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Hair and Nail Changes During Long-term Therapy With Ibrutinib for Chronic Lymphocytic Leukemia

Hair and Nail Changes During Long-term Therapy With Ibrutinib for Chronic Lymphocytic Leukemia Abstract Importance Ibrutinib, a Bruton tyrosine kinase inhibitor, is a new targeted agent approved by the US Food and Drug Administration for the treatment of chronic lymphocytic leukemia (CLL), mantle cell lymphoma, and Waldenström macroglobulinemia. Ibrutinib is overall well tolerated but long-term treatment is required until disease progression or intolerable toxic effects occur. Little is known regarding its cutaneous adverse effects. Objective To describe the hair and nail manifestations associated with the long-term use of ibrutinib for the treatment of CLL. Design, Setting, and Participants Prospective study of 66 patients with CLL enrolled in a single-arm phase 2 clinical trial of ibrutinib for CLL between March 2014 and October 2015 at the National Institutes of Health. Main Outcomes and Measures The primary outcome, nail and hair changes associated with ibrutinib therapy, was assessed by an 11-question survey. In addition, the severity of nail changes was determined from a 0 to 3 rating scale for both onychoschizia and onychorrhexis. Results Among 66 patients (43 men and 23 women with ages ranging from 55 to 85 years), 44 (67%) reported brittle fingernails at a median of 6.5 (95% CI, 6-12) months after starting ibrutinib therapy. Fifteen patients (23%) developed brittle toenails after a median of 9 (95% CI, 6-15) months of ibrutinib therapy. Textural hair changes were reported in 17 patients (26%), at a median of 9 (95% CI, 6-12) months of ibrutinib treatment. Conclusions and relevance Hair and nail abnormalities are commonly associated with ibrutinib and appear several months after initiating therapy. Ibrutinib inhibits Bruton tyrosine kinase by covalently binding to cysteine 481. Whether ibrutinib affects the hair and nails by binding and altering cysteine-rich proteins of hair and nails or by means of another mechanism remains unknown. Trial Registration clinicaltrials.gov Identifier: NCT01500733 The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is an orally bioavailable molecule that was approved by the US Food and Drug Administration for mantle cell lymphoma in 2013 (560 mg once daily) and for chronic lymphocytic leukemia (CLL) in 2014 (420 mg once daily).1-4 Ibrutinib inhibits BTK, a key kinase for B-cell signaling, by covalently binding to cysteine 481, resulting in decreased proliferation and survival of malignant B cells.5 A limited number of kinases possess a homologous cysteine residue, making ibrutinib highly selective for BTK.6 Adverse events include fatigue, diarrhea, upper respiratory tract infections, skin rash,7 and ecchymosis.2-4 Ibrutinib is administered until disease progression or intolerable and/or severe toxic effects occur; however, as with other tyrosine kinase inhibitors, cutaneous toxicity represents a potential barrier to long-term tolerability.8 Ibrutinib is generally well tolerated, but we noted that patients frequently described nail and hair changes with long-term use.9 In this article, we provide specific details on hair and nail manifestations and introduce a potential therapeutic intervention. Box Section Ref ID Key Points Question What is the incidence of brittle nails and hair changes in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib? Findings In this observational study of 66 patients with CLL treated with ibrutinib, 67% developed brittle fingernails, 26% developed hair changes, and 23% developed brittle toenails. Most changes were reported after ibrutinib treatment of 6 months or longer. Meaning Ibrutinib, a novel treatment for CLL, is associated with long-term hair and nail changes, possibly due to binding to cysteine residues in hair and nails. Methods Eighty-six patients with CLL were enrolled to treatment with ibrutinib at the National Institutes of Health (NCT01500733). All patients provided written informed consent. Two patients died and 2 patients withdrew from the study prior to data collection. Of the 82 patients remaining, 66 were available for detailed review of hair and nail abnormalities (March 2014 through October 2015). Fifteen patients withdrew from the study and in 1 patient the survey was not completed. This study was approved by the institutional review board of