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Table of Contents
DRUG REVIEW
Year : 2020  |  Volume : 3  |  Issue : 4  |  Page : 767-784

Ibrutinib: A narrative drug review


1 Department of Medical Oncology, Tata Memorial Hospital and Homi Bhabha National Institute, Mumbai, Maharashtra, India
2 Department of Medical Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India

Date of Submission06-Jul-2020
Date of Decision27-Sep-2020
Date of Acceptance05-Dec-2020
Date of Web Publication25-Dec-2020

Correspondence Address:
Bhausaheb P Bagal
Department of Medical Oncology, Tata Memorial Hospital and Homi Bhabha National Institute, Parel, Mumbai - 400 012, Maharashtra
India
Nikita Mehra
Department of Medical Oncology, Cancer Institute (WIA), Chennai - 600 036, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CRST.CRST_234_20

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  Abstract 


Ibrutinib is an oral, irreversible covalent inhibitor of the Bruton tyrosine kinase, that plays a major role in B-cell differentiation, proliferation, migration, survival, and apoptosis. It has been found to be active against a number of B-cell malignancies. Ibrutinib has shifted the treatment strategy for malignancies away from cytotoxic chemotherapies toward a more targeted approach. It has already been approved for a number of B-cell malignancies such as mantle cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, and chronic graft-versus-host disease in allogeneic stem cell transplant recipients, and still continues to be evaluated for a number of other B-cell malignancies in various settings. We comprehensively searched the PubMed database to identify and compile the current scenarios in which ibrutinib is indicated for use in oncological practice.

Keywords: Chronic lymphocytic lymphoma, ibrutinib, mantle cell lymphoma, primary central nervous system lymphoma, Waldenstrom's macroglobulinemia


How to cite this article:
Munot PN, Mirgh S, Mehra N, Bagal BP. Ibrutinib: A narrative drug review. Cancer Res Stat Treat 2020;3:767-84

How to cite this URL:
Munot PN, Mirgh S, Mehra N, Bagal BP. Ibrutinib: A narrative drug review. Cancer Res Stat Treat [serial online] 2020 [cited 2021 Jan 18];3:767-84. Available from: https://www.crstonline.com/text.asp?2020/3/4/767/304951




  Introduction Top


Non-Hodgkin's lymphoma (NHL), the most common form of lymphoma, is a malignancy of B or T lymphocytes. About 85% of all lymphomas are B-cell lymphomas. NHLs account for about 5% of all cancers seen worldwide.[1] Traditionally, chemotherapy and chemoimmunotherapy are used in the treatment of NHLs. However, these therapies need to be administered intravenously, require frequent hospital visits, and cause significant hematological toxicity. Therefore, like imatinib, that changed the paradigm of management of chronic myeloid leukemia, there was an unmet need for a targeted agent for chronic lymphocytic leukemia (CLL) as well. Ibrutinib (PCI-32765) was developed by scientists at Celera Genomics, as a compound to study the functions of Bruton's tyrosine kinase (BTK).[2],[3] It was approved by the United States Food and Drug Administration (US-FDA) initially for mantle cell lymphoma (MCL) in 2013 and later for CLL in 2014. Subsequently, it was approved for Waldenstrom macroglobulinemia (WM) and marginal zone lymphoma (MZL). It was also approved for non-malignant conditions such as chronic graft-versus-host disease (cGVHD) in patients receiving allogeneic transplants based on a Phase II study.[4] From being one of the options for relapsed-refractory disorders, ibrutinib has already been approved for subsets of patients with CLL/SLL as frontline therapy.[5] Trials are ongoing for utilizing ibrutinib as an oral indefinite monotherapy as a time-defined treatment in combination with other agents. Here, we present a drug review on ibrutinib to offer a clearer understanding of the drug, its uses, side effects, and future prospects [Table 1].
Table 1: Key features of ibrutinib

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  Methods Top


We performed a comprehensive search of the PUBMED database for randomized controlled trials, meta-analyses, clinical trials, practice guidelines, reviews, and systematic reviews on ibrutinib published in the last 10 years with full text available in the English language. The following search terms were used and combined: “Ibrutinib,” “Chronic lymphocytic leukemia,” “Waldenstrom macroglobulinemia,” “Mantle cell lymphoma,” “Primary CNS lymphoma,” “Chronic Graft-versus-Host disease,” and “marginal zone lymphoma.” Package inserts and the website of the FDA were referred to for the chemical details of the drug. Out of a total of 213 studies, 121 were excluded because of duplication, nonrelevance to the topic of discussion, lack of an English version of the publication, nonavailability of full-text versions, or because they were describing Phase I studies or were not cancer related. In all, we reviewed a total of 92 studies [Figure 1].
Figure 1: Flowchart of the study selection process for Ibrutinib drug review

