US Pharm. 2020;45(2)(Specialty&Oncology suppl):11-16.
ABSTRACT: Over the last two decades, the discovery of novel signaling pathways in B-cell lymphoid malignancies has fueled the development of new drug therapies. Oral agents that target B-cell receptor–associated kinases, such as ibrutinib, acalabrutinib, and zanubrutinib for Bruton tyrosine kinase and idelalisib and duvelisib for phosphatidylinositol 3-kinase, have enhanced the treatment of B-cell lymphomas. Each of these agents requires specific monitoring for the management of adverse effects. Pharmacists are uniquely positioned to enhance medication safety and improve outcome by mitigating the adverse effects of these agents.
Lymphomas are a heterogeneous, phenotypically diverse set of neoplasms comprising numerous biological subtypes that have distinct clinical behaviors. They originate from the clonal expansion of B lymphocytes (85% of cases in the United States), T lymphocytes (15% of U.S. cases), or natural killer cells. Multiple classification systems exist, and lymphomas may be grouped according to histology, immunophenotype (based on the presence of lymphocyte antigens or cluster of differentiation [CD] antigens), or clinical aggressiveness (such as indolent or aggressive disease), with varied responses to therapy.1 Lymphomas may also be categorized as either non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma (HL). Reed-Sternberg cells, which are a hallmark of HL, are absent in NHL. In the past two decades, the discovery of novel genomic and molecular biomarkers has changed the paradigm in disease prognosis and treatment decisions. The World Health Organization has incorporated genomic and molecular data into its classification of lymphomas.
In the U.S., the number of new cases of NHL in 2019 is estimated to be 74,200, accounting for 4.2% of all new cancer cases in the country.2 Current treatment options for NHL depend primarily on the histologic type, clinical aggressiveness (indolent, aggressive, or highly aggressive), and disease stage. Options include surveillance, radiation therapy, single-agent therapy, combination chemotherapy, and high-dose chemotherapy with autologous or allogeneic stem-cell transplantation. Chemoimmunotherapy (rituximab or similar CD20 agent added to multiagent systemic chemotherapy) is widely regarded as the standard of care for B-cell malignancies in many treatment settings.1 However, early treatment failure, disease progression, relapsed or refractory disease, and poor tolerance to systemic chemotherapy have made it necessary to develop targeted therapies to improve survival and minimize toxicity.
Over the last two decades, the discovery of novel signaling pathways in B-cell lymphoid malignancies has fueled the development of new drug therapies. This article describes the clinical efficacy, adverse effects, and supportive care for current FDA-approved oral targeted therapies for B-cell lymphomas.
The B-Cell Receptor Signaling Pathway
A unique property of B cells is the presence of a transmembrane protein—i.e., B-cell receptor (BCR)—that is encoded by the immunoglobulin (Ig) genes. The role of BCR is to target a multitude of antigens. BCR consists of a transmembrane Ig receptor associated with two Ig chains (coreceptors): CD79-alpha (Ig-alpha) and CD79-beta (Ig-beta).3 BCR acts as the receptor for an antigen, which activates downstream signaling pathways through tyrosine kinases LYN and SYK, resulting in the activation of transcription factors, including nuclear factor-kappa B, thereby modulating growth and survival of both normal and malignant B cells.
Persistent BCR signaling may also occur during the physiological process of lymphocytes or in the pathogenesis of lymphoma.4 Therefore, constitutive BCR signaling may or may not be antigen (or ligand) dependent.
