Thomas Kipps, MD, PhD, discusses the chronic lymphocytic leukemia treatment spectrum and the explosion of targeted therapies in the field.
Thomas Kipps, MD, PhD
TARGETED ONCOLOGYTM:Can you reflect on the implications of rapid development in the chronic lymphocytic leukemia (CLL) treatment landscape?
KIPPS:The treatment landscape for patients with CLL has changed dramatically with the advent of targeted therapies. Drugs such as ibrutinib, which targets the enzyme Bruton tyrosine kinase (BTK), or venetoclax, which targets the survival protein BCL2, have demonstrated therapeutic activity in patients who had failed treatment with chemotherapy. Over the last few years, we have seen head-to-head clinical trials that challenge the notion that traditional therapy, such as chemotherapy, or chemotherapy with an anti-CD20 antibody (chemoimmunotherapy), is superior to targeted therapies, showing instead that targeted therapies may be better tolerated and more effective. Indeed, targeted therapies have ushered in a paradigm shift in how we treat our patients.
The benefit of targeted therapies is most evident in those patients who have prognostic features indicating they may fare poorly with chemoimmunotherapy. We have learned that patients who have CLL cells with del(17p) or mutations in the gene TP53, which encodes P53, typically are resistant to chemotherapy, which can cause highly problematic suppression of marrow function, particularly in such patients. Also, patients with leukemia cells that express unmutated immunoglobulin variable region genes (IGHV genes) typically do not enjoy a particularly long progression-free survival [PFS] after chemoimmunotherapy, even if they had an apparently successful clinical response at the end of treatment. On the other hand, some patients with CLL cells that use mutated IGHV can experience long-term remissions following chemoimmunotherapy lasting more than a decade. These findings encouraged development of treatment algorithms that initially recommended targeted therapies only for patients with leukemia cells that use unmutated IGHV and/or that have del(17p) or mutations in TP53.
However, recent head-to-head clinical trials of chemoimmunotherapy versus targeted therapies are challenging this view, even for patients who have CLL cells with good-risk features. For example, patients randomized to receive treatment with drugs such as ibrutinib experienced longer PFS and/or fewer adverse events than patients randomized to receive chemotherapy or chemoimmunotherapy regimens, such as chlorambucil or bendamustine and rituximab. Furthermore, patients with relapsed disease who were randomized to receive treatment with venetoclax and rituximab, fared better than patients randomized to receive treatment with bendamustine and rituximab. Also, recent phase III studies involving patients over age 65 who have medical comorbidities showed that initial therapy with venetoclax and obinutuzumab provided more effective treatment than chlorambucil and obinutuzumab. Finally, an Eastern cooperative group study for younger patients in need of therapy demonstrated a superior outcome for patients treated with ibrutinib and obinutuzumab than those treated with fludarabine, cyclophosphamide, and obinutuzumab. This improved out-come also appeared evident for patients with leukemia cells that use mutated IGHV and/or do not have del(17p) or TP53 mutations. The results of these studies have challenged the notion that targeted therapy should be considered only for a subset of patients with adverse prognostic features.
TARGETED ONCOLOGYTM:What are some of the more significant challenges with the growth of the treatment armamentarium, particularly when it comes to the use of targeted monotherapies and combination regimens?
KIPPS:Success with targeted therapies unfortunately has [led to] new challenges. One challenge is the need for continuous therapy with some of these targeted therapies. Long-term therapy with ibrutinib can be well tolerated but is not able to cure the disease or even induce a complete response [CR] in most patients. Even after a year of therapy, only about 5% of patients will achieve a CR. Such a low CR would be considered unsatisfactory for chemoimmunotherapy regimens, which generally are of a fixed duration. However, fixed-duration therapy with targeted drugs, such as ibrutinib, generally is not recommended, as the discontinuation of therapy can result in a disease flare associated with marked increases in lymphadenopathy and/or recurrence of disease-related cytopenias, particularly if the therapy is discontinued within the first year of therapy. However, continuous therapy raises issues regarding the cost of treatment, possible complications of long-term therapy, and patient preferences. Moreover, chronic therapy with drugs such as ibrutinib can increase the risk for hypertension or atrial fibrillation. Although the risk for atrial fibrillation fortunately is very low, it is nevertheless a complication that we have to be aware of and manage appropriately. The problems associated with chronic therapy have resulted in a push to develop treatments with combinations of targeted drugs that result in higher CR rates and that possibly allow for fixed-durations of treatment.
