Receiving Maintenance Chemotherapy Research Articles

7410 Bevacizumab Induced Hypothyroidism

Abstract Disclosure: A.L. McKenna: None. S. Thota-Kammili: None. K. Grennan: None. S. Rao: None. It is known that thyroid dysfunction is an adverse effect of tyrosine kinase inhibitors (TKIs) via inhibition of the vascular endothelial growth factor receptor (VEGFR). The VEGF signaling pathway is important in regulating angiogenesis in tumors and normal tissue. As a highly vascularized gland, it is expected the thyroid may be compromised because of VEGFR inhibitors. Proposed mechanisms of thyroid dysfunction include capillary regression and constriction leading to reduced vascular perfusion to the gland. Bevacizumab is a monoclonal antibody that targets VEGF and inhibits activation of VEGFR, reducing angiogenesis; interestingly, this is not commonly reported in the literature. Here we present a case where bevacizumab altered thyroid function in a patient with pre-existing primary hypothyroidism. A 60-year-old woman presented with worsening hypothyroidism. She reported a history of nonautoimmune primary hypothyroidism diagnosed in her early 20s; she still had an intact thyroid with no history of head/neck radiation. In the months leading to the presentation, she had been receiving maintenance chemotherapy with 5 fluorouracil and bevacizumab every 2 weeks for metastatic duodenal carcinoma. Prior to starting chemotherapy, she had been on a steady dose of 112 mcg of levothyroxine (LT4) daily. After 6 months on chemotherapy, she reported symptoms of fatigue and hair loss. Workup revealed an elevated TSH of 41 mIU/L (reference 0.3-4.2 mIU/L). She denied any significant changes in weight or malabsorption issues. Aside from the chemotherapy, no other new medications were introduced. Her LT4 dose was increased to 137 mcg daily, and 3 months later, there was improvement in TSH to 6.5 mIU/L as well as her symptoms. At this point, bevacizumab was briefly on hold for 2 months due to an upcoming procedure, hence there was no change to LT4 to avoid over correction. Her TSH normalized and was trending lower while bevacizumab was on hold. Once bevacizumab resumed, LT4 was preemptively increased to 150 mcg daily. Four months after resuming bevacizumab, her TSH remains within the normal reference range on 150 mcg LT4. It is hypothesized that this VEGF blocker led to worsening of her underlying hypothyroidism.Given the shared down regulation in the VEGF signaling pathway, it would be expected that TKIs and monoclonal antibodies against VEGF would share similar adverse reactions to the thyroid. However, to our knowledge, there have been limited reports of bevacizumab induced thyroid dysfunction in the literature. Explanations to this may include the more targeted VEGF inhibition with bevacizumab versus the inhibition of multiple kinase receptors from the TKIs. Further research into this will be needed. This case demonstrates that bevacizumab can impact thyroid function and thyroid labs may need to be monitored at the onset and during VEGF inhibitor therapies. Presentation: 6/3/2024

Correlation of maintenance chemotherapy and improved survival in patients with locally advanced unresectable pancreatic head adenocarcinoma receiving neoadjuvant chemotherapy and concurrent chemoradiotherapy.

To assess the efficacy of maintenance chemotherapy in the management of unresectable locally advanced pancreatic head adenocarcinoma (PHA) cancer after neoadjuvant chemotherapy and concurrent chemoradiation therapy (CCRT). This study, a large-scale head-to-head propensity score matching (PSM) cohort study, employed real-world data. PSM was used to evaluate the impact of maintenance chemotherapy on overall survival and cancer-specific survival in patients with unresectable locally advanced PHA who underwent neoadjuvant chemotherapy and CCRT. A total of 148 patients with locally advanced pancreatic head adenocarcinoma were included in the study after PSM. These patients were equally divided into two groups, those receiving maintenance chemotherapy and those who did not. Confounding factors were balanced between the groups. The adjusted hazard ratios for all-cause mortality and cancer-specific mortality were 0.56 (95% CI: 0.40-0.77; P = 0.0005) and 0.56 (95% CI: 0.40-0.78; P = 0.0007), respectively, in patients receiving maintenance chemotherapy compared to those who did not. Our large-scale, real-world study demonstrates that maintenance chemotherapy may enhance survival outcomes for patients with unresectable locally advanced pancreatic head adenocarcinoma who underwent neoadjuvant chemotherapy and concurrent chemoradiation therapy.

Efficacy of continuous arterial perfusion chemotherapy combined with transarterial chemoembolization regional arterial thermal perfusion in the treatment of pancreatic cancer with liver metastases

Abstract Background The aim of the study was to investigate the efficacy of continuous transcatheter arterial infusion chemotherapy combined with transarterial chemoembolization (TACE) for the treatment of advanced pancreatic cancer with liver metastasis. Methods Sixty patients with advanced pancreatic cancer and liver metastases were enrolled in this study. In the treatment group, 31 patients underwent continuous transcatheter arterial infusion chemotherapy combined with TACE regional arterial thermal perfusion, whereas 29 patients included in the control group received intravenous chemotherapy with gemcitabine and S-1. All patients received maintenance chemotherapy with S-1 after 4 cycles of the study regimen. Treatment efficacy, quality of life, survival, and toxicity were evaluated. Results Efficacy was better in the treatment group than in the control group, as reflected by the objective remission, partial remission, and disease progression rates (all P < 0.05). The Eastern Cooperative Oncology Group and Numerical Rating Scale pain scores were also higher in the treatment group (both P < 0.05). In survival analysis, the 1-year overall survival rates in the treatment and control groups were 64.516% and 10.345%, respectively, whereas the median overall survival times were 16 and 6 months, respectively (both P < 0.05). The 6-month progression-free survival rates in the treatment and control groups were 77.419% and 13.790%, respectively, and the median progression-free survival times were 12 and 3 months, respectively (both P < 0.05). The rates of hematological and nonhematological toxicological adverse effects were also lower in the treatment group (both P < 0.05). Although the rate of liver dysfunction was higher in the treatment group, this finding had no adverse effects on prognosis. Conclusions Continuous transcatheter arterial infusion chemotherapy combined with TACE regional arterial perfusion chemotherapy resulted in better efficacy and safety outcomes in patients with pancreatic cancer and liver metastasis, suggesting its utility as a reference method for the clinical treatment of advanced pancreatic cancer.

