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Blood, Vol. 93 No. 11 (June 1), 1999:
pp. 3931-3939
By
From the Roswell Park Cancer Institute, Buffalo, NY; the CALGB
Statistical Center, Durham, NC; Georgetown University Medical Center,
Washington, DC; State University of New York Health Science Center at
Syracuse, Syracuse, NY; Wake Forest University School of Medicine,
Winston-Salem, NC; New York Hospital-Cornell Medical Center, NY, NY;
Karmanos Cancer Institute, Wayne State University School of Medicine,
Detroit, MI; the University of Chicago, Chicago, IL; and Comprehensive
Cancer Center of the Ohio State University, Columbus, OH.
The prognostic value of immunophenotype in adult acute lymphoblastic
leukemia (ALL) has varied based on the methods used, surface markers
studied, and therapy administered. From April 1991 to September 1996, samples of leukemic marrow or blood from 259 eligible and evaluable
adult ALL patients entering dose-intensive Cancer and Leukemia Group B
(CALGB) front-line treatment protocols were prospectively studied for
immunophenotypic classification by multiparameter flow cytometry (MFC)
in a central laboratory. A B-lineage (B-LIN) phenotype was expressed in
79% of cases, with one third coexpressing myeloid antigens. A
T-lineage (T-LIN) phenotype was expressed in 17% of cases, with one
quarter coexpressing myeloid antigens. Since the advent of more
intensive CALGB therapy which incorporated cyclophosphamide and the
early use of L-asparaginase into the backbone of daunorubicin,
vincristine and prednisone, together with central nervous system
prophylaxis for adult ALL, no significant differences in response
rates, remission duration, or survival have been seen in those patients
coexpressing myeloid antigens. The T-LIN phenotype was associated with
younger age (P = .01), a higher male to female ratio
(P = .01), higher white blood cell count
(P = .001) and hemoglobin (P < .001) levels, presence of a mediastinal mass (P < .001), and longer
survival (P = .01) and disease-free survival (DFS)
(P = .01) when compared to patients with a B-LIN phenotype.
The 3-year probability of survival and DFS (95% confidence interval
[CI]) of T-LIN adult ALL was 0.62 (0.46 to 0.76) and 0.62 (0.44 to
0.77), respectively. Comparatively, the 3-year probability of survival
and DFS (95% CI) of B-LIN adult ALL was 0.42 (0.35 to 0.50) and 0.39 (0.31 to 0.47), respectively. The number of T markers expressed in
T-LIN ALL cases was shown to have prognostic significance. In
particular, patients expressing six or more markers compared with
patients expressing three or fewer markers had longer DFS
(P = .003) and survival (P = .004). The
presence of the Philadelphia chromosome was significantly associated
with B-LIN ALL cases which coexpressed CD19+,
CD34+, and CD10+ (49%;
P = .003), whereas the majority of t(4;11) cases were
CD19+, CD34+ but CD10
ACUTE LYMPHOBLASTIC leukemia (ALL) is
biologically and clinically a heterogeneous group of diseases
characterized by malignant proliferation and accumulation of immature
lymphoid cells within the bone marrow, blood, and lymphoid organs.
Historically, prognostic data were obtained from routine physical
examination, serum biochemical profiles, bone marrow morphology, and
peripheral blood counts. More recently, information obtained from
karyotype, molecular genetics, and surface immunophenotype have
contributed to a better understanding of this complex disease and its
treatment.1-3 Immunophenotyping by flow cytometry aids in
distinguishing ALL from acute myeloid leukemia (AML) in approximately
10% to 15% of cases in which morphology and cytochemistry are
inadequate to make a definitive diagnosis.
Immunophenotyping of ALL is accomplished by use of panels of specific
monoclonal antibodies (MoAbs) that recognize distinct epitopes of
cellular membrane antigens. Normal lymphocytes are derived from
pluripotent stem cells that become committed to the lymphoid
developmental pathway. As normal B-cell and T-cell ontogeny occurs,
these committed cells acquire and lose various surface molecules that
represent typical changes in cytokine-induced metabolic, and adhesive
function which occur at various stages of
differentiation.4-6
The neoplastic process that leads to leukemogenesis is characterized by
cellular and molecular dysregulation. The net result is that the
leukemic cell is phenotypically different from any normal cell, but the
degree of difference is extremely variable. Although the functions of
many of these surface molecules still remain unknown,
fluorochrome-conjugated antibodies against them, when used in
combination, allow resolution of a unique repertoire with variable
expression that can differentiate between normal and leukemic cells.
