Impact of cyclosporine-A concentration on aGvHD incidence after Haplo-HCT

For patients lacking a fully matched sibling or a well-matched unrelated donor, undergoing allogeneic hematopoietic stem cell transplantation, using a related haploidentical donor (Haplo-HCT) is an alternative option. The limitation of Halpo-HTC is often an immunologic recognition and destruction of the host tissue, ultimately leading to graft-versus-host disease (GvHD). Therefore, strategies to prevent GvHD development are needed.

Nicolas Stocker from the Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), F-75012 Paris, France, FR, and colleagues carried out a retrospective study to analyze the impact of early cyclosporine-A (CsA) initiation on the risk of acute graft-versus-host disease (aGvHD) after Haplo-HCT using post-transplant cyclophosphamide. The results of the study have been published ahead of print in the European Journal of Haematology.[1]

The primary endpoint of the study was to determine the impact of the serum CsA concentration on the risk of grade II-IV aGvHD.

Patients and methods

• All patients who had received Haplo-HCT with PTCy and a PBSC graft were included
• Patients were given post-transplant cyclosporine-A (PTCy) and mycophenolate mofetil (MMF)

Table 1: Univariant analysis of risk factors for Grade II-IV aGvHD : Abbreviation: CMV, cytomegalovirus

Characteristics	Patients with no or Grade I aGvHD n = 43 (%)	Patients with no or Grade II-IV aGvHD n= 18 (%)	P  value
Patient age, (yrs) median (range)	54 (15-72)	49 (16-66)	0.14
Patient age > 60 yrs	15 (35)	4 (22)	0.38
Patient gender
Male	28 (65)	11 (61)	0.77
Female	15 (35)	7 (39)
Donor gender
Female to male	11 (26)	5 (28)	1.0
ABO mismatch	24 (56)	7 (39)	0.27
CMV serologic status
Seronegative donor-recipient pair	3 (7)	3 (17)	0.34
Diagnosis
Myeloid malignancies	28 (65)	11 (61)	0.77
Lymphoid malignancies	15 (35)	7 (39)
Disease Risk Index
Low-Intermediate	27 (63)	12 (67)	1.0
High-Very High)	16 (37)	6 (33)

Table 2: Conditioning regime *Abbreviations: ATG, antithymo-globulins; CsA, cyclosporine A; RIC, reduced-intensity conditioning; RTC; reduced toxicity conditioning.

Characteristics	Patients with no or Grade I aGvHD n = 43 (%)	Patients with no or Grade II-IV aGvHD n = 18 (%)	P  value
RIC/RTC	25 (58)	11 (61)	1.0
Sequential conditioning	18 (42)	7 (39)
ATG
Without	5 (12)	5 (28)	0.14
With	38 (88)	13 (72)
Post-transplant cyclophosphamide
D+3	8 (19)	1 (6)	0.25
D+3/D+5	35 (81)	17 (94)
CsA blood concentrations during the first week after Haplo-HCT, median (ng/ml; range
< 301 ng/ml	25 (58)	16 (89)	0.03
≥ 301 ng/ml	18 (42)	2 (11)
CsA blood concentrations during the second week after Haplo-HCT, median (ng/ml; range)
< 297 ng/ml	23 (54)	8 (44)	0.58
≥ 297 ng/ml	20 (46)	10 (56)
CsA blood concentrations during the third week after Haplo-HCT, median (ng/ml; range)
< 261 ng/ml	25 (58)	9 (50)	0.59
≥ 261 ng/ml	18 (42	9 (50)
CsA blood concentrations during the fourth week after Haplo-HCT, median (ng/ml; range)
< 238 ng/ml	20 (46)	10 (56)	0.58
≥ 238 ng/ml	23 (54)	8 (44)

Results

• The study indicated that at day +180 the CI of grade II-IV and grade III-IV aGvHD were 39% and 18%
• Patients having a CsA concentration below 301 ng/ml the first week after Haplo‐HCT had a significantly higher risk of grade II‐IV aGvHD (P = 0.02), severe grade III‐IV aGvHD (P = 0.03), cGvHD (P = 0.02) and extensive cGvHD (P = 0.04)
• Multivariate analysis indicated a higher CsA concentration (≥301 ng/mL) during the first week following Haplo‐HCT was the only parameter significantly associated with a reduced risk of grade II‐IV and grade III‐IV aGvHD

Table 3: Engraftment and clinical outcomes after Haplo-HCT. Abbreviations: CI, confidence interval; GPFS, graft-versus-host disease, and progression-free survival. Bold denotes statistical significance.

