Hodgson, David C.

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.

10019 Background: The reported incidence of second malignant neoplasms (SMN) in long-term survivors of Hodgkin lymphoma (HL) is derived from patients treated with outdated radiation therapy (RT) techniques. We modeled the risk of SMN in pediatric patients with high-risk classic HL treated with modern mediastinal RT. Methods: In patients who received mediastinal RT on the Children’s Oncology Group study AHOD1331, we modeled the lifetime attributable risk (LAR) at 70 years of age of thyroid, lung, and breast carcinoma. This value indicates the absolute increased risk of SMN at 70 years of age due to RT, above the baseline population risk (mean baseline rates at 70 years of age are 0.7%, 3.3%, and 8.9% for thyroid, lung, and breast carcinoma, respectively, https://seer.cancer.gov/data/ ). Results: In 296 patients who received protocol-directed mediastinal RT, median age at diagnosis was 15.1 years, 55% were female, and 98% had large mediastinal adenopathy. Following 5 cycles of chemotherapy, patients received RT targeting the mediastinum based on criteria of this study; in addition, some patients received RT to other supradiaphragmatic sites that contained slowly responding lesions, including the axilla (n = 3, 1%), lung (n = 7, 2.4%), upper neck (n = 4, 1.3%), and lower neck (n = 8, 2.7%). The RT modality was proton therapy in 25.3%, photon intensity modulated RT (IMRT) in 45.6%, and photon 3-dimensional conformal RT (3D-CRT) in 27.7%. The RT prescription dose was 21 Gy in 83% and 30 Gy in 16% who had a partial metabolic response at the completion of chemotherapy. The mean (range) doses to the thyroid, lungs, and breasts were 12.8 Gy (0-30.3), 8.0 Gy (0.1-15.2), and 4.2 Gy (0.2-14.5), respectively. For the complete cohort, the mean LAR at 70 years of age of thyroid carcinoma was 0.063% and of lung carcinoma was 5.34%. For females, the mean LAR at 70 years of age of breast carcinoma was 2.92%. The Table summarizes the LAR for each SMN, stratified by RT modality. Conclusions: In patients treated with mediastinal RT on a recent multi-institutional study of pediatric HL, the predicted long-term risk of SMN is substantially lower than in historical cohorts. Clinicians should consider the toxicity associated with a current RT approach when selecting therapies and counseling patients. Clinical trial information: NCT02166463 , this is a post hoc modeling study that includes patients enrolled on this study. Mean [range] lifetime attributable risk (%) at an attained age of 70 years for thyroid, lung, and breast carcinoma. Thyroid Lung Breast (females) 3D-CRT 0.046 [0.002-0.332]N=81 5.07 [0.12-10.82]N=82 1.82 [0.67-5.98]N=46 IMRT 0.064 [0.001-0.386]N=135 6.24 [2.22-11.79]N=135 4.36 [0.66-8.43]N=76 Proton 0.086 [0-1.160]N=74 4.15 [0.94-7.77]N=75 1.45 [0.17-7.23]N=40

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).

AbstractPurpose/objectiveWe compared the prognostic value of chest radiograph (CXR)‐ and computed tomography (CT)‐derived definition of large mediastinal adenopathy (LMA) in pediatric Hodgkin lymphoma (HL).Materials/methodsTotal 143 patients treated for stage IIIB/IVB HL on COG AHOD0831 were included in this study. Six definitions of LMA were investigated: (i) mediastinal mass ratio on CXR (MRCXR) > 1/3; (ii) mediastinal mass ratio on CT (MRCT) > 1/3; (iii) mediastinal mass volume on CT (MVCT) > 200 mL; (iv) normalized mediastinal mass volume (MVCT/thoracic diameter [TD]) > 1 mL/mm; (v) mediastinal mass diameter on CT (MDCT) > 10 cm; and (vi) normalized mediastinal mass diameter (MDCT/TD) > 1/3.ResultsMedian age at diagnosis was 15.8 years (range: 5.2–21.3 years). In patients with a slow early response (SER) to chemotherapy, MVCT > 200 mL, MDCT > 10 cm, and MDCT/TD > 1/3 were associated with worse relapse‐free survival (RFS) on MVA, while MRCXR > 1/3, MRCT > 1/3, and MVCT/TD > 1 mL/mm trended toward worse RFS; MDCT/TD was the most strongly prognostic for inferior RFS, with a hazard ratio of 6.41 for MDCT/TD > 1/3 versus ≤1/3 on MVA (p = .02).ConclusionLMA according to MVCT > 200 mL, MDCT > 10 cm, and MDCT/TD > 1/3 is associated with poor prognosis in advanced‐stage HL patients with SER. The normalized mediastinal diameter, MDCT/TD > 1/3 appears to be the strongest predictor of inferior RFS.