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Germline mutations in RUNX1 result in autosomal dominant familial platelet disorder with associated myeloid malignancy (FPDMM). To characterize the hematopathologic features associated with a germline RUNX1 mutation, we reviewed a total of 42 bone marrow aspirates from 14 FPDMM patients, including 24 cases with no cytogenetic clonal abnormalities, and 18 with clonal karyotypes or leukemia. We found that all aspirate smears had ≥10% atypical megakaryocytes, predominantly characterized by small forms with hypolobated and eccentric nuclei, and forms with high nuclear-to-cytoplasmic ratios. Core biopsies showed variable cellularity and variable numbers of megakaryocytes with similar features to those in the aspirates. Granulocytic and/or erythroid dysplasia (≥10% cells per lineage) were present infrequently. Megakaryocytes with separate nuclear lobes were increased in patients with myelodysplastic syndrome (MDS) and acute leukemia. Comparison to an immune thrombocytopenic purpura cohort confirms increased megakaryocytes with hypolobated eccentric nuclei in FPDMM patients. As such, patients with FPDMM often have atypical megakaryocytes with small hypolobated and eccentric nuclei even in the absence of clonal cytogenetic abnormalities; these findings are related to the underlying RUNX1 germline mutation and not diagnostic of MDS. Isolated megakaryocytic dysplasia in patients with unexplained thrombocytopenia should raise the possibility of an underlying germline RUNX1 mutation.

Purpose Pediatric oncology patients undergoing active chemotherapy are suspected to be at a high risk for severe disease secondary to severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection; however, data to support this are lacking. We aim to describe the characteristics of coronavirus disease 2019 (COVID‐19) in this population and also its impact on pediatric cancer care in the New York region during the peak of the pandemic. Patients and Methods This multicenter, retrospective study included 13 institutions. Clinical and laboratory information on 98 patients ≤21 years of age receiving active anticancer therapy, who tested positive for SARS‐CoV‐2 by nasopharyngeal swab polymerase chain reaction (PCR), was collected. Results Of the 578 pediatric oncology patients tested for COVID‐19, 98 were positive, of whom 73 were symptomatic. Most experienced mild disease, 28 required inpatient management, 25 needed oxygen support, and seven required mechanical ventilation. There is a slightly higher risk of severe disease in males and obese patients, though not statistically significant. Persistent lymphopenia was noted in severe cases. Delays in cancer therapy occurred in 67% of SARS‐CoV‐2‐positive patients. Of four deaths, none were solely attributable to COVID‐19. The impact of the pandemic on pediatric oncology care was significant, with 54% of institutions reporting delays in chemotherapy, 46% delays in surgery, and 30% delays in transplant. Conclusion In this large multi‐institutional cohort, we observed that mortality and morbidity from COVID‐19 amongst pediatric oncology patients were low overall, but higher than reported in general pediatrics. Certain subgroups might be at higher risk of severe disease. Delays in cancer care due to SARS‐CoV‐2 remain a concern.

Summary Treatment with dose-adjusted EPOCH (etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone) chemotherapy and rituximab (DA-EPOCH-R) has become the standard of care for primary mediastinal B-cell lymphoma (PMBCL) at many institutions despite limited data in the multi-centre setting. We report a large, multi-centre retrospective analysis of children and adults with PMBCL treated with DA-EPOCH-R to characterize outcomes and evaluate prognostic factors. We assessed 156 patients with PMBCL treated with DA-EPOCH-R across 24 academic centres, including 38 children and 118 adults. All patients received at least one cycle of DA-EPOCH-R. Radiation therapy was administered in 14·9% of patients. With median follow-up of 22·6 months, the estimated 3-year event-free survival (EFS) was 85·9% [95% confidence interval (CI) 80·3–91·5] and overall survival was 95·4% (95% CI 91·8–99·0). Outcomes were not statistically different between paediatric and adult patients. Thrombotic complications were reported in 28·2% of patients and were more common in paediatric patients (45·9% vs. 22·9%, P = 0·011). Seventy-five per cent of patients had a negative fluorodeoxyglucose positron emission tomography (FDG-PET) scan at the completion of DA-EPOCH-R, defined as Deauville score 1–3. Negative FDG-PET at end-of-therapy was associated with improved EFS (95·4% vs. 54·9%, P

Purpose 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. Procedure 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. Results 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. Conclusion 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.

