Detection of residual leukemic cells in adult acute lymphoblastic leukemia by analysis of gene rearrangements and correlation with early relapses.
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Adolescent↗
Biomedical subjects
A D Ho
Publications and source records attributed to A D Ho.
Detection of circulating monoclonal lymphocytes in multiple myeloma patients by analysis of gene rearrangements: correlation with progressive disease.
Multiple myeloma is characterized by the proliferation of a monoclonal plasma cell population that essentially spreads in the bone marrow. However, immunological data and studies on clonal gene rearrangements have provided evidence for circulating malignant B-lymphocytes. Herein, we report on the detection and clinical significance of monoclonal lymphocytes in the peripheral blood of multiple myeloma patients. Applying the analysis of immunoglobulin gene rearrangements, clonal circulating lymphocytes were found in 8 out of 37 patients. In three of these eight patients, DNA from the bone marrow could be examined as well, and the same gene rearrangement as in peripheral blood was detected. This observation indicates that the monoclonal lymphocytes in the peripheral blood are part of the malignant plasma cell clone in the bone marrow. There was a strong correlation between progressive stage III disease and the detection of circulating tumour cells, whereas neither in stable stage III nor stage I disease could clonal gene rearrangements be detected. Our findings indicate the high incidence of monoclonal lymphocytes in the peripheral blood from patients with progressive multiple myeloma. This may be of importance with respect to cell harvesting strategies for autologous peripheral stem cell transplantation in multiple myeloma.
Aged↗
Long-term follow-up of patients with hairy cell leukaemia treated with pentostatin: lymphocyte subpopulations and residual bone marrow infiltration.
Peripheral blood lymphocyte (PBL) subsets and bone marrow biopsies were analysed in six patients with hairy cell leukaemia (HCL) treated with 2'-deoxycoformycin (pentostatin, DCF) according to a phase II trial of the EORTC Leukemia Cooperative Group. All patients responded to DCF with four complete and two partial remissions according to conventional criteria. Within the PBL subsets, major changes concerned the CD4+ T cells, which during DCF therapy were distinctly suppressed to nadir values of 0.038-0.18 (median 0.126) x 10(9)/l. In five patients these cells returned to normal 3.0-49.5 (median 14.5) months after the last DCF injection. CD8+ cells were decreased to a lesser extent, and NK cell numbers improved during treatment. Bone marrow immunohistology applying the MoAb B-ly7 demonstrated residual hairy cells (HCs) in all of the six patients following DCF treatment with nadir HC numbers of 0.2-3.0% of bone marrow cells. Immunoglobulin gene rearrangement analysis of DNA obtained from these biopsies showed only germline bands, whereas rearranged bands had been present on the pretreatment specimens. Within the observation period of 15.5-54.0 (median 47.0) months after discontinuation of DCF therapy, immunohistology demonstrated a continuous increase in HC numbers in five of the six patients with clonal rearrangement detectable in bone marrow specimens from three of these patients at last follow-up date. Although established on the basis of a small number of patients, these data suggest that DCF treatment as currently employed in HCL is unable to eradicate the malignant B cell clone.
Adult↗
Optimal timing for collections of blood progenitor cells following induction chemotherapy and granulocyte-macrophage colony-stimulating factor for autologous transplantation in advanced breast cancer.
