idelalisib and Pneumonia

Despite the proven effective approach to targeting the phosphatidylinositol-3-kinase (PI3K) pathway in B-cell malignancies, the approved PI3K inhibitors idelalisib and duvelisib have been less commonly selected for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), given the availability of other more tolerable agents. However, patients with CLL/SLL can experience a disease course that is multiply relapsed, refractory, or intolerant to treatment, and PI3K inhibitors can achieve meaningful responses. This article reviews the common early- and late-onset (considered immune-mediated) toxicities with PI3K inhibitors, including infections, hepatotoxicity, diarrhea and/or colitis, and pneumonitis. Data on pretreatment considerations, toxicity management, and drug rechallenge are presented. In addition, next-generation PI3K inhibitors and novel treatment approaches with PI3K inhibitors, including combinations, time-limited treatments, and intermittent dosing, are highlighted.

Topics: Aged; Antineoplastic Agents; Colitis; Diarrhea; Disease Management; Humans; Infections; Isoquinolines; Leukemia, Lymphocytic, Chronic, B-Cell; Liver; Male; Neutropenia; Phosphoinositide-3 Kinase Inhibitors; Pneumonia; Purines; Quinazolinones

Activation of phosphatidylinositol-3-kinase (PI3K) and downstream signalling by AKT/mammalian target of rapamycin (mTOR) modulates cellular processes such as increased cell growth, cell proliferation and increased cell migration as well as deregulated apoptosis and oncogenesis. The PI3K/AKT/mTOR pathway (particularly Class I PI3K isoforms) is frequently activated in a variety of solid tumours and haematological malignancies, making PI3K an attractive therapeutic target in oncology. Inhibitors of PI3K also have the potential to restore sensitivity to other modalities of treatments when administered as part of combination regimens. Although many PI3K inhibitors have reached different stages of clinical development, only two (idelalisib and copanlisib) have been currently approved for use in the treatment of B cell lymphoma and leukaemias. While these two agents are effective clinically, their use is associated with a number of serious class-related as well as drug-specific adverse effects. Some of these are immune-mediated and include cutaneous reactions, severe diarrhoea with or without colitis, hepatotoxicity and pneumonitis. They also induce various metabolic abnormalities such as hyperglycaemia and hypertriglyceridaemia. Not surprisingly, therefore, many new PI3K inhibitors with a varying degree of target selectivity have been synthesised in expectations of improved safety and efficacy, and are currently under clinical investigations for use in a variety of solid tumours as well as haematological malignancies. However, evidence from early clinical trials, reviewed herein, suggests that these newer agents are also associated not only with class-related but also other serious and unexpected adverse effects. Their risk/benefit evaluations have resulted in a number of them being discontinued from further development. Cumulative experience with the use of PI3K inhibitors under development suggests that, compared with their use as monotherapy, combining them with other anticancer therapies may be a more effective strategy in improving current standard-of-care and clinical outcomes in cancers beyond haematological cancers. For example, combination of alpelisib with fulvestrant has recently demonstrated unexpectedly superior efficacy compared to fulvestrant alone. Furthermore, the immunomodulatory activity of PI3Kδ and PI3Kγ inhibitors also provides unexpected opportunities for their use in cancer immunotherapy, as is currently being tested in several clinical

Topics: Animals; Antineoplastic Agents; Diarrhea; Enzyme Inhibitors; Humans; Neoplasms; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Pneumonia; Purines; Quinazolinones

Inhibitors of the B cell receptor (BCR) represent an attractive therapeutic option for patients with chronic lymphocytic leukemia. Recently approved inhibitors of Bruton's tyrosine kinase (ibrutinib) and phosphatidylinositol 3-kinase (idelalisib), are promising agents because they are generally well tolerated and highly effective. These agents may be particularly important in the treatment of older patients who are less able to tolerate the myelosuppression (and infections) associated with chemoimmunotherapy. As a class of medications, BCR inhibitors have some unique side effects including redistribution lymphocytosis. Ibrutinib has specific toxicities including increased risk for bleeding and atrial fibrillation. Idelalisib also has some unique toxicities consisting of transaminitis, diarrhea and pneumonitis. Ongoing clinical trials are evaluating these agents in combination with antibodies, chemotherapy and other small molecules.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Age Factors; Atrial Fibrillation; Diarrhea; Hemorrhage; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocytosis; Neoplasm Proteins; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Pneumonia; Protein-Tyrosine Kinases; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell

Although agents targeting B-cell receptor signaling have provided practice-changing results in relapsed chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), they require prolonged administration and provide incomplete responses. Given synergistic preclinical activity with phosphatidylinositol 3-kinase δ and spleen tyrosine kinase inhibition, this phase 2 study evaluated the safety and efficacy of the combination of idelalisib and entospletinib. Eligible patients with relapsed or refractory CLL or NHL underwent intrapatient dose escalation with each agent. With a median treatment exposure of 10 weeks, 60% and 36% of patients with CLL or follicular lymphoma, respectively, achieved objective responses. However, the study was terminated early because of treatment-emergent pneumonitis in 18% of patients (severe in 11 of 12 cases). Although most patients recovered with supportive measures and systemic steroids, 2 fatalities occurred and were attributed to treatment-emergent pneumonitis. Increases of interferon-γ and interleukins 6, 7, and 8 occurred over time in patients who developed pneumonitis. Future studies of novel combinations should employ conservative designs that incorporate pharmacodynamics/biomarker monitoring. These investigations should also prospectively evaluate plasma cytokine/chemokine levels in an attempt to validate biomarkers predictive of response and toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01796470.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Class I Phosphatidylinositol 3-Kinases; Cytokines; Early Termination of Clinical Trials; Female; Humans; Indazoles; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Male; Middle Aged; Neoplasm Proteins; Pneumonia; Protein Kinase Inhibitors; Purines; Pyrazines; Quinazolinones; Salvage Therapy; Syk Kinase

Idelalisib is a potent and selective inhibitor of the PI3Kδ approved since September 2014 for the treatment of several types of B cell malignancies. Pulmonary adverse events related to idelalisib are an emerging serious adverse event. We report here a single centre cohort of 16 patients who initiated idelalisib as routine treatment. Five of them experienced severe pulmonary adverse events related to idelalisib therapy. Comparison of the 5 patients with severe pulmonary events versus the 11 patients without identified no predisposing factors. Severe pulmonary adverse events were related to infectious pneumonia and/or to a drug-induced pneumonitis. The mechanisms of idelalisib-associated pneumonitis are unknown but consistent with the drug-induced pneumonitis described with mTOR inhibitors. Indeed, by inhibiting PI3Kδ, idelalisib also inhibits the mTOR pathway. Clinicians should be aware that any idelalisib-treated patient who presents with pulmonary symptoms should be evaluated for pneumonitis. Corticosteroids should be considered in addition to anti-infective therapy in case of severe pneumonitis or persistent pulmonary symptoms despite adequate antibiotic therapy.

Topics: Aged; Antineoplastic Agents; Drug-Related Side Effects and Adverse Reactions; Humans; Lung; Male; Middle Aged; Pneumonia; Purines; Quinazolinones; TOR Serine-Threonine Kinases

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lung; Male; Pneumonia; Purines; Quinazolinones; Rituximab; Tomography, X-Ray Computed; Treatment Outcome

Topics: Adult; Antineoplastic Agents; Cough; Dyspnea; Female; Humans; Lymphoma, Follicular; Neoplasm Recurrence, Local; Pneumonia; Purines; Quinazolinones; Tomography, X-Ray Computed