Lymphocyte subset recovery and outcome after T-cell replete allogeneic hematopoietic SCT.

Rapid recovery of lymphocytes after T-cell depleted hematopoietic SCT (HSCT) protects from relapse of myeloid malignancies. Whether lymphocyte reconstitution has a similar role after non-manipulated transplantation is controversial. We assessed numbers of CD4 and CD8 T-cells, natural killer (NK) cells and B-cells, before and 1, 3, 6, 12 and 24 months after T-cell replete transplantation in 345 patients. Lymphocyte subset counts up to 6 months post transplant had no effect on relapse. Elevated number of NK cells 12 months post transplant protected from relapse. As a novel finding, early recovery of NK cells was associated with significant protection from TRM already at the 3 and 6 months time points (P=0.03, P=0.02). In Cox multivariable models, patients with NK cells above 150/µL were significantly protected from TRM (hazard ratio (HR) 0.45, 95% confidence interval (95% CI) 0.21-0.95, P=0.03), an effect comparable in magnitude with that of carrying >200 CD4 T-cells/µL (HR 0.37, 95% CI 0.19-0.74, P=0.005). CD8 T-cell and B-cell recovery did not affect the rates of relapse or TRM. Early reconstitution of NK cells and CD4 T-cells in patients undergoing T-cell replete HSCT independently protected from TRM. Only a weak protection from disease relapse was noted for patients with high numbers of NK cells, and this occurred only late after transplantation.

Double allogeneic hematopoietic SCT as a rescue therapy for poor-risk hematological malignancies.

The prognosis of patients with poor-risk or relapsed hematological malignancies is dismal. The dose intensification necessary to achieve subsequent CR is limited by the toxicity of chemotherapy. Treatment intensification with double allogeneic HSCT (dHSCT) may enhance the antileukemic effect and reduces treatment-related toxicity associated with prolonged aplasia during reinduction. We evaluated this approach in 23 patients, nine with primary refractory disease or relapse after conventional chemotherapy (group I) and 14 with relapses after allogeneic HSCT (group II). Double HSCT was feasible in all patients. At the end of the observation period, 6 of 23 (26%) patients were still alive and in remission with a median observation time of 60 months (1-153). The overall survival probability at 1 year was 41% (95% confidence interval (CI), 21-62%), transplant-related mortality (TRM) 28% (9-47%) and the incidence of relapse 42% (18-66%). The TRM in groups I and II were 22 and 36% and the relapse rate 33 and 50%, respectively. In conclusion, we have shown the feasibility of dHSCT with an acceptable TRM, irrespective of a previous allogeneic HSCT. Whether this approach offers a survival benefit for patients with poor-risk leukemias has to be tested in larger prospective trials.

High-dose chemotherapy using BEAM without autologous rescue followed by reduced-intensity conditioning allogeneic stem-cell transplantation for refractory or relapsing lymphomas: a comparison of delayed versus immediate transplantation.

Patients with refractory/relapsing lymphoma are rarely cured by chemotherapy. High-dose chemotherapy (HDC) for tumor debulking followed by reduced-intensity conditioning (RIC) hematopoietic stem-cell transplantation (HSCT) has been advocated as a concept. We previously treated 10 patients (group A) with BEAM chemotherapy followed by delayed RIC HSCT at day 28. We now report on the subsequent 11 patients receiving BEAM followed immediately by fludarabine/total body irradiation and allogeneic HSCT (group B), and compare the outcome to group A patients. Non-hematological toxicity before engraftment was comparable, only gut toxicity was higher in group B. Days in aplasia, days on antibiotics and length of hospital stay were significantly longer in group A. Cumulative incidence of acute (GvHD) >or=grade II and incidence of chronic GvHD were lower in group B. At last follow-up, seven patients in group A were alive, with six of them in complete remission. In group B, nine patients were alive, seven of them in complete remission. No significant difference in estimated 3-year overall survival was seen. These data challenge the initial concept of debulking first and delaying allogeneic RIC HSCT. Allogeneic HSCT with standard BEAM conditioning is a valid alternative for patients with resistant/relapsed lymphoma, which might be considered earlier in the disease course.

High-dose chemotherapy using BEAM for tumor debulking without stem cell support followed by early allogeneic reduced intensity conditioning transplantation to induce a graft-versus-lymphoma effect in patients with high risk or refractory lymphoma.

In patients with refractory lymphoma, we tested the hypothesis that high-dose chemotherapy (BEAM) without stem cell support followed by a reduced intensity (RIC) allogeneic transplant with fludarabine and 2 Gy TBI 28 days later results in tumor debulking and establishment of a graft vs lymphoma effect, with acceptable toxicity. In a pilot protocol we treated 10 patients, 22-62 (median 47) years of age with high-risk or refractory Hodgkin's or non-Hodgkin's lymphoma. Donors were HLA identical siblings (eight) or unrelated volunteers. None died during the neutropenic phase after BEAM which lasted up to the RIC HSCT. The duration of neutropenia was 31-43 (median 36) days. All patients engrafted and nine achieved CR. All developed acute GvHD (median grade III) and all patients at risk developed chronic GvHD. Three patients died of GvHD. One relapsed and six patients are in continuous CR 10-32 (median 15) months after HSCT. This approach appears feasible and results in a high response rate. Neutropenia duration is of concern. It remains to be tested whether separation of debulking chemotherapy and induction of allogeneic effects confers an advantage.