Long-term follow-up of high-dose treatment with autologous haematopoietic progenitor cell support in 693 patients with follicular lymphoma: an EBMT registry study.

To evaluate the outcome of a large series of patients who received high-dose treatment (HDT) for follicular lymphoma (FL), 693 patients undergoing HDT (total-body irradiation (TBI)-containing regimen: 58%; autologous bone marrow (BM)/peripheral blood progenitor cells (PBPCs): 378/285 patients) were included in the study. A total of 375 patients (54%) developed recurrent lymphoma, 10-year progression-free survival (PFS) being 31%. On multivariate analysis, younger age (P=0.003) and HDT in first complete remission (CR1) (P<0.001) correlated with longer PFS. With a median follow-up of 10.3 years, 330 patients died. Ten-year overall survival (OS) from HDT was 52%. Shorter OS was associated on multivariate analysis with older age (P<0.001), chemoresistant disease (P<0.001), BM+PBPC as source of stem cells (P=0.007) and TBI-containing regimens (P=0.004). Thirty-nine patients developed secondary myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML), in 34 cases having received TBI as the conditioning regimen. The 5-year non-relapse mortality (NRM) was 9%. On multivariate analysis, older age (P<0.001), refractory disease (P<0.001) and TBI (P=0.04) were associated with a higher NRM. This long follow-up study shows a plateau in the PFS curve, suggesting that a selected group of patients might be cured with HDT. On the downside, TBI-containing regimens are associated with a negative impact on survival.

Role of a second transplant in the management of poor-prognosis lymphomas: a report from the European Blood and Bone Marrow Registry.

PURPOSE: Treatment of selected patients with poor-prognosis lymphomas with high-dose chemotherapy and marrow or peripheral stem-cell rescue improves prognosis. A second course of myeloablative chemotherapy has been given to some patients, but few data are available on the indications, morbidity, and overall survival associated with this approach. This study was undertaken to evaluate morbidity and identify subgroups of patients who may benefit from a second transplant. PATIENTS AND METHODS: Thirty-four patients with lymphoma given two cycles of myeloablative chemotherapy and entered onto the European Blood and Bone Marrow Transplant (EBMT) registry between 1982 and 1995 were included in this study: Hodgkin's disease (HD), n = 12; intermediate/high-grade non-Hodgkin's lymphoma (HG-NHL), n = 17; and low-grade non-Hodgkin's lymphoma (LG-NHL), n = 5. The reason for second transplant, status at transplant, conditioning regimen, morbidity, and both progression-free survival (PFS) and overall survival (OS) were assessed. RESULTS: The second procedure was performed for the following reasons: (1) elective double procedure in four patients, (2) relapse after first transplant in 20, (3) partial remission (PR) after first transplant in eight, and (4) refractory disease after first transplant in two. The OS rate at 2 years for patients who underwent two transplants (estimated from the date of second transplant) was 49%, with a median follow-up time of 44 months. The OS rate at 2 years by histologic subtype was as follows; HD, 50%; HG-NHL, 60%; and LG-NHL, 0%. Seven of 15 patients with HD or HG-NHL who relapsed after they had achieved a posttransplant complete remission (CR) remain in CR 13 to 36 months after the second transplant, compared with two of 10 patients in CR (at 6 and 19 months after second transplant) who achieved a PR or had refractory disease after the first transplant. There were eight deaths (24%) before 3 months, of which three (9%) were transplant-related and the remainder due to persistent disease. Three late toxic deaths occurred: two of cardiovascular disease and one of secondary leukemia. CONCLUSION: Selected patients with HD and HG-NHL whose disease recurs after one transplant may benefit from a second transplant. Patients with refractory disease and LG-NHL did not benefit from a second transplant.

Autologous stem-cell transplantation for non-Hodgkin's lymphomas: the role of graft purging and radiotherapy posttransplantation--results of a retrospective analysis on 120 patients autografted in a single institution.

