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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Departments of Hematology-Oncology,
Biostatistics and Epidemiology, and Pathology, St Jude Children's
Research Hospital, and University of Tennessee, Memphis, TN.
By using rapid flow cytometric techniques capable of
detecting one leukemic cell in 104 normal cells, we
prospectively studied minimal residual disease (MRD) in 195 children
with newly diagnosed acute lymphoblastic leukemia (ALL) in clinical
remission. Bone marrow aspirates (n = 629) were collected at the end
of remission induction therapy and at 3 intervals thereafter.
Detectable MRD (ie, Leukemic relapse occurs in at least 20% of
children with acute lymphoblastic leukemia (ALL) who are treated in
contemporary programs of chemotherapy.1 A number of
clinical and biologic presenting features can be used to estimate the
relapse hazard in such patients, but none is completely
reliable.1 Sequential monitoring of the cellular response
to chemotherapy in vivo promises to be an important strategy for
determining the prognosis of individual patients. However, morphologic
examination of peripheral blood or bone marrow cells, the traditional
approach to identifying residual disease, is subjective and quite
limited in sensitivity. To be detected with certainty, the leukemic
blast cells must constitute at least 5% of the total nucleated cell
population.2 Thus, a patient declared to be in complete
clinical remission may, in fact, harbor as many as 1010
leukemic cells.
A variety of methods to detect submicroscopic levels of leukemia in
patients with ALL have been developed.2 The most promising are flow cytometric detection of aberrant immunophenotypes and polymerase chain reaction (PCR) analysis of clonal antigen-receptor gene rearrangements.3,4 Detection of minimal residual
disease (MRD) with these methods during clinical remission appears to be independently associated with treatment outcome.5-11
Nevertheless, before using MRD findings to guide therapy, further
analysis is required to establish (1) the relative prognostic strength
of different levels of MRD at various times during therapy, (2) the clinical significance of MRD fluctuations during clinical remission, (3) the relation of MRD findings to presenting clinical and biologic features of ALL, and (4) the predictive value of MRD findings in
relation to other measurements of early response to therapy.
To determine the utility of sequential measurements of MRD relative to
other prognostic parameters and to clarify the significance of MRD
findings in clinical remission, we analyzed the results of a
prospective MRD study of 629 bone marrow aspirates collected from 195 children with ALL in first clinical remission. The mononuclear cells
were studied by a rapid and highly sensitive flow cytometric method
that can detect one leukemic cell per 104 normal bone
marrow cells or greater.3
Patients
Diagnostic immunophenotyping and chromosomal and genetic analyses were
performed by standard techniques.
Treatment protocol
Flow cytometric assessment of minimal residual disease Bone marrow aspirates were collected in preservative-free heparin at the end of remission induction (6 weeks after diagnosis) and during weeks 14, 32, and 56 of continuation therapy. Leukemia-associated immunophenotypes (found on leukemic cells but not on normal bone marrow cells) were determined by multiparameter flow cytometry, with various combinations of monoclonal antibodies and/or heterologous antisera conjugated to fluorescein isothiocyanate, phycoerythrin, peridinin chlorophyll protein, and allophycocyanin.3 The marker combinations currently used in our laboratory allow monitoring of MRD in more than 90% of patients and are shown in Table 1. Matched nonreactive fluorochrome-conjugated antibodies served as controls. The staining procedure has been described.3 For each case, marker combinations allowing the identification of one leukemic cell per 104 normal nucleated bone marrow cells or greater were selected at diagnosis and then applied during clinical remission.3,13 In the early part of the study, we used a FACScan flow cytometer with Lysis II or Cell Quest software, switching later to a dual laser-FACScalibur flow cytometer with Cell Quest software (cytometers and softwares were from Becton Dickinson, San Jose, CA).
The flow cytometry protocol used for MRD detection has been described in detail previously.3 In all samples, we acquired data from all mononuclear cells in each test tube (more than 1 × 105). Flow cytometric data were recorded within 24 hours after sample collection and processing, with no observer knowledge of a patient's clinical status or diagnostic features (excluding immunophenotype). Statistical analysis Differences in the distribution of clinicobiologic presenting features by level of residual disease at the end of remission induction were compared by the exact chi-square test. The cumulative incidence of ALL relapse, was estimated, with other competing risks (ie, second malignancy and death while in remission), as described by Kalbfleisch and Prentice,14 and compared by Gray's test, applied to follow-up observations through November 1999; 98.7% of patients had complete follow-up information within 1 year of the analysis. To assess the prognostic value of different levels of MRD after adjustment for competing prognostic factors, we stratified the data by treatment, and then separately for each of age, leukocyte count, and adverse genetic features. For these cumulative incidence analyses, missing residual disease determinations during continuation therapy (4.38% of all tests) were imputed when the immediately preceding and following measurements were identical. Patients who underwent bone marrow transplantation were followed until they experienced a relapse, competing event, or until their last follow-up date.
