Graft-v-host disease is associated with autoimmune-like thrombocytopenia [see comments]

Persistent thrombocytopenia after allogeneic marrow transplantation is associated with poor patient survival. To identify the mechanisms of the thrombocytopenia, we studied platelet and fibrinogen kinetics and antiplatelet antibodies in 20 patients between 60 and 649 days (median 90) after transplantation. Seventeen patients had isolated thrombocytopenia (less than 100 X 10(9) platelets/L): the marrow cellularity was normal in five patients and slightly reduced in 12, and there was no discrepancy between thrombopoiesis and myeloerythropoiesis. Three patients had pancytopenia following marrow graft rejection (two) and relapse of leukemia (one). Only three patients had evidence of increased platelet production, indicating that in most cases there is a poor marrow response to thrombocytopenia early after marrow grafting. There was no correlation between platelet count and splenic pooling, suggesting that hypersplenism was an unlikely mechanism of the thrombocytopenia. Although there was a direct relationship between platelet count and platelet survival, the reduction in platelet survival was greater than what could be explained by the fixed platelet removal found in thrombocytopenic patients; this suggests increased platelet destruction. Seven patients had intercurrent infections that reduced both platelet and fibrinogen survivals. In addition, platelet antibodies bound to autologous or marrow donor platelets were present in five of the 12 patients studied. Patients with antiplatelet antibodies had lower platelet counts (30 +/- 10 X 10(9)/L v. 49.1 +/- 28.7 X 10(9)/L, P less than 0.05) and platelet survivals (1.32 +/- 0.92 days v. 3.58 +/- 2.02 days, P less than 0.05) than patients without antiplatelet antibodies. Furthermore, platelet- bound autoantibodies were present in five of six patients with grade II- IV acute or chronic graft-versus-host disease (GVHD), but were not present in six patients free of GVHD (P less than 0.01). We conclude that persistent thrombocytopenia after marrow transplantation is most often secondary to increased platelet destruction mediated by multiple mechanisms and that platelet autoantibodies are found in patients with acute or chronic GVHD.     

Abnormal liver function tests following bone marrow transplantation: aetiology and role of liver biopsy

INTRODUCTION: Liver dysfunction is common in bone marrow transplant recipients. Common causes are graft-versus-host disease, drugs, veno-occlusive disease, sepsis and iron overload. We studied the prevalence and aetiology of abnormal liver function tests following bone marrow transplantation and the role of liver biopsy. METHODS: All allogeneic and autologous bone marrow transplantations undertaken in our institution over a 2-year period were studied. Subsequent liver function tests, the use and timing of liver biopsy and the final cause of liver dysfunction were determined in each case. RESULTS: We studied 121 patients (58 allogeneic, 63 autologous). Abnormal liver function tests were found in 52% of bone marrow transplant recipients (72% allogeneic and 33% autologous; P = 0.015). The most common causes of liver dysfunction were graft-versus-host disease, drugs and iron overload in the allogeneic group, and drugs and sepsis in the autologous group. Nineteen patients (16%; 18 allogeneic) underwent liver biopsy. The majority of liver biopsies were carried out in the late post-transplant period to exclude or confirm graft-versus-host disease, although only one case was confirmed. Sixteen of the 19 patients who underwent biopsy had significant hepatic iron overload, but no biopsy revealed evidence of fibrosis or cirrhosis. CONCLUSION: Liver dysfunction following bone marrow transplantation is common and most diagnoses can be ascertained without resorting to liver biopsy. In our series, hepatic iron overload was the most common finding in those who underwent liver biopsy.     

A randomized multicenter comparison of bone marrow and peripheral blood in recipients of matched sibling allogeneic transplants for myeloid malignancies