PURPOSE: The presented protocol for pediatric intermediate-risk Hodgkin lymphoma evaluated the use of a dose-intensive chemotherapy regimen (ABVE-PC [doxorubicin, bleomycin, vincristine, etoposide, cyclophosphamide, prednisone]) with response-based therapy augmentation (addition of DECA [dexamethasone, etoposide, cisplatin, cytarabine]) or therapy reduction (elimination of radiation). METHODS AND MATERIALS: A central review of the radiation therapy data for quality assurance was performed, and the association between radiation protocol deviation (RPD) and relapse was assessed in the pediatric group (age

Background Histologic prognostic factors have been described for nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). This study examines histologic and immunophenotypic variants in a clinical trial for pediatric NLPHL. Procedure One hundred sixty-eight cases of localized NLPHL were examined for histologic variants, CD30 and immunoglobulin D (IgD) expression, and outcome. Histologic types were scored categorically as 0 = 0, 1 ≤ 25%, and 2 > 25% of the sample. Results Fifty-eight (35.1%) cases showed only typical nodular with or without serpiginous histology (types A and B). The remainder showed mixtures of histologies. The numbers of patients with score 2 are 85 (50.6%) type A, 21 (12.5%) type B, 46 (27.4%) with extranodular large B cells (type C), 3 with T-cell-rich nodular pattern (type D), 55 (32.7%) with diffuse T-cell-rich (type E) pattern, and 2 (1.2%) with diffuse B-cell pattern (type F). Higher level of types C (P = 0.048) and D (P = 0.033) resulted in lower event-free survival (EFS). Cytoplasmic IgD was found in 65 of 130 tested (50%), did not significantly associate with EFS but positively correlated with types C and E histology (P < 0.0001) and negatively correlated with types A (P = 0.0003) and B (P = 0.006). Seventeen (10%) expressed CD30, with no adverse effect. Conclusions Variant histology is common in pediatric NLPHL, especially types C and E, which are associated with IgD expression. Type C variant histology and possibly type D are associated with decreased EFS, but neither IgD nor CD30 are adverse features. Variant histology may warrant increased surveillance, but did not affect overall survival.

In childhood Hodgkin lymphoma, estimated 5 years survival rates exceed 90%. Long-term survival continues to decline from delayed toxicities. Key findings from recent Children's Oncology Group trials include: (1) Radiotherapy selection may be based on early chemotherapy response assessed by both FDG-PET and CT imaging, (2) A new prognostic factor score stratifies patients into risk categories; and (3) novel retrieval regimens were identified. A phase I/II trial is investigating Brentuximab vedotin (Bv) with gemcitabine in relapsed patients. A phase 3 trial will modify conventional chemotherapy and radiotherapy approaches through the addition of Bv, while incorporating translational biology to identify molecular targets. Pediatr Blood Cancer 2013; 60: 972–978. © 2012 Wiley Periodicals, Inc.

Purpose Children’s Oncology Group study AHOD03P1 was designed to determine whether excellent outcomes can be maintained for patients with low-risk, pediatric lymphocyte-predominant Hodgkin lymphoma (LPHL) with a strategy of resection alone or minimal chemotherapy. Patients and Methods Patients with stage IA LPHL in a single node that was completely resected were observed without further therapy; recurrences were treated with three cycles of doxorubicin/vincristine/prednisone/cyclophosphamide (AV-PC). Patients with unresected stage IA or stage IIA LPHL were treated with three cycles of AV-PC. Patients with less than a complete response (CR) to AV-PC received 21-Gy involved-field radiation therapy (IFRT). Results A total of 183 eligible patients were enrolled; 178 were evaluable. Of these, 52 patients underwent complete resection of a single node. There were 13 relapses at a median of 11.5 months; 5-year event-free survival (EFS) was 77% (range, 62% to 87%). A total of 135 patients received AV-PC; 126 were treated at diagnosis and nine at relapse after surgery alone. Eleven patients receiving AV-PC had less than CR and received IFRT. Fourteen first events occurred among 135 patients (12 relapses and two second malignancies). Two relapses occurred in patients who had received IFRT. Five-year EFS was 88.8% (95% CI, 81.8% to 93.2%). Five-year EFS for the entire cohort was 85.5% (95% CI, 79.2% to 90.1%); overall survival was 100%. Conclusion Some 75% of highly selected pediatric patients with LPHL may be spared chemotherapy after surgical resection alone. Pediatric LPHL has excellent EFS with chemotherapy that is less intensive than standard regimens; > 90% of patients can avoid radiation therapy. The salvage rate for the few relapses is high, with 100% survival overall.

