- © 2004 by American Society of Clinical Oncology
Acute Monocytic Leukemia (French-American-British classification M5) Does Not Have a Worse Prognosis Than Other Subtypes of Acute Myeloid Leukemia: A Report From the Eastern Cooperative Oncology Group
- Martin S. Tallman,
- Haesook T. Kim,
- Elisabeth Paietta,
- John M. Bennett,
- Gordon Dewald,
- Peter A. Cassileth,
- Peter H. Wiernik and
- Jacob M. Rowe
- From the Northwestern University Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center, Chicago, IL; Biostatistics, Dana-Farber Cancer Institute, Boston, MA; Our Lady of Mercy Cancer Center, New York Medical College, Bronx, NY; University of Rochester, The James P. Wilmot Cancer Center, Rochester, NY; Mayo Clinic, Rochester, MN; University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL; Rambam Medical Center, Technion Institute of Technology, Haifa, Israel; for the Eastern Cooperative Oncology Group, Brookline, MA
- Address reprint requests to Martin S. Tallman, MD, Department of Medicine, Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center, 676 N St Clair St, Suite 850, Chicago, IL 60611; e-mail: m-tallman{at}northwestern.edu
Abstract
Purpose Acute monocytic leukemia is a distinct subtype of acute myeloid leukemia (AML) with characteristic biologic and clinical features. This study was designed to compare the outcome of patients with M5 to that of other subtypes of AML, and to identify differences in M5a and M5b.
Patients and Methods We reviewed all patients with AML M5 entered in three clinical trials for newly diagnosed AML conducted by the Eastern Cooperative Oncology Group between 1989 and 1998. Eighty-one patients, 21 with M5a and 60 with M5b, were identified.
Results The complete remission rate was 62% for all patients with M5; 52% for patients with M5a and 65% for patients with M5b (P = .3), and 60% for the 1,122 patients with non-M5 AML entered on the same clinical trials (P = .8 for M5 v non-M5). The 3-year disease-free survival was 26% for all M5 patients; 18% for M5a and 28% for M5b (P = .31), and 33% for non-M5 patients (P = .13 for M5 v non-M5). The 3-year overall survival was 31% for all M5 patients; 33% for M5a and 30% for M5b (P = .65), and 30% for non-M5 (P = .74 for M5 v non-M5). The karyotypes of patients with AML M5 were heterogeneous. CD11b was the only leukemic cell antigen expressed differently in M5a (53%) compared to M5b (77%) to a significant degree (P = .02).
Conclusion AML M5 represents an immunologically heterogeneous population similar to non-M5 AML with a prognosis that is not dependent on morphology. The disease-free survival and overall survival of patients with M5a, M5b, and non-M5 appear not to differ with currently available therapy.
INTRODUCTION
The subtype of acute myeloid leukemia (AML) classified by the French-American-British (FAB) Classification as M5 or acute monocytic leukemia, is a distinct subtype with characteristic clinical features.1-3 The disease may develop after chemotherapy exposure, particularly following epipodophyllotoxins and anthracyclines.4 AML FAB M5 is frequently associated with specific chromosomal translocations including t(8;16)(p11;p13) and various translocations involving the MLL locus at 11q23 such as t(9;11)(p22;q23), t(10;11)(p13;q23), t(11;19)(q23;p13), and others.5-21 Clinically, the disease is associated with hyperleukocytosis,22-25 extramedullary involvement,11,26-33 and coagulation abnormalities including disseminated intravascular coagulation.2,34-36 The disease has been reported to have a poor prognosis compared to other subtypes of AML, although this has not been clearly established.2,3,37,38 Overexpression of differentiation inhibitory factor (nm23 protein) may account for an unfavorable prognosis in some patients.39 Furthermore, significantly more patients with AML M5 have mutations in the Flt3 gene (approximately 40%) either internal tandem duplications of the juxtamembrane region or point mutations in the second tyrosine kinase domain, compared to other subtypes (26.4% overall), and such mutations are associated with an unfavorable outcome.40-43 Several reports of small numbers of patients have suggested that despite their potential etiologic role, the epipodophyllotoxins are particularly effective agents in the treatment of this disease.44-46 However, large prospective group studies have not confirmed any long-term benefit.46,47
Few series have reported the outcomes of large numbers of adults with AML M5 treated with contemporary intensive chemotherapy. Furthermore, FAB M5 may be divided based on morphology into M5a and M5b, distinguished by the relative proportion to monoblasts and promonocytes.48 To compare the outcome of patients with AML M5 to other subtypes of AML and identify differences between M5a (poorly differentiated) and M5b (differentiated), we studied all patients with newly-diagnosed AML M5 entered on clinical trials conducted by the Eastern Cooperative Oncology Group (ECOG) between 1989 and 1998.
