Citations

Abstract We evaluated outcomes by management type for patients with stage IA nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) in the Global NLPHL One Working Group retrospective database of 2243 patients with stages I to IV disease diagnosed from 1992 to 2021 at 38 international institutions. A total of 779 patients had stage IA disease with median age of 35 years (range, 3-89) and median follow-up of 6.1 years. The 6-year progression-free survival (PFS) and overall survival were 86.3% and 97.7%, respectively. Outcomes were analyzed for the 2 groups: complete resection and unresected disease. Patients with a complete resection and observation alone (n = 99) had a 6-year PFS of 65.5% vs 90.5% for those who received radiotherapy (RT) (n = 53). Patients with unresected disease (n = 627; 80.5%) had a 6-year PFS of 62.0% for rituximab alone (n = 31), 89.6% for RT alone (n = 325), 76.8% for ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) alone (n = 40), and 94.3% for ABVD plus RT (n = 130). A total of 127 patients relapsed (16.3%), of which 25 (19.7%) had transformation. Our analysis suggests the following: (1) RT improves the PFS in patients with completely resected disease; (2) rituximab or ABVD alone does not appear to achieve a durable response; and (3) chemotherapy was not observed to add additional PFS benefit when used in combination with RT. Thus, for stage IA NLPHL, RT alone is likely sufficient for definitive treatment.

Abstract Modern radiation therapy (RT) technologies allow for improved sparing of normal tissues, decreasing the risk of both acute and long-term toxicities. Existing RT dose constraints for prospective trials within the National Clinical Trials Network (NCTN) were formulated in the context of solid malignancies. As patients with hematologic malignancies are often treated with lower RT doses and are usually younger with more favorable prognoses, customized dose constraints are needed. The NRG Oncology Hematologic Malignancies Working Group (NRG HEME) commissioned a review of existing organ-at-risk (OAR) constraints from published primary literature, the NRG Center for Innovation in Radiation Oncology (CIRO), and national guidelines. Customized constraints were developed by iterative review by NRG HEME. Final recommendations were approved by radiation oncology representatives from all the lymphoma NCTN groups (NRG Oncology, Children’s Oncology Group, Alliance, ECOG-ACRIN, SWOG, Canadian Cancer Trials Group). For 49 OARs, a strict recommended constraint was determined, of which 20 were not present in CIRO. Of the remaining 29 constraints, 20 were lower, 2 were the same, and 5 used different metrics; 2 were higher than at least 1 CIRO trial constraint. Acceptable variations were determined and unacceptable variations were added for select critical OARs for plan scoring. While doses to OARs without explicit unacceptable variations should not exceed acceptable variations, violations should not be considered for plan quality assessment on trials. This consensus list of standard OAR constraints should be incorporated for all future NCTN trials in hematologic malignancies. Strict dose constraints will minimize long-term toxicities in this patient population.

Abstract Radiotherapy is an established treatment for low-grade primary cutaneous B-cell lymphoma. Recommendations on its use differ internationally, which prompted our group to conduct this analysis. Twenty-two institutions participated in this international study. Patient eligibility required a diagnosis of limited (T1/T2) primary cutaneous marginal zone or follicle center lymphoma treated with radiotherapy between 1995 and 2023. Data were collected retrospectively until February 2024 within the framework of the International Lymphoma Radiation Oncology Group. Overall, 535 patients were analyzed. Predominant locations were the head (40%) and trunk (36%). Radiotherapy had a median dose of 24 Gy in fractions of 2 Gy. Complete responses were observed in 91% at a median time of 3.6 months following radiotherapy. There was no statistically significant difference between treatments ≤4 Gy and >4 Gy for complete or overall response rates (P = .077 and P = .056, respectively). However, there was an inferior duration of local control with ≤4 Gy (5-year local control 73% ± 12% vs 96% ± 2%; P< .001). Radiation dose was the main prognostic factor in the univariate and multivariable Cox analysis; however, higher doses did not translate into an overall survival benefit. Toxicities rarely exceeded grade 2 but were more frequent in the >4 Gy group. Radiotherapy remains an effective treatment option for indolent skin lymphoma with low toxicity. High response rates are observed with low doses of ≤4 Gy. In comparison to conventional doses, these treatments have a shorter duration of local control but a favorable toxicity profile.

