How I manage CLL with venetoclax-based treatments

Remarkable progress has been made over the past 6 years in targeted therapy for patients with chronic lymphocytic leukemia (CLL). Prior evolution in chemoimmunotherapy (CIT) led to development of progressively more effective combinations, but at the cost of myelosuppression and risk for infection and long-term marrow damage. High levels of B-cell lymphoma-2 (BCL2) protein are expressed in CLL, contributing to resistance to apoptosis. Venetoclax is an oral BCL2 inhibitor (BCL2i) that is highly potent at inducing apoptosis in CLL cells by a p53-independent mechanism and was initially approved for treatment of relapsed/refractory (R/R) del(17p) CLL (M13-982; Table 1)^1-5  and then more broadly with rituximab in relapsed CLL based on the phase 3 MURANO trial that showed improved progression-free survival (PFS) over CIT-based therapy (Table 1).⁶  First-line treatment with venetoclax plus obinutuzumab showed improved PFS vs CIT in patients with comorbidities who tended to be older (CLL14; Table 1).⁷  Bruton tyrosine kinase (BTK) is an important molecule in the B cell receptor signaling pathway. The era of targeted therapy for CLL was ushered in with development of the irreversible oral small-molecule inhibitor of BTK (BTKi) ibrutinib. Multiple phase 3 trials recently reported improved PFS with BTKi-based treatment vs CIT, comparing across the spectrum of patient age, comorbidities and CIT intensity.^8-11  Acalabrutinib, a second-generation BTKi, was recently approved for treatment of both first-line and relapsed CLL. No trial has shown clear clinical benefit with early treatment of CLL, including with targeted therapy; therefore, treatment is only initiated when patients develop active disease requiring treatment according to the standard International Working Group on CLL criteria.¹² 

The therapeutic strategy with CIT was to treat with several courses (typically 6) to remission, and then observation in remission until progression and retreatment for recurrent active, progressive disease; CIT was not considered curative for most patients. Venetoclax-based treatment is highly potent at eliminating CLL and able to achieve deep remission with fixed-duration therapy.^6,7  Retreatment at relapse, progression, and active disease is anticipated, and limited data support this concept.¹³  BTKi-based treatment is highly effective at gaining disease control and reducing bulk of disease, especially nodal disease; deep remissions are uncommon but can occur with very prolonged therapy, and treatment is typically continuous, until progression.^14-17  Both venetoclax- and BTKi-based treatments are effective for high-risk CLL, particularly del(17p) and TP53-mutated CLL, where CIT should not be used.^14,18  Furthermore, they are effective in treating immunoglobulin heavy chain variable gene (IGHV)-unmutated CLL. Venetoclax- and BTKi-based treatments each have unique toxicities and side-effect profiles that must be considered in selecting treatment; resistance mechanisms are also unique. Because neither is currently considered curative and owing to the chronicity of CLL, therapeutic sequencing is an important consideration and should be kept in mind, including when selecting first-line treatment. Table 1 summarizes studies with venetoclax-based treatments, including trials in first-line and R/R CLL and monotherapy and combinations with continuous and fixed-duration treatment.

A thoughtful strategy for managing CLL requires selecting first-line treatment based on patient characteristics, especially given multiple current treatment options, including CIT and BTKi- and venetoclax-based treatments. Owing to multiple treatment options and approaches, it is ever more important to clearly articulate the rationale and goals for treatment selection. Essential considerations for fist-line treatment are patient age and comorbidities, TP53 status (including del(17p) and TP53 mutation status), IGHV mutation status, and goal(s) of treatment (Table 2). In addition, cardiac history and status, concomitant medications, renal function, bulk of CLL, and financial and patient and logistic access are important. In selecting targeted therapy according to goals of treatment, fixed-duration treatment achieving deep remission and prolonged treatment-free interval is appealing over continuous therapy, given the reduced exposure time, reduced potential for toxicities, and long-term convenience with fixed-duration therapy (Table 2). With venetoclax-based treatment, there is an initial requirement for close monitoring on initiation and ramp-up, but once on the target dose, monitoring is similar to BTKi-based treatment.

