Optimizing survival outcomes with post-remission therapy in acute myeloid leukemia.

Optimization of post-remission therapies to maintain complete remission and prevent relapse is a major challenge in treating patients with acute myeloid leukemia (AML). Monitoring patients for measurable residual disease (MRD) is helpful to identify those at risk for relapse. Hypomethylating agents are being investigated as post-remission therapy. Identification of recurrent genetic alterations that drive disease progression has enabled the design of new, personalized approaches to therapy for patients with AML. Emerging data suggest that targeted post-remission therapy, alone or in combination with chemotherapy, may improve outcomes. Results of ongoing clinical trials will further define potential clinical benefits

Unique Case of Anca-Negative Pauci-Immune Necrotizing Glomerulonephritis With Diffuse Alveolar Hemorrhage, Potentially Associated With Midostaurin

We present a 61-year-old male with FLT3-mutated acute myeloid leukemia treated with midostaurin who developed acute kidney injury requiring hemodialysis and pulmonary renal syndrome. Antibodies to proteinase-3, myeloperoxidase, and glomerular basement membrane were negative. Renal biopsy confirmed acute pauci-immune focal necrotizing glomerulonephritis (GN) with fibrin crescents indicating rapidly progressing glomerulonephritis. He improved with pulse methylprednisolone, intravenous cyclophosphamide, and plasma exchange with resolution of hemoptysis. This case highlights the importance of prompt renal biopsy to guide early initiation of life-saving therapies. To our knowledge, this is the first reported case of ANCA-negative pauci-immune necrotizing GN likely secondary to midostaurin

Antibody Therapies for the Treatment of Acute Myeloid Leukemia: Exploring Current and Emerging Therapeutic Targets

INTRODUCTION: Acute myeloid leukemia (AML) is the most common and deadly type of leukemia affecting adults. It is typically managed with rounds of non-targeted chemotherapy followed by hematopoietic stem cell transplants, but this is only possible in patients who can tolerate these harsh treatments and many are elderly and frail. With the identification of novel tumor-specific cell surface receptors, there is great conviction that targeted antibody therapies will soon become available for these patients. AREAS COVERED: In this review, we describe the current landscape of known target receptors for monospecific and bispecific antibody-based therapeutics for AML. Here, we characterize each of the receptors and targeted antibody-based therapeutics in development, illustrating the rational design behind each therapeutic compound. We then discuss the bispecific antibodies in development and how they improve immune surveillance of AML. For each therapeutic, we also summarize the available pre-clinical and clinical data, including data from discontinued trials. EXPERT OPINION: One antibody-based therapeutic has already been approved for AML treatment, the CD33-targeting antibody-drug conjugate, gemtuzumab ozogamicin. Many more are currently in pre-clinical and clinical studies. These antibody-based therapeutics can perform tumor-specific, elaborate cytotoxic functions and there is growing confidence they will soon lead to personalized, safe AML treatment options that induce durable remissions

Primary gastric chorioadenocarcinoma: a needle in a haystack

Primary gastric chorioadenocarcinoma (PGC) is an exceedingly rare neoplasm which is often misdiagnosed as gastric adenocarcinoma at presentation. A markedly elevated serum beta human chorionic gonadotrophin (Beta HCG) level is a characteristic feature of this tumor. A 44 year old white male presented with generalized abdominal pain and fullness, tarry black stools and weight loss of 3 months duration. Medical work-up including imaging with CT scans revealed the presence of a gastric mass and multiple liver metastases. Tumor markers were significant for a Betahuman chorionic gonadotrophin (Beta HCG) of 23717.5 MIU/ML. Scrotal ultrasound did not show the presence of a testicular mass. Upper GI endoscopy with biopsy was positive for a poorly differentiated adenocarcinoma with Beta HCG staining on immunohistochemistry. The patient was diagnosed with metastatic PGC. He received four cycles of chemotherapy with Bleomycin, Etoposide and Cisplatinum. At the end of the fourth cycle, Beta HCG was 23 MIU/ML. CT scan for restaging, however showed an increase in the size of the metastatic lesions. The patient subsequently became profoundly pancytopenic, developed disseminated intravascular coagulation (DIC) and expired 12 months after initial presentation. PGC genetically and morphologically represents an adenocarcinoma and a choriocarcinoma. The significance of an elevated serum Beta HCG is controversial and it may have a role in evaluating response to treatment and tumor recurrence. Curative resection, appropriate chemotherapy and the absence of metastatic lesions is associated with improved survival. Hence, a high index of suspicion must be maintained to diagnose this tumor correctly at presentation and tailor therapy accordingly

