Acute megakaryocytic leukemia presenting as hypercalcemia with skeletal lytic lesions

Acute megakaryocytic leukemia (AML M7) is a rare type of acute myelogenous leukemia in adults, commonly presenting with myelofibrosis. This report describes a case of a 32-yr-old male who presented with hypercalcemia and bony lytic lesions, in the absence of myelofibrosis. The diagnosis of AML M7 should be considered in a patient with pancytopenia, lytic lesions and hypercalcemia.     

Surface Features of Leukaemic Megakaryocytic Precursors

Megakaryoblasts and maturing megakaryocytic precursor cells from 5 patients with megakaryoblastic leukaemia were studied by scanning electron microscopy (SEM). The diagnosis in all cases had been established by ultrastructural cytochemistry on the basis of a positive platelet peroxidase reaction with negative staining for myeloperoxidase. 1 case presented as acute myelofibrosis and 4 as acute megakaryoblastic transformation of chronic granulocytic leukaemia. Under the SEM, megakaryoblasts and maturing megakaryocytic precursors showed typical surface features including the presence of rounded and irregular blebs, broad folds and pseudopodia. The nature of these surface blebs is still unclear but they probably represent surface membrane alterations relating to imminent platelet shedding at least in the more mature precursors. These surface microprojections are distinctly different from those encountered on leukaemic lymphoblasts, myeloblasts and monoblasts. It is suggested that SEM may be used in conjunction with the PPO reaction as in aid in the diagnosis of megakaryocytic leukaemias.     

Target cell of leukemic transformation in acute megakaryoblastic leukemia

Acute megakaryoblastic leukemia (AMkL) is a newly defined acute leukemia in which the differentiation of proliferating blasts is arrested at the megakaryocytic precursor stage. In order to clarify whether a target cell of leukemic transformation in AMkL is a cell committed to megakaryocytic lineage, or a multipotential stem cell, we examined AMkL patients with regard to: a) the presence of myelodyplastic features in residual erythroid and granulocytic cells, b) coexistence of myeloperoxidase (MPO)-positive blasts with megakaryoblasts, and c) the presence of the same chromosomal abnormality in erythroid and granuloid colony-forming cells as seen in megakaryoblasts. Regarding the former two items, results were compared with those from megakaryoblastic crisis of chronic myelocytic leukemia (CML-MkBC) and transient myeloproliferative disorder in Down syndrome (DS-TMD), which are thought to be multipotential stem cell disorders. Among 18 patients with AMkL, three, all complicating myelofibrosis, had marked myelodysplastic changes of erythroid series and/or granulocytic series. In 4 out of 7 patients with CML-MkBC, 5 out of 8 patients with DS-TMD, and 7 out of 18 patients with AMkL, MPO-positive blasts, even though rare, were observed in addition to PPO-positive blasts. All except one of these patients with AMkL also showed complicating myelofibrosis. In one case of AMkL with myelofibrosis, chromosomal analysis of cultured cells of individual colonies revealed that all the analysable metaphases from both CFU-GM and BFU-E had the same chromosomal abnormality as megakaryoblasts. This study has clarified that a considerable proportion of AMkL cases, particularly those with complicating myelofibrosis or showing acute myelofibrosis, arise against the background of a multipotential stem cell disorder, even if blasts are exclusively megakaryocytic in phenotype.     

Unusual diffuse liver fibrosis accompanying transient myeloproliferative disorder in Down's syndrome: a report of four autopsy cases and proposal of a hypothesis.

Transient myeloproliferative disorder (TMD), an acute leukemia-like disorder in neonates with Down's syndrome, is characterized by spontaneous regression of abnormal blast growth. Because proliferating blasts frequently express phenotypes of megakaryocytic lineage and, as a result, this disorder resembles acute megakaryoblastic leukemia (AMKL), it would be of interest to determine whether myelofibrosis, a common complication of AMKL, is also present in TMD. Pathologic observations of four autopsy cases of TMD showed that myelofibrosis was not present in any of them, whereas intralobular diffuse liver fibrosis was present in all of them. Laboratory data of four additional cases showed hepatic dysfunction in all of them, suggesting a close association between hepatic lesions and TMD. From these results, we propose a hypothesis that the abnormal blasts with megakaryocytic properties in TMD originate from the fetal liver and cause liver fibrosis, as AMKL cells are thought to cause myelofibrosis by producing collagen-stimulating cytokines in the bone marrow. This hypothesis also seems to explain some other unique aspects of TMD.     