Patient 1 is a 77-year-old physically active, retired physician with hypertension and coronary artery disease (prior cardiac stent) and a Cumulative Illness Rating Scale (CIRS) score of 5. CLL was diagnosed 8 years ago (currently, no palpable lymph nodes, no del(17p), TP53 wild-type, IGHV mutated [5.6% deviation from germline]; absolute lymphocyte count [ALC] 145 × 10⁹/L, hemoglobin [Hgb] 10.6 g/dL, platelet [PLT] count 137 × 10⁹/L, and creatinine clearance [CrCl] 65 mL/min). Indications for treatment included progressive anemia and fatigue.

First-line treatment options for this older patient with comorbidities include lower-intensity CIT, BTKi-based, and venetoclax-based regimens. Improved PFS, but not overall survival (OS), was demonstrated in phase 3 first-line trials with both targeted therapies over CIT.^7-10  Although this patient had intact TP53, a TP53 abnormality (either deletion or mutation) would certainly exclude CIT as a treatment option. PFS has been considered a surrogate for OS with traditional fixed-duration CIT, and differences in OS are difficult to appreciate in first-line trials for CLL; longer follow-up may be needed to identify the superior treatment in this regard for targeted therapy trials. The authors’ selection of venetoclax over BTKi is based on advanced age, history of cardiac disease, IGHV-mutated status, and desire for fixed-duration treatment. The deep remission that is expected with fixed-duration venetoclax-based treatment in a patient with IGHV-mutated may eliminate the need for any future treatment in this 77 year old.

This patient was treated with venetoclax-based treatment according to the CLL14 regimen.⁷  Allopurinol was initiated before treatment and course 1 treatment was with obinutuzumab monotherapy, which typically results in rapid resolution of lymphocytosis. Indeed, treatment of course 1 with obinutuzumab monotherapy can effectively decrease tumor lysis syndrome (TLS) risk category, notably bringing most high- and medium-risk patients down to medium- and low-risk TLS category, respectively.^7,19  We typically also begin herpesvirus prophylaxis prior to starting therapy. There is no clear indication for routine Pneumocystis jirovecii pneumonia bacterial or fungal prophylaxis in the first-line setting. Prior to initiating venetoclax in course 2, the patient should have had a staging computed tomography (CT) of chest, abdomen, and pelvis to fully evaluate risk for TLS upon starting the venetoclax ramp-up. Course 1 of obinutuzumab typically resolves lymphocytosis in most patients and has variable effect in reducing nodal disease; therefore, it is the authors’ opinion that CT is best performed toward the end of course 1 and prior to course 2. Venetoclax ramp-up is initiated with course 2 with TLS monitoring based on extent of CLL and according to prescribing information for risk mitigation. First-line, fixed-duration treatment begins course 1, day 1 with obinutuzumab, and venetoclax ramp-up begins on course 1, day 22. Total therapy consists of 12 courses; the first 6 courses include obinutuzumab (8 doses total), and venetoclax (28-day courses) continues through course 12, according to CLL14 trial design. Patient 1 had CrCl of 65 mL/min, no lymph nodes >2 cm on CT, and ALC <25 × 10⁹/L and was therefore managed as a low-risk for TLS with venetoclax initiation. If he were medium or higher risk for TLS, he might need admission and monitoring for first dose and first dose escalation. Weekly dose escalations can be monitored as outpatient. Risk for clinically significant TLS is very low if the prescribing information is followed for venetoclax ramp-up.

