Breastfeeding is important in childhood development, and medications are often necessary for lactating individuals, yet information on the potential risk of infant drug exposure through human milk is limited. Establishing a lactation modeling framework can advance our understanding of this topic and potentiate clinical decision making. We expanded the modeling framework previously developed for sotalol using pregabalin as a second prototypical probe compound with similar absorption, distribution, metabolism, and elimination (ADME) properties. Adult oral models were developed in PK-Sim® and used to build a lactation model in MoBi® to simulate drug transfer into human milk. The adult model was applied to breastfeeding pediatrics (ages 1 to 23 months) and subsequently integrated with the lactation model to simulate infant drug exposure according to age, size, and breastfeeding frequency. Physiologically based pharmacokinetic (PBPK) model simulations captured the data used for verification both in adults and pediatrics. Lactation simulations captured observed milk and plasma data corresponding to doses of 150 mg administered twice daily to lactating individuals, and estimated a relative infant dose (RID) of approximately 7% of the maternal dose. The infant drug exposure simulations showed peak plasma concentrations of 0.44 μg/mL occurring within the first 2 weeks of life, followed by gradual decline with age after week four. The modeling framework performs well for this second prototypical drug and warrants expansion to other drugs for further validation. PBPK modeling and simulation approaches together with clinical lactation data could ultimately help inform infant drug exposure risk assessments to guide clinical decision making.

Maternal medication use may expose the developing fetus through placental transfer or the infant through lactational transfer. Because pregnant and lactating individuals have been historically excluded from early drug development trials, there is often limited to no human data available to inform pharmacokinetics (PK) and safety in these populations at the time of drug approval. We describe the known mechanisms of placental or lactational transfer of IgG-based therapeutic proteins and use clinical examples to highlight the potential for fetal or infant exposure during pregnancy and lactation. Placental transfer of IgG-based therapeutic proteins may result in systemic exposure to the developing fetus. A lactational transfer may be associated with local gastrointestinal (GI) exposure in the infant and may also result in systemic exposure, although data are very limited as proteins have shown instability in the GI tract. Understanding of PK and pharmacodynamic (PD) effects of IgG-based therapeutic proteins in infants exposed in utero as well as the potential exposure through human milk and its clinical implications is critical for developing treatment strategies for pregnant or lactating individuals. We share the current knowledge gaps and considerations for future evaluations to inform PK, PD, and the safety of IgG-based therapeutic proteins for safe use during pregnancy and lactation. With the increasing use of IgG-based therapeutic proteins in treating chronic diseases during pregnancy and lactation, there is a need to improve the quantity and quality of data to inform the safe use in pregnant and lactating individuals.

Organizations such as the American Academy of Pediatrics,WorldHealth Organization, and Centers for Disease Control and Prevention recommend breastfeeding because of multiple health benefits and early motherinfant bonding. However, it is reported that lactating individuals take an average of 4 medications during the lactation period.1 Information on drug presence in human milk and resulting exposure to the breastfed infant is necessary to assess the potential risk to the breastfed infant and critical to the lactating individual’s benefit-risk decision whether to use the medication. Unfortunately, data collected from clinical lactation studies may be limited, and evaluating all possible drug combinations would be challenging, if not impossible, to study experimentally. New opportunities in clinical pharmacology are arising in the translation of available concentration (exposure) data to further inform risk to breastfeeding infants.

Many of the conditions for the safe and effective use of new molecular entities (NMEs) are understood at the time of initial drug approval. However, some remaining knowledge gaps can be addressed after drug approval through postmarketing requirements (PMRs) or commitments (PMCs) established by the US Food and Drug Administration (FDA). Our objective was to conduct an assessment of clinical pharmacology-related PMRs and PMCs established at the time of approval and evaluate the impact of fulfilled PMRs and PMCs on prescription information (PI). This analysis included clinical pharmacology-related PMRs and PMCs established for NMEs approved between 2009 and 2020. Of the 1171 PMRs and PMCs, over one-third were clinical pharmacology-related. Of these, 46% were to evaluate drug interactions, 16% were to evaluate drug dosing in patients with hepatic impairment, and 10% were related to dose. The majority (57%) of PMRs and PMCs were fulfilled at the time of analysis, with a median time to fulfillment of approximately 2.3 years. The majority (94%) of the fulfilled PMRs and PMCs, either with or without a PI revision, resulted in new or modified instructions for use or supported existing instructions for use. This is the first time that clinical pharmacology-related PMRs and PMCs have been catalogued and analyzed to understand their impact on PI. An understanding of the knowledge gaps that exist at the time of drug approval could inform the most effective and efficient methods for evidence generation prior to and after new drug approval.

