The study, led by Shira Buchrits and colleagues at the Institute of Hematology at the Davidoff Cancer Center, Rabin Medical Center, in collaboration with the Israeli CML Patients’ Organization, recruited 233 adults with CML. To be eligible, participants had to have received tyrosine kinase inhibitor therapy for at least three months, or to have discontinued therapy at least three months before taking part. Each participant completed validated Hebrew versions of two widely used patient-reported outcome instruments: the EORTC QLQ-C30, a general cancer quality-of-life questionnaire, and the QLQ-CML24, a disease-specific module designed to capture the symptoms and concerns unique to living with CML and its treatment.

The researchers divided participants into clinically meaningful groups reflecting the current therapeutic landscape: patients in treatment-free remission, those on first-generation TKIs such as imatinib, those on second-generation TKIs such as dasatinib and nilotinib, those on third-generation agents, and those receiving asciminib, a newer molecule that targets a distinct pocket of the BCR-ABL fusion protein. This grouping matters because the drugs differ substantially in their side-effect profiles. First-generation imatinib is associated with fluid retention, muscle cramps, and gastrointestinal upset; second-generation agents can produce fatigue, cardiovascular events, and metabolic changes; asciminib was designed with improved selectivity in the hope of reducing off-target toxicity.

The headline finding is reassuring: global health-related quality of life was generally preserved across all treatment groups. In other words, most people living with CML in Israel report an overall quality of life that remains intact regardless of which TKI they take or whether they have stopped treatment entirely. Treatment satisfaction and social functioning also remained high across the cohort, suggesting that the day-to-day social and practical lives of patients are largely unaffected by their treatment status. This is a striking testament to how far CML care has come since the pre-TKI era, when the disease carried a median survival of only a few years.

Beneath that reassuring surface, however, the survey revealed clinically meaningful differences in symptom burden between groups. Patients receiving second-generation TKIs reported a greater symptom burden in selected domains, including fatigue and gastrointestinal symptoms, compared with patients in treatment-free remission and those in other treatment groups. Mood disturbance also differed significantly across treatment groups, with numerically higher scores among patients taking second-generation agents. These are not trivial complaints. Fatigue in particular is one of the most commonly reported and most disabling symptoms among CML patients on long-term therapy, and it can erode work capacity, exercise tolerance, and social participation even when blood counts are perfectly controlled.

At the opposite end of the spectrum stood two groups: patients in treatment-free remission and those receiving asciminib. Both consistently reported lower symptom burden and more favorable quality-of-life profiles. For patients in treatment-free remission, the finding is intuitive but important to document. Treatment-free remission, in which patients with sustained deep molecular response stop their TKI under close molecular monitoring, has become an achievable goal for a substantial minority of patients since large stopping studies demonstrated its feasibility. The new data confirm that successful discontinuation is associated with a real and measurable improvement in how patients feel, not merely with freedom from the cost and inconvenience of daily pills.

The favorable profile of asciminib is perhaps the more novel observation. Asciminib works through allosteric binding to the myristoyl pocket of the BCR-ABL kinase, a mechanism distinct from the ATP-binding site targeted by all earlier TKIs. This selectivity was expected to translate into fewer off-target effects, and the new survey provides patient-reported evidence consistent with that expectation in a real-world setting. Because asciminib is often prescribed precisely for patients who have experienced intolerance or resistance to earlier agents, the fact that these patients report low symptom burden is notable, although the cross-sectional design means that differences in who receives which drug could influence the comparison.

That caveat points to the broader interpretive limits of the study. As a cross-sectional survey, it captures a snapshot rather than a trajectory, and patients are not randomized to treatment groups. Patients on later-generation drugs may have more resistant disease or more prior toxicity, which could color their self-reported experience. Nevertheless, the nationwide scope of the survey, its partnership with the national patient organization, and its use of validated instruments in the patients’ native language give the findings a credibility that smaller, single-center studies often lack. The study was approved by the Institutional Review Board of Rabin Medical Center and conducted in accordance with the Declaration of Helsinki.

The clinical implications are straightforward. As the authors emphasize, the results underscore the importance of integrating patient-reported outcomes into individualized therapeutic decision-making in modern CML care. With several TKIs now available, each with comparable efficacy in many settings, the choice among them increasingly hinges on tolerability, comorbidities, and patient preference. Systematic collection of patient-reported outcomes can make those conversations concrete, revealing fatigue, gastrointestinal symptoms, or mood disturbance that might otherwise go unmentioned in a brief clinic visit focused on molecular response levels.

