11/50. Pulsed ATRA as single therapy restores long-term remission in PML-RARalpha-positive acute promyelocytic leukemia patients: real time quantification of minimal residual disease. A pilot study.All-trans retinoic acid (ATRA), alone or combined with chemotherapy (CHT) is widely used to induce complete remission (CR) in newly diagnosed acute promyelocytic leukemia (APL). If used alone, ATRA results in a substantial proportion of CRs. To maintain remission further, ATRA is commonly used with cycles of CHT, frequently followed by autologous (auto) or allogeneic (allo) stem cell transplantation (SCT), as early reports have shown that the continuous administration of ATRA as single therapy almost invariably leads to relapse in a short period of time (months). Pharmacokinetic studies have shown that induced resistance to ATRA is frequently suppressed by the intermittent use of the drug. In this study we applied an intermittent therapeutic protocol with ATRA in five APL patients who were either molecularly refractory after combined ATRA/CHT treatment, or relapsed, or at diagnosis, but not eligible for the combination treatment because of previous toxicity. They were treated with ATRA (45 mg/m2/day) for 21 days. The treatment was then prolonged continuously for 1 week every 2 weeks. Molecular analysis was performed by qualitative and quantitative reverse transcription-polymerase chain reaction (RT-PCR). All patients obtained molecular remission, as assessed by qualitative RT-PCR, in a median of 3 months (range 1-15). Quantitative RT-PCR confirmed these data, showing a progressive reduction (1 or 2 logs) to a 'negligible quantity' of PML-RARalpha fusion transcript (ratio PML-RARalpha/ABL x 10(4) ABL < 10(-1)) in all but one patient treated with pulsed ATRA therapy. These data were confirmed with qualitative and quantitative RT-PCR. After a median follow-up of 17 months from the start of ATRA therapy, 4/5 patients (80%) are in continuous complete molecular remission. To our knowledge, this is the first clinical observation that intermittent ATRA therapy (without chemotherapy) is effective not only in inducing but also in maintaining long-term molecular remission in APL patients. This approach could therefore be effective, if confirmed in larger series, in relapsed/refractory patients unsuitable for high-dose therapy and SCT; it may be proposed as induction therapy for selected older APL patients if considered not to be eligible for combined ATRA/CHT due to inadequate performance status or concurrent disease.- - - - - - - - - - ranking = 1keywords = leukemia (Clic here for more details about this article) |
12/50. Early relapse after high-dose chemotherapy rescued by tumor-free autologous peripheral blood stem cells in acute lymphoblastic leukemia: importance of monitoring for WT1-mRNA quantitatively.A 24-year-old woman who suffered from ALL with MLL gene rearrangement received high-dose chemotherapy followed by autologous PBSC transplantation during complete remission (CR). Reverse transcriptase-polymerase chain reaction (RT-PCR) used to detect MLL/LTG4 chimeric mRNA showed no minimal residual disease (MRD) in the graft or bone marrow at the transplantation. However, the leukemia relapsed four months after transplantation. Retrospective analysis of quantitative measurement of wilms tumor gene (WT-1) mRNA showed an increased level in the bone marrow although it was within the normal range. These observations suggest that careful monitoring of MRD by quantitative measurement of WT-1 mRNA in addition to disease-specific chimeric mRNA is required to predict relapse.- - - - - - - - - - ranking = 1keywords = leukemia (Clic here for more details about this article) |
13/50. Hematologic and cytogenetic remission by STI571 (Glivec) in a patient relapsing with accelerated phase CML after second allogeneic stem cell transplantation.We describe the clinical activity of the ABL kinase inhibitor STI571 in a patient with accelerated phase of chronic myeloid leukemia (CML) relapsing after a second allogeneic BMT and with minimal levels of donor chimerism. STI571 resulted in rapid elimination of leukemic cells with ensuing prolonged severe leukopenia and neutropenia complicated by neutropenic fever and colitis. Subsequent hematopoietic recovery was driven by donor derived cells and was associated with grade 3 graft-versus-host disease (GVHD). STI571 induced sustained hematological and cytogenetic remission combined with controllable GvHD, therapeutic goals not achieved by two preceding allogeneic transplants and repeated donor lymphocyte transfusions (DLT).- - - - - - - - - - ranking = 0.2keywords = leukemia (Clic here for more details about this article) |