Background Treatment of pediatric lymphocyte-predominant Hodgkin lymphoma (LPHL) is controversial but has typically consisted of both chemotherapy and radiation. Radiation therapy is associated with potential late effects in children and adolescents. We examined the impact of radiation therapy on long-term outcome of patients with LPHL treated on CCG-5942, a large pediatric cooperative group study of Hodgkin lymphoma (HL). Procedure Eighty-two patients with LPHL were registered on CCG-5942. Fifty-two patients (63%) received chemotherapy alone; 29 patients (35%) received chemotherapy followed by involved-field radiation therapy (IFRT). Results The median follow-up of the LPHL patients is 7.7 years; 63 patients (77%) have >5 years of follow-up. The 5-year event-free survival (EFS) and overall survival (OS) were 97% and 100%. Two relapses occurred, both in patients who did not receive IFRT. There were no significant differences in EFS or OS between patients who received or did not receive IFRT. Conclusions This subset analysis demonstrates the chemosensitivity of pediatric LPHL. Patients who had a complete response to chemotherapy had an excellent EFS and OS without the addition of radiotherapy. Pediatr Blood Cancer 2012; 59: 1284–1289. © 2012 Wiley Periodicals, Inc.

Background: Children's Oncology Group (COG) AHOD0031 demonstrated that early response assessment in pediatric intermediate-risk Hodgkin lymphoma (HL) permits reduction or augmentation in therapy with maintenance of excellent event-free (EFS) and overall survival (OS). While the majority of patients on this trial had classical HL (cHL), patients with lymphocyte-predominant HL (LPHL) were included. Pediatric patients with LPHL typically present with localized disease and such low risk patients have excellent outcomes with surgical resection alone or minimal chemotherapy. However, management of patients with intermediate-risk LPHL is less clear due to their small number in most clinical trials. We report the outcomes of these patients on AHOD0031 and present directions for future therapeutic strategies. Methods: Eligible patients had clinical stage I-IIA with bulk, I-IIAE, I-II B, IIIA-IVA with or without bulk. Patients initially received 2 cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone and cyclophosphamide (ABVE-PC), followed by a response evaluation of rapid early (RER) versus slow early responder (SER) status. All SER patients were randomized to an additional two cycles of ABVE-PC +/- 2 cycles of dexamethasone, etoposide, cisplatin and cytarabine (DECA). All SER patients received 21 Gy involved field radiotherapy (IFRT) following completion of chemotherapy. RER patients received 2 additional cycles of ABVE-PC. RER with complete responder (CR) status (RER/CR) patients were randomized to involved field radiotherapy (IFRT) or no further therapy. RER/non-CR patients were non-randomly assigned to IFRT. Results: Ninety-seven (5.7%) of the 1712 eligible patients on AHOD0031 had LPHL, with the remainder cHL. Compared to patients with cHL, patients with LPHL were younger (p=0.0001), more often male (p Discussion: Children and adolescents with intermediate-risk LPHL represent ideal candidates for response-adapted therapy based on their favorable outcomes as demonstrated in this analysis. The majority of patients treated with the ABVE-PC backbone achieve RER/CR status and can be successfully treated without radiation therapy. Future therapeutic strategies should focus on further reduction in cytotoxic therapy for these patients. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

