Patients
126 patients, 74(58%) males, with median age at allo-HSCT 46 years (range 18-71) were included into the analysis. For twelve patients it was the second allo-HSCT. The most prevalent diagnoses were acute leukemia, both myeloid (AML)- 54%, and lymphoblastic (ALL)- 13.5%. Baseline patients’ characteristics are shown in Table 1.
Table 1. Baseline patients’ characteristics (AA- aplastic anemia, AML- acute myeloid leukemia, ALL- acute lymphoblastic leukemia, GVHD- graft versus host disease, MAC- myeloablative conditioning, MDS- myelodysplastic syndrome, MPN- myeloproliferative neoplasm, MMUD- mismatched unrelated donor, MRD- matched related donor, MUD- matched unrelated donor, NMA- non-myeloablative conditioning, RIC- reduced intensity conditioning)
|
Number of patients
|
Share of the total (%)
|
Gender
|
|
|
|
Male
|
74
|
59
|
|
Female
|
52
|
41
|
Age in years
|
|
|
|
18-40
|
49
|
39
|
|
40-60
|
55
|
44
|
|
>=60
|
22
|
17
|
Diagnosis
|
|
|
|
AML
|
68
|
54
|
|
MDS
|
13
|
10
|
|
ALL
|
17
|
14
|
|
AA
|
6
|
5
|
|
MPN
|
9
|
7
|
|
Lymphoma
|
13
|
10
|
Conditioning
|
|
|
|
MAC
|
86
|
68
|
|
NMA
|
5
|
4
|
|
RIC
|
35
|
28
|
Donor
|
|
|
|
MRD
|
37
|
30
|
|
MUD
|
66
|
52
|
|
MMUD
|
19
|
15
|
|
haplo
|
4
|
3
|
Acute GvHD
|
|
|
|
Grade 1-2
|
28
|
22
|
|
Grade 3-4
|
11
|
9
|
Chronic GvHD
|
|
|
|
Mild
|
13
|
10
|
|
Moderate
|
46
|
37
|
|
Severe
|
22
|
17
|
Transplantations
HLA-identical siblings were used for 38(30.2%) patients, matched unrelated donors for 66(52.4%), mismatched unrelated donors for 19(15.1%) and haploidentical related donors for 3(2.4%). There were 86(68,2%) patients, who received myeloablative conditioning (MAC), 35(27.8%) reduced-intensity conditioning (RIC), and 5(4%) non-myeloablative conditioning (NMA).
Treatment after transplantation
Thirty-four patients (27%) received additional therapy after transplantation (mainly azacitidine) aimed at preventing relapse. The detailed information on this treatment is provided in the Supplement.
Immunosuppressive therapy
All patients received prophylactic anti-GvHD treatment, including 84 patients (67%)‑cyclosporine A(CsA) and 28(22%)- tacrolimus (TAC), together with short course of methotrexate. Other protocols included: CsA or TAC combined with mycophenolate mofetil (MMF) (4 patients(3%)) or TAC with sirolimus (6 patients(5%)). Three patients received either MMF (2 patients(2%)) or sirolimus (1 patient(1%)).
GvHD
Acute graft-versus-host disease (aGvHD) was diagnosed in 39 patients (30.9%) including 28(22.2%) with grade 1-2, and 11(8.7%) with grade 3-4. Chronic graft-versus-host disease (cGvHD) was diagnosed in 81 patients (64%), including 13(10%) with mild, 46(37%)- moderate, and 22(17%)- severe cGvHD.
Prevalence of IgG deficiencies after allo-HSCT
Hypogammaglobulinemia below 500mg/dL detected at least once occurred in 32.5% of patients (41 out of 126). In most patients, hypogammaglobulinemia was occasional and transient, and only in 10.3% of patients (13 out of 126), it was chronic. Additionally, in 25 patients IgG level below 700mg/dL but above 500mg/dL was observed making the total number of IgG deficient patients 66 out of 126(52.4%). 47% of patients did not have a decreased IgG level and about 4% of them had hypergammaglobulinemia. Eight patients developed monoclonal gammopathy. IgG deficiencies and the use of IgG supplementation are summarized in Table 2.
Table 2. IgG deficiency and the use of IgG supplementation in all analyzed patients
IgG (mg/dL)
|
Number of patients (Share of the total)
|
Prophylactic IgG (Share of the total)
|
Therapeutic IgG (Share of the total)
|
Relapse (Share of the total)
|
Death (Share of the total)
|
|
|
< 200
|
1 (0,1%)
|
1 (0,1%)
|
0
|
0
|
0
|
|
200 - 300
|
8 (6.3%)
|
4 (3.1%)
|
4 (3.1%)
|
1 (0.1%)
|
1 (0.1%)
|
|
300 - 400
|
13 (10.3%)
|
10 (7.9%)
|
3 (2.4%)
|
3 (2.4%)
|
3 (2.4%)
|
|
400 - 500
|
19 (15%)
|
10 (7.9%)
|
9 (7%)
|
4 (3.1%)
|
5 (4.4%)
|
|
500 - 700
|
25 (20%)
|
0
|
12 (9.4%)
|
3 (2.4%)
|
4 (3.1%)
|
|
700 - 1600
|
55 (44%)
|
0
|
0
|
6 (4.9%)
|
6 (4.9%)
|
|
> 1600
|
5 (4.3%)
|
0
|
0
|
1 (0.1%)
|
1 (0.1%)
|
|
Total
|
126 (100%)
|
25 (19%)
|
28 (22%)
|
18 (13%)
|
20 (15%)
|
|
Altogether 53 out of 126 patients (42%) required IgG supplementation with exogenous immunoglobulin. Immunoglobulin facilitated subcutaneously by recombinant human hyaluronidase was used in 85% cases and solution 165mg/mL- in 15% cases.