Cytokine-mobilized peripheral blood is increasingly used instead of bone marrow as the source of cells for allogeneic transplantation. Although cells lead to faster hematologic recovery, their effects on graft-versus-host disease, relapse, and survival are less certain. Between January 1996 and February 2000, 228 patients with chronic myeloid leukemia, acute myeloid leukemia, or myelodysplasia were randomized to receive either bone marrow or peripheral blood allografts from HLA-matched siblings. All patients received busulfan and cyclophosphamide as conditioning chemotherapy and cyclosporine and methotrexate as graft-versus-host disease prophylaxis. We compared the times to neutrophil and platelet recovery, acute and chronic graft-versus-host disease, relapse, and overall survival between the groups. The median times to neutrophil recovery were 19 days and 23 days and the times to platelet recovery were 16 days and 22 days in the peripheral blood and bone marrow groups, respectively (P <.0001 for both comparisons). The cumulative incidence of grades II to IV acute graft-versus-host disease 100 days after transplantation was 44% in both groups (hazard ratio, 0.99; 95% confidence interval, 0.66-1.49; P >.9), and the incidence of extensive chronic graft-versus-host disease at 30 months after transplantation was 40% with peripheral blood and 30% with bone marrow (hazard ratio, 1.23; 95% confidence interval, 0.78-1.96; P =.37). There was no statistically significant difference in the probability of relapse of the underlying disease between the groups. The probabilities of survival at 30 months after transplantation were 68% and 60% in the peripheral blood and bone marrow groups, respectively (hazard ratio, 0.62; 95% confidence interval, 0.39-0.97; P =.04). In patients with chronic myeloid leukemia, acute myeloid leukemia, and myelodysplasia undergoing allogeneic transplantation from matched siblings, the use of peripheral blood instead of bone marrow leads to faster hematologic recovery, similar risk of graft-versus-host disease, and improved survival.     

Cytomegalovirus infection causes delayed platelet recovery after bone marrow transplantation.

The pathogenic effect of cytomegalovirus (CMV) infection on the hematopoietic recovery after bone marrow transplantation (BMT) was retrospectively studied in 87 recipients of (nonpurged) autologous BMT and in 56 recipients of allogeneic BMT from HLA-identical siblings. Indications for autologous BMT were lymphomas or acute leukemias and for allogeneic BMT various malignancies or aplastic anemia. Patients were divided for the study in two groups, CMV-positive and CMV-negative on the basis of the CMV status pretransplant, and CMV-negative patients were kept CMV-negative by the local transfusion policy. In allogeneic BMT recipients, platelet recovery was significantly slower in CMV-positive patients than in CMV-negative patients (platelets greater than 50,000 cells/microL after 41 days v 27 days, P = .007). This difference held true when patients with acute graft-versus-host disease above grade I were excluded (platelets greater than 50,000 cells/microL after 42 days v 24 days, P = .01). In autologous BMT, the negative effect on platelet recovery was present in patients with lymphomas, but absent in patients with acute leukemias. Patients with acute leukemias had a very delayed recovery of platelets and granulocytes after autologous BMT, irrespective of the CMV status, probably due to the original stem cell disorder. Platelet recovery was significantly slower in CMV-positive autologous BMT recipients with lymphomas than in those not infected (platelets greater than 50,000 cells/microL after 36 days v 24 days, P = .0002). The presence of CMV infection had no effect on the recovery of granulocytes in autologous or allogeneic BMT. These data show that CMV infection causes delayed platelet recovery after BMT; however, in autologous BMT, the underlying disease (ie, acute leukemia) is more determinant for hematopoiesis after BMT.     

Bone marrow transplantation for chronic myelogenous leukemia in chronic phase. Increased risk for relapse associated with T-cell depletion

Data on 405 patients with chronic myelogenous leukemia who received bone marrow transplants in chronic phase were analyzed for factors predictive of outcome. The 4-year actuarial probability of relapse was 19% (95% confidence interval [CI], 12% to 28%) and of survival, 55%. In multivariate analyses the probability of relapse was higher for recipients of T-cell-depleted bone marrow compared with recipients of non-T-cell-depleted bone marrow (relative risk, 5.4; P less than 0.0001) and for patients who did not develop chronic graft-versus-host disease (95% CI, 50% to 60%) with patients who did (relative risk, 3.1; P less than 0.01). The probability of survival was lower for patients who developed moderate to severe acute graft-versus-host disease than for patients with no or mild acute graft-versus-host disease (relative risk, 3.7; P less than 0.0001), and in patients aged 20 or older than in younger patients (relative risk, 2.6; P less than 0.0002). Duration of disease before transplant was not associated with outcome. Bone marrow transplantation done in the chronic phase of chronic myelogenous leukemia offers some patients prolonged leukemia-free survival. The T-cell-depleted grafts are associated with an increased probability of relapse.     

Comparisons between allogeneic peripheral blood stem cell transplantation and allogeneic bone marrow transplantation in adult hematologic disease: a single center experience

This retrospective study compared the outcomes in 32 adult patients with hematologic diseases (acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, severe aplastic anemia) who received allogeneic bone marrow transplantation (BMT, n = 14; median age, 28 years) or allogeneic peripheral blood stem cell transplantation (PBSCT, n = 18; median age, 29 years) from human leukocyte antigen-identical sibling donors. Median follow-up was 58 months in BMT recipients and 18 months in PBSCT recipients. Neutrophil (median, Day 8 vs Day 13, p < 0.001) and platelet engraftment (median, Day 9 vs Day 17, p < 0.001) was faster in the PBSCT group than in the BMT group. Patients receiving PBSCT required less platelet transfusion than those receiving BMT (median, 54 units vs 144 units, p < 0.001), but there was no significant difference in red cell transfusion. At 100 days, there was no difference in the incidence of acute graft-versus-host disease (GVHD) (42.9% vs 33.3%, p = 0.72) or grade II-IV acute GVHD (14.3% vs 5.6%, p = 0.57), and there was no difference in the cumulative incidence of chronic GVHD (20% vs 33.3%, p = 0.67). No chronic GVHD was noted in any relapsed patients (BMT, 5; PBSCT, 3), and no patients with chronic GVHD during follow-up had a relapse. Relapse was the most frequent cause of death inboth groups (BMT, 5/9, 55.6%; PBSCT, 3/4, 75%; p = 0.25); all relapses occurred within 1 year after transplantation. Overall survival was significantly better in the PBSCT group (35.7% vs 77.8%, p = 0.029), but this difference was lost if only hematologic malignancies were analyzed (30.8% vs 63.6%, p = 0.20). Our results are similar to those reported previously, with faster neutrophil and platelet engraftment and less severe acute GVHD and extensive chronic GVHD with PBSCT. Allogeneic PBSCT is a feasible and beneficial alternative to allogeneic BMT in adult hematologic disease.     

Long-term follow-up of allogeneic bone marrow transplantation after reduced-intensity conditioning in patients with chronic myelogenous leukemia in the chronic phase

Although allogeneic transplantation is a curative therapy for chronic myelogenous leukemia (CML), treatment-related mortality is still a major cause of death after transplantation, especially in older patients. We investigated the safety and efficacy of reduced-intensity conditioning consisting of low-dose (600 cGy) total body irradiation and cytosine arabinoside (1 g/m2) together with a continuous infusion of granulocyte colony-stimulating factor and cyclophosphamide (120 mg/kg) in patients with CML in the chronic phase. Fractionated splenic irradiation (5 Gy) was also administered as part of the conditioning treatment. Eight patients older than 40 years underwent allogeneic bone marrow transplantation from an HLA-matched sibling following this conditioning. Regimen-related toxicities (equal to or greater than grade III) were not observed. Rapid restoration of 100% donor chimerism was confirmed by fluorescence in situ hybridization methods in 5 sex-mismatched transplant recipients. One patient died from severe acute graft-versus-host disease and another from Pneumocystis carinii pneumonia early in the course of transplantation. A sustained engraftment was achieved in 5 long-term survivors; in 1 case, the graft was rejected but the Philadelphia chromosome and BCR/ABL-negative autologous hemopoiesis were restored. After a minimum follow-up period of 60 months, 6 patients, including the patient with restored autologous hemopoiesis, were still alive and in remission with 100% donor chimerism. Six years after the transplantation, 1 patient experienced a cytogenetic relapse, which was successfully treated with donor lymphocyte infusions. In summary, this reduced-intensity conditioning resulted in a cure with markedly reduced regimen-related toxicities in this relatively older cohort of patients with CML.     

Sj?gren-type syndrome after allogeneic bone-marrow transplantation.

