|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Northwestern University Medical School, Robert
H. Lurie Cancer Center, Chicago IL; Biostatistics, Dana-Farber Cancer
Institute, Boston, MA; University of Rochester Medical Center,
Rochester, NY; Our Lady of Mercy Medical Center, Bronx, NY;
Cytogenetics Laboratory, Mayo Clinic, Rochester, MN; University of
Miami, Sylvester Comprehensive Cancer Center, Miami, FL; Virginia Piper
Cancer Institute, Minneapolis, MN; Rambam Medical Center, Technion
Haifa, Israel; For The Eastern Cooperative Oncology Group, Brookline,
MA.
Acute megakaryocytic leukemia (AMegL) is a rare subtype of acute
myeloid leukemia (AML) evolving from primitive megakaryoblasts. Because
of its rarity and the lack of precise diagnostic criteria in the past,
few series of adults treated with contemporary therapy have been
reported. Twenty among 1649 (1.2%) patients with newly diagnosed AML
entered on Eastern Cooperative Oncology Group (ECOG) trials between
1984 and 1997 were found to have AMegL. The median age was 42.5 years
(range 18-70). Marrow fibrosis, usually extensive, was present in the
bone marrow. Of the 8 patients who had cytogenetic studies performed,
abnormalities of chromosome 3 were the most frequent. The most
consistent immunophenotypic finding was absence of myeloperoxidase in
blast cells from 5 patients. In the most typical 3 cases, the leukemic
cells were positive for one to 2 platelet-specific antigens in addition
to lacking myeloperoxidase or an antigen consistent with a lymphoid
leukemia. Myeloid antigens other than myeloperoxidase and selected
T-cell antigens (CD7 and/or CD2) were frequently expressed. Induction
therapy included an anthracycline and cytarabine in all cases. Complete
remission (CR) was achieved in 10 of 20 patients (50%). Two patients
remain alive, one in CR at 160+ months. Resistant disease was the
cause of induction failure in all but 3 patients. The median CR
duration was 10.6 months (range 1-160+ months). The median survival for all patients was 10.4 months (range 1-160+ months). Although half of
the patients achieved CR, the long-term outcome is extremely poor,
primarily attributable to resistant disease. New therapeutic strategies
are needed.
(Blood. 2000;96:2405-2411) Acute megakaryocytic leukemia (AMegL) is a rare
subtype of acute myeloid leukemia (AML) developing from primitive
megakaryoblasts, first described by Von Boros and colleagues in
1931.1 The disease can be identified by antibodies to
glycoprotein IIb/IIIa and is often associated with extensive
myelofibrosis.2-9 Reports in the literature have been
sporadic because of both the rarity of the disease and the lack of
well-established diagnostic criteria. Precise diagnostic criteria were
added to the French-American-British (FAB) classification only
relatively recently and the disease is also referred to as FAB
M7.10 Therefore, because many cases were reported in older
literature, patients previously categorized as AMegL represent a
heterogenous group.
Despite the paucity of reports, several unusual associations with AMegL
have been identified. First, AMegL has been linked to primary
mediastinal germ cell tumors.11-13 Second, children with
Down syndrome appear to have an increased incidence of AMegL and such
patients have a more favorable outcome than when AMegL occurs without
such an association in adults.14-19 Patients also have
been described with AMegL without Down syndrome, but whose leukemic
cells have abnormalities of chromosome 21, the specific chromosome
associated with Down syndrome.20,21 Third, extensive fibrosis is frequently, but not invariably, present.22-25
Although some patients achieve complete remission (CR), few patients
survive beyond 3 years.26-29 Clinical experience with this
rare leukemia remains limited. This analysis was designed to
determine the laboratory and clinical features, biologic
characteristics, and outcome of patients with AMegL treated with a
contemporary induction regimen that included an anthracycline and
cytarabine on Eastern Cooperative Oncology Group acute leukemia protocols.
