A Phase I Trial of Nab-Paclitaxel/Bevacizumab (AB160) Nano-Immunoconjugate Therapy for Gynecologic Malignancies.

PURPOSE: AB160 is a 160-nm nano-immunoconjugate consisting of nab-paclitaxel (ABX) nanoparticles noncovalently coated with bevacizumab (BEV) for targeted delivery into tissues expressing high levels of VEGF. Preclinical data showed that AB160 resulted in greater tumor targeting and tumor inhibition compared with sequential treatment with ABX then BEV. Given individual drug activity, we investigated the safety and toxicity of AB160 in patients with gynecologic cancers. PATIENTS AND METHODS: A 3+3 phase I trial was conducted with three potential dose levels in patients with previously treated endometrial, cervical, and platinum-resistant ovarian cancer to ascertain the recommended phase II dose (RP2D). AB160 was administered intravenously on days 1, 8, and 15 of a 28-day cycle (ABX 75-175 mg/m2, BEV 30-70 mg/m2). Pharmacokinetic analyses were performed. RESULTS: No dose-limiting toxicities (DLT) were seen among the three dose levels tested. Grade 3/4 toxicities included neutropenia, thromboembolic events, and leukopenia. DL2 (ABX 150 mg/m2, BEV 60 mg/m2) was chosen as the RP2D. Seven of the 19 patients with measurable disease (36.8%) had confirmed partial responses (95% confidence interval, 16.3%-61.6%). Pharmacokinetic analyses demonstrated that AB160 allowed 50% higher paclitaxel dosing and that paclitaxel clearance mirrored that of therapeutic antibodies. CONCLUSIONS: The safety profile and clinical activity of AB160 supports further clinical testing in patients with gynecologic cancers; the RP2D is DL2 (ABX 150 mg/m2, BEV 60 mg/m2).

High-Dose Methotrexate in Patients With Lymphoma: Predictors of a Complicated Course.

PURPOSE: High-dose methotrexate (HDMTX; > 500 mg/m2) is an important component of lymphoma therapy. Serum MTX monitoring at 48 hours is the standard approach to identify those at increased risk of developing MTX toxicity. Our aim was to characterize the incidence of complications and their association with MTX levels. METHODS: A retrospective review of our institutional electronic medical record was conducted to identify patients with lymphoma who received HDMTX between January 1, 2002, and December 31, 2018. We characterized the incidence of acute kidney injury (AKI), intensive care unit (ICU) admission, length of hospital stay (LOS), and 30-day mortality across 48-hour MTX levels. To establish an association between 48-hour MTX levels and the complications listed, we performed chi-square analysis for dichotomous variables and Kruskal-Wallis for nonparametric data. Receiver operator characteristic curve analysis was performed to identify the MTX level where AKI grade ≥ 2 was more likely. Multivariate logistic regression analysis was performed to identify risk factors for this MTX level. RESULTS: We identified 642 patients with 2,804 cycles of HDMTX. The incidence of AKI was 19.1% with AKI grade ≥ 2 making up 21% of cases. Rates of AKI, ICU admission, and 30-day mortality are associated with elevated 48-hour MTX levels. There was a significant increase in median LOS with elevated MTX levels (P < .001). Receiver operator characteristic curve analysis for AKI grade ≥ 2 demonstrated a 48-hour MTX level threshold of 1.28 µmol/L. Multivariate logistic regression analysis revealed age, male sex, elevated body surface area, higher MTX dose, monotherapy, and first cycle as independent factors. CONCLUSION: Elevated MTX levels are associated with a significant increased rate of AKI, ICU admission, prolonged LOS, and 30-day mortality. Elevated 48-hour MTX levels, particularly > 1.28 µmol/L, should alert clinicians for complications and to initiate measures to reduce MTX levels.

Fibroblast growth factor receptor (FGFR) inhibitors in cholangiocarcinoma: current status, insight on resistance mechanisms and toxicity management.

