With the availability of a number of effective targeted agents for the treatment of chronic lymphocytic leukemia (CLL), the question arises whether chemotherapy still has a role in treating this malignancy. At the 2019 American Society of Hematology (ASH) Annual Meeting & Exposition, CLL experts Susan M. O’Brien, MD, and Stephan Stilgenbauer, MD, debated this topic—as well as various other key issues in managing patients with this type of leukemia—at a point-counterpoint session called “Is Chemotherapy for CLL on Life Support.” For the most part, both experts were in agreement, but some differences in approach may reflect U.S. vs European/German perspectives.
Susan M. O’Brien, MD
Stephan Stilgenbauer, MD
Dr. O’Brien is Associate Director for Clinical Science, Chao Family Comprehensive Cancer Center UCI, Orange, California. Dr. Stilgenbauer is Professor at the Ulm University and Saarland University, Germany.
Asymptomatic Disease
Is testing necessary for asymptomatic, early-stage, asymptomatic CLL?
Dr. O’Brien: There are two ways to look at this. If the patient is asymptomatic, one could argue that test results would not lead to treatment. For patients with asymptomatic CLL, we still use “watch and wait,” and test results wouldn’t change that. The rationale for obtaining the tests would be for prognostic value. Patients with CLL can have different outcomes, and many patients will want to know what to expect in the future. Without tests, you can’t tell them what to expect.
Dr. Stilgenbauer: Guidelines for early-stage asymptomatic CLL recommend no required testing, because there are no treatment decisions to make. Nevertheless, most patients want their cytogenetics, and this information can inform our future treatment strategies. IGHV mutation status can differentiate patients at an early stage who will have a good outcome. I would argue that we shouldn’t make treatment decisions at this stage, but it would be great to inform patients about genomics (eg, del[17p)] del[11q–]) and IGHV mutation status.
What if the patient has IGHV-mutated disease?
Dr. O’Brien: Nobody here would be inclined to treat that patient. You treat that disease when it causes a problem. IGHV-mutated CLL is often indolent, and most patients are asymptomatic. The median age at diagnosis is early 70s, and patients may die of other causes.
You might think this position goes against the whole paradigm of treating cancer, but in CLL, early initiation of older therapies in this setting compared with watch and wait (in randomized trials) showed no difference in survival; one-third of asymptomatic patients may never need treatment.
“Nobody here would be inclined to treat a patient with IGHV-mutated CLL. You treat that disease when it causes a problem.”— Susan M. O'Brien, MD
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Symptomatic Disease
The patient is 5 years out from diagnosis and has been managed with active observation. Signs and symptoms include a palpable spleen and right axillary node, worsening fatigue, and one sinus infection. At this point, what tests would you order?
Dr. O’Brien: Although there was no fluorescence in situ hybridization (FISH) abnormality at presentation, there could be a change in cytogenetics. I would want a FISH panel, particularly for del(17p) and assessment of P53 mutation status. If these mutations are present, then I would not treat this patient with chemotherapy.
Dr. Stilgenbauer: I couldn’t agree more. If we find a 17p deletion or TP53 mutation, the patient will have a worse outcome than if he did not, particularly when treated with chemotherapy.
Treatment Decisions Based on Genetic Mutations
What treatment would you give a healthy 62-year-old without 17p deletion and TP53 mutation who has IGHV-mutated disease?
Dr. O’Brien: I would choose fludarabine/cytarabine/rituximab (FCR). We have a randomized trial comparing ibrutinib/rituximab with FCR in younger patients with no 17p deletion. Progression-free survival is superior with ibrutinib/rituximab in the intent-to-treat analysis and in eligible patients.1
It is important to note that outcome differs by IGHV mutation status, and we’ve seen the benefit in patients with unmutated IGHV so far. Patients with unmutated IGHV have a much shorter progression-free survival with chemotherapy. Thus far, there is no difference between ibrutinib/rituximab and FCR in progression-free survival for patients with a mutated IGHV gene.
I’m very swayed by the long-term data with FCR. Patients treated with FCR who have mutated IGHV have a favorable long-term progression-free survival; there is a plateau on the progression-free survival curve at about 60% at 11 to 16 years. If the patient becomes minimal residual disease (MRD)-negative, this percentage rises to 80%. I firmly believe that some patients are cured after FCR. The ability to tolerate the regimen is important. In this setting, FCR is the way to go.