PURPOSE: To analyze retrospectively survival and prognostic factors of patients with non-Hodgkin's lymphoma (NHL) autografted from 1979 to 1995 in a single institution. PATIENTS AND METHODS: A total of 120 patients, 64 with aggressive and 56 with low-grade NHL, were autografted. The carmustine (BCNU), etoposide, cytarabine, and melphalan (BEAM) regimen was used in 104. The autograft was marrow in 101 patients. Marrow was purged in vitro by mafosfamide for 63 patients (adjusted dose [AD] in 32; unique dose [UD] in 31); 27 patients received a CD34+-selected graft. Following intensification, 45 patients received additional radiotherapy on previous sites of involvement. RESULTS: Outcome at 5 years for patients transplanted with low-grade NHL in first complete remission (CR1), in first partial remission (PR1), and in second complete remission (CR2) or beyond showed an event-free survival (EFS) of 75% +/- 12%, 46% +/- 18%, and 57% +/- 24%, a relapse incidence (RI) of 21% +/- 12%, 49% +/- 19%, and 43% +/- 25%, and a transplant-related mortality (TRM) of 5% +/- 5%, 10% +/- 7%, and 0%, respectively. For patients with aggressive NHL transplanted in CR1, in PR1, in CR2 or beyond, and in resistant relapse or in primary refractory disease, the EFS was of 73% +/- 9%, 58% +/- 19%, 29% +/- 16%, and 10% +/- 9%, the RI 22% +/- 9%, 14% +/- 9%, 77% +/- 18%, and 66% +/- 20%, and the TRM 6% +/- 6%, 32% +/- 21%, 11% +/- 10%, and 71% +/- 22%, respectively. In patients autografted upfront in first remission, additional radiotherapy was associated with a higher EFS, in univariate (P = .03) and multivariate analysis (P = .02, relative risk [RR] = .021). The role of graft purging with mafosfamide on the outcome reflected by the dose of colony-forming unit-granulocyte-macrophage (CFU-GM) per kilogram infused postpurging was assessed by univariate analysis: patients in first remission who received lower doses of CFU-GM had a lower RI and a higher EFS. CONCLUSION: This retrospective analysis suggests that marrow purging and posttransplant radiotherapy improve the outcome of patients with NHL autografted in first remission.

A long-term follow-up of 33 patients with non-Hodgkin's lymphoma who received the BEAM high-dose intensification regimen with cytokine support only and no transplant.

High-dose intensification and autologous stem-cell transplantation (ASCT) is widely used to consolidate patients with non-Hodgkin's lymphoma (NHL), who have reached a stage of minimal residual disease. However, patients with persisting marrow and/or blood involvement and those who fail peripheral blood hemopoietic progenitor mobilization are excluded from ASCT. For such patients with no available graft to infuse, we developed 15 years ago, before the anti-CD20 monoclonal antibody therapeutic era, the use of the BEAM pretransplant regimen followed only by the administration of three cytokines (erythropoietin, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor). We report here on the long-term follow-up of 33 patients treated with this approach. In all, 33 NHL patients underwent the BEAM (carmustine, VP-16, cytosine-arabinoside, melphalan) followed by the administration of the three cytokines from January 1994-2000. A backup marrow, albeit infiltrated by tumor cells, had been collected earlier and stored in all. A total of 30 patients (91%) recovered normal hematopoiesis. In total, 32 patients (97%) recovered neutrophils (>500/microl) at a median of 19 days and 30 patients (91%) recovered platelets (>20,000/microl) at a median of 26 days. Age, richness of backup graft and blood-hemoglobin level at intensification had an impact on the time for hematopoietic recovery (P=0.014, P=0.014, P=0.048). The median follow-up was 62 months. Five patients died from toxicity related to the procedure. Eight patients relapsed and died. A total of 20 patients (61%) are alive, 16 (49%) in complete remission. A 5-year disease-free survival was 52+/-9%, relapse incidence 35+/-16%, mortality due to the procedure 12+/-12% and overall survival 61+/-10%. The BEAM regimen is not myeloablative. The BEAM+3CK procedure is a feasible therapeutic option that has shown efficacy in poor risk NHL patients who were not eligible for autografting because of persisting marrow/blood tumor contamination, or poor hemopoietic progenitor harvesting. It is unclear today whether some of these patients would have cleared their marrow/peripheral blood with the additional use of anti-CD20 treatment, thereby making the classical approach (BEAM followed by the infusion of a clean autograft) feasible.

