Third-party virus-specific T cells for the treatment of double-stranded DNA viral reactivation and posttransplant lymphoproliferative disease after solid organ transplant.

Reactivation or primary infection with double-stranded DNA viruses is common in recipients of solid organ transplants (SOTs) and is associated with significant morbidity and mortality. Treatment with conventional antiviral medications is limited by toxicities, resistance, and a lack of effective options for adenovirus (ADV) and BK polyomavirus (BKPyV). Virus-specific T cells (VSTs) have been shown to be an effective treatment for infections with ADV, BKPyV, cytomegalovirus (CMV), and Epstein-Barr virus (EBV).

Virus-Specific T Cells for the Treatment of Systemic Infections Following Allogeneic Hematopoietic Cell and Solid Organ Transplantation.

Viral infections are a major source of morbidity and mortality in the context of immune deficiency and immunosuppression following allogeneic hematopoietic cell (allo-HCT) and solid organ transplantation (SOT). The pharmacological treatment of viral infections is challenging and often complicated by limited efficacy, the development of resistance, and intolerable side effects. A promising strategy to rapidly restore antiviral immunity is the adoptive transfer of virus-specific T cells (VST).

Inotuzumab ozogamicin in B-cell precursor acute lymphoblastic leukemia: efficacy, toxicity, and practical considerations.

Inotuzumab ozogamicin (InO) is an antibody drug conjugate composed of a humanized monoclonal antibody targeting the cell surface receptor CD22 coupled to a cytotoxic calicheamicin payload an acid labile linker. InO has shown significant activity in relapsed and refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in both single agent and combination chemotherapy regimens in adult and pediatric trials. Its use in newly diagnosed elderly patients has also been established while clinical trials investigating its use in newly diagnosed pediatric patients and fit adults are ongoing.

Needle in a haystack or elephant in the room? Identifying germline predisposition syndromes in the setting of a new myeloid malignancy diagnosis.

Myeloid malignancies associated with germline predisposition syndromes account for up to 10% of myeloid neoplasms. They are classified into three categories by the proposed 5 Edition of the World Health Organization Classification of Hematolymphoid Tumors: (1) neoplasms with germline predisposition without a pre-existing platelet disorder or organ dysfunction, (2) neoplasms with germline predisposition and pre-existing platelet disorder, or (3) neoplasms with germline predisposition and potential organ dysfunction. Recognizing these entities is critical because patients and affected family members benefit from interfacing with hematologists who specialize in these disorders and can facilitate tailored treatment strategies.

Post-transplant lymphoproliferative disease in children, adolescents, and young adults.

Post-transplant lymphoproliferative disease (PTLD) remains a major complication of transplantation. PTLD is a rare entity and very heterogenous making consensus on diagnosis and treatment very challenging. The majority are Epstein-Barr virus (EBV) driven, CD20+ B-cell proliferations.

Durable remissions achieved with reinfusion of CD19-directed CAR-T despite failure to induce or maintain B-cell aplasia and single-center experience with reinfusion of tisagenlecleucel.

CD19-directed chimeric antigen receptor T lymphocytes (CAR-T) have led to durable remissions in children with refractory and/or multiply relapsed B-lymphoblastic leukemia. For those who relapse or lose B-cell aplasia post CAR-T, the role of CAR-T reinfusion is unclear. We report two cases of durable remission with tisagenlecleucel reinfusion despite failure to achieve or maintain B-cell aplasia, and compare these cases to six additional children who received multiple tisagenlecleucel infusions at our institution.

The Choice of Either Conventional Chemotherapy or Inotuzumab Ozogamicin as Bridging Regimen Does Not Appear To Impact Clinical Response to CD19-Directed CAR-T Therapy in Pediatric B-ALL.

