Reduced dose intravenous immunoglobulin does not decrease ...

Biology of Blood and Marrow Transplantation 5:369–378 (1999) © 1999 American Society for Blood and Marrow Transplantation

Reduced dose intravenous immunoglobulin does not decrease transplant-related complications in adults given related donor marrow allografts Lyle C. Feinstein, Kristy Seidel, Jane Jocum, Raleigh A. Bowden, Claudio Anasetti, H. Joachim Deeg, Mary E.D. Flowers, Emin Kansu, Paul J. Martin, Richard A. Nash, Jan Storek, Ruth Etzioni, Frederick R. Applebaum, John A. Hansen, Rainer Storb, Keith M. Sullivan Fred Hutchinson Cancer Research Center and the University of Washington School of Medicine, Seattle, Washington Correspondence and reprint requests: Keith M. Sullivan, MD, Division of Medical Oncology and Transplantation, Duke University Medical Center, DUMC 3476, Durham, NC 27710 (Received 27 November 1998; accepted 2 September 1999)

ABSTRACT Graft-vs.-host disease (GVHD) and infection are major complications of allogeneic bone marrow transplantation. Intravenous immunoglobulin (IVIg) given at a dose of 500 mg/kg/wk has been shown to decrease the risk of acute GVHD, interstitial pneumonia, and infection in adults early after allogeneic transplantation. The current study is a controlled trial to determine whether a lower total dose of IVIg given with pretransplant loading reduces the incidence of transplant-related complications. In a randomized trial of 241 patients $20 years of age who were given related donor marrow allografts, 121 individuals receiving Ig prophylaxis (500 mg/kg/d loading from day –6 to –1 and then 100 mg/kg every 3 days from day 3 to 90) were compared with 120 control patients who did not receive IVIg. Randomization was stratified by human leucocyte antigen–matching, remission status of malignancy, GVHD prophylaxis, and cytomegalovirus (CMV) serology. The study was powered to detect a reduction in acute GVHD by 18% and a decrease in transplant-related mortality by 17%. Pretransplant IVIg loading and posttransplant maintenance achieved median serum IgG levels .1350 mg/dL, which were approximately twofold greater than the untreated controls (p , 0.01). White blood cell and platelet recoveries were similar for the two groups, although control patients required fewer units of platelets per day (2.5 vs. 3.3, p 5 0.008). No significant differences in the incidence of CMV infection, interstitial pneumonia, or bacteremia were observed. The incidence of acute GVHD did not differ between the two groups; however, acute GVHD was less frequent among IVIg recipients achieving maximum serum IgG levels .3000 mg/dL (60 vs. 79%). Neither transplant-related mortality nor disease-free survival was significantly altered by Ig prophylaxis. However, the cumulative incidence of relapse of malignancy was higher in IVIg recipients than in controls (31 vs. 18%, p 5 0.03). Multivariable regression analysis demonstrated a 1.89 increased relative risk of relapse for individuals given IVIg (p 5 0.021). We conclude that pretransplant loading and a shorter course and lower total dose of IVIg prophylaxis did not appear to decrease the risk of acute GVHD or mortality among adults receiving related donor marrow transplants. Note, IVIg administration may be associated with an increased risk of recurrent malignancy, a finding that warrants further investigation.

KEY WORDS Bone marrow transplantation

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Graft-vs.-host disease

NTRODUCTION Graft-vs.-host-disease (GVHD) and associated infections remain major determinants of morbidity and mortality follow-

This study was supported by grants from the National Cancer Institute (CA 18029, CA 15704, and CA 18221); the National Heart, Lung, and Blood Institute (HL 36444); and Miles Laboratories of the Bayer Corporation.

