Author:

Marta Paterlini

Abstract

Over the past forty years, adult acute lymphoblastic leukaemia (ALL) has moved from heavy “one-size-fits-all” chemotherapy to highly tailored, biology-driven care. In the early 1980s, Dieter Hoelzer’s landmark multicentre trial in Germany applied paediatric-inspired combinations – vincristine, prednisone, daunorubicin, asparaginase, cytarabine and 6-mercaptopurine – raising complete remission rates to nearly 78% but still grappling with severe toxicity and frequent relapse. Building on that foundation, the 1990s saw modified childhood protocols systematically adapted for adults (with higher-dose methotrexate, fractionated cyclophosphamide or ifosfamide, and adjusted anthracyclines), boosting remission durability to over 70% in B-cell ALL while emphasizing supportive care. The early 2000s ushered in targeted approaches borrowed from chronic myeloid leukaemia, as BCR-ABL tyrosine kinase inhibitors transformed Philadelphia-positive ALL, and monoclonal antibodies (rituximab), antibody – drug conjugates (inotuzumab ozogamicin) and bispecific T-cell engagers (blinatumomab) began delivering deeper, less toxic remissions. Minimal residual disease (MRD) monitoring – detecting <0.01% leukemic blasts by flow cytometry or PCR –has become central: MRD-negative patients enjoy ≥70% five-year survival, whereas MRD positivity triggers early escalation to novel immunotherapies or transplant. The pivotal global CAR-T trials of 2017–18 demonstrated that CD19-directed cellular therapy can achieve sustained remissions in relapsed/refractory B-ALL, reshaping the role of allogeneic transplantation. Today’s 2024 European Leukaemia Net (ELN)/ESMO guidelines weave together molecular profiling, risk-adapted chemo-immunotherapy and MRD-guided algorithms to personalize treatment intensity by age, genetics and response. As genomic tools and immune therapies continue to advance, the goal is clear: durable, low-toxicity cures for all adult ALL patients.

Q&A You have been one of the key figures in the evolution of ALL treatment in Europe. In your view, when was the turning point in disease management?

(Dieter Hoelzer): Our understanding began in paediatric ALL, where early single-agent chemotherapy –most notably the discovery of methotrexate’s antileukemic properties by Sydney Farber in Boston during the 1940s – demonstrated that leukemic blasts could be induced to undergo temporary remission. From there, combination regimens expanded to include four drugs (e.g., vincristine, prednisone, anthracyclines, methotrexate), achieving cure rates of around 60-70% in children by the 1970s. In adult ALL, however, this intensity proved too myelotoxic, limiting full dosing and resulting in far lower long-term survival (circa 50%).

The next leap was the refinement of polychemotherapy protocols, with up to eight agents staggered in induction, consolidation, and maintenance phases. These optimized regimens pushed adult 5 year disease free survival from 50% in the 1980s to roughly 70% by the early 2000s, but toxicity remained a barrier for older patients.

Targeted therapies then emerged along two fronts. Chronic myeloid leukaemia (CML) was revolutionized by BCR–ABL tyrosine kinase inhibitors (e.g., imatinib) in the early 2000s, transforming a fatal disease into a manageable chronic condition. In ALL, monoclonal antibodies (e.g., rituximab for CD20-positive disease, blinatumomab targeting CD19/CD3) and antibody–drug conjugates (inotuzumab ozogamicin) have markedly improved remission rates. Most recently, CD19-directed CAR T cell therapies have achieved sustained remissions in relapsed/refractory B ALL, raising the question of how and when to incorporate allogeneic stem cell transplantation in this era.

How critical have pan-European collaborations been in establishing treatment guidelines?

In adults, the European Working Group on Adult ALL fostered consensus protocols across Germany, France, Spain, and beyond. While national variations exist – medicine needn’t be as fragmented as politics! – the basic principles align. Shared guidelines in smaller nations and even in Asia have harmonized practice, standardized toxicity management, and facilitated multinational trials.

Over these 40 years, was there ever scepticism or significant debate among clinicians?

Absolutely. There were extended periods – especially in adult ALL – when progress plateaued. I recall a decade with virtually no improvement in survival, prompting doubts about whether to continue escalating chemotherapy. Yet persistence paid off: once targeted agents arrived, we witnessed a paradigm shift.

Historically, how have B cell and T cell ALL treatments diverged?

T cell ALL (about 15% of adult ALL) initially responded to the same multi agent chemotherapies as B lineage ALL, but it did not benefit from most of the subsequent immunotherapeutic advances targeting B cell antigens. More recently, agents such as nelarabine (approved in the early 2000s) have improved outcomes in T ALL, yet the explosion of novel antibodies, bispecific constructs (e.g., blinatumomab for CD19), antibody–drug conjugates, and especially CD19 directed CAR T cells has largely been limited to B ALL, driving frontline long term remission rates above 80%.

