Biomedical subjects
Publications and source records attributed to C Aul.
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Following conventional chemotherapy, eight myeloma patients presenting with advanced tumor stages were treated with an intensified high-dose regimen and autologous peripheral blood stem cell transplantation. High-dose chemotherapy consisted of idarubicin 20 mg/m2 on days -13, -12 and -11, melphalan 100 mg/m2 on days -5 and -4 and cyclophosphamide 60 mg/kg (plus mesna 60 mg/kg) on days -3 and -2 (IMC). Seven patients achieved a complete remission or a very good partial remission (reduction of M-component > or =90%). There were no toxic deaths. Severe mucositis and fever of unknown origin were seen in all patients. Reversible supraventricular tachycardias without clinical signs of cardiac failure occurred in five patients. One patient developed a persistent deterioration of cardiac function. We surmise that high-dose chemotherapy with IMC is very effective and well tolerated in myeloma patients.
OBJECTIVE: To assess the prognostic value of serum thymidine kinase (sTK) activity in patients with the myelodysplastic syndrome (MDS). PATIENTS AND METHODS: The study included 255 patients (144 men, 111 women, median age 67 [14-97] years) in whom primary MDS had been diagnosed between 1986 and 1995 (refractory anaemia [RA]: n = 40; RA with ring sideroblasts: n = 38; RA with increased blasts: n = 76; RA with increased blasts in transformation: n = 45; chronic myelomonocytic leukaemia: n = 56). 69 healthy persons (28 men, 41 women, median age 33 [24-62] years) served as controls. The normal laboratory range for sTK was between 0.9 and 4.9 U/microliter. RESULTS: At time of diagnosis 83% of patients had sTK levels higher than 5 U/microliter. There was no relationship between sTK levels and the proportion of medullary blasts. But serum sTK levels correlated with LDH activity (P < 0.0005) and with peripheral leukocyte count (P = 0.003). At all times patients with sTK levels < 10 U/microliter had a higher survival rate than those > or = 10 U/microliter. Cumulative survival rates in both groups was 69 +/- 10% (< 10 U/microliter) and 43 +/- 11% (> or = 10 U/microliter), respectively, after 2 years and 37 +/- 9% (< 10 U/microliter) and 20 +/- 7% (> or = 10 U/microliter) after 5 years (P = 0.0002). Multivariate analysis showed that sTK, haemoglobin concentration and proportion of medullary blasts were independent prognostic survival factors. CONCLUSIONS: Most patients with MDS have an increased sTK level when the diagnosis is made. This reflects the impaired proliferation and differentiation of haematopoiesis. sTK is a simply and rapidly measured prognostic indicator for estimating survival probability of patients with MDS.
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The option of bone marrow transplantation (BMT) significantly improved prognosis of adult patients with hematologic malignancies aged less than 50 years. Allogeneic BMT using the marrow of an HLA-identical family member still provides the most effective method of BMT. Conventional indications for this form of BMT are chronic myeloid leukemia (CML), acute leukemias presenting with adverse risk factors, myelodysplastic syndromes and severe aplastic anemia. If performed early in the disease course (e.g. during the chronic phase of CML or first remission of acute leukemia and MDS) allogeneic BMT cures 50 to 60% of patients. About 20% die of therapy related complications, e.g. graft versus host disease (GvHD), fatal infections or venoocclusive disease of the liver (VOD) and about 20% of patients succumb to relapse of their hematologic disorder. 80% presenting with severe aplastic anemia can be cured, if allogeneic BMT is performed soon after diagnosis without previous immunosuppressive therapy and blood transfusions. BMT with the marrow of a matched unrelated donor or autologous BMT are increasingly used as alternative procedures. A rate of lethal complications as high as 50% hinders rapid extension of BMT with unrelated donors. Therefore, this form of BMT should be restricted to young patients with leukemias, who cannot achieve long-term remission with conventional chemotherapy (in case of acute leukemias) or alpha-interferon (in case of CML). Reconstitution of hematopoiesis is more rapid after peripheral blood stem cell transplantation (PBSCT) compared with autologous BMT. Therefore, PBSCT will replace autologous BMT in most cases. Most favourable results of PBSCT have been reported in patients with malignant lymphomas after relapse or inferior response to primary induction therapy. Due to the higher relapse rate autologous BMT is inferior to allogeneic BMT in leukemia patients. Trials are required to clarify the potential role of myeloablative therapy with stem cell support in the treatment of patients with solid tumors. Many of the preliminary results already published are unsatisfactory and data of larger trials are still lacking. Therefore, BMT or PBSCT cannot be recommended generally for the therapy of patients with solid tumors.
