5-year EFS Research Articles

Integrated response analysis of pediatric low-grade gliomas during and after targeted therapy treatment.

Pediatric low-grade gliomas (pLGGs) are the most common central nervous system tumor in children, characterized by RAS/MAPK pathway driver alterations. Genomic advances have facilitated the use of molecular targeted therapies, however, their long-term impact on tumor behavior remains critically unanswered. We performed an IRB-approved, retrospective chart and imaging review of pLGGs treated with off-label targeted therapy at Dana-Farber/Boston Children's from 2010 to 2020. Response analysis was performed for BRAFV600E and BRAF fusion/duplication-driven pLGG subsets. Fifty-five patients were identified (dabrafenib n = 15, everolimus n = 26, trametinib n = 11, and vemurafenib n = 3). Median duration of targeted therapy was 9.48 months (0.12-58.44). The 1-year, 3-year, and 5-year EFS from targeted therapy initiation were 62.1%, 38.2%, and 31.8%, respectively. Mean volumetric change for BRAFV600E mutated pLGG on BRAF inhibitors was -54.11%; median time to best volumetric response was 8.28 months with 9 of 12 (75%) objective RAPNO responses. Median time to largest volume post-treatment was 2.86 months (+13.49%); mean volume by the last follow-up was -14.02%. Mean volumetric change for BRAF fusion/duplication pLGG on trametinib was +7.34%; median time to best volumetric response was 6.71 months with 3 of 7 (43%) objective RAPNO responses. Median time to largest volume post-treatment was 2.38 months (+71.86%); mean volume by the last follow-up was +39.41%. Our integrated analysis suggests variability in response by pLGG molecular subgroup and targeted therapy, as well as the transience of some tumor growth following targeted therapy cessation.

The Prognostic Effect of IKZF1 Deletions in ETV6::RUNX1 and High Hyperdiploid Childhood Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is the most prevalent childhood malignancy and recent cure rates approach 90% on first line therapy. IKZF1 deletions have been reported as an unfavorable prognostic factor and are rare in ETV6::RUNX1 and high hyperdiploid (HeH) ALL, the two cytogenetic subgroups with the most favorable prognosis. Due to its rarity, the prognostic effect of IKZF1deletions within this subset of patients remains unclear. Therefore, we assessed the prognostic impact of IKZF1deletions in 939 ETV6::RUNX1 and 968 HeH ALL patients. We performed this retrospective analysis on data of children and adolescents of 1-18 years with B-cell precursor ALL diagnosed in 1991-2016 and treated on one of 16 trials from 9 study groups, of which 6 were minimal residual disease (MRD) guided. Cytogenetic, fluorescence in-situ hybridization, and RT-PCR analyses of pre-treatment bone marrow samples to determine ploidy and fusion gene status were performed locally. Trials using MRD for risk stratification applied either PCR or flow cytometry analyses. The IKZF1 status was determined by multiplex ligation-dependent probe amplification by each individual study group. 3% of ETV6::RUNX1 (n=26) cases had an IKZF1 deletion; this affected survival adversely overall (5-year event free survival [EFS]: 79% vs. 92%, p = 0.02) (Table 1). However, in minimal residual disease (MRD) guided protocols, IKZF1 did not affect outcome in ETV6::RUNX1 cases ( 5-year EFS: 100% vs. 93%, p = 0.34) (Table 1). 9% of HeH cases had an IKZF1 deletion (n=85); this adversely affected survival overall (5-year EFS: 76% vs. 89%, p = 0.006), and in MRD-guided protocols (73% vs. 88%, p = 0.004) (Table 1). Multivariate cox regression showed that IKZF1deletions negatively affected survival independent of sex, age, and white blood cell count at diagnosis in HeH ALL (Hazard ratio of EFS [95% CI]: 2.00 [1.20-3.30]) (Table 1). As the prognostic effect of IKZF1 deletions has been shown to vary by MRD risk group, we examined the prognostic effect of IKZF1deletions in HeH cases with detectable MRD <5% at end of induction in more detail. Of these cases, 10% carried an IKZF1deletion (n=34) which negatively affected outcome (5-year EFS: 78% vs. 92%, p = 0.01) Multivariate cox regression showed that IKZF1deletions negatively affected survival independent of sex, age, and white blood cell count at diagnosis in this intermediate MRD HeH ALL (Hazard ratio of EFS [95% CI]: 2.90 [1.20-6.80]). However, cases with an IKZF1 deletion had significantly higher MRD values than their wild-type counterparts (p = 0.03, Figure 1). In conclusion, our analysis of a large composite cohort consisting of 16 trials shows that IKZF1deletions do not affect survival in ETV6::RUNX1 ALL when treated on MRD-guided protocols. In contrast, our data shows that in HeH ALL IKZF1deletions are associated with lower survival rates, higher relapse rates, and higher MRD values. Future results of current trials such as the ALLTogether will likely reveal whether risk stratification predominantly reliant on MRD is adequate for HeH patients or whether stratification by copy number alteration profile, including IKZF1 status, or by other methods would be more suitable. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Evaluation of High-Dose Cytarabine Induction Therapy and Flow Cytometric Measurable Residual Disease Monitoring for Children with De Novo Acute Myeloid Leukemia: A Report from the JPLSG-AML-12 Trial

Background: High-dose cytarabine (HDAC) in initial induction therapy has been tested in several clinical trials both in children and adults with acute myeloid leukemia (AML), however, the trial results are conflicting. In addition, there is growing evidence on significance of measurable residual disease (MRD) monitoring to predict subsequent relapse, but MRD in AML is still challenging in terms of methodology and quality control. In the nationwide clinical trial AML-12 by the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG), the hematological malignancy subgroup of the Japan Children's Cancer Group (JCCG), a role of HDAC in initial induction and feasibility and efficacy of central reference laboratory-based flow cytometric MRD (FCM-MRD) monitoring were evaluated in children with AML. Patients & Methods: JPLSG-AML-12 trial (registered as jRCTs041180128) was designed as a seamless phase II/III trial; because of a safety concern in HDAC induction, children (0-18 years old) with newly diagnosed de novo AML (excluding acute promyelocytic leukemia and AML in Down syndrome patients) registered in selected institutions were randomized to receive either standard ECM (etoposide, standard-dose cytarabine, and mitoxantrone) or experimental HD-ECM (etoposide, HDAC, and mitoxantrone) induction, while patients registered in non-selected institutions were non-randomly allocated to receive standard ECM; in the following phase III part, all the patients were randomized. FCM-MRD were measured at two time points [end of Induction-1 (EOI-1) and end of Induction-2 (EOI-2)] at either of the two central reference laboratories (Mie University or Kyoto University) but was not used to guide subsequent therapies. Following complete remission (CR) evaluation at EOI-2, patients achieving CR were allocated to either of the 3 risk groups and received post-remission chemotherapies; core-binding-factor standard risk (CBF SR), non-CBF SR, or high risk (HR) group. Only HR patients were allocated to receive allogeneic hematopoietic stem cell transplantation in first CR. Primary endpoints of the trial were 3-year EFS and positive FCM-MRD (≥0.1%) rate at EOI-1. Results: Total 359 eligible patients were registered at 102 institutions between 2014-2018. CR, 3-year EFS, and 3-year OS rates of all patients were 94.0%, 63.1% (95%CI, 57.9-67.9%), and 80.3% (95%CI, 75.8-84.1%), respectively. Among all, 324 patients were randomized (ECM, n=168; HD-ECM, n=156). Median follow-up period of these patients was 50.9 months (range, 0.2 - 84.7 months). No significant difference in outcomes were observed between the 2 arms; CR rates were 94.2% vs. 93.8% (p=0.998), 3-year EFS rates were 64.3% (95%CI, 56.5-71.0%) vs. 61.2% (53.1-68.4%) (p=0.551), 3-year OS rates were 84.4% (95%CI, 78.0-89.1%) vs. 75.3% (95%CI, 67.7-81.4%) (p=0.053), 3-year cumulative incidence of relapse were 28.6% (95%CI, 21.5-36.0%) vs. 30.9% (95%CI, 23.3-38.8%) (p=0.585), and 3-year non-relapse mortality rates were 0.9% (95%CI, 0.1-6.4%) vs. 1.8% (95%CI, 0.4-7.1%) (p=0.832). These outcome parameters were not different within each risk groups as well. FCM-MRD at EOI-1 was evaluated in 135 patients (80.4%) in the ECM arm and 127 patients (81.4%) in the HD-ECM arm; the positive FCM-MRD rates were 21.5% vs. 25.2% (p=0.575). Regarding grade 3 or higher adverse events (AEs) evaluated by CTCAE version 4 during Induction-1, disseminated intravascular coagulation was more frequent in the HD-ECM arm (1.8% vs. 6.4%, p=0.046), but no significant difference was observed for other AEs. Univariable Cox regression analysis for baseline characteristics revealed that the intermediate-risk cytogenetics and positive FLT3-ITD were significantly associated with decreased EFS rate. However, in multivariable analyses for EFS after EOI-1 and EOI-2, FCM-MRD was the sole poor prognostic factor; hazard ratios were 5.24 (95%CI, 3.19-8.63) (p<0.001) at EOI-1 and 5.56 (95%CI, 2.93-10.54) (p<0.001) at EOI-2. Conclusions: Although HDAC in initial induction did not improve the outcome of children with AML, overall outcomes were comparable to the recently completed pediatric AML trials worldwide. Central reference laboratory-based FCM-MRD measurement was feasible and MRD at both EOI-1 and EOI-2 were the most powerful prognostic factors to predict outcome of children with AML. Therefore, FCM-MRD should be included in future risk stratification for children with AML. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Outcomes of Non-Myeloablative HLA-Haploidentical Bone Marrow Transplant with Thiotepa and Post-Transplant Cyclophosphamide in Children and Adults with Sickle Cell Disease, a Phase II Trial: Vanderbilt Global Haploidentical Transplant Learning Collaborative (VGC2)

