Publications by authors named "Bayard L Powell"

136 Publications

Molecular associations, clinical, and prognostic implications of PTPN11 mutations in acute myeloid leukemia (Alliance).

Blood Adv 2021 Nov 30. Epub 2021 Nov 30.

The Ohio State University, United States.

Prognostic factors associated with chemotherapy outcomes in patients with acute myeloid leukemia (AML) are extensively reported, and one gene whose mutation is recognized as conferring resistance to several newer targeted therapies is protein tyrosine phosphatase non-receptor type 11 (PTPN11). The broader clinical implications of PTPN11 mutations in AML are still not well understood. The objective of this study was to determine which cytogenetic abnormalities and gene mutations co-occur with PTPN11 mutations and how PTPN11 mutations impact outcomes of patients treated with intensive chemotherapy. We studied 1,725 newly diagnosed AML patients (excluding acute promyelocytic leukemia) enrolled onto the Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology trials. In 140 PTPN11-mutated patient samples, PTPN11 most commonly co-occurred with mutations in NPM1, DNMT3A, and TET2. PTPN11 mutations were relatively common in patients with an inv(3)(q21q26)/t(3;3)(q21;q26) and a normal karyotype but were very rare in patients with typical complex karyotype and core-binding factor AML. Mutations in the N-terminal SH2 domain of PTPN11 were associated with a higher early death rate than those in the phosphatase domain. PTPN11 mutations did not affect outcomes of NPM1-mutated patients, but these patients were less likely to have co-occurring kinase mutations (i.e., FLT3-ITD), suggesting activation of overlapping signaling pathways. However, in AML patients with wild-type NPM1, PTPN11 mutations were associated with adverse patient outcomes providing a rationale to study the biology and treatment approaches in this molecular group.
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http://dx.doi.org/10.1182/bloodadvances.2021006242DOI Listing
November 2021

Re-induction therapy in adult patients with acute myeloid leukemia with ≤20 % blasts: A retrospective cohort study.

Leuk Res 2021 12 21;111:106731. Epub 2021 Oct 21.

Department of Internal Medicine, Section on Hematology and Oncology, Comprehensive Cancer Center of Wake Forest Baptist Health, USA; Department of Cancer Biology, Comprehensive Cancer Center of Wake Forest Baptist Health, USA. Electronic address:

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http://dx.doi.org/10.1016/j.leukres.2021.106731DOI Listing
December 2021

Dasatinib and dexamethasone followed by hematopoietic cell transplantation for adults with Ph-positive ALL.

Blood Adv 2021 11;5(22):4691-4700

University of Chicago Comprehensive Cancer Center, Chicago, IL.

Post-remission strategies after dasatinib-corticosteroid induction in adult Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) are not well studied. We evaluated dasatinib and dexamethasone induction then protocol-defined post-remission therapies, including hematopoietic cell transplantation (HCT). Adults (N = 65) with Ph-positive ALL received dasatinib-dexamethasone induction, methotrexate-based central nervous system (CNS) prophylaxis, reduced-intensity conditioning (RIC) allogeneic HCT, autologous HCT, or chemotherapy alone, and dasatinib-based maintenance. Key end points were disease-free survival (DFS) and overall survival (OS). The median age was 60 years (range, 22-87 years). The complete remission rate was 98.5%. With a median follow-up of 59 months, 5-year DFS and OS were 37% (median, 30 months) and 48% (median, 56 months), respectively. For patients receiving RIC allogeneic HCT, autologous HCT, or chemotherapy, 5-year DFS were 49%, 29%, and 34%, and 5-year OS were 62%, 57%, and 46%, respectively. Complete molecular response rate after CNS prophylaxis was 40%. Relative to the p190 isoform, p210 had shorter DFS (median 10 vs 34 months, P = .002) and OS (median 16 months vs not reached, P = .05). Relapse occurred in 25% of allogeneic HCT, 57% of autologous HCT, and 36% of chemotherapy patients. T315I mutation was detected in 6 of 8 marrow relapses. Dasatinib CNS concentrations were low. Dasatinib-dexamethasone followed by RIC allogeneic HCT, autologous HCT, or chemotherapy was feasible and efficacious, especially with RIC allogeneic HCT. Future studies should address the major causes of failure: T315I mutation, the p210 BCR-ABL1 isoform, and CNS relapse. This study was registered at www.clinicaltrials.gov as #NCT01256398.
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http://dx.doi.org/10.1182/bloodadvances.2021004813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8759134PMC
November 2021

Clinical and molecular relevance of genetic variants in the non-coding transcriptome of patients with cytogenetically normal acute myeloid leukemia.

Haematologica 2021 Jul 15. Epub 2021 Jul 15.

The Ohio State University, Comprehensive Cancer Center, Columbus.

Expression levels of long non-coding RNAs (lncRNAs) have been shown to associate with clinical outcome of patients with cytogenetically normal acute myeloid leukemia (CN-AML). However, the frequency and clinical significance of genetic variants in the nucleotide sequences of lncRNAs in AML patients is unknown. Herein, we analyzed total RNA sequencing data of 377 younger adults (aged.
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http://dx.doi.org/10.3324/haematol.2021.266643DOI Listing
July 2021

Precision oncology in AML: validation of the prognostic value of the knowledge bank approach and suggestions for improvement.

J Hematol Oncol 2021 07 6;14(1):107. Epub 2021 Jul 6.

The Ohio State University Comprehensive Cancer Center, 460 West 12th Avenue, Columbus, OH, 43210-1228, USA.

