Hydroxyurea-Induced Pneumonitis in a Patient with Chronic Myelomonocytic Leukemia: an Autopsy Case

□ CASE REPORT □

Hydroxyurea-induced Pneumonitis in a Patient with Chronic Myelomonocytic Leukemia: An Autopsy Case

Hisao Imai 1, Nozomi Matsumura 2, Yuichi Yamazaki 1, Yuki Kanayama 1, Tomomi Masuda 1, Tomohito Kuwako 1, Yosuke Kamide 1,TakuTomizawa1, Shunichi Matsumoto 1, Takeki Mitsui 3, Kyoichi Kaira 4, Akihiro Ono 1, Yasuhiko Koga 1, Nobuyuki Shibusawa 1, Noriaki Sunaga 1, Takeshi Hisada 1, Hideaki Yokoo 2 and Masanobu Yamada 1

Abstract

We describe the case of an 85-year-old man diagnosed with chronic myelomonocytic leukemia whose disease was treated with hydroxyurea for 3 months. He developed respiratory symptoms that were extensively investigated. Despite the intensive treatment, he died of respiratory failure eleven days later. An autopsy revealed diffuse interstitial inflammation of both lungs consistent with drug-induced inflammation. A drug lymphocyte stimulation test was positive for hydroxyurea. Taken together these findings demonstrated that severe interstitial pneumonitis was induced by this drug. Physicians using hydroxyurea must be aware of its potentially life-threatening pulmonary toxicity.

Key words: chronic myelomonocytic leukemia, hydroxyurea, drug-induced pneumonitis

(Intern Med 54: 3171-3176, 2015) (DOI: 10.2169/internalmedicine.54.5069)

that can help to palliate symptoms related to massive Introduction splenomegaly and control elevated blood counts (3). It may cause myelosuppression at higher doses. Other complica- Chronic myelomonocytic leukemia (CMML) is a clonal tions include nausea, hepatitis, skin pigmentation, and ul- hematopoietic stem cell disorder with overlapping myelo- ceration. Various pulmonary disorders have arisen from the dysplastic and myeloproliferative features, and an inherent deleterious effects of drugs on the lungs. Certain cytotoxic tendency to transform into acute myeloid leukemia (1, 2). agents have been implicated in the production of widespread Bone marrow (BM) samples in CMML are typically hyper- alveolar damage (4, 5), including bleomycin, busulphan, cellular with predominant granulocytic/myeloid hyperplasia melphalan and chlorambucil. Hydroxyurea-induced pneu- and dysplasia. Monocytic proliferation is typically present in monitis is a rare complication. We herein report a case of the BM, but is often very difficult to detect in either the BM hydroxyurea-induced pneumonitis, and present the radiologi- aspirate or in biopsy specimens (1). The treatment for cal and histological findings of this disorder. CMML is broadly divided into supportive care and directed/ targeted therapies, including allogeneic hematopoietic stem Case Report cell transplantation (allo-HSCT) (1). Supportive care focuses on symptom management/palliation and applies to patients An 84-year-old man presented with exanthema in Decem- that are either ineligible for, have failed, or are concurrently ber 2013. He had no significant medical history except hy- undergoing CMML-directed therapy (1). Hydroxyurea (also pertension, and was not being prescribed any medications. known as hydroxycarbamide) is a myelosuppressive agent Blood tests revealed leukocytosis (21.0×109/L) accompanied

１Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Japan, ２Department of Human Pathology, Gunma University Graduate School of Medicine, Japan, ３Department of Medicine and Clinical Science, Gunma University Graduate School of Medicine, Japan and ４Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Japan Received for publication January 31, 2015; Accepted for publication March 31, 2015 Correspondence to Dr. Hisao Imai, [email protected]

3171 Intern Med 54: 3171-3176, 2015 DOI: 10.2169/internalmedicine.54.5069

Figure 1. (A) No pulmonary abnormalities were observed prior to the start of hydroxyurea administration. (B) At the onset of interstitial pneumonia, a chest radiograph revealed bilateral reticular shadows, mainly in the middle and lower regions of the bilateral lungs. (C) Progressive deterioration of the patient’s clinical condition was reflected by worsened chest radiograph findings on the eleventh day of hospitalization.