Introduction: Related reduced-intensity HLA-Haploidentical bone marrow transplant (haplo-BMT) expands the donor pool to approximately 90% of children and adults with sickle cell disease (SCD). In 2013, we developed the multi-institutional Vanderbilt Global Haploidentical Learning Collaborative to optimize haplo-BMT for SCD. In a Phase II clinical trial, we developed a protocol focused on improving engraftment rates by augmenting the original Hopkins haplo-BMT approach (Bolaños-Meade et al. Blood 2012) with thiotepa. We initially demonstrated durable engraftment in 93% (14/15) of participants (including 2 with previous graft rejection) and a 100% overall survival after a median follow-up of 13.3 months (de la Fuente et al. BBMT 2019). We present the results of our phase-II trial (ClinicalTrials.gov identifier NCT01850108). Material and methods: The trial opened in October 2013, and each site has a standalone Institutional Review Board-approved protocol with institutional-specific eligibility criteria and a data-sharing agreement with Vanderbilt University Medical Center. A DSMB assessed the aggregate results for participant safety and clinical trial futility. Collaborators met via videoconferencing initially weekly and then bi-weekly to discuss best practices. The common conditioning regimen included: thymoglobulin 4.5 mg/kg, thiotepa 10 mg/kg, fludarabine 150 mg/m2, cyclophosphamide 29 mg/kg and TBI 2Gy. Graft-versus-host disease (GVHD) prophylaxis included post-transplant cyclophosphamide 100 mg/kg, mycophenolate mofetil, and sirolimus. Bone marrow was the donor source and was primed with filgrastim (5-10 μg/kg/d x5 days) in 11% (9/80) of haploidentical donors. Primary and secondary graft failure was defined as <5% donor myeloid/lymphoid whole blood chimerism at Day>28 and >Day+28 (after initial engraftment), respectively. Primary endpoints were 1-year and 2-year EFS. Primary or secondary graft failure and death were considered events. Safety stopping rules were implemented, independent of age, based on graft failure, death, grade III or IV acute GVHD, or moderate or severe chronic GVHD. Local treating physicians classified the severity of chronic GVHD. Results: At the interim analysis of May 1, 2022, we report results from patients enrolled from 8/14/2014 - 2/28/2022. Final enrollment is a total of 80 participants from 7 sites, 45% were male. Donors were siblings (42.5%), parents (53.8%), daughters (2.5%) and cousins (1.3%); 83.8% (n=67) had sickle cell trait. Participants clinical and laboratory data are listed in table 1. Graft failure occurred in 12.5% (10/80) of the participants, with 4 primary and 6 secondary graft failures, table 2. All graft failures were in participants <18 years of age, and all had autologous reconstitution. For engrafted participants, the median whole blood chimerism values for D+180 and D+365 post-transplant was 100% (n=67; IQR: 99.8 - 100; Range 30.0 - 100) and 100% (n=50; IQR: 100 - 100; Range 95.0 - 100), respectively. Among engrafted participants, 97.7% (43/44) were off immunosuppression at D+365 post-transplant. The incidence of grades III-IV acute and moderate/severe chronic GVHD were 8.8% (7/80) each. The median follow-up time was 1.4 years, based on the time of graft failure, death, or May 1, 2022. Mortality was 5.0% (4/80), Table 2. A Kaplan-Meier analysis for survival found no difference by age group <18 years or >18 years of age (p=0.760). Kaplan-Meier based probability of overall survival was 96.7% (95% CI 87.1% - 99.2%) at one year and 94.3% (95% CI 83.0% - 98.2%) at two years. Results of the final analysis of primary and secondary endpoints (1- and 2-year EFS) will be submitted for publication after all participants have been followed for a minimum of one year (anticipated 2/23). Conclusion: Our Vanderbilt Global Haploidentical learning collaborative is a successful and efficient approach to sharing best practices and implementing curative therapy for SCD. After 8 years, we have shown low mortality rate and 100% engraftment in adults using our haplo-BMT regimen. Three new research questions have emerged in the consortium: 1. What strategies can we develop to address the high graft failure in children? 2. How can we optimize supportive care practices and minimize severe infectious complications in adults? 3. What are the heart, lung, kidney, and other late-health effects after curative therapy? Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Targeting Hyperactivated Lck in PAX5 Rearranged Pediatric B-Cell Precursors Acute Lymphoblastic Leukemia