Levels of residual leukemia as a predictor of clinical outcome We identified cells with leukemia-associated immunophenotypes in 75 (11.9%) of the 629 remission marrow samples studied. MRD was most prevalent in bone marrow collected at the end of remission induction (25.5%; Table 2). The percentage of samples with residual disease decreased to 13.8%, 3.8%, and 4.3% at weeks 14, 32, and 56 of continuation chemotherapy, respectively. At each sampling interval, the detection of MRD was significantly associated with a greater likelihood of leukemic relapse (P < .001; Table 2). Among patients with positive findings at the end of induction therapy, the 5-year cumulative incidence of relapse (± SE) was 43% ± 11%, compared with 10% ± 3% for those with negative findings. In the latter group, 2 of the 9 patients who relapsed had detectable leukemic cells in subsequent testing, whereas in another patient, resurgent blast cells lacked the leukemia-specific markers observed at diagnosis, providing an explanation for the persistently negative MRD findings. By contrast, in the positive group, all relapses could be attributed to cells with the same leukemia-specific immunophenotype seen at diagnosis and at the end of induction therapy. Detection of MRD during continuation chemotherapy was also strongly predictive of leukemic relapse (P < .001; Table 2).
To determine whether levels of MRD were associated with relapse
hazard, we segregated positive cases at the end of remission induction
and at week 14 of continuation therapy into 3 groups according to
levels of residual disease: 0.01% to less than 0.1%, 0.1% to less
than 1%, and 1% or higher. MRD levels of 1% or higher at the end of
remission induction were associated with a particularly high relapse
hazard (Figure 1): only 2 of 9 patients
in this group, one of whom underwent allogeneic stem cell
transplantation, were alive and in remission at 2.5 and 4.5 years after
diagnosis. Levels of 0.1% or higher at week 14 of continuation therapy
also identified patients at high risk of relapse: 5 of 6 patients in
this category have relapsed.
Sequential determination of residual disease and treatment outcome The prevalence of residual disease during clinical remission declined progressively during treatment. Samples collected sequentially from individual patients either remained positive or negative throughout the analysis or converted from positivity to negativity. The only exceptions were 2 of 123 cases that were MRD-negative cases at the end of remission induction. Both became MRD positive at weeks 56 and 67, 7 and 4 months before clinical relapse. Figure 2 illustrates the prognostic significance of a progressive decline in MRD levels during clinical remission. Among patients who were MRD positive at the end of remission induction and remained positive at week 14 of continuation therapy, the 4-year cumulative incidence of relapse was 68% ± 16%. By contrast, it was only 7% ± 7% in those who became MRD negative at week 14 (P = .035). Ten of 18 patients in the positive group relapsed, compared with only one of the 14 patients who became MRD negative. A similar analysis was performed for cases that were positive at week 14. All 4 patients who remained positive through week 32 subsequently relapsed, compared with 2 patients of 8 in whom MRD became undetectable (P = .021). These results indicate relatively good treatment outcome even in patients with a slow response to therapy, providing that MRD levels decrease below the less than 0.01% threshold during the first 10 months of therapy.
