Correspondence Karl Haslam1 Stephen E. Langabeer1 Karen Molloy1 Mary F. McMullin2 Eibhlin Conneally3
lin, Ireland E-mail: [email protected]
Keywords: myelofibrosis, CALR mutations, allogeneic stem cell transplantation
1
Cancer Molecular Diagnostics, St. James’s Hospital, Dublin, Ireland,
2
First published online 21 April 2014
fast, UK and 3Department of Haematology, St. James’s Hospital, Dub-
doi: 10.1111/bjh.12904
Centre for Cancer Research & Cell Biology, Queen’s University, Bel-
References Alchalby, H., Badbaran, A., Zabelina, T., Kobbe, G., Hahn, J., Wolff, D., Bornh€auser, M., Thiede, C., Baurmann, H., Bethge, W., Hildebrandt, Y., Bacher, U., Fehse, B., Zander, A.R. & Kr€ oger, N. (2010a) Impact of JAK2 V617F mutation status, allele burden, and clearance after allogeneic stem cell transplantation for myelofibrosis. Blood, 116, 3572–3581. Alchalby, H., Badbaran, A., Bock, O., Fehse, B., Bacher, U., Zander, A.R. & Kr€ oger, N. (2010b) Screening and monitoring of MPL W515L mutation with real-time PCR in patients with myelofibrosis undergoing allogeneic-SCT. Bone Marrow Transplantation, 45, 1404–1407. Klampfl, T., Gisslinger, H., Harutyunyan, A.S., Nivarthi, H., Rumi, E., Milosevic, J.D., Them, N.C., Berg, T., Gisslinger, B., Pietra, D., Chen, D., Vladimer, G.I., Bagienski, K., Milanesi, C., Casetti, I.C., Sant’Antonio, E., Ferretti, V., Elena, C., Schischlik, F., Cleary, C., Six, M., Schalling, M., Sch€ onegger, A., Bock, C., Malcovati, L., Pascutto, C., Superti-Furga, G., Cazzola, M. & Kralovics, R. (2013) Somatic mutations of calreticulin in myeloproliferative neoplasms. New England Journal of Medicine, 369, 2379– 2390. Kr€ oger, N., Alchalby, H., Klyuchnikov, E., Badbaran, A., Hildebrandt, Y., Ayuk, F., Bacher, U., Bock, O., Kvasnicka, M., Fehse, B. & Zander, A.
(2009) JAK2 V617F-triggered preemptive and salvage adoptive immunotherapy with donorlymphocyte infusion in patients with myelofibrosis after allogeneic stem cell transplantation. Blood, 113, 1866–1868. Lange, T., Edelmann, A., Siebolts, U., Krahl, R., Nehring, C., J€akel, N., Cross, M., Maier, J., Niederwieser, D. & Wickenhauser, C. (2013) JAK2 p.V617F allele burden in myeloproliferative neoplasms one month after allogeneic stem cell transplantation significantly predicts outcome and risk of relapse. Haematologica, 98, 722–728. Lion, T., Watzinger, F., Preuner, S., Kreyenberg, H., Tilanus, M., de Weger, R., van Loon, J., de Vries, L., Cave, H., Acquaviva, C., Lawler, M., Crampe, M., Serra, A., Saglio, B., Colnaghi, F., Biondi, A., van Dongen, J.J., van der Burg, M., Gonzalez, M., Alcoceba, M., Barbany, G., Hermanson, M., Roosnek, E., Steward, C., Harvey, J., Frommlet, F. & Bader, P. (2012) The Eurochimerism concept for a standardized approach to chimerism analysis after allogeneic stem cell transplantation. Leukemia, 26, 1821–1828. McLornan, D.P., Mead, A.J., Jackson, G. & Harrison, C.N. (2012) Allogeneic stem cell transplantation for myelofibrosis in 2012. British Journal of Haematology, 157, 413–425. Nangalia, J., Massie, C.E., Baxter, E.J., Nice, F.L., Gundem, G., Wedge, D.C., Avezov, E.,
Li, J., Kollman, K., Kent, D.G., Aziz, A., Godfrey, A.L., Hinton, J., Martincorena, I., Van Loo, P., Jones, A.V., Guglielmelli, P., Tarpey, P., Harding, H.P., Fitzpatrick, J.D., Goudie, C.T., Ortmann, C.A., Loughran, S.J., Raine, K., Jones, D.R., Butler, A.P., Teague, J.W., O’Meara, S., Mc Laren, S., Bianchi, M., Silber, Y., Dimitropoulou, D., Bloxham, D., Mudie, L., Maddison, M., Robinson, B., Keohane, C., Maclean, C., Hill, K., Orchard, K., Tauro, S., Du, M.Q., Greaves, M., Bowen, D., Huntly, B.J., Harrison, C.N., Cross, N.C., Ron, D., Vannucchi, A.M., Papaemmanuil, E., Campbell, P.J. & Green, A.R. (2013) Somatic CALR mutations in