CAMPATH-1 (CD52) Abs are used in stem-cell transplantation for prevention of GvHD and rejection. The humanized Ab CAMPATH- 1H has recently replaced the rat Ab CAMPATH-1G. There was a concern whether ...it might have a longer half-life in vivo and, possibly, cause prolonged immunosuppression post-transplant.
Serum samples were collected pre- and post-transplant from patients receiving CAMPATH-1H at 10mg/day according to two protocols: (A) from Day –5 to Day +4 (total dose, 100mg), (B) from Day –10 to Day –6 (total dose, 50mg). The Ab concentrations were measured using an immunofluorescence assay.
Lymphocytes were substantially depleted by the second day of treatment and were below 0.1×109/L by the day of transplant and for at least 1 month post-transplant. By Day 90 there was a greater recovery in Group B, to a median of 0.32×109/L compared with 0.25×109/L in Group A. By Day 180, both groups had recovered to approx 0.52×109/L. Serum concentrations of CAMPATH-1H on the day of transplant were well above the level necessary for opsonization of lymphocytes. The peak Ab concentration was 6.1 μg/mL in Group A and 2.5μg/mL in Group B. CAMPATH-1H could be detected in Group A for 23 days post-transplant, significantly longer than in Group B (11 days). The terminal half-life in the two groups was similar (range 15–21 days) and contrasts with the half-life of <1 day previously estimated for CAMPATH-1G. There were no cases of graft failure and the incidence of GvHD was similar in the two groups.
The humanized Ab CAMPATH-1H appears to persist in the circulation for longer than the original rat Ab CAMPATH-1G. This might contribute to delayed lymphocyte recovery and prohibit the use of early donor-lymphocyte infusions. A short course of treatment given early pre-transplant is likely to be preferable to the extended course given both pre- and post-transplant.
The European Clinical Trials Directive (EU 2001; 2001/20/EC) was introduced to improve the efficiency of commercial and academic clinical trials. Concerns have been raised by interested organizations ...and institutions regarding the potential for negative impact of the Directive on non-commercial European clinical research. Interested researchers within the European Group for Blood and Marrow Transplantation (EBMT) were surveyed to determine whether researcher experiences confirmed this view. Following a pilot study, an internet-based questionnaire was distributed to individuals in key research positions in the European haemopoietic SCT community. Seventy-one usable questionnaires were returned from participants in different EU member states. The results indicate that the perceived impact of the European Clinical Trials Directive has been negative, at least in the research areas of interest to the EBMT.
We report the outcome of 229 patients who received an allograft for myeloma with reduced-intensity conditioning (RIC) regimens from 33 centers within the European Group for Blood and Marrow ...Transplantation (EBMT). The median age was 52 years and 64% were male. Conditioning regimens were heterogeneous, but most were fludarabine based and T cell depleted with antithymocyte globulin or alemtuzumab. Transplantation-related mortality (TRM) at 1 year was 22%. The 3-year overall survival (OS) and progression-free survival (PFS) were 41% and 21%, respectively. Adverse OS was associated with chemoresistant disease (relative risk RR, 2.9), more than 1 prior transplantation (RR, 2.0), and male patients with female donors (RR, 1.45). Adverse PFS was associated with chemoresistance (RR, 2.4) and alemtuzumab (RR, 1.8). TRM was increased with female-to-male donation (RR, 2.5) and transplantation more than 1 year from diagnosis (RR, 2.3). Grades II to IV acute graft-versus-host disease (aGvHD) occurred in 31%. Chronic GvHD was associated with better OS and PFS and were 84% and 46% for limited, 58% and 30% for extensive, and 29% and 12% in its absence suggesting that a graft-versus-myeloma effect is important. While RIC is feasible, heavily pretreated patients and patients with progressive disease do not benefit.
Summary
We investigated the risk factors for graft‐versus‐host disease (GVHD) in 82 patients treated with donor lymphocyte infusions (DLI) using an escalating dose regimen for chronic myeloid ...leukaemia in relapse following conventional allografting. Two factors emerged as predictors of both acute and chronic GVHD: the infusion of male recipients with lymphocytes from a female donor and the interval between transplant and last DLI, but only the first remained significant at multivariate analysis. Surprisingly, lymphocyte dose did not influence the incidence of GVHD. Our results suggest that DLI can be given in large cell doses without increasing the risk of GVHD.
: Autologous (ASCT) and allogeneic stem cell transplantations (alloBMT) are well‐established therapies for multiple myeloma. However, patients continue to relapse at a constant rate. We present here ...15 out of 163 patients who underwent SCT and relapsed with plasmacytomas only without evidence of bone marrow disease progression (14/147 post‐ASCT and 1/16 post‐alloBMT). The median time from SCT to plasmacytoma relapse was 24 months. The sites of plasmacytoma included bone, skin, rectum, and testicles. Five patients were treated with local radiotherapy, while seven patients received a combination of radiotherapy and chemotherapy or thalidomide, and two patients received chemotherapy alone with or without thalidomide. The recipient of alloBMT was initially treated with VAD‐chemotherapy and local radiotherapy followed by a mini‐allograft from the original donor. Eleven patients died at a median of 10 months following diagnosis of the plasmacytoma. Four are still alive, 12–20 months post‐plasmacytoma diagnosis. These cases of unconventional disease recurrence are likely to be seen due to sub‐clinical seeding of tumour cells suggestive of the presence of an extramedullary (EM) clone of plasma cells with a high degree of chemoresistance. We also review all the available data in the literature for the optimal therapy for patients with isolated EM relapse.
Graft‐versus‐host disease (GVHD) remains a major cause of morbidity and mortality after haematopoietic stem cell transplantation from matched unrelated donors (MUD). The role of T‐cell depletion ...(TCD) as a strategy to prevent GVHD is controversial because of the associated increased risk of leukaemic relapse, graft failure and delayed immune reconstitution. The demonstration that donor lymphocyte infusion (DLI) is effective salvage therapy if patients relapse after transplantation for chronic myeloid leukaemia (CML) prompted us to examine the proposal that TCD may be a form of GVHD prophylaxis particularly suited to this disease in patients undergoing MUD transplantation. We analysed the outcome of 106 consecutive patients with CML in first chronic phase who underwent MUD transplantation. Patients were conditioned with cyclophosphamide and total body irradiation (TBI), and received in vivo TCD, using CD52 monoclonal antibody, as GVHD prophylaxis. Donor lymphocytes were infused at the time of leukaemic relapse. The projected survival at 5 years for all patients was 52·6%. The probability of developing severe acute GVHD (grade 3 or 4) was 14·5%. The only significant predictor of overall survival in univariate and multivariate analysis was patient cytomegalovirus (CMV) serostatus: in CMV‐negative patients survival at 5 years was 60% vs. 42% in CMV‐positive patients (P = 0·006). The use of TCD was associated with an increased risk of relapse (62% probability at 5 years after transplant), but 80% of patients who received DLI achieved molecular remission that was durable in all but two cases. In vivo TCD, in conjunction with DLI at relapse, is a valuable GVHD prophylactic regimen in CMV‐seronegative recipients of MUD allografts, but in CMV‐seropositive patients this approach is associated with an increased non‐relapse mortality. Consequently, GVHD prophylactic regimens in MUD transplantation should be tailored according to the patient and donor pretransplant characteristics.
Donor lymphocyte infusions (DLI) are an effective treatment for patients with chronic myeloid leukemia (CML) in relapse after allografting but the optimal cell dose has yet to be identified. To ...address this question, we investigated the factors affecting the dose required to achieve remission (effective cell dose, (ECD)) in 81 patients treated with an escalating dose regimen. The overall proportion of patients who achieved a molecular remission was 88%. The cumulative proportion of remitters increased significantly at each dose level. With a CD3(+) cell dose < or =10(7)/kg, 56% of patients in molecular/cytogenetic relapse obtained molecular remission, whereas only 20% of those in hematologic relapse did so. At the same cell dose, 58% of patients who received lymphocytes from volunteer unrelated donors achieved remission, as compared to 29% of those who received DLI from sibling donors. We conclude that the response to DLI is dose-dependent and that the ECD is influenced by the quantity and phase of CML at relapse and degree of donor/recipient histocompatibility.
We assessed clinical results in 145 patients with chronic myeloid leukaemia in chronic phase who satisfied criteria for interferon-alpha failure and were thus eligible for treatment with imatinib at ...the Hammersmith Hospital. We used univariate and multivariate analyses to develop a risk score based on features defined after treatment for 3 months. We identified a low neutrophil count and poor cytogenetic response (<35% Ph-negative marrow metaphases) at 3 months as principal independent predictive factors and incorporated them into a three-tier prognostic scoring system for individual patients. For patients in the low-, intermediate- and high-risk groups, the probabilities of survival at 24 months were 100, 82 and 40% (P<0.0001) and progression-free survival 100, 66 and 15% (P<0.0001), respectively. This Hammersmith prognostic scoring system was validated with an independent cohort of patients treated at another UK centre.
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