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The first autologous hematopoietic stem cell transplantation in Europe for a patient with severe refractory systemic lupus erythematosus (SLE) was performed in Genoa in 1996. Since then, 32 patients with a wide spectrum of autoimmune diseases (ADs) received autologous transplants, 22 of them with multiple sclerosis (MS). There were no fatal adverse events. All patients had complete or very good partial remissions, but relapses were frequent, especially in SLE, though never as aggressive as pretransplant. The mechanism of action of this intervention remains not completely understood, as briefly discussed here.

We assessed the outcome of 170 patients with AML in first complete remission, aged 1-47 years (median 29), who had undergone an allogeneic BMT before or after 1990 (n=80 and n=90, respectively); all patients were prepared with cyclophosphamide and TBI; the median follow-up for surviving patients was 13 years. The donor was an HLA-identical sibling in 164 patients. Transplant-related mortality (TRM) was 30% before and 7% after 1990 (P<0.001); relapse-related death (RRD) was 26 and 11% (P=0.002); and actuarial 10-year survival was 42 and 79% (P<0.00001). Patients transplanted after 1990 were older, had a shorter interval diagnosis-BMT, had less FAB-M3 cases, received a higher dose of TBI, a higher marrow cell dose and combined (cyclosporine+methotrexate) GVHD prophylaxis. Patients relapsing after transplant had an actuarial survival of 0 vs 31% if grafted before or after 1990 (P=0.01), and their median follow-up exceeds 10 years. In conclusion, the overall survival of first remission AML undergoing an allogeneic BMT has almost doubled in the past two decades, despite older age and fewer M3 cases. Improvement has come not only from changes in transplant procedures, but also from effective rescue of patients relapsing after transplant.

The anti-CD20 chimaeric monoclonal antibody Rituximab has recently been shown to induce significant clinical response in a proportion of patients with refractory chronic graft-versus-host disease (cGVHD). We now report 38 patients, median age 48 years (22-61), receiving Rituximab for refractory cGVHD, assessed for clinical response and survival. Median duration of cGVHD before Rituximab was 23 months (range 2-116), the median number of failed treatment lines was 3 (range 1 to > or =6) and the median follow-up after Rituximab was 11 months (1-88). Overall response rate was 65%: skin 17/20 (63%), mouth 10/21 (48%), eyes 6/14 (43%), liver 3/12 (25%), lung 3/8 (37.5%), joints 4/5, gut 3/4, thrombocytopaenia 2/3, vagina 0/2, pure red cell aplasia 0/1 and, myasthenia gravis 1/1. During the study period 8/38 died: causes of death were cGVHD progression (n=3), disease relapse (n=1), infection (n=3), sudden death (n=1). The actuarial 2 year survival is currently 76%. We confirm that Rituximab is effective in over 50% of patients with refractory cGVHD and may have a beneficial impact on survival.

We report the final results of a prospective multi-centre trial testing the combination of chemotherapy (fludarabine, cytosine arabinoside and idarubicin; FLAI) followed by low-dose gemtuzumab ozogamicin (GO), for induction treatment of patients with CD33+ acute myeloid leukaemia (AML). Forty-six consecutive patients were treated: the median age was 66 (range: 60-80) years; the karyotype was unfavourable in 12 patients (26%), intermediate in 33 (71%) and favourable in one (3%). Eleven major infectious complications were recorded. There was one early death. Of the 45 evaluable patients, 24 achieved a complete response (CR; 52%), 66% and 33% in good-intermediate/poor karyotype patients. Median duration of CR was 7 (3-24) months. The cumulative incidence of relapse was 37% with an actuarial 2-year survival of 54%. These results were compared with 47 patients matched for age and karyotype who received FLAI, without GO. The proportion of patients achieving CR was comparable. However, patients with de novo AML receiving GO (n = 26) had a significantly lower risk of relapse at 2 years when compared with patients not receiving GO (n = 35) (40% vs. 80%, P = 0.01) and significantly better overall 2-year survival (40% vs. 14%P = 0.02). Patients with secondary AML had comparable outcome whether or not they received GO. This GO-based induction chemotherapy has a good toxicity profile. In keeping with a recent prospective randomised trial, the addition of GO seems to prolong disease-free survival.

A total of 315 patients who underwent allogeneic Hematopoietic Stem Cell Transplantation (HSCT) during a 4-year period were analysed with the aim of collecting information on bloodstream infections (BSI). Eighty-four patients (27%) developed 112 BSI, with a cumulative risk of 20.6% at 30 days and 27.7% at 180 days. Overall, 127 pathogens were isolated, 95 (75%) gram-positive cocci, 27 (21%) gram-negative rods and 5 (4%) fungi. Enterococcus sp. accounted for 46 of 127 (36%) isolates. In a multivariable analysis only including baseline factors, the type of transplant was the only factor significantly associated with the risk of BSI and the risk was higher for patients receiving transplant from mismatched or unrelated donors. In a case-control study aimed at evaluating the predictive role of additional factors during transplant, the risk appeared to be higher in patients with a positive CMV antigenemia (p = 0.03; OR of 4.82; 95% CI, 1.21-19.17), long duration of severe granulocytopenia (p = 0.015; OR 7.53; 95% CI, 1.92 - 29.58) and lower platelet count (p < 0.001; OR 0.14; 95% CI, 0.05 - 0.40). By day 180 post-transplant, 87 (28%) out of 314 patients had died. The cumulative risk of death was significantly higher among patients with BSI than among other patients.

We assessed the long-term outcome of patients with relapsed acute myeloid (n=86) or acute lymphoid leukemia (n=66), undergoing an allogeneic hemopoietic stem cell transplantation in our unit. The median blast count in the marrow was 30%. Conditioning regimen included total body irradiation (TBI) (10-12 Gy) in 115 patients. The donor was a matched donor (n=132) or a family mismatched donor (n=20). Twenty-two patients (15%) survive disease free, with a median follow-up of 14 years: 18 are off medications. The cumulative incidence of transplant related mortality is 40% and the cumulative incidence of relapse related death (RRD) is 45%. In multivariate analysis of survival, favorable predictors were chronic graft-versus-host disease (GvHD) (P=0.0003), donor other than family mismatched (P=0.02), donor age less than 34 years (P=0.02) and blast count less than 30% (P=0.07). Patients with all four favorable predictors had a 54% survival. In multivariate analysis of relapse, protective variables were the use of TBI (P=0.005) and cGvHD (P=0.01). This study confirms that a fraction of relapsed leukemias is cured with an allogeneic transplant: selection of patients with a blast count <30%, identification of young, human leukocyte antigen-matched donors and the use of total body radiation may significantly improve the outcome.

Background and Objectives: The aim of this study was to evaluate the incidence and outcome of invasive fungal infections (IFI) in patients with hematologic malignancies., Design and Methods: This was a retrospective cohort study of patients admitted between 1999 and 2003 to 18 hematology wards in Italy. Each participating center provided information on all patients with newly diagnosed hematologic malignancies admitted during the survery period and on all episodes of IFI experienced by these patients., Results: The cohort was formed of 11,802 patients with hematologic malignacies: acute leukemia (myeloid 3012, lymphoid 1173), chronic leukemia (myeloid 596, lymphoid 1104), lymphoma (Hodgkin's 844, non-Hodgkin's 3457), or multiple myeloma (1616). There were 538 proven or probable IFI (4.6%); 373 (69%) occurred in patients with acute myeloid leukemia. Over half (346/538) were caused by molds (2.9%), in most cases Aspergillus spp. (310/346). The 192 yeast infections (1.6%) included 175 cases of candidemia. Overall and IFI-attributable mortality rates were 2% (209/11802) and 39% (209/538), respectively. The highest IFI-attributable mortality rates were associated with zygomycosis (64%) followed by fusariosis (53%), aspergillosis (42%), and candidemia (33%)., Interpretation and Conclusions: Patients with hematologic malignancies are currently at higher risk of IFI caused by molds than by yeasts, and the incidence of IFI is highest among patients with acute myeloid leukemia. Aspergillus spp are still the most common pathogens, followed by Candida spp. Other agents are rare. The attributable mortality rate for aspergillosis has dropped from 60-70% to approximately 40%. Candidemia-related mortality remains within the 30-40% range reported in literature although the incidence has decreased.

