The fundamental interest of the Myeloid Malignancies Section is the detection, prevention and treatment of acute myeloid leukemia (AML) relapse with particular focus on novel immunotherapy. Foundational to this objective has been the development of high sensitivity biomarkers for residual AML in those patients who have been treated to apparent remission but remain at risk of clinical relapse. Previous work in our laboratory involved the development of molecular and genomic assays for AML measurable residual disease (MRD). We have demonstrated the ability to risk stratify AML patients into groups with either high and low leukemic relapse rates, based on pre-transplant a peripheral blood sample, prior to either allogeneic (PMID: 25665046, 27185839) or autologous hematopoietic stem cell transplantation (PMID: 27544285). During the past year the findings of our work on AML MRD were validated by a meta-analysis of similar studies (PMID 28126965) and also formed part of the evidence base for an international clinical consensus opinion in this area (PMID: 28386105). We are now extending this work by testing if changes in MRD measurements during cytotoxic chemotherapy can provide an early biomarker of lack of therapeutic efficacy. In late 2015 we opened a clinical trial for AML patients with relapsed or refractory disease, PEARL15: Personalized Early Assessment of Response During Salvage Chemotherapy in People With Relapsed or Refractory Acute Myeloid Leukemia (PEARL15, 15-H-0176, NCT02527447). This trial seeks to test the hypothesis that high-sensitivity blood based assays for residual disease burden may allow much earlier assessment (prior to day 8 compared with day 28-42 conventionally) of the success of therapy for relapsed and refractory AML. We have supplemented samples from this NIH trial of relapsed and refractory patients with samples from a cohort of forty-seven newly diagnosed AML patients who underwent initial induction chemotherapy at Duke Cancer Institute between 2014-2016, with evaluation of changes in gene expression and somatic mutation burden during therapy ongoing. A major interest of the Myeloid Malignancies Section is the assessment of the feasibility of immunotherapy for the treatment of AML relapse. Acute leukemia was the first cancer for which immunotherapy (allogeneic transplantation, allo-HCT) was sufficiently successful to be adopted as a clinical standard of care. Use of this consolidative immunotherapy is unfortunately limited by toxicity, patient eligibility and logistical constraints such that most AML patients do not receive this treatment. However, drugs have recently become available (eg: immune checkpoint inhibitors) which potentially allow delivery of immunotherapy in AML outside of the context of allo-HCT. Given this long-term objective of investigating if AML is potentially susceptible to control by the immune system outside the allo-HCT setting, the first clinical protocol initiated by the Myeloid Malignancies Section focused on characterizing the state of the immune system in AML patients who had finished chemotherapy treatment but remained at risk of relapse (ie: potential candidates for immunotherapy approaches to prevent or treat relapse). In collaboration with Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, the trans-NIH Center for Human Immunology, Autoimmunity and Inflammation (CHI) and the US Food and Drug Administration, we conducted a study named J1293 Cellular and molecular characterization of the immune response before and after immunization with the seasonal influenza vaccine in adult patients who have completed treatment for acute myeloid leukemia. Of ten AML patients included in this protocol, only two generated protective titers against influenza after vaccination. Deep immunophenotyping revealed B-cell deficiencies of several types: loss of the memory B-cell compartment, an excess of immature/transitional B-cells, and a lack of nave of B-cell development into specific, class-switched effectors of the antibody response, which together likely account for humoral immune incompetence. Importantly, the frequencies and ratios of nave and memory CD4+ and CD8+ T-cells were similar to those seen in healthy controls, and CD8+ T-cells demonstrated increased influenza-specific cytokine release after vaccination. Gene expression profiling and deep sequencing of the B-cell receptor heavy chain (IgH) repertoire revealed an antigen-inexperienced B-cell repertoire. Our results suggest that while some aspects of cellular immunity may recover comparatively quickly, the humoral immune system is incompletely reconstituted in the year following intensive cytotoxic chemotherapy for AML. Increased transitional and decreased resting memory B-cells may explain the poor response to vaccination often seen in AML patients after chemotherapy. Furthermore, the uncoupled recovery of B-cell and T-cell immune capacity observed here has implications for the success of AML immunotherapy based on vaccination versus other modalities (PMID: 28693586). Our work described above both on high-sensitivity detection of AML MRD and on the immune status of AML patients has led to our latest clinical trial, PD-AML (17-H-0026, NCT02996474, FDA IND: 131826), which tests the feasibility of a novel combination of pembrolizumab (anti-PD1 immune checkpoint inhibitor) and decitabine (hypomethylating epigenetic modulator) for patients with relapsed/refractory AML. This is a single arm, open label, investigator sponsored study for ten subjects. Up to 8 cycles of pembrolizumab (every 21 days) will be given during the initial induction phase. Ten days of decitabine will be given on alternative cycles. Our central hypothesis is that pembrolizumab therapy for refractory and relapsed AML may be associated with changes in the AML clonal composition due to differences in immunogenicity between clones. The oligoclonal nature of AML biology, together with a blood and bone marrow distribution highly amenable to repeated sampling of the sites of disease burden, provides a near unique opportunity to investigate fundamental mechanisms underpinning any treatment efficacy in this new class of immunotherapeutic drugs. This trial opened in Feb 2017 and is ongoing. In summary, the primary interest of the Myeloid Malignancies Section remains the detection, prevention and treatment of AML relapse, with the long-term objective of using immunotherapy without the need for hematopoietic stem cell transplantation. Our laboratory work to develop novel methods to detect and quantify AML disease burden with high sensitivity continues, but already provides a foundation to allow correlative assessment of the efficacy of traditional stem cell transplantation and more innovative immunotherapy approaches as tested in clinical trials. We are also extending our interest in the human immune system within the bone marrow compartment both in healthy individuals and in patients with AML in parallel with clinical trials of immunotherapy for both the prevention and treatment of AML relapse. In the future, we anticipate that the laboratory work of the section will continue to focus both on molecular methods for AML MRD detection and the investigation of the human immunology resident within the bone marrow microenvironment, particularly in those receiving immunotherapy.
Showing the most recent 10 out of 45 publications
