Laura Finn's research while affiliated with Mayo Foundation for Medical Education and Research and other places

L. Finn, A. R. Roche Green (eds.), Supportive Care Strategies, Advances and Controversies in Hematopoietic Transplantation and Cell Therapy

For decades acute myeloid leukemia, the primary acute leukemia affecting adults, had limited treatment options. Since 2017, we have seen discovery and development in cytogenetic and molecular classification of acute myeloid leukemia, improved understanding of cell signaling pathways, and development of new treatment for acute myeloid leukemia. These new treatments include novel combinations of agents and therapy targeting molecular alterations improving rates of remission and overall survival. Treatment discovery provides therapeutic opportunity to older patients and populations previously excluded from intense induction chemotherapy. In this review, we discuss the timing of first therapy, non-intense treatment regimens achieving remission, and new targets for directed therapy. We reference key clinical trials to expand our discussion of newly approved agents for acute myeloid leukemia. In this review, we highlight the discovery of treatment strategies to improve patient outcomes and ongoing research in leukemia.

Introduction: Population studies have identified genes with germline polymorphisms associated with acute myeloid leukemia (AML) risk and outcome. However, somatic mutations in these genes have not been reported in an AML clinical population and whether they are associated with epidemiologic exposures, clinical AML phenotypes and outcome after therapy. Methods: We systemically interrogated PubMed database (1998-2018), to identify genes with germline polymorphisms associated with AML risk, response to chemotherapy or outcome. To determine the prevalence and relevance of somatic mutations in these genes in an unselected AML population, we performed an analysis using Whole-Exome Sequencing (WES) on remnant diagnostic cytogenetic pellets from 98 patients from the Mayo Clinic AML Epidemiology Cohort, a detailed and highly-annotated cohort of 295 consecutive AML patients treated at Mayo Clinic Florida & Arizona between October, 2000 and December, 2011. Patient characteristics are shown in Table 1. Samples were sequenced at a depth of ~100 million paired-end 100bp reads using Agilent SureSelectXT Human All Exon V5 + UTRs target enrichment kit. Sequencing reads were aligned to human reference genome, and somatic mutations including non-synonymous and truncating single nucleotide variants and small INDELs were identified and filtered using Exome Sequencing Project, 1000 genome, HapMap, & Mayo Clinic internal biobank genetic variants database. Copy number aberrations were identified & filtered using public copy number polymorphism databases. The association analyses were performed at the gene level, with a primary endpoint of whether a given patient harbored a somatic mutation in any genes linked to AML risk or outcome in literature, and to determine the associations of these mutations with epidemiologic exposures, AML phenotype and clinical outcomes. Results: From the literature search, we identified 77 unique genes with known germline polymorphisms associated with AML risk, response to chemotherapy or outcome. Fifty-eight of these were found to be somatically mutated in our WES dataset, with subsequent analysis focusing on the 11 genes (ABCB1, CYP1A1, CYP2B6, EPHX1, ERCC1, ERCC2, ERCC5, JAK2, MEFV, MTRR, and TERT) that had greater than 5 patients with nonsynonymous somatic mutations in the given gene. Significant associations with epidemiologic exposures and outcomes were noted in patients with somatic mutations in ERCC2, CYP1A1 and ERCC5 genes. Table 2 shows a comparison of patient characteristics and associations according to the presence of somatic mutations in these genes. Patients with mutations in CYP1A1 had a significantly younger age at AML diagnosis (Median: 51.7 vs. 71.0 years, P=.02) and significantly shorter OS in age-adjusted analysis (HR=4.45, P=.003). The former is a novel finding, whereas the latter is consistent with previous reports. Patients with mutations in ERCC2 more commonly used statins (66.7% vs. 21.7%, P=.03). Patients with ERCC5 mutations had a lower rate of tobacco use (20.0% vs. 54.5%, P=.049). In unadjusted analysis, there was a significant association between presence of somatic mutations in JAK2 and poorer survival after AML diagnosis (HR=2.83, P=.017), but this attenuated and did not retain significance when adjusting for age at AML diagnosis (HR=2.22, P=.067). Conclusion: Our exploratory study describes a novel association of CYP1A1 somatic nonsynonymous mutations with age of AML onset, as well as novel associations of ERCC2 and ERCC5 mutations with epidemiologic exposures in an unselect cohort of patients with AML. We confirm the association of CYP1A1 with inferior overall survival after AML diagnosis. These findings suggest that some genes associated with AML risk may also harbor somatic mutations that are clinically relevant. These results will guide a planned confirmatory prospective study to determine frequency and impact of both germline and somatic mutations of risk genes in AML patients, and may contribute to a better understanding leukemia risk assessment and potentially to prevention strategies. Disclosures Finn: Jazz Pharmaceuticals: Speakers Bureau; Celgene: Speakers Bureau; Seattle Genetics: Speakers Bureau. Cerhan:BMS/Celgene: Research Funding; NanoString: Research Funding. Foran:Revolution Medicine: Consultancy; Servier: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Research Funding; H3Biosciences: Research Funding; Xencor: Research Funding; Trillium: Research Funding; Takeda: Research Funding; Kura Oncology: Research Funding; Aptose: Research Funding; Aprea: Research Funding; Actinium: Research Funding; Agios: Honoraria, Research Funding.

