A high migratory capacity of donor T-cells in response to the lymph node homing receptor CCR7 increases the incidence and severity of GvHD.

The pathogenesis of GvHD involves migration of donor T-cells into the secondary lymphoid organs in the recipient, which is steered by two homing molecules, CD62L and CCR7. Therefore, we investigated whether the migratory capacity of donor T-cells is associated with GvHD. This single center prospective study included 85 donor-recipient pairs. In vitro chemotaxis assays of the lymphocytes of the apheresis product were performed in parallel to the analysis of CD62L and CCR7 by flow cytometry. The migratory index to the CCR7 ligands, CCL19 and CCL21, was higher in T-cells from donors whose recipients will develop GvHD. Similarly, the acute GvHD (aGvHD) group received higher percentage of CD4+CCR7+ T-cells, whereas chronic GvHD (cGvHD) patients were transplanted with higher percentages of CD8+CCR7+ T-cells compared with the non-GvHD group. These results were confirmed when patients were subdivided according to degrees of severity. Further, multivariate analysis confirmed that the proportions of CCR7+ CD4+ and CCR7+ CD8+ T-cells are risk factors for the development and severity of aGvHD and cGvHD, respectively. Functional experiments demonstrated that CCR7+ T-cells exhibited higher potential for activation than CCR7- T-cells did. We therefore propose that the selective depletion of CCR7-expressing T-cells may be an effective preventive therapy for GvHD.

[Treatment of leukemia relapsed after allogenic bone marrow transplantation with donor lymphocyte infusion: report of 11 cases]. / Tratamiento de la recidiva leucémica post-trasplante alogénico de medula ósea con infusión de leucocitos del donante: a propósito de 11 casos.

PURPOSE: Donor leukocyte infusions (DLI) are useful for treating leukaemic relapse after allogeneic bone marrow transplantation (BMT). We reviewed our experience with eleven patients who received DLI between 1995 and 1997. PATIENTS AND METHODS: The diagnoses prior to DLI were: chronic myeloid leukaemia (CML) in chronic phase (CP) (two patients) or accelerated phase (two patients), acute myeloid leukaemia (AML) (two patients), acute lymphoid leukaemia (ALL) (two patients), and refractory anaemia with excess blasts under transformation (tRAEB) (three patients). The patients received a median of 1.72 x 10(8) CD3+ cells/Kg (range: 0.58 x 10(8) CD3+ cells/Kg). Four patients were infused cryopreserved cells. Six patients received interferon alpha (IFN alpha) concomitantly. RESULTS: Seven patients (four CML, one AML, one ALL, one tRAEB) obtained complete remission (CR). Graft-versus-host disease (GVHD) was observed in all patients with CR and one without response. Marrow hypoplasia or severe bicytopenia occurred in four patients. Of all patients achieving CR, two died after relapsing within 3 months of DLI, while three others died of GVHD. Four patients had no response to DLI or were not evauable. Only two patients--both with CML--are alive 1096 and 374 days after DLI, the former in clinical, cytogenetic and molecular CR, and the latter in second CP after 2 months in CR. CONCLUSIONS: DLI results in CR in most patients with relapsing leukaemia or myelodysplasia after BMT, especially in CML patients. The anti-leukaemia effect is highly correlated with GVHD. This complication and marrow hypoplasia remain major causes of morbidity and mortality of this procedure.

Hepatitis C and G virus infection and liver dysfunction after allogeneic bone marrow transplantation: results from a prospective study.

Acute and chronic liver dysfunction is common after allogeneic bone marrow transplantation (BMT). Although toxicity, graft versus-host disease (GVHD), and viral infections are the major causes, etiologic diagnosis is difficult and often remains unknown. We conducted a prospective study to establish the role of the infection with both the hepatitis C virus (HCV) and the recently discovered hepatitis G virus (HGV) in liver dysfunction after BMT. From January 1994 to December 1995, 59 patients who had undergone an allogeneic BMT at our institution were enrolled in the study. HGV-RNA was identified in serum by nested polymerase chain reaction (PCR), and HCV was studied by the presence of second generation enzyme-linked immunosorbent assay (ELISA)-antibodies and HCV-RNA by nested PCR. HGV-RNA was detected in 25 patients (42%) (before BMT in 18 and after BMT in 7). HCV-RNA was present in 12 patients (20%) (before BMT in 11 and after BMT in one). The presence of HCV-RNA and HGV-RNA was clearly associated with a previous history of blood transfusions. No significant association was found between viral infection and acute liver toxicity. Some degree of liver dysfunction was present 6 months after BMT in 25 of 40 evaluable patients (62%). Long-term liver dysfunction was more common among patients infected with HCV alone (3 of 4) or with both HCV and HGV (3 of 3) than in those infected with either HGV alone (eight of 13) or with no virus infection (10 of 20). We found a high prevalence of HGV infection in our BMT population. However, no role for HGV in liver disease could be established in this study, and the relationship between HGV infection and liver dysfunction requires further clarification.

