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T-Cell Lymphoma to Crizotinib
LETTERS TO THE EDITOR
Complete Response of Anaplastic Lymphoma KinaseeMutated Refractory Extranodal Natural Killer/ T-Cell Lymphoma to Crizotinib To the Editor: Extranodal natural killer/T-cell lymphoma, nasal type (ENKTL) is an uncommon, aggressive non-Hodgkin lymphoma that is associated with a high level of chemotherapy resistance.1 Frontline regimens for localized disease include radiotherapy or chemotherapy with radiation.2 Patients who have refractory
disease or who experience relapse after initial therapy have a dismal prognosis. Mutations in anaplastic lymphoma kinase (ALK) and response to targeted agents directed at these alterations have been described in anaplastic large cell lymphoma3,4 but not in ENKTL, which remains a challenge to manage in the salvage setting. We describe a complete response in a patient with airway obstruction due to relapse of ALK-positive ENKTL with endobronchial involvement. Report of Case. A 29-year-old woman had ENKTL initially diagnosed on biopsy of the right middle turbinate and nasal septum after months of odynophagia. She received frontline
chemotherapy and radiation with dexamethasone, etoposide, ifosfamide, and carboplatin in January 2015. Although response was observed in the nasopharynx on initial posttherapy positron emission tomography (PET), her disease relapsed shortly after in the carina and left main stem bronchus. The patient presented with severe airway obstruction and intermittent fevers at relapse. She had persistent, biopsy-proven, refractory plaquelike endobronchial tumor after 2 cycles of standard L-asparaginaseecontaining salvage chemotherapy. She remained hospitalized because of the need for bronchial stenting and numerous emergent bronchoscopies for tumor debulking with regrowth days later, and she had
FIGURE. Response to crizotinib in a patient with anaplastic lymphoma kinaseepositive extranodal natural killer/T-cell lymphoma, nasal type, documented on positron emission tomography (PET) and bronchoschopy. A, PET before initiation of crizotinib, showing tumorrelated plaquelike hypermetabolism of left main stem bronchus. B, Metabolic response of endobronchial tumor on PET after 6 weeks of crizotinib. C, Tumor occlusion of the left main stem bronchus before initiation of crizotinib. D, Bronchoscopic view of main carina; silicone stent in left main stem bronchus on day 7 of crizotinib. E, Bronchoscopic view of main carina; biopsy was negative for recurrent disease after 6 weeks of crizotinib therapy.
Mayo Clin Proc. n September 2016;91(9):1319-1321 www.mayoclinicproceedings.org n ª 2016 Mayo Foundation for Medical Education and Research
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MAYO CLINIC PROCEEDINGS
only transient stabilization of her airway with high-dose corticosteroids. In September 2015, nextgeneration sequencing identified a mutation in the ALK gene (ALK R214H). Crizotinib (250 mg twice daily), an ALK inhibitor, was administered in October 2015. The patient was in the intensive care unit for airway catastrophe at the time of drug initiation. Bronchoscopy performed on day 7 of crizotinib therapy revealed an improved airway without gross tumor. The patient was discharged on the same day, afebrile and breathing room air. She subsequently underwent periodic bronchoscopic evaluation. She did not require further tumor debridement. Biopsy of the site of prior tumor and PET in December 2015 yielded negative results (Figure). The patient has remained in complete remission confirmed by computed tomography of the chest, abdomen, and pelvis as well as bronchoscopic evaluation in May 2016. Adverse events included grade 1 transaminitis and grade 1 lymphopenia, both of which have resolved. She is currently in her tenth month of treatment. To our knowledge, this is the first reported case of ENKTL responding to crizotinib identified in a precision medicine approach to cancer therapy. This patient’s disease underscores the presence and potential for therapeutic targeting of ALK mutations in chemotherapy-refractory ENTKL. Gita Thanarajasingam, MD Eric S. Edell, MD Svetomir M. Markovic, MD, PhD Mayo Clinic Rochester, MN
1. Yamaguchi M, Tobinai K, Oguchi M, et al. Phase I/II study of concurrent chemoradiotherapy for localized nasal natural killer/T-cell lymphoma: Japan Clinical Oncology Group Study JCOG0211. J Clin Oncol. 2009;27(33):5594-5600. 2. Yang Y, Zhu Y, Cao J-Z, et al. Risk-adapted therapy for early-stage extranodal nasal-type NK/T-cell lymphoma: analysis from a multicenter study. Blood. 2015;126(12):1424-1432.
