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Ibrutinib-Induced Vasculitis in a Patient with Metastatic Colon Cancer Treated in Combination with Cetuximab

Ibrutinib-Induced Vasculitis in a Patient with Metastatic Colon Cancer Treated in Combination... Hindawi Case Reports in Oncological Medicine Volume 2020, Article ID 6154213, 4 pages https://doi.org/10.1155/2020/6154213 Case Report Ibrutinib-Induced Vasculitis in a Patient with Metastatic Colon Cancer Treated in Combination with Cetuximab Jeffrey Chi , Jennifer Park, and Muhammad Wasif Saif Department of Hematology/Oncology, Northwell Cancer Institute, Lake Success, NY, USA Correspondence should be addressed to Muhammad Wasif Saif; wsaif@northwell.edu Received 15 October 2019; Revised 17 January 2020; Accepted 30 January 2020; Published 14 February 2020 Academic Editor: Peter F. Lenehan Copyright © 2020 Jeffrey Chi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Combination therapy with ibrutinib and cetuximab is being studied in a phase 1b/2 trial in patients with advanced gastrointestinal and genitourinary malignancies. Rash is a common cutaneous adverse effect for both medications. Ibrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor approved for the treatment of several hematologic malignancies. The rash can be asymptomatic, nonpalpable, mild skin eruption, or palpable purpuric rash. A rarer panniculitis form has also been reported. Cetuximab, an epidermal growth factor (EGFR) inhibitor, approved for treatment in head and neck and advanced gastrointestinal malignancies is also known to cause acneiform rash in majority of patients. The rash is due to inhibition of EGFR in the basal keratinocytes and hair follicles. In the case of ibrutinib, the off-target effects on EGFR, c-kit, and platelet-derived growth factor receptor (PDGFR) are thought to be responsible for the cutaneous eruption of various forms of rash. The combination therapy with the BTK inhibitor and a direct EGFR inhibitor may potentiate the rash inducing effects of the drugs. Here, we describe a case of vasculitis in a patient with metastatic colon cancer who received both ibrutinib and cetuximab on a phase Ib/II clinical trial. 1. Introduction can be managed with observation without dose disruption, whereas a more severe palpable rash may need topical ste- roid and require ibrutinib dose disruption. Most patients Combination therapy of ibrutinib and cetuximab is being studied in a phase Ib/II trial in patients with advanced colo- are able to resume after the resolution of rash. Cetuximab is an EGFR inhibitor, currently approved by rectal and genitourinary malignancies who have failed multi- ple lines of therapy. Cutaneous toxicity is commonly seen in FDA for treatment for head and neck cancer and metastatic colon cancer. One of the most common cutaneous side patients when treated individually with ibrutinib or cetuxi- effects of cetuximab is eruption of acneiform rash over mab. The combined use of ibrutinib and cetuximab may potentiate the cutaneous toxicity. the face and trunk, affecting 45-100% of patients [5]. The rash can range from asymptomatic maculopapular rash to Ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, is approved by Food and Drug Administration (FDA) for the severe generalized exfoliative, ulcerative, or bullous derma- titis [6]. Severity is graded by the Common Terminology treatment of chronic lymphocytic leukemia (CLL), mantle Criteria for Adverse Events (CTCAE). Grade 3-4 rash cell lymphoma (MCL), marginal zone lymphoma (MZL), Waldenstrom macroglobulinemia, and chronic graft versus requires dose disruption and treatment with topical antimi- crobial cream. The onset of the rash is typically within the host disease. Ibrutinib is known to cause rash in 13-27% of CLL and MZL patients [1–4]. The rash can vary from first month of the treatment in majority of the patients even though it can occur in any time during the treatment asymptomatic ecchymosis, nonpalpable petechial rash, to course. Eruption of cutaneous rash