A bone marrow harvest is filtered either in the operating room, in the laboratory or during infusion to the patient. Filters are usually discarded. Little is known of haemopoietic progenitor cells (HPCs) trapped in the filters. The aim of the study was to evaluate HPC content in the filters and to assess the outcome of transplants with filter-discarded or filter-recovered cells. Haemopoietic progenitors were grown from filters of 19 marrow transplants. We then compared the outcome of 39 filter-recovered transplants from HLA-identical siblings (years 2001-2004) with a matched cohort of 43 filter-discarded marrow grafts (years 1997-2000). Filters contained on average 21% long-term culture-initiating cells (LTC-IC) and 15% fibroblasts colony-forming units (CFU-F) of the total progenitor cell content. Filter-discarded transplants had significantly more grade II-IV graft-versus-host disease (GvHD) (42 vs 15%, P=0.008) as compared to filter-recovered transplants, and more transplant-related mortality (TRM) (20 vs 3%, P=0.04). The actuarial survival at 5 years is 69 vs 87%, respectively (P=0.15). This study suggests that a significant proportion of LTC-IC is lost in the filters together with CFU-F. Recovery and add back of progenitors trapped in the filters may reduce GvHD and TRM.

Background and Objectives: A proportion of patients develop poor graft function (PGF) following an allogeneic hemopoietic stem cell transplant (HSCT). It is uncertain whether a boost of donor marrow or blood cells is beneficial in terms of trilineage recovery and non-relapse-related mortality (NRM)., Design and Methods: The aim of this study was to compare outcomes in patients with PGF and full donor chimerism following an allogeneic HSCT who did or did not receive a boost of donor stem cells. The study included patients with primary PGF--i.e. those failing to achieve sustained graft function- and secondary PGF--i.e. those developing PGF after complete hematologic recovery. We studied 54 patients with PGF: 20 patients received no further donor cell infusion (group A), 14 received a boost of unmanipulated marrow or blood cells from the original donor, without further conditioning (group B), and 20 received donor cells after CD34 selection without conditioning (group C). The three groups were comparable for disease phase, patients' age, donor type, primary or secondary PGF, full donor chimerism and duration of PGF., Results: Trilineage recovery was seen in 40%, 36% and 75% of the patients in, respectively, groups A, B and C (p=0.02). In multivariate Cox analysis trilineage recovery was more frequent in patients with secondary PGF (RR of complete recovery 2.82, p=0.01) and in patients receiving CD34+-selected cells (RR of complete recovery 3.0; p=0.007). There was no effect of donor type on hematologic recovery. The rate of NRM was 55%, 64%, 20% in groups A, B and C, respectively (p=0.06) and was highly correlated with trilineage recovery (RR 0.36, p<0.0001). PGF was the primary cause of death in 30%, 21% and 10% of the patients in the three groups, graft-versus-host disease (GVHD) in 5%, 36%, and 10%., Interpretations and Conclusions: In patients with poor graft function (a) a boost of CD34+-selected peripheral blood donor cells is associated with a high chance of trilineage recovery and a low risk of acute GVHD; (b) a boost of unmanipulated donor cells does not seem to offer a survival advantage over no infusion of cells; and (c) NRM is lower when using peripheral blood cells for the boost. These data may be useful when discussing second stem cell donations for patients with poor graft function.

Newly diagnosed patients with acute graft-versus-host disease (GvHD, grades I-IV; n = 211) were given 6-methylprednisolone (6MPred) 2 mg/kg per day for 5 consecutive days; 150 patients (71%) tapered 6MPred on day +5 and were considered responders; 61 patients (29%) could not taper their steroid dose and were considered nonresponders. The cumulative incidence of transplant-related mortality (TRM) for responders and nonresponders is, respectively, 27% and 49% (P = .009), and the 5-year survival is 53% and 35% (P = .007). Nonresponders on day +5 (n = 61) were randomized to receive 6MPred 5 mg/kg per day for 10 days alone (n = 34) or in combination with rabbit anti-thymocyte globulin (ATG, 6.25 mg/kg in 10 days; n = 27). The 2 groups were balanced for clinical and GvHD characteristics. One month after randomization, 26% had a complete response; 23%, a partial response; 33%, stable GvHD; 10%, worsened; and 8%, died. There was no significant difference in response, TRM, and survival between the non-ATG and ATG group. In conclusion, 5 days of prednisolone as first-line therapy of acute GvHD identifies patients with different risk of TRM, and second-line therapy with a combination of 6MPred + ATG does not improve patient outcome, compared with 6MPred alone.

This is an update of a randomized study on antithymocyte globulin (ATG; Thymoglobulin) before transplantation in patients undergoing unmanipulated marrow transplantation from unrelated donors. The median follow-up for surviving patients is 5.7 years. At last follow-up, chronic graft-versus-host disease (GVHD) was scored in 60% of non-ATG and in 37% of ATG patients (P=.05), and extensive chronic GVHD was present in 41% and 15%, respectively (P=.01). Chronic lung dysfunction was diagnosed in 51% versus 19% of patients (P=.005). Forced vital capacity decreased significantly with time in non-ATG patients (P=.005), but not in patients who received ATG (P=.30). The proportion of patients with Karnofsky scores of >or=90% at 4 years was 57% versus 89% in non-ATG versus ATG patients (P=.03). The actuarial 6-year survival for all patients randomized was 31% versus 44% (non-ATG versus ATG; P=.80). The cumulative incidence of transplant-related mortality was 51% versus 41% (P=.70) and of relapse was 32% versus 40% (P=.90). For patients who survived 1 year, transplant-related mortality was 25% versus 3% (P=.03), and actuarial survival was 58% versus 85% (P=.09). In conclusion, the addition of ATG to cyclosporine/methotrexate provides significant protection against extensive chronic GVHD and chronic lung dysfunction, reduces late transplant mortality, and improves quality of life in patients undergoing unrelated donor transplantation.

More than 40000 hematopoietic cell transplants (HCTs) are performed worldwide each year. With improvements in transplant technology, larger numbers of transplant recipients survive free of the disease for which they were transplanted. However, there are late complications that can cause substantial morbidity. Many survivors are no longer under the care of transplant centers, and many community health care providers may be unfamiliar with health matters relevant to HCT. The Center for International Blood and Marrow Transplant Research (CIBMTR), European Group for Blood and Marrow Transplantation (EBMT), and American Society for Bone Marrow Transplantation (ASBMT) have developed these recommendations to offer care providers suggested screening and prevention practices for autologous and allogeneic HCT survivors.

More than 40,000 hematopoietic cell transplants (HCTs) are performed worldwide each year. With improvements in transplant technology, larger numbers of transplant recipients survive free of the disease for which they were transplanted. However, there are late complications that can cause substantial morbidity. Many survivors are no longer under the care of transplant centers and many community health-care providers may be unfamiliar with health matters relevant to HCT. The Center for International Blood and Marrow Transplant Research (CIBMTR), European Group for Blood and Marrow Transplantation (EBMT), and American Society for Blood and Marrow Transplantation (ASBMT) have developed these recommendations to offer care providers suggested screening and prevention practices for autologous and allogeneic HCT survivors.

Autologous haematopoietic stem cell transplantation has become an accepted powerful therapeutic procedure for patients with severe, intractable SLE. Here we describe a 26-year old patient with stage IV-G diffuse global proliferative lupus nephritis and refractory nephrotic syndrome who responded to autologous peripheral stem cell transplantation (ASCT) after two mobilization procedures. Five years later the patient is in complete clinical and immunologic remission. The indications for ASCT and its mechanism of action are briefly discussed.

