Significance of one human leukocyte antigen mismatch on outcome of nonmyeloablative allogeneic stem cell transplantation from related donors using the Mexican schedule.

Using the Mexican approach to conduct nonablative stem cell transplantation (NST), we have prospectively performed 58 allografts in individuals with various malignant and nonmalignant hematological diseases using sibling donors, either HLA identical (6/6) or compatible, with one mismatch (5/6). When comparing allografts obtained from HLA identical (n=40) or compatible (n=18) siblings, respectively, the overall median survival was found to be 33 vs 8 months (P<0.01), the 52-month survival was 47 vs 38% (P>0.2), the prevalence of acute graft-versus-host disease (GVHD) 57 vs 38%, that of chronic GVHD 25 vs 11% and the relapse rate 45 vs 55%. The two patients who failed to engraft were both 5/6 matches. Probably stemming from the low number of patients, and despite a trend toward worse results in patients allografted from HLA compatible (5/6) siblings, most differences in outcome were not significant. It seems that NST can be offered to individuals with either an HLA identical or a compatible sibling donor.

Leukaemia and nutrition. I: Malnutrition is an adverse prognostic factor in the outcome of treatment of patients with standard-risk acute lymphoblastic leukaemia.

A group of 43 pediatric patients with standard-risk ALL were studied. Thirty-seven per cent of them presented with malnutrition at diagnosis. Malnourished children had a significantly worse outcome than well-nourished children. Five-year DFS was 83% for well-nourished children (WNC) and 26% for under-nourished children (UNC) (p less than 0.001). Relapses presented more frequently in the bone marrow in UNC than in WNC (56% vs 7%, p less than 0.0001). The doses of maintenance chemotherapy had to be reduced in 68% of UNC and 11% of WNC (p less than 0.005); the doses of maintenance myelosuppressive chemotherapy (6-MP, oral MTX and hydroxyldaunorubicin) received by UNC were approximately 50% of those received by WNC (p less than 0.01). The correlation between malnutrition and compromised treatment was 0.92. Malnutrition might be included as an adverse prognostic factor in acute lymphoblastic leukaemia (ALL).

The incidence of hybrid acute leukaemias.

During a 4-yr period, 292 patients with acute leukaemia were studied using morphology, cytochemistry and immunologic reagents to determine the cell lineage of the leukaemia. One hundred and sixty-three cases were shown to be acute lymphoblastic leukaemia (ALL), 127 acute myeloblastic leukaemia (AML) and two cases (0.6%) were classified as hybrid acute leukaemias. One was biphenotypic in which the blast cells displayed both T-lymphoid (60% E-rosettes) and megakaryocytic markers (47% CDw41/glycoprotein IIb/IIIa antigen, 50% myeloperoxidase). The second was a bilineal acute leukaemia in which some blast cells displayed B-lymphoid (47% CD10/CALLA, 40% acid phosphatase) features and other megakaryocytic (33% coagulation factor VIII:WVf antigen)/myeloid (30% Sudan Black) features. This study suggests that hybrid acute leukaemia are rare.

Granulomonopoiesis and production of granulomonopoietic regulating factors in Hodgkin's disease and non-Hodgkin's lymphomas.

Quantitative and functional abnormalities of T and B lymphocytes and monocytes have been described in Hodgkin's disease (HD) and non-Hodgkin's lymphomas (NHL), thus making both diseases suitable models to study the interactions between lymphoid and myeloid systems. We evaluated the growth of colony-forming units of granulocytes and monocytes/macrophages (CFU-GM), as well as the colony-stimulating activity (GM-CSA) produced by monocytes and the colony-inhibiting activity (GM-CIA) released by autologous rosette-forming T-cells (Tar cells), a postthymic precursor subpopulation, in peripheral blood samples from 7 patients with HD and 5 with NHL. CFU-GM growth in HD and NHL patients was similar to that observed in controls. However, GM-CSA and GM-CIA were significantly decreased in both HD (p = 0.002 and p = 0.012, respectively) and NHL (p = 0.003 and p = 0.017, respectively) patients as compared to controls. These data suggest that cytokine-dependent mechanisms regulating normal CFU-GM proliferation are impaired in HD and NHL.

