Targeted PI3Kδ inhibition by the small molecule idelalisib as a novel therapy in indolent non-Hodgkin lymphoma

Abstract

Indolent Non-Hodgkin Lymphomas (iNHL) are typically B-cell malignancies and are incurable with current standard approaches. Thus, there is a demand for novel agents specific for this group of disorders. In a phase II study published by Gopal et al. in the New England Journal of Medicine, idelalisib, a small molecule inhibitor of PI3Kδ that was FDA approved in July of 2014, was shown to be effective when combined with rituximab in patients who cannot tolerate chemotherapy and as last line therapy in patients with iNHL refractory to 2 prior systemic therapies. Idelalisib demonstrated tolerable diarrhea, fatigue, nausea, pyrexia, and cough. While this novel agent is a clinically significant addition to the iNHL arsenal, further research is needed to determine its most appropriate place in iNHL therapy.

Keywords:

• B-cell chronic lymphocytic leukemia
• follicular lymphoma
• Furman et al
• Gopal et al
• indolent Non-Hogkin Lymphoma
• idelalisb
• PI3Kδ Inhibition
• rituximab
• small lymphocytic lymphoma
• targeted therapy

Non-Hodgkin Lymphoma (NHL) is a malignancy of the lymphoid tissue and the fifth most common cause of newly diagnosed cancer in the United States. An estimated 70,800 new cases and 18,990 deaths are expected from NHL this year.¹ NHL is classified by the growth rate of the disease (indolent, aggressive, and very aggressive) and the dysfunctional cell type (B- or T-lymphocytes). Specifically, indolent NHL (iNHL) is a malignancy of B-lymphocytes which can be further subtyped as B-cell chronic lymphocytic leukemia (B-CLL)/small lymphocytic lymphoma (B-SLL), lymphoplasmacytic lymphoma (LPL), follicular lymphoma (FL), marginal zone B-cell lymphoma (MZL), mucosa-associated lymphoid tissue (MALT) lymphoma, or nodal lymphoma.²

While iNHL is highly responsive to rituximab, chemotherapy and other treatment approaches, it is ultimately incurable with today's standard therapies². Therefore, there is a need to develop novel agents for these diseases. To fulfill this need, rituximab, an anti-CD20 chimeric monoclonal antibody, was approved in November 1997 as the first non-chemotherapeutic, targeted agent approved for iNHL. In addition to the watch and wait option, rituximab monotherapy is often used due to proven progression free survival (PFS).^3,4

Recently a newly approved drug has ignited similar interest particularly for its targeted mechanism of action. Idelalisib, a potent, first-in-class, highly selective, small molecule inhibitor of phosphoinositide-3-kinase delta (PI3Kδ), represents a novel treatment option for patients with B-cell malignancies.^5,6 Although PI3Kα and β can be found in all tissues, PI3Kδ is primarily expressed on haematopoietic cells.⁷ The inhibition of PI3Kδ hinders serine/threonine protein kinase B (AKT) activity and therefore downstream signaling and activation of mammalian target of rapamycin (mTOR) that is heavily involved in protein synthesis, cell proliferation, and survival, thus promoting apoptosis.⁸ Idelalisib demonstrated good efficacy with low toxicity in patients with indolent lymphoma in a recent study published in the New England Journal of Medicine.

Gopal et al. conducted a multi-national, multi-center, single-group, open-label, phase II study of idelalisib in 125 patients with relapsed indolent lymphoma.⁵ Refractory or relapsed was defined as no response with rituximab and an alkylating agent or relapse in ≤6 months of treatment with those agents. The subtypes of iNHL represented in this study included FL (58%), B-SLL (22%), MZL (12%), and LPL (8%). The patients had a median of 4 therapies (range 2–12), with previous regimens consisting of combination rituximab and alkylating agents (91%), the most potent alkylator bendamustine (65%), anthracyclines (65%), purine analogs (34%), and/or stem-cell transplantation (11%). To negate sampling bias, the inclusion of a number of iNHL subtypes and prior therapies was necessary. Participants were given idelalisib 150 mg twice daily by mouth until disease progression, unacceptable toxicity, or death.⁵

