Evaluation of intervention strategy based on CMV-specific immune responses after allogeneic SCT

Late occurring CMV disease is an important problem after allogeneic SCT and has been associated with poor CMV-specific immunity. We conducted a prospective study of 58 patients studied at 3-6 months after allo-SCT, to base the antiviral therapy on monitoring of CMV-specific immunity. Reactivation of CMV was measured by quantitative PCR, and intracellular IFN-gamma production was analysed by FACS and enzyme-linked immunospot. Antiviral therapy was deferred in patients with documented CMV-specific immunity without symptoms of CMV disease or severe GVHD. Nineteen episodes of CMV reactivation were assessable. The strategy was correctly applied in 16/19 episodes. Therapy was deferred in 5/19 (none of these patients developed CMV disease) and was given according to the strategy in 11/19 episodes. Two patients received antiviral therapy despite having T cell-specific immunity. There was a tendency that patients with late CMV reactivation had weak CD8 T cell immunity at 3 months (P=0.06). The donors' serostatus influenced the strength of both CD4 and CD8 immunity at 3 months after SCT (P<0.01). There was no effect as regards the type of conditioning, donor type, stem cell source or acute GVHD. Monitoring the immunity of SCT patients may allow more targeted use of antiviral therapy.     

Reconstitution of HLA-A*2402-Restricted Cytomegalovirus-Specific T-Cells Following Stem Cell Transplantation

Cytomegalovirus (CMV)-specific immune reconstitution early after stem cell transplantation (SCT) was evaluated prospectively by detecting CD8+ T-cells, which recognize the peptide QYDPVAALF in the context of HLA-A*2402. Fifteen allogeneic SCT recipients were included in the study. All recipients and donors were seropositive for CMV and had the HLA-A*2402 allele. CMV-specific T-cells were detected as early as 1 month after transplantation, and their numbers increased to peak levels 2 to 5 months after transplantation. The numbers of CMV-specific T-cells in patients who developed grade II to IV acute graft-versus-host disease (GVHD) and received corticosteroids for acute GVHD were low in the early period after allogeneic SCT. There was a trend toward earlier reconstitution of CMV-specific CD8+ T-cells in allogeneic peripheral blood SCT (PBSCT) patients than in allogeneic bone marrow transplantation patients. The contribution of T-cells in the graft to the recovery of CMV-specific immune responses was also suggested by the finding that the reconstitution of CMV-specific CD8+ T-cells was delayed in CD34-selected autologous PBSCT compared with unpurged autologous PBSCT. The reconstitution of CMV-specific CD8+ T-cells was delayed in patients with CMV disease or recurrent CMV reactivation. These observations suggest that the detection of CMV-specific T-cells with an HLA-peptide tetramer is useful to assess immune reconstitution against CMV and to identify patients at risk for CMV disease or recurrent CMV reactivation after SCT.     

A Low Incidence of Cytomegalo Virus Infection Following Allogeneic Hematopoietic Stem Cell Transplantation Despite a High Seroprevalence

Cytomegalovirus (CMV) infection remains an important cause of morbidity and mortality following allogeneic stem cell transplantation (SCT). We wanted to study if the high sero-prevalence seen in our population translated into a high incidence of CMV infection following SCT. This is a retrospective analysis of patients who underwent allogeneic SCT between January 2008 and December 2012 at our centre. 475 patients underwent allogeneic SCT for malignant (46.5%) and non-malignant (53.5%) haematological disorders. 463 (97.4%) SCT recipients and 403 (84.8%) SCT donors were IgG seropositive for CMV. CMV reactivation within 100 days post SCT was seen in 174 (36.6%) at a median of 41 days (range 10–100) post SCT. Ganciclovir was used in 166 patients (95.4%) for a mean duration of 16 days (range 5–32). 157 patients (90%) responded to therapy. Sixty-six patients (42.3%) had secondary reactivation of the virus. Use of a male donor (p?=?0.000), donor and recipient age?>?15 (p?=?0.005 and 0.000), unrelated donor (p?=?0.000), degree of HLA mismatch (p?=?0.000), occurrence of acute GVHD (p?=?0.000) and steroid refractory acute GVHD (p?=?0.026) were identified as risk factors for CMV reactivation while early neutrophil recovery (<?15 days) was found to be protective (p?=?0.004). On multivariate analysis, male donor (p?=?0.042), degree of HLA mismatch (p?=?0.006), the occurrence of acute GVHD (p?=?0.000) and steroid refractory acute GVHD (p?=?0.031) continued to remain significant. 5-year overall survival was significantly better in patients without CMV reactivation compared to those who developed reactivation of CMV (68.9?±?3.7 vs 58.2?±?4.9% p?=?0.004). The incidence of CMV infection does not seem to be higher despite a high sero-prevalence of CMV. However, patients who developed CMV infection post SCT had inferior outcomes.     