Protocol 8364: "Immunologic diagnostic studies in adult ALL" was
activated by the Cancer and Leukemia Group B (CALGB) on June 27, 1983 to allow specific immunophenotyping questions to be answered independent of a given therapy protocol. Initial studies of ALL patients prospectively studied and uniformly treated on CALGB treatment
protocols (8011, 8411, 8513, and 8811) were among the first to
establish the incidence of specific lineages in adult ALL patients.
Approximately 50% to 60% had B-lineage disease, 15% had T-lineage
disease, and the remaining 25% had unusual immunophenotypes including
expression of myeloid lineage-associated antigens.7-9 These
and other early studies analyzed the expression of a single antigen at
a time by direct immunofluorescence microscopy or uniparameter flow cytometry.
In the Spring of 1991, ALL immunophenotyping studies began to be
performed using multiparameter flow cytometry (MFC), thus allowing
definitive assignment of surface antigens to leukemic cells or normal
cells. In uniparameter flow cytometry, cells are stained with a single
antibody and the mononuclear cell population is analyzed. In MFC, a
single tube of cells is simultaneously stained with three or more
different antibodies to define a distinct cluster pattern of up to
eight different populations. Each of the following characteristics
allow identification of leukemia cells: expression of antigens that are
not typically coexpressed on normal cells, lack of expression of
antigens that are typically coexpressed on normal cells, or abnormal
antigen density. The data used for clinical correlations and prognosis
by MFC are considered more accurate than data obtained by uniparameter
methods because they more closely represent the true phenotype of the
leukemic cells and allows them to be objectively resolved from normal
cells. Thus, the immunophenotypic pattern defined by multiparameter
techniques may more precisely reflect the biology of ALL and provide
prognostic information.
Patients
Multiparameter Flow Cytometry Studies
Procedure.
Submitted specimens were filtered through a 75-µm mesh and then
washed twice in a phosphate-buffered saline (PBS)-heparin solution.
Specimens were incubated with 200 µg/mL murine IgG per milliliter of
specimen to block Fc receptors. Trios of diagnostic MoAbs shown in
Table 1 were individually labeled with the
fluorochromes fluorescein (F), phycoerythrin (PE), and tandem complexes
(TC) of phycoerythrin Texas-red-biotin or phycoerythrin-cyanine 5 (Cy5)-biotin or directly conjugated with TC or peridinin chlorophyll a
Protein (Per CP). If a biotinyated antibody was used (before
availability of direct conjugates), the TC-avidin was added to the
cells for an additional 15 minutes of incubation. A detailed
explanation of staining, data acquisition, and analysis has been
described elsewhere.14,15 Light-activated
ethidium-monoxide-treated aliquots were used to detect dead cells.
Isotype and autofluorescence controls were performed. Leukemia gates
were used for analysis. Data were obtained using a dedicated Becton
Dickinson FACScan flow cytometer (Becton Dickinson, San
Jose, CA). Events are recorded on disk and files analyzed using the
Winlist multiparameter analysis software package (Verity Software
House, Topsham, ME). Results of analysis with appropriate clinical
comments were transferred electronically to a report template and the
original bidimensional data plots for each antibody panel were reviewed
and interpreted by the principal investigators (M.S.C., S.R.F., and
C.C.S.). Hard copies of final reports were signed manually and then
electronically transferred via an Ethernet link between the Laboratory
of Flow Cytometry at Roswell Park Cancer Institute and the CALGB Data
Management Center in Durham, NC.
