An analysis of factors predisposing to chronic graft-versus-host disease.

Among 75 consecutive allogeneic bone marrow transplant recipients, 24 developed chronic graft-versus-host disease (GVHD), which was diagnosed from day 31 to day 368 after transplantation. Eight (33%) patients had more extensive chronic GVHD, and five patients died. The actuarial incidence of chronic GVHD was 48% at 400 days. A number of factors were analyzed for their association with chronic GVHD. Recipients of marrow from donors over 17 years of age had an actuarial incidence of chronic GVHD at 400 days of 74%, compared with 27% if the donors were under 17 years of age (log-rank test on survival curves, p less than 0.001). Other factors that appeared to predispose for chronic GVHD in bivariate analysis were recipient age above 17 years (p less than 0.02), treatment with donor unirradiated buffy-coat cells (p less than 0.01), grade-II-IV acute GVHD (p less than 0.01), and a preceding cytomegalovirus (CMV) infection (p less than 0.01). In multi-variate analysis, however, only donor age above 17 years, treatment with donor buffy-coat cells, and grade-II-IV acute GVHD were significantly associated with chronic GVHD. The possible role of CMV infection in the development of chronic GVHD is discussed.

The role of cyclosporine dosage and plasma levels in efficacy and toxicity in bone marrow transplant recipients.

The efficacy and toxicity of cyclosporine (CsA) treatment for graft-versus-host disease (GVHD) was studied in 53 bone marrow transplant recipients. No correlation was found between acute or chronic GVHD and CsA dosage (daily or cumulative) or CsA plasma levels. Acute nephrotoxicity developed in 63% of the patients. Patients with nephrotoxicity had significantly higher CsA plasma levels during the first month after transplantation compared with patients without nephrotoxicity (P less than 0.05) although the cumulative CsA doses did not differ. Children had significantly fewer episodes of nephrotoxicity compared with adults (P less than 0.01). In spite of this, children received a significantly higher cumulative CsA dose (P less than 0.001). However, CsA plasma levels did not differ between children and adults, suggesting a difference in availability or elimination of the drug. Hypertension developed in 28% of the patients. Hypertensive patients tended to be younger compared with normotensive patients (P = 0.07). Nephrotoxicity tended to be less common in patients with hypertension (P = 0.06). No correlation existed between hypertension and CsA dose or CsA plasma levels. In conclusion, no correlation was found between CsA dose and GVHD or CsA toxicity, and in the single patient CsA plasma levels were of no value in predicting side effects of CsA treatment.

Faster immunological recovery after bone marrow transplantation in patients without cytomegalovirus infection.

The following findings were noted among 45 bone marrow transplant recipients. The patients without cytomegalovirus (CMV) infection or chronic graft-versus-host disease (GVHD) showed normal lymphocyte stimulation in vitro by concanavalin A (Con A) more than 3 months after transplantation, and normal stimulation by phytohemagglutinin (PHA), anti-beta 2-microglobulin (A-beta 2m) and protein A (SpA) after 6 months. In contrast, the patients who had CMV infection without chronic GVHD had Con A and SpA responses within the normal range after 12 months and reduced lymphocyte responses to PHA and A-beta 2m more than 12 months after transplantation. The patients with chronic GVHD had reduced responses to all of these four mitogens after more than 12 months. In comparison with other patients those who later developed chronic GVHD showed an increased mixed lymphocyte culture stimulation during the first 3 months that decreased between 6-12 months. Patients with chronic GVHD still had reduced IgA levels at 12 months after transplantation. Patients with CMV infection, but without chronic GVHD, had higher percentages of lymphocytes with surface membrane Ig than healthy controls during the first 3 months after transplantation. The data suggest that CMV infection, regardless of chronic GVHD, delays immunologic recovery after marrow transplantation.

Variables predicting bacterial and fungal infections after allogeneic marrow engraftment.

Sixty-seven consecutive patients with aplastic anemia or leukemia who had been treated by allogeneic marrow transplantation and had survived for more than 1 month were surveyed in order to determine the incidence of nonviral infections occurring from 1 month to 3 years after transplantation. Twenty-eight of the 67 patients had one or more infections during this period. Around 20% suffered from pulmonary infections and 20% were classified as having a systemic infection. Ten patients died of bacterial or fungal infection, of whom 6 had graft-versus-host disease. In multivariate analyses acute graft-versus-host disease (P less than 0.0009), splenectomy (P less than 0.02), cytomegalovirus infection (P less than 0.05), and a low marrow cell dose (P less than 0.07) were correlated with nonviral infections.