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History

X-linked agammaglobulinemia (XLA) is an inherited disorder characterized by low blood levels of B cells and immunoglobulins and an increased risk of infections.[6] It was first described in 1952. In 1993, the gene causing XLA was identified and was named BTK in memory of Dr. Bruton who described the disease in 1952.[7] With subsequent studies, it was shown that BTK also plays an important role in B-cell signaling and proliferation. Additionally, BTK was found to help in the maturation of B cells into immune cells.[8],[9] Hence, BTK inhibition was initially tested in autoimmune diseases such as rheumatoid arthritis, where one pathogenic aspect of the disease is the increased B-cell signaling and activity.[10] It was later shown that the drug suppresses the survival, migration, and adhesion of B cells, which provided a rationale for it to be used against B-cell malignancies.[11],[12],[13] This small BTK inhibitor was initially created by Celera Genomics. Thereafter, Pharmacyclics bought the compound and named it PCI-32765 in 2006. In 2011, when PCI-32765 completed Phase II trials and was shown to be effective in B-cell malignancies, Pharmacyclics and Johnson & Johnson decided to further develop and market this drug. Pharmacyclics was later taken over by AbbVie. In 2013, the drug received FDA approval for relapsed/refractory MCL. Following this, it was also FDA approved for relapsed/refractory CLL in 2014 and WM in 2015. In 2017, ibrutinib was approved for use in relapsed/refractory MZL and cGVHD. The latest development in the use of ibrutinib occurred in April 2020 when ibrutinib was approved for use with rituximab in treatment-naive adults with CLL.

Chemistry

The chemical name of ibrutinib is 1-[(3R)-3-[4-amino-3-(4-phenoxy phenyl)pyrazolo [3,4-d] pyrimidin-1-yl] piperidin-1-yl]prop-2-en-1-one. Its molecular weight is 440.5 g/mol, and the chemical formula is C25 H 24 N 6 O 2.[14]

Chemical and physical properties

It is white or off-white in color with a melting point of 149°C–158°C. It is insoluble in water and freely soluble in methanol and dimethyl sulfoxide.[15]

Mechanism of action

The B-cell receptor (BCR) gives the B cells their identity. BCR signaling is the central pathologic mechanism in B-cell malignancies.[16] The BCR pathway regulates multiple cellular processes such as proliferation, differentiation, and apoptosis.[9],[17] After the antigen triggers the BCR, protein tyrosine kinases (PTKs) such as Lyn and Syk activate BTK, which is a cytoplasmic enzyme present in all hematopoietic cells, except the plasma cells and T lymphocytes.[18] BTK, in turn, activates the phosphatidylinositol 3-kinase (PI3K) which converts phosphatidylinositol 4,5-biphosphate (PIP2) into phosphatidylinositol 3, 4, 5-triphosphate (PIP3). This leads to an increase in the intracellular calcium release and activation of the downstream mammalian target of rapamycin (mTOR) pathway.[19] It also activates 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 which further increases the release of intracellular calcium, diacylglycerol, and inositol triphosphate (IP3). This leads to an increase in the level of nuclear factor-kappa B (NF-κB), which, in turn, promotes cell proliferation and inhibits apoptosis.[19]

The PTKs are found to be overactivated in malignant B cells. Among the different PTKs, BTK is a distinct therapeutic target and central to the process of action of PTKs. Ibrutinib, a selective and irreversible small-molecule inhibitor of BTK, forms a covalent bond with a cysteine residue (CYS-481) in the active site of the enzyme. This prevents further downstream activation of the BCR pathway and subsequently inhibits cell growth, proliferation, and survival of the malignant B cells.[9],[20] Additionally, it alters the immune microenvironment and disrupts signals involved in CLL cell survival and migration, and has demonstrated reduced levels of pro-inflammatory cytokines (interleukin-8 [IL8], tumor necrosis factor-alpha [TNFα]) and chemokines for homing (CXCL12, CXCL13) to lymph nodes. The latter explains the peripheral blood lymphocytosis commonly seen after the initiation of treatment with ibrutinib. Lastly, ibrutinib is also active against IL-2-inducible kinase (ITK), a protein expressed by the T cells. By irreversibly binding to ITK, ibrutinib skews the CD4 T-cell populations toward a Th1 profile, thereby enhancing tumor immune surveillance.[21] Ibrutinib also downregulates the CD20 expression on B cells by targeting the CXCR4/SDF1 axis.[22] However, the fact that ibrutinib given with rituximab, a CD20 inhibitor, has a significant response rate indicates that there could be some more mechanisms of action of ibrutinib that are yet to be verified.[22]

Pharmacokinetics

Ibrutinib is rapidly absorbed after oral administration with a Tmax of 1–2 h. Its Cmax is 35 ng/ml, and the area under the curve (AUC) at a dose of 560 mg is 953 ± 705 ng.h/ml and at a dose of 420 mg is 680 ± 517 ng.h/mL.[23] Its action begins 4 h after oral administration and is sustained for at least 24 h, thus explaining the rationale for once-a-day administration. Although food increases its exposure compared to the fasting state, there are no recommended food restrictions.[21] In plasma, it binds irreversibly to albumin and alpha-glycoprotein. Protein binding can account for 97.3% of the administered dose. Ibrutinib is primarily metabolized by CYP3A5 and CYP3A4 and to a minor extent by CYP2D6. The major route of elimination is through the feces (80%).[24] Less than 10% of the drug is excreted in the urine. The elimination half-life of ibrutinib is approximately 4–6 h.[24]

Dosage

It is available in two forms, capsules and tablets. Capsules are available in doses of 70 and 140 mg and tablets in doses of 140, 280, 420, and 560 mg [Table 2].
Table 2: Approved doses of ibrutinib

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Dosing guidelines

It is advisable to take ibrutinib orally with a glass of water. The capsules/tablets should not be opened, broken, crushed, cut, or chewed.[14]

Doses in approved indications

Missed dose

If ibrutinib is not taken at the scheduled time, it can be taken as soon as possible on the same day. The normal schedule should be followed from the next day. If a dose is missed, an extra dose should not be taken on the next day.

