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Bosutinib is a second-generation tyrosine kinase inhibitor indicated for the treatment of patients with newly diagnosed Philadelphia chromosome–positive chronic phase chronic myeloid leukemia (CML), and for patients with Ph + chronic phase, accelerated phase, or blast phase CML resistant or intolerant to prior therapy. As is the case for all TKIs approved for treatment of CML, bosutinib is associated with adverse events (AEs) that require appropriate management to ensure adherence to treatment and optimized outcomes. The aim of this review is to provide physicians with updated practical information for the prevention and management of AEs occurring during treatment with bosutinib, including dosing strategies, based on the latest published evidence and clinical experience. Clinical studies and real-world evidence have shown bosutinib has a generally favorable safety profile, which has remained consistent across lines of therapy and in long-term reports. Adjusting the starting dose and/or modifying the dose during treatment with bosutinib are important strategies to manage AEs and improve tolerability, which are recognized within the label and in treatment guidelines. Dosing adjustment strategies to manage AEs are a recognized management approach for other TKIs in the treatment of CML and are not exclusive to bosutinib. In summary, long-term results from clinical trials and emerging real-world evidence demonstrate bosutinib has a safety profile that can largely be managed with treatment modifications and/or supportive care. Increased experience in managing toxicities and by using a personalized dosing approach may further improve adherence and outcomes with bosutinib. [ABSTRACT FROM AUTHOR]

Due to the remarkable success of tyrosine kinase inhibitors (TKI) in chronic myeloid leukemia (CML), allogeneic stem cell transplantation (alloSCT) is not first-line treatment for delivering durable, long-term survival. Consequently, alloSCT is reserved for patients with TKI-resistant or TKI-intolerant chronic phase CML (CP-CML) and advanced phase CML (AP-CML). Advances in transplant technology, such as high-resolution HLA typing, introduction of reduced intensity conditioning and increased alternative donor availability, coupled with improved supportive care, have significantly reduced transplant-related mortality and expanded the pool of transplant-eligible patients. Refinement of conditioning regimens, innovative use of post-transplant cellular and pharmacological therapies, and judicious post-transplant monitoring are important strategies for reducing risk of relapse. Given its potential to cure, alloSCT will invariably remain a key part of the treatment algorithm. This article reviews the data underpinning the role and outcomes of alloSCT and provides an update on current recommendations. [ABSTRACT FROM AUTHOR]

Tyrosine kinase inhibitors (TKIs) have revolutionized the management of patients with chronic myelogenous leukemia (CML); however, they may cause cardiovascular (CV) toxicities. In this cross-sectional study, we explored whether high-sensitivity C-reactive protein (hsCRP) and novel markers of vascular dysfunction were associated with exposure to specific TKIs, in 262 CML patients. Hs-CRP level was not associated with CML disease activity or treatment with a specific TKI. Body mass index (OR: 1.15, 95% CI: 1.108–1.246; p < 0.001) and CML duration (OR: 1.004, 95% CI: 1.001–1.008; p = 0.024) were independently associated with higher hs-CRP. In exploratory analyses, novel endothelial-centric markers (e.g. ET-1 and VCAM-1) were differential across the various TKIs, particularly amongst nilotinib- and ponatinib-treated patients. While Levels of hs-CRP do not appear to be correlated with specific TKIs, circulating markers of vascular dysfunction were altered in patients treated with specific TKIs and should be explored as potential markers of TKI-associated CV risk. [ABSTRACT FROM AUTHOR]

Summary: Multiple studies have reported a significant treatment‐free remission (TFR) rate of 50%–60% in patients with chronic myeloid leukaemia (CML) who discontinue tyrosine kinase inhibitor (TKI) therapy. However, the remaining half of these patients still require re‐initiation of TKI therapy for leukaemia control. It remains unclear if TKI drugs should be switched for re‐therapy in patients who failed the first TFR (TFR1) attempt. Our study attempted to determine whether dasatinib therapy after TFR1 failure post‐imatinib discontinuation could improve the likelihood of TFR2. Of 59 patients who lost molecular response after imatinib discontinuation for TFR1, 55 patients (93.2%) were treated with dasatinib, of whom 49 (89.1%) regained MR4.5 or deeper response, with a median time of 1.85 months to achieve MR4.5. Dasatinib was discontinued in 35 patients for TFR2 attempt, of whom 26 patients (74.28%) lost MMR and 6 (17.14%) MR4. Risk factor analysis for the TFR2 after dasatinib discontinuation suggested three significant factors: (1) doubling time of BCR::ABL1 transcript following TFR1 attempt, (2) rapid regaining of molecular response following dasatinib therapy and (3) undetectable BCR::ABL1 transcript prior to TFR2 attempt. The present study showed that dasatinib does not increase the TFR2 rate in general, but a selected group of patients could benefit from this approach. [ABSTRACT FROM AUTHOR]

