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 remission but remain at risk of relapse. Previous work in our laboratory involved the development of a multi-gene RQ-PCR expression panel for AML measurable residual disease (MRD). This panel demonstrated the ability to risk stratify, based on a peripheral blood sample collected prior to transplantation, AML patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT) into groups with high and low leukemic relapse rates (PMID: 25665046). During the past year we also performed a re-analysis of this data to show that there was no significant difference in overall survival between those who underwent allo-HCT with active disease and those in morphologic complete remission but with detectable minimal residual disease, confirming similar data from the Fred Hutchinson cancer center using a different MRD detection method on an independent cohort (PMID: 27185839) We have now extended this work by testing this MRD multigene approach on the autograft of a cohort of 72 adult AML patients who underwent autologous hematopoietic stem cell transplantation (auto-HCT) between 2004 and 2013 at a single academic medical center (University of California San Francisco). This is the largest study to date of MRD in auto-HCT for AML. We showed, contrary to multiple prior smaller studies, that WT1 RQ-PCR testing of the autograft has low sensitivity for AML relapse prediction post auto-HCT. We further demonstrated that cryopreserved autograft material presents unique challenges for AML MRD testing because of the masking effects of previous GCSF exposure on gene expression and flow cytometry signatures. Increased personalization of MRD monitoring by use of a multigene panel, particularly incorporation of assays for detection of somatic mutations or chromosomal abnormalities, however improved the ability to risk stratify patients for post-auto-HCT relapse. In multivariate analysis of clinical variables, including age, gender, race, cytogenetic risk category, and CD34+ cell dose, only autograft multigene MRD as assessed by RQ-PCR was statistically significantly associated with relapse risk (PMID: 27544285). The predominant activity of the section in the past year however has been the establishment and development of a new clinical program for the prevention and treatment of adults with relapsed and refractory AML at the NIH clinical center. In September 2015 we opened a new 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 integrates the MRD multigene assay described above, performed in real time by our laboratory such that the results after day 4 of treatment are available by day 8. We have exceeded our patient recruitment goals for this trial, with clinical outcomes that appear equal or better than expected. We have also established a weekly AML clinic, which serves as a teaching clinic for medical oncology clinical fellows, and developed a referral network of medical oncologists in the local area. In addition, we have opened the NIH clinical center as a site and enrolled patients onto a randomized phase 2 clinical trial of Nivolumab (anti PD-1 immune checkpoint inhibitor) to eliminate minimal residual disease and prevent relapse in patients with AML in remission after chemotherapy (REMAIN, 16-H-0015, NCI CIRB 15-0185/CTEP 9706/NCT02275533). We also serve as a central laboratory site for assessing AML MRD on this trial. Given that AML is already known to be an immunogenic malignancy, as demonstrated by the measurable efficacy of allogeneic transplantation and donor lymphocyte infusion, we have also started a program of laboratory investigation of the human immune system present within the bone marrow of both AML patients and healthy adult donors. Examination of bone marrow samples from patients with relapsed or refractory AML on our PEARL15 clinical trial, as compared with healthy donors, revealed that the bone marrow tumor microenvironment appears enriched for PD-1 positive CD8 positive marrow-infiltrating lymphocytes, and high-throughput genomic sequencing of productive TCRB gene rearrangements demonstrated significantly higher average marrow T-cell clonality. Such T-cell oligoclonality was however found in only 25% of bone marrow from an independent cohort of twenty newly diagnosed untreated AML patients. These findings are suggestive that relapsed and refractory AML patients, for whom cytotoxic chemotherapy is often suboptimal, may benefit from immune checkpoint blockade therapies, particularly PD-1 axis inhibition, to enable improved immunologic control of AML by autologous T-lymphocytes already resident in the tumor microenvironment. Based in part on these data, a clinical trial of anti-PD-1 immunotherapy in combination with a hypomethylating agent for the treatment of relapsed and refractory AML patients has been written and we aim to open this study at our institution in the next six months. 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 (including genomics and digital droplet PCR) for AML MRD detection and investigation of the human immunology resident within the bone marrow microenvironment. The clinical work of the section will focus on biomarker and novel combination immunotherapy in a highly translational program of investigation on the prevention and treatment of AML relapse.
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