INTRODUCTION: Cholangiocarcinoma (CCA) frequently presents with an advanced disease precluding curative surgery and shows modest response to chemotherapy. Advancements in genomic profiling have unfolded critical pathophysiologic underpinnings of CCA, leading to the development of targeted therapies with encouraging early results. Of the targetable genomic alterations, fibroblast growth factor receptor-2 (FGFR-2) fusions or rearrangements are present in 10-15% of patients with intrahepatic CCA. Clinical trials demonstrating significant antitumor activity of FGFR inhibitors in FGFR-2 fusion or rearrangement enriched chemotherapy-refractory patients led to FDA approval of FGFR inhibitors, pemigatinib and infigratinib, in the second-line setting. We identified peer-reviewed articles on FGFR inhibitors utilizing the PubMed database published between 2015 and 2021. AREAS COVERED: This article provides an overview of clinical and biological characteristics of FGFR-driven CCA, pharmacology and antitumor activity of currently available FGFR inhibitors, and the evolving knowledge of drug resistance mechanisms. Additionally, toxicities associated with FGFR inhibitor use and their management have been described. EXPERT OPINION: The development of FGFR inhibitors is a significant advancement in the therapeutic paradigm of advanced CCA. Ongoing research utilizing FGFR inhibitors in treatment-naïve patients, elucidation of resistance mechanisms to harness future trials, and exploration of combination strategies will transform the treatment landscape of CCA.

Successful encorafenib desensitization in a patient with recurrent metastatic melanoma.

Type I hypersensitivity reactions (HSR) to dabrafenib are rare but have been previously described. We present a case where a 72-year-old woman with recurrent, metastatic BRAF-mutated melanoma developed a type I HSR to dabrafenib. We, therefore, developed a desensitization protocol with encorafenib, a similar class agent, to allow the patient to continue with treatment. Patients with a history of HSR to dabrafenib may be considered for encorafenib desensitization when other therapeutic options are limited.

2019-2020 Drug Updates in Hematologic Malignancies.

During JADPRO Live Virtual 2020, Heidi D. Finnes, PharmD, BCOP, FHOPA, discussed the pharmacology and indications of medications approved from late 2019 to late 2020 for the management of patients with hematologic malignancies, reviewed pivotal clinical trial data, and covered the adverse events of these hematologic medications.

Incidence and risk of tumor lysis syndrome in patients with relapsed chronic lymphocytic leukemia (CLL) treated with venetoclax in routine clinical practice.

The risk of TLS in patients with relapsed CLL treated outside of clinical trials is not well described. Using the Mayo Clinic CLL Database, 48 patients treated with venetoclax for relapsed CLL in routine practice were identified; chart review determined baseline risk for TLS and laboratory abnormalities during venetoclax ramp-up. Overall, 6 (13%) patients developed laboratory TLS, 3 of whom demonstrated clinical TLS. The majority of patients who developed TLS were stratified as low or medium risk by the package insert. Of the 42 patients who did not meet Howard criteria for TLS, isolated hyperphosphatemia occurred in 19 patients (45%), hyperkalemia in 13 patients (31%), hyperuricemia in 2 patients (5%), and hypocalcemia in 1 patient (2%). In routine practice, the incidence of TLS appears higher than reported in clinical trials (3-6%). Half of patients who did not meet criteria for TLS developed clinically significant electrolyte abnormalities that required medical intervention.

Efficacy of Second-Line Chemotherapy in Extrapulmonary Neuroendocrine Carcinoma.

OBJECTIVES: A platinum/etoposide doublet is standard first-line therapy for poorly differentiated neuroendocrine carcinoma (PD NEC); however, evidence to guide treatment beyond first-line regimens is lacking. This study aimed to evaluate the efficacy of second-line regimens in PD NEC. METHODS: We performed a retrospective analysis of patients treated with second-line chemotherapy for PD NEC. Inclusion criteria were previous first-line therapy with platinum/etoposide, extrapulmonary PD NEC, and follow-up data. The primary end points were overall survival (OS) and progression-free survival (PFS) after second-line therapy. Secondary end points included OS and PFS from first-line therapy. RESULTS: Sixty-four patients were included. The median OS from initiation of second-line therapy was 6.2 months (95% confidence interval [CI], 4.9-8.9). The median PFS was 2.3 months (95% CI, 2.0-3.2). No second-line regimen showed a statistically significant difference in OS or PFS. There was a significant increase in OS for cisplatin first-line regimens compared with carboplatin (17.0 months [95% CI, 12.5-22.6] vs 11.7 months [95% CI, 8.0-14.0]). CONCLUSIONS: The efficacy of current second-line therapy in PD NEC is poor. No second-line regimen showed statistically significant superiority. Cisplatin was associated with longer OS regardless of second-line regimen or age. However, unmeasured confounders such as performance status or comorbidities may explain this effect.