Implications of creatine kinase (CK) elevation, a frequent complication of tyrosine kinase inhibitor (TKI) treatment for chronic myeloid leukemia (CML), on its key treatment outcomes (overall survival (OS) and event-free survival (EFS)), remain unknown. In this single center, retrospective study on 283 chronic phase CML patients on first-line TKI (median follow-up of 8.8 years), 71.7% patients had hyperCKemia with no difference in incidence between imatinib and second generation TKIs (SG-TKIs). In multivariable Cox regression analysis, hyperCKemia was associated with better OS and intermediate- and high-Sokal risk score with worse OS. In multivariable Cox regression for EFS, hyperCKemia and treatment with SG-TKI were associated with improved EFS while intermediate or high Sokal index and higher comorbidities showed worse EFS. Our study provides an evidence on the prognostic value of hyperCKemia in CML and informs clinicians not to change TKI based solely on laboratory elevations of CK. [ABSTRACT FROM AUTHOR]

Treatment-free remission is achievable in approximately half of patients with chronic myeloid leukemia who attain a sustained, deep molecular response with tyrosine-kinase inhibitor (TKI) therapy. We aimed to identify potential predictors of future achievement of stable MR4.5, defined as a sustained 4.5-log reduction in BCR-ABL1 transcripts for a minimum of 2 years, in 593 patients treated with imatinib as first-line TKI therapy. In multivariable analyses of patient and disease variables including baseline blood counts, disease phase, additional cytogenetic abnormalities, prior therapy, depth and rapidity of molecular response, the only predictor for future achievement of stable MR4.5 was molecular response at 6 months. In this study, patients failing to attain a molecular response of BCR-ABL1≤ 0.16%IS after 6 months of imatinib therapy were unlikely to subsequently achieve stable MR4.5 with imatinib. Our data suggest that achievement of BCR-ABL1≤ 0.16%IS at 6 months is predictive of future stable MR4.5. [ABSTRACT FROM AUTHOR]

Summary: The doubling time (DT) of the BCR–ABL1 quantitative polymerase chain reaction (qPCR) transcript level reflects the re‐growing fraction of leukaemic cells after discontinuation of tyrosine kinase inhibitor (TKI). The present study analyzed monthly DT within six months after imatinib discontinuation in 131 patients. Monthly DT was calculated as x = ln(2)/K, where x is the DT and K is the fold BCR–ABL1 change from the previous value divided by the number of days between each measurement. The optimal DT value was determined as 12·75 days at two months using a recursive partitioning method. The patients were stratified into three groups: the high‐risk group (DT<12·75 days but >0, with rapidly proliferating chronic myeloid leukaemia (CML) cells; n = 26) showed the lowest molecular relapse‐free survival (mRFS) of 7·7% at 12 months, compared to 53·6% in the intermediate‐risk group (DT≥12·75 days, with slowly proliferating CML cells; n = 16) or 90·0% in the low‐risk group (DT≤0, i.e., without proliferating CML cells; n = 71; P < 0·001). Monthly assessment of DT helps identify high‐risk patients for treatment‐free remission failure with an imminent risk of molecular recurrence, and to define low‐risk patients who can be spared the frequent monitoring of monthly molecular tests. [ABSTRACT FROM AUTHOR]

Summary: Although total duration of tyrosine kinase inhibitor (TKI) therapy and of molecular response at 4 log reduction or deeper (MR4) correlates with treatment‐free remission (TFR) success after TKI discontinuation, the optimal cut‐off values of the duration remain unresolved. Thus, 131 patients were enrolled into the Canadian TKI discontinuation study. The molecular relapse‐free survival (mRFS) was defined from imatinib discontinuation till molecular recurrence, that is, major molecular response (MMR) loss and/or MR4 loss. We evaluated mRFS at 12 months after imatinib discontinuation, analyzed it according to the imatinib treatment duration and MR4 duration, and calculated P value, positive (PPV) and negative predictive value (NPV) in the yearly cut‐off period of time. The shortest cut‐off was sought that met the joint criteria of a P value ≤ 0·05, PPV ≥ 60% and NPV ≥ 60%. We propose six years as the shortest imatinib duration cut‐off with a P value 0·01, PPV 68% and NPV 62%: The patients treated with imatinib duration ≥ 6 years showed a superior mRFS rate (61·8%) compared to those with less treatment (36·0%). Also, 4·5 years MR4 duration as the shortest cut‐off with a P value 0·003, PPV 63% and NPV 61%: those with MR4 duration ≥ 4·5 years showed a higher mRFS rate (64·2%) than those with a shorter MR4 duration (41·9%). [ABSTRACT FROM AUTHOR]

