Inflammatory marker changes in a 24-month dietary and physical activity randomised intervention trial in postmenopausal women.

Chronic low-grade inflammation plays a role in the pathogenesis of several chronic diseases including cancer. Physical activity (PA) and diet have been supposed to modulate inflammatory markers. We evaluated the effects of a 24-month dietary and/or PA intervention on plasma levels of pro-inflammatory cytokines, a secondary analysis in the DAMA factorial trial. The 234 study participants (healthy postmenopausal women with high breast density, 50-69 years, non smokers, no hormone therapy) were randomised to four arms: (1) isocaloric dietary intervention mainly based on plant-foods; (2) moderate-intensity PA intervention with at least 1 h/week of supervised strenuous activity; (3) both interventions; (4) general recommendations on healthy dietary and PA patterns. Interleukins (IL)-1α, -1ß, -6, tumor necrosis factor-α and C-reactive protein were measured at baseline and at the end of the intervention. Intention-to-treat-analyses were carried out using Tobit regression. Although all cytokines tended to increase over time, after 24 months women in the PA intervention (arms 2 + 3) showed lower levels of IL-1α (exp(ß) = 0.66; p = 0.04) and IL-6 (exp(ß) = 0.70; p = 0.01) in comparison with women in the control group (arms 1 + 4). No effects of the dietary intervention emerged. In healthy postmenopausal women with high breast density a moderate-intensity PA appears to slow the age-related increase of pro-inflammatory cytokines.

Physical activity and blood pressure in 10,000 Mediterranean adults: The EPIC-Florence cohort.

BACKGROUND AND AIMS: The relevant role of physical activity (PA) in cardiovascular risk prevention is widely agreed. We aimed to evaluate, in a large Mediterranean population, the influence of PA on systolic (SBP) and diastolic blood pressure (DBP), taking into account individual characteristics and lifestyle habits. METHODS AND RESULTS: In the Florence section of the European Prospective Investigation into Cancer and Nutrition 10,163 individuals, 35-64 years, without a previous diagnosis of hypertension were recruited. Information on occupational and leisure-time PA and blood pressure were collected at recruitment, together with data on lifestyle, dietary habits and anthropometry. Multivariate regression models were applied to evaluate the effect of total, occupational and leisure-time PA on SBP and DBP. Mean values of SBP and DBP in the study subjects were 124.4 (SD 15.6) and 79.7 mmHg (SD 9.4), respectively. Overall, a total PA index and an index including cycling, fitness and occupational PA (Cambridge index) were inversely associated with DBP (beta -0.87, p-value 0.02 actives vs inactives, p for trend 0.02 and beta -0.84, p value 0.003 actives vs inactives, p for trend 0.002, respectively), while SBP was associated only with the latter index (beta -1.14, p-value 0.01 actives vs inactives, p for trend 0.006). An inverse association emerged between manual/heavy manual occupation and DBP (p 0.02, ref sedentary/standing occupation) and between increasing cycling activity and SBP (p for trend 0.04). CONCLUSIONS: In this large cohort of Mediterranean adults without a diagnosis of hypertension we confirm the role of overall PA in modulating SBP and DBP values. Cycling and manual occupations were associated with lower DBP values.

Extracorporeal photopheresis for the treatment of steroid refractory acute GVHD.

Extracorporeal photopheresis (ECP) was given to 23 patients with steroid-refractory acute GVHD (aGVHD, grade II (n=10), III (n=7) or IV (n=6)). The median duration of ECP was 7 months (1-33) and the median number of ECP cycles in each patient was 10. Twelve patients (52%) had complete responses. Eleven patients (48%) survived and 12 died, 10 of GVHD with or without infections and two of leukaemia relapse. The average grade of GVHD was reduced from 2.8 (on the first day of ECP) to 1.4 (on day +90 from ECP) (P=0.08), and the average dose of i.v. methylprednisolone from 2.17 to 0.2 mg/kg/d (P=0.004). Complete responses were obtained in 70, 42 and 0% of patients, respectively, with grades II, III and IV aGVHD; complete responses in the skin, liver and gut were 66, 27 and 40%. Patients treated within 35 days from onset of aGVHD had higher responses (83 vs 47%; P=0.1). A trend for improved survival was seen in grade III-IV aGVHD treated with ECP as compared to matched controls (38 vs 16%; P 0.08). ECP is a treatment option for patients with steroid refractory aGVHD and should be considered early in the course of the disease.

