Asciminib monotherapy in patients with chronic-phase chronic myeloid leukemia with the T315I mutation after ≥1 prior tyrosine kinase inhibitor: 2-year follow-up results.

Asciminib targets the BCR::ABL1 myristoyl pocket, maintaining activity against BCR::ABL1T315I, which is resistant to most approved adenosine triphosphate-competitive tyrosine kinase inhibitors. We report updated phase I results (NCT02081378) assessing safety/tolerability and antileukemic activity of asciminib monotherapy 200 mg twice daily in 48 heavily pretreated patients with T315I-mutated chronic-phase chronic myeloid leukemia (CML-CP; data cutoff: January 6, 2021). With 2 years' median exposure, 56.3% of patients continued receiving asciminib. Overall, 62.2% of evaluable patients achieved BCR::ABL1 ≤1% on the International Scale (IS); 47.6% and 81.3% of ponatinib-pretreated and -naive patients, respectively, achieved BCR::ABL1IS ≤1%. Of 45 evaluable patients, 48.9% achieved a major molecular response (MMR, BCR::ABL1IS ≤0.1%), including 34.6% and 68.4% of ponatinib-pretreated and -naive patients, respectively. MMR was maintained until data cutoff in 19 of 22 patients who achieved it. The most common grade ≥3 adverse events (AEs) included increased lipase level (18.8%) and thrombocytopenia (14.6%). Five (10.4%) patients experienced AEs leading to discontinuation, including 2 who discontinued asciminib and died due to COVID-19; these were the only deaths reported. These results show asciminib's effectiveness, including in almost 50% of ponatinib pretreated patients, and confirm its risk-benefit profile, supporting its use as a treatment option for T315I-mutated CML-CP.

European Stop Tyrosine Kinase Inhibitor Trial (EURO-SKI) in Chronic Myeloid Leukemia: Final Analysis and Novel Prognostic Factors for Treatment-Free Remission.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The European Stop Kinase Inhibitors (EURO-SKI) study is the largest clinical trial for investigating the cessation of tyrosine kinase inhibitors (TKIs) in patients with chronic myeloid leukemia in stable deep molecular remission (DMR). Among 728 patients, 434 patients (61%; 95% CI, 57 to 64) remained in major molecular response (MMR) at 6 months and 309 patients of 678 (46%; 95% CI, 42 to 49) at 36 months. Duration of TKI treatment and DMR before TKI stop were confirmed as significant factors for the prediction of MMR loss at 6 months. In addition, the type of BCR::ABL1 transcript was identified as a prognostic factor. For late MMR losses after 6 months, TKI treatment duration, percentage of blasts in peripheral blood, and platelet count at diagnosis were significant factors in multivariate analysis. For the entire study period of 36 months, multiple logistic regression models confirmed duration of treatment, blasts, and transcript type as independent factors for MMR maintenance. In addition to the duration of treatment, transcript type as well as blasts in peripheral blood at diagnosis should be considered as important factors to predict treatment-free remission.

Treatment-free remission after a second TKI discontinuation attempt in patients with Chronic Myeloid Leukemia re-treated with dasatinib - interim results from the DAstop2 trial.

Tyrosine kinase inhibitor (TKI) discontinuation in chronic myeloid leukemia (CML) has become part of routine care for patients with a sustained deep molecular response (DMR). Approximately 50% experience a molecular relapse upon TKI cessation. Most of them quickly regain DMR upon TKI resumption. Whether these patients can achieve a second treatment-free remission (TFR) remains unclear. DAstop2 (ClinicalTrials.gov ID: NCT03573596) is a prospective study including patients with a failed first TFR attempt re-treated with any TKI for ≥ one year. Upon entering the study, patients received the TKI dasatinib for additional two years. Patients with sustained DMR for ≥1 year qualified for a second TKI stop. Ninety-four patients were included between Oct 2017-Dec 2021. At the time of data analysis, 62 patients had attempted a 2nd stop. After a median follow-up of 27 months from 2nd stop, TFR rates were 61, 56 and 46% at 6, 12 and 24 months respectively. No progression to advanced stage disease was seen and 87% had re-achieved MR4 within a median of 3 months from TKI re-initiation. In summary, we show that a 2nd TFR attempt after dasatinib treatment is safe, feasible and TFR rates seem in the range of those reported in trials of a first TKI stop.

Impact of hemodilution on flow cytometry based measurable residual disease assessment in acute myeloid leukemia.

