Children's Oncology Group's 2023 blueprint for research: Non-Hodgkin lymphoma.

Pediatric non-Hodgkin lymphoma (NHL) includes over 30 histologies (many with subtypes), with approximately 800 cases per year in the United States. Improvements in survival in NHL over the past 5 decades align with the overall success of the cooperative trial model with dramatic improvements in outcomes. As an example, survival for advanced Burkitt lymphoma is now >95%. Major remaining challenges include survival for relapsed and refractory disease and long-term morbidity in NHL survivors. Langerhans cell histiocytosis (LCH) was added to the NHL Committee portfolio in recognition of LCH as a neoplastic disorder and the tremendous unmet need for improved outcomes. The goal of the Children' Oncology Group NHL Committee is to identify optimal cures for every child and young adult with NHL (and LCH). Further advances will require creative solutions, including engineering study groups to combine rare populations, biology-based eligibility, alternative endpoints, facilitating international collaborations, and coordinated correlative biology.

Brentuximab vedotin use in pediatric anaplastic large cell lymphoma.

Anaplastic large cell lymphoma (ALCL) is the most common type of mature T-cell non-Hodgkin lymphoma in children/adolescents. ALCL is characterized by expression of CD30 in the neoplastic lymphoid cells with frequent expression of anaplastic lymphoma kinase (ALK), especially within the pediatric population. Despite multiple efforts to optimize the use of conventional chemotherapy, outcomes in children, adolescents, and adults with ALCL remain suboptimal. Thus, there is a need to improve survival for those with high-risk disease and decrease therapy exposures and toxicities for those with low-risk disease. Targeted therapies, such as the anti-CD30 antibody-drug conjugate, brentuximab vedotin, are new important therapeutic options. Phase I and II studies in adults with relapsed/refractory CD30+ lymphomas, including ALCL, demonstrated the safety and efficacy of brentuximab vedotin, leading to FDA approval for relapsed/refractory ALCL in adults and successful incorporation into frontline therapies. Clinical trials in the pediatric population demonstrated similar results in those with relapsed/refractory ALCL. Incorporation of brentuximab vedotin into upfront therapy for children and adolescents with ALCL showed that this novel combination therapy has clinical advantages in comparison to conventional agents alone. Brentuximab vedotin is well-tolerated in both the pediatric and adult populations, even when used in combination with conventional agents. Brentuximab vedotin is an ideal agent to treat ALCL with excellent targeted activity and limited toxicity. Future studies are needed to identify how brentuximab vedotin should be utilized when combined with immunotherapy or other targeted agents (e.g., ALK inhibitors) in both the upfront and relapsed/refractory setting.

Crizotinib in Combination With Chemotherapy for Pediatric Patients With ALK+ Anaplastic Large-Cell Lymphoma: The Results of Children's Oncology Group Trial ANHL12P1.

PURPOSE: Arm crizotinib (CZ) of the Children's Oncology Group trial ANHL12P1 (ClinicalTrials.gov identifier: NCT01979536) examined the efficacy and toxicity of adding CZ to standard chemotherapy for children with newly diagnosed, nonlocalized ALK+ CD30+ anaplastic large-cell lymphoma (ALCL). PATIENTS AND METHODS: Between 2013 and 2019, 66 enrolled children received CZ with chemotherapy. Patients received a 5-day prophase followed by six chemotherapy cycles at 21-day intervals with CZ administered twice daily during each 21-day cycle. The study was temporarily closed for two periods (total 12 months) to evaluate toxicity, during which CZ was discontinued. Measurements of NPM-ALK fusion transcripts in peripheral blood were performed at diagnosis for minimal disseminated disease (MDD). RESULTS: The 2-year event-free survival (EFS) is 76.8% (95% CI, 68.5 to 88.1) and the 2-year overall survival is 95.2% (95% CI, 85.7 to 98.4). Fifteen patients relapsed and one patient died; median time to relapse was 7.4 months from diagnosis, with relapses occurring after chemotherapy was complete. The 66 patients completed 384 cycles of chemotherapy. Thirteen of the 66 patients experienced a grade 2+ thromboembolic adverse event (19.7%; 95% CI, 11.1 to 31.3). In the 25 patients who received mandated prophylactic anticoagulation, there were two thromboembolic events (8.0%; 95% CI, 0.01 to 26). Patients with negative MDD had a superior outcome, with an EFS of 85.6% (95% CI, 68.6 to 93.8); positive MDD was associated with a lower EFS of 58.1% (95% CI, 33.4 to 76.4). CONCLUSION: Arm CZ of ANHL12P1 demonstrated that the addition of CZ to standard treatment prevented relapses during therapy for children with ALCL, MDD predicted EFS, and the addition of CZ resulted in unexpected thromboembolic events. Overall survival and EFS rates are consistent with the highest reported outcomes for children with ALCL.

