 1. Two cycles of therapy were offered (cycle 1: CPX-351; cycle 2: FLAG [fludarabine 30 mg/m/dose on days 1-5; cytarabine 2,000 mg/m/dose on days 1-5; and granulocyte-colony stimulating factor 5 µg/kg/dose, days 1-5 and day 15 through absolute neutrophil count &gt; 500/µL]). Response was assessed after each cycle.</p>

<p><strong>RESULTS: </strong>Thirty-eight patients enrolled: 6 in the dose-finding phase and 32 in the efficacy phase. During dose finding, 1/6 patients experienced a DLT (grade 3 decrease in ejection fraction). The RP2D was 135 units/m on days 1, 3, and 5. Toxicities of grade ≥ 3 during cycle 1 included fever/neutropenia (45%), infection (47%), and rash (40%). There was no toxic mortality. Best responses included 20 complete response (CR; 54%), 5 CR with partial recovery of platelet count (CRp; 14%), and 5 CR with incomplete blood count recovery (14%). Twenty-one of 25 with CR/CRp had no detectable residual disease (RD; 84%) by flow cytometry. Hematopoietic stem cell transplantation (HSCT) was used as consolidation in 29/30 responders (96.7%); 20/25 (80%) had no RD before HSCT.</p>

<p><strong>CONCLUSION: </strong>The RP2D of CPX-351 is 135 units/m/dose on days 1, 3, and 5. Toxicity was manageable, and protocol therapy was effective. Response rates are superior to prior published North American cooperative group clinical trials for children with AML in first relapse.</p>

10.1200/JCO.19.03306

J. Clin. Oncol.

32401633

Effect of Dexrazoxane on Left Ventricular Systolic Function and Treatment Outcomes in Patients With Acute Myeloid Leukemia: A Report From the Children's Oncology Group.

2020

JCO1902856

2020 Apr 28

1527-7755

<p><strong>PURPOSE: </strong>To determine whether dexrazoxane provides effective cardioprotection during frontline treatment of pediatric acute myeloid leukemia (AML) without increasing relapse risk or noncardiac toxicities of the chemotherapy regimens.</p>

<p><strong>PATIENTS AND METHODS: </strong>This was a multicenter study of all pediatric patients with AML without high allelic ratio FLT3/ITD treated in the Children's Oncology Group trial AAML1031 between 2011 and 2016. Median follow-up was 3.5 years. Dexrazoxane was administered at the discretion of treating physicians and documented at each course. Ejection fraction (EF) and shortening fraction (SF) were recorded after each course and at regular intervals in follow-up. Per protocol, anthracyclines were to be withheld if there was evidence of left ventricular systolic dysfunction (LVSD) defined as SF &lt; 28% or EF &lt; 55%. Occurrence of LVSD, trends in EF and SF, 5-year event-free survival (EFS) and overall survival (OS), and treatment-related mortality (TRM) were compared by dexrazoxane exposure.</p>

<p><strong>RESULTS: </strong>A total of 1,014 patients were included in the analyses; 96 were exposed to dexrazoxane at every anthracycline course, and 918 were never exposed. Distributions of sex, age, race, presenting WBC count, risk group, treatment arm, and compliance with cardiac monitoring were similar for dexrazoxane-exposed and -unexposed patients. Dexrazoxane-exposed patients had significantly smaller EF and SF declines than unexposed patients across courses and a lower risk for LVSD (26.5% 42.2%; hazard ratio, 0.55; 95% CI, 0.36 to 0.86; = .009). Dexrazoxane-exposed patients had similar 5-year EFS (49.0% 45.1%; = .534) and OS (65.0% 61.9%; = .613) to those unexposed; however, there was a suggestion of lower TRM with dexrazoxane (5.7% 12.7%; = .068).</p>

<p><strong>CONCLUSION: </strong>Dexrazoxane preserved cardiac function without compromising EFS and OS or increasing noncardiac toxicities. Dexrazoxane should be considered for cardioprotection during frontline treatment of pediatric AML.</p>

10.1200/JCO.19.02856

J. Clin. Oncol.

32343641

Bortezomib with standard chemotherapy for children with acute myeloid leukemia does not improve treatment outcomes: a report from the Children's Oncology Group.