Donor cytomegalovirus seropositivity and the risk of leukemic relapse after reduced-intensity transplants

OBJECTIVES: Despite effective preemptive and prophylactic therapeutic strategies, cytomegalovirus (CMV) seropositivity of either recipient and/or donor still remains an important parameter for outcome even after reduced-intensity allogeneic stem cell transplantation (SCT). Whether CMV seropositivity of the donor might have an impact on leukemic relapse is unknown. PATIENTS: Between June 1999 and February 2004 48 patients ineligible for conventional allotransplantation underwent reduced-intensity transplants at our institution. Twenty-seven (56%) patients had a CMV-seropositive donor. RESULTS: While donor CMV seropositivity had no effect on overall survival, having a CMV-seropositive donor was associated with a significantly lower risk for relapse (20% vs. 52%, P = 0.02). The beneficial effect of a CMV-seropositive donor, however, was offset by a higher transplant-related mortality (42% vs. 19% in patients with a CMV-seronegative donor, P = 0.2). Donor CMV serostatus had no effect on the incidence of CMV infection/disease, and acute or chronic graft-vs.-host disease. Overall, 27 patients died during the observation period. Causes of death in patients with a CMV-seropositive donor were primarily transplant-related (11 vs. 4 in patients with CMV-seronegative donors), whereas leukemic relapse was the leading cause of death in patients with a CMV-seronegative donor (8 vs. 4 in patients with a CMV-seropositive donor, P = 0.038, chi-squared test). Multivariate Cox regression analysis showed risk category by the underlying disease and donor CMV seropositivity to be significant predictors of leukemic relapse following reduced-intensity transplants. CONCLUSIONS: These preliminary results suggest a possible role of donor CMV serostatus on the risk of relapse following reduced-intensity allogeneic SCT.     

The use of ATG abrogates the antileukemic effect of cytomegalovirus reactivation in patients with acute myeloid leukemia receiving grafts from unrelated donors

Several studies provided evidence of a consistent antileukemic effect induced by cytomegalovirus (CMV) replication in acute myeloid leukemia (AML) patients receiving allogeneic hematopoietic stem cell transplantation (HSCT), however the use of antithymocyte globulin (ATG) as graft‐versus‐host disease prophylaxis, may potentially abrogate the protective effect of CMV infection. To address this issue, we retrospectively analyzed the risk of relapse in a cohort of 101 patients with AML who received grafts from an unrelated donor after a conditioning regimen including ATG. The cumulative incidence of CMV reactivation, evaluated by RT qPCR, was 59% at 12 months, and 93% of CMV reactivations occurred within the first 100 days post HSCT. The 5‐year cumulative incidence of relapse in patients with CMV reactivation was 29% compared with 37% for patients without CMV reactivation, and the only factor associated with a reduced 5‐year cumulative incidence of relapse was the disease status at HSCT (P < 0.001). In the multivariable model adverse cytogenetics (HR 2.42, 95% CI 1.02‐5.72; P = 0.044) and acute GVHD (HR 3.36, 95% CI 1.32‐8.54; P = 0.011) were independent risk factors for reducing overall survival (OS), while the presence of chronic GVHD was associated with a better OS (HR 0.37, 95% CI 0.15‐0.89; P = 0.027). CMV replication was not an independent risk factor for OS (HR 1.06, 95% CI 0.07‐15.75; P = 0.965). In Conclusion, the results of present study suggest that relapse prevention in patients with AML receiving T‐cell depleted HSCT using ATG do not benefit from CMV reactivation. Am. J. Hematol. 90:E117–E121, 2015. © 2015 Wiley Periodicals, Inc.     

