KIR-favorable TCR-αß/CD19-depleted haploidentical HCT in children with ALL/AML/MDS: primary analysis of the PTCTC ONC1401 trial.

We performed a prospective multicenter study of T-cell receptor αß (TCR-αß)/CD19-depleted haploidentical hematopoietic cell transplantation (HCT) in children with acute leukemia and myelodysplastic syndrome (MDS), to determine 1-year disease-free survival (DFS) and compare 2-year outcomes with recipients of other donor cell sources. Fifty-one patients aged 0.7 to 21 years were enrolled; donors were killer immunoglobulin-like receptor (KIR) favorable based on ligand mismatch and/or high B content. The 1-year DFS was 78%. Superior 2-year DFS and overall survival (OS) were noted in patients <10 years of age, those treated with reduced toxicity conditioning (RTC) rather than myeloablative conditioning, and children with minimal residual disease <0.01% before HCT. Multivariate analysis comparing the KIR-favorable haploidentical cohort with controls showed similar DFS and OS compared with other donor cell sources. Multivariate analysis also showed a marked decrease in the risk of grades 2 to 4 and 3 to 4 acute graft versus host disease (aGVHD), chronic GVHD, and transplant-related mortality vs other donor cell sources. Ethnic and racial minorities accounted for 53% of enrolled patients, and data from a large cohort of recipients/donors screened for KIR showed that >80% of recipients had a KIR-favorable donor by our definition, demonstrating that this approach is broadly applicable to groups often unable to find donors. This prospective, multicenter study showed improved outcomes using TCR-αß/CD19-depleted haploidentical donors using RTC for children with acute leukemia and MDS. Randomized trials comparing this approach with matched unrelated donors are warranted. This trial was registered at https://clinicaltrials.gov as #NCT02646839.

Risk-adapted chemoimmunotherapy using brentuximab vedotin and rituximab in children, adolescents, and young adults with newly diagnosed Hodgkin's lymphoma: a phase II, non-randomized controlled trial.

BACKGROUND: Cure rates for Hodgkin's lymphoma are excellent, but excess short-term and long-term morbidities from treatment remain a concern. Immunotherapy targeting both tumor antigens and the immunosuppressive tumor microenvironment in children, adolescents, and young adults with Hodgkin's lymphoma may improve early response rates and eliminate toxic chemotherapy and radiation, thus minimizing toxicity. We conducted a phase II study to evaluate the safety and overall response rate of brentuximab vedotin and rituximab in combination with risk-adapted chemotherapy in children, adolescents, and young adults with newly diagnosed classic Hodgkin's lymphoma (cHL). METHODS: This is a prospective, phase II, non-randomized, risk-assigned study. Patients were treated and evaluated between 2012 and 2020. Eligible patients were aged ≥1 and ≤30 years old with advanced stage, intermediate-risk, and high-risk newly diagnosed cHL. Patients received four or six cycles of brentuximab vedotin (1.2 mg/kg), doxorubicin (25 mg/m2), vinblastine (6 mg/m2), dacarbazine (375 mg/m2), and rituximab (375 mg/m2). Early response was evaluated following two cycles of therapy. Involved field radiotherapy (IFRT) was restricted to high-risk patients with both bulky disease and slow response or those not in complete response at the end of chemoimmunotherapy. RESULTS: Thirty patients were enrolled, with a median age of 15 years (4-23). There were 18 intermediate-risk and 12 high-risk patients. Toxicities included grade III mucositis (3%), infusion reaction (3%), and peripheral neuropathy (6%). There was a 100% complete response rate on completion of chemoimmunotherapy. Eighteen patients (60%) achieved a rapid early response. Four patients (13%) required IFRT. The 5-year event-free and overall survival rates were 100%, with a median follow-up of 62 months (18-105). CONCLUSIONS: Immunotherapy with brentuximab vedotin, rituximab, and risk-adapted chemotherapy is safe in children, adolescents, and young adults with newly diagnosed cHL. We have demonstrated 100% complete response and 100% event-free and overall survival rates at a median 5-year follow-up, with a significant reduction in use of more toxic chemotherapy and IFRT. A larger cohort is required to confirm these preliminary findings. TRIAL REGISTRATION NUMBER: NCT02398240.

Significant improvement of child physical and emotional functioning after familial haploidentical stem cell transplant.