Myelodysplastic syndromes (MDS) are diagnosed with increasing frequency in recent years. Their crude annual incidence (ca. 4/100,000), is now about twice that of acute myeloid leukemias (AML). In over 70-year-old patients (age-related incidence more than 20/100,000), MDS rival CLL as the most common hematological neoplasias. Diagnosis of MDS is based on cytological and histological examination of bone marrow specimens, which may show various dysplastic features of hematopoietic precursors and an increased percentage of blast cells. In difficult cases the diagnosis of MDS is supported if cytogenetic investigation reveals an abnormal karyotype. Most patients with MDS (60 bis 80%) die from their bone marrow disorder, with infections, hemorrhages and leukemic transformation being the most frequent causes of death. Treatment must take into account the age and general condition of the individual patient as well as the natural course of his MDS. The comparatively favourable prognosis of patients with early-stage MDS should not be jeopardized by therapies carrying a high risk of treatment-related death. Therefore, treatment is often confined to supportive measures (blood transfusions, antibiotics). Patients with increased percentage of blasts, however, have such a poor prognosis that more aggressive approaches including intensive chemotherapy appear justified. Only very few patients can be treated with allogeneic bone marrow transplantation, which offers a chance for cure.
A total of 68 adult patients with B-cell acute lymphoblastic leukemia (B-ALL) were treated in three consecutive adult multicenter ALL studies. The diagnosis of B-ALL was confirmed by L3 morphology and/or by surface immunoglobulin (Slg) expression with > 25% blast cell infiltration in the bone marrow (BM). They were characterized by male predominance (78%) and a median age of 34 years (15 to 65 y) with only 9% adolescents (15 to 20 y), but 28% elderly patients (50 to 65 y). The patients received either a conventional (N = 9) ALL treatment regimen (ALL study 01/81) or protocols adapted from childhood B-ALL with six short, intensive 5-day cycles, alternately A and B. In study B-NHL83 (N = 24) cycle A consisted of fractionated doses of cyclophosphamide 200 mg/m2 for 5 days, intermediate-dose methotrexate (IdM) 500 mg/m2 (24 hours), in addition to cytarabine (AraC), teniposide (VM26) and prednisone. Cycle B was similar except that AraC and VM26 were replaced by doxorubicin. Major changes in study B-NHL86 (N = 35) were replacement of cyclophosphamide by ifosphamide 800 mg/m2 for 5 days, an increase of IdM to high-dose, 1,500 mg/m2 (HdM) and the addition of vincristine. A cytoreductive pretreatment with cyclophosphamide 200 mg/m2, and prednisone 60 mg/m2, each for 5 days was recommended in study B-NHL83 for patients with high white blood cell (WBC) count (> 2,500/m2) or large tumor burden and was obligatory for all patients in study B-NHL86. Central nervous system (CNS) prophylaxis/treatment consisted of intrathecal methotrexate (MTX) therapy, later extended to the triple combination of MTX, AraC, and dexamethasone, and a CNS irradiation (24 Gy) after the second cycle. Compared with the ALL 01/81 study where all the patients died, results obtained with the pediatric protocols B-NHL83 and B-NHL86 were greatly improved. The complete remission (CR) rates increased from 44% to 63% and 74%, the probability of leukemia free survival (LFS) from 0% to 50% and 71% (P = .04), and the overall survival rates from 0% to 49% and 51% (P = .001). Toxicity, mostly hematotoxicity and mucositis, was severe but manageable. In both studies B-NHL83 and B-NHL86, almost all relapses occurred within 1 year. The time to relapse was different for BM, 92 days, and for isolated CNS and combined BM and CNS relapses, 190 days (P = .08). The overall CNS relapses changed from 50% to 57% and 17%, most probably attributable to the high-dose MTX and the triple intrathecal therapy. LFS in studies B-NHL83 and B-NHL86 was significantly influenced by the initial WBC count < or > 50,000/microL, LFS 71% versus 29% (P = .003) and hemoglobin value > or < 8 g/dL, LFS 67% versus 27% (P = .02). Initial CNS involvement had no adverse impact on the outcome. Elderly B-ALL patients (> 50 years) also benefited from this treatment with a CR rate of 56% and a LFS of 56%. It is concluded that this short intensive therapy with six cycles is effective in adult B-ALL. HdM and fractionated higher doses of cyclophosphamide or ifosphamide seem the two major components of treatment.