Circulating progenitor cells collected during periods of rapid hematopoietic reconstitution can be used successfully as hematopoietic support for super-dose chemotherapy. A major problem for collection of peripheral blood progenitor cells has been determination of optimal time to start leukapheresis and of the adequate amount of progenitor cells. This study has demonstrated that an induction chemotherapy with augmented dosage of CEF (cyclophosphamide, epirubicin, 5-fluorouracil) in conjunction with granulocyte-macrophage colony-stimulating factor (CM-CSF) successfully mobilized peripheral blood progenitor cells in 15 patients with metastatic breast cancer. By monitoring the granulocyte-macrophage colony-forming units (CFU-GM), erythrocyte burst-forming units (BFU-E), and CD34+ cells in peripheral blood daily after leukocyte nadir, we have identified an optimal 'window' in which concentrations of blood progenitor cells reached a maximum range. Although the time interval between chemotherapy and the time for maximum stimulation could vary from between 13 days to 19 days, maximum mobilization started consistently 2 days after the white blood cells (WBC) recovered to > 2.0 x 10(9)/l after nadir, and remained elevated for 4 to 5 days. A significant reduction of progenitor cells in peripheral blood and in the corresponding leukapheresis products was observed, however, from cycle 1 versus subsequent cycles (p < 0.0001), but there was no significant difference between cycles 2 and 3. When used as the sole source of hematopoietic support for super-dose chemotherapy with cyclophosphamide, mitoxantrone, and carboplatin, these progenitor cells induce rapid and sustained reconstitution in all patients. The median time from reinfusion to recovery of absolute neutrophil count (ANC) to > 0.5 x 10(9)/l was 13 days (range 9-18 days) and to an unmaintained platelet count of > 50 x 10(9)/l, 12 days (range 10-35 days). Autologous transplantation with stimulated blood progenitor cells can be an efficient alternative to bone marrow transplantation. With optimal timing for collections, as few as two leukapheresis procedures are required to obtain an adequate progenitor cell dose.
Adolescent↗
Idarubicin/cytosine arabinoside and mitoxantrone/etoposide for the treatment of de novo acute myelogenous leukemia.
Since January 1989, 56 patients (31 females and 25 males) with de novo acute myelogenous leukemia have been included in the study. Their median age was 43 years (range, 15 to 60 years) with a distribution according to French-American-British morphologic subtypes as follows: six M1, 14 M2, four M3, 19 M4, nine M5, two M6, and two M7. The induction regimen (IDAC) consisted of idarubicin (12 mg/m2/d intravenously [IV] days 1 to 3) in combination with cytarabine (100 mg/m2/d continuous IV days 1 to 7). Patients achieving complete remission (CR) or partial remission received another cycle of IDAC followed by NOVE (mitoxantrone 10 mg/m2/d IV days 1 to 5 and etoposide 100 mg/m2/d IV days 1 to 5). Fifty-four patients are evaluable for response: after two cycles of IDAC, 42 patients had attained CR (78%), while 76% of these had already reached CR after the first cycle. Of the initial 11 nonresponders to IDAC, four obtained CR after NOVE. Thus, 46 of 54 patients (85%) achieved CR after sequential treatment with IDAC and NOVE. In the last 17 patients who entered CR or partial remission after the first cycle of IDAC, recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF; 3 micrograms/kg/d) was administered for 6 days starting 3 days prior to the second cycle of IDAC. For consolidation with NOVE, rhGM-CSF was given according to the same dosage schedule. After 72 hours of rhGM-CSF treatment, the white blood cell count showed a median 3.9-fold increase, without appearance of myeloblasts in the peripheral blood. During sequential chemotherapy, no significant complications (in particular, no major cardiac toxicity) were observed. Postremission, patients were either given bone marrow transplants, received late consolidation with high-dose cytarabine/mitoxantrone, or were followed up without any further treatment. Of the 46 patients evaluable for disease-free survival, 21 patients (45%) remain in CR with a 34% probability of disease-free survival at 37 months. The response-adapted treatment with IDAC/NOVE is effective and very well tolerated. To define the therapeutic impact of rhGM-CSF, a randomized trial will be required.
Acute Disease↗
Bcl-2 gene rearrangements in primary B-cell lymphoma of the gastrointestinal tract reveal follicular lymphoma as a subtype.
