Patient-reported symptom monitoring and adherence to therapy in patients with newly diagnosed chronic myeloid leukemia.

BACKGROUND: The authors assessed the clinical utility of patient-reported symptom monitoring in the setting of newly diagnosed chronic myeloid leukemia (CML). The primary objective was to evaluate adherence to therapy. METHODS: The authors conducted an international prospective study that included patients with newly diagnosed, chronic-phase CML. Before clinical consultation, patients were provided a tablet computer to self-rate their symptoms, and the results were available in real time to each physician during the patient's visit. Adherence was assessed by pill count and with a validated self-reported questionnaire. The proportions of optimal responders at 3 and 6 months were assessed according to the European LeukemiaNet criteria. RESULTS: Between July 2020 and August 2021, 94 patients with a median age of 57 years were enrolled. Pill count adherence analysis indicated that 86 of 93 evaluable patients (92.5%) took at least 90% of prescribed tyrosine kinase inhibitor therapy during the 6-month observation period. The online platform was well accepted by patients and physicians. An optimal response was achieved by 69 of 79 patients (87.3%) at 3 months and by 61 of 81 patients (75.3%) at 6 months. CONCLUSIONS: Patient-reported symptom monitoring from the beginning of therapy in patients with CML may be critical to improve adherence to therapy and early molecular response rates (ClinicalTrials.gov identifier NCT04384848).

Risk of progression in chronic phase-chronic myeloid leukemia patients eligible for tyrosine kinase inhibitor discontinuation: Final analysis of the TFR-PRO study.

Disease progression to accelerated/blast phase (AP/BP) in patients with chronic phase chronic myeloid leukemia (CP-CML) after treatment discontinuation (TD) has never been systematically reported in clinical trials. However, recent reports of several such cases has raised concern. To estimate the risk of AP/BP among TD-eligible patients, we conducted TFR-PRO, a cohort retro-prospective study: 870 CP-CML patients eligible for TD formed a discontinuation cohort (505 patients) and a reference one (365 patients). The primary objective was the time adjusted rate (TAR) of progression in relation to TD. Secondary endpoints included the TAR of molecular relapse, that is, loss of major molecular response (MMR). With a median follow up of 5.5 years and 5188.2 person-years available, no events occurred in the TD cohort. One event of progression was registered 55 months after the end of TD, when the patient was contributing to the reference cohort. The TAR of progression was 0.019/100 person-years (95% CI [0.003-0.138]) in the overall group; 0.0 (95% CI [0-0.163]) in the discontinuation cohort; and 0.030 (95% CI [0.004-0.215]) in the reference cohort. These differences are not statistically significant. Molecular relapses occurred in 172/505 (34.1%) patients after TD, and in 64/365 (17.5%) patients in the reference cohort, p < .0001. Similar rates were observed in TD patients in first, second or third line of treatment. CML progression in patients eligible for TD is rare and not related to TD. Fears about the risk of disease progression among patients attempting TD should be dissipated.

Determinants of frontline tyrosine kinase inhibitor choice for patients with chronic-phase chronic myeloid leukemia: A study from the Registro Italiano LMC and Campus CML.

BACKGROUND: Imatinib, dasatinib, and nilotinib are tyrosine kinase inhibitors (TKIs) approved in Italy for frontline treatment of chronic-phase chronic myeloid leukemia (CP-CML). The choice of TKI is based on a combined evaluation of the patient's and the disease characteristics. The aim of this study was to analyze the use of frontline TKI therapy in an unselected cohort of Italian patients with CP-CML to correlate the choice with the patient's features. METHODS: A total of 1967 patients with CP-CML diagnosed between 2012 and 2019 at 36 centers throughout Italy were retrospectively evaluated; 1089 patients (55.4%) received imatinib and 878 patients (44.6%) received a second-generation (2G) TKI. RESULTS: Second-generation TKIs were chosen for most patients aged <45 years (69.2%), whereas imatinib was used in 76.7% of patients aged >65 years (p < .001). There was a predominant use of imatinib in intermediate/high European long-term survival risk patients (60.0%/66.0% vs. 49.7% in low-risk patients) and a limited use of 2G-TKIs in patients with comorbidities such as hypertension, diabetes, chronic obstructive pulmonary disease, previous neoplasms, ischemic heart disease, or stroke and in those with >3 concomitant drugs. We observed a greater use of imatinib (61.1%) in patients diagnosed in 2018-2019 compared to 2012-2017 (53.2%; p = .002). In multivariable analysis, factors correlated with imatinib use were age > 65 years, spleen size, the presence of comorbidities, and ≥3 concomitant medications. CONCLUSIONS: This observational study of almost 2000 cases of CML shows that imatinib is the frontline drug of choice in 55% of Italian patients with CP-CML, with 2G-TKIs prevalently used in younger patients and in those with no concomitant clinical conditions. Introduction of the generic formulation in 2018 seems to have fostered imatinib use.

