Rapid Early Responders Research Articles

Targeted Immunotherapy and Checkpoint Blockade in Children, Adolescents, and Young Adults with Lymphoma: Radical Hodgkin Cohort

Background: Significant chronic health conditions continue to increase over time among pediatric, adolescent, and young adult (CAYA) classical Hodgkin lymphoma (cHL) survivors. Targeting the tumor microenvironment (TME) and tumor-specific antigens are emerging as effective and safe treatments for cHL patients which may help reduce toxicity. Recently, we completed a phase 2 trial evaluating the use of an antibody-drug conjugate targeting CD30 (brentuximab vedotin, Bv) and an anti-CD20 antibody targeting regulatory B-cells (rituximab, RTX) added to risk-adapted chemotherapy in newly diagnosed cHL CAYA patients. The combination was safe and resulted in significant reduction to toxic chemotherapy and radiation therapy (RT), while keeping superior outcomes (5-year OS/EFS 100%) [Hochberg/Cairo, JITC 2022]. Adding the checkpoint inhibitor nivolumab to chemoimmunotherapy with RTX + Bv may allow further anthracycline dose reduction and reduce the need for RT in intermediate-/high-risk cHL in CAYA. Methods: This is a multicenter study for patients with intermediate- and high-risk cHL. Intermediate-risk cHL patients receive 2 cycles of Bv, doxorubicin, vinblastine, dacarbazine, and RTX (Bv-AVD-R). Rapid early responders (RER) or slow early responders (SER) by FDG-PET scan receive 2 or 4 cycles of Bv, vinblastine, dacarbazine, nivolumab, and RTX (Bv-NVD-R), respectively without further anthracycline. High-risk cHL patients receive 2 cycles of Bv-AVD-R. RERs by FDG-PET scan receive 4 cycles of Bv-NVD-R; SERs receive 2 cycles of Bv, nivolumab, doxorubicin, vinblastine, dacarbazine and RTX (Bv-NAVD-R), followed by 4 cycles of Bv-NVD-R. RT will only be given to patients not achieving CR at the end of therapy. Results: Nine patients have received at least one dose of nivolumab to date and are included in the safety analysis, including 4 intermediate- and 5 high-risk patients. All 9 of these patients have completed interim FDG-PET following 2 cycles of Bv-AVD-R to evaluate early response status. All intermediate-risk patients and 3 high risk patients evaluated to date have been RER, achieving a complete response (CR) at interim FDG-PET. Two high-risk patients have been SER, with a partial response (PR) at interim FDG-PET. Both SER patients achieved a CR following the 6 additional cycles of chemotherapy as detailed above. No patients have required radiation therapy. Accrual is ongoing. We have completed the planned nivolumab safety run in phase. There have been no unexpected grade III/IV adverse events secondary to nivolumab and no dose-limiting toxicities. Conclusions: Targeting the Hodgkin Reed-Sternberg cell as well as the TME (regulatory B-cells) and PD1/PD-L1 axis is a promising approach in CAYA with cHL. (NCT05253495).

Performance of Positron Emission Tomography at Diagnosis and Response Assessment in Low and Intermediate-Risk Nodular Lymphocyte Predominant Hodgkin Lymphoma

Background: Nodular lymphocyte predominant Hodgkin lymphoma (nLPHL) has different histology, clinical presentation, and outcomes than classical Hodgkin Lymphoma (cHL). Positron Emission Tomography (PET) plays an important role in staging and response assessment in cHL, but little is published about the use of PET to guide treatment in nLPHL. A better understanding of the clinical significance of PET response in nLPHL is critical for incorporating PET into prospective trials. Methods: Children's Oncology Group study AHOD03P1 (NCT00107198) enrolled patients with low-risk nLPHL and AHOD0031 (NCT00025259) enrolled patients with intermediate-risk cHL and nLPHL <22 years of age. AHOD03P1 patients with stage IA and >1 lymph node or stage IIA nLPHL were treated with 3 cycles of doxorubicin, vincristine, prednisone, and cyclophosphamide (AV-PC) chemotherapy, given every 21 days. Patients with a complete response (CR) based on anatomic response and qualitative reading (<mediastinal blood pool) of negative PET on central review did not receive radiation therapy while patients with <CR received 21-Gy involved field radiation therapy (IFRT). AHOD0031 patients with stages IB, IAE, IIB, IIAE, IIIA, IVA with or without bulk disease, and IA or IIA with bulk disease received 2 cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone and cyclophosphamide (ABVE-PC) followed by response evaluation. Slow early responders were randomized to an additional 2 cycles of ABVE-PC with or without 2 cycles of dexamethasone, etoposide, cisplatin and cytarabine (DECA) and all received IFRT. Rapid early responders (RERs) received 2 additional cycles of ABVE-PC. RERs with CR were randomized to IFRT or no further therapy. RER/non-CRs were non-randomly assigned to IFRT. PET scans from both trials available in the Imaging and Radiation Oncology Core (IROC) were retrospectively reviewed and assigned a score of 1-5 on the Deauville 5-point scale (5PS). Patients who did not have evaluable imaging due to either scans not performed, on CD-ROM and inaccessible, or poor quality, were excluded from this analysis. Three-year event-free survival (EFS) was analyzed by 5PS at end of therapy using the Kaplan Meier method. Results: AHOD03P1 enrolled 135 patients with low-risk nLPHL who received chemotherapy and AHOD0031 enrolled 96 patients with intermediate-risk nLPHL. PET imaging available for review at diagnosis in 99 low-risk patients, 92% 5PS=5, and 55 intermediate-risk patients, 98% 5PS=5. Median age 13.4 years (range 16.5), 84.9% male, 29.9% Stage I, 49.8% Stage II, 18.6% Stage III, and 1.7% Stage IV. After 3 cycles of chemotherapy, 106 low-risk patients had available PET scans, 5PS 1 n=50, 5PS 2 n=35, 5PS 3 n=11, 5PS 4 n=7, and 5PS 5 n=3. Three-year EFS for patients with end of chemotherapy 5PS was: 5PS 1 89.9% (95% CI 77.3-95.7%), 5PS 2 97.1% (95% CI 81.4-99.6%), 5PS 3 90.9% (95% CI 50.8-98.7%), 5PS 4 28.6% (95% CI 1.0-71.1%), 5PS 5 66.7% (95% CI 5.4-94.5%) p=0.0081. When categorized as PET negative (5PS 1-3) and PET positive (5PS 4-5), 3-year EFS was 92.6% (95% CI 85.2-96.4%) for PET negative and 45.0% (95% CI 10.6-75.3%) for PET positive patients, p=0.0036 (Figure 1A). Forty-nine intermediate-risk patients had available PET scans after 2 cycles of chemotherapy, 5PS 1 n=9, 5PS 2 n=26, 5PS 3 n=10, 5PS 4 n=3, and 5PS 5 n=1. Three-year EFS by interim response was: 5PS 1 88.9% (95% CI 43.3-98.4%), 5PS 2 96.0% (95% CI 74.8-99.4%), 5PS 3 100%, 5PS 4 100%, 5PS 5 0%, p<0.0001. Thirty-six patients had available PET scans after 4 cycles of chemotherapy, 5PS 1 n=20, 5PS 2 n=11, 5PS 3 n=3, 5PS 4 n=1, and 5PS 5 n=1. Three-year EFS by response after 4 cycles of chemotherapy: 5PS 1 95.0% (95% CI 69.5-99.3%), 5PS 2 100%, 5PS 3 100%, 5PS 4 100%, 5PS 5 0% p<0.0001. When divided into PET negative (5PS 1-3) and PET positive (5PS 4-5), 3-year EFS 97.0% (95% CI 80.4-99.6%) for PET negative and 50.0% (95% CI 0.6-91.0%) for PET positive patients after 4 cycles of chemotherapy, p=0.1449 (Figure 1B). Conclusions: At diagnosis, low and intermediate-risk nLPHL lesions are almost always PET avid with 5PS=5. PET response following 3 cycles of AV-PC chemotherapy is highly predictive of outcome in pediatric patients with low-risk nLPHL when considering 5PS=3 as PET negative. Intermediate-risk patients with negative PET following ABVE-PC achieved excellent outcomes. Whether PET maintains prognostic significance in patients with nLPHL treated with rituximab needs to be studied.