Four patients, treated for hematologic disorders with bone-marrow transplants from HLA-identical siblings, spontaneously complained of dry eyes 8 to 12 months after transplantation. Four allograft recipients and two recipients of autologous bone-marrow transplants were evaluated for xerophthalmia and xerostomia. Three allogeneic marrow recipients had evidence of keratoconjunctivitis sicca, and two had decreased parotid gland function. All four allograft recipients had minor salivary gland histopathology identical to that of Sj?gren's syndrome. The severity of symptoms and histologic lesions corresponded with the severity of chronic graft-versus-host disease. In addition, one patient developed sclerodermatous skin changes, another had discoid lupus erythematosus, and two patients had laboratory evidence of cholestasis. None of the patients had autoantibodies but all had hypergammaglobulinemia. In contrast, none of the recipients of autologous bone marrow had clinical, laboratory, or histologic findings resembling Sj?gren's syndrome.     

Use of recombinant human granulocyte-macrophage colony-stimulating factor in graft failure after bone marrow transplantation

The effect of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) was evaluated in 37 patients with marrow graft failure after allogeneic (n = 15), autologous (n = 21), or syngeneic (n = 1) bone marrow transplantation. rhGM-CSF was administered by 2-hour infusion at doses between 60 and 1,000 micrograms/m2/d for 14 or 21 days. At doses of less than 500 micrograms/m2, rhGM-CSF was well-tolerated and did not exacerbate graft-versus-host disease in allogeneic transplant recipients. No patient with myelogenous leukemia relapsed while receiving rhGM-CSF. Twenty-one patients reached an absolute neutrophil count (ANC) greater than or equal to 0.5 x 10(9)/L within 2 weeks of starting therapy while 16 did not. None of seven patients who received chemically purged autologous marrow grafts responded to rhGM-CSF. The survival rates of GM-CSF-treated patients were significantly better than those of a historical control group.     

Evidence of a graft-versus-lymphoma effect associated with allogeneic bone marrow transplantation

The existence of an immunologic antileukemia reaction associated with allogeneic bone marrow transplantation (BMT) is well established. However, a similar graft-versus-tumor effect against lymphomas has not been demonstrated. We analyzed the results of BMT in 118 consecutive patients with relapsed Hodgkin's disease or aggressive non-Hodgkin's lymphoma. The 38 patients less than 50 years of age with HLA-matched donors had allogenic marrow transplants, and the other 80 patients received purged autologous grafts. The median age was 26 years in both the allogeneic and the autologous graft recipients. The patient's response to conventional salvage therapy before transplant was the only factor that influenced the event-free survival after BMT (P less than .001). Both the patient's response to salvage therapy before BMT (P less than .001) and the type of graft (P = .02) significantly influenced the probability of relapse after BMT. The actuarial probability of relapse in patients who responded to conventional salvage therapy before BMT was only 18% after allogenic BMT compared with 46% after autologous BMT. However, the actuarial probability of event-free survival at 4 years was the same, 47% versus 41%, for patients with responsive lymphomas who received allogeneic and autologous transplants, respectively (P = .8). The beneficial antitumor effect of allogeneic BMT was offset by its higher transplant-related mortality (P = .01), largely resulting from graft-versus-host disease. Allogeneic BMT appears to induce a clinically significant graft-versus-lymphoma effect. The magnitude of this effect is similar to that reported against leukemias.     

Neutrophil function and pyogenic infections in bone marrow transplant recipients.

In a consecutive entry trial, the incidence and time course of decreased neutrophil function was assessed in 20 patients treated with allogeneic bone marrow transplantation (BMT). The aim of the study was to assess the prognostic value of low neutrophil function for late pyogenic infections. Chemotaxis, superoxide production, and phagocytic-bactericidal activity were studied before and 2, 6, 9, and 12 months after BMT. Skin window migration was quantitatively assessed 2 months after BMT. Infectious complications were recorded prospectively with preset criteria during 1 year. Six of the 20 leukemic patients had defective neutrophil function before BMT. Two months after BMT all 10 patients with greater than stage II graft-versus-host disease (GVHD), and 6 of 10 patients with less than or equal to stage II GVHD had at least one decreased function. At this time, patients with subsequent pyogenic infections had lower chemotaxis (P less than .05), phagocytic-bactericidal activity (P less than .005), and superoxide production (P less than .025) than those without. Defective skin window migration and combined defects were predictive for late pyogenic infections. At 9 months all tests were normal in seven patients surviving without GVHD. In contrast, at 9 months three of three patients, and at 1 year two of three with chronic GVHD had still decreased neutrophil function. In conclusion, neutrophil function is frequently impaired during the first months after BMT. Combined neutrophil defects predispose to pyogenic infections and indicate the patient at risk.     

