Frequent EVI1 translocations in myeloid blast crisis CML that evolves through tyrosine kinase inhibitors

Clinical variables associated with ecotropic viral integration site 1 (EVI1) translocations were evaluated in 42 consecutive chronic myeloid leukemia (CML) patients in myeloid blast crisis (MBC). Translocations were confirmed with fluorescence in situ hybridization, and Western blot analysis demonstrated EVI1 expression. Translocations of EVI1 were present in 3 of 24 (12%) patients whose disease evolved MBC before tyrosine kinase inhibitor (TKI) exposure, and 7 of 18 (39%) patients who had received one or more TKIs. Univariate analysis showed that prior TKI therapy was the only clinical variable that was significantly associated with EVI1 translocation (P = 0.047). TKI-resistant BCR-ABL1 mutations were present in 71% of MBC patients with EVI1 translocations at the time of disease progression. These observations suggest that EVI1 overexpression collaborates with BCR-ABL1 in the evolution of TKI-resistant MBC. Inhibition of c-ABL kinase-mediated DNA double-strand repair by TKIs may predispose to EVI1 translocation in this setting.     

Tyrosine kinase inhibitors as a first‐line treatment in patients with newly diagnosed chronic myeloid leukemia in chronic phase: A mixed‐treatment comparison

Tyrosine kinase inhibitors (TKI) are the initial treatment for majority of newly diagnosed patients with chronic myelogenous leukemia (CML) in chronic phase (CP) and are associated with marked improvement in hematological, cytogenetic, molecular response and survival rates compared with other therapies. In this review, we summarize the evidence of TKI efficacy for patients with newly diagnosed CP‐CML. Six trials at low risk of bias evaluating TKIs as an initial treatment in adults with newly diagnosed CP‐CML and enrolling 2,456 patients were included. Follow‐up times ranged from a median of 3 months to 5 years. Direct comparison showed statistically higher rates of major molecular response (MMR ≤ 0.1%^IS) achievement with second‐generation TKIs at 12 months which was sustained throughout treatment period. Bayesian mixed‐treatment comparison (MTC) analysis demonstrated superiority of both nilotinib and dasatinib over imatinib in terms of efficacy. Nilotinib was associated with higher deeper molecular responses (MR^4.5 ≤ 0.0032%^IS) at 60 months than dasatinib but no difference in MMR. The differences between nilotinib and dasatinib are likely clinically trivial. Among TKIs, nilotinib was found to have the best survival profile. Both nilotinib and dasatinib are associated with significantly better MMR compared to imatinib that is sustained over 60 months. This analysis shows that new‐generation TKIs are not only showing faster response but also maintaining a more potent one through longer follow‐up period. It is important to note out that MTC is not a substitute for well‐conducted RCTs investigating direct comparisons.     

Long-term outcomes in the second-line treatment of chronic myeloid leukemia: a review of tyrosine kinase inhibitors

Chronic myeloid leukemia (CML) is a progressive and often fatal myeloproliferative neoplasm. The hallmark of CML is an acquired chromosomal translocation known as the Philadelphia chromosome (Ph), which results in the synthesis of the breakpoint cluster region-Abelson murine leukemia (BCR-ABL) fusion oncoprotein, a constitutively active tyrosine kinase. The introduction of imatinib, a tyrosine kinase inhibitor (TKI) that is specific for BCR-ABL, was a major breakthrough in CML therapy. Although most patients respond to first-line imatinib therapy, some experience loss of response (resistance) or require treatment discontinuation because of toxicity (intolerance). For patients with CML, failure on standard-dose imatinib therapy (400 mg daily), imatinib dose escalation (600-800 mg daily) is a second-line option. However, high-dose imatinib is not an appropriate approach for patients who experience drug toxicity, and there remain questions over the durability of responses achieved with this strategy. Alternative second-line options include the TKIs dasatinib and nilotinib. A substantial amount of long-term data for these agents is available. Although both are potent and specific BCR-ABL TKIs, dasatinib and nilotinib exhibit unique pharmacologic profiles and response patterns relative to different patient characteristics, such as disease stage and BCR-ABL mutation status. To optimize therapeutic benefit, clinicians should select treatment based on each patient's historic response, adverse-event tolerance, and risk factors.     