Efficacy and Safety of Modified BV-AVD-R Regimen in Chinese Children with Previously Untreated Intermediate- and High-Risk Classical Hodgkin's Lymphoma: An Open Label, Non-Randomized, Single-Arm, Phase 2 Study from Single Center

Introduction Classical Hodgkin lymphoma (cHL) accounts for about 4.8% of childhood malignant neoplasm, and the incidence of cHL in Chinese children and adolescents (0-19 years old) is about 1.78/million, which is a group of relatively low malignancy and curable tumor. With the prolonged survival of children and adolescents with cHL, the incidence of muscle and skeletal malformations, lung and cardiovascular diseases, infertility and secondary tumors increased significantly during long-term follow-up. Therefore, the goal of childhood cHL treatment is to achieve and maintain the high efficacy while reduce the treatment-related complications. Brentuximab vedotin (BV), an antibody-drug conjugates (ADC) targeting CD30, has been evaluated well in American children and some regions, but no clinical studies to explore the efficacy and safety of BV in Chinese children with cHL. Therefore, the objective of our study is to evaluate the efficacy (objective response rate, including CR and PR) and safety (short - and long-term safety) of modified BV-AVD-R regimen (Brentuximab vedotin + Rituximab + Doxorubicin + Vinblastine + Dacarbazine) in Chinese children with previously untreated intermediate- and high-risk classical HL. Methods This study is a prospective study with period from October 2022 to December 2024, and planned to enroll 44 children with newly diagnosed intermediate- and high-risk classical HL. All patients will undergo PET/CT at the time of initial diagnosis and after 2 cycles of modified BV+R+AVD regimen to determine early response. Rapid early responders (RER) defined as CR after 2 cycles of therapy. Slow early responders (SER) defined as no CR (partial response (PR) or stable disease) after 2 cycles of therapy. Intermediate-risk patients were stage IA bulk/E, IB, IIA bulk/E, IIB, and IIIA. High-risk patients were stage IIB bulk/E, IIIA bulk/E, IIIB, and IVA/B(Figure 1). The primary endpoints include ORR (CR+PR) and adverse events. The secondary endpoints include progression-free survival (PFS), event-free survival (EFS) and overall survival (OS) at 6 months and 1 year. Results From October 2022 to July 2023, a total of 14 children with newly diagnosed classical HL were enrolled, and 12 patients who had completed at least 2 cycles treatment were eligible for evaluation. 9 boys and 3 girls were enrolled, with median age of 10 years (range 7-15 years). Risk group: 9 patients in high-risk group, 3 patients in intermediate-risk group; Clinical stage: 5 patients in stage IIIA, 2 patients in stage IIIB, 4 patients in stage IVA, and 1 patient in stage IVB. Pathologic subtype: 7 patients of nodular sclerosis type and 5 patients of mixed cell type. Treatment: A total of 33 cycles of modified BV+R+AVD regimen were completed, with 66 doses of BV. The median number of treatment cycles was 3 cycles (range 2-6). 11 patients achieved CR and 1 patient achieved PR after 2 cycles, and the ORR was 100% (12/12). As of July 28, 2023, 4 children had stopped follow-up and achieved CR without sequential radiotherapy. The median follow-up was 6 months (range 2-10). 12 patients successfully received and completed BV infusions, mild nausea and vomiting (10/12), alopecia (9/12) and sensory abnormalities (3/12) were observed. Serious adverse events were mainly grade ≥3 blood cell abnormalities (10/12), none of which had an impact on the treatment flow. No patient withdrew from the study, indicating good adherence to the regimen. Conclusion The risk-adapted modified BV+R+AVD regimen for newly diagnosed Chinese children and adolescents with classical HL showed favorable treatment outcomes with good early response rate and sustained response rate. The regimen could also reduce sequential radiotherapy and demonstrated well safety and tolerability. The study is still ongoing.

Improved survival of children and adolescents with classical Hodgkin lymphoma treated on a harmonised protocol in South Africa.

Historic South African 5-year overall survival (OS) rates for Hodgkin lymphoma (HL) from 2000 to 2010 were 46% and 84% for human immunodeficiency virus (HIV)-positive and HIV-negative children, respectively. We investigated whether a harmonised treatment protocol using risk stratification and response-adapted therapy could increase the OS of childhood and adolescent HL. Seventeen units prospectively enrolled patients less than 18years, newly diagnosed with classical HL onto a risk-stratified, response-adapted treatment protocol from July 2016 to December 2022. Low- and intermediate-risk patients received four and six courses of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD), respectively. High-risk patients received two courses of ABVD, followed by four courses of cyclophosphamide, vincristine, prednisone, and dacarbazine (COPDac). Those with a slow early response and bulky disease received consolidation radiotherapy. HIV-positive patients could receive granulocyte colony-stimulating factor and less intensive therapy if stratified as high risk, at the treating clinician's discretion. Kaplan-Meier survival analysis was performed to determine 2-year OS and Cox regression to elucidate prognostic factors. The cohort comprised 132 patients (19 HIV-positive, 113 HIV-negative), median age of 9.7years, with a median follow-up of 2.2years. Risk grouping comprised nine (7%) low risk, 36 (27%) intermediate risk and 87 (66%) high risk, with 71 (54%) rapid early responders and 45 (34%) slow early responders, and 16 (12%) undocumented. Two-year OS was 100% for low-risk, 93% for intermediate-risk, and 91% for high-risk patients. OS for HIV-negative (93%) and HIV-positive (89%) patients were similar (p=.53). Absolute lymphocyte count greater than 0.6×109 predicted survival (94% vs. 83%, p=.02). In the first South African harmonised HL treatment protocol, risk stratification correlated with prognosis. Two-year OS of HIV-positive and HIV-negative patients improved since 2010, partially ascribed to standardised treatment and increased supportive care. This improved survival strengthens the harmonisation movement and gives hope that South Africa will achieve the WHO Global Initiative for Childhood Cancer goals.

The Role of Radiation Therapy in the Management of Gray Zone Lymphoma.

Gray zone lymphoma (GZL) is a relatively rare disease predominantly affecting young adults with purportedly poor outcomes with current treatment approaches. The role of radiation therapy (RT) in the management of GZL is not well established. This is the largest study to report on the outcomes of GZL patients treated with and without RT. A retrospective review of 30 patients with GZL treated across 3 institutions from 2009 to 2021 was performed. Event-free survival (EFS) was defined from initiation of frontline chemotherapy (CHT) to disease progression/relapse, initiation of salvage therapy, or death. Local control (LC) was defined from RT start date to in-field recurrence. The median age was 32 (range: 18-86) years, and 16 (53%) patients had early stage (I-II) disease. Bulky mediastinal disease was present in 63% of patients, and the median tumor diameter was 10 (range: 1.5-18) cm. Patients received ABVD (20%), RCHOP (33%), or REPOCH (47%) as frontline CHT. Among 25 patients with interim PET/CT scan, there were 6 rapid early responders and 14 slow early responders (SER), with 2-year EFS of 33% and 24%, respectively (p = 0.13). After the completion of CHT, 15 (50%) patients achieved complete response (CR) and 10 (33%) achieved partial response (PR), with 2-year EFS of 46% and 10%, respectively (p = 0.004). RT was given to 9 patients in CR (n = 3) or in PR (n = 6). The median RT dose was 36 (30.6-48.6) Gy, at 1.8-2 Gy/fraction. Those receiving RT had bulkier disease at diagnosis (p = 0.049) and lower rates of CR following CHT (p = 0.03). After RT, 3/6 (50%) PR patients converted to CR. At a median follow-up of 4 years, the 2-year EFS was 26% for all patients, 33% for RT and 23% for noRT (p = 0.44). Among patients who did not receive upfront RT and experienced progression (n = 17), 16 (94%) relapsed in pre-existing sites. The 5-year OS was 80% for all patients, 88% for RT and 78% for no RT (p = 0.63). Patients who achieved PR to CHT and received RT had better 2-year EFS (17% vs 0%, p = 0.007) compared to patients who did not receive RT. Similarly, patients with SER who received RT had superior 2-year EFS (33% vs 13%, p = 0.038). Patients with bulky mediastinal disease had a 2-year EFS of 43% with RT and 11% without RT (p = 0.08). After 1st line treatment, 22 (73%) patients relapsed and 18 were successfully salvaged with a sustained CR. The most common salvage regimen involved high dose CHT followed by hematopoietic cell transplantation (HCT) (n = 15). RT was given for 7 patients in the relapsed/refractory setting (consolidative peri-HCT n = 4; definitive salvage n = 3) and 5 (71%) achieved a sustained CR. Among the 16 patients who received RT in the upfront (n = 9) or salvage (n = 7) setting, 3 patients experienced in-field recurrence translating to 2-year LC of 79%. GZL patients have high risk of relapse and maximal upfront combined modality therapy should be considered. RT provides good local control and improves EFS particularly for SER, PR, and bulky mediastinal disease.

Baseline metabolic tumour burden improves risk stratification in Hodgkin lymphoma: A Children's Oncology Group study.

The Children's Oncology Group AHOD0831 study used a positron emission tomography (PET) response-adapted approach in high-risk Hodgkin lymphoma, whereby slow early responders (SERs) received more intensive therapy than rapid early responders (RERs). We explored if baseline PET-based characteristics would improve risk stratification. Of 166 patients enrolled in the COG AHOD0831 study, 94 (57%) had baseline PET scans evaluable for quantitative analysis. For these patients, total body metabolic tumour volume (MTV), total lesion glycolysis (TLG), maximum standardized uptake value (SUVmax ) and peak SUV (SUVpeak ) were obtained. MTV/TLG thresholds were an SUV of 2.5 (MTV2.5 /TLG2.5 ) and 40% of the tumour SUVmax (MTV40% /TLG40% ). TLG2.5 was associated with event-free survival (EFS) in the complete cohort (p= 0.04) and in RERs (p= 0.01), but not in SERs (p= 0.8). The Youden index cut-off for TLG2.5 was 1841. Four-year EFS was 92% for RER/TLG2.5 up to 1841, 60% for RER/TLG2.5 greater than 1841, 74% for SER/TLG2.5 up to 1841 and 79% for SER/TLG2.5 greater than 1841. Second EFS for RER/TLG2.5 up to 1841 was 100%. Thus, RERs with a low baseline TLG2.5 experienced excellent EFS with less intensive therapy, whereas RERs with a high baseline TLG2.5 experienced poor EFS. These findings suggest that patients with a high upfront tumour burden may benefit from intensified therapy, even if they achieve a RER.

Clinical Profile and Induction Outcome of Children with T-cell Acute Lymphoblastic Leukemia and T-cell Lymphoblastic Lymphoma

Objective: To study the clinical profile and induction outcome in children diagnosed with T-cell acute lymphoblastic leukaemia and lymphoblastic lymphoma.
 Study Design: Cross-sectional study.
 Place and Duration of Study: Paediatric Oncology Unit, Combined Military Hospital, Rawalpindi Pakistan, from Jan 2012 to Dec 2020.
 Methodology: One hundered and twenty-one diagnosed patients of T-ALL and LBL were evaluated with bone marrow biopsy and Contrast-enhanced CT scan of the active region after induction chemotherapy with Dexamethasone, Vincristine, Asparaginase and Daunorubicin along with intrathecal Methotrexate. This was carried out on days-8 and 29 to determine the early remission status and end of induction response, respectively.
 Results: Out of 121 patients, 99(81.8 %) had T–ALL, while 22(18.18%) had LBL. Day-8 assessment showed that 94(77.7%) patients were rapid early responders, 24(19.4%) were slow early responders, while 3(2.4%) patients expired before the day eight assessment. Day-29 bone marrow assessment of 88 T-ALL patients showed complete remission in 77 patients (87.5%), incomplete remission in 5(5.68%) patients and treatment failure in 2(2.27%) patients. 20(93.1%) patients with LBL achieved remission by Day-29, while 2 (0.02%) LBL patients died before the Day-29 assessment.
 Conclusion: The remission induction rates and mortality rates in our setup are encouraging and comparable to international data. Further improvements can be made by early management of the affected cases and more accessible pediatric oncology health services.