Acute myelofibrosis terminating in acute lymphoblastic leukemia: Case report and review of the literature

Acute myelofibrosis (AMF), as defined by an acute panmyelopathy associated with marked megakaryocytic hyperplasia and marrow fibrosis, appears to be a stem cell disorder. Even though it is most difficult to distinguish from various myeloproliferative and myelodysplastic disorders as well as acute myelogenous leukemia, it has rarely been reported to terminate as acute lymphoblastic leukemia (ALL). Only five cases have been reported in the literature; two from the pediatric literature and only three from the adult literature. Of the three adult cases, two were defined by light microscopy alone. Among the cases with follow-up (3/5), all died within 2 weeks to 2 months of diagnosis. We report an additional case in an adult; the ALL was defined by morphology, flow cytometric immunophenotyping, and cytogenetic analysis. The interval from diagnosis of AMF to ALL was 3 months. Our patient was treated with standard therapy for ALL, was in complete remission at last follow-up (3 months off maintenance therapy), and represents the only reported case who attained a complete remission. There are too few cases to determine the prognostic significance of termination of AMF in an acute leukemia of lymphoid origin vs. myeloid origin. © 1996 Wiley-Liss, Inc.     

JAK2 mutation 1849G>T is rare in acute leukemias but can be found in CMML, Philadelphia chromosome-negative CML, and megakaryocytic leukemia

An activating 1849G>T mutation of JAK2 (Janus kinase 2) tyrosine kinase was recently described in chronic myeloproliferative disorders (MPDs). Its role in other hematologic neoplasms is unclear. We developed a quantitative pyrosequencing assay and analyzed 374 samples of hematologic neoplasms. The mutation was frequent in polycythemia vera (PV) (86%) and myelofibrosis (95%) but less prevalent in acute myeloid leukemia (AML) with an antecedent PV or myelofibrosis (5 [36%] of 14 patients). JAK2 mutation was also detected in 3 (19%) of 16 patients with Philadelphia-chromosome (Ph)-negative chronic myelogenous leukemia (CML), 2 (18%) of 11 patients with megakaryocytic AML, 7 (13%) of 52 patients with chronic myelomonocytic leukemia, and 1 (1%) of 68 patients with myelodysplastic syndromes. No mutation was found in Ph(+)CML (99 patients), AML M0-M6 (28 patients), or acute lymphoblastic leukemia (20 patients). We conclude that the JAK2 1849G>T mutation is common in Ph(-) MPD but not critical for transformation to the acute phase of these diseases and that it is generally rare in aggressive leukemias.     

Acute toxicity and effectiveness of idarubicin in childhood acute lymphoblastic leukemia

Abstract: Anthracyclines have become important components of multi-agent remission induction and continuation therapy of acute lymphoblastic leukemia (ALL). New anthracycline derivatives are being investigated in an attempt to shift the balance of side effects and antileukemic potency. To evaluate the toxicity and efficacy of idarubicin (IDA) in childhood ALL, a prospective multicenter phase-II study was performed. A total of 51 children with prognostically poor recurrences of ALL were enrolled, all of whom had been exposed to anthracyclines during front-line treatment. A single 48-h continuous infusion of IDA at 24 mg/m² was started on the first day of salvage treatment without concomitant systemic cytostatic agents. The response was assessed by reduction of leukemic blasts in the bone marrow and other compartments 2 wk later. IDA monotherapy caused complete and partial remissions in 5 and 20 patients, respectively (49%). Delays of treatment with subsequent polychemotherapy courses were frequent and mainly caused by prolonged intervals of myelosuppression and high rates of systemic infection. Non-hematological toxicities including acute cardiac reactions were transient and moderate. Our findings suggest that IDA is an effective drug for remission induction in children with ALL, with acute hematological toxicity being dose-limiting.     