Bruton Tyrosine Kinase Inhibitors
The observation that constitutive activation of the BCR signaling pathway is essential for the growth and survival of malignant B cells has led to the development of inhibitors that target BCR-associated kinases.4 One of these enzymes, Bruton tyrosine kinase (BTK), is immediately downstream of the B-cell receptor and is an essential component of the BCR signaling pathway. The BTK gene encodes a cytoplasmic (nonreceptor) tyrosine kinase. Its pivotal role in B-cell development and maturation was discovered through the study of defective BTK genes that cause X-linked agammaglobulinemia.5 In the last decade, small-molecule inhibitors against BTK demonstrated excellent antitumor activity in both preclinical and clinical studies.6,7 In particular, the orally administered irreversible BTK inhibitor ibrutinib is associated with high response rates in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) or mantle cell lymphoma (MCL), including those with high-risk genetic lesions.8-10 In addition to exerting their classic role in BCR signaling in B-cell lymphomas, BTK inhibitors are involved in other signaling pathways central to B-cell survival and proliferation or adhesion of malignant lymphocytes within the tumor microenvironment (e.g., lymph nodes, spleen, and bone marrow), which contribute to the maintenance and proliferation of these malignant cells.8-10
Phosphatidylinositol 3-Kinase Inhibitors
Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that catalyzes the phosphorylation of the substrate phosphoinositol 4,5-bisphosphosphate (PIP2) into phosphoinositol 3,4,5-trisphosphate (PIP3). It is widely expressed and links several signaling pathways to cellular growth, proliferation, and survival.11
PI3K has four different isoforms: alpha, beta, gamma, and delta. Whereas alpha and beta subunits are ubiquitously expressed in human tissue, gamma and delta subunits are restricted to hematopoietic cells, and the delta subunit is necessary for antigen-induced BCR signaling.11 PI3K has three different classes based on structure and specificity for the substrate. In particular, class I enzymes are heterodimers composed of a regulatory subunit (p85-alpha, p85-beta, p55-gamma, p50-alpha, p55-alpha, p101), and a catalytic subunit (p110-alpha, p110-beta, p110-delta, p110-gamma).12 Class IA PI3K enzymes (e.g., those with p110-delta) are activated by receptor-associated tyrosine kinases, whereas class IB PI3K enzymes (those with p110-gamma) are activated by G protein–coupled receptors.13
Upstream agonists, including receptor-associated tyrosine kinases and G protein–coupled receptors, activate PI3K by freeing the catalytic subunit of the PI3K from its associated regulatory subunit.14 The generated PIP3 molecules serve as lipid second messengers that recruit and activate multiple intracellular signaling molecules, which regulate cell growth and survival.
In addition, PI3K-alpha participates in BCR signaling and stimulates cell survival. The PI3K-delta signaling pathway is hyperactive in B-cell malignancies and confers resistance to chemotherapy, rendering inhibition of PI3K-delta a promising therapeutic target. Moreover, PI3K plays a critical role in innate and adaptive immune response.14,15
During the first few weeks of treatment, BCR inhibitors—including those that act against BTK and PI3K—may cause transient lymphocytosis because of redistribution of malignant B cells from the tumor microenvironment to the peripheral blood (caused by disruption of the homing mechanisms of B cells by these inhibitors).16 Transient lymphocytosis should not be confused with disease progression and should not lead to discontinuation of therapy.
The following sections provide a nonexhaustive review of oral BTK- and PI3K-directed therapies currently approved by the FDA for B-cell lymphomas (TABLE 1).
Oral BTK Inhibitors
Ibrutinib: Ibrutinib (Imbruvica) inactivates BTK by binding covalently to cysteine 481 in the ATP binding site in an irreversible manner. It has been shown to prevent lymphocyte adhesion and homing and to potently inhibit BCR signaling and the tumor-protective effects of the microenvironment. However, ibrutinib is also associated with deleterious off-target toxicities, such as inhibition of platelet function, because of its postulated effects on other kinases (e.g., epidermal growth factor receptor [EGFR] and Janus kinase 3).17 Similarly, atrial fibrillation (AF)—another off-target toxicity—is thought to be due to the binding of ibrutinib to kinases, such as BTK and Tec, in the heart and subsequent inhibition of the cardioprotective PI3K-Akt signaling pathway.18
On the basis of antitumor effects conferred by ibrutinib, an open-label phase II trial was conducted to assess the efficacy and safety of ibrutinib 560 mg by mouth daily in patients with relapsed or refractory MCL.19 This strategy resulted in an overall response rate of 68%. Mean duration of response was 17.5 months (range, 0-19.6 mo). The most common treatment-related adverse events were mild-to-moderate diarrhea, fatigue, and nausea. Grade 3 or higher hematologic events, which were infrequent, included neutropenia (16% of patients), thrombocytopenia (11%), and anemia (10%). Based on these results, ibrutinib gained regulatory approval in 2013 for patients with MCL who have received one prior therapy. Ibrutinib is also approved for patients with marginal zone lymphoma who require systemic therapy and have received one or more anti-CD20–based therapies and for patients with CLL/SLL.20
Although ibrutinib demonstrated improved response, trials have been conducted using combinations of ibrutinib and other agents to improve the duration and depth of response. In a single-center phase II trial, an ibrutinib-rituximab combination had an overall response rate of 88% and a complete response rate of 44%.21 Further follow-up showed that patients with poor prognostic factors had inferior outcomes, confirming the need for novel therapies in these high-risk patients.22
The overall frequency of AF associated with ibrutinib ranged from 6% to 16%, with the highest rate occurring in the first 6 months and lower rates occurring thereafter.23 The current recommendation for patients receiving ibrutinib states that therapy should be interrupted for new-onset or worsening grade 3 or higher nonhematologic toxicity, including AF.23 Once symptoms resolve to grade 1 or baseline, treatment may be resumed at the starting dose. Recently, a comprehensive safety analysis using pooled data from four randomized trials in patients with CLL/SLL or relapsed/refractory MCL demonstrated that ibrutinib had a favorable safety profile.24 Adverse effects of ibrutinib were primarily grades 1 and 2. Except for hypertension, adverse effects of clinical interest resolved in most ibrutinib-treated patients, with limited treatment discontinuations, dose reductions, or deaths from these adverse effects.