Recently, a novel knowledge bank (KB) approach to predict outcomes of individual patients with acute myeloid leukemia (AML) was developed using unbiased machine learning. To validate its prognostic value, we analyzed 1612 adults with de novo AML treated on Cancer and Leukemia Group B front-line trials who had pretreatment clinical, cytogenetics, and mutation data on 81 leukemia/cancer-associated genes available. We used receiver operating characteristic (ROC) curves and the area under the curve (AUC) to evaluate the predictive values of the KB algorithm and other risk classifications. The KB algorithm predicted 3-year overall survival (OS) probability in the entire patient cohort (AUC = 0.799), and both younger (< 60 years) (AUC = 0.747) and older patients (AUC = 0.770). The KB algorithm predicted non-remission death (AUC = 0.860) well but was less accurate in predicting relapse death (AUC = 0.695) and death in first complete remission (AUC = 0.603). The KB algorithm's 3-year OS predictive value was higher than that of the 2017 European LeukemiaNet (ELN) classification (AUC = 0.707, p < 0.001) and 2010 ELN classification (AUC = 0.721, p < 0.001) but did not differ significantly from that of the 17-gene stemness score (AUC = 0.732, p = 0.10). Analysis of additional cytogenetic and molecular markers not included in the KB algorithm revealed that taking into account atypical complex karyotype, infrequent recurrent balanced chromosome rearrangements and mutational status of the SAMHD1, AXL and NOTCH1 genes may improve the KB algorithm. We conclude that the KB algorithm has a high predictive value that is higher than those of the 2017 and 2010 ELN classifications. Inclusion of additional genetic features might refine the KB algorithm.
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http://dx.doi.org/10.1186/s13045-021-01118-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261916PMC
July 2021

A precision medicine classification for treatment of acute myeloid leukemia in older patients.

J Hematol Oncol 2021 06 23;14(1):96. Epub 2021 Jun 23.

The Ohio State University Comprehensive Cancer Center, 320 West 10th Avenue, Starling Loving Hall B302, Columbus, OH, 43210, USA.

Background: Older patients (≥ 60 years) with acute myeloid leukemia (AML) often have multiple, sequentially acquired, somatic mutations that drive leukemogenesis and are associated with poor outcome. Beat AML is a Leukemia and Lymphoma Society-sponsored, multicenter umbrella study that algorithmically segregates AML patients based upon cytogenetic and dominant molecular abnormalities (variant allele frequencies (VAF) ≥ 0.2) into different cohorts to select for targeted therapies. During the conception of the Beat AML design, a historical dataset was needed to help in the design of the genomic algorithm for patient assignment and serve as the basis for the statistical design of individual genomic treatment substudies for the Beat AML study.

Methods: We classified 563 newly diagnosed older AML patients treated with standard intensive chemotherapy on trials conducted by Cancer and Leukemia Group B based on the same genomic algorithm and assessed clinical outcomes.

Results: Our classification identified core-binding factor and NPM1-mutated/FLT3-ITD-negative groups as having the best outcomes, with 30-day early death (ED) rates of 0 and 20%, respectively, and median overall survival (OS) of > 1 year and 3-year OS rates of ≥ 20%. All other genomic groups had ED rates of 17-42%, median OS ≤ 1 year and 3-year OS rates of ≤ 15%.

Conclusions: By classifying patients through this genomic algorithm, outcomes were poor and not unexpected from a non-algorithmic, non-dominant VAF approach. The exception is 30-day ED rate typically is not available for intensive induction for individual genomic groups and therefore difficult to compare outcomes with targeted therapeutics. This Alliance data supported the use of this algorithm for patient assignment at the initiation of the Beat AML study. This outcome data was also used for statistical design for Beat AML substudies for individual genomic groups to determine goals for improvement from intensive induction and hopefully lead to more rapid approval of new therapies. Trial registration ClinicalTrials.gov Identifiers: NCT00048958 (CALGB 8461), NCT00900224 (CALGB 20202), NCT00003190 (CALGB 9720), NCT00085124 (CALGB 10201), NCT00742625 (CALGB 10502), NCT01420926 (CALGB 11002), NCT00039377 (CALGB 10801), and NCT01253070 (CALGB 11001).
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http://dx.doi.org/10.1186/s13045-021-01110-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220739PMC
June 2021

Gene expression signature predicts relapse in adult patients with cytogenetically normal acute myeloid leukemia.

Blood Adv 2021 03;5(5):1474-1482

The Ohio State University Comprehensive Cancer Center, Columbus OH.

Although ∼80% of adult patients with cytogenetically normal acute myeloid leukemia (CN-AML) achieve a complete remission (CR), more than half of them relapse. Better identification of patients who are likely to relapse can help to inform clinical decisions. We performed RNA sequencing on pretreatment samples from 268 adults with de novo CN-AML who were younger than 60 years of age and achieved a CR after induction treatment with standard "7+3" chemotherapy. After filtering for genes whose expressions were associated with gene mutations known to impact outcome (ie, CEBPA, NPM1, and FLT3-internal tandem duplication [FLT3-ITD]), we identified a 10-gene signature that was strongly predictive of patient relapse (area under the receiver operating characteristics curve [AUC], 0.81). The signature consisted of 7 coding genes (GAS6, PSD3, PLCB4, DEXI, JMY, NRP1, C10orf55) and 3 long noncoding RNAs. In multivariable analysis, the 10-gene signature was strongly associated with relapse (P < .001), after adjustment for the FLT3-ITD, CEBPA, and NPM1 mutational status. Validation of the expression signature in an independent patient set from The Cancer Genome Atlas showed the signature's strong predictive value, with AUC = 0.78. Implementation of the 10-gene signature into clinical prognostic stratification could be useful for identifying patients who are likely to relapse.
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http://dx.doi.org/10.1182/bloodadvances.2020003727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948288PMC
March 2021

A Pilot Phase II Study of the Feasibility and Efficacy of Vincristine Sulfate Liposome Injection in Patients With Relapsed or Refractory Acute Myeloid Leukemia.

J Hematol 2021 Feb 6;10(1):1-7. Epub 2021 Feb 6.

Department of Internal Medicine, Section on Hematology and Oncology, Comprehensive Cancer Center of Wake Forest Baptist Health, Winston-Salem, NC 27157, USA.

Background: Resistance to therapy and a poor outcome characterize relapsed or refractory acute myeloid leukemia (AML). There is a clear need for additional palliative approaches with acceptable toxicities. Vincristine sulfate liposome injection (VSLI) confers enhanced pharmacokinetics and activity when compared to the parent compound. It is effective and well tolerated in heavily pretreated acute lymphoblastic leukemia (ALL) patients. Preclinically VSLI has activity in vincristine-resistant cancers. As relapsed or refractory AML patients would have minimal exposure to vincristine it was hypothesized that VSLI would be well tolerated and may have activity.

Methods: A pilot phase II clinical trial was conducted. Five patients with relapsed or refractory disease were treated using the Food and Drug Administration (FDA)-approved dose and schedule.

Results: Of the five patients treated none completed more than one cycle; there were no responses and two patients did not complete one cycle of therapy. Surprisingly, three of the five patients had treatment-related constipation, and two had neuropathy consistent with the known toxicities of VSLI. Given the toxicity and lack of response, the trial was terminated early.

Conclusions: VSLI had no activity against relapsed or refractory AML in this limited, single institution dataset.
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http://dx.doi.org/10.14740/jh771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891907PMC
February 2021

Efficacy of 10-day decitabine in acute myeloid leukemia.

Leuk Res 2021 04 12;103:106524. Epub 2021 Feb 12.

Comprehensive Cancer Center of Wake Forest Baptist Health, Winston-Salem, NC 27157, USA. Electronic address:

The azanucleotide decitabine is used in the treatment of acute myeloid leukemia (AML). Studies have shown conflicting results with 10-day regimens used in previously untreated AML patients. Additionally, there is little data on 10-day decitabine regimens in the relapsed setting. This study investigated outcomes of 108 adult patients with AML in the upfront and relapsed setting treated with a 10-day decitabine regimen. In the upfront group, the overall response rate (ORR, CR + CRi) was 36.1% and the median overall survival (OS) was 6.6 months, while the relapsed/refractory group had an ORR of 25% with an OS of 4.8 months. When analyzed with respect to cytogenetics, the upfront group featured an ORR of 28.1% with an OS of 9.4 months in the intermediate cytogenetic cohort compared to a 40.5% ORR and an OS of 5.4 months in the unfavorable cytogenetic cohort. An analysis of the relapsed/refractory group demonstrated an ORR of 26.3% with an OS of 7.9 months for intermediate cytogenetics versus 25.0% with an OS of 1.8 months in the unfavorable cohort. While these response rates are similar to previously published data, the median OS appears shorter.
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http://dx.doi.org/10.1016/j.leukres.2021.106524DOI Listing
April 2021

Poor Survival and Differential Impact of Genetic Features of Black Patients with Acute Myeloid Leukemia.

Cancer Discov 2021 03 4;11(3):626-637. Epub 2020 Dec 4.

The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.

Clinical outcome of patients with acute myeloid leukemia (AML) is associated with cytogenetic and molecular factors and patient demographics (e.g., age and race). We compared survival of 25,523 non-Hispanic Black and White adults with AML using Surveillance Epidemiology and End Results (SEER) Program data and performed mutational profiling of 1,339 patients with AML treated on frontline Alliance for Clinical Trials in Oncology (Alliance) protocols. Black patients had shorter survival than White patients, both in SEER and in the setting of Alliance clinical trials. The disparity was especially pronounced in Black patients <60 years, after adjustment for socioeconomic (SEER) and molecular (Alliance) factors. Black race was an independent prognosticator of poor survival. Gene mutation profiles showed fewer and more mutations in younger Black patients. Overall survival of younger Black patients was adversely affected by mutations and -ITD, but, in contrast to White patients, was not improved by mutations. SIGNIFICANCE: We show that young Black patients have not benefited as much as White patients from recent progress in AML treatment in the United States. Our data suggest that both socioeconomic factors and differences in disease biology contribute to the survival disparity and need to be urgently addressed...
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http://dx.doi.org/10.1158/2159-8290.CD-20-1579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933110PMC
March 2021

SMARCA4 mutations in KRAS-mutant lung adenocarcinoma: a multi-cohort analysis.

Mol Oncol 2021 02 17;15(2):462-472. Epub 2020 Dec 17.

Center for Cancer Genomics and Precision Oncology, Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC, USA.

KRAS is a key oncogenic driver in lung adenocarcinoma (LUAD). Chromatin-remodeling gene SMARCA4 is comutated with KRAS in LUAD; however, the impact of SMARCA4 mutations on clinical outcome has not been adequately established. This study sought to shed light on the clinical significance of SMARCA4 mutations in LUAD. The association of SMARCA4 mutations with survival outcomes was interrogated in four independent cohorts totaling 564 patients: KRAS-mutant patients with LUAD who received nonimmunotherapy treatment from (a) The Cancer Genome Atlas (TCGA) and (b) the MSK-IMPACT Clinical Sequencing (MSK-CT) cohorts; and KRAS-mutant patients with LUAD who received immune checkpoint inhibitor-based immunotherapy treatment from (c) the MSK-IMPACT (MSK-IO) and (d) the Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) immunotherapy cohorts. Of the patients receiving nonimmunotherapy treatment, in the TCGA cohort (n = 155), KRAS-mutant patients harboring SMARCA4 mutations (KS) showed poorer clinical outcome [P = 6e-04 for disease-free survival (DFS) and 0.031 for overall survival (OS), respectively], compared to KRAS-TP53 comutant (KP) and KRAS-only mutant (K) patients; in the MSK-CT cohort (n = 314), KS patients also exhibited shorter OS than KP (P = 0.03) or K (P = 0.022) patients. Of patients receiving immunotherapy, KS patients consistently exhibited the shortest progression-free survival (PFS; P = 0.0091) in the MSK-IO (n = 77), and the shortest PFS (P = 0.0026) and OS (P = 0.0014) in the WFBCCC (n = 18) cohorts, respectively. Therefore, mutations of SMARCA4 represent a genetic factor leading to adverse clinical outcome in lung adenocarcinoma treated by either nonimmunotherapy or immunotherapy.
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http://dx.doi.org/10.1002/1878-0261.12831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858279PMC
February 2021

Mutational landscape and clinical outcome of patients with de novo acute myeloid leukemia and rearrangements involving 11q23/.

Proc Natl Acad Sci U S A 2020 10 5;117(42):26340-26346. Epub 2020 Oct 5.

The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210.

Balanced rearrangements involving the gene, located at 11q23, are among the most frequent chromosome aberrations in acute myeloid leukemia (AML). Because of numerous fusion partners, the mutational landscape and prognostic impact of specific 11q23/ rearrangements are not fully understood. We analyzed clinical features of 172 adults with AML and recurrent 11q23/ rearrangements, 141 of whom had outcome data available. We compared outcomes of these patients with outcomes of 1,097 patients without an 11q23/ rearrangement categorized according to the 2017 European LeukemiaNet (ELN) classification. Using targeted next-generation sequencing, we investigated the mutational status of 81 leukemia/cancer-associated genes in 96 patients with 11q23/ rearrangements with material for molecular studies available. Patients with 11q23/ rearrangements had a low number of additional gene mutations (median, 1; range 0 to 6), which involved the RAS pathway (, , and ) in 32% of patients. mutations occurred more often in patients with t(6;11)(q27;q23)/- compared with patients with the other 11q23/ subsets. Specific gene mutations were too infrequent in patients with specific 11q23/ rearrangements to assess their associations with outcomes. We demonstrate that younger (age <60 y) patients with t(9;11)(p22;q23)/- had better outcomes than patients with other 11q23/ rearrangements and those without 11q23/ rearrangements classified in the 2017 ELN intermediate-risk group. Conversely, outcomes of older patients (age ≥60 y) with t(9;11)(p22;q23) were poor and comparable to those of the ELN adverse-risk group patients. Our study shows that patients with an 11q23/ rearrangement have distinct mutational patterns and outcomes depending on the fusion partner.
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http://dx.doi.org/10.1073/pnas.2014732117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584992PMC
October 2020

Fusion Transcripts Detectable 8 Months prior to Promyelocytic Blast Crisis in Chronic Myeloid Leukemia.

Case Rep Hematol 2020 1;2020:8830595. Epub 2020 Sep 1.

Wake Forest Baptist Medical Center, Department of Pathology, Winston-Salem, NC, USA.

Promyelocytic blast crisis arising from chronic myeloid leukemia (CML) is rare. We present a 40-year-old male who developed promyelocytic blast crisis 17 months after CML diagnosis, confirmed by the presence of the (15;17) and (9;22) translocations in the leukemic cells. Preserved nucleic acids from routine testing provided a unique opportunity to evaluate clonal progression over time. Retrospective analysis demonstrated fusion transcripts were first detectable 8 months prior to blast crisis presentation. A review of 21 cases of promyelocytic blasts crisis published in the literature reveals a male predominance with earlier age at onset as compared to females. Interestingly, TKI therapy during chronic phase did not impact the time interval between diagnosis and promyelocytic blast crisis. Treatment with standard acute promyelocytic leukemia regimens provides more favorable outcomes with complete molecular remission. Although rare, it is important to consider a promyelocytic blast crisis when evaluating for transformation of CML due to its effective treatment with specific therapies.
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http://dx.doi.org/10.1155/2020/8830595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481999PMC
September 2020

Multicenter Study of Risk-Adapted Therapy With Dose-Adjusted EPOCH-R in Adults With Untreated Burkitt Lymphoma.

J Clin Oncol 2020 08 26;38(22):2519-2529. Epub 2020 May 26.

Lymphoid Malignancies Branch, National Cancer Institute, Bethesda, MD.

Purpose: Burkitt lymphoma is an aggressive B-cell lymphoma curable with dose-intensive chemotherapy derived from pediatric leukemia regimens. Treatment is acutely toxic with late sequelae. We hypothesized that dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and rituximab (DA-EPOCH-R) may obviate the need for highly dose-intensive chemotherapy in adults with Burkitt lymphoma.

Methods: We conducted a multicenter risk-adapted study of DA-EPOCH-R in untreated adult Burkitt lymphoma. Low-risk patients received three cycles without CNS prophylaxis, and high-risk patients received six cycles with intrathecal CNS prophylaxis or extended intrathecal treatment if leptomeninges were involved. The primary endpoint was event-free survival (EFS), and secondary endpoints were toxicity and predictors of EFS and overall survival (OS).

Results: Between 2010 and 2017, 113 patients were enrolled across 22 centers, and 98 (87%) were high risk. The median age was 49 (range, 18-86) years, and 62% were ≥ 40 years. Bone marrow and/or CSF was involved in 29 (26%) of patients, and 28 (25%) were HIV positive. At a median follow-up of 58.7 months, EFS and OS were 84.5% and 87.0%, respectively, and EFS was 100% and 82.1% in low- and high-risk patients. Therapy was equally effective across age groups, HIV status, and International Prognostic Index risk groups. Involvement of the CSF identified the group at greatest risk for early toxicity-related death or treatment failure. Five treatment-related deaths (4%) occurred during therapy. Febrile neutropenia occurred in 16% of cycles, and tumor lysis syndrome was rare.

Conclusion: Risk-adapted DA-EPOCH-R therapy is effective in adult Burkitt lymphoma regardless of age or HIV status and was well tolerated. Improved therapeutic strategies for adults with CSF involvement are needed (funded by the National Cancer Institute; ClinicalTrials.gov identifier: NCT01092182).
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http://dx.doi.org/10.1200/JCO.20.00303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392744PMC
August 2020

The prognostic value of standardized phase angle in adults with acute leukemia: A prospective study.

Cancer Med 2020 04 12;9(7):2403-2413. Epub 2020 Feb 12.

Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC, USA.

Standardized phase angle (SPhA) is a tool used to estimate body composition and cell membrane integrity. Standardized phase angle has been shown to predict survival in solid malignancies and hematopoietic stem cell transplant patients. We investigated the predictive value of SPhA on 60-day mortality, overall survival (OS), and length of hospital stay (LHS) for adults with acute myelogenous and lymphoblastic leukemia (AML and ALL). Consecutive patients ≥18 years with newly diagnosed acute leukemia receiving intensive chemotherapy were enrolled. Phase angle measurements were taken on day 1 of therapy for all patients and on the day of nadir marrow for AML patients. Measurements were standardized by BMI, gender, and age to calculate the SPhA. The difference between SPhA at nadir bone marrow compared to day 1 of induction was used to calculate change in SPhA. A cutoff of 25th percentile was used to dichotomize baseline SPhA. Among 100 patients, 88% were AML, 56% were female, and mean age was 59 years. Though not statistically significant, OS by Kaplan-Meier analysis was shorter for those below the 25th percentile SPhA compared to those above (median OS: 11.0 months vs 19.5 months; P = .09). Lower baseline SPhA was associated with increased incidence of 60-day mortality in univariable (odds ratio [OR] = 5.25; 1.35, 20.44; P = .02) but not multivariable analysis (OR = 3.12; 0.67, 14.48; P = .15) adjusted for age, creatinine, and cytogenetics. Increased change in SPhA was associated with worse OS (hazard ratio = 1.15; 1.00,1.33; P = .05) in multivariable analysis. Standardized phase angle is a rapid, noninvasive, and objective measure that may be used to inform risk stratification.
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http://dx.doi.org/10.1002/cam4.2835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7131844PMC
April 2020

Rapid Donor Identification Improves Survival in High-Risk First-Remission Patients With Acute Myeloid Leukemia.

JCO Oncol Pract 2020 06 27;16(6):e464-e475. Epub 2020 Jan 27.

Fred Hutchinson Cancer Research Center, Seattle, WA.

Purpose: Patients with acute myeloid leukemia with high-risk cytogenetics in first complete remission (CR1) achieve better outcomes if they undergo allogeneic hematopoietic cell transplantation (HCT) compared with consolidation chemotherapy alone. However, only approximately 40% of such patients typically proceed to HCT.

Methods: We used a prospective organized approach to rapidly identify donors to improve the allogeneic HCT rate in adults with high-risk acute myeloid leukemia in CR1. Newly diagnosed patients had cytogenetics obtained at enrollment, and those with high-risk cytogenetics underwent expedited HLA typing and were encouraged to be referred for consultation with a transplantation team with the goal of conducting an allogeneic HCT in CR1.

Results: Of 738 eligible patients (median age, 49 years; range, 18-60 years of age), 159 (22%) had high-risk cytogenetics and 107 of these patients (67%) achieved CR1. Seventy (65%) of the high-risk patients underwent transplantation in CR1 ( < .001 compared with the historical rate of 40%). Median time to HCT from CR1 was 77 days (range, 20-356 days). In landmark analysis, overall survival (OS) among patients who underwent transplantation was significantly better compared with that of patients who did not undergo transplantation (2-year OS, 48% 35%, respectively [ = .031]). Median relapse-free survival after transplantation in the high-risk cohort who underwent transplantation in CR1 (n = 70) was 11.5 months (range, 4-47 months), and median OS after transplantation was 14 months (range, 4-44 months).

Conclusion: Early cytogenetic testing with an organized effort to identify a suitable allogeneic HCT donor led to a CR1 transplantation rate of 65% in the high-risk group, which, in turn, led to an improvement in OS when compared with the OS of patients who did not undergo transplantation.
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http://dx.doi.org/10.1200/JOP.19.00133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291544PMC
June 2020

Clinical and functional significance of circular RNAs in cytogenetically normal AML.

Blood Adv 2020 01;4(2):239-251

The Ohio State University Comprehensive Cancer Center, Columbus, OH.

Circular RNAs (circRNAs) are noncoding RNA molecules that display a perturbed arrangement of exons, called backsplicing. To examine the prognostic and biologic significance of circRNA expression in cytogenetically normal acute myeloid leukemia (CN-AML), we conducted whole-transcriptome profiling in 365 younger adults (age 18-60 years) with CN-AML. We applied a novel pipeline, called Massive Scan for circRNA, to identify and quantify circRNA expression. We validated the high sensitivity and specificity of our pipeline by performing RNase R treatment and RNA sequencing in samples of AML patients and cell lines. Unsupervised clustering analyses identified 3 distinct circRNA expression-based clusters with different frequencies of clinical and molecular features. After dividing our cohort into training and validation data sets, we identified 4 circRNAs (circCFLAR, circKLHL8, circSMC1A, and circFCHO2) that were prognostic in both data sets; high expression of each prognostic circRNA was associated with longer disease-free, overall, and event-free survival. In multivariable analyses, high circKLHL8 and high circFCHO2 expression were independently associated with better clinical outcome of CN-AML patients, after adjusting for other covariates. To examine the biologic relevance of circRNA expression, we performed knockdown screening experiments in a subset of prognostic and gene mutation-related candidate circRNAs. We identified circFBXW7, but not its linear messenger RNA, as a regulator of the proliferative capacity of AML blasts. In summary, our findings underscore the molecular associations, prognostic significance, and functional relevance of circRNA expression in CN-AML.
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http://dx.doi.org/10.1182/bloodadvances.2019000568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988408PMC
January 2020

Geriatric assessment among older adults receiving intensive therapy for acute myeloid leukemia: Report of CALGB 361006 (Alliance).

J Geriatr Oncol 2020 01 24;11(1):107-113. Epub 2019 Oct 24.

Washington University School of Medicine, St. Louis, MO, United States of America.

Objective: To demonstrate feasibility of performing geriatric assessment (GA) in the National Clinical Trials Network (NCTN) and to explore the utility of GA to characterize treatment tolerance.

Materials And Methods: We conducted a multisite companion study (CALGB 361006) to CALGB 11001, a phase 2 trial of adults ≥60 years old with newly diagnosed FLT3- mutated AML, testing the efficacy of adding sorafenib to intensive chemotherapy. On 361006, a GA was administered prior to induction and prior to post-remission therapy. The GA is divided into items requiring administration by a health care professional (HCP) and patient self-administered questionnaires. Feasibility outcomes were recruitment rate, time to GA completion, difficulty with GA administration, percent of patients requiring assistance, and satisfaction. Change in GA measures pre- and post-induction were compared using Wilcoxon signed rank test and McNemar's tests.

Results: The recruitment rate was 80% (N = 43, median age 68 years). Median completion time of the GA was 30 min; (10 and 21 min for HCP and patients, respectively). HCP reported no difficulty completing assessments (100%). Most patients completed questionnaires without assistance (77%), and were satisfied with the length (89%). Self-reported physical function, mental health, social activity and nutritional parameters worsened after induction.

Conclusion: GA is feasible to administer in the setting of intensive induction for older adults with AML in the NCTN and provides evidence of the impact of induction therapy on physical and emotional health.
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http://dx.doi.org/10.1016/j.jgo.2019.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943189PMC
January 2020

Devimistat in combination with high dose cytarabine and mitoxantrone compared with high dose cytarabine and mitoxantrone in older patients with relapsed/refractory acute myeloid leukemia: ARMADA 2000 Phase III study.

Future Oncol 2019 Oct 12;15(28):3197-3208. Epub 2019 Sep 12.

Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA.

Devimistat (CPI-613) is an intravenously administered, novel lipoate analog that inhibits two key tricarboxcylic acid (TCA) cycle enzymes, pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase complexes (KGDH). These complexes control TCA cycle entry of glucose and glutamine-derived carbons, respectively. Acute myeloid leukemia (AML) cells upregulate the TCA cycle in response to DNA damaging agents and treatment with devimistat increases sensitivity to them. A Phase I study of devimistat in combination with cytarabine and mitoxantrone produced a complete remission rate of 50% in patients with relapsed or refractory AML. In the combined Phase I/II experience, older patients with R/R AML treated with 2000 mg/m of devimistat had a 52% complete remission/complete remission with incomplete hematologic recovery rate and a median survival of 12.4 months. This report outlines the rationale and design of the ARMADA 2000 study, a Phase III clinical trial of devimistat in combination with high dose cytarabine and mitoxantrone compared with high dose cytarabine and mitoxantrone alone for older patients (≥60 years of age) with relapsed or refractory AML. Clinical trial registration: NCT#03504410.
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http://dx.doi.org/10.2217/fon-2019-0201DOI Listing
October 2019

Clinical and molecular characterization of patients with acute myeloid leukemia and sole trisomies of chromosomes 4, 8, 11, 13 or 21.

Leukemia 2020 02 28;34(2):358-368. Epub 2019 Aug 28.

Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.

Sole trisomies of chromosomes 4, 8, 11, 13 and 21 account for 89-95% of all sole trisomies in adult AML patients. We analyzed clinical and molecular characteristics of 138 de novo AML patients with sole +4, +8, +11, +13 or +21, and compared them with AML patients with those trisomies occurring in addition to other chromosome abnormalities (non-sole trisomy) and with cytogenetically normal AML (CN-AML) patients. Mutations in methylation-related genes were most commonly observed within each sole trisomy group (+4, 55%; +8, 58%; +11, 71%; +13, 71%; +21, 75% of patients). Patients with sole trisomies, excluding +4, also had frequent mutations in spliceosome genes (+8, 43%; +11, 65%; +13, 65%; +21, 45% of patients). In contrast, +4 patients frequently had mutations in transcription factor genes (44%) and NPM1 (36%). While 48% of patients with sole trisomies harbored mutations in a spliceosome gene, spliceosome mutations were observed in only 24% of non-sole trisomy (n = 131, P < 0.001) and 19% of CN-AML patients (n = 716, P < 0.001). Our data suggest that mutations affecting methylation-related genes are a molecular hallmark of sole trisomies. Mutations in spliceosome genes were also commonly observed in many sole trisomy patients and represent a novel finding in this cytogenetic subgroup.
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http://dx.doi.org/10.1038/s41375-019-0560-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995758PMC
February 2020

Mutations associated with a 17-gene leukemia stem cell score and the score's prognostic relevance in the context of the European LeukemiaNet classification of acute myeloid leukemia.

Haematologica 2020 03 14;105(3):721-729. Epub 2019 Aug 14.

The Ohio State University Comprehensive Cancer Center, Columbus, OH

Leukemia stem cells (LSC) are more resistant to standard chemotherapy and their persistence during remission can cause relapse, which is still one of the major clinical challenges in the treatment of acute myeloid leukemia (AML). A better understanding of the mutational patterns and the prognostic impact of molecular markers associated with stemness could lead to better clinical management and improve patients' outcomes. We applied a previously described 17-gene expression score comprising genes differently expressed between LSC and leukemic bulk blasts, for 934 adult patients with AML, and studied associations of the 17-gene LSC score with clinical data and mutation status of 81 genes recurrently mutated in cancer and leukemia. We found that patients with a high 17-gene score were older and had more mutations. The 17-gene score was found to have a prognostic impact in both younger (aged <60 years) and older (aged ≥60 years) patients with AML. We also analyzed the 17-gene LSC score in the context of the 2017 European LeukemiaNet genetic-risk classification and found that for younger patients the score refined the classification, and identified patients currently classified in the European LeukemiaNet Favorable-risk category who had a worse outcome.
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http://dx.doi.org/10.3324/haematol.2019.225003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049376PMC
March 2020

Genetic Characterization and Prognostic Relevance of Acquired Uniparental Disomies in Cytogenetically Normal Acute Myeloid Leukemia.

Clin Cancer Res 2019 11 2;25(21):6524-6531. Epub 2019 Aug 2.

The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.

Purpose: Uniparental disomy (UPD) is a way cancer cells duplicate a mutated gene, causing loss of heterozygosity (LOH). Patients with cytogenetically normal acute myeloid leukemia (CN-AML) do not have microscopically detectable chromosome abnormalities, but can harbor UPDs. We examined the prognostic significance of UPDs and frequency of LOH in patients with CN-AML. We examined the frequency and prognostic significance of UPDs in a set of 425 adult patients with CN-AML who were previously sequenced for 81 genes typically mutated in cancer. Associations of UPDs with outcome were analyzed in the 315 patients with CN-AML younger than 60 years.

Results: We detected 127 UPDs in 109 patients. Most UPDs were large and typically encompassed all or most of the affected chromosome arm. The most common UPDs occurred on chromosome arms 13q (7.5% of patients), 6p (2.8%), and 11p (2.8%). Many UPDs significantly cooccurred with mutations in genes they encompassed, including 13q UPD with -internal tandem duplication (-ITD; < 0.001), and 11p UPD with mutations ( = 0.02). Among patients younger than 60 years, UPD of 11p was associated with longer overall survival (OS) and 13q UPD with shorter disease-free survival (DFS) and OS. In multivariable models that accounted for known prognostic markers, including -ITD and mutations, UPD of 13q maintained association with shorter DFS, and UPD of 11p maintained association with longer OS.

Conclusions: LOH mediated by UPD is a recurrent feature of CN-AML. Detection of UPDs of 13q and 11p might be useful for genetic risk stratification of patients with CN-AML.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825549PMC
November 2019

Inflammatory biomarkers, geriatric assessment, and treatment outcomes in acute myeloid leukemia.

J Geriatr Oncol 2020 04 5;11(3):410-416. Epub 2019 Apr 5.

Section on Hematology and Oncology, Wake Forest Baptist Health, Winston-Salem, NC, United States.

Objectives: To investigate changes in inflammatory biomarkers during induction therapy for older adults with acute myeloid leukemia (AML) and their associations with geriatric assessment (GA) measures and outcomes.

Methods: This was a single institution ancillary study to a prospective observational study (N = 20 consecutive adults aged ≥60 with newly diagnosed AML who received induction chemotherapy). Biomarkers (Interleukin-6 [IL-6], IL-6 soluble receptor [IL-6 sR], tumor necrosis factor alpha [TNFα], TNFα soluble receptor 1 [TNFα sR1], interleukin-3 [IL-3], C-reactive protein [CRP]) were collected at start of induction, weekly for three weeks, and post-induction and were compared over time using paired t-tests. GA was administered at baseline and post-induction, and correlated with biomarker levels using Spearman correlations. Survival was estimated using Kaplan-Meier and compared by categorized biomarker level using Wilcoxon tests.

Results: Biomarker levels were stable during induction, except for CRP and IL-6 sR. Declines in objectively measured physical function [Short Physical Performance Battery (SPPB); r = 0.71, p < 0.01] and increases in self-reported limitation in instrumental activities of daily living (r = 0.81, p < 0.01) were correlated with increased TNFα sR1. Declines in SPPB were correlated with increased CRP (r = -0.73, p < 0.01). Improvement in depression was correlated with increased IL-6 sR (r = -0.59 p = 0.02). Survival was shorter in those with baseline TNFα or CRP levels above the median (6.1 vs. 40.2 months and 5.5 vs. 27.6 months respectively, p = 0.04 for both).

Conclusion: Among older adults with AML, the relationships between TNFα sR1, CRP, and IL-6 sR with change in physical and emotional health during treatment warrants further investigation.
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http://dx.doi.org/10.1016/j.jgo.2019.03.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778500PMC
April 2020

Complex karyotype in de novo acute myeloid leukemia: typical and atypical subtypes differ molecularly and clinically.

Leukemia 2019 07 8;33(7):1620-1634. Epub 2019 Feb 8.

The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.

Complex karyotype (CK) with ≥ 3 abnormalities is detected in 10-12% of patients with acute myeloid leukemia (AML) and associated with poor prognosis. The most common unbalanced abnormalities found in CK result in loss of material from the 5q, 7q, and/or 17p chromosome arms. The presence of 5q, 7q, and/or 17p abnormalities denotes typical CK and their absence denotes atypical CK. Since molecular features of CK-AML are not well characterized, we investigated mutational status of 81 leukemia/cancer-associated genes in 160 clinically well-characterized patients. They included 136 patients with ≥ 3 exclusively unbalanced chromosome abnormalities, 96 of whom had a typical CK and 40 atypical CK, and 24 patients with ≥ 1 balanced abnormality in addition to ≥ 2 unbalanced ones. Patients with atypical CK-AML differed from those with typical CK-AML: they carried TP53 mutations less often (P < 0.001) and more often PHF6 (P = 0.008), FLT3-TKD (P = 0.02), MED12 (P = 0.02), and NPM1 (P = 0.02) mutations. They were younger (P = 0.007), had higher WBC (P = 0.001) and percentages of marrow (P < 0.001) and blood (P = 0.006) blasts, higher complete remission rates (P = 0.02), and longer overall survival (P < 0.001), thus indicating that atypical and typical CK-AMLs constitute distinct disease subtypes. We also identified smaller patient subsets within both typical and atypical CK-AML that differed molecularly and clinically.
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http://dx.doi.org/10.1038/s41375-019-0390-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609457PMC
July 2019

Randomized trial of 10 days of decitabine ± bortezomib in untreated older patients with AML: CALGB 11002 (Alliance).

Blood Adv 2018 12;2(24):3608-3617

University of Chicago Comprehensive Cancer Center, Chicago, IL.

Novel treatment strategies are needed for older patients with acute myeloid leukemia (AML). This randomized phase 2 trial compared the efficacy and safety of 20 mg/m of IV decitabine on days 1 to 10 alone (arm A) with those of 1.3 mg/m of subcutaneous bortezomib (arm B) on days 1, 4, 8, and 11 for up to 4 10-day cycles followed by monthly 5-day cycles. Previously untreated AML patients age ≥60 years (excluding those with mutations and favorable-risk cytogenetics) without restrictions in performance status (PS) or organ function were eligible. Median age was 72.4 years (range, 60.5-92.3 years); 31 patients (19%) had baseline PS ≥2, 35 (22%) had an antecedent hematological disorder, 58 had (39%) adverse cytogenetics, and 7 (5%) and 23 (14%) had abnormal cardiac or renal function. There were no statistically significant differences in overall survival (OS) or responses between the 2 treatment arms. The overall response rate (complete remission + complete remission with incomplete blood count recovery) was 39% (n = 64), with median OS of 9.3 months. Nineteen responders (31%) underwent allogeneic stem cell transplantation. The most common adverse event was febrile neutropenia, and there were no unexpected toxicities. Adding bortezomib to decitabine did not improve outcomes, but responses were better than those in previous trials using 5-day decitabine cycles. This trial was registered at www.clinicaltrials.gov as #NCT01420926.
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http://dx.doi.org/10.1182/bloodadvances.2018023689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306886PMC
December 2018

Association between glycemic control, age, and outcomes among intensively treated patients with acute myeloid leukemia.

Support Care Cancer 2019 Aug 15;27(8):2877-2884. Epub 2018 Dec 15.

Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC, 27157, USA.

Purpose: To investigate the impact of hyperglycemia and glycemic variability during intensive acute myeloid leukemia therapy (AML) on outcomes by age.

Methods: Retrospective study of 262 consecutive patients with newly diagnosed AML hospitalized for intensive induction. Hyperglycemia was assessed by mean blood glucose (BG) (mg/dL) during hospitalization and glycemic variability was determined by the standard deviation (SD) of mean BG. Outcomes were complete remission ± incomplete count recovery (CR + CRi), and overall survival (OS). We used logistic regression to evaluate CR + CRi, and Cox proportional hazard models for OS, stratified by age (< 60 vs ≥ 60 years).

Results: Older patients (N = 138, median age 70) had higher baseline comorbidity (CCI > 1 60.1% vs 25.8%) and prevalence of diabetes (20.3% vs 7.3%) compared to younger (N = 124, median age 47). The mean ± SD number of BG values obtained per patient during hospitalization was 61 ± 71. The mean (± SD) glucose (mg/dL) during hospitalization was 121.7 (25.9) in older patients (≥ 60 years) versus 111.6 (16.4) in younger. In older patients, higher mean glucose and greater glycemic variability were associated with lower odds of remission (OR 0.80, 95% CI 0.69-0.93 and OR 0.73, 95% CI 0.61-0.88 respectively, per 10-unit increase) and higher mortality rates (HR 1.13, 95% CI 1.05-1.21 and HR 1.17, 95% CI 1.09-1.26, respectively, per 10-unit increase) in multivariate analyses.

Conclusions: Our observations that hyperglycemia and increased glycemic variability were associated with lower remission rates and increased mortality in older patients suggest glycemic control may be a potentially modifiable factor to improve AML outcomes.
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http://dx.doi.org/10.1007/s00520-018-4582-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6571065PMC
August 2019

Outcome for pediatric acute promyelocytic leukemia patients at Children's Oncology Group sites on the Leukemia Intergroup Study CALGB 9710 (Alliance).

Pediatr Blood Cancer 2019 03 4;66(3):e27542. Epub 2018 Nov 4.

Division of Hematology/Oncology, Children's Hospital and Research Center Oakland, Oakland, California.

Background: Acute promyelocytic leukemia (APL) is a unique leukemia subtype requiring specialized treatment including all-trans retinoic acid (ATRA). A prior report demonstrated worse outcome among young children <5 years old compared with older children.

Methods: We evaluated outcomes for pediatric patients (<18 years old; N = 83) with APL treated on North American intergroup study CALGB 9710 at Children's Oncology Group sites. Induction and consolidation included ATRA, cytarabine, and anthracyclines. Patients ≥15 years old were randomized to addition of arsenic trioxide (ATO) consolidation. All patients were randomized to ATRA maintenance with versus without oral chemotherapy.

Results: The estimated 5-year overall survival (OS) rate was 82%, and the event-free survival (EFS) rate was 54%. Seven patients (8.4%) died during induction due to coagulopathy. Maintenance randomization demonstrated that addition of oral chemotherapy to ATRA significantly reduced relapse rate, but difference in EFS did not reach statistical significance (P = 0.12; 5-year rates [95% CI]: 41% [17%-64%] ATRA only vs 72% [56%-88%] ATRA plus chemotherapy). There was no difference (P = 0.93) in EFS for age <5 years versus 5-12.99 years versus 13-17.99 years (5-year rates: 56%, 47%, and 45%, respectively). Among adolescents 15-17.99 years old in the ATO randomization, there was a significantly lower relapse risk at 5 years for those receiving ATO (0% ATO vs 44% no ATO; P = 0.02).

Conclusion: Our data demonstrate that intensified ATRA, cytarabine, and anthracycline chemotherapy is effective for pediatric APL including very young patients, but early deaths and relapses remain barriers to cure. Further improvements are likely with incorporation of ATO into pediatric APL regimens.
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http://dx.doi.org/10.1002/pbc.27542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6392047PMC
March 2019
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