Dr. Stilgenbauer: These data are from a single-arm trial at MD Anderson, a highly specialized center. Only a minority of patients with CLL requiring treatment have mutated IGHV and cure cannot be assumed, as there is a continuous pattern of late relapses. The ECOG1912 randomized controlled trial showed more deaths with FCR than ibrutinib/rituximab, mostly due to CLL progression. Tolerability is better with ibrutinib/rituximab—neutropenia, thrombocytopenia, anemia, infection, and neutropenic fever are significantly more common with FCR.2
Dr. O’Brien: Data from the trial are interesting in that the deaths were from CLL.
The next question is, who are these early progressors? Other molecular abnormalities may be able to identify them. If they experience disease progression, why did they die and not receive other treatments? The real question is whether ibrutinib will produce the same progression-free survival plateau as FCR. We need longer follow-up to determine that.
Role of MRD Testing
The patient received six cycles of FCR and is MRD-disease at completion of therapy. Is MRD testing important?
Dr. Stilgenbauer: Although I am in favor of laboratory analyses, I would not recommend MRD testing in routine clinical practice. There is no evidence whatsoever that we would change treatment based on MRD status. This should not be pursued outside of clinical trials.
“Although I am in favor of laboratory analyses, I would not recommend MRD testing in routine clinical practice.”— Stephan Stilgenbauer, MD
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Dr. O’Brien: We clearly know MRD status is important and MRD-negative status predicts better outcomes. However, one could argue that outside of a clinical trial, there is no reason to get the test. The reason is that, for patients who are not MRD-undetectable, we don’t have a strategy. We know they won’t have as durable a remission, but we don’t know what to do at that point to convert them to MRD-undetectable. The only reason to get the test is that, if a patient is MRD-positive after FCR treatment, I don’t want to offer false hope that they are not likely to relapse, since they are.
Treatment Options for Older Patients
A new patient who is 74 years old needs treatment. He has mutated IGHV, normal FISH, a good performance status, and is considered to have favorable-risk disease. How would you treat him?
Dr. O’Brien: Based on the iLLUMINATE trial, there was a dramatic difference in progression-free survival favoring ibrutinib/obinutuzumab vs chlorambucil/obinutuzumab in untreated patients with CLL: median progression-free survival was not reached in the ibrutinib arm vs 19 months in the control arm. Patients with unmutated IGHV (high-risk) had even worse outcomes on the control arm.3
The ALLIANCE trial enrolled untreated older patients with CLL and compared ibrutinib plus or minus rituximab vs bendamustine/rituximab.4 Both of the ibrutinib-containing arms had significantly better progression-free survival than bendamustine/rituximab.
I never use bendamustine/rituximab; I use FCR for the possibility of pronounced long-term, progression-free survival and a cure fraction. However, that is much less relevant in a 74-year-old patient; in such an older patient, irrespective of mutation status, I would rather give a regimen that is not associated with myelosuppression and an increased risk of infection. Older patients become deconditioned so rapidly if they do get an infection. My own choice is a nonchemotherapy regimen. Ibrutinib has the best outcome and is my first choice.
Dr. Stilgenbauer: In the ELEVATE TN trial (acalabrutinib with or without obinutuzumab versus chlorambucil with obinutuzumab) presented at ASH 2019, there was a marked benefit in the acalabrutinib arm. Follow-up is short, at just over 2 years.5
Despite the opportunity to crossover, there is a trend for an overall survival advantage with a novel therapy. It is better to have a chemotherapy-free option in the front-line setting.
The multicenter phase III CLL 14 trial enrolled 432 untreated patients with CLL with “active disease” and compared chlorambucil/obinutuzumab vs venetoclax/obinutuzumab.6 Adverse events were not much different between the arms. Venetoclax/obinutuzumab yielded significantly better progression-free survival than did chlorambucil/obinutuzumab. Patients with unmutated IGVH benefited most, but patients with IGHV-mutated status also did better on the venetoclax/obinutuzumab arm. I would opt for the novel treatment combination.
How would you treat a patient who is 62 years old and has del(17p)?
Dr. O’Brien: Up until recently, the answer was ibrutinib. These patients fare poorly on chemotherapy. However, only about 5% of previously untreated patients with CLL have del(17p).
Dr. Stilgenbauer: In this population, chemotherapy is not an option. I would argue that in addition to Bruton’s tyrosine kinase (BTK) inhibitors, we now have also other options available, including venetoclax/obinutuzumab, based on the CLL14 trial.