Early infections in adults undergoing matched related and matched unrelated/mismatched donor stem cell transplantation: a comparison of incidence

We compared the incidence of early infectious complications between matched related (MR) and matched unrelated/mismatched (MU/MM) allogeneic stem cell transplant (allo-SCT) recipients in a single centre over a 6-year period in 214 consecutive adult patients. Early infections were defined as occurring from hospital admission for SCT until discharge. One hundred and fifty-nine patients received an allograft from MR donors and 55 patients received MU/MM allo-SCT. One hundred and eight of 214 patients had 147 episodes of fever. Ninety-three episodes (63%) were due to clinically or microbiologically documented infections and 54 episodes (37%) to fever not related to infection. Patients undergoing MU/MM transplantation tended to have more documented infections compared to recipients of MR allo-SCT (P = 0.06). Significantly more MU/MM transplant recipients had breakthrough infections with Herpes simplex virus type 1 (HSV-1, P = 0.003), and more CMV reactivation (P = 0.015). The mortality rate in all patients during hospitalisation post-SCT was 6.3% in MR and 18.2% in MU/MM allo-SCT recipients (P = 0.009). Early mortality was associated with infection in 70% of the patients, with a similar distribution between MR and MU/MM transplant recipients. However, MU/MM transplant recipients had significantly more early deaths due to toxic causes (P < 0.001). We conclude that early post-transplant MU/MM transplant recipients tend to have more documented infections, and have significantly more breakthrough infections with HSV-1 and more CMV reactivation. MU/MM transplant recipients are at higher risk of early mortality, especially due to toxic causes.     

Sirolimus-based graft-versus-host disease prophylaxis protects against cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation: a cohort analysis

Sirolimus-based immunosuppressive regimens in organ transplantation have been associated with a lower than expected incidence of cytomegalovirus (CMV) disease. Whether sirolimus has a similar effect on CMV reactivation after allogeneic hematopoietic stem cell transplantation (HSCT) is not known. We evaluated 606 patients who underwent HSCT between April 2000 and June 2004 to identify risk factors for CMV reactivation 100 days after transplantation. The cohort included 252 patients who received sirolimus-tacrolimus for graft-versus-host disease (GVHD) prophylaxis; the rest received non-sirolimus-based regimens. An initial positive CMV DNA hybrid capture assay was observed in 225 patients (37.1%) at a median 39 days after HSCT for an incidence rate of 0.50 cases/100 patient-days (95% confidence interval [CI], 0.44-0.57). Multivariable Cox modeling adjusting for CMV donor-recipient serostatus pairs, incident acute GVHD, as well as other important covariates, confirmed a significant reduction in CMV reactivation associated with sirolimus-tacrolimus-based GVHD prophylaxis, with an adjusted HR of 0.46 (95% CI, 0.27-0.78; P = .004). The adjusted HR was 0.22 (95% CI, 0.09-0.55; P = .001) when persistent CMV viremia was modeled. Tacrolimus use without sirolimus was not significantly protective in either model (adjusted HR, 0.66; P = .14 and P = .35, respectively). The protective effect of sirolimus-containing GVHD prophylaxis regimens on CMV reactivation should be confirmed in randomized trials.     