Chronic myeloid leukemia: clinical impact of BCR-ABL1 mutations and other lesions associated with disease progression

The introduction of the tyrosine kinase inhibitors (TKIs) imatinib, dasatinib, and nilotinib has dramatically improved the treatment of chronic myeloid leukemia (CML). However, a minority of CML patients in chronic phase (CP) and a substantial proportion of patients in advanced phase are either initially refractory to TKIs or eventually develop resistance. Rates of resistance and relapse directly correlate with disease progression. The most frequently identified mechanism of acquired TKI resistance is BCR-ABL1 kinase domain (KD) mutations that impair TKI binding by disrupting the drug contact sites or causing conformational changes that make the contact sites inaccessible. The underlying mechanisms of disease progression are heterogeneous and only poorly understood. So far the most frequent and best characterized include genomic instability, loss of tumor-suppressor functions, and differentiation arrest. Clinical data indicate that both development of a BCR-ABL1 KD mutation during TKI treatment and/or disease progression are associated with a poorer outcome. Thus, therapeutic strategies are needed for the treatment or prevention of resistance and disease progression. They include, for example, TKI dose escalation, treatment interruption to stop selection of resistant cells, and allogeneic stem cell transplantation in eligible patients, as well as the use of novel TKIs with activity against resistant mutations and/or inhibition of alternative pathways.     

Mechanisms and novel approaches in overriding tyrosine kinase inhibitor resistance in chronic myeloid leukemia

Chronic myeloid leukemia is a stem cell-initiated but progenitor-driven disease induced by the BCR-ABL oncogene. Tyrosine kinase inhibitors (TKIs) were introduced in the late 1990s and have revolutionized the management of chronic myeloid leukemia in chronic phase. The majority of patients can now expect to live a normal life as long as they continue to comply with TKI treatment. However, in a significant proportion of cases TKI resistance develops over time, requiring a switch of therapy. The most frequent mechanism for drug resistance is the development of kinase domain mutations that reduce or completely ablate drug efficacy. Fortunately, the last 10 years have seen an impressive array of new drugs, some modeled on the mechanism of action of imatinib, others employing more novel approaches, for these patients.     

All tyrosine kinase inhibitor-resistant chronic myelogenous cells are highly sensitive to Ponatinib

The advent of tyrosine kinase inhibitor (TKI) therapy has considerably improved the survival of patients suffering chronic myelogenous leukemia (CML). Indeed, inhibition of BCR-ABL by imatinib, dasatinib or nilotinib triggers durable responses in most patients suffering from this disease. Moreover, resistance to imatinib due to kinase domain mutations can be generally circumvented using dasatinib or nilotinib, but the multi-resistant T315I mutation that is insensitive to these TKIs, remains to date a major clinical problem. In this line, ponatinib (AP24534) has emerged as a promising therapeutic option in patients with all kinds of BCR-ABL mutations, especially the T315I one. However and surprisingly, the effect of ponatinib has not been extensively studied on imatinib-resistant CML cell lines. Therefore, in the present study, we used several CML cell lines with different mechanisms of resistance to TKI to evaluate the effect of ponatinib on cell viability, apoptosis and signaling. Our results show that ponatinib is highly effective on both sensitive and resistant CML cell lines, whatever the mode of resistance and also on BaF3 murine B cells carrying native BCR-ABL or T315I mutation. We conclude that ponatinib could be effectively used for all types of TKI-resistant patients.     

BCR-ABL messenger RNA levels continue to decline in patients with chronic phase chronic myeloid leukemia treated with imatinib for more than 5 years and approximately half of all first-line treated patients have stable undetectable BCR-ABL using strict sensitivity criteria.

PURPOSE: In the first years of imatinib treatment, BCR-ABL remained detectable in all but a small minority of patients with chronic myeloid leukemia. We determined whether BCR-ABL continues to decline with longer imatinib exposure and the incidence and consequence of undetectable BCR-ABL. EXPERIMENTAL DESIGN: BCR-ABL levels were measured in a subset of 53 imatinib-treated IRIS trial patients for up to 7 years (29 first-line, 24 second-line). Levels were deemed undetectable using strict PCR sensitivity criteria. RESULTS: By 18 months, the majority achieved a 3-log reduction [major molecular response (MMR)]. BCR-ABL continued to decline but at a slower rate (median time to 4-log reduction and undetectable BCR-ABL of 45 and 66 months for first-line). The probability of undetectable BCR-ABL increased considerably from 36 to 81 months of first-line imatinib {7% [95% confidence interval (95% CI), 0-17%] versus 52% (95% CI, 32-72%)}. Undetectable BCR-ABL was achieved in 18 of 53 patients and none of these 18 lost MMR after a median follow-up of 33 months. Conversely, MMR was lost in 6 of 22 (27%) patients with sustained detectable BCR-ABL and was associated with BCR-ABL mutations in 3 of 6. Loss of MMR was recently defined as suboptimal imatinib response. There was no difference in the probability of achieving molecular responses between first- and second-line patients but first-line had a significantly higher probability of maintaining MMR [P = 0.03; 96% (95% CI, 88-100%) versus 71% (95% CI, 48-93%)]. CONCLUSIONS: With prolonged therapy, BCR-ABL continued to decline in most patients and undetectable BCR-ABL was no longer a rare event. Loss of MMR was only observed in patients with sustained detectable BCR-ABL.     