When did the field recognize CAR T as a true turning point?

It was incremental. Early proof of concept CAR T studies emerged in China around 2012 and in the U.S.A. by 2014, but widespread clinical acceptance did not occur until the pivotal global trials reported in 2017 –2018, which demonstrated remarkable remission rates in relapsed/refractory B ALL and led to regulatory approvals. From that point forward, CAR T therapy became an integral component of management for relapsed/refractory B ALL, with ongoing trials now exploring its frontline incorporation and the optimal role of subsequent allogeneic transplantation.

Looking ahead, what challenges do you see in managing ALL?

The main challenge will be the rational integration of new technologies. We have extraordinary therapies but must learn to use them at the right time and in the right patient. Ensuring access to these treatments beyond major academic centres is also essential.

Another challenge is the biology of relapse: understanding mechanisms of immune escape, antigen loss (e.g., CD19 loss post-CAR-T), and discovering new therapeutic targets.

Which research area most urgently requires further investment?

It is difficult to answer, because we don’t invest in any new drugs. Let’s think about the already mentioned Chronic myeloid leukaemia (Philadelphia-chromosome positive). It used to have a long-term survival of only about 10 percent. Once tyrosine-kinase inhibitors came along, that jumped to 60–70 percent. B-lineage ALL is another success story: after chemotherapy milestones in children, antibody therapies – and now CAR-T cells – have produced very promising remissions in relapsed disease. “So, if you ask me where to invest next, I’d say refining and combining targeted and immune therapies – especially in the leukaemia that still lack those options. That means optimizing TKIs, bispecific antibodies, CAR-T constructs and their sequencing; figuring out which patients still need transplant after CAR-T, and when; translating the lessons from CML and B-ALL into T-ALL and other high-risk subtypes. By leveraging what already works – and tailoring it to each leukaemia’s biology – we can move every patient closer to a deep, durable, and tolerable cure.

Chronological Overview

Introduction

The management of adult acute lymphoblastic leukaemia (ALL) has undergone dramatic evolution over the past four decades. Early treatment regimens, which were largely borrowed from paediatric protocols, were later refined through intensified chemotherapy trials. Over time, the introduction of immunotherapy and targeted therapies has ushered in an era where biological markers - most notably minimal residual disease (MRD) - dictate treatment pathways. This article traces the historical journey from the foundational work of intensive chemotherapy in the early 1980s through the introduction of immunotherapeutic approaches and targeted treatment strategies today, culminating in the contemporary European Leukaemia Net (ELN) 2024 recommendations for managing adult ALL.

Early Efforts and Intensified Chemotherapy (1980s)

In the early 1980s, the treatment landscape for adult ALL was still in its emerging stage. The seminal work by Dieter Hoelzer and colleagues, published in 1984, represented a turning point in the effort to adapt paediatric-inspired treatment regimens to the adult population. First demonstrated in paediatric ALL by Farber’s landmark 1948 JAMA paper on methotrexate’s antileukemic properties, clinicians realized that leukemic blasts could be driven into remission, albeit temporarily. During this period, clinical trials focused on achieving complete remission (CR) using intensified induction and consolidation therapies.

Hoelzer et al. (1984) reported that an intensified therapeutic strategy could yield promising remission rates and possibly extend remission duration in adults – even though the overall survival remained modest due to high rates of treatment-related toxicity and relapse. This pioneering study included 170 adult patients enrolled in a multicentre trial across Germany. The central aim was to test an intensive chemotherapy approach that borrowed heavily from successful paediatric protocols, while simultaneously attempting to classify patients immunologically. This study was groundbreaking in two respects. First, it combined conventional agents – vincristine, prednisone, daunorubicin, and asparaginase – with successive cycles of cytosine arabinoside and 6-mercaptopurine. Second, it was one of the earliest to use cell-surface markers for markers for risk stratification, laying the groundwork for personalized prognosis in ALL.

The study achieved a CR rate of 77.8%, with a median overall survival of 26 months (32 months for responders vs. 4 months for nonresponders). Among the 126 patients who attained CR, the median remission duration was 20 months—underscoring the intrinsic challenges associated with adult ALL treatment. Nonetheless, this work laid a robust foundation by demonstrating that chemotherapy intensification could improve short-term outcomes, and it paved the way for subsequent research aimed at refining patient selection and extending remission durability.