Brentuximab vedotin in combination with chemotherapy for pediatric patients with ALK+ ALCL: results of COG trial ANHL12P1.

Approximately 30% of pediatric patients with anaplastic large cell lymphoma (ALCL) relapse. Although brentuximab vedotin has demonstrated excellent activity in ALCL, it has not been used for newly diagnosed patients. Children's Oncology Group (COG) trial ANHL12P1 determined the toxicity and efficacy of brentuximab vedotin with chemotherapy in children with newly diagnosed nonlocalized anaplastic large cell lymphoma kinase (ALK)+/CD30+ ALCL. From 2013 to 2017, 68 children with ALK+ ALCL were enrolled and received brentuximab vedotin. All patients received 5-day prophase, followed by 6 cycles of chemotherapy. Brentuximab vedotin was given on day 1 of each of the 6 cycles. Of the 67 patients eligible for toxicity evaluation, 66 completed all 6 cycles of chemotherapy, resulting in 399 evaluable cycles. There were no toxic deaths, no case of progressive multifocal leukoencephalopathy syndrome, and no case of grade 3 or 4 neuropathy. The 2-year event-free survival (EFS) was 79.1% (95% confidence interval [CI], 67.2-87.1). The 2-year overall survival (OS) was 97.0% (95% CI, 88.1-99.2). Fourteen patients relapsed. Eleven of 14 (79%) relapses occurred within 10 months of diagnosis; only 1 patient (1.5%) relapsed during therapy. Quantitative reverse transcription polymerase chain reaction for NPM-ALK at baseline (minimal disseminated disease) demonstrated prognostic value for EFS (P = .0004). Overall, the addition of brentuximab vedotin to standard chemotherapy does not add significant toxicity or alter the desired interval between cycles. The addition of brentuximab vedotin prevented relapses during therapy, and the OS and EFS estimates compare favorably with results obtained using conventional chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT01979536.

From bench to bedside: the past, present and future of therapy for systemic paediatric ALCL, ALK.

Anaplastic large cell lymphoma (ALCL) is a T cell Non-Hodgkin Lymphoma that mainly presents in paediatric and young adult patients. The majority of cases express a chimeric fusion protein resulting in hyperactivation of anaplastic lymphoma kinase (ALK) as the consequence of a chromosomal translocation. Rarer cases lack expression of ALK fusion proteins and are categorised as ALCL, ALK-. An adapted regimen of an historic chemotherapy backbone is still used to this day, yielding overall survival (OS) of over 90% but with event-free survival (EFS) at an unacceptable 70%, improving little over the past 30 years. It is clear that continued adaption of current therapies will probably not improve these statistics and, for progress to be made, integration of biology with the design and implementation of future clinical trials is required. Indeed, advances in our understanding of the biology of ALCL are outstripping our ability to clinically translate them; laboratory-based research has highlighted a plethora of potential therapeutic targets but, with high survival rates combined with a scarcity of funding and patients to implement paediatric trials of novel agents, progress is slow. However, advances must be made to reduce the side-effects of intensive chemotherapy regimens whilst maintaining, if not improving, OS and EFS.

Spontaneous Remission of Monosomy 7 Six Years After Diagnosis.

Monosomy 7 may be a poor prognostic indicator in pediatric myelodysplastic syndrome. There are case reports of children with monosomy 7 who undergo spontaneous remission 2 to 24 months after diagnosis. We report a case of a child with bone marrow failure and monosomy 7 who underwent spontaneous remission 75 months after diagnosis. The patient had no exposure to chemotherapeutic or immunosuppressive agents. The patient did not receive chemotherapy or other treatment during the 75 months. Despite remaining positive for monosomy 7, he never developed myelodysplasia or acute myeloid leukemia. Spontaneous remission of monosomy 7 may occur years after diagnosis in some patients.