Relation between residual disease and clinicobiologic features at diagnosis Rates of MRD detection on completion of induction therapy were not significantly related to gender, race, leukocyte count, presence of a mediastinal mass, or CNS status (Table 3). However, residual disease was significantly more frequent in infants and patients 10 years of age or older than in children of intermediate ages (P = .007). Notably, 4 of 6 infants had 0.01% leukemic cells at the end of
remission induction. Among cellular features, rates of detection did
not differ significantly in comparisons based on cell lineage. There
was, however, a remarkable association between MRD detection and the
Philadelphia chromosome: all 8 cases with this prognostically
unfavorable abnormality15 had positive findings
(P < .001). This contrasts with MRD positivity in 2 of 15 cases with a TEL gene rearrangement and 8 of 42 cases with hyperdiploid (greater than 50 chromosomes) B-lineage ALL, both considered favorable prognostic signs.16-20
The prognostic value of MRD detection by flow cytometric assay remained
significant after adjustment for competing covariates, including age
(P < .001), leukocyte count (P < .001), and
adverse genetic features (Philadelphia chromosome:
P < .001; MLL gene rearrangement:
P < .001; or either: P = .004). This result
was confirmed by an analysis that excluded patients with known
unfavorable (Philadelphia chromosome and leukocyte counts more than
25 × 109/L; MLL gene rearrangement and less
than 1 year of age) and favorable (B-lineage phenotype with DNA index
more than 1.16 or TEL gene rearrangement, or leukocyte
counts less than 50 × 109/L and 1 to 9 years of age,
without CNS or testicular involvement, and without Philadelphia
chromosome, E2A-PBX1 or MLL rearrangement) presenting prognostic features.1 In this
"standard-risk" group, MRD levels
Finally, we determined the prognostic significance of MRD detection in
B-lineage ALL patients stratified by the National Cancer Institute
(NCI)/Rome criteria.21 As shown in Figure
4A, results of MRD at the end of
remission induction correlated well with treatment outcome within the
NCI high-risk group (ie, patients with age less than 1 or 10 years or
older, or leukocyte counts
Relation between residual disease and clearance of circulating lymphoblasts Persistence of circulating lymphoblasts after the first week of treatment identifies children with ALL at a higher risk of relapse.22-26 We therefore determined whether MRD studies at the end of remission induction would add to the prognostic information provided by the earlier morphologic assessment of circulating lymphoblasts. Data on circulating lymphoblasts after 7 days of initiation of treatment were available for 160 of the 165 patients with MRD studies at the end of the induction phase. The 5-year cumulative incidence of relapse for the 63 patients with circulating lymphoblasts was 28.6% ± 7.6% versus 11.8% ± 3.8% for the 97 patients without circulating lymphoblasts (P = .018). As shown in Figure 5, results of MRD at the end of induction correlated well with treatment outcome within either group of patients.
Because the treatment protocol in this study had a "window"
administration of methotrexate 3 to 4 days preceding remission induction treatment, we also examined the results of circulating lymphoblasts at day 10. Of the 158 patients with available information, 35 had circulating lymphoblasts. The 5-year cumulative incidence of
relapse for these patients was 51.2% ± 13.9% versus
9.2% ± 2.8% for the 123 patients without circulating blasts
(P < .001). MRD findings at the end of the induction
phase correlated well with treatment outcome in patients without
circulating blasts (P < .001; Figure
6A). No statistically significant
differences were noted among the 35 patients with circulating blasts
(Figure 6B).
The measurement of MRD at critical intervals during the disease
course is a new tool to gauge the effectiveness of therapy in children
with ALL. In this study, we attempted to define criteria that might aid
in clinical decision making, based on monitoring of MRD. At any point
during clinical remission, the detection of MRD (ie, one or more
leukemic cells among 10 000 normal bone marrow mononuclear cells) was
associated with a higher risk of subsequent relapse, reinforcing our
previous studies5 and those of other
laboratories10,11 in which PCR assays were used to detect
MRD. We found, among MRD-positive patients, that the extent of residual
disease was of utmost importance in predicting treatment outcome.
