Chronic lymphocytic leukaemia (CLL)
Poor prognostic factors in relapsed/refractory CLL
There has been significant progress in the treatment of patients with CLL with improved knowledge of disease biology leading to the introduction of targeted agents and immunotherapies. Thus, when treating a patient with CLL, physicians may face the difficult task of choosing the most appropriate therapeutic regimen given this rapidly evolving field. Carol Moreno, Barcelona, Spain, explored standard approaches to relapsed CLL after first-line chemoimmunotherapy, along with the challenges of choosing the right regimen. Historically, treatment options for patients with relapsed/refractory (R/R) CLL have been limited, but this scenario has since changed following the introduction of pathway inhibitors, including Bruton tyrosine kinase (BTK) inhibitors (ibrutinib, acalabrutinib), phosphatidylinositol 3-kinase (PI3K) inhibitors (idelalisib, duvelisib), and time-limited therapy with venetoclax-based regimens. Patient-related factors, disease-related factors, and prior therapies need to be taken into consideration when selecting second-line therapy. In addition, treatment should be initiated only when International Workshop on Chronic Lymphocytic Leukemia criteria are met in the presence of signs or symptoms of disease activity, as in newly diagnosed patients.
"Selecting therapy for R/R CLL requires clinicians to take into consideration several patient, disease, prior therapy, and socioeconomic aspects.”
Carol Moreno, Barcelona, Spain
Continuous therapy with BTK inhibitors and fixed duration of venetoclax with anti-CD20 monoclonal antibodies have significantly improved the outcomes of patients with R/R CLL when compared with chemoimmunotherapy. However, TP53 aberrations are negative outcome predictors for BTK inhibitors and venetoclax-based regimens.
Standard approaches to relapsed/refractory CLL after 1st-line chemoimmunotherapy
Jacqueline Barrientos, New York, USA, explored the challenge of selecting chemotherapy-free first-line therapy in patients with CLL. Dr Barrientos presented data showing that fit patients with immunoglobulin heavy chain variable region gene (IGHV) mutations benefit from chemotherapy-based first-line treatment, while the following patients with CLL will benefit from chemotherapy-free first-line treatment:
- High-risk genomic features (IGHV unmutated, TP53 mutation)
- High-risk cytogenetics (17p deletion, complex karyotype)
- Patients with comorbid medical conditions
First-line, chemotherapy-free treatments for CLL include ibrutinib with/without rituximab or obinutuzumab, acalabrutinib with/without obinutuzumab, and venetoclax with/without obinutuzumab. Early intervention is not recommended, with consensus guidelines from the International Workshop on Chronic Lymphocytic Leukemia recommending initiating treatment only at the onset of constitutional symptoms. In addition, data are lacking at this time to suggest a benefit of early intervention based on prior studies utilising chemoimmunotherapy at the time of diagnosis.
“First-line treatment options should be tailored to patient’s age, comorbidities, CLL risk factors, and patient preference or treatment duration.”
Jacqueline Barrientos, New York, USA
First-line, chemotherapy-free treatment algorithm for CLL
Anthony Mato, New York, USA, explored treatment strategies for relapsed CLL after chemotherapy-free first-line regimens. When thinking about patients treated on chemotherapy-free pathways in the first-line setting, there are two groups to consider: BTK inhibitor-treated patients and venetoclax-treated patients. In either case, three major factors need to be considered:
- Reasons for discontinuation
- Available treatment options
- Levels of evidence to support clinical decision making
Dr Mato highlighted that it was important to recognise that CLL may not require therapy immediately on progression. Instead, therapy should be initiated when CLL becomes symptomatic.
Trigger symptoms for progressing CLL
Novel agents approved in the R/R CLL setting include ibrutinib, acalabrutinib, idelalisib (in combination with rituximab), duvelisib, and venetoclax (in combination with rituximab). Dr Mato noted that although these agents have demonstrated efficacy in R/R CLL cohorts, the studies that led to their approvals largely examined patients who had previously received prior chemoimmunotherapy and rarely novel agents as first-line treatment.