IgG was administered to all patients in whom IgG level was below 500mg/dL (41 patients (32.5%)). In 25 of them, it was only prophylactic, while in the remaining 16 also therapeutic because of recurrent infections. Additionally, 12 patients with IgG in the range 500-700mg/dL with accompanying severe and recurrent infections also received IgG supplementation. Therefore, the entire group of patients with infection receiving IgG supplementation comprised 28 patients (16 with IgG below 500mg/dL and 12 with IgG in the range 500-700mg/dL). The median number of IgG administrations was 3.5 (range 1-8) in the prophylactic, and 2 (range 1-8) in the group with infection.
The occurrence of the following invasive or life-threatening infections was used as an indication for IgG administration: fungal pneumonia- 7 patients (25%), bacterial pneumonia‑ 2(7%), sepsis within preceding months- 15(53%), recurrent local infection‑ 7(24%), viral infection- 25(89%)(including BK virus infection of the urinary tract‑ 10(35.7%), CMV reactivation- 10 (35.7%)) and polymicrobial infections- 13 patients(46%).
Beside IgG supplementation, they received appropriate routine antimycotic, antibacterial or/and antiviral treatment. Patients with BK virus infection did not receive any antiviral treatment.
The median time to the first IgG administration was 4.1 months (range 1.1-74.2) after allo-HSCT, and 13 months after diagnosis (for the entire group)(range 4.1-173.9).
Median IgG levels before IgG therapy initiation was 460mg/dL (range 190-480) in the prophylaxis group, 446mg/dL (range 200-494) in patients with IgG level below 500mg/dL and recurrent infections and 557mg/dL (range 519-670) in the group of patients with infections and IgG level below 700 but above 500mg/dL.
Thirteen of 126(10.3%) patients (3 out of 3 with chronic lymphocytic leukemia (CLL), 1 out of 4 with Hodgkin lymphoma (HL), 6 out of 68 with AML and 3 out of 17 with ALL) required regular IgG supplementation throughout the follow-up period with median 8 administrations per year (range 8-9).
While it is a retrospective and not a prospective study aiming at assessing regular pharmacokinetics, patients were controlled for IgG concentration at various time points after IgG subcutaneous administration. Nevertheless, subcutaneous IgG significantly increased IgG concentration that was maintained for 6-8 weeks (Fig.1). Patients originally suffering from ALL(82%) and lymphoma(58%) most frequently met the criteria for IgG supplementation and were accordingly treated. The characteristics of patients treated with IgG are shown in Table S3 (supplement).
Survival analysis
The 1-year overall survival (1-y OS) was 97.1%(95% CI, 89.1-99.3), 95.8%(95% CI, 73.9-99.4), 80.6%(95% CI, 51-93.3), 63.5%(95% CI, 28.9-84.7) in the group that never required immunoglobulin supplementation, in the prophylactic IgG group, in the group with recurrent infections treated with IgG because of IgG level below 500mg/dL, and finally, in the group treated with IgG because of recurrent infections and IgG 500-700mg/dL respectively. Relapse was the primary cause of death in 7 out of 7 patients, 4 out of 5 patients, 4 out of 4 patients and 3 out of 4 patients respectively.
The 1-y OS differences were not statistically significant with one exception; in the group with recurrent infections treated with IgG because of IgG level within 500-700mg/dL 1-y OS was significantly lower compared to the group never required immunoglobulin supplementation (p=0.009). The survival curves for all groups using Kaplan-Meier estimator are presented in Fig.2. Detailed results of the statistically significant 1-y OS differences for all groups are shown in Table S5.
Despite the fact that relapse contributed to death of 90% of all deceased patients, various infections complicated the course of relapse (mainly pneumonia or sepsis). Nine out of 10 patients (90%) with BKV infection receiving IgG improved, and thus achieved successful control of hemorrhagic cystitis, while 1 patient died (10%) due to relapse of the underlying disease. Detailed causes of death and diagnosed infections that occurred during the last 14 days of patients' lives are presented in Table S4.
Factors predictive for IgG supportive treatment
In the logistic regression model, the diagnosis of ALL or CLL and the use of systemic corticosteroid therapy were associated with the need for IgG supplementation. The average probability that a patient diagnosed with ALL or CLL will require IgG supplementation was 83.8%, while for patients with other diagnoses the average probability was 39.3% (p=0.0001). The use of corticosteroids was associated with the average probability of hypogammaglobulinemia requiring IgG supplementation in 64.2%, while no corticosteroid use with 31.5% (p=0.005) only.
Toxicity
Adverse events were observed in 53% patients treated with fscIgG, including 49%‑ grade 1 and 4%- grade 2. In two male patients (5%) transient scrotal oedema was observed, which resolved without any medical intervention. Malaise was reported in 2 patients (4%) and discomfort at the injection site in 10 patients (22%) patients. In 6 patients (13%) who suffered from chronic kidney disease- a clinically insignificant transient decrease in creatinine clearance was observed. In 3 patients (6%) of all treated patients, the change of the type of IgG products was required due to an allergic skin reaction at the application site.