Therapeutic success and epidemiological failure in hematology

What is the goal of onco‐hematology? While perspectives may differ, improving cure rates for patients with hematological malignancies (HMs) is widely considered as the primary objective. Encouragingly, substantial progress has been made toward this goal, as reflected by the marked improvement in 5‐year overall survival (OS) for patients with HMs over the past three decades according to the Surveillance, Epidemiology, and End Results (SEER) database ¹ (Figure 1A). Between 1992 and 2017, major gains in 5‐year OS were observed in chronic myeloid leukemia (CML, 31%–69%, +38%), multiple myeloma (MM, 27%–64%, +37%), and non‐Hodgkin lymphomas (NHLs, 51%–78%, +27%). These improvements are consistent with already published data,2, 3, 4 and largely attributable to therapeutic innovations, including targeted therapies (e.g., imatinib, bortezomib, and thalidomide derivatives) and monoclonal antibodies (such as rituximab). Significant advances have also been achieved in acute leukemias, including acute lymphoblastic leukemia (ALL, 58%–76%, +18%) and acute myeloid leukemia (AML, 18%–34%, +16%). Improvements have likewise been observed in diseases that already had relatively high 5‐year OS rates in 1992, such as chronic lymphocytic leukemia (CLL, 77%–92%, +15%) and Hodgkin lymphoma (HL, 85%–93%, +8%). The continued integration of highly effective treatments such as CAR T‐cell therapies, bispecific antibodies, and novel targeted agents like menin inhibitors is expected to drive further progress in the coming years.

Figure 1.

Trends in overall survival, mortality, and incidence of hematological malignancies according to the Surveillance, Epidemiology, and End Results (SEER) database. (A) Evolution of 5‐year overall survival (%). (B) Evolution of overall mortality and (C) evolution of incidence (ratio to 1975, age standardized). ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CLL, chronic lymphoid leukemia; CML, chronic myeloid leukemia; HL, Hodgkin lymphoma; MM, multiple myeloma; NHL, non‐Hodgkin lymphoma; OS, overall survival.

On the basis of these impressive therapeutic advances, one might conclude that hematology is on track to achieve its goal, moving toward the cure or chronic management of most HMs. However, this conclusion warrants reconsideration. The ultimate objective of hematology should not be limited to improve survival, but also to reduce the burden of diseases in the overall population.

From this perspective, epidemiological data paint a more sobering picture. According to SEER data, which are adjusted on age and population size, disease‐specific mortality has declined between 1975 and 2022 for HL (−80%), childhood leukemia (−73%), CML (−71%), ALL (−41%), CLL (−23%), and NHL (−16%). In contrast, mortality has remained relatively stable for MM (−3%) and AML (+4%) (Figure 1B). These trends appear inconsistent with major therapeutic advances observed over the same period.

This apparent paradox can largely be explained by concurrent changes in disease incidence. The age‐adjusted SEER data show that, with the exception of HL, whose incidence is decreasing since 1975 (−27%), and CML, whose incidence is stable (−2%), all other HM are more frequent in 2022: AML (+21%), childhood leukemia (+22%), CLL (+26%), MM (+43%), ALL (+58%), and NHL (+69%) (Figure 1C).

When incidence and mortality are considered jointly, five distinct epidemiological patterns emerge (Figure 2). The most favorable pattern—declining incidence and mortality—is observed only in HL. A second pattern, seen in CML, combines stable incidence with declining mortality, reflecting highly effective therapies. A third pattern, affecting MM and NHL, shows that therapeutic gains are offset by increasing incidence. A fourth pattern, observed in CLL, ALL, and childhood leukemia, shows declining mortality despite rising incidence. Finally, AML represents the least favorable scenario, with increases in both incidence and mortality. Even where mortality declines, these gains come at the cost of long‐term toxicities and growing financial burden for patients and healthcare systems.

Figure 2.

Patterns of evolution of incidence and mortality of hematological malignancies according to the Surveillance, Epidemiology, and End Results (SEER) database. Evolution of incidence and overall mortality (ratio to 1975, age standardized) of the main hematological malignancies between 1975 and 2022. ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CLL, chronic lymphoid leukemia; CML, chronic myeloid leukemia; HL, Hodgkin lymphoma; MM, multiple myeloma; NHL, non‐Hodgkin lymphoma.

These observations raise a fundamental question: how can the incidence of HMs be reduced? Unlike many solid tumors, HMs are not strongly associated with behavioral risk factors such as smoking ⁵ or alcohol ⁶ consumption. Instead, the most well‐established risk factors relate to occupational and environmental exposures, including pesticides, ⁷ , ⁸ hydrocarbons such as benzene, ⁹ ionizing radiation ¹⁰ among others. Importantly, these exposures are recognized as risk factors but are far more difficult to quantify at the individual level than, for example, tobacco use. This likely leads to an underestimation of their true associated risks. ¹¹

Because these exposures cannot be effectively addressed through individual behavioral interventions alone, reducing HM incidence requires broader structural approaches. In this context, hematologists should have a critical role—not only as clinicians and researchers but also as advocates for public health.

First, the hematologist as a community should actively advocate for a reduction in the global use of pesticides, whose worldwide consumption has doubled since 1990, ¹² and for stricter regulation or prohibition of the most hazardous compounds. Second, clinicians should systematically assess and document the potential occupational origin of HMs in affected patients and strongly support their access to appropriate recognition and compensation. Such recognition not only serves patients' interests but also provides a strong incentive for employers and industries to implement effective preventive measures. Third, further research is deeply needed to better understand the mechanisms by which environmental and occupational exposures contribute to HM oncogenesis. These works could be inspired by innovative methodologies that have recently established unrecognized associations between pesticides and cancer by using epigenetic signatures ¹³ or high‐quality spatial mapping of pesticide exposure at a country level. ¹⁴ These epidemiological and scientific approaches will improve risk assessment and address current gaps in the regulatory evaluation of new compounds.

Therapeutic innovation has transformed the prognosis of many HMs. However, without parallel efforts to address their causes, these advances will have a limited impact at the population level. If the hematologist community can become as effective in influencing public health policies as it has been in improving patient survival, only then will it be able to claim that it has fulfilled its true mission.

AI DISCLOSURE

ChatGPT (OpenAI, USA) was used to assist with English language editing (spelling and grammar). No content generation or scientific interpretation was performed by the model. The author reviewed and takes full responsibility for the final content.

AUTHOR CONTRIBUTIONS

Pierre Sujobert: Conceptualization; writing—original draft; methodology; writing—review and editing; validation; formal analysis.

CONFLICT OF INTEREST STATEMENT

P.S. reports personal fees for consultancy from Gilead, Janssen, Astellas, and AbbVie.

FUNDING

This research received no funding.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available in SEER at https://seer.cancer.gov/statfacts/. These data were derived from the following resources available in the public domain: SEER, https://seer.cancer.gov/statfacts/.