Radiation Recall Phenomenon Associated with Arsenic Trioxide

Home , Arsenic trioxide, Bleomycin, Capecitabine, Cyclophosphamide, Dacarbazine, Dactinomycin

CORRESPONDENCE

Radiation recall phenomenon associated with arsenic trioxide

Leukemia (2003) 17, 1417–1418. doi:10.1038/sj.leu.2402992

TO THE EDITOR

Arsenic trioxide has been shown to be effective and approved by the US Food and Drug Administration in treating patients with relapsed acute promyelocytic leukemia (APL).1,2 The dermatologic side effects of arsenic trioxide such as pruritus and dermatitis are usually mild and self-limiting. We report a case of severe radiation recall dermatitis in a patient with APL treated with arsenic trioxide. This patient was a 49-year-old African-American female when she was diagnosed with stage IIb left breast cancer in 1999 treated with modified radial mastectomy. After surgery, she received adjuvant chemotherapy with four cycles of adriamycin/cyclophosphamide and four cycles of paclitaxel, followed by adjuvant radiation to the left chest wall, left supraclavicular and left internal mammary nodes, 5000 cGy in 25 daily fractions, and tamoxifen. She had done extremely well until September 2001 when her white blood cell (WBC) decreased to 3700/ml, Hgb to 9.9 g/dl with MCV being 100.6 fl, and platelet count 220 000/ml. When she was referred to Figure 1 Radiation recall phenomenon on the chest wall received this institution in February 2002, the WBC was 1500/ml. Serum prior radiation. haptoglobin was 182 mg/dl, serum iron 140 mg/dl, TIBC 236 mg/dl, edatrexate, idarubicin, methotrexate, gemcitabine, dacarbazine, vitamin B12 level 489 pg/ml (normal 210–705), RBC folate level 760 ng/ml (normal 4164). Bone marrow examination revealed 80% oxaliplatin, capecitabine, troxacitabine, etc in chronological order cellularity and 68% promyelocytes and blasts with prominent Auer of reporting. Radiation recall has also been associated with noncytotoxic agents such as antibiotics, acyclovir, interferon, rods consistent with APL. The diagnosis was confirmed by 4,5 cytogenetic study and florescence in situ hybridization of the bone tamoxifen, sunlight, etc. However, the mechanism of radiation recall is poorly understood and it may be related to sequential marrow showing 46,XX,t(15;17)(q22;q21)[20]. She was treated 6 with all-trans-retinoic acid (ATRA) 45 mg/m2/day, daunorubicin damage and depletion of ‘stem cells’ in the skin. 50 mg/m2/day days 3–6, and cytarabine 200 mg/m2/day continuous While the dry skin peeling in the hands and feet are commonly infusion days 3–9 with complete morphologic and molecular described in patients on arsenic trioxide, the severe radiation recall remission achieved in 5 weeks. Intravenous dexrazoxane confined to the previously irradiated field in our patient has not been 500 mg/m2 was also added because her left ventricular ejection reported before. After radiation treatment for her breast carcinoma, our patient received tamoxifen that has been associated with fraction was only 44% probably secondary to prior Adriamycin and 4,5 chest wall radiation. She then received consolidation therapy radiation recall phenomenon. The fact that the dermatitis consisting of arsenic trioxide 0.15 mg/kg/day for 5 days each week improved despite continuation of tamoxifen make it an unlikely for 5 weeks, repeat once after 2 weeks of rest. By day 2 at week 3 of culprit in our case. Since the radiation recall occurred 11 weeks the second cycle of arsenic trioxide, she started noticing skin after induction and the patient did not develop any more radiation peeling off her feet and hands. In addition, she also noticed recall during her subsequent consolidation with daunorubicin, hyperpigmentation, vesicular formation and superficial desquama- daunorubicin is unlikely to be the inciting agent. Similarly, tion of the left chest wall, well demarcated to her previous radiation dexrazoxane is unlikely to be the inciting agent. field (Figure 1). In view of a possible radiation recall reaction, The onset of radiation recall reaction is temporally related and arsenic trioxide was discontinued. No systemic antibiotic was most likely causally related to arsenic trioxide since the skin prescribed because cellulitis was unlikely with such a well-defined reaction resolved after the medication was discontinued. We margin. The skin lesions were treated with topical triamcinolone/ believe that this is the first case of radiation recall reaction silver sulfadiazine cream with good response. She proceeded with associated with arsenic trioxide. Although the mechanism of action further consolidation of ATRA and daunorubicin/dexrazoxane may be different from radiation recall, it is intriguing that both organic arsenicals and arsenic trioxide have been shown to have without further problem. She is currently on maintenance ATRA 7,8 and in continuous remission 1 year after diagnosis. radiosensitizing effect in vitro. Radiation recall is an inflammatory reaction at a previously 1 1 Y-K Keung Section on Hematology and Oncology, irradiated fields usually associated but not limited to cytotoxic ES Lyerly1 Comprehensive Cancer Center at Wake Forest drugs. The common inciting agents (complete list of references of BL Powell1 University, Winston-Salem, NC, USA the inciting agents is available through e-mail from the correspond- ing author) include adriamycin,3 dactinomycin, etoposide, trime- trexate, melphalan, vinblastine, bleomycin, paclitaxel, docetaxel,