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Intravenous immunoglobulin

ing allogeneic marrow grafting [1,2]. In a previous controlled trial we found that the rates of acute GVHD, interstitial pneumonia, and infection were reduced in adults who received intravenous immunoglobulin (IVIg) prophylaxis following marrow transplantation from related marrow donors [3]. In that study, IVIg initially was given at a weekly dose of 500 mg/kg until day 90, then monthly until day 360 posttransplant. This 12 g/kg regimen (500 mg/kg for 24 infusions)

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was lower than the 19 g/kg regimen reported by Winston et al. [4] (1000 mg/kg for 19 infusions), which also showed a significant reduction in acute GVHD. Recently, in a randomized trial comparing doses of 250 and 500 mg/kg of IVIg given to transplant recipients weekly from day –8 to day 111, AbdelMageed et al. [5] demonstrated that the higher dose was associated with less acute GVHD (p 5 0.03). Pharmacokinetic studies of IVIg administration in marrow graft recipients have shown a shortened serum IgG half-life relative to nontransplant individuals [6–9], and continuous infusion of IVIg appears to yield higher IgG levels than does intermittent dosing [10]. Cottler-Fox et al. [11] observed that after receiving IVIg at 500 mg/kg/wk, patients who developed acute GVHD had significantly lower trough IgG levels (,1200 mg/dL) at and after day 20 posttransplant than did patients without GVHD (trough levels $1200 mg/dL). Pharmacokinetic modeling by these investigators determined that when analyses were restricted to days before the diagnosis of GVHD, serum IgG patterns did not significantly differ between GVHD and non-GVHD groups [12]. However, once patients developed GVHD, their serum IgG levels decreased more rapidly than in individuals free of GVHD. If serum levels of IgG were of causal importance in modifying GVHD, then intensive IVIg loading before transplantation followed by replacement maintenance dosing might further enhance the beneficial effect. The following controlled trial was designed to test whether pretransplant loading of IVIg with a lower and less costly 6 mg/kg total dose would decrease the incidence of acute GVHD and transplant-related mortality in adults undergoing related donor transplantation.

METHODS Study design The trial was a stratified randomized comparison of patients who received Ig prophylaxis and control patients who did not. Study endpoints were acute GVHD and transplant-related mortality. Stratification factors for randomization included type of marrow transplant (human leukocyte antigen [HLA]-identical or HLA-nonidentical), remission status of malignancy, cytomegalovirus (CMV) serostatus, and GVHD prophylaxis. Patients were eligible for study if they were $20 years of age and undergoing related donor marrow transplantation for hematologic malignancy. Kinetic values in a one-compartment model with firstorder elimination allowed estimation of the IVIg schedule needed to reach and maintain a desired serum concentration. Using values reported by Schiff [13] of volume of distribution 5 0.5 L/kg, half-life 5 25 days, and serum clearance 5 2 mL/kg/d, respectively, we derived estimates of loading and maintenance doses of IVIg required to maintain an average serum concentration. A loading dose of 500 mg/kg/d for 6 days was calculated to produce a serum IgG concentration of ~4500 mg/dL at the end of the sixth infusion. To achieve a steady-state IgG concentration of 1700 mg/dL through day 75, the estimated maintenance dosing re q u i red was 100 mg/kg IVIg given e v e ry 3 days after loading.

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Treatment pr otocol Consent forms were approved by the institutional review b o a rd. To evaluate pharmacokinetic models, nine pilot patients received 500 mg/kg infusions of IVIg through a Hickman catheter from days –6 to –1 pretransplant. These patients did not receive additional IVIg. Subsequent study patients were randomized to receive IVIg infusions of 500 mg/kg daily from days –6 to –1 pretransplant followed by 100 mg/kg every third day posttransplant from day 3 to day 90 (total 6 g/kg). The rate of infusion was 0.01 mL/kg/min for the initial 15 minutes, followed by 0.02 mL/kg/min for 15 minutes, followed by 0.04 mL/kg/min for 30 minutes, and then 0.08 mL/kg/min thereafter. The IVIg product (Gamimune Ν; Cutter Biological, Miles, West Haven, CT) was manufactured using the CohnOncley method of cold ethanol fractionation and purified by diafiltration with water at pH 4 [3,13]. Transplantation r egimen The characteristics of the study groups are presented in Table 1. Pat ie nts we re pre p a red for transpl ant with cyclophosphamide (120 mg/kg) and either busulfan or, more c o m m o n l y, total-body irradiation from opposing cobalt

