Correspondence †Spirometry results were expressed as percentage of predicted based on recently published all-age/multiethnic reference equations using the fifth percentile as the lower limit of normal (LLN) for the set of equations derived for black individuals (Aggarwal and Agarwal 2007).

References Ballas, S.K., Lieff, S., Benjamin, L.J., Dampier, C.D., Heeney, M.M., Hoppe, C., Johnson, C.S., Rogers, Z.R., Smith-Whitley, K., Wang, W.C., Telen, M.J. & Investigators, C.S.C.C. (2010) Definitions of the phenotypic manifestations of sickle cell disease. American Journal of Hematology, 85, 6–13. Cohen, R.T., Madadi, A., Blinder, M.A., DeBaun, M.R., Strunk, R.C. & Field, J.J. (2011) Recurrent, severe wheezing is associated with morbidity and mortality in adults with sickle cell disease. American Journal of Hematology, 86, 756–761. Field, J.J., Stocks, J., Kirkham, F.J., Rosen, C.L., Dietzen, D.J., Semon, T., Kirkby, J., Bates, P., Seicean, S., DeBaun, M.R., Redline, S. & Strunk, R.C. (2011) Airway hyperresponsiveness in children with sickle cell anemia. Chest, 139, 563– 568.

††Obstructive spirometry patterns were defined as a FEV1/ FVC ratio below LLN. Restrictive spirometry patterns were defined as a FVC below LLN. Mixed spirometry patterns were defined as both a FVC and FEV1/FVC ratio below LLN. BDR, Bronchodilator Response; BD, Bronchodilator.

Glassberg, J.A., Chow, A., Wisnivesky, J., Hoffman, R., Debaun, M.R. & Richardson, L.D. (2012) Wheezing and asthma are independent risk factors for increased sickle cell disease morbidity. British Journal of Haematology, 159, 472–479. Knight-Madden, J.M., Barton-Gooden, A., Weaver, S.R., Reid, M. & Greenough, A. (2013) Mortality, asthma, smoking and acute chest syndrome in young adults with sickle cell disease. Lung, 191, 95–100. Morris, C.R., Vichinsky, E.P., van Warmerdam, J., Machado, L., Kepka-Lenhart, D., Morris, Jr, S.M. & Kuypers, F.A. (2003) Hydroxyurea and arginine therapy: impact on nitric oxide production in sickle cell disease. Journal of Pediatric Hematology/Oncology, 25, 629–634. Nandedkar, S.D., Feroah, T.R., Hutchins, W., Weihrauch, D., Konduri, K.S., Wang, J., Strunk, R.C., DeBaun, M.R., Hillery, C.A. & Pritchard, K.A. (2008) Histopathology of experimentally

induced asthma in a murine model of sickle cell disease. Blood, 112, 2529–2538. Pawar, S.S., Panepinto, J.A. & Brousseau, D.C. (2008) The effect of acute pain crisis on exhaled nitric oxide levels in children with sickle cell disease. Pediatric Blood & Cancer, 50, 111–113. Pritchard, Jr, K.A., Ou, J., Ou, Z., Shi, Y., Franciosi, J.P., Signorino, P., Kaul, S., Ackland-Berglund, C., Witte, K., Holzhauer, S., Mohandas, N., Guice, K.S., Oldham, K.T. & Hillery, C.A. (2004) Hypoxia-induced acute lung injury in murine models of sickle cell disease. American Journal of Physiology. Lung Cellular and Molecular Physiology, 286, L705–L714. Pritchard, K.A., Feroah, T.R., Nandedkar, S.D., Holzhauer, S.L., Hutchins, W., Schulte, M.L., Strunk, R.C., Debaun, M.R. & Hillery, C.A. (2012) Effects of experimental asthma on inflammation and lung mechanics in sickle cell mice. American Journal of Respiratory Cell and Molecular Biology, 46, 389–396.

Ibrutinib is an effective treatment of autoimmune haemolytic anaemia in chronic lymphocytic leukaemia