PURPOSE Nodular lymphocyte–predominant Hodgkin lymphoma (NLPHL) is a rare cancer, and large international cooperative efforts are needed to evaluate the significance of clinical risk factors and immunoarchitectural patterns (IAPs) for all stages of pediatric and adult patients with NLPHL. METHODS Thirty-eight institutions participated in the Global nLPHL One Working Group retrospective study of NLPHL cases from 1992 to 2021. We measured progression-free survival (PFS), overall survival (OS), transformation rate, and lymphoma-specific death rate. We performed uni- and multivariable (MVA) Cox regression stratified by management to select factors for the lymphocyte-predominant international prognostic score (LP-IPS) validated by five-fold cross-validation. RESULTS We identified 2,243 patients with a median age of 37 years (IQR, 23-51). The median follow-up was 6.3 years (IQR, 3.4-10.8). Most had stage I to II (72.9%) and few B symptoms (9.9%) or splenic involvement (5.4%). IAP was scored for 916 (40.8%). Frontline management included chemotherapy alone (32.4%), combined modality therapy (30.5%), radiotherapy alone (24.0%), observation after excision (4.6%), rituximab alone (4.0%), active surveillance (3.4%), and rituximab and radiotherapy (1.1%). The PFS, OS, transformation, and lymphoma-specific death rates at 10 years were 70.8%, 91.6%, 4.8%, and 3.3%, respectively. On MVA, IAPs were not associated with PFS or OS, but IAP E had higher risk of transformation (hazard ratio [HR], 1.81; P < .05). We developed the LP-IPS with 1 point each for age ≥45 years, stage III-IV, hemoglobin <10.5 g/dL, and splenic involvement. Increasing LP-IPS was significantly associated with worse PFS (HR, 1.52) and OS (HR, 2.31) and increased risk of lymphoma-specific death (HR, 2.63) and transformation (HR, 1.41). CONCLUSION In this comprehensive study of all ages of patients with NLPHL, we develop the LP-IPS to identify high-risk patients and inform upcoming prospective clinical trials evaluating de-escalation of therapy for patients with low LP-IPS scores (<2).

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. ARST1321 was a phase II study designed to compare the near complete pathologic response rate after preoperative chemoradiation with/without pazopanib in children and adults with intermediate-/high-risk chemotherapy-sensitive body wall/extremity non-Rhabdomyosarcoma Soft Tissue Sarcoma (ClinicalTrials.gov identifier: NCT02180867 ). Enrollment was stopped early following a predetermined interim analysis that found the rate of near complete pathologic response to be significantly greater with the addition of pazopanib. As a planned secondary aim of the study, the outcome data for this cohort were analyzed. Eight-five eligible patients were randomly assigned to receive (regimen A) or not receive (regimen B) pazopanib in combination with ifosfamide and doxorubicin + preoperative radiotherapy followed by primary resection at week 13 and then further chemotherapy at week 25. As of December 31, 2021, at a median survivor follow-up of 3.3 years (range, 0.1-5.8 years), the 3-year event-free survival for all patients in the intent-to-treat analysis was 52.5% (95% CI, 34.8 to 70.2) for regimen A and 50.6% (95% CI, 32 to 69.2) for regimen B ( P = .8677, log-rank test); the 3-year overall survival was 75.7% (95% CI, 59.7 to 91.7) for regimen A and 65.4% (95% CI, 48.1 to 82.7) for regimen B ( P = .1919, log-rank test). Although the rate of near complete pathologic response was significantly greater with the addition of pazopanib, outcomes were not statistically significantly different between the two regimens.

AbstractBackground and ObjectivesThe impact upon wound healing of targeted molecular therapies, when incorporated into neoadjuvant therapy of soft tissue sarcoma, is largely unknown. Here, we describe wound complications following addition of pazopanib, a tyrosine kinase inhibitor (TKI), to neoadjuvant radiotherapy (RT) +/− chemotherapy for soft tissue sarcoma.MethodsWound complications were evaluated on dose‐finding and randomized arms of ARST1321, a phase II/III study incorporating neoadjuvant RT, +/− pazopanib, +/− ifosfamide/doxorubicin (ID) for sarcoma therapy.ResultsOf 85 evaluable patients, 35 (41%) experienced postoperative wound complications. Most (57%) were grade III. Randomization to pazopanib + RT + ID carried a 50% wound complication rate (17/34, with 47% grade III), compared to 22% (5/23) with ID + RT alone. In nonchemotherapy study arms, pazopanib + RT resulted in a 59% wound complication rate versus 25% for those receiving RT alone. Grade III wound complications occurred among 26% (15/58) of all patients receiving pazopanib. Wound complications occurred a median of 35 days postoperatively. Some occurred following diagnostic biopsies and at remote surgical sites.ConclusionThe addition of pazopanib to neoadjuvant chemotherapy and RT resulted in a higher wound complication rate following therapy of soft tissue sarcoma. The rate of grade III complications remained comparable to that reported in contemporary literature.

