Regardless of line of therapy, treatment goals in chronic phase chronic myeloid leukemia (CML) are: avoid progression to accelerated phase or blast crisis CML such that patients achieve a life ...expectancy comparable with that of the general population; avoid adverse events (AEs); and restore and maintain quality of life. The most important prognostic factor for achieving these goals is response to tyrosine kinase inhibitors (TKIs) at key milestones. For patients failing a TKI, a treatment change is mandatory to limit the risk of progression and death. There is currently no precise guideline for patients that fail a second-generation TKI, and there is a paucity of data to guide clinical decision making in this setting. There is, therefore, an unmet need for practical and actionable guidance on how to manage patients who fail a second-generation TKI. Although the term 'failure' includes patients failing for resistance or intolerance, the focus of this paper is failure of a second-generation TKI because of resistance. CML patients who fail their first second-generation TKI for true resistance need a more potent therapy. In these patients, the key issues to consider are the relative appropriateness of early allogeneic hematopoietic stem cell transplantation or the use of a further TKI. Selection of the next line of treatment after second-generation TKI resistance should be individualized and must be based on patient-specific factors including cytogenetics, mutation profile, comorbidities, age, previous history of AEs with prior TKI therapy, and risk profile for AEs on specific TKIs. This expert opinion paper is not in conflict with existing recommendations, but instead represents an evolution of previous notions, based on new data, insights, and clinical experience. We review the treatment options for patients resistant to second-generation TKI therapy and provide our clinical opinions and guidance on key considerations for treatment decision making.
The management of chronic myeloid leukaemia (CML) has changed extensively over the past 15 years. Prior to the development of targeted therapies and in the absence of allogeneic haematopoetic ...stem-cell transplantation (HSCT), the median survival was 5-7 years. HSCT was quickly established as the standard of care for eligible patients through the 1980s and 1990s, when considerable advances were made in the optimization of conditioning regimens and supportive care. Exploiting a deeper understanding of the molecular basis of CML, the development of tyrosine kinase inhibitors (TKIs) in the late 1990s revolutionized the management of the disease. TKIs offer the prospect of long-term disease control with a simple oral therapy, and are the first-line treatment in the 21(st) century. The majority of patients treated with TKIs achieve excellent responses with sustained treatment, and some even continue to have undetectable or exceptionally low level disease upon TKI withdrawal; however, for an almost equal number of patients, an adequate response cannot be achieved with any of the currently available TKIs. For those patients who fail to respond adequately to TKIs, HSCT offers the best prospect of long-term survival.
SARS-CoV-2 infection, and resulting disease, COVID-19, has a high mortality amongst patients with haematological malignancies. Global vaccine rollouts have reduced hospitalisations and deaths, but ...vaccine efficacy in patients with haematological malignancies is known to be reduced. The UK-strategy offered a third, mRNA-based, vaccine as an extension to the primary course in these patients. The MARCH database is a retrospective observational study of serological responses in patients with blood disorders. Here we present data on 381 patients with haematological malignancies. By comparison with healthy controls, we report suboptimal responses following two primary vaccines, with significantly enhanced responses following the third primary dose. These responses however are heterogeneous and determined by haematological malignancy sub-type and therapy. We identify a group of patients with continued suboptimal vaccine responses who may benefit from additional doses, prophylactic extended half-life neutralising monoclonal therapies (nMAB) or prompt nMAB treatment in the event of SARS-CoV-2 infection.
To review and update the European LeukemiaNet (ELN) recommendations for the management of chronic myeloid leukemia with imatinib and second-generation tyrosine kinase inhibitors (TKIs), including ...monitoring, response definition, and first- and second-line therapy.
These recommendations are based on a critical and comprehensive review of the relevant papers up to February 2009 and the results of four consensus conferences held by the panel of experts appointed by ELN in 2008.
Cytogenetic monitoring was required at 3, 6, 12, and 18 months. Molecular monitoring was required every 3 months. On the basis of the degree and the timing of hematologic, cytogenetic, and molecular results, the response to first-line imatinib was defined as optimal, suboptimal, or failure, and the response to second-generation TKIs was defined as suboptimal or failure.
Initial treatment was confirmed as imatinib 400 mg daily. Imatinib should be continued indefinitely in optimal responders. Suboptimal responders may continue on imatinb, at the same or higher dose, or may be eligible for investigational therapy with second-generation TKIs. In instances of imatinib failure, second-generation TKIs are recommended, followed by allogeneic hematopoietic stem-cell transplantation only in instances of failure and, sometimes, suboptimal response, depending on transplantation risk.
Asciminib, the first BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP), is approved worldwide for the treatment of adults with Philadelphia chromosome-positive chronic ...myeloid leukemia in chronic phase (CML-CP) treated with ≥2 prior tyrosine kinase inhibitors (TKIs). In ASCEMBL, patients with CML-CP treated with ≥2 prior TKIs were randomized (stratified by baseline major cytogenetic response MCyR) 2:1 to asciminib 40 mg twice daily or bosutinib 500 mg once daily. Consistent with previously published primary analysis results, after a median follow-up of 2.3 years, asciminib continued to demonstrate superior efficacy and better safety and tolerability than bosutinib. The major molecular response (MMR) rate at week 96 (key secondary endpoint) was 37.6% with asciminib vs 15.8% with bosutinib; the MMR rate difference between the arms, after adjusting for baseline MCyR, was 21.7% (95% CI, 10.53-32.95; two-sided p = 0.001). Fewer grade ≥3 adverse events (AEs) (56.4% vs 68.4%) and AEs leading to treatment discontinuation (7.7% vs 26.3%) occurred with asciminib than with bosutinib. A higher proportion of patients on asciminib than bosutinib remained on treatment and continued to derive benefit over time, supporting asciminib as a standard of care for patients with CML-CP previously treated with ≥2 TKIs.
Bosutinib, a BCR-ABL1 tyrosine kinase inhibitor (TKI), has been available for several years as a treatment for chronic-, accelerated-, and blast-phase chronic myeloid leukemia (CML), for patients ...with resistance or intolerance to prior therapy. In 2017, the BFORE trial demonstrated efficacy of bosutinib as first-line treatment in adult patients with newly diagnosed chronic-phase chronic myeloid leukemia (CP-CML). The most common adverse events (AEs) of any grade in bosutinib-treated patients in BFORE were diarrhea, nausea, thrombocytopenia, increased alanine aminotransferase, and increased aspartate aminotransferase, consistent with the most commonly reported AEs in earlier studies. To balance the efficacy and tolerability of treatment to optimize patient adherence with medications, treating physicians commonly use various strategies such as initiating treatment at a lower dose, dose reduction, or dose interruption, depending on the type and severity of the AEs and the clinical setting. In light of the recent data from first-line treatment, an expert panel of hematologists reviewed management strategies for the use of bosutinib in treatment of CP-CML and made the recommendations reported here. Although the panel focused on first-line treatment, the principles can be for the most part extended to bosutinib use in later lines of treatment. Recommendations include advice regarding prophylaxis and management for diarrhea. The panel also considered optimum timing for referral to a specialist for specific AEs. Across the commonly occurring AEs, the panel highlighted the importance of education and communication with patients about anticipated AEs.
Summary
Targeted therapy for chronic myeloid leukaemia (CML) has allowed for a near‐normal patient life‐expectancy; however, quality of life and aggravation of existing co‐morbidities have posed new ...treatment challenges. In clinical practice, TKI dose reduction occurs frequently, often on multiple occasions, because of intolerance. We conducted a retrospective ‘real‐world practice’ review of 246 patients receiving lower than standard dose (LD) TKI after the achievement of major molecular response (MR3), because of intolerable adverse events. In 274 of 298 cases of dose reduction (91·9%), MR3 was maintained at median follow‐up of 27·3 months. One patient progressed to blast crisis while on LD TKI. Two patients developed two new ABL kinase domain mutations (T315I and V299L), of whom one had achieved deep molecular response on an alternative LD TKI at last follow‐up. Seventy‐six patients eventually discontinued LD TKI and the two‐year treatment‐free remission (TFR) rate in these patients was 74·1%. The majority of patients with CML in at least MR3 appear to be safely managed with LD TKI, although three of 246 patients had new events (progression and new mutation), indicating that this approach requires vigilance. TKI LD does not prevent the achievement of TFR in this patient population.
Chronic graft-versus-host disease (cGVHD) is a major limitation of successful hematopoietic cell transplantation. The safety and efficacy of extracorporeal photopheresis (ECP) for 12 to 24 weeks ...together with standard therapy was compared with standard therapy alone in patients with cutaneous manifestations of cGVHD that could not be adequately controlled by corticosteroid treatment. The primary efficacy end point was a blinded quantitative comparison of percent change from baseline in Total Skin Score (TSS) of 10 body regions at week 12. Ninety-five patients were randomized to either ECP and standard therapy (n = 48) or standard therapy alone (n = 47). The median percentage improvement in TSS at week 12 was 14.5% for the ECP arm and 8.5% for the control arm (P = .48). The proportion of patients who had at least a 50% reduction in steroid dose and at least a 25% decrease from baseline in TSS was 8.3% in the ECP arm at week 12 and 0% in the control arm (P = .04). The nonblinded investigator assessment of skin complete or partial responses revealed a significant improvement in favor of ECP (P < .001). ECP was generally well tolerated. These results suggest that ECP may have a steroid-sparing effect in the treatment of cGVHD. Clinical trials registered at www.ClinicalTrials.gov as NCT00054613.
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