ABSTRACT:Langerhans cell histiocytosis (LCH) and non-Langerhans cell (non-LC) histiocytosis are rare neoplastic diseases with variable behavior. Although chemotherapy is often effective, some patients respond poorly to treatment, experience disease recurrence and/or develop long-term complications. Clofarabine (Clolar), a deoxyadenosine analog, has shown encouraging activity in histiocytic disorders. Here, we report a prospective, multicenter, phase 2 study evaluating the efficacy and toxicity of clofarabine in recurrent/refractory (R/R) LCH (stratum 1) and non-LC histiocytosis (stratum 2). All participants received clofarabine on days 1 through 5 of each 28-day cycle. Response was assessed after 2 cycles; participants without evidence of disease progression received 4 additional cycles. A total of 25 participants enrolled: 20 in stratum 1 and 5 in stratum 2. In stratum 1, 17 of 20 participants (85%; 95% confidence interval [CI], 62%-97%) were responders, and 3 had stable disease after cycle 2. Overall, 19 stratum-1 participants completed 6 cycles; 1 withdrew after cycle 3. No stratum-1 participants progressed during treatment and 3 had disease recurrence after cycle 6, resulting in 2-year progression-free survival ± standard error and overall survival of 89% ± 7% and 100%, respectively (n = 20; median follow-up, 40.9 months [range, 2.7-49.4]). In stratum 2, 3 of 4 evaluable participants (75%; 95% CI, 19%-99%) had partial response. Overall, 20 of 25 (80%) of participants had ≥1 grade ≥3 toxicity attributed to protocol therapy. In conclusion, clofarabine is active and tolerable in children with R/R LCH and warrants further study in patients with non-LC histiocytosis. Further study of clofarabine in these populations is warranted. This trial was registered at www.clinicaltrials.gov (#NCT02425904).

The Pediatric Hodgkin Consortium (PHC) hypothesized that increasing chemotherapeutic dose-density for Hodgkin lymphoma (HL) they could increase the complete response rate among favorable risk patients with HL after 8 weeks of Stanford V compared to 8 weeks of VAMP. This would translate to a decrease in patients who required radiation therapy (RT) to achieve a cure. HOD08 (NCT00846742) was a phase II multicenter investigator-initiated single- arm trial for patients ≤ 21 years of age with previously untreated stage IA or IIA HL without mediastinal bulk or extranodal disease extension and fewer than three sites of disease. Treatment consisted of a modified 8-week Stanford V regimen (vinblastine, doxorubicin, vincristine, bleomycin, mechlorethamine, etoposide and prednisone). Modified tailored field RT was administered only to disease sites achieving less than a CR. The primary objective was to increase CR rate after 8 weeks of chemotherapy by at least 20% (from an estimated 44% to 64%) compared to patients treated on a previous trial (HOD99). HOD08 enrolled 85 patients with HL and 72 were evaluable for the primary objective of whom 55 (76.4%) achieved a CR at all sites and did not receive RT. The 5-year event-free survival (EFS) and overall survival (OS) rates for the entire cohort were 87.4% (95% confidence interval (CI) 80.4%-95.0%) and 98.7% (95% CI 96.2%-100%), respectively. A dose-dense modified Stanford V regimen reduced the proportion of low-risk pediatric patients with HL who received RT while maintaining excellent outcomes. NCT00846742

BACKGROUND:Limited data inform the outcomes of patients with high-risk neuroblastoma (HR-NBL) who relapse after high-dose chemotherapy, autologous stem cell transplantation (ASCT), and external beam radiotherapy (EBRT). METHODS:This is a multi-institutional retrospective study of 84 patients with HR-NBL diagnosed between 1997-2021 with a first recurrence after definitive upfront treatment, including ≥1 ASCT and EBRT. Site(s) of first relapse were defined with relation to a patient's primary tumor location. Progression-free survival (PFS) and overall survival (OS) outcomes were analyzed using Kaplan-Meier curves and log-rank tests. Cox proportional hazard models were used for univariate and multivariable analyses. RESULTS:Twenty-four patients had local recurrences with or without distant relapses (LR) and 60 had distant relapses only. The LR cohort had higher rates of MYCN amplification (70% vs. 36%, p = 0.016). At relapse, the LR cohort had lower rates of additional radiotherapy (32% vs. 61%, p = 0.029) and higher rates of additional surgery (29% vs. 5%, p = 0.005), with similar rates of chemotherapy for both cohorts. With a median follow-up after first relapse of 1.53 years (range: 0.03-15.82), there were no significant differences in interval PFS and OS between the cohorts. After controlling for age at diagnosis and pattern of recurrence, time to interval relapse ≥ 2 years was a significant predictor of improved OS (HR: 0.50, 95% CI: 0.29-0.85, p = 0.011). CONCLUSIONS:Patients with relapsed HR-NBL have poor outcomes with median OS < 2 years. Time to relapse was a significant predictor of OS.

10018 Background: The AEPA/CAPDac (brentuximab vedotin, etoposide, prednisone, doxorubicin [cumulative dose = 160mg/m 2 ], cyclophosphamide, brentuximab vedotin, prednisone, and dacarbazine) regimen results in excellent EFS and OS rates for pediatric cHL but resulted in 65% of patients requiring RNRT using metabolic and anatomic response criteria. We aimed to determine if use of a metabolic-only response assessment would allow omission of consolidative prednisone and RNRT for the majority of high-risk patients while maintaining a high EFS. Methods: cHOD17 is an open-label, single-arm, multicenter, phase 2 trial with a stratum for patients ≤25 yrs of age at diagnosis of high-risk (stage IIB, IIIB, or IV), CD30+ cHL. 18 FDG-PET only (rather than + anatomic) was used to guide therapy following 2 cycles of AEPA [adapted from the HLHR13 trial (NCT01920932), without mandated growth factor] at the early response assessment (ERA). Complete (CMR) and inadequate metabolic responses (IR) were defined as Deauville ≤3 and ≥4, respectively. Patients in overall CMR received 4 CADac cycles without prednisone or RNRT. IR patients received 4 CAPDac (with prednisone) followed by consolidative IR site directed RNRT (25.5 Gy). The primary objective was to estimate EFS utilizing this approach. Results: 114 patients were enrolled at 7 institutions from January 2019 to February 2024. Median (range) age at diagnosis was 16.4 (6.7-24.1) yrs and follow-up 2.5 (0.4-5.7) yrs. Most (79.8%) were nodular sclerosing histology. Stages included 22.8% IIB, 16.7% IIIB, 20.2% IVA, and 40.4% IVB. One patient discontinued therapy due to treatment-related toxicity and was unavailable for response assessment. Of 113 remaining, 69 (61.1%) achieved a CMR at ERA and were spared RNRT and glucocorticoids during the CAPDac cycles. The 2-yr EFS was 94.7% (95% CI: 90.3%-99.4%) and OS 100% (95% CI: 100%-100%). Five of six relapses ( < 3 mo (N = 1), 3-12 mo (N = 2), and > 12 mos (N = 3) following therapy) occurred in individuals with an IR. The most frequent grade ≥3 toxicities were lymphopenia (84.2%) and neutropenia (91.2%). Grade 3 and 4 febrile neutropenia occurred in 21.1% and 1%, respectively. Neuropathy grade ≥3 was not observed. Serious adverse events were rare (n = 4) and included: multi-organ failure during cycle 1 that recovered (n = 2), therapy-related myeloid leukemia in remission following allotransplant (n = 1), and infection-related death during allotransplant for relapse (n = 1). Conclusions: A metabolic-only response assessment in the AEPA-CAPDac regimen results in high rates of omission of consolidative RT and glucocorticoids while limiting cumulative anthracycline exposure and maintaining excellent 2-year EFS of 94.7% and OS of 100%. Clinical trial information: NCT03755804 .

Background: Prognosis for patients with high -risk neuroblastoma (HR-NBL) is guarded despite aggressive therapy, and few studies have characterized outcomes after radiotherapy in relation to radiation treatment fields. Methods: Multi -institutional retrospective cohort of 293 patients with HR-NBL who received autologous stem cell transplant (ASCT) and EBRT between 1997 -2021. LRR was defined as recurrence at the primary site or within one nodal echelon beyond disease present at diagnosis. Follow-up was defined from the end of EBRT. Event -free survival (EFS) and OS were analyzed by Kaplan -Meier method. Cumulative incidence of locoregional progression (CILP) was analyzed using competing risks of distant -only relapse and death with Gray 's test. Results: Median follow-up was 7.0 years (range: 0.01 -22.4). Five-year CILP, EFS, and OS were 11.9 %, 65.2 %, and 77.5 %, respectively. Of the 31 patients with LRR and imaging review, 15 (48.4 %) had in -field recurrences ( >12 Gy), 6 (19.4 %) had marginal failures ( <= 12 Gy), and 10 (32.3 %) had both in -field and marginal recurrences. No patients receiving total body irradiation (12 Gy) experienced marginal -only failures (p = 0.069). On multivariable analyses, MYCN amplification had higher risk of LRR (HR: 2.42, 95 % CI: 1.06 -5.50, p = 0.035) and post -consolidation isotretinoin and anti-GD2 antibody therapy (HR: 0.42, 95 % CI: 0.19 -0.94, p = 0.035) had lower risk of LRR. Conclusions: Despite EBRT, LRR remains a contributor to treatment failure in HR-NBL with approximately half of LRRs including a component of marginal failure. Future prospective studies are needed to explore whether radiation fields and doses should be defined based on molecular features such as MYCN amplification, and/or response to chemotherapy.