Patients
Diagnosis of acute megakaryocytic leukemia (FAB M7)
Treatment Patients with AMegL were identified from the ECOG database of patients entered on the following 5 clinical trials for previously untreated AML. EST 3483 was a prospective randomized phase III trial of postremission therapy in AML.34 Patients with previously untreated AML were given one to 2 courses of induction with daunorubicin 60 mg/m2 intravenously per day for 3 days, cytosine arabinoside 200 mg/m2 continuous intravenous (IV) infusion for 5 days plus 6-thioguanine 100 mg/m2 orally every 12 hours for 5 days, and then randomized to either one course of intensive consolidation therapy with high-dose cytosine arabinoside 3 gm/m2 IV every 12 hours days 1 to 6, plus amsacrine 100 mg/m2 per day IV on days 7 to 9 or maintenance therapy for 2 years with 6-thiogranine 40 mg/m2 twice daily each week plus cytosine arabinoside 60 mg/m2 subcutaneously on day 5 each week or observation. Patients younger than 41 years with a histocompatible sibling were to undergo allogeneic transplantation. EST 1490 was a randomized placebo-controlled phase III study of granulocyte-macrophage colony-stimulating factor (GM-CSF) in adult patients (older than 55-70 years) with AML.35 Induction consisted of one to 2 courses of daunorubicin 60 mg/m2 for 3 days and cytosine arabinoside 100 mg/m2 daily for 7 days by continuous IV infusion. If the day-10 bone marrow was hypoplastic, patients were randomized to receive GM-CSF 250 µg/m2 IV or placebo until neutrophil recovery. Consolidation therapy consisted of cytosine arabinoside 1.5 gm/m2 IV every 12 hours for 6 days. PC 486 was a phase II pilot study of autologous bone marrow transplantation in patients with AML in first CR using 4-hydroperoxy-cyclophosphamide-treated marrow.36,37 Induction consisted of daunorubicin 60 mg/m2 per day by IV push for 3 days on days 1 to 3 and cytarabine 25 mg/m2 IV push, followed by continuous plus thioguanine 100 mg/m2 every 12 hours orally on days 1 to 5. In EST 3489, remission was induced by idarubicin 12 mg/m2 IV for 3 days and cytosine arabinoside IV continuous infusion days 1 to 7. Subsequently, patients with a suitably HLA-matched donor were assigned to allogeneic transplantation and others were randomized to either autologous bone marrow transplantation or conventional consolidation chemotherapy.38 Postremission chemotherapy included high-dose cytosine arabinoside 3 gm/m2 every 12 hours for 6 days and allogeneic bone marrow transplantation. EST 4995 was a phase II study of an intensified induction regimen, including daunorubicin 45 mg/m2 IV days 1 to 3, cytosine arabinoside 100 mg/m2 per day IV days 1 to 7 and 3 days of high-dose cytosine arabinoside 2 g/m2 IV days 8 to 10, followed by 2 cycles of consolidation chemotherapy that includes high-dose cytosine arabinoside 3 gm/m2 IV every 12 hours days 1, 3, and 5, followed by either allogeneic or autologous bone marrow or stem cell transplantation.39
Clinical and laboratory characteristics at presentation Twenty patients among 1649 (1.2%) patients entered on the 6 ECOG trials between 1984 and 1997 for previously untreated AML had AMegL. Fourteen of the 20 patients (70%) were men and 6 (30%) were women (Table 1). The median age was 42.5 years with a range of 18 to 70 years. The median white blood cell (WBC) count was 2.0 × 109L (range 0.8-35.2), the median hemoglobin was 8.8 g/dL (range 4-14), and the median platelet count was 65 × 109/L (range 12-1450). Three patients had a platelet count greater than 1000 × 109/L. The median peripheral blast percentage was 7.5% (range 0%-84%) and the median percentage of blasts in the bone marrow was 59% (range 5%-99%). Marrow fibrosis was present in the bone marrow core biopsy specimens from all 17 patients in whom it could be assessed. Fifteen patients (75%) had extensive fibrosis (scattered or diffuse coarse fibers). Extramedullary disease was present on clinical grounds at the time of diagnosis in the spleen (one patient); and liver, spleen, and skin (one patient). None of the patients had Down syndrome.
Cytogenetic studies Eight of the 20 patients had cytogenetic studies carried out (Table 2). Karyotype analysis was normal in 2 cases. Abnormalities involving chromosome 3 were the most frequent. Two patients had a t(3;3) (q21;q26) translocation, one had a t(3;12)(q25;p11.2) translocation, and one patient had an inv3(q21;q26) abnormality. Twelve patients had no cytogenetic studies performed. Two other cases had different chromosomally abnormal clones.
Central immunophenotyping For patients entered on the early AML treatment study E3483, central immunophenotyping was not yet performed in the ECOG. Material for immunophenotyping was submitted to the ECOG's reference laboratory for 9 of the more recent patients. Because of marrow fibrosis, immunophenotyping studies were successful in only 7 of these patients (patients 1, 4, 5, 6, 7, 8, ad 15) (Table 2). The most consistent and significant finding with respect to diagnosis was the absence of myeloperoxidase in the blast cells from 5 of the patients. HLA-DR and CD34 were commonly expressed. In the immunophenotypically most typical cases of AMegL, patients 6, 7, and 8, the leukemic cells were positive for one to 2 platelet-specific antigens in addition to lacking myeloperoxidase or an antigen profile consistent with a lymphoid leukemia. Myeloid antigens other than myeloperoxidase and selected T-cell antigens (CD7 and/or CD2) were frequently expressed. B-cell antigens were not detected. Blast cells from 2 patients expressed myeloperoxidase (cases 4 and 15) as well as myelomonocytic antigens, but lacked megakaryocytic markers.Cytoimmunochemistry All patients had a morphologic and/or histologic description consistent with a diagnosis of AMegL. Platelet glycoprotein staining was positive in the institution or ECOG reference laboratory in patients 1, 3, 7, and 8 (Table 3). Factor VIII was positive in patients 2, 4, 7, 8, 9, 11, and 20. Therefore, in 13 of the 20 cases, either myeloperoxidase was negative and/or platelet glycoprotein CD41 and/or factor VIII was positive. Although nonspecific, the alpha naphthyl acetate stain was negative in 2 cases (patients 11 and 18) and positive in only one case (patient 3). Granulocytic dysplasia was present in patients 3, 5, 6, 8, and 15. Erythroid dysplasia was present in patient 12.