Autoimmune haemolytic anaemia (AIHA) is a life-threatening complication of chronic lymphocytic leukaemia (CLL). It is the most common variant of autoimmune cytopenia in CLL, with an incidence of ~23% as reported in a recent retrospective analysis of 1750 patients (Zent et al, 2009). AIHA most commonly develops after CLL diagnosis, but may be the presenting feature in a minority of patients. AIHA in CLL typically results from production of ‘warm’ immunoglobulin G (IgG) type antibodies (directed against red blood cells) by the non-malignant B-cells (Hamblin et al, 1986). Furthermore, monoclonal CLL cell-derived IgM antibodies were also implicated in autoimmunity (Broker et al, 1988), but cases of IgM-mediated AIHA in CLL are extremely infrequent. AIHA in CLL is treated with prednisone at 1 mg/kg for 2–4 weeks, followed by slow taper over 2–3 months (Hamblin, 2006; Visco et al, 2014). While generally safe, this therapy is associated with significant side effects in older patients, which represent the majority of patients with CLL. Furthermore, refractoriness to steroid therapy as well as necessity to administer high maintenance doses of prednisone to achieve adequate haemoglobin levels establish a need 734

for further therapy. Single agent rituximab, splenectomy, ciclosporin and chemotherapy regimens (cyclophosphamide, vincristine, prednisone) have shown efficacy (Bowen et al, 2010; Visco et al, 2014). Recently, inhibitors of B-cell receptor-associated kinases have been introduced into clinical practice (Awan & Byrd, 2014). A Bruton tyrosine kinase inhibitor, ibrutinib, has been approved for therapy of relapsed/refractory CLL and upfront therapy of CLL with del (17p). However, clinical trials involving this agent excluded patients with uncontrolled haemolysis. Here we report a case of a patient with CLL with del (17p) presenting with AIHA in whom control of a haemolytic process was achieved with ibrutinib. A 70-year-old man was diagnosed with asymptomatic CLL, Rai stage 0. At the time of diagnosis, his white blood cell count (WBC) was 382 9 109/l with 80% lymphocytes, haemoglobin 122 g/l and a platelet count of 162 9 109/l. Peripheral blood immunophenotyping demonstrated a population of CD5/CD19 positive, CD20-dim j-restricted B-cells that were CD38-negative and ZAP70-negative. The patient was lost to follow-up and 12 months later presented ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 170, 727–736

Correspondence with complaints of fatigue, generalized weakness, dyspnea and chest pain on mild exertion. A complete blood count showed a WBC of 726 9 109/l with 80% lymphocytes, haemoglobin 68 g/l and a platelet count of 172 9 109/l. Further work-up demonstrated an elevated lactate-dehydrogenase (LDH) at 708 u/l, haptoglobin of 011 g/l, reticulocyte count of 64%, elevated total and direct bilirubin as well as an IgM level of 27 g/l. Serum protein electrophoresis revealed a monoclonal IgMj, consistent with surface j-expression in CLL cells. A computerized tomography scan showed scattered retroperitoneal lymphadenopathy and moderate splenomegaly. Evaluation of the bone marrow demonstrated diffuse and nodular infiltrates of abnormal lymphocytes, which accounted for 80% of total marrow cellularity. Chromosomal analysis demonstrated presence of del (17p) in 50% of bone marrow cells by fluorescence in situ hybridization. A direct antiglobulin test (DAT) was strongly positive with 4+ reactivity with anti-IgG and 2+ reactivity with anti-C3d reagents. Elution was performed on the DAT specimen and demonstrated an IgG antibody that reacted with all cells tested (panagglutinin). A cold panel revealed a panagglutinin reacting at room temperature and below, but not at 37°C. Due to lack of reactivity at 37°C, the coldreactive antibody was deemed not clinically significant. Thermal amplitude testing was not performed as the patient already had a strongly positive IgG, which could account for the haemolytic process. The patient was diagnosed with AIHA and received prednisone 1 mg/kg. Two weeks later, he remained symptomatic, demonstrated a rise in his total WBC to 120 9 109/l (assumed to be a consequence of treatment with prednisone), a mild improvement in haemoglobin to 79 g/l, LDH of 500 u/l, and a rise in IgM level to 356 g/l. Given his ongoing symptoms, the patient received cyclophosphamide (500 mg/m2) and vincristine (2 mg) in addition to steroid therapy. Rituximab was held due to concerns of IgM flare and a potential infusion reaction with high circulating CLL count. Despite this therapy, 2 weeks later, the patient was found to have worsening anaemia (haemoglobin 76 g/l), persistently high LDH at 430 u/l and an IgM level of 475 g/l. Therefore, the patient was started on ibrutinib 420 mg daily. A repeat complete blood count 3 weeks later demonstrated a dramatic improvement in anaemia (haemoglobin 115 g/l) and haemolysis (LDH 275 u/l, haptoglobin 109 g/l) with complete resolution of symptoms. The patient was continued on ibrutinib and underwent a rapid steroid taper resulting in normalization of haemoglobin and LDH levels within a month.

