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.

Role of bone marrow examination in staging Hodgkin's disease: experience in México.

We assessed the value of bone marrow biopsy prospectively in a group of 91 individuals with Hodgkin's disease. The median age of our population was 29 years (range 4-87 years); 59 were males. Most patients (45%) had nodular sclerosing disease and most patients (44%) were in pathological stage II at diagnosis. The bone marrow biopsy showed infiltration by Hodgkin's disease in only three individuals (3.3%); two of these patients displayed constitutional symptoms and had been assigned to stage III before the biopsy. In one case, bone marrow biopsy was the diagnostic procedure, which was performed as part of the investigation of fever of unknown origin. Follow-up periods ranged between 1 and 117 months (median 16 months). All patients achieved complete remission, seven patients relapsed and four were given autologous stem cell transplants. The median survival of the whole group was 117 months, while the 3500-day survival was 76%. As bone marrow biopsy was the diagnostic procedure in one case, bone marrow biopsy was a useful staging procedure in only 2.2% of patients (two out of 90 patients). We suggest that bone marrow biopsy should be only be performed as a staging procedure in a selected subset of patients with Hodgkin's disease (clinical stage III, B symptoms, etc.).

[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.

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.

All trans-retinoic acid decreases early mortality in patients with promyelocytic leukemia and can be given entirely on an outpatient basis.

The results of the treatment of 43 patients with acute promyelocytic leukemia (PML) are reported: 27 were treated initially with all-trans-retinoic acid (ATRA), whereas 16 were treated with conventional chemotherapy. All patients received myelosuppressive chemotherapy after the initial treatment. Respectively, the complete remission rate was 92% and 37% (P < 0.01), the 5-day mortality rate was 0% and 44% (P < 0.001), and the 28-day mortality rate was 4% and 44% (P < 0.001). The median disease-free survival was 12 and 1 months (P < 0.01), whereas the 12-month disease-free survival was 50% and 13% (P < 0.01) and the 36-month disease-free survival was 41% and 9% (P < 0.01). Thirteen of the patients treated with ATRA were given the treatment fully as outpatients. ATRA given as initial therapy decreased significantly early mortality in promyelocytic leukemia patients; because some promyelocytic leukemia patients given ATRA as initial therapy can be treated as outpatients, the costs of this treatment modality may be diminished.

A modified spectrophotometric assay for porphobilinogen deaminase: its application in the detection of both carriers and patients with acute intermittent porphyria.

A spectrophotometric method for porphobilinogen deaminase assay in erythrocytes is described. This test is determinant for the definite diagnosis of acute intermittent porphyria. In the method described, delta-aminolevulinic acid is used as substrate. Mercaptoethanol and zinc ions are introduced to maintain delta-aminolevulinic acid dehydratase in optimal conditions and to guarantee the in vitro production of porphobilinogen. An incubation temperature of 45 degrees C leads to the production of uroporphyrins, which are measured spectrophotometrically at 405 nm, giving reproducible results. The assay can be performed easily in any clinical laboratory and is valuable for detecting both patients and carriers of acute intermittent porphyria.

Long-term treatment results for acute megakaryoblastic leukaemia patients: a multicentre study.

The prognosis and long-term results of a group of 57 acute megakaryoblastic leukaemia (M7-AML) patients was analysed from a multicentre perspective. Ages ranged from 4 to 83 years, median 49 years; 30 were males and 27 were females. The median follow-up time was 7 months, range 1-24 months. Early exits occurred in 12 cases, their median age being 71 years. Forty-five patients were treated with combined aggressive chemotherapy (CT) (n = 26) or low-dose cytarabine (LD-AraC) (n = 19). The following results were obtained with combined CT or AraC, respectively. Complete remission (CR) rates were 73% and 84%, 12-month survival (SV) were 37% and 26%, 24-month SV were 12% and 11%, median SV 10 and 4 months, and relapse rates (RR) were 68% and 94%. These differences were not statistically significant. Irrespective of the treatment modality, the results were better for children (n = 10) than for adults (n = 35): RR rates were 90% and 74%, median SV: 7 and 5 months, 12-month SV: 40% and 22%, 24-month SV; 30% and 9%, and RR: 78% and 81%, respectively; these differences also were not statistically significant. In addition, a literature review of 42 patients from 18 previous reports is presented, including seven cases treated with allogeneic bone marrow transplantation (BMT). The best results were obtained with BMT: 12 and 24 month SV was 86% and the RR was 0%. On the above-mentioned basis, we feel that children and young adults with M7-AML should be offered BMT. In patients over 60 years old or not eligible for aggressive chemotherapy or BMT, an interesting possibility would be the use of LD-AraC which allows a high CR rate, followed by a classical consolidation regimen in order to prevent early relapses.

[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)

[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)

[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)

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.

Disturbances in the tissue plasminogen activator/plasminogen activator inhibitor (TPA/PAI) system in systemic lupus erythematosus.