Primary CNS lymphoma is a rare condition, with annual incidence of about 1400 cases in the US. Patients with aggressive systemic lymphomas also have high incidence of CNS involvement, with poor overall prognosis. Use of high dose methotrexate based therapies has substantially altered the outlook for these patients. We present the outcomes data of patients with primary CNS lymphoma and those with secondary CNS involvement treated with high dose methotrexate from a single , FACT accredited academic transplant center. We reviewed patients treated at our center over a 42 month period between Jan 2017- June 2020. There were 19 patients with primary CNS lymphoma and 24 with secondary CNS involvement who received high dose methotrexate. There were equal number of men and women, and were mostly Caucasian. Median age at diagnosis was 60 years. Majority were HIV negative (95%). 3 of the 19 patients had EBV infection at the time of diagnosis. Majority had performance status of ECOG 1 (range: 0-4). 1 patient had CNS lymphoma in the post transplant setting (had bilateral lung transplant). 2 out of 19 patients had concurrent solid organ malignancies. 17 patients (90 %) had newly diagnosed primary CNS lymphoma. 2 patients (10 %) had relapsed disease. Patients received a median of 6 induction treatments (range 1-12) . Majority of patients (17/19) received high dose methotrexate with rituximab. 1 patient received only high dose methotrexate. 1 patient received methotrexate, procarbazine, rituximab and vincristine (R MPV). 5 patients (26%) progressed during induction. There were 7 deaths (37 %) during induction phase. Majority of the deaths occured early during induction. Majority had partial response. 1 patient had complete response . No patient has received stem cell transplant. There were no chemotherapy delays due to COVID 19 . No patient with primary CNS lymphoma was hospitalized or died due to COVID 19. 1 patient elected to defer chemotherapy due to fear of contracting COVID 19 in the hospital. No patient received the full,planned doses of high dose methotrexate during induction. Dose reductions were due to poor performance status or impaired renal function. Consolidation was mainly with high dose methotrexate. Those progressing received whole brain radiation, Ara C , or best supportive care. The PFS and OS are being evaluated at the time of this submission. There were 24 patients with secondary CNS involvement . 12 had concurrent systemic and CNS involvement. 12 patients had history of systemic lymphoma but with CNS only relapse. There were equal males and females. Median age at diagnosis was 64 years. (range 33-81). They had good performance status, with majority having PS of ECOG 1 (range 1-3). Majority were caucasian. There were 4 patients (17%) with EBV infection. 2 patients (8 %) had HIV. They received a median of 2 high dose methotrexate inductions (range: 1-10). 4 patients (17%) eventually received stem cell transplants. PFS, survival data are being evaluated at the time of this submission. In general, high dose methotrexate was well tolerated in both primary CNS lymphoma and systemic lymphoma with CNS involvement. Stem cell transplants are still being done infrequently for these patients. Disclosures Finn: Jazz Pharmaceuticals:Speakers Bureau;Celgene:Speakers Bureau;Seattle Genetics:Speakers Bureau.

Hematopoietic stem cell transplant results in a variety of treatment-related side effects other than pain. The side effects encountered may include prolonged, late, or permanent side effects of prior cancer therapy in addition to treatment-related effects from transplant chemotherapy, prolonged cytopenias, and therapy used for supportive care during transplant. Systemic side effects to address during and after transplant may include fatigue, delirium, and malnutrition. Gastrointestinal side effects may include mucositis, nausea, vomiting, diarrhea, and constipation. In this chapter we discuss the recognition, approach, and therapeutic interventions for the management of these non-pain-related side effects of Hematopoietic stem cell transplant.

Hematologists are tasked with treating and potentially curing patients with terminal cancers through the constantly evolving field of hematopoietic cell transplant. Transplant has progressed dramatically over the past decade(s) with an enduring increase in the number of hematopoietic cell transplants performed, an increase in patient populations offered transplant, and an expansion of the variety of sources of CD34+ cells donated for transplant. Patient outcomes during and after transplant have improved during this evolution through changes in patient selection and greater improvements in supportive care. Supportive care has improved through understanding and management of complications and side effects, immune suppression, and infection control, though the need for improvement remains in areas of mental health, patient and caregiver quality of life, management of refractory transplant complications, and long-term survivorship concerns. As the process of transplant continues to advance, hematopoietic cell transplant and cellular therapy programs have begun to foster relationships with palliative medicine to strengthen their comprehensive patient care and further improve the hematopoietic cell transplant trajectory. This relationship may seem counter-intuitive, but the affiliation upon appraisal is natural for both services and advantageous to patients and their families.

