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.

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Summary:the diagnosis of MDS may improve prognosis due to a lower treatment-related mortality and a lower relapse risk. Allogeneic bone marrow transplantation (BMT) offers a potential cure for younger patients with myelodysplasticKeywords: allogeneic bone marrow transplantation; HLA-identical sibling; first-line treatment; myelodysplastic syndromes (MDS) or secondary acute myeloid leukemia (sAML). More than 600 patients from 50 European censyndrome; secondary acute myelogenous leukemia ters have now been reported to the European Group for Blood and Marrow Transplantation (EBMT). We retrospectively analyzed 131 patients reported to the Myelodysplastic syndromes (MDS) comprise a heteroChronic Leukemia Working Party of the EBMT who geneous group of hematopoietic stem cell disorders with underwent BMT from HLA-identical siblings without varying clinical, laboratory and morphological features. prior remission induction chemotherapy. At the time ofAccording to the proposals of the French-American-British BMT 46 patients had refractory anemia (RA) or RA Cooperative Group (FAB) five morphological entities can with ringed sideroblasts, 67 patients had more advanced be distinguished, including refractory anaemia (RA), refrac-MDS subtypes and 18 patients had progressed to sAML.tory anaemia with ring sideroblasts (RARS), refractory aneThe 5-year disease-free (DFS) and overall survival (OS) mia with excess of blasts (RAEB), refractory anemia with for the entire group of patients was 34 and 41%, excess of blasts in transformation (RAEB/T), and chronic respectively. Fifty patients died from transplant-related myelomonocytic leukemia (CMML). 1 Treatment of MDS complications, most commonly graft-versus-host disease and secondary acute myelogenous leukemia (sAML) has and/or infections. Relapse occurred in 28 patients generally been unsatisfactory. Because of their advanced between 1 and 33 months after BMT, resulting in an age most patients have been treated solely with supportive actuarial probability of relapse of 39% at 5 years. DFS measures. Limited success has been reported with low-dose and OS were dependent on pretransplant bone marrow cytosine arabinoside, 2 retinoic acid, 3 corticosteroids, 4 and blast counts. Patients with RA/RARS, RAEB, RAEB/T hematopoietic growth factors. 5 Young patients with and sAML had a 5-year DFS of 52, 34, 19 and 26%, advanced MDS may achieve prolonged, disease-free surrespectively. The 5-year OS for the respective patient vival when treated with intensive antileukemic chemogroups was 57, 42, 24 and 28%. In a multivariate analytherapy. 6 However, remission duration has generally been sis, younger age, shorter disease duration, and absence short. 7 Nowadays, allogeneic BMT is considered the treatof excess of blasts were associated with improved outment of choice for younger patients with histocompatible come. From these data we conclude that patients with siblings. The timing of transplant in the management of myelodysplasia who have appropriate marrow donors, the disease remains controversial....

Acute graft-versus-host disease, interstitial pneumonitis, endothelial leakage syndrome, and veno-occlusive disease are major complications of bone marrow transplantation. Though several new regimens for prophylaxis and treatment of these syndromes have been introduced, the overall incidence has been only slightly reduced over the last few years. We retrospectively analyzed tumor necrosis factor alpha (TNF alpha) serum levels between day -8 and day 100 after bone marrow transplantation in 56 patients transplanted in our unit for a variety of hematological diseases. In 34 patients with uneventful courses, mean TNF alpha levels rose to a maximum of 76 +/- 29 pg/mL. In contrast, 22 patients with major transplant related complications showed mean increases of TNF alpha of 492 +/- 235 pg/mL (P less than .0001). Increases of TNF alpha occurred before interstitial pneumonitis and severe acute graft-versus-host disease with a latency of 25 to 54 days. Early complications such as endothelial leakage syndrome and veno- occlusive disease were closely associated with increases of TNF alpha serum levels. Our study suggests two pathways of TNF alpha release: activation of host macrophages and stimulation of donor cells in the course of acute graft-versus-host disease. Cytokine monitoring should be helpful for prediction and earlier treatment of major transplant related complications.

As curative bone marrow transplantation is available only to a minority of patients with chronic myelogenous leukemia (CML), drug therapy remains of central interest. Several nonrandomized studies have suggested that interferon-alpha (IFN) may prolong survival in CML. In a randomized multicenter study the influence of IFN versus busulfan or hydroxyurea (HU) on survival of Philadelphia-positive (Ph+) CML was examined. A total of 513 Ph+ patients were randomized for treatment as follows: 133 for IFN, 186 for busulfan, and 194 for HU. IFN-treated CML patients have a significant survival advantage over busulfan-treated (P = .008), but not over HU-treated patients (P = .44). The longer survival is due to slower progression to blast crisis. Median survival of IFN-treated patients is 5.5 years [5-year survival, 59%; 95% confidence interval (CI), 48%-70%], of busulfan-treated patients, 3.8 years (5-year survival, 32%; CI, 24%-40%), and of HU-treated patients, 4.7 years (5-year survival, 44%; CI, 36%-53%). Patients who continue on IFN survive longer than those in whom IFN is discontinued before blast crisis (P = .007). Complete hematologic IFN-responders have a survival advantage over partial responders or nonresponders (P = .02). Cytogenetic IFN-responders have no significant survival advantage over nonresponders (P = .2). Patients who attain white blood cell (WBC) counts of 10 x 10(9)/L or less have a survival advantage in the IFN (P = .007) and HU (P = .05) groups. Whereas toxicity in the IFN group was considerably higher than in the busulfan or HU groups, long-lasting cytopenias necessitating discontinuation of therapy as observed with busulfan have not been seen with IFN or HU. The problems of conventional prognostic scores (Sokal's score, Score 1) that we observed in IFN-treated patients support the idea that IFN changes the natural course of CML. We conclude that, with regard to survival of CML in the chronic phase, IFN is superior to busulfan and as effective as HU. Whether and to what extent IFN is superior to HU appears to depend, at least in part, on the degree of WBC suppression by HU-therapy and on the risk profile of the patients.