3q−, 3q+ anomaly in malignant proliferations in humans

Anomalies of both No. 3 chromosomes, of the t(3q?; 3q+) type can be observed in human malignancy as reported previously. It is our experience that this anomaly is found predominantly in myeloproliferative disorders, as a rather rare event, though occurring more frequently than similar exchanges between other homologous chromosomes. Previous claims about a relationship between this anomaly and thrombocytosis could not be confirmed, but the features found in a few patients indicate that further research should be undertaken to clarify this point.     

TEL gene is involved in myelodysplastic syndromes with either the typical t(5;12)(q33;p13) translocation or its variant t(10;12)(q24;p13)

A t(5;12)(q33;p13) translocation is a recurrent chromosome abnormality in a subgroup of myeloid malignancies with features of both myeloproliferative disorders and myelodysplastic syndromes (MDSs). The molecular consequence of a t(5;12) is a fusion between the platelet- derived growth factor receptor-B gene on chromosome 5 and a novel ETS- like gene, TEL, on chromosome 12. We report on three patients with a t(5;12)(q33;p13) diagnosed as chronic myelomonocytic leukemia, and one case of a t(10;12)(q24;p13) in a progressive MDS, with eosinophilia and monocytosis. Involvement of the TEL gene in these chromosome translocations was investigated by fluorescence in situ hybridization (FISH) with cosmid probes containing selectively the 5' end or 3' end of TEL. Hybridization of these cosmids to the der(5)/der(10) or a der(12), respectively, demonstrated a rearrangement of TEL in both translocations, showing that the t(10;12) is a variant translocation of the t(5;12). Cloning of the fusion cDNA of one case of t(5;12) showed that the breakpoint occurred at the RNA level at exactly the same position as reported by Golub et al (Cell 77:307, 1994). In addition, the TEL gene on chromosome 12 could be localized between two probes previously mapped to 12p13, namely PRB1 and D12S178, leading to a better definition of the position of TEL in this chromosome region. Moreover, in the case involving chromosome 10, the breakpoint occurred between cKTN206 and cKTN312/LYT-10 at 10q24. Clinicohematological data in these studies as well as the restriction mapping of chromosomal breakpoints strongly suggest that (1) common features in MDSs involving the TEL gene are monocytosis and eosinophilia, (2) chromosomes other than no. 5 may be involved and at least a t(10;12)(q24;p13) variant chromosome translocation does exist in these MDSs, and (3) both standard and variant 12p/TEL translocations may be identified by FISH with appropriate probes.     

Acute lymphoblastic leukemia in the elderly

We report our findings in 18 patients with acute lymphoblastic leukemia (ALL) aged 60 years or older. A preleukemic syndrome was observed in 2 patients. Compared to younger adults with ALL, L3 morphology was unexpectedly frequent (4/16). T-ALL was not observed. Other criteria of poor prognosis (high white blood cell count, CNS involvement, organomegaly, high serum LDH) were similar to those reported in young adults. 12 patients were treated with an OPAL-derived regimen, 4 with the MAV regimen, 1 with vincristine and prednisone, 1 with 6-mercaptopurine. Complete remission was achieved in 8 patients but proved short-lived. 5 patients died in aplasia and 5 failed to achieve remission. Median survival for the whole group was 3 months. ALL in the elderly raises the dilemma of an aggressive disease in patients with poor tolerance to intensive therapy.     

Prognosis of hematologic malignancies does not predict intensive care unit mortality