Acute myelofibrosis: multifocal bone marrow infiltration detected by scintigraphy and magnetic resonance imaging

 Acute myelofibrosis is a rare, malignant hematological disorder of unknown etiology with an inevitably fatal outcome. Here we present the study of a 63-year-old Caucasian man with acute onset of pancytopenia. Repeated bone marrow biopsies showed dense fibrosis and hypoplastic hematopoiesis raising various differential diagnoses of malignant and nonmalignant conditions. Bone marrow scintigraphy and magnetic resonance imaging (MRI) showed areas suggesting neoplastic infiltration, mainly in both femurs and tibias. Histological examination of a surgical biopsy of the left tibia revealed acute megakaryoblastic leukemia. As the patient refused polychemotherapy, therapy with interferon gamma was initiated but discontinued prematurely because of intolerable side effects. The presented case therefore suggests that the combination of bone marrow scintigraphy and MRI is a valuable diagnostic tool in patients presenting with myelofibrosis of unknown origin. Received: 22 March 1999 / Accepted: 28 September 1999     

Megakaryoblastic Leukaemia (Acute Myelofibrosis): a Report of Three Cases

Three patients with megakaryoblastic leukaemia are described. All three presented with pancytopenia, a few blast cells in the peripheral blood and absence of overt hepatosplenomegaly. In two of them bone marrow aspiration yielded a dry tap. Histological investigation of the bone marrow indicated that the megakaryocytic cell line was the dominant proliferating lineage. Cytochemical and EM investigation supported these findings. The isomorphic isoenzyme pattern of the elevated serum lactic dehydrogenase might be of diagnostic importance. Despite chemotherapy, there was a rapidly fatal terminal leukaemic phase with high blast cell counts. The differentiation from other haematological malignancies, especially acute (aleukaemic) leukaemias and the accelerated phase of primary (chronic) myelofibrosis, is discussed. The picture appears to be identical with acute (malignant) myelofibrosis.     

Surface features of leukaemic megakaryocytic precursors. A study of 5 cases of megakaryoblastic leukaemia with scanning electron microscopy

Megakaryoblasts and maturing megakaryocytic precursor cells from 5 patients with megakaryoblastic leukaemia were studied by scanning electron microscopy (SEM). The diagnosis in all cases had been established by ultrastructural cytochemistry on the basis of a positive platelet peroxidase reaction with negative staining for myeloperoxidase. 1 case presented as acute myelofibrosis and 4 as acute megakaryoblastic transformation of chronic granulocytic leukaemia. Under the SEM, megakaryoblasts and maturing megakaryocytic precursors showed typical surface features including the presence of rounded and irregular blebs, broad folds and pseudopodia. The nature of these surface blebs is still unclear but they probably represent surface membrane alterations relating to imminent platelet shedding at least in the more mature precursors. These surface microprojections are distinctly different from those encountered on leukaemic lymphoblasts, myeloblasts and monoblasts. It is suggested that SEM may be used in conjunction with the PPO reaction as in aid in the diagnosis of megakaryocytic leukaemias.     

Myelodysplastic syndrome with myelofibrosis: myelodysplastic syndrome as a major primary disorder for acute myelofibrosis

Summary Seven cases of myelodysplastic syndrome with myelofibrosis, which is defined using the following criteria: (1) pancytopenia with < 5% blasts in the peripheral blood; (2) minimal or no splenomegaly; (3) myelofibrosis with cellular marrow; (4) absence of diffuse proliferation of blasts in the bone marrow; and (5) presence of myelodysplastic features of bone marrow or peripheral blood cells, are presented. They were in the range of 52–82 years old and consisted of 3 males and 4 females. Six out of 7 cases developed into acute leukaemia after 5 to 8 months from the onset and died from between 2 weeks to 8 months from the evolution to leukaemia. The type of leukaemia was acute myeloblastic in 3 patients, and acute myelo-megakaryoblastic in 3 patients. Another patient died of severe hepatic injury after 5 months from the onset of the disease. These findings revealed that the complication of myelofibrosis in the patients with myelodysplastic syndrome was an indicative sign of rapid progression to overt leukaemia or otherwise poor prognosis for survival. In addition myelodysplastic syndrome is thought to be major primary disorder for acute myelofibrosis. Myelodysplastic syndrome with myelofibrosis is closely associated with the neoplastic proliferation of megakaryoblasts in a considerable number of patients.     

