Editor's Note: At the 2026 European Hematology Association (EHA) Annual Meeting, Prof. Josep Maria Ribera from the Josep Carreras Leukemia Research Institute and the Catalan Institute of Oncology (ICO) was honored with the "EHA Clinical Excellence Award." In his subsequent award lecture, Prof. Ribera systematically reviewed the successful transformation of Acute Lymphoblastic Leukemia (ALL) from a "diagnostic deficiency period" to a "precision immunotherapy period," shared the successful experiences of the Spanish PETEMA group, and outlined a future "chemo-free" treatment blueprint. 01 Historical Mirror: From Single Morphological Diagnosis to Deep Biological Subtyping
Prof. Josep Maria Ribera first revealed the immense changes in ALL diagnosis and treatment by comparing the clinical status when he wrote his doctoral thesis in 1987. In the late 1980s, ALL diagnosis relied almost entirely on morphology (FAB classification), and karyotype analysis was rarely performed and of poor quality. Immunophenotyping at that time could only crudely classify ALL into Common-ALL, Null-ALL, and T-ALL, lacking deep biological understanding. Entering 2026, ALL is no longer regarded as a single disease. Prof. Ribera pointed out that at least 29 subtypes of B-cell precursor ALL (B-ALL) and 11 subtypes of T-ALL have been identified. Diagnostic technology has evolved into a multi-dimensional assessment combining flow cytometry, cytogenetics, and high-throughput sequencing (NGS). In addition to primary alterations, research on epigenetics, proteomics, and the hematopoietic niche is further enriching the connotation of precision diagnosis, providing a solid biological foundation for individualized treatment.
02 Ph+ ALL Paradigm Shift: From the Worst Prognosis to Leading Cure Rates
Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is a paradigm in the human process of overcoming ALL. Prof. Ribera recalled that during his residency, Ph+ ALL was almost synonymous with an “incurable disease.” However, with the iteration of tyrosine kinase inhibitors (TKIs) and the addition of immunotherapy, its clinical outcome has undergone world-shaking changes. Data showed that in the era of the first-generation TKI imatinib, the survival curve of patients improved but remained suboptimal. With the entry of the third-generation TKI ponatinib into frontline treatment, combined with chemotherapy or immunotherapy (such as blinatumomab), the medium-to-long-term survival rate of patients has achieved a massive leap. The latest research presented by Prof. Ribera shows that “chemo-free” or “chemo-reduced” regimens of ponatinib combined with blinatumomab can bring the survival rate of Ph+ ALL patients close to or even exceed 80%. This model not only improves efficacy but also significantly reduces the toxic side effects brought by high-intensity chemotherapy, making it applicable to patients of all age groups.
03 Steady Progress in Ph- ALL: Dual Benefits for Young and Elderly Patients
For Philadelphia chromosome-negative (Ph- ALL) patients, treatment progress has been equally significant. Prof. Ribera cited data from the Spanish PETEMA group: around 2003, the overall survival rate of Ph- ALL patients was less than 40%; by 2026, through optimizing chemotherapy regimens and introducing rituximab targeting CD20 as well as bispecific antibodies, the survival rate of young adults has exceeded 60%. Although elderly Ph- ALL patients progress relatively slowly due to tolerability issues, their prognosis is also entering an upward channel with the forward movement of immunotherapy strategies. Current clinical efforts are focused on tailoring treatment intensity for patients of different age groups through more refined risk stratification.
04 Immunotherapy and Cell Therapy: Reshaping R/R and Frontline Consolidation Strategies
Prof. Ribera emphasized that the past 10 years have been the “golden age” of immunotherapy. Blinatumomab, inotuzumab ozogamicin, and chimeric antigen receptor T-cell (CAR-T) therapies (such as tisagenlecleucel, brexucabtagene autoleucel) have been approved successively. In clinical application, immunotherapy is penetrating from the relapsed/refractory (R/R) stage to the frontline. For example, in a pivotal Phase III clinical study, incorporating blinatumomab into consolidation therapy for patients in complete remission (CR) and minimal residual disease (MRD) negative status further significantly improved patients’ event-free survival (EFS) and overall survival (OS). Furthermore, more efficient combination strategies (such as Hyper-CVAD chemotherapy followed by inotuzumab ozogamicin + blinatumomab) have shown attractive clinical benefits in young adults. Looking ahead, subcutaneous blinatumomab and constructs targeting new targets (such as CD19/CD22 dual-targets) are under development, which will further optimize the immunotherapy matrix for ALL.
05 MRD-Driven Decision System: The Core Beacon of Precision Medicine
Regarding treatment monitoring, MRD has become the core for guiding ALL treatment decisions. Prof. Ribera pointed out that MRD is not only a powerful predictor of prognosis but also a decisive factor in adjusting treatment strategies (such as whether to proceed with allogeneic hematopoietic stem cell transplantation). Through high-sensitivity MRD monitoring using flow cytometry or NGS, clinicians can identify patients who have achieved morphological CR but still have a risk of molecular relapse, allowing for timely intervention with immunotherapy. This “MRD-driven” model effectively avoids over-treatment while capturing the best timing for salvage, which is key to achieving long-term survival in ALL.
06 Medical Humanism and Global Collaboration: Integrated Care Beyond Clinical Trials
At the end of the lecture, Prof. Ribera movingly reminded his colleagues: “We are treating ‘patients,’ not just participating in clinical trials.” He called for attention to the physical, emotional, and social status of patients, advocating for the provision of comprehensive and multi-dimensional integrated care. At the same time, Prof. Ribera emphasized the power of collaboration. Whether it is the Spanish PETEMA group, the medical networks in the Catalonia region, or the European Working Group on Adult ALL (EWALL), this cross-institutional and cross-border scientific research cooperation is the necessary path to promote progress in the study of rare and difficult-to-treat tumors.
Expert Outlook: Professor Josep Maria Ribera concluded that the treatment of ALL has entered the “Era of Hope.” Future directions will focus on:
- Chemo-free: Especially in Ph+ ALL and some B-ALL, gradually reducing the proportion of chemotherapy and replacing it with TKIs, immunotherapy, and cell therapy;
- Target Precision: Developing new targeted drugs for rare subtypes and T-ALL;
- Strategy Forward-shift: Applying high-efficiency therapies such as CAR-T and bispecific antibodies to frontline consolidation, aiming to achieve higher molecular cure rates;
- Global Collaboration: Further perfecting standardized processes for diagnosis and follow-up through groups like PETEMA