Dose modification for adverse reactions

In the case of any Grade 3 or higher nonhematological toxicity, or any Grade 4 hematological toxicity or any Grade 3 neutropenia with fever/signs suggestive of infections, stopping the drug till toxicity resolves is advised.[25] Once the toxicity resolves, restarting the drug at the initial dose is recommended. If the toxicity recurs, reducing the dose by 140 mg and starting at the new dose after the toxicity resolves is advised. If the toxicity still occurs, a second reduction of the dose by 140 mg is advised. If the toxicity persists or recurs following two dose reductions, discontinuing ibrutinib is advised [Table 3].
Table 3: Dose modifications of ibrutinib with toxicities

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Special populations

  1. Pediatric patients: The safety and efficacy of the drug have not been studied in the pediatric population.[25] A clinical trial studying the efficacy and safety of ibrutinib in pediatric and adolescents is ongoing (NCT02703272)[26]
  2. Geriatric patients: There are no specific differences in the way the drug acts in the younger and older populations. However, Grade 3 or higher toxicities observed are more in the geriatric as compared to the younger population. There are no recommended dose changes advised in the geriatric population
  3. Pregnant women: Animal studies have found ibrutinib to be embryotoxic at varying doses. Hence, it is advisable to not give the drug during pregnancy (category D). It is advisable for men and women of reproductive potential to use effective contraception during and 1–3 months after discontinuation of therapy
  4. Lactating mothers: It is not known if ibrutinib is secreted in breastmilk, but as 97% of the drug is bound to plasma proteins, its secretion in breastmilk is supposedly low. However, due to the risk of toxicities posed by the drug to the newborn infants, it is advised to avoid the drug when breastfeeding
  5. Renal insufficiency: Ibrutinib has not been studied in patients with severe renal impairment (creatinine clearance<30 mL/min). However, it is excreted by the kidneys to a minor extent (<10%). No dose modification is advised for renal impairment
  6. Hepatic insufficiency: For patients with mild hepatic impairment (Child–Pugh class A), the recommended dose is 140 mg/day.[27] Ibrutinib is advised at a dose of 70 mg/day in patients with moderate hepatic impairment (Child–Pugh class B). However, in patients with severe hepatic impairment, ibrutinib is contraindicated. Similarly, a pharmacokinetic study of single-dose ibrutinib (140 mg) showed that it could be considered in patients with mild-to-moderate hepatic impairment, but not in those with severe hepatic dysfunction (Child Pugh class C).[28]


Indications

Chronic lymphocytic leukemia

In B-cell malignancies such as CLL, BTK is overexpressed as it plays a role in cell maturation, and, therefore, is a rational target for therapy.

Ibrutinib has been approved for newly diagnosed and relapsed/refractory CLL. This is based on the studies [Table 4] comparing ibrutinib with chemo-immunotherapy in newly diagnosed CLL. RESONATE-2, the first Phase III randomized study, compared ibrutinib with chlorambucil, and showed improved progression-free survival (PFS) and overall survival (OS) with ibrutinib.[29] The study had a long follow-up period of 5 years, and the results were impressive despite more than half of the patients crossing over and receiving ibrutinib at progression. In addition, the benefit of ibrutinib was seen in the overall prognostic risk groups. A major drawback of this study was the use of chlorambucil as a comparator in the control arm.[5] The ALLIANCE study compared bendamustine and rituximab (BR) to ibrutinib and ibrutinib with rituximab and established the superiority of the ibrutinib-containing arms over the BR arm. This study also showed no benefit from the addition of rituximab to ibrutinib.[30] iLLUMINATE, the third study involving older patients with newly diagnosed CLL, compared ibrutinib plus obinutuzumab to chlorambucil and obinutuzumab, establishing the superiority of the ibrutinib–obinutuzumab combination. However, unlike rituximab, the value of obinutuzumab in addition to ibrutinib remains to be evaluated.[31] Similar to the above studies, ibrutinib has been evaluated against standard chemo-immunotherapy regimens in a younger cohort of patients. In the Eastern Cooperative Oncology Group (ECOG)-ACRIN study, patients with newly diagnosed CLL were randomized to receive fludarabine, cyclophosphamide, and rituximab (FCR), or ibrutinib and rituximab. The study showed both improved PFS and OS with ibrutinib compared to that of the FCR regimen. This benefit was mainly due to the subset of IgVH unmutated patients, and both arms did equally well in the IgVH-mutated patients.[32] Benefit was also seen in other high-risk subgroups, including Rai Stage III or IV and chromosome 11q22.3 deletion. Given the potential for cure with FCR in IgVH-mutated patients, this is probably the only subset (young fit patients with IGVH mutation) where chemo-immunotherapy may be considered in newly diagnosed CLL patients.[33],[34]
Table 4: Studies on ibrutinib for newly diagnosed chronic lymphocytic leukemia and small lymphocytic lymphoma

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Single-agent ibrutinib in relapsed/refractory chronic lymphocytic leukemia

