Coexistence of Essential Thrombocythemia and Waldenström Macroglobulinemia: A Case Report.

Waldenström macroglobulinemia (WM) and essential thrombocythemia (ET) are distinct hematologic malignancies that have only been reported to co-occur in one previous patient. We present a 64-year-old man with a significant family history for WM who was found to have both ET and WM. He had symptomatic ET, diagnosed by elevated platelets and a positive JAK2 V617F mutation, and asymptomatic WM was found on serum electrophoresis done for screening due to family history.

Phase 1 trial of venetoclax with cladribine, cytarabine, G-CSF, and mitoxantrone for AML and high-grade myeloid neoplasm.

Intensifying induction by combining venetoclax with a high-dose cytarabine regimen may improve outcomes for high-risk populations such as adult patients with adverse-risk newly diagnosed or relapsed acute myeloid leukemia. In a phase 1 trial testing the novel combination of venetoclax and CLAG-M (cladribine, high-dose cytarabine, granulocyte colony-stimulating factor [G-CSF], and mitoxantrone), the maximum tolerated dose was venetoclax 400 mg on days 1 through 14, combined with cladribine 5 mg/m on days 1 through 5, cytarabine 1.5 g/m on days 1 through 5, G-CSF 5 μg/kg on days 0 through 5, and mitoxantrone 16 or 18 mg/m on days 1 through 3 (for relapsed/refractory and newly diagnosed adverse-risk patients, respectively).

Distal gut colonization by oral bacteria during intensive chemotherapy: direct evidence from strain-level analysis of paired samples.

Oral bacteria have been found in the colon in pathologies such as inflammatory bowel disease. To ascertain niche coalescence, 2 elements are essential: (i) paired oral/fecal samples and (ii) strain-level resolution. We profiled the microbiota in 283 samples from 39 patients undergoing intensive chemotherapy at baseline (saliva: 49, plaque: 51, stool: 43), week 2 (saliva: 18, plaque: 17, stool: 17), week 3 (saliva: 18, plaque: 21, stool: 21), and week 4 (saliva: 8, plaque: 10, stool: 10) of chemotherapy.

Predictors of Cardiac Recovery in Adults With AML Who Develop Heart Failure During Treatment.

Purpose: Heart failure is a leading cause of death in patients with AML, who face higher risks of cardiac complications than nonleukemic cancer patients treated with anthracyclines. This study examines factors associated with myocardial dysfunction and recovery occurring during treatment of AML.

Methods: We retrospectively analyzed patients with AML who sustained reduced left ventricular ejection fraction (LVEF) during induction therapy at the University of Washington/Fred Hutchinson Cancer Center (2008-2022).

Social determinants of health and access to allogeneic hematopoietic cell transplantation for acute myeloid leukemia.

Whether allogeneic hematopoietic cell transplant (allo-HCT) to treat acute myeloid leukemia (AML) is equitably accessible regardless of social determinants of health (SDOH) remains unknown. We examined associations of SDOH with access to allo-HCT and other outcomes. Patients presenting for treatment (n = 692) at 13 AML treatment centers were prospectively recruited to a registered clinical trial (number NCT01929408).

Drug-regulated CD33-targeted CAR T cells control AML using clinically optimized rapamycin dosing.

Chimeric antigen receptor (CAR) designs that incorporate pharmacologic control are desirable; however, designs suitable for clinical translation are needed. We designed a fully human, rapamycin-regulated drug product for targeting CD33+ tumors called dimerizaing agent-regulated immunoreceptor complex (DARIC33). T cell products demonstrated target-specific and rapamycin-dependent cytokine release, transcriptional responses, cytotoxicity, and in vivo antileukemic activity in the presence of as little as 1 nM rapamycin.

Context-specific synthetic T cell promoters from assembled transcriptional elements.

Genetic engineering of human lymphocytes for therapeutic applications is constrained by a lack of transgene transcriptional control, resulting in a compromised therapeutic index. Incomplete understanding of transcriptional logic limits the rational design of contextually responsive genetic modules1. Here, we juxtaposed rationally curated transcriptional response element (TRE) oligonucleotides by random concatemerization to generate a library from which we selected context-specific inducible synthetic promoters (iSynPros).