myeloproliferative neoplasms with unmutated JAK2. New England Journal of Medicine, 369, 2391–2405. Panagiota, V., Thol, F., Markus, B., Fehse, B., Alchalby, H., Badbaran, A., Lehmann, U., Koenecke, C., Shahswar, R., Chaturvedi, A., Stadler, M., Eder, M., G€ ohring, G., Koeningsmann, M., Kloos, A., Trummer, A., Schroeder, T., Kobbe, G., Thiede, C., Platzbecker, U., Schlegelberger, B., Kreipe, H.H., Ganser, A., Kr€ oger, N. & Heuser, M. (2014) Prognostic effect of calreticulin mutations in patients with myelofibrosis after allogeneic hematopoietic stem cell transplantation. Leukemia, doi: 10.1038/leu.2014.66. Tefferi, A. & Pardanani, A. (2014) CALR mutations and a new diagnostic algorithm for MPN. Nature Reviews Clinical Oncology, 11, 125–126.
Malignancy and thrombotic microangiopathy or atypical haemolytic and uraemic syndrome?
Thrombotic microangiopathy (TMA) is a vascular disorder defined by the occurrence of platelet and/or fibrin thrombi in the microvasculature of various organs, most particularly the kidney, in the setting of haemolytic and uraemic syndrome (HUS). Among several origins, TMAs may be related to malignancies (Lechner & Obermeier, 2012). Malignancy-related TMA is similar to atypical HUS (aHUS) when acute kidney injury (AKI) is present. Dysregulation 802
of the complement alternative pathway accounts for aHUS pathogenesis (Fremeaux-Bacchi et al, 2013) but the pathogenesis of malignancy-related TMA is poorly understood. We report on two patients with AKI and TMA who had genomic disorders predisposing to aHUS and who went on to develop malignancies. Both patients had been successfully treated with eculizumab before the diagnosis of cancer was made. ª 2014 John Wiley & Sons Ltd British Journal of Haematology, 2014, 166, 792–805
Correspondence Both patients were admitted for AKI with thrombocytopenia and schistocytic haemolytic anaemia (Table I). Thrombotic thrombocytopenic purpura was excluded because ADAMTS 13 (a disintegrin and metalloproteinase with thrombospondin motif, member 13) plasma activity was detectable (>10%). Stool tests for entero-haemorrhagic Escherichia coli were negative and plasma complement assays were normal. Kidney biopsy disclosed typical lesion of TMA, namely mesangiolysis and arteriolosclerosis associated with acute tubular necrosis in Patient 1. A mutation in the CFH gene was detected in the first patient and a CFR1-CFHR3 deletion was found in the second patient (Table I). After plasma exchanges failed to control TMA, eculizumab was started at the initial dose of 900 mg weekly for a month and subsequently 1200 mg every fortnight. In the first patient, schistocytic haemolytic anaemia completely resolved within 7 d, kidney function progressively recovered and dialysis was stopped (Fig 1A). In the second patient, platelet count improved, haemolysis completely resolved and dialysis was stopped (Fig 1B). Patient 1 presented with persistent cough and dyspnea 4 months later. A chest computerized tomography scan revealed the presence of a tumour in the left inferior pulmonary lobe (60 9 20 mm). A lung biopsy revealed a well-differentiated carcinoid tumour, which was treated by a left inferior lobectomy (Fig 1A). Patient 2 presented with circulating blast cells and was diagnosed with acute myeloid leukaemia (AML), M2 subtype, 3 months after the onset of TMA. Chemotherapy with cytarabine and doxorubicin was started and eculizumab was continued (1200 mg/2 weeks). This patient died 2 weeks after the start of chemotherapy as a result of veno-occlusive disease of the liver and acute heart failure (Fig 1B). Predisposing genomic conditions may be associated with sporadic aHUS, as previously documented (Noris et al, 2010). In the present report, Patient 1 had a CFH mutation