has also been shown to leukocytoclastic vasculitis-like palpable purpura and panni- culitis [2–4]. The onset of the rash can vary from days to have a positive correlation to clinical response of the tumor to cetuximab [7]. months after initiation of ibrutinib. Mild, nonpalpable rash 2 Case Reports in Oncological Medicine Subsequently, decision was made to reintroduce ibrutinib Here, we describe a case of vasculitic rash eruption in a patient with metastatic colon cancer who received ibrutinib at a lower dose and cetuximab at full dose. The patient and cetuximab combination therapy on a phase Ib/II clin- was able to tolerate the combination therapy without fur- ther dose reduction. ical trial. 3. Discussion 2. Case Presentation The use of ibrutinib has expanded from hematologic malig- A 62-year-old male presented with rash one week after he nancies to clinical trials in solid tumors. In our case, it was started taking ibrutinib and cetuximab for metastatic colon used in combination with cetuximab in a stage IV colon can- cancer. The patient history was significant for stage IVa cer patient who had progression of disease on multiple lines (T4aN2M1a) colon cancer with metastasis to the liver. He of treatment. Rash is the most common cutaneous adverse underwent partial colon resection and radiofrequency abla- effect of both of these medications. When rash occurred, it tion to liver metastasis. The patient received multiple lines was difficult to determine the offending drug. of adjuvant chemotherapies (5-fluorouracil (5-FU), leucov- The cutaneous adverse effects of EGFR inhibitors are orin, oxaliplatin, irinotecan+bevacizumab; 5-FU+bevacizu- believed to be due to inhibition of EGFR in basal keratino- mab; capecitabine+oxaliplatin) from October 2017 to April cytes and hair follicles [7]. These receptors are highly 2018 due to progression of the disease. He was enrolled into expressed in skin cells and certain types of tumor cells. the phase Ib/II study PCYC-1128-CA and received daily Cetuximab-induced rash typically manifests as sterile acnei- ibrutinib and weekly cetuximab combination therapy. One form, erythematous papules, and pustules that develop on week after the initiation of therapy, the patient presented the face, upper trunk, and scalp. It often appears within the with macular rash with erythematous base on the face and first month after starting therapy in 45-100% of the patients. torso (grade 1). The rash was initially thought to be due to Other EGFR inhibitors (panitumumab, pertuzumab, etc.) cetuximab which is known to cause acneiform rash that is and EGFR tyrosine kinase inhibitors (erlotinib, gefitinib, osi- often associated with pain and pruritus. He was treated with mertinib, etc.) can also cause a similar form of rash [8]. His- minocycline and clobetasol cream for symptomatic relief. A topathology typically shows superficial inflammatory cell week later, the rash worsened to involve the arms and back infiltrate surrounding upper portion hair follicles or superfi- (grade 3) (Figure 1). Cetuximab was held. During that time, cial neutrophilic suppurative folliculitis with rupture of epi- he continued to take ibrutinib. However, the rash continued thelia lining. Dermal capillaries, sebaceous glands, and to spread to the lower extremities. Both cetuximab and ibru- eccrine glands are usually not involved. The eruption of cuta- tinib were held. Within a week, the patient’s rash improved to neous rash in patients treated with cetuximab has been grade 1 on the face and grade 2 on the hands, forearms, and shown to positively correlate with tumor response rate in lower extremities. Decision was made to resume cetuximab at patients with colorectal cancer. Rash can be induced by half the dose (200 g/m2) and ibrutinib at same dose. How- increasing the dose of cetuximab to improve response rate ever, the rash at the lower extremity worsened significantly. in patients who do not develop the skin rash at the standard Both agents were held again. Biopsy of the lower extremity dose [9]. Rash of grade 0-2 per CTCAE can be managed by rash showed parakeratosis with a subcorneal neutrophilic topical corticosteroids, emollients, and antibiotics. Dose pustule, perivascular inflammatory infiltrate composed of reduction is typically not required. Rash of grade 3 and lymphocytes, neutrophils, and eosinophils in association higher requires dose reduction or cessation. with leukocytoclasia. Perivascular fibrin deposition was iden- For ibrutinib, cutaneous adverse events have been tified. The findings were consistent with small vessel vasculi- reported as one of the most common nonhematologic side tis. Suspicion for other causes of small vessel vasculitis was effects that occur in 13-27% of patients with hematologic low as the rash resolved with discontinuation of both medica- malignancies [2]. The rash can vary from asymptomatic tions. Blood culture, hepatitis B and C panels, and periodic ecchymosis, nonpalpable petechial rash, to leukocytoclastic acid-Schiff staining were negative making cryoglobulinemia vasculitis-like palpable purpura and panniculitis [2]. Ecchy- or infectious associated vasculitis unlikely. Based on the clin- mosis is due to collagen-dependent platelet activation defect ical and pathological findings, it was determined that the vas- and absent adherence to von Willebrand factor [10]. The culitic rash was drug induced. eruption of rash is thought to be due to the off-target effect Adverse Drug Reaction Probability Scale (Naranjo) was of ibrutinib on EGFR despite its high selectivity of BTK. It used to assess the causal relationship of the drugs to the skin has been shown that ibrutinib inhibits EGFR in a dose- rash. It is a questionnaire designed to determine the likeli- dependent manner [11] which in turn can lead to similar hood of whether an adverse reaction is attributable to the cutaneous eruptions seen in patients treated with cetuximab. medication. A score of greater than 9 suggests a definite asso- Another proposed mechanism of ibrutinib-induced rash is ciation of the drug to the adverse reaction; a score of 5-8 sug- through its ability to inhibit platelet-derived growth factor gests probable association; a score of 1-4 suggests possible receptor (PDGFR) or c-kit [11]. However, the exact mecha- association; and a score of zero suggests an unlikely associa- nism is unclear. Histopathology shows inflammatory infil- tion of the drug to the adverse reaction. In this case, the score trate with neutrophils, lymphocytes, and eosinophils with for ibrutinib was 7 and the score of cetuximab was 3, making associated leukocytoclasia in the superficial dermal layer ibrutinib a more probable cause of the rash. (Table 1). and perivascular tissues. Lobular and septal panniculitis with Case Reports in Oncological Medicine 3 (a) (b) (c) Figure 1: Papular rash with erythematous base: (a) on the face, (b) on the lower face and torso, and (c) on the back. associated small vessel vasculitis has also been reported [12]. Our case is unique because the patient was on combina- The onset of the rash can vary from within 7 days to over 1 tion treatment with ibrutinib and cetuximab. Both of which year after initiation of ibrutinib. The rash is typically grade are known to cause rash. Both drugs, when given individu- 0-2 which often resolves spontaneously without any specific ally, inhibit EGFR in a dose-dependent manner. The skin treatment. Topical corticosteroid therapy and antihistamine toxicity-inducing effect may be amplified when both medica- can be given for pruritic rash. Rash of grade 3 and higher tions are used in combination. It is important to discern the requires dose reduction or discontinuation. causative agent so that appropriate dose adjustment can be 4 Case Reports in Oncological Medicine Table 1: Adverse Drug Reaction Probability Scale. Question Yes No Do not know Ibrutinib Cetuximab 1. Are there previous conclusive reports on this reaction? +1 0 0 1 1 2. Did the adverse event appear after the suspected drug was administered? +2 -1 0 2 2 3. Did the adverse event improve when the drug was discontinued or a specific antagonist +1 0 0 1 0 was administered? 