Blood Journal
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Adult acute megakaryocytic leukemia: an analysis of 37 patients treated at M.D. Anderson Cancer Center

  1. Yasuhiro Oki,
  2. Hagop M. Kantarjian,
  3. Xian Zhou,
  4. Jorge Cortes,
  5. Stefan Faderl,
  6. Srdan Verstovsek,
  7. Susan O'Brien,
  8. Charles Koller,
  9. Miloslav Beran,
  10. B. Nebiyou Bekele,
  11. Sherry Pierce,
  12. Deborah Thomas,
  13. Farhad Ravandi,
  14. William G. Wierda,
  15. Francis Giles,
  16. Alessandra Ferrajoli,
  17. Elias Jabbour,
  18. Michael J. Keating,
  19. Carlos E. Bueso-Ramos,
  20. Elihu Estey, and
  21. Guillermo Garcia-Manero
  1. From the Departments of Leukemia, Biostatistics and Applied Mathematics, and Hematopathology, University of Texas M.D. Anderson Cancer Center, Houston, TX.

Abstract

To characterize acute megakaryocytic leukemia (FAB M7 AML), we identified 37 patients with M7 AML treated at M.D. Anderson Cancer Center between 1987 and 2003 and compared them with 1800 patients with non-M7, non-M3 AML treated during the same period. The median age of the M7 AML group was 56 years (range, 21-78 years); 22 patients (59%) had an antecedent hematologic disorder or myelodysplastic syndrome or both, and 7 patients (19%) had previously received chemotherapy for other malignancies. Extensive bone marrow fibrosis was found in 23 patients (62%). Poor cytogenetic characteristics were observed in 49% of patients with M7 AML versus 33% of others (P < .001). Complete remission rates were 43% with M7 AML and 57% with non-M7 AML (P = .089). Median overall survival (OS) was 23 and 38 weeks, respectively (P = .006). Median disease-free survivals were 23 versus 52 weeks, respectively (P < .001). By multivariate analysis, M7 AML was an independent adverse prognostic factor for OS, independent of other factors including cytogenetic abnormalities (hazard ratio 1.51, P = .049). These results confirm the poor prognosis of M7 AML and indicate that other biologic characteristics beyond cytogenetic abnormalities likely play a role in this disease.

Introduction

Acute megakaryocytic leukemia was first described as a subtype of acute myelogenous leukemia (AML) in 19311 and was incorporated into the French-American-British (FAB) classification of AML as M7 in 1985.2 Bone marrow characteristics include proliferation of abnormal megakaryoblasts identified by the presence of platelet-specific surface glycoprotein and frequently extensive myelofibrosis.

M7 AML is a common form of childhood AML, occurring in 7% to 10% of cases3 and is associated with poor prognosis. Patients with Down syndrome appear to have an increased incidence of M7 AML but have a more favorable prognosis compared to patients without Down syndrome.3 In contrast, M7 AML is rare in adults, occurring in about 1% of all AML cases.4,5 Because of its low incidence, the reported clinical experience with this type of adult leukemia is limited.

Herein, we summarize our experience with M7 AML at M.D. Anderson Cancer Center (MDACC) between 1987 and 2003. The purpose is to describe the clinical and biologic characteristics of patients with M7 AML, to compare them to patients with other forms of AML, and to assess the impact of this pathologic finding on prognosis.

Patients, materials, and methods

Study group

Patients with newly diagnosed M7 AML at MDACC between 1987 and 2003 were analyzed. Patients with newly diagnosed other AMLs, excluding acute promyelocytic leukemia (APL), referred during the same period of time were used as a control group. Informed consent was obtained from all patients, according to the institutional guidelines and the Declaration of Helsinki.

AML was diagnosed by the presence of at least 30% blasts in the bone marrow.6 In patients with poor-quality marrow aspiration smears, the presence of clusters of blasts in the marrow core biopsy or 5% or more circulating blasts were used to support the diagnosis of AML. Diagnosis of M7 AML was established by the FAB criteria2; blast cells needed to be identified as being of megakaryocyte lineage by positive immunocytochemistry stain for platelet-specific antigens including factor VIII, CD41, and CD61.

Laboratory data

Bone marrow cytogenetic characteristics were classified into 3 prognostic groups (modified from previous reports7-9): poor (-5, -7, + 8, or 11q involvement); favorable (t(8;21), inv(16), t(16,16)); and other (neither poor or favorable).

Treatment

Patients received several different induction regimens depending on time period, age, performance status, and availability of clinical trials. Induction regimens were categorized into 5 groups. Regimens containing cytarabine (ara-C) and anthracyclines were group 1. Regimens containing ara-C and fludarabine but not containing anthracyclines were group 2. Regimens containing topotecan were group 3. Regimens containing ara-C and not containing anthracyclines, fludarabine, or topotecan were group 4. Regimens not containing ara-C were group 5.

