We all recognize the scene: treatment has gone well, the last bone marrow looks reassuring, blood counts are normal, and the patient asks the question they have rehearsed for months: “Doctor, am I cured?” Our instinct is to respond in a way that is both honest and hopeful. Yet the word cure encompasses a wide range of biological and clinical realities, and modern hematology has made those distinctions more visible than ever. The concept of cure in oncology has long been debated, with distinctions between statistical, clinical, and biological definitions proposed across both solid tumors and hematologic malignancies. However, these frameworks have often remained implicit or inconsistently applied in clinical practice. Building on these concepts, we propose a pragmatic synthesis encompassing sterilizing, functional, and operational cure, integrating advances in measurable residual disease (MRD) assessment, targeted therapies, and long-term survival modeling. In this context, we focus on these three clinically relevant modalities. Clarifying these concepts is important for how we design studies, counsel patients, and evaluate therapeutic success (Figure 1). A sterilizing cure—here used to denote complete eradication of malignant cells and not to be confused with treatment-related gonadal toxicity—implies complete eradication of disease; a functional cure describes a state in which residual disease may persist but has no clinical relevance; and an operational cure reflects a situation in which long-term data indicate such a low risk of relapse that patients can be considered cured in practical terms. These categories overlap rather than forming rigid boundaries, but distinguishing them sharpens clinical thinking. A sterilizing cure—here used to denote complete eradication of malignant cells and not to be confused with treatment-related gonadal toxicity—implies complete eradication of disease; a functional cure describes a state in which residual disease may persist but has no clinical relevance; and an operational cure reflects a situation in which long-term data indicate such a low risk of relapse that patients can be considered cured in practical terms. These categories overlap rather than forming rigid boundaries, but distinguishing them sharpens clinical thinking. Historically, cure in oncology was largely time-based. Patients with acute lymphoblastic leukemia or Hodgkin lymphoma who remained in continuous complete remission for 5 years were often considered cured, reflecting the plateau of survival curves and the rarity of late relapse. Over the past two decades, however, this framework has been challenged by three major developments. First, MRD has shown that morphological remission frequently coexists with low-level disease detectable by flow cytometry, PCR, or next-generation sequencing. In acute myeloid leukemia (AML), MRD status before and after allogeneic transplantation refines risk assessment, yet MRD negativity does not guarantee freedom from relapse, and some MRD-positive patients experience prolonged survival 1. “No detectable disease” is therefore not equivalent to “no disease.” Importantly, MRD assessment is not uniform across diseases or technologies. Sensitivity varies substantially between multiparameter flow cytometry, PCR-based assays, and next-generation sequencing, and its prognostic implications are disease-specific. Efforts toward assay harmonization and standardized thresholds are ongoing, but interpretation remains context-dependent. Second, targeted therapies and immunotherapies have transformed several malignancies into chronic or intermittently active conditions. Chronic myeloid leukemia (CML) is the clearest example: many patients now live for decades with excellent quality of life on tyrosine kinase inhibitors, and an increasing proportion achieve sustained treatment-free remission (TFR) 2, 3. Third, in multiple myeloma and indolent lymphomas, long-term follow-up and conditional survival analyses reveal emerging plateaus in selected subgroups, even when residual malignant clones are likely to persist. Additional complexity arises in the context of cellular therapies and transplantation. Chimeric antigen receptor (CAR) T-cell therapies can induce deep and durable remissions, in some cases suggestive of cure, yet long-term relapse patterns and mechanisms of resistance remain incompletely defined. Similarly, allogeneic transplantation introduces unique dynamics, including graft-versus-leukemia effects and late relapses, which challenge traditional distinctions between eradication and long-term control. These observations have led to growing use of the concepts of functional and operational cure, supported by MRD-guided strategies and extended survival data 4-8. Against this background, sterilizing cure remains largely an ideal. Conceptually, it implies complete elimination of all malignant cells and disease-defining molecular lesions. If this state could be proven, relapse would be biologically impossible. In practice, however, sterilizing cure is inferred rather than demonstrated. Even in highly curable diseases—such as acute promyelocytic leukemia or certain pediatric leukemias—confidence rests on long-term outcomes and the absence of detectable MRD, not on direct evidence that the last malignant cell has been eliminated 1. Thus, sterilizing cure is best understood as an asymptotic goal rather than a clinically verifiable state. By contrast, functional cure is directly relevant to contemporary clinical practice. Here, residual disease or clonal abnormalities may persist, but they no longer influence the patient's life. There is no clinically meaningful relapse, no need for ongoing intensive therapy, and overall survival approximates that of the general population. CML illustrates this paradigm. Patients who achieve deep and sustained molecular responses may discontinue therapy and enter