4. Did the adverse event reappear when the drug was readministered? +2 -1 0 2 -1 5. Are there alternative causes that could on their own have caused the reaction? -1 +2 0 -1 -1 6. Did the reaction reappear when a placebo was given? -1 +1 0 0 0 7. Was the drug detected in blood or other fluids in concentrations known to be toxic? +1 0 0 0 0 8. Was the reaction more severe when the dose was increased or less severe when the dose +1 0 0 1 1 was decreased? 9. Did the patient have a similar reaction to the same or similar drugs in any previous +1 0 0 0 0 exposure? 10. Was the adverse event confirmed by any objective evidence? +1 0 0 1 1 Total 7 3 made. In our case, ibrutinib, rather than cetuximab, was [4] J. J. Mulvey, G. J. Nuovo, and C. M. Magro, “Cutaneous, pur- puric painful nodules upon addition of ibrutinib to RCVP found to have a higher causal correlation to the rash as therapy in a CLL patient: a distinctive reaction pattern reflect- assessed by Naranjo’s Adverse Drug Reaction Probability ing iatrogenic Th2 to Th1 milieu reversal,” The American Jour- Scale. Biopsy of the rash also showed small vessel vasculitis nal of Dermatopathology, vol. 38, no. 7, pp. 492–498, 2016. which is more commonly seen in rash associated with ibruti- [5] M. E. Lacouture, “Mechanisms of cutaneous toxicities to EGFR nib but rarely with cetuximab. Dermal capillaries are typi- inhibitors,” Nature Reviews Cancer, vol. 6, no. 10, pp. 803–812, cally spared in cetuximab rash. The patient was able to tolerate the combination therapy with reduced dose of ibru- [6] C. Robert, J. C. Soria, A. Spatz et al., “Cutaneous side-effects of tinib. Cetuximab was continued at the same dose. kinase inhibitors and blocking antibodies,” The Lancet Oncol- ogy, vol. 6, no. 7, pp. 491–500, 2005. 4. Conclusion [7] M. Holcmann and M. Sibilia, “Mechanisms underlying skin disorders induced by EGFR inhibitors,” Molecular & Cellular Diagnosis of ibrutinib-induced vasculitis was challenging in Oncology, vol. 2, no. 4, article e1004969, 2015. our patient as he was on combination therapy with cetuxi- [8] G. Fabbrocini, L. Panariello, G. Caro, and S. Cacciapuoti, mab. Clinicians should be aware that despite a higher inci- “Acneiform rash induced by EGFR inhibitors: review of the dence rate of skin toxicity with cetuximab, ibrutinib can literature and new insights,” Skin Appendage Disorders,vol. 1, also be the trigger for the rash when the drugs are used in no.1,pp.31–37, 2015. combination. Dose adjustments can be made accordingly [9] E. Van Cutsem, S. Tejpar, D. Vanbeckevoort et al., “Intrapati- once the offending drug is identified. ent cetuximab dose escalation in metastatic colorectal cancer according to the grade of early skin reactions: the randomized EVEREST study,” Journal of Clinical Oncology, vol. 30, no. 23, Conflicts of Interest pp. 2861–2868, 2012. Authors report no biomedical financial interests or potential [10] M. Levade, E. David, C. Garcia et al., “Ibrutinib treatment conflicts of interest. affects collagen and von Willebrand factor-dependent platelet functions,” Blood, vol. 124, no. 26, pp. 3991–3995, 2014. [11] O. J. D’Cruz and F. Uckun, “Novel Bruton’s tyrosine kinase References inhibitors currently in development,” OncoTargets and Ther- apy, vol. 6, pp. 161–176, 2013. [1] M. Z. H. Farooqui, J. Valdez, S. Martyr et al., “Ibrutinib for pre- [12] J. A. Hammel, G. M. Roth, N. Ferguson, and J. A. Fairley, viously untreated and relapsed or refractory chronic lympho- cytic leukaemia with TP53 aberrations: a phase 2, single-arm “Lower extremity ecchymotic nodules in a patient being treated with ibrutinib for chronic lymphocytic leukemia,” trial,” The Lancet Oncology, vol. 16, no. 2, pp. 169–176, 2015. JAAD Case Reports, vol. 3, no. 3, pp. 178-179, 2017. [2] D. J. Iberri, B. Kwong, L. Stevens et al., “Ibrutinib-associated rash: single-center experience of clinicopathologic features and management,” Blood, vol. 126, no. 23, pp. 4860–4860, [3] S. K. Fabbro, S. M. Smith, J. A. Dubovsky, A. A. Gru, and J. A. Jones, “Panniculitis in patients undergoing treatment with the Bruton tyrosine kinase inhibitor ibrutinib for lymphoid leuke- mias,” JAMA Oncology, vol. 1, no. 5, pp. 684–686, 2015. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Case Reports in Oncological Medicine Hindawi Publishing Corporation