The impact of dose modification and temporary interruption of ibrutinib on outcomes of chronic lymphocytic leukemia patients in routine clinical practice.

To study the impact of dose modification and temporary interruption of ibrutinib in routine clinical practice, we conducted a retrospective study of consecutive CLL patients treated with ibrutinib outside the context of a clinical trial at Mayo Clinic, (Rochester, MN) from 11/2013 to 12/2017. Of 209 patients, 131 (74%) had unmutated IGHV, 38 (20%) had TP53 disruption, and 47 (22%) were previously untreated. A total of 87/209 (42%) patients started reduced dose ibrutinib (<420 mg daily; n = 43, physician preference; n = 33, concomitant medications; and n = 11, other). During 281 person-years of treatment, 91/209 patients had temporary dose interruption (54%, nonhematologic toxicity; 29%, surgical procedures; 10%, hematologic toxicity; and 7%, other). After a median follow-up of 24 months, the estimated median event-free survival (EFS) was 36 months, and median overall survival (OS) was not reached. On multivariable analyses, temporary ibrutinib interruption (hazard ratio [HR]: 2.37, P = .006) and TP53 disruption at ibrutinib initiation (HR: 1.81, P = .048) were associated with shorter EFS, whereas only TP53 disruption (HR: 2.38, P = .015) was associated with shorter OS. Initial ibrutinib dose and dose modification during therapy did not appear to impact EFS or OS. These findings illustrate the challenges associated with continuous oral therapy with ibrutinib in patients with CLL.

Defining current gaps in quality measures for cancer immunotherapy: consensus report from the Society for Immunotherapy of Cancer (SITC) 2019 Quality Summit.

BACKGROUND: Quality measures are important because they can help improve and standardize the delivery of cancer care among healthcare providers and across tumor types. In an environment characterized by a rapidly shifting immunotherapeutic landscape and lack of associated long-term outcome data, defining quality measures for cancer immunotherapy is a high priority yet fraught with many challenges. METHODS: Thus, the Society for Immunotherapy of Cancer convened a multistakeholder expert panel to, first, identify the current gaps in measures of quality cancer care delivery as it relates to immunotherapy and to, second, advance priority concepts surrounding quality measures that could be developed and broadly adopted by the field. RESULTS: After reviewing the existing quality measure landscape employed for immunotherapeutic-based cancer care, the expert panel identified four relevant National Quality Strategy domains (patient safety, person and family-centered care, care coordination and communication, appropriate treatment selection) with significant gaps in immunotherapy-based quality cancer care delivery. Furthermore, these domains offer opportunities for the development of quality measures as they relate to cancer immunotherapy. These four quality measure concepts are presented in this consensus statement. CONCLUSIONS: This work represents a first step toward defining and standardizing quality delivery of cancer immunotherapy in order to realize its optimal application and benefit for patients.

Acute Interstitial Nephritis and Checkpoint Inhibitor Therapy: Single Center Experience of Management and Drug Rechallenge.

Background: The objective of this case cohort study was to describe our experience in the care of patients with immune checkpoint inhibitor-related acute interstitial nephritis (ICI-AIN) including rechallenge. Methods: A descriptive case series of patients that received an ICI and had an AKI (defined as a ≥1.5-fold increase in serum creatinine) as an immune-related adverse event (irAE), with biopsy-proven or clinically suspected ICI-AIN from January 1, 2014 to December 1, 2018 at Mayo Clinic, Rochester. We studied details regarding diagnosis, clinical course, management, and outcomes of rechallenge of immunotherapy. Complete response (CR) was defined as return of kidney function back to baseline or <0.3 mg/dl above baseline creatinine; partial response (PR) was defined as creatinine >0.3 mg/dl from baseline, but less than twofold above the baseline by the end of steroid course. Results: A total of 14 cases of biopsy-proven (35%) or clinically suspected (65%) ICI-AIN was identified. All patients had their ICI withheld and 12 patients received steroids. Steroid regimens were highly variable. The starting equivalent dose of prednisone was higher in those that had a CR versus a PR (median 0.77 mg/kg versus 0.66 mg/kg). Proton pump inhibitors (PPIs) were used in 11 patients and were stopped in eight (73%) patients at the time of the AKI event. A CR was seen in five (63%) of the eight patients who discontinued PPIs. Rechallenge was attempted in four of the 14 patients: three were successful with no recurrence of AKI, but one patient had recurrent AKI and fatal pneumonitis. Conclusions: Careful review, withholding ICI and concomitant known AIN-inducing medications, along with prompt initial steroid management were the key in complete renal kidney recovery. A kidney biopsy should be strongly considered. Rechallenge of immunotherapy after a kidney irAE, although challenging, is possible and would need careful evaluation on an individual basis. Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/K360/2020_01_30_KID0000152019.mp3.