TFR, with a substantial proportion maintaining remission for years 2, 3. Importantly, low-level molecular “blips” do not necessarily predict relapse; minimal residual disease may persist without clinical consequence 2. In this context, the disease has lost practical relevance, even if it has not been eradicated. A similar perspective is emerging in multiple myeloma. Increasingly, patients achieve prolonged MRD negativity and durable disease control, with survival curves showing early signs of plateauing 4, 9. Although true eradication is unlikely in most cases, the combination of deep response, sustained remission, and patient-specific factors—particularly age and comorbidity—can render residual disease clinically irrelevant 4, 9. Indolent lymphomas occupy an intermediate position. These diseases have long demonstrated that biological persistence can coexist with prolonged survival and minimal symptoms. Modern management emphasizes treatment-sparing approaches and sustained disease control 5-8. While a minority of patients—particularly those with early-stage disease treated definitively—may achieve durable remission consistent with cure 8, 10, 11, for most, functional cure represents the most realistic and meaningful goal. Operational cure, in contrast, is a population-level statistical construct rather than a direct reflection of individual disease biology. Thus, while functional cure describes what occurs within an individual patient, operational cure reflects what can be inferred from long-term outcomes across populations. It reflects the point at which, in large cohorts, the hazard of relapse declines to a negligible level. When survival curves plateau with long follow-up, a proportion of patients can be considered cured in an operational sense, even though residual disease may persist in some individuals 4. This concept underpinned the recognition of cure in diseases such as Hodgkin lymphoma and diffuse large B-cell lymphoma long before the advent of MRD technologies. Today, similar patterns are emerging in subsets of myeloma and AML, where long-term follow-up reveals sustained remission plateaus 1, 4. Distinguishing among these modalities has practical implications. First, it improves communication. Patients may interpret the word cure as complete eradication, whereas clinicians may be referring to durable control or statistical likelihood. This distinction is particularly relevant in clinical conversations, where patients may interpret the term “cure” as absolute eradication. Explicitly differentiating between biological elimination, durable control, and statistical likelihood can reduce misunderstanding and support shared decision-making. Communication strategies may also differ across age groups. In pediatric settings, discussions with families often rely more explicitly on disease-specific risk stratification and cohort-based outcomes rather than fixed temporal definitions of cure. In high-risk scenarios, discussions about prognosis and potential treatment failure may appropriately begin early, underscoring the need for precise and context-sensitive use of the term “cure.” Second, it informs decision-making. In CML, the pursuit of TFR reflects acceptance of functional cure as a meaningful endpoint 2, 3. In AML, MRD positivity often prompts treatment intensification, reflecting an attempt to approach a sterilizing cure 1. In multiple myeloma, the debate over how aggressively to pursue MRD negativity hinges on whether deeper responses meaningfully increase the probability of long-term disease control or simply add toxicity 4. Third, it shapes clinical research. Trial endpoints such as MRD-negative survival, TFR, or long-term plateau reflect different conceptualizations of cure and are increasingly incorporated into trial design and regulatory frameworks 1, 2, 4, 9, 12. From a research perspective, these distinctions have implications for endpoint selection. MRD negativity, TFR, and long-term survival plateaus represent fundamentally different dimensions of therapeutic success and should not be used interchangeably. Aligning endpoints with the intended modality of cure may improve both trial design and interpretability. These distinctions are not absolute. Advances in MRD detection, evolving understanding of clonal hematopoiesis, and disease-specific variability continue to blur the boundaries between categories 1, and it is likely that current conceptual frameworks will require revision as therapeutic strategies and disease monitoring technologies evolve. Moreover, individual patients differ in how they perceive and weigh residual risk. Nevertheless, clarifying the language of cure remains valuable. When we tell a patient that we have eliminated all detectable disease and that relapse is highly unlikely, we approach the concept of sterilizing—or at least operational—cure. When we explain that residual disease may persist but is unlikely to cause harm, we describe a functional cure. And when long-term follow-up indicates that relapse risk has become negligible, we invoke operational cure. Ultimately, the question “Am I cured?” is not only biological or statistical—it is existential. Our role is not to eliminate uncertainty, which is impossible, but to define it clearly while preserving hope. Distinguishing between sterilizing, functional, and operational cure provides a framework for doing so, aligning scientific precision with the realities of patient care. A precise vocabulary of cure does not eliminate uncertainty, but it allows us to navigate it with greater clarity, consistency, and honesty. All authors contributed to the manuscript and were involved in revisions and proofreading. All authors approved the submitted version. The authors have nothing to report. The authors have nothing to report. The authors declare no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
Morabito et al. (Wed,) studied this question.