Etienne Vilmer

Outcome of treatment in childhood acute lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region

BACKGROUNDnThe prognosis and optimum treatment of childhood acute lymphoblastic leukaemia (ALL) with abnormalities of chromosomal band 11q23 are controversial. We aimed to identify prognostic factors that might help in planning future therapy, and to assess the effectiveness of haemopoietic stem-cell transplantation in patients with the t(4;11) translocation, which is associated with a particularly poor outcome.nnnMETHODSnWe reviewed data on 497 children and young adults who had ALL with various 11q23 abnormalities, including the translocations t(4;11), t(9;11), and t(11;19). All patients were treated with intensive chemotherapy, with or without haemopoietic stem-cell transplantation in first complete remission, by 11 study groups and single institutions from 1983 to 1995.nnnFINDINGSnAge was the most important prognostic factor. In a Coxs proportional-hazard model stratified by 11q23 abnormalities, infants younger than 1 year fared significantly worse than patients 1 year of age or older (hazard ratio for event-free survival 1 84 [95% CI 1 38-2 47], p=0 0001). Among infants, any category of 11q23 abnormality conferred a dismal outcome, whereas in older patients, t(4;11) and t(9;11) were associated with a worse outcome than were other 11q23 changes. In the largest subgroup--256 patients with t(4;11)--any type of transplantation was associated with significantly worse disease-free survival (1 61 [1 10-2 35], p=0 014) and overall survival (1 76 [1 08-2 45], p=0 004) compared with chemotherapy only. Even transplantation with stem cells from HLA-matched related or HLA-matched unrelated donors tended to be associated with a worse outcome than chemotherapy alone.nnnINTERPRETATIONnThe prognosis of acute lymphoblastic leukaemia with an 11q23 abnormality is particularly dismal in infants. Allogeneic transplantation with haemopoietic stem cells from an HLA-matched related donor does not seem to improve the clinical outcome in patients with t(4;11)-positive leukaemia.

Clinical heterogeneity in childhood acute lymphoblastic leukemia with 11q23 rearrangements.

To assess the clinical heterogeneity among patients with acute lymphoblastic leukemia (ALL) and various 11q23 abnormalities, we analyzed data on 497 infants, children and young adults treated between 1983 and 1995 by 11 cooperative groups and single institutions. The substantial sample size allowed separate analyses according to age younger or older than 12 months for the various cytogenetic subsets. Infants with t(4;11) ALL had an especially dismal prognosis when their disease was characterized by a poor early response to prednisone (P=0.0005 for overall comparison; 5-year event-free survival (EFS), 0 vs 23±12% s.e. for those with good response), or age less than 3 months (P=0.0003, 5-year EFS, 5±5% vs 23.4±4% for those over 3 months). A poor prednisone response also appeared to confer a worse outcome for older children with t(4;11) ALL. Hematopoietic stem cell transplantation failed to improve outcome in either age group. Among patients with t(11;19) ALL, those with a T-lineage immunophenotype, who were all over 1 year of age, had a better outcome than patients over 1 year of age with B-lineage ALL (overall comparison, P=0.065; 5-year EFS, 88±13 vs 46±14%). In the heterogeneous subgroup with del(11)(q23), National Cancer Institute-Rome risk criteria based on age and leukocyte count had prognostic significance (P=0.04 for overall comparison; 5-year EFS, 64±8% (high risk) vs 83±6% (standard risk)). This study illustrates the marked clinical heterogeneity among and within subgroups of infants or older children with ALL and specific 11q23 abnormalities, and identifies patients at particularly high risk of failure who may benefit from innovative therapy.

Long-term results of large prospective trials in childhood acute lymphoblastic leukemia.

