Incident Rate Limitations in Retrospective Observational Military Cancer Research.

The unique jobs, exposures, and deployments in the military generate questions regarding cancer risks; however, incidence rates alone from retrospective observational studies provide limited information. Incorporating screening rates, staging, and mortality rates allows a more comprehensive perspective regarding cancer risk in the military.

Real-World Pitfalls of Analyzing Real-World Data: A Cautionary Note and Path Forward.

PURPOSE: Real-world data (RWD) are pervasive in oncology research and offer insights into clinical trends and patient outcomes. However, RWD have shortcomings, making them prone to pitfalls during survival analyses. The American Society of Clinical Oncology (ASCO) CancerLinQ Discovery (CLQD) multiple myeloma (MM) data set was used to demonstrate some common pitfalls when analyzing survival from RWD: using incorrect surrogate markers for missing data and/or classification errors, ignoring deaths at time zero, and failing to account for guarantee-time bias. METHODS: The ASCO CLQD MM data set (July 19, 2021, release) was used to compare overall survival (OS) in patients with a known versus presumed date of MM diagnosis, in patients with secondary AML (sAML) with early deaths (ie, 0 months) included versus dropped, and in patients with second primary malignancies (SPMs) matched versus unmatched to control for time-related confounding factors (ie, guarantee-time bias). Analyses were conducted using STATA Version 17.0 (College Station, TX). RESULTS: In the CLQD MM data set, 28% of patients were missing a diagnosis date. Attempts to use the presumed diagnosis date (ie, first bortezomib or lenalidomide administration) as a surrogate marker for missing diagnosis dates were not successful as median OS was significantly different in patients with a recorded versus presumed diagnosis date (107 v 40 months, hazard ratio [HR], 2.5; 95% CI, 2.39 to 2.64; P < .001). Dropping deaths within 1 month of sAML diagnosis resulted in an exaggerated median OS (46 v 39 months). OS in patients with MM with SPMs differed substantially before and after incorporation of matching methods to account for guarantee-time bias (HR, 0.73; 95% CI, 0.67 to 0.78; P < .001 before matching, HR, 1.30; 95% CI, 1.18 to 1.43; P < .001 after matching). CONCLUSION: To fully maximize the benefits of RWD in oncology research, clinicians must be aware of analytic methods that can overcome pitfalls in survival analyses.

Survival of U.S. Military Service Members With Lymphoma.

INTRODUCTION: Cancer is a prominent cause of mortality in today's active duty service members (ADSMs), killing over 700 ADSMs between 2004 and 2015. Hence, more research is needed to better understand the survival of U.S. service members with cancer. Lymphoma is the most common hematologic malignancy diagnosed in ADSMs, serving as a good cancer type to study. MATERIALS AND METHODS: The Department of Defense tumor registry and the Surveillance, Epidemiology, and End Result (SEER) databases were retrospectively accessed to analyze overall survival (OS) of ADSMs with lymphoma and to compare outcomes with matched civilians. ADSMs with Hodgkin lymphoma (HL), diffuse large B-cell lymphoma (DLBCL), and indolent lymphoma diagnosed between 1997 and 2017 were included, and SEER comparator patients were matched by age, sex, race, stage, and year of diagnosis using a 4:1 ratio of civilians to ADSMs. RESULTS: There were 1,170, 443, and 284 ADSMs with HL, DLBCL, and indolent lymphoma, respectively, and all three groups had superior OS when compared to their matched civilian counterparts with 35%, 49%, and 48% reductions in the risk of death, respectively. There were no differences in ADSM survival based on race, sex, or rank, despite disparities being pervasive in the civilian sector. CONCLUSIONS: Service members with lymphoma have superior survival than their matched civilian counterparts, without evident racial or sex disparities. Results of this study are favorable in terms of readiness. Further research on cancer mortality in ADSMs is needed to improve long-term outcomes.

CAR T-Cell Therapy for Patients with Multiple Myeloma: Current Evidence and Challenges.