Improved outcome in young adults with de novo acute myeloid leukemia in first remission, undergoing an allogeneic bone marrow transplant.

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.

Allogeneic hemopoietic stem cell transplants for patients with relapsed acute leukemia: long-term outcome.

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.

Catastrophic relapse of Evans syndrome five years after allogeneic BMT notwithstanding full donor chimerism. Terminal hemolytic-uremic syndrome.

A patient with severe Evans syndrome received an allo-BMT from his HLA-identical sister on November, 2000. Full marrow and blood donor chimerism were achieved only after 5 donor lymphocyte infusions (DLI), and coincided with complete clinical remission and disappearence of auto-antibodies. Five years later, hemolytic anemia recurred with rapid increase of serum bilirubin to over 50 mg%: he responded to combined therapy, but died on day +17 from admission of an acute hemolytic uremic syndrome (HUS). All circulating blood cells, including erythrocytes, were 100% donor. Ex vivo cultured and expanded T and B cells from the peripheral blood were also 100% donor. The supernatants from B cell cultures, containing either IgM or IgG, did not react with a panel of erythrocytes. Thus in this typical autoimmune disease with a predominant B cell pathogenesis the donor immune system resulted "innocent of autoimmunity". The persistence of long-lived recipient autoreactive plasma-cell lines in survival niches, still producing autoantibodies, may be hypothesized for this and similar cases. The postulated graft-versus-autoimmunity (GVA) effect was apparently not sufficient to eradicate autoimmunity in this patient.

Factors predicting response and graft-versus-host disease after donor lymphocyte infusions: a study on 593 infusions.

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.

Prophylactic antithymocyte globulin reduces the risk of chronic graft-versus-host disease in alternative-donor bone marrow transplants.

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.

Acute intravascular hemolysis in two patients transfused with dry-platelet units obtained from the same ABO incompatible donor.

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.

Quality of life in 244 recipients of allogeneic bone marrow transplantation.

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.

Early predictors of transplant-related mortality (TRM) after allogeneic bone marrow transplants (BMT): blood urea nitrogen (BUN) and bilirubin.

Transplant-related mortality (TRM) following allo- geneic bone marrow transplantation (BMT) remains a major concern and early identification of patients at risk may be clinically relevant. In this study we describe a predictive score based on bilirubin and blood urea nitrogen (BUN) levels on day +7 after BMT. The patient population consisted of 309 consecutive patients who underwent BMT from sibling (n = 263) or unrelated donors (n = 46) for hematologic disorders between December 1990 and December 1996. Of 27 laboratory tests taken on day +7 after BMT, serum bilirubin (P = 0.02) and BUN (P = 0.007) were found to be independent predictors of TRM in multivariate analysis. The median levels of bilirubin (0.9 mg/dl) and of BUN (21 mg/dl) were then used as a cut-off and a score of 1 was given for values equal/greater than the median. There were 216 patients with scores 0-1 (low risk) on day +7 (bilirubin <0.9 and/or BUN <21) and 93 patients with score 2 (high risk) (bilirubin >/=0.9 and BUN >/=21): the latter had more grade III-IV acute graft-versus-host disease (P = 0.03), slower neutrophil (P = 0.02) and slower platelet engraftment (P = 0.002). The actuarial 5 year TRM is 22% for low risk vs44% for high risk patients (P = 0.0003). For HLA-identical siblings TRM is 20% vs35% (P = 0.01), for unrelated donors it is 20% vs 65% (P = 0.01). Day +7 score was highly predictive of TRM on multivariate analysis (hazard ratio 1.9, P < 0.01), after adjustment for year of transplant (P < 0.00001), unrelated vs sibling donors (P = 0.001), patient age (P = 0.01) and diagnosis (P = 0.01). These results were validated on an independent group of 82 allogeneic BMT recipients in a pediatric Unit who showed an actuarial TRM of 16% for low risk vs 46% for high risk patients (P = 0.002). This study suggests that it may be possible to identify patients with different risks of TRM on day +7 after BMT: high risk patients could be eligible for programs designed to intensify prophylaxis of post-transplant complications.