Despite intensive risk-based treatment protocols, 15% of pediatric patients with B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) experience relapse. There is urgent need of novel strategies to target poor prognosis subgroups. We considered 135 B-other cases consecutively enrolled in Italy in the AIEOP-BFM ALL2000/R2006 protocols without recurrent genetic rearrangements and excluding Down syndrome and High Hyper Diploid cases. By integrating gene expression, copy number analyses and fusion genes discovery by target-capture NGS, we identified 59 patients (43·7%) having a Ph-like signature; in addition to ERG-related (26%), High Hyperdiploid-like (17%), ETV6::RUNX1-like (8·9%), MEF2D-rearranged (2·2%) or KMT2A-like (1·5%). CRLF2 rearrangements were almost exclusively found in the Ph-like group, and also the IKZF1-plus profile was prevalent in Ph-like cases (8/9) and associated with a poor outcome (5-year EFS (SE) 37·5% (17·1) vs. 65·5% (7·0) for non-IKZF1-plus cases). Interestingly, PAX5 gene lesions were mostly associated with the Ph-like signature, with CNAs and translocations in 43/131 B-other patients (32·8%), with 31/57 (54·3%) in Ph-like and 12/74 (16%) in non-Ph-like cases. Notably, all the 7 PAX5t were found in the Ph-like group. EFS (p<0·001) and OS (p=0·009) analyses according to the fusion classes reveal statistical significance in Ph-like cases, classified accordingly to different class fusions, such as ABL/JAK-class, PAX5-class, other fusions and negative cases after NGS analysis. In fact, the PAX5t cases have a poor EFS, similar to ABL/JAK-class patients (53% and 50%, respectively) and lower than Ph-like cases negative for any fusion gene (78%). Moreover, PAX5t OS was inferior compared to ABL/JAK-class and negative cases (about 53% vs. 83·3% and 88·9%). These features of PAX5t cases prompted us to explore the feasibility of targeting this aberration. By applying the NetBID2 data-driven network interference algorithms, we constructed the BCP-ALL interactome and identified the hub drivers' activity (DA) based on network gene interaction on either PAX5 translocated patients versus all BCP-ALL excluding Ph-like or versus Ph-like. We also assessed a Differential Expression (DE) of genes belonging to these pathways. Interestingly, in the top NetBID2 drivers we identified the LCK signaling factor showing a significantly higher activity in PAX5t compared to other BCP-ALL subgroups. Furthermore, analysis of LCK activity in BCP-ALL patients with known PAX5 status revealed that it is an exclusive signature of PAX5t cases. Moreover, 22 genes resulted with a positive driver activity in PAX5t vs. Ph-like (p<0.05) and bioinformatic analysis to identify drug approved interactions found 7 targetable genes, including LCK. As previously showed by us, we demonstrated the efficacy of the LCK-inhibitor Nintedanib, as single agent or in combination with conventional chemotherapy, both ex-vivo and in a patient-derived xenograft model, showing a synergistic effect with dexamethasone. We herewith applied a wider ex-vivo drug screening with 174 FDA-approved drugs, by comparative cellular viability of different sub-groups of leukemia PAX5t samples and control-B-lymphoblastoid cell lines (CTR-B-LCSs) in addition to NALL-1 cell lines (carrying PAX5/ETV6 fusion), measured by ATP-Glo based luminescent based assay after exposure of the depicted drugs, whereas Staurosporin was taken as a positive control. Drug sensitivity scores (DSS) are plotted as a clustered heat map, followed by unsupervised hierarchical clustering. From the drug screening, we selected Dasatinib, Bosutinib and Foretinib, known to be among the top 10 most potent LCK ligands. Here we demonstrated their efficacy in PAX5t cases by evaluating the differential DSS, i.e., by avoiding toxicity in CTR-B-LCSs. This study provides new insights in the pathogenic mechanisms of poor risk Ph-like leukemia and identifies a potential novel therapy for targeting the PAX5t group. Moreover, in general this study opens the scenario to target LCK kinase activity in further BCP-ALL subgroups.

Prognostic Factors and Outcomes of Adolescent and Adult Burkitt Lymphoma and Leukemiafrom a Low-Middle Income Country: An Experience from Hematology Cancer Consortium

The treatment of BL/L has evolved on the principles of short-course, intensive, non-cross resistant, alternating chemotherapy. These intensive high-dose methotrexate-based treatment regimens (CODOX-M/IVAC, Hyper-CVAD, BFM, LMB) have led to high response rates and cures in a significant proportion of children and young adults. The addition of rituximab has led to overall survival benefit. There is limited data that dose adjusted EPOCH-R provides a low intensity treatment option for patients who may not be able to tolerate high-dose methotrexate-based regimens. Efficacy of these regimens in real-world, more so in an LMIC setting need to be evaluated given the delays in seeking care, higher risk of treatment-related complications including infections and antecedent treatment interruptions. This retrospective multicentric study collected the data from eight-member centers of Hematology Cancer Consortium (www.hemecancer.org) using an electronic database, to analyze the clinical characteristics, treatment patterns, outcomes and prognostic factors in adolescent and adult newly diagnosed Burkitt lymphoma and leukemia diagnosed between 2012-2019 (including HIV positive). Patients who had received more than 2 weeks of chemotherapy or steroids prior to presentation were excluded. The data included demographic details, performance status (ECOG), HIV serology, bone marrow and CNS involvement, stage, treatment type, use of rituximab, response to treatment, and treatment-related mortality as assessed by the investigator of the respective centre. The primary objective was to evaluate event-free survival at 2 years. Secondary objectives were to evaluate the overall survival, impact of the treatment protocol, use of rituximab, stage, age, performance status, CNS involvement, and HIV positive status on the overall and event-free survival. A total of 312 patients were included in this study. Out of these 257 patients received treatment and were analyzed for the outcome and prognostic factors. The treated and untreated cohorts differed in age [ median age 37 years (range-25-49 years) versus 42 years (range-32-51 years); with the untreated cohort being older. Table 1 provides the baseline characteristics of the patients who received treatment. The HIV positive patients (in treated cohort) had higher LDH [median - 967.5 (range, 509- 2355) vs 589 (311-1141), p=0.003). A total of 100 (42%) patients received intensive and high-dose methotrexate-based chemotherapy, 81 (34%) patients received dose-adjusted EPOCH-based treatment whereas 56 (24%) received other low-intensity or palliative chemotherapy. Patients with HIV were largely treated with a dose-adjusted EPOCH-based regimen (25/32 patients). Patients who received a high-dose methotrexate-based regimen were younger than those who received dose-adjusted EPOCH and other lower intensity regimens (Mean age 29 years versus 42.4 and 43.9 years) At the median follow-up of 36.5 months, the 2-year EFS was 61% and 2-year OS was 73%. There was no significant difference in outcomes in HIV-positive and negative patients. On univariate analysis lack of use of rituximab and use of protocols other than high-dose methotrexate and dose-adjusted EPOCH negatively affected EFS and OS. Age had an adverse impact on the OS but not EFS whereas stage 2 or above had a negative impact on EFS. On multivariate analysis use of regimens other than high-dose methotrexate-based and dose-adjusted EPOCH was a negative prognostic factor for both EFS and OS. The HR favored high dose methotrexate and dose-adjusted EPOCH-based regimen for both EFS and OS; HR- 0.42 (95% CI,0.22,0.77) and 0.27(95% CI,0.13-0.59), respectively. Use of rituximab was associated with better OS HR-0.44(95% CI,0.21-0.93) and a trend toward better EFS - HR-0.58 (95%CI, 0.31-1.07). The treatment-related mortality was 11.2% (29/257) and high serum LDH was associated with higher mortality (p=0.003). Treatment of adolescent and adult Burkitt lymphoma and leukemia with intensive regimens (high-dose methotrexate-based) and dose-adjusted EPOCH regimen resulted in similar survival. Dose-adjusted EPOCH-based regimen was preferred in older patients. The use of rituximab in these patients adds to the overall survival benefit. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Robust Long Non-Coding RNA Expression Classifier for Risk Stratification in Pediatric AML