10000 Background: LPHL, an uncommon subtype of HL, typically presents with low stage disease and responds to regimens used for classical HL. Recurrence is uncommon, but second malignant neoplasms (SMN) or development of non-Hodgkin lymphoma (NHL) can occur. Therefore, reducing radiation exposure may be of benefit. We report the results of a prospective trial in which a selected subset of patients had surgery alone and the remainder were treated with limited chemotherapy +/- involved-field radiation therapy (IFRT). Methods: Patients ages 0-21 years with newly diagnosed, low risk LPHL were eligible for AHOD03P1. Low risk was defined as clinical Stage IA or IIA without bulk disease (mediastinal mass > 1/3 of the thoracic diameter or nodal aggregate > 6 cm). Patients with Stage IA LPHL with an unresected node or more than a single involved node or Stage IIA were treated with 3 cycles of AV-PC (doxorubicin/vincristine/prednisone/cyclophosphamide). Patients with Stage IA LPHL in a single node that was completely resected were initially observed without further therapy; those who recurred after surgery with low risk LPHL received AV-PC x 3. Patients with < complete response (CR) to AV-PC x 3 received 2100 cGY IFRT. Results: 180 eligible patients with low risk LPHL were enrolled and completed study therapy. 52 patients underwent initial surgery alone; their 3 year EFS = 81.5%. 137 patients received AV-PC x 3; 128 were treated at diagnosis and 9 upon relapsing after surgery alone. 11 patients receiving AV-PC had < CR and received IFRT. 12 first events occurred among these 137 patients (11 relapses and 1 SMN, a NHL). One relapse occurred in a patient who received IFRT. The median follow-up among the 125 remaining patients is 39 (range 3 -76) months. Current 4-year EFS estimate is 88.1% (95% CI: 79.5%-93.3%) for these 137 patients. 4 year EFS for the entire cohort of 180 patients = 86.2%; their overall survival (OS) is 100%. Conclusions: Pediatric LPHL patients have an excellent EFS with chemotherapy that is less intensive than standard regimens; >90% of patients can avoid RT. NHL as a first event may be related to the underlying LPHL and not an effect of treatment. The salvage rate for the few relapses is high, and OS to date is excellent. Clinical trial information: NCT00107198.

9524 Background: Lymphocyte-predominant Hodgkin lymphoma (LPHL) is an uncommon histologic subtype comprising up to 10% of cases in pediatric series. Patients with LPHL typically present with low stage disease and are responsive to regimens used for classical HL. Recurrence is uncommon; secondary malignant neoplasms or evolution to non-Hodgkin lymphoma are more common events. Small retrospective studies have suggested that some patients with stage I LPHL can be cured with surgery alone. We report the results of a large prospective study using a treatment algorithm in which a selected subset of patients received surgery alone. Methods: Patients ages 0-21 years with newly-diagnosed, low risk LPHL were eligible for AHOD03P1. Low risk was defined as clinical Stage IA and IIA in the absence of bulk disease (a mediastinal mass > 1/3 of the thoracic diameter or a nodal aggregate > 6 cm). Central pathology review was performed to confirm LPHL histology. Baseline evaluations included CT and FDG-PET. Patients with Stage IA disease in a single node that was completely resected were observed without further therapy. Total resection (TR) was confirmed by rapid central review of CT and FDG-PET. In some cases the extent of resection was equivocal; repeat imaging 6-7 weeks after initial evaluation was used to allocate such patients to either observation or chemotherapy. Patients who recurred were assigned to treatment with 3 cycles of AV-PC (doxorubicin/vincristine/prednisone/cyclophosphamide). Results: Between January 2006 and November 2010, 52 patients with Stage IA, single node LPHL were enrolled with a confirmed TR. Nine patients have experienced a relapse; 8 were Stage I and 1 was Stage II at relapse. The median time to relapse was 10 (range 1-17) months. The median follow up among the 43 remaining patients is 26 (range 4-60) months. The current 2 year EFS estimate among these patients is 80.3% (95% CI: 65.3% -89.3%). Overall survival for the 52 patients is 100%. Conclusions: With this strategy of surgical resection followed by observation in a highly select cohort of pediatric LPHL, up to 80% of patients may be spared chemotherapy. Follow up is limited but overall survival to date is excellent.