We compared the occurrence of severe infections following 71 reduced-intensity conditioning (RIC) allogeneic peripheral blood stem cell transplants (PBSCT) and 123 standard myeloablative PBSCT (MINI and STAND groups, respectively) from HLA-identical siblings. The probability of 1-year infection-related mortality (IRM) was 19% in the STAND group and 10% in the MINI group (log-rank, P = 0.3). On multivariate analysis the only significant variable associated with a higher risk of IRM was the development of moderate-to-severe GVHD (P = 0.005). The probability of developing CMV infection was 39% in the STAND group and 21% in the MINI group (P = 0.03) (43% and 21%, respectively, in seropositive donor/recipient pairs, P = 0.01), and the probability of developing CMV disease was 9.5% and 1%, respectively (P = 0.05) (11% and 1%, respectively, in seropositive donor/recipient pairs, P = 0.03). Multivariate analysis of CMV infection identified four variables associated with a higher risk: CMV positive serostatus (P = 0.05), STAND transplant group (P = 0.02), the development of moderate-to-severe GVHD (P < 0.001) and a dose of CD34+ cells infused below 6 × 106/kg (P = 0.01). Invasive fungal infections and pneumonias of unknown origin did not differ between groups, and neither did other severe non-CMV viral infections and bacterial infections. Our results suggest that RIC allogeneic PBSCT may decrease the risk of dying from an opportunistic infection and reduces the occurrence of CMV infection and disease. Overall, the development of GVHD (acute or chronic) is an important risk factor for these complications. Other infections continue to pose a significant threat to recipients of RIC allografts, stressing that prophylactic and supportive measures are an important aspect in their care. Bone Marrow Transplantation (2001) 28, 341–347.
Following conventional allogeneic hematopoietic stem cell transplantation (HSCT) all patients experience a period of profound neutropenia and immunodeficiency that are significantly responsible for the serious infectious complications that ensue post transplant. Standard conditioning regimens for HSCT involve high-dose chemoradiotherapy given in doses that are myeloablative or at least severely myelotoxic. However, over the past years several groups of investigators have developed reduced-intensity conditioning (RIC) or non-myeloablative regimens, which lead to engraftment of donor lymphoid and hematopoietic stem cells without the extrahematologic toxicities of traditional myeloablative transplants.1,2,3,4,5,6,7 This reduced extrahematologic toxicity may lead to a reduction in infectious complications post transplant, since disruption of the gastrointestinal mucosa and/or damage to other key organs is a significant triggering mechanism of many of the infections that occur post transplant.8,9 On the other hand, graft-versus-host disease (GVHD) and its treatment has a profound negative impact on immune reconstitution following HSCT,10 and the impact of RIC regimens on the risk of acute and chronic GVHD is currently uncertain. The potential benefit on the risk of early infections derived from reduction of the intensity of the conditioning regimen may be negated by the immunodeficiency resulting from GVHD and its therapies. The overall clinical impact of these opposing effects is unknown, since there have been no studies comparing infectious complications after RIC and conventional allogeneic HSCT.
We compared the occurrence of severe infections following RIC allogeneic peripheral blood stem cell transplantation (PBSCT) and standard or conventional unmanipulated PBSCT, with special emphasis on infection-related mortality and cytomegalovirus infections.
Patients and methods
The group of patients who had received a RIC transplant from an HLA-identical sibling comprised adults who were entered into a prospective study in eight transplant centers in Spain. In summary, the inclusion criteria were presence of a myeloid or lymphoid malignancy potentially treatable by allogeneic transplantation, age ⩾45 years and/or having received a prior autologous HSCT. Patients gave written informed consent for inclusion in the protocol, which was approved by all local ethical review boards and the Spanish Drug Agency (protocol 99–0151). Between December 1998 and October 2000, 71 patients were included in the study, and thus at the time of data analysis (1 February 2001) all surviving patients had at least 100 days of post-transplant follow-up. This group will be referred to as the RIC group throughout the manuscript.
The comparison group of patients who had received a standard conditioning regimen (STAND group) prior to PBSCT were obtained from the database of the Spanish Group for Hematopoietic Transplantation (GETH) subcommittee on allogeneic PBSCT. All consecutive transplants are reported to this database, which contains details on the underlying disease, transplantation procedure and outcome of all recipients. At the time the study was begun, the GETH database included 323 unmanipulated PBSCT from an HLA-identical sibling. Since the baseline characteristics of these patients were very different from those in the RIC group, it was not possible to obtain appropriate matched controls. In order to homogenize baseline patients characteristics as much as possible, the following criteria were used to select the STAND group: transplants performed in the same institutions as the RIC group between 1996 and 1999 and who received the same GVHD prophylaxis (cyclosporine plus short-course methotrexate). All surviving patients in the STAND group had at least 9 months follow-up at the time of analysis.