Criteria for response and definition of disease-free survival

Complete remission (CR) was defined by the presence of less than 5% blasts in the bone marrow, absence of extramedullary leukemia, and peripheral blood count recovery with a neutrophil count of at least 1 × 109/L and a platelet count of at least 100 × 109/L.10,11 Treatment failure was defined by the absence of documented CR, including induction death or refractory disease. Relapse was defined by an excess of 10% leukemic blasts in a marrow aspirate unrelated to recovery of normal hematopoiesis or the development of new extramedullary leukemia. Disease-free survival (DFS) was calculated from the time of first documented CR to relapse or death in CR.

Statistical methods

The Fisher exact tests and t tests were used for the descriptive statistical analysis on categorical and continuous data, respectively.12 Survival curves were estimated according to the Kaplan-Meier product-limit method.13 Univariate and multivariate logistic regression models14 were used to evaluate the associations between multiple characteristics and CR. Clinical and biologic characteristics were also analyzed for their association with survival using Cox proportional hazards models.15 Survival times between patients with different characteristics were compared by the log-rank test.16 Characteristics with P values below 10 in the univariate Cox proportional hazards model were included in the multivariate model. In this model a backward elimination with a P cutoff of .05 was used. Any variable previously deleted could re-enter the final model if it had a P value below .05 when added to that model. All computations were carried out in SAS (Cary, NC).

Results

Patient characteristics

From January 1987 to November 2003, 1837 patients were diagnosed with untreated AML (excluding M3) at MDACC. Of these, 37 patients (2%) were characterized as having M7 AML. The proportion of patients with M7 AML did not change significantly over the time period: 3 (1.0%) of 313 during 1987-1990, 8 (2.3%) of 352 during 1991-1994, 12 (2.8%) of 429 during 1995-1998, and 14 (1.9%) of 743 during 1999-2003. Patient characteristics are summarized in Table 1. Several characteristics at presentation were different between the 2 groups. M7 AML was associated more frequently with antecedent hematologic disorder (AHD) or myelodysplastic syndrome (MDS) (P = .012), poor cytogenetics (P = .045), lower white blood cell (WBC) count (P < .001), and a lower percentage of bone marrow blasts (P < .001). Assignment to different treatment groups was not significantly different between M7 and non-M7 groups.

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Table 1.

Patient characteristics

Figure 1.

Overall survival of patients with M7 and non-M7 AML. The median survival time for patients with M7 and non-M7 AML was 23 and 38 weeks, respectively (P = .006).

Figure 2.

Disease-free survival of patients with M7 and non-M7 AML. The median of disease-free survival for patients with M7 and non-M7 was 23 and 52 weeks, respectively (P < .001).

In the M7 AML group, 10 patients (27%) had prior MDS, with median duration of 4 months (range, 2-160 months) prior to the diagnosis of M7 AML. Twelve (32%) other patients had various AHDs (6 with myeloproliferative disorder, 2 with cytopenias, and 4 with other disorders). Two patients with myeloproliferative disorder had received chlorambucil. Four patients with MDS had previously received chemotherapy for other malignancies (breast, ovarian, non-small-cell lung cancer, and Waldenstrom macroglobulinemia). One patient without AHD/MDS had a previous history of non-Hodgkin lymphoma. None of the patients with M7 AML had Down syndrome or mediastinal germ cell tumor.18

Detailed results of the cytogenetic findings in patients with M7 AML are summarized in Table 2. It should be noted that 18 patients (49%) had one or more of poor cytogenetic abnormalities (-5, -7, +8, or 11q involvement). Abnormalities in chromosome 3 were also frequently observed (6 patients, 16%), often associated with other poor cytogenetic abnormalities (4 patients, 11%). The Philadelphia chromosome abnormality was detected in 3 patients (8%) without prior history or clinical features of chronic myeloid leukemia, such as splenomegaly, basophilia, or thrombocytosis.

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Table 2.

Summary of cytogenetic abnormalities in patients with M7 AML

Outcome

The CR rate with M7 AML was 43% versus 57% with non-M7 AML (P = .089). Median OS times were 23 weeks and 38 weeks, respectively (P = .006; Figure 1). Among patients who achieved CR, the median DFS durations were 23 weeks and 52 weeks, respectively (P < .001; Figure 2). Twenty-three (62%) patients with M7 AML had refractory disease after first induction chemotherapy. None achieved CR after salvage induction chemotherapy. All 3 patients with Philadelphia chromosome-positive M7 AML achieved CR after induction therapy; their survivals were 12, 56, and 92 weeks. Two patients with primary refractory disease and 3 patients with relapsed disease underwent allogeneic stem cell transplantation with active disease. Median survival after stem cell transplantation in those 5 patients was 21 weeks (range, 8-72 weeks).