Purpose/Objective(s) This prospective phase II trial was designed to assess disease control and late effects following proton radiotherapy in children and young adults with non-metastatic Ewing Family of Tumors (EFT) or other bone sarcomas and non-rhabdomyosarcoma soft tissue sarcomas (NRSTS). Materials/Methods Sixty-nine pediatric and young adult patients (age<30) with NRSTS or bone sarcomas were enrolled between September 2006 and July 2016. Chemotherapy and surgery were administered to patients in accordance with current standard practices or according to co-enrollment on cooperative group protocols. Results Median follow-up was 7.7 years (range 0.4-15.7). 39 patients had EWS sarcoma, 5 patients had osteosarcoma, and 25 patients had other histologies. Eight-year overall survival (OS), event-free survival (EFS), local regional control (LC), and distant control (DC) rates for the whole cohort were 77.5%, 67.2%, 82.1%, and 87.9%, respectively and 81.0%, 76.8%, 92.3%, and 89.7% for EWS and 73.2%, 56.5%, 69.7%, and 86.3% for other histologies. The median age at the time of radiation therapy was 12.3 years (range 1-22). The most common primary tumor locations were head and neck (42%); abdomen/pelvis (26%) and paraspinal (23%). Seventy percent of patients had gross residual disease at the time of radiotherapy. The median radiation dose was 55.8GyE (range 41.4-72). Patients with a GTR had no difference in EFS (8-year: 69.9% vs 65.8%, p = 0.9) or LC (8-year: 74.7% vs 85.3%, p = 0.4). The non-significant relationship between surgical extent and EFS/LC did not change across histology (among EWS, 8-year EFS was GTR: 85.7% vs STR 75.0%, p = 0.6 and 8-year LC was GTR: 85.7% vs STR 93.8%, p = 0.5; among all other histologies, 8-year EFS was GTR: 64.3% vs STR 49.2%, p = 0.6 and 8-year LC was GTR: 71.4% vs STR 68.8%, p = 0.8). Eight-year follow-up toxicity assessments showed 22 patients (31.9%) with at least one grade 2 toxicity and 13 patients (18.8%) with at least one grade 3 toxicity, both at least partially attributable to radiation therapy. There were no grade 4 toxicities reported. Conclusion Eight-year OS, EFS, LC, and DC rates were similar to those observed in comparable studies of photon radiation. Proton radiation represents a safe and effective radiation modality for pediatric non-rhabdomyosarcoma bone and soft tissue sarcomas.

A 6-week-old boy is brought to the hospital for fussiness and abdominal distension. He was febrile on presentation and was admitted to the hospital for further evaluation. On subsequent examinations, he continued to demonstrate abdominal distension and tenderness to palpation. Ultrasonography of the abdomen was performed and revealed a heterogeneous liver mass. With further diagnostics, a diagnosis was made and treatment initiated, with the infant experiencing resolution of his symptoms. Our panel of experts first discuss the management of an infant with abdominal distension, then discuss the evaluation of a liver mass in an infant, including oncologic, vascular, and infectious etiologies.