For both groups of patients, each center completed a detailed case report form on infection prophylaxis and the infections observed post-transplant for each patient included in the study.
Disease phase at transplant was categorized as early (acute leukemia or poor-risk myelodysplasia in first complete remission, untreated good-risk myelodysplasia, first chronic-phase chronic myelogenous leukemia, lymphoid malignancy in first remission) and non-early (all other status at transplant). Assessment, grading and treatment of acute and chronic GVHD were done using standard methods.11 Infection data were collected retrospectively by each investigator until the patient's death or last follow-up. Infectious complications were defined as follows: (1) A severe bacterial infection was defined as bacteremia by any bacterial organism in a febrile patient, except for coagulase-negative staphylococci, Micrococcus spp. and saprophytic Corynebacterium spp., which were not included in the present analysis. Bacterial infections were divided into early (occurring within the first 30 days post transplant) and late infections (occurring beyond day 30). In patients with bacteremia septic shock was defined by at least two of the following three criteria: systolic blood pressure <90 mmHg (in a previously normotensive patient), heart rate ≥120 per min and respiratory rate ⩾28 per minute; (2) invasive fungal infections were divided into candidemia, invasive aspergillosis and other mycoses. Invasive aspergillosis was defined as possible (clinical signs and symptoms plus a compatible thoracic CT scan or X-ray), probable (clinical signs and symptoms, compatible X-ray findings plus a positive respiratory tract culture for Aspergillus spp.) and definite (positive histology for an invasive mould infection by aspergillus) infections; (3) cytomegalovirus (CMV) infection was defined as the presence of a single pp65 antigen-positive leukocyte or a positive viremia in peripheral blood, as well as documentation of CMV disease without prior positive antigenemia or viremia. CMV disease was defined as the demonstration of CMV in biopsy or autopsy specimens from clinically involved visceral sites by culture and/or histology, or if CMV was detected in culture (conventional or shell-vial) of BAL samples in the presence of new or changing pulmonary infiltrates; (4) pneumonia of unknown origin was defined as any new radiological lung infiltrate in a febrile patient with respiratory symptoms in the absence of a known pathogen.
Patients were considered to have died from infection (ie infection-related mortality) if death was attributable to a recent severe infection by each local investigator and/or an infection was identified at autopsy.
The primary outcomes that were analyzed in our study were infection-related mortality (IRM) and CMV infection. Since the follow-up for patients in the STAND group was longer than those in the RIC group, 1-year IRM was analyzed in addition to overall IRM. Other outcomes analyzed were bacterial infections, severe non-CMV viral infections, invasive fungal infections, pneumonia of unknown origin and other severe infections.
The chi-square statistic or Fisher's exact test were used to establish differences in the distribution of discontinuous variables and Student's t-test or Mann–Whitney's U-test to compare continuous variables. All reported P values are two-sided, and a significance level of 0.05 was used. All infectious events were calculated from the time of transplantation using Kaplan–Meier product-limit estimates. Patients who died with an active life-threatening infection were categorized as an IRM, which was determined from the date of transplantation until death. Patients who died from other causes were censored at the date of death, and those who were still alive at the time of reporting were censored at the last follow-up date. For the analysis of 1-year IRM all surviving patients were censored at day +365 post transplant. Since relapse or progression of the underlying malignancy may lead to immunodeficiency and secondary infections not related to the transplant procedure itself, patients were censored at the time of disease progression. Times to acute GVHD (aGVHD) grades II–IV and chronic GVHD (cGVHD) were calculated from the date of transplantation until occurrence of GVHD.
Univariate analyses of the different infections studied were performed using the log-rank test to see whether there was a difference in survival between groups, and univariate Cox regression was used to determine whether the relation was monotonous. To examine the effect of the type of transplant on the two primary outcomes of the study (1-year IRM and CMV infection), the variables that appeared significant on univariate analysis and those that were relevant in prior studies were used in a multivariate Cox proportional hazards regression analysis, with occurrence of aGVHD grades II–IV or extensive cGVHD included as a time-dependent covariate. The assumption of proportional hazards over time was tested for all explanatory covariates using a time-dependent covariate.