Patient Adherence
The patient was treated with upfront ibrutinib. Do you use supportive care during treatment with oral agents? Do you have any tips on adherence?
Dr. O’Brien: I don’t use supportive care with prophylactic antibiotics. I don’t have any great ideas about how to fix adherence. My only strategy is to ask how many doses the patient has missed, rather than whether they have missed any doses. That wording might make it more acceptable for them to admit they missed doses.
Dr. Stilgenbauer: Shorter treatment durations have a theoretical benefit for adherence. I would not use prophylactic measures in the front-line setting. However, with novel agents, we have to be aware of drug interactions. We need to pay attention to the possibility of invasive infections with BTK inhibitors and follow the prescription information with regard to tumor-lysis syndrome and hydration with venetoclax.
The initial patient (fit and young without 17p deletion/TP53 mutation and with mutated IGHV) has been in remission for 56 months following FCR. There are no symptoms, but the white blood cell count is beginning to rise, and the patient has thrombocytopenia.
Dr. O’Brien: If the only indication was thrombocytopenia, think about immune thrombocytopenia as the underlying cause. If you suspect that and treat it, you might not need to treat the underlying disease. If the patient doesn’t have much disease, I would then watch and wait, monitoring for more disease.
Dr. Stilgenbauer: Any development or worsening of cytopenia due to CLL can justify treatment. Follow the patient and check blood cell counts.
A few months later, the platelet count dropped. Let’s say this patient did not have immune thrombocytopenia.
Dr. O’Brien: RESONATE was a randomized trial in relapsed or refractory CLL that compared ibrutinib vs obinutuzumab; ibrutinib was given until progressive disease.7 (The protocol was later amended to allow crossover.) A dramatic difference was observed in favor of ibrutinib in the total population and in high-risk patients. By lines of prior therapy, the best outcomes were with only one prior therapy. In the current era of novel agents, no one would give four prior lines of therapy before giving a targeted therapy.
Dr. Stilgenbauer: The phase III MURANO trial compared venetoclax/rituximab vs bendamustine/rituximab, with time-limited venetoclax for 2 years. Prior bendamustine was allowed if the duration of response was more than 24 months.8 The vast majority of patients had received prior fludarabine-based therapy. At a median follow-up of 4 years, a dramatic difference in progression-free survival favored venetoclax/rituximab. The patients were off the drug for a median of 22 months. Even more remarkable is the difference in overall survival: 4-year overall survival was 85% with venetoclax/rituximab vs 67% with bendamustine/rituximab.
There is no role for chemotherapy in the relapsed setting. We do see higher rates of neutropenia with venetoclax/rituximab, but pneumonia and infections are not more common.
Relapse After Ibrutinib Treatment
The patient received ibrutinib and subsequently relapsed.
Dr. O’Brien: I suspect that this could be Richter’s transformation because of the markedly elevated lactate dehydrogenase level. A biopsy is used to determine this, but the cells are often admixed with the CLL cells, and you might miss the transformation. This is where the positron-emission tomography (PET) scan is helpful. It helps identify a hot node for biopsy. Usually, this will show transformation, but you still need the biopsy, since a significant minority of patients with a hot lymph node on PET scan may have infections as the cause. We tend to see transformation early on with ibrutinib.
“If a patient experiences disease progression early on ibrutinib, that should trigger suspicion of Richter’s transformation.”— Susan M. O'Brien, MD
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In retrospect, some patients enrolled in the early trials of ibrutinib went on to Richter’s transformation, and this occurred early. These patients were likely to have occult transformation ahead of time and were found to be transformed when they didn’t respond well to ibrutinib. If a patient experiences disease progression early on ibrutinib, that should trigger suspicion of Richter’s transformation.
Dr. Stilgenbauer: The data are sparse on patients who relapse after ibrutinib or idelalisib.
Dr. O’Brien: There is a fair amount of data supporting the use of venetoclax in patients who are refractory to ibrutinib or idelalisib. There are now emerging data suggesting that if you choose venetoclax before ibrutinib, patients will respond to ibrutinib at relapse.
What if the patient receives ibrutinib and venetoclax? What treatment would you use in the third-line setting?
Dr. O’Brien: My feeling would be to avoid chemotherapy. Perhaps PI3K inhibitors, but the data suggest they are not very effective. Chimeric antigen receptor T-cell therapy is coming up, but it’s not yet approved.
