Optimizing frontline therapy of CLL based on clinical and biological factors

The initial diagnosis of chronic lymphocytic leukemia (CLL) (for overview¹ ) is based on physical and laboratory assessment including blood cell count and immunophenotyping in peripheral blood. The presence of a lymphocytosis with ≥5.0 × 10⁹/L and immunophenotyping by peripheral blood flow cytometry to differentiate CLL from other lymphoproliferative diseases is required to confirm the initial diagnosis of CLL.²  Typically, clonal B-lymphocytes express CD5, CD19, CD23, and either κ or λ immunoglobulin light chains and show weak or no expression of CD79b and FMC7. Due to their simplicity and low costs associated with them, the clinical staging systems developed by Rai et al and Binet et al are still the major backbone for prognostication in CLL; as for initial evaluation, assessment of CT scans is not required.^3,4  Today, patients are usually diagnosed with asymptomatic, early stage (Rai 0-I, Binet A) CLL. A large number of patients have indolent disease and may have a normal life expectancy, whereas others show rapid disease progression and have poor outcome.⁵  Yet, the majority of patients (39%) have an intermediate course of disease with a median time to first treatment of 5 years.⁶  Until today, there is no evidence for a potential benefit of early intervention for CLL.^7,8 

Multiple clinical and biological factors may prognosticate the patient's individual course.⁹  Factors that are significantly associated with poorer outcome include male sex, >65 years of age, poor performance status and medical comorbidities, short lymphocyte doubling time (<12 months), high serum levels of thymidine kinase (>10.0 U/L), high serum levels of β₂-microglobulin (>3.5 mg/L), the expression of unmutated immunoglobulin heavy chain variable region (IGHV), the presence of del(17p) or del(11q), and complex karyotype (defined as the presence of 3 or more chromosomal aberrations observed on a karyotype test) or gene mutations (most prominently TP53). Further parameters such as high CD49d expression (>30%),¹⁰  are under investigation. Del(17p) is often associated with mutations in TP53 and predicts a shorter survival and refractoriness to chemoimmunotherapy.^11,12  Recently, next-generation sequencing has identified novel gene mutations or deletions, including NOTCH1, SF3B1, MYD88, and BIRC,^12-16  which seem to be associated with shorter survival. A number of multivariable models, prognostic scores, or nomograms have been developed to create a comprehensive set of factors for prognostication.^17-24  The CLL-international prognostic index (CLL-IPI) (Table 1 and Table 2) incorporates the most validated and established factors and provides a prognostic tool that has been tested in over 3000 patients following chemotherapy or chemoimmunotherapy.¹⁷  The CLL-IPI is aimed to improve the physicians' ability to counsel patients regarding potential future implications of their diagnosis. Recently, the CLL-IPI has been validated for various populations.^25,26  However, there is a need for further prospective validations of the CLL-IPI and other scores within clinical trials, in particular with targeted inhibitors.

Historically, response to therapy defined as partial or complete response is performed by clinical response assessment according to International Workshop on CLL criteria.²  More recently, minimal residual disease (MRD) assessment has been introduced to assess the response to therapy with more accuracy. Assessment of MRD can be performed by flow cytometry from bone marrow or peripheral blood or by PCR and might now advance into clinical routine, in particular when it comes to the decision of treatment termination with targeted inhibitors. MRD negativity (by detection of malignant cells with a sensitivity of 1 tumor cell in 10 000 cells [10⁻⁴] with negativity defined as <10⁻⁴) determined at the end of chemoimmunotherapy is highly significant for prognosis of progression-free survival (PFS) and OS.^27-29  Thus far, therapy with kinase inhibitors rarely describes MRD results.³⁰  Conversely, when kinase inhibitors or a BCL2 inhibitor was combined with CD20 antibodies or chemoimmunotherapy, treatment was reported to induce MRD negativity in previously untreated patients in a relatively high percentage (11 of 12 patients).³¹  Future studies will have to determine whether MRD negativity can be used as a tool to tailor and terminate the combination therapy with targeted agents.