Antibody panels. Ten panels containing three conjugated antibodies each were used for ALL immunophenotyping studies, and their composition is shown in Table 1 along with a brief rationale for their combination. Clusters of both normal and abnormal cells were explicitly resolved, and the pattern of these cell clusters served to provide another dimension for visualizing aberrant antigen expression. Definitions. The criterion for surface marker positivity was coexpression of an antigen by at least 10% of the leukemia blast population. Ten percent positivity was selected as a cutoff to eliminate the possibility that coexpression was caused by a nonspecific binding process or to dead cells. B-lineage (B-LIN) antigen expression was defined as CD19 or CD20 positivity; T-lineage (T-LIN) antigen expression as either (1) CD2 or CD7 positivity with CD1 or CD3 or CD4 or CD5 or CD8 positivity, or (2) CD5 positivity without CD19 or CD20 positivity; myeloid (My) antigen expression as CD13 and/or CD33 positivity coexpressed with either CD19 or CD2 and/or CD7; and stem cell phenotype as CD34 expression in the absence of positivity with any other lymphoid or myeloid lineage markers. Cases expressing combinations of antigens were classified as BMy, TMy, BTMy, BT, or unclassified ALL. For analysis purposes, the BMy cases were considered to be B-LIN and the TMy cases were considered to be T-LIN. Cases of FAB-L3 (Burkitt type ALL) were not included in our analyses, nor were cases that were strictly myeloid (ie, AML-MO). Cytogenetics. Many of these ALL patients also underwent genetic studies. Cytogenetic analysis of adult ALL specimens was performed as part of CALGB study 8461 (a prospective study of chromosomes in acute leukemia) as previously described.16 The companion cytogenetics study was not mandatory for patient enrollment on CALGB ALL clinical therapy trials or CALGB 8364. Sixty-one percent of the samples submitted for patients registered to both studies were evaluable by central review of karyotypes and available for this report. In addition, molecular detection of the Philadelphia (Ph) chromosome using reverse-transcriptase polymerase chain reaction (PCR) to detect the BCR-ABL fusion gene was a main objective of CALGB study 8762.17 In our statistical analyses, Ph+ patients are those who were classified by either cytogenetic or molecular methods, unless otherwise specified. A "better-risk B-LIN" subgroup was defined as patients with B/BMy immunophenotype who were studied by cytogenetic and/or molecular methods and known not to be Ph+, BCR/ABL+, or having the t(4;11) cytogenetic abnormality. Statistical analysis. The relationship between immunophenotypic subgroups and the endpoints of disease-free survival (DFS) and overall survival were the main statistical analyses undertaken for this study. Some of the analyses were confirmatory (eg, the comparison of B-LIN and T-LIN), while other analyses were exploratory in an attempt to define new prognostic groups based on marker expression.
Patient Accrual Between April 1, 1991 and September 30, 1996, 351 adult ALL patients were registered to CALGB 8364 and underwent MFC immunophenotyping studies. Of these 351 patients, 22 with ALL-L3 were treated on CALGB 9251, a protocol for Burkitt-type leukemia and diffuse, small noncleaved cell lymphoma, and excluded from this analysis. There were 4 additional L3 cases that were registered and treated on one of the four front-line ALL trials, but recognized as Burkitt-type leukemia after central review and, therefore, also excluded. In addition, patients were excluded from these analyses if they were found ineligible for the planned CALGB treatment study (n = 18) or if their specimens were found to be not evaluable (n = 31), with normal marker expression (n = 4), or not received at the central laboratory or evaluated at time of analysis (n = 13). Thus, a total of 259 evaluable samples were analyzed by MFC. These patients were treated on the following protocols: 8811 (n = 12), 9111 (n = 148), 9311 (n = 74), and 9511 (n = 25); the results of these studies have been reported in detail or in part.10-13 During the time period stated above, 96% of the patients accrued to these four studies had samples submitted for MFC immunophenotyping. These studies were comparable with respect to CR rates (82% to 85%) and estimated 3-year DFS (40% to 46%).ALL Lineage Frequency Lineage assignment by MFC in patients with adult ALL entering consecutive, similarly intensive CALGB front-line treatment protocols (8811, 9111, 9311, 9511) was determined. Features of a B-lineage phenotype were expressed in 79% of cases, with one third of this group coexpressing myeloid antigens. Seventeen percent of cases had a T-lineage phenotype, with one quarter of the group coexpressing myeloid antigens. BT, BTMy, stem cell, and unclassifiable phenotype comprised 1% or less of the remaining groups, respectively (Table 2), and were dropped from further evaluation.
Frequency of Individual Antigen Expression on B-LIN and T-LIN ALL In addition to lineage analysis, the frequency of individual marker expression for the B-LIN and T-LIN immunophenotypic subgroups was evaluated (Table 3).
Clinical Correlates Associated With Immunophenotype Clinical and biological features by immunophenotype.
The median follow-up time for these patients has been 3.8 years (range,
1 month to 6.5 years); only 3 patients have had less than 1 year of
follow-up. There were no differences in survival or DFS between
patients with ALL expressing B antigens only and those expressing B
plus myeloid antigens (P = .84, and P = .82, respectively; Fig 1). Similarly, there were
no differences observed between patients with ALL expressing T antigens
only and those expressing T plus myeloid antigens (p = .81, and
p = .53, respectively; Fig 1). Hence, B and BMy patients were
combined, as were T and TMy patients, for comparison purposes. Three
groups were studied: B/BMy (n = 206), T/TMy (n = 44), and a
"Better risk B" subgroup (n = 53), which consisted of only the
B/BMy patients who had adequate cytogenetics and excluded patients with
cytogenetic or molecular evidence of the Ph chromosome
(Ph+) or t(4;11)(q21;q23). Statistical comparisons of these
features between T-LIN cases and each B group are given in Table
4.
