Agnès Devergie

HEMATOPOIETIC RECONSTITUTION IN A PATIENT WITH FANCONI'S ANEMIA BY MEANS OF UMBILICAL-CORD BLOOD FROM AN HLA-IDENTICAL SIBLING

THE clinical manifestations of Fanconis anemia, an autosomal recessive disorder, include progressive pancytopenia, a predisposition to neoplasia, and nonhematopoietic developmental anomalies.1 2 3...

Risk assessment for patients with chronic myeloid leukaemia before allogeneic blood or marrow transplantation

Summary Background Transplantation of blood or bone-marrow stem cells is the treatment of choice for selected patients with chronic myeloid leukaemia (CML). Transplantation is used with increasing frequency and success, but remains associated with substantial risks of morbidity and mortality. Other treatments with satisfactory short-term outcome are available. For appropriate counselling of patients, a rapid and simple way to assess risk is needed. Methods Data from 3142 patients (1873 [60%] male, 1269 [40%] female; mean age 34 years, range Findings At the time of analysis, 1922 (61%) of the 3142 patients were alive—1567 (65%) of those with HLA-identical sibling donors and 417 (57%) of those with unrelated donors. 1682 (54%) were alive without relapse. 1220 (39%) patients had died, 1013 (83%) of transplant-related causes, 207 (17%) of relapse. 447 (14%) patients had relapsed. The final scoring system was highly predictive for leukaemia-free survival, survival and transplant-related mortality. Survival at 5 years was 72%, 70%, 62%, 48%, 40%, 18%, and 22% for patients with scores 0, 1, 2, 3, 4, 5, and 6, respectively. Risk of transplant-related mortality was 20%, 23%, 31%, 46%, 51%, 71%, and 73%. Data showed the same trends for HLA—identical sibling transplants and unrelated transplants for transplants done in 1989–93 and 1994–96. Interpretation Pretransplant risk factors are cumulative for individual patients with CML having blood or marrow transplantation. A simple system based on five main factors gives adequate risk assessment for counselling of patients and taking decisions.

Survival and Prognostic Factors of Invasive Aspergillosis After Allogeneic Bone Marrow Transplantation

To determine prognostic factors for survival in bone marrow transplant recipients with invasive aspergillosis (IA), we retrospectively reviewed 27 IA cases observed in our bone marrow transplantation unit between January 1994 and October 1994. On 30 September 1997, six patients were alive and disease-free. The median survival after IA diagnosis was 36 days. Of eight variables found to be related to survival according to the univariate analysis, graft-versus-host disease (GVHD) status at IA diagnosis (P = .0008) and the cumulative prednisolone dose taken during the week preceding IA diagnosis (CPDlw) (P < .0001) were selected by a backward stepwise Cox regression model. A three-stage classification was established: CPD1w of < or =7 mg/kg (3 of 8 patients died; 60-day survival rate, 88%), CPD1w of >7 mg/kg and no GVHD (9 of 10 patients died; 60-day survival rate, 20%), and CPD1w of >7 mg/kg and active acute grade 2 or more or extensive chronic GVHD (9 of 9 patients died; 30-day survival rate, 0) (P < .0001).

Haematopoietic stem cell transplantation for patients with myelo- dysplastic syndromes and secondary acute myeloid leukaemias: a report on behalf of the Chronic Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT)

Allogeneic stem cell transplantation from an HLA‐identical sibling donor is a curative treatment option for a young patient with myelodysplastic syndrome, limited by age and lack of sibling donors. Alternative stem cell sources have been used more recently, such as unrelated donors, non‐identical family members or autologous transplants. This analysis of 1378 transplants reported to the European Group for Blood and Marrow Transplantation (EBMT) addresses the outcome of the varying procedures according to the known risk factors. The estimated disease‐free survival (DFS) and estimated relapse risk at 3 years were both 36% for 885 patients transplanted with stem cells from matched siblings. In the multivariate analysis, age and stage of disease had independent prognostic significance for DFS, survival and treatment‐related mortality. Patients transplanted at an early stage of disease had a significantly lower risk of relapse than patients transplanted at more advanced stages. The estimated DFS at 3 years was 25% for the 198 patients with voluntary unrelated donors, 28% for the 91 patients with alternative family donors and 33% for the 126 patients autografted in first complete remission. The non‐relapse mortality was 58% for patients with unrelated donors, 66% for patients with non‐identical family donors and 25% for autografted patients. The relapse rate of 18% was relatively low for patients with non‐identical family donors, 41% for patients with unrelated donors and 55% for patients treated with autologous stem cell transplantation. Both allogeneic and autologous stem cell transplantation have emerged as treatment options for patients with myelodysplastic syndromes. Transplantation with an HLA‐identical sibling donor is the preferred treatment option. Patients without an HLA‐identical sibling donor may be treated with either autologous stem cell transplantation or an alternative donor transplantation. Patients younger than 20 years may be treated with an unrelated donor transplantation. Patients older than 40 years, and probably also patients between 20 and 40 years, may benefit most from an autologous stem cell transplantation.