Measurable residual disease (MRD) measured in the bone marrow (BM) of acute myeloid leukemia (AML) patients after induction chemotherapy is an established prognostic factor. Hemodilution, stemming from peripheral blood (PB) mixing within BM during aspiration, can yield false-negative MRD results. We prospectively examined hemodilution by measuring MRD in BM aspirates obtained from three consecutive 2 mL pulls, along with PB samples. Our results demonstrated a significant decrease in MRD percentages between the first and second pulls (P = 0.025) and between the second and third pulls (P = 0.025), highlighting the impact of hemodilution. Initially, 39% of MRD levels (18/46 leukemia-associated immunophenotypes) exceeded the 0.1% cut-off, decreasing to 30% (14/46) in the third pull. Additionally, we assessed the performance of six published methods and parameters for distinguishing BM from PB samples, addressing or compensating for hemodilution. The most promising results relied on the percentages of CD16dim granulocytic population (scarce in BM) and CD117high mast cells (exclusive to BM). Our findings highlight the importance of estimating hemodilution in MRD assessment to qualify MRD results, particularly near the common 0.1% cut-off. To avoid false-negative results by hemodilution, it is essential to collect high-quality BM aspirations and preferably utilizing the initial pull for MRD testing.

Phase Ib study of sabatolimab (MBG453), a novel immunotherapy targeting TIM-3 antibody, in combination with decitabine or azacitidine in high- or very high-risk myelodysplastic syndromes.

The safety and efficacy of sabatolimab, a novel immunotherapy targeting T-cell immunoglobulin domain and mucin domain-3 (TIM-3), was assessed in combination with hypomethylating agents (HMAs) in patients with HMA-naive revised International Prognostic System Score (IPSS-R) high- or very high-risk myelodysplastic syndromes (HR/vHR-MDS) or chronic myelomonocytic leukemia (CMML). Sabatolimab + HMA had a safety profile similar to that reported for HMA alone and demonstrated durable clinical responses in patients with HR/vHR-MDS. These results support the ongoing evaluation of sabatolimab-based combination therapy in MDS, CMML, and acute myeloid leukemia.

Transporter-Mediated Cellular Distribution of Tyrosine Kinase Inhibitors as a Potential Resistance Mechanism in Chronic Myeloid Leukemia.

Chronic myeloid leukemia (CML) is a hematologic neoplasm characterized by the expression of the BCR::ABL1 oncoprotein, a constitutively active tyrosine kinase, resulting in uncontrolled growth and proliferation of cells in the myeloid lineage. Targeted therapy using tyrosine kinase inhibitors (TKIs) such as imatinib, nilotinib, dasatinib, bosutinib, ponatinib and asciminib has drastically improved the life expectancy of CML patients. However, treatment resistance occurs in 10-20% of CML patients, which is a multifactorial problem that is only partially clarified by the presence of TKI inactivating BCR::ABL1 mutations. It may also be a consequence of a reduction in cytosolic TKI concentrations in the target cells due to transporter-mediated cellular distribution. This review focuses on drug-transporting proteins in stem cells and progenitor cells involved in the distribution of TKIs approved for the treatment of CML. Special attention will be given to ATP-binding cassette transporters expressed in lysosomes, which may facilitate the extracytosolic sequestration of these compounds.

A Digital Gaming Intervention to Strengthen the Social Networks of Older Dutch Adults: Mixed Methods Process Evaluation of a Digitally Conducted Randomized Controlled Trial.

BACKGROUND: Digital loneliness interventions for older adults are promising, yet conclusive evidence is lacking due to a lack of randomized controlled trials (RCTs) and difficulties with recruitment. Process evaluation of performed RCTs is essential to inform future interventions. Still, it is rarely carried out, resulting in an overly optimistic view of the impact of eHealth interventions on loneliness in older adults and options to conduct such research entirely remotely. OBJECTIVE: We describe a mixed methods process evaluation of a digitally conducted RCT assessing the effectiveness of a mobile social gaming app to facilitate meaningful social interactions in older adults. METHODS: We analyzed the questionnaire and game data of the RCT participants to evaluate recruitment and onboarding, intervention adherence, and intervention acceptability. The RCT participants were allocated either to the main group of older adults (aged 65 years or older) or the side group (aged between 18 and 64 years). The side group used networking to play with the older adults. We also conducted 6 post-RCT evaluation interviews and 1 focus group with a total of 4 RCT participants and 5 welfare organization representatives that aided in RCT recruitment. RESULTS: In total, 371 people aged 18 years or older signed up for the RCT, of which 64% (238/371) were aged 65 years or older. Of the total sample, 20% (76/371) installed the app and signed informed consent, showing a large dropout during onboarding. The high number of questions was a relevant barrier for participants. Both questionnaire and gameplay adherence were low. Participants indicated that the games elicited contact and a feeling of togetherness and proposed challenging and competitive games with increasing difficulty levels. They suggested focusing on enjoying the games rather than administering questionnaires. CONCLUSIONS: Conducting a remote digital trial of a social gaming intervention for older adults is a great challenge. Remote recruitment and informed consent acquisition may often not result in sufficient participation. Personal engagement with fellow participants and researchers might be essential for adherence and enjoyment. Future digital gaming interventions should start with small-scale studies with in-person contact, repeated instructions, and fewer questionnaires.

