From Disease Control to Precision Care: The Enduring Legacy of Michele Baccarani in Chronic Myeloid Leukemia

1. Michele Baccarani and CML as a Model of Modern Hematology

The history of chronic myeloid leukemia (CML) is one of the clearest demonstrations of how biological insight, therapeutic innovation, and disciplined clinical observation can transform the natural history of a malignant disease. Michele Baccarani was among the hematologists who shaped that transformation and, crucially, helped convert rapidly accumulating evidence into a shared language for clinical practice. His contribution extended well beyond the evaluation of individual treatments. Through successive European LeukemiaNet (ELN) recommendations, he promoted disease definitions, molecular milestones, categories of response, and decision points that allowed clinicians and investigators across countries to interpret results consistently and improve care collectively [1,2,3,4]. The 2025 ELN recommendations explicitly acknowledge his vision and leadership in developing this enduring series of management guidelines [5].

This method may be the most durable part of his scientific legacy: define the disease precisely, measure the response reproducibly, revise therapeutic objectives when evidence changes, and keep the patient, rather than the drug, at the center of decision-making. These principles helped make CML a model for targeted therapy and, subsequently, for measurable residual disease monitoring, risk-adapted treatment, survivorship, and treatment discontinuation.

The seven contributions collected in this Memorial Issue reflect different consequences of that success. They address molecular monitoring and treatment-free remission (TFR), childhood CML, cardiovascular toxicity, the continuing role of allogeneic hematopoietic cell transplantation (HCT), population-level outcomes, and the more complex challenge of precision medicine in TP53-mutated acute myeloid leukemia (AML). Read together, these contributions describe a field that has moved from preventing death from leukemia to pursuing a longer, safer, treatment-free, and more equitable life. They also show that therapeutic success does not eliminate uncertainty; it changes the questions that matter.

2. From Survival to Treatment-Free Living

The introduction of BCR::ABL1 tyrosine kinase inhibitors (TKIs) changed chronic-phase CML from life-threatening leukemia into a condition with which life expectancy can approach that of the general population [6]. Once progression and leukemia-related mortality became uncommon among optimally responding patients, major molecular response (MMR), deep molecular response (DMR), tolerability, quality of life, and ultimately TFR became increasingly relevant treatment goals. This evolution required more than effective drugs: it depended on standardized molecular monitoring, one of the central themes of Baccarani’s work.

Bernardi et al. reviewed digital polymerase chain reaction (dPCR) as a tool for assessing residual disease and refining the selection of patients who discontinue TKIs [7]. Reverse-transcription quantitative PCR (RT-qPCR) on the International Scale remains the established standard, but its precision is limited at very low transcript/disease levels. By partitioning a sample into a large number of reactions, dPCR can provide absolute quantification without a calibration curve and may offer higher precision near the limits of detection. In the studies discussed by the authors, residual BCR::ABL1 detected with dPCR despite undetectable RT-qPCR was associated with a higher probability of molecular recurrence after discontinuation. These findings are biologically and clinically plausible: “undetectable” disease is a property of an assay and a sample, not proof that the leukemic clone has been eradicated.

The crucial distinction, however, is between analytical sensitivity and demonstrated clinical utility. Interplatform variability, preanalytical factors, transcript-specific performance, reference gene selection, thresholds, and interlaboratory reproducibility still limit the use of dPCR as an independent decision tool. Current ELN laboratory recommendations recognize optimized RT-dPCR as a valid alternative to RT-qPCR, with particular value at very low transcript/disease levels, while emphasizing quality assurance and standardized interpretation [8]. Thus, dPCR should not simply replace one number with a more sensitive number. Its value will depend on whether prospectively validated thresholds improve decisions beyond established clinical predictors such as the duration of TKI exposure and the duration and depth of the molecular response.