Outcome Complete remission was achieved in 10 of the 20 patients (50%) (Table 4). Ten patients (50%) had no response. One patient remains alive and in remission at 160+ months. Resistant disease was the cause for induction failure in all but 3 patients who died of respiratory failure, sepsis, and probable infection.
Remission duration The median remission duration among patients achieving CR was 10.6 months with a range of 1 to 160+ months (Figure 1).
Overall survival The median overall survival for all patients was 10.4 months with a range of 1 to 160+ months (Figure 1). Six patients survived for more than 1 year beyond study entry. Of these, 5 achieved CR. The sixth patient was treated on PC486, a transplant study and died 3.1 years after study entry. One patient treated on E3483 remained alive 6.8 years after study entry, and updated survival information was last obtained in February 1992. Two patients remain alive, one treated on E3483 remains alive in CR at 160+ months and one treated recently on E4995, who received a peripheral blood stem cell transplant off study, has relapsed and survives 22 months after study entry.
Although the first description of AMegL appeared in the literature almost 70 years ago,1 reports of the natural history of the disease have generally been confined to either sporadic small series,2-9 reports of one or 2 cases40-44 or descriptions of the clinical course in infants and children.45-50 Many cases previously reported antedated the establishment of precise diagnostic methods. In fact, this subtype became part of the FAB classification only in 1985.10 Since then, immunophenotyping by flow cytometry has emerged as a useful method to improve the diagnostic sensitivity because cells from patients with AMegL express the megakaryocyte platelet lineage-specific marker CD61.51-53 Historically, the lack of specific criteria for the diagnosis has led to reports of patients who likely had AMegL, but whose disease was labeled acute myelofibrosis or myelosclerosis.54-60 Given the sophisticated methods now available to assist in the diagnosis and advances in therapeutic strategies for patients with AML, data regarding the biologic characteristics, response to contemporary induction therapy and natural history of AMegL in adults are needed. This analysis of 20 patients with AMegL represents cases with morphology confirmed at central review, and treated with anthracycline plus cytarabine-based induction. We found that the incidence of AMegL in adults was lower (1.2%) than often reported (3%-10%), although many earlier series include infants and children.8,9,27,53 Ribeiro and colleagues27 identified 14 cases among 150 consecutive patients (9.3%) seen at St. Jude Children's Research Hospital. The well-described, but unexplained association of AMegL with Down syndrome may account for the apparent higher incidence in the pediatric population. It is possible that the true incidence of AMegL was underestimated in this patient population, because strict FAB criteria were used requiring the presence of at least 30% blasts.10 Under the revised World Health Organization (WHO) criteria, the presence of 20% blasts would be sufficient.61 In addition, inaspirable bone marrows have contributed to the difficulty in establishing the diagnosis. Furthermore, patients with particularly poor prognoses may not be entered on multiinstitutional clinical trials. However, the precise incidence will require further study because of the historical difficulty in establishing the diagnosis. Clinically, AMegL and acute myelofibrosis are indistinguishable and careful examination of the morphology of marrow blasts, together with immunoperoxidase staining or immunophenotyping for expression of factor VIII are often required. 62 Although a formal comparison of the distinctive clinical features of only 20 cases of AMegL with other subtypes of AML is difficult because of the small numbers of cases, several observations can be made. The median age of the patients reported here is relatively young (42.5 years), compared with patients with other subtypes of AML (63 years). However, all the protocols onto which the patients reported here were entered, except one (E1490), focused on relatively young patients for whom transplant was a consideration. The median age of patients with other subtypes of AML on these trials was 41 years. Therefore, no definitive statement can be made about the median age of patients with AMegL compared with that of patients with other subtypes of AML. Marrow fibrosis is present in virtually all patients, in contrast to most other patients with AML. Abnormalities of chromosome 3, particularly 3q abnormalities, are often present and may be associated with preservation of the peripheral platelet count, as reported here.64 When the disease occurs in children, AMegL shows close associations with either of 2 cytogenetic abnormalities, t(1;22)(p13;q13) or numeric abnormalities of chromosome 21, especially trisomy 21. However, cytogenetic changes in adults with this disease are less clearly defined, but may involve rearrangements of chromosome 3, especially at 3q21 and 3q26-27, monosomy 7, monosomy or deletions of chromosome 5, and trisomy 8.65,66 In the patients reported here, 20% showed a t(3;3) or inv3, which when observed in other subtypes of AML are often associated with thrombocytosis and other platelet abnormalities.67,68 Two other patients demonstrated a monosomy 7 or deletion 5q. Although morphologic and cytochemical criteria are used to exclude other subtypes of AML, immunophenotyping is most valuable to