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Prognostic parameters in myeloid metaplasia: agnogenic versus postpolycythemic.

Thirty-nine patients with myelofibrosis and myeloid metaplasia were diagnosed and followed during the period 1955-74. Twenty-eight suffered from agnogenic myeloid metaplasia and 11 from myeloid metaplasia following polycythemia vera. In an attempt to compare the two groups and to define prognostic guidelines, an analysis of survival with respect to various clinical parameters was made. The median survival time of patients with agnogenic myeloid metaplasia was seven years as opposed to only 28 months for the poltpolycythemic group. Older age at diagnosis, a large spleen, or its rapid enlargement, anemia and leukocytosis, but not thrombocytopenia, had a marked negative effect on survival. The clinical condition of most patients was remarkably stable during the entire course of their disease. If a significant drop in hemoglobin occurred, it was sudden, and caused by gastrointestinal hemorrhage or the development of acute leukemia. No demonstrable effect of therapy on survival was found.

Adolescent↗

Successful treatment of essential thrombocythemia evolving into agnogenic myeloid metaplasia with interferon-alpha.

PURPOSE: Essential thrombocythemia and agnogenic myeloid metaplasia as one form of idiopathic myelofibrosis are myeloproliferative disorders and are quite rare in children. A patient with essential thrombocythemia that transformed to "adult-type" agnogenic myeloid metaplasia is described. PATIENTS AND METHODS: A routine examination of an 8-year-old girl with bronchial asthma showed thrombocytosis. Essential thrombocythemia was diagnosed 2 years later. During a 3-year follow-up without treatment, transition of the essential thrombocythemia to agnogenic myeloid metaplasia was noticed. The patient had an excellent response to interferon (IFN)-alpha therapy. CONCLUSION: This case is unique because of the availability of premorbid hematologic data and the natural progression of essential thrombocythemia to agnogenic myeloid metaplasia. Whether IFN-alpha therapy can prevent the progression of idiopathic myelofibrosis to leukemia has not yet been determined.

Child↗

Clearance of the Janus kinase 2 (JAK2) V617F mutation after allogeneic stem cell transplantation in a patient with myelofibrosis with myeloid metaplasia.

A patient with myelofibrosis with myeloid metaplasia displaying the V617F mutation of the JAK2 gene was given an allogeneic stem cell transplantation using a reduced-intensity conditioning regimen. The patient engrafted, and as he became a chimera, the expression of the V617F mutation of the JAK2 gene decreased progressively until its disappearance. Accordingly, the concept of "molecular remission" of the myelofibrosis with myeloid metaplasia could be entertained and added to the categories of response to treatment which have been recently described.

Biomarkers↗

Agnogenic myeloid metaplasia in childhood: a report of two cases and efficiency of intravenous high dose methylprednisolone treatment.

Myelofibrosis with myeloid metaplasia, or agnogenic myeloid metaplasia (AMM) is a chronic myeloproliferative disorder characterized by fibrosis of the bone marrow accompanied by aniso- and poikilocytosis, leukoerythroblastosis and hepatosplenomegaly with extramedullary hematopoiesis. Agnogenic myeloid metaplasia is very rare in children. In this report, two cases of AMM in whom the onset of the illness were at 3 and 12 months of age, are presented. Both had severe anemia, hepatosplenomegaly and bone marrow fibrosis. Lymph node biopsy of the first patient and liver biopsy of the second revealed extramedullary hematopoiesis. They were treated with an intravenous high dose of methylprednisolone (daily 30 mg/kg for 3 days, 20 mg/kg for 4 days, 10 mg/kg for 1 week, 5 mg/kg for 1 week). A complete improvement of hematological and clinical findings was observed.

Anemia↗

Gastric myeloid metaplasia: a case report and review of the literature.

We report a case of gastric myeloid metaplasia in an 89- year-old woman with agnogenic myeloid metaplasia. The lesions were fortuitously discovered on upper endoscopy. The antral mucosa was thickened and polypoid, and on histologic examination contained immature granulocytes, megakaryocytes, and a few erythroblasts without desmoplastic stromal reaction. The granulocytes were positive for CD15, CD68, and myeloperoxidase on immunohistochemistry, and the megakaryocytes showed positive reactivity for factor VIII. Gastric myeloid metaplasia is a very rare event, and to our knowledge only 6 cases have been reported in the literature to date. It usually occurs in patients with advanced myeloproliferative syndrome. Gastric myeloid metaplasia often has a pseudotumoral appearance, leading to digestive symptoms. Histologic diagnosis is straightforward when trilinear hematopoietic elements are identified in gastric biopsies. Immunohistochemistry with anti-factor VIII antibody can be useful to confirm the presence of megakaryocytes.