Frailty in Children and Adolescents with Lymphoblastic Leukemia or Lymphoma Receiving Maintenance Chemotherapy - a Pilot Study

Background: Increased survivorship of childhood cancer has revealed a number of long-term morbidities related to treatment. Evidence suggests that cancer and its treatment may accelerate normal loss of physiologic capacity that occurs during aging.The advanced physiologic aging and related morbidities often seen in childhood cancer survivors suggests that these patients may present with signs of early-onset frailty. Frailty is a measure of global infirmity and impaired physical function and has been correlated with adverse health outcomes and elevated incidence of mortality in the general population. Research into the incidence and applicability of the frailty phenotype in children being treated for cancer may aid in the identification of the most vulnerable patients and identify those who may require intervention. The purpose of this study is to explore the frailty phenotype in children and adolescents receiving maintenance chemotherapy for acute lymphoblastic leukemia or lymphoma. Methods: We prospectively recruited children and adolescents (aged 5-18 years-old) diagnosed with acute lymphoblastic leukemia or lymphoma in the first cycle of their maintenance chemotherapy. Frailty was assessed twice: at an initial visit in cycle 1 maintenance treatment (V1), and 6-months following the initial assessment (V2). The frailty phenotype consists of 5 domains, which were assessed using developmentally appropriate measures: 1) Slowness: 6-minute walk test; 2) Weakness: Handgrip strength dynamometry - calibrated to the size of the participant's hand; 3) Exhaustion/Fatigue: The PedsQL TM Multidimensional Fatigue Scale; 4) Body Composition: InBody 270 body composition analyzer; and 5) Physical activity/Energy expenditure: Self-administered physical activity questionnaire for older children (PAQ-C) and physical activity questionnaire for adolescents (PAQ-A).Each assessment was scored individually and “Frailty points” were assigned based on age and sex-based normative z-scores or survey scores, and a composite “Frailty Score” ranging from 0=least frail to 25=most frail. Wilcoxon signed-rank test was used to compare V1 and V2 frailty scores. Results:The analysis sample consisted of 19 participants (mean age 9.1 [SD=3.4] years old; 63% female) who completed V1 and 7 participants that completed V2. Diagnoses of participants who completed V1 include precursor B-Cell acute lymphoblastic leukemia (n=15), T-Cell acute lymphoblastic leukemia (n=3), and T-Cell lymphoblastic Lymphoma (n=1). Median V1 z-scores and survey scores per domain are as follows: Slowness: z-score -3.11 [-4.02, -2.48]; Weakness: z-score -1.48 [-2.06, -1.38]; Exhaustion/Fatigue: score 58.3 [46.5, 70.8]; Body composition: z-score (total body fat) 0.90 [0.47, 1.79]; Physical activity/Energy expenditure: score 2.26 [1.73, 2.54]. Domain specific frailty score for V1 are displayed in Figure 1. Of the 7 participants with a V2 frailty assessment, paired analysis demonstrated significant improvement in Exhaustion/Fatigue (median score V1=56.94, V2=70.83 [p=0.016]). However, improvements in weakness, body composition, and physical activity/energy expenditure did not reach statistical significance. Median slowness z-scores at V2 were similar to V1. Median composite frailty score improved from 12 to 11 in V2 but was not statistically significant (p=0.054). Comparison of V1 and V2 overall composite scores are displayed in Figure 2. Conclusion: Children and adolescents receiving maintenance chemotherapy for acute lymphoblastic leukemia or lymphoma scored poorly in all five domains of frailty. We observed some improvements in exhaustion/fatigue, and trending improvements in subdomain and composite frailty scores in the small sample of participants with V1 and V2 assessments. Given that frailty has been shown to persist into adulthood in survivors of childhood cancer, the frailty assessment may be an effective tool for identifying patients who may require additional intervention. Initial and follow-up frailty measurements for this study are currently ongoing.

Comparison of Maintenance Therapy Regimens of Patients Treated for Multiple Myeloma

Background: Despite significant progress in treatment modalities and improved survival and response rates in patients diagnosed with multiple myeloma (MM), it remains an incurable disease with a poor outcome, especially in high-risk groups. Though not all patients are eligible, autologous stem-cell transplantation (ASCT) remains an integral part of the treatment of patients with both newly diagnosed and relapsed MM. Regardless of whether patients receive a transplant, they do receive maintenance therapy, and recent evidence has demonstrated that maintenance therapies offer an advantage in progression free and overall survival. While Revlimid is the standard of care, data regarding the specifics of maintenance therapy in high-risk patients is limited and the overall impact of various regimens on survival needs to be further investigated. In our retrospective chart review we reviewed all adult patients with advanced MM within Henry Ford Cancer Institute in the last 10 years to determine the impact of maintenance therapy on progression free survival (PFS) and overall survival (OS). Methods: We conducted a retrospective chart review of adult patients with MM who underwent ASCT between January 1, 2012 to December 31, 2022. Those who received maintenance chemotherapy after transplant were included in the study. Patients who were lost to follow-up or who had largely incomplete records were excluded. Data points including age, ethnicity, cytogenetic analysis, risk category, maintenance regimen after transplant, last chemotherapy regimen, last follow-up, and date of death (if applicable) were recorded. Maintenance chemotherapy regimens were recorded as Revlimid versus other. Patients were split into 2 categories based on risk - high risk and standard risk. Kaplan-Meier plots were used to illustrate overall survival and time to relapse between groups for various variables. Statistical significance was set at p<0.05 Results: 158 patients were included in the study of which 44 were considered high-risk based on cytogenetics, 106 were standard-risk and 8 were missing. Most of the patients (n=137, 87.3%) received Revlimid, while 20 (12.7%) received maintenance therapy other than Revlimid, and for 1 patient, the type of maintenance therapy was unknown. Within the high-risk group, no statistical significance in OS or PFS was found between patients that received Revlimid versus those that did not. Furthermore, there was no statistical significance in OS and PFS within high risk versus standard cytogenetic risk groups. Conclusions: We did not see a difference in outcome based on risk and believe all patients would derive equal benefit from maintenance therapy We also did not see a difference in outcome between high and standard risk patients, and for the high-risk subgroup, there was a separation in curves suggesting that maintenance therapy has benefit compared to no maintenance.