differentiate between a lymphoid and a megakaryocytic nature of myeloperoxidase negative acute leukemia.33 An antigen profile typical of AMegL was observed in 3 of our 7 patients in whom immunophenotyping was successfully performed. The leukemic blasts were negative by staining with antibody to myeloperoxidase, lacked lymphoid antigens with the exception of selected T-antigens (CD2 or CD7), and expressed platelet-specific antigens on their surface (CD41, blood group H antigen, CD36). As observed by others, CD41 was associated with CD34 expression.69,70 Interestingly, blast cells from patient 7 also stained for CD36, which is generally considered a late differentiation marker of CD34 negative megakaryocytic cells.33 Myeloid antigens such as CD33 and CD13, as found in all 3 patients, are not uncommon in this disease. Patient 1, while lacking megakaryocytic antigens, also failed to express any of the other lineage-associated antigens tested. In view of the t(3;3) found in this patient's leukemic cells and taking into consideration the morphologic picture, the overall scheme suggests the diagnosis of AMegL. Blast cells from the other myeloperoxidase negative, platelet glycoprotein negative case, patient 5, expressed early myeloid antigens CD33 and CD13 but none of the later myeloid antigens, such as CD65s or CD15, or monocytic antigens, CD11b and CD14. Given the myeloperoxidase negativity and the AMegL morphology, the most likely immunodiagnosis in this case would also be AMegL. The 2 remaining patients, however, present a diagnostic dilemma. Blast cells from both patients 4 and 15 were positive for myeloperoxidase by antibody staining as well as for all myeloid antigens tested, as well as for the prototype monocytic antigen CD14. Without morphologic information, this antigen profile is most consistent with acute monocytic leukemia. Whenever tested, CD14 has been found to be negative in other reports of AMegL immunophenotyping.65,66,69 Although in patient 4, the t(3;3) would support the AMegL morphologic diagnosis, patient 15 demonstrated a normal karyotype, thereby adding to the diagnostic controversy. These immunophenotypic findings in a small group of patients characterized as AMegL by morphology further emphasize the importance of sophisticated laboratory studies in the diagnosis of this rare, clinically problematic group of patients. All patients reported here were initially treated with cytarabine and an anthracycline (daunorubicin or idarubicin) or a nonanthracycline DNA intercalator (amsacrine or mitoxantrone). In contrast, other reports have described the outcome with a variety of treatment including low-dose cytarabine,8,9,27 etoposide,8 and bone marrow transplantation.8,42,71 The CR rate achieved among patients reported here was 50%, which is somewhat lower than that generally achieved among patients with other morphologic subtypes of AML but is higher than that generally reported in the literature for adults with AMegL (25%-30%).3,8,59 It must be emphasized that no definite statement can be made about the CR rate with such relatively small numbers. The same applies to the few other series that have been reported, each evaluating a small number of cases treated in a heterogeneous way. Furthermore, many reported patients have not received a conventional anthracycline plus cytarabine combination for induction. In the series by Ribeiro et al,27 the CR rate among 24 children and adolescents was 42% (ages 4 months to 21 years, median 23.5 months). The highest CR rates have been reported by Ruiz-Arguelles and colleagues,26 who observed a CR rate of 73% for 26 patients treated with aggressive chemotherapy and 84% for the 19 patients given low-dose cytarabine, with median survivals of 10 and 4 months, respectively. The major cause of induction failure among patients reported here was resistant disease. Furthermore, despite a CR rate of 50%, the long-term outcome was extremely poor. Almost every patient died of the disease with relatively short remission durations. Only one patient remains alive and free of disease, a 59-year-old man treated on E3483 who is well 12 years after the diagnosis. This suggests that, although improvement in the CR rate is needed, improved postremission therapy is mandatory. The results of high-dose chemoradiotherapy and allogeneic stem cell transplantation have been reported only anecdotally.71 New therapeutic strategies need to be pursued, including biologic agents such as interferon72 and the apoptosis-inducing agent arsenic trioxide, which has recently been shown to cause an inhibition of growth and survival in megakaryocytic leukemia cell lines.73 The evaluation of such novel treatments will require the collaboration of multiple cooperative oncology groups.
Submitted December 23, 1999; accepted June 8, 2000.
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.
Presented in part at the American Society of Hematology meeting, New Orleans, LA, December 1999. Reprints: Martin S. Tallman, Division of Hematology/Oncology, Department of Medicine, Northwestern University Medical School, Robert H. Lurie Cancer Center, 676 N St Clair St, #850, Chicago, IL 60611-2927; e-mail: m-tallman{at}nwu.edu.
1. Von Boros J, Korenyi A. Uber einen fall von akuter megakaryocyblasten-leukamie, zugleich einige bemerkungen zum Problem der akuten leukemie. Z Klin Med. 1931;118:679-718.
2.
Breton-Gorius J, Reyes F, Duhamel G, Najman A, Gorin NC.
Megakaryoblastic acute leukemia: identification by the ultrastructural demonstration of platelet peroxidase.
Blood.
1978;51:45-60
3.
Bain BJ, Catovsky D, O'Brien M, et al.