Acalabrutinib: Acalabrutinib (Calquence), a second-generation BTK inhibitor, is more selective than ibrutinib and was designed to minimize the off-target toxicities of ibrutinib based on the observation that side effects are among the main reasons that patients discontinue ibrutinib.25,26 Acalabrutinib received regulatory approval in 2017 following a phase II trial that demonstrated an overall response rate of 81% and a complete response rate of 40%.25,27 Kaplan-Meier estimated medians for duration of response, progression-free survival, and overall survival were not attained during the study period. Compared with patients receiving ibrutinib, those receiving acalabrutinib were less heavily treated (median prior therapies, two vs. three); this may have contributed to the difference in overall response rate of these two agents. As with ibrutinib, most adverse events were grades 1 and 2. No cases of AF were reported, and one case (0.8%) of grade 3 hemorrhage occurred.25
Acalabrutinib has rapid absorption and a short half-life (1 h for acalabrutinib vs. 4-6 h for ibrutinib). Its twice-daily dosing resulted in near-complete and continuous BTK inhibition in patients with CLL/SLL.28 Additionally, acalabrutinib does not inhibit EGFR and other off-targets. Overall, off-target toxicities such as severe diarrhea, rash, arthralgia or myalgia, bruising, and bleeding events occurred in no more than 2% of trial subjects. No major hemorrhage or AF was noted.28 Acalabrutinib may have a place in therapy for patients at risk for cardiac toxicity or in need of anticoagulation or antiplatelet therapy. However, long-term follow-up is needed.
Zanubrutinib: Zanubrutinib (Brukinsa) is a second-generation BTK inhibitor that recently gained FDA approval for treatment of adult patients with MCL who have received at least one prior therapy; approval was based on findings of a single-arm trial of 86 patients with previously treated MCL who received the BTK inhibitor, as well as an additional single-arm trial of 32 patients with MCL.29,30
The first study, a multicenter phase II trial conducted in China, included patients with relapsed or refractory MCL who had received one to four prior therapies.30 Patients were given zanubrutinib 160 mg twice daily until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) based on imaging by an independent review committee. The ORR was 83.5% and the partial response rate was 24.7% among 85 evaluable patients. Common treatment-related adverse effects were mostly hematologic (e.g., neutropenia, thrombocytopenia); other common adverse effects were upper respiratory tract infection (29.1%) and rash (29.1%). Of the four deaths that occurred during the trial, three were from health-related causes (infection, pneumonia, and cerebral hemorrhage). Treatment-related adverse effects were diarrhea (10.5%), hypertension (8.1%), and petechiae/purpura/contusion (4.7%). The second trial demonstrated tumor shrinkage in 84% of patients, and median duration of response was 18.5 months.31
Although a phase III head-to-head trial of ibrutinib versus zanubrutinib is still in the planning stage, zanubrutinib is thought to display greater selectivity for BTK relative to other kinases in the BCR signaling pathway. However, it demonstrates less global kinase selectivity for BTK compared with acalabrutinib or tirabrutinib, another investigational BTK inhibitor.32 Notably, ibrutinib and acalabrutinib undergo hepatic metabolism via CYP450 3A4 to give rise to the less potent but active metabolites PCI-45227 and ACP-5862, respectively (zanubrutinib undergoes hepatic metabolism, but its metabolites have not been characterized). Therefore, dose reductions for ibrutinib, acalabrutinib, and zanubrutinib are recommended in patients with hepatic impairment and in those taking moderate CYP3A4 inhibitors concomitantly.
