Withdrawal Syndrome After Tyrosine Kinase Inhibitor Discontinuation in Patients With Chronic Myeloid Leukemia in the Russian Prospective Study RU-SKI

We aimed to characterize withdrawal syndrome (WS) and evaluate factors associated with its development in the prospective clinical study RU-SKI in patients with chronic myeloid leukemia with deep molecular response who discontinued tyrosine kinase inhibitor (TKI) therapy. In total, 98 adult patients with chronic myeloid leukemia chronic phase, TKI therapy ≥ 3 years, and deep molecular response (BCR-ABL ≤ 0.01%) ≥ 2 years were enrolled and observed without treatment. WS was defined as newly observed or worsening musculoskeletal pain after TKI cessation. WS symptoms were found in 41 (42%) of 98 patients with a median time of observation of 25 months (range, 12-42 months). WS grades 1 to 2 and grade 3 were observed in 39 (95%) and in 2 (5%) patients, respectively. The median duration of WS was 5 months (range, 1-25 months). WS was resolved in 37 (90%) patients. Anti-inflammatory therapy was used in 21 (51%) patients. Older age (P = .039) and longer TKI therapy (P = .001) were associated with WS. The 2-month landmark analysis found no association of WS development and the rate of molecular relapses. In total, 42% of the patients experienced WS after TKI therapy discontinuation in the RU-SKI study. Physicians should be warned about the possibility of WS development, and patients of older age and with longer TKI treatment need special attention.     

Tyrosine Kinase Inhibitors as Initial Therapy for Patients With Chronic Myeloid Leukemia in Accelerated Phase

BackgroundAccelerated phase CML most frequently represents a progression state in CML. However, some patients present with AP features at the time of diagnosis. There is limited information on the outcome of these patients who received TKIs as initial therapy.Patients and MethodsWe analyzed the outcome of 51 consecutive patients with CML who presented with features of AP at the time of diagnosis, including blasts ≥ 15% (n = 6), basophils ≥ 20% (n = 22), platelets < 100 × 10⁹/L (n = 3), cytogenetic clonal evolution (n = 17), or more than 1 feature (n = 3). Patients received initial therapy with imatinib (n = 30), dasatinib (n = 5), or nilotinib (n = 16).ResultsThe rate of complete cytogenetic response for patients treated with imatinib was 80%, and with dasatinib or nilotinib was 90%. Major molecular response (MMR) (Breakpoint Cluster Region (BCR)-Abelson (ABL)/ABL ≤ 0.1%, International Scale [IS]) was achieved in 69% of patients including complete molecular response (BCR-ABL/ABL ≤ 0.0032% IS) in 49%. MMR rates for patients treated with imatinib were 63%, and with 2GTKIs, 76%. Overall survival at 36 months was 87% with imatinib and 95% with 2GTKIs.ConclusionTKIs should be considered standard initial therapy for patients with AP at the time of diagnosis.     

Final 3-year Results of the Dasatinib Discontinuation Trial in Patients With Chronic Myeloid Leukemia Who Received Dasatinib as a Second-line Treatment

Introduction

We previously reported an interim analysis of the DADI (dasatinib discontinuation) trial. The results showed that 48% of patients with chronic myeloid leukemia in the chronic phase who maintained a deep molecular response (DMR) for ≥ 1 year could discontinue second- or subsequent-line dasatinib treatment safely at a median follow-up of 20 months. However, the results from longer follow-up periods would be much more useful from a clinical perspective.