Some but not all benefits of intravenous immunoglobulin therapy after marrow transplantation appear to correlate with IgG trough levels.

Multiple benefits of intravenous immunoglobulin (IVIG) therapy after marrow transplantation have been reported, including decreased incidence of acute graft-versus-host disease (GVHD), infection, sepsis, cytomegalovirus (CMV) pneumonitis and platelet use. To test the hypothesis that the observed beneficial effects of IVIG are related to the serum IgG levels achieved, we followed IgG levels (pre-infusion, 1 h and 24 h post-infusion) in 45 consecutive marrow transplant recipients. IVIG 500 mg/kg was given weekly for six doses starting day -8 pre-transplant, then every other week for a total of 11 doses. Forty-one patients (22 allogeneic, 17 autologous, two syngeneic) were evaluable. Patients with acute GVHD had significantly lower serum IgG trough levels (less than 1200 mg/dl) noted at day +20 post-transplant and afterwards than patients without GVHD (greater than or equal to 1200 mg/dl). Pharmacokinetic modeling of the data indicates that IgG half-life between day -8 and day +6 may predict which recipients are at increased risk of acute GVHD. Allogeneic recipients in the group with trough levels less than 1200 mg/dl required more platelet transfusions. Although there was no significant difference in fungal infection rates or bacteremia, sepsis was noted in only two recipients (one allogeneic, one autologous), both with serum IgG trough levels less than 1200 mg/dl. In addition, three allogeneic recipients had cytomegalovirus pneumonitis, all in the group with lower IgG trough levels. Thus, while serum IgG trough levels less than 1200 mg/dl appear to be strongly associated with acute GVHD, low levels may also be associated with increased platelet utilization, with cytomegalovirus pneumonitis, and sepsis, but not with the overall incidence of infection.     

Graft-versus-leukemia reactions after bone marrow transplantation

To determine whether graft-versus-leukemia (GVL) reactions are important in preventing leukemia recurrence after bone marrow transplantation, we studied 2,254 persons receiving HLA-identical sibling bone marrow transplants for acute myelogenous leukemia (AML) in first remission, acute lymphoblastic leukemia (ALL) in first remission, and chronic myelogenous leukemia (CML) in first chronic phase. Four groups were investigated in detail: recipients of non--T-cell depleted allografts without graft-versus-host disease (GVHD), recipients of non-- T-cell depleted allografts with GVHD, recipients of T-cell depleted allografts, and recipients of genetically identical twin transplants. Decreased relapse was observed in recipients of non--T-cell depleted allografts with acute (relative risk 0.68, P = .03), chronic (relative risk 0.43, P = .01), and both acute and chronic GVDH (relative risk 0.33, P = .0001) as compared with recipients of non--T-cell depleted allografts without GVHD. These data support an antileukemia effect of GVHD. AML patients who received identical twin transplants had an increased probability of relapse (relative risk 2.58, P = .008) compared with allograft recipients without GVHD. These data support an antileukemia effect of allogeneic grafts independent of GVHD. CML patients who received T-cell depleted transplants with or without GVHD had higher probabilities of relapse (relative risks 4.45 and 6.91, respectively, P = .0001) than recipients of non--T-cell depleted allografts without GVHD. These data support an antileukemia effect independent of GVHD that is altered by T-cell depletion. These results explain the efficacy of allogeneic bone marrow transplantation in eradicating leukemia, provide evidence for a role of the immune system in controlling human cancers, and suggest future directions to improve leukemia therapy.     

Respiratory ciliary function in bone marrow recipients

Bone marrow transplantation (BMT) recipients, particularly those with chronic graft-versus-host disease (GVHD), suffer from respiratory tract problems, including bronchiolitis obliterans (BO) and recurrent lower respiratory tract infections. Minute cilia beat continuously on the surface of respiratory mucosa, and this beating maintains the sterility of the lower respiratory tract. Dysfunction of respiratory cilia could lead to development of recurrent respiratory tract infections, which are also features of BMT recipients, although ciliary function has not been systematically studied among these subjects. We have, therefore, investigated the ciliary beat frequency (CBF) of 36 Chinese patients who had undergone allogeneic BMT. The CBF was significantly lower in the BMT group compared to controls (P < 0.001). The reduction in CBF was more severe in patients with cGVHD and BO compared with their counterparts (P = 0.048 and P = 0.077, respectively). There was a correlation between CBF with forced expiratory flow rate FEF (P = 0.024) and forced expiratory volume FEV (P = 0.044). We conclude that abnormal ciliary clearance is a common feature after allogeneic BMT, particularly among patients with BO and cGVHD. Further studies are indicated to evaluate this important phenomenon, which could be an important cause of the susceptibility for BMT recipients to respiratory infections.     