PATIENTS AND METHODS
Diagnosis
The diagnosis of M5 (acute monocytic or monoblastic leukemia) was established as follows: all patients fulfilled all criteria; 1) 80% of the leukemic cells are morphologically of monocytic lineage, including monoblasts, promonocytes, and monocytes; 2) a minor granulocytic component may be present (< 20%); 3) in FAB M5a, the percentage of monoblasts is ≥ 80% (Fig 1); 4) in FAB M5b, the majority of the monocytic cells are promonocytes (blasts < 80%; Fig 2); 5) usually, the leukemic population shows intense nonspecific esterase activity, inhibited by sodium fluoride; 6) the peripheral blood monocyte count usually exceeds 5 × 103/L;1 7) patients were required to have 30% bone marrow blasts.
Acute monocytic leukemia (French-American-British classification M5a): Wright-Giemsa stain 1,000x.
Acute monocytic leukemia (French-American-British classification M5b): Wright-Giemsa stain 1,000x.
Immunophenotype Analysis
All cases were characterized for expression of monocytic (CD11b, CD14) and myeloid (CD33, CD13, CD65s, CD15/15s) differentiation markers. All patients were typed centrally in ECOG's immunophenotyping reference laboratory by multiparameter flow cytometry.
Cytogenetics
The ECOG Cytogenetic Committee reviewed data for a subset of patients enrolled in E3489, E3993, and E4995, and based their evaluations primarily on karyotype preparations and laboratory reports. Cytogenetic studies were obtained prospectively as part of treatment studies. Chromosome studies were considered acceptable for statistical analysis when there was documentation of bone marrow or peripheral blood metaphases demonstrating an abnormal clone, or ≥ 20 normal bone marrow metaphases. Sixty cytogenetic laboratories provided data for 79 AML M5 patients with approximately 75% acceptable cytogenetic data for statistical analysis.
Patients
All patients with AML M5 entered on three clinical trials for newly diagnosed patients with AML, conducted by the ECOG between 1989 and 1998, were studied. None of the three protocols permitted patients to enroll who had a known antecedent myelodysplastic syndrome or who had received any prior chemotherapy except hydroxyurea. Central pathology review was carried out and all patients were reviewed both at diagnosis and again at the time of this report. All patients received an anthracycline and cytarabine for induction followed by cytarabine 1.5 to 3gm/m2 dose for consolidation. Of the 81 patients identified, 30 were entered on Protocol E3993, 47 were entered on Protocol E3489, and four were entered on Protocol E4995. Among the patients in E3489, 14 underwent bone marrow transplantation, six allogeneic and eight autologous. Among patients treated on E4995, two underwent autologous peripheral blood stem-cell transplantation and one underwent allogeneic transplantation. There were 21 patients with M5a and 60 with M5b. Cases of M5a versus M5b were distinguished by the relative proportion of monoblasts and promonocytes.
Protocols and Therapies
Protocol E3993 was a trial in which older adults (age ≥ 55 years) with previously untreated AML were randomly assigned to one of three induction regimens: daunorubicin 45 mg/m2 per day, days 1 to 3, plus cytarabine 100/mg/m2 per day by continuous intravenous (IV) infusions days 1 to 7; idarubicin 12 mg/m2 days 1 to 3 plus cytarabine 100 mg/m2 per day by IV infusions days 1 to 7; or mitoxantrone 12 mg/m2 per day, days 1 to 3, plus cytarabine 100 mg/m2 per day by continuous IV days 1 to 7.49 Patients were permitted up to two courses of induction. Subsequently, patients received consolidation chemotherapy that included cytarabine 1.5 gm/m2 twice daily for 6 days. Patients older than 70 years received 1.5 gm/m2 twice daily for only 3 days.