The pivotal study leading to the first approval for the use of ibrutinib in relapsed/refractory CLL by Byrd et al. was a Phase Ib/II trial for use of ibrutinib as a single agent [Table 5]. A total of 85 patients were included in the study, of which 51 received 420-mg ibrutinib and 34 received 840 mg. No difference in the time to peak (median Tmax 2 h) or the terminal half-life (7.8 ± 3.6 h for 420 and 8.1 ± for 840 mg) was seen between the doses. Assessments done for BTK occupancy showed full occupancy at both doses. The overall response rate was 71% in both the groups with complete response (CR) and partial response (PR) without lymphocytosis, whereas an additional 20% in the 420-mg group and 5% in the 840-mg group had a PR with persistent lymphocytosis. At 26 months, the estimated PFS rate was 75% and OS rate was 83%.[35]
Table 5: Studies of single-agent ibrutinib in relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma

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In 2014, Byrd et al. published a Phase III trial (RESONATE) that compared ibrutinib against ofatumumab in patients previously treated for CLL. They concluded that ibrutinib significantly improves the PFS, OS, and responses in the relapsed/refractory cases compared to that of ofatumumab. The improvement was seen across all prognostic subgroups as well as in those who had crossed over from ofatumumab to ibrutinib due to disease progression.[36] Even after 5 years, the improvements in PFS and OS were seen in the ibrutinib arm, despite the sizable (about 68%) crossover of patients from ofatumumab to ibrutinib due to progression.[37],[38]

Ibrutinib in combination with chemo-immunotherapy

Given the superiority of ibrutinib to the chemo-immunotherapy regimen, attempts have been made to combine ibrutinib with chemo-immunotherapy. The Phase III trial, HELIOS, compared ibrutinib + bendamustine + rituximab versus bendamustine + rituximab for low-risk treated and relapsed CLL/SLL [Table 6]. Patients with del(17p) were excluded from the study because of their known poor response to BR. The study showed a significantly higher PFS benefit of adding ibrutinib to bendamustine + rituximab in a relapsed/refractory setting.[39] In the ECOG-ACRIN study described above, a benefit of ibrutinib + retuximab (IR) was seen in the first-line setting on the response rates in cases with unmutated IgHV, whereas the response rates were similar in cases with mutated IgHV. A study by Jain et al. from the MD Anderson Cancer Center explored the feasibility of ibrutinib in combination with fludarabine, cyclophosphamide, and obinutuzumab (iFCG) in patients with mutated IgHV and without del(17p) [Table 7]. iFCG was developed with the intent to limit the use of fludarabine and cyclophosphamide to three courses, potentially reducing short- (myelosuppression) and long-term (secondary malignancies) toxicities, while maintaining efficacy through the addition of ibrutinib and obinutuzumab. Moreover, the achievement of absence of minimal residual disease (MRD) brought in the much-awaited concept of time-bound therapy in CLL. The study also aimed at achieving time-limited dosing of ibrutinib, which all the other major studies had not attempted. As per their reports, it seems that iFCG is an effective time-limited treatment strategy for young patients with mutated IgHV and without del(17p).[40] Another study conducted by Davids and Brown for the use of ibrutinib for a limited duration showed that CR and bone marrow undetectable MRD (BM U-MRD) rates were better than those for the historical FCR regimen in young, fit patients with newly diagnosed CLL.[41] Follow-up results of the above studies are not yet available, but it would be interesting to see whether limited duration of the use of ibrutinib and chemoimmunotherapy can offer similar results as compared to the other studies advocating the use of ibrutinib.
Table 6: Studies of ibrutinib in combination with chemo-immunotherapy

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Table 7: Studies of ibrutinib in combination with chemo-immunotherapy (continuous)

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Ibrutinib combinations aimed at limited-duration therapies

Apart from Davids and Brown's and Jain et al.'sstudies, a couple of more studies have been conducted on the limited-duration use of ibrutinib [Table 8]. The CLARITY study, a Phase II trial, evaluated the use of venetoclax, a BCL2 inhibitor with ibrutinib for a period of 12 months in relapsed/refractory cases. It showed a high BM MRD negativity, which indicates that the combination can be given for a limited period of time and then stopped in patients achieving deep remission.[42] Further follow-up studies to see whether there is permanent eradication of the disease and also Phase III trials are required to validate this approach. Another study by Jain et al. conducted in newly diagnosed older patients with CLL with at least one high-risk feature found a PFS of 98% and a OS of 99% at 1 year with higher rates of CR and BM U-MRD as compared to that of ibrutinib or venetoclax monotherapy. Again, a longer follow-up is required to actually suggest whether stopping therapy is advisable.[43]
Table 8: Studies of ibrutinib use in limited-duration therapy

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Ibrutinib versus wait and watch studies

Observation has been the standard of care for early-stage Binet A CLL. However, there are certain prognostic factors that indicate early progression of disease.[44] The German CLL 12 study utilized one such prognostic score, which included characteristics such as age, gender, ECOG-performance status, del(17p), IgHV mutation status, serum B2 microglobulin, and thymidine kinase. Ibrutinib was administered to intermediate-, high-, and very high-risk patients, and it was observed that event-free survival and PFS were higher in the ibrutinib group compared to that of the placebo group. However, whether this transforms into a survival benefit is still unknown. The toxicity profile of CLL 12 is better than that of CLL 7, which compared early treatment with the FCR-based regimen to deferred therapy as a standard of care for Binet A stage CLL [Table 9].[44],[45]
Table 9: Studies of ibrutinib versus observation in chronic lymphocytic leukemia

