Authors:

Irina Amitai

Arnon Nagler

Abstract

Acute myeloid leukaemia (AML) was uniformly fatal until the mid-twentieth century. Its transformation into a curable disease is one of the defining achievements of European oncology. This article traces that arc, from Rudolf Virchow’s identification of leukaemia in Berlin in 1845 to the current era of precision medicine. It describes how European pioneers, notably Jean Bernard in Paris, built upon the earliest antimetabolite remissions to establish combination chemotherapy for leukaemia, how French and Italian teams independently discovered daunorubicin, and how the “3+7” induction regimen became the universal backbone of AML therapy. The article examines the critical role of European cooperative groups, particularly HOVON under Bob Löwenberg and the UK Medical Research Council under Alan Burnett, in defining optimal anthracycline dosing and validating high-dose cytarabine consolidation through large randomised trials. The conquest of acute promyelocytic leukaemia by French and Italian investigators is highlighted as a paradigm of translational success. The evolution of allogeneic transplantation as a curative modality from Georges Mathé’s pioneering 1958 bone marrow infusions to the modern era, shaped by the European Society for Blood and Marrow Transplantation, is discussed, alongside Jean Dausset’s foundational discovery of the HLA system. The article then follows the molecular revolution driven by Brunangelo Falini’s discovery of NPM1 mutations codified in the European LeukemiaNet recommendations and concludes with the targeted therapy era and the European regulatory landscape. Throughout, the narrative asks how European collaboration from bench to bedside has served as the principal engine of progress in AML.

Introduction

Acute myeloid leukaemia (AML) is the most common acute leukaemia in adults. For over a century after its initial description, it remained uniformly fatal. The story of how AML became a curable disease is, in large measure, a European story shaped by continental cooperation, translational insight, and the collaborative infrastructure of large randomised trials. This article traces that arc, asking: what were the ideas, institutions, and individuals that drove the transformation of AML treatment from therapeutic nihilism to the current era of precision medicine?

From Morphology to First Remissions (1845–1960s)

The concept of leukaemia originated in Europe. In 1845, Rudolf Virchow in Berlin described a patient with “weisses Blut” (white blood), recognizing an excess of colourless cells in the circulation (Virchow 1845). Almost simultaneously, John Hughes Bennett in Edinburgh reported a similar case. Virchow’s work in cellular pathology provided the intellectual framework: leukaemia was a disease of disordered cell growth, not “bad blood.” Paul Ehrlich’s aniline staining techniques (1878) enabled the distinction between myeloid and lymphoid forms.

The therapeutic era began with Sidney Farber and Louis Diamond’s demonstration in 1948 that aminopterin could induce remissions in childhood leukaemia (Farber et al. 1948). Although these remissions were transient, they shattered the prevailing fatalism. In Europe, Jean Bernard at Hôpital Saint-Louis in Paris was among the foremost pioneers who built upon these early antimetabolite findings to develop combination chemotherapy programmes for acute leukaemia through the 1950s and 1960s. Bernard and his colleagues later made seminal contributions to the understanding and treatment of acute promyelocytic leukaemia (Bernard et al. 1973). The cooperative group infrastructure that Bernard helped establish in France became a model for European leukaemia research.

The Anthracycline Revolution and the Birth of 3+7 (1960s–1970s)

A pivotal European contribution was the discovery of daunorubicin. In the early 1960s, the compound was isolated independently by French (Rhône-Poulenc) and Italian (Farmitalia) teams from Streptomyces species named rubidomycin in France and daunomycin in Italy (Jacquillat et al. 1966). Daunorubicin proved to be the first agent with significant single-agent activity in AML.

The critical next step was combination therapy. Through the late 1960s and early 1970s, investigators recognised that daunorubicin paired with continuous-infusion cytarabine produced remission rates far exceeding those of either drug alone. This combination was formalised as the “3+7” regimen: three days of intravenous daunorubicin followed by seven days of continuous cytarabine infusion (Yates et al. 1973). The regimen was rapidly adopted across European centres and cooperative groups, becoming the near-universal backbone of AML induction. Remarkably, despite decades of attempts to improve upon it, 3+7 remained the standard induction platform for almost fifty years, a testament to the robustness of its original design.

In parallel, the French-American-British (FAB) cooperative group, a predominantly Franco-British initiative, published the first standardised morphological classification of AML in 1976 (Bennett et al. 1976), providing the common language that made international trial comparisons possible.

