INTAC Study Group: Alemtuzumab Induction in Renal Transplantation

Incomplete

Hanaway MJ, et al. "Alemtuzumab induction in renal transplantation". New England Journal of Medicine. 2011. 364(20):1909-1919.
PubMed • Full text

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Clinical Question

How does alemtuzumab compare to basiliximab or thymoglobulin as an induction immunosuppressant, as part of an early steroid-withdrawal regimen in kidney transplant recipients?

Bottom Line

Alemtuzumab demonstrated lower rejection rates at 1 year when compared to conventional induction therapy with basixilimab or thymoglobulin in kidney transplant recipients. Alemtuzumab demonstrated superiority in rejection rates among low-risk immunologic risk patients compared to basiliximab, but similar rejection rates when compared to thymoglobulin in high-risk kidney transplant recipients.

Major Points

Antibody induction therapy is used in a majority of kidney transplant recipients, and is recommended by KDIHO guideline recommendations. However, the optimal induction agent is not well defined. A previous study applying a steroid-withdrawal regimen using induction therapy had shown a trend towards higher rejection rates with interleukin-2 receptor antagonists when compared to thymoglobulin.

This study conducted by the INTAC Study Group was an open-label, multicenter, randomized controlled trial evaluating alemtuzumab vs. conventional induction with basiliximab or thymoglobulin, in low-immunologic risk and high-immunologic risk kidney transplant recipients, respectively. All patients had early steroid withdrawal, and received tacrolimus and mycophenolate maintenance therapy. Rejection rates at 6, 12 and 36 months were lower in the alemtuzumab-treated patients when compared to those that received conventional induction. Alemtuzumab showed superior rejection rates in the low-risk subgroup and similar rejection rates in the high-risk subgroup. Patient and graft survival were similar in all comparisons.

Alemtuzumab may provide an alternative to conventional induction agents. KDIGO guidelines were published prior to this study’s publication, although it is mentioned as a possible depleting induction agent (KDIGO). Alemtuzumab has never been FDA approved for this indication, and is not available commercially at this time, but remains available through a manufacturer-run distribution program.

Guidelines

KDIGO Care of Kidney Transplant Recipients (2009, adapted)

• NOTE: These guidelines pre-date this publication.
• Recommendations for Induction Therapy:
  • We recommend including induction therapy with a biologic agent as part of the initial immunosuppressive regimen in KTRs. (1A)
  • We recommend that an IL2RA be the first-line induction therapy. (1B)
  • We suggest using a lymphocyte-depleting agent, rather than an IL2RA, for KTRs at high immunologic risk. (2B)

Design

• Prospective, open-label, multicenter, randomized controlled trial
• N=474
  • All patients
    • Alemtuzumab (n=234)
    • Conventional Therapy (n=240)
  • High-Risk Subgroup
    • Defined as repeat transplant, peak or current panel reactive antibody ≥ 20%, or black race.
    • Alemtuzumab (n=70)
    • Thymoglobulin (n=69)
  • Low-Risk Subgroup
    • Alemtuzumab (n=164)
    • Thymoglobulin (n=171)
• Setting: 30 centers in the U.S.
• Enrollment: 2005-2006
• Mean follow-up: 3 years
• Analysis: intention-to-treat
• Primary outcome: rate of biopsy-confirmed acute rejection at 6 months and 12 months.

Population

Inclusion Criteria

• Age ≥ 18 years
• Recipient of live-donor or deceased donor kidney

Exclusion Criteria

• Recipients of kidneys from expanded-criteria donors (ECD)
• Recipients of kidneys from donation after cardiac death (DCD) donors
• Recipients of kidneys from donor age ≤ 2 years or ≥ 60 years
• Kidneys with ischemic times >36 hours
• Positive cytotoxic or flow cytometry crossmatch
• Positive T-cell cytolytic crossmatch
• Kidneys from HLA-identical donors
• ABO incompatible donor
• Recipient with prior or concurrent non-renal transplant
• Donor serology positive for Hepatitis B, Hepatitis C or HIV
• Recipients with any of the following:
  • Malignancy in 5 years
  • Liver disease
  • Uncontrolled concomitant infection or unstable medical condition
  • Current or previous investigational drug use within 30 days
  • Known hypersensitivity to study drugs
  • On chronic steroids at time of transplant
  • Pregnant or lactating
  • Inability to comply with study visits
  • History or substance abuse or psychiatric history

Baseline Characteristics

For the combined Alemtuzumab group:

• Demographics: 65% Male; Mean age 48.0 years; 74% white, 22 % black
• Previous kidney transplant: 7%
• Type of donor: 41% deceased, 36% living related, 22% living unrelated
• HLA mismatch: 77% ≥ 3
• Panel-reactive antibody ≥ 20%: 12%
• Cold-ischemic time: 8.5 hrs
• Delayed graft function: 8%
• Donor demographics: 53% male; Mean age 37.6 years
  • There were more female donors (57%) in the conventional group
• CMV high-risk (donor positive, recipient negative): 26%

Interventions

• High-risk kidney transplant recipients:
  • Randomized to receive Alemtuzumab 30mg IV x1 dose vs. Basiliximab 20mg IV x2 doses
• Low-risk kidney transplant recipients:
  • Randomized to Alemtuzumab 30mg IV x1 dose vs. Thymoglobulin 1.5mg/kg IV x4 doses
• All patients received maintenance immunosuppression as follows:
  • Tacrolimus (target trough level 7-14 ng/mL for 90 days, then 4-12 ng/mL after day 90)
  • Mycophenolate mofetil (2g/day)
  • Steroids were given at a dose of 1g or less over 5 days, and were discontinued by day post-operative day 5.

Outcomes

Comparisons are alemtuzumab vs. conventional therapy.

Primary Outcomes

Biopsy proven acute rejection at 6 months

3% vs. 15% (P<0.001)

Biopsy proven acute rejection at 12 months

5% vs. 17% (P<0.001)

Secondary Outcomes

Biopsy proven acute rejection at 36 months

13% vs. 20% (P=0.03)

Patient survival at 36 months

96% vs. 96% (P=0.38)

Death-censored graft survival at 36 months

95% vs. 93% (P=0.38)

Subgroup Analysis

High-risk Subgroup - Biopsy proven acute rejection at 6 months

6% vs. 9% (P=0.49)

High-risk Subgroup - Biopsy proven acute rejection at 12 months

10% vs. 13% (P=0.53)

High-risk Subgroup - Biopsy proven acute rejection at 36 months

18% vs. 15% (P=0.63)

High-risk Subgroup - Patient survival at 36 months

99% vs. 91% (P=0.07)

High-risk Subgroup - Death-censored graft survival at 36 months

91% vs. 91% (P=0.88)

High-risk Subgroup - Efficacy composite (freedom from biopsy proven acute rejection, death or graft loss) at 36 months

76% vs. 70% (P=0.42)

Low-risk Subgroup - Biopsy proven acute rejection at 6 months

2% vs. 18% (P<0.001)

Low-risk Subgroup - Biopsy proven acute rejection at 12 months

3% vs. 20% (P<0.001)

Low-risk Subgroup - Biopsy proven acute rejection at 36 months

10% vs. 22% (P=0.003)

Low-risk Subgroup - Patient survival at 36 months

95% vs. 98% (P=0.19)

Low-risk Subgroup - Death-censored graft survival at 36 months

97% vs. 94% (P=0.17)

Low-risk Subgroup - Efficacy composite (freedom from biopsy proven acute rejection, death or graft loss) at 36 months

85% vs. 76% (P=0.04)

Adverse Events

All patients - Serious infection from 0-36 months

32% vs. 25% (P=0.10)

High-risk subgroup - Serious infection from 0-36 months

27% vs. 33% (P=0.46)

Low-risk subgroup - Serious infection from 0-36 months

35% vs. 22% (P=0.02)

All patients - Any infection from 0-36 months

73% vs. 75% (P=0.75)

High-risk subgroup - Any infection from 0-36 months

60% vs. 81% (P=0.009)

Low-risk subgroup - Any infection from 0-36 months

79% vs. 72% (P=0.17)

All patients - Serious adverse event related to cancer from 0-36 months

5% vs. 1% (P=0.03)

High-risk subgroup - Serious adverse event related to cancer from 0-36 months

6% vs. 0% (P=0.12)

Low-risk subgroup - Serious adverse event related to cancer from 0-36 months

4% vs. 2% (P=0.21)

All patients - White cell count <3000/mm3 from 0-36 months

57% vs. 35% (P=<0.001)

High-risk subgroup - White cell count <3000/mm3 from 0-36 months

63% vs. 49% (P=0.17)

Low-risk subgroup - White cell count <3000/mm3 from 0-36 months

54% vs. 29% (P<0.001)

Criticisms

• Low rates of rejection could be attributed to the exclusion of higher risk donors, and high proportion of living donors.
• This study did not assess for antibody-mediated rejection or alloantibody formation.

Funding

This study was funded by Astellas Pharma Global Development.