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Mantle cell lymphoma

It is a rare but aggressive B-NHL that remains incurable, and patients typically require multiple lines of therapies. BTK inhibitors have proven effective and represent one of the most effective treatment options for relapsed MCL. Agents approved before BTK inhibitors typically led to response rates of 20%–50% with a PFS of 4–9 months. [Table 10] summarizes the studies on ibrutinib in relapsed MCL. As is evident from the table, ibrutinib has led to an objective response rate (ORR) of 55%–75% and PFS of consistently more than a year, thus clearly surpassing the other approved agents in the setting.
Table 10: Studies of ibrutinib in mantle cell lymphoma

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Wang et al. in 2013 published a study that forms the basis of the FDA approval of ibrutinib in relapsed/refractory cases of MCL. They found that single-agent ibrutinib had a high response rate (68%) and durable response (median PFS, 13 months) irrespective of the factors having a poor outcome.[2]

The RAY Phase III trial of ibrutinib versus temsirolimus showed that single-agent ibrutinib is better than temsirolimus in terms of PFS (median PFS 15.6 vs. 6.2 months) and trends toward improved OS (median OS 30 vs. 23 months).[46]

Combinations of ibrutinib with other drugs have been explored in order to further improve these outcomes. A Phase II trial by Wang et al. evaluated the role of the combination of ibrutinib and rituximab in relapsed/refractory MCL. The study subjects had an ORR of 88%, and there were no unexpected side effects. About 54% of the patients discontinued therapy at the median follow-up either due to progression (18%) or adverse effects (24%) or stem cell transplantation (12%). However, this was a nonrandomized study, and the number of patients is relatively small to advocate the combination at present.[47]

In vitro models suggest synergism of inhibition of BTK and Bcl2. Subsequently, Tam et al. in a Phase II trial showed improved outcomes with the venetoclax combination in patients with relapsed/refractory MCL as compared to that of either ibrutinib or venetoclax alone. Both the drugs act by different pathways to inhibit the malignant B cells, and overlapping toxicities are minor. About 33% of the patients discontinued treatment either because of disease progression or adverse effects. The most common side effects were diarrhea (43%) and fatigue (75%). Tumor lysis syndrome occurred in 8.3% of the patients. Currently, the combination is being tested in Phase III studies (NCT032112174).[48] The PHILEMON Phase II trial by Jerkeman et al. in 2018 evaluated the role of ibrutinib, rituximab, and lenalidomide in cases of relapsed/refractory MCL and the triplet regimen was not found to be superior to the combination of ibrutinib and rituximab. However, the rate of CR was higher with the triplet regimen. Furthermore, the study divided the cases based on the status of p53 and CDKN2A mutations and found that irrespective of the mutation status, the response rates were similar. About 40% (n = 20) of the patients died during the study, 17 due to progression, and 3 due to adverse effects.[49]

A study of single-agent acalabrutinib by Wang et al. for relapsed MCL showed encouraging response rates (81%) and PFS (median 20 months). However, this study included less heavily pretreated patients than the ibrutinib registration trial, questioning the superiority of acalabrutinib over ibrutinib.[50]

LPL/WM

MYD88 L265P (leucine to proline change at position 265 of MYD88) and CXCR4 WHIM mutations are common and seen in more than 90% and 30–40% patients with WM, respectively. MYD88 L265P triggers tumor growth by activating NF-kB through BTK and IL-1 related kinases (IRAKs), and thus makes an ideal candidate for targeting by BTK inhibition.

Ibrutinib has been approved for the treatment of newly diagnosed and relapsed WM. [Table 11] summarizes the studies involving ibrutinib in WM. The approval is based on the findings of higher response rates and better PFS reported with ibrutinib in relapsed and newly diagnosed settings. For example, the typical ORR and PFS in newly diagnosed WM with alkylator-based therapies (CDR, BR), single-agent rituximab, and proteasome-based therapies are 40-50% and 12–24 months, 80%–90% and 36–60 months, and 90% and 48–60 months, respectively. However, ibrutinib resulted in an ORR of more than 90% with PFS not reached at 5-years follow-up, thus surpassing all the other available treatment options.
Table 11: Studies on ibrutinib in lymphoplasmacytic lymphoma and Waldenstrom macroglobulinemia

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Ibrutinib responses have been linked to the presence of MYD88 mutations, and co-occurrence of the CXCR4 mutation leads to lower response rates with few very good partial responses (VGPR) and a longer time to major response. To overcome the problem of BTK resistance due to the activating CXCR4 mutations, CXCR4 inhibitors (ulocuplumab and mavorixafor) have been tried in combination with ibrutinib and have shown encouraging early results. Addition of rituximab to inrutinib has also been shown to improve the response rates and time to major response in patients with MYD88 mutation co-occurring with CXCR4 mutation.

Patients with wild-type MYD88 do poorly with ibrutinib and single-agent rituximab, and hence, should be treated with bendamustine or proteasome-based therapies.

Patients with the Bing-Neel syndrome, an increasingly reported central nervous system (CNS) manifestation of WM due to improved survival, seem to be particularly benefitted by ibrutinib. Besides exquisite sensitivity, ability to penetrate the blood-brain barrier makes it the drug of choice in this difficult-to-treat situation. Mason et al. measured levels of ibrutinib and its metabolite in the cerebrospinal fluid (CSF) in a case of WM and showed that its CSF concentration was above the 50% inhibitory concentration (IC50) for BTK inhibition.[52]

The hematopoietic cell kinase (HCK) has been shown to be concomitantly upregulated in patients with MYD88 mutation and contributes to cell proliferation and survival. Amongst the available BTK inhibitors, ibrutinib and zanubrutinib have been shown to inhibit HCK besides BTK, possibly making these the better BTK inhibitors to consider amongst the available ones. In fact, zanubritinib seems to have higher response and VGPR rates than ibrutinib, possibly because of its ability to inhibit various kinases and better BTK occupancy with twice-daily dosing. A randomized phase III study, ASPEN, was conducted for patients with newly diagnosed and relapsed WM and was reported at the annual meeting of the American Society of Clinical Oncology. The study showed that zanubrutinib led to higher response rates than ibrutinib (28% versus 17% P = 0.09), but more importantly had a better safety profile, especially in terms of atrial fibrillation and severe infections.

Given its safety profile, ibrutinib is being studied in combination with various drugs with sound scientific rationale. For example, high BCL2 expression and impressive single-agent activity of venetoclax makes a case for combination studies of ibrutinib with venetoclax. Ibrutinib is also being evaluated in combination with the SYK kinase inhibitor, dasatinib, in clinical trials. No study has compared ibrutinib with and without rituximab directly, and hence, the benefit of adding rituximab remains to be demonstrated. Nevertheless, the addition of rituximab has been shown to shorten the time to response and increase the response rates in patients with CXCR4 mutation, which in turn has been demonstrated to confer clinical and in vitro resistance to ibrutinib.

Marginal zone lymphoma

MZL is frequently linked to chronic infection, which may induce BCR signaling, resulting in aberrant B-cell survival and proliferation. Depending on the subtype and organ involved, the primary treatment options range from local therapy, such as surgery or radiotherapy, to systemic therapy ranging from antimicrobials to combination chemo-immunotherapy. There is no standard therapy for relapsed disease. PI3 kinase inhibitors have been reported to be active, but gastrointestinal and hepatic toxicity are important concerns.[57] Ibrutinib got an expedited approval for use in patients with relapsed MZL who have received at least one line of chemo-immunotherapy based on the study by Noy et al. This Phase II study on sixty patients reported an ORR of 48% and a median PFS of 14.2 months.[58] The reported response rates in nodal MZL subtypes were lower with a shorter PFS. In the AIM study, presented at the 2019 annual meeting of the American Society of Hematology, patients with relapsed MZL were treated with a combination of ibrutinib and venetoclax and showed an ORR of 83% (38% CR) with median PFS not reached at a median follow-up of 10 months.[48]

Chronic graft-versus-host disease

The potential of B-cell targeting agents in cGVHD is demonstrated by the activity of rituximab in steroid-refractory GVHD.[59] Ibrutinib inhibits BTK in the B cells and THE IL2-inducible T-cell kinase (ITK) in the T cells. ITK signaling plays an important role in T cell activation, cytokine release, and proliferation in cGVHD. Miklos et al. conducted a Phase Ib/II study based on the fact that GVHD, a serious complication of allogeneic stem cell transplantation, involves both B and T cells. Ibrutinib was given to 42 patients who had failed the previous 1–3 lines of therapy. At the median follow-up of 13.9 months, 67% had a response (CR rate of 21% and PR rate of 45%). Five patients had progressed.[4] Based on these results, ibrutinib has been approved for cGVHD that is refractory to steroids and is being actively studied for use in earlier lines of therapy and prophylaxis of GVHD.

Primary central nervous system lymphoma

While ibrutinib is not approved for PCNSL, it has shown encouraging activity as a single agent. Systemic diffuse large B-cell lymphoma (DLBCL) is associated with a lower response rate to ibrutinib in relapsed/refractory patients, however a higher response rate is reported in the activated B cell-like (ABC) subtype. Most PCNSLs are ABC subtype DLBCLs, and the BCR signaling pathway mutations are more common in them and often affect the downstream signaling. The most common mutations are gain-of-function mutations in MYD88 and CD79B. Besides this, the small size of the molecule and the low molecular weight of 440 KD, allow for its penetration through the blood–brain barrier, leading to a CSF-to-blood ratio of 0.7. Ibrutinib was initially reported to be active in MCL with CNS involvement, and later studied as a single agent and combinations in PCNSL.

[Table 12] summarizes some of the important studies of ibrutinib in PCNSL as a single agent and in a combination setting.
Table 12: Studies on ibrutinib in primary central nervous system lymphoma