Protocol E3489 was a prospective trial for newly-diagnosed patients ages 16 to 55 years.50 All patients received induction chemotherapy which included idarubicin 12 mg/m2 per day given intervenously days 1 to 3 + cytarabine 100 mg/m2 intravenously by continuous IV infusion days 1 to 7. Patients were permitted up to two courses of induction. Patients achieving complete remission received one course of attenuated consolidation chemotherapy, which included idarubicin 12 mg/m2 IV per day given on days 1 and 2, plus cytarabine 100 mg/m2 per day by continuous IV infusion on days 1 to 5. Subsequently, patients with a histocompatible sibling donor underwent human leukocyte antigen-matched allogeneic bone marrow transplantation. All other patients were randomly assigned to either autologous bone marrow transplantation or consolidation chemotherapy using cytarabine 3gm/m2 given intravenously over 1 hour every 12 hours on days 1 to 6 (12 doses).
Protocol E4995 for patients with newly diagnosed AML younger than age 56 years was designed to test the benefits of autologous stem-cell transplantation following intensive consolidation chemotherapy with high-dose cytarabine.51 Patients were induced with daunorubicin 45 mg/m2 per day on days 1 to 3 and cytarabine 100 mg/m2 per day by continuous IV infusion on days 1 to 7. Patients were permitted up to two courses of induction. Subsequently, patients were given consolidation chemotherapy that included cytarabine 3 gm/m2 per day twice daily on days 1, 3, and 5 for two courses. Subsequently, peripheral blood stem cells were collected as the peripheral blood counts were recovering from a second course of high-dose cytarabine consolidation. Patients then underwent high-dose chemotherapy with busulfan and cyclophosphamide followed by reinfusion of autologous stem cells. None of the patients received prior topoisomerase inhibitors (other than standard dose anthracyclines for induction).
Response Definitions
Complete remission was defined in each protocol as absence of leukemia in the bone marrow indicated by less than 5 % blasts, recovery of normal peripheral blood counts as indicated by absolute neutrophil count ≥ 1,500/μL, and platelet count ≥ 100,000/μL in the absence of extramedullary leukemia. None of the studies permitted registration of patients with secondary AML.
Statistical Analyses
Patient baseline characteristics and immunophenotype characteristics in M5a patients were compared with that in M5b patients using the Wilcoxon rank sum test for continuous variables and Fisher's exact test or χ2 test for dichotomous variables. A similar analysis was performed to compare M5 patients to non-M5 patients. Disease-free survival (DFS) was measured from the time of documented complete remission until relapse or death from any cause. Overall survival (OS) was calculated from the time of study entry until date of death from any cause. Patients without death information are censored at the date of last contact. DFS and OS were calculated by the Kaplan and Meier method and compared between two groups (M5 v M5b, M5 v non-M5) using the log-rank test.52 Proportional hazards model was also performed for DFS and OS. To assess differences in immunodiagnoses between M5a and M5b, Fisher's exact test was performed.
RESULTS
Patient Characteristics
Of the 81 patients, 21 had M5a and 60 had M5b (Table 1). The median age for all M5 patients was 49 years (range, 20 to 79 years); 48 years (range, 20 to 73 years) for M5a and 51.5 years (range, 22 to 79 years) for M5b, compared to 45 years (range, 16 to 86 years) for the 1,122 non-M5 patients (range, 16 to 86; P = .01). The median WBC count x 103/mm3 for all M5 patients was 30.0 (range, 1.3 to 178.0); 19.0 (range, 1.3 to 102.9) for M5a and 37.1 (range, 2.1 to 178.0) for M5b, compared to 11.3 (range, 0.2 to 409) for the 1,119 non-M5 (P < .001). More patients with M5 had extramedullary disease in the liver and skin (20% v 5%, P < .001 and 16% v 5%, P < .001, respectively). The presence of extramedullary disease was determined clinically by the treating physician. Data were not available to compare the incidence of CNS disease. The type of postremission therapy given in protocols E3489 and E4995 is shown in Table 2.
Patient Characteristics
Postremission Treatment for M5 and Non-M5 Patients in Protocols E3489 and E4995
Cytogenetic Analyses
Cytogenetic results for patients with M5 are summarized in Table 3. We identified the primary chromosome anomaly in the abnormal clone of each patient. We considered well-known chromosome anomalies associated with myeloid disorders or the observation of a sole anomaly as primary chromosome anomalies. The cytogenetic nomenclature for each patient with AML M5 that had either an abnormal clone or uncertain result is shown in Table 4. Ten of 32 patients (31%) with AML M5 who had a chromosomally abnormal clone had a translocation involving 11q23 (Table 3). In addition, five of nine patients (56%) with M5a who had a chromosomally abnormal clone had a translocation involving 11q23 compared with five of 23 patients (22%) with M5b.
Comparison of Cytogenetic Results for Patients With AML M5
Abnormal Cytogenetic Results for 34 Patients With AML M5
Of the 32 AML M5 patients with an abnormal cytogenetic clone, 10 (31%; patients 23 to 32) had a translocation involving 11q23; three had t(9;11)(p22;q23), three had t(10;11)(p11;q23), two had t(11;19)(q23;p13), one had t(6;11)(q27;q23), and one had dic(8;11)(p11;q23). These are common chromosome anomalies associated with AML M5.
In 11 (34%) of the 32 AML M5 patients (patients 3 to 13) with an abnormal clone, the primary anomaly was a numeric cytogenetic event. Notably, seven (22%) of these patients had trisomy 8.
Among patients with AML M5 with an abnormal clone, nine (28%; patients 17 to 19) had a chromosome deletion that was the primary cytogenetic event. Notably, four patients had deletions involving chromosome 11, and three of these patients had deletions in the q-arm with breakpoints at 11q21 or 11q23.
Among AML M5 patients with an abnormal clone, two (6%; patients 33 and 34) had complex karyotypes without classical chromosome anomalies associated with AML. The cytogenetics were not known to be associated specifically with AML and were therefore categorized as “other.”
Immunophenotype Analyses
All cases were immunophenotypically characterized for the expression of monocytic (CD11b, CD14) and myeloid (CD33, CD13, CD65s, and CD15/15s) differentiation markers. Table 5 summarizes the percentage of patients who were positive (using the 20% cutoff point) for a given antigen and the median and interquartile ranges of expression for each marker on gated leukemic cells in M5a compared with M5b patients. Only the expression frequency of CD11b, a marker of early monocytic differentiation, was statistically different between M5a and M5b (P = .02). The median percent CD11b+ leukemic cells for M5a was 53% versus 77% for M5b. ECOG purposely avoids the a priori definition of arbitrary cutoff levels of antigen expression to describe “positivity” of a given antigen. However, this data set has been added to facilitate comparisons with other published information that use the common 20% cutoff level for defining antigen expression. An immunophenotype consistent with acute monocytic leukemia (CD11b+ and CD14+) was seen in 27 (33%) of 75 of all M5 cases. An immunophenotype consistent with immature monocytic leukemia (CD11b+ and CD14−) was seen in 24 (32%) of 75 M5 cases. An antigen profile consistent with acute myelomonocytic leukemia was seen in 14 (19%) of 75 cases. In seven (9%) of 75 of all M5 cases, immunophenotyping failed to identify monocytic antigens, although the blast cells demonstrated a classical cytochemical monocytic reaction pattern. These patients who had an immunophenotype of differentiated acute myeloid leukemia were more frequent in the M5a (32%) than the M5b (2%) group (P < .01).
Two-Sample Test on Antigen Expression
Complete Remission
The complete remission rate was 52% for M5a patients, 65% for M5b patients, and 62% for all M5 patients, compared to 60% for non-M5 patients (P = .8; Tables 1 and 2).