and a homozygous aHUS at-risk CD46/CAPG polymorphism. Patient 2 had a complete CFHR1-CFHR3 deletion, a rare genetic variation that is highly associated with anti Factor H antibody (absent in this patient). A triggering condition, such as drug administration, infection or cancer, may be associated with the occurrence of aHUS in patients with predisposing genomic dysregulation of the alternative complement pathway (Noris et al, 2010). Therefore, the underlying malignancy could have triggered aHUS in these cases. However, to the best of our knowledge, the role of complement dysregulation in malignancy-related TMA has not been addressed. No data regarding the incidence of acquired or constitutional complement dysregulation are available because patients with cancer are usually excluded from large series of aHUS patients screened for complement dysregulation. Thus, the pathogenesis of malignancy-TMA remains poorly understood. Intravascular dissemination of malignant cells and/or endothelial cell activation induced by various cytokines released by malignant cells are suspected. ª 2014 John Wiley & Sons Ltd British Journal of Haematology, 2014, 166, 792–805
Table I. Main biological findings in two patients with malignancyrelated thrombotic microangiopathy treated with eculizumab.
Serum creatinine (lmol/l) Platelet count (9109/l) Haemoglobin (g/l) LDH (9ULN) Haptoglobin Proteinuria (g/day) Schizocytes Leucocyte count (9109/l) Prothrombin time (%) CKT (9normal) Fibrinogen (g/l) C3 (660–1250 mg/l) C4 (93–380 mg/l) CFH (mg/l) CFI (mg/l) Anti-factor H antibody Screen for complement genes Mutation in CFH gene Mutation in CFI gene Muation in MCP gene Homozygous CFH aHUS at risk haplotype Homozygous MCP aHUS at risk haplotype Complete CFHR1-CFHR3 deletion
Patient 1
Patient 2
895 183 94 35 Undetectable 7 Present 37 101 1 46 1010 253 540 56 Absent
225 51 86 63 Undetectable 47 Present 113 100 1 310 1140 293 510 62 Absent
Yes (p.Y1016C) No No No
No No No No
Yes
Yes
No (2 copies)
Yes
LDH, lactate dehydrogenase; ULN, upper limit of normal; CKT, cephalin kaolin time; C3, complement component 3; C4, complement component 4; CFH, complement factor H; CFI, complement factor I.
Interestingly, haemolysis resolved and renal function improved with eculizumab administration in our two aHUS patients before the diagnosis of cancer was made. Eculizumab is a humanized monoclonal antibody that inhibits all complement pathways by preventing the cleavage of C5 by the C5 convertase and thus inhibiting the release of C5a and C5b that ultimately initiates the formation of the membrane attack complex. Accumulating case series and preliminary results from prospective studies indicate that eculizumab dramatically improves the renal outcome of aHUS patients (Legendre et al, 2013; Zuber et al, 2013). Eculizumab has been used as rescue therapy in many forms of secondary TMAs, including post-bone marrow transplantation (Peffault de Latour et al, 2013), anti-phospholipid syndrome-related TMA (Shapira et al, 2012) and severe typical HUS (Menne et al, 2012). Because of the infrequency of the association of carcinoid tumour and acute leukaemia with TMA, complement dysregulation should not be suspected in every patient with cancer and TMA. Malignancies related with TMA are mostly metastatic solid tumours from stomach, prostate, lung or breast. 803
Correspondence
(A)
(B)
Fig 1. Course of disease in patients with malignancy-related thrombotic microangiopathy treated with eculizumab. (A) evolution of serum creatinine and platelet count in Patient 1. (B) evolution of serum creatinine and platelet count in Patient 2. HD, haemodialysis; PE, plasma exchange; KB, kidney biopsy; W, weeks; SCr, serum creatinine; Plts, platelet count; M, months.
