Autoimmune hemolytic anemia (AIHA) is a rare and heterogeneous disease with a presentation/phenotype ranging from mild/compensated to life-threatening.1, 2 Moreover, some cases show refractoriness to/relapse after first and further therapy lines, leading to significant and underestimated healthcare burden. Here, we retrospectively analyzed 378 primary AIHA cases (135 M and 243 F, median age 61 years, range 5-94) from eight Italian hematological centers and followed for a median of 4.3 years (range 1-27) focusing on predictors of multiple refractoriness to second and further therapy lines and healthcare resource utilization. Figure 1A shows clinical and laboratory characteristics of AIHA patients at onset, divided according to the serological type in warm (direct antiglobulin test-[DAT]-positive for IgG or IgG + C), cold (CAD, usually IgM driven, DAT-positive for C), mixed (both IgG and high titer cold agglutinins), and atypical forms (DAT negative, IgA only or warm IgM). Hemoglobin values were significantly lower and LDH higher in IgG + C wAIHA, mixed and atypical cases (P < .001 and P = .0034, respectively), and hemoglobin and LDH values were negatively correlated (P < .001). Absolute reticulocytes were reduced in CAD and mixed forms (P = .0013), and the reticulocyte index was lower in CAD (P = .023) and in cases with Hb ≤ 6 g/dL (53 vs 86 P < .001) (Figure 1B). Overall, inadequate reticulocytosis was observed in more than half of patients. Second therapy line was mostly administered in mixed, IgG + C wAIHA, and in CAD (P = .011), and the ultrarefractory cases requiring four or more lines of therapy were mainly CAD, mixed, and atypical AIHA. Infections were observed in 14% of cases, mostly wAIHA and mixed forms (P = .02). Thrombosis occurred in 15% mostly IgG + C wAIHA and atypical AIHA (P = .04). Evans' syndrome was more frequent in mixed AIHA and, to a lesser extent, in atypical (P = .033) and in severe forms (74% with Hb < 8 g/dL vs 26%, P = .005). Acute renal failure was reported in 3% of patients, with no relationship with AIHA type/Hb values. Predictors of relapse/refractoriness were analyzed in a total of 304 relapses, of whom 211 (69%) after first-line, 69 (23%) after second-line, 19 (6%) after third-line, and 5 (2%) after further therapy lines. Multivariate Cox regression analysis demonstrated that anemia severity at onset was associated with an increased risk of relapse, with the following hazard ratios: 1.98 (95%CI 1.22-3.21) for patients with Hb ≤ 6 g/dL, 1.74 (95%CI 1.09-2.77) for cases with Hb 6.1-8 g/dL, and 1.61 (95%CI 0.99-2.62) for those with Hb 8.1-10 g/dL. Even considering hemoglobin as a continuous variable, each gram of reduction yielded a 7% greater risk of relapse (95%CI 2-13, P < .013). In addition, analysis showed increased hazard risks for forms other than wAIHA (1.21, 95%CI 0.95-1.54), and for Evans association (1.84, 95%CI 1.24-2.74). Notably, the presentation of an AIHA other than wAIHA together with Evans syndrome or with Hb < 8 g/dL resulted in a 2-fold higher risk of relapse; the presence of both Hb < 8 g/dL and Evans syndrome gave a 3-fold increased risk, and the association of the three conditions led to a ~4-fold increased risk of multiple relapses. Seventy-five patients died during the follow-up, of whom 13 because of AIHA. Overall mortality was higher in more severe cases (24% for cases with Hb <6 g/dL vs 18% for those with Hb >6 g/dL, P = .04), with the following hazard risks: Evans syndrome (8, 95% CI 2.5-26, P = .001), acute renal failure (6.3, 95% CI 1.4-29, P = .016), and infections (4.8, 95% CI 1.5-15, P = .007). Thrombotic events did not result in increased risk of death. Response to treatment is shown in supplementary material. In summary, ~80% of cases displayed an overall response (OR) after first line treatment with glucocorticoids, however only 25% had a sustained response. Rituximab and immunosuppressants were comparably used in second line (31% and 26%), with better responses for the former (88% OR, 53% complete responses, CR); immunosuppressants gave mainly partial responses (PR, 46%) and were generally administered together with glucocorticoids. Rituximab had a longer relapse free survival compared with immunosuppressants (22 months, range 2-71 vs 12 months, range 2-43), and a greater proportion of sustained responses (23/35, 51% vs 13/31, 42%). Splenectomy (n = 38, ~10% of the whole series) had been performed mostly in second line (63%), particularly before 2000 (8/9), with very good responses (85%). Regarding third line therapy, rituximab was preferred compared to immunosuppressants (46% vs 15%). Importantly, OR and CR to rituximab were comparable to those observed in second line (92% and 41%). Splenectomy had become a third line option in most recent years (11/24, 46%) and confirmed its excellent performance. Further lines were required in 29 multirefractory patients (8% of cases), and included glucocorticoids/rituximab, glucocorticoids/immunosuppressants, regular transfusions, bortezomib (1.3 mg/m2 iv single agent on days 1, 4, 8, 11, n = 8), plasma-exchange (N = 5), eculizumab (N = 2), erythropoietin (N = 12), high dose cyclophosphamyde/vincristine (N = 1), and autologous peripheral stem cell transplant (N = 1). Response to treatments is difficult to assess, due to their combinations/overlap. Notably, six cases underwent splenectomy as forth or further line, all obtaining a response. Considering all the 32 cases that respond to splenectomy (either performed in second, third, or