Targeted radiotherapy for early-stage, low-risk pediatric Hodgkin lymphoma slow early responders: a COG AHOD0431 analysis

AbstractChildren's Oncology Group (COG) trial AHOD0431 reduced systemic therapy and used response-adapted involved-field radiotherapy (IFRT) in early-stage pediatric classic Hodgkin lymphoma. We investigated the impact of positron emission tomographic response after 1 cycle (PET1) and on IFRT outcomes and pattern of relapse. Patients in AHOD0431 underwent PET1 response assessment after AVPC (doxorubicin, vincristine, prednisone, and cyclophosphamide). “Rapid early responders” (RERs) had a negative PET1 (PET1−); “slow early responders” (SERs) had a positive PET1 (PET1+). Patients with a partial response by computed tomographic and functional imaging after 3 chemotherapy cycles received 21-Gy IFRT, whereas complete responders had no IFRT. Progression-free survival (PFS) was evaluated for RERs and SERs treated with or without IFRT. Recurrence sites were initial, new, or both. Relapses involving initial sites were characterized as “within the PET1+ site” or “initially involved but outside the PET1+ site.” Median follow-up was 118 months. The 10-year PFS rate among RERs was 96.6% with IFRT and 84.1% without IFRT (P = .10), whereas SERs were 80.9% with IFRT and 64.0% without IFRT (P = .03). Among 90 RERs who did not receive IFRT, all 14 relapses included an initial site. Among 45 SERs receiving no IFRT, 14 of 16 relapses were in the initial site (9 PET1+ site only). Among 58 patients receiving IFRT, 5 of 10 relapses were in the PET1+ site. After 3 cycles of AVPC alone, RERs showed favorable results. Conversely, SERs had unfavorable outcomes with AVPC alone, although they improved with 21-Gy IFRT. RT remains an important component of treatment for SERs. This trial was registered at www.clinicaltrials.gov as #NCT00302003.

PET-Based Quantification of Baseline Metabolic Tumor Burden Improves Risk Stratification in High-Risk Hodgkin Lymphoma: A Children's Oncology Group Study

<h3>Purpose/Objective(s)</h3> COG AHOD0831 was a multi-center, prospective study that used a response-adapted approach for patients < 22-years-old with high-risk Hodgkin lymphoma. After 2 cycles of chemotherapy, response evaluation was performed by ¹⁸F-fluorodeoxyglucose (FDG) positron-emission tomography (PET) scan. Rapid early responders (RERs) received less intensive therapy than slow early responders (SERs). In this study, both 1^st & 2^nd event-free survival (EFS) rates were below the pre-specified targets. We explored if measures of baseline tumor burden improve risk stratification. <h3>Materials/Methods</h3> Patients from AHOD0831 were identified who had baseline PET scans that were amenable to quantitative analyses. For each patient, metabolic tumor volume (MTV), total lesion glycolysis (TLG), maximum standardized uptake value (SUVmax), and peak SUV (SUVpeak) were obtained for mediastinal (m) and total body (t) disease. MTV was defined based on thresholds of SUV > 2.5 or > 40% SUVmax. TLG was defined as MTV * tumor SUVmean. EFS was assessed by Kaplan-Meier analyses. 2^nd EFS was defined as the time to a second event, reflecting rates of successful salvage after a 1^st relapse. Receiver operating characteristic analyses estimated the ability of PET parameters to predict EFS; optimized cutoff values were identified using a Youden index. <h3>Results</h3> Of 166 patients enrolled on AHOD0831, 94 (57%) had PET scans evaluable for quantitative analysis. For this subset: median age 15.5 years; 62% male; 67% white; 45% stage III, 55% stage IV; 86% bulk; 60% nodular sclerosis histology; 54% RER, 46% SER. These characteristics did not differ significantly from the complete AHOD0831 cohort. At a median follow-up of 49 months, 4-year EFS was 76% for the complete cohort (76% RERs, 75% SERs). Patients with high tMTVs and tTLGs, based on each threshold, were significantly more likely to be SERs (all <i>P</i> < 0.02). tTLG_2.5 was significantly associated with EFS, with an optimal cutoff value of 1841 to distinguish low- and high-risk groups (<i>P</i> = 0.04). tTLG_2.5 was significantly associated with EFS in RERs (<i>P</i> = 0.01) but not in SERs (<i>P</i> = 0.8). Patients were stratified by RER vs. SER and high vs. low tTLG_2.5. The best EFS was associated with RER & low tTLG_2.5, the worst EFS with RER & high tTLG_2.5, and intermediate EFS with SER regardless of tTLG_2.5 (4-year EFS: 92%, n = 25; 60%, n = 26; 79%, n = 14; 74%, n = 29, respectively). EFS was superior in patients with tTLG_2.5 ≤1841 & RER when compared to the rest of the cohort (94% vs. 71%, <i>P</i> = 0.02). For this favorable subgroup, 2^nd EFS was 100%. <h3>Conclusion</h3> RERs with a low baseline metabolic tumor burden experienced excellent EFS with less intensive therapy. Conversely, RERs with a high baseline tumor burden experienced poor EFS that was even worse than that of SERs. Thus, patients with a high metabolic tumor burden upfront may benefit from intensified therapy, even if they achieve a RER. PET-based measures of initial disease burden may contribute to risk-based treatment algorithms and improve outcomes in HL.

Comprehensive Cell Specific Transcriptome Profiling of a Pediatric Hodgkin Lymphoma Cohort