There was no age restriction for enrollment on CLL14, only requirement for CIRS >6, but patients treated on this trial tended to be older, with median age of 72 yrs.⁷  For patients such as Patient 1, with no abnormality in TP53 [no del(17p) or mutated TP53] and IGHV-mutated, the complete remission (CR) rate was 51.3%, blood undetectable minimal residual disease (uMRD) (10⁻⁴ sensitivity) rate was 73.7% and 24-month PFS rate was ∼90% with 1 year of fixed-duration treatment. While the 24-month PFS rate was not significantly different for venetoclax-based treatment vs CIT for patients with IGHV-mutated, the blood uMRD rate was nearly twice (74% vs 43%, respectively). With this difference in uMRD, there is an expectation for improved PFS with venetoclax-based treatment with longer follow-up. Overall, rates of grade ≥3 neutropenia (52.8% vs 48.1%, respectively) and infection (17.5% and 15.0%, respectively) were not significantly different, and there was no difference in OS (24-month survival of 91.8% vs 93.3%, respectively) in this trial with venetoclax- vs chlorambucil-based first-line treatment.

Patient 2 is a 60-year-old architect with no notable comorbidities but with progressive fatigue resulting in elimination of regular exercise and drenching night sweats occurring twice weekly on average. CLL was diagnosed 4.5 year ago (currently, bilateral palpable 2-cm axillary lymph nodes, no del(17p), TP53 wild-type, IGHV unmutated [0% deviation from germline]; ALC 70 × 10⁹/L, Hgb 11.3 g/dL, PLT count 103 × 10⁹/L, CrCl 92 mL/min).

Patient 2 was symptomatic with progressive cytopenias indicating active CLL needing treatment. Options for treatment of this patient included CIT and BTKi- and venetoclax-based treatment. Factors important for selecting first-line treatment of this patient included his younger age and IGHV-unmutated status (Table 2). The most effective CIT is FCR. The median PFS with FCR is ∼55 months compared with 42 months with bendamustine plus rituximab, with >90% expected to progress with follow-up for patients with IGHV unmutated.²⁰  CIT employs genotoxic therapy, and its use is associated with a risk for secondary hematologic malignancies such as myelodysplastic syndrome and acute myeloid leukemia in 3% to 5% of patients who receive FCR.^21,22  A phase 3 trial evaluated first-line ibrutinib and rituximab to standard FCR in untreated patients <70 years old.¹¹  This trial showed improved PFS for ibrutinib and rituximab vs FCR (hazard ratio, 0.35; P < .001) and OS of 98.8% vs 91.5% at 3 years (hazard ratio for death, 0.17; P < .001). The expected 5-year PFS is 70% with first-line ibrutinib-based continuous treatment,⁹  and the expected 2-year PFS is 88% with venetoclax-based 1-year fixed-duration first-line treatment.⁷  Both BCL2i- and BTKi-based therapies have superior PFS over CIT and eliminate exposure to genotoxic treatment. The authors prefer nongenotoxic, targeted, fixed-duration therapy and are comfortable extrapolating the outcomes expectations of CLL14 to a younger, fit population. Therefore, venetoclax plus obinutuzumab was chosen to treat patient 2. Of note, the long-term risk for secondary myelodysplastic syndrome/acute myeloid leukemia and for Richter transformation with targeted therapy is unknown and requires further long-term follow-up in large numbers of patients treated with these treatments.

Allopurinol was started, and then treatment was initiated with course 1 obinutuzumab and CT of the chest, abdomen, and pelvis was performed to assess TLS risk with venetoclax. Venetoclax ramp-up was initiated with course 2 to the target dose of 400 mg/day, according to the prescribing information, to avoid TLS. The patient was noted to have an absolute neutrophil count (ANC) of 0.467 × 10⁹/L at the 200 mg/day dose during the venetoclax ramp-up. Pegylated filgrastim was administered and continued intermittently to maintain ANC >1 × 10⁹/L through ramp-up to the target 400 mg/day dose and for first 3 months of treatment without venetoclax dose interruption to maintain the venetoclax target dose. Intermittent filgrastim may be similarly effective and sufficient but requires blood count checks and closer monitoring for dosing. The rationale for achieving the venetoclax target dose, not interrupting venetoclax dosing, and maintaining target dose with the use of neutrophil growth factor support to maintain ANC >1 × 10⁹/L is that the CLL bone marrow burden is initially high, and maintaining venetoclax dose intensity early will clear the marrow and allow for better recovery of counts. Venetoclax is myelosuppressive; 53% of patients treated with venetoclax and obinutuzumab in CLL14 experienced grade ≥3 neutropenia, and 14% experienced grade ≥3 thrombocytopenia.⁷  Infection grade ≥3 occurred in 18% of patients treated with venetoclax-based therapy in this study.