Objective: To compare the suppressive effect of mesenchymal stem cells (MSC), derived from normal individuals or severe aplastic anemia patients (SAA), on T-cell activation., Patients and Methods: We studied bone marrow MSC from 19 healthy donors and 23 SAA patients in different phases of the disease: at diagnosis (n = 3), following immunosuppressive therapy (IS) (n = 16), or after a bone marrow transplant (BMT) (n = 4). MSC were tested for T-cell suppression in the following assays: mixed lymphocyte reaction (MLR), phytohemaglutinin (PHA)-primed cultures, activation surface markers, gamma-IFN production, hematopoietic colony formation (CFC), production of cyclic ADP-ribose (cADPR)., Results: The abnormalities of SAA MSC included: 1) significantly lower suppression of T-cell proliferation induced by alloantigens (p = 0.009) or PHA (p = 0.006); 2) impaired capacity to suppress CD38 expression on PHA-primed T cells (p = 0.001); 3) impaired ability to suppress gamma-IFN production in PHA cultures, resulting in an 11-fold higher gamma-IFN concentration; 4) no preventive effect on T cell-mediated inhibition of CFC; and 5) significantly reduced (p = 0.009) production of cADPR, a universal calcium mobilizer. MSC-mediated suppression of PHA-induced T-cell proliferation was restored to control levels in 3 of 4 patients post-BMT., Conclusion: The ability of MSC to downregulate T-cell priming, proliferation, and cytokine release is deficient in patients with SAA, persists indefinitely after immunosuppressive therapy, but seems to be restored after BMT. Whether these abnormalities are relevant to the pathogenesis of aplastic anemia remains to be determined.

Background and Objectives: Transplant-related mortality (TRM) following allogeneic hematopoietic stem cell transplantation (HSCT) has been reported to be related to disease stage, duratiion of disease and type of donor. Furthermore, the outcome of transplants performed in the 1990s appears to be better than that of transplants done in the previous decade. The aims of this study were to determine whether these relationships still hold and whether the outcome of transplants is continuing to improve., Design and Methods: We analyzed 1180 consecutive patients with leukemia (n=979) or other hematologic malignancies (n=201) undergoing HSCT in 4 time periods: before 1990, 1991-1995, 1996-2000, and 2001-2002. Changes during these eras include increasing patient age, more unrelated transplants, more patients with advanced disease, different graft-versus-host disease (GvHD) prophylaxis, and different management of infections., Results: The actuarial 2-year transplant-related mortality (TRM) differed significantly between the transplant eras (p<0.001) with a significant interaction with disease phase (p=0.018). In patients in first remission (n=585) TRM was 34%, 25%, 21% and 6% in the four transplant eras. The reduction in TRM was less evident in patients in second remission (n=284) (37%, 35%, 30%, 25%) and absent in relapsed patients (n=311) (TRM=45%, 41%, 29%, 51%). This is a consequence of reductions in GvHD, infections and multiorgan failure among patients in remission but not among those who relapse. The actuarial 2-year survival has improved significantly in patients in first remission (54%, 66%, 72%, 78%) but not in those in second remission (38%, 46%, 52%,45%), or relapsed patients (31%, 25%, 36%, 21%)., Interpretation and Conclusions: In conclusion, TRM has been significantly reduced in first remission patients, suggesting an allograft should be considered in this phase, when appropriate, without delay. There has been no improvement in survival for patients beyond first remission, due to persisting high risk of infections and organ toxicity, a possible consequence of prolonged pre-transplant chemotherapy and neutropenia.

At the bone marrow transplantation center of the San Martino Hospital (Genoa), we observed an increase in the rate of patients with positive Platelia Aspergillus (PA; Bio-Rad) test results, from 10% (38 of 386 patients) in the period from January 1999 through January 2003 to 36% (21 of 59 patients) in the period from February 2003 through May 2003. Positivity was significantly (P<.001) associated with the administration of piperacillin-tazobactam (PT) (17 [74%] of 23 patients who received PT had positive results vs. 4 [11%] of 36 who did not receive PT). Multivariate analysis found administration of PT ( chi 2=34.7; P<.001) and underlying disease ( chi 2=21.14; P<.001) to be associated with PA positivity. Of 15 PT batches tested, 12 had positive PA test results.

Background and Objectives: Graft-versus-host disease (GVHD) is a complex syndrome observed after bone marrow transplantation (BMT) affecting several organs including the lower genital female tract. We tried to evaluate the incidence of genital tract involvement and whether there are specific risk factors., Design and Methods: A retrospective study was conducted in order to describe genital manifestations of GVHD and evaluate its incidence, severity and remission among 213 females who underwent BMT. The risk factors studied were previous pregnancies, vaginal cultures just before BMT and hormonal replacement therapy (HRT)., Results: Genital lesions considered as expression of GVHD were found in 53 patients (24.9%). They appeared in the first 100 days after BMT in 12 women and beyond in 41 cases. Seventy-three percent of patients with such lesions showed some evidence of chronic GVHD elsewhere. The proposed grading, the first attempt of its kind, showed that genital chronic GVHD was minimal in 66%, moderate in 22% and severe in 12% of patients. Vaginal fibrosis, sometimes with complete obstruction, was seen in this last form. This occurred in 86.8% of patients after 2-157 months (median 22) while persistent GVHD was observed in 7 of them. In our sample no significant association was found between genital GVHD and previous pregnancies or vaginal infections at BMT, while HRT seems poorly associated with gynecological manifestations of GVHD (p=0.049)., Interpretation and Conclusions: Genital GVHD is not unusual after BMT. It can seriously affect female sexuality and the overall quality of life. We suggest stressing the importance of early detection of genital involvement in order to prevent the most serious lesions. Further studies are needed to identify the triggering factors associated with the development of genital GVHD.

We have previously described a scoring system for patients undergoing hemopoietic stem cell transplantation (HSCT) based on day +7 blood urea nitrogen (BUN) and serum bilirubin levels. We have revised that scoring system using a formal multivariate approach based on a training phase (305 patients) and a validation phase (217 patients). Day +7 BUN, serum cholinesterase (CHE), total proteins (TP), gamma glutamyl transferase (gammaGT), donor type and cell dose at transplant were included in the new score. The score distribution identified three groups of patients in the training set (<25, 25-75, >75 percentile of the score) which were classified as low, intermediate and high risk. Their actuarial risk of transplant-related mortality (TRM) at 6 years was, respectively, 12, 38 and 60%. In the validation set the 6 year actuarial TRM was, respectively, 15, 40 and 69%. High risk patients had more graft-versus-host disease (GvHD) (P <0.0001) and lower platelet counts (P <0.0001). This study confirms that GvHD and TRM can be predicted on day +7 after HSCT: pre-emptive GvHD therapy may be one option for high-risk patients and is being tested in a prospective randomized trial. The score for single patients can be calculated on the web site http://213.26.110.20/lrm/day&#95;seven&#95;score.html.

In the present study, we analyze factors predicting graft-versus-host disease (GvHD) and response after donor lymphocyte infusions (DLI). A total of 100 patients received 593 DLI between June 1990 and December 2000 in a bulk dose (n=14) or in escalating dose infusions (n=86). Patients were analyzed after stratification for type of relapse: (1). molecular relapse (n=6), (2). cytogenetic relapse (n=20), (3). chronic phase of chronic myeloid leukemia (CML) or complete remission of other disease post chemotherapy (n=24), (4). CML in accelerated/blastic phase (n=14), (5). resistant disease not responding to chemotherapy (n=36). The proportion of responders to DLI in these five groups was 100, 90, 75, 36 and 0% (P<0.0001). Factors predicting response by multivariate analysis were type of relapse (P<0.0001), post-DLI GvHD (P=0.005), pancytopenia (P=0.008), and a diagnosis of CML (P=0.04). Acute GvHD (grades II-IV) occurred in 21 patients (21%), and correlated in multivariate analysis with pancytopenia and less than four DLI. Other predictors of GvHD were the number of CD3+cells/infusion and serum levels of gamma-glutamyl transferase (gammaGT). The actuarial probability of treatment-related mortality was 9% for HLA identical siblings and 44% for alternative donor transplants (P=0.006). Response to DLI is predicted by tumor burden and is associated with GvHD and pancytopenia.