High-Dose Cytarabine Consolidation: From Concept to European Standard

Achieving remission was only half the battle. Without effective post-remission therapy, virtually all patients relapsed. The landmark CALGB 8525 trial demonstrated that four cycles of high-dose cytarabine (HiDAC; 3 g/m² every 12 hours on days 1, 3, and 5) significantly improved disease-free survival in patients under 60, particularly those with favourable-risk cytogenetics (Mayer et al. 1994). This established HiDAC consolidation as the standard post-remission strategy for younger patients.

European cooperative groups played a central role in validating, refining, and extending this approach. The HOVON-SAKK collaborative, under Bob Löwenberg, addressed practical questions the original CALGB study left open: how many cycles of HiDAC are optimal? Is the benefit maintained in intermediate-risk disease? Can consolidation intensity be adapted according to molecular risk? HOVON trials demonstrated that a limited number of HiDAC consolidation cycles offered a pragmatic balance between efficacy and toxicity, and that consolidation strategy should be integrated with molecular risk assessment and transplant planning (Löwenberg et al. 1998). The MRC AML trials, led by Alan Burnett, took a complementary approach, testing additional courses of intensive consolidation and evaluating the role of autologous transplantation as a post-remission option (Burnett et al. 2011).

The European contribution was not merely replication but genuine refinement. By embedding consolidation questions within large, molecularly annotated trials, European groups moved the field from a one-size-fits-all approach toward risk-adapted post-remission therapy, a principle that now governs modern AML management.

HOVON, Bob Löwenberg, and the Optimisation of Induction

Beyond consolidation, HOVON’s contributions to induction therapy were equally transformative. The question of optimal anthracycline dosing had been debated since the inception of 3+7. In a landmark randomised trial, Löwenberg and colleagues compared standard-dose daunorubicin (45 mg/m²) with escalated-dose daunorubicin (90 mg/m²) in patients aged 60–65 (Löwenberg et al. 2009). The escalated-dose arm achieved significantly higher complete remission rates and improved overall survival, establishing dose-intensified induction as a viable strategy for fit older patients. This trial, together with the parallel ECOG study (Fernandez et al. 2009), changed induction practice worldwide.

Löwenberg’s broader vision extended beyond individual trials. Under his leadership, HOVON developed an integrated model of AML research in which induction optimisation, molecular risk stratification, consolidation tailoring, and transplant decision-making were addressed within a single trial framework. This holistic approach, treating the trial program as a continuum rather than a series of isolated questions, became a blueprint for European cooperative AML research.

The APL Paradigm: Differentiation Therapy (1980s–2010s)

Perhaps the most dramatic chapter in European AML history is the conquest of acute promyelocytic leukaemia (APL). In 1990, Castaigne, Chomienne, Laurent Degos, and colleagues at Hôpital Saint-Louis, building on work by Zhen-Yi Wang in Shanghai, demonstrated that all-trans retinoic acid (ATRA) could induce complete remissions in APL patients harbouring the PML-RARA fusion (Castaigne et al. 1990). This was the first successful “targeted” therapy in leukaemia, predating imatinib by a decade.

Francesco Lo-Coco and the Italian GIMEMA group subsequently proved that ATRA combined with arsenic trioxide could cure APL without conventional chemotherapy (Lo-Coco et al. 2013). The landmark APL0406 trial converted the historically most lethal AML subtype into one with long-term survival exceeding 95%, an enduring model of translational medicine.

Allogeneic Transplantation: The European Contribution

The European contribution to allogeneic haematopoietic stem cell transplantation (allo-HSCT) predates its establishment as standard therapy. In 1958, Georges Mathé in Paris performed the first allogeneic bone marrow infusions in Europe, treating Yugoslav physicists who had been accidentally irradiated in the Vinča nuclear accident (Mathé et al. 1959). Although engraftment was transient, Mathé’s work provided early proof-of-concept that donor haematopoietic cells could restore marrow function, a principle upon which the entire field was subsequently built. Mathé also introduced the concept of “adoptive immunotherapy,” recognising the immune-mediated antileukaemic effect of the graft.

Equally foundational was Jean Dausset’s discovery in 1952 of leukocyte alloantibodies, which led to the identification of the human leukocyte antigen (HLA) system. By establishing that immune recognition is genetically determined, Dausset enabled donor-recipient matching and transformed transplantation from a largely empirical endeavour into a rational clinical discipline. For this work, Dausset received the 1980 Nobel Prize in Physiology or Medicine.

Following E. Donnall Thomas’s demonstration of transplant’s curative potential in the 1970s (Thomas et al. 1977), European centres rapidly became leaders in refining the procedure and expanding its applicability. The European Society for Blood and Marrow Transplantation (EBMT), established in 1974, built the world’s largest transplant registry and provided the infrastructure for landmark studies that defined transplant indications, conditioning intensity, and donor selection in AML.