Of all the cancers, chronic myeloid leukaemia (CML) has witnessed the most rapid evolution of the therapeutic milieu in recent decades. The introduction of tyrosine kinase inhibitors (TKIs) as a therapeutic option has profoundly changed patient experience and outcome. The availability of multiple new highly effective therapies has increasingly underscored the importance of a good understanding of the underlying pathophysiological basis in CML, as well as patient-specific factors in choosing the right treatment for every individual. The treatment of CML has migrated in many jurisdictions from the office of a highly specialized malignant hematologist to the general hematologist or even a general practitioner. The goal of this review is to offer an overview of the modern approach to the treatment of CML, with an emphasis on chronic phase (CP) CML, including both TKI-based therapies such as imatinib, dasatinib, nilotinib, bosutinib and ponatinib, and non-TKI medications, such as omacetaxine. We discuss evidence behind each drug, most common and material adverse reactions and outline how this information can be used in selecting the right drug for the right patient. We also discuss evidence as it relates to other therapies, including stem cell transplant (SCT), and patients in accelerated (AP) and blastic phase (BP). [ABSTRACT FROM AUTHOR]

Background: Ponatinib has shown potent activity against chronic myeloid leukaemia that is resistant to available treatment, although it is associated with arterial occlusion. We investigated whether this activity and safety profile would result in superior outcomes compared with imatinib in previously untreated patients with chronic myeloid leukaemia.Methods: The Evaluation of Ponatinib versus Imatinib in Chronic Myeloid Leukemia (EPIC) study was a randomised, open-label, phase 3 trial designed to assess the efficacy and safety of ponatinib, compared with imatinib, in newly diagnosed patients with chronic-phase chronic myeloid leukaemia. Patients from 106 centres in 21 countries were randomly assigned (1:1, with stratification by Sokal score at diagnosis) using an interactive voice and web response system to receive oral ponatinib (45 mg) or imatinib (400 mg) once daily until progression, unacceptable toxicity, or other criteria for withdrawal were met. Eligible patients were at least 18 years of age, within 6 months of diagnosis, and Philadelphia chromosome-positive by cytogenetic assessment, with Eastern Cooperative Oncology Group performance status of 0-2, and had not previously been treated with tyrosine kinase inhibitors. The primary endpoint was major molecular response at 12 months. Patients who remained on study and had molecular assessments at specified timepoints were studied at those timepoints. Safety analyses included all treated patients, as per study protocol. This trial is registered with ClinicalTrials.gov, number NCT01650805.Findings: Between Aug 14, 2012, and Oct 9, 2013, 307 patients were randomly assigned to receive ponatinib (n=155) or imatinib (n=152). The trial was terminated early, on Oct 17, 2013, following concerns about vascular adverse events observed in patients given ponatinib in other trials. Trial termination limited assessment of the primary endpoint of major molecular response at 12 months, as only 13 patients in the imatinib group and ten patients in the ponatinib group could be assessed at this timepoint; the proportion of patients achieving a major molecular response at 12 months did not differ significantly between the two groups (eight [80%] of ten patients given ponatinib and five [38%] of 13 patients given imatinib; p=0·074). 11 (7%) of 154 patients given ponatinib and three (2%) of 152 patients given imatinib had arterial occlusive events (p=0·052); arterial occlusive events were designated serious in ten (6%) of 154 patients given ponatinib and in one (1%) of 152 patients given imatinib (p=0·010). The data monitoring committee criterion for risk assessment (significant difference in serious grade 3 or 4 ischaemic events between groups) was not met (five [3%] of 154 vs one [1%] of 152; p=0·21). Grade 3 or 4 adverse events observed in more than 5% of patients in the ponatinib group were increased lipase (22 [14%] of 154 vs three [2%] of 152 with imatinib), thrombocytopenia (19 [12%] of 154 vs ten [7%] of 152 with imatinib), rash (ten [6%] of 154 vs two [1%] of 152 with imatinib). In the imatinib group, grade 3 or 4 adverse events observed in more than 5% of patients were neutropenia (12 [8%] of 152 vs five [3%] of 154 with ponatinib) and thrombocytopenia (ten [7%] of 152 vs 19 [12%] of 154 with ponatinib). Serious adverse events that occurred in three or more patients given ponatinib were pancreatitis (n=5), atrial fibrillation (n=3), and thrombocytopenia (n=3). No serious adverse event occurred in three or more patients given imatinib.Interpretation: The efficacy of ponatinib treatment of newly diagnosed chronic-phase chronic myeloid leukaemia compared with imatinib could not be assessed due to trial termination, but preliminary data suggest there might be benefit, although with more arterial occlusive events than with imatinib at the doses studied. Because the EPIC trial was terminated early, efficacy of ponatinib in this setting remains to be established.Funding: ARIAD Pharmaceuticals. [ABSTRACT FROM AUTHOR]