Allogeneic stem cell transplantation (AlloSCT) represents the only curative therapy for sickle cell disease (SCD). However, limited availability of matched related donors and suboptimal outcomes following AlloSCT with unrelated donors has led to investigation of alternative donors. Among children with high-risk SCD, we evaluated health-related quality of life (HRQoL) impact in the two years following familial haploidentical SCT. HRQoL was collected from parent and child raters, using the Child Health Ratings Inventories Generic measure and haploidentical SCT-specific module. Repeated measures models were fit to assess HRQoL changes over time and by rater. Nineteen children (mean age 12.9 yrs [standard deviation, 5.3]; 63% male) and their parents were included. There were no differences in the 2-yr trajectories of child physical or emotional functioning (EF) by rater. Child physical functioning and EF scores were significantly lower at day +45 than baseline, but scores recovered by day +180. There was significant improvement in EF (p = 0.03) at 2 yrs vs baseline. A similar pattern of scores over time was seen for parent ratings of child's global HRQoL. Despite treatment intensity in the initial months following AlloSCT, patient scores recovered or exceeded baseline scores at two years. This trial is registered at clinicaltrials.gov (NCT01461837).

Stable to improved cardiac and pulmonary function in children with high-risk sickle cell disease following haploidentical stem cell transplantation.

Children with sickle cell disease (SCD) are at high-risk of progressive, chronic pulmonary and cardiac dysfunction. In this prospective multicenter Phase II trial of myeloimmunoablative conditioning followed by haploidentical stem cell transplantation in children with high-risk SCD, 19 patients, 2.0-21.0 years of age, were enrolled with one or more of the following: history of (1) overt stroke; (2) silent stroke; (3) elevated transcranial Doppler velocity; (4) multiple vaso-occlusive crises; and/or (5) two or more acute chest syndromes and received haploidentical transplants from 18 parental donors. Cardiac and pulmonary centralized cores were established. Pulmonary function results were expressed as percent of the median of healthy reference cohorts, matched for age, sex, height and race. At 2 years, pulmonary functions including forced expiratory volume (FEV), FEV1/ forced vital capacity (FVC), total lung capacity (TLC), diffusing capacity of lung for carbon monoxide (DLCO) were stable to improved compared to baseline values. Importantly, specific airway conductance was significantly improved at 2 years (p < 0.004). Left ventricular systolic function (fractional shortening) and tricuspid regurgitant velocity were stable at 2 years. These results demonstrate that haploidentical stem cell transplantation can stabilize or improve cardiopulmonary function in patients with SCD.

Immune profile differences between chronic GVHD and late acute GVHD: results of the ABLE/PBMTC 1202 studies.

Human graft-versus-host disease (GVHD) biology beyond 3 months after hematopoietic stem cell transplantation (HSCT) is complex. The Applied Biomarker in Late Effects of Childhood Cancer study (ABLE/PBMTC1202, NCT02067832) evaluated the immune profiles in chronic GVHD (cGVHD) and late acute GVHD (L-aGVHD). Peripheral blood immune cell and plasma markers were analyzed at day 100 post-HSCT and correlated with GVHD diagnosed according to the National Institutes of Health consensus criteria (NIH-CC) for cGVHD. Of 302 children enrolled, 241 were evaluable as L-aGVHD, cGVHD, active L-aGVHD or cGVHD, and no cGVHD/L-aGVHD. Significant marker differences, adjusted for major clinical factors, were defined as meeting all 3 criteria: receiver-operating characteristic area under the curve ≥0.60, P ≤ .05, and effect ratio ≥1.3 or ≤0.75. Patients with only distinctive features but determined as cGVHD by the adjudication committee (non-NIH-CC) had immune profiles similar to NIH-CC. Both cGVHD and L-aGVHD had decreased transitional B cells and increased cytolytic natural killer (NK) cells. cGVHD had additional abnormalities, with increased activated T cells, naive helper T (Th) and cytotoxic T cells, loss of CD56bright regulatory NK cells, and increased ST2 and soluble CD13. Active L-aGVHD before day 114 had additional abnormalities in naive Th, naive regulatory T (Treg) cell populations, and cytokines, and active cGVHD had an increase in PD-1- and a decrease in PD-1+ memory Treg cells. Unsupervised analysis appeared to show a progression of immune abnormalities from no cGVHD/L-aGVHD to L-aGVHD, with the most complex pattern in cGVHD. Comprehensive immune profiling will allow us to better understand how to minimize L-aGVHD and cGVHD. Further confirmation in adult and pediatric cohorts is needed.

Benefits and challenges with diagnosing chronic and late acute GVHD in children using the NIH consensus criteria.