DNA synthesis in human blood mononuclear cells correlates with severity of acute graft-versus-host disease

'Spontaneous' blood mononuclear cell DNA synthesis was studied in 83 bone marrow transplantation (BMT) recipients and 58 controls. Prior to BMT, patients with chronic myeloid leukemia had increased DNA synthesis, which decreased dramatically after conditioning and transplantation. After engraftment, patients with syngeneic marrow or allogeneic marrow without graft-versus-host disease (GVHD) had increased DNA synthesis compared to healthy controls. However, patients with acute GVHD (AGVHD) had a significantly increased DNA synthesis compared to patients without GVHD (p less than 0.001). DNA synthesis increased with increasing grade of AGVHD. Among patients with severe AGVHD, recipients of HLA-mismatched marrow had higher lymphocyte DNA synthesis at diagnosis of GVHD and maximum values compared to HLA-matched siblings (p less than 0.05). At diagnosis of GVHD, patients who developed grades II-IV GVHD with progressive disease had higher DNA synthesis, 23.9 +/- 4.0 x 10(3) c.p.m. (mean +/- SE) compared to 11.1 +/- 2.7 x 10(3) c.p.m. in patients in whom GVHD resolved (p less than 0.02). DNA synthesis during GVHD was lower in sheep erythrocyte rosette-forming cells (E-RFC) compared to enriched non-E-RFC. Herpes simplex virus, cytomegalovirus, bacterial septicemia and chronic GVHD had no major effect on lymphocyte DNA synthesis in these patients.     

T lymphocyte repopulation and differentiation after bone marrow transplantation. Early shifts in the ratio between T4+ and T8+ T lymphocytes correlate with the occurrence of acute graft-versus-host disease

Acute graft-versus-host disease (GVHD), a major complication of allogeneic bone marrow transplantation (BMT), is probably mediated by T lymphocytes present in the marrow graft. In this study, the repopulation of the peripheral blood with T4+ and T8+ T cells was investigated during the period preceding the occurrence of acute GVHD. Twenty-four allogeneic and 11 autologous BMT recipients were monitored from day 4 post-BMT onward by the use of monoclonal antibodies, indirect immunofluorescence, and flow cytometry. The recipients of allogeneic transplants received methotrexate as GVHD prophylaxis. Similar recovery patterns for T4+ and T8+ T cells were found following autologous and allogeneic BMT. However, lymphoid repopulation occurred at a clearly faster rate after autologous BMT. T4+ T cells were the first to reappear in the peripheral blood, followed by T8+ T cells 4-7 days later. The T8+ T cell reconstitution occurred at an even faster rate in patients who were to develop grade II-IV GVHD, as compared with those with grade O-I GVHD, thus leading to an earlier decrease in the T4/T8 ratio. Of 10 patients with a T4/T8 ratio less than 2.5 at day 19, 9 developed grade II-IV GVHD and 1 showed no GVHD. Of 14 patients with a ratio greater than 2.5 at that time, only 2 developed grade II-IV and 12 grade O-I GVHD (p less than 0.001). In the 11 patients developing grade II-IV GVHD, the T4/T8 ratio decreased to values less than 2.5 before the first clinical symptoms of GVHD in 9; it coincided in one and occurred later in another patient. Thus, early monitoring of the T4/T8 ratio can distinguish patients at risk of developing grade II-IV GVHD.     