The final EURO-SKI analysis has reinforced the importance of treatment duration and DMR duration, but no available biomarker can yet identify with certainty who will maintain TFR [9]. Approximately half of the appropriately selected patients remain in molecular remission after stopping therapy, and most patients with molecular recurrence regain response after prompt TKI reintroduction [5,9]. The next step is therefore not the indiscriminate expansion of discontinuation but the more accurate estimation of individual probability, supported by reliable access to frequent molecular monitoring and a clear plan for restarting treatment.

Therapeutic innovation may enlarge the population reaching DMR. Asciminib, the first inhibitor to specifically target the ABL myristoyl pocket, has already expanded options after treatment with multiple TKIs. In the ASC4FIRST trial for newly diagnosed CML, MMR was achieved at week 48 by 67.7% of patients receiving asciminib and 49.0% receiving an investigator-selected TKI, with fewer high-grade adverse events and treatment discontinuations in the asciminib arm [10]. Longer follow-up remains necessary, particularly for uncommon late toxicities and definitive survival outcomes. Moreover, a faster molecular response should not automatically be equated with a higher probability of durable TFR. This relationship must be demonstrated through sufficiently mature discontinuation studies.

Giona and Bianchi remind us that these achievements in adults cannot simply be transferred to children and adolescents [11]. Pediatric CML is rare and often presents with higher leukocyte counts, greater splenomegaly, and clinical features suggesting more aggressive biology, yet most recommendations necessarily rely on adult evidence. Imatinib, dasatinib, and nilotinib have markedly improved disease control, but treatment may extend across growth, puberty, education, and reproductive life. Growth impairment, altered bone metabolism, endocrine effects, adherence, fertility, and the unknown consequences of prolonged exposure are therefore especially important. Recent international pediatric recommendations provide a more specific framework, but evidence supporting optimal first-line selection, dose, long-term toxicity, and TFR remains limited [12]. For children, the goal is not merely to reproduce adult molecular outcomes: the goal is to preserve normal development across an entire lifetime.

3. The Price of Success: Making Long-Term Therapy Sustainable

Two complementary reviews in this Memorial Issue address the cardiovascular consequences of prolonged TKI therapy. Berisha, Placci, and Piccaluga summarize the cardiac toxicities reported for BCR::ABL1 inhibitors in Philadelphia-positive leukemias [13], whereas Costa et al. provide a broader mechanistic and clinical account of the direct and indirect cardiovascular effects in CML [14]. Their shared message is not that TKIs have an unfavorable risk–benefit profile; the opposite is true. A treatment intended for years or decades must be selected and managed differently than a short course of antineoplastic therapy.

Cardiovascular toxicity is heterogeneous and cannot be treated as a uniform class effect. Imatinib generally has a favorable cardiovascular profile. Dasatinib is particularly associated with pleural effusion and, less commonly but importantly, pulmonary arterial hypertension. Nilotinib can aggravate metabolic risk and is associated with peripheral and other arterial occlusive events. Ponatinib is indispensable for some resistant disease and for the T315I mutation, but arterial events and hypertension require careful risk assessment and dose optimization. Bosutinib has a different profile, dominated more often by gastrointestinal and hepatic toxicities. Asciminib may reduce some off-target effects, but continued surveillance is necessary before its long-term cardiovascular profile can be considered fully defined.

Mechanistically, endothelial injury, impaired vascular repair, proatherogenic signaling, platelet activation, hypertension, and metabolic disturbances may interact with age, smoking, diabetes, dyslipidemia, renal dysfunction, and previous cardiovascular disease. The clinically relevant question is therefore not only which TKI is most potent but which treatment offers the best overall balance for this patient at this stage of disease. Baseline cardiovascular evaluation, correction of modifiable risk factors, avoidance of TKIs with an unfavorable profile when effective alternatives exist, and structured follow-up are now integral to CML care. The 2022 European Society of Cardiology cardio-oncology guidelines provide a framework for risk-based surveillance and multidisciplinary management [15].