Aged↗

Agnogenic myeloid metaplasia with pleural extramedullary leukemic transformation.

Agnogenic myeloid metaplasia (AMM) is one of the myeloproliferative disorders, and is usually accompanied by extramedullary hematopoiesis (EMH) in various organs, mainly in the liver, spleen and lymph nodes. Extramedullary hematopoiesis and/or leukemic transformation of EMH in the pleura is a rare occurrence and is usually asymptomatic. Pleural involvement is usually diagnosed on postmortem examination. Herein we describe a 71-year-old man with newly diagnosed agnogenic myeloid metaplasia who was evaluated for progressively worsening dyspnea, pulmonary hypertension and bilateral pleural effusions. EMH involving the lungs and pleura was suspected. A sulfur colloid technetium 99m bone marrow scan performed to detect extramedullary hematopoiesis was negative. The diagnostic thoracentesis yielded bloody fluid that contained a large population of myeloblasts, indicating pleural leukemic transformation. The patient received 100 cGy to the whole lung for treatment of pulmonary hypertension due to EMH. This was followed by 1500 cGy total dose of radiation to the left lung for pleural extramedullary leukemic transformation. Pleural effusions resolved and repeat echocardiography showed reduction of the pulmonary artery pressure. Three months later he had leukemic transformation involving the skin and lymph nodes. Four months after radiation therapy, he had full-blown acute myeloid leukemia. He received 2 cycles of Gemtuzumab ozogamicin (Mylotarg), allopurinol and hydroxyurea. Three months after initiation of chemotherapy, he deteriorated and received salvage chemotherapy of prednisone, VP-16 and imatinib mesylate (Gleevec). He was hospitalized for neutropenic fever and was diagnosed to have pulmonary aspergillosis. He died of multisystem failure 8 1/2 months after being diagnosed with AMM.

Aged↗

Hematopoietic progenitor cells in a patient with myeloid metaplasia without myelofibrosis.

A rare case of myeloid metaplasia without myelofibrosis is presented. Findings that the increase in blood megakaryocyte progenitor cells was not as prominent as the increase in granulocyte-monocyte and erythroid progenitor cells, and that the increase in bone marrow megakaryocytes was only slight might explain the absence of bone marrow fibrosis in this case. However, it is not clear whether the disease is a subtype or merely an early stage of myelofibrosis with myeloid metaplasia.

Aged↗

Mechanism of extramedullary haematopoiesis in rabbits with saponin-induced myelofibrosis and myeloid metaplasia.

The saponin-induced myelofibrosis and myeloid metaplasia model in the rabbit was used to study mechanisms of extramedullary haematopoiesis. Haematopoietic progenitor cells, erythroid colony forming units (CFU-E) and burst forming units (BFU-E) were assayed serially in the peripheral blood, spleen and bone marrow after saponin administration, employing the in vitro methylcellulose culture technique. Animals that had undergone splenectomy prior to saponin administration were also studied. The results demonstrated increases of progenitor cells in the blood and spleen and a simultaneous depletion of such cells in marrow after saponin treatment. The results in splenectomized animals were similar to those observed in non-splenectomized animals after saponin administration. The findings indicate that following saponin administration there is a release of CFU-E and BFU-E from bone marrow into periphery and probably deposition in the spleen, and suggest that myeloid metaplasia in myelofibrosis may result from colonization of extramedullary sites originating from the bone marrow.

Animals↗

Bone marrow angiogenesis and its clinical correlates in myelofibrosis with myeloid metaplasia.

BACKGROUND AND OBJECTIVES: Previous retrospective studies have indicated markedly increased bone marrow angiogenesis (BMA) in myelofibrosis with myeloid metaplasia (MMM). This issue is further examined in the current prospective study and clinico-pathological correlates sought. DESIGN AND METHODS: This was a prospective single institutional study of 66 patients with bone marrow biopsy-proven MMM who were consecutively accrued. Bone marrow angiogenesis was evaluated by assessing microvessel density through immunohistochemical staining for the CD34 antigen. Laboratory and clinical information was collected concurrently. RESULTS: The 66 patients (median age 62 years, 46 males) included 36 with fibrotic phase agnogenic myeloid metaplasia (AMM), 6 with cellular phase AMM, 4 with hypocellular variant AMM, 10 with post-polycythemic myeloid metaplasia, and 10 with post-thrombocythemic myeloid metaplasia. Overall, increased BMA was documented in 61 patients (92%). All of the aforementioned sub-categories of MMM were similarly affected in terms of either grade 3 or 4 BMA but differed in the prevalence of grade 4 BMA (25%, 0%, 0%, 10%, and 10%, respectively). In a univariate analysis the only histological feature that significantly correlated with BMA was the degree of megakaryocyte clustering. Among clinical features, increased BMA was significantly associated with younger age of the patient, lower hemoglobin level, intact spleen, and absence of active therapy. On multivariate analysis, only the latter two retained their significance. INTERPRETATION AND CONCLUSIONS: The current prospective study confirms the consistent association of BMA with MMM and suggests that the process starts early, is progressive, and might be dampened by both splenectomy and drug therapy. The study also suggests either a megakaryocyte origin or a megakaryocyte effect for the putative angiogenic cytokine.