Congenital Acute Megakaryoblastic Leukaemia in Down's Syndrome.

The case of a newborn with Down's syndrome and congenital leukaemia is reported. The malignant white blood cells displayed the CD41 antigen (glycoprotein Ilb/IIIa) identified by monoclonal antibodies HP1-ld and FMC24 and the CD9/p24 antigen identified by monoclonal antibody FMC27. The number of cells in S-phase was 14%, as assessed by the incorporation of 5-bromo 2-deoxyuridine. No other chromosomal abnormalities were identified in addition to 47 XY + 21. The patient died 15 days after the diagnosis, due to Pneumocystis Carinii pneumonia. Post-mortem examination showed heavy leukaemic infiltration and cardiac abnormalities including inter-atrial septal defect and a patent Ductus arteriosus. This patient appears to be the first identified case of congenital leukaemia with megakaryocytic differentiation, although previous instances of transient abnormal myelopoiesis with megakaryocytic differentiation have been recorded in Down's syndrome.

Non-cryopreserved unmanipulated hematopoietic peripheral blood stem cell autotransplant program: long-term results.

BACKGROUND: Methods to simplify bone marrow transplantation procedures are needed mainly in developing countries. METHODS: Between May 1993 and February 1999 in a private-practice setting, we performed 29 autotransplants in 28 patients using non-cryopreserved and unmanipulated peripheral blood stem cells mobilized from the bone marrow to the peripheral blood by means of hematopoietic growth factors. The autografting procedure was performed entirely on an outpatient basis in 19 cases (65%). The median age of the patients was 30 years, with a range of 9-67. There were 15 patients with acute leukemia (9 with acute myelogenous leukemia), 3 with chronic myelogenous leukemia, 2 with multiple myeloma, 3 with Hodgkin's disease, 2 with non-Hodgkin's lymphoma, and 4 with metastatic breast carcinoma. RESULTS: The median time to achieve > 0.5 x 10(9)/L granulocytes was 14 days (range 7-42), whereas the median time to achieve > 20 x 10(9)/L platelets was 20 days (range 5-49). The 64-month post-transplant survival was 38%, whereas the median post-transplant survival was 18 months. The transplant-related mortality was 3.4%. The approximate cost of this simplified procedure was 10.8% for in-hospital procedures and for outpatient autografts, substantially lower than figures reported from the U.S. for autotransplants. CONCLUSIONS: This simplified method for autografting patients, avoiding in-hospital stays, purging procedures and cryopreservation of the cells is feasible and results in a substantial decrease of the cost of autologous hematopoietic stem cell transplantation methods.

[Thrombophilia, thromboembolism and the use of the unfractionated and low-molecular-weight heparins]. / Trombofilia, tromboembolia y el uso de las heparinas no fraccionadas y de bajo peso molecular.

An overview of the key concepts about detection of thrombophilic states, establishment of risk factors for thrombosis, the current strategies on diagnosis of thrombophilia, as well as an analysis of the current experience with the use of fractionated and unfractionated heparins, is presented. It is well known that thrombotic disease is multifactorial and that its treatment must be interdisciplinary and multidisciplinary in order to perform an opportune diagnosis and to establish an adequate prophylaxis and anti-thrombotic therapy. Even though several advantages are observed when low molecular weight heparins are used, unfractionated heparins still have some specific indications. Furthermore, under specific conditions, they can work synergistically to achieve a maximal effect on the thromboembolic states. We propose that every medical unit should establish its own criteria and diagnostic and therapeutic algorithms that allow to detect, to diagnose, and to treat the thrombotic events in the best way thus diminishing the morbidity and mortality associated with these thrombotic events.

[Low doses of azidothymidine in the treatment of HIV-1 virus infection]. / Dosis bajas de azidotimidina en el tratamiento de la infección por virus VIH-1.