For patients, the message is equally clear. Living well with CML is now the norm, not the exception, and feeling unwell on treatment should prompt a conversation rather than quiet endurance. Whether through switching to a better-tolerated agent such as asciminib, or through a carefully monitored attempt at treatment-free remission for those with deep sustained responses, the therapeutic toolkit now offers multiple paths to not only controlling the leukemia but also minimizing its footprint on daily life. This study adds real-world, patient-voiced evidence that those paths lead to measurably different experiences, and that the goal of CML medicine has genuinely moved beyond disease control.

Subject of Research: Health-related quality of life across tyrosine kinase inhibitors and treatment-free remission in chronic myeloid leukemia

Article Title: Beyond disease control in chronic myeloid leukemia: Real-world quality of life across TKIs and treatment-free remission

Article References: Buchrits, S., Sharf, G., Raanani, P., & Abulafia, A. S. (2026). Beyond disease control in chronic myeloid leukemia: Real-world quality of life across TKIs and treatment-free remission. Annals of Hematology. https://doi.org/10.1007/s00277-026-07298-1

Image Credits: AI Generated

DOI: 10.1007/s00277-026-07298-1

Keywords: chronic myeloid leukemia, tyrosine kinase inhibitors, quality of life, patient-reported outcomes, treatment-free remission, asciminib, fatigue, EORTC QLQ-C30, QLQ-CML24, hematology, drug tolerability, molecular response

The study, led by Gianni Binotto of the University of Padova and Carmen Fava of the University of Turin, together with colleagues from major Italian haematology centres in Milan, Turin, Bari, Pavia and Bologna, focused on six adult patients with Philadelphia chromosome–positive chronic myeloid leukaemia in chronic phase. This form of leukaemia is defined by a characteristic genetic swap between chromosomes 9 and 22, which creates the BCR-ABL1 fusion gene encoding a constitutively active tyrosine kinase. It is this rogue enzyme that tyrosine kinase inhibitors are designed to block, and the Philadelphia chromosome serves as the molecular fingerprint of the disease. All six patients in the series had already been exposed to at least two prior tyrosine kinase inhibitors and had either become resistant to them or suffered intolerable side effects, placing them among the most challenging cases that clinicians encounter in routine practice.

What set these patients apart was not only their treatment history but their overall health profile. The cohort carried a substantial burden of comorbidities, predominantly cardiovascular in nature. Hypertension, peripheral arterial disease, ischaemic heart disease and metabolic disorders featured prominently among their conditions. This detail matters because several first- and second-generation tyrosine kinase inhibitors, notably nilotinib and ponatinib, have been associated with arterial occlusive events, including heart attacks, strokes and peripheral vascular complications. For patients whose blood cancer is under control but whose arteries are compromised, the choice of therapy becomes a delicate balancing act between suppressing the leukaemia and protecting the cardiovascular system. Asciminib, with its distinctive mechanism of action, has been proposed as a particularly attractive option for exactly this population.

The reason lies in the drug’s unusual binding mode. Whereas earlier tyrosine kinase inhibitors target the ATP-binding site of the ABL1 kinase, asciminib selectively targets the myristoyl pocket, a regulatory region of the protein that is otherwise not exploited by any other approved drug in the class. This allosteric mechanism gives asciminib high specificity for its target and is thought to underpin its potentially improved safety profile. Because the myristoyl pocket is a distinct structural feature of ABL1, the drug can remain active against certain mutations that confer resistance to ATP-site competitors. Among these is the notorious T315I mutation, often described as the most formidable resistance mutation in chronic myeloid leukaemia, which has historically limited treatment options dramatically. Asciminib’s efficacy has been demonstrated in both clinical trials and real-world settings, including heavily pretreated patients and those carrying the T315I mutation, making it a valuable addition to the therapeutic arsenal.

In the Italian case series, asciminib was administered for a median duration of 16.5 months, providing a meaningful window in which to observe both efficacy and tolerability. The results were strikingly consistent. All six patients achieved or maintained clinically meaningful molecular responses, including major molecular responses and deep molecular responses. These endpoints are measured by tracking the level of BCR-ABL1 transcript in the blood using sensitive polymerase chain reaction assays, and deeper responses correlate with better long-term outcomes and, in some cases, the possibility of treatment-free remission. For patients who had already cycled through multiple therapies without success, the ability of asciminib to induce or sustain such responses represents a significant clinical benefit.