Only one case of neuroendocrine tumour associated-TMA has been previously documented (Elliott et al, 2010), even though other types of endocrine tumours (pheochromocytoma, pituitary tumours) have been associated with TMA. Thrombotic microangiopathy has been associated with haemopathies, mostly lymphoma (Lechner & Obermeier, 2012). The association of TMA with acute leukaemia has been rarely reported, mostly in children, and TMA may precede acute leukaemia by several months (Clarke & Mitchell, 2010). In conclusion, atypical HUS and malignancy-related TMA are two distinct entities that share common traits. Both require multidisciplinary and intensive care and have a poor prognosis. Our observations suggest that malignancy-related TMA may be included in the expanding spectrum of complement pathway dysregulation-associated disorders. Accord804
ingly, patients with cancer who develop TMA and AKI should be screened for complement pathway dysregulation and eculizumab should be considered in order to improve TMA features and allow an optimal malignancy-targeted therapy.
Acknowledgments All authors have paid substantial contributions to the analysis of the presented data and to the redaction of the paper. Guillaume Favre and Fadi Fakhouri wrote the paper. All authors have approved the final version of the manuscript. Guillaume A. Favre1,2 Maxime Touzot3 Veronique Fremeaux-Bacchi4 ª 2014 John Wiley & Sons Ltd British Journal of Haematology, 2014, 166, 792–805
Correspondence Herve Hyvernat5 Jean-Pierre Gueffet6 Pierre S. Rohrlich7 Viviane Queyrel8 Vincent Esnault1,2 Fadi Fakhouri3
tes University Hospital, 7Department of Haematology, Nice University Hospital, and 8Department of Internal Medicine, Nice University Hospital, Nice, France E-mail: [email protected]
1
Department of nephrology, CHU de Nice, 2Aging and Diabetes Team,
IRCAN, UMR-INSERM 1081, Nice, 3Department of Nephrology, Nan-
Keywords: thrombotic microangiopathy, acute kidney injury, atypical haemolytic and uraemic syndrome, acute myeloid leukaemia, carcinoid tumour
tes University Hospital and ITUN, UMR S-1064, Nantes, 4Department of Immunology, Georges Pompidou European Hospital, Paris, 5Intensive 6
Care Unit, Nice University Hospital, Department of Cardiology, Nan-
References Clarke, R.T. & Mitchell, C. (2010) Haemolytic uraemic syndrome in a patient with acute lymphoblastic leukaemia. Pediatric Blood & Cancer, 55, 1402–1405. Elliott, M.A., Letendre, L., Gastineau, D.A., Winters, J.L., Pruthi, R.K. & Heit, J.A. (2010) Cancer-associated microangiopathic hemolytic anemia with thrombocytopenia: an important diagnostic consideration. European Journal of Haematology, 85, 43–50. Fremeaux-Bacchi, V., Fakhouri, F., Garnier, A., Bienaime, F., Dragon-Durey, M.A., Ngo, S., Moulin, B., Servais, A., Provot, F., Rostaing, L., Burtey, S., Niaudet, P., Deschenes, G., Lebranchu, Y., Zuber, J. & Loirat, C. (2013) Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults. Clinical Journal of the American Society of Nephrology, 8, 554–562. Lechner, K. & Obermeier, H.L. (2012) Cancerrelated microangiopathic hemolytic anemia: clinical and laboratory features in 168 reported cases. Medicine (Baltimore), 91, 195–205. Legendre, C.M., Licht, C., Muus, P., Greenbaum, L.A., Babu, S., Bedrosian, C., Bingham, C., Cohen, D.J., Delmas, Y., Douglas, K., Eitner, F., Feldkamp, T., Fouque, D., Furman, R.R., Gaber, O., Herthelius, M., Hourmant, M., Karpman, D., Lebranchu, Y., Mariat, C., Menne, J., Mou-
First published online 21 April 2014 doi: 10.1111/bjh.12907