As pregnant individuals have traditionally been excluded from clinical trials, there is a gap in knowledge at the time of drug approval regarding safety, efficacy, and appropriate dosing for most prescription medications used during pregnancy. Physiologic changes in pregnancy can result in changes in pharmacokinetics that can impact safety or efficacy. This highlights the need to foster further research and collection of pharmacokinetic data in pregnancy to ensure appropriate drug dosing in pregnant individuals. Therefore, the US Food and Drug Administration and the University of Maryland Center of Excellence in Regulatory Science and Innovation hosted a workshop on May 16 and 17, 2022, titled "Pharmacokinetic Evaluation in Pregnancy." This is a summary of the workshop proceedings.

Characterization of infant drug exposure through human milk is important and underexplored. Because infant plasma concentrations are not frequently collected in clinical lactation studies, modeling and simulation approaches can integrate physiology, available milk concentrations, and pediatric data to inform exposure in breastfeeding infants. A physiologically based pharmacokinetic model was built for sotalol, a renally eliminated drug, to simulate infant drug exposure from human milk. Intravenous and oral adult models were built, optimized, and scaled to an oral pediatric model for a breastfeeding‐relevant age group (<2 years). Model simulations captured the data that were put aside for verification. The resulting pediatric model was applied to predict the impacts of sex, infant body size, breastfeeding frequency, age, and maternal dose (240 and 433 mg) on drug exposure during breastfeeding. Simulations suggest a minimal effect of sex or frequency on total sotalol exposure. Infants in the 90th percentile in height and weight have predicted exposures ≈20% higher than infants of the same age in the 10th percentile due to increased milk intake. The simulated infant exposures increase throughout the first 2 weeks of life and are maintained at the highest concentrations in weeks 2‐4, with a consistent decrease observed as infants age. Simulations suggest that breastfeeding infants will have plasma concentrations in the lower range observed in infants administered sotalol. With further validation on additional drugs, physiologically based pharmacokinetic modeling approaches could use lactation data to a greater extent and provide comprehensive information to support decisions regarding medication use during breastfeeding.

All authors declared no competing interests for this work. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

The Research Acceleration for Cure and Equity (RACE) for Children Act requires sponsors to submit a Pediatric Study Plan (PSP) with a proposed pediatric investigation of new molecularly targeted drugs and biologics that are intended for treatment of adult cancers, and whose target is relevant to pediatric cancer or provide a justification for a plan to request a deferral or waiver of the required investigation. A landscape analysis was performed to identify trends in information gaps associated with a sponsor's first initial PSP (iPSP) submission for oncologic new molecular entities received in 2021. Comments sent to sponsors by the US Food and Drug Administration (FDA) during the review process of each evaluated iPSP were categorized using nine flags relating to different portions of the PSP. For iPSPs that included a plan for a full waiver request, the most common information gap was inadequate justification based on molecular target relevance. All other sponsor proposed plans (deferral and/or partial waiver or investigation) were found to have information gaps related to clinical study features, clinical pharmacology, and/or missing clinical or nonclinical data. This landscape analysis of iPSPs shows the trends in comments that often occur during initial review and may help to provide sponsors with more direction for preparing an adequate iPSP to fulfill statutory requirements aimed at ensuring pediatric patients are considered in the development of new molecularly targeted drugs.

Basket trials pool histologic indications sharing molecular pathophysiology, improving development efficiency. Currently, basket trials have been confirmatory only for exceptional therapies. Our previous randomized basket design may be generally suitable in the resource-intensive confirmatory phase, maintains high power even with modest effect sizes, and provides nearly k-fold increased efficiency for k indications, but controls false positives for the pooled result only. Since family wise error rate by indications may sometimes be required, we now simulate a variant of this basket design controlling family wise error rate at 0.025k, the total family wise error rate of k separate randomized trials. We simulated this modified design under numerous scenarios varying design parameters. Only designs controlling family wise error rate and minimizing estimation bias were allowable. Optimal performance results when k = 3, 4. We report efficiency (expected # true positives/expected sample size) relative to k parallel studies, at 90% power ("uncorrected") or at the power achieved in the basket trial ("corrected," because conventional designs could also increase efficiency by sacrificing power). Efficiency and power (percentage active indications identified) improve with a higher percentage of initial indications active. Up to 92% uncorrected and 38% corrected efficiency improvement is possible. Even under family wise error rate control, randomized confirmatory basket trials substantially improve development efficiency. Initial indication selection is critical.

Changes that accompany older age can alter the pharmacokinetics (PK), pharmacodynamics (PD), and likelihood of adverse effects (AEs) of a drug. However, older adults, especially the oldest or those with multiple chronic health conditions, polypharmacy, or frailty, are often under-represented in clinical trials of new drugs. Deficits in the current conduct of clinical evaluation of drugs for older adults and potential steps to fill those knowledge gaps are presented in this communication. The most important step is to increase clinical trial enrollment of older adults who are representative of the target treatment population. Unnecessary eligibility criteria should be eliminated. Physical and financial barriers to participation should be removed. Incentives could be created for inclusion of older adults. Enrollment goals should be established based on intended treatment indications, prevalence of the condition, and feasibility. Relevant clinical pharmacology data need to be obtained early enough to guide dosing and reduce risk for participation of older adults. Relevant PK and PD data as well as patient-centered outcomes should be measured during trials. Trial data should be analyzed for differences in PK, PD, effectiveness, and safety arising from differences in age or from the presence of conditions common in older adults. Postmarket evaluations with real-world evidence and drug labeling updates throughout the product lifecycle reflecting new knowledge are also needed. A comprehensive plan is needed to ensure adequate evaluation of the safety and effectiveness of drugs in older adults.

A key goal in drug development is optimized dosing for patients. Interactions between drug developers and regulatory scientists throughout development are important for the optimization of dosing and serve as a forum to discuss approaches for optimal dosing, such as precision or individualized dosing. To date, there has not been a systematic assessment of the advice provided by the US Food and Drug Administration (FDA) to drug developers from an individualized dosing perspective. Here, we reviewed FDA recommendations on dose selection for efficacy trials at end‐of‐phase meetings between the FDA and drug developers for 76 new molecular entities approved between 2013 and 2017 that are considered amenable for an individualized dosing method, response‐guided titration. Forty FDA dosing recommendations were identified as specific to dose selection and design of the respective efficacy trials and subsequently: (i) characterized based on if they were supportive of individualized dosing and (ii) compared with dosing regimens used in efficacy trials and labeling at approval to evaluate if FDA recommendations were implemented. Of these 40 recommendations for efficacy trials, 35 (88%) were considered supportive of individualized dosing. Eighteen of these 40 recommendations (45%) were incorporated into efficacy trials and 11 (28%) were incorporated into labeling. This research suggests that early FDA‐sponsor interactions can support the study of doses in efficacy trials that may lead to individualized dosing strategies in labeling.

Background Communicating the clinical impact of immunogenicity in labeling is important for safe and effective use of certain prescription products. Current U.S. Food and Drug Administration (FDA) guidance does not provide comprehensive recommendations on the communication of clinical impact of immunogenicity in labeling. To understand current labeling practice, we evaluated the immunogenicity data and clinical impact information in labeling of selected prescription products. Methods We created a database of 71 therapeutic biologics and drug products that had an immunogenicity assessment initially approved by FDA’s Center for Drug Evaluation and Research between 2014 and 2018. We analyzed the content and format of immunogenicity information (e.g., anti-drug antibody incidence and/or immunogenicity impact on pharmacokinetics (PK), safety, and/or effectiveness) in the most recent approved labeling. Results Immunogenicity information was in the ADVERSE REACTIONS section in 98% of the reviewed labeling. Immunogenicity impact on PK was reported in 52% of the labeling, typically within the ADVERSE REACTIONS section, but supportive PK data were often not included in the CLINICAL PHARMACOLOGY section. Additionally, the immunogenicity impact on safety and/or effectiveness was communicated in 70% of the labeling, with 23% clearly communicating the effect as clinically meaningful, and 10% providing actionable recommendations. Conclusions Most of the reviewed labeling includes immunogenicity information within the ADVERSE REACTIONS section. However, there is inconsistency in providing supportive PK data and high variability in reporting immunogenicity impact on safety and effectiveness in labeling. Development of a communication framework that allows for consistent inclusion of immunogenicity impact statements in labeling could improve how immunogenicity risk is conveyed in prescription drug labeling.

