The degree of HLA matching determines the incidence of cytokine release syndrome and associated nonrelapse mortality in matched related and unrelated allogeneic stem cell transplantation with post-transplant cyclophosphamide

Figures & data

Table 1. Patient, donor, disease and transplant characteristics.

	n (%)
	n = 126
Patient related
Sex, male	90 (71)
Recipient age, median (range), y	61 (19–77)
Recipient age group
<45	23 (18)
45–54	17 (13)
55–64	40 (32)
> =65	46 (37)
WHO performance at alloSCT
0	39 (31)
1	77 (61)
2	10 (8)
HCT-CI
0	62 (49)
1–2	37 (29)
3–4	21 (17)
5+	6 (5)
EBMT risk score
1–2	19 (15)
3	47 (37)
4	38 (30)
> =5	22 (17)
Donor related
Donor age, median (range), y	27 (18–75)
Donor age
<25	50 (40)
25–35	42 (33)
>35	34 (27)
Donor–recipient sex match
Male–male	64 (51)
Male–female	24 (19)
Female–male	26 (21)
Female–female	12 (10)
Donor–recipient CMV status
+/+	57 (45)
+/−	9 (7)
−/+	13 (10)
−/−	47 (37)
Donor–recipient relation
Sibling matched	19 (15)
Sibling mismatched	1 (1)
Unrelated matched	68 (54)
Unrelated mismatched	38 (30)
Donor–recipient HLA match
12/12 related donor	19 (15)
12/12 unrelated donor	8 (6)
10/10 unrelated donor	60 (48)
9/10 related donor	1 (1)
9/10 unrelated donor	38(30)
Disease related
Disease
Acute myeloid leukemia	62 (49)
Myelodysplastic syndrome	23 (18)
Acute lymphoblastic leukemia	11 (9)
T-cell lymphoma	10 (8)
Myeloproliferative neoplasia	6 (5)
B-cell lymphoma	3 (2)
Chronic myelomonocytic leukemia	3 (2)
M. Hodgkin	2 (2)
Myeloma	2 (2)
Other	4 (3)
Disease status at transplantation
Complete remission	100 (79)
Partial remission	8 (6)
Stable disease	1 (1)
Progressive disease	1 (1)
Untreated	14 (11)
Refined Disease risk index
Low	10 (8)
Intermediate	72 (57)
High	41 (33)
Very high	3 (2)
Time from diagnosis to transplant
< = 1 y	79 (63)
>1 y	47 (37)
Transplant related
AlloSCT sequence
First alloSCT	124 (98)
Second alloSCT	2 (2)
Graft type
Peripheral blood	126 (100)
Frozen	60 (48)
Fresh	66 (52)
Conditioning regimen intensity
Non-myeloablative	100 (79)
Myeloablative	26 (21)
GVHD prophylaxis
Tacrolimus and mycophenolate	126 (100)
CD34+ cell number (× 10^6/kg), median (range)	6.9 (1.9–16.5)
<5 × 10^6/kg	17 (13)
> =5 × 10^6/kg	109 (87)
TNC number (× 10^8/kg), median (range)	7.6 (3.6–20.1)

WHO: World Health Organization, HCT-CI: hematopoietic stem cell transplantation comorbidity index, EBMT: European Bone Marrow Transplantation, TNC: total nucleated cells.

Figure 1. Significant effects of HLA matching differences on CRS and maximum temperature developing after PTCy-alloSCT in patients transplanted with 12/12, 10/10 and 9/10 matched donors.

Horizontal bars show median values.

A) Differences in CRS. P-values indicate differences between groups with combined CRS grade 1 and 2 by Fisher’s exact test.

B) Differences in maximum temperature. Temperatures of 37, 38, 39, 40 and 41°C correspond with 98.6, 100.4, 102.2, 104 and 105.8°F, respectively. P-values indicate differences between groups by Kruskal-Wallis test with pairwise comparisons after Bonferroni correction (global p-value p < 0.001).

Figure 2. Effects of differences in HLA matching on maximum temperature developing after alloSCT with PTCy.