Introduction: Pathogenic Hodgkin Reed-Sternberg (HRS) cells constitute approximately 1% of Hodgkin lymphoma (HL) tumor cells. Studies characterizing genomic lesions and gene expression of HRS gene cells have been limited due to technical challenges of studying these rare cells, and the majority of existing data has focused on adult HL. We therefore developed a multi-parameter flow sorting strategy to isolate viable cells from pediatric HL tumors and to define the transcriptomes of HRS cells and infiltrating lymphocytes in order to inform underlying mechanisms of HL pathogenesis and also create an opportunity to identify cell-specific biomarkers to predict disease risk and response to therapy. Methods : Flow cytometry was used to sort HRS cells, CD4+ T cells, CD8+ T cells, and CD20+/30+B cells from pediatric subjects' HL lesions and control tonsils. Purity was confirmed by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC). Affymetrix GeneChip HTA 2.0 was used to assess the gene expression profiles (GEPs) for 16 HRS primary tumor cell samples, 14 HL CD4+ and CD8+ T cell samples, 6 control tonsillar CD20+, CD30+, CD4+, and CD8+ cell samples, and 6 HL cell lines. Unsupervised hierarchical clustering and principal component analysis (PCA) were used to determine relatedness, and Cibersort was performed to confirm the phenotype of the sorted cell types. GEPs of HRS, HL CD4+, and HL CD8+ cells were compared to respective controls using a univariate t-test. Significance was determined using a multivariate permutation test with the confidence level of FDR assessment at 80 percent and the maximum allowed proportion of false-positive proteins at 0.1. Gene set enrichment analysis (GSEA) and ingenuity pathway analysis (IPA) were performed to analyze DEGs. Results: Effectiveness of the sorting strategy of HRS cells was confirmed by quantitative RT-PCR and IHC that demonstrated significant enrichment of CD30expression and CD30+ cells in the sorted HRS cell fraction. GEP comparisons were performed for 13 HL samples with matched HRS/CD4+/CD8+ cells: HRS vs. control tonsil CD20+/CD30+ (1934 and 3846 DEGs, respectively), HL CD4+ vs. control CD4+ (635 DEGs), HL CD8+ vs. control CD8+ (2 DEGs). We carried out a transcriptomic analysis of HRS cells, and a set of multifunctional genes were more than 2-fold downregulated (P &lt; .001), involved in telomere maintenance and packaging (TERF2, RFC3, DNA2 and a group of HIST1) when compared to healthy lymph node CD30+ cells. A set of genes related to cytokine/chemokine dysregulation was also upregulated in HRS cells, including IL6, CCL18, and CXCL9. IPA and GSEA of specific HRS genes were also performed and demonstrated pathways associated with HL pathogenesis, including NFĸB activation and T cell exhaustion. Over-expression of genes associated with T cell pathways was demonstrated in HRS cells. While this may be a result of T cell rosetting and contamination, it may also reflect innate T cell signature within HRS cells, as HRS cells clustered separately from T cells in both unsupervised hierarchical clustering and PCA. Cibersort analysis of HRS cells revealed a heterogeneous phenotype that may reflect aberrant differentiation. In comparing clinical characteristics within HRS cells, TCEAL1 was elevated in slow vs. rapid early responders and 3 DEGs were identified when comparing EBV+/- samples. Within HL CD8 cells, KLF2 was elevated in EBV- samples. Conclusions: This study was the first to successfully isolate highly purified HRS cell populations from whole HL lesions in a pediatric HL cohort. Transcriptomic analysis of pediatric HRS cells identified mechanisms previously associated with HL pathogenesis, and also identified potential novel mechanisms, including telomere maintenance. Additional analyses demonstrated significant heterogeneity of HRS trasncriptomes across specimens that may reflect distinct differentiation pathways and differences in HRS-immune cell interactions. Finally, this study identified increased expression of some genes associated with EBV status and response to therapy. Future studies in an expanded cohort will validate these findings, compare pediatric and adult GEPs, and test these cell-specific biomarkers into the current risk stratification strategies of prospective clinical trials. Disclosures No relevant conflicts of interest to declare.

Outcomes in intermediate-risk pediatric lymphocyte-predominant Hodgkin lymphoma: A report from the Children's Oncology Group.

Optimal management of patients with intermediate-risk lymphocyte-predominant Hodgkin lymphoma (LPHL) is unclear due to their small numbers in most clinical trials. Children's Oncology Group AHOD0031, a randomized phase III trial of pediatric patients with intermediate-risk Hodgkin lymphoma (HL), included patients with LPHL. We report the outcomes of these patients and present directions for future therapeutic strategies. Patients received two cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC) followed by response evaluation. Slow early responders were randomized to two additional ABVE-PC cycles ± two dexamethasone, etoposide, cisplatin, and cytarabine cycles and all received involved field radiotherapy(IFRT). Rapid early responders (RERs) received two additional ABVE-PC cycles. RERs with complete response (CR) were randomized to IFRT or no further therapy. RERs without CR received IFRT. Ninety-six (5.6%) of 1711 patients on AHOD0031 had LPHL. Patients with LPHL were more likely to achieve RER (93.6% vs. 81.0%; P=0.002) and CR (74.2% vs. 49.3%; P=0.000005) following chemotherapy compared with patients with classical HL. Five-year event-free survival (EFS) was superior in patients with LPHL (92.2%) versus classical HL (83.5%) (P=0.04), without difference in overall survival (OS). Among RERs with CR following chemotherapy (n=33), there was no difference in EFS or OS between those randomized to receive or not receive IFRT. Children and adolescents with intermediate-risk LPHL represent ideal candidates for response-adapted therapy based on their favorable outcomes. The majority of patients treated with the ABVE-PC backbone achieve RER with CR status and can be treated successfully without IFRT.

Clinic study progress of Hodgkin lymphoma in children and adolescents

Current 5-year overall survival rates (OS) for children and adolescents treated for Hodgkin lymphoma (HL) exceed 90%.However, this early success is negatively impacted by late mortality due to adverse health-related squeal of therapy.This challenge has resulted in the development of various strategies aimed at identifying the optimal balance between maintaining OS and avoidance of long-term morbidity of therapy.With new imaging techniques, the success of reducing therapy in a subset of rapid early responders is demonstrated.Treatment strategy is not only a risk-adjusted but also response-based combined-modality therapy. Key words: Hodgkin lymphoma; Child; Chemotherapy

Use of Morphological Early Response Data to Predict Relapse in Teenage and Young Adult (TYA) Patients with Acute Lymphoblastic Leukaemia (ALL)

IntroductionTreatment outcomes for teenage and young adult (TYA) patients with Acute Lymphoblastic Leukaemia (ALL) lag behind those of younger patients when treated on equivalent protocols, with higher rates of toxicity and relapse reported for those aged >10 years. Outcomes of relapsed ALL are poor so more accurate identification of those destined to relapse is required. Whilst minimal residual disease (MRD) is a powerful tool to predict those at low risk and in whom treatment can be de-escalated, improved strategies are required for early identification of high risk patients. This study aimed to determine if the morphological early response assessment could be used as a predictor of relapse in TYA patients with ALL.MethodsAll patients treated on the national prospective UKALL2003 trial aged 10 - 24 years who had not relapsed by day 35 (i.e. could potentially have treatment escalated) were included in the study. Early response in patients aged >10 years was defined as percentage of blasts by morphology at day 8: rapid early responders had ≤ 25% blasts and slow early responders >25% blasts. We analysed the following patient characteristics which were previously associated with differential outcomes: age at diagnosis, presenting white cell count, rapid or slow early response (RER or SER); MRD status at day 28; immunophenotype (B/T/other) and cytogenetic risk group (high risk, good risk, poor risk, T-ALL, other). Cox regression was used to assess the association of these factors with time to relapse and logistic regression (LR) was used to assess their association with relapse by the end of treatment (EOT: 2.5 years for girls and 3.5 years for boys). Using backwards selection (cut off for inclusion: p=0.1) a multivariable LR model was established and a receiver operating characteristic curve (ROC) was used to assess how well it could predict relapse before the EOT.Results820 consecutive patients were included in the analysis of whom 597 were aged 10 - 15 years and 223 were aged 16 - 24 years. 332 patients were classified as MRD high risk and 184 as SER on the basis of morphology. RER was significantly associated with a reduced risk of relapse even after adjustment for other factors including MRD, age, WBC and risk status (Hazard Ratio (HR) 0.64 (95% CI 0.42 - 0.97, p<0.001).697 patients with an outcome available at the EOT could be included in the LR analysis. The final multivariable model included day 28 MRD, day 8 response, age, WBC and cytogenetic risk group. The predictor generated by this model gives a ROC area under the curve of 81.2% (95% CI: 76.8 - 85.6) but there were no cut points which resulted in acceptable detection (DR) and false positive rates (FPR). As the intervention for the poor prognosis group would potentially include an allogeneic transplant with associated high mortality and morbidity a low FPR would be key to clinical utility. In order to achieve a clinically useful DR of 79.5% we would have to accept a false positive rate of 30.5%. As only 11% pf patients relapsed by EOT but 36% of patients fell into our bad prognosis group this would mean that for every 100 patients, ~27 would be transplanted unnecessarily. In the subgroup analysis of those aged 16 - 24 early response was not significantly associated with either time to relapse (HR RER: 0.74 (0.36 - 1.51, p = 0.4) or relapse by the EOT (Odds ratio RER: 0.63 (0.26 - 1.49, p =0.3)ConclusionsSlow early response is significantly associated with both time to relapse and relapse by EOT in this patient cohort aged 10 - 24 years and this effect is independent of other prognostic factors including MRD. However, even when over-fit the prognostic model generated (which included SER) resulted in FPRs which were too high to be clinically useful. Future work should focus on novel alternative methods of relapse risk prediction for the adolescent patient with ALL. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Patterns of Relapse From a Phase 3 Study of Response-Based Therapy for Intermediate-Risk Hodgkin Lymphoma (AHOD0031): A Report From the Children's Oncology Group