Megakaryoblastic leukemia which developed from therapy-related MDS with myelofibrosis]

A 56-year-old man had a leiomyosarcoma of the small intestine in 1987. After surgery, he received cyclophosphamide for 2 years. In December, 1990, he exhibited severe pancytopenia. His hematological data were as follows: Hb 7.4g/dl, ret. 0.8%, WBC 1,700/microliters with leukoerythroblastosis and 2.8 x 10(4)/microliters platelets. A bone marrow aspiration was a dry tap. A bone marrow biopsy specimen showed a hypercellular marrow with myelofibrosis, leukemic infiltration (10.2%) and slight dyserythropoiesis. Both PPO and GPIIb/IIIa reaction were positive for blast cells and atypical megakaryoblasts. A diagnosis of MDS with an abnormality in megakaryocytic lineage was made. The patient was treated with 1,25-dihydroxy-vitamin D3, however this therapy was temporary and he developed into acute megakaryoblastic leukemia (M7). This report suggested that some cases of therapy-related leukemia (TRL) mainly involve megakaryocytic lineage and are diagnosed as MDS with myelofibrosis which transform to M7. The fact that PAS stain of erythroblasts in the patient reported here was positive may suggest involvement of development of more precise immunological markers of differentiation and EM study will permit better diagnosis of TRL and may therefore facilitate new therapeutic approaches.     

Diagnosis and therapy of acute leukemia in adults]

Apart from the most essential aspects of the diagnosis and differential diagnosis of acute leukaemias concerning the early diagnosis of leukaemias the author deals with the so-called praeleukaemia. On the basis of a survey of international literature the modern polychemotherapy and its successes are characterized as well as the necessary supportive haemotherapy) are dealt with. Despite the improved frequency of remissions the survival time of acute leukaemias could only little be prolonged, that of the first remission could not be prolonged. Perhaps it is possible by an in future improved immunotherapy and by allogenic transplantation of the bone-marrow after supralethal total body irradiation to set new measures in the treatment of acute leukaemias.     

Thrombopoietin activates the growth of megakaryoblasts in patients with chronic myeloproliferative disorders and myelodysplastic syndrome

The effects of thrombopoietin (TPO) on cell proliferation and differentiation, and the relation between these effects and the expression of c-mpl on leukemia cells were studied in seven acute myelogeneous leukemia cell lines and seven myelogeneous blast cell preparations from patients with chronic myeloproliferative disorders (CMPDs) and myelodysplastic syndrome (MDS). Among the leukemia cells, five preparations of megakaryoblastic leukemia cells from patients and one megakaryoblastic cell line, CMK 11.5, proliferated in response to TPO in vitro. CMK 11.5 and the blastic cells from one patient diagnosed with MDS with myelofibrosis differentiated with increasing expression of CD41a in response to TPO. However, TPO had no effect on the cells lacking megakaryocytic characteristics. Some patients with CMPD and MDS develop acute transformation with blasts demonstrating megakaryocytic features, and some of these cells show growth in response to TPO. Therefore, in vivo administration of TPO should be considered carefully for patients with CMPD or MDS, since TPO may induce leukemic cell proliferation.     

Myelodysplasia predominantly involving in megakaryocytic lineage successfully treated with low-dose Ara-C

