Lessons from very severe, refractory, and fatal primary autoimmune hemolytic anemias
Authors: Bruno Fattizzo, Anna Zaninoni, Francesco Nesa, Veronica M. Sciumbata, Alberto Zanella, Agostino Cortelezzi, Wilma Barcellini
Journal: American Journal of Hematology (2015)

Here, we describe 13 challenging primary autoimmune hemolytic anemias (AIHA), of whom seven died because of uncontrolled hemolysis and related complications. This is the largest series of life-threatening AIHA so far reported. Patients were identified among 157 primary AIHA followed from 1996 to 2014 at our institution on the basis of very severe presentation (Hb < 6 g/dL, 51 cases) and requirement of at least three lines of therapy [steroids +/– intravenous immunoglobulins (IVIG), splenectomy, rituximab, various immunesuppressants, plasma-exchange (PEX)]. All displayed marked intravascular hemolysis and hemoglobinuria (median LDH 960 U/L, range 703–12,787), eight reticulocytopenia, and six were diagnosed with Evans syndrome, both known detrimental factors 1-3. As shown in Fig. 1, Case 1 and 2 were characterized by a long relapsing multitreated AIHA history and pulmonary embolism, but a fatal outcome occurred only in the former because of multiorgan failure. The clinical history of Case 3 was complicated by several infections, acute renal failure, acute respiratory insufficiency, sepsis, and death. Case 4 was a direct antiglobulin test (DAT) negative AIHA who, notwithstanding Evans syndrome and associated thrombotic complications, reached complete remission after rituximab treatment. Case 5 and 6 were splenectomized after several immunosuppressive therapies: the former developed an early postsplenectomy fatal sepsis, whereas the latter is still in remission. Case 7 was a refractory/relapsed Evans syndrome with previously treated HCV-related hepatitis, who had several infections (pneumonias and HCV reactivation) and finally died. Case 8 (Jeovah's witness) was a cold AIHA who experienced pulmonary embolism and several infections, and reached AIHA remission only after rituximab and erythropoietin (for inadequate reticulocytosis). Case 9 showed an unexpected fatal course because of Pneumocystis jiroveci interstitial pneumonia and respiratory insufficiency after a short history of relapsing AIHA treated with low-dose rituximab. Case 10 and 11 were characterized by an abrupt AIHA onset, with associated infectious and thrombotic complications, promptly controlled by aggressive therapy including steroid boluses and PEX in both cases, and rituximab and cyclophosphamyde in the latter. The clinical history of case 12 was characterized by a questionable clinical management, as the patient had been heavy-treated with steroids, cyclophosphamide, and transfusions long-term before referral, and reached complete remission after rituximab. Finally, case 13 displayed a fulminating AIHA with associated Mycoplasma spp pneumonia notwithstanding steroid boluses, four daily courses of plasma exchange, a first rituximab dose, and intensive transfusion support. Hemoglobin values and treatment in the 13 very severe and refractory AIHA cases. Seven patients were DAT positive with IgG+C antisera, 4 with IgG (Cases 1, 3, 11, and 12), and Case 8 with C; Case 4 was DAT negative. Antinuclear, antimitochondrial, anti-DNA, anti-ENA, (SS-A, SS-B, Sm, RNP, Scl-70 autoantibodies), anticardiolipin, anti-beta-2-glycoprotein, and lupus anticoagulant were negative. An underlying lymphoproliferative disorder was excluded by bone marrow biopsy and CT scan in all patients. Shaded areas indicate steroid treatment (methylprednisolone 1 mg/kg/day for 20–30 days subsequently tapered) and/or steroid boluses. Rituximab was given at standard dose of 375 mg/m2/week x4, or at fixed low dose of 100 mg/week x4; in Case 3 rituximab was administered every 2 weeks for a total of eight cycles; in Case 4 it was given weekly for 4 weeks, then every 2 weeks for a total of eight courses. Azathioprine was given at 100 mg/day p.o., cyclosporine at 5 mg/kg/day p.o, vincristine at 2 mg/week i.v., and cyclophosphamyde at various dosages detailed as follows: Case 1: 1 g/m2 bolus; Case 2: 75 mg/day p.o. and 800 mg/m2 monthly; Case 3: 1 g bolus; Case 4: 1.5 g bolus; Case 6 and 8: 100 mg/day p.o; Case 11: 800 mg/m2. Infectious complications (≥ grade 3) included 8 pneumonias (3 with respiratory insufficiency, patient 3, 9 and 10), and 3 sepsis (Cases 3, 5, and 12). Acute renal failure occurred in cases 1, 3, and 10, and multiorgan failure in 1, 3, 5, 7, and 13. On the whole all patients (but the Jeovah's witness) received transfusions and steroids +/– IVIG, 11 rituximab, 9 immunosuppressants, 5 PEX, 3 