Background: Improving risk stratification of patients with Hodgkin lymphoma (HL) allows for optimization of treatment allocation and minimization of late effects when possible. The Childhood Hodgkin International Prognostic Score (CHIPS) was developed as a predictive model for event-free survival (EFS) in pediatric and adolescent HL using clinical data at diagnosis from patients with intermediate-risk HL treated on Children's Oncology Group protocol AHOD0031 (NCT00025259) with doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide (ABVE-PC) chemotherapy and response-adapted radiation. Stage IV, large mediastinal mass, albumin <3.5 g/deciliter, and fever were identified as independent predictors of EFS and assigned one point each, resulting in CHIPS ranging from 0 to 4. CHIPS was highly predictive of EFS in this patient cohort, but has not been validated in high-risk patients or in patients treated with other therapeutic regimens. We aim to validate the CHIPS as a risk stratification tool for patients with intermediate or high-risk HL treated with Stanford V chemotherapy by the Pediatric Hodgkin Consortium (PHC). Methods: The PHC trial HOD99 (NCT00145600) enrolled patients on the high-risk arm with stage IIB, IIIB, or IV disease <22 years (n=123). HOD05 (NCT00352027) enrolled patients with intermediate-risk HL with stage IB, IA or IIA with “E” lesions, ≥3 nodal sites, or bulky mediastinal adenopathy, or IIIA disease <22 years (n=49). All patients received 12 weeks of Stanford V chemotherapy with doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, and prednisone followed by low-dose, response-adapted radiation therapy. All patients with absent B symptoms were deemed afebrile; patients missing documentation of any elements of CHIPS were excluded from the analysis. Results: Our final analysis included a total of 164 patients, 116 with high-risk HL from HOD99 and 48 with intermediate-risk HL from HOD05. One patient was excluded for missing fever data and 7 were excluded due to missing albumin values. Patients were classified into 2 groups based on their CHIPS value: CHIPS 0-1 (n=88, 53.7%) and CHIPS 2-4 (n=76, 46.3%). The EFS for patients in the CHIPS 0-1 and CHIPS 2-4 groups was analyzed using Kaplan-Meier curves (Figure 1). The 2-year EFS estimates for patients with CHIPS 0-1 and CHIPS 2-4 were 95.5% (95% confidence interval (CI) 91.2%-99.9%) and 80.3% (95% CI 71.8%-89.7%), respectively, with a log-rank p-value of 0.003. Similarly, the 4-year EFS estimates for patients with CHIPS 0-1 and CHIPS 2-4 were 93.2% (95% CI 88.0%-98.6%) and 77.6% (95% CI 68.7%-87.6%), respectively, with a log-rank p-value of 0.004. The reduced EFS in patients with higher CHIPS is consistent across different stages and early response assessment (Table 1). Conclusions: CHIPS is highly predictive of EFS in pediatric and adolescent patients with intermediate and high-risk HL treated with Stanford V chemotherapy, as it identifies a subset (CHIPS 2-4) with significantly lower EFS compared to the other subset (CHIPS 0-1). Assessment of CHIPS alongside novel approaches such as circulating tumor DNA and total metabolic tumor volume should be analyzed across trials to allow for further enhancements to risk stratification for pediatric, adolescent and young adult HL.

In 2007, the Pediatric Hodgkin Consortium (PHC) published the results of a trial using combined modality therapy with vinblastine, doxorubicin, methotrexate, and prednisone (VAMP) and involved-fi eld radiation (IFRT) for pediatric patients with low-risk Hodgkin lymphoma (HL) between 1990 and 2000. 1 This trial (HOD90) included both patients with classical HL (cHL) and those with nodular lymphocyte – predominant Hodgkin lymphoma (NLPHL). Analysis of event-free survival (EFS) rate was performed based on the number of sites of disease at diagnosis. This revealed an inferior 10-year EFS rate of 80% for patients with ≥ 3 sites of disease compared with a 10-year EFS rate of 92.7% for patients with <3 sites of disease. 1 These data formed the basis for risk strati fi cation in subsequent PHC trials, which incorporated a restriction of <3 sites of disease for patients at low risk. 2 However, evolution in our understanding of the biology of NLPHL and increasing use of targeted therapies has led to the exclusion of patients with NLPHL from contemporary frontline clinical trials for cHL. 3 Given the superior outcomes for patients with NLPHL compared with those with cHL on HOD90 (10-year EFS of 100% for the NLPHL cohort vs 85.4% for those with cHL) 1 and the preponderance of patients with NLPHL with 1 or 2 sites of disease, 1 we hypothesized that the number of sites may be less predictive of the outcome among patients with cHL who otherwise met the criteria for low-risk disease. We performed an analysis of HOD90 trial data to assess for the prognostic signi fi cance of the number of sites of disease in cHL