Disease-Free Survival
The median DFS for all M5 patients was 7.3 months (95% CI, 5.5 to 15); 5.4 months for M5a (95% CI, 2.7 to 24) compared to 11.3 months (95% CI, 6.4 to 19.8) for M5b patients, and the 3-year DFS was 26% (Table 6; Fig 3). The median DFS for all non-M5 patients on these 3 studies was 13.3 months (95% C.I. 11.7, 15.8) and the 3-year DFS was 33% (Fig 4). An additional, proportional hazards model was performed to examine the impact of FAB type (M5 v non-M5) on DFS in the presence of age, WBC, platelet count, hemoglobin, and allogeneic transplant for the studies E3489 and E4995. The FAB type was not significant. Of note, because of the small sample size (three M5a and 26 M5b who received consolidation treatment in E3489 and E4995), modeling for M5a and M5b was not performed.
Disease-free survival (DFS) of patients from Eastern Cooperative Group studies E3489, E4995, and E3993 with acute monocytic leukemia M5a and M5b.
Disease-free survival (DFS) of patients with acute monocytic leukemia (AML) M5 and non-M5 AML.
Disease-Free Survival
Overall Survival
The OS for all M5 patients was 12.5 months (95% CI, 9.4 to 20.9). The median OS for the M5a patients was 11.3 months (95% CI, 4.8 to not estimable) and 13 months (95% CI, 9.4 to 22.0) for the M5b patients (Fig 5; Table 7). For non-M5 patients, the median OS was 13.7 months (95% CI, 12.6 to 14.8; P = .74 for M5 v non-M5 patients; Fig 6). Proportional hazards model was also performed for OS to examine the impact of FAB type (M5 v non-M5) on OS in the presence of age, WBC, platelet count, Hgb, and allogeneic transplant for the studies E3489 and E4995. The FAB type was not significant.
Overall survival of patients with acute monocytic leukemia M5 and M5b.
Overall survival of patients with acute monocytic leukemia (AML) M5 and non-M5 AML.
Overall Survival
DISCUSSION
Historically, patients with AML M5 have been considered to have a poorer prognosis than other subtypes of AML. This impression comes from the association of M5 with hyperleukocytosis22-25 which confers a poor prognosis,53 extramedullary disease,26-33,54 and abnormal coagulation2,34-36 However, few studies have evaluated the outcome of this subset of patients treated with contemporary therapeutic strategies that include both more intensive consolidation than in the past and better supportive care.55
The experience reported here shows that the complete remission rate, 3-year DFS, and OS of patients with AML M5 were not statistically different than other subtypes of AML. These data stand in contrast to earlier reports from single institutions that suggest, with respect to complete remission rate56-58 and OS,2,3,56,57 that patients with AML-M5 have a long-term outcome of less than 20% at 5 years. Furthermore, the ECOG 20-year experience among newly diagnosed patients with AML, which includes patients treated before current intensive postremission strategies, showed that the 5-year long-term survival rate for patients with AML M5 is only 5%.37 However, this latter series of studies included trials with increasingly intensive postremission chemotherapy; in early studies, patients received either no consolidation chemotherapy, only maintenance therapy following induction, or less intensive consolidation than is currently routinely administered.59 Stein et al58 reported a 5-year event-free survival of only 13%, but only eight patients were reported and patients older than 50 years of age received a reduced dose of cytarabine (1.5 gm/m2 v 3 gm/m2). In the large study by Fenaux et al,2 patients were not intensively consolidated and the OS at 5 years is less than 20%. However, consistent with the data here, the 5-year DFS and OS for 160 patients with M5 treated with intensive cyclic consolidation (albeit with a maximum high-dose cytarabine dose of 1gm/m2) were 40% and 33%, respectively, in the Medical Research Council AML 10 trial with no difference in outcome for any FAB subtype.47 Since two of the three studies in the present report were restricted to younger patients, data on median age and perhaps other clinical characteristics may be different than the entire population of M5 patients.