The authors’ practice is to reduce the dose of venetoclax if there is recurrent neutropenia beyond the first 3 or 4 months on the highest tolerated dose of venetoclax with neutrophil growth factor support or if treatment with neutrophil growth factor dose not result in improvement in ANC. Grade >3 obinutuzumab-related infusion reactions occurred in 9% of patients treated on CLL14. Although uncommon, grade 4 thrombocytopenia may require venetoclax dose reduction.²³  Venetoclax is a cytochrome P450 3A (CYP3A) substrate, and when taken concurrently with CYP3A inhibitors, such as “azole” antibiotics, the pharmacokinetics are altered, leading to increased exposure. Therefore, venetoclax dose reduction by 50% and 75% is recommended when combined with moderate and strong inhibitors of CYP3A, respectively.²⁴ 

Consistent with CLL14, the intended treatment course for patient 2 is obinutuzumab for the first 6 courses and venetoclax for a total of 12 courses, followed by response assessment with CT scan, blood count, and blood MRD evaluation (10⁻⁴ sensitivity). This enables estimation of PFS and time off treatment; uMRD is correlated with longer PFS. Follow-up monitoring is every 3 to 6 months with routine clinic visit and blood counts. Patients are not monitored with scheduled CT scans or bone marrow evaluations during follow-up.

Patient 3 is a 75-year-old retired teacher with hypertension and reflux disease and a CIRS score of 7. CLL was diagnosed 5 years ago; ibrutinib was started 3 years ago for active del(17p) CLL and was well tolerated with no dose adjustments (currently, ALC is increasing with a newly noted 2-cm palpable cervical lymph node, del(17p), TP53 mutated, IGHV unmutated [0%], BTK-mutated [C481S]; ALC 55 × 10⁹/L, Hgb 10.6 g/dL, PLT count 145 × 10⁹/L, CrCl 70 mL/min).

This patient is developing ibrutinib-refractory CLL with rising ALC and newly noted lymph node and rising ALC while on ibrutinib and mutation in BTK (C481S); a new treatment is indicated for this patient with high-risk CLL. CIT is contraindicated for this patient with defective TP53; switching to an alternative irreversible BTKi is contraindicated due to the presence of BTK mutation, and switching to an alternative inhibitor of the B-cell receptor signaling pathway such as phosphatidylinositol 3 kinase (PI3K) inhibitor is unlikely to result in a response. BCL2i-based therapy with venetoclax has shown durable responses in patients who develop BTKi-refractory CLL, and is the best treatment choice for this patient. Continuous venetoclax monotherapy was initially approved for patients with R/R del(17p) CLL, like this patient. Table 3 illustrates considerations for selecting treatment of R/R CLL, which are heavily dependent on prior treatment and refractoriness to treatment. In addition, while not the case for this patient, suspicion for Richter transformation should be evaluated with positron emission tomography/CT followed by biopsy of fluorodeoxyglucose-avid nodes (standardized uptake value >5).²⁵ 

