Prognostic factors for the response to basiliximab treatment and the long-term clinical outcomes of patients with SR-aGvHD

Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for hematological malignancies, it is frequently associated with graft-versus-host disease (GvHD) causing early mortality.¹ Corticosteroids are often used as first-line treatment for GvHD, however their prolonged use is associated with toxicities and development of resistance. Currently, the only approved treatment for steroid-refractory acute GvHD (SR-aGvHD) is ibrutinib. A recent study has demonstrated that basiliximab, a chimeric monoclonal antibody that blocks the alpha-chain of the interleukin-2 receptor complex, is also an effective treatment for SR-aGvHD in pediatric patients.²

In a retrospective study, Si-Ning Liu and colleagues from Peking University People's Hospital, Beijing, China aimed to identify the prognostic factors for the therapeutic response to basiliximab treatment and the long-term clinical outcomes of patients with SR-aGvHD.³ This study was recently published in the American Journal of Hematology.

Study design and patient characteristics (Table 1)

• 230 patients who had SR-aGvHD and received basiliximab treatment after allo-HSCT at the Peking University Institute of Hematology between January 1^st, 2015 and December 31^st, 2016 were included in the study

Table 1. Patient characteristics

HCT-CI, hematopoietic cell transplantation-comorbidity index; HSCT, hematopoietic stem cell transplantation
Variable	% of patients
Age at HSCT, Years
< 18	32.2
≥ 18	67.8
Underlying disease
Acute leukemia	70.4
Myelodysplastic syndrome	13.9
Chronic myeloid leukemia	2.6
Severe aplastic anemia	8.3
Non-Hodgkin's lymphoma	2.2
Multiple myeloma	1.3
Other	1.3
HCT-CI score
Low risk	68.7
Intermediate risk	23.5
High risk	7.8
Donor type
Identical sibling	7.4
Haploidentical related	90.4
Unrelated	2.2
Graft type
Bone marrow	96.5
Bone marrow and peripheral blood	3.5

• First-line treatment of aGvHD was the administration of methylprednisolone at a dose of 2 mg/kg per day for patients aged < 10 years or weighing < 30 kg, or 1 mg/kg per day for all other patients
• Basiliximab was administered when aGvHD progressed within 3 days or did not respond by 5 days after initiation of methylprednisolone, or if the patient displayed worsening of aGvHD during steroid tapering
• Basiliximab was continued weekly on Days 1 and 3 until aGvHD improved to less than Grade II, or patients showed no response after 4 doses
• Endpoints of the study were overall response rate (ORR), non-relapse mortality (NRM), overall survival (OS), and disease-free survival (DFS)

Results

Response

• Cumulative incidence of ORR was 38.3% (95% confidence interval [CI], 32.0–44.6) at 14 days, 65.7% (95% CI, 59.6–71.8) at 28 days, and 77.8% (95% CI, 72.4–83.2) at 56 days after basiliximab treatment
• Best ORR was 78.7% with a complete responses (CR) rate of 60.9% and partial response (PR) rate of 17.8%
• Median duration from beginning of basiliximab treatment to ORR was 12 days (range, 8–50) for identical sibling donors, 15 days (range, 3–64) for haploidentical related donors, and 12 days (range, 7–20) for unrelated donors
• Multivariate analysis showed the only risk factor for lower ORR was Grade III–IV aGvHD before basiliximab treatment (HR = 0.50; 95% CI, 0.32–0.76; p = 0.001) (Table 2)

Table 2. Cumulative incidence of ORR after basiliximab treatment

aGvHD, acute graft-versus-host disease; CI, confidence interval; ORR, overall response rate
Days after basiliximab treatment	Grade II aGvHD		Grade III–IV aGvHD		p
ORR, %	95% CI	ORR, %	95% CI
14	41.4	34.4–48.4	23.1	9.7–36.5	0.023
28	70.2	63.7–76.7	43.6	27.7–59.5	0.002
56	80.1	74.4–85.8	66.7	51.2–82.2	0.013

Toxicities and infections

• No obvious infusion related, allergic, or other toxic reactions were observed after basiliximab treatment
• Patients receiving > 4 doses of basiliximab had higher rates of infection compared with those receiving < 4 doses
• Rate of viral, bacterial, and fungal infection after basiliximab treatment were 52.6%, 16.1%, and 3.8%, respectively.
• Lung infections were the most common (12%) followed by central nervous system infection (4.3%) and bloodstream infection (3.8%).

Long-term clinical outcomes

• The 4-year cumulative incidence of relapse, NRM, DFS, and OS after basiliximab treatment was 11.3%, 30.0%, 58.7%, and 61.7%, respectively
• The 4-year cumulative incidence of total and severe chronic GvHD after basiliximab treatment was 44.8% and 2.2%, respectively

Multivariate analysis showed that the hematopoietic cell transplantation-comorbidity index (HCT-CI) score and refined Minnesota aGvHD risk score were prognostic factors for OS, DFS, and NRM (Table 3)

• High-risk Minnesota aGVHD risk score showed a higher risk of decreased ORR, increased NRM, decreased DFS, and decreased OS compared with those in the standard-risk group

Table 3. Multivariate analysis for clinical outcomes after basiliximab treatment

aGvHD, acute graft-versus-host disease; DFS, disease free survival; HCT-CI; hematopoietic cell transplantation-comorbidity index; NRM, non-relapse mortality; OS, overall survival
		HR (95% CI)	p
OS	Minnesota aGvHD risk score
Standard	1
High	2.82 (1.61–4.93)	0.022
HCT-CI score
Low	1
Intermediate	1.71 (1.06–2.76)	0.028
	High	2.21 (1.12–4.36)	0.023
DFS	Minnesota aGvHD risk score
Standard	1
High	2.79 (1.62–4.80)	<0.001
HCT-CI score
Low	1
Intermediate	1.70 (1.07–2.69)	0.025
High	1.97 (1.01–3.87)	0.048
NRM	Minnesota aGvHD risk score
Standard	1
High	2.32 (1.22–4.41)	0.024
HCT-CI score
Low	1
Intermediate	1.48 (0.85–2.58)	0.170
High	2.64 (1.30–5.35)	0.007

Conclusion

• Basiliximab was an effective treatment for patients with SR-aGvHD achieving high rates of ORR after Day 28 and Day 56
• Severe aGvHD (Grade III to IV) before basiliximab treatment was identified as an independent prognostic marker of poorer response to basiliximab
• The total rate of infection was 59.6%. Patients receiving more than 4 doses of basiliximab had higher rates of infections. Infection rates appeared similar to those obtained with other second-line treatments for SR-GvHD
• Comorbidities before allo-HSCT and refined Minnesota aGvHD risk score at diagnosis had significant influence on long-term survival
• The authors noted that the limitations of the study included a relatively low proportion of patients with Grade III–IV aGvHD, potentially contributing to the favorable results. Furthermore, more than 90% of patients received haploidentical related donor HSCT, which makes a comparison to other donor types difficult.