The significance of early warning in chronic myeloid leukemia

We have read with great interest the manuscript by Eskazan and colleagues entitled \u201cCritical appraisal of European LeukemiaNet (ELN) 2013 recommendations for the management of chronic myeloid leukemia: is it early for a warning?\u201d. After a revision of the relatively limited literature, the Authors conclude that there are still no solid data to suggest a switch of therapy in patients with warning signs and that long-term survival remains a highly significant endpoint in CML patients. While we generally agree with these thoughts, we would like to stress a couple of additional points on the issue of ELN 2013 \u2013 defined \u201cwarning\u201d. The ELN recommendations defines warning as less than partial cytogenetic response (PCyR) and/or BCR-ABL1 >10% (according to the International Scale \u2013 IS) at 3 months, less than complete cytogenetic response (CCyR) and/or BCR-ABL1 >1%IS at 6 months, and BCR-ABL1 >0.1% IS, i.e. no major molecular response (MMR) at 12 months. So, at the first two time-points, conventionally considered as \u201cearly\u201d, both cytogenetic and molecular status define response, while at 12 months only BCR-ABL1 level >0.1 to 1%IS identifies warning patients, as anything less than CCyR is regarded as a failure. Our group analyzed the outcome of 216 CML patients treated with front-line standard dose (400 mg/day) imatinib with discordant cytogenetic and molecular responses at 3 and 6 months. Patients with even a single warning sign at 3 months (i.e. no PCyR or BCR-ABL1 >10%IS) had a significantly lower chance to obtain a subsequent CCyR (37% compared to 85% in patients with concordant optimal cytogenetic and molecular responses) and worse failure-free survival (FFS) (39% vs 81% at 48 months). Similarly, a warning sign at 6 months identified patients less prone to attain a MMR at 12 months (17% vs 82% in concordantly optimal patients) and with worse FFS (62% vs 88%). In our experience, most discordant patients had a \u201cmolecular warning\u201d, as 15/17 discordant at 3 months were in PCyR or better but with BCR-ABL1 transcript >10%IS and at 6 months 20/25 discordant were in CCyR with BCR-ABL1 >1%IS. This finding is an indirect confirmation of the importance of a BCR-ABL1 transcript level <10%IS at 3 months (now defined \u201cearly molecular response\u201d, EMR) as a positive predictor of long-term outcome, as reported by different studies. Despite EMR is gaining ground as a factor for an early switch of therapy, as suggested by NCCN guidelines, some reports indicate, in line with ELN recommendations, to consider also the 6-month cytogenetic or molecular status to assess a two-point evaluation of response to TKI therapy. The MDACC group analyzed the outcome of 453 CML patients treated with different TKIs, finding that 19 out of 44 patients (43%) not achieving major (i.e. optimal) cytogenetic response (MCyR) at 3 months obtained this response at 6 months and had an outcome comparable to patients achieving an earlier MCyR [8]. A Canadian study reviewed 320 patients receiving imatinib therapy with 3 and 6 month BCR-ABL1 transcript levels available, reporting that patients not achieving an EMR at 3 months but with BCR-ABL1 transcript <1% at 6 months (n=18) had similar FFS, progression-free survival (PFS) and overall survival (OS) compared to patients in EMR (n=184). Taken together, these data suggest that cytogenetic and molecular response at 6 months can identify a subgroup with favorable outcome among patients \u201cwarning\u201d at 3 months. However, considering patients with cytogenetic and/or molecular warning at 3 months in our series (n=41), only 2 had a subsequent optimal cytogenetic and molecular response at 6 months (unpublished). Moreover, we found that the rates of warning responses at 3 and 6 months were higher in cases with b2a2 BCR-ABL1 transcript type compared to those with b3a2 variant (32% vs 24% at 3 months and 31% vs 12% at 6 months, respectively). If there is still debate on the practical significance of a warning at 3 or 6 months, even less consensus and significantly less data are about the meaning of a late (i.e. at 12 months) warning. Starting from their database of 483 patients treated with four different TKI strategies, colleagues at MDACC found no benefit, in term of survival, in patients achieving MMR while in CCyR, even if their landmark analysis was performed at 18 and 24 months, and not at the 12-months timepoint. A landmark analysis of PFS and OS on the bases of molecular response at 12 months of imatinib performed in 128 patients from our database did not find any difference between patients in MMR or not (personal data, unpublished). Concordantly, a Spanish group showed that, in 198 patients treated with standard-dose imatinib and in CCyR without MMR at 12 months, a switch to a second-generation TKI was associated with a higher probability of subsequently major and deep molecular response, but no advantage in terms of PFS and OS and higher rates of discontinuation for adverse events, compared to patients continuing imatinib. Hopefully, more information on the therapeutic approach to \u201cwarning\u201d patients will come from an upcoming study of the GIMEMA Working Party on CML study aimed to evaluate efficacy of nilotinib frontline versus imatinib followed by switch to nilotinib in the case of absence of ELN-defined optimal response at 3, 6 or 12 months