Although not formally demonstrated in a randomized clinical trial, it is the opinion of the authors that the addition of a CD20 mAb improves efficacy of venetoclax therapy. Therefore, this patient was treated with venetoclax plus rituximab similar to in the MURANO trial, which included patients previously treated with BTKi-based treatment. Due to this patient having progressive CLL while on ibrutinib, ibrutinib should be continued through venetoclax ramp-up for overlap of these agents to avoid the explosive CLL disease flare that is commonly seen with BTKi discontinuation in patients who are progressing on BTKi.²⁶  TLS risk assessment is important for this patient; therefore, a staging CT scan should be performed prior to initiating venetoclax, and the patient must be started on allopurinol or equivalent. TLS risk mitigation measures should be taken according to the prescribing information. Venetoclax ramp-up was initiated first, with rituximab planned to begin during course 2 when up to 400 mg/day dose. An alternative CD20 mAb to consider is obinutuzumab, which is a superior CD20 mAb for treating CLL; however, it is not currently US Food and Drug Administration approved for R/R CLL, but it has been studied with venetoclax in a limited number of patients with R/R CLL.²⁷  Rituximab was given for 6 monthly doses as in MURANO. Although the MURANO trial studied 24-course fixed-duration treatment, there are 2 situations where continuing venetoclax beyond this could be considered: (1) in relapsed patients with defective TP53, such as patient 3; and (2) in patients who are blood MRD positive after 24 courses of venetoclax. Both are at risk for shorter PFS if venetoclax is discontinued.²⁸  Patient 3 was both MRD positive after 24 courses and had defective TP53 and therefore continued venetoclax monotherapy. He experienced neutropenia (ANC 0.755 × 10⁹/L) in course 9 of venetoclax. Pegylated filgrastim was given, but neutropenia recurred 1 month later, so the venetoclax dose was decreased to 300 mg/day without recurrence of neutropenia.

The median PFS for R/R del(17p) CLL with venetoclax monotherapy was 24 months, but this might be improved with the addition of rituximab. Of note, while not useful in selecting next therapy, a prognostic model to predict OS for relapsed patients going on targeted therapy was developed based on β-2 microglobulin, lactate dehydrogenase, Hgb, and time from last therapy.²⁹  Patient 3 has very-high-risk CLL by virtue of having defective TP53, relapsed, and BTKi-refractory disease; therefore, long-term disease control should consider allo-SCT as an option. This patient is older and may not have a suitable available donor. Allo-SCT should be considered when patient achieves best response with venetoclax-based treatment, if this is an option. In addition, clinical trials of CD19-chimeric antigen receptor T-cell therapy, reversible BTKi, or another novel strategy are reasonable considerations for this patient.

While CLL14 enrolled patients with comorbidities who tended to be older, the authors are comfortable extrapolating the efficacy results of this trial to younger fit patients, making venetoclax plus obinutuzumab a highly active first-line fixed-duration treatment option also available for these patients who might not want continuous BTKi-based therapy or CIT. Bone marrow and blood uMRD status has been associated with longer PFS and OS, and it is a treatment goal with venetoclax-based therapy to allow fixed-duration therapy with treatment-free interval. We now have a treatment with venetoclax, which can be administered to older patients with comorbidities to achieve blood uMRD remission in the majority of these patients, many of whom may never need another treatment given their advanced age.

Characteristics associated with lower complete remission rate and shorter duration of response with venetoclax-based treatment in R/R CLL include presence of bulky lymph nodes (≥5 cm) and refractoriness to BTKi.³⁰  Shorter duration of response was also associated with abnormality in TP53 and mutated NOTCH1.³⁰  These might be patients for whom active allo-SCT planning is initiated. Longer duration of response was clearly associated with achieving uMRD status. Consideration for continued venetoclax monotherapy after combination with rituximab for relapse/refractory CLL should be given to patients with persistent MRD at the end of 24 cycles of venetoclax and for those with TP53 abnormality (deletion or mutation), since these patients are more likely to progress sooner upon discontinuing venetoclax.²⁸ 

Further progress in treatment of CLL will come with developing treatments that achieve a higher proportion of patients with uMRD remission with shorter fixed-duration treatment. Deeper remissions are expected with longer PFS and OS and may result in immune-reconstitution and reduced risk for infection, autoimmunity, and second cancers. Key objectives include reducing and eliminating the risk of developing (1) Richter transformation, (2) CLL clonal evolution, and (3) refractory disease. Access and affordability of these highly effective treatments are key considerations. Treatment with combined targeted agents certainly has the potential to increase cost, so we must strive for shorter fixed-duration treatments to be feasible and practical.

