Stem Cells, Vol. 18, No. 5, 343-351,
September 2000
© 2000 AlphaMed Press
New Strategies in the Treatment of Acute Myelogenous Leukemia: Mobilization and Transplantation of Autologous Peripheral Blood Stem Cells in Adult Patients
Øystein Bruseruda,
Geir Tjønnfjordb,
Bjørn Tore Gjertsena,
Brynjar Fossa,
Peter Ernsta
a Division for Hematology, Department of Medicine, Haukeland University Hospital and The University of Bergen, Bergen, Norway;
b Division for Hematology, Department of Medicine, The National Hospital, Oslo, Norway
Key Words. Acute myelogenous leukemia • Autologous bone marrow transplantation • Peripheral blood stem cell • Minimal residual disease
Øystein Bruserud, M.D., Medical Department, Haukeland University Hospital, N-5021 Bergen, Norway. Telephone 47-55-29-80-60; Fax 47-55-97-29-50; e-mail: oystein.bruserud{at}haukeland.no
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ABSTRACT
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During the last decade high-dose Ara-C (HIDAC; single doses of 3 g/m2) and autologous stem cell transplantation have been increasingly used as postremission therapy in adult acute myelogenous leukemia (AML). Controlled clinical trials have demonstrated a long-term disease-free survival of 40%-50% for patients treated with at least two courses of HIDAC. Other studies have demonstrated that postremission autologous bone marrow transplantation results in a disease-free survival equal to or better than conventional chemotherapy. However, autotransplantation with mobilized peripheral blood stem cells (PBSC) would now be preferred instead of autologous bone marrow, due to the shorter hematopoietic reconstitution period. The results reviewed in the present article suggest that HIDAC and autologous PBSC transplantation can be combined in the postremission treatment of adult AML, and this combination therapy may also reduce minimal residual disease and the risk of posttransplant relapse. From the available studies it cannot be concluded whether graft purging further reduces the relapse risk. However, the possible advantage of combination therapy with repeated courses of HIDAC and autologous PBSC transplantation needs to be demonstrated in prospective clinical trials before it can be recommended as a part of the routine treatment in AML.
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INTRODUCTION
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During the last decade high-dose cytarabine/Ara-C (HIDAC) and autologous stem cell transplantation have been increasingly used in the treatment of acute myelogenous leukemia (AML) [1-8]. Controlled clinical trials have demonstrated a long-term disease-free survival of 40%-50% for patients treated with at least two courses of HIDAC [2, 3]. Other studies have demonstrated that postremission autologous bone marrow transplantation (auto-BMT) results in a disease-free survival equal to or better than conventional chemotherapy [5-8], but in these studies the control patients did not receive repeated courses of HIDAC. Furthermore, autotransplantation with mobilized peripheral blood stem cells (PBSC) instead of bone marrow (BM) would now be preferred due to the shorter period needed to achieve hematopoietic reconstitution. Thus, a major question is whether repeated cycles with HIDAC, stem cell mobilization and autotransplantation should be combined in future postremission therapy of AML.
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POSTREMISSION THERAPY IN AML
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Intensive Chemotherapy
The advantage of HIDAC was first demonstrated in a large, randomized clinical study reported by Mayer et al. [2]. This study demonstrated that for patients in remission, four courses of Ara-C at a dose of 3 g/m2 (referred to as HIDAC) twice daily for three out of five days were superior to equivalent courses of 400 or 1,000 mg/m2 given as continuous infusions over a period of five days. The overall survival rate four years after randomization was 46% in the high-dose group. Another study of HIDAC therapy reported similar results, although in that study HIDAC was combined with anthracycline plus etoposide, and only two courses were given as remission induction [3]. A dose-response effect of Ara-C seems to be present even in high-risk AML patients [4]. Taken together these data support the conclusion that the optimal therapy for AML in younger adults should include at least two courses with HIDAC [2-4]. The risk of serious neurotoxicity will limit the use of HIDAC in patients over 60 years of age [2, 9]. For selected subsets of the elderly patients, autotransplantation may thus become an alternative rather than a supplement to HIDAC.
Auto-BMT
The rationale for PBSC transplantation in AML is based on the experience with auto-BMT reported in large, randomized, clinical studies (Table 1
). Although the BM grafts were harvested after remission induction and postremission intensification in all these studies, they differed in several other aspects. First, one study used autotransplantation in addition to standard consolidation therapy [5], whereas in the other studies patients were randomized to either autotransplantation or additional chemotherapy [6-8]. Second, the studies differed with regard to chemotherapy regimens before randomization and therapy in the control arms. Only two studies included HIDAC therapy, and only one cycle was given. Third, the studies showed differences in the median time from complete hematological remission to start of the last postremission treatment, the pretransplant conditioning therapy, and the use of graft purging (Table 1). Although the long-term disease-free survival for autotransplanted patients was either similar to or better than that for control patients, it should be emphasized that none of the studies compared autotransplantation with optimal consolidation therapy including at least two HIDAC courses. Based on the present evidence, the following major conclusions thus seem to be justified: A) auto-BMT is effective as postremission therapy and seems to have an additional antileukemic effect compared with intermediate-dose Ara-C alone [5], and B) even auto-BMT is associated with a relatively high risk of posttransplant relapse and a late platelet reconstitution (Table 1).