Autografting with philadelphia chromosome-negative mobilized hematopoietic progenitor cells in chronic myelogenous leukemia.

Intensive chemotherapy given in early chronic phase of chronic myelogenous leukemia (CML) has resulted in high numbers of circulating Philadelphia (Ph) chromosome-negative hematopoietic progenitor cells (HPC). We have autografted 30 consecutive patients with CML in chronic phase with HPC collected in this way to facilitate restoration of Ph-negative hematopoiesis in bone marrow after high-dose therapy. Hematopoietic recovery to greater than 0.5 x10(9)/L neutrophils and to greater than 25 x 10(9)/L platelets occurred in all patients, a median of 13 (range, 9 to 32) days and 16 (range, 6 to 106) days postautograft, respectively. Regenerating marrow cells were Ph-negative in 16 (53%) patients and greater than 66% Ph-negative in 10 (33%) patients. Twenty-eight patients are alive 6 to 76 months (median, 24 months) after autografting. Three patients have developed blast crisis from which 2 have died. Eight patients are in complete cytogenetic remission at a median of 20 (range, 6 to 44) months with a median ratio BCR-ABL/ABL of 0.002 (range, <0.001 to 0.01). Eight patients are in major cytogenetic remission at a median of 22 (range, 6 to 48) months. No patient died as a consequence of the treatment. All patients had some degree of stomatitis that was severe in 15 (50%) patients. Gastrointestinal and hepatic toxicities were observed in about one fourth of patients. Thus, autografting with Ph-negative mobilized HPC can result in prolonged restoration of Ph-negative hematopoiesis for some patients with CML; moreover, most autograft recipients report normal or near normal activity levels, suggesting that this procedure need not to be associated either with prolonged convalescence or with chronic debility.

Failure of autologous stem cell transplantation in refractory thrombocytopenic purpura.

A 44-year-old man with splenectomised refractory autoimmune thrombocytopenic purpura (AITP) of 10 years' duration underwent an autologous, T cell-depleted marrow transplant following conditioning with thiotepa and CY. There was no response to the transplant procedure. This is the fourth case in the literature to show failure following autologous stem cell transplantation, although complete, steroid-independent remissions were obtained in the first two patients for over 1 year.

Allogeneic hemopoietic stem cell transplantation for patients with high risk acute lymphoblastic leukemia: favorable impact of chronic graft-versus-host disease on survival and relapse.

BACKGROUND AND OBJECTIVE: The best post-remission therapy for patients with acute lymphoblastic leukemia (ALL) is controversial, and hemopoietic stem cell transplantation (HSCT) is one therapeutic option. The goal of this study is to describe long term results of HSCT in high risk ALL patients. DESIGN AND METHODS: Between 1978 and 1996, 170 patient with ALL and a median age of 22 years (1-49), underwent an allogeneic HSCT from HLA-identical siblings (n = 149), family mismatched donors (n = 18) or unrelated HLA matched donors (n = 3); 92% of patients had at least one adverse prognostic factor for high risk ALL at diagnosis; one third (33%) were in first remission (CR1) and the majority (85%) received an unmanipulated HSCT with cyclosporin-methotrexate prophylaxis of graft-versus-host disease (GvHD). RESULTS: After a median follow-up of over 6 years, 59 patients are alive and 111 patients have died of leukemia (46%) or transplant related complications (54%). The actuarial 10 year survival is 53%, 38% and 20%, for patients in CR1, CR2 or advanced phase, respectively. The actuarial survival of patients with (n = 24) of without (n = 46) cytogenetic abnormalities, grafted in CR1/CR2 was respectively 45% and 48% (p = 0.5). The year of transplant had a significant impact in multivariate analysis on transplant related mortality (TRM) (p = 0.0009) but not on relapse (p = 0.3). Chronic GvHD was the most important favorable prognostic factor for survival (p = 0.0014) and relapse (p = 0.0019). INTERPRETATION AND CONCLUSIONS: This study confirms that long term survival can be achieved with HSCT in ALL patients, even those with cytogenetic abnormalities. Transplant mortality has been significantly reduced in recent years, whereas leukemia rate relapse has remained unchanged: the latter is influenced by the occurrence of chronic GvHD. Immune intervention post-HSCT may be considered to address this problem.

