Chronic lymphocytic leukemia (CLL) is the most common form of leukemia diagnosed in adults residing in Western countries, and is a monoclonal disorder that is characterized by a progressive accumulation of functionally incompetent lymphocytes. Early-stage CLL is generally not treated, with therapy initiated only after symptoms appear of there is evidence of rapid disease progression. Treatment options have widened during the past decade, especially with targeted therapy.
Venetoclax received approval from the US Food and Drug Administration (FDA) in April 2016, with an indication for CLL patients harboring a 17p deletion who have received at least 1 prior therapy. It is a selective inhibitor of the B-cell lymphoma 2 (Bcl-2) regulator protein, and high levels of BCL2 protein are expressed in CLL, which in turn contributes to resistance to apoptosis. While the original approval was for treatment of relapsed/refractory del(17p) CLL, it was expanded to include combination therapy with rituximab in relapsed CLL. In addition, venetoclax plus obinutuzumab has improved progression-free survival, as compared to standard chemoimmunotherapy (CIT), in older patients with comorbidities.
Traditional CIT is generally administered over several courses, until remission is obtained, and then the patient is observed until progression and then treatment begins again. CIT was not considered curative for most patients but venetoclax-based treatment have demonstrated the ability to eliminate CLL and then achieve deep remission with fixed-duration therapy.
In a review article published in Blood, William G. Wierda, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, and Francesco Paolo Tambaro, MD, PhD, of the Azienda Ospedaliera di Rilievo Nazionale Santobono- Pausilipon in Italy, describe how they use venetoclax-based regimens as first-line therapy and in the setting of relapsed and refractory CLL, using a series of case studies.
As there are now many treatment options and strategies for front-line therapy, clinicians should base their management decisions on patient characteristics. It is essential to take into account patient age and comorbidities, TP53 status [including del(17p) and TP53 mutation status], IGHV-mutation status, and the goals of treatment. Cardiac history and status, the use of concomitant medications, renal function, and bulk of CLL should also be taken into consideration, in addition to financial considerations.
In the first case study, the patient was 77 years old and physically active, but with hypertension and coronary artery disease (prior cardiac stent), and a CIRS score 5. He was diagnosed with CLL 8 years ago, and currently has no palpable lymph nodes, no del(17p), and is TP53-wildtype and IGHV-mutated (5.6% deviation from germline). He has progressive anemia and fatigue with indications that treatment should be initiated.
Several first-line options exist for this patient, and the authors chose venetoclax over a Bruton’s tyrosine kinase inhibitor (BTKi) based on the patient’s age, his history of cardiac disease, IGHV-mutated status, and his desire for fixed-duration treatment. Additionally, if the patient achieves the deep remission that is expected with fixed-duration venetoclax-based treatment in an individual with IGHV-mutated disease, it may eliminate the need for any future treatment, given his age. His venetoclax-based treatment used the regimen in the CLL14 trial (ClinicalTrials.gov Identifier: NCT02242942), in which the median patient age was 72 years. After 1 year of fixed duration therapy, results of the CLL14 trial showed a complete remission (CR) rate was 51.3%, blood undetectable minimal residual disease (uMRD) (10-4 sensitivity) rate was 73.7% and 24-month progression-free survival rate was approximately 90%.
The second patient was a 60-year old architect without any significant comorbidities, but who presented with progressive fatigue that made him too tired to exercise, along with night sweats that left him drenched. His CLL was diagnosed 4.5 years ago and at the time of treatment initiation had bilateral palpable 2 cm axillary lymph nodes, no del(17p), TP53-wildtype, and IGHV-unmutated (0% deviation from germline). He was symptomatic and presented with progressive cytopenias indicating active disease, and several options were available to him including CIT, BTKi- and venetoclax-based regimens.
His younger age and IGHV-unmutated status were important factors when selecting first-line treatment, and after comparing outcomes and toxicities for the available options, the authors decided on venetoclax plus obinutuzumab. The CLL14 trial enrolled patients with comorbidities who tended to be older, but they felt comfortable extrapolating the efficacy results of this trial to younger fit patients and preferred a non-genotoxic, targeted, fixed duration therapy. However, the long-term risk for secondary myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) and for Richter’s transformation has not been defined with targeted therapy and long term follow-up with larger numbers of patients is needed.