Incidence, risk factors and outcomes of bronchiolitis obliterans after allogeneic stem cell transplantation

Bronchiolitis obliterans (BO) after allogeneic stem cell transplantation (allo-SCT) is a late-onset, life-threatening respiratory complication that significantly reduces a patient's quality of life. We retrospectively analysed the incidence of and risk factors for BO in allo-SCT recipients. In 2087 patients who underwent allo-SCT between January 1994 and June 2005 and survived >90 days after transplantation, 57 patients developed BO with a 5-year cumulative incidence of 2.8%. The median time interval from transplantation to BO diagnosis was 335 days (range 83-907 days). The 5-year cumulative incidence of BO was 1.62% in bone marrow transplantation (BMT) from related donors, 3.83% in peripheral blood stem cell transplantation (PBSCT) from related donors (R-PBSCT), 2.91% in BMT from unrelated donors and 2.65% in unrelated cord blood transplantation. The incidence of BO after R-PBSCT was significantly higher than that after any other type of allo-SCT (p = 0.02). R-PBSCT (p = 0.019) and preceding chronic graft-versus-host disease (GVHD) (p < 0.001) were BO-associated risk factors. Overall 5-year survival of patients with BO from the time of diagnosis was 45.4%, significantly less than those without (77.5% from day 335, p < 0.001). R-PBSCT recipients with existent chronic GVHD have a high risk of developing BO, and need extensive care and repeated pulmonary function tests.     

Allogeneic bone marrow transplantation for leukemia: factors of importance for long-term survival and relapse

From 1977 until June 1987, 139 patients with leukemia underwent allogeneic bone marrow transplantation at Huddinge Hospital. Among recipients of HLA identical bone marrow the survival plateau for 30 patients with acute myeloid leukemia in first remission was 71% from 3 to 7 years. Children (n = 11) had a survival of 100% compared with 52% (n = 19) in adults (p = 0.01). Among patients with acute lymphoblastic leukemia in first remission (n = 15) the actuarial 5-year survival was 73% compared with 31% for those (n = 25) in second to fourth remissions. The probability of relapse in these two groups was 9% and 45% respectively (p less than 0.05). Patients with chronic myeloid leukemia in first chronic phase (n = 27) had a survival plateau from 1 to 6 years of 65%. In Cox's multivariate regression analysis, improved survival was associated with grade 0-I acute graft-versus-host disease (GVHD) (p less than 0.0001), HLA-matched siblings (p less than 0.001), recipient age less than 17 years (p = 0.02), first remission and first chronic phase (p = 0.03), cytomegalovirus (CMV) seronegative recipients (p = 0.04) and absence of symptomatic CMV infection (p = 0.04). A decreased risk of relapse was seen in patients with first remission or first chronic phase (p less than 0.001) and in patients with asymptomatic CMV infection (p = 0.03). In multivariate analysis the p values were 0.002 and 0.09 for these two groups respectively. In these patients acute GVHD was the major obstacle to successful outcome.     

Obstructive lung disease after allogeneic marrow transplantation. Clinical presentation and course

To describe the clinical presentation and progression of obstructive lung disease after marrow transplantation, we examined a sequential sample of 35 patients who had allogeneic marrow transplantation between January 1980 and January 1987, were 16 years or older, had normal pulmonary function tests before transplantation, and developed airflow obstruction defined as FEV1/FVC less than 70% and FEV1 less than 80% predicted 50 days or more after transplantation. Cases were selected from 1029 adult (older than 16 years) patients who underwent allogeneic marrow transplantation during the same period. Patients with airflow obstruction presented with symptoms of cough, dyspnea, or wheezing, or a combination. In 80% the chest radiograph was normal. Airflow obstruction was diagnosed within 1.5 years after transplantation in 33 of 35 patients. Clinical, extensive, chronic graft-versus-host disease was present in 24 patients. Only 4 patients had a complete response to primary therapy of chronic graft-versus-host disease. Serum IgG and IgA levels were decreased in 15 and 25 patients, respectively. The FEV1 declined rapidly (decrease in FEV1 greater than 30% between tests) in 21 patients, but 14 patients with slowly progressive or reversible disease were identified. Mortality was 65% at 3 years after transplant, a significantly higher value (P = 0.016) than the 3-year mortality rate of 44% in a comparison group of 412 concurrent patients with chronic graft-versus-host disease who were 16 years or older, survived more than 80 days after transplantation, and had normal pulmonary function. We concluded that obstructive lung disease after marrow transplantation may be variable with respect to time of onset and rate of progression. Obstructive lung disease was frequently associated with serum immunoglobulin deficiency and clinical, extensive, chronic graft-versus-host disease that was not readily responsive to treatment. Mortality was high but long-term survivors were identified.     

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.