Scientific Publications

My academic focus over the past two decades has been on patients with myeloid malignancies, specifically myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) in older adults. I took the approach of asking research questions about each step in the course of a patient’s disease, from diagnosis to cure or death, to better understand it, predict outcomes, and improve patient experience and survival.

These questions include investigating the epidemiologic factors that led to a patient’s diagnosis and examining what contributes to treatment decision-making; identifying prognostic factors for treatment response and survival at diagnosis and dynamically, over time; exploring novel therapies and therapeutic combinations; improving clinical trial design in the context of clinically meaningful regulatory endpoints; and identifying appropriate translational correlates, from bedside to bench and back, again dynamically and with a focus on the genetics of myeloid neoplasia, to illuminate the underlying pathobiology and to make biologically relevant clinical associations. 

In addition, as I became more involved with cancer drug research and regulatory issues as a former member and chair of the Oncologic Drugs Advisory Committee (ODAC) of the U.S. Food and Drug Administration, as former Chair of the Cleveland Clinic Enterprise Pharmacy & Therapeutics Committee, and as a former Vice-chair and Associate Director for Clinical Research at Cleveland Clinic and at the Case Comprehensive Cancer Center, I have devoted more time to defining clinical trial endpoints and issues surrounding intermediate markers of drug efficacy.

My h-index is 94 and i10-index is 396, with over 38,000 citations.

Seminal aspects of this work:

Starting at the diagnosis of MDS or AML, epidemiologic research has included the first study on U.S. MDS disease characteristics among incident and prevalent populations (JNCI 2008) and defining the impact of time from diagnosis to treatment initiation in AML patients (Blood 2009). We were first to identify differences in remission rates and survival for Blacks and whites with AML with a possible karyotypic link (Blood 2004) and molecular basis (Blood Cancer J 2017) and followed that with studies showing no differences in post-remission treatment intensity by race (Leuk Res 2011), in outcome by sociodemographic status (Leuk Res 2008), or by weekend vs. weekday hospital admission (Cancer 2010). We were first to call into question the link between radiation exposure for treatment of prostate cancer and subsequent MDS diagnosis (JNCI 2014) and to establish the link between radioactive iodine treatment for thyroid cancer and MDS (Leukemia 2018) and AML (JCO 2018). We identified discrepancies in diagnosis between pathologists 20% of the time, with 7% of patients consequently receiving the wrong treatment (Blood Advances 2023).

Focusing on research into the patient experience with myeloid malignancies, we conducted the first study exploring quality of life and discrepancies in disease understanding between patients and their doctors, with patients vastly overestimating their chances of cure (Leukemia, 2004). A follow-up study in MDS patients again found patient overestimation of cure with non-curative therapies, and depictions of disease by healthcare providers that undercut disease severity, potentially leading to premature therapy discontinuation (Oncologist 2011, Cancer 2014). Consequences of these studies included identification of high-risk myeloid malignancy groups; acknowledgement of undercounting of MDS diagnoses by the NCI/CDC SEER program; adjustment in risk/benefit discussions for solid tumor therapies; revamping of online and print patient education materials by patient organizations; recognition that treatment of AML in younger adults is a medical emergency, but in older adults can be delayed until genetic results return to guide therapy; and the ability to inform the ASH Guidelines for Treatment of Older Adults with AML (Blood Advances 2020). We then developed a novel method for quantifying periods of time patients with MDS go without requiring transfusions (Haematologica 2022) and identified frailty as a risk for outcome (Blood Advances 2023).