Allogeneic Hematopoietic Stem-Cell Transplantation for Patients 50 Years or Older With Myelodysplastic Syndromes or Secondary Acute Myeloid Leukemia

PURPOSE This study was performed to examine the characteristics of transplant activity for patients with myelodysplastic syndromes (MDS) older than 50 years within the European Group for Blood and Marrow Transplantation, and to evaluate the factors predicting outcome within this group of patients. PATIENTS AND METHODS We performed a retrospective multicenter analysis of 1,333 MDS patients age 50 years or older who received transplantation within the EBMT since 1998. The median recipient age was 56 years, with 884 patients (66%) age 50 to 60 years and 449 (34%) patients older than 60 years. There were 811 HLA-matched sibling (61%) and 522 (39%) unrelated donor transplants. Five hundred patients (38%) received standard myeloablative conditioning (SMC), and 833 (62%) received reduced intensity conditioning (RIC). RESULTS The 4-year estimate for overall survival of the whole cohort was 31%. On multivariate analysis, use of RIC (hazard ratio [HR], 1.44; 95% CI, 1.13 to 1.84; P < .01) and advanced disease stage at transplantation (HR, 1.51; 95% CI, 1.18 to 1.93; P < .01) were associated with an increased relapse rate. In contrast, advanced disease stage at transplantation (HR, 1.43; 95% CI, 1.13 to 1.79; P = .01), use of an unrelated donor (P = .03), and RIC (HR, 0.79; 95% CI, 0.65 to 0.97; P = .03) were independent variables associated with nonrelapse mortality. Advanced disease stage at transplantation (HR, 1.55; 95% CI, 1.32 to 1.83; P < .01) was the major independent variable associated with an inferior 4-year overall survival. CONCLUSION Allogeneic hematopoietic stem-cell transplantation remains a potential curative therapeutic option for many older patients with MDS. In this analysis, disease stage at time of transplantation, but not recipient age or the intensity of the conditioning regimens, was the most important factor influencing outcomes.

Long-term follow-up of severe aplastic anaemia patients treated with antithymocyte globulin

Summary. 468 severe aplastic anaemia (SAA) patients registered in the EBMT‐SAA registry who did not undergo bone marrow transplantation and were treated with immunosuppressive therapy (IS; 96% of patients received ATG) were evaluated. Their median age was 23 years (range 1–73) at initial IS therapy, 59% were males; in 69% the aetiology of SAA was idiopathic. Of these 468 patients, 245 had a follow‐up of <2 years after IS 166/245 died, 71/245 are still alive, 8/245 are lost to follow‐up. Of 223 patients who survived ≥2 years (LTS long‐term survivors), 191 are alive, 21 died >2 years and 11 are lost. Median follow‐up of 223 LTS was 4.1 years (range 2.0–10.9). Comparison of 166 patients who died <2 years and 223 LTS revealed no difference at time of initial IS therapy as regards sex, duration of AA, or its aetiology, but the age distribution and, in particular, severity of SAA differed significantly: more LTS were between 21 and 40 years old (44%v. 32%, P<0.02), less LTS had reticulocytes <20 × 109/l (63%v. 80%, P<0.001), polymorphonuclear granulocytes (PMN) <0.2 × 109/l (30%v. 57%. P<0.001), haemorrhages (58%v. 79%, P<0.002) and infection (30%v. 49%, P<0.005) at time of IS. A gradual improvement of blood counts was seen in patients alive ≥ 2 years after IS. At 2 years after IS 80% had a normal haemoglobin and PMN >0.5 × 109/l, but only after 5 years 80% of cases had platelets > 50 × 109/l. Development of clonal disease was reported of 31 LTS: 19 developed paroxysmal nocturnal haemoglobinuria (PNH), one acute leukaemia, 11 myelodysplastic syndromes and of these 11 five subsequently acute leukaemia. The majority of these patients (23/31) are still alive. Actuarial mortality of LTS is 22% at 8 years, but so far no plateau was achieved. It is concluded that SAA patients who become LTS following IS, show an improvement in haematological status but are probably not cured and are prone to develop clonal (malignant) disease.