Risk factors for late cytomegalovirus infection after allogeneic stem cell transplantation using HLA-matched sibling donor: donor lymphocyte infusion and previous history of early CMV infection

An increased incidence of late cytomegalovirus (CMV) infection has been reported during the last decade since the introduction of ganciclovir (GCV) prophylaxis or GCV pre-emptive therapy. Given that a donor lymphocyte infusion (DLI) can induce more severe GVHD, this may predispose a patient to late CMV infection. In all, 64 patients (median age 36, M/F 38/26) underwent allogeneic stem cell transplantation (SCT) using a matched sibling donor with bone marrow (n=9) or peripheral blood stem cells (n=55). The overall incidence of CMV infection, early and late CMV infection was 46.9 (30/64), 42.2 (27/64), and 16.4% (9/55), respectively. Early CMV infection was treated with GCV pre-emptive therapy that produced a 92.6% success rate. Among the 20 patients who received 35 DLIs, late CMV infection developed in eight (42.1%) of 19 evaluable cases with a median onset at 127 days post transplant. Risk factors for late CMV infection in a logistic regression analysis included DLIs (P=0.001) and a previous history of CMV infection (P=0.006). In conclusion, late CMV infection was strongly associated with DLIs and a previous history of early CMV infection. Accordingly, extended surveillance of CMV antigenemia is recommended for patients receiving DLIs or who have a previous history of CMV infection.     

Virological, clinical, and ophthalmologic features of cytomegalovirus retinitis after hematopoietic stem cell transplantation.

We identified 10 patients who developed cytomegalovirus (CMV) retinitis after HSCT during a 14-year period. The median day of diagnosis of CMV retinitis after transplantation was day 251 (range, days 106--365). CMV retinitis was associated with CMV serostatus of donor or recipient (P=0.01), CMV reactivation before day 100 (P=0.007), delayed lymphocyte engraftment (P<0.05), and chronic graft versus host disease (GVHD; P<0.001). In allogeneic recipients of HSCT who were alive at day 100 after transplantation and had chronic clinical extensive GVHD, the incidence of GVHD was 1.4% (8 of 577). Five of 10 patients had other manifestation of CMV disease before retinitis occurred (4 with gastrointestinal disease and 1 with interstitial pneumonia; median time, 70 days before onset of CMV retinitis; range, 58--279 days), and 4 others had CMV excretion. CMV retinitis was bilateral in 4 patients; 9 of 10 patients had ocular symptoms (i.e., decreased vision and floaters). Six of 7 patients responded well to ganciclovir or foscarnet systemic treatment, 1 improved only after switching to cidofovir, and 1 patient who received a transplant in 1983 did not respond to acyclovir treatment. In conclusion, CMV retinitis is an uncommon late complication after HSCT that occurs mainly in seropositive allograft recipients with previous CMV reactivation and chronic GVHD, and with delayed engraftment of lymphocytes.     

Early and late invasive pneumococcal infection following stem cell transplantation: a European Bone Marrow Transplantation survey

Streptococcus pneumoniae (S. pneumoniae) may cause severe and lethal infections months and years following stem cell transplantation (SCT). In a prospective survey over a 3.5-year period, we assessed the incidence, risk factors and outcome for invasive pneumococcal infection (IPI) following SCT. Fifty-one episodes of IPI were reported: 43 episodes after bone marrow transplantation (BMT) and 8 after peripheral blood stem cell transplantation (PBSCT); 35 after allogeneic SCT and 16 after autologous SCT. Seven IPI episodes, all bacteraemias, were defined as early, occurring 1-35 d (median 3 d) post transplantation. Forty-four episodes were defined as late (> or = 100 d post SCT), occurring 4 months to 10 years (median 17 months) post transplantation. The incidences of early and late IPI were 2.03/1000 and 8.63/1000 transplantations respectively (P = 0.001). A higher incidence of late IPI was observed after BMT than after PBSCT (10.99 versus 3.23/1000; P < 0.01) and after allogeneic versus autologous SCT (12.20 versus 4.60/1000; P < 0.01). There was a higher estimated incidence of IPI in allogeneic patients with than in those without graft-versus-host disease (GVHD) (18.85 versus 8.25/1000; P = 0.015). The mortality rate was 20%, including 2/7 of early and 8/44 of late IPI. S. pneumoniae is a rare but important complication during the aplastic phase after SCT. In conclusion, S. pneumoniae is a significant cause of morbidity late post-transplantation, especially in allogeneic patients, and particularly those with GVHD. The high IPI mortality rate, both early and late post-transplantation, requires preventive approaches, mainly effective immunization.     

