Survival by age in paediatric and adolescent patients with Hodgkin lymphoma: a retrospective pooled analysis of children's oncology group trials.

BACKGROUND: Adolescents with Hodgkin lymphoma have worse disease outcomes than children. Whether these differences persist within clinical trials is unknown. We examined survival, by age, in patients receiving response-adapted therapy for Hodgkin lymphoma on Children's Oncology Group (COG) trials. METHODS: Patients (aged 1-21 years) diagnosed with classical Hodgkin lymphoma and enrolled between Sept 23, 2002, and Jan 19, 2012, on one of three phase 3 COG trials in the USA and Canada were eligible for inclusion. The three COG trials were defined by risk group according to Ann Arbor stage, B-symptoms, and bulk (AHOD0431 [low risk; NCT00302003], AHOD0031 [intermediate risk; NCT00025259], or AHOD0831 [high risk; NCT01026220]). The outcomes of this study were event-free survival (death, relapse, or subsequent neoplasm) and overall survival. Cox proportional hazards models estimated survival, adjusting for disease and treatment factors both overall and in patients with mixed cellularity or non-mixed cellularity (nodular sclerosing and not-otherwise-specified) disease. FINDINGS: Of 2155 patients enrolled on the three trials, 1907 (88·4%; 968 [50·8%] male and 939 [49·2%] female; 1227 [64·3%] non-Hispanic White) were included in this analysis. After a median follow-up of 7·4 years (IQR 4·3-10·2), older patients (aged ≥15 years) had worse unadjusted 5-year event-free survival (80% [95% CI 78-83]) than did younger patients (aged <15 years; 86% [83-88]; HR 1·38 [1·11-1·71]; p=0·0038). Older patients also had worse unadjusted 5-year overall survival than did younger patients (96% [95% CI 95-97] vs 99% [98-99]; HR 2·50 [1·41-4·45]; p=0·0012). In patients with non-mixed cellularity histology, older patients had a significantly increased risk of having an event than did younger patients with the same histology (HR 1·32 [1·03-1·68]; p=0·027). Older patients with mixed cellularity had significantly worse 5-year event-free survival than did younger patients in unadjusted (77% [95% CI 65-86] for older patients vs 94% [88-97] for younger patients; HR 2·93 [1·37-6·29]; p=0·0039) and multivariable models (HR 3·72 [1·56-8·91]; p=0·0032). Overall, older patients were more likely to die than younger patients (HR 3·08 [1·49-6·39]; p=0·0025). INTERPRETATION: Adolescents (≥15 years) treated on COG Hodgkin lymphoma trials had worse event-free survival and increased risk of death compared with children (<15 years). Our findings highlight the need for prospective studies to examine tumour and host biology, and to test novel therapies across the age spectrum. FUNDING: National Institutes of Health, St Baldrick's Foundation, and Lymphoma Research Foundation.

Hematopoietic stem cell transplant in two pediatric patients testing positive for SARS-CoV-2: A case report.

BACKGROUND: The SARS-CoV-2 pandemic brought challenges to all areas of medicine. In pediatric bone marrow transplant (BMT), one of the biggest challenges was determining how and when to transplant patients infected with SARS-CoV-2 while mitigating the risks of COVID-related complications. METHODS: Our joint adult and pediatric BMT program developed protocols for performing BMT during the pandemic, including guidelines for screening and isolation. For patients who tested positive for SARS-CoV-2, the general recommendation was to delay BMT for at least 14 days from the start of infection and until symptoms improved and the patient twice tested negative by polymerase chain reaction (PCR). However, delaying BMT in patients with malignancy increases the risk of relapse. RESULTS: We opted to transplant two SARS-CoV-2 persistently PCR positive patients with leukemia at high risk of relapse. One patient passed away early post-BMT of a transplant-related complication. The other patient is currently in remission and doing well. CONCLUSION: These cases demonstrate that when the risk associated with delaying BMT is high, it may be reasonable to proceed to transplant in pediatric leukemia patients infected with SARS-CoV-2.

Characterization of COVID-19 disease in pediatric oncology patients: The New York-New Jersey regional experience.

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.

Bone Marrow Morphology Associated With Germline RUNX1 Mutations in Patients With Familial Platelet Disorder With Associated Myeloid Malignancy.

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.

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

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.

Patterns of Involved-Field Radiation Therapy Protocol Deviations in Pediatric Versus Adolescent and Young Adults With Hodgkin Lymphoma: A Report From the Children's Oncology Group AHOD0031.

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 <15 years) and adolescent and young adult (AYA) group (age ≥15-21 years). Involved-field radiation therapy (IFRT) planning was reviewed before the start of treatment and at treatment completion. The records were reviewed through the Quality Assurance Review Center's central review to identify RPD, classified according to dose deviation (DD), volume deviation (VD), undertreatment (UT), and overtreatment (OT). DDs and VDs were further classified as major or minor. RESULTS: Of the 1712 patients enrolled, 1155 received IFRT, of whom, 216 (18.7%) had RPDs. The DD and VD patterns were similar between the pediatric and AYA groups. Minor VDs were most common. UT RPDs accounted for 69% in the pediatric group and 75% in the AYA group. Of the 35 patients with relapse and a RPD, 29 had an undertreatment RPD. Among the patients who received IFRT, a significant difference was found in the cumulative incidence rates of relapse between the pediatric and AYA groups (P = .03); however, no significant difference was found between patients with and without RPD (P = .2). CONCLUSIONS: Most RPDs were minor and consisted of UT in the AYA and pediatric populations both. No difference was observed in RPDs between the pediatric and AYA patients. Thus, in a well-defined and standardized protocol, the RPD distributions for AYA patients will be similar to those for pediatric population. However, the increased cumulative incidence of relapse in the AYA patients who had received IFRT compared with the pediatric population requires further exploration, given the potential differences in clinical outcomes in the AYA population.

Variant histology, IgD and CD30 expression in low-risk pediatric nodular lymphocyte predominant Hodgkin lymphoma: A report from the Children's Oncology Group.

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.

Outcomes of adults and children with primary mediastinal B-cell lymphoma treated with dose-adjusted EPOCH-R.

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 < 0·001). Our data support the use of DA-EPOCH-R for the treatment of PMBCL in children and adults. Patients with a positive end-of-therapy FDG-PET scan have an inferior outcome.

Minimal Treatment of Low-Risk, Pediatric Lymphocyte-Predominant Hodgkin Lymphoma: A Report From the Children's Oncology Group.

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.

Children's Oncology Group's 2013 blueprint for research: Hodgkin lymphoma.

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.

Impact of low-dose involved-field radiation therapy on pediatric patients with lymphocyte-predominant Hodgkin lymphoma treated with chemotherapy: a report from the Children's Oncology Group.

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.