Forscarnet vs ganciclovir for cytomegalovirus (CMV) antigenemia after allogeneic hemopoietic stem cell transplantation (HSCT): a randomised study.

This trial was designed to compare foscarnet with ganciclovir as pre-emptive therapy for CMV infection in patients undergoing allogeneic hemopoietic stem cell transplant (HSCT). Thirty-nine patients were randomized to receive foscarnet 90 mg/kg every 12 h (n = 20) or ganciclovir 5 mg/kg every 12 h (n = 19) for 15 days at the time of development of CMVAg-emia. Primary-end points of the study were (1) outcome of CMVAg-emia; (2) progression to CMV disease; and (3) side-effects of treatment. The secondary end-point was transplant-related mortality (TRM). The two groups were comparable for diagnosis, status of disease, donor type, acute graft-versus-host (aGVHD) prophylaxis, interval between HSCT and CMVAg-emia and number of CMVAg positive cells; the donor and recipient age were borderline older in the foscarnet group. Increments of serum creatinine in the foscarnet group, and cytopenia in the ganciclovir group were controlled by reducing the administered dose: in the first 15 days of therapy 9/20 foscarnet and 10/19 ganciclovir patients had a dose reduction greater than 20% (P = 0.43). Clearance of CMVAg-emia was faster in the foscarnet group although with borderline statistical significance. Failures of treatment occurred in 3/20 patients in foscarnet group vs 8/19 patients in ganciclovir group (P= 0.06): causes of failure were the need for combination therapy to control antigenemia (1/20 vs 5/19), and reactivation during treatment for 2 vs 3 patients, respectively. CMV disease was diagnosed in 1 vs 2 patients (P = 0.5) who subsequently died. The actuarial 1-year TRM was 25 vs 12%, respectively (P = 0.3). This study suggests that foscarnet and ganciclovir are both effective for pre-emptive therapy of CMVAg-emia, although the number of failures would seem to be slightly higher in the ganciclovir patients. Side-effects are seen in both groups and can be managed with appropriate dose reduction.

Allogeneic bone marrow or peripheral blood cell transplants in adults with hematologic malignancies: a single-center experience.

This is a retrospective study of 97 patients who received either allogeneic bone marrow transplant (BMT) (n=52) or peripheral blood cell transplant (PBCT) (n=45) at our institution from human leukocyte antigen (HLA)-identical sibling donors between January 1994 and January 1997. The two groups were comparable with respect to diagnosis, age, sex, interval from diagnosis, and disease phase. They were prepared with cyclophosphamide (CY) and fractionated total-body irradiation (TBI) (n=51) or CY and thiotepa (n=46). Graft-vs.-host disease (GVHD) prophylaxis consisted of cyclosporin A and methotrexate. Patients who received PBCT exhibited faster neutrophil engraftment (day 14 vs. day 16, p = 0.002) than those in the BMT group, as well as higher platelet counts on day 20 (32x10(9)/kg vs. 21x10(9)/kg, p = 0.001), but graft function as assessed by platelet counts on days 50, 100, and thereafter was comparable. The number of days spent in the hospital, days on intravenous antibiotics, and days of fever were lower in the PBCT group, but not significantly. Acute GVHD, chronic GVHD, and cytomegalovirus infections were comparable between the two groups. The overall actuarial 3-year transplant-related mortality (TRM) rate for BMT vs. PBCT patients was 20 vs. 33% (p = 0.1), the survival rate was 53 vs. 48% (p = 0.3), and the relapse rate was 42 vs. 43% (p = 0.8). For patients in first complete remission, these figures were TRM 12 vs. 22% (p = 0.2), survival rate 75 vs. 70% (p = 0.4) and relapse rate 31 vs. 9% (p = 0.4), respectively, for the BMT and PBCT groups. These data suggest that the short-term outcome of allogeneic PBCT is not significantly different from that of allogeneic BMT in patients with hematologic malignancies. Long-term results are not available at present.

Low transplant mortality in allogeneic bone marrow transplantation for acute myeloid leukemia: a randomized study of low-dose cyclosporin versus low-dose cyclosporin and low-dose methotrexate.

