Antibody based therapeutics for autoimmune hemolytic anemia

Figures & data

Table 1. Epidemiology and classification of autoimmune hemolytic anemia.

		Autoantibody characteristics
	Prevalence	Class	Optimal temperature of reaction (range)	Specificity	DAT positivity	In vivo hemolysis (RBC sequestration)	Clinical association
Warm AIHA	60–70%	IgG (possibile complement fixation)	37°C (0–40)	Rh system	IgG or IgG+C	Extravascular (spleen)	Primary or secondary to autoimmune, lymphoproliferative or neoplastic disease
Cold AIHA CAD, CAS	20–25%	IgM (common complement fixation)	4°C (4–34)	I/I system	C	Intravascular and extravascular (liver/spleen)	Cold agglutinin syndrome (CAS) is secondary to infections (acute and transitory) or lymphoproliferative disease (chronic)
Cold AIHA, PCH	1–5%	IgG (common complement fixation)	Reacts to 4° and hemolyses at 37°C	P antigen	Positive Donath-Landsteiner test	Intravascular and extravascular (liver/spleen)	Primary or secondary to syphilis (chronic) or other infections (acute and transitory)
Mixed AIHA	5–10%	Warm IgG and cold IgM	4°C and 37°C		IgG + high titer cold IgM	Extravascular and intravascular (spleen/liver)	Primary or secondary to lymphoproliferative or autoimmune diseases

AIHA, autoimmune hemolytic anemia; CAD, cold agglutinin disease; CAS, cold agglutinin syndrome; PCH, paroxysmal cold hemoglobinuria.

Table 2. Rituximab in autoimmune hemolytic anemia.

Reference	Disease	Study type	Number of patients	Main findings	Notes
Motto et al. [24]	AHIA (ND)	Prospective study	4	Transfusion-independence in all pts
Narat et al. [25]	wAIHA	ND	11	ORR of 64% (CR 27%, PR 28%)
Bussone et al. [26]	wAIHA	Retrospective study	27	ORR of 93% (CR 30%; PR 63%) 5/26 pts relapsed and 3/5 were successfully retreated with RTX
Birgens et al. [27]	wAHIA (first line)	Multicentre, randomized, open-label phase 3 trial	64	1 year-ORR 75% (all CR) with RTX versus 39% (all CR) with placebo. RFS significantly higher in pts who received RTX along with steroids	RTX+steroid versus steroid alone
Maung et al. [28]	wAIHA	Multicentric retrospective study	34	ORR of 70.6% (CR 26.5%, PR 44.1%). Median DOR 36 months
Michel et al. [29]	wAHIA (first line)	Multicentre randomized double-blind and placebo-controlled phase 3 trial	32	1 year-ORR 75% in pts treated with steroid plus RTX versus 31% in pts treated with steroid alone. At 36 months 70% of pts treated with steroid plus RTX still in remission	RTX+steroid versus steroid alone
Gutierrez et al. [30]	wAIHA	Retrospective study	93	RTX alone or with steroids in 34 pts: ORR of 100% (CR of 40–60%)
Berentsen et al. [31]	CAD	Phase 2 trial	27	14/27 pts respondend to the first course of RTX
Schöllkopf et al. [32]	CAD	Muticentric phase 2 trial	20	ORR of 45% (CR 5%, PR 45%)
Berentsen et al. [33]	CAD	Prospective, uncontrolled multicenter phase 2 trial	29	ORR 76% (CR 21%, PR 55%) Grade 3–4 hematologic toxicity 41%	RTX+fludarabine
Berentsen et al. [34]	CAD	Prospective, uncontrolled multicenter phase 2 trial	45	ORR 71% (CR 40%, PR 31%) Grade 3–4 neutropenia 33% (but only 11% infections)	RTX+bendamustine
Berentsen 2020 [35]	CAD	Observational study	232	RTX monotherapy (104 pts): ORR of 59% RTX plus fludarabine (29 pts): ORR 62% RTX plus bendamustine (45 pts): ORR of 78% (CR of 53%, PR of 24%)
Zaja et al. [36]	wAIHA, CAD	ND	3 (2 wAIHA, 1 CAD)	CR in CAD (DOR 96 weeks)
Zecca et al. [37]	wAHIA, CAD, DAT-negative	Prospective study	15 (13 wAHIA, 1 CAD, 1 DAT-negative)	With a median follow up of 13 months, ORR of 87%
Dierickx et al. [38]	wAHIA, CAD	Retrospective analysis	53 (36 wAHIA, 14 CAD, 3 ND)	ORR 79.2% (CR 47%, PR 42%); wAIHA ORR 83.3% (CR 50%, PR 33.3%); CAD 64.3% (CR 28.6%, PR 35.7%)	Type of antibody not statistically predictive of response
Peñalver et al. [39]	wAIHA, CAD	Retrospective multicentric study	36 (27 wAIHA, 9 CAD)	ORR of 77% (CR 61%, PR 16%); pts who achieved CR maintened the response >6 months
Barcellini et al. [40]	wAHIA, CAD	Multicentre single-arm, prosepective phase 2 trial	32 (18 wAHIA, 14 CAD)	ORR of 90%, 100%, 100%, and 89% and RFS of 87%, 79%, 68%, and 68% at 6, 12, 24, and 36 months, respectively. Better RR in wAIHA than in CAD
Reynaud et al. [10]	wAHIA, CAD	Meta-analysis	409 (183 wAHIA, 118 CAD, 109 ND)	ORR of 73% (~70% for wAIHA, 57% for CAD); CR of 37% (42% for wAIHA, 21% for CAD) ORR and CR significantly associated with wAIHA and mean age
Ducassou et al. [41]	wAIHA, CAD	Observational prospective study	61 (60 wAIHA, 1 CAD)	ORR of 75%, 6y-RFS of 48% One death potentially attributable to RTX
Chao et al. [42]	wAIHA, CAD	Systematic review	746	ORR of 79% (CR of 44%); wAIHA: ORR of 79% (CR of 49%); CAD: ORR of 66% (CR of 14%)