Table 1. Patient characteristics Factor

IVIg

No IVIg

Number of patients Age 20–39 years 40–60 1 years Disease Malignancy-Rem or CP Malignancy-Rel or BC Other Related donor HLA-identical HLA-nonidentical Preparative regimen CY 1 .1200 cGy TBI BU/CY CY 1 1200 cGy TBI BU/CY/TBI Other GVHD prophylaxis CSP 1 MTX CSP alone CSP 1 prednisone MTX alone Other T-cell–depleted Growth factors Pentoxifylline CMV seropositive Entered LAF Second transplant

120

121

64 56

67 54

57 48 15

54 51 16

94 23

89 31

50 30 16 10 14

59 24 17 16 5

79 8 12 5 13 3 17 38 65 37 8

81 10 8 5 16 1 15 32 70 39 3

BC, blast crisis; BU, busulfan; CMV, cytomegalovirus; CP, chronic phase; CSP, cyclosporine; CY, cyclophosphamide; IVIg , intravenous immunoglobulin; LAF, laminar air flow; MTX, methotrexate; Rel, relapse; Rem, remission; TBI, total-body irradiation.

sources in fractionated total doses of 12–15.75 Gy given over several days at 6–7 cGy per minute. The day of marrow infusion was designated day 0. Most individuals received GVHD prophylaxis with methotrexate and cyclosporine [14]. The assessment and grading of acute and chro n i c GVHD have been previously described [15,16]. Acute GVHD of grades II–IV severity was treated with methylp rednisolone (2 mg/kg/d), antithymocyte globulin (15 mg/kg given daily for six doses), cyclosporine (3 mg/kg/d intravenously or 12.5 mg/kg/d orally), or a combination of these agents [17]. Chronic GVHD was treated with prednisone alone (1 mg/kg every other day) or in combination with cyclosporine (12.0 mg/kg every other day) [18,19]. Supportiv e care The following care was routinely given to both Ig recipients and control patients. To prevent P n e u m o c y s t i s c a r i n i i infection, administration of trimethoprim/sulfamethoxazole was initiated in each patient on arrival at the transplant center and continued until day –2. Upon return of neutrophil counts to $500/mm3 for 2 days consecutively, trimethoprim/sulfamethoxazole was resumed twice weekly until day 180. To prevent exogenous acquisition of primary CMV infection, all seronegative patients with seronegative marrow donors received red blood cell and platelet transfusions from seronegative blood donors exclusively [20,21]. Seropositive patients did not receive screened blood products. To prevent endogenous reactivation of CMV in seropositive patients, ganciclovir was initiated at engraftment (absolute neutrophil count .7 5 0 / m m3 for 2 days consecutively) and administered at a dose of 5 m g / k g twice daily for 5 days followed by 5 mg/kg/d 6 days per week until day 100, or whenever CMV antigenemia developed [22]. To prevent reactivation of herpes simplex virus in seropositive patients, acyclovir 250 mg/m2 twice daily was started on the day of conditioning and given until day 30, or the day of hospital discharge if it occurred before day 30. Acyclovir was discontinued if ganciclovir was initiated. Ceftazidime was used prophylactically during neutropenia to prevent bacterial infection. Fluconazole was given for fungal prophylaxis from the start of conditioning through day 75 posttransplant [23]. Ig could be given off protocol under only three conditions: 1) patients in either group could receive ganciclovir and Ig for treatment of CMV pneumonia that was confirmed by tissue examination [24], 2) patients in the control group could receive Ig as necessary if hypogammaglobulinemia (IgG levels ,500 mg/dL) developed, and 3) patients in either group could receive Ig for treatment of idiopathic thrombocytopenia purpura to control bleeding or to permit surgery. In both study groups, serum IgG levels were tested before protocol entry, on days –3 through 7, and on days 30, 60, 90, 120, 150, 180, 270, and 360. Patients entered into the pharmacokinetics study had testing discontinued after day 90. Definition and evaluation of inf ection The following conventions were established before the study began. Bacteremia was defined as the occurrence of one or more blood cultures positive for any org a n i s m , regardless of associated symptoms. Septicemia was defined as the occurrence of bac teremi a in conjunction with