PURPOSE Monoclonal antibodies directed against insulin-like growth factor-1 receptor (IGF-1R) have shown activity in patients with relapsed Ewing sarcoma. The primary objective of Children's Oncology Group trial AEWS1221 was to determine if the addition of the IGF-1R monoclonal antibody ganitumab to interval-compressed chemotherapy improves event-free survival (EFS) in patients with newly diagnosed metastatic Ewing sarcoma. METHODS Patients were randomly assigned 1:1 at enrollment to standard arm (interval-compressed vincristine/doxorubicin/cyclophosphamide alternating once every 2 weeks with ifosfamide/etoposide = VDC/IE) or to experimental arm (VDC/IE with ganitumab at cycle starts and as monotherapy once every 3 weeks for 6 months after conventional therapy). A planned sample size of 300 patients was projected to provide 81% power to detect an EFS hazard ratio of 0.67 or smaller for the experimental arm compared with the standard arm with a one-sided α of .025. RESULTS Two hundred ninety-eight eligible patients enrolled (148 in standard arm; 150 in experimental arm). The 3-year EFS estimates were 37.4% (95% CI, 29.3 to 45.5) for the standard arm and 39.1% (95% CI, 31.3 to 46.7) for the experimental arm (stratified EFS-event hazard ratio for experimental arm 1.00; 95% CI, 0.76 to 1.33; 1-sided, P = .50). The 3-year overall survival estimates were 59.5% (95% CI, 50.8 to 67.3) for the standard arm and 56.7% (95% CI, 48.3 to 64.2) for the experimental arm. More cases of pneumonitis after radiation involving thoracic fields and nominally higher rates of febrile neutropenia and ALT elevation were reported on the experimental arm. CONCLUSION Ganitumab added to interval-compressed chemotherapy did not significantly reduce the risk of EFS event in patients with newly diagnosed metastatic Ewing sarcoma, with outcomes similar to prior trials without IGF-1R inhibition or interval compression. The addition of ganitumab may be associated with increased toxicity.

11504 Background: Pazopanib is a multi-targeted tyrosine kinase inhibitor (TKI) with activity in advanced soft tissue sarcoma. ARST1321 was a phase II study designed to compare the near complete pathologic response rate (≥ 90% necrosis) following preoperative chemoradiation +/- pazopanib in children and adults with intermediate/high risk chemotherapy-sensitive body wall/extremity NRSTS. Enrollment was stopped early following a predetermined interim analysis that found the rate of near complete pathologic response to be significantly greater with the addition of pazopanib. As a planned secondary analysis of the study, we now report the outcome data for this cohort. Methods: ARST1321 was a jointly designed COG and NRG Oncology study open to enrollment July 2014-October 2018. Eligible adult (≥18 years) and pediatric (< 18 years) patients with newly-diagnosed unresected body wall/extremity NRSTS were enrolled into the Chemotherapy Cohort (> 5 cm, FNCLCC grade 2/3, protocol-designated chemotherapy-sensitive histology). Following a dose-finding phase, patients were randomized to receive (Regimen A) or not receive (Regimen B) pazopanib (< 18 years: 350 mg/m2/day; ≥ 18 years: 600 mg/day) in combination with ifosfamide (7.5 gm/m2/cycle) and doxorubicin (75 mg/m2/cycle) + 45 Gy preoperative RT followed by primary resection at week 13, then further chemotherapy to week 25. Results: Eighty-five eligible patients were enrolled in the Chemotherapy Cohort and randomized to receive or not receive pazopanib. Median age 22.1 years (range: 5.7-64.2 years); 30 patients < 18 years. Most common histologies were synovial sarcoma (n = 42) and undifferentiated pleomorphic sarcoma (n = 19). As of December 31, 2021, at a median survivor follow-up of 3.3 years (range: 0.1 – 5.8 years), the 3-year event-free survival (EFS) for all patients in the intent-to-treat analysis was 52.5% (95% CI: 34.8%-70.2%) for Regimen A and 50.6% (32%-69.2%) for Regimen B (p = 0.8677); 3-year overall survival (OS) was 75.7% (59.7%-91.7%) for Regimen A and 65.4% (48.1%-82.7%) for Regimen B (p = 0.1919). Conclusions: Although the rate of near complete pathologic response was significantly greater with the addition of pazopanib to preoperative chemoradiation in children and adults with intermediate/high risk body wall/extremity NRSTS, outcomes were not statistically significantly different between the two regimens. Pathologic response could be a TKI-related phenomenon and may not be a good surrogate marker of outcome in future studies. Clinical trial information: NCT02180867.