Plasmacytoma-like Posttransplant Lymphoproliferative Disorder in a Pediatric Heart Transplant Recipient.

Posttransplant lymphoproliferative disorder (PTLD) is a diversely manifesting group of lymphoid or plasmacytic proliferations found in solid organ and bone marrow transplant recipients. PTLD occurs as a result of immunosuppression and is often driven by the Epstein Barr virus. Although most commonly of B-cell origin, similar to B-cell lymphomas, PTLD can rarely present as a plasmacytic process, resembling multiple myeloma. Although more common in adults, 8 cases of plasmacytoma-like PTLD have been reported in pediatric renal and combined small bowel-liver transplant recipients. Here, we present a rare report of a plasmacytoma-like PTLD case in a pediatric heart transplant recipient.

Anaplastic large cell lymphoma in children and adolescents.

Anaplastic Large Cell Lymphoma (ALCL) is the most common mature T-cell neoplasm in children and adolescents. ALCLs comprise approximately 15% of all non-Hodgkin lymphomas (NHL) in children and adolescents and commonly present with advanced systemic disease. Dissimilar from ALCL in adults, ALCL in children is nearly universally anaplastic large cell lymphoma kinase (ALK) positive. Despite the relative rarity of the disease, a great deal of insight into the pathogenesis of ALCL has been learned by researching the essential oncogenic role of ALK. Many different treatment strategies have been utilized with similar event free survival (EFS) rates of 65-75%. This review will provide an overview of the pathology, clinical features, prognostics factors, and treatment for children and adolescents with ALK positive ALCL.

Potential therapies for anaplastic lymphoma kinase-driven tumors in children: progress to date.

Anaplastic lymphoma kinase (ALK) is an oncogenic tyrosine kinase that is deregulated due to a variety of molecular mechanisms in pediatric cancer. They include chromosomal translocations, activation mutations, and gene amplifications. Since the initial discovery of ALK as an oncogenic tyrosine kinase involved in the chromosomal translocation t(2, 5)(p23;q35) in 1994, more than 20 translocation partners of ALK have been identified in various cancers. Furthermore, deregulation of ALK tyrosine kinase activity is critical for the pathogenesis of several other pediatric tumors, including neuroblastomas and inflammatory myofibroblastic tumors. The recent discovery of ALK translocations in adult lung cancer patients (non-small cell lung cancer) has accelerated the development of inhibitors of ALK tyrosine kinase as therapeutic agents. While excellent clinical response has been observed in many patients, the acquisition of clinical resistance to ALK inhibition highlights the need for development of second-generation ALK kinase inhibitors and/or combination therapies that target downstream signaling mediators or antibody drug conjugates. This article provides an update on the spectrum of ALK-driven tumors in the pediatric population and the potential therapies which target these tumors.

Clinicopathologic features of histiocytic lesions following ALL, with a review of the literature.

We describe the clinicopathologic features of 15 patients who had histiocytic lesions that followed acute lymphoblastic leukemia (ALL). Twenty-one separate histiocytic lesions were evaluated that covered a wide spectrum, some conforming to the usual categories of juvenile xanthogranulomas (5), Langerhans' cell histiocytosis (1), Langerhans' cell sarcoma (4), Rosai-Dorfman disease (1), and histiocytic sarcoma (4). Most were atypical for the category by histology, phenotype, or abnormally high turnover rate. Seven low-grade lesions defied easy categorization and were characterized only as "atypical histiocytic lesion" following ALL. For those evaluated, the molecular signature of the prior leukemia was present in the histiocytic lesion. In 3 of 15 patients, the leukemia and histiocytic lesion shared immunoglobulin H or monoclonal TCR gene rearrangements and, in 4 of 15 patients, clonal identity was documented by fluorescence in situ hybridization. Four patients died of progressive disease, 3 of whom had histiocytic sarcoma and 1 who had an atypical lesion. One patient died of recurrent ALL. The other 10 patients are alive, 7 after recurrences and treatment with surgery and/or chemotherapy. The post-ALL lesions are more aggressive than their native counterparts, but despite the demonstration of the presence of the leukemia signature in 7 of 15 patients, the prognosis is generally favorable, except for patients with histiocytic sarcoma. It remains unclear whether the histiocytic lesions arise as a line from the original ALL or whether transdifferentiation is involved.