lin, B., N€ urnberger, J., Ogawa, M., Remuzzi, G., Richard, T., Sberro-Soussan, R., Severino, B., Sheerin, N.S., Trivelli, A., Zimmerhackl, L.B., Goodship, T. & Loirat, C. (2013) Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. New England Journal of Medicine, 368, 2169–2181. Menne, J., Nitschke, M., Stingele, R., Abu-Tair, M., Beneke, J., Bramstedt, J., Bremer, J.P., Brunkhorst, R., Busch, V., Dengler, R., Deuschl, G., Fellermann, K., Fickenscher, H., Gerigk, C., Goettsche, A., Greeve, J., Hafer, C., Hagenmuller, F., Haller, H., Herget-Rosenthal, S., Hertenstein, B., Hofmann, C., Lang, M., Kielstein, J.T., Klostermeier, U.C., Knobloch, J., Kuehbacher, M., Kunzendorf, U., Lehnert, H., Manns, M.P., Menne, T.F., Meyer, T.N., Michael, C., Munte, T., Neumann-Grutzeck, C., Nuernberger, J., Pavenstaedt, H., Ramazan, L., Renders, L., Repenthin, J., Ries, W., Rohr, A., Rump, L.C., Samuelsson, O., Sayk, F., Schmidt, B.M., Schnatter, S., Schocklmann, H., Schreiber, S., von Seydewitz, C.U., Steinhoff, J., Stracke, S., Suerbaum, S., van de Loo, A., Vischedyk, M., Weissenborn, K., Wellhoner, P., Wiesner, M., Zeissig, S., Buning, J., Schiffer, M. & Kuehbacher, T. (2012) Validation of treatment strategies for enterohaemorrhagic Escherichia coli O104:H4 induced haemolytic
ª 2014 John Wiley & Sons Ltd British Journal of Haematology, 2014, 166, 792–805
uraemic syndrome: case-control study. British Medical Journal, 345, e4565. Noris, M., Caprioli, J., Bresin, E., Mossali, C., Pianetti, G., Gamba, S., Daina, E., Fenili, C., Castelletti, F., Sorosina, A., Piras, R., Donadelli, R., Maranta, R., van der Meer, I., Conway, E.M., Zipfel, P.F., Goodship, T.H. & Remuzzi, G. (2010) Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clinical Journal of the American Society of Nephrology, 5, 1844–1859. Peffault de Latour, R., Xhaard, A., Fremeaux-Bacchi, V., Coppo, P., Fischer, A.M., Helley, D. & Socie, G. (2013) Successful use of eculizumab in a patient with post-transplant thrombotic microangiopathy. British Journal of Haematology, 161, 279–280. Shapira, I., Andrade, D., Allen, S.L. & Salmon, J.E. (2012) Brief report: induction of sustained remission in recurrent catastrophic antiphospholipid syndrome via inhibition of terminal complement with eculizumab. Arthritis and Rheumatism, 64, 2719–2723. Zuber, J., Fakhouri, F., Roumenina, L.T., Loirat, C. & Fremeaux-Bacchi, V. (2013) Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies. Nature Reviews. Nephrology, 8, 643–657.
805
lin, Ireland E-mail: [email protected]
Keywords: myelofibrosis, CALR mutations, allogeneic stem cell transplantation
1
Cancer Molecular Diagnostics, St. James’s Hospital, Dublin, Ireland,
2
First published online 21 April 2014
fast, UK and 3Department of Haematology, St. James’s Hospital, Dub-
doi: 10.1111/bjh.12904
Centre for Cancer Research & Cell Biology, Queen’s University, Bel-
References Alchalby, H., Badbaran, A., Zabelina, T., Kobbe, G., Hahn, J., Wolff, D., Bornh€auser, M., Thiede, C., Baurmann, H., Bethge, W., Hildebrandt, Y., Bacher, U., Fehse, B., Zander, A.R. & Kr€ oger, N. (2010a) Impact of JAK2 V617F mutation status, allele burden, and clearance after allogeneic stem cell transplantation for myelofibrosis. Blood, 116, 3572–3581. Alchalby, H., Badbaran, A., Bock, O., Fehse, B., Bacher, U., Zander, A.R. & Kr€ oger, N. (2010b) Screening and monitoring of MPL W515L mutation with real-time PCR in patients with myelofibrosis undergoing allogeneic-SCT. Bone Marrow Transplantation, 45, 1404–1407. Klampfl, T., Gisslinger, H., Harutyunyan, A.S., Nivarthi, H., Rumi, E., Milosevic, J.D., Them, N.C., Berg, T., Gisslinger, B., Pietra, D., Chen, D., Vladimer, G.I., Bagienski, K., Milanesi, C., Casetti, I.C., Sant’Antonio, E., Ferretti, V., Elena, C., Schischlik, F., Cleary, C., Six, M., Schalling, M., Sch€ onegger, A., Bock, C., Malcovati, L., Pascutto, C., Superti-Furga, G., Cazzola, M. & Kralovics, R. (2013) Somatic mutations of calreticulin in myeloproliferative neoplasms. New England Journal of Medicine, 369, 2379– 2390. Kr€ oger, N., Alchalby, H., Klyuchnikov, E., Badbaran, A., Hildebrandt, Y., Ayuk, F., Bacher, U., Bock, O., Kvasnicka, M., Fehse, B. & Zander, A.