Detection of Dormant Chronic Myeloid Leukemia Clones in the Bone Marrow of Patients in Complete Molecular Remission

BackgroundSeveral methods are available to detect MRD in patients with CML in complete molecular remission (CMR) and taking tyrosine kinase inhibitor (TKI) therapy.Materials and MethodsWe performed clonogenic assays on mononuclear bone marrow cells from 14 patients. Of the 10 assessable samples, 6 were from patients in CMR and 4 from patients in complete cytogenetic remission but had detectable MRD using polymerase chain reaction (PCR) analysis (positive controls). At least 10 colonies per sample were microaspirated and individual colonies were subjected to PCR analysis.ResultsOf the 6 patients in CMR, 5 harbored breakpoint cluster region abelson (BCR-ABL1) negative colonies but in 1 sample, 1 of the 10 colonies analyzed was positive for BCR-ABL1. Of the 4 patients with evidence of MRD in peripheral blood, 2 had negative and 2 had positive BCR-ABL1 colonies.ConclusionMRD is still detectable using clonogenic assays in some patients with CML after achieving CMR using TKI therapy, which is likely responsible for relapse on TKI discontinuation. Because of the large number of single colonies that need to be analyzed, the use of clonogenic assays in clinical practice to determine the feasibility of TKI discontinuation is not recommended.     

Similar Outcome of Patients With Chronic Myeloid Leukemia Treated With Imatinib in or Out of Clinical Trials

IntroductionOutcomes of CML-CP patients treated in clinical trials are frequently perceived to be not representative of those treated outside of clinical trials.Patients and MethodsWe investigated the outcomes of patients receiving imatinib outside of a clinical trial (off protocol) or in a clinical trial (on protocol) for CML-CP.ResultsWe identified 65 patients treated with imatinib off protocol and 71 patients treated on protocol with standard-dose imatinib. The overall complete cytogenetic response (CCyR) rate was 83% for patients treated on and off protocol. CCyR rates 12 months after initiation of imatinib were not statistically different (61% vs. 66%, respectively; P = .15). Patients treated off protocol had similar rates of overall major molecular response (72% vs. 73%) compared with the patients treated on protocol. The 5-year event-free survival rates were 84% and 86% for off and on protocol patients, respectively. There was also no significant difference in 5-year transformation free survival (94% vs. 96%) and overall survival (96% vs. 90%).ConclusionThese results suggest that patients with CML treated outside of a clinical trial might have the same excellent outcome as those treated in a clinical trial provided they are followed with the same rigor.     

Long-Term Outcomes with Sequential Tyrosine Kinase Inhibitors Treatment in Chronic Myeloid Leukemia Patients

Objective: Tyrosine kinase inhibitor (TKI) is the standard treatment for chronic myeloid leukemia (CML). In the national list of essential medicines in Thailand, the first, second, and third-line treatments are imatinib, nilotinib, and dasatinib, sequentially, different from the European Leukemia Net guidelines. This study aimed to evaluate the outcomes of CML patients who received sequential treatment with TKI. Methods: This study enrolled CML patients diagnosed between 2008 and 2020 at Chiang Mai University Hospital who received TKI. Medical records were reviewed for demographic data, risk score, treatment response, event-free survival (EFS), and overall survival (OS). Result: One hundred and fifty patients were included in the study, 68 patients (45.3%) were female. The mean age is 45.9 ± 15.8 years. Most patients (88.6%) had good ECOG status (0-1). The CML diagnosis was in the chronic phase in 136 patients (90.6%). The EUTOS long-term survival (ELTS) score revealed a high of 36.7%. At the median follow-up of 8.3 years, 88.6% of patients were in complete cytogenetic response (CCyR), whereas 58.0% were in major molecular response (MMR). The 10-year OS and EFS were 81.33% and 79.33%, respectively. The factors associated with poor OS were high ELTS score (P = 0.01), poor ECOG performance status (P < 0.001), not achieved MMR within 15 months (P = 0.014), and not achieved CCyR within 12 months (P < 0.001). Conclusion: The sequential treatment for CML patients had a good response. Factors predicting survival were ELTS score, ECOG performance status, and early achieving MMR and CCyR.     

Role of Sequential Monitoring of WT1 Gene Expression in Patients With Acute Myeloid Leukemia for the Early Detection of Leukemia Relapse

Background

Wilms' tumor 1 (WT1) mRNA expression is a universal marker of minimal residual disease in patients with acute myeloid leukemia (AML). The aim of this retrospective study was to evaluate the ability of serial measurement of peripheral blood WT1 mRNA levels to predict relapse in patients with AML in remission.