Figure 2. (A) No ground-glass infiltrate was observed before the initiation of hydroxyurea administration. (B) At the onset of interstitial pneumonia, a chest computed tomography (CT) scan revealed bilateral reticular shadows. (C) Chest CT of the thorax at the same level as that shown in A and B, performed on the third day of hospitalization, revealed more extensive ground-glass infiltrate. by anemia (hemoglobin 9.3 g/dL), and thrombocytopenia tations could be heard in his chest. A chest radiograph dem- (119×109/L). The differential blood count showed 3.0% onstrated bilateral diffuse shadows (Fig. 1B), and a CT scan blasts, 20.0% monocytes, 46.0% neutrophils, and 17.0% demonstrated interstitial change with diffuse ground-glass lymphocytes. The BM was hypercellular and was comprised opacification in a mosaic pattern throughout both lung of 4.4% myeloblasts with dysplasia, and conventional karyo- fields, together with small ground-glass areas in the upper typing revealed 46,XY,add (4) (p11) [19] / 46,XY [1]. Com- lobes (Fig. 2B). On admission, he was hypoxic, despite be- puted tomography (CT) revealed hepatosplenomegaly. From ing afebrile, and oxygen therapy was promptly started. The these findings, a diagnosis of chronic myelomonocytic leu- administration of hydroxyurea was stopped and the patient kemia was made. was given intravenous levofloxacin. The laboratory findings The pruritus in the patient’s eczema worsened gradually on admission included elevated serum levels of KL-6 and and the number of monocytes increased. Treatment with hy- SP-D (Table 1). A bronchoalveolar lavage (BAL) was per- droxyurea was started at a dose of 500 mg once daily, to- formed on admission, but no evidence of infection was re- gether with prednisolone 10 mg once daily. Blood transfu- vealed either by microscopy or by cultures for bacteria (in- sion was also started to treat the patient’s anemia. Before cluding mycobacterium), fungi, and viruses. The BAL fluid the initiation of hydroxyurea administration, a chest radio- analysis revealed 122,000 cells/mL (25% macrophages, 73% graph and CT were performed. These diagnostic modalities lymphocytes). The CD4+/CD8+ lymphocyte ratio was 1.38. did not reveal the presence of any ground-glass infiltrates Cytology (including staining for Pneumocystis jirovecii)was (Fig. 1A, 2A). He was maintained on this dose of hydroxy- negative, and the results of a subsequent serological test for urea. Three months later, the patient complained of breath- Legionella pneumophila and Mycoplasma pneumoniae were lessness and a dry cough, and reported that his symptoms also negative. On the second day of hospitalization, he was had worsened over the previous week. Bilateral basal crepi- febrile, with a temperature of 39.0°C, and his respiratory

