The development and utilization of novel therapies, including small-molecule agents, have undoubtedly altered the treatment landscape for many indolent non-Hodgkin B-cell malignancies in the frontline and relapsed/ refractory settings. The availability of such agents as Bruton tyrosine kinase, BCL2, and phosphoinositide 3-kinase (PI3K) inhibitors addresses an unmet need among oncologists and advanced practice providers (APPs) who are seeking additional therapeutic options for their patients, particularly those with relapsed/refractory disease. As new therapeutic targets are identified and agents are brought to market, clinicians are challenged to understand and manage unique toxicities not previously observed with standard chemoimmunotherapy regimens.
The introduction of PI3K inhibitors for the treatment of relapsed/refractory indolent non-Hodgkin B-cell lymphomas offers an effective therapeutic option based on their mechanism of action and increased efficacy with dual inhibition of PI3K isoforms for some agents. In clinical practice, concerns regarding the use of PI3K inhibitors involve whether the modest median duration of response and median progression- free survival rates, along with the low complete response rates reported in clinial trials, justify the potential risks. Clearly, the use of these targeted agents requires recognition of the potential serious and life-threatening complications that may occur. It is vital for clinicians to be aware of the potential adverse effects associated with PI3K inhibitors as well as strategies for early intervention. This will allow them to better educate patients and caregivers on possible side effects and the importance of prompt symptom reporting. Members of the oncology care team must also educate their colleagues in other specialties on the potential toxicities associated with the use of these agents, as these professionals may be consulted regarding the management of patients who experience serious adverse events. The use of a multidisciplinary care team that includes physicians, APPs, nurses, pharmacists, and, when appropriate, specialists in dermatology, gastroenterology, infectious disease, and/or hepatology can optimize patient assessment and toxicity management going forward.
The PI3K inhibitor–related toxicities discussed in the main article of this publication provide an accurate representation of the most common—as well as the less common but more severe—adverse events that clinicians may encounter when caring for their patients. Although oncologists are well versed in the assessment and management of hematologic toxicities, based on their experience with standard chemoimmunotherapy regimens, it is the nonhematologic toxicities that may be less well known and more easily overlooked. Thus, it is imperative to follow patients closely with laboratory and physical assessments in the early phases of treatment, to assess for toxicities and to initiate appropriate interventions as needed.
Clinicians must also be aware of the bimodal distribution of potential toxicities (eg, diarrhea, colitis), and the need to remain vigilant for the development of adverse events throughout the course of treatment. Healthcare professionals should tailor the review of systems to include specific questions that pertain to known PI3K inhibitor–related toxicities. The incorporation of baseline and monthly laboratory testing, such as CD4+ and cytomegalovirus, and the initiation of primary prophylaxis for opportunistic infections into clinical practice, may be critical in the prevention of infection during treatment. Additionally, early intervention at the onset of noninfectious and infectious symptoms is imperative to prevent the development of serious complications.
The recommendations for managing select toxicities reviewed in Table 3 of the main article are extremely useful to guide the management of patients receiving PI3K inhibitor therapy. The use of oral or systemic corticosteroids for certain grade 2 or higher immune-related toxicities is an effective management strategy for noninfectious pneumonitis, colitis and diarrhea, and cutaneous reactions, as described in the article. However, despite current management guidelines, a new unmet need has developed with the use of this class of drugs. Clinical trial data on the efficacy of current toxicity interventions are needed, along with clinical trials designed to develop alternate management strategies for patients who do not respond well to current interventions. The more knowledge garnered on the appropriate management of adverse events, the more likely clinicians will be to consider these agents safe for use in their practices.
Although it is an exciting time to be working in the field of hematology and oncology, given the pace of new treatment options and the shift to precision medicine, we must recognize the nuances and responsibilities involved in caring for patients receiving agents with various therapeutic targets, such as PI3K inhibitors. As research continues to explore the combination of novel agents with one another and with current chemoimmunotherapy regimens, in addition to investigating their use for other indications, the utilization of targeted agents in the treatment paradigm will only continue to expand. Clinicians must be responsible for keeping up to date with evolving knowledge in the field, to provide safe and effective therapies for their patients.