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Table 1. Recent randomized studies comparing consolidation therapy with auto-BMT and intensive chemotherapy in AML
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THE USE OF HEMATOPOIETIC GROWTH FACTORS IN AML PATIENTS
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The most commonly used stem cell mobilization regimens are chemotherapy followed by either G-CSF or granulocyte-macrophage (GM)-CSF [10]. Interleukin 3 (IL-3) and stem cell factor (SCF) can also be used for stem cell mobilization, either as single factors or as a part of growth factor combinations [11, 12]. Because all these cytokines can function as growth factors for AML blasts [13, 14], possible harmful effects by using these agents for stem cell mobilization have to be considered.
The effect of combining G-CSF (5 µg/kg or 200 µg/m2 daily [15-18]) or GM-CSF (5 µg/kg or 250 µg/m2 daily [19-23]) with chemotherapy for AML has been investigated in several randomized clinical studies. The aims of all these studies were to investigate whether G-CSF/GM-CSF therapy could increase the susceptibility of AML blasts to chemotherapy or shorten the time until hematopoietic reconstitution. In one study the complete remission rate was decreased in GM-CSF-treated patients [21], whereas in the other studies the remission rate was either increased [17] or unaltered [15, 16, 18-20, 22, 23]. Furthermore, the long-term disease-free survival was either improved [20] or unaltered [15-19, 21-23] by growth factor therapy. These results strongly suggest that the use of chemotherapy plus G-CSF/GM-CSF for stem cell mobilization is a safe procedure even in AML patients. In contrast, the combination of IL-3 plus chemotherapy in AML has only been investigated in a small phase I/II study including 20 patients [24], and SCF therapy has not been reported in AML patients. Thus, the safety of postchemotherapy growth factor treatment has only been documented for G-CSF and GM-CSF.
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MOBILIZATION OF PBSC IN AML
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A major advantage of using autotransplantation with PBSC instead of auto-BMT is a shorter hematopoietic reconstitution, especially a shorter time until stabilization of platelet counts [25, 26]. It is often difficult to get enough PBSC and several apheresis procedures are usually needed when chemotherapy alone is used for mobilization [27], but fewer apheresis are usually needed to reach a sufficient number of stem cells when chemotherapy plus growth factors are used. PBSC can then be harvested by administering growth factor therapy directly following the first consolidation course; or PBSC can be harvested following postremission intensification and then new intensive chemotherapy plus growth factor for mobilization. Several observations support the approach of harvesting PBSC after postremission intensification. First, the antileukemic effect of auto-BMT was demonstrated in randomized studies that included postremission intensification before BM harvest (Table 1
). Second, nonrandomized studies suggest that the long-term disease-free survival is increased when stem cells are mobilized after postremission intensification [28]. Third, studies of minimal residual disease (MRD) in AML patients with t(8;21) suggest that the AML cell contamination in PBSC grafts can be reduced by postremission intensification [29].
As already mentioned the optimal conventional therapy for AML should probably include at least two courses of HIDAC [2-4]. This experience, together with the results discussed above, seems to suggest that stem cell mobilization should be done by administering G-CSF/GM-CSF after postremission intensification, e.g., following treatment with high doses of cytarabine as described in several recent studies [28, 30-35]. In all these studies G-CSF was used, and the doses corresponded to those used in previous studies of G-CSF therapy in AML (5-10 µg/kg/day, 300 µg/day or 50 µg/m2) [15-18]. The results when using cytarabine 2 and 3 g/m2 are summarized in Table 2 and demonstrate that for the majority of patients, a sufficient number of stem cells can be harvested by combining high/intermediate-dose Ara-C with G-CSF [30-34]. This conclusion is supported both by the estimation of CD34+ cells and clonogenic progenitors in the grafts, and the early hematopoietic reconstitution in autografted patients. Similar results have been described for cytarabine doses of 1.5 g/m2 [28, 35]. However, long-lasting thrombocytopenia remains a problem for a minority of patients even when using PBSC grafts (Table 2).
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Table 2. Mobilization of PBSC by G-CSF in combination with intermediate or high-dose Ara-C; studies of AML patients in first complete remission
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Stem cell mobilization with HIDAC plus G-CSF has only been investigated in patients receiving a single high-dose cycle. One would expect PBSC mobilization to be possible even in patients treated with repeated courses of HIDAC, because the time until hematopoietic reconstitution seems to be relatively short when using up to four cycles with HIDAC [2]. However, this assumption needs to be confirmed in clinical studies.