BCR::ABL1 kinase domain mutation testing and clinical outcome in a nationwide chronic myeloid leukemia patient population.

OBJECTIVES: Acquired missense mutations in the BCR::ABL1 kinase domain (KD) may cause tyrosine kinase inhibitor (TKI) treatment failure. Based on mutation-specific in vitro derived IC50-values, alternative TKI may be selected. We assessed clinical practice of BCR::ABL1 KD mutation testing, clinical response in relation to IC50-values, and clinical outcome of tested patients. METHODS: Patients from six Dutch CML reference centers and a national registry were included once a mutational analysis was performed. Reasons for testing were categorized as suboptimal TKI response, and primary or secondary TKI resistance. RESULTS: Four hundred twenty analyses were performed in 275 patients. Sixty-nine patients harbored at least one mutation. Most analyses were performed because of suboptimal TKI response but with low mutation incidence (4%), while most mutations were found in primary and secondary resistant patients (21% and 51%, respectively). Harboring a BCR::ABL1 mutation was associated with inferior overall survival (HR 3.2 [95% CI, 1.7-6.1; p < .001]). Clinically observed responses to TKI usually corresponded with the predicted TKI sensitivity based on the IC50-values, but a high IC50-value did not preclude a good clinical response per se. CONCLUSIONS: We recommend BCR::ABL1 KD mutation testing in particular in the context of primary or secondary resistance. IC50-values can direct the TKI choice for CML patients, but clinical efficacy can be seen despite adverse in vitro resistance.

Measuring chronic myeloid leukaemia TKI-related toxic effects in the real world: a systematic review and critical assessment of content validity of patient-reported outcome measures.

Insight into real-world treatment-related toxic effects reported by patients has the potential to improve care, benchmark trials, and fill knowledge gaps, especially in patients with chronic myeloid leukaemia, which is treated in the majority of patients continually with tyrosine-kinase inhibitors (TKIs). The aim of our systematic review was to investigate the content validity of instruments that elicit TKI-related toxic effects reported by patients with chronic myeloid leukaemia in the real world. We searched PubMed and Embase from Jan 1, 2017 to Oct 21, 2022. Studies on instruments used in or developed for patients with chronic myeloid leukaemia that assess a patient's symptoms were eligible. Content validity was assessed according to the Consensus-Based Standards for the Selection of Health Measurement Instruments (COSMIN): none of the six identified instruments were rated as sufficient. Five instruments (European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire for chronic myeloid leukaemia with 24 items [EORTC QLQ-CML24], EORTC symptom set, Functional Assessment of Cancer Therapy-Leukaemia [FACT-LEU], haematological malignancies patient-reported outcomes [HM-PRO], and MD Anderson Symptom Inventory for chronic myeloid leukaemia [MDASI-CML]) were rated as inconsistent due to not being evaluated by professionals post-development, having very few patients with chronic myeloid leukaemia involved, or missing key symptoms. Moderate-quality to very low-quality evidence underpinned these ratings. The two EORTC instruments were the only ones not to miss key toxic effects (eg, muscle cramps). However, their relevance was rated as inconsistent: the QLQ-CML24 includes questions on health-related quality-of-life, whereas the symptom set includes items sourced from solid cancer treatments. This Review shows the need for an instrument with sufficient content validity to measure toxic effects from TKI treatment in patients with chronic myeloid leukaemia. Until then, stakeholders can make an informed choice from currently used instruments with our assessment.

ATG versus PTCy in matched unrelated donor haematopoietic stem cell transplantations with non-myeloablative conditioning.