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3. Gambacorti Passerini C, Farina F, Stasia A, et al. Crizotinib in advanced, chemoresistant anaplastic lymphoma kinaseepositive lymphoma patients. J Natl Cancer Inst. 2014;106(2):djt378. 4. Gambacorti-Passerini C, Messa C, Pogliani EM. Crizotinib in anaplastic large-cell lymphoma [letter]. N Engl J Med. 2011;364(8):775-776. http://dx.doi.org/10.1016/j.mayocp.2016.06.014
Predictive Validity of a Medical-Related Cardiorespiratory Fitness Algorithm in Predicting Cardiovascular Diseasee and All-Cause Mortality: Implications for Integration Into Clinical Practice To the Editor: The use of cardiorespiratory fitness (CRF), an important predictor of cardiovascular disease (CVD) risk,1-6 has been limited in the clinical setting because of the prerequisite expertise and equipment for conducting specialized assessments of CRF.1,2 As a result, Stamatakis et al1 and Artero et al2 explored the utility of predictive CRF algorithms that are estimated via nonexercise testing methods and reported inverse associations between CRF and mortality risk. In addition to the feasibility advantage, this method would potentially be of practical use in clinical settings among individuals who have limitations for performing exercise protocols. In 2014, Artero et al2 utilized a longitudinal algorithm to examine the association of calculated CRF and allcause mortality, CVD-specific mortality, and nonfatal CVD among adults from the Aerobics Center Longitudinal Study. Cardiorespiratory fitness was estimated as maximal metabolic equivalents (METs).2 Parameters employed in the CRF algorithm include sex, age, body mass index, waist circumference, resting heart rate, self-reported physical activity level, and smoking status.2 To our knowledge, this CRF algorithm (Figure footnote) has yet to
be validated in an independent cohort. Thus, the objective of our study was to assess the association of calculated CRF (using the aforementioned algorithm) with all-cause and CVDspecific mortality in a nationally representative sample of US adults. Data from the 1999-2006 National Health and Nutrition Examination Survey were employed, with followup through December 31, 2011. After excluding those with missing data for any of the algorithm variables and those with a physician diagnosis of coronary artery disease, congestive heart failure, myocardial infarction, angina, stroke, cancer, hypertension, diabetes, liver disease, or emphysema, 9974 participants (aged 20-85 years) remained and constituted the analytic sample. Among the 9974 participants, 490 (4.91%) died over the follow-up period, with 79 deaths (16.12%) being attributed to CVD. The duration of the unweighted median follow-up was 105 months (interquartile range, 81129 months). The entire sample encompassed 1,043,449 personmonths, with an incidence rate of 0.47 (95% CI, 0.43-0.51) all-cause deaths per 1000 person-months. The mean estimated MET level was 10.3 (95% CI, 10.2-10.4). In a Cox proportional hazards model, for every 1-MET increase (from the CRF algorithm), participants had a 24% reduced hazard of all-cause mortality (hazard ratio [HR], 0.76; 95% CI, 0.72-0.80; P<.001). The proportional hazards assumption (via Schoenfeld residuals) was not violated (P¼.39). The Kaplan-Meier survival curve, comparing those above and below the median MET level (9.8), is shown in the Figure. Results were unchanged when restricting the sample to those aged 50 years or older (HR, 0.79; 95% CI, 0.74-0.85; P<.001) or stratifying by men (HR, 0.71; 95% CI, 0.68-0.75; P<.001) or women (HR, 0.56; 95% CI, 0.510.61; P<.001). Results were similar Mayo Clin Proc.
