Combination chemotherapy of adult acute lymphoblastic leukemia with randomized central nervous system prophylaxis

Although major progress has been made in the treatment of childhood leukemia, the optimal chemotherapy of acute lymphoblastic leukemia (ALL) in adults has been unclear. In addition, the value of central nervous system prophylaxis (CNS-P) in adults has been assumed, but not established in a systematic fashion. The Southeastern Cancer Study Group has completed a prospective study in which the use of vincristine plus low-dose methotrexate and high-dose prednisone in adult acute lymphoblastic leukemia has produced an 80% (79/99) complete remission rate in patients age 15 yr and over. Younger patients had a significantly higher remission rate but no increase in remission duration. This induction regimen was associated with minimal toxicity. Random assignment to CNS-P or to no prophylaxis, after a multidrug consolidation regimen, has demonstrated a significant prolongation of CNS relapse-free interval (p=0.008) in favor of CNS-P. CNS-P did not improve hematologic remission duration or survival. All complete remitters were maintained on mercaptopurine, methotrexate, and cyclophosphamide with pulses of prednisone and vincristine; the median time from remission to either hematologic or CNS relapse was 19.3 mo after CNS-P, and survival for these patients was 26.1 mo. We conclude that our current induction regimen is highly effective in adult ALL and that CNS-P prophylaxis is indicated in such patients.     

Alterations of the p53 tumor suppressor gene in diffuse large cell lymphomas with translocations of the c-MYC and BCL-2 proto-oncogenes

Diffuse large cell lymphomas are aggressive tumors of B-cell origin. In some cases they arise from low-grade follicular lymphomas carrying the t(14;18) translocation, an event that leads to the overexpression of the BCL-2 gene product. More frequently, however, they lack the t(14;18) translocation. Rearrangements of the c-MYC proto-oncogene and mutations of the p53 tumor suppressor gene have also been documented in these lymphomas. This study examines the extent to which alterations in the BCL-2, c-MYC, and p53 genes co-exist within individual lymphomas. Eight diffuse large cell lymphoma cell lines and 11 diffuse large cell lymphoma tumors were assessed for genetic alterations in these three genes. Our results indicate that there is a heterogeneity in the oncogene/suppressor gene profile among diffuse large cell lymphomas. Two cell lines and one tumor carried alterations in all three genes, one cell line carried alterations of c-MYC and p53, and one primary tumor and one cell line carried p53 mutations and the t(14;18). Single alterations of BCL-2 and p53 were also observed. Another cell line had no alterations in any of these genes. The heterogeneity indicates that varied mechanisms may be involved in the generation of diffuse large cell lymphomas.     

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.     

Graft failure following bone marrow transplantation for severe aplastic anemia: risk factors and treatment results

Graft failure was analyzed in 625 patients receiving allogeneic bone marrow transplants from HLA-identical sibling donors as treatment for severe aplastic anemia. Sixty-eight (11%) had no or only transient engraftment. Second bone marrow transplants were successful in achieving extended survival in 16 of 27 patients with transient initial engraftment but in none of ten patients with no sign of engraftment after the first transplant. The major factors associated with a reduced risk of graft failure were use of radiation for pretransplant immunosuppression and use of cyclosporine rather than methotrexate or T- cell depletion of the donor bone marrow for prophylaxis against graft-v- host disease (GVHD). Among 266 patients prepared for transplantation with cyclophosphamide alone, the risk of graft failure was increased in patients who received previous transfusions and reduced in those who received corticosteroids for previous therapy. Neither cell dose nor administration of donor buffy coat cells affected the probability of engraftment. Although use of radiation in conditioning reduced graft failure, survival was not improved. Posttransplant treatment with cyclosporine and avoidance of pretransplant blood transfusions were associated with improved survival.     

Clinical factors influencing the efficacy of pooled platelet transfusions

To determine the relative importance of clinical factors on the efficacy of platelet transfusions, 941 pooled platelet transfusions from HLA-unmatched donors were studied prospectively in 133 patients with bone marrow failure. Multiple linear regression analyses identified the major factors influencing one-hour-corrected increments (CI) as prior splenectomy, bone marrow transplantation, disseminated intravascular coagulation, concurrent intravenous amphotericin B, splenomegaly, and HLA antibody grade. The relative impact of these factors on CI has been quantitated by using a formula developed from these data. A linear relationship was demonstrated between increasing percentage of HLA antibody grade and decreasing CI. A number of other factors were less important in the linear regression model than the aforementioned major factors. These included platelet-specific antibodies, concurrent antibacterial antibiotics, clinical bleeding grade, and temperature. Factors that did not influence CI included the number of prior platelet transfusions, prior granulocyte transfusions, prior red cell transfusions, infection, age, blood group, diagnosis, sex, pretransfusion platelet count, prior pregnancies, and concurrent antineoplastic drugs. This study identified major clinical factors that significantly influenced CI and were major causes of refractoriness to pooled platelet transfusions.     

HLA associations with leukemia

Frequencies of 35 HLA A, B, C, and DR antigens were determined in 1,834 leukemic Caucasoids to evaluate possible associations between HLA and leukemia. In comparison with the frequencies of HLA antigens in published controls, the frequency of Cw3 was significantly higher in patients with acute lymphoblastic leukemia (relative risk = 2.64, P less than 0.0002), acute myelogenous leukemia (relative risk = 1.92, P less than 0.0007), and chronic myelogenous leukemia (relative risk = 2.07, P less than 0.002; P values adjusted for multiple comparisons). The frequency of Cw4 was elevated in patients with acute lymphoblastic leukemia (relative risk = 2.01, P less than 0.0003), acute myelogenous leukemia (relative risk = 2.06, P less than 0.0002), and chronic myelogenous leukemia (relative risk = 2.14, P less than 0.0008). The frequency of Aw19 was significantly decreased in patients with acute myelogenous leukemia (relative risk = 0.68, P less than 0.01) and chronic myelogenous leukemia (relative risk = 0.59, P less than 0.005). None of the other 32 HLA antigens investigated had a statistically significant association with leukemia. The data suggest that Cw3 and Cw4 may be markers for leukemia susceptibility genes, while Aw19 may be a marker for decreased susceptibility to leukemia.     

Acute nonlymphocytic leukemia following etoposide and cisplatin combination chemotherapy for advanced non-small-cell carcinoma of the lung

Combination chemotherapy is frequently used in the therapy of advanced non-small-cell lung cancer (NSCLC), but late complications are rarely recognized because of the short survival of most patients. Of 119 patients with advanced NSCLC treated with cisplatin and other drugs, four patients developed acute nonlymphocytic leukemia (ANLL). All four patients received etoposide and cisplatin with or without vindesine. Leukemia was diagnosed at 13, 19, 28, and 35 months after start of treatment. Three patients had morphologic and/or cytogenetic features of acute leukemia with significant monoblastic involvement; the fourth patient had trilineage dysplasia and cytogenetic abnormalities more commonly associated with therapy-related leukemia. Detailed analysis of the subgroup who survived longer than 1 year (24 patients) suggests that high cumulative doses of etoposide are leukemogenic; the median etoposide dose was 6,795 mg/m2 (first year only) in the four leukemic patients compared with 3,025 mg/m2 in the 20 nonleukemic patients (P less than .01). The rate of ANLL was 0.30 per person-year after the first year (95% confidence limits 0.11 to 0.90), with a cumulative risk of 15% +/- 11% at 2 years, and 44% +/- 24% at 2.5 years. We conclude that high doses of etoposide are potentially leukemogenic, and can induce a syndrome with features of acute monoblastic leukemia de novo that is distinct from other secondary leukemias.