A group of 26 patients (18 males and 8 females) infected with HIV (42% through sexual route and 58% through blood/blood products transfusion) was prospectively studied to assess the efficacy of low doses (300 mg/day) of AZT combined (n = 15) or not (n = 11) with ACV (600 mg/day). According to CDC stages, 12% were in stage II, 73% in stage III and 15% in stage IV. Patients were followed for a maximum of 156 weeks. An objective response was observed in all patients who improved significantly in: performance status (Karnofsky 74.5 versus 97.6%, p less than 0.01), weight 58.9 versus 68.6 kg, p less than 0.01), and absolute CD4 T cell count (329/microL versus 480/microL, p less than 0.01). The levels of hemoglobin dropped after treatment (12.8 versus 11.5, p less than 0.01). Median survival was 114 weeks for all the group. With the exception of granulocytopenia in 42% of patients treated with AZT + ACV versus only in 22% of those treated solely with AZT (p = 0.02), similar effects were recorded in both treatments: 114-week survival was 60% for those treated solely with AZT, whereas 156-week survival was 93% for those treated with AZT + ACV (p NS), but the response was better for the combination of antivirals in the group of patients with more than 200 CD4 cells/microL at diagnosis as compared with those with less than 200 cells (110-week survival of 100% versus 50% respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

[Protein C, protein S and thrombomodulin: one of the natural antithrombotic mechanisms]. / Proteína C, proteína S y trombomodulina: uno de los mecanismos antitrombóticos naturales.

In this review paper, the salient features of the anticoagulant/fibrinolytic mechanism depending on coagulation protein C, protein S and thrombomodulin are reviewed. Coagulation protein C, activated at the endothelial cell surface in the presence of the complex thrombin/thrombomodulin exerts two anti-thrombotic effects: one anticoagulant dependent on the free protein S and the other pro-fibrinolytic, independent of protein S. Both inherited and acquired deficiencies of protein C and/or protein S lead to a thrombosis-prone state that has to be identified promptly to avoid vaso-occlusive episodes. The experience in Mexico with both the identification and treatment of these deficiencies is reviewed; it is interesting that we have found that patients with autoimmune disorders, mainly systemic lupus erythematosus and primary anti-phospholipid syndrome, have acquired deficiencies of this anticoagulant mechanism that may be related to the thrombogenesis observed in these patients.

[Leukemia and malnutrition. II. The magnitude of maintenance chemotherapy as a prognostic factor in the survival of patients with standard-risk acute lymphoblastic leukemia]. / Leucemia y desnutrición. II. La magnitud de la quimioterapia de mantenimiento como factor pronóstico de la supervivencia de pacientes con leucemia aguda linfoblástica de riesgo habitual.

In previous papers we have shown that malnutrition is an adverse prognostic factor in the outcome of treatment in patients with standard-risk acute lymphoblastic leukemia. The reason why undernourished children do poorly as compared with well nourished children is that malnourishment leads to a diminished bone marrow reserve thus making necessary to delivery of suboptimal doses of maintenance chemotherapy (less than that calculated according to body surface). Undernourished children receive less 6-MP and MTX and relapse more frequently in the bone marrow, finally reflecting a 5 yr disease-free survival of 26% as compared with 83% in well-nourished children (p less than 0.001). In this paper we have analyzed the impact of the variable delivery of sub-optimal doses of maintenance chemotherapy in a group of 43 pediatric patient with standard-risk acute lymphoblastic leukemia. The 5 year disease free survival of children receiving suboptimal maintenance chemotherapy was 7% as compared with 65% for those receiving full doses of both 6-MP and MTX (p less than 0.001), and more frequent relapse involving the bone marrow in children receiving low doses (71% versus 3%, p = 0.000005). The impact of the variable suboptimal doses of chemotherapy was present in children with both normal and deficient nourishment status. It is concluded that the delivery of suboptimal doses of maintenance chemotherapy, due to bone marrow toxicity related to an abnormal myelopoietic reserve, is an adverse prognostic factor in the outcome to treatment of patients with lymphoblastic leukemia.

[Dyshemopoietic anemias (AD) (myelodysplastic syndromes). Retrospective analysis of 40 cases from the Instituto Nacional de la Nutrición Salvador Zubirán (INNSZ)]. / Anemias dishemopoyéticas (AD) (síndromes mielodisplásicos). Análisis retrospectivo de 40 casos del Instituto Nacional de la Nutrición "Salvador Zubirán" (INNSZ).