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hypotension (systolic blood pressure ,90 mmHg or diastolic blood pressure ,60 mmHg) or disseminated intravascular coagulation (decreased fibrinogen and increased fibrin degradation products) documented within 24 hours of the positive blood cultures. Cellulitis was defined as a localized erythema and swelling associated with either a positive aspirate or biopsy culture for an organism other than coagulasenegative Staphylococcus or a positive blood culture (or two positive blood cultures when the organism was coagulasenegative Staphylococcus) in the absence of a positive local culture. Pneumonia was defined as a new or progressive pulmonary radiographic infiltrate and the identification of an infectious pathogen by bronchial alveolar lavage, bronchial washi ng, or biopsy of lung parenchym a. A Hickman catheter infection was denoted as either a local erythema at the exit site with purulent drainage positive for a single or predominant organism or inflammation (including redness and tenderness) at least 1 cm or more up the line from the exit site or at any other point along the tract with an associated positive blood culture in the absence of a positive local site culture. Urinary tract infection was defined as a urine culture with $50,000 colonies of a single organism with or without symptoms. Seronegativity for CMV was indicated by negative serologic result (titer ,1:8) by both latex agglutination and complement fixation. CMV infection was demonstrated by isolation of the virus from any site in previously uninfected patients, whereas CMV disease was indicated by any tissue evidence of virus with associated signs and symptoms of infection. Viral, fungal, and bacterial cultures were ro u t i n e l y obtained from biopsy and autopsy specimens and during diagnostic evaluations of fever. Patients were examined for infection daily in the hospital and at least weekly in the clinic until discharge from the Seattle center, which occurred a median of 99 days after transplantation. P atients A total of 260 patients were registered and 241 were evaluable. Those who were nonevaluable received no study drug. Patients were designated as nonevaluable for the following reasons: randomization to a competing pro t o c o l (eight patients), refusal to participate after initially enrolling (six), not having undergone transplantation (two), diagnosis of multiple myeloma for which IVIg infusions are standard of care (one), allergy to IVIg (one), and loss of eligibility due to change in status variables (one). Table 1 shows the characteristics of the study groups. Statistical anal yses The trial was a two-armed open-label randomized comparison of patients who received IVIg and control patients who did not. The primary endpoints were grades II–IV acute GVHD and transplant-related mortality. A sample size of 240 patients was chosen to allow detection of an 18% de cline in the incidence of acut e GVHD or a 17% decline in nonrelapse mortality with a statistical power of $0.80 (a level 5 0.05). Descriptive statistics were used to summarize patient and transplant characteristics within each study gro u p . Median serum IgG levels were plotted over time for both the loading period and the maintenance phase. Acute

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Figure 1. Kinetics of pretransplant intravenous immunoglobulin (IVIg) loading in nine pilot study patients. Posttransplant IVIg was not given. Values are means 6 SE. Cmax, maximum concentration; CLS, serum clearance; and Vd, volume of distribution.

GVHD, bacteremia, septicemia, local infections, CMV disease, interstitial pneumonia, and relapse were summarized and compared between study arms using cumulative incidence methodology [25]. This approach is necessary because all endpoints are subject to the competing risk of death as well as to ordinary censoring. The endpoint of transplant-

related mortality has the competing risk of relapse, and so was also analyzed using cumulative incidence. Disease-free survival was summarized graphically with Kaplan-Meier curves and compared between study arms by logrank test. Cox regression analysis was used to assess risk factors in multivariable models.

Figure 2. Serum IgG levels (mg/dL) among treatment arm patients during the loading period. Posttransplant IVIg was given.

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Figure 3. Median serum IgG levels (with 25th and 75th percentiles) of IVIg recipients and controls who did not receive Ig.