Increased thrombogenesis observed in systemic lupus erythematosus (SLE) is derived from multiple mechanisms, including: Enhanced coagulation factor VIII:VWf activity, lupus anticoagulants, anti-phospholipid antibodies, acquired deficiencies of natural anti-thrombotic mechanisms (protein C, protein S, anti-thrombin III), and impaired fibrinolytic mechanisms. We studied the fibrinolytic mechanisms of 18 patients with systemic lupus erythematosus, selected carefully to avoid other possible causes of abnormalities in the fibrinolytic activity. Despite the fact that the euglobulin lysis time in steady state was normal in all instances, disturbances in the tissue plasminogen activator/plasminogen activator inhibitor (TPA/PAI) system were found in all SLE patients: TPA activity was undetectable in all cases, whereas it was above 0.4 IU/ml in a control group. In 72 percent of patients, the undetectable TPA activity was correlated with abnormally high PAI activity; PAI levels were normal in all members of the control group, their mean value being 0.74 versus 8.63 IU/ml for SLE patients (P less than .01). Coagulation protein C deficiency was found in 3 patients (17%). Even though within normal range, fibrinogen levels were significantly higher in SLE than in normal controls (219 versus 192 mg/dl, P less than .01) and plasminogen levels were significantly higher in SLE than in controls (117 versus 78.2%, P less than .01). Cross-linked fibrin derivatives (D-D dimers) were negative in all patients with SLE. Sixty-eight percent of SLE patients had high levels of antiphospholipid antibodies, but no correlation with the disturbances of the TPA/PAI system was found. It is concluded that most patients with SLE display severe abnormalities in the TPA/PAI anti-thrombotic system and that these abnormalities may be related to the lupus thrombophilia, apparently multifactorial in its origin.

[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.

[Prevalence and features of pre-B-cell acute lymphoblastic leukemia in Mexico: description of 9 patients]. / Prevalencia y características de la leucemia aguda linfoblástica de células pre-B en México: descripción de 9 pacientes.

A group of 9 patients with pre-B cell acute lymphoblastic leukaemia (pre-B ALL) was identified prospectively within 209 patients with ALL. This variant of leukaemia was defined by the presence of heavy mu-chains in the cytoplasm of the malignant cells, and no surface immunoglobulins. Four patients displayed the CD10 (CALLA) antigen, in addition to cytoplasmic mu chains. A G-0 acute leukaemia (no blast cells in S-phase) was identified in two cases. Response to treatment of the patients was poor: Only four achieved complete remission; median survival was 24 weeks and the 40-week disease free survival was 20%. These figures are significantly worse than those obtained in patients with early-pre-B (CD10+) ALL. We conclude that the prevalence of pre-B ALL is low in our experience (4.6% of all patients with ALL) and that a poor outcome of treatment was related to it.

[Primary gastric lymphoma: incidence, prognostic factors and effect of treatment with chemotherapy]. / Linfoma gástrico primario: incidencia, factores pronósticos y efecto del tratamiento con quimioterapia.

This paper deals with the prevalence, clinical features and therapeutic response of 19 patients with primary gastric lymphoma studied and treated at Centro de Hematologia y Medicina Interna de Puebla, Mexico and Instituto Nacional de la Nutricion Salvador Zubiran, Mexico City, Mexico, in a 10 year period (1979-1989). The main findings were as follows: 1) The prevalence of gastric lymphoma has increased in Mexico: Between 1950 and 1980 the prevalence was found at 4.5% of all gastric tumors, whereas between 1980 and 1990 it was found at the 7.6% level (chi square = .0001). 2) The significant prognostic factors for survival were in this series the clinico-pathologic stage and the degree of infiltration of the gastric wall: 80-month disease free survival was 80% and 44% respectively for stages I and III (p less than 0.02); 10-year disease free survival was 100% and 23% respectively for mucosal/submucosal infiltration VS mucosal/serosal infiltration (p less than 0.01). 3) The 10-year disease free survival was 68% for patients treated with chemotherapy and surgery; this figure is similar to those obtained using radiotherapy and surgery, but with a lower relapse rate. Two patients with lymphomatous lesion less than 3 cm. and invading only mucosae/submucosae were treated solely with chemotherapy and both of them remain disease free after 20 months of follow-up.

[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.

[Leukemia and malnutrition. III. Effect of chemotherapeutic treatment on the nutritional state and its repercussion on the therapeutic response of patients with acute lymphoblastic leukemia with standard risk]. / Leucemia y desnutrición. III. Efecto del tratamiento quimioterápico sobre el estado nutricional y su repercusión en la respuesta terapéutica de pacientes con leucemia aguda linfoblástica de riesgo estandar.

This is the third part of a series of papers dealing with the relationship between malnutrition and poor prognosis of patients with standard-risk acute lymphoblastic leukaemia (ALL). The first part shows that undernourishment is an adverse prognostic factor in the outcome of treatment of patients with ALL inasmuch as malnourished children, due to diminished bone marrow reserve, receive approximately 50% of the optimal doses of so-called "maintenance" chemotherapy, thus leading into frequent bone marrow leukaemic relapses and into a shortened disease-free survival--DFS--(5 year DFS was 83% for well nourished children and only 26% for undernourished children, p less than 0.001). The second part demonstrates that the delivery of sub-optimal doses of myelosuppressive maintenance chemotherapy is by itself, an adverse prognostic factor in the outcome of treatment of children with ALL: five year disease free-survival was 65% and 7% for children receiving either optimal or sub-optimal doses of ablative maintenance chemotherapy (p less than 0.001); accordingly, suboptimal doses of chemotherapy were delivered mainly in undernourished children, due to the abnormally low bone marrow reserve. This third part deals with two additional points: the degree of undernourishment as related to the prognosis and the changes in the nutritional status along with the anti-leukaemic chemotherapy, together with its relationship to the prognosis. In a group of 43 children with standard-risk ALL, we have found that those with a mild to moderate degree of undernourishment do better than those with severe forms of malnutrition (2 year-DFS was 50% and 25% respectively, p less than 0.02), but significantly worse than those with normal nourishment status.(ABSTRACT TRUNCATED AT 250 WORDS)