Acquired idiopathic sideroblastic anaemia (AISA) has been proposed to be a disorder of mitochondrial DNA (mtDNA). The hallmark of mitochondrial iron overload may be attributable to a respiratory chain defeat leading to impaired reduction of ferric iron (Fe3+) to ferrous iron (Fe2+), which is essential to the last step of mitochondrial haem biosynthesis. In a 71-year-old patient we identified a point mutation in one of the two mitochondrial transfer-RNAs coding for leucine (tRNA(leu)(CUN)). The mutation involves a G --> A transition in the anticodon loop, immediately adjacent to the anticodon triplet (mtDNA position 12301). The mutated guanine is highly conserved in a wide range of species. The mutation is heteroplasmic, i.e. there is a mixture of normal and mutated mitochondrial genomes (ratio c. 50:50). Heteroplasmy of mtDNA is not found in normal individuals, but is a typical feature of mitochondrial cytopathies. The point mutation was present in the patient's bone marrow and whole blood samples, in purified platelets, and in the granulocyte/erythrocyte pellet after mononuclear cell separation by density gradient centrifugation. The mutation was not found in T- and B-lymphocytes isolated by immunomagnetic bead separation. It was also absent from buccal mucosa cells and cultured skin fibroblasts. This pattern of involvement suggests that the mutation occurred in a self-renewing myeloid stem cell of the CFU-GEMM type.
The spread of leukemia extends from mobilization of leukemic blast cells from the bone marrow to extramedullary tissue infiltration. Migration of leukemic blasts resembles that of neutrophils and may be regulated by activated endothelial cells via endothelial adhesion molecules such as E-selectin, VCAM-1 and ICAM-1. Plasma levels of soluble adhesion molecules may therefore indicate interaction between leukemic blasts and endothelium, and may be related to leukemic cell mass or subtype of leukemia. In this study, plasma levels of soluble E-selectin, VCAM-1 and ICAM-1 were analyzed in 40 untreated patients with acute leukemia (35 ANLL, five ALL). Plasma concentrations of all three receptors were significantly elevated when compared to healthy controls (P = 0.006, P = 0.0001, and P = 0.0001, respectively) but demonstrated high interindividual variations among leukemic patients. sE-selectin but not sVCAM-1 and sICAM-1 levels correlated with peripheral leukocyte and blast cell counts. Increased levels of either sE-selctin or sVCAM-1 were present in 32 out 40 leukemic patients (80%). FAB subgroups differed in levels of sVCAM-1. The highest levels were measured in acute myelomonocytic and lymphoblastic leukemia, ie in leukemia subtypes with a high incidence of extramedullary blast cell infiltration.
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Treatment of myelodysplastic syndromes (MDS) with recombinant human erythropoietin (Epo) is successful in only 10% to 25% of patients. We performed a pilot study in 10 anaemic patients with MDS to examine whether sequentially applied recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) and Epo improves haemoglobin levels and/or reduces red blood cell transfusion requirements. Morphological diagnoses of patients were refractory anaemia (RA) in 3 cases, RA with ring sideroblasts in 3 cases and RA with excess blasts in 4 cases. GM-CSF was given subcutaneously at a dose of 150 micrograms/m2/d during the initial 10 days. From day 11, Epo was administered by subcutaneous injections for 8 weeks at a dose of 100 U/kg/d and subsequently at an escalated dose of 200 U/kg/d in 3 patients. Changes in reticulocyte counts, haemoglobin levels, RBC support and ferrokinetic parameters were compared with pretreatment values. Two out of 8 evaluable patients showed a rise in haemoglobin levels at week 8 and 10, respectively, and lost their transfusion dependency for a period of 13 and 27 weeks. In 1 patient, haemoglobin level increased only after dose escalation of Epo (200 U/kg/d). Leukocyte counts remained uneffected by treatment with Epo, while 1 patient showed a 4-fold increase in platelet numbers. Toxicity was mild. Two patients died of pneumonia and global heart failure, respectively, unrelated to growth factor therapy. Based on this pilot study, we conclude that sequential treatment with GM-CSF and Epo does not increase erythroid responses in anaemic patients with MDS. Because of the delayed increase in haemoglobin in both responders, we surmise that the beneficial effects were induced by Epo alone.