the National Heart, Lung, and Blood Institute, National Institutes of Health. Study results, in part, have been reported previously.9 A survey was completed by a member of the study team at the time of each follow-up visit. The survey was composed of 11 questions: (1) time of onset of nail changes after ibrutinib treatment, (2) onychoschizia and onychorrhexis of fingernails, (3) severity of fingernail changes, (4) brittle toenails, (5) hair changes, (6) other skin or mucosal involvement, (7) pain, (8) bleeding, (9) treatment of hair and nail changes, (10) progression of hair and nail abnormalities over the course of therapy with ibrutinib, and (11) impact on quality of life. The degree of severity was based on the grading score by Van de Kerkhof et al.10 Onychoschizia was defined as lamellar splitting and graded from 0 to 3: 0, none; 1, mild: splitting not involving the whole free edge of the nail plate; 2, moderate: splitting involving the whole free edge of the nail plate; 3, severe: splitting involving the whole free edge of the nail plate and covering 1/3 of the nail plate. Onychorrhexis was defined as longitudinal ridging and also graded from 0 to 3: 0, none; 1, mild: few superficial longitudinal ridges and grooves; 2, moderate: few deep ridges and grooves; and 3, severe: more than 70% of the nail plate showing deep ridges and corresponding grooves. Results The age range of the 66 study participants was 55 to 85 years old, with 43 men and 23 women. Forty-four (67%) participants described new-onset fingernail changes after a median of 6.5 months (95% CI, 6-12 months). Fifteen (23%) developed brittle toenails after a median of 9 months (95% CI, 6-15 months) of ibrutinib therapy (Table). Nail changes manifested as mild to moderate onychoschizia and onychorrhexis, corresponding to grade 1 and 2 Common Terminology Criteria for Adverse Events, version 3.0, adverse events, respectively (Figure 1, Figure 2).10 Seventeen (26%) patients developed hair changes at a median of 9 months (95% CI, 6-12 months) after starting ibrutinib therapy. Most hair changes manifested as straightening and softening of the hair, although 4 of 17 patients reported increased curliness of hair. Among 5 patients who used oral biotin at 2.5 mg daily, 3 reported substantial improvement in their nails. Twenty-four (55%) of the 44 affected individuals reported a negative impact of hair and nail changes on their quality of life. Discussion Nail brittleness affects approximately 20% of the population, most frequently older adults and women, and is associated with onychoschizia, onychorrhexis, or both.10 The pathogenesis of brittle nails is multifactorial, and may result from disruption of intercellular adhesion between corneocytes, as well as factors affecting the nail matrix.10 Nail texture is influenced by corneocytes, keratin filaments, keratin-associated fibrous proteins, water content, lipid bilayers, and the nail matrix.10,11 The integrity of keratin-associated fibrous proteins is maintained by disulfide bonds between cysteine residues, resulting in the formation of the sulfur-containing amino acid cystine.11 Ibrutinib covalently binds to the cysteine residue at the active site of BTK.1 Because cysteines are critical for nail hardness, ibrutinib-induced disruption of the disulfide bonds between cysteine residues could be responsible for increased nail brittleness. Fingernails require 3 to 6 months to complete a growth cycle. This time interval is consistent with the reported delay of 6.5 months between initiation of ibrutinib therapy and the appearance of nail changes. Toenail abnormalities were reported a median of 9 months after initiation of therapy, consistent with the slower growth rate of the toenail plate (12-18 months). We consider the nail abnormalities to be related to ibrutinib therapy because these changes arose during ibrutinib use and were not preexisting, such changes are not part of disease-related complications or associated with standard chemotherapy, and because the timing of appearance of nail changes correlated well with the growth rate of the nail plates. Unfortunately, no pretreatment photographs were available for comparison at the time of the study. Keratinocyte-associated proteins in the hair are also rich in sulfur-containing amino acids and form disulfide bonds that contribute to hair structure and tensile strength.12 Hair permanents that contain reducing agents straighten hair through