Immune-mediated cytopenias (IMCs) after HSCT for pediatric non-malignant disorders: epidemiology, risk factors, pathogenesis, and treatment.

Hematopoietic stem cell transplantation (HSCT) represents a curative option for pediatric patients affected by malignant and non-malignant disorders. Several complications may arise during the post-transplantation period, including immune-mediated disorders. Immune-mediated cytopenias (IMCs) account for up to 22% of pediatric HSCT complications, representing an important cause of morbidity and mortality post-HSCT. So far, their pathogenesis is not well-understood, and their management may be very challenging. Further, most patients are refractory to first-line treatment which is based on high-dose intravenous steroids, immunoglobulin, and the monoclonal anti-CD20 antibody - rituximab. No clear consensus has been reached for second- and third-line therapeutic options. CONCLUSION: We reviewed the epidemiology, risk factors, pathogenesis, and treatment of IMCs, aiming to offer a deeper understanding of these complications as a guide to improving the management of these fragile patients and a cue for the design of tailored clinical trials. WHAT IS KNOWN: • IMCs arising in the post-HSCT setting represent a rare but potentially life-threatening complication. Younger patients affected by non-malignant disorders are at the greatest risk of IMCs arising after HSCT. Corticosteroids, intravenous immunoglobulin, and rituximab represent the undiscussed first-line therapeutic approach. WHAT IS NEW: • This review highlitghts how children present unique risk factors for post HSCT IMCs, which are the result of the complex relationship between the immaturity of their infantile immune system and all the perturbing agents and factors which characterize the post-HSCT setting. Future efforts are warranted to establish the best option for refractory patients, for whom a standard and validated approach is not currently available. Among new agents, ibrutinib or bortezomib and fostamatinib or low-dose IL-2 could represent a good therapeutic option for patients with graft-versus-host disease and hemolytic anemia or graft-versus-host disease and thrombocytopenia, respectively.

Off-label and compassionate use of targeted anticancer therapies: The experience of an Italian pediatric cancer center.

INTRODUCTION: In Europe, despite recent advances in clinical development, most of the drugs currently used to treat childhood cancers are adult medicines, prescribed outside of the authorized indication. In this context, a monocentric retrospective cohort analysis was conducted, evaluating pediatric, adolescent, and young adult patients affected by onco-hematologic disease, treated with targeted therapies used off-label or as compassionate use. METHODS: The analysis was conducted on 45 patients aged less than or equal to 30 years with cancer, having received at least one targeted therapy prescribed as off-label or compassionate use at a large Italian pediatric center between January 1, 2016 and June 30, 2021. Data collected included information on the patient and tumor, data on off-label/compassionate treatment, and data on safety and efficacy. RESULTS: Total 25 out of 45 patients treated with off-label or compassionate targeted therapies were affected by onco-hematological diseases. Overall, 22 out of the 52 agents (42%) were prescribed in patients with relapsed neoplasm and 39% (20/52) in patients with refractory diseases. Complete response was observed in more than half (27/52) of treatments. At least one adverse reaction occurred in 76% (n = 22) of agents administered to patients with onco-hematological tumor and in 43% (n = 10) of agents prescribed to patients with solid tumor. CONCLUSION: This work aims to provide a snapshot of off-label and compassionate use prescriptions in a large Italian pediatric cancer center. This study confirms that targeted agents for unauthorized indications are often prescribed in pediatric patients with cancer, especially after disease relapse and that these treatments are mostly tolerable and effective.

Outcome of chimeric antigen receptor T-cell therapy following treatment with inotuzumab ozogamicin in children with relapsed or refractory acute lymphoblastic leukemia.

Chimeric antigen receptor T cells targeting CD19 (CART-19) have shown remarkable efficacy for relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (BCP-ALL). We investigated whether prior use of inotuzumab ozogamicin (InO), an anti-CD22 antibody conjugated to calicheamicin, may impact CAR T-cell manufacturing or efficacy via pre-CART-19 depletion of the B-cell compartment. In this international, retrospective analysis, 39 children and young adults receiving InO before (n = 12) and/or after (n = 27) T-cell apheresis as bridging therapy to CART-19 treatment were analyzed. Median age at infusion was 13 years (range 1.4-23 years). Thirty-four out of 39 patients (87.2%) obtained complete remission. With a median follow-up of 18.2 months after CART-19 infusion, 12-month event-free survival (EFS) was 53.3% (95% confidence interval (CI): 38.7-73.4) and overall survival (OS) was 77.8% (95% CI: 64.5-93.9). Seventeen patients (44%) relapsed with a median of 159 days (range 28-655) after CART-19 infusion. No difference in day 28 minimal residual disease negative complete response rate, 12-month OS/EFS, or incidence of CD19-positive or -negative relapses was observed among patients receiving InO before or after apheresis. Compared to published data for patients treated with CART-19 therapy without prior InO exposure, response and OS/EFS for patients treated with InO prior to CART-19 are similar.

The PedAL/EuPAL Project: A Global Initiative to Address the Unmet Medical Needs of Pediatric Patients with Relapsed or Refractory Acute Myeloid Leukemia.

The prognosis of children with acute myeloid leukemia (AML) has improved incrementally over the last few decades. However, at relapse, overall survival (OS) is approximately 40-50% and is even lower for patients with chemo-refractory disease. Effective and less toxic therapies are urgently needed for these children. The Pediatric Acute Leukemia (PedAL) program is a strategic global initiative that aims to overcome the obstacles in treating children with relapsed/refractory acute leukemia and is supported by the Leukemia and Lymphoma Society in collaboration with the Children's Oncology Group, the Innovative Therapies for Children with Cancer consortium, and the European Pediatric Acute Leukemia (EuPAL) foundation, amongst others. In Europe, the study is set up as a complex clinical trial with a stratification approach to allocate patients to sub-trials of targeted inhibitors at relapse and employing harmonized response and safety definitions across sub-trials. The PedAL/EuPAL international collaboration aims to determine new standards of care for AML in a first and second relapse, using biology-based selection markers for treatment stratification, and deliver essential data to move drugs to front-line pediatric AML studies. An overview of potential treatment targets in pediatric AML, focused on drugs that are planned to be included in the PedAL/EuPAL project, is provided in this manuscript.

Guillain-Barré syndrome after bortezomib therapy in a child with relapsed acute lymphoblastic leukemia.

A 12-year-old male being treated for a high-risk relapsed T-acute lymphoblastic leukemia presented progressive weakness and numbness of both legs after having received a chemotherapy regimen that included bortezomib. Diagnosis of acute Guillain-Barré syndrome-like inflammatory demyelinating polyneuropathy was made following clinical examination, cerebrospinal fluid analysis, electrodiagnostic studies, magnetic resonance imaging, and serum immunoglobulin antibodies to anti-ganglioside. Intravenous immunoglobulin treatment was started, resulting in complete clinical recovery. Although in rare cases, Guillain-Barré syndrome after bortezomib therapy has been reported; this paper suggests that GBS may occur when bortezomib is administered and high­dose intravenous immunoglobulin lead to a resolution of the symptoms.

Gynecomastia after euthyroidism restoration in a patient with type 1 diabetes and Graves' disease.

In patients with autoimmune disease, gynecomastia should not be considered as 1 of the first signs of hyperthyroidism, rather it is a breast pathology that can be present even when euthyroidism restoration is achieved. It is unknown whether the autoimmune nature of thyroid disorders or simply the hyperthyroidism effects breast changes.