Minimal Residual Disease and Survival Outcomes in Patients With Chronic Lymphocytic Leukemia: A Systematic Review and Meta-analysis

BackgroundPatients with chronic lymphocytic leukemia (CLL) who achieve undetectable minimal residual disease (U-MRD) (ie, < 10^-4 detectable leukemic cells in peripheral blood or bone marrow) have better outcomes than those with detectable MRD. To assess the magnitude of improvement of progression-free survival (PFS) or overall survival (OS) in patients who achieved U-MRD after upfront chemotherapy (CT) or chemo-immunotherapy (CIT), we conducted a systematic review and meta-analysis.Materials and MethodsThe screening process adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Guidelines. The search strategy yielded 365 records, including 22 articles assessed for eligibility.ResultsEleven studies comprising 2457 patients with CLL treated in upfront with CT or CIT were considered suitable for inclusion in the quantitative meta-analysis. Nine studies (n = 2088) provided data on the impact of MRD on PFS and 6 (n = 1234) on OS. MRD was the main endpoint in only 2 of these studies (n = 213). Tests of heterogeneity revealed significant differences among studies for PFS and OS, which highlights differences across studies. U-MRD status was associated with significantly better PFS overall (P < .001) and in patients who achieved conventional complete remission (P = .01). Regarding OS, U-MRD predicted longer OS globally (P < .001) but not in patients having achieved complete remission (P = .82).ConclusionsU-MRD status after treatment with CT or CIT in newly diagnosed CLL is associated with long-term survival. These findings provide quantitative evidence to support the integration of MRD assessment as an end point in clinical trials of CLL.     

Analysis of the Mortality of Russian Patients With Chronic Myeloid Leukemia in the Multicenter EUTOS ELN Population-based Study (EUTOS-PBS)

IntroductionRussia took part in the multicenter population-based study (Europe) and included 6.8% adult patients with newly diagnosed chronic myeloid leukemia (CML). The objective of this study was to analyze the mortality in the Russian cohort of patients with newly diagnosed CML in the EUTOS PBS observational study.Patients and MethodsThe analyzed cohort consisted of 197 patients (>18 years) with Ph+/BCR-ABL1+ CML diagnosed in the period from October 1, 2009 through December 31, 2012 from 6 regions of Russia. The distribution of the phases of CML were: chronic phase (CP), 93.4% and accelerated phase (AP) + blast crisis (BC), 6% + 0.6%. The median age was 50 years (range, 18-82 years); the male/female ratio was equal.ResultsThe overall survival (OS) at 5, 6, and 7 years was 80% (95% confidence interval [CI], 72%-86%), 78% (95% CI, 65%-80%), and 73% (95% CI, 65%-80%), respectively (P < .001). The 5-year OS in patients with AP and BC was 39%. In Russia, the study was prolonged, with a median follow-up of 77 months (range, 0.7-108 months): 141 (71.5%) patients were alive, 47 (24%) patients died, and the status of 9 (4.5%) patients is was unknown. Forty-seven (23.8%) patients died during the follow-up period. The largest number of deaths was observed in the first year after the CML diagnosis: 17 (36%) of 47 cases, 3 of 17 died refusing the CML treatment. At the seventh year of CML therapy, 1 patient died after allogenic hematopoietic stem cell transplantation. The causes of death were: (1) progression of CML to AP/BC in 20 (43%) patients; (2) death in remission in 5 (11%) patients with complete cytogenetic response (CCyR) and/or major molecular response; and (3) death without progression to AP/BC but with signs of leukemia in 22 (46%) patients. The 5-year cumulative incidence of death from all reasons was 20%; the cumulative incidence of CML-related and non–CML-related death at the fifth year was 18% and 11%, respectively.ConclusionIn general, the results of treatment in the Russian population sample of non-selected patients with CML were comparable with the data of the total European cohort. The CML-related deaths prevailed in the first year of CML therapy. The appropriate monitoring and therapy interventions during the first year of CML treatment are apparently important for the long-term treatment results.     