Intensive chemotherapy for systemic anaplastic large cell lymphoma in children and adolescents: final results of Children's Cancer Group Study 5941.

BACKGROUND: Anaplastic large cell lymphoma (ALCL) is characterized by advanced disease at presentation (70-80% of pediatric cases) and accounts for 10-15% of all childhood lymphomas. Treatment strategies for pediatric ALCL vary from short pulse B-NHL chemotherapy to prolonged leukemia like therapy. The optimal treatment strategy is unknown. METHODS: CCG-5941 used a compressed aggressive multiagent T-cell lineage chemotherapy regimen consisting of a 3-week induction therapy (vincristine, prednisone, cyclophosphamide, daunomycin, asparaginase) followed by a 3-week consolidation period (vincristine, prednisone, etoposide, 6-thioguanine, cytarabine, asparaginase, methotrexate) followed by six courses of maintenance chemotherapy at 7-week intervals (cyclophosphamide, 6-thioguanine, vincristine, prednisone, doxorubicin, asparaginase, methotrexate etoposide, cytarabine). Total therapy was 48 weeks. RESULTS: Eighty-six children (male 56%, female 44%) with non-localized ALCL (CD30+) were treated. The majority of tumors were positive for ALK (90%) and of T lineage (83%). Extranodal disease was common (mediastinum 35%, skin 15%, lung 14%, bone 12%, bone marrow 13%, liver 6%, and other viscera 17%). Grade 4 neutropenia occurred in 82% of patients. The 5-year EFS was 68% (95% CI of 57-78%) and the 5-year OS was 80% (95% CI of 69-87%). There were 21 relapses and 4 toxic deaths as first events. Relapse occurred early with 17 (81%) relapses occurring within 2 years of diagnosis and 12 (57%) while receiving therapy. Univariate analysis for risk factors only identified bone marrow involvement predicting lower EFS (P = 0.03). CONCLUSIONS: CCG-5941 demonstrated efficacy similar to previously reported regimens but with significant hematologic toxicity.

Aggressive Digital Papillary Adenocarcinoma in a 15-year-old Female.

Aggressive digital papillary adenocarcinoma is a rare neoplasm of eccrine sweat gland origin that typically presents as a mass on a finger, toe, or the adjacent skin. Less than 100 cases have been reported. The majority of these cases are described in males in their fifth to seventh decade. We report a case of an aggressive digital papillary adenocarcinoma of the right second toe in a 15-year-old white female. A metastatic work-up, computed tomography of the chest, abdomen, pelvis, and a bone scan, was negative. The patient underwent amputation of the right second toe through the metatarsophalangeal joint. Two sentinel lymph nodes were biopsied and found to be negative for metastatic disease. One year after surgery the patient has no evidence of disease recurrence. To our knowledge, this is the youngest reported case of an aggressive digital papillary adenocarcinoma.

Childhood anaplastic large cell lymphoma has a high incidence of ALK gene rearrangement as determined by immunohistochemical staining and fluorescent in situ hybridisation: a genetic and pathological correlation.

Anaplastic large cell lymphoma (ALCL) comprises 10-15% of childhood non-Hodgkin lymphomas (NHL). Systemic ALCL is highly associated with anaplastic lymphoma kinase (ALK) gene translocations with over-expression of ALK protein. We studied ALK rearrangements using fluorescence in situ hybridisation (FISH) and ALK immunohistochemical staining in 43 paediatric systemic ALCLs. FISH (performed on 35 cases) identified a translocation in 29 cases (83%). Immunohistochemistry identified ALK over-expression in 42/43 cases (97%) with the single ALK-negative case demonstrating an ALK rearrangement by FISH, indicating 100% incidence of ALK translocations.

Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome in children and adolescents.

Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are both uncommon disorders that present with a microangiopathic hemolytic anemia and thrombocytopenia. Although for TTP, neurologic manifestations predominate, and in HUS renal dysfunction is virtually always present, there is significant overlap in their clinical presentation. In recent years, tremendous progress has been made in our understanding of the pathogenesis of these disorders. It is now apparent that there are subcategories of both TTP and HUS that can differ in their clinical manifestations, etiology, and management. For instance, although most cases of HUS are due to infection with organisms that produce Shiga-like toxin, other cases may be caused by defined genetic abnormalities. Similarly, TTP is usually caused by genetic or acquired deficiency of the ADAMTS13 enzyme; however, in other cases the relationship with this enzyme remains to be established. Management includes supportive care, plasma transfusions for genetic protein deficiencies, and plasma exchange transfusion for autoimmune TTP.

