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Background: Evidence about the impact of marital status before hematopoietic cell transplantation (hct) on outcomes after hct is conflicting., Methods: We identified patients 40 years of age and older within the Center for International Blood and Marrow Transplant Research registry who underwent hct between January 2008 and December 2015. Marital status before hct was declared as one of: married or living with a partner, single (never married), separated or divorced, and widowed. We performed a multivariable analysis to determine the association of marital status with outcomes after hct., Results: We identified 10,226 allogeneic and 5714 autologous hct cases with, respectively, a median follow-up of 37 months (range: 1-102 months) and 40 months (range: 1-106 months). No association between marital status and overall survival was observed in either the allogeneic ( p = 0.58) or autologous ( p = 0.17) setting. However, marital status was associated with grades 2-4 acute graft-versus-host disease (gvhd), p < 0.001, and chronic gvhd, p = 0.04. The risk of grades 2-4 acute gvhd was increased in separated compared with married patients [hazard ratio (hr): 1.13; 95% confidence interval (ci): 1.03 to 1.24], and single patients had a reduced risk of grades 2-4 acute gvhd (hr: 0.87; 95% ci: 0.77 to 0.98). The risk of chronic gvhd was lower in widowed compared with married patients (hr: 0.82; 95% ci: 0.67 to 0.99)., Conclusions: Overall survival after hct is not influenced by marital status, but associations were evident between marital status and grades 2-4 acute and chronic gvhd. To better appreciate the effects of marital status and social support, future research should consider using validated scales to measure social support and patient and caregiver reports of caregiver commitment, and to assess health-related quality of life together with health care utilization., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare that we have none., (2020 Multimed Inc.)

Background: Graft-versus-host disease (GVHD) complicates half of hematopoietic stem cell transplants (HCT), and the gastrointestinal tract is commonly affected. Endoscopic biopsies have a key role in the diagnosis. The optimal procedure(s) to perform and site(s) to biopsy remain unclear., Methods: We retrospectively analyzed the charts of all adult patients who underwent allogeneic HCT at Duke University Medical Center between 1/1/05 and 1/1/11 and extracted data from those who underwent endoscopic biopsy for suspected GVHD. All histology was re-evaluated by blinded pathologists using 2006 NIH diagnostic criteria and then compared to the original clinical diagnosis of GVHD., Results: A total of 169 adult patients underwent 250 endoscopic procedures to evaluate GVHD. The sensitivity of biopsies for clinical GVHD was 76 and 72% for upper and lower tract sites, respectively. In the presence of nausea, upper tract biopsies were positive for GVHD in 65%, 70% while lower tract biopsies were positive in 61-70%. In the presence of diarrhea, lower tract biopsies were positive in 65%, while upper tract sites were positive in 64-69%. Twenty six (40%) of the sixty-five endoscopies that simultaneously sampled upper and lower tract sites had discordant results. All were histologically positive for GVHD, yet 15% of upper tract biopsies and 25% of lower tract biopsies were negative., Conclusions: In this large review, the overall sensitivity of biopsies taken during EGD and Flex-Sig was 76 and 72%, respectively. A symptom-driven biopsy approach was not clearly supported as upper tract and lower tract biopsies were similarly diagnostic for GVHD regardless of symptoms.

We evaluated the pharmacokinetics and efficacy of oral mycophenolate mofetil (MMF) for treatment of refractory GVHD. In a prospective study of acute GVHD, 9 of 19 patients (47%) had a response and 10 (53%) had no improvement. Survival at 6 and 12 months after the start of MMF was 37 and 16%, respectively. In a retrospective study of acute GVHD, 14 of 29 patients (48%) had a response and 15 (52%) had no improvement. Survival at 6 and 12 months was 55 and 52%, respectively. In a prospective study of chronic GVHD, the cumulative incidence of disease resolution and withdrawal of all systemic immunosuppressive treatment was 9, 17 and 26% at 12, 24 and 36 months, respectively, after starting MMF. Thirteen patients (59%) required additional systemic immunosuppressive treatment for chronic GVHD. Nine of the 42 patients (21%) in the prospective studies discontinued MMF treatment because of toxicity. The area under the curve plasma concentrations of mycophenolic acid seemed to be suboptimal among patients with acute GVHD but not among those with chronic GVHD. MMF can be used effectively for treatment of GVHD.

Objective: Chronic graft-versus-host disease (GVHD) after haematopoietic stem cell transplantation (HSCT) has similarities to some idiopathic autoimmune diseases, including polymyositis. To investigate the relationship between chronic GVHD and idiopathic myositis we conducted a detailed analysis of all cases of myositis occurring in a large series of HSCT patients., Methods: We conducted a retrospective chart review of all cases of myositis that developed in 7161 patients who underwent HSCT at the Fred Hutchinson Cancer Research Center between 1969 and 1999., Results: Among 1859 individuals who developed chronic GVHD, 12 developed myositis. No patients developed myositis without chronic GVHD. Myositis was first identified between 7 and 55 months after transplantation. In histopathology, electromyography, laboratory values and response to immunosuppressive therapy, the cases resembled idiopathic polymyositis. Autoantibodies were found in eight cases., Conclusions: Myositis in the chronic GVHD population occurred with an incidence higher than expected by chance, suggesting that muscle may be a target tissue for chronic GVHD. Recent studies have implicated allogeneic cells persisting after maternal-fetal cell transfer in selected autoimmune diseases, including myositis. This report lends support to the possibility that both idiopathic myositis and chronic GVHD-related myositis could involve allo-autoimmune responses.

Background: In a pilot trial we evaluated the toxicity and efficacy of sirolimus (rapamycin) as second-line therapy for the treatment of acute graft-versus-host disease (GVHD) in 21 patients (1-46 years of age) after allogeneic hematopoietic stem cell transplantation (HSCT)., Methods: All patients were treated with methylprednisolone at 2 mg/kg/day, but failed to respond satisfactorily. Sirolimus was started 19-78 (median 37) days after HSCT when 10 patients had grade III and 11 had grade IV GVHD. The first four patients received a loading dose (15 mg/m2) of oral sirolimus on day 1 followed by 5 mg/m2/day for 13 days. The next 17 patients received either 5 (n=7) or 4 (n=10) mg/m2/day for 14 days without a loading dose. Eleven patients completed the 14-day sirolimus course. Five patients were treated for 9-13 days, two for 6 days, and three for 1-3 days., Results: Sirolimus was discontinued early in 10 patients because of lack of improvement in GVHD (n=5), myelosuppression (n=2), seizure (n=2), and attending physician preference (n=1). The most common and significant adverse events were thrombocytopenia (n=7) and neutropenia (n=4). Other side effects included increased blood triglycerides (n=8) and cholesterol (n=3). Five patients had evidence of a hemolytic uremic syndrome concurrently with or after sirolimus treatment. Eighteen of the 21 patients received 6 or more doses of sirolimus and 12 responded, 5 with complete and 7 with partial responses. Six of the 12 responders (28% of all patients enrolled) and 1 nonresponder are currently alive at 400-907 days after HSCT, 3 with chronic GVHD. Fourteen of the 21 patients (66%) died 40-263 days after transplant., Conclusion: These data suggest that sirolimus has activity in the treatment of steroid-refractory acute GVHD. However, there was considerable toxicity and further dose optimization studies seem warranted.