The study was designed to determine whether response-based therapy improves outcomes in intermediate-risk Hodgkin lymphoma. We examined patterns of first relapse in the study. From September 2002 to July 2010, 1712 patients <22 years old with stage I-IIA with bulk, I-IIAE, I-IIB, and IIIA-IVA with or without doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide were enrolled. Patients were categorized as rapid (RER) or slow early responders (SER) after 2 cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC). The SER patients were randomized to 2 additional ABVE-PC cycles or augmented chemotherapy with 21 Gy involved field radiation therapy (IFRT). RER patients were stipulated to undergo 2 additional ABVE-PC cycles and were then randomized to 21 Gy IFRT or no further treatment if complete response (CR) was achieved. RER without CR patients were non-randomly assigned to 21 Gy IFRT. Relapses were characterized without respect to site (initial, new, or both; and initial bulk or initial nonbulk), and involved field radiation therapy field (in-field, out-of-field, or both). Patients were grouped by treatment assignment (SER; RER/no CR; RER/CR/IFRT; and RER/CR/no IFRT). Summary statistics were reported. At 4-year median follow-up, 244 patients had experienced relapse, 198 of whom were fully evaluable for review. Those who progressed during treatment (n=30) or lacked relapse imaging (n=16) were excluded. The median time to relapse was 12.8 months. Of the 198 evaluable patients, 30% were RER/no CR, 26% were SER, 26% were RER/CR/no IFRT, 16% were RER/CR/IFRT, and 2% remained uncategorized. The 74% and 75% relapses involved initially bulky and nonbulky sites, respectively. First relapses rarely occurred at exclusively new or out-of-field sites. By contrast, relapses usually occurred at nodal sites of initial bulky and nonbulky disease. Although response-based therapy has helped define treatment for selected RER patients, it has not improved outcome for SER patients or facilitated refinement of IFRT volumes or doses.

Improved Outcome for Children and Young People with T-Acute Lymphoblastic Leukaemia: Results of the UKALL 2003 Trial

▪T-ALL accounts for around 15% of paediatric ALL and carries a less favourable prognosis than B-ALL due to a higher relapse rate (RR) and poor response to salvage therapy. We sought to determine if the outcome for patients with T-ALL had improved on a contemporary, response based treatment protocol, UKALL 2003, which did not include pre-emptive cranial radiotherapy or high dose methotrexate. NCI standard risk patients received a 3 drug induction with dexamethasone, vincristine and pegylated asparaginase (1000 units/m2) (regimen A). NCI high risk (HR) patients also received daunorubicin (regimen B). Early morphological marrow response was measured on day 8 for NCI HR patients and day 15 for NCI standard risk patients except patients > 16 years. Rapid early responders were stratified by minimal residual disease (MRD) at day 29 which was measured by RQ-PCR. MRD negative patients were randomised to standard or reduced intensity therapy. MRD high risk (>0.01%) patients were randomised to standard therapy (regimen A/B) or an intensified regime consisting of augmented BFM consolidation, escalating Capizzi methotrexate and 2 delayed intensifications (regimen C). Patients with high risk cytogenetics or a slow early morphological response received regimen C, regardless of MRD. Regimen A and B patients received 4 doses of pegylated asparaginase (2 in induction and 1 in each DI) and Regimen C patients received an additional 8 doses.Of 3126 patients in the trial, 388 (12.4%) had T-ALL. Of those, 73% were male with a median age of 10 yrs (range 1-24). Median WCC was 94x109/L (range 1-881) and 85% were HR by NCI criteria. 76% had a rapid early response (RER), defined as <25% bone marrow blasts. MRD was evaluable for 72% of patients. MRD at day 29 was ≥0.1% in 37%, detectable at a level of <0.1% in 22% and undetectable in 41%. Compared to the trial population as a whole, patients with T-ALL were more often stratified to receive the higher intensity regimens. T-ALL 11%, 52% and 37% treated on Regimens A, B and C compared with 51%, 26% and 23% for trial overall.With a median follow up of 5 yrs 7 mths (range 1 yr 4 mths – 9 yrs 11 mths), patients with T-ALL had an inferior outcome compared to those with B-ALL due to a higher risk of relapse (p=0.0003) and death in remission (p=0.04); 5 year event free survival (EFS) 81.2% (95% CI 77.3-85.1) vs 88.1% (86.6-89.5), overall survival (OS) 86.4% (82.9-89.9) vs 92.4% (91.4-93.4), RR 13.5% (10.0-17.0) vs 8.2% (7.0-9.4) and death in remission 4.3% (2.3-6.3) vs 2.4% (1.8-3.0). The site of excess relapses in T-ALL was both bone marrow (10.1% (7.0-13.2) vs 5.9% (4.9-6.9)) and isolated CNS (3.5% (1.5-5.5) vs 1.9% (1.3-2.5)). However, the CNS relapse rate is comparable to other protocols containing cranial radiotherapy and high dose methotrexate. The excess deaths in remission are a reflection of the higher intensity regimens that a majority of T-ALL patients received. In contrast to B-ALL (data not shown), increasing WCC was not a risk factor for relapse in T-ALL. 5 year EFS for T-ALL patients with a WCC <100 was 85% vs 81% for those with a WCC ≥100. CNS relapse rate was not different between the two groups, 5% vs 8% (p=0.3). There was no difference in outcome between those with a WCC of 100-300 and ≥300. Response to induction was the strongest predictor of relapse. Patients with a slow early response had a high relapse risk (Hazard Ratio=2.31 (1.11-4.84), p = 0.03 in multivariate analysis) despite receiving Regimen C. Patients with MRD ≥0.1% had a 5 year EFS of 71.5% compared to 89.6% for the MRD <0.1% group and 90.3% for the MRD negative group (log rank p(trend)=0.001), RR 23.2% vs 7.1% vs 8% (p=0.003). There was a trend for a worse outcome in the patients aged ≥16 although this was not statistically significant, 5 year EFS 74.1% vs 82.8% (log rank p=0.7), RR 20.8 vs 11.9%, (p=0.09). Compared with our previous trial, UKALL97/99, outcome for T-ALL patients has improved with a higher EFS, 81.7% vs 72.8% at 5 years (log rank p=0.08), due mainly to a non-significantly lower relapse rate 13.5% vs 20.6% (p=0.09).T-ALL outcomes have improved with better risk stratification and the use of dexamethasone and pegylated asparaginase. Pre-emptive cranial radiotherapy or high dose methotrexate are not essential to preventing CNS relapse. The outcome for patients with T-ALL, however, remains inferior to those with B-ALL highlighting the need for novel therapies for patients with high risk T-lineage disease. DisclosuresNo relevant conflicts of interest to declare.