Early complications in children with acute lymphoblastic leukemia presenting with hyperleukocytosis.

BACKGROUND: The optimal management of childhood acute lymphoblastic leukemia (ALL) with hyperleukocytosis is unclear, largely because the risk of leukostasis-related complications is poorly characterized. PROCEDURE: We reviewed the presenting characteristics, initial management, and frequency and type of complications in all children seen at St. Jude Children's Research Hospital with previously untreated ALL and an initial leukocyte count >200 x 10(9)/L. RESULTS: A total of 178 children, representing 8% of all children with ALL, had an initial leukocyte count >200 x 10(9)/L; 67 patients had a leukocyte count >400 x 10(9)/L. Sixteen patients (9%) had neurological complications with 12 of these patients experiencing symptoms at presentation. Four patients (2%), all with initial leukocyte counts >400 x 10(9)/L, suffered a CNS hemorrhage. Pulmonary leukostasis occurred in 11 patients (6%). The degree of hyperleukocytosis was significantly predictive of neurological (P = 0.006) and respiratory (P = 0.014) complications. The majority of complications occurred at presentation. Cytoreduction (94 patients) decreased the leukocyte count but delayed initiation of chemotherapy (P = 0.013). CONCLUSIONS: Serious leukostasis-related complications are relatively uncommon in childhood ALL and most occur at presentation. Their incidence increases in proportion to the leukocyte count. A large subset of cases can be managed successfully without cytoreduction. Cytoreduction may be considered for patients with leukocyte counts >400 x 10(9)/L or patients who have complications at presentation.

T-cell alloreactivity dominates natural killer cell alloreactivity in minimally T-cell-depleted HLA-non-identical paediatric bone marrow transplantation.

Natural killer (NK) cell alloreactivity resulting from killer immunoglobulin-like receptor (KIR) ligand incompatibility improves outcomes in patients receiving extensively T-cell-depleted bone marrow (BM) grafts. Patients with KIR ligand incompatibility are at risk for donor T-cell alloreactivity. We investigated the relative significance of NK-cell and T-cell alloreactivity in 105 paediatric patients who received a minimally T-cell-depleted human leucocyte antigen-non-identical BM transplantation. Donor NK-cell incompatibility did not improve patient outcome [engraftment, graft-versus-host disease (GVHD), relapse or overall survival]. In contrast, donor T-cell incompatibility was a risk factor for acute GVHD, chronic GVHD and death. Thus, T-cell alloreactivity dominated that of NK cells in minimally T-cell-depleted grafts.

Idiopathic thrombocytopenic purpura diagnosed during the second decade of life.

OBJECTIVE: To retrospectively review our institutional experience of adolescents with idiopathic thrombocytopenic purpura (ITP). STUDY DESIGN: Medical record review of all patients diagnosed with ITP between the ages of 10 and 18 years seen at our center from January 1976 to March 2000. RESULTS: Data were collected from 126 patients. Of the evaluable 110 cases, 63 (57%) satisfied the criteria for chronic ITP, 30 (27%) for acute ITP, and 17 (15%) were uncertain. Sex distribution and mean ages were similar in all 3 groups. Platelet count at presentation was higher in patients with chronic ITP. Splenectomy was performed in 24 patients, with 17 (77%) of 22 having normal platelet counts at last follow-up. Outcome for the nonsplenectomized patients with chronic ITP included normalization of platelet count (n = 4), minimal or no bleeding without treatment (n = 29), treatment for ongoing symptoms (n = 5), and unknown (n = 1). Two patients died, 1 from intracranial hemorrhage and 1 from Escherichia coli sepsis and pulmonary hemorrhage. CONCLUSIONS: Patients 10 to 18 years of age with ITP are more likely than younger children to have chronic disease. Many patients with ITP recover without drug therapy or need for splenectomy. ITP in adolescents shares features of both childhood and adult ITP.