RESULTS Antibody titers, side effects, and engraftment The kinetics of IVIg loading in nine pilot patients are displayed in Figure 1. Serum IgG levels during IVIg loading in the randomized patients are presented in Figure 2. As shown in Figure 3, the treatment group achieved higher IgG levels than did the controls (p , 0.01). Median IgG values in IVIg recipients exceeded 1350 mg/dL on days 30–90 posttransplant. Some control patients received supplemental IVIg before day 82 for medical indications, and observations collected on these individuals after administration of the first dose were excluded from calculation of the curves in Figure 3. Only 10 such patients received their first dose of IVIg before day 80, whereas another 22 received the initial dose on days 80–100. Adverse reactions occurred in eight patients during 10 (0.27%) of the 3704 infusions. These included chills (two infusions), dizziness (one), bradycardia (one), headache (one), rash (one), and other symptoms (four). There was no apparent hepatotoxicity. As shown in Table 2, total bilirubin levels in the Ig recipients were lower than those in controls (median 0.85 mg/dL vs. 1.1, p 5 0.03). Recovery of the white cell counts was similar in the two study groups. Control patients re q u i red fewer units of platelets per day than those receiving IVIg (median 2.5 units vs. 3.3, p 5 0.008). The median day to platelet independence did not differ significantly between the two groups. Inf ection and interstitial pneumonia Table 3 summarizes infection data in the two cohorts. The rates of bacteremia, septicemia, and local infection did not differ significantly between the groups. Coagulasenegative staphylococcus was the most common isolate. The overall incidence of CMV infection was not altered in a statistically significant manner by use of IVIg in CMV seronegative patients (p 5 0.085) or seropositive individuals (p 5 0.38). The cumulative incidence of first bacteremia

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in CMV seronegative patients (p 5 0.24) and seropositive patients (p 5 0.79) also did not differ. No significant diff e rences in the incidence of first interstitial pneumonia were noted in CMV seropositive (p 5 0.8) or seronegative (p 5 0.53) individuals. Acute GVHD As shown in Figure 4, grades II–IV acute GVHD were nearly 20% less frequent among IVIg recipients achieving maximum serum IgG levels $3000 mg/dL (60% vs. 79%). However, the cumulative incidence of acute GVHD did not differ significantly between the two treatment groups as a whole (placebo 73% vs. IVIg 65%, p . 0.20). The incidence of acute GVHD was similar between treatment arms, both among HLA-identical patients (placebo 67% vs. IVIg 61%) and among HLA nonidentical patients (placebo 90% vs. IVIg 83%). Administration of IVIg also did not influence the incidence of grades III–IV acute GVHD (placebo 39% vs. IVIg 38%). Hospital days and costs The number of hospital days and days from transplant to return home were similar for the two groups. Mean hospital and outpatient charges, independent of the cost of IVIg, also did not differ substantially. Sur vival, r elapse , and mor tality As shown in Figure 5, overall survival at 6 years did not differ between control and treatment groups (placebo 49% vs. IVIg 38%, p 5 0.11). We noted a trend toward decreased disease-free survival in IVIg recipients compared with controls (p 5 0.07). The magnitude of the increase in risk was similar for HLA-identical individuals and HLA-nonidentical recipients (relative risk 5 1.4 in both subgroups). Transplant-related mortality did not differ between treatment groups (p 5 0.92). As shown in Figure 5, the cumulative incidence of overall relapse was greater among patients

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Table 2. Posttransplant events Factor Engraftment (median day) ANC . 200 ANC . 500 ANC . 1000 Platelet recovery (median) Days to platelets .50,000 Days to last platelet transfusion Days of platelet transfusions Units/d Total units Median day 90 liver function tests AST Alkaline phosphatase Total bilirubin Mean days First hospital stay Total hospital stays BMT to day home

No IVIg

IVIg

17 20 23

17 20 23

36

33 55 25 3.3 115

70 37 2.5 ( p 5 0.008) 100 34 74 1.1 ( p 5 0.03)

41 92 0.85

30 40 99

31 41 96

ANC, absolute neutrophil count; AST, aspartate aminotransferase; BMT, bone marrow transplant; IVIg, intravenous immunoglobulin.

randomized to receive IVIg (31% vs. 18%, p 5 0.03). Cox regression analysis, adjusting for stage of malignant disease at transplant and donor type (HLA-identical, HLA-nonidentical, or T-cell–depleted) revealed a 1.89 increased relative risk of relapse among IVIg patients compared with controls (p 5 0.021).