This retrospective study describes the outcome in 53 patients who had immunosuppressive treatment changed from cyclosporine (CSP) to tacrolimus for resistant acute GVHD (n = 23), hemolytic uremic syndrome (HUS) (n = 13) or CSP-associated neurotoxicity (n = 17). Tacrolimus was administered at doses of 0.03 mg/kg/day intravenously or 0.12 mg/kg/day orally in divided doses, as tolerated. Median time of conversion to tacrolimus after transplant was day 47. Nineteen patients had treatment changed to tacrolimus for resistant acute GVHD grades III or IV, with the median day of conversion being day 49 after transplant. Two of 20 evaluable patients had a complete resolution of GVHD after changing treatment to tacrolimus, with 18 showing no improvement. Eleven evaluable patients had therapy changed to tacrolimus for CSP-associated neurotoxicity at a median of 36 days after transplant. Eight patients had resolution of neurotoxicity and three had partial improvement. Eleven evaluable patients had therapy changed to tacrolimus for HUS at a median of 46 days after transplant. One patient had complete resolution of HUS and 10 showed no response. Side-effects related to tacrolimus included renal toxicity (34%), neurotoxicity (15%) and HUS (9%). Nine (17%) patients remain alive, including six patients who had therapy changed to tacrolimus for CSP-associated neurotoxicity. While often successful for dealing with neurotoxicity, only a rare patient improved after therapy was changed from CSP to tacrolimus for HUS or resistant acute GVHD.

Chronic graft-versus-host disease (GVHD) is the principal cause of transplantation-related morbidity and nonrelapse mortality late after allogeneic hematopoietic stem cell transplantation. The safety and potential efficacy of tacrolimus for the salvage treatment of chronic GVHD was evaluated in a single-arm, open-label phase 2 study. A total of 39 evaluable patients with chronic GVHD who failed previous immunosuppressive therapy with cyclosporine and prednisone were treated with tacrolimus starting at a median of 20 months (range, 3-68 months) after transplantation. At 3 years after the start of treatment, 5 patients (13%) had discontinued tacrolimus and were in complete remission, and 3 were considered clinically stable but not able to discontinue tacrolimus. A total of 31 patients (79%) experienced treatment failure; 22 (56%) who failed therapy had a change in immunosuppressive regimen because of progression (n = 18) or toxicity (n = 4). Nine patients (23%) died during continued treatment with tacrolimus. Two patients were lost to follow-up, at 11 and 19 months. The median duration of treatment with tacrolimus was 9 months (range, 1-29 months). Infections (144 episodes) were the most frequent adverse event. Nephrotoxicity occurred in 16 patients (41%); tacrolimus was discontinued in only 2 patients because of progressive deterioration in renal function. The Kaplan-Meier estimate of survival was 64% (95% confidence interval, 49%-79%) at 3 years posttransplantation. Seven patients had discontinued all immunosuppression at last contact, leading to an estimated 29% probability of stopping all immunosuppression by 3 years posttransplantation. Four patients died after relapse of malignancy. The response rate is consistent with previous reports of salvage treatment for chronic GVHD, indicating that a small group of patients failing cyclosporine may respond or stabilize with tacrolimus.

Acute graft-versus-host disease denotes a distinctive syndrome characterized by a triad of dermatitis (rash), hepatitis (jaundice), and gastroenteritis (abdominal pain, diarrhea) developing in the first 100 days after allogeneic hematopoietic cell transplantation. Chronic graft-versus-host disease designates a more diverse syndrome, usually presenting with multiorgan involvement and commonly developing 100 days after hematopoietic cell transplantation. This article discusses the pathophysiology, incidence and predictive factors, clinical manifestations, diagnosis and grading, prevention, and treatment for both types of the disease.

The value of routine chronic graft-versus-host disease (GVHD) screening studies performed between 70 and 120 days after allogeneic marrow transplantation was retrospectively evaluated among 241 patients. All patients received methotrexate and cyclosporine for GVHD prophylaxis and survived without relapse more than 4 months after transplant. Ninety-one patients (38%) developed clinical extensive chronic GVHD requiring systemic therapy. Data on patients who developed clinical extensive chronic GVHD were compared with those on patients without chronic GVHD to determine which of the following screening tests predicted the subsequent development of clinical extensive chronic GVHD: skin biopsy, oral exam, lip biopsy, Schirmer's test, serum alkaline phosphatase, aspartate transaminase, immunoglobulin level and platelet count. In a univariable analysis, a positive oral examination and a low platelet count were predictive of chronic extensive GVHD development. In a multivariable analysis which adjusted for the contribution of other chronic GVHD risk factors, such as age and a history of acute GVHD none of the screening tests were predictive of chronic GVHD development. The risk factors in this multivariable analysis which had the strongest association with the development of chronic GVHD was a history of acute GVHD and use of corticosteroids at day 100 (RR = 3.9, P = 0.001). The use of corticosteroids for acute GVHD at day 100 had a predictive effect on chronic GVHD development independent of the grade of acute GVHD (RR = 2.1, P = 0.004). Based on these study results, the use of chronic GVHD screening tests may not be of value in predicting who will develop this complication. Patients on corticosteroids at day 100 should be considered for clinical trials to determine the efficacy of new immunosuppressive agents in preventing chronic GVHD.

Chronic graft-versus-host disease (GVHD) is likely caused by donor T lymphocytes. Because unmodified blood stem cell grafts contain one log more T lymphocytes than unmodified marrow grafts, we evaluated the incidence of chronic GVHD in previously reported 37 blood stem cell recipients and 37 computer-matched historical control marrow recipients (Bensinger et al, Blood 88:2794, 1996). All patients have been followed until death, relapse, or occurrence of chronic GVHD or for a minimum of 2 years. In a univariable proportional hazards regression model, the relative risk of developing clinical chronic GVHD (includes clinical limited and clinical extensive disease) by 2 years posttransplant among the peripheral blood stem cell recipients compared with the marrow recipients was 2.22 (95% confidence interval, 1.04 to 4.74; P = .039). For clinical extensive chronic GVHD, the relative risk was 2.37 (95% confidence interval, 1.07 to 5. 29; P = .035). In multivariable analyses, considering also the covariables of patient age, patient cytomegalovirus serostatus, and donor cytomegalovirus serostatus, the relative risks of clinical chronic GVHD and clinical extensive chronic GVHD were also greater than 2 (P < .05). We conclude that the transplantation of unmanipulated filgrastim-mobilized blood stem cells may result in a relatively high incidence of chronic GVHD.