Correspondence: Y-K Keung, Section on Hematology and Oncology, References Comprehensive Cancer Center of Wake Forest University, Medical Center Boulevard, Winston-Salem, NC, USA; Fax: +1 336 716 5687 1 Hu J, Shen ZX, Sun GL, Chen SJ, Wang ZY, Chen Z. Long-term survival Received 6 February 2003; accepted 17 March 2003 and prognostic study in acute promyelocytic leukemia treated with Correspondence 1418 all-trans-retinoic acid, chemotherapy, and As2O3: an experience of 120 6 Yeo W, Johnson PJ. Radiation-recall skin disorders associated with the patients at a single institution. Int J Hematol 1999; 70: 248–260. use of antineoplastic drugs. Pathogenesis, prevalence, and management 2 Soignet SL, Frankel SR, Douer D, Tallman MS, Kantarjian H, Calleja E (Review) (31 references). Am J Clin Dermatol 2000; 1: 113–116. et al. United States multicenter study of arsenic trioxide in relapsed acute 7 Bump EA, Jacobs GP, Lee WW, Brown JM. Radiosensitization by promyelocytic leukemia. J Clin Oncol 2001; 19: 3852–3860. diamide analogs and arsenicals. Int J Radiat Oncol Biol Phys 1986; 12: 3 Donaldson SS, Glick JM, Wilbur JR. Letter: adriamycin activating a recall 1533–1535. phenomenon after radiation therapy. Ann Intern Med 1974; 81: 8 Chun YJ, Park IC, Park MJ, Woo SH, Hong SI, Chung HY et al. 407–408. Enhancement of radiation response in human cervical cancer cells in 4 Parry BR. Radiation recall induced by tamoxifen. Lancet 1992; vitro and in vivo by arsenic trioxide (As2O3). FEBS Lett 2002; 519: 340: 49. 195–200. 5 Bostrom A, Sjolin-Forsberg G, Wilking N, Bergh J. Radiation recall – another call with tamoxifen. Acta Oncol 1999; 38: 955–959.

Acute promyelocytic leukemia and aural recurrence: the importance of otoscopy in early diagnosis