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Single-agent ibrutinib has been reported to be active in relapsed/refractory PCNSL with response rates of 75%–80% and median PFS and OS of 4–6 and 18–20 months, respectively.[60],[61],[62],[63] Such responses are often incomplete and short lived, and this has led to combination studies in the relapsed/refractory and maintenance settings. Two combination studies of ibrutinib have been reported in relapsed/refractory PCNSL. The first study by Lionakis et al. involved newly diagnosed (n = 5) and relapsed (n = 13) patients with PCNSL.[65] The regimen used had a run-in phase of single-agent ibrutinib for 14 days followed by an induction regimen DA-TEDDi-R, an infusional regimen of temozolomide, etoposide, liposomal doxorubicin, dexamethasone, ibrutinib, and rituximab. The study reported a quick response in majority of the patients (ORR 72%) and lasting remission in eight patients at a median follow-up of more than a year. The study reported an alarmingly high incidence of Aspergillus infections (39% of the patients) with a treatment-related mortality of 28%. The second study evaluated the combination of ibrutinib with high-dose methotrexate and rituximab in relapsed/refractory CNS lymphoma (CNSL).[64] The study included patients with primary (n= 9) as well as secondary (n = 6) CNSL. The regimen was well tolerated and with no Grade 5 events and an ORR of 80%. The dose-limiting toxicity was not reached, and the authors recommended a dose of 840 mg for future studies. The median PFS was 9.2 months for the whole cohort, while PFS and OS were not reached for patients with PCNSL. Despite the small sample size and almost equivalent ORR to other high-dose methotrexate-based regimens used in the relapsed settings, this study hints toward the additional benefit of the combination therapy. The ORR in this study is much higher than that previously reported by the same authors using single-agent ibrutinib in relapsed/refractory patients. Furthermore, these ORR and PFS/OS compare favorably with those for methotrexate-based salvage regimens when considered in the context of a shorter progression-free interval after the initial therapy. However, this requires validation in a larger cohort of patients. The ease of oral administration also makes ibrutinib an attractive candidate for maintenance therapy. A study from Israel by Bairey et al. reported on the feasibility of ibrutinib maintenance.[66] This ongoing study showed that ibrutinib is active and well tolerated in this setting. The median PFS for the 12 enrolled patients is 22.5 months, and ibrutinib converted three PRs into CRs after initiation of maintenance. The reported tolerance to ibrutinib is similar to that of other indications, except for the higher reported incidence of aspergillosis (5%–39%). Inhibition of both BTK and ITK in neutrophils and macrophages (including the CNS macrophages called the microglia) seems to underlie this risk and is possibly enhanced by the use of steroids in patients with PCNSL.[65] Though data about mutations in the BCR pathways and response are limited in PCNSL, the initial reports give conflicting results. A study by Grommes et al. reported resistance in patients with CARD11 mutations and incomplete responses when MYD88 and CD79b mutations co-occurred, whereas the French study by Soussan et al. reported resistance in the absence of CARD11 mutation and in the presence of MYD88, which predicts enhanced sensitivity.[61],[62] Additionally, the study by Grommes et al. identified the constitutional activation of PI3K-mTOR signaling in the presence of CD79b mutations, an additional possible mechanism for resistance to ibrutinib in PCNSL. Both the studies support the notion of a higher incidence of BCR pathway mutations in PCNSL, and a comprehensive genomic profiling in a larger cohort of patients is needed to dissect out the genomic determinants of response.

Thus, along with immunomodulatory drugs (lenalidomide and pomalidomide, ORR 48% and 67% and PFS 5.3 and 7.8 months, respectively) and immune checkpoint inhibitors, ibrutinib broadens the therapeutic landscape of PCNSL. The available data support the exploration of ibrutinib in combination with chemotherapy and/or biological targeted agents (e.g., of PI3K/mTOR pathway inhibitors) in PCNSL.

Diffuse large B-cell lymphoma

Ibrutinib was found to be effective in DLBCL in the same study that showed response rates to the various B-cell malignancies.[67],[68] It was hypothesized that patients with both c-myc and BCL-2 overexpression (double-expressor lymphoma [DEL]) have upregulated BCR signaling. Moreover, DEL represents a cohort with shorter survival after frontline R-CHOP, thereby representing a group with an unmet need. In their retrospective analysis, Winter et al. showed that ibrutinib alone led to responses in 60% of the patients with non-GCB DELs.[68] A Phase I study showed that when used in combination in relapsed/refractory DLBCL, ibrutinib + rituximab, ifosfamide, carboplatin, and etoposide phosphate (R-ICE) showed nearly 90% response rates, and nearly all patients with non-GCB DLBCL achieved a response.[69] Similarly, after in vitro demonstration of synergism, a recent study explored the combination of ibrutinib + lenalidomide + rituximab in relapsed/refractory DLBCL. Nearly half of the patients responded, with two-thirds of those having non-GCB DLBCL.[70] Hence, there appears to be a bright future of relapsed/refractory non-GCB DLBCL in the ibrutinib era. The PHOENIX study evaluated the ibrutinib + R-CHOP combination in newly diagnosed non-GCB DLBCL, and found a PFS and OS benefit in younger patients (aged<60 years), albeit at the cost of more adverse events.[71]

Adverse effects

Though ibrutinib is considered to be relatively well tolerated than conventional chemo-immunotherapy, it is associated with potentially serious side effects [Table 13]. Proper anticipation, monitoring, and appropriate management including dose modification are key to the optimal outcomes, as ibrutinib dose reduction has an adverse impact on disease control.[72] Long-term follow-up studies with ibrutinib have revealed that up to 50% of the patients have discontinued the therapy, and the most common reason was disease progression.[61] Roughly less than half of the dose discontinuations are because of toxicities, and, hence, appropriate patient selection and monitoring is required to obtain optimal outcomes [Table 14]. Most of the side effects of ibrutinib are mild (Grade 1/2) toxicities and are easily manageable. However, Grade 3/4 toxicities require either discontinuation of the drug or dose modification. The frequency of adverse events and their management is listed in [Table 13]. Strict monitoring is required for the prevention of further toxicities. Apart from the clinical adverse events mentioned in [Table 13], lymphocytosis is seen in nearly two-thirds of the patients within the first month of ibrutinib therapy. This is accompanied by reduction in lymphadenopathy, thereby justifying it as a redistribution phenomenon without any clinical significance. It is reversible in 95% of the patients, and even prolonged lymphocytosis has not been shown to be predictive of relapse.[21]{Table 12}
Table 13: Adverse events due to ibrutinib: Frequency, mechanism, prevention, and management