This is also an area in which the philosophy of response milestones must be complemented by the philosophy of dose optimization. The 2025 ELN recommendations place more importance on dose reduction than on automatic switching when a patient has an adequate molecular response but experiences persistent toxicity [5]. The OPTIC study similarly demonstrated that response-based ponatinib dose reduction can retain substantial efficacy while improving the benefit–risk balance [16]. These strategies indicate a broader change in CML management: the most appropriate dose is not necessarily the maximum tolerated dose, and the most suitable TKI is not necessarily the agent producing the fastest response. Sustainable disease control requires shared decisions that integrate leukemia risk, comorbidities, adverse event profile, reproductive plans, adherence, quality of life, and the patient’s preference regarding TFR.

4. When Targeted Therapy Is Not Enough

The case-based review by Tiribelli et al. places allogeneic HCT within the modern CML treatment sequence [17]. The large decline in transplant activity after the introduction of imatinib can create the misleading impression that HCT has become obsolete. In reality, its role has become narrower, later, and more selective. HCT remains a potentially curative option for patients presenting in or progressing to blast phase, for chronic-phase disease resistant to multiple TKIs, for selected patients with high-risk mutations, and for those in whom severe recurrent toxicity prevents effective long-term pharmacological treatment.

The cases presented illustrate an important principle: TKIs and transplantation are complementary rather than competing strategies. A potent TKI, sometimes combined with acute-leukemia-directed therapy, may serve as a bridge to a second chronic phase before HCT. Conversely, molecular monitoring and TKIs can contribute to preventing or treating relapse after transplant. Advances in alternative donors, reduced-intensity conditioning, graft-versus-host disease prophylaxis, and supportive care have broadened transplant access beyond the young patient with a matched sibling [5,18]. Nevertheless, outcomes remain strongly dependent on disease phase at HCT, and the opportunity for referral can be lost if transplant evaluation is postponed through repeated ineffective TKI switches.

Several uncertainties remain. The definition of accelerated phase has changed, with the World Health Organization favoring a biphasic model, whereas many clinical datasets and treatment algorithms retain an intermediate category. The optimal pretransplant regimen for the blast phase depends on the lineage and mutation profile and is supported mostly by nonrandomized evidence. After HCT, the appropriate duration and dose of prophylactic TKI therapy, the threshold for pre-emptive treatment, and the respective roles of TKI and donor lymphocyte infusion have not been standardized. These questions require prospective collaboration because the relevant patient population has become small.

5. From Clinical Trial Efficacy to Population-Level Impact

The original study by Shivarov et al. provides an important counterpoint to the predominantly biological and therapeutic focus of this Memorial Issue [19]. Using data from 1513 Bulgarian patients, the authors observed progressive increases in overall survival through the 2010–2014 diagnostic period, but no further increase among patients diagnosed in 2015–2019. This apparent plateau occurred despite increasing expenditure on TKIs and an increase in the number of patients receiving at least one TKI from 5.9 per 100,000 inhabitants in 2014 to 11.3 per 100,000 in 2022.

These results must be interpreted with appropriate caution. Follow-up differed between periods, the national registry underwent reorganization with possible delayed or incomplete reporting, cause-specific mortality was unavailable, and the COVID-19 pandemic affected the later cohorts. Yet, the authors asked a question that cannot be answered by registration trials: how much of therapeutic efficacy translates to population benefit? The availability of several TKIs is necessary, but this alone is not sufficient. Timely diagnosis, standardized molecular testing, adherence support, appropriate switching, cardiovascular prevention, expert referral, reliable registries, and continuity of care determine whether access translates into survival.

Precision medicine cannot be considered fully successful if its benefits remain dependent on geography, healthcare organization, or the quality of outcome reporting. Disease-specific registries with granular information on phase, risk, treatment sequence, molecular response, comorbidities, toxicity, progression, and cause of death are not administrative luxuries: these registries are instruments of clinical quality. The Bulgarian experience therefore broadens the meaning of precision care: it includes not only selecting the right molecule but building a system capable of delivering, monitoring, and evaluating that choice.