Rheumatic Syndromes Associated With Immune Checkpoint Inhibitors: A Single-Center Cohort of Sixty-One Patients.

OBJECTIVE: To describe the prevalence, clinical presentation, and management of rheumatic immune-related adverse effects (Rh-irAEs) from immune checkpoint inhibitor (ICI) therapy. METHODS: From a database of all patients who received any ICI at the Mayo Clinic Rochester, Minnesota campus between January 1, 2011 and March 1, 2018, we retrospectively identified those with Rh-irAEs, using diagnostic codes, search terms, and manual chart review. RESULTS: Of the 1,293 patients who received any ICI, Rh-irAEs were clinically diagnosed in 43. Eighteen patients with Rh-irAEs who received ICI therapy elsewhere were also analyzed. Clinical syndromes included inflammatory arthritis (n = 34 [prevalence 2%]), myopathy (n = 10), and other rheumatic syndromes (n = 17). Inflammatory arthritis was most commonly polyarticular, and glucocorticoid treatment was required in 26 patients (76%). The mean ± SD duration of treatment was 18 ± 18 weeks. Five patients (15%) also received disease-modifying antirheumatic drugs, and ICI therapy had to be discontinued in 3 patients (9%). Myopathy was treated with glucocorticoids in all cases (mean ± SD treatment duration 15 ± 17 weeks) and led to 2 deaths and permanent ICI discontinuation in 9 patients (90%). Other syndromes included connective tissue diseases, vasculitis, polymyalgia rheumatica-like syndrome, and flare of preexisting rheumatic disease. Most (71%) were treated with immunosuppression, with 12% requiring ICI discontinuation. CONCLUSION: This study represents the largest cohort of patients with Rh-irAEs reported to date. Most patients received long courses of immunosuppressive treatment, although discontinuation of ICI therapy was required in only a minority.

Bolus 5-fluorouracil (5-FU) In Combination With Oxaliplatin Is Safe and Well Tolerated in Patients Who Experienced Coronary Vasospasm With Infusional 5-FU or Capecitabine.

INTRODUCTION: Coronary vasospasm associated with fluoropyrimidine (FP)-based chemotherapy is a potentially serious complication and reported to occur more often with infusional 5-fluorouracil (5-FU) or capecitabine than with bolus 5-FU. Given the additional benefit of oxaliplatin over FP alone in the management of colorectal cancer, retaining oxaliplatin in the treatment regimen is desirable, but the safety of combining bolus 5-FU with oxaliplatin in patients with FP-induced vasospasm is not well established. We performed a retrospective review to explore the safety of substituting FLOX (bolus 5-FU, oxaliplatin, leucovorin) for FOLFOX (infusional 5-FU, oxaliplatin, leucovorin) and CAPOX (capecitabine, oxaliplatin) in patients who had FP-induced coronary vasospasm. PATIENTS AND METHODS: The pharmacy database of Mayo Clinic was queried to identify patients who developed coronary vasospasm associated with FOLFOX or CAPOX between January 2011 and January 2018 and were subsequently treated with FLOX. Detailed information was obtained on these patients by retrospective electronic chart review. RESULTS: A total of 10 patients (median age, 56.5 years; range, 36-77 years) were identified, 9 with FOLFOX and 1 with CAPOX. Among the patients treated with FOLFOX, 8 patients had chest pain as the presenting complaint that had started within 48 hours of beginning of the 5-FU infusion. In 9 of 10 patients, coronary vasospasm occurred with the first cycle of therapy. All patients made full recovery after discontinuation of infusional 5-FU or capecitabine. All patients subsequently received FLOX with 7 median bolus 5-FU doses (range, 2-22 doses) and 7 median oxaliplatin doses (range, 2-12 doses) at 7 days to 18 months after the event, with 7 patients treated within 4 weeks of the event. FLOX did not cause any cardiovascular adverse events in any of the 10 patients. CONCLUSION: Bolus 5-FU in combination with oxaliplatin is safe in patients who have experienced coronary vasospasm with infusional 5-FU or capecitabine.

