Elimination of chemotherapy from our combination regimens should be a shared goal among researchers that will move us a step closer to more patient-friendly and scientifically driven therapies for CLL.
Over the past 5 years, the most exciting therapeutic advance in chronic lymphocytic leukemia (CLL) has been the development and subsequent widespread adoption of targeted therapies. A brief glance at the CLL trials accruing on ClinicalTrials.gov will show that targeted therapies, with or without the addition of chemotherapy, are of great interest. Here I will propose that chemotherapy can be eliminated altogether in the management of CLL.
It is a fairly easy argument that chemotherapy does not have a role in the management of relapsed CLL. The 5-year follow-up data from the phase Ib/II PCYC-1102 study of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib as a single agent show a median progression-free survival (PFS) of 52 months, which is clearly better than any chemotherapy-only regimen that has been studied. For patients with only one or two previous lines of therapy, PFS was further improved to 63 months; for those without a complex karyotype, the median PFS has yet to be reached. While data for the combination of ibrutinib plus chemotherapy have also been impressive, no data exist to demonstrate that chemotherapy adds to the durable remissions seen with ibrutinib.
Other single-agent BTK inhibitors have also shown impressive efficacy, although follow-up is shorter.[3-5] Data are less mature for the BCL2 inhibitor venetoclax, but in a phase I study, the 15-month PFS rate was 69% for those on the 400-mg dose, again demonstrating a significant advantage over historical data with chemotherapy. Currently, the National Comprehensive Cancer Network (NCCN) guidelines list ibrutinib, idelalisib plus rituximab, and venetoclax as the preferred agents for relapsed/refractory CLL. While there may still be situations in which chemotherapy could be considered, such as resource-constrained settings, if targeted agents are available, chemotherapy does not have a place in the management of relapsed CLL.
In the frontline setting, the role of chemotherapy is more complicated, and best discussed separately for older and younger patients. For the older patient population, while bendamustine plus rituximab and chlorambucil plus obinutuzumab are effective, ibrutinib appears to have superior efficacy when looking across trials. In the PCYC-1102 study noted previously, the cohort of 31 treatment-naive patients had a 5-year PFS rate of 92%. The phase III RESONATE-2 study has similarly impressive data, with a PFS rate of 89% at 29 months. These data compare extremely favorably with the data that have been published for frontline studies of chemoimmunotherapy in CLL. While it can be argued that ibrutinib has not yet been compared with a standard frontline therapy in CLL, the phase III Alliance A041202 study (NCT01886872) is comparing ibrutinib alone vs ibrutinib in combination with rituximab vs bendamustine plus rituximab in patients 65 years and older. Once completed, this trial will establish whether ibrutinib is superior to the most effective chemoimmunotherapy regimen for older patients.
For younger patients, the question of whether chemotherapy can be eliminated entirely is less straightforward, and may somewhat depend on genetic risk. It is possible that of the group of patients who are IGHV mutated with good-risk cytogenetics, some would benefit from chemoimmunotherapy over a targeted therapy in terms of inducing a cure. However, those patients are also very likely to do well on ibrutinib as frontline therapy, without the associated risk of a therapy-related myeloid neoplasm. For young patients with IGHV-unmutated disease or poor-risk cytogenetics, cross-trial comparisons seem to favor ibrutinib, even when compared against the fludarabine, cyclophosphamide, and rituximab (FCR) regimen. In the CLL8 study, patients with IGHV-unmutated disease had a 3-year PFS rate of 55% after FCR. In RESONATE-2, the 18-month PFS rate for this group of patients was 89%; this rate was the same as that for mutated patients. Assuming that this lack of disease progression persists, these patients likely would have a longer PFS with ibrutinib than FCR. However, just like for elderly patients, a completed and maturing phase III study-ECOG-E1912 (NCT02048813)-will definitively determine which combination is more effective in younger CLL patients.
Equally important to efficacy for our patients is tolerability, and ibrutinib has been well tolerated in clinical studies. In RESONATE-2, the most common toxicities were diarrhea, fatigue, nausea, and cough. The rate of discontinuation due to toxicities was 9%. Serious toxicities included atrial fibrillation and bleeding. Atrial fibrillation often can be managed without permanent discontinuation of ibrutinib. Hemorrhage has usually been associated with the use of anticoagulants, so they should be administered with care in patients taking ibrutinib. Notably, no studies with longer follow-up have shown evidence of cumulative toxicity, with the exception of hypertension. Hypertension rates do increase over time, which will likely be an issue in patients who remain on these drugs for long periods. Attention will need to be paid to long-term cardiac complications that may arise.