One hundred three patients with leukemia, aplastic anemia, or myelodysplastic syndrome were treated by marrow transplantation from genotypically HLA-identical siblings (n = 92) or HLA haploidentical family members differing for one HLA antigen on the nonshared haplotype (n = 11). To prevent graft-vs.-host disease (GVHD), they were administered postgrafting immunosuppression with a short course of intermittent methotrexate with daily cyclosporine for no more than 11 days. Customarily, we have given cyclosporine for 180 days after transplant. In the current study, we asked whether cyclosporine could be stopped earlier without affecting the risk of chronic GVHD. By day 60, patients who never had acute GVHD, or whose acute GVHD had resolved, were randomized to have cyclosporine stopped (n = 52) or continued for the usual 180 days (n = 51). Results were analyzed with a median follow-up of 9.3 years after transplant, and showed that patients in whom cyclosporine was discontinued on day 60 had a significantly more rapid onset (p = 0.001), but not a significantly higher overall incidence of chronic GVHD than those in whom the drug was stopped on day 180 (43 vs. 54%; p = 0.26). Transplant-related mortality was comparable among patients without preceding acute GVHD, regardless of when cyclosporine was discontinued (11% for both study arms). However, transplant-related mortality appeared to increase among patients with preceding acute GVHD in whom cyclosporine was stopped by day 60 (38 vs. 17%). Results suggest that cyclosporine can safely be discontinued early in patients who never had evidence of acute GVHD, while those with preceding acute GVHD would benefit from a longer course of the drug. Because of the relatively small sample sizes, these results would best be treated as promising preliminary findings that should be confirmed in larger randomized studies.

Patients with a lymphohematopoietic malignancy considered to be at high risk for posttransplant relapse were enrolled in a study to compare the use of cyclosporine (CSP) as a single agent with a combination of methylprednisolone (MP) and CSP for graft-versus-host disease (GVHD) prophylaxis after marrow transplantation from an HLA-identical sibling donor. Sixty patients were randomized to receive CSP only and 62 were randomized to receive CSP plus MP. Daily CSP was started on day -1 (5 mg/kg/d intravenously) and administered at gradually reduced doses until day 180. MP was started on day 7 at 0.5 mg/kg/d, increased to 1.0 mg/kg/d on day 15, started on a taper schedule on day 29, and discontinued on day 72. All 104 evaluable patients (surviving > or =28 days) had sustained engraftment. The incidence rates of grades II-IV acute GVHD were 73% and 60% for patients receiving CSP and CSP plus MP, respectively (P = .01). No difference was seen for grades III-IV GVHD. However, chronic GVHD occurred somewhat more frequently in patients receiving CSP plus MP (44%) than in patients receiving only CSP (21%; P = .02). The incidence of de novo chronic GVHD was marginally higher in patients receiving CSP plus MP (P = .08). No significant differences in the risk of infections were observed. There was a suggestion that the risk of relapse was lower in patients receiving CSP plus MP (P = .10) and, although the overall survival in the two groups was not different (P = .44), there was a slight advantage in favor of CSP plus MP-treated patients for relapse-free survival (P = .07). These results suggest that prophylactic MP, when combined with CSP, has only limited efficacy in acute GVHD prevention and may increase the probability of chronic GVHD.

The success of marrow or blood stem cell transplantation may depend upon events arising months to years later. Transplant regimen related toxicity may include cataract formation due to corticosteroids or total body irradiation (TBI) and endocrine or gonadal dysfunction requiring hormonal replacement. By 15 to 20 years post-transplant, the cumulative incidence of secondary malignancies (including skin cancers) ranges from 4% (no TBI) to 14% (prior irradiation) in patients with previous aplastic anemia. Chronic graft versus-host-disease (GVHD) develops in 33% of HLA-identical sibling transplants and requires 1 to 2 years of immunosuppressive therapy. In allograft recipients free of GVHD, there are very few late infections or complications. These findings are confirmed by multidimensional studies of the quality of life of adult patients surviving 6 to 18 years after marrow transplantation and demonstrate that 80% of patients rate their quality of life as good to excellent and 5%, as poor. Considerations of late effects of transplant and maintenance of quality of life are key considerations when weighing the risks and benefits of stem cell grafts for the treatment of severe autoimmune diseases. Careful followup and reporting of these initial patient cohorts will be vital in determining the longterm success of stem cell transplantation.

Some types of severe autoimmune disease are associated with significant morbidity and a high mortality rate. Many of these cases occur in young adults who, even if they survive, become severely debilitated. Systemic sclerosis (SSc) is a paradigm for other severe autoimmune diseases in which patients with poor prognostic features can be identified early in the course of the disease. Allogeneic marrow transplantation may be effective for the control of autoimmune diseases like SSc because the preparative regimen will significantly suppress the host immune system and the antihost effects of the donor immune system in the engrafted marrow will help maintain the suppression of the host immune system. Considering the morbidity and poor prognosis associated with severe SSc and the favorable outcome now associated with allogeneic marrow transplantation from HLA identical siblings for other nonmalignant diseases, Phase I and II studies are warranted. These will evaluate the safety of allogeneic marrow transplantation and explore its role in the management and control of a severe autoimmune disease. We review issues important in the development of an allogeneic marrow transplant protocol for severe SSc, including patient selection, plan of treatment, prevention of graft versus host disease, supportive care, and evaluation after transplant.

The safety and potential efficacy of FK506 in combination with a short course of methotrexate (MTX) for the prevention of acute graft-versus-host disease (GVHD) after marrow transplantation from HLA-matched unrelated donors was evaluated in a single-arm Phase II study conducted at two centers. Forty-three patients, 15 to 54 (median 41) years of age, were transplanted for hematologic malignancies. Thirty-seven of 43 evaluable patients had evidence of sustained marrow engraftment. Five patients died before day 17 after transplantation. The median time to an absolute neutrophil count of > 0.5 x 10(5)/L was 21 (range, 14 to 30) days. Nephrotoxicity (serum creatinine concentration > 2 mg/dL or doubling of baseline) occurred in 32 patients (74% cumulative incidence during the first 100 days after transplant). Other adverse effects included hypertension (n = 27), hyperglycemia (n = 27), neurotoxicity (n = 9) and thrombotic thrombocytopenic purpura (n = 2). Severe veno-occlusive disease of the liver occurred in 9 (21%) of the 43 patients. Eighteen patients (42%) developed grades II to IV acute GVHD and five (12%) developed grades III to IV acute GVHD. Twelve of 25 evaluable patients developed extensive chronic GVHD within 1 year of marrow transplantation resulting in an estimate of the probability of developing this complication of 48%. The cumulative incidence of transplant-related mortality during the first 100 days was 37%. Kaplan-Meier estimates of disease-free survival at 2 years for good-risk, poor-risk, and all patients were 65%, 4%, and 32%, respectively. FK506 in combination with a short course of MTX appears active in preventing acute GVHD after marrow transplantation from unrelated donors. Further studies comparing the combination of FK506 and MTX with cyclosporine and MTX for the prevention of acute GVHD are warranted.