Evans' syndrome, a combination of autoimmune haemolytic anaemia and autoimmune (idiopathic) thrombocytopenic purpura, is generally harder to treat and more refractory than the single entities. In a male patient with refractory disease, predominantly thrombocytopenic, an allogeneic reduced intensity BMT from his human leukocyte antigen (HLA)-identical sister was followed by a dramatic platelet peak while he was still experiencing initial engraftment (presumably of autologous origin), but subsequently by progressive relapse associated with mixed chimerism. Five gradually incremental DLI achieved complete donor chimerism, which was associated not only with grade II graft-versus-host disease (GVHD), but also with complete clinical and biological remission for 2 years post-transplant. Long-term FU is necessary before claiming that allogeneic stem cell transplantation (SCT) is capable of curing an autoimmune blood disease. However, there is evidence for a graft-versus-autoimmunity effect in this case.

We have studied the impact of cell dose on short- and long-term graft function and outcome in 905 patients undergoing an unmanipulated allogeneic bone marrow transplantation (BMT) from an HLA-identical sibling (n = 735), a one-antigen mismatched related donor (n = 35), or a matched unrelated donor (n = 135). Median number of nucleated cells infused was 3.4 x 10(8)/kg (25th percentile 2.4 x 10(8)/kg, 75th percentile 5 x 10(8)/kg). Patients were stratified according to cells infused in 3 groups: < or = 2.4 x 10(8)/kg (n = 247; low dose); >2.4 x 10(8)/kg and < or = 5 x 10(8)/kg (n = 452; intermediate dose); and >5 x 10(8)/kg (n = 206; high dose). Patients receiving high cell dose had significantly higher platelet counts on days +20, +50, +100, +180, and +365 after BMT (P <.01) and higher white blood cell counts on days +50, +100, and +180 after BMT (P <.01) as compared with other patients. The actuarial 5-year transplant-related mortality (TRM) was 41% versus 36% versus 28% (P =.01); overall survival was 45% versus 51% versus 56% (P =.0008); and disease-free survival was 41% versus 42% versus 48%, respectively, (P =.04) in patients receiving low, intermediate, or high cell dose. The cell dose effect was more pronounced in patients older than 30 years of age, with advanced disease, with chronic myeloid leukemia, and with alternative donors. In multivariate Cox analysis on TRM, cell dose was a significant predictor (P =.002; relative risk 0.6) together with donor type (P =.0001), year of transplantation (P =.0001), conditioning regimen (P =.02), and recipient age (P =.02). In conclusion, transplantation of high marrow cell dose is associated with reduced transplant mortality and improved survival and results in improved graft function both short and long term.

Background and Objectives: The efficacy of antithymocyte globulin (ATG) in the treatment of graft-versus-host disease (GvHD) is controversial. In the present study we report on the use of low dose ATG (thymoglobuline, Sangstat) and steroids in 28 patients with moderate to severe acute GvHD., Design and Methods: Fifteen patients received ATG as first-line treatment within 14 days of the diagnosis of GvHD (median 8 days, range 4-13). Twelve patients received ATG as second-line therapy, more than 14 days after diagnosis (median 32 days, range 14 to 98). The proportion of patients with severe (grade III-IV) GvHD at the time of ATG therapy was 4/15 in the former group and 7/13 in the latter (p=0.1)., Results: On day 30 after ATG the overall proportion of responders was 80% in the group administered ATG early and 38% in those given it later (p=0.03). The overall actuarial 3-year transplant-related mortality was 40% vs 74% for the early vs late ATG groups (p=0.03); the actuarial 3-year survival was, respectively, 49% vs 23% (p=0.04). For patients with GvHD grade III-IV the actuarial 1-year TRM was 47% for those given ATG early, 87% for the late ATG group and 82% for a concurrent control group of 26 patients not treated with ATG., Interpretation and Conclusions: In conclusion, ATG may be considered for early treatment of acute GvHD, within a few days from the onset of the disease. A prospective trial has been started to test whether, in this setting, low dose ATG with steroids is superior to steroids alone.

Background and Objectives: Peripheral blood (PB) stem cell transplants are being increasingly used in the allogeneic setting, and are often preferred to the conventional bone marrow (BM) source. The aim of this report is to review available data on PB vs BM hematopoietic stem cell transplantation (HSCT). The discussion is restricted to unmanipulated HLA identical sibling transplants., Evidence and Information Sources: Data with appropriate follow-up are available only for this type of comparison: we have preliminary data on the use of PB from unrelated donors, and on the use of T-cell depletion/CD34+ selection methods. The latter are rapidly evolving and it may be difficult to find a concurrent group of patients receiving T-cell depleted or CD34-selected marrow., State of Art: The results of retrospective and prospective studies are quite similar: hematologic and immune recovery is faster after PB grafts, acute graft-versus-host disease (GvHD) is comparable, whereas chronic GvHD is increased in recipients of PB transplants. Transplant-related mortality (TRM) is similar in the two groups, whereas disease recurrence is lower after PB grafts., Perspectives: The general feeling is that PB grafts are indicated for patients with advanced disease, whereas for early phase patients the two sources may give comparable results.

Several lines of experimental evidence suggest that sex hormones may influence the development and activity of chronic graft-versus-host disease (cGVHD), which frequently occurs in patients undergoing allogeneic bone marrow transplantation (ABMT). Following ABMT, young women are commonly treated with hormone replacement therapy (HRT) because of irreversible gonadal failure. It seemed therefore worthwhile to investigate the effects of this therapy on the activity of cGVHD. Premenopausal women treated with ABMT for hematological malignancies between January 1997 and December 2000 were evaluated for cGVHD activity. They were divided into two groups, depending on whether or not they were treated with HRT. Seventy-one women qualified for the present study: 39 received HRT (treated group), while 32 did not (controls). In both groups of patients, cGVHD activity score was comparable before the start of HRT. No differences were observed in cGVHD activity score between the HRT group and controls after 3, 6, 12, and 24 months from the start of HRT. Furthermore, HRT did not induce any increase in the cGVHD activity score in the treated group of patients at any time from the start of HRT. According to present data, HRT did not appear to influence the activity of cGVHD in young women who underwent ABMT for hematological malignancies. Therefore, we can safely propose this therapy for women with gonadal failure after ABMT.

The Aspergillus galactomannan test was performed on cerebrospinal fluid and serum samples from 5 patients with probable cerebral aspergillosis and from 16 control patients. Cerebrospinal fluid galactomannan levels were significantly higher in aspergillosis patients, and most galactomannan was produced intrathecally. Comparison of serum galactomannan values in pulmonary and cerebral aspergillosis patients showed significant overlapping. Detection of Aspergillus galactomannan in cerebrospinal fluid may be diagnostic of cerebral aspergillosis.

We studied the impact of preparative regimens with or without antithymocyte globulin (ATG) on chronic GVHD in 160 patients undergoing marrow transplants from unrelated donors (n = 127) or partially mismatched related donors (n = 33). A conditioning regimen that included rabbit ATG, 7.5 to 15 mg/kg (Thymoglobuline; Sangstat, Lyon, France), was given to 102 patients, whereas a conditioning regimen without ATG was given to 58 patients. The median patient age was 34 years for the ATG group and 29 years for the non-ATG group (P = .002); otherwise the 2 groups were matched for disease phase, diagnosis, donor age, interval from diagnosis to transplantation, and number of cells infused at the time of transplant. Median follow-up for surviving patients was 4.5 years (range, l.5-9 years). The conditioning regimen was cyclophosphamide (CY) and total body irradiation (TBI) in 95 patients and CY-thiotepa in 65 patients; the source of stem cells was bone marrow for all patients. Acute GVHD grades II-IV and grades III-IV were reduced in patients receiving ATG compared to patients not receiving ATG (51% versus 74%, P = .004 and 14% versus 28%, P = .03, respectively). There were significantly fewer patients with chronic GVHD in the ATG group than in the non-ATG group at 6 months (14% versus 30%, P = .03), 1 year (7% versus 41%, P = .0001), 2 years (16% versus 36%, P = .02), and 4 years (5% versus 34%, P = .002) and beyond 4 years (0% in 19 patients at risk versus 29% in 24 patients at risk, P = .01). More patients in the ATG group than in the non-ATG group had a performance status (Karnowski score) greater than 90 at last follow-up (93% versus 56%, P = .01) and had discontinued cyclosporin treatment 2 years posttransplant (28% versus 3%, P = .003). Survival rates were comparable in the ATG and non-ATG groups for patients who received TBI (56% versus 59%, P = .7) and those who received thiotepa (33% versus 18%, P = .3). Transplant mortality and relapse rates were also comparable in the 2 groups for these patients. We conclude that pretransplant ATG administration reduces the risk of acute and chronic GVHD, improves quality of life, and increases the likelihood that discontinuation of immunosuppressive therapy will be possible.