Patient cytomegalovirus seropositivity with or without reactivation is the most important prognostic factor for survival and treatment-related mortality in stem cell transplantation from unrelated donors using pretransplant in vivo T-cell depletion with anti-thymocyte globulin

We evaluated the cytomegalovirus (CMV) serostatus as a risk factor for survival and treatment-related mortality (TRM) in 125 patients allografted from an unrelated donor between 1994 and 1999. All patients received pretransplant in vivo T-cell depletion using rabbit anti-thymocyte globulin (ATG). Only one patient had primary graft failure and severe grade III/IV graft-versus-host disease occurred in 14% of the patients. The overall survival (OS) at 3 years was 70% for CMV-negative patients (n = 76) and 29% in the seropositive cohort (n = 49) (P > 0.001). In multivariate analyses, CMV seropositivity remained an independent negative prognostic factor for OS (RR: 2.1; CI: 1.2-3.8; P = 0.014), apart from age > 20 years (RR: 2.74; CI: 1.2-3.8; P = 0.004) and late leucocyte engraftment (RR: 2.4; CI: 1.2-4.9; P = 0.015). The TRM for all patients was 27%. Despite monitoring for CMV antigenaemia and preemptive therapy with ganciclovir when reactivation occurred, seropositive patients had a three times higher risk of fatal treatment-related complications than seronegative patients. In multivariate analyses, CMV seropositivity remained the strongest independent negative factor for TRM (RR: 5.3; CI: 1.9-14.6; P = 0.002), followed by age > 20 years (RR: 4.8; CI: 1.3-18.1; P = 0.02) and delayed leucocyte engraftment (RR: 3.6; CI: 1.2-11; P = 0.02). The TRM was identical in seropositive patients with (n = 27) or without (n = 22) CMV reactivation (44% versus 50%). We conclude that CMV seropositivity, despite preemptive ganciclovir therapy and even without reactivation, is a major negative prognostic factor for survival as well as for TRM in unrelated stem cell transplantation using pretransplant in vivo T-cell depletion with ATG.     

The impact of transfusion of leucodepleted platelet concentrates on cytomegalovirus disease after allogeneic stem cell transplantation

The impact of transfusion of leucodepleted platelet concentrates (PCs) on cytomegalovirus (CMV) disease was assessed in 215 allogeneic (145 unrelated and 70 related donor) transplants over 3 years. In 43%, both donor and patient were CMV seronegative (CMV-/-). All received CMV-seronegative red cells and random leucodepleted PCs. No CMV disease occurred in any CMV-/- (low risk) transplant. CMV infection occurred in 31 seropositive patients (26%); 13 died and five deaths were attributable to CMV disease. When compared with historical controls, who received CMV-seronegative PCs, we found no difference in transfusion-acquired CMV in the current cohort.     

Pulmonary complications after T-cell-depleted allogeneic stem cell transplantation: low incidence and strong association with acute graft-versus-host disease

Lung injury limits the success of allogeneic stem cell transplantation (SCT). The overall incidence varies from 30 to 50% and non-infectious causes occur in one-third to one-half of these. We reviewed pulmonary complications in 369 consecutive patients who received a partially T-cell-depleted myeloablative allogeneic hematopoietic SCT at our institution between 1993 and 2003. All patients were treated uniformly with cyclophosphamide followed by total body irradiation. Control subjects were matched on sex, underlying diagnosis, age, type of transplantation and cytomegalovirus (CMV)-serostatus. Sixty-one patients (16.5%) developed pulmonary complications. Twenty-one patients (5.7%) developed infectious pneumonia. Forty patients developed non-infectious complications which were further subclassified as bronchiolitis obliterans (3.5%), bronchiolitis obliterans-organizing pneumonia (0.5%), diffuse alveolar hemorrhage (0.8%), idiopathic pneumonia syndrome (5.5%) or mixed etiology (0.5%). Acute graft-versus-host disease (GVHD) > or =grade II was significantly more common in pulmonary patients than in the controls (36/61 versus 22/61 patients, P=0.02). There was no significant difference in the incidence of chronic GVHD (P=0.09). CMV reactivation was significantly more frequent in patients with lung injury (P=0.02). Median survival was 41 weeks for the pulmonary patients and 350 weeks for the controls (P=0.001). Altogether, the incidence of pulmonary complications is low after T-cell-depleted SCT and is associated with acute GVHD and CMV reactivation.     