Megakaryoblastic leukemia presenting as acute myelofibrosis 4. Bevan D, Rose M, Greaves M. Leukaemia of platelet precursors: diverse features in four cases. Br J Haematol. 1982;51:147-164[Medline] [Order article via Infotrieve]. 5. Innes DJ, Mills SE, Walker GK. Megakaryocytic leukemia: identification utilizing anti-factor VIII immunoperoxidase. Am J Clin Pathol. 1982;77:107-110[Medline] [Order article via Infotrieve]. 6. Mehta AB, Baughan AS, Catovsky D, et al. Reversal of marrow fibrosis in acute megakaryoblastic leukemia after remission-induction and consolidation chemotherapy followed by bone marrow transplantation. Br J Haematol. 1983;53:445-459[Medline] [Order article via Infotrieve]. 7. Mirchandani I, Palutke M. Acute megakaryoblastic leukemia. Cancer. 1983;50:2866-2872.
8.
Huang M-J, Li CY, Nichols WL, Young JH, Katzmann JA.
Acute leukemia with megakaryocytic differentiation: a study of 12 cases identified immunocytochemical.
Blood.
1984;64:427-439 9. Ruiz-Arguelles GJ, Marin-Lopez A, Lobato-Mendizabal E, Ruiz-Arguelles A, Nichols WL, Katzman JA. Acute megakaryoblastic leukemia: a prospective study of its identification and treatment. Br J Haematol. 1986;62:55-63[Medline] [Order article via Infotrieve]. 10. Bennett JM, Catovsky D, Daniel MT, et al. Criteria for the diagnosis of acute leukemia of megakaryocyte lineage (M7): a report of the French-American-British Cooperative Group. Ann Intern Med. 1985;103:460-462. 11. Nichols CR, Hoffman R, Einhorn LH, Williams SD, Wheeler LA, Garnick MB. Hematologic malignancies associated with primary mediastinal germ-cell tumors. Ann Intern Med. 1985;102:603-609. 12. Nichols CR, Hoffman R, Glant MD, Goheen M. Malignant disorders of megakaryocytes associated with primary germ cell tumors. Prog Clin Biol Res. 1986;215:347-353[Medline] [Order article via Infotrieve]. 13. Domingo A, Romagosa V, Callis M, Vivancos P, Guionnet N, Soler J. Mediastinal germ cell tumor and acute megakaryoblastic leukemia [letter]. Ann Intern Med. 1989;111:539. 14. Zipursky A, Peeters M, Poon A. Megakaryoblastic leukemia and Down's syndrome: a review. Prog Clin Biol Res. 1987;246:33-56[Medline] [Order article via Infotrieve].
15.
Evans DIK.
Acute myelofibrosis in children with Down's syndrome.
Arch Dis Child.
1975;50:458-462 16. Eguchi M, Ozawa T, Sakakibara H, Sugita K, Iwama Y, Furukawa T. Ultrastructural and ultracytochemical differences between megakaryoblastic leukemia in children and adults: analysis of 49 patients. Cancer. 1992;70:451-458[Medline] [Order article via Infotrieve]. 17. Eguchi M, Sakakibara H, Suda J, et al. Ultrastructural and ultracytochemical differences between transient myeloproliferative disorders and megakaryoblastic leukemia in Down's syndrome. Br J Haematol. 1989;73:315-322[Medline] [Order article via Infotrieve]. 18. Simon JH, Tebbi CK, Freeman AI, Brecher ML, Green DM, Sandberg AA. Acute megakaryoblastic leukemia associated with mosaic Down's syndrome. Cancer. 1987;60:2515-2520[Medline] [Order article via Infotrieve]. 19. Zipursky A, Christiensen H, De Harven E. Ultrastructural studies of the megakaryoblastic leukemias of Down syndrome. Leuk Lymphoma. 1995;18:341-347[Medline] [Order article via Infotrieve]. 20. Cosson A, Despres P, Gazengai C, Breton-Garius J, Perieur M, Joso F. Nouveau-ne trisomique 21, proliferation trisomique 21, proliferation megacaryocyto-plaquettaire: syndrome de coagulation intravescular e diffuse. Nouv Rev Fr Hematol. 1974;14:181-198. 21. Pui C-H, Williams DL, Scarborough V, Jackson CW, Price R, Murphy S. Acute megakaryoblastic leukemia associated with intrinsic platelet dysfunction and constitutional ring 2 chromosome in a young boy. Br J Haematol. 1982;50:191-200[Medline] [Order article via Infotrieve].
22.
San Miguel JF, Gonzales M, Canizo MC, et al.
Leukemia with megakaryoblastic involvement: clinical, hematological and immunological characteristics.
Blood.
1988;72:402-407 23. Breton-Gorius J, Tabilio A, Vainchenker W, et al. Diagnosis of megakaryoblastic leukemia. Verh Dtsch Ges Pathol. 1983;67:166-168[Medline] [Order article via Infotrieve].
24.
Cuneo A, Mecuci C, Kerim S, et al.
Multipotent stem cell involvement in megakaryoblastic leukemia: cytologic and cytogenetic evidence in 15 patients.
Blood.
