William G. Wierda, MD, PhD, and Francesco Paolo Tambaro, MD, PhD, review the role of venetoclax and other targeted therapies in the treatment of patients with chronic lymphocytic leukemia.
This material is repurposed from “How I manage CLL with venetoclax-based treatments,” published in the April 23, 2020, edition of Blood.
- Both venetoclax- and BTK inhibitor–based treatments are effective for high-risk CLL, particularly del17p and TP53-mutated CLL, where CIT should not be used.
- Extended, fixed-duration venetoclax treatment is well tolerated, with potential for mild myelosuppression and infrequent need for dose-adjustment for toxicity (most commonly neutropenia).
- Venetoclax initiation and ramp-up require TLS risk assessment and risk-stratified monitoring and mitigation measures.
- The addition of CD20 monoclonal antibodies is thought to improve responses, and fixed-duration treatment is recommended for first-line treatment and treatment of standard-risk relapsed CLL.
- Because there is patient heterogeneity in kinetics of response to venetoclax, the optimal exposure duration has not been defined and is likely multifactorial.
The era of targeted therapy for chronic lymphocytic leukemia (CLL) was ushered in with development of the irreversible oral small-molecule inhibitor Bruton tyrosine kinase (BTK) ibrutinib. BTK inhibitor–based treatment is highly effective at gaining 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.
Venetoclax is a potent oral B-cell lymphoma 2 (BCL2) inhibitor that is effective at eliminating CLL, including high-risk del17p/mutated-TP53 CLL and CLL refractory to chemoimmunotherapy (CIT), with fixed-duration therapy. It was initially approved for treatment of relapsed/refractory del17p CLL and then more broadly with rituximab in relapsed CLL.
Both BCL2- and BTK inhibitor–based treatments are effective for high-risk CLL, particularly del17p and TP53-mutated CLL, where CIT should not be used. Furthermore, they are effective in treating immunoglobulin heavy chain variable gene (IGHV)–unmutated CLL.
Each approach has 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.
Patient 1: First-Line Treatment of CLL
A 77-year-old, physically active, retired physician with hypertension and coronary artery disease (prior cardiac stent) and a Cumulative Illness Rating Scale score of 5 was diagnosed with CLL eight years ago. The patient currently has no palpable lymph nodes, no del17p, TP53 wild-type, and IGHV-mutated disease, as well as an absolute lymphocyte count (ALC) of 145×109/L, a hemoglobin (Hb) count of 10.6 g/dL, a platelet count of 137×109/L, and a creatinine clearance (CrCl) rate of 65 mL/min.
Patient 1 Treatment Considerations
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. Indications for treatment in this patient include progressive anemia and fatigue.
First-line treatment decisions are based on patient characteristics (TABLE 1). Essential considerations for first-line treatment are patient age and comorbidities, TP53 status (including both del17p and TP53 mutations), IGHV mutation status, and goals of treatment. In addition, cardiac history and status, concomitant medications, renal function, bulk of CLL, and financial and patient and logistic access are important considerations.
This patient was treated with venetoclax-based therapy according to the CLL14 regimen (a total of 12 courses of obinutuzumab and venetoclax). The selection of venetoclax over BTK inhibitor is based on advanced age, history of cardiac disease, IGHV mutation status, and desire for fixed-duration 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. The deep remission that is expected with fixed-duration venetoclax-based treatment in a patient with IGHV-mutated CLL may eliminate the need for any future treatment in this older patient. 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 BTK inhibitor–based treatment.
The patient had a CrCl of 65 mL/min, no lymph nodes >2 cm on CT scan, and an absolute lymphocyte count (ALC) <25×109/L and was therefore managed as a low risk for tumor lysis syndrome (TLS) with venetoclax initiation. For TLS mitigation, allopurinol was initiated before treatment and the first course of obinutuzumab monotherapy. The first course of obinutuzumab typically resolves lymphocytosis in most patients and has variable effect in reducing nodal disease; therefore, a CT scan is best performed toward the end of course one and prior to course two.
For a patient at medium or higher risk for TLS, admission and monitoring for first venetoclax dose and first dose escalation might be needed. Weekly dose escalations can be monitored as outpatient.
Patient 2: Management of Venetoclax-Associated Neutropenia
A 60-year-old architect was diagnosed with CLL 4.5 years ago. Currently, he has bilateral palpable 2-cm axillary lymph nodes, no del17p, TP53 wild-type, and IGHV-unmutated disease. His ALC is 70×109/L, Hb is 11.3 g/dL, platelet count is 103×109/L, and CrCl is 92 mL/min. The patient was symptomatic with progressive cytopenias indicating active CLL needing treatment.