Patients and transplantation procedure
Table 1 details patient characteristics in both groups. As can be seen, the main relevant differences between the groups were age, underlying disease, disease phase and CMV serostatus. As conditioning, patients in the RIC group received fludarabine plus busulphan or melphalan, as previously described in detail.12 Prophylaxis for GVHD consisted of cyclosporine plus short-course methotrexate in all cases.
Most patients received antibiotic prophylaxis during neutropenia, which consisted of a fluoroquinolone in 86% of STAND group and 65% of RIC group patients (P < 0.001) and a broad-spectrum systemic antibiotic in 11% and 35%, respectively. Most patients in both groups also received antiviral prophylaxis with standard-dose (80% and 97%, respectively, P = 0.006) or high-dose acyclovir (14% and 3%, respectively) during neutropenia. Antifungal prophylaxis consisted of fluconazole during neutropenia in 80% and 83% of cases, respectively, while other systemically active antifungals were used in 11% and 4%. Intravenous immunoglobulin was used until day +100 post transplant in a higher proportion of RIC graft recipients (46% vs 82%, P < 0.001), while the use of G-CSF post-transplant was somewhat higher in the STAND group (30% vs 11%, respectively, P = 0.001). All patients were housed in single rooms with either laminar air flow or HEPA filtration systems during the early post-transplant course.
Graft-versus-host disease and follow-up
Median time to reach a neutrophil count of 0.5 × 109/l was day +15 post-transplant in both groups, with the exception of seven (6%) patients in the STAND group and two (3%) in the RIC group who died early (<day +15) without leukocyte recovery (P = 0.3).
The probability of developing grades II to IV aGVHD was 44% in the STAND group and 26% in the RIC group (P = 0.01), while the probability of developing extensive cGVHD was 40% in the STAND group and 44% in the RIC group. Since moderate-to-severe GVHD (both acute and chronic) is a well-known risk factor for infectious complications post-transplant, we calculated the probability of developing either grades II to IV aGVHD or extensive cGVHD, which was 60% in the STAND group and 54% in the RIC group (P = 0.1). This latter variable has been referred to as moderate-to-severe GVHD in the text.
Fifty-two per cent of patients in the STAND group and 70% in the RIC group were alive at last follow-up with a median follow-up of 815 (range 174–1876) and 236 days (100–915), respectively (P < 0.001). The follow-up times for patients who died were similar in both groups (median 131 and 94 days, respectively).
Infection-related mortality (IRM)
Table 2 shows the causes of IRM in both groups of patients. All but one infectious death occurred within the first year post-transplant. The probability of IRM was 19% in the STAND group and 17% in the RIC group, and the 1-year IRM were 19% and 10%, respectively (Figure 1). There were no apparent differences in the specific causes of IRM between either transplant group. On univariate and multivariate analyses the following variables were not related to the probability of 1-year IRM: transplant group, disease phase at transplant, donor/recipient CMV serostatus, recipient sex, recipient age and dose of CD34+ cells infused. On univariate analysis, the development of moderate-to-severe GVHD after transplant was not significant (21% 1-year IRM in those who developed GVHD vs 12% in those who did not, P = 0.3), but on Cox regression multivariate analysis it was an independent risk factor for 1-year IRM (RR 3.7 (95% CI 1.6–9.6), P = 0.005).
