Real-World Use of Isavuconazole as Primary Therapy for Invasive Fungal Infections in High-Risk Patients with Hematologic Malignancy or Stem Cell Transplant

(1) Introduction: Invasive fungal infections (IFIs) are a major cause of morbidity and mortality among immunocompromised patients with hematologic malignancies (HM) and stem cell transplants (SCT). Isavuconazole was approved by FDA as a primary therapy for Invasive Aspergillosis (IA) and Mucormycosis. The aim of this study is to look at the real-world use of Isavuconazole in patients with HM and evaluate their clinical outcomes and safety. (2) Methods: We conducted a retrospective study of HM patients at MD Anderson Cancer Center who had definite, probable or possible mold infections between 1 April 2016 and 31 January 2020 and were treated with Isavuconazole for a period of at least 7 days. Clinical and radiological findings were assessed at baseline and at 6 and 12 weeks of follow up. (3) Results: We included 200 HM patients with IFIs that were classified as definite (11), probable (63) and possible (126). Aspergillus spp was the most commonly isolated pathogen. The majority of patients (59%) received prophylaxis with anti-mold therapy and Isavuconazole was used as a primary therapy in 43% of patients, and as salvage therapy in 58%. The switch to Isavuconazole was driven by the failure of the primary therapy in 66% of the cases and by adverse effects in 29%. Isavuconazole was used as monotherapy in 30% of the cases and in combination in 70%. Adverse events possibly related to Isavuconazole were reported in eight patients (4%) leading to drug discontinuation. Moreover, a favorable response with Isavuconazole was observed in 40% at 6 weeks and in 60% at 12 weeks. There was no significant difference between isavuconazole monotherapy and combination therapy (p = 0.16 at 6 weeks and p = 0.06 at 12 weeks). Finally, there was no significant difference in outcome when Isavuconazole was used after failure of other anti-mold prophylaxis or treatment versus when used de novo as an anti-mold therapy (p = 0.68 at 6 weeks and p = 0.25 at 12 weeks). (4) Conclusions: Whether used as first-line therapy or after the failure of other azole and non-azole prophylaxis or therapies, isavuconazole seems to have a promising clinical response and a good safety profile as an antifungal therapy in high-risk cancer patients with hematologic malignancies. Moreover, combination therapy did not improve the outcome compared to Isavuconazole therapy.

Post-hoc Analysis of Pharmacodynamics and Single-Agent Activity of CD3xCD123 Bispecific Antibody APVO436 in Relapsed/Refractory AML and MDS Resistant to HMA or Venetoclax Plus HMA

APVO436 is a recombinant bispecific antibody designed to direct host cytotoxic T-cells to CD123-expressing blast cells in patients with hematologic malignancies. APVO436 showed promising tolerability and single-agent activity in relapsed or refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The primary purpose of this post-hoc analysis was to evaluate the therapeutic and pharmacodynamic effects of APVO436 in 14 R/R AML/MDS patients who had failed treatment with hypomethylating agents (HMA) or venetoclax plus HMA prior to being enrolled in the APVO436 Phase 1 dose-escalation study that was recently completed. Eight of these 14 patients had R/R AML and had failed treatment with HMA (N=2) or venetoclax plus HMA (N=6). The remaining 6 patients had R/R MDS and had also failed treatment with HMA (N=5) or venetoclax plus HMA (N=1). They were treated with APVO436 at submicrogram dose levels >0.08 mcg/kg that were active in preclinical NOD/SCID mouse xenograft models of AML. APVO436 activated patients’ T-cells as evidenced by reduced numbers of circulating CD123+CD34+ and CD33+CD34+ peripheral blasts. Single-agent activity was observed at dose levels ranging from 0.1 mcg/kg to 0.7 mcg/kg in 4 R/R AML patients (50%), including 3 patients with prolonged stable disease (SD) and one patient with complete remission (CR). Likewise, 3 MDS patients had SD (50%) and 3 additional MDS patients (50%) had a marrow CR at dose levels ranging from 0.1 mcg/kg to 0.8 mcg/kg. The median survival for the combined group of 14 R/R AML/MDS patients was 282 days. This early evidence of single-agent activity of APVO436 in R/R AML/MDS patients who failed HMA with or without venetoclax provides proof of concept supporting its in vivo immunomodulatory and anti-leukemic activity and warrants further investigation of its clinical impact potential.

The Role of N6-Methyladenosine (m6A) Methylation Modifications in Hematological Malignancies

Epigenetics is identified as the study of heritable modifications in gene expression and regulation that do not involve DNA sequence alterations, such as DNA methylation, histone modifications, etc. Importantly, N6-methyladenosine (m6A) methylation modification is one of the most common epigenetic modifications of eukaryotic messenger RNA (mRNA), which plays a key role in various cellular processes. It can not only mediate various RNA metabolic processes such as RNA splicing, translation, and decay under the catalytic regulation of related enzymes but can also affect the normal development of bone marrow hematopoiesis by regulating the self-renewal, proliferation, and differentiation of pluripotent stem cells in the hematopoietic microenvironment of bone marrow. In recent years, numerous studies have demonstrated that m6A methylation modifications play an important role in the development and progression of hematologic malignancies (e.g., leukemia, lymphoma, myelodysplastic syndromes [MDS], multiple myeloma [MM], etc.). Targeting the inhibition of m6A-associated factors can contribute to increased susceptibility of patients with hematologic malignancies to therapeutic agents. Therefore, this review elaborates on the biological characteristics and normal hematopoietic regulatory functions of m6A methylation modifications and their role in the pathogenesis of hematologic malignancies.

