Chronic lymphocytic leukemia (CLL) has long been considered an incurable disease. The goal of traditional frontline treatments is to minimize disease burden and allow patients to achieve durable remissions. However, with the advent of new targeted agents and immunotherapeutic options, investigators are devising new drug combinations that some believe may finally cure the disease. The term "cure" also needs to be defined.
In this edition of Drawing First Blood, ASH Clinical News invited Matthew Davids, MD, MMSc, and Jennifer Woyach, MD, to debate whether newer agents will transform CLL into a curable disease. Dr. Davids, of Dana-Farber Cancer Institute, will argue on the "pro" side, and Dr. Woyach, of The Ohio State University Comprehensive Cancer Center, will argue on the "con" side.
Matthew Davids, MD: Historically, CLL has been considered an incurable disease but, with recent evidence from trials of chemoimmunotherapy combination regimens, we have seen that these approaches have curative potential in subsets of younger, fit patients with CLL and IGHV-mutated disease.
For example, the combination of fludarabine, cyclophosphamide, and rituximab (FCR) led to long-term progression-free survival (PFS) after a median follow-up of nearly 13 years in this patient group.1
I am optimistic that with several of the highly active novel agents – including PI3K inhibitors like idelalisib, BCL2 inhibitors like venetoclax, and anti-CD20 monoclonal antibodies like rituximab and obinutuzumab – entering the treatment landscape, we will be able to increase the curative potential of our available regimens. That is the rationale behind our ibrutinib plus FCR (iFCR) study – in which we saw a 37-percent complete response rate in previously untreated patients – as well as the ibrutinib plus FCG study at MD Anderson Cancer Center.2,3
Jennifer Woyach, MD: I agree, especially about the great responses that have been seen with adding novel agents to chemoimmunotherapy in the attempt to cure CLL. However, we don't yet have enough data about newer agents without chemotherapy to say that we can cure the disease. I also think it's important for us, as a field, to decide for which patients curing disease should be our treatment goal, because that will not necessarily be the goal for every patient – especially if we can induce long-term remissions with continuous therapy.
Dr. Davids: We are fortunate in CLL to have a variety of effective chemoimmunotherapy regimens for frontline treatment (including FCR, bendamustine plus rituximab, and chlorambucil plus obinutuzumab), but each of these regimens carries substantial risks and toxicities, particularly for older, frailer patients who often have multiple medical comorbidities. That has been part of the inspiration to develop novel agents that are both better tolerated than existing regimens and highly effective for our patients.
Dr. Woyach: The first novel agent that was approved by the U.S. Food and Drug Administration (FDA) for the frontline treatment of CLL was ibrutinib, which is an irreversible inhibitor of Bruton tyrosine kinase (BTK). Ibrutinib is effective, with the limitation that it has to be given indefinitely. Ongoing research is focused on whether we can combine ibrutinib or other BTK inhibitors with additional newer agents or chemoimmunotherapy regimens to get patients to a point where they can safely discontinue therapy.
Also, if we're discussing potentially curative therapies, we have to mention that chimeric antigen receptor (CAR) T-cell therapies are being investigated in CLL. Most target the CD19 antigen, although there are other targets in development. I believe this approach has the potential to induce minimal residual disease (MRD)– negative complete responses and, hopefully, a long duration of remission and potential cure for some patients.
Dr. Davids: In the last couple of years, long-term data from trials of FCR or other chemoimmunotherapy regimens have started to emerge that will help us determine in whom a cure is possible. These are truly long-term data for FCR, in particular from the FCR300 trial at MD Anderson Cancer Center, which now has up to 15 years of follow-up data available.1 The phase II trial enrolled younger patients – the median age of participants was 57 years, and 24 percent were aged 65 or older – with IGHV-mutated disease. The investigators found that this patient subgroup has a good chance of achieving long-term disease-free survival after FCR. Half of patients achieved MRD-negative status, and, in this group, the PFS rate at 12.8 years was approximately 80 percent.
Similar data, albeit with shorter follow-up, are now emerging from the CLL8 trial from the German CLL Study Group – validating the findings reported in the older MD Anderson trial.4 After approximately six years of follow-up, the FCR combination improved PFS and overall survival in patients with previously untreated, IGHV-mutated CLL, compared with fludarabine plus cyclophosphamide.
We also recently saw a robust retrospective dataset from the Italian group with similar findings; these data, though, only apply to a relatively small subset of patients with CLL who are young, fit, and have IGHV-mutated, low-risk CLL without other cytogenetic features like del11q or del17p.5 Still, for patients like these trial participants, who can tolerate more aggressive therapy, I believe FCR should be the standard of care and the backbone regimen upon which combination approaches with novel agents should be studied.