Acute graft-versus-host disease (GVHD) is most often treated with high dose glucocorticoids, but less than half of patients have durable overall improvement. Previous phase I and phase II studies suggested that treatment with a CD5-specific immunotoxin (XomaZyme-CD5 Plus) could ameliorate symptoms of GVHD. In a randomized, double-blind trial, we compared XomaZyme-CD5 Plus and glucocorticoids versus placebo and glucocorticoids as initial therapy for 243 patients who developed acute GVHD after allogeneic marrow transplantation. The study drug (XomaZyme. CD5-Plus or an identical appearing placebo) was administered at a dose of 0.1 mg/kg body weight on each of 14 consecutive days. All patients were treated concomitantly with a standard regimen of methylprednisolone. At the time of entry on study, 94% of patients had a rash, 56% had hyperbilirubinemia, 61% had diarrhea, and 84% had nausea and vomiting. At 3, 4, and 5 weeks after starting treatment, symptom severity was less in the CD5 group than in the placebo group. At 4 weeks, 40% of patients assigned to the CD5 group had complete response compared with 25% of those assigned to the control group (P = .019). At 6 weeks, 44% of patients assigned to the CD5 group had complete response as compared with 38% in the placebo group (P = .36). Clinical extensive chronic GVHD developed in 65% of patients in the CD5 group compared with 72% in the control group (P = .35). Survival at 1 year after treatment was 49% in the CD5 group and 45% in the control group (P = .68). Side effects required close monitoring and appropriate adjustment of treatment. The combined administration of a CD5-specific immunotoxin and glucocorticoids controls GVHD manifestations more effectively than treatment with glucocorticoids alone during the first 5 weeks after starting treatment. Use of this immunotoxin does not result in any long-term clinical benefit for patients with acute GVHD.

Intravenous immune globulin (IVIG) has been used with success to prevent and treat infection in patients with immunodeficiencies of humoral immune function. More recently, IVIG has been shown to modulate immune responses and to treat successfully several autoimmune disease. Initial trials in bone marrow transplant recipients were aimed at the prevention of cytomegalovirus (CMV) disease. Although most studies showed such a benefit, CMV prophylaxis is now commonly provided by use of CMV-negative blood products or ganciclovir prophylaxis in, respectively, CMV-seronegative and CMV-seropositive patients. Acute and chronic graft-versus-host disease (GVHD) and associated infections remain critical barriers to the wider application of allogeneic blood or marrow transplantation, especially among patients given HLA-disparate grafts. To date, four controlled clinical trials have shown a significant reduction in acute GVHD in patients given IVIG (500-1000 mg/kg) weekly until 90-120 days post-transplant. In addition, bacterial infection in the early transplant period appears reduced. Meta-analysis of controlled trials reporting acute GVHD endpoints in 379 patients found a relative risk of acute GVHD of 0.68 (95% CI, 0.45-1.02) in IVIG recipients compared to untreated controls. Overall mortality reported in 809 patients in these trials showed an odds ratio of mortality of 0.74 (0.55-0.99) in IVIG recipients compared to controls (values < 1.0 suggest that IVIG was effective in preventing the event). More recently it has been shown that in the absence of hypogammaglobulinaemia, IVIG (500 mg/kg) given monthly from day 90 to 360 did not reduce the incidence of chronic GVHD or late complications. Future research is aimed at characterizing the mechanism of action of suppression of acute GVHD with weekly IVIG prophylaxis and the role of IVIG prophylaxis in patients receiving unrelated marrow grafts.

Nine adult patients 31-47 (median 39) years of age treated with prednisone and cyclosporin A (CsA) for chronic graft-versus-host disease (GVHD) were evaluated for biochemical factors associated with skeletal turnover at initiation of immunosuppressive therapy (3 months after marrow transplant) and 9 months later (follow-up). Absorptiometry studies of the wrist and lumbar spine were also performed. Serum levels of 1,25-dihydroxycholecalciferol (1,25(OH)2D) were decreased at enrollment, particularly in the six males. Values for all nine patients remained low at follow-up. Levels of serum 25-hydroxycholecalciferol (25(OH)D), parathyroid hormone, and ionized calcium were normal at enrollment and follow-up. Mean urine hydroxyproline and calcium levels were elevated at enrollment, suggesting increased bone resorption; the mean values decreased to the high normal range at follow-up. Urine magnesium excretion was elevated in eight of nine patients at baseline and remained elevated at follow-up in three of eight evaluable patients. Single and dual photon absorptiometry of the wrist and spine, respectively, and dual energy X-ray absorptiometry of the spine, were utilized to evaluate bone mineral density over time. The precision of these tests was, respectively, +/- 3.5%, +/- 3.1% and +/- 1.0%. Results showed a significant ( > 2.5 times the precision) decrease over 9 months in bone mineral density in three of five evaluable males and all three females. The findings indicate increased collagen and bone turnover, increased urinary magnesium and calcium excretion and a significant risk of osteoporosis in patients receiving treatment for chronic GVHD. Preventive measures, including gonadal hormone replacement in females, should be initiated early after transplantation. Further studies are needed to identify patients at highest risk of bone loss and to monitor the effects of preventive therapy.

To determine whether intravenous immunoglobulin (IVIg) given monthly from day 90 to day 360 posttransplantation decreased the incidence of late infection, chronic graft-vs.-host disease (GVHD), and obliterative bronchiolitis after marrow transplantation, patients were assigned randomly to receive either IVIg (500 mg/kg/month) or no IVIg prophylaxis. Participants were registered before transplantation, and 250 patients (123 IVIg and 127 control) were evaluable for events after day 100. The two groups were balanced for age, marrow source, cytomegalovirus (CMV) seropositivity, pretransplantation conditioning, and prophylaxis for infection and GVHD. Between days 100 and 365 posttransplantation, the incidence of bacteremia or septicemia per 100 patient-days of risk was 0.10 in the IVIg group and 0.12 in the controls (p = not significant). During the same period, the incidence of localized infection was marginally higher in control patients than in IVIg recipients (0.44 vs. 0.24, respectively; relative risk [RR] 1.46, p < 0.07). Administration of IVIg prophylaxis had no effect on survival, the incidence of obliterative bronchiolitis, severity of airflow obstruction, or the incidence or mortality of chronic GVHD. After discontinuing IVIg prophylaxis at day 360, subsequent recovery of endogeneous humoral immunity was impaired (serum IgG1 and IgA levels were significantly lower than controls at day 730), and total infections were less common in the second year in control patients than in former IVIg recipients (0.12 vs 0.19, respectively; RR 0.61, p = 0.03). We conclude that in the absence of hypogammaglobulinemia, monthly administration of IVIg given from day 90 to 360 does not reduce late complications and may impair long-term humoral immune recovery after marrow transplantation.

