Management of refractory autoimmune hemolytic anemia after allogeneic hematopoietic stem cell transplantation: current perspectives

Figures & data

Figure 1 Main complications and risks factors for fatality in primary AIHAs. AIHAs show great clinical heterogeneity, including symptoms related to anemia, thrombotic events, infectious complication, acute renal failure, and circulatory disabling symptoms (typical of cold AIHA).

Abbreviations: DIC, disseminated intravascular coagulation; DVT, deep vein thrombosis; AIHA, autoimmune hemolytic anemia.

Table 1 Clinical and laboratory characteristics of patients at onset divided according to AIHA serological type

	Median age at diagnosis (years, range)	Hb (g/dL), median (range)	LDH (ULN), median (range)	Ret (x10^9/L), median (range)	Inadequate reticulocytosis, n of pts (%)
wAIHA (n=225)
IgG (n=158)	67 (5–94)	7.3 (2.1–14.1)	1.7 (0.6–26.7)	180 (22–644)	86 (54)
IgG+C (n=67)	65 (21–92)	6.5 (2.0–11.5)	1.8 (0.8–7.2)	143 (53–641)	35 (52)
CAD (n=107)	70 (28–94)	8.2 (4.0–13.5)	1.4 (0.3–12.2)	123 (13–644)	69 (64)
Mixed AIHA (n=24)	61 (20–86)	6.4 (4.3–10.7)	1.7 (0.6–9.8)	181 (45–576)	15 (62)
Atypical AIHA (n=22)	45 (25–78)	6.6 (3.0–10.9)	2 (0.7–18.1)	195 (29–780)	14 (64)

Abbreviations: wAIHA, warm autoimmune hemolytic anemia; CAD, cold agglutinin disease; AIHA, autoimmune hemolytic anemia; IgG, DAT positive for IgG; IgG+C, DAT positive IgG+C; LDH (ULN), LDH is expressed as folds of the upper limit of normal.

Table 2 Available therapies for primary warm and cold AIHAs, and for the most common secondary forms

	Treatment	Dose	Response	Comments/side effects
Primary AIHA
Warm AIHA
	Prednisone	1–1.5 mg/kg/day for 1–3 weeks, thereafter gradually tapered off, during a period no shorter than 4–6 months	75–80% (estimated cure rate in 20–30% only)	In patients with particularly rapid hemolysis and very severe anemia, or complex cases with concomitant thrombocytopenia (Evans syndrome), intravenous methylprednisolone 250–1000 mg/day for 1–3 days may be indicated
	Rituximab	375 mg/m^2 weekly x 4 weeks	80% (relapse-free survival of ~60% at 3 years)	Side effects include infusion reactions, infections, and hypogammaglobulinemia. Screening for hepatitis B virus surface antigen and core antibody is recommended for proper prophylaxis
	Low-dose rituximab	100 mg fixed dose weekly x 4 weeks	80–90% (sustained response in half cases at 6 years)
	Splenectomy	–	80% (curative rate 20–50%)	Possible complications include serious infectious (even after pre-splenectomy vaccination) and thrombotic events. Discouraged for patients older than 65–70 years, with cardiopulmonary disorders, thrombotic risk, immunodeficiency, lymphoproliferative diseases, and systemic autoimmune conditions
	Azathioprine	2–4 mg/kg for at least 1–3 months	60% (usually in association with steroids, as steroid-sparing agent)	Side effects include myelosuppression, infections, urotoxicity, secondary malignancy, fertility problems, and potential teratogenicity
	Cyclophosphamide	50–100 mg or 800 mg/m^2 IV monthly for 4–5 cycles	60% (few sustained responses)
	Cyclosporin	2.5 mg/kg twice/day	58% (small case series)	Side effects include kidney damage, hypertension, infections, nausea, excessive hair growth
	Mycophenolate mofetil	500 mg twice daily	25–100% (small case series)	Generally well tolerated (side effects include nausea, headache, diarrhea)
Cold AIHA
	Rituximab	375 mg/m^2 weekly x 4 weeks	50% (mostly partial, with a median duration <12 months	As above
	Rituximab plus bendamustine	Rituximab 375 mg/m^2 day 1 plus bendamustine 90 mg/m^2 day 1 and 2×4 cycles every 28 days	71% overall response (40% complete)	Grade 4 neutropenia in 20% and infections in 11% of patients
	Rituximab plus fludarabine	Rituximab 375 mg/m^2 days 1, 29, 57 and 85, and fludarabine orally, 40 mg/m^2 on days 1–5, 29–34, 57–61 and 85–89	76% overall response (21% complete)	Grades 3–4 hematologic toxicity in 41% of cases (including grade 4 neutropenia); grades 1–3 infection in 59% of patients
	Cyclophosphamide	50–100 mg or 800 mg/m^2 IV monthly for 4–5 cycles	60% (few sustained responses)	As above
	Bortezomib	1.3 mg/m^2 IV days 1, 4, 8, 11	32% overall response (16% complete)	No neurotoxicity was observed; infection and pulmonary embolism reported.
Secondary AIHA
Chronic lymphocytic leukemia-associated	Rituximab cyclophosphamide bendamustine plus rituximab	As above	Not available	In patients with Binet stage A or in whom AIHA is the predominant feature, therapy should be based as for primary wAIHA
	Alemtuzumab	30 mg IVx3 weekly for 8 wk	100% (small case series)	Infections
Systemic lupus erythematosus-associated	Steroids rituximab azathioprine mycophenolate mofetil			Splenectomy contraindicated
Common variable immunodeficiency-associated	Similar to primary AIHA			Maintenance immunoglobulin are fundamental to reduce infectious complications, and lifelong prophylactic antibiotics is mandatory for patients undergoing splenectomy

