Correspondence

Marrow Transplants from Unrelated Donors

N Engl J Med 1993; 329:362-363July 29, 1993

Article

To the Editor:

Kernan et al. (March 4 issue)1 report that patients who received marrow mismatched for one HLA antigen, as opposed to none, had delayed engraftment and an increased risk of a relapse of leukemia. However, there was no difference in the incidence of acute or chronic graft-versus-host disease, the incidence of secondary graft failure, or the Karnofsky score. These encouraging results suggest that more transplantations of marrow mismatched for one HLA antigen will be performed in the future. The paper describes HLA mismatches as minor if the mismatched antigen was cross-reactive and as major if the antigen was not cross-reactive. If completely matched transplants are not available, clinicians will opt for transplants with a minor mismatch, which implies that it is the second-best choice. This concept is misleading because there is no clinical or theoretical basis to support it.

Cross-reactive HLA antigens share antigenic determinants recognized by alloantibodies. When little was known about the structure of HLA molecules, it was thought that HLA antigens would be more similar to antigens that are cross-reactive than to those that are not. The concept is applied to HLA matching for platelet transfusions, but the benefit is still unclear. Antibody responses to cross-reactive antigens occur,2 and some are as frequent as those against non-cross-reactive antigens3. In renal transplantation, cross-reactive antigens (“splits”) seem to behave like any other mismatched HLA antigen,4 although the issue is still controversial. Kernan et al. do not provide information in this regard relevant to bone marrow transplantation. In addition, the lists of cross-reactive antigens encompass only antibody responses and not T-cell responses.

Now that the amino acid sequence of most HLA antigens is known, it is apparent that some cross-reactive antigens are structurally similar, but others are not5. A difference of one amino acid, even in inaccessible parts of the HLA molecule, can be sufficient to elicit an antibody or T-cell response. A logical inference is that the more amino acid differences there are with a mismatched HLA antigen, the higher the probability that an immune response will be induced. Therefore, until specific clinical information becomes available, it would be more rational to avoid the use of the terms “minor mismatch” and “major mismatch” and select the donor with the fewest amino acid differences in the mismatched antigen.

Juan C. Scornik, M.D.
University of Florida College of Medicine, Gainesville, FL 32610

5 References

1. 1

   Kernan NA, Bartsch G, Ash RC, et al. Analysis of 462 transplantations from unrelated donors facilitated by the National Marrow Donor Program. N Engl J Med 1993;328:593-602
   Full Text | Web of Science | Medline

2. 2

   Kakaiya RM, Rosen D, Cable RG. Transfusion of cross-reactive HLA antigens is immunogenic. N Engl J Med 1982;307:254-255
   Web of Science | Medline

3. 3

   Scornik JC, LeFor WM. Antibodies to crossreactive HLA antigens: evaluation by cytotoxicity, flow cytometry, and inhibition of monoclonal antibody binding. Transplantation 1987;43:235-240
   CrossRef | Web of Science | Medline

4. 4

   Opelz G. Importance of HLA antigen splits for kidney transplant matching. Lancet 1988;2:61-64
   CrossRef | Web of Science | Medline

5. 5

   Hildebrand WH, Madrigal JA, Belich MP, et al. Serologic cross-reactivities poorly reflect allelic relationships in the HLA-B12 and HLA-B21 groups: dominant epitopes of the alpha₂ helix. J Immunol 1992;149:3563-3568
   Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: We agree with Dr. Scornik that the definitions of minor and major HLA mismatches that we used were based on serologic data and thus do not necessarily relate directly to the known structure and sequence polymorphisms of the HLA class I and II molecules. Dr. Scornik is also correct in stating that there was no difference in the incidence of acute or chronic graft-versus-host disease, the incidence of secondary graft failure, or the Karnofsky score in our study. However, in both our study and the study by McGlave et al.,1 of patients with chronic myelogenous leukemia, leukemia-free survival was correlated favorably with matching for HLA-A, B, and DR (P<0.001 and P = 0.01, respectively).

Beatty et al. reported a large single-center study in which all pairs of donors and recipients underwent serologic typing in the same laboratory: the degree of serologic cross-reactivity was found to correlate with clinically relevant acute graft-versus-host disease2. It is conceivable, although unproved, that a classification of mismatching based quantitatively on the degree of disparity between donor and recipient alleles, as measured by the number of amino acid differences, might correlate with clinically relevant events. Unfortunately, the sequences of the alleles encoding HLA antigens in most pairs of marrow-transplant donors and recipients are unknown. It is not yet possible to test vigorously the alternative hypothesis proposed by Dr. Scornik. The National Marrow Donor Program has attempted to cryopreserve peripheral-blood mononuclear cells and DNA from each donor-recipient pair. Once the technological means are available to sequence each allele of the HLA class I and II molecules rapidly and accurately, a retrospective analysis can be performed to answer Dr. Scornik's very important question.

Nancy A. Kernan, M.D.
Memorial Sloan-Kettering Cancer Center, New York, NY 10021

John A. Hansen, M.D.
Fred Hutchinson Cancer Research Center, Seattle, WA 98104

Karl G. Blume, M.D.
Stanford University Medical Center, Stanford, CA 94305

2 References

1. 1

   McGlave P, Bartsch G, Anasetti C, et al. Unrelated donor marrow transplantation therapy for chronic myelogenous leukemia: initial experience of the National Marrow Donor Program. Blood 1993;81:543-550
   Web of Science | Medline

2. 2

   Beatty PG, Anasetti C, Hansen JA, et al. Marrow transplantation from unrelated donors for treatment of hematologic malignancies: effect of mismatching for one HLA locus. Blood 1993;81:249-253
   Web of Science | Medline

Citing Articles (3)

Citing Articles

1. 1

   Ying Han, Jinpu Yu, Shui Cao, Hui Li, Baozhu Ren, Xiumei An, Naining Zhang, Jing Qi, Xiubao Ren. (2010) Fetal–Maternal Microchimerism Enhances the Survival Effect of Interleukin-2-Activated Haploidentical Peripheral Blood Stem Cell Treatment in Patients with Advanced Solid Cancer. Cancer Biotherapy & Radiopharmaceuticals 25:6, 741-746
   CrossRef

2. 2

   Hassane Izzedine, Irina Buhaescu, Bahram Bodaghi, Valerie Martinez, Eric Caumes, Phuc LeHoang, Gilbert Deray. (2004) Oculo-renal Disorders in Infectious Diseases. International Ophthalmology 25:5-6, 299-319
   CrossRef

3. 3

   M. Macheta, J. A. Liu Yin. (2001) Recent advances in the treatment of AML. Hematological Oncology 19:3, 107-118
   CrossRef