We should not forget that another approach with curative potential in CLL is allogeneic hematopoietic cell transplantation (alloHCT). We have data about this approach going back for decades, and experience suggests that around 40 percent of patients will have long-term, disease-free survival, even in patients with high-risk CLL.6
Of course, alloHCT has many potential risks and toxicities, such as graft-versus-host disease and infection. I am hopeful that newer cellular-based therapies such as CAR T-cell therapies will induce similar response and survival rates to alloHCT, but with less toxicity.
Dr. Woyach: Right, we obviously do not have as much longterm data on the novel agents as we do for chemotherapy, which has been the standard approach for years. With ibrutinib, which has the longest follow-up of the newer agents, we still only have five- to seven-year follow-up.
Focusing on studies conducted in this setting, the phase Ib/II PCYC-1102 trial evaluated single-agent ibrutinib in 132 patients with symptomatic, treatmentnaÃ¯ve or relapsed/refractory CLL, including a subset of 31 treatment-naÃ¯ve patients older than 65 years.7 At five years after treatment initiation, 29 out of the 31 remained in remission. This is an excellent outcome, but does not indicate a path to a cure, as most of these patients still had detectable disease, despite remaining on drug. We also don't know what happens if patients discontinue therapy.
It seems that, for ibrutinib at least, combination therapy will be required to permit treatment discontinuation, and hence the potential for a cure. As Dr. Davids mentioned before, there are data looking at ibrutinib in combination with FCR, with great response rates – including both MRD negativity and duration of remission in the short term.
Researchers also have been evaluating ibrutinib in combination with the BCL2 inhibitor venetoclax, as well as venetoclax plus obinutuzumab, which look promising – with the caveat that limited follow-up data are available.8,9 For either of these combinations, though, it remains to be seen whether patients will be able to discontinue treatment without risking relapse.
Dr. Davids: The definition of cure also will affect our choice of which patients we will attempt to cure. For me, to cure CLL, we need to reach an MRD-undetectable state, both in the blood and in the bone marrow. However, getting to an MRD-undetectable state is just the first step, because we have certainly seen patients who reach that state and then later relapse once therapy is discontinued.
MRD-negative status is a useful surrogate for outcome, but clinicians' ultimate goal is to prolong patients' survival. The challenge is knowing how long we need to wait until we can tell a patient that his or her disease is cured. Getting to MRD-undetectability is certainly not enough. In other cancers, we use five years of disease-free survival as a benchmark; in CLL, that's not long enough. We know that patients can experience late relapses. In the long-term FCR data that I mentioned, the number of relapses decreases as patients near five or 10 years of disease-free survival; still, there were almost no relapses after 10 years.1 So, I think if a patient with IGHV-mutated CLL has remained bone marrow MRD-undetectable 10 years after finishing FCR, he or she is likely to be cured.
Dr. Woyach: I agree with you. Ten years is probably a good benchmark. There definitely are some relapses after FCR between five and 10 years, and we don't have much data to say whether achieving an MRD-negative state in patients receiving a novel therapy alone is clinically important, or whether it signifies long-term survival. MRD negativity clearly is important for remission duration after chemoimmunotherapy, but we don't know if the same will hold true with novel therapy combinations.
Dr. Davids: There are some early data that patients with CLL who achieve an MRD-undetectable state while taking venetoclax have better PFS at two or three years, compared with patients who remain MRD-positive. But, with such short follow-up, we don't know if that will translate into a longer-term, disease-free survival benefit.
It's true: MRD-undetectability after treatment with newer agents may not be the same as what we have seen with chemoimmunotherapy. Theoretically, if a patient achieves MRD-undetectability, it shouldn't matter which way he or she gets there (chemotherapy or novel agents), but we actually need to show that with clinical trial data.
Dr. Woyach: It might be a sampling difference, too. If a patient is truly MRD-negative, it probably doesn't matter how he or she got there, but we don't know that MRD-negativity in bone marrow or peripheral blood also means that the lymph nodes are completely clear of disease. The ability to eradicate malignant cells from the lymph nodes might differ between chemoimmunotherapy and newer therapies.
With MRD, we also have to consider the level of detection with available MRD analyses. Both chemoimmunotherapy and novel agent combinations can produce MRD-negative bone marrow to a sensitivity of 1Ã—10–4, but there could still be differences in the absolute number of remaining malignant cells below the level of detection.