Therapy initiation should be postponed until symptomatic or active disease, defined according to the International Workshop on CLL guidelines, is documented.²  Clinical trials evaluating the early use of novel inhibitors are currently under investigation.^7,8 

For patients in need of treatment, the presence of TP53 dysfunction is the most significant biological factor that is currently influencing the choice of therapy (Table 3). The most significant clinical factors when making a treatment decision are advanced age and the presence of medical comorbidities. Currently, besides a small proportion (∼30%)³²  of fit and IGHV-mutated patients who are suitable for chemoimmunotherapy with FCR, which may achieve very long-lasting remissions, only allogeneic stem cell transplantation has curative potential for patients with CLL.³³  However, because highly effective agents are now available for high-risk patients, they are increasingly used in this high-risk patient group. A summary of therapies that have been tested in phase 3 trials is given in Table 4, and a selection of ongoing phase 3 trials is summarized in Table 5.

For decades, patients with CLL have been treated by chemotherapy (eg, fludarabine and cyclophosphamide, chlorambucil, or bendamustine) in combination with anti-CD20 monoclonal antibodies. Three trials in previously untreated patients with CLL, fit patients for CLL8, and unfit patients for both CLL11 and COMPLEMENT 1 led to the approval of the anti-CD20 monoclonal antibodies rituximab, obinutuzumab, or ofatumumab in combination with chemotherapy for frontline treatment of patients with CLL (Table 4). These antibodies are therefore considered as part of the current standard therapies.^34-36  Long-term follow-up data showed that fit patients with mutated IGHV genes achieve very long-term disease control and survival prolongation following the FCR regimen.^32,37,38  The observed benefit of FCR for the majority of patients with IGHV mutation encourages the use of the IGHV mutational status before initiating a frontline therapy in fit patients with CLL. Several phase 3 trials comparing the chemotherapy-free treatment strategies with FCR or other chemoimmunotherapies are currently underway (Tables 4 and 5).

BR yields good response rates in treatment-naive patients without del(17p).^39,40  Based on the efficacy results of the CLL10 protocol, FCR remains the standard frontline therapy in fit patients with CLL. However, in comparison, the BR regimen was associated with less myelosuppression and less infections. Moreover, no significant difference in OS was observed between the 2 treatment arms. In some countries, BR is therefore considered an appropriate frontline treatment of elderly fit patients with CLL. The final results on the randomized MaBLe trial evaluating BR in comparison to chlorambucil plus rituximab in this elderly patient population are forthcoming (Table 4).⁴¹  In frontline therapy, bendamustine has also been evaluated in combination with obinutuzumab within a phase 1b trial reporting good results that warrant further investigation within larger trials⁴²  as well as in combination with ofatumumab.⁴³  The ongoing RIAltO trial (investigating the combination of bendamustine plus ofatumumab vs chlorambucil plus ofatumumab) may help further improve the standard treatment of unfit patients not suitable for FCR (Table 5).

The role of immunmodulatory agents also targeting the tumor microenvironment in frontline therapy of CLL such as lenalidomide (for overview⁴⁴ ) is uncertain. Recently, a phase 3 trial comparing lenalidomide vs chlorambucil in previously untreated patients >65 years of age showed negative results for lenalidomide with no improvement in PFS and higher toxicity including fatal events compared to chlorambucil. Therefore, lenalidomide monotherapy cannot be recommended for frontline therapy of elderly patients with CLL.⁴⁵  Moreover, lenalidomide in combination with bendamustine or fludarabine and rituximab is not an appropriate treatment option because of tumor flare and skin and hematological toxicities, whereas the combination of lenalidomide and rituximab seems to be better tolerated with response rates of 78% for older and 95% for younger pretreated patients with CLL.^46-48  The use of a lenalidomide maintenance therapy after frontline chemoimmunotherapy has been evaluated in the phase 3 CLLM1 trial (Table 4). The results suggest that lenalidomide is a well-tolerated and efficacious maintenance therapy that reduces the relative risk of progression in high-risk patients (as assessed by the combined use of genetic markers and detectable minimal residual disease) by >83%. However, no advantage for OS has been demonstrated thus far.⁴⁹  Therefore, lenalidomide may be considered for selected high-risk patients with CLL who fail to achieve a stable, minimal residual disease negative remission with frontline chemoimmunotherapy.