Impact of Race on Progression-Free Survival and Overall Survival in Patients with Multiple Myeloma

Background: Multiple myeloma (MM) is a disorder of plasma cells. Management typically includes induction therapy, autologous stem-cell transplantation (ASCT) and maintenance therapy. Despite significant progress in treatment modalities and improved survival and response rates in patients diagnosed with MM, it remains an incurable disease with a poor outcome, especially in high-risk groups. Black patients have been shown to have a higher incidence of MM than white patients. Multiple studies have been done to examine racial disparities among white and black patients, specifically in overall survival (OS) and progression free survival (PFS). However, data has been overall inconclusive with some studies suggesting there is a difference in survival based on race, while other studies suggesting the opposite. Thus, racial disparities among white and black patients' needs to be further investigated. In our retrospective chart review we reviewed all adult patients with advanced MM within Henry Ford Cancer Institute in the last 10 years to determine the impact of maintenance therapy on PFS and overall survival OS. Methods: We conducted a retrospective chart review of adult patients with MM who underwent autologous stem cell transplantation (ASCT) between January 1, 2012 to December 31, 2022. Those who received maintenance chemotherapy after transplant were included in the study. Patients who were lost to follow-up or who had largely incomplete records were excluded. Data points including age, gender, race, date of transplant, maintenance chemotherapy regimen, last follow-up, and date of death (if applicable) were recorded. Kaplan-Meier plots were used to illustrate overall survival and time to relapse between various races. Statistical significance was set at p<0.05. Results: There were 158 patients included in the study. Of the 158 patients, 82 (51.9%) were male, and 76 (48.1%) were female. The average age of patients included was 61.66 + 9.30 years, spanning from 32 to 78 years old. There were 71 (44.9%) White patients, 76 (48.1%) Black patients, and 11 (7.0%) patients that were of another race. There was no statistical significance in PFS and OS between Black, White and Other race categories. Conclusions: We did not see a difference in outcome based on race and believe all patients would derive equal benefit from maintenance therapy. Further prospective studies are warranted to examine racial disparities in patients with multiple myeloma.

A retrospective evaluation of the presentation, prognostic factors and outcomes of neuroblastoma in Ugandan children

Neuroblastoma (NB) is the most common extracranial solid tumor of childhood. The complete burden and outcomes in Uganda are unknown. The study was a multicenter retrospective chart review of children aged between 0 to 15 years diagnosed with NB from 2010 to 2020. Demographic, clinical and tumor-related characteristics were extracted for analysis. Kaplan-Meier survival curves and Cox regression models were used to determine the one-year overall survival (OS) and identify prognostic factors. Seventy-five patients were evaluated, with a median age at diagnosis of 48 months (IQR 26-108 months). Fever (74.7%), weight loss (74.7%), high blood pressure (70.3%) and abdominal swelling/mass (65.3%) were the most common features at diagnosis. Suprarenal tumors (52%) and stage 4 disease (70.7%) were also common. The one-year OS was 60.0% (95%CI 56.8%; 64.3%) with a median survival time of 12.6 months (95% CI: 8.1; 20.8). The one-year OS for non-metastatic and metastatic disease was 67.3% and 42.6% (p = 0.11) respectively. Leukocytosis (p < 0.001) at diagnosis was of prognostic significance while clinical remission after induction chemotherapy (p < 0.001) provided survival advantages. Children who received maintenance chemotherapy had a longer median survival time of 38.5 months (range 10.8–69.5). Age (p = 0.001), lung metastasis (p < 0.001), and leukocytosis (p < 0.001) remained significant on multivariate analysis. In this Ugandan study, leukocytosis was a clinical predictor of prognosis, metastatic disease had management challenges and maintenance chemotherapy prolonged the survival time but not OS.

IKZF1 Deletions Are Markers of Treatment Resistance in Adult Ph-Negative B-Cell Acute Lymphoblastic Leukemia Patients Treated within the Ongoing Risk-Adapted Pethema LAL19 Trial