Bridging therapy (BT) given during the period between T-cell collection and initiation of lymphodepleting chemotherapy is indicated for most children with B-cell acute lymphoblastic leukemia (B-ALL) undergoing treatment with tisagenlecleucel (tisa-cel), a CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy. Both conventional chemotherapy agents and B-cell directed antibody-based therapies such as antibody-drug conjugates and bispecific T-cell engagers have been used as systemic forms of BT. The purpose of this retrospective study was to evaluate if there are detectable differences in clinical outcomes based on the type of BT given (conventional chemotherapy or inotuzumab).

Third-Party and Patient-Specific Donor-Derived Virus-Specific T Cells Demonstrate Similar Efficacy and Safety for Management of Viral Infections after Hematopoietic Stem Cell Transplantation in Children and Young Adults.

Infections with double-stranded DNA viruses are a common complication after hematopoietic stem cell transplantation (HSCT) and cause significant morbidity and mortality in the post-transplantation period. Both donor-derived (DD) and third-party (TP) virus-specific T cells (VSTs) have shown efficacy and safety in viral management following HSCT in children and young adults. Owing to a greater degree of HLA matching between the recipient and stem cell donor, DD VSTs potentially persist longer in circulation compared to TP VSTs, because they are collected from a well-matched donor.

Use of gemcitabine, oxaliplatin, and anti-CD20 therapy in children and adolescents with non-Hodgkin lymphoma unfit for intensive therapy.

Multiagent immunochemotherapy affords excellent outcomes in pediatric non-Hodgkin lymphoma (NHL); however, scarce data exist for patients unfit for intensive treatment. Rituximab, gemcitabine, and oxaliplatin (R-GemOx) is well tolerated and efficacious in elderly adults with NHL; however, its use has not been described in pediatrics. In this retrospective, single-center study, six children with mature B-cell NHL and significant comorbidities received anti-CD20 therapy with GemOx (rituximab or obinutuzumab or ofatumumab with gemcitabine and oxaliplatin [R/O-GemOx]).

Acute myeloid leukemia in -mutated congenital neutropenia.

mutations have recently been implicated in congenital neutropenia (CN) and the in-frame deletion, p.Thr117del, is the most common pathogenic mutation reported. The largest study of -mutated CN to-date followed 23 patients for a median of 15 years.

Scheduled administration of virus-specific T cells for viral prophylaxis after pediatric allogeneic stem cell transplant.

Infections with double-stranded DNA viruses are a significant cause of morbidity and mortality in pediatric patients following allogeneic hematopoietic stem cell transplantation (HSCT). Virus-specific T-cell therapies (VSTs) have been shown to be an effective treatment for infections with adenovirus, BK virus, cytomegalovirus (CMV), and Epstein-Barr virus (EBV). To date, prophylactic regimens to prevent or mitigate these infections using conventional antiviral medications provide suboptimal response rates.

Off-the-Shelf Third-Party Virus-Specific T Cell Therapy to Treat JC Polyomavirus Infection in Hematopoietic Stem Cell Transplantation Recipients.

Progressive multifocal leukoencephalopathy (PML) is a progressive and generally fatal demyelinating neurologic disease that occurs in profoundly immunocompromised patients due to infection with the human polyomavirus JC virus (JCPyV). Treatment options are limited and are largely focused on restoring T cell immunity, and outcomes are historically poor. Control of JCPyV in the setting of an immunocompromised patient by adoptive transfer of third-party virus specific T cells (VSTs) has been described in a small number of cases.

Virus-specific T cells for adenovirus infection after stem cell transplantation are highly effective and class II HLA restricted.

Infection with adenoviruses is a common and significant complication in pediatric patients after allogeneic hematopoietic stem cell transplantation. Treatment options with traditional antivirals are limited by poor efficacy and significant toxicities. T-cell reconstitution is critical for the management of adenoviral infections, but it generally takes place months after transplantation.

Treatment of posttransplant lymphoproliferative disorder with poor prognostic features in children and young adults: Short-course EPOCH regimens are safe and effective.