Additionally, toxicities that are grade 1 or grade 2, such as joint pain, may be well tolerated for short periods of time, but difficult for patients to tolerate for years. While ibrutinib appears to be well tolerated over time in clinical trials, analyses of real-world patients showed toxicity to be the main reason for drug discontinuation, especially in the frontline setting. Since these real-world data are in contrast with the low discontinuation rates due to toxicity seen in trials, it will be important to see if these rates change as ibrutinib becomes even more commonly prescribed in the community setting.
Even with the limited currently available data, it appears that targeted therapy is superior to chemotherapy in terms of efficacy and safety for the vast majority of patients. However, the cost of an indefinitely dosed drug remains an issue. Careful studies of cost-effectiveness will need to be performed to determine whether the safety and efficacy of targeted therapies outweigh the cost, even if dosed indefinitely. In addition, combination studies of targeted therapies with or without antibody therapies may be an alternative strategy to potentially discontinue therapy and reduce drug costs. For example, ibrutinib in combination with venetoclax[14,15] and ibrutinib in combination with venetoclax and obinutuzumab have both recently been shown to induce high response rates and complete response rates, with eradication of minimal residual disease; trials of discontinuation are ongoing. If these targeted therapy combinations can lead to durable remissions in the absence of continuous therapy, the financial burden should be dramatically reduced.
With the promising current data on targeted therapies alone and in US Food and Drug Administration–approved combinations with antibodies, as well as ongoing studies with targeted combinations, the future for CLL is bright. Except for rare cases such as lymphodepletion for CAR T cells or preparative regimens for stem cell transplantation, I do not see a role for chemotherapy in the future of CLL. Elimination of chemotherapy from our combination regimens should be a shared goal among researchers that will move us a step closer to more patient-friendly and scientifically driven therapies for CLL.
Financial Disclosure:Dr. Woyach has received research funding from AbbVie, Karyopharm Therapeutics, and MorphoSys.
1. O’Brien S, Furman R, Coutre S, et al. Single-agent ibrutinib in treatment-naÃ¯ve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood. 2018;131:1910-9.
2. Chanan-Khan A, Cramer P, Demirkan F, et al. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol. 2016;17:200-11.
3. Byrd JC, Harrington B, O’Brien S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374:323-32.
4. Walter HS, Rule SA, Dyer MJ, et al. A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies. Blood. 2016;127:411-9.
5. Tam C, Grigg AP, Opat S, et al. The BTK inhibitor, BGB-3111, is safe, tolerable, and highly active in patients with relapsed/refractory B-cell malignancies: initial report of a phase 1 first-in-human trial. Blood. 2015;126:832.
6. Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374:311-22.
7. National Comprehensive Cancer Network. Chronic lymphocytic leukemia/small lymphocytic lymphoma. https://www.nccn.org/professionals/physician_gls/default.aspx.
8. Barr P, Robak T, Owen C, et al. Updated efficacy and safety from the phase 3 RESONATE-2 study: ibrutinib as first-line treatment option in patients 65 years and older with chronic lymphocytic leukemia/small lymphocytic leukemia. Blood. 2016;128:234.
9. Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010;376:1164-74.
10. Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373:2425-37.
11. Vrontikis A, Carey J, Gilreath JA, et al. Proposed algorithm for managing ibrutinib-related atrial fibrillation. Oncology (Williston Park). 2016;30:970-4,980-1,C3.
12. Mato AR, Nabhan C, Barr PM, et al. Outcomes of CLL patients treated with sequential kinase inhibitor therapy: a real world experience. Blood. 2016;128:2199-205.
13. Mato AR, Nabhan C, Thompson MC, et al. Toxicities and outcomes of 616 ibrutinib-treated chronic lymphocytic leukemia patients in the United States: a real-world analysis. Haematologica. 2018;103:874-9.
14. Hillmen P, Munir T, Rawstron A, et al. Initial results of ibrutinib plus venetoclax in relapsed, refractory CLL (Bloodwise TAP CLARITY study): high rates of overall response, complete remission and MRD eradication after 6 months of combination therapy. Blood. 2017;130:428.
15. Jain N, Thompson PA, Ferrajoli A, et al. Combined venetoclax and ibrutinib for patients with previously untreated high-risk CLL, and relapsed/refractory CLL: a phase II trial. Blood. 2017;130:429.
16. Rogers K, Huang Y, Stark A, et al. Initial results of the phase 2 treatment naive cohort in a phase 1b/2 study of obinutuzumab, ibrutinib, and venetoclax in chronic lymphocytic leukemia. Blood. 2017;130:431.