Much progress has been made in the biological characterization of acute lymphoblastic leukemia (ALL). Many biologic features with prognostic significance have been used together with clinical factors to define patient groups for risk-adapted therapy. However, it is well recognized that the prognostic significance of virtually all variables depends on the type and intensity of treatment. The differences in risk classification, eligibility (eg upper or lower age limit) and composition of ethnic or racial population have made it difficult to compare results between study groups. The comparison is further complicated by the inclusion of only subsets of patients in some publications. In October 1985, an international workshop (organized by R Mastrangelo) was held in Rome during which recommendations were made to report study results by common, easily available criteria (age and presenting leukocyte count); to collect prospectively information on organ involvement, immunphenotype, genetics and treatment response; and to use standard statistical methods to analyze data.4 Despite this effort, different risk classifications continue to be used, and a large number of clinical trials had been conducted on subgroups of ALL, especially in the USA. In 1993, the US National Cancer Institute organized a workshop for the US cooperative study groups and major institutions to develop uniform risk criteria. The recommendations published in 19965 were more widely accepted. The major groups defined by age and leukocyte count were identical to that of the Rome workshop (Table 1). While the importance of cytogenetics and molecular genetics were recognized, they were not included in the risk criteria because the tests were not widely available at that time. The

ANTIMONIOTUNGSTATE (HPA 23) TREATMENT OF THREE PATIENTS WITH AIDS AND ONE WITH PRODROME

The antiviral activity of HPA 23 was assessed by viral isolation studies in the lymphocytes of 4 patients with acquired immunodeficiency syndrome (AIDS) or related syndromes. HPA 23 reduced lymphadenopathy-associated virus (LAV) in all 4 patients. LAV could no longer be detected in peripheral blood lymphocytes during or after treatment. Assays of infectivity showed that HPA 23 was inhibiting virus replication without killing virus infected cells. LAV was not isolated for 1 month after the end of treatment in 2 patients; in the remaining 2 patients LAV was detectable by co-cultivation indicating incomplete inhibition. This is the 1st demonstration of inhibition of the growth of LAV in AIDS patients. Particularly significant is the clinical improvement observed in the study subject who has been followed for 1 year after the end of HPA 23 treatment--an AIDS patient with cerebral toxoplasmosis. On the other hand it remains to be established whether antiviral drugs can cure AIDS. Inhibition of LAV replication may not completely correct complex autoimmune dysfunctions.

Interleukin-6 and interleukin-1β production in a pediatric plasma cell granuloma of the lung

Plasma cell granuloma (PCG) is a pseudotumor of unknown origin. It is frequently accompanied by acute-phase clinical and biological signs that resume after complete surgical removal, suggesting production of soluble mediators. We therefore investigated the role of cytokines in a previously healthy 10-year-old boy with a PCG of the lung and systemic symptoms. In this case, very high serum levels of interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6) were found before tumor excision, associated with inflammatory signs including major hyper-gamma-globulinemia. Pathologic analysis of the tumor showed an accumulation of fibroblasts and plasma cells producing immunoglobulins. Local production of IL-1 beta and IL-6 could be demonstrated at the messenger RNA (mRNA) level by the reverse transcriptase polymerase chain reaction and could be attributed to inflammatory cells by in situ hybridization and immunohistochemistry, whereas plasma cells exhibited membrane expression of the IL-6 receptor. Postsurgery follow-up showed rapid normalization of serum IL-1 beta and IL-6, whereas inflammatory protein levels decreased. This confirms the local production of cytokine within the PCG and raises the question of whether a dysregulation of cytokine production initiates the disease.

Delineation of a 6 cM commonly deleted region in childhood acute lymphoblastic leukemia on the 6q chromosomal arm

Deletion of the long arm of human chromosome 6 in acute lymphoblastic leukemia (ALL) has been shown by cytogenetic studies in 4–11% of cases. To characterize further the region of deletion and to precisely establish its frequency, we studied loss of heterozygozity (LOH) in 120 children with ALL using polymorphic markers located from the 6q14-15 chromosomal band to the telomere. LOH was detected in eight patients. A single region of LOH, flanked distally by D6S1594 and proximally by D6S301 was detected. These DNA markers are separated by 6u2009cM and are approximately located at the 6q21-22 band. Our present results delineate a region that is likely to contain a tumor-suppressor gene involved in a subset of childhood ALLs.