Insufficient availability of data to evaluate immunogenicity incidence or clinical impact during regulatory review could require further evaluation postapproval. Through a keyword search of all postmarketing requirements and commitments (PMRs/PMCs) associated with products with their original US Food and Drug Administration (FDA) approvals between 2009 and 2018, we identified products that had PMRs/PMCs established to address concerns or uncertainty related to immunogenicity. Of the 113 relevant products, 50% had an immunogenicity‐related PMR/PMC; of these, 68% were related to developing immunogenicity assays and 48% requested an assessment of clinical impact. Fifty‐five percent of the products with a fulfilled PMR/PMC had a change in the immunogenicity information in their labeling immediately following fulfillment. This work highlights that there are often unknowns associated with immunogenicity incidence and/or impact at the time of approval. Earlier regulatory discussions on immunogenicity assessments in premarket development could improve the understanding and communication of the risk/benefit profile and reduce the need for some immunogenicity PMRs/PMCs.

BACKGROUND:Confirmatory phase III trials aim to provide decisive evidence about a medical product's safety and efficacy. Although these trials are planned and conducted based on accumulated knowledge, they are not without risk or uncertainty. A trial prematurely concluding contributes to great loss in both financial and human research resources.METHODS:We categorized and evaluated trials concluded prematurely after recruitment had begun, as registered in Clinical Trials.gov between January 2013 and August 2017.RESULTS:We found 9828 registered interventional phase III trials; of those, 320 were concluded prematurely. Many clinical trials were concluded prematurely for reasons related to reducing participant risk, such as interim stopping for safety, efficacy, or futility. Yet, 70% trials were halted for other reasons, such as insufficient recruitment (the most often cited reason) or unspecified business decisions. Of all prematurely concluded trials, 102 trials evaluated 72 different novel therapeutics; in 66.7% of these trials, the clinical development program was stopped entirely. Most of the prematurely concluded trials (78%) had not provided results to ClinicalTrials.gov at the time of this analysis.CONCLUSIONS:Evaluation of the factors that influence premature conclusion could inform solutions for improving research participation and help ensure trial completion. Registering and reporting results acknowledges the voluntary contribution and consent expectations of research participants.

Electronic health records (EHRs) have changed how medical information is captured, and they have the potential to be a rich source of information to improve drug development and clinical care. Accelerated in USA by the Health Information Technology for Economic and Clinical Health (HITECH) Act of 2009, the majority of US healthcare providers use EHRs in practice. Although the Office of the National Coordinator for Health Information Technology within the US Department of Health and Human Services (HHS) set forth standards with the intention to create EHRs that could be used to advance healthcare processes,1–3 there is still much room for improvement to adequately capture patient-provided and clinically relevant data needed to support learning healthcare systems that adapt as new clinical knowledge is gained.4 Currently, stakeholders within regulatory agencies, professional organisations, the pharmaceutical industry and payer groups are exploring how data collected during the delivery of routine healthcare or data related to a patient’s health status, defined as real-world data (RWD), can be analysed to generate clinical evidence, known as real-world evidence, to enhance healthcare and medical product development.5 6 This shared interest has led workshops exploring the incentives that are important to each stakeholder group.6–8 Multistakeholder collaborations have formed to empower RWD projects, such as the work being done by the Food and Drug Administration (FDA) Oncology Center of Excellence, healthcare technology company, Flatiron Health, and the American Society of Clinical Oncology CancerLinQ, which will focus on determining the characteristics and clinical outcomes associated with patients with advanced cancer using RWD collected from the EHR.9 The RWD effort is supported with legislative action. The 21st Century Cures Act requires the US FDA to explore and produce guidance on how RWD can inform decision-making, including label expansion for approved products and postmarket commitments.10 Investigating RWD applications is also a …

The clinical success of ibrutinib validates Bruton tyrosine kinase (BTK) inhibition as an effective strategy for treating hematologic malignancies, including chronic lymphocytic leukemia (CLL). Despite ibrutinib's ability to produce durable remissions in patients, acquired resistance can develop, mostly commonly by mutation of C481 of BTK in the ibrutinib binding site. Here, we characterize a novel BTK inhibitor, GDC-0853, to evaluate its preclinical efficacy in ibrutinib-naive and ibrutinib-resistant CLL. GDC-0853 is unique among reported BTK inhibitors in that it does not rely upon covalent reaction with C481 to stabilize its occupancy within BTK's adenosine triphosphate binding site. As with ibrutinib, GDC-0853 potently reduces B-cell receptor signaling, viability, NF-κB-dependent transcription, activation, and migration in treatment naïve CLL cells. We found that GDC-0853 also inhibits the most commonly reported ibrutinib-resistant BTK mutant (C481S) both in a biochemical enzyme activity assay and in a stably transfected 293T cell line and maintains cytotoxicity against patient CLL cells harboring C481S BTK mutations. Additionally, GDC-0853 does not inhibit endothelial growth factor receptor or ITK, 2 alternative targets of ibrutinib that are likely responsible for some adverse events and may reduce the efficacy of ibrutinib-antibody combinations, respectively. Our results using GDC-0853 indicate that noncovalent, selective BTK inhibition may be effective in CLL either as monotherapy or in combination with therapeutic antibodies, especially among the emerging population of patients with acquired resistance to ibrutinib therapy.

The increasing cost of clinical drug development has led innovators to reassess the sources of data that could be useful to inform regulatory decision-making. Real-world data (RWD) can be collected from diverse sources and represents patients' healthcare experience during routine clinical care. The refinement and analysis of data collected from RWD sources can produce real-world evidence (RWE). Currently, stakeholders are evaluating ways to apply RWD sources in current medical product development programs, including incentives for use and projects to explore novel applications. Until now, RWD has been primarily used in the post-market setting for pharmacovigilance. Moving forward, RWD could be applied in pre-market development as a suitable source for informing innovative clinical trial designs, such as platform, basket, and umbrella trials. RWD sources, such as electronic health records, claims databases, and registries could inform the selection of indications, study sites, and clinical endpoints. They may also be useful in estimating effect sizes, performing trial simulation, and providing a historical control. To collect meaningful evidence from RWD sources, bias and confounding variables must be assessed. The focus for the future will be developing novel methods for RWD collection, extraction, and analysis to modernize clinical drug development.

Abstract Introduction: In order to address the issue of acquired resistance to ibrutinib, we sought to characterize the Bruton agammaglobulinemia tyrosine kinase (BTK) inhibitor SNS-062 in preclinical models of chronic lymphocytic leukemia (CLL). Methods: Primary CLL B cells were isolated from the whole blood of consented patients by ficoll density centrifugation and Rosette-Sep negative selection. Annexin V and propidium iodide flow cytometry was used to measure patient CLL cell viability and 7-AAD was used to measure viability in stromal co-culture. CD40 and CD86 expression was evaluated via flow cytometry subsequent to sustained 3.2uM CpG stimulation. BCR signaling in primary CLL cells was investigated by immunoblot following 1 hour treatment and following 1 hour or 24 hours of incubation with SNS-062 in XLA cell lines. ITK inhibition was investigated via immunoblot after stimulation with anti-CD3 and anti-CD28 and incubation with SNS-062 for 1 hour. SNS-062 was used at a concentration of 1uM in preclinical studies unless otherwise noted. Measurement of kinase activity in human recombinant WT BTK or C481S BTK was performed in a FRET kinase assay. Results: Immunoblots of BTK and ERK phosphorylation of XLA cells transfected with WT or C481S BTK demonstrated that SNS-062 inhibition is comparable to that of ibrutinib in WT BTK and greater than that of ibrutinib in C481S BTK. Using a recombinant kinase assay, we found the IC50 of SNS-062 against WT BTK to be 4.6nM and C481S BTK to be 1.1nM, suggesting that SNS-062 retains activity against the mutated BTK variant. Additionally, SNS-062 was found to be six times more potent than ibrutinib and greater than 640 times more potent than acalabrutinib against C481S BTK. SNS-062 demonstrates dose-dependent inhibition of BTK in primary patient CLL cells comparable to ibrutinib via immunoblot for BTK phosphorylation. The viability of primary patient cells treated with 0.1uM, 1.0uM, and 10.0uM SNS-062 for 48 hours was measured to be 96.7%, 96.1%, and 88.1%, respectively, that of the untreated condition. At 48 hours, SNS-062 decreased viability of primary CLL cells in the presence of HS5 stromal protection by 5.5%. SNS-062 was found to decrease CpG induced CD40 and CD86 expression by 8.7% and 15.7%, respectively. Using an in vitro kinase assay, SNS-062 inhibited ITK with an IC50 value of 24nM. An immunoblot of anti-CD3/CD28 stimulated Jurkat cells revealed that SNS-062 decreased the phosphorylation of ERK, implying inhibition of ITK. Conclusion: Unlike ibrutinib, SNS-062 inhibits BTK signaling in the presence of the C481S mutation and may address acquired resistance to covalent BTK inhibitors. SNS-062 decreases B cell activation markers, viability, and stromal cell protection in primary patient CLL cells and was shown to inhibit ITK, suggesting support of T cell mediated antitumor activities. These data support further investigation of this molecule and advancement into clinical trials. Citation Format: Catherine A. Fabian, Sean D. Reiff, Daphne Guinn, Linda Neuman, Judith A. Fox, Wendy Wilson, John C. Byrd, Jennifer A. Woyach, Amy J. Johnson. SNS-062 demonstrates efficacy in chronic lymphocytic leukemia in vitro and inhibits C481S mutated Bruton tyrosine kinase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1207. doi:10.1158/1538-7445.AM2017-1207