All BTK inhibitor options are continuous therapies, with treatment to CLL progression, transformation, or adverse events. In contrast, treatment with venetoclax plus obinutuzumab is time limited for 12 months, with treatment to completion of therapy, CLL progression, transformation, or adverse events. For patients experiencing progression while receiving BTK inhibitor therapy, discontinuation of treatment can result in tumour flare, which can be both difficult to control and life threatening. In this case, treatment with a BTK inhibitor should be continued despite progression until the next therapy is ready to be administered.
“The optimal sequencing of therapies within a chemotherapy-free paradigm will continue to be a pressing issue in the care of patients with relapsed/refractory CLL.”
Anthony Mato, New York, USA
Factors to consider for BTK inhibitor versus venetoclax/rituximab combination
Recognising limitations of applying available data to patients who have received only one prior line of therapy, venetoclax with/without rituximab after BTK inhibitor failure appears to produce higher response rates and improved outcomes than other standard of care options (PI3K inhibitors, anti-CD20 monoclonal antibodies, or chemoimmunotherapy).
Thus, Dr Mato recommended second-line treatment with venetoclax as a continuous therapy or venetoclax with rituximab as a 2-year fixed duration therapy as standard-of-care options, with selection between these regimens dependent upon patient preference. For patients who have progressed after first-line venetoclax and obinutuzumab, initial data suggest that a BTK inhibitor is likely to produce high response rates and durable remissions. For patients who had deep responses and/or prolonged treatment-free intervals after fixed duration venetoclax therapy, retreatment with a venetoclax-based regimen is an appealing option, although additional data on the efficacy of this approach are needed.
Acute myeloid leukaemia (AML)
Therapeutic outcomes remain poor for patients aged >60 years with AML, which is compounded by the ‘paralysing’ problem of too many treatment options. Jacqueline S. Garcia, Boston, USA, discussed whether patient fitness continues to play a role in determining first-line treatment choice for AML. Traditionally, a patient’s underlying fitness has been a key factor when determining initial treatment choice following a diagnosis of AML, given that physicians were limited to cytotoxic chemotherapeutic agents. However, more recently, relatively effective and less intensive AML treatments have become more widely available. These include hypomethylating agent- and cytarabine-based combinations with venetoclax or glasdegib, and current first-line non-intensive options include the targeted isocitrate dehydrogenase 1 (IDH1) inhibitor ivosidenib. Importantly, clinical benefit with these newer, less intensive combination strategies have been observed across historically difficult-to-treat secondary AML and poor-risk cytogenetic and molecular subgroups commonly enriched in the older AML population.
While tools such as the Ferrara et al. consensus criteria (Leukemia 2013;27:997–9) can be useful for determining fitness level for intensive induction chemotherapy, functional and genomic biomarkers are now becoming increasingly integrated to guide treatment selection. Azacitidine plus venetoclax is a new standard of care, which benefits most unfit patients including IDH1/IDH2 mutated patients. However, there is room for improvement given that patients aged <75 years appear to achieve less therapeutic effect.
Alison R. Walker, Columbus, USA, discussed recommendations for best practice to help guide the increasingly complex treatment discussions that are needed for patients at each stage of their disease. Dr Walker highlighted the importance of helping patients make an informed decision by weighing the risk of relapse with their wishes and desired quality of life. Most clinicians would agree that shared-decision making is an approach for those situations where there is more than one correct choice for a patient. While many physicians may think that they already adhere to shared-decision making, Dr Walker was keen to highlight many new diagnosis physician-patient discussions tend to be one-sided and technical, focus on information delivery, list all treatment options, and are less likely to ask patients about what they know/want to know and how they want to participate in the decision-making process.
“Shared decision making is based on the belief that a patient’s needs and desired outcomes should form the basis for all clinical decisions.”