Patient 2 Treatment Considerations
Factors important for selecting first-line treatment of this patient included his younger age and IGHV-unmutated status. Consistent with CLL14, the intended treatment course for this patient is obinutuzumab for the first six courses and venetoclax for a total of 12 courses, followed by response assessment with CT scan, blood count, and evaluation of measurable residual disease (MRD). Follow-up monitoring is every three to six months with routine clinic visits and blood counts.
During the venetoclax ramp-up, the patient was noted to have an absolute neutrophil count (ANC) of 0.467×109/L at the 200 mg/day dose. 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 the first three months of treatment.
Neutrophil growth factor support was used because 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. If there is recurrent neutropenia beyond the first three or four months with the highest tolerated dose of venetoclax despite neutrophil growth factor support, or if treatment with neutrophil growth factor does not result in improvement in ANC, one could reduce the venetoclax dose.
Patient 3: Treatment of Relapsed/Refractory CLL
A 75-year-old retired teacher was diagnosed with CLL five years ago; ibrutinib was started three years ago for active del17p CLL and was well tolerated with no dose adjustments. Currently, ALC is increasing with a newly noted 2-cm palpable cervical lymph node and del17p, TP53-mutated, BTK-mutated, and IGHV-unmutated disease. A new treatment is indicated for this patient with high-risk CLL.
Patient 3 Treatment Considerations
Considerations for the treatment of relapsed/refractory CLL are heavily dependent on prior treatment and refractoriness to treatment (TABLE 2). CIT is contraindicated for this patient with defective TP53. Switching to an alternative irreversible BTK inhibitor is contraindicated due to the presence of BTK mutation and switching to an alternative inhibitor of the B-cell receptor signaling pathway, such as a phosphatidylinositol 3 kinase (PI3K) inhibitor, is unlikely to result in a response. BCL2 inhibitor–based therapy with venetoclax has shown durable responses in patients who develop BTK inhibitor–refractory CLL and is the best treatment choice for this patient.
Although not formally demonstrated in a randomized clinical trial, the addition of a CD20 monoclonal antibody may improve efficacy of venetoclax therapy. Therefore, this patient was treated with venetoclax plus rituximab. Due to this patient having progressive CLL while on ibrutinib, ibrutinib should be continued through venetoclax ramp-up. This is to avoid an explosive CLL disease flare that is commonly seen with the abrupt withdrawal of BTK inhibition in patients whose disease is progressing while on a BTK inhibitor.
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.
Because this patient has very-high-risk CLL by virtue of having defective TP53 and relapsed and BTK inhibitor–refractory disease, long-term disease control should consider allogeneic hematopoietic cell transplantation. Transplantation should be considered when patient achieves best response with venetoclax-based treatment, if this is an option. In addition, clinical trials of CD19-targeted chimeric antigen receptor T-cell therapy, reversible BTK inhibitors, or another investigational strategy are reasonable considerations for this patient.
With venetoclax, we now have a treatment that can be administered to older patients with comorbidities to achieve blood undetectable MRD remission in most of these patients, many of whom may never need another treatment given their advanced age.
Further progress in the treatment of CLL will come with developing treatments that achieve a higher proportion of patients with undetectable MRD remission with shorter fixed-duration treatment. Deeper remissions are expected with longer progression-free and overall survival 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 Richter transformation, CLL clonal evolution, and refractory disease.
Another important concept is the therapeutic plateau with targeted therapy. With BTK inhibitor-based treatment, there is continued clinical benefit and disease control with continued exposure. Deeper remissions are reported with prolonged exposure, but remissions typically are not deep enough to consider discontinuing treatment in most patients. Moreover, there is a concern for selecting resistant clones when BTK inhibition is cycled on and off over the treatment course.
With venetoclax-based treatment, there is patient heterogeneity in kinetics of response; the optimal exposure duration has not been defined and is likely multifactorial. Venetoclax appears to be a very appealing partner for combination therapies, given the potency in debulking of CLL and its apparent ability to lower the threshold for apoptosis and potentially synergize with most therapeutic agents.
The rationale for combining BTK inhibitors with BCL2 inhibitors was built on clinically complementary activity; BTK inhibitors are highly active in treating and shrinking nodal disease, and BCL2 inhibition effectively clears blood and bone marrow. Questions remain surrounding the role of CD20 monoclonal antibodies, predictive markers for response and outcomes, optimal duration of combined therapy, management of relapsed disease, and clinical characteristics of CLL refractory to targeted therapy.