Adverse events in chemotherapy-based regimens include myelosuppression, an increased risk for infections, and, in a small subset of patients (∼2%-5%), posttherapy myelodysplasia or other hematological neoplasia, such as acute myeloid leukemia.^32,37,39  One of the most relevant side effects following chemoimmunotherapy is the occurrence of secondary malignancies. Two large retrospective analyses have demonstrated that after chemoimmunotherapy patients with CLL have an increased incidence and risk of secondary malignancies.⁵⁰  One trial reported that patients showed a 1.23-fold increased risk of solid tumors in comparison with the age-matched general population from a German cancer registry. The second analysis showed that the risk of second cancers was 2.38 times higher than the expected risk for the general population.⁵¹  However, the increased risk for second malignancies in CLL may be partly attributed to immune deficiency associated to the CLL itself. Therefore, the long-term incidence of secondary malignancies of patients with CLL who are not receiving chemoimmunotherapy still needs to be defined. It is suggested to perform very long-term follow-up studies of patients after therapy to accurately assess how therapies influence the risk of secondary malignancies.⁵² 

The most advanced approved targeted agents that have helped evolve the current frontline treatment of patients with CLL include 3 drugs. Two of those agents are kinase inhibitors, the Bruton tyrosine kinase inhibitor ibrutinib and the PI3K δ inhibitor idelalisib. The third agent is the BCL-2 inhibitor venetoclax.

Ibrutinib has been approved in the United States and Europe for use as frontline therapy on the basis of 2 registration trials. The phase 2 RESONATE-17 trial focused on patients with relapsed del(17p) with 1 to 4 prior therapies, and early results led to approval in 2014 for patients with CLL after at least 1 prior therapy or patients with CLL with del(17p) in any line of therapy, although data for frontline were not available at that time point.⁵³  The phase 3 RESONATE-2 trial showed a significant improvement in median PFS and OS in patients ≥65 years of age without del(17p) who were treated indefinitely with ibrutinib compared with patients treated for up to 48 weeks with chlorambucil alone (Table 4).^54,55  The trial led to approval for ibrutinib monotherapy in patients with previously untreated CLL. The Alliance A041202 study (Table 4) is conducted to compare bendamustine plus rituximab vs ibrutinib plus rituximab vs ibrutinib alone in untreated older patients >65 years. Long-term follow-up of 2 initial phase 1b/2 trials with ibrutinib monotherapy that included both relapsed or refractory patients and previously untreated patients demonstrated an increase in PFS, indicating that ibrutinib can maintain long-term remissions with no new toxicities identified.^30,55  For previously untreated fit patients, the phase 3 FLAIR trial and similarly the ECOG 1912 study currently evaluate ibrutinib in combination with rituximab against the standard FCR regimen (Table 5). Further trials of combinational strategies with ibrutinib in frontline therapy either combined with chemoimmunotherapy (including a phase 2 trial on ibrutinib plus FCR⁵⁶ ) or combined with a second novel agent such as venetoclax have demonstrated preliminary results or have only just begun (Table 5). Results are forthcoming and may influence the choice of frontline therapy. There is an ongoing debate on the potential duration of therapy with ibrutinib. First, there is consensus that patients generally favor a finite use of an oral medication. Second, especially when frontline therapy is addressed, the reduction of toxicity and the potential risk of resistance mutations⁵⁷  should be taken into consideration when choosing the appropriate therapy. The phase 2 CLL2-BIG trial evaluated a sequential, finite treatment of bendamustine, obinutuzumab, and ibrutinib and studied whether MRD negativity may serve as a biological indicator for treatment discontinuation; preliminary results are very promising.⁵⁸  Toxicity of ibrutinib includes fatigue, diarrhea, bleeding, ecchymosis, rash, arthralgia, myalgia, increased blood pressure, and atrial fibrillation; the latter was recently evaluated within systematic meta-analyses and reviews to provide additional data and context.⁵⁹  Due to the increased risk of major hemorrhage, ibrutinib should be cautiously combined with anticoagulation.⁶⁰  Patients who require anticoagulant and/or antiplatelet medications while on ibrutinib need to consider the risks and benefits given the higher incidence of bleeding in this population.⁶¹ 