Direct visualization of cytomegalovirus-specific T-cell reconstitution after allogeneic stem cell transplantation

Cytomegalovirus (CMV) remains an important cause of morbidity and mortality after allogeneic stem cell transplantation (SCT), but cytotoxic T lymphocytes (CTL) may play a critical role in controlling CMV reactivation. Fluorescent HLA-peptide tetramers containing immunodominant peptides from CMV were used to prospectively monitor the recovery of CMV CTL in recipients of allogeneic transplants from siblings (n = 13) or unrelated donors (n = 11). In patients given allografts from a sibling when both the patient and donor were seropositive for CMV before SCT, recovery of CMV-specific CTL was rapid and reached up to 21% of all CD8(+) T cells. Early reconstitution of CMV-specific immunity was not observed if either the donor or recipient was seronegative for CMV. In recipients of transplants from volunteer unrelated donors, recovery of CMV-specific CTL was delayed in comparison to that in recipients of transplants from siblings and no CTL were observed within the first 100 days after SCT. CTL numbers were increased after episodes of CMV reactivation but were suppressed by prednisolone therapy. Recovery of CMV-specific CTL to levels greater than 10 x 10(6)/L was associated with protection from CMV disease. It was concluded that use of HLA-peptide tetramers to quantify CMV CTL is valuable for studying T-cell responses after allogeneic SCT. It should allow prediction of CMV reactivation in individual patients and assist in the development of adoptive T-cell immunotherapy.     

Pre‐transplant cytomegalovirus (CMV) serostatus remains the most important determinant of CMV reactivation after allogeneic hematopoietic stem cell transplantation in the era of surveillance and preemptive therapy

B. George, N. Pati, N. Gilroy, M. Ratnamohan, G. Huang, I. Kerridge, M. Hertzberg, D. Gottlieb, K. Bradstock. Pre‐transplant cytomegalovirus (CMV) serostatus remains the most important determinant of CMV reactivation after allogeneic hematopoietic stem cell transplantation in the era of surveillance and preemptive therapy.
Transpl Infect Dis 2010: 12: 322–329. All rights reserved Abstract: Between January 2001 and June 2008, 315 adult patients (median age 43 years, range 16–65) including 203 males and 112 females undergoing hematopoietic stem cell transplantation (HSCT) had serial monitoring for cytomegalovirus (CMV) followed by initiation of preemptive therapy. The majority (62.1%) had a conventional myeloablative transplant with 116 (36.9%) having a reduced‐intensity conditioning (RIC) transplant, using either matched sibling/family (63.3%) or unrelated donors (36.7%). Graft source was peripheral blood stem cells in 257 (81.5%), bone marrow in 41 (13.1%), and cord blood in 16 (5.4%). T‐cell depletion with anti‐thymocyte globulin or alemtuzumab was used in 35%. Based upon CMV serostatus, patients were classified into low risk (donor [D]?/recipient [R]?), intermediate risk (D+/R?), or high risk (D?/R+ or D+/R+). Serial weekly monitoring for CMV viremia was performed using a qualitative polymerase chain reaction (PCR) and when positive, quantification was done using either pp65 antigen or a quantitative PCR. CMV reactivation was seen in 123 patients (39.1%) at a median of 50 days post HSCT (range 22–1978). CMV serostatus was the most important risk factor with incidence of 53% in the high‐risk group (53.3%) compared with 10.2% in the intermediate risk and 0% in the low‐risk group (P<0.0001). Other significant risk factors identified included use of alemtuzumab during conditioning (P=0.03), RIC transplants (P=0.06), and the presence of acute graft‐versus‐host disease (GVHD) (P<0.0001). On a multivariate analysis, CMV serostatus, RIC transplants, and acute GVHD remained independent predictors of CMV reactivation. All were treated with antiviral therapy with responses seen in 109 (88.6%). Sixteen patients (13%) developed CMV disease at a median of 59 days post HSCT (range 26 days–46 months), 8 of whom died. At a median follow up of 43 months (range 6–93), 166 patients (52.6%) are alive with a significantly higher survival among patients without CMV reactivation (57.2%) as compared with patients with CMV reactivation (45.5%; P=0.049). CMV reactivation and disease remains a major problem in high‐risk patients undergoing allogeneic HSCT. Novel prophylactic measures such as immunotherapy and drug prophylaxis need to be considered in this specific group of patients.     