Equally important was the drug’s tolerability. Treatment was well tolerated across the cohort, with no discontinuations due to adverse events. No arterial occlusive events were observed, and no significant cardiovascular worsening occurred during the observation period. This is a notable finding given the cardiovascular vulnerability of the patients involved. Even more remarkably, no haematologic toxicity was recorded, even in a patient with underlying bone marrow hypoplasia, a condition in which the bone marrow’s capacity to produce blood cells is already diminished. Myelosuppression is a common concern with many anticancer therapies, and the absence of this toxicity in a compromised patient suggests that asciminib’s high target specificity translates into a genuinely gentler profile at the level of normal blood-forming tissue.

The authors are careful to frame these observations appropriately. With only six patients, the series cannot deliver the statistical power of a randomised trial, and the findings are presented as a summary of the drug’s clinical data alongside real-world experience rather than as definitive evidence. Nevertheless, the study argues that real-world data of this kind play an essential role in supporting treatment decisions, because patients seen in everyday practice are often older, more comorbid and more heavily pretreated than those enrolled in pivotal clinical trials. Regulatory trials typically exclude individuals with uncontrolled hypertension, prior arterial events or reduced bone marrow reserve, precisely the characteristics that defined this Italian cohort. Demonstrating that asciminib can be used safely and effectively in such patients fills an important evidence gap that trial data alone cannot address.

The broader context of chronic myeloid leukaemia treatment makes these findings resonate. Since the introduction of imatinib at the turn of the millennium, survival in chronic myeloid leukaemia has risen to near-normal life expectancy for many patients, turning a fatal disease into a chronic condition managed with daily oral therapy. But this success has created its own challenges: patients now live for decades with their disease and their medication, so long-term tolerability, cardiovascular safety and quality of life have become central concerns. Second-generation inhibitors improved response rates but introduced new toxicity profiles, and resistance mutations continue to emerge. Drugs that combine deep molecular activity with a favourable cardiovascular and haematologic safety profile address the most pressing unmet needs in the field, particularly for the growing population of long-term survivors with age-related comorbidities.

Asciminib’s allosteric mechanism also represents a conceptual milestone in targeted cancer therapy. Rather than competing with ATP at the active site, the drug locks the kinase into its inactive conformation by engaging a pocket used naturally by the protein’s own regulatory lipid, myristate. This approach, sometimes described as a STAMP inhibitor, an acronym for specifically targeting the ABL myristoyl pocket, illustrates how structural biology can be exploited to design molecules with exquisite selectivity. The Italian case series adds a practical, bedside-level dimension to this molecular story, showing that the elegance of the mechanism is reflected in clinical outcomes for patients who have few alternatives left.

For clinicians managing chronic myeloid leukaemia, the message from this small study is one of cautious encouragement. In a real-world cohort of heavily pretreated patients with substantial comorbidity burden, asciminib demonstrated sustained efficacy and a favourable safety profile, with cardiovascular tolerability standing out as a particular strength. The authors conclude that these findings reinforce the potential role of asciminib for patients with resistance or intolerance to multiple tyrosine kinase inhibitors, as well as for those at high cardiovascular risk. As more real-world data accumulate across centres and countries, the picture of who benefits most from this allosteric inhibitor will continue to sharpen, helping physicians tailor therapy to the individual patient rather than to the average trial participant. For the six Italian patients documented here, and for the many others like them worldwide, that individualisation may make all the difference between merely surviving with leukaemia and truly living well with it.

Subject of Research: Real-world efficacy and safety of the allosteric BCR-ABL1 inhibitor asciminib in heavily pretreated chronic myeloid leukaemia patients

Article Title: Real-world Italian experience with asciminib in chronic myeloid leukaemia–chronic phase: case series and drug profile overview

Article References: Binotto, G., Cattaneo, D., Di Biase, F., Ditonno, P., Elena, C., Restuccia, R., & Fava, C. (2026). Real-world Italian experience with asciminib in chronic myeloid leukaemia–chronic phase: case series and drug profile overview. Annals of Hematology. https://doi.org/10.1007/s00277-026-07284-7