A 17 year old male was admitted because of pancytopenia. Bone marrow aspiration revealed myelodysplasia, no increase of blast cells and excessive expansion of megakaryocytic lineage. Although mild increase of bone marrow reticulin fiber was observed, no hepatosplenomegaly was recognized. Therefore he was diagnosed as refractory anemia (RA) or MDS with myelofibrosis and treated with low dose Ara-C regimen. Remission was achieved in June 1987, but the relapse occurred in Oct. 1987. His bone marrow at the relapse showed more remarkable dysplastic change than before. Sequential bone marrow examinations thereafter, revealed an increase of megakaryocytic lineage, especially immature dysplastic megakaryocytes, leading to the appearance of the abnormal megakaryoblasts (detected with anti GP IIb/IIIa antibody) as well as uncharacterized blast cells in his terminal stage. Transformation from MDS to megakaryocytic leukemia was strongly suggested. He died of severe pneumonia in March 1989. The invasion of abnormal immature megakaryocytic cells including megakaryoblasts was observed in liver, spleen and lymph nodes at autopsy. There are several reports on cases having a common hematological features such as 1) pancytopenia in peripheral blood, 2) myelodysplasia, 3) excessive growth of megakaryocytic lineage, 4) myelofibrosis without hepatosplenomegaly, although other clinical features were different. We propose all these cases should be reviewed at the point of MDS mainly involved in megakaryocytic lineage.     

Acute nonlymphocytic leukemia (M7 subtype) with erythrocytic internalization

A case of acute nonlymphocytic leukemia of megakaryocytic lineage or M7 with a conspicuous phenomenon of erythrocytic internalization present in nearly 3% of the leukemic megakaryocytic precursors (LMP) is reported. The phagocytosis was detected at light microscopy and ultrastructural levels. The erythrocyte might have reached the interior of the LMP through cytoplasmic vacuoles that are connected with the extracellular space and that can be considered rudimentary equivalents of the demarcation membrane system (DMS). Erythrocytic internalization is not a specific feature of the mononuclear phagocytic system and can be misleading in the classification of undifferentiated blast cells.     

Megakaryocytic Leukaemia as a Phase of Myeloproliferative Disorders

2 cases of megakaryocytic leukaemia are presented as a variant of myeloproliferative disorders. The uncontrolled proliferation of the megakaryocyte-platelet cell line occurred after splenectomy and treatment of blastic phase. Applicability of the term megakaryocytic leukaemia is discussed as well as its relationship to similar disorders. It is suggested that an extensive neoplastic proliferation of megakaryocytes with abnormal maturation and thereby formation of large dysplastic platelets in extra-medullary organs especially the liver in the end stage of myelofibrosis is a possible mechanism for this disorder. Treatment with platelet-pheresis may be an effective part of therapy.     

Cell surface phenotyping of megakaryoblasts

Surface phenotypic characterization of megakaryoblasts, identified by platelet peroxidase activity, was investigated in four patients who showed increased proliferation of megakaryoblasts: one patient with typical features of acute leukemia, one presenting with acute myelofibrosis, and two with Down's syndrome in whom blasts disappeared spontaneously (transient abnormal myelopoiesis, TAM). MY10 and/or MY9 antigens were expressed on the surface of some megakaryoblasts, but MY7, and MY4, antigens specific to granulocytic or monocytic cells, were not. Some megakaryoblasts were positive for only anti-HLA-DR antibodies. It was speculated that, during the differentiation of the megakaryocytic lineage, MY9 antigen appears transiently on the surface of megakaryoblasts that have lost HLA-DR antigens and have gained the glycoprotein IIb/IIIa antigen. This study also demonstrated that the proliferating blasts in some patients with TAM were mainly megakaryoblasts and suggested that the target cells in TAM are CFU-GEMM.     

Elevated levels of basic fibroblast growth factor in megakaryocytes and platelets from patients with idiopathic myelofibrosis

Idiopathic myelofibrosis, or agnogenic myeloid metaplasia, is a chronic myeloproliferative disorder characterized by clonal expansion and marrow fibrosis. Although marrow fibrosis appears to be a reactive process, it substantially contributes to impaired haemopoiesis. During the last few years the implication of megakaryocyte-derived growth factors in its pathogenesis has been documented.
We previously reported increased expression of TGF-β in patients with idiopathic myelofibrosis. In the present study we show that circulating megakaryocytic cells from such patients expressed high levels of basic fibroblast growth factor (bFGF). An increased expression of bFGF was also detected in patients' platelets. Under culture conditions, bFGF present in megakaryocytic cells was not exported into the medium, consistent with the fact that bFGF is devoid of a secretion peptide signal. Interestingly, this lack of bFGF secretion was observed in all patients but one, who was in an accelerated phase of the disease and presented an important percentage of circulating megakaryoblasts.