disruption of disulfide bonds.12 Reduced disulfide bonds have free thiols that can migrate and form new disulfide bonds creating more curls as seen with permanent waving agents.12 Ibrutinib disruption of hair disulfide bonds may act in a similar manner to cause alterations in hair strength or texture. Although ibrutinib demonstrates high selectivity for BTK (inhibitory concentration 50% [IC50] = 0.5 nM), it also inhibits other kinases, including human epidermal growth factor receptors 1 (EGFR, IC50 = 12 nM) and 2 (ERBB2 [formerly HER2 or HER2/neu], IC50 = 22 nM).6 Ibrutinib at 560 mg/d can reach a maximum concentration of more than 100 ng/mL in the plasma,13 which is equivalent to 227 nM. At maximum concentration, ibrutinib may inhibit other target kinases, including the EGFR. Inhibition of EGFR by tyrosine kinase inhibitors leads to well-established cutaneous adverse events, including papulopustular rash and nail and hair changes.8 However, papulopustular rash, one of the most common manifestations of EGFR inhibitor use, has not been described with ibrutinib use.9 Conclusions Concern over cosmetic appearance and nail discomfort may negatively affect quality of life in diseases affecting the nails.10 In our study, 55% of affected patients expressed concern related to nail appearance or pain. Treatment options for brittle nails include biotin supplementation and topical solutions such as hydrosoluble nail lacquer and poly-ureaurethane. In 1 study of 32 patients with brittle nails, 25% improvement in nail thickness was noted following ingestion of 2.5 mg of biotin daily for 6 to 15 months.14 In another study of 44 patients with brittle nails, 63% reported improvement after 2 months of biotin use, with reemergence of brittle nails after treatment was discontinued.11 Biotin is a cofactor for several enzymes involved in fatty acid formation and thereby may enhance the lipid content of the nail plate and improve keratinocyte binding.15 The benign nature of biotin and the absence of drug-drug interactions suggest that supplementation may be reasonable; however, further clinical study is needed to confirm efficacy in the setting of ibrutinib therapy. Back to top Article Information Accepted for Publication: January 29, 2016. Corresponding Author: Edward W. Cowen, MD, MHSc, Dermatology Branch, Center for Cancer Research, NCI, NIH10 Center Dr, Bldg 10, Bethesda, MD 20892 (cowene@mail.nih.gov). Published Online: March 16, 2016. doi:10.1001/jamadermatol.2016.0225. Author Contributions: Drs Bitar and Cowen had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Wiestner and Cowen contributed equally to this work. Study concept and design: Bitar, Farooqui, Marti, Wiestner. Acquisition, analysis, or interpretation of data: Bitar, Valdez, Saba, Soto, Bray, Wiestner, Cowen. Drafting of the manuscript: Bitar. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Bitar. Obtained funding: Wiestner. Administrative, technical, or material support: Farooqui, Bray, Wiestner. Study supervision: Farooqui, Wiestner. Conflict of Interest Disclosures: Dr Wiestner received research funding from Pharmacyclics. Dr Saba serves as consultant and a speaker for Pharmacyclics and has received honoraria from Pharmacyclics. No other disclosures are reported. Funding/Support: This study was supported in part by the Intramural Research Program of the National Institutes of Health, the National, Heart, Lung, and Blood Institute (NHLBI), and by Pharmacyclics, which provided ibrutinib, research support, and comments on the manuscript. Role of the Funder/Sponsor: Pharmacyclics reviewed the manuscript but had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, or approval of the manuscript; and decision to submit the manuscript for publication. The other funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Additional Contributions: We are indebted to the patients who participated in this trial and their families; Pharmacyclics for providing ibrutinib, research support, and comments on the manuscript; and the Intramural Research Program of the NHLBI. References 1. Wiestner A. The role of B-cell receptor inhibitors in the treatment of patients with chronic lymphocytic leukemia. Haematologica. 2015;100(12):1495-1507.PubMedGoogle ScholarCrossref 2. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32-42.PubMedGoogle ScholarCrossref 3. Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369(6):507-516.PubMedGoogle ScholarCrossref 4. Treon SP, Tripsas CK, Meid K, et al. Ibrutinib in previously treated Waldenström’s macroglobulinemia. N Engl J Med. 2015;372(15):1430-1440.PubMedGoogle ScholarCrossref 5. Herman SE, Mustafa RZ, Gyamfi JA, et al. Ibrutinib inhibits BCR and NF-κB signaling and reduces tumor proliferation in tissue-resident cells of patients with CLL. Blood. 2014;123(21):3286-3295.PubMedGoogle ScholarCrossref 6. Burger JA, Buggy JJ. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765). Leuk Lymphoma. 2013;54(11):2385-2391.PubMedGoogle ScholarCrossref 7. Mannis G, Wu D, Dea T, Mauro T, Hsu G. Ibrutinib rash in a patient with 17p del chronic lymphocytic leukemia. Am J Hematol. 2015;90(2):179.PubMedGoogle ScholarCrossref 8. Robert C, Soria JC, Spatz A, et al. Cutaneous side-effects of kinase inhibitors and blocking antibodies. Lancet Oncol. 2005;6(7):491-500.PubMedGoogle ScholarCrossref 9. Farooqui MZ, Valdez J, Martyr S, et al. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol. 2015;16(2):169-176.PubMedGoogle ScholarCrossref 10. van de Kerkhof PC, Pasch MC, Scher RK, et al. Brittle nail syndrome: a pathogenesis-based approach with a proposed grading system. J Am Acad Dermatol. 2005;53(4):644-651.PubMedGoogle ScholarCrossref 11. Cashman MW, Sloan SB. Nutrition and nail disease. Clin Dermatol. 2010;28(4):420-425.PubMedGoogle ScholarCrossref 12. de Sá Dias TC, Baby AR, Kaneko TM, Robles Velasco MV. Relaxing/straightening of Afro-ethnic hair: historical overview. J Cosmet Dermatol. 2007;6(1):2-5.PubMedGoogle ScholarCrossref 13. Advani RH, Buggy JJ, Sharman JP, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol. 2013;31(1):88-94.PubMedGoogle ScholarCrossref 14. Colombo VE, Gerber F, Bronhofer M, Floersheim GL. Treatment of brittle fingernails and onychoschizia with biotin: scanning electron microscopy. J Am Acad Dermatol. 1990;23(6, pt 1):1127-1132.PubMedGoogle ScholarCrossref 15. Iorizzo M, Pazzaglia M, M Piraccini B, Tullo S, Tosti A. Brittle nails. J Cosmet Dermatol. 2004;3(3):138-144.PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Dermatology American Medical Association

Hair and Nail Changes During Long-term Therapy With Ibrutinib for Chronic Lymphocytic Leukemia

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References (17)

Publisher
American Medical Association
Copyright
Copyright © 2016 American Medical Association. All Rights Reserved.
ISSN
2168-6068
eISSN
2168-6084
DOI
10.1001/jamadermatol.2016.0225
pmid
26982511
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Abstract

Abstract Importance Ibrutinib, a Bruton tyrosine kinase inhibitor, is a new targeted agent approved by the US Food and Drug Administration for the treatment of chronic lymphocytic leukemia (CLL), mantle cell lymphoma, and Waldenström macroglobulinemia. Ibrutinib is overall well tolerated but long-term treatment is required until disease progression or intolerable toxic effects occur. Little is known regarding its cutaneous adverse effects. Objective To describe the hair and nail manifestations associated with the long-term use of ibrutinib for the treatment of CLL. Design, Setting, and Participants Prospective study of 66 patients with CLL enrolled in a single-arm phase 2 clinical trial of ibrutinib for CLL between March 2014 and October 2015 at the National Institutes of Health. Main Outcomes and Measures The primary outcome, nail and hair changes associated with ibrutinib therapy, was assessed by an 11-question survey. In addition, the severity of nail changes was determined from a 0 to 3 rating scale for both onychoschizia and onychorrhexis. Results Among 66 patients (43 men and 23 women with ages ranging from 55 to 85 years), 44 (67%) reported brittle fingernails at a median of 6.5 (95% CI, 6-12) months after starting ibrutinib therapy. Fifteen patients (23%) developed brittle toenails after a median of 9 (95% CI, 6-15) months of ibrutinib therapy. Textural hair changes were reported in 17 patients (26%), at a median of 9 (95% CI, 6-12) months of ibrutinib treatment. Conclusions and relevance Hair and nail abnormalities are commonly associated with ibrutinib and appear several months after initiating therapy. Ibrutinib inhibits Bruton tyrosine kinase by covalently binding to cysteine 481. Whether ibrutinib affects the hair and nails by binding and altering cysteine-rich proteins of hair and nails or by means of another mechanism remains unknown. Trial Registration clinicaltrials.gov Identifier: NCT01500733 The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is an orally bioavailable molecule that was approved by the US Food and Drug Administration for mantle cell lymphoma in 2013 (560 mg once daily) and for chronic lymphocytic leukemia (CLL) in 2014 (420 mg once daily).1-4 Ibrutinib inhibits BTK, a key kinase for B-cell signaling, by covalently binding to cysteine 481, resulting in decreased proliferation and survival of malignant B cells.5 A limited number of kinases possess a homologous cysteine residue, making ibrutinib highly selective for BTK.6 Adverse events include fatigue, diarrhea, upper respiratory tract infections, skin rash,7 and ecchymosis.2-4 Ibrutinib is administered until disease progression or intolerable and/or severe toxic effects occur; however, as with other tyrosine kinase inhibitors, cutaneous toxicity represents a potential barrier to long-term tolerability.8 Ibrutinib is generally well tolerated, but we noted that patients frequently described nail and hair changes with long-term use.9 In this article, we provide specific details on hair and nail manifestations and introduce a potential therapeutic intervention. Box Section Ref ID Key Points Question What is the incidence of brittle nails and hair changes in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib? Findings In this observational study of 66 patients with CLL treated with ibrutinib, 67% developed brittle fingernails, 26% developed hair changes, and 23% developed brittle toenails. Most changes were reported after ibrutinib treatment of 6 months or longer. Meaning Ibrutinib, a novel treatment for CLL, is associated with long-term hair and nail changes, possibly due to binding to cysteine residues in hair and nails. Methods Eighty-six patients with CLL were enrolled to treatment with ibrutinib at the National Institutes of Health (NCT01500733). All patients provided written informed consent. Two patients died and 2 patients withdrew from the study prior to data collection. Of the 82 patients remaining, 66 were available for detailed review of hair and nail abnormalities (March 2014 through October 2015). Fifteen patients withdrew from the study and in 1 patient the survey was not completed. This study was approved by the institutional review board of the National Heart, Lung, and Blood Institute, National Institutes of Health. Study results, in part, have been reported previously.9 A survey was completed by a member of the study team at the time of each follow-up visit. The survey was composed of 11 questions: (1) time of onset of nail changes after ibrutinib treatment, (2) onychoschizia and onychorrhexis of fingernails, (3) severity of fingernail changes, (4) brittle toenails, (5) hair changes, (6) other skin or mucosal involvement, (7) pain, (8) bleeding, (9) treatment of hair and nail changes, (10) progression of hair and nail abnormalities over the course of therapy with ibrutinib, and (11) impact on quality of life. The degree of severity was based on the grading score by Van de Kerkhof et al.10 Onychoschizia was defined as lamellar splitting and graded from 0 to 3: 0, none; 1, mild: splitting not involving the whole free edge of the nail plate; 2, moderate: splitting involving the whole free edge of the nail plate; 3, severe: splitting involving the whole free edge of the nail plate and covering 1/3 of the nail plate. Onychorrhexis was defined as longitudinal ridging and also graded from 0 to 3: 0, none; 1, mild: few superficial longitudinal ridges and grooves; 2, moderate: few deep ridges and grooves; and 3, severe: more than 70% of the nail plate showing deep ridges and corresponding grooves. Results The age range of the 66 study participants was 55 to 85 years old, with 43 men and 23 women. Forty-four (67%) participants described new-onset fingernail changes after a median of 6.5 months (95% CI, 6-12 months). Fifteen (23%) developed brittle toenails after a median of 9 months (95% CI, 6-15 months) of ibrutinib therapy (Table). Nail changes manifested as mild to moderate onychoschizia and onychorrhexis, corresponding to grade 1 and 2 Common Terminology Criteria for Adverse Events, version 3.0, adverse events, respectively (Figure 1, Figure 2).10 Seventeen (26%) patients developed hair changes at a median of 9 months (95% CI, 6-12 months) after starting ibrutinib therapy. Most hair changes manifested as straightening and softening of the hair, although 4 of 17 patients reported