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MRD IN AML
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Detection of Abnormal Transcripts by Polymerase Chain Reaction (PCR)-Based Techniques
Detection of AML-specific transcripts encoded by translocated or mutated genes has been used for evaluation of MRD in AML [36, 37]. However, these results must be interpreted with caution because several observations suggest that abnormal transcripts do not always represent detection of a malignant disease/leukemic relapse. First, abnormal transcripts can be detected even in healthy individuals. Both the bcr-abl translocation t(9;22) [38, 39], as well as the preleukemic paroxysmal nocturnal hemoglobinuria genotype (mutations in the PIG-A gene) and phenotype [40, 41], can be present in healthy individuals. Other abnormalities that have also been detected in normals are t(14;18), t(8;14), the MLL tandem duplication and the MLL/AF4 rearrangement formed by the t(4;11) translocation [37]. It is at present unclear whether the finding of such abnormalities in normals has any impact on MRD detection and significance in AML patients. Second, a recent publication described that three independent genetic events were required for tumorigenic conversion of normal cells [42]. However, even in the case of multistep pathogenesis, one single abnormality may have a dominant role and its correction may then reverse the malignant cell phenotype [43, 44]. This may also be the case in human acute promyelocytic leukemia (APL) where epidemiological data suggest that one single step is rate-limiting [45]. Taken together these observations demonstrate that detection of a single genetic abnormality may not always represent detection of cells with a malignant phenotype (e.g., AML cells).
Even when detection of an abnormal transcript represents detection of AML cells, it may represent the detection of committed progenitors and not leukemic stem cells [46]. Furthermore, detection of leukemic stem cells may not represent early detection of AML relapse because a low burden of leukemia cells may be suppressed or eliminated by antileukemic immune reactivity [47]. The overall data thus suggest that one should be very careful when using detection of abnormal transcripts in the evaluation of relapse risk in AML.
Detection of Abnormal Transcripts in Bone Marrow
A major part of MRD studies has been done in AML patients with t(15;17) (PML-RARA transcripts in APL), t(8;21) (AML-MTG8 fusion transcripts) and inv16/t(16;16) (CBFB-MYH11 fusion transcripts). These abnormalities are associated with good prognosis [1, 48], and therefore the results may not be representative for standard or high-risk AML.
PCR-monitoring of PML-RARA was used in a prospective study of 163 patients with t(15;17) APL who were in complete remission and PCR-negative at the end of consolidation therapy, and conversion to PCR positivity was then highly predictive of subsequent relapse [49]. However, other studies using more sensitive techniques have demonstrated PML-RARA positivity even in patients in long-term remission [50], and these results indicate that there may only be a quantitative difference between long-term remitters and patients with later APL relapse.
Although several studies have demonstrated that AML1-MTG8 (ETO) transcripts can be detected in patients with t(8;21) in long-term remission, other investigators have failed to demonstrate the transcript in long-term remitters [36]. This apparent discrepancy may be explained by different sensitivities of various PCR assays [36], because recent studies suggest that increased transcript levels are detected before AML relapse compared with patients in stable remission [51, 52]. Preliminary data also suggest that the CBFB-MYH11 fusion transcript can be detected in long-term remitters with inv16/t(16;16) AML [53].
The overall results from these MRD studies are thus consistent with the hypothesis that quantitative rather than qualitative differences in the expression of abnormal transcripts are important for the prediction of relapse in patients with low-risk AML. However, with the possible exception of PCR-conversion in patients with t(15;17), detection of abnormal transcripts should be interpreted with great care in individual patients, as a possible clinical advantage of earlier relapse detection has not been documented in prospective studies.
Detection of Abnormal Transcripts in Autologous Stem Cell Grafts
The AML1/MTG8 transcript is often detected at lower levels in PBSC harvests than in corresponding BM samples in patients with t(8;21) [29]. Furthermore, there seems to be no correlation between the number of infused AML1/MTG8 transcripts and the risk of posttransplant AML relapse, and a substantial decrease of fusion transcripts in BM has been observed following both repeated cycles of consolidation therapy and autologous PBSC transplantation [29]. Although it is difficult to generalize from these studies of relatively few patients with favorable prognosis, the overall results suggest that autologous stem cell transplantation may improve the prognosis in AML, even when MRD-free grafts cannot be achieved. This is also suggested by two case reports describing prolonged molecular remission after transplantation of PML-RARA-positive autografts to PML-RARA-negative patients [54].
Detection of MRD by Flow Cytometry
Flow cytometry can be used to detect cells with a phenotype similar to the original AML blasts [55, 56]. The current strategies for MRD detection rely on combinations of leukocyte markers that are not expressed by normal cells in blood or BM, and the leukemia-associated phenotypes are then detected by double or multiple-color staining techniques [55]. Differences in immunophenotype between AML cells and normal progenitors may then be qualitative, quantitative or both. However, this technique requires that the protocols for cell collection, separation, staining and analysis are followed meticulously [55], and as for the PCR methodology, the clinical implications of this approach still have to be evaluated in prospective studies.