In the present analysis, patients with M5a morphology (poorly differentiated) showed a lower complete remission rate and shorter DFS compared to those with M5b or non-M5 patients (52% v 65% v 60% and 18% DFS at 3 years v 28% v 33%), but it is possible that the numbers of patients are too small to reach any conclusions. Fenaux et al2 also found no significant difference in complete remission rate of DFS between patients with M5a and M5b. The outcome for all M5 patients was less favorable than reported here. Many of the patients in the analysis by Fenaux et al received epipodophyllotoxins including etoposide and teniposide, but not high-dose cytarabine. The outcome of patients with both M5a and M5b in the report by Fung et al35 is also less favorable than reported here. Only four patients were classified as M5b or differentiated M5. Six patients in this series had received prior therapy for another malignancy. This is not surprising since six of the 27 patients achieving complete remission did not receive consolidation.
Ten (31%) of 32 AML M5 patients with an abnormal clone had a translocation involving 11q23. Translocations involving 11q23 are commonly associated with AML M55-20 and are reported to predict a poor outcome.60 However, not all patients with the 11q23 abnormality have similar outcomes.32,49,61 Those patients with 11q23 anomalies associated with t(9;11) have a better outcome than those with other translocations involving 11q23.60,61 Such differences may explain some of the variety in outcome in the literature. Too few patients with each cytogenetic subgroup are available in this study for meaningful subset analysis, though more patients with M5a had a translocation involving 11q23 than patients with M5b. This observation would be consistent with Haferlach et al,62 who suggested that the incidence of translocations involving 11q23 is higher among patients with M5a. Nevertheless, it is clear that patients with AML M5 represent a cytogenetically heterogeneous population.
We found that AML M5 represents an immunologically heterogenous population of patients. Interestingly, within the group of morphologically poorly differentiated M5a patients, one third lacked monocytic antigens (CD11b and CD14) despite typical monocytic cytochemical studies. The antigen profile of these patients was consistent with differentiated AML. Only one of the 56 M5b patients demonstrated this phenotype. Cytogenetic analysis in three of five undifferentiated M5a patients and in the one differentiated M5b patient revealed translocations involving 11q23 suggesting that contrary to previously published information,11 AML with 11q23 translocations are not invariably associated with monocytic features when analyzed by multiparameter flow cytometry. Although M5b cases showed a higher percentage of CD11b expressing leukemic cells, the incidence of CD11b+ AML did not differ between M5a and M5b. We have previously reported that CD11b+ AML, characterized by presence of CD11b in the absence of CD14, should be considered a distinct leukemic syndrome associated with poor prognosis.63
Although with currently available therapies, the outcome of patients with AML M5 does not appear to be different than other subtypes of AML, OS is unsatisfactory. New approaches are needed for AML in general. A recent small series reported disappointing results with human leukocyte antigen-matched sibling/allogeneic stem-cell transplantation for patients with 11q23 abnormalities, most of whom had M4 or M5 disease.64 The growth of monocytic leukemia cells is inhibited in a dose-dependent fashion by the deoxyadenosine analog, 2-deoxycoformycin.65-67 Furthermore, 2-deoxycoformycin enhances the differentiation of monocytic leukemia cells induced by cytarabine.68 Among 73 pediatric patients with previously untreated AML, patients with M5 had a higher complete remission rate after treatment with 2-CDA, another deoxyadenosine analog (45% after one course and 71% after two courses) than did other subtypes (P = .002).69 Strategies incorporating 2-deoxycoformycin into the treatment of patients with AML M5 should be pursued. In AML blast cells from children, Flt3 receptor expression is common, but proliferative responses to the ligand appear to be confined to AML M5 blasts, suggesting a strategy of administering an Flt3 inhibitor may be effective. Flt3 length mutations have been reported to be more frequent in patients with M5b compared to M5a (28.8% v 6.9%; P = .0014).62 Furthermore, interleukin-4 inhibits proliferation induced by Flt3 ligand and such combinations may prove worthwhile to explore.70
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Footnotes
-
Presented in part at the Annual Meeting of the American Society of Hematology, Orlando, FL, December 7-11, 2001.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
- Received August 8, 2003.
- Accepted January 12, 2004.