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

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

Excellent outcomes of 2G-TKI therapy after imatinib failure in chronic phase CML patients

Second-generation tyrosine kinase inhibitors (2G-TKIs) dasatinib and nilotinib produced historical rates of about 50% complete cytogenetic response (CCyR) and about 40% major molecular response (MMR) in chronic myeloid leukaemia (CML) patients failing imatinib. Direct comparisons between dasatinib and nilotinib are lacking, and few studies addressed the dynamics of deep molecular response (DMR) in a "real-life" setting. We retrospectively analyzed 163 patients receiving dasatinib (n= 95) or nilotinib (n= 68) as second-line therapy after imatinib. The two cohorts were comparable for disease's characteristics, although there was a higher rate of dasatinib use in imatinib-resistant and of nilotinib in intolerant patients. Overall, 75% patients not in CCyR and 60% patients not in MMR at 2G-TKI start attained this response. DMR was achieved by 61 patients (37.4%), with estimated rate of stable DMR at 5 years of 24%. After a median follow-up of 48 months, 60% of patients persisted on their second-line treatment. Rates and kinetics of cytogenetic and molecular responses, progression-free and overall survival were similar for dasatinib and nilotinib. In a "real-life" setting, dasatinib and nilotinib resulted equally effective and safe after imatinib failure, determining high rates of CCyR and MMR, and a significant chance of stable DMR, a prerequisite for treatment discontinuation

Health-related quality of life in patients with chronic myeloid leukemia receiving first-line therapy with nilotinib

BACKGROUND: Although a wealth of efficacy and safety data is available for many tyrosine kinase inhibitors used in chronic myeloid leukemia (CML), there is a dearth of information on their impact on patients' health-related quality of life (HRQOL). The primary objective of this study was to evaluate HRQOL and fatigue outcomes in patients with CML receiving first-line therapy with nilotinib. METHODS: This was a multicenter, prospective study enrolling 130 patients with chronic-phase CML. HRQOL and fatigue were evaluated with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and its validated Fatigue module at the baseline and then at 3, 6, 12, 18, and 24 months. The primary prespecified HRQOL endpoints defined in the study protocol for longitudinal analysis were the Physical Functioning, Social Functioning, Role Functioning, and Fatigue scales. The remaining scales were investigated on an exploratory basis. RESULTS: The rate of baseline compliance with the HRQOL assessment was 95.4% (124 of 130), and the rate of overall compliance with HRQOL forms was 91%. Among the 4 prespecified primary HRQOL endpoints, statistically significant improvements over time were found for Physical Functioning (P =.013), Role Functioning (P =.004), and Fatigue (P <.001). Clinically meaningful improvements were found already 3 months after the treatment start. The baseline patient self-reported fatigue severity was an independent predictive factor for the achievement of a major molecular response with an odds ratio of 0.960 (95% confidence interval, 0.934-0.988; P =.005). CONCLUSIONS: For most patients, HRQOL improvements with nilotinib occur during the early phase of therapy and are maintained over time. Also, a more systematic HRQOL evaluation during the diagnostic workup of CML may help to predict clinical outcomes. Cancer 2018;124:2228-37. © 2018 American Cancer Society

A straightforward multiparametric quality control protocol for proton magnetic resonance spectroscopy: Validation and comparison of various 1.5 T and 3 T clinical scanner systems

Purpose: The aim of this study was to propose and validate across various clinical scanner systems a straightforward multiparametric quality assurance procedure for proton magnetic resonance spectroscopy (MRS). Methods: Eighteen clinical 1.5 T and 3 T scanner systems for MRS, from 16 centres and 3 different manufacturers, were enrolled in the study. A standard spherical water phantom was employed by all centres. The acquisition protocol included 3 sets of single (isotropic) voxel (size 20 mm) PRESS acquisitions with unsuppressed water signal and acquisition voxel position at isocenter as well as off-center, repeated 4/5 times within approximately 2 months. Water peak linewidth (LW) and area under the water peak (AP) were estimated. Results: LW values [mean (standard deviation)] were 1.4 (1.0) Hz and 0.8 (0.3) Hz for 3 T and 1.5 T scanners, respectively. The mean (standard deviation) (across all scanners) coefficient of variation of LW and AP for different spatial positions of acquisition voxel were 43% (20%) and 11% (11%), respectively. The mean (standard deviation) phantom T2 values were 1145 (50) ms and 1010 (95) ms for 1.5 T and 3 T scanners, respectively. The mean (standard deviation) (across all scanners) coefficients of variation for repeated measurements of LW, AP and T2 were 25% (20%), 10% (14%) and 5% (2%), respectively. Conclusions: We proposed a straightforward multiparametric and not time consuming quality control protocol for MRS, which can be included in routine and periodic quality assurance procedures. The protocol has been validated and proven to be feasible in a multicentre comparison study of a fairly large number of clinical 1.5 T and 3 T scanner systems

The new Systematic Coronary Risk Evaluation (SCORE2 and SCORE2-OP) estimates the risk of arterial occlusive events in chronic myeloid leukemia patients treated with nilotinib or ponatinib

Patients with chronic myeloid leukemia (CML) treated with nilotinib or ponatinib may experience arterial occlusive events (AOEs). It is currently recommended to thoroughly assess cardiovascular risk factors before treating CML. We identified 455 consecutive CML adult patients, 335 treated with nilotinib and 120 with ponatinib; 380 patients without previous cardiovascular diseases or diabetes were stratified according to the Systematic Coronary Risk Evaluation (SCORE2) and SCORE2-Older Persons (SCORE2-OP). This updated algorithm from the European Society of Cardiology (ESC) estimates a 10-year risk of fatal and non-fatal cardiovascular diseases. It is based on sex, age, smoking habits, systolic blood pressure, non-high-density lipoprotein cholesterol, and European geographical region of cardiovascular risk. The SCORE2/SCORE2-OP algorithm translated more patients (50.2%) to the high-very high cardiovascular risk category than the previous SCORE (25.3%). Patients with a high to very high SCORE2/SCORE2-OP risk showed a significantly higher incidence rate of AOEs (69.2% vs. 46.5%, p &lt; 0.001). The older SCORE was less specific in estimating AOEs in patients classified as low-intermediate risk (69.8 vs. 54.2%). In multivariate analysis, no associations were found between AOEs and gender, age, and type or dose of tyrosine kinase inhibitor. Only the SCORE2/SCORE2-OP risk was confirmed as a significant predictive factor (p = 0.028; hazard ratio = 2.2; 95% confidence interval = 1.1-4.5). Patients with AOEs required, in most cases, imaging diagnostic tests, additional drugs, and sometimes invasive procedures, increasing access to visits and hospital management. This real-life study suggested that the SCORE2 and SCORE2-OP charts could help identify cardiovascular fragility in CML patients providing them with more attention and a proper TKI selection