Long-term results after allogeneic bone marrow transplantation for chronic myelogenous leukemia in chronic phase: a report from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation

The purpose of this study was to determine the long-term results of allogeneic bone marrow transplantation for chronic myeloid leukemia. A retrospective analysis was carried out of the outcome of 373 consecutive transplants performed at 38 European institutions between 1980 and 1988 and reported to the registry of the European Group for Blood and Marrow Transplantation. All transplants were carried out for first chronic phase of chronic myelogenous leukemia using unmanipulated marow cells from HLA-identical sibling donors. The probability of survival and leukemia-free survival at 8 years were 54% (95% CI: 49–59) and 47% (95% CI: 41–52) respectively. The probabilities of developing acute GVHD (II–IV) at 100 days and chronic GVHD at 4 years after transplant were 47% (95% CI: 41–53) and 52% (95% CI: 46–58) respectively. The probabilities of transplant-related mortality and leukemic relapse 8 years after BMT were 41% (95% CI: 36–48) and 19% (95% CI: 14–25), respectively. Transplant within 12 months of diagnosis was associated with reduced transplant-related mortality (34 vs 45%, P = 0.013) and resulted in improved leukemia-free survival (52 vs 44%, P = 0.03). The probability of relapse was significantly reduced in patients who developed chronic GVHD (RR = 0.33, P = 0.004). The probability of relapse occurring more than 2 years after transplant was increased more than five-fold in patients transplanted from a male donor (RR = 5.5, P = 0.006). Sixty-seven patients in hematologic remission were studied for residual disease by two-step RT/PCR for BCR-ABL mRNA and 61 (91%) tested negative. We conclude that bone marrow transplantation can induce long-term survival in approximately one-half of CML patients; the majority of survivors have no evidence of residual leukemia cells when studied by molecular techniques. The probability of late relapse is increased with use of a male donor.

Resistant Herpes Simplex Virus Type 1 Infection: An Emerging Concern after Allogeneic Stem Cell Transplantation

Fourteen cases of severe acyclovir-resistant herpes simplex virus type 1 (HSV-1) infection, 7 of which showed resistance to foscarnet, were diagnosed among 196 allogeneic stem cell transplant recipients within a 29-month period. Recipients of unrelated stem cell transplants were at higher risk. All patients received foscarnet; 8 subsequently received cidofovir. Strains were initially foscarnet-resistant in 3 patients and secondarily so in 4 patients. In vitro resistance to acyclovir or foscarnet was associated with clinical failure of these drugs; however, in vitro susceptibility to foscarnet was associated with complete response in only 5 of 7 patients. No strain from any of the 7 patients was resistant in vitro to cidofovir; however, only 3 of 7 patients achieved complete response. Therefore, acyclovir- and/or foscarnet-resistant HSV-1 infections after allogeneic stem cell transplantation have become a concern; current strategies need to be reassessed and new strategies must be evaluated in this setting.

Prolonged immune deficiency following allogeneic stem cell transplantation: risk factors and complications in adult patients.

To evaluate the long‐term immune reconstitution after allogeneic haematopoietic stem cell transplantation (SCT), we prospectively screened standard immune parameters in a series of 105 patients, at a median time of 15 months after SCT. Analysing lymphoid phenotypes, in vitro immune functions and immunoglobulin levels, we found that, more than 1 year post SCT, cellular and humoral immunity was still altered in a significant number of patients. CD4+ T cells were < 200/µl in one third of patients, and the CD4/CD8 ratio was still reversed in 78% of patients. Almost all patients showed positive T‐cell responses against mitogens, but antigen‐specific proliferation assays identified 20% to 80% of non‐responders. B‐cell counts were reconstituted in 61% of the patients, but levels of total immunoglobulins were still low in 59%. In multivariate analyses, human leucocyte antigen (HLA) disparity between donor and recipient and chronic graft‐versus‐host disease were the leading causes affecting immune reconstitution. Interestingly, cytomegalovirus (CMV) infections were strongly associated with normal CD8+ T‐cell counts. Studying the impact of impaired immune reconstitution on the rate of infections occurring in the 6 years following screening, we identified three parameters (low B‐cell count, inverted CD4/CD8 ratio, and negative response to tetanus toxin) as significant risk factors for developing such late infections.

Transplantation for Fanconi's anaemia: long‐term follow‐up of fifty patients transplanted from a sibling donor after low‐dose cyclophosphamide and thoraco‐abdominal irradiation for conditioning

We describe the long‐term follow‐up of 50 Fanconis anaemia patients who were transplanted from a related donor with a median follow‐up of >6 years. The survival estimate was 74.4% at 54 months and 58.5% at 100 months. All patients were conditioned with low‐dose cyclophosphamide and thoraco‐abdominal irradiation. Acute graft‐versus‐host disease (GvHD) of grade II or more developed in 26 patients and chronic GvHD developed in 30/43 (69.9%) patients. The survival of patients without chronic GvHD (n = 13) was 100%. In addition to chronic GvHD, 20 pre‐transplant transfusions was shown to have an adverse impact on survival by multivariate analysis (relative risk = 7.08, P = 0.0003). Prospective follow‐up of growth and endocrine function could be performed in 31 patients. Of 20 boys, six have already reached normal puberty within the expected time. Among the 11 girls, three were at the pubertal age at the time of analysis. Growth retardation was common, whereas late complications (e.g. peripheral hypothyroidism, cataract) were rare. However, the most important long‐term complication was the occurrence of cancer in seven patients (8‐year projected incidence 24%).