14/50. Eradication of residual bcr-abl-positive clones by inducing graft-versus-host disease after allogeneic stem cell transplantation in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia.Persistence of bcr-abl transcripts after marrow grafting is thought to convey a high risk for relapse in patients with philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). Donor leukocyte infusion (DLI) is closely associated with development of graft-versus-host disease (GVHD) and has well-defined activity against relapsed chronic myelogenous leukemia (CML) but not ALL. We report two patients with Ph-positive ALL who remained bcr-abl positive by reverse transcriptase polymerase chain reaction (RT-PCR) after marrow grafting. Residual bcr-abl transcripts in both patients were eliminated following acute GVHD, which was induced by either DLI or rapid reduction of immunosuppression. Both patients have continued in complete molecular remission for 18 months and 8 months following transplantation, respectively. Our observation suggests that induction of GVHD may eliminate minimal residual disease, thereby preventing leukemia relapse in patients transplanted for Ph-positive ALL.- - - - - - - - - - ranking = 1.4keywords = leukemia (Clic here for more details about this article) |
15/50. Detection of minimal residual disease in peripheral blood stem cells from two acute myeloid leukemia patients with trisomy 8 predicts early relapse after autologous bone marrow transplantation.We report two cases of acute myeloid leukemia (AML) French-American-British M4 classification with trisomy 8 at diagnosis as the sole chromosome abnormality. Both patients were treated with the GIMEMA AML-10 protocol and underwent autologous bone marrow transplantation (ABMT) in hematologic remission. Peripheral blood stem cells (PBSC), and bone marrow in one patient, were collected after consolidation therapy and tested by fluorescence in situ hybridization (FISH) analysis with an alpha-satellite probe for chromosome 8. It revealed that all samples were positive for minimal residual disease (MRD) as the value of trisomic cells exceeded the mean 3 standard deviations of the controls. ABMT was done following a myeloablative regimen (busulphan/cyclophosphamide) and PBSC were reinfused. Both patients relapsed, 4 and 2 months, respectively, after autotransplant. Although more data are needed, these results suggest that the persistence of MRD, as detected by FISH, in stem cell collections, is associated with a poor outcome in AML patients with trisomy 8 undergoing ABMT.- - - - - - - - - - ranking = 1keywords = leukemia (Clic here for more details about this article) |
16/50. Multiple bone lesions after allogeneic bone marrow transplantation in a patient with relapsed adult acute lymphoblastic leukemia: minimal residual disease analysis may predict extramedullary relapse.We describe a patient with acute lymphoblastic leukemia (ALL, L2) who relapsed with multiple bone lesions after allogeneic bone marrow transplantation (allo-BMT). Allo-BMT was performed from an HLA-identical sibling during the first hematological complete remission (CR). Minimal residual disease (MRD) assessed by polymerase chain reaction (PCR) with primers for T cell receptor delta (TCRdelta) gene became positive in the bone marrow sample on day 46 after allo-BMT. On day 113, the patient complained of a painful tumor at the right clavicle. The examination of biopsy specimen revealed infiltration of leukemic cells. After partial response was achieved by local radiotherapy, disseminated bone lesions were demonstrated by 99mTC scintigraphy scan, followed by bone marrow relapse on day 137. The patient died of cardiac tamponade on day 236 after Allo-BMT. MRD assessed by PCR assay for TCRdelta gene in the bone marrow is useful for the prediction of extramedullary as well as medullary relapse after BMT.- - - - - - - - - - ranking = 1keywords = leukemia (Clic here for more details about this article) |
17/50. Monitoring minimal residual disease in patients with MLL-AF6 fusion transcript-positive acute myeloid leukemia following allogeneic bone marrow transplantation.Acute myeloid leukemia (AML) patients with chromosome 11q23 abnormalities or MLL rearrangements have a poor prognosis when treated with conventional chemotherapy. However, the efficacy of allogeneic bone marrow transplantation (BMT) for this type of leukemia is not yet clear. We describe 2 MLL-AF6 fusion transcript-positive AML patients treated with allogeneic BMT who were monitored for minimal residual disease (MRD) by reverse transcriptase polymerase chain reaction. Although long survival or cure of this type of AML is rarely reported, 1 patient had durable remissions. Fusion transcripts disappeared in 1 patient but not in the other, even after the graft-versus-host disease effect was increased by the discontinuation of immmunosuppressive therapy. This is the first report of MRD and the probability of graft-versus-leukemia effects following BMT in AML patients who are MLL-AF6 fusion transcript positive.- - - - - - - - - - ranking = 1.4keywords = leukemia (Clic here for more details about this article) |
