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Successful Desensitization of Two Patients with ALK-Positive Lung Cancer and Hypersensitivity to Crizotinib

      The tyrosine kinase inhibitor crizotinib is an effective therapy for patients with cancers harboring rearrangements of the anaplastic lymphoma kinase (ALK) gene. Here, we describe two patients with advanced ALK-positive lung cancer who developed hypersensitivity to crizotinib, requiring temporary discontinuation of the drug. Both patients were treated with a rapid oral desensitization protocol allowing them to resume crizotinib without further signs or symptoms of hypersensitivity.

      Key Words

      About 3–7% of nonsmall cell lung cancers (NSCLC) harbor chromosomal rearrangements that result in activation of anaplastic lymphoma kinase (ALK).
      • Soda M
      • Choi YL
      • Enomoto M
      • et al.
      Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer.
      ,
      • Shaw AT
      • Yeap BY
      • Mino-Kenudson M
      • et al.
      Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK.
      Crizotinib, a small molecule tyrosine kinase inhibitor of ALK, ROS1, and MET, is associated with high response rates (∼60%),
      • Kwak EL
      • Bang YJ
      • Camidge DR
      • et al.
      Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.
      prolonged progression-free survival (PFS), and superiority to chemotherapy in patients with advanced ALK-positive lung cancer.
      • Shaw AT
      • Kim DW
      • Nakagawa K
      • et al.
      Crizotinib versus chemotherapy in advanced ALK-positive lung cancer.
      • Mok T
      • Kim D-W
      • Wu Y-L
      • et al.
      First-line crizotinib versus pemetrexed-cisplatin or pemetrexed-carboplatin in patients (pts) with advanced ALK-positive non-squamous non-small cell lung cancer (NSCLC): results of a phase III study (PROFILE 1014).
      • Shaw AT
      • Yeap BY
      • Solomon BJ
      • et al.
      Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis.
      Most side effects of crizotinib are mild and manageable. Common grade 1/2 side effects include visual disturbance (incidence 60%), diarrhea (60%), nausea (55%), vomiting (47%), constipation (42%), edema (31%), and fatigue (27%). Rash has been observed in only approximately 9% of crizotinib-treated patients and there have been no reported cases of grade 3/4 rash. Grade 3/4 adverse events are less common and include increased alanine aminotransferase (17%), increased aspartate aminotransferase (9%), and neutropenia (12%). Hypersensitivity reactions to crizotinib have not been reported.
      The National Cancer Center Network (NCCN) guidelines recommend crizotinib as first-line treatment for patients with advanced ALK-positive NSCLC. The next generation ALK inhibitor ceritinib was also recently approved in the United States for ALK-positive patients with disease progression on or intolerance to crizotinib. Because there are limited data on the benefit of ceritinib in crizotinib-naive patients or in other crizotinib-responsive cancers, such as those with ROS1 rearrangements
      • Ou S-HI
      • Bang Y-J
      • Camidge DR
      • et al.
      Efficacy and safety of crizotinib in patients with advanced ROS1-rearranged non-small cell lung cancer (NSCLC).
      crizotinib may be the most effective treatment option for many patients.
      Hypersensitivity reactions to cancer therapies pose a particular challenge for patients if few other active drugs are available, but standardized 12-step rapid desensitization protocols have been developed as a safe method for achieving temporary tolerance to a variety of intravenous chemotherapy agents, including platinums, taxanes, anthracyclines, and monoclonal antibodies.
      • Castells MC
      • Tennant NM
      • Sloane DE
      • et al.
      Hypersensitivity reactions to chemotherapy: outcomes and safety of rapid desensitization in 413 cases.
      Here, we report two cases of ALK-positive NSCLC patients who developed a hypersensitivity reaction soon after starting crizotinib, necessitating discontinuation of this drug. Through the use of a rapid 12-step desensitization clinical protocol, crizotinib was successfully reintroduced with no additional symptoms concerning for a hypersensitivity reaction.