Clinical and immunological restoration in patients with AIDS after marrow transplantation, using lymphocyte transfusions from the marrow donor.

The diagnosis of transfusion-associated acquired immunodeficiency syndrome (AIDS) was made in 2 patients who developed delayed opportunistic infections and severe cytopenias--56 months for the former (patient 1) and 22 months for the latter, (patient 2) following bone marrow transplantation (BMT) for aplastic anemia. In the third case, grafting for acute leukemia (patient 3) (HIV) infection was probably responsible for the failure of hematological and immunological reconstitution 8 months after allogeneic BMT. Each patient received 6 lymphocyte transfusions from the marrow donor for 3 weeks, combined with a 3-month course of low-dose recombinant alpha interferon. This treatment was followed by recombinant gamma interferon for 3 months. We showed that these 3 patients could resume a normal life for 9 months, at least, and that hematological restoration was observed. Our treatment succeeded in correcting the defect of proliferative response to Candida and the impairment of gamma interferon generation for 4 months in one patient and for more than 12 months in the other two recipients. Nevertheless T4 lymphocyte levels increased only slightly and HIV can still be isolated from the patients blood. At the time of writing, patients 1 and 3 remain in good health with a partial immunological restoration while patient 2 has died of neurological impairment 2 years after the AIDS diagnosis. Although we cannot generalize this successful therapeutic approach to all patients with AIDS, the results may provide an interesting model of the potential effect of lymphocyte transfusions and the role of interferon therapy.

A competitive PCR-based method using TCRD, TCRG and IGH rearrangements for rapid detection of patients with high levels of minimal residual disease in acute lymphoblastic leukemia.

A competitive PCR-based method using TCRD , TCRG and IGH rearrangements for rapid detection of patients with high levels of minimal residual disease in acute lymphoblastic leukemia

Clinical significance of cytomegalovirus viremia in bone marrow transplantation

Cytomegalovirus (CMV) viremia was systematically studied in 56 patients having undergone bone marrow transplantation for leukemia or aplastic anemia. Of the patients who survived at least three months, 57% had CMV viremia with a frequency peak between the 7th and the 9th weeks. We describe possible clinical signs associated with viremia, particularly late peripheral and/or central thrombocytopenia. The occurrence of viremia was studied according to the specific preexisting immune status of recipients and donors; granulocyte transfusions and graft-versus-host disease. The relationship between these parameters and viremia provides a basis for the analysis of prophylactic treatments of CMV infection.

High-resolution allelotype analysis of childhood B-lineage acute lymphoblastic leukemia

Knowledge of the patterns of allelic loss has been useful in identifying tumor suppressor genes in many solid tumors. Although the loss of genetic material in acute lymphoblastic leukemias has been documented by cytogenetic studies and microsatellite typing, a global overview of losses of heterozygosity occurring throughout the genome was not yet available. We have performed a high resolution allelotype analysis in 63 childhood B-lineage acute lymphoblastic leukemia. A total of 247 microsatellite markers, evenly distributed along the autosomes were typed in blast and in remission samples from every patient. An average of 41 patients were informative for each marker. LOH at one or several loci was observed in 41 of the 63 patients (64%). The mean values for the fractional allelic loss (FAL) and the hemizygosity index, calculated for each patient, were 0.03 (range 0 to 0.23) and 0.024 (range 0 to 0.18), respectively. The most frequently involved chromosomal arms were 9p (36%), 12p (31%), 20q (15%), 6q (12%), 5p (10%) and 10p (10%). Three regions on chromosomal arms 9p, 12p and 6q were previously identified as the targets of recurring deletions, the target genes being identified for two of them (9p and 12p). The three new regions defined by this allelotype may contain tumor-suppressor genes implicated in the initiation or progression of childhood B-ALLs.