AIHA, autoimmune hemolytic anemia; CAD, cold agglutinin disease; CR, complete response; DOR, duration of response; ND, not determined; ORR, overall response rate; PR, partial response; pt(s), patient(s); RTX, rituximab; wAIHA, warm autoimmune hemolytic anemia.

Table 3. Daratumumab in autoimmune hemolytic anemia.

Reference	Disease	Study type	Number of patients	Main findings
Schuetz et al. [54]	wAHIA	Case series	3 (pediatric)	Curative effect of daratumumab in 2/3 pts with post HCT wAHIA
Cooling et al. [55]	wAHIA	Case report	1	Initial response in a patient with AHIA with daratumumab in combination with standard treatment
Blennerhassett et al. [56]	Evans Syndrome (wAHIA+ITP)	Case report	1	Response in a pluri-reftactory post HCT Evans Syndrome
Even-Or et al. [57]	AHIA (not specified)	Case report	1	Successful treatment of a pediatric pt with post HCT AHIA
Rieger et al. [58]	wAHIA	Case series	4	Fast benefit of daratumumab in 4 pts with rituximab-refractory wAIHA. Eventually 2 pts relapsed
Jain 2021 [59]	wAHIA	Case report	1	Successful treatment of a refractory wAHIA
Tomkins 2020 [60]	CAD	Case report	1	Response in a pt with CAD refratory to rituximab, bortezomib and lenalidomide
Zaninoni et al. [61]	CAD	Case report	1	Response in a pt with CAD refratory to rituximab and bortezomib
Driouk et al. [62]	Mixed AHIA	Case report	1	Post HCT mixed AHIA that did not respond to salvage treatment with daratumumab

AIHA, autoimmune hemolytic anemia; CAD, cold agglutinin disease; HCT, hematopoietic cells transplant; ITP, immune thrombocytopenia; pt(s), patient(s); wAIHA, warm autoimmune hemolytic anemia.

Table 4. Eculizumab in autoimmune hemolytic anemia.

