scholarly journals Impact of corticosteroid pretreatment in pediatric patients with newly diagnosed B-lymphoblastic leukemia: a report from the Children’s Oncology Group

Haematologica ◽  
2019 ◽  
Vol 104 (11) ◽  
pp. e517-e520
Author(s):  
Elizabeth A. Raetz ◽  
Mignon L. Loh ◽  
Meenakshi Devidas ◽  
Kelly Maloney ◽  
Leonard A. Mattano ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Lymphoblastic Leukemia ◽  
Newly Diagnosed ◽  
Oncology Group

scholarly journals P-Glycoprotein Expression on Patients with Acute Lymphoblastic Leukemia

2017 ◽  
Vol 1 (1) ◽  
pp. 39
Author(s):  
R. Niiruri ◽  
I. Narayani ◽  
K. Ariawati ◽  
S. Herawati
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Cancer Patients ◽  
Pediatric Patients ◽  
Lymphoblastic Leukemia ◽  
Drug Efficacy ◽  
Expression Level ◽  
Newly Diagnosed ◽  
Glycoprotein P ◽  
P Glycoprotein

Abstract Objective: P-glycoprotein (P-gp) overexpression on neoplastic cells can deteriorate the therapeutic outcome on cancer patients. P-gp plays important role on drug efficacy and toxicity. This research aimed to measure P-gp expression on children with Acute Lymphoblastic Leukemia (ALL) on Sanglah Hospital, Denpasar. Method: Flowcytometry method was used to measure P-gp expression level on Bone Marrow samples from pediatric patients (0-12 years old) who were newly diagnosed with ALL in Sanglah Hospital. P-gp overexpression were based on the percentage of cell stained. Ten percent of P-gp expression were considered as the cut-off value of P-gp overexpression. Result: On this study, 11 samples were obtained with the range value of 56-97% on P-gp expression. Conclusion: All 11 patients had P-gp overexpression.

A phase II study of larotrectinib for children with newly diagnosed solid tumors and relapsed acute leukemias harboring TRK fusions: Children’s Oncology Group study ADVL1823.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS10560-TPS10560
Author(s):  
Theodore Willis Laetsch ◽  
Kathleen Ludwig ◽  
Donald A. Barkauskas ◽  
Steven G. DuBois ◽  
Joan Ronan ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Solid Tumors ◽  
Lymphoblastic Leukemia ◽  
Soft Tissue Sarcomas ◽  
Progression Free Survival ◽  
Low Grade ◽  
Newly Diagnosed ◽  
Oncology Group ◽  
Acute Leukemias ◽  
Oncology Group Study

TPS10560 Background: In children, fusions of the NTRK1/2/3 genes (TRK fusions) occur in soft tissue sarcomas, including infantile fibrosarcoma (IFS), congenital mesoblastic nephroma, high- and low-grade gliomas, secretory breast carcinoma, and papillary thyroid cancer. Rarely, TRK fusions also occur in Ph-like acute lymphoblastic leukemia and acute myeloid leukemia. Larotrectinib is a selective TRK inhibitor FDA-approved for the treatment of TRK fusion solid tumors in patients with no satisfactory alternative treatments or whose cancer has progressed following initial treatment. In children, larotrectinib demonstrated a 94% overall response rate (ORR) with a 12-month progression free survival rate of 75% (1). Methods: Patients <30 years with any newly diagnosed unresectable solid tumor or relapsed/refractory acute leukemia with TRK fusions are eligible. TRK fusions must be locally identified in a CLIA/CAP laboratory and are confirmed centrally using a targeted RNA sequencing panel. Patients with high-grade gliomas are excluded. Patients receive larotrectinib 100 mg/m2/dose BID (max of 100 mg/dose) continuously in 28-day cycles. Patients with solid tumors who achieve CR will discontinue larotrectinib at the completion of at least 12 total cycles of therapy and 6 cycles after achieving CR. Those whose tumors become surgically resectable may undergo on study resection and discontinue therapy if an R0/R1 (IFS) or R0 (other tumors) resection is obtained. All other patients will receive 26 cycles in the absence of unacceptable toxicity or progressive disease. The primary endpoint is the ORR to larotrectinib according to RECIST 1.1 in children with IFS. The study uses a Simon 2-stage minimax design, and the regimen will be considered of sufficient interest if 16 of 21 (76%) patients with IFS demonstrate response. Patients with other solid tumors and leukemias will be analyzed in separate cohorts as secondary objectives. Correlative studies include serial sampling of circulating tumor DNA and neurocognitive assessments. This is the first Children’s Oncology Group study to assign frontline therapy based on the presence of a molecular marker independent of histology, and the first clinical trial to evaluate larotrectinib for the treatment of leukemia. Enrollment began in October 2019 (NCT03834961). 1. Tilburg CMv, DuBois SG, Albert CM, et al: Larotrectinib efficacy and safety in pediatric TRK fusion cancer patients. Journal of Clinical Oncology 37:10010-10010, 2019 Clinical trial information: NCT03834961.

