Chronic myeloid leukaemia Apperley, Jane F, Prof
The Lancet (British edition),
04/2015, Letnik:
385, Številka:
9976
Journal Article
Recenzirano
Summary In less than 10 years, the prognosis of chronic myeloid leukaemia has changed from that of a fatal disease to a disorder amenable simply to lifelong oral medication and compatible with a ...normal lifespan. This change has been made possible by a deep understanding of the molecular pathogenesis and a determination to develop targeted and selective drugs. This Seminar summarises the presentation, pathophysiology, diagnosis and monitoring technology, treatment options, side-effects, and outcomes of chronic myeloid leukaemia, and discusses the possibility of cure—ie, stable undetectable or low level disease in the absence of medication. Chronic myeloid leukaemia continues to instruct us in the mechanisms of leukaemogenesis and provides hope not only for similar developments in management of other malignancies, but also for the remarkable speed with which these can move from bench to bedside.
Summary The introduction of selective tyrosine-kinase inhibitors (TKIs) for the treatment of chronic myeloid leukaemia has changed patient outcome and, consequently, management of this disease. ...Imatinib is now the treatment of choice for most newly diagnosed patients. Excellent responses, in terms of symptom control and haematological parameters, are usually obtained. However, failure to completely eradicate leukaemic cells and the escape of these cells from previous control has led to an intensive search for the mechanisms of resistance and subsequent treatments by which to overcome this resistance. Up to now, there has been considerable focus on the role of ABL-kinase-domain mutations as mediators of resistance to imatinib, thereby encouraging the development of a second generation of TKIs capable of inhibiting these mutant proteins. However, studies have increasingly shown that these mutations do not account for all cases of resistance and have a negligible role in the inability of TKIs to eradicate residual disease in patients who are good responders. More recently, attention has turned to the relative roles of drug bioavailability and drug efflux and drug influx proteins in the development of resistance to imatinib. This review is the first of two papers and discusses imatinib resistance and its potential causes. The second paper will focus on the assessment and subsequent management of patients with less than optimum responses to imatinib.
Chronic myeloid leukemia is characterized by a single genetic abnormality resulting in a fusion gene whose mRNA product is easily detected and quantified by reverse-transcriptase polymerase chain ...reaction analysis. Measuring residual disease was originally introduced to identify patients relapsing after allogeneic stem cell transplantation but rapidly adopted to quantify responses to tyrosine kinase inhibitors. Real-time quantitative polymerase chain reaction is now an essential tool for the management of patients and is used to influence treatment decisions. In this review we track this development including the international collaboration to standardize results, discuss the integration of molecular monitoring with other factors that affect patients' management, and describe emerging technology. Four case histories describe varying scenarios in which the accurate measurement of residual disease identified patients at risk of disease progression and allowed appropriate investigations and timely clinical intervention.
Ponatinib has potent activity against native and mutant BCR-ABL1, including BCR-ABL1T315I. The pivotal phase 2 Ponatinib Ph+ ALL and CML Evaluation (PACE) trial evaluated efficacy and safety of ...ponatinib at a starting dose of 45 mg once daily in 449 patients with chronic myeloid leukemia (CML) or Philadelphia chromosome–positive acute lymphoblastic leukemia (ALL) resistant/intolerant to dasatinib or nilotinib, or with BCR-ABL1T315I. This analysis focuses on chronic-phase CML (CP-CML) patients (n = 270) with 56.8-month median follow-up. Among 267 evaluable patients, 60%, 40%, and 24% achieved major cytogenetic response (MCyR), major molecular response (MMR), and 4.5-log molecular response, respectively. The probability of maintaining MCyR for 5 years was 82% among responders. Dose reductions were implemented in October 2013 to decrease the risk of arterial occlusive events (AOEs); ≥90% of CP-CML patients who had achieved MCyR or MMR maintained response 40 months after elective dose reductions. Estimated 5-year overall survival was 73%. In CP-CML patients, the most common treatment-emergent adverse events were rash (47%), abdominal pain (46%), thrombocytopenia (46%), headache (43%), dry skin (42%), and constipation (41%). The cumulative incidence of AOEs in CP-CML patients increased over time to 31%, while the exposure-adjusted incidence of new AOEs (15.8 and 4.9 per 100 patient-years in years 1 and 5, respectively) did not increase over time. These final PACE results demonstrate ponatinib provides durable and clinically meaningful responses, irrespective of dose reductions, in this population of heavily pretreated CP-CML patients. This trial was registered at www.clinicaltrials.gov as #NCT01207440.
•Ponatinib continued to provide deep, durable responses in heavily pretreated patients with CP-CML.•Tolerability was acceptable in this heavily pretreated population with 5 years of follow-up.
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Patients with chronic myeloid leukemia in chronic phase (CML-CP) resistant/intolerant to ≥2 tyrosine kinase inhibitors (TKIs) are at high risk of experiencing poor outcomes because of disease biology ...and inadequate efficacy and/or safety of current therapies. Asciminib, a first-in-class BCR-ABL1 inhibitor Specifically Targeting the ABL Myristoyl Pocket (STAMP), has the potential to overcome resistance/intolerance to approved TKIs. In this phase 3, open-label study, patients with CML-CP previously treated with ≥2 TKIs were randomized (2:1) to receive asciminib 40 mg twice daily vs bosutinib 500 mg once daily. Randomization was stratified by major cytogenetic response (MCyR) status at baseline. The primary objective was to compare the major molecular response (MMR) rate at week 24 for asciminib vs bosutinib. A total of 233 patients were randomized to asciminib (n = 157) or bosutinib (n = 76). Median follow-up was 14.9 months. The MMR rate at week 24 was 25.5% with asciminib and 13.2% with bosutinib. The difference in MMR rate between treatment arms, after adjusting for MCyR at baseline, was 12.2% (95% confidence interval, 2.19-22.30; 2-sided P = .029). Fewer grade ≥3 adverse events (50.6% vs 60.5%) and adverse events leading to treatment discontinuation (5.8% vs 21.1%) occurred with asciminib than with bosutinib. The study showed a superior efficacy of asciminib compared with that of bosutinib, together with a favorable safety profile. These results support the use of asciminib as a new therapy in patients with CML-CP who are resistant/intolerant to ≥2 prior TKIs. This trial was registered at www.clinicaltrials.gov as #NCT03106779.