Ibrutinib-Induced Vasculitis in a Patient with Metastatic Colon Cancer Treated in Combination with Cetuximab

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Hindawi Publishing Corporation
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Copyright © 2020 Jeffrey Chi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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2090-6706
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2090-6714
DOI
10.1155/2020/6154213
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Abstract

Hindawi Case Reports in Oncological Medicine Volume 2020, Article ID 6154213, 4 pages https://doi.org/10.1155/2020/6154213 Case Report Ibrutinib-Induced Vasculitis in a Patient with Metastatic Colon Cancer Treated in Combination with Cetuximab Jeffrey Chi , Jennifer Park, and Muhammad Wasif Saif Department of Hematology/Oncology, Northwell Cancer Institute, Lake Success, NY, USA Correspondence should be addressed to Muhammad Wasif Saif; wsaif@northwell.edu Received 15 October 2019; Revised 17 January 2020; Accepted 30 January 2020; Published 14 February 2020 Academic Editor: Peter F. Lenehan Copyright © 2020 Jeffrey Chi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Combination therapy with ibrutinib and cetuximab is being studied in a phase 1b/2 trial in patients with advanced gastrointestinal and genitourinary malignancies. Rash is a common cutaneous adverse effect for both medications. Ibrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor approved for the treatment of several hematologic malignancies. The rash can be asymptomatic, nonpalpable, mild skin eruption, or palpable purpuric rash. A rarer panniculitis form has also been reported. Cetuximab, an epidermal growth factor (EGFR) inhibitor, approved for treatment in head and neck and advanced gastrointestinal malignancies is also known to cause acneiform rash in majority of patients. The rash is due to inhibition of EGFR in the basal keratinocytes and hair follicles. In the case of ibrutinib, the off-target effects on EGFR, c-kit, and platelet-derived growth factor receptor (PDGFR) are thought to be responsible for the cutaneous eruption of various forms of rash. The combination therapy with the BTK inhibitor and a direct EGFR inhibitor may potentiate the rash inducing effects of the drugs. Here, we describe a case of vasculitis in a patient with metastatic colon cancer who received both ibrutinib and cetuximab on a phase Ib/II clinical trial. 1. Introduction can be managed with observation without dose disruption, whereas a more severe palpable rash may need topical ste- roid and require ibrutinib dose disruption. Most patients Combination therapy of ibrutinib and cetuximab is being studied in a phase Ib/II trial in patients with advanced colo- are able to resume after the resolution of rash. Cetuximab is an EGFR inhibitor, currently approved by rectal and genitourinary malignancies who have failed multi- ple lines of therapy. Cutaneous toxicity is commonly seen in FDA for treatment for head and neck cancer and metastatic colon cancer. One of the most common cutaneous side patients when treated individually with ibrutinib or cetuxi- effects of cetuximab is eruption of acneiform rash over mab. The combined use of ibrutinib and cetuximab may potentiate the cutaneous toxicity. the face and trunk, affecting 45-100% of patients [5]. The rash can range from asymptomatic maculopapular rash to Ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, is approved by Food and Drug Administration (FDA) for the severe generalized exfoliative, ulcerative, or bullous derma- titis [6]. Severity is graded by