The Proteostasis Network is a Therapeutic Target in Acute Myeloid Leukemia.

Oncogenic growth places great strain and dependence on the proteostasis network. This has made proteostasis pathways attractive therapeutic targets in cancer, but efforts to drug these pathways have yielded disappointing clinical outcomes. One exception is proteasome inhibitors, which are approved for frontline treatment of multiple myeloma.

A Rare Case of Richter Transformation to Both Clonally Unrelated and Clonally Related Diffuse Large B-Cell Lymphoma in the Same Patient.

Richter transformation (RT) is a rare sequelae of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). The clonal relationship of the RT to the underlined CLL/SLL is an important prognostic factor as clonally related RT has a worse prognosis than that of clonally unrelated RT. The development of more than one RT in the same patient is exceedingly rare and prior reports have shown cases consisting of RT to diffuse large B-cell lymphoma (DLBCL) and a subsequent or synchronous Hodgkin lymphoma.

A global study for acute myeloid leukemia with RARG rearrangement.

Acute myeloid leukemia (AML) with retinoic acid receptor γ (RARG) rearrangement has clinical, morphologic, and immunophenotypic features similar to classic acute promyelocytic leukemia. However, AML with RARG rearrangement is insensitive to alltrans retinoic acid (ATRA) and arsenic trioxide (ATO) and carries a poor prognosis. We initiated a global cooperative study to define the clinicopathological features, genomic and transcriptomic landscape, and outcomes of AML with RARG rearrangements collected from 29 study groups/institutions worldwide.

Extracorporeal photopheresis for the treatment of chronic graft versus host disease.

Objectives: Chronic graft versus host disease (chronic GVHD) still remains the leading cause of late morbidity and mortality for allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. In this retrospective study, 53 consecutive allo-HSCT patients with chronic GVHD refractory to corticosteroids were treated with extracorporeal photopheresis (ECP).

Methods: This study was performed as a retrospective single-center study.

Assessing CAR T-Cell Therapy Response Using Genome-Wide Sequencing of Cell-Free DNA in Patients With B-Cell Lymphomas.

Methods that enable monitoring of therapeutic efficacy of autologous chimeric antigen receptor (CAR) T-cell therapy will be clinically useful. The aim of this study is to demonstrate the feasibility of blood-derived cell-free DNA (cfDNA) to predict CAR T-cell therapy response in patients with refractory B-cell lymphomas. Whole blood was collected before and throughout CAR T-cell therapy until day 154.

Alternative polyadenylation dysregulation contributes to the differentiation block of acute myeloid leukemia.

Posttranscriptional regulation has emerged as a driver for leukemia development and an avenue for therapeutic targeting. Among posttranscriptional processes, alternative polyadenylation (APA) is globally dysregulated across cancer types. However, limited studies have focused on the prevalence and role of APA in myeloid leukemia.

MicroRNA let-7b downregulates AML1-ETO oncogene expression in t(8;21) AML by targeting its 3'UTR.

Background: Acute myeloid leukemia (AML) with the t(8;21)(q22;q22) chromosomal translocation is among the most common subtypes of AML and produces the AML1-ETO (RUNX1-ETO, RUNX1-RUNX1T1) oncogenic fusion gene. AML1-ETO functions as an aberrant transcription factor which plays a key role in blocking normal hematopoiesis. Thus, the expression of AML1-ETO is critical to t(8;21) AML leukemogenesis and maintenance.

Predicting Responses to Checkpoint Inhibitors in Lymphoma: Are We Up to the Standards of Solid Tumors?

Treatment of cancer has transformed with the introduction of checkpoint inhibitors. However, the majority of solid tumor patients do not respond to checkpoint blockade. In contrast, the response rate to programmed cell death 1 (PD-1) blockade in relapsed/refractory classical Hodgkin lymphoma (cHL) is 65% to 84% which is the highest among all cancers.

In vitro induction of neoantigen-specific T cells in myelodysplastic syndrome, a disease with low mutational burden.

Therapies that utilize immune checkpoint inhibition work by leveraging mutation-derived neoantigens and have shown greater clinical efficacy in tumors with higher mutational burden. Whether tumors with a low mutational burden are susceptible to neoantigen-targeted therapy has not been fully addressed. To examine the feasibility of neoantigen-specific adoptive T-cell therapy, the authors studied the T-cell response against somatic variants in five patients with myelodysplastic syndrome (MDS), a malignancy with a very low tumor mutational burden.