Table 3 details the life-threatening viral infections observed in both groups. The probability of developing CMV infection was 39% in the STAND group and 21% in the RIC group (P = 0.03) (Figure 2a); in seropositive donor/recipient pairs these probabilities were 43% and 21%, respectively (P = 0.01). The probability of CMV disease also differed between groups (9.5% in the STAND group and 1% in the RIC group, P = 0.05); in seropositive donor/recipient pairs these probabilities were 11% and 1%, respectively (P = 0.03). Treatment for CMV infection based on positive antigenemia or viremia did not differ between groups, and consisted of ganciclovir in 94% and 92% of cases, and foscarnet in 4% and 8%, respectively. One patient in the STAND group was not treated for CMV disease, while all other cases were treated either with ganciclovir alone (n = 4) or combined with high-dose IVIG (n = 6). Three patients in the STAND group and none in the RIC group died from CMV disease. Univariate analysis of the probability of developing CMV infection showed that recipient age, recipient sex and disease phase at transplant were not statistically significant, while the variables that were associated with this infection were transplant group (see above), donor/recipient CMV serostatus (35% in seropositives vs 6% in seronegatives, P = 0.04), the dose of CD34+/kg cells infused (26% if >6 × 106/kg vs 42% if ⩽6 × 106/kg) and the development of moderate-to-severe GVHD (41% in those who did and 22% in those who did not develop GVHD, P = 0.01). On Cox regression multivariate analysis, these same five variables were associated with a higher risk of CMV infection: transplant group (RR 2.2 (95% CI 1.1–4.3) for STAND vs RIC group, P = 0.02), CMV serostatus (RR 6.6 (95% CI 1.2–49.5) for seropositive vs seronegative donor/recipient pairs, P = 0.05), the dose of CD34+ cells/kg recipient weight infused in the graft (RR 2 (95% CI 1.2–3.4) for cellularity below vs above 6 × 106/kg, P = 0.01) and the development of moderate-to-severe GVHD (RR 2.8 (95% CI 1.6–4.9), P < 0.001). Figure 2b and c shows the Kaplan–Meier curves of CMV infection according to the development of moderate-to-severe GVHD in both groups of transplants. As seen in Figure 2b, the difference in CMV infection according to GVHD is especially relevant in the STAND group, with probabilities of 49% in the 64 patients who developed GVHD vs 24% in the 59 subjects who did not develop GVHD (P = 0.02). In the RIC group, however, the probabilities were low in both subgroups although somewhat higher in those who developed GVHD (24% and 19%, respectively, P = 0.5; Figure 2c). With respect to CMV disease, 10/11 patients had previously developed moderate-to-severe GVHD.
Other life-threatening viral infections were uncommon, without apparent differences between groups (Table 3), and there were no cases of post-transplant lymphoproliferative disease.
Bacterial infections and pneumonia
Fifty patients in the RIC group (70%) and 119 (97%) in the STAND group developed neutropenic fever (P = 0.01). Early invasive bacterial infections occurred in 14% (n = 17) of patients in the STAND group and 10% (n = 7) in the RIC group (P = 0.4), with 22 cases of bacteremia and two pneumonias. The species isolated in the STAND group were viridans-group streptococci in seven cases, Escherichia coli in four, Pseudomonas aeruginosa (n = 2), Stenotrophomonas maltophilia (n = 2) and other species in two cases; in the RIC group isolates included Escherichia coli in four, Pseudomonas aeruginosa (n = 2) and Staphylococcus aureus (n = 2). Late bacterial infections occurred in 17 patients in the STAND group and seven in the RIC group, with nine cases of bacteremia, two septic shocks, four pneumonias, five catheter-related infections and four soft-tissue infections. Many different species were isolated without apparent differences between groups: enterobacteria in 10 cases, non-glucose-fermenting gram-negative bacilli in five, other gram-negative bacilli in three, gram-positive bacteria in four and other bacteria in three patients.
The probability of developing pneumonia of unknown origin was similar in both groups (24% in the STAND group and 22% in the RIC group (P = 0.7)), as was death from this cause (9% in both groups). Pneumonia occurred early post-transplant (⩽day +30) in 3/21 patients and 2/11, respectively, while pneumonias occurred late post-transplant (>day +30) in 18/21 and 9/11 cases, respectively.
Invasive fungal infections
The probability of developing an invasive fungal infection was the same in both transplant groups (15 cases (14%) in the STAND group and six cases (11%) in the RIC group, P = 0.5). In the STAND group there were four cases of possible, three cases of probable and three cases of definite invasive aspergillosis. In the RIC group, there were two definite and one probable case. Moderate-to-severe GVHD preceded the onset of aspergillosis in 8/10 and 3/3 cases, respectively. There were four and two cases, respectively, of invasive candidiasis in each group. Other invasive mycosis included one penicillinosis and one mucormycosis in the STAND group, and one mucormycosis in the RIC group.
Other life-threatening infections
There were two cases of encephalitis of unknown origin in the STAND group, and five cases of Pneumocystis carinii pneumonia (PCP), one in the STAND and four in the RIC group (one patient in this latter group died from pulmonary aspergillosis plus PCP). Cases of PCP occurred on days +60 (n = 2), +92 and +150 in the RIC group in the context of treatment for GVHD in 3/4 patients. The fourth patient had advanced chronic lymphocytic leukemia with prior extensive treatment with fludarabine.