Combining Immune Checkpoint Inhibitors With Conventional Cancer Therapy.

Immune checkpoint inhibitors (ICIs) have recently revolutionized cancer treatment, providing unprecedented clinical benefits. However, primary or acquired therapy resistance can affect up to two-thirds of patients receiving ICIs, underscoring the urgency to elucidate the mechanisms of treatment resistance and to design more effective therapeutic strategies. Conventional cancer treatments, including cytotoxic chemotherapy, radiation therapy, and targeted therapy, have immunomodulatory effects in addition to direct cancer cell-killing activities. Their clinical utilities in combination with ICIs have been explored, aiming to achieve synergetic effects with improved and durable clinical response. Here, we will review the immunomodulatory effects of chemotherapy, targeted therapy, and radiation therapy, in the setting of ICI, and their clinical implications in reshaping modern cancer immunotherapy.

Brief Report: Cancer Immunotherapy in Patients With Preexisting Rheumatic Disease: The Mayo Clinic Experience.

OBJECTIVE: To determine the risk of rheumatic disease flare and adverse effects in patients with preexisting rheumatic disease who were receiving immune checkpoint inhibitor (ICI) therapy. METHODS: A retrospective medical record review was performed to identify all patients who received ICI therapy at Mayo Clinic in Rochester, Minnesota between 2011 and 2016 (~700 patients). Those with a preexisting rheumatic disease were identified using specific diagnostic codes. RESULTS: Sixteen patients were identified (81% female, median age 68.5 years). The most common rheumatic diseases were rheumatoid arthritis (n = 5), polymyalgia rheumatica (n = 5), Sjögren's syndrome (n = 2), and systemic lupus erythematosus (n = 2). Seven patients were receiving immunosuppressive therapy or glucocorticoids for their rheumatic disease at the time of initiation of the ICI. The primary malignancies were melanoma (n = 10), pulmonary (n = 4), or hematologic (n = 2). In most cases, ICIs were offered only after failure of several other therapies. Immune-related adverse effects (IRAEs) occurred in 6 patients, and all were treated successfully with glucocorticoids and discontinuation of the ICI therapy. There were no significant differences in time from cancer diagnosis to immunotherapy, duration of immunotherapy, age, or sex between the patients with and those without IRAEs. CONCLUSION: To our knowledge, this represents the largest single-center cohort of patients with rheumatic diseases who were exposed to modern cancer immunotherapy. Only a minority of these patients experienced a flare of their preexisting rheumatic disease or any other IRAE.

Neurological Complications Associated With Anti-Programmed Death 1 (PD-1) Antibodies.

Importance: Neurological complications are an increasingly recognized consequence of the use of anti-programmed death 1 (PD-1) antibodies in the treatment of solid-organ tumors, with an estimated frequency of 4.2%. To date, the clinical spectrum and optimum treatment approach are not established. Objective: To investigate the frequency, clinical spectrum, and optimum treatment approach to neurological complications associated with anti-PD-1 therapy. Design, Setting, and Participants: This single-center, retrospective cohort study was conducted from either September or December 2014 (the approval dates of the study drugs by the US Food and Drug Administration) to May 19, 2016. All patients receiving anti-PD-1 monoclonal antibodies were identified using the Mayo Cancer Pharmacy Database. Patients with development of neurological symptoms within 12 months of anti-PD-1 therapy were included. Patients with neurological complications directly attributable to metastatic disease or other concurrent cancer-related treatments were excluded. Main Outcomes and Measures: Clinical and pathological characteristics, time to development of neurological symptoms, and modified Rankin Scale (mRS) score. Results: Among 347 patients treated with anti-PD1 monoclonal antibodies (pembrolizumab or nivolumab), 10 (2.9%) developed subacute onset of neurological complications. Seven patients were receiving pembrolizumab, and 3 patients were receiving nivolumab. The patients included 8 men and 2 women. Their median age was 71 years (age range, 31-78 years). Neurological complications occurred after a median of 5.5 (range, 1-20) cycles of anti-PD-1 inhibitors. Complications included myopathy (n = 2), varied neuropathies (n = 4), cerebellar ataxia (n = 1), autoimmune retinopathy (n = 1), bilateral internuclear ophthalmoplegia (n = 1), and headache (n = 1). Peripheral neuropathies included axonal and demyelinating polyradiculoneuropathies (n = 2), length-dependent neuropathies (n = 1), and asymmetric vasculitic neuropathy (n = 1). The time to maximum symptom severity varied from 1 day to more than 3 months. The median mRS score was 2.5 (range, 1-5), indicating mild to moderate disability. Five patients experienced other systemic immune-mediated complications, including hypothyroidism (n = 3), colitis (n = 2), and hepatitis (n = 1). Treatment with anti-PD-1 antibodies was discontinued in 7 patients. Treatment included corticosteroids (n = 7), intravenous immunoglobulin (n = 3), and plasma exchange (n = 1). Nine patients improved, with a median mRS score of 2 (range, 0-6). One patient with severe necrotizing myopathy died. Conclusions and Relevance: Neurological adverse events associated with anti-PD-1 therapy have a diverse phenotype, with more frequent neuromuscular complications. Although rare, they will likely be encountered with increasing frequency as anti-PD-1 therapy expands to other cancers. The time of onset is unpredictable, and evolution may be rapid and life-threatening. Prompt recognition and discontinuation of anti-PD-1 therapy is recommended. In some cases, immune rescue treatment may be required.