Autologous bone marrow transplantation as consolidation therapy may prolong remission in newly diagnosed high-risk follicular lymphoma: a pilot study of 34 cases.

We evaluated early intensification followed by autologous bone marrow transplantation (ABMT) using marrow purged by mafosfamide in patients with high-risk low-grade follicular lymphoma (LGFL) reaching a status of minimal disease (MD). Thirty-four patients entered the program. All fulfilled at least one of the following criteria at diagnosis: a bulky tumor > 7 cm; three or more adenopathies > 3 cm; massive pleural or peritoneal effusion; massive splenomegaly; B symptoms; platelet count < 100 x 10(9)/l. Twenty-one patients had bone marrow involvement. Twenty-six patients received ACVBP, and eight CVP as front-line therapy. Twenty-one (62%) patients achieved MD status, 18 reached intensification. At 4 years, the time to treatment failure is 55 +/- 9%, and the probability of persisting remission is 75 +/- 11%. Comparison by intention to treat of the 26 patients who received ACVBP as front-line therapy to 14 historical high-risk LGFL similarly treated in our institution without intensification, showed better results for the intensified group (P = 0.04 for both probability of persisting remission and time to treatment failure). These results indicate that early intensification using marrow purged with mafosfamide is a therapeutic option which may bring benefit to patients with high-risk LGFL.

Importance of marrow dose on posttransplant outcome in acute leukemia: models derived from patients autografted with mafosfamide-purged marrow at a single institution.

Several prospective randomized trials in acute myelocytic leukemia (AML) documented a lower relapse rate with autologous bone marrow transplantation (ABMT) than with conventional chemotherapy. However, they also identified some transplant difficulties, such as failure to collect sufficient numbers of stem cells, slow kinetics of engraftment, and a high transplant-related mortality that diminished or negated positive impact on overall survival. Data for ABMT are inconclusive in acute lymphocytic leukemia (ALL) in adults. We retrospectively analyzed patients with acute leukemia autografted with marrow purged with mafosfamide after January 1983 in our institution. The population comprised 229 consecutive patients; 165 with AML [123 in first remission (CR1), 32 in second remission (CR2)]; 61 with ALL (46 in CR1, 4 in CR2); and 3 with undifferentiated acute leukemia. All patients were autografted with marrow purged with mafosfamide. Mafosfamide was given at a constant dose of 50 microg/mL in 103 and adjusted individually to produce a CFU-GM LD 95 (5% residual CFU-GM post purging) in 126. The outcome was analyzed for correlation with patient characteristics, the disease including cytogenetics, and the graft itself. Prognostic factors identified by multivariate analysis were used to derive a prognostic classification. Patients receiving higher doses of marrow submitted to purging (>5.46 x 10(4) CFU-GM/kg) experienced a lower treatment-related mortality (RR = 0.11, p = 0.005) and a higher leukemia-free (RR = 0.5, p = 0.005) and overall survival (RR = 0.4, p = 0.001). Patients receiving <0.004% CFU-GM of marrow actually infused post purging had a lower relapse rate (RR = 0.51, p = 0.003). Modeling of prognostic groups identified good-, intermediate-, and poor-risk categories. Patients receiving a stem cell dose evaluated before purging of >5.46 x 10(4) CFU-GM/kg and doses actually infused post purging of < or =0.02 x 10(4)/kg had a treatment-related mortality of only 2+/-2%, a leukemia-free survival of 70%, and an overall survival of 77+/-7% at 10 years. In this study of autotransplantation for acute leukemia using mafosfamide-purged marrow, the stem cell dose used for purging and the intensity of purging were the most important factors predicting outcome.

Outcome of 5651 hematopoietic stem cell transplants for hematological malignancies carried out in Europe in 1993: a reliability study of the registry.

Outcome results of observational databases are frequently criticized as relying on incomplete information from incomplete patient populations. Few data are available to dispute these arguments of selection bias. The European Group for Blood and Marrow transplantation (EBMT) decided to address this question by evaluating the hematopoietic stem cell transplants performed in 1993. A comprehensive survey was launched in an effort to collect informations on all transplants for hematological malignancies performed throughout Europe during the year 1993. The main goals of this effort were to compare the group of spontaneously reported patients with the group of retrospectively solicited patients, and to give an accurate estimate of the outcome of all patients. For the year 1993, the annual EBMT activity survey indicated 6336 transplants performed for hematological malignancies in Europe. A total of 5651 transplants could be analyzed; 2595 were reported spontaneously by the teams (group A) and 3056 were retrieved on solicitation (group B). Patients and transplant characteristics for group A and B were very similar for most parameters with a few exceptions. There was no statistical difference for outcome at 3 years between groups A and B: disease-free survival (DFS) was 45 +/- 1% and 44 +/- 1%, relapse incidence (RI) 41 +/- 1% and 42 +/- 1%, transplant-related mortality (TRM) 23 +/- 1% and 23 +/- 1%, and overall survival (OS) 54 +/- 1% and 55 +/- 1%, respectively, for group A and group B. The real outcome at 3 years for the 5651 patients (group A + group B) transplanted in 1993 was 44 +/- 1%, 41 +/- 1%, 23 +/- 1%, and 54 +/- 1%, for DFS, RI, TRM and OS, respectively. The outcome at 3 years by transplant modality, autologous or allogeneic transplants, and by disease categories showed no difference between groups A and B.

Patients with acute lymphoblastic leukaemia allografted with a matched unrelated donor may have a lower survival with a peripheral blood stem cell graft compared to bone marrow.

We analysed data for 213 patients with ALL and AML who received either peripheral blood stem cells (PBSC) (n=74) or bone marrow (BM) (n=139) from an HLA-matched unrelated donor (EBMT acute leukaemia registry; January 1994 to January 1999). The two groups of patients (by cell source) were comparable with respect to age, sex, disease status, year at transplant and graft T cell depletion. Engraftment was achieved in about 90% regardless of stem cell source or leukaemia type. Kinetics of neutrophil and platelet recovery, similar for both sources in ALL patients, were faster for PBSC in AML patients. The incidence of acute graft-versus-host disease was similar for both sources in AML patients, but higher for PBSC in ALL patients (74 vs 54%, P=0.05). The 1-year probability of chronic graft-versus-host disease was 40 and 45% (P=0.66) in ALL patients compared to 49 and 35% (P=0.13) in AML patients (PBSC vs BM). In AML patients, none of the following differed significantly with cell source: transplant-related mortality, relapse incidence, leukaemia-free survival and overall survival. In ALL patients, the transplant-related mortality for PBSC vs BM was 61 vs 47% (P=0.13), the relapse incidence was 47 vs 39% (P=0.17), the leukaemia-free survival was 21 vs 32% (P=0.04) and the overall survival was 24 vs 34% (P=0.04). These data suggest that the short-term outcome of allogeneic PBSC is not significantly different from that of BM in AML patients who underwent a transplant from a matched unrelated donor but, conversely, that survival with PBSC may be decreased in ALL patients. In conclusion, the source of transplant cells needs to be evaluated by disease, especially when dealing with unrelated donors.

Severe respiratory syncytial virus pneumonia after autologous bone marrow transplantation: a report of three cases and review.

Three patients with acute leukemia who underwent autologous bone marrow transplantation (BMT) in complete remission, developed a severe respiratory syncytial virus (RSV) pneumonia, which was fatal in two. Identification of RSV was made on the products of bronchoalveolar lavage by direct immunofluorescence. As already described by others, the initial course of RSV infection varies, depending on whether it occurs sooner or later after BMT with a better prognosis in the latter situation. Treatment consists of aerosolized ribavirin. Infection by RSV is caused by manual contact with infected persons and contaminated surfaces. The severity of lung RSV infection in the course of BMT suggests the need for prophylactic measures in addition to standard isolation precautions.

Prolonged remission and autologous recovery in two patients with chronic myelogenous leukemia after graft failure of allogeneic bone marrow transplantation.

Two patients with Philadelphia-positive chronic myelogenous leukemia underwent allogeneic bone marrow transplantation from a related HLA mismatched donor (patient 1) or from an unrelated HLA-identical donor (patient 2). Following bone marrow transplantation partial engraftment (patient 1) or graft failure (patient 2) occurred followed by autologous Philadelphia negative hematopoietic recovery either spontaneously (patient 1) or after infusion of autologous bone marrow rescue (patient 2). Neither Philadelphia chromosome, nor bcr-abl rearrangement was detectable by PCR analysis up to 7 years (patient 1) and 9 years (patient 2) post-transplantation. These two observations indicate that sustained engraftment of allogeneic bone marrow stem cells following a myeloablative regimen is not necessary to cure chronic myelogenous leukemia. It is hypothesized that the proliferative advantage of Philadelphia-negative progenitors and the anti-leukemic effect of lymphocytes in the graft have resulted in prolonged remission of the patients.

Value of autologous bone marrow transplantation in follicular lymphoma: a France Autogreffe retrospective study of 42 patients.

The value of high-dose chemotherapy with hematologic stem cell rescue has not been established in the treatment of low-grade non-Hodgkin's lymphoma. We report the results of a retrospective 'France Autogreffe' study of 42 patients grafted in first partial remission (n = 13) or chemosensitive relapse (n = 29) for follicular lymphoma before January 1990. The median age was 38 years (range 26-61 years). Preparative therapy was chemotherapy alone in 22 patients and total body irradiation (TBI)-containing regimens in 20 patients. Thirty-seven patients received hematopoietic marrow stem cells. Bone marrow purging was performed in 15 patients. Five patients received peripheral blood stem cells. Three patients died of bone marrow transplantation toxicity and two others died in complete remission 10 months after autologous bone marrow transplantation. With a median follow-up of 43 months, relapse-free survival is 60%, event-free survival 58% and overall survival 83%. To date no prognostic factors have been shown.

The dismal outcome in patients with acute leukaemia who relapse after an autograft is improved if a second autograft or a matched allograft is performed. Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT).

All patients receiving autografts for acute leukaemia in remission between 1 January 1981 and 31 December 1996 and reported to the European Group for Blood and Marrow Transplantation and had a relapse, were included. The patients underwent an allograft (n = 90, group A), were treated with chemotherapy (n = 2584, group B) or received a second autograft (n = 74, group C). The 2-year survival after relapse was 32 +/- 5%, 11 +/- 1% and 42 +/- 6% in groups A, B and C, respectively. In group A, those with an HLA-A, -B and -DR compatible related or unrelated donor had a 2-year survival of 37 +/- 7% compared to 13 +/- 8% for those receiving a graft from an HLA mismatched donor (n = 20). The following factors were associated with better survival in multivariate analyses: an interval from first autograft to relapse >5 months (P < 0.00001), a first autograft performed later than 1991 (P < 0.00001), patient age below 26 years (median, P < 0.002), group B vs HLA mismatches from group A (P = 0.002), group C vs group B (P < 0.005), patients who were not treated with total body irradiation at first autograft (P < 0.02) and patients in first remission at first autograft (P = 0.02). To conclude, the poor outcome in these patients was improved if a second autograft was feasible (P < 0.005), or if an HLA-matched allograft was performed (NS). Bone Marrow Transplantation (2000).

In vivo effects of GM-CSF and IL-3 on hematopoietic cell recovery in bone marrow and blood after autologous transplantation with mafosfamide-purged marrow in lymphoid malignancies.

This retrospective study evaluates the impact of GM-CSF and interleukin 3 (IL-3) on bone marrow (BM) and peripheral blood (PB) cell recovery following autologous bone marrow transplantation (ABMT) with mafosfamide-purged BM in patients with lymphoid malignancies compared with a control group receiving no colony-stimulating factor. GM-CSF was administered at 250 micrograms/m2/day (8 patients) as a continuous infusion from day of autologous BMT until the absolute neutrophil count (ANC) reached 0.5 x 10(9)/l for 7 days or until day 30, whichever was first. IL-3 was administered daily starting on the first day of transplant at a dose of 1 microgram/kg/day (6 patients) and 5 micrograms/kg/day (6 patients) for 30 days. CFU-GM and BFU-E were sequentially evaluated in BM and PB at days 7, 14, 21, 28, and 56 post-graft. The neutrophil recovery (ANC > 0.5 x 10(9)/l) was significantly faster in the GM-CSF group compared with IL-3 5 micrograms, IL-3 1 microgram and control group (respectively, days 15, 21, 22, 24) (p < 0.05 to p < 0.01). Similarly, leukocyte recovery was faster in the GM-CSF group compared with control and IL-3 1 microgram groups (p < 0.01 and p < 0.05). No difference was noticed between the two IL-3 groups. Although no difference was observed in platelet recoveries (> 50 x 10(9)/l), it appeared that the GM-CSF group required more units of platelets than either the IL-3 1 microgram or 5 micrograms groups (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Autologous bone marrow transplantation is feasible in patients with a prior history of invasive pulmonary aspergillosis.

We report on seven adult leukemic patients who were autografted in spite of a prior history of invasive pulmonary aspergillosis (IPA). Their median age was 41 years (range: 19-61); six patients were male and one female. All seven had acute myeloblastic leukemia (AML) and underwent an autologous marrow transplantation (ABMT) with a marrow purged in vitro by mafosfamide. IPA was suspected prior to ABMT on clinical and radiological features. CT scan confirmed nodular infiltrates and cavitations in six cases. Microbiological documentation consisted of: identification of the fungus from bronchoalveolar lavage: one case, positive antigenemia: one case, positive antibodies: two cases. Prior ABMT patients received amphotericin B for a median total dose of 1915 mg (range: 970-3300). No patient underwent surgery. The median time from diagnosis of IPA to ABMT was 7.3 months (range: 3-10). During ABMT all patients received prophylactic amphotericin B and itraconazole. No patient died from toxicity and no IPA reactivation was observed in any patients. Post-graft, itraconazole was kept on for a median of 3 months (range: 3-5). This study demonstrates that IPA occurring during the management of AML patients is not necessarily a contraindication to subsequent ABMT.

Ex vivo expansion of CD34-positive peripheral blood progenitor cells from patients with non-Hodgkin's lymphoma: no evidence of concomitant expansion of contaminating bcl2/JH-positive lymphoma cells.

The aim of the present study was to evaluate the capacity to expand of hematopoietic stem cell (HSC) samples from eight patients with NHL, and to follow in parallel the fate of tumor cells in four of eight samples still containing bcl2/JH+ tumor cells after CD34+ or CD19-/20-/34+ cell selection. The presence of bcl2/JH+ cells was also investigated after expansion in four of eight samples, two of which were bcl2/JH at harvesting and two which were initially bcl2/JH+ but became bcl2/JH (below the level of PCR detection) after cell selection, to assess a possible reappearance of occult tumor cells after expansion culture. We used culture conditions that we previously had established to allow high level expansion of normal precursors, progenitors and LTC-ICs. In this study, particular attention was given to the role of Flt3-ligand, known to favor the growth of B cells. The expansion conditions were: 1.5 x 10(3) cells/ml in serum-free medium containing stem cell factor (SCF), interleukin-3 (IL-3), IL-6, granulocyte-stimulating factor (G-CSF), erythropoietin (Epo) +/- Flt3-ligand (Flt3-L) for 10 days. After culture, total cells, CFU-GMs, BFU-Es and LTC-ICs were expanded to a mean of 833-, 6.6-, 4.6-, and 1.8-fold, respectively with the cocktail of cytokines not including Flt3-L. When Flt3-L was added, the mean expansion values were 1095-, 31-, 15- and three-fold, respectively. Residual bcl2/JH+ cells present in four of eight samples before expansion were not detected after expansion. Similarly, no tumor cells reappeared after expansion of the two samples which had become negative after selection, as well as in the two samples which were bcl2/JH- at harvesting. These results suggest first that ex vivo expansion of hematopoietic stem cells in patients with non-Hodgkin's lymphoma is feasible without incurring the parallel risk of amplifying tumor cells; second, that Flt3-L did not stimulate the growth of tumor cells while it clearly favored the growth of normal progenitors.

Polymerase chain reaction: a method for monitoring tumor cell purge by long-term culture in BCR/ABL positive acute lymphoblastic leukemia.

We report the successful purging of leukemia cells bearing the Philadelphia chromosome and BCR/ABL transcripts by long-term marrow culture (LTC), and subsequent grafting of the purged marrow in a case of refractory acute lymphoblastic leukemia. The efficiency of the purge was evaluated by polymerase chain reaction (PCR) for BCR/ABL transcripts. In two LTCs initiated in the blastic stage, we demonstrated the selective effect of three culture media (serum dependent, serum-free (SF) supplemented or not with IL3 and GM-CSF) on the proliferative potential of normal hematopoietic (CFU-GM/BFU-E) and leukemic progenitors (CFU-ALL). BCR/ABL positive cells disappeared after 3 to 4 weeks of culture. The addition of IL3 and GM-CSF to the SF medium enhanced the growth of CFU-GM/BFU-E and shortened the purging period. We therefore carried out a LTC in the presence of IL3 and GM-CSF with marrow harvested in morphological remission. BCR/ABL positivity was detected at the outset, although no leukemia cells could be identified. The BCR/ABL was no longer found by PCR in the 7 and 14 day LTCs. The patient, consolidated by high dose polychemotherapy and total body irradiation, was infused with the 14 day LTC. This study indicates that PCR is a useful and sensitive technique for monitoring tumor cell reduction after LTC prior to autografting.

Donor search or autografting in patients with acute leukaemia who lack an HLA-identical sibling? A matched-pair analysis. Acute Leukaemia Working Party of the European Cooperative Group for Blood and Marrow Transplantation (EBMT) and the International Marrow Unrelated Search and Transplant (IMUST) Study.

One hundred and ninety-one patients with acute leukaemia who received bone marrow from HLA-A, -B and -DR identical unrelated donors and were reported to EBMT and/or IMUST, were matched with 382 patients receiving autologous bone marrow for diagnosis, age, stage of disease and year of transplantation. Transplant-related mortality (TRM) was significantly higher in recipients of unrelated marrow compared to autograft recipients, 44 +/- 4% (+/- 95% confidence interval) and 15 +/- 3% at 2 years in the two groups, respectively (P < 10(-4)). In contrast, relapse probability was lower in recipients of unrelated marrow, being 32 +/- 5% at 2 years compared to 55 +/- 3% in recipients of autografts (P < 10(-4)). Two-year leukaemia-free survival (LFS) in patients with acute lymphoblastic leukaemia was 39 +/- 5% and 32 +/- 3% in the two groups, respectively. Among patients with acute myeloid leukaemia (AML), the corresponding figures were 36 +/- 6% and 46 +/- 5% in the two groups, respectively (P = NS). In AML in first remission (CR-1), the 2-year survival was 42 +/- 10% in recipients of unrelated bone marrow, compared to 69 +/- 8% in autograft recipients (P = 0.008). When all patients with acute leukaemia were included, the 2-year LFS was 38% in recipients of unrelated marrow, compared to 37% in autograft recipients (NS). In conclusion, this retrospective analysis supports the design of a prospective randomized study in patients with high-risk/advanced acute leukaemia who lack a suitable related bone marrow donor, to ascertain which of the two strategies, if any, should be favoured.

Retrospective evaluation of autologous bone marrow transplantation vs allogeneic bone marrow transplantation from an HLA identical related donor in acute myelocytic leukemia. A study of the European Cooperative Group for Blood and Marrow Transplantation (EBMT).

We analyzed retrospectively data from 1696 patients with AML transplanted in Europe from January 1987 to December 1992 and reported to the acute leukemia EBMT registry. Groups of patients were analyzed according to age (adults and children) and status at transplant (first remission = CR1; second remission = CR2). (1) 1114 adult patients were transplanted in CR1; 516 received an allograft; 598 received an autograft. Following alloBMT, the transplant-related mortality (TRM) was significantly higher (27 vs 13%, P < 10(-4)), the relapse incidence (RI) lower (25 vs 52%, P < 10(-4)) and the leukemia-free survival (LFS) better (55 vs 42%, P = 0.006). Favorable prognostic factors for alloBMT were a FAB type other than M4-M5, a donor-recipient combination excluding a female donor to a male recipient, and a younger age. Favorable prognostic factors for ABMT were a younger age of the patients at time of transplant, the AML3 FAB type, and a longer interval from CR1 to ABMT. (2) 288 adult patients were transplanted in CR2: 98 received an allograft; 190 received an autograft. The TRM was higher following allogeneic BMT (32 vs 20%, P = 0.02) and the RI lower (42 vs 63%, P = 0.001). The LFS was not significantly different (alloBMT: 39%; ABMT: 30%, P = 0.22). (3) 242 children were transplanted in CR1; 129 received an allograft; 113 received an autograft. Following alloBMT, the RI was lower (25 + 5 vs 48 + 6%, P < 10(-4)), and the LFS better (68 vs 47%, P = 0.002). The use of TBI was a favorable prognostic factor in allografted patients with a lower RI and a better LFS. (4) The number of children transplanted in CR2 was too small for a comparative analysis. These results confirm that both allogeneic and autologous BMT are suitable curative approaches for AML. They favor the use of an HLA identical related allogeneic transplant when available, especially in younger patients, over ABMT with unpurged marrow. The role of purging in ABMT could not be addressed in this study.

Improved efficiency of remission induction facilitates autologous BMT harvesting and improves overall survival in adults with AML: 108 patients treated at a single institution.

A hundred and eight patients less than 60 years old with de novo acute myeloid leukemia were treated between 1982 and 1994 by protocols including final intensification with a transplant using autologous bone marrow purged by mafosfamide in first remission in the absence of an HLA-matched sibling donor available for allograft. From 1989, we attempted to improve tumor control by using high-dose anthracyclines in induction, by increasing from one to two the number of consolidation courses pre-transplant and by introducing intermediate doses of cytarabine in the first consolidation course. The CR rate was 77% (33/43) before 1989 and 90% (59/65) after 1989 (P = 0.06). Forty-five out of the 59 patients (76%) who achieved CR after 1989 could undergo bone marrow grafting in CR1 vs 16/33 (48%) before 1989 (P = 0.01). In spite of the higher proportion of patients above 50 years after 1989 (32%) toxicity was mild and an adequate graft was obtained more frequently after one collection. The principal factor relating to improvement in graft feasibility was the post-1989 modification of induction and consolidation regimens. This improvement in graft feasibility was associated with a better disease-free survival (DFS) (48 +/- 7% vs 32 +/- 8%, P = 0.04) and overall survival (OS) (53 +/- 6% vs 30 +/- 7%, P = 0.007) at 5 years. By multivariate analysis four factors were associated with overall survival (OS): karyotype, white blood cell count at diagnosis, treatment regimen and bone marrow grafting in CR1. This global approach should be prospectively compared with intensive chemotherapy.

Autologous haematopoietic stem cell transplants for autoimmune disease--feasibility and transplant-related mortality. Autoimmune Disease and Lymphoma Working Parties of the European Group for Blood and Marrow Transplantation, the European League Against Rheumatism and the International Stem Cell Project for Autoimmune Disease.

This ongoing multicentre prospective phase I/II trial enrolled 74 consecutive patients from 22 centres worldwide with severe autoimmune disease, 35 with rheumatological disorders, 31 with neurological, five with haematological and three with vasculitides. They were treated with autologous peripheral blood or bone marrow transplants according to predetermined criteria. Two patients died after mobilisation before transplant. Seventy-two patients were given 73 transplants, seven bone marrow, and 66 mobilised peripheral blood stem cell transplants. The graft was manipulated to remove T and/or B cells in 43 cases. All 73 transplants engrafted. Five patients died of transplant-related complications: two from bleeding, three from infections. Two patients died of progressive disease. The transplant-related mortality at 1 year of 9% (1-17%; 95% CI) is comparable to the transplant-related mortality of 6% (3-9%; 95% CI) in patients transplanted during the same period in Europe for non-Hodgkin's lymphoma in sensitive relapse (P = 0.39). Sixty patients are evaluable for response, 40 patients (65%) showed some improvement in their disease. Haematopoietic stem cell transplants are feasible for patients with severe refractory autoimmune disease. Transplant-related mortality is comparable to results in patients with non-Hodgkin's lymphoma in responsive relapse. Two-thirds of the patients show at least some response. These preliminary data are promising. Although associated with considerable risk, randomised trials comparing autologous stem cell transplants to conventional therapy are warranted.