Levels of MRD Certain presenting features of ALL, such as the patient's age and the presence or absence of adverse genetic abnormalities, are directly related to the speed and extent of initial cytoreduction.1 This generalization is well supported by findings of this study. For example, MRD at the end of remission induction was most frequently detected in patients with unfavorable age or, as previously noted by Brisco et al,28 the Philadelphia chromosome. Other factors, not examined here, can also affect the cytoreductive capacity of ALL therapy. These include pharmacokinetic and pharmacogenetic variables,29 and the sensitivity of blast cells to chemotherapy.30 In vivo measurements of leukemia cytoreduction should reflect the collective effect of these variables. Indeed, the presence of circulating blasts after 1 week of therapy,22-26 and the detection of blast cells in the bone marrow by morphologic criteria during remission induction therapy31,32 predict a higher incidence of relapse. In this study, we found that MRD studies significantly enhanced the prognostic information provided by the determination of circulating blasts during the early stages of remission induction chemotherapy. Thus, detection of MRD at the end of remission induction identified patients with higher relapse hazard, despite rapid clearance of circulating blasts. Several methods for detecting MRD in patients with ALL have been proposed,2 but flow cytometric detection of leukemia-associated immunophenotypes and PCR amplification of antigen-receptor genes appear to be the most reliable. The flow cytometric assay described in this study also fulfills the requirements for a routinely and widely applicable technique because of its speed (a reliable result can be obtained within a few hours of sample collection) and its accuracy of cell quantitation.3 We have previously shown that measurements of MRD by flow cytometry and PCR are comparable,13 so that definitions of remission by either method should be equally valid. A major limitation of our MRD assay was its lack of applicability in a substantial proportion of newly diagnosed cases (approximately 40%), including mainly cases with B-cell phenotype. We have attempted to increase the number of assessable cases by using a dual laser flow cytometer,3 which allows the simultaneous detection of 4 cell markers, and by identifying new leukemia-specific immunophenotypes.33 Since the introduction of 4-color analysis, for example, successful studies were achieved with marrow samples of 68 of 72 consecutive ALL patients (E. Coustan-Smith and D. Campana, unpublished data, March 2000). Because PCR may detect residual leukemic cells in cases not amenable to flow cytometric investigation, and vice versa, we advocate applying the 2 techniques in tandem. This approach has enabled us to monitor MRD in the last 96 consecutive patients (E. Coustan-Smith, G. Neale et al, unpublished data, March 2000) and should eliminate the possibility of false-negative results due to immunophenotypic shifts (flow cytometry) or oligoclonality and clonal evolution (PCR).3,34,35 One of the most important challenges in leukemia treatment is to
accurately distinguish patients who require more intensive (and
potentially more toxic) therapy from those in whom high cure rates can
be achieved with less intensive therapy. MRD studies provide direct
measurements of leukemic cell responses to chemotherapy in individual
patients, reflecting the combined effects of clinical, cellular, and
pharmacologic variables. This information can be used to improve
strategies of risk assessment and treatment selection in the management
of children with ALL. Patients with less than 0.01% leukemic cells at
the end of remission induction are likely to have an excellent
treatment outcome, whereas alternative treatments should be considered
for patients with high levels (ie,
Submitted September 29, 1999; accepted June 12, 2000.
Supported by grants CA60419, CA21765, and CA20180 from the National Cancer Institute, and by the American Lebanese Syrian Associated Charities (ALSAC).
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: D. Campana, Department of Hematology-Oncology, St Jude Children's Research Hospital, 332 N Lauderdale, Memphis, TN 38105; e-mail: dario.campana{at}stjude.org.
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J.-M. Ribera, J.-J. Ortega, and A. Oriol In Reply J. Clin. Oncol., June 20, 2007; 25(18): 2627 - 2628. [Full Text] [PDF]
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A. Moghrabi, D. E. Levy, B. Asselin, R. Barr, L. Clavell, C. Hurwitz, Y. Samson, M. Schorin, V. K. Dalton, S. E. Lipshultz, et al. Results of the Dana-Farber Cancer Institute ALL Consortium Protocol 95-01 for children with acute lymphoblastic leukemia Blood, February 1, 2007; 109(3): 896 - 904. [Abstract] [Full Text] [PDF]