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Table 14: Checklist for Ibrutinib use

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Drug interactions

Ibrutinib is metabolized majorly by CYP3A4 and to a lesser extent by CYP2D6. Hence, it has to be used with care in patients using CYP3A4 inhibitors and inducers. Drugs that inhibit CYP3A4 increase the concentration of ibrutinib, and those that induce CYP3A4 reduce the concentration of ibrutinib.[25] Concomitant use of moderate (ciprofloxacin, erythromycin, diltiazem, verapamil, ritonavir, imatinib, and crizotinib) or strong (clarithromycin, ketoconazole, itraconazole, indinavir, nelfinavir, and cobicistat) CYP3A4 inhibitors should be avoided.[85] Importantly, when given with voriconazole or posaconazole, its dose needs to be reduced to 140 mg and 70 mg, respectively. Ibrutinib use should be avoided with strong CYP3A4 inhibitors as it can cause drug toxicity. Furthermore, when using strong inhibitors of CYP3A4 for a short term, it is advisable to interrupt the use of ibrutinib.[86]

In vitro studies show that ibrutinib inhibits P-gp transporters. Hence, co-administration of P-gp inhibitors and ibrutinib may increase the levels and toxicity of Pgp substrates (methotrexate, digoxin, etc.).[86]

Contraindications

Apart from avoiding its use during pregnancy, lactation, or severe hepatic diseases (Child–Pugh class C), there are no contraindications to the use of ibrutinib.

Molecular mechanisms of resistance

Resistance to ibrutinib and its underlying mechanisms have quickly become apparent as the drug is being used more widely. This has led to the exploration of potential combinations with other compounds in such refractory populations.

Depending on the disease, varying proportions of patients show primary resistance. For example, 10%–30% of patients with CLL show no initial response to ibrutinib. Certain risk factors such as del(17p), p53 mutation, and complex karyotype have been reported.[87] Similarly, DLBCL of germinal center origin, overexpression of CD79b, and CARD11 mutations have been linked to primary resistance in DLBCL. Overall, tumors with less active BCR signaling or mutations downstream to BTK in the BCR signaling pathway tend to be primarily refractory.

More well characterized and widely studied is the problem of secondary resistance. The most common mechanism seems to be the point mutation Cys481Ser leading to reduced binding and ineffective BTK inhibition, which can potentially be overcome by molecules with different binding pockets. Interestingly, this mutation could be detected in the peripheral blood of patients up to a year before clinical relapse becomes apparent. Surprisingly, this mutation has been seen in a minor subclone, pointing toward an interesting hypothesis of this minor subclone driving the resistance of the rest of the cells without the Cys481Ser mutation. Experiments have shown this to be mediated through inflammatory cytokines such as IL-6 and IL-10 produced via ERK upregulation. This has led to studies adding ERK inhibitors to ibrutinib in patients who harbor the Cys481Ser mutations.

A small proportion of patients have also been reported to have a gain-of-function mutation in PLCG2, which is downstream to BTK. In such cases, BTK inhibitors have no activity, but it opens a possibility for the inhibition of the SYK and LYN pathways. Deletion of 8p has also been reported in cases of secondary ibrutinib resistance. The deletion leads to haplo-insufficiency of the TNF-related apoptosis-inducing ligand receptors (TRAIL-R), thus leading to insensitivity to TRAIL.[88] Gain of chromosome 2p leads to the overexpression of exportin-1 gene (XPO1), which can potentially be targeted with selinexor.[89]

The upregulation of other cell signaling pathways such as the AKT, ERG, and noncanonical NF-KB pathways has also been reported with ibrutinib therapy and provides a rationale for combination therapy.


  Indian Perspective Top


As a result of the cost constraints and requirement of indefinite therapy, reported experience with Indian patients is limited. With biosimilars for ibrutinib being available in India, the drug cost has drastically reduced from around ₹400,000/month to ₹40,000/month, and it is now affordable to a larger proportion of the population. However, it is still unaffordable for a majority of outpatients.[90] Real-world data on ibrutinib show high rates of discontinuation and adverse events in the Western population.[28] A report from India by Agarwal et al. on a small cohort of eight patients suggests a comparable efficacy and safety profile to that reported in literature for ibrutinib used in the later lines of therapy.[91] Cost constraints might lead to dose reduction, and such an experience may be valuable as reported by Lad et al.[92] Similarly, the tolerance is likely to be different and safety data on Indian patients are therefore worth reporting, as it will inform the Indian physicians about the management of patients receiving ibrutinib.[84]


  Conclusions Top


Ibrutinib being an irreversible BTK inhibitor has come a long way from being considered for autoimmune diseases to malignancies. Initially approved for relapsed/refractory patients, it is being increasingly recognized as a frontline drug with good response rates. The relatively fewer side effects and ease of administration make it a good option for older as well as young adults. However, the high costs still do not allow a lot of patients to benefit from the use of this drug, but this will certainly change with time.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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