      CASE 1

      A 77-year-old female never smoker underwent left lower lobectomy for a stage IIB lung adenocarcinoma followed by four cycles of adjuvant cisplatin and pemetrexed. About 18 months later, surveillance scans revealed enlarging mediastinal nodes and a new splenic lesion. An endobronchial biopsy of a subcarinal lymph node confirmed recurrent adenocarcinoma, and an EML4-ALK fusion was detected by FoundationOne testing. The patient was started on crizotinib 250 mg twice daily for metastatic NSCLC.
      The first two doses of crizotinib were well tolerated. Approximately 3 hours after the third dose of crizotinib, the patient developed pruritic urticarial lesions involving the torso and extremities. There were no other systemic symptoms associated with the rash at that time. The lesions spontaneously resolved over the course of 2 hours without any intervention. The patient continued with the fourth dose of crizotinib, and within 4 hours she again developed an urticarial rash involving the face and trunk, as well as edema of the periorbital and perioral regions. The patient's daughter administered 100 mg of diphenhydramine, and crizotinib was discontinued. Her swelling resolved over the next 24–48 hours. The patient had no prior history of urticaria, angioedema, or drug allergies. Her other medications included lisinopril and esomeprazole, which she had been taking for over 5 years, and which she continued taking after the hypersensitivity reaction with no adverse events.
      Due to concern over recurrent hypersensitivity reactions with administration of crizotinib, and because no other Food and Drug Administration (FDA)-approved ALK inhibitor was available at that time, the patient was referred to our hospital for further management. She was treated as an inpatient with a 12-step oral desensitization clinical protocol as described in Table 1. In brief, the patient was given 10 mg of both loratidine and cetirizine the night before and the morning of desensitization. She was also given a dose of fexofenadine 180 mg before the start of desensitization. A total of 250 mg of crizotinib was given in 12 steps over 3 hours. The contents of crizotinib capsules were dissolved in sterile water and diluted to make three concentrations (0.05, 0.5, and 5 mg/ml). The desensitization started at 0.0625 mg with a doubling of each subsequent administration of crizotinib until a final dose of 125 mg was reached. After each step, the patient was observed for 15 minutes for evidence of a hypersensitivity reaction. The patient tolerated this desensitization protocol well with no symptoms or signs of a hypersensitivity reaction. She then received a dose of 250 mg crizotinib 12 hours after completion of desensitization, and she was continued on crizotinib 250 mg twice daily thereafter. Her first restaging scans after crizotinib showed a partial response with decreases in the size and 18F-fluorodeoxyglucose avidity of mediastinal lymph nodes and the splenic metastasis (imaging not shown). Since completing the desensitization, she has continued crizotinib 250 mg every 12 hours without incident for 4 months.
      Table 1Crizotinib Desensitization Protocol
       Dose NumberCrizotinib Concentration (mg/ml)Time Observed After Each Dose (min)Volume (ml)Dose (mg)Cumulative dose (mg)
       10.05151.250.06250.06
       20.05152.50.1250.19
       30.5150.50.250.44
       40.51510.50.94
       50.515211.94
       65150.423.94
       75150.847.94
       85151.6815.94
       95153.21631.94
       105156.2531.2563.19
       1151512.562.5125.69
       1251525125250.69
      Total time: 180 min
      P.O., per os (orally).
      Twelve hours before the first dose of crizotinib, administer loratidine 10 mg P.O. × 1 dose and cetirizine 10 mg P.O. × 1 dose.
      One hour before the first dose of crizotinib, administer loratidine 10 mg P.O. × 1 dose, cetirizine 10 mg P.O. × 1 dose, and fexofenadine 180 mg P.O. × 1 dose.

      CASE 2

      A 45-year-old female never smoker presented with stage IV lung adenocarcinoma with metastases to the brain, liver, and bone. Owing to cerebral edema from her brain metastases, she was initially treated with glucocorticoids and then started on whole brain radiation therapy. After completion of radiation, while on a dexamethasone taper, her tumor was found to have an ALK rearrangement by fluorescence in situ hybridization, and she was started on crizotinib 250 mg twice daily.
      Three days after she completed the course of steroids (on her 15th day of crizotinib), she developed an erythematous maculopapular rash on her trunk and extremities. Crizotinib was discontinued and the rash resolved over the course of 5 days with the use of topical hydrocortisone as well as oral solumedrol and diphenhydramine. After resolution of the rash, crizotinib was immediately reintroduced at a reduced dose of 200 mg twice daily. Within 12 hours of the first dose, she developed a pruritic, erythematous, raised rash over her entire body concerning for urticaria. There were no other systemic symptoms such as dyspnea, wheezing, tongue/lip swelling or abdominal pain. Crizotinib was again discontinued with rapid resolution of the rash. She had no history of urticaria, angioedema, or drug allergies. Her other medications included omeprazole, hydromorphone, oxycodone, lorazepam, and megestrol acetate.
      The patient was then treated with two cycles of cisplatin and pemetrexed, but developed progressive disease. She was referred to our institution for further management and consideration of a clinical trial with a next generation ALK inhibitor. Because of abnormal liver function tests due to hepatic metastases, the patient was ineligible for a clinical trial, and crizotinib was the only FDA-approved ALK inhibitor available to her at that time. She was admitted to the hospital and treated with the desensitization clinical protocol described in Table 1. She tolerated desensitization well with no further signs or symptoms of a hypersensitivity reaction. She continued on crizotinib 250 mg twice daily for 1 week, but then developed rapid disease progression and was transitioned to comfort measures.