Cytomegalovirus seropositivity adversely influences outcome after T-depleted unrelated donor transplant in patients with chronic myeloid leukaemia: the case for tailored graft-versus-host disease prophylaxis

Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after haematopoietic stem cell transplantation from matched unrelated donors (MUD). The role of T-cell depletion (TCD) as a strategy to prevent GVHD is controversial because of the associated increased risk of leukaemic relapse, graft failure and delayed immune reconstitution. The demonstration that donor lymphocyte infusion (DLI) is effective salvage therapy if patients relapse after transplantation for chronic myeloid leukaemia (CML) prompted us to examine the proposal that TCD may be a form of GVHD prophylaxis particularly suited to this disease in patients undergoing MUD transplantation. We analysed the outcome of 106 consecutive patients with CML in first chronic phase who underwent MUD transplantation. Patients were conditioned with cyclophosphamide and total body irradiation (TBI), and received in vivo TCD, using CD52 monoclonal antibody, as GVHD prophylaxis. Donor lymphocytes were infused at the time of leukaemic relapse. The projected survival at 5 years for all patients was 52.6%. The probability of developing severe acute GVHD (grade 3 or 4) was 14.5%. The only significant predictor of overall survival in univariate and multivariate analysis was patient cytomegalovirus (CMV) serostatus: in CMV-negative patients survival at 5 years was 60% vs. 42% in CMV-positive patients (P = 0.006). The use of TCD was associated with an increased risk of relapse (62% probability at 5 years after transplant), but 80% of patients who received DLI achieved molecular remission that was durable in all but two cases. In vivo TCD, in conjunction with DLI at relapse, is a valuable GVHD prophylactic regimen in CMV-seronegative recipients of MUD allografts, but in CMV-seropositive patients this approach is associated with an increased non-relapse mortality. Consequently, GVHD prophylactic regimens in MUD transplantation should be tailored according to the patient and donor pretransplant characteristics.     

Severe acute graft-versus-host disease after T-cell depleted allogeneic stem cell graft from a second donor caused by persisting T-cells from the first donor

HLA disparity is a major risk factor for graft rejection and GVHD. We report a patient with CML (accelerated phase) who underwent allogeneic SCT from a mismatched unrelated donor and developed acute GVHD. With immunosuppression, GVHD symptoms improved but graft rejection occurred. After a second conditioning regimen, the patient received a second graft from a haploidentical related donor. Engraftment occurred, but the patient died from GVHD and pulmonary aspergillosis. Chimeric analysis revealed that all leukocytes were of donor 2 origin apart from CD3+ T cells, which were 100% donor 1 type. Thus, in spite of intensified immunosuppression and successful transplantation of a second graft, T cells from the first donor persisted and induced severe acute GVHD.     