Introduction IKZF1 (Ikaros) deletion has been related with poor outcome in pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL). However, its impact in adult patients (pts) treated with MRD-oriented trials has not been fully established. This study aimed to assess if IKZF1 deletions are markers of poor prognosis in adults with Ph-negative BCP ALL treated within the ongoing risk-adapted PETHEMA LAL19 trial (NCT04179929). The impact of IKZF1 loss in these pts and those from the EWALL Group (European Working group on ALL) is being evaluated in a HARMONY (Healthcare Alliance for Resourceful Medicine Offensive against Neoplasms in Hematology) project (Project Ref ALL2). Methods In the PETHEMA LAL19 trial, pts with poor end-induction MRD clearance (MRD>0.01%) or high-risk genetics (low-hypodiploid, KMT2Ar, TP53 biallelic alteration or IKZF1+CDKN2A/B deletion) are assigned to allogeneic stem cell transplantation, the remaining pts receive maintenance chemotherapy. All pts are analyzed by G-banding, FISH, NGS (DNA gene panel) and SNP array. Next generation flow cytometry is used for MRD assessment. Main outcome measures: i) Complete Remission (CR): absence of extramedullary disease, neutrophil level >1x109/L, platelet level >100x109/L, and bone marrow blast level < 5%; ii) Cumulative Incidence of Relapse (CIR) and non-relapse mortality (NRM): calculated using cumulative incidence rates to accommodate competing risks and compared by Gray's test; iii) Overall survival (OS): measured from the time of protocol entry to the time of death or last contact. Results 147pts were analyzed. Mean age 40y [range 18-60], 56% males, 10% CNS involvement, 78% common B, 15% pro-B and 7% pre-B ALL. Ph-like (12%) was the most common genetic subtype followed by KMT2Ar (11%), PAX5 P80R (8%), low-hypodiploid (7%), TCF3::PBX1 and high-hyperdiploid (6% each), iAMP21 and ETV6::RUNX1 (2% each). More uncommon biological entities such as ZNF384r, MEF2Dr, MYCr, IDH1 R132C and IDH2 R140Q were seen in single pts (<1% each).The remaining patients (41%) were B-other,no growth or normal karyotype. IKZF1 deletion (IK DEL) was observed in 66/147(45%) pts. Deletions involved the whole gene (37/66, 56%) or a subset of exons (partial gene deletions). The most recurrent partial gene deletions (n=29) were: loss of exons 4-7 (n=6, 21%), 4-8 (n=5, 17%), 2-8 and 1-7 (n=4, 14% each), 1-3 (n=3, 10%), 2&3 and 2-7 (n=2, 7% each). The IKZF1plus profile was observed in 37/147 (25%) pts. IK DEL were more frequent in low-hypodiploid (100%) and Ph-like ALL (88%), and less prevalent in KMT2Ar (19%), PAX5 P80R (18%) and TCF3::PBX1 ALL (11%), p<0.001. Median follow up was 11.4 months. IKDEL pts showed lower CR rate than pts without Ikaros loss (75% vs. 91%, p=0.027). The IKZF1plus signature showed similar CR rate to IK DEL without IKZF1plus profile (IKZF1not plus) (73% vs. 78%, p=ns). IKDEL pts showed poorer MRD clearance than WT individuals. Interestingly, this fact was mainly attributable to partial gene deletions (MRD≥0.01% partial 79% vs. whole 42% vs. WT 29%, p=0.003). IKZF1plus was also correlated with positive MRD, however IKZF1not plus pts showed higher frequency of MRD positivity than IKZF1plus pts (MRD≥0.01% plus 47% vs. not plus 71% vs. WT 29%, p=0.012). Pts with whole gene loss showed lower OS than pts with partial gene losses or IKZF1 WT (1y-OS 62% vs. 88% vs. 89%, p=0.012)(Figure 1A). Of note, relapse was not the main cause of death of IK DEL whole gene pts (n=26) as only 1 patient died due to disease progression. Instead, NRM was the main cause of death in whole gene-deleted pts (4 died in Ind-1, 3 in Ind-2, 1 due to TRM and 1 due to Covid19 infection). Accordingly, the 1y-CIR of IK DEL whole pts was lower than that of IKZF1 WT individuals, who showed similar CIR to IK DEL partial ones (1y-CIR whole 7% vs. WT 30% vs. partial 32%, p=0.059) (Figure 1B). Pts with IKZF1plus signature did not show differences in OS and CIR compared to IKZF1 WT or IKZF1not plus individuals (data not shown). Conclusions This preliminary data suggest that IK DEL may be marker of poor treatment response in adult Ph-negative BCP ALL. Further analyses including all patients of the HARMONY project may identify which isoforms or in which genetic ALL subtypes IKZF1 DEL are particularly deleterious. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

RADT-26. PATTERNS OF RECURRENCE IN PATIENTS TREATED WITH RE-IRRADIATION FOR RECURRENT HIGH-GRADE GLIOMA

Abstract Purpose/Objective(s) Re-irradiation (ReRT) is often used to treat recurrent high grade glioma (HGG). There is limited literature regarding the patterns of recurrence following ReRT, which was investigated in the current study. Materials/METHODS Patients with available radiation (RT) contours, dosimetry, and imaging-based evidence of recurrence were included in the retrospective study. All patients were treated with fractionated RT using conformal technique. Recurrence was documented as per decision in tumor board based on imaging with magnetic resonance imaging (MRI) or Flouroethyl-L-Tyrosine (FET) positron emission tomography (PET), which was registered with the planning CT. Failure patterns were classified as in-field, marginal, and out-field as decided by &amp;gt;50% recurrence volume within 95%, 20-95%, and outside 20% isodose lines, respectively. RESULTS Study population included 37 patients treated with median dose of 54 Gy (range 50.4-54 Gy). Before ReRT, 92% patients had undergone surgery (biopsy in 3, gross total resection in 9, subtotal resection in 22), 62% received concurrent chemo with ReRT, and 49% received maintenance chemotherapy. Median time to recurrence was 9 months (7-16 months, median 10 and 8 months respectively for in-field and marginal/out-field recurrence). In-field, marginal, and out-field recurrence were seen in 24 (65%), 10 (27%), and 3 (8%), respectively. Recurrence mapping was done using MRI, PET, or both in 27, 3, and 7, respectively. Of 24 patients with in-field recurrence, 8 and 16 had disease volume within gross tumor volume and clinical target volume, respectively. 2 patients had leptomeningeal dissemination (1 with majority of recurrence volume in-field and 1 with marginal failure in addition to metastatic disease). CONCLUSION Following ReRT for HGG, the majority of recurrence was in the high dose region, suggesting the use of conservative target volumes. Future studies are required for feasibility of dose-escalation to improve control rates, particularly in patients with long intervals from first course of RT.