disease patients indicate a half-life of IgG of 23 days or greater [32,33]. However, serum concentrations may not follow first-order kinetics over a broad range of concentrations and disease states [34]. Pharmacokinetic studies of IVIg in marrow graft recipients are inconsistent; some report findings similar to those expected for healthy subjects, whereas many others suggest a shortened half-life of ~3–10 days [6–9]. Using values reported by Schiff [13] for volume of distribution, half-life, and clearance of IVIg in p r i m a ry immunodeficiency patients, a loading dose of 500 mg/kg/d for 6 days was estimated to produce a serum concentration of about 4500 mg/dL at the end of the sixth infusion. This was nearly achieved in the pilot study of nine patients demonstrating a peak serum IgG concentration of 4027 6 165 mg/dL. Because of the decreased half-life and increased clearance of IgG observed in marrow allografts, patients were maintained on a dosage of 100 mg/kg IVIg every 3 days to sustain a target steady-state concentration of ~1700 mg/dL. Failure to achieve these levels of serum IgG may be explained by the reduced half-life and increased clearance of IVIg in transplant recipients compared with patients with primary immunodeficiency. Unique circumstances in marrow graft recipients such as protein-losing enteropathies, increased macrophage priming, and acute GVHD may further explain some of the observed differences [35–37]. Despite there being no significant difference in cumulative incidence of grades II–IV acute GVHD between randomized groups in the current study, the potential importance of serum IgG levels was demonstrated by the finding that acute GVHD was less frequent among patients achieving maximum serum IgG levels .3000 mg /dL. It is unclear, however, whether this is a cause or an effect in relation to the development of GVHD.

DISCUSSION The current study found that patients randomized to receive pretransplant loading and subsequent reduced doses of IVIg did not have a significant reduction in acute GVHD compared with patients who did not receive Ig. However, among HLA-identical patients .20 years of age treated with IVIg in the current study, the 61% cumulative incidence of grades II–IV acute GVHD was substantially higher than the 28% incidence in adult IVIg recipients in our previous report [3], despite a similar methotrexate/cyclosporine regimen for GVHD prophylaxis. Factors influencing the development of acute GVHD include HLA matching, stage of malignant disease at transplantation, intensity of the preparative regimen, patient age, GVHD prophylaxis, and donor-recipient gender [26–31]. To better understand the effect of IVIg on acute GVHD in the prior and the current randomized trials, data from the previous study were reevaluated using only related allogeneic recipients .20 years old. Of the 264 patients selected, major differences in risk factors for GVHD between the studies were not noted. Given that these factors did not differ between the two trials, the increased incidence of acute GVHD in the current study might be attributable to lower serum IgG levels achieved due to the reduced IVIg dosing. Catabolism of IgG follows a multicompartmental model of first-order elimination [13]. Numerous studies in primary immunodeficiency

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Table 3. Posttransplant infections Factor Number of infections per patient No infection 1 2 3–4 $5 Total Organisms CN staphylococcus Herpes simplex virus Clostridium difficile Candida Aspergillus Cytomegalovirus Other organisms Total Rates/100 days (day 0–100) Patient days at risk Septicemia Bacteremia Local infection

CN, coagulase negative.

No IVIg

IVIg

31 (26%) 36 (30%) 14 (12%) 26 (21%) 14 (11%) 121 (100%)

32 (27%) 33 (28%) 21 (18%) 17 (14%) 17 (14%) 120 (100%)

46 22 16 7 5 10 136 242 10,903 0.13 0.77 1.32

47 26 25 13 10 3 126 250 10,419 0.07 1.13 1.20

Figure 4. Cumulative incidence of grades II–IV acute graft-vs.-host disease (GVHD) among IVIg recipients achieving maximum serum IgG levels .3000 mg/dL and ,3000 mg/dL.

Differences in neither risk factors for acute GVHD nor serum IgG levels can explain the discrepancy in incidence of acute GVHD among HLA-identical controls in the current and previous studies (67% vs. 43%). The increased incidence of acute GVHD for both control patients and those receiving IVIg may, in part, be related to differences in the expression or grading of acute GVHD or other currently unrecognized factors [38]. As described in a meta-analysis of 12 controlled trials of IVIg prophylaxis after marrow transplantation, for studies

reporting endpoints of acute GVHD in 379 patients, the pooled odds ratio of developing acute GVHD was 0.68 (95% confidence interval, 0.45–1.02) among IVIg recipients compared with controls not given IVIg [39]. Overall mortality reported in 809 patients showed an odds ratio of mortality of 0.74 (0.55–0.99) (values ,1.0 suggest that IVIg was effective). Meta-analysis of controlled trials of IVIg on symptomatic CMV infection showed a pooled odds ratio of 0.55 for CMV seronegative patients and 1.07 for CMV seropositive patients given IVIg. The pooled odds ratio for the effect

Figure 5. Kaplan-Meier estimates of overall survival among of IVIg recipients and controls and cumulative incidence of relapse of malignancy.

