Management of Refractory Autoimmune Hemolytic Anemia Via Allogeneic Stem Cell Transplantation

LETTER TO THE EDITOR Management of refractory autoimmune hemolytic anemia via allogeneic stem cell transplantation

Bone Marrow Transplantation (2016) 51, 1504–1506; doi:10.1038/ urine output and nausea. Physical examination was otherwise bmt.2016.152; published online 6 June 2016 normal. Her laboratory evaluation was notable for a hematocrit of 17%, reticulocyte count of 6.8%, haptoglobin below assay limits and an Waldenström’s macroglobulinemia (WM) represents a subset LDH (lactate dehydrogenase) that was not reportable due to of lymphoplasmacytic lymphomas in which clonally related hemolysis (Table 1). Creatinine was 1.1 mg/dL, total bilirubin was lymphoplasmacytic cells secrete a monoclonal IgM Ab.1 6.7 mg/dL with a direct bilirubin of 0.3 mg/dL and lactate was Overproduced IgMs can act as cold agglutinins in WM. Upon 5 mmol/L. Over 4 h, her hematocrit decreased to 6% and her exposure to cooler temperatures in the periphery, they cause creatinine rose to 1.6 mg/dL. Given concern for acute hemolytic anemia via binding to the erythrocyte Ii-antigen group and anemia due to cold agglutinins, she was warmed and received classical complement cascade initiation.2 Treatment of seven units of warmed, packed RBC, broad-spectrum antibiotics, cold-agglutinin-mediated autoimmune hemolytic anemia (AIHA) high-dose steroids and underwent emergent plasmapheresis. She in WM typically targets the pathogenic B-cell clone1–4 or the also underwent hemodialysis for presumed pigment nephropathy. Following initial stabilization, she was treated with the terminal classical complement cascade.2,5,6 Plasmapheresis rapidly lowers complement inhibitor, eculizumab. IgM concentrations for immediate disease control.1 We report Further laboratory investigation revealed a positive polyspecific for the first time a case of WM with presumed cold-agglutinin- direct antiglobulin test (DAT) and a positive DAT against mediated AIHA refractory to typical therapy, ultimately requiring ’ fi complement, with a negative DAT against IgG. The patient s hematopoietic stem cell transplantation, speci cally for anemia M-spike was 0.32 g/dL and the serum kappa-to-lambda free control. light-chain ratio was 220.70. Her IgM level was 310 mg/dL (her A 52-year-old female with a history of hypertension, Raynaud’s – 4 baseline range was 240 480 mg/dL), IgG level was 462 mg/dL, IgA syndrome, and familial WM (low level myd88 c.794T C level was 28 mg/dL, C3 level was within normal limits and C4 level (p.Leu265Pro) mutation present; father and grandfather have was below assay limits. Cold-agglutinin screen was negative and a WM, and brother has WM with related angioedema) presented screen for antibodies against RBC was negative, as noted during to the emergency room with worsening livedo reticularis and prior hemolysis episodes. A Donath-Landsteiner test, flow cytome- fatigue. try for paroxysmal nocturnal hemoglobinuria (CD55, CD59 and ’ Since her diagnosis of WM in 2007, the patient s treatment CD14), and repeated cryoglobulin screens were all negative. There consisted of multiple regimens, including combination therapy with was no evidence of iron deficiency. rituximab and bortezomib (2007); rituximab, bortezomib and On hospital day (HD) 18, the patient was found to be – everolimus with maintenance everolimus (2009 2011) on a clinical unresponsive with diffuse livedo reticularis and a hematocrit of trial; rituximab with plasmapheresis for severe hemolysis (2012); 5.5%, down from 19.7% the previous day. Hemolysis labs were weekly rituximab followed by maintenance rituximab every strikingly positive (Table 1), including a plasma hemoglobin of 3 months (2013) for persistent hemolysis; and cyclophosphamide, 135 mg%. She received warmed packed RBC and high-dose bortezomib, dexamethasone and rituximab (2014; also for con- steroids, and daily plasmapheresis was resumed. Following tinued severe hemolysis). A bone marrow aspirate performed at the stabilization, she was initiated on a regimen of daily plasmapheresis end of her 2014 treatment showed limited (o5%) bone marrow with eculizumab and hemodialysis as needed. This was eventually involvement by lymphoplasmacytic cells and a PET-CT showed no spaced to twice weekly plasmapheresis. The patient’shematocrit evidence of active malignancy. At the time of her acute stabilized. Workup revealed no new causes for the sudden drop presentation in mid-2015, she was being treated with bortezomib in hematocrit. Throughout this time, no infectious sources every other week and rituximab with i.v. Ig every 3 months. were identified. Blood cultures, computed tomography of the On arrival to the emergency room, the patient appeared to be ill chest/abdomen/pelvis, cholescintigraphy, and screens for adeno- and lethargic. She had mildly icteric sclera and as in previous virus, parvovirus, influenza, RSV, mycoplasma, CMV, Epstein Barr hemolytic episodes, her entire body (including her palms) was Virus, HIV, HTLV, syphilis, Ehrlichia, Babesia and Hepatitis B/C were covered with a purple, lacy, reticular rash. She reported decreased all negative.

