Publications by authors named "Raul C Ribeiro"

249 Publications

Early mortality and survival improvements for adolescents and young adults with acute promyelocytic leukemia in California: an updated analysis.

Haematologica 2021 Jul 29. Epub 2021 Jul 29.

Center for Oncology Hematology Outcomes Research and Training (COHORT), Division of Hematology and Oncology, University of California Comprehensive Cancer Center, Sacramento-CA.

Not available.
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http://dx.doi.org/10.3324/haematol.2021.278851DOI Listing
July 2021

Clinical significance of novel subtypes of acute lymphoblastic leukemia in the context of minimal residual disease-directed therapy.

Blood Cancer Discov 2021 Jul;2(4):326-337

Department of Oncology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

We evaluate clinical significance of recently identified subtypes of acute lymphoblastic leukemia (ALL) in 598 children treated with minimal residual disease (MRD)-directed therapy. Among the 16 B-ALL and 8 T-ALL subtypes identified by next generation sequencing, , high-hyperdiploid and -rearranged B-ALL had the best five-year event-free survival rates (95% to 98.4%); , PAX5alt, T-cell, ETP, iAMP21, and hypodiploid ALL intermediate rates (80.0% to 88.2%); and , -like and -like and -rearranged ALL the worst rates (64.1% to 76.2%). All but three of the 142 patients with day-8 blood MRD <0.01% remained in remission. Among new subtypes, intensified therapy based on day-15 MRD≥1% improved outcome of -rearranged, -like, and -rearranged ALL, and achievement of day-42 MRD<0.01% did not preclude relapse of PAX5alt, -rearranged and -like ALL. Thus, new subtypes including -rearranged, PAX5alt, -like, -like, -rearranged and -rearranged ALL have important prognostic and therapeutic implications.
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http://dx.doi.org/10.1158/2643-3230.bcd-20-0229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265990PMC
July 2021

Comprehensive analysis of dose intensity of acute lymphoblastic leukemia chemotherapy.

Haematologica 2021 Jul 1. Epub 2021 Jul 1.

Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN.

Chemotherapy dosages are often compromised, but most reports lack data on dosages that are actually delivered. In two consecutive acute lymphoblastic leukemia (ALL) trials that differed in their asparaginase formulation, native E. coli L-asparaginase in St. Jude Total 15 (T15, n=365) and pegaspargase in Total 16 (T16, n=524), we tallied the dose intensities (DIs) for all medications on the low-risk (LR) or standard-risk (SR) arms, analyzing 504,039 dosing records. The median DI for each drug ranged from 61-100%; DIs for several drugs were over 10% higher on T15 than on T16: cyclophosphamide (p < 0.0001 for SR), cytarabine (p < 0.0001 for SR), and mercaptopurine (p < 0.0001 for LR and < 0.0001 for SR). We attributed the lower dosages on T16 to the higher asparaginase dosages on T16 than T15 (p.
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http://dx.doi.org/10.3324/haematol.2021.278411DOI Listing
July 2021

Treatment of Pediatric Adrenocortical Carcinoma With Surgery, Retroperitoneal Lymph Node Dissection, and Chemotherapy: The Children's Oncology Group ARAR0332 Protocol.

J Clin Oncol 2021 Aug 6;39(22):2463-2473. Epub 2021 Apr 6.

Department of Oncology, St Jude Children's Research Hospital, Memphis, TN.

Purpose: Adrenocortical carcinoma (ACC) is a rare aggressive pediatric malignancy with distinct biology. Its treatment follows the principles developed for adults; pediatric-specific studies are scarce.

Patients And Methods: Prospective single-arm risk-stratified interventional study. Study objectives were (1) to describe the outcome of patients with stage I ACC treated with adrenalectomy alone; (2) to describe the outcome of stage II patients (completely resected > 200 cc or > 100 g) treated with adrenalectomy and retroperitoneal lymph node dissection; and (3) to describe the outcome of patients with stage III or IV treated with mitotane and chemotherapy.

Results: Between September 2006 and May 2013, 78 patients (77 eligible, 51 females) were enrolled. The 5-year event-free survival estimates for stages I (24 patients), II (15 patients), III (24 patients), and IV (14 patients) were 86.2%, 53.3%, 81%, and 7.1%, respectively. The corresponding 5-year overall survival estimates were 95.2%, 78.8%, 94.7%, and 15.6%, respectively. On univariate analysis, age, stage, presence of virilization, Cushing syndrome, or hypertension, germline status, and presence of a somatic mutation were associated with outcome. On multivariable analysis, only stage and age were significantly associated with outcome. The probabilities of mitotane and chemotherapy feasibility events were 10.5% and 31.6%, respectively.

Conclusion: Outcome for children with stage I ACC is excellent with surgery. Outcome for patients with stage II disease is inferior despite retroperitoneal lymph node dissection. Patients with stage III ACC have an excellent outcome combining surgery and chemotherapy. Patients with stage IV ACC are older and have a poor outcome; new treatments should be explored for this high-risk group. The combination of mitotane and chemotherapy as prescribed in ARAR0332 resulted in significant toxicity; one third of patients with advanced disease could not complete the scheduled treatment.
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http://dx.doi.org/10.1200/JCO.20.02871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8462560PMC
August 2021

Minimally myelosuppressive regimen for remission induction in pediatric AML: long-term results of an observational study.

Blood Adv 2021 04;5(7):1837-1847

Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, China.