A recent study used 5-parametric flow cytometry to investigate MRD in BM and PBSC grafts derived from AML patients. The relapse risk showed only a weak correlation with pretransplant MRD in BM, but a strong correlation was observed with MRD in the PBSC graft [57]. These results strongly suggest that MRD in autografts can be important as a risk factor for posttransplant AML relapse.
The Risk of Posttransplant AML Relapse Derived from Graft Contamination
Several observations suggest that the pretransplant leukemia cell burden (and thereby also the relapse risk) should be reduced by postremission intensification (e.g., HIDAC therapy) before PBSC mobilization and transplantation. First, the antileukemic effect of auto-BMT was demonstrated by using BM grafts harvested after postremission intensification therapy [5-8]. Second, postremission intensification before PBSC transplantation is associated with a reduction in MRD and reduced risk of posttransplant AML relapse [28]. Third, the quantitative rather than qualitative difference in the amount of abnormal fusion transcripts between PCR-positive long-term remitters and patients with later relapse also supports the approach of reducing the AML burden to a minimum before stem cell harvest and transplantation [36].
Autotransplantation is still associated with a relatively high risk of posttransplant AML relapse [5-8]. Postremission intensification before mobilization can reduce the relapse risk and decrease MRD [28, 29], and an important question is therefore whether residual host disease or reinfused AML cells is the cause of posttransplant leukemia relapse. The importance of reinfused AML cells is supported by the following observations: A) gene marker studies have demonstrated that posttransplant relapse can be derived from contaminating cells in the autograft [58], and B) in a recent study the risk of posttransplant AML relapse showed a stronger correlation with flow-cytometric MRD in PBSC autografts than MRD in pretransplant BM [57]. On the other hand, the importance of residual host disease is supported by two other observations: A) prolonged molecular remission has been observed after transplantation of PML-RARA-positive autografts to PCR-negative patients [54], and B) the amount of abnormal transcripts may decrease following autotransplantation even when MRD-free grafts cannot be achieved [29]. Thus, it seems most likely that posttransplant AML relapse can be derived both from residual host disease and reinfused AML cells.
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EX VIVO REDUCTION OF RESIDUAL DISEASE IN AUTOLOGOUS STEM CELL GRAFTS
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Several in vitro techniques have been tried to reduce MRD in autografts, but most of these approaches have only been tried in experimental models without any clinical evaluation.
The Cryopreservation Procedure
A recent study reported that the effect on cell viability of uncontrolled-rate cryopreservation and mechanical freezer storage differs between various subsets of normal progenitors [59]. These results may indicate that the effect of different cryopreservation procedures on normal and AML progenitors should be compared to further investigate modulated cryopreservation as a possible method of graft purging.
Ex Vivo Culture
The effect of ex vivo culture as a purging method in leukemia patients seems to depend on the culture system [60, 61]. However, recent studies of telomerase activity in AML blasts suggest that in vitro culture may become useful for autograft purging [62]. Each cell division results in DNA loss and telomere shortening, leading to senescence when telomeres become critically short [62]. Telomerase is an enzyme that adds telomeric repeats, and its expression may thereby allow cells to bypass replicative senescence. Native AML blasts have increased telomerase activity that becomes reduced after one week of culture, whereas normal stem cells show increased activity after culture [62]. This difference between normal and malignant cells may thus become useful in graft purging.
Pharmacological Purging
A relatively selective toxicity on AML cells has been described for several agents, including perfosfamide, resveratrol, mafosfamide, nitrogen mustard, etoposide, and the vitamin D3 analog EB 1089 [8, 63-65]. Perfosfamide is the only agent that has been investigated in large clinical studies [8], but the results do not allow any conclusion about the possible role of pharmacological purging in future AML therapy.
Hyperthermic Purging
After hyperthermic treatment for 120 min at 43°C, AML progenitors are reduced by 5-log, whereas normal committed progenitors are reduced only by 1-log [66]. This selective effect on AML cells can be further enhanced by goralatide that causes cell cycle inhibition in normal stem cells and thereby a relative protection against hyperthermia-induced killing [66].
Photochemical Purging
Tumor cells accumulate more conjugated cationic molecules in mitochondria than normal cells, and therefore mitochondrial targeting by the phototoxic triarylmethane dyes shows a relative selectivity for leukemic cells compared with normal progenitors [67]. A combination of phototoxic substances and protective agents may further enhance this selectivity [68].
Selection of Normal Stem Cell
Positive selection of normal stem cells is usually based on the enrichment of CD34+ cells. However, recent studies suggest that AML stem cells are included in different progenitor compartments, including the CD34+ as well as the CD34– cells [69-71]. This similarity in membrane molecule expression between normal and leukemic progenitors suggests that it may be difficult to use selection procedures to reduce MRD in stem cell grafts. However, a recent study suggested that the Thy-1 molecule may be used as a marker for normal stem cells in AML [71].