ALL-268 Genetic Classification of B-Cell Precursor Adult Acute Lymphoblastic Leukemia Patients Enrolled in LAL19 Trial from the Pethema Group: Response to Treatment and Survival

B-cell precursor acute lymphoblastic leukemia (BCP ALL) is a genetically heterogeneous neoplasm with >20 biologic subtypes. Each subtype shows specific genetic traits that determine relapse risk and patients' survival. To establish the genetic subtype (primary alteration) of adult BCP ALL patients enrolled in the PETHEMA LAL19 trial (NCT04179929) and to correlate them with measurable residual disease (MRD) level and survival. In the LAL19 trial (NCT04179929), Ph-negative patients (18-65 y) with MRD≥0.01% at day+35 or high-risk genetics receive alloHSCT and MRD<0.01% patients with standard-risk genetics receive maintenance chemotherapy. The genetic analyses are centralized: FISH and NGS DNA panel (Hospital de Salamanca), RNAseq panel (Hospital 12 de Octubre), FISH panel (Hospital La Fe), and SNP array (Josep Carreras Institute/ICO-Hospital Germans Trias i Pujol). MRD determinations are centrally done by next-generation flow cytometry in the Cytometry Service, NUCLEUS, University of Salamanca. The genetic subtype was identified in 54% (82/152) of patients. The most recurrent subtypes were KMT2Ar (11%), Ph-like (mostly CRLF2::IGH, 11%), low-hypodiploid (7%), PAX5 P80R (7%), high-hyperdiploid (6%), and t(1;19)/TCF3::PBX1 (6%). In addition, t(12;21)/ETV6::RUNX1, ZNF384r, and iAMP21 subtypes (1.5% each) and MEF2Dr, MYCr, IDH1 R132 subtypes (<1% each) were found. Regarding secondary alterations, NRAS (15%), TP53 (13%), PAX5 (13%), and KRAS (10%) mutations were the most frequently observed. Twelve patients were refractory (mainly low-hypodiploid, Ph-like, MYCr, and B-other/unclassified patients). Statistically significant differences were observed for day+35 MRD levels between genetic subtypes. Ph-like, low-hypodiploid, and KMT2Ar showed lower frequencies of MRD<0.01% (17%, 33%, and 57%, respectively) than patients with PAX5P80R (100%), t(1;19)/TCF3::PBX1 (83%), and high-hyperdiploid (75%) (P=0.006). Despite the short median follow-up (11 months), differences in response to treatment were reflected in patients' survival. Significant differences in survival were observed between poor-response subtypes (Ph-like, KMT2Ar, and low-hypodiploid) and good-response subtypes (PAX5 P80R, t(1;19)/TCF3::PBX1, and high-hyperdiploid). Knowing the genetic subtype of each ALL is crucial to better predict relapse risk and offer the best (personalized) treatment for each patient.

Metronomic oral maintenance chemotherapy in patients with localized high-risk rhabdomyosarcoma (RMS) and RMS-like tumors: A report from a randomized, multicenter, phase III trial CWS-2007HR.

10033 Background: Low dose maintenance therapy as consolidation after multimodal standard therapy has been shown to improve survival in patients with sarcoma. It is however unclear which drugs and how long would be optimal. We investigated whether adding oral maintenance chemotherapy after standard multimodal therapy (ST) in patients with localized RMS and RMS-like sarcoma defined as high and very-high risk (HR and VHR), according to CWS stratification, would improve survival. Methods: Patients (pts) age &gt; 6 months &lt; 21 years, with 1. embryonal RMS N0, incompletely resected, (Group II or III), tumor size &gt; 5cm and/or ≥10 years, in unfavorable primary sites and all N1 (HR RMS Group), 2. alveolar RMS N0/N1 (VHR RMS Group) 3.Unidfferentiated sarcoma (UDS), extraskeletal Ewing sarcoma (EES) and primary non resectable (Group III) synovial sarcoma (SS) (HR RMS-like Group) in complete remission after ST including 9 cycles of ifosfamide, vincristine and actinomycin D +/- doxorubicin, surgery and/or radiotherapy were eligible for randomization to stop treatment (S-arm) or receive maintenance chemotherapy (M-arm) with eight 10-days courses consisting of trofosfamide (2x 75mg/m²/day) and idarubicine (1 x 5mg/m²/day 1,4,7,10) alternating with trofosfamide and etoposide (2x 25mg/m²/day). The study was designed with 80% power and a two-sided alpha level of 5% to detect an increase in 3 yr EFS from 60 to 75%. Randomisation was stratified according to risk groups. To reduce possible imbalances in the number of treatment assignments, a permuted block design was used. The initial calculated sample size was 145 pts in each group (recruitment period six years). Due to the lower than planned recruitement rate, the accrual was extended to 10 years and sample size recalculated to 98 pts in each group. Results: Between 1.7.2009 and 30.6.2019, 441 pts were eligible at diagnosis and 337 at the end of ST. 195 pts were randomized: 99 were assigned to the S-arm and 96 to M-arm. The distribution of the following clinical features:age, gender, tumor size, IRS-Group, T-Status, N-Status, histology and localisation showed no significant difference between the treatment groups. In the intent to treat population, with a median follow up of 4.9 years (IQR 3.0-5.7) in surviving pts, 3yr EFS and OS in M-arm vs S-arm were respectively: EFS 66.2% (95% IC 57.1-76.79) vs 75.0% (95% IC 66.8-84.3) (p 0.07) and OS 81.9% (95% IC 74.2-90.4) vs 84.6 (95% IC 77.5-92.4) (p 0.15). Toxicity grade 3 (no grade 4) in the M-arm was: hematological in 51 %, febrile infection 5%, sensory neuropathy in 1% pts. Conclusions: The addition of maintenance therapy with trofosfamide, etoposide and idarubicine after ST does not improve EFS and OS in patients with high risk RMS and RMS-like sarcomas. Clinical trial information: 2007-0001478-10.

