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

May 14, 2020

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. 1Corticosteroids 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- refractoryacute 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. 3This 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.
  1. Gratwohl A, Brand R, Frassoni F, et al. Cause of death after allogeneic haematopoietic stem cell transplantation (HSCT) in early leukaemias: an EBMT analysis of lethal infectious complications and changes over calendar time. Bone Marrow Transplant . 2005;36(9):757-769. DOI: 1038/sj.bmt.1705140

  2. Tang FF, Cheng YF, Xu LP, et al. Basiliximab as treatment for steroid-refractory acute graft-versus-host disease in pediatric patients after haploidentical hematopoietic stem cell transplantation.  Biol Blood Marrow Transplant . 2020;26(2):351-357. DOI: 1016/j.bbmt.2019.10.031

  3. Liu SN, Zhang XH, Xu LP, et al. Prognostic factors and long-term follow-up of basiliximab for steroid-refractory acute graft-versus-host disease: updated experienced from a large-scale study. Am J Hematol. 2020. DOI: 1002/ajh.25839