BCR::ABL1 levels at first month after TKI discontinuation predict subsequent maintenance of treatment-free remission: A study from the "GRUPPO TRIVENETO LMC".

We analyzed BCR::ABL1 expression at stop and in the first month after discontinuation in 168 chronic myeloid leukemia patients who stopped imatinib or 2nd generation tyrosine kinase inhibitors (2G-TKIs) while in sustained deep molecular response. Patients were divided among those who maintained response (group 1, n = 123) and those who lost major molecular response (group 2, n = 45). Mean BCR::ABL1 RNA levels 1 month after discontinuation were higher in group 2 than in group 1 (p = 0.0005) and the difference was more evident 2 months after stop (p < 0.0001). The same trend was found both for imatinib and 2G-TKIs. A receiver operating characteristic (ROC) analysis to determine a threshold value of BCR::ABL1 at 1 month after discontinuation identified a cut-off value of 0.0051%, with 92.2% specificity, 31.7% sensitivity and a likelihood ratio of 4.087.

Treatment-Free Remission in Chronic Myeloid Leukemia Patients Treated With Low-Dose TKIs: A Feasible Option Also in the Real-Life. A Campus CML Study.

Treatment-free remission (TFR) has become a primary therapeutic goal in CML and is also considered feasible by international guidelines. TKIs dose reduction is often used in real-life practice to reduce adverse events, although its impact on TFR is still a matter of debate. This study aimed to explore the attitude of Italian hematologists towards prescribing TKIs at reduced doses and its impact on TFR. In September 2020, a questionnaire was sent to 54 hematology centers in Italy participating to the Campus CML network. For each patient, data on the main disease characteristics were collected. Most of the hematologists involved (64.4%) believed that low-dose TKIs should not influence TFR. Indeed, this approach was offered to 194 patients. At the time of TFR, all but 3 patients had already achieved a DMR, with a median duration of 61.0 months. After a median follow-up of 29.2 months, 138 (71.1%) patients were still in TFR. Interestingly, TFR outcome was not impaired by any of the variables examined, including sex, risk scores, BCR-ABL1 transcript types, previous interferon, type and number of TKIs used before treatment cessation, degree of DMR or median duration of TKIs therapy. On the contrary, TFR was significantly better after dose reduction due to AEs; furthermore, patients with a longer DMR duration showed a trend towards prolonged TFR. This survey indicates that low-dose TKI treatment is an important reality. While one third of Italian hematologists still had some uncertainties on TFR feasibility after using reduced doses of TKIs outside of clinical trials, TFR has often been considered a safe option even in patients treated with low-dose TKIs in the real-life setting. It should be noted that only 28.9% of our cases had a molecular recurrence, less than reported during standard dose treatment. Consequently, TFR is not impaired using low-dose TKIs.

Making Treatment-Free Remission (TFR) Easier in Chronic Myeloid Leukemia: Fact-Checking and Practical Management Tools.