Molecular Modeling and Functional Analysis of Exome Sequencing-Derived Variants of Unknown Significance Identify a Novel, Constitutively Active FGFR2 Mutant in Cholangiocarcinoma.

PURPOSE: Genomic testing has increased the quantity of information available to oncologists. Unfortunately, many identified sequence alterations are variants of unknown significance (VUSs), which thus limit the clinician's ability to use these findings to inform treatment. We applied a combination of in silico prediction and molecular modeling tools and laboratory techniques to rapidly define actionable VUSs. MATERIALS AND METHODS: Exome sequencing was conducted on 308 tumors from various origins. Most single nucleotide alterations within gene coding regions were VUSs. These VUSs were filtered to identify a subset of therapeutically targetable genes that were predicted with in silico tools to be altered in function by their variant sequence. A subset of receptor tyrosine kinase VUSs was characterized by laboratory comparison of each VUS versus its wild-type counterpart in terms of expression and signaling activity. RESULTS: The study identified 4,327 point mutations of which 3,833 were VUSs. Filtering for mutations in genes that were therapeutically targetable and predicted to affect protein function reduced these to 522VUSs of interest, including a large number of kinases. Ten receptortyrosine kinase VUSs were selected to explore in the laboratory. Of these, seven were found to be functionally altered. Three VUSs (FGFR2 F276C, FGFR4 R78H, and KDR G539R) showed increased basal or ligand-stimulated ERK phosphorylation compared with their wild-type counterparts, which suggests that they support transformation. Treatment of a patient who carried FGFR2 F276C with an FGFR inhibitor resulted in significant and sustained tumor response with clinical benefit. CONCLUSION: The findings demonstrate the feasibility of rapid identification of the biologic relevance of somatic mutations, which thus advances clinicians' ability to make informed treatment decisions.

Pharmacovigilance during ibrutinib therapy for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) in routine clinical practice.

Due to Cytochrome P450 3A (CYP3A) metabolism, clinical trials of ibrutinib-treated chronic lymphocytic leukemia (CLL) patients prohibited concurrent medications metabolized by CYP3A. We evaluated concomitant medication use in 118 ibrutinib-treated CLL patients outside the context of clinical trials. Seventy-five (64%) patients were on medications that could increase ibrutinib toxicity and 4 (3%) were on drugs that could decrease ibrutinib efficacy. Nineteen (16%) patients were on concomitant CYP3A inhibitors (11 moderate, 8 strong), and 4 (3%) were on CYP3A inducers (two patients were on both CYP3A inhibitors and inducers). Although the ibrutinib starting dose was changed in 18 patients on CYP3A interacting medications, no difference in 18-month progression-free survival or rate of ibrutinib discontinuation was observed in patients who were not. In routine clinical practice, 2 of 3 CLL patients commencing ibrutinib are on a concomitant medication with potential to influence ibrutinib metabolism. Formal medication review by a pharmacist should be considered in all patients initiating ibrutinib.