Lymphocyte responses after cytomegalovirus infection in bone marrow transplant recipients--a one-year follow-up.

A group of 46 bone marrow transplant (BMT) recipients were studied by lymphocyte stimulation with cytomegalovirus (CMV) antigen before, and repeatedly in the first year after, BMT. Of these, 25 patients developed CMV infection and 68% of these got a positive lymphocyte response to CMV. The recipients with an early response (up to 3 months) to CMV antigen after the CMV infection were less prone to develop chronic graft-versus-host disease (GVHD) than those who responded later or not at all (P = 0.002). After the CMV infection, the increased lymphocyte CMV reactivity remained in recipients without chronic GVHD, but recipients with chronic GVHD usually lost their reactivity. The results suggest that it may be possible to predict patients who are not going to develop chronic GVHD by studying lymphocyte responses to CMV infections.

Cytomegalovirus infection associated with and preceding chronic graft-versus-host disease.

Of 68 consecutive allogeneic bone marrow transplant patients, 53 survived more than three months after transplantation. Twenty-two (42%) developed chronic graft-versus-host disease (GVHD). Chronic GVHD was more common among patients who had previously experienced cytomegalovirus (CMV) infection (20/36, 56%) than among those without signs of active CMV infection (2/17, 12%) (P less than 0.01). The CMV infections preceded the development of chronic GVHD by a median of 128 days (range 23-322 days). Children below 14 years of age who had had CMV infection developed chronic GVHD as often as older patients (8/14 vs. 12/22). CMV infection may pave the way for chronic GVHD.

Ontogeny of immunoglobulins in bone marrow-transplanted individuals. An analysis of serum and salivary levels.

Unstimulated whole saliva and serum samples were collected from ten allogeneic bone marrow transplant recipients before and after bone marrow transplantation, seven donors, and from twenty healthy individuals. Two patterns with regard to salivary IgA were found after transplantation. In five patients, a short-lasting peak of excessive IgA production was noted shortly after BMT. Two of these patients had an increase of both secretory and the nonsecretory form of IgA, whereas the other three only demonstrated elevated nonsecretory IgA levels. After the IgA peak the IgA level decreased below the level before BMT. In five patients a different pattern was seen, with a marked decrease in salivary IgA, IgG, and IgM as well as albumin after grafting. A highly variable pattern of reconstitution was seen after one year, when three out of seven patients were still deficient in secretory IgA.

IgG-subclass-specific CMV reactivity in bone marrow transplant recipients.

IgG subclasses of cytomegalovirus (CMV) antiviral antibodies were determined in 37 donor-recipient pairs of bone marrow transplants (BMT). Bone marrow transplant recipients, like healthy persons, have a restricted immune reactivity, producing mainly two types of anti-CMV IgG: IgG1 and IgG3. Passively transfused specific antibody subclasses were readily measurable. Take of the transplant could be detected from the production of subclass IgG antiviral antibody 1-3 months after BMT of seronegative recipients with marrow from seropositive donors. Patients with protracted CMV infections or other severe diseases initially also produced CMV IgG1 and IgG3, but anti-CMV subclass titers then decreased. In severe disease, CMV was isolated from blood cells as well as from urine. In moderate infections, in which the patients recovered, CMV was isolated from urine but usually not from blood, and a strong and durable antiviral subclass response was measured.

Serum immunoglobulin levels in relation to levels of specific antibodies in allogeneic and autologous bone marrow transplant recipients.

BACKGROUND: The aim of this study was to investigate the correlation of total levels of immunoglobulins to levels of specific antibodies after allogeneic and autologous bone marrow transplantation. Autologous transplant patients had normal levels of IgA and IgG antibodies already at 6 months after transplantation. In allogeneic transplanted patients without chronic graft versus host disease the immunological recovery was slower. The IgA and IgG levels were at the limit for deficiency at 6 months after transplantation. In allogeneic transplant patients with chronic chronic graft versus host disease the immunological recovery was delayed further. The total IgG levels were low at 12 months after transplantation and the IgG subclass pattern did not normalize until 24 months after transplantation. IgA levels remained low at 24 months after transplantation in all allogeneic transplanted patients with chronic chronic graft versus host disease. Protective levels of specific antibodies against tetanus and pneumococci decreased during the first year after transplantation regardless of the total immunoglobulin levels, regardless of the donors immunity. Pneumococcal antibodies decreased only in allogeneic transplanted patients, although autologous transplant patients retained pretransplant immunity against pneumococci. There was no difference in levels of specific antibodies between patients with and without chronic chronic graft versus host disease at 12 months after transplantation. There was no correlation between total immunoglobulin levels to levels of specific antibodies against tetanus and pneumococci after transplantation in our study. Taken together, normalized immunoglobulin levels do not predict normalization of levels of specific antibodies against tetanus and pneumococci after transplantation.