One hundred nine patients with hematologic malignancies, undergoing bone marrow transplants (BMT) from unrelated donors, were randomized in 2 consecutive trials to receive or not to receive antithymocyte globulin (ATG) in the conditioning regimen, as follows: (A) 54 patients (median age, 28 years; 39% with advanced disease) were randomized to no ATG (n = 25) versus 7.5 mg/kg rabbit ATG (Thymoglobulin; Sangstat, Lyon, France) (n = 29); (B) 55 patients (median age, 31 years, 71% with advanced disease) were randomized to no ATG (n = 28) versus 15 mg/kg rabbit ATG (n = 27). Grade III-IV graft-versus-host disease (GVHD) was diagnosed in 36% versus 41% (P =.8) in the first and in 50% versus 11% (P =.001) in the second trial. Transplant-related mortality (TRM), relapse, and actuarial 3-year survival rates were comparable in both trials. In fact, despite the reduction of GVHD in the second trial, a higher risk for lethal infections (30% vs 7%; P =.02) was seen in the arm given 15 mg/kg ATG. Extensive chronic GVHD developed overall more frequently in patients given no ATG (62% vs 39%; P =.04), as confirmed by multivariate analysis (P =.03). Time to 50 x 10(9)/L platelets was comparable in the first trial (21 vs 24 days; P =.3) and delayed in the ATG arm in the second trial (23 vs 38 days; P =.02). These trials suggest that (1) 15 mg/kg ATG before BMT significantly reduces the risk for grade III-IV acute GVHD, (2) this does not translate to a reduction in TRM because of the increased risk for infections, and (3) though survival is unchanged, extensive chronic GVHD is significantly reduced in patients receiving ATG.

Background and Objectives: The risk of relapse after autologous bone marrow transplantation (ASCT) is high and is related to the type of malignancy and phase of the disease. The outcome for the patient who relapses after an autologous transplant is poor. Some of these patients achieve a remission with conventional chemotherapy, but it is usually short-lasting. Most of them succumb to the original disease. One further therapeutic possibility is an allogeneic transplant which would confer the potential advantage of a graft-versus-leukemia effect in addition to the lack of tumor contamination of the graft and to a high-dose intensity conditioning regimen., Design and Methods: We have studied the outcome of 31 patients with hematologic malignancies who underwent an allogeneic hematopoietic stem cell transplant (HSCT) after failing an autologous transplant because of relapse (n=29) or persistent aplasia (n=2). The median age at allograft was 36 years (18-55) and the interval from autograft to allograft was 21 months (3-141). The source of stem-cells was unmanipulated bone marrow (n=26) or growth-factor-mobilized peripheral blood (n=5). The donor was an HLA-identical sibling (n=7), or an alternative donor (n=24) (family mismatched n=11, or matched unrelated n=13). The conditioning regimen was cyclophosphamide and thiotepa (n=22), or cyclophosphamide and total body irradiation (n=9) Graft-versus-host disease (GvHD) prophylaxis consisted of cyclosporine (CyA) + methotrexate (MTX)., Results: Acute GvHD was scored as 0-I, II, or III-IV in 39%, 48%, and 13% of the patients, respectively. Sixteen patients died of transplant-related complications and one of progressive disease. With a median follow-up of 220 days (9-2104) the actuarial 2-year transplant-related mortality (TRM) was 51%, the actuarial relapse risk 37%, the actuarial survival 46%. Fifteen patients (48%) are alive in complete remission, with a median follow-up of 32 months (range 2-71)., Interpretation and Conclusions: These data suggest that patients relapsing after an autotransplant should be screened for potential related or unrelated donors: although TRM remains high there is a definite chance of long-term disease-free survival if these patients are allografted.

Platelet recovery after allogeneic haemopoietic stem cell transplant (HSCT) and predictive factors were analysed in 342 patients with haematological malignancies. All patients were prepared with cyclophosphamide plus total body irradiation, and received an unmanipulated HSCT from an HLA-identical sibling (n = 270), a matched unrelated donor (n = 67) or an identical twin (n = 5). The source of stem cells was peripheral blood (n = 15) or bone marrow (n = 327). Graft-vs.-host disease (GvHD) prophylaxis consisted of cyclosporin A with or without methotrexate. The proportion of patients with < 50 x 10(9)/l platelets on d +50, d +100, d +200 and d +365 after HSCT was 26%, 27%, 14% and 11% respectively. Thrombocytopenia was independent of the degree of complete donor chimaerism. Four variables were predictive of platelet recovery: donor type, acute GvHD, cytomegalovirus (CMV) infection and number of cells infused at transplant. Recipients of an unrelated graft had lower platelet counts (49 x 10(9)/l) on d +50 than identical sibling grafts (10(8) x 10(9)/l) (P < 0.001) and twin grafts (149 x 10(9)/l) (P < 0.001). Patients with GvHD grades 0, I, II, III and IV had significantly different platelet counts on d +50 (153 x 10(9)/l, 102 x 10(9)/l, 85 x 10(9)/l, 32 x 10(9)/l and 22 x 10(9)/l; P < 0.001) and thereafter. Thrombocytopenia was more frequent in patients with high-level CMV antigenaemia (> four positive cells/2 x 105) (P < 0.0001) and in patients who received a low cell dose at transplant (< or = 4.1 x 10(8)/kg) (P = 0.009). Platelet counts predicted transplant-related mortality (TRM) and were higher at all time intervals in patients surviving the transplant. Patients with grade II GvHD and > 50 x 10(9)/l platelets had a lower TRM than patients with grade II GvHD and < or = 50 x 10(9)/l platelets (14% vs. 40%, P < 0.0001). In conclusion, (i) a significant proportion of allogeneic HSCT recipients are thrombocytopenic long-term, irrespective of complete donor chimaerism, (ii) thrombocytopenia identifies patients at greater risk of lethal complications, and (iii) platelet recovery is influenced by GvHD, donor type, CMV infections and cell dose, not by stem cell source or other patient-disease-related variables.

Peripheral blood stem cell transplants are being increasingly used in the allogeneic setting and are often preferred to the conventional bone marrow source. The aim of this report is to review available data on peripheral blood versus bone marrow hematopoietic stem cell transplantation. The discussion is restricted to HLA-identical sibling transplants receiving unmanipulated grafts. This is because data with appropriate follow-up are available only for this type of comparison: we have preliminary data on the use of peripheral blood from unrelated donors, and on the use of T-cell depletion/CD34+ selection methods. The latter are evolving rapidly and it may be difficult to find a concurrent group of patients receiving T-cell-depleted or CD34-selected marrow. The results of retrospective and prospective studies are similar: hematologic and immune recovery are faster after peripheral blood grafts, acute graft-versus-host disease is comparable, whereas chronic graft-versus-host disease is increased in recipients of peripheral blood transplants. Transplant-related mortality is similar in the two groups, whereas disease recurrence is lower after peripheral blood grafts. The general opinion is that peripheral blood grafts are indicated for patients with advanced disease, whereas for patients with early-phase disease the two sources may give comparable results.

Since 1989 we have been collecting dry-platelets on a routine basis. Dry-platelets are those collected along with 25-30 ml of contaminating plasma cell with separators such as the Amicus, AS 104 and the Excel Pro. Platelets are resuspended in non plasma media for storage and for at least 60 hours their viability and functionality are not impaired. In this article we report on two hemolytic crises determined by two O Rh D + units of single donor platelets (SPD) taken from the same donor in a double-apheresis session. The two split units were administered to two A Rh D + patients suffering from metastatic breast cancer and severe aplastic anemia (SAA) respectively. In both cases the hemolytic reaction was of the intravascular type, with a drop in hemoglobin (Hgb) level from 8.6 to 5.4 and from 8.8 down to 5.3 g/dl respectively. From the patients' RBC only alpha agglutinins were eluted and donor's indirect antiglobulin test (IAT) was negative with extended panel RBCs. In the first case the clinical course after erythroexchange (Erex) was uneventful whereas in the second one, that suffering from SAA, after Erex, acute renal failure and shock did complicate the clinical course and the patient died seven days after the incriminated platelet transfusion.