Graft-versus-host disease (GvHD) is a serious complication of allogeneic haematopoietic stem cell transplantation (HSCT). Both anti-thymocyte globulin (ATG) and post-transplant cyclophosphamide (PTCy) are used as lymphocyte-depleting strategies, yet a systematic comparison of transplantation outcomes between these two methods in matched unrelated donors (MUD) transplantations with non-myeloablative conditioning (NMC) is lacking. Adult patients with haematological malignancies who had undergone MUD HSCT with NMC regimens between 2014 and 2021 at 2 centres in Amsterdam (ATG: n = 95, PTCy: n = 90), were included in this retrospective study. Patient characteristics were comparable between the groups. The cumulative incidence of acute GvHD grade II-IV was 48% in the ATG group compared to 21% in the PTCy group (p < 0.001). The 3-year moderate/severe chronic GvHD was similar in both groups (p = 0.69). While the relapse rate was comparable between the groups (ATG 31% vs. PTCy 34%, p = 0.94), non-relapse mortality tended to be higher in the ATG group (17% vs. 9%, p = 0.069). Overall survival was similar in both groups (p = 0.12). In conclusion, PTCy-based regimens resulted in a significantly lower rate of acute GvHD than ATG-containing regimens in MUD transplantations with NMC. Whether PTCy results in improved overall survival as compared to ATG needs to be elucidated in larger prospective studies.

Team- and task-related knowledge in shared mental models in operating room teams: A survey study.

Objective: The operating room is a highly complex environment, where patient care is delivered by interprofessional teams. Unfortunately, issues with communication and teamwork occur, potentially leading to patient harm. A shared mental model is one prerequisite to function effectively as a team, and consists of task- and team-related knowledge. We aimed to explore potential differences in task- and team-related knowledge between the different professions working in the operating room. The assessed team-related knowledge consisted of knowledge regarding other professions' training and work activities, and of perceived traits of a high-performing and underperforming colleague. Task-related knowledge was assessed by mapping the perceived allocation of responsibilities for certain tasks, using a Likert-type scale. Design: A single sample cross-sectional study. Setting: The study was performed in three hospitals in the Netherlands, one academic center and two regional teaching hospitals. Participants: 106 health care professionals participated, of four professions. Most respondents (77%) were certified professionals, the others were still in training. Results: Participants generally were well informed about each other's training and work activities and nearly everyone mentioned the importance of adequate communication and teamwork. Discrepancies were also observed. The other professions knew on average the least about the profession of anesthesiologists and most about the profession of surgeons. When assessing the responsibilities regarding tasks we found consensus in well-defined and/or protocolized tasks, but variation in less clearly defined tasks. Conclusions: Team- and task-related knowledge in the operating room team is reasonably well developed, but irregularly, with potentially crucial differences in knowledge related to patient care. Awareness of these discrepancies is the first step in further optimization of team performance.

Switching from imatinib to nilotinib plus pegylated interferon-α2b in chronic phase CML failing to achieve deep molecular response: clinical and immunological effects.

In order to improve molecular response for a discontinuation attempt in chronic myeloid leukemia (CML) patients in chronic phase, who had not achieved at least a molecular response <0.01% BCR-ABL1IS (MR4.0) after at least 2 years of imatinib therapy, we prospectively evaluated whether they could attain MR4.0 after a switch to a combination of nilotinib and 9 months of pegylated interferon-α2b (PegIFN). The primary endpoint of confirmed MR4.0 at month 12 (a BCR-ABL1IS level ≤ 0.01% both at 12 and 15 months) was reached by 44% (7/16 patients, 95% confidence interval (CI): 23- 67%) of patients, with 81% (13/16 patients, 95% CI: 57-93%) of patients achieving an unconfirmed MR4.0. The scheduled combination was completed by 56% of the patients, with premature discontinuations, mainly due to mood disturbances after the introduction of PegIFN, questioning the feasibility of the combination of nilotinib and PegIFN for this patient population and treatment goal. A comprehensive clinical substudy program was implemented to characterize the impact of the treatment changes on the immunological profile. This trial was registered at www.clinicaltrials.gov as #NCT01866553.

Clinical Impact of Polymerase Chain Reaction-Based Aspergillus and Azole Resistance Detection in Invasive Aspergillosis: A Prospective Multicenter Study.