      DISCUSSION

      Small molecule kinase inhibitors have revolutionized the treatment and prognosis of many cancer types, but patients who develop hypersensitivity reactions to these agents are often unable to continue receiving these life-prolonging therapies. Standardized desensitization protocols can overcome this therapeutic barrier by helping patients achieve temporary tolerance to drug allergens. In chronic myelogenous leukemia, for example, a 4-hour oral desensitization protocol was used in 10 patients who had developed cutaneous drug reactions to imatinib; eight were able to continue taking imatinib without recurrent rash or adverse events.
      • Nelson Jr, RP
      • Cornetta K
      • Ward KE
      • Ramanuja S
      • Fausel C
      • Cripe LD
      Desensitization to imatinib in patients with leukemia.
      In another case, a patient with BRAF V600E-mutant metastatic melanoma who developed Stevens-Johnson syndrome from vemurafenib was able to resume vemurafenib safely over the course of a 3-week desensitization program.
      • Minor DR
      • Rodvien R
      • Kashani-Sabet M
      Successful desensitization in a case of Stevens-Johnson syndrome due to vemurafenib.
      Hypersensitivity reactions to crizotinib have not been previously reported. Crizotinib was granted accelerated approval by the U.S. FDA in 2011 and has been shown to be superior to standard chemotherapy in the first- and second-line settings for ALK-positive NSCLC patients.
      • Shaw AT
      • Kim DW
      • Nakagawa K
      • et al.
      Crizotinib versus chemotherapy in advanced ALK-positive lung cancer.
      ,
      • Mok T
      • Kim D-W
      • Wu Y-L
      • et al.
      First-line crizotinib versus pemetrexed-cisplatin or pemetrexed-carboplatin in patients (pts) with advanced ALK-positive non-squamous non-small cell lung cancer (NSCLC): results of a phase III study (PROFILE 1014).
      Ceritinib was approved in 2014 for ALK-positive patients who are resistant to or intolerant of crizotinib.
      • Shaw AT
      • Kim DW
      • Mehra R
      • et al.
      Ceritinib in ALK-rearranged non-small-cell lung cancer.
      These two agents are currently the only two FDA-approved targeted therapies for patients with advanced ALK-positive NSCLC.
      Although patients with crizotinib hypersensitivity can potentially be switched to ceritinib as an alternative ALK inhibitor, continuing crizotinib after desensitization may be a more preferable option for a variety of reasons. First, the sequencing of first-line crizotinib followed by ceritinib may potentially result in longer PFS compared with that afforded by upfront treatment with ceritinib. In the phase 1 study of ceritinib, median PFS among 34 patients who had not received crizotinib previously was 10.4 months,
      • Shaw AT
      • Kim DW
      • Mehra R
      • et al.
      Ceritinib in ALK-rearranged non-small-cell lung cancer.
      similar to that reported with first line crizotinib.
      • Mok T
      • Kim D-W
      • Wu Y-L
      • et al.
      First-line crizotinib versus pemetrexed-cisplatin or pemetrexed-carboplatin in patients (pts) with advanced ALK-positive non-squamous non-small cell lung cancer (NSCLC): results of a phase III study (PROFILE 1014).
      Among patients who previously received crizotinib, median PFS with ceritinib was 6.9 months.
      • Shaw AT
      • Kim DW
      • Mehra R
      • et al.
      Ceritinib in ALK-rearranged non-small-cell lung cancer.
      Thus, in theory, sequential therapy with crizotinib followed by ceritinib could lead to a “total” PFS of almost 18 months. Second, crizotinib has a more favorable side effect profile than ceritinib, with milder gastrointestinal side effects, and possibly less impact on daily functioning and overall quality of life. Finally, to date, hypersensitivity reactions to ceritinib have not been observed, though rash has been reported in 16% of patients treated with ceritinib. Whether patients who develop hypersensitivity to crizotinib may be predisposed to hypersensitivity to ceritinib is unknown, but cross-reactivity to the two drugs is a theoretical possibility.
      In this report, we describe the first cases of crizotinib hypersensitivity in two ALK-positive NSCLC patients. Both patients were able to safely resume the drug after being treated with a 12-step oral desensitization clinical protocol. With an increasing number of potent kinase inhibitors on the horizon in oncology, desensitization procedures such as the one described here may be an important tool to allow patients to continue on effective targeted therapies for their cancers.

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