References Awan, F.T. & Byrd, J.C. (2014) New strategies in chronic lymphocytic leukemia: shifting treatment paradigms. Clinical Cancer Research, 20, 5869–5874.

Due to the advanced age of patients who are diagnosed with CLL, safer approaches are necessary to treat AIHA, a life-threatening complication. Furthermore, despite recent advances in targeted therapy, CLL with del(17p) remains an area of unmet clinical need (Shindiapina et al, 2014), and treatment of AIHA in this group of patients is difficult due to the refractory nature of their disease. To our knowledge, this is the first report highlighting the successful use of ibrutinib to control steroid-refractory AIHA in high-risk CLL. While we could not fully exclude a possibility that CLL cellderived IgM antibodies with broad thermal amplitude propagated haemolytic anaemia in this case, the rarity of such cases and a strongly positive DAT reactive with IgG implicate IgG antibodies in this process. Ibrutinib has been shown to inhibit production of auto-antibodies in murine models of autoimmunity (Honigberg et al, 2010). While its exact mechanism of action in AIHA needs to be investigated, our report, in conjunction with pre-clinical data, provides a rationale to study ibrutinib in AIHA in CLL.

Conflict of interest No conflict of interest.

Acknowledgements This work was supported by the Lymphoma Research Foundation Clinical Investigator Career Development Award to AVD.

Author contributions AVD, SM, CRM-W and ND analysed the data; AVD, SM and ND wrote the paper. Sudhir Manda1 Nancy Dunbar1 Cynthia R. Marx-Wood1 Alexey V. Danilov1,2 1

Dartmouth-Hitchcock Medical Center, Lebanon, NH, and 2Knight

Cancer Institute, Oregon Health and Science University, Portland, OR, USA. E-mail: [email protected]

Keywords: chronic lymphocytic leukaemia, ibrutinib, autoimmune haemolytic anaemia First published online 25 February 2015 doi: 10.1111/bjh.13328

Bowen, D.A., Call, T.G., Shanafelt, T.D., Kay, N.E., Schwager, S.M., Reinalda, M.S., Rabe, K.G., Slager, S.L. & Zent, C.S. (2010) Treatment of autoimmune cytopenia complicating progressive chronic lymphocytic leukemia/small lymphocytic lymphoma with rituximab, cyclophosphamide,

ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 170, 727–736

vincristine, and prednisone. Leukaemia & Lymphoma, 51, 620–627. Broker, B.M., Klajman, A., Youinou, P., Jouquan, J., Worman, C.P., Murphy, J., Mackenzie, L., Quartey-Papafio, R., Blaschek, M., Collins, P., Lal, S., Lydyard, P.M. (1988) Chronic lymphocytic

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Correspondence leukemic (CLL) cells secrete multispecific autoantibodies. Journal of Autoimmunity, 1, 469–481. Hamblin, T.J. (2006) Autoimmune complications of chronic lymphocytic leukemia. Seminars in Oncology, 33, 230–239. Hamblin, T.J., Oscier, D.G. & Young, B.J. (1986) Autoimmunity in chronic lymphocytic leukaemia. Journal of Clinical Pathology, 39, 713–716. Honigberg, L.A., Smith, A.M., Sirisawad, M., Verner, E., Loury, D., Chang, B., Li, S., Pan, Z., Thamm, D.H., Miller, R.A. & Buggy, J.J. (2010) The Bruton tyrosine kinase inhibitor PCI-32765

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blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proceedings of the National Academy of Sciences of the United States of America, 107, 13075–13080. Shindiapina, P., Brown, J.R. & Danilov, A.V. (2014) A new hope: novel therapeutic approaches to treatment of chronic lymphocytic leukaemia with defects in TP53. British Journal of Haematology, 167, 149–161. Visco, C., Barcellini, W., Maura, F., Neri, A., Cortelezzi, A. & Rodeghiero, F. (2014) Autoimmune cytopenias in chronic lymphocytic leuke-

mia. American Journal of Hematology, 89, 1055–1062. Zent, C.S., Ding, W., Reinalda, M.S., Schwager, S.M., Hoyer, J.D., Bowen, D.A., Jelinek, D.F., Tschumper, R.C., Call, T.G., Shanafelt, T.D., Kay, N.E. & Slager, S.L. (2009) Autoimmune cytopenia in chronic lymphocytic leukemia/small lymphocytic lymphoma: changes in clinical presentation and prognosis. Leukaemia & Lymphoma, 50, 1261–1268.

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Ibrutinib is an effective treatment of autoimmune haemolytic anaemia in chronic lymphocytic leukaemia.

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