BCR-ABL expression is presumed to effect clonal expansion in chronic myeloid leukemia (CML) by deregulation of cell proliferation. However, most studies have found that relative rates of cell proliferation are not increased in CML. Moreover, we found that CML progenitors display a normal proliferative response to growth factors and do not manifest greater proliferative potential than normal progenitors. Growth of malignancies depends on an imbalance between the rate of cell production and the rate of cell death. We found that BCR-ABL expression inappropriately prolongs the growth factor-independent survival of CML myeloid progenitors and granulocytes by inhibiting apoptosis, a genetically programmed process of active cell death; inhibition of BCR- ABL expression by antisense oligonucleotides reversed the suppression of apoptosis as well as the enhancement of survival. The decreased rate of programmed cell death appears to be the primary mechanism by which BCR-ABL effects expansion of the leukemic clone in CML.

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.

CSA-induced GVHD can be safely augmented by IFN-gamma in women treated with high-dose alkylating agents and autologous bone marrow transplantation. There is little evidence of increased toxicity. Evidence of antitumor efficacy awaits further investigation.

Two hundred eleven patients with advanced breast cancer were randomized to receive either epirubicin (E) 50 mg/m2 and prednisolone (LEP) or E 100 mg/m2 and prednisolone (HEP). The intended treatment consisted of 16 courses of LEP or eight courses of HEP given at 3-weekly intervals. Reasons for stopping treatment early included progressive disease, stable disease without symptomatic improvement, or severe toxicity deemed intolerable by either the patient or physician. Toxicity was recorded at 3-weekly and response at 9-weekly intervals using the World Health Organization (WHO) criteria of response and toxicity. Two hundred nine patients were eligible for analysis, 98% of whom have been followed for more than a year. One hundred four patients received LEP and 105 HEP. Significantly worse myelosuppression, alopecia, nausea and vomiting, and mucositis were seen in the high-dose arm (P less than or equal to .001). More patients in the LEP arm stopped treatment before the fourth course than in the HEP arm, and the commonest reason for stopping was progressive disease. A similar median number of courses was given in each arm. There was a significantly higher response in the HEP arm (HEP - complete response [CR] + partial response [PR] = 41%, LEP - CR + PR = 23%). Despite this, no statistically significant differences was seen in overall survival or progression-free interval. The median survival for HEP and LEP was 44 and 46 weeks, respectively.

Summary:Shwachman-Diamond syndrome is a rare autosomal recessive disorder characterized by exocrine pancreatic dysfunction, metaphyseal dysostosis and bone marrow dysfunction with a predilection towards severe hematologic complications. Allogeneic bone marrow transplantation has been used as a theraputic approach for SDS patients with serious hematologic abnormalities with mixed results. There is some concern that these patients may be more suceptible to early (Ͻ100 days) transplantrelated complications than other transplant groups. We report a patient who received a matched allogeneic transplant without developing serious early transplantrelated complications, but eventually died from relapse of his disease. Although experience is limited, a review of the reported cases suggests patients with SDS may be transplanted without significant short-term morbidity and mortality. Bone Marrow Transplantation (2002) 30, 255-258. doi:10.1038/sj.bmt.1703631 Keywords: Shwachman-Diamond syndrome; allogeneic transplant; aplastic anemia; myelodysplasia; congenital anemia; pancreatic insufficiency Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder first described in 1964. 1 The syndrome is characterized by exocrine pancreatic insufficiency, metaphyseal dysostosis and bone marrow dysfunction. 2 The hematologic abnormalities associated with SDS include varying cytopenias, marrow aplasia and myelodysplasia. About 20% of SDS patients develop aplastic anemia, 3 20-33% develop myelodysplasia 4,5 and 12-25% eventually transform into acute leukemia. [3][4][5][6] Since its initial description, approximately 300 cases have been reported.There is limited information on long-term survival. The projected median survival for all patients is 35 years, with infections and hemorrhage being the major causes of mortality. Predictably, survival is shorter for patients with significant hematologic problems with median survivals of 14 years in patients with aplastic anemia and 9 years in patients with leukemia. 2 Supportive treatment with transfusions, antibiotics and pancreatic enzymes allow for prolonged survival without altering the risk of developing severe hematologic complications. Treatment of myelodysplasia or leukemic transformation with chemotheraputic agents, however, is associated with low response rates and a poor prognosis.Allogeneic bone marrow transplantation is emerging as a valuable therapeutic option, especially when leukemia or marrow aplasia have developed. Because of the rarity of the syndrome, experience is limited and no definitive indications for transplantation have been established. Early attempts were associated with significant toxicity and mortality which were thought to be related to nonspecific organ dysfunction caused by the syndrome. 7 We report a patient with SDS who received an allotransplant without significant 100 day transplant-related toxicity. We also reviewed the outcomes of other patients published in the literature and noticed several trends that may provide some guidance in the timing ...