Outcome of Imatinib Treatment in Yemeni Patients With Chronic Myeloid Leukemia and the Influence of Nonadherence to Treatment and Duration of Previous Hydroxyurea Therapy

BackgroundIn a developing country like Yemen, data are limited regarding the outcome of imatinib treatment of chronic myeloid leukemia and the effect of nonadherence to imatinib treatment and previous duration of hydroxyurea treatment.Patients and MethodsA longitudinal cohort study, which included 164 Yemeni patients, was performed. Data regarding the disease characteristics, adherence to treatment (the medication possession ratio) and outcome were analyzed.ResultsAfter a median follow-up of 60 months and a median duration of imatinib treatment of 46 months, 79 (48.2%) patients were adherent to treatment. In adherent patients, the overall survival and progression-free survival (PFS) were 78 (98.7%) and 73 patients (92.4%), respectively and major molecular response (MMR) rates at 12 months and at 46 months were 32 (41.0%) and 45 patients (57.0%), respectively, compared with 67 (78.8%), 51 (60%), 5 (6.9%), and 2 patients (2.4%), respectively, in nonadherent patients (P < .001 for all parameters). Nonadherence to imatinib treatment and duration of hydroxyurea treatment of more than 12 months before starting imatinib were found to adversely affect PFS in univariate (hazard ratio [HR], 7.5 and 9.7, respectively and P < .001 for both) and multivariate (HR, 5.6 and 9.3; P = .001 and P < .001, respectively) analysis. High risk Sokal score was found to adversely affect PFS in univariate analysis (HR of high to low risk, 2.8; P < .022) but not in multivariate analysis.ConclusionYemeni patients who were adherent to imatinib therapy achieved response rates similar to that of international standards. Nonadherence to imatinib treatment and previous duration of hydroxyurea treatment for more than 12 months, as a proxy of long interval between diagnosis and starting imatinib treatment, reduced the optimal response to imatinib therapy.     

Second-Line Therapy for Patients With Chronic Myeloid Leukemia Resistant to First-Line Imatinib

The treatment of chronic myeloid leukemia (CML) with BCR-ABL1 tyrosine kinase inhibitors (TKIs) is highly effective in reducing disease burden and prolonging overall survival in the majority of patients. Up to one-third of patients who initiate first-line TKI therapy with imatinib, however, experience resistance to treatment, presenting as a lack or loss of response or as disease progression. Sokal or Hasford risk score at baseline and achievement of early molecular response to treatment may help identify patients at risk for resistance to first-line TKI therapy and poor prognosis. Approximately half of the patients with resistance to TKI treatment have mutations in the BCR-ABL1 kinase domain. Mutation status can be informative and should be considered alongside other factors, including patient history and drug safety profile, in second-line treatment choice. Factors present at the time of initiation of second-line TKI therapy, such as response to initial therapy, as well as achievement of molecular response within the first 6 months of second-line TKI therapy, have value in predicting response and survival outcomes. Given the expanding number of therapeutic options currently approved (FDA), an understanding of the clinical data supporting each of the options for second-line treatment would enable clinicians to develop treatment plans based on the best evidence-based information. This review estimates the incidence rate of TKI resistance that might be expected in the first-line setting, outlines practical approaches to determine TKI resistance, and discusses the factors that clinicians should consider when making a second-line treatment choice.     

Clinical Significance of Minimal Residual Disease in Leukemia Detected by Polymerase Chain Reaction: Is Molecular Remission a Milestone for Achieving a Cure?