Dr. Stilgenbauer: Most studies include patients whose disease failed to respond to chemotherapy and went on to novel agents. Now patients receive novel agents in the front-line setting, so we are seeing patients whose disease failed to respond to venetoclax and ibrutinib but had no prior chemotherapy, and this may still be an option. However, the hope is to combine novel agents in this setting and not use chemotherapy.
Dr. O’Brien: We are clearly moving toward combinations of novel agents for relapsed or refractory CLL.
Role of Chemotherapy
What is the current role for chemotherapy in CLL?
Dr. O’Brien: I still discuss using FCR, including the pros and cons of using chemotherapy in that setting. Discussions were easier when we just had continuous ibrutinib vs time-limited chemotherapy. Now we have time-limited venetoclax. How we present the information to patients matters. I would not use chemotherapy in the relapsed setting.
Dr. Stilgenbauer: After using novel agents, there may be a role for chemotherapy in the third or higher line of therapy. The place where chemoimmunotherapy may have a role in front-line therapy is the patient with IGHV-mutated CLL and no del(17p) TP53 mutation, where you can discuss chemotherapy vs a novel agent as options.
Dr. O’Brien: Our remarks should be taken in the context of an ideal situation where patients have access to all treatments. It depends on the country. In the United States, you have many choices, but this is not universal.
DISCLOSURE: Dr. O’Brien has received honoraria from AbbVie, Alexion Pharmaceuticals, Amgen, Aptose Biosciences, Astellas Pharma, Celgene, Eisai, Gilead Sciences, GlaxoSmithKline, Janssen, Loxo, Pfizer, Pharmacyclics, Sunesis Pharmaceuticals, TG Therapeutics, and Vaniam Group; has served as a consultant or advisor to AbbVie/Genentech, Alexion Pharmaceuticals, Amgen, Aptose Biosciences, Astellas Pharma, Celgene, Gilead Sciences, GlaxoSmithKline, Janssen Oncology, Pfizer, Pharmacyclics, Sunesis Pharmaceuticals, TG Therapeutics, and Vaniam Group; has received institutional research funding from Acerta Pharma, Gilead Sciences, Kite Pharma, Pfizer, Pharmacyclics, Regeneron, Sunesis Pharmaceuticals, and TG Therapeutics; and has been reimbursed for travel, accommodations, or other expenses by Celgene, Gilead Sciences, Janssen, Janssen Oncology, and Regeneron. Dr. Stilgenbauer has received honoraria from AbbVie, AstraZeneca, Celgene, Gilead Sciences, GlaxoSmithKline, Janssen, and Roche; has served as a consultant or advisor to AbbVie, AstraZeneca, Celgene, Gilead Sciences, GlaxoSmithKline, Janssen, and Roche; has participated in a speakers bureau for AbbVie, AstraZeneca, Celgene, Gilead Sciences, GlaxoSmithKline, Janssen, and Roche; has received research funding from AbbVie, AstraZeneca, Celgene, Gilead Sciences, GlaxoSmithKline, Janssen, and Roche; and has been reimbursed for travel, accommodations, or other expenses by AbbVie, AstraZeneca, Celgene, Gilead Sciences, GlaxoSmithKline, Janssen, and Roche.
REFERENCES
1. 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 127:303-309, 2016.
2. Shanafelt TD, Wang XV, Kay NE, et al: Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med 381:432-443, 2019.
3. Moreno C, Greil R, Demirkan F, et al: Ibrutinib plus obinutuzumab vs chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukemia (iLLUMINATE): A multicenter, randomized, open-label, phase III trial. Lancet Oncol 20:43-56, 2019.
4. Woyach JA, Ruppert AS, Heerema NA, et al: Ibrutinib regimens vs chemoimmunotherapy in older patients with untreated CLL. N Engl J Med 379:2517-2528, 2018.
5. Sharman JP, Banerji V, Fogliatto LM, et al: ELEVATE TN: Phase III study of acalabrutinib combined with obinutuzumab or alone vs obinutuzumab plus chlorambucil in patients with treatment-naive chronic lymphocytic leukemia. 2019 ASH Annual Meeting & Exposition. Abstract 31. Presented December 7, 2019.
6. Fischer K, Al-Sawaf O, Bahlo J, et al: Venetoclax and obinutuzumab in patients with CLL and co-existing conditions. N Engl J Med 380:2225-2236, 2019.
7. Byrd JC, Brown JR, O’Brien S, et al: Ibrutinib vs ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 371:213-223, 2014.
8. Seymour JF, Kipps TJ, Eichhorst B, et al: Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med 378:1107-1120, 2018.