The therapeutic landscape of multiple myeloma (MM) has benefited from an emergence of novel therapies over the last decade. By inducing T-cell kill of target cancer cells, chimeric antigen receptor (CAR) T-cell therapies have improved outcomes of patients with hematologic malignancies. B-cell maturation antigen (BCMA) is the current target antigen of choice for most CAR T-cell products under investigation for MM. However, their shortcomings deal with logistical and clinical challenges, including limited availability, manufacturing times, and toxicities. This article provides an overview of recently developed and investigational CAR T-cell therapies for MM, highlighting current evidence and challenges.

The emerging importance and evolving understanding of clonal hematopoiesis in multiple myeloma.

Multiple myeloma (MM) is the second most common hematologic malignancy diagnosed in the United States. With a growing arsenal of novel therapies, patients are living longer and hence are at increased risk of secondary cancers such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). While MDS-associated cytogenetic abnormalities have been described in patients with a diagnosis of for decades, clonal hematopoiesis (CH) has been described only recently. CH has been shown to correlate with inferior survival in MM due to increased risk of disease progression in patients who are treated with high-dose melphalan without lenalidomide maintenance. When involving specific high-risk genes, multiple genes, or when present at high variant allelic frequencies, CH could also potentially elevate the risk of secondary MDS and/or AML, cardiovascular events, and venous thromboembolic events. Despite growing knowledge about CH in patients with MM, many questions remain unanswered. Further studies are needed to better understand the prognostic and therapeutic significance of CH in MM and its precursor conditions, as well as the effect of specific treatments on long-term outcome.

Pembrolizumab and decitabine for refractory or relapsed acute myeloid leukemia.

BACKGROUND: The powerful 'graft versus leukemia' effect thought partly responsible for the therapeutic effect of allogeneic hematopoietic cell transplantation in acute myeloid leukemia (AML) provides rationale for investigation of immune-based therapies in this high-risk blood cancer. There is considerable preclinical evidence for potential synergy between PD-1 immune checkpoint blockade and the hypomethylating agents already commonly used for this disease. METHODS: We report here the results of 17 H-0026 (PD-AML, NCT02996474), an investigator sponsored, single-institution, single-arm open-label 10-subject pilot study to test the feasibility of the first-in-human combination of pembrolizumab and decitabine in adult patients with refractory or relapsed AML (R-AML). RESULTS: In this cohort of previously treated patients, this novel combination of anti-PD-1 and hypomethylating therapy was feasible and associated with a best response of stable disease or better in 6 of 10 patients. Considerable immunological changes were identified using T cell receptor ß sequencing as well as single-cell immunophenotypic and RNA expression analyses on sorted CD3+ T cells in patients who developed immune-related adverse events (irAEs) during treatment. Clonal T cell expansions occurred at irAE onset; single-cell sequencing demonstrated that these expanded clones were predominately CD8+ effector memory T cells with high cell surface PD-1 expression and transcriptional profiles indicative of activation and cytotoxicity. In contrast, no such distinctive immune changes were detectable in those experiencing a measurable antileukemic response during treatment. CONCLUSION: Addition of pembrolizumab to 10-day decitabine therapy was clinically feasible in patients with R-AML, with immunological changes from PD-1 blockade observed in patients experiencing irAEs.

Personalized Single-Cell Proteogenomics to Distinguish Acute Myeloid Leukemia from Non-Malignant Clonal Hematopoiesis.

Genetic mutations associated with acute myeloid leukemia (AML) also occur in age-related clonal hematopoiesis, often in the same individual. This makes confident assignment of detected variants to malignancy challenging. The issue is particularly crucial for AML post-treatment measurable residual disease monitoring, where results can be discordant between genetic sequencing and flow cytometry. We show here, that it is possible to distinguish AML from clonal hematopoiesis and to resolve the immunophenotypic identity of clonal architecture. To achieve this, we first design patient-specific DNA probes based on patient's whole-genome sequencing, and then use them for patient-personalized single-cell DNA sequencing with simultaneous single-cell antibody-oligonucleotide sequencing. Examples illustrate AML arising from DNMT3A and TET2 mutated clones as well as independently. The ability to personalize single-cell proteogenomic assessment for individual patients based on leukemia-specific genomic features has implications for ongoing AML precision medicine efforts.

The Evolving AML Genomic Landscape: Therapeutic Implications.

