The following criteria should be met for a desensitization protocol to be considered eligible for coverage:

RENAL TRANSPLANT

1.  A suitable non-reactive live or cadaveric donor is unavailable.

A.  Living Donors - patients should exhibit:

• A current positive cross-match or may be defined by any of the following:
  • Flow cytometric crossmatch (FCXM) positive for T and/or B cells
  • National Institute of Health Complement dependent cytotoxicity (NIH-CDC) positive and dithiothreitol (DTT) treated
  • Antihuman globulin (AHG-CDC) assay positive
• ABO blood group incompatibility (ABOi) with or without splenectomy. May be defined as isoagglutinin titer >1:4

B.  Deceased Donors

• Panel reactive antibody (PRA) of HLA >50% or
• Donor specific antibody (DSA) positive or
• ABO blood group incompatibility (ABOi) with or without splenectomy

Various protocols (e.g., Johns Hopkins University Hospital, Cedars-Sinai Medical Center, etc.) utilize the following medications/procedures in desensitization treatment:

IVIG

• prior to solid organ transplant, treatment of patients at high risk of antibody-mediated rejection, including highly sensitized patients, and those receiving an ABO incompatible organ
• following solid-organ transplant, treatment of antibody-mediated rejection

Plasmapheresis

• prior to solid organ transplant, treatment of patients at high risk of antibody-mediated rejection, including highly sensitized patients, and those receiving an ABO incompatible organ
• following solid-organ transplant, treatment of antibody-mediated rejection

Rituximab (Rituxan®)

• prior to solid organ transplant, treatment of patients at high risk of antibody-mediated rejection, including highly sensitized patients, and those receiving an ABO incompatible organ
• the efficacy of more than two infusions in 48 weeks is unknown

HEART TRANSPLANT

Recommendations for the risk-assessment and prophylaxis strategies for allosensitized heart transplant candidates are as follows:

Class IIa:

1. A complete patient sensitization history, including previous PRA (panel reactive antibody) determinations, blood transfusions, pregnancies, implant of homograft materials, previous transplantation, and use of a VAD is required to assess the risk of heart allograft anti-body-mediated rejection.
2. A PRA ≥ 10% indicates significant allosensitization and it should raise the question of whether therapies aimed at reducing allosensitization should be instituted to minimize the need for a prospective donor/recipient crossmatch.
3. The results of the retrospective donor recipient crossmatch may be considered to make decisions regarding immunosuppressive therapy.

Class IIb:

1. Desensitization therapy should be considered when the calculated PRA is considered by the individual transplant center to be high enough to significantly decrease the likelihood for a compatible donor match or to decrease the likelihood of donor heart rejection where unavoidable mismatches occur.
2. Choices to consider as desensitization therapies include IV immunoglobulin (Ig) infusion, plasmapheresis, either alone or combined, rituximab, and in very selected cases, splenectomy.

The use of a desensitization treatment protocol that does not meet these criteria or for any other transplant other than heart or renal is considered experimental/investigational, and therefore, non-covered. A participating, preferred, or network provider can bill the member for the non-covered service.

NOTE:

Coverage is determined according to individual or group customer benefits.

Refer to Medical Policy Bulletin I-14 for information on intravenous immune globulin.

Refer to Medical Policy Bulletin S-11 for information on pheresis therapy.

Refer to Pharmacy Policy Bulletin J-500 for information on immune globulin.

Description

Immunological sensitization is defined as exposure of the immune system to antigen sufficient to generate an immune response. In the context of transplantation, the antigen is frequently encoded in the major histocompatibility complex (MHC), and although cell-mediated responses are involved, such sensitization is usually identified in terms of humoral immunity. Transplant patients are said to be immunologically sensitized if circulating antibody reacts with more than 10% of a panel of lymphocytes or human leukocyte antigen (HLA)-bearing beads, i.e. panel-reactive antibody or percent-reactive antibody (PRA).

Sensitization is problematic in human orthotopic heart transplantation (OHT) for the following reasons.  Identification of a crossmatch-negative donor extends the candidates time on the waiting list and increases the risk of rejection. Even if the crossmatch is negative, sensitized OHT recipients have significantly lower survival and experience earlier and more severe cardiac rejection episodes. The development of donor-specific antibodies post-OHT also has a deleterious effect on the outcome of such operations.

Sensitization is a growing problem in kidney transplantation. Approximately 30% of patients on the deceased donor waiting list have high levels of preformed anti-HLA antibodies. Alloantibodies develop after exposure to foreign antigens in the setting of blood transfusion, pregnancy and previous organ transplantation. With a growing number of patients returning to dialysis after a failed allograft, a different pattern has emerged over the past 10 years with previous transplantation now the leading cause of sensitization.  These numbers are projected to grow with the increasing disparity between organ supply and demand, the utilization of extended criteria donors and the high rate of graft loss from chronic allograft injury.

Presensitization poses a difficult problem in kidney transplantation. Highly sensitized patients face extended waiting times on dialysis thus, depriving them of improved quality of life and survival afforded by early kidney transplantation. After transplantation, they often have inferior outcomes compared with unsensitized patients due to a higher risk of rejection and the need for intensified immunosuppression. As such, the challenge of finding suitable organs for highly sensitized patients has renewed interest in developing novel strategies to detect and eliminate reactive alloantibodies to allow for a successful transplantation.

The two main strategies utilized over the years in overcoming sensitization are physical removal of alloantibodies using plasmapheresis and immunomodulation using intravenous immune-globulin (IVIG). In the early eighties, after it was shown that renal transplantation may be successful in patients with a negative crossmatch despite having historically positive reactivity; several strategies were developed to remove anti-HLA antibodies. Plasmapheresis (PP) or immunoadsorption (IA) were used to eliminate preformed antibodies in highly sensitized patients using protocols based on those used for Goodpasture’s syndrome to remove and prevent resynthesis of antiglomerular basement membrane antibodies.

Although these methods successfully removed anti-HLA antibodies, initial results were limited by resynthesis of antibodies and high rates of rejection and graft loss. It was clear that the effects of these treatments were temporary and unpredictable, especially in patients with high alloantibody titers and, current immunosuppressive drugs that are mainly centered on T cell mechanisms are inadequate in suppressing resynthesis of alloantibodies.

Recent application of solid-phase antibody screening techniques now allows for more sensitive screening of donor specific antibodies that may not be readily detected by conventional cytotoxic assays. Protocols for desensitization have also been developed in several centers. Although there are variations in strategies, the use of IVIG has been the primary immune-modulating agent integrated with other adjunctive therapies including plasmapheresis.

While current desensitization protocols have made possible successful transplantation in highly sensitized patients, there are limitations. Acute rejection rates remain high within the first 12 months and, it is also evident that response to treatment is not consistent on all patients. The reasons for these are not clear but maybe confounded by factors such as cause of sensitization, DSA class, techniques used to detect anti HLA antibodies, and continued immunologic stimulus from a failed allograft. In many cases, low levels of donor specific antibodies persist despite treatment and, it is often difficult to determine acceptable donor specific antibody levels that will allow successful engraftment. On the other hand, hyperacute rejection is rare and early rejections are often salvaged with additional IVIG/PP treatments.

NOTE:

This policy is designed to address medical guidelines that are appropriate for the majority of individuals with a particular disease, illness, or condition. Each person's unique clinical circumstances may warrant individual consideration, based on review of applicable medical records.

Under the Federal Employee Program, all services that utilize FDA-approved drugs, devices, or biological products are eligible when intended for the treatment of a serious life-threatening condition and when medically necessary and appropriate for the patient's condition.

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