Introduction

In 2015, the Institute of Medicine (IOM) convened a workshop regarding policy issues in the development and adoption of biomarkers for molecularly targeted cancer therapies, otherwise known as precision medicine, and currently efforts are actively underway to promote these technological, personalized advances [1••, 2]. Precision medicine holds great promise to improve cancer outcomes as the premise relies on risk-stratification of disease management either through the testing of biomarkers to identify proper therapy or recognizing genes linked to drug response [1••, 2]. Personalized and risk-based stratifications have long been used to optimize treatments for a wide array of cancer diagnoses. Such agents as imatinib, used in treatment of patients with chronic myeloid leukemia [3], traztuzumab, used for treatment of patients with breast cancer expression of Her2-neu [4], and erlotinib, used in non-small cell lung cancers that harbor epidermal growth factor receptor-activating mutations [5], are but a few older examples of therapeutic, precision-medicine discoveries that have resulted in dramatic outcomes for patients with these select molecular alterations in their tumors. Over the past 2 years, there have been continued rapid development and approval of newer targeted drugs for biomarker aberrations [6].

While these advancements have great potential to provide more effective treatment resulting in improved outcomes, continued barriers exist in equitable access and delivery of these scientific achievements given inequitable distribution of very basic, long-standing evidence-based therapies [7••, 8–11]. Figure 1 from Kilbourne et al. demonstrates a conceptual model for understanding the origins of health and health care disparities from a health services research perspective. This figure demonstrates the underlying individual, provider, and organizational/systems-level factors that contribute to health outcomes [12]. The IOM and the American Society of Clinical Oncology highlight similar challenges such as economic factors, cultural factors, and geographic diversity that may hinder public availability of the benefits that precision medicine has to offer [1••, 13]. To overcome these barriers, the IOM recommends to “promote equity in access to biomarker tests for molecularly targeted therapies and the expertise for effective use of the results in clinical decision making” [1••].

Fig. 1
figure 1

Understanding the origins of health and health care disparities from a health services research perspective (Adapted from Kilbourne et al. 2006 [12])

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Among patients with cancer, studies, including our own work, over the past two decades consistently show that despite access to our currently available risk-stratification testing techniques, such as cytogenetic testing among patients with acute leukemia, survival disparities persist for patients from specific racial, ethnic, and socio-demographic backgrounds [7••, 14, 15••]. Furthermore, despite access to risk-stratification testing among these patient populations, as our previous studies show, discrepancies remain in ensuring receipt of treatments that target these actionable molecular and cytogenetic factors [15••]. Acute leukemia disparities research specifically confirms the concerns raised regarding inherent challenges of precision medicine to improve outcomes equitably. Below are key recent works published within the past 2 years that highlight persistent acute leukemia disparities despite recent scientific advancements. The articles highlight potentially widened disparities gaps in these heterogeneous diseases. We report on studies previously published and therefore did not conduct studies with human or animal subjects for this review.

Recent Advancements in Acute Leukemia

Acute leukemia, a group of heterogeneous diseases characterized by rapidly proliferating clonal malignancies, is highly responsive to chemotherapy, but fatal if not treated timely [16]. Scientific advancements in leukemia-directed treatments and supportive care, which improve tolerability to treatments such as chemotherapy and hematopoietic stem cell transplantation, have steadily increased survival from these diseases [17]. Risk-stratification advancements, such as identification of karyotype abnormalities and molecular aberrations, have led to prognostic-based treatment decisions that have also resulted in improved outcomes [18]. Recently, novel chemotherapeutics and combinations, such as chimeric antigen receptor-modified T cells [19, 20] and clofarabine [21], less toxic treatment protocols [22], and improved hematopoietic stem cell transplantation techniques [23] [24], have also improved outcomes from acute leukemia. Future progress in acute leukemia is inevitable given the attention to precision medicine and other advances that will greatly expand the identification of prognostic features and direct our treatment recommendations.

Scientific Advancements in Acute Leukemia May Not Reach Everyone

Over the past two decades, some patient populations have witnessed an increased overall increased survival from acute leukemia, while other patients, namely those from specific racial and ethnic backgrounds, continue to experience disparate outcomes [7••, 14, 15••, 25••, 26••]. These outcome disparities are similarly reported for patients with other cancer diagnoses [27], suggesting more systems-level barriers, such as inequitable delivery of acute leukemia advancements [7••]. Less access to highly conventional therapies that improve outcomes in clinical trials [28•], insurance status [29], and other socioeconomic challenges repeatedly are shown to impact survival outcomes among patients diagnosed with these and other malignancies [30, 31].