We have conducted a number of studies refining prognostication in myeloid malignancies, including the first to associate treatment-related cytopenias with therapeutic response (JCO 2008) and a decision analysis to recommend erythropoiesis stimulating agents to MDS patients (Cancer 2007). The International Prognostic Scoring System (IPSS) is the standard clinical tool for risk stratification and treatment recommendation in MDS. We have studied its accuracy in patients with therapy-related MDS (Leuk Lymphoma 2015) and modified it in developing the first tool in patients already exposed to hypomethylating agents (Blood Cancer J 2017). We were the first group to incorporate molecular data into clinical prognostic systems (Leukemia 2017) and the first to use machine learning approaches to predict response to hypomethylating agents (JCO Precis Oncol 2019), which then applied to markedly improve the test characteristics of the IPSS, dynamically, irrespective of treatment, and were able to cross-validate (JCO 2021). Consequences of these studies include clinical adaptation of more accurate risk stratification and treatment recommendations; modifications in defining adverse events and dose-limiting toxicities in clinical trials; and adaption of these tools into clinical trial eligibility criteria.

We have pioneered the use of novel combination therapies to treat MDS, including arsenic trioxide and gemtuzumab ozogamicin (Cancer 2011), azacitidine and pevonedistat (Leukemia 2020, Blood Advances 2023), the monoclonal antibody lintuzumab  and cytarabine for older adults with AML (Haematologica 2013), combinations with gladegib (Leukemia 2023), and azacitidine combined with lenalidomide (JCO 2010, Blood 2012), which led to the North American Intergroup MDS study, the largest prospective trial in higher-risk MDS ever conducted in North America (JCO 2017). We were the first to design a clinical trial targeting patients with MDS/myeloproliferative neoplasm overlap disorders (Cancer 2012), the response definitions for which formed the bulk of subsequent international working group response criteria for this indication. I have also participated collaboratively in dozens of trials including transformative ones that led to the regulatory approvals of the IDH1 inhibitor ivosidenib (NEJM 2018), the IDH2 inhibitor enasidenib (Blood 2019), and luspatercept (NEJM 2020).

We then studied published randomized trials in hematologic malignancies and determined that eligibility criteria did not reflect either previously known or realized adverse events (Leukemia 2017) and that patients enrolled on NCI Cooperative Group leukemia trials who were found to be ineligible for those studies a posteriori had similar rates of serious adverse events and remissions as eligible patients (Blood 2018), thus demonstrating that trial eligibility criteria are overly restrictive. We also found an underrepresentation of patients with therapy-related MDS enrolled to clinical trials over two decades (Blood Advances 2019). We used this vast clinical trial experience in patients with myeloid malignancies to define relapsed/refractory MDS and what constitutes prior therapy (Blood 2009); to identify reasons for the paucity of drugs approved for older adults with AML (JCO 2012) and the causes for low MDS clinical trial accrual (Cancer 2018); and we made recommendations to modify International Working Group MDS response criteria to better reflect clinically meaningful endpoints (Leukemia 2019, Blood 2019, and Blood 2023) and collaborated with the FDA on MDS endpoint definitions (Clin Cancer Research 2022).

My translational work has focused mainly on identifying molecular abnormalities associated with myeloid malignancies, including the deadbox helicase mutation DDX41 (located on chromosome 5), which we discovered as a germline lesion in identical twins with MDS whom I treated, both of whom responded to lenalidomide. Among others in our clinical database-linked biobank with DDX41, 100% treated with lenalidomide also responded, indicating that this may be the cryptic abnormality associated with non-del(5q) MDS responders (Cancer Cell 2015). Other collaborative discoveries include mutations in JAK2 V617F and SF3B1 in refractory anemia with ring sideroblasts (Blood 2006; Leukemia 2012; Blood 2012); the E3 Ubiquitin ligase CBL (Cancer Res 2008; JCO 2009) and EZH2 (Leukemia 2010) in myeloid malignancies; UTX, EZH2, and DNMT3A in CMML (Blood 2011); SETBP1 in myeloid malignancies (Nat Genet 2013); cohesion complexes (Blood 2014); SAMD9 and SAMD9L in MDS (Blood 2018); and clonal evolution in myeloid malignancies (Nat Genet 2016; Nat Commun 2019), among others. These findings have illuminated myeloid disease evolution and recapitulated the disease phenotype.