6. Extending the Precision Medicine Paradigm Beyond CML

The review by Zingarelli, Zannoni, and Curti on TP53-mutated AML may initially appear outside the central CML theme, but the authors provide a useful contrast [20]. CML is driven by a highly actionable founding lesion that can be quantitatively measured and inhibited over decades. TP53-mutated AML is characterized by genomic instability, complex clonal architecture, intrinsic drug resistance, and interactions among leukemia cells, metabolism, and an immunosuppressive microenvironment. In this setting, precision medicine cannot rely on a single target–response relationship.

The authors’ biological framework remains relevant, but developments since their 2022 review also illustrate the distance between compelling rationale and clinical benefit. Eprenetapopt and CD47-directed approaches generated encouraging early-phase signals, yet randomized studies did not confirm the expected benefit. In ENHANCE-2, magrolimab plus azacitidine failed to improve overall survival compared with the physician’s choice in untreated TP53-mutated AML [21]. This negative result does not diminish the importance of studying immune–metabolic dependencies; it indicates the urgency of biomarker refinement, clonal assessment, rational combinations, and randomized validation. The lesson shared with CML is methodological: targets must be linked to reproducible endpoints, and promising biological activity must ultimately improve outcomes that are meaningful to patients.

7. Unanswered Questions and Future Directions

The contributions to this Memorial Issue define an agenda for the next phase of CML research. First, treatment selection must become more individualized. Molecular risk, additional cytogenetic abnormalities, BCR::ABL1 kinase-domain mutations, comorbidity, age, lifestyle, pregnancy plans, access, and patient goals should guide not only which TKI is used but also the dose and sequence. Asciminib introduces a new mechanism and may alter first-line practice, but comparative effectiveness, late safety, cost-effectiveness, and its ability to increase successful TFR require longer observation.

Second, TFR should evolve from eligibility criteria based mainly on the time and depth of response toward validated estimates of individual probability. More-sensitive molecular assays, kinetics of residual disease, immune profiles, leukemic-stem-cell biology, and host factors may each contribute, but no marker should be adopted without demonstrating incremental clinical value. Standardization must precede routine use, and any discontinuation program must guarantee rapid, high-quality molecular monitoring.

Third, long-term toxicity and survivorship deserve the same scientific rigor previously devoted to response. Cardiovascular events, renal and metabolic effects, fatigue, neurocognitive symptoms, sexual and reproductive health, and treatment burden are not secondary outcomes in a disease with near-normal survival. Pediatric CML makes this especially clear, but the principle applies across the lifespan. Patient-reported outcomes and quality-adjusted survival should be incorporated into trials and registries.

Fourth, advanced-phase and multiresistant CML remain areas with unmet needs. Integrated genomic studies are required to understand progression beyond BCR::ABL1, identify lineage-specific vulnerabilities, and determine which combinations can achieve transplantable remission. Early referral for HCT assessment, rather than referral only after all pharmacological options have been exhausted, should be evaluated within explicit risk-based pathways. Prospective studies are also needed to define post-HCT molecular interventions.

Finally, innovation must be judged at the population level. International standards were central to Baccarani’s work, making results comparable across centers and countries. The same collaborative logic should now extend to access, outcome reporting, survivorship, and health system performance. High-quality registries, interoperable molecular data, and partnerships that include resource-constrained settings are essential if the therapeutic revolution is to be complete.

8. Conclusions: A Legacy That Continues to Evolve

This Memorial Issue shows that the success of CML therapy has not brought the field to an endpoint: it has moved the endpoint. Survival remains fundamental, but it is now accompanied by the possibility of treatment-free living, the obligation to prevent late toxicity, the challenge of caring for children over decades, the need to recognize when transplantation offers the best chance of cure, and the responsibility to ensure that advances reach patients outside specialized trials.

Michele Baccarani helped establish the intellectual and organizational framework that made this evolution possible. His legacy resides in specific recommendations and response definitions, but even more in the way of practicing hematology: collaborative, quantitative, critical, and willing to revise accepted standards when new evidence emerges. The ultimate measure of progress in CML is no longer limited to the depth of molecular response but now includes the ability to translate that response into a longer, safer, treatment-free, and more equitable life. Continuing to pursue that objective may be the most meaningful tribute to his work.