1989;74:1781-1790 25. Koike T, Urushiyama M, Narita M, et al. Target cell of leukemic transformation in acute megakaryocytic leukemia. Am J Hematol. 1990;34:252-258[Medline] [Order article via Infotrieve]. 26. Ruiz-Arguelles GJ, Lobato-Mendizabal E, San-Miguel JF, et al. Long-term treatment results for acute megakaryoblastic leukemia patients: a multicentre study. Br J Haematol. 1992;82:671-675[Medline] [Order article via Infotrieve]. 27. Ribeiro RC, Oliveira MS, Fairclough D, et al. Acute megakaryoblastic leukemia in children and adolescents: a retrospective analysis of 24 cases. Leuk Lymphoma. 1993;10:299-306[Medline] [Order article via Infotrieve]. 28. Rowe JM, Andersen JW, Cassileth PA, Oken MM, Bennett JM, Wiernik PH. Postremission therapy in adults with acute myelogenous leukemia: the Eastern Cooperative Oncology Group (ECOG) experience. Leukemia Res. 1991;15:223-227[Medline] [Order article via Infotrieve]. 29. Bennett JM, Young ML, Andersen JW, et al. Long-term survival in acute myeloid leukemia. Cancer. 1997;80:2205-2209[Medline] [Order article via Infotrieve]. 30. Matsuo T, Bennett JM. Acute leukemia of megakaryocytic lineage (M7). Cancer Genet Cytogenet. 1988;34:1-3[Medline] [Order article via Infotrieve].
31.
Bauermeister DE.
Quantification of bone marrow reticulin 32. Paietta E, Racevskis J, Bennett JM, et al. Biologic heterogeneity in Philadelphia chromosome-positive acute leukemia with myeloid morphology: the Eastern Cooperative Oncology Group experience. Leukemia. 1998;12:1881-1885[Medline] [Order article via Infotrieve]. 33. Paietta E. Immunology of acute leukemia. In: Wiernik PH,Canellos GP,Dutcher JP,Kyle RA, eds. Neoplastic Diseases of the Blood. 3rd ed. New York, NY: Churchill Livingstone; 1996:211-247. 34. Cassileth PA, Lynch E, Hines JD, et al. Varying intensity of post-remission therapy in acute myeloid leukemia. Blood. 1992;797:1924-1930.
35.
Rowe JM, Andersen J, Mazza JJ, et al.
A randomized placebo-controlled phase III study of granulocyte macrophage colony stimulating factor in adult patients (>55-70 years of age) with acute myelogenous leukemia: a study of the Eastern Cooperative Oncology Group (E1490).
Blood.
1995;86:457-462 36. Cassileth PA, Andersen J, Bennett JM, et al. Escalating the intensity of post-remission therapy improves the outcome in acute myeloid leukemia: the ECOG experience. Leukemia. 1992;6:116-119.
37.
Cassileth PA, Andersen J, Lazarus HM, et al.
Autologous transplant in acute myeloid leukemia in first remission.
J Clin Oncol.
1993;11:314-319
38.
Cassileth PA, Harrington D, Appelbaum FR, et al.
A comparison of chemotherapy versus autologous bone marrow transplantation versus allogeneic bone marrow transplantation in first remission of adult acute myeloid leukemia: an intergroup study (E3489).
N Engl J Med.
1998;339:1649-1656 39. Cassileth PA, Lee SJ, Miller KB, et al. Feasibility study of adding high-dose cytarabine (HDAC) in induction (IND) and in consolidation transplant (ASCT) in adult acute myeloid leukemia [abstract]. Blood. 1998;92:4559a. 40. Reilly JT, Barnett D, Dolan G, Forrest P, Easthan J, Smith A. Characterization of an acute micromegakaryocytic leukemia: evidence for the pathogenesis of myelofibrosis. Br J Haematol. 1993;83:58-62[Medline] [Order article via Infotrieve]. 41. Slarc I, Urban C, Haas OA, Kroisel PM, Koller U. Acute megakaryocytic leukemia in children: clinical immunologic and cytogenetic findings in two patients. Cancer. 1991;68:2266-2272[Medline] [Order article via Infotrieve]. 42. Bullorsky EO, Shanley CM, Stemmelin G, Venditti J, Lajous JR. Acute megakaryoblastic leukemia with massive myelofibrosis: complete remission and reversal of marrow fibrosis with allogeneic bone marrow transplantation as the only treatment. Bone Marrow Transplant. 1990;6:449-452[Medline] [Order article via Infotrieve]. 43. Johansson B, Mertens F, Heim S, et al. Cytogenetic findings in acute megakaryoblastic leukemia (ANLL-M7). Cancer Genet Cytogenet. 1990;218:119-123. 44. Akahoshi M, Oshimi K, Mizoguchi H, Okada M, Enomoto Y, Watanabe Y. Myeloproliferative disorders terminating in acute megakaryoblastic leukemia with chromosome 3 or 26 abnormality. Cancer. 1987;60:2654-2661[Medline] [Order article via Infotrieve]. 45. Brissette MD, Duval-Arnold BJ, Gordon BG, Cotelingam JD. Acute megakaryoblastic leukemia following transient myeloproliferative disorder in a patient without Down syndrome. Am J Hematol. 1994;47:316-319[Medline] [Order article via Infotrieve]. 46. Chan WC, Carrol A, Alvarado CS, et al. Acute megakaryoblastic leukemia in infants with t(1;22) (p13;q13) abnormality. Am J Clin Pathol. 1992;98:2114-2121.