Characteristics and Outcome Of Children and Young Adults With Early T-Precusor (ETP) ALL Treated On UKALL 2003

Early T-precursor (ETP) ALL is a recently described poor prognostic sub-group of childhood T-ALL identified by a distinctive gene expression profile and immunophenotype (CD1a-, CD5 weak, CD8- and presence of myeloid or stem cell markers). It accounts for around 12% of T-ALL and is associated with a poor outcome in retrospective US and Italian studies with a 5 year event-free survival (EFS) of less than 50% on historical treatment protocols. We sought to determine the outcome for this sub-group on a contemporary MRD stratified treatment protocol, UKALL 2003.As full immunophenotype data was not collected centrally, individual centres were asked to provide individual patient data retrospectively. Of 387 T-ALL cases in the trial, immunophenotype data to classify ETP status was not available for 148 patients. Of the remaining 239 cases, 35 (15%) were classified as definite/probable (CD8 and 1a neg with stem cell or myeloid antigen expression) and 17 (7%) as possible (CD8 neg and stem cell or myeloid antigen expression, 1a not available) ETP. The definite, probable and possible ETP groups had similar patient characteristics and outcomes and have, therefore, been analysed together. Compared to those without an ETP phenotype, ETP patients were more likely to present with a low (<50x109/l) white cell count (56% vs 26%, p<0.0001) but were less likely to be morphological rapid early responders at day 8/15 (63% vs 83% p =0.002) or MRD low risk at the end of induction (4% vs 27%, p = 0.008). Unlike previous reports, the risk of induction failure was not significantly higher in the ETP group (n= 2 vs 1 among non-ETP cases).With a median follow-up of 4 years 10 months (range 1 year 4 months - 9 years), the ETP sub-group have a non-significantly inferior EFS (76.0% (95% CI: 64.0-88.0%) vs 84.6% (79.3-89.9%) at 5 years, p = 0.2) and OS (84.1% (73.9-94.3%) vs 90.9% (86.6-95.2%), p = 0.08) compared to the non-ETP sub-group, due primarily to a non-significantly higher relapse rate (17.7% (6.5-28.9%) vs 9.6% (5.1-14.1%), p = 0.1). Although MRD risk group was a determinant of outcome in the non-ETP group (p=0.05), its significance within the ETP group could not be reliably determined since only 2 patients were MRD low risk, of whom 1 suffered a relapse. Interestingly, of the 8 relapses in the ETP group, 7 were isolated marrow relapses and there was one isolated testicular relapse, whereas 12 of the 17 relapses in the non-ETP group involved the CNS (5 isolated and 7 combined).Although ETP ALL is associated with an adverse outcome compared with non-ETP T-ALL, a 5 year EFS of 76% on a contemporary MRD stratified protocol is not sufficiently poor to warrant experimental treatment or first remission allogeneic transplant for the group universally. Disclosures:No relevant conflicts of interest to declare.

A comparison of traditional vs. response-based involved-field radiotherapy on clinical target volume and organs at risk for pediatric rapid early responders with high-risk Hodgkin lymphoma

The purpose of this study was to compare the traditional involved-field radiation therapy (IFRT) which includes all sites of initial disease to response-based IFRT which includes only sites of bulky disease for rapid early responders (RER) in high-risk Hodgkin lymphoma. IFRT treatment plans (one traditional and one response-based), each delivering 21 Gy, were designed for seven pediatric patients with stage IIIB/IVB Hodgkin lymphoma. Dose–volume histograms (DVH) were created to determine the dose to the clinical target volume (CTV) and each organ at risk (OAR) for each treatment plan. The average CTV for the traditional IFRT was 1,491.3 cm3 and for response-based IFRT was 566.7 cm3 (p = 0.02). Response-based treatment reduced the average dose to the lungs from 13.3 to 6.5 Gy (p = 0.006), heart from 17.2 to 6.5 Gy (p = 0.004), breasts from 9.8 to 2.5 Gy (p = 0.003), thyroid from 21.7 to 6.1 Gy (p = 0.003), parotid glands from 8.6 to 0.8 Gy (p = 0.01), kidneys from 5.2 to 0.4 Gy (p = 0.02), liver from 8 to 0.5 Gy (p = 0.005), and spinal cord from 17.5 to 5.7 Gy (p = 0.001). Treating response-adapted reduced IFRT to sites of initial bulky disease for RER resulted in significant volume and dose reductions to the CTV and OAR when compared to the traditional IFRT. This reduction of dose to OAR may translate to a reduction of normal tissue toxicity and radiation late effects.

Assessment of end induction minimal residual disease (MRD) in childhood B precursor acute lymphoblastic leukemia (ALL) to eliminate the need for day 14 marrow examination: A Children’s Oncology Group study.

