Bunjes et al recently reported encouraging results of a phase 1 to 2 study on the ability of Rhenium 188 (188Re)–labeled anti-CD66 (a, b, c, e) monoclonal antibodies (mAbs) to intensify the conditioning regimen prior to stem cell transplantation for patients with high-risk acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).1 Bunjes et al gave 32 patients allografts after a conditioning with the radiolabeled mAb in combination with total body irradiation (TBI) or busulfan-based conditioning regimens.1 Thirty patients received T-cell–depleted peripheral blood stem cells or bone marrow. The authors observed a transplantation-related mortality (TRM) of 24%. Only 3 patients developed a clinically relevant acute graft-versus-host disease (GvHD) grade II; no patient developed a severe GvHD.
Here we report our results on 19 patients receiving allografts after conditioning regimens intensified by 188Re-labeled anti-CD66 (a, b, c, e) mAbs as listed in Table1. In contrast to Bunjes and colleagues we experienced a very high rate of severe acute GvHD and TRM. All patients suffered from advanced or high-risk leukemia (10 patients, Philadelphia chromosome–positive ALL; 2 patients, Philadelphia chromosome–negative ALL; 5 patients, AML; 1 patient, MDS; and 1 patient, chronic myeloid leukemia [CML]). Similar doses of188Re-labeled anti-CD66 (a, b, c, e) mAbs were administered at the same nuclear medicine department as that reported by Bunjes et al. Subsequently, all patients received TBI in combination with cyclophosphamide, melphalan alone, or chemotherapy alone (fludarabin + busulfan, fludarabin + melphalan, or thiotepa + melphalan). Ten patients received allografts from HLA-identical sibling donors and 9 from unrelated donors. Seventeen patients received allografts of peripheral blood stem cells and 2 received allografts of bone marrow. The main difference between our protocol and Bunjes et al's protocol was the policy of immunosuppression, T-cell depletion, and T-cell add backs. Bunjes and colleagues allografted T-cell–depleted grafts without additional posttransplantation immunosuppression and without any T-cell add backs. Thirteen of our patients received unmanipulated grafts in combination with immunosuppressive therapy (ciclosporin A and mycophenolate mofetil). Six patients received allografts with CliniMACS (Miltenyi, Bergisch Gladbach, Germany)–selected CD34+ cells. These patients received T-cell add backs every 4 to 6 weeks starting at day + 28 after transplantation with incremental doses until the occurrence of GvHD symptoms (first T-cell dose, 5 × 104/kg; second T-cell dose, 5 × 105/kg; third T-cell dose, 5 × 106/kg).
Out of 19 patients 15 developed acute GvHD, 14 had a GvHD of at least overall stage 2, and 8 patients had GvHD of stage 3 or 4. The frequency of intestinal involvement was unusually high (11/19). Four patients died of acute intestinal GvHD. Two other deaths may also be related to gastrointestinal toxicity; 1 patient died of hemorrhagic colitis, a second of Candida septicemia. The overall TRM was 9 of 19. In 2 subgroups the TRM was even higher: unrelated donors, 6/9; grafts without T-cell depletion, 8/13.
What are the probable reasons for the high rate of gastrointestinal complications and TRM? In contrast to the cohort of Bunjes the majority of our patients suffered from Philadelphia chromosome–positive ALL. Several studies demonstrated a high TRM in patients with this disease.2,3 However, this does not explain the high frequency of acute intestinal GvHD. The second obvious difference was the use of unmanipulated grafts or early incremental T-cell add backs. We therefore assume that the combination of anti-CD66 (a, b, c, e) mAb therapy and early exposure to allogeneic T cells might be the reason for intestinal toxicity. Since anti-CD66 (a, b, c, e) antibodies (clone BW250/183) bind intestinal epithelial cells, radioimmunotherapy might cause tissue damage in the bowel.4 This might also trigger intestinal GvHD. Moreover, the antigen CD66a is expressed on the surface of small intestinal intraepithelial lymphocytes (iIEL).5 6 Via cross fire radiolabeled intraepithelial T-cell binding, mAb might cause additional tissue damage.
In summary, allografting without T-cell depletion or with early T-cell add backs after conditioning regimens including188Re-labeled anti-CD66 (a, b, c, e) mAb is associated with a high risk of severe intestinal acute GvHD and a high TRM. We therefore suggest that efficient T-cell depletion is strongly recommended for allogeneic hematopoietic cell grafts after a radioimmunotherapy conditioning with anti-CD66 (a, b, c, e) mAb. Furthermore, the anticipated benefit of early T-cell add backs should be weighed out carefully with the risk of severe intestinal GvHD.
Factors influencing gut GvHD after intensified conditioning with Rhenium 188–labeled anti-CD66 monoclonal antibody
We are grateful to Klein et al for emphasizing one aspect of our study that received comparatively little attention in the original publication, namely the fact that all patients but one received T-cell–depleted grafts. Therefore the conclusions with respect to organ toxicity and the incidence of graft-versus-host disease (GvHD) only apply to T-cell–depleted stem cell transplantations and cannot be transferred to patients receiving conventional GvHD prophylaxis. Klein et al report a high incidence of gut GvHD in a cohort of patients receiving non–T-cell–depleted grafts after intensified conditioning according to our radioimmunotherapy protocol. We cannot entirely exclude the possibility that the specificity of the anti-CD66 antibody used in our study could have contributed to the gut problems observed. However, we have never observed localization of the antibody to the gut in our dosimetry studies, and we have data demonstrating that the labeled antibody per se does not induce a systemic release of cytokines involved in GvHD (interleukin-1, tumor necrosis factor–alpha, gamma-interferon [Buchmann et al, unpublished observations, December 2001]). We have only observed localization of the antibody to the gut in rare patients with significant infectious complications such as severe appendicitis. We therefore feel that this high incidence of intestinal GvHD is due to the use of conventional GvHD prophylaxis, and in particular to the early application of donor lymphocyte transfusions.