Spirituality is a vital component of human life and healing. While spiritual assessment is important to patient assessment, it is grossly underperformed and poorly utilized. Both patients and physicians recognize the importance of spirituality in patient care. This chapter describes spirituality and the reasons for spiritual assessment. Example models of spiritual assessment to use in practice are provided. Expert recommendation provides considerations for improvement in spiritual assessment and research potential.

Informal caregivers are vital members of the comprehensive care team for hematopoietic cell transplant (HCT) patients. Without the identification and presence of caregivers, most if not all transplant centers would not be able to provide their services for patients. Caregivers of this patient population represent a unique entity with under-recognized challenges and long-term health and economic obstacles that require recognition, discussion, and support. In this chapter, we discuss the role of the HCT patients and caregivers; their health challenges that are compounded by this role, and both the social and economic debt that the patient and caregiver dyad experience. Furthermore, the chapter guides the options available for caregiver support.

Introduction: While many data have been emerging regarding the outcomes of cancer patients infected with SARS-CoV-2 and their increased risk of mortality, emphasis on patients with hematologic malignancies and how they have been affected during this pandemic is lacking. Louisiana, particularly New Orleans, one of the pandemic epicenters, has a higher-than-average cancer diagnosis rate of multiple myeloma as well as cancer-related deaths. Ochsner Cancer Institute was fortunately prepared for the crisis, which allowed our center to continue taking care of both inpatients and outpatients as needed during the pandemic. Hence, we accumulated ample data among cancer patients and the effects of COVID-19. Here we provide novel initial mortality data on multiple myeloma patients infected with SARS-CoV-2. Methods: Our retrospective, electronic medical record review included 15 patients with a history of multiple myeloma who tested positive for SARS-CoV-2 PCR from March 1st to April 30th, 2020. Medical records were reviewed for inpatient/outpatient status of infection, outcome of infection, multiple myeloma disease and treatment history, and history of autologous stem cell transplant. Results: Out of the 15 patients infected, there were 6 deaths (40%). A total of 11 patients were on active treatment, including all 6 patients who died (54.5%), though active treatment did not appear to be a significant risk factor when compared to off-therapy patients (p=.103). Patients older than 65 years seem to be at increased risk of death when compared to patients less than 65 years of age (p=.011). Hospitalized patients were more likely to succumb to infection compared to non-hospitalized patients (p=.044). Of the 15 patients, 4 had a history of autologous stem cell transplant and this was not found to affect mortality (p=.103). Chronic kidney disease was present in 7 patients and did not appear to impact mortality (p=.315). Of these (n=9), 7 patients had hypogammaglobulinemia and 5 of these patients died (71.4%). Overall, 5 of the 6 patients who died were found to have hypogammaglobulinemia (the 6th death did not have immunoglobulins eligible for review). However, the presence of hypogammaglobulinemia did not appear to increase mortality overall (p=.167). Conclusion: Patients older than 65 years of age with a history of multiple myeloma seem to be at risk of death from COVID-19. Interestingly, a history of autologous stem cell transplant did not appear to affect mortality. While the presence of hypogammaglobulinemia did not affect mortality, its overwhelming finding in the patients who died warrants further discussion in the future. Larger studies are needed to expand on these findings and uncover further characteristics to help stratify at-risk patients in the future. Citation Format: Michael John Lunski, Karine Tawagi, Diana Maslov, Laura Finn. Outcomes of patients with multiple myeloma with COVID-19 infection [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr PO-081.

Traditional cytogenetic testing methodologies, including conventional chromosome analysis and fluorescence in situ hybridization (FISH), are invaluable for the detection or recurrent genetic abnormalities in various hematologic malignancies. However, technological advances, including a novel next-generation sequencing technique termed mate-pair sequencing (MPseq), continue to revolutionize the field of cytogenetics by enabling the characterization of structural variants at a significantly higher resolution compared to traditional methodologies. To illustrate the power of MPseq, we present a 27-year-old male diagnosed with chronic myeloid leukemia in myeloid blast crisis with multiple chromosomal abnormalities observed in all 20 metaphases from a peripheral blood specimen, including t(9;22)(q34;q11.2) and t(4;11)(q12;p15). Suspicious of a novel NUP98/PDGFRA fusion [t(4;11)(q12;p15)], break-apart FISH probe sets for the PDGFRA (4q12) and NUP98 (11p15.4) gene regions were performed and were both positive in approximately 86% of 200 interphase nuclei. However, subsequent MPseq testing revealed breakpoints located within the NUP98 gene and within an intergenic region (4q12) located between the CHIC2 and PDGFRA genes, indicating this 4;11 translocation does not result in the predicted NUP98/PDGFRA gene fusion as inferred from FISH and conventional chromosome results. This case demonstrates the clinical utility of MPseq, particularly for characterizing novel gene fusion events which may ultimately identify a false-positive FISH result.