In chronic-phase chronic myeloid leukemia (CML), tyrosine kinase inhibitors (TKIs) are the standard of care, and treatment-free remission (TFR) following the achievement of a stable deep molecular response (DMR) has become, alongside survival, a primary goal for virtually all patients. The GIMEMA CML working party recently suggested that the possibility of achieving TFR cannot be denied to any patient, and proposed specific treatment policies according to the patient's age and risk. However, other international recommendations (including 2020 ELN recommendations) are more focused on survival and provide less detailed suggestions on how to choose first and subsequent lines of treatment. Consequently, some grey areas remain. After literature review, a panel of Italian experts discussed the following controversial issues: (1) early prediction of DMR and TFR: female sex, non-high disease risk score, e14a2 transcript and early MR achievement have been associated with stable DMR, but the lack of these criteria is not sufficient to exclude any patient from TFR; (2) criteria for first and subsequent line therapy choice: a number of patient and drug characteristics have been proposed to make a personalized decision; (3) monitoring of residual disease after discontinuation: after the first 6 months, the frequency of molecular tests can be reduced based on MR4.5 persistence and short turnaround time; (4) prognosis of TFR: therapy and DMR duration are important to predict TFR; although immunological control of CML plays a role, no immunological predictive phenotype is currently available. This guidance is intended as a practical tool to support physicians in decision making.

Prognostic Factors for Overall Survival In Chronic Myeloid Leukemia Patients: A Multicentric Cohort Study by the Italian CML GIMEMA Network.

An observational prospective study was conducted by the CML Italian network to analyze the role of baseline patient characteristics and first line treatments on overall survival and CML-related mortality in 1206 newly diagnosed CML patients, 608 treated with imatinib (IMA) and 598 with 2nd generation tyrosine kinase inhibitors (2GTKI). IMA-treated patients were much older (median age 69 years, IQR 58-77) than the 2GTKI group (52, IQR 41-63) and had more comorbidities. Estimated 4-year overall survival of the entire cohort was 89% (95%CI 85.9-91.4). Overall, 73 patients (6.1%) died: 17 (2.8%) in the 2GTKI vs 56 (9.2%) in the IMA cohort (adjusted HR=0.50; 95% CI=0.26-0.94), but no differences were detected for CML-related mortality (10 (1.7%) vs 11 (1.8%) in the 2GTKIs vs IMA cohort (sHR=1.61; 0.52-4.96). The ELTS score was associated to CML mortality (high risk vs low, HR=9.67; 95%CI 2.94-31.74; p<0.001), while age (per year, HR=1.03; 95%CI 1.00-1.06; p=0.064), CCI (4-5 vs 2, HR=5.22; 95%CI 2.56-10.65; p<0.001), ELTS score (high risk vs low, HR=3.11; 95%CI 1.52-6.35, p=0.002) and 2GTKI vs IMA (HR=0.26; 95%CI 0.10-0.65, p=0.004) were associated to an increased risk of non-related CML mortality. The ELTS score showed a better discriminant ability than the Sokal score in all comparisons.

The serological prevalence of SARS-CoV-2 infection in patients with chronic myeloid leukemia is similar to that in the general population.

BACKGROUND: Patients with hematological malignancies are at an increased risk of SARS-CoV-2 disease (COVID-19) and adverse outcome. However, a low mortality rate has been reported in patients with chronic myeloid leukemia (CML). Preclinical evidence suggests that tyrosine kinase inhibitors (TKIs) may have a protective role against severe COVID-19. METHODS: We conducted a cross-sectional study of 564 consecutive patients with CML who were tested for anti-SARS-CoV-2 IgG/IgM antibodies at their first outpatient visit between May and early November 2020 in five hematologic centers representative of three Italian regions. RESULTS: The estimated serological prevalence of SARS-CoV-2 infection in patients with CML after the first pandemic wave was similar to that in the general population (about 2%), both at national and regional levels. CML patients with positive anti-SARS-CoV-2 serology were more frequently male (p = 0.027) and active workers (p = 0.012), while there was no significant association with TKI treatment type. Only 3 out of 11 IgG-positive patients had previously received a molecular diagnosis of COVID-19, while the remainders were asymptomatic or with mild symptoms. CONCLUSIONS: Our data confirm that the course of SARS-CoV-2 infection in patients with CML is generally mild and reassure about the safety of continuing TKIs during the COVID-19 pandemic. Furthermore, we suggest that patients with CML succeed to mount an antibody response after exposure to SARS-CoV-2, similar to the general population.