The principal objective of this study was to investigate whether follicular center cell lymphomas occur among B-cell lymphoma of mucosa-associated lymphoid tissue (MALT). We used a molecular genetic/immunohistochemical approach and analysed 21 cases with the primary site in the gastrointestinal tract. Only two bcl-2 gene rearrangements were detected in our series and were found in two out of seven lymphomas with a nodular growth pattern. A chromosomal translocation t(14;18) was demonstrated by comigration of rearranged bcl-2 and JH sequences in one of these two cases. Additionally, both lymphomas showed bcl-2 protein positive neoplastic follicles, CD10 expression, and lack of vimentin. Therefore, these two cases were defined as follicular lymphomas. In contrast to the two follicular lymphomas of MALT, three other, nodular growing, bcl-2 protein positive lymphomas were found to have no bcl-2 gene rearrangements, to be CD10 negative and to express vimentin. These three lymphomas might be composed of neoplastic extrafollicular cells which secondarily invaded reactive follicles. We conclude that the presence of bcl-2 protein positive follicles is consistent with both a follicular and extrafollicular origin of a B lymphoma of MALT. However, the detection of a bcl-2 gene rearrangement is the most valuable criterion in such a situation, and additional immunophenotypic criteria, such as CD10 expression and lack of vimentin within the neoplastic population, further substantiate the diagnosis of a follicular lymphoma in MALT.
Adult↗
S1 nuclease hypersensitive sites in an oligopurine/oligopyrimidine DNA from the t(10;14) breakpoint cluster region.
Recurring chromosomal translocations are frequently seen in cancers, especially in leukemias and lymphomas. The genes affected by these chromosomal translocations appear to play an important role in oncogenesis. The mechanism underlying the formation of chromosomal translocation is a subject under extensive study. In chromosomal translocations involving the Ig and TCR loci, complete heptamer-spacer-nonamer signal motifs are usually present at the break of the Ig and TCR genes, indicating the involvement of V-D-J recombinase(s). On the other hand, in only about 50% of the cases signal motif sequences have been found at the break in the other participating chromosome, suggesting that different mechanisms may be involved in the scission of the corresponding chromosome. Here we report the identification of an oligopurine/oligopyrimidine DNA in the t(10;14) breakpoint cluster region associated with T-cell acute lymphoblastic leukemia. S1 nuclease mapping revealed multiple S1 hypersensitive sites in the oligopurine/oligopyrimidine DNA. These data suggest a role for oligopurine/oligopyrimidine sequences (non-B DNA) in the formation of chromosomal translocation.
Base Sequence↗
Deficiency in interferon production of peripheral blood leukocytes from patients with non-Hodgkin lymphoma.
In search for a rationale for the use of interferons (IFNs) in treatment of non-Hodgkin lymphoma (NHL), we have investigated the IFN system of 13 patients with low-grade NHL, 15 patients with high-grade NHL, and 20 patients with chronic lymphocytic leukemia or leukemic immunocytoma (CLL/IC). Production of IFN induced by phytohemagglutinin (PHA), concanavalin A (Con A), pokeweed mitogen (PWM), Corynebacterium parvum, Herpes simplex virus (HSV), Newcastle disease virus (NDV), and interleukin 2 (IL-2) were studied in the peripheral leukocytes from the patients and from 21 control persons by means of a whole blood technique. All three groups of patients with NHL had significantly reduced production upon stimulation by NDV (p ranged between 0.0038 and less than 0.0001) compared to controls. Similarly, C. parvum also induced lower titers of IFN in the leukocytes of patients with non-leukemic NHL (p = 0.0015 for low-grade NHL and p = 0.0038 for high-grade NHL). When stimulated by PHA, the IFN response of all groups of patients was within normal range. With the exception in low-grade NHL, Con A also induced normal titers of IFN in the patients with NHL. The levels of IFN induced by PWM, HSV, and IL-2 were very low and no differences between controls and patients could be found. As NDV and C. parvum induce mainly IFN-alpha and the mitogens PHA and Con A mainly IFN-gamma, our results suggest that there is a deficiency in the IFN-alpha response in the patients with NHL but normal response in IFN-gamma.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Genomic organization of the putative human homeobox proto-oncogene HOX-11 (TCL-3) and its endogenous expression in T cells.
