A closer look at specific therapeutic strategies in leukemia.

Leukemia-associated fusion genes are detected in a significant proportion of newly diagnosed cases, where genes encoding transcription factors are usually found at one of the breakpoints. Activated fusion proteins, such as PML-RARalpha and AML1-ETO, have been shown to inhibit cellular differentiation by recruitment of nuclear corepressor complexes, which maintain local histone deacetylase (HDAC) in a variety of hematologic lineage-specific gene promoters. This HDAC-dependent transcriptional repression appears as a common pathway in the development of leukemia and could represent an important target for new therapeutic agents. On the other hand, the Bcr-Abl oncoprotein shows high tyrosine kinase activity and deregulates signal transduction pathways involved normally in both apoptosis and proliferation. This aberrant activity is affected by signal transduction inhibitors (STIs), which block or prevent the oncogenic pathway. In this review, we present a closer look at our understanding of both the reversible transcriptional repression controlled by HDAC and the deregulated Bcr-Abl signal transduction. In addition, the application of low molecular weight drugs for human leukemia treatment based in this knowledge results in durable clinical remission and acceptable risk of toxic effects that should increase the cure rate. We hope that this review will provide timely information to the readers.

[Experience with 22 bone marrow donors]. / Experiencia con 22 donadores de médula ósea.

We describe our experience of the Instituto Nacional de Cancerología in Mexico City in the management of 22 healthy donors of the allogeneic bone marrow transplantation program. Twenty three bone marrow products were harvested from the 22 healthy donors (7 male, 15 female) with a median age of 26 (range 16 to 47). All were seronegative for HIV, HBV and HCV. The volume harvested ranged from 750 to 1500 mL. The postoperative hemoglobin dropped more than 3 g/dL in 14 donors but only seven required the transfusion of autologous blood collected before the procedure. All donors received a standard analgesic regimen with meperidene, dextropropoxiphene and ketoprofen for 24 hours after the harvest. Only two instances of procedure complications were recorded (9%) and were successfully resolved. Currently all donors are alive and in good health with a median follow up of two years. We conclude that bone marrow donation is a safe procedure with some predictable complications, the most common, anemia, easily corrected with autologous blood transfusion.

Chemotherapy-associated oral mucosal lesions in patients with leukaemia or lymphoma.

In order to determine the incidence rate of oral lesions associated with chemotherapy, as well as well as its association with clinical and laboratory parameters and potential risk factors, 50 in-patients with non-Hodgkin's lymphoma or leukaemia under chemotherapy were followed from January 1993 to May 1994. Basal and weekly oral examinations were performed. Clinical and laboratory data were registered. Wilcoxon's rank sum test, chi square test, univariate and multivariate logistic regression analyses were used, 36 individuals with leukaemia and 14 with non-Hodgkin's lymphoma were followed for 158 weeks; mean age was 33 years (range 15-85). Oral lesion incidence rate was 45/100 patients-week. Exfoliative cheilitis and infections (herpes and candidosis) were the most common oral complications, followed by haemorrhagic lesions and mucositis. Haemorrhagic lesions correlated with thrombocytopenia (RR = 30.5). Etoposide administration (RR = 8.6), alkylating agents (RR = 15.6), a prior course of chemotherapy (RR = 23.2) and neutropenia (RR = 4.16) were predictors of mucositis. Oral lesions were a common complication in this study, and a possible association of mucositis with several factors is suggested.

Misoprostol prophylaxis for high-dose chemotherapy-induced mucositis: a randomized double-blind study.

From April 1993 to September 1993, 15 patients with lymphoid or solid neoplasms underwent 16 non-cryopreserved peripheral stem cell transplantation courses using the ICE (ifosfamide, carboplatin, etoposide) program. They were randomized in a double-blind clinical trial to received oral misoprostol or placebo for mucositis prophylaxis. The active drug or placebo administration began jointly with chemotherapy at day -4 and was continued until day 16. The mucositis incidence and severity was significantly higher in patients who received misoprostol. We found no differences regarding myelosuppression, infections or other chemotherapy complications. Our results do not support the use of oral misoprostol as administered in this study, for high-dose chemotherapy-induced mucositis prophylaxis.

[Prevention of myelotoxicity in a case of bone marrow transplantation using granulocyte-macrophage colony-stimulating factor along with ganciclovir]. / Prevención de mielotoxicidad en un caso de trasplante medular con factor estimulante de colonias granulocito-macrófago asociado a ganciclovir.

We report the first experience of the use of GM-CSF as prophylaxis of ganciclovir induced severe bone marrow suppression in a CMV seropositive patient with acute myeloid leukemia who underwent a complete remission after an allogeneic bone marrow transplantation from an identical HLA sibling who also was CMV seropositive. A successful bone marrow engraftment was documented by day 14. Once peripheral blood counts stabilized, the patient received ganciclovir 5 mg/kg TIW. By day 73 severe neutropenia was documented but a spontaneous improvement occurred with discontinuation of ganciclovir. From day 100 to day. 110 he received daily ganciclovir at a dose of 5 mg/kg and the same dose of GM-CSF without signs of toxicity. There was no evidence of either acute graft versus host disease or of CMV infection. One year after transplantation he relapsed and died of complications of acute leukemia.

Peripheral neuroectodermal tumor of the chest wall in a patient treated for Hodgkin's disease.

The occurrence of second malignancies after treatment for Hodgkin's disease is a well recognized phenomenon. In this report we describe a case of a 22-year-old male who developed a peripheral neuroectodermal tumor of the chest wall four years after completing successful treatment with combined chemotherapy and radiotherapy for Hodgkin's disease.

[Response to treatment and survival of adults with acute leukemia classified with immunophenotyping and cytochemistry]. / Respuesta al tratamiento y supervivencia de adultos con leucemia aguda clasificados mediante inmunofenotipo y citoquímica.

We studied the response to treatment and survival of 30 adults with acute lymphocytic leukemia (ALL) and 19 with acute non lymphoid leukemia (ANLL) classified on basis of immunophenotype (monoclonal antibodies) and cytochemistry. For the ALL cases 70% corresponded to common ALL (CALLA positive), 23% to B lymphocytes and 7% to T cells. We had 68% of the ANLL patients classified as myeloid, 21% as hybrid (positive both myeloid and lymphoid markers) and 11% as undifferentiated. We analyzed demographic data (gender and age), basic laboratory values (hemoglobin, leucocytes, platelets and cytomorphology in peripheral blood and bone marrow) using the French-American-British classification, and found no statistically significant differences between ALL and ANLL. Three of four patients (75%) with hybrid ANLL achieved complete remission (CR), while 46% of cases with myeloid ANLL and none of the subjects with undifferentiated ANLL reached CR; these differences were not statistically significant. Patients with common ALL had a median survival (SV) of 499 days, for B cell ALL it was of 212 days, and for T cell ALL of 285 days. Our data suggest that: a) expression of lymphoid markers in patients with ANLL is probably associated with a higher CR ratio, and b) SV in adults with common ALL seems to be longer than in those with B and T cell ALL.