Characteristics	All patients (n=61)	CsA < 301 ng/ml  (n=41)	CsA ≥ 301 ng/ml  (n=20)	P  value
Graft failure	3 (5)	2 (5)	1 (5)	1.00
Median time for neutrophil > 0.5 x 109/L (range), days	18 (13-35)	17 (13-31)	18 (13-35)	0.66
Median time for platelets > 50 x 109/L (range), days	26 (14-88)	24 (12-88)	29 (13-55)	0.71
aGvHD incidence at day +180, % (95%CI)	63 (47-74)	66 (46-78)	59 (26-77)	0.38
Grade II-IV	39 (22-52)	49 (27-64)	18 (0-39)	0.02
Grade III-IV	18 (7-31)	26 (8-41)	0	0.03
cGvHD incidence at month 18, % (95%CI)	41 (22-56)	55 (28-72)	16 (0-35)	0.02
Extensive	19 (1-33)	31 (2-52)	0	0.04
Non-relapse mortality at month 18, % (95%CI)	20 (9-30)	23 (8-36)	15 (0-29)	0.50
Relapse incidence at month 18, % (95%CI)	35 (18-48)	32 (11-48)	44 (9-65)	0.43
Progression-free survival at month 18, % (95%CI)	55 (42-67)	53 (36-67)	60 (35-77)	0.87
GPFS at month 18, % (95%CI)	48 (34-60)	42 (26-57)	60 (35-77)	0.39
Overall survival at month 18, % (95%CI)	60 (46-71)	58 (41-72)	64 (39-81)	0.67
Median follow-up, months (range)	21 (10-53)	30 (10-53)	19 (13-52)	0.64

Table 4: Engraftment, risk of GvHD development and clinical outcomes depending on CsA concentration. Abbreviations: ATG, antithymoglobulin; CMV, cytomegalovirus; CsA, cyclosporine A; MAC, myeloablative conditioning regimen; RTC, reduced-toxicity conditioning regimen. Bold denotes statistical significance.

Outcome	Hazard ratio (95% CI)	P  value
Grade II-IV acute GvHD
Age <60vs > 60  years	0.68 (0.22-2.05)	0.49
ATG vs no ATG	0.36 (0.12-1.09)	0.07
CsA ≥ 301 ng/ml vs CsA < 301 ng/ml	0.21 (0.05-0.99)	0.049
CMV donor/recipient negative vs others	0.98 (0.19-4.97)	0.98
Female donor to male recipient vs others	0.96 (0.31-2.99)	0.95
Grade III-IV acute GvHD
Age > 60 vs <60 years	0.72 (0.13-3.99)	0.70
ATG vs no ATG	0.25 (0.05-1.29)	0.98
CsA ≥ 301 ng/ml vs CsA < 301 ng/ml	< 0.001 (0.000007-0.00005)	< 0.001
CMV donor/recipient negative vs others	1.29 (0.15-10.9)	0.82
Female donor to male recipient vs others	0.86 (0.15-4.92)	0.87
Chronic GvHD
Age > 60 vs <60 years	0.46 (0.09-2.36)	0.35
ATG vs no ATG	1.93 (0.38-9.90)	0.43
CsA ≥ 301 ng/ml vs CsA < 301 ng/ml	0.31 (0.07-1.44)	0.13
CMV donor/recipient negative vs others	3.52 (0.55-22.34)	0.18
Female donor to male recipient vs others	2.00 (0.79-5.00)	0.14
Relapse incidence
Age > 60 vs <60 years	2.06 (0.71-6.05)	0.18
ATG vs no ATG	0.28 (0.11-0.73)	0.009
CsA ≥ 301 ng/ml vs CsA < 301 ng/ml	1.69 (0.65-4.38)	0.28
RTC vs MAC	0.74 (0.10-5.83)	0.78
DRI very-high/high vs low/very-low	6.16 (0.72-53.05)	0.10

The authors found no correlation between CsA concentration and relapse, non‐relapse mortality (NRM), progression-free survival (PFS), GvHD‐free, and progression-free survival (GFPFS) or overall survival (OS).

Conclusion

Previous studies have indicated that a low CsA concentration increases the risk of aGvHD and that concentrations should be monitored in BM transplant recipients.[2] However, Dr. Stocker and colleagues evaluated the impact of serum CsA concentration on the incidence of aGvHD in a homogenous group of adult patients undergoing Haplo-HCT with PBSC and PTCy as GvHD prophylaxis given in combination with ATG, CsA, and MMF. The team identified that CsA could be initiated early before Haplo-HCT without negative impact on outcome (relapse, NRM, PFS, GFPFS, OS)and that the achievement of high CsA concentration to reduce the risk of aGvHD without any detrimental effect on relapse. The authors acknowledged the limitations of a retrospective study, especially the lack of data on renal function which might have been impacted by the early start of CsA.