Oral PI3K Inhibitors
Idelalisib: Idelalisib (Zydelig) is a small-molecule inhibitor of PI3K-delta that is highly selective for the delta isoform compared with the alpha, beta, and gamma isoforms.33 In an open-label phase II study, 125 patients with relapsed or refractory indolent NHL were administered idelalisib 150 mg twice daily by mouth until disease progression or withdrawal.34 Responses with continued administration of idelalisib were rapid (median time to response, 1.9 mo; range, 1.6-8.3) and durable (median duration of response, 12.5 mo; range, 0.03-14.8). The response rate was 57% (71 of 125 patients), and median progression-free survival was 11 months (range, 0.03-16.6). Similar response rates were observed across all subtypes of indolent NHL. Based on these results, idelalisib gained regulatory approval as monotherapy for the treatment of relapsed follicular lymphoma in patients who received at least two prior systemic therapies.35
Most common adverse events of grade 3 or higher were neutropenia (27% of patients), elevations in aminotransferase levels (13%), diarrhea (13%), and pneumonia (7%). Because of these treatment-related adverse effects, idelalisib carries a black box warning regarding the increased risk of fatal or severe hepatotoxicity, diarrhea, intestinal perforation, colitis, and pneumonitis. Liver function should be evaluated prior to and during treatment. Fatal or serious infections occurred in 21% of patients receivings idelalisib monotherapy. Idelalisib is associated with an increased risk of opportunistic infections, prompting the manufacturer to recommend prophylaxis for Pneumocystis jirovecii pneumonia (PJP) and monitoring for cytomegalovirus reactivation.35
Duvelisib: Continuous, selective PI3K-delta inhibition may cause upregulation of alternative isoforms, resulting in resistance to idelalisib therapy.36 To mitigate the aforementioned toxicities and improve efficacy, new inhibitors for different PI3K isoforms have been developed. An example is duvelisib (Copiktra), an oral dual inhibitor of PI3K-delta and PI3K-gamma, which was approved in 2018 for treatment of relapsed or refractory follicular lymphoma after at least two prior systemic therapies based on a multicenter trial (DYNAMO trial).37 The overall response rate was 35%, with 43% (15/35) and 17% (6/35) of patients maintaining durable response at 6 and 12 months, respectively. It also received approval for treatment of relapsed or refractory CLL/SLL after at least two prior therapies, based on results of the DUO trial.38
The PI3K-delta isoform is constitutively expressed in hematologic malignancies, thereby opening up the therapeutic opportunity to design a targeted agent that can minimize off-target toxicities. Subsequent studies showed that PI3K-delta inhibition blocks the survival and proliferation of malignant B cells while allowing survival of normal immune cells.14,39,40 On the other hand, PI3K-gamma inhibition disrupts the differentiation and migration of key support cells in the tumor microenvironment, such as CD4+ T cells and tumor-associated macrophages, which assist in the maintenance of malignant leukemia and lymphoma cells within the tumor microenvironment.40-42
In preclinical models involving CLL, dual PI3K-delta,gamma demonstrated greater activity inhibition than either isoform alone.43-46 As a dual PI3K-delta,gamma inhibitor, duvelisib has the potential to target not only survival signaling, but also the tumor microenvironment that supports malignant cell proliferation.47,48 The efficacy and safety of duvelisib monotherapy for hematologic malignancies were demonstrated in a cohort of relapsed/refractory CLL/SLL patients, who had a 56% overall response rate and median progression-free survival of 15.7 months (range, 5.4-30.2 mo).49
The toxicities seen with PI3K inhibitors, including colitis, hepatitis, and pneumonitis, are presumed to be autoimmune in origin (based on T-cell activation by these inhibitors) and may be managed with steroids. Diarrhea and colitis represent common on-target toxicities associated with PI3K-delta inhibitors.50 Consistent with observations of PI3K inhibitors in other studies, transaminitis (onset, 2 mo) and diarrhea (onset, 5-6 mo) were frequent but manageable with dose modifications. Two cases of PJP pneumonia were reported, prompting the initiation of Pneumocystis prophylaxis.49
Notably, hyperglycemia is an on-target effect of PI3K-alpha inhibition that results in transiently reduced utilization of tissue glucose or in insulin resistance.51 Its occurrence is consistent with incidents reported for other pan-PI3K inhibitors.52 Inhibitors of PI3K-delta or BTK may exacerbate the severity of infection. Serious febrile neutropenia was infrequent (n = 3) in the trial, as were opportunistic infections (n = 2) and pneumonitis (n = 3). Absent in the trial were the increased rates of infectious and autoimmune toxicities reported in studies that combined idelalisib with other agents.53-55
Recent FDA-approved oral therapies include agents that target the B-cell receptor signaling pathway, which plays a key role in malignant B-cell initiation and progression. Inhibitors of BTK and PI3K enzymes in the aberrant B-cell receptor signaling pathway have improved outcomes in patients with BCLs and have been integrated into existing treatment options. Each of these agents requires specific monitoring for the management of adverse effects. Whereas the adverse effects associated with first-generation BTK inhibitors (AF, rash, diarrhea, and inhibition of platelet aggregation) are considered off-target toxicities, the toxicities of PI3K inhibitors (opportunistic infections, colitis, hepatitis, and pneumonitis) are presumed to be autoimmune in origin. Pharmacists are uniquely positioned to enhance medication safety and improve patient outcomes by mitigating the adverse effects of these agents.
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