Introduction: Risk stratification in pediatric acute myeloid leukemia (pAML) is required to determine length and intensity of consolidative therapy. The present scheme employed by COG is complex, relying on numerous upfront cytogenetic and molecular assays along with induction response assessment by flow cytometry to determine final risk status. lncRNAs expression has been reported as a predictive marker in adult AML but has not been comprehensively evaluated in the pediatric population. Methods: We assayed 68 normal bone marrow (NBM) specimens, 1298 de novo AML cases from Children's Oncology Group (COG) studies and 96 adult AML cases from SWOG Cancer Research Network trials by RNA-seq to enumerate annotated lncRNAs. After updating all pAML cases to modern risk criteria, data were split by blocked randomization by key molecular groups into training, two pediatric validation (60, 20, and 20% of cases, respectively) and an adult validation set. Differentially upregulated lncRNA identified in the training set compared to NBM controls were used to establish a regularized Cox proportional hazards model of EFS; model coefficients from significant lncRNA features were used to calculate a 37-gene lncScore. Survival associations between lncScore and outcomes were tested by Kaplan Meier estimates and the log-rank test. Predictive performance was assessed by concordance testing. Results: We identified 1346 differentially expressed lncRNA transcripts in comparison of training set pAML to NBM; 647 were upregulated, among which 37 showed a significant survival association. lncScores calculated as the weighted sum of expression by application of these model coefficients to expression data showed nearly equal numbers of patients with positive and negative values in the training cohort (range -1.24 to +1.31), motivating dichotomizing cases by positive or negative lncScore for further analysis. Training set cases with positive lncScores had 5-year EFS and OS rates of 26.7 and 42.7% compared to 56.9 and 76.3% with negative lncScores (hazard ratio, HR, 2.48 and 3.16, p<0.001). Pediatric validation cohorts and an adult AML group yielded comparable results both in lncScore distribution as well as magnitude and significance of outcome effects (pediatric OS HR = 2.87 and 3 respectively, p < 0.001 and EFS HR = 2.38 and 2.36, p < 0.001; adult OS HR=3.21, p < 0.001, EFS HR=2.36, p < 0.001). lncScore remained independently prognostic in multivariable models of pediatric cases including key factors in pre-treatment risk (training set HR 2.07, 1.84, and 1.82 for OS, EFS, and RR from EOI1, all p < 0.001). Concordance statistics exceeded 66% for each survival metric (OS: 0.7, EFS 0.667, RR 0.679). Comparable results were observed in the combined pediatric validation group, (HR OS: 1.75, P=0.001, C-stat 0.672; EFS: 1.56, P=0.001, C-stat 0.671; RR: 1.67, P=0.004, C-stat 0.689). Estimates of the concordance difference between sub-models containing traditional classification compared to lncScore showed negligible differences (p range 0.15 - 0.51) suggesting that the lncScore provides comparable accuracy to current pre-therapy classification metrics. Subgroup analysis suggested that lncScores provide additional outcome information in heterogenous subgroups currently classified as indeterminate risk, such as KMT2A-rearranged (Figure 1). To test whether lncScores could replace or augment a modern stratification scheme, we compared lncScore to final risk (which includes traditional cytogenetic/molecular and induction response). Point estimates for HR were slightly higher by lncScore than final risk, with all CIs showing substantial overlap. Comparison of single term sub-models in both training and validation groups showed similar trends, slightly favoring lncScore, but with non-significant concordance differential estimates. (Validation set HR for OS 3.41 vs 3.19, C-index diff -0.004, p=0.867, Validation set DFS HR 2.44 vs 2.16, C-index diff -0.014, p=0.483). As with initial risk features, a full model containing final risk and lncScore outperformed either alone, with significant p-values in both possible comparisons (Validation p-value range 0.008 - <0.001, Table 1). Conclusion: Inclusion of the lncScore enhances predictive power of traditional stratification in pAML with potential, as a single assay, to replace these complex stratification schemes with comparable predictive accuracy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

RADT-37. THE OUTCOMES OF INTRACRANIAL GERM CELL TUMOR PATIENTS WITH CHORIOCARCINOMA COMPONENT AND/OR Β-HCG HIGHER THAN 500IU/L UNDER RADIOTHERAPY-BASED TREATMENTS

Abstract BACKGROUND In the previous studies, intracranial germ cell tumor (iGCTs) patients with pure choriocarcinoma or mixed germ cell tumors containing choriocarcinoma components showed similar dismal prognoses with median overall survival of 22 months and a one-year survival rate around 60%. However, those conclusions need update since radiotherapy, a milestone for this disease, was not applied to many patients in the published reports. Patients and METHODS Clinical data of iGCTs patients with histologically confirmed choriocarcinoma component and/or β-HCG &amp;gt; 500IU/L were collected from the archive of our institute and studied retrospectively. RESULTS Totally, 76 patients were eligible for the study. 11 patients took surgery as initial treatment, followed by chemoradiotherapy in terms of treatments. Sixty-one patients initiated their treatments with chemotherapy. Among them, twelve patients received second-look surgery due to residue disease. Subsequently, all received radiotherapy except for two early deaths. Four patients received radiotherapy initially, followed by chemotherapy. The median follow-up time was 63 months. The 5-year EFS and OS were 81.5% and 84.1%, respectively. Among patients who did not suffer from early death or progressed disease after induction chemotherapy (n = 68), multivariate analysis found chemotherapy cycles ( &amp;gt; 4 vs ≤ 4) (Hazard ratio [HR] for EFS 0.156, p = 0.021; HR for OS 0.110, p = 0.032), β-HCG level ( &amp;gt; 3000IU/L vs ≤ 3000IU/L) (HR for EFS 4.512, p = 0.052; HR for OS 6.604, p=0.028), and intertumoral hemorrhage (Yes vs No) (HR for EFS 23.177, p = 0.006; HR for OS 12.173, p = 0.081) were independent factors for survival. While radiation field (CSI vs non-CSI) was not proved to be a prognostic factor, either for EFS or OS. CONCLUSIONS iGCTs patients with choriocarcinoma component or β-HCG &amp;gt; 500IU/L showed improved survival with radiotherapy-based treatments. Patients with higher β-HCG levels and hemorrhage had a poorer prognosis. More chemotherapy cycles could bring additional survival benefits.

P019: Unfavorable prognostic value of the predominance of THRLBCL-like histopathological growth patterns in nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL)

Introduction: NLPHL is characterized by variable morphology and histopathological growth patterns of the tumor substrate. Our study demonstrated the prognostic significance of THRLBCL-like histopathological growth patterns. Purpose: to evaluate the efficacy of 1st line therapy of NLHLP depending on THRLBCL-like histopathological growth patterns in the tumor substrate. Materials and Methods: We analyzed the results of 1st line therapy in 150 patients with NLHLP from 2010 to 2021 yrs. Growth patterns without THRLBCL-like sites were noted in 87/150 (58%), THRLBCL-like patterns - in 63/150 (42%). Additionally, patients with a predominance of THRLBCL-like areas (more than 50% of the cut area) were identified - 32/150 (21%) pts. Results: In 87 (58%) pts with growth patterns without THRLBCL-like areas, 30/87 (34%) pts did not receive chemotherapy; radiation therapy was applied in 20/30 (complete remission (CR) was achieved in all 20 pts); observation after surgical treatment - 10/30 pts; 5 pts - no data. Chemotherapy (R-ABVD - 44%; R-BEACOPP-14–38%; other - 17% pts) was performed in 52/87 (60%) pts; CR was achieved in 68/87 (78%). In 63 (42%) pts with THRLBCL-like patterns, 2/63 (3%) did not receive chemotherapy; 1 patient - in CR after radiation therapy; 1 - under observation after surgical treatment; 4 patients - no data. Chemotherapy (R-ABVD - 18%; R-BEACOPP-14–54%; R-CHOP - 21%; other - 7% pts) received 57/63(90%) pts; CR was achieved in 31/63(49%) pts, partial remission (PR) - in 15/63(24%), stabilization (S) - 2(3%), progression - 4(6%) pts. In 32 (21%) pts with predominance of THRLBCL-like areas, 30 pts underwent chemotherapy (R-ABVD - 16%; R-BEACORP-14–57%; R-CHOP- 27% pts); CR was achieved in 12 (37%), PR-10 (31%), S-1 (3%), progression - 4 (13%) pts. In 2 pts - no data. The 5-year OS for groups with the absence, presence and predominance of THRLBCL-like patterns was 99%, 100%, 68% (p-<0.0001), respectively, the 5-year EFS was 75%, 68%, 32% (p-< 0.0001) respectively. Median follow-up is 34 months. Conclusion: In NLHLP the group of patients with a predominance of THRLBCL-like patterns has the most unfavorable prognosis - CR achieved in 37%, 5-year OS does not exceed 68%, EFS - 32%. Therefore an intensification of first-line therapy is needed for this group of patients.