The present study was performed as a retrospective analysis of the role of pretransplant splenectomy to determine the incidence of late bacterial infections, acute and chronic graft-versus-host disease (GVHD), relapse, and survival among 358 patients receiving HLA-identical marrow grafts for chronic myelogenous leukemia. Sixty-eight (19%) of the 358 patients had undergone splenectomy before transplantation. There was a trend towards more grade II-IV acute GVHD among splenectomized patients, but this was not significant in the multivariate analysis. The incidence of chronic GVHD was similar for splenectomized and nonsplenectomized patients. Late infectious complications did not significantly differ between splenectomized and control patients (rates per patient year were 0.16 and 0.14, respectively). The overall risk of leukemic relapse was significantly increased for splenectomized patients (56% v 32% for controls, P = .001) and control patients with splenomegaly (P < .0001). Splenectomy and splenomegaly remained significant and independent hazards for relapse in the multivariate analysis (hazard ratio [HR], 1.82, P = .029; and HR, 1.49, P = .002; respectively). Relapse was also increased in patients with advanced disease (HR, 2.95; P = .0001), in patients with T-cell-depleted marrow (HR, 4.51; P = .0001), and in the female donor and male recipient combination (HR, 1.74; P = .044). Patients with splenectomy had an increased overall mortality (HR, 1.18), but this was not statistically significant in the multivariate analysis. In summary, our study showed no significant influence of splenectomy on late posttransplant infections, acute or chronic GVHD, or overall survival. There was no evidence that splenectomy decreased recurrence of chronic myelogenous leukemia.

This study evaluated the acute toxicity of trimetrexate (TMTX) used in combination with cyclosporine (CsA) for prevention of acute graft-versus-host disease (GVHD) in patients undergoing allogeneic marrow transplantation from HLA-mismatched, related donors. TMTX has a mechanism of action similar to that of methotrexate (MTX); however, unlike MTX, TMTX is not primarily dependent on renal excretion. Patients were conditioned for transplant with cyclophosphamide, anti-thymocyte globulin, and total body irradiation. TMTX, 10 mg/m2 i.v., was administered on days 1, 3, 6, 11, 18, 25, 32, and 39 after transplant. CsA, 1.5 mg/kg i.v., was administered every 12 hr beginning on day-1. Eleven patients with hematologic malignancies or aplastic anemia (median age = 34 yr) received TMTX. Toxicity assessed included nausea, vomiting, fever, rash, time to myeloid and platelet engraftment, mucositis, and hepatic and renal dysfunction. Toxicity of TMTX was not different from that observed with MTX in a similar patient population. One patient died on day 16 before engraftment. The other 10 patients all engrafted and all developed acute GVHD at a median time of 11 days after transplant. The major manifestation of acute GVHD was in the skin, and all but one patient responded to primary therapy with corticosteroids. Seven patients have survived a median of 447 days after transplant. No significant toxicity from TMTX was observed. Further trials are warranted to define the role of TMTX in marrow transplantation.

Chronic graft-versus-host disease (GVHD) is a major cause of late morbidity and mortality following allogeneic marrow transplantation. The pathogenesis and clinical features of chronic GVHD resemble those of several autoimmune diseases including progressive systemic sclerosis, systemic lupus erythematous, lichen planus, Sjögren's syndrome, rheumatoid arthritis, and primary biliary cirrhosis. Chronic GVHD retards the tempo of immune reconstitution following allogeneic transplantation and is a major risk factor for late infections. Although in vivo immunosuppression and in vitro depletion of T-cells can reduce the incidence of acute GVHD, improved long-term survival free of chronic GVHD has not been observed. Early treatment of multiorgan extensive chronic GVHD with an alternating-day regimen of cyclosporine and prednisone has led to improved disability-free survival. Functional performance of the long-term survivors receiving combination immunosuppressive therapy remained near normal and the incidence of disabling scleroderma has decreased from over 50% to 6%. However, infections remain a frequent cause of morbidity especially in high-risk patients with advanced age, HLA-nonidentical marrow grafts, progressive onset of chronic GVHD and continued thrombocytopenia.

The development of spontaneously acquired Factor VIII inhibitors is rare and may lead to serious hemorrhagic sequelae. We report here the case of a patient who acquired a Factor VIII inhibitor two years after an allogeneic bone marrow transplant for CML. This occurred in association with a flare of chronic graft versus host disease (GVDH). He responded to corticosteroid therapy. A review of autoimmune phenomena associated with chronic GVDH and the treatment of Factor VIII inhibitors is discussed.

Background: Some cases of blood transfusion-associated (TA) graft-vs-host disease (GVHD) in immunocompetent patients have been reported, but those dermatologic findings were not precisely mentioned. We describe patients with clinicopathologically TA-GVHD and compare TA-GVHD and acute GVHD after bone marrow transplantation., Observations: Two cases of TA-GVHD after open heart surgery are reported. In both immunocompetent patients, severe erythema multiformelike skin rash developed over the entire body, followed by fever, diarrhea, jaundice, transaminitis, pancytopenia, and marrow alpasia approximately 10 days after operation. The rash in one patient changed from erythema multiformelike to toxic epidermal necrolysis at death. Skin biopsy specimens revealed eosinophilic bodies, basal vacuolation, and exocytosis in the epidermis. Eosinophilic bodies tend to appear in the upper epidermis. Immunohistochemistry studies revealed that infiltrating cells were CD4 and CD8. While acute GVHD in immunosuppressed patients who have undergone bone marrow transplantations often shows lichenoid histologic features, TA-GVHD in our patients who were immunocompetent may resemble severe erythema multiforme or toxic epidermal necrolysis. The difference in TA-GVHD may be related to lack of host modification by immunosuppression., Conclusions: Irradiation of the blood products should be required in open heart surgery, for TA-GVHD in immunocompetent patients is almost always fatal.

Treatment with the monoclonal antibody OKT3 specific for the CD3 complex associated with the T cell antigen receptor can reverse acute rejection of human renal allografts. However, efficacy of anti-CD3 antibodies for treatment of patients with acute graft-versus-host disease after marrow transplantation has not been established. The dose-limiting side effects resulting from T cell activation induced by some anti-CD3 antibodies in vivo have discouraged their use for this application. We now report a phase I-II study of GVHD treatment with the anti-CD3 antibody BC3, a monoclonal murine IgG2b that, unlike OKT3, does not activate T cells. Fourteen patients were treated with BC3 after progression of acute GVHD despite treatment with cyclosporine and corticosteroids, and three patients received BC3 as primary treatment for GVHD. BC3 was administered at a dose of 0.1 or 0.2 mg/kg/day for seven or eight days. Five patients achieved complete resolution of GVHD, eight patients had partial improvement, two patients had no change, and two patients had progression of GVHD on therapy. Responses were sustained in 8 of 13 patients. Mild chills, fever, hypertension, and chest discomfort occurred in various combinations following 6 of 17 (35%) initial infusions of BC3 and following 4 of 99 (4%) subsequent infusions. In each instance it was possible to continue BC3 therapy without adjusting the dose or treatment schedule. In each patient treated, the absolute count of peripheral blood lymphocytes decreased transiently but returned to baseline within 22 hr after the first infusion. Circulating T cells had surface CD3 molecules saturated by the infused antibody in all but one patient. Four patients survived longer than one year after treatment with antibody BC3, and 13 patients died of infection or organ failure. Administration of the nonmitogenic anti-CD3 antibody BC3 was associated with improvement in the clinical manifestations of GVHD with minimal acute toxicity. Efficacy of antibody treatment did not depend on depletion of circulating T cells. Therefore, antibody BC3 may be achieving therapeutic immunosuppression by modulating T cell function. Controlled studies in patients treated earlier in the course of GVHD should determine whether antibody BC3 can improve survival.