T-lineage ALL.
Adult T-lineage ALL currently treated with more intensive chemotherapy
regimens now show more favorable results than adult B-lineage
ALL.10,22 When we analyzed individual T-cell markers in our
T-lineage group, those patients with CD1, CD2, CD4, and CD5 expression
were all associated with a significant improvement in survival
(P = .006, P = .04, P = .05, and
P = .05, respectively) compared with those patients not
expressing these antigens (data not presented). The 44 individual T-LIN
patients expressed a varying number of T markers. Ten patients
expressed 1-3 markers, 20 patients expressed 4-5 markers, and 14 patients expressed 6-7 T-cell markers. Of the 10 patients with 1-3 markers, 6 were classified as pre-T ALL defined by expression of CD7
and lack of expression of CD1, CD2, CD4, and CD8. The 1-3 marker group
had a shorter survival compared to those patients with at least 6 markers positive (P = .004). Furthermore, the same
relationship between these two groups was also found for DFS
(P = .003) (see Table 5 and Fig 2). The group
expressing 4-5 T-cell markers had an intermediate outcome. The
incidence of individual T-cell markers was reviewed among the three
groups. CD5 and CD7 were coexpressed in the majority of T-cell ALL
patients tested. CD1, CD2, CD3, CD4, and CD8 were seldom expressed in
the 1-3 marker group (25%, 10%, 0%, 20%, and 0% respectively)
compared with the 4-5 marker group (62%, 85%, 40%, 60%, and 50%,
respectively), and the 6-7 marker group (91%, 93%, 71%, 93%, and
100%, respectively).
B-lineage ALL.
A B-lineage immunophenotype was found in 79% of the 259 evaluable ALL
patients. In addition to analysis by lineage or individual markers, MFC
allows analysis by groups of antigens expressed on individual cell
populations. This technique was used in an attempt to subclassify 206 patients with B-lineage (CD19+) ALL. CD34 and CD10 were
evaluated because these antigens have been previously reported as
having prognostic importance in ALL.23-25 In our current
study, analysis of individual antigen markers demonstrated that only
CD34-positivity in the B-LIN group was associated with shorter survival
(P = .06) and DFS (P = .02) when compared with CD34
Correlation of immunophenotype with cytogenetics.
Cytogenetic abnormalities were analyzed in 111 of the 250 patients with
B-LIN or T-LIN immunophenotypes. The most common cytogenetic abnormalities seen (ie, 5 cases or more) and their corresponding lineage immunophenotype are described in Table
7. The majority (36 of 38, 95%) of the
cases with karyotypes of either t(4;11) or t(9;22) were associated with
a B-LIN immunophenotype. These patients had shorter survival
(P = .005) and DFS (P = .02) than B-LIN patients
with other cytogenetic abnormalities or a normal karyotype. Of
interest, two t(9;22) cases (not shown in Table 7) were found to have a
mixed (B + T) lineage immunophenotype. The majority of patients had
more than one karyotypic abnormality found. When studied only in those
cases where they were expressed as the sole chromosomal abnormality,
relatively specific surface antigen combinations were associated with
the t(9;22) and t(4;11) karyotypes. Ph+ cases usually
demonstrate CD19+ (11 of 12), CD10+ (9 of 12),
CD34+ (12 of 12); these results are consistent with the
previous finding that the B-LIN subgroup coexpressing
CD10+/34+ was associated with a significantly
higher than expected number of Ph+ cases (49%) compared
with the three other subgroups. The majority of t(4;11) cases showed
CD19+ (13 of 13) and CD34+ (9 of 13), but no
CD10+ (0 of 13). The lack of CD10 expression in adult ALL
patients with the t(4;11) karyotype has been independently noted by
Ludwig et al from German multicenter trials.26
Immunophenotype of ALL at relapse.
A total of 37 evaluable pairs of pretreatment and relapsed specimens
have been analyzed by MFC. The immunophenotypes are shown in Table
8. In 25 of 37 patients (68%), the same
pretreatment immunophenotypic lineage markers were seen at time of
relapse. In the remaining one third, the change at time of relapse
consisted primarily of a minor shift with loss or gain of a myeloid
marker. As the number of relapsed cases studied increases, future
subset analysis may help in determining if any clinical or lab
correlations are associated with specific immunological marker shifts.
Because approximately two thirds of patients do not change their
pretreatment immunophenotypic lineage, the possibility of evaluating
minimal residual disease by MFC in serial samples during and following therapy remains a promising area of research.