Successful Treatment of Intracranial Hemorrhage with Recombinant Activated Factor VII in a Patient with Newly Diagnosed Acute Myeloid Leukemia: A Case Report and Review of the Literature

Intracranial hemorrhage (ICH) is a common complication in acute myeloid leukemia (AML) patients with an incidence rate of 6.3% [1]. Bleeding disorders related to disseminated intravascular coagulation (DIC) are common complications in AML cases [2]. Recombinant activated Factor VII (rFVIIa [NovoSeven®]) is approved for the treatment of bleeding complications with FVIII or FIX inhibitors in patients with congenital FVII deficiency. Use of rFVIIa for the treatment of acute hemorrhage in patients without hemophilia has been successful [3,4]. Herein, we describe the successful use of rFVIIa in a patient with acute ICH in the setting of newly diagnosed AML

Pembrolizumab Enhances the Anti-Leukemia Activity of Antigen Specific Cytotoxic T Lymphocytes

https://openworks.mdanderson.org/sumexp23/1074/thumbnail.jp

Effective Menin inhibitor-based combinations against AML with MLL rearrangement or NPM1 mutation (NPM1c)

Treatment with Menin inhibitor (MI) disrupts the interaction between Menin and MLL1 or MLL1-fusion protein (FP), inhibits HOXA9/MEIS1, induces differentiation and loss of survival of AML harboring MLL1 re-arrangement (r) and FP, or expressing mutant (mt)-NPM1. Following MI treatment, although clinical responses are common, the majority of patients with AML with MLL1-r or mt-NPM1 succumb to their disease. Pre-clinical studies presented here demonstrate that genetic knockout or degradation of Menin or treatment with the MI SNDX-50469 reduces MLL1/MLL1-FP targets, associated with MI-induced differentiation and loss of viability. MI treatment also attenuates BCL2 and CDK6 levels. Co-treatment with SNDX-50469 and BCL2 inhibitor (venetoclax), or CDK6 inhibitor (abemaciclib) induces synergistic lethality in cell lines and patient-derived AML cells harboring MLL1-r or mtNPM1. Combined therapy with SNDX-5613 and venetoclax exerts superior in vivo efficacy in a cell line or PD AML cell xenografts harboring MLL1-r or mt-NPM1. Synergy with the MI-based combinations is preserved against MLL1-r AML cells expressing FLT3 mutation, also CRISPR-edited to introduce mtTP53. These findings highlight the promise of clinically testing these MI-based combinations against AML harboring MLL1-r or mtNPM1

Targeting of epigenetic co-dependencies enhances anti-AML efficacy of Menin inhibitor in AML with MLL1-r or mutant NPM1

Monotherapy with Menin inhibitor (MI), e.g., SNDX-5613, induces clinical remissions in patients with relapsed/refractory AML harboring MLL1-r or mtNPM1, but most patients either fail to respond or eventually relapse. Utilizing single-cell RNA-Seq, ChiP-Seq, ATAC-Seq, RNA-Seq, RPPA, and mass cytometry (CyTOF) analyses, present pre-clinical studies elucidate gene-expression correlates of MI efficacy in AML cells harboring MLL1-r or mtNPM1. Notably, MI-mediated genome-wide, concordant, log2 fold-perturbations in ATAC-Seq and RNA-Seq peaks were observed at the loci of MLL-FP target genes, with upregulation of mRNAs associated with AML differentiation. MI treatment also reduced the number of AML cells expressing the stem/progenitor cell signature. A protein domain-focused CRISPR-Cas9 screen in MLL1-r AML cells identified targetable co-dependencies with MI treatment, including BRD4, EP300, MOZ and KDM1A. Consistent with this, in vitro co-treatment with MI and BET, MOZ, LSD1 or CBP/p300 inhibitor induced synergistic loss of viability of AML cells with MLL1-r or mtNPM1. Co-treatment with MI and BET or CBP/p300 inhibitor also exerted significantly superior in vivo efficacy in xenograft models of AML with MLL1-r. These findings highlight novel, MI-based combinations that could prevent escape of AML stem/progenitor cells following MI monotherapy, which is responsible for therapy-refractory AML relapse