Objective: To determine the safety and efficacy of ursodeoxycholic acid treatment in patients with chronic graft-versus-host disease (GVHD) of the liver., Design: Open-label study in which each patient served as his or her own control., Setting: Private practice and a university bone marrow transplant center., Patients: Twelve patients with refractory chronic GVHD of the liver were studied after allogeneic bone marrow transplantation., Interventions: After baseline data collection, patients were given ursodeoxycholic acid (UDCA, 10 to 15 mg/kg body weight per day) for 6 weeks. After discontinuation of the drug, patients were followed for an additional 6 weeks. Doses of immunosuppressive drugs were unchanged for these 12 weeks., Measurements: Signs, symptoms, Karnofsky performance scores, hematocrit, total leukocyte count, absolute neutrophil count, platelet count, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, gamma-glutamyltransferase (GGT), total serum bilirubin, prothrombin time, serum creatinine, and blood urea nitrogen were assessed., Results: Serum tests of cholestatic liver injury measured at 2, 4, and 6 weeks showed improvement compared with baseline. At 6 weeks, the percent decrease from baseline in total serum bilirubin was 33% (P less than 0.005); in alkaline phosphatase the decrease was 32% (P less than 0.038); and in AST the decrease was 37% (P less than 0.007). After discontinuation of UDCA therapy, 11 patients were followed for 6 additional weeks. All showed significant worsening in liver function test results. Symptom scores were unchanged throughout the study. One patient with pruritus improved while receiving therapy with UDCA. No adverse effects were observed., Conclusion: Therapy with UDCA was safe, well-tolerated, and efficacious in the short-term treatment of refractory chronic GVHD of the liver. Further investigation is needed to evaluate the long-term effects of UDCA therapy.

The results of pretransplant mixed leukocyte culture (MLC) assays were compared to subsequent risk of graft-versus-host disease (GVHD) in 783 patients receiving marrow transplants from HLA genotypically identical sibling donors. The mean MLC response observed between 1303 normal HLA identical sibling pairs was 0.0 +/- 4.2% RR. The donor anti-recipient MLC reaction, an in vitro response that presumably might be relevant to GVHD, was significantly increased (greater than mean + 2 sd) in 83 (10.6%) of the cases, most often in patients in relapse at the time of testing. No association was found, however, between this increased donor anti-recipient MLC reactivity pretransplant and the incidence or severity of subsequent acute or chronic GVHD. These data suggest that the increased MLC responses sometimes observed between leukemia patients and their HLA identical sibling donors prior to marrow transplantation do not represent genetic differences capable of causing GVHD.

Ultraviolet (UV) irradiation affects eukaryotic cells in numerous ways. Exposure of blood transfusion products to UVC (200-280 nm) or UVB (280-320 nm) reduces or abrogates their immunogenicity and thereby prevents allosensitization and transfusion refractoriness in several models. Although the exact mechanism is not known, in vitro studies suggest that UV exposure results in a loss of class II histocompatibility antigens from the cell surface, alterations of calcium homeostasis, and a lack of interaction between antigen presenting and responding cells. In the UVB and UVA (320-400 nm) range, lymphocytes appear to be more sensitive than hemopoietic cells. In murine transplant models, UVB irradiation of spleen and marrow cells can be used to prevent the development of graft-versus-host disease while allowing for complete hemopoietic reconstitution. Furthermore, in clinical marrow transplantation, pilot studies of UVA in conjunction with psoralen administration have yielded encouraging results in patients with steroid refractory graft-versus-host disease of the skin. Thus, UV irradiation provides an interesting tool to study cell/cell and donor/host interactions and may have some applications in transfusion medicine and bone marrow transplantation.

Nineteen patients with leukaemia, preleukaemia, and aplastic anaemia were treated by marrow transplantation from HLA-identical siblings. All were given postgrafting immunosuppression with a combination of methotrexate (days 1, 3, 6 and 11) and cyclosporin (days--1 to 180). In an attempt at reducing cyclosporin-associated toxicity, we explored whether the cyclosporin dose during the first 2 weeks could be decreased by 50% (from 3.0 to 1.5 mg/kg/d intravenously) without adversely affecting the incidence, onset, and severity of acute graft-versus-host disease (GVHD) and overall survival. Results from this pilot study were compared to those of a matched cohort of 38 patients given a standard dose of 3.0 mg cyclosporin/kg/d starting on day--1. The cumulative incidence of grade II and III acute GVHD in the 'low dose' cyclosporin group was 42% compared to 51% in the 'standard dose' group (P = 0.60). Three-year survival was 63% and 54% respectively (P = 0.59). Patients receiving the reduced cyclosporin dose during the first 14 d appeared to have less hepatotoxicity, and the methotrexate and cyclosporin doses administered were closer to the doses intended per protocol. We suggest that 'low dose' cyclosporin from day--1 to day 15 postgrafting might be as effective as 'standard dose' cyclosporin during that time period for the prevention of acute GVHD.

The effect of random red cell transfusions given shortly before allogeneic bone marrow transplantation (BMT) was evaluated in 969 leukemic patients transplanted from an HLA-identical sibling donor. Patients were divided into two groups: 501 who received a transfusion shortly before BMT, and 468 who did not. Both groups had a similar incidence of acute graft-versus-host disease (GVHD), but the recently-transfused group had a significantly lower incidence of chronic GVHD (35.9% vs 48.9%). These differences remained significant in a multivariate analysis of time to chronic GVHD (p = 0.022), taking into account other differences between the two groups and known risk factors for chronic GVHD.

Background: Graft-versus-host disease (GVHD) and infection are major complications of allogeneic bone marrow transplantation. Since intravenous immunoglobulin has shown benefit in several immunodeficiency and autoimmune disorders, we studied its antimicrobial and immunomodulatory role after marrow transplantation., Methods: In a randomized trial of 382 patients, transplant recipients given immunoglobulin (500 mg per kilogram of body weight weekly to day 90, then monthly to day 360 after transplantation) were compared with controls not given immunoglobulin. By chance, the immunoglobulin group included more patients with advanced-stage neoplasms; otherwise, the study groups were balanced for prognostic factors., Results: Control patients seronegative for cytomegalovirus who received seronegative blood products remained seronegative, but seronegative patients who received immunoglobulin and screened blood had a passive transfer of cytomegalovirus antibody (median titer, 1:64). Among the 61 seronegative patients who could be evaluated, none contracted interstitial pneumonia; among the 308 seropositive patients evaluated, 22 percent of control patients and 13 percent of immunoglobulin recipients had this complication (P = 0.021). Control patients had an increased risk of gram-negative septicemia (relative risk = 2.65, P = 0.0039) and local infection (relative risk = 1.36, P = 0.029) and received 51 more units of platelets than did immunoglobulin recipients. Neither survival nor the risk of relapse was altered by immunoglobulin. However, among patients greater than or equal to 20 years old, there was a reduction in the incidence of acute GVHD (51 percent in controls vs. 34 percent in immunoglobulin recipients; P = 0.0051) and a decrease in deaths due to transplant-related causes after transplantation of HLA-identical marrow (46 percent vs. 30 percent; P = 0.023)., Conclusions: Passive immunotherapy with intravenous immunoglobulin decreases the risk of acute GVHD, associated interstitial pneumonia, and infections after bone marrow transplantation.