n
September 2016;91(9):1319-1321 www.mayoclinicproceedings.org
Complete Response of Anaplastic Lymphoma KinaseeMutated Refractory Extranodal Natural Killer/ T-Cell Lymphoma to Crizotinib To the Editor: Extranodal natural killer/T-cell lymphoma, nasal type (ENKTL) is an uncommon, aggressive non-Hodgkin lymphoma that is associated with a high level of chemotherapy resistance.1 Frontline regimens for localized disease include radiotherapy or chemotherapy with radiation.2 Patients who have refractory
disease or who experience relapse after initial therapy have a dismal prognosis. Mutations in anaplastic lymphoma kinase (ALK) and response to targeted agents directed at these alterations have been described in anaplastic large cell lymphoma3,4 but not in ENKTL, which remains a challenge to manage in the salvage setting. We describe a complete response in a patient with airway obstruction due to relapse of ALK-positive ENKTL with endobronchial involvement. Report of Case. A 29-year-old woman had ENKTL initially diagnosed on biopsy of the right middle turbinate and nasal septum after months of odynophagia. She received frontline
chemotherapy and radiation with dexamethasone, etoposide, ifosfamide, and carboplatin in January 2015. Although response was observed in the nasopharynx on initial posttherapy positron emission tomography (PET), her disease relapsed shortly after in the carina and left main stem bronchus. The patient presented with severe airway obstruction and intermittent fevers at relapse. She had persistent, biopsy-proven, refractory plaquelike endobronchial tumor after 2 cycles of standard L-asparaginaseecontaining salvage chemotherapy. She remained hospitalized because of the need for bronchial stenting and numerous emergent bronchoscopies for tumor debulking with regrowth days later, and she had
FIGURE. Response to crizotinib in a patient with anaplastic lymphoma kinaseepositive extranodal natural killer/T-cell lymphoma, nasal type, documented on positron emission tomography (PET) and bronchoschopy. A, PET before initiation of crizotinib, showing tumorrelated plaquelike hypermetabolism of left main stem bronchus. B, Metabolic response of endobronchial tumor on PET after 6 weeks of crizotinib. C, Tumor occlusion of the left main stem bronchus before initiation of crizotinib. D, Bronchoscopic view of main carina; silicone stent in left main stem bronchus on day 7 of crizotinib. E, Bronchoscopic view of main carina; biopsy was negative for recurrent disease after 6 weeks of crizotinib therapy.
Mayo Clin Proc. n September 2016;91(9):1319-1321 www.mayoclinicproceedings.org n ª 2016 Mayo Foundation for Medical Education and Research
1319
MAYO CLINIC PROCEEDINGS
only transient stabilization of her airway with high-dose corticosteroids. In September 2015, nextgeneration sequencing identified a mutation in the ALK gene (ALK R214H). Crizotinib (250 mg twice daily), an ALK inhibitor, was administered in October 2015. The patient was in the intensive care unit for airway catastrophe at the time of drug initiation. Bronchoscopy performed on day 7 of crizotinib therapy revealed an improved airway without gross tumor. The patient was discharged on the same day, afebrile and breathing room air. She subsequently underwent periodic bronchoscopic evaluation. She did not require further tumor debridement. Biopsy of the site of prior tumor and PET in December 2015 yielded negative results (Figure). The patient has remained in complete remission confirmed by computed tomography of the chest, abdomen, and pelvis as well as bronchoscopic evaluation in May 2016. Adverse events included grade 1 transaminitis and grade 1 lymphopenia, both of which have resolved. She is currently in her tenth month of treatment. To our knowledge, this is the first reported case of ENKTL responding to crizotinib identified in a precision medicine approach to cancer therapy. This patient’s disease underscores the presence and potential for therapeutic targeting of ALK mutations in chemotherapy-refractory ENTKL. Gita Thanarajasingam, MD Eric S. Edell, MD Svetomir M. Markovic, MD, PhD Mayo Clinic Rochester, MN
1. Yamaguchi M, Tobinai K, Oguchi M, et al. Phase I/II study of concurrent chemoradiotherapy for localized nasal natural killer/T-cell lymphoma: Japan Clinical Oncology Group Study JCOG0211. J Clin Oncol. 2009;27(33):5594-5600. 2. Yang Y, Zhu Y, Cao J-Z, et al. Risk-adapted therapy for early-stage extranodal nasal-type NK/T-cell lymphoma: analysis from a multicenter study. Blood. 2015;126(12):1424-1432.