No guidelines exist for which intensive chemotherapy regimen is best in pediatric or young adult patients with high-risk posttransplant lymphoproliferative disorder (PTLD). We retrospectively reviewed patients with PTLD who received interval-compressed short-course etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (SC-EPOCH) regimens at our institution. Eight patients were included with median age of 12 years.

Tolerance of dinutuximab therapy for treatment of high-risk neuroblastoma in two patients with end-stage renal disease on dialysis.

Autologous hematopoietic cell transplant (aHCT) has a significant survival advantage in patients with high-risk (HR) neuroblastoma. Transplant-associated thrombotic microangiopathy (TA-TMA) is a serious complication and may result in chronic renal disease leading to delay in subsequent posttransplant therapy and limitations of treatment options. Dinutuximab represents an important therapeutic advance in the treatment of pediatric HR neuroblastoma, but historically has not been administered in patients with GFR < 60 mL/m /min.

Virus-specific T-cell therapy to treat BK polyomavirus infection in bone marrow and solid organ transplant recipients.

BK polyomavirus (BKPyV) infection is a major complication of hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT). Treatment options are limited, poorly effective, and have significant toxicities. Cellular therapy using T cells directed against BKPyV is an emerging therapy, and we report efficacy in controlling BKPyV-associated disease in highly immunocompromised patients.

Chimeric Antigen Receptor T Cell Therapy in Patients with Multiply Relapsed or Refractory Extramedullary Leukemia.

Autologous CD19-directed chimeric antigen receptor T lymphocyte (CAR-T) therapy is an approved and effective treatment for the management of patients with refractory and multiply relapsed B cell precursor acute lymphoblastic leukemia (B-ALL). Experience using this therapy in pediatric patients with extramedullary (EM) disease is limited, in part because these patients have frequently been excluded from clinical trials owing to concerns for an increased risk of immune effector cell-associated neurotoxicity syndrome (ICANS). We infused 7 patients with refractory or multiply relapsed B-ALL who presented with isolated EM relapse with tisagenlecleucel.

Complement inhibition does not impair the clinical antiviral capabilities of virus-specific T-cell therapy.

The use of terminal complement blockade is compatible with virus-specific T-cell (VST) expansion and clinical effectiveness. VST and complement-blocking agent concurrent therapy may be safely used in patients with thrombotic microangiopathy and viral infections.

Chimeric antigen receptor T-cell therapy in patients with neurologic comorbidities.

Chimeric antigen receptor T cells (CAR-T) are an effective and potentially durable treatment for refractory and multiply relapsed B-cell acute lymphoblastic leukemia. Neurotoxicity is frequent after CAR-T cell therapy. Mechanisms driving neurotoxicity are incompletely understood, and symptoms can range from transient and mild to severe and life-threatening.

EBV-directed viral-specific T-lymphocyte therapy for the treatment of EBV-driven lymphoma in two patients with primary immunodeficiency and DNA repair defects.

Children with ataxia telangiectasia (AT), a primary immunodeficiency caused by mutations in ATM, which is critical for repairing DNA defects, are at risk for the development of hematologic malignancy, frequently driven by infection with Epstein-Barr virus (EBV). Conventional chemotherapy is poorly tolerated by patients with AT, with excessive toxicity even when doses are reduced. Here, we report on two patients with AT and EBV-positive neoplasms who were treated with EBV-targeted viral-specific T cells (VST).

Calpain 2 activation of P-TEFb drives megakaryocyte morphogenesis and is disrupted by leukemogenic GATA1 mutation.

Megakaryocyte morphogenesis employs a "hypertrophy-like" developmental program that is dependent on P-TEFb kinase activation and cytoskeletal remodeling. P-TEFb activation classically occurs by a feedback-regulated process of signal-induced, reversible release of active Cdk9-cyclin T modules from large, inactive 7SK small nuclear ribonucleoprotein particle (snRNP) complexes. Here, we have identified an alternative pathway of irreversible P-TEFb activation in megakaryopoiesis that is mediated by dissolution of the 7SK snRNP complex.