Purpose/Objective(s) In high-risk neuroblastoma (HRNBL), locoregional relapse (LRR) is a significant contributor to treatment failure despite intensive multimodal therapy, including radiotherapy (RT). A recent Children's Oncology Group study found no benefit to boost RT for gross residual disease. Thus, we sought to characterize patterns of LRR after RT for patients (pts) with HRNBL. Materials/Methods The Institutional Review Boards approved this multi-institutional retrospective cohort study of pts who received ≥1 autologous stem cell transplant (ASCT) and external beam RT for HRNBL from 1997-2021. Pts who progressed prior to ASCT were excluded. LRR was defined as recurrence at the primary site or within one nodal echelon beyond disease present at diagnosis. In-field and marginal recurrences were defined as sites receiving >12 Gy and ≤12 Gy, respectively. Follow-up (FU) was from end of RT. Event-free survival (EFS) and overall survival (OS) were analyzed by Kaplan-Meier method. Cumulative incidence of locoregional progression (CILP) was analyzed using competing risks of distant-only relapse, secondary cancer, and death with Gray's test. Results We identified 311 pts with median age at diagnosis of 3.0 years (range: 0.02-28.7). The most common primary site was adrenal/abdominal (n=280, 90.0%). 271 (87.1%), 126 (40.5%) and 240 (77.2%) pts had metastatic disease at diagnosis, MYCN amplification, and unfavorable histology, respectively. 108 pts (34.7%) received proton RT. Of the 167 (53.7%) pts who underwent tandem ASCT, 68 (40.7%) received TBI-based conditioning. No pts received TBI after 2012. Of the 115 (37.0%) pts with subtotal resection (STR), 54 (47.0%) received ≥36 Gy. 202 (65.0%) received post-Consolidation anti-GD2 immunotherapy. Median FU was 6.5 years (range: 0.01-22.4). For the cohort, 5-year CILP, EFS and OS were 10.8%, 66.7% and 78.9%, respectively. After STR, ≥36 Gy did not decrease 5-year CILP (11.8% vs. 13.1%, p=0.80). 5-year CILP was significantly lower for pts receiving immunotherapy (6.4% vs. 21.5%, p<0.001). For pts receiving immunotherapy, 5-year CILP was similar for photon and proton RT (6.1% vs. 6.6%, p=0.78). Of the 29 pts with LRR and imaging for review, 13 (44.8%) were in-field only, 6 (20.7%) were marginal only, and 10 (34.5%) were both in-field and marginal. In pts receiving immunotherapy, 4 LRRs were in-field only, 3 were marginal only, and 4 were both in-field and marginal with 6/7 (85.7%) marginal recurrences occurring at sites of disease present at diagnosis with complete response after induction chemotherapy. Conclusion LRR contributes to treatment failure in HRNBL with most occurring in-field. CILP was lower for pts receiving immunotherapy and there was no difference in CILP between photon and proton RT. In pts receiving immunotherapy, approximately 25% of LRRs were marginal only. Future studies are needed to examine the optimal RT fields and dose in the era of anti-GD2 immunotherapy.

PURPOSE Brentuximab vedotin, an effective anti-CD30 antibody-drug conjugate approved for use in adults with classical Hodgkin lymphoma (HL), was introduced in this frontline trial to reduce prescribed radiation in children and adolescents with classical HL. METHODS Open-label, single-arm, multicenter trial for patients (age ≤ 18 years) with stage IIB, IIIB, or IV classical HL was conducted. Brentuximab vedotin replaced each vincristine in the OEPA/COPDac (vincristine, etoposide, prednisone, and doxorubicin/cyclophosphamide, vincristine, prednisone, and dacarbazine) regimen according to GPOH-HD2002 treatment group 3 (TG3); two cycles of AEPA and four cycles of CAPDac. Residual node radiotherapy (25.5 Gy) was given at the end of all chemotherapy only to nodal sites that did not achieve a complete response (CR) at the early response assessment (ERA) after two cycles of therapy. Primary objectives were to evaluate the safety and efficacy (complete remission at ERA) of this combination and the 3-year event-free (EFS) and overall survival (OS). The trials are registered at ClinicalTrials.gov (identifier: NCT01920932). RESULTS Of the 77 patients enrolled in the study, 27 (35%) achieved complete remission at ERA and were spared radiation. Patients who were irradiated received radiation to individual residual nodal tissue. At a median follow-up of 3.4 years, the 3-year EFS was 97.4% (SE 2.3%) and the OS was 98.7% (SE 1.6%). One irradiated patient experienced disease progression at the end of therapy and now remains disease free more than 6 years following salvage therapy, and one unexpected death occurred. Only 4% of patients experienced grade 3 neuropathy. CONCLUSION The integration of brentuximab vedotin in the frontline treatment of pediatric high-risk HL is highly tolerable, facilitated significant reduction in radiation exposure, and yielded excellent outcomes.

Background Histiocytic and dendritic cell neoplasms are a diverse group of tumors arising from monocytic or dendritic cell lineage. Whereas the genomic features for Langerhans cell histiocytosis and Erdheim-Chester disease have been well described, other less common and often aggressive tumors in this broad category remain poorly characterized, and comparison studies across the World Health Organization diagnostic categories are lacking. Methods Tumor samples from a total of 102 patient cases within four major subtypes of malignant histiocytic and dendritic cell neoplasms, including 44 follicular dendritic cell sarcomas (FDCSs), 41 histiocytic sarcomas (HSs), 7 interdigitating dendritic cell sarcomas (IDCSs), and 10 Langerhans cell sarcomas (LCSs), underwent hybridization capture with analysis of up to 406 cancer-related genes. Results Among the entire cohort of 102 patients, CDKN2A mutations were most frequent across subtypes and made up 32% of cases, followed by TP53 mutations (22%). Mitogen-activated protein kinase (MAPK) pathway mutations were present and enriched among the malignant histiocytosis (M) group (HS, IDCS, and LCS) but absent in FDCS (72% vs. 0%; p < .0001). In contrast, NF-kappa B pathway mutations were frequent in FDCSs but rare in M group histiocytoses (61% vs. 12%; p < .0001). Tumor mutational burden was significantly higher in M group histiocytoses as compared with FDCSs (median 4.0/Mb vs. 2.4/Mb; p = .012). We also describe a pediatric patient with recurrent secondary histiocytic sarcoma treated with targeted therapy and interrogated by molecular analysis to identify mechanisms of therapeutic resistance. Conclusion A total of 42 patient tumors (41%) harbored pathogenic mutations that were potentially targetable by approved and/or investigative therapies. Our findings highlight the potential value of molecular testing to enable precise tumor classification, identify candidate oncogenic drivers, and define personalized therapeutic options for patients with these aggressive tumors. Implications for Practice This study presents comprehensive genomic profiling results on 102 patient cases within four major subtypes of malignant histiocytic and dendritic cell neoplasms, including 44 follicular dendritic cell sarcomas (FDCSs), 41 histiocytic sarcomas (HSs), 7 interdigitating dendritic cell sarcomas (IDCSs), and 10 Langerhans cell sarcomas (LCSs). MAPK pathway mutations were present and enriched among the malignant histiocytosis (M) group (HS, IDCS, and LCS) but absent in FDCSs. In contrast, NF-kappa B pathway mutations were frequent in FDCSs but rare in M group histiocytosis. A total of 42 patient tumors (41%) harbored pathogenic mutations that were potentially targetable by approved and/or investigative therapies.

Pediatric Blood & CancerVolume 68, Issue 10 e29166 LETTER TO THE EDITOR Secondary histiocytic sarcoma with BRAFV600E mutation responsive to MAPK-targeted therapy presenting with recurrence with mTOR mutation responsive to mTOR-targeted therapy Vinayak Venkataraman, Vinayak Venkataraman orcid.org/0000-0003-0941-2354 Departments of Medicine and Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USASearch for more papers by this authorLucas R. Massoth, Lucas R. Massoth Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USASearch for more papers by this authorRyan J. Sullivan, Ryan J. Sullivan Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USASearch for more papers by this authorAlison M. Friedmann, Corresponding Author Alison M. Friedmann afriedmann@partners.org Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USA Correspondence Alison M. Friedmann, Department of Pediatrics, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA. Email: afriedmann@partners.orgSearch for more papers by this author Vinayak Venkataraman, Vinayak Venkataraman orcid.org/0000-0003-0941-2354 Departments of Medicine and Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USASearch for more papers by this authorLucas R. Massoth, Lucas R. Massoth Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USASearch for more papers by this authorRyan J. Sullivan, Ryan J. Sullivan Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USASearch for more papers by this authorAlison M. Friedmann, Corresponding Author Alison M. Friedmann afriedmann@partners.org Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USA Correspondence Alison M. Friedmann, Department of Pediatrics, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA. Email: afriedmann@partners.orgSearch for more papers by this author First published: 01 June 2021 https://doi.org/10.1002/pbc.29166Citations: 1Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume68, Issue10October 2021e29166 RelatedInformation

PURPOSE Children's Oncology Group (COG) AALL0331 tested whether pegaspargase intensification on a low-intensity chemotherapy backbone would improve the continuous complete remission (CCR) rate in a low-risk subset of children with standard-risk B-acute lymphoblastic leukemia (ALL). METHODS AALL0331 enrolled 5,377 patients with National Cancer Institute standard-risk B-ALL (age 1-9 years, WBC < 50,000/μL) between 2005 and 2010. Following a common three-drug induction, a cohort of 1,857 eligible patients participated in the low-risk ALL random assignment. Low-risk criteria included no extramedullary disease, < 5% marrow blasts by day 15, end-induction marrow minimal residual disease < 0.1%, and favorable cytogenetics ( ETV6-RUNX1 fusion or simultaneous trisomies of chromosomes 4, 10, and 17). Random assignment was to standard COG low-intensity therapy (including two pegaspargase doses, one each during induction and delayed intensification) with or without four additional pegaspargase doses at 3-week intervals during consolidation and interim maintenance. The study was powered to detect a 4% improvement in 6-year CCR rate from 92% to 96%. RESULTS The 6-year CCR and overall survival (OS) rates for the entire low-risk cohort were 94.7% ± 0.6% and 98.7% ± 0.3%, respectively. The CCR rates were similar between arms (intensified pegaspargase 95.3% ± 0.8% v standard 94.0% ± 0.8%; P = .13) with no difference in OS (98.1% ± 0.5% v 99.2% ± 0.3%; P = .99). Compared to a subset of standard-risk study patients given identical therapy who had the same early response characteristics but did not have favorable or unfavorable cytogenetics, outcomes were significantly superior for low-risk patients (CCR hazard ratio 1.95; P = .0004; OS hazard ratio 5.42; P < .0001). CONCLUSION Standard COG therapy without intensified pegaspargase, which can easily be given as an outpatient with limited toxicity, cures nearly all children with B-ALL identified as low-risk by clinical, early response, and favorable cytogenetic criteria.

To report clinical outcomes in a prospective phase II pediatric cohort of rhabdomyosarcoma (RMS) treated with proton radiotherapy (PRT) and modern standard VAC-based chemotherapy. The study enrolled patients (<25 years) treated with PRT between 03/2003 - 11/2019 at 2 institutions. CTCAEv3.0, was used to grade adverse effects. Patient/parent reported prospective quality of life inventory (PedsQL) was offered twice during PRT and annually thereafter. PRT and tumor-related characteristics were analyzed with respect to health outcomes, measured from PRT start to the event of interest: log-rank test method to assess clinical variable effect on survival outcome, Fine-Gray competing risks regression for local control (LC), students T-Test for baseline and follow-up (FU) PedsQL scores, and univariate linear regression for clinical characteristics score comparison. One hundred three RMS patients (embryonal/FOX01-, n = 81, 78.6%; alveolar/FOX01+, n = 22, 21.4%), with a median age of 4.2 years (range: 0.1-24.6), had 23.3% low-, 72.8% intermediate- and 3.9% high-risk disease, and were staged according to the Intergroup Rhabdomyosarcoma Study in group I/II (n = 13, 12.6%), III (n = 85, 82.5%) and IV (n = 5, 4.9%). Median total dose delivered was 50.4 GyRBE (range: 36.0-59.4 GyRBE) and median FU was 5.9 years (range: 0.1-14.4). Significant predictors for local failure (LF) were tumor size >5cm (HR 2.61, p = 0.04), and age <2 or >10 vs. 2-10 at PT time (HR 2.6, p = 0.05). 5-year EFS, OS, and LC were 66.5%, 76.2%, and 80.8%, respectively, and 22 (21.4%) died, all from tumor progression. Three (2.9%) patients with embryonal RMS developed a second malignant neoplasm (SMN) (leukemia, pleomorphic adenoma and sarcoma). Excluding recurrences (n = 22), late toxicity (>90 days post-PRT) assessments were available for 69 (85.2%) patients, with no grade 4. Maximum grade late toxicity of 2 and 3 was 30 (43.5%) and 13 (18.8%), respectively. Thirty-six patients had baseline and FU PedsQL data. At baseline the mean total mean core (TCS) and physical and psychosocial summary scores were 67.6, 65.9, and 68.9, increasing over time to 81.9, 89.1, and 78.1 (p = 0.0007, <0.0001 and 0.03, respectively). Patients with tumor sizes ≤5cm reported lower baseline TCS than those >5cm (mean 62.2 vs 77.2; p = 0.04). Alveolar/undifferentiated histology showed higher baseline TCS compared to embryonal (mean 85.6 vs. 64.1; p = 0.02). No clinical variables significantly correlated with long-term TCS. Disease control and SMN are in line with other pediatric RMS proton/photon series. Late toxicity seems favorable compared to photon cohorts. PedsQL scores increased over time.