Validation and reference values of the EORTC QLQ-CML24 questionnaire to assess health-related quality of life in patients with chronic myeloid leukemia.

Health-related quality of life (HRQOL) assessment is important to facilitate decisions in the current treatment landscape of chronic myeloid leukemia (CML). Therefore, the availability of a validated HRQOL questionnaire, specifically developed for CML patients treated with tyrosine kinase inhibitors (TKIs), may enhance quality of research in this area. We performed an international study including 782 CML patients to assess the validity of the EORTC QLQ-CML 24 questionnaire, and to generate HRQOL reference values to facilitate interpretation of results in future studies. Internal consistency, assessed with Cronbach's alpha coefficients, ranged from 0.66 to 0.83. In the confirmatory factor analysis, all standardized factor loadings exceeded the threshold of 0.40 (range 0.49-0.97), confirming the hypothesized scale structure. Reference values stratified by age and sex were also generated. Our findings support the use of the EORTC QLQ-CML 24, in conjunction with the EORTC QLQ-C30, as a valuable measure to assess HRQOL in CML patients.

Managing chronic myeloid leukemia for treatment-free remission: a proposal from the GIMEMA CML WP.

Several papers authored by international experts have proposed recommendations on the management of BCR-ABL1+ chronic myeloid leukemia (CML). Following these recommendations, survival of CML patients has become very close to normal. The next, ambitious, step is to bring as many patients as possible into a condition of treatment-free remission (TFR). The Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA; Italian Group for Hematologic Diseases of the Adult) CML Working Party (WP) has developed a project aimed at selecting the treatment policies that may increase the probability of TFR, taking into account 4 variables: the need for TFR, the tyrosine kinase inhibitors (TKIs), the characteristics of leukemia, and the patient. A Delphi-like method was used to reach a consensus among the representatives of 50 centers of the CML WP. A consensus was reached on the assessment of disease risk (EUTOS Long Term Survival [ELTS] score), on the definition of the most appropriate age boundaries for the choice of first-line treatment, on the choice of the TKI for first-line treatment, and on the definition of the responses that do not require a change of the TKI (BCR-ABL1 ≤10% at 3 months, ≤1% at 6 months, ≤0.1% at 12 months, ≤0.01% at 24 months), and of the responses that require a change of the TKI, when the goal is TFR (BCR-ABL1 >10% at 3 and 6 months, >1% at 12 months, and >0.1% at 24 months). These suggestions may help optimize the treatment strategy for TFR.

Safety and efficacy of switching from branded to generic imatinib in chronic phase chronic myeloid leukemia patients treated in Italy.

The use of generic drugs after patent expiration of their originators is a relative novelty in the treatment of chronic cancer patients in Western countries. In this observational study we analyzed a cohort of 294 Italian chronic phase chronic myeloid leukemia patients treated frontline with branded imatinib (Glivec®) for at least 6 months and then uniformly switched to generic imatinib upon requirement of health authorities in early 2017. Median age at diagnosis was 57 years (range 19-87). Sokal risk was low/intermediate/high in 55%, 32% and 8% of cases, respectively. Median duration of branded imatinib treatment was 7.4 years (range 0.5-16.7). At a median follow-up of 7.5 months after switch to generic imatinib, 17% of patients reported new or worsening side effects, but grade 3-4 non-hematological adverse events were rare. Six patients switched back to branded imatinib, with improvement in the side effect profile, and 4 pts moved to bosutinib or nilotinib for resistance/intolerance. The majority of patients were in major (26%) or deep molecular response (66%) at the time of switch. Molecular responses remained stable, improved or worsened in 61%, 25% and 14% of patients, respectively. We conclude that switch to generic imatinib for patients who have been receiving branded imatinib appears to be effective and safe. Molecular responses may continue to improve over time. Some patients experienced new or worsened side effects but less than 5% of the whole cohort needed to switch back to branded imatinib or move to other treatments. Savings were around 3 million Euros.