Polymerase chain reaction (PCR) technology has been useful in clarifying molecular or minimal residual disease (MRD) status in patients with leukemia. Although PCR has several inherent problems, accumulated data have demonstrated that patients with leukemia harbor PCR-detectable residual disease for a certain period despite clinical remission. This has been for approximately 1 year in childhood acute lymphoblastic leukemia and adult acute promyelocytic leukemia after chemotherapy and for approximately 2 years in chronic myelogenous leukemia after bone marrow transplantation. Ultimately, PCR-undetectable residual disease is necessary for achieving cures in most patients. However, it is difficult to make an early prediction of subsequent relapse after obtaining PCR negativity, since the emergence of PCR-detectable disease occurs only several months before clinical relapse. Therefore, PCR negativity is necessary but not sufficient for achieving cures in most patients with leukemia. Periods of persistent PCR-detectable disease will require further investigations for relapse prediction. More accurate serial quantitation would clarify a precise MRD status in leukemia patients and might allow for more accurate prediction of relapse. Since PCR-undetectable residual disease is necessary for cures in most patients, it can be proposed that a “molecular remission”, defined as PCR-undetectable disease, is a milestone and target for achieving cure by cytoreductive therapy.     

Tyrosine Kinase Inhibitor Dosing Patterns in Elderly Patients With Chronic Myeloid Leukemia

IntroductionTyrosine kinase inhibitors (TKIs) improve the survival rate of patients with chronic myeloid leukemia (CML). However, elderly patients often experience adverse events and require dose adjustments, leading to dose interruptions or treatment discontinuation. We therefore investigated TKI dosing patterns and subsequent outcomes in elderly CML patients.Patients and MethodsUsing the National Health Information Database, we identified patients with CML aged ≥ 70 years who were prescribed TKIs (imatinib, dasatinib, nilotinib, or radotinib) during 2007-2013. Data on age, sex, prescribed medication, and date of death were extracted.ResultsAmong the 378 patients, the median age was 75 (range, 70-92) years; the median follow-up period was 53 (range, 1-133) months. Imatinib, dasatinib, nilotinib, and radotinib were prescribed to 324 (85.7%), 110 (29.1%), 93 (24.6%), and 15 (4.0%) patients, respectively. In 42 patients (12.2%), the initial dose was lower than the recommended dose for chronic-phase CML. At last follow-up, 249 patients (65.9%) were receiving a reduced dose. The mean ± standard deviation dose densities of imatinib, dasatinib, nilotinib, and radotinib were 207 ± 121.6, 29 ± 26.7, 235 ± 197, and 123 ± 95.4 mg/day, respectively. The estimated 5-year overall survival probability was 61.0%. Initial TKI dose or dose reduction within first year did not affect the overall survival (P = .0571 and .1826, respectively).ConclusionDose reduction was observed in 65.9% of the patients at their last visit; except for imatinib, TKI dose densities were < 50% of the recommended dose for the chronic phase. Therefore, the recommended TKI doses might be too high for elderly patients with CML.     

Pleural Effusion in Dasatinib-Treated Patients With Chronic Myeloid Leukemia in Chronic Phase: Identification and Management

Dasatinib has demonstrated durable clinical responses in patients, both as first-line and subsequent lines of therapy. Dasatinib use can result in pleural effusion in some patients, occurring any time during treatment and commonly characterized as mild to moderate in severity. Early identification of symptoms is essential in the proper management of pleural effusion. Prompt confirmation of diagnosis and management of pleural effusion can minimize morbidity and maximize the ability to preserve long-term clinical benefits with dasatinib. Here, we provide guidance on early identification and management of dasatinib-related pleural effusion.     

Analysis of Real-world Data on Postremission Therapy for Acute Myeloid Leukemia With Intermediate Risk Cytogenetics in First Complete Remission

Background

We retrospectively analyzed data from 310 patients with acute myeloid leukemia with intermediate-risk cytogenetics in first complete remission (CR1) to evaluate the usage and efficacy of various types of postremission therapy.

Cardiovascular Risk and Cardiovascular Events in Patients With Chronic Myeloid Leukemia Treated With Tyrosine Kinase Inhibitors

Background

Cardiovascular events (CVEs) have been observed in patients with chronic myeloid leukemia treated with second-generation tyrosine kinase inhibitors.