Image Credits: AI Generated

DOI: 10.1007/s00277-026-07284-7

Keywords: asciminib, chronic myeloid leukaemia, tyrosine kinase inhibitors, BCR-ABL1, myristoyl pocket, cardiovascular safety, molecular response, T315I mutation, real-world evidence, haematology, drug resistance, Annals of Hematology

The myeloproliferative neoplasms encompass essential thrombocythaemia, polycythaemia vera, prefibrotic primary myelofibrosis, and overt primary myelofibrosis, all disorders driven by mutated haematopoietic stem cells, most commonly carrying the JAK2V617F mutation. These conditions predispose patients to life-threatening blood clots and bleeding, and conventional cytoreductive therapy has primarily aimed at reducing this thrombotic risk. Hydroxyurea has long served as the default first-line option, yet it leaves 10 to 40 percent of patients intolerant or resistant, and lingering concerns about its long-term leukemogenic potential have fuelled the search for alternatives.

Interferon alpha occupies a fundamentally different therapeutic niche. Rather than simply poisoning dividing cells, this immunomodulating agent acts directly on haematopoietic stem and progenitor cells. Animal studies have shown that interferon alpha rouses quiescent malignant stem cells from dormancy, with a striking preference for cells carrying the JAK2V617F mutation, ultimately driving the malignant clone toward functional exhaustion. This disease-modifying potential, combined with the improved tolerability conferred by pegylation, prompted Danish investigators to design DALIAH as the earliest and largest randomised trial of long-term pegylated interferon in newly diagnosed patients across all myeloproliferative neoplasm subtypes.

Between February 2012 and July 2015, the trial enrolled 206 patients, of whom 203 formed the modified intention-to-treat population. Adults with newly diagnosed or treatment-naive disease were eligible regardless of risk score, a deliberate design choice that broadened the trial beyond the high-risk patients targeted by most prior studies. Older patients, aged over sixty, were randomised among hydroxyurea, pegylated interferon alpha-2a, or pegylated interferon alpha-2b, while younger patients avoided hydroxyurea owing to its theoretical leukemogenic risk and were randomised between the two interferon formulations. The cohort comprised 73 patients with essential thrombocythaemia, 89 with polycythaemia vera, 16 with prefibrotic myelofibrosis, and 25 with overt primary myelofibrosis. The median age was 62 years, and JAK2V617F was the dominant driver mutation, present in 74 percent of participants with a median baseline variant allele frequency of 34 percent.

The primary endpoint was the rate of molecular response, defined by European LeukemiaNet criteria as a substantial or complete reduction in the JAK2V617F variant allele frequency, measured serially by quantitative polymerase chain reaction at eight time points up to 60 months. By intention-to-treat analysis, which counted patients who discontinued treatment as non-responders, molecular response rates were statistically indistinguishable between the two drugs: 23 percent in the hydroxyurea arm versus 24 percent in the interferon arm at 60 months. This apparent parity, however, masks a profound divergence revealed when the analysis was restricted to patients who remained on their assigned therapy.

Among those who stayed the course, pegylated interferon proved decisively superior from 36 months onward. At that juncture, 56 percent of interferon-treated patients had achieved a molecular response, compared with just 23 percent of those on hydroxyurea, a gap that widened to 67 percent versus 35 percent by 60 months. Three interferon-treated patients reached complete molecular remission, with the JAK2V617F mutation rendered undetectable by an assay sensitive to 0.1 percent. Moreover, patients on hydroxyurea lost their responses far more frequently, with 62 percent losing molecular response versus only 13 percent of interferon patients, a difference that proved highly significant. The kinetics told a parallel story: the median relative reduction in variant allele frequency from baseline to 60 months was 75 percent with interferon compared with only 20 percent under hydroxyurea.

On secondary endpoints, the two drugs traded advantages. Complete clinicohaematological response at 12 months was similar between groups, and by intention-to-treat analysis hydroxyurea held a modest edge at 18 months, 58 percent versus 38 percent, though per-protocol analysis later favoured interferon at 36 and 60 months. Hydroxyurea normalised blood counts faster, with haematological response reached in a median of 1.6 months versus 3.8 months for interferon, a predictable consequence of its direct cytorepressive action. Conversely, more hydroxyurea patients lost their haematological responses over time, 86 percent compared with 44 percent on interferon. Bone marrow histopathology delivered an unexpected finding: by intention-to-treat analysis, histopathological remission at 60 months favoured hydroxyurea, 18 percent versus 5 percent, though paired analyses and per-protocol comparisons blurred this difference, and the investigators caution that fibrosis grading was inconclusive in significantly more hydroxyurea patients.