3172 Intern Med 54: 3171-3176, 2015 DOI: 10.2169/internalmedicine.54.5069

Table 1. Laboratory Data on Admission. examination revealed three different patterns of interstitial pneumonia; diffuse alveolar damage (DAD), organizing Complete blood counts WBC 19,ǍL pneumonia (OP), and non-specific interstitial pneumonia Neutrophils 46.0% (NSIP). In the bilateral lung, interstitial fibrosis and mild to Lymphocytes 16.0% moderate chronic inflammation was observed. Even in areas Monocytes 27.0% of dense fibrosis, the alveolar architecture was almost com- Eosinophils 2.0% Basophils 0.0% pletely preserved (Fig. 3A). These findings were consistent Myelocyte 7.0% with NSIP. However, the distribution of fibrosis was patchy RBC 257×104/ǍL (Fig. 3B), with some polypoid fibrosis (Fig. 3C), but no fi- Hb 7.7 g/dL broblastic foci. These features are common in OP. There Ht 22.9% Platelets 50.0×104/ǍL were also extensive exudates, and diffuse hyaline mem- Blood chemistry branes, which are a key feature of acute-phase DAD T.P. 7.5 g/dL (Fig. 3D). These different interstitial pneumonia patterns Alb 3.0 g/dL were intermingled, and the acute-phase DAD pattern was T-bil 0.5 mg/dL AST 35 IU/L predominant. No organization could be detected in the DAD ALT 11 IU/L pattern. On the basis of these complex findings, it was not ALP 215 IU/L possible to identify a specific subtype of interstitial pneumo- Ǆ-GTP 12 IU/L nia. Clinical investigations suggested that the lung disease LDH 735 IU/L BUN 35 mg/dL may have been caused by hydroxyurea, and this was sup- Cre 1.21 mg/dL ported by the pathological findings. In addition to interstitial Na 142 mEq/L pneumonia, severe acute inflammation was observed in the K 4.2 mEq/L bilateral lung, and an abscess was present in the right lung. Cl 112 mEq/L CRP 0.61 mg/dL Histologically, no leukemic cell infiltration was detected. Serological studies Based on these findings, the severe interstitial pneumonitis RF <10 IU/mL was thought to have been induced by hydroxyurea. ANA negative PR3-ANCA <×1.0 U/mL MPO-ANCA <×1.0 U/mL Discussion KL-6 1,361 U/mL SP-D 1,840 ng/mL Hydroxyurea is increasingly used in the treatment of WBC: white blood cells, RBC: red blood cells, Alb: myeloproliferative disorders because it causes relatively few albumin, Cre: creatinine, CRP: C-reactive protein severe side effects. However, our patient developed life- threatening breathlessness and a dry cough during therapy with hydroxyurea for myeloproliferative disease. Hydroxy- symptoms persisted despite antibiotic therapy. His hypoxia urea induced pneumonia is extremely rare, and only 8 other could not be improved with antibiotics. Pulmonary embo- case reports of hydroxyurea-induced alveolitis or interstitial lism and acute heart failure were excluded. The antibiotic pneumonitis have been published in the English literature. therapy was stopped after four days of treatment due to a The differential diagnosis of respiratory disorders in patients lack of improvement and the negative microbiological cul- with myeloproliferative disease can include common condi- ture of lavage samples. The patient’s abnormal chest radio- tions such as respiratory infections, perhaps exacerbated by graph and CT findings had not improved (Fig. 2C). Treat- myelosuppressive therapy, and more specific complications, ment with methylprednisolone 1,000 mg once daily for three for example, pulmonary hypertension of unclear etiol- days was started. Subsequently, he was treated with predni- ogy (6), or extramedullary hematopoiesis within the solone 50 mg once daily. Over the next six days there was a lung (7). A precise diagnosis is essential for determining the progressive deterioration in his clinical condition, as ob- appropriate treatment. served by chest radiograph imaging (Fig. 1C) and a blood On rare occasions, acute exposure to hydroxyurea, over a gas analysis, with his pO2 on oxygen (O2 mask 8 L/min) number of weeks, can lead to pneumonitis (8). There are falling to 67 Torr. His pulmonary situation gradually wors- also reports of pneumonitis following chronic exposure ened. Adequate oxygenation became impossible. Subse- (longer than a year) to this drug (9, 10). In the case we re- quently, on the eleventh day of hospitalization, the patient port here, hydroxyurea led to this complication after three died. The drug lymphocyte stimulation test (DLST) gave a months of use. On the basis of persistent adverse clinical positive result for hydroxyurea (peripheral blood lympho- and radiological findings, despite an abbreviated course of cytes; stimulation index 590%). antibiotics, and the findings of the BAL analysis, the pres- At autopsy, the bilateral lungs were markedly enlarged ence of DLST (which was positive for hydroxyurea), and and heavy, and each weighed over 1,000 g (left: 1,090 g; the autopsy findings, we concluded that the pneumonitis was right: 1,100 g). The cut surface was dark red to brown, and due to hydroxyurea rather than a coincidental infectious a hemorrhage was observed in the right lung. A histological process. It is not clear whether there were triggering factors

3173 Intern Med 54: 3171-3176, 2015 DOI: 10.2169/internalmedicine.54.5069

Figure 3. (A) Intraluminal severe fibrosis was apparent, although the alveolar architecture was relatively well preserved (Elastica van Gieson staining). (B) There was a patchy distribution of fibrosis, but no fibroblastic foci were seen [Hematoxylin and Eosin (H&E) staining]. (C) Polypoid intraluminal plugs were sometimes seen (arrow; Masson’s trichrome staining). (D) A hyaline membrane was diffusely observed, and the alveolar septal interstitium were expanded by fibrosis and mild inflammation (H&E staining).

Table 2. A Summary of Reports Regarding Hydroxyurea-induced Alveolitis or Interstitial Pneumonitis.