Gemtuzumab ozogamicin for the treatment of acute myeloid leukemia in adults.

Introduction: Treatment of acute myeloid leukemia (AML) has changed dramatically in the past ten years with the approval of targeted agents, the first of which was the anti-CD33 antibody-drug conjugate gemtuzumab ozogamicin (GO). Despite withdrawal from the market after accelerated approval, GO was reapproved and now has a well-established role in treating select AML patients. CD33 has proven to be an important target for drug development in AML as evidenced by the improvement in survival with GO treatment.

A multicenter phase 1 study of nivolumab for relapsed hematologic malignancies after allogeneic transplantation.

Programmed cell death-1 (PD-1)/programmed death ligand-1 blockade may potentially augment graft-vs-tumor effects following allogeneic hematopoietic cell transplantation (alloHCT), but retrospective studies of anti-PD-1 therapy reported substantial toxicity from graft-versus-host-disease (GVHD). Here, we report the results of a prospective clinical trial of PD-1 blockade for relapsed hematologic malignancies (HMs) after alloHCT (NCT01822509). The primary objective in this phase 1 multicenter, investigator-initiated study was to determine maximum tolerated dose and safety.

MHC-I genotype and tumor mutational burden predict response to immunotherapy.

Background: Immune checkpoint blockade (ICB) with antibodies inhibiting cytotoxic T lymphocyte-associated protein-4 (CTLA-4) and programmed cell death protein-1 (PD-1) (or its ligand (PD-L1)) can stimulate immune responses against cancer and have revolutionized the treatment of tumors. The influence of host germline genetics and its interaction with tumor neoantigens remains poorly defined. We sought to determine the interaction between tumor mutational burden (TMB) and the ability of a patient's major histocompatibility complex class I (MHC-I) to efficiently present mutated driver neoantigens in predicting response ICB.

Intensive Induction Therapy Compared With CHOP for Hepatosplenic T-cell Lymphoma.

Introduction: Hepatosplenic T-cell lymphoma (HSTCL) is a rare peripheral T-cell lymphoma that disproportionately affects individuals with a clinical history of immunosuppression. It carries a poor prognosis, and, owing to its rarity, there is no single or well-established treatment.

Patients And Methods: We conducted the largest-to-date individual-level meta-analysis based on literature searches to determine the best induction therapy for HSTCL.

Higher Risks of Toxicity and Incomplete Recovery in 13- to 17-Year-Old Females after Marrow Donation: RDSafe Peds Results.

Although donation of bone marrow (BM) or peripheral blood stem cells (PBSCs) from children to family members undergoing allogeneic transplantation are well-established procedures, studies detailing levels of pain, symptoms, and long-term recovery are lacking. To address this lack, we prospectively enrolled 294 donors age <18 years at 25 pediatric transplantation centers in North America, assessing them predonation, peridonation, and at 1 month, 6 months, and 1 year postdonation. We noted that 71% of children reported pain and 59% reported other symptoms peridonation, with resolution to 14% and 12% at 1 month postdonation.

Effect of Aging and Predonation Comorbidities on the Related Peripheral Blood Stem Cell Donor Experience: Report from the Related Donor Safety Study.

The development of reduced-intensity approaches for allogeneic hematopoietic cell transplantation has resulted in growing numbers of older related donors (RDs) of peripheral blood stem cells (PBSCs). The effects of age on donation efficacy, toxicity, and long-term recovery in RDs are poorly understood. To address this we analyzed hematologic variables, pain, donation-related symptoms, and recovery in 1211 PBSC RDs aged 18 to 79 enrolled in the Related Donor Safety Study.

Related peripheral blood stem cell donors experience more severe symptoms and less complete recovery at one year compared to unrelated donors.

Unlike unrelated donor registries, transplant centers lack uniform approaches to related donor assessment and deferral. To test whether related donors are at increased risk for donation-related toxicities, we conducted a prospective observational trial of 11,942 related and unrelated donors aged 18-60 years. Bone marrow (BM) was collected at 37 transplant and 78 National Marrow Donor Program centers, and peripheral blood stem cells (PBSC) were collected at 42 transplant and 87 unrelated donor centers in North America.