Safety data underscored the trial’s central challenge. At 60 months, 60 percent of all patients had discontinued study treatment, and discontinuation was significantly more frequent with interferon at 65 percent than with hydroxyurea at 37 percent. Toxicity drove the disparity: 45 percent of interferon patients stopped treatment for adverse events, most commonly flu-like illness, injection-site irritation, fatigue, and neuropsychiatric symptoms, while only 13 percent of hydroxyurea patients discontinued for that reason. Notably, discontinuation for toxicity clustered among younger and female patients and varied dramatically between study sites, from 30 to 69 percent, leading the authors to speculate that investigator enthusiasm may have shaped dosing decisions. Yet a subgroup of patients tolerated interferon long-term, and no treatment-related events of grade 3 or higher occurred beyond 24 months among those continuing therapy.

Thrombosis, the cardinal clinical concern in these diseases, was not prevented by interferon. Nineteen major thrombotic events occurred during treatment, with a rate of 5.5 events per 100 patient-years among older interferon patients versus 2.8 per 100 patient-years with hydroxyurea, a difference lacking statistical significance but clinically noteworthy. Importantly, 68 percent of thrombotic events occurred while blood counts remained normalised and before any substantial molecular reduction, reinforcing the multifactorial nature of clotting risk in myeloproliferative neoplasms. No patient progressed to myelofibrosis, acute myeloid leukaemia, or myelodysplastic syndrome, and five deaths were recorded across the cohort without an evident treatment-related pattern.

The DALIAH results arrive amid converging evidence that molecular response is not merely a laboratory curiosity. Data from the CONTINUATION-PV and MAJIC-PV trials link deepening JAK2V617F depletion with prolonged event-free survival, suggesting that eradicating the malignant clone may genuinely alter disease course. Within this framework, interferon’s slow but sustained molecular advantage, even as hydroxyurea’s responses eroded, positions low-dose pegylated interferon alpha-2a as a viable first-line option for carefully selected patients, particularly younger individuals in whom decades of cytoreductive therapy loom ahead. The trial’s authors call for biomarkers capable of predicting both response and tolerability at diagnosis, noting that mutated DNMT3A may confer interferon resistance. They also propose an intriguing strategy: an initial six to twelve months of combination therapy using hydroxyurea to rapidly normalise counts while interferon gradually strips away the malignant clone, followed by interferon monotherapy. With pegylated interferon alpha-2b withdrawn from the European market but alpha-2a still available and mono-pegylated ropeginterferon expanding the armamentarium, the era of disease-modifying first-line therapy for myeloproliferative neoplasms may finally be within reach.

Subject of Research: A five-year randomised phase 3 trial comparing pegylated interferon alpha with hydroxyurea as first-line cytoreductive therapy in myeloproliferative neoplasms.

Article Title: Interferon-α vs hydroxyurea in patients with myeloproliferative neoplasms (DALIAH): a multicentre, randomised, open-label, phase 3 trial in Denmark

Article References: Knudsen, T. A., Hansen, D. L., Ocias, L. F., Bjerrum, O. W., Brabrand, M., Christensen, S. F., Eickhardt-Dalbøge, C. S., Ellervik, C., El Fassi, D., Frederiksen, M., Kjær, L., Kristensen, T. K., Kruse, T. A., Larsen, M. K., Mourits-Andersen, T., Möller, S., Overgaard, U. M., Severinsen, M. T., Skov, V., … Hasselbalch, H. C. (2026). Interferon-α vs hydroxyurea in patients with myeloproliferative neoplasms (DALIAH): a multicentre, randomised, open-label, phase 3 trial in Denmark. eClinicalMedicine, 100, Article 104193. https://doi.org/10.1016/j.eclinm.2026.104193

Image Credits: AI Generated

DOI: 10.1016/j.eclinm.2026.104193

Keywords: myeloproliferative neoplasms, pegylated interferon alpha, hydroxyurea, JAK2V617F, molecular response, DALIAH trial, polycythaemia vera, essential thrombocythaemia, primary myelofibrosis, phase 3 trial, cytoreductive therapy, haematology