Autologous and allogeneic stem cell transplantation in adult ALL: the Swedish Adult ALL Group experience

Adult patients with acute lymphoblastic leukaemia (ALL) have been treated according to national protocols in Sweden since 1986. Stem cell transplantation (SCT) has been recommended in first remission for patients with risk factors for relapse, and for standard risk patients only after relapse. In this retrospective study, the results of autologous and allogeneic SCT in these populations were evaluated. In total, 187 patients with a median age of 34 years (17-66 years) underwent SCT. The 5-year disease-free survival (DFS), for all patients, was 26% (Confidence intervals (CI) 20-32%). The 5-year DFS was higher for patients transplanted in first remission 32% (CI 24-40%) compared to 14% (CI 5-23%; P<0.0001) in patients transplanted beyond first remission. No significant differences in DFS (P=0.06) were determined between autologous, related donor and unrelated donor SCT in the whole cohort. A lower relapse rate was counterbalanced by higher treatment-related mortality in patients undergoing allogeneic SCT. In Philadelphia-positive ALL, allogeneic SCT was superior to autologous SCT, with a 5-year DFS of 30% (CI 12-47%) vs 0% (P=0.04). Limited chronic graft-versus-host-disease (GVHD) was associated with an improved DFS of 53% (CI 38-69%) compared to no chronic GVHD of 22% (CI 10-36%; P=0.0008), indicating a clinically important graft-versus-leukaemia effect.     

Risk factors for acute graft-versus-host disease after allogeneic blood stem cell transplantation.

We evaluated demographic characteristics and graft composition as risk factors for acute graft-versus-host disease (GVHD) in 160 adult recipients of HLA-identical allogeneic blood stem cell transplants. The patients received a median nucleated cell dose of 7.9 x 10(8)/kg and median C34(+) cell dose of 5.6 x 10(6)/kg. GVHD prophylaxis consisted of cyclosporine (CSA) and steroids, tacrolimus (FK506) and steroids, or FK506 and methotrexate. Grades 2 to 4 GVHD occurred in 31% (95% CI, 23% to 39%), and grades 3 to 4 GVHD in 14% (95% CI, 8% to 20%). In univariate analyses, GVHD prophylaxis with CSA and high CD34(+) cell doses were significant risk factors for grades 2 to 4 GVHD, but diagnosis, age, use of total body irradiation, donor sex, female donor for male recipient, donor parity, donor alloimmunization, viral serology, nucleated cell dose, CD3(+) cell dose, and CD56(+) cell dose did not alter the incidence of GVHD significantly. With a CD34(+) cell dose less than 8 x 10(6) CD34(+) cells/kg, the risk of grades 2 to 4 GVHD was significantly higher for those who received CSA (39%, 95% CI, 21% to 47%) in comparison with those on FK506 (18%, 95% CI, 10% to 26%) (P =.03), but GVHD prophylaxis regimen had less impact with a higher CD34(+) cell dose (overall grades 2 to 4 GVHD rate 52%, 95% CI, 37% to 67%). GVHD prophylaxis and CD34(+) cell dose are independent risk factors for acute GVHD after allogeneic blood stem cell transplantation.     

Outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation (RISCT) using antilymphocyte antibodies in patients with high-risk acute myeloid leukemia (AML)

Hemopoietic stem cell transplantation (SCT) with fully ablative conditioning is associated with an age-related increase in treatment-related mortality. It is therefore particularly unsuited to older individuals, who are most at risk of developing acute myeloid leukemia (AML). Reduced-intensity SCT (RISCT) may be of value in this group. We report 17 consecutive patients with high-risk AML whose median age was 58 years and who received stem cells from HLA-matched siblings (n=5), or alternative donors (n=12). We used lymphodepleting antibodies as a part of the reduced-intensity conditioning regimen to limit the risk of graft rejection and graft-versus-host disease (GVHD). All patients engrafted. One patient developed severe fatal GVHD, and two patients died of infection. At a median follow-up of 861 days (372-1957 days), seven patients are alive in remission, which includes two patients treated in relapse and five patients who lacked an MHC identical sibling donor. Both progression-free survival and overall survival are 40% (95% CI, 17-64%). Hence, RISCT using lymphodepleting antibodies may be of value for older patients with AML, even in those with active or high-risk disease, and even if they lack an MHC-identical sibling donor.