Outcomes of Patients with CRLF2-Overexpressing Acute Lymphoblastic Leukemia without Down Syndrome: A Report from the Children's Oncology Group

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 45-46
Author(s):  
Sarah K Tasian ◽  
Yunfeng Dai ◽  
Meenakshi Devidas ◽  
Kathryn G Roberts ◽  
Richard C Harvey ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Down Syndrome ◽  
Acute Lymphoblastic Leukemia ◽  
Board Of Directors ◽  
Clinical Outcomes ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Newly Diagnosed ◽  
Oncology Group ◽  
Advisory Committees

Background: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) occurs in 5-30% of children and adolescents/young adults (AYAs) with B-ALL, is driven by genetic alterations that induce constitutive cytokine receptor and kinase signaling, and is associated with poor clinical outcomes across the older pediatric-to-adult age spectrum (Tasian Blood 2017c, Reshmi Blood 2017, Roberts Blood 2018). Rearrangement and/or overexpression of cytokine receptor-like factor 2 (CRLF2+) occurs in 50% of Ph-like ALL cases with frequently co-occurring JAK2 or JAK1 point mutations or IL7R indel mutations. This study reports the clinical outcomes of children and AYAs with newly-diagnosed National Cancer Institute (NCI) standard-risk (SR) or high-risk (HR) CRLF2+ ALL without Down syndrome treated on four successive Children's Oncology Group (COG) phase 3 clinical trials from 2003 to 2018. Methods: We retrospectively assessed demographic characteristics, laboratory data, and clinical outcomes of 3757 patients with B-ALL treated on COG trials AALL0331 and AALL0932 (SR) and AALL0232 and AALL1131 (HR) whose diagnostic leukemia specimens were analysed by low-density microarray (LDA), fluorescence in situ hybridization, polymerase chain reaction (PCR), and/or anchored multiplex PCR testing (Harvey and Tasian Blood Advances 2020). Minimal residual disease (MRD) was assessed by flow cytometry at the end of induction (EOI) and at the end of consolidation for a subset of EOI MRD+ patients. Results: We identified 77/1541 (5.0%) SR and 244/2216 (11.0%) HR patients with CRLF2+ B-ALL in this cohort. Amongst those with diagnostic leukemia specimens analysed by LDA, 57/72 (79.2%) of SR CRLF2+ and 175/213 (82.2%) of HR CRLF2+ patients were positive for the Ph-like gene expression profile with an 8-gene score ≥0.5. P2RY8-CRLF2 fusions and IGH-CRLF2 translocations were detected in 64/77 (83.1%) and 10/77 (13.0%) of SR CRLF2+ patients and in 98/244 (40.2%) and 103/244 (42.2%) of HR CRLF2+ patients, respectively. CRLF2 rearrangements or F232C mutations were not found in the remaining 3 SR and 43 HR CRLF2+ patients, although other Ph-like alterations were discovered in some (n=3 IGH-EPOR fusions, 1 IL7R indel). Importantly, CRLF2+ vs non-CRLF2-overexpressing (CRLF2-) status was associated with older age (10.8 ±6.5 vs 7.8 ±5.8 years [mean ±SD], p&lt;0.0001), leukocytosis (diagnostic white blood cell count 77.5 ±98.5 vs 49.8 ±119.4 x 10e9/L [mean ±SD], p&lt;0.0001), and higher rates of EOI MRD positivity at a ≥0.01% threshold (47.9% vs 30.1%, p&lt;0.0001), which appeared largely driven by the Ph-like HR cohort as expected (57.9% MRD+ vs 42.1% MRD- in HR CRLF2+ and 44.6% MRD+ vs 55.4% MRD- in SR CRLF2+ patients, p&lt;0.003). Overall, CRLF2+ patients had inferior 5-year event-free survival (EFS; 63.3% ±3.1 vs 82.1% ±0.7, p&lt;0.0001) and overall survival (OS; 79.6% ±2.6 vs 90.5% ±0.6, p&lt;0.0001) compared to CRLF2- patients (Figure 1A-B) and a greater 5-year cumulative incidence of relapse (CIR; 30.4% ±2.7 vs 13.2% ±0.6, p&lt;0.001). While 5-year EFS and OS were particularly poor in Ph-like CRLF2+ HR patients (56.3% ±4.6 and 75.4% ± 3.9, respectively) and non-Ph-like CRLF2+ HR patients (EFS 63.7% ±10.2 and OS 74.4% ±8.9), outcomes for Ph-like CRLF2+ SR (EFS 87.2% ±4.5 and OS 94.5% ±3.1) and non-Ph-like CRLF2+ SR patients (EFS 86.2% ±9.3 and OS 100%) were quite good (p&lt;0.0001 for both EFS and OS; Figure 1C-D). Discussion: Patients with newly-diagnosed CRLF2+ B-ALL treated on frontline COG trials have higher rates of EOI MRD positivity, inferior survival, and increased CIR compared to their CRLF2- counterparts. EFS is especially poor in children and AYAs with NCI HR CRLF2+ ALL, particularly those with the Ph-like expression profile. Conversely, outcomes for children with NCI SR CRLF2+ ALL are reasonably favourable, irrespective of Ph-like status. Development of successful treatment strategies to decrease relapse and to improve survival remains a major therapeutic gap for NCI HR CRLF2+ ALL patients. Current clinical trials are studying the potential efficacy of kinase inhibitor addition to chemotherapy for children, adolescents, and adults with HR Ph-like ALL harboring CRLF2 rearrangements/other JAK pathway alterations or ABL class kinase fusions (NCT0240717, NCT02723994, NCT02883049, NCT03571321). Figure 1 Disclosures Tasian: Gilead Sciences: Research Funding; Incyte Corporation: Research Funding; Aleta Biotherapeutics: Membership on an entity's Board of Directors or advisory committees. Borowitz:Amgen: Honoraria. Mullighan:AbbVie, Inc.: Research Funding; Illumina: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau. Hunger:Novartis: Consultancy; Amgen: Current equity holder in publicly-traded company, Honoraria. Raetz:Pfizer: Research Funding; Celgene/BMS: Other. Loh:Pfizer: Other: Institutional Research Funding; Medisix Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Invasive Fungal Infections in Pediatric Patients with High-Risk Acute Lymphoblastic Leukemia during Initial Phases of Therapy: A Retrospective Evaluation