Recent Studies on Disparities Among Pediatric Patient Populations

Among the pediatric patient population, disparities have been extensively described. A study published within the past year showed that non-Hispanic black, Hispanic, and Asian children experienced worse outcomes after a diagnosis of acute leukemia as compared to non-Hispanic white children [26••]. The study demonstrated the influence of socioeconomic status on outcomes, showing that children living in low socioeconomic status neighborhoods also experienced disproportionately lower survival from acute leukemia as compared to children living in high socioeconomic status neighborhoods. Although the authors state that this study highlights the influence of precision medicine in helping to identify genomic predictors of racial and ethnic disparities, the concerns raised previously regarding the positive influence of precision medicine on disparities are again highlighted here. This particular study, along with the many others that describe disparate outcomes in acute leukemia, do not evaluate the etiology of these disparities, such as the influence of receipt of treatment on the disparities revealed [25••, 26••]. How can newer advances in treatment for these patient populations help to eliminate these disparities if there are other inherent systems-level factors that may be associated with the disparate outcomes the authors report? Identification of potential modifiable factors that contribute to these disparities could greatly help to validate the authors’ conclusions regarding the impact precision medicine has on improving acute leukemia outcomes equitably [7••].

Disparities Are Persistent Among Adult Populations With Acute Leukemia

Unlike studies from the pediatric population, as we have previously reported, there are few studies describing disparities among adults with acute leukemia [14]. Recently, a few studies reported survival disparities among non-Hispanic black and Hispanic adults as compared to patients from other racial and ethnic populations, corroborating earlier data [7••, 14, 15••, 25••]. Although survival advancements have improved among adults with acute leukemia, these advances do not equitably distribute across all populations. A recent study showed persistent disparities in survival over the past decade for adult minority populations as compared to non-Hispanic white patients [25••]. While non-Hispanic white patients were found to have increasingly improved survival over the past 10 years, these improvements in survival were not consistent among all patient populations and disproportionately less so for Hispanic and non-Hispanic black patients with acute lymphocytic leukemia (ALL). Among patients with acute myeloid leukemia (AML), survival increased substantially only for non-Hispanic white and Asian Pacific Islander populations [25••], thus widening the reported disparities gap in these diseases.

In our previous work, to uncover potential etiologies for worse survival outcomes among non-Hispanic black and Hispanic patients, we examined whether these populations have a higher proportion of poor-risk factors at diagnosis. Increasing age and specific cytogenetic abnormalities have consistently been shown to predict worse outcomes among patients in older [32, 33] and more recent studies conducted over the past 2 years [15••, 25••]. In our work, published last year, despite a higher proportion of better prognostic factors at diagnosis, survival disparities persisted for non-Hispanic black and Hispanic patients as compared to non-Hispanic white patients [15••]. In ours and other studies, minority populations are more likely to be diagnosed with acute leukemia at a younger ages, a positive prognostic factor [15••, 25••]; however, these patients continue to have worse survival outcomes as compared to non-Hispanic white patients after a diagnosis of both ALL and AML [14, 25••].

Studies report similar findings in terms of other prognostic factors, such as cytogenetic abnormalities. Identification of cytogenetic subtypes through technologies such as karyotype is one of the most powerful prognostication tools in acute leukemia and can direct personalized, risk-adapted treatment approaches [34]. For example, identification of the core-binding factor leukemias such as t(8;21), through karyotype, has directly resulted in favorable treatment decisions, with patient receiving more doses of cytarabine therapy, thereby resulting in improved outcomes [35]. Similarly, patients with the identified acute promyelocytic leukemia (APL) subtype have benefitted from better survival outcomes due to targeted treatment with all-trans retinoic acid (ATRA), a therapy specifically indicated for patients with this cytogenetic subtype [36]. In our previous work, among other studies, we showed that these cytogenetic AML subtypes are independently associated with improved survival [15••]. We also showed that non-Hispanic black and Hispanic patients, when diagnosed with AML, have a higher proportion of these cytogenetic subtypes (i.e., t(8;21) and APL). Despite the higher proportion of these favorable subtypes among non-Hispanic black and Hispanic patients, the survival disparities we previously described previously persisted [15••].

To evaluate whether systems-level factors may contribute to these continued acute leukemia outcome disparities among these populations, given that these populations had higher proportion of positive prognostic factors at diagnosis, we examined whether these populations faced discrepancies in the receipt of evidence-based treatment and the impact of treatment discrepancies on AML survival outcomes [7••]. In a work published this past year, we revealed that Hispanic and non-Hispanic black populations have lower receipt of evidence-based treatment, including both chemotherapy and hematopoietic stem cell transplant. Other studies have similarly shown systems-level factors influencing receipt of hematopoietic stem cell transplant [37]. However, when high quality care is delivered, including targeted treatment when indicated, survival outcomes are equalized among all racial and ethnic populations [7••]. The impact of high quality care delivery on outcomes has also been shown among pediatric populations [38]. Despite targeted therapies conferring better outcomes among patients with these cytogenetic subtypes [36], studies, including ours [7••, 39], demonstrate the consistent inequitable distribution of these evidence-based strategies.