The PI3K inhibitor idelalisib was approved in the United States and Europe for the treatment of patients with relapsed CLL.⁵⁵  Two studies were conducted to investigate idelalisib and rituximab combination therapy for frontline treatment of CLL.^62,63  Because of a higher number of infections and deaths observed in the experimental arm, FDA recommended the closure of clinical trials in 2016.⁶⁴  Patients undergoing therapy with idelalisib and rituximab should be considered for concomitant treatment with prophylactic low-dose acyclovir to protect against reactivation of varicella zoster virus. Patients also should be treated with prophylactic antibiotics to minimize the risk for opportunistic infection, such as that caused by Pneumocystis jiroveci. Patients should be screened for active infection with hepatitis B virus before the initiation of therapy, and periodically monitored for reactivation of cytomegalovirus, especially in the event of unexplained symptoms of infection. Other adverse effects of idelalisib include transaminitis (usually in the first few months of therapy), pneumonitis, and colitis; the latter usually occurs >6 months after the initiation of therapy with this drug and is often severe enough to require termination of therapy.⁶⁴ 

Venetoclax is a BH3-mimetic compound that selectively antagonizes BCL-2 and induces apoptosis of CLL cells. Its efficacy as monotherapy was previously described in patients with relapsed/refractory CLL, including those with del(17p).^65,66  Venetoclax received approval in 2016 on the basis of a phase 2 trial evaluating patients with relapsed disease with del(17p) who received continuous single-agent venetoclax treatment.⁶⁶  Venetoclax monotherapy is either approved for patients with del(17p) and relapsed or refractory to at least 1 prior therapy (FDA) or indicated for the treatment of CLL in the presence of TP53 dysfunction in patients who are unsuitable for or have failed a kinase inhibitor and in the absence of TP53 dysfunction for the treatment of patients who have failed both chemoimmunotherapy and a kinase inhibitor (EMA). Ongoing phase 2 trials in CLL have shown that venetoclax can be safely combined with rituximab (in relapsed or refractory patients) or with obinutuzumab (in combination with bendamustine) reporting very high response rates to therapy.^67,68  In frontline therapy, the phase 3 CLL14 trial examined venetoclax and obinutuzumab followed by venetoclax monotherapy in patients with previously untreated CLL and coexisting medical conditions compared to chlorambucil and obinutuzumab (Table 5).³¹  Preliminary results received within a small run-in patient population of 12 patients suggest that the chemotherapy-free regimen with 6 cycles of venetoclax and obinutuzumab followed by 6 additional cycles of venetoclax can be safely administered in previously untreated patients of advanced age with CLL and with coexisting medical conditions resulting in considerably high rates of MRD negative remissions. Results from the main randomized phase of the larger patient population will determine whether these responses remain durable. Moreover, recently activated trials are examining the combination of venetoclax with ibrutinib, which might provide higher response rates to therapy than that with venetoclax alone or in combination with an anti-CD20 antibody (Table 5).^31,69  Toxicities of venetoclax include gastrointestinal events, neutropenia, and tumor lysis syndrome (TLS). To avoid TLS, it is recommended that patients start venetoclax with a low daily dose (20 mg/day) escalated in 1-week intervals to a daily dose of up to 400 mg over 5 weeks to minimize the risk of developing TLS.⁶⁷  Additionally, patients who are at high risk for TLS because of bulky lymphadenopathy and/or lymphocytosis of >25 000 cells per μl must be hydrated and closely monitored during therapy initiation and dose escalation.