further lines), 13 (41%) relapsed after a median of 16 months (range 2-147), while 19 (59%) cases are still on remission at the time of the study. Regarding response to treatment according to AIHA type, a CR to glucocorticoids was mostly observed in wAIHA, mixed and atypical cases (~50%), whereas CR rate was lower in CAD (24%) (P = .0015), and generally observed at high dosages. A complete response to rituximab was mainly observed in IgG wAIHA (62%), whereas the drug was less effective in IgG + C wAIHA, CAD, and mixed forms (44%-54%). Figure 1C and Supporting Information show healthcare utilization in a subgroup of 190 cases comparable to the remaining 188 in terms of demographics, hematological parameters, number, and type of therapy lines. One hundred twenty-one patients (64%) required at least one hospital admission, with 9% needing three or more. The median admission duration was 15 days, with 13% of cases needing more than 30 days, and admissions length was negatively correlated to Hb levels (r = −0.26, P < .001). The higher frequency was observed in IgG + C wAIHA, mixed and atypical cases (P = .006). Concerning outpatients, median number of visits per year was five, but 42 cases (22%) required more than a monthly visit. As regards therapeutic procedures, 103 patients (54%) required at least one transfusion, with 11/103 patients (11%) needing more than 20 transfusions (the established threshold for chelation), and six cases more than 50. Transfusion need was higher in IgG + C wAIHA, mixed and atypical cases (P = .004), and correlated with a more severe disease, that is, anemia, hemolysis and inadequate bone marrow compensation (Hb r = −.26, P < .001; LDH r = .21, P < .01; BMRI r = .15, P < .05). Considering transfusions as a function of follow-up length, the median was 2 per year, with 27 cases necessitating 4 or more (one subject about a weekly support). Highly expensive drugs were administered in 65 cases (34%, 56 rituximab, 8 bortezomib, and 2 eculizumab), and splenectomy performed in 20 patients (11%). The administration of highly expensive drugs was higher in CAD and mixed cases (P = .01). In conclusion, this is the largest study aimed at identifying predictors of refractoriness to multiple therapy lines and healthcare resource utilization in primary AIHA in the real-life and outside clinical trials. We found that hemoglobin level at onset is the only laboratory parameter associated with an increased risk of refractoriness, from 2-fold for moderate to 3-fold for severe cases. Anemia severity was associated with reticulocytopenia/inadequate reticulocytosis, present in more than a half of patients, typically CAD and mixed forms. Thrombocytopenia (Evans syndrome) resulted in a 2-fold increased relapse risk, highlighting the detrimental effect of a more complex immune dysregulation involving multiple hematological lineages. Moreover, refractory/relapsing AIHAs were those with complement involvement (warm IgG + C, mixed, and CAD), suggesting the primary role of this powerful amplification system in the degree of AIHA immune dysregulation. Regarding therapy, known to be mainly based on experts opinion,3-5 rituximab had a longer relapse free survival (~2 years), and was effective in ~50% of cases in first and further lines. The drug was used as first or early-second line in very severe cases, particularly in CAD cases that are known to respond to unacceptable high glucocorticoid doses only. At variance, immunosuppressants induced partial responses with decreasing efficacy after first line. Splenectomy had high response rates (~85%) and was curative in ~60% of warm AIHA cases, even when performed as third or further lines. This option, although marked by infectious and thrombotic complications, and contraindicated in CAD, should not be forgotten, given its potential curative ability, as recently suggested for immune thrombocytopenia.6 Healthcare resource utilization was important in AIHA, with ~2/3 of patients requiring hospital admissions, 1/2 transfusions, and ~1/3 highly expensive drugs. In a small group of severe/ultrarefractory cases (10%-15%, mainly CAD, IgG + C wAIHA, mixed and atypical forms) admissions lasted more than 30 days, transfusion need exceeded 20 units per year, the established threshold for chelation, and several highly expensive drugs were administered, representing a significant burden on the patient and the medical system. This work was supported by research funding from Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, grant number RC 2016-17. All the Authors disclose no commercial affiliation as well as consultancies, stock or equity interests, and patent licensing that could be considered to pose a conflict of interest regarding the submitted article. Study design: WB Patients follow-up: JAG, ML, AF, APL, NM, LS, SC, FC, PDF Data collection: WB, AZ, BF, JAG, ML, AF, APL, NM, LS, SC, FC, PDF Data analysis: WB, AZ, BF, DC Data interpretation: WB, DC Manuscript writing: WB, AZ, BF Revised manuscript: JAG, ML, AF, APL, NM, LS, SC, FC, PDF, GR, DC, JAG, AZ, AC Supporting Information Table S1. Response to treatments according to therapy line and AIHA type. Supporting Information Table S2. Healthcare resource utilization in AIHA Supporting Information Figure S1. Response to treatments according to therapy line and AIHA type Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
No takes yet. Share an insight, caveat, or question.
Barcellini et al. (2018) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: