Didier Blaise

DEFINING THE INTENSITY OF CONDITIONING REGIMENS : working definitions

Defining conditioning regimen intensity has become a critical issue for the hemopoietic stem cell transplant (HSCT) community. In the present report we propose to define conditioning regimens in 3 categories: (1) myeloablative (MA) conditioning, (2) reduced-intensity conditioning (RIC), and (3) nonmyeloablative (NMA) conditioning. Assignment to these categories is based on the duration of cytopenia and on the requirement for stem cell (SC) support: MA regimens cause irreversible cytopenia and SC support is mandatory. NMA regimens cause minimal cytopenia, and can be given also without SC support. RIC regimens do not fit criteria for MA or NMA regimens: they cause cytopenia of variable duration, and should be given with stem cell support, although cytopenia may not be irreversible. This report also assigns commonly used regimens to one of these categories, based upon the agents, dose, or combinations. Standardized classification of conditioning regimen intensities will allow comparison across studies and interpretation of study results.

Targeting natural killer cells and natural killer T cells in cancer.

Natural killer (NK) cells and natural killer T (NKT) cells are subsets of lymphocytes that share some phenotypical and functional similarities. Both cell types can rapidly respond to the presence of tumour cells and participate in antitumour immune responses. This has prompted interest in the development of innovative cancer therapies that are based on the manipulation of NK and NKT cells. Recent studies have highlighted how the immune reactivity of NK and NKT cells is shaped by the environment in which they develop. The rational use of these cells in cancer immunotherapies awaits a better understanding of their effector functions, migratory patterns and survival properties in humans.

Randomized Trial of Bone Marrow Versus Lenograstim-Primed Blood Cell Allogeneic Transplantation in Patients With Early-Stage Leukemia: A Report From the Société Française de Greffe de Moelle

PURPOSE To compare hematologic recovery in patients receiving allogeneic blood cell transplantation (BCT) with those receiving allogeneic bone marrow transplantation (BMT). PATIENTS AND METHODS One hundred eleven patients with leukemia in the early stages and with HLA-matched sibling donors were randomized in this study. One hundred one underwent transplantation. Standard procedures for collection and transplantation were used. Patients did not receive prophylactic granulocyte colony-stimulating factor after undergoing transplantation. In addition to clinical end points being established, a prospective and comparative economic evaluation of the first 6 months after transplantation was performed. RESULTS Groups were balanced for patient, donor, and transplant characteristics. Blood cell collection led to the collection of a higher number of CD34(+) and CD3(+) cells than did bone marrow collection (P < 10(-6)) without reported side effects for the donor. Patients in the BCT group reached platelet counts of 25 and 50 x 10(9) platelets/L 8 and 11 days earlier than did the BMT group (P < 10(-4) and P < 10(-5)), respectively. This resulted in fewer platelet transfusions during the first 180 days after transplantation (P =.002) for the former group. The time to reach neutrophil counts of 0.5 and 1 x 10(9) neutrophils/L was 6 and 7 days shorter, respectively, in the BCT group than in the BMT group (P < 10(-5)). This quicker hematologic recovery was associated with a shorter length of hospitalization and a decrease in total cost of procedure during the first 6 months. CONCLUSION This study establishes that allogeneic BCT results in quicker hematologic recovery but is associated with a higher occurrence of chronic graft-versus-host disease.

Allogeneic peripheral blood stem-cell compared with bone marrow transplantation in the management of hematologic malignancies: An individual patient data meta-analysis of nine randomized trials

PURPOSE Considerable uncertainty exists regarding relative effects of allogeneic peripheral blood stem cells transplantation (PBSCT) versus bone marrow transplantation (BMT) on outcomes of patients with hematologic malignancies. PATIENTS AND METHODS To provide the totality of research evidence related to the effects of PBSCT versus BMT, we conducted an individual-patient data meta-analysis using data from nine randomized trials enrolling 1,111 adult patients. RESULTS Compared with BMT, PBSCT led to faster neutrophil (odds ratio [OR] = 0.31; 95% CI, 0.25 to 0.38; P < .00001) and platelet engraftment (OR = 0.52; 95% CI, 0.44 to 0.61; P < .00001). PBSCT was associated with a significant increase in the development of grade 3-4 acute graft-versus-host disease (GVHD; OR = 1.39; 95% CI, 1.03 to 1.88) and extensive (47% v 31% at 3 years; OR = 1.89; 95% CI, 1.47 to 2.42; P < .000001) and overall chronic GVHD (68% v 52% at 3 years; OR = 1.92; 95% CI, 1.47 to 2.49; P < .000001), but not grade 2-4 acute GVHD (54% v 53%; P = .49). PBSCT was associated with a decrease in relapse (21% v 27% at 3 years; OR = 0.71; 95% CI, 0.54 to 0.93; P = .01) in both late-stage-(33% v 51% at 3 years; OR = 0.59; 95% CI, 0.38 to 0.93; P = .02) and early-stage-disease patients (16% v 20% at 3 years; OR = 0.69; 95% CI, 0.49 to 0.98; P = .04). Nonrelapse mortality was not different between groups. Overall and disease-free survival were only statistically significantly improved in patients with late-stage disease (overall survival: 46% v 31% at 3 years; OR = 0.64; 95% CI, 0.46 to 0.90; P = .01; disease-free survival: 41% v 27% at 3 years; OR = 0.63 95% CI, 0.45 to 0.87; P = .01). CONCLUSION PBSCT is associated with a decreased relapse rate in hematologic malignancies and improvement in overall and disease-free survival in patients with late-stage disease. PBSCT is also associated with a significant risk of extensive chronic GVHD.

IMPACT OF T-CELL DEPLETION ON OUTCOME OF ALLOGENEIC BONE-MARROW TRANSPLANTATION FOR STANDARD-RISK LEUKAEMIAS

71 leukaemic patients having HLA-matched bone-marrow transplants (BMT) were randomised to receive whole marrow (group A) or marrow depleted of T cells by treatment with monoclonal antibodies (anti CD4-CD5-CD8, group B; anti CD2-CD5-CD7, group C) plus complement. All patients received cyclophosphamide and total body irradiation before transplantation and cyclosporin after BMT. Marrow treatment removed 97% of T cells (median) in group B and 99% in group C. Although both serious and mild graft-versus-host disease (GVHD) were reduced in T-cell depleted patients, graft failure and relapse were increased. Graft failure was caused by GVHD and transplant complications in the controls and by rejection and relapse in the T-cell depleted groups; relapse-free survival did not differ between the groups. Without better control of host immunity and of the residual leukaemia T-cell depletion of the marrow, BMT should not be pursued in standard-risk patients.

An EBMT registry matched study of allogeneic stem cell transplants for lymphoma : allogeneic transplantation is associated with a lower relapse rate but a higher procedure-related mortality rate than autologous transplantation

Summary:The role of allogeneic bone marrow transplantation in lymphoma remains uncertain. We have analyzed 1185 allogeneic transplants for lymphoma reported to the EBMT registry between 1982 and 1998 and compared the results with those of 14 687 autologous procedures performed over the same period. Patients receiving allogeneic transplants were subdivided according to histology: low-grade non-Hodgkins lymphoma (NHL) 231 patients; intermediate-grade NHL 147 patients; high-grade NHL 255 patients; lymphoblastic NHL 314 patients; Burkitts lymphoma 71 patients; and Hodgkins disease 167 patients. These patients received allogeneic transplants as their first transplant procedure. Actuarial overall survival (OS) at 4 years from transplantation was: low-grade NHL 51.1%; intermediate-grade NHL 38.3%; high-grade NHL 41.2%; lymphoblastic lymphoma 42.0% years; Burkitts lymphoma 37.1%; and Hodgkins disease 24.7% years. These outcomes are relatively poor because of the high procedure-related mortality associated with these procedures, particularly in patients with Hodgkins disease (51.7% actuarial procedure-related mortality at 4 years). Multivariate analysis showed that for all lymphomas apart from Hodgkins disease, status at transplantation significantly affected outcome. A matched analysis was performed: for all categories of lymphoma, OS was better for autologous than for allogeneic transplantation. Relapse rate was better in the allogeneic group for low-, intermediate- and high-grade, and lymphoblastic NHL. It was equivalent for Burkitts lymphoma and worse in the allogeneic group for Hodgkins disease. Allogeneic transplantation appears to be superior to autologous procedures in terms of producing a lower relapse rate. The toxicity of allogeneic procedures must however be reduced before this translates into an improvement in OS.

Graft-Versus-Lymphoma Effect for Aggressive T-Cell Lymphomas in Adults: A Study by the Société Française de Greffe de Moëlle et de Thérapie Cellulaire

PURPOSE Aggressive T-cell lymphomas (ATCLs) represent 10% to 15% of non-Hodgkins lymphomas (NHLs) in adults. ATCLs show a worse prognosis than B-cell lymphomas. PATIENTS AND METHODS On behalf of the Société Française de Greffe de Moëlle et de Thérapie Cellulaire, we conducted a retrospective analysis including 77 ATCL patients who underwent allogeneic stem-cell transplantation (alloSCT). RESULTS The different diagnosis included anaplastic large-cell lymphoma (ALCL; n = 27), peripheral T-cell lymphoma not otherwise specified (PTCL-NOS; n = 27), angioimmunoblastic T-cell lymphoma (AITL; n = 11), hepatosplenic gamma/delta lymphoma (HSL; n = 3), T-cell granular lymphocytic leukemia (T-GLL; n = 1), nasal natural killer (NK)/T-cell lymphoma (nasal-NK/L; n = 3) or non-nasal NK/T-cell lymphoma (non-nasal-NK/L; n = 2), enteropathy-type T-cell (n = 1), and human T-lymphotropic virus (HTLV)-1 lymphoma (n = 2). Fifty-seven patients received a myeloablative conditioning regimen. Donors were human leukocyte antigen (HLA)-matched in 70 cases and related in 60 cases. Thirty-one patients were in complete remission (CR) at the time of alloSCT, whereas 26 were in partial response (PR). Five-year toxicity-related mortality (TRM) incidence was 33% (95% CI, 24% to 46%). The 5-year overall survival (OS) and event-free survival (EFS) rates were 57% (95% CI, 45% to 68%) and 53% (95% CI, 41% to 64%), respectively. In multivariate analysis, chemoresistant disease (stable, refractory, or progressing disease) at the time of alloSCT and the occurrence of severe grade 3 to 4 acute graft-versus-host disease (aGVHD) were the strongest adverse prognostic factors for OS (P = .03 and .03, respectively). Disease status at transplantation significantly influenced the 5-year EFS (P = .003), and an HLA-mismatched donor increased TRM (P = .04). CONCLUSION We conclude that alloSCT is a potentially efficient therapy for NK/T lymphomas and is worth further investigation through prospective clinical trials.

Long-term outcome after allogeneic hematopoietic stem cell transplantation for advanced stage acute myeloblastic leukemia: a retrospective study of 379 patients reported to the Société Française de Greffe de Moelle (SFGM)

To assess the place of allogeneic hematopoietic stem cell transplantation (HSCT) in the advanced stage of acute myeloid leukemia (AML), we retrospectively analyzed 379 consecutive patients who underwent allogeneic HSCT for advanced AML. The median follow-up of the entire cohort was 7.5 years. Sixty-nine patients (18%) were transplanted with primary resistant disease. Three hundred and ten (82%) were relapsed patients, 94 (30%) of whom were in untreated relapse, 67 (22%) in refractory relapse and 149 (48%) in 2nd or 3rd complete remission at time of transplantation. The 5-year probabilities of overall survival (OS), disease-free survival (DFS), and transplant-related mortality (TRM) were 22 ± 4% 20 ± 4%, 45 ± 6%, respectively. In multivariate analysis, we demonstrated the favorable impact on OS, DFS and TRM of two factors over which we have no control (age <15 years, complete remission achievement) and three factors over which we have some control (female donor, acute and chronic graft-versus-host disease). The results of this study suggest that the graft-versus-leukemia effect is important in advanced AML and that new HSCT modalities are needed for some patients with this indication. Bone Marrow Transplantation (2000) 26, 1157–1163.

Comparison of High-Dose Therapy and Autologous Stem-Cell Transplantation With Conventional Therapy for Hodgkin's Disease Induction Failure: A Case-Control Study

PURPOSE To determine the prognostic factors and outcome of first-line induction failure Hodgkins disease patients who were treated with a salvage regimen of high-dose chemotherapy and autologous stem-cell transplantation, and to compare them with matched, conventionally treated patients. PATIENTS AND METHODS We retrospectively analyzed data relating to 86 Hodgkins disease patients who underwent autologous stem-cell transplantation after failure of the first chemotherapy regimen, either because they did not enter a complete remission and experienced progression of disease less than 3 months after the end of their first-line treatment or because they showed evidence of disease progression during first-line therapy. Graft patients were matched with 258 conventionally treated patients (three controls per case) for age, sex, clinical stage, B symptoms, and time at risk; patient data were obtained from international databases. RESULTS Among the 86 graft patients, the median age at diagnosis was 29 years (range, 14 to 57 years). Thirty-nine percent of patients had stage II disease, 23% had stage III disease, and 38% had stage IV disease. Seventy percent of the patients received chemotherapy and 30% received combined modality therapy; 60% of the patients received a seven- or eight-drug regimen. After this first-line treatment, 91% had disease progression and 9% had a brief partial response. Eighty patients received a second-line treatment; pretransplantation status was as follows: 24% of patients had a complete remission, 38% had a partial remission (PR), 14% had stable disease, and disease progression occurred in 24%. With a median follow-up of 22 months (range, 4 to 105 months) from diagnosis, the 5-year event-free survival and overall survival rates from transplantation were 25% and 35% (95% confidence intervals, 15 to 36 and 23 to 49), respectively. In multivariate analysis, the pretransplantation disease status after salvage therapy was the only significant prognostic factor for survival (PR: relative risk = 2.8, P = .017; progressive disease: relative risk (RR) = 5.26, P < .001). From diagnosis, the 6-year overall survival rates of the graft patients and 258 matched conventionally treated patients were 38% and 29%, respectively (P = .058). CONCLUSION Autologous stem-cell transplantation represents the best therapeutic option currently available for patients with primary induction failure and is associated with acceptable toxicity. Response to second-line treatment before high-dose chemotherapy is the only prognostic factor that can be correlated with survival.

High rate of secondary viral and bacterial infections in patients undergoing allogeneic bone marrow mini-transplantation.

New approaches using nonmyeloablative-conditioning regimens have been developed to cause minimal procedure-related toxicity. Such novel therapeutic options are being explored with good preliminary results concerning feasibility and engraftment. However many aspects remain under-evaluated, and few data are available about viral and nonviral infections after these highly immunosuppressive regimens. We present our preliminary data on 21 patients receiving a highly immunosuppressive conditioning strategy, focusing on early infectious complications. Early viral infections before day 45, especially CMV, occurred at a high rate (65%). Furthermore, 33% of patients presented with late bacterial infections (predominately gram negative) although they were not neutropenic compared to conventional conditioning regimens. Although there is presently real interest in these new conditioning regimens which result in reduced immediate transplant-related mortality, it is important that investigators be aware of these pitfalls which may secondarily increase transplant toxicity. Further studies are needed to confirm these findings. Bone Marrow Transplantation (2000) 26, 251–255.