Adherence and future discontinuation of tyrosine kinase inhibitors in chronic phase chronic myeloid leukemia. A patient-based survey on 1133 patients

Therapeutic approach for chronic myeloid leukemia (CML) patients has undergone a revolutionary change with the introduction of tyrosine kinase inhibitors, which improved overall survival and quality of life. Optimal therapy adherence has become of paramount importance to maximize the benefits in the long-term outcome. Several evidences have been reported that personal factors, such as social support, psychological and subjective perceptions about the drug used and the future, could influence adherence. We here report the results of a questionnaire specifically designed to evaluate factors influencing adherence and perceptions about the future, distributed to patients during regional Italian meetings. Overall, 1133 patients compiled the questionnaire: median age was 57 years. High rate of adherence was reported, but 42% of interviewed patients admitted that they had occasionally postponed a dose and 58% had discontinued therapy mainly for forgetfulness. The majority of patients discussed with personal physician about the importance of adherence and received sufficient information about illness and treatment, but would like to have discussed more about discomfort, anxiety and fear of the future. Summarizing personal drug compliance and estimating how many days a month, on average, the patients did not take the drug, the majority answered that it was less than 3 days (55%) and only a minority (4%) admitted that it was more than 7 days. Interviewed about discontinuation, 49% of patients answered that wouldn't interrupt because of fear of losing all the results achieved so far. This study suggests a higher level of satisfaction with more information received but the need of improving communication about possible future treatment free remission

Ruxolitinib rechallenge in resistant or intolerant patients with myelofibrosis: Frequency, therapeutic effects, and impact on outcome

BACKGROUND After ruxolitinib discontinuation, the outcome of patients with myelofibrosis (MF) is poor with scarce therapeutic possibilities. METHODS The authors performed a subanalysis of an observational, retrospective study (RUX-MF) that included 703 MF patients treated with ruxolitinib to investigate 1) the frequency and reasons for ruxolitinib rechallenge, 2) its therapeutic effects, and 3) its impact on overall survival. RESULTS A total of 219 patients (31.2%) discontinued ruxolitinib for &gt;= 14 days and survived for &gt;= 30 days. In 60 patients (27.4%), ruxolitinib was rechallenged for &gt;= 14 days (RUX-again patients), whereas 159 patients (72.6%) discontinued it permanently (RUX-stop patients). The baseline characteristics of the 2 cohorts were comparable, but discontinuation due to a lack/loss of spleen response was lower in RUX-again patients (P = .004). In comparison with the disease status at the first ruxolitinib stop, at its restart, there was a significant increase in patients with large splenomegaly (P &lt; .001) and a high Total Symptom Score (TSS; P &lt; .001). During the rechallenge, 44.6% and 48.3% of the patients had spleen and symptom improvements, respectively, with a significant increase in the number of patients with a TSS reduction (P = .01). Although the use of a ruxolitinib dose &gt; 10 mg twice daily predicted better spleen (P = .05) and symptom improvements (P = .02), the reasons for/duration of ruxolitinib discontinuation and the use of other therapies before rechallenge were not associated with rechallenge efficacy. At 1 and 2 years, 33.3% and 48.3% of RUX-again patients, respectively, had permanently discontinued ruxolitinib. The median overall survival was 27.9 months, and it was significantly longer for RUX-again patients (P = .004). CONCLUSIONS Ruxolitinib rechallenge was mainly used in intolerant patients; there were clinical improvements and a possible survival advantage in many cases, but there was a substantial rate of permanent discontinuation. Ruxolitinib rechallenge should be balanced against newer therapeutic possibilities

Cardiovascular toxicity in patients with chronic myeloid leukemia treated with second-generation tyrosine kinase inhibitors in the real-life practice: Identification of risk factors and the role of prophylaxis

No abstract availabl