Enhancement of Antileukemic Immune Reactivity
PBSC grafts have a unique microenvironment created by their increased content of normal blood cells, e.g., activated platelets, monocytes, and lymphocytes [72-74]. The high numbers of immunocompetent cells may represent potential targets for ex vivo enhancement of antileukemic immune reactivity [73, 74]. An enhancement of this reactivity in autografts may then mediate both pretransplant (MRD in the graft) as well as posttransplant antileukemic effects [47].
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CONCLUDING REMARKS
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Postremission therapy with HIDAC and/or autologous stem cell transplantation are promising approaches for the treatment of adult AML. The results discussed in this review suggest that a combination of these two treatment strategies is possible and may further improve long-term disease-free survival in AML. However, the possible advantage of combination therapy needs to be demonstrated in prospective clinical trials before it can be recommended for routine therapy in AML.
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ACKNOWLEDGMENTS
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The study was supported by The Norwegian Cancer Society and the Meltzer Foundation.
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References
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|---|
-
Löwenberg B, Downing JR, Burnett AK. Acute myeloid leukemia. N Engl J Med 1999;341:1051-1062.[Free Full Text]
-
Mayer RJ, Davis RB, Schiffer CA et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. N Engl J Med 1994;331:896-903.[Abstract/Free Full Text]
-
Bishop JF, Matthews JP, Young GA et al. A randomized study of high-dose cytarabine in induction in acute myeloid leukemia. Blood 1996;87:1710-1717.[Abstract/Free Full Text]
-
Kern W, Aul C, Maschmeyer G et al. Superiority of high-dose over intermediate-dose cytosine arabinoside in the treatment of patients with high-risk acute myeloid leukemia: results of an age-adjusted prospective randomized comparison. Leukemia 1998;12:1049-1055.[CrossRef][Medline]
-
Burnett AK, Goldstone AH, Stevens RMF et al. Randomised comparison of addition of autologous transplantation to intensive chemotherapy for acute myeloid leukemia in first remission: results of MRC AML 10 trial. Lancet 1998;351:700-708.[CrossRef][Medline]
-
Zittoun RA, Mandelli F, Willemze R et al. Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. N Engl J Med 1995;332:217-223.[Abstract/Free Full Text]
-
Harousseau JL, Cahn JY, Pignon B et al. Comparison of autologous bone marrow transplantation and intensive chemotherapy as postremission therapy in adult acute myeloid leukemia. Blood 1997;90:2978-2986.[Abstract/Free Full Text]
-
Cassileth PA, Harrington DP, Appelbaum FR et al. Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission. N Engl J Med 1998;339:1649-1656.[Abstract/Free Full Text]
-
Baker WJ, Royer GL, Weiss RB. Cytarabine and neurologic toxicity. J Clin Oncol 1991;9:679-693.[Abstract]
-
Demirer T, Bensinger WI, Buckner CD. Peripheral blood stem cell mobilization for high-dose chemotherapy. J Hematother 1999;8:103-113.[CrossRef][Medline]
-
Kolbe K, Peschel C, Rupilius B et al. Peripheral blood stem cell (PBSC) mobilization with chemotherapy followed by sequential IL3 and G-CSF administration in extensively pretreated patients. Bone Marrow Transplant 1997;20:1027-1032.[CrossRef][Medline]
-
Weaver A, Ryder D, Crowther D et al. Increased numbers of long-term initiating cells in the apheresis product of patients randomized to receive increasing doses of stem cell factor administered in combination with chemotherapy and a standard dose of granulocyte colony-stimulating factor. Blood 1996;88:3323-3328.[Abstract/Free Full Text]
-
Schwartz S, Heinecke A, Zimmermann M et al. Expression of the c-kit receptor (CD117) is a feature of almost all subtypes of de novo acute myeloblastic leukemia (AML), including cytogenetically good-risk AML, and lacks prognostic significance. Leuk Lymphoma 1999;34:85-94.[Medline]
-
Bruserud Ø, Gjertsen BT, Brustugun OT et al. Effects of interleukin 10 on blast cells derived from patients with acute myelogenous leukemia. Leukemia 1995;9:1910-1920.[Medline]
-
Ohno R, Tomonaga M, Kobayashi T et al. Effect of granulocyte colony-stimulating factor after intensive induction therapy in relapsed or refractory acute leukemia. N Engl J Med 1990;323:871-877.[Abstract]
-
Ohno R, Naoe T, Kanamura A et al. A double-blind controlled study of granulocyte colony-stimulating factor started two days before induction chemotherapy in refractory acute myeloid leukemia. Blood 1994;83:2086-2092.[Abstract/Free Full Text]
-
Dombret H, Chastang C, Fenaux P et al. A controlled study of recombinant granulocyte colony-stimulating factor in elderly patients after treatment for acute myelogenous leukemia. N Engl J Med 1995;332:1678-1683.[Abstract/Free Full Text]