Table 1. Temporal progression of selected hemolysis parameters.

Presentation Recovery Second event Pretransplant Post- (HD 1) (HD 17) (HD 18) (HD 66) transplant (Day 138)

Hematocrit (normal: 33.9–44.3%) 17.0% 19.7% 5.0% 25.7% 25.8% ↓ 6.0% 4 h later Reticulocyte % (normal: 0.7–2.5%) 6.8% 2.2% 3.3% 9.2% 1.8% LDH (normal: 125–225 U/L) Out of range due to hemolysis; 826, 4 days later 370 1959 144 121 Abbreviations: HD = hospital day; LDH = lactate dehydrogenase. Letter to the Editor 1505 Ibrutinib was initiated on HD 29 given continued breakthrough severe hemolysis, but must be combined with concomitant of disease and was accompanied by twice-weekly plasmapheresis immunosuppressive therapy.8 More recently, eculizumab, a with immediate post-pheresis eculizumab dosing. Despite monoclonal Ab that targets the complement protein C5 has initial improved control on ibrutinib, the patient had several shown promise for treating disorders of intravascular recurrences of acute albeit milder hemolysis. hemolysis.5,6,14,15 In the setting of cold-agglutinin disease, it has Given recurrent episodes of acute hemolysis despite multiple resulted in reduced hemolysis, reduced transfusion requirements regimens to control her underlying WM and the use of and improved quality of life even in the absence of a reduction in complement inhibitors, the decision was made to proceed with cold-agglutinin titers.5,14 allogeneic hematopoietic stem cell transplantation. Until a The patient described experienced inadequate disease control match was found, she continued on daily plasmapheresis. from all of the above methods. Despite not having evidence A 21-year-old matched unrelated donor was identified, and the of a significant imaging or laboratory burden of WM, she has patient underwent conditioning with melphalan and fludarabine now had a sustained response to allogeneic hematopoietic on HD 65. She received the allo-graft on HD 71 and subsequently stem cell transplantation with sirolimus and tacrolimus therapy. initiated sirolimus, tacrolimus and methotrexate for GvHD We thus report for the first time the use of allogeneic stem prophylaxis. cell transplantation to treat severe, refractory presumed After transplantation, she demonstrated no further evidence of cold-agglutinin disease secondary to a lymphoproliferative hemolysis and plasmapheresis was discontinued. She was disorder. discharged home on HD 91 and remains without evidence of recurrent hemolysis or transplant complications 48 months after transplantation. No complement gene mutations were identified CONFLICT OF INTEREST upon pretransplant whole-exome sequencing. AP has received compensation as a consultant for Alexion, the manufacturer of Fifty-one percent of patients experience autoimmune eculizumab. The remaining authors declare no conflict of interest. phenomena in conjunction with their WM, and cold agglutinins are present in 5–10% of patients with WM. AIHA is found in 1 2 3 3 4 – 7 L Rotenstein , A Nathan , I Ghobrial , J Antin and A Parnes 10 20% of those with WM. However, in contrast to the severe, 1Harvard Medical School, Boston, MA, USA; refractory hemolysis seen in this patient, the hemolysis observed 2Department of Internal Medicine, Brigham and Women’s in association with chronic lymphoproliferative disorders is 8 Hospital, Boston, MA, USA; typically mild and chronic. 3Department of Medical Oncology, Dana Farber Cancer The case presented here is unique owing to the lack of Institute, Boston, MA, USA and association between the pace of hemolysis and burden of WM, the 4 fi ’ Division of Hematology, Department of Medicine, Brigham and lack of an identi able autoantibody, and the patient s lack of Women's Hospital, Boston, MA, USA response to multiple lines of therapy used in WM and AIHA. 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