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Targeted Therapy for iNHL
Targeted Therapy for Indolent Lymphomas: Where We Are and Where We Are Heading

Released: May 26, 2015

Expiration: May 24, 2016

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Follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL) are the 2 most common subtypes of indolent non-Hodgkin’s lymphomas (NHL) and consequently most of the therapeutic data exists in these subtypes. Historically, the treatment of some of the less common indolent lymphomas such as Waldenström’s macroglobulinemia and lymphoplasmacytic lymphoma, and the various subtypes of marginal zone lymphoma (splenic marginal zone lymphoma, nodal marginal zone lymphoma, and extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue) has been based on extrapolation from data primarily in the more common subtypes. When considering nontargeted or less targeted therapies such as chemotherapy and, to a certain, extent rituximab, extrapolation was rarely problematic. However, in less than 18 months, we have seen FDA approval of 2 groundbreaking targeted therapies for use in low-grade NHL. Ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, was granted accelerated approval in November 2013 for use in patients with mantle cell lymphoma. Soon thereafter, in February 2014, it was approved for use in patients with CLL. In July 2014, the PI3-kinase delta inhibitor idelalisib received approval for use in combination with rituximab in patients with CLL, FL, or small lymphocytic lymphoma.

Where We Are
Although the majority of data generated to date with ibrutinib and idelalisib is in patients with these common subtypes of indolent NHL, many of the trials have included smaller numbers of subjects with the less common indolent lymphomas and a few small studies have been conducted exclusively in patients with rare forms of indolent NHL. The best example is the use of ibrutinib in patients with Waldenström’s macroglobulinemia. Treon and colleagues reported a phase II study in which 63 patients with previously treated Waldenström’s macroglobulinemia received ibrutinib at a standard dose of 420 mg/day. The overall response rate (ORR) in the trial was 90.5%, with many durable responses. The mechanistic underpinning of the efficacy of ibrutinib in this population is the high prevalence (> 90%) of the MYD88 L265P mutation among patients with Waldenström’s macroglobulinemia, as MYD88 L265P promotes malignant growth via BTK signaling. Based on these data, the ibrutinib label was expanded in January 2015 to include Waldenström’s macroglobulinemia.

In a much smaller dataset, 8 of 10 subjects with Waldenström’s macroglobulinemia or lymphoplasmacytic lymphoma responded to treatment with idelalisib in the pivotal trial of single agent idelalisib in patients with indolent NHL. The median progression-free survival in this small group was 22.2 months. In that same study, 15 subjects with marginal zone lymphoma achieved 1 complete and 6 partial responses for an ORR of 47%.

In an early-phase I study of ibrutinib in patients with mantle cell lymphoma or indolent NHL, the ORR across various dose levels was 54%. Responses were seen in 6 of 16 subjects with FL (including 3 complete responses), 3 of 4 subjects with Waldenström’s macroglobulinemia, and 1 of 4 subjects with marginal zone lymphoma. However, in a phase II trial of ibrutinib at 560 mg/day in 40 patients with relapsed or refractory FL, the ORR was lower at 28%. A multicenter phase II trial of ibrutinib in patients with marginal zone lymphomas has recently been completed, and the results are eagerly awaited.

Where Are We Heading?
We are in a tremendously exciting time with new targeted therapies available and in development. However, these advances and opportunities also bring challenges as treatments become increasingly targeted and individualized. When giving combination chemo-immunotherapy, it is often reasonable to assume activity across similar lymphomas. However, with many newer agents, important pathways in one indolent lymphoma may not be critical in other lymphomas. More clinical trials in these rare subtypes of indolent NHL will be necessary to identify how to best incorporate these new agents into therapeutic strategies.

Your Thoughts?
How do you anticipate recent and ongoing advances in targeted therapies will affect your management strategies for patients with rare forms of indolent NHL? I invite readers to post their comments in the comments section below.

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Have you incorporated ibrutinib and/or idelalisib into your treatment strategies for patients with rare forms of indolent NHL?
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