-
Heil G, Hoelzer D, Sanz MA et al. A randomized double-blind placebo-controlled phase III study of filgrastim in remission induction and consolidation therapy for adults with de novo acute myeloid leukemia. Blood 1997;90:4710-4718.[Abstract/Free Full Text]
-
Rowe JM, Andersen JW, Mazza JJ et al. A randomized placebo-controlled phase III study of granulocyte-macrophage colony-stimulating factor in adult patients (>55 to 70 years of age) with acute myelogenous leukemia: a study of the Eastern Cooperative Oncology Group (E1490). Blood 1995;86:457-462.[Abstract/Free Full Text]
-
Stone RM, Berg DT, George SL et al. Granulocyte-macrophage colony-stimulating factor after initial chemotherapy for elderly patients with primary acute myelogenous leukemia. N Engl J Med 1995;332:1671-1677.[Abstract/Free Full Text]
-
Zittoun R, Suciu S, Mandelli F et al. Granulocyte-macrophage colony-stimulating factor associated with induction treatment of acute myelogenous leukemia: a randomized trial by the European Organization for Research and Treatment of Cancer Leukemia Cooperative Group. J Clin Oncol 1996;14:2150-2159.[Abstract/Free Full Text]
-
Witz F, Sadoun A, Perrin MC et al. A placebo-controlled study of recombinant human granulocyte-macrophage colony-stimulating factor administered during and after induction treatment for de novo acute myelogenous leukemia in elderly patients. Blood 1998;91:2722-2730.[Abstract/Free Full Text]
-
Heil G, Chadid L, Hoelzer D et al. GM-CSF in a double-blind randomized placebo-controlled trial in therapy of adult patients with de novo acute myeloid leukemia (AML). Leukemia 1995;9:3-9.[Medline]
-
Wielenga JJ, Vellenga E, Groenewegen A et al. Recombinant human interleukin-3 (rh-IL3) in combination with remission induction chemotherapy in patients with relapsed acute myelogenous leukemia. Leukemia 1996;10:43-47.[Medline]
-
Visani G, Lemoli RM, Tosi P et al. Use of peripheral blood stem cells for autologous transplantation in acute myeloid leukemia allows faster engraftment and equivalent disease-free survival compared with bone marrow. Bone Marrow Transplant 1999;24:467-472.[CrossRef][Medline]
-
Löwenberg B, van Putten WLJ, Ferrant A et al. Peripheral blood progenitor transplantation as an alternative to autologous marrow transplantation in the treatment of acute myeloid leukemia. STEM CELLS 1997;15(suppl 1):177-181.
-
de la Rubia J, Sanz MA. Autologous peripheral blood stem cell transplantation for acute leukemias. Balliere's Clin Haematol 1999;12:139-150.
-
Martin C, Torres A, Leon A et al. Autologous peripheral blood stem cell transplantation (PBSCT) mobilized with G-CSF in AML in first complete remission. Role of intensification therapy in outcome. Bone Marrow Transplant 1998;21:375-382.[CrossRef][Medline]
-
Miyamato T, Nagafuji K, Harada M et al. Significance of quantitative analysis of AML1/ETO transcripts in peripheral blood stem cells from t(8;21) acute myelogenous leukemia. Leuk Lymphoma 1997;25:69-75.[Medline]
-
Schlenk RF, Döhner H, Pförsich M et al. Successful collection of peripheral blood progenitor cells in patients with acute myeloid leukemia following early consolidation therapy with granulocyte colony-stimulating factor-supported high-dose cytarabine and mitoxantrone. Br J Haematol 1997;99:386-393.[CrossRef][Medline]
-
Shimazaki C, Oku N, Ashihara E et al. Collection of peripheral blood stem cells mobilized by high-dose Ara-C plus VP-16 or aclarubicin followed by recombinant human granulocyte colony-stimulating factor. Bone Marrow Transplant 1992;10:341-346.[Medline]
-
Pavlovsky S, Fernandez I, Milone G et al. Autologous peripheral blood progenitor cell transplantation mobilized with high-dose cytarabine in acute myeloid leukemia in first complete remission. Ann Oncol 1998;9:151-157.[Abstract/Free Full Text]
-
Schiller G, Lee M, Paquette R et al. Transplantation of autologous peripheral blood progenitor cells procured after high-dose cytarabine-based consolidation chemotherapy for adults with secondary acute myelogenous leukemia in first remission. Leuk Lymphoma 1999;33:475-484.[Medline]
-
Linker CA, Ries CA, Damon LE et al. Autologous stem cell transplantation for acute myeloid leukemia in first remission. Biol Blood Marrow Transplant 2000;6:50-57.[CrossRef][Medline]
-
Jowitt SN, Chang J, Morgenstern GR et al. Factors which affect the CFU-GM content of the peripheral blood haematopoietic progenitor cell harvests in patients with acute myeloid leukemia. Br J Haematol 1998;100:688-694.[CrossRef][Medline]
-
Yin JAL, Tobal K. Detection of minimal residual disease in acute myeloid leukemia: methodologies, clinical and biological significance. Br J Haematol 1999;106:578-590.[CrossRef][Medline]
-
Radich JP. Clinical applicability of the evaluation of minimal residual disease in acute leukemia. Curr Opin Oncol 2000;12:36-40.[CrossRef][Medline]
-