Phase 1/2 study of sorafenib added to cladribine, high-dose cytarabine, G-CSF, and mitoxantrone in untreated AML.

The multikinase inhibitor sorafenib improves event-free survival (EFS) when used with 7 + 3 in adults with newly-diagnosed acute myeloid leukemia (AML), irrespective of the FLT3-mutation status. Here, we evaluated adding sorafenib to cladribine, high-dose cytarabine, granulocyte colony-stimulating factor, and mitoxantrone (CLAG-M) in a phase 1/2 trial of 81 adults aged ≤60 years with newly diagnosed AML. Forty-six patients were treated in phase 1 with escalating doses of sorafenib and mitoxantrone.

Poor post-induction outcomes in patients with acute myeloid leukemia previously treated with hypomethylating agents.

Patients with acute myeloid leukemia (AML) who have failed hypomethylating agents (HMA) have a poor prognosis. We examined whether high intensity induction chemotherapy could abrogate negative outcomes in 270 patients with AML or other high-grade myeloid neoplasms. Prior HMA therapy was significantly associated with a lower overall survival (OS) as compared to a reference group of patients with secondary disease without prior HMA therapy (median 7.

Phase 1/2 Trial of CLAG-M with Dose-Escalated Mitoxantrone in Combination with Fractionated-Dose Gemtuzumab Ozogamicin for Newly Diagnosed Acute Myeloid Leukemia and Other High-Grade Myeloid Neoplasms.

Gemtuzumab ozogamicin (GO) improves outcomes when added to intensive AML chemotherapy. A meta-analysis suggested the greatest benefit when combining fractionated doses of GO (GO3) with 7 + 3. To test whether GO3 can be safely used with high intensity chemotherapy, we conducted a phase 1/2 study of cladribine, high-dose cytarabine, G-CSF, and dose-escalated mitoxantrone (CLAG-M) in adults with newly diagnosed AML or other high-grade myeloid neoplasm (NCT03531918).

Management of cytokine release syndrome and neurotoxicity in chimeric antigen receptor (CAR) T cell therapy.

Chimeric antigen receptor (CAR) T cell immunotherapy has demonstrated remarkable anti-tumor activity in B-cell malignancies and is under investigation in other hematologic malignancies and solid tumors. While highly efficacious, post-infusion T cell activity often results in massive cytokine release precipitating cytokine release syndrome (CRS), the signature toxicity of CAR T cells. This toxicity is characterized by systemic immune activation resulting in fever, hypotension, respiratory insufficiency and capillary leak.

Hematopoietic Stem Cell Transplantation in the Era of Engineered Cell Therapy.

Purpose Of Review: Cellular therapy using T cells modified to express chimeric antigen receptors (CAR-T cells) has had striking success in patients that have failed previous treatment for CD19 B cell non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), or acute lymphoblastic leukemia (ALL). Curative therapy for this group of diseases has previously been limited to allogeneic hematopoietic cell transplantation HCT (alloHCT). The recent results of CAR-T cell therapy raise the question of how best to integrate CAR-T cell therapy and alloHCT in the care of these patients.

Fatal enteric plexus neuropathy after one dose of ipilimumab plus nivolumab: a case report.

Background: Immune checkpoint inhibitors (ICIs) are the treatment of choice for several cancers and can be associated with remarkable clinical benefit, but can also cause serious immune-related adverse events (irAEs). Management of rare and severe irAEs is challenged by an incomplete knowledge of their natural history and pathogenetic mechanisms. We report a case of fatal acute-onset gastro-intestinal (GI) hypomotility from myenteric plexus neuropathy following a single dose of ipilimumab plus nivolumab given for treatment of Merkel cell carcinoma (MCC).

Improved assays for determining the cytosolic access of peptides, proteins, and their mimetics.

Proteins and other macromolecules that cross biological membranes have great potential as tools for research and next-generation therapeutics. Here, we describe two assays that effectively quantify the cytosolic localization of a number of previously reported peptides and protein domains. One assay, which we call GIGI (glucocorticoid-induced eGFP induction), is an amplified assay that informs on relative cytosolic access without the need for sophisticated imaging equipment or adherent cells.