Refinements in Paediatric-Inspired Protocols for Adult B-ALL (1990s)

Building upon the early experiences, the early 1990s witnessed a decisive shift when modified paediatric protocols were systematically applied to adult B-cell ALL (B-ALL), a distinct and rarer subset of adult ALL. In a landmark 1996 study, Hoelzer and colleagues reported on three consecutive multicenter trials, focusing specifically on adult patients with B-ALL. These trials implemented protocols modified from successful paediatric regimens that featured key changes such as the incorporation of fractionated, higher doses of cyclophosphamide or ifosfamide; an escalation from intermediate-dose methotrexate to high-dose methotrexate; the addition of agents like vincristine and modifications in anthracycline dosing schedules. The study showed significant improvements in CR rates – from 44% in the conventional ALL protocol to 63% and 74% in the modified regimens – and enhanced leukaemia-free survival rates. In addition to demonstrating that paediatric-inspired approaches could be successfully translated to an adult population, the study underscored that strategic intensification of therapy, with due consideration to toxicity and supportive care measures, was key to optimizing outcomes in adult B-ALL. These findings provided critical evidence that helped bridge early chemotherapeutic efforts with later developments in immunotherapy and personalized medicine.

Shifting Paradigms: The Role of Immunotherapy and Targeted Treatments (Early 2020s)

Over the following decades, the field of haematology witnessed tremendous progress. Throughout the 1990s and 2000s, incremental advances in supportive care, risk stratification through genetic analysis, and better understanding of chemotherapy pharmacodynamics gradually improved overall outcomes. However, the real paradigm shift began with the integration of immunotherapy and targeted treatments, marking a departure from the one-size-fits-all high-intensity regimens of previous decades.

The 2024 European Society for Medical Oncology (ESMO) Clinical Practice Guideline update offers a detailed account of how immunotherapeutic agents, such as monoclonal antibodies and bispecific T-cell engagers, transformed the treatment landscape. The advent of drugs like monoclonal antibodies (e.g. rituximab), antibody-drug conjugates (inotuzumab ozogamicin), and bispecific T-cell engagers (blinatumomab) have each expanded our arsenal and brought the promise of improved survival rates by directly targeting leukemic blasts while minimizing non-specific toxicity. The guideline underscores that immunotherapy is no longer a last-resort measure but has become a frontline option – either in combination with traditional chemotherapy or as a stand-alone treatment in selected patient groups. One of the crucial developments discussed in these guidelines is the assessment of MRD. MRD is defined as <0.01% leukemic blasts by flow cytometry or quantitative PCR on immunoglobulin/T-cell receptor rearrangements and can be measured in over 95% of B-lineage ALL patients. The 2024 ESMO update reports that MRD negativity after induction or consolidation therapy is achieved in approximately 70% of standard-risk adults – who then enjoy a 5-year overall survival (OS) rate of ≥70% – whereas only about 50% of high-risk patients clear MRD at these time points. Patients remaining MRD-positive relapse in nearly all cases and have very poor long-term outcomes.

Another transformative aspect highlighted in the ESMO guidelines is the use of tyrosine kinase inhibitors (TKIs) in Philadelphia-chromosome-positive (Ph+) ALL. Targeted inhibition of aberrant tyrosine kinases has markedly improved patient prognosis, enhanced remission rates and reducing reliance on allogeneic stem cell transplantation (allo-SCT) and its attendant treatment-related mortality.

The Modern Approach: Comprehensive ELN Recommendations (2024)

Building on decades of clinical research and guided by the findings from both early intensification studies and recent targeted therapy trials, the ELN released a comprehensive set of management guidelines for adult ALL in early 2024. These recommendations, spearheaded by Gökbuget, Hoelzer et al., mark another significant milestone in the field. They encapsulate the current state-of-the-art by integrating molecular diagnostics, risk-adapted therapy, and innovative immunotherapies into a unified treatment framework. A key aspect of the ELN recommendations is the emphasis on individualized treatment. The guidelines recommend that therapy be tailored according to both the molecular profile of the leukaemia and the patient’s clinical status. For instance, MRD-based treatment modifications are central to the guidelines –patients who fail to achieve MRD negativity are considered for additional immunotherapeutic interventions or an early transition to transplant-based approaches. This risk-adapted strategy represents a direct evolution from the early studies of the 1980s, where the focus was simply to induce remission. Now, treatment is optimized to ensure long-term remission with minimal toxicity. Furthermore, the ELN guidelines provide detailed algorithms that incorporate new immunotherapies and supportive care measures. Newer agents such as blinatumomab are recommended not only as salvage therapy but also during consolidation phases to enhance the depth of remission. The guidelines also stress that modern ALL treatment requires a multidisciplinary approach including expert haematologists, transplant specialists, and supportive care teams to manage the complex toxicities associated with both chemotherapy and immunotherapy. A vital contribution of the ELN recommendations is the consolidation of evidence on the management of specific subgroups – elderly patients, Ph+ ALL patients, and those with significant comorbidities. Historically, these groups were excluded from clinical trials due to concerns over treatment tolerability and comorbidity-related risks. The 2024 ELN guidelines specifically address these challenges by recommending reduced-intensity chemotherapy regimens, tyrosine kinase inhibitor–based mono- or combination therapies in Ph+ ALL, and antibody-based approaches such as blinatumomab for frail patients. This risk-adapted guidance is informed by real-time MRD monitoring to guide decisions on therapy escalation or de-escalation. The guidelines then succinctly summarize ongoing clinical trials and provide practical recommendations for adapting treatment protocols based on patient-specific risk factors and MRD status.