Notes: Treatments and response rates are derived from: Barcellini et al;¹ Kafta;² Hill et al;^3,4 Berentsen;⁵ Berentsen et al;^10,11 Barcellini et al;¹² Birgens et al;¹³ Michel et al;¹⁴ Barcellini et al.^15,16

Abbreviation: AIHA, autoimmune hemolytic anemia.

Table 3 Risk factors for the occurrence of post-transplant AIHA

Risk factor	Estimated risk	95% CI	P-value	Reference
Unrelated donor	1.45 (Relative risk)	1.05–1.99	0.02	Sanz et al, BMT (2007)^Citation17
Unrelated donor	5.28 (Hazard risk)	1.22−22.9	0.026	Wang et al, Biol Blood Marrow Transplant (2015)^Citation6
HLA mismatch donor	n.a.	n.a.	0.005	González-Vicent et al, Transf Med Rev (2018)^Citation7
Development of chronic GVHD	12.17 (Relative risk)	96–1.54	0.018	Sanz et al, BMT (2007)^Citation17
Cord blood use	n.a.	n.a.	0.005	González-Vicent et al, Transf Med Rev (2018)^Citation7
Age <15 years	n.a.	n.a.	0.005	González-Vicent et al, Transf Med Rev (2018)^Citation7
CMV reactivation	3.4 (Hazard risk)^a	1.2–9.6	0.02	Kruizinga et al, Biol Blood Marrow Transplant (2018)^Citation8
Alemtuzumab use	2.5 (Hazard risk)^a	1.1–5.7	0.028	Kruizinga et al, Biol Blood Marrow Transplant (2018)^Citation8
Nonmalignant diagnosis pre-HSCT	3.5 (Hazard risk)^a	1.1–10.9	0.031	Kruizinga et al, Biol Blood Marrow Transplant (2018)^Citation8

Notes: ^aRefers to all the autoimmune complications.

Factors not associated with post-BMT AIHA in different studies: 1) Wang et al.⁶ – recipient gender, primary hematological disease, source of hematopoietic stem cells, conditioning regimen, HLA mismatch between donor and recipient, ABO antigen mismatch, recipient CMV status, and concurrent chronic GVHD. 2) González-Vicent et al.⁷ – acute GVHD. 3) Kruizinga et al.⁸ – gender, donor type, stem cell source, conditioning regimen, T cell depletion, GVHD prophylaxis, ATG serotherapy pre-HSCT, ABO match, HLA mismatch, acute and chronic GVHD, EBV reactivation, adenovirus infection/reactivation, platelet recovery, absolute neutrophil count recovery, and chimerism in peripheral blood mononuclear cells. 4) Sanz et al.¹⁷ – ex vivo T-cell depletion, CD3 dose, total-nucleated cell dose, ABO mismatch, CMV status (donor or recipient), GVHD prophylaxis, acute GVHD.

Abbreviations: n.a. not available; AIHA, autoimmune hemolytic  anemia.