erythropoietin, and 5 underwent splenectomy. As regards rituximab, the drug was given as third/fourth therapy line until 2009; thereafter it was administered as early second line, no later than 7–10 days if steroids and transfusions failed to stabilize/ameliorate hemoglobin levels. The prompt resolution of the clinical emergency in all cases that completed therapy and the duration of the response (1–3 years) is in favor of an early use of rituximab in very severe AIHAs. Splenectomy was performed either early in the clinical history, or after several therapeutic lines. It is known that splenectomy is associated with overwhelming sepsis (reported risk 3.3%–5% and mortality rate up to 50%) 1, 2. Three of our splenectomised cases, two of whom late in the clinical history, died of sepsis, suggesting that splenectomy performed after multiple immunosuppressive therapies is really a challenging option. It is worth noting that transfusion support was ineffective in cases 1 and 13, who died in few days without hemoglobin increase in spite of continuous and intense blood transfusion, which may even have fuelled the hemolytic process contributing to multiorgan failure. PEX was effective in stabilizing hemoglobin in four out of five patients; although its efficacy is controversial, with favorable effects generally short-lived, this procedure may have contributed to reduce hemolysis in very severe cases, particularly in the presence of inadequate reticulocytosis. Finally, the use of erythropoietin may have reduced transfusion need and avoided hemolysis related to overtransfusion. Thrombotic events occurred in eight patients (61%), of whom four pulmonary embolism and three disseminated intravascular coagulopathy, with a higher rate than generally observed in AIHA (10–15%) 3, 4; this may be due to the important intravascular hemolysis, as reported in thrombotic microangiopathies and paroxysmal nocturnal hemoglobinuria. Pulmonary embolism was not fatal, in contrast with older series 4 and in line with more recent studies 3, and occurred more frequently in splenectomised cases. Therefore, we recommend being aware of the increased thrombotic risk in severe forms and suggest an antithrombotic prophylaxis in cases with massive intravascular hemolysis and/or splenectomised, although prospective studies are advisable to give precise recommendations. The mortality rate in the severe cases presented was about 50%, greater than that of AIHA series reported in the literature (5–11%) 2, 3; although limited by the number of patients, this finding underlines that primary forms may be life-threatening, even more than that frequently observed in AIHA secondary to lymphoproliferative diseases 5 and bone marrow transplantation 6. In our cases, death was due to sepsis and multiple organ failure, and was related with multitreatment, particularly splenectomy, and with concomitant thrombocytopenia. Consistently, of the five cases characterized by multiple relapses requiring several lines of therapy including splenectomy, three were fatal. However, death occurred also in Case 9 who was treated with rituximab only, and in Case 13 who displayed a few-day fulminating course, underlining the high heterogeneity and unpredictability of this disease. In conclusion, what we learnt from these severe AIHA cases is that clinicians should be alerted for rapidly evolving patients, particularly in the presence of intravascular hemolysis, hemoglobinuria, DAT positive for IgG+C, reticulocytopenia, and/or Evans syndrome. Steroid boluses should be generously given, and rituximab early considered. Antithrombotic prophylaxis is suggested, particularly in splenectomised patients. Splenectomy is advisable soon after rituximab failure, because of its poor prognosis after multiple immunosuppressive therapies. PEX may be useful in critical conditions and erythropoietin can reduce overtransfusion. Above all a scrupulous attention is required to avoid a delay in potentially life-saving strategies. BF and WB designed the study, analyzed data and wrote the paper; AnZ analyzed data and wrote the paper; FN and VMS partially wrote the paper; AlZ interpreted data and critically revised the paper; AC critically revised the paper; All authors revised the paper and approved submission. Bruno Fattizzo1, Anna Zaninoni BS1, Francesco Nesa1, Veronica M. Sciumbata1, Alberto Zanella1, Agostino Cortelezzi2, Wilma Barcellini1* 1UO Oncoematologia, Fondazione Istituto Di Ricovero E Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy 2UO Oncoematologia, Fondazione Istituto Di Ricovero E Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico; Università Degli Studi Di Milano, Milano, Italy