Chronic graft-versus-host disease (cGVHD) and late acute graft-versus-host disease (L-aGVHD) are understudied complications of allogeneic hematopoietic stem cell transplantation in children. The National Institutes of Health Consensus Criteria (NIH-CC) were designed to improve the diagnostic accuracy of cGVHD and to better classify graft-versus-host disease (GVHD) syndromes but have not been validated in patients <18 years of age. The objectives of this prospective multi-institution study were to determine: (1) whether the NIH-CC could be used to diagnose pediatric cGVHD and whether the criteria operationalize well in a multi-institution study; (2) the frequency of cGVHD and L-aGVHD in children using the NIH-CC; and (3) the clinical features and risk factors for cGVHD and L-aGVHD using the NIH-CC. Twenty-seven transplant centers enrolled 302 patients <18 years of age before conditioning and prospectively followed them for 1 year posttransplant for development of cGVHD. Centers justified their cGVHD diagnosis according to the NIH-CC using central review and a study adjudication committee. A total of 28.2% of reported cGVHD cases was reclassified, usually as L-aGVHD, following study committee review. Similar incidence of cGVHD and L-aGVHD was found (21% and 24.7%, respectively). The most common organs involved with diagnostic or distinctive manifestations of cGVHD in children include the mouth, skin, eyes, and lungs. Importantly, the 2014 NIH-CC for bronchiolitis obliterans syndrome perform poorly in children. Past acute GVHD and peripheral blood grafts are major risk factors for cGVHD and L-aGVHD, with recipients ≥12 years of age being at risk for cGVHD. Applying the NIH-CC in pediatrics is feasible and reliable; however, further refinement of the criteria specifically for children is needed.

An unusual case of hemophagocytic lymphohistiocytosis diagnosed by spinal nerve root biopsy.

Hemophagocytic lymphohistiocytosis (HLH) is a rare disease process characterized by aberrant immune system activation and an exaggerated inflammatory response. Establishing the diagnosis may be challenging and is achieved by satisfying a number of clinical criteria, in addition to demonstrating tissue hemophagocytosis. This syndrome is rapidly fatal if prompt diagnosis and treatment are not achieved. The authors present the case of a 17-year-old male patient with CNS HLH involving both the brain and spinal cord, highlighting the variable CNS manifestations in pediatric patients with HLH and the challenges that accompany establishing diagnosis.

An Argument for Adolescent and Young Adult Cancer Registry: One Model.

Over the last several years, there has been increasing awareness around the unique challenges faced by adolescent and young adult (AYA) cancer patients. More cancer centers across the United States are introducing AYA-specific programs to help improve outcomes for these patients. However, given the nature of the United States health care system, there is little ability to track the efficacy of these programs and identify important variables with respect to both interdisciplinary interventions offered and medical and psychosocial outcomes. One program offers an argument as to why tracking these data is important, with a description of the registry they have developed.

Mature (non-anaplastic, non-cutaneous) T-/NK-cell lymphomas in children, adolescents and young adults: state of the science.

Mature (non-anaplastic) T-cell and natural killer (NK)-lymphomas rarely occur in children or adolescents. Due to the low incidence and heterogeneity, information regarding the aetiology, physiopathology and genetics of paediatric mature (non-anaplastic) T/NK-cell lymphoma is lacking. In addition, standard treatments have not yet been established. In the absence of randomised clinical trials, anthracycline-containing regimens are usually considered as the first treatment option, but with discouraging outcomes, especially in patients with advanced disease. The implementation of autologous or allogeneic stem cell transplantation as upfront consolidation therapy or for chemotherapy-sensitive relapsed disease have resulted in improved survival for some patient subsets. The recent use of novel targeted molecular and immunotherapeutic agents has also been shown to be promising in small numbers of patients. In this context, we will review the current state of the scientific knowledge on the most common mature (non-anaplastic, non-cutaneous) T/NK-cell lymphomas occurring in children, adolescent and young adults.

NHL in adolescents and young adults: A unique population.

Non-Hodgkin lymphoma (NHL) is a heterogeneous group of lymphoid malignancies with high incidence in adolescents and young adults (AYAs). The most common diseases include diffuse large B-cell lymphoma, anaplastic large cell lymphoma, Burkitt lymphoma, lymphoblastic lymphoma, and primary mediastinal large B-cell lymphoma. In comparison to younger children and adults, AYAs (15-39 years) with NHL present a specific set of challenges including variations in tumor biology, inconsistent treatment, pharmacodynamics, and psychosocial barriers. While survival of AYAs with NHL has improved, cure rates remain suboptimal. Incorporation of novel agents into pediatric-inspired treatment regimens specifically designed for NHL in AYAs has led to improved outcomes. Consideration of AYAs as a distinct population in the diagnosis and treatment of NHL is encouraged.

Levocarnitine for asparaginase-induced hepatic injury: a multi-institutional case series and review of the literature.

Asparaginase, an important treatment component for acute lymphoblastic leukemia (ALL), causes severe hepatotoxicity in some patients. Levocarnitine is a mitochondrial co-factor that can potentially ameliorate the mitochondrial toxicity of asparaginase. In this retrospective case series, we describe the clinical presentation and management of six pediatric and young adult patients (mean age 12.7, range 9-24 years) with ALL who developed Grade 3-4 hyperbilirubinemia following administration of asparaginase as part of induction/re-induction therapy. Five of these patients were treated with levocarnitine with subsequent improvement of hyperbilirubinemia, while one patient was given levocarnitine prophylactically during induction and developed Grade 3 hyperbilirubinemia, but did not require therapy adjustments or delays. Increased awareness in the pediatric oncology community regarding asparaginase-associated hepatic toxicity and the potential role of levocarnitine in management is warranted.