Improved understanding of the genomic and molecular landscape of acute myeloid leukemia (AML) has resulted in a significant evolution of our understanding of AML biology and allows refined prognostication for those receiving standard combination chemotherapy induction. This dramatic increase in knowledge preceded, and was somewhat responsible for, at least some of eight new FDA drug approvals for AML. This review discusses the impact of genomics on clinical care of AML patients and highlights newly approved FDA drugs. Despite these recent clinical advances, however, the outcome for most patients diagnosed with AML remains dire. Thus, we describe here some of the challenges identified with treating AML including off-target toxicity, drug transporters, clonal heterogeneity, and adaptive resistance, and some of the most promising opportunities for improved therapy.

Timed sequential salvage chemotherapy for relapsed or refractory acute myeloid leukemia.

Therapy for those with relapsed or refractory acute myeloid leukemia is suboptimal. Studies have suggested that timed sequential salvage combination cytotoxic chemotherapy may have particular utility for that indication. We report here a series of ten such adult patients treated sequentially at a single center with EMA (cytarabine 500 mg/m2/day as continuous infusion on days 1-3 and days 8-10, mitoxantrone 12 mg/m2/day on days 1-3, and etoposide 200 mg/m2/day as continuous infusion on days 8-10). The overall complete remission rate was 40% (including 3 of 4 of those with relapsed disease) but use of this regimen was associated with prolonged cytopenia and a high rate of infectious adverse events. Even with the availability of modern infectious prophylaxis and therapies, the EMA regimen is likely best reserved for those with relapsed disease treated with curative intent prior to an allogeneic hematopoietic cell transplant.

Heterogeneity in refractory acute myeloid leukemia.

Successful clinical remission to therapy for acute myeloid leukemia (AML) is required for long-term survival to be achieved. Despite trends in improved survival due to better supportive care, up to 40% of patients will have refractory disease, which has a poorly understood biology and carries a dismal prognosis. The development of effective treatment strategies has been hindered by a general lack of knowledge about mechanisms of chemotherapy resistance. Here, through transcriptomic analysis of 154 cases of treatment-naive AML, three chemorefractory patient groups with distinct expression profiles are identified. A classifier, four key refractory gene signatures (RG4), trained based on the expression profile of the highest risk refractory patients, validated in an independent cohort (n = 131), was prognostic for overall survival (OS) and refined an established 17-gene stemness score. Refractory subpopulations have differential expression in pathways involved in cell cycle, transcription, translation, metabolism, and/or stem cell properties. Ex vivo drug sensitivity to 122 small-molecule inhibitors revealed effective group-specific targeting of pathways among these three refractory groups. Gene expression profiling by RNA sequencing had a suboptimal ability to correctly predict those individuals resistant to conventional cytotoxic induction therapy, but could risk-stratify for OS and identify subjects most likely to have superior responses to a specific alternative therapy. Such personalized therapy may be studied prospectively in clinical trials.

The impact of environmental ultraviolet exposure on the clinical course of mycosis fungoides.

BACKGROUND: As phototherapy plays an important role in the treatment of early-stage mycosis fungoides (MF), it is possible that environmental ultraviolet (UV) exposure affects the natural history of the disease. OBJECTIVE: To assess the impact of environmental UV exposure on the clinical course of MF. METHODS: The National Solar Radiation Database was used to identify the top and bottom registries for UV exposure from the Surveillance, Epidemiology, and End Results-18 database. Incidence and survival were determined. RESULTS: The high-UV cohort had a 30% lower risk of developing MF than did the low-UV cohort (hazard ratio, 1.3; 95% confidence interval, 1.20-1.41; P < .001). When stratified by stage and race, this difference was appreciable only among those with early-stage disease and white race. There was no difference in survival between the high- and low-UV cohorts (P = .098); however, a small difference was observed among those with early-stage disease and white race, favoring high UV exposure. LIMITATIONS: Retrospective design, use of the National Solar Radiation Database as a surrogate for individual sunlight exposure. CONCLUSION: It is possible that environmental solar UV exposure may play a role in controlling early-stage MF among patients with photosensitive features.

Personalizing initial therapy in acute myeloid leukemia: incorporating novel agents into clinical practice.

