As reviewed in this issue of The ASCO Post, Shanafelt and colleagues recently published the interim analysis of E1912, a U.S. Intergroup–led randomized phase III trial comparing ibrutinib/rituximab, followed by ibrutinib to disease progression vs 6 months of fludarabine, cyclophosphamide, and rituximab (FCR) among patients with chronic lymphocytic leukemia (CLL) younger than age 70 and in need of disease-specific therapy.1 The progression-free survival results favored ibrutinib/rituximab, with estimated 3-year rates of 89.4%, compared with 72.9% with FCR.1 Although a difference in overall survival was also reported, this difference was based on few deaths, several of which appeared unrelated to disease progression or therapy; longer follow-up is certainly required for this endpoint.
Results Driven by IgHV Mutation Status
Although the study was not stratified by IgHV mutation status, the results are clearly driven by outcomes in IgHV-unmutated patients, in whom 3-year progression-free survival was 90.7% vs 62.5% for FCR. Among IgHV-mutated patients, in contrast, 3-year progression-free survival was identical, at 87.7% for ibrutinib/rituximab and 88% for FCR, with just three deaths occurring (two with ibrutinib and one with FCR). This analysis is particularly important given that among IgHV-mutated patients, three different studies have demonstrated long-term, treatment-free, prolonged progression-free survival (possibly cure!) after 6 months of FCR, with a 54% plateau in the progression-free survival curve with 12-year follow-up.2-4
Fludarabine, cyclophosphamide, and rituximab should remain the preferred therapy for the majority of young, fit patients in the IgHV-mutated subgroup.— Jennifer R. Brown, MD, PhD
Tweet this quote
Given these long-term data with FCR and the similar outcomes with ibrutinib/rituximab and FCR in the E1912 study, FCR should remain the preferred therapy for the majority of patients in the IgHV-mutated subgroup. Patients with normal fluorescence in situ hybridization (FISH) findings or trisomy 12 also did not show a significant progression-free survival benefit with ibrutinib/rituximab in E1912, which is of interest given that trisomy 12 does show a particular benefit with chemoimmunotherapy, even among IgHV-unmutated patients.2,5,6 The availability of increasingly nuanced prognostication allows us to understand the overall natural history of a given patient’s CLL and to consider the full range of therapeutic options that may be appropriate. Our patients have a heterogeneous disease, and we can best serve them through this individualized approach.
Toxicity Burden of Different Therapies
It is also essential to understand the toxicity burden of different therapies. Adverse events of grade 3 or higher were similar between the ibrutinib/rituximab and FCR arms, with more nonhematologic toxicity with ibrutinib/rituximab and more hematologic toxicity with FCR. Both the number of second cancers (27 with ibrutinib/rituximab and 13 with FCR) and deaths due to solid tumors (1 and 2 events, respectively) were similar in each arm. One death due to infection occurred in each arm.
The toxicity of FCR is primarily acute hematologic toxicity, with an associated risk of infection, and is age-dependent, as demonstrated by the CLL10 study, in which the optimal cutoff for switching from FCR to bendamustine/rituximab was found to be age 65.7 E1912 enrolled patients up to age 70, which may have contributed to the higher infection rate, as well as to the two cases of acute myeloid leukemia seen on the FCR arm8; this age cutoff is arguably older than can be recommended as a general cutoff for FCR-based therapy.
Ibrutinib was associated with significant excess grade 3 or higher atrial fibrillation and hypertension, as well as a 1% risk of ventricular arrhythmia and one sudden death; all of these risks are likely to continue over time with ibrutinib, further underscoring why it may not make sense to expose patients with a low disease risk to continuous ibrutinib until clearly necessary for disease control. This observation is even more relevant for older patients, who had higher rates of ibrutinib-associated cardiac toxicities and death in the randomized older patient trial led by Alliance (median patient age = 71 years).9
Randomized trial data are starting to emerge with next-generation Bruton’s tyrosine kinase (BTK) inhibitors such as acalabrutinib10 and zanubrutinib; these agents are more specific inhibitors of BTK and may improve on the toxicity profile of ibrutinib, making prolonged therapy more tolerable. Head-to-head randomized trials comparing each agent with ibrutinib are ongoing.
Search Continues for Optimal Regimen for Higher-Risk Patients
For those higher-risk patients in whom ibrutinib-based therapy is a preferred option, ibrutinib given with rituximab, as in this trial, may nonetheless not be the optimal regimen. The addition of rituximab to ibrutinib has had no progression-free survival benefit in two randomized trials.9,11 Furthermore, complete remission was seen in only 17.2% of patients treated with ibrutinib/rituximab in E1912, with undetectable minimal residual disease in peripheral blood in just 8.3%, necessitating continuous, indefinite therapy with concomitant toxicity and perhaps allowing ongoing clonal evolution.
MORE ON IBRUTINIB THERAPY IN CLL
For more on ibrutinib-based therapy for untreated younger patients with CLL, see an interview with Tait D. Shanafelt, MD, on The ASCO Post Newsreels at www.ascopost.com/videos.
Newer combinations that achieve high rates of undetectable minimal residual disease in bone marrow have been reported recently. Our group has reported on the ibrutinib-plus-FCR regimen, which achieved 84% undetectable minimal residual disease in bone marrow at best response, with 16.5-months of follow-up.12 The MD Anderson group has reported on front-line ibrutinib with venetoclax, with 61% undetectable minimal residual disease in bone marrow at 12 months.13 Venetoclax with obinutuzumab achieved 57% undetectable minimal residual disease in bone marrow in the CLL14 trial, with a 2-year progression-free survival rate of 88.2%.14 These regimens have planned discontinuation of therapy in deep remission, which has many advantages: likely prolonged treatment-free remission, decreased toxicity, decreased cost, decreased selection pressure for resistance, and patient satisfaction.
The field of CLL is moving very quickly, and the goal, particularly for younger, fit patients, remains undetectable minimal residual disease and time-limited therapy. Only in this way will we eventually reach a cure. ■
Dr. Brown is Director, Chronic Lymphocytic Leukemia Center, Dana-Farber Cancer Institute, and Professor of Medicine, Harvard Medical School.
DISCLOSURE: Dr. Brown has received honoraria from AbbVie, Teva, and Janssen Oncology; has served as a consultant or advisor to AbbVie, Acerta, AstraZeneca, BeiGene, Catapult, Dynamo, Genentech/Roche, Gilead Sciences, Juno/Celgene, Kite, Loxo, Novartis, Octapharma, Pfizer, Pharmacyclics, Sunesis, TG Therapeutics, and Verastem; and has received research funding from Gilead Sciences, Loxo, Pharmacyclics, Sun Pharma, and Verastem.
REFERENCES
1. Shanafelt TD, et al: N Engl J Med 381:432-443, 2019.
2. Fischer K, et al: Blood 127:208-215, 2016.
3. Rossi D, et al: Blood 126:1921-1924, 2015.
4. Thompson PA, et al: Blood 127:303-309, 2016.
5. Hallek M, et al: Lancet 376:1164-1174, 2010.
6. Strati P, et al: Blood 123:3727-3732, 2014.
7. Eichhorst B, et al: Lancet Oncol 17:928-942, 2016.
8. Benjamini O, et al: Leuk Lymphoma 56:1643-1650, 2015.
9. Woyach JA, et al: N Engl J Med 379:2517-2528, 2018.
10. Ghia P, et al: 2019 European Hematology Association. Abstract LB2606. Presented June 16, 2019.
11. Burger JA, et al: Blood 133:1011-1019, 2019.
12. Davids MS, et al: Lancet Haematol 6:e419-e428, 2019.