CMV-colitis in a pediatric non-transplant ALL patient receiving chemotherapy; A case report

Cytomegalovirus (CMV) is the leading cause of viral-associated congenital infections. Moreover, it can also be acquired. Between 50 to 80 percent of the world’s population is seropositive for CMV and most clinical disease occurs in individuals previously infected with CMV. Rarely, serious CMV infection has occurred in individuals with healthy immune system. In contrast to immunocompetent patients, higher morbidity and mortality of CMV end organ disease is considered in immunocompromised patients. According to available evidence, gastrointestinal (GI) disease has lower prevalence in case of CMV-induced organ involvement, especially in pediatric non-transplant acute leukemia. In this report, we present a 12-year-old girl, known case of acute lymphoblastic leukemia (ALL) receiving maintenance chemotherapy with manifestations of gastroenteritis and significant weight loss. Initial laboratory data, demonstrated mild pancytopenia especially lymphopenia and thrombocytopenia. After excluding more common etiologies, colonoscopy with multiple biopsies were taken which was indicative of CMV-colitis. Intravenous (IV) ganciclovir for 3 weeks and oral valganciclovir for about 9 months were initiated. Follow-up courses for CMV surveillance included blood qualitative CMV polymerase chain reaction (PCR) and colonoscopy with biopsy which were negative for CMV but tissue qualitative CMV PCR was positive for CMV in about 7 months after initiation of treatment. Oral treatment was decided to be continued. To sum up, plenty of guidelines have been developed in stem cell transplantation and human immunodeficiency virus (HIV) patients but non-transplant leukemic setting, is a neglected area in the field of CMV infection management.

How essential are in-person clinic visits during maintenance treatment of children with acute lymphoblastic leukemia?

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Treatment consists of an initial intensive phase of chemotherapy, followed by a prolonged period of maintenance chemotherapy intended to reduce the risk of relapse. During the COVID-19 pandemic, the need arose to identify and reduce non-essential hospital visits. We aimed to determine which proportion of in-person clinic visits during ALL maintenance therapy was associated with a change of management based on the results of the physical examination. Medical records of children receiving maintenance chemotherapy for B-precursor ALL between September 2019 and February 2020 were reviewed. Visits with a new finding on physical examination were divided into those where an in-person assessment was deemed essential versus not essential. Finally, we determined the proportion of essential in-person visits that resulted in a change of management. A total of 240 maintenance visits by 75 children were analyzed. An abnormal finding on physical examination was noted during 20 visits (8.3%). Of those, 14 (5.8%) uncovered a new finding, six (2.5%) were classified as "in-person visit essential," and among those six visits, three (1.2%) resulted in a change of patient management (one for acute otitis media, one for wheezing, and one for limp). Our findings support the evaluation of care delivery models other than in-person visits during ALL maintenance therapy. A prospective study is required to delineate criteria, benefits/risks, and families' perspectives associated with virtual care delivery and the optimal frequency of in-person visits.

Patterns of Care in Maintenance Therapy in US Patients Undergoing Definitive Chemoradiation for Stage 3 Non-Small Cell Lung Cancer (NSCLC).

The recommended treatment for patients with unresectable stage 3 non-small cell lung cancer (NSCLC) is definitive chemoradiation followed by 1 year of maintenance durvalumab. Our objective was to assess the rate of maintenance durvalumab use after chemoradiation. Analyses were conducted in both open claims (IQVIA pharmacy and medical claims data) and adjudicated closed claims (IQVIA PharMetrics Plus Health Plan Claims Database). Patients with a lung cancer diagnosis between November 2017 and November 2020 who received definitive chemoradiation were included. Of the 5802 NSCLC patients included in the open claims source, 1794 (31%) received durvalumab, 1403 (24%) received maintenance chemotherapy, and 2605 (45%) did not receive any maintenance therapy. Of the 239 NSCLC patients included in the closed claims source, 127 (53%) received durvalumab, 40 (17%) received maintenance chemotherapy, and 72 (30%) did not receive any maintenance therapy. The most common maintenance chemotherapy agents patients received were carboplatin, pemetrexed, and paclitaxel. The rate of durvalumab utilization was overall low in both the open and closed claims data sources (31% and 53%, respectively). It remains unknown what percent of eligible patients end up receiving durvalumab, as our analysis was unable to filter out patients who were unfit for durvalumab or if they had progression after chemoradiation. Future efforts are needed to increase maintenance durvalumab utilization and to determine how best to manage patients who are unfit for durvalumab.

Intensive chemotherapy perturbs heart rate variability in children with cancer

ObjectivesIn children, cancer chemotherapy may impair the functioning of the cardiac autonomic nervous system. Moreover, it is not known whether there are any differences between intensive and maintenance phases of chemotherapy. Therefore, the aim of the current study was to assess autonomic nervous system activity using heart rate variability, in children receiving intensive or maintenance cancer chemotherapy. MethodsFor that purpose, children who were healthy (healthy control, n = 30), receiving intensive chemotherapy (chemotherapy, n = 30), and receiving maintenance chemotherapy (maintenance, n = 25) were included in the study. Autonomic nervous system activity was measured by means of heart rate variability. Electrocardiogram recordings were used to calculate time- and frequency-domain heart rate variability parameters. ResultsTime-domain parameters such as standard deviation of NN intervals and frequency-domain parameters such as total power were lower during the intensive chemotherapy but not during maintenance phase (standard deviation of NN intervals: 50±5, 33±3, and 48±3 ms, and total power: 2613±504, 1379±296 and 2295±264 ms2, respectively for healthy control, chemotherapy and maintenance groups, P<0.001 for both standard deviation of NN intervals and total power). DiscussionThe present results indicate that intensive chemotherapy perturbs the function of heart rate variability in children, with recovery during the maintenance phase. This suggests that intensive chemotherapy is likely to affect the autonomic nervous system but this effect does not appear to be permanent.