18/50. Quantification of minimal residual disease in patients with e1a2 BCR-ABL-positive acute lymphoblastic leukemia using a real-time RT-PCR assay.Using a real-time RT-PCR method, we analyzed the expression of e1a2 BCR-ABL mRNA in bone marrow samples from 13 patients with e1a2 BCR-ABL-positive acute lymphoblastic leukemia (ALL) at different time points during chemotherapy and after bone marrow transplantation (BMT). The detection limit of the method, assessed using serial dilutions of ALL/MIK cells, was found to be 1:10(5), similar to what is observed for the conventional RT-nested PCR method. The e1a2 BCR-ABL values were normalized with respect to those of the housekeeping gene GAPDH. The decrease in the e1a2 BCR-ABL/GAPDH ratio after remission induction chemotherapy reflects well the response to chemotherapy and consequently correlates with the prognosis. Although molecular remission was achieved by chemotherapy alone, some patients relapsed, and the e1a2 BCR-ABL/GAPDH ratios in these cases progressively increased to the levels seen prior to hematological relapse. Long-term hematological complete remission (more than 30 months) could be achieved in cases in which a more than 4.0 log decrease in the e1a2 BCR-ABL/GAPDH ratio was obtained by chemotherapy alone, and BMT was then performed. In conclusion, real-time RT-PCR allows for an evaluation of the kinetics of e1a2 BCR-ABL/GAPDH expression during the various phases of chemotherapy or after BMT and may be effective for the indication and control of disease relapse in Ph-positive ALL patients.- - - - - - - - - - ranking = 1keywords = leukemia (Clic here for more details about this article) |
19/50. Assessment of minimal residual disease (MRD) in CBFbeta/MYH11-positive acute myeloid leukemias by qualitative and quantitative RT-PCR amplification of fusion transcripts.The inv(16)(p13q22) chromosomal rearrangement associated with FAB M4Eo acute myeloid leukemia (AML) subtype is characterized by the presence of the CBFbeta/MYH11 fusion transcript that can be used to detect minimal residual disease (MRD). However, qualitative RT-PCR studies of MRD have so far produced conflicting results and seem of limited prognostic value. We have evaluated retrospectively MRD in a large series of CBFbeta/MYH11-positive patients employing both qualitative and quantitative (real-time PCR) approaches. 186 bone marrow samples from 36 patients were examined with a median follow-up of 27.5 months; 15 patients relapsed during follow-up. In qualitative studies, carried out by 'nested' RT-PCR assay, all patients in complete remission (CR) immediately after induction/consolidation therapy were found to be PCR positive. However, follow-up samples at later time points were persistently negative (except one case) in patients remaining in continuous CR (CCR) for more than 12 months. 16 patients were evaluated by quantitative real-time PCR assay: CBFbeta/MYH11 transcript copy number was normalized for expression of the housekeeping gene ABL, expressed as fusion gene copy number per 10(4) copies of ABL. A 2-3 log decline in leukemic transcript copy number was observed after induction/consolidation therapy. After achieving CR, the mean copy number was significantly higher in patients destined to relapse compared to patients remaining in CCR (151 vs 9, P < 0.0001 by Mann-Whitney test). Moreover, in CCR patients, the copy number dropped below the detection threshold after the treatment protocol was completed and remained undetectable in subsequent MRD analysis in accordance with results obtained by qualitative RT-PCR. On the contrary, in the seven patients who relapsed, the copy number in CR never declined below the detection threshold; thus a cut-off value discriminating these two groups of patients could be established. The findings of our study, if confirmed, might confer an important predictive value to quantitative real-time PCR determinations of MRD in patients with inv(16) leukemia.- - - - - - - - - - ranking = 1.2keywords = leukemia (Clic here for more details about this article) |
20/50. chimerism testing and detection of minimal residual disease after allogeneic hematopoietic transplantation using the bioView (Duet) combined morphological and cytogenetical analysis.Recurrent disease remains a major obstacle to cure after allogeneic transplantation. Various methods have been developed to detect minimal residual disease (MRD) after transplantation to identify patients at risk for relapse. chimerism tests differentiate recipient and donor cells and are used to identify MRD when there are no other disease-specific markers. The detection of MRD does not always correlate with relapse risk. chimerism testing may also identify normal hematopoietic cells or other cells not contributing to relapse. In this study we report our initial experience with a novel system that provides combined morphological and cytogenetical analysis on the same cells. This system allows rapid automatic scanning of a large number of cells, thus increasing the sensitivity of detection of small recipient population. The clinical significance of MRD detection is improved by identifying the morphology of recipient cells. Identification of recipient characteristics within blasts predicts overt relapse in leukemia patients and precedes it by a few weeks to months. Identification within mature hematopoietic cells may not be closely associated with relapse. The system also allows chimerism testing after sex-mismatched transplants, within cellular subsets, with no need for sorting of cells. The system merits further study in larger scale trials.- - - - - - - - - - ranking = 0.2keywords = leukemia (Clic here for more details about this article) |
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