Alison R. Walker, Columbus, USA
Three-talk model for shared decision making
Eunice S. Wang, Buffalo, USA, discussed the management of toxicities associated with targeted therapies for AML. While the ability to treat AML in the outpatient setting with efficacious novel agents has been transformative, many patients are still frail and remain at risk for treatmentrelated complications. Thus, an understanding of how best to manage the adverse effects of these agents remains important.
“Knowing when to push through and when to stop therapy is essential to striking the elusive balance between prolonging survival and preserving meaningful quality of life.”
Eunice S. Wang, Buffalo, USA
When to stop and when to push through with AML treatments
The changing treatment landscape in AML
The availability of a number of new therapeutic options suitable for outpatient administration has led to a fundamental shift in the treatment landscape for acute leukaemia. Thus, there is increased interest in treating acute leukaemia patients in the community rather than referring them to academic centres. Anna Halpern, Seattle, USA, explored practice patterns and outcomes for patients treated in the community compared with academic centres, with a focus on potential reasons for any differences.
Data suggest that patients with AML treated at higher-volume hospitals have lower early mortality rates and lower rates of transfer to hospice care. Patients treated at academic centres have lower short-term mortality and longer 5-year survival after adjusting for covariates. Of note, better supportive care may play a role, leading to lower rates of respiratory and renal failure and cardiac arrest. Specific patient subsets also appear to benefit most from care at academic centres – these include acute promyelocytic leukaemia, adolescent and young adults with favourable disease, and adolescent and young adults with acute lymphoblastic leukaemia. When considering the impact of newer therapeutic agents, the availability of effective oral drugs and/or IV lower-intensity drugs will increase the proportion of patients treated at community centres, including those individuals who are old and/or have low fitness. However, the risk(s)/benefit(s) of delivering lower-intensity therapies at academic versus community centres currently remain unknown. As therapies can lead to prolonged cytopenia and toxicities, the question of which centres provide better supportive care remains relevant. In addition, use of these therapeutic agents requires access to timely molecular testing.
“With rapidly changing AML treatment landscape, the pros and cons of academic versus community setting treatment should be revisited continuously.”
Anna Halpern, Seattle, USA
Chronic myeloid leukaemia (CML)
Life expectancy is unaffected by a diagnosis of CML for the majority of patients with chronic phase disease because of the unparalleled efficacy of BCR-ABL-targeted tyrosine kinase inhibitors (TKIs) in halting disease progression. However in daily clinical practice, patients with CML frequently have medical comorbidities that can lead to an increased risk of adverse events with TKI therapy. Thus, a key goal is to optimise patient outcomes weighing CML disease risk factors, patient age and medical history. Vivian Oehler, Seattle, USA, briefly discussed the evidence guiding selection between the first-generation TKI imatinib and the second-generation TKIs bosutinib, dasatinib, and nilotinib as first-line therapy in the context of patient-specific CML disease risk factors, therapy-related risks, and treatment goals.
Although rare, identifying patients with CML at higher risk for disease progression or resistance is important and influences first-line TKI selection. These patients require close monitoring to ensure that they achieve treatment milestones and rapid transition to alternative therapies when they do not. To date, when looking at all patients, no statistically significant improvement in OS or PFS has been reported for any second-generation TKI, used at recommended first-line doses, as compared with imatinib. However, first-line Phase III studies have observed that:
- Patients receiving second-generation TKIs achieve more rapid molecular responses
- Dasatinib- and nilotinib-treated patients develop fewer mutations conferring TKI resistance and achieve responses allowing treatment-free remission (TFR) consideration more rapidly
- Although rare, nilotinib-treated patients have fewer progression events to accelerated phase or blast phase.
A clinically relevant question is whether sequencing a second-generation TKI after imatinib rather than starting a first-line second-generation TKI misses a critical treatment window. However, for many patients with appropriate monitoring, switching from imatinib to a second-generation TKI for resistance will result in good outcomes. ‘Hitting’ high-risk CML ‘hard’ upfront with a second-generation TKI is appealing because the longer the time the patient spends with higher levels of unopposed BCR-ABL1, the more likely it is that new ABL-independent genetic and molecular changes will appear.
Response rates with imatinib
Considerations when selecting first-line therapy
“Second-generation TKI use is associated with a higher probability of achieving early molecular response, MMR, and deeper molecular responses, than imatinib.”
Vivian Oehler, Seattle, USA
Delphine Rea, Paris, France, discussed the selection of patients with CML who may safely discontinue TKI therapy. Dr Rea explained how the paradigm for managing patients with CML is evolving. Up until recently, the best achievable therapeutic outcome was the restoration of a normal life expectancy via never-ending targeted therapy with BCR-ABL1 TKIs – this approach aims to prevent disease progression to blast phase along with mitigation of iatrogenic risks. However, long-term TFR with continued response off TKI therapy is now recognised as the most optimal benefit of treatment, with numerous independent clinical trials providing solid proof that TKI discontinuation is feasible in those patients with deep and sustained molecular responses. Based on deep molecular response (DMR) probabilities and success rates of TFR attempts in clinical studies ranging between 40–65%, it is estimated that with current array of TKIs and management strategies, approximately 10–30% of all patients with CML may achieve TFR. However, suitable patients need to be able to maintain an optimal molecular response after therapy cessation. Clinical practice recommendations are now available to guide physicians regarding the selection of patients for TKI discontinuation. In the first-line setting, the likelihood of gaining a DMR depends on ≥3 parameters:
Likelihood of developing a deep molecular response
For those patients incapable of reaching DMR or deemed to have a low likelihood of DMR, a change of TKI or combination therapy as a way to achieve DMR is currently being explored. So when is the right time to discontinue TKIs in patients with DMR? Although some patients may obtain DMR rapidly, stopping TKIs before the third year of therapy is not advisable, because most CML progression events occur during the first 2 to 3 years of treatment. Of note, optimal durations of TKI therapy and DMR and best DMR levels before TKI discontinuation remain under debate.
Benefits and risk of TKI withdrawal
Jorge Cortes, Augusta, USA, examined how patient comorbidities, particularly cardiovascular (CV) risk factors, impact upon the risk for serious adverse events and subsequent monitoring and management in CML. Patients with CML often have comorbidities, many of which have made them ineligible for clinical trials. Thus, information about how to manage patients with comorbidities and their concomitant medications remains limited. Comorbidities have been shown to increase the risk of developing adverse events such as arterio-occlusive events, which are now the main cause of death for patients with CML treated with TKIs. While there is no direct comparison between the second-generation TKIs, randomised studies of dasatinib, nilotinib, and bosutinib versus imatinib have established the relative incidence of arterio-occlusive events using imatinib as a ‘control’. As such, TKI selection for CML patients with high-risk features for arterio-occlusive events should consider the patient’s risk and goals. The ABCDE approach, recommended for the general population, can be considered for patients receiving TKIs, particularly those with comorbidities, and those with the highest-risk disease (e.g. by Sokal) for whom control of the disease is better served by a second-generation TKI despite the higher risk of arterio-occlusive events. Monitoring blood pressure remains important, given that systolic and diastolic blood pressures increase after TKI treatment is initiated. In addition, there is an ongoing need to actively manage all other comorbidities and support lifestyle changes, where needed, to reduce the risk of these events.
“Treatment-free remission is the best achievable outcome of therapy with TKIs in CML.”
Delphine Rea, Paris, France
ABCDE approach to CV risk
“There are two elements to treating a CML patient with several comorbidities – deciding what the best TKI option is and managing their comorbidities.”
Jorge Cortes, Augusta, USA
ASH 2020 was a successful meeting with attendees able to remotely access new data and insights, which will hopefully stimulate new ways of thinking and ultimately translate into optimal patient care within the haematology field. In addition, the virtual format provided the opportunity for participants, particularly those outside the US, to attend ASH perhaps for the first time. This revised format for 2020 will have also enabled more institutions around the world to gain access to the meeting content.
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