ALL-237 Bortezomib and Rituximab in De Novo Adolescent/Adult CD20-Positive, Ph-Negative Pre-B-Cell Acute Lymphoblastic Leukaemia: Updated 3-Year Results

CD20 expression in B-cell precursor acute lymphoblastic leukemia (B-ALL) is associated with inferior outcomes. Treatment approaches involve the incorporation of rituximab (variable doses and scheduling between trials), intensification of chemotherapy, and allogeneic stem cell transplant in patients who continue to remain MRD- positive post-induction. Treatment intensification with chemotherapy or allogeneic stem cell transplantation for EOI MRD-positive patients is limited in resource constraint areas due to cost and infection-related morbidity and mortality. Hence, there is an unmet need to identify active and safe drugs to improve EOI MRD negative rates which can reduce the need for transplant and chemotherapy intensification. To test the activity of bortezomib and rituximab in combination with a pediatric-inspired regimen during induction therapy in newly diagnosed adolescents and adults (aged >14 years) with CD20 positive, Philadelphia-negative precursor B-ALL. Here we present updated results with longer follow up. Single-center, phase 2, nonrandomized open-label trial (Simon's two-stage design) conducted between December 2017 and August 2019. The primary endpoint of the study was the rate of (end of induction) EOI BM-MRD negativity. Secondary endpoints were EFS and OS. A total of 35 patients were enrolled between December 2017 and August 2019. EOI MRD negative rates were 70.1% compared with 51.7% in a historical cohort treated with chemotherapy. On longer follow up (median follow up 38months), 3-year EFS and OS rates were 75.6% (95% CI 62.3-91.9%), and 75.6% (95% CI 62.3-91.9%) respectively. 3-year rates of EFS based on post-induction (week 4) MRD status was 55.6% (31-99.7%) in MRD positive group compared with 86.1% (72.7-100%) in MRD negative group. 3-year rates of OS based on EOI MRD status was 55.6% (31-99.7%) in MRD positive group compared with 86.1% (72.7-100%) in MRD negative group. The median OS for patients who attained CR was not reached versus 8 months in patients who fail to achieve CR. On longer follow-up, the activity of the combination of bortezomib and rituximab is maintained without any new safety concerns. EOI MRD positivity and lack of complete remission post-induction are strong predictors of poor outcomes.

Shifting gears to differentiation agents in acute promyelocytic leukemia with resource constraints—a cohort study

Background Treatment of acute promyelocytic leukaemia has emerged as a major success in hemato-oncology. While literature from the developed world boasts of outstanding outcomes, there is a paucity of data from the developing world. This study aimed to assess complications and outcomes of acute promyelocytic leukaemia in a resource-constrained setting. Methods We retrospectively collected data from patients diagnosed with APL from January 2016 to December 2020. Results Sixty-four patients were treated-32 in both the Sanz high and low-risk groups. In the Sanz low-risk group, 12.5% of patients received ATRA with daunorubicin and 81.25% received ATRA with ATO. In the Sanz high-risk group, 18.8% of patients received ATRA with daunorubicin, 34.3% received ATRA with daunorubicin and ATO while 40.6% received ATRA with ATO. 56.25% of patients developed differentiation syndrome. The incidence was higher in Sanz high-risk group as compared to Sanz low-risk group. 57.4% of patients had an infection at the time of presentation. 62.5% of patients developed neutropenic fever during treatment. 17.2% of patients developed pseudotumor cerebri. The 4-year EFS and OS were 71.25 and 73.13%, respectively. Sanz low-risk group had a better 4-year EFS and OS as compared to the Sanz high-risk group. Haemoglobin at presentation and Sanz high-risk group were associated with poorer outcomes with a hazard ratio of 0.8 and 3.1, respectively. Outcomes in high-risk patients were better with the use of ATRA + ATO + daunorubicin. Conclusion In the Indian population, APL patients have a high incidence of differentiation syndrome, pseudotumor cerebri, and infections during induction. CR, EFS, and OS compared to the developed world can be achieved with optimal therapy. Low haemoglobin at presentation and Sanz high-risk group were associated with poorer outcomes. ATRA, ATO, and daunorubicin combination is the preferred protocol for treating high-risk patients.

PB1947: ELTROMBOPAG COMBINED WITH IST AS A MULTICENTER STUDY OF THE FIRST LINE TREATMENT OF CHILDREN WITH SAA.

Background: Eltrombopag and Improved Hematopoiesis in Refractory Aplastic was published in the New England Journal of Medicine in 2012 The research found that Eltrombopag monotherapy showed significant hematologic reaction in adult patients with refractory SAA, of which 44%(11/25) patients had clinically significant hematologic performance. Important progress has also been made in the treatment of SAA with Eltrombopag combined with IST: A nonrandomized, historically-controlled study funded by the NHLBI intramural Research Program of the National Institutes of Health compared the efficacy and safety of conventional IST therapy with Eltrombopag in combination with IST for SAA. The research results were published in Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia in 2017 in the New England Journal of Medicine. In this study, a total of 92 SAA patients aged 2 years and above were enrolled, and the results showed that the overall effective rate and complete response rate of Eltrombopag combined with IST in the treatment of SAA were higher than that of traditional IST standard treatment. However, there is no research on Eltrombopag therapy for children SAA in China. The aim of this study was to improve the hematologic response rate and quality, and to prevent late complications such as recurrence and clonal progression, by adding Eltrombopag to standard IST therapy. Aims: To evaluate the efficacy and safety of attriboma combined with IST as first-line treatment for SAA patients, and to study the clonal transformation and the incidence of PNH cloning in attriboma combined with IST patients. Methods: This study was a non-randomized, multi-center, historical controlled study, with traditional IST standard therapy as the historical control. All patients in the experimental group received “IST+ Attribopal” combined therapy, in which ATG dose was 3.5mg. Kg-1.d-1 for a total of 5 days. The initial dose was 1.25 mg · kg-1 · d-1 for 2-5 years old children, 37.5mg · d-1 for 6-11 years old, 75mg · d-1 for 12-18 years old, and continued for 6 months. A total of 31 children were included in the Altrupalpa group and 136 in the historical control group. Results: There were no differences in gender, severity of disease, co-infection before ATG, co-infection within 1 month after ATG, incidence of serum disease, CD3, CD4, CD8, TREG cell count, hemoglobin level, platelet count, neutrophil count and ferritin level between the attripopa group and the historical control group. In terms of the effective rate, the effective rate of attriboma group was 62.5% vs 68.8% (P= 0.548) in June and 86.4% vs 76%(P=0.285) in September, showing no statistical significance. Among them, neutrophil count recovery was better in the attriboma group than in the historical control group at 1 month, 3 months, 6 months, 9 months and 12 months after the application of ATG, the difference was statistically significant (P < 0.05), while platelet and hemoglobin recovery was not different. 2-year EFS 80.4% VS 83.4% (P=0.799) and 2-year OS 93.3% VS 91.3% (P=0.548) in the attriboma group and the historical control group. None of the patients with clone transformation or PNH clone were found in all the follow-up of attriboma group. Summary/Conclusion: There was no difference in infection rate, serum disease rate and overall effective rate between the two groups within 1 month, but the neutrophil count level of the attriboma groups was better than that of the historical control group.