Bose S, Deininger M, Gora-Tybor J et al. The presence of typical and atypical bcr-abl fusion genes in leukocytes of normal individuals: biological significance and implications for the assessment of minimal residual disease. Blood 1998;92:3362-3367.[Abstract/Free Full Text]
-
Biernaux C, Loos M, Sels A et al. Detection of bcr-abl gene expression at a very low level in blood cells of some healthy individuals. Blood 1995;86:3118-3122.[Abstract/Free Full Text]
-
Araten DJ, Nafa K, Pakdeesuwan K et al. Clonal populations of hematopoietic progenitor cells with paroxysmal nocturnal hemoglobinuria genotype and phenotype are present in normal individuals. Proc Natl Acad Sci USA 1999;96:5209-5214.[Abstract/Free Full Text]
-
Harris JW, Koscick R, Lazarus HM et al. Leukemia arising out of paroxysmal nocturnal hemoglobinuria. Leuk Lymphoma 1999;32:401-426.[Medline]
-
Hahn WC, Counter CM, Lundberg AS et al. Creation of human tumour cells with defined genetic elements. Nature 1999;400:464-468.[CrossRef][Medline]
-
Goyette MC, Cho K, Fasching CL et al. Progression of colorectal cancer is associated with multiple tumor suppressor gene defects but inhibition is accomplished by correction of any single defect via chromosome transfer. Mol Cell Biol 1992;12:1387-1395.[Abstract/Free Full Text]
-
Kashani-Sabet M, Funato T, Tone T et al. Reversal of malignant phenotype by an anti-ras ribozyme. Antisense Res Dev 1992;2:3-15.[Medline]
-
Vickers M, Jackson G, Taylor P. The incidence of acute promyelocytic leukemia appears constant over most of a human lifespan, implying only one rate-limiting step. Leukemia 2000;14:722-726.[CrossRef][Medline]
-
Miyamoto T, Nagafuji K, Akashi K et al. Persistence of multipotent progenitors expressing AML1/ETO transcripts in long-term remission patients with t(8;21) acute myelogenous leukemia. Blood 1996;87:4789-4796.[Abstract/Free Full Text]
-
Bruserud Ø. Acute myelogenous leukemia blasts as accessory cells during T lymphocyte activation: possible implications for future therapeutic strategies. Leukemia 1999;13:1175-1187.[CrossRef][Medline]
-
Harris NL, Jaffe ES, Diebold J et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the clinical advisory comittee meeting—Airlie House, Virginia, November 1997. J Clin Oncol 1999;17:3835-3849.[Abstract/Free Full Text]
-
Diverio D, Rossi V, Avvisati G et al. Early detection of relapse by prospective reverse transcriptase polymerase chain reaction analysis of the PML-RARA fusion gene in patients with acute promyelocytic leukemia enrolled in the GIMEMA-AIEOP multicenter AIDA trial. Blood 1998;92:784-789.[Abstract/Free Full Text]
-
Tobal K, Yin JAL. RT-PCR method with increased sensitivity shows persistence of PML-RARA fusion transcripts in patients with long-term remission of APL. Leukemia 1998;12:1349-1354.[CrossRef][Medline]
-
Tobal K, Newton J, Macheta M et al. Molecular quantitation of minimal residual disease in acute myeloid leukemia with t(8;21) can identify patients in durable remission and predict clinical relapse. Blood 2000;95:815-819.[Abstract/Free Full Text]
-
Marschlauser F, Cayuela JM, Martini S et al. Evaluation of minimal residual disease using reverse-transcription polymerase chain reaction in t(8;21) acute myeloid leukemia: a multicenter study of 51 patients. J Clin Oncol 2000;18:788-794.[Abstract/Free Full Text]
-
Tobal K, Johnson PRE, Saunders MJ et al. Detection of CBFB/MYH11 transcripts in patients with inversion and other abnormalities of chromosome 16 at presentation and remission. Br J Haematol 1995;91:104-108.[Medline]
-
Sanz MA, de la Rubia J, Bonanad S et al. Prolonged molecular remission after PML/RAR
-positive autologous peripheral blood stem cell transplantation in acute promyelocytic leukemia: is relevant pretransplant minimal residual disease in the graft? Leukemia 1998;12:992-995.[CrossRef][Medline]
-
Campana D, Coustan-Smith E. Detection of minimal residual disease in acute leukemia by flow cytometry. Cytometry 1999;38:139-152.[CrossRef][Medline]
-
San Miguel JF, Ciudad J, Vidriales MB et al. Immunophenotypical detection of minimal residual disease in acute leukemia. Crit Rev Oncol Hematol 1999;32:175-185.[Medline]
-
Reichle A, Rothe G, Krause S et al. Transplant characteristics: minimal residual disease and impaired megakaryocytic colony growth as sensitive parameters for predicting relapse in acute myeloid leukemia. Leukemia 1999:13:1227-1234.[CrossRef][Medline]
-
Brenner MK, Rill DR, Moen RC et al. Gene-marking to trace origin of relapse after autologous bone marrow transplantation. Lancet 1993;341:85-86.[CrossRef][Medline]
-
Cilloni D, Garau D, Regazzi E et al. Primitive hematopoietic progenitors within mobilized blood are spared by uncontrolled rate freezing. Bone Marrow Transplant 1999;23:497-503.[CrossRef][Medline]
-
Chang J, Coutinho L, Morgenstern G et al. Reconstitution of hematopoietic system with autologous marrow taken during relapse of acute myeloblastic leukaemia and grown in long-term culture. Lancet 1986;i:294-295.