Myelodysplastic syndromes (MDS) are increasingly recognized as a cause of bone marrow failure, and are at least as frequent as acute myeloid leukemias. While the overall incidence is about 2-4/100,000/year, incidence figures rise steeply with age. Incidence rates of 20-30/100,000/year in persons over 70 demonstrate that MDS are among the most common hematological neoplasias in this age group. However, due to difficulties of diagnosis and classification, patient registration in population-based registers is far from complete. As a prerequisite for truly representative statistics, future revisions of disease classification systems must incorporate MDS as a separate group of disorders. The difficulties in conducting epidemiological studies also impede the identification of risk factors for the development of MDS. Current knowledge of occupational risk factors is also reviewed here. More rapid progress in our understanding of MDS may come from recent advances in methodology that have begun to shed some light on the cytogenetic and molecular aspects of leukemogenesis in general, and MDS in particular. Non-random chromosomal changes can be found in about 50% of cases at diagnosis, but they are probably late events in the evolution of MDS, reflecting the progressive genomic instability of the premalignant clone. Proto-oncogene mutations have also been suggested to be relevant to the pathogenesis of MDS, but longitudinal studies of point mutations of the N-ras proto-oncogene revealed that such events, although often associated with rapid deterioration and transformation to AML, also appear to be late events during the course of disease. Therefore, it remains a major challenge to identify those lesions that initiate the multistep development of preleukemia. As the incidence of MDS correlates strongly with age, it is reasonable to presume that age-dependent changes of the hematopoietic system may play a role in the initiation of MDS. Aging is probably associated with a compromised marrow reserve through reduction in the size of the stem cell pool. Through increased proliferative activity, the remaining stem cells may be particularly vulnerable to mutagenic insults. Immunological attack on stem cells, mitochondrial DNA mutations, and the regulatory influence of the hematopoietic microenvironment must also be considered as possibly contributing to the early stages of MDS.
In recent years, a variety of chronic degenerative diseases that mainly involve brain, heart and muscle have been shown to result from mutations in mitochondrial DNA (mtDNA). A 4977-bp deletion (mtDNA-4977, also known as the common deletion) is the most frequent abnormality in patients with mitochondrial myopathies. A low percentage of mtDNA-4977 is also found in various tissues of normal ageing individuals. Accumulation of this deletion as well as other mtDNA deletions and point mutations is thought to contribute to normal cell ageing. We examined blood and bone marrow samples of 63 hematologically normal patients undergoing sternotomy for cardiac surgery. Using short-cycle PCR, which favors the amplification of molecules carrying large deletions, we detected the common deletion in 22 (35%) of the patients. In one of the probands, a hitherto unknown 4867-bp deletion was identified (nt 8561-13429). In each sample the percentage of mtDNA-4977 was very low, since detection always required primer-shift reamplification of a primary PCR product. Because mtDNA molecules with large deletions are known to be progressively enriched through their tendency to replicate more rapidly than full-size mtDNA, the small amount of mtDNA-4977 detected is likely to be concentrated in a small fraction of cells. The common deletion was not detectable in 20 patients with myelodysplastic syndromes (MDS), 20 patients with acute myeloid leukemia (AML), and 10 patients with chronic myeloid leukemia (CML). The seeming paradox of detectability of mtDNA-4977 in hematologically normal individuals and its absence in clonal myeloid disorders is explained by varying selection against self-renewing stem cells harboring the common deletion. Selection appears to be effective under circumstances of proliferative stress (eg among continuously proliferating stem cells in clonal hematopoiesis), whereas in normal steady-state hematopoiesis, affected stem cells persist because they are rarely recruited into cell cycle and can thus tolerate mitochondrial dysfunction.