increased curliness of hair. Among 5 patients who used oral biotin at 2.5 mg daily, 3 reported substantial improvement in their nails. Twenty-four (55%) of the 44 affected individuals reported a negative impact of hair and nail changes on their quality of life. Discussion Nail brittleness affects approximately 20% of the population, most frequently older adults and women, and is associated with onychoschizia, onychorrhexis, or both.10 The pathogenesis of brittle nails is multifactorial, and may result from disruption of intercellular adhesion between corneocytes, as well as factors affecting the nail matrix.10 Nail texture is influenced by corneocytes, keratin filaments, keratin-associated fibrous proteins, water content, lipid bilayers, and the nail matrix.10,11 The integrity of keratin-associated fibrous proteins is maintained by disulfide bonds between cysteine residues, resulting in the formation of the sulfur-containing amino acid cystine.11 Ibrutinib covalently binds to the cysteine residue at the active site of BTK.1 Because cysteines are critical for nail hardness, ibrutinib-induced disruption of the disulfide bonds between cysteine residues could be responsible for increased nail brittleness. Fingernails require 3 to 6 months to complete a growth cycle. This time interval is consistent with the reported delay of 6.5 months between initiation of ibrutinib therapy and the appearance of nail changes. Toenail abnormalities were reported a median of 9 months after initiation of therapy, consistent with the slower growth rate of the toenail plate (12-18 months). We consider the nail abnormalities to be related to ibrutinib therapy because these changes arose during ibrutinib use and were not preexisting, such changes are not part of disease-related complications or associated with standard chemotherapy, and because the timing of appearance of nail changes correlated well with the growth rate of the nail plates. Unfortunately, no pretreatment photographs were available for comparison at the time of the study. Keratinocyte-associated proteins in the hair are also rich in sulfur-containing amino acids and form disulfide bonds that contribute to hair structure and tensile strength.12 Hair permanents that contain reducing agents straighten hair through disruption of disulfide bonds.12 Reduced disulfide bonds have free thiols that can migrate and form new disulfide bonds creating more curls as seen with permanent waving agents.12 Ibrutinib disruption of hair disulfide bonds may act in a similar manner to cause alterations in hair strength or texture. Although ibrutinib demonstrates high selectivity for BTK (inhibitory concentration 50% [IC50] = 0.5 nM), it also inhibits other kinases, including human epidermal growth factor receptors 1 (EGFR, IC50 = 12 nM) and 2 (ERBB2 [formerly HER2 or HER2/neu], IC50 = 22 nM).6 Ibrutinib at 560 mg/d can reach a maximum concentration of more than 100 ng/mL in the plasma,13 which is equivalent to 227 nM. At maximum concentration, ibrutinib may inhibit other target kinases, including the EGFR. Inhibition of EGFR by tyrosine kinase inhibitors leads to well-established cutaneous adverse events, including papulopustular rash and nail and hair changes.8 However, papulopustular rash, one of the most common manifestations of EGFR inhibitor use, has not been described with ibrutinib use.9 Conclusions Concern over cosmetic appearance and nail discomfort may negatively affect quality of life in diseases affecting the nails.10 In our study, 55% of affected patients expressed concern related to nail appearance or pain. Treatment options for brittle nails include biotin supplementation and topical solutions such as hydrosoluble nail lacquer and poly-ureaurethane. In 1 study of 32 patients with brittle nails, 25% improvement in nail thickness was noted following ingestion of 2.5 mg of biotin daily for 6 to 15 months.14 In another study of 44 patients with brittle nails, 63% reported improvement after 2 months of biotin use, with reemergence of brittle nails after treatment was discontinued.11 Biotin is a cofactor for several enzymes involved in fatty acid formation and thereby may enhance the lipid content of the nail plate and improve keratinocyte binding.15 The benign nature of biotin and the absence of drug-drug interactions suggest that supplementation may be reasonable; however, further clinical study is needed to confirm efficacy in the setting of ibrutinib therapy. Back to top Article Information Accepted for Publication: January 29, 2016. Corresponding Author: Edward W. Cowen, MD, MHSc, Dermatology Branch, Center for Cancer Research, NCI, NIH10 Center Dr, Bldg 10, Bethesda, MD 20892 (cowene@mail.nih.gov). Published Online: March 16, 2016. doi:10.1001/jamadermatol.2016.0225. Author Contributions: Drs Bitar and Cowen had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Wiestner and Cowen contributed equally to this work. Study concept and design: Bitar, Farooqui, Marti, Wiestner. Acquisition, analysis, or interpretation of data: Bitar, Valdez, Saba, Soto, Bray, Wiestner, Cowen. Drafting of the manuscript: Bitar. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Bitar. Obtained funding: Wiestner. Administrative, technical, or material support: Farooqui, Bray, Wiestner. Study supervision: Farooqui, Wiestner. Conflict of Interest Disclosures: Dr Wiestner received research funding from Pharmacyclics. Dr Saba serves as consultant and a speaker for Pharmacyclics and has received honoraria from Pharmacyclics. No other disclosures are reported. Funding/Support: This study was supported in part by the Intramural Research Program of the National Institutes of Health, the National, Heart, Lung, and Blood Institute (NHLBI), and by Pharmacyclics, which provided ibrutinib, research support, and comments on the manuscript. Role of the Funder/Sponsor: Pharmacyclics reviewed the manuscript but had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, or approval of the manuscript; and decision to submit the manuscript for publication. The other funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Additional Contributions: We are indebted to the patients who participated in this trial and their families; Pharmacyclics for providing ibrutinib, research support, and comments on the manuscript; and the Intramural Research Program of the NHLBI. References 1. Wiestner A. The role of B-cell receptor inhibitors in the treatment of patients with chronic lymphocytic leukemia. Haematologica. 2015;100(12):1495-1507.PubMedGoogle ScholarCrossref 2. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32-42.PubMedGoogle ScholarCrossref 3. Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369(6):507-516.PubMedGoogle ScholarCrossref 4. Treon SP, Tripsas CK, Meid K, et al. Ibrutinib in previously treated Waldenström’s macroglobulinemia. N Engl J Med. 2015;372(15):1430-1440.PubMedGoogle ScholarCrossref 5. Herman SE, Mustafa RZ, Gyamfi JA, et al. Ibrutinib inhibits BCR and NF-κB signaling and reduces tumor proliferation in tissue-resident cells of patients with CLL. Blood. 2014;123(21):3286-3295.PubMedGoogle ScholarCrossref 6. Burger JA, Buggy JJ. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765). Leuk Lymphoma. 2013;54(11):2385-2391.PubMedGoogle ScholarCrossref 7. Mannis G, Wu D, Dea T, Mauro T, Hsu G. Ibrutinib rash in a patient with 17p del chronic lymphocytic leukemia. Am J Hematol. 2015;90(2):179.PubMedGoogle ScholarCrossref 8. Robert C, Soria JC, Spatz A, et al. Cutaneous side-effects of kinase inhibitors and blocking antibodies. Lancet Oncol. 2005;6(7):491-500.PubMedGoogle ScholarCrossref 9. Farooqui MZ, Valdez J, Martyr S, et al. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol. 2015;16(2):169-176.PubMedGoogle ScholarCrossref 10. van de Kerkhof PC, Pasch MC, Scher RK, et al. Brittle nail syndrome: a pathogenesis-based approach with a proposed grading system. J Am Acad Dermatol. 2005;53(4):644-651.PubMedGoogle ScholarCrossref 11. Cashman MW, Sloan SB. Nutrition and nail disease. Clin Dermatol. 2010;28(4):420-425.PubMedGoogle ScholarCrossref 12. de Sá Dias TC, Baby AR, Kaneko TM, Robles Velasco MV. Relaxing/straightening of Afro-ethnic hair: historical overview. J Cosmet Dermatol. 2007;6(1):2-5.PubMedGoogle ScholarCrossref 13. Advani RH, Buggy JJ, Sharman JP, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol. 2013;31(1):88-94.PubMedGoogle ScholarCrossref 14. Colombo VE, Gerber F, Bronhofer M, Floersheim GL. Treatment of brittle fingernails and onychoschizia with biotin: scanning electron microscopy. J Am Acad Dermatol. 1990;23(6, pt 1):1127-1132.PubMedGoogle ScholarCrossref 15. Iorizzo M, Pazzaglia M, M Piraccini B, Tullo S, Tosti A. Brittle nails. J Cosmet Dermatol. 2004;3(3):138-144.PubMedGoogle ScholarCrossref

Journal

JAMA Dermatology – American Medical Association

Published: Jun 1, 2016

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