Treatment refusal and death as a result of toxicity account for most treatment failures among children with acute myeloid leukemia (AML) in resource-constrained settings. We recently reported the results of treating children with AML with a combination of low-dose cytarabine and mitoxantrone or omacetaxine mepesuccinate with concurrent granulocyte colony-stimulating factor (G-CSF) (low-dose chemotherapy [LDC]) for remission induction followed by standard postremission strategies. We have now expanded the initial cohort and have provided long-term follow-up. Eighty-three patients with AML were treated with the LDC regimen. During the study period, another 100 children with AML received a standard-dose chemotherapy (SDC) regimen. Complete remission was attained in 88.8% and 86.4% of patients after induction in the LDC and SDC groups, respectively (P = .436). Twenty-two patients in the LDC group received SDC for the second induction course. Significantly more high-risk AML patients were treated with the SDC regimen (P = .035). There were no significant differences between the LDC and SDC groups in 5-year event-free survival (61.4% ± 8.7% vs 65.2% ± 7.4%, respectively; P = .462), overall survival (72.7% ± 6.9% vs 72.5% ± 6.2%, respectively; P = .933), and incidence of relapse (20.5% ± 4.5% vs 17.6% ± 3.9%, respectively; P = .484). Clearance of mutations based on the average variant allele frequency at complete remission in the LDC and SDC groups was 1.9% vs 0.6% (P < .001) after induction I and 0.17% vs 0.078% (P = .052) after induction II. In conclusion, our study corroborated the high remission rate reported for children with AML who received at least 1 course of LDC. The results, although preliminary, also suggest that long-term survival of these children is comparable to that of children who receive SDC regimens.
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http://dx.doi.org/10.1182/bloodadvances.2020003453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045515PMC
April 2021

Management of ETV6-ABL1-positive childhood acute lymphoblastic leukaemia: report of two cases, a literature review and a call for action.

Br J Haematol 2021 04 3;193(1):197-200. Epub 2021 Mar 3.

Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, People's Republic of China.

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http://dx.doi.org/10.1111/bjh.17271DOI Listing
April 2021

The Common Germline Mutation Is Hypomorphic and Confers Incomplete Penetrance and Late Tumor Onset in a Mouse Model.

Cancer Res 2021 05 26;81(9):2442-2456. Epub 2021 Feb 26.

Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.

The TP53-R337H founder mutation exists at a high frequency throughout southern Brazil and represents one of the most common germline TP53 mutations reported to date. It was identified in pediatric adrenocortical tumors in families with a low incidence of cancer. The R337H mutation has since been found in association with early-onset breast cancers and Li-Fraumeni syndrome (LFS). To study this variability in tumor susceptibility, we generated a knockin mutant p53 mouse model (R334H). Endogenous murine p53-R334H protein was naturally expressed at high levels in multiple tissues and was functionally compromised in a tissue- and stress-specific manner. Mutant p53-R334H mice developed tumors with long latency and incomplete penetrance, consistent with many human carriers being at a low but elevated risk for cancer. These findings suggest the involvement of additional cooperating genetic alterations when TP53-R337H occurs in the context of LFS, which has important implications for genetic counseling and long-term clinical follow-up. SIGNIFICANCE: A p53-R334H knockin mouse serves as an important model for studying the most common inherited germline TP53 mutation (R337H) that is associated with variable tumor susceptibility.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137600PMC
May 2021

Phase 1 study of bendamustine in combination with clofarabine, etoposide, and dexamethasone in pediatric patients with relapsed or refractory hematologic malignancies.

Cancer 2021 Jun 17;127(12):2074-2082. Epub 2021 Feb 17.

Children's Hospital Los Angeles, Los Angeles, California.

Background: A phase 1 study was conducted to determine the maximum tolerated dose of bendamustine when given in combination with clofarabine, etoposide, and dexamethasone daily for 5 days in children and adolescents with relapsed or refractory hematologic malignancies.

Methods: Patients younger than 22 years with second or greater relapsed or refractory acute leukemia or lymphoma after 2 or more prior regimens were eligible. With the rolling 6 design, participants received escalating doses of bendamustine (30, 40, or 60 mg/m /d) in combination with clofarabine (40 mg/m ), etoposide (100 mg/m ), and dexamethasone (8 mg/m ) daily for 5 days. Optional pharmacokinetic studies were performed in cycle 1 on day 1 and day 5.

Results: Sixteen patients were enrolled. Six patients were treated at the dose level of 30 mg/m /d, 6 were treated at the dose level of 40 mg/m /d, and 4 were treated at the dose level of 60 mg/m /d. The dose-limiting toxicity was prolonged myelosuppression. The combination was otherwise well tolerated. The recommended dose of bendamustine in this combination was 30 mg/m /d for 5 days. Ten responses were observed after 1 cycle: 6 complete remissions, 1 durable minimal residual disease-negative complete remission without platelet recovery in a patient with early T-cell precursor leukemia, and 3 partial remissions. Six patients proceeded to transplantation. The event-free survival rate was 40.6% (95% confidence interval [CI], 17.5%-63.7%) at 1 year and 33.9% (95% CI, 11.9%-55.9%) at 3 years.

Conclusions: Bendamustine is well tolerated in combination with clofarabine, etoposide, and dexamethasone. The combination administered over 5 days is effective for multiple relapsed and refractory hematologic malignancies. This trial is registered with ClinicalTrials.gov (NCT01900509).

Lay Summary: Improvements to the existing chemotherapy regimen are still needed for patients who relapse after targeted therapies and immunotherapies and for those who are not eligible for or have no access to such therapies. A regimen combining cyclophosphamide, clofarabine, and etoposide has been used in relapsed and refractory pediatric patients with hematologic malignancies. This study shows that substituting bendamustine for cyclophosphamide in combination with clofarabine and etoposide is safe and effective.
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http://dx.doi.org/10.1002/cncr.33465DOI Listing
June 2021

Reduced-intensity therapy for pediatric lymphoblastic leukemia: impact of residual disease early in remission induction.

Blood 2021 01;137(1):20-28

Division of Leukemia and Lymphoma, Department of Oncology, and.