40 patients with DMPS were studied and diagnosed at the INNSZ during 1980-1985. Eighteen were males and twenty two females; age average of 55.7 years (17-82), with 72.5% over 50 years old. Their distribution according to the FAB classification was: 55% type I, 10% type II, 27.5% type III, 2.5% type IV and 5% type V. All of them had an anemic syndrome and 47.5% had bled, 52.5% had pancytopenia; there was anemia and thrombocytopenia in 32.5%, anemia and leukopenia in 7.5%, and anemia only in 7.5%. The bone marrow was normocellular in 42.5%, hypercellular in 40% and hypocellular in 17.5%, 45% of the patients survived; 22% achieved a complete remission (CR) and 9 patients (22.5%) died of causes related to DMPS. The rest was lost to follow up.

["Occupational" infection caused by the human immunodeficiency virus in 6 members of a single family]. / Infección "ocupacional" por el virus de inmunodeficiencia humana en seis miembros de una misma familia.

The risk groups for AIDS have been defined and include homosexuals, bisexuals, polytransfused patients, drug addicts, sexual partners of any of the above groups and sons of infected fathers. We have previously proposed that paid donors should be considered also as high risk individuals. We report here a family in which six of its eight members had HIV infection without other risk factor than being paid blood donors.

[High doses of cytosine arabinoside in the treatment of patients with acute relapsing or refractory leukemia]. / Dosis altas de arabinósido de citosina en el tratamiento de pacientes con leucemia aguda refractaria o en recaída.

Ten patients either in relapse (n = 7) or refractory (n = 3) acute leukemia were treated with high-dose Ara-C (3000 mg/m2) every 12 hours to a total of eight 2 doses (24,000 mg/m2). Myeloblastic (n = 5), lymphoblastic (n = 4) and hybrid (n = 1) acute leukemias were included. In the total group, complete remission was achieved in 6 of 10 cases (60%); the remission rate was higher in the relapsed than in the refractory acute leukemia group (71 versus 33%;) the duration of the complete remission ranged between 1 and 13 months, with a median of 2 months; the remission duration was also higher in the relapsed than in the refractory acute leukemia group (4 versus 1 month). Refractoriness to the high-doses of Ara-C was observed in two cases, and fatal iatrogenic myelosuppression was produced in two patients. The rate of complete remission was 80% in myelogenous leukemia and 50% in lymphoblastic leukemia. It is concluded that high-dose Ara-C is another therapeutic choice in the treatment of relapsed and perhaps refractory acute leukemia.

Infusion of anti-CD10 monoclonal antibody (J5) following ablative chemotherapy in a patient with refractory pre-B acute lymphoblastic leukemia.

The case of a 9-year old girl with end-stage refractory pre-B CD10/CALLA positive acute lymphoblastic leukaemia is described. The patient was treated with high doses of cytarabine followed by intravenous anti-CD10 monoclonal antibody (J5) in an effort to prevent the recovery of the leukemic CD10 positive clone following the bone marrow hypoplasia resulting from the chemotherapy. The number of CD10 positive cells dissapeared both in the peripheral blood as well as in the bone marrow, but when granulocytic recovery ensued, the patient died from respiratory infection. No evidence of antigenic modulation of the CD10 antigen was observed in the blast cells.

[High prevalence of acquired immunodeficiency syndrome (AIDS) associated with transfusion in Puebla, Mexico]. / Prevalencia alta de síndrome de inmunodeficiencia adquirida (SIDA) asociado a transfusion en Puebla, México.

The salient clinical and epidemiological features of the first cases of AIDS diagnosed in the city of Puebla, Mexico, are reviewed. Puebla has 2 million inhabitants and 37 cases of AIDS have been diagnosed since 1984. Thirty-two percent of patients acquired AIDS by blood transfusion, 20% were paid blood donors and 48% acquired the HIV infection by the sexual route, thus making a 52% prevalence of transfusion-related HIV infection. These data are substantially different from those reported in other countries and in other cities within Mexico, where the prevalence of transfusion-associated HIV infection is about 11.5%. The high prevalence of transfusion-related AIDS seems to be due to existence of "blood centers" where paid donors are bled using non-disposable material, and they are poorly selected. HIV infection is thus transmitted to paid-blood donors which in turn become transmitters of the disease. The new regulations on blood donation adopted in Mexico abolish paid blood-donation and the selection of blood donors is more stringent. This should result in reducing the serious problem of transfusion-associated HIV infection in the city of Puebla, Mexico.