EPID-07. EPIDEMIOLOGICAL CHARACTERISTICS AND SURVIVAL OF PATIENTS WITH DIFFUSE GLIOMA IN BRAZIL: PRELIMINARY RESULTS OF A MULTICENTRIC RETROSPECTIVE STUDY - LACOG 0619

Abstract INTRODUCTION In Brazil, most of the 9,196 deaths due to brain cancers in 2017 were gliomas. There is a dearth of epidemiological data on diffuse glioma in Brazil. METHODS LACOG 0619 is a multicentric retrospective cohort study, which included patients from nine tertiary oncology centers. Patients aged ≥18 years with histologically proven astrocytoma, oligodendroglioma, oligoastrocytoma or glioblastoma diagnosed from June 2010 to June 2019 were included. The study protocol was approved by each Institutional Review Board. RESULTS 642 patients were included in the analysis. Median age was 51.0 (19-91) years. Most patients were male (n=364, 56.8%), 175 (27.3%) had ECOG 0-1, and 480 (74.8%) had private healthcare insurance. Neurological symptoms were present in 568 (88.5%) patients at diagnosis, and 263 (41.0%) had a history of seizure before surgery. Regarding histology, 361 (56.2%) had glioblastoma, 162 (25.2%) had astrocytoma, 90 (14.0%) had oligodendroglioma, and 23 (3.6%) had glioma NOS. Gross total resection was performed in 168 (26.2%), subtotal resection in 292 (45.5%), biopsy in 108 (16.8%), conventional radiotherapy in 380 (59.2%), and hypofractionation in 44 (6.9%) patients. Concomitant chemoradiotherapy was administered to 370 (57.6%) patients, mostly with temozolamide (n=362, 97.8%). Furthermore, 434 (67.7%) patients received maintenance chemotherapy, 398 with temozolamide (&amp;lt; 6 cycles in 112 [28.4%], 6 cycles in 75 [18.8%], and &amp;gt;6 cycles in 214 [3.8%]). Median follow-up was 29 months (26-33). Median OS according to histology was: 35 months (95%CI 26-46) for glioblastoma, 91 months (95%CI 35-NR) for glioma NOS, and not reached for astrocytoma and oligodendroglioma. Median OS by number of temozolamide maintenance cycles was 18 months (95%CI 15-24) for &amp;lt; 6 cycles and not reached for 6 cycles or more. CONCLUSIONS This is the first multicentric cohort evaluating Brazilian patients with diffuse glioma, providing important data on epidemiology, treatment patterns, and survival in the country.

Association of APEX1 and NUDT15 Polymorphisms with Mercaptopurine-Related Neutropenia in Pediatric Acute Lymphoblastic Leukemia

Introduction: Mercaptopurine (MP) is one of the main chemotherapeutics for acute lymphoblastic leukemia (ALL), and constant MP dose titration is essential to maintain steady drug exposure, while minimizing myelosuppression. Throughout previous studies, thiopurine methyltransferase (TPMT) is proved to be one of the most responsible genes in the pharmacogenetics of MP. However, most of East Asian patients still show sensitivity to MP after adjusting for TPMT variants, suggesting the existence of other yet unknown factors that are related to MP sensitivity. In this study, the genetic factors affecting the toxicity of MP were investigated in Korean children with ALL.Methods: Two-stage pharmacogenetic analyses were performed to identify genetic determinants of MP-related neutropenia in Korean pediatric ALL patients who received maintenance chemotherapy including daily MP. A total of 287 patients with ALL who were diagnosed and treated at the Seoul National University Children's Hospital and Asan medical center were included. First, targeted sequencing was carried out using a novel gene panel of 147 pharmacogenetics related genes and 8 SNPs in 44 patients who received less than 25% of initial dose during maintenance therapy due to MP intolerance. Next, significant genes identified in the first analysis were re-sequenced in a total of 287 patients. The relationship between mutation of each gene identified through sequencing and toxicity or dose of MP were analyzed.Results: As a result of the first stage analysis, 4 functionally interesting variants other than NUDT15 were selected (ABCC4, APEX1 , CYP1A1 ,and CYP4F2). Including these 4 variants, total 23 variants in 12 genes potentially linked to MP adverse reactions were selected as final candidates for subsequent analysis in 287 patients. The distribution of variant alleles were NUDT15 rs116855232 (20.7%), APEX1 rs2307486 (13.0%), ABCC4 rs2274407 (36.2%), ABCC4 rs3765534 (15.4%), ABCC4 rs11568658 (26.2%), CYP4F2 rs2108622 (54.5%), CYP1A1 rs4646422 (30.6%), SLCO1B1 rs11045879 (52.1%), SLCOB1 rs4149056 (27.0%), ITPA rs1127354 (25.6%), ITPA rs7270101 (0%), MTHFR rs1801131 (28.2%), MTHFR rs1801133 (68.3%), MTHFR rs1901133 (54.1%), GRIA1 rs4958351 (2.4%), MOCOS rs594445 (50.3%), PACSIN2 rs2413739 (9.4%), BAG3 rs78439745 (8.4%) and TPMT (* 1 / * 3C and *6, 3.1%). Grade 4 neutropenia (neutrophil<500/㎕) was observed in 177 patients (61.7%) during the administration of MP. When frequency of neutropenia during MP administration was crosstabulated with variant frequencies, the risk of neutropenia was 4.64 times higher in patients with T allele in ABCC4 rs3765534 (95% CI; 1.4 to 20.7, P=0.013). The cumulative incidence of neutropenia was significantly higher in patients with variant forms of APEX1 rs2307486 (AA:AG:GG=59.2%:66.7%:100%, P=0.005) (Figure 1). The cumulative incidence of neutropenia was also significantly increased in patients with NUDT15 rs116855232 mutations (CC:CT:TT=56.2%:73.6%:100%, P <0.001). According to the Cox regression analysis regarding neutropenia, GG genotype in APEX1 rs2307486 conferred a multivariate hazard ratio of 12.03 (95% CI; 1.4 to 101.2, P=0.022), and TT genotype in NUDT15 rs116855232 showed a hazard ratio of 11.42 (95% CI; 3.35 to 38.97, P <0.001). Comparing the average doses of MP used in the study, the T allele type of NUDT15 rs116855232 was significantly associated with a lower tolerated dose of MP as 61.7, 44.6, 20.1% of initially planned doses for CC, CT, and TT genotypes (P <0.001). However, MP doses by TPMT mutations were not significantly different in this study.Conclusion: This study revealed that genetic variations APEX1 increases the cumulative incidence of neutropenia associated with MP, and the variant allele in NUDT15 was related to MP intolerance. APEX1 and NUDT15 both contribute to cell protection from DNA damage or misincorporation, so alleles that impair the function of either gene may affect MP sensitivities, thereby inducing MP-related neutropenia. In Korean ALL patients, toxicity and tolerance of MP were more affected by APEX1 and NUDT15 than by TPMT, which has a lower variant allele frequency in Asian.Figure 1. Estimated cumulative incidence of mercaptopurine-related neutropenia according to the (A) APEX1 rs2307486 and (B) NUDT15 rs116855232 genotypes. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Access to Technology and Preferences for an mHealth Intervention to Promote Medication Adherence in Pediatric Acute Lymphoblastic Leukemia: Approach Leveraging Behavior Change Techniques.