Besides leading to severe pancytopenia, standard ablative conditioning regimens produce numerous extrahematologic toxicities that contribute to the development of infectious complications post-transplant or complicate their diagnosis and treatment. Among these, damage to the mucocutaneous barriers, especially the gastrointestinal mucosa, is of special importance.9 Despite these theoretical considerations, there have been no studies on the impact of the conditioning regimen on the risk of suffering severe infections post-HSCT. Nonetheless, indirect evidence from randomized studies conducted in Seattle shows that intensifying the dose of TBI in the conditioning regimen from 12 Gy to 15.75 Gy may increase the risk of severe infections, increasing the IRM and possibly the incidence of specific infections such as CMV pneumonia.13,14 Our study is the first to show that reducing the intensity of the conditioning regimen may lead to the opposite effect: ie a reduction in the risk of suffering various severe infections post-transplant. Patients in the RIC group developed less neutropenic fever than did those in the STAND group, despite developing severe neutropenia post-transplant and recovering the neutrophil count in a similar fashion. Additionally, although the rates of early bacterial infections were similar between groups, it should be noted that viridans group streptococcal bacteremia occurred in 7/123 patients in the STAND group and none in the RIC group. This observation is consistent with the more modest damage to the gastrointestinal mucosa seen in recipients of RIC allografts. Late bacterial infections, however, did not differ between groups, and the occurrence of pneumonia of unknown origin late post-transplant, invasive fungal infections and non-CMV viral infections were also similar between groups. These observations are consistent with an early reduction of infectious morbidity followed by continued immunoincompetence due to GVHD and its treatment, similar to that seen after conventional HSCT.
Few other studies have analyzed the infectious complications after RIC allografts, and most have been reported in abstract form. Several studies have found a high rate of CMV infection with little CMV disease after such procedures,15,16,17,18 but in all of these RIC protocols antilymphocyte globulin15,16,18 or CAMPATH-lH17 were used in the conditioning regimen for promoting engraftment, which may lead to delayed reconstitution of CMV-specific T cell responses post transplant.19 On the other hand, a matched cohort study comparing 55 recipients of an RIC transplant without antilymphocyte antibodies with 110 matched recipients of a myeloablative transplant found a lower probability of CMV antigenemia (52% vs 71%, respectively, P = 0.1), CMV viremia (18% vs 33%, respectively, P = 0.03) and disease (6% vs 17%, respectively, P = 0.05) in the former group.20
The main pitfall of our study is the differences in baseline patient characteristics between both transplant groups. Since RIC allografts are currently offered to patients who are poor candidates for conventional myeloablative therapies because of older age or comorbidity, we were unable to perform a well-matched cohort study. Notwithstanding this pitfall, one should note that all major variables that may influence the transplant-related mortality, and specifically the IRM favor the control STAND group: lower patient age, more early-phase malignancies, no second transplants and lower rate of seropositivity for CMV pre-transplant. Despite this advantage of the STAND group, there was a clear trend for a lower 1-year IRM in the RIC group, although this did not reach statistical significance on univariate or multivariate analysis. On multivariate analysis the only risk factor for IRM was the development of moderate-to-severe GVHD post transplant. Again, this finding supports the fact that although recipients of RIC allografts may have a lower risk of early fatal infectious events, the development of, and treatment for acute and chronic GVHD will be a major determining factor in their risk of dying from an infection.
An interesting finding in our study was the significantly lower risk of developing CMV infection and disease post-transplant in the RIC group. These differences were more marked in seropositive donor/recipient pairs, an important subanalysis since there were more seronegative pairs in the STAND group. In our study, other risk factors for CMV infection found on univariate and multivariate analyses were CMV seropositive status, development of moderate-to-severe GVHD and higher infused doses of CD34+ cells. The protective effect of higher infused doses of CD34+ cells on CMV infection may seem unexpected, despite the fact that high stem cell doses have been reported to reduce transplant-related mortality and improve other transplant outcomes following conventional HSCT.21,22,23,24,25 Of note, the protective effect of high CD34+ cell doses on CMV infection was also found in a previous retrospective study from our group comparing the infectious complications between unmanipulated and CD34+-cell selected PBSCT.26 If other studies confirm these observations, then the intensity of the conditioning regimen used and the stem cell dose infused would be modifiable risk factors for the development of CMV infection.
In summary, the results from our study suggest that RIC allogeneic PBSCT may decrease the risk of dying from an opportunistic infection during the first year post-transplant. The risk of CMV infection and disease was lower in these patients. Overall, the development of moderate-to-severe GVHD (acute or chronic) was an important risk factor for 1-year IRM and CMV infection. Of special relevance for the management of recipients of RIC allografts is that the risk of developing severe non-CMV viral infections, invasive fungal infections, pneumonia of unknown origin and other opportunistic infections appears to be as high as after a conventional transplant, and in these patients maximum efforts for the prevention and early treatment of opportunistic infections should be pursued.
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