[Preliminary report on the effect of low doses of azidothymidine (AZT) in the treatment of patients with stage III infection by human immunodeficiency virus (HIV)]. / Informe preliminar del efecto de las dosis bajas de azidotimidina (AZT) en el tratamiento de pacientes con estadio III de infección por el virus de la inmunodeficiencia humana (VIH).

Ten patients with CDC stage III of infection by HIV were treated with AZT at doses of 300 mg/day (100 mg tid). There were 5 males and 5 females, the median age being 40.5 yr' (range 26-46). Seventy percent of them had transfusion-associated HIV infection and the rest had been infected by the sexual route. A positive clinical response was observed in 100% of the group after 16-24 weeks of treatment: the Karnofsky performance status increased from 64% to 94% (p less than 0.01), the white blood cell count raised from 3.7 to 6.0 K/microL (p less than 0.01), the number of helper lymphocytes (CD4+) also raised significantly from 248.2 to 470.7/uL (p less than .01). Only two patients required red blood cells transfusions. The life expectancy at 82 weeks was 90%. Toxicity was both moderate and transitory. It is concluded that low doses of AZT (300 mg/day) produce similar clinical results as doses of 1200-1500 mg/day. A larger study is needed to support our preliminary findings.

[Hypercalcemia and osteolytic lesions associated with pre-B-cell primary lymphoma of the bone marrow. A case report]. / Hipercalcemia y lesiones osteolíticas asociadas a linfoma primario de médula ósea de células pre-B. Informe de un caso.

Primary bone marrow lymphomata are infrequent; most of them are of B-cell origin, and those of a T-cell lineage produce mainly both hypercalcemia and osteolytic lesions apparently due to abnormal production of osteoclast-activating factor. We report a 15-year old patient with a primary bone marrow lymphoma: 85% of his infiltrating malignant lymphocytes displayed cytoplasmic mu-chains compatible with a pre-B phenotype. The cells failed to display the CALLA/CD 10 antigen. Serum calcium was 7.5 mEq/L (range 4-5 mEq/L); the bone biopsy of an osteolytic lesion disclosed a large-cell, diffuse non-Hodgkin's lymphoma. No malignant cells were found in the peripheral blood and there were no enlarged lymph nodes. The patient was treated with 6 courses of chemotherapy: hydroxyldaunorubicin, vincristine and prednisone (HOP). Complete remission was achieved and the patient was placed on continuation chemotherapy with daily six-mercaptopurine and weekly methotrexate, together with HOP pulses every three months. The hypercalcemia disappeared together with the fever and the bone pain: the patient has been followed 6 months. Data on this case are discussed together with those previously published in regard to the low prevalence of bone lesions in primary B-cell lymphomas of the bone marrow, and to the similarity of this B-cell malignancy to others that produce both hypercalcemia and bone lesions, i.e. multiple myeloma.

[Long-term treatment and prognostic factors in adult acute myeloblastic leukemia. Experience of the INNSZ group Puebla-Monterrey-Mexico)]. / Tratamiento a largo plazo y factores pronósticos en leucemia aguda mieloblástica del adulto. Experiencia del grupo INNSZ (Puebla-Monterrey-México).

The results of the treatment in a group of 43 adult patients with acute myelogenous leukemia (AML) are analyzed. All patients were induced to remission with a 7/3 schedule: cytarabine in continuous infusion during seven days and an anthracycline in push during three days; consolidation was done with the same regimen and no maintenance therapy was used. Complete remission (CR) was achieved in 60%, median survival of those achieving CR was 21 months. Mortality during induction was 30%; relapses occurred in 61% of those achieving CR. Twelve and 78 months overall-survival was 50 and 18% respectively, whereas 12 and 78 months disease-free-survival was 46 and 16% respectively. Fourteen variables were analyzed in their impact in both CR achievement and long term survival. Four variables were found to be associated with CR achievement: hemoglobin levels, major bleeding and infection at diagnosis, and site of treatment (private practice vs city hospital). All variables were associated with the 78 months survival, but two variables were related to 12 months survival: time of recovery of the bone marrow after ablative chemotherapy and amount of platelets transfused during the chemotherapy-induced hypoplasia. With regard to the first variable, the 12 months survival was 90 and 55% for patients recovering a normal bone marrow, before or after 25 days of initiation of chemotherapy (p less than 0.05). On the other hand, the hemorrhage-associated-mortality during induction was 9 and 36% for patients receiving more or less than 20 units of platelets during hypoplasia respectively (p = 0.038).(ABSTRACT TRUNCATED AT 250 WORDS)