While the past decade has seen a revolution in understanding of the genetic and molecular etiology of the disease, in clinical practice, initial therapy for acute myeloid leukemia (AML) patients has been a relatively straightforward choice between intensive combination cytotoxic induction therapy as used for decades or less-intensive hypomethylating therapy. The year 2017, however, witnessed US Food and Drug Administration approvals of midostaurin, enasidenib, gemtuzumab ozogamicin and CPX-351 for AML patients, with many other promising agents currently in clinical trials. This review discusses these options, highlights unanswered questions regarding optimal combinations and proposes some suggested approaches for the personalization of initial therapy for AML patients.

Management of post-transplant lymphoproliferative disorders.

The post-transplant lymphoproliferative disorders (PTLDs) are a heterogeneous group of neoplasms that are one of the most serious complications of bone marrow and solid organ transplants. Because these disorders are rare, there are no randomized trials from which to derive optimal treatment. Management can be challenging and must balance the goal of PTLD eradication with the risks of graft rejection, graft-versus-host disease, further delays in immune reconstitution and life-threatening infections, among others. This paper will provide a comprehensive review of PTLD following solid organ transplant and haematopoietic stem cell transplant with a focus on management. Included is a discussion of novel agents that are being studied in clinical trials and, when combined or sequenced with conventional therapy, have the potential to improve outcomes.

Molecular Measurable Residual Disease Testing of Blood During AML Cytotoxic Therapy for Early Prediction of Clinical Response.

Measurable residual disease (MRD) testing after initial chemotherapy treatment can predict relapse and survival in acute myeloid leukemia (AML). However, it has not been established if repeat molecular or genetic testing during chemotherapy can offer information regarding the chemotherapy sensitivity of the leukemic clone. Blood from 45 adult AML patients at day 1 and 4 of induction (n = 35) or salvage (n = 10) cytotoxic chemotherapy was collected for both quantitative real-time PCR (qPCR) assessment (WT1) and next generation sequencing (>500 × depth) of 49 gene regions recurrently mutated in MDS/AML. The median age of subjects was 62 (23-78); 42% achieved a complete response. WT1 was overexpressed in most patients tested but was uninformative for very early MRD assessment. A median of 4 non-synonymous variants (range 0-7) were detected by DNA sequencing of blood on day 1 of therapy [median variant allele frequency (VAF): 29%]. Only two patients had no variants detectable. All mutations remained detectable in blood on day 4 of intensive chemotherapy and remarkably the ratio of mutated to wild-type sequence was often maintained. This phenomenon was not limited to variants in DNMT3A, TET2, and ASXL1. The kinetics of NPM1 and TP53 variant burden early during chemotherapy appeared to be exceptions and exhibited consistent trends in this cohort. In summary, molecular testing of blood on day 4 of chemotherapy is not predictive of clinical response to cytotoxic induction therapy in AML. The observed stability in variant allele frequency suggests that cytotoxic therapy may have a limited therapeutic index for clones circulating in blood containing these mutations. Further validation is required to confirm the utility of monitoring NPM1 and TP53 kinetics in blood during cytotoxic therapy.

DA-EPOCH-R for post-transplant lymphoproliferative disorders.

BACKGROUND: Post-transplant lymphoproliferative disorders (PTLD) are a potentially fatal group of neoplasms arising in an immunodeficient environment. Although the cornerstone of treatment is reduced immunosuppression (RI), advanced cases often warrant treatment with chemoimmunotherapy. The chemoimmunotherapy regimen of dose-adjusted (DA)-EPOCH-R is superior to R-CHOP in HIV associated aggressive lymphomas, suggesting that it might also be favorable in the setting of PTLD. METHODS: We performed a retrospective analysis of patients with advanced monomorphic PTLD treated with first line DA-EPOCH-R in addition to RI at our institution from 2003-2016. RESULTS: Seven patients were included. Mean age was 51 and mean time from transplant to diagnosis was 71 months. Six of the seven patients received a kidney transplant, six had stage III or IV disease, six had tumors that were EBV positive, and six completed therapy. All six patients who completed therapy achieved a complete response. Mean PFS and OS were 46.6 and 52.6 months, respectively. Treatment was well-tolerated with no significant treatment related morbidity or mortality. CONCLUSIONS: Our findings support several observations in the literature that DA-EPOCH-R is efficacious and well-tolerated for the treatment of advanced, monomorphic PTLD.