1320
3. Gambacorti Passerini C, Farina F, Stasia A, et al. Crizotinib in advanced, chemoresistant anaplastic lymphoma kinaseepositive lymphoma patients. J Natl Cancer Inst. 2014;106(2):djt378. 4. Gambacorti-Passerini C, Messa C, Pogliani EM. Crizotinib in anaplastic large-cell lymphoma [letter]. N Engl J Med. 2011;364(8):775-776. http://dx.doi.org/10.1016/j.mayocp.2016.06.014
Predictive Validity of a Medical-Related Cardiorespiratory Fitness Algorithm in Predicting Cardiovascular Diseasee and All-Cause Mortality: Implications for Integration Into Clinical Practice To the Editor: The use of cardiorespiratory fitness (CRF), an important predictor of cardiovascular disease (CVD) risk,1-6 has been limited in the clinical setting because of the prerequisite expertise and equipment for conducting specialized assessments of CRF.1,2 As a result, Stamatakis et al1 and Artero et al2 explored the utility of predictive CRF algorithms that are estimated via nonexercise testing methods and reported inverse associations between CRF and mortality risk. In addition to the feasibility advantage, this method would potentially be of practical use in clinical settings among individuals who have limitations for performing exercise protocols. In 2014, Artero et al2 utilized a longitudinal algorithm to examine the association of calculated CRF and allcause mortality, CVD-specific mortality, and nonfatal CVD among adults from the Aerobics Center Longitudinal Study. Cardiorespiratory fitness was estimated as maximal metabolic equivalents (METs).2 Parameters employed in the CRF algorithm include sex, age, body mass index, waist circumference, resting heart rate, self-reported physical activity level, and smoking status.2 To our knowledge, this CRF algorithm (Figure footnote) has yet to
be validated in an independent cohort. Thus, the objective of our study was to assess the association of calculated CRF (using the aforementioned algorithm) with all-cause and CVDspecific mortality in a nationally representative sample of US adults. Data from the 1999-2006 National Health and Nutrition Examination Survey were employed, with followup through December 31, 2011. After excluding those with missing data for any of the algorithm variables and those with a physician diagnosis of coronary artery disease, congestive heart failure, myocardial infarction, angina, stroke, cancer, hypertension, diabetes, liver disease, or emphysema, 9974 participants (aged 20-85 years) remained and constituted the analytic sample. Among the 9974 participants, 490 (4.91%) died over the follow-up period, with 79 deaths (16.12%) being attributed to CVD. The duration of the unweighted median follow-up was 105 months (interquartile range, 81129 months). The entire sample encompassed 1,043,449 personmonths, with an incidence rate of 0.47 (95% CI, 0.43-0.51) all-cause deaths per 1000 person-months. The mean estimated MET level was 10.3 (95% CI, 10.2-10.4). In a Cox proportional hazards model, for every 1-MET increase (from the CRF algorithm), participants had a 24% reduced hazard of all-cause mortality (hazard ratio [HR], 0.76; 95% CI, 0.72-0.80; P<.001). The proportional hazards assumption (via Schoenfeld residuals) was not violated (P¼.39). The Kaplan-Meier survival curve, comparing those above and below the median MET level (9.8), is shown in the Figure. Results were unchanged when restricting the sample to those aged 50 years or older (HR, 0.79; 95% CI, 0.74-0.85; P<.001) or stratifying by men (HR, 0.71; 95% CI, 0.68-0.75; P<.001) or women (HR, 0.56; 95% CI, 0.510.61; P<.001). Results were similar Mayo Clin Proc.
n
September 2016;91(9):1319-1321 www.mayoclinicproceedings.org