2020

2020 Feb 06

1592-8721

<p>New therapeutic strategies are needed for pediatric acute myeloid leukemia to reduce disease recurrence and treatment-related morbidity. The Children's Oncology Group Phase III AAML1031 trial tested whether the addition of bortezomib to standard chemotherapy improves survival in pediatric patients with newly diagnosed acute myeloid leukemia. AAML1031 randomized patients younger than 30 years of age with de novo acute myeloid leukemia to standard treatment with or without bortezomib. All patients received the identical chemotherapy backbone with either four intensive chemotherapy courses or three courses followed by allogeneic hematopoietic stem cell transplantation for high-risk patients. For those randomized to the intervention arm, bortezomib 1.3 mg/m2 was given on days 1, 4 and 8 of each chemotherapy course. For those randomized to the control arm, bortezomib was not administered. In total, 1097 patients were randomized to standard chemotherapy (n=542) or standard chemotherapy with bortezomib (n=555). Remission induction rate did not differ between bortezomib and control treatment arms (89% vs 91%, p=0.531). Bortezomib failed to improve three-year event-free survival (44.8+/-4.5% vs 47.0+/-4.5%, p=0.236) or overall survival (63.6+/-4.5 vs 67.2+/-4.3, p=0.356) compared with the control arm. However, bortezomib was associated with significantly more peripheral neuropathy (p=0.006), and intensive care unit admissions (p=0.025) during the first course. The addition of bortezomib to standard chemotherapy increased toxicity but did not improve survival. These data do not support the addition of bortezomib to standard chemotherapy in children with de novo acute myeloid leukemia. (NCT01371981; https://www.cancer.gov/clinicaltrials/NCT01371981).</p>

10.3324/haematol.2019.220962

Haematologica

32029509

Comprehensive Transcriptome Profiling of Cryptic CBFA2T3-GLIS2 Fusion-positive AML Defines Novel Therapeutic Options - A COG and TARGET Pediatric AML Study.

2019

2019 Nov 12

1078-0432

<p><strong>PURPOSE: </strong>A cryptic inv(16)(p13.3q24.3) encoding the CBFA2T3-GLIS2 fusion is associated with poor outcome in infants with acute megakaryocytic leukemia. We aimed to broaden our understanding of the pathogenesis of this fusion through transcriptome profiling.</p>

<p><strong>EXPERIMENTAL DESIGN: </strong>Available RNA from children and young adults with de novo AML (N=1,049) underwent transcriptome sequencing (mRNA and miRNA). Transcriptome profiles for those with the CBFA2T3-GLIS2 fusion (N=24) and without (N=1,025) were contrasted to define fusion-specific miRNAs, genes, and pathways. Clinical annotations defined distinct fusion-associated disease characteristics and outcomes.</p>

<p><strong>RESULTS: </strong>The CBFA2T3-GLIS2 fusion was restricted to infants &lt; 3 years-old (p&lt;0.001) and presence of this fusion was highly associated with adverse outcome (p&lt;0.001) across all morphological classifications. Further, there was a striking paucity of recurrent cooperating mutations and transduction of cord blood stem cells with this fusion was sufficient for malignant transformation. CBFA2T3-GLIS2 positive cases displayed marked up-regulation of genes with cell membrane/extracellular matrix localization potential, including NCAM1 and GABRE. Additionally, miRNA profiling revealed significant over-expression of mature miR-224 and miR-452, which are intronic miRNAs transcribed from the GABRE locus. Gene-set enrichment identified dysregulated Hippo, TGFβ, and hedgehog signaling, as well as NCAM1 (CD56) Interaction pathways. Therapeutic targeting of fusion-positive leukemic cells with CD56-directed ADC caused significant cytotoxicity in leukemic blasts.</p>

<p><strong>CONCLUSIONS: </strong>The CBFA2T3-GLIS2 fusion defines a highly refractory entity limited to infants that appears to be sufficient for malignant transformation. Transcriptome profiling elucidated several highly targetable genes and pathways, including the identification of CD56, providing a highly plausible target for therapeutic intervention.</p>

10.1158/1078-0432.CCR-19-1800

Clin. Cancer Res.

31719049

Functional Properties of KIT Mutations are Associated with Differential Clinical Outcomes and Response to Targeted Therapeutics in CBF Acute Myeloid Leukemia.

2019

2019 Jun 10

1078-0432

<p><strong>PURPOSE: </strong> mutations (+) are common in core binding factor (CBF) AML and have been associated with varying prognostic significance. We sought to define the functional and clinical significance of distinct mutations in CBF pediatric AML.</p>

<p><strong>EXPERIMENTAL DESIGN: </strong>Following transfection of exon 17 (E17) and exon 8 (E8) mutations into HEK293 and Ba/F3 cells, KIT phosphorylation, cytokine independent growth, and response to tyrosine kinase inhibitors (TKI) were evaluated. Clinical outcomes of patients treated on COG AAML0531 (NCT01407757), a phase III study of gemtuzumab ozogamicin (GO), were analyzed according to mutation status (+ vs wild type (-)) and mutation location (E8 vs. E17).</p>

