J. Maciej Zaucha

Engraftment of early erythroid progenitors is not delayed after non‐myeloablative major ABO‐incompatible haematopoietic stem cell transplantation

Summary. We hypothesized that patients undergoing major ABO‐incompatible non‐myeloablative haematopoietic stem cell transplantation (nm‐HSCT) might experience prolonged haemolysis after transplant due to the delayed disappearance of host plasma cells producing anti‐donor isohaemagglutinins (HAs). To address this question, we analysed data from 107 consecutive patients transplanted with allogeneic peripheral blood stem cells from human leucocyte antigen‐matched (related, n = 84; unrelated, n = 23) donors after non‐myeloablative conditioning (200 cGy total body irradiation ± fludarabine). In total, 23 out of the 107 patients received major or major/minor ABO‐incompatible transplants. Red blood cell (RBC) transfusion requirements during the first 120 d post transplant were higher in major ABO‐mismatched than in ABO‐matched recipients (0·12 vs 0·03 median units RBC concentrate/d, P = 0·04). Two patients developed transient pure red cell aplasia, which had resolved spontaneously by 9 months after transplant. Major ABO incompatibility did not influence rates of engraftment. Patients with sustained engraftment experienced gradual declines of anti‐donor HAs, and the estimated median time to reaching IgM and IgG titres of < 1:1 was at least 133 d in evaluable patients, approximately twice longer than reported after myeloablative conditioning. There was a strong correlation between degrees of donor chimaerism in erythroid burst‐forming units, granulocyte macrophage colony‐forming units and granulocytes, indicating that donor erythroid engraftment, defined by early erythroid progenitors, was as prompt as myeloid engraftment. In conclusion, our data suggest that major ABO‐incompatibility is not a barrier to successful non‐myeloablative HSCT.

IL-2 does not enhance the conversion to complete donor chimerism following nonmyeloablative hematopoietic cell transplantation in dogs.

Summary:A dog model of stable mixed hematopoietic chimerism was established in which leukocyte-antigen-identical littermates receive nonmyeloablative total body irradiation before hematopoietic cell transplantation and postgrafting immunosuppression with mycophenolate mofetil and cyclosporine. Unmodified donor lymphocyte infusion (DLI) into stable mixed chimeras failed to increase donor chimerism, while DLI from donors sensitized to recipient minor-histocompatibility antigens promptly converted all recipients to complete donor chimerism. This established a model for studying approaches to enhance the graft-versus-host (GVH)-effect, a potential surrogate for graft-versus-leukemia activity. We asked if interleukin-2 (IL-2) given after unmodified DLI could result in reliable conversion to complete donor chimerism. IL-2, 4 × 105 IU/kg/day, was administered to six mixed chimeric dogs for 14 days. Four dogs received unmodified DLI with IL-2. At 20–40 weeks after DLI, all dogs remained mixed chimeras. For the two recipients of IL-2 only, mixed chimerism also remained unchanged. These results show that IL-2 given with DLI after nonmyeloablative transplantation in dogs is not effective in reliably converting mixed to complete donor chimerism.

Allogeneic Hematopoietic Stem Cell Transplantation with a Nonmyeloablative Conditioning Regimen

The development of nonmyeloablative allogeneic hematopoietic stem cell transplantation (HSCT) from the preclinical studies to the clinic has permitted the treatment of a larger number of patients who previously had not been candidates for the standard approach with myeloablation. This includes older patients and those patients who had contraindications to intensive cytotoxic regimens. Regimen-related toxicities (RRT) after myeloablation result in prolonged periods of hospitalization and the development of significant morbidity and potential mortality including veno-occlusive disease and idiopathic interstitial pneumonitis. Severe RRT can generally be avoided after nonmyeloablative conditioning. A graft-versus-leukemia reaction is critical to the eradication of many hematological malignancies after transplantation and has been shown to be effective in those patients who have been infused with lymphocytes from the donor (DLI) after relapse.