Leukemia (2003) 17, 1418–1419. doi:10.1038/sj.leu.2402987 biological analyses indicated a relapse of leukemia (transformation from negative to positive PCR for PML-RAR alfa). Biopsy of the TO THE EDITOR EAC was carried out and the histopathological tests confirmed Acute promyelocytic leukemia (APL) (type M3 FAB) is a relatively the suspected diagnosis of recurrence of APL. The patient was rare pathology that represents approximately 10% of all the acute then transferred to the hematology department for the appropriate forms of myeloblastic leukemia. It is most important to identify this treatment. particular subtype of leukemia because of its potential to cause life- Only 16 cases (including ours) of otological extramedullary APL exist in the literature, 10 involving the EAC (two of which bilaterally) threatening disseminated intravascular coagulation and the clinical 1,4–6 5 response to all-trans retinoic acid treatment limited to this form of and six involving the mastoid. Breccia et al explain ear involvement by the presence of bone marrow in the mastoid and leukemia. 5 The typical cytogenetic abnormality in APL is characterized by a leukemic cells spreading to the auditory canal. This hypothesis is specific chromosome translocation between the long arm of suggestive, nevertheless it does not explain the cases in which chromosome 15 and 17, t(15:17), that involves the fusion of the relapse is primarily localized in the EAC. Of the otological relapses reported in the literature, 65% retinoic acid receptor-a (RAR-a) gene on chromosome 17 with the 1,4–6 putative transcription factor PML on chromosome 15. The result is a involve the EAC, and in these cases it would seem more hybrid PML–RAR-a gene, which is easily identified by the reverse reasonable in our opinion to attribute the site of origin to the transcriptase-polymerase chain reaction (RT-PCR). On cytogenetic skin rather than the mastoid. It is a common knowledge that the site most frequently affected by EMD at relapse is the skin, being examination, the presence of the t(15;17) is pathognomonic for APL 3 and is highly correlated with a positive response to all-trans retinoic involved in half of the reported cases; therefore, we are of the acid. opinion that the previous conclusion does not apply when the EAC It is highly rare for APL to be complicated by extramedullary is involved. disease (EMD) or recurrence. The latter usually affect the skin or the The cases of contemporary involvement of the mastoid and the central nervous system, but may also on occasion involve the ear, EAC are more complex and less easily interpreted. In our case, the lung and mediastinum, the gums, the thymus, the breast, the the first site of disease was the EAC with spreading in the middle ear testicles and the optic nerve.1,2 and the epitympanum. We are led to believe that ear relapse is not We present a case of APL relapse revealed by a earache and due to marrow involvement, but to a neighboring invasion hearing loss as a result of leukemic infiltration of the external originating in the cutaneous structure of the EAC. This site is presumably in line with the tendency of APL to involve the skin, auditory canal (EAC). A 22-year-old female was referred to our 3 department complaining of a headache that had persisted for 2 days, which Sanz et al has hypothesized to occur at the site of vascular severe earache and sudden loss of hearing in the left ear. She has disruption accompained by secondary bleeding that is not, however, related to the hemorrhagic properties of the disease. In been treated successfully 2 years earlier for APL that had receded 3 into dermatologic and medullary remission. She did not complain view of this Sanz et al strongly recommend a thorough follow-up period with timely cutaneous biopsies and hematological tests in of sore throat, fever, cold, cough and/or other disturbances of 3 the upper airways. Otomicroscopy was performed revealing the case of doubt. auditory canal to be edematous with an irregular reddish mass on It should be remembered that otological recurrence of APL often the upper posterior external wall. The results of the occurs late and/or casually; therefore, it follows that patients with blood tests showed mild leukocytosis, a high erythrocyte sedimen- leukemia in remission must necessarily undergo time regular tation rate (86 mm/h) and an increase in the alfa 1 and alfa 2 otoscopy. This examination is straightforward and easily performed, globulin value. Amoxycilline plus clavulanic acid were admini- not being invasive and on its own may indicate a suspected strated intravenously for 5 days with the result that the earache diagnosis, thus proving to be of crucial importance in early disappeared, but the state of the auditory mass remained practically diagnosis. unchanged. Although the hematological tests with bone marrow Four different clinical patterns may emerge from the otoscopic aspiration and lumbar puncture resulted negative, the molecular results, which we believe give indications as to the procedure of diagnosis to be followed.

Correspondence: Dr M Fusconi, via R D’Aronco 18, Rome 00163, (1) Isolated involvement of the EAC: Aural biopsy and Italy; Fax: +39 0 6 4460 378; E-mail: [email protected] histological examination in order to establish the nature of Received 18 February 2003; accepted 27 February 2003 the tumor.

Leukemia