<p><strong>RESULTS: </strong> mutations were detected in 63/205(31%) patients; 22 (35%) involved only E8, 32(51%) only E17, 6(10%) both exons, and 3(5%) alternative exons. Functional studies demonstrated that E17, but not E8, mutations result in aberrant KIT phosphorylation and growth. TKI exposure significantly impacted growth of E17, but not E8, transfected cells. + CBF AML patients had comparable overall survival (OS) to that of - (78%, vs. 81%, p=0.905) but higher relapse rates (RR 43% vs. 21%, p=0.005). E17 + outcomes were inferior to patients [disease free survival (DFS) 51% vs. 73%, p=0.027; RR 21% vs. 46%, p=0.007)] although GO abrogated this negative prognostic impact. E8 mutations lacked significant prognostic impact and GO failed to significantly improve outcome.</p>

<p><strong>CONCLUSIONS: </strong>E17 mutations impact prognosis in CBF AML, as well as response to GO and TKIs, thus clinical trials utilizing both agents should be considered for + patients.</p>

10.1158/1078-0432.CCR-18-1897

Clin. Cancer Res.

31182436

Quality of life in pediatric acute myeloid leukemia: Report from the Children's Oncology Group.

2019

2019 Jun 12

2045-7634

<p><strong>INTRODUCTION: </strong>Objectives were used to describe guardian proxy-report and child self-report quality of life (QoL) during chemotherapy for pediatric acute myeloid leukemia (AML) patients.</p>

<p><strong>METHODS: </strong>Patients enrolled on the phase 3 AML trial AAML1031 who were 2-18&nbsp;years of age with English-speaking guardians were eligible. Instruments used were the PedsQL Generic Core Scales, Acute Cancer Module, and Multidimensional Fatigue Scale. Assessments were obtained at the beginning of Induction 1 and following completion of cycles 2-4. Potential predictors of QoL included the total number of nonhematological grade 3-4 Common Terminology Criteria for Adverse Event (CTCAE) submissions.</p>

<p><strong>RESULTS: </strong>There were 505 eligible guardians who consented to participate and 348 of their children provided at least one self-report assessment. The number of submitted CTCAE toxicities was significantly associated with worse physical health summary scores (β&nbsp;±&nbsp;standard error (SE) -3.00&nbsp;±&nbsp;0.69; P&nbsp;&lt;&nbsp;0.001) and general fatigue (β&nbsp;±&nbsp;SE -2.50&nbsp;±&nbsp;0.66; P&nbsp;&lt;&nbsp;0.001). Older age was significantly associated with more fatigue (β&nbsp;±&nbsp;SE -0.58&nbsp;±&nbsp;0.25; P&nbsp;=&nbsp;0.022). Gender, white race, Hispanic ethnicity, private insurance status, risk status, bortezomib assignment, and duration of neutropenia were not significantly associated with QoL.</p>

<p><strong>DISCUSSION: </strong>The number of CTCAE toxicities was the primary factor influencing QoL among children with AML. Reducing toxicities should improve QoL; identifying approaches to ameliorate them should be a priority.</p>

10.1002/cam4.2337

Cancer Med

31190442

ABCB1 SNP predicts outcome in patients with acute myeloid leukemia treated with Gemtuzumab ozogamicin: a report from Children's Oncology Group AAML0531 Trial.

2019

51

2019 May 21

2044-5385

<p>Gemtuzumab-ozogamicin (GO), a humanized-anti-CD33 antibody linked with the toxin-calicheamicin-γ is a reemerging and promising drug for AML. Calicheamicin a key element of GO, induces DNA-damage and cell-death once the linked CD33-antibody facilitates its uptake. Calicheamicin efflux by the drug-transporter PgP-1 have been implicated in GO response thus in this study, we evaluated impact of ABCB1-SNPs on GO response. Genomic-DNA samples from 942 patients randomized to receive standard therapy with or without addition of GO (COG-AAML0531) were genotyped for ABCB1-SNPs. Our most interesting results show that for rs1045642, patients with minor-T-allele (CT/TT) had better outcome as compared to patients with CC genotype in GO-arm (Event-free survival-EFS: p = 0.022; and risk of relapse-RR, p = 0.007). In contrast, no difference between genotypes was observed for any of the clinical endpoints within No-GO arm (all p &gt; 0.05). Consistent results were obtained when genotype groups were compared by GO and No-GO arms. The in vitro evaluation using HL60-cells further demonstrated consistent impact of rs1045642-T-allele on calicheamicin induced DNA-damage and cell-viability. Our results show the significance of ABCB1 SNPs on GO response in AML and warrants the need to investigate this in other cohorts. Once validated, ABCB1-SNPs in conjunction with CD33-SNPs can open up opportunities to personalize GO-therapy.</p>

10.1038/s41408-019-0211-y

Blood Cancer J

31113932

Occurrence of Treatment-Related Cardiotoxicity and Its Impact on Outcomes Among Children Treated in the AAML0531 Clinical Trial: A Report From the Children's Oncology Group.