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 4-5
Author(s):  
Ksenya Shliakhtsitsava ◽  
Jillian Grapsy ◽  
Christina Hsu ◽  
Mohammad Almatrafi ◽  
Michael Sebert ◽  
...  
Keyword(s):  
Risk Factors ◽  
T Cell ◽  
Pediatric Patients ◽  
Fungal Infections ◽  
Lymphoblastic Leukemia ◽  
Antifungal Prophylaxis ◽  
Induction Phase ◽  
Newly Diagnosed ◽  
Potential Risk Factors ◽  
Group 1

BACKGROUND Patients with newly diagnosed acute lymphoblastic leukemia (ALL) are at increased risk of infection. While previously published guidelines recommend primary antifungal prophylaxis in patients with T-cell ALL, we sought to determine the pattern of invasive fungal disease (IFI) at our center so as to assess risk factors for IFI, beyond the diagnosis of T-ALL, with the administration of dexamethasone and an anthracycline during induction. The current practice at Children's Health Children's Medical Center Dallas is to provide primary antifungal prophylaxis with micafungin during induction therapy for hospitalized patients with T-cell ALL and those with Down Syndrome. Additionally, we recently decided to provide primary antifungal prophylaxis to patients with HR B-ALL with hyperglycemia who remain hospitalized during induction. The primary objective of this study was to capture the institution-specific five-year incidence of IFI prior to the start of delayed intensification (DI) phase chemotherapy among pediatric patients with ALL. Secondary objectives were to identify potential IFI risk factors specifically amongst pediatric patients with HR ALL. METHODS This retrospective chart review included patients younger than 21 years with newly diagnosed ALL between July 1, 2014 and June 30, 2019. Patients with secondary leukemia, infantile leukemia, or those receiving treatment for a fungal infection at presentation were excluded. The primary outcome was the development of probable or proven IFI, as defined by the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group criteria, prior to the start of the DI phase of therapy. Statistical methods included Chi-square test, t-test, and Wilcoxon Rank Sum test, as appropriate to the variable's level of measurement and distribution. Time series analyses were used to assess overall and seasonal trends of IFI incidence over the study period. RESULTS Of 220 included patients, there were 13 cases of IFI diagnosed during the induction and consolidation phases of therapy during the five-year period. IFI occurred in 15.3% of the HR group (11/72), 5.9% of the T-cell ALL group (1/17), and 0.8% of the standard risk (SR) group (1/131). Among individuals with HR ALL, the majority of cases occurred in the absence of primary antifungal prophylaxis (90.9%). The most common sites of IFI included the lungs (n=6) and sinuses (n=4). Implicated fungal pathogens included Aspergillus, Candida, Curvularia, Exserohilum, and Bipolaris. Univariate analysis of the potential IFI risk factors in HR ALL patients did not identify any significant differences between those patients that did or did not develop IFI, with respect to pre-existing comorbidities, body mass index, laboratory results at diagnosis, or hospital exposures during induction including length of stay, intensive care admissions, and receipt of systemic antibiotics (Table). Race and ethnicity was significantly different likely due to the skewed distribution of IFI among patients who identified as Asian (p = 0.03; 8/8 identified as Asian and did not develop IFI). With respect to seasonality of ALL diagnosis, the percent of patients in each group (winter, spring, summer, and fall) that developed IFI were 7.4%, 18.2%, 20%, and 31.2%, respectively. However, time series analysis did not show an association between seasonality of diagnosis and development of IFI (p=0.89). During the induction phase of therapy, hyperglycemia, defined as blood glucose 140-200 mg/dL for ≥ 2 days or &gt;200 mg/dL for 1 day, was present in 100% of the HR patients that developed IFI and 74% of the HR patients that did not develop IFI (p=0.12). CONCLUSION In this pediatric population, patients with HR B-ALL developed more fungal infections during the early phases of therapy then those with SR disease (15.6% versus 0.8%). In analysis of potential risk factors, there were no significant differences between HR ALL groups that did or did not develop IFI. Larger-scale studies are needed in order to identify potential risk factors that will guide decisions on the routine use of primary antifungal prophylaxis in patients with HR ALL during induction therapy. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Micafungin use for primary antifungal prophylaxis during induction phase of therapy.