The number of long-term survivors after allogeneic bone marrow transplantation (BMT) has been increasing over the past years, and quality of life (QOL) has become an important end-point. We studied 244 patients undergoing an allogeneic BMT to identify factors and events influencing psychosocial outcome. Patients enrolled received the Psychosocial Adjustment to Illness Scale (PAIS) questionnaire assessing psychological and social adjustment to chronic illness or its sequelae. Eighty-two per cent of patients had a haematological disease. The median age was 28 years at BMT, and the median follow-up was 61 months. The median overall PAIS score for all patients was 56 (range 22-76): 25% (n = 61) of patients were considered to have a good QOL ( 75 percentile score). Factors associated with a poor QOL in multivariate analysis were: patients' age at BMT (> 25 years, P < 0.01); presence of long-term sequelae (P < 0.01); chronic graft-versus-host disease (GVHD) (P < 0.05); and a short interval from BMT (< 5 years; P < 0.05). The QOL improved with time: 12% of patients reported a good QOL within 5 years compared with 38% after this time point and, conversely, 38% reported a poor QOL within 5 years compared with 24% after this time point (P < 0. 0001). Older patients had significantly poorer QOL compared with younger patients (< or = 25 years; P = 0.01). Females had significantly poorer scores when compared with males in the sexual (P < 0.0001) and psychological domains (P = 0.001). The data suggest that (i) one-third of patients undergoing allogeneic BMT report a poor QOL; (ii) factors associated with poor QOL are older age, presence of long-term sequelae, chronic GVHD and short follow-up; (iii) QOL is superior in long-term survivors; and (iv) BMT affects different aspects of life in males and females. A longitudinal study is ongoing to prove the effect of time on quality of life.

A randomized trial was carried out comparing cyclosporin A (CsA) and short-term methotrexate (MTX) versus CsA alone for graft versus host disease (GVHD) prophylaxis in patients with severe aplastic anemia (SAA) undergoing allogeneic bone marrow transplantation (BMT) from a compatible sibling. Seventy-one patients (median age, 19 years; range, 4-46 years) were randomized to receive either CsA and MTX or CsA alone for the first 3 weeks after BMT. Subsequently, both groups received CsA orally, with gradual drug reduction until discontinuation 8 to 12 months after BMT. Patients randomized in both arms had comparable characteristics and received the same preparative regimen (ie, cyclophosphamide 200 mg/kg over 4 days). The median time for neutrophil engraftment was 17 days (range, 11-31 days) and 12 days (range, 4-45 days) for patients in the CsA/MTX group and the CsA alone group, respectively (P =.01). No significant difference was observed in the probability of either grade 2, grade 3, or grade 4 acute GVHD or chronic GVHD developing in the 2 groups. The Kaplan-Meier estimates of 1-year transplantation-related mortality rates for patients given either CsA/MTX or CsA alone were 3% and 15%, respectively (P =.07). With a median follow-up of 48 months from BMT, the 5-year survival probability is 94% for patients in the CsA/MTX group and 78% for those in the CsA alone group (P =. 05). These data indicate that the use of CsA with MTX is associated with improved survival in patients with SAA who receive transplants from compatible siblings. (Blood. 2000;96:1690-1697)

This report describes the diagnosis and management of a 16-year-old boy who developed neurological signs and symptoms suggestive of cerebral aspergillosis following a haploidentical bone marrow transplant. A new sandwich enzyme-linked immunosorbent assay (ELISA) for the detection of Aspergillus galactomannan circulating antigens (Platelia Aspergillus, Sanofi Diagnostic Pasteur, France) was used on serum and cerebrospinal fluid to obtain a presumptive diagnosis and to monitor the course of the disease. Having failed conventional therapy with amphotericin B, the patient received compassionate treatment with voriconazole for a period of 37 days. High levels of voriconazole were observed in both serum and cerebrospinal fluid (CSF), with a trend toward accumulation. After 7 days a marked improvement in the patient's neurological symptoms was noted, and ELISA data indicated a corresponding decrease in Aspergillus galactomannan levels in both serum and CSF. Voriconazole was well tolerated, with only transient increases in ALT/AST recorded during therapy. Although the patient survived the acute Aspergillus infection, he subsequently died of an unrelated infection.

Unlabelled: Transplant-related mortality (TRM) remains a major problem in older patients undergoing allogeneic haemopoietic stem cell transplants (HSCTs). We have therefore explored a less intensive conditioning in 33 patients with a median age of 52 years (range 43-60) transplanted from human leucocyte antigen (HLA)-identical siblings. The underlying disease was chronic myeloid leukaemia (n = 15), acute myeloid leukaemia (n = 6), myelodysplasia (n = 7) or a chronic lymphoproliferative disorder (n = 5); 15 patients (45%) had advanced disease. The regimen consisted of thiotepa (THIO; 10 mg/kg) on day -5 and cyclophosphamide (CY; 50 mg/kg) on days -3 and -2 (total dose 100 mg/kg). The source was bone marrow (BM) (n = 17) or granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood (PB) (n = 16), which were infused without manipulation. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporin A (CyA) and a short course of methotrexate. Mean time to achieve a neutrophil count of 0.5 x 109/l was 17 d (range 11-23) and full donor chimaerism was detected in 79% of patients by day 100. Acute GVHD grade III or IV occurred in 3% of patients. Chronic GVHD was seen in 45% of patients, with a significant difference for PB (69%) compared with BM transplants (23%) (P = 0.009). For BM grafts, the actuarial 2-year TRM was 6%, the relapse 56% and survival 87%; for PB grafts, these figures were, respectively, 27%, 33% and 68%. Twenty-five patients are alive at a median follow-up of 762 d (range 216-1615) and 20 patients (60%) remain free of disease. Thirteen patients (39%) received donor lymphocyte infusion (DLI) either for persisting or relapsing disease and six patients had complete remission., In Conclusion: (i) patients up to the age of 60 years can be allografted with reduced intensity conditioning; (ii) the procedure was associated with a low transplant-related mortality, particularly for bone marrow grafts, because of a lower risk of chronic GVHD; and (iii) DLI were required after transplant in half the patients for persisting disease or relapse.

We have analyzed 2,002 patients grafted in Europe between 1976 and 1998 from an identical twin (n = 34), from an HLA-identical sibling (n = 1,699) or from an alternative donor (n = 269), which included unrelated and family mismatched donors. The proportions of patients surviving in these three groups are, respectively, 91, 66 and 37%: major causes of failure were acute graft-versus host disease (GvHD) (11%), infection (12%), pneumonitis (4%), rejection (4%). In multivariate Cox analysis, factors predicting outcome were patient's age (p < 0.0001), donor type (p < 0.0001), interval between diagnosis and bone marrow transplantation (BMT) (p < 0.0005), year of BMT (p = 0.0005) and female donor for a male recipient (p = 0.02). Patients were then divided in two groups according to the year of BMT: up to or after 1990. The overall death rate dropped from 43 to 24% (p < 0.00001). Improvements were seen mostly for grafts from identical siblings (from 54 to 75%, p < 0.0001), and less so for alternative-donor grafts (from 28 to 35%; p = 0.07). Major changes have occurred in the BMT protocol: decreasing use of radiotherapy in the conditioning regimen (from 35 to 24%; p < 0.0001) and increasing use of cyclosporin (with or without methotrexate) for GvHD prophylaxis (from 70 to 98%; p < 0.0001). In conclusion, the outcome of allogeneic BMT for patients with severe aplastic anemia has considerably improved over the past two decades: young patients, grafted early after diagnosis from an identical sibling, have currently an over 80% chance of long-term survival. Transplants from twins are very successful as well. The risk of complications with alternative donor transplants is still high., (Copyright 2000 S. Karger AG, Basel)

