Polatuzumab Vedotin: Current Role and Future Applications in the Treatment of Patients with Diffuse Large B-Cell Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous disease. Despite good responses to standard of care frontline chemoimmunotherapy, the prognosis of relapsed/refractory (R/R) patients remains obscured by the possible inadequate responses to salvage therapy, eligibility for autologous transplantation, age and comorbidities. Polatuzumab vedotin is an antibody-drug conjugate formed by a CD79b antibody conjugated to the highly cytotoxic agent monomethyl auristatin E by means of a cleavable linker. Following significant clinical efficacy in R/R DLBCL, polatuzumab vedotin was granted accelerated Food and Drug Administration (FDA) approval in combination with bendamustine plus rituximab for patients who have failed at least two prior therapies. Other clinical studies involving polatuzumab vedotin in combination with other therapy regimens are also under evaluation for previously untreated DLBCL patients. In this article, we review the different phases from the preclinical development of polatuzumab vedotin to studies leading to its first approval, and highlight the potential future roles of this molecule in the treatment landscape of DLBCL.

Post-Transplant Maintenance Therapy for Patients with Acute Myeloid Leukemia: Current Approaches and the Need for More Trials.

Relapse rates following allogeneic stem cell transplantation for acute myeloid leukemia remain unacceptably high and a major cause of death. Maintenance therapies post-transplant administered either to patients with impending relapse or at high risk of relapse could present a strategy to improve survival and overall outcomes. With the increasing use of molecular and genomic characterization of the disease, more novel therapies became available as maintenance strategies. These options were, however, hindered by excessive toxicities, mostly hematologic, especially with the use of myeloablative conditioning regimens. Several key questions have also emerged including the efficacy of these therapies, the duration of maintenance, as well as the potential modulation of the graft and the immune microenvironment. These issues are further complicated by the paucity of well-designed prospective randomized clinical trials evaluating these agents. Future directions in this field should include better risk stratification and patient selection based on assays of minimal residual disease, as well as the incorporation of novel targets and pathways of leukemogenesis. In this article, we highlight the current evidence behind the use of post-transplant maintenance therapy, the optimal patient and disease selection, as well as the challenges faced by these strategies in an area that remains quite controversial. We will focus on therapies targeting leukemia stem cells that directly or indirectly modulate the allografted immune microenvironment and augment the graft-versus-leukemia impact.

DIABETIC KETOACIDOSIS ASSOCIATED WITH ALPELISIB TREATMENT OF METASTATIC BREAST CANCER.

OBJECTIVE: Alpelisib-induced diabetic ketoacidosis (DKA) is a rare, but life-threatening, adverse event. There have been only 2 reported cases in the literature. We describe such a case, with emphasis on the importance of screening and achieving adequate glycemic control prior to and after initiation of therapy. METHODS: A 49-year-old woman, known to have advanced breast cancer, presented with a 3-day history of nausea, vomiting, and diffuse abdominal pain. She had started alpelisib at 300 mg/day 2 months prior to presentation, after failing other options. She was diagnosed with DKA using her clinical and laboratory features, leading to treatment with hydration and intravenous insulin therapy. RESULTS: Laboratory data showed high anion gap metabolic acidosis, hyperglycemia, and ketonemia with negative GAD-65 antibodies, leading to the diagnosis of alpelisib-associated DKA. Alpelisib was held, and she was treated with intravenous insulin and hydration. When DKA and hyperglycemia resolved, alpelisib was resumed at a lower dose (200 mg/day) and her blood glucose was managed using a regimen combining insulin and metformin. CONCLUSION: Phosphatidylinositol-3 kinase signaling is important for the metabolic actions of insulin, and alpelisib has been associated with severe hyperglycemia. Metformin is the first-line treatment, however when DKA is the presenting syndrome, insulin needs to be considered. Blood glucose and hemoglobin A1c should be checked prior to treatment initiation and monitored closely after drug initiation. DKA, albeit rare, must be considered in an acutely ill, alpelisib-treated patients presenting with metabolic acidosis, and if drug discontinuation is not an option, insulin treatment may be required to control glycemia.

A novel homozygous RTEL1 variant in a consanguineous Lebanese family: phenotypic heterogeneity and disease anticipation.

Phenotypic heterogeneity is often observed in patients with telomeropathies caused by pathogenic variants in telomere biology genes. However, the roles of recessive variants in these different phenotypes are not fully characterized. Our goal is to describe the biological roles of a novel homozygous RTEL1 variant identified in a consanguineous Lebanese family with unusual presentation of telomeropathies. A proband was screened for germline variants in telomere biology genes by whole exome sequencing. Leukocytes' telomere length was measured in the proband and eight relatives. We identified a novel homozygous p.E665K RTEL1 variant in the proband, his mother, and seven siblings that associated with telomere shortening and a broad spectrum of clinical manifestations, ranging from mild unspecific findings to severe phenotypes. Consanguinity in at least three family generations led to increased frequency of the homozygous p.E665K variant in the youngest generation and progressive telomere shortening. The increased frequency of the homozygous RTEL1 variant due to consanguinity in this Lebanese family allowed us to infer novel behaviors of recessive RTEL1 variants, as the expressivity and penetrance of this gene are very heterogenous between inter- and intra-generations. Progressive telomere shortening was associated with disease anticipation, first reported in recessive autosomal telomeropathies. Both genetic testing and telomere length measurement were critical for the clinical diagnosis of this family with telomere diseases marked by phenotypic heterogeneity.