Venetoclax has factored in development of fixed-duration therapy. Venetoclax inhibits BCL2, which protects the cell from undergoing cell death. It is quite effective, so much so, that patients may develop severe, and potentially lifethreatening tumor lysis syndrome [TLS] when they initiate therapy. This is apparent for patients who have large tumor burdens; the lysis of many tumor cells all at once can result in a marked increase in the plasma potassium level, which, if too high, can cause cardiac arrest. This complication of therapy needs to be avoided at all costs.
One strategy that has been successful in mitigating the complications of TLS is to identify patients prior to therapy who are at risk for developing severe TLS. The relative risk of TLS relates to the amount of tumor the patients have prior to treatment. Patients with bulky (large) lymph nodes and/or high leukemia-cell counts are at highest risk for TLS. Also, patients with impaired renal function may be more susceptible to the hazards of TLS even when their tumor burden is relatively modest. On the other hand, patients with leukemia cell counts less than 25,000 and lymph nodes less 5 cm in diameter may be considered at low risk for severe TLS; such patients may be initiated on therapy as an outpatient provided there is close monitoring of the patient’s renal status and electrolytes before during and after initiation of therapy. Patients at intermediate and high risk may require hospitalization with close monitoring. Regardless of a patient’s risk for TLS, the current strategy is to ramp up therapy in stages, starting at a low dose of 20 mg per day of venetoclax, and then increasing the dose each week over a 5-week period to the final dose of 400 mg per day, monitoring the renal status and electrolytes with each weekly ramp up.
Strategies are in development to reduce the amount of tumor burden prior to the initiation of venetoclax. In particular, monoclonal antibodies, such as rituximab or obinutuzumab, have been tested in combination with venetoclax. Such studies have shown that such anti-CD20 antibodies can improve the CR rate to venetoclax. If the antibodies are given prior to the institution of venetoclax, the patient’s risk for TLS actually can be lowered, providing for easier initiation of venetoclax therapy.
This strategy was used in a large international phase III study that compared the response to treatment with obinutuzumab and venetoclax versus obinutuzumab and chlorambucil in patients over age 65 and who had medical comorbidities that precluded them from being candidates for more aggressive forms of chemoimmunotherapy. The duration of therapy for patients in this trial was 1 year. Patients in either arm received obinutuzumab for 6 months and then received either chlorambucil or venetoclax for 12 months. Therapy with obinutuzumab plus venetoclax was very well tolerated and produced very high rates of clinical response (both complete and partial) that were significantly higher than the rates observed for patients treated with obinutuzumab and chlorambucil. Moreover, patients treated with obinutuzumab and venetoclax also experienced high rates of clearance of detectable minimal residual disease (MRD), which prior studies noted was associated with a particularly long PFS after therapy. Based on these data, the FDA has allowed for treatment of patients with this combination as a frontline regimen.
TARGETED ONCOLOGYTM:Can you address combination regimens based on ibrutinib?
KIPPS:Ibrutinib has been used in combination with anti-CD20 antibodies, such as rituximab, with the goal of improving the response to therapy. Although patients treated with such combinations may have less lymphocytosis after initiation of ibrutinib therapy, such combinations have not been found to allow most patients to come off therapy.
A very notable study by the ALLIANCE group was presented at ASH 2018 and published in theNew England Journal of Medicine. In this study, [investigators] compared treatment outcomes of patients over age 65 who were randomly assigned therapy with either bendamustine and rituximab, ibrutinib and rituximab, or ibrutinib alone. It was apparent from this study that patients treated with ibrutinib, or ibru- tinib and rituximab, fared very well compared with patients treated with bendamustine and rituximab. However, the PFS of patients treated with ibrutinib and rituximab was identical to that of patients treated with rituximab alone. This finding has challenged the assumption that more is invariably better; in my opinion, the data do not yet show a benefit to using anti-CD20 antibodies in combination with ibrutinib.
TARGETED ONCOLOGYTM:What do you anticipate for the future of combination regimens in the treatment of CLL? What concerns do you have about the current treatment approaches and directions in research?
KIPPS:Quite frankly, I’m alarmed by some of the combinations that I see being tested. Oncologists have a way of combining agents with one another based solely on whether or not the drugs used in a combination regimen have different toxicities. The idea behind this approach is that we can combine such drugs together and eke out a higher therapeutic index with the drug combination.
A better approach, in my opinion, is to develop combinations that target distinctive tumor-survival or tumor-growth-promoting pathways. Such combinations may have a higher chance of having synergistic clinical activity. In the case of developing combination therapy with drugs such as ibrutinib, we need to ask the question of why patients are not achieving CRs in response to single-agent ibrutinib. In other words, what keeps the leukemia cells alive in the setting of ibrutinib therapy?