-
Johnsen HE, Gaarsdal E, Jensen L et al. Short-term liquid marrow cultures are supported by a mixture of haematopoietic cytokines but do not purge for acute myeloid or lymphoid marrow cells. Leukemia 1993;7:1402-1408.[Medline]
-
Engelhardt M, Mackenzie K, Drullinsky P et al. Telomerase activity and telomere length in acute and chronic leukemia, pre- and post-ex vivo culture. Cancer Res 2000;60:610-617.[Abstract/Free Full Text]
-
Gautam SC, Xu YX, Dumaguin M et al. Resveratrol selectively inhibits leukemia cells: a prospective agent for ex vivo bone marrow purging. Bone Marrow Transplant 2000;25:639-645.[CrossRef][Medline]
-
Motta MR, Mangianti S, Rizzi S et al. Pharmacological purging of minimal residual disease from peripheral blood stem cell collections of acute myeloblastic leukemia patients: preclinical studies. Exp Hematol 1997;25:1261-1269.[Medline]
-
Lee YY, Kim ES, Seol JG et al. Effect of a vitamin D3 analog, EB1089, on hematopoietic stem cells from normal and myeloid leukemic blasts. Leukemia 1996;10:1751-1757.[Medline]
-
Wierenga PK, Brenner MK, Konings AWT. Enhanced selectivity of hyperthermic purging of human progenitor cells using Goralatide, an inhibitor of cell cycle progression. Bone Marrow Transplant 1998;21:73-78.[CrossRef][Medline]
-
Indig GL, Anderson GS, Nichols MG et al. Effect of molecular structure on the performance of triarylmethane dyes as therapeutic agents for photodynamic purging of autologous bone marrow grafts from residual tumors. J Pharm Sci 2000;89:88-99.[CrossRef][Medline]
-
Danilatou V, Lydaki E, Dimitriou H et al. Bone marrow purging by photodynamic treatment in children with acute leukemia. Cytoprotective action of amifostine. Leuk Res 2000;24:427-435.[CrossRef][Medline]
-
Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997;3:730-737.[CrossRef][Medline]
-
Blair A, Hogge DE, Sutherland HJ. Most acute myeloid leukemia progenitor cells with long-term proliferative ability in vitro and in vivo have the phenotype CD34+/CD71–/HLA-DR–. Blood 1998;92:4325-4335.[Abstract/Free Full Text]
-
Blair A, Hogge DE, Ailles LE et al. Lack of expression of Thy-1 (CD90) on acute myeloid leukemia cells with long-term proliferative ability in vitro and in vivo. Blood 1997;89:3104-3112.[Abstract/Free Full Text]
-
Bruserud Ø, Foss B, Abrahamsen JF et al. Autologous stem cell transplantation as postremission therapy in adult acute myelogenous leukemia; does the platelet contamination of peripheral blood mobilized stem cell grafts influence the risk of leukemia relapse? J Hematother Stem Cell Res 2000 (in press).
-
Singh RK, Ino K, Varney ML et al. Immunoregulatory cytokines in bone marrow and peripheral blood stem cell products. Bone Marrow Transplant 1999;23:53-62.[CrossRef][Medline]
-
Ageitos AG, Varney ML, Bierman PJ et al. Comparison of monocyte-dependent T cell inhibitory activity in GM-CSF vs G-CSF mobilized PBSC products. Bone Marrow Transplant 1999;23:63-69.[CrossRef][Medline]
Received June 23, 2000;
accepted for publication June 27, 2000.
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Abstract
Introduction