BackgroundSuboptimal adherence to 6-mercaptopurine (6-MP) is prevalent in pediatric acute lymphoblastic leukemia (ALL) and associated with increased risk of relapse. Rapid uptake of personal technology makes mobile health (mHealth) an attractive platform to promote adherence.ObjectiveStudy objectives were to examine access to mobile technology and preferences for an mHealth intervention to improve medication adherence in pediatric ALL.MethodsA cross-sectional survey was administered in oncology clinic to parents of children with ALL as well as adolescents and young adults (AYAs) with ALL receiving maintenance chemotherapy.ResultsA total of 49 parents (median age [IQR] 39 [33-42] years; female 76% [37/49]) and 15 patients (median age [IQR] 17 [16-19]; male 80% [12/15]) participated. All parents and AYAs owned electronic tablets, smartphones, or both. Parents’ most endorsed mHealth app features included a list of medications (71%, 35/49), information about 6-MP (71%, 35/49), refill reminders (71%, 35/49), and reminders to take 6-MP (71%, 35/49). AYAs' most endorsed features included refill reminders (73%, 11/15), reminders to take 6-MP (73%, 11/15), and tracking 6-MP (73%, 11/15).ConclusionsParents and AYAs reported ubiquitous access to mobile technology and strong interest in multiple adherence-specific mHealth app features. Parents and AYAs provided valuable insight into preferred features for a multifunctional behavioral intervention (mHealth app) to promote medication adherence in pediatric ALL.

A case series of pediatric survivors of anaplastic pleomorphic xanthoastrocytoma.

BackgroundAnaplastic pleomorphic xanthoastrocytoma (APXA) is a rare subtype of CNS astrocytoma. They are generally treated as high-grade gliomas; however, uncertainty exists regarding the optimal therapy. Here, we report on 3 pediatric cases of APXA.MethodsOur institutional database was queried for cases of APXA and 3 cases were identified. Surgical samples were processed for methylation profiling and chromosomal microarray analysis. Methylation data were uploaded to the online CNS tumor classifier to determine methylation-based diagnoses to determine copy number variations (CNVs).ResultsTwo patients were male, 1 female, and all were aged 12 years at diagnosis. All underwent a gross total resection (GTR) and were diagnosed with an APXA. Immunohistochemical analysis demonstrated that 2 cases were BRAF V600E positive. Methylation-based tumor classification supported the APXA diagnosis in all cases. CNV analyses revealed homozygous CKDN2A deletions in all and chromosome 9p loss in 2 cases. All patients received radiation therapy (54 Gy in 30 fractions) with concurrent temozolomide. Two patients received maintenance chemotherapy with temozolomide and lomustine for 6 cycles as per the Children’s Oncology Group ACNS0423. The third patient recurred and went on to receive a second GTR and 6 cycles of lomustine, vincristine, and procarbazine. All are alive with no evidence of disease >4 years post-treatment completion (overall survival = 100%, event free survival = 67%).ConclusionsThe natural history and optimal treatment of this rare pediatric tumor are not well understood. This case series supports the use of adjuvant chemoradiotherapy in the treatment of APXA. The genetic landscape may be informative for optimizing treatment and prognosis.

Maintenance Chemotherapy with S-1 Following SOX Regimen Chemotherapy Improves Prognosis of Stage 3 Gastric Cancer After D2 Gastrectomy: A 5-Year Analysis.

ObjectiveTo assess the effectiveness and safety of treatment consisting of maintenance chemotherapy (MCT) with S-1 following S-1 plus oxaliplatin (SOX) chemotherapy for stage 3 gastric cancer (GC) after D2 gastrectomy.MethodsIn this retrospective study, we enrolled 255 patients with stage 3 GC who underwent D2 gastrectomy between February 2011 and May 2014. The SOX regimen chemotherapy was administrated to all of the patients as adjuvant therapy. The SOX regimen consisted of S-1 (for patients with a body surface area [BSA] of less than 1.25 m2, 80 mg/d; 100 mg/d for BSA=1.25 m2- <1.5 m2, and 120 mg/d for BSA≥1.5 m2, in 2 divided doses for 14 d) and oxaliplatin (130 mg/m2 given on Day 1), repeated every 21 d for 8 cycles. Following SOX chemotherapy, 122 of these patients received maintenance chemotherapy (the MCT group) with S-1, whereas 133 patients (the control group) received no MCT. The MCT consisted of S-1 (80, 100, or 120 mg daily based on BSA, in 2 divided doses for 14 d), repeated every 21 d for 8 cycles at most. The chemotherapy was discontinued if unacceptable toxicity or disease progression occurred or upon the request of the patient. All cases were followed up, and overall survival (OS), recurrence-free survival (RFS), and toxicities were compared.ResultsThe MCT group exhibited a distinctly higher 5-year OS (P=0.0425) and RFS (P=0.0479) than those of the control group. The incidence of hand-foot syndrome was markedly greater in the MCT group (P=0.0026). No toxicity-related death occurred.ConclusionMaintenance chemotherapy with S-1 following the SOX regimen chemotherapy provides significant survival benefit for stage 3 GC after D2 gastrectomy.