Chronic Lymphocytic Leukemia: New Treatment Approaches Highlighted at ASCO 2019
Nitin Jain, MD
Blood Cancers, Chronic Lymphocytic Leukemia
Hospital and Institutional Affiliations
Associate Professor, Department of Leukemia,
The University of Texas MD Anderson Cancer Center, Houston
Question 1. In your opinion, what were the most clinically relevant CLL data presented at ASCO this year?
The most important abstract for CLL at ASCO this year was the CLL14 study.1 This was a randomized phase 3 frontline study for patients with CLL comparing venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab. It was a registration study that showed that for patients with CLL, progression-free survival favored venetoclax/obinutuzumab compared with chlorambucil/obinutuzumab, which was, until recently, the standard of care for older patients with CLL or for those patients with significant comorbidities. This study led to the approval of venetoclax/obinutuzumab for frontline therapy in patients with CLL.2
This is a very important study in the field. First of all, it provides effective therapy in the frontline setting. Second, it is a time-limited therapy, where the treatment is given for 1 year and all patients stop therapy. This is different than ibrutinib, which is already approved for frontline CLL. Ibrutinib has to be given daily, indefinitely.
Question 2. Can you discuss the importance/significance of achieving a negative minimal residual disease (MRD) status after treatment for CLL?
The MRD field is changing. When we started using chemoimmunotherapy such as FCR [fludarabine, cyclophosphamide, rituximab], many studies had shown that if a patient becomes MRD-negative after treatment, those patients had longer progression-free survival and overall survival compared to if they remained MRD-positive.
With the introduction of targeted therapy, what was realized was that hardly any patients become MRD-negative with ibrutinib, but they can still have long-lasting remissions. Therefore, the concept of MRD was not pursued much because no patients were becoming MRD-negative with ibrutinib, and the treatment was being continued for a long time.
With the use of venetoclax, especially the combination of venetoclax with other agents such as rituximab or obinutuzumab, and also data with venetoclax plus ibrutinib, we are seeing high rates of MRD negativity for patients. There is an emerging concept that for these time-limited therapies, MRD may play a role at the time of treatment discontinuation, meaning if the patient is MRD-negative at the end of the proposed time duration of treatment, then it is likely safe to discontinue the treatment. On the flip side, if you MRD-positive, there is a higher likelihood that disease will relapse. How should we follow those patients who remain MRD-positive? Should we continue more therapy? That remains up for discussion and is the focus of clinical trials at this time.
Question 3. What is your view on the recent developments in the field of chimeric antigen receptor T-cell (CAR-T) therapies in CLL?
CAR-T cell therapy has been a revolutionary therapy, particularly for patients with acute lymphoblastic leukemia and in non-Hodgkin lymphoma, where it is already FDA-approved.
CAR-T development in the field of CLL has lagged behind, but this year we are seeing more and more studies being reported with the use of autologous CD19-directed CAR-T cells. These are showing improved efficacy in patients with CLL.
A few years ago data showed that complete remission rates or the MRD-negative rates in CLL patients was much lower than what was seen with ALL patients, and that led to somewhat of an early disappointment in CLL, especially with respect to CAR-T.
Now, with more recent data reported, we are seeing a resurgence in terms of the activity of CAR-T patients and high rates of complete remission as well as MRD-negative remission. I think CAR-T will play a major role for patients with CLL who have failed standard approaches.
Question 4. Real-world data seem to suggest that use of tyrosine kinase inhibitors (TKIs) for CLL is associated with high discontinuation rates because of adverse events. What are your strategies for monitoring and addressing adverse events in patients being treated with TKIs?
An important aspect is patient education. Once we plan to start a patient on ibrutinib we discuss the potential side effects they may experience, which can range from loose stool, skin rash, and joint pains, to somewhat more serious but less common complications like atrial fibrillation and bleeding complications. Those are things that patients need to be told upfront. They should be told that if they are having any of these side effects they should let us know in the clinic so we can optimally manage them with respect to holding the drug for few days or decreasing the dose of the drug depending on the situation.
Patient education is certainly important, but at the same time having active clinic staff that can make calls and report this information in real time is also important so that those adjustments and those holds can be done.
Question 5. What impact does genome sequencing have on treatment selection, and how do you communicate with patients about genetic testing?
In terms of genetic sequencing, one major area is p53 sequencing, which goes hand in hand with deletion 17p. Mutation of the TP53 gene can be tested by DNA sequencing, while deletion 17p can be assessed by FISH [fluorescence in situ hybridization] testing. Both these markers convey the same meaning, which is high risk for relapse if treated with chemoimmunotherapy. It has already become standard that if a patient has either one, the patient should not receive chemoimmunotherapy; these patients should be treated with novel therapies such as ibrutinib or venetoclax, or on a clinical trial focusing on novel therapies.
Another important sequencing test is the IGHV sequencing, which is the immunoglobulin variable region heavy chain (IGHV) gene. That is reported by the lab as either a mutated IGHV or unmutated IGHV. We know that if you do chemoimmunotherapy, such as FCR, patients with mutated IGHV are the ones who derive long-term benefit, where upwards of 50% of patients are without disease progression at 10+ years after receiving 6 cycles of FCR.
Our group, for some years, has used chemoimmunotherapy only for patients with mutated IGHV without deletion 17p or p53 mutation. There were data reported at the 2019 American Society of Hematology Meeting from the ECOG trial3 (where the patients were randomized to receive FCR versus ibrutinib/rituximab) that showed that the benefit of ibrutinib plus rituximab was largely seen in unmutated IGHV, but if you look at the mutated IGHV patients, the curves were overlapping. The strategy, therefore, is to use the IGHV testing if you have a patient where you are thinking about using chemoimmunotherapy such as FCR. Please make sure that the patient is IGHV-mutated. On the flipside, if the patient is IGHV-unmutated, it would be recommended to use a targeted therapy approach.
- Fischer K, Al-Sawaf O, Bahlo J, et al. Effect of fixed-duration venetoclax plus obinutuzumab (VenG) on progression-free survival (PFS), and rates and duration of minimal residual disease negativity (MRD-) in previously untreated patients (pts) with chronic lymphocytic leukemia (CLL) and comorbidities. Presented at: ASCO Annual Meeting; June 4, 2019; Chicago. Abstract 7502.
- US Food and Drug Administration. FDA approves venetoclax for CLL and SLL. Published May 15, 2019. Accessed July 8, 2019.
- Shanafelt TD, Wang V, Kay NE, et al. A randomized phase III study of ibrutinib (PCI-32765)-based therapy vs. standard fludarabine, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy in untreated younger patients with chronic lymphocytic leukemia (CLL): a trial of the ECOG-ACRIN Cancer Research Group (E1912). Blood. 2018;132(suppl_1):LBA-4.