Age Factors↗

Idiopathic myelofibrosis with myeloid metaplasia involving the renal pelves, ureters and bladder.

Myeloid metaplasia associated with idiopathic myelofibrosis most commonly involves the reticuloendothelial organs, such as the spleen, liver and retroperitoneal lymph nodes. We report on a patient with myeloid metaplasia (extramedullary hematopoiesis) of the renal pelves, ureters and bladder. The pathogenesis, clinical characteristics, treatment and prognosis of this condition are discussed.

Adult↗

Subtotal splenectomy for treatment of patients with myelofibrosis and myeloid metaplasia.

Idiopathic myelofibrosis is a chronic myeloproliferative disorder that may course with myeloid metaplasia involving several organs. Occasionally, the spleen reaches giant proportions and must be withdrawn. However, this procedure is followed by greater morbidity and mortality. Partial splenectomies, preserving the splenic pedicle, have been proposed in order to reduce postoperative complications. After an early postoperative improvement, some patients present symptomatic recurrence of their disease. This communication presents a new alternative for the treatment of complicated myeloid metaplasia: subtotal splenectomy, preserving the upper splenic pole supplied only by the splenogastric vessels. We performed this procedure in three patients. Their almost two years postoperative follow-up and health improvement suggest that this operation should be considered for the treatment of huge spleens due to myelofibrosis with myeloid metaplasia.

Adult↗

Secondary myelofibrosis with metastatic breast cancer simulating agnogenic myeloid metaplasia: report of a case and review of the literature.

A patient with carcinoma of the breast, who developed a clinical syndrome resembling agnogenic myeloid metaplasia, is described. She was found to have secondary myelofibrosis with metastatic carcinoma of the marrow, extensive extramedullary hematopoiesis resulting in massive splenomegaly, and leukoerythroblastosis. These findings are rare and myeloid metaplasia with striking extramedullary hematopoiesis causing massive splenomegaly and mimicking agnogenic myeloid metaplasia is seldom seen in patients with metastatic carcinoma. Previous case reports of secondary extramedullary hematopoiesis simulating agnogenic myeloid metaplasia (AMM) in patients with solid tumors are also reviewed.

Adult↗

Blastic phase of agnogenic myeloid metaplasia simulating malignant lymphoma.

A patient with angogenic myeloid metaplasia in blastic transformation with unusually prominent lymphadenopathy simulating lymphoma is described. Interestingly, the initial evidence of myeloblastic transformation was present in the lymph nodes but not in the marrow. Serial bone marrow biopsies showed fibrosis throughout the course of the disease, in spite of a gradual increase in the percentage of peripheral blood myeloblasts. Aneuploidy with a marker chromosome and a Philadelphia-like chromosome was present in the lymph node, bone marrow, and peripheral blood cells. The literature is reviewed regarding the incidence of prominent lymphadenopathy and chromosome abnormalities in agnogenic myeloid metaplasia and other myeloproliferative disorders.

Aneuploidy↗

Splenectomy for agnogenic myeloid metaplasia.

Only a fraction of the patients with myeloid metaplasia have indications for splenectomy develop. Palliation for symptomatic splenomegaly is highly successful. Significant relief from hypersplenism, anemia or thrombocytopenia was achieved, however, in less than half of the patients. Since patients with severe thrombocytopenia are at continuing risk of spontaneous hemorrhage and of bleeding after minor trauma, splenectomy appears to be justified in these patients, provided that studies of peripheral blood and bone marrow have excluded those with leukemic conversion. The benefit obtained from splenectomy in patients with chronic anemia requiring frequent transfusions in less certain, particularly in men and in patients converting to myeloid metaplasia from polycythemia vera. In some instances, the continuation of transfusions may result in less morbidity and better palliation than operation. Although the course of this myeloproliferative disorder from first symptoms to death frequently extends for more than a decade, the manifestations which may provide an indication for splenectomy usually occur late in the course of the disease. The element as well as the morbidity of the operation makes a thorough evaluation of each patients essential before splenectomy is considered.