The introduction of miR profiling of chronic lymphocytic leukemia (CLL) patients with different cytogenetic profiles and responses to therapy has allowed incorporation of important miR‐mRNA interactions into the understanding of disease biology. In this study, we performed miR expression analysis using NanoString nCounter to discover differentially regulated miRs after therapy with the Bruton tyrosine kinase inhibitor ibrutinib. Of the differentially regulated miRs in the discovery set, miR‐29c and miR‐126 were confirmed using real‐time PCR to be upregulated in CLL patient cells with ibrutinib therapy. In the validation set, an inverse correlation was observed between miR‐126 levels and expression of its putative target p85β, an isoform of the phosphoinositide 3‐kinase p85 regulatory subunit. We found that mRNA for the host gene EGFL7, primary unprocessed miR‐126, and mature miR‐126 are all downregulated in CLL cells compared to normal B cells. Patients in later stages of disease have a greater decrease in miR‐126 expression compared to treatment‐naive patients, indicating that lower miR‐126 levels may associate with disease progression. Overexpression of miR‐126 in leukemia cell lines significantly downregulates p85β expression and decreases activation of prosurvival mitogen‐activated protein kinase (MAPK) signaling. These results implicate miR‐126 in the pathology of CLL.

Purpose Therapeutic targeting of Bruton tyrosine kinase (BTK) with ibrutinib in chronic lymphocytic leukemia has led to a paradigm shift in therapy, and relapse has been uncommon with current follow-up. Acquired mutations in BTK and PLCG2 can cause relapse, but data regarding the prevalence and natural history of these mutations are limited. Patients and Methods Patients accrued to four sequential studies of ibrutinib were included in these analyses. Deep sequencing for BTK and PLCG2 was performed retrospectively on patients who experienced relapse and prospectively on a screening population. Results With a median follow-up time of 3.4 years, the estimated cumulative incidence of progression at 4 years is 19% (95% CI, 14% to 24%). Baseline karyotypic complexity, presence of del(17)(p13.1), and age less than 65 years were risk factors for progression. Among patients who experienced relapse, acquired mutations of BTK or PLCG2 were found in 85% (95% CI, 71% to 94%), and these mutations were detected an estimated median of 9.3 months (95% CI, 7.6 to 11.7 months) before relapse. Of a group of 112 patients examined prospectively, eight patients have experienced relapse, and all of these patients had acquired resistance mutations before relapse. A resistance mutation was detected in an additional eight patients who have not yet met criteria for clinical relapse. Conclusion Relapse of chronic lymphocytic leukemia after ibrutinib is an issue of increasing clinical significance. We show that mutations in BTK and PLCG2 appear early and have the potential to be used as a biomarker for future relapse, suggesting an opportunity for intervention.