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.     

Attenuated Dose Dasatinib in Newly Diagnosed Chronic Myeloid Leukemia Chronic Phase Patients in India.

BackgroundBCR-ABL Tyrosine kinase inhibitors (TKI's) are most successful of targeted therapies and are currently considered the cornerstone in the management of patients with chronic myeloid leukemia (CML). A recent study reported excellent outcomes of Dasatinib 50mg with better sustained response. Therefore, we aim to evaluate the molecular responses and safety of upfront Dasatinib 50mg in Indian CML-Chronic Phase patients.MethodsIt was an observational single-centre study. CML-CP patients started on Dasatinib 50mg daily were offered to participate in this study. Data of imatinib was collected retrospectively as a comparator group.ResultsBetween June 2020 to Feb 2022, fifty patients were included in the dasatinib 50mg once daily group. Median age was 40 yrs. ranging from (19 to73) years. At a median follow up of 9.2 months, 49 patients completed three months treatment, out of which 48 patients were evaluated as one patient stopped medication after a month due to financial constraints. The response rate at three months for dasatinib 50mg daily and Imatinib were 68.75% and 69.7% respectively. At 12 months, 68% and 66.6% patients achieved major molecular response [MMR] in dasatinib 50mg and imatinib groups respectively.ConclusionIn conclusion, low dose dasatinib is safe and effective as an upfront therapy in CML-CP. Early molecular response [EMR] rates were comparable in low dose dasatinib and imatinib arm but deep molecular responses were significantly higher in low dose dasatinib arm. Dasatinib, taken daily at a dose of 50mg, may offer a new, alternative choice as generic versions are available now for frontline therapy in CML-CP.     

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.     

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.     

Tailoring tyrosine kinase inhibitor therapy to tackle specific BCR-ABL1 mutant clones

Several tyrosine kinase inhibitors (TKIs) are currently under development for the treatment of patients with chronic myelogenous leukemia (CML) resistant or intolerant of imatinib therapy, including nilotinib, dasatinib, and bosutinib. The current paradigm of TKI therapy involves a sequential use of these compounds, with imatinib invariably used as frontline therapy followed by either dasatinib or nilotinib on an empiric basis. A more sensible approach to this sequence is the selection of the TKI best suited to overcome the resistance conferred by BCR-ABL1 mutations detected at each time-point. As more TKIs are becoming available, the management of patients with CML will require degree of “finesse” to better match each patient with the best TKI available. This match is best made based on available in vitro data regarding the activity of each agent against each specific mutation. The case herein reported supports such strategy.     

Improving Outcomes in Chronic Myeloid Leukemia Over Time in the Era of Tyrosine Kinase Inhibitors

Most patients with chronic myeloid leukemia (CML) receiving treatment with BCR-ABL1 tyrosine kinase inhibitors (TKIs) will achieve favorable responses. Moreover, TKI therapy enables patients to experience long-term survival, with survival rates similar to those of individuals without CML. This enhanced survival has resulted from the availability of multiple BCR-ABL1 TKIs with efficacy, not only in frontline treatment, but, importantly, also in second- and third-line treatment. We have reviewed the changes in long-term outcomes in the era of TKI therapy and how these changes have affected treatment practices. We discuss the development of imatinib, the first BCR-ABL1 TKI, followed by newer TKIs, including nilotinib, dasatinib, bosutinib, and ponatinib. We consider the key studies that led to their development as frontline or later-line therapies, their safety profiles, and their effect on improving patient outcomes. With these improved outcomes, the definition of an optimal response has become more stringent, and treatment monitoring strategies have changed. Second-line patient populations have evolved from those with resistance to, or intolerance of, imatinib to those with moderate responses to, or low-grade adverse events with, imatinib. Although all TKIs are associated with high survival rates, newer TKIs have been associated with lower disease progression rates and, importantly, deeper treatment responses and, potentially, a greater chance of future treatment-free remission. Finally, we consider the unmet needs of patients with CML, including the challenges remaining for those without optimal responses during TKI therapy and new therapies and strategies to identify such patients at diagnosis.     