the Common Terminology treatment of chronic lymphocytic leukemia (CLL), mantle Criteria for Adverse Events (CTCAE). Grade 3-4 rash cell lymphoma (MCL), marginal zone lymphoma (MZL), Waldenstrom macroglobulinemia, and chronic graft versus requires dose disruption and treatment with topical antimi- crobial cream. The onset of the rash is typically within the host disease. Ibrutinib is known to cause rash in 13-27% of CLL and MZL patients [1–4]. The rash can vary from first month of the treatment in majority of the patients even though it can occur in any time during the treatment asymptomatic ecchymosis, nonpalpable petechial rash, to course. Eruption of cutaneous rash has also been shown to leukocytoclastic vasculitis-like palpable purpura and panni- culitis [2–4]. The onset of the rash can vary from days to have a positive correlation to clinical response of the tumor to cetuximab [7]. months after initiation of ibrutinib. Mild, nonpalpable rash 2 Case Reports in Oncological Medicine Subsequently, decision was made to reintroduce ibrutinib Here, we describe a case of vasculitic rash eruption in a patient with metastatic colon cancer who received ibrutinib at a lower dose and cetuximab at full dose. The patient and cetuximab combination therapy on a phase Ib/II clin- was able to tolerate the combination therapy without fur- ther dose reduction. ical trial. 3. Discussion 2. Case Presentation The use of ibrutinib has expanded from hematologic malig- A 62-year-old male presented with rash one week after he nancies to clinical trials in solid tumors. In our case, it was started taking ibrutinib and cetuximab for metastatic colon used in combination with cetuximab in a stage IV colon can- cancer. The patient history was significant for stage IVa cer patient who had progression of disease on multiple lines (T4aN2M1a) colon cancer with metastasis to the liver. He of treatment. Rash is the most common cutaneous adverse underwent partial colon resection and radiofrequency abla- effect of both of these medications. When rash occurred, it tion to liver metastasis. The patient received multiple lines was difficult to determine the offending drug. of adjuvant chemotherapies (5-fluorouracil (5-FU), leucov- The cutaneous adverse effects of EGFR inhibitors are orin, oxaliplatin, irinotecan+bevacizumab; 5-FU+bevacizu- believed to be due to inhibition of EGFR in basal keratino- mab; capecitabine+oxaliplatin) from October 2017 to April cytes and hair follicles [7]. These receptors are highly 2018 due to progression of the disease. He was enrolled into expressed in skin cells and certain types of tumor cells. the phase Ib/II study PCYC-1128-CA and received daily Cetuximab-induced rash typically manifests as sterile acnei- ibrutinib and weekly cetuximab combination therapy. One form, erythematous papules, and pustules that develop on week after the initiation of therapy, the patient presented the face, upper trunk, and scalp. It often appears within the with macular rash with erythematous base on the face and first month after starting therapy in 45-100% of the patients. torso (grade 1). The rash was initially thought to be due to Other EGFR inhibitors (panitumumab, pertuzumab, etc.) cetuximab which is known to cause acneiform rash that is and EGFR tyrosine kinase inhibitors (erlotinib, gefitinib, osi- often associated with pain and pruritus. He was treated with mertinib, etc.) can also cause a similar form of rash [8]. His- minocycline and clobetasol cream for symptomatic relief. A topathology typically shows superficial inflammatory cell week later, the rash worsened to involve the arms and back infiltrate surrounding upper portion hair follicles or superfi- (grade 3) (Figure 1). Cetuximab was held. During that time, cial neutrophilic suppurative folliculitis with rupture of epi- he continued to take ibrutinib. However, the rash continued thelia lining. Dermal capillaries, sebaceous glands, and to spread to the lower extremities. Both cetuximab and ibru- eccrine glands are usually not involved. The eruption of cuta- tinib were held. Within a week, the patient’s rash improved to neous rash in patients treated with cetuximab has been grade 1 on the face and grade 2 on the hands, forearms, and shown to positively correlate with tumor response rate in lower extremities. Decision was made to resume cetuximab at patients with colorectal cancer. Rash can be induced by half the dose (200 g/m2) and ibrutinib at same dose. How- increasing the dose of cetuximab to improve response rate ever, the rash at the lower extremity worsened significantly. in patients who do not develop the skin rash at the standard Both agents were held again. Biopsy of the lower extremity dose [9]. Rash of grade 0-2 per CTCAE can be managed by rash showed parakeratosis with a subcorneal neutrophilic topical corticosteroids, emollients, and antibiotics. Dose pustule, perivascular inflammatory infiltrate composed of reduction is typically not required. Rash of grade 3 and lymphocytes, neutrophils, and eosinophils in association higher requires dose reduction or cessation. with leukocytoclasia. Perivascular fibrin deposition was iden- For ibrutinib, cutaneous adverse events have been tified. The findings were consistent with small vessel vasculi- reported as one of the most common nonhematologic side tis. Suspicion for other causes of small vessel vasculitis was effects that occur in 13-27% of patients with hematologic low as the rash resolved with discontinuation of both medica- malignancies [2]. The rash can vary from asymptomatic tions. Blood culture, hepatitis B and C panels, and periodic ecchymosis, nonpalpable petechial rash, to leukocytoclastic acid-Schiff staining were negative making cryoglobulinemia vasculitis-like palpable purpura and panniculitis [2]. Ecchy- or infectious associated vasculitis unlikely. Based on the clin- mosis is due to collagen-dependent platelet activation defect ical and pathological findings, it was determined that the vas- and absent adherence to von Willebrand factor [10]. The culitic rash was drug induced. eruption of rash is thought to be due to the off-target effect Adverse Drug Reaction Probability Scale (Naranjo) was of ibrutinib on EGFR despite its high selectivity of BTK. It used to assess the causal relationship of the drugs to the skin has been shown that ibrutinib inhibits EGFR in a dose- rash. It is a questionnaire designed to determine the likeli- dependent manner [11] which in turn can lead to similar hood of whether an adverse reaction is attributable to the cutaneous eruptions seen in patients treated with cetuximab. medication. A score of greater than 9 suggests a definite asso- Another proposed mechanism of ibrutinib-induced rash is ciation of the drug to the adverse reaction; a score of 5-8 sug- through its ability to inhibit platelet-derived growth factor gests probable association; a score of 1-4 suggests possible receptor (PDGFR) or c-kit [11]. However, the exact mecha- association; and a score of zero suggests an unlikely associa- nism is unclear. Histopathology shows inflammatory infil- tion of the drug to the adverse reaction. In this case, the score trate with neutrophils, lymphocytes, and eosinophils with for ibrutinib was 7 and the score of cetuximab was 3, making associated leukocytoclasia in the superficial dermal layer ibrutinib a more probable cause of the rash. (Table 1). and perivascular tissues. Lobular and septal panniculitis with Case Reports in Oncological Medicine 3 (a) (b) (c) Figure 1: Papular rash with erythematous base: (a) on the face, (b) on the lower face and torso, and (c) on the back. associated small vessel vasculitis has also been reported [12]. Our case is unique because the patient was on combina- The onset of the rash can vary from within 7 days to over 1 tion treatment with ibrutinib and cetuximab. Both of which year after initiation of ibrutinib. The rash is typically grade are known to cause rash. Both drugs, when given individu- 0-2 which often resolves spontaneously without any specific ally, inhibit EGFR in a dose-dependent manner. The skin treatment. Topical corticosteroid therapy and antihistamine toxicity-inducing effect may be amplified when both medica- can be given for pruritic rash. Rash of grade 3 and higher tions are used in combination. It is important to discern the requires dose reduction or discontinuation. causative agent so that appropriate dose adjustment can be 4 Case Reports in Oncological Medicine Table 1: Adverse Drug Reaction Probability Scale. Question Yes No Do not know Ibrutinib Cetuximab 1. Are there previous conclusive reports on this reaction? +1 0 0 1 1 2. Did the adverse event appear after the suspected drug was administered? +2 -1 0 2 2 3. Did the adverse event improve when the drug was discontinued or a specific antagonist +1 0 0 1 0 was administered? 4. Did the adverse event reappear when the drug was readministered? +2 -1 0 2 -1 5. Are there alternative causes that could on their own have caused the reaction? -1 +2 0 -1 -1 6. Did the reaction reappear when a placebo was given? -1 +1 0 0 0 7. Was the drug detected in blood or other fluids in concentrations known to be toxic? +1 0 0 0 0 8. Was the reaction more severe when the dose was increased or less severe when the dose +1 0 0 1 1 was decreased? 9. Did the patient have a similar reaction to the same or similar drugs in any previous +1 0 0 0 0 exposure? 10. Was the adverse event confirmed by any objective evidence? +1 0 0 1 1 Total 7 3 made. In our case, ibrutinib, rather than cetuximab, was [4] J. J. Mulvey, G. J. Nuovo, and C. M. Magro, “Cutaneous, pur- puric painful nodules upon addition of ibrutinib to RCVP found to have a higher causal correlation to the rash as therapy in a CLL patient: a distinctive reaction pattern reflect- assessed by Naranjo’s Adverse Drug Reaction Probability ing iatrogenic Th2 to Th1 milieu reversal,” The American Jour- Scale. Biopsy of the rash also showed small vessel vasculitis nal of Dermatopathology, vol. 38, no. 7, pp. 492–498, 2016. which is more commonly seen in rash associated with ibruti- [5] M. E. Lacouture, “Mechanisms of cutaneous toxicities to EGFR nib but rarely with cetuximab. Dermal capillaries are typi- inhibitors,” Nature Reviews Cancer, vol. 6, no. 10, pp. 803–812, cally spared in cetuximab rash. The patient was able to tolerate the combination therapy with reduced dose of ibru- [6] C. Robert, J. C. Soria, A. Spatz et al., “Cutaneous side-effects of tinib. Cetuximab was continued at the same dose. kinase inhibitors and blocking antibodies,” The Lancet Oncol- ogy, vol. 6, no. 7, pp. 491–500, 2005. 4. Conclusion [7] M. Holcmann and M. Sibilia, “Mechanisms underlying skin disorders induced by EGFR inhibitors,” Molecular & Cellular Diagnosis of ibrutinib-induced vasculitis was challenging in Oncology, vol. 2, no. 4, article e1004969, 2015. our patient as he was on combination therapy with cetuxi- [8] G. Fabbrocini, L. Panariello, G. Caro, and S. Cacciapuoti, mab. Clinicians should be aware that despite a higher inci- “Acneiform rash induced by EGFR inhibitors: review of the dence rate of skin toxicity with cetuximab, ibrutinib can literature and new insights,” Skin Appendage Disorders,vol. 1, also be the trigger for the rash when the drugs are used in no.1,pp.31–37, 2015. combination. Dose adjustments can be made accordingly [9] E. Van Cutsem, S. Tejpar, D. Vanbeckevoort et al., “Intrapati- once the offending drug is identified. ent cetuximab dose escalation in metastatic colorectal cancer according to the grade of early skin reactions: the randomized EVEREST study,” Journal of Clinical Oncology, vol. 30, no. 23, Conflicts of Interest pp. 2861–2868, 2012. Authors report no biomedical financial interests or potential [10] M. Levade, E. David, C. Garcia et al., “Ibrutinib treatment conflicts of interest. affects collagen and von Willebrand factor-dependent platelet functions,” Blood, vol. 124, no. 26, pp. 3991–3995, 2014. [11] O. J. 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Published: Feb 14, 2020

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