47.
Lion T, Haas OA, Harbott J, et al.
The translocation t(1;22) (p13;q13) is a nonrandom marker specifically associated with acute megakaryocytic leukemia in young children.
Blood.
1992;79:3325-3330
48.
Carroll A, Civin C, Schneider N, et al.
The t(1;22) (p13;q13) is nonrandom and restricted to infants with acute megakaryocytic: a pediatric oncology group study.
Blood.
1991;78:748-752 49. Gavel D, Mielot F, Gauland P, Quillard J, Dommergues JP, Tehernia G. Acute megakaryocytic leukemia (AMKL) with major myelofibrosis in an infant: diagnosis by liver biopsy and response to treatment. Nouv Rev Fr Hematol. 1991;33:5-8. 50. Windebank KP, Tefferi A, Smithson WA, et al. Acute megakaryocytic leukemia (M7) in children. Mayo Clin Proc. 1989;64:1339-1351[Medline] [Order article via Infotrieve].
51.
Debili N, Issaad C, Masse JM, et al.
Expression of CD34 and platelet glycoproteins during human megakaryocytic differentiation.
Blood.
1992;80:3022-3035
52.
Zucker-Franklin D, Yang JS, Grusky G.
Characterization of glycoprotein IIb/IIIa
53.
Helleberg C, Knudgen H, Hansen PB, et al.
CD34+ megakaryoblastic leukemic cells are CD38 54. den Ottolander GJ, te Veide J, Brederoo P, et al. Megakaryoblastic leukemia (acute myelofibrosis): a report of three cases. Br J Haematol. 1979;42:9-20[Medline] [Order article via Infotrieve]. 55. Ali NO, Janes WO. Malignant myelofibrosis (acute myelofibrosis): report of 2 cases following cytotoxic chemotherapy. Cancer. 1979;43:1211-1215[Medline] [Order article via Infotrieve]. 56. Sultan C, Sigaux F, Imber TM, Reyes F. Acute myelodysplasia with myelofibrosis: a report of eight cases. Br J Haematol. 1981;49:11-16[Medline] [Order article via Infotrieve]. 57. Weisenburger DD. Acute myelofibrosis terminating as acute myeloblastic leukemia. Am J Clin Pathol. 1980;73:128-132[Medline] [Order article via Infotrieve]. 58. Bearman RM, Pangalis GA, Rappaport H. Acute ("malignant") myelosclerosis. Cancer. 1979;43:279-293[Medline] [Order article via Infotrieve]. 59. Bird T, Proctor SJ. Malignant myelosclerosis: myeloproliferative disorder or leukemia? Am J Clin Pathol. 1977;67:512-520[Medline] [Order article via Infotrieve]. 60. Cuneo A, Mecucci C, Kerim S, et al. Multipotent stem cell involvement in megakaryoblastic leukemia: cytologic and cytogenetic evidence in 15 patients. Blood. 1989;74:1781-1790.
61.
Harris NL, Jaffe ES, Diebold J, et al.
The World Health Organization classification of hematological malignancies: report of the Clinical Advisory Committee.
J Clin Oncol.
1999;17:3835-3849 62. Hruban RH, Kuhajda FP, Mann RS. Acute myelofibrosis: immunohistochemical study of four cases and comparison with acute megakaryocytic leukemia. Am J Clin Pathol. 1987;88:578-588[Medline] [Order article via Infotrieve]. 63. Anderlini P, Ghaddar HM, Smith TL, et al. Factors predicting complete remission and subsequent disease-free survival after a second course of induction therapy in patients with acute myelogenous leukemia resistant to the first. Leukemia. 1996;10:964-969[Medline] [Order article via Infotrieve]. 64. Fonatsch C, Gudat H, Lengfelder E, et al. Correlation of cytogenetic findings with clinical features in 18 patients with inv(3)(q21;q26) or t(3;3)(q21;q26). Leukemia. 1994;8:1318-1326[Medline] [Order article via Infotrieve]. 65. Glassman W, Loeffler H. Acute megakaryocytic leukemia. Leuk Lymphoma. 1995;18:69-73. 66. Sandberg AA, Chen Z. Cytogenetics of acute leukemia. In: Wiernik PH,Canellos GP,Dutcher JP,Kyle RA, eds. Neoplastic Diseases of the Blood 3rd ed. New York, NY: Churchill Livingstone; 1996:249-267. 67. Lu G, Alton AJ, Benn PA. A review of the cytogenetic changes in acute megakaryoblastic leukemia: one disease or several? Cancer Genet Cytogenet. 1993;67:81-89[Medline] [Order article via Infotrieve]. 68. Jotterand Bellomo M, Parlier V, Muhlematter D, Grob JP, Beris PH. Three new cases of chromosome 3 rearrangement in bands q21 and q26 with abnormal thrombopoiesis bring further evidence to the existence of a 3q21q26q syndrome. Cancer Genet Cytogenet. 1992;59:138-160[Medline] [Order article via Infotrieve].