Period of Reference Age Sex Disease Pathology Treatment Outcome onset Marked interstitial inflammation with poorly 8 48 Male Chronic myeloid leukemia 4 weeks Withdrawal and steroids Recovery formed granulomas 9 63 Male Chronic idiopathic myelofibrosis Desquamative interstitial pneumonitis 2 years Withdrawal Recovery

10 77 Female Essential thrombocythemia NR 4 years Withdrawal and steroids Recovery

17 77 Male Myeloproliferative syndrome NR 2 weeks Withdrawal and steroids Recovery Interstitial fibrosis and hyperplasia of 18 78 Female Myeloproliferative syndrome 3 months Withdrawal and steroids Recovery alveolar lining cells 19 58 Male Essential thrombocythemia NR 4 weeks Withdrawal Recovery

Mixed cellular and fibrotic inflammation 20 62 Female Polycythemia rubra vera within the interstitium together with 12 years Withdrawal Recovery granulomas 21 66 Male Chronic myeloid leukemia NR 3 weeks Withdrawal and steroids Recovery Three distinct patterns of interstitial pneumonia; diffuse alveolar damage, Current study 84 Male Chronic myelomonocytic leukemia 3 months Withdrawal and steroids Dead non-specific interstitial pneumonia, and organizing pneumonia NR: not reported preceding the development of pneumonitis. Interestingly, condition can contribute to the development of pneumonitis. cases of hydroxyurea-induced pneumonitis have only been However, it may simply reflect the fact that hydroxyurea has described in patients with an underlying myeloproliferative been extensively used in the treatment of myeloproliferative disorder, which may suggest that an existing hematological disorders. Because hydroxyurea is increasingly used to treat