The rationale for combining BTKi with BCL2i was built on clinically complimentary activity; BTKi’s are highly active in treating and shrinking nodal disease, and BCL2i is highly effective at clearing blood and bone marrow. In vitro studies demonstrated reduced MCL1 with BTKi treatment potentially making cells more vulnerable to BCL2i-induced apoptosis.³¹  Promising early results with this combination were reported in first-line and relapsed CLL.^32-34  Remaining questions with this strategy include the role of CD20 mAb, predictive markers for response and outcomes, optimal duration of combined therapy, how to manage relapsed disease, and clinical characteristics of CLL refractory to targeted therapy. Indeed, a randomized comparison of venetoclax plus obinutuzumab vs venetoclax plus BTKi is planned by the German CLL Study Group with CLL17.

Another important concept is understanding the therapeutic plateau with targeted therapy. With BTKi-based treatment, there is continued clinical benefit and disease control with continued exposure, and deeper remissions are reported with prolonged (years) exposure, but remissions typically are not deep enough to consider discontinuing treatment of the majority of patients, and there is a concern for selecting for resistance with cycling off and on BTKi treatment. With venetoclax-based treatment, there is patient heterogeneity in kinetics of response; the optimal exposure duration has not been defined and is likely multifactorial. Responses with venetoclax-based treatment tend to take longer, and duration of response is generally shorter during the treatment-free follow-up for patients with R/R CLL compared with patients receiving first-line treatment. Patients with R/R CLL tend to have more proliferative disease, and deeper remissions are likely necessary to have a reasonable remission duration off treatment. Venetoclax appears to be a very appealing partner for combination therapies, given the potency in reducing bulk of CLL and its apparent ability to lower the threshold for apoptosis and potentially synergize with most therapeutic agents.

Venetoclax offers a targeted therapy that is extremely potent at eliminating CLL, including high-risk del(17p)/mutated-TP53 CLL and CLL refractory to CIT. Venetoclax initiation and ramp-up require TLS risk assessment and risk-stratified monitoring and mitigation measures, which can be cumbersome but allow for universally safe initiation and escalation. Extended, fixed-duration venetoclax treatment is well tolerated, with potential for mild myelosuppression and infrequent need for dose-adjustment for toxicity (most commonly neutropenia). The addition of CD20 mAb is thought to improve responses, and fixed-duration treatment is recommended for first-line treatment and treatment of standard-risk relapsed CLL. There are clear data supporting use of obinutuzumab with venetoclax in first-line treatment and with rituximab in relapsed CLL, but no data supporting use of obinutuzumab with venetoclax in relapse disease. Undetectable MRD status with fixed-duration treatment is achieved in the majority of patients treated with venetoclax-based treatment. This is appealing, since it offers potential for a treatment-free interval of remission for most patients, which could be very long for patients with favorable disease features, such as intact TP53 and IGHV mutated. Indeed, current work is focused on developing regimens with combined targeted therapy that achieve the highest uMRD rate with shorter fixed-duration treatment. It will require longer follow-up to assess potential for cure with this strategy and clarify outstanding questions delineated above.

Contribution: W.G.W. reviewed the literature, developed patient cases, constructed and assembled content, wrote the review, and reviewed the manuscript; and F.P.T. reviewed the literature, developed patient cases, wrote the review, and reviewed the manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: William G. Wierda, Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 428, Houston, TX 77030; e-mail: wwierda@mdanderson.org.