Prognostic factors for treatment response

The characteristics of patients with AML (including M7 AML) with and without CR are shown in Table 3. By univariate analysis, older age, poor performance status, induction therapy not in the laminar flow room, AHD/MDS, lower hemoglobin level, higher prothrombin time, higher β2-microglobulin concentration, higher total bilirubin level, higher lactate dehydrogenase (LDH) level, poor cytogenetics, and treatment group 4 (containing ara-C, not containing anthracycline, fludarabine, topotecan) were associated with treatment failure. M7 AML was marginally associated with treatment failure by univariate analysis (P = .093). By multivariate analysis, older age, treatment outside the laminar flow room, poor performance status, AHD/MDS, higher β2-microglobulin level, higher prothrombin time, poor cytogenetics, and treatment group 4 were independent predictive factors for treatment failure (Table 4). M7 AML was not an independent predictive factor for treatment failure. Subset analysis of patients without the Philadelphia chromosome abnormality identified the same parameters to be associated with treatment failure.

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Table 3.

Characteristics of all AML patients with CR versus no CR

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Table 4.

Multivariate analysis for CR

Prognostic factors for OS

By univariate analysis, older age, treatment outside the laminar flow room, poor performance status, AHD/MDS, higher WBC count, lower hemoglobin concentration, higher prothrombin time, higher β2-microglobulin level, higher total bilirubin level, lower bone marrow blast percentage, higher LDH concentration, poor cytogenetics, treatment group 4 (containing ara-C and not containing anthracycline, fludarabine, and topotecan), and M7 AML were independent negative factors for OS. By multivariate analysis, older age, treatment outside laminar flow room, poor performance status, AHD/MDS, higher WBC count, lower hemoglobin level, higher β2-microglobulin concentration, higher total bilirubin level, lower bone marrow blast percentage, higher LDH level, poor cytogenetics, treatment group 4, and M7 AML were independent negative factors for OS (Table 5). Subset analysis of patients without Philadelphia chromosome revealed the same results.

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Table 5.

Multivariate analysis for survival

Discussion

In this report, we analyzed the clinical and laboratory characteristics of patients with M7 AML and compared them with those of a large cohort of patients with other AMLs diagnosed during the same time period. As in previous reports,4,5,19 we confirmed the poor prognosis of patients with M7 AML. Although M7 AML was not significantly associated with a lower CR rate compared with other forms AML, OS and DFS were significantly worse in the M7 AML group. By multivariate analysis, M7 AML was an independent adverse prognostic factor for OS along with other factors such as cytogenetic abnormalities and the presence of AHD/MDS.

Previous reports of adult M7 AML are summarized in Table 6.4,5,19 The characteristics of our patients were similar to those seen in previous reports. Despite the fact that as many as 50% of patients achieved CR, DFS of M7 AML was short, with a median duration of 6 to 10 months. OS was also poor, with a median survival of only 4 to 10 months.

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Table 6.

Summary of reports on adult M7 AML

Multiple chromosome aberrations have been identified in patients with M7 AML (Table 2). Abnormalities of chromosome 3 have been typical in all series to date. Other common cytogenetic findings include abnormalities of chromosome 5 or 7 or both, which were most common in our study and that of the Groupe Francais d'Hematologie Cellulaire (GFHC).19 Although pediatric M7 AML is often associated with t(1;22)(p13;q13) resulting in the OTT-MAL fusion transcript, this abnormality has not been reported in adults with M7 AML.

A recent report from the European Group of Blood and Marrow Transplantation (EBMT) described the characteristics and prognosis of patients with M7 AML undergoing stem cell transplantation (37 autologous and 32 allogeneic) after first CR.20 Median times from diagnosis to autologous and allogeneic transplantation were 29 weeks (range, 15-114 weeks) and 20 weeks (range, 9-117), respectively. The 3-year OS rates were 30% and 43%, respectively. The 3-year DFS rates were 27% and 46%, respectively. Given the dismal outcome of M7 AML even after achieving CR in our study and others, allogeneic transplantation during first CR appears to be beneficial in these patients.

The most important finding of our study is that a histopathologic diagnosis of M7 AML was an independent adverse prognostic factor for OS. Thus, the poor prognosis of M7 AML is not fully dependent on cytogenetic abnormalities. It indicates that distinctive biologic mechanisms play a role in M7 AML.

In conclusion, M7 AML is a rare form of adult AML, which is often observed in the setting of prior AHD/MDS or therapy-related leukemia. Histopathologic evidence of M7 AML itself is an independent poor prognostic factor for OS. A better understanding of the pathophysiology of M7 AML and new therapeutic strategies are needed for patients with M7 AML.

Footnotes

  • Reprints:

    Guillermo Garcia-Manero, Department of Leukemia, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: ggarciam{at}mdanderson.org.
  • Prepublished online as Blood First Edition Paper, August 25, 2005; DOI 10.1182/blood-2005-06-2450.

  • 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.

  • Submitted June 21, 2005.
  • Accepted July 22, 2005.

References

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