69.
Bitter MA, Neilly ME, LeBeau MM, Pearson MG, Rowley JD.
Rearrangements of chromosome 3 involving 3q21 and 3q26 are associated with normal or elevated platelet counts in acute nonlymphocytic leukemia.
Blood.
1985;66:1362-1370 70. Yumura-Yagi K, Hara J, Kurahashi H, et al. Mixed phenotype of blasts in acute megakaryocytic leukemia and transient abnormal myelopoiesis in Down's syndrome. Br J Haematol. 1992;81:520-525[Medline] [Order article via Infotrieve]. 71. Mehta ABV, Baughan ASJ, Catovsky D, Goldman JM, Johnson SA, Galton DAG. Reversal of marrow fibrosis in acute megakaryoblastic leukaemia after remission-induction and consolidation chemotherapy followed by bone marrow transplantation. Br J Haematol. 1983;53:445-449. 72. Hassan HT, Grell S, Borrmann-Danso U, Freund M. Effect of recombinant human interferons in inducing differentiation of acute megakaryoblastic leukemia blast cells. Leuk Lymphoma. 1995;16:329-333[Medline] [Order article via Infotrieve]. 73. Lu M, Levin J, Sulpice E, et al. Effect of arsenic trioxide on viability, proliferation and apoptosis in human megakaryocytic leukemia cell lines. Exp Hematol. 1999;27:845-852[Medline] [Order article via Infotrieve].
© 2000 by The American Society of Hematology.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
|
 |
|
  H. Edwards, C. Xie, K. M. LaFiura, A. A. Dombkowski, S. A. Buck, J. L. Boerner, J. W. Taub, L. H. Matherly, and Y. Ge RUNX1 regulates phosphoinositide 3-kinase/AKT pathway: role in chemotherapy sensitivity in acute megakaryocytic leukemia Blood, September 24, 2009; 114(13): 2744 - 2752. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. J. Jabbour, E. Estey, and H. M. Kantarjian Adult Acute Myeloid Leukemia Mayo Clin. Proc., February 1, 2006; 81(2): 247 - 260. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Oki, H. M. Kantarjian, X. Zhou, J. Cortes, S. Faderl, S. Verstovsek, S. O'Brien, C. Koller, M. Beran, B. N. Bekele, et al. Adult acute megakaryocytic leukemia: an analysis of 37 patients treated at M.D. Anderson Cancer Center Blood, February 1, 2006; 107(3): 880 - 884. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Mesa, C.-Y. Li, R. P. Ketterling, G. S. Schroeder, R. A. Knudson, and A. Tefferi Leukemic transformation in myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases Blood, February 1, 2005; 105(3): 973 - 977. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Garderet, M. Labopin, N.-C. Gorin, E. Polge, A. Baruchel, G. Meloni, J. Ortega, J. Vossen, D. Bunjes, G. Leverger, et al. Hematopoietic stem cell transplantation for de novo acute megakaryocytic leukemia in first complete remission: a retrospective study of the European Group for Blood and Marrow Transplantation (EBMT) Blood, January 1, 2005; 105(1): 405 - 409. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Ge, T. L. Jensen, L. H. Matherly, and J. W. Taub Transcriptional regulation of the cystathionine-beta -synthase gene in Down syndrome and non-Down syndrome megakaryocytic leukemia cell lines Blood, February 15, 2003; 101(4): 1551 - 1557. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Dastugue, M. Lafage-Pochitaloff, M.-P. Pages, I. Radford, C. Bastard, P. Talmant, M. J. Mozziconacci, C. Leonard, C. Bilhou-Nabera, C. Cabrol, et al. Cytogenetic profile of childhood and adult megakaryoblastic leukemia (M7): a study of the Groupe Francais de Cytogenetique Hematologique (GFCH) Blood, June 28, 2002; 100(2): 618 - 626. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. H. Athale, B. I. Razzouk, S. C. Raimondi, X. Tong, F. G. Behm, D. R. Head, D. K. Srivastava, J. E. Rubnitz, L. Bowman, C.-H. Pui, et al. Biology and outcome of childhood acute megakaryoblastic leukemia: a single institution's experience Blood, June 15, 2001; 97(12): 3727 - 3732. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Strauchen, M. S. Tallman, and J. M. Bennett Criteria for the diagnosis of acute megakaryocytic leukemia Blood, March 15, 2001; 97(6): 1898 - 1898. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|||||||
 |
 |
 |
 |
 |
 |
 |
 |
||
| Copyright © 2000 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Top
Abstract
Introduction
a study of four cases with the platelet-peroxidase reaction.
Blood.
1981;58:206-213
, but CD61+ and glycophorin A+: improved criteria for diagnosis of AML-M7?
Leukemia.
1997;11:830-834