Long-term follow-up of a randomized trial comparing T cell depletion with a combination of methotrexate and cyclosporine in adult leukemic marrow transplant recipients.

Forty-eight adult leukemic recipients of HLA-identical sibling marrow were randomized to T cell depletion using anti-CD8 and anti-CD6 antibodies plus complement (n = 28) or prophylaxis with methotrexate (MTX) and cyclosporine (CsA) (n = 25). Patient characteristics were comparable in the two groups. The median observation time was 5 1/2 years. Transfusions, infections, and acute GVHD did not differ between the groups. Chronic GVHD occurred in 52% of patients receiving T cell-depleted marrow and 23% of those receiving MTX + CsA (P = 0.06). Overall probability of relapse was similar in both groups and actuarial leukemia-free survivals at 5 years were 39% and 35% in the two groups, respectively. Among patients with chronic myeloid leukemia (CML), leukemia-free survival at 5 years was 25% in patients receiving T cell-depleted marrow compared with 51% in those given MTX + CsA (P = 0.09). In patients with acute leukemia the probability of relapse was 24% in the group receiving T cell-depleted marrow compared with 73% in those treated with MTX + CsA (P = 0.06). Leukemia-free survival was 55% and 21% in the two groups, respectively (NS). CML patients tended to have a poorer prognosis and those with acute-leukemia better outcome with T cell depletion than with combined MTX + CsA. It is concluded that T cell depletion is unsuitable for patients with CML, but may be considered in patients with acute leukemia.

Results of different strategies for reducing cytomegalovirus-associated mortality in allogeneic stem cell transplant recipients.

BACKGROUND: Several preventive strategies against cytomegalovirus (CMV) disease have been developed during the last decade. These have frequently been used in combination, and it has been difficult to identify each strategy's contribution. METHODS: Risk factors for CMV disease, death in CMV disease and transplant-related mortality were analyzed in 584 patients, who underwent a total of 594 allogeneic bone marrow transplants. RESULTS: The overall probability of CMV disease was 8.9%. No seronegative patient who had a seronegative marrow donor developed CMV disease. The corresponding probabilities for seronegative patients with seropositive donors, seropositive patients with seronegative donors, and seropositive patients with seropositive donors were 5.4%, 13.7%, and 11.7%, respectively. In multivariate Cox models, the use of preemptive antiviral therapy and being CMV-seronegative reduced the risk for CMV disease, CMV-associated death, and transplant-related mortality (TRM). Patients who received unrelated or mismatched family donor transplants had increased risks for CMV disease, CMV-associated death, and TRM. Older age was a significant risk factor for CMV disease and TRM. A total of 258 patients who were monitored by polymerase chain reaction for CMV DNA were analyzed separately to assess whether addition of another CMV preventive strategy could give benefit. Patients who received mismatched or unrelated donor transplants had increased risk for CMV disease, death in CMV disease, and TRM. High-dose acyclovir prophylaxis or addition of intravenous immune globulin had no influence. CONCLUSIONS: Preemptive therapy based on polymerase chain reaction for CMV DNA was associated with reduced risks for CMV disease, CMV-associated death, and TRM, whereas other prophylactic modalities did not give additional benefit.

Treatment of hepatic venoocclusive disease with recombinant human tissue plasminogen activator or orthotopic liver transplantation after allogeneic bone marrow transplantation.

Ten allogeneic bone marrow transplant (BMT) recipients with hepatic venoocclusive disease (VOD) were treated with recombinant human tissue plasminogen activator (rt-PA). Two of them subsequently underwent orthotopic liver transplantation (OLT). One additional patient with VOD underwent OLT without prior rt-PA treatment. Treatment with rt-PA was started a median of 14 (1--35) days after BMT. The dose of rt-PA given to adults was 10-50 mg i.v. and that given to children was 3-10 mg i.v. Treatment was given for 2-4 days. In three patients, the dose was administered over a longer period or it was repeated. Four patients responded to rt-PA therapy and six did not. Eight patients suffered from hemorrhages, one intracranial and three gastrointestinal. Four patients required blood transfusions. Four had minor subcutaneous hemorrhages and/or epistaxis. One patient died of intracranial hemorrhage and five from hepatic and/or multiorgan failure. Two patients treated with rt-PA, 10 mg/day for 4 days, are alive; one is alive and well 3 months after BMT, the other has relapsed after 7 months. The three patients undergoing OLT died of chronic hepatic failure, cerebral edema, and pneumonia. Our experience suggests that rt-PA should not be administered in high doses and that the treatment should not be given over a longer period, because of the risk of severe hemorrhages.