Dr. Davids: If we're defining cure in terms of MRD status, we also should mention that patients taking ibrutinib often do not get to an MRD-undetectable state. As long as they stay on ibrutinib, though, they can do extremely well for long periods of time. So, for many patients with CLL, particularly those who are older and frailer, achieving MRD-undetectability may not be important.
Another consideration for deciding our ultimate treatment goal – and how we will get there – is that there are not many predictive biomarkers in CLL. The most important one we have is TP53 status, which is a solid predictor of poor response to chemoimmunotherapy. Also, if patients have a somatic mutation of TP53 or del17p, they are unlikely to have a durable response to chemoimmunotherapy. These are patients for whom we could recommend a newer agent–based approach, even in the frontline setting.
The other important predictive biomarker in CLL is IGHV mutation status. Patients with IGHV-unmutated disease tend to have shorter responses to chemoimmunotherapy. For these patients in our practice, we are increasingly recommending starting with an approach incorporating novel agents.
Dr. Woyach: I think that age is going to end up being important, as well. With chemoimmunotherapy, only the FCR combination has demonstrated curative potential, and we know that this regimen is not suitable for older patients. Looking at the gold-standard regimens in older patients (including fludarabine, chlorambucil, or rituximab combinations), most don't appear to have the potential to induce cures, or even very durable remissions.
Dr. Davids: We have seen excellent responses early in the disease course when patients are treated with combinations containing novel agents, like ibrutinib plus venetoclax with or without obinutuzumab. CAR T-cell therapy development has great potential in CLL, both alone and possibly in combination with other new agents. For example, results from a small study of patients treated with ibrutinib and anti-CD19 CAR T-cell therapy suggested that adding this new agent may increase the curative potential of CAR T cells in CLL.10 I'm optimistic that we will be able to cure more patients with CLL by using the novel agents in the future.
Dr. Woyach: New agents may be able to induce cures in certain patients with CLL, but, I would argue that if a patient is doing well on a novel agent like ibrutinib or other single-agent therapy, and he is not experiencing much toxicity, he may have an excellent quality of life, despite being on indefinite drug therapy. For these patients, the potential toxicity of combination therapy may not be worth the potential benefit, particularly because their treatment goal likely is not a cure. Instead, we want these patients to maintain a remission that allows them to continue to experience an excellent quality of life for as long as possible.
- Thompson PA, Tam CS, O'Brien SM, et al. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood. 2016;127:303-9.
- Davids MS, Kim HT, Brander DM, et al. A multicenter, phase II study of ibrutinib plus FCR (iFCR) as frontline therapy for younger CLL patients. Abstract #496. Presented at the 2017 ASH Annual Meeting, December 12, 2017; Atlanta, GA.
- ClinicalTrials.gov. First-line therapy with ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (GA-101) (iFCG) for patients with chronic lymphocytic leukemia (CLL). Accessed July 26, 2018, from https://clinicaltrials.gov/ct2/show/NCT02629809.
- Fischer K, Bahlo J, Fink AM, et al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016;127:208-15.
- Rossi D, Terzi-di-Bergamo L, De Paoli L, et al. Molecular prediction of durable remission after first-line fludarabine-cyclophosphamide-rituximab in chronic lymphocytic leukemia. Blood. 2015;126;1921-4.
- Delgado J, Milligan DW, Dreger P. Allogeneic hematopoietic cell transplantation for chronic lymphocytic leukemia: ready for prime time? Blood. 2009;114:2581-8.
- Byrd JC, Furman RR, Coutre SE, et al. Three-year follow-up of treatment-naÃ¯ve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015;125:2497-506.
- Wierda WG, Siddiqi T, Flinn I, et al. Phase 2 CAPTIVATE results of ibrutinib (ibr) plus venetoclax (ven) in first-line chronic lymphocytic leukemia (CLL). Abstract #7502. Presented at the 2018 American Society of Clinical Oncology Annual Meeting, June 3, 2018; Chicago, IL.
- Flinn IW, Gribben JG, Dyer MJS, et al. Safety, efficacy and MRD negativity of a combination of venetoclax and obinutuzumab in patients with previously untreated chronic lymphocytic leukemia – results from a phase 1b study (GP28331). Abstract #430. Presented at the 2017 ASH Annual Meeting, December 10, 2017; Atlanta, GA.
- Turtle CJ, Hay KA, Hanafi L-A, et al. Durable molecular remissions in chronic lymphocytic leukemia treated with CD19-specific chimeric antigen receptor–modified T cells after failure of ibrutinib. J Clin Oncol. 2017;35:3010-20.