Anti-thymocyte globulin pre-treatment plus standard GvHD prophylaxis beneficial for patients undergoing unrelated donor transplantation

Chronic graft-versus-host disease (cGvHD) is a severe complication of bone marrow transplant affecting 40–60% of patients, with rising incidence.^1,2 Previous studies have shown anti-thymocyte globulin to reduce the incidence of cGvHD, and to a lesser extent acute GvHD (aGvHD), after transplantation.^3–6 However, one of the studies raised concerns over reduced overall survival of patients receiving anti-thymocyte globulin due to disease relapse.³

A phase III study (NCT01217723), evaluating the addition of anti-thymocyte globulin prior to transplantation in addition to the standard GvHD prophylaxis in recipients receiving hematopoietic stem cell transplantation (HSCT) from unrelated donors, previously reported results after 12 months follow-up. The study was carried out on behalf of Cell Therapy Transplantation Canada and demonstrated a 21% reduction in the need for immunosuppressive therapy, as well as a decrease in patient-reported cGvHD symptoms.⁶ Irwin Walker, McMaster University, Hamilton, CA, and colleagues, recently published a final analysis of the trial, with a 24-month follow-up, in Lancet Haematology.¹ The article below outlines the key findings from the manuscript.

Methods

A randomized, multicenter, parallel arm, open-label, phase III clinical study of anti-thymocyte globulin plus standard GvHD prophylaxis (cyclosporine or tacrolimus plus methotrexate or mycophenolate) vs. standard GvHD prophylaxis alone in patients receiving HSCT from unrelated donors.

Key eligibility criteria

• Age 16–70 years
• Diagnosed hematologic malignancy
• Transplant eligible
• Karnofsky score ≥ 60
• Availability of fully matched or one-locus mismatched donor
• Myeloablative or non-myeloablative reduced-intensity conditioning

Treatment

• Patients in the anti-thymocyte globulin plus standard GvHD prophylaxis arm received:
  • rabbit anti-thymocyte globulin 4.5 mg/kg intravenously over 3 days (0.5 mg/kg on Day −2, and 2.0 mg/kg on Days −1 and +1)
  • cyclosporine or tacrolimus plus methotrexate or mycophenolate
• Patients in the GvHD prophylaxis arm received a standard preparative regimen
• Treatment of GvHD was according to center preferences
• Routine use of growth factors, γ-globulin, or alemtuzumab for cytomegalovirus primary prophylaxis was not allowed

The primary outcome of the study was to evaluate the rate of patients with absence of  cGvHD 12 months after transplantation, defined as the withdrawal of all systemic immunosuppressive agents without resumption up to 12 months after transplantation.

Results

In total, 203 patients were randomized to pretreatment with anti-thymocyte globulin plus GvHD prophylaxis (n = 101) or standard GvHD prophylaxis alone (n = 102).

• Three patients relapsed before transplant and four patients withdrew from the study
• Patients were well-matched between study arms and baseline characteristics of patients included in the analysis is presented in Table 1
• Median follow-up time was 24 months

Table 1. Selected baseline characteristics¹

*as per haemopoietic cell transplantation-comorbidity index GvHD, graft-versus-host disease; HLA, human leukocyte antigen
	Anti-thymocyte plus standard GvHD prophylaxis arm (n = 99)	Standard GvHD prophylaxis arm (n = 97)
Hematological disease, % Chronic myeloid leukemia Acute myeloid leukemia Acute lymphocytic leukemia Myelodysplastic syndrome Chronic lymphocytic leukemia Lymphoma Other	7 39 13 11 8 14 7	5 40 17 12 8 13 4
Disease stage Early Late Other	58 34 8	61 35 4
Conditioning regimen Myeloablative Non-myeloablative/reduced intensity conditioning	67 33	68 32
Recipient median age, years (range) > 50 years, % Donor median age, years (range) ≥ 30 years, %	49 (40–57) 45 30 (24–39) 44	49 (40–56) 44 31 (25–39) 52
Full HLA match, % Male recipient, %	84 64	81 67
Comorbidities* 0 1–2 ≥ 3	62 15 23	52 26 23
Graft cells from bone marrow, %	11	12

 

• At 24 months, 38% of patients in the anti-thymocyte globulin plus GvHD prophylaxis arm did not require immunosuppressive therapy compared with 19% in the standard prophylaxis alone arm
  • Odds ratio (OR): 2.73; 95% CI, 1.42–5.25; p = 0.0021
  • Absolute risk reduction: 19.7% (95% CI, 7.8%–34.0%)
  • Relative risk reduction: 51.7% (95% CI, 21.4%–70.3%)
• Most patients did not change the immunosuppressive therapy status from 12 to 24 months
  • 75% of patients in the anti-thymocyte globulin plus GvHD prophylaxis arm and 81% in the standard prophylaxis arm
• Subgroup analysis for freedom of cGvHD at 24 months from transplantation revealed that anti-thymocyte addition was associated with:
  • an overall benefit (OR 2.7; 95% CI, 1.4–5.3; p = 0.0016)
  • significant advantage for patients receiving peripheral blood as source of progenitor cells compared to bone marrow (p = 0.026)
  • patients with acute myeloid leukemia experiencing the biggest benefit of all hematologic malignancies tested (OR 4.7; 95% CI, 1.6–13.8)
• Patient-reported outcomes
  • Symptoms of cGvHD were less prevalent in patients with anti-thymocyte globulin
    • Lee scale score of 13.27 ± 10.94 vs. 20.38 ± 14·68 in the standard GvHD prophylaxis arm (p = 0.040)
  • Standard GvHD prophylaxis was associated with more depressive symptoms
    • Mean Center for Epidemiological Studies Depression scale (CES-D) score of 14.62 ± 12.26 in the standard GvHD prophylaxis arm vs. 10.40 ± 9.88 in the anti-thymocyte globulin arm (p = 0.034)
  • There were no significant differences for the remaining patient-reported outcomes
• Results of the remaining secondary efficacy endpoints are summarized in Table 2

Table 2. Patient outcomes at 24 months¹

CI, confidence interval; cGvHD, chronic graft-versus-host disease; GvHD, graft-versus-host disease; HR, hazard ratio; NA, not available
	Anti-thymocyte plus standard GvHD prophylaxis arm	Standard GvHD prophylaxis arm	HR (95% CI)	p value
The cumulative incidence of relapse (95% CI)	16.3% (8.9–23.7)	17.5% (9.9–25.1)	NA	0.73
The cumulative incidence of cGvHD (95% CI)	26.3% (17.5–35.1)	41·3% (31.3–51.3)	NA	0.032
Overall survival (95% CI)	70.6% (60.6–78.6)	53.3% (42.8–62.8)	0.56 (0.35–0.90)	0.017
Non-relapse mortality (95% CI)	21.2% (13.2–29.2)	31.3% (21.9–40.7)	NA	0.15

Adverse events

There was a trend towards a lower number of serious adverse events (CTCAE Grade 4 or 5) in the anti-thymocyte globulin arm compared to the standard GvHD prophylaxis arm (38% vs. 51%; p = 0.11).

There were no differences in the incidence of serious infections between study arms, with 42% in the anti-thymocyte globulin plus standard GvHD prophylaxis vs. 40% in the standard GvHD prophylaxis arm (p = 0.77). However, patients receiving anti-thymocyte globulin had a higher incidence of Epstein-Barr virus reactivation requiring treatment: 20 patients (including one death due to Epstein-Barr virus hepatitis) vs. two patients in the standard GvHD prophylaxis arm. There were no deaths linked to the treatment with anti-thymocyte globulin.

Conclusion

The results of this randomized phase III study support the addition of anti-thymocyte globulin to the standard GvHD prophylaxis therapy for patients undergoing unrelated donor transplantation. The 24-month follow-up showed a significant reduction of cGvHD and associated symptoms, improved overall survival, decreased need for immunosuppressive therapy and similar relapse rates in patients who received anti-thymocyte globulin plus standard prophylaxis compared to standard prophylaxis alone.