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.     

Total body irradiation–high-dose cytosine arabinoside and melphalan followed by allogeneic bone marrow transplantation from HLA-identical siblings in the treatment of children with acute lymphoblastic leukaemia after relapse while receiving chemotherapy: a Société Française de Greffe de Moelle study

We investigated the use of a new conditioning regimen followed by allogeneic bone marrow transplantation (BMT) for treating children with acute lymphoblastic leukaemia (ALL) after relapse within 6 months of the completion of therapy. One hundred and sixteen children with acute lymphoblastic leukaemia in second or subsequent complete remission (CR) underwent allogeneic bone marrow transplantation from HLA-identical siblings after a preparative regimen comprising total body irradiation (TBI), high-dose cytosine arabinoside and melphalan (TAM regimen). The Kaplan-Meier product-limit estimate (mean ± SE) of disease-free survival (DFS) at 7 years was 59.5 ± 9% (95% confidence interval). The estimated chance of relapse was 22.5 ± 15% with a median follow-up of 88.5 months (range 51–132). 26 patients (22.4%) died with no evidence of recurrent leukaemia, mainly from interstitial pneumonitis, veno-occlusive disease or acute graft-versus-host disease (GVHD). Three factors significantly affected DFS: acute GVHD, site of relapse and, for children in second remission after a marrow relapse, the disease status at the time of transplantation. The DFS were 59.02 ± 12.6%, 37.5 ± 19.8% and 77.4 ± 15% among patients in CR2 after a marrow relapse, in CR3 or in untreated partial marrow relapse, and in CR2 after an isolated CNS relapse, respectively. The lowest DFS was seen in children with acute GVHD grades 3–4. Two significant factors were associated with relapse: the marrow status at the time of transplantation and chronic GVHD. The relapse rate was lower among children in CR2 or with chronic GVHD. We conclude that transplantation after the TAM regimen is an effective therapy for this population with acceptable toxicity, particularly for children in second remission after a very early marrow relapse, or those with early isolated CNS involvement.     

Allogeneic stem cell transplantation improves the outcome of adults with t(1;19)/E2A-PBX1 and t(4;11)/MLL-AF4 positive B-cell acute lymphoblastic leukemia: results of the prospective multicenter LALA-94 study.

Adult patients with acute lymphoblastic leukemia (ALL) and t(1;19)/E2A-PBX1 or t(4;11)/MLL-AF4 have a poor outcome. We have evaluated the impact of an intensified post-remission therapy using a high-dose chemotherapy course followed by allogeneic or autologous SCT on the outcome of 58 patients with t(1;19)/E2A-PBX1 (E2A group, n=24) or t(4;11)/MLL-AF4 (MLL group, n=34) treated in the LALA-94 multicenter prospective study. Patients in the MLL group had higher WBC counts and more frequent DIC. CR rates achieved by MLL and E2A groups were similar to other B-cell ALL (87, 82 and 86% respectively). While in CR, patients with a donor were assigned to alloSCT (n=22), the remaining patients with were randomized between autoSCT (n=15) or chemotherapy (n=8). Five-year overall survival was 31 and 45% for E2A and MLL groups, respectively. In both groups, DFS was higher in the alloSCT arm as compared to autoSCT and chemotherapy arms. The results of this study show that chemotherapy intensification did not overcome the poor prognosis of adults with t(1;19)/E2A-PBX1. Allogeneic SCT should thus be offered in first CR to patients with t(1;19)/E2A-PBX1 or t(4;11)/MLL-AF4. New therapeutic approaches are needed for patients without donor.     

Drug-induced benign intracranial hypertension. Apropos of a case with amphotericin B. Review of the literature]

Benign intracranial hypertension (BICH) is a rare adverse event. We report the case of a 31-year-old female drug addict who had been seropositive for HIV since 1987. She had stage IV C1 AIDS, and was receiving intravenous amphotericin B for generalized cryptococcosis with no neuromeningeal involvement. She developed BICH that regressed when the antifungal drug was withdrawn and treatment for cerebral edema was started. BICH is a clinical entity involving intracranial hypertension with no focal neurological signs or detectable intracranial lesion. The manifestations include headache, transitory or permanent visual disturbances (diplopia, loss of visual acuity) and the perception of intracranial noise. The cerebrospinal fluid is under increased pressure but the composition is normal. The eye fundus examination shows papillary edema, and the neuroradiological workup is normal. BICH can only be diagnosed once an expansive intracranial process, neuromeningeal infection, and non-communicative hydrocephalus have been ruled out. In the majority of cases, no etiology is found. Such cases of idiopathic BICH usually occur in overweight young women, although drugs can be implicated. Amphotericin B has not previously been held responsible for BICH. On the basis of this observation, we present a review of the literature.     

Prior treatment with alpha interferon does not adversely affect the outcome of allogeneic transplantation for chronic myeloid leukaemia

Summary. The timing of transplantation in chronic myeloid leukaemia is still debated and previous treatment with interferon (IFN) alpha has been reported to be deleterious. We have analysed the outcome of 438 allogeneic transplants performed between 1984 and 1995 and reported to the Société Française de Greffe de Moelle (SFGM) registry. One hundred and two patients (group I) received IFN for more than 6 weeks (median = 9 months) before transplant. Their outcome was compared with 336 other patients (group II) not pretreated with IFN. There were no significant differences between the groups for engraftment and chronic graft‐versus‐host disease (GVHD) incidence. However, other significant differences included the incidence of acute GVHD ≥ 2 at 3 months which was higher in group I (65 ± 10%) than in group II (38 ± 5%; P = 0·01). Moreover, disease‐free survival (DFS) and overall survival (OS) at 5 years were significantly shorter for group I than for group II (33 ± 10% vs. 41 ± 6%; P = 0·005)(95% CI) and (41 ± 10% vs. 55 ± 6%; P = 0·002)(95% CI) respectively. After adjustment for patient and transplant covariables in a multivariate analysis, prior IFN was not found to adversely affect transplant outcome.     

Selective depletion of marrow-T cytotoxic lymphocytes (CD8) in the prevention of graft-versus-host disease after allogeneic bone-marrow transplantation

In vitro depletion of mature pan-T lymphocytes has been widely and successfully used to prevent acute graft-versus-host disease (GVHD) after allogeneic bone-marrow transplantation (BMT). However, this procedure has been associated with a high incidence of graft failure and leukemic relapse. In this pilot study, we evaluated the efficiency of a selective depletion of human marrow T cytotoxic lymphocytes (CD8), a subset essential to induce GVHD in mice. Eleven patients with hematologic malignancies were included (7 HLA-matched BMT, 4 HLA-mismatched BMT). Marrow treatment with 7 anti-CD8 mAbs and rabbit complement resulted in a marked reduction of CD8+lymphocytes from 15% (median value; range 7%–31%) to 1% (median value; range<1%–11%). Acute GVHD was not abolished by this procedure despite postgraft immunosuppression. One patient (HLA-mismatched BMT) rejected his graft and had a full autologous recovery. In conclusion, when compared to the data in the literature, CD8 depletion was shown to be less efficient than pan-T-cell depletion in the prevention of GVHD after allogeneic BMT and was still associated with a major complication associated with this procedure, i.e., graft failure.     

Selective depletion of marrow-T cytotoxic lymphocytes (CD8) in the prevention of graft-versus-host disease after allogeneic bone-marrow transplantation

Abstract. In vitro depletion of mature pan-T lymphocytes has been widely and successfully used to prevent acute graft-versus-host disease (GVHD) after allogeneic bone-marrow transplantation (BMT). Hpwever, this procedure has been associated with a high incidence of graft failure and leukemic relapse. In this pilot study, we evaluated the efficiency of a selective depletion of human marrow T cytotoxic lymphocytes (CD8), a subset essential to induce GVHD in mice. Eleven patients with hematologic malignancies were included (7 HLA-matched BMT, 4 HLA-mismatched BMT). Marrow treatment with 7 anti-CD8 mAbs and rabbit complement resulted in a marked reduction of CD8 + lymphocytes from 15% (median value; range 7%-31%) to 1% (median value; range <1%-11%). Acute GVHD was not abolished by this procedure despite postgraft immunosuppression. One patient (HLA-mismatched BMT) rejected his graft and had a full autologous recovery. In conclusion, when compared to the data in the literature, CD8 depletion was shown to be less efficient than pan-T-cell depletion in the prevention of GVHD after allogeneic BMT and was still associated with a major complication associated with this procedure, i.e., graft failure.     

Allogeneic bone marrow transplantation for therapy-related myelodysplastic syndrome and acute myeloid leukemia: a long-term study of 70 patients-report of the French society of bone marrow transplantation.

PURPOSE: To identify predictive factors of survival, relapse, and transplantation-related mortality (TRM) among patients with therapy-related myelodysplastic syndrome (t-MDS) or acute leukemia (t-AML) who underwent allogeneic bone marrow transplantation (BMT). PATIENTS AND METHODS: From 1980 to 1998, 70 patients underwent allogeneic BMT for t-MDS (n = 31) or t-AML (n = 39) after prior cytotoxic exposure. Thirty-three patients had received induction-type chemotherapy before BMT. At the time of transplantation, there were 24 patients in complete remission (CR) and 46 with active disease. RESULTS: With a median follow-up of 7.9 years (range, 1.1 to 18.8 years) after BMT, 16 patients are alive, whereas 19 died of relapse, 34 of TRM, and one of relapse of the primary disease. The estimated 2-year overall survival, event-free survival, relapse, and TRM rates were 30% (95% confidence interval [CI], 19% to 40%), 28% (95% CI, 18% to 39%), 42% (95% CI, 26% to 57%), and 49% (95% CI, 36% to 62%), respectively. In multivariable analysis, age greater than 37 years, male sex, positive recipient cytomegalovirus (CMV) serology, absence of CR at BMT, and intensive schedules used for conditioning were associated with poor outcome. CONCLUSION: BMT is an effective treatment for patients with t-MDS or t-AML who have responsive disease and, in particular, who have no poor-risk cytogenetic features. The poor results of the other patients, especially those with active disease at BMT, emphasize the need to delineate indications and perform prospective protocols.