The HOX-11 (TCL-3) gene, which is abnormally expressed in the leukemic cells of some patients with T-cell acute lymphoblastic leukemia, is a new member of the homeobox gene family. It is structurally altered by the t(10;14) chromosomal translocation, resulting in head-to-tail juxtaposition of HOX-11 with the T-cell receptor delta-chain gene. In order to understand the normal functions of HOX-11 and its role in T-cell leukemia, we have determined the exon-intron structure of the HOX-11 gene. By using oligonucleotide primers flanking an intron of the HOX-11 gene, we have developed a quantitative reverse transcription-polymerase chain reaction (RT-PCR) assay for the expression of HOX-11. We detected HOX-11 expression in multiple cell lineages including normal T cells and two T-cell lines in which the HOX-11 gene appeared to be unaltered in structure. Our results suggest that deregulation of the endogenous expression of HOX-11 in normal T cells represents an essential step towards the formation of this type of T-cell leukemia.
Amino Acid Sequence↗
Induction of intracellular and plasma 2',5'-oligoadenylate synthetase by pentostatin.
Similar to interferon alpha, pentostatin is highly effective in hairy cell leukemia and moderately active in other chronic lymphoid malignancies. In ten patients with hairy cell leukemia (HCL) and seven patients with other B-cell chronic leukemias (BCL), we have studied the intracellular 2',5'-oligoadenylate synthetase (2,5OAS) activity of the mononuclear cells before, 4 h, 24 h, and 48 h after pentostatin administration. In patients with HCL the median level of intracellular 2,5OAS increased 4.6-fold at 4 h and 11.5-fold at 24 h compared to the pretreatment value. Among the other seven patients, the median intracellular 2,5OAS remained unchanged in three patients and rose slightly by 2 to 14 times in four patients. Eleven patients (eight with HCL and two with BCL) responded to pentostatin. The median increase in 2,5OAS among the responders was 13.0-fold (range 4.8-30.0) whereas that among non-responders was 2.2-fold (range 0.2-6.3). The difference was highly significant (p less than 0.0001). In five of the total seventeen patients, the plasma levels of 2,5OAS activity were also determined and changes in plasma levels paralleled those measured intracellularly. To determine if the elevation of 2,5OAS is mediated by induction of interferon alpha, the expressions of mRNA for interferon alpha and beta were investigated by means of reverse transcription and polymerase chain reaction using the corresponding sense primers. In none of the five patients thus studied could we find an induction of mRNA for interferon alpha or beta in the leukemic cells during treatment with pentostatin. Thus, response to pentostatin correlates with induction of 2,5OAS directly and the 2',5'-oligoadenylate system seems to be involved in cytotoxicity.
2',5'-Oligoadenylate Synthetase↗
Detection of bone marrow infiltration by non-Hodgkin's lymphoma--comparison of histological findings, analysis of gene rearrangements, and examination by magnetic resonance imaging.
The histological examination of bone marrow specimens is one of the standard procedures in staging non-Hodgkin's lymphoma. To investigate the validity of a conventional unilateral iliac crest biopsy, we performed a prospective study comparing histological findings with analysis of gene rearrangements in bone marrow samples and magnetic resonance imaging of bone marrow. Twenty-seven consecutive patients with non-Hodgkin's lymphoma (ten with high grade, seventeen with low grade) were studied. In twelve patients, histological examination revealed bone marrow infiltration. Results of histology and magnetic resonance imaging were discordant in three of the twenty-seven patients. With magnetic resonance imaging, suspected infiltration was found in two patients without histological evidence for bone marrow involvement in the disease. In one patient, an infiltration was described by histology but MRI revealed no pathological findings. In this case, DNA analysis confirmed bone marrow infiltration by detection of a clonal rearrangement of the immunoglobulin heavy chain gene. Analysis of gene rearrangements was performed in ten patients. As examined by histology, five of them had bone marrow involvement in the disease and five had not. In all these cases, analysis of gene rearrangements confirmed the histological findings. Our data show that, despite the small volume of bone marrow specimens, the sensitivity of an iliac crest biopsy seems to be high in staging non-Hodgkin's lymphoma.
Adult↗
Etoposide in acute leukemia. Past experience and future perspectives.