European groups were instrumental in the development of reduced-intensity conditioning (RIC), which extended transplant eligibility to older and less fit patients who constitute the majority of AML cases. EBMT registry analyses and prospective cooperative group studies conducted by HOVON, GIMEMA, the French ALFA group, and others established that RIC allo-HSCT could deliver meaningful graft-versus-leukaemia effects with acceptable toxicity, fundamentally altering the age boundary for curative therapy. More recently, the expansion of haploidentical transplantation and post-transplant cyclophosphamide platforms, validated in large European series, has addressed the longstanding barrier of donor availability. The integration of MRD-guided transplant decisions, now endorsed by the ELN, represents the latest evolution — ensuring that the considerable risks of transplantation are directed toward patients most likely to benefit.

##The Molecular Era and the ELN Framework (2005–present)

The transition from morphology to molecular biology fundamentally reshaped AML. European laboratories were at the forefront. In 2005, Brunangelo Falini and colleagues at the University of Perugia made the landmark discovery that nucleophosmin (NPM1) is aberrantly localised to the cytoplasm in approximately one-third of adult AML cases, leading to the identification of NPM1 mutations as a distinct molecular subtype (Falini et al. 2005). This discovery had profound prognostic implications and established NPM1-mutated AML as a separate entity in the WHO classification.

The Ulm group, led by Hartmut Döhner, integrated Falini’s discovery alongside FLT3 internal tandem duplications and biallelic CEBPA mutations into a unified risk stratification framework. In 2010, Döhner and colleagues published the first European LeukemiaNet recommendations, integrating molecular markers into a comprehensive risk classification (Döhner et al. 2010). The ELN recommendations were updated in 2017 and 2022; a 2024 ELN genetic risk classification was additionally proposed for patients receiving less-intensive therapy. The ELN framework has become the global standard guiding treatment decisions, including transplant in first remission, and serving as the stratification backbone for contemporary AML trials worldwide.

The Targeted Therapy Revolution (2017–present)

The most recent chapter has seen the introduction of molecularly targeted agents. Midostaurin, validated in the RATIFY trial with significant European participation, became the first targeted agent approved for FLT3-mutated AML (Stone et al. 2017), heralding a wave of mutation-specific therapies that has reshaped the treatment landscape.

From a European perspective, AML treatment is increasingly organised around rapid molecular profiling by next-generation sequencing at diagnosis, particularly for FLT3 and IDH1 mutations. In the European Union, midostaurin is authorised for newly diagnosed FLT3-mutated AML in combination with chemotherapy. Gilteritinib is authorised for relapsed/refractory FLT3-mutated AML. Quizartinib, a selective type II FLT3 inhibitor, was approved by the European Commission in November 2023 in combination with chemotherapy for newly diagnosed FLT3-ITD–positive AML, representing the first FLT3 inhibitor approved in the EU specifically for this disease subtype.

For IDH1-mutated AML, Europe now has a defined regulatory position: ivosidenib (Tibsovo) was authorised by the European Commission in May 2023 in combination with azacitidine for adults with newly diagnosed IDH1 R132-mutated AML who are not eligible for standard induction chemotherapy. Enasidenib (IDH2 inhibitor) has not been approved in the EU. Menin inhibitors, targeting NPM1-mutated and KMT2A-rearranged AML, remain largely a clinical trial strategy in Europe and have not yet received EMA authorisation.

Perhaps most transformative has been venetoclax in combination with hypomethylating agents, now the standard of care for patients ineligible for intensive chemotherapy (DiNardo et al. 2020). European real-world studies have confirmed its efficacy while highlighting the challenge of venetoclax resistance. MRD monitoring, driven by European standardisation efforts, is being integrated into treatment algorithms, guiding decisions on transplant, maintenance, and therapy de-escalation.

Conclusions

The history of AML treatment is inseparable from the history of European medicine. From Virchow’s identification of the disease to Bernard’s pioneering European leukemia programmes, from the Franco-Italian discovery of daunorubicin and the establishment of 3+7 induction to Löwenberg’s optimisation of dose-intensified therapy and HiDAC consolidation, from Mathé’s first European bone marrow infusions and Dausset’s discovery of the HLA system to the APL revolution, from Falini’s identification of NPM1 mutations to Döhner’s molecular framework, European clinicians and scientists have provided the foundational insights, therapeutic tools, and collaborative structures that drove progress. The cooperative group model and the EBMT transplant infrastructure have been the engines of evidence generation. As AML enters the era of precision medicine, this collaborative tradition remains as vital as ever.

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