Experience with a cooperative bone marrow transplantation program in Stockholm.

Twenty-seven patients (age range from 1 to 55 years) were included in a cooperative bone marrow transplantation program in Stockholm. Of eight patients with severe aplastic anemia (SAA), two died following graft rejection and six (75%) are alive between 3 months and 4 1/2 years after transplantation. Two patients with end stage leukemia died of septicemia and bleeding shortly after transplantation. Thirteen of 17 patients (76%) with acute leukemia in their first or second remission are alive 1 to 16 months after transplantation. Death was caused by septicemia in two patients, interstitial Candida pneumonitis in one and gastrointestinal bleeding in association with graft-versus-host disease in one. Among the leukemic patients all deaths occurred in subjects over 17 years of age and all 10 children are alive. No relapse has yet been seen. Successful bone marrow transplantations were carried out utilizing ordinary hospital resources only. This justifies the practice of performing transplantations in subjects with SAA and acute leukemia in remission even outside specially equipped and designed bone marrow transplantation units.

Low incidence of acute graft-versus-host disease, using unrelated HLA-A-, HLA-B-, and HLA-DR-compatible donors and conditioning, including anti-T-cell antibodies.

BACKGROUND: Using unrelated bone marrow, there is an increased risk of graft-versus-host disease (GVHD). METHODS: HLA-A-, HLA-B-, and HLA-DR-compatible unrelated bone marrow was given to 132 patients. The diagnoses included chronic myeloid leukemia (n=43), acute lymphoblastic leukemia (n=29), acute myeloid leukemia (n=27), myelodysplastic syndrome (n=4), lymphoma (n=3), myeloma (n=1), myelofibrosis (n=1), severe aplastic anemia (n=12), and metabolic disorders (n=12). The median age was 25 years (range 1-55 years). HLA class I was typed serologically, and class II was typed by polymerase chain reaction using sequence-specific primer pairs. Immunosuppression consisted of antithymocyte globulin or OKT3 for 5 days before transplantation and methotrexate combined with cyclosporine. RESULTS: Engraftment was seen in 127 of 132 patients (96%). Bacteremia occurred in 47%, cytomegalovirus (CMV) infection in 49%, and CMV disease in 8%. The cumulative incidences of acute GVHD > or = grade II and of chronic GVHD were 23% and 50%, respectively. The 5-year transplant-related mortality rate was 39%. The overall 5-year patient survival rate was 49%; in patients with metabolic disorders and severe aplastic anemia, it was 61% and 48%, respectively. The disease-free survival rate was 47% in patients with hematological malignancies in first remission or first chronic phase and 38% in patients with more advanced disease (P=0.04). Acute GVHD was associated with early engraftment of white blood count (P=0.02). Poor outcome in multivariate analysis was associated with acute myeloid leukemia (P=0.01) and CMV disease (P=0.04). CONCLUSION: Using HLA-A-, HLA-B-, and HLA-DR-compatible unrelated bone marrow and immunosuppression with antithymocyte globulin, methotrexate, and cyclosporine, the probability of GVHD was low and survival was favorable.

Lymphoblastoid human interferon and low dose IL-2 combined with donor lymphocyte infusion as therapy of a third relapse of CML--a case report.

A patient, who was treated twice with donor lymphocyte infusions for relapse of CML after an allogeneic BMT was given lymphoblastoid human alpha-IFN after a third relapse. Further donor lymphocyte infusions were followed by repeated courses of 30 days treatment with a low dosage of IL-2 subcutaneously, alternately with alpha-IFN. This treatment resulted in a hematologic and cytogenetic remission. He also developed a limited degree of chronic GVHD. At the latest follow-up at 20 months after the third course of lymphocyte infusions he is in continuous hematologic and cytogenetic remission. Furthermore, a qualitative PCR analysis for the bcr/abl translocation is negative.

An increased risk of relapse in cyclosporin-treated compared with methotrexate-treated patients: long-term follow-up of a randomized trial.