Table 4 Current and emerging treatments of post-allo-HSCT AIHA

Drug	Dose	N of patients	ORR	N of line	Reference
Wait & See	–	6	5 (83%)	–	Kruizinga et al, 2018^Citation8
Steroids	1–2 mg/kg day	9	5 (55%)	1st line	Sanz et al, BMT 2014^Citation22
		92	12 (13%)	1st line	Hosoba et al, Transfusion 2015^Citation19
		18	2 (11%)	1st line	Wang et al, Biol Blood Marrow Transplant 2015^Citation6
		15	3 (20%)	1st line	Chang et al, Medicine 2016^Citation18
		53	16 (30%)	1st line	Gonzalez-Vincent et al, Transf Med Rev 2018^Citation7
		15	2 (13%)	1st line	Kruizinga MD et al, Biol Blood Marrow Transplant 2018^Citation8
IVIG	2 g/kg x 2 days	2	2 (100%)	1st line	Sanz et al, BMT 2014^Citation22
		38	3 (8%)	1st line	Gonzalez-Vincent et al, Transf Med Rev 2018^Citation7
		11	1/11 (9%)	1st line	Kruizinga et al, Biol Blood Marrow Transplant 2018^Citation8
Splenectomy	–	2	1/2 (50%)	2nd line	Sanz et al, BMT 2014^Citation22
		3	3/3 (100%)	2nd line	Bhatt et al, BMT 2016^Citation23
		7	1/7 (14%)	2nd line	Gonzalez-Vincent et al, Transf Med Rev 2018^Citation7
		3	2/3 (67%)	2nd line	Kruizinga et al, Biol Blood Marrow Transplant 2018^Citation8
		3	0/3 (0%)	>2nd line	Wang et al, Biol Blood Marrow Transplant 2015^Citation6
PEX	–	2	0/2 (0%)	>2nd line	Wang et al, Biol Blood Marrow Transplant 2015^Citation6
		7	1/7 (14%)	>2nd line	Gonzalez-Vincent et al, Transf Med Rev 2018^Citation7
		1	0/1 (0%)	>2nd line	Kruizinga et al, Biol Blood Marrow Transplant 2018^Citation8
Rituximab	375 mg/sm/week x 4 weeks	8	6 (75%)	1st line	Sanz et al, BMT 2014^Citation22
		4	4/4 (100%)	2nd line	Sanz et al, BMT 2014^Citation22
		8	8 (100%)	2nd line	Faraci et al, Biol Blood Marrow Transplant 2014^Citation24
		32	19/32 (60%)	2nd line	Hosoba et al, Transfusion 2015^Citation19
		13	6/13 (46%)	2nd line	Wang et al, Biol Blood Marrow Transplant 2015^Citation6
		9	5/9 (56%)	2nd line	Chang et al, Medicine 2016^Citation18
		9	9 (100%)	1st line	Bhatt et al, BMT 2016^Citation23
		1	1 (100%)	1st line	Kruizinga et al, Biol Blood Marrow Transplant 2018^Citation8
		4	3/4 (75%)	2nd line	Bhatt et al, BMT 2017
		40	15/40 (38%)	2nd line	Gonzalez-Vincent et al, Transf Med Rev 2018^Citation7
		14	5/14 (36%)	2nd line	Kruizinga et al, Biol Blood Marrow Transplant 2018^Citation8
		1	1/1 (100%)	2nd line	Minakawa et al, Transfusion 2018^Citation25
Alemtuzumab	15 mg/day x3/wk	1	1 (100%)	>2nd line	Chao et al, Pediatr Blood Cancer 2008^Citation27
		1	0 (0%)	>2nd line	Gonzalez-Vincent et al, Transf Med Rev 2018^Citation26
Bortezomib	1.3 mg/mq	1	1 (100%)	>2nd line	Poon et al, BMT 2012^Citation32
		1	1 (100%)	>2nd line	Rovira et al, Trans Med Rev 2013^Citation33
		2	2 (100%)	>2nd line	Khandelwal et al, Biol Blood Marrow Transplant 2014^Citation34
		1	1 (100%)	>2nd line	Hosoba et al, Transfusion 2015^Citation19
		4	1 (25%)	>2nd line	Gonzalez-Vincent et al, Transf Med Rev 2018^Citation26
		7	4 (57%)	>2nd line	Kruizinga et al, Biol Blood Marrow Transplant 2018^Citation8
		3	2 (67%)	>2nd line	Schuetz et al, Blood Adv 2018^Citation35
Sirolimus	3 mg/sm D1 – 1 mg/sm day	1	1/1 (100%)	>2nd line	Park et al, Transf Med Rev 2016^Citation28
		2	2/2 (100%)	>2nd line	Wang et al, Biol Blood Marrow Transplant 2015^Citation6
		3	3/3 (100%)	>2nd line	Kruizinga et al, Biol Blood Marrow Transplant 2018^Citation8
Eculizumab	900 mg	1	0(0%)	>2nd line	Schuetz et al, Blood Adv 2018^Citation35
		2	1 (50%)	>2nd line	Gonzalez-Vincent et al, Transf Med Rev 2018^Citation26
Daratumumab	16 mg/kg/week	3	3 (100%)	>2nd line	Schuetz et al, Blood Adv 2018^Citation35
Abatacept	10 mg/kg day	3	3/3 (100%)	>2nd line	Hess et al, Transfusion 2018^Citation49

Abbreviations: PEX, plasma exchange; AIHA, autoimmune hemolytic  anemia.

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