This also applies for drugs such as venetoclax. We now know that not all patients will clear MRD with venetoclax therapy, even when used in combination with anti-CD20 antibodies and/or drugs such as ibrutinib. We need to think about combinations with venetoclax [that may] lead to eradication of the leukemia even in patients who fail to clear MRD. This does not appear likely through the addition of standard chemotherapy to therapy with venetoclax, as venetoclax in one sense mimics the mechanism used by chemoimmunotherapy to kill the tumor cell. Indeed, the capacity of most chemotherapy drugs to kill leukemia cells revolves around their ability to induce expression of P53, which in turn induces pro-apoptotic molecules of the BCL2 family, such as PUMA or NOXA, which in turn active like venetoclax to inhibit BCL2. Because the mechanisms for killing cells of venetoclax or chemotherapy revolves around the inhibition of BCL2, it seems less likely that chemotherapy in combination with venetoclax will be synergistic. The possibility for achieving synergy is increased if we know we’re targeting distinctive pathways.
There is a combination of ibrutinib with venetoclax that is also worth discussing. This combination does seem to be better tolerated than I thought it would be, given the fact that both ibrutinib and venetoclax are metabolized via the same pathway. Moreover, we know that using both drugs together increases the plasma concentrations of each. This may account for the higher rates of neutropenia observed in patients treated with this combination. However, I am not sure whether we are achieving a much better response to therapy than with treatment with venetoclax and antiCD20 antibodies, as the same percentages of patients who fail to clear MRD appear similar for either combination. I am hopeful we can devise combinations that truly take into consideration the biology of the leukemia and how this biology is distinctive from that of normal cells. Such combi- nations may be more effective and potentially curative for a large proportion of patients.
TARGETED ONCOLOGYTM:What is your advice to clinicians who have the ability to incorporate various combination approaches?
KIPPS:A major message is borrowed from history, namely “doctor, do no harm.” It is important to recognize that there is perhaps no therapy that lacks potential for causing adverse effects. We need to be aware that there are patients with CLL who have indolent disease that is asymptomatic and does not appear to shorten their life expectancy, particularly for patients of advanced age and/or who have other major medical comorbidities. Subjecting such patients to therapy would not have a low risk-benefit ratio, no matter how safe the therapy. We also do not know whether patients with indolent disease that ultimately will require therapy will benefit from early intervention prior to when they develop disease-related complications, symptoms, or clear evidence for more-rapid disease progression. This also applies for patients who have disease features associated with a high-risk for early disease progression, such as leukemia-cells that use unmutated IGHV. Certainly, studies are in progress to determine whether we can improve the long-term outcome of such patients through early intervention. Until we know the outcome of such studies, it prudent to withhold even targeted therapies from patients who lack disease-related complications or symptomatic disease, as per the guidelines of the international workshop on CLL [iwCLL].
For patients requiring therapy as per iwCLL guidelines, the first things to consider are the associated risks and costs of therapy and how therapy may complicate other medical comorbidities. Of course, we should not attempt to eradicate CLL at the cost of the patient’s life. Furthermore, when using any drug, it’s important to know what to look for in terms of potential toxicities or complications so that you can take steps to mitigate the risk of complications and/or identify therapy-related adverse events as they occur. For example, drugs such ibrutinib cause impairment in platelet function, enhancing the risk for bleeding, especially when the platelet counts are subnormal. Patients should be cautioned to hold therapy with ibrutinib prior to elective surgery for a few days, as they would be advised to stop drugs such as aspirin. However, therapy should not be held for periods longer than 1 to 2 weeks, as this risks having the patient experience a flair in disease progression. For patients who require systemic anti-coagulation, then extra caution should be exercised when deciding whether to initiate therapy with drugs such as ibrutinib.
TARGETED ONCOLOGYTM:As you reflect on the CLL treatment spectrum and the explosion of targeted therapies, what are some of most prevalent questions that need to be answered? What do you think should be emphasized on the research front?
KIPPS:What’s very important to understand is not just the issues that have given us success, but also to study the challenges that define our current treatment failures. Why do patients fail to obtain a CR with ibrutinib therapy even after protracted therapy duration? Why do patients fail to clear the disease with venetoclax even in combination with ibrutinib or rituximab or obinutuzumab? Until we figure these things out, we will be left with situations in which we won’t have therapies that will be successful in all patients. [Moreover], we will have patients who may do well for a time, but then come back with recurrent relapsed disease that might prove refractory even to the targeted therapies of today.
We should continue research aimed at discovering the answers to these questions and continue our development of therapies that can complement today’s targeted therapies. Indeed, patients are living longer with these improved treatments. As the prevalence of patients with CLL increases so will the challenges increase for defining improvements in therapy. Such improvements will come through continued research on the biology this disease, addressing what accounts for the resistance to today’s targeted therapies.