To the Editor: We report an unusual case of a child with infant T-cell acute lymphoblastic leukemia (T-ALL) who presented during maintenance chemotherapy with BRAFV600E-mutant histiocytic sarcoma (HS) that responded to mitogen-activated protein kinase (MAPK)-targeted therapy with dabrafenib and trametinib. A male infant presented at 5 months of age with fevers, hepatosplenomegaly, and white blood cell count over 600 000/mm3. Bone marrow aspiration (BMA) demonstrated 91% lymphoblasts with an immature T-cell immunophenotype. Cytogenetic studies identified t(8;14)(q24;q11.2), resulting in a TRA-MYC rearrangement. Cerebrospinal fluid (CSF) contained 70white blood cells permicroliter with 90% blasts. He received induction chemotherapy following a Children’s Oncology Group (COG) infant ALL trial, AALL15P1. Postinduction BMA showed complete remission with flow cytometry negative for minimal residual disease (<0.01%) and clearance of CSF leukemia. Postinduction therapy employed a Berlin-Frankfurt-Munster chemotherapy backbone following the intermediate risk arm of COG T-ALL trial AALL1231. Four months after starting maintenance therapy, the patient presented with a rapidly growing temporal mass (Figure 1A, parental consent obtained). Computed tomography (CT) and magnetic resonance imaging (MRI) showed a 3.6 cm right temporal skull masswith intracranial and extracranial components. BMA showed no evidence of T-ALL; ALL therapy was discontinued during diagnostic evaluation. Biopsy of the mass revealed morphologic features of HS with immunohistochemical stains positive for CD68, CD163, PU.1, CD45, CD4, MYC, S100 (faint), and BRAFV600E (VE1 antibody) (Figure 2A-C). Negative staining was demonstrated for CD3, CD34, CD117, TdT, as well as specific markers of melanocytic, Langerhans cell, and follicular dendritic cell lineage. Fluorescence in situ hybridization (FISH) testing identified rearrangement of MYC, indicating a clonal relationship with the patient’s prior T-ALL (Figure 2D). Additionally, CDKN2A copy loss and BRAF p.V600E were identified by targeted sequencing. The tumor expanded during 5 days of clofarabine and dexamethasone. Dabrafenib (BRAF inhibitor) and trametinib (MEK1/2 inhibitor) were obtained in liquid formulations through a compassionate use, IRB-approved protocol—dabrafenib twice daily at 2.625 mg/kg, and trametinib once daily at 0.025 mg/kg. Significant response was observed over the first few days (Figure 1B-C). The trametinib dose was increased 7 weeks later to 0.032 mg/kg when the tumor showed some regrowth. Restaging scans showed significant improvement but persistent skull-based tumor, prompting complete surgical resection with cranioplasty that achieved negative margins. The posttreatment excision showed residual tumor with weak BRAFV600E expression by immunohistochemistry. Dabrafenib/trametinib was continued until 1 year after resection. ALL therapy was never resumed given lack of data regarding combining therapies. He remains at risk for relapse; however, there is no evidence of disease 14 months after HS diagnosis and 28months after T-ALL diagnosis. This is the first report of a child with infant T-ALL developing secondary BRAFV600E-mutant HS responding to MAPK-targeted therapy. Five reported cases of secondary HS after ALL show patients in the age group of 4-10 years, all presented duringmaintenance chemotherapy, sharing molecular markers of the initial ALL,1-5 two with CDKN2A mutations2,5 and nonewith BRAFV600E mutation. In HS, broadly, activating genomic alterations of the MAPK pathway are present in the majority of cases and tumor suppressor CDKN2A copy number loss is frequent.6-8 Medications that target the MAPK pathway, including BRAF and MEK, have demonstrated activity in BRAFV600E-mutant solid tumors, such as melanoma,9-13 anaplastic thyroid cancer,14 non-small cell lung carcinoma,15 colorectal cancer,16 and Erdheim-Chester disease.17 Two reports show response to vemurafenib in BRAFV600E-mutant HS.18,19 Additionally, combined BRAF/MEK inhibitionhasbeen shown tobemoreeffective than singleagent BRAF inhibitors in four randomized phase III trials in metastatic melanoma.9–12 In summary, we treated a very young child with aggressive secondary BRAFV600E-mutant HS with dabrafenib and trametinib; he remains in remission 14 months later, demonstrating a therapeutic benefit ofMAPK-targeted therapy in BRAF-mutant HS.