How do we treat frontline CLL with the currently approved agents? We currently consider the following parameters before choosing therapy: (1) the clinical stage, (2) the fitness of the patient, (3) the IGHV mutational status, (4) the presence of TP53 dysfunction, and (5) the symptoms of CLL. Using these 5 parameters, we propose the following algorithm for frontline therapy (Table 3): In patients with advanced (Binet C, Rai III-IV) or active, symptomatic disease, treatment should be initiated. In this situation, patients´ physical condition (including assessment of their comorbidity, eg, by use of Cumulative Illness Rating Scale score) should be evaluated.⁷⁰  Fit patients with no presence of TP53 dysfunction should be offered chemoimmunotherapy. It is uncertain whether young fit patients (and, similarly, older fit patients) with unmutated IGHV mutational status where chemoimmunotherapy is not shown to achieve as long-lasting remissions compared with patients with mutated IGHV benefit from ibrutinib. Fit patients who are older than 65 years of age without TP53 dysfunction may be offered chemoimmunotherapy with BR. Fit patients with the presence TP53 dysfunction should be offered ibrutinib monotherapy. If patients are unsuitable for ibrutinib, venetoclax monotherapy should be considered, which requires prophylaxis including hospitalization according to the patient’s risk to develop TLS. Caution should be taken for idelalisib plus rituximab because of the immune-mediated adverse events observed especially in frontline therapy.⁶²  Unfit patients with no presence of TP53 dysfunction have several options. We think that they should be offered chemoimmunotherapy with chlorambucil plus obinutuzumab (or with somewhat less efficacious combinations of chlorambucil plus ofatumumab or rituximab). However, results of the RESONATE-2 study justify the use of ibrutinib in these patients as well, and ibrutinib is approved for this indication. It remains to be shown whether ibrutinib monotherapy is more efficacious than chemoimmunotherapy in this patient population. Unfit patients with TP53 dysfunction should be offered ibrutinib monotherapy. If patients are unsuitable for ibrutinib, venetoclax monotherapy or idelalisib plus rituximab should be considered. Frail (no-go) patients should generally receive supportive treatment including steroids. Allogeneic stem cell transplantation may be individually discussed with patients who have both very high-risk CLL and sufficient physical fitness. Despite the lack of data evaluated in randomized trials, there seems to be a rationale for withholding allogeneic stem cell transplantation from patients with TP53 dysfunction CLL in the first remission, given the proven efficacy of the signal transduction inhibitors. However, most high-risk patients may undergo allogeneic transplantation in second or third remission. Finally, all patients should preferentially be treated within clinical trials whenever possible.

The prognosis for patients with CLL has improved substantially over the past decade. Based on our improved knowledge of clinical and biological factors of CLL, patients can be stratified into subgroups with distinctive clinical and biological features. These findings have evolved the assessment of prognosis and the options of therapy. However, there remain many unanswered questions: For instance, it is unknown how kinase inhibitors contribute to drug resistance and/or clonal evolution.⁷¹  It may become evident that a combination of the currently available targeted drugs may yield optimal results with major improvements in OS. The currently available data suggest that achieving a very good disease control (ie, MRD negativity as a surrogate parameter) may prolong the survival of patients with CLL.⁷²  The combination targeted therapy with agents that have synergistic activity will provide a highly effective treatment for patients with CLL that may avoid clonal evolution of resistance to therapy. Additionally, finite treatment may also have a positive impact on the financial toxicity of temporal unrestricted treatment with cost-intensive novel agents.⁷³  The current challenge is to identify the best combination of treatments with a finite duration to achieve the long-term control of CLL with optimal quality of life. To study these questions, it is necessary to perform clinical trials that address the long-term consequences of these novel therapies.

The authors thank both the study investigators and their patients for participation in the German CLL Study Group trials. The authors also thank all team members of the study office of the German CLL Study Group for their continuous invaluable contribution. In particular, the authors acknowledge Jasmin Bahlo, Anna Fink, Othman Al-Sawaf, Barbara Eichhorst, Carmen Diana Herling, and Valentin Goede for their excellent support to this manuscript and Stephan Stilgenbauer, Michael Kneba, Karl-Anton Kreuzer, Matthias Ritgen, Sebastian Boettcher, and Clemens-Martin Wendtner for their exceptional continuous collaboration.

Kirsten Fischer, Department I for Internal Medicine and Centre of Integrated Oncology, University of Cologne, Kerpener Strasse 62, 50937 Cologne, Germany; e-mail: kirsten.fischer@uk-koeln.de; and Michael Hallek, Department I of Internal Medicine, Center of Integrated Oncology Cologne Bonn, University of Cologne, Kerpener Strasse 62, 50937 Cologne, Germany; e-mail: michael.hallek@uni-koeln.de.