One hundred forty-seven consecutive patients with leukemia, myelodysplastic syndrome, or aplastic anemia were treated by marrow grafts from genotypically HLA-identical siblings (n = 122) or HLA-haploidentical family members (n = 25). Haploidentical recipients differed from their donors for no more than one HLA locus on the nonshared haplotype. All were given postgrafting immunosuppression with a combination of methotrexate and cyclosporine. In a randomized study we explored whether prednisone administered from day 0 through 35 along with methotrexate/cyclosporine could improve prevention of acute graft-versus-host disease (GVHD). The GVHD incidence in patients not given prednisone was comparable with that previously reported with methotrexate/cyclosporine. Unexpectedly, significant increases in acute and also chronic GVHD were seen in HLA-identical recipients administered prednisone, but not in the small number of patients administered HLA-nonidentical grafts. However, the resultant increase in transplant-related mortality in patients administered prednisone was offset by an increase in leukemic relapse in patients not administered prednisone, presumably related to the absence of a graft-versus-leukemia effect. Therefore, overall disease-free survival of the two groups of patients was comparable, with slightly more than 50% of the patients being alive at more than 2 years after transplantation. We speculated that prednisone adversely affected GVHD prophylaxis, interfering with methotrexate's cell cycle-dependent suppression of donor lymphocyte proliferation in response to host antigens. In a pilot study we explored whether beginning prednisone on day 15, after completion of methotrexate administration, would avoid this adverse effect. The GVHD incidence in patients administered methotrexate/cyclosporine along with "late" prednisone was comparable with that in patients not administered prednisone. We conclude that methotrexate/cyclosporine is effective in decreasing the incidence of grade II through IV GVHD, and that the addition of prednisone to this regimen is not beneficial in recipients of HLA-identical marrow grafts.

We prospectively evaluated 169 patients with a number of screening studies performed between 71 to 121 days after allogeneic marrow transplantation to detect the development of chronic graft-versus-host disease (GVHD). Group 1 patients (n = 78) were asymptomatic and had normal physical examinations at the time of screening and, with a minimum of 8 years follow-up, have not developed chronic GVHD. Group 2 patients (n = 38) had signs and symptoms of chronic GVHD at time of testing. Group 3 patients (n = 53) were similar to those in group 1 in having no clinically evident GVHD at the time of testing, but later developed clinical chronic GVHD. Using time to an event analysis, we compared patients in groups 1 and 3 to determine which of 17 clinical and laboratory factors evaluated at screening accurately predicted the development of subsequent chronic GVHD. Multivariate analyses showed several factors to have independent predictive value. In the first model, results of oral biopsies were excluded since these were done only in one half of the patients. Predictive factors in this analysis included: (1) histologic findings of GVHD on skin biopsy, relative risk 3.23 (95% confidence interval 1.75 to 5.94), P = .0002; and (2) history of grade II through IV acute GVHD, relative risk 3.12 (95% confidence interval 1.72 to 5.64), P = .0002. When oral biopsy results were included in the second model, independent risk factors included: (1) histologic findings of GVHD on skin biopsy, relative risk 5.96 (95% confidence interval 1.95 to 18.19), P = .0017; and (2) low numbers of immunoglobulin A (IgA)-bearing plasma cells detected by direct immunofluorescence in salivary gland areas on oral biopsy, relative risk 11.53 (95% confidence interval 2.51 to 52.03), P = .0017. Our study demonstrates the value of day 100 screening studies for predicting subsequent development of clinical chronic GVHD.

The nutritional status and prevalence of nutrition-related problems in 192 adult and child allogeneic marrow transplant recipients were evaluated 1 year after transplant in a retrospective chart review. Among these patients, 63% exhibited evidence of chronic graft-versus-host disease (GVHD) at the time of nutrition evaluation, including 44% with extensive disease who were receiving immunosuppressive therapy. Oral sensitivity was observed in 23% of all patients reviewed, and frank stomatitis occurred in 8%. The frequency of xerostomia was 18%; anorexia, 8%; reflux symptoms, 7%; diarrhea, 7%; steatorrhea, 5%; dysgeusia, 3%; and limited exercise tolerance because of dyspnea or joint contractures, 4%. Weight loss 3 to 12 months after transplant was experienced by 28%. Nutrition-related problems, changes in anthropometric indexes indicative of suboptimal nutritional status, and inadequate energy intake were observed more frequently in patients with extensive chronic GVHD than in patients without GVHD or in those with limited GVHD. Our findings indicate a high prevalence of nutrition problems among recipients of allogeneic marrow transplantation 1 year after transplant and, further, suggest the need for ongoing, community-based nutrition monitoring after discharge from a transplant center.

To determine if previous donor pregnancies influence the development of acute graft-versus-host disease (GVHD) we evaluated data from 136 patients with aplastic anaemia greater than 15 years of age and given marrow grafts from HLA-identical sibling donors. Of the 136 marrow donors, 30 were parous females (previous history of pregnancy), 30 were nulliparous females (no history of pregnancy or abortions), and 76 were males. The cumulative incidence of grade II-IV GVHD was 57%, 21% and 46% for patients with parous, nulliparous and male donors, respectively. A multivariate analysis of the data confirmed that the risk of grade II-IV acute GVHD was significantly increased among patients receiving marrow from parous females as compared to those from nulliparous females (relative risk = 2.5, P = 0.02). There was no statistically significant difference in the incidence of acute GVHD, however, between patients with parous donors and male donors (relative risk = 1.3, P = 0.26). Male patients given grafts from parous donors showed a higher incidence of acute GVHD (63%) than female patients (45%), though this difference was not statistically significant. The 5-year probability of survival was 47% for patients with parous donors, 68% for patients with nulliparous donors and 70% for those with male donors. We confirm that prior donor pregnancy represents an important factor in selecting marrow donors or designing clinical protocols for GVHD prophylaxis.