Omacetaxine mepesuccinate (Synribo®) is an inhibitor of protein synthesis indicated for the treatment of patients with chronic- or accelerated-phase chronic myeloid leukemia (CML) with resistance and/or intolerance to two or more tyrosine kinase inhibitors. Myelosuppression is the most common and clinically significant toxicity experienced by patients treated with omacetaxine. Here, we further examine the patterns of hematologic toxicity observed in clinical trials and describe the approach to management as well as resolution of events. Omacetaxine-related myelosuppression typically occurs more frequently during induction cycles. In general, the myelosuppression observed with omacetaxine treatment is manageable and reversible, and long-term administration is feasible. Careful monitoring, dose delays and reduction in administration days, and appropriate supportive care are critical for successful management of hematologic toxicity. Concerns regarding myelosuppression, observed with many cancer treatments, should not prevent eligible patients from receiving omacetaxine, particularly CML patients with unsatisfactory responses to multiple lines of prior treatment. [ABSTRACT FROM AUTHOR]

Lymphoproliferative disorders presenting simultaneously with or subsequent to the occurrence of chronic myeloid leukemia (CML) have rarely been reported. Herein, we report 8 cases of a variety of lymphoproliferative conditions associated with CML at different times during the course of the disease. All 8 patients were treated with tyrosine kinase inhibitors at some point during the course of their illness. The literature regarding the uncommon association of these apparently unrelated disorders is reviewed as well as the possible underlying mechanisms that could be associated with this phenomenon. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Although the combination of tyrosine kinase inhibitors with chemotherapy is widely used for young adults with Philadelphia chromosome positive-acute lymphoblastic leukaemia (Ph+ ALL), the outcome and safety of this combination using intensive paediatric-based protocols has not been well described. The clinical course of 32 adults age 18-60 years with Ph+ ALL treated with a paediatric-based protocol plus imatinib was evaluated. The complete response rate was 94%. Grade 3-4 infections, neuropathy, myopathy and liver function abnormalities were common, resulting in major treatment delays and dose reductions, and declines in performance status (physical deconditioning), particularly in patients aged 41-60 years. Median and 3-year overall survival ( OS) was 40·7 months and 53%, respectively, and median and 3-year even-free survival ( EFS) was 30·1 months and 50%, respectively. OS and EFS were inferior in deconditioned patients. Of 16 patients who underwent haematopoietic stem cell transplantation ( HSCT) in first complete remission, six died of non-relapse complications. There was no significant difference in OS and EFS between transplanted and non-transplanted patients, based on an intention-to-treat and time-to-donor identification analysis. The combination of imatinib with a paediatric-based regimen in adults produced high response rates, but was associated with considerable toxicity and high non-relapse mortality post- HSCT. [ABSTRACT FROM AUTHOR]

Simple Summary: Approximately 50–60% of patients with chronic myeloid leukemia (CML) achieve a stable deep molecular response (DMR) after tyrosine kinase inhibitor (TKI) therapy. The achievement of DMR is a prerequisite for treatment-free remission. Repurposing statins is a straightforward strategy for enhancing molecular response in CML treatment. Second-generation TKIs have been reported to exhibit cardiovascular toxicity. Thus, statins have been widely prescribed for patients with CML undergoing second-generation TKI therapy for modifying cardiovascular risk factors, such as hyperlipidemia. Furthermore, the results of this study support the therapeutic benefit of the concomitant use of statins in TKI therapy for patients with CML. Additionally, the potential additive effects of statins and TKIs enhance the DMR rate in patients with CML, rendering these effects clinically relevant in these patients. In particular, this combination is a strong candidate for the achievement of DMR in patients with CML who have not achieved DMR with TKI therapy alone. Previous studies have suggested that statins can be repurposed for cancer treatment. However, the therapeutic efficacy of statins in chronic myeloid leukemia (CML) has not yet been demonstrated. In this study, we retrospectively evaluated the outcomes of 408 CML patients who underwent imatinib therapy. The deep molecular response rates in patients treated with the statin/TKI combination were significantly higher than those in patients treated with TKI alone (p = 0.0016). The statin/TKI combination exerted potent cytotoxic effects against wild-type and ABL1 mutant CML, BaF3, and K562/T315I mutant cells. Furthermore, the statin/TKI combination additively inhibited the colony-forming capacity of murine CML-KLS+ cells in vitro. In addition, we examined the additive growth-inhibitory effects of the statin/tyrosine kinase inhibitor (TKI) combination against CML patient-derived CD34+ cells. The growth-inhibitory effects of the statin/imatinib combination against CD34+/CML primary cells were higher than those against CD34+/Norm cells (p = 0.005), suggesting that the combination of rosuvastatin and imatinib exerted growth-inhibitory effects against CML CD34+ cells, but not against normal CD34+ cells. Furthermore, results from RNA sequencing of control and statin-treated cells suggested that statins inhibited c-Myc-mediated and hematopoietic cell differentiation pathways. Thus, statins can be potentially repurposed to improve treatment outcomes in CML patients when combined with TKI therapy. [ABSTRACT FROM AUTHOR]