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of IVIg on fatal CMV infection was 0.47. In that analysis, the authors suggested that a significant decrease in fatal CMV infection without a significant decrease in all symptomatic CMV infections (when considering CMV negative and CMV positive recipients together) was consistent with the theory that IVIg reduces microbial disease by facilitating a regulated inflammatory response to infection rather than decreasing the incidence of infection. If this theory is valid, the lack of a reduction in infection may be due to a failure to achieve immunomodulatory levels of serum IgG. In addition, the hypogammaglobulinemia seen in the untreated control patients in the previous study [3] may have been an important cofactor. In contrast, hypogammaglobulinemia was less common in the current control group, and it was treated when it occurred. Failure of the current IVIg regimen to reduce the incidence of interstitial pneumonia and infection early after transplant may be related to the lower serum IgG levels achieved or the lack of effect on GVHD and the subsequent risk of infection. The latter hypothesis is supported by the finding that when IVIg is given on a monthly basis, IgG levels decreased sharply and IVIg prophylaxis had no apparent effect on chronic GVHD or late infection [40]. In the previous trial, transplant-related mortality was significantly reduced among IVIg recipients .20 years of age who received HLA-identical marrow [3]. In these adult patients, relapse rates were similar for IVIg recipients and untreated controls. The relapse rate, however, was higher in patients ,20 years of age who received IVIg prophylaxis [3]. The data from this pediatric group receiving IVIg were confounded by a markedly higher number of patients entering transplantation programs in relapse compared with controls who were not given IVIg. In the present study of adults given related-donor transplants, the cumulative incidence of relapse was greater among individuals randomized to receive IVIg (31% vs. 18%, p 5 0.03). Multivariable regression analysis, adjusting for stage of disease at transplantation and donor type (HLA-identical, HLA-nonidentical, or T-cell–depleted) failed to alter this finding. It is important to note that the 5.7-year median duration of follow-up in the current study is substantially longer than the 2.0-year median follow-up in the previous report. Thus, the power to discriminate between the two study arms increased, perhaps allowing a detection of late differences. The apparent increased incidence of relapse in patients randomized to Ig prophylaxis may also be due to other unknown factors. The immunomodulatory effect of IVIg in the treatment of autoimmune disease has been well described [41–44]. In addition, the antileukemic effect of acute and chronic GVHD is well known [45–47]. Intravenous Ig may attenuate this graft-vs.-leukemia eff e c t without an overt reduction in associated clinical GVHD, suggesting that the two processes may be more mechanistically distinct than was previously thought. A multicenter randomized controlled trial comparing IVIg with placebo in unrelated-donor marrow recipients has recently completed the accrual of 500 patients. Before entry, patients were stratified according to factors influencing relapse and GVHD. This placebo-controlled trial of conventional dose Ig (500 mg/kg/wk to day 90 without pretransplant loading) will offer an opportunity to further study the effect of IVIg on posttransplant disease recurrence.

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In conclusion, pretransplant loading with a short e r course and lower total dose of IVIg prophylaxis did not decrease the risk of acute GVHD, infection, or mortality among adults receiving allogeneic marrow from re l a t e d donors. Serum IgG levels were lower than those observed in our previous study and may have lessened the benefit. Moreover, with a longer follow-up period, reduced-dose IVIg may be associated with an increased risk of posttransplant relapse of malignancy that appears to be independent of GVHD.

ACKNOWLEDGMENTS We are indebted to our referring physicians and the nurses and support staff of the Fred Hutchinson Cancer Research Center and the Swedish Hospital Medical Center for carrying out this study.

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