[Access to bone marrow transplantation in acute myeloblastic leukemia. Study of 52 patients treated in a single center]. / Accesibilidad al trasplante de médula ósea en la leucemia aguda mieloblástica. Estudio de 52 pacientes tratados en un solo centro.

BACKGROUND: A single-center experience review about accessibility to bone marrow transplantation (BMT) as postremission therapy for acute myeloid leukemia (AML) is analyzed. PATIENTS AND METHODS: From January 1988 to December 1994, 86 patients were diagnosed from de novo AML in our institution. A BMT was the treatment of choice for all patients younger than 55 years. An allogenic BMT (Allo-BMT) was offered for all patients younger than 35 years with a compatible sibling donor or those older patients, 35-55 years, with bad prognosis features. An autologus BMT (ABMT) was offered to those patients older than 35 years or those younger than 35 without an histocompatible donor. RESULTS: 52 out of 86 diagnosed patients were younger than 50 years (60%). 29 of them were candidates to Allo-BMT (24 patients younger than 35 years and 5 patients older than 35 with refractory disease) and the rest 23 to ABMT. 22 out of the 24 candidates to Allo-BMT entered complete remission (CR) and 12 of them had an HLA-identical donor. The Allo-BMT was performed in CR1 in 7 patients in CR2 in three patients and with refractory disease in two cases. An ABMT was finally planned in 30 patients, 18 patients older than 35 who entered CR and the rest 12 patients younger than 35 years in CR without a sibling donor. Only 11 out of this 30 patients underwent an ABMT in first CR. Reasons for this low number were: early relapse (B), toxicity (6), refuse (2), lost of follow-up (2) and suicide (1). Five out of this early relapse patients underwent an ABMT in CR2. Disease-free survival (DFS) at three years was 23 +/- 10% for the 52 patients included in the study. DFS obtained with Allo-BMT and AMBT were 39 +/- 16% and 63 +/- 22% respectively. CONCLUSIONS: In spite of the new postremission treatment modalities available for AML the rate of longer survivals are still low. When data from BMT is analyzed we must be awared because only a small fraction of patients assigned to BMT will finally access to this treatment.

[Bone marrow autotransplantation in acute myeloblastic leukemia in its first complete remission. The clinical results in 41 patients]. / Autotrasplante de médula ósea en la leucemia aguda mieloblástica en primera remisión completa. Resultados clínicos en 41 pacientes.

BACKGROUND: A single-center experience using autologous bone marrow transplantation (ABMT) as postremission therapy for acute myeloid leukemia (AML) in first complete remission (CR1) in 41 patients is analyzed. PATIENTS AND METHODS: From July 1986 to March 1994, 41 patients with AML in CR1 underwent an ABMT. Source of hematopoietic stem cells was bone marrow in all cases. In eleven patients the marrow was purged with mafosfamide (ASTA-Z 7654). Median age was 31 years (17-59) and median time from CR to ABMT was 7 months (3-27). Busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) was employed as conditioning regimen in 36 patients. The rest 5 patients were prepared with cyclophosphamide (120 mg/kg) and fractioned total body irradiation (12 Gy). Eleven patients received G-CSF after AMBT because of an absolute neutrophil count lower than 0.5 x 10(9) on day +30. Survival analysis was performed according to the methods of Kaplan and Meier and comparison between groups used the log-rank test. RESULTS: With a median follow-up of 26 months (12-75) 21 patients remain alive in CR. Disease-free survival (DFS) at five years was 40% (95% CI: 25-55%). Transplant-related mortality, mainly for infection and hemorrhage, occurred in 6/41 patients (16%). Leukemia relapse was the main cause of treatment failure: 14/35 (40%). Probability of DFS and relapse was similar for those patients with purged ABMT on unpurged ABMT 45 +/- 23% vs 38 +/- 16% and 37 +/- 14% vs 54 +/- 22% respectively. A significantly longer engraftment time for neutrophils (> 0.5 x 10(9)) and platelets (> 20 x 10(9)) was observed in those patients who received a bone marrow treated with mafosfamide compared with the unpurged group (54 vs 29 days for neutrophils and 102 vs 58 for platelets respectively) (p < 0.05). CONCLUSIONS: ABMT is a feasible treatment for AML in CR1. Using bone marrow as hematopoietic stem cell support we observed that delayed engraftment was a common finding among AML patients, specially when the marrow was treatment with mafosfamide. Leukemia relapse remains as the main cause of treatment failure for ABMT.