Leukemia in pregnancy remains a challenging therapeutic prospect. The prevalence is low at ∼1 in 10 000 pregnancies, and as a result data are limited to small retrospective series and case reports, ...rendering evidence-based recommendations for management strategies difficult. The management of the leukemias in pregnancy requires close collaboration with obstetric and neonatology colleagues as both the maternal and fetal outcomes must be taken into consideration. The decision to introduce or delay chemotherapy must be balanced against the impact on maternal and fetal survival and morbidity. Invariably, acute leukemia diagnosed in the first trimester necessitates intensive chemotherapy that is likely to induce fetal malformations. As delaying treatment in this situation is usually inappropriate, counseling with regard to termination of pregnancy is often essential. For chronic disease and acute leukemia diagnosed after the second trimester, therapeutic termination of the pregnancy is not inevitable and often, standard management approaches similar to those in nongravid patients can be used. Here, the management of the acute and chronic leukemias will be addressed.
The International Society for Stem Cell Research (ISSCR) presents its 2016 Guidelines for Stem Cell Research and Clinical Translation (ISSCR, 2016). The 2016 guidelines reflect the revision and ...extension of two past sets of guidelines (ISSCR, 2006; ISSCR, 2008) to address new and emerging areas of stem cell discovery and application and evolving ethical, social, and policy challenges. These guidelines provide an integrated set of principles and best practices to drive progress in basic, translational, and clinical research. The guidelines demand rigor, oversight, and transparency in all aspects of practice, providing confidence to practitioners and public alike that stem cell science can proceed efficiently and remain responsive to public and patient interests. Here, we highlight key elements and recommendations in the guidelines and summarize the recommendations and deliberations behind them.
•The ISSCR presents its new Guidelines for Stem Cell Research and Clinical Translation•The guidelines outline core principles and best practices for the field•Recommendations drive rigor and transparency in all aspects of stem cell research•The guidelines build widespread confidence in the integrity of the research enterprise
The International Society for Stem Cell Research (ISSCR) presents its 2016 Guidelines for Stem Cell Research and Clinical Translation (ISSCR, 2016). The 2016 guidelines reflect the revision and extension of two past sets of guidelines (ISSCR, 2006; ISSCR, 2008) to address new and emerging areas of stem cell discovery and application and evolving ethical, social, and policy challenges. These guidelines provide an integrated set of principles and best practices to drive progress in basic, translational, and clinical research. The guidelines demand rigor, oversight, and transparency in all aspects of practice, providing confidence to practitioners and public alike that stem cell science can proceed efficiently and remain responsive to public and patient interests. Here, we highlight key elements and recommendations in the guidelines and summarize the recommendations and deliberations behind them.
Imatinib has now been in use for almost 10 years. Despite this cumulative experience, little is known about its effects on pregnancy; as a result, there are few published data to facilitate the ...counseling of women who conceive while taking imatinib. The results we now present provide information which may be of use in such circumstances. Of 180 women exposed to imatinib during pregnancy, outcome data are available for 125 (69%). Of those with known outcomes, 50% delivered normal infants and 28% underwent elective terminations, 3 following the identification of abnormalities. There were a total of 12 infants in whom abnormalities were identified, 3 of which had strikingly similar complex malformations that are clearly a cause for concern. It appears that although most pregnancies exposed to imatinib are likely to have a successful outcome, there remains a risk that exposure may result in serious fetal malformations.
We studied BCR-ABL1 transcript levels in patients with chronic myeloid leukemia in chronic phase (CML-CP) at 3, 6, and 12 months after starting imatinib to identify molecular milestones that would ...predict for overall survival (OS) and other outcomes more reliably than serial marrow cytogenetics.
We analyzed 282 patients with CML-CP who received imatinib 400 mg/d as first-line therapy followed by dasatinib or nilotinib if treatment with imatinib failed. We used a receiver operating characteristic curve to identify the cutoffs in transcript levels at 3, 6, and 12 months that would best predict patient outcome. We validated our findings in an independent cohort of 95 patients treated elsewhere.
Patients with transcript levels of more than 9.84% (n = 68) at 3 months had significantly lower 8-year probabilities of OS (56.9% v 93.3%; P < .001), progression-free survival, cumulative incidence of complete cytogenetic response, and complete molecular response than those with higher transcript levels. Similarly, transcript levels of more than 1.67% (n = 87) at 6 months and more than 0.53% (n = 93) at 12 months identified high-risk patients. However, transcript levels at 3 months were the most strongly predictive for the various outcomes. When we compared OS for the groups defined molecularly at 6 and 12 months with the usual cytogenetic milestones, categorization by transcript numbers was the only independent predictor for OS (relative risk, 0.207; P < .001 and relative risk, 0.158; P < .001, respectively).
A single measurement of BCR-ABL1 transcripts performed at 3 months is the best way to identify patients destined to fare poorly, thereby allowing early clinical intervention.
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