[Comparison of 2 chemotherapy protocols in adult acute myeloblastic leukemia. Results of the Instituto Nacional de la Nutrición Salvador Zubirán cooperative group]. / Comparación de dos esquemas de quimioterapia en la leucemia aguda mieloblástica del adulto. Resultados del grupo cooperativo INNSZ.

Up to now, the best treatment for patients with acute myelogenous leukemia (AML) is the induction of bone marrow hypoplasia by ablative combined chemotherapy; the prototype of these schedules is the so-called 7 + 3 (seven days of continuous infusion of cytarabine and three days of one-hour infusion of any anthracycline); these schedules require the support of both platelet transfusions and antibiotics. Other non-ablative schedules have also been tried in the treatment of such patients. Here we analyze the results of the treatment of 76 adult patients with AML; 43 were treated with the classical 7 + 3 schedule, whereas 33 were treated with a combination of chemotherapy used in non-ablative doses (TADOP: thioguanine, arabinosyl-citosine, doxorrubicin, vincristine and prednisone). The results were as follows, respectively, for 7 + 3 and TADOP: complete remission (CR) was achieved in 60 and 48% of patients (p NS); the number of cycles to achieve CR had a median of 1 and 5 months (p less than 0.001); the median duration of the CR was 21 and 10 months (p less than 0.05); fatal myelotoxicity was 30 and 42% (p NS), one-year disease free survival (DFS) was 45 and 46% (p NS) and three-year survival was 22% and 15% (p NS). Additionally, patients treated with 7 + 3 were divided into two groups according to the type of platelet transfusion support; those supported with apheresis equipment and those with centrifugation-derived platelets.(ABSTRACT TRUNCATED AT 250 WORDS)

[Malnutrition is an adverse prognostic factor in the response to treatment and survival of patients with acute lymphoblastic leukemia at the usual risk]. / La desnutrición es un factor pronóstico adverso en la respuesta al tratamiento y supervivencia de pacientes con leucemia aguda linfoblástica de riesgo habitual.

A group of 43 pediatric patients with standard risk acute lymphoblastic leukemia (ALL) was studied prospectively and treated with a protocol that included adriamycin, vincristine and prednisone (HOP) to induce remission; cranial irradiation and intrathecal methotrexate (MTX) as CNS prophylaxis and mercaptopurine and MTX together with pulses of HOP every three months to maintain remission. Complete remission (CR) was achieved in 95.3% of the group; 5-year survival was 67%. The following variables were analyzed in the outcome to treatment: Age, sex, WBC at diagnosis, FAB morphology, CALLA/CD10 reactivity of the blast cells, lymph node, liver or spleen enlargement, site of treatment (private practice versus city hospital) and malnutrition. None of these variables had a significant impact in survival, but malnutrition. Under-nourished children (UNC) n = 16, had a significant worse outcome than well-nourished children (WNC) n = 27. Although CR was achieved in 98% of WNC versus 94% of UNC, five-year survival was 83% for WNC and 26% for UNC (p less than .001); relapses were observed in 18% of WNC and 75% of UNC (p less than .0005). Relapses presented more frequently in the bone marrow in UNC than in WNC (56% versus 7% p less than .0001). The doses of maintenance chemotherapy had to be reduced in 68% of UNC and 10% of WNC (p less than .005). The poor outcome to treatment observed in UNC was due to systemic relapses, apparently related to a poor tolerance to maintenance chemotherapy. Malnutrition might be included as an adverse prognostic factor in the outcome to treatment of children with ALL, in developing countries.