Somatic mutations commonly detected in a variety of myeloid neoplasms have not been systematically investigated in chronic myeloid leukemia (CML). We performed targeted deep sequencing on a total of 300 serial samples from 100 CML patients; 37 patients carried mutations. Sixteen of these had evidence of mutations originating from preleukemic clones. Using unsupervised hierarchical clustering, we identified 5 distinct patterns of mutation dynamics arising following tyrosine kinase inhibitor (TKI) therapy. This study demonstrates that patterns of mutation acquisition, persistence, and clearance vary but have a number of interesting correlations with clinical outcomes. Mutation burden often persisted despite successful TKI response (pattern 1), providing indirect evidence that these mutations also originated from preleukemic mutations, whereas patients exhibiting mutation clearance (pattern 3) showed mixed clinical outcomes. Unsurprisingly, patients acquiring new mutations during treatment failed TKI therapy (pattern 2). These patterns show that CML mutation dynamics following TKI therapy are markedly distinct from other myeloid neoplasms. In summary, clinical implications of mutation profiles and dynamics in CML should be interpreted with caution. [ABSTRACT FROM AUTHOR]

Summary Ponatinib is the only currently approved tyrosine kinase inhibitor (TKI) that suppresses all BCR-ABL1 single mutants in Philadelphia chromosome-positive (Ph + ) leukemia, including the recalcitrant BCR-ABL1 T315I mutant. However, emergence of compound mutations in a BCR-ABL1 allele may confer ponatinib resistance. We found that clinically reported BCR-ABL1 compound mutants center on 12 key positions and confer varying resistance to imatinib, nilotinib, dasatinib, ponatinib, rebastinib, and bosutinib. T315I-inclusive compound mutants confer high-level resistance to TKIs, including ponatinib. In vitro resistance profiling was predictive of treatment outcomes in Ph + leukemia patients. Structural explanations for compound mutation-based resistance were obtained through molecular dynamics simulations. Our findings demonstrate that BCR-ABL1 compound mutants confer different levels of TKI resistance, necessitating rational treatment selection to optimize clinical outcome. [ABSTRACT FROM AUTHOR]

Advances in chronic myeloid leukemia treatment, particularly regarding tyrosine kinase inhibitors, mandate regular updating of concepts and management. A European LeukemiaNet expert panel reviewed prior and new studies to update recommendations made in 2009. We recommend as initial treatment imatinib, nilo-tinib, or dasatinib. Response is assessed with standardized real quantitative polymerase chain reaction and/or cytogenetics at 3, 6, and 12 months. BCR-ABL1 transcript levels ⩽10% at 3 months, <1% at 6 months, and ⩽0.1% from 12 months onward define optimal response, whereas >10% at 6 months and >1 % from 12 months onward define failure, mandating a change in treatment. Similarly, partial cytogenetic response (PCyR) at 3 months and complete cytogenetic response (CCyR) from 6 months onward define optimal response, whereas no CyR (Philadelphia chromosome-positive [Ph+] >95%) at 3 months, less than PCyR at 6 months, and less than CCyR from 12 months onward define failure. Between optimal and failure, there is an intermediate warning zone requiring more frequent monitoring. Similar definitions are provided for response to second-line therapy. Specific recommendations are made for patients in the accelerated and blastic phases, and for allogeneic stem cell transplantation. Optimal responders should continue therapy indefinitely, with careful surveillance, or they can be enrolled in controlled studies of treatment discontinuation once a deeper molecular response is achieved. [ABSTRACT FROM AUTHOR]