Patients with haematological malignancies and HLA-identical marrow donors were randomized to treatment with cyclosporin A (CSA, n = 30) or methotrexate (MTX, n = 29) with a follow-up ranging from 32 to 70 months. The two groups were comparable regarding disease status and age. Acute graft-versus-host disease (GVHD) was similar and the cumulative incidences of chronic GVHD was 42% in both groups. The overall incidence of cytomegalovirus (CMV) infection and other late infections were also the same in the two groups. Interstitial CMV pneumonitis occurred in 13% in the CSA group compared with 32% in the MTX group (ns). The probability of relapse was 42% after 4 years among the CSA patients and was significantly higher than the probability of relapse in the MTX patients which was found to be 10% (p = 0.03). The actuarial survival after 5 years was 53% for the CSA patients and 57% for the MTX patients (ns). The relapse-free survival was 41% and 59%, respectively (ns). There were no differences between the two groups in terms of renal or hepatic function, incidence of cataracts, blood cell counts, bone marrow cellularity or Karnofsky scores at 2 and 4 years after transplantation.

Dry eye syndrome in long-term follow-up of bone marrow transplanted patients.

Out of 77 bone marrow transplanted patients surviving at least 1 year, 43% developed ocular manifestations of the sicca syndrome. This reaction was more frequent in patients with graft-versus-host disease (GVHD). Kerato-conjunctivitis sicca (KCS) developed in 28 patients (54%) who had survived acute GVHD but in only five cases (20%) of those without that complication. The incidence of dry eyes was 62% in the chronic GVHD group. All seven sicca cases in patients with aplastic anemia were seen in patients with chronic GVHD, while 10 out of 26 patients with hematological malignancies and without chronic GVHD had KCS. Two of these had not experienced any acute GVHD. Irradiation may contribute to the development of KCS, since all patients with hematological malignancies, in contrast to aplastic anemia patients, had undergone total body irradiation.

Oral condition in children treated with bone marrow transplantation.

Oral health was studied in 49 children below 12 years of age treated with bone marrow transplantation (BMT). Dental treatment prior to BMT was required in 41% of the children. Ulceration of the mucous membranes in the mouth was observed in 37% of the patients during treatment. Those given methotrexate as prophylaxis against graft-versus-host disease (GVHD) exhibited oral ulcerations more frequently (p less than 0.05) than those given cyclosporin. One year after BMT all patients with a clinical chronic GVHD exhibited changes in the oral mucosa. During the first year after BMT 31% of the children developed carious lesions. Children treated with 10 Gy total body irradiation (TBI) had a significantly (p less than 0.05) reduced salivary secretion rate. Dental development was severely affected in children treated with TBI. These disturbances consisted of arrested root development, enamel hypoplasias and microdontia.

Rejection of the second allogeneic graft in a patient with severe aplastic anemia reversed by antilymphocyte globulin and donor lymphocyte infusions.

Rejection after allogeneic BMT for aplastic anemia is a complication with a high risk of mortality. We describe a patient who, following a second episode of rejection after a second BMT entered a third durable remission subsequent to treatment with ALG, donor lymphocyte infusions, GM-CSF, and erythropoietin. Therapy was well tolerated. At 5 years after rejection treatment, his hematopoiesis is of complete donor origin as determined by analyses of short tandem repeats. Thus, donor lymphocyte infusions can be considered as a therapy option for marrow rejection after allogeneic BMT for aplastic anemia.

Hemorrhagic cystitis--a manifestation of graft versus host disease?

In 125 allogeneic bone marrow transplant recipients conditioned with cyclophosphamide (CY) with or without total body irradiation (TBI), three different protocols for prevention of CY urotoxicity have been used. The three protocols consisted of forced alkaline diuresis alone and then in combination with mesna (sodium 2-mercaptoethane sulfonate) at a low or high dose (60-90% and 150% of the CY dose, respectively). Hemorrhagic cystitis (HC) occurred in 21 patients: there were four immediate episodes without subjective symptoms which healed within a week after starting CY and 20 late episodes, starting between 17 and 51 (median 27) days. There was no correlation between the occurrence of HC and the different protocols used for prevention of urothelial toxicity. Late HC, however, except in one patient, always appeared together with acute graft-versus-host disease (GVHD) and the severity of the HC correlated with the severity of the GVHD (p less than 0.001). When acute GVHD commenced the HC started within 24 hours in three patients and in 11 patients when the dose of prednisolone given for an ongoing GVHD was reduced. In four other patients CY was not used for conditioning, but mustargen or melphalan in combination with TBI. In this group no urothelial protection was used. One of these patients developed a severe HC together with a grade II GVHD. Adenovirus and cytomegalovirus infections were not associated with HC.