Adult ALL is a heterogeneous disease with leukemic blasts showing various immunophenotypes and variable responsiveness to systemic therapies. Karyotype and molecular genetics, in addition to surface immunophenotype, have refined the diagnosis and prognosis of adult ALL beyond the information available from physical examination, peripheral blood counts, serum biochemical profiles, and bone marrow morphology. Immunophenotyping is essential for confirmation of the diagnosis of ALL. Immunophenotyping permits recognition of misdiagnosed cases of AML (M0), which typically may occur in 10% to 15% of cases of ALL being evaluated by morphology and standard immunohistochemical stains alone (C. Stewart, personal communication, 1998). Immunophenotyping also provides a biologic definition of the disease that may be useful in assigning prognosis and choosing appropriate therapy. In recent years the use of uniform criteria (including age, WBC count at presentation, DNA index, early response to therapy, cytogenetics, CNS status, and immunophenotype) to assign risk-based therapy for patients with pediatric ALL has been advocated.27
The following institutions participated in the study: University of
Alabama, Birmingham, AL: Robert Diasio, MD, supported by CA47545;
Bowman Gray School of Medicine, Winston-Salem, NC: M. Robert Cooper,
MD, supported by CA03927; University of North Carolina, Chapel Hill,
NC: Thomas Shea, MD, supported by CA47559; University of Chicago
Medical Center, Chicago, IL: Nicholas J. Vogelzang, MD, supported by
CA41287; Dana-Farber Cancer Institute, Boston, MA: George P. Canellos,
MD, supported by CA32291; Dartmouth-Hitchcock Medical Center, Hanover,
NH: L. Herbert Maurer, MD, supported by CA04326; Duke University
Medical Center, Durham, NC: Jeffrey Crawford, MD, supported by CA47577;
University of Iowa Hospitals, Iowa City, IA: Gerald Clamon, MD,
supported by CA47642; Long Island Jewish Medical Center, New Hyde Park,
NY: Marc Citron, MD, supported by CA11028; University of Maryland
Cancer Center, Baltimore, MD: Ernest Borden, MD, supported by CA31983;
University of Massachusetts Medical Center, Worcester, MA: F. Marc
Stewart, MD, supported by CA37135; Massachusetts General Hospital,
Boston, MA: Michael Grossbard, MD, supported by CA12449; McGill Cancer
Center, Montreal, Quebec, Canada: Brian Leyland-Jones, MD, supported by
CA31809; Medical University of South Carolina, Charleston, SC: Mark
Green, MD, supported by CA03927; University of Minnesota, Minneapolis, MN: Bruce Peterson, MD, supported by CA16450; University of Missouri, Ellis Fischel Cancer Center, Columbia, MO: Michael C. Perry, MD, supported by CA12046; Mount Sinai Hospital, New York, NY: James Holland, MD, supported by CA04457; New York Hospital, Cornell Medical
Center, New York, NY: Ted Szatrowski, MD, supported by CA07968; North
Shore University Hospital, Manhasset, NY: Daniel R. Budman, MD,
supported by CA35279; Rhode Island Hospital, Providence, RI: Louis A. Leone, MD, supported by CA08025; Roswell Park Memorial Institute,
Buffalo, NY: Ellis Levine, MD; supported by CA02599; SUNY Health
Science Center at Syracuse, Syracuse, NY: Stephen Graziano, MD,
supported by CA21060; University of Tennessee, Memphis, TN: Alvin
Mauer, MD, supported by CA47555; University of California at San Diego,
San Diego, CA: Stephen Seagren, MD, supported by CA11789; University of
California at San Francisco, San Francisco, CA: Alan Venook, MD,
supported by CA60138; Washington University, Barnes Hospital, St Louis,
MO: Daniel Ihde, MD, supported by CA47546; Walter Reed Army Medical
Center, Washington, DC: Nancy Dawson, MD, supported by CA26806.
Submitted September 22, 1998; accepted January 21, 1999.
The research for CALGB 8364 was supported, in part, by grants from the
National Cancer Institute (CA31946) to the Cancer and Leukemia Group B
(Richard L. Schilsky, Chairman). Its contents are solely the
responsibility of the authors and do not necessarily represent the
official views of the National Cancer Institute.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Myron S. Czuczman, MD, Roswell Park Cancer
Institute, Elm and Carlton St, Buffalo, NY 14263.
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TOP
ABSTRACT
INTRODUCTION
. The
knowledge gained from this study of MFC of a large number of patients
will permit a reduction in the number of antigens to be evaluated in
future studies. Overall, this should lead to cost savings without loss
of valuable information. A rational approach for future studies would
be to use four-color flow cytometry (instead of the current
three-color) to help further streamline the study of immunophenotype of
adult ALL by MFC.