Coexpression of myeloid, B-, and T-lineage associated markers was found in a patient with morphologically and cytochemically undifferentiated acute leukemia. Surface marker analysis using two-color immunofluorescence staining characterized blast cells to express CD34, CD38, CD117, and class II antigens, coexpressing TdT, CD4, CD7, CD13, CD19, and CD33. Cytoplasmic expression of myeloperoxidase, CD3, and CD22 could not be demonstrated. Monosomy for chromosome 7 was found by cytogenetic analysis. The absence of clonal rearrangements of immunoglobulin or T-cell receptor genes was shown by Southern blot analysis. Using a 3H-thymidine incorporation assay, DNA synthesis of leukemic blasts could be stimulated by IL-3, IL-6 and G-CSF in vitro. The present case did not offer specific criteria of lineage commitment. Corresponding to an equivalent counterpart in normal hematopoiesis, the involved cell population may reflect an early, most immature developmental stage within a multipotent progenitor cell compartment.
BACKGROUND: Previous studies have shown that serum levels of deoxythymidine kinase (sTK) provide useful prognostic information in various malignancies, such as Hodgkin's disease, non-Hodgkin's lymphomas, multiple myeloma, and acute myeloid leukemia (AML). METHODS: Using a radioenzyme assay, the authors determined sTK in 146 patients with primary myelodysplastic syndromes (MDS). Morphologic subtypes were refractory anemia (RA) in 18 patients, RA with ring sideroblasts (RARS) in 24, RA with excess of blasts (RAEB) in 41, RAEB in transformation (RAEB/T) in 29, and chronic myelomonocytic leukemia (CMML) in 34. RESULTS: Enzyme levels ranged from 1.1 to 829 U/microliters. One hundred fifteen (79%) patients had elevated sTK levels (more than 5 U/microliters) at the time of diagnosis. In advanced stages of MDS (RAEB, CMML, and RAEB/T) enzyme activities were higher than in early stages (RA and RARS) (P < 0.05). However, sTK levels were not correlated with the percentage of medullary blast cells. Among other parameters tested, the best correlation with sTK was found for serum lactate dehydrogenase (LDH) activity (r = 0.29; P < 0.0005). As shown by life table analysis, sTK activity at diagnosis provided useful information regarding the prognosis of patients. For patients with sTK levels of less than 10 U/microliters, actuarial survival after 2 years was 65%, compared with 33% for those with enzyme values of 10 U/microliters or greater. The 5-year cumulative survival rates were 34% and 14%, respectively (P < 0.0005). However, sTK levels at diagnosis were not useful for predicting transformation to AML. Nine of 61 (15%) patients with sTK of less than 10 U/microliters had AML develop, whereas 15 of 57 (26%) patients with sTK of 10 U/microliters or greater had disease progress to acute leukemia (chi-square, 1.64; P = 0.2). CONCLUSIONS: Considering the lack of correlation with bone marrow blasts, the authors conclude that increased sTK levels in MDS are primarily attributable to intramedullary destruction of hematopoietic precursors and do not reflect the leukemic blast cell burden. This appears similar to the ineffective hematopoiesis of vitamin B12 deficiency, which is associated with elevated levels of sTK and LDH. The data suggest that sTK is a prognostic parameter that can be used to predict the survival of patients with MDS. However, multivariate analysis shows that the predictive value of sTK is not superior to that of LDH.
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Conventional-dose Ara-C (200 mg/m2 d 1-5) combined with idarubicin (12 mg/m2 d 1-3) was employed as remission induction and consolidation therapy in 23 elderly AML patients with a median age of 66 years (range, 60-75) with AML according to the FAB criteria (M1 n = 3, M2 n = 10, M4 n = 6, M5 n = 2, M6 n = 2), eligible for the study. In seven patients earlier MDS had been documented by previous bone marrow aspirates. The CR rate after one induction course was 65% (15/23). Toxicity was acceptable, with four patients dying during the chemotherapy-induced hypoplasia (4/23). Although 80% of the CR patients received two additional cycles of Ara-C and idarubicin as consolidation therapy, only two patients are still in continuous complete remission more than 12 months after achieving CR. The median disease-free survival of the CR patients was 11.5 months and the median survival of the entire group was 10 months. We conclude that conventional dose Ara-C/idarubicin is an effective protocol for inducing complete remission in elderly patients with AML, but that consolidation therapy consisting of two courses of the same regimen does not produce a relevant rate of long-term disease-free survival.