Venetoclax and dinaciclib elicit synergistic preclinical efficacy against hypodiploid acute lymphoblastic leukemia.

Hypodiploid acute lymphoblastic leukemia (ALL) is an aggressive blood cancer with a poor prognosis despite intensive chemotherapy or stem cell transplant. Children and adolescents with positive end-of-induction minimal residual disease have an overall survival lower than 30%. However, data regarding therapeutic alternatives for this disease is nearly nonexistent, emphasizing the critical need for new or adjunctive therapies that can improve outcomes. We previously reported on the therapeutic efficacy of venetoclax (ABT-199) in hypodiploid B-lineage ALL but with limitations as monotherapy. In this study, we set out to identify drugs enhancing the anti-leukemic effect of venetoclax in hypodiploid ALL. Using a highthroughput drug screen, we identified dinaciclib, a cyclin-dependent kinase inhibitor that worked synergistically with venetoclax to induce cell death in hypodiploid cell lines. This combination eradicated leukemic blasts within hypodiploid ALL patient-derived xenografts mice with low off-target toxicity. Our findings suggest that dual inhibition of BCL-2 (venetoclax) and CDK9/MCL-1 (dinaciclib) is a promising therapeutic approach in hypodiploid ALL, warranting further investigation to inform clinical trials in this high-risk patient population.

Busulfan, fludarabine, and melphalan are effective conditioning for pediatric and young adult patients with myeloid malignancies underdoing matched sibling or alternative donor transplantation.

BACKGROUND: Allogeneic hematopoietic cell transplantation (allo-HCT) remains a curative option for patients with high-risk myeloid malignancies. PROCEDURE: We present our 10-year experience (October 2012 to October 2021) of consecutive allo-HCT in patients with myeloid malignancies treated on the pediatric HCT service and conditioned with myeloablative targeted dose-busulfan (BU), fludarabine (FLU), and melphalan (MEL). Twenty-three children, adolescents, and young adult patients (CAYA) (median age 15.4 years) with acute myeloid leukemia (AML, n = 17), myelodysplastic syndrome (MDS, n = 4), or chronic myeloid leukemia (CML, n = 2) underwent allo-HCT post-BU-FLU-MEL. Four patients had treatment-related AML/MDS. Donor/stem cell source was matched sibling donor (MSD) PBSC (n = 7), matched unrelated donor (MUD) PBSC (n = 2), umbilical cord blood (UCB) (n = 3), or haploidentical-BMT (n = 11). Risk stratification was low (n = 2), intermediate (n = 15), high (n = 3), and very high risk (n = 1). The two patients with CML had failed tyrosine kinase inhibitor therapies. RESULTS: With a median follow-up of 41.6 months, the relapse rate is only 4.5% with an overall survival (OS) 100%, progression-free survival (PFS) 95.5%, and graft-versus-host-free-relapse-free survival (GRFS) 67.8%. The donor source and the acute graft-versus-host disease (GvHD) prophylaxis regimen significantly impacted grade II-IV aGvHD 66.7% versus 19.2% (p = .039) and chronic graft-versus-host-disease (cGvHD) 66.7% versus 0% (p = .002) in the patients receiving MSD or MUD PBSC compared to haplo-BMT, respectively, resulting in improved GRFS in haplo-BMT, 83.3% compared to 40% matched donor peripheral blood stem cell transplant (PBSCT) (p = .025). CONCLUSIONS: Our results demonstrate that BU-FLU-MEL is efficacious conditioning for disease control in young patients with myeloid malignancies undergoing MSD or alternative donor allo-HCT, but in the setting of PBSC grafts with cyclosporine A-methotrexate (CSA-MTX) GvHD prophylaxis, it results in an unacceptably high incidence of GvHD.

Have CD19-directed immunotherapy and haploidentical hematopoietic cell transplantation transformed pediatric B-cell acute lymphoblastic leukemia into a chronic disease?

The treatment of pediatric B-cell acute lymphoblastic leukemia (B-ALL) has undergone several recent advancements, leading to an increased amount of treatment options for relapsed patients. The development of immunotherapies such as anti-CD19 chimeric antigen receptor(CAR) T cells and bispecific T-cell engagers has given clinicians therapeutic options with less expected toxicity when compared to standard re-induction chemotherapy. This is especially beneficial in patients with toxicities from their prior treatment. Along with this, the emergence of haploidentical hematopoietic cell transplantation (HCT) has increased opportunity for patients to receive HCT who may not have had an available matched donor. We present four patients who have received all of these therapies in different combinations to treat multiple relapses. Because of the success of achieving remission as well as decreasing toxicity, the patients are alive and well up to 15 y after the original B-ALL diagnosis, rendering this as a chronic disease for them.

Extracranial Metastases From Glioblastoma With Primitive Neuronal Components on FDG PET/CT.

A 17-year-old girl with World Health Organization grade IV glioblastoma with primitive neuronal components (histone H3 G34-mutant and IDH1 wild type) underwent whole-body FDG PET/CT staging due to vertebral metastases on initial MRI. PET/CT revealed extracranial metastatic disease with spinal leptomeningeal dissemination, osseous metastases, and peritoneal seeding via a ventriculoperitoneal shunt. Glioblastoma is uncommon in pediatric patients and particularly those with primitive neuronal components. Extracranial metastases from glioblastoma are more common in those with primitive neuronal components. This case demonstrates the utility of FDG PET/CT for revealing distant metastases from glioblastoma.

Potassium supplementation mitigates corticosteroid-induced neuropsychiatric effects in pediatric oncology patients.

Corticosteroids play an essential role in the treatment of pediatric malignancies, but have many untoward side effects including behavioral and mood disturbances which can be quite burdensome to families. Potassium chloride has been used anecdotally to decrease these neuropsychiatric effects but this experience has not been studied systematically. We therefore retrospectively reviewed our experience utilizing KCl supplementation to reduce corticosteroid-induced neuropsychiatric effects among children with acute lymphoblastic leukemia. Thirteen of 16 patients (81%) had a objective benefit with KCl at a median dose of 0.5 mEq/kg/day, with no reported adverse effects. Further prospective study is required to confirm these data.

Pediatric ovarian angiosarcoma treated with systemic chemotherapy and cytoreductive surgery with heated intraperitoneal chemotherapy: Case report and review of therapy.

Ovarian angiosarcoma is a rare and aggressive vascular tumor, which has a 5-year overall survival of less than 30% for patients with nonmetastatic disease and almost certain death within 1 year for those with metastasis. Here, we briefly review historical approaches to therapy and present a long-term survivor in the case of an 11-year-old female with metastatic ovarian angiosarcoma. This is the second reported case to utilize heated intraperitoneal chemotherapy in the treatment of this disease. Our patient is currently alive and well 3 years after initial diagnosis, significantly longer than any reported case of advanced-stage ovarian angiosarcoma.

A Stinging Suspicion Something Was Just Not Right: Methamphetamine Toxicity in Infant Mimics Scorpion Envenomation.

The sting from Centuroides sculpturatus, commonly known as the bark scorpion, is a serious medical problem and can be potentially fatal to young children. Centuroides sculpturatus envenomation can cause a wide spectrum of symptoms, often including autonomic dysfunction, cranial nerve abnormalities, and somatic motor abnormalities. We discuss a 6-month-old male infant who presented with signs and symptoms consistent with bark scorpion envenomation, later found to be secondary to methamphetamine toxicity. Emergency pediatricians should be aware of the strong similarities between scorpion envenomation and methamphetamine toxicity in pediatric patients residing in or having visited the southwestern region of the United States. Methamphetamine toxicity should be considered in their differential diagnosis.