Interplay Between Past and Present: A Chronological Perspective

By juxtaposing the work of Hoelzer et al. (1984) with the recent guidelines and updates, one can appreciate the dramatic transformation in the approach to adult ALL. In 1984, the predominant goal was to induce remission through the aggressive use of chemotherapy. This was a time when treatment options were limited, and prognostic indicators were rudimentary at best. The pioneering efforts by Hoelzer’s group established that intensifying therapy could improve remission rates, albeit with a heavy toxicity burden.

Fast forward to the early 2020s, immunotherapy has emerged as an indispensable tool. The transition from broad-spectrum chemotherapeutic regimens to precision medicine is marked by a better understanding of the disease’s biology – specifically, the identification of distinct immunophenotypic and genetic subtypes of ALL. This advancement has allowed clinicians to employ targeted agents that have a dual benefit: increasing the efficacy of treatment while substantially reducing the risk of non-specific organ toxicity. Indeed, the 2024 ESMO guidelines highlight the importance of targeted therapies in improving survival outcomes, particularly in patients with high-risk cytogenetic profiles.

The evolution of supportive care measures also merits attention. In the early studies, the management of chemotherapy-induced complications was rudimentary, leading to a high rate of treatment-related mortality. Over the decades, improvements in supportive care – ranging from enhanced anti-infective prophylaxis to sophisticated methods of monitoring organ function – have transformed the overall tolerability of intensive treatment regimens. This progress is echoed in the ELN recommendations, which not only integrate novel therapeutic agents but also underscore the importance of an optimized aftercare strategy to mitigate long-term side effects.

Additionally, the integration of MRD as a decision-making tool represents a significant advancement in the personalized treatment approach. Early studies could only monitor the clinical response through morphological assessments, which often underestimated the residual disease burden. In contrast, the current guidelines advocate for serial MRD assessments that guide therapeutic intensification or de-escalation. Achieving MRD negativity has become a surrogate marker for long-term disease control, a concept that was in its infancy in the 1980s but now forms the cornerstone of therapeutic decision-making.

Future Directions

Despite the remarkable progress, challenges remain. Resistance to targeted therapies, the optimal sequencing of immunotherapy in relation to conventional chemotherapy, and the management of late effects continue to be areas of intense clinical investigation. Looking ahead, the future of adult ALL treatment is likely to be shaped by further approaches.

Genomic and Liquid Biopsy Profiling

Next generation sequencing and circulating tumour DNA will enable detection of emerging resistance mutations in real time.

Novel Immunotherapeutics

CAR T constructs beyond CD19, trispecific engagers, and checkpoint modulation are under clinical investigation.

Therapy De Escalation Studies

Trials are exploring reduced intensity backbones for MRD negative patients to minimize long term toxicity.

Global Collaboration and Data Sharing

International consortia will harmonize protocols and accelerate the translation of trial findings into practice.

Conclusions

The trajectory of adult ALL management – from Farber’s first remissions in the late 1940s, through Hoelzer’s intensification trials of the 1980s and paediatric inspired refinements of the 1990s, to today’s targeted and immunotherapeutic era – demonstrates the power of iterative clinical research. Current ESMO and ELN guidelines embody this evolution, offering risk adapted, MRD guided frameworks that prioritize both efficacy and quality of life. As genomic technologies and novel agents mature, the goal of durable, low toxicity remissions becomes increasingly attainable.

Aknowledgment

The author wishes to express sincere gratitude to Ms. Lea Acera Kastner, Scientific Assistant to Prof. Dr. Dieter Hoelzer, for her prompt feedback.

References

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George P, Hernández K, Hustu O, Borella L, Holton C, Pinkel D. A study of “total therapy” of acute lymphocytic leukemia in children. Journal of Pediatrics. 1968 Mar;72(3):399–408.

Hoelzer D, et al. Intensified Therapy in Acute Lymphoblastic and Acute Undifferentiated Leukemia in Adults. Blood. 1984;64(1):38–47.

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Hoelzer D, et al. ESMO Clinical Practice Guideline interim update on the use of targeted therapy in acute lymphoblastic leukaemia. Annals of Oncology. 2024;35(1):15–28.

Gökbuget N, Hoelzer D, et al. Management of ALL in Adults: 2023 ELN Recommendations from a European Expert Panel. Blood. 2024;143(19):1903–1930.