Sixty patients undergoing allogeneic bone marrow transplant for acute myeloid leukemia (AML) in first remission (CR1; n = 49) or more advanced phase (n = 11) were entered in a prospective trial of graft-versus-host disease (GvHD) prophylaxis: low-dose cyclosporin A (IdCSA; 1 mg/kg/d from day -1 to +20 day; n = 28) or IdCSA plus low-dose methotrexate (IdMTX; 10 mg/m2 for day +1, 8 mg/m2 for days +3, +6, and +11; n = 32). Primary end points were acute GvHD (aGvHD) and transplant-related mortality (TRM); secondary end points were relapse and survival. The conditioning regimen consisted of cyclophosphamide (120 mg/kg) and fractionated total body irradiation (3.3 Gy/d for 3 consecutive days). The actuarial risk of developing aGvHD grade II-III was 61% for IdCSA alone and 34% for IdCSA + IdMTX (P = .02). The actuarial risk of TRM at 1 year was 11% versus 13%, respectively, and older patients (>/= 29 years) had higher TRM than younger patients (22% v 5%, P = .01). The age effect was significant in the IdCSA group (P = .04) but not in the IdCSA + IdMTX group (P = .1). The median follow-up is 4.4 years, with an overall actuarial survival of 78% for CR1 patients and 36% for patients with advanced disease. For patients in CR1 the outcome of the two regimens was as follows: survival 77% versus 80% (P = .6), relapse 20% versus 9% (P = .1), and TRM 13% versus 17% (P = .6). This study suggests that TRM can be reduced in AML patients undergoing allogeneic marrow transplants with a mild conditioning regimen and low-dose immunosuppression, and this translates in a 78% 5-year survival for CR1 patients. Beyond CR1 the major obstacle remains leukemia relapse, which is not prevented by low-dose in vivo immunosuppression.

A randomized trial of high dose polyvalent intravenous immunoglobulin (HDIgG) vs. Cytomegalovirus (CMV) hyperimmune IgG in allogeneic hemopoietic stem cell transplants (HSCT).

BACKGROUND AND OBJECTIVE: The role of high dose intravenous IgG (HDIgG) and of hyperimmune CMV IgG (CMV-IgG) in patients undergoing allogeneic hemopoietic stem cell transplantation (HSCT) is still unclear. The aim of this study was to compare prophylactic CMV-IgG with HDIgGin a randomized prospective trial in allogeneic HSCT recipients: primary end point of the study was the occurrence of post-transplant CMV antigenemia (CMVAg-emia). Secondary end-points were severity of acute and chronic graft-versus-host disease (GvHD), infections and transplant related mortality (TRM). DESIGN AND METHODS: Patients were randomized to receive 100 mg/kg/week of CMV-IgG (group A; n = 64) or 400 mg/kg/week of HDIgG (group B; n = 64) from day -7 to day +100. The two groups were comparable for age, diagnosis, disease status, and acute graft-versus host (aGvHD) prophylaxis. RESULTS: The actuarial risk at 1 year of CMV antigenemia was lower for CMV-IgG (61% vs. 71%) but not significantly (p = 0.37); CMVAg-emia occurred at the same interval from HSCT (47 vs. 48 days, p = 0.9), with a comparable number of CMVAg positive cells (3 vs. 3 p = 0.9). Eight patients died of interstitial pneumonia (IP) (4 in each group), two in group A of CMV-IP. Acute GvHD was scored as O-I, II and III-IV in 39 vs. 35, 23 vs. 22 and 2 vs. 7 patients respectively for the two groups (p = not significant). The actuarial risk of developing acute GvHD grade II-IV was lower for CMV-IgG (39% vs. 45%) but not significantly (p = 0.43). Chronic GvHD scored as absent in 7 vs. 10 patients, limited in 39 vs. 37 and extensive in 19 vs. 17 patients respectively (p = not significant). Numbered days with intravenous antibiotics, days in hospital, days of fever, number of local and disseminated infections, number of patients with fever of unknown origin were not significantly different. Actuarial 1 year TRM is 18% vs. 19%, respectively (p = 0.9). INTERPRETATION AND CONCLUSIONS: This study confirms that CMV antigenemia is comparable in recipients of hyperimmune CMV-IgG and of polyvalent HDIgG, although the former had a 32% lower cost. It also shows that the potential immunomodulating effect on acute GvHD and transplant mortality is similar with 100 or 400 mg of IgG/kg/week: this is relevant, in view of the high cost of prophylactic HDIgG.