A Novel Agent, Ibrutinib, Shows Potential as a Safe, Effective, Targeted Treatment

A mechanism-driven treatment for patients with relapsed chronic lymphocytic leukaemia and relapsed or refractory mantle cell lymphoma

Two clinical studies published in the New England Journal of Medicine with an accompanying editorial article suggest that the novel agent ibrutinib shows real potential as a safe, effective, targeted treatment for adults with chronic lymphocytic leukaemia (CLL) and for patients with mantle cell lymphoma. Both studies were published in the Journal's June 19, 2013 online edition. Ibrutinib is the first drug designed to target Bruton's tyrosine kinase (BTK), a protein critical in the B-cell receptor pathway.

Targeting BTK with Ibrutinib in Patients with Relapsed CLL

CLL is the most common leukaemia in adults. Therapy for symptomatic CLL has consisted predominantly of chemotherapeutic agents (including chlorambucil, cyclophosphamide, fludarabine, and combinations of these agents) that are effective for palliation, but do not improve survival. The addition of the anti-CD20 antibody rituximab to chemotherapy (fludarabine alone or in combination with cyclophosphamide) results in higher response rates, extended remissions, and improved overall survival.

However, a subgroup of patients with deletion of 17p13.1 has a poor response to chemo-immunotherapy, and patients with tumours expressing unmutated immunoglobulin variable-region heavy-chain genes have shorter remissions than those with mutated genes. Furthermore, chemo-immunotherapy is not curative, and treatment options for relapsed disease tend to have increased toxicity and reduced anti-tumour activity.

Unlike chronic myeloid leukemia, CLL lacks a common genetic target. However, B-cell–receptor signalling has emerged as a driving factor for CLL tumour-cell survival. BTK is an essential component of B-cell–receptor signalling, it mediates interactions with the tumour microenvironment and promotes the survival and proliferation of CLL cells. It is essential for activation of several constitutively active pathways of CLL-cell survival. Given the importance of B-cell–receptor signalling in CLL and the central role of BTK in this pathway, an attractive strategy is to target inhibition of this kinase.

Ibrutinib is an orally bioavailable, potent inhibitor that covalently binds to the cysteine-481 amino acid of the BTK enzyme. Preclinical studies have shown that ibrutinib treatment inhibits numerous processes, including ERK signalling, NF-κB DNA binding, cytosine–phosphate–guanine–mediated CLL-cell proliferation, and tumour-cell migration. Ibrutinib does not have toxic effects on normal T cells; this distinguishes it from most regimens used for CLL.

A phase I study of ibrutinib showed mild-to-moderate toxicity and clinical anti-tumour activity in patients with relapsed or refractory B-cell cancers; 11 of the 16 patients in the study had CLL or small lymphocytic lymphoma. These preliminary results prompted the initiation of a phase Ib–II study of ibrutinib in CLL; this study involved two different therapeutic doses in patients with relapsed or refractory disease.

Results from the phase Ib/II trial showed an overall response rate (complete and partial) of 71%. At 26 months the estimated progression-free survival rate was 75% and overall survival was 83%.

Ibrutinib was associated with a high frequency of durable remissions in patients with relapsed or refractory CLL and small lymphocytic lymphoma, including patients with high-risk genetic lesions.

Ibrutinib kills malignant B cells but has little effect on healthy T cells – unlike other CLL therapies. This leaves an important arm of the immune system largely intact.

The trial involved 85 relapsed CLL patients (median age, 66) who took ibrutinib once daily. Fifty-one patients received a 420 mg dose and 34 patients received an 840 mg dose. Long-term therapy was associated with modest side effects such as diarrhoea, fatigue, and infection that usually resolved with no treatment delay.

Ibrutinib has a favourable therapeutic index, which may facilitate its use in combination with other agents for the treatment of CLL. However, the durable remissions obtained thus far suggest that many patients may be treated successfully with monotherapy. Randomised clinical trials of ibrutinib in patients with CLL or small lymphocytic lymphoma are ongoing.

Funding for the study was provided by Pharmacyclics, Inc.; the Leukemia and Lymphoma Society; D. Warren Brown Foundation; Mr. and Mrs. Michael Thomas; the Harry Mangurian Foundation; and the USA NIH/National Cancer Institute (grant CA140158 and CA095426).

The study was presented in part at the Annual Meeting of the American Society of Hematology in Atlanta, December 8–11, 2012.

Ibrutinib in Patients with Relapsed or Refractory Mantle Cell Lymphoma

As already mentioned in the text above, BTK is a mediator of the B-cell–receptor signalling pathway implicated in the pathogenesis of B-cell malignancies. In a phase I study, ibrutinib, a BTK inhibitor, showed anti-tumour activity in several types of non-Hodgkin's lymphoma, including mantle cell lymphoma.

Results from the phase II trial showed an overall response rate of 68%, with 21% of patients achieving a complete response and 47% achieving a partial response. Estimated overall survival was 58% at 18 months.

This is remarkable because the last agent approved by the USA Food and Drug Administration for mantle cell lymphoma had a 30% response rate. 

Currently the treatment of mantle cell lymphoma is a combination chemotherapy or intensive chemotherapy plus immunotherapy, followed by stem-cell transplantation.

The trial involved 111 patients with relapsed or refractory disease who took ibrutinib. The trial was conducted at 18 sites. Participants had received one to five prior treatments, which could include bortezomib. The estimated median response duration was 17.5 months and estimated median progression-free survival was 14 months.

The study authors concluded that ibrutinib showed durable single-agent efficacy in relapsed or refractory mantle cell lymphoma.

The study results were presented in part at the Annual Meeting of the American Society of Hematology in San Diego, December 11–13, 2011; and in part at the Annual Meeting of the American Society of Hematology in Atlanta, December 8–11, 2012.

The study was supported by Pharmacyclics and Janssen Biotech and by philanthropic funding provided to the MD Anderson Cancer Center by Edward Crutchfield.

Targeting Bruton's Tyrosine Kinase

Dr Robin Foà and Anna Guarini, PhD of the Department of Hematology, Sapienza University of Rome, Rome, Italy in an accompanied editorial summarised that ibrutinib monotherapy was capable of inducing high response rates among patients with relapsed or refractory CLL or small lymphocytic lymphoma who had received a median of four previous therapies. Toxic effects were limited, and responses were often durable with prolonged therapy. Treatment was associated with an initial lymphocytosis that was not due to disease progression but rather to the unique mechanism of action of the drug that induces a mobilization of leukemic B cells from the bone marrow, lymph nodes, and spleen into the blood. Responses were also seen in high-risk genetic subgroups.

According too Drs Foà and Guarini, this study triggered a number of considerations. The complete remission rate with ibrutinib appears to be low. The activity of this agent will need to be assessed in patients who have received less number of previous lines of the treatment. They questioned if ibrutinib alone will be adequate for patients with more aggressive disease, such as those with 17p13.1 deletion and p53 disruption. Furthermore they questioned if aggressive treatment is required for all patients with CLL. Most patients are older than 70 years of age at the time of treatment, and they frequently have major coexisting conditions that make aggressive chemo-immunotherapy, currently the standard treatment, impracticable, but they doubted if aggressive treatment is ideal for such patients.

The editorialists elaborated if it would be preferable to control the disease with non-cytotoxic compounds that are capable of targeting a primary player in tumour signalling, such as the B-cell receptor. Since CLL most often affects older patients, individual expectations and quality of life should be considered in choosing treatments. In these patients, oral compounds offer an appreciable advantage.

The results with ibrutinib are a further advance in the ever-changing management of hematologic malignancies, which is shifting from a chemotherapy-based approach to treatments aimed at the underlying biologic mechanisms of disease occurrence and progression. This shift began first with the use of retinoic acid and subsequently with arsenic trioxide in acute promyelocytic leukaemia. It continued with tyrosine kinase inhibitors in chronic myeloid leukaemia and in Philadelphia chromosome–positive acute lymphoblastic leukaemia, and it is progressing to other targets in other types, including BRAF mutations in hairy-cell leukaemia and ALK translocations in anaplastic large-cell lymphoma.

BTK inhibitors certainly represent an important step forward and a potential turning point in the treatment of CLL, the editorialists pointed out. The challenges are to define their effectiveness as front-line treatment both alone and in combination with other agents, as well as their long-term effects.