scholarly journals Cardioprotection and Safety of Dexrazoxane in Patients Treated for Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia or Advanced-Stage Lymphoblastic Non-Hodgkin Lymphoma: A Report of the Children’s Oncology Group Randomized Trial Pediatric Oncology Group 9404

2016 ◽  
Vol 34 (8) ◽  
pp. 854-862 ◽  
Author(s):  
Barbara L. Asselin ◽  
Meenakshi Devidas ◽  
Lu Chen ◽  
Vivian I. Franco ◽  
Jeanette Pullen ◽  
...  
Keyword(s):  
Lymphoblastic Leukemia ◽  
Left Ventricular ◽  
Newly Diagnosed ◽  
Second Malignancies ◽  
Oncology Group ◽  
Non Hodgkin Lymphoma ◽  
Z Scores ◽  
Pediatric Oncology Group ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Fractional Shortening

Purpose To determine the oncologic efficacy, cardioprotective effectiveness, and safety of dexrazoxane added to chemotherapy that included a cumulative doxorubicin dose of 360 mg/m2 to treat children and adolescents with newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL) or lymphoblastic non-Hodgkin lymphoma (L-NHL). Patients and Methods Patients were treated on Pediatric Oncology Group Protocol POG 9404, which included random assignment to treatment with or without dexrazoxane given as a bolus infusion immediately before every dose of doxorubicin. Cardiac effects were assessed by echocardiographic measurements of left ventricular function and structure. Results Of 573 enrolled patients, 537 were eligible, evaluable, and randomly assigned to an arm with or without dexrazoxane. The 5-year event-free survival (with standard error) did not differ between groups: 77.2% (2.7%) for the dexrazoxane group versus 76.0% (2.7%) for the doxorubicin-only group (P = .9). The frequencies of severe grade 3 or 4 hematologic toxicity, infection, CNS events, and toxic deaths were similar in both groups (P ranged from .26 to .64). Of 11 second malignancies, eight occurred in patients who received dexrazoxane (P = .17). The mean left ventricular fractional shortening, wall thickness, and thickness-to-dimension ratio z scores measured 3 years after diagnosis were worse in the doxorubicin-alone group (n = 79-84 per group; P ≤ .01 for all comparisons). Mean fractional shortening z scores measured 3.5 to 6.4 years after diagnosis remained diminished and were lower in the 21 patients who received doxorubicin alone than in the 31 patients who received dexrazoxane (−2.03 v −0.24; P ≤ .001). Conclusion Dexrazoxane was cardioprotective and did not compromise antitumor efficacy, did not increase the frequencies of toxicities, and was not associated with a significant increase in second malignancies with this doxorubicin-containing chemotherapy regimen. We recommend dexrazoxane as a cardioprotectant for children and adolescents who have malignancies treated with anthracyclines.

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