Despite availability of already established personalized, precision medicine techniques, such as ATRA for APL, disparities remain in how these therapies are deployed to the subpopulations of patients who may derive the most benefit. Furthermore, other modifiable factors, such as improving differential adherence to treatment [40], can also ensure that these technological advances are complied with to achieve equitable outcomes. Unless scientific advancements are implemented with assurance that all patients can reap the benefits of appropriate, high quality, evidence-based, and personalized treatments, the acute leukemia disparity gaps, that others and we repeatedly show, have immense potential to widen.

Cost Implications of Precision Medicine

In the setting of rising health expenditures, and as with many other technological advances, costs of novel approaches to improving care are often another challenge to ensuring equitable access to these therapies. Although outcomes are expected to improve with these personalized therapies with a potential for reduction in downstream healthcare expenditures, the associated high costs of these treatments remain an overwhelming challenge. As technology advances, however, many stakeholders believe that the costs of these advances will significantly decrease, as exemplified with rapid whole genome sequencing where costs, initially nearly $3 billion, have now decreased due to recent developments to approximately $1000 [41]. Skeptics remain concerned, given other examples, such as the OncoType DX 21-gene assay for estrogen-receptor positive breast cancer, which continues to cost nearly $4000 [42]. While paid for by insurance companies, due to a potential downstream reduction in chemotherapy costs for approximately 16 % of patients with early stage diseases [43], the cost of this technology prohibits equitable access to all patients [44]. The continued access disparities due to costs lead to a widening of outcome disparities gaps among patients. Given these implications of potential widening of disparities gaps due to costs and access to these novel advances, President Obama suggested during the White House Precision Medicine Initiative Summit on February 25, 2016, that all-stakeholder approaches are needed to reduce the costs and ensure equitable access to these novel advances. Greater attention to the balance of costs and quality requires collaborations between the public and private sectors, payers, and providers alike. Alternative payment models are one way that stakeholders can collaborate to ensure improved outcomes and access to technology. These models incentivize the use of care protocols, clinical pathways, and other clinical decision support tools such as those offered by precision medicine, to improve population-based outcomes. Efforts by advocacy groups, such as the Personalized Medicine Coalition, are another way to encourage continued education regarding the benefits of personalized medicine and advocacy of public policies and reimbursement that encourage investment in these technological advances that, if equitably implemented and accessible, can improve outcomes for all.

Conclusions

While impressive therapeutic advancements continue in acute leukemia, resulting in improved survival rates after diagnosis, striking outcomes disparities remain by race and ethnicity and socioeconomic status. Fair access to healthcare for acute leukemia continues to be challenged by socioeconomic status, insurance status, and the locations in which care is delivered [30]. Among populations with acute leukemia, previously and recently published research consistently demonstrate inequitable distribution of our current evidence-based treatments [7••, 26••, 29]. In the context of precision medicine, which holds great promise for improving risk-stratification evidence-based treatments, among patients with acute leukemia and other cancers, questions remain regarding how these personalized treatment advances may influence disparities. The recent studies published over the past 2 years, showing persistent disparities in acute leukemia despite scientific advancements in survival outcomes overall, validate the grave concerns previously raised regarding the influence of precision medicine to widen disparities gaps.

The fundamental linkage of personalized treatments and cancer disparities should, therefore, be at the forefront of our research agenda, especially as scientific advancements are made in acute leukemia treatments. Research questions should help to address how to ensure equitable dissemination of precision, personalized medicine. How can we ensure fair reach of scientific advancements to all populations, specifically among those who are currently underserved? As demonstrated in the studies highlighting persistent disparities in acute leukemia, population-wide access to provision of standard evidence-based treatments is unattainable presently. The current challenges in equitable delivery of high quality care raise many questions regarding how we can sustainably and appropriately overcome barriers in access, capital, health literacy, and other socio-demographic features that influence appropriate receipt of our evidence-based treatment options. How can we ensure equitable availability and application of precision medicine, and, further, ensure that the targets identified by precision medicine will result in appropriate receipt of the indicated treatments?

The IOM recommendations are but one step in raising awareness of the influence of precision medicine to further widened our already established disparities gaps [1••]. The passing of the Affordable Care Act is also an important component that can improve access and serves as a giant step forward in the journey to eliminating disparities [45]. Despite these advances, however, an all-stakeholder approach is needed to truly realize the elimination of cancer disparities through equitable distribution of our basic, standard of care and newer scientific advancements. Emerging alternative payment models that reward population-based, appropriate, equitable, high-value treatment, such as the ones proposed by Medicare [46], can financially align application of scientific advancements to eliminate disparities. Likewise, research priorities with aligned funding and supportive infrastructure can also help us to rigorously move from merely describing disparities to the identification of interventions that can modify the etiologies. The elimination of health disparities, especially among patients with acute leukemia, will take a village of individuals who vigilantly seek to deeply understand current challenges in equitable population-wide distribution of appropriate treatment and who will lead thoughtful interventions and influence policy to improve equitable access and implementation of scientific advancements for all patients.