Implications of BCR-ABL1 kinase domain-mediated resistance in chronic myeloid leukemia

Patients with chronic myeloid leukemia develop resistance to both first-generation and second-generation tyrosine kinase inhibitors (TKIs) as a result of mutations in the kinase domain (KD) of BCR-ABL1. A wide range of BCR-ABL1 KD mutations that confer resistance to TKIs have been identified, and the T315I mutant has proven particularly difficult to target. This review summarizes the prevalence, impact, and prognostic implications of BCR-ABL1 KD mutations in patients with chronic myeloid leukemia who are treated with current TKIs and provides an overview of recent treatment guidelines and future trends for the detection of mutations.     

Practical advice for determining the role of BCR-ABL mutations in guiding tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia

Data demonstrating the superiority of nilotinib over imatinib in the frontline treatment of chronic myeloid leukemia (CML) and ongoing studies with dasatinib and bosutinib are rapidly changing the treatment landscape for CML. In this review, the authors discuss currently available therapies for CML, focusing on mechanisms of resistance to imatinib and treatment strategies to overcome resistance. Relevant articles were identified through searches of PubMed and abstracts from international hematology/oncology congresses. Additional information sources were identified from the bibliographies of these references and from the authors' own libraries and expertise. In vitro 50% inhibitory concentration (IC(50) ) data alone are not sufficient to guide the choice of a tyrosine kinase inhibitor (TKI) in the presence of a mutant breakpoint cluster region-v-abl Abelson murine leukemia viral oncogene homolog (BCR-ABL) clone, because there is a lack of data regarding how well such IC(50) values correlate with clinical response. A small subset of BCR-ABL mutant clones have been associated with impaired responses to second-generation TKIs (tyrosine to histidine mutation at codon 253 [Y253H], glutamic acid to lysine or valine mutation at codon 255 [E255K/V], and phenylalanine to cysteine or valine mutation at codon 359 [F359C/V] for nilotinib; valine to leucine mutation at codon 299 [V299L] and F317L for dasatinib); neither nilotinib nor dasatinib is active against the threonine to isoleucine mutation at codon 315 (T315I). For each second-generation TKI, the detection of 1 of a small subset of mutations at the time of resistance may be helpful in the selection of second-line therapy. For the majority of patients, comorbidities and drug safety profiles should be the basis for choosing a second-line agent. Clinical trial data from an evaluation of the response of specific mutant BCR-ABL clones to TKIs is needed to establish the role of mutation testing in the management of CML.     

Kinase domain point mutations in Philadelphia chromosome-positive acute lymphoblastic leukemia emerge after therapy with BCR-ABL kinase inhibitors

BACKGROUND: BCR-ABL kinase domain (KD) mutations are detected in approximately 45% of patients with imatinib-resistant chronic myeloid leukemia. Patterns of KD mutations in Philadelphia chromosome (Ph)-positive acute lympho- blastic leukemia (ALL) are less well studied. METHODS: The authors assessed KD mutations in patients with recurrent Ph-positive ALL after treatments that included 1 or more kinase inhibitors (n = 24 patients) or no prior kinase inhibitor (KI) therapy (n = 12 patients). RESULTS: ABL KD mutations were detected by direct sequencing in 15 of 17 patients (88%) who had recurrent Ph-positive ALL and received prior imatinib (n = 16) or dasatinib (n = 1) treatment and in 6 of 7 patients (86%) who had resistant/recurrent tumors treated with >or=2 KIs compared with 0 of 12 patients with recurrent Ph-positive ALL who never received KIs. A restricted set of mutations was observed, mostly Y253H and T315I, and were detected on average 10 months after KI initiation, and mutations were not detected in the initial tumor samples before KI therapy in 12 patients who were assessed. Using a more sensitive pyrosequencing method, mutations were not detected at codons 315 and 253 in the diagnostic samples from those 12 patients or in 30 patients with Ph-positive ALL who never developed recurrent disease. CONCLUSIONS: ABL KD mutations, especially at codons 315 and 253, emerged at the time of disease recurrence in the vast majority of patients who had Ph-positive ALL and received maintenance KI therapy. Thus, the authors concluded that ongoing KI exposure may alter the patterns of recurrence and favor the outgrowth of clones with KI-resistant mutations.