3174 Intern Med 54: 3171-3176, 2015 DOI: 10.2169/internalmedicine.54.5069 diseases such as essential thrombocythemia, polycythemia Acknowledgement vera, and sickle cell anemia (11-14), cases of hydroxyurea- We wish to thank Ms. Mamiko Sakurai, Ms. Risa Kanai, Ms. induced pneumonitis, although rare, may become more com- Keiko Kogure, Dr. Yuta Inoue, Dr. Yuri Ozawa, and Dr. Ikue mon, and it is important to recognize this possibility. Okamura for their assistance in preparing this manuscript. In our patient, the HRCT findings were compatible with a References diagnosis of interstitial pneumonitis evolving into pulmonary fibrosis. Such CT characteristics have been well described in 1. Patnaik MM, Parikh SA, Hanson CA, Tefferi A. Chronic myelo- drug-induced lung disease (15), although they cannot be monocytic leukaemia: a concise clinical and pathophysiological used alone to predict a histological pattern or progno- review. Br J Haematol 165: 273-286, 2014. 2. Parikh SA, Tefferi A. Chronic myelomonocytic leukemia: 2013 sis (16). The autopsy in this case revealed diffuse alveolar update on diagnosis, risk stratification, and management. Am J damage, and both non-specific interstitial and organizing Hematol 88: 967-974, 2013. pneumonia. To the best of our knowledge, this is the first 3. Wattel E, Guerci A, Hecquet B, et al. A randomized trial of hy- reported case in which an autopsy was performed to investi- droxyurea versus VP16 in adult chronic myelomonocytic leuke- gate hydroxyurea-induced pneumonitis, and we are only mia. Groupe Francais des Myelodysplasies and European CMML Group. Blood 88: 2480-2487, 1996. aware of eight other cases of hydroxyurea-induced alveolitis 4. Twohig KJ, Matthay RA. Pulmonary effects of cytotoxic agents or interstitial pneumonitis published in the English litera- other than bleomycin. Clin Chest Med 11: 31-54, 1990. ture (8-10, 17-21). The relevant findings from these cases 5. Kreisman H, Wolkove N. Pulmonary toxicity of antineoplastic are summarized in Table 2. Only four of these cases de- therapy. Semin Oncol 19: 508-520, 1992. scribed pathological findings, and these were rather non- 6. Dingli D, Utz JP, Krowka MJ, Oberg AL, Tefferi A. Unexplained pulmonary hypertension in chronic myeloproliferative disorders. specific: marked interstitial inflammation with poorly Chest 120: 801-808, 2001. formed granulomas (8), a desquamative interstitial pneu- 7. Yusen RD, Kollef MH. Acute respiratory failure due to extrame- monitis pattern (9), non-specific interstitial fibrosis and dullary hematopoiesis. Chest 108: 1170-1172, 1995. pneumocyte hyperplasia (18), and a mixed pattern of cellu- 8. Sandhu HS, Barnes PJ, Hernandez P. Hydroxyurea-induced hyper- lar and fibrotic interstitial pneumonia with granulomas, con- sensitivity pneumonitis: a case report and literature review. Can sistent with a hypersensitivity reaction (20). The histological Respir J 7: 491-495, 2000. 9. Wong CC, Brown D, Howling SJ, Parker NE. Hydroxyurea- responses to pulmonary drug reactions often vary. Drug re- induced pneumonitis in a patient with chronic idiopathic myelofi- actions of the lungs are generally represented through either brosis after prolonged drug exposure. Eur J Haematol 71: 388- direct or indirect effects of the drug. We considered the pos- 390, 2003. sible causes of the various histological findings in our case 10. Internullo M, Giannelli V, Sardo L, et al. Hydroxyurea-induced in- (i.e. a complex hydroxyurea-toxic effect, the differing sensi- terstitial pneumonitis: case report and review of the literature. Eur Rev Med Pharmacol Sci 18: 190-193, 2014. tivity of alveolar epithelial cells, or the time course of cellu- 11. Cortelazzo S, Finazzi G, Ruggeri M, et al. Hydroxyurea for pa- lar injury). However, the mechanism of the toxic effect of tients with essential thrombocythemia and a high risk of thrombo- hydroxyurea remains to be elucidated and further study on sis. N Engl J Med 332: 1132-1136, 1995. hydroxyurea is needed. The BAL fluid contained lympho- 12. Gowin K, Mesa R. Management of thrombocythemia. F1000Res cytes, which may have been sensitized by hydroxyurea, and 3: 227, 2014. 13. Stein BL, Moliterno AR, Tiu RV. Polycythemia vera disease bur- could therefore account for the pathogenesis of den: contributing factors, impact on quality of life, and emerging hydroxyurea-induced interstitial pneumonia. Although eight treatment options. Ann Hematol 93: 1965-1976, 2014. other patients were alive when their cases were reported, our 14. Halsey C, Roberts IA. The role of hydroxyurea in sickle cell dis- patient died. The reason for this is unclear. However, our ease. Br J Haematol 120: 177-186, 2003. patient was 84 years old and his organ standby capacity was 15. Rossi SE, Erasmus JJ, McAdams HP, Sporn TA, Goodman PC. Pulmonary drug toxicity: radiologic and pathologic manifestations. lower than that of patients described in other reports. Al- Radiographics 20: 1245-1259, 2000. though the administration of hydroxyurea was withdrawn 16. Cleverley JR, Screaton NJ, Hiorns MP, Flint JD, Müller NL. and steroids were promptly administered, his physical condi- Drug-induced lung disease: high-resolution CT and histological tion was too poor to allow for a recovery. findings. Clin Radiol 57: 292-299, 2002. The present case highlights the fact that hydroxyurea can 17. Hennemann B, Bross KJ, Reichle A, Andreesen R. Acute alveolitis induced by hydroxyurea in a patient with myeloproliferative lead to severe pneumonitis. This complication, although syndrome. Ann Hematol 67: 133-134, 1993. rare, is important to recognize, as early cessation of hy- 18. Kavuru MS, Gadsden T, Lichtin A, Gephardt G. Hydroxyurea- droxyurea may lead to a substantial improvement in the as- induced acute interstitial lung disease. South Med J 87: 767-769, sociated symptoms. The case reported here also demon- 1994. strates the possibility of a fatal outcome of this reaction, 19. Quintas-Cardama A, Pérez-Encinas M, Gonzalez S, Bendaña A, Bello JL. Hydroxyurea-induced acute interstitial pneumonitis in a which mimics an infectious process. Physicians using hy- patient with essential thrombocythemia. Ann Hematol 78: 187- droxyurea must be aware of its potentially life-threatening 188, 1999. pulmonary toxicity. 20. Loo PS, Khan M, Currie GP, Husain E, Kerr KM. Hydroxycarbamide-induced pneumonitis. Histopathology 55: 234- The authors state that they havenoConflictofInterest(COI). 236, 2009. 21. Jackson GH, Wallis J, Ledingham J, Lennard A, Proctor SJ.

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Hydroxyurea-induced acute alveolitis in a patient with chronic 1990. myeloid leukaemia. Cancer Chemother Pharmacol 27: 168-169,

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