2018

JCO1800313

2018 Oct 31

1527-7755

<p><strong>PURPOSE: </strong>Late cardiotoxicity after pediatric acute myeloid leukemia therapy causes substantial morbidity and mortality. The impact of early-onset cardiotoxicity on treatment outcomes is less well understood. Thus, we evaluated the risk factors for incident early cardiotoxicity and the impacts of cardiotoxicity on event-free survival (EFS) and overall survival (OS).</p>

<p><strong>METHODS: </strong>Cardiotoxicity was ascertained through adverse event monitoring over the course of follow-up among 1,022 pediatric patients with acute myeloid leukemia treated in the Children's Oncology Group trial AAML0531. It was defined as grade 2 or higher left ventricular systolic dysfunction on the basis of Common Terminology Criteria for Adverse Events (version 3) definitions.</p>

<p><strong>RESULTS: </strong>Approximately 12% of patients experienced cardiotoxicity over a 5-year follow-up, with more than 70% of incident events occurring during on-protocol therapy. Documented cardiotoxicity during on-protocol therapy was significantly associated with subsequent off-protocol toxicity. Overall, the incidence was higher among noninfants and black patients, and in the setting of a bloodstream infection. Both EFS (hazard ratio [HR], 1.6; 95% CI, 1.2 to 2.1; P = .004) and OS (HR, 1.6; 95% CI, 1.2 to 2.2, P = .005) were significantly worse in patients with documented cardiotoxicity. Impacts on EFS were equivalent whether the incident cardiotoxicity event occurred in the absence (HR, 1.6; 95% CI, 1.1 to 2.2; P = .017) or presence of infection (HR, 1.6; 95% CI, 1.0 to 2.7; P = .069) compared with patients without documented cardiotoxicity. However, the reduction in OS was more pronounced for cardiotoxicity not associated with infection (HR, 1.7; 95% CI, 1.2 to 2.5; P = .004) than for infection-associated cardiotoxicity (HR, 1.3; 95% CI, 0.7 to 2.4; P = .387).</p>

<p><strong>CONCLUSION: </strong>Early treatment-related cardiotoxicity may be associated with decreased EFS and OS. Cardioprotective strategies are urgently needed to improve relapse risk and both short- and long-term mortality outcomes.</p>

10.1200/JCO.18.00313

J. Clin. Oncol.

30379624

MicroRNA Expression-Based Model Indicates Event-Free Survival in Pediatric Acute Myeloid Leukemia.

2017

JCO2017747451

2017 Oct 25

1527-7755

<p>Purpose Children with acute myeloid leukemia (AML) whose disease is refractory to standard induction chemotherapy therapy or who experience relapse after initial response have dismal outcomes. We sought to comprehensively profile pediatric AML microRNA (miRNA) samples to identify dysregulated genes and assess the utility of miRNAs for improved outcome prediction. Patients and Methods To identify miRNA biomarkers that are associated with treatment failure, we performed a comprehensive sequence-based characterization of the pediatric AML miRNA landscape. miRNA sequencing was performed on 1,362 samples-1,303 primary, 22 refractory, and 37 relapse samples. One hundred sixty-four matched samples-127 primary and 37 relapse samples-were analyzed by using RNA sequencing. Results By using penalized lasso Cox proportional hazards regression, we identified 36 miRNAs the expression levels at diagnosis of which were highly associated with event-free survival. Combined expression of the 36 miRNAs was used to create a novel miRNA-based risk classification scheme (AMLmiR36). This new miRNA-based risk classifier identifies those patients who are at high risk (hazard ratio, 2.830; P ≤ .001) or low risk (hazard ratio, 0.323; P ≤ .001) of experiencing treatment failure, independent of conventional karyotype or mutation status. The performance of AMLmiR36 was independently assessed by using 878 patients from two different clinical trials (AAML0531 and AAML1031). Our analysis also revealed that miR-106a-363 was abundantly expressed in relapse and refractory samples, and several candidate targets of miR-106a-5p were involved in oxidative phosphorylation, a process that is suppressed in treatment-resistant leukemic cells. Conclusion To assess the utility of miRNAs for outcome prediction in patients with pediatric AML, we designed and validated a miRNA-based risk classification scheme. We also hypothesized that the abundant expression of miR-106a could increase treatment resistance via modulation of genes that are involved in oxidative phosphorylation.</p>

10.1200/JCO.2017.74.7451

J. Clin. Oncol.

29068783

Gemtuzumab ozogamicin in infants with AML: results from the Children's Oncology Group trials, AAML03P1 and AAML0531.

2017

2017 Jul 03

1528-0020

10.1182/blood-2017-01-762336

Blood

28674028