Carmen Martín

Clinical value of immunological monitoring of minimal residual disease in acute lymphoblastic leukaemia after allogeneic transplantation

Summary. In this study, we used multiparameter flow cytometry to quantify minimal residual disease (MRD) in 165 serial bone marrow samples from 40 patients diagnosed with acute lymphoblastic leukaemia (ALL) who underwent allogeneic stem cell transplantation (allo‐SCT) from siblings (n = 34) or unrelated donors (n = 6). Samples were prospectively taken from 24 patients before starting the conditioning regimen, at days +30, +60 and +90 and subsequently every 2–3 months. Samples from 16 patients in complete remission (CR) after allo‐SCT were taken at least twice. Six of 24 patients harboured MRD (0·2–10% of mononuclear cells) at transplant and 18 were negative. Estimated disease‐free survival for the MRD+ and MRD– groups at transplant was 33·3% and 73·5% respectively (P = 0·03). During follow‐up, increasing MRD levels were detected in nine patients, a finding that preceded marrow relapse by 1–6 months. Two patients with stable low MRD levels remained in CR. When we used flow cytometry to test the effect of donor leucocyte infusions (DLI) in six patients, we observed that the only sustained remission was achieved when DLI was applied prior to overt relapse. We conclude that MRD by flow cytometry can rapidly assess tumoral burden before transplant to predict outcome, and can be clinically useful for the timing of DLI for increasing levels of leukaemia after transplant.

Kinetic of regulatory CD25high and activated CD134+ (OX40) T lymphocytes during acute and chronic graft-versus-host disease after allogeneic bone marrow transplantation

Graft‐versus‐host disease (GVHD) is still a major complication after allogeneic stem cell transplantation. In murine models, freshly isolated or ex vivo expanded CD4+CD25high regulatory T cells (Treg) are able to ameliorate GVHD while maintaining graft‐versus‐leukaemia reactions. However, in the human setting, prospective studies of this population and its interaction with activated non‐regulatory CD134+ (OX40) lymphocytes during post‐transplant follow‐up are lacking. In this study, we prospectively quantified CD4+CD25high and activated CD134+ lymphocytes in 119 peripheral blood samples from 35 consecutive patients who underwent allogeneic bone marrow transplantation (BMT). Fifty‐five samples obtained less than 100 d after allogeneic BMT, were not statistically different regarding CD4+CD25high Treg or CD134+ lymphocytes compared with those obtained from patients with (n = 35) or without (n = 20) acute GVHD. Chronic GVHD was associated with a small, but not statistically significant, increase in the number of Treg (9·9 vs. 6·7 × 106/L). However, the CD134/CD25high ratio was significantly higher during chronic GVHD (cGHVD) when compared with either patients without cGVHD (67·7 ± 40·3 vs. 4·0 ± 0·9, P < 0·01) or cGVHD after treatment (67·7 ± 40·3 vs. 3·7 ± 0·8, P < 0·01). Our findings suggest that the suppressive activity of CD4+CD25high Treg could be abrogated in vivo during cGVHD by CD134 expression in a much higher number of activated donor T lymphocytes. In addition to CD4+CD25highex vivo expansion protocols, OX40 blocking might be crucial to optimize the use of Treg to prevent GVHD.

Disparity for the minor histocompatibility antigen HA-1 is associated with an increased risk of acute graft-versus-host disease (GvHD) but it does not affect chronic GvHD incidence, disease-free survival or overall survival after allogeneic human leucocyte antigen-identical sibling donor transplantation

Disparity for the minor histocompatibility antigen HA‐1 between patient and donor has been associated with an increased risk of acute graft‐versus‐host disease (GvHD) after allogeneic human leucocyte antigen (HLA)‐identical sibling donor stem cell transplantation (SCT). However, no data concerning the impact of such disparity on chronic GvHD, relapse or overall survival are available. A retrospective multicentre study was performed on 215 HLA‐A2‐positive patients who received an HLA‐identical sibling SCT, in order to determine the differences in acute and chronic GvHD incidence on the basis of the presence or absence of the HA‐1 antigen mismatch. Disease‐free survival and overall survival were also analysed. We detected 34 patient–donor pairs mismatched for HA‐1 antigen (15·8%). Grades II–IV acute GvHD occurred in 51·6% of the HA‐1‐mismatched pairs compared with 37·1% of the non‐mismatched. The multivariate logistic regression model showed statistical significance (P: 0·035, OR: 2·96, 95% CI: 1·07–8·14). No differences were observed between the two groups for grades III–IV acute GvHD, chronic GvHD, disease‐free survival or overall survival. These results confirmed the association between HA‐1 mismatch and risk of mild acute GvHD, but HA‐1 mismatch was not associated with an increased incidence of chronic GvHD and did not affect relapse or overall survival.

Recomendaciones GESITRA-SEIMC y RESITRA sobre prevención y tratamiento de la infección por citomegalovirus en pacientes trasplantados

La infeccion por citomegalovirus (CMV) es una complicacion importante del trasplante. La ultima decada se ha caracterizado por los avances en su tratamiento, reduciendo su morbilidad y la mortalidad. Estos avances han sido decisivos en el diagnostico y prevencion. Se han desarrollado tecnicas de diagnostico rapidas y sensibles. Entre las estrategias de prevencion destaca el uso correcto de los productos sanguineos, las inmunoglobulinas y los farmacos antivirales, empleados en profilaxis o en terapia anticipada. El reciente desarrollo de farmacos eficaces por via oral como el valganciclovir permitira el tratamiento ambulatorio de los pacientes infectados. Es necesario trasladar este conocimiento a la practica clinica diaria. Con este objetivo el Grupo de Estudio de la Infeccion en el Trasplante (GESITRA) de la Sociedad Espanola de Microbiologia Clinica y Enfermedades Infecciosas (SEIMC) ha desarrollado este documento de consenso que incluye las ultimas recomendaciones en el tratamiento de la infeccion por CMV postrasplante.

Control of Epstein-Barr Virus Load and Lymphoproliferative Disease by Maintenance of CD8+ T Lymphocytes in the T Lymphocyte- Depleted Graft after Bone Marrow Transplantation

Of 100 bone marrow transplant recipients, 30 (30%) received a CD4(+) lymphocyte-depleted graft (1x10(6) CD8(+) T lymphocytes/kg of body weight). Replication of Epstein-Barr virus (EBV) was observed in 40 patients (40%). The use of a CD4(+) lymphocyte-depleted graft was the only independent risk factor for replication of EBV (relative risk, 11.5; 95% confidence interval, 5.8-22.8; P<.0001). Nevertheless, EBV load in those patients was not higher than in the rest of patients, and the low EBV load prevented the development of lymphoproliferative disease. These results suggest that the presence of CD8(+) T lymphocytes in the bone marrow graft can control EBV load, thereby reducing the risk of developing lymphoproliferative disease.