10001 Background: Response to initial therapy is a powerful prognostic factor in pediatric ALL. Traditionally, slow early response (SER) has been defined by marrow morphology 8 or 15 days after start of induction therapy. More recently, MRD has been identified as the most important predictor of adverse outcome. The value of morphologic assessment of response in the setting of MRD has not been established. Methods: In COG studies AALL0331 (for NCI Standard Risk (SR) B ALL patients (pts)) and AALL0232 (High Risk (HR) B ALL pts), SER was defined by morphology as either ≥5% blasts in a day 15 marrow, or by flow cytometry as ≥0.1% MRD in a d29 marrow (SER MRD). Assignment to treatment arms also depended upon cytogenetic findings and extramedullary disease; each protocol had randomized treatment questions. SER pts were non-randomly assigned to receive augmented BFM therapy (ABFM) with 2 interim maintenance and delayed intensification phases (and CNS radiation for HR SER pts only). All pt treatment groups were combined for these analyses. Rapid early responders (RER) had a better outcome than SER pts (Table). However, pts who were SER only by morphology had a 5y DFS that was not significantly different from that of RER pts, and superior to that of pts who were SER MRD, or SER by both morphology and MRD. In multivariate analysis, SER by morphology was not an adverse prognostic factor after adjusting for risk group and MRD, or separately in SR or HR pts after adjusting for MRD. However, pts with .01-.1% MRD who were SER by morphology had a better 5y DFS than the.01-.1% MRD pts who were RER (90±6%, n=91 vs 77±3%, n=592). Only the former group received ABFM, suggesting intensification based on response rescues some poor risk pts. We conclude that a day 15 marrow is not needed to assess response if MRD is measured at end induction, provided that SER MRD is defined using a .01% cutoff, the threshold for intensifying therapy in current COG ALL trials. Clinical trial information: NCT00103285, NCT00075725. [Table: see text]

Effects of Dexamethasone (DEX) Vs Prednisone (PDN) and High-Dose Methotrexate (HD-MTX) Vs Capizzi Methotrexate/Asparaginase (C-MTX/ASNase) On Osteonecrosis (ON) Incidence in Children and Young Adults with High Risk Acute Lymphoblastic Leukemia (HR-ALL): A Report From the Children's Oncology Group (COG) Study AALL0232

AbstractAbstract ▪665▪This icon denotes a clinically relevant abstractImproved treatment outcomes for HR-ALL are associated with a significant risk of symptomatic ON, particularly in adolescents. Causes are multifactorial, including exposure to DEX, MTX and ASNase. This was first noted on CCG-1882 (1991–1995), which showed more ON in slow early responders (SER) given 2 vs 1 interim maintenance/delayed intensification (IM/DI) phases as part of therapy that included C-MTX/ASNase during IM and continuous DEX (d1-21) during DI (Mattano, JCO 2000). Since 1996 the COG has prospectively monitored the occurrence of symptomatic ON in HR ALL trials. CCG-1961 (1996–2002) showed that alternate-week DEX (AWD) (d1-7, 15–21) during 2 DIs reduced ON compared with continuous DEX during 1 DI in rapid early responders (RER) (Mattano, Lancet Oncol 2012). AALL0232 (2003–2011) enrolled a total of 3154 HR-ALL patients (pts) 1–30 yr and included COG augmented therapy with a 2×2 randomization to DEX (10 mg/M2 d1-14) vs PDN (60 mg/M2 d1-28) during induction (IND) and HD-MTX vs escalating-dose C-MTX plus pegaspargase during IM. RER pts received 1 IM/DI, SER pts received 2 IM/DI; all initially received monthly DEX maintenance (MTC) pulses (6 mg/M2 d1-5). To limit ON, pts 13+ yr received AWD during 1 or 2 DI, while pts <13 yr received continuous DEX. Based on interim analyses, the study was amended twice to address unexpectedly high ON rates. After 10/2006 all pts 10+ yr received AWD during DI; after 6/2008 all pts 10+ yr were non-randomly assigned to PDN during IND, and pts of all ages received AWD during DI and PDN pulses in MTC. Detailed analyses of 2701 pts with reportable data (1405 with 24+ month follow-up) showed ON in 249 pts (228 10+ yr, 21 1–9 yr; 119 males, 130 females). Symptom onset was pre-MTC in 17.7%, during MTC in 77.9%, after therapy completion in 4.4%, and within 36 months from ALL diagnosis in 98.0%. The 36-month cumulative ON incidence was 13.5±1.1%, was higher for pts 10+ yr (19.6±1.6 vs 3.1±0.9%, RHR 6.7, p<0.0001), and increased with age (1–9 yr 3.1±0.9%, 10–12 yr 17.2±2.5%, 13–15 yr 21.9±2.7%, 16+ yr 21.2±3.3%, p<0.0001). For pts 10+ yr, ON incidence was higher in females (22.2±2.5 vs 17.4±2.1%, RHR 1.4, p=0.01). Among randomized RER pts 10+ yr (Table), ON incidence was higher for DEX vs PDN (RHR 1.8); for pts 1–9 yr, rates were similarly low but modestly higher for PDN (borderline significance). There was no difference between C-MTX/ASNase vs HD-MTX overall. However, for pts 10+ yr randomized to PDN, pairwise comparison showed a higher ON rate for C-MTX/ASNase (17.2±3.8 vs 10.3±2.7%, RHR=1.7, p=0.01). Comparison of ON incidences between randomized RER regimens showed significant differences in pts 1–9 yr (DC 1.5±1.4, DH 0.7±1.0, PC 5.6±2.6, PH 1.9±1.6%, p=0.04) and 10+ yr (DC 23.9±4.0, DH 24.7±3.7, PC 20.9±4.0, PH 9.8±2.7%, p=0.0004). Comparison of ON incidences for pts 10–12 yr given continuous DEX vs AWD in DI (pre- vs post-2006 amendment) confirmed a significantly lower rate with AWD (28.9±3.8 vs 10.3±3.1%, RHR 3.1, p<0.0001). Maximum patient ON clinical severity (CTCAE v3.0) reported for 210 of 249 pts: 6.7% grade 1, 63.3% grade 2, 29% grade 3, 1.0% grade 4. The most common sites were knee > hip > ankle. In conclusion, DEX is associated with a higher incidence of ON among pts 10+ yr receiving augmented therapy. Children 1–9 yr appear to tolerate DEX and PDN during IND with similar low ON rates. ON risk can be significantly reduced by using AWD during DI, and by using HD-MTX rather than C-MTX/ASNase with PDN based regimens. Studies are presently underway that include prospective MRI screening to further define the natural history of ON in HR ALL and to identify additional risk factors for this common toxicity.Randomized RER, 36-Month Incidence Rate (% ± SE)DEXPDNP1-9 yr1.1 ± 0.93.7 ± 1.50.0510+ yr24.3 ± 2.715.1 ± 2.40.000716+ yr25.6 ± 6.013.7 ± 4.90.04C-MTXHD-MTXP1-9 yr3.6 ± 1.41.6 ± 0.90.0910+ yr19.1 ± 2.418.3 ± 2.20.416+ yr16.4 ± 4.724.0 ± 4.50.2 Disclosures:Mattano: Pfizer: Employed 2009–2012 Other, Equity Ownership.

A Comparison of Traditional Versus Response-based Involved-Field Radiation Therapy on Clinical Target Volume and Organs-at-Risk for Pediatric Rapid Early Responders With High-Risk Hodgkin Lymphoma

A Comparison of Traditional Versus Response-based Involved-Field Radiation Therapy on Clinical Target Volume and Organs-at-Risk for Pediatric Rapid Early Responders With High-Risk Hodgkin Lymphoma