(2009) JAK2 V617F-triggered preemptive and salvage adoptive immunotherapy with donorlymphocyte infusion in patients with myelofibrosis after allogeneic stem cell transplantation. Blood, 113, 1866–1868. Lange, T., Edelmann, A., Siebolts, U., Krahl, R., Nehring, C., J€akel, N., Cross, M., Maier, J., Niederwieser, D. & Wickenhauser, C. (2013) JAK2 p.V617F allele burden in myeloproliferative neoplasms one month after allogeneic stem cell transplantation significantly predicts outcome and risk of relapse. Haematologica, 98, 722–728. Lion, T., Watzinger, F., Preuner, S., Kreyenberg, H., Tilanus, M., de Weger, R., van Loon, J., de Vries, L., Cave, H., Acquaviva, C., Lawler, M., Crampe, M., Serra, A., Saglio, B., Colnaghi, F., Biondi, A., van Dongen, J.J., van der Burg, M., Gonzalez, M., Alcoceba, M., Barbany, G., Hermanson, M., Roosnek, E., Steward, C., Harvey, J., Frommlet, F. & Bader, P. (2012) The Eurochimerism concept for a standardized approach to chimerism analysis after allogeneic stem cell transplantation. Leukemia, 26, 1821–1828. McLornan, D.P., Mead, A.J., Jackson, G. & Harrison, C.N. (2012) Allogeneic stem cell transplantation for myelofibrosis in 2012. British Journal of Haematology, 157, 413–425. Nangalia, J., Massie, C.E., Baxter, E.J., Nice, F.L., Gundem, G., Wedge, D.C., Avezov, E.,
Li, J., Kollman, K., Kent, D.G., Aziz, A., Godfrey, A.L., Hinton, J., Martincorena, I., Van Loo, P., Jones, A.V., Guglielmelli, P., Tarpey, P., Harding, H.P., Fitzpatrick, J.D., Goudie, C.T., Ortmann, C.A., Loughran, S.J., Raine, K., Jones, D.R., Butler, A.P., Teague, J.W., O’Meara, S., Mc Laren, S., Bianchi, M., Silber, Y., Dimitropoulou, D., Bloxham, D., Mudie, L., Maddison, M., Robinson, B., Keohane, C., Maclean, C., Hill, K., Orchard, K., Tauro, S., Du, M.Q., Greaves, M., Bowen, D., Huntly, B.J., Harrison, C.N., Cross, N.C., Ron, D., Vannucchi, A.M., Papaemmanuil, E., Campbell, P.J. & Green, A.R. (2013) Somatic CALR mutations in myeloproliferative neoplasms with unmutated JAK2. New England Journal of Medicine, 369, 2391–2405. Panagiota, V., Thol, F., Markus, B., Fehse, B., Alchalby, H., Badbaran, A., Lehmann, U., Koenecke, C., Shahswar, R., Chaturvedi, A., Stadler, M., Eder, M., G€ ohring, G., Koeningsmann, M., Kloos, A., Trummer, A., Schroeder, T., Kobbe, G., Thiede, C., Platzbecker, U., Schlegelberger, B., Kreipe, H.H., Ganser, A., Kr€ oger, N. & Heuser, M. (2014) Prognostic effect of calreticulin mutations in patients with myelofibrosis after allogeneic hematopoietic stem cell transplantation. Leukemia, doi: 10.1038/leu.2014.66. Tefferi, A. & Pardanani, A. (2014) CALR mutations and a new diagnostic algorithm for MPN. Nature Reviews Clinical Oncology, 11, 125–126.
Malignancy and thrombotic microangiopathy or atypical haemolytic and uraemic syndrome?
Thrombotic microangiopathy (TMA) is a vascular disorder defined by the occurrence of platelet and/or fibrin thrombi in the microvasculature of various organs, most particularly the kidney, in the setting of haemolytic and uraemic syndrome (HUS). Among several origins, TMAs may be related to malignancies (Lechner & Obermeier, 2012). Malignancy-related TMA is similar to atypical HUS (aHUS) when acute kidney injury (AKI) is present. Dysregulation 802
of the complement alternative pathway accounts for aHUS pathogenesis (Fremeaux-Bacchi et al, 2013) but the pathogenesis of malignancy-related TMA is poorly understood. We report on two patients with AKI and TMA who had genomic disorders predisposing to aHUS and who went on to develop malignancies. Both patients had been successfully treated with eculizumab before the diagnosis of cancer was made. ª 2014 John Wiley & Sons Ltd British Journal of Haematology, 2014, 166, 792–805
Correspondence Both patients were admitted for AKI with thrombocytopenia and schistocytic haemolytic anaemia (Table I). Thrombotic thrombocytopenic purpura was excluded because ADAMTS 13 (a disintegrin and metalloproteinase with thrombospondin motif, member 13) plasma activity was detectable (>10%). Stool tests for entero-haemorrhagic Escherichia coli were negative and plasma complement assays were normal. Kidney biopsy disclosed typical lesion of TMA, namely mesangiolysis and arteriolosclerosis associated with acute tubular necrosis in Patient 1. A mutation in the CFH gene was detected in the first patient and a CFR1-CFHR3 deletion was found in the second patient (Table I). After plasma exchanges failed to control TMA, eculizumab was started at the initial dose of 900 mg weekly for a month and subsequently 1200 mg every fortnight. In the first patient, schistocytic haemolytic anaemia completely resolved within 7 d, kidney function progressively recovered and dialysis was stopped (Fig 1A). In the second patient, platelet count improved, haemolysis completely resolved and dialysis was stopped (Fig 1B). Patient 1 presented with persistent cough and dyspnea 4 months later. A chest computerized tomography scan revealed the presence of a tumour in the left inferior pulmonary lobe (60 9 20 mm). A lung biopsy revealed a well-differentiated carcinoid tumour, which was treated by a left inferior lobectomy (Fig 1A). Patient 2 presented with circulating blast cells and was diagnosed with acute myeloid leukaemia (AML), M2 subtype, 3 months after the onset of TMA. Chemotherapy with cytarabine and doxorubicin was started and eculizumab was continued (1200 mg/2 weeks). This patient died 2 weeks after the start of chemotherapy as a result of veno-occlusive disease of the liver and acute heart failure (Fig 1B). Predisposing genomic conditions may be associated with sporadic aHUS, as previously documented (Noris et al, 2010). In the present report, Patient 1 had a CFH mutation and a homozygous aHUS at-risk CD46/CAPG polymorphism. Patient 2 had a complete CFHR1-CFHR3 deletion, a rare genetic variation that is highly associated with anti Factor H antibody (absent in this patient). A triggering condition, such as drug administration, infection or cancer, may be associated with the occurrence of aHUS in patients with predisposing genomic dysregulation of the alternative complement pathway (Noris et al, 2010). Therefore, the underlying malignancy could have triggered aHUS in these cases. However, to the best of our knowledge, the role of complement dysregulation in malignancy-related TMA has not been addressed. No data regarding the incidence of acquired or constitutional complement dysregulation are available because patients with cancer are usually excluded from large series of aHUS patients screened for complement dysregulation. Thus, the pathogenesis of malignancy-TMA remains poorly understood. Intravascular dissemination of malignant cells and/or endothelial cell activation induced by various cytokines released by malignant cells are suspected. ª 2014 John Wiley & Sons Ltd British Journal of Haematology, 2014, 166, 792–805
Table I. Main biological findings in two patients with malignancyrelated thrombotic microangiopathy treated with eculizumab.
Serum creatinine (lmol/l) Platelet count (9109/l) Haemoglobin (g/l) LDH (9ULN) Haptoglobin Proteinuria (g/day) Schizocytes Leucocyte count (9109/l) Prothrombin time (%) CKT (9normal) Fibrinogen (g/l) C3 (660–1250 mg/l) C4 (93–380 mg/l) CFH (mg/l) CFI (mg/l) Anti-factor H antibody Screen for complement genes Mutation in CFH gene Mutation in CFI gene Muation in MCP gene Homozygous CFH aHUS at risk haplotype Homozygous MCP aHUS at risk haplotype Complete CFHR1-CFHR3 deletion
Patient 1
Patient 2
895 183 94 35 Undetectable 7 Present 37 101 1 46 1010 253 540 56 Absent
225 51 86 63 Undetectable 47 Present 113 100 1 310 1140 293 510 62 Absent
Yes (p.Y1016C) No No No
No No No No
Yes
Yes
No (2 copies)
Yes
LDH, lactate dehydrogenase; ULN, upper limit of normal; CKT, cephalin kaolin time; C3, complement component 3; C4, complement component 4; CFH, complement factor H; CFI, complement factor I.