The evolution of allogeneic stem cell transplant for children and adolescents with acute myeloid leukemia.

Survival rates in subsets of pediatric patients who have acute myeloid leukemia (AML) with favorable risk features are now greater than 90%. However, outcomes for patients with high-risk (HR) features remain unacceptably poor. As novel technologies for the identification of HR biomarkers and the detection of residual disease are developed, risk stratification and the application of allogeneic hematopoietic stem cell transplant (HSCT) are evolving. HSCT has been shown to benefit subpopulations of pediatric patients with AML, including those with HR cytogenetic translocations, genetic mutations, and/or residual disease after induction. Targeted therapies have shown promise for improving outcomes, and their integration into standard therapy and HSCT regimens is a critical area of interest. Also, expansion of the donor pool has led to the successful use of alternative donor sources for those patients without a matched sibling. However, transplant-related morbidity and mortality and late effects are major limiting factors. Reduced-intensity conditioning regimens have resulted in outcomes equivalent to those achieved with myeloablative regimens among patients in complete remission. The limitation of transplant-related morbidity and mortality through reduced-intensity conditioning and supportive care, and improved survival through optimal alloreactivity in combination with targeted therapy, are steps toward advancing outcomes for pediatric patients who have AML with HR features.

Genetically re-engineered K562 cells significantly expand and functionally activate cord blood natural killer cells: Potential for adoptive cellular immunotherapy.

Natural killer (NK) cells play a significant role in reducing relapse in patients with hematological malignancies after allogeneic stem cell transplantation, but NK cell number and naturally occurring inhibitory signals limit their capability. Interleukin-15 (IL-15) and 4-1BBL are important modulators of NK expansion and functional activation. To overcome these limitations, cord blood mononuclear cells (CB MNCs) were ex vivo expanded for 7 days with genetically modified K562-mbIL15-41BBL (MODK562) or wild-type K562 (WTK562). NK cell expansion; expression of lysosome-associated membrane protein-1 (LAMP-1), granzyme B, and perforin; and in vitro and in vivo cytotoxicity against B-cell non-Hodgkin lymphoma (B-NHL) were evaluated. In vivo tumor growth in B-NHL-xenografted nonobese diabetic severe combined immune deficient (NOD-scid) gamma (NSG) mice was monitored by tumor volume, cell number, and survival. CB MNCs cultured with MODK562 compared with WTK562 demonstrated significantly increased NK expansion (thirty-fivefold, p < 0.05); LAMP-1 (p < 0.05), granzyme B, and perforin expression (p < 0.001); and in vitro cytotoxicity against B-NHL (p < 0.01). Xenografted mice treated with MODK562 CB experienced significantly decreased B-NHL tumor volume (p = 0.0086) and B-NHL cell numbers (p < 0.01) at 5 weeks and significantly increased survival (p < 0.001) at 10 weeks compared with WTK562. In summary, MODK562 significantly enhanced CB NK expansion and cytotoxicity, enhanced survival in a human Burkitt's lymphoma xenograft NSG model, and could be used in the future as adoptive cellular immunotherapy after umbilical CB transplantation. Future directions include expanding anti-CD20 chimeric receptor-modified CB NK cells to enhance B-NHL targeting in vitro and in vivo.

Modification of Expanded NK Cells with Chimeric Antigen Receptor mRNA for Adoptive Cellular Therapy.

NK cells are bone marrow-derived cytotoxic lymphocytes that play a major role in the rejection of tumors and cells infected by viruses. The regulation of NK activation vs inhibition is regulated by the expression of a variety of NK receptors (NKRs) and specific NKRs' ligands expressed on their targets. However, factors limiting NK therapy include small numbers of active NK cells in unexpanded peripheral blood and lack of specific tumor targeting. Chimeric antigen receptors (CAR) usually include a single-chain Fv variable fragment from a monoclonal antibody, a transmembrane hinge region, and a signaling domain such as CD28, CD3-zeta, 4-1BB (CD137), or 2B4 (CD244) endodimers. Redirecting NK cells with a CAR will circumvent the limitations of the lack of NK targeting specificity. This chapter focuses on the methods to expand human NK cells from peripheral blood by co-culturing with feeder cells and to modify the expanded NK cells efficiently with the in vitro transcribed CAR mRNA by electroporation and to test the functionality of the CAR-modified expanded NK cells for use in adoptive cellular immunotherapy.