Etoposide as a single agent is active in relapsed and refractory acute myelogenous leukemia (AML), with complete responses (CR) rates of 10% to 25%. The drug has been safely combined with cytarabine, azacytidine, vinca alkaloids, and anthracyclines, inducing remission rates of 20% to 60% in patients with previously treated AML. The experience with etoposide in acute lymphoblastic leukemia is less extensive, but the drug seems to be active in combination with cytarabine or aclacinomycin. In addition, etoposide is combined with cytarabine and anthracyclines for the primary treatment of AML. The response rates thus achieved are comparable with those obtained with standard regimens. A Phase I/II trial was initiated to study the efficacy of the NOVE combination (mitoxantrone [10 mg/m2/d, days 1 to 5] plus etoposide [100 mg/m2/d for 3, 4, or 5 days] in patients with refractory AML. The results showed that extended duration of etoposide administration is associated with higher CR rates. Overall, a CR rate of 43% was achieved in 61 patients. A sequential regimen with IDAC (idarubicin/cytarabine) and NOVE was designed for primary treatment of adult patients with AML. Cycles of IDAC or NOVE are applied depending on response. The results of the pilot study with this strategy were encouraging with 18 of 20 patients achieving CR. Further studies are under way to verify the efficacy of this strategy.
Antineoplastic Combined Chemotherapy Protocols↗
The tcl-3 proto-oncogene altered by chromosomal translocation in T-cell leukemia codes for a homeobox protein.
The t(10;14)(q24;q11) chromosomal translocation found in malignant cells of 5-10% of patients with T-cell acute lymphoblastic leukemia (T-ALL) involves the T-cell receptor delta chain gene on chromosome 14 and a breakpoint cluster region on chromosome 10. The candidate proto-oncogene tcl-3, thought to be involved in the pathogenesis of t(10;14) T-ALL, was cloned and found to be elevated in expression in leukemic cells harboring the t(10;14) translocation. Sequence analysis revealed that tcl-3 is a new homeobox-containing gene. Comparison of the tcl-3 cDNA and its 5' genomic sequences with DNA sequences from the t(10;14) translocation breakpoints showed that this gene is structurally altered in four patients with t(10;14)(q24;q11) T-ALL. These findings suggest that homeobox-containing genes that normally act as transcription factors may contribute to T-cell leukemogenesis when abnormally expressed.
Amino Acid Sequence↗
Decrease in soluble CD8 antigen levels in splenectomized patients as an index for reduced suppressor/cytotoxic cell activity.
To investigate the effect of splenectomy on lymphocyte subpopulations we monitored changes in serum concentrations of soluble suppressor/cytotoxic (sCD8) and soluble helper/inducer (sCD4) antigen in 11 splenectomized patients. Indications for splenectomy were hereditary spherocytosis in 2, idiopathic thrombocytopenic purpura in 2, gastric carcinoma in 4, Hodgkin's disease in 2 and pancreatitis in 1 patient. Lymphocyte subpopulations were also analyzed by means of conventional immunophenotyping with monoclonal antibodies to CD4 and CD8. We consistently found an early postoperative drop of sCD8 and sCD4 levels within the first week after splenectomy, paralleling changes in the percentages of CD4+ and CD8+ lymphocytes. While alterations of lymphocyte subsets in the peripheral blood were completely reversible and sCD4 levels returned to preoperative values, sCD8 concentrations remained suppressed even 3 months after splenectomy. SCD8 levels at the nadir and those 3 months after splenectomy were significantly lower than preoperative values (P = 0.003, P = 0.149 respectively). Since sCD8 levels reflect suppressor/cytotoxic cell activity, we suggest that suppressor cell activity is reduced in splenectomized patients.
Adult↗
Chemotherapy of chronic haematological malignancies.
