How Do Targeted Therapies Change the Management of Indolent Lymphomas?

September 15, 2016

Prior to the advent of targeted therapies, there were few options other than chemotherapy for the treatment of patients with indolent B-cell lymphomas or chronic lymphocytic leukemia.

Prior to the advent of targeted therapies, there were few options other than chemotherapy for the treatment of patients with indolent B-cell lymphomas or chronic lymphocytic leukemia (CLL). Although chemotherapy could yield clinical responses, which improved when treatment was combined with anti-CD20 monoclonal antibodies-so-called chemoimmunotherapy[1]-it also could compromise bone marrow function and cause toxicities that were poorly tolerated by elderly patients.[2] Moreover, chemotherapy alone was not curative. Instead, patients generally relapsed after therapy, often developing disease that had acquired inactivating mutations in genes such as TP53, which allowed their disease to become resistant to repeated use of chemotherapy. Because of this, and because of the large variation noted in the pace of disease progression among patients, therapy generally was not recommended unless a patient developed disease-related symptoms or complications. In this issue of ONCOLOGY, Drs. Choe and Ruan provide an excellent review of the emerging targeted therapies that can overcome the aforementioned problems.[3] By targeting kinases involved in B-cell receptor (BCR) signaling, or the anti-apoptotic protein B-cell lymphoma-2 (BCL-2), these newer drugs generally do not cause myelotoxicity, and may be effective even in patients with lymphomas that lack functional TP53. It is certain that the advent of such targeted therapies has significantly improved the outlook for many patients with indolent non-Hodgkin lymphoma or CLL. Despite such advances, there still appears to be a role for chemoimmunotherapy in the management of patients with indolent lymphomas or CLL. For example, patients with CLL cells that have mutated IGHV genes or that lack certain cytogenetic features, such as 17p deletion or 11q deletion, may respond well to chemoimmunotherapy and experience remissions lasting more than 5 years.[4-6] Also, some patients may not be inclined to make a commitment to treatment with targeted therapies for the remainder of their lives, or they may decide to discontinue targeted therapy upon experiencing side effects that become intolerable over time. It also is not established with certainty that the tolerability and durability of ibrutinib will be superior to results achieved with chemoimmunotherapy, at least for all patients, given that data on patients with CLL and small lymphocytic lymphoma treated for more than 4 years are currently lacking.[7] Therefore, when deciding on a course of therapy, it is important to consider an individual patient’s disease biology, as well as clinical and even social characteristics. Patients who desire therapy with a limited duration, or those who achieve a long-lasting remission without the need for continuous treatment, may find chemoimmunotherapy more attractive than the currently available targeted therapies. Ultimately, important information will be gained from comparative trials and exploratory studies investigating rational drug sequencing of these agents.

Remaining Questions

The value of using targeted therapy earlier in the management of patients with indolent lymphomas is uncertain. An ongoing phase III clinical trial will compare the outcomes of CLL patients with high-risk features, such as expression of 70-kDa zeta-associated protein (ZAP-70) or adverse cytogenetics, when they are treated with ibrutinib early vs when ibrutinib is initiated based on current treatment guidelines.[8] Until this question is resolved, it is recommended that patients be treated with ibrutinib or other targeted therapies when they become symptomatic or have disease-related complications, or if there is clear evidence of more rapid disease progression. There is significant interest in determining how to rationally combine or sequence targeted agents with existing therapies for lymphoma. The BCL-2 inhibitor venetoclax has been studied in combination with anti-CD20 monoclonal antibodies and with chemoimmunotherapy. Similarly, trials are exploring the use of BCR signaling inhibitors in conjunction with chemoimmunotherapy. Some investigators are testing whether it would be preferable for targeted therapies to be sequenced, rather than combined, in the management of CLL-for example, using BCR signaling inhibitors or chemoimmunotherapy to debulk the disease, followed by administration of a BCL-2 inhibitor to achieve a minimal residual disease–negative remission that might ultimately allow the patient to discontinue treatment altogether. There is also the possibility that targeted therapies by themselves may not be curative and that patients may develop resistance to these agents over time. Patients with resistance to ibrutinib appear to have a very poor prognosis, with a median survival of 3.1 months reported in one study.[9] Mutations in BTK or PLCγ have been found to account for some cases of ibrutinib resistance.[10,11] However, other mechanisms by which disease resistance or persistence may develop after treatment with ibrutinib, idelalisib, or venetoclax have not yet been elucidated. It also is likely that selected targeted agents used in the treatment of CLL may activate alternative signaling pathways that can serve as escape mechanisms. It is critical that we continue our study of the biology of these diseases to help define the optimal use of these agents.

Financial Disclosure:Dr. Choi has received research funding from, and participated in advisory boards for, AbbVie and Pharmacyclics; he has also participated in a speakers bureau for Gilead. Dr. Kipps has received research funding from AbbVie; provided consultancy for AbbVie, Gilead, and Pharmacyclics; and participated in a speakers bureau for Gilead.

References:

1. 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.

2. Strati P, Wierda W, Burger J, et al. Myelosuppression after frontline fludarabine, cyclophosphamide, and rituximab in patients with chronic lymphocytic leukemia: analysis of persistent and new-onset cytopenia. Cancer. 2013;119:3805-11.

3. Choe H, Ruan J. Next generation of targeted molecules for non-Hodgkin lymphomas: small-molecule inhibitors of intracellular targets and signaling pathways. Oncology (Williston Park). 2016;30:847-58.

4. 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.

5. 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.

6. 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.

7. Byrd JC, Furman RR, Coutre SE, et al. Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015;125:2497-506.

8. Langerbeins P, Bahlo J, Rhein C, et al. Ibrutinib in early stage CLL: preliminary safety results of a placebo controlled phase III study. Blood. 2015;126(suppl 23):abstr 2934.

9. Jain P, Keating M, Wierda W, et al. Outcomes of patients with chronic lymphocytic leukemia after discontinuing ibrutinib. Blood. 2015;125:2062-7.

10. Furman RR, Cheng S, Lu P, et al. Ibrutinib resistance in chronic lymphocytic leukemia. N Engl J Med. 2014;370:2352-4.

11. Woyach JA, Furman RR, Liu TM, et al. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014;370:2286-94.