The primary endpoint was overall rate of response (ORR) with secondary endpoints such as time to response (TR), duration of response (DR), progression-free survival (PFS), and overall survival (OS). The safety endpoints were adverse effects (AEs) and laboratory abnormalities that began or worsened during the treatment period and 30 days post-final dose. Although the ORR was 57% with a 6% CR, 90% of patients had a reduction in the size of lymph nodes during treatment. Criterion for lymphadenopathy response is in accordance to Cheson et al. The median TR, DR, PFS, and OS were 1.9, 12.5, 11, 20.3 months, respectively. The response rates were consistent across distinct baseline characteristics of the patients, prior therapy, and treatment disposition. Keeping in mind that the median number of prior regimens was 4, idelalisib demonstrated promising activity.⁵

Furthermore, 82% of patients experienced adverse effects, of which 54% were ≥3 in accordance to the Common Terminology Criteria for Adverse Events (CTCAE). The most common adverse effects included diarrhea (43%), fatigue (30%), nausea (30%), cough (29%), and pyrexia (28%). AEs due to treatment resulted in the discontinuation of idelalisib in 20% of participants. These AEs included elevations in levels of serum alanine or aspartate aminotransferase (5), colitis (4), pneumonia and pneumonitis (3) and diarrhea (2), and neutropenia (2). There was a total of 28 deaths due to progressive disease (20; 17 during long term follow-up), pneumonitis and pneumonia (4), cardiac arrest (1), cardiac failure (1), splenic infarction (1), and septic shock (1).⁵

A multi-center, randomized, double-blind, placebo-controlled, phase III study conducted by Furman et al. not only further confirmed the safety and efficacy of idelalisib but also expanded its application in iNHL treatment to include patients unfit for chemotherapy. A total of 220 patients with relapsed B-CLL having renal dysfunction (CrCl <60 mL/min), additional comorbidities (CIRS score >6), or previous therapy-induced myelosuppression were randomized into either the rituximab only arm or combination rituximab and idelalisib arm of the study. Stratification with respect to Ig heavy chain variable region (IGHV) mutation, 17p deletion, and TP53 mutation were accounted for in the randomization, although they eventually showed to have no bearing on outcomes.⁹

Median PFS, the primary endpoint, was not reached in the idelalisib group and was 5.5 months for the control group with a hazard ratio of 0.15, P<0.001 in favor of idelalisib. The secondary endpoints of ORR (83% vs 13%; all partial responses), lymph-node response (93% vs 4%), and OS (92% vs 80% at 12 months) were all statistically significant in favor of the idelalisib group. Due to overwhelming treatment efficacy, the trial was terminated early and all patients were given the dual therapy. Lastly, AEs of varying degrees were comparable across treatment groups (91% of the idelalisib arm vs 94% of the control arm) and similar to that experienced in the Gopal et al. study. Serious adverse and grade ≥ 3 adverse events were slightly higher in the idelalisib arm.^5,9

While idelalisib has demonstrated sufficient efficacy and tolerability in relapsed iNHL as a last line option, there is insufficient evidence to determine its most appropriate position among NHL therapies. Idelalisib was FDA approved for relapsed B-CLL in combination with rituximab, and relapsed B-SLL and FL following at least 2 prior systemic therapies but there is no evidence indicating whether concurrent or sequential treatment is the most effective option.^5,9-11 Lastly, as previously stated, idelalisib is a targeted inhibitor of PI3Kδ, which is highly expressed on haematopoietic cells. Therefore, it should be effective against all cancers of haematopoietic origin, lymphomas and leukemias alike, but clinical studies so far have only investigated its use in B-cell lymphomas.

Despite these unresolved issues, there is no question that idelalisib is an effective option for iNHL. Idelalisib joins a host of anti-CD20 agents (rituximab, ofatumumab, obinutuzumab, and ⁹⁰Y-ibritumomab tiuxetan) and ibrutinib, a novel bruton tyrosine kinase (BTK) inhibitor approved in November 2013, as novel effective agents in development. Other agents in development include GS-9973, a spleen tyrosine kinase (Syk) inhibitor; dinaciclib (SCH727965) and flavopiridol (HMR-1275), cyclin-dependent kinase inhibitors; MLN9708, CEP-18770, and orpozomib, proteasome inhibitors; GDC-0199/ABT-199, a selective BCL^-2 inhibitor; and MLN4924, Nedd8 inhibitor. Dasatinib, a dual c-Src-Abl tyrosine kinase inhibitor and carfilzomib, a proteasome inhibitor, are being studied for repurposed use in B-lymphocytic cancers.^12,13 With the development of exciting new classes of targeted drugs for the treatment of indolent lymphomas, there is a potential for improved quality of life and longevity among suffers.

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Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.