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J.-M. Ribera, J.-J. Ortega, A. Oriol, P. Bastida, C. Calvo, J.-M. Perez-Hurtado, M.-E. Gonzalez-Valentin, V. Martin-Reina, A. Molines, F. Ortega-Rivas, et al. Comparison of Intensive Chemotherapy, Allogeneic, or Autologous Stem-Cell Transplantation As Postremission Treatment for Children With Very High Risk Acute Lymphoblastic Leukemia: PETHEMA ALL-93 Trial J. Clin. Oncol., January 1, 2007; 25(1): 16 - 24. [Abstract] [Full Text] [PDF]
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E. Coustan-Smith, R. C. Ribeiro, P. Stow, Y. Zhou, C.-H. Pui, G. K. Rivera, F. Pedrosa, and D. Campana A simplified flow cytometric assay identifies children with acute lymphoblastic leukemia who have a superior clinical outcome Blood, July 1, 2006; 108(1): 97 - 102. [Abstract] [Full Text] [PDF]
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M. Stanulla, E. Schaeffeler, T. Flohr, G. Cario, A. Schrauder, M. Zimmermann, K. Welte, W.-D. Ludwig, C. R. Bartram, U. M. Zanger, et al. Thiopurine Methyltransferase (TPMT) Genotype and Early Treatment Response to Mercaptopurine in Childhood Acute Lymphoblastic Leukemia JAMA, March 23, 2005; 293(12): 1485 - 1489. [Abstract] [Full Text] [PDF]
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A. Li, J. Zhou, D. Zuckerman, M. Rue, V. Dalton, C. Lyons, L. B. Silverman, S. E. Sallan, and J. G. Gribben Sequence analysis of clonal immunoglobulin and T-cell receptor gene rearrangements in children with acute lymphoblastic leukemia at diagnosis and at relapse: implications for pathogenesis and for the clinical utility of PCR-based methods of minimal residual disease detection Blood, December 15, 2003; 102(13): 4520 - 4526. [Abstract] [Full Text] [PDF]
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M.-B. Vidriales, J. J. Perez, M. C. Lopez-Berges, N. Gutierrez, J. Ciudad, P. Lucio, L. Vazquez, R. Garcia-Sanz, M. C. del Canizo, J. Fernandez-Calvo, et al. Minimal residual disease in adolescent (older than 14 years) and adult acute lymphoblastic leukemias: early immunophenotypic evaluation has high clinical value Blood, June 15, 2003; 101(12): 4695 - 4700. [Abstract] [Full Text] [PDF]
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W. L. Carroll, D. Bhojwani, D.-J. Min, E. Raetz, M. Relling, S. Davies, J. R. Downing, C. L. Willman, and J. C. Reed Pediatric Acute Lymphoblastic Leukemia Hematology, January 1, 2003; 2003(1): 102 - 131. [Abstract] [Full Text] [PDF]
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E. Coustan-Smith, J. Sancho, M. L. Hancock, B. I. Razzouk, R. C. Ribeiro, G. K. Rivera, J. E. Rubnitz, J. T. Sandlund, C.-H. Pui, and D. Campana Use of peripheral blood instead of bone marrow to monitor residual disease in children with acute lymphoblastic leukemia Blood, September 18, 2002; 100(7): 2399 - 2402. [Abstract] [Full Text] [PDF]
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M. Hotfilder, S. Rottgers, A. Rosemann, H. Jurgens, J. Harbott, and J. Vormoor Immature CD34+CD19- progenitor/stem cells in TEL/AML1-positive acute lymphoblastic leukemia are genetically and functionally normal Blood, June 28, 2002; 100(2): 640 - 646. [Abstract] [Full Text] [PDF]
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E. Coustan-Smith, J. Sancho, F. G. Behm, M. L. Hancock, B. I. Razzouk, R. C. Ribeiro, G. K. Rivera, J. E. Rubnitz, J. T. Sandlund, C.-H. Pui, et al. Prognostic importance of measuring early clearance of leukemic cells by flow cytometry in childhood acute lymphoblastic leukemia Blood, June 17, 2002; 100(1): 52 - 58. [Abstract] [Full Text] [PDF]
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M. N. Dworzak, G. Froschl, D. Printz, G. Mann, U. Potschger, N. Muhlegger, G. Fritsch, and H. Gadner Prognostic significance and modalities of flow cytometric minimal residual disease detection in childhood acute lymphoblastic leukemia Blood, March 15, 2002; 99(6): 1952 - 1958. [Abstract] [Full Text] [PDF]
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C. Nyvold, H. O. Madsen, L. P. Ryder, J. Seyfarth, A. Svejgaard, N. Clausen, F. Wesenberg, O. G. Jonsson, E. Forestier, and K. Schmiegelow Precise quantification of minimal residual disease at day 29 allows identification of children with acute lymphoblastic leukemia and an excellent outcome Blood, February 15, 2002; 99(4): 1253 - 1258. [Abstract] [Full Text] [PDF]
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D. Hoelzer, N. Gokbuget, O. Ottmann, C.-H. Pui, M. V. Relling, F. R. Appelbaum, J. J.M. van Dongen, and T. Szczepanski Acute Lymphoblastic Leukemia Hematology, January 1, 2002; 2002(1): 162 - 192. [Abstract] [Full Text] [PDF]
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J.-S. Chen, E. Coustan-Smith, T. Suzuki, G. A. Neale, K. Mihara, C.-H. Pui, and D. Campana Identification of novel markers for monitoring minimal residual disease in acute lymphoblastic leukemia Blood, April 1, 2001; 97(7): 2115 - 2120. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
Childhood Leukemia Cooperative Group.
N Engl J Med.
1998;339:591-598