Adult↗

Allogeneic bone marrow transplantation for agnogenic myeloid metaplasia. French Society of Bone Marrow Transplantation.

Agnogenic myeloid metaplasia is a rare indication for allogeneic bone marrow transplantation (BMT). We have retrospectively studied 12 patients allografted for this disease within the French BMT group. Prior to BMT, the mean age was 40 years (range 14-49). Diagnosis was based on the Polycythaemia Vera Study Group criteria. Before BMT, 10 patients had been splenectomized, eight required transfusions, and four had received at least two lines of chemotherapy. Cyclophosphamide and total body irradiation was the main conditioning regimen used (n=8). The donor was an HLA-identical sibling except in one case where there was one HLA-DR mismatch. Acute graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate and cyclosporine A. 11 patients engrafted with median times to achieve absolute neutrophil count > 0.5 x 10(9)/l and platelet count > 50 x 10(9)/l of 17 (range 12-44) and 29 (range 12-196) days respectively. One primary graft failure occurred. 10 patients developed grade II-IV acute GVHD, four developed extensive chronic GVHD. One patient relapsed 16 months post-BMT and was untreated and well 14 months later. Three patients died from the BMT procedure. In May 1996 the median follow-up was 25 months and the 4-year overall and event-free survivals were 71% and 59%, respectively. Thus, we conclude that extensive myelofibrosis is not associated with delayed engraftment, and that HLA-identical sibling allogeneic BMT can be considered in a small proportion of patients with agnogenic myeloid metaplasia.

Adolescent↗

Surgical and radiotherapeutic approaches for myelofibrosis with myeloid metaplasia.

Sequestration of circulating immature myeloid progenitors in the chronic myeloproliferative disorder myelofibrosis with myeloid metaplasia (MMM) leads to extramedullary hematopoiesis (EMH), as well as end organ enlargement and dysfunction. When medical therapy is inadequate to control symptomatic myeloproliferation, both surgical resection and/or external beam radiotherapy may provide palliative cytoreduction in specific situations. Therapeutic splenectomy may provide relief of pain, mass effect, an improvement in cytopenias, or even palliation of portal hypertension. However, the risks of perioperative and long-term complications limit the use of splenectomy in MMM to specific candidates. In addition to splenectomy, portal hypertension has been palliated by either elective esophageal variceal ligation or porto-systemic shunting (through either open or invasive radiographic means). External beam radiotherapy can provide palliative cytoreduction in afflicted organs, with the greatest benefit seen in the lungs and spine. Splenic radiation also can provide a decrease in the size of the organ but carries the risk of myelosuppression and potentially increases the risk associated with subsequent splenectomy. Hepatic and abdominal radiation may palliate hepatomegaly and/or ascites, but cytopenias are common and responses brief. Novel therapies aimed at the pathogenesis of the disorder are needed for more efficacious and targeted therapy of MMM.

Algorithms↗

Splenic irradiation in myelofibrosis with myeloid metaplasia: a review.

Morbidity from myeloid metaplasia and myelofibrosis arises from progressive anemia and abdominal discomfort related to massive splenomegaly, which may be associated with hypercatabolic symptoms. To date, no therapy, other than allogeneic bone marrow transplantation, has been shown to cure or to prolong the survival of these patients. Thus, current management strategies are palliative and include red cell transfusional support and androgen therapy for anemia; chemotherapeutic agents for control of thrombocytosis, leukocytosis, and hypermetabolic symptoms; and splenectomy or splenic irradiation for symptomatic splenomegaly. The major indication for splenic irradiation is left upper quadrant discomfort related to massive splenomegaly, usually in patients for whom splenectomy is contraindicated or has been declined. In most patients, it provides relief from abdominal pain and a moderate reduction in splenic size. Although responses are transient, some patients may experience prolonged relief. Splenic irradiation can result in prolonged myelosuppression in certain patients. This calls for cautious dosing, because individual sensitivity is variable and cannot be predicted. The use of splenic irradiation does not preclude subsequent splenectomy; however, the increased risk of postoperative hemorrhage should discourage consideration of splenic irradiation as an alternative or a temporizing measure before splenectomy when indicated.

Humans↗

The association between autoimmunity and agnogenic myeloid metaplasia.

A patient with agnogenic myeloid metaplasia (AMM) associated with an ill-defined autoimmune disease is described and the literature on autoimmunity in AMM is reviewed. In view of the available data, it seems that the association between AMM and autoimmunity observed in our patient is not fortuitous.

Adult↗