After years of stagnation in the treatment of chronic haematological malignancies, some interesting agents have emerged which might improve the prognosis of these diseases. For chronic leukaemias of lymphoid lineage, three new chemical agents, all purine analogues, seem to be of particular interest. Pentostatin is a specific inhibitor of ADA and has been shown to be highly efficient in producing CR in patients with HCL. Its relative merit compared with IFN-alpha for the treatment of HCL is being studied in ongoing randomized trials. Pentostatin is also active in B-CLL and promising activities have been demonstrated in T- or B-PLL and ATCL. Fludarabine is an analogue of adenine which is resistant to the deamination of ADA. It has been reported to be highly active for patients with both pretreated or non-treated B-CLL. CR rates of 13% with overall response rates of 57% can be achieved, even in heavily pretreated patients. Its activity in the other lymphoid malignancies is not yet known. CdA, a substrate analogue of ADA, has also produced encouraging results in B-CLL, HCL and T cell malignancies, and in some patients with just one single course. Thus far, experience with this drug comes from one institution and requires further confirmation. For chronic myeloproliferative diseases, little progress has yet been made. Although IFN-alpha seems to be active in CML and to result in cytogenetic remissions in bone marrow, a definite advantage of this biological agent over conventional chemotherapy as regards survival and life quality has not yet been proven. Allogeneic bone marrow transplantation is beneficial for those patients who are eligible. No remarkable advances have been made in the treatment of myeloproliferative disorders except for the development of an antiplatelet drug, anagrelide. This agent seems to be highly effective in controlling thrombocytosis. The relative merit of this agent as compared with IFN-alpha, as well as the impact of this agent on the survival and on life-quality of patients with myeloproliferative disorders, have yet to be defined.
Antineoplastic Agents↗
Utilization of recombinant human GM-CSF to enhance peripheral progenitor cell yield for autologous transplantation.
Evidence has accumulated which indicates that efficacy of chemotherapy correlates with dose intensity and with total dose. For most cytotoxic agents, the major limiting factor for escalation of dose intensity is myelotoxicity. Attempts have been made to circumvent myelotoxicity by autologous bone marrow transplantation. Recently, it has been demonstrated that progenitors enriched from the peripheral blood can also be used successfully for autografting. The concentration of progenitor cells in peripheral blood is lower than that in bone marrow but myelosuppressive chemotherapy or hematopoietic growth factors, or a combination of both can be exploited to enhance the progenitor cell yield. The studies reported here are sequential. In the first study, eight patients with advanced Hodgkin's disease received myelosuppressive regimen consisting of cytarabine (100 mg/m2/12h SC days 1 to 5) and daunorubicin (45 mg/m2/d, days 3 and 4). Progenitor cell leukapheresis was performed during the rebound phase of hematopoiesis. All eight patients were treated with super-dose chemotherapy with progenitor cell transplantation. One patient died of CNS toxicity 48 days after transplantation but all other seven had sustained engraftment. In the second study, human recombinant GM-CSF (at 250 micrograms/m2/d as continuous infusion) was administered to twelve patients. Leukapheresis was started at a white blood count (WBC) of greater than 10 x 10(9)/L and the dosage of rhGM-CSF adjusted to keep the WBC between 10 x 10(9)/L and 20 x 10(9)/L. The median duration of rhGM-CSF application was 11.5 days and a median number of six leukaphereses performed. The median increase in the number of granulocyte-macrophage colony forming units (CFU-GM)/ml of peripheral blood was 8.5 fold.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Assessment of bone marrow infiltration by magnetic resonance imaging in patients with hairy cell leukemia treated with pentostatin or alpha-interferon.
The bone marrow of five patients with progressive hairy cell leukemia was examined histologically and by magnetic resonance imaging in a prospective study. Iliac crest biopsies and magnetic resonance scans were performed before and after nine months of therapy with pentostatin (four patients) and alpha-interferon (one patient). T1-weighted scans were evaluated quantitatively and in terms of their visual appearance in three regions of interest (lumbar spine, pelvis and femur). In contrast to bone marrow histology, it was possible to detect differences in the degree of infiltration between these marrow regions in four patients by magnetic resonance imaging. After treatment, three patients had no residual bone marrow infiltration as determined histologically; in parallel, the magnetic resonance images had normalized. The remaining two patients achieved partial remission: marrow infiltration was estimated to be 20% histologically, corresponding well to the signal reduction obtained by magnetic resonance imaging. These data suggest that magnetic resonance imaging of the bone marrow is a sensitive method for assessing responses to treatment with pentostatin and alpha-interferon in patients with hairy cell leukemia.
Adult↗
[The therapy of hairy-cell leukemia].
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Combined Modality Therapy↗