Autoimmune hemolytic anemia: causes and consequences

Figures & data

Figure 1. Pathogenic mechanisms involved in autoimmune hemolytic anemia (AIHA). Several predisposing conditions are involved in AIHA development including genetic background, presence of underlying immunodeficiencies, infections, solid and hematologic neoplasms. The main immune mechanisms responsible for tolerance breakdown are molecular mimicry, emergence of forbidden clones, and polyclonal B-cell activation. Additionally, drugs and hematologic treatments, such as checkpoint inhibitors (CPI) and hematopoietic stem cell transplant (HSCT) may induce immune dysregulation or generation of neoantigens. The resulting immunologic activation involves antigen presenting cells (APC), T- and B-cells, and cytokines and leads to the production of autoantibodies of several classes. B-cells interact with T helper (Th) cells via CD40 and its ligands but also present cognate antigens, acting as professional APC. This interaction also contributes to generate class-switched autoantibodies. Concerning cytokines, interleukin (IL)-4, IL-6, and IL-10 levels are increased and interferon gamma (IFN-γ) decreased favoring Th2 response and boosting humoral autoimmunity; the IL-2 and IL-12 levels are also increased contributing to Th1 differentiation and cellular autoimmunity. Transforming growth factor beta (TGF-β) is elevated favoring Th17 differentiation and production of IL-17 that decrease T-regulatory (Treg) levels. Once produced, IgG autoantibodies may weakly activate the complement cascade, and mainly destroy erythrocytes via antibody dependent cellular cytotoxicity and phagocytosis primarily in the spleen. IgM autoantibodies strongly activate complement system and cause erythrocyte destruction via C3b opsonization and phagocytosis primarily in the liver. These mechanisms are both called extravascular hemolysis. IgM may lead to terminal complement activation until the formation of the membrane attack complex (MAC) with consequent intravascular hemolysis.

Table 1. Standard therapies for warm AIHA (wAIHA) and cold agglutinin disease (CAD).

Treatment	Route and dose	Response rates %	Comments
wAIHA
1st line
Steroids	Oral or IVPrednisone or methylprednisolone 1 mg/Kg/day	75–80	Curative in 20–30% only; short-term side effects (mood swings, psychosis); long-term side effects (diabetes, hypertension, infections, osteoporosis, cushingoid syndrome)
2nd line
Rituximab	IV 375 mg/m^2 or 100 mg/week x 4 weeks	80–90	Effective even at low-dose; re-treatment equally effective; well-established safety profile
Further lines
Splenectomy	/	80	Potentially curative; unsuitable for elderly; surgical complications; thrombotic risk; life-long immune suppression; infection prophylaxis required
Azathioprine	Oral 50–100 mg/day	40–60	Steroid-sparing agent; myelosuppression; infections; secondary malignancy; hepatic toxicity
Cyclophospamide	Oral 50 mg day	40–60	Steroid-sparing; myelosuppression; infections; urotoxicity; secondary malignancy; fertility problems/teratogenic
Cyclosporin A	Oral 3–5 mg/Kg/day	40–60	Steroid-sparing; possible dose adjustment; hypertension; arrhythmia; myelosuppression; infections; nephrotoxicity
Mycophenolate Mofetil	Oral 1–1.5 g/day	80–100	Steroid-sparing; particularly effective in children; good safety profile; mild myelosuppression
Danazol	Oral 200–600 mg/day	40	Steroid-sparing agent; low effectiveness in refractory cases; long-term hepatotoxicity
High dose cyclophosphamide	IV boluses 800 mg/m^2	70	Response in small series; high toxicity (myelosuppression; infections; urotoxicity; secondary malignancy; infertility)
Additional therapies
Intravenous immunoglobulin	IV 0.4 g/Kg x 5 days or 1 g/Kg x 2 days	40	Effective in AIHA secondary to infections; particularly effective in pediatric settings (60%); low toxicity
Recombinant erythropoietin	Subcutaneous 40,000 IU/week	50–70	Effective in multi-refractory AIHA particularly with reticulocytopenia; useful in very severe presentation
CAD
Watch and wait	-	-	keeping patient and room warm and transfusion of pre-warmed to 37°C blood
First line
Steroids	Oral or IV prednisone or methylprednisolone 1 mg/Kg/day	15–30	Effective only at high dose; short-term side effects (mood swings, psychosis); long-term side effects (diabetes, hypertension, infections, osteoporosis, cushingoid syndrome)
Rituximab	IV 375 mg/m^2/week x 4 weeks	50	Re-treatment equally effective; well-established safety profile
Further lines
Rituximab/fludarabine	Oral 40 mg/m^2 days 1–5, 29–34, 57–61 and 85–89	75	Sustained remissions (median response duration 6.5 years); hematologic and infectious toxicity mostly in older and frail patients
Rituximab/Bendamustine	IV 90 mg/m^2 days 1–2 for 4 cycles of 28 days	70	Sustained remissions; infectious complications
Bortezomib	IV or subctuaneous 1.3 mg/m^2 days 1,4, 8,11	30	Side effects (neuropathy, neutropenia, thrombocytopenia, diarrhea, fatigue and rash)
Additional therapies
Recombinant erythropoietin	Subcutaneous 40,000 IU/week	50–70	Effective in multi-refractory cases particularly with reticulocytopenia

Table 2. New drugs in warm AIHA (wAIHA) and cold agglutinin disease (CAD).

	Mechanism	Route of Administration	Study Phase	Setting
B-cell directed therapies
Ofatumumab	Anti-CD20	IV	Case report	Secondary AIHA
Alemtuzumab	Anti-CD52	SC	Case reports	Secondary AIHA
Daratumumab	Anti-CD38	IV	Case reports	wAIHA/CAD/Secondary AIHA
Isatuximab	Anti-CD38	SC	Phase 1	wAIHA
Ibrutinib	BTKi	Oral	Case reports, Phase 2 plus rituximab	Secondary AIHA
Rilzabrutinib	BTKi	Oral	Phase 1	wAIHA
Venetoclax	Bcl2i	Oral	Case reports	Secondary AIHA
Parsaclisib	PI3Kδi	Oral	Phase 2, Phase 3	wAIHA/CAD
Complement inhibitors
Eculizumab	Anti-C5	IV	Case reports and Phase 2	CAD/Mixed AIHA
Sutimlimab	Anti-C1s	IV	Phase 1b and 3	CAD
Pegcetacoplan	Anti-C3/C3b	SC	Phase 1/2 and Phase 3	CAD/wAIHA
ANX005	Anti-C1q	IV	Phase 1	wAIHA IgG+C
IgG-mediated phagocytosis inhibitors
Fostamatinib *	Syki	Oral	Phase 2	wAIHA
Orilanolimab	Anti-FcRn	IV	Phase 1b	wAIHA
Nipocalimab	Anti-FcRn	IV	Phase 2	wAIHA
RVT-1401	Anti-FcRn	SC	Phase 2	wAIHA

*Fostamatinib is also a B-cell receptor inhibitor; BTKi: Bruton tyrosine kinase inhibitor; Bcl2: B-cell lymphoma 2; δPI3Ki: phosphatidylinositol 3-kinase-δ inhibitor; MoAb: monoclonal antibody; mTORi: mammalian target of Rapamycin inhibitor; Syki: Spleen tyrosine kinase inhibitor; FcRn: neonatal Fc receptor