One hundred and fifty acute myeloid leukaemia (AML) patients in first remission received an allogeneic bone marrow transplant (BMT), after conditioning with cyclophosphamide 120 mg/kg and total body irradiation (TBI) 3.3 Gy x 3 (total nominal dose 9.9). The received dose, as recorded by thermoluminescent dosimeters, ranged between 7. 83 and 12.25 Gy. Patients who received TBI < 9.9 Gy (n = 34) had a significantly higher relapse rate when compared with patients receiving >/= 9.9 Gy (n = 116) (43% vs. 19%; P = 0.002). Graft versus host disease (GvHD) prophylaxis consisted of cyclosporin A (CyA) with or without methotrexate (MTX). The dose of CyA was either 1 or 5 mg/kg/day i.v. from day -1 to + 20, then 10 mg/kg/day orally until day + 365. Patients receiving 5 mg/kg CyA (n = 40) had a higher risk of relapse (49% vs. 15%; P = 0.0001). Thus, low-dose TBI (< 9.9 Gy) and high-dose CyA (5 mg/kg) were significant predictors of leukaemia relapse. Patients were then divided into three groups: those who had both negative predictors (< 9.9 Gy TBI and 5 mg/kg CyA; n = 26); those who had only one (either < 9.9 Gy TBI or 5 mg/kg CyA; n = 22); and those who had neither (>/= 9.9 Gy TBI and 1 mg/kg CyA; n = 102). The three groups were comparable for FAB subtype, interval diagnosis transplant and age. The 5-year actuarial relapse rate for these three groups of patients was 49%, 41% and 15%, with no difference between the first two and a significant difference when compared with the latter (P < 0.01). These data indicate that acute myeloid leukaemia can be cured with allogeneic bone marrow transplantation given an intensive conditioning regimen and low-dose immunosuppression post-graft. Either alone is insufficient to produce long-term disease-free survival. These results may be relevant for programmes of reduced intensity conditioning designed for patients with acute leukaemia.

Patients with severe aplastic anemia (SAA) can be successfully treated with bone marrow transplantation (BMT) or immunosuppressive therapy (IS). The current outcome using both forms of therapy among 3,669 patients treated in Europe between 1976 and 1998 is reviewed. Significant progress has been made and the overall risk of failure is now low, with survival rates greater than 80% for both treatments. Chronic graft-versus-host disease (GvHD) remains a problem for BMT patients, and carries a high risk of lethal complications. On the other hand, IS patients are exposed to late failure due to relapse or clonal/malignant diseases. First-line BMT from identical siblings is compared with IS therapy in an intent-to-treat analysis of 1,765 patients, regardless of subsequent transplant status. The outcome of SAA patients has improved considerably over time and is influenced by patient variables such as severity of the disease and age, but also by the choice of the initial treatment.

Background and Objective: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal disease of the hemopoietic stem cell (HSC) characterized by intravascular hemolysis and increased risk of venous thrombosis. There are different therapeutic approaches for PNH which do not cure the disease, but can decrease its complications. Allogeneic bone marrow transplantation (BMT) may cure PNH. We reports here our experience of seven PNH patients who underwent allogeneic BMT., Design and Methods: Between January 1991 and January 1999 seven patients with PNH, aged 23 to 37, were transplanted with unmanipulated bone marrow from HLA identical siblings. Median time from diagnosis to BMT was 2.5 years (range: 1-16). All patients were transfusion-dependent and had received various treatments before BMT: steroids, vitamins, cyclosporin A (CyA), growth factors. One patient had also been treated with anti-thymocyte globulin. One patient was HbsAg positive and one anti-HCV positive. At the time of BMT the median value of hemoglobin (Hb) was 9 g/dL (range 6.5-11), white blood cells 5&10(9)/L (range: 2.9-7.7), platelets 97&10(9)/L (range: 31-355), LDH: 2726 U/L. The conditioning regimen was cyclophosphamide (160 mg/kg) and busulfan (10-14 mg/kg), followed by unmanipulated bone marrow (median of 5&10(8) cells/kg) and CyA (+MTX in two patients) for prophylaxis of graft-versus-host disease (GvHD)., Results: All seven patients are alive, full chimeras, with complete hematologic recovery and no evidence of PNH, at a median follow up of 51 months post-BMT (6-103). Time to achieve a granulocyte count of 0.5&10(9)/L, platelets 30&10(9)/L and Hb 10 g/dL was respectively 16, 19 and 22 days. Acute GvHD was limited or mild in six patients, and severe in one. Chronic GvHD was extensive in two patients., Interpretation and Conclusions: This study confirms that HLA identical sibling BMT is an effective therapeutic option for PNH, also in the hemolytic phase of the disease: it also suggests that HBV and HCV infections are not an absolute contraindication.

Cytogenetic abnormalities and paroxysmal nocturnal haemoglobinuria (PNH) phenotype are frequent findings in aplastic anaemia patients treated with immunosuppressive therapy (IST). In this study we investigated whether the appearance of clonal haemopoiesis influences patient outcome and survival. 97 patients entered this study and were followed from the onset of the disease for a median follow-up (FU) of 53 months. 93% are alive, 56% achieved complete remission, 30% partial remission, both transfusion independent, and 14% did not respond. Three groups were identified: (A) patients without evidence of emerging clones (71/97); (B) patients who acquired chromosomal abnormalities (13/97); (C) patients who showed low expression of glycosyl phosphatidylinositol anchored proteins (GPI-AP) (PNH phenotype) at presentation or later (16/97). Three patients showed both PIG-AP deficiency and chromosomal abnormalities. The actuarial survival of patients without clonal haemopoiesis (n = 71) at 6 years was 95%, for patients with chromosomal abnormalities (n = 13), 88%, and for patients with PIG-AP deficiency (n = 16), 89%. There was no difference in the probability of becoming transfusion independent in the three groups (93%, 92% and 88% respectively). This study confirmed that a proportion of severe aplastic anaemia (SAA) patients exhibit clonal markers during the time after IST, often coexisting with cytogenetically or phenotypically normal haemopoiesis. There was no significant clinical impact of these abnormalities on transfusion independence and survival at the median follow-up of 4 years.

Background: Patients who receive bone marrow transplants have increased risk for new malignant conditions because of several risk factors, including conditioning with radiation and chemotherapy, immune stimulation, and malignant primary disease. The occurrence of and risk factors for malignant neoplasm in long-term survivors must be assessed., Objective: To determine the risk and define potential risk factors for new malignant conditions in long-term survivors after marrow transplantation., Design: Retrospective multicenter study., Setting: Study of the Late Effects Working Party with 45 transplantation centers cooperating in the European Cooperative Group for Blood and Marrow Transplantation., Patients: 1036 consecutive patients who underwent transplantation for leukemia, lymphoma, inborn diseases of the hematopoietic and immune systems, or severe aplastic anemia. Transplantation was done before December 1985, and patients had survived more than 5 years., Measurements: Reports on malignant neoplasms were evaluated, and the incidence was compared to that in the general population. Patient age and sex, primary disease and status at transplantation, histocompatibility of the donor, conditioning regimen, type of prophylaxis of graft-versus-host disease, development of acute and chronic graft-versus-host disease, and treatment of chronic graft-versus-host disease were evaluated as variables., Results: Median follow-up since transplantation was 10.7 years (range, 5 to 22.1 years). Malignant neoplasms were seen in 53 patients; the actuarial incidence (+/- SE) was 3.5% +/- 0.6% at 10 years and 12.8% +/- 2.6% at 15 years. The rate of new malignant disease was 3.8-fold higher than that in an age-matched control population (P < 0.001). The most frequent malignant diseases were neoplasms of the skin (14 patients), oral cavity (7 patients), uterus (including cervix) (5 patients), thyroid gland (5 patients), breast (4 patients), and glial tissue (3 patients). Median age of patients and their donors was 21 years. Malignant neoplasms were more frequent in older patients and in patients with chronic graft-versus-host disease. Older patient age and treatment of chronic graft-versus-host disease with cyclosporine were significant risk factors for new malignant neoplasms after bone marrow transplantation., Conclusions: The spectrum of neoplasms and immunosuppressive treatment with cyclosporine for chronic graft-versus-host disease as dominant risk factors indicate that immunosuppression is the major cause of malignant neoplasms in patients receiving marrow transplants.