Acute and chronic graft-versus-host disease (GVHD) are significant complications of allogeneic bone marrow transplantation that occur when immunologically active T-cell lymphocytes are transplanted into an immunosuppressed recipient who is genetically disparate from the marrow donor. Oral GVHD lesions closely resemble those seen with a number of autoimmune connective tissue disease, including lichen planus, systemic sclerosis, lupus erythematosus, and Sjögren's syndrome. Mucosal erythema, atrophy, and ulceration are noted clinically; lichen planus-like lesions are the most distinctive oral lesions. Salivary gland changes include changes in both flow rate and sialochemistry. Oral involvement ranges between 33% and 75% for patients with acute GVHD and upwards of 80% for those with chronic GVHD. Management of oral GVHD lesions depends on successful systemic therapy, although topical steroids can be of help in some instances.

Acute and chronic GVHD remain major impediments to the wider application of allogeneic marrow transplantation. It is presumed that human acute GVHD is analogous to the murine model which is initiated by donor T lymphocytes reacting with recipient 'minor' histocompatibility antigens. Chronic GVHD may result from immunoaggression of donor lymphoid cells that have developed and differentiated within the host. Lack of GVHD (i.e., the development of tolerance) may be due either to generation within the host of specific suppressor lymphocytes or to clonal deletion of alloreactive donor cells. Over the last five years progress has been made in the recognition, early diagnosis and successful therapy of chronic GVHD. Methods of prevention and therapy of acute GVHD are still largely unsuccessful. With improved understanding of immune regulation, it is hoped that GVHD can be eliminated in patients transplanted for non-malignant conditions and adroitly modified (without loss of anti-leukaemic potential) in patients with malignant disorders. The challenge of the coming decade is to reach these goals while speeding the return of full immunological competence in the marrow transplant recipient.

Therapy of chronic graft-v-host disease (GVHD) has been unsatisfactory in patients with platelet counts less than 100,000/microL. Survival at 5 years after marrow transplant is only 26% in such patients treated with trimethoprim-sulfamethoxazole (TMP-SMX) and every other day with prednisone. Since October 1982, 61 patients with high-risk extensive chronic GVHD were treated with a new alternating-day regimen of prednisone (1 mg/kg every other day) and oral cyclosporine (6 mg/kg every 12 hours every other day) with one double-strength TMP-SMX tablet twice daily. Forty patients (group I) received primary treatment of thrombocytopenic chronic GVHD (median platelet count 35 [range 7 to 87] x 10(3)/microL). Twenty-one patients (group II) received salvage treatment after failing initial prednisone +/- azathioprine. Twenty-one patients in group I and 15 in group II survive with a minimum of 2 years and a median of 3.7 years follow-up. At 4 years after transplant, actuarial survival is 51% (group I) and 67% (group II). Causes of death included interstitial pneumonia (six), relapse (five), GVHD without infection (five), infection (four), organ failure (three), and hemorrhage (two). Mortality increased with the progressive type onset of chronic GVHD and treatment failure. Toxicity included hypertension (13), nephrotoxicity (nine), nausea (seven), aseptic necrosis (five), neurologic abnormalities (four), and diabetes (three). Median cyclosporine levels at four and 36 hours were 296 and 64 ng/mL, respectively. Four patients required permanent discontinuation of cyclosporine, but none required renal dialysis. Karnofsky performance scores for 25 survivors are 90% to 100%, scores for six survivors are 70% to 89%, and scores for five survivors are less than 70%. Alternating-day cyclosporine and prednisone has acceptable toxicity and appears to improve survival in patients with high-risk chronic GVHD.

To study the effect of acute and chronic graft-versus-host disease (GVHD) on recurrent leukemia, we analysed data on patients with acute leukemia receiving allogeneic marrow transplants in Seattle between 1970 and 1986. Four hundred fifty-four patients survived in remission 150 days after HLA-identical transplant and 114 currently survive five to fifteen years after marrow grafting. At the time of transplant, 252 patients had acute nonlymphocytic leukemia in remission or relapse and 202 had acute lymphocytic leukemia in remission or relapse. According to Kaplan-Meier estimates, recurrence of leukemia following transplantation was observed in 28% of patients developing moderate to severe (grade II-IV) acute GVHD and 48% of patients with no or mild (grade O-I) acute GVHD (p = 0.0028). Relapse was observed in 34% of patients developing clinical extensive chronic GVHD and 45% of patients free of chronic GVHD (p = 0.0001). The incidence of recurrent leukemia was 28% in recipients developing both acute and chronic GVHD and 52% in patients free of both acute and chronic GVHD (p = 0.0001). These data confirm an apparent graft-versus-leukemia effect in patients developing GVHD after allogeneic marrow grafting. Current studies are aimed at determining the influence of such apparent adoptive immunotherapy within the different categories of leukemia and methods to manipulate and augment the clinical benefit of this observation.

Following ablative treatment with supralethal doses of chemotherapy and total body irradiation, patients demonstrate multiple immunologic deficiencies after bone marrow transplantation. Immune function usually recovers and the risk of infection decreases within six to 12 months. However, patients in whom chronic graft-versus-host disease (GVHD) develops have persisting B and T cell abnormalities, and in vivo and in vitro studies show impaired immunoglobulin regulation and function despite normal levels of serum immunoglobulin G. This review summarizes 12 published clinical trials of immunoglobulin therapy to correct immunodeficiency and prevent infection after marrow grafting. In five controlled studies, cytomegalovirus infection developed in a total of 52 of 172 (30 percent) immunoglobulin recipients and 71 of 165 (43 percent) control patients not given globulin. In four controlled trials, interstitial pneumonia developed in a total of 21 of 127 (17 percent) immunoglobulin recipients and 40 of 94 (43 percent) control patients. Three randomized trials reported a reduced rate of GVHD or post-engraftment septicemia in immunoglobulin recipients. However, methods of immunoglobulin preparation, antibody titer, and dose and schedule of prophylaxis varied widely in these studies, as did other critical patient, transplant regimen, and supportive care factors. Accordingly, data should be interpreted with caution. Ongoing controlled clinical trials will further define the proper role of immunoglobulin therapy in bone marrow transplantation.

One hundred fourteen children with acute lymphoblastic leukemia were treated with allogeneic marrow transplantation from HLA-identical siblings after conditioning with cyclophosphamide and total body irradiation. Methotrexate was given posttransplantation for prophylaxis of graft-versus-host disease. The minimum follow-up after transplantation was 2 years. Sixteen of 51 patients transplanted in marrow remission survive from 2.1 to 8.9 years (median 2.7), 13 in continuous remission, one in remission following testicular relapse, and two after marrow relapse. Sixty-three were transplanted in relapse and eight survived 3-10 years (median 5.7), five in continuous remission, and three in remission following testicular relapse. In a multivariate analysis, factors significantly related to increased survival were marrow remission at transplant (p less than 0.007) and chronic graft-versus-host disease (p less than 0.005). Factors associated with increased relapse were marrow relapse at transplant (p less than 0.002) and absence of significant graft-versus-host disease (p less than 0.004). The development of acute graft-versus-host disease was associated with high marrow cell doses (p less than 0.04). These data suggest that some children with acute lymphoblastic leukemia and a poor prognosis with conventional chemotherapy may be cured with marrow transplantation.