OBJECTIVE: To evaluate the correlation between specific prognosis of hematologic malignancies on the one hand and intensive care unit and hospital mortality in critically ill patients with hematologic malignancies on the other hand. DESIGN: Observational study during a 10-yr period. SETTING: A 22-bed medical-surgical intensive care unit. PATIENTS: A total of 84 consecutive patients with nonterminal hematologic malignancies with medical complications requiring intensive care. INTERVENTIONS: None. MEASUREMENTS: Demographic factors, acute physiology and organ dysfunction scores, microbiology, therapeutic support, and hematologic factors data on admission and during the intensive care unit stay were collected, together with mortality follow-up. Based on specific-disease prognostic factors and related published survival curves, the prognosis of hematologic malignancies was assessed and defined as good, intermediate, or poor according to a 3-yr survival probability of >50%, 20-50%, or <20%, respectively. MAIN RESULTS: Prognosis of hematologic malignancies does not predict intensive care unit or hospital mortality and almost reaches significance for 6-mo mortality (53%, 71%, and 84% rate for patients with good, intermediate, and poor prognosis, respectively, p =.058), but it determines long-term survival (p =.008). Intensive care unit, hospital, and 6-mo overall mortality rates were 38%, 61%, and 75%, respectively. Using multivariate analysis, intensive care unit mortality was best predicted on admission by respiratory failure and fungal infection, whereas hospital mortality was predicted by the number of organ failures, the bone marrow transplant status, and the presence of fungal infection. The Acute Physiology and Chronic Health Evaluation II and the Simplified Acute Physiology Score II had no prognostic value, whereas the difference of the Multiple Organ Dysfunction Score between at the time of admission and at day 5 allowed quick prediction of hospital mortality. Diseases with the poorest 6-mo prognosis were acute myeloid leukemia and non-Hodgkin lymphoma.CONCLUSION The severity of the underlying hematologic malignancies does not influence intensive care unit or hospital mortality. Short-term prognosis is exclusively predicted by acute organ dysfunctions and by a pathogen's aggressiveness. Therefore, reluctance to admit patients with nonterminal hematologic malignancies to the intensive care unit based only on the prognosis of their underlying hematologic malignancy does not seem justified.     

Bone marrow transplantation prolongs survival after relapse in aggressive-lymphoma patients treated with the LNH-84 regimen.

PURPOSE: Of the 737 patients with aggressive lymphoma who were treated with the LNH-84 regimen, 244 with progressive disease after complete remission or partial response were analyzed retrospectively to determine the influence of intensive chemotherapy with bone marrow transplantation (BMT) on survival. PATIENTS AND METHODS: Forty-four patients were treated with salvage chemotherapy, followed by autologous bone marrow transplantation (ABMT) in 40 and allogeneic BMT in four. The other 200 patients were treated with chemotherapy only. RESULTS: Salvage treatment produced an objective response in 57% of the patients; 23% achieved a second complete remission. Median overall survival was longer for patients who were treated with ABMT than for those who were treated with chemotherapy only (12.4 v 6.7 months), as was median freedom from progression (FFP) survival (7.7 v 4 months). In multiparametric analysis, ABMT and normal initial lactic dehydrogenase (LDH) level were the primary parameters associated with longer survival. This is also true when (1) only patients younger than 60 years of age, (2) only patients who responded to salvage regimen, or (3) only patients with both conditions were included in the analysis. Patients who were not transplanted had a 1.69 to 2.26 relative risk of dying from their disease compared with those who were treated with intensive chemotherapy plus ABMT. CONCLUSION: This study produced more evidence of the favorable impact of intensive chemotherapy with bone marrow rescue on survival in lymphoma patients who had relapsed.     

High-dose cytosine arabinoside and amsacrine or mitoxantrone in relapsed and refractory acute myeloid leukaemia: a prospective randomized study

52 patients with refractory or relapsed acute myeloid leukaemia (AML) were randomly assigned to receive a combination of high-dose cytosine arabinoside (HD Ara-C), 3 g/m2/d and either mitoxantrone (MTX), 7 mg/m2/d (5 mg if older than 60 yr) or m-amsacrine (AMSA), 120 mg/m2/d (90 mg if older than 60 yr) for 5 d. The overall response rate was 50% and did not differ significantly in the two groups (46% for AMSA and 56% for MTX, p = 0.415). The median survival was 11 months (8 months for AMSA and 12 months for MTX, p = 0.326) and the median duration of complete remission (CR) was 11 months for AMSA and 12 months for MTX (p = 0.643). In relapsed patients, the only significant predictive factor for obtaining a complete response was the length of first complete remission. Patients with a first CR shorter than 6 months had a CR rate of 36% while it was 65% if the first CR lasted more than 6 months (p = 0.03). Severe (WHO grade III-IV) gastro-intestinal toxicity was more frequent in the AMSA group (27% vs 4%, p = 0.021). Treatment-related death occurred in 4 patients in the AMSA group and in 2 patients in the MTX group (p = 0.097). We conclude that neither of these two treatment modalities was shown to be superior in terms of CR rate and survival, with a better tolerance for MTX.