Cancer-driving mutations are enriched in genic regions intolerant to germline variation

Large reference datasets of protein-coding variation in human populations have allowed us to determine which genes and genic sub-regions are intolerant to germline genetic variation. There is also a growing number of genes implicated in severe Mendelian diseases that overlap with genes implicated in cancer. Here, we hypothesized that mitotically mutable genic sub-regions that are intolerant to germline variation are enriched for cancer-driving mutations. We introduce a new metric, OncMTR, which uses 125,748 exomes in the gnomAD database to identify genic sub-regions intolerant to germline variation but enriched for hematologic somatic variants. We demonstrate that OncMTR can significantly predict driver mutations implicated in hematologic malignancies. Divergent OncMTR regions were enriched for cancer-relevant protein domains, and overlaying OncMTR scores on protein structures identified functionally important protein residues. Finally, we performed a rare variant, gene-based collapsing analysis on an independent set of 394,694 exomes from the UK Biobank and find that OncMTR dramatically improves genetic signals for hematologic malignancies. Our web app enables easy visualization of OncMTR scores for each protein-coding gene (https://astrazeneca-cgr-publications.github.io/OncMTR-Viewer/).

Outcomes of Patients With Hematologic Malignancies Who Received Inpatient Palliative Care Consultation

PURPOSE: Palliative care (PC) plays an established role in improving outcomes in patients with solid tumors, yet these services are underutilized in hematologic malignancies (HMs). We reviewed records of hospitalized patients with active HM to determine associations between PC consultation and length of stay, intensive care unit stay, 30-day readmission, and 6-month mortality compared with those who were not seen by PC. METHODS: We reviewed all oncology admissions at our institution between 2013 and 2019 and included patients with HM actively on treatment, stratified by those seen by PC to controls not seen by PC. Groups were compared using Wilcoxon rank-sum, chi-square, and Fisher's exact tests on the basis of the type and distribution of data. Multiple logistic regression models with stepwise variable selection methods were used to find predictors of outcomes. RESULTS: Three thousand six hundred fifty-four admissions were reviewed, among which 370 unique patients with HM were included. Among these, 102 (28%) patients saw PC, whereas the remaining 268 were controls with similar comorbidities. When compared with controls, PC consultation was associated with a statistically significant reduction in 30-day readmissions (16% v 27%; P = .024), increased length of stay (11.5 v 6 days; P < .001), increased intensive care unit admission (28% v 9%; P < .001), and increased 6-month mortality (67% v 15%; P < .001). These data were confirmed in multivariable models. CONCLUSION: In this retrospective study, more than two thirds of patients with HM did not receive PC consultation despite having similar comorbidities, suggesting that inpatient PC consultation is underutilized in patients with HM, despite the potential for decreased readmission rates.

Arrhythmia Patterns in Patients on Ibrutinib

Introduction: Ibrutinib, a Bruton's tyrosine kinase inhibitor (TKI) used primarily in the treatment of hematologic malignancies, has been associated with increased incidence of atrial fibrillation (AF), with limited data on its association with other tachyarrhythmias. There are limited reports that comprehensively analyze atrial and ventricular arrhythmia (VA) burden in patients on ibrutinib. We hypothesized that long-term event monitors could reveal a high burden of atrial and VAs in patients on ibrutinib.Methods: A retrospective data analysis at a single center using electronic medical records database search tools and individual chart review was conducted to identify consecutive patients who had event monitors while on ibrutinib therapy.Results: Seventy-two patients were included in the analysis with a mean age of 76.9 ± 9.9 years and 13 patients (18%) had a diagnosis of AF prior to the ibrutinib therapy. During ibrutinib therapy, most common arrhythmias documented were non-AF supraventricular tachycardia (n = 32, 44.4%), AF (n = 32, 44%), and non-sustained ventricular tachycardia (n = 31, 43%). Thirteen (18%) patients had &gt;1% premature atrial contraction burden; 16 (22.2%) patients had &gt;1% premature ventricular contraction burden. In 25% of the patients, ibrutinib was held because of arrhythmias. Overall 8.3% of patients were started on antiarrhythmic drugs during ibrutinib therapy to manage these arrhythmias.Conclusions: In this large dataset of ambulatory cardiac monitors on patients treated with ibrutinib, we report a high prevalence of atrial and VAs, with a high incidence of treatment interruption secondary to arrhythmias and related symptoms. Further research is warranted to optimize strategies to diagnose, monitor, and manage ibrutinib-related arrhythmias.