Abstract 3479: UBTF tandem duplications (UBTF-TD) in childhood AML: Enrichment in FLT3-ITD and association with clinical outcome

Abstract Childhood AML is an aggressive disease with high rates of failures and poor survival. We have demonstrated that the molecular landscape of AML in children is distinct, and co-occurrence of variants modulate outcomes. Recent discovery of tandem duplication (TD) of the UBTF gene in AML, with enrichment in FLT3-ITD has implicated yet another mutation whose cooperation with FLT3-ITD may modify outcome. Here, we provide a comprehensive evaluation of UBTF-TD in de novo AML and define its clinical implications within FLT3-ITD patients. Initial interrogation of transcriptome data from 1,158 children enrolled on COG AAML1031 identified 50 cases of UBTF-TD (4.3%). Overwhelming majority of UBTF-TD cases were observed in FLT3-ITD cases (77%), vs. that of 1.2% in those without FLT3-ITD (p&amp;lt;0.001). Given extreme enrichment of UBTF-TD in FLT3-ITD, we inquired whether cooperation of UBTF-TD and FLT3-ITD creates a distinct clinical entity. To this end we screened diagnostic DNA from 400 FLT3-ITD patients treated on three consecutive CCG/COG trials (COG AAML1031, COG AAML0531, and CCG-2961) by PCR and fragment analysis. UBTF-TD was identified in 61 FLT3-ITD cases (15.3%). The data presented here forth focuses on evaluation of implications of UBTF-TD in FLT3-ITD positive patients only. Within the FLT3-ITD patients, initial correlation of UBTF-TD with demographics, disease characteristics, and associated genomic variants was conducted. Patients with and without UBTF-TD had a similar median age at diagnosis (p=0.322), lower diagnostic WBC (p=0.010) and higher marrow blast % (p&amp;lt;0.001). There was a stark paucity of cooperating variants that commonly co-occur with FLT3-ITD, with a single NPM1 mutation (1.6% vs. 29%, p&amp;lt;0.001) and no NUP98 fusions (0% vs. 23%, p&amp;lt;0.001). There was a significant enrichment of WT1 mutations, with 45% UBTF-TD patients with a WT1 mutation (FLT3-ITD/UBTF-TD/WT1), vs. 11% in UBTF-WT (p&amp;lt;0.001). Trisomy 8 (Tri8) was seen in 15% of UBTF-TD. Patients with UBTF-TD had a lower CR rate (44% vs. 60%, p = 0.018), and Higher MRD rate (38% vs. 21%, p&amp;lt;0.001). Patients with and without UBTF-TD had an EFS of 28% vs. 42% (p=0.047) with a corresponding OS of 40% and 57% (p=0.019). Given enrichment of WT1 mutations and Tri8 in patients with UBTF-TD, we studied the outcome UBTF-TD patients in the context of these two variants. FLT3-ITD/UBTF-TD/WT1 patients had a 5-year EFS of 17% vs. 38% for similar patients without WT1 mutations (p=0.0062). Patients with UBTF-TD with additional Tri8 had a similarly poor outcome with an EFS of 23% with a corresponding OS of 33%, providing a distinct high risk UBTF-TD cohort (+WT1 or Tri8), whereas the remaining UBTF-TD patients had a more favorable outcome with EFS and OS of 64% and 86%, respectively (p&amp;lt;0.0001, and p&amp;lt;0.0001). UBTF-TD is a novel genomic entity with high enrichment in patients with FLT3-ITD and a distinct clinical outcome driven by cooperating WT1 mutation and Tri8. Citation Format: Leila Robinson, Amanda Leonti, Todd A. Alonzo, Yi-Cheng Wang, Michele S. Redell, Rhonda E. Ries, Jenny L. Smith, Tiffany A. Hylkema, Quy Le, E Anders Kolb, Richard Aplenc, Xiaotu Ma, Jeffrey Klco, Katherine Tarlock, Soheil Meshinchi. UBTF tandem duplications (UBTF-TD) in childhood AML: Enrichment in FLT3-ITD and association with clinical outcome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3479.

Abstract CT004: Product attributes of axicabtagene ciloleucel (axi-cel) that associate differentially with efficacy and toxicity in second-line large B-cell lymphoma

Abstract Background: Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for the treatment of relapsed or refractory large B-cell lymphoma after ≥2 lines of systemic therapy. ZUMA-7, a global Phase 3 randomized study, showed superiority of axi-cel over standard second-line therapy (N=359; event-free survival [EFS] HR 0.398, P&amp;lt;.0001; median EFS 8.3 vs 2 months; estimated 2-year EFS 41% vs 16%; objective response rate [ORR] 83% vs 50%, Locke et al. N Engl J Med. 2021). Here we report axi-cel pharmacokinetics (PK), pharmacodynamics (PD), and product attributes associated with ZUMA-7 clinical outcomes. Methods: Samples from patients who received axi-cel (n=170) were analyzed. PK, PD, and axi-cel T-cell composition (naive, CCR7+CD45RA+; differentiated, CCR7-) were assessed for associations with safety and efficacy using previously described methodologies (Neelapu et al. NEJM. 2017; Locke et al. Blood Adv. 2020). Results: The median (Q1, Q3; n=162) peak CAR T-cell level, time to peak, and area under the curve within the first 28 days of treatment (AUC0-28) were 25.8 cells/μL (8.2, 57.9), 8 days (8, 9), and 236.2 cells/μL*days (76.4, 758.0), respectively. CAR T-cell peak and AUC0-28 correlated with higher ORR (P=.0224 and .0054, respectively) and increased Grade (Gr) ≥3 neurologic events (NEs; P=.0006) but not with durability of response (P=.4894). Rapid transient increases in serum analytes, including granzyme B, ferritin, IL-6, IL-10, CXCL-10, IL-15, ICAM-1, and GM-CSF, occurred early (median peak ≤7 days) and were associated with increased Gr ≥3 NEs and Gr ≥3 cytokine release syndrome (CRS; P&amp;lt;.05). Infusion products richer in naive-like T cells expressing CD27 and CD28 associated with increased EFS, ORR, and complete response (P&amp;lt;.05). In contrast, infusion products richer in differentiated T cells (CCR7-) and with lower % of CCR7+CD45RA+ T cells associated with higher postinfusion peak levels and AUC0-28 of several proinflammatory and immunomodulatory serum analytes (eg, IL-15, ferritin, IFN-γ). Increased rates of Gr ≥3 NEs were found in patients who received axi-cel richer in CCR7- T cells (above median: 30% vs below median: 10%). Similarly, a trend of higher rates of Gr ≥3 NEs and CRS were observed in patients who received axi-cel that secreted higher levels of IFN-γ in co-culture with CD19-expressing targets. Conclusions: Preinfusion axi-cel features and postinfusion PK/PD profiles in the randomized phase 3 ZUMA-7 trial were associated with safety and efficacy outcomes and supported that optimizing product composition towards a juvenile T-cell phenotype (CCR7+CD45RA+) may improve axi-cel therapeutic index. These findings could result in future trials to evaluate if preemptive interventions, including enrichment of naive T cells in the product, could improve outcomes. [SF and SV contributed equally] Citation Format: Simone Filosto, Saran Vardhanabhuti, Miguel Canales, Xavier Poiré, Lazaros J. Lekakis, Sven de Vos, Craig A. Portell, Zixing Wang, Christina To, Paul Cheng, Justin Chou, Adrian Bot, Rhine Shen, Jason R. Westin. Product attributes of axicabtagene ciloleucel (axi-cel) that associate differentially with efficacy and toxicity in second-line large B-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT004.

LGG-32. Integrated biologic, radiologic and clinical analysis of pediatric low-grade gliomas during and after targeted therapy treatment

BACKGROUND: Pediatric low grade gliomas (pLGGs) are the most common central nervous system tumor in children, characterized by driver alterations in the RAS and MAPK pathways. Genomic advances have facilitated use of molecular targeted therapies, however their long-term impact on tumor behavior remains critically unanswered. METHODS: We performed an IRB-approved, retrospective chart and imaging review of pLGGs treated with off-label targeted therapy at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center from 2010 to 2020. Volumetric analysis was performed for BRAFV600E and BRAF fusion/duplication driven pLGG subsets. RESULTS: Fifty-five patients were identified (dabrafenib n = 15, everolimus n = 26, trametinib n = 11, and vemurafenib n = 3). Targeted agent was used as first or second-line therapy for 58% (32/55). Median duration of targeted therapy was 0.79 years (0.01 – 4.87), and overall median follow-up was 2.50 years (0.01 – 7.39). The 1-year, 3-year, and 5-year EFS from targeted therapy initiation were 62.1%, 38.2%, and 31.8%, respectively. Mean volumetric change for BRAFV600E mutated pLGG on BRAF inhibitors was -54.11%, and median time to best volumetric response was 8.28 months (n = 12). Median time to largest volume post-treatment was 2.86 months. Mean volumetric change for BRAF fusion/duplication pLGG on MEK inhibitors was +7.34% with median time to best volumetric response of 6.71 months (n = 7). Median time to largest volume post-treatment was 2.38 months. CONCLUSIONS: Our integrated clinical and volumetric data suggest the majority of patients receiving BRAF inhibitors or trametinib achieve reduction in tumor volume while on therapy and that tumor stability can be achieved following targeted therapy cessation. Moreover, volumetric analysis shows promise as a tool to assess targeted therapeutic response in pLGGs.

A phase II trial of a chemotherapy-free combination of ponatinib and blinatumomab in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).

7009 Background: Ponatinib and blinatumomab are highly active in Ph+ ALL. A chemotherapy-free combination of these agents may lead to durable remissions and reduce the need for stem cell transplant (SCT) in first remission. Methods: In this phase II study, adults with newly diagnosed (ND) Ph+ ALL, relapsed/refractory (R/R) Ph+ ALL, or CML in lymphoid blast phase (CML-LBP) received up to 5 cycles of blinatumomab. Ponatinib 30mg daily was given during cycle 1 and decreased to 15mg daily once a complete molecular response (CMR) was achieved. After completion of blinatumomab, ponatinib was continued for at least 5 years. All patients (pts) received 12 doses of prophylactic IT chemotherapy. Results: Between 2/2018 and 1/2022, 55 pts were treated (35 ND, 14 R/R and 6 CML-LBP). Baseline characteristics and responses are shown in Table. Among 23 pts with ND Ph+ ALL evaluable for response, 22 (96%) achieved CR/CRi; 1 pt had early death due to myelosuppression from prior chemotherapy. Among 13 evaluable pts with R/R Ph+ ALL, 12 (92%) achieved CR/CRi. The CMR rates for the ND, R/R and CML-LBP cohorts were 64%, 71%, and 17% after cycle 1 and were 85%, 79%, and 33% overall, respectively. In the ND cohort, 4/17 evaluable pts (24%) achieved CMR in the peripheral blood within 1 week, and 9/15 (60%) within 2 weeks. The median follow-up is 11 months (range, 1-46+ months). Among the 35 pts in the ND cohort, 33 pts (94%) are alive and in continuous remission. Only 1 pt in the ND underwent SCT in first remission (due to persistent MRD positivity), and no relapses have been observed. The 2-year EFS and OS rates in the ND cohort are 93%. Among the 13 responding pts in the R/R cohort, 6 (46%) underwent SCT. The 2-year EFS and OS rates for the R/R cohort are 42% and 61%, and for the CML-LBP cohort are 33% and 60%, respectively. Most side effects were grade 1-2 and were consistent with the known toxicity profile of the two agents individually. Two pts discontinued ponatinib due to toxicity (1 due to stroke and 1 due to DVT). One pt discontinued blinatumomab due to recurrent neurotoxicity. Conclusions: The chemotherapy-free combination of ponatinib and blinatumomab was safe and effective in Ph+ ALL and CML-LBP. Longer follow-up continues to demonstrate durable remissions, particularly in ND Ph+ ALL, even without SCT in first remission. Clinical trial information: NCT03263572. [Table: see text]

Survival of patients with neuroblastoma before versus after reduction of therapy due to the change in age cut-off from 12 to 18 months in Children’s Oncology Group (COG) risk stratification.

10013 Background: In 2006, COG reclassified subgroups of toddlers diagnosed with neuroblastoma from high-(HR) to intermediate-risk (IR), when the age cut-off for increased risk was raised from 365 days (12 mo) to 547 days (18 mo) (London, J Clin Onc 2005). The aim of this retrospective study was to determine if excellent outcome was maintained after a reduction of therapy. Methods: Children &lt; 3 yrs old at diagnosis, enrolled on a COG biology study from 1990-2018, were eligible (n = 9,189). Therapy was reduced for two “cohorts of interest” based on the age cut-off change: 365-546 days old with INSS stage 4, MYCN not amplified, favorable INPC, hyperdiploid tumors (12-18mo/Stage4/FavBiology); and, 365-546 days old with INSS stage 3 tumors with non-amplified MYCN and unfavorable INPC (12-18mo/Stage3/NotAmp/UnfavINPC). Log rank tests compared event-free (EFS) and overall survival (OS) curves. Results: In the cohorts of interest, patient (pt) characteristics were similar for ≤2006 vs &gt; 2006. For 12-18mo/Stage4/FavBiology, 5-year EFS and OS (± std error) before (≤2006; n = 40) versus after (&gt; 2006; n = 55) the reduction in therapy were similar: 89±5.1% versus 87±4.6% (p = 0.7), and 89±5.1% versus 94±3.2% (p = 0.4), respectively (Table). For 12-18mo/Stage3/NotAmp/UnfavINPC, the 5-year EFS and OS were both 100%, before (n = 6) and after (n = 4) 2006. For the combined cohorts for ≤2006 versus &gt; 2006, EFS and OS were 91±4.4% versus 88±4.3% (p = 0.6), and 91±4.5% versus 95±2.9% (p = 0.5), respectively. Within HR pts diagnosed ≤2006, EFS/OS were 91±4.4%/91±4.5% for (12-18mo/Stage4/FavBiology plus 12-18mo/Stage3/NotAmp/UnfavINPC) vs 38±1.3%/43±1.3% for all other HR pts &lt; 3 yrs old (p &lt; 0.0001; Table). Within IR pts diagnosed &gt; 2006, EFS/OS were 88±4.3%/95±2.9% for (12-18mo/Stage4/FavBiology plus 12-18mo/Stage3/NotAmp/UnfavINPC) vs 88±0.9%/95±0.6% for all other IR pts &lt; 3 yrs old (p = 0.9). Conclusions: Our 19 year study demonstrates that excellent outcome is maintained among toddlers with Stage4/FavBiology and Stage3/Not Amp/Unfav INPC neuroblastoma with a significant reduction of therapy from high- to intermediate-risk treatment. Importantly, pts were likely spared acute toxicity and late effects known to be associated with HR therapy. Efforts to identify additional pt cohorts who may not require HR therapy to achieve long-term survival are critical to improve the long-term health of children with neuroblastoma. [Table: see text]

Impact of diagnostic and end-of-induction Curie scores in tandem autologous hematopoietic cell transplant for patients with high-risk neuroblastoma: A report from the Children’s Oncology Group.

10027 Background: Diagnostic mIBG (meta-iodobenzylguanidine) scans are an integral component of response assessment in children with high-risk neuroblastoma. The role of end of induction (EOI) Curie Scores (CS) has been previously described in patients undergoing a single autologous hematopoietic cell transplant (AHCT) as consolidation therapy. We now examine the prognostic significance of CS in patients randomized to tandem or single AHCT on the Children’s Oncology Group (COG) trial ANBL0532. Methods: A retrospective analysis of mIBG scans obtained from patients enrolled in COG ANBL0532 (n = 652) was performed. Evaluable patients (n = 179) had mIBG-avid, International Neuroblastoma Staging System (INSS) stage 4 disease, did not progress during induction therapy, consented to consolidation randomization, and received either a single (n = 99) or tandem AHCT (n = 80). In addition, evaluable patients had paired mIBG scans at time of initial diagnosis and EOI. Optimal CS cut points maximized the outcome difference (≤ vs &gt; CS cut-off) according to the Youden index. Log-rank tests compared EFS subgroups, with p &lt; 0.05 considered statistically significant. 3-year EFS is presented ± standard error. EFS was estimated for relative reductions in CS of 50% and 75% from diagnosis to EOI. Results: For recipients of tandem AHCT, the optimal cut point at diagnosis was CS = 12, with superior EFS from study enrollment for patients with CS&lt;12 (74.2±7.9%; n = 31) vs CS &gt; 12 (59.2±7.1%; n = 49) (p = 0.002). At EOI, the optimal cut point was CS = 0, with superior EFS from EOI for patients with CS = 0 (72.9±6.4%; n = 48) vs CS &gt; 0 (46.5±9.1%; n = 32) (p = 0.002). The cut point at diagnosis for recipients of single AHCT was CS = 21 (p = 0.04), while the EOI CS had an optimal cut point of 2, but without a significant difference in EFS (p = 0.29). Absolute CS at diagnosis and at EOI had a greater impact on outcome than the relative reduction in CS between diagnosis and EOI, for both single and tandem AHCT. Conclusions: In the setting of tandem transplantation for children with high-risk neuroblastoma, Curie scores at diagnosis and end-induction may identify a more favorable patient group. Patients treated with tandem AHCT who exhibited a CS&lt;12 at diagnosis or CS = 0 at EOI had superior EFS compared to those with CS above these cut points. Similar to prior reports, a CS&lt;2 was the optimal cut point for single transplant recipients. Clinical trial information: NCT00567567.

Risk-adapted local therapy and intensive chemotherapy in patients with high-risk rhabdomyosarcoma.

10031 Background: Outcomes for patients with metastatic RMS remain poor. Dose escalation of radiation may reduce risk of local failure, and maintenance therapy has prolonged survival in intermediate risk patients. We investigated a multimodal chemotherapeutic regimen with risk adapted local therapy and the addition of maintenance therapy following intensive chemotherapy to improve the outcome for patients with high-risk RMS. Methods: We conducted a phase 2 multi-center trial for patients with newly diagnosed high-risk (stage 4) RMS. Patients received 54 weeks of chemotherapy (vincristine/irinotecan, interval compressed vincristine/doxorubicin/cyclophosphamide and ifosfamide/etoposide, and vincristine/dactinomycin/cyclophosphamide) followed by 4 cycles of anti-angiogenic maintenance therapy (bevacizumab, sorafenib, cyclophosphamide). Primary tumor local control consisted of surgery and photon/proton radiation therapy (RT) dependent on the degree of resection (negative margin – no RT, positive margin – 36 GyRBE, unresected ≤5cm – 50.4 GyRBE, unresected &gt; 5cm – 59.4 GyRBE). RT was administered at Week 4 or 20 based on size/location, and to radiographically visible (non-CR) sites of metastatic disease at end of treatment. Results: Thirty-nine eligible patients with high-risk RMS (64% FOXO1 fusion positive, 74% with nodal disease, 67% Oberlin score &gt; 1) were enrolled. Two of 13 patients with Oberlin score ≤ 1 were FOXO1 fusion positive whereas 23 of 26 patients with Oberlin score &gt; 1 were fusion positive. Seventeen patients received maintenance therapy as planned (progression, n = 12; received alternate maintenance regimen, n = 4; other, n = 6) with a median of 4 cycles (range 1-4). Common toxicities of maintenance included palmar-plantar erythrodysesthesia (n = 9), rash (n = 7), and cystitis (n = 6). At a median follow-up of 43.5 months for survivors, 3-year EFS was 29.5% (95% CI 15.4-45.1%). Fusion positive status significantly predicted EFS (negative, 60.6% vs. positive, 9.6%, p = 0.019), whereas low Oberlin score approached significance for EFS (≤1, 56.6% vs. &gt; 1, 16.4%, p = 0.064). The cumulative incidence of local failure was 17.5% (95% CI 6.9-32.2%). Twenty-one patients achieved CR of all metastatic sites and did not receive metastatic site RT. Of those, 7 experienced disease recurrence in a pre-existing metastatic soft tissue site. Among 4 patients who received metastatic site RT at the end of treatment, one patient experienced disease recurrence in a pre-existing metastatic site. Conclusions: The addition of maintenance therapy to intensive chemotherapy and risk adapted radiotherapy did not improve EFS in this population. Consolidative radiation should be considered for soft tissue metastatic sites regardless of radiographic response. Clinical trial information: NCT01871766.

Racial, ethnic, and socioeconomic survival disparities among children with high-risk neuroblastoma treated on upfront Children’s Oncology Group clinical trials.

10005 Background: Racial and socioeconomic disparities have not been comprehensively investigated in high-risk neuroblastoma (HR NBL). Prior Children’s Oncology Group (COG) investigations have demonstrated population-based disparities in late relapse rates among Black children, and trial-based disparities in relapse and survival among children living in poverty receiving post-consolidation immunotherapy. It is unknown whether these disparities persist in upfront trials for newly diagnosed patients. We leveraged COG data to investigate race, ethnicity, and socioeconomic disparities in a cohort of children with HR NBL treated on upfront clinical trials from 2007-2016. Methods: Retrospective cohort study of children enrolled on upfront COG HR NBL trials ANBL0532, ANBL09P1, and ANBL12P1. Race and ethnicity were the primary exposures categorized as: Black Non-Hispanic (BNH); Hispanic; Other Non-Hispanic (ONH); or White Non-Hispanic (WNH). Poverty was the secondary exposure, defined as household (public insurance only vs others), area (census-defined high-poverty ZIP code with &gt;20% of population living below 100% Federal Poverty Level (FPL) vs &lt;20% below 100% FPL), and rural (Census-defined rurality measures linked to ZIP code). Overall (OS) and event-free (EFS) survival from time of trial enrollment were plotted by Kaplan-Meier methods; associations with race/ethnicity and poverty were evaluated by log-rank tests. Results: Among 696 children, 16% were BNH, 11% Hispanic, 4% ONH, and 69% WNH. One-third (33%) of children were household poverty-exposed, 26% area poverty-exposed, and 15% rural-exposed. Tumor stage and biology did not differ by race/ethnicity or poverty measures. Five-year OS differed significantly by race/ethnicity (47% Hispanic vs. 50% ONH vs. 61% WNH vs. 62% BNH; p=0.047). Five-year OS was inferior among children exposed to household-poverty (53% vs. 63%; p=0.036) and neighborhood-poverty (54% vs. 62%; p=0.050) compared to unexposed children. There was no difference in OS by rurality. Similar directionality in 5-year EFS outcomes by race/ethnicity and poverty were observed without statistical significance. Conclusions: Race/ethnicity and poverty-exposure are associated with inferior OS outcomes among children with HR NBL despite uniform planned treatment on upfront COG trials. Investigation of mechanisms driving these disparities, including disparate early phase trial enrollment are ongoing to inform targeted health equity interventions to improve outcomes.