Temperatures of 37, 38, 39, 40 and 41°C correspond with 98.6, 100.4, 102.2, 104 and 105.8°F, respectively. Horizontal bars show median values. Patients transplanted with 12/12 matched donors are subdivided in RD (related donor) and UD (unrelated donor). Patients transplanted with 10/10 matched donors are subdivided in DP P (HLA-DPB1 permissive mismatch) and DP NP (HLA-DPB1 non-permissive mismatch), two-sided Mann-Whitney shows significant difference between these groups. Patients transplanted with 9/10 matched donors are subdivided according to MM (mismatch) in HLA-A, B, C, DR (DRB1) or DQ (DQB1), Kruskal–Wallis test shows statistical difference within these groups (global p-value = 0.003), post hoc testing with Bonferroni adjustment shows significant difference between HLA-DRB1 and HLA-C subgroups.

Table 2. Description of patients with non-relapse mortality after PTCy-alloSCT.

	Age	MA/NMA	Daydiagnosis	DayNRM	HLA match	MM	DPB1MM	DRB3/4/5 MM	Fever grade	CRS grade	Cause of death
1	> =65	NMA	+8	+12	9/10	C	NP	DRB4	2	2	Acute cardiac failure
3	> =65	NMA	+11	+14	10/10		NP		3	2	Encephalopathy without identifiable cause
3	> =65	NMA	+18	+33	10/10		P	DRB3	3	1	Encephalopathy without identifiable cause
4	<50	MA	+28	+33	9/10	DRB1	NP	DRB3	3	2	Multi-organ failure
5	> =65	NMA	+26	+39	10/10		P		0	0	Encephalopathy without identifiable cause
6	> =65	NMA	+29	+43	9/10	DRB1	P		3	2	Encephalopathy without identifiable cause
7	51–64	NMA	+28	+48	9/10	A	NP		3	2	Primary graft failure
8	<50	MA	+36	+71	10/10		P		1	1	Sinusoidal-obstruction syndrome
9	> =65	NMA	+40	+96	9/10	B	NP		3	2	Cryptogenic organizing pneumonia
10	<50	MA	+50	+153	12/12				0	0	Acute GVHD grade 4
11	<50	MA	+99	+187	9/10	A	P		3	1	Cryptogenic organizing pneumonia
12	> =65	NMA	+117	+203	10/10		P		0	0	Cerebral lymphoma
13	> =65	NMA	+393	+404	9/10	A	P		1	1	Adenocarcinoma
14	51-64	NMA	+527	+567	12/12				0	0	Acute GVHD grade 3 after DLI for mixed chimerism
15	> =65	NMA	+751	+757	10/10		NP		3	1	VZV hepatitis

Both the day of diagnosis of the condition causing NRM and the day that NRM occurred are included. To prevent recognition the age of patients is presented in different cohorts. Encephalopathy without identifiable cause was characterized by progressive confusion or somnolence, without diagnosis despite analysis, without clinical improvement after discontinuation of tacrolimus. COP was characterized as a pulmonary syndrome with progressive shortness of breath and pulmonary consolidations on CT, without a causative pulmonary infection and, if possible, pathological confirmation. COP: cryptogenic organizing pneumonia, MA: myeloablative, NMA: non-myeloablative, MM: mismatch, NP: non-permissive, P: permissive.

Figure 3. Effect of the grade of CRS and maximum grade of fever during CRS on survival and non-relapse mortality (NRM) after PTCy-alloSCT.

Figures A and C show effects of grade of CRS on survival and NRM, figures B and D effects of maximum grade of fever during CRS on survival and NRM. Both for the log-rank test (survival) and for Grays’s test (NRM), global p-values are shown. Also p-values for the comparison of grade 3 fever versus grade 0-2 fever and grade 2 CRS versus grade 0-1 CRS are shown.

Table 3. Multivariable analysis of overall survival.

	Hazard ratio (95% CI)	p-value
CRS grade 2 versus CRS grade 0–1	8.3 (3.2–21.8)	<0.001
Age ≥65 versus <65	3.0 (1.3–7.2)	0.015
Donor age ≥35 versus <35	3.0 (1.2–7.5)	0.013
Active disease versus remission at SCT	0.6 (0.2–1.4)	0.224
Fever grade 3 versus fever grade 0–2	4.5 (1.9–11.2)	<0.001
Age ≥65 versus <65	3.2 (1.3–7.6)	0.008
Donor age ≥35 versus <35	3.7 (1.5–9.0)	0.005
Active disease versus remission at SCT	0.4 (0.2–1.0)	0.045

CRS and height of fever during CRS were analyzed separately because of the high correlation between these variables. Because of their nonlinear impact, patient age and donor age were not analyzed as continuous variables but dichotomized at 65 and 35 years, respectively.