Improved accuracy of clinical HLA genotyping by next-generation DNA sequencing affects unrelated donor search results for hematopoietic stem cell transplantation.

Matching of human leukocyte antigen (HLA) genes is critically important in hematopoietic stem cell transplantation (HSCT). HLA genes are highly polymorphic and HLA matching has historically been limited by technologies that are unable to unambiguously determine HLA genotypes. Next generation DNA sequencing (NGS) overcomes these limitations by enabling near full-gene sequences with phase determination for heterozygous alleles.

A Phase I/II Trial of the Combination of Azacitidine and Gemtuzumab Ozogamicin for Treatment of Relapsed Acute Myeloid Leukemia.

Introduction: Treatment with hypomethylating agent therapy might enhance anti-CD33 monoclonal antibody-mediated cytotoxicity against acute myeloid leukemia (AML) blasts through epigenetic effects on Syk and SHP-1 expression.

Patients And Methods: In the present phase I/II study, we treated patients with relapsed or refractory AML with azacitidine, followed by 2 doses of gemtuzumab ozogamicin (GO) at 6 mg/m, the Food and Drug Administration-approved dose and schedule at study initiation. We sought to determine the maximum tolerated dose and clinical activity of this combination therapy.

Proinflammatory Dual Receptor T Cells in Chronic Graft-versus-Host Disease.

Defective post-transplantation thymopoiesis is associated with chronic graft-versus-host disease (GVHD), a multiorgan pathology affecting up to 80% of patients after allogeneic hematopoietic stem cell transplantation (HSCT). Previous work demonstrated that the subset of T cells expressing 2 T cell receptors (TCRs) is predisposed to alloreactivity, driving selective and disproportionate activity in acute GVHD in both mouse models and HSCT patients. Here we investigate a potential role for this pathogenic T cell subset in chronic GVHD (cGVHD).

Increased Foxp3Helios Regulatory T Cells and Decreased Acute Graft-versus-Host Disease after Allogeneic Bone Marrow Transplantation in Patients Receiving Sirolimus and RGI-2001, an Activator of Invariant Natural Killer T Cells.

Regulatory T (Treg) cells play a central role in immune tolerance and prevention of aberrant immune responses. Several studies have suggested that the risk of graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT) can be ameliorated by increasing Tregs. We have developed an approach of in vivo expansion of Tregs with RGI-2001, a novel liposomal formulation of a synthetic derivative of alpha-galactosylceramide, a naturally occurring ligand that binds to CD1 and activates and expands invariant natural killer cells.

CD98-Mediated Adhesive Signaling Enables the Establishment and Propagation of Acute Myelogenous Leukemia.

Acute myelogenous leukemia (AML) is an aggressive disease associated with drug resistance and relapse. To improve therapeutic strategies, it is critical to better understand the mechanisms that underlie AML progression. Here we show that the integrin binding glycoprotein CD98 plays a central role in AML.

RNA Splicing Modulation Selectively Impairs Leukemia Stem Cell Maintenance in Secondary Human AML.

Age-related human hematopoietic stem cell (HSC) exhaustion and myeloid-lineage skewing promote oncogenic transformation of hematopoietic progenitor cells into therapy-resistant leukemia stem cells (LSCs) in secondary acute myeloid leukemia (AML). While acquisition of clonal DNA mutations has been linked to increased rates of secondary AML for individuals older than 60 years, the contribution of RNA processing alterations to human hematopoietic stem and progenitor aging and LSC generation remains unclear. Comprehensive RNA sequencing and splice-isoform-specific PCR uncovered characteristic RNA splice isoform expression patterns that distinguished normal young and aged human stem and progenitor cells (HSPCs) from malignant myelodysplastic syndrome (MDS) and AML progenitors.

Ipilimumab for Patients with Relapse after Allogeneic Transplantation.

Background: Loss of donor-mediated immune antitumor activity after allogeneic hematopoietic stem-cell transplantation (HSCT) permits relapse of hematologic cancers. We hypothesized that immune checkpoint blockade established by targeting cytotoxic T-lymphocyte-associated protein 4 with ipilimumab could restore antitumor reactivity through a graft-versus-tumor effect.

Methods: We conducted a phase 1/1b multicenter, investigator-initiated study to determine the safety and efficacy of ipilimumab in patients with relapsed hematologic cancer after allogeneic HSCT.