BACKGROUND: Invasive aspergillosis (IA) by a triazole-resistant Aspergillus fumigatus is associated with high mortality. Real-time resistance detection will result in earlier initiation of appropriate therapy. METHODS: In a prospective study, we evaluated the clinical value of the AsperGenius polymerase chain reaction (PCR) assay in hematology patients from 12 centers. This PCR assay detects the most frequent cyp51A mutations in A. fumigatus conferring azole resistance. Patients were included when a computed tomography scan showed a pulmonary infiltrate and bronchoalveolar fluid (BALf) sampling was performed. The primary end point was antifungal treatment failure in patients with azole-resistant IA. RESULTS: Of 323 patients enrolled, complete mycological and radiological information was available for 276 (94%), and probable IA was diagnosed in 99/276 (36%). Sufficient BALf for PCR testing was available for 293/323 (91%). Aspergillus DNA was detected in 116/293 (40%) and A. fumigatus DNA in 89/293 (30%). The resistance PCR was conclusive in 58/89 (65%) and resistance detected in 8/58 (14%). Two had a mixed azole-susceptible/azole-resistant infection. In the 6 remaining patients, treatment failure was observed in 1. Galactomannan positivity was associated with mortality (P = .004) while an isolated positive Aspergillus PCR was not (P = .83). CONCLUSIONS: Real-time PCR-based resistance testing may help to limit the clinical impact of triazole resistance. In contrast, the clinical impact of an isolated positive Aspergillus PCR on BALf seems limited. The interpretation of the EORTC/MSGERC PCR criterion for BALf may need further specification (eg, minimum cycle threshold value and/or PCR positive on >1 BALf sample).

Asciminib monotherapy in patients with CML-CP without BCR::ABL1 T315I mutations treated with at least two prior TKIs: 4-year phase 1 safety and efficacy results.

Asciminib is approved for patients with Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia (CML-CP) who received ≥2 prior tyrosine kinase inhibitors or have the T315I mutation. We report updated results of a phase 1, open-label, nonrandomized trial (NCT02081378) assessing the safety, tolerability, and antileukemic activity of asciminib monotherapy 10-200 mg once or twice daily in 115 patients with CML-CP without T315I (data cutoff: January 6, 2021). After ≈4-year median exposure, 69.6% of patients remained on asciminib. The most common grade ≥3 adverse events (AEs) included increased pancreatic enzymes (22.6%), thrombocytopenia (13.9%), hypertension (13.0%), and neutropenia (12.2%); all-grade AEs (mostly grade 1/2) included musculoskeletal pain (59.1%), upper respiratory tract infection (41.7%), and fatigue (40.9%). Clinical pancreatitis and arterial occlusive events (AOEs) occurred in 7.0% and 8.7%, respectively. Most AEs occurred during year 1; the subsequent likelihood of new events, including AOEs, was low. By data cutoff, among patients without the indicated response at baseline, 61.3% achieved BCR::ABL1 ≤ 1%, 61.6% achieved ≤0.1% (major molecular response [MMR]), and 33.7% achieved ≤0.01% on the International Scale. MMR was maintained in 48/53 patients who achieved it and 19/20 who were in MMR at screening, supporting the long-term safety and efficacy of asciminib in this population.

Construct Validation of the Rainbow Model of Integrated Care Measurement Tool in Dutch Primary Care for Older Adults.

Introduction: Care integration in primary elderly care is suboptimal. Validated instruments are needed to enable the implementation of integrated primary care. We aimed to assess construct validity of the Rainbow Model of Integrated Care measurement tool (RMIC-MT) for healthcare professionals working in an integrated primary elderly care setting in the Netherlands. Methods: In a cross-sectional study, the RMIC-MT, a 36-item questionnaire covering all domains of the Rainbow Model of Integrated Care (RMIC), was sent out to local networks of primary elderly care professionals. Confirmatory factor analysis with maximum likelihood estimation was used for the validation of the factor structure of the RMIC-MT. Model fit was assessed by the chi-square test and fit indices. Results: The RMIC-MT was completed by 323 professionals, primarily general practitioners, community nurses, practice nurses, and case managers. Confirmatory factor analysis and corresponding fit indices showed moderate to good fit, thereby confirming a nine factor model with a total of 36 items. Conclusions: The RMIC-MT is promising for the primary elderly care setting in the Netherlands. It can be used for evaluating integrated care initiatives in a primary care setting, thereby contributing to implementation of integrated primary elderly care.

The effectiveness of Collaborative Online International Learning (COIL) on intercultural competence development in higher education.

In this study we measured the effect of COIL on intercultural competence development using a quasi-experimental design. Our sample consisted of 108 undergraduate students from two universities, one located in the Netherlands (NL) and one in the United States (US). Students' self-reported intercultural competence was measured using a pre-post survey which included the Cultural Intelligence Scale (CQS) and Multicultural Personality Questionnaire (MPQ). Qualitative data were collected to complement our quantitative findings and to give a deeper insight into the student experience. The data showed a significantly bigger increase in intercultural competence for the US experimental group compared to the US control group, supporting our hypothesis that COIL develops intercultural competence. This difference was not observed for the NL students, possibly due to the NL control group being exposed to other international input during the course. Supplementary Information: The online version contains supplementary material available at 10.1186/s41239-022-00373-3.