Autologous or allogeneic bone marrow transplantation for acute myeloblastic leukemia in second complete remission. Importance of duration of first complete remission in final outcome.

Between May 1983 and March 1994, 31 patients with AML in second CR underwent BMT. Fifteen underwent allogeneic BMT from an HLA-identical sibling donor and 16 without a donor, unpurged ABMT. Two different preparative regimens were used: CY (120 mg/kg) and 12 Gy of fractioned TBI (19 patients), and Bu (16 mg/kg) and Cy (120 mg/kg) (BuCy2) in 12 patients. Main clinical characteristics including age, sex, length of first remission, FAB type, and number of leukocytes at diagnosis were similar in both groups. A combination of MTX and CsA was used in 13 cases whereas either CsA or MTX alone was employed in the other two patients. With a median follow-up of 5 years the actuarial 5 year probability of disease-free survival (DFS) for the whole group was 39.8% (95% CI: 29.5-50.1%). The 5 year DFS was equivalent for those who received either ABMT (41.6 +/- 14.2%) or allogeneic BMT (40 +/- 15%). Probabilities of relapse and non-relapse mortality for ABMT and allo BMT patients were 48.7 +/- 16.1 and 18.7 +/- 14.3, and 30.1 +/- 19.2 and 40.7 +/- 16.9, respectively. DFS was better in those patients with a longer duration of first CR (> 18 months) 62.5 +/- 14.4 vs 30.4 +/- 17.9%, attributable to a significantly lower relapse rate in this group of patients 16.6 +/- 12.8 vs 57.8 +/- 22.7 (P 0.05). In conclusion, similar results were observed when ABMT and allo BMT were compared for AML in CR2. A higher antileukemic effect associated with the allo BMT is balanced by an increase in transplant-related mortality. Duration of first remission was the most important factor affecting DFS and better outcome was observed for patients with longer CR1.

[Allogeneic bone marrow transplantation in chronic myeloid leukemia. The clinical results and risk factors in 70 patients]. / Trasplante alogénico de médula ósea en la leucemia mieloide crónica. Resultados clínicos y factores de riesgo en 70 pacientes.

BACKGROUND: The 10 year experience of a single center performing allogeneic bone marrow transplantation in 70 patients with chronic myeloid leukemia (CML) is analyzed. METHODS: Seventy patients transplanted for CML between November 1982 and October 1992 were evaluated. Fifty-two patients were in the first chronic phase (FC), 10 in an accelerated phase, 4 in blast crisis and 4 in the second chronic phase. The combination of cyclosporin and methotrexate was the most commonly used prophylactic schedule for graft versus host disease (GVHD) (60 cases) and T depletion was not performed in any case. The combination of cyclophosphamide (120 mg/kg) and total body irradiation was used in 48 patients with the remaining patients received busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg). The estimation of survival was performed using the Kaplan-Meier limit product method. The prognostic factors influencing survival, disease free period and relapse were evaluated by Cox multivariate models of proportional risk. RESULTS: Actuarial survival at four years was 40% (95% Cl: 26-58%). Multivariate analysis selected variables associated with lower survival, the presence of acute GVHD (relative risk-RR-4.75), advanced disease phase (RR: 3.26) and age over 30 years (RR: 3.57). Eleven patients had relapsed. Multivariate analysis found the absence of chronic GVHD (RR: 5.3) and advanced phase (RR: 1.91) to be associated to a higher probability of relapse. In a separate analysis of the 48 patients transplanted in chronic phase who received cyclosporin and methotrexate, the disease free survival was longer for those under the age of 30 years (71.4% vs. 36%) without acute GVHD (68.8% vs. 39.6%) and those transplanted from a male donor (64.6% vs. 30%). CONCLUSIONS: Advanced phase of the disease, the presence of acute graft versus host disease and the age and female sex of the donor are the main factors associated to shorter survival in allogeneic bone marrow transplant for chronic myeloid leukemia. In contrast, the presence of chronic graft versus host disease decreases the possibilities of relapse.