Interestingly, haemolysis resolved and renal function improved with eculizumab administration in our two aHUS patients before the diagnosis of cancer was made. Eculizumab is a humanized monoclonal antibody that inhibits all complement pathways by preventing the cleavage of C5 by the C5 convertase and thus inhibiting the release of C5a and C5b that ultimately initiates the formation of the membrane attack complex. Accumulating case series and preliminary results from prospective studies indicate that eculizumab dramatically improves the renal outcome of aHUS patients (Legendre et al, 2013; Zuber et al, 2013). Eculizumab has been used as rescue therapy in many forms of secondary TMAs, including post-bone marrow transplantation (Peffault de Latour et al, 2013), anti-phospholipid syndrome-related TMA (Shapira et al, 2012) and severe typical HUS (Menne et al, 2012). Because of the infrequency of the association of carcinoid tumour and acute leukaemia with TMA, complement dysregulation should not be suspected in every patient with cancer and TMA. Malignancies related with TMA are mostly metastatic solid tumours from stomach, prostate, lung or breast. 803
Correspondence
(A)
(B)
Fig 1. Course of disease in patients with malignancy-related thrombotic microangiopathy treated with eculizumab. (A) evolution of serum creatinine and platelet count in Patient 1. (B) evolution of serum creatinine and platelet count in Patient 2. HD, haemodialysis; PE, plasma exchange; KB, kidney biopsy; W, weeks; SCr, serum creatinine; Plts, platelet count; M, months.
Only one case of neuroendocrine tumour associated-TMA has been previously documented (Elliott et al, 2010), even though other types of endocrine tumours (pheochromocytoma, pituitary tumours) have been associated with TMA. Thrombotic microangiopathy has been associated with haemopathies, mostly lymphoma (Lechner & Obermeier, 2012). The association of TMA with acute leukaemia has been rarely reported, mostly in children, and TMA may precede acute leukaemia by several months (Clarke & Mitchell, 2010). In conclusion, atypical HUS and malignancy-related TMA are two distinct entities that share common traits. Both require multidisciplinary and intensive care and have a poor prognosis. Our observations suggest that malignancy-related TMA may be included in the expanding spectrum of complement pathway dysregulation-associated disorders. Accord804
ingly, patients with cancer who develop TMA and AKI should be screened for complement pathway dysregulation and eculizumab should be considered in order to improve TMA features and allow an optimal malignancy-targeted therapy.
Acknowledgments All authors have paid substantial contributions to the analysis of the presented data and to the redaction of the paper. Guillaume Favre and Fadi Fakhouri wrote the paper. All authors have approved the final version of the manuscript. Guillaume A. Favre1,2 Maxime Touzot3 Veronique Fremeaux-Bacchi4 ª 2014 John Wiley & Sons Ltd British Journal of Haematology, 2014, 166, 792–805
Correspondence Herve Hyvernat5 Jean-Pierre Gueffet6 Pierre S. Rohrlich7 Viviane Queyrel8 Vincent Esnault1,2 Fadi Fakhouri3
tes University Hospital, 7Department of Haematology, Nice University Hospital, and 8Department of Internal Medicine, Nice University Hospital, Nice, France E-mail: [email protected]
1
Department of nephrology, CHU de Nice, 2Aging and Diabetes Team,
IRCAN, UMR-INSERM 1081, Nice, 3Department of Nephrology, Nan-
Keywords: thrombotic microangiopathy, acute kidney injury, atypical haemolytic and uraemic syndrome, acute myeloid leukaemia, carcinoid tumour
tes University Hospital and ITUN, UMR S-1064, Nantes, 4Department of Immunology, Georges Pompidou European Hospital, Paris, 5Intensive 6
Care Unit, Nice University Hospital, Department of Cardiology, Nan-
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