Few data are available on the long-term effect of bone marrow transplantation (BMT) on growth. This study examines those factors that play a role in the final height outcome of patients who underwent BMT during childhood. Data on 181 of 230 patients with aplastic anemia, leukemias, and lymphomas who had BMT before puberty (mean age, 9.8 +/- 2.6 years) and who had reached their final height were analyzed. An overall decrease in final height standard deviation score (SDS) value was found compared with the height at BMT (P < 10(7)) and with the genetic height (P < 10(7)). Girls did better than boys, and the younger in age the person was at time of BMT, the greater the loss in height. Previous cranial irradiation + single-dose total body irradiation (TBI) caused the greatest negative effect on final height achievement (P < 10(4)). Fractionation of TBI reduces this effect significantly and conditioning with busulfan and cyclophosphamide seems to eliminate it. The type of transplantation, graft-versus-host disease, growth hormone, or steroid treatment did not influence final height. Irradiation, male gender and young age at BMT were found to be major factors for long-term height loss. Nevertheless, the majority of patients (140/181) have reached adult height within the normal range of the general population.

The therapeutic options for patients with acute leukemia who relapse after the initial transplant include second bone marrow transplantation (2BMT) and conventional chemotherapy (CC). In this work, we conducted an analysis of published survival data and we evaluated the cost-effectiveness of 2BMT in comparison with CC. We retrieved survival information on 167 patients treated with 2BMT and 299 patients treated with CC. Survival figures were derived from individual patient data and were compared between 2BMT and CC. The mean lifetime survival (MLS) was estimated for each of the two patient cohorts using standard techniques of survival-curve extrapolation. The cost data of patients given 2BMT or CC were estimated from published data. Our analysis of individual survival data showed that 2BMT improved survival at levels of statistical significance (survival gain = 19.6 months per patient). Using an incremental cost of $90000 per patient, the cost-effectiveness ratio of 2BMT in comparison with CC was calculated as $52215 discounted dollars per discounted life year gained. Our results indicate that, in patients with acute leukemia who relapse after their first transplant, 2BMT significantly prolongs survival in comparison with CC and seems to have an acceptable cost-effectiveness profile.

Purpose: To investigate whether different procedure variables involved in the delivery of fractionated total body irradiation (TBI) impact on prognosis of patients affected by acute lymphoblastic leukemia (ALL) receiving allogeneic bone marrow transplant (BMT)., Methods and Materials: Ninety-three consecutive patients with ALL receiving a human leukocyte antigen (HLA) identical allogeneic BMT between 1 August 1983 and 30 September 1995 were conditioned with the same protocol consisting of cyclophosphamide and fractionated TBI. The planned total dose of TBI was 12 Gy (2 Gy, twice a day for 3 days). Along the 12-year period, variations in delivering TBI schedule occurred with regard to used radiation source, instantaneous dose rate, technical setting, and actual total dose received by the patient. We tested these different TBI variables as well as factors related to patient, state of disease, and transplant-induced disease to investigate their influence on transplant-related mortality, leukemia relapse, and survival., Results: At median follow-up of 7 years (range 3-15 years) the probabilities of leukemia-free survival (LFS) and overall survival (OS) for the 93 patients were 60% and 41%, respectively. At univariate analysis, chronic graft versus host disease (cGvHd) (p = 0.0005), age (p = 0.01), and state of disease (p = 0.03) were factors affecting LFS whereas chronic GvHd (p = 0.0005), acute GvHd (p = 0.03), age (p = 0.0001), and GvHd prophylaxis (p = 0.01) were factors affecting overall survival. The occurrence of chronic GvHd was correlated with actually delivered TBI dose (p = 0.04). Combined stratification of prognostic factors showed that patients who received the planned total dose of TBI (12 Gy) and were affected by chronic GvHd had higher probabilities of LFS (p = 0.01) and OS (p = n.s.) than patients receiving less than 12 Gy and/or without occurrence of chronic GvHd. Moreover, TBI dose had a significant impact on LFS in patients transplanted in first remission (p = 0.05). At multivariate analysis, TBI dose was an independent factor affecting overall survival (p = 0.05) as well as chronic GvHd (p = 0.001) and age (p = 0.04)., Conclusions: This retrospective analysis showed that different variables involved in TBI delivery may influence the occurrence of cGvHd and affect prognosis of patients with ALL receiving allogeneic BMT. The total dose of 12 Gy, administered in six fractions over 3 days, appears to be an effective and low toxic regimen for ALL patients transplanted in first remission.

Purpose: To describe molecular monitoring of minimal residual disease in patients with myeloma who have achieved complete remission (CR) after autologous or allogeneic transplantation of hematopoietic cells., Materials and Methods: Clonal markers based upon the rearrangement of immunoglobulin heavy-chain genes were generated for each patient and used for polymerase chain reaction (PCR) detection of residual myeloma cells. Fifty-one patients entered the program and 36 achieved CR. After transplantation, molecular monitoring was performed on 29 patients (15 autologous and 14 allogeneic transplants) who had molecular markers., Results: Our data show that molecular remissions are rarely achieved (7%) with high-dose chemotherapy followed by single or double autografting. In addition, virtually all peripheral blood progenitor cell and bone marrow samples contained residual myeloma cells, even when sample collection was scheduled after repeated courses of high-dose chemotherapy. All patients autografted with PCR-positive cells remain positive, and eight of 15 have relapsed. Two patients were autografted with PCR-negative cells: one is in clinical and molecular remission, and one relapsed 25 months after the transplant. In the allografting setting, a higher proportion of patients (50%) achieved molecular remission; there were two relapses, one in the PCR-positive group and one in the PCR-negative group., Conclusion: This is the first large study of molecular remissions in myeloma patients to use a PCR-based approach utilizing patient-specific tumor markers. The sizeable fraction of patients who achieved molecular remission after allografting with peripheral blood progenitor cells represents a promising finding in an incurable disease.

Ninety-five patients undergoing an allogeneic bone marrow transplant (BMT) and developing acute graft-versus-host disease (aGvHD) were randomized to receive low-dose intravenous 6-methylprednisolone (6MPred; 2 mg/kg /d; n = 47) or high-dose 6MPred (10 mg/kg/d; n = 48) for 5 days, with subsequent tapering doses. On day 5 patients not responding or progressing on low-dose 6MPred could be switched to high-dose 6MPred. All patients, aged 1 to 55 years, were recipients of unmanipulated BMT from HLA identical sibling donors. Patients were stratified at randomization for age (/= 20 years), disease (acute leukemia, chronic myeloid leukemia [CML], nonneoplastic disease), disease status (early/advanced), and GvHD prophylaxis (cyclosporin/cyclosporin + methotrexate). Primary endpoints were response to treatment and evolution of aGvHD to grade III-IV. Secondary endpoints were cytomegalovirus (CMV) infections, transplant-related mortality (TRM), and relapse. The median interval between BMT and treatment was 12 days (6 to 43). Results in the two groups (2 v 10 mg/kg) were as follows: response of aGvHD 68% versus 71% (P = .9), evolution to aGvHD grade III-IV 17% versus 20% (P = . 6), CMV infections 55% versus 60% (P = .7), 3-year actuarial TRM 28% versus 32% (P = .7), relapse 17% versus 7% (P = .1). The actuarial survival at 3 years was 63% versus 62% (P = .9) with a median follow up of 580 and 778 days. On day 5 of therapy, 26 patients assigned to low-dose (2 mg/kg) 6MPred were switched to a higher dose of 6MPred because of no response or progression. Their actuarial TRM was 46%, which is significantly higher than TRM of patients who responded on 2 mg/kg and continued with tapering doses (TRM = 16%, P = .007). In conclusion, early treatment of acute GvHD with 6MPred 10 mg/kg/d does not improve the response rate as compared with 2 mg/kg/d, nor does it prevent evolution to aGvHD grade III-IV. CMV infections, TRM, and survival were also comparable. A group of patients at high risk of TRM can be identified after 5 days of treatment with 6MPred 2 mg/kg and could be eligible for alternative forms of therapy.