Reference	Disease	Study type	Number of patients	Main findings
Roth et al. [15]	CAD	Case report	1	Transfusion independence in a pt refractory to steroid, RTX and intravenous immunoglobulin
Gupta et al. [64]	CAD	Case report	1	Transfusion independence in a pt refractory to steroid, RTX and plasmapheresis
Shapiro et al. [65]	CAD	Case report	1	ECU as a bridge to IST in a pt with severe CAD and hemodinamic instability
Roth et al. [16]	CAD	Phase 2 clinical trial	13 (12 chronic CAD, 1 acute CAD)	ECU significantly reduced hemolysis and transfusion requirement
Makishima et al. [66]	CAD	Case report	1	ECU achieved a rapid response in an acute case of CAD refractory to steroid
Herbreteau et al. [67]	CAD	Case report	1	Achievement of transfusion idependence in a pt with CAD secondary to CLL refractory to Rituximab-chemotherapy and BTKi
Dawudi et al. [68]	CAD	Case report	1	Rapid onset response in a critically-ill pt with CAD secondary to SARS-Cov2
Chao et al. [69]	wAHIA (IgM)	Case report	1	Rapid onset response to a single dose of ECU in a pt with wAHIA and eosinophilic granulomatosis with polyangiitis
Ma et al. [17]	wAHIA	Case report	1	Tranfusion independence in a pt with wAHIA secondary to WD refractory to prednisone, RTX, splenectomy, and plasmapheresis
Neave et al. [70]	wAHIA	Case report	1	Rapid response onset with ECU in a pt with wAHIA refractory to corticosteroids, intravenous immunoglobulin, mycophenolate mofetil and RTX
Gauchy et al. [71]	wAHIA	Case report	1	Transfusion independence in a pt with wAHIA secondary to CMML, refratory to prednisone, RTX, endovenous immunoglobulin, and plasmapheresis
Garg et al. [72]	wAHIA (IgM)	Case report	1	Rapid response onset with a single dose eculizumab in a pt with wAHIA refractory to corticosteroids, intravenous immunoglobulin, mycophenolate mofetil and rituximab
Jackson et al. [73]	wAHIA	Case report	1	Achievement of response with eculizumab in a pt with life-treatening wAHIA refractory to steroids, rituximab and emergency splenectomy

AIHA, autoimmune hemolytic anemia; BTKi, Bruton tyrosine kinase inhibitor; CAD, cold agglutinin disease; CMML, chronic myelomonocytic leukemia; CLL, chronic lymphocytic leukemia; ECU, eculizumab; IST, immunosuppressive therapy; pt(s), patient(s); RTX, rituximab; wAIHA, warm autoimmune hemolytic anemia, WD, Waldenstrom disease.

Table 5. Sutimlimab in autoimmune hemolytic anemia.

Reference	Disease	Study type	Number of patients	Main findings
Jager et al. [75]	CAD	Phase 1b trial	10	>2 g/dl increase in Hb levels in 7/10 patients. Rapid reduction of extravascular hemolysis. No serious adverse event
Roth et al. [76]	CAD	Phase 3 trial (CARDINAL trial)	24 (with recent transfusion history)	Least-squares mean increase in Hb of 2.6 g/dl. Normalization of mean bilirubin levels by week 3. No SAE related to SUT reported
Roth et al. [18]	CAD	Phase 3 trial (CARDINAL trial 2 years extension)	22	Sustained increase in Hb level of >2 g/dL from week 3 to week 53; normalized Hb in 11/22 pts; mean total bilirubin decreased by week 1 and normalized by week 3. 19/22 pts remained transfusion free from week 27 to 53. One pt discontinued the study due to non-serious TEAE
Roth et al. [19]	CAD	Phase 3 trial (CADENZA trail)	42 (without recent transfusion history) 22 pts received sutimlimab, 20 pts received placebo	SUT significantly increased Hb levels, reduced bilirubin levels by week 1. 3 SUT pts discontinued because of adverse events
Tvedt et al. [77]	CAD	Case report	1	Efficacy of prophylactic SUT in a patient with CAD undergoing cardiac surgery
Tahhan et al. [72]	wAHIA	Case report	1	Sustained decrease of bilirubin level and transfusion requirement in a case of refractory wAHIA

AIHA, autoimmune hemolytic anemia; BTKi, Bruton tyrosine kinase inhibitor; CAD, cold agglutinin disease; pt(s), patient(s); SAE, severe adverse event; SUT, sutimlimab; wAIHA, warm autoimmune hemolytic anemia.

Figure 1. Monoclonal antibody-based therapies for autoimmune hemolytic anemia (AIHA).

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