Legacy data show that ∼40% of children with acute lymphoblastic leukemia (ALL) were cured with limited antimetabolite-based chemotherapy regimens. However, identifying patients with very-low-risk (VLR) ALL remains imprecise. Patients selected based on a combination of presenting features and a minimal residual disease (MRD) level <0.01% on day 19 of induction therapy had excellent outcomes with low-intensity treatment. We investigated the impact of MRD levels between 0.001% and <0.01% early in remission induction on the outcome of VLR ALL treated with a low-intensity regimen. Between October of 2011 and September of 2015, 200 consecutive patients with B-precursor ALL with favorable clinicopathologic features and MRD levels <0.01%, as assessed by flow cytometry in the bone marrow on day 19 and at the end of induction therapy, received reduced-intensity therapy. The 5-year event-free survival was 89.5% (± 2.2% standard error [SE]), and the overall survival was 95.5% (± 1.5% SE). The 5-year cumulative incidence of relapse (CIR) was 7% (95% confidence interval, 4-11%). MRD levels were between 0.001% and <0.01% on day 19 in 29 patients. These patients had a 5-year CIR that was significantly higher than that of patients with undetectable residual leukemia (17.2% ± 7.2% vs 5.3% ± 1.7%, respectively; P = .02). Our study shows that children with VLR ALL can be treated successfully with decreased-intensity therapy, and it suggests that the classification criteria for VLR can be further refined by using a more sensitive MRD assay.
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http://dx.doi.org/10.1182/blood.2020007977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215189PMC
January 2021

Second Primary Malignancy after Acute Promyelocytic Leukemia: A Population-Based Study.

Cancers (Basel) 2020 Dec 3;12(12). Epub 2020 Dec 3.

Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba, Paraná 80250-060, Brazil.

Acute promyelocytic leukemia (APL), is now highly curable with treatment approaches that include all-trans retinoic acid (ATRA). The high incidence of APL in the Hispanics suggests an association with genetic variants in this population. Information on second primary malignancies (SPMs) in patients with APL is limited. The Surveillance, Epidemiology, and End Results (SEER) database was used to interrogate whether the rate of SPMs in patients with APL was associated with ethnicity and/or ATRA treatment. Between 2000 and 2016, 116 cases of SPM were diagnosed among 4019 patients with APL. The mean age at diagnosis of primary APL was 53.9 years (±15.7 years), and the mean age at diagnosis of SPMs was 59.0 years (±14.5 years). Comparisons with 3774 APL survivors who did not develop SPMs revealed that age ≥40 years at diagnosis of APL ( < 0.001) and non-Hispanic white ethnicity ( = 0.025) were associated with SPMs in APL survivors. Salivary gland, liver, and soft tissue malignancies were significantly more common in patients with primary APL than in individuals with non-APL malignancies. A risk analysis comparing patients who had APL with patients who had non-APL AML suggests that SPMs after APL is associated with ATRA treatment. Therefore, patient follow-up after APL should focus on early diagnosis of SPMs.
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http://dx.doi.org/10.3390/cancers12123610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761603PMC
December 2020

Pulmonary Manifestations of Hematologic and Oncologic Diseases in Children.

Pediatr Clin North Am 2021 02;68(1):61-80

Leukemia/Lymphoma Division, International Outreach Program, Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.

Pulmonary complications are common in children with hematologic or oncologic diseases, and many experience long-term effects even after the primary disease has been cured. This article reviews pulmonary complications in children with cancer, after hematopoietic stem cell transplant, and caused by sickle cell disease and discusses their management.
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http://dx.doi.org/10.1016/j.pcl.2020.09.003DOI Listing
February 2021

Reduced SLIT2 is Associated with Increased Cell Proliferation and Arsenic Trioxide Resistance in Acute Promyelocytic Leukemia.

Cancers (Basel) 2020 Oct 27;12(11). Epub 2020 Oct 27.

Department of Experimental Hematology, Cancer Research Centre Groningen, University Medical Centre Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.

The SLIT-ROBO axis plays an important role in normal stem-cell biology, with possible repercussions on cancer stem cell emergence. Although the Promyelocytic Leukemia (PML) protein can regulate expression in the central nervous system, little is known about SLIT2 in acute promyelocytic leukemia. Hence, we aimed to investigate the levels of SLIT2 in acute promyelocytic leukemia (APL) and assess its biological activity in vitro and in vivo. Our analysis indicated that blasts with transcript levels were associated with cell cycle arrest, while APL blasts displayed a more stem-cell like phenotype. In a retrospective analysis using a cohort of patients treated with all-trans retinoic acid (ATRA) and anthracyclines, high expression was correlated with reduced leukocyte count ( = 0.024), and independently associated with improved overall survival (hazard ratio: 0.94; 95% confidence interval: 0.92-0.97; < 0.001). Functionally, -knockdown in primary APL blasts and cell lines led to increased cell proliferation and resistance to arsenic trioxide induced apoptosis. Finally, in vivo transplant of Slit2-silenced primary APL blasts promoted increased leukocyte count ( = 0.001) and decreased overall survival ( = 0.002) compared with the control. In summary, our data highlight the tumor suppressive function of SLIT2 in APL and its deteriorating effects on disease progression when downregulated.
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http://dx.doi.org/10.3390/cancers12113134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693375PMC
October 2020

DNA Methylation Profiling Reveals Prognostically Significant Groups in Pediatric Adrenocortical Tumors: A Report From the International Pediatric Adrenocortical Tumor Registry.

JCO Precis Oncol 2019 18;3. Epub 2019 Nov 18.

St Jude Children's Research Hospital, Memphis, TN.

Purpose: Pediatric adrenocortical carcinomas (ACCs) are aggressive; the overall survival of patients with ACCs is 40%-50%. Appropriate staging and histologic classification are crucial because children with incomplete resections, metastases, or relapsed disease have a dismal prognosis. The clinical course of pediatric adrenocortical tumors (ACTs) is difficult to predict using the current classification schemas, which rely on subjective microscopic and gross macroscopic variables. Recent advances in adult ACT studies have revealed distinct DNA methylation patterns with prognostic significance that have not been systematically interrogated in the pediatric population.

Patients And Methods: We performed DNA methylation analyses on 48 newly diagnosed ACTs from the International Pediatric Adrenocortical Tumor Registry and 12 pediatric adrenal controls to evaluate for distinct methylation groups. Pediatric methylation data were also compared systematically with the adult ACC cohort from The Cancer Genome Atlas (TCGA).

Results: Two pediatric ACT methylation groups were identified and showed differences in selected clinicopathologic and outcome characteristics. The A1 group was enriched for variants and unfavorable outcome. The A2 group was enriched for germline variants, younger age at onset, and favorable outcome. Pediatric ACT methylation groups were maintained when International Pediatric Adrenocortical Tumor Registry cohort data were combined with TCGA cohort data. The CpG-island hypermethylator phenotype characterizing the TCGA cohort was not identified in the pediatric patients. When methylome findings were combined with independent histopathologic review using the Wieneke criteria, a high-risk population was identified with uniform fatal outcome.

Conclusion: Our results indicate DNA methylation analysis can enhance current diagnostic algorithms. A combination of methylation and histologic classification produced the strongest prediction model and may prove useful in future risk-adapted therapeutic trials.
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http://dx.doi.org/10.1200/PO.19.00163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446418PMC
November 2019

Safety, pharmacokinetics, and pharmacodynamics of panobinostat in children, adolescents, and young adults with relapsed acute myeloid leukemia.

Cancer 2020 11 18;126(21):4800-4805. Epub 2020 Aug 18.

St. Jude Children's Research Hospital, Memphis, Tennessee.

Background: Novel therapies are urgently needed for pediatric patients with relapsed acute myeloid leukemia (AML).

Methods: To determine whether the histone deacetylase inhibitor panobinostat could be safely given in combination with intensive chemotherapy, a phase 1 trial was performed in which 17 pediatric patients with relapsed or refractory AML received panobinostat (10, 15, or 20 mg/m ) before and in combination with fludarabine and cytarabine.

Results: All dose levels were tolerated, with no dose-limiting toxicities observed at any dose level. Pharmacokinetic studies demonstrated that exposure to panobinostat was proportional to the dose given, with no associations between pharmacokinetic parameters and age, weight, or body surface area. Among the 9 patients who had sufficient (>2%) circulating blasts on which histone acetylation studies could be performed, 7 demonstrated at least 1.5-fold increases in acetylation. Although no patients had a decrease in circulating blasts after single-agent panobinostat, 8 of the 17 patients (47%), including 5 of the 6 patients treated at dose level 3, achieved complete remission. Among the 8 complete responders, 6 (75%) attained negative minimal residual disease status.

Conclusions: Panobinostat can be safely administered with chemotherapy and results in increased blast histone acetylation. This suggests that it should be further studied in AML.
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http://dx.doi.org/10.1002/cncr.33156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722063PMC
November 2020

A Rare Mutation Predominant in Ashkenazi Jews Confers Risk of Multiple Cancers.

Cancer Res 2020 09 16;80(17):3732-3744. Epub 2020 Jul 16.

Cohen Children's Medical Center of New York, New Hyde Park, New York.

Germline mutations in cause a rare high penetrance cancer syndrome, Li-Fraumeni syndrome (LFS). Here, we identified a rare tetramerization domain missense mutation, c.1000G>C;p.G334R, in a family with multiple late-onset LFS-spectrum cancers. Twenty additional c.1000G>C probands and one c.1000G>A proband were identified, and available tumors showed biallelic somatic inactivation of . The majority of families were of Ashkenazi Jewish descent, and the c.1000G>C allele was found on a commonly inherited chromosome 17p13.1 haplotype. Transient transfection of the p.G334R allele conferred a mild defect in colony suppression assays. Lymphoblastoid cell lines from the index family in comparison with normal lines showed that although classical p53 target gene activation was maintained, a subset of p53 target genes (including , and ) showed defective transactivation when treated with Nutlin-3a. Structural analysis demonstrated thermal instability of the G334R-mutant tetramer, and the G334R-mutant protein showed increased preponderance of mutant conformation. Clinical case review in comparison with classic LFS cohorts demonstrated similar rates of pediatric adrenocortical tumors and other LFS component cancers, but the latter at significantly later ages of onset. Our data show that c.1000G>C;p.G334R is found predominantly in Ashkenazi Jewish individuals, causes a mild defect in p53 function, and leads to low penetrance LFS. SIGNIFICANCE: c.1000C>G;p.G334R is a pathogenic, Ashkenazi Jewish-predominant mutation associated with a familial multiple cancer syndrome in which carriers should undergo screening and preventive measures to reduce cancer risk.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484045PMC
September 2020

XAF1 as a modifier of p53 function and cancer susceptibility.

Sci Adv 2020 Jun 24;6(26):eaba3231. Epub 2020 Jun 24.

School of Medicine, University of Sao Paulo, Sao Paulo, SP, Brazil.

Cancer risk is highly variable in carriers of the common R337H founder allele, possibly due to the influence of modifier genes. Whole-genome sequencing identified a variant in the tumor suppressor (E134*/Glu134Ter/rs146752602) in a subset of R337H carriers. Haplotype-defining variants were verified in 203 patients with cancer, 582 relatives, and 42,438 newborns. The compound mutant haplotype was enriched in patients with cancer, conferring risk for sarcoma ( = 0.003) and subsequent malignancies ( = 0.006). Functional analyses demonstrated that wild-type XAF1 enhances transactivation of wild-type and hypomorphic variants, whereas -E134* is markedly attenuated in this activity. We propose that cosegregation of E134* and R337H mutations leads to a more aggressive cancer phenotype than R337H alone, with implications for genetic counseling and clinical management of hypomorphic mutant carriers.
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http://dx.doi.org/10.1126/sciadv.aba3231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314530PMC
June 2020

NTAL is associated with treatment outcome, cell proliferation and differentiation in acute promyelocytic leukemia.

Sci Rep 2020 06 25;10(1):10315. Epub 2020 Jun 25.

Department of Hematology, Erasmus University Medical Center, Rotterdam, Netherlands.

Non-T cell activation linker (NTAL) is a lipid raft-membrane protein expressed by normal and leukemic cells and involved in cell signaling. In acute promyelocytic leukemia (APL), NTAL depletion from lipid rafts decreases cell viability through regulation of the Akt/PI3K pathway. The role of NTAL in APL cell processes, and its association with clinical outcome, has not, however, been established. Here, we show that reduced levels of NTAL were associated with increased all-trans retinoic acid (ATRA)-induced differentiation, generation of reactive oxygen species, and mitochondrial dysfunction. Additionally, NTAL-knockdown (NTAL-KD) in APL cell lines led to activation of Ras, inhibition of Akt/mTOR pathways, and increased expression of autophagy markers, leading to an increased apoptosis rate following arsenic trioxide treatment. Furthermore, NTAL-KD in NB4 cells decreased the tumor burden in (NOD scid gamma) NSG mice, suggesting its implication in tumor growth. A retrospective analysis of NTAL expression in a cohort of patients treated with ATRA and anthracyclines, revealed that NTAL overexpression was associated with a high leukocyte count (P = 0.007) and was independently associated with shorter overall survival (Hazard Ratio: 3.6; 95% Confidence Interval: 1.17-11.28; P = 0.026). Taken together, our data highlights the importance of NTAL in APL cell survival and response to treatment.
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http://dx.doi.org/10.1038/s41598-020-66223-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316767PMC
June 2020

Whole-joint magnetic resonance imaging to assess osteonecrosis in pediatric patients with acute lymphoblastic lymphoma.

Pediatr Blood Cancer 2020 08 30;67(8):e28336. Epub 2020 May 30.

Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee.

Background: Osteonecrosis is a debilitating complication in children and adolescents with acute lymphoblastic leukemia or acute lymphoblastic lymphoma (LLy). An objective screening test to identify patients at risk for symptomatic, extensive joint involvement will help manage osteonecrosis.

Methods: We performed a prospective, longitudinal pilot study with whole-joint magnetic resonance imaging (MRI) of shoulders, elbows, hips, knees, ankles, and hindfeet to evaluate the incidence and timing of osteonecrosis involving multiple joints in 15 patients with LLy aged 9-21 years at diagnosis.

Results: Osteonecrosis affecting ≥30% of the epiphysis occurred in eight of 15 patients, with a high prevalence in hips (12 of 26 examined [46%]) and knees (10 of 26 [38%]) post reinduction I and in shoulders (seven of 20 [35%]) post reinduction II. Most osteonecrotic hips and knees with ≥30% epiphyseal involvement became symptomatic and/or underwent surgery (100% and 82%, respectively). All eight patients with ≥30% epiphyseal involvement had multijoint involvement. Seven of these patients had hip or knee osteonecrosis by the end of remission induction, and only these patients developed osteonecrosis that became symptomatic and/or underwent surgery in their hips, knees, shoulders, ankles, and/or feet; all of these joints were associated with epiphyseal abnormalities on post reinduction I imaging.

Conclusions: MRI screening in adolescent patients with LLy revealed osteonecrosis in multiple joints. Initial screening with hip and knee MRI at the end of induction may identify susceptible patients who could benefit from referrals to subspecialties, more extensive follow-up imaging of other joints, and early medical and surgical interventions.
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http://dx.doi.org/10.1002/pbc.28336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391358PMC
August 2020

Germline Variants in Phosphodiesterase Genes and Genetic Predisposition to Pediatric Adrenocortical Tumors.

Cancers (Basel) 2020 Feb 22;12(2). Epub 2020 Feb 22.

Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105-2794, USA.

Phosphodiesterases (PDEs) form a superfamily of enzymes that catalyze the hydrolysis of cyclic nucleotides adenosine 3'5'-cyclic monophosphate (cAMP) and guanosine 3'5'-cyclic monophosphate (cGMP) to their inactive 5' monophosphates. cAMP plays a critical role as a second messenger in endocrine tissues, and activation of cAMP signaling has been reported in endocrine tumors. Germline variants in PDEs have been associated with benign cortisol-secreting adrenocortical adenomas and testicular germ cell cancer but not adrenocortical carcinoma. We performed whole genome sequencing (WGS) and whole exome sequencing (WES) of paired blood and tumor samples from 37 pediatric adrenocortical tumors (ACTs). Germline inactivating variants in PDEs were observed in 9 of 37 (24%) patients. Tumor DNA analysis revealed loss of heterozygosity, with maintenance of the mutated allele in all cases. Our results suggest that germline variants in PDEs and other regulators of the cAMP-signaling pathway may contribute to pediatric adrenocortical tumorigenesis, perhaps by cooperating with germline hypomorphic mutant alleles and uniparental disomy of chromosome 11p15 (Beckwith-Wiedemann syndrome).
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http://dx.doi.org/10.3390/cancers12020506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072638PMC
February 2020

Chronic medical conditions and late effects following non-Hodgkin lymphoma in HIV-uninfected and HIV-infected adolescents and young adults: a population-based study.

Br J Haematol 2020 08 20;190(3):371-384. Epub 2020 Feb 20.

Center for Oncology Hematology Outcomes Research and Training (COHORT), Division of Hematology and Oncology, University of California, Davis, School of Medicine, Sacramento, CA, USA.

Little is known about the incidence of late effects following non-Hodgkin lymphoma (NHL) among adolescent and young adult (AYA, 15-39 years) survivors. Using data from the California Cancer Registry linked to hospital discharge, we estimated the cumulative incidence of late effects at 10 years among AYAs diagnosed with NHL during 1996-2012, who survived ≥2 years. Cox proportional-hazards models were used to investigate the influence of sociodemographic and clinical factors on the occurrence of late effects. Of 4392 HIV-uninfected patients, the highest incident diseases were: endocrine (18·5%), cardiovascular (11·7%), and respiratory (5·0%), followed by secondary primary malignancy (SPM, 2·6%), renal and neurologic (2·2%), liver/pancreatic (2·0%), and avascular necrosis (1·2%). Among the 425 HIV-infected survivors, incidence was higher for all late effects, especially over threefold increased risk of SPM, compared to HIV-uninfected patients (8·1% vs. 2·6%). In multivariable models for HIV-uninfected patients, public or no health insurance (vs. private), residence in lower socioeconomic neighbourhoods (vs. higher), and receipt of a haematopoietic stem cell transplant were associated with a greater risk of most late effects. Our findings of substantial incidence of late effects among NHL AYA survivors emphasise the need for longterm follow-up and appropriate survivorship care to reduce morbidity and mortality in this vulnerable population.
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http://dx.doi.org/10.1111/bjh.16539DOI Listing
August 2020

Reduced-dose intensity therapy for pediatric lymphoblastic leukemia: long-term results of the Recife RELLA05 pilot study.

Blood 2020 04;135(17):1458-1466

Department of Global Pediatric Medicine.

Treatment-related mortality is common among children with acute lymphoblastic leukemia (ALL) treated in poor-resource settings. We applied a simplified flow cytometric assay to identify patients with precursor B-cell ALL (B-ALL) at very low risk (VLR) of relapse and treated them with a reduced-intensity treatment plan (RELLA05). VLR criteria include favorable presenting features (age ≥ 1 and < 10 years), white blood cell count of <50 ×109/L, lack of extramedullary leukemia, and minimal residual disease level of <0.01% on remission induction day 19. Except for 2 doses of daunorubicin, treatment of patients with VLR B-ALL consisted of a combination of agents with relatively low myelotoxicity profiles, including corticosteroids, vincristine, L-asparaginase, methotrexate, and 6-mercaptopurine. Cyclophosphamide, systemic cytarabine, and central nervous system radiotherapy were not used. Of 454 patients with ALL treated at the Instituto de Medicina Integral Professor Fernando Figueira in Recife, Brazil, between December 2005 and June 2015, 101 were classified as having VLR B-ALL. There were no cases of death resulting from toxicity or treatment abandonment during remission induction. At a median follow-up of 6.6 years, there were 8 major adverse events: 6 relapses, 1 treatment-related death (from septicemia) during remission, and 1 secondary myeloid leukemia. The estimated 5-year event-free and overall survival rates were 92.0% ± 3.9% and 96.0% ± 2.8%, respectively. The 5-year cumulative risk of relapse was 4.24% ± 2.0%. The treatment was well tolerated. Episodes of neutropenia were of short duration. Patients with B-ALL selected by a combination of presenting features and degree of early response can be successfully treated with a mildly myelosuppressive chemotherapy regimen.
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http://dx.doi.org/10.1182/blood.2019004215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180080PMC
April 2020

SIOP PODC adapted risk stratification and treatment guidelines: Recommendations for acute myeloid leukemia in resource-limited settings.

Pediatr Blood Cancer 2019 Nov 27:e28087. Epub 2019 Nov 27.

Department of Pediatric Oncology, Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit, Amsterdam, The Netherlands.

In low- and middle-income countries (LMICs), limited resources, suboptimal risk stratification, and disproportionate patient-to-infrastructure ratio result in low survival of patients with acute myeloid leukemia (AML). A high incidence of relapse, inherent to the biology, renders management arduous. The challenge of treating AML in LMICs is of balancing the intensity of myelosuppressive chemotherapy, which appears necessary for cure, with available supportive care, which influences treatment-related mortality. The recommendations outlined in this paper are based on published evidence and expert opinion. The principle of this adapted protocol is to tailor treatment to available resources, reduce preventable toxic death, and direct limited resources toward those children who are most likely to be cured.
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http://dx.doi.org/10.1002/pbc.28087DOI Listing
November 2019

Improved CNS Control of Childhood Acute Lymphoblastic Leukemia Without Cranial Irradiation: St Jude Total Therapy Study 16.

J Clin Oncol 2019 12 28;37(35):3377-3391. Epub 2019 Oct 28.

St Jude Children's Research Hospital, Memphis, TN.

Purpose: Despite contemporary treatment, up to 10% of children with acute lymphoblastic leukemia still experience relapse. We evaluated whether a higher dosage of PEG-asparaginase and early intensification of triple intrathecal therapy would improve systemic and CNS control.

Patients And Methods: Between 2007 and 2017, 598 consecutive patients age 0 to 18 years received risk-directed chemotherapy without prophylactic cranial irradiation in the St Jude Total Therapy Study 16. Patients were randomly assigned to receive PEG-asparaginase 3,500 U/m versus the conventional 2,500 U/m. Patients presenting features that were associated with increased risk of CNS relapse received two extra doses of intrathecal therapy during the first 2 weeks of remission induction.

Results: The 5-year event-free survival and overall survival rates for the 598 patients were 88.2% (95% CI, 84.9% to 91.5%) and 94.1% (95% CI, 91.7% to 96.5%), respectively. Cumulative risk of any-isolated or combined-CNS relapse was 1.5% (95% CI, 0.5% to 2.5%). Higher doses of PEG-asparaginase did not affect treatment outcome. T-cell phenotype was the only independent risk factor for any CNS relapse (hazard ratio, 5.15; 95% CI, 1.3 to 20.6; = . 021). Among 359 patients with features that were associated with increased risk for CNS relapse, the 5-year rate of any CNS relapse was significantly lower than that among 248 patients with the same features treated in the previous Total Therapy Study 15 (1.8% [95% CI, 0.4% to 3.3%] 5.7% [95% CI, 2.8% to 8.6%]; = .008). There were no significant differences in the cumulative risk of seizure or infection during induction between patients who did or did not receive the two extra doses of intrathecal treatment.

Conclusion: Higher doses of PEG-asparaginase failed to improve outcome, but additional intrathecal therapy during early induction seemed to contribute to improved CNS control without excessive toxicity for high-risk patients.
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http://dx.doi.org/10.1200/JCO.19.01692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351342PMC
December 2019

The Impact of Gene Mutations in Acute Promyelocytic Leukemia: A Meta-Analysis.

Cancers (Basel) 2019 Sep 5;11(9). Epub 2019 Sep 5.

Instituto de Pesquisa Pelé Pequeno Príncipe, 1532 Silva Jardim, AV., Curitiba, Paraná 80250-200, Brazil.

The association of mutations with white blood cell (WBC) counts at diagnosis and early death was studied in patients with acute promyelocytic leukemia (APL). Publications indexed in databases of biomedical literature were analyzed. Potential publication bias was evaluated by analyzing the standard error in funnel plots using the estimated relative risk (RR). Mixed-effect models were used to obtain the consolidated RR. All analyses were conducted using the R statistical software package. We used 24 publications in the final meta-analysis. Of 1005 males and 1376 females included in these 24 publications, 645 had -ITD (internal tandem duplication) mutations. Information on -D835 mutations was available in 10 publications for 175 patients. Concurrent occurrence of the two mutations was rare. WBC count at diagnosis was ≥10 × 10/L in 351 patients. For patients with the -ITD mutation, RR was 0.59 for overall survival (OS) and 1.62 for death during induction. For those with -D835 mutations, the RR was 0.50 for OS and 1.77 for death during induction. RR for WBC count ≥10 × 10/L was 3.29 and 1.48 for patients with -ITD and -D835, respectively. APL patients with -ITD or -D835 are more likely to present with elevated WBC counts and poorer prognosis than those without these mutations.
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http://dx.doi.org/10.3390/cancers11091311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770268PMC
September 2019

Sorafenib Population Pharmacokinetics and Skin Toxicities in Children and Adolescents with Refractory/Relapsed Leukemia or Solid Tumor Malignancies.

Clin Cancer Res 2019 12 27;25(24):7320-7330. Epub 2019 Aug 27.

Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.

Purpose: To determine the pharmacokinetics and skin toxicity profile of sorafenib in children with refractory/relapsed malignancies.

Patients And Methods: Sorafenib was administered concurrently or sequentially with clofarabine and cytarabine to patients with leukemia or with bevacizumab and cyclophosphamide to patients with solid tumor malignancies. The population pharmacokinetics (PPK) of sorafenib and its metabolites and skin toxicities were evaluated.

Results: In PPK analysis, older age, bevacizumab and cyclophosphamide regimen, and higher creatinine were associated with decreased sorafenib apparent clearance (CL/f; < 0.0001 for all), and concurrent clofarabine and cytarabine administration was associated with decreased sorafenib N-oxide CL/f ( = 7e-4). Higher bilirubin was associated with decreased sorafenib N-oxide and glucuronide CL/f ( = 1e-4). Concurrent use of organic anion-transporting polypeptide 1B1 inhibitors was associated with increased sorafenib and decreased sorafenib glucuronide CL/f ( < 0.003). In exposure-toxicity analysis, a shorter time to development of grade 2-3 hand-foot skin reaction (HFSR) was associated with concurrent ( = 0.0015) but not with sequential ( = 0.59) clofarabine and cytarabine administration, compared with bevacizumab and cyclophosphamide, and with higher steady-state concentrations of sorafenib ( = 0.0004) and sorafenib N-oxide ( = 0.0275). In the Bayes information criterion model selection, concurrent clofarabine and cytarabine administration, higher sorafenib steady-state concentrations, larger body surface area, and previous occurrence of rash appeared in the four best two-predictor models of HFSR. Pharmacokinetic simulations showed that once-daily and every-other-day sorafenib schedules would minimize exposure to sorafenib steady-state concentrations associated with HFSR.

Conclusions: Sorafenib skin toxicities can be affected by concurrent medications and sorafenib steady-state concentrations. The described PPK model can be used to refine exposure-response relations for alternative dosing strategies to minimize skin toxicity.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911639PMC
December 2019

Uncovering the Genomic Landscape in Newly Diagnosed and Relapsed Pediatric Cytogenetically Normal FLT3-ITD AML.

Clin Transl Sci 2019 11 20;12(6):641-647. Epub 2019 Aug 20.

Division of Pharmaceutics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.

Fms-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations, common in pediatric acute myeloid leukemia (AML), associate with early relapse and poor prognosis. Past studies have suggested additional cooperative mutations are required for leukemogenesis in FLT3-ITD+ AML. Using RNA sequencing and a next-generation targeted gene panel, we broadly characterize the co-occurring genomic alterations in pediatric cytogenetically normal (CN) FLT3-ITD+ AML to gain a deeper understanding of the clonal patterns and heterogeneity at diagnosis and relapse. We show that chimeric transcripts were present in 21 of 34 (62%) of de novo samples, 2 (6%) of these samples included a rare reoccurring fusion partner BCL11B. At diagnosis, the median number of mutations other than FLT3 per patient was 1 (range 0-3), which involved 8 gene pathways; WT1 and NPM1 mutations were frequently observed (35% and 24%, respectively). Fusion transcripts and high variant allele frequency (VAF) mutants, which included WT1, NPM1, SMARCA2, RAD21, and TYK2, were retained from diagnosis to relapse. We did observe reduction in VAF of simple or single mutation clones, but VAFs were preserved or expanded in more complex clones with multiple mutations. Our data provide the first insight into the genomic complexity of pediatric CN FLT3-ITD+ AML and could help stratify future targeted treatment strategies.
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http://dx.doi.org/10.1111/cts.12669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853146PMC
November 2019

Combining gene mutation with gene expression analysis improves outcome prediction in acute promyelocytic leukemia.

Blood 2019 09 10;134(12):951-959. Epub 2019 Jul 10.

Department of Internal Medicine, Medical School of Ribeirao Preto, and.

By combining the analysis of mutations with aberrant expression of genes previously related to poorer prognosis in both acute promyelocytic leukemia (APL) and acute myeloid leukemia, we arrived at an integrative score in APL (ISAPL) and demonstrated its relationship with clinical outcomes of patients treated with all- retinoic acid (ATRA) in combination with anthracycline-based chemotherapy. Based on fms-like tyrosine kinase-3-internal tandem duplication mutational status; the ΔNp73/TAp73 expression ratio; and , , , and gene expression levels, we modeled ISAPL in 159 patients (median ISAPL score, 3; range, 0-10). ISAPL modeling identified 2 distinct groups of patients, with significant differences in early mortality ( < .001), remission ( = .004), overall survival ( < .001), cumulative incidence of relapse ( = .028), disease-free survival ( = .03), and event-free survival ( < .001). These data were internally validated by using a bootstrap resampling procedure. At least for patients treated with ATRA and anthracycline-based chemotherapy, ISAPL modeling may identify those who need to be treated differently to maximize their chances for a cure.
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http://dx.doi.org/10.1182/blood.2019000239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484742PMC
September 2019

Clofarabine Can Replace Anthracyclines and Etoposide in Remission Induction Therapy for Childhood Acute Myeloid Leukemia: The AML08 Multicenter, Randomized Phase III Trial.

J Clin Oncol 2019 08 27;37(23):2072-2081. Epub 2019 Jun 27.

1St Jude Children's Research Hospital and the University of Tennessee Health Science Center, College of Medicine, Memphis, TN.

Purpose: To identify effective and less toxic therapy for children with acute myeloid leukemia, we introduced clofarabine into the first course of remission induction to reduce exposure to daunorubicin and etoposide.

Patients And Methods: From 2008 through 2017, 285 patients were enrolled at eight centers; 262 were randomly assigned to receive clofarabine and cytarabine (Clo+AraC, n = 129) or high-dose cytarabine, daunorubicin, and etoposide (HD-ADE, n = 133) as induction I. Induction II consisted of low-dose ADE given alone or combined with sorafenib or vorinostat. Consolidation therapy comprised two or three additional courses of chemotherapy or hematopoietic cell transplantation. Genetic abnormalities and the level of minimal residual disease (MRD) at day 22 of initial remission induction determined final risk classification. The primary end point was MRD at day 22.

Results: Complete remission was induced after two courses of therapy in 263 (92.3%) of the 285 patients; induction failures included four early deaths and 15 cases of resistant leukemia. Day 22 MRD was positive in 57 of 121 randomly assigned evaluable patients (47%) who received Clo+AraC and 42 of 121 patients (35%) who received HD-ADE (odds ratio, 1.86; 95% CI, 1.03 to 3.41; = .04). Despite this result, the 3-year event-free survival rate (52.9% [44.6% to 62.8%] for Clo+AraC 52.4% [44.0% to 62.4%] for HD-ADE, = .94) and overall survival rate (74.8% [67.1% to 83.3%] for Clo+AraC 64.6% [56.2% to 74.2%] for HD-ADE, = .1) did not differ significantly across the two arms.

Conclusion: Our findings suggest that the use of clofarabine with cytarabine during remission induction might reduce the need for anthracycline and etoposide in pediatric patients with acute myeloid leukemia and may reduce rates of cardiomyopathy and treatment-related cancer.
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http://dx.doi.org/10.1200/JCO.19.00327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001777PMC
August 2019

A high-throughput screen indicates gemcitabine and JAK inhibitors may be useful for treating pediatric AML.

Nat Commun 2019 05 16;10(1):2189. Epub 2019 May 16.

Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA.

Improvement in survival has been achieved for children and adolescents with AML but is largely attributed to enhanced supportive care as opposed to the development of better treatment regimens. High risk subtypes continue to have poor outcomes with event free survival rates <40% despite the use of high intensity chemotherapy in combination with hematopoietic stem cell transplant. Here we combine high-throughput screening, intracellular accumulation assays, and in vivo efficacy studies to identify therapeutic strategies for pediatric AML. We report therapeutics not currently used to treat AML, gemcitabine and cabazitaxel, have broad anti-leukemic activity across subtypes and are more effective relative to the AML standard of care, cytarabine, both in vitro and in vivo. JAK inhibitors are selective for